The CHASIT study: sequential chemo-immunotherapy in patients with locally advanced urothelial cancer - a non-randomized phase II clinical trial.

BACKGROUND: Patients with locally advanced irresectable or clinically node positive urothelial cancer (UC) have a poor outcome. Currently, these patients can only be cured by receiving induction chemotherapy and, if an adequate radiological response is obtained, radical surgical resection. Long-term survival, however, strongly depends on the absence of residual tumor in the surgical resection specimen, i.e. a pathological complete response (pCR). The reported pCR rate following induction chemotherapy in locally advanced or clinically node-positive UC is 15%. The 5-year overall survival rate for patients achieving a pCR is 70-80% versus 20% for patients who have residual disease or nodal metastases. This clearly demonstrates the unmet need to improve clinical outcome of these patients. Recently, the JAVELIN Bladder 100 study demonstrated an overall survival benefit of sequential chemo-immunotherapy in patients with metastatic UC. The CHASIT study aims to translate these findings to the induction setting by assessing the efficacy and safety of sequential chemo-immunotherapy in patients with locally advanced or clinically node-positive UC. In addition, patient biomaterials are collected to investigate biological mechanisms of response and resistance to chemo-immunotherapy. METHODS: This multicenter, prospective phase II clinical trial includes patients with stage cT4NxM0 or cTxN1-N3M0 UC of the bladder, upper urinary tract or urethra. Patients who do not experience disease progression after 3 or 4 cycles of platinum-based chemotherapy are eligible for inclusion. Included patients receive 3 cycles of anti-PD-1 immunotherapy with avelumab followed by radical surgery. Primary endpoint is the pCR rate. It is hypothesized that sequential chemo-immunotherapy results in a pCR rate of ≥ 30%. To obtain a power of 80%, 64 patients are screened and 58 patients are included in the efficacy analysis. Secondary endpoints are toxicity, postoperative surgical complications, progression-free, cancer-specific and overall survival at 24 months. DISCUSSION: This is the first study to assess the potential benefit of sequential chemo-immunotherapy in patients with locally advanced or node positive UC. If the primary endpoint of the CHASIT study is met, i.e. a pCR rate of ≥ 30%, a randomized controlled trial is foreseen to compare this new treatment regimen to standard care. TRIAL REGISTRATION: NCT05600127 at Clinicaltrials gov, registered on 31/10/2022.

[Para-arortic lymhadenectomy and pelvic gynecological cancers: Extraperitoneal or transperitoneal laparoscopy?] / Curage lombo-aortique et cancers gynécologiques pelviens : cœlioscopie rétroperitonéale ou transpéritonéale ?

INTRODUCTION: Para-aortic lymphadenectomy plays a fundamental role in the surgical management of pelvic gynecological cancers. Two laparoscopic approaches exist: the transperitoneal (TP) and the extraperitoneal (EP). The aim of this study was to compare these 2 approaches in terms of surgical outcomes, specially the number of removed lymph nodes according to the surgical technique, and morbidity. MATERIALS AND METHOD: A single-center retrospective study was carried out at the Lariboisiere University Hospital between January 2011 and March 2020 including all patients who underwent para-aortic lymphadenectomy for the management of a pelvic gynecological cancer (cervix, endometrium, ovary). Univariate and multivariate analysis (logistic regression) were performed to compare the TP and the EP groups. RESULTS: 143 patients were included: 74 in the TP group and 69 in the RP group. The total duration of surgery was 220.8minutes in the TP group and 166.4minutes in the EP group (P<0.001 in multivariate analysis). No significant difference between groups were found in the average total number of lymph nodes removed but there was a statistically significant difference in the average latero-aortic number of lymph nodes removed: 8.5 lymph nodes in the TP group and 11.3 lymph nodes in the group RP (P<0.001 in multivariate analysis). There was no difference between groups in peri and postoperative morbidity. CONCLUSION: EP para-aortic lymphadenectomy reduces duration of surgery and increases the average latero-aortic number of lymph nodes removed with same morbidity compared to TP para-aortic lymphadenectomy, this confirming its preferred indication in endometrial and in cervical cancers.

[Predictive factors of immediate post-operative acute urinary retention or voiding dysfunction following mid-urethral sling surgery: A literature review]. / Facteurs prédictifs de rétention aiguë d'urine ou de dysurie en postopératoire immédiat après pose de bandelette sous urétrale : revue de la littérature.

