tbuckley/cabot-search huggingface dataset:
Real-world first-line serplulimab-based immunochemotherapy for extensive-stage small cell lung cancer: The multicenter ASTRUM-005R study.
Authors: Lin Wu, ChengPing Hu, Wenzhong Su, Yan Yu, Wei Hong, Zhigang Liu, Haichuan Su, Zhentian Liu, Caixia Wang, Qing Pu, Hui Guo, Xuhong Min, Yifei Chen
Journal: Journal of Clinical Oncology (2024)

e20106 Background: In the phase 3 ASTRUM-005 study (NCT04063163), serplulimab, an anti-PD-1 monoclonal antibody, combined with chemotherapy, demonstrated promising antitumor activity as first-line treatment in patients with extensive-stage small cell lung cancer (ES-SCLC). This led to its approval by the NMPA and designation as an orphan drug by the FDA. Here, we present a multicenter cohort study investigating the real-world efficacy and safety of first-line serplulimab-based immunochemotherapy for ES-SCLC in China. Methods: This cohort study enrolled adult patients with ES-SCLC at 12 sites in China from April 2022 to December 2023. These patients received at least two cycles of first-line serplulimab combined with an etoposide-platinum regimen and underwent at least one response assessment. The primary endpoint was real-world progression-free survival (rwPFS). Secondary endpoints included overall survival (OS), objective response rate (ORR), and safety profiles. Results: A total of 420 patients were enrolled and evaluated for both efficacy and safety. The participants had a median age of 63 years (range 30-84), with 361 (85.95%) being male and 310 (73.81%) having a history of smoking. Most patients (386, 91.91%) had an ECOG PS of 0 or 1. Comorbidities, excluding other primary tumors, were present in 40.95% (172 patients). Liver and brain metastases were observed in 32.14% (n = 135) and 21.67% (n = 91), respectively. The median number of immunochemotherapy cycles was 4 (range 2-6), with 45.24% (n = 190) receiving more than 4 cycles. The median rwPFS was 9.1 months (95% CI 8.2-9.7), with a 1-year rwPFS rate of 34.3%, surpassing the 1-year PFS rate of 28.2% reported for the Asian in the ASTRUM-005 study. The median rwPFS was 9.8 months (95% CI 9.1-12.8) in patients without liver metastasis, significantly longer than the 6.7 months (95% CI 6.1-8.7) in patients with liver metastasis ( P &lt; 0.0001). Patients who received radiotherapy also had a significantly longer median rwPFS of 9.8 months (95% CI 8.6-15.1) compared to 8.7 months (95% CI 7.3-9.6) for patients who did not receive radiotherapy ( P = 0.022). Additionally, patients who received &gt; 4 cycles of immunochemotherapy had a median rwPFS of 10.5 months (95% CI 9.3-13.3), which was significantly longer than the 6.6 months (95% CI 5.6-9.1) in patients who received ≤4 cycles ( P &lt; 0.0001). The ORR was 69.71%, and OS was not yet mature. Safety analysis revealed grade ≥3 AEs occurring in 19.05% of the cases. Conclusions: This cohort study reports the real-world survival outcomes of first-line serplulimab-based immunochemotherapy and provides valuable insights in a clinical setting. The study complements the ASTRUM-005 study, offering further evidence in ES-SCLC.
Tislelizumab combined with chemotherapy in advanced thymic tumors.
Authors: Shuke Li, Lantian Zhang, Jing He, Wen Gao
Journal: Journal of Clinical Oncology (2024)

