[Supramalleolar derotation osteotomy for torsion of the leg in children and adolescents. Techniques and results: apropos of 22 patients (32 legs)]. We have performed 32 supramalleolar osteotomies described by Mc Nicol to correct excessive internal or external tibial torsion in 22 patients (aged from 4 to 8 years, with different indications, with a follow-up of 16 months to 7 years). The consolidation of the osteotomy was obtained in 6 weeks. Eighteen patients (27 osteotomy) have a good result, 2 results are fair and 2 patients have a poor result. The indications for correction of excessive internal or external tibial torsion are very uncommon, and reserved to cases with functional disorbility of fitting appliances, or unaesthetic or uncomfortable gait.


[Echo-endoscopy of the digestive system]. Endoscopic ultrasonography of the gastrointestinal tract allows a precise ultrasound study of the accessible gastrointestinal walls (oesophagus, stomach, duodenum, rectum) and, through these walls, of the adjacent organs (lymph nodes, posterior mediastinum, pancreas, extrahepatic biliary ducts and perirectal region). This method is better than computerized tomography to evaluate the local and regional extension of oesophageal and cardial carcinomas producing little or no stenosis and of gastric and rectum carcinomas and lymphomas. It is the examination of choice to detect a perianastomotic recurrence of these cancers and to evaluate submucosal tumors of the gastrointestinal tract. This method, with no morbidity, is better than computerized tomography or ultrasonography in the aetiological diagnosis of obstacles in the biliary tract and in the diagnosis and pretherapeutic assessment of pancreatic cancer or endocrine tumors.


[Intraperitoneal resorbable mesh in the prevention of postoperative wound dehiscence. A comparative study]. The purpose of this study was to compare efficiency of polyamide mesh externally applied to the skin and intraperitoneal resorbable mesh of polyglactine 910, for the prevention of wound dehiscence. Two consecutive and homogenous groups of 100 patients, operated by the same surgical team and presenting one or more risk factors of evisceration, were retrospectively compared. Use of intraperitoneal polyglactine mesh, significantly reduced rate of wound dehiscence (4% vs 13%), lowered frequency of reoperation in eviscerated patients (25% vs 61%), but did not improve prognosis of this complication (50% mortality). Potential effect of resorbable mesh on late fascial disruption remains controversial.


[Darier-Ferrand dermatofibroma. An unusual tumor of the soft tissues]. Darier and Ferrand dermatofibroma is a rare skin tumour arising in the dermal connective tissue. It has a slow course over several years and presents very unusual histological features. It is characterised by a marked potential for local recurrence, frequently multiple due to insufficient primary resection. It has a very low metastatic potential. Its diagnosis is difficult but essential in order to perform an appropriate surgical procedure which ensures its excellent prognosis.


[Peristomal pyoderma gangrenosum after colectomy for Crohn disease. Successful medical treatment]. A case of Pyoderma gangrenosum with two different abdominal sites in a female patient suffering from colonic Crohn's disease is presented. Local trauma on the midline scar of an incisional hernia and around the stoma were the possible triggering factors. Despite the major abdominal wall defect and an infected parietal collection, steroid therapy was very effective without the need for surgery.


[Endometriosis and diaphragmatic defect in catamenial pneumothorax]. Two cases of catamenial pneumothorax are reported, a rare condition characterized by its sudden occurrence in a female patient between the ages of 30 and 40 years, always at the onset of the menstrual cycle. Its exact origin is unknown, but the frequent co-existence of endometriosis and a defect in the diaphragm suggests that endometriosis may be important in the etiology both of the pneumothorax and the diaphragmatic lesion. Pelvic endometriosis was present in both our patients, one of whom also had diaphragmatic endometriosis. The treatment of the pneumothorax in both our cases consisted of pleural decortication with excellent results so far.


[Evaluation of the arrhythmogenic potential 3 months after myocardial infarction]. An evaluation of the ventricular arrhythmia potential was conducted 3 months after a myocardial infarction (anterior n = 32, inferior n = 58) in 90 patients with a group mean age of 58 +/- 9.3 years, using 24-hour ambulatory ECG monitoring, an exercise test, recording of late ventricular potentials and programmed right ventricular stimulation. Eighteen patients (20%) had a ventricular extrasystole > or = Lown grade III on the Holter, which was more frequent in patients with ventricular dyskinesia (41% vs 15%; p < 0.05); 10 patients (11.1%) had ventricular extrasystoles > or = Lown grade III during the exercise test; 19 patients had late ventricular potentials. Programmed ventricular stimulation induced monomorphic ventricular tachycardia in 10 patients (11.1%) (sustained, n = 5, unsustained n = 5) and the prevalence of late ventricular potentials was higher in this group (60% vs 16.2%; p < 0.01). In the medium term (32 months), 2 patients had died: one suddenly and the other of a recurrence of myocardial infarction. Five patients had an episode of spontaneous ventricular tachycardia. The risk of sudden death or ventricular tachycardia was higher in patients with late ventricular potentials (positive predictive value = 21%) and in patients with electro-induced ventricular tachycardia (positive predictive value = 66%). In the absence of late ventricular potentials, the risk of a serious arrhythmic event is slight (2.8%). After myocardial infarction, the presence of late ventricular potentials can be used to isolate a group of patients with a high risk of serious ventricular arrhythmia; this risk is higher if programmed ventricular stimulation triggers monomorphic ventricular tachycardia.


[Nocturnal-diurnal changes of norepinephrine blood levels in patients with chronic cardiac insufficiency. Practical values]. The purpose of this study was to investigate circadian changes in noradrenaline (norepinephrine) levels in patients presenting with congestive heart failure. Eighteen patients were investigated with a group mean age of 66 years, 12 in NYHA class III and 6 in class IV. The cause of the heart failure was ischemia in 7 cases, valvular in 1 case and idiopathic in the other 10 cases. The mean follow-up time of the disease was 3.9 years. Six healthy volunteers were investigated following the same protocol. Blood samples were taken while the patient was lying down over a period of 24 hours, after installing a peripheral venous catheter. The assay was carried out by means of high performance liquid chromatography with electrochemical detection. In the controls, the mean noradrenaline level (norepinephrine) was 220 +/- 62 pg/ml, with daytime peaks. The heart failure patients showed a high mean level (230 +/- 404 pg/ml), with less daytime variability than the controls (92% vs 127%; p < 0.05). The 8 a.m. value was reproducible, and there was close correlation between this value and the mean value for the 24 hours (p < 0.001). Thus, the morning sample provides a good estimation of the levels over the 24 hours.


[Predictive factors of regularization and maintenance of sinus rhythm in chronic atrial fibrillation]. The aim in treating chronic atrial fibrillation, is not limited to simply achieving immediate regularization. What matters, is sustaining the sinus rhythm. The various methods of regularization, using either medical procedures or cardioversion, involve constraints and risks. Investigation of the relapse predicting factor is of great value in evaluating the benefit/risk ratio. For regularization, the absence ultrasound signs of heart disease, an undilated left atrium, recent atrial fibrillation and all forms of heart disease which are curable, albeit surgically, are indicative of success. With regard to prophylaxis, relapses occur more frequently in cases involving mitral valve disease, long-standing atrial fibrillation or a dilated left atrium.


[Extracorporeal circulation in acute ischemia of the lower limb with late detection]. The authors report a case of acute limb ischemia in a 19 years old patient seen at 9 hours of the injury. They describe a technique of "washing-reperfusion" by a cardio-pulmonary limb bypass (CPLB). Blood pH and kaliema measurements during CPLB were noted. The good clinical result except on the initial nerves deficit, should lead to think that this technique could take a place in the treatment of acute limb ischemia seen lately.


[Apropos of a rare cause of torsades de pointe: hypokalemia caused by dietary deficiency]. The authors report a case of wave burst arrhythmia in a young immigrant woman of Laotian origin aged 32. The main cause of the arrhythmia was related to potassium deficiency of dietary origin. Some contributory factors may have had a promoting effect: theophylline treatment, beta-mimetics and adrenaline (epinephrine). This case can therefore be related to the cases of wave burst arrhythmia and hypokalemia previously reported in anorexic subjects. This case suggests that special attention should be paid to the diet of some ethnic groups who have been displaced by economic causes. Their very unusual dietary habits may induce or aggravate hypokalemia, which may also be promoted in some cases by drugs. Some treatments should therefore be introduced with caution in this context due to the potential risk of inducing severe arrhythmia.


[Efficacy of the combination of nicardipine-enalapril and atenolol in severe hypertension secondary to chronic renal disease]. The antihypertensive efficacy of combination therapy with N-E-A was evaluated during 6 months in 15 patients with hypertension associated with mild to moderate kidney failure. After 6 months a significant reduction of SBP and DBP (p < 0.001), with improvement of creatinine clearance and with no adverse effects on ECG, heart rate and routine laboratory tests test, was observed in 3 patients treated with N 20 mg x 2/d + E 10 mg/d + A 50 mg/d and in 8 patients treated with N 20 mg x 3 + E 10 mg x 2, + A 50 mg x 2. Four patients did not respond to this therapy.


Reference values of serum and urine creatinine, and of creatinine clearance by a new enzymatic method. A new, totally enzymatic procedure for the determination of creatinine in serum and urine, using creatinine amidohydrolase, creatine amidinohydrolase, sarcosine oxidase and formaldehyde dehydrogenase is described. The assay was adapted to a discontinuous analyser with each analysis requiring only 20 microL of serum or 3 microL of urine. Analytical recovery of creatinine in serum and urine averaged 100.6%. Within-run and between-run precision studies gave coefficients of variation of 1.1% and 1.8%, respectively, for a serum with mean values of 83 mumol/L (9.4 mg/L) creatinine. Creatinine concentrations in serum and urine were measured by this procedure, in Japanese children and adults. The reference intervals for serum creatinine concentrations in adults were 55-96 mumol/L (6.2-10.9 mg/L) in men and 40-66 mumol/L (4.5-7.5 mg/L) in women, and for urine, 9.46-19.01 mmol/day (1070-2150 mg/day) in men and 6.75-10.61 mmol/day (764-1200 mg/day) in women. The reference intervals of creatinine clearance were 88.0-176.4 mL/min in men and 75.7-173.0 mL/min in women.


The steatocrit: an improved procedure.

The steatocrit: an improved procedure. The steatocrit is a simple and easily repeated assay for measuring the fat content of infants' stools. However, we and others have experienced technical difficulties in its use. Three modifications were therefore made to the original procedure: incorporation of a lipid-soluble dye, improved homogenization and a heating step. The modified method was used to measure the stool fat content of young children with and without clinical steatorrhoea. Validation of the modified steatocrit is presented, together with examples of its application to both clinical research and clinical practice.


