tbuckley/cabot-search huggingface dataset:
Successful rapid desensitization in a glioma patient with procarbazine‐mediated anaphylaxis
Authors: Evelien M. Hutten, Annechien J. A. Lambeck, Hilda Dijkstra, Janine Nuver, Hanneke N. G. Oude Elberink, Annick A. J. M. Van de Ven
Journal: Allergy (2021)

Erythropoietin (EPO) is a haematopoietic hormone that regulates erythropoiesis, but the EPO-receptor (EpoR) is also expressed in non-haematopoietic tissues.Stimulation of the EpoR in cardiac and skeletal muscle provides protection from various forms of pathological stress, but its relevance for normal muscle physiology remains unclear.We aimed to determine the contribution of the tissue-specific EpoR to exercise-induced remodelling of cardiac and skeletal muscle.Baseline phenotyping was performed on left ventricle and m. gastrocnemius of mice that only express the EpoR in haematopoietic tissues (EpoR-tKO).Subsequently, mice were caged in the presence or absence of a running wheel for 4 weeks and exercise performance, cardiac function and histological and molecular markers for physiological adaptation were assessed.While gross morphology of both muscles was normal in EpoR-tKO mice, mitochondrial content in skeletal muscle was decreased by 50%, associated with similar reductions in mitochondrial biogenesis, while mitophagy was unaltered.When subjected to exercise, EpoR-tKO mice ran slower and covered less distance than wild-type (WT) mice (5.5 ± 0.6 vs. 8.0 ± 0.4 km/day, p < 0.01).The impaired exercise performance was paralleled by reductions in myocyte growth and angiogenesis in both muscle types.Our findings indicate that the endogenous EPO-EpoR system controls mitochondrial biogenesis in skeletal muscle.The reductions in mitochondrial content were associated with reduced exercise capacity in response to voluntary exercise, supporting a critical role for the extra-haematopoietic EpoR in exercise performance.
Doubling of median overall survival in a nationwide cohort of veterans with stage III non-small cell lung cancer in the durvalumab era.
Authors: Kamya Sankar, Alex K. Bryant, Michael Green, Nithya Ramnath
Journal: Journal of Clinical Oncology (2021)

8546 Background: The standard of care for patients with unresectable stage III non-small cell lung cancer (NSCLC) is concurrent chemoradiotherapy followed by durvalumab maintenance based on outcomes from the PACIFIC trial. However, PACIFIC did not include Veterans, a unique population with significant co-morbidities; thus, the impact of durvalumab on survival of Veterans with stage III NSCLC is unknown. Methods: Using the U.S. Department of Veterans Affairs Corporate Data Warehouse, patients with stage III non-small cell lung cancer who received chemoradiotherapy and at least one dose of durvalumab were selected. Kaplan-Meier survival analysis and univariate Cox proportional hazards modeling were used to determine progression-free survival (PFS), overall survival (OS) and independent predictors of PFS and OS. PFS was manually extracted by review of serial surveillance scans. All statistical computations were performed using SAS 9.4 software. Results: 1106 Veterans met our inclusion criteria. The median age was 69. 95.1% (n = 1052) were male. The median Charlson Comorbidity Index was 1. 86.4% (n = 956) reported current or former tobacco use. 48.1% (n = 532) had adenocarcinoma histology, 48.4% (n = 535) squamous cell, 0.5% (n = 5) large cell, 0.3% (n = 3) neuroendocrine, and 0.1% (n = 1) sarcomatoid. 60% (n = 619) had AJCC 8 th edition stage IIIA disease, 34.5% (n = 382) stage IIIB, and 3.3% (n = 36) stage IIIC. Median PFS was 19.9 months (95% CI: 16.9 – 23.6) and median OS was 34.9 months (95% CI: 29.7 – not reached). In univariate survival analyses, adenocarcinoma histology (HR 1.14, p = 0.03) predicted progression. Older age (HR 1.03, p &lt; 0.0001) and stage IIIB/IIIC disease (HR 1.05, p = 0.008) predicted inferior OS. 18.4% (n = 204) of patients completed all planned cycles of adjuvant durvalumab. The median number of durvalumab infusions received was 6 (range: 1 – 38). Among evaluable patients, 175 (19.4%) discontinued durvalumab for progression, 211 (23.4%) discontinued for suspected immune-related toxicity and 17 (1.9%) died during treatment. Conclusions: While several factors have led to the improvement of OS in patients with stage III NSCLC over time, we report a doubling of median OS in Veterans with stage III NSCLC who received chemoradiotherapy plus durvalumab as compared to historical cohorts who received chemoradiotherapy alone (1). Veterans in our study received a lower median number of durvalumab infusions as compared to patients in the PACIFIC trial (6 vs. 14), and a significant proportion discontinued durvalumab due to suspected immune-mediated toxicity (23.4%). If further analyses confirm our findings, investigation of alternative dosing regimens and/or dosing intervals of durvalumab in order to balance safety and efficacy of durvalumab therapy in Veterans is warranted. (1) Santana-Davila R et al. J Clin Oncol. 2015 Feb 20;33(6):567-74.
Cardiac function in patients receiving dual anti-Her2 antibodies (trastuzumab and pertuzumab) combined with chemotherapy for breast cancer in routine practice.
Authors: Jamal Zekri, Haleem J. Rasool, Syed Azhar J Rizvi, Ehab Mosaad Abdel Ghany Mahmoud, Ayman Ahamd Rasmy, Aboelkhair Al-Gahmi, Kamel Farag
Journal: Journal of Clinical Oncology (2021)

