Late toxicities and clinical outcome at 5 years of the ACCORD 12/0405-PRODIGE 02 trial comparing two neoadjuvant chemoradiotherapy regimens for intermediate-risk rectal cancer.

BACKGROUND: Outcome of intermediate risk rectal cancer may be improved by the addition of oxaliplatin during 5-fluoruracil concomitant neoadjuvant chemoradiotherapy. The purpose of this study is to analyze the main clinical results of the ACCORD12 trial (NCT00227747) in rectal cancer after 5 years of follow-up. PATIENTS AND METHODS: Inclusion criteria were as follows: rectal adenocarcinoma accessible to digital examination staged T3-T4 Nx M0 (or T2 Nx distal anterior rectum). Two neoadjuvant chemoradiotherapy regimens were randomized: CAP45 (RT 45 Gy + capecitabine) and CAPOX50 (RT 50 Gy + capecitabine and oxaliplatin). Main end point was sterilization of the operative specimen. Acute and late toxicities were prospectively analyzed with dedicated questionnaires. RESULTS: Between November 2005 and July 2008, 598 patients were included in the trial. After a median follow-up of 60.2 months, there was no difference between treatment arms in multivariate analysis either for disease-free survival or overall survival (OS) [P = 0.9, hazard ratio (HR)=1.02; 95% confidence interval (CI), 0.76-1.36 and P = 0.3, HR = 0.87; 95% CI, 0.66-1.15, respectively]. There was also no difference of local control in univariate analysis (P = 0.7, HR = 0.92; 95% CI, 0.51-1.66). Late toxicities were acceptable with 1.6% G3 anal incontinence, and <1% G3 diarrhea, G3 rectal bleeding, G3 stenosis, G3-4 pain, G3 urinary incontinence, G3 urinary retention and G3 skeletal toxicity. There was a slight increase of erectile dysfunction over time with a 63% rate of erectile dysfunction at 5 years. There was no significant statistical difference for these toxicities between treatment arms. CONCLUSIONS: The CAPOX50 regimen did not improve local control, disease-free survival and overall survival in the ACCORD12 trial. Late toxicities did not differ between treatment arms.

Nivolumab in patients with advanced renal cell carcinoma in France: interim results of the observational, real-world WITNESS study.

BACKGROUND: Nivolumab is the first immune checkpoint inhibitor approved in Europe for the treatment of advanced renal cell carcinoma (aRCC) in patients resistant to prior antiangiogenic therapy. WITNESS is an ongoing, prospective, observational study designed to evaluate the effectiveness and safety of nivolumab in patients with aRCC treated in real life (or routine practice) in France (ClinicalTrials.gov identifier: NCT03455452). PATIENTS AND METHODS: This study includes adult patients with a confirmed diagnosis of aRCC who have initiated nivolumab after 1-2 prior lines of antiangiogenic therapy. Endpoints include overall survival (OS), progression-free survival (PFS), duration of treatment (DOT), duration of response (DOR), overall response rate (ORR), subgroup analyses, and treatment-related adverse events (TRAEs). Results after a median follow-up of 12.3 months are presented here. RESULTS: A total of 325 patients with aRCC were included, of whom 38.2% had a Karnofsky score <80, 77.8% received nivolumab as second-line therapy, and 69.5% had undergone a previous nephrectomy. In the overall population, median OS was 20.5 [95% confidence interval (CI) 17.6-25.0] months and median PFS was 5.2 (95% CI 4.5-5.9) months. ORR was 34.5%, median DOT was 3.8 months, and median DOR was 16.5 months. Nivolumab was effective in different subgroups including patients with bone or glandular metastases and those receiving baseline corticosteroids. Moreover, effectiveness was observed irrespective of prior nephrectomy and line of treatment. No new safety signals were identified; TRAEs of any grade were reported in 32.0% of patients, grade ≥3 and serious TRAEs in 11.1% each, and TRAEs leading to discontinuation in 8.9%. CONCLUSIONS: Preliminary results of the ongoing WITNESS study confirm the real-world effectiveness and safety of nivolumab monotherapy in previously treated patients with aRCC. Treatment benefits were similar to those observed in the pivotal phase III CheckMate 025 randomized clinical trial, despite a broader, real-life study population.