Comparison of post-mortem urinary and vitreous humour organic acids. We have analysed organic acid profiles in 74 samples of post-mortem vitreous humour from the sudden infant death syndrome and compared the profiles to those obtained from the corresponding urine or bladder wall swab. There was a high degree of correlation indicating that vitreous humour analysis in high-risk infants is an appropriate analytical strategy when urine is not available. In our patient sample two infants had evidence of abnormal methylmalonic acid metabolism, one had glyceric aciduria (and elevated levels of vitreous humour glyceric acid), one had evidence of pre-existing liver damage as judged by the presence of 4-hydroxyphenyllactic acid, one had a non-ketotic dicarboxylic aciduria indicating inhibited fatty acid oxidation and two patients had significant long-chain 3-hydroxydicarboxylic acids and evidence of paracetamol ingestion.


Investigation of the use of impermeable fluid barriers between pelleted and supernatant enzyme activity in a pseudohomogeneous enzyme immunoassay. We have investigated the feasibility of performing an automated pseudohomogeneous enzyme immunoassay in which a separation step is not apparent to the user. This was achieved using a layer of silicone fluid, which is immiscible with aqueous solutions, as a physical barrier between the pelleted and supernatant enzyme. Initially we produced a manual assay based on the Serozyme T4 assay to demonstrate the feasibility of the approach. This assay showed good precision, parallelism and correlated with 'in house' results on patients' samples. Production of a fully automated assay was made difficult by the design of available equipment but none the less we demonstrated the feasibility of the automated approach by producing a standard curve for T4.


New automated nonisotopic immunoassays for free thyroxin: effect of albumin and thyroxin-binding globulin concentrations. Recently, nonisotopic (often automated) immunoassays for measuring serum free thyroxin (FT4) have become available. Though more costly than radioimmunoassays, they are considerably more convenient. We studied the influence of endogenous albumin and thyroxin-binding globulin concentration on five automated, nonisotopic methods of measuring FT4 [Enzymun on ES300 (one-step), Stratus I and II (essentially two-step), Delfia (two-step), and IMx (two-step)] in a mixed patient population. We observed that they (a) are influenced very little by endogenous serum binding proteins and (b) seem to have sufficient within-run precision to justify performing single measurements on patients' specimens.


Method comparison--a different approach. The commonly accepted method of analysing data from method comparison studies is regression analysis, a method which has limitations. This study illustrates the use of a graphical presentation of data, the difference plot, which can be used as an alternative to least squares regression analysis. The data from comparison studies performed on five methods were analysed both by Deming's regression analysis, with calculation of the correlation coefficient, and by the difference plot. The results show that in most cases much more relevant information was obtained from the difference plot.


[Insulin resistance and polycystic ovary syndrome]. The causes and consequences of the insulin resistance that accompanies the polycystic ovary Syndrome (PCOS) are still controversial. The hyperandrogenism does not appear any more as a causal factor but on the contrary is likely to be a consequence, via the ovarian effects of hyperinsulinism. These are still not clearly understood in their molecular aspects, but their reality is undoubtful in view of some clinical studies which showed an improvement following by the reduction of hyperinsulinism. Therefore, the aetiopathogenic role of the insulin resistance in PCOS becomes more and more obvious but it cannot be split from the likely implication of the intra-ovarian growth factors, and more especially the IGF 1 which could act synergistically with it. Moreover, the presence of LH seems to be still a pre-requisite to the ovarian action of insulin. The therapeutical incidences of these hypothesis are obvious and should improve in the next future the medical management of PCOS.


The influence of oxytocin, vasopressin and their analogues on progesterone and testosterone production by porcine granulosa cells in vitro. Effects of nonapeptide hormones and some of their chemical analogues on progesterone and testosterone production by culture of porcine granulosa cells have been investigated. Oxytocin (0.01-10 IU/ml), arginine-8-vasopressin (0.01-10 micrograms/ml), arginine-8-vasotocin (0.01-10 micrograms/ml) and, in a lesser degree, 2-0-methyl-tyrosine (deamino-1-karba)-oxytocin (0.01-10 micrograms/ml, but no 1-deamino-8-vasopressin (0.01-10 micrograms/ml) stimulated a progesterone surge. Testosterone production was significantly stimulated by oxytocin and inhibited by vasopressin or vasotocin additions. 2-0-methyl-tyrosine (deamino-1-karba)-oxytocin or 1-deamino-8-vasopressin had little or no effect on testosterone secretion. The present results suggest the existence of a direct influence of nonapeptide hormones on porcine ovarian progestagen and androgen production.


[Cholecystokinin, neurotensin and corticotropin-releasing factor, three important anorexic peptides]. This paper updates the informations on the three most important anorexigenic peptides: cholecystokinin, neurotensin and corticotropin-releasing factor. Their peripheral and/or central effects on food and water intakes as well as on dietary preferences are detailed. Their mechanisms of action and regulation are examined. This includes the interactions with classical neurotransmitters (norepinephrine, dopamine, etc...) as well as the description of the brain nuclei and neuronal networks involved. Finally, their variations in disturbed feeding behavior (hyperphagia, anorexia) in man or in animal models are reviewed.


[Evaluation of nuclear magnetic resonance imaging in tridimensional acquisition in the investigation of prolactin microadenoma]. Twenty one patients with suspected prolactin-secreting microadenoma were evaluated with MRI. MRI is the most sensitive means for detecting focal microadenomas. In these patients who were clinically and endocrinologically considered to harbor a microadenoma, MR detected a focal pituitary signal abnormality in 100% when the patients had not previously taken bromocriptine therapy. On the other hand MR demonstrated a focal abnormality in only 30% of cases when the patients had been on dopamine agonist therapy: the MRI findings in the group of bromocriptine treated patients are not affected by neither the duration and dosage of the therapy or the delay between MR examination and the bromocriptine therapy discontinuation. Among the 9 cases in which MRI did not demonstrate a focal abnormality, MRI was strictly normal in 3 cases only; MR showed a localized expansion of the subarachnoid space in two cases; the pituitary gland was large and round, and had a homogeneous signal in one case; the pituitary gland had a heterogeneous signal in 3 cases. In our study the microadenoma had a high signal intensity on the precontrast T1 weighted sequence in 5 cases. The focal abnormality was not seen on the precontrast MR images in 2 cases. The microadenoma enhanced in 3 cases on the postcontrast three dimensional MR images. This MR technique allows thin section slices (1 mm) and therefore the detection of small focal abnormality of the pituitary gland (2.5 x 3 mm). Thus three points have to the emphasized: a) MRI always detected a microadenoma when the patients had never received a bromocriptine therapy.(ABSTRACT TRUNCATED AT 250 WORDS)


[Measurement of impedance of hepatic tissue transformed by pathological process. A preliminary communication]. Intrahepatic impedance was measured using a special electrode in 44 patients, 38 of whom identified abnormalities of the hepatic parenchyma. Impedance values were compared with ultrasound findings and with the histological results of needle biopsy. Impedance was relatively unaffected in the presence of cirrhosis (n = 7) or chronic hepatitis (n = 5). It was markedly decreased in the presence of cysts (n = 4) and of hepatocarcinoma (n = 4). Values were variable in secondary carcinoma of the liver (n = 16). This preliminary study suggests that the measurement of intrahepatic impedance could contribute to the etiological diagnosis of hepatic tumour lesions.


[Hepatic amebiasis in a metropolis. Apropos of 9 cases]. From 1981 to 1990 nine patients suffering from amebic liver abscess were under observation at the Tours hospital. Hepatic amebiasis is scarce in France. Most of the subjects have stayed in endemic areas. Most of the time patients are male adults suffering from fever and abdominal pains. In most cases the liver ultrasonography shows a single cut of the right lobe with variable and non specific aspects. Once the diagnosis has been given a metronidazole treatment must be prescribed. The diagnosis will be confirmed by serology reactions. Clinical supervision is essential. The clinical effectiveness of the treatment is spectacular. Comparatively it will take about six months until serology reactions and liver ultrasonography get back to normal. Management of hepatic amebiasis need exceptionally echo-guided percutaneous puncture or surgery.


[Hiccup caused by epigastric compression in a hemiplegic patient]. The authors report the case of a patient with permanent, refractory hiccup, resistant at all classical treatment methods. Hiccup was due to compression of the epigastric region by the left fist of the patient immobilised by a spastic hemiplegia. Passive mobilisation of the diseased upper limb resulted in the disappearance of hiccup.


[Gastric metastasis of breast cancer occurring after a cancer-free interval of 30 years]. The authors report the case of a 75-year-old female patient who presented with a deterioration in her general health and epigastralgia 30 years after mastectomy for cancer. The findings of an exhaustive assessment was normal apart from an inflammatory syndrome with hyperleukocytosis and subcardial ulceration, which gave negative endoscopic biopsies. The patient underwent surgery and the total gastrectomy ablation demonstrated that this was a metastasis of a mammary adenoma. Follow-up for two years did not reveal any recurrence. The mean time to the development of gastric metastases of breast cancers is 2 to 4 years. Life expectancy appears to be greater the longer this latency time. The usual blood-borne spread explains why endoscopic biopsies may be falsely reassuring, since the first layers to be affected are the serous and submucosal layers. Localized forms may simulate ulcers; nodular forms are more appropriate for curative surgery than the more common infiltrating forms (which resemble linitis). These infiltrating forms are often combined with peritoneal damage and/or extradigestive metastases.


Anal endosonography.

Anal endosonography. Endosonography of the anal canal is capable of imaging the internal and external sphincters in detail. Abnormalities of thickness may be seen in the internal sphincters and defects in both. The examination is indicated in the investigation of incontinence and anal pain, and may be of value in anal sepsis and malignancy.


[Epidemiology and prevention of colorectal cancer]. Colorectal carcinoma is very common in western countries. It is in the front line of malignant pathology in France. The estimated number of new cases is almost 26,000 per year. The role played by diet in the onset of colorectal carcinomas is well established. The majority of studies indicate the protective role played by green vegetables. The role of other factors remains controversial: protective role of fibres, calcium and vitamins and favorizing role of fats, proteins, red meat, alcohol and calorie intake. The role of bile salts in increasing the size of adenomas and their malignant change is accepted. A number of therapeutic trials have involved modifications in bile salt concentrations. These should enable the proposal of a primary prevention strategy. The early detection of carcinomas and the secondary prevention of colorectal carcinoma (by detection of the adenomas which precede a high proportion of carcinomas) are areas of great interest. Detection of occult blood in stools as a mass screening test is currently being evaluated. Methods used to obtain a high participation rate among the population vary from one country to another, but are now well-defined. It will be necessary to wait for 2 years before being able to determine the effect on mortality and an even longer period to evaluate the effect on the incidence of colorectal carcinoma.


