tbuckley/cabot-search huggingface dataset:
Barriers to next-generation sequencing despite increased utilization: U.S. physician survey results.
Authors: Allysen Kaminski, Elizabeth A. Szamreta, Ruchit Shah, Ning Ning, Jyoti Aggarwal, Arif Hussain, Gboyega Adeboyeje
Journal: Journal of Clinical Oncology (2021)

e18754 Background: The value of using next-generation sequencing (NGS) to inform oncology care decisions is increasingly apparent, yet many challenges persist that may inhibit routine adoption of NGS into clinical care. The purpose of this study was to identify existing barriers to NGS access and possible solutions from the physician perspective. Methods: A cross-sectional online survey, including both closed- and open-ended questions, was sent to a nationally representative sample of oncologists/hematologists, surgeons, and pathologists (N=201). The survey gathered information on physician demographics, practice characteristics, perceived barriers to testing, and strategies for increasing adoption. Results: Over 99% of physicians, 20.5% of whom worked in an academic setting, reported using NGS in the past 12 months, and 73.0% used NGS always or most of the time. Despite this high utilization, 80.1% of physicians experienced at least one barrier to testing. Reimbursement challenges were among the top reported barriers (87.5%), followed by a lack of knowledge of NGS testing methodologies (81.0%), and lacking evidence of clinical utility (80.1%). These barriers were more likely to be reported by pathologists and surgeons compared to oncologists/hematologists. Potential strategies for addressing these differed by specialty: While most oncologists/hematologists (84.0%) reported increased NGS coverage as a top priority, most surgeons (88.0%) prioritized improved multidisciplinary communications, and most pathologists (84.4%) prioritized increased access to educational content on cancer genomics and resources for physicians. Conclusions: Despite the high utilization of NGS among the surveyed stakeholders, several barriers, including limited reimbursement, knowledge gaps, and lack of clinical utility evidence were reported that may impact clinical optimization. Interestingly, the perceived barriers to NGS use varied by specialty, which may be driven by the differing roles these specialists play in patient management. Oncologists/hematologists, who are more likely involved in long-term patient care, were most concerned with identifying strategies to improve coverage of technology, whereas surgeons and pathologists were most concerned with strategies that would improve understanding and education. This research highlights the need for multi-faceted strategies to address barriers to NGS adoption. [Table: see text]
Update on overall survival (OS) of RESCUE: An open-label, phase 2 trial of camrelizumab (C) in combination with apatinib (A) in patients with advanced hepatocellular carcinoma (HCC).
Authors: Yun Zhang, Jianming Xu, Jie Shen, Shanzhi Gu, Lihua Wu, Jian Wu, Guoliang Shao, Yanqiao Zhang, Li Xu, Tao Yin, Jingfeng Liu, Zhenggang Ren, Jianping Xiong, Xianhai Mao, Ling Zhang, Jiayin Yang, Lequn Li, Xiaoming Chen, Zhiming Wang, Quanren Wang
Journal: Journal of Clinical Oncology (2021)

4076 Background: C+A combination therapy displayed high objective response rate, disease control rate, and durable response with a manageable safety profile in patients (pts) with advanced HCC. Here we performed an updated analysis of OS to characterize the OS benefit of C+A in HCC pts. Methods: 70 pts in first-line cohort and 120 pts in second-line cohort were enrolled. Median OS and 2-year OS rate were evaluated via updated data (data cutoff, 3 January, 2021). Median time from enrollment to data cutoff of the total population (N = 190) was 29.1 months (range, 24.0-33.7). Results: OS events had occurred in 58.6% pts in first-line cohort and 60.0% pts in second-line cohort. The median OS was 20.1 months (95% CI, 14.9-NR) and 2-year OS rate was 43.3% (95% CI, 31.3-54.7) in first-line cohort. The median OS was 21.8 months (95% CI, 17.3-26.8) and 2-year OS rate was 44.6% (95% CI, 35.5-53.3) in second-line cohort. Conclusions: Long-term follow-up of C+A demonstrated remarkable survival benefit in advanced HCC pts, which further suggested that C+A is a promising combination therapy in advanced HCC pts. Clinical trial information: NCT03463876.
Co-occurrence of Pituitary Neuroendocrine Tumors (PitNETs) and Tumors of the Neurohypophysis
Authors: Wolfgang Saeger, Jannik von Schöning, Jörg Flitsch, Günther Jautzke, Markus Bergmann, Christian Hagel, Ulrich J. Knappe
Journal: Endocrine Pathology (2021)
Phase I/II study of H3B-6545, a novel selective estrogen receptor covalent antagonist (SERCA), in estrogen receptor positive (ER+), human epidermal growth factor receptor 2 negative (HER2-) advanced breast cancer.
Authors: Erika P. Hamilton, Judy S. Wang, Timothy J. Pluard, Stephen R. D. Johnston, Aki Morikawa, Elizabeth Claire Dees, Robert Hugh Jones, Barbara B. Haley, Anne Caroline Armstrong, Adam Louis Cohen, Pamela N. Munster, Gail Lynn Shaw Wright, Fadi Kayali, Manav Korpal, Jianjun Alan Xiao, Jenny Long, Benoit Destenaves, Lei Gao, Antonio Gualberto, Dejan Juric
Journal: Journal of Clinical Oncology (2021)