OBJECTIVE: Immediate postoperative urinary retention (UR) and voiding dysfunction (VD) are some factors limiting outpatient procedure for mid-urethral sling (MUS) surgery in women presenting with stress urinary incontinence. The objective of the current review was to report the main predictive factors associated with immediate postoperative UR/VD following MUS surgery in women. METHODS: A systematic review was performed using Medline database, according to PRISMA methodology, using following keywords midurethral sling; tension-free vaginal tape; TVT; transobturator tape; TOT; predicting factor; voiding dysfunction; urinary retention; postvoid residual; postoperative residue of urine. RESULTS: Thirteen studies were included. Main clinical predictive factors associated with immediate postoperative urinary retention (UR) and voiding dysfunction (VD) were: previous pelvic surgery (hysterectomy, incontinence or pelvic organ prolapse surgery) [OR: from 3.7 ((CI95%: 1.14-12.33); P=0.029)] to 8.93 [(CI95%:1.17-61.1); P=0.035)], previous UR [OR: 415 (CI95%: 20-8619); P<0.001], age over 65 y/o [OR: 3,72 (CI95%:1.40-9.9); P<0.01], and general anesthesia [OR: 4.5 (CI95%:1.1-18.9); P=0.02]. Urodynamic predictive factors were underactive bladder at cystometry [OR: from 2.52 ([CI95%: 1.03-6.13]; P=0.042) to 5.6 ([IC95%: 1.6-19.2]; P=0.02] and preoperative maximum flow rate (Qmax) (the prevalence of UR was ranging from 12 to 35% when Qmax was under 15ml/s, versus 0% when Qmax was over 30ml/s). CONCLUSION: Predictive factors associated with immediate postoperative UR/VD following MUS surgery in women were age over 65 y/o, previous pelvic surgery or previous UR, underactive bladder and preoperative Qmax under 15ml/s.

[Birth-related retinal hemorrhages in the newborn: incidence and relationship with maternal, obstetric and neonatal factors. Prospective study of 2,031 cases]. / Hémorragies rétiniennes liées à l'accouchement chez le nouveau-né : fréquence et relation avec les facteurs maternels, néonataux et obstétricaux. Étude prospective de 2031 cas.

PURPOSE: To assess the prevalence, morphology and distribution of retinal hemorrhages in healthy newborns and their relationship to neonatal, maternal and obstetrical factors, and to determine their natural history. PATIENTS AND METHODS: The present study prospectively included 2,031 consecutive healthy newborns. Indirect ophthalmoscopy was performed within 24 hours after birth in all newborns. Infants with retinal hemorrhages were reexamined weekly until the hemorrhage resolved. Annual ophthalmologic follow-up was also scheduled in these children. Neonatal, maternal and obstetric parameters were analyzed in all newborns and compared between newborns with retinal hemorrhages and those without retinal hemorrhages. RESULTS: 31.8 % of newborns exhibited retinal hemorrhages. 72.6 % of hemorrhages were bilateral. They tended to be localized around the optic discs and in the posterior pole, but their distribution was variable. Retinal hemorrhages were of variable shapes. The prevalence of retinal hemorrhages was higher in newborns delivered with vacuum-assisted extraction (38 %, P<0.001), intermediate during normal vaginal delivery (32.6 %, P<0.001) and lower with cesarean section (20.8 %). Comparative analysis between elective cesarean section and emergency cesarean showed a higher incidence of retinal hemorrhages in the emergency cesarean group (P=0.006). On multivariate analysis, vacuum-assisted delivery was the only factor associated with a higher prevalence of retinal hemorrhages in newborns (P=0.045). Two thirds of hemorrhages had disappeared by one week after birth. Retinal hemorrhages had resolved in all newborns within four weeks. CONCLUSION: Birth-related retinal hemorrhages are common (1/3 of our newborns). Vacuum-assisted delivery is the main risk factor in this study. All hemorrhages resolved by one month of age. These findings may help in differential diagnosis with shaken baby syndrome.

The impact of prior platinum therapy on survival in patients with metastatic urothelial cancer receiving vinflunine.

