tbuckley/cabot-search huggingface dataset:
Genomic characterization of rectal cancer and molecular determinants of response to neoadjuvant chemoradiotherapy.
Authors: Walid Khaled Chatila, Michael Marco, Xuan Qu, Henry S. Walch, Anisha Luthra, Chin-Tung Chen, Ritika Kundra, Nikolaus Schultz, Rona Yaeger, Jesse Joshua Smith, Francisco Sanchez Vega, Julio Garcia-Aguilar
Journal: Journal of Clinical Oncology (2020)

192 Background: Rectal cancers are clinically different from colon cancers and have not yet been molecularly characterized due to the scarcity of pretreatment specimens. Discovery of molecular determinants of response to chemotherapy and radiation in patients with locally advanced rectal cancer (LARC, stage II and III) are needed to select those who can avoid surgery and benefit from watch-and-wait strategies. Methods: We profiled 371 pre-treatment specimens using targeted-exome sequencing of 468 cancer genes (n = 325), whole-exome sequencing (n = 100), and RNA-sequencing (n = 113). The targeted-sequencing cohort included patients with stage I (n = 44), II (n = 41), III (n = 176), and IV (n = 64) disease. Primary tumors were divided into lower (LR: 0-4 cm to anal verge, n = 62), middle (MR: 4-8 cm, n = 115), and upper rectum (UR: 8-12 cm, n = 107). We examined molecular determinants of complete response (CR) and relapse free survival (RFS) in LARC patients treated with chemoradiotherapy only (CRT: n = 39), induction chemotherapy + CRT (INCT: n = 87) and consolidation chemotherapy after CRT (CCNT: n = 63). Results: Among MSS cases, oncogenic gene and signaling pathway alterations did not vary by clinical stage. WNT pathway alterations, driven by APC mutations, were more frequent in the UR (89% UR v 86% MR v 60% LR, p &lt; 0.001) while RTK/RAS alterations were more frequent in the LR (54% UR v 69% MR v 72% LR, p &lt; 0.03). A set of genes enriched in mTOR signaling, G2M checkpoint, EMT transition, and DNA repair were overexpressed in the UR (FDR &lt; 0.1). The 5-yr RFS rate for LARC was 75% (CI: 68%-82%) and 24% of the cases had a CR (n = 45). MSI cases had a higher rate of CR compared to MSS cases (50% v 23%, p = 0.07) and none relapsed (n = 8). KRAS-altered MSS tumors exhibited worse RFS in cases treated with CNCT (5-yr: 74% v 97%, p = 0.01), but not in cases treated with INCT (5-yr: 67% v 72%, p = 0.7). Conclusions: WNT alterations are more frequent in the UR while RTK/RAS alterations are more frequent in the LR, suggesting differences in tumor biology between proximal and distal rectal cancer. Further, we report correlations between distinct molecular profiles and response to treatment paradigms that could guide the design of future clinical trials.
Gemcitabine and nab-paclitaxel in older adults with metastatic pancreatic cancer: Are two doses per cycle enough?
