Efficacy of subsequent chemotherapy for patients with BRCA1/2-mutated recurrent epithelial ovarian cancer progressing on olaparib versus placebo maintenance: post-hoc analyses of the SOLO2/ENGOT Ov-21 trial.

BACKGROUND: In the SOLO2 trial (ENGOT Ov-21; NCT01874353), maintenance olaparib in patients with platinum-sensitive relapsed ovarian cancer (PSROC) and BRCA mutation significantly improved progression-free survival (PFS) and prolonged overall survival (OS). Following disease progression on olaparib, efficacy of subsequent chemotherapy remains unknown. PATIENTS AND METHODS: We conducted a post-hoc hypothesis-generating analysis of SOLO2 data to determine the efficacy of different chemotherapy regimens following RECIST disease progression in patients who received olaparib or placebo. We evaluated time to second progression (TTSP) calculated from the date of RECIST progression to the next progression/death. RESULTS: The study population comprised 147 patients who received chemotherapy as their first subsequent treatment after RECIST progression. Of these, 69 (47%) and 78 (53%) were originally randomized to placebo and olaparib arms, respectively. In the placebo-treated cohort, 27/69 and 42/69 received non-platinum and platinum-based chemotherapy, respectively, compared with 24/78 and 54/78, respectively, in the olaparib-treated cohort. Among patients treated with chemotherapy (N = 147), TTSP was significantly longer in the placebo than in the olaparib arm: 12.1 versus 6.9 months [hazard ratio (HR) 2.17, 95% confidence interval (CI) 1.47-3.19]. Similar result was obtained on multivariable analysis adjusting for prognostic factors at RECIST progression (HR 2.13, 95% CI 1.41-3.22). Among patients treated with platinum-based chemotherapy (n = 96), TTSP was significantly longer in the placebo arm: 14.3 versus 7.0 months (HR 2.89, 95% CI 1.73-4.82). Conversely, among patients treated with non-platinum-based chemotherapy (n = 51), the TTSP was comparable in the placebo and olaparib arms: 8.3 versus 6.0 months (HR 1.58, 95% CI 0.86-2.90). CONCLUSIONS: Following progression from maintenance olaparib in the recurrent setting, the efficacy of platinum-based subsequent chemotherapy seems to be reduced in BRCA1/2-mutated patients with PSROC compared to patients not previously receiving poly (ADP-ribose) polymerase inhibitors (PARPi). The optimal strategy for patients who relapse after PARPi is an area of ongoing research.

The French national network dedicated to rare gynecological cancers diagnosis and management could improve the quality of surgery in daily practice of granulosa cell tumors. A TMRG and GINECO group Study.

OBJECTIVE: The French national rare gynecological tumor network has been established to improve the quality of care through offering expertise in double reading histological diagnosis, reviewing cases and guiding management of these tumors through specialized multidisciplinary tumor boards and online clinical guidelines (www.ovaire-rare.com). The aim of this study is to evaluate the impact of the development and implementation of this network by assessing the conformity of medical practice with the guidelines concerning the granulosa cell tumors (GCTs). METHODS: This is a French nationwide study, including 463 patients (out of the 639 identified patients) with a definitive diagnosis of GCT between 2011 and 2016. Surgical practices were analyzed for conformity with the current guidelines (www.ovaire-rare.org). Medical records, surgical and pathological reports were systematically analyzed. Total conformity was defined by a conservative (unilateral salpingo-oophorectomy) or radical surgery (hysterectomy and bilateral salpingo-oophorectomy) including surgical staging (omentectomy, peritoneal biopsies and peritoneal cytology) according to the FIGO stage. Partial conformity referred to a conservative or radical surgery without surgical staging and non-conformity was defined as a non-optimal surgery as recommended by the guidelines. RESULTS: Median age at diagnosis was 49 years old (range 10-89). The median size of tumor was 94 mm (range 5-400). Radical surgery was performed in 240 patients (52%); while a fertility-sparing surgery was performed in 98 cases (21%). A surgical staging was performed in 76 cases (16%) and an evaluation of the endometrium in 289 cases (62%). Surgery was fully compliant with the guidelines in 65 patients (14%), partially compliant in 213 patients (46%), non-compliant in 137 patients (30%) and not assessable in 48 cases (10%). A statistically significant difference for compliance was observed in restaging surgery (p < 0,001), radical surgery (p = 0,017) and the period (before or after) of the implementation of the network (p < 0,001). Survival analyses did not allow us to demonstrate a significant difference in overall survival nor in PFS although there was a trend in favor of optimal surgery compared to incomplete/non optimal surgery. CONCLUSION: Surgical management's conformity to the guidelines increases over time from 2011 to 2016. According to this study, the implementation of a national network dedicated to rare gynecologic tumors seems to significantly improve the surgical management of the patients with ovarian granulosa cell tumors.

Effects of bicarbonate on oxyhaemoglobin desaturation and exercise performance in athletes.