e13009 Background: Chemotherapy regimens (C) containing a combination of anti-Her2 antibodies are associated with a risk of cardiac toxicity in landmark clinical trials. We evaluate the cardiac function of patients with Her2 over-expressed (Her2OE) breast cancer (BC) receiving C combined with trastuzumab (T) and pertuzumab (P) in routine clinical practice setting. Methods: The initial cohort of patients who started C in combination with TP (CTP) in standard doses and schedules before September 2019 in 4 cancer units were included. All patients had regular measurement of left ventricular ejection fraction (LVEF) by Doppler ultrasound studies. Data was collected retrospectively and was limited to the first 24 months after initiation of CTP treatment. The paired sample T-test was used to test the significance of the difference in LVEF. Results: Sixty seven patients were identified. CTP treatment was administered in the neoadjuvant and palliative settings in 28 (41.8%) and 39 (58.2%) respectively. None of the patients received concomitant anthracycline with TP. All patients underwent LVEF assessment prior to starting CTP treatment and at 3 and 6 months later. Subsequently LVEF was measured at 9, 12, 15, 18, 21 and 24 months as long as patients are still receiving CTP treatment (table). LVEF was measured in 11 patients for 24 months. Compared to baseline, mean LVEF was not significantly different at any of the subsequent time points (range; decrease by -0.936% to increase by 1.087%) (Table). Dual anti-Her2 antibodies (TP) administration was omitted temporarily once for 2 patients due to clinically suspected cardiac toxicity which was excluded on further investigations. Conclusions: In this cohort describing our limited initial experience, dual anti-Her2 antibodies (T&amp;P) combined with chemotherapy is not associated with significant cardiac toxicity when LVEF is measured every 3 months. Further studies investigating less frequent LVEF monitoring (e.g. every 5-6 months) may be warranted.[Table: see text]
Demethylzeylasteral inhibits proliferation, migration, and invasion through FBXW7/c‐Myc axis in gastric cancer
Authors: Yongsen Li, Yongyue Su, Yuzu Zhao, Xiaosong Hu, Gaichao Zhao, Jiang He, Sicheng Wan, Muhan Lü, Hongjuan Cui
Journal: MedComm (2021)

Gastric cancer (GC) is one of the most familiar malignancy in the digestive system. Demethylzeylasteral (Dem), a natural functional monomer extracted from Tripterygium wilfordii Hook F, shows anti-tumor effects in a variety of cancers, including GC, however, with the underlying mechanism poorly understood. In our study, we show that Dem inhibits the proliferation, migration, and invasion of GC cells, which are mediated by down-regulating c-Myc protein levels. Mechanistically, Dem reduces the stability of c-Myc by up-regulating FBXW7, an E3 ubiquitin ligase. Moreover, in xenograft tumor model experiment, Dem also inhibits GC, which depends on suppressing c-Myc expression. Finally, Dem enhances GC cell chemosensitivity to the combination treatment of 5-Fluorouracil (5-Fu) and doxorubicin (DOX) in vitro. Together, Dem exerts anti-neoplastic activities through destabilizing and suppressing c-Myc, establishing a theory foundation for using it in future treatment of GC.
Atezolizumab and Bevacizumab in Patients with Unresectable Hepatocellular Carcinoma: Pharmacokinetic and Safety Assessments Based on Hepatic Impairment Status and Geographic Region
Authors: Colby S. Shemesh, Phyllis Chan, Hui Shao, Derek-Zhen Xu, Daniel Combs, Shweta Vadhavkar, René Bruno, Benjamin Wu
Journal: Liver Cancer (2021)