[Should subdivision of regressive ischemic colitis be envisaged?]. The term "regressive ischemic colitis" is generally accepted and refers to acute hemorrhagic colitis which may occur at any age and recovers spontaneously in most cases, sometimes leaving colonic stenosis due to scarring. Critical analysis of the literature reveals that there is no formal diagnostic criterion for this condition and no real proof that the mechanism is ischemic, particularly in young subjects who have no vascular disorder or hemodynamic triggering factor. The number of clinical, radiological, endoscopic and even histological similarities between regressive ischemic colitis and some forms of infectious colitis, particularly due to enterohemorrhagic E. coli O157:H7 and hemorrhagic colitis due to penicillin derivatives and non-steroid anti-inflammatory drugs is also striking. These observations logically lead us to wonder whether the term "regressive ischemic colitis" does really correspond to a well-defined entity rather than to a group of acute colitis of miscellaneous etiology but with many common features.


The role of granulocyte-macrophage colony-stimulating factor in induction of monocytic differentiation of HL-60 cells: synergistic interaction with 1 alpha, 25-dihydroxyvitamin D3 and interferon-gamma in inducing interleukin-1 beta. 1 alpha, 25-Dihydroxyvitamin D3 (D3) (100 nM) and interferon-gamma (IFN-gamma) (100 U/ml) cooperatively inhibited the proliferation of HL-60 cells, and synergistically induced their monocytic differentiation. The growth-promoting effect of granulocyte-macrophage colony-stimulating factor (GM-CSF) (10 ng/ml) was inhibited appreciably by D3 and slightly by IFN-gamma. Despite the clear difference in their effects on growth of HL-60 cells, both IFN-gamma and GM-CSF in combination with D3 induced cell cycle changes, decreasing the number of cells in the S phase and increasing their percentage in the G1/0 phase. GM-CSF alone had no effect on differentiation, but enhanced differentiation induced by D3 distinctly though to a limited extent, and also enhanced monocytic differentiation, including morphological changes of HL-60 cells in the presence of D3 and IFN-gamma. GM-CSF as well as D3 and IFN-gamma induced interleukin-1 beta (IL-1 beta) production by the HL-60 cells, clearly indicating their importance in differentiation of these cells. IFN-gamma and GM-CSF had mutually potentiating effects and induced maximum IL-1 beta production in response to lipopolysaccharide (LPS) in the presence of D3. Thus despite its growth-promoting effect, GM-CSF is a potential inducer of monocytic differentiation of human myeloid leukemia cells, because in cooperation with IFN-gamma it induced monocyte-macrophage differentiation of HL-60 cells in the presence of D3.


Antineoplastic activities and cytotoxicity of 1-acyl and 1,2-diacyl-1,2,4-triazolidine-3,5-diones in murine and human tissue culture cells. 1-Acyl- and 1,2-diacyl-1,2,4-triazolidine-3,5-diones were found to be potent cytotoxic agents in murine and human cancer cell lines, e.g. L1210, P388, Tmolt3, colon adenocarcinoma, Hela cells and glioma. In vivo activity was demonstrated at 8 mg/kg/day against Ehrlich ascites carcinoma growth. In L1210 cells, 1-acetyl-4-phenyl-1,2,4-triazolidine-3,5-dione, 41, reduced DNA synthesis significantly with moderate reduction in RNA synthesis. Enzyme sites in L1210 cells which were markedly affected were m- and r-RNA polymerase, PRPP amidotransferase, IMP dehydrogenase, dihydrofolate reductase, thymidine, TMP and TDP kinases. Kinetic studies suggest the inhibition of rate limiting enzymes in the purine pathway by 41 was responsible for its cytotoxicity. Acute toxicity studies in mice indicated 41 was safe for therapeutic use at 20, 50, and 100 mg/ky/day.


An experimental model for the study of thermochemotherapy in vivo. Human melanomas serially passaged in nude mice as xenotransplants were used as models for the study of the effects of thermochemotherapy of human malignant tumours in vivo. Three such melanomas, one (BRO) fast-growing, one (SCH) slow-growing, and one (BEL) of intermediate growth rate, were chosen. One group was left untreated as a control, one received chemotherapy (cyclophosphamide), one received hyperthermia, and one a combination of both treatments. In all three tumours, the best results were obtained associating chemotherapy with hyperthermia. The fastest growing tumor responded more than the slower, which responded better than the slowest. This model should prove useful in testing the effectiveness of anticancer agents used in association with hyperthermia.


Stimulation by estrogen and progesterone of the in vivo growth of transformed murine Leydig cells only at the limited early phase of growth. B-1 F is a cell line established from estrogen-responsive murine Leydig cell tumor and maintained in vitro. We investigated the effects of steroid hormones on the growth of tumors produced by the inoculation of B-1 F cells into mice. When tumor tissues were transplanted into castrated male mice, injections of estradiol-17 beta (E2) or progesterone shortened the period before tumors became palpable, but did not affect the growth rates of tumors after tumors became palpable. Injections of E2 or progesterone from the time when tumors became palpable did not affect the growth of tumors, and the discontinuation of injections of E2 or progesterone during the middle growth phase showed no effect on the growth of tumors. E2 or progesterone also did not increase the mitotic indices of tumors after they became palpable. E2 and progesterone did not stimulate the proliferation of dispersed tumor cells in vitro. The present results suggested that steroid hormones might exert their actions only at the limited early phase of growth of transplanted steroid hormone-responsive tumors in vivo.


Chemosensitivity testing of clinical gastrointestinal cancers using histoculture and the MTT end-point. Three-dimensional histoculture with the 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2H tetrazolium bromide (MTT) end-point was utilized for chemosensitivity testing of 100 clinical gastrointestinal cancers and the results were compared with those obtained with cell-suspension culture with the MTT end-point. Of the 100 surgical specimens, 91 were evaluable using histoculture assay and 66 were evaluable using the cell-suspension assay. When the assay results were compared with historical frequency of clinical response to chemotherapy, the results of the histoculture assay showed a closer correlation than those of the cell-suspension assay. Therefore, the histoculture assay seems to have a higher evaluability rate and a closer correlation with clinical chemosensitivity of gastrointestinal cancers than the cell-suspension assay.


Correlation of drug response in human tumors histocultured in vitro with an image-analysis MTT end point and in vivo xenografted in nude mice. We have in this study used the 3-(4,5-dimethyl-2- thiazoyl) -2,5-diphenyl 2-H-tetrazolium bromide (MTT) end point in our histoculture drug-response assay. We have previously demonstrated that the formazan crystals formed by MTT reduction by mitochondrial succinate dehydrogenase reflect polarized light and can be measured by pixel analysis in intact tissue. The results described here indicate a total specificity of 93.8% and a total accuracy of 74.6% of the MTT end point for drug response in histoculture correlating with nine different human xenograft tumors grown in nude mice with respect to the in vivo drug response data. This in vitro system allows prediction of positive and negative responses to drugs, with a rate of 70% and 71.8%, respectively. The system described here has potential for clinical use because of the possibility of simultaneous description of the MTT values and heterogeneous response to drugs within individual tumors.


Extensive liver metastasis from human colon cancer in nude and scid mice after orthotopic onplantation of histologically-intact human colon carcinoma tissue. Clinically-relevant animal models of human cancer are greatly needed for the study of human cancer biology and the development of new cancer therapeutics and diagnostics. We report here that by orthotopically transplanting histologically-intact human colon cancer to the colon of the immunodeficient nude and scid mouse mutants that extensive local growth and liver metastases occur consistently even after extensive in vivo orthotopic passage. We demonstrate that the liver metastases arise by hematogenous spread. The models described in this report for human colon cancer should prove useful for individual cancer patients as well as for basic and applied studies to develop improved treatment.


A patient-like metastasizing model of human lung adenocarcinoma constructed via thoracotomy in nude mice. A new nude-mouse metastasizing orthotopic transplant model of human adenocarcinoma of the lung is described. Histologically-intact human A549 adenocarcinoma lung tumors were transplanted to the left lung of nude mice via a thoracotomy procedure we have developed. The transplanted tumors grew extensively locally and metastasized to the opposite lung, lymph nodes and other clinically-relevant sites. The results described indicate the model developed could have clinical relevance and contrast with models of the A549 lung adenocarcinoma constructed orthotopically with injections of cell suspensions which result in low metastatic potential.


Clinical stage I and II endometrial carcinoma: multivariate analysis of prognostic factors. In 221 patients with FIGO stage I and II endometrial carcinoma, the impact on survival of age at diagnosis, menopausal status, FIGO stage, myometrial invasion, tumor grade and histology was evaluated by univariate and multivariate analysis. At a median follow-up of 50 months (range 45-210), 42 patients had died, and therefore overall survival was 81% (179/221). Univariate analysis showed that age, menopausal status and histology did not influence survival, whereas FIGO stage, myometrial invasion and tumor grade were important prognostic factors. Multivariate analysis showed that tumor grade had a significant and independent impact on survival and confirmed that FIGO stage is the most important parameter influencing survival.


Improved immunohistochemical detection of p53 protein in paraffin--embedded tissues reveals elevated levels in most head and neck and lung carcinomas: correlation with clinicopathological parameters. We have analyzed the expression of the p53 tumor suppressor gene in paraffin-embedded sections of normal and malignant head and neck and lung tumors by immunohistochemistry using the PAb 1801 monoclonal antibody (MAb). The PAb 1801 does not consistently detect its p53 epitope in tissue fixed in 10% buffered formaldehyde. However, the antibody is effective in AMeX-fixed specimens, thereby permitting the improved morphologic localization of p53 phosphoprotein in paraffin embedded tissue. Of 33 primary head and neck carcinomas analyzed from AMeX-fixed, paraffin-embedded sections, 21 (64%) showed heterogeneous staining with PAb 1801. All 33 normal samples of head and neck tissues were negative. Similarly, 13 out of 20 lung carcinomas (65%) showed heterogeneous staining while none of normal lung tissues were positive. The data indicate a strong positive correlation between p53 detection by PAb 1801 and carcinomas of the head and neck and of lung. However, there was no obvious correlation between p53 staining and the number of involved nodes, the stage of disease or the degree of differentiation in these carcinomas.


Relationship between pi-electron distribution and anticancer activity of benzo[a]phenothiazines. In order to study the correlation between the anti-tumor activity of benzo[a]phenothiazines and the electron densities, the Huckel orbital method and modified-neglect-of-diatomic overlap (MNDO) orbital method were used. 9-Methyl-12H-benzo[a]phenothiazine (2), which showed the most potent anticancer activity among benzo[a]phenothiazines, had the highest charge of nitrogen atom (QN), L-region (QL) and M-region (QM) in the molecule. The other derivatives, which showed weaker anticancer activity, had a much reduced value of these charges (QN, QL, QM). The data suggest that stability of pi-electron in 1 benzene ring and 1 naphthalene ring in the benzo[a]phenothiazine skeleton might be responsible for the induction of anticancer activity.


