Overall survival and role of programmed death ligand 1 expression in patients with metastatic non-small-cell lung cancer and immunotherapy: an observational study from central Switzerland.

BACKGROUND In clinical trials, therapy with immune checkpoint inhibitors has improved the survival of patients with metastatic non-small-cell lung cancer (NSCLC). These trials were important for drug approval and for defining new treatment standards but the effect of checkpoint inhibitors in patients treated outside of clinical trials is not well known. The goal of this study was to assess the effect of immunotherapy on the overall survival of patients with metastatic NSCLC in the region of central Switzerland. MATERIALS AND METHODS The study included 274 patients with histologically confirmed metastatic (stage IV) NSCLC in central Switzerland in the years 2015 to 2018. Patients with NSCLC and actionable driver mutations were excluded. Patients with checkpoint inhibitor treatment (immuno-oncology [IO] group, n = 122) were compared with patients without checkpoint inhibitor treatment (no-IO group, n = 152). Baseline demographics, disease characteristics and therapies applied were collected retrospectively. The primary endpoint was median overall survival calculated either from diagnosis or from the start of checkpoint inhibitor therapy to death or data cut-off (21 July 2021). We used the Kaplan-Meier method and an adjusted Cox proportional-hazards regression model. The expression of programmed-death ligand 1 (PD-L1) on tumour cells was used for exploratory analysis. RESULTS Patients had a median age of 68.4 years, most were male (61.7%) and more than half were current or former smokers (65%). A test for PD-L1 expression was available for 55.8% of the tumours. Patients in the IO group were younger than patients in the no-IO group. Among the 122 patients in the IO group, the median overall survival was 15 months (95% confidence interval [CI] 12-20). In the no-IO group, the median overall survival was 4 months (95% CI 3-7) with chemotherapy and 2 months (95% CI 1-2) with best supportive care. Patients with high (≥50%) PD-L1 expression and checkpoint inhibitor therapy had a slightly longer overall survival than patients with low PD-L1 and checkpoint inhibitor therapy. CONCLUSION These results suggest that treatment with checkpoint inhibitors improves overall survival in patients with metastatic NSCLC and that PD-L1 expression could have a predictive value in patients treated outside of clinical trials. Further studies are needed to study the magnitude of the benefit of checkpoint inhibitors according to molecular NSCLC subtype

Racial and Ethnic Differences in Individuals with Sporadic Creutzfeldt-Jakob Disease in the United States of America

BACKGROUND: Little is known about racial and ethnic differences in individuals with sporadic Creutzfeldt-Jakob disease (sCJD). The authors sought to examine potential clinical, diagnostic, genetic, and neuropathological differences in sCJD patients of different races/ethnicities. METHODOLOGY/PRINCIPAL FINDINGS: A retrospective study of 116 definite and probable sCJD cases from Johns Hopkins and the Department of Veterans Affairs Healthcare Systems was conducted that examined differences in demographic, clinical, diagnostic, genetic, and neuropathological characteristics among racial/ethnic groups. Age at disease onset differed among racial/ethnic groups. Non-Hispanic Whites had a significantly older age at disease onset compared to the other groups (65 vs. 60, p = 0.036). Non-Whites were accurately diagnosed more rapidly than Whites (p = 0.008) and non-Hispanic Whites were more likely to have normal appearing basal ganglia on brain magnetic resonance imaging (MRI) compared to minorities (p = 0.02). Whites were also more likely to undergo post-mortem evaluation compared to non-Whites (p = 0.02). CONCLUSIONS/SIGNIFICANCE: Racial/ethnic groups affected by sCJD demonstrated differences in age at disease onset, time to correct diagnosis, clinical presentation, and diagnostic test results. Whites were more likely to undergo autopsy compared to non-Whites. These results have implications in regards to case ascertainment, diagnosis, and surveillance of sCJD and possibly other human prion diseases

The James Webb Space Telescope Mission

Twenty-six years ago a small committee report, building on earlier studies, expounded a compelling and poetic vision for the future of astronomy, calling for an infrared-optimized space telescope with an aperture of at least $4m$. With the support of their governments in the US, Europe, and Canada, 20,000 people realized that vision as the $6.5m$ James Webb Space Telescope. A generation of astronomers will celebrate their accomplishments for the life of the mission, potentially as long as 20 years, and beyond. This report and the scientific discoveries that follow are extended thank-you notes to the 20,000 team members. The telescope is working perfectly, with much better image quality than expected. In this and accompanying papers, we give a brief history, describe the observatory, outline its objectives and current observing program, and discuss the inventions and people who made it possible. We cite detailed reports on the design and the measured performance on orbit.Comment: Accepted by PASP for the special issue on The James Webb Space Telescope Overview, 29 pages, 4 figure

a prospective, multicenter, open phase-II trial in PTLD after solid organ transplantation