Phase 1b GO30140 and phase 3 IMbrave150 studies evaluated first-line atezolizumab + bevacizumab for unresectable hepatocellular carcinoma (HCC). Here, we evaluated pharmacokinetics (PK) and safety by hepatic impairment status and geographic region.Patients received atezolizumab 1,200 mg + bevacizumab 15 mg/kg IV every 3 weeks. Drug concentrations were evaluated by descriptive statistics and population PK. PK and adverse event frequencies were evaluated by hepatic impairment status and region.323 IMbrave150 patients and 162 GO30140 patients were PK evaluable. Compared with IMbrave150 patients who had normal hepatic function per the National Cancer Institute Organ Dysfunction Working Group (NCI-ODWG) criteria (n = 123), patients with mild impairment (n = 171) had a geometric mean ratio (GMR) of 0.92 for cycle 1 atezolizumab area under the concentration-time curve (AUC); patients with moderate impairment (n = 27) had a GMR of 0.88. Patients in Asia ([n = 162] vs. outside [n = 161]) had a GMR of 1.25 for cycle 1 atezolizumab AUC. Compared with GO30140 patients who had normal hepatic function (NCI-ODWG [n = 61]), patients with mild impairment (n = 92) had a GMR of 0.97 for cycle 1 peak bevacizumab concentrations; those with moderate impairment (n = 9) had a GMR of 0.94. Patients in Asia (n = 111) versus outside Asia (n = 51) had a GMR of 0.94 for cycle 1 peak bevacizumab concentration. PK results were generally comparable when evaluated based on additional hepatic functional definitions (Child-Pugh or albumin/bilirubin criteria) or study enrollment in Japan. No associations between atezolizumab PK and HCC etiology were seen. Adverse event frequencies were similar across evaluated groups.IMbrave150 and GO30140 patients with unresectable HCC had varying baseline hepatic impairment and high enrollment from Asia. PK data demonstrated considerable exposure overlap across groups. Treatment was tolerable across groups. No need for dose adjustment based on mild or moderate hepatic impairment or region is recommended based on this analysis.
Detailed incidence and mortality trends of early-onset colorectal cancer in Canada.
Authors: Dylan E. O'Sullivan, Yibing Ruan, Robert Liam Sutherland, Winson Y. Cheung, Steven J. Heitman, Robert Hilsden, Darren Brenner
Journal: Journal of Clinical Oncology (2021)

e15539 Background: There has been a consistent increase in the incidence of early-onset colorectal cancer (eoCRC), under the age of 50, in Canada since the late 1990s. Questions remain surrounding how these trends vary by topography, histology, and stage, and related trends with CRC-specific mortality. Methods: CRC incidence data were obtained from the Canadian Cancer Registry and CRC-specific mortality data from the Canadian Vital Statistics – Death Database for the years 2000 to 2017. Age-specific average annual percent changes (AAPC) in the incidence (by topography and histology) and mortality rates of CRC were estimated using the National Cancer Institute’s Joinpoint Regression Program. To determine age-specific differences (5-year age groups) in CRC diagnosis at late stage (III and IV) for years 2011 to 2017 combined, a logistic regression model adjusting for sex with the 50-54 age group as the referent was conducted. Results: AAPCs and 95% confidence intervals in the rates of incidence (topography and histology) and mortality of eoCRC from 2000 to 2017 in Canada are presented in Table. Different trends in topography were observed across sexes with the largest increases in the distal colon (splenic flexure, descending, and sigmoid) and rectum among males and rectum only among females. Significant increases were observed for non-mucinous adenocarcinomas, while significant decreases were observed for mucinous adenocarcinomas among the 40-49 age group. Compared to the 50-54 age group, only the 45-49 group had a significantly higher odds of developing late-stage colon cancer, while men and adults 25-49 had a higher odds of developing late stage rectal cancer. Despite increases in the incidence of eoCRC there has only been a significant increase in mortality for men aged 20-39. Trends in mortality vary by site, with significant decreases observed for colon cancer-specific mortality among the 40-49 age group and increases in rectal cancer-specific mortality for adults aged 20-49. Conclusions: These results indicate that the largest increases in incidence and mortality for eoCRC have occurred in the rectum and trends have varied by sex. Further research on the etiology and treatment outcomes of eoCRC patients are warranted for this patient population.[Table: see text]
Vaginal biocenosis in patients with gynecological cancers.
Authors: Vera P. Nikitina, Tatiana A. Zykova, Elena A. Shevyakova, Oksana E. Zhenilo, Ekaterina V. Verenikina, Viktoria A. Ivanova, Polina A. Kruze
Journal: Journal of Clinical Oncology (2021)