e20139 Background: Thymic tumors refer to tumors derived from thymic epithelial cells, including thymoma and thymic carcinoma. Most cases in advanced stages when detected, and treatment is still controversial. Since 2018, immunotherapy has gradually been used for a variety of solid tumors and the curative efficacy has been notable. The efficacy of immunotherapy is increasingly improved with the increased expression of programmed death-ligand 1 (PD-L1) by tumor cells. The thymus is an immune-rich organ. PD-L1 expression ranges from 23% to 92% in thymoma, and from 36% to 100% in thymic carcinoma. Thus, immunotherapy has been implicated as having broad prospects in the treatment of thymic tumors. Tislelizumab is an inhibitor of PD-1, which has shown preliminary anti-tumor effects in various solid tumors. The combination of immunotherapy and chemotherapy has produced excellent anti-tumor activity for various types of tumors. However, there is a lack of clinical trial data to support the application of tislelizumab for the treatment of advanced thymic tumors. In this article, the efficacy and safety of tislelizumab combined with chemotherapy were analyzed in eight patients with advanced thymic tumors to provide data for the use of this monoclonal antibody as first-line treatment of advanced thymic tumors. Methods: Here, after obtaining fully informed consent, we report cases involving eight patients with advanced thymic tumors treated with tislelizumab combined with chemotherapy. The clinical characteristics, lesion changes, treatment process, drugs used, drug efficacy, complications or adverse reactions were recorded and followed up to evaluate the efficacy and safety of tislelizumab combined with chemotherapy in the treatment of advanced thymic tumors. Results: This article reports eight cases of advanced thymic tumor treated with tislelizumab combined with chemotherapy. Two patients received tislelizumab combined with chemotherapy as first-line treatment, and the remaining six patients were treated with tislelizumab after poor response to chemotherapy. Five patients achieved a partial response to the combined treatment. Of these, the partial response was retained in three patients after switching to tislelizumab monotherapy. The remaining three patients displayed stable disease after the combined treatment. There were no serious immune-related adverse events during treatment. The side effects of tislelizumab combined with chemotherapy were well tolerated. Conclusions: No clinical study of immunotherapy combined with standard chemotherapy as first-line treatment for advanced unresectable or metastatic thymic epithelial tumors has been described. This article provides strong evidence for the early application or even first-line use of tislelizumab combined with chemotherapy for advanced thymic epithelial tumors. More clinical studies are needed to evaluate the efficacy and safety of tislelizumab in thymic tumors.
APP fragment controls both ionotropic and non-ionotropic signaling of NMDA receptors
Authors: Jade Dunot, Sebastien Moreno, Carine Gandin, Paula A. Pousinha, Mascia Amici, Julien Dupuis, Margarita Anisimova, Alex Winschel, Magalie Uriot, Samuel J. Petshow, Maria Mensch, Ingrid Bethus, Camilla Giudici, Heike Hampel, Benedikt Wefers, Wolfgang Wurst, Ronald Naumann, Michael C. Ashby, Bodo Laube, Karen Zito, Jack R. Mellor, Laurent Groc, Michael Willem, Hélène Marie
Journal: Neuron (2024)

NMDA receptors (NMDARs) are ionotropic receptors crucial for brain information processing. Yet, evidence also supports an ion-flux-independent signaling mode mediating synaptic long-term depression (LTD) and spine shrinkage. Here, we identify AETA (Aη), an amyloid-β precursor protein (APP) cleavage product, as an NMDAR modulator with the unique dual regulatory capacity to impact both signaling modes. AETA inhibits ionotropic NMDAR activity by competing with the co-agonist and induces an intracellular conformational modification of GluN1 subunits. This favors non-ionotropic NMDAR signaling leading to enhanced LTD and favors spine shrinkage. Endogenously, AETA production is increased by in vivo chemogenetically induced neuronal activity. Genetic deletion of AETA production alters NMDAR transmission and prevents LTD, phenotypes rescued by acute exogenous AETA application. This genetic deletion also impairs contextual fear memory. Our findings demonstrate AETA-dependent NMDAR activation (ADNA), characterizing AETA as a unique type of endogenous NMDAR modulator that exerts bidirectional control over NMDAR signaling and associated information processing.
The Adipose Tissue Confined in the Atrio-Ventricular Groove can be used to Assess Atrial Epicardial Adipose Tissue and Atrial Dysfunction during Cardiac Magnetic Resonance Imaging
Authors: Jonathan Bialobroda, Khaoula Bouazizi, Maharajah Ponnaiah, Nadjia Kachenoura, Etienne Charpentier, Mohamed Zarai, Karine Clement, Fabrizio Andreelli, Judith Aron-Wisnewsky, Stéphane N Hatem, Alban Redheuil
Journal:  (2024)