Enhanced chromosomal fragility in neuroblastoma: correlation with poor prognosis. In a previous study we demonstrated spontaneous fragility and hypersensitivity to fragile site induction by aphidicolin in lymphocytes from some neuroblastoma patients and their parents. Here we report data based on a total of 40 patients and 37 families. Possible correlations between higher sensitivity to aphidicolin and a variety of personal and clinical characteristics were verified. Patients with a poor prognosis generally proved to be more susceptible to fragile site induction.


Augmentation of antineoplastic effects by the combination of recombinant human tumor necrosis factor and mitoxantrone on primary culture of human ovarian cancer cells. Recombinant human tumor Necrosis Factor (rHuTNF) produced dose-dependent cytotoxicity against human ovarian cancer cells, OSC and OMC, obtained from fresh ascites. A combination of rHuTNF and the topoisomerase II inhibitor, Mitoxantrone, produced dose-dependent synergistic cytotoxicity on OSC and OMC cells. When OMC cells were incubated simultaneously for one hour with rHuTNF and Mitoxantrone, increased numbers of DNA single-strands breaks were produced. rHuTNF alone did not induce DNA single-strands breaks. These data are consistent with a role for topoisomerase-linked DNA lesions in the rHuTNF mediated potentiation of killing cells by Mitoxantrone.


Complications of total gastrectomy for gastric cancer--with special reference to anastomotic failure. We have reviewed the data on patients totally gastrectomized for gastric cancer during a 12 year period at our hospital. Our findings are summarized, as follows: 1. Advanced cases (stage III, IV) accounted for 85.4% (276/323) of them. Combined resection of other organs was performed on 87.6% of them. Twelve percent of the patients had peritoneal dissemination of P2 or higher grade and 5.9% hepatic metastases of H1 or higher grade. 2. Roux-en Y anastomosis was the most frequent (83.3%) reconstructive procedure. There were a total of 124 episodes of postoperative complications in 76 cases (23.5%). The lung and liver were often involved. Twenty-four cases (7.4%) suffered from postoperative anastomotic failure, which developed commonly at the site of oesophago-jejunostomy. Major leakage from this portion was the cause of death in 62.5% of the cases. The mortality rate was not notably different between the groups subjected to different reconstructive procedures or between the autosuture group (using an EEA stapler) and the hand suture group. The incidence of death due to the surgical intervention was 1.9%. 4. The 5-year survival after total gastrectomy was 25.2%, which was not necessarily satisfactory. However, it was significantly higher in the curative resection group than in the non-curative resection group (40.2% vs 3.3%).


A decision support system for predicting a recurrence of breast cancer; a prospective study of serum tumour markers TAG 12, CA 15-3 and MCA. The aim of the present study was to evaluate the clinical value of the preoperative serum tumour markers TAG 12, CA 15-3 and MCA in predicting a recurrence of breast cancer patients. The sensitivity of the TAG 12 test was 54%, that of the CA 15-3 test 15% and that of the MCA test 15% in predicting a recurrence of breast cancer. The most important predictor of breast cancer recurrence was TAG 12. In order to evaluate the contributions of different tumour marker serum test, a stepwise discriminant analysis was carried out. The discriminant function (DF) is DF = TAG 12 x 0.061 - CA 15-3 x 0.1336 - 0.396. The sensitivity of the DF in detecting recurrence of breast cancer was 63% with a specificity of 90% and an efficiency of 75%. In conclusion, the results indicate that a new tumour marker TAG 12 is superior to CA 15-3 and MCA in predicting breast cancer recurrence. In this study the discriminant function including TAG 12 and CA 15-3 was superior to single preoperative tumour marker tests. The results speak for the use of a decision support system to aid in predicting a recurrence of breast cancer.


An oligomer complementary to the 5' end region of MDR1 gene decreases resistance to doxorubicin of human adenocarcinoma-resistant cells. Acquired resistance to doxorubicin and other anti-cancer drugs is generally dependent on gene amplification of a specific nucleotide sequence, the MDR1 gene. Verapamil, cyclosporin and other drugs have been used to circumvent the resistance in experimental models in vitro and/or in vivo. We have attempted to reverse the MDR phenotype by treating human adenocarcinoma resistant cells with 20 mers of synthetic unmodified oligodeoxynucleotide MDR1 antisenses. Five ODNs towards different mRNA regions and three different schedules of ODN antisense administration were tested. We found that FCS concentration greatly influenced the stability of ODN, whereas heat-inactivated FCS had no effect. The kinetics of ODN cellular uptake suggest the presence of a saturable receptor. Among the five antisense ODNs used, the most efficient was the oligomer (ODN-1) complementary to 20 bases upstream of the AUG initiation codon. No effect was observed with antisense complementary to the nucleotide binding sites. Administration of ODN-1 every 12 hr for 72 hr partially reversed the MDR phenotype. Approximately 60% of the cells lost their resistance to doxorubicin and did not form colonies in the presence of the drug. The MDR1 mRNA was transiently down-regulated so that the level of gp170 was slightly reduced. The incomplete switch off of MDR1 gene expression may be ascribed to the large abundance and great stability of MDR1 messenger RNA. Moreover, the inactivity of the two ODNs complementary to the NBS protein domains suggests that translation inhibition is ineffective. It is likely that ODN-4 and ODN-5 complement a large number of mRNAs competing for duplex formation, because these sequences are highly conserved among many proteins.


A novel triple label method validates the double label technique of defining cell cycle kinetics in HL-60 cells. HL-60 cells were sequentially labeled with the thymidine analogues iododeoxyuridine (IUdR) and bromodeoxyuridine (BrdU). The labeling index (LI), the duration of S-phase (Ts) and the total cell cycle time (Tc) were measured immediately. It was therefore possible to predict the next time when the single versus double labeled cells would re-enter the S-phase. In our study, the Tc was calculated to be 20 hours. The third label, tritiated thymidine (3HTdR), was introduced at the predicted time of 20 hours to confirm the validity of the previously calculated Tc. The actual percentage of cells which were labeled by (3HTdR) was very similar to the predicted value. We conclude, therefore, that the calculated cell cycle time correlated well with the actual cell cycle time, at least in a controlled in vitro culture system. This novel triple label method validates our double-label technique developed for cell cycle measurements.


Polyamine deprivation enhances antitumoral efficacy of chemotherapy. We reported previously that polyamine deprivation by feeding a polyamine deficient diet combined with gastrointestinal tract decontamination and polyamine oxidase inhibition considerably enhanced the antitumoral effect of DFMO, a selective inhibitor of ornithine decarboxylase. The combination of polyamine deprivation and administration of well established cytotoxic drugs was expected to improve further the antitumoral effect of polyamine deprivation in Lewis lung carcinoma grafted in mice. Simultaneous treatment, i.e. administration of the cytotoxic drugs during the polyamine deprivation regimen, reduced tumor growth, but enhanced toxic effects. By alternating treatment and polyamine deprivation (1st day methotrexate (1.7 mg/kg), 2nd day cyclophosphamide (90 mg/kg), 3rd day vindesine (0.25 mg/kg), followed by five days of polyamine deprivation), tumor growth was reduced by 90% and an increase of 64% in the survival time of the animals was observed, demonstrating that a significant enhancement of the efficacy of chemotherapy was achieved without concomitant enhancement of toxic effects.


A comparison of biochemical and immunohistochemical assessment of EGFR expression in ovarian cancer. The presence of epidermal growth factor receptor (EGFR) was determined both by immunohistochemistry and ligand binding assay in 118 samples from 96 cases of ovarian cancer. EGFR was present in 47.5% of tumours biochemically and in 39.8% of tumours analysed immunohistochemically. The concordance rate for the techniques varied between 40% in endometrioid carcinomas to 85.7% in undifferentiated carcinomas with an overall concordance of 69.5% (p < 0.001). There was no significant difference between the presence of the high, low or high plus low affinity receptor components and tumour immunoreactivity. Although the ligand binding assay is more sensitive than immunohistochemistry for detecting the epidermal growth factor receptor, some cases are positive only on immunohistochemical screening. We would recommend that both techniques should be performed in prospective studies in order to elucidate the role of EGFR expression in ovarian cancer.


Agrimoniin, an antitumor tannin of Agrimonia pilosa Ledeb., induces interleukin-1. The induction of interleukin-1 (IL-1) by agrimoniin, a tannin of Agrimonia pilosa Ledeb., in human peripheral blood mononuclear cells (PBMC) in vitro and in mouse adherent peritoneal exudate cells (PEC) in vivo was studied. A significant amount of IL-1 beta in the culture supernatant of the human PBMC stimulated with agrimoniin was detected with an enzyme-linked immunoadherent assay. Agrimoniin induced IL-1 beta secretion dose- and time-dependently. The adherent PEC from mice intraperitoneally injected with agrimoniin (10 mg/kg) also secreted IL-1 4 days later. These results suggest that agrimoniin, a plant tannin, is a novel cytokine inducer.


Opposite effects of dehydroepiandrosterone on the growth of 7,12-dimethylbenz(a)anthracene-induced rat mammary carcinomas. The effect of dehydroepiandrosterone (DHEA) (2 mg, twice daily p.o.) on the growth of the dimethylbenz (a) anthracene (DMBA)-induced mammary carcinoma was studied in intact and ovariectomized adult female rats. DHEA treatment stimulated the tumor growth in ovariectomized animals. Conversely, the tumors of intact rats treated with DHEA progressed to a lesser extent than those of intact untreated animals (p < 0.01). Plasma levels of DHEA were higher in DHEA-fed than in untreated animals (p < .01), whereas E2 concentrations were unchanged after DHEA administration. Estrogen receptor (ER) concentrations in tumor tissue of ovariectomized animals given DHEA were no different form those found in intact rats, whereas ER were undetectable in untreated ovariectomized rats. The data indicate that DHEA stimulates the growth of DMBA-induced mammary tumors in ovariectomized rats, while it reduces the tumor progression in intact animals.


Effects of high and low single dose irradiation on glioma spheroid invasion into normal rat brain tissue in vitro. The effects of radiation on direction on directional migration in monolayer cultures and brain tissue invasion by two glioblastoma cell lines (D-54 MG, D-247 MG) were investigated. The Leksell Gamma Unit was the radiation source and invasion was registered in an in vitro invasion assay developed in our laboratory. As tumor spheroids and brain tissue aggregates were treated simultaneously in cocultures; the effects of radiation on the interaction between the two tissues could be investigated. Tumor spheroids from both cell lines retained their ability to invade and destroy normal brain tissue, even after irradiation with 47.6 Gy. However, while the D-54 MG tumor spheroids showed a dose-dependent reduction of invasion, tumor spheroids from the D-247 MG cell line did not. In addition, radiation produced a dose dependent inhibition of directional migration of cells from D-54 MG spheroids. A similar significant inhibition of directional migration was found in D-247 MG, but it was not dose-dependent. Transmission electron microscopy revealed a loosening of the neuropil in the brain tissue of irradiated cocultures. However, this structural change did not seem to affect the invasiveness of the tumor. In this preliminary study, irradiation could not prevent invasion of two different glioblastoma cell lines into fetal rat brain tissue. Further studies using the same technique may help to understand the influence of ionizing radiation upon the invasion process in gliomas.