Authors: Arthur Winer, Elizabeth A. Handorf, Efrat Dotan
Journal: Journal of Clinical Oncology (2020)

655 Background: The dosing of Gemcitabine and Nab-Paclitaxel (GA), a frontline regimen to treat metastatic pancreatic cancer (mPC), is frequently altered from the traditional dosing schedule (TDS) of day 1, 8, and 15 of a 28 day cycle to a modified dosing schedule (MDS) of 2 doses/cycle. Previous work showed that overall survival (OS) was similar between patients (pts) treated with the MDS vs the TDS. We sought to analyze a larger real-world database to assess these trends. Methods: We retrospectively analyzed de-identified pts with mPC ≥ 65 y/o treated with GA in the Flatiron Health nationwide EHR-derived database. Demographics, treatments (tx), and outcomes were collected. Pts were grouped as either starting with the TDS or MDS. Analysis included time on treatment (TOT) as well as OS. A Cox model was used to test non-inferiority of the MDS vs the TDS for both TOT and OS, adjusting performance status, age, race, gender, and line of therapy (LOT). The upper bound for non-inferiority was a Hazard Ratio (HR) = 1.2. Results: 1497 pts were treated between 1/1/14-5/31/19; 883 pts with the TDS and 614 with the MDS. Median TDS age was 72 (65-85) and MDS was 73 (65-84) (p&lt;0.001). 1237 pts received first- line GA; 60% received the TDS, 40% the MDS. The use of the TDS vs MDS did not vary significantly by LOT, gender, or race, but more pts with a PS of ≥2 received the MDS (p=0.03). In the first-line, outcomes were better for the TDS vs the MDS (unadjusted median TOT 5.3 vs 3.2 mo, p&lt;0.001, OS 9.2 vs 5.3 mo; p&lt;0.001), with consistent results in the ≥ second-line. The MDS did not meet its non-inferiority boundary: first-line TOT HR=1.4 [95% CI 1.2-1.6]; second+ line TOT HR=1.3 [95% CI 1.0-1.7]; first-line OS HR=1.6 [95% CI 1.4-1.8]; second+ line OS HR=1.3 [95% CI 1.0-1.8]. Results were consistent when additionally stratified by PS 0-1 vs 2+. Conclusions: In this large real-world cohort, first-line GA tx with a MDS did not meet criteria for non-inferiority for TOT and OS vs a TDS in older adults with mPC. With the caveats of potential confounding that exist in a de-identified retrospective database, these results suggest that dose intensity may be important in pts with mPC. Further prospective studies are necessary to ensure we utilize effective tx strategies in older adults with mPC.
Sitters as a Patient Safety Strategy to Reduce Hospital Falls
Authors: Adela M. Greeley, Elizabeth P. Tanner, Selene Mak, Meron M. Begashaw, Isomi M. Miake-Lye, Paul G. Shekelle
Journal: Annals of Internal Medicine (2020)

Background: Bedside "sitters" are often used for patients at high risk for falls, but they are expensive and their effectiveness is unclear. Purpose: To review evidence about the effect of sitters and alternatives to sitters on patient falls in acute care hospitals. Data Sources: PubMed searches to 8 October 2019, other databases from inception to December 2018, citation searches on key articles, and a Google search (22 October 2019). Study Selection: English-language studies of any design that assessed the effect of adding sitters to usual care or compared alternatives to sitters (for example, video monitors or "close observation units") for adult patients on general wards of acute care hospitals and reported falls as a primary outcome. Data Extraction: Dual-reviewer extraction of study data and risk of bias; single reviewer with group discussion for GRADE (Grading of Recommendations Assessment, Development and Evaluation) certainty of evidence. Data Synthesis: Of 20 studies meeting inclusion criteria, 2 added sitters to usual care and 18 compared alternatives to sitters. There were no randomized trials, 11 time-series studies, 1 retrospective quasi-experimental study, and 8 pre–post studies. All studies had at least 1 methodological limitation. Two studies provided very-low-certainty evidence that adding sitters reduced falls. Eight studies provided moderate-certainty evidence that interventions that included video monitoring reduced sitter use and either did not affect or reduced the number of falls. Very-low-certainty evidence suggested that interventions that included nurse assessment tools (3 studies) or a close observation unit (2 studies) were effective alternatives to sitters. Limitation: No studies had low risk of bias, publication bias is likely, and studies may have been missed. Conclusion: Despite a compelling rationale, evidence is scant that adding sitters to usual care reduces falls. Primary Funding Source: Veterans Affairs Quality Enhancement Research Initiative. (PROSPERO: CRD42019127424)
Serum glycoproteomic-based liquid biopsy for the detection of pancreatic ductal adenocarcinoma.