BACKGROUND: A phase III trial demonstrated an overall survival advantage with the addition of vinflunine to best supportive care (BSC) in platinum-refractory advanced urothelial cancer. We subsequently examined the impact of an additional 2 years of survival follow-up and evaluated the influence of first-line platinum therapy on survival. METHODS: The 357 eligible patients from the phase III study were categorised into two cohorts depending on prior cisplatin treatment: cisplatin or non-cisplatin. Survival was calculated using the Kaplan-Meier method. RESULTS: The majority had received prior cisplatin (70.3%). Survival was higher in the cisplatin group (HR: 0.76; CI 95% 0.58-0.99; P=0.04) irrespective of treatment arm. Multivariate analysis including known prognostic factors (liver involvement, haemoglobin, performance status) and prior platinum administration did not show an independent effect of cisplatin. Vinflunine reduced the risk of death by 24% in the cisplatin-group (HR: 0.76; CI 95% 0.58-0.99; P=0.04) and by 35% in non-cisplatin patients (HR: 0.65; CI 95% 0.41-1.04; P=0.07). INTERPRETATION: Differences in prognostic factors between patients who can receive prior cisplatin and those who cannot may explain the survival differences in patients who undergo second line therapy. Prior cisplatin administration did not diminish the subsequent benefit of vinflunine over BSC.

Long-term survival results of a randomized phase III trial of vinflunine plus best supportive care versus best supportive care alone in advanced urothelial carcinoma patients after failure of platinum-based chemotherapy.

BACKGROUND: To compare long-term, updated overall survival (OS) of patients with advanced transitional cell carcinoma of the urothelium (TCCU) treated with vinflunine plus best supportive care (BSC) or BSC alone, after failure of platinum-based chemotherapy. PATIENTS AND METHODS: Three hundred and seventy patients were randomly assigned in a phase III trial and allocated (2:1) to vinflunine (320 or 280 mg/m(2)) plus BSC or BSC alone. The first report (Bellmunt J, Theodore C, Demkov T et al. Phase III trial of vinflunine plus best supportive care compared with best supportive care alone after a platinumcontaining regimen in patients with advanced transitional cell carcinoma of the urothelial tract. J Clin Oncol 2009; 27(27): 4454-4461) had a median follow-up of 22.1 m and the current report has a follow-up of 45.4 m. RESULTS: Three hundred and fifty-two patients had died (censoring rate 5%). In the intention-to-treat (ITT) population, the median OS was 6.9 m and 4.6 m for vinflunine plus BSC versus BSC alone, respectively (n.s.). In multivariate Cox analysis, the addition of vinflunine was independently correlated with improved survival (HR: 0.719; 95% CI:0.570-0.906, P = 0.0052). In the eligible population, the median OS in both the arms was 6.9 and 4.3 m, respectively (HR: 0.78; 95% CI:0.61-0.96; P = 0.0227), indicating an estimated 22% reduction in the risk of death. CONCLUSIONS: The updated OS data confirm the positive treatment effect of vinflunine on survival that was previously reported. These results are consistent over time and confirm that vinflunine is a valuable option for second-line treatment in patients with advanced TCCU after failure of platinum-based regimens.

[Xeroderma pigmentosum associated with intracerebral tumor: a case report]. / Xeroderma pigmentosum compliqué d'une tumeur intracérébrale : à propos d'un cas.

Patients with the genetic disease xeroderma pigmentosum (XP) lack the ability to carry out a specific type of DNA repair process called nucleotide excision repair (NER). The NER pathway plays a critical role in the repair of DNA damage resulting from ultraviolet (UV) radiation. We report a case of a patient presenting a cutaneous form of XP. She presented acute paralysis of the third cranial nerve with cutaneous anesthesia. Nuclear magnetic resonance imaging revealed an intracranial tumor. She underwent surgery with incomplete tumor resection; anatomopathological study showed a schwannoma. Complementary radiosurgery was performed. The association between XP and neurological cancer is rare but not impossible. A priori, it would be assumed that the major medical outcome of hereditary deficiencies in DNA repair processes would be an increased risk of cancer. Indeed, there is an increased risk of cancer in several known DNA repair deficiencies including XP.

Phase II study of ecteinascidin-743 in advanced pretreated soft tissue sarcoma patients.