AIM: Decrease in peripheral oxygen delivery may impact exercise performance in athletes with exercise-related arterial oxygen desaturation (ERD). We evaluated whether sodium bicarbonate ingestion would be effective to reduce ERD and what is the consequences upon exercise performance. METHODS: Seventy highly trained athletes performed an incremental treadmill cardiopulmonary exercise test (incCPX) and a high intensity constant speed test (ctCPX) on separate days. Subjects who developed ERD by pulse oximetry were randomly allocated to oral sodium bicarbonate or placebo during 5 days. At the end of treatment subjects repeated both tests. RESULTS: ERD prevalence was 33% during the incCPX (17 % severe, 48% moderate and 35% mild) and 34% (5 % severe, 37% moderate and 58% mild) in the ctCPX. Athletes who developed ERD have greater aerobic capacity (incCPX) and endurance time (ctCPX). Active treatment, but not placebo, reduced ERD during ctCPX (P<0.05). However, there were no significant positive effects on main parameters of aerobic function and endurance exercise capacity (P>0.05). CONCLUSION: Sodium bicarbonate was effective in lessening ERD during ctCPX in athletes. However, this intervention failed to improve maximal and submaximal exercise capacity in these subjects.

Respiratory muscle unloading improves leg muscle oxygenation during exercise in patients with COPD.

BACKGROUND: Respiratory muscle unloading during exercise could improve locomotor muscle oxygenation by increasing oxygen delivery (higher cardiac output and/or arterial oxygen content) in patients with chronic obstructive pulmonary disease (COPD). METHODS: Sixteen non-hypoxaemic men (forced expiratory volume in 1 s 42.2 (13.9)% predicted) undertook, on different days, two constant work rate (70-80% peak) exercise tests receiving proportional assisted ventilation (PAV) or sham ventilation. Relative changes (Delta%) in deoxyhaemoglobin (HHb), oxyhaemoglobin (O(2)Hb), tissue oxygenation index (TOI) and total haemoglobin (Hb(tot)) in the vastus lateralis muscle were measured by near-infrared spectroscopy. In order to estimate oxygen delivery (Do(2)est, l/min), cardiac output and oxygen saturation (Spo(2)) were continuously monitored by impedance cardiography and pulse oximetry, respectively. RESULTS: Exercise tolerance (Tlim) and oxygen uptake were increased with PAV compared with sham ventilation. In contrast, end-exercise blood lactate/Tlim and leg effort/Tlim ratios were lower with PAV (p<0.05). There were no between-treatment differences in cardiac output and Spo(2) either at submaximal exercise or at Tlim (ie, Do(2)est remained unchanged with PAV; p>0.05). Leg muscle oxygenation, however, was significantly enhanced with PAV as the exercise-related decrease in Delta(O(2)Hb)% was lessened and TOI was improved; moreover, Delta(Hb(tot))%, an index of local blood volume, was increased compared with sham ventilation (p<0.01). CONCLUSIONS: Respiratory muscle unloading during high-intensity exercise can improve peripheral muscle oxygenation despite unaltered systemic Do(2 )in patients with advanced COPD. These findings might indicate that a fraction of the available cardiac output had been redirected from ventilatory to appendicular muscles as a consequence of respiratory muscle unloading.

Determination of levocetirizine in human plasma by liquid chromatography-electrospray tandem mass spectrometry: application to a bioequivalence study.

We describe a liquid chromatography-tandem mass spectrometric method (LC-MS/MS) for levocetirizine quantification (I) in human plasma. Sample preparation was made using a fexofenadine (II) addition as internal standard (IS), liquid-liquid extraction using cold dichloromethane, and dissolving the final extract in acetonitrile. I and II (IS) were injected in a C18 column and the mobile phase composed of acetonitrile:water:formic acid (80.00:19.90:0.10, v/v/v) and monitored using positive electrospray source with tandem mass spectrometry analyses. The selected reaction monitoring (SRM) was set using precursor ion and product ion combinations of m/z 389>201 for I and m/z 502>467 for II. The limit of quantification and the dynamic range achieved were 0.5ng/mL and 0.5-500.0ng/mL. Validation results on linearity, specificity, accuracy, precision and stability, as well as its application to the analysis of plasma samples taken up to 48h after oral administration of 5mg of levocetirizine dichloridrate in healthy volunteers demonstrate its applicability to bioavailability studies.

Phase II study of interferon-alpha and all-trans retinoic acid in metastatic renal cell carcinoma.

Interferon-alpha is an accepted treatment for renal cell carcinoma, with a response rate approximately 14%. Retinoic acid has been claimed to improve such a response rate when combined with interferon. We present the results of a phase II study combining interferon alpha and all-trans retinoic acid (ATRA) in patients with metastatic renal cell carcinoma. Thirty-one patients who were not eligible for a trial of high-dose interleukin-2 treatment (because of low performance status: 7 patients; prior immunotherapy: 11 patients; age > 70: 8 patients, cardiac or respiratory failure: 4 patients; refusal for randomization: 1 patient) were enrolled in this study. Only one partial response was observed (3%). Despite the good tolerance observed with this association, ATRA does not improve the efficacy of interferon in this selected patient population (with poor prognosis). Such a treatment combination should not be further recommended in patients with metastatic renal cell carcinoma.

[Outcome of patients with inoperable multivessel coronary disease]. / Evolution des coronariens pluritronculaires impontables.

The authors studied the clinical course of 100 patients with two or three vessel coronary artery disease who were unsuitable for surgery because of the poor quality of the distal vascular bed or excessively depressed left ventricular function. The 6 year actuarial survival was 58 per cent; 43 of the 100 patients did not present any serious cardiac events causing death or requiring further admission to hospital, over this follow-up period. The severity of the clinical course in women and the presence of heart failure prior to coronary angiography were considered to be among the most important clinical prognostic factors. On the basis of the haemodynamic survey, the probability of survival or the risk of a further coronary accident appears to depend more on the extent of the left ventricular kinetic abnormalities than on the ejection fraction or the severity of the coronary lesions.