Authors: Pashtoon Murtaza Kasi, Ling Shen, Prasanna Ramachandran, Kaitlynn Moser, Gege Xu, Padraig Buckley, Daniel Serie, Carlito Lebrilla, Hui Xu, Carlos Hou Fai Chan
Journal: Journal of Clinical Oncology (2020)

763 Background: Non-invasive biomarkers with high sensitivity and specificity would be of great value for patients with Pancreatic Ductal Adenocarcinoma (PDAC). This would aid in early detection and serve other purposes that 'liquid biopsies' are being explored in. Besides circulating tumor DNA (ctDNA) and methylation markers, glycosylation markers hold great potential promise. We developed a novel workflow using high-resolution quantification of site-specific protein glycosylation by liquid chromatography and tandem mass spectrometry to evaluate the clinical utility of glycoprotemics signature for patients with PDAC. Methods: Serum samples from newly diagnosed PDAC patients and controls were obtained from a commercial biobank (Indivumed, Hamburg, Germany), and a panel of 504 glycan motifs, representing 73 previously reported proteomic markers, was determined. Age-adjusted generalized linear regression models were used to evaluate the differential abundance of each marker, and stepwise variable selection was used for model construction. Results: We analyzed 45 PDAC and 136 control samples. PDAC patients (60% male) had a mean age of 67 (±11) years. with 4.4%, 71.1%, 4.4%, and 20% at stage 1, 2, 3,4, respectively. Controls were women with benign histology after pelvic mass surgery; with a mean age of 61 (±11) years. Twenty-six glycoproteomic markers showed statistically highly significant differential abundance among cases and controls (p&lt;1e-4 each) and were highly reproducible(Pearson’s r &gt; 0.85), which were glycoforms in proteins that have previously been found to be associated with PDAC. Fourteen of these markers displayed &gt;0.8 area under the curve of the receiver operating characteristic (AUC). Multivariate logistic regression modeling with backward selection yielded a classification model with an AUC of 0.94 (95% CI: 0.89-0.99), sensitivity of 91% (95% CI: 75-97%) and specificity of 86% (95% CI: 81-92%). Conclusions: Circulating glycoproteomic biomarkers may be useful in the early detection and clinical management of PDAC patients; offering a new platform to explore and validate.
Another Targeted Therapy for <i>ERBB2</i>-Positive Breast Cancer
Authors: Rebecca Voelker
Journal: JAMA (2020)

The FDA recently granted accelerated approval to an antibody-drug combination for adults who’ve already received at least 2 treatment regimens for unresectable or metastatic breast cancer that is positive for human epidermal growth factor receptor 2 (ERBB2; formerly HER2/neu).
Efficacy and safety of treatment with biologicals (benralizumab, dupilumab, mepolizumab, omalizumab and reslizumab) for severe eosinophilic asthma. A systematic review for the EAACI Guidelines ‐ recommendations on the use of biologicals in severe asthma
Authors: Ioana Agache, Jessica Beltran, Cezmi Akdis, Mubeccel Akdis, Carlos Canelo‐Aybar, Giorgio Walter Canonica, Thomas Casale, Tomas Chivato, Jonathan Corren, Stefano Del Giacco, Thomas Eiwegger, Davide Firinu, James E. Gern, Eckard Hamelmann, Nicola Hanania, Mika Mäkelä, Irene Hernández‐Martín, Parameswaran Nair, Liam O'Mahony, Nikolaos G. Papadopoulos, Alberto Papi, Hae‐Sim Park, Luis Pérez de Llano, Margarita Posso, Claudio Rocha, Santiago Quirce, Joaquin Sastre, Mohamed Shamji, Yang Song, Corinna Steiner, Jurgen Schwarze, Pablo Alonso‐Coello, Oscar Palomares, Marek Jutel
Journal: Allergy (2020)

Abstract Five biologicals have been approved for severe eosinophilic asthma, a well‐recognized phenotype. Systematic reviews (SR) evaluated the efficacy and safety of benralizumab, dupilumab, mepolizumab, omalizumab and reslizumab (alphabetical order) compared to standard of care for severe eosinophilic asthma. PubMed, Embase and Cochrane Library were searched to identify RCTs and health economic evaluations, published in English. Critical and important asthma‐related outcomes were evaluated for each of the biologicals. The risk of bias and the certainty of the evidence were assessed using GRADE. 