tbuckley/cabot-search huggingface dataset:
Sex‐Specific Regulation of Interferon‐γ Cytotoxicity in Mouse Liver by Autophagy
Authors: Yang Shen, Francesca Cingolani, Shoaib Ahmad Malik, Jing Wen, Yunshan Liu, Mark J. Czaja
Journal: Hepatology (2021)

Background and Aims Interferon‐γ (IFNγ) is a central activator of immune responses in the liver and other organs. IFNγ triggers tissue injury and inflammation in immune diseases, which occur predominantly in females for unknown reasons. Recent findings that autophagy regulates hepatotoxicity from proinflammatory cytokines led to an examination of whether defective hepatocyte autophagy underlies sex‐specific liver injury and inflammation induced by IFNγ. Approach and Results A lentiviral autophagy‐related 5 ( Atg5 ) knockdown was performed to decrease autophagy‐sensitized alpha mouse liver (AML 12) hepatocytes to death from IFNγ in combination with IL‐1β or TNF. Death was necrosis attributable to impaired energy homeostasis and adenosine triphosphate depletion. Male mice with decreased autophagy from a tamoxifen‐inducible, hepatocyte‐specific Atg5 knockout were resistant to IFNγ hepatotoxicity whereas female knockout mice developed liver injury and inflammation. Female mice had increased IFNγ‐induced signal transducer and activator of transcription 1 (STAT1) levels compared to males. Blocking STAT1, but not interferon regulatory factor 1, signaling prevented IFNγ‐induced hepatocyte death in autophagy‐deficient AML12 cells and female mice. The mechanism of death is STAT1‐induced overexpression of nitric oxide synthase 2 (NOS2) as in vitro hepatocyte death and in vivo liver injury were blocked by NOS2 inhibition. Conclusions Decreased hepatocyte autophagy sensitizes mice to IFNγ‐induced liver injury and inflammation through overactivation of STAT1 signaling that causes NOS2 overexpression. Hepatotoxicity is restricted to female mice, suggesting that sex‐specific effects of defective autophagy may underlie the increased susceptibility of females to IFNγ‐mediated immune diseases.
Pharmacological Inhibition of the Nod-Like Receptor Family Pyrin Domain Containing 3 Inflammasome with MCC950
Authors: Sarah E. Corcoran, Reena Halai, Matthew A. Cooper
Journal: Pharmacological Reviews (2021)

Activation of the Nod-like receptor family pyrin domain containing 3 (NLRP3) inflammasome drives release of the proinflammatory cytokines interleukin (IL)-1<i>β</i> and IL-18 and induces pyroptosis (lytic cell death). These events drive chronic inflammation, and as such, NLRP3 has been implicated in a large number of human diseases. These range from autoimmune conditions, the simplest of which is NLRP3 gain-of-function mutations leading to an orphan disease, cryopyrin-associated period syndrome, to large disease burden indications, such as atherosclerosis, heart failure, stroke, neurodegeneration, asthma, ulcerative colitis, and arthritis. The potential clinical utility of NLRP3 inhibitors is substantiated by an expanding list of indications in which NLRP3 activation has been shown to play a detrimental role. Studies of pharmacological inhibition of NLRP3 in nonclinical models of disease using MCC950 in combination with human genetics, epigenetics, and analyses of the efficacy of biologic inhibitors of IL-1<i>β</i>, such as anakinra and canakinumab, can help to prioritize clinical trials of NLRP3-directed therapeutics. Although MCC950 shows excellent (nanomolar) potency and high target selectivity, its pharmacokinetic and toxicokinetic properties limited its therapeutic development in the clinic. Several improved, next-generation inhibitors are now in clinical trials. Hence the body of research in a plethora of conditions reviewed herein may inform analysis of the potential translational value of NLRP3 inhibition in diseases with significant unmet medical need. <h3>Significance Statement</h3> The nod-like receptor family pyrin domain containing 3 (NLRP3) inflammasome is one of the most widely studied and best validated biological targets in innate immunity. Activation of NLRP3 can be inhibited with MCC950, resulting in efficacy in more than 100 nonclinical models of inflammatory diseases. As several next-generation NLRP3 inhibitors are entering proof-of-concept clinical trials in 2020, a review of the pharmacology of MCC950 is timely and significant.
A novel leukemic route of mutant NPM1 through nuclear import of the overexpressed long noncoding RNA LONA
Authors: Morgane Gourvest, Etienne De Clara, Hsin-Chieh Wu, Christian Touriol, Fabienne Meggetto, Hugues De Thé, Stéphane Pyronnet, Pierre Brousset, Marina Bousquet
Journal: Leukemia (2021)
Evaluating the role of aromatase inhibitors (AIs) in the treatment of endometrial stromal sarcomas (ESS).
Authors: Fionnuala Crowley, Karen Anne Cadoo, Sarah Chiang, Jennifer Jean Mueller, Martee Leigh Hensley, Roisin Eilish O'Cearbhaill
Journal: Journal of Clinical Oncology (2021)

