IMpower210: A phase III study of second-line atezolizumab vs. docetaxel in East Asian patients with non-small cell lung cancer.

Objective: IMpower210 (NCT02813785) explored the efficacy and safety of single-agent atezolizumab vs. docetaxel as second-line treatment for advanced non-small cell lung cancer (NSCLC) in East Asian patients. Methods: Key eligibility criteria for this phase III, open-label, randomized study included age ≥18 years; histologically documented advanced NSCLC per the Union for International Cancer Control/American Joint Committee on Cancer staging system (7th edition); Eastern Cooperative Oncology Group performance status of 0 or 1; and disease progression following platinum-based chemotherapy for advanced or metastatic NSCLC. Patients were randomized 2:1 to receive either atezolizumab (1,200 mg) or docetaxel (75 mg/m2). The primary study endpoint was overall survival (OS) in the intention-to-treat (ITT) population with wild-type epidermal growth factor receptor expression (ITT EGFR-WT) and in the overall ITT population. Results: Median OS in the ITT EGFR-WT population (n=467) was 12.3 [95% confidence interval (95% CI), 10.3-13.8] months in the atezolizumab arm (n=312) and 9.9 (95% CI, 7.8-13.9) months in the docetaxel arm [n=155; stratified hazard ratio (HR), 0.82; 95% CI, 0.66-1.03]. Median OS in the overall ITT population was 12.5 (95% CI, 10.8-13.8) months with atezolizumab treatment and 11.1 (95% CI, 8.4-14.2) months (n=377) with docetaxel treatment (n=188; stratified HR, 0.87; 95% CI, 0.71-1.08). Grade 3/4 treatment-related adverse events (TRAEs) occurred in 18.4% of patients in the atezolizumab arm and 50.0% of patients in the docetaxel arm. Conclusions: IMpower210 did not meet its primary efficacy endpoint of OS in the ITT EGFR-WT or overall ITT populations. Atezolizumab was comparatively more tolerable than docetaxel, with a lower incidence of grade 3/4 TRAEs.

Efficacy and safety of the C5 inhibitor crovalimab in complement inhibitor-naive patients with PNH (COMMODORE 3): A multicenter, Phase 3, single-arm study.

The Phase 3 single-arm COMMODORE 3 study (ClinicalTrials.gov, NCT04654468) evaluated efficacy and safety of crovalimab (novel C5 inhibitor) in complement inhibitor-naive patients with paroxysmal nocturnal hemoglobinuria (PNH). COMMODORE 3 enrolled patients from five China centers. Eligible complement inhibitor-naive patients with PNH were ≥12 years old, had lactate dehydrogenase (LDH) ≥2 × upper limit of normal (ULN), and had ≥4 transfusions of packed red blood cells within the prior 12 months. Patients received crovalimab loading doses (one intravenous, four subcutaneous) and subsequent every-4-weeks subcutaneous maintenance doses per weight-based tiered-dosing schedule. Co-primary efficacy endpoints were mean proportion of patients with hemolysis control (LDH ≤1.5 × ULN) from Week (W)5 through W25 and difference in proportion of patients with transfusion avoidance from baseline through W25 versus within 24 weeks of prescreening in patients who had ≥1 crovalimab dose and ≥1 central LDH assessment after first dose. Between March 17 and August 24, 2021, 51 patients (15-58 years old) were enrolled; all received treatment. At primary analysis, both co-primary efficacy endpoints were met. Estimated mean proportion of patients with hemolysis control was 78.7% (95% CI: 67.8-86.6). Difference between proportion of patients with transfusion avoidance from baseline through W25 (51.0%; n = 26) versus within 24 weeks of prescreening (0%) was statistically significant (p < .0001). No adverse events led to treatment discontinuation. One treatment-unrelated death (subdural hematoma following a fall) occurred. In conclusion, crovalimab, with every-4-weeks subcutaneous dosing is efficacious and well tolerated in complement inhibitor-naive patients with PNH.

Successful culture of human transition zone cells.