The growing interest in epicardial adipose tissue (EAT) as a biomarker of atrial fibrillation is limited by the difficulties in isolating EAT from other paracardial adipose tissues. We tested the feasibility and value of measuring the pure EAT contained in the atrioventricular groove (GEAT) using cardiovascular magnetic resonance (CMR) imaging in patients with distinct metabolic disorders.
Phase II study of anlotinib plus durvalumab and chemotherapy as first-line treatment in extensive-stage small cell lung cancer (ES-SCLC): Efficacy and safety analysis.
Authors: Lijuan Chen, Yanqiu Zhao
Journal: Journal of Clinical Oncology (2024)

e20131 Background: The combination of PD-L1 Checkpoint inhibitor and chemotherapy has revolutionized the first-line standard of care of ES-SCLC, yet the prognosis still need to be improved. In this phase 2 study, we aimed to enhance the patients benefit by adding anlotinib to durvalumab and chemotherapy, assessing its efficacy and safety. Methods: Eligible treatment naïve ES-SCLC patients, aged 18-75 years, were enrolled. Anlotinib + durvalumab + etoposide + carboplatin or cisplatin was administered for 4-6 cycles, followed by anlotinib and durvalumab maintenance until disease progression or intolerable toxicity. During the treatment, dose reduction of anlotinib was permitted, which could be reduced to 10mg or 8mg if it was intolerable. The primary endpoint is overall objective response rate (ORR), secondary endpoints are PFS and safety. Results: Between December 2020 and June 2022, 22 patients with extensive-stage SCLC were enrolled, including 8 patients (36.4%) with brain metastases and 11 patients (50%) with liver metastases. The median age was (39-73) years, 15 patients were males (68.2%). ORR was 100%, with 27.3% complete response rate (CR). The median PFS of all patients was 8.51months, and the PFS of patients with liver metastasis and brain metastasis were 9.43 months and 8.51 months respectively. The median OS was not reached. The most common grade ≥3 TEAEs ( &gt; 10% incidence) included neutropenia and leukopenia (each 16.7%, 2/22), no new safety signals were observed. No grade 5 AE occurred. Conclusions: Durvalumab plus anlotinib and chemotherapy demonstrated promising PFS, ORR and manageable safety profile for the first-line treatment of ES-SCLC. Clinical trial information: NCT04660097 .
Clinical outcomes, demographics and associative analysis of lung cancer patients with Lambert-Eaton myasthenic syndrome: Insights from the National Inpatient Sample (NIS) database.
Authors: Fehmida Laxmidhar, Rushin Patel, Darshil Patel, Zalak Patel, Mrunal Patel, Khushboo Lakhatariya, Dhruvkumar Gadhiya
Journal: Journal of Clinical Oncology (2024)