PURPOSE: A multicenter phase II study evaluating efficacy, safety, and pharmacokinetics of ecteinascidin-743 (ET-743) in pretreated advanced soft tissue sarcoma patients. PATIENTS AND METHODS: Patients received ET-743 1,500 microg/m(2) (24-hour intravenous infusion) every 3 weeks (group 1, 26 patients with one to two prior single agents or one previous combination chemotherapy; group 2, 28 patients with three or more prior single agents or two or more previous combination chemotherapies). Results Patients (30 women, 24 men) had a median age of 48 years (range, 22 to 71 years); 41% had leiomyosarcoma (eight of 22 of uterine origin), a median of two involved organs (range, one to four), and 93% had documented progressive disease at study entry. Patients received a median of three cycles (range, one to 20); 28% received six or more cycles. Fifty-two patients were assessable for response (WHO criteria): two partial responses, four minor responses, and nine with stable disease (> or = 6 months). Three patients were rendered tumor free after surgery. Median progression-free survival was 1.9 months (range, 0.69 to 17.90 months); 24% of patients were progression free at 6 months. Median survival was 12.8 months, with 30% of patients alive at 2 years. Four patients withdrew because of treatment-related toxicity. Two treatment-related deaths occurred (renal failure and febrile neutropenia, and rhabdomyolysis and decompensated cirrhosis, respectively) that were probably related to protocol eligibility violations. Reversible grade 3 to 4 AST or ALT occurred in 50% of patients and grade 3 to 4 neutropenia occurred in 61% of patients, with six episodes of febrile neutropenia. Nausea, vomiting, and asthenia were prevalent but mild and manageable. CONCLUSION: With a 4% overall response rate (95% CI, 0.5 to 12.8) and an 11% rate of third-party-verified tumor regression (overall response rate + minor response), ET-743 has a 24% 6-month disease progression control rate, confirming evidence of antitumoral activity and a manageable safety profile in patients experiencing disease progression with pretreated soft tissue sarcoma.

Sexual dysfunction in 156 ambulatory HIV-infected men receiving highly active antiretroviral therapy combinations with and without protease inhibitors.

We conducted a cross-sectional study of 156 ambulatory HIV-infected homosexual or bisexual men to assess and compare the prevalence and characteristics of sexual dysfunction according to treatment combinations (group A, protease inhibitor [PI] treatment; group B, no PI treatment; and C, PI treatment interrupted >1 month previously). The study was based on a self-administered 163-item questionnaire that included a French translation of the International Index of Erectile Function, five sections of the Derogatis Sexual Functioning Inventory, and open questions. Data analysis was performed using Mann-Whitney and Kruskal-Wallis H nonparametric tests (quantitative values) and chi2 tests (qualitative values) using SPSS software (SPSS, Chicago, IL, U.S.A.). One hundred fifty-six patients completed the study. The median age +/- SD of the patients was 40.5 +/- 7.7 years, and the median CD4+ cell count +/- SD was 415 +/- 236/mm3. One hundred eleven (71%) of 156 patients reported some degree of sexual dysfunction since the beginning of their treatment (65 [71%] of 91 group A patients; 15 [65%] of 23 group B patients; and 31 [74%] of 42 group C patients), with no significant difference among the groups. Of the 111 patients, 99 (89%) reported decrease or loss of libido, 76 (68%) reported orgasmic perturbation, 96 (86%) reported erectile dysfunction, and 65 (59%) reported ejaculation perturbation, with no significant difference among the three groups. There were no significant differences among the three groups regarding the International Index of Erectile Function and Derogatis Sexual Functioning Inventory scores. These data suggest that PI-based therapy does not seem to increase sexual dysfunction in this patient population.

Factors predictive of disease progression and death in AIDS-related Kaposi's sarcoma.

BACKGROUND: The natural history of Kaposi's sarcoma (KS) is poorly documented. We attempted to identify factors predictive of progression and survival in HIV-infected patients with KS and CD4+ cell counts greater than 100/microL. PATIENTS AND METHODS: We studied retrospectively 78 HIV-infected patients diagnosed as having KS between 1989 and 1995. The following variables were assessed as potential predictors of progression and death, in a Cox proportional hazards model: age, sex, ethnic group, transmission group, site of the first KS lesions, duration of KS, concomitant opportunistic infections or malignancies, antiretroviral drug therapy (excluding protease inhibitors), antiherpes treatments, neutrophil counts, CD4+ and CD8+ cell counts, plasma HIV load, p24 antigenaemia, beta2-microglobulinaemia and immunoglobin A and G serum levels. RESULTS: During a median follow-up of 22 months (3-81 months), KS progressed in 66 of the 78 patients. The median survival time after progression was 68 months (9-126 months). Multivariate analysis identified only visceral KS, a high neutrophil count and a high serum immunoglobulin (Ig) level as independent predictors of progression (P < 0.05). Previous and concomitant opportunistic diseases (P = 0.003) and low CD4+ cell counts (P = 0.013) were independently associated with shorter survival; in contrast KS therapy did not independently influence survival. CONCLUSION: Progression of KS is predicted by markers of KS severity, while overall survival is best predicted by markers of immunodeficiency (opportunistic diseases and the CD4+ cell count).