5575 Background: Endometrial stromal sarcomas (ESS) account for &lt; 20% of uterine sarcomas. They usually express estrogen and progesterone receptors (ER/PR) and are considered hormone sensitive. Due to the rarity of these tumors, large clinical trials studying optimal treatment have not been possible. This study represents the largest retrospective study of ESS treated with AI. Methods: The clinicopathological variables and outcomes of patients (pts) with pathologically confirmed low grade ESS treated with AI at our institution between 1998-2020 were recorded. Results: 48 pts with ESS treated with AI were identified. They had a median age of 54 years (range 23-84) and BMI of 27 (range 20-50). 79% were white. 6 (12%), 9 (19%), 14 (29%) and 19 pts (40%) had stage 1,2,3,4 ESS, respectively. 37 (77%) were ER+/PR+; 2 (4%) ER+/PR- and 9 pts (19%) had unknown ER/PR status. All pts were postmenopausal at AI initiation. 12 pts (25%) had a synchronous cancer (5 of these had breast cancer {3 of the 5 presented post tamoxifen}). 23 pts (48%) received megestrol acetate and 25 (52%) an AI as first line hormonal manipulation. During their disease course, 35 pts (73%) received letrozole, 21 (44%) anastrozole and 19 (39.6%) exemestane. 22 pts (46%) were treated with more than one AI. 28 pts (58%) reported side-effects; arthralgia (33%) being the most common. 10 pts (21%) discontinued AI due to toxicity; 12 pts (25%) switched AI for toxicity (with improved tolerance in 67% of these pts). Among the 24 pts (50%) with measurable disease there were 2 partial responses (objective response rate of 8.3%). 1-year disease control rate (DCR) was (79%) for all pts and 58% in stage 4 disease. Median PFS for 1 st line AI was 161.6 months (95% CI 48.5 to 274.7). Conclusions: This study represents the largest study of AI use in ESS to date. We found the ORR to be more modest than previously reported. The majority of pts had prolonged stable disease with a DCR of 58% even in stage 4 disease. Pts who progress on one AI may benefit from trial of a 2 nd AI. A phase 2 study of interruption versus maintenance AI in locally advanced/metastatic ESS is currently underway (NCT03624244).
HERIZON: A phase 1B/2 open-label study of imu-131 HER2/neu peptide vaccine PLUS standard of care chemotherapy with randomization in phase 2 in patients with HER2/neu overexpressing metastatic or advanced adenocarcinoma of the stomach or gastroesophageal junction.
Authors: Rita Laeufle, Marina Maglakelidze, Iurie Bulat, Dinara Ryspayeva, Andric Zoran, Tanuj Chawla, Ivan Nikolic, Rajnish Nagarkar, Giri Venkata, Vaibhav Choudhary, Davorin Radosavljevic, Rajesh Kumar Singh, Ursula Wiedermann, Anthony J Good, Nick Ede, Leslie Mi Ok Chong
Journal: Journal of Clinical Oncology (2021)

