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2018-05-08T17:57:14.696Z | 0001-01-01T00:00:00.000Z | 216097745 | s2orc/train | Blood Cancer Journal
Predicting the response of multiple myeloma to the proteasome inhibitor Bortezomib by evaluation of the unfolded protein response Multiple myeloma (MM) remains a predominantly incurable malignancy despite high-dose chemotherapy, autologous stem cell transplant and novel agents. 1 Proteasome inhibitors (PI) such as Bortezomib have increased the response rate and survival of patients with MM. The overall patient response rate of newly diagnosed MM to Bortezomib and Dexamethasone is about 67%. 2 In relapsed refractory MM, the response rate is reduced to about 40–60%. 3,4 Therefore, there are a significant number of MM patients who are resistant to Bortezomib. Combining Bortezomib with another class of novel drugs, for example, immunomodulatory drugs (IMIDs), such as Lenalido-mide, is associated with increased overall response rate of 94% in newly diagnosed myeloma patients 5 and 64% in relapsed or refractory myeloma. 6 Although the combination of a protea-some inhibitor and an IMID may yield an improved response rate, it is not always possible due to the cost, availability, local regulatory policies, side-effects profile, convenience and personal preference. Therefore the choice of novel agents (PI or IMID) is predominantly empirical and based on other factors such as side effects and tolerability, making it difficult to choose the best therapy. Currently there is no way of predetermining if a patient will respond to Bortezomib treatment. However, previous studies have shown that XBP1, a key regulator of the unfolded protein response (UPR), predicts sensitivity to Bortezomib, and its level correlates proportionally with sensitivity to Bortezomib. 4 We therefore aimed to assess if the sensitivity to Bortezomib is dependent on the UPR, and that the expression level of ATF6 mRNA and the size of the endoplasmic reticulum can predict sensitivity to the drug. ATF6 is a regulator of the UPR and is capable of activating XBP1, 7 which is a regulator of the UPR and correlates with Bortezomib sensitivity. 4 Previous studies have shown that the protein expression of ATF6 is reduced in MM cell lines resistant to Bortezomib compared with their parent cell line. 4 We therefore analysed ATF6 gene expression in Bortezomib sensitive and resistant KMS11 cells (Supplementary Information). Our results showed that ATF6 gene expression decreased with increasing Bortezomib resistance. KMS11 cells resistant to Bortezomib were seen to have substantially lower ATF6 mRNA levels compared with parent sensitive cells (Figures 1a, P = 0.06), resembling the same trend as seen in protein expression. 4 These results …
Predicting the response of multiple myeloma to the proteasome inhibitor Bortezomib by evaluation of the unfolded protein response Multiple myeloma (MM) remains a predominantly incurable malignancy despite high-dose chemotherapy, autologous stem cell transplant and novel agents. 1 Proteasome inhibitors (PI) such as Bortezomib have increased the response rate and survival of patients with MM. The overall patient response rate of newly diagnosed MM to Bortezomib and Dexamethasone is about 67%. 2 In relapsed refractory MM, the response rate is reduced to about 40-60%. 3,4 Therefore, there are a significant number of MM patients who are resistant to Bortezomib. Combining Bortezomib with another class of novel drugs, for example, immunomodulatory drugs (IMIDs), such as Lenalidomide, is associated with increased overall response rate of 94% in newly diagnosed myeloma patients 5 and 64% in relapsed or refractory myeloma. 6 Although the combination of a proteasome inhibitor and an IMID may yield an improved response rate, it is not always possible due to the cost, availability, local regulatory policies, side-effects profile, convenience and personal preference. Therefore the choice of novel agents (PI or IMID) is predominantly empirical and based on other factors such as side effects and tolerability, making it difficult to choose the best therapy. Currently there is no way of predetermining if a patient will respond to Bortezomib treatment. However, previous studies have shown that XBP1, a key regulator of the unfolded protein response (UPR), predicts sensitivity to Bortezomib, and its level correlates proportionally with sensitivity to Bortezomib. 4 We therefore aimed to assess if the sensitivity to Bortezomib is dependent on the UPR, and that the expression level of ATF6 mRNA and the size of the endoplasmic reticulum can predict sensitivity to the drug.
ATF6 is a regulator of the UPR and is capable of activating XBP1, 7 which is a regulator of the UPR and correlates with Bortezomib sensitivity. 4 Previous studies have shown that the protein expression of ATF6 is reduced in MM cell lines resistant to Bortezomib compared with their parent cell line. 4 We therefore analysed ATF6 gene expression in Bortezomib sensitive and resistant KMS11 cells (Supplementary Information). Our results showed that ATF6 gene expression decreased with increasing Bortezomib resistance. KMS11 cells resistant to Bortezomib were seen to have substantially lower ATF6 mRNA levels compared with parent sensitive cells (Figures 1a, P = 0.06), resembling the same trend as seen in protein expression. 4 These results were also seen in 45 MM patients with various levels of resistance (Supplementary Information). Patient responses after completion of cycle 2 of therapy with Bortezomib were categorized according to the International Myeloma Working Group (IMWG) uniform response criteria. 8 Complete response (CR), very good partial response (VGPR) or partial response (PR) patients had significantly higher levels of ATF6 mRNA compared with patients with stable disease (SD) or of progressive disease (PD; Figure 1b; P = 0.007). The mean ATF6 expression of the CR, VGPR and PR patient groups were 3.92-fold higher compared with patients of SD and PD groups. On an individual group basis, there was no significant difference between each group, however there was a significant difference between PR patients vs SD+PD patients (Figure 1b; P = 0.01). Nonetheless, gene expression levels of ATF6 in SD+PD patients were significantly lower than those seen in patients with CR+VGPR +PR to Bortezomib. Therefore, ATF6 mRNA, a regulator of the UPR is predictive of sensitivity to Bortezomib in vitro and in patients.
Expansion of the ER is an important aspect of the UPR when dealing with ER stressed caused by increases in unfolded/ misfolded protein. This morphological change assists the UPR by accommodating the flux in protein levels. This has been demonstrated within secretory cells, which have been seen to undergo ER expansion for the production and secretion of large protein quantities. 9 Therefore, we next examined ER morphology within KMS11-sensitive and -resistant cells, to determine the importance and activity of the UPR in Bortezomib resistance. We first assessed ER morphology by live imaging of sensitive and resistant KMS11 cells using an ER tracker dye and a BioStation IM-Q Time Lapse Imaging System. Comparing the mean fluorescent intensity of the ER in KMS11-resistant cells against KMS11-sensitive cells, there was a 1.35-fold decrease in size (Figures 2a and b; P = 0.02352; Supplementary Information). ER sizes were larger in sensitive cells, compared with the resistant cells, indicating a higher level of UPR activity. The range of fluorescent measurements from sensitive cells were also seen to be more widely distributed (range of 144 037 CTCF/U) in comparison with resistant cells, which showed a tighter range in fluorescence (44 856 CTCF/U). This is likely a result of Bortezomib-sensitive cells having a highly functional UPR pathway, while Bortezomibresistant cells have an under functioning or compromised UPR.
To further assess the size of the ER in Bortezomib sensitive and resistant cells, we measured the rough ER (RER) lumen by electron microscopy (see Supplementary Information). At a 40 000 × magnification, up to 10 images were captured of the RER within Bortezomib sensitive and resistant KMS11 cells. The RER lumen of each cell was measured at the 4 widest points, totaling 40 measurements. The RER lumen within the resistant cells was seen to be significantly smaller than those of the sensitive cells (Figures 2c and d; P ⩽ 0.0001), with the mean RER lumen width of resistant cells being 10 nm smaller than the mean lumen width of the sensitive cells. The RER measurements of the Bortezomib-sensitive cells were more broadly distributed (range of 36 nm), with the range being substantially greater than those seen in the resistant cells (range of 23 nm). Therefore, the size of the ER is predictive of sensitivity to Bortezomib.
We conclude that UPR activity and function, as measured by ATF6 expression and the size of the ER is reduced in Bortezomib resistance. Further studies are required to determine whether ATF6 expression and ER size are useful predictors of Bortezomib sensitivity and resistance in the clinical setting. Our findings suggest that reduced UPR activity may mediate Bortezomib resistance. | v2 |
2022-04-18T13:20:34.503Z | 0001-01-01T00:00:00.000Z | 248219544 | s2ag/train | CanSig: Discovering de novo shared transcriptional programs in single cancer cells
Human tumors are highly heterogeneous in their cell composition; specifically, they exhibit heterogeneity in transcriptional states of malignant cells, as has been recently discovered through single-cell RNA sequencing (scRNA-seq). Distinct states of malignant cells have been linked to variability in tumorigenic properties and resistance to anti-cancer treatment. Despite the fact that scRNA-seq data contain all necessary information to uncover shared transcriptional states of malignant cells in tumors, jointly analyzing cells from multiple cancer patients comes with its set of challenges including batch correction and accounting for patient-specific genetic background driving differences between gene expression vectors. We propose CanSig, an easy-to-use approach designed to discover known and de novo shared signatures in cancer single cells. CanSig preprocesses, integrates and analyzes scRNA-seq data to provide new signatures of shared transcriptional states and links these states to known pathways. We show that CanSig successfully rediscovers ground truth pathways determining shared transcriptional states in two simulated and three experimental datasets; the latter spanning 135 patients and 72,000 cells. We then illustrate CanSig’s investigative potential by discovering novel signatures in esophageal squamous cell carcinoma possibly linked to targeted patient treatment; we also point out a de novo signature in breast cancer predictive of patients’ survival. In the cancer types studied, we juxtapose copy number variation with discovered shared transcriptional states and uncover a genetic component predisposing cancer cells to activation of specific transcriptional programs. In sum, CanSig, specifically developed to analyze shared transcriptional heterogeneity of malignant cells of different genetic backgrounds, can greatly facilitate the exploratory analysis of scRNA-seq cancer data and efficiently identify novel transcriptional signatures linked to known biological pathways. | v2 |
2018-12-01T02:15:33.226Z | 1882-01-01T00:00:00.000Z | 53424420 | s2orc/train | Medical Items
rectum, are usually very difficult to treat antiseptically. In such cases iodoform, applied on gauze compresses, has been found to completely prevent offensive smell, and to cause no discomfort to the patients. In a case of removal of an abdominal tumour, iodoform was sprinkled into the cavity and the wound jclosed at once. The patient recovered without a bad symptom. In septic gangrenous or sloughing wounds the results were especially satisfactory. Sprinkling with iodoform removed all smell in from four to six hours, and the wounds healed
MEDICAL
ITEMS. UNDER In open wounds the iodoform is sprinkled on the surface and covered with lint and gutta-percha tissue, fixed by a bandage. The results have been very satisfactory; the dressings require changing but seldom, discharge is slight, decomposition never occurs, and there is rapid formation of healthy granulations. In incised wounds healing is even more certain than with carbolic acid, and there is much less fear of absorption causing constitutional disturbance.
Wounds implicating mucous surfaces, as of the mouth or rectum, are usually very difficult to treat antiseptically. In such cases iodoform, applied on gauze compresses, has been found to completely prevent offensive smell, and to cause no discomfort to the patients.
In a case of removal of an abdominal tumour, iodoform was sprinkled into the cavity and the wound jclosed at once. The patient recovered without a bad symptom.
In septic gangrenous or sloughing wounds the results were especially satisfactory. Sprinkling with iodoform removed all smell in from four to six hours, and the wounds healed rapidly and without discharge, even in some cases where severe constitutional symptoms had already appeared.
In strumous diseases iodoform is said to give such brilliant results as almost to entitle it to the rank of a specific. (See also Y. Mosetig-Moorhof in Wien. Med. Woch., 1881, No. 13.) Fungating ulcers with spreading undermined edges and offensive discharge, healed rapidly and completely under a thick layer of iodoform.
In lupus also its effects are gratifying. Riehl (Wien. Med. Woch., 1881, No. 19), gives the results of twenty cases in Kaposi's clinique. The epidermis, when necessary, having been removed by the application of 5 to 10 per cent solution of caustic potash, the iodoform is laid on in a layer several millimetres thick, and fixed as above described. On removal of the dressings in from three to eight days the disease is found completely removed, redness and swelling gone, and the sore skinned over.
In deep wounds, when the powder would be difficult to apply, Mikulicz recommends pencils composed of one part of iodoform to two of cacao butter, and for injection a 20 per cent ethereal solution.
The smell of the drug can be overcome by adding 1 tt[ bergamot to 10 gr. of the iodoform, or moistening with an ethereal or alcoholic extract of Tonquin bean. Local irritation can be effectually prevented by previously oiling the sound skin near where the iodoform is to be applied.?Centralbl. f. Chir., 1881. Nos. 32 and 39.?D. M'P.
Iodoform Subcutaneously in Syphilis.?Dr. E. Thomann, of Graz, has treated a series of cases of recent syphilis, with well marked skin manifestations and glandular enlargements, by the administration of iodoform subcutaneously, and states that even after ten to twelve injections great improvement in all the symptoms is manifest. The preparation he used consisted of 6 parts of iodoform suspended in 20 parts of glycerine ; this was administered in doses of 0-3 grm., increasing gradually to 0*75 grm. No abscesses were produced, though the skin became slightly red and tender, and the spots operated on were harder than the surrounding parts, and slightly swollen for a few days. Iodine may be detected in the urine in two hours after the first injection ; no smell of iodoform was perceptible, either in the breath, perspiration, or urine.
There was no constitutional disturbance or drowsiness, and the temperature and pulse were unaffected. A solution of iodoform in almond oil (0*3 grm. in 6 ccm.) was also tried, but proved too irritating; it caused an erysipelatous reddening of the skin.
The feeling of local hardness was absent however, as the oil was so much more quickly absorbed than the glycerine preparation.?Gbl.f. d. Med. Wiss. 29th Oct., 1881.
Experiments on the Infectiousness of the Blood and Urine of Tuberculous Animals.?V. Lentz, of Greifswald, in his inaugural dissertation, describes the results of a series of experiments on rabbits.
In six rabbits he injected fresh blood of tuberculous rabbits into the lungs through a tracheotomy incision. In all of these, killed in from 92 to 216 days afterwards, he found miliary tubercles in the lungs, and in four of them in the liver as well. In one he found caseous masses in the lungs. In all of four in which the blood was injected subcutaneously (killed after from 125 to 148 days), he found miliary tubercles in the lungs, and in two of them in the liver as well.
In one the blood was injected into the joint and adjoining connective tissue.
The knee became swollen by the third day; on the 18th the animal died, and dissection showed stinking caseous suppuration in the joint, and tubercles in the lungs. y Two rabbits were subjected daily, for 71 days, to an atmosphere charged with steam, containing from 30 to 40 c. cm. of freshly voided urine from tuberculous animals.
After death the lungs were found full of minute subpleural ecchymoses and numerous peribronchial tubercles.
With three others " phthisical" urine, which had been allowed to stand for several days in a warm room, was used. One died on the ninth day. after aborting, and examination showed in the peribronchial connective tissues numerous masses of round, well defined nucleated cells, " undoubtedly commencing tubercles." In the others (killed on the 48th and GOth days), tubercules, less numerous, but more uniform in nature and position than in the rabbit treated with fresh urine, were found.
In all the sections of tissue examined, a decided thickening of the arterial coats was observed.?Centralbl. f. Chir., 1881.
Treatment of Eczema.?Dr. Puntz advocates the use of the soot from burnt pine in the treatment of eczema. He claims for it that it is entirely painless; is applicable to all forms of the disease ; causes no irritation either in the ear or in the eye; is not poisonous, so that it can be applied to the breasts of a nursing woman ; and that its curative powers are surprising.
He mixes the soot with lard, and applies it every morning and evening for six days, then rubs it gently off, and repeats the operation till all is healed. He has had good results from this treatment in impetigo, prurigo, lichen, erythema papulatum, &c. Chlorosis.?Dr. Zander's article on Chlorosis bears par-ticularly upon the matter of treatment. The effects of iron, he remarks, are apt to be transitory?so soon as its administration is suspended, the phenomena of the disease reappear. The pathology of the affection lies not so much in a mere deficiency of iron in the blood as in a lowered state of the general nutrition, usually dependent on enfeebled digestion. Treatment founded on this theory has given excellent results in the author's hands. He makes use of hydrochloric acid chiefly according to the following formula:?Hydrochloric acid 20-40 grammes (J to 1 drachm); water 200 0 grammes (about ounces). One or two tablespoonfuls to be taken a quarter of an hour after meals. Mistletoe (Viscum Album) in Heart Diseases.?Dr. R. Park states that in this drug will be found a remedy of no mean physiological power, and an excellent substitute for digitalis. He has used it in a large number of cases of heart disease in which, whatever the exact pathological condition might be, incompetency and tumultuous distressing cardiac action were the immediate symptoms calling for treatment, giving half-drachm doses of the tincture every four hours, "with the very best results." No formula for the preparation of the tincture is given.?The Practitioner. November, 1881.
[Dorvault says, in L'Officine, p. 535, that mistletoe is an astringent and emetic, that it was formerly much used against epilepsy, and that its powers as an abortive are equal to those of ergot of rye. From the bark and berries is extracted the proximate principle named glu by the French chemists, the substance to which bird lime owes its viscosity; treated with ether, gin yields viscine, which is soluble, and viscosine, which is insoluble. Wood & Bache, in the U. S. Dispensatory, 1867, p. 1620, observe that this drug is said to be capable of producing vomiting and purging when largely taken. A case is mentioned in which a child three years old was poisoned by eating the berries, the symptoms being vomiting, prostration, insensibility, fixed and contracted pupils, coldness of skin, and convulsive movements of the extremities; an emetic brought away a number of berries, and the child recovered. The plant was formerly regarded as a powerful anti-spasmodic, and was employed in " epilepsy, palsy, and other nervous diseases." The leaves and the wood were given in the dose of a drachm in substance, and of an ounce in decoction.] Nasal Polypi Treated with Tannin.?M. S. Martin states that in six cases of nasal polypus he has succeeded in effecting a cure by means of injection of a watery solution of tannin. The solution he employs consists of one part of officinal tannin dissolved in ten parts of distilled water; this is injected into the nasal cavities morning and evening, with a glass syringe.?Bull. Gen Surgery in the University of the City of New York, states that, while having full confidence in Mr. Lister's antiseptic method, he, like many others, has long recognised the great difficulty that must needs be experienced by the general practitioner in attempting to carry out the minute details of the dressing. Dr. Little has for several years been surgeon to a large factory in New York, in which three thousand hands are employed, and where injuries by machinery are quite frequent. These injuries consist chiefly of wounds of the hands and fingers, caused by their being caught in the cogwheels and other parts of the machinery. In many cases the fingers are torn off, tendons are pulled from their sheaths, joints are opened, and the hands are often severely crushed and lacerated. In all of thes6 cases he has, for the past six years, been using the following simple antiseptic dressing:? Having put the parts in a condition for dressing, he washes the wound in a solution of carbolic acid of the strength of one to twenty; he then covers the parts with a thick layer of borated cotton, and then snugly and evenly applies a simple gauze bandage. At first he used bandages made of antiseptic gauze, but for the past three years has used those of plain uncarbolised cheese cloth. These thin bandages distribute the pressure more evenly over the cotton, and are more easily saturated with fluids than those made of unbleached muslin.
The patient is instructed to keep the outside of the dressing wet with a solution of carbolic acid of the strength of one to one hundred. The author employs Squibb's solution of impure carbolic acid, which is of the strength of one to fifty, and which, when mixed with an equal bulk of water, gives a solution of the desired strength. The parts should be kept at rest, and the dressings may be left undisturbed for several days, unless there is pain, rise of temperature, or discharge through the dressings. These conditions are always to be considered indications for renewing the dressing. In many cases where rubber drainage tubes have been used they may be removed at the second dressing, and, if catgut has been used for sutures, this second dressing can be allowed to remain on for an indefinite period. In a number of cases of lacerated wounds the first dressing has been allowed to remain on until the wound has entirely healed. In these cases the external use of carbolic lotion was discontinued after the fifth or sixth day, and the dressings would become dry and hard, the wound healing, as it were, " under a scab." The patient should be instructed to loosen the bandage at once if any pain occurs. Out of nearly three hundred cases of open wounds involving the fingers and hands, thus treated, not one has been followed by inflammatory symptoms.
