PURPOSE: To evaluate the addition of the humanized monoclonal antiprogrammed death ligand-1 (PD-L1) antibody, atezolizumab, to platinum-based chemotherapy and bevacizumab in newly diagnosed stage III or IV ovarian cancer (OC). METHODS: This multicenter placebo-controlled double-blind randomized phase III trial (ClinicalTrials.gov identifier: NCT03038100 ) enrolled patients with newly diagnosed untreated International Federation of Gynecology and Obstetrics (FIGO) stage III or IV OC who either had undergone primary cytoreductive surgery with macroscopic residual disease or were planned to receive neoadjuvant chemotherapy and interval surgery. Patients were stratified by FIGO stage, Eastern Cooperative Oncology Group performance status, tumor immune cell PD-L1 staining, and treatment strategy and randomly assigned 1:1 to receive 3-weekly cycles of atezolizumab 1,200 mg or placebo (day 1, cycles 1-22), with paclitaxel plus carboplatin (day 1, cycles 1-6) plus bevacizumab 15 mg/kg (day 1, cycles 2-22), omitting perioperative bevacizumab in neoadjuvant patients. The co-primary end points were investigator-assessed progression-free survival and overall survival in the intention-to-treat and PD-L1–positive populations. RESULTS: Between March 8, 2017, and March 26, 2019, 1,301 patients were enrolled. The median progression-free survival was 19.5 versus 18.4 months with atezolizumab versus placebo, respectively (hazard ratio, 0.92; 95% CI, 0.79 to 1.07; stratified log-rank P = .28), in the intention-to-treat population and 20.8 versus 18.5 months, respectively (hazard ratio, 0.80; 95% CI, 0.65 to 0.99; P = .038), in the PD-L1–positive population. The interim (immature) overall survival results showed no significant benefit from atezolizumab. The most common grade 3 or 4 adverse events were neutropenia (21% with atezolizumab v 21% with placebo), hypertension (18% v 20%, respectively), and anemia (12% v 12%). CONCLUSION: Current evidence does not support the use of immune checkpoint inhibitors in newly diagnosed OC. Insight from this trial should inform further evaluation of immunotherapy in OC.

Oncogene-induced reactive oxygen species (ROS) have been proposed to be signaling molecules that mediate proliferative cues. However, ROS may also cause DNA damage and proliferative arrest. How these apparently opposite roles can be reconciled, especially in the context of oncogene-induced cellular senescence, which is associated both with aberrant mitogenic signaling and DNA damage response (DDR)-mediated arrest, is unclear. Here, we show that ROS are indeed mitogenic signaling molecules that fuel oncogene-driven aberrant cell proliferation. However, by their very same ability to mediate cell hyperproliferation, ROS eventually cause DDR activation. We also show that oncogenic Ras-induced ROS are produced in a Rac1 and NADPH oxidase (Nox4)-dependent manner. In addition, we show that Ras-induced ROS can be detected and modulated in a living transparent animal: the zebrafish. Finally, in cancer we show that Nox4 is increased in both human tumors and a mouse model of pancreatic cancer and specific Nox4 small-molecule inhibitors act synergistically with existing chemotherapic agents.

Aims: To identify factors contributing to laboratory overutilisation in an academic medical department, and to assess the effect of an educational feedback strategy on inappropriate test-ordering behaviour. Methods: The records of 426 patients admitted during a 6-month period were reviewed. The usefulness of 25 investigations (haematology, basic biochemistry and arterial blood gases) was assessed according to implicit criteria. Trainees’ acquaintance with investigation costs was assessed via a multiple-choice questionnaire. The medical staff was informed about their test-ordering behaviour, cost awareness and the factors associated with overuse of diagnostic tests. The test-ordering behaviour of the same doctors was reassessed on 214 patients managed during 6 months after the intervention. Results: Overall, 24 482 laboratory tests were ordered before the intervention (mean 2.96 tests/patient/day). Among those, 67.9% were not considered to have contributed towards management of patients (mean avoidable 2.01 tests/patient/day). Patient age ⩾65 years, hospitalisation beyond 7 days and increased case difficulty (death or inability to establish a diagnosis) were factors independently associated with overuse of laboratory tests. Senior trainees ordered more laboratory examinations, but the percentage of avoidable tests requested by junior trainees was higher. A moderate and disparate level of trainees’ awareness about the cost of common laboratory examinations was disclosed. The avoidable tests/patient/day were significantly decreased after the intervention (mean 1.58, p = 0.002), but containment of unnecessary ordering of tests gradually waned during the semester after the intervention. Conclusion: Repeated audit, continuous education and alertness of doctors, on the basis of assessment of factors contributing to laboratory overutilisation, result in restraining the redundant ordering of tests in the hospital setting.