19 RCTs (three RCTs for benralizumab, three RCTs for dupilumab, three RCTs for mepolizumab, five RCTs for omalizumab and five RCTs for reslizumab), including subjects 12 to 75 years old (except for omalizumab including also subjects 6‐11 years old), ranging from 12 to 56 weeks were evaluated. All biologicals reduce exacerbation rates with high certainty of evidence: benralizumab incidence rate ratio (IRR) 0.53 (95% CI 0.39 to 0.72), dupilumab (IRR) 0.43 (95% CI 0.32 to 0.59), mepolizumab IRR 0.49 (95% CI 0.38 to 0.66), omalizumab (IRR) 0.56 (95% CI 0.40 to 0.77) and reslizumab (IRR) 0.46 (95% CI 0.37 to 0.58). Benralizumab, dupilumab and mepolizumab reduce the daily dose of oral corticosteroids (OCS) with high certainty of evidence. All evaluated biologicals probably improve asthma control, QoL and FEV 1 , without reaching the minimal important difference (moderate certainty). Benralizumab, mepolizumab and reslizumab slightly increase drug‐related adverse events (AE) and drug‐related serious AE (low to very low certainty of evidence). The incremental cost‐effectiveness ratio per quality‐adjusted life year value is above the willingness to pay threshold for all biologicals (moderate certainty). Potential savings are driven by decrease in hospitalizations, emergency and primary care visits. There is high certainty that all approved biologicals reduce the rate of severe asthma exacerbations and for benralizumab, dupilumab and mepolizumab for reducing OCS. There is moderate certainty for improving asthma control, QoL, FEV 1 . More data on long‐term safety are needed together with more efficacy data in the paediatric population.
Phase II study of lamivudine in p53 mutant metastatic colorectal cancer (mCRC).
Authors: Aparna Raj Parikh, Mihir Rajurkar, Emily E. Van Seventer, Angelo J. Gemma, Jill N. Allen, Lawrence Scott Blaszkowsky, Jeffrey William Clark, Lipika Goyal, Theodore S. Hong, Jennifer Yon-Li Wo, Ryan Bruce Corcoran, Alexander Solovyov, Benjamin Greenbaum, Annamaria Szabolcs, Eric C. Tai, Jasmin Joseph, Vishal Thapar, Hui Zheng, David P. Ryan, David Tsai Ting
Journal: Journal of Clinical Oncology (2020)

149 Background: Non-coding repeat RNAs in cancers are pervasive and “mimic” viruses with activation of pattern recognition receptors and the innate immune response. Many repeat RNAs replicate in cancer genomes through a reverse transcriptional intermediate analogous to retroviruses. Nucleoside reverse transcriptase inhibitors (NRTIs) block this retroviral life cycle to increases repeat RNAs in p53 mutant colon cancer cell cancer lines. We initiated a Phase 2 study of lamivudine (3TC) in TP53 mutant mCRC. Methods: Two-stage design with target accrual of 20 patients (pts) in stage 1 and total of 32. Eligibility: pts with p53 mutant refractory mCRC with progression on or intolerance to 5FU, oxaliplatin and irinotecan and anti-EGFR if RAS WT. RNA sequencing was performed on pre-treatment (tx) and on tx biopsy to evaluate for repeat RNA expression and expression of other genes linked to 3TC response/resistance. Radiation was allowed. 9 pts were treated with 3TC 150 mg po bid for 28-day cycles, the maximum FDA approved dose of 3TC in HIV. Subsequent pts were treated at 600 mg po bid, previously tested in P1 trials. Tumor assessments were performed every 8 weeks until documented disease progression by RECIST 1.1 criteria or drug intolerance. Results: 29/32 pts have been treated. Median age: 60 yrs. (27-82) 18 males, 11 females. 2/ 9 (22%) pts on standard 3TC dosing had stable disease (SD) on single agent 3TC with a duration of tx of 169 and 167 days, respectively. Both pts had an initial drop in CEA upon initiation of 3TC. Of the next 20 pts on high dose 3TC, 19 were evaluable. 4 had SD, for 110, 159, 130 and 228+ days. 14 pts had tx-related adverse events (TRAE). 1 pt with a definite Grade 1 TRAE (fatigue). No pts with Grade ≥3 TRAEs. We obtained pre-tx fresh frozen biopsies on 24/29 pts. Of those with SD, 4 had biopsies and differential expression identified significantly higher HSATII repeat RNA in pts with SD compared to PD. There was an association of decreased epigenetic gene expression in HSATII repeat RNA high tumors. Conclusions: This proof-of-concept study demonstrates the safety and activity of single-agent 3TC. Repeat RNA levels appear to correlate with clinical benefit and can be measured in biopsies. Further combination studies and correlatives are planned. Clinical trial information: NCT03144804.