Ol. Santalis Flav.?With reference to this remedy, Dr. R. Park finds that it is no use prescribing it for the purpose of curing a gonorrhoea, if by the term is meant the urethritis or other pathological condition causing discharge. But it will get rid of the most troublesome symptom?the "running;" this it will restrain at once, frequently stopping it in course of 48 hours. It must be continued for quite a fortnight after entire cessation of the discharge. If within 48 hours the running is not arrested?and this happens in some cases? another drug should be employed or therapeutic procedure adopted. Twenty drops is a full dose, as this quantity invariably produces griping of the bowels, and dull lumbar aching. Dr. Park suggests that the drug acts in two ways? on the pelvic and genital nervous system, and on the suppurating surface as an antiseptic or contra-purulent. It certainly has a drying effect on all the mucous surfaces, and also appears to be a special stimulant to unstriated muscular fibre, and in this way is probably constringent.?The Practitioner.
Injections of Bromide of Potassium in Gonorrhoea.? Dr. Cambillard, in the Journal de Therapeutique for 25th October, 1881, points out how all authors acknowledge the exhausting sleeplessness, the malaise, the nervous irritability, and the intolerable suffering that nocturnal erections induce ? in gonorrhoea. After having indicated the various modes of treatment directed against this symptom, camphor, lupulin, essence of santal, subcutaneous injections of morphia in the perinseum, injections of chloral into the urethra, pills of extract of opium or opium fomentations, he, following the example of his teacher, M. Mauriac, insists upon the superior efficacy of injections of bromide of potassium into the urethra. These injections are by no means painful; at the most, in some cases, a slight smarting is caused. They are repeated four times in the day, and the last is administered just before going to bed. They are allowed to remain in the canal one or two minutes, otherwise they are inefficacious. Perchloride of Iron in Internal Haemorrhages.?In a thesis presented to the Societe de Therapeutique de Paris, Dr. Guestre protests against the practice of prescribing the perchloride of iron indiscriminately in all cases of internal haemorrhages. Its action as a local haemostatic, due to its coagulant powers (the formation of insoluble albuminates), is undeniable. But if the drug acted in this way internally, either along the digestive tube or in the capillaries, gastroenteritis and thrombosis would result. Nor does it act directly by causing contraction of the smaller vessels; even when applied directly, and in concentrated solution, it has no such action. Dr. Guestre seems to adopt the views of Rabuteau and of Cervello with regard to the perchloride of iron: that it is not eliminated by the kidneys in any quantity; that it acts internally, not as a coagulant, but as a simple astringent; that the protochloride might be used instead of the perchloride with the same results, the latter being reduced to the state of proto-salt before absorption ; that the influence of the chlorides of iron is exerted principally on the heart and vessels, cardiac action becoming slower and feebler, the vessels contracting, and the blood-pressure rising ; and that it is on these cardiac and vascular effects that the haemostatic properties of iron depend. Dr. Guestre also proved, by experiment on himself, that half a gramme of perchloride iron taken internally, at first reduced the amplitude of the pulse-tracing, and diminished the dicrotism ; a further half-gramme dose taken half-an-hour after, produced still further diminution, and also made the heart's action slower ; eighty minutes after taking one gramme the volume of the pulse was much reduced, dicrotism had almost disappeared, the line of descent was longer, while the retardation of the heart's action was very marked. Dr.
Guestre concludes that the ferrous salts are as powerful haemostatics as the ferric salts. Clinical evidence is also against the ferric salts; it is shown with regard to purpura in particular, that treatment without iron is more successful than with that drug. Bearing in mind the excellent results obtained with ipecacuanha in haemoptysis and ergotine in metrorrhagia, and on the contrary, the frequently injurious action of the perchloride of iron in gastrorrhagia, it seems scarcely advisable to administer this remedy as a haemostatic, at least by the mouth.?Bull, et Mem. de la Soc. de Therap.
Substitutes for Nitro-Hydrochloric and Nitrous Acids. ?Dr. E. A. Cook is of opinion that the conflicting statements made regarding the therapeutic action of the above named acids are due to the changes which these bodies undergo soon after preparation. Thus, it is well known that with nitrohydrochloric acid the best results are obtained by mixing the strong nitric and strong hydrochloric acids in due proportions, and using them shortly thereafter. Such a mixture is orange coloured; after a time, however, its colour changes to lemon-yellow, the odour of chlorine is lost, and the mixture, though as powerful chemically as ever, is therapeutically useless, the difference in action being probably due to the disappearance of some unstable compound, such as (1) an oxide of nitrogen; (2) free chlorine; (3) an oxide of chlorine ; (4) or a compound of an oxide of nitrogen with an oxide of chlorine. In the case of adclum nitrosum, which, as sold in the shops, consists simply of strong nitric acid charged with vapours of some of the lower oxides of nitrogen, the good effect must be due, if not to nitric acid, to the lower oxides referred to.
In Dr. Cook's first efforts in this direction, he provided the nurse with two separate bottles of strong acid, with instructions as to dropping, mixing, and diluting; and though improvement in cases of torpid liver with congestion was great and rapid, the objections to this mode of administration were too obvious.
A substitute for the old nitro-hydrochloric acid was therefore desirable ; and as the virtues of that remedy do not depend on either of its component acids, it struck Dr. Cook that the end would be attained if a compound could be given, containing but a small quantity of those acids, and at the same time highly charged with the products of their decomposition.
Nitrite of soda mixed with dilute hydrochloric acid evolves free oxides of nitrogen; chlorate of potash, with a dilute acid, gives off oxides of chlorine ; and a mixture of these salts with an acid or with the acid gastric juice will give rise to these mixed oxides. The most convenient prescription is :? R. Sol. Sodse Nitritis (1 in 4).
One teaspoonful of each mixture to be added separately to a wine-glassful of water, and taken after meals. When nitrous acid is to be administered without the chance of any chlorine oxides being present, the solution of chlorate of potash is omitted, and replaced by an equal quantity of water.
Cases suitable for the mixed acids are those of torpor of the liver with congestion and catarrh of the bile ducts. The relief obtained in every case from their administration has been most marked, the motions becoming healthy, and the skin and conjunctivae clear. The cases suitable for the nitrite and hydrochloric acid alone are those of loose diarrhoea, dyspepsia, and chronic irritability of the stomach.?The Practitioner. Nov. 1881.
Treatment of Goitre by Ammonium Chloride.?Dr. A. D. Stevens records six cases of cure of large goitres by the administration of ammonium chloride. The dose given was 10 grains, dissolved in water, and repeated thrice daily for two months or more. There was no deterioration of the general health from the prolonged use of the drug, but rather the reverse.?New York Medical Tribune. Feb., 1881.?G. S. M.
Radical Cure of Goitre.?In the case of a young man, 24 years of age, who had suffered from goitre for eight years, all treatment of which had been of no avail, Dr. Paolo Droecchi, of San Francisco, recently successfully performed extirpation. The method adopted wras that of Fiorani (of Lodi, Italy). He makes an incision through the skin from one pole of the tumour to the other, and cuts stratum after stratum, as in the operation for hernia. If large blood-vessels are met with, he cuts them between two ligatures.
When the tumour is reached, it is very easy, by the aid of the finger, to isolate it down to the peduncle; the operator then applies interrupted sutures, and separates the connecting stitches, so as to allow the tumour to pass through like a button. An elastic ligature is now passed round the neck of the tumour, and the stitches tied. The operation is quickly performed, and the tumour falls off in ten or twelve days. Fiorani has had three successful cases. In Droecchi's case the elastic ligature was applied, but owing to threatened asphyxia, it was cut, and the tumour was carefully dissected out. Few unimportant vessels had to be tied. Drainage tubes were inserted, and the wound treated antiseptically. In a fortnight perfect recovery had taken place. The tumour weighed sixteen ounces.?San Francisco Western Lancet. August, 1881.?G. S. M.
Effects Produced by Cantharidine.?M. Cornil records the effects produced in the rabbit by the internal exhibition of cantharidine as follows. Twenty minutes after injection the cavity of a glomerulus of the kidney presents the following lesions:?A large number of white corpuscles are found between the envelope of the capsule of Mliller and the vessels which compose the glomerulus of Malpighi; besides, the uriniferous tubules contain a granular exudation which fills and obliterates them. At the end of an hour the lesions are characterised by the proliferation of the cells, which, although they are round, become by mutual pressure irregularly pavemented: then there exists a true catarrh of the uriniferous tubules. In the bladder the lesions are similar, but superficial. In the lungs the smaller bronchi are filled with white corpuscles, pus corpuscles; these lesions, which indicate inflammation of the mucous membrane, are found also in the parenchyma, and are due to the cantharidine being carried to the organs in the circulation. In the larynx and trachea similar lesions, are seen. When cantharidine is applied to the skin sufficiently long, similar lesions are found. Hence M. Cornil concludes that blisters should only be applied for three or four hours, and not for fifteen or twenty, as seems to be the custom In his lecture (which is given in full in the Med. Times and Gaz., 1st October, 1881), he indicates the relative importance of many of these symptoms. He regards fulgurating, cutaneous pains, and plantar and dorsal, limited anaesthesia, as infallible signs of the pre-ataxic stage. He also places much reliance on the eye-symptoms. To the knee-reflex he does not attach the same value as other physicians. He records several interesting cases in which this reflex was absent on examination, but returned immediately on a continuous current of electricity being passed through the cord. In many cases of so-called nervous dyspepsia and biliousness, he has recognised the nature of the disease by finding diminution or absence of this reflex. While admitting that many cases of advanced ataxia have proved obstinate to all his treatment, he maintains that there is a stage of the disease when, by prompt and energetic treatment, " we may safely hope for good and successful results." His treatment of that stage consists in dry cupping and the actual cautery, with the internal exhibition of iodide of potassium, mercury, bromide of potassium, and ergot, &c., according to the requirements of each case.? G. S. M. Puerperal Temperatures.?Dr. A. D. Leith Napier summarises a series of observations on puerperal temperatures, in the following sentences :?
(1.) Temperature varies in the normal puerperal condition. In certain individuals it may be as low as 97? F. or as high as 09*5? for a week or more without a single bad symptom. The average for .the three or four days immediately succeeding parturition is 98*5? to 99?; the subsequent heat is modified safe from relapse. No anxiety need be felt so long as the | v2 |
2019-02-17T03:47:45.635Z | 1892-10-01T00:00:00.000Z | 215600797 | s2orc/train | Medicine
Background: To evaluate the efficacy and safety of strengthening the body’s resistance to eliminate pathogenic factors in Chinese medicinal formulas combined with chemotherapy (hereafter referred to as combined therapy [CT]) in triple-negative breast cancer. Methods: By searching the 7 electronic databases, PubMed, EMBASE, Web of Science, Cochrane Library, Chinese Academic Journal, Wanfang Database, and Chinese Science and Technology Journal, from the beginning of the establishment to April 2022 to identify eligible randomized controlled trial studies. Results: The meta-analysis showed that compared with chemotherapy, CT can effectively improve the objective remission rate (risk ratio [RR]: 1.39; 95% confidence interval [CI]: 1.28, 1.52; P < .00001, I 2 = 3%), reduce the recurrence rate (RR: 0.33; 95% CI: 0.14, 0.78; P = .01, I 2 = 0%) metastasis rate (RR: 0.48; 95% CI: 0.31, 0.73; P = .0006, I 2 = 0%) and the incidence of toxic and side reactions, lower tumor marker levels, regulated T lymphocyte subset changes, and increased average progression-free survival (standardized mean difference: 2.78; 95% CI: 1.41, 4.14; P < .0001, I 2 = 97%), and improve the quality of life (RR: 1.55; 95% CI: 1.21, 1.99; P = .0005, I 2 = 52%). Conclusion: This study suggests that CT appears to be an effective and safe treatment approach. Although this conclusion requires further confirmation owing to insufficient quality of the included trials.
these present morbid changes. This would bring acromegaly into the sartie series with myxcedema, cachexia strumipriva, cretinism, and Basedow's disease.
Another question is, whether other circumstances besides the amount of the poison, and the resisting power of the body, may affect alterations we meet with in pulmonary osteoarthropathy. An observation by the author has led him to believe that nervous influences may play their part. A locksmith, set. 51, began to suffer from cough and general weakness. In the course of a few weeks the expectoration became foul-smelling, but the general condition improved. A month later, pain set in in the little finger, and the ulnar side of the ring finger of the right hand, and gradually extended up to the elbow.
The pain was relieved in a week or two, but the hand continued to grow weaker and more useless until the patient was induced to apply for advice.
On examination of the affected digits, there was found to be marked curving and thickening of the terminal phalanges. There was paresis and atrophy of the hand-muscles supplied by the ulnar nerve, with some degree of the reaction of degeneration, and diminution of tactile sensation in the same region. The nails were enlarged and strongly curved. The remaining fingers of the right hand, and those of the left, were very slightly affected. There was deficiency of movement on respiration on the left side of the chest, with dulness, bronchial breathing, and rales at the left base posteriorly. In the mornings especially, the patient put up a large quantity of fcetid expectoration.
Otherwise, however, nothing noteworthy was detected. It would appear, then, that in the course of the pulmonary disease there was developed in this case, 011 the one hand, a tendency to clubbing of the fingerends, and on the other, an inflammation or degeneration of the right ulnar nerve, the latter, possibly, in consequence of a bruise which the patient had sustained some time previously. We may suppose that the injury had weakened the nerve, and that an infectious neuritis had supervened in the seat of least resistance.
In the same way, the poison developed in the diseased lung would act with special severity on the parts supplied by the affected nerve.?(Deut. Med.-Zeitung, 25th July, 1892.) Tic Douloureux. By Professor Benedikt, Vienna.?Though this affection is now generally admitted to be a central neurosis, it is yet capable of giving rise to important secondary changes in the periphery. Such are oedema and redness of the skin of the face, or cyanosis with tortuous small blood-vessels. After the disease has persisted for a long time, we may find atrophy of the nerve-trunks, and even considerable alterations in the carotid. With regard to treatment, galvanisation of the sympathetic, and galvanism and faradism applied to the seat of pain, are to be recommended. Compression of the carotid is not employed so often as it ought to be, but ligature of the vessel does not yield encouraging results. These methods, however, often fail, and it is necessary to have recourse to operation. Resection of the nerve naturally suggests itself first; but, curiously enough, cases are sometimes met with, where division of the nerve is not followed by the slightest degree of anaesthesia. The author had the opportunity of discovering the cause of this. In a patient who consulted him on account of a relapse, the infra-orbital canal had, in a previous operation, been completely obliterated. On the present occasion, the author, in dissecting out the infra-orbital nerve, found the canal and its exit quite closed ; but a thick trunk stretched from the nose to this situation, forming a swelling from which the nerves radiated outwards towards the periphery. It was thus proved that in this disease there is an abnormal development of nerves, which are able to assume the function of normal nervous tissue.
The most important point in operating is to tear the central portion of the nerve as thoroughly as possible. Resection is not nearly so beneficial, although it produces temporary relief by cutting off the periphery from the centre. As to stretching of the nerve, it is to be remarked that the less recent the case, the less good result can we expect, because the altered nerve will break when a comparatively slight strain is put upon it. A few weeks or months are sufficient to cause atrophy in an acute case, and, as the extent to which the development of new fibres has proceeded will also depend 011 the duration, it is manifest that this latter will greatly influence the prognosis. Our procedure should therefore be to use galvanism for 10 or 14 days. If this gives no relief, we should at once operate. Sometimes the pain persists for days or weeks after operation ; it is then, as a rule, amenable to treatment by therapeutic measures which were at first powerless. Frequently the pain is quite gone when the patient awakes from the influence of the anaesthetic ; in such cases, slight relapses yield to electricity. The author has never met with a case where operation completely failed.?(Deut. Med.-Zeitung, 14th July, 1892.) Lesions of the Spinal Cord in Scleroderma.?In ?, case of general vitiliginous scleroderma, Jacquet and De Saint-Germain found luhat microscopic cavities were present in the grey axis of the cord ; these were situated chiefly in the lower part of the cervical enlargement. Microscopic changes were detected in almost the whole cord, particularly in the region of Clarke's columns.
The most obvious alteration was a pigmentary atrophy, but the network of the neuroglia was less fibrous and more granular than normal. Sections of the affected skin showed the arteritis described by Mt^ry. Changes of this kind in the spinal cord are of the nature of syringomyelia, and it will be remembered that, in this disease, trophic disturbances in the skin are very frequent.?[Deut. 14th July, 1892.) A New Occupation-Neurosis.?Dr. Tranjen, a Bulgarian military surgeon, reports the case of an officer, who is troubled with an unusual spasm of the ocular muscles.
When the patient turns his head to the right, and then tries to move his eyes still more in the same direction without further movement of the head, a tonic spasm takes place in the superior oblique [? Ed.] and internal rectus muscles of the left eye, so that this eye looks as if it were stitched to the upper, inner angle of the orbit. So long as the head remains in this position, the left eye does not respond to the impulse of the will, nor does it move in harmony with its fellow. In such circumstances, it appears remarkably like an artificial eye.
To arrest the spasm, the patient requires first to turn his head back to the middle line, and then to make a few blinking movements with his eyelids, whereupon the troublesome eyeball returns, as it were, with a spring, to its normal position. In every other respect, the eyes appear to be healthy, and the ocular muscles, with the exception of the two which have been mentioned, discharge their functions perfectly.
The patient, who is now aged 27, acquired this affection in the military school at Sofia in 1884. His health previously had been excellent, and there is no neuropathic element in his family history, beyond the circumstance that a younger brother had a congenital club-foot. The patient, according to his own statement, occupied, during two whole years, a position in the left wing of the company with which he used to exercise in the military school. He had, therefore, at every " sichrichten," to turn his head to the right about 40?, and his eyes had to be directed still further round.
His head was thus placed somewhat obliquely, and, for the sake of binocular vision, the left eye was turned strongly upwards and to the right, so that an excessive contraction of the left superior oblique [? Ed.] and internal rectus muscles was thus brought about.
Tranjen looks upon the patient's explanation as being probably the correct one, and is therefore disposed to classify the affection with writers' cramp and the other occupation-neuroses.?(Berliner Klin. Wocheivschr., 15th Aug.,
1892.)
The Influence of Old-standing Disease of the Liver on the Prognosis of Operation-Cases.?M. Verneuil has always taken a special interest in this subject since the time when, as an assistant of Bazin in 1846, he saw a patient with a cirrhotic liver rapidly die after simple puncture of the abdomen. Attention was also drawn to this matter by Norman Che vers in Guy's Hospital Reports for 1845, by Gubler in 1853, and especially by Monneret in 1854.
M. Verneuil has himself, during the last decade, made several communications on this question, and he closes the present article with a bibliography. He now relates three cases which came under his notice within a few weeks.
The first was that of a middle-aged woman who had always enjoyed good health. A plastic operation was performed by M. Ricard on the tibio-tarsal joint, to remedy the condition left after a badly treated fracture.
The wound healed without drainage and without fever. But icterus appeared on the third day, and became continuously deeper up till death.
Pneumonia of the right base began three days later than the icterus. Death took place from asthenia three weeks after the operation. The autopsy revealed fatty hypertrophic cirrhosis of the liver, ascites, and alcoholic gastritis ; the pneumonia was cured. In the second instance, the patient was in a state of extreme anaemia, in consequence of severe metrorrhagia of five years' duration. The cause was a large uterine polypus, which was accordingly removed under the most careful antiseptic precautions. Unfortunately, however, the already existing septicaemia was not alleviated, and death from asthenia occurred after three days. The only post-mortem lesion that could be detected was an advanced fatty change in the liver. In the third case, an old woman, who was suffering from cancer of the liver, underwent an operation for strangulated hernia with complete success. All went well for ten days, and then the temperature rose, basal pneumonia set in, and the fatal issue followed a week afterwards.
