tbuckley/cabot-search huggingface dataset:
First analysis of same-day pegfilgrastim use with concurrent capecitabine-based regimens in pts with GI malignancies.
Authors: Nausheen Hakim, Jeffrey Chi, Hasan Rehman, Shreya Prasad Goyal, Coral Olazagasti, Linda Moriarty, Jyothi Jose, Carol Lamont, Wasif M. Saif
Journal: Journal of Clinical Oncology (2020)

817 Background: Pegfilgastrim is administered 24 hrs after chemotherapy to reduce risks of myelosuppression. This requires an additional clinic visit, which can be difficult for some patients (pts) due to work and transportation issues. In GI malignancies, pts receiving capecitabine-based regimens also require pegfilgastrim to reduce myelotoxicity. Capecitabine is converted to active 5-FU by cytidine deaminase which is present in humans in low levels and generally does not cause severe myelosupression. Therefore, administering pefilgastrim concurrently with chemotherapy may be an option. We present here the first study to analyze safety and efficacy of administering pegfilgrastim on the same day as capecitabine-based regimens in patients with GI malignancies. Methods: We evaluated 157 pts with GI malignancies who received a capecitabine-based chemotherapy regimens, including XELOX, EOX, ECX, XELIRI, MIXE, gemcitabine-capecitabine and same-day pegfilgrastim (6 mg) within 1 hr of completion of systemic agents. As per institutional guidelines, pts were counseled on risks of same-day pegfilgrastim prior to its administration. Pts were followed to determine the degree of neutropenia and toxicity. Results: A total of 914 chemotherapy cycles in 157 pts were analyzed. Median ANC nadir for all cycles was 5634/uL (range: 450-23800). Grade 1 and 2 neutropenia developed in 11 of 914 cycles. Bone pain reported in 9 pts. There was 1 episode of grade &gt;3 neutropenia resulting in infection and antibiotic use. No other pt required dose reductions, chemotherapy delays, or hospitalizations. No increased toxicity of capecitabine was noticed. Conclusions: We believe our study is the first in GI malignancies to report that same-day pegfilgrastim administration with capecitabine-based regimens may be as effective and safe as next-day administration. Additionally, given the absence of CD in human bone marrow, it appears capecitabine can be used concurrently with pegfilgastrim. Prospective studies should be done to further investigate, as this practice can benefit pts clinically, decrease office visits, increase pt satisfaction and reduce healthcare costs.
Efficacy of Single-Operator Cholangioscopy-Guided Lithotripsy Compared With Large Balloon Sphincteroplasty in Management of Difficult Bile Duct Stones in a Randomized Trial
Authors: Ji Young Bang, Bryce Sutton, Udayakumar Navaneethan, Robert Hawes, Shyam Varadarajulu
Journal: Clinical Gastroenterology and Hepatology (2020)
Expression of antibody-drug conjugates (ADC) biomarkers in colorectal cancer.
Authors: Sheeno P. Thyparambil, Wei-Li Liao, Eunkyung An, Yuan Tian, Robert Heaton, Karl G. Sylvester, Xuefeng B. Ling
Journal: Journal of Clinical Oncology (2020)