Development of a gene panel for 18F-FDG PET positivity prediction in gastric cancer.
Authors: Seong-Woo Bae, Felix Berlth, Hongyoon Choi, Kyoung-Yun Jeong, Jimin Min, Ji-Hyeon Park, Jong-Ho Choi, Shin-Hoo Park, Seong-Ho Kong, Do Joong Park, Hyuk-Joon Lee, June-Key Chung, Han-Kwang Yang
Journal: Journal of Clinical Oncology (2020)

420 Background: 18F-FDG PET is widely used in clinical cancer diagnostics. However, 18F-FDG PET scan in gastric cancer (GC) is still controversial because of its lower sensitivity in diagnosis and staging compared to other imaging modalities. The purpose of this study was to establish a gene panel for 18F-FDG PET positivity in GC by using patient-derived xenografts (PDXs). Methods: BALB/c nude mice were subcutaneously implanted with 30 cases of GC PDX tissues and underwent a simultaneous PET/MRI scanner. Using RNA-seq data of the 30 GC PDXs for training set, we constructed a gene co-expression network which was correlated with the maximal standardized uptake values (SUVmax). The least absolute shrinkage and selection operator (LASSO) was used for identification of genomic signature for the PET positivity and a prediction model was established. By using qRT-PCR, a gene panel (PredictionScore) based on the gene signature was developed. Results: We found that the PDXs could recapitulate FDG avidity of those parental tumors between 15 Patient-PDX pairs (Spearman r = 0.54, p-value = 0.04). The prediction model with the identified five genes ( PLS1, PYY, HBQ1, SLC6A5, NAT16) provided excellent prediction values compared with actual SUVmax for 15 patients as a validation set (Spearman r = 0.56, p-value = 0.03) and for 8 patients as a test set (Spearman r = 0.90, p-value = 0.005). The PredictionScore showed significant positive correlation with the actual SUVmax for 7 patients as an external validation set (Spearman r = 0.82, p-value = 0.03). Conclusions: PDX can be used to develop a gene panel for the PET positivity prediction in GC. Our results showed that the scoring system can be clinically applicable for developing a predicted stratification model. Future studies will aim to evaluate the panel for a higher number of PET-scanned GC patients to establish a rational patient selection for PET scan in clinical settings.
Identification of Antibodies with Non-overlapping Neutralization Sites that Target Coxsackievirus A16
Authors: Maozhou He, Longfa Xu, Qingbing Zheng, Rui Zhu, Zhichao Yin, Zhenghui Zha, Yu Lin, Lisheng Yang, Yang Huang, Xiangzhong Ye, Shuxuan Li, Wangheng Hou, Yangtao Wu, Jinle Han, Dongxiao Liu, Zekai Li, Zhenqin Chen, Hai Yu, Yuqiong Que, Yingbin Wang, Xiaodong Yan, Jun Zhang, Ying Gu, Z. Hong Zhou, Tong Cheng, Shaowei Li, Ningshao Xia
Journal: Cell Host & Microbe (2020)
A retrospective analysis of factors affecting palliative care consult in patients undergoing cytoreductive surgery and HIPEC.