Commenting on these cases, Verneuil remarks that, as it would be unjust to attribute the fatal results to the old fracture, the uterine polypus, or the strangulated hernia, or to the operations which in themselves were completely successful, it seems natural to throw the blame on the pre-existing disease of the liver, without which, probably, all three patients would at the present day have been alive, and cured of their local disorders. Or we may put it thus?either the hepatic disease caused the death of patients who had undergone operative treatment, or the operative traumatism brought about the fatal termination prematurely in those who were suffering from hepatic disease. In this latter view of it, especially, the responsibility of the surgeon in deciding for or against operation becomes very manifest.
Although the three cases above related came to the same termination, it must not be supposed that all diseases of the liver are of like gravity in the prognosis after operations. Verneuil would reckon cancer as undoubtedly the most serious ; then follow, in order, cirrhosis, alcoholic fatty degeneration, suppurative, haemorrhagic, and biliary calculous disease. In the last place may be mentioned?but quite hypothetically as yet?amyloid disease, retention of bile, chronic congestion, and hydatid cysts.?(Bulletin cle VAcademie de Mddecine, 2nd August, 1892.) Syphilis of the Heart.?This is a form of heart disease which has not as yet received sufficient attention, particularly in view of the great benefit to be derived from specific treatment. This statement, however, is not intended to apply to cardiopathies which are secondary to syphilitic arteritis, more or less localised, or to those which are due to diffuse arteriosclerosis, or to sclerosis of the coronary arteries. Neither is reference made now to valvular disease of rheumatic origin, complicated, it may be, by a syphilitic lesion of the heart. We refer, rather, to a class of cardiopathies which may arise in syphilitic cases of old standing, and may be of the most insidious and yet terrible nature; for they often commence with trifling functional disorders, which are apt to be regarded as simply nervous ; and, indeed, at this stage neither auscultation nor percussion may furnish any evidence of organic disease. The patient, and even the medical attendant, make light of these minor symptoms, and so put off until the specific lesion has given rise to secondary inflammatory and degenerative changes in the myocardium. One of these functional disorders is persistent arhythmia, either alone,-or accompanied, as it often is, by tachycardia. It is peculiarly intractable to the ordinary therapeutic measures, and if the practitioner meet with a case of arhythmia of such a character, he should proceed to administer mercury before it is too late.
The author was consulted, in 1883, by a medical man, who presented all the symptoms of an advanced, uncompensated cardiac lesion. The usual treatment by cardiac tonics had been tried, but without avail, and the condition of the patient was now desperate. It appeared, however, from the history of the case, that there had been several very grave syphilitic relapses, from all of which the patient had been rescued by the use of mercury and iodine. At the present time, there was not a trace of syphilis to be detected ; nevertheless, the author began specific treatment at once, in accordance with a principle he learned from his master Ricord, 35 years ago ; that is, with a patient vsho is undoubtedly syphilitic everything is possible, even the impossible. The doctor was put upon large doses of iodide of sodium (5 grammes daily), together with the subcutaneous injection of corrosive sublimate ; and after four weeks of this treatment, he was almost free from dyspnoea, and had no oedema, palpitation, or arhythmia. The improvement continued until, at length, he was able to return to practice without any need to take digitalis or other cardiac tonic.
The author is especially disposed to employ antisyphilitic remedies if there are no very obvious signs of changes in the valvular structures, and particularly if tonics have failed. Of course, the specific treatment also fails in a number of cases, but even then, it may be shown to have been justified by an estimation of the haemoglobin in the blood. The increase of colouring matter under the influence of mercury proves the existence of a specific receptivity for the bio-chemical action of that metal; for otherwise there would certainly be a destruction of red corpuscles. Nevertheless, such amelioration of the general state cannot influence the secondary changes due to the presence of the syphilitic lesion of the myocardium. The case of the doctor above related must therefore be looked upon as quite exceptional.
The conclusion the author comes to from his experiences in a considerable number of cases is, that if an old syphilitic subject presents the symptoms of continuous, obstinate arhythmia, with or without respiratory embarrassment, and not amenable to the hygienic and pharmaceutical measures commonly employed in the regulation of the heart's action, the practitioner is entitled to suspect a syphilitic process, and to recommend a carefully directed specific treatment, even though there is no longer any symptom that could demonstrate the existence of constitutional syphilis.?(M. Semmola of Naples in Bulletin de VAcad. de Med., 2nd August, 1892.) Muscular Dystrophy.?To the opening number of the new Deutsche Zeitschrift fur Nervevheilkunde Erb contributes the most exhaustive monograph that has yet appeared upon this subject. The clinical types of dystrophies generally recognised are the "juvenile" form of Erb, beginning in youth, occurring in families, affecting primarily the muscles of the shoulder and upper arm, and often associated with true or false hypertrophy ; second, the ordinary pseudo-hypertrophy; third, the "infantile" facio-scapulo-humeral type of Duchenne, recently described by Landouzy and Dejerine ; and, lastly, the " hereditary " form of Leyden, beginning usually in the legs. Erb has collected nearly ninety cases. . . . From the harmony in all the essential features, from the occurrence of transition forms, and from the occurrence of several forms in the same family, Erb concludes that clinically these four forms are essentially one.
In considering the pathology, he considers that the changes in the muscular fibres are primary and essential, and that the connective tissue changes are secondary, for changes in the muscle are often found alone, but changes confined to the connective tissue are never seen.
The muscular changes are hypertrophy, atrophy, increase of nuclei, vacuoli, and fissure-formation. Hypertrophy is regarded as a distinct pathological lesion, not due to prepara-tion for the microscope or to increased activity, an'l is probably the initial process, followed by atrophy ; just as we find weakness the first symptom, followed by atrophy. The changes in the connective tissue, increase of nuclei and slight hyperplasia, followed, as the muscular fibres atrophy, by marked hyperplasia and lipomatosis, are secondary. The whole process cannot well be regarded as inflammatory. In spite of the absence of discoverable changes in the nervous system, and the present belief that the trouble is a primary myopathy, Erb is inclined to believe that the muscular changes are due to dynamic, as yet undiscoverable, changes in the nerve-centres ; this opinion is based upon the heredity, the localisation of the morbid process in definite muscles and nerve-territories, and the co-existence of other nervous troubles, such as epilepsy and idiocy, and the occurrence of similar muscular changes in undoubted spinal disease.?(Boston Medical and Surgical Journal, 28th January, 1892.)?D. M'P. | v2 |
2019-12-10T14:04:14.300Z | 1908-04-01T00:00:00.000Z | 208955812 | s2orc/train | [Miscellaneous].
Mosher, H. C.—A Specimen of an Encapsulated Brain Abscess. " Boston Med. and Surg. Journ.V' July 15, 1909. The specimen was taken from a man, aged forty, who had been operated upon for acute mastoid three months before. A brain abscess was evacuated by operation immediately. The patient became worse next day, after some amelioration, and was again explored, and an encapsulated abscess was discovered. The patient died forty-eight hours after admission. The pathological findings are described and illustrated by two excellent photographs. Macleod Yeamiey.
Endoscopic microscope assisted CO2 laser surgery of neoplastic head and neck tumors has nowadays become a standard procedure in the treatment of these diseases. Indiciations for laser surgery have increased in the past ten years. The timetable management in therapy of cervical lymphatic metastasis is handled differently. Taking into account possible complications, for instance bleeding, obtruction of the upper airways and feeding problems, it becomes clear, that choosing the right time for neck dissection is of great significance. Basically the following two major therapeutical strategies compete with each other: the single time procedure including laser surgery of the primary neoplasm and neck dissection (possibly percutaneous endoscopic gastrostomy and tracheotomy); versus the two time procedure in which the neck dissection is being performed after an interval when laser surgery of the primary neoplasm had already been practised. An improtant advantage of the single time treatment is the control of complications, like postoperative bleedings. In order to prevent postoperative bleedings the branches of the external carotid artery can be ligated simultaneously. On the other hand the almost obligational tracheotomy due to tissue swelling, presents a great disadvantage of the single time procedure. Depending on the location of the primary neoplasm, the goal of the presented examination was to find out, when the single time procedure was absolutely necessary. From 01-01-1995 until 24-10-1997 we examined 155 patients retrospectively who were treated by laser surgery. In 36 cases we performed a single time procedure where laser surgery and neck dissection were done simultaneously. In ten patients we practised the two time treatment. All cases were analysed with respect to potential complications such as post operational bleedings, obstruction of the upper airways and dysphagia. Our results show that tumors of the oropharynx and of the tongue base should be treated with a single time procedure, because of the danger of postoperational bleedings and obstruction of the upper airways. A two time treatment with no tracheotomy is recommended only for tumors in the glottic region and the region of the sinus piriformis. Purpose: In a Dutch multicentric retrospective study (1985)(1986)(1987)(1988)(1989)(1990)(1991)(1992)(1993)(1994) necknode metastases in salivary gland carcinomas were evaluated. Material and methods: Results were obtained of 568 patients with a mean follow-up of 5 years (parotid 59%, submandibular 14%, oral cavity 24%, elsewhere 3%). The distribution according to T-stage was: TI 26%, T2 44%, T3 19% and T4 11%. The histologic type was adenoid cystic carcinoma in 26%, adenocarcinoma NOS 24%, mucoepidermoid carcinoma 16%, acinic cell carcinoma in 12%, carcinoma in pleomorphic adenoma 8%, undifferentiated carcinoma 7%, squamous cell carcinoma 6%.
5.2
The importance of correct stage grouping of oropharyngeal carcinoma for adequate selection for treatment I.-C. Kiricuta, Inst. of Radiation Oncology, St. Vincenz Hospital, Limburg, Germany Background: An accurate and rational stage system for oropharyngeal carcinoma is presented using the actual T, N, M-categories. Methods: Five hundred twenty cases of oropharyngeal carcinoma treated at the Department of Radiation Oncology of the University of Wuerzburg between 1985 and 1994, with computed tomography scanning before initial treatment are analysed. Survival curves of various kinds of T, N and M stages are compared. A new staging system is proposed by studying the actual UICC system.
Results: According to the new staging system, the very heterogenous stage IV from the UICC TNM-classification is now divided in two subgroups, stage IVA and IVB. The stage IVA is restricted to a homogenous group what prognosis concerns including only T3-T4 and N2-N3 MO patients. The stage IVB includes all patients with any T and a supraclavicular lymph node metatases as well as all patients with an Ml stage. Stage III includes T3-T4 NI MO and T2 N2-N3 MO patients. Stage II includes T3-T4 NO MO and T2 N2-N3 MO patients. Stage I is restricted to T 1-T2 NO MO patients.
Conclusions: This new staging system allows a proper classification of patients with similar prognosis, and will allow adequate selection of patients for treatment, to evaluate results of management more reliable and to compare statistics reported.
5.6
Proliferative activity and metastases in adenoid cystic carcinomas of the salivary glands S. Nordgird, G. Franzen*, M. Boysen**, Depts. of ORL and *Plastic Surgery, University of Trondheim, **Dept. of ORL, The National Hospital, Oslo, Norway Purpose: To study the predictive value of proliferative activity for the early development ofmetastases in adenoid cystic carcinomas. Material and methods: The proliferative activity was studied by the expression of the Ki-67 antigen in formalin-fixed, paraffinembedded tissue from 44 patients treated for adenoid cystic carcinoma of the salivary glands. The results were compared with DNA ploidy, clinical factors, histopathological grading and the development of metastases after primary treatment. Results: Metastases developed in eight patients, none in those with free surgical margins at surgery. In the analysis ofthe diseasefree period, high Ki-67 expression was the only significant, prognostic parameter (p<0,01). When limited to tumors with violated surgical margins (n=25), high proliferation still predicted early metastases (p=0,01). Free margins were more difficult to obtain in tumors with high proliferative activity even when adjusted for size (TI/T2). Ki-67 expression was significantly related to ploidy and histological grade, but not to tumor size or stage. Conclusions: High proliferative activity in the primary tumor increases the risk for developing early metastases after treatment for adenoid cystic carcinoma ofthe salivary glands and reduces the chance to obtain free surgical margins at primary surgery. These patients should be followed closely for early detection of metastases irrespective oftumor size and grade.
5.7
Risk factors for metastasis in squamous cell carcinoma of the skin J. Wehner-Caroli, H. Breuninger, Dept. of Dermatology, University of Tubingen, Germany Aim of the study was to determine histological and clinical parameters correlating with high risk for metastizing of squamous cell carcinoma (SCC) ofthe skin. Course of disease was observed in 822 tumors and compared to clinical and histological features of the underlying SCC. Following datas were recorded: immunsuppression, localisation, entity, tumor thickness (Breslow), clinical size, depth of invasion (Clark), degree of differentiation (Broders). Course of disease was evaluated by computerised data based follow up investigations (Tumor Center Tuebingen). The mean lapse of obervation was 4 years. The rate of metastasis over all carcinomas was 5,5% (45 tumors).
The results show the importance of regular follow up investigations of squamous cell carcinomas of the skin with one or more clinical or histological criterias shown as above. | v2 |
2018-04-03T05:16:46.068Z | 1911-07-01T00:00:00.000Z | 42265786 | s2ag/train | Sarcomatosis Cutis of the "Perrin" Type in a Man, aged 25.
THE disease had begun probably nine weeks ago, with lesions on the chest. There had been no subjective symptoms, and this patient had seemed in his usual robust health. He was seen at St. Mary's Hospital for the first time a fortnight ago, and then had an efflorescence of the following character: Scattered over the chest, the back, and the upper part of the arms and thighs there were very numerous roundish elevations, the skin covering them being of a faint pink colour, and showing rather accentuated " pores." There was no scaling or other alteration of the surface. On palpation the pink surface was found to cover a tumour mass of considerable firmness, but not hard, and the size and elevation of the swelling was about that of a half-walnut. The largest of these tumours was on the middle of the front aspect of the left thigh. He had, in addition, a hoarse voice and great congestion of the fauces, uvula, and throat; the tonsils were swollen as well. He was seen by Dr. William Hill, who regarded the throat as probably syphilitic. The opinion at first formed by the exhibitor of the eruption was that it was mycosis fungoides of the "tumour d'emblee " type described by French authors, but the complete absence of any itching or other subjective sensation and the rapidity of the increase seemed to forbid this diagnosis. At the instance of Dr. Hill a Wassermann reaction was tested in the Inoculation Department, and was reported to be negative. A small tumour the size of a shilling was excised from the shoulder, and on microscopic examination the diagnosis of large roundcelled sarcoma was made bv the exhibitor. Sections were submitted to the meeting, and this diagnosis was confirmed. The sarcomatosis cutis was apparently primary, for no earlier accident or operation was mentioned, inquiry being pressed in this direction. There was considerable general enlargement of glands in the neck and | v2 |
2019-03-13T13:28:05.221Z | 1914-03-01T00:00:00.000Z | 75849920 | s2ag/train | VIII. A New Esophagoscope
I presume that you may consider it somewhat unusual for a general surgeon to present before your meeting a newinstrument for throat work. I have been interested for a number of years in the clinical and surgical aspects of dis eases of the esophagus, and especially cancer. You know that diseases of the esophagus, since the introduction of the Sauerbruch chamber, are amenable to surgical interference. It is true, up to a few months ago all cases of resection of the esophagus for cancer have ended fatally. However, all the work done in Europe and in this country along these lines has not been in vain, and has, after many years of disappoint ing efforts, resulted in the first successful resection of an intrathoracic esophageal cancer by Dr. Torek in New York. To further the work in this special field, to be able to make the diagnosis of esophageal cancer in its very early stages, we need an instrument for examination which can be easily intro duced without general anesthesia and without great discomfort to the patient. | v2 |
2019-03-31T13:43:30.056Z | 1915-04-01T00:00:00.000Z | 87936285 | s2ag/train | Tumor-like growths in rat stomach following irritation
Fibiger's announcement of the production of carcinoma in the rat stomach through the agency of nematodes has not as yet been controverted. We wish briefly to record the fact that somewhat similar pictures can be produced by other means of irritation. By suspending in the stomach cavity woolen balls saturated with chemical irritants or by injecting the chemical irritants into the wall itself, polypoid growths of stratified squamous epithelium can be produced. By using celluloid balls with spinous processes these polypoid growths can be made to reach considerable dimensions. When these irritants are applied to the glandular portions of the organ, marked localized thickenings of the mucosa are produced. The chemical irritants cause a marked downgrowth of stratified epithelium resembling the cancroid type described by Fibiger, while the mechanically induced proliferations are characterized by a marked overgrowth of the cornified layers and relatively slight downgrowth. In the glandular portions of the organ the proliferation under chemical irritation assumes the character of a cystadenoma which involves the stomach wall to a considerable depth. | v2 |
2018-04-03T00:50:07.748Z | 1917-05-01T00:00:00.000Z | 26810539 | s2ag/train | Two Cases of Primary Carcinoma in the Liver, in One of Which Thrombosis of the Inferior Vena Cava Occurred
THE patient, J. T., a shoemaker, aged 66, was admitted to hospital on November 17, 1916, with ascites of some four weeks' duration, during which time he had been too ill to follow his employment. He had been ailing for the last four' months. On admission he seemed extremely feeble, and there was marked mental hebetude. He was not, however, emaciated, the subcutaneous fat being fairly abundant. Paracentesis abdominis, on the day of admission, yielded 6,000 c.c. clear ascitic fluid, of rather deeper yellow colour than usual, and of specific gravity 1004. After tapping the peritoneum a hard tumour, connected with the liver, could be felt in the abdomen below the ribs on the right side. The ascites rapidly re-accumulated, and by a second paracentesis (on November 29) 6,400 c.c. of similar ascitic fluid (specific gravity 1005) was withdrawn. There was never any fever. The pulse was about 74 to 88, and the respiration about 20, per minute. The urine, when tested on November 17, was of specific gravity 1015, acid, free from albumin and sugar. The conjunctiva had a subicteric tinge. There was great loss of strength. Death occurred on December 7, 1916. | v2 |
2018-04-03T06:18:03.441Z | 1917-07-01T00:00:00.000Z | 46266857 | s2ag/train | Congenital Hirsuties of the Simian Type in a Child.
THE patient is a girl, E. W., aged 4, born in London. The hypertrichosis affects the forehead, temples, sides of face, the back (especially the upper and lower portions and the vertical line over the spinal column), and the upper and lower extremities. The regions of the -axillke, groins, pubes, and front of the trunk, and the neighbourhood of the mouth and nose, are not hairy. The child has corneal opacities from old phlyctenular keratitis, and has been treated for adenoid vegetations, enlarged tonsils and otorrhoea, but otherwise shows no signs of disease, and is mentally normal. There is no marked prognathism of either jaw, and, when the jaws are closed, the lower teeth come behind the upper teeth, as they do in ordinary individuals. The nose and lips and cheeks are thick, and the bridge of the nose is low. There is nothing to suggest the presence of a hypernephromatous tumour in the abdomen, and a Rbntgen skiagram of the base of the skull shows nothing abnormal about the pituitary fossa. There is no sign of any precocious or abnormal sexual condition. The moderate degree of hirsuties present is rather of the "Simian" type (see further on), than of a type suggesting suprarenal or other endocrine disturbance. In the present case it is, according to the mother, congenital, but not familial. The mother's two other children (a girl and a boy) are said to be quite normal, and there is no history of hypertrichosis in any other members of the family. The mother is Irish, the father (deceased) was Austrian (not Hebrew Austrian). There is the usual history of "maternal impression." The mother says that whilst she was pregnant, about three months or so before the birth of this child, she used frequently to see a monkey, which belonged to a lady in the neighbourhood. Excluding cases of local hypertrichosis of the "nrevus pilosus" kind, I think cases of hypertrichosis or hirsuties may be roughly classified as approximating more or less to one or the other of two main types. In the first, which may be termed the " Simian type," the hypertrichosis is congenital or developmental, and sometimes familial, and may be regarded as an example of so-called " degenerative" 175 | v2 |
2018-01-23T22:42:45.310Z | 1920-06-01T00:00:00.000Z | 212620369 | s2orc/train | Abstracts
Objectives: The relationship between circulating microRNAs (miRNAs) and HBV associated acute-on-chronic liver failure (HBVACLF) need to be further investigated. The purpose of our study was to identify the aberrant expression of miRNAs in HBV-ACLF and to investigate its potential role during the progression of HBV-ACLF. Methods: miRNA expression profile by miRNA microarray analysis was performed on Peripheral Blood Mononuclear Cell (PBMC) obtained from patients with mild chronic hepatitis B (CHB) or HBVACLF, respectively. Selected unnormal expressed miRNAs were verified in more clinical samples by quantitative real-time PCR (qRTPCR). A luciferase reporter assay was conducted to confirm direct target of miR-181c. mmu-miR-181c agomir was delivered by tail vein injection into mouse hepatitis virus-3(MHV-3)-infected BALB/cJ mice to evaluate its interference effect in fulminant viral hepatitis mouse model. Results: 7 kinds of miRNAs were down-regulated and 9 kinds of miRNAs were up-regulated in the PBMC of HBV-ACLF patients compared with that of patients with mild CHB. Among the deregulated miRNAs, the expression of Hsa-miRNA-181c was significantly down-regulated in HBV-ACLF by qRT-PCR. While serum TNF-a significantly increased in HBV-ACLF. A luciferase reporter assay was conducted to confirm TNF-a was verified as a target of miR181c. miR-181c significantly improved fulminant viral hepatitis mice survival rate. Conclusion: These data suggested that miR-181c might have potentially therapeutic potential for the treatment of fulminant hepatitis. Abstract #689
Abstracts.