Cytogenetic and corresponding flow cytometric DNA analysis of renal cell neoplasms. Results of flow cytometric DNA content and cytogenetic analyses of six neoplasms representing the spectrum of the morphologic subtypes of renal cell neoplasms are compared. Flow cytometric determinations of DNA diploidy and near diploidy in two renal cortical neoplasms correlated with modal chromosome numbers; however, in three of four neoplasms with a highly aneuploid DNA content, the modal chromosome numbers indicated diploidy or near-diploidy. Our data suggest that the short-term culture conditions used in cytogenetic analysis may favor growth of cells with diploid or near-diploid DNA content. This may explain the discrepancy frequently observed between results obtained using flow cytometry and karyotyping after short-term culture. We also observed (1) abnormalities in the short arm of chromosome 3 in all three nonpapillary neoplasms, (both clear and granular cell types); (2) aberrations in chromosomes 3 and 17 in the two papillary tumors; and (3) normal chromosome 3 in the presence of various random karyotypic anomalies including telomeric associations and a pseudo-diploid modal chromosome number in the only oncocytic neoplasm studied.


Clinical, histological and quantitative prognostic factors in cutaneous malignant melanoma. A retrospective study including 55 cutaneous melanoma patients with 9.5 years follow-up was carried out to assess the significance of various prognostic factors. The histological samples were evaluated according to Clark's and Breslow's classifications and six nuclear features were measured by interactive morphometry. Mitotic activity was assessed by two different methods: mitotic activity index (MAI) and volume corrected mitotic index (M/V index). The overall disease-related five-year survival of patients was 76.4%. TNM stage (p = 0.0001), sex (p = 0.0024), M/V index (p = 0.003), standard deviation of nuclear form factor (p = 0.023), MAI (p = 0.02), shortest nuclear axis (p = 0.023) and Breslow's classification (p = 0.044) predicted survival in univariate analysis. A multivariate analysis including clinical, histological and morphometric features pointed the Clark's classification as the most important predictor of survival (p = 0.002), while the other variables included had no independent prognostic value. The prognostic importance of mitotic indices and morphometric features is clearly a subject for further studies in superficial melanomas.


Immunomodulating effects of the hydrolysis products of formosanin C and beta-ecdysone from Paris formosana Hayata. Formosanin C (PF-3, I), a diosgenin glycoside with four sugars isolated from Paris formosana Hayata as main constituent, significantly showed immunomodulating effects on the proliferative response of mouse lymphocytes to concanavalin A (Con A). The partialy hydrolysis products of formosanin C, dioscin (II) and prosapogenin A of dioscin (III), also increased 3H-thymidine incorporation of Con A-stimulated lymphocytes maximally at 0.01 micrograms/ml, whereas formosanin C did so at 0.0001 micrograms/ml. However, trillin (IV) and diosgenin (V) obtained from the partial hydrolysis of formosanin C had no effects on these immune responses. Evidently, the immunomodulating activities increased in the order of increasing polarity. Probably the solubility in water was a factor. This demonstrated that the sugar moiety in the structure of formosanin C (I) displays a very important pattern for the effect on the proliferative response of mouse lymphocytes to Con A. On the other hand, these hydrolysis products at higher concentrations of 1 and 10 micrograms/ml reduced the cytotoxic effects on spleen cells as compared with formosanin C. The other constituent, beta-ecdysone (VI) isolated from the stems of Paris formosana Hayata also increased 3H-thymidine incorporation of Con A-stimulated splenocytes. At the concentration of 0.001 micrograms/ml, the stimulation index of beta-ecdysone (2) is higher than that of formosanin C (1.65), and at the concentration of 100 micrograms/ml, beta-ecdysone had no cytotoxicity for normal spleen cells whereas formosanin C at the lower concentration of 10 micrograms/ml showed cytotoxicity. Based on this study, beta-ecdysone (VI) is therefore a better immunomodulator than formosanin C.


Effects of dietary fatty acid composition on tumor growth and metastasis. Unsaturated fatty acids of the n-6 and n-3 class have been shown to affect tumor growth and metastasis. The very long chain polyunsaturated fatty acids of the n-3 family, e.g. eicosapentaenoic acids (C20:5n-3) and docosahexaenoic acids (C22:5n-3), have an inhibiting effect on tumor growth. Metastasis is promoted by n-6 polyunsaturated fatty acids, e.g. linoleic acid (C18:2n-6) and gamma-linolenic acid (C18:3n-6). The mechanisms of promotion and inhibition are described in the present review. The mechanisms of lipid peroxidation, which appears to be an important factor in the inhibition of tumor growth, are discussed. Lipid peroxidation is induced by polyunsaturated fatty acids involving autoperoxidation a.o. and the enzymes cytochrome P450, cyclooxygenase and lipoxygenase. In tumor cells these enzymes are decreased in activity but at present the reason for this reduction is not known. Lipid peroxidation products such as hydroxyeicosatetraenoic acids (HETES), hydroperoxy eicosatetraenoic acids (HPETES) and malondialdehyde may have a regulating effect on DNA duplication enzymes (e.g. polymerases). Prostaglandin synthesis in tumor cells and macrophages is also affected by polyunsaturated fatty acids. The fish oil fatty acids are known to reduce prostaglandin synthesis by competing with arachidonic acid for the enzyme cyclooxygenase. However, fish oil fatty acids have an antagonistic effect on cyclooxygenase. Polyunsaturated fatty acids also have an effect on the immune system and particularly on macrophages. Macrophages, but also T-cells and B-cells, are inhibited by prostaglandins such as PGE2, while immunosuppressor cells are stimulated by PGE2.


Thermal effects on DNA synthesis in bone marrow cells of patients with acute myeloblastic leukemia. It has been known that thymidylate synthetase (TS) and thymidine kinase (TK) are DNA-synthesizing enzymes via the de novo and salvage pathways, respectively, in pyrimidine metabolism, and an immunological method using a monoclonal antibody to bromodeoxyuridine (BrdU) is useful for the detection of S-phase cells. We investigated the effects of hyperthermia on DNA synthesis in bone marrow cells obtained from patients with acute myeloblastic leukemia. TK isozymes in bone marrow cells of patients with acute myeloblastic leukemia were separated into two types, i.e., fetal type isozyme in cytosolic cell fraction and adult type isozyme in mitochondrial cell fraction. Heating at over 43 degrees C as a hyperthermia markedly suppressed enzyme activity of fetal type TK isozyme and number of S-phase cells labelled with BrdU, but not activities of adult type TK isozyme and TS. These results indicate that hyperthermia may regulate the proliferation of S-phase cells by the suppression of salvage synthesis of DNA.


Southern travelling habits with special reference to tumour site in Swedish melanoma patients. Southern travelling habits were recorded for 127 melanoma patients from southern parts of Sweden (the 56th latitude), 55 thyroid cancer patients, 100 non-Hodgkin's patients and 794 healthy controls from the same region. Melanoma patients were found to travel significantly more often south of the 45th latitude, as compared with patients with non-Hodgkin's lymphoma or thyroid carcinoma (RR = 2.2 for a difference of + 10 trips), and with the healthy controls (RR = 1.4 for a difference of + 10 trips). Considering men and women separately, the difference was significant only for men. Patients with melanoma had a higher educational level than the tumour controls and the healthy controls (p < 0.001 and p < 0.001 respectively). There was a significant correlation between high travelling frequency and high education. An increased risk related to southern travelling was present for patients with melanoma on the extremities and head and neck, as well as for patients with truncal melanoma. These findings support the concept that acute exposure to sunburn may be a risk factor for malignant melanoma.


Growth effects of tamoxifen on Lovo colon carcinoma cells and cultured cells from normal colonic mucosa. The growth effects of tamoxifen (TAM) were studied using normal and malignant colonic epithelial cells. Addition of TAM (0.8 to 10 microM) to cultured normal human colon epithelial cells and Lovo colon adenocarcinoma cells produced a dose response decrease in growth of 42 to 76%. Histamine (1 to 10 microM) did not affect cell growth and did not negate the TAM effect. Calmodulin (2 micrograms/ml) totally blocked growth inhibitory effects of a calmodulin antagonist, trifluoperazine (10 microM), but did not block the TAM inhibitory effect. These data suggest that antiestrogen binding sites (AEBS) may play an important role in the growth-inhibitory effects of TAM on colon cells. Competition with estrogen and antagonism with histamine or calmodulin do not appear to be significant in this regard.


Prognostic factors in node positive primary breast cancer patients treated with adjuvant CMF. The influence of various patient and disease-related parameters on survival (S) and disease-free survival (DFS) in 217 node positive primary breast cancer patients treated with surgery followed by adjuvant i.v. cyclophosphamide, methotrexate, and 5-fluorouracil (CMF) was evaluated by univariate and multivariate analyses. Five year actuarial S and DFS were 73.3% and 54.8%, respectively. Univariate analysis revealed that patient age, number of involved axillary nodes and ER status had a significant impact on both S and DFS. PgR positive tumors had improved DFS but no S difference was observed. Menopausal status predicted S but not DFS. Primary tumor size and CMF-induced amenorrhea did not predict disease outcome. Multivariate analysis demonstrated that only degree of nodal involvement and PgR status had independent significant impact on prognosis. Both S and DFS are significantly influenced by the number of involved nodes, whereas improved DFS but not S was evident in patients with PgR positive tumors.


Histological and quantitative prognostic factors in transitional cell bladder cancer treated by cystectomy. A cohort of 103 transitional cell bladder tumours (TCC) treated by cystectomy was followed up over 9 years. Patients treated with radiation and cystectomy had a more unfavorable prognosis than patients treated by cystectomy alone (p < 0.0001). Old patients had an unfavorable prognosis after cystectomy, whereas none of the patients under the age of 50 died of TCC after cystectomy (p = 0.027). WHO grade (p = 0.002), high mitotic rate (p = 0.012) and nodular growth pattern (p = 0.004) were signs of ominous disease outcome in univariate survival analysis. Dense inflammatory cell infiltrates in the tumour itself or around invasive tumour cells were signs of good prognosis after cystectomy (p = 0.001) in a multivariate analysis. Clinical stage or nuclear morphometric factors had no independent prognostic value after cystectomy. The results clearly show that the intrinsic malignancy of TCC and host defence mechanisms together determine the prognosis after cystectomy. The evaluation of malignant features in TCC alone is an insufficient means of predicting prognosis in invasive TCC and the analysis of host immune response should be included in the prognostic evaluation.


