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Substantial COVID-19 research investment has been allocated to randomized clinical trials (RCTs) on hydroxychloroquine/chloroquine, which currently face recruitment challenges or early discontinuation. We aim to estimate the effects of hydroxychloroquine and chloroquine on survival in COVID-19 from all currently available RCT evidence, published and unpublished. We present a rapid meta-analysis of ongoing, completed, or discontinued RCTs on hydroxychloroquine or chloroquine treatment for any COVID-19 patients (protocol: https://osf.io/QESV4/). We systematically identified unpublished RCTs (ClinicalTrials.gov, WHO International Clinical Trials Registry Platform, Cochrane COVID-registry up to June 11, 2020), and published RCTs (PubMed, medRxiv and bioRxiv up to October 16, 2020). All-cause mortality has been extracted (publications/preprints) or requested from investigators and combined in random-effects meta-analyses, calculating odds ratios (ORs) with 95% confidence intervals (CIs), separately for hydroxychloroquine and chloroquine. Prespecified subgroup analyses include patient setting, diagnostic confirmation, control type, and publication status. Sixty-three trials were potentially eligible. We included 14 unpublished trials (1308 patients) and 14 publications/preprints (9011 patients). Results for hydroxychloroquine are dominated by RECOVERY and WHO SOLIDARITY, two highly pragmatic trials, which employed relatively high doses and included 4716 and 1853 patients, respectively (67% of the total sample size). The combined OR on all-cause mortality for hydroxychloroquine is 1.11 (95% CI: 1.02, 1.20; I² = 0%; 26 trials; 10,012 patients) and for chloroquine 1.77 (95%CI: 0.15, 21.13, I² = 0%; 4 trials; 307 patients). We identified no subgroup effects. We found that treatment with hydroxychloroquine is associated with increased mortality in COVID-19 patients, and there is no benefit of chloroquine. Findings have unclear generalizability to outpatients, children, pregnant women, and people with comorbidities. Hydroxychloroquine and chloroquine have been investigated as a potential treatment for Covid-19 in several clinical trials. Here the authors report a meta-analysis of published and unpublished trials, and show that treatment with hydroxychloroquine for patients with Covid-19 was associated with increased mortality, and there was no benefit from chloroquine. [ABSTRACT FROM AUTHOR]

Background: Immune checkpoint blockade (ICB) has transformed melanoma treatment, but optimal sequencing of ICB and surgery for clinically evident nodal metastasis remains undefined. We evaluated adjuvant-only (AT) and neoadjuvant/adjuvant (NAT) ICB with respect to survival outcomes in this patient population. Methods: Patients who underwent lymphadenectomy (1 January 2011 to 31 July 2018) and received perioperative ICB at an academic center were identified. AT was defined as postoperative ICB, and NAT was defined as one to two cycles of ICB prior to resection with continuation of therapy following surgery. Three-year disease-free survival (DFS), locoregional recurrence-free survival (LRFS), distant disease-free survival (DDFS), and melanoma-specific survival (MSS) were estimated. Results: Of 59 patients, 18 (31%) received AT and 41 (69%) received NAT. The AT and NAT groups did not differ in age (median 53 vs. 62 years, p = 0.16) or stage (IIIB 33% vs. 29%, IIIC 56% vs. 68%, IIID 11% vs. 2%, p = 0.34). Although 3-year DFS did not differ significantly by treatment sequencing (NAT vs. AT, hazard ratio [HR] 0.56, p = 0.17), NAT was associated with improved 3-year DDFS (HR 0.38, p = 0.028). Of 39 NAT patients with evaluable pathologic response, 23 (59%) and 5 (13%) had a pathologic partial response (pPR) and pathologic complete response (pCR), respectively. Patients with pPR/pCR experienced improved 3-year DFS (HR 0.16, p = 0.001), LRFS (HR 0.17, p = 0.003), and DDFS (HR 0.26, p = 0.029) compared with those with no response. Three-year MSS did not differ significantly by response (p = 0.062). Conclusion: NAT may be associated with improved 3-year DDFS compared with AT sequencing, and allows for early assessment of pathologic response. Further prospective evaluation of treatment sequencing is warranted. [ABSTRACT FROM AUTHOR]