e20134 Background: Lambert-Eaton myasthenic syndrome (LEMS) is a rare neuromuscular junction disorder that may present as a paraneoplastic syndrome or a primary autoimmune disorder. Approximately 60% of LEMS patients have an underlying tumor, with the paraneoplastic form predominantly associated with small cell lung cancer (SCLC). Understanding the clinical outcomes and risks associated in lung cancer patients with LEMS is crucial in effective management of such patients. Methods: This retrospective study utilized inpatient hospitalization data from the National Inpatient Sample (NIS) between January 1, 2016, and December 31, 2019. Data of patients with a primary or secondary discharge diagnosis of lung cancer (ICD10-CM codes C34, C78.0, C46.5, D02.2) were obtained. Then, out of this population, we identified Lambert-Eaton myasthenic syndrome with ICD-10 codes (G70.80, G70.81, G73.1). The objective was to run a descriptive analysis of clinical outcomes, risks, demographics and associations of LEMS in patients with lung cancer. Results: A total of 204 cases of lung cancer hospitalizations with LEMS were analyzed. The mean age was 68.23 years, with a slight female (51.72%) preponderance as compared to male (48.28%). Race distribution revealed increased prevalence in White Caucasians (83%), followed by Black (7%), Hispanic (4.5%), Asian or Pacific Islander (3%), Native American (0.5%), and Other (2%). The majority were covered by Medicare (66.33%), followed by private insurance (26.13%). The mortality rate was 8.9%, with a mean length of stay of 10.35 days and mean hospital charges of $118,676. Clinical outcomes and risks were analyzed, with sepsis occurring in 17.6% of cases, pneumonia in 22.5%, and acute respiratory failure in 26.9%. Intubation/mechanical ventilation was necessary in 18.1% of cases. The incidence of urinary tract infection (UTI) was 16.7%, acute kidney injury (AKI) was 17.2%, and venous thromboembolism (VTE) was 6.4%. Additionally, interventions such as intravenous immunoglobulin (IVIG) therapy and blood transfusions were also noted. Conclusions: This study provides insights into the demographic characteristics and clinical outcomes of lung cancer patients with Lambert-Eaton myasthenic syndrome (LEMS). The findings highlight the need for comprehensive management strategies targeting associated complications like acute respiratory failure, intubation and need for mechanical ventilation, pneumonia, UTI, AKI, and VTE to improve patient outcomes, quality of care and effective patient education with regards to their diagnosis of LEMS in lung cancer.
Safety in the use of granulocyte-colony stimulating factor during concurrent chemotherapy and thoracic radiotherapy in patients with small-cell lung cancer: A meta-analysis.
Authors: Fabíola Furtuoso Zarpelão, Larissa Irigoyen Teixeira Barbosa, Jhefferson da Silva Sousa, Luísa Napoleão, Abner Lucas De Souza, Maysa Vilbert
Journal: Journal of Clinical Oncology (2024)

e20124 Background: There is an ongoing debate about whether patients with small cell lung cancer (SCLC) undergoing concurrent chemoradiotherapy should receive granulocyte-colony stimulating factor (G-CSF). The main concern relies on safety issues. Therefore, we performed a systematic review and meta-analysis to assess the safety and efficacy of prophylactic G-CSF use in patients with SCLC receiving concurrent chemoradiotherapy. Methods: We systematically searched the MEDLINE, Cochrane, and EMBASE databases up to December 2023 for studies assessing prophylactic use of G-CSFs versus non-prophylactic use in SCLC undergoing concurrent chemoradiotherapy. We included randomized and non-randomized clinical trials. The main safety outcomes were thrombocytopenia, febrile neutropenia, anemia, and radiotherapy toxicity. We performed statistical analysis using RevMan 5.4.1 and pooled odds ratio (OR) and 95% confidence interval (95%CI) of binary outcomes. We defined a significant threshold as p-value &lt; 0.05. We used I² statistics for heterogeneity, with I² &gt; 25% being defined as high heterogeneity. Results: We included five studies with a total of 774 patients, of whom 322 (42%) received G-CSF prophylactically, and 452 (58%) were in the control group. The majority of patients (97.5%) presented with Limited Stage disease. The minimum follow-up period had a median duration of 16.9 months, while the maximum follow-up extended to a median of 45 months (Table). Patients in the prophylactic group had a significantly lower incidence of neutropenia (OR: 0.34; 95% CI: 0.14-0.85; p = 0.02) than those who did not use G-CSF prophylactically. Radiotherapy toxicity (OR: 0.98; 95% CI: 0.63-1.53; p = 0.93) and severe hematological toxicity (grade III-IV) were similar in both groups. Hematological toxicity included thrombocytopenia (OR: 1.21; 95% CI: 0.32-4.58; p = 0.78), febrile neutropenia (OR: 1.11; 95% CI: 0.29-4.28; p = 0.88), and anemia (OR: 0.51; 95% CI: 0.13-1.97; p = 0.33). Conclusions: Our systematic review and meta-analysis supports the prophylactic use of G-CSF during concurrent chemoradiotherapy for patients with SCLC. Prophylactic G-CSF promoted a significant reduction in the incidence of neutropenia without any hematologic or radiotherapy-related toxicity increase. Incorporating G-CSF prophylaxis into SCLC chemoradiotherapy regimens can be a beneficial strategy for minimizing neutropenic complications without compromising overall treatment safety. [Table: see text]
Biases in ARG-based inference of historical population size in populations experiencing selection
Authors: Jacob I Marsh, Parul Johri
Journal: Molecular Biology and Evolution (2024)