Proliferative effect of dexamethasone on a human glioblastoma cell line (HU 197) is mediated by glucocorticoid receptors. The relationship between Dexamethasone proliferative activity and the presence of glucocorticoid receptors was studied on a human glioblastoma cell line (HU 197). For this purpose, the 17 beta-Carboxamide steroid DXB, a glucocorticoid antagonist that competes with Dexamethasone for binding to the intracellular glucocorticoid receptor but does not trigger the glucocorticoid effect, was used. Concurrent treatments with Dexamethasone and DXB caused an inhibition of the proliferative effect obtained by Dexamethasone. The results obtained demonstrated that the Dexamethasone activity on cell proliferation is a specific receptor-mediated effect.


Modulation by l-leucovorin of 1-hexylcarbamoyl-5-fluorouracil antitumor activity on human gastric and colon carcinomas serially transplanted into nude mice. Experimental biochemical modulation of 1-hexylcarbamoyl-5-fluorouracil (HCFU) with l-leucovorin (LV) was carried out using human gastric (H-111) and colon (Co-4) carcinoma xenografts serially transplanted into nude mice. Thirty-five or 70 mg/kg HCFU dissolved in 0.2 ml of 1% hydroxymethyl cellulose was administered po daily for 3 weeks except Sundays, and 50, 100, 200 or 300 mg/kg LV dissolved in 0.2 ml physiological saline was administered po 30 min before administration of HCFU. The biochemically modulated antitumor activity was evaluated in terms of actual tumor weight, the relative mean tumor weight and the degree of inhibition of thymidylate synthetase (TS) in the tumors at the end of the experiments, assayed according to the method of Spears et al. Although 35 mg/kg HCFU was ineffective against gastric carcinoma H-111, combination with 200 or 300 mg/kg LV resulted in a positive antitumor effect of HCFU on this strain without any increase of side effects in terms of body weight loss and mouse mortality. The colon carcinoma strain Co-4 showed marginal sensitivity to HCFU (35 mg/kg) alone, but 50 or 100 mg/kg LV modulated the antitumor activity of HCFU on Co-4 to produce a significant positive effect without any increase in toxicity, and HCFU administered with 100 mg/kg LV was more effective than the maximum tolerated dose of HCFU (70 mg/kg) alone. The TS inhibition rate was closely related to the biochemical modulation of HCFU antitumor activity by LV, suggesting that the modulation involves an increase of the ternary complex of TS, 5,10-methylene tetrahydrofolate from LV and 5-fluorodeoxyuridine 5'-monophosphate (FdUMP). Combination of HCFU and LV is therefore thought to be useful in increasing the antitumor activity of HCFU on gastrointestinal carcinomas without enhancing its toxicity.


DNA ploidy, S-phase fraction and mitotic indices as prognostic predictors of female breast cancer. DNA ploidy, S-phase fraction (SPF), mitotic index (MI), volume corrected mitotic index (M/V index) and standard prognostic factors were related to disease outcome in a series of 363 women with breast cancer followed-up for over 10 years in our clinic. DNA ploidy and SPF were significantly related to histological type, tumour grade and mitotic indices (p < 0.001). In univariate survival analysis, pN status (p < 0.0001), tumour diameter (p < 0.0001), MI (p = 0.001), M/V index (p = 0.0003) and SPF (p = 0.015) predicted survival. In pN(-) tumours. MI (p = 0.059) was related to survival. In pN(+) tumours, tumour diameter (p = 0.0004), M/V index (p = 0.023) and SPF (p = 0.045) predicted survival. In multivariate survival analysis, tumour diameter (p < 0.001). M/V index (p < 0.007), pN status (p = 0.014) and patient age (p = 0.09) were independently related to survival. In pN(-) tumours, tumour diameter independently predicted survival (p = 0.033). In pN(+) tumours, tumour diameter (p < 0.001), M/V index (p = 0.006) and the year of treatment (p = 0.08) were independent predictors. The results show that tumour diameter, pN status and proliferative activity of cancer cells are important prognostic factors in breast cancer. Of the proliferation indices, M/V index and SPF are equally powerful predictors, and the use of M/V index is advocated due to simplicity of the assessment.


Effect of calcium-modifying agents on the growth of human gastric carcinoma cells in vitro. The antiproliferative effects of various calcium-modifying agents were investigated in human AGS gastric carcinoma cells in culture. Variation of the extracellular calcium concentration, achieved by addition of calcium to the growth medium or binding of calcium to the calcium-chelating agent EDTA, appeared to have little influence on growth of the tumor cells. In contrast, the calcium antagonist verapamil, the calcium ionophore A 23.187 and the calmodulin antagonist W 7, agents supposed to interfere with the regulation of the intracellular calcium concentration, all exerted marked growth inhibiting effects. Our results provide evidence for an important role of intracellular calcium-dependent mechanisms in growth regulation of the human gastric adenocarcinoma cell line AGS.


Cytotoxic action of cyclosporins on human tumor cell lines is not dependent on immunosuppressive activity. The cytotoxic activity of cyclosporin A (CsA) and the three non-immuno-suppressive CsA analogues B3-243, WO-039 and B3-665 were studied in tumor cell lines representing both classical and atypical forms of multidrug resistance (MDR): T-ALL GM3639 L100 cells selected for vincristine (vcr) resistance and displaying characteristics of classical MDR, including P-glycoprotein (pgp) expression and increased drug efflux which can be inhibited by pgp blockers (e.g. verapamil), and U-1285/ADR, a small cell lung cancer (SCLC) cell line selected for doxorubicin resistance which lacks pgp, is insensitive to pgp-blockers and shows cross resistance to cis-platinum. At 1 micrograms/ml CsA was the most active agent in reversing Vcr resistance in L100 cells followed by B3-243 and WO-039, with no effect of B3-665. Parental LO cells were only marginally sensitized to Vcr by these agents. No reversing effect of any cyclosporin was observed in the U-1285/ADR or its parental cell line. Compared to LO cells, L100 cells showed a marked hypersensitivity to CsA > B3-243 > WO-039 with B3-665 being inactive. No collateral sensitivity was observed for cyclosporins in U-1285/ADR cells. Although of different magnitude, the pattern of cytotoxic activity for the different cyclosporins alone closely parallelled that of L100 cells for U-1285, U1285/ADR and LO cells. The results indicate that not only the collateral sensitivity in classical MDR but also the cytotoxic actions of cyclosporins per se on tumor cells alone are independent of immunosuppressive activity. The results also suggest a structure-activity relationship for cyclosporin-induced cytotoxicity similar to, but independent of, MDR reversing activity.


Synergistic cytotoxic effects of tumor necrosis factor, interferon-gamma and tamoxifen on breast cancer cell lines. The combined effects of recombinant human tumor necrosis factor (TNF), interferon-gamma (IFN) and tamoxifen (TAM) on the proliferation of human breast cancer cell lines were investigated. In estrogen receptor positive MCF-7 cells, relatively resistant to TAM or TNF, cytotoxicity significantly increased in combinations of TNF and IFN, and of a cytokine and TAM. The cytotoxicity of TNF increased when cells were pretreated with IFN, but not vice versa. Sequential treatment with IFN following TNF and TAM also exhibited significant antiproliferative effect on both cell lines. The combined or sequential cytokines and TAM treatments are possible modalities to overcome breast cancers unresponsive to endocrine treatment.


Relation between the hormonal and epidemiological aspects of ovarian cancer patients in Japan. We compared the hormonal and epidemiological aspects of ovarian cancer patients in search of the etiology of this neoplasia. Case-control studies of Japanese women with and without cancer were conducted in parallel, with regard to both the excretion of 14 urinary steroids and the pertinent physical and physiological parameters. The results obtained are as follows: 1) premenopausal ovarian cancer patients before and after radical ovariectomy and postmenopausal-postoperative patients were associated with a specified steroid deviation profile characterized by a combination of general depression of androgens, progestins and corticosteroids with sole rescue of tetrahydrocortisol (THF) in urine. 2) The deviation profile of postmenopausal-preoperative cancer patients was distinguished from the 3 partner profiles by its preservation of normalcy in the excretions of androgen and progestin in urine. 3) Ovarian cancer patients were associated with growth retardation, when compared with urban healthy controls and patients with either breast cancer or endometrial cancer by the age-matching method. Ovarian cancer patients were also less fertile than age-matched normal controls, and were as infertile as age-matched patients with either breast cancer or endometrial cancer. 4) Epidemiological evidence was presented to suggest that the incidence of ovarian cancer in Japan was increasing in parallel with the recent increase of social tension in Japan. The possible relevance of the hormonal characteristics of ovarian cancer patients to both the epidemiological characteristics of the same cancer patients and the genesis of this neoplasia is discussed in the light of the 2-step carcinogenesis theory.


Modulation of DNA damage by vitamin A in developing Sprague-Dawley rats. Prenatal and neonatal Sprague-Dawley rats were given a diet deficient in or with an excess of Vitamin A and at the age of 55 days female progeny were treated with a single i.g. dose of 80 mg/kg DMBA or 50 mg/kg MNU. Under these experimental conditions it was found that the exposure of perinatal rats to a diet containing an excess of Vitamin A caused a decrease in the amount of DMBA- and MNU-induced DNA damage in the mammary gland and the liver of the female offspring. When diets were deficient in Vitamin A there was a dual effect in terms of DNA damage detected in the same organs, namely DMBA caused an amount of DNA damage comparable to controls, while the extent of DNA damage induced by MNU greatly increased in both organs. These results indicate that Vitamin A can permanently change the sensitivity of adult progeny to chemically induced DNA damage when it is given to pregnant and lactating females.


Does surgical stress cause tumor metastasis? The purpose of this study was to test the validity of our working hypothesis that the stress of radical surgery may affect the prognosis of a cancer patient by precipitating hematogenous tumor metastasis, and that enhancement of this type of tumor metastasis is mediated by an increase of glucocorticoid activity that is induced in a cancer patient by surgical stress. Practically, we looked for the presence of glucocorticosteroid excess in cervical cancer patients in the course of radical surgery, and also tested the possible impact of glucocorticoid excess on the development of tumor metastasis in mice with i.v. inoculated Ehrlich ascites clone 1 tumor cells. The results obtained indicated that: 1) a state of glucocorticoid excess was observed in cancer patients at an early stage of postoperative convalescence. 2) Development of lung metastasis of blood-borne Ehrlich ascites tumor cells was facilitated in mice by hydrocortisone pretreatment--a substitute for surgical stress conditioning. 3) In the enhancement of lung metastasis, the hormone was found to induce constriction of the lung capillary lumen on the one hand, and acceleration of microvillus growth of the tumor cell surface on the other hand two morphological changes that may facilitate intrapulmonary retention of tumor cells. 4) Cyclophosphamide, as tested in a series of adjuvant chemotherapy experiments, was effective in either retarding or arresting the progress of tumor metastasis in hydrocortisone-conditioned mice. The possible impact of surgical stress on the spread of blood-borne tumor cells to the lung and liver, as well as on the therapeutic effect of cyclophosphamide for the prevention of postoperative micrometastasis, is discussed in the light of glucocorticoid actions on its target tissues.