Die PTLD ist mit einer Inzidenz zwischen 1% und 10%, in Abhängigkeit vom transplantierten Organ, einer stetig zunehmenden Zahl an Transplantationen von soliden Organen und zunehmenden Überlebenszeiten eine wichtige Komplikation mit entscheidendem Einfluss auf die Langzeitergebnisse nach Organtransplantation. Die Therapie dieser zum grossen Teil aggressiven Lymphome gestaltet sich schwierig. Verminderte Organfunktionen, insbesondere von Knochenmark, Leber und Niere, sowie die eingeschränkte Immunkompetenz erschweren die konventionelle zytostatische Therapie und erhöhen das Risiko von schweren infektiologischen Komplikationen. Zudem sind die Patientenzahlen klein und die Entität recht jung, wodurch bislang kein Konsensus in der Therapie der PTLD gefunden werden konnte. Standard ist eine initiale Reduktion der Immunsuppression, was in einem Teil der Fälle zu Krankheitskontrolle bis zu vollständiger Regredienz der Lymphome führen kann. Antivirale Medikation stellt eine supportive Option dar und konnte als Monotherapie keinen signifikanten Therapieerfolg erreichen. Mit dem anti-CD20 Antikörper Rituximab ergibt sich in der Therapie der PTLD eine neue effektive und nebenwirkungsarme Behandlungsoption. Im Rahmen der vorliegenden Arbeit wurden 25 Patienten mit PTLD nach solider Organtransplantation prospektiv mit vier aufeinanderfolgenden wöchentlichen Gaben von 375 mg/m2 behandelt. Bei achtzehn Studienpatienten erfolgte Rituximab als Erstlinientherapie. Es konnte für diese Therapieoption eine Gesamtansprechen (CR+PR) von 64% (95%-Konfidenzintervall: 44-80%) und eine komplette Remissionsrate von 52% (95%-Konfidenzintervall: 34-70%) gezeigt werden, welches sich in nachfolgenden Studien bestätigt wurde. Ein Problem der Rituximab- Monotherapie in der Behandlung der PTLD stellen Frührezidive und ein nicht ausreichendes Ansprechen auf die Therapie dar. Remissionen, welche mehr als ein Jahr Bestand haben, zeigen sich in der vorliegenden Arbeit, als auch in vergleichbaren Untersuchungen als anhaltend stabil. Bei Patienten mit Frührezidiv oder unzureichendem Ansprechen auf die Therapie können mit nachfolgender Radio- oder Chemotherapie stabile komplette Remission erreicht werden. Der frühzeitige Einsatz von Chemotherapie (CHOP) unmittelbar nach einer vorangehenden Rituximab- Monotherapie scheint allerdings ein deutlich besseres Gesamtüberleben zu erreichen. Möglicherweise kann künftig ein risiko- adaptiertes Vorgehen, welches derzeit international prospektiv geprüft wird, zu einer weiteren Verbesserung der Prognose beitragen und definieren welche Patienten mit einer Rituximab-Monotherapie ausreichend behandelt werden können und welche zusätzlich Chemotherapie brauchen. Aktuelle Daten lassen vermuten, dass Patienten mit niedrigerer Tumormasse und positiver EBV-Assoziation Kandidaten für eine Rituximab Monotherapie sein könnten. Bei limitierender Komorbidität stellt die Rituximab Monotherapie schon heute die vermutlich effektivste Behandlungsoption dar.PTLD, with an incidence between 1% and 10%, is a serious complication in patients after solid organ transplantation due to an increasing number of transplantation and prolonged survival times. The treatment of these aggressive lymphomas is difficult. Decreased organ function, especially of bone marrow, liver and kidney, as well as the impaired immune competence complicate conventional cytostatic therapy. The risk of infectious complications is high. In addition patient numbers are small, the entity is young and consensus on treatment needs to be confirmed in international prospective trials. Initial treatment consists of reduction of immunosuppression resulting in cases of long-term disease control or even complete remission in a number of patients. Antiviral treatment is a supportive option but does not achieve therapeutic success as monotherapy. With the anti-CD20 antibody rituximab a new and effective treatment option with a favourite side effect profile became available. In the present study 25 patients with PTLD after solid organ transplantation were prospectively treated with four weekly doses of rituximab (375 mg/m2). Eighteen study patients received rituximab as first-line therapy. The overall response rate (CR + PR) was 64% (95% CI: 44-80%) with a complete remission rate of 52% (95% CI: 34-70%). These findings were confirmed in subsequent studies. Remissions of one year or longer continued to be stable in this trial and others. Unfortunately rituximab monotherapy can result in early recurrences or inadequate response. In patients with early relapse or inadequate response second line treatment with radiotherapy or chemotherapy stable complete remissions could be achieved. The early initiation of chemotherapy (CHOP) immediately after a previous rituximab monotherapy , however, seems to achieve a significantly better overall survival. In the future a risk-adapted approach, currently investigated in a prospective trial, will result in further improvement of prognosis. It might help to define patients who can be adequately managed by rituximab monotherapy or if additional chemotherapy is necessary. Recent data suggest that patients with a lower tumor burden EBV associated tumors are candidates for rituximab monotherapy. In case of limiting comorbidities rituximab monotherapy probably represents already the most effective treatment option