17 Background: Multiple ADCs are in clinical trials for CRC and the optimal strategy for selecting patients who may benefit from the treatment is evolving. Due to the unique mechanism of ADCs, patient selection should involve screening not only for the presence of the antibody target, but also for markers of resistance or response to the payload. We have built a multiplexed ADC biomarker panel in FFPE tumor tissue that simultaneously quantifies the protein levels of the antibody targets and also the payload markers. Methods: FFPE tumor tissues from 363 CRC patients were microdissected and solubilized for mass spectrometry-based targeted proteomic analysis in our CLIA certified laboratory. We quantified protein levels of EGFR, HER2, HER3, Axl, Mesothelin, FRalpha, Trop2 (antibody targets), tubulin-beta3 and TOPO1 (payload resistance and response markers, respectively) simultaneously. The multiplexed assay also quantified additional 22 clinically relevant proteins. Results: Expression of EGFR(83%), HER2(52%), HER3(21.5%), Axl(3.7%), Mesothelin(26.5%), FRalpha(3.7%), and Trop2(59.8%) may indicate likely response to ADCs. Expression of TUBB3(+) and TOPO1 (&gt;1350amol/µg) in antibody target-positive subset may suggest resistance or response to payloads, such as taxanes and irinotecan, respectively (Table). Previously we identified that HER2 expression &gt;750amol/µg correlated with HER2 positivity. Accordingly, 1.4% (5/355) of CRC patients were HER2 positive, of which 40% (2/5) had TOPO1 expression &gt;1350amol/µg (75th percentile) suggesting that these 2 patients may receive benefit from a HER2/TOPO1 ADC. (+) indicates expression ≥LOQ; (-) indicates expression &lt;LOQ. Conclusions: In patients with CRC, quantitative proteomics identified both antibody targets and markers of resistance or response to the payloads for multiple approved and investigational ADC therapies. [Table: see text]
Not Yet Another Negative Trial–ReACTing on Recent Glioblastoma Trials
Authors: Wolfgang Wick, Robin J. Wagener
Journal: Clinical Cancer Research (2020)

The present ReACT trial provides data from a small randomized controlled vaccination trial that in addition to other recent immunotherapy trials in glioblastoma allows sketching a rational, advanced trial design for the development of (immune) therapies in glioblastoma elaborating on but not restricting to biological monitoring and endpoints.See related article by Reardon et al., p. 1586.
The pretreatment lymphocyte-to-monocyte ratio (LMR) to predict treatment efficacy and prognosis in metastatic colorectal cancer treated with the combination of TAS-102 and bevacizumab (TAS-CC3 Study).
Authors: Akihisa Matsuda, Yoichiro Yoshida, Hirohiko Kamiyama, Chihiro Kosugi, Hiroshi Yoshida, Keiichiro Ishibashi, Keisuke Ihara, Makoto Takahashi, Hidekazu Kuramochi, Atsuko Fukazawa, Hiromichi Sonoda, Kazuhiko Yoshimatsu, Satoru Yamaguchi, Hideyuki Ishida, Suguru Hasegawa, Takeshi Yamada, Kazuhiro Sakamoto, Keiji Koda
Journal: Journal of Clinical Oncology (2020)

224 Background: The combination regimen of TAS-102 and bevacizumab as salvage-line therapy for metastatic colorectal cancer (mCRC) was established based on its high clinical effectiveness (C-TASK FORCE). Recently, our current phase II TAS-CC3 study demonstrated comparable median progression-free survival (PFS: 4.5m) and overall survival (OS: 9.2m) with exclusive inclusion of 3 rd line therapy patients. However, practical predictors for its efficacy are lacking. This study evaluated inflammation-based scores as potential predictors for this combination therapy. Methods: This is a post hoc analysis of investigator-initiated, open-label, single-arm, multicentered phase II study (TAS-CC3) in Japan with 32 mCRC patients treated with the combination therapy. We investigated the predictive and prognostic values of pretreatment blood inflammation-based scores, including neutrophil-to-lymphocyte (NLR), platelet-to-lymphocyte (PLR), and lymphocyte-monocyte ratios (LMR), on disease-control (DC), PFS and OS. These were divided into two groups (high and low) using cut-off of each median values. This study was registered at the University Hospital Medical Information Network, as UMIN#000022438. Results: ROC curve analyses of 3 inflammation-based scores versus DC showed a best predictive performance in LMR, followed by NLR and PLR (AUC: 0.89, 0.85, and 0.68, respectively). The high LMR group had a significantly higher DC rate than the low group (87.5 vs. 43.8%, P= 0.023). Two patients showing partial responses were in the high group. The high LMR group showed significantly longer survivals compared with the low group (4.9 vs. 2.3m, respectively for median PFS, P= 0.014) (20.5 vs. 5.1m, respectively for median OS, P&lt; 0.001). The values of LMR were significantly correlated with PFS and OS (r = 0.56: P&lt; 0.001 and 0.62: P&lt; 0.001, respectively). Conclusions: Pretreatment LMR is a valid predictive and prognostic biomarker for mCRC patients with TAS-102 and bevacizumab treatment and might be clinically useful for selecting patients of the responder. Clinical trial information: 000022438.
Methionine Metabolism Shapes T Helper Cell Responses through Regulation of Epigenetic Reprogramming
Authors: Dominic G. Roy, Jocelyn Chen, Victoria Mamane, Eric H. Ma, Brejnev M. Muhire, Ryan D. Sheldon, Tatiana Shorstova, Rutger Koning, Radia M. Johnson, Ekaterina Esaulova, Kelsey S. Williams, Sebastian Hayes, Mya Steadman, Bozena Samborska, Amanda Swain, Audrey Daigneault, Victor Chubukov, Thomas P. Roddy, William Foulkes, J. Andrew Pospisilik, Marie-Claude Bourgeois-Daigneault, Maxim N. Artyomov, Michael Witcher, Connie M. Krawczyk, Catherine Larochelle, Russell G. Jones
Journal: Cell Metabolism (2020)