Cisplatin-docetaxel induction plus concurrent 3-D conformal radiotherapy and weekly chemotherapy for locally advanced non-small cell lung cancer patients: a phase II trial.

Concurrent chemoradiotherapy (CHRT) is the standard of care for unresectable locally advanced stage III non-small cell lung cancer. However, the optimal combination remains unclear. The aim of this study was to evaluate the efficacy of 2 induction chemotherapy cycles (days 1 and 22) with docetaxel 75 mg/m(2) and cisplatin 75 mg/m(2) followed by concurrent chemotherapy (weekly docetaxel-cisplatin, 20 mg/m(2)) and 3-D conformal radiotherapy for 6 weeks (66 Gy/5 fractions per week/2 Gy per fraction). The primary endpoint was the response rate. Secondary objectives were toxicity, time to progression, and overall survival. Forty-four patients were included and 40 were eligible. The mean age was 60.5 years (range 40.7-72.1), and 75% had stage IIIB disease. Six patients underwent complete R0 resection including 2 pathologic complete responses after a planned intermediate evaluation. Thirty-three patients completed CHRT. The objective response rate was 65% (95% CI 50.2-79.8). Grade 3-4 hematologic and digestive toxicities were observed mainly during the induction phase. Grade 3 esophagitis (5%) was experienced during CHRT. With a median follow-up of 38.7 months, the median progression-free survival was 28.3 months (95% CI 11.0-35.0) and the median survival rate was 31.4 months. Cisplatin-docetaxel induction followed by concurrent 3-D conformal radiotherapy and weekly chemotherapy is a feasible protocol associated with a promising response rate and acceptable toxicity.

[What a healthy lifestyle stands for at the menopause: the role of the gynaecologist]. / Intérêt d'une bonne hygiène de vie à la ménopause: rôle du gynécologue.

Post-menopausal osteoporosis is a public health problem, because of its extreme frequency and its related fractures. Gynaecologists play an important role in the early detection of patients whose bones are at risk. During the consultation, a routine examination, asking pertinent questions and taking height and weight measurements, allows for the discovery of modifiable risk factors - diet, life style: physical activity, alcohol and tobacco consumption, etc. Gynaecologists are in a particularly good position to intervene. Indeed, they can inform and advise these patients at risk, by recommending a diet rich in calcium, vitamin D and protein, maintaining a healthy BMI, a sufficient exposure to sunlight, daily physical activity with a preference for weight-bearing exercise, avoiding smoking and excessive alcohol. These simple changes for a healthy life style can slow down the loss of bone density, and this well before any loss due to estrogen deficiency.

[Staying fit after fifty]. / Comment rester en forme(s) après 50 ans?

It is common knowledge that when women reach the menopause, they put on weight and change body shape. The menopause is particularly feared as a sign of aging. The deficiency in estrogen at the menopause is responsible for the change from a gynoid fat pattern to an android one (i.e. fat accumulates on the upper portion of the abdomen instead of on the hips). In addition, women are no longer protected against CardioVascular Diseases (CVD), and will rapidly share the same risks as men. The menopause is marked by an increase in the prevalence of various CVD risk factors: elevated blood pressure, hypertriglyceridemia, Diabetes, etc. This phenomenon may be explained by an increase in the occurrence of the polymetabolic (PM) syndrome at this time of life. In the IDF ((International Diabetics Federation) 2005 definition, waist circumference becomes the main criterion of PM syndrome. Keeping a slim waist can no longer be considered a woman's vain obsession but a justified health concern, since the waist to height ratio is a better predictor of CVD than BMI (Body Mass Index). A diet and healthcare program is now available which, if followed from the age of 35, can help women live 'in good shape' and for longer.

Outpatient treatment with subcutaneous interleukin-2 and interferon alfa administration in combination with fluorouracil in patients with metastatic renal cell carcinoma: results of a sequential nonrandomized phase II study. Subcutaneous Administration Propeukin Program Cooperative Group.