P H A R Y N X . On the Lymphatic Eelations between the Nasal Fossae and the Tonsils.
Amedes Pugnat. " Rev. de Laryngol." July, 1918. It is no uncommon occurrence for a tonsillitis to develop after operations on the nose, and opinions vary as to whether the infection is conveyed through the lymphatics, through the blood-stream, or merely by passage of septic material over the tonsils.
SchSnemann held that the infection was through the lymphatics. He injected a solution containing iodine into the inferior turbinal and removed the tonsil of the same side six hours later. Iodine was demonstrated in the tonsil. Lenart, and also Henke did experiments of the same nature in dogs and came to the same conclusion. Amersbach, later, after similar experiments, could find no trace of the foreign substance in the tonsil.
Pugnat last year, in children who were to have their tonsils removed, injected an emulsion of soot into the turbinates twenty-four, thirty-six, and forty-eight hours beforehand and examined the removed tonsils microscopically. In no single case out of some hundred experiments did he find any soot particles in the tonsils. He concluded from this that there is no direct connection between the lymphatics of the nose and the tonsils, and that the latter should therefore not be regarded as lymphatic glands. He belives that post-operative angina cannot be compared to an adenitis.
NOSE.
Atrophic Rhinitis treated with Ichthyol Ointment.-Robert H. Fowler. "The Laryngoscope," December, 1917, p. 904. Fowler advocates the use of an ointment consisting of ichthyol, 20 gr. ; menthol, 2 gr.; and petrolatum, 2 oz. This to be applied three times a day on cotton in each nostril. Application of the ointment abolishes the bad smell so long as the patient continues the treatment. Fowler does not claim that the treatment is more than palliative.
/ . S. Fraser. A Wax Model of the Nasal Cavity and Paranasal Sinuses.-C. M. Jackson and C. E. Connor. " Annals of Otology, etc.," xxvi, p. 585. This carefully made wax cavity, taken from a well-developed head, was made by sectional method. It includes the nasopharynx. The description requires to be read in extenso. It is the intention to have this model reproduced and placed on the market.
LARYNX.
Abscess of the Thyro-glosso-epiglottic Space.-Bellin and Vernet. "La Presse Medicale," March 7th, 1918. The authors report this case as one of few that have been recorded ; the first being reported by Brausse and Brault in 1893.
The abscess is evolved entirely in the space comprised between the base of the tongue, the larnyx, and the epiglottis. The patient, a sergeant in the French Army, on leave from the Front, reported on November 11, suffering from violent dyspnoea and inability to swallow. Saliva mixed with blood and pus, and of a putrid odour, dribbled from the mouth. The tongue was fairly mobile ; there was no trismus. On depressing the tongue swelling at the right base could be seen ; lingual and faueial tonsils and velum normal.
Laryngoscopic examination revealed a swelling, the size of a walnut, occupying the left side of the glosso-epiglottic space. Epiglottis winered and swollen, deviated to right. (Edema of the entire vestibule of the larynx, particularly of the left side. The glottis was obstructed by oedema; view of left vocal cord obstructed by swelling; right cord normal. The tumour did not extend beyond the median glosso-epiglottic fold. There was a history of exposure to cold and wet while fatigued. Operation was done at once. The abscess was opened by " transverse sub thyroid pharyngotomy under local anaesthesia, the incision crossing the middle line but chiefly to the left." Foul-smelling pus was evacuated, and the opening examined and enlarged by the finger carried to the anterior face of the epiglottis. A drain was inserted. Difficulty in breathing continuing, a tracheotomy was done under local anaesthesia. Condition of patient was grave for three days; delirium accompanied by temperature of 40° C. Drain removed on second day, and wound packed with iodoform gauze Delirium disappeared on third day and temperature dropped to 39° C. During lavage with Dakin's solution on the fourth day there was a violent and copious haemorrhage from the mouth, patient stopped breathing, and the cannula of the tracheotomy tube was removed and breathing restored by artificial respiration. After the fourth day patient improved rapidly. The wound was not entirely closed until the fortieth day. For the first few days the patient was fed through a nasal tube.
It is claimed that the extent of the swelling and the grave condition of the patient indicated evacuation of the pus by an external operation rather than by an entrance in the buccal cavity. Entrance to the thyroglosso-epiglottic space is easy. The anterior wall of the space is formed by the thyrohyoid and hyoglossal membranes ; the posterior wall by the anterior face <'i the epiglottis. The glosso-epiglottic ligament divides the space into two distinct compartments.
The patient of Brausse and Brault, at first operated on by a lateral cervical pharyngotomy, was not relieved, and was again operated on by a subhyoid transverse incision.
Bacteriological examination of the pus demonstrated the presence of a club-shaped bacillus. Gram positive, analogous to B. perfrinyens ; also a monococcus, Gram negative, arranged in short chains, analogous to diplococcus reniformis.
The article, which is very interesting and should be read in the original, concludes with differential diagnoses of : (a) Abscess of the base of the tongue. Complete Unilateral Deafness, resulting from Acute Parotitis.-George H. Willcutt. " The Laryngoscope," November, 1917, p. 811. Of thirty-four (collected) cases of deafness following mumps the affection was bilateral in seventeen. In many there was tinnitus and vertigo, the latter lasting from a few hours to some days. Pour patients suffered, from vomiting. The deafness usually comes on about the fourth or fifth day, sometimes as late as the tenth or fifteenth. Willcutt reports the case of a female, aged twenty-nine, with previously normal hearing. The patient developed parotitis with bilateral swelling, but no temperature. Six days later there was nausea, vomiting, and vertigo, and the patient was unable to lift her head from the pillow. Two days later the vomiting had ceased, and the nausea was slight, but the vertigo persisted, and for a week the patient could not walk without staggering. In three weeks Willcutt examined the patient, and found complete deafness in the left ear with a normal right ear. Both drumheads were healthy. Injections of 2 per cent, pilocarpine (5 minims) were begun, and the patient showed a good reaction. In all, seven injections were given, but there was no improvement in the condition of the left ear. Examination after three months showed complete unilateral deafness. Attacks of vertigo were still present, most marked when turning to the right.
REVIEW.
Operative The publication of the second volume of this extensive work has been delayed for a considerable time, but the time has not been lost, as the collaborators have obviously been at great pains to bring their information well up to date.
Whether recent or not they have learnt one lesson, and they convey it with proper insistence-that operations, especially in the nasal cavities, should not be lightly undertaken. Dr, Hanau Loeb points out the great desirability of carrying them out under hospital conditions. The article begins with the surgery of the septum, which, in accordance with modern ideas, centres itself mainly on the submucous operation as worked out by Killian, Freer, and Hajek. Of the non-submucous operations Moure's seems the most acceptable. Among operations on the turbinate bodies the use of the snare for the posterior extremity of the inferior one is recommended, and to facilitate it Beck's ingenious clip with thread attached is described. There is no reference to the forceps of Prince, of Springfield, which is certainly most effective and speedy in action when used to complete an " adenoid " operation. Among the | v2 |
2018-04-03T04:12:19.796Z | 1920-07-01T00:00:00.000Z | 38069899 | s2ag/train | Case of unilaterally distributed Molluscum Fibrosum Tumours, with a History suggesting Recurrence.
THIS woman presents an example of the condition known as sclerodermia guttata, or herpetic morphoea, one of the divisions of what has been called, rather loosely, white-spot disease. The lesions are on the back, chest, wrist, and one has just started on the face. The condition only dates from eighteen months ago. What makes the case more interesting is, that the patient has myxcedema, and has had it for fourteen years. For this she has been taking thyroid tablets regularly, a drug which is frequently exhibited in cases of sclerodermia. She is anxious about the lesion on the face, and I shall be glad of suggestions as to treatment. | v2 |
2018-04-03T05:06:34.029Z | 1923-03-01T00:00:00.000Z | 41630365 | s2ag/train | A case of dermatomyositis.
History.— P. E. C., aged 37, a fireman, married, was admitted to Long Island College Hospital, Dec. 28, 1921; discharged, Jan. 4, 1922. His chief complaints were: (1) swelling of the head, wrists and legs; (2) stiffness of muscles throughout the body; (3) the presence of lumps at the back of the head, and (4) "gastritis." His mother died of cancer of the breast, at the age of 56. The patient had had pneumonia at the age of 4. The past history was otherwise negative. In July, 1921, the patient noticed painless swelling of the head and neck, which necessitated an increase in the size of his collar from 15 to 15¾. He also noticed that he was rapidly gaining fat over his chest and abdomen. The swelling of the face did not cause any puffiness of the eyelids but was enough to change his facial expression by obliterating the | v2 |
2018-04-03T01:04:48.214Z | 1925-06-01T00:00:00.000Z | 20179191 | s2ag/train | Two Specimens Clinically Simulating Ovarian Cysts: (1) Carcinoma of the Gall-bladder; (2) Enlargement of the Spleen
1922, xCiv, p. 635. [f5] O'CONOR, V. J., Journ. Urol., 1924, xii, p. 159. [6] VENOT, A., and PARCELIEIR, A., Rev. de Chir., 1921, lix, p. 565. [7] CROSSEN, H. S., Tran8. Amer. Gyn. Soc., 1915, xl, pp. 111-126. [8] MELCHIORI. Quoted by Venot and Parcelier. [9] VoN WINCKEL. Quoted by Veliot and Parcelier. 10] CUTHBERT LOCKYER, Proc. Roy. Soc. Med., 1911-12, v (Sect. Obst. and Gyn.), p. 136. [11] BOYD, FLORENCE, N., Tourn. Obst. and Gyn. Brit. Emp., 1906, ix, p. 40. Discussionz.-Dr. H. RUSSELL ANDREWS (President) asked Mr. Palmer if he had any reason for not removing the inguinal glands as he would have done if the growth had been just outside the urethra instead of inside it. Dr. FAIRBAIRN said he had only had one case of urethral carcinoma on which operation had been possible and the result in that case was not fortunate, as in the majority of cases mentioned by Mr. Palmer. In his case the patient was a young woman of 34 and the whole urethra was involved; complete incontinence followed, as part of the neck of the bladder was excised. She died four months later with both local recurrence and diffusion in the pelvis. The case was recorded in the Journal of Obstetrics and Gyn?cology of the British Empire, xx, p. 306. At the time the case was seen treatment by radium was not available, but now it was clear that better results might be expected from local treatment by radium with clearing out of the glands of the groin by operation. Dr. T. W. EDEN said that he had only seen two cases of primary urethral cancer; one was inoperable, the other he had operated upon, but as the case had been lost sight of, he could not give the after-history. He thought that this condition could probably be most hopefully dealt with by combining operation with irradiation, radium being used for the regioll of the primary growth and X-rays for the glands in the inguinal region. | v2 |
2019-11-25T14:01:37.991Z | 1928-01-01T00:00:00.000Z | 208258474 | s2ag/train | Chapter VIII: Cysts in the Liver
liminary puncture, which caused the outflow of some clear fluid containing echinococcus elements, echinococcotomy was made, and a number of daughter-sacs removed from a cavity in the sacrum. Later Course: There remained a fistule after the operation. Excochleation of the cavity was made a couple of times during the following years, the last time in April, 1920. The patient is able to work, and his general condition is good. There are no functional disturbances in the lower extremities. From time to time the fistule opens up, and a number of very small cysts come out. At our request, he presents himself at the Clinic for renewed examination, seven years after. Roentgen Examination, Oct. rSth, 1925 (Fig. LXXXII): In the upper portion of the sacrum, to the left of the median line, is seen a sharply outlined, kidney-shaped defectuosity about six centimeters long, besides one or two smaller, roundish ones. The left margin of the bone, below the sacroiliac articulation is uneven, with small defectuosities in the bone, and its structure atrophic. The upper margin of the sacrum is uneven. Comment: A positive roentgen diagnosis is not possible in this case independently of the anamnesis and the clinical symptoms. Against tuberculosis spoke the fact that the patient was otherwise in sound health and that there was no abscess in spite of the great extent of the destruction. Against a malignant tumor spoke the rather protracted course of the disease, the good general condition of the patient, and the circumstance that there was no palpable deformation of the bone. Against an echinococcus there could be no other argument than the fact that the lodgment of that parasite in the bony structures is very rare. In trying to account for the defectuosities in the bones, as seen in Fig. LXXXII, the fact of the successive operative interventions must be borne in mind. | v2 |
2018-04-03T06:25:32.324Z | 1928-03-24T00:00:00.000Z | 30008842 | s2orc/train | Pulmonary tuberculosis: diagnosis and treatment.
Tuberculosis remains a worldwide problem despite well documented, well publicised methods of prevention and cure. Poverty and HIV infection are major reasons for its persistence.1 2 We review the diagnosis, treatment, and prevention of tuberculosis.
### Symptoms and signs
Literature, opera, and art have popularised the traditional symptoms and signs of pulmonary tuberculosis (box): cough, sputum, haemoptysis, breathlessness, weight loss, anorexia, fever, malaise, wasting, and terminal cachexia figure in various combinations, not only in the descriptions of the heroes, heroines, and villains but also among the artists, poets, and musicians themselves.3 However, none of these symptoms is peculiar to tuberculosis. Nowadays, patients with pulmonary tuberculosis who present the full spectrum of symptoms and signs are unusual in developed countries, but doctors and health workers often see such patients in developing countries. Lung cancer has become a more common cause of some or all of these symptoms in developed countries, and, as cigarette smoking increases, this may well become the case in developing countries.
### Epidemiological clues to diagnosis
Among immigrants to the West from the Indian subcontinent, sub-Saharan Africa, South East Asia, the Baltic states and Russia (especially if they were previously imprisoned4), the prevalence of tuberculosis is much higher than among the native white population.2 5 In the native population, tuberculosis is most commonly found among people living in poor conditions and in deprived areas, especially in elderly people and those with unstable social or psychiatric backgrounds, such as hostel dwellers, street dwellers, alcoholics, and drug misusers, as well as in immunocompromised patients.6–8 In developing countries, tuberculosis is most common among very poor people, especially those who are severely malnourished or HIV positive.1 8 9 Awareness, in both primary and secondary care, of these epidemiological facts increases the chances of prompt diagnosis of tuberculosis. Whereas postviral cough, asthma, reflux oesophagitis, …
specimens of sputum for tubercle bacilli, one of which should be an early morning specimen. 10 Prompt diagnosis is essential to ensure prompt treatment and thus rapid reduction in infectivity.
Confirming the diagnosis
Most tuberculosis programmes use direct smear examination of sputum but, if resources permit, culture is desirable. Reliable susceptibility testing is a luxury few developing countries can afford, although it is especially desirable for purposes of re-treatment. Rapid methods of culture and susceptibility testing are widely available in the wealthier nations. Molecular techniques have provided quick, sensitive, and specific tests for Mycobacterium tuberculosis-such as polymerase chain reaction, DNA and RNA probes, and interferon tests-but these are expensive and technically demanding. 5 They are most useful in diagnosing multi-drug resistant organisms quickly and in differentiating M tuberculosis from other, non-infectious mycobacterial species.
What are the roles of tuberculin skin testing and chest radiography? Tuberculin testing is helpful in ranking tuberculosis among the differential diagnoses of conditions with symptoms, signs, and radiological changes that would
Symptoms and signs of tuberculosis
Cough-usually productive Sputum-usually mucopurulent or purulent Haemoptysis-not always a feature, volume variable Breathlessness-gradual increase rather than sudden Weight loss-gradual Anorexia-variable Fever-may be associated with night sweats Malaise-patient may realise only retrospectively, when feeling better after treatment Wasting and terminal cachexia-late, ominous signs
Sources and selection criteria
We both have considerable experience in tuberculosis and of the research and guidelines that underpin modern management. The review is based on this experience and on our knowledge of the literature over the past 50 years. The references provide access to this literature, in themselves and in their own lists of references be compatible with pulmonary tuberculosis but where sputum is negative on direct smear or culture. A strongly positive tuberculin test in such a patient who has not previously had BCG vaccination or tuberculosis increases the probability that tuberculosis is the diagnosis. In those who have previously received BCG vaccination, interferon tests will differentiate between that and M tuberculosis as a cause of the strongly positive tuberculin test. 5 Chest radiography is a more expensive test than examination of sputum by direct smear, but when available and reliable it is an important investigation, especially when clinical suspicion of tuberculosis exists but the sputum is negative. Fluffy upper zone shadowing, frequently bilateral and often associated with cavitation, is classic, as is miliary shadowing. New, soft shadowing among old, fibrotic changes often indicates relapse of previous disease. Paratracheal, mediastinal, and hilar lymphadenopathy are not unusual in African and Indian patients with tuberculosis. In patients infected with HIV, the radiological appearances are often less specific, just as symptoms and signs may not be classical and sputum may be negative on direct smear.
Diagnosis in children
Diagnosing tuberculosis is quite difficult in children. [11][12][13] Although they may cough, they rarely produce sputum and may present in a non-specific manner with failure to thrive or loss of weight, reduced energy, and, perhaps, persistent fever. Contact with a relative with tuberculosis is an important pointer. Tuberculin testing may be helpful, and, when possible, a chest radiograph should be obtained or laryngeal swabs or gastric washings taken for culture. [11][12][13] Treatment of tuberculosis: the modern approach Successful treatment is as much about building rapport with the patient as about using appropriate chemotherapy. An empathic doctor or other health worker who can build a good relationship with patients is crucial to compliance with treatment and follow-up. National tuberculosis programmes that ensure, by appropriate selection and training, that health workers treat patients with respect and understanding are likely to achieve more than those that place less emphasis on good relationships with patients.
Standard chemotherapy, as recommended by the British Thoracic Society, International Union Against Tuberculosis and Lung Disease, World Health Organization, and National Institute for Health and Clinical Excellence (NICE), consists of six months of rifampicin and isoniazid (usually given as combination tablets), initially supplemented by two months of pyrazinamide and ethambutol (table). 5 14-16 A reliable preparation containing rifampicin, isoniazid, and pyrazinamide in combination is available, as is a combination tablet of all four of these first line drugs. Fixed dose combinations of drugs in a single tablet have the great advantage of reducing the possibility of emergence of drug resistance. Pyridoxine is indicated only in malnourished patients or those with conditions predisposing to peripheral neuropathy. 14 The results of susceptibility tests are nowadays usually available before the end of the two month period of intensive treatment: providing the organisms are sensitive to rifampicin and isoniazid, the other two drugs can be discontinued at the end of the first two months and rifampicin and isoniazid continued for a further four months. Whenever possible, cure should be confirmed by smear and culture of sputum at the end of treatment. If the pleural cavities are involved, the chemotherapy regimen is the same, but pleural aspiration may be needed to reduce breathlessness. If the effusion recurs, glucocorticoids for three to six weeks help to prevent or reduce further reaccumulation. 14 How to manage drug resistance The six month regimen has been shown to be effective only when the combination of rifampicin and isoniazid is used. If mono-resistance to rifampicin is present, then the British Thoracic Society guidelines recommend that isoniazid and ethambutol or pyrazinamide should be continued for a total of 18 months. For mono-resistance to isoniazid, these guidelines recommend continuing rifampicin and ethambutol (or Antituberculosis regimens for various scenarios 5 pyrazinamide) for 12 months. The same provisos apply in situations in which drug intolerance precludes the use of rifampicin or isoniazid. 14 A single drug should never be added to a failing regimen, as this may lead to resistance arising to that drug as well. If resistance to both rifampicin and isoniazid is present, the patient must be managed primarily by a chest physician with expertise in treating multi-drug resistant tuberculosis. 5 14 17 By necessity, the regimen will include second line drugs that often have unwanted effects. Even with an expert chest physician, backed by a reliable tuberculosis laboratory, management remains challenging and mortality is high.