Inferring the demographic history of populations provides fundamental insights into species dynamics and is essential for developing a null model to accurately study selective processes. However, background selection and selective sweeps can produce genomic signatures at linked sites that mimic or mask signals associated with historical population size change. While the theoretical biases introduced by the linked effects of selection have been well established, it is unclear whether ancestral recombination graph (ARG)-based approaches to demographic inference in typical empirical analyses are susceptible to misinference due to these effects. To address this, we developed highly realistic forward simulations of human and Drosophila melanogaster populations, including empirically estimated variability of gene density, mutation rates, recombination rates, purifying, and positive selection, across different historical demographic scenarios, to broadly assess the impact of selection on demographic inference using a genealogy-based approach. Our results indicate that the linked effects of selection minimally impact demographic inference for human populations, although it could cause misinference in populations with similar genome architecture and population parameters experiencing more frequent recurrent sweeps. We found that accurate demographic inference of D. melanogaster populations by ARG-based methods is compromised by the presence of pervasive background selection alone, leading to spurious inferences of recent population expansion, which may be further worsened by recurrent sweeps, depending on the proportion and strength of beneficial mutations. Caution and additional testing with species-specific simulations are needed when inferring population history with non-human populations using ARG-based approaches to avoid misinference due to the linked effects of selection.
The brain microvasculature is a primary mediator of interferon-α neurotoxicity in human cerebral interferonopathies
Authors: Barney Viengkhou, Emina Hayashida, Sarah McGlasson, Katie Emelianova, Deborah Forbes, Stewart Wiseman, Joanna Wardlaw, Rovin Verdillo, Sarosh R. Irani, Darragh Duffy, Fredrik Piehl, Lipin Loo, Axel Pagenstecher, G. Greg Neely, Yanick J. Crow, Iain L. Campbell, David P.J. Hunt, Markus J. Hofer
Journal: Immunity (2024)

Aicardi-Goutières syndrome (AGS) is an autoinflammatory disease characterized by aberrant interferon (IFN)-α production. The major cause of morbidity in AGS is brain disease, yet the primary source and target of neurotoxic IFN-α remain unclear. Here, we demonstrated that the brain was the primary source of neurotoxic IFN-α in AGS and confirmed the neurotoxicity of intracerebral IFN-α using astrocyte-driven Ifna1 misexpression in mice. Using single-cell RNA sequencing, we demonstrated that intracerebral IFN-α-activated receptor (IFNAR) signaling within cerebral endothelial cells caused a distinctive cerebral small vessel disease similar to that observed in individuals with AGS. Magnetic resonance imaging (MRI) and single-molecule ELISA revealed that central and not peripheral IFN-α was the primary determinant of microvascular disease in humans. Ablation of endothelial Ifnar1 in mice rescued microvascular disease, stopped the development of diffuse brain disease, and prolonged lifespan. These results identify the cerebral microvasculature as a primary mediator of IFN-α neurotoxicity in AGS, representing an accessible target for therapeutic intervention.
Candidaemia and <i>Candida</i> colonization in patients with epidermal necrolysis: a retrospective case series
Authors: Louise Chantelot, Antoine Gaillet, Françoise Botterel, Saskia Ingen-Housz-Oro, Nicolas de Prost
Journal: British Journal of Dermatology (2024)