PURPOSE: We report the results of the Subcutaneous Administration Propeukin Program (SCAPP) II trial of an outpatient treatment in renal cell carcinoma using interleukin-2 (IL-2) and interferon alfa-2a (IFN-alpha) administered subcutaneously in combination with fluorouracil (5-FU). The objective of this multicenter trial was to confirm that the combination of IL-2, IFN-alpha, and 5-FU leads to a response rate greater than 20%. PATIENTS AND METHODS: Patients with metastatic renal cell carcinoma were included in this study. During the induction phase of the treatment, which lasted 10 weeks, IL-2 and IFN-alpha were administered subcutaneously three times a week for 8 weeks at doses of 18 MIU and 9 MIU, respectively. During these 8 weeks, every Monday, 5-FU was administered at a dose of 750 mg by intravenous infusion over 30 minutes. After evaluation, responding patients or patients with stable disease (SD) were given maintenance treatment, until disease progression (PD) or the appearance of unacceptable toxicity. Each maintenance cycle consisted of a 2-week treatment followed by a three-week rest period. During treatment, IL-2 and IFN-alpha were administered subcutaneously three times a week at doses of 18 MIU and 9 MIU, respectively. Every Monday, 5-FU was administered at a dose of 750 mg by intravenous infusion over 30 minutes. RESULTS: This trial was closed when the sixth sequential analysis showed the lack of benefit from this combination. At the end of the induction period, of 62 patients, 12 (19%; 95% confidence interval [CI], 10% to 31%) reached an objective response, including one complete response (CR), 16 presented with SD, and 27 showed PD. Twenty-seven patients (43%) developed severe toxicity that required reduction of the planned doses (13 patients), delayed treatment (eight patients), or treatment termination (six patients). Seventeen patients were given maintenance treatment. One- and 2-year survival rates were estimated at 55% and 33%, respectively. The 2-year survival rate was 15% in 11 patients who presented with three poor-prognosis factors and 41% in 51 patients who initially presented with no, one, or two poor-prognosis factors (P = .04). CONCLUSION: As in other recently published studies that used 5-FU, IL-2, and IFN-alpha, the multicenter SCAPP II trial in patients with metastatic renal cell carcinoma generated severe toxicity. This sequential trial failed to confirm the favorable results previously obtained by Atzpodien and Sella with this combination of three drugs. Its efficacy, assessed on the response and survival rates, is near to the results observed in programs that used IL-2 alone given subcutaneously.

Use of immunocytochemistry of progesterone and estrogen receptors for endometrial dating.

Endometrial progesterone and estrogen receptors were studied by immunocytochemistry using monoclonal antibodies during the menstrual cycle in normal women. We initially compared immunocytochemical staining of progesterone and estradiol receptors on endometrial fragments obtained by either aspiration or endometrial biopsy and found that immunocytochemistry could be performed easily on tissue obtained in either way. The immunocytochemical studies showed that the concentration and distribution of receptors changed markedly during the normal menstrual cycle. These changes were distributed in three characteristic phases. During phase I, corresponding to the midfollicular period (days 7-8), a small proportion (25%) of stromal and glandular cells stained positively for the progesterone receptor, whereas estrogen receptor staining was more intense and more frequent (50% of cells). Phase II, which included both the late follicular and early luteal periods (days 9-19), was characterized by a marked staining of progesterone receptors in the majority of glandular cells (75%) and somewhat less abundant and less frequent staining in stromal cells (50%). Estrogen receptor staining was present in about half of the glandular and stromal cells. Phase III, the mid- and late luteal period (days 21-27), was characterized by the disappearance of estrogen and progesterone receptor staining in glandular cells, although faint staining for both receptors was found in stromal cells. These variations in progesterone receptor staining are potentially useful for determining the effect of progesterone on endometrial maturation.

[Possible value of variations in the serum alkaline DNAse activity in the prognosis of cancers of the upper respiratory-digestive tract treated by chemotherapy]. / Valeur prédictive des variations de l'activité sérique de la DNAse alcaline dans le pronostic des cancers des voies aérodigestives supérieures traités par chimiothérapie.