What if the budget is inadequate for rifampicin?
Lately the Global Drug Facility, through the Stop TB Partnership, has enabled many countries to provide the standard six month regimen used in the developed world. In other countries that cannot afford rifampicin for six months, the recommended regimen consists of rifampicin, isoniazid, pyrazinamide, and ethambutol or streptomycin for the first two months, followed by six further months of isoniazid and ethambutol or, if ethambutol is not available and the prevalence of HIV/AIDS is low, isoniazid and thiacetazone. 12 15 16 After the initial intensive phase, some countries may be able to choose a continuation phase of thrice or twice weekly high dose isoniazid and rifampicin for four months, regimens of proved efficacy when the taking of each dose is supervised. Supervised chemotherapy is one of the five cornerstones of the DOTS (directly observed therapy, short course) policy; the other four components are government commitment to the national tuberculosis programme, a reliable tuberculosis microscopy and laboratory service, good recording and reporting, and regular, uninterrupted drug supplies. Motivated health workers, managed and supervised competently and fairly, are important, whether or not the programme uses full DOTS, partial DOTS, family/community DOTS, or unsupervised chemotherapy. 16 Despite initial insistence by WHO that health workers supervise every dose, a Cochrane review of clinical trials has not been able to show that such supervision ensures better results than those obtained by other ways of giving chemotherapy. 18 Treatment of pulmonary tuberculosis in patients with HIV/AIDS is complicated by interactions between antiretroviral and antituberculosis drugs, particularly rifampicin. The standard regimens for the two conditions are usually modified to minimise unwanted effects. 14 16 19 20
Control and prevention of tuberculosis: public health measures
Good nutrition and housing contributed to the decline of tuberculosis in western Europe before effective antituberculosis drugs were available, but prompt diagnosis and treatment remain the most effective means of controlling tuberculosis.
What is the current role of BCG vaccination?
BCG vaccination in infants provides a certain degree of protection against serious forms of tuberculosis, especially tuberculous meningitis and disseminated tuberculosis. 13 21 In the United Kingdom, at a time when tuberculosis was more common, BCG vaccination of adolescents was 70-80% effective in reducing the incidence of all forms of tuberculosis later in life. 17 In the UK today, the annual increase in tuberculosis stems mainly from London (especially boroughs with large populations of immigrants) and the larger conurbations of the Midlands, north west England, and north east England. The national programme of BCG vaccination for schoolchildren has been discontinued and replaced by a policy of selective vaccination of neonates and older people at high risk of infection, such as schoolchildren in areas where prevalence is ≥ 40 per 100 000, health workers, prison staff, hospital workers, and immigrants from countries with high prevalence. 5 In high prevalence countries, WHO and the International Union Against Tuberculosis and Lung Disease still recommend universal neonatal BCG vaccination, 12 15 16 pending development of a more effective vaccine.
How to deal with the problem of cross infection
Cross infection is much more likely to occur from patients whose sputum is positive on direct smear than from those with negative smears. The people most likely to be infected are close contacts (family and others who share living accommodation, especially children, or those who work closely and regularly with the patient or socialise regularly in an enclosed area). Prompt tracing of the close contacts of patients with sputum smear positive pulmonary tuberculosis is important in finding and treating the source of the original infection and people infected by the patient. Procedures will depend on BCG status and may include tuberculin testing, chest radiography, or both as outlined by the British Thoracic Society and the NICE guidelines. 5 17 People with disease should be fully treated. Some of those with infection, but no evidence of disease, will need prophylaxis with isoniazid for six months or rifampicin and isoniazid for three months. 5 17 Casual contacts are at low risk and should be traced only if 10% or more of the close contacts develop disease. 17 If resources are available, developing countries too should have protocols for identifying, tracing, and examining close contacts of patients with pulmonary tuberculosis, especially of smear positive patients.
Cross infection usually occurs among household contacts before treatment is started: the Madras study showed that treating patients at home was not associated with more cross infection than admitting them to hospital for treatment. 22 Chemotherapy should be started as soon as possible after diagnosis. Referral to secondary care can follow later, if such referral is national practice. Within two weeks of starting chemotherapy the patient becomes non-infectious, even though bacilli may still be seen on direct smear. 23 Therefore, if patients need to be admitted to hospital, and circumstances permit, they should be segregated from other patients on the ward until 10-14 days of chemotherapy have been given. 5 17 Barrier nursing is not necessary, except for patients with multi-drug resistant tuberculosis, who should be managed in a negative pressure room vented to the outside. 5 17 In countries without such facilities, as much segregation as is feasible should be the aim, and the patient should be discharged home as soon as possible. Better still, admission should be avoided unless clinically imperative.
If they are to be effective, control and prevention programmes need adequate funding, just as treatment programmes need proper resources of manpower, drugs, and recording and reporting systems. The Stop TB Partnership's second global plan to stop tuberculosis identifies the strategy and resources necessary to reduce tuberculosis. 24 It is now up to governments in developing countries to commit sufficient resources to tuberculosis control and to donor agencies and countries to follow the generous example set by the Bill and Melinda Gates Foundation.
Summary points
In Western countries, tuberculosis is most common among immigrants and poor or malnourished people The diagnosis should be confirmed by sputum examination for Mycobacterium tuberculosis and, if available, chest radiography Tuberculosis should be treated promptly with the recommended four drug regimen, reducing to two drugs after two months and continuing for four further months Admission to hospital is necessary only if the patient is too ill to be managed at home or cannot tolerate the treatment After two weeks' treatment, smear positive patients can be considered non-infectious; smear negative patients are rarely infectious anyway BCG vaccination can be used selectively in a population, but in areas with high prevalence it should be given to all neonates An adequately resourced, well organised tuberculosis programme should be a priority in developing and developed countries | v2 |
2018-04-03T05:40:50.380Z | 1930-02-01T00:00:00.000Z | 43752393 | s2ag/train | Tumour of Lung. Case for Diagnosis
X-ray Examination.-" The shadow of the gall-bladder after two doses of dye mass was very faint, and there is biloculation of the gall-bladder. The appearance suggests chronic cholecystitis with cholecystic adhesions." On September, 27, 1929, Dr. H. Cecil Bull re-examined the patient at my request and reported: "The gall-bladder filled well, showing patency of the cystic duct. The outline was well rounded, but there was a peculiar constriction in the lower two-thirds of the gall-bladder. The shadow of the gall-bladder was of even density and there was no evidence of gall-stones . . . . The gall-bladder appears to indent the pyloric end of the stomach. It was not apparent when the patient was in the erect position . . . The shadow of the gall-bladder is normal, except for a constriction in its lower third." The patient felt well while on strict diet and rest. But as he did not keep to the prescribed regime, he had frequent attacks of abdominal pain. On consultation with Mr. T. Twistington Higgins it was decided that there were adhesions and typhlitis in the abdomen, and an operation was performed on October 17. The omentum was extensively matted, and adherent to the structures in the lower right abdomen. These adhesions were divided, and considerable portions of the omentum containing large perforations were removed. Inflammation of the caecum was observed. The gall-bladder was of a peculiar shape, with an annular constriction of the fundus about two-thirds of its length down. No adhesions and no stones were found. There was no kind of obstruction to the passage of the bile. In all probability this is a rare case of congenital malformation of the gall-bladder. | v2 |
2018-04-03T05:42:19.868Z | 1931-12-01T00:00:00.000Z | 19232740 | s2ag/train | Squamous-Celled Carcinoma of the Maxillary Antrum and Ethmoid. Operation—Deep X-Ray Therapy. No Recurrence Five Years Later
of long duration, predominate in the male sex, and usually appear in the second or third decades. There are no pre-operative features, signs, or symptoms which are peculiar to them, as contrasted with other " angle " tumours, and their true nature is only revealed at operation or autopsy. Mr. E. WATSON-WILLIAMS said that he had had a case similar to the last in the group in an adult male patient whom he had been able to keep under observation from 1922 to 1930. When first seen there was weakness of the voice due to paralysis of the left vocal cord; there had been weakness of the left side of the face for about a year; in 1917 deafness began, and this was followed by giddiness; there was severe nerve deafness of the left side, with a vestibule insensitive to caloric test. The facial paralysis increased and was complete in September, 1924 for a month, then diminished until February, 1925, when it recurred for ten mnonths. At this time there was wasting of the left half of the tongue and weakness of the left shoulder, although the sterno-mastoid muscle was not involved. In April there was aniesthesia of the left half of the face and the cornea was nearly insensitive. The hair began to fall out in four symmetrical patches, two on the right, two on the left. By September, the hair was growing again round the edges of the patches, but was quite white; there was severe neuralgia in the left frontal and temporal regions. The pain spread by December to the lower jaw, at which time facial movements began to return; the bald patches had been covered with grey hair; the other hair was still brown; the corneal sensitivity had returned, but the patient still had some vertigo, and fell to the left if he closed the eyes. Th eremas complete paralysis of the ninth, tenth and twelfth nerves. Later the pain disappeared, the facial movement further improved and sensation became normal; the affection of the eighth and posterior nerves was unchanged. The Wassermann reaction had been negative in blood and cerebrospinal fluid on several occasions. The diagnosis had been polio-encephalitis. | v2 |
2018-04-03T03:16:23.835Z | 1935-11-01T00:00:00.000Z | 1952228 | s2ag/train | Early Spondylose Rhizomélique (Marie) in a Young Man, Superficially Resembling Post-Encephalitic Parkinsonism
Dr. E. STOLKIND said that he had seen a rare case (of cancer) in a female patient who coughed a great deal. After a paroxysm of coughing she had brought up a piece of tissue about 1 cm. in diameter and a few days later another similar piece. On examination (at Charing Cross Hospital Pathological Institute) it was found that this tissue was carcinomatous. Neither X-ray examination of the chest nor laryngoscopy had shown anything abnormal. During the last five years the patient had had no further signs of cancer and at present seemed to be well. | v2 |
2018-04-03T06:07:54.678Z | 1941-02-15T00:00:00.000Z | 45625560 | s2ag/train | Sterilization of Instruments
denture (that is. outer and inner rims) reasonably deep ; it is a simple matter to reduce the depth, and therefore it is wiser to err in making it too deep rather than not deep enough. Consequently, it is usuiallynecessary sooner or later to reduce the depth, or, to use the dentist's term, " ease " a denture. Patients vary greatly in their sensitiveness to the pressure of dentures: some describe the slightest abrasion of mucous membrane as acute discomfort, while others will tolerate, with little or no inconvenience, a denture which is cutting deeply into the gums. If for some reason or other the necessary, easing of a denture is not carried out, the condition described by Mr. Simmons may in time result, and is more likely to do so in those patients with less sensitive gums who are, consequently, less likely to seek relief. The condition is simply an ulceration due to pressure (that is, trauma), such as would occur in other parts of the body under similar conditions. It does, as Mr. Simmons states, appear to occur more often in the front than the back of the mouth and in the lower rather than in the upper jaw. The groove or grooves in which the denture lodges or dislodges is/are formed by an overgrowth of the gums (that is, mucous membrane) rather than by a destruction of the gums; the condition is similar to that of a tightly fitting ring which may become embedded in the tissues if the finger should swell. The gums eventually become " ploughed" into deep furrows and ridges by constant movement of the denture, especially if its edges are sharp. In a pronounced case this may take months or years to develop. The situation is determined by the site of pressure; the fraenum of the upper and lower lip may account for its more frequent appearance in the middle line. Atrophy of the alveolus, by allowing the denture to sink more deeply into the gums, and also by favouring its mobility, is probably an important factor in' initiating this condition. I have observed this condition in varying degrees on very manv occasions-probably a hundred or even more-and have rarely seen, as far as I can recollect, malignancy as a result, although naturally the condition does not confer immunity. Ulceration, even in the deeper portions of the furrows, is not necessarily present, but, if present, the lymphatic glands in the neighbourhood may be enlarged, as with anv other form of surface infection. Age, sex, and site play no very important part provided the above conditions are present, but it is undoubtedly more common, as Mr. Simmons remarks, in edentulous mouths, which are usually associated with advance in vears. The treatment I have adopted in those cases requiring operation is: (1) To infiltrate with a local anaesthetic the linear ridges or fringes of mucous membrane. (2) To grasp the free margin of the fringe with one or more pairs of pressure forceps according to its extent. (3) To excise the fringe (nearly at a level with its base or origin) with scissors curved on the flat, the fringe being held taut meanwhile by means of the pressure forceps. (4) To deal with any secondary fringes in a similar way. (5) To bring the edges of the wound together with one or more stitches, if this is necessary. (6) To instruct patients to discard their dentures until the wound has soundly healed (usually two or three months) and then to have either their present denture modified or preferably a new one made to the altered conditions of the mouth. Reducing the edge of the denture alone is insufficient except in slight cases, when the commencing elevations or ridges consist of vascular granulation tissue and not the firm fibrous tissue which is formed later. I described this method of treatment in 1911 (Annual Reports, Royal Dental Hospital, published by John Bale Sons and Danielsson. London).-I am, etc., | v2 |
2018-04-03T01:40:06.605Z | 1941-08-16T00:00:00.000Z | 30557330 | s2ag/train | Treatment by Hypothermia
About two years ago Prof. Temple Fay and Dr. Lawrence Smith of Philadelphia issued their first clinical report on the effects upon cancer growth of a general lowering of the body temperature by about 10' F. They termed this general depression of body temperature " hibernation," while local cooling of a tumour was called "refrigeration." This earlier work has already been reviewed in our columns.' A group of workers at the Lenox Hill Hospital, New York, reinvestigated2 the effects of this method of general cooling, but called it " crymotherapy." A third careful research has appeared under the authorship of Dr. J. H. Talbot' of Boston, and he has introduced the term " hypothermia," which on the whole seems more satisfactory and comprehensive than any of the other terms. He has reviewed the literature and points out that the local application of cold for treatment of cancer dates back as early as 1865. Recent studies have shown that regressive changes in tumours are most obvious when local hypothermia can be carried out at a temperature between 400 and 50' F. Special fitting coils through which a refrigerant circulates are applied and necrosis of tumour tissue may follow. Dr. A. McCravey' has reported favourable results with local hypothermia in five cases of carcinoma of the bladder in which the bladder cavity had been marsupialized and exteriorized. In all cases the patient's life was prolonged beyond that expected for a patient not treated with hypothermia. It is possible that radiation combined with cold might be more effective than either alone, as the effects of cold upon the tumour cells are not so unlike those of radiation with x rays. Talbot emphasizes that hypothermia is not looked on as a cure for cancer by even the most sanguine of its advocates, yet it does have a place in the treatment of a selected group of patients suffering from this disease. The Lenox Hill Hospital authorities publish a list of cases which are unsuitable for treatment by general hypothermia; it needs more careful consideration than does the local therapy. Contrary to what has been taught hitherto, the lowest internal temperature that man can bear probably lies somewhere between 70' and 750 and not between 90' and 950 F. Two patients of Talbot and his colleague Tillotson had rectal temperatures of 74' and 750 F. respectively, and both made an uneventful recovery from this coqling. The heat regulatory mechanism presumably ceases to operate below 750 F. in animals, and the continued fall in body temperature proceeds at the same rate as that in a dead animal in similar circumstances. | v2 |
2018-04-03T04:57:48.693Z | 1945-09-08T00:00:00.000Z | 41118676 | s2ag/train | Malignant Tumours of Nasopharynx
A series of 115 patients with malignant tumours of the nasopharynx were primarily irradiated. All the cases of carcinoma were TNM classified in retrospect. 60Co irradiation appeared to afford a somewhat better prognosis than conventional irradiation previously used. The 5-year crude survival rate for the patients with lymphoma and with carcinoma was 40.0 per cent and 23.8 per cent respectively. A distinctly better prognosis was found for women than for men and the prognosis was independent of whether or not lymph node metastases were present. There seems to be no indication for maintaining lympho-epithelial carcinoma as a special group of tumour. Surgical procedures are rarely indicated in the treatment of malignant nasopharyngeal tumours. | v2 |
2018-04-03T04:51:36.382Z | 1951-01-26T00:00:00.000Z | 40583015 | s2ag/train | [Diagnostic value of breast cytology (author's transl)].
The comparison between clinical examination, mammography, thermography and fine needle aspiration cytology shows the usefulness of cytology in differential diagnosis of benign and malignant breast tumours. The cytology shows the real nature of benign suspicious and malignant mammographic and thermographic results. Specially in the younger patients cytology identifies early tissue changes, invisible on mammography. Application of the TNM classification shows TOT1 T2 tumours 72% of the material, with 90% positive cytologic results. | v2 |
2018-04-03T04:22:53.974Z | 1951-03-01T00:00:00.000Z | 38802724 | s2ag/train | Endothelial cells in tumours: the challenge.
Histological examination of 18 breast and axillary nodes removed by operation following irradiation revealed viable carcinoma in 17 primary sites and in 6 out of 11 patients with axillary lymph nodes. Irradiation techniques and histological changes are described. Attention is drawn to the increase in elastic tissue following irradiation. If residual tumour remains in the primary site or the axilla it should be removed by radical mastectomy. | v2 |
2017-11-08T17:43:26.863Z | 1953-03-01T00:00:00.000Z | 26435049 | s2orc/train | The Spread of Tumours in the Human Body
Price £4.50. This book, containing 649 separate items, is a valuable source of information on terato-genic agents for both clinician and scientist. References are predominantly concerned with experimental teratology but the information is linked to that on congenital defects found in man. Also included are a number of compounds often considered to be teratogenic but with substantially negative effects although, overall, the book is a catalogue and does not attempt to make a critical analysis of the data. Preparation has been simplified by the use of a computer programme which makes the format unattractive. However, this is justified on the grounds of speed of assembly and low production cost. There appear, on a quick assessment, to be a number of minor errors in the spelling despite the computer's scrutiny. The use of an initial oo-for all the catalogue numbers is unnecessary suggesting only a rather different kind of special agent. There is also a table comparing the timing of stages in embryonic and foetal development for different species which might have been more appropriately located with the notes in the text rather than on the endpapers. This is a paperback volume of 109 pages devoted mainly to cancer of the lung in its many aspects but with supplementary chapters on secondary deposits in the lungs and in the mediastinum. The author's objective is to present a broad picture which may improve the understanding of the more specialized reader and help to achieve greater inter-disciplinary cooperation. He deserves to succeed for his style is easy, his presentation is balanced and he does not overload his text with indigestible facts. Having stimulated his reader however, he has a duty to provide him with directions to a wide range of further reading; limited bibliographies and references are included but these could be expanded with advantage and without interfering with the clarity of the text. This book can be recommended as part of the general reading for a trainee in any of the disciplines covered by oncology, from basic science through medicine to education, and it will also be of value to nurses and radiographers. The Spread of Tumours in the Human Body. R. A. WILLIS. (1973). 3rd edition. London: Butterworths. Price £8. The first edition of this well-known book appeared in 1934, the earliest of a series of volumes which put Professor Willis in the forefront of authors writing on human pathology. This …
This book, containing 649 separate items, is a valuable source of information on teratogenic agents for both clinician and scientist. References are predominantly concerned with experimental teratology but the information is linked to that on congenital defects found in man. Also included are a number of compounds often considered to be teratogenic but with substantially negative effects although, overall, the book is a catalogue and does not attempt to make a critical analysis of the data. Preparation has been simplified by the use of a computer programme which makes the format unattractive. However, this is justified on the grounds of speed of assembly and low production cost. There appear, on a quick assessment, to be a number of minor errors in the spelling despite the computer's scrutiny. The use of an initial oo-for all the catalogue numbers is unnecessary suggesting only a rather different kind of special agent. There is also a table comparing the timing of stages in embryonic and foetal development for different species which might have been more appropriately located with the notes in the text rather than on the endpapers.