POLR1A variants underlie phenotypic heterogeneity in craniofacial, neural, and cardiac anomalies

Heterozygous pathogenic variants in POLR1A, which encodes the largest subunit of RNA Polymerase I, were previously identified as the cause of acrofacial dysostosis, Cincinnati-type. The predominant phenotypes observed in the cohort of 3 individuals were craniofacial anomalies reminiscent of Treacher Collins syndrome. We subsequently identified 17 additional individuals with 12 unique heterozygous variants in POLR1A and observed numerous additional phenotypes including neurodevelopmental abnormalities and structural cardiac defects, in combination with highly prevalent craniofacial anomalies and variable limb defects. To understand the pathogenesis of this pleiotropy, we modeled an allelic series of POLR1A variants in vitro and in vivo. In vitro assessments demonstrate variable effects of individual pathogenic variants on ribosomal RNA synthesis and nucleolar morphology, which supports the possibility of variant-specific phenotypic effects in affected individuals. To further explore variant-specific effects in vivo, we used CRISPR-Cas9 gene editing to recapitulate two human variants in mice. Additionally, spatiotemporal requirements for Polr1a in developmental lineages contributing to congenital anomalies in affected individuals were examined via conditional mutagenesis in neural crest cells (face and heart), the second heart field (cardiac outflow tract and right ventricle), and forebrain precursors in mice. Consistent with its ubiquitous role in the essential function of ribosome biogenesis, we observed that loss of Polr1a in any of these lineages causes cell-autonomous apoptosis resulting in embryonic malformations. Altogether, our work greatly expands the phenotype of human POLR1A-related disorders and demonstrates variant-specific effects that provide insights into the underlying pathogenesis of ribosomopathies

Targeting RET in Patients With RET-Rearranged Lung Cancers: Results From the Global, Multicenter RET Registry

Purpose In addition to prospective trials for non-small-cell lung cancers (NSCLCs) that are driven by less common genomic alterations, registries provide complementary information on patient response to targeted therapies. Here, we present the results of an international registry of patients with RET-rearranged NSCLCs, providing the largest data set, to our knowledge, on outcomes of RET-directed therapy thus far. Methods A global, multicenter network of thoracic oncologists identified patients with pathologically confirmed NSCLC that harbored a RET rearrangement. Molecular profiling was performed locally by reverse transcriptase polymerase chain reaction, fluorescence in situ hybridization, or next-generation sequencing. Anonymized data-clinical, pathologic, and molecular features-were collected centrally and analyzed by an independent statistician. Best response to RET tyrosine kinase inhibition administered outside of a clinical trial was determined by RECIST v1.1. Results By April 2016, 165 patients with RET-rearranged NSCLC from 29 centers across Europe, Asia, and the United States were accrued. Median age was 61 years (range, 29 to 89 years). The majority of patients were never smokers (63%) with lung adenocarcinomas (98%) and advanced disease (91%). The most frequent rearrangement was KIF5B-RET (72%). Of those patients, 53 received one or more RET tyrosine kinase inhibitors in sequence: cabozantinib (21 patients), vandetanib (11 patients), sunitinib (10 patients), sorafenib (two patients), alectinib (two patients), lenvatinib (two patients), nintedanib (two patients), ponatinib (two patients), and regorafenib (one patient). The rate of any complete or partial response to cabozantinib, vandetanib, and sunitinib was 37%, 18%, and 22%, respectively. Further responses were observed with lenvantinib and nintedanib. Median progression-free survival was 2.3 months (95% CI, 1.6 to 5.0 months), and median overall survival was 6.8 months (95% CI, 3.9 to 14.3 months). Conclusion Available multikinase inhibitors had limited activity in patients with RET-rearranged NSCLC in this retrospective study. Further investigation of the biology of RET-rearranged lung cancers and identification of new targeted therapeutics will be required to improve outcomes for these patients. (C) 2017 by American Society of Clinical Oncolog