Variations in serum alkaline DNase activity before and repeatedly after standardized chemotherapy were examined in patients with head and neck carcinomas. The enzyme activity was measured by way of a modified spectrophotometric method. No variations of such activity observed in patients without therapeutic response or with minor response could be considered as a marker of primary or acquired resistance to chemotherapy. Distinct variations in serum alkaline DNase activity (a steep decrease after therapy followed a few weeks later by a regain of values higher than the initial value) correspond to complete or partial positive responses. Such observations of the variations in enzyme activity in relation to individual initial values measured before therapy could be considered as a reliable prognostic test for the therapy of many head and neck carcinomas.

[Doppler echocardiographic evaluation of aortic valve prosthesis. Analysis of the reproducibility of pressure gradients and surface measurements]. / Evaluation des prothèses valvulaires aortiques par échocardiographie Doppler. Analyse de la reproductibilité des measures de gradients et de surfaces.

Doppler echocardiography has become the method of choice for the evaluation of cardiac valve prostheses. In order to determine the reproducibility of the measurements of pressure gradient and valve surface area, 55 patients with aortic valve prostheses without clinical dysfunction and having at most a trivial regurgitation on color Doppler examination underwent a double evaluation during an average interval of 9 +/- 5 months. The maximum and mean pressure gradients were recorded and the valve surface area calculated using the continuity equation in all cases. The subaortic diameter was taken to be constant and equal to the external diameter of the prosthesis. No significant differences were found between the two evaluations of mean pressure gradient and valve surface area. The intra-patient variability was +/- 8 mmHg for the maximum pressure gradient, +/- 6 mmHg for the mean pressure gradient, +/- 0.33 cm2 for valve surface area calculated using the maximum velocities and +/- 0.44 cm2 when the velocity-time integrals were used. When expressed as a percentage, the mean coefficient of variation was 21 +/- 17% for the maximum pressure gradient, 21 +/- 18% for the mean pressure gradients, 21 +/- 15% for the valve surface area calculated using the maximum velocities and 22 +/- 14% when the ratio of velocity-time integrals was used.(ABSTRACT TRUNCATED AT 250 WORDS)

[Predictive factors of coronary lesions in aortic stenosis in adults]. / Facteurs prédictifs des lésions coronariennes au cours du rétrécissement aortique de l'adulte.

The frequent coexistence in adults of a tight aortic stenosis and coronary arterial lesions raises problems of therapeutic and diagnostic approach. In an attempt at selecting indications for coronary arteriography, we studied 253 patients with severe aortic stenosis who were explored by that method. 177 patients (70 p. 100) had no coronary disease (group I); 76 patients (30 p. 100) had significant coronary lesions (group II). Group II patients differed from group I patients in several respects: they were older: 65 +/- 9 years on average as against 61 +/- 9 years (p less than 0.01); there was a greater proportion of men in that group: 76 p. 100 vs 58 p. 100 (p less than 0.01); more patients had a history of myocardial infarction: 7 p. 100 vs 0.5 p. 100 (p less than 0.05); calcifications of the coronary arteries were found in 43 p. 100 of the cases as against 15 p. 100 in group I (p less than 0.001); the transvalvular pressure gradient was lower: 50 +/- 30 mmHg vs 72 +/- 31 mmHg (p less than 0.01). There were no other significant differences in risk factors between the two groups, except for overweight which was greater in group II. Attacks of angina were not statistically more frequent in group II (80 p. 100) than in group I (73 p. 100, N.S.). A multifactorial analysis enabled us to establish a discriminant relation involving the patient's age, sex and history of infarction as well as coronary calcifications.(ABSTRACT TRUNCATED AT 250 WORDS)

[Prognosis of ischemic mitral valve insufficiency]. / Pronostic de l'insuffisance mitrale ischémique.