1018 Background: H3B-6545, a selective, small molecule covalent antagonist of ERα demonstrated preclinical and preliminary clinical activity against ER+ breast cancer (Hamilton EP, SABCS, 2020). This study evaluated the activity and tolerability of H3B-6545 in patients (pts) with metastatic ER+, HER2-, breast cancer refractory to endocrine therapy. Methods: Patients received H3B-6545 once daily at the recommended phase II dose of 450 mg. The primary objective of the phase II is to estimate the objective response rate (ORR), progression-free survival (PFS), clinical benefit rate (CBR) and secondary objectives include safety. Results: 83 pts were treated with 450 mg in the phase II part of the trial. Additionally, 11 pts were treated with 450 mg in the phase I part of the trial and are included in this analysis. Median age was 62 years (range: 38 to 87 years), 81% had liver and/or lung metastases, and the median number of prior therapies for metastatic disease was 3 (range: 1 to 8). Prior CDK4/6 inhibitors, aromatase inhibitors, fulvestrant, and chemotherapy were received by 85%, 80%, 72%, and 50% of the pts, respectively. 58 pts (62%) had detectable ESR1 mutations in liquid biopsies, including 10 (11%) and 19 pts (20%) who had clonal Y537S and clonal D538G mutation, respectively. As of January 29, 2021, grade (gr) 2 or higher adverse events (AE) reported in ≥10% were anemia (19%), fatigue (16%), nausea (17%), and diarrhea (12%). Laboratory gr 2 or higher abnormalities reported in ≥10% pts were creatinine clearance decrease (38%), hemoglobin decrease (37%), bilirubin increase (12%), ALT increase (14%), AST increase (13%), and creatinine increase (11%). AE of gr 1 sinus bradycardia (asymptomatic) was reported in 34% and gr 2 (symptomatic, no intervention needed) was reported in 5%. Gr 2 and 3 QTcF prolongation were reported in 2 and 3 pts, respectively. There were no treatment-related deaths. Efficacy estimates are presented in the table below. Responses were observed in heavily pretreated pts, pts with visceral metastases and in pts who received prior fulvestrant, CDK4/6 inhibitor, and/or chemotherapy in the metastatic setting. Conclusions: H3B-6545 has a manageable safety profile and demonstrated single-agent anti-tumor activity in heavily pretreated ER+, HER2- mBC patients. Clinical activity was observed in pts with ESR1 mutations. Clinical trial information: NCT03250676 .[Table: see text]
Assessing duration of breakthrough chemotherapy-induced nausea and vomiting (CINV): A pooled study analysis of NEPA versus aprepitant.
Authors: Rudolph M. Navari, Gary Binder, Erminio Bonizzoni, Rebecca Clark-Snow, Silvia Olivari Tilola, Eric Roeland
Journal: Journal of Clinical Oncology (2021)