Epigenetic modifications on DNA and histones regulate gene expression by modulating chromatin accessibility to transcription machinery. Here we identify methionine as a key nutrient affecting epigenetic reprogramming in CD4+ T helper (Th) cells. Using metabolomics, we showed that methionine is rapidly taken up by activated T cells and serves as the major substrate for biosynthesis of the universal methyl donor S-adenosyl-L-methionine (SAM). Methionine was required to maintain intracellular SAM pools in T cells. Methionine restriction reduced histone H3K4 methylation (H3K4me3) at the promoter regions of key genes involved in Th17 cell proliferation and cytokine production. Applied to the mouse model of multiple sclerosis (experimental autoimmune encephalomyelitis), dietary methionine restriction reduced the expansion of pathogenic Th17 cells in vivo, leading to reduced T cell-mediated neuroinflammation and disease onset. Our data identify methionine as a key nutritional factor shaping Th cell proliferation and function in part through regulation of histone methylation.
Prognostic value of circulating tumor DNA (ctDNA) detection during adjuvant chemotherapy in patients with stage III colorectal cancer: The interim report of a prospective, observational study.
Authors: Junjie Peng, Yaqi Li, Shaobo Mo, Xiaoji Ma, Xiang Hu, Long Zhang, Dan Huang, Sanjun Cai
Journal: Journal of Clinical Oncology (2020)