e17574 Background: The purpose of the study was to assess vaginal biocenosis in patients with gynecological cancers (GCs) and in non-cancer women. Methods: The study included 50 patients aged 52.3+2 years with histologically verified GCs (cervical cancer – 23, endometrial cancer – 27) – group 1, and 22 non-cancer women aged 42.4+2.3 – group 2. Vaginal swabs were taken prior to antitumor treatment. Real-time PCR was used to determine the total bacteria mass (TBM) and DNAs of 16 groups of microorganisms: Lactobacillus spp., Enterobacteriaceae, Streptococcus spp., Staphylococcus spp., Gardnerella vaginalis+Prevotella bivia+Porphyromonas spp., Eubacterium spp., Sneathia spp.+Leptotrichia spp.+Fusobacterium spp., Megasphaera spp.+Veillonella spp.+Dialister spp., Lachnobacterium spp.+Clostridium spp., Mobiluncus spp.+Corynebacterium spp., Peptostreptococcus spp., Atopobium vaginae, Candida spp., Mycoplasma hominis, Ureaplasma (urealyticum+ parvum), Mycoplasma genitalium. Results: Vaginal biocenosis was assessed as normocenosis in 12 (24%) women in group 1 and 12 (54.5%, p = 0.012) women in group 2; conditional normocenosis - 2 (4%) and 3 (13.6%, p &gt; 0.05); dysbiosis - 36 (72%) and 7 (31.8%, p = 0.0017), respectively. Anaerobic bacteria prevailed in women with dysbiosis in both groups (46% and 22.7%, p = 0.005); aerobic dysbiosis was registered in 16% and 4.5% (p &gt; 0.05), mixed dysbiosis – in 10% and 4.5% (p &gt; 0.05) of women of groups 1 and 2, respectively. Normal flora ( Lactobacillus spp.) was observed in 23 (46.0%) in group 1 and 17 (77.3%, p = 0.02) in group 2. Streptococcus spp. &gt;10% of TBM were found in 9 (21.9%) women in group 1 and not found in group 2 (p = 0.049). Gardnerella vaginalis+Prevotella bivia+Porphyromonas spp. &gt;10% of TBM were found in 27 (54.0%) in group 1 and 6 (27.3%, p = 0.031) in group 2; Staphylococcus spp. - 13 (26.0%) in group 1 and 12 (54.5%, p = 0.031) in group 2. Conclusions: Development of gynecological tumors was accompanied by a sharp decrease in Lactobacillus spp., a significant increase in Gardnerella vaginalis+ Prevotella bivia+ Porphyromonas spp. and Streptococcus spp., vaginal dysbiosis with a predominance of anaerobic and mixed microflora.
Cooperative group and pharmaceutical sponsored clinical trials: Perceptions of U.S. community oncologists.
Authors: Richard Scott Swain, Marjorie E. Zettler, Yolaine Jeune-Smith, Bruce A. Feinberg, Ajeet Gajra
Journal: Journal of Clinical Oncology (2021)