12091 Background: The historical standard clinical trial endpoint for preventing chemotherapy-induced nausea and vomiting (CINV) has been assessment of complete response (CR: no emesis and no rescue medication use) over five days. Recent evaluations focused on the duration of breakthrough CINV suggest that long duration of CINV results in more lost work time and impaired activity and is also a strong predictor for CINV in subsequent cycles. A recent pooled analysis of three similarly designed registration trials of NEPA, a fixed oral combination NK 1 receptor antagonist (RA) (netupitant)/5-HT 3 RA (palonosetron), showed significantly higher CR rates during the delayed phase (≥24-120h) for NEPA compared to an aprepitant (APR) regimen. In this post-hoc analysis, we evaluated the extent and duration of breakthrough CINV in these pooled studies. Methods: Chemotherapy-naïve patients who received cisplatin-based chemotherapy and antiemetic prophylaxis of either a single dose of NEPA plus dexamethasone (DEX) or a 3-day APR/5-HT 3 RA/DEX regimen from three randomized, double-blind pivotal trials were included. Patients without a CR were defined as treatment failures. Extent of CINV was evaluated using proportions of patients with treatment failure, emesis, and significant nausea (defined as &gt;25 mm on a 100 mm visual analog scale). Over the 5-day overall phase, duration was categorized as 1-2, and ≥3 days. Pearsons chi-square test was employed to compare risks between treatments for each duration category in each of the previously mentioned endpoints. Results: Among all 621 NEPA and 576 APR patients, a significantly greater proportion of APR patients experienced treatment failure, emesis, and significant nausea for ≥3 days. Specifically, among patients with treatment failure, 31% (41/134) who received NEPA and 43% (61/143) who received APR experienced breakthrough CINV for ≥3 days. Conclusions: Expanding on data suggesting single-day NEPA is more effective than 3-day APR in preventing delayed CINV, NEPA is also more effective in minimizing the extent and duration of CINV in patients with breakthrough emesis and nausea.[Table: see text]
Microbiome signature, global methylation and immune landscape in early onset colorectal cancer.
Authors: Ning Jin, Xiaokui Mo, Rebecca Hoyd, Ayse Selen Yilmaz, YunZhou Liu, Malvenderjit Jagjit Singh, Mitchell Muniak, Heather Hampel, Daniel Spakowicz
Journal: Journal of Clinical Oncology (2021)

3519 Background: The incidence of colorectal cancer (CRC) in young adults ( &lt; 50 years old) has been rapidly increasing by 2% per year since early 1990. Approximately 20% of early-onset (EO) CRC cases are due to germline gene mutations. However, the etiology of sporadic EO CRC remains poorly understood. Research suggests that environmental factors such as the Western diet (high in fat and low in fiber) may be associated with an increased incidence of sporadic EO CRC. The gut microbiota decompose and ferment dietary fibers to produce microbial metabolites, which play pivotal roles in maintaining the integrity of intestinal epithelium as well as the immune cell homeostasis. Also, these microbial metabolites may influence the host epigenome by altering either the activity of epigenetic enzymes or by modifying the availability of cofactors needed for epigenetic modifications. The aim of our research is to associate intratumoral microbiota with methylation pattern and immune cell composition in EO CRC. Methods: A total of 358 CRC cases, including 54 cases of EO CRC (age &lt; 50 years) and 304 cases of late onset (LO) CRC (age ≥ 50 years), with matched methylation array (Infinium HM450), RNA-sequencing (Illumina HiSeq) from colon adenocarcinomas (COAD) and rectal adenocarcinomas (READ), and clinicopathological information of each patient, were extracted from the Cancer Genome Atlas (TCGA). We characterized and compared the intra-tumoral microbiota composition, tumor-infiltrating lymphocytes (TILs), and methylation profile between EO and LO CRC. Results: We found that there is a distinct microbial distribution, gene expression and methylation pattern in the EO CRC when compared with LO CRC. Non-human sequences from several kingdoms including bacteria, fungi and viruses were found and the incidences were consistent with reported values by other methods, e.g. Fusobacterium incidence. The EO CRC cases showed global hypomethylation, even though hypermethylation pattern is expected in the young chronological age group (known as Horvath’s clock). Pathway overrepresentation analysis of differentially expressed genes showed significant activation of p53 and pentose phosphate pathways and de novo nucleotide synthesis in EO CRC. Integration across datasets showed positive correlations between microbes and inflammasome pathway, positive correlation with regulatory T cells (Tregs), and negative correlations with CD4 memory T cells. Conclusions: These data suggest a mechanism by which the colorectal cancer-associated microbiota may be associated with epigenetic regulation and host immune response.
Assessment of the alignment between research funding allocation and consensus research priority areas in kidney cancer.
Authors: Steven Lu, Jeenan Kaiser, Michael A.S. Jewett, Daniel Yick Chin Heng, Nimira S. Alimohamed, Bimal Bhindi
Journal: Journal of Clinical Oncology (2021)