Sepsis is a leading cause of death in patients with epidermal necrolysis (EN). However, fungal infections have rarely been reported. From a monocentric retrospective study conducted between 2000 and 2023 in the medical intensive care unit of the reference centre for severe drug reactions in France, we report on the epidemiology of candidaemia and Candida sp. colonization in patients with EN. Of 155 patients with EN who were admitted to the ICU, 36 had a positive Candida sp. skin culture without candidaemia, 12 developed candidaemia and 107 had a negative skin culture and no candidaemia. Skin cultures showed a good sensitivity [89%; 95% CI (52–100%)] and excellent negative predictive values [99%; 95% CI (94–100%)] for candidaemia.
NRG-BN002: Phase I study of ipilimumab, nivolumab, and the combination in patients with newly diagnosed glioblastoma
Authors: Andrew E Sloan, Kathryn Winter, Mark R Gilbert, Kenneth Aldape, Serah Choi, Patrick Y Wen, Nicholas Butowski, Fabio M Iwamoto, Raju R Raval, Alfredo D Voloschin, Carlos Kamiya-Matsuoka, Minhee Won, Minesh P Mehta
Journal: Neuro-Oncology (2024)

Abstract Background Immune checkpoint inhibitors (ICIs) have efficacy in several solid tumors but limited efficacy in glioblastoma (GBM). This study evaluated the safety of anti-CTLA-4 and anti-PD-1 ICIs alone or in combination in newly diagnosed GBM after completion of standard radiochemotherapy with the subsequent intent to test combinatorial ICIs in this setting. Methods The primary endpoint was dose-limiting toxicity (DLT) for adults with unifocal, supratentorial newly diagnosed GBM after resection and chemoradiation. Ipilimumab and nivolumab were tested separately and in combination with a planned expansion cohort dependent upon DLT results. Results Thirty-two patients were enrolled at 9 institutions: 6 to each DLT assessment cohort and 14 to the expansion cohort. Median age: 55 years, 67.7% male, 83.9% White. Treatment was well tolerated with 16% Grade 4 events; the combination did not have unexpectedly increased toxicity, with no Grade 5 events. One DLT was seen in each single-agent treatment; none were observed in the combination, leading to expanded accrual of the combined treatment. The median follow-up was 19.6 months. For all patients receiving combination treatment, median overall survival (OS) and progression-free survival (PFS) were 20.7 and 16.1 months, respectively. Conclusions IPI and NIVO are safe and tolerable with toxicities similar to those noted with other cancers when given in combination with adjuvant temozolomide for newly diagnosed GBM. Combination IPI + NIVO is not substantially more toxic than single agents. These results support a subsequent efficacy trial to test the combination of ICIs in Phase II/III for patients with newly diagnosed GBM. ClinicalTrials.gov Registration NCT02311920
Uncertain Answers — Proton-Pump Inhibition in the ICU
Authors: Samuel M Brown
Journal: New England Journal of Medicine (2024)

A critical care clinician's job includes administering timely and tailored antibiotics, expediting appropriate surgery, supporting a patient's beleaguered body and mind until they are ready to recover, and preventing complications in this vulnerable state. This is surprisingly strenuous work, even if it is often, appropriately, protocolized. The aphorism "an ounce of prevention is worth a pound of cure" persists because it feels true. So, when trial data suggest that an ounce of prevention may actually kill you, it cuts hard against the grain — which brings us to the question of gastric acid suppression among patients undergoing mechanical ventilation in . . .