Adverse metabolic disorders during highly active antiretroviral treatments (HAART) of HIV disease.

Protease inhibitor treatment has dramatically improved rates of morbidity and mortality in HIV-infected patients. However, it has recently been shown that this medication is associated with long-term side effects characterized by metabolic, clinical and biological alterations. These modifications have been described in patients treated with highly active antiretroviral therapy (HAART), including nucleoside analogue reverse transcriptase inhibitors (NRTI) and generally (but not always) protease inhibitors (PI). Clinical alterations are characterised by a body fat redistribution syndrome or lipodystrophy, with peripheral lipoatrophy and/or central fat accumulation. They are often associated with biological alterations, i.e. insulin resistance, hyperglycaemia and dyslipidaemia, which can also be observed alone. The pathophysiology of these alterations is presently unknown. The deleterious effect of PI on adipose tissue could be direct or indirect, and is probably modulated by genetic or environmental factors. NRTI could also be involved because of their mitochondrial toxicity. The purpose of the treatment is to control metabolic disturbances in order to prevent immediate complications such as acute pancreatitis and limit possible cardiovascular and diabetic complications at longer term. Studies are in progress to evaluate the possibility of therapeutic alternatives to PI when major metabolic disturbances are present.

Diabetes, insulin resistance and dyslipidaemia in lipodystrophic HIV-infected patients on highly active antiretroviral therapy (HAART).

This study assessed glucose tolerance, insulin sensitivity and lipid parameters in HIV-infected patients presenting with lipodystrophy during HAART including protease inhibitors. Fourteen consecutive patients from Rothschild Hospital treated with HAART and presenting with marked facial lipoatrophy were evaluated. A 75 g oral glucose tolerance test (OGTT) with measurement of plasma glucose, insulin, proinsulin and free fatty acids at T0, 30, 60, 90 and 120 min was performed. Lipid parameters (triglycerides, cholesterol, apolipoproteins A1 and B) were studied as well as nutritional and inflammatory markers (albumin, prealbumin, transferrin, haptoglobin, orosomucoid, C-reactive protein), endocrine and cytokine parameters (thyrotropin, cortisol, leptin, interleukin-6), HIV viral load and CD4-lymphocyte count. These patients were compared with 20 non-lipodystrophic protease inhibitor-treated patients. The measurements performed during OGTT showed that among the 14 lipodystrophic patients, 11 (79%) presented with diabetes (5 patients) or normal glucose tolerance but with insulin resistance (6 patients). This frequency was strikingly different in the group of nonlipodystrophic patients, which included only 4 (20%) presenting with diabetes (1 patient), or impaired glucose tolerance (2 patients), or normal glucose tolerance but with insulin resistance (1 patient). Hypertriglyceridaemia was present in 11 lipodystrophic (79%) versus 7 nonlipodystrophic patients (35%). Nutritional and endocrine measurements were normal. An abnormal processing of proinsulin to insulin was excluded. Thus, lipodystrophy during HAART was associated with diabetes, insulin resistance and hypertriglyceridaemia. Diabetes, diagnosed by basal and/or 120 min-OGTT glycaemia, seems more frequent than previously described. The therapeutic consequences of these results deserve evaluation in clinical trials.

Serum ferritin, desferrioxamine, and evolution of HIV-1 infection in thalassemic patients.

To study the respective roles of mean serum ferritin level and the mean desferrioxamine (DFX) dose on progression of HIV-1 infection, data from 49 HIV-seropositive thalassemic patients were analyzed using a Cox proportional hazards model including known confounding variables. Nine years after seroconversion, 10% of those who had been prescribed >40 mg/kg of DFX daily had entered stage IV versus 39% of those who had been prescribed a lower dose. Patients with ferritin level >1935 g/L entered stage IV more rapidly than those with a lower level (31% versus 16%). In multivariate analysis, the ferritin level was found to be an independent predictor of progression of HIV disease, whereas the mean daily dose of DFX was not. Similar results were obtained when death was the endpoint. Our results support a hypothesis that was recently expressed, that iron overload could be associated with a more rapid progression of HIV-1 infection.