e16538 Background: Finite resources are available to fund research, and it is important to ensure stakeholder input is identified and prioritized. In this light, the KCRNC and CIHR sponsored a consensus-based priority-setting partnership that brought together a group of patients, caregivers, and clinicians to identify the top 10 research priorities in kidney cancer (Table), with a consensus document published in 2017. The final step of the prioritization process was to determine how research funding allocation has aligned with these previously identified priority areas. We report the results of this assessment. Methods: We queried publicly available Canadian and American research databases to identify all research funds allocated to kidney cancer from 2018-2020. Each funded project was assessed to determine which priority areas were addressed. We evaluated the percent of projects and percent of funding dollars (converted to USD) allocated to priority areas. Projects were stratified by country, type of research (basic science/translational or clinical), and cancer stage of focus (localized and/or metastatic). Results: A total of 121 kidney cancer research projects were funded between 2018-2020, with 15 Canadian projects (total $ = 1,906,398 USD) and 106 American projects (total $ = 56,317,386 USD). Most projects were basic science or translational (88%). Half (50%) of the projects focused on localized cancer while 26% of projects focused on metastatic kidney cancer. Overall, 49% of projects aligned to one priority area, 47% of projects aligned to multiple priority areas, and 4% of projects were not aligned to priority areas. The priority areas which received the most funding were causes of kidney cancer (priority #10, 64% of funds), biomarkers (priorities #1b+1c+5, 59%), and immunotherapies (priority #4, 41%)(Table). Unfunded priority areas were supportive care (priority #6) and the role of biopsy in kidney cancer management (priority #8). Conclusions: Nearly all kidney cancer projects funded since 2018 were aligned with one or multiple stakeholder-identified research priority areas, although some priority areas remain underfunded. Mechanisms to improve distribution of funding to all priority areas may be warranted.[Table: see text]
Feasibility of shortening intravenous antibiotic therapy for bronchiectasis based on bacterial load: a proof-of-concept randomised controlled trial
Authors: Pallavi Bedi, Manjit K. Cartlidge, Yang Zhang, Kim Turnbull, Samantha Donaldson, Andrea Clarke, Jane Crowe, Kadiga Campbell, Catriona Graham, Ruzanna Franguylan, Adriano G. Rossi, Adam T. Hill
Journal: European Respiratory Journal (2021)

Background There is a lack of evidence to guide the duration of intravenous antibiotics for bronchiectasis exacerbations. Aims The aim of this study was to assess whether it is feasible, based on bacterial load, to shorten intravenous antibiotics during exacerbations and whether 14 days of treatment is superior. Methods We recruited participants requiring intravenous antibiotics for exacerbations. Participants were randomised into two groups: to receive antibiotics for 14 days (14-day group) or to have a shorter duration of treatment based on bacterial load (bacterial load-guided group (BLGG)). Bacterial load was checked on days 0, 7, 10, 14 and 21. If the bacterial load was &lt;10 6 CFU·mL −1 on day 7 or day 10 in the BLGG, antibiotics were stopped the following day. Results A total of 47 participants were in the 14-day group and 43 were in the BLGG. 88% of participants in the BLGG were able to stop antibiotics by day 8 and potentially 81% of participants in the 14-day group could have stopped antibiotics at day 8. There was a nonsignificant trend for increased clinical improvement by day 21 in the 14-day group compared to the BLGG. However, overall group data showed the median (interquartile range) time to next exacerbation was 27.5 days (12.5–60 days) in the 14-day group and 60 days (18–110 days) in the in BLGG (p=0.0034). In a Cox proportional hazard model, participants in the 14-day group were more likely to experience exacerbations (HR 1.80, 95% CI 1.16–2.80, p=0.009) than those in the BLGG, and those with mild bronchiectasis were less likely to experience exacerbations than patients with more severe bronchiectasis (HR 0.359, 95% CI 0.13–0.99, p=0.048). Conclusions Bacterial load-guided therapy is feasible in most exacerbations requiring intravenous antibiotics. There was a nonsignificant trend for increased clinical improvement by day 21 with 14 days of antibiotics compared with bacterial load-guided therapy but paradoxically there was a prolonged time to next exacerbation in the BLGG.
Longitudinal Single-Cell Dynamics of Chromatin Accessibility and Mitochondrial Mutations in Chronic Lymphocytic Leukemia Mirror Disease History
Authors: Livius Penter, Satyen H. Gohil, Caleb Lareau, Leif S. Ludwig, Erin M. Parry, Teddy Huang, Shuqiang Li, Wandi Zhang, Dimitri Livitz, Ignaty Leshchiner, Laxmi Parida, Gad Getz, Laura Z. Rassenti, Thomas J. Kipps, Jennifer R. Brown, Matthew S. Davids, Donna S. Neuberg, Kenneth J. Livak, Vijay G. Sankaran, Catherine J. Wu
Journal: Cancer Discovery (2021)