Cytostatic effect of homo-aza-steroidal esters in vivo and in vitro. Structure-activity relationships. The p-[N,N-bis (2-chloroethyl)amino]phenylacetate esters of 3 beta-hydroxy-N-methyl-17 alpha-aza-D-homo-5 alpha-androstan-17-one and 3 beta-hydroxy-17 alpha-aza-D-homo-5 alpha-androstane have been prepared and their antitumor activity evaluated against L1210 leukemia, P388 leukemia, Ehrlich ascites tumor (EAT) and Lewis Lung Carcinoma (LLC). The results are compared with those of the p-[N,N-bis (2-chloroethyl)amino]phenylacetate of 3 beta-hydroxy-17 alpha-aza-D-homo- 5 alpha-androstan-17-one. The above compounds were also tested in vitro against L1210, P 388, EAT and BHX cell cultures. All compounds were found to be active and their structure-activity relationship is discussed.


Nucleolar organiser regions (AgNORs) related to histopathological characteristics and survival in prostatic adenocarcinoma. The number of silver stained nucleolar organiser regions (AgNORs) was assessed in biopsy specimens of 78 patients with prostatic adenocarcinoma followed up for a mean of 15.6 years. The number of Ag-NORs was related to histological features, clinical stage, DNA ploidy, S-phase fraction (SPF) and clinical outcome. In 31/36 (86%) of grade I tumours on average less than 3.5 AgNORs/nucleus were present, whereas of grade III tumours 8/18 (44%) showed usually more than 3.5 Ag-NORs/nucleus (p = 0.0163). The number of Ag-NORs was significantly related to mean nuclear area (NA) (p = 0.017) and to SD of nuclear area (p = 0.05). The Ag-NORs were not related significantly to clinical stage, perineural infiltration, lymphatic infiltration, DNA ploidy, SPF, G2 fraction or M/V index, although there was a clear trend between the variables. In survival analysis, the degree of lymphatic infiltration (LI) (P = 0.009) predicted survival, whereas AgNORs had no significant prognostic value albeit a trend was observed. In T1-T2 tumours, histological grade (p = 0.05), PNI (p = 0.04) and SPF (p = 0.0076) predicted survival.


Flow cytometric DNA characteristics of radiation colitis--a preliminary study. The DNA status of 12 rectal biopsies, taken during the investigation of radiation proctitis, was investigated. Of these six were in the acute phase and six in the chronic phase. All of the acute biopsies had diploid DNA, despite bizarre histological epithelial cell appearances. Two of the chronic phase biopsies were to have aneuploid DNA profiles. This finding may be relevant to the increased risk of malignancy in irradiated tissues.


Non-toxic sensitization of cancer chemotherapy by combined vitamin C and K3 pretreatment in a mouse tumor resistant to oncovin. The effects of combined vitamin C and K3 i.p. injected 3 hours before i.p. administration of single dose of oncovin, to which the ascites liver tumor in mouse (T.L.T.) was completely resistant, were investigated. This pretreatment sensitized the tumor resistant to oncovin, whereas a separate pretreatment with vitamin C or K3 alone was without any effect. This tumor sensitization to the chemotherapy was completely suppressed by catalase pretreatment, thus indicating that hydrogen peroxide generation with subsequent oxidative stress and its consequences may be involved here. Since this sensitization was without any increased general and organ toxicity, its possible introduction into classical protocols of human cancer treatment would be without any supplementary risk.


Inhibition of tumor induction in tobacco by Agrobacterium tumefaciens and nodulation induced by Rhizobium meliloti in the presence of phenothiazines and structurally related compounds. Plasmids of Agrobacterium tumefaciens and Rhizobium meliloti carrying Kanamycin resistance genes were eliminated from 1.4 to 0.2% of the growing bacterial cultures by promethazine and imipramine. As a result of plasmid elimination, the A. tumefaciens plasmidless isolate was not able to induce crown gall tumor on tobacco plants. The plasmidless R. meliloti strain failed to induce nodule formation on alfalfa plants. The efficiency of nodulation was decreased when the bacteria were grown in the presence of the drugs. The antiplasmid effects of the drugs were not prevented by opines, (nopaline and octopine) in Escherichia coli F'lac cells.


The relationship between cellular ether glycerophospholipid content and sensitivity of cancer cells to 1-O-octadecyl-2-O-methyl-glycerophosphocholine. Cancer cells are more susceptible to the growth-inhibitory effects of alkyl lysophospholipids than normal cells, but the mechanism of this selectivity is unknown. In this study we have investigated the hypothesis that the sensitivity of cells to alkyl lysophospholipids is related to the cellular ether lipid content. The order of decreasing sensitivity of the cells to the growth-inhibitory effect of 1-O-octadecyl-2-O-methyl-glycerophosphocholine (ET-18-OCH3) was MCF 7 > T84 > Malme 3M > A427 > A549, while the order of decreasing ether phospholipid content as a proportion of the total phospholipid was T84 > A427 = A549 = Malme 3M > MCF7. There was also no correlation between ET-18-OCH3-sensitivity and the proportion of ether lipid in the cholineglycerophospholipid or ethanolamineglycerophospholipid classes. Our results clearly indicate that the postulated relationship between ether phospholipid content and ET-18-OCH3-susceptibility may have very limited applicability and is unlikely to be the underlying reason for the selective effects of alkyl lysophospholipids.


[Prenatal screening in utero of urinary abnormalities. Management]. The major benefit of antenatal ultrasonography is to allow early diagnosis of urinary tract malformations before postnatal infection worsens the prognosis. In the majority of cases, there is a unilateral and moderate dilatation requiring a check-up only during the second week of life; treatment subsequently depends on the etiology of the uropathy and the consequences on the kidney. Unilateral severe dilatations and bilateral, but moderate, dilatations must be managed immediately after birth in a pediatric surgical center. In the rare cases of severe bilateral obstructive uropathy, in utero decompression by catheterisation or surgery is now considered to be uselessly invasive, considering that renal dysplasia is already present when the malformation is detected.


[Ureteroceles].

[Ureteroceles]. Four types of ureteroceles are described: A) ureterocele with single ureter (10%); B) ureterocele with total duplication and intra-vesical development (10%); C) ureterocele with total duplication and extra-vesical development (62%); D) ureterocele with ectopic ureter (3%). Most ureteroceles are now detected by antenatal ultrasonography, allowing early management. The treatment of types A and B is simple depending on the status of the above kidney and ureter: abstention, meatomy, ureterocelectomy with ureteral reimplantation, nephrectomy. In type C, the upper kidney is always destroyed. Two treatments are proposed: upper pole nephrectomy with ureterocelectomy which is a difficult but safe procedure, upper pole nephrectomy with aspiration of the ureterocele which is called the "simplified technique" but requires reoperation in 40% cases. The complicated forms may require either meatotomy for decompression, or diversion by percutaneous nephrostomy. Strangulation of the ureterocele constitutes an emergency.


Age-related decrease in transplantability of human tumours in nu/nu mice. Experiments were designed to assess age-related changes in the transplantability of human tumours xenografted in congenitally athymic (nu/nu) mice. It has been found that the number of progressively growing human tumour xenografts decreased significantly with increasing age of BALB/c nu/nu recipients. These findings, taken together with a previously recognized increase in the frequency of endogenous interleukin 2 (IL-2)-producing cells with age of nu/nu mice, prompted us to investigate whether administration of exogenous IL-2 to young adult nu/nu mice could change the transplantability of human tumours in the mice. Peritumoral administration of exogenous interleukin 2 to 8-week-old nu/nu mice inhibited the growth of the human tumour xenografts. In vitro activation of nu/nu splenocytes with exogenous Il-2 resulted in the generation of killer cells which have been found to be cytolytic when allowed to react with human tumour targets in 51Cr cytotoxicity assay. In addition, it has been found that the percentage of IL-2-activated Thy 1.2+ and ASGM1+ cells substantially increased with increasing age of nu/nu spleen cell donors. These findings are compatible with the hypothesis that the observed age-related decrease in takes of human tumour xenografts might be determined by the increasing level of IL-2 production and subsequent maturation of IL-2-dependent effector cells.


[Enuresis].

[Enuresis]. The word "enuresis" is the greek word for incontinence. Enuresis has to be considered as a symptom and not as a disease. We have to keep in mind that urine leaking may be due to an anatomical anomaly (epispadias, ectopic ureter, spinal coral lesion, urethral obstacle) in which case treatment of the underlying disease constitutes treatment of enuresis. Nevertheless, enuresis is isolated in 95% of cases. Three groups are defined depending on whether the bladder is normal, hyperactive or retentionnist with bladder-sphincter dyssynergia. We emphasize the frequency of coexistence of these three aspects and the gravity of a wrong diagnosis. The onset or presence of bladder-sphincter dyssynergia is a major concern for the pediatric urologist due to its severity and the difficulties of treatment.


Relation between the hormonal and epidemiological aspects of esophageal cancer in Japan. Esophageal cancer with endemic distribution of high-risk areas in the world is also known to be more prevalent in the male--and in the aged-populations than in their counterparts. The hormonal characteristics of esophageal cancer patients and the geographical distribution of high and low-risk areas in Japan were comparatively investigated in search of the etiology of this neoplasia. A case-control study of 14 urinary steroids indicated that cancer patients of both sexes were associated with an acceleration of cortisone to hydrocortisone conversion within their bodies. Evidence was presented to suggest that the above state of glucocorticoid excess could be related to the production of hyperplasia as well as malignant transformation in the epithelial cells of the esophagus. The 10 highest risk areas and the 7 lowest risk areas were clearly separated by the 2 fault lines of the Japan Islands, a finding to suggest that some microelements of the soil play a role in conditioning the cancer risk. The possible linkage of the observed hormonal characteristics of Japanese patients to both the geochemistry of the soil and the genesis of this neoplasia is discussed in the light of the competitive relationship between the intake of vitamin C and endogenous nitrosation.