Seventy-nine patients with ischemic mitral regurgitation were followed up for a period of 20 +/- 8 months. The risk of death increased with age and cardiac failure at the time of inclusion. The risk of cardiac events increased with these factors and also with raised serum creatinine and decreased echocardiographic fractional shortening. The global 2 year survival was 72.8% and survival without a further cardiac event was 48.7%. Surgery and angioplasty increased global survival and freedom from cardiac events of patients with severe regurgitation (74.9% and 68.8% versus 59.4% and 46.1% for medical therapy alone). The functional improvement was also greater in patients undergoing surgery or angioplasty (80% of patients in NYHA Stage I versus 53.8% in the medical group). Angioplasty was only performed in cases of paroxysmal mitral regurgitation by reversible papillary muscle ischemia. Surgery (coronary bypass usually associated with mitral valve replacement) was associated with better results than medical therapy alone in permanent mitral regurgitation by papillary muscle dysfunction or rupture. Despite a high immediate mortality, this option should be considered rapidly in cases of severe ischemic mitral regurgitation with pulmonary oedema.

[Holter electrocardiography before and after coronary angioplasty. Angiographic correlation after 24 hours and 6 months]. / Electrocardiogramme Holter avant et après angioplastie coronaire. Corrélations angiographiques à 24 heures et à 6 mois.

Myocardial ischaemia was searched for by Holter monitoring before and after coronary angioplasty with primary success in 31 patients. Control angiography was performed at 24 hours and 6 months after angioplasty. Twelve patients had signs of myocardial ischaemia before angioplasty (cumulated ischaemia: 743 minutes). The degree of coronary stenosis was 92 +/- 6% before angioplasty, 25 +/- 17% immediately after the dilatation increasing to 34 +/- 25% at the 24th hour (p less than 0.002). Despite successful angioplasty myocardial ischaemia persisted in 6 patients (cumulated ischaemia: 184 minutes) and was silent in 5 of the 6 cases. In these 6 cases, control angiography at 24 hours showed either a dissection (n = 4) or a filling defect (n = 2). The angiographic outcome of the postangioplasty stenosis and at 24 hours was the same in Group I without restenosis (25 +/- 14% versus 33 +/- 22%) as in Group II with restenosis (25 +/- 22% versus 37 +/- 30%). In Group I, the degradation of the result at 24 hours was reversible at 6 months (33 +/- 22% vs 23 +/- 14%). After angiographic success, postangioplasty ischaemia present in 20% of cases was frequently silent. No correlation was observed with restenosis at 6 months which raises the possibility of a reversible microthrombotic etiology. These results justify antiaggregant and anticoagulant therapy in the 48 hours following angioplasty.

[Doppler parameters of systolic function and heart rate]. / Paramètres Doppler de fonction systolique et fréquence cardiaque.

This prospective study had two aims, to study the Doppler parameters of left ventricular systolic function with respect to heart rate, and to determine the influence of ischaemic heart disease on these variations. The Doppler indices (velocity time integral, maximum velocity and average acceleration of systolic flow in the left ventricular outflow tract) were measured and averaged over 3 beats after digitization: the measurements were repeated in 30 patients under basal conditions and after 2 minutes transoesophageal atrial pacing at 150 beats/min. These 30 patients were divided into 3 groups: group 1 control subjects with normal coronary arteries, n = 13, EF = 71 +/- 8.9%; group 2 coronary patients without myocardial infarction (greater than 70% stenosis on coronary angiography), n = 9, EF = 64.3 +/- 10.3%; group 3, coronary patients with previous infarction, n = 8, EF = 51.8 +/- 10.9% (p less than 0.0006). Variance analysis for repeated measurements showed significant decreases in velocity time integrals and maximum velocities after pacing (11.8% +/- 2.2 and 0.86 +/- 0.1 versus 18.3 +/- 2.2 and 0.91 +/- 0.1, p less than 0.0001 and p less than 0.05 respectively). This decrease was identical in the three groups. The variations observed were therefore related to the increase in heart rate and not to coronary status or left ventricular function.

[Is the prognosis of non-thrombolysed inferior infarction benign?]. / Le pronostic des infarctus postérieurs non thrombolysés est-il bénin?