Background: Immune checkpoint and BRAF-targeted inhibitors have demonstrated significant survival benefits for advanced melanoma patients within the context of clinical trials. We sought to determine their impact on overall survival (OS) at a population level in order to better understand the current landscape for patients diagnosed with clinical stage III melanoma. Methods: A retrospective study was performed using the National Cancer Database. Patients diagnosed with clinical stage III melanoma were categorized by diagnosis year into two cohorts preceding the advent of novel therapies (P1: 2004–2005, P2: 2008–2009) and a contemporary group (P3: 2012–2013). OS was estimated using standard time-to-event statistical methods. Results: Of 3720 patients, 525 (14%) were diagnosed in P1, 1375 (37%) in P2, and 1820 (49%) in P3. Median age at diagnosis increased over time (58, 59, and 61 years in P1, P2, and P3, respectively, P = 0.004). OS increased between P2 (median 49.3 months) and P3 (median 58.2 months, Bonferroni-corrected log-rank P < 0.001) but did not differ between P1 (median 50.5 months) and P2 (Bonferroni-corrected log-rank P > 0.99). These differences persisted on multivariable analysis. OS improved for patients diagnosed in P3 compared with P1 [hazard ratio (HR) 0.76, P < 0.001] but not P2 compared with P1 (HR 0.96, P = 0.52). Conclusions: OS has significantly improved nationally for patients newly diagnosed with clinical stage III melanoma in the era of novel melanoma therapies. OS outcomes will likely continue to evolve as these agents are increasingly utilized in the adjuvant setting. These data may help to better inform affected patients with respect to prognosis. [ABSTRACT FROM AUTHOR]

Exhausted CD8+ T (Tex) cells in chronic infections and cancer have limited effector function, high co-expression of inhibitory receptors and extensive transcriptional changes compared with effector (Teff) or memory (Tmem) CD8+ T cells. Tex cells are important clinical targets of checkpoint blockade and other immunotherapies. Epigenetically, Tex cells are a distinct immune subset, with a unique chromatin landscape compared with Teff and Tmem cells. However, the mechanisms that govern the transcriptional and epigenetic development of Tex cells remain unknown. Here we identify the HMG-box transcription factor TOX as a central regulator of Tex cells in mice. TOX is largely dispensable for the formation of Teff and Tmem cells, but it is critical for exhaustion: in the absence of TOX, Tex cells do not form. TOX is induced by calcineurin and NFAT2, and operates in a feed-forward loop in which it becomes calcineurin-independent and sustained in Tex cells. Robust expression of TOX therefore results in commitment to Tex cells by translating persistent stimulation into a distinct Tex cell transcriptional and epigenetic developmental program. The transcription factor TOX is a central regulator of the transcriptional and epigenetic development of exhausted T cells. [ABSTRACT FROM AUTHOR]