Authors: Laila Babar, Herman Lo, Obaid Ashraf, Ashish Sethi, Zara Alvi, Gene Grant Finley, Dulabh K. Monga, Suzanne Schiffman, Moses S. Raj
Journal: Journal of Clinical Oncology (2020)

815 Background: The National Cancer Institute defines palliative care as care given to improve the quality of life (QOL) for patients with life threatening diseases. The role of palliative care (PC) within oncology is ever evolving and as more studies are being conducted, its role in the improvement of QOL for patients is being widely recognized. Patients undergoing cytoreductive surgery (CRS) are at a higher risk for morbidity and mortality and often have severe post-operative symptoms that can worsen their QOL. Here we studied the factors affecting PC consult in order to better overcome them. Methods: We queried our Electronic Medical Record EPIC for a list of patients who underwent cytoreductive surgery with HIPEC or HITEC in the hospital from April 2016-April 2019. Data was manually extracted and patients who didn’t meet our criteria were excluded. Patients were divided on the basis of palliative care consults and differences between the groups were analyzed. Odds ratios(OR) with p-value 0.05 and confidence interval (CI) 95% were calculated. Results: We identified 55 patients of whom 34 met our inclusion criteria, 11 male and 23 female with an average age of 56.3 years at the time of diagnosis. 8 patients (23%) had PC; more than 1 comorbidity and age &gt; 40 was associated with a higher likelihood of PC (OR:0.12; CI:0.02-0.76; p:0.02) and (OR: 0.015; CI: 0.0007-0.3029; P: 0.006) respectively. Gender, insurance type and marital status did not corelate with PC. Mean age (58.1 vs 55.7) showed a trend towards higher rates of PC in older population. Conclusions: Approximately one quarter of patients undergoing CRS with HIPEC had a concurrent PC consult. Though this is better than the national average of 11-16%, it continues to be a very small number. PC is not only an end of life service, in fact studies have shown early consultations lead to higher patient satisfaction, improved QOL and better communication. Efforts must be made to engage PC early in the course of treatment and recognize it as an integral part of cancer care.
Immune monitoring of blood in advanced gastroesophageal adenocarcinoma patients treated with an anti-MMP9 monoclonal antibody in combination with nivolumab.
Authors: Shigehisa Kitano, Makiko Yamashita, Kei Muro, Taroh Satoh, Kensei Yamaguchi, Shigenori Kadowaki, Daisuke Sakai, Takashi Ichimura, Seiichiro Mitani, Toshihiro Kudo, Keisho Chin, Masato Fukui, Pankaj Bhargava, Carrie Brachmann, Marianna Zavodovskaya
Journal: Journal of Clinical Oncology (2020)

13 Background: A phase 1b study was conducted in Japanese patients with &gt;2 nd line advanced gastroesophageal adenocarcinoma (GEA) to evaluate the safety, tolerability and explore efficacy and biomarkers, of andecaliximab (ADX), an anti-MMP9 monoclonal antibody, in combination with nivolumab (nivo). In this study, 5 of the 10 enrolled patients had a partial response and the remaining 5 had progressive disease. A larger parallel study in western patients showed no improvement in response or survival for the addition of ADX to nivo. A biomarker study is reported here which explored the hypothesis that baseline levels or early changes in the frequency of peripheral immune cells might identify responders to immunotherapy. Methods: Blood samples were collected at screen, C1D1, C1D8, C1D15, C2D1, C2D15 and then at CXD1 until end of treatment and processed to viably-frozen PBMCs. Immune cell analysis was conducted by flow cytometry (FCM), and included evaluation of T cells, B cells, myeloid derived suppressor cells, NK cells, monocytes, and dendritic cells (DCs). Baseline status and on treatment changes were explored. Results: FCM analysis of peripheral blood showed that the 5 responders had higher frequency of LAG3 + CD8 + T cells and myeloid DCs, and lower frequency of plasmacytoid DC than non-responders at baseline. The number of CD8 + T cells decreased at C1D8 and then recovered in responders. In contrast, no CD8 + T cell changes were observed in non-responders. CTLA-4 + CD4 + T cells also increased after treatment in responders but not in non-responders. Changes in other evaluated cell populations were not observed. Conclusions: The observation that baseline levels of LAG3 + CD8 + T cells and DCs were higher in responders is consistent with a prior anti-tumor immune response. Transient decreased peripheral CD8 + T cells might reflect T-cell trafficking into tumor in response to immunotherapy, and increased peripheral CTLA-4 + CD4 + T cells may also relate to tumor-localized response. Although in a very small number of patients, the observations are consistent with early changes in peripheral immune cells that may relate to response to immunotherapy. Clinical trial information: NCT02862535.