A. W. CRAIG Monographs on Oncology-The Chest.
THOMAS J. DEELEY. (1973). London: Butterworths. Price £2.25. This is a paperback volume of 109 pages devoted mainly to cancer of the lung in its many aspects but with supplementary chapters on secondary deposits in the lungs and in the mediastinum. The author's objective is to present a broad picture which may improve the understanding of the more specialized reader and help to achieve greater inter-disciplinary co-operation. He deserves to succeed for his style is easy, his presentation is balanced and he does not overload his text with indigestible facts.
Having stimulated his reader however, he has a duty to provide him with directions to a wide range of further reading; limited bibliographies and references are included but these could be expanded with advantage and without interfering with the clarity of the text.
This book can be recommended as part of the general reading for a trainee in any of the disciplines covered by oncology, from basic science through medicine to education, and it will also be of value to nurses and radiographers.
The first edition of this well-known book appeared in 1934, the earliest of a series of volumes which put Professor Willis in the forefront of authors writing on human pathology. This book is based on the results of a consecutive series of 500 necropsies on cases of malignant disease, together with an exhaustive review of the literature up to that time. A second edition appeared in 1952. As Professor Willis notes in his preface to this third edition, it is impossible to read and assimilate the enormous volume of recent publications on the subject of tumour spread, and he has therefore selected 350 representative recent references for inclusion, as well as rewriting parts of the text.
Essentially, therefore, this is the same book as the original. The reader will not find much discussion of, say, the roles of local cell-mediated immunity, or of proteolytic enzymes, in the spread of neoplasms. Most of the references are to' papers published before 1939, and indeed a substantial proportion date from the previous century.
However, any criticism on these grounds would be beside the point, because this book is now itself one of the classical texts in human pathology, a work of scrupulous scholarship, based on careful personal observations and a critical and exhaustive appraisal of the earlier literature. It is written with the clarity and trenchancy characteristic of its author; no one in recent years has done more to clear the field of tumour pathology of the debris of bogus entities and ill-founded theories. The book has been re-set, and the illustrations (mostly photomicrographs) gathered together at the end of the text. One or two of the prints (such as Figs. 10 and 66) might have been improved, but on the whole the illustrations wear their years well.
Those who possess earlier editions of this book may not, perhaps, feel justified in acquiring this new edition, but the book itself should be in the library of every hospital or research laboratory concerned with human tumours.
Meeting Annoucements
ELEVENTH INTERNATIONAL CANCER CONGRESS Florence, 20-26 October, 1974 The XI International Cancer Congress will be held in the Tuscany-Umbria area and will be centred chiefly in Florence. Historical and cultural reasons explain this choice, for Florence and most of the neighbouring cities have been seats of Universities and Academies over the centuries. Furthermore, this region is peculiarly suitable for a multicentred congress because the cities where the scientific sessions will take place can easily be reached from the 2 residential centres of the Congress, Florence and Montecatini.
The International Cancer Congresses are multipurpose events and must provide for people of varying interests and background.
The design of the XI International Cancer Congress was patterned on the preceding one successfully held in Houston, Texas, in 1970. The Opening Ceremony will take place in Florence on 20 October.
During the first 2 days, 10 Conferences will be held in 6 different towns. Participants are required to make a choice as to the Conference they wish to attend because it is the deliberate intent of the Union to prevent participants from moving from one Conference to another. The following 3 days will be devoted to Symposia and Proffered Papers. All sessions will be held in Florence itself thus affording many opportunities for participants to meet.
The Memorial Lecture and the closing ceremony will take place on Friday, 25 October, in the afternoon. Advanced Courses on Clinical Oncology will be given in Florence on Saturday, 26 October. | v2 |
2018-04-03T04:28:07.149Z | 1954-10-30T00:00:00.000Z | 39040450 | s2ag/train | Carcinoma of Body of the Uterus
Only in recent years has an attempt been made in the mortality statistics of England and Wales to separate endometrial from cervical carcinoma. In the three years 1950-2 deaths in women from all malignant neoplasms numbered 125,361, of which 12,221 were uterine. Of all malignant neoplasms 6.2% were cervical, 2.8% endometrial, 0.08% " others including chorionepithelioma," and 0.6% " unspecified." The reliability of mortality statistics for uterine carcinoma is open to question, for even experienced histologists may be unable in some cases to distinguish between endometrial and cervical adenocarcinoma. However, there has certainly been a change in the incidence of the types of cancer prevalent in women since the beginning of this century. As Hoffman's collection of statistical data' shows, uterine carcinoma was the commonest form of cancer in women in the early part of the century, and in 1908-12 constituted 20% of all deaths due to malignant disease, when cancer of the breast accounted for 17%. In recent years the breast has accounted for 20% and the uterus for 12%, or less still latterly. The estimates of the relative incidence of the three types of uterine carcinoma vary widely,2 but it is probable that cervical is three times as common as endometrial and that cervical epidermoid is at least ten times as common as cervical adenocarcinoma. Corporeal carcinoma occurs some 8-10 years later in life than cervical. Cullen3 found the maximum incidence to occur in the sixth decade of life; the figures of Norris and Vogt' showed an average age of 53.3 years and Speert's' series an average age of 56.6 years. Rarely does the disease occur before the age of 30 years, but, unlike cervical carcinoma, it is not uncommon after the age of 65 years. Nine of Willis's 31 patients were over this age. In Jewesses endometrial carcinoma is relatively more common than cervical carcinoma, since the latter form has a very low incidence in this race.5 6 A matter of some' interest here is the low incidence of penile carcinoma among Jews. Negroes apparently have a low incidence of corpus cancer and a high incidence of uterine myoma.: If the Hebrew race is left out of account, child-bearing is found to predispose to carcinoma of the cervix, while carcinoma of the corpus is more frequent in the nulliparous.41 In a recent article on the aetiology of corpus carcinoma Way8 has reported a series of 153 cases and concluded that " there is some evidence to show that overactivity of the anterior pituitary may lead to many different manifestations including fibroids, diabetes or carcinoma of the corpus, either singly or in combination." The supposed association of diabetes with corpus carcinoma is probably not widely recognized in Britain, though there have been reports in the American literature quoted by Way,8 Scheffey et al.,9 Moss,10 and Palmer et al.1' As deduced from the glucose-tolerance test, Way found 29% of diabetics and 48% of pre-diabetics in his cancer series. Of 133 women without endometrial cancer who had ceased to menstruate after the age of 50 years-and who may be more liable to develop this disease-12% were found to be diabetic and 41% pre-diabetic. Five of these pre-diabetics subsequently developed diabetes. In a control group of 58 patients, 30% were diabetics and 30% pre-diabetic. This diabetes is of the insulin-resistant or pituitary type, more common in women than men, and with its greatest incidence in the fifth and sixth decades of life. In his cancer series and in a group of 88 diabetic women Way8 found evidence of a late cessation of menstruation, the figures for the former group being comparable to those of Crossen and Hobbs.'" Since Crossen and Hobbs first published their findings there have been many conflicting reports on this relation, and Speert' and Willis2 state that there are no significant abnormalities of menstruation in these cases. Way's figures, however, seem significant, and it is unfortunate that no indication is given of the incidence of'diabetes in the patients with cancer who ceased menstruating before the age of 50 and who appear to form at least 34% of the series. | v2 |
2018-04-03T00:05:41.026Z | 1966-10-01T00:00:00.000Z | 8931788 | s2ag/train | Recurrent Cervical Cancer After Treatment by a Primary Surgical Program
Cervical cancer recurred in 222 patients after definitive surgical treatment. Among 179 patients with positive biopsies, only 1 of 92 who had been given palliative treatment lived 5 years; 19 of 87 (21.8%) receiving definitive curative treatment lived 5 or more years. The incidence of positive nodes at the time of initial operation was almost twice as great as in those living 5 or more years without evidence of recurrence. Among patients subjected to pelvie exenteration for recurrence, the disease recurred at a more advanced level. | v2 |
2018-04-03T03:07:55.869Z | 1968-07-27T00:00:00.000Z | 435854 | s2ag/train | Nasal cancer in woodworkers.
SIR,-In your leading article on Pott's paraplegia (15 June, p. 638) you state that "The classical condition described by Pott is a paraplegia of early onset, in which pressure is due to tuberculous pus, granulation tissue, and necrotic material." This statement is, I fear, incorrect. Pott in his monographs entitled " Remarks on that kind of palsy of the lower limbs which is frequently found to accompany a curvature of the spine and is supposed to be caused by it'"L and " Further remarks on the useless state of the lower limbs, in consequence of a curvature of the spine "' described paraplegia associated with spinal deformity. He said nothing about early onset, he did not know that the disease was tuberculous; he therefore made no mention of tuberculous pus. No reference to granulation tissue or to necrotic material will be found in any of Pott's writings on the paraplegia in question. The fact that Pott's disease is a manifestation of tuberculosis, though surmised by earlier writers as a possibility, was not really established until the writing of J. M. Deipech.'-I am, etc., | v2 |
2018-04-03T03:29:37.784Z | 1968-10-01T00:00:00.000Z | 6489353 | s2ag/train | The Palpebral Spring for Paralysis of the Upper Eyelid
W HEN seventh nerve dysfunction is accompanied by some degree of fifth nerve dysfunction, as may occur following total removal of acoustic tumors, there is always the possibility of corneal ulceration. The transient weakness or paralysis of the seventh nerve following acoustic surgery has classically been handled by surgical closure of the eyelid, a disfiguring operation. Morel-Fat io and Lalardr iC described the use of a stainless steel wire spring as an alternative means for correction of the eyelid in patients with facial paralysis. We have used the palpebral spring in nine patients. Eight of these had facial paralysis due to removal of an acoustic neuroma; one was due | v2 |
2018-04-03T03:29:02.960Z | 1969-02-01T00:00:00.000Z | 5709525 | s2ag/train | Contact Spread of Carcinoma of the Skin.
The case history of a patient with basal cell carcinomas on the thumb and the ear is presented. The patient had burnt the thumb 17 months prior to presentation and the burn had never fully healed. He volunteered that he habitually slept on his side with the thumb in contact with the ear. The histological features of the two lesions were identical. Similar reported cases and the experimental data on basal cell tumour implantation are reviewed in an attempt to prove that this case is one of implantation metastasis. Some of the evidence is strongly in favour of this possibility, but the verdict must be one of "not proven".
SUMMARY
A case of simultaneously occurring basal cell carcinomas with identical histology is presented. In the light of published clinical cases and experimental data, an attempt has been made to prove that one lesion was an implantation metastasis of the other. The available evidence allows only the Scottish verdict of "not proven" to be made. The points for and against a diagnosis of implantation metastasis are listed. Points in favour are the long history of contact, the rarity of basal cell carcinoma of the thumb, the histological features of the tumours, the unusual time interval if the tumour was a "burn cancer", and the suitable "culture medium" for metastasis following the burn. Points against such a diagnosis are the occurrence of many histologically similar basal cell carcinomas in a series of ten cases, the possibility that the tumour was a burn cancer, the experimental difficulty in transplanting basal cell carcinomas, and the experimental evidence that stroma is required to transplant basal cell carcinomas successfully. | v2 |
2018-04-03T00:50:21.677Z | 1969-04-19T00:00:00.000Z | 26826629 | s2ag/train | Benign Diseases of the Breast
Probably more clinical research has been carried out on breast cancer than on any other tumour. Not only is it the commonest cancer in women, but it is readily accessible, can be identified early, and has certain unique features in its growth and maintenance which make it an ideal tumour to investigate. And yet, in terms of recurrence and survival, the patient has gained little from this research. Improved results have not necessarily followed new methods of treatment, and, indeed, the death rate from breast cancer has changed little throughout this century; if anything the incidence may be slowly rising. Recently efforts to check this trend have been directed away from treatment and more towards early detection and even prevention. Breast cancer can now be detected in its very earliest stages, and there is at least circumstantial evidence that the earlier the discate is diagnosed the better the prognosis.1 A combination of mammography and clinical examination is capable of detecting very small lesions ; some tumours which can be identified by mammography are so small as to be impalpable. Nevertheless, mammography amination are time consuming and expensive, y to be widely available in the foreseeable fu ening service. Some method is required fo small high risk group which could then be rement of the hormone environment may i ng susceptible women,2 but it will be some time before this becomes a practical routine investigation. Some small high risk groups can already be identified. Women whose mothers or sisters have had breast cancer stand two to three times the normal chance of developing a tumour.3 The incidence is high in single women4 and probably in married women who have not had children.5 Similarly, women who have had a tumour in one breast are likely to develop a new primary on the opposite side. It is also possible that benign breast disease predisposes to future malignancy. If a woman has had fibroadenosis, a cyst, or an intraduct papilloma, what are the chances of her developing a breast carcinoma in the future ? Should we follow up patients with benign breast disease indefinitely ? J. F. Potter, W. P. Slimbaugh, and S. C. Woodward7 have recently reported on the fate of women who, 16 to 20 years previously, had been subjected to a breast biopsy for a benign condition. Three hundred consecutive patients were contacted. Only 110 of the original 300 returned questionaries sent to them, and the incidence of subsequent breast cancer in these 110 was five times the expected rate. When the patients' records were studied it was found that those with fibroadenomata had the highest incidence of subsequent carcinoma but that no single benign lesion uniquely predisposed to subsequent cancer. Nevertheless, the authors suggested that patients v. benign breast disease should be followed up indefinitely. Though the observed incidence of subsequent carcinoma was more than expected, these figures should be regarded with some reservation. They are based on very small numbers, and the fact that only 110 out of 300 patients were available for study means there was considerable, if unavoidable, selection. Furthermore, the finding that carcinoma occurred most commonly in patients who had had fibroadenomata is unexpected and does not suggest a cause-andeffect relationship. Many series have now been reported suggesting that carcinoma occurs more frequently in patients who have previously had benign breast disease'8-"-particularly cystic diseasebut the clinical and pathological changes of cystic disease still defy cataloguing, and hence there is little agreement among authors on the exact entity they are considering as premalignant. All the data have come from retrospective studies, which often provide useful guides for further study but seldom give completely reliable results. So two conclusions can be drawn. Firstly, the evidence of a high incidence of breast cancer occurring in patients previously suffering from benign breast disease is sufficiently suggestive to make a prospective study worthwhile. Secondly, until such a study is carried out, and until the precise relationship between various benign conditions and future malignancy is known, it is not our duty to caution our patients about what, at present, amounts to a hypothetical situation. It would be quite unjustifiable to suggest that a danger exists when, as with so many of thcse conditions, reassurance is part of the treatmient and does much to rid the patient of her symptoms. | v2 |
2018-04-03T02:48:13.425Z | 1969-05-01T00:00:00.000Z | 35278372 | s2ag/train | Primary lymphoma of the gastrointestinal tract.
Only a small percentage of patients in whom a malignant lymphoma develops present with evidence of gastrointestinal involvement. A number of authors have indicated that long-term survival can be obtained by surgery alone in selected cases with well localized disease (1-5). This study was initiated to review the experience at The Ontario Cancer Institute incorporating The Princess Margaret Hospital to try to evaluate the indications for and value of radiation therapy in the management of primary lymphoma of the gastrointestinal tract. Material The case reports of patients over the age of sixteen years who have been seen at The Princess Margaret Hospital during the period from 1950 to 1965 with proved gastrointestinal tract involvement have been reviewed. During this period the total number of patients with a diagnosis of malignant lymphoma is 1,555. Of all those who presented with abdominal symptoms, gastrointestinal involvement could be proved by laparotomy or radiological methods in only 83. Those in who... | v2 |
2017-09-01T15:41:19.863Z | 1969-11-22T00:00:00.000Z | 42203414 | s2ag/train | Cancer from mineral oil.
Medicines Commission: Membership (p. 504). B.M.A. Committees: Overseas Affairs, Public Health, Armed Forces, and Charities (Supplement, pp. 41-43). Lis 0Cancer from Mineral Oil ar Skin cancer due to mineral oil was first noted during the latter part of the ie nineteenth century among mule spinners ini the cotton industry. The first id patient that S. A. Henry' could trace died in 1875. Between 1920 and 1943 no fewer than 1,441 cases of skin cancer attributable to industrial exposure to mineral oil were notified. Of these the scrotum was affected | v2 |
2017-08-28T01:31:16.565Z | 1969-12-31T00:00:00.000Z | 10688681 | s2orc/train | Preoperative Serum Tumor Marker Levels in Gastric Cancer
Objective: Tumor markers have shown little benefit as a method for screening. However, they can be used clinically for the monitoring of tumor recurrence and used as prognostic factors because higher levels have been observed in advanced disease. This study aimed to investigate the relationship between the preoperative tumor marker levels and different clinical aspects of gastric cancer. Methods: One hundred and six consecutive patients with confirmed diagnosis of gastric cancer and 106 subjects (age and sex matched) with no malignancy as control group were included prospectively in this study in 3 years. The relationships between tumor markers CEA, CA 19-9 and stage of disease, tumor differentiation, presence of ringlet cell type, presence of peritoneal carcinomatozis were investigated. Results: The serum CEA and CA 125 levels were found to be significantly elevated in gastric cancer patients than in controls. The serum level of CEA had showed a significant elevation with the presence of distant metastasis. The CA 19-9 and CA 125 levels had showed significant elevations with the presence of peritoneal carcinomatozis. Conclusions: This study showed that there is a limited clinical benefit of preoperative tumor marker measurements in gastric cancer such as estimation of peritoneal dissemination.
INTRODUCTION
Gastric cancer remains one of the most common causes of cancer related death worldwide and the predicted incidence for 2010 is over one million as expected in previous reports. Gastric malignancies also show extensive tumor invasion and early spread to either regional lymph nodes or distant sites [1][2][3][4] and this aggressive stance gives rise to the challenging questions about the way of the preoperative management strategies.
The stage oriented management of gastric cancer is one of the recent proposals and it is crucial to improve the outcome of patients with operable gastric cancer. [5][6][7] Currently, preoperative staging relies on imaging studies. None of the available imaging modalities is sufficient to reliably confirm the presence or the number of regional lymph node metastasis and are inefficient to guide a clinical decision depending on nodal status. 8 Carcinoembryonic antigen (CEA) and carbohydrate antigen are commonly used markers for gastric cancer. 9 Although both markers are often measured in patients with gastric cancer preoperatively, the clinical correlation between CEA and CA 19-9 is reported as unclear and controversial. [10][11][12] In addition to these common used markers; carbohydrate antigen 125 (CA 125) and carbohydrate antigen 72-4 (CA 72-4) have been reported to be elevated in advanced gastric cancer. 13 Tumor markers have shown little benefit as a method for screening in the general population due to their low sensitivity and specificity in detecting early primary tumor, however, they can be used clinically for the monitoring of tumor recurrence and used as prognostic factors because higher levels have been observed in advanced disease. [14][15][16] With respect to controversial reports about the impact of tumor markers on the management of gastric cancer, we aimed to investigate the relationship between the preoperative tumor marker levels and different clinical aspects of gastric cancer.
METHODS
This study was approved by local ethics committee and we got written informed consent from all subjects included in this study. Between January 2009 and January 2012, 106 consecutive patients with confirmed diagnosis of gastric cancer and 106 subjects (age and sex matched) with no malignancy as control group were included prospectively in this study. The subjects in control group were selected from the group of patients with no determined malignancy (underwent gastroscopy and / or colonoscopy, abdominal computed tomography for different reasons and having no malignant or premalignant findings in their history, physical and diagnostic examinations).
The exclusion criteria were operation history of any malignancy, having any malignancy except gastric cancer, already being a smoker, having pancreatitis. Patients' mean age was 61.3 years (range 31-91 years); 71 were males and 35 were females.