[Treatment of idiopathic vesico-ureteral reflux in children]. Vesicoureteral reflux is the principal cause of pyelonephritis in children. Medical treatment is designed to prevent the development of renal parenchymal scars, as these lesions are irreversible and frequently interfere with growth of the kidney. Treatment must therefore be specific and sufficiently prolonged. In infants under the age of 2 years, reflux may resolve in 50% of cases as the ureterovesical junction develops. During this period, treatment consisting of alternating antiseptics should be proposed to prevent the development of pyelonephritis. In all other cases, reflux must be corrected. Two techniques can be proposed at the present time: surgery which gives 98% immediate and permanent good results, using Cohen's technique, and injection of Teflon, which is much less reliable, with risks of distant dissemination, particularly to the brain, and the possibility of developing ureteric stenosis and bladder stones. These problems have led many paediatric urologists to abandon endoscopic treatment.


Detection of K-ras mutations by denaturing gradient gel electrophoresis (DGGE): a study on pancreatic cancer. In pancreatic neoplasias mutations in the first exon (codon 12) of K-ras gene occur at high frequency and seem to have a diagnostic significance. We set up the DGGE conditions to search for these mutations in pancreatic tumor sample DNAs. All samples were directly classified by simply comparing their DGGE patterns with those of control cell lines carrying known K-ras base substitutions. We found a mutation frequency of 73% in pancreatic adenocarcinoma, whereas no mutations were observed in benign lesions. The non-isotopic method we used turned out to be rapid and sensitive. DGGE could therefore be utilized for the detection of K-ras mutations in pancreatic lesions, to evaluate their actual or potential malignancy. In general, DGGE could be useful for K-ras gene screening on pathological tissue samples.


The response of breast cancer cells to steroid and peptide growth factors. Four breast cancer cell lines covering a wide range of receptor characteristics were examined for their growth responses to oestradiol, insulin, EGF and the anti-oestrogen, tamoxifen. Stimulated cellular growth using both the MTT assay and 3H-thymidine incorporation into DNA, was measured against controls grown in a steroid reduced environment. The ER positive MCF-7 cell line showed clear growth responses to E2, insulin and EGF. This was also demonstrated, although to a lesser extent in the ZR-75-1 line which expresses lower levels of ER. In combination, these factors gave an additive growth response but the addition of EGF to maximal concentrations of insulin and oestradiol produced no further increase in growth. In contrast to these results, the two ER negative cell lines examined, MCF-7 Adr and MDA-MB-231 showed no growth response to exogenously applied steroids and in the case of MCF-7 Adr high concentrations of EGF were able to inhibit the growth of this cell line. They also showed high rates of growth in a steroid depleted environment which tends to suggest these cells are growing autonomously through autocrine growth factor induction.


[Current treatment of bladder exstrophy]. The treatment of vesical exstrophy has greatly improved over the last twenty years. The most important progresses are: closing the bladder before the 72nd hour of life; iliac osteotomy allowing fusion of the pubis when closing the bladder; lengthening of the penis by liberation of the corpora cavernosa; entero-cystoplasty when the reconstructed bladder is too small. Most surgeons practice the same timing for the different operations. Urinary and genital anomalies can be cured at the same time. In relation to urinary problems, about 80% of cases achieve good continence. An urinary diversion, using "Coffey's" technique, must be performed in the presence of incontinence. Concerning genital problems in boys and girls, reconstructive surgery allows restoration of almost normal genital organs. Intercourse seems to be satisfactory in most cases. There is a high sterility rate in men.


Pharmacology, bio-analysis and pharmacokinetics of the vinca alkaloids and semi-synthetic derivatives (review). Vinca alkaloids have been used as chemotherapeutic agents now for over three decades. Especially during recent years, the development of a considerable number of semi-synthetic derivatives, showing attractive properties in preclinical or clinical investigations, has been reported. In this paper we shall give a critical review of the investigations presented on this matter.


[Cystoplasties in children].

[Cystoplasties in children]. Whenever the reservoir function of the bladder is impaired (neuropathic bladder and exstrophy), an enterocystoplasty constitutes a satisfactory solution in children to enlarge the bladder. The various techniques must take into account the degree of alteration of the bladder. The bowel segment must be detubularized, regardless of its origin. The main challenge is to obtain adequate peripheral resistance with easy voiding and filling of the bladder without urine leak, particularly in boys. In girls, the combination of enterocystoplasty and Gobbel-Stockel procedure ensures perfect continence between two self-catheterisations.


[Renal transplantation in children. Surgical aspects]. The renal transplantation in children has some specificities: urologic anomalies (vesico ureteral reflux, posterior urethral valves) are frequently the cause of the renal failure, and necessitate a thorough surgical preparation before transplantation (nephrectomy, reconstitution of urinary tract). The child must have a sterile, compliant and continent urinary tract on the day of the operation. In small children (< 15 kg), it is often necessary to operate through a transperitoneal incision, especially if the donor is an adult: the anastomoses will then concern the aorta and vena cava. The results are good, even better than in adults, except for very young children (under six years of age). Transplantation with living related donor (LRD) give the best results. Currently, the graft survival is 87% to 90% after three years with LRD, versus 65 to 77% with cadaveric donors.


Analysis of c-myc oncogene in human esophageal carcinoma: immunohistochemistry, in situ hybridization and northern and Southern blot studies. We have examined the c-myc gene expression and the gene organization in resected human esophageal squamous cell carcinomas, and in the adjacent normal esophageal mucosa from 20 patients undergoing radical surgery. Immunohistochemistry of p62c-myc was compared with that of proliferating cell nuclear antigen (PCNA) in order to examine the biologic significance of p62c-myc. Relative c-myc expression detected by Northern blot analysis ranged from 0.41 to 2.8, but the degree of c-myc expression did not correlate with other clinicopathological prognostic parameters. In sity hybridization localized the elevated c-myc mRNA expression to tumor cells and basal and parabasal cells of the adjacent normal mucosa. Immunohistochemistry showed altered localization of p62c-myc, i.e., both cytoplasmic and nuclear immunostaining in advanced carcinomas. c-myc immunoreactivity exhibited wider distribution compared with that of PCNA, a cell cycle related antigen, which may indicate induction of cell proliferation by p62c-myc. DNA hybridization showed mild amplification in one out of 17 tumors and no evidence of gene rearrangement. There was no distinct correlation between the results of Northern or Southern blot analysis and the results of in situ hybridization or immunohistochemistry. Gene alteration of the c-myc locus, as well as overexpression of the c-myc oncogene, appeared to be limited, and analysis of the c-myc gene yielded limited prognostic value in human esophageal carcinomas.


Prevention of myelosuppression does not improve the therapeutic efficacy of chemo-immunotherapy. This study was designed to investigate whether the prevention of doxorubicin (DOX) induced myelosuppression could further improve the therapeutic efficacy of chemoimmunotherapy with DOX, interleukin-2 (IL-2) and interferon gamma (IFN-gamma). The antitumour activity of systemic IL-2/IFN-gamma immunotherapy in combination with DOX administered either systemically, regionally or on ion-exchange microspheres, was assessed in WAG rats bearing hind limb solid colonic adenocarcinoma implants. Whilst the use of microspheres to transport DOX clearly avoided the myelosuppression, systemic and renal toxicity associated with the use of free DOX, it did not provide any therapeutic advantage over chemo-immunotherapy with free systemic or regional drug.


Control of cell density and pattern by intercellular signaling in Myxococcus development. Myxococcus xanthus cells feed, move, and develop cooperatively. Genetic, biochemical, and cell mosaic studies demonstrate that cells coordinate their multicellular behavior by transmission of intercellular signals. Starvation for amino acids at sufficiently high density on a solid surface initiates a series of events culminating in the formation of a multicellular structure called a fruiting body filled with dormant, environmentally resistant spores. This review discusses how myxobacteria use extracellular signals to sequentially check the density and arrangement of cells at different stages during development. For at least one early and one late developmental signal, cell density determines the efficiency of intercellular signaling. In turn, proper signaling insures that the appropriate cell density exists, thus controlling the progress of multicellular development in M. xanthus.


Genetics of ribosomally synthesized peptide antibiotics. In recent years many peptide antibiotics have been shown to be ribosomally synthesized. Among these are many microcins, produced by diverse strains of gram-negative bacteria. While the structures and modes of action of these peptide antibiotics vary widely, many of them share several important features. Their synthesis is often induced by the cessation of growth. In addition, many of them undergo unusual posttranslational modifications to yield the mature molecule, which is often exported from the cell by a dedicated export apparatus. The genes involved in modification and export of the peptide antibiotics are generally found adjacent to the structural gene and are under the same regulation. The results supporting these conclusions are reviewed and discussed in this chapter.


Influence of radiation treatment on serum transferrin and tumor necrosis factor-alpha. This study deals with the effect of radiation treatment (RT) on serum transferrin and tumor necrosis factor-alpha (TNF-alpha) in patients with malignant tumors. In 21 patients who received 36-60 Gy in 20 to 30 sessions of RT, serum transferrin and TNF-alpha were determined pre-RT, after 10 to 15 sessions (middle of RT) and after 20 to 30 sessions (end of RT). The values of serum transferrin pre-RT were significantly higher than those in the middle and at the end of RT (p < 0.001). The values of TNF-alpha were increased by RT and were significantly higher at the end of RT as compared to the pre-RT values (p < 0.05). The values of serum transferrin and TNF-alpha show a tendency to negative correlation, either as a whole or separately pre- and under-RT. However, no correlation was statistically significant.


Molecular biology of methanogens.

Molecular biology of methanogens. Methanogens are a very diverse group of the Archaea (Archaebacteria). Their genomic DNAs range from 26 to 68 mol% G+C; they exhibit all known prokaryotic morphologies and inhabit anaerobic environments as varied as the human gut and deep-sea volcanic vents. They are, nevertheless, unified by their ability to gain energy by reducing CO, CO2, formate, methanol, methylamines, or acetate to methane. Methanogen genes are reviewed and analyzed in terms of their organization, structure, and expression and are compared with their bacterial (eubacterial) and eukaryal (eukaryotic) counterparts. Many methanogens are thermophiles, and some are hyperthermophiles. The influence of these extreme environments on their macromolecular structures is also addressed. Methanogens are oxygen-sensitive, fastidious anaerobes, and therefore their experimental manipulation in research laboratories has been very limited. The majority of the information currently available describing their molecular biology has been gained by gene cloning. With improvements in anaerobic handling procedures, this is beginning to change, and several experimentally tractable regulated systems of gene expression in methanogens are discussed. Anaerobic biodegradation terminating in methane biogenesis is an established, economically very important biotechnology used world-wide both to reduce waste and to generate fuel-grade biogas. The substantial progress made over the past decade, reviewed here, in understanding the molecular biology of methanogens should now provide a data base for considering genetic approaches to improving this process.