e16065 Background: The phase 2 part of the study hypothesizes HER-Vaxx (IMU-131) will provide treatment benefits consistent with traditional monoclonal antibodies that target HER2 in patients with confirmed Her2+ advanced or metastatic gastric cancer with a corresponding adaptive immune response without added toxicity. In the phase 1b dose finding part of the study tumor response of patients who received 50ug dose strongly correlated with antibody levels with 50ug selected as the phase 2 dose (Wiedermann et. al., 2019). Phase 2 is a randomized two arm study of either HER-Vaxx plus standard chemotherapy or standard chemotherapy alone. The primary endpoint is overall survival, with progression-free survival, safety and immune related changes in humoral and cellular immunogenicity secondary endpoints. Methods: Patients received SOC chemotherapy for a maximum of 6 cycles with the HER-Vaxx group also receiving 50ug dose of IMU-131 at Baseline/Day 0, Day 14, Day 35, Day 77 and then every 63 days until disease progression. The per protocol pre-planned first interim analysis (OS, PFS and safety) in a total of 27 patients after 15 progression events was reviewed by the independent data monitoring committee (IDMC). Results: Within ITT analysis, 8 of 27 patients died on the control arm and 4 on the HER-Vaxx plus SOC chemotherapy arm with an overall survival HR of 0.418 (2 sided 80% CI: 0.186, 0.942) and a 1-sided p-value of 0.083. Out of 27 patients, 9 patients progressed on the control arm while 6 patients progressed on the HER-Vaxx plus SOC chemotherapy arm with a HR of 0.532 (2 sided 80% CI: 0.267, 1.060) and a 1-sided p-value of 0.086. A robust HER2 specific antibody response developed in the HER-Vaxx arm compared to the control arm whereas there was no difference in safety between the two treatment arms. Conclusions: The IDMC confirmed that the safety of the study was favorable with no added toxicity of HER-Vaxx and SOC chemotherapy with a favorable risk-benefit for the combination. The study has completed enrollment and final data is expected in late 2021. Clinical trial information: NCT02795988.
Invasive Pulmonary Aspergillosis in Acute Leukemia in the Era of New Antifungal Treatment and Prophylaxis Is Still Frequent, Even in Patients with Acute Lymphoblastic Leukemia, and Adversely Affects the Overall Treatment Outcome. Results of a 5-Year Study at a Single Institution
Authors: Chiara Cattaneo, Doriana Gramegna, Chiara Pagani, Erika Borlenghi, Michele Malagola, Elisa Cerqui, Angela Passi, Francesca Schieppati, Claudia Crippa, Daniela Dalceggio, Cecilia Carbone, Anna Maria Pelizzari, Margherita Sciumé, Alessandro Re, Domenico Russo, Giuseppe Rossi
Journal: Blood (2017)
Excess body weight association with various cancer: A United States population-based study 2021.
Authors: Akram Alkrekshi, Raul Arroyo Suarez, Ahmad Nader Kassem
Journal: Journal of Clinical Oncology (2021)

e18558 Background: Excess body weight (EW) is a rising healthcare issue affecting over two-thirds of the United States (US) population, and it is a risk factor for various cancer. Methods: We used Explorys, IBM, a US database that includes ̃ 73 million patients. We evaluated non-gastrointestinal cancers prevalence based on age (18-64 and ≥ 65 years; for female cancers 18-49 and ≥ 50 years), race; Caucasians (C) and African-Americans (AA), and weight; normal weight (N) with BMI 18.5- 24.9 kg/m 2 and EW for BMI ≥ 25 kg/m 2 . Compared to NW, the odds ratio (OR) and 95% confidence interval (CI) for multiple cancer rates in the EW group were calculated. p-value of &lt;0.001 was considered significant (S) and &gt; 0.001 as non-significant (NS). Results: A population of 26.9 million was included. C 85.6%, AA 14.4%. See table. Conclusions: A strong association between EW and urological cancers (prostate, bladder, renal), non-Hodgkin's lymphoma, multiple myelomas (MM), breast cancer, endometrial cancer, ovarian cancer in C 18-64 yrs but not in C ≥ 65 yrs with the exception for kidney cancer. A similar finding in AA 18-64 yrs for cancers of prostate, renal, breast, uterus, and MM compared to AA ≥ 65 yrs. EW is possibly more oncogenic earlier in life, especially in C.[Table: see text]
Concordancy of immunocytochemistry profiling of circulating tumor cells with immunohistochemistry for analysis of therapeutically relevant biomarkers.
Authors: Dadasaheb B Akolkar, Darshana Patil, Sudha S Murthy, Kiran Bendale, Revati Patil, Vineet Datta, Pradip Fulmali, Pooja Fulmali, Archana Adhav, Shoeb Patel, Rohit Chougule, Vishal Ranjan, Shabista Khan, Raja Dhasarathan, Sachin Apurwa, Stefan Schuster, Ajay Srinivasan, Rajan Datar
Journal: Journal of Clinical Oncology (2021)

3047 Background: Immunohistochemistry (IHC) profiling of tumor tissue is the present standard for evaluation of therapeutically relevant biomarkers such as ER, PR, HER2, AR, ARv7, PD-L1 and MMR for selection of targeted, endocrine and checkpoint inhibitor therapy selection. However, this critical analysis is dependent on availability of tumor tissue obtained by an invasive biopsy. Challenges to this analysis include insufficient tumor tissue and inability to perform a repeat biopsy to obtain fresh tumor tissue. We have previously described an approach for negative enrichment of Circulating Tumor Cells (CTCs) from peripheral blood and for Immunocytochemistry (ICC) profiling of these CTCs for detection of diagnostically relevant tissue of origin and subtype specific markers, concordant with tumor tissue analysis. Methods: In the present study, we determined concordance between tumor tissue (HPE) and CTCs (ICC) for ascertaining the status of therapeutically relevant markers ER, PR, HER2, AR, ARv7 PD-L1 and MMR. We evaluated 201 matched pairs of tumor tissue (FFPE blocks) and CTCs obtained from peripheral blood. Results: Among the 743 paired assays on matched tumor tissue and CTCs, concordance (positive or negative) was observed in 651 matched pairs (87.6%). The concordance was 82.9% for ER, 100% for PR, 90.2 % for Her2, 93.8% for AR, 90% for Arv7, 85.1% and 87.6% for PD-L1 clones 22c3 and 28-8, and 85.6% for MMR (MLH1, MSH2, MSH6, and PMS2). Conclusions: The study findings indicate that ICC analysis of CTCs may be able to substitute IHC analysis of tumor tissue for profiling of therapeutically relevant markers. This approach may have application in cases where tumor tissue may be limiting and / or where an invasive biopsy to obtain tumor tissue may be unviable.
Cancer stem cells as markers of bladder cancer recurrence.
Authors: Lyubov I. Belyakova, Aleksandr B. Sagakyants, Alexey N. Shevchenko, Elena V. Filatova, Viktor K. Khvan, Irina A. Khomutenko, Dmitry A. Shvyrev, Elena P. Ulianova, Elena S. Bondarenko, Inna A. Novikova
Journal: Journal of Clinical Oncology (2021)

e16511 Background: Bladder cancer (BC) is an urgent problem of oncology in the world, and without appropriate and timely treatment it can lead to severe disability and a significant deterioration in the quality of life of patients. BC accounts for 4.5% of the total cancer incidence. Cancer stem cells (CSCs) are actively involved in the development of recurrent malignant tumors, and also play an important role in the development of chemotherapy and radioresistance of tumor cells. CSCs in BC are poorly studied. Our purpose was to determine the CSC numbers in patients with non-muscle invasive BC. Methods: The study included 7 patients with newly diagnosed stage I BC, G2, intermediate prognosis according to the EORTC scoring system. All patients underwent transurethral resection of the bladder, and tumor tissues (TT, size up to 1.5 cm) and perifocal tissues (PT, at least 1.0 cm from the tumor) were obtained. The specimens were disintegrated to obtain the cell suspension, and the CSC percentages were determined using the FACS Canto II flow cytometer with monoclonal antibodies to CD45-APC-Cy7, CD24-FITC, and CD133–PE according to the manufacturer's instructions (BD, USA). Numbers of cells with CSC markers (CD24+, CD44+, CD133+, CD24+CD44+, CD44+CD133+) were calculated as the percentage from the total number of CD45 - -cells. The results of statistical processing were presented as the arithmetic mean and the standard error of the arithmetic mean. The significance of differences between the samples was assessed using the Mann-Whitney’s nonparametric test. Results: The numbers of CD45 - -cells were similar in TT and PT (61.3±5.8 and 71.8±12.6). The relative numbers of cells with CSC phenotypic markers, such as CD24, CD44, were 77% and 58% higher in TT than in PT: 18.3±3.5 vs. 4.3±2.1 and 15.5±5.3 vs. 6.5±0.8, respectively; p≤0.05. The number of CD133+ cells was 83% higher in PT compared to TT - 41.6±12.1 vs. 22.7±7.6. The numbers of CD44+CD24+ and CD44+CD133+ cells in TT were higher than in PT by 80% and 63%, respectively: 10.3±4.9 vs. 2.1±0.4, 9.0±4.5 vs. 3.3±0.9, p≤0.05. CD44-CD24+ CD133+ cells were not detected in PT. Conclusions: The results indicate the peculiarities of the distribution of CSCs in TT and PT, which can be used to predict the risk of the disease recurrence and/or progression, and also help to evaluate results of the treatment.
Association of LRP1B mutants with immune biomarkers in Chinese non-small cell lung cancer patients.
Authors: Yi Zhang, Taiyan Guo, Xia You, Qin Zhang, Qianqian Duan, Chuang Qi
Journal: Journal of Clinical Oncology (2021)

e21060 Background: LRP1B (low-density lipoprotein receptor-related protein 1B) is frequently mutated in non-small cell lung cancer (NSCLC). Previous studies showed LRP1B mutations were associated with prolonged survival in melanoma and NSCLC immunotherapy cohort. Higher tumor mutation burden was found in LRP1B mutated patients, suggesting potential benefit of immunotherapy. Herein, we investigate the relationship of LRP1B and immunotherapy biomarker in lager cohort of Chinese and Western NSCLC patients. Methods: Next-generation sequencing data and clinical data were collected from 1053 TCGA NSCLC patients (Western cohort). A 539-gene panel targeted sequencing assay was performed on FFPE tumor samples from 1056 Chinese pan-cancer patients (Chinese cohort). Both LRP1B mutation ratio and TMB were calculated on the two cohorts following the same criteria. TMB-H was defined as the top quartile of all TMB values. Results: In total, 208 (20%) of the 1056 Chinese patients and 385 (37%) of the 1053 Western patients had at least one mutation of LRP1B genes (LRP1B mutant group). The frequency of LRP1B mutation between Western cohort and Chinese cohort had significant difference (20% vs. 37%, p＜0.001). In both cohorts, TMB was higher in the LRP1B mutant group compared to non-LRP1B mutant group. In Chinese cohort, PD-L1 positive was not associated with LRP1B mutation. Patients with LRP1B mutation were associated with prolonged survival in Western immunotherapy cohort. Conclusions: Our study provided a landscape of LRP1B mutations in a much larger Chinese NSCLC group, which could be a valuable complement to TCGA dataset and previous study. Results of our study was consistent with previous studies. Both in Chinese and Western cohorts, the higher TMB in LRP1B mutant patients suggested potential efficacy from immunotherapy of LRP1B mutant group. This result and the potential predictive value of LRP1B in immunotherapy should be validation in a larger Chinese LRP1B mutant cohort in the further.
The effect and safety of anlotinib combined with irinotecan or docetaxel in small-cell lung cancer (SCLC) relapsed within six months: A single-arm phase I study.
Authors: Minna Zhang, Xueqin Chen, Hong Jiang, Jiaoli Wang, Jian Ye, Shenglin Ma, Bing Xia
Journal: Journal of Clinical Oncology (2021)

e20583 Background: Current standard of care for SCLC relapsed within six months after first-line treatment was mainly chemotherapy alone, such as irinotecan or docetaxel, of which the clinical benefit is unsatisfactory. Anlotinib, a novel oral multi-target tyrosine kinase inhibitor primarily targeting VEGFR2/3, FGFR1-4, PDGFRα/β and c-Kit, significantly improved progression-free survival (PFS) and overall survival (OS) for SCLC in third-line setting and beyond treatment (ALTER1202 trial). Here, we conducted a single-arm phase II trial to evaluate the efficacy and safety of anlotinib combined with irinotecan or docetaxel in SCLC relapsed within six months after first-line treatment. Methods: Eligible patients with cytologically or histologically confirmed SCLC, aged 18-75 years, ECOG PS 0-1, relapsed within six months after first-line platinum-based treatment, received anlotinib (12mg, QD, from day 1 to 14 of a 21-day cycle) combined with irinotecan (65mg/m 2 , day1,8, q3w, up to 4 cycles) or docetaxel (60mg/m 2 , q3w, up to 4 cycles) until disease progression or intolerable toxicity. The primary endpoint was the objective response rate (ORR). Secondary endpoints included PFS, the disease control rate (DCR), OS and safety. Results: Between March 2020 and February 2021, 21 patients with a median age of 61.7 years, male (76.2%), ECOG PS 1 (81.0%), brain metastasis (42.9%), liver metastasis (38.1%), were enrolled in this trial. At data cut-off (February 8, 2021), 15 patients were evaluable, among which 5 patients reached partial response (PR) and 8 had stable disease (SD). The ORR was 33.3% (5/15) and the DCR was 86.7% (13/15), respectively. The median PFS was 4.0 months (95%Cl: 3.18-4.83). The most common grade 1-2 treatment-related adverse events (TRAEs) were weakness (64.7%), anorexia (41.2%), anemia (29.4%), hypertension (23.5%), leukopenia (17.6%), oral mucositis (17.6%). Grade 3 TRAEs mainly included leukopenia (11.8%), thrombocytopenia (11.8%) and anemia (5.9%). There were no grade 4 or higher toxicities. Conclusions: Anlotinib combined with irinotecan or docetaxel showed promising ORR, DCR and PFS in SCLC relapsed within six months after first-line platinum-based treatment and was well-tolerated. No unexpected toxicities were observed. Further exploration and longer follow-up are ongoing. Clinical trial information: NCT04757779.