Routine preoperative evaluation protocol of our departments consisted of clinical examination, gastroscopy and colonoscopy if indicated for clinical suspicion, abdominal computed tomography, chest radiography and computed tomography for thorax if indicated and serum levels of CEA, CA 19-9 and CA 125. We aimed to evaluate only preoperative tumor marker levels in relation with different clinical or histopathological aspects of gastric cancer. Blood samples were obtained at least one week before surgery for patient group. Serum CEA, CA 19-9 and CA 125 levels were determined with the upper limit of normal defined as 5ng/ml for CEA, 38U/ml for CA 19-9 and 35U/ml for CA 125.
The relationships between tumor markers CEA, CA 19-9 and stage of disease (with respect to American Joint Committee on Cancer, gastric cancer staging, TNM), tumor differentiation (grade), presence of ringlet cell type, presence of peritoneal carcinomatozis were investigated. IBM ® The Statistical Package for Social Sciences (SPSS ® ) version 20 software was used for statistical analysis of data. All values were expressed as median (minimum-maximum). After the homogeneity tests; non -parametric tests (Mann -Whitney and Kruskal -Wallis tests) were used for statistical evaluation and p<0.05 was accepted as the level of significance.
RESULTS
There was no statistical difference between serum CA 19-9 levels of gastric cancer patients and controls (p=0.103). On the other hand; the serum CEA and CA 125 levels were found to be significantly elevated in gastric cancer patients than in controls (p<0.001 for both) ( Table-I).
The serum tumor marker levels of patients didn't show any significant difference according to either T stage or N stage of the disease (p>0.05 for all markers) ( Table-II). The serum level of CEA had showed a significant elevation with the presence of distant metastasis (M1) (p=0.019) ( Table-II).
The CA 19-9 and CA 125 levels had showed significant elevations where the CEA levels showed no significance with the presence of peritoneal carcinomatozis (p=0.007, p=0.018 and p=0.644 respectively) ( Table-III). There was no significant difference between serum tumor marker levels of patients with respect to tumor grade or the presence of ringlet cell type of tumor cells.
DISCUSSION
The increased levels of tumor markers such as CEA and CA 19-9 are proposed to be correlated with clinic and pathological features of gastric cancer. [17][18][19][20] In clinical practice; the tumor markers CEA and CA 19-9 are used to assess the efficacy of adjuvant treatment as a supplementary evidence for response. 21,22 Despite numerous reports on the usefulness of preoperative and periodic postoperative CEA measurements to predict stage, 23 tumor progression, 24 recurrence 25-27 and prognosis 10,28,29 in patients with gastric cancer, already tumor markers have limited clinical utility due to their low sensitivity and specificity. [30][31][32] The positive rate of serum CEA and CA 19-9 at the initial diagnosis of gastric cancer has been reported to be 11.8%-37% 33-37 and 18%-45% 22,37 respectively. Although serum CA 19-9 levels had showed no significant difference between gastric cancer patients and controls in our study, the serum levels of CEA and CA 125 were found to be significantly elevated in patients than controls. The available data from previous studies confirm that the conventional tumor markers such as CEA and CA 19-9 don't allow diagnosis of gastric cancer with adequate sensitivity and specificity. 21,38 In a previous study by Ishigami et al; 38 it is reported that serum CEA and CA 19-9 levels are significantly and positively correlated with the depth of invasion, nodal involvement, cure possibility and distant metastasis. Our results showed that there is no significant difference correlated with depth of invasion (T stage) and lymph node involvement (N stage). However, the serum level of CEA had showed a significant elevation with the presence of distant metastasis (M1 patients). In the view of combined CEA and CA 19-9 positivity, the positivity of CEA and/or CA 19-9 may reflect biologic malignant properties such as lymphatic spread or distant metastasis. 12,14,38 Although some studies proposed that there appears to be clinical significance in detecting CEA and CA 19-9, some studies express doubt to confirm this way of management. [10][11][12]39 The positivity of CEA and CA 19-9 was significantly correlated with TNM stage, depth of invasion and lymph node metastasis in a more recent study. 40 Despite the numerous reports on the usefulness of preoperative and postoperative CEA measurements to predict stage, 23 tumor progression, 24 recurrence 25 or prognosis; 28 there is no agreement as to what kinetics of change is likely to be significant and over what period of time such a change should be maintained for significance. 41 The positivity of CEA in the presence of distant metastasis may be explained with the direct role of CEA by acting like an adhesion molecule in invasion and metastasis so the cancer cells producing CEA have more chance of metastasis. 42,43 Peritoneal dissemination is frequent and life threatening form of metastasis and recurrence in patients with gastric cancer. Intraperitoneal chemotherapy has been shown to have a considerable positive effect on peritoneal dissemination. Although the systemic chemotherapy has been shown to prolong the survival of gastric cancer patients, there is a lack of complete success. [44][45][46] Serum CA 125 levels are known to be elevated in peritoneal inflammation and in carcinomatozis 47,48 and a significant relationship between CA 125 and Tumor markers in Gastric Cancer gastric cancer with peritoneal dissemination has been reported. [49][50][51] The CA 19-9 and CA 125 levels had showed significant elevations with the presence of peritoneal carcinomatozis in our study. The presence of ascites, level of ascites and the degree of peritoneal metastasis are not correlated with CEA and CA 19-9; however they have a significant correlation with CA 125 positivity. 44 The serum level of CA 125 was reported to be more sensitive in combination with other tumor markers such as CA 19-9 for peritoneal dissemination. 44 Some authors have tried to explain the low sensitivity of tumor markers in their studies in terms of the histology of the tumor, with the diffuse type of gastric cancer presenting the lowest positivity rate of the tumor markers. On the other hand, some previous reports made this hypothesis controversial with the higher positivity rate of CEA, CA 72-4 and CA 19-9 in the diffuse type of gastric cancer. 38,52 Our results showed that there was no significant difference between serum tumor marker levels of patients with respect to tumor grade or the presence of ringlet cell type of tumor cells. It is also shown that no correlation between tumor marker levels and the histology of gastric cancer. 14 As a conclusion; there seems to be many controversial and conflicting reports about the relationship of tumor markers and the clinical properties of gastric cancer. Our results also showed that there is a limited clinical benefit of preoperative tumor marker measurements in gastric cancer such as estimation of peritoneal dissemination. The various types of biological behaviors of gastric cancer need further studies on molecular basis of tumor cells and tumor markers. | v2 |
2018-04-03T00:11:00.623Z | 1970-01-01T00:00:00.000Z | 9776946 | s2ag/train | Neurotic bodily pain in children.
Children are fascinating people, and three-year-old Jenny was no exception. She had a medical diagnosis of orbital tumor (rhabdomyosarcoma) and she proved to be an excellent example of a patient with neurotic bodily pain, providing an opportunity for nursing intervention. Neurotic bodily pain is pain experienced because of unpleasant past stimuli, but it is no less real to the patient than pain experienced | v2 |
2018-04-03T00:21:08.178Z | 1970-01-01T00:00:00.000Z | 10947217 | s2ag/train | Action of Pronase and Neuraminidase on the Electrophoretic Mobility of Erythrocytes from Normal Cats and those with Spontaneous Tumours
Summary. The electrophoretic mobility of cat erythrocytes has been determined and compared to the mobility of erythrocytes from some other animal species. The cellular mobility decreases by 53 to 70% on treatment with neuraminidase and increases with Pronase treatment of cells from normal cats by 18 to 36% and increases by about 18% in the case of cells from cats with spontaneous tumours (mammary and tongue carcinoma). This remarkable behaviour of Pronase‐treated erythrocytes has not been observed with Pronase‐treated erythrocytes from humans or other animal species and supports the model of the cat erythrocyte membrane with the extraordinary arrangement of glycoproteins and glycolipids proposed by Uhlenbruck. | v2 |
2018-04-03T00:56:22.615Z | 1970-01-01T00:00:00.000Z | 27251918 | s2ag/train | Effectiveness of radiation therapy in the treatment of carcinoma of the esophagus. A retrospective study.
A review of 90 patients with carcinoma of the esophagus, treated at the Medical College of Virginia from January, 1961 through December, 1966, is presented.Factors affecting survival and symptomatic relief are discussed. The following points are stressed: (1) obstruction requiring gastrostomy before or during radiation therapy is a contraindication to starting or continuing radiation therapy due to the poor survival and lack of symptomatic relief; (2) the development of a tracheoesophageal fistula before or during the course of radiation therapy is a contraindication to further irradiation; (3) a tumor dose of at least 5,000 to 6,000 rads or above should be our goal whenever there are no contraindications; (4) palliative radiation therapy should be attempted to prevent esophageal obstruction when more radical therapy is not indicated; (5) in this series the addition of radiation therapy to surgery whether pre- or postoperatively did not significantly alter the cure or survival statistics. | v2 |
2018-04-03T01:28:11.875Z | 1970-01-01T00:00:00.000Z | 22962778 | s2ag/train | Ischaemic enterocolitis in the newborn.
the presence of ulcerative colitis and one year prior to operation he had suffered an exacerbation of this. At the age of 31 he complained of some pain in the left upper quadrant of the abdomen, and barium enema showed a long stricture ofthe upper descending colon and a filling defect of the splenic flexure. At laparotomy a large tumour mass was found in the left upper quadrant of the abdomen with invasion of the surrounding diaphragm and chest wall. Using a thoraco-abdominal incision a left hemicolectomy was undertaken with excision of the spleen, tail of pancreas, anterior layer of perinephric fat and portions of the diaphragm and chest wall including three ribs in this area. Because of the extent of the operation involved in the resection, a transverse colostomy was established, and the distal sigmoid colon also brought through the lower part of the wound as a colostomy. The chest wall-defect was not repaired, but the margins of the chest wall were sutured to the outer parietal muscles to stop herniation of abdominal contents. The diaphragm was again attached above the chest wall defect. Subsequently this patient underwent right hemicolectomy and ileorectal anastomosis leaving a rectal stump of 12 cm. Pathology: The specimen showed two carcinomas, and changes of chronic ulcerative colitis (Fig 2). The tumour was of average grade malignancy and examination of 36 lymph nodes showed no metastases. There was a marked inflammatory response around this tumour, and actual tumour substance did not invade the periostium and bone of the excised ribs. | v2 |
2018-04-03T02:21:30.837Z | 1970-01-01T00:00:00.000Z | 33200094 | s2ag/train | The "fee for service" system.
out of hand. I did not mean that every cardiologist is unafraid of using large doses of niacin. However, it is true that a physician's beliefs and attitudes help determine whether patients accept drugs. This is why double-blind experiments are so strongly endorsed. My attitude to niacin is more benevolent: for over 35 years most of my patients whom I think need niacin have been able to use it with little difficulty. Contrary to the opinion of Appeltauer and his colleagues the consensus of medical leaders in Canada and the United States is that niacin is a useful treatment for lowering cholesterol levels.'-3 It is also the most cost-effective method of doing so:4 treatment for a year costs $327 compared with $1881 for lovastatin. Niacin does have a variety of side effects, but it does not cause acanthosis nigricans, which is described by Haynes and Fitzpatrick5 as a highly significant marker of probable malignant disease when it develops in adults. I am not aware of even one report showing that niacin has caused acanthosis nigricans or cancer. In a few people niacin will increase melanin pigmentation in flexor areas, which wears away like an old suntan, leaving clear, healthy skin. It would certainly be helpful to have niacin preparations that minimize the flush. One of these, inositol niacinate (Linodil), was recently taken off the market; Complamin, a niacin-xanthine compound, is still available. Perhaps companies will develop a patented product with the costeffective properties of niacin. This would allay Appeltauer's fears. | v2 |
2018-04-03T02:33:05.027Z | 1970-01-01T00:00:00.000Z | 34011275 | s2ag/train | Evaluation of a Complement-Dependent Human Cytotoxic Antibody Reactive with Burkitt's Lymphoma Biopsy Cells 1
Summary An antibody in human sera that reacts with Burkitt's lymphoma biopsy cells and with leukemic lymphoblasts was detected by use of a complement-dependent cytotoxicity test. This antibody was detected in the sera of patients with Burkitt's lymphoma and also in the sera of other indivdiuals. The studies indicate that the antibody reacted with an antigen that is not tumor-specific but is also present on lymphoid cell lines and on normal peripheral lymphocytes. | v2 |
2018-04-03T02:36:56.405Z | 1970-01-01T00:00:00.000Z | 34335986 | s2ag/train | [Organ culture on tumor of the urinary bladder. 2. Clinical application of hyperbaric organ cultures].
The method of organ culture under hyper-baric oxygen was applied in the present report for they determination of in vitro effects of several anticancer agents onto human bladder carcinomas. Anticancer agents currently being used on clinical cases of bladder carcinoma, such as Mitomycin C, Thio-Tepa and saccharolactone were added to the culture medium at each concentration to be tested. Tissues of transitional cell carcinoma grade 1 to 3 from 21 cases were cultured under 2 atmospheres for 40 hours, temperature at 37C and pH at 7.2 to 7.4. Cultured tissues were studied histologically, electronmicroscopically and also studied with autoradiography. The autoradiographs were made by 3H-thymidine added to the medium at the last 2 hours of culture period. In control cultures, tissues from grade 2 of transitional cell carcinoma were well maintained under 2 atmospheres for 48 hours and autoradiographs revealed that the labeling indices of the superficial zone of the explants were higher than the deeper zone where cancer cells were still synthesizing DNA. In cultures with Mitomycin C 1.0 mcg per ml, cancer cells near the surface of explants were markedly degenerated, while the cells in deeper zones partly survived and the labeled cells were seen. In cultures with ThioTepa 1.0 mcg per ml cancer cells of the entire specimen were degenerated. The DNA synthesizing cells were not recognized so far with 3H-thymidine autoradiography of Thio-Tepa group. In cultures with saccharolactone 1.0 mcg per ml, the degenerated foci were seen in entire specimens but the degree of degeneration was slight. By electronmicroscopy, cancer cells near the basement membrane showed deformities of nuclei and nucleoli with a minimum dosis of Thio-Tepa, while the cytoplasmic organellae were affected with Mitomycin C. The different modes of action of each anticancer agents can be studied with this hyperbaric organn culture system. The results are applicable for the local instillation therapy of carcinoma of the urinary bladder. | v2 |
2018-04-03T02:47:38.073Z | 1970-01-01T00:00:00.000Z | 34913273 | s2ag/train | Carcinoma of the Vulva: Influence of Radical Operation on Cure Rate
The clinical features, treatment, and results in a series of 78 patients with vulvar malignancies are presented. Appropriate statistical methods are used to evaluate the effect of radical operation on survival rates. The results obtained demonstrate that more aggressive surgical management can result in significantly better cure rates than previously achieved. | v2 |
2018-04-03T02:59:07.569Z | 1970-01-01T00:00:00.000Z | 35673160 | s2ag/train | Blood groups and cancer of the cervix uteri.
This paper reports the results of a study of the incidence of A, B, O. and AB blood groups in 700 patients with cervical cancer. Reports of studies by others are quoted. Patients had been admitted to wards of S.N. Hospital, Agra. The diagnoses of cervical cancer had been established by clinical, cytological, and histopathological examinations. ABO blood groups were determined by the slide method using standard Anti-A and Anti-B sera. The grouping was confirmed by serum grouping using known group A and group B cells. A control series consisted of 2000 healthy females. Although and increased incidence of cervical cancer was observed incidence of cervical cancer was observed among patients belonging to group O, as compared to controls, statistical analysis of data revealed no significant difference. The chi square for 3 degrees of freedom was 5.875. Conclusions were that no significant statistical difference in the A,B,O, and AB blood groups distribution was present among these 700 patients with cancer of the uterine cervix.
| v2 |
2018-04-03T03:27:56.965Z | 1970-01-01T00:00:00.000Z | 5946495 | s2ag/train | Inhibition of the in Vitro Synthesis of Pituitary Prolactin and Growth Hormone by Mouse Pituitary Isografts 1
Summary Pituitary glands from mice bearing pituitary isografts in the renal capsule for 6-74 weeks were incubated with 14C- labeled amino acids, and the incorporation into prolactin and growth hormone was determined. Mice with isografts for 23 weeks synthesized 60% less prolactin and growth hormone than did normal intact mice. Implantation of isografts for periods up to 74 weeks further decreased the ability of the pituitary gland to synthesize the prolactin hormone; however, at 74 weeks, the extent of this inhibition in growth hormone synthesis was some-what decreased. It is proposed that the decrease in prolactin and growth hormone synthesis is mediated by hormone(s) secreted by the tumor acting at the hypothalamo-pituitary level through an autofeedback process. The author thanks Prof. O. Muhlbock and Drs. L. M. Boot and H. W. Kwa for providing the laboratory facilities and fruitful discussions during his visit to the Netherlands Cancer Institute. | v2 |
2018-04-03T04:39:34.765Z | 1970-01-01T00:00:00.000Z | 39774999 | s2ag/train | Erythropoietin release in hypophysectomized, adrenalectomized man
Erythropoietin (ESF) levels were assayed in 19 female and male patients with intact kidneys with pituitary tumors or following open hypophysectomy or combined hypophysectomy and adrenalectomy for disseminated tumor states. Saline‐injected control mice had 0.38 ± 0.04% Fe59 uptake (ESF). Hypophysectomized, adrenalectomized, castrated females had 2.96 ± 1.24% Fe59 uptake (ESF) with an average peripheral hematocrit of 29.2 vol %. Hypophysectomized, castrated males had 1.59 ± 0.30% Fe59 uptake (ESF) with an average peripheral hematocrit of 30.1 vol %. Thus, absence of the adrenals or functioning anterior pituitary gland does not prevent increased ESF activity. The presence of a pituitary tumor is also not consistently associated with increased ESF activity or release. The role of these endocrine organs in the regulation of ESF release in these states is therefore not essential but more likely represents a normal synergistic mechanism. Elevation of peripheral ESF levels is associated with improvement of anemia after hypophysectomy and may be an additional objective criterion and prognostic indicator of beneficial patient response to hypophysectomy in certain tumor states. | v2 |
2018-04-03T06:02:40.212Z | 1970-01-01T00:00:00.000Z | 45432484 | s2ag/train | Free urinary amino acid excretion in patients with familial polyposis of the colon
The free urinary amino acids excretion per 24 hr of the neutral and acidic amino acids did not reveal any diagnostic abnormality in five patients with familial polyposis of the colon with or without associated desmoid tumors and osteomas. One patient with Klinefelter's syndrome and familial polyposis had a urinary acid excretion pattern indistinguishable from his brother, who had familial polyposis and normal chromosomes. It is suggested that patients with familial polyposis deserve intensive biochemical study as this represents a prototype hereditary malignant disease. | v2 |
2019-09-16T20:33:42.046Z | 1970-01-01T00:00:00.000Z | 209361468 | s2ag/train | Book Review: Diseases of Children
Renin and Hypertension A Modern Synthesis by Michael Radcliffe Lee MA BM Bch Dphil MRCP pp viii+224 45s London: Lloyd-Luke 1969 The parts played by renin and angiotensin in human hypertension are still obscure and in this monograph, described as a modern synthesis, a useful account is given of the renin-angiotensin system and our present knowledge of the biological functions of these substances is discussed. Accounts of the chemical properties of renin, its preparation, and its origin and fate in the body are followed by a chapter on the renin substrate and on the properties of the angiotensins. There is an extensive review of recent experimental work and many interesting problems are discussed; among these are the important development of the enzyme kinetic technique for assay of renin in human plasma, the fascinating subject of factors modifying reactivity of the vascular system to angiotensin, and the possible mechanisms for control of the release of renin from the juxtaglomerular cells of the kidney. In later chapters the relationship between the renal hormone and clinical disorders presenting with hypertension, adrenal tumours, and the secretion of aldosterone are considered; and there is an account of the recently described Robertson's syndrome. Each chapter is well supported by an extensive bibliography, and this monograph may be recommended as a helpful introduction to this difficult subject for the research worker and for the physician interested in hypertension. It is hoped that before long, in a further edition, we shall be able to read that some of the gaps in our present knowledge have been closed. | v2 |
2022-07-21T10:48:10.594Z | 1970-01-01T00:00:00.000Z | 250777019 | s2ag/train | Measurement of changes in the oxygen and carbon concentration of tissues during fractionated high energy X-ray treatment
During treatment with 33 Mev x-rays from a medical betatron, the tumour and normal tissue of the irradiated region are activated by photon-neutron reactions, mainly 16O(γ,n)15O and 12C(γ,n)11C. These give rise to annihilation radiation which is measurable after treatment. The method can thus be used to determine variations in the oxygen and carbon concentrations of both irradiated normal and tumour tissues. Measurements have been made on patients undergoing a fractionated course of radiotherapeutic treatments; the results indicate a periodicity in the tumour carbon concentration, with an amplitude of about ±10% (max. ± 20%) and a period between 3 and 14 days. | v2 |
2017-04-20T19:00:10.084Z | 1970-02-01T00:00:00.000Z | 17237120 | s2ag/train | Transfer RNA methylase activities of SV40-transformed cells and cells infected with animal viruses.