Between 1978 and 1983, 2,970 coronary angiographies were performed at the Cardiology Clinic of Necker Hospital; 220 survivors of an initial Q-wave inferior infarction who had not received thrombolytic therapy were selected. The ejection fraction was 55 +/- 11 per cent, and the indexed end diastolic left ventricular volume was 108 +/- 29 ml/m2. The left anterior descending artery was diseased in 57 per cent of cases. The incidence of multivessel disease was 67 per cent. Two hundred and eleven patients (96%) were followed up for 79 +/- 22 months. The prevalence of cardiovascular events was: cardiac deaths: 22 (10%), recurrent infarction: 20 (9%), angina requiring coronary bypass surgery: 60 (28%), cardiac failure: 22 (10%). The 10 year actuarial survival was significantly lower in patients with an ejection fraction less than 45 per cent (46% vs 91%) and in patients with triple vessel disease (62% vs 92% and 88%). The survival was not lower in patients with stenosis of the left anterior descending artery.

[Autoimmune thyroid diseases and Horton disease]. / Thyréopathies autoimmunes et maladie de Horton.

In a retrospective study of 115 patients with giant cell arteritis, 5 clinically patent autoimmune diseases were recorded; including 2 patients (1.8%) with Grave's disease and 1 with hypothyroidism. Among these patients, 46 had systematic assays of blood thyroid hormones and 39 were systematically investigated for anti-thyroid antibodies (ATAb):3 (6.5%) had biological hypothyroidism and 4 (10.3%) had ATAb. These findings were not significantly different from those of a control group of 39 age and sex matched patients.

[Multiple autoimmune syndrome]. / Syndrome auto-immun multiple.

Report a case of multiple auto-immune syndrome with auto-immune thyroiditis, Sjögren's syndrome, primary biliary cirrhosis. Moreover the patient suffered from neuropsychiatric symptoms and anti-cardiolipid antibodies were significantly elevated.

[Death in Horton disease. Prognostic factors]. / Les décès dans la maladie de Horton. Facteurs de pronostic.

The authors reported causes of death and searched for prognosis factors in Giant Cell Arteritis (GCA). The diagnosis was confirmed by temporal biopsy in all cases. Fourteen patients died during treatment; thirty-six patients had completely recovered (follow up > 6 months after withdrawal of steroid therapy). The commonest causes of death were cardiovascular (n = 7) and digestive (n = 4); they occurred after an average of 195 days of treatment, half of them during the first three months. One death was due to GCA (autopsy) and five deaths were attributed to the treatment with corticosteroids. The prognosis factors were searched for by comparing age, sex, clinical signs, laboratory data before treatment, past medical history in the both series; further more initial dose of Prednisone and the dose after 180 days of steroid therapy were compared in the two groups. The adverse prognosis factors revealed by this study were: advanced age (p < 0.01), previous ischaemic heart disease (p < 0.05) and higher dose of corticosteroids administered at 6 months of treatment (< 0.01).

[Isolated inflammatory syndrome: think of benign tumors of the liver]. / Syndrome inflammatoire isolé: penser aux tumeurs bénignes du foie.

The authors report seven cases of benign tumors of the liver revealed by elevated acute phase reactants. They show that these elevated acute phase reactants are not linked with a particular histological diagnosis, the presence of tumor necrosis and that they disappear with the chirurgical cure of the tumor.

[Study of the efficacy and safety of fosinopril in general practice in 19,435 hypertensive patients (FLIGHT Study)]. / Etude de l'efficacité et de la tolérance du fosinopril en médecine praticienne chez 19,435 hypertendus (etude flight).

The efficacy and good safety of fosinopril, an angiotensin converting enzyme inhibitor recently made available to the medical profession in France, has been demonstrated by several controlled studies versus placebo and reference antihypertensives. A phase IV multicentre clinical trial was conducted among general practitioners in order to assess, on a larger scale and under conditions of daily practice, the results obtained in terms of blood pressure control and quality of life as well as the clinical and laboratory safety of the drug. This analysis was based on 19,435 hypertensive patients, 989 of whom were over the age of 75 years, followed for 12 weeks after introduction of fosinopril either as monotherapy or in combination with the antihypertensive treatment(s) already prescribed. Under these conditions, after 12 weeks of treatment, blood pressure was controlled in 79.8% of patients, with improvement of all items of the quality of life scale. The very low incidence of clinical and laboratory adverse events, even among the oldest patients, confirms the safety of use of fosinopril, predictive of good long-term compliance with treatment.