While cancers evolve during disease progression and in response to therapy, temporal dynamics remain difficult to study in humans due to the lack of consistent barcodes marking individual clones in vivo. We employ mitochondrial single-cell assay for transposase-accessible chromatin with sequencing to profile 163,279 cells from 9 patients with chronic lymphocytic leukemia (CLL) collected across disease course and utilize mitochondrial DNA (mtDNA) mutations as natural genetic markers of cancer clones. We observe stable propagation of mtDNA mutations over years in the absence of strong selective pressure, indicating clonal persistence, but dramatic changes following tight bottlenecks, including disease transformation and relapse posttherapy, paralleled by acquisition of copy-number variants and changes in chromatin accessibility and gene expression. Furthermore, we link CLL subclones to distinct chromatin states, providing insight into nongenetic sources of relapse. mtDNA mutations thus mirror disease history and provide naturally occurring genetic barcodes to enable patient-specific study of cancer subclonal dynamics. Single-cell multi-omic profiling of CLL reveals the utility of somatic mtDNA mutations as in vivo barcodes, which mark subclones that can evolve over time along with changes in accessible chromatin and gene expression profiles to capture dynamics of disease evolution. See related commentary by Hilton and Scott, p. 2965. This article is highlighted in the In This Issue feature, p. 2945.
HGG-33. EXPLOITING METABOLIC DEFECTS WITH NAMPT INHIBITORS IN DIPG
Authors: Ranjithmenon Muraleedharan, Collin Heer, Ranjini Sundam, Charles Brenner
Journal: Neuro-Oncology (2021)

Abstract Diffuse intrinsic pontine glioma (DIPG) are universally lethal pediatric brain tumors with limited treatment options. We recently performed synthetic lethal drug screen with a panel of DNA repair and metabolic inhibitors in vitro, in patient-derived DIPG cells and isogenic cell lines engineered to contain key DIPG-associated mutations. Nearly 80% of DIPGs harbor a recurrent H3K27M mutation in H3.3 (H3F3A) or H3.1 (HIST1H3B) histones. This has prompted us to consider H3K27M mutation-induced exploitable defects for a therapeutic gain. This screen identified synthetic lethal interactions between H3K27M mutations and the nicotinamide phosphoribosyl transferase (NAMPT) inhibitor, FK866. The association between H3K27M mutations and NAMPTi sensitivity was validated in follow-up studies using isogenic WT and H3K27M-mutant expressing pairs of human immortalized astrocytes and neural progenitor cells (NPCs). In addition, we tested the effects of FK866 in a panel of unique DIPG patient-derived tumor neurospheres in short-term viability assays. We found that FK866 induced depletion of NAD and exhibited toxicity towards H3K27M mutant DIPG cell lines with an IC50 of ~2.5 nM. These findings were consistent across three structurally unique NAMPT inhibitors. Finally, we found that inducible expression of mutant H3K27M results in a gradual, 50% decrease in cellular NAD levels over the course of five days, suggesting that H3K27M mutations may induce an inherent NAD metabolic defect that is exploited by NAMPTi’s. We now seek to understand the mechanistic basis for the observed metabolic defect and NAMPTi sensitivity associated with mutant H3K27M. In addition, we aim to identify specific NAMPTi and DNA damaging agent combinations which maximally exploit this H3K27M-associated NAD metabolic defects.