Summary The possible induction of new transfer RNA-methylating enzymes by the tumor-producing virus, Simian Virus 40 (SV40), and by other DNA-containing animal viruses has been studied in connection with the aberrant methylation hypothesis of vital carcinogenesis. The tRNA methylase “activity” and the tRNA methylase “capacity” were measured after productive infection of African green monkey kidney (CV-1) cells by SV40, vaccinia, and herpes simplex viruses. The methylase “activity” and the methylase “capacity” were also studied after abortive infection of primary mouse kidney cultures by SV40. Methylase “activity” was assayed with limiting amounts of enzyme and with excess tRNA (yeast, Escherichia coli, Bacillus subtillis , and rabbit liver). Methylase “capacity” was assayed in the presence of limiting amounts of tRNA but with excess enzyme. Neither the tRNA methylase “activity” nor the tRNA methylase “capacity” was enhanced by infecting cells with any of three DNA-containing viruses. However, control experiments with the same cell extracts confirmed the fact that all three viruses did induce thymidine kinase activity. Although the tRNA methylases were not enhanced in virus-infected cells, both the tRNA methylase “activity” and the tRNA methylase “capacity” were increased about 2- to 4-fold in various mouse kidney cell lines transformed by SV40. To learn whether the increases were dependent on the metabolic state of the transformed cells, we studied the tRNA methylases at various times after subculture of the cells. The changes in the tRNA methylase during growth were relatively small compared with changes in thymidine kinase activity. Unlike tRNA methylase, thymidine kinase increased markedly in activity during exponential cell growth and then declined sharply as the cells entered the stationary growth phase. Thus, tRNA methylase fluctuations during cell growth probably do not account for the high levels of tRNA methylase in SV40-transformed cells. The enhanced tRNA methylases of SV40-transformed cells have been interpreted as indicative of a generalized derepression of host cell functions related to growth rather than the induction of a new tRNA methylase controlled directly by SV40 genes. | v2 |
2018-04-03T01:26:32.761Z | 1970-02-01T00:00:00.000Z | 29548257 | s2ag/train | A comparison of ultrasonic and isotope scanning in the diagnosis of liver disease.
Abstract Scintiscans using technetium 99m sulphur colloid, and ultrasonic scans were carried out on 99 patients. Twentythree had normal livers, 21 had cirrhosis, 15 had tumour in the liver, six had obstructive jaundice, seven had fatty livers, five had abnormal livers without histological confirmation, six had cysts or abscesses of the liver, ten had miscellaneous conditions and in six one or other scan was unsatisfactory. In the normal group only two patients had abnormal scans by both methods, although ten had an abnormal isotope scan. In patients with cirrhosis both scans were usually abnormal. When tumour was present in the liver it was usually detected by the scintiscan, but in only half the ultrasonic scans could this abnormality be distinguished from that produced by obstructive jaundice or cirrhosis of the liver. The ultrasonic scan could distinguish cystic from solid lesions in the liver whereas the scintiscan could not. | v2 |
2018-04-03T02:48:16.028Z | 1970-02-01T00:00:00.000Z | 35074448 | s2ag/train | Impaired immunologic reactivity and recurrence following cancer surgery
One hundred patients were tested for their ability to react to 7 commonly encountered skin test antigens and to develop delayed cutaneous hypersensitivity to 2, 4‐dinitrochlorobenzene (DNCB). Following sensitization, more than 95% of normal patients, but only 60% of patients with potentially resectable neoplasms, exhibited delayed cutaneous hypersensitivity to DNCB. A correlation is suggested between the inability to react to DNCB and the incidence of either inoperability, local recurrence, or distant metastases within 6 months post‐operatively. Ninety‐three percent (27/29) of patients who failed to react to DNCB were inoperable or developed early recurrence, whereas 92% (50/54) of patients who reacted to DNCB were free of disease for 6 months; but many of these patients were nonreactive to all of the common skin test antigens. These studies suggest that there is a significant correlation between cell mediated immunologic reactivity as measured by delayed cutaneous hypersensitivity to DNCB and the course of malignant disease following definitive cancer surgery. | v2 |
2018-04-03T03:24:21.010Z | 1970-02-01T00:00:00.000Z | 3112341 | s2ag/train | Prechiasmal infarction associated with intrachiasmal and suprasellar tumors.
T HERE is a little heralded lesion of the chiasmal region that occurs occasionally and has not, as yet, received sufficient attention, namely, the blue, domeshaped, or "blueberry" infarct of the prechiasmal or anterolateral portion of the chiasm. It is apparently due to simultaneous impairment of the superior and inferior vascular supply to the optic nerve and chiasm. We are reporting two cases of this lesion: an optic nerve glioma, and an infarction of a suprasellar pituitary tumor. Both of these patients underwent a craniotomy with surgical incision of the lesion in the prechiasmal area, and both required intrachiasmal aspiration with a tiny sucker to remove the clotted blood and necrotic tissue. There was partial improvement of the vision in one patient and none in the other. The two cases are presented to emphasize the importance of early diagnosis and treatment and to propose an anatomical concept of how these lesions may occur secondary to impairment of the vascular supply to the optic nerve and chiasm. | v2 |
2018-04-03T06:23:22.792Z | 1970-02-01T00:00:00.000Z | 46608904 | s2ag/train | Mithramycin treatment of hypercalcemia
An experience with Mithramycin in the treatment of hypercalcemia of malignancy is reported. Mithramycin given by direct, single, intravenous injection of 25 μg/kg was effective in lowering serum calciums within 24 to 48 hours in the majority of patients studied. The duration of this effect has been quite variable, but repeated doses of single injections have proven to be successful in most cases treated. The potential clinical usefulness of this agent in the treatment of hypercalcemia is apparent. It is reasonable to continue such studies on a long‐term basis. Such studies are currently in progress. | v2 |
2019-08-16T04:00:57.903Z | 1970-02-01T00:00:00.000Z | 199622764 | s2ag/train | Book Review: The Management of Infertility
report of 1932 that was very much like our own Dawson Committee Report of 1920, in that both recommended insurance against ill-health, community medical centres and total care in an organized fashion. He then takes us through more recent events, the Coggeshall Report to the AMA (1965), the Kennedy years with the Commission on Heart Disease, Cancer and Stroke (1964), and the follow-through by President Johnson in legislation on Medicare and Medicaid, the Office of Economic Opportunity and Comprehensive Health Planning. Since Dr Richmond completed his book the great problems of Medicare and Medicaid have become obvious and the USA is still faced with the very major problems in applying the concept that medical care is now a human and civic right that should be available to all in times ofneed. | v2 |
2019-02-14T14:18:12.697Z | 1970-02-28T00:00:00.000Z | 62767776 | s2ag/train | Pharmacology of the Autonomic System
stated. Methods of administration are described, the relation of toxicity to carcinoma regression evaluated, and factors influencing response reviewed. Regarding results, a slightly more favourabie result overall is shown for the 5-FU group as compared with the survival of the selecred control patients. Observations on other drugs used include the comments that mitomycin C produces regression comparable with the fluorinated pyrimidines but is of limited usefulness owing to toxic and other effects, and though B.C.N.U. is therapeutically active it has no practical role in treatment. Regional perfusion or infusion it seems has no advantage to offer over systemic chemotherapy, but combined 5-FU and supervoltage radiotherapy produced a significant prolongation of life in adenocarcinoma of the stomach and pancreas. This book is helpful in looking at a very bleak problem, for it shows what can be done for these patients and eliminates for us some measures which might prove harmful. And it does demonstrate the fact that we can consider the treatment of intractable solid cancers with chemicals. RONALD W. RAVEN. | v2 |
2014-10-01T00:00:00.000Z | 1970-03-01T00:00:00.000Z | 16283024 | s2orc/train | The kinetics of cellular proliferation in human tissues. Determination of duration of DNA synthesis using double labeling autoradiography.
The duration of the DNA synthesis period in normal and malignant human tissues from the larynx, trachea bronchus and esophagus of 13 patient has been estimated by a tritiated thymidine, carbon-14 thymidine double-labeling method in vitro. The DNA synthesis times range from approximately 10 to 25 hours, are shortest in normal tissues, and are longer in malignant tumor cells than in benign tumor cells. The double-labeling method, the analysis of thymidine labeling index data for the measurement of the S period, and a model for determining potential doubling times in human tissues are described and discussed. ImagesFig. 1
THE mammalian cell cycle consists of four clearly definable periods-G1, S, G2 and M (Howard and Pelc, 1953;Lajtha, Oliver and Ellis, 1954;Prescott, 1968). At the present time little is known about the durations of these phases in proliferating human cell systems, since the widely used experimental methods for analysis of cell population kinetics* preclude their application in man (for reviews, Baserga, 1965Baserga, , 1968Bresciani, 1968). We have been studying cell population kinetics in human tissues using a method whereby surgical and biopsy specimens may be labeled with tritiated thymidine (3HTdR) in vitro under high pressure oxygenation, but under conditions in which the incorporation of the label occurs only in those cells which were synthesizing DNA in the patient (Fabrikant and Wisseman, 1968;Fabrikant, Wisseman and Vitak, 1969;Fabrikant and Cherry, 1969). This has provided a pattern of 3HTdR labeling similar to that obtained by in vivo methods (Fabrikant et al., 1969). However, in phase distribution models for predicting cell cycle times and potential tissue doubling times for measured values of the labeling index in asynchronously proliferating cell populations, some assumption must be made for the duration and position of DNA synthesis in the cell cycle. The duration of the S phase has been measured in a wide variety of mammalian cell systems and it has been found that while there are certainly exceptions, in general, the duration of DNA synthesis is of the order of 8-10 hour (Bresciani, 1968;Steel, 1968). Until measurements of the length of the duration * The following abbreviations are used in analysis of cell population kinetics (Quastler, 1963): S, cells in DNA synthesis (S period); Gl, cells in presynthetic period; G2, cells in postsynthetic period; M, cells in mitosis (M period); N, number of cells in population; Ns, number of cells in the population in DNA synthesis; LI, labeling index (NsIN); Nl4C number ofcells labeled with 14CTdR; N3Hnumber of cells labeled with 3HTdR only; tc, duration of the cell cycle; t,, duration of S period; ta, time between labels; T, potential tissue doubling time in the absence of cell loss. of DNA synthesis in human tissues become available, there has been some justification for assuming a period of '-98-10 hour. To this end, therefore, we have carried out a series of studies which examine the duration of DNA synthesis in human tissues by a 3HTdR, 14CTdR double labeling method adapted to the in vitro technique previously reported (Fabrikant and Wisseman, 1968;Fabrikant et al., 1969;Fabrikant and Cherry, 1969). This communication describes the in vitroin vitro double labeling method, the analysis of labeling index data for the measurement of the duration of the DNA synthesis period in human biopsy specimens of neoplastic cell populations from the esophagus, larynx and bronchus of 13 patients, and a model for determining the potential tissue doubling time (T), i.e. the expected cell population doubling time in the absence of cell loss.
MATERIAL AND METHODS
Small tissue samples (1 x 1 x 2 mm.) obtained in the operating room are placed immediately into M-199 (Earle base) medium (4-17 ml.) with 20% fetal calf serum (0-83 ml.) and 3HTdR (0.025 ml., 0 5 #tCi/ml., specific activity 16-6 Ci/ mmole). The container is sealed in a specially designed hyperbaric oxygen chamber and the tissue is incubated in the agitated medium at 37.5 C., pH ' 7 5 and 2280 mm.Hg PO2 for 55 minutes. Normally, anoxic cells are present within the specimen, and the increased oxygen pressure permits utilization of the available thymidine (Steel and Bensted, 1965). The tissue samples are removed from the chamber and thoroughly washed in nonradioactive medium with fetal calf serum (5.0 ml.) at 37.50 C. for 5 minutes. The specimens are placed in fresh M-199-fetal calf serum medium and 14CTdR (0.05 ml., 1 0 #sCi/ml., specific activity 53X8 mCi/ mmole). The tissue specimens are incubated under hyperbaric oxygen conditions at 37.50 C., pH 7*5 and 2280 mm.Hg P02 for 60 minutes. The tissue is fixed in ethanol-formalin-acetic acid mixture for 24 hours and histological sections (4 ,u thick) from wax embedded tissue are prepared for high resolution autoradiography (liquid-emulsion-dipping technique using Kodak NTB2 nuclear emulsion). Autoradiographs are exposed at 40 C. for 3-4 weeks, developed (Kodak D19 developer), fixed (Kodak acid fixer) and stained with hematoxylin and eosin. In representative tissue samples, labeling indices were determined as a percentage of all nuclei of cells of a spatially and morphologically defined population in the tissue. Counts of more than 2000 cells of each class in a tissue were recorded.
The rationale of the double labeling autoradiographic method is that an asynchronously proliferating cell population is pulse labeled with 3HTdR and after an interval of time equal to or less than the duration of the G2 period, pulse labeled again with 14CTdR; the tissue is fixed promptly after the administration of the second label (Pilgrim and Maurer, 1963;Wimber and Quastler, 1963). Three groups of cells are identified on autoradiographs: cells labeled with 3H only; cells labeled with 14C with or without 3H; and cells with no label. The labeled cell populations may be distinguished autoradiographically because of the different energies of the , particles from 3H and 14C. Since the f8 particles of 3H travel a mean distance of ,1 It and those of 14C -.,50 ,u, the reduced silver grains in the 3H autoradiograph is localized in one plane directly over the nucleus, whereas the 14C autoradiograph extends into many planes and appears as a spray or halo of grains over and around the nucleus. The 14C population is a double population; some cells are labeled with 14C only and some with 14C + 3H, but the latter group cannot be measured with precision. The double labeling method has been used for the accurate determination of ts in mammalian and plant cell systems (Pilgrim andMaurer, 1963, 1965;Wimber and Quastler, 1963). Lala, Maloney and Patt (1965) measured ts for myeloid-erythroid precursors in canine marrow by (1) an in vivo-in vitro procedure, by pulse-labeling with 3HTdR in vivo followed at a short interval by relabeling in vitro with 14CTdR, and (2) an in vitro-in vitro procedure, by labeling with 3HTdR in vitro followed by relabeling with l4CTdR in vitro. Lala (1968) has used the in vivo-in vitro double-labeling procedure to obtain data for the measurement of the S period in growing populations of Ehrlich ascites tumor cells in mice. Fig. 1 is an autoradiograph of cells from a carcinoma of the bronchus in a 62 year old man. The 14C-labeled cell has a spray of grains in a number of planes around the nucleus. The cell labeled with 3H only has grains in one plane directly over the nucleus.
Fabrikant.
VOl. XXIV, NO. 1. perturbations within the system, then the duration of DNA synthesis can be measured. During the interval between labels, 3H-labeled cells pass out of DNA synthesis and their number will be proportional to the time between labels. All 14C-labeled cells were in the S phase and their number will be proportional to the duration of DNA synthesis. The duration of synthesis can be determined from ts/ta = N14C /N3H in an asynchronously proliferating cell population with a relatively uniform age distribution of cells in the proliferative compartment. In addition, some information is available on the duration of the potential tissue doubling time from determination of the LI, where LI = NS/N, and T = A(ta + ts)/LI or T = A(ta + ts)N/Ns. A is a growth constant of proportionality and depends on the duration and position of DNA syntheis in the cell cycle and thus on the age distribution of the proliferating cells. The value of A must be determined from the appropriate phase distribution diagram for each proliferating population (Bresciani, 1968;Fabrikant and Wisseman, 1968;Johnson, 1961;Steel and Bensted, 1965). For linear growth, A = 1P0; this occurs in steady-state cell renewal systems. For exponential growth, A =ln 2/t,; this may occur in human cell systems such as lymphomas and early metastatic growth in lymph nodes. If the rate of cell loss is AN, then the net rate of growth is dN/dt = AN AN. For the cell renewal system in the steady state, dN/dt = 0 and 8 ln 2/t,. For tumor cell populations, A is~.-.0O75-08, based on very limited information available, and this value cannot be estimated with any precisioni (Fabrikant and Wisseman, 1968;Steel and Bensted, 1965;Steel, 1968). The analysis of human cell population kinetics determined from the double labeled autoradiographs (Table I) is based on ta = 1 hour and A = 10 for linear growth and A = 0 75 for tumor growth. However, at present, the values assumed for A are poorly supported by sparse experimental evidence, and it is expected that estimates of T based in thymidine labeling indices and growth rate constants will require constant revision as new data become available.
In the past, the estimates of kinetic parameters in human tissues have been limited primarily to 3HTdR labeling indices following a single injection just before surgery; T values were usually calculated from labeling indices, assuming an arbitrary value for ts and all cells in the population proliferating, i.e. the growth fraction (Mendelsohn, 1962) is unity. Since the growth fraction varies in different tissues, and particularly among neoplasms, such estimates have been inaccurate. Recently, several normal patients and patients with leukemia, neoplastic effusions and solid tumors have been studied using serial sample techniques after 3HTdRlabeling in vivo (Bennington, 1969;Clarkson et al., 1965;Lala et al., 1965;Lipkin, Bell and Sherlock, 1963;Lipkin, Sherlock and Bell, 1963;Mauer andFisher, 1963, 1966;Stryckmans et al., 1966). The human data indicate ts values in some normal tissues and leukemic blast cells of -.10-15 hours, and in neoplastic tissues, -20-30 hours. Until further data are available, -10-15 hours is the best approximation for average DNA synthesis time in the bone marrow precursor cells in man. These values compare favorably with those determined with the in vitro double labeling method reported here (Table I). In addition, tc and T values are much longer in man than in experimental animals.
The 14C_ 3HTdR double labeling technique can be used for determining ts by one double labeling sequence if it is assumed that (1) there is a constant flux of cells into and out of S, and (2) there is an asynchronous distribution of cells within the cell cycle. Normally, the procedure measures cell fluxes through DNA 125S synthesis in steady state renewal tissues, but corrections can be made for growing cell populations with characteristics between steady state and exponential growth. This can be done if there is random cell loss during the cycle or at the end of mitosis, and the growth fraction is known. Lala (1968) applied the analysis to the Ehrlich ascites tumor in mice, where the growth fraction declines with increasing tumor age due to transition from a dividing to a nondividing state occurring mostly at the end of mitosis (Lala et al., 1965).
The double labeling method can be used to determine tc with precision only in the steady state renewal system which is dividing asynchronously, in which there is no cell loss during S, a growth fraction of unity, and a relatively narrow distribution of cell cycle times. However, the data on the LI and ts can predict a potential tissue doubling time, that is, the time for the cell population to double if there is no cell loss. Steel (1968) has demonstrated in 6 different experimental tumor cell systems in mammals that when the tumors were small, the measured volume doubling times in vivo were very similar to the potential doubling times determined from 3HTdR, LI and accurate values of t,. As the tumors grew, however, changes in the sizes of the growth fraction and the continuous loss of cells through cell death, metastasis or emigration, gave rise to a difference between the median cell cycle time, the potential tumor doubling time, and the actual doubling time. The effect of these processes-changes in the growth fraction and cell loss-on the rate of growth in human tumors is not as yet known. | v2 |
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