tbuckley/cabot-search huggingface dataset:
Genomic surveillance for hypervirulence and multi-drug resistance in invasive Klebsiella pneumoniae from South and Southeast Asia
Authors: Kelly L. Wyres, To N. T. Nguyen, Margaret M. C. Lam, Louise M. Judd, Nguyen van Vinh Chau, David A. B. Dance, Margaret Ip, Abhilasha Karkey, Clare L. Ling, Thyl Miliya, Paul N. Newton, Nguyen Phu Huong Lan, Amphone Sengduangphachanh, Paul Turner, Balaji Veeraraghavan, Phat Voong Vinh, Manivanh Vongsouvath, Nicholas R. Thomson, Stephen Baker, Kathryn E. Holt
Journal: Genome Medicine (2020)

Klebsiella pneumoniae is a leading cause of bloodstream infection (BSI). Strains producing extended-spectrum beta-lactamases (ESBLs) or carbapenemases are considered global priority pathogens for which new treatment and prevention strategies are urgently required, due to severely limited therapeutic options. South and Southeast Asia are major hubs for antimicrobial-resistant (AMR) K. pneumoniae and also for the characteristically antimicrobial-sensitive, community-acquired "hypervirulent" strains. The emergence of hypervirulent AMR strains and lack of data on exopolysaccharide diversity pose a challenge for K. pneumoniae BSI control strategies worldwide.
Pancreatic cancer (PaC)-specific health-related quality of life (HRQoL) with maintenance olaparib (O) in patients (pts) with metastatic (m) PaC and a germline <i>BRCA</i> mutation (g<i>BRCA</i>m): Phase III POLO trial.
Authors: Michael J. Hall, Talia Golan, Pascal Hammel, Michele Reni, Eric Van Cutsem, Teresa Macarulla, Joon Oh Park, Daniel Hochhauser, Dirk Arnold, Do-Youn Oh, Anke C. Reinacher-Schick, Giampaolo Tortora, Hana Algül, Eileen Mary O'Reilly, David McGuinness, Karen Cui, Seongjung Joo, Hyun Kyoo Yoo, Nikunj Patel, Hedy L. Kindler
Journal: Journal of Clinical Oncology (2020)

648 Background: In POLO (NCT02184195), maintenance O significantly improved progression-free survival vs placebo (P) in pts with a gBRCAm and mPaC without compromising HRQoL (Hammel Ann Oncol 2019). We report additional predefined exploratory HRQoL data from the PaC-specific EORTC QLQ-PAN26 questionnaire. Methods: Pts were randomized to O (300 mg bid; tablets) or P. QLQ-PAN26 was completed at baseline (BL), after 1, 2, 3 + 4 weeks (wk) of treatment, every 4 wks until progression, at discontinuation, and 30 days after last dose. Scale range = 1–100 (higher score = greater symptoms); a 10-point change was predefined as clinically meaningful. Adjusted mean change from BL (CFBL) was analyzed by mixed model for repeated measures; time to sustained clinically meaningful deterioration (TSCMD) by log-rank test. Results: Analyses included the 89/92 O- and 58/62 P-arm pts with BL data (overall compliance: 97.8% vs 98.3%). Symptom scores were well balanced in both groups at BL and remained low and stable over time (Table). There were no clinically meaningful between-group differences in adjusted mean CFBL symptom scores. TSCMD in symptoms were not significantly different with O vs P. Conclusions: HRQoL was preserved with maintenance O, as shown by a low and stable PaC symptom burden over time, with no difference vs P. These data support the clinical benefit of O in pts with a gBRCAm and mPaC. Clinical trial information: NCT02184195 . [Table: see text]
Radiomics Response Signature for Identification of Metastatic Colorectal Cancer Sensitive to Therapies Targeting EGFR Pathway
Authors: Laurent Dercle, Lin Lu, Lawrence H Schwartz, Min Qian, Sabine Tejpar, Peter Eggleton, Binsheng Zhao, Hubert Piessevaux
Journal: JNCI Journal of the National Cancer Institute (2020)