Immune checkpoint inhibitors result in impressive clinical responses, but optimal results will require combination with each other and other therapies. This raises fundamental questions about mechanisms of non-redundancy and resistance. Here we report major tumour regressions in a subset of patients with metastatic melanoma treated with an anti-CTLA4 antibody (anti-CTLA4) and radiation, and reproduced this effect in mouse models. Although combined treatment improved responses in irradiated and unirradiated tumours, resistance was common. Unbiased analyses of mice revealed that resistance was due to upregulation of PD-L1 on melanoma cells and associated with T-cell exhaustion. Accordingly, optimal response in melanoma and other cancer types requires radiation, anti-CTLA4 and anti-PD-L1/PD-1. Anti-CTLA4 predominantly inhibits T-regulatory cells (Treg cells), thereby increasing the CD8 T-cell to Treg (CD8/Treg) ratio. Radiation enhances the diversity of the T-cell receptor (TCR) repertoire of intratumoral T cells. Together, anti-CTLA4 promotes expansion of T cells, while radiation shapes the TCR repertoire of the expanded peripheral clones. Addition of PD-L1 blockade reverses T-cell exhaustion to mitigate depression in the CD8/Treg ratio and further encourages oligoclonal T-cell expansion. Similarly to results from mice, patients on our clinical trial with melanoma showing high PD-L1 did not respond to radiation plus anti-CTLA4, demonstrated persistent T-cell exhaustion, and rapidly progressed. Thus, PD-L1 on melanoma cells allows tumours to escape anti-CTLA4-based therapy, and the combination of radiation, anti-CTLA4 and anti-PD-L1 promotes response and immunity through distinct mechanisms. [ABSTRACT FROM AUTHOR]

The original version of this Article contained an error in the spelling of the author Muhammad Shahzad, which was incorrectly given as Muhammad Shehzad. These authors contributed equally: Cathrine Axfors, Andreas M. Schmitt. [Extracted from the article]

Objective: To determine if having a night-time nurse-to-patient ratio (NNPR) of one nurse caring for one or two patients (> 1:2) versus one nurse caring for three or more patients (< 1:2) in the intensive care unit (ICU) is associated with clinical and economic outcomes following esophageal resection.Design: State-wide observational cohort study. Hospital discharge data was linked to a prospective survey of ICU organizational characteristics. Multivariate analysis adjusting for case-mix, hospital and surgeon volume was used to determine the association of NNPR with in-hospital mortality, length of stay (LOS), hospital cost and specific postoperative complications.Setting: Non-federal acute care hospitals (n = 35) in Maryland that performed esophageal resection.Patients and Participants: Adult patients who had esophageal resection in Maryland, 1994 to 1998 (n = 366 patients).Measurements and Results: Two hundred twenty-five patients at nine hospitals had a NNPR > 1:2;128 patients in 23 hospitals had a NNPR < 1:2. No significant association between NNPR and in-hospital mortality was seen. A 39 % increase in median in-hospital LOS (4.3 days; 95% CI, (2, 5 days); p < 0.001), and a 32% increase in costs ($4,810; 95 % CI, ($2,094, $7,952) was associated with a NNPR < 1:2. Pneumonia (OR 2.4; 95 % CI (1.2, 4.7); p = 0.012), reintubation (OR 2.6; 95% CI(1.4, 4.5);p = 0.001), and septicemia (OR 3.6; 95 % CI(1.1, 12.5); p = 0.04), were specific complications associated with a NNPR < 1:2.Conclusions: A nurse caring for more than two ICU patients at night increases the risk of several postoperative pulmonary and infectious complications and was associated with increased resource use in patients undergoing esophageal resection. [ABSTRACT FROM AUTHOR]

Deregulation of the cell cycle machinery is a hallmark of cancer. While CDK4/6 inhibitors are FDA approved (palbociclib) for treating advanced estrogen receptor-positive breast cancer, two major clinical challenges remain: (i) adverse events leading to therapy discontinuation and (ii) lack of reliable biomarkers. Here we report that breast cancer cells activate autophagy in response to palbociclib, and that the combination of autophagy and CDK4/6 inhibitors induces irreversible growth inhibition and senescence in vitro, and diminishes growth of cell line and patient-derived xenograft tumours in vivo. Furthermore, intact G1/S transition (Rb-positive and low-molecular-weight isoform of cyclin E (cytoplasmic)-negative) is a reliable prognostic biomarker in ER positive breast cancer patients, and predictive of preclinical sensitivity to this drug combination. Inhibition of CDK4/6 and autophagy is also synergistic in other solid cancers with an intact G1/S checkpoint, providing a novel and promising biomarker-driven combination therapeutic strategy to treat breast and other solid tumours. [ABSTRACT FROM AUTHOR]