BACKGROUND: Human corneal endothelial cells undergo very little or no proliferation and respond to cell loss by migration and cellular enlargement. Significant cell loss or damage may result in corneal oedema, opacity and loss of vision. In vitro expansion of corneal endothelial cells (CECs) is a promising strategy for corneal regeneration. The transition zone (TZ) may be an alternative source of CECs. The objective of this study was to establish a protocol for TZ cell culture, and to determine their potential to proliferate and differentiate into cells that resemble CECs in vitro. METHODS: An explant culture protocol for the human TZ was established. Cell proliferation was assessed using 5-ethynyl-2'-deoxyuridine (EdU) assay. The expression of stem cell and endothelial markers was assessed using immunohistochemistry and quantitative polymerase chain reaction. RESULTS: TZ cells can be passaged up to 12 times; cells became polygonal 3 to 4 passages before senescence. An average of 41% of cells incorporated EdU over a 5-day period. TZ cells expressed the corneal endothelial proteins ZO-1 and Na+ /K+ ATPase, Col8A2, the periocular mesenchyme marker PITX2, and the neural crest stem cell markers Nestin and Sox10. TZ cells expressed mRNA of a range of neural crest, periocular mesenchyme, and corneal endothelial genes. CONCLUSIONS: TZ cells can proliferate and differentiate into cells that resemble CECs, demonstrating their potential to be an alternative cell source for corneal endothelial cell therapy.

Double labeling of vagal preganglionic and sympathetic postganglionic fibers in celiac ganglion, superior mesenteric arteries and myenteric plexus.

Sympathetic efferents regulate the "fight-or-flight" response and sympathetic and vagal fibers have been suggested to retrogradely and centrally spread pathogens associated with Parkinson's disease. To examine the arrangement of the vagal and sympathetic motor fibers in the celiac ganglion (CG), gastrointestinal tract, and along the superior mesenteric artery and its sub-branches, we double-labeled the vagal efferents by injecting Dextran-Texas Red into the dorsal motor nucleus of the vagus and the sympathetic postganglionics with tyrosine hydroxylase immunohistochemistry in male Sprague-Dawley rats (n = 18). The laser scanning confocal microscope was used for image analysis. Vagal nerve endings were densely distributed around the CG neurons, and the right CG received more. Vagal and sympathetic efferent endings formed various ring or string shapes that tangled closely in the myenteric plexus of the forestomach, duodenum, jejunum and ileum. Vagal and sympathetic efferents coursed within the same nerve bundles before reaching the myenteric plexus, had in-apposition varicosities, and ran parallel with the superior mesenteric artery and its sub-branches. Although a complete sympathetic tracing and an incomplete tracing and/or damage to the vagal preganglionic neurons may lead to a sampling bias, the sympathetic innervations in the blood vessels and myenteric plexus are stronger than in the vagus. The in-apposition innervation varicosities of the vagal and sympathetic efferents within the same nerve bundles and in the myenteric plexus of the gut with complex innervation patterns may offer a network to automatically control gastrointestinal functions and an infection route of the Parkinson's disease between the autonomic efferent endings.

A review of neuro-ophthalmic sequelae following COVID-19 infection and vaccination.

Background: It has become increasingly clear that the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) can affect most organs in the human body, including the neurologic and ophthalmic systems. Vaccination campaigns have been developed at rapid pace around the world to protect the population from the fast-mutating virus. This review seeks to summarise current knowledge of the neuro-ophthalmic manifestations of both COVID-19 infection and vaccination. Evidence acquisition: Electronic searches for published literature were conducted using EMBASE and MEDLINE on the 30th of July 2023. The search strategy comprised of controlled vocabulary and free-text synonyms for the following terms in various combinations: "coronavirus, COVID-19, SARS-CoV-2, 2019-nCoV, vaccination, vaccine, immunisation and neuro-ophthalmology". No time range limits were set for the literature search. Published English abstracts for articles written in a different language were screened if available. Results: A total of 54 case reports and case series were selected for use in the final report. 34 articles documenting neuro-ophthalmic manifestations following COVID-19 infection and 20 articles with neuro-ophthalmic complications following COVID-19 vaccination were included, comprising of 79 patients in total. The most commonly occurring condition was optic neuritis, with 25 cases following COVID-19 infection and 27 cases following vaccination against COVID-19. Conclusions: The various COVID-19 vaccines that are currently available are part of the global effort to protect the most vulnerable of the human population. The incidence of neuro-ophthalmic consequences following infection with COVID-19 is hundred-folds higher and associated with more harrowing systemic effects than vaccination against the virus.

Parent and adolescent emotional variability and adolescent psychopathology.

Emotional variability has been posited as a risk factor for adolescent psychopathology. However, it is unclear whether parent emotional variability may also function as a risk factor that heightens adolescent mental health problems. To fill this gap, the present study examined whether parent and adolescent emotional variability in both positive emotion (PE) and negative emotion (NE) is associated with adolescent psychopathology and potential sex differences in these associations. Participants were 147 adolescents and their parents in Taiwan who completed a baseline assessment, a 10-day daily diary study, and a 3-month follow-up assessment. The results indicated that parent NE variability was associated with risk for adolescent internalizing problems and depressive symptoms, after accounting for baseline levels, adolescent NE variability, parent internalizing problems, and mean levels of parent and adolescent NE. Adolescent PE variability was also associated with the risk for adolescent externalizing problems. Furthermore, higher parent PE variability was associated with more internalizing problems only for female but not male adolescents. The findings highlight the importance of assessing emotion dynamics in both parents and adolescents to better understand the development of adolescent psychopathology. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Results from the IMpower132 China cohort: Atezolizumab plus platinum-based chemotherapy in advanced non-small cell lung cancer.

BACKGROUND: The global Phase III IMpower132 study evaluating atezolizumab plus pemetrexed and carboplatin or cisplatin (APP) versus pemetrexed plus carboplatin or cisplatin (PP) for first-line treatment of non-squamous advanced non-small cell lung cancer (NSCLC) met its co-primary progression-free survival (PFS) endpoint at the primary analysis in the intention-to-treat (ITT) population. Although the co-primary overall survival (OS) endpoint was not met, numerical OS improvement favoring APP over PP was observed at the final analysis. We report primary results for Chinese patients in IMpower132. METHODS: Treatment-naive Chinese patients with non-squamous stage IV EGFR/ALK mutation-negative NSCLC were randomized 1:1 to receive 4 or 6 cycles of APP or PP, followed by maintenance atezolizumab plus pemetrexed or pemetrexed. Co-primary endpoints were investigator-assessed PFS and OS. RESULTS: The ITT population included 163 Chinese patients (82 in the APP arm and 81 in the PP arm). At data cutoff (median follow-up, 11.7 months), the median PFS in the APP and PP arms was 8.3 and 5.8 months, respectively; the unstratified hazard ratio (HR) was 0.73 (95% CI: 0.50, 1.08). At the interim OS analysis, median OS was not estimable in either arm; the unstratified HR was 0.70 (95% CI: 0.40, 1.24). No new safety signals were observed. CONCLUSION: Among Chinese patients in IMpower132, PFS benefit was seen with APP versus PP. Though interim OS data were immature, there was a trend toward OS benefit favoring APP versus PP. The safety profile of the APP was consistent with the known risks of the individual treatment components. CLINICALTRIALS: gov: NCT02657434.

Enhanced diagnosis of pandemic (H1N1) 2009 influenza infection using molecular and serological testing in intensive care unit patients with suspected influenza.

During the 2009 outbreak of pandemic (H1N1) 2009 influenza (pH1N1) in Australia, acute and convalescent serum specimens were collected from 33 patients with severe respiratory disease admitted to intensive care units. Using hemagglutination inhibition of pH1N1, 29 paired serum samples showed significant increases in specific antibody titers. Of these 29 patients, 18 had pH1N1 RNA detected by routine nucleic acid testing. These results indicate that up to one-third of pH1N1 cases may not have laboratory confirmation of infection unless serological testing is included for suspected cases.

Pan-cancer population pharmacokinetics and exposure-safety and -efficacy analyses of atezolizumab in patients with high tumor mutational burden.

We retrospectively investigated the pharmacokinetics and exposure-efficacy/safety relationships of single-agent atezolizumab based on tissue tumor mutational burden (tTMB) status (high vs low [≥16 vs <16 mutations/megabase]) in a pan-tumor population from seven clinical trials. Data sources included the OAK, POPLAR, BIRCH, FIR, IMvigor210, IMvigor211, and PCD4989g studies; 986 of 2894 treated patients (34%) had TMB data. Exposure metrics were obtained using a prior two-compartment intravenous-infusion population-pharmacokinetics model, merged with prognostic, biomarker, efficacy, and safety variables. Baseline demographic/clinical characteristics and prognostic factors were well balanced between patients with high (n = 175) and low (n = 811) tTMB. Exposure was similar in the high- and low-tTMB subgroups, with no difference seen in the evaluable vs total treated populations. The objective response rate (ORR) was 29.7% vs 13.4%, complete response rate was 6.9% vs 3.2%, and median duration of response (95% CI) was 29.0 (18.6-NE) months vs 15.9 (12.5-20.5) months for patients with high-tTMB vs low-tTMB tumors, respectively. A flat exposure-efficacy relationship was seen for ORR in patients with high-tTMB based on the cycle 1 minimum atezolizumab concentration and area under the serum concentration time curve (AUC). A nonsignificant exposure-safety profile was seen for grade 3/4 adverse events and adverse events of special interest based on the AUC of atezolizumab in the high-tTMB population. tTMB is an additional predictive biological factor affecting response to atezolizumab, and quantitative investigations of atezolizumab exposure and relationships of exposure with safety and efficacy support the use of a 1200-mg, every 3-week regimen in a tumor-agnostic high-tTMB population.