29 Background: Adjuvant chemotherapy (ACT) is the standard treatment for stage III colorectal cancers (CRC). However, optimal biomarker were still needed for individualized adjuvant strategies. Here, we conducted a prospective study in patients with stage III CRCs with combined ACT, to explore the prognostic effect of circulating tumor DNA (ctDNA) before and after ACT. Methods: The study enrolled 130 patients with stage III colon and rectal cancer (≥10cm from anal) who received curative resection without neoadjuvant therapy at Fudan University Shanghai Cancer Center. All patients received 3 or 6 months of ACT. The Roche AVENIO Surveillance Kit was used to assess somatic mutations by next-generation sequencing (NGS) in tissue, pre- and post-chemo plasma samples. The plasmas were collected 3-5 weeks after surgery and after last cycle of ACT, respectively. Patients were classified as ctDNA (+) or (-) based on the detection of SNVs identified in tumor tissue at an AF of at least 5%. Results: In the interim analysis, 116 tissues, 123 pre-chemo and 98 post-chemo plasmas were prospectively collected and detected, and a total of 86 matched samples were analyzed with a median follow-up of 12.0 months. ctDNA was detectable in 14 of 86 patients (16.3%) before ACT, and in 10 (11.6%) patients after ACT. After 1-year follow-up, longitudinal ctDNA analysis identified 6 of 12 early relapses (50.0%), while 6 in 69 patients (8.7%) who were both ctDNA (-) in pre- and post-chemo samples had early relapse. Before ACT, ctDNA(+) patients were 7 times more likely to relapse early than ctDNA(-) patients (HR, 7.372; 95% CI, 1.543-35.22; P = 0.012). Similarly, after ACT, ctDNA(+) patients were 13 times (HR, 13.37; 95% CI, 2.026-88.23; P = 0.007) more likely to relapse. Monitoring after ACT indicated that 7 of the 14 ctDNA(+) patients (50.0%) were cleared, and the early relapse rate decreased from 43.9% (3/7) to 28.6% (2/7) if ctDNA turned negative. Conclusions: ctDNA analysis can potentially change the postoperative management and surveillance strategies for stage III CRC by enabling risk stratification, monitoring ACT efficacy, and detecting early relapse. Clinical trial information: ChiCTR1800018754.
Molecular Mechanisms of Acquired Resistance to MET Tyrosine Kinase Inhibitors in Patients with MET Exon 14–Mutant NSCLC
Authors: Gonzalo Recondo, Magda Bahcall, Liam F. Spurr, Jianwei Che, Biagio Ricciuti, Giulia C. Leonardi, Ying-Chun Lo, Yvonne Y. Li, Giuseppe Lamberti, Tom Nguyen, Marina S.D. Milan, Deepti Venkatraman, Renato Umeton, Cloud P. Paweletz, Adem Albayrak, Andrew D. Cherniack, Kristin S. Price, Stephen R. Fairclough, Mizuki Nishino, Lynette M. Sholl, Geoffrey R. Oxnard, Pasi A. Jänne, Mark M. Awad
Journal: Clinical Cancer Research (2020)

Molecular mechanisms of acquired resistance to MET tyrosine kinase inhibitors (TKI) are poorly understood. We aimed to characterize the genomic mechanisms of resistance to type I and type II MET TKIs and their impact on sequential MET TKI therapy outcomes in patients with metastatic MET exon 14-mutant NSCLC.Genomic alterations occurring at the time of progression on MET TKIs were studied using plasma and tissue next-generation sequencing (NGS).A total of 20 patients had tissue or plasma available for analysis at the time of acquired resistance to a MET TKI. Genomic alterations known or suspected to be mechanisms of resistance were detected in 15 patients (75%). On-target acquired mechanisms of resistance, including single and polyclonal MET kinase domain mutations in codons H1094, G1163, L1195, D1228, Y1230, and high levels of amplification of the MET exon 14-mutant allele, were observed in 7 patients (35%). A number of off-target mechanisms of resistance were detected in 9 patients (45%), including KRAS mutations and amplifications in KRAS, EGFR, HER3, and BRAF; one case displayed both on- and off-target mechanisms of resistance. In 2 patients with on-target resistant mutations, switching between type I and type II MET TKIs resulted in second partial responses.On-target secondary mutations and activation of bypass signaling drive resistance to MET TKIs. A deeper understanding of these molecular mechanisms can support the development of sequential or combinatorial therapeutic strategies to overcome resistance.
Detection of circulating tumor DNA in pancreas cancer.
Authors: Daniel King, Ash A. Alizadeh, George A. Fisher
Journal: Journal of Clinical Oncology (2020)