Abstract Background The authors sought to forecast survival and enhance treatment decisions for patients with liver metastatic colorectal cancer by using on-treatment radiomics signature to predict tumor sensitiveness to irinotecan, 5-fluorouracil, and leucovorin (FOLFIRI) alone (F) or in combination with cetuximab (FC). Methods We retrospectively analyzed 667 metastatic colorectal cancer patients treated with F or FC. Computed tomography quality was classified as high (HQ) or standard (SD). Four datasets were created using the nomenclature (treatment) – (quality). Patients were randomly assigned (2:1) to training or validation sets: FCHQ: 78:38, FCSD: 124:62, FHQ: 78:51, FSD: 158:78. Four tumor-imaging biomarkers measured quantitative radiomics changes between standard of care computed tomography scans at baseline and 8 weeks. Using machine learning, the performance of the signature to classify tumors as treatment sensitive or treatment insensitive was trained and validated using receiver operating characteristic (ROC) curves. Hazard ratio and Cox regression models evaluated association with overall survival (OS). Results The signature (area under the ROC curve [95% confidence interval (CI)]) used temporal decrease in tumor spatial heterogeneity plus boundary infiltration to successfully predict sensitivity to antiepidermal growth factor receptor therapy (FCHQ: 0.80 [95% CI = 0.69 to 0.94], FCSD: 0.72 [95% CI = 0.59 to 0.83]) but failed with chemotherapy (FHQ: 0.59 [95% CI = 0.44 to 0.72], FSD: 0.55 [95% CI = 0.43 to 0.66]). In cetuximab-containing sets, radiomics signature outperformed existing biomarkers (KRAS-mutational status, and tumor shrinkage by RECIST 1.1) for detection of treatment sensitivity and was strongly associated with OS (two-sided P &amp;lt; .005). Conclusions Radiomics response signature can serve as an intermediate surrogate marker of OS. The signature outperformed known biomarkers in providing an early prediction of treatment sensitivity and could be used to guide cetuximab treatment continuation decisions.
ENETS single center of excellence experience with the NETest: A real-world assessment of 565 patients.
Authors: Anna Malczewska, Mateusz Rydel, Amanda Robek, Katarzyna Kusnierz, Izabela Les-Zielinska, Damian Czyzewski, Dariusz Ziora, Joanna Pilch-Kowalczyk, Wojciech Zajecki, Beata Kos-Kudla, Irvin Mark Modlin
Journal: Journal of Clinical Oncology (2020)

605 Background: There is a substantial clinical unmet need for an accurate and effective blood biomarker of NET disease. We therefore evaluated under real-world conditions the clinical utility of the NETest in a NET Center of Excellence and compare it with the biomarker CgA. Methods: Cohorts: GEP-NET (253), BP-NET (49), colon cancer (37), lung cancers (80), benign lung disease (59) and controls (86). GEP-NETs: 164 (65%) had image-detectable disease or were resection-margin (R1) positive. Grading included G1 [106], G2 [49] and G3 [9]. BP-NETs, 28 of 49 (57%) had evidence of disease. Grading was TC [14], AC [14]. Disease status (stable [SD] or progressive [PD]) determined by RECIST 1.1. Blood sampling: NETest ( n= 565) and NETest/CgA matched samples (135). NETest (PCR) (0-100 score) with positive &gt; 20; progressive &gt; 40. CgA (ELISA). All samples deidentified, and measurement/ analyses blinded. Statistics: Mann-Whitney U-test, McNemar’s test and AUROC. Results: GEPNET: NETest was significantly higher (34.4±1.8, p&lt; 0.0001) in NET disease versus no NET disease (10.5±1, p&lt; 0.0001), non-NET disease (18±4, p= 0.0004) or controls (7±0.5, p&lt; 0.0001). Diagnostic sensitivity was 89%, and specificity 94%. NETest levels were not related to grade (G1: 32±2 vs. G2: 38±3, p= 0.09). BPNET: NETest was significantly higher (30±1.3) vs no NET disease (24.1±1.3, p= 0.0049). Diagnostic sensitivity 100%. Levels were elevated vs controls ( p&lt; 0.0001) and non-NET disease (20±2, p= 0.0001). NETest levels were not related to grade (TC 30±2 vs. AC: 30±2, p= NS). Levels were elevated in PD (55±5.5) vs SD (33.6±2, p= 0.0005). AUCs for detecting disease ranged between 0.89 (GEP-NET) to 1.0 (BE-NET) ( p&lt; 0.0001). Matched GEP-NETS (135): NETest was significantly more accurate for detecting NETS (99%) than CgA (53%, McNemar’s test Chi 2 = 87, p= 0.0001). sensitivity (99%) and specificity (96%) were better than CgA (37% and 96% respectively). Conclusions: The NETest is an accurate diagnostic test for both GEP- and BP-NEN. It defines clinical status (stable or progressive disease). NETest is significantly more accurate than CgA. The multianalyte genomic blood assessment of NET disease provided clinical information of utility in management.
Baseline sputum eosinophil + neutrophil subgroups’ clinical characteristics and longitudinal trajectories for NHLBI Severe Asthma Research Program (SARP 3) cohort
Authors: Annette T. Hastie, David T. Mauger, Loren C. Denlinger, Andrea Coverstone, Mario Castro, Serpil Erzurum, Nijar Jarjour, Bruce D. Levy, Deborah A. Meyers, Wendy C. Moore, Brenda Phillips, Sally E. Wenzel, John V. Fahy, Elliot Israel, Eugene R. Bleecker, Allison Crosby-Thompson, Carