First-Line Nivolumab Plus Chemotherapy for Advanced Gastric, Gastroesophageal Junction, and Esophageal Adenocarcinoma: 3-Year Follow-Up of the Phase III CheckMate 649 Trial.

Clinical trials frequently include multiple end points that mature at different times. The initial report, typically based on the primary end point, may be published when key planned co-primary or secondary analyses are not yet available. Clinical Trial Updates provide an opportunity to disseminate additional results from studies, published in JCO or elsewhere, for which the primary end point has already been reported.We report 3-year efficacy and safety results from the phase III CheckMate 649 trial. Patients with previously untreated advanced or metastatic gastroesophageal adenocarcinoma were randomly assigned to nivolumab plus chemotherapy or chemotherapy. Primary end points were overall survival (OS) and progression-free survival (PFS) by blinded independent central review (BICR) in patients whose tumors expressed PD-L1 combined positive score (CPS) ≥5. With 36.2-month minimum follow-up, for patients with PD-L1 CPS ≥5, the OS hazard ratio (HR) for nivolumab plus chemotherapy versus chemotherapy was 0.70 (95% CI, 0.61 to 0.81); 21% versus 10% of patients were alive at 36 months, respectively; the PFS HR was 0.70 (95% CI, 0.60 to 0.81); 36-month PFS rates were 13% versus 8%, respectively. The objective response rate (ORR) per BICR was 60% (95% CI, 55 to 65) with nivolumab plus chemotherapy versus 45% (95% CI, 40 to 50) with chemotherapy; median duration of response was 9.6 months (95% CI, 8.2 to 12.4) versus 7.0 months (95% CI, 5.6 to 7.9), respectively. Nivolumab plus chemotherapy also continued to show improvement in OS, PFS, and ORR versus chemotherapy in the overall population. Adding nivolumab to chemotherapy maintained clinically meaningful long-term survival benefit versus chemotherapy alone, with an acceptable safety profile, supporting the continued use of nivolumab plus chemotherapy as standard first-line treatment for advanced gastroesophageal adenocarcinoma.

A New Cell Topology for 4H-SiC Planar Power MOSFETs for High-Frequency Switching.

A new cell topology named the dodecagonal (a polygon with twelve sides, short for Dod) cell is proposed to optimize the gate-to-drain capacitance (Cgd) and reduce the specific ON-resistance (Ron,sp) of 4H-SiC planar power MOSFETs. The Dod and the octagonal (Oct) cells are used in the layout design of the 650 V SiC MOSFETs in this work. The experimental results confirm that the Dod-cell MOSFET achieves a 2.2× lower Ron,sp, 2.1× smaller high-frequency figure of merit (HF-FOM), higher turn on/off dv/dt, and 29% less switching loss than the fabricated Oct-cell MOSFET. The results demonstrate that the Dod cell is an attractive candidate for high-frequency power applications.

Effects of JFET Region Design and Gate Oxide Thickness on the Static and Dynamic Performance of 650 V SiC Planar Power MOSFETs.

650 V SiC planar MOSFETs with various JFET widths, JFET doping concentrations, and gate oxide thicknesses were fabricated by a commercial SiC foundry on two six-inch SiC epitaxial wafers. An orthogonal P+ layout was used for the 650 V SiC MOSFETs to reduce the ON-resistance. The devices were packaged into open-cavity TO-247 packages for evaluation. Trade-off analysis of the static and dynamic performance of the 650 V SiC power MOSFETs was conducted. The measurement results show that a short JFET region with an enhanced JFET doping concentration reduces specific ON-resistance (Ron,sp) and lowers the gate-drain capacitance (Cgd). It was experimentally shown that a thinner gate oxide further reduces Ron,sp, although with a penalty in terms of increased Cgd. A design with 0.5 µm half JFET width, enhanced JFET doping concentration of 5.5×1016 cm-3, and thin gate oxide produces an excellent high-frequency figure of merit (HF-FOM) among recently published studies on 650 V SiC devices.

Phase I trial of ribociclib with platinum chemotherapy in ovarian cancer.

BACKGROUNDNew therapeutic combinations to improve outcomes of patients with ovarian cancer are clearly needed. Preclinical studies with ribociclib (LEE-011), a CDK4/6 cell cycle checkpoint inhibitor, demonstrate a synergistic effect with platinum chemotherapy and efficacy as a maintenance therapy after chemotherapy. We tested the safety and initial efficacy of ribociclib in combination with platinum-based chemotherapy in recurrent ovarian cancer.METHODSThis phase I trial combined weekly carboplatin and paclitaxel chemotherapy with ribociclib, followed by ribociclib maintenance in patients with recurrent platinum-sensitive ovarian cancer. Primary objectives were safety and maximum tolerated dose (MTD) of ribociclib when given with platinum and taxane chemotherapy. Secondary endpoints were response rate (RR) and progression-free survival (PFS).RESULTSThirty-five patients were enrolled. Patients had a mean of 2.5 prior lines of chemotherapy, and 51% received prior maintenance therapy with poly(ADP-ribose) polymerase inhibitors and/or bevacizumab. The MTD was 400 mg. The most common adverse events included anemia (82.9%), neutropenia (82.9%), fatigue (82.9%), and nausea (77.1%). The overall RR was 79.3%, with a stable disease rate of 18%, resulting in a clinical benefit rate of 96.6%. Median PFS was 11.4 months. RR and PFS did not differ based on the number of lines of prior chemotherapy or prior maintenance therapy.CONCLUSIONThis work demonstrates that the combination of ribociclib with chemotherapy in ovarian cancer is feasible and safe. With a clinical benefit rate of 97%, this work provides encouraging evidence of clinical efficacy in patients with recurrent platinum-sensitive disease.TRIAL REGISTRATIONClinicalTrials.gov NCT03056833.FUNDINGThis investigator-initiated trial was supported by Novartis, which provided drugs and funds for trial execution.

Size-fractionated particle-bound heavy metals and perfluoroalkyl substances in dust from different indoor air.

The indoor air quality issue and its potential health problems are attracting increasingly attentions. In this study, micro-orifice uniform deposit impactor (MOUDI) was used to sample suspended particles from four typical indoor environments, including residence, office, cyber classroom, and chemical analysis room. Size-dependent concentrations of perfluoroalkyl substances (PFASs) and heavy metals in suspended particles were analyzed. Then, the International Commission on Radiological Protection deposition model was employed to estimate deposition efficiencies and fluxes of size-fractioned PFASs and heavy metals in the human respiratory tract. Most of the contaminants deposited in head airways, where coarse particles (aerodynamic diameter or Dp > 1.8 µm) contributed the most. By contrast, in the alveolar region fine particles (Dp < 1.8 µm) were dominant. The chronic daily intake through inhalation of PFASs and heavy metals via airborne particles were 10.3-37.5 pg kg-1days-1 and 3.1-25.9 mg kg-1days-1, respectively. The estimated total hazardous quotient of PFASs and heavy metals were 4.4 × 10-5-1.7 × 10-3 and 9.9 × 10-3-1.05 × 10-1, which is far lower than the acceptable threshold of 1. However, the incremental lifetime cancer risk induced by As, Cd, Co, Cr, and Ni were estimated to be 1.11 × 10-5-1.41 × 10-4 in total, which exceeded the acceptable threshold of 10-6. These findings implicate that there were health risks, especially cancer risks caused by heavy metals associated with airborne particles in urban indoor environments.

The double edge sword of fibrosis in cancer.

Cancer-associated fibrosis is a critical component of the tumor microenvironment (TME) which significantly impacts cancer behavior. However, there is significant controversy regarding fibrosis as a predominantly tumor promoting or tumor suppressing factor. Cells essential to the generation of tissue fibrosis such as fibroblasts and mesenchymal stem cells (MSCs) have dual phenotypes dependent upon their independence or association with cancer cells. Cancer-associated fibroblasts and cancer-associated MSCs have unique molecular profiles which facilitate cancer cell cross talk, influence extracellular matrix deposition, and direct the immune system to generate a protumorigenic environment. In contrast, normal tissue fibroblasts and MSCs are important in restraining cancer initiation, influencing epithelial cell differentiation, and limiting cancer cell invasion. We propose this apparent dichotomy of function is due to (1) cancer mediated stromal reprogramming; (2) tissue stromal source; (3) unique subtypes of fibrosis; and (4) the impact of fibrosis on other TME elements. First, as cancer progresses, tumor cells influence their surrounding stroma to move from a cancer restraining phenotype into a cancer supportive role. Second, cancer has specific organ tropism, thus stroma derived from preferred metastatic organs support growth while less preferred metastatic tissues do not. Third, there are subtypes of fibrosis which have unique function to support or inhibit cancer growth. Fourth, depleting fibrosis influences other TME components which drive the cancer response. Collectively, this review highlights the complexity of cancer-associated fibrosis and supports a dual function of fibrosis which evolves during the continuum of cancer growth.