645 Background: Pancreas cancer remains a leading cause of cancer-related death. Improved detection of early relapse or early failure of chemotherapy also has the potential to further improve outcomes. Exploring circulating tumor DNA (ctDNA) in this setting is an area of active investigation. Methods: We previously developed an approach, CAPP-Seq, combining high-depth sequencing with several strategies of error-suppression to identify minute amounts of circulating tumor DNA. We then trained and validated a new capture panel for pancreas cancer from 640 tumors from three data sources (TCGA, ICGC, UTSW), targeting 265 kb of the genome. We enrolled two cohorts of patients with pancreatic cancers at Stanford Cancer Center: (1) patients with localized tumors undergoing resection with curative intent, and (2) patients with unresectable or metastatic disease undergoing systemic therapy. Results: As of August 2019, we recruited 131 patients with at least one blood collection, with 63% having resectable disease and 27% having advanced disease; 59 patients had 2 or more blood collections. Stage distribution included 34% stage I, 33% stage II, 18% III, 16% IV disease. Approximately 15% had normal CA19-9 levels. Deep sequencing (4,000x unique depth) of an initial set of resected pancreatic tumors and matched germline specimens identified 1-6 non-synonymous coding mutations per case (median=3, n=14), with the most frequently mutated genes involving KRAS (79%), TP53 (50%), SMAD4 (29%). Among newly diagnosed treatment-naïve patients with resectable adenocarcinoma (n=9), we detected ctDNA in 4 patients (44%) prior to surgery including with AFs ranging from 0.27% - 0.88%. Subsequent sequencing will compare patients with and without neoadjuvant therapy prior to resection, selection of unresectable patients across a larger range of tumor burden and across multiple timepoints, and integration of large-scale copy number variant detection using low-pass whole-genome sequencing. Conclusions: Circulating tumor DNA monitoring with CAPP-Seq shows promise for improved detection of PDAC. Two key applications include early detection of minimal residual disease after resection and early assessment of response to chemotherapy.
Minimal spatial heterogeneity in chronic lymphocytic leukemia at diagnosis
Authors: Ferran Nadeu, Romina Royo, Francesco Maura, Kevin J. Dawson, Ana Dueso-Barroso, Marta Aymerich, Magda Pinyol, Sílvia Beà, Armando López-Guillermo, Julio Delgado, Xose S. Puente, Elías Campo
Journal: Leukemia (2020)
A phase I study of nanoliposomal irinotecan and 5-fluorouracil/folinic acid in combination with interleukin-1-alpha antagonist for advanced pancreatic cancer patients with cachexia (OnFX).
Authors: Katelyn Mae Atkins, Jun Gong, Mourad Tighiouart, Samuel J. Klempner, Richard Tuli, Veronica Placencio-Hickok, Andrew Eugene Hendifar
Journal: Journal of Clinical Oncology (2020)

TPS780 Background: Patients with pancreatic cancer have the highest rate of weight loss among all advanced cancers. Of which, the majority develop cachexia, characterized by progressive and involuntary loss of weight and skeletal muscle mass. In preclinical studies, interleukin-1-alpha (IL-1α) antagonism has been found to neutralize tumor angiogenesis and onco-inflammation. Early phase single-agent studies in cancer cachexia have demonstrated increased lean body mass and decreased fatigue, pain, and appetite loss. The present study aims to establish the safety of an IL-1α antagonist (Bermekimab) in combination with nanoliposomal irinotecan (Nal-Iri) and 5-fluorouracil (5FU)/folinic acid (FA) in patients with advanced pancreatic adenocarcinoma and cachexia who have failed gemcitabine-based chemotherapy. Methods: This is a single arm, single center, phase I study. The primary objective is to assess the maximum tolerated dose (MTD) of Bermekimab in combination with Nal-Iri and 5FU/FA. MTD is defined as the dose such that the probability of dose-limiting toxicities at MTD is θ = 0.33. The first cohort of up to 3 patients will receive 7.5 mg/kg Bermekimab, 50 mg/m2 nanoliposomal irinotecan, 2000 mg/m2 5FU, and 400 mg/m2 FA and the subsequent doses will be determined by the escalation with overdose control (EWOC) algorithm. Treatment is administered on days 1 and 15 of each 28-day cycle. Key inclusion criteria include: advanced or locally advanced pancreatic adenocarcinoma that has progressed through or intolerant of gemcitabine-based chemotherapy, cachexia defined as &gt; 5% unexplained weight loss 6 months prior to screening or as documented by physician, ECOG PS 0-2 or KPS ≥ 60%, and normal organ and marrow function. Secondary objectives are to assess weight, lean body mass, inflammatory cytokines, overall survival, progression free survival, patient quality of life, and functional status. Since January 2019, 23 patients have been screened and 21 enrolled. Clinical trial information: NCT03207724.
Transcarotid Artery Revascularization With Flow Reversal—Reply
Authors: Arash Fereydooni, Jolanta Gorecka, Alan Dardik
Journal: JAMA Surgery (2020)