e13571 Background: Many community-based oncologists in the US participate in clinical trials. These trials largely fall into two categories: trials run by cooperative (co-op) groups, funded and supported by the National Cancer Institute and trials developed, and supported by the pharmaceutical (pharma) industry. This study aimed to assess participation in, and perceptions regarding, co-op versus pharma trials among US community oncologists. Methods: We invited healthcare providers (HCP) across the continental US to attend 4 virtual meetings held between September and November 2020. Participants submitted their demographic information and responses to targeted questions regarding their opinions about co-op- and pharma-sponsored trials via a web-based pre-meeting survey. We evaluated participant HCP practice demographics and survey responses using descriptive statistics. Results: Of 259 surveyed participants, HCPs specialized in hematology-oncology (57%) and medical oncology (40%) with mean (median) 19 (18) years’ clinical experience. Most HCPs (178; 69%) reported participating in clinical research, and of these, 137 (77%) participated in co-op-led and 156 (88%) participated in pharma-led clinical research. HCPs preferred participating in both pharma and co-op (49%), pharma only (22%), and co-op only (11%) trials, while 18% preferred not to participate. Co-op trials were considered more prestigious to lead (86%), less likely to imply a conflict of interest (59%), and to address more pertinent questions (58%), while pharma trials had perceived advantages of better compensation (61%) and superior efficiency (48%). Co-op trials were perceived as not being financially sustainable (69%) and slower to accrue patients (85%) than pharma-led trials. Relatedly, in a hypothetical scenario of competing trials with identical design, the majority (60%) of HCPs preferred enrolling a loved one in a co-op trial. HCPs practicing in facilities with academic affiliation (34%) and in non-academic (66%) settings reported similar perceptions about co-op- and pharma-led trials; though, HCPs in academic settings were more likely to participate in clinical research compared to those in non-academic settings (82% vs. 62% [ P=0.001], respectively). Conclusions: In our survey of experienced HCPs, co-op-led clinical trials were perceived generally more favorably than pharma-led trials, even with concerns regarding cost, feasibility, and slower recruitment. However, despite their preference for co-op trials, HCPs were more likely to participate in pharma-led trials. Almost a third of surveyed HCPs are not participating in clinical trials and a fifth do not wish to. These findings can inform stakeholders (co-op trial leadership, pharma drug development teams, and patient advocacy groups) regarding appropriate education, design, and messaging regarding future clinical trials in oncology.
Outcomes of first-line (1L) ipilimumab and nivolumab (IPI-NIVO) and subsequent therapy in metastatic renal cell carcinoma (mRCC): Results from the International mRCC Database Consortium (IMDC).
Authors: Chun Loo Gan, J Connor Wells, Andrew Lachlan Schmidt, Thomas Powles, Ben Tran, Luis A Meza, Chris Labaki, Jae-Lyun Lee, Lori Wood, Julia Shapiro, D. Scott Ernst, Anil Kapoor, Christina M. Canil, Takeshi Yuasa, Rana R. McKay, Benoit Beuselinck, Frede Donskov, Shaan Dudani, Toni K. Choueiri, Daniel Yick Chin Heng
Journal: Journal of Clinical Oncology (2021)

4554 Background: IPI NIVO is approved for 1L treatment of IMDC intermediate/poor risk mRCC based on the CHECKMATE 214 trial. Herein, we report the clinical effectiveness of 1L IPI NIVO and second line (2L) therapy in the real-world setting. Methods: Using the IMDC dataset, patients (pts) treated with 1L IPI NIVO were identified. The outcomes of interest were 1L and 2L overall response rate (ORR), treatment duration (TD), time to next treatment (TTNT), and overall survival (OS). Results: 706 pts were included: 9% (57/614), 58% (354/614), and 33% (203/614) were IMDC favorable (fav), intermediate (int), and poor risk, respectively. Median age was 61 years. The majority of pts were males (71%), had clear cell histology (85%), and underwent nephrectomy (61%). 36%, 19%, and 8% of patients had bone, liver, and brain metastases, respectively. The 12-month OS for pts with IMDC fav, int, and poor risk disease was 92%, 79%, and 56%, respectively (p&lt;0.01). The corresponding estimates for 24 months were 80%, 69%, and 38% (p&lt;0.01). Pts who responded (39%) were more likely to have better IMDC risk category (p=0.02), received nephrectomy (p=0.04), normal neutrophil count (p&lt;0.01), and clear cell histology (p=0.01). Pts with progressive disease as best response (27%) were more likely to have not received nephrectomy (p&lt;0.01), worse IMDC risk category (p=0.02), bone metastases (p=0.01), liver metastases (p=0.04), and non-clear cell histology (p=0.01). Of the 66% (466/706) of pts who discontinued 1L IPI NIVO, 51% (236/466) received 2L therapy: sunitinib (40%), cabozantinib (25%), pazopanib (18%), axitinib (8%), and others (9%). The ORR, median TD, and median OS for those who received either sunitinib, cabozantinib, pazopanib or axitinib was 16%, 4.5 months (mo) (95% CI 3.7-5.6), and 14.5 mo (95% CI 10.9-25.9), respectively. 33% (129/386) of pts discontinued IPI NIVO due to irAEs. Conclusions: Our study benchmarks the real-world experience of 1L IPI NIVO in mRCC. IMDC criteria is prognostic for clinical outcome. Tyrosine kinase inhibitors have clinical activity post IPI NIVO.[Table: see text]
Development and evaluation of a nanopore 16S rRNA gene sequencing service for same day targeted treatment of bacterial respiratory infection in the intensive care unit
Authors: Rossella Baldan, Penelope R. Cliff, Sarah Burns, Adela Medina, Graeme C. Smith, Rahul Batra, Alberto Cerda, Rebekah Wilson, Tammy Merrill, Shona J. Lewis, Amita Patel, Dakshika Jeyaratnam, Duncan L. Wyncoll, Nicholas Barrett, Meera A. Chand, Jonathan D. Edgeworth
Journal: Journal of Infection (2021)