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Michael Frederick Hasenfuss
Authors: Niall Sinclair
Journal: BMJ (2020)

Michael Frederick Hasenfuss (“Fred”) passed his finals in 1970 and swore never to sit another exam. He undertook house jobs at Dundee and Stracathro hospitals in 1970-71. In 1971 he joined the newly formed Doncaster vocational training scheme as one of the first four trainees, when formal general practitioner training was in its infancy.

After successfully completing this, he joined a singlehanded GP in Doncaster with an additional appointment as GP course organiser (the original course organiser, the late Malcolm Taylor, had become the Sheffield Deanery’s regional adviser). Fred was instrumental in ensuring …
血液中特定 DNA 片段的水平及其与黑色素瘤分期的相关性
Authors: N. Calbet‐Llopart, M. Potrony, G. Tell‐Martí, C. Carrera, A. Barreiro, P. Aguilera, S. Podlipnik, S. Puig, J. Malvehy, J.A. Puig‐Butillé
Journal: British Journal of Dermatology (2020)
Efficacy of somatostatin analog (SSA) monotherapy for well-differentiated grade 3 (G3) gastroenteropancreatic neuroendocrine tumors (NETs).
Authors: Patrick Walsh McGarrah, Timothy J. Hobday, Jason Scott Starr, Ayse T. Kendi, Rondell P. Graham, Mohamad Bassam Sonbol, Thorvardur Ragnar Halfdanarson
Journal: Journal of Clinical Oncology (2020)

617 Background: Currently, there is no published data on the efficacy of SSAs for well-differentiated G3 NETs. Randomized trials have demonstrated a progression-free survival (PFS) benefit and limited tumor response for lower grade 1-2 NETs, but the optimal systemic therapy for metastatic/unresectable G3 NETs is unknown. We sought to evaluate the efficacy of SSAs in G3 NETs. Methods: We performed a retrospective analysis of Mayo Clinic patients treated with SSAs for metastatic/unresectable G3 NETs, querying data from 1992 - present. Inclusion criteria were: centrally reviewed pathology confirming well-differentiated morphology, G3 based on WHO classification, SSA monotherapy, and radiological data available to assess response. Patients who had prior lines of treatment were included as long they subsequently were treated with single-agent SSA. Poorly-differentiated tumors were excluded. The primary endpoint was PFS. Best overall response was determined by radiographic regression, stabilization, or progression of tumor size. Results: Ninety patient records were reviewed, with 14 meeting inclusion criteria (diagnosed 2014 – 2018). Median Ki-67 proliferative index was 25%. Two patients (14%) had a partial response to SSA therapy, five (36%) had stable disease, and seven (50%) had progressive disease. The estimated median PFS was 4.4 months (95% CI 2.9 – 24). Of the 7 patients with stable disease or partial response, the median time to progression was 8.7 months. Three patients had stable disease for greater than 9 months (24, 29 and 42 months, respectively). Overall survival was not estimable. There was no association of Ki-67 index with PFS based on a proportional hazards model. Conclusions: This is the first report on the efficacy of SSAs for G3 NETs. Although half of the patients in our series had at least stable disease, the PFS was modest at only 4.4 months. Given their favorable side-effect profile compared to cytotoxic chemotherapy, SSAs may present an attractive option to be further explored in a prospective fashion. We are presently updating this data by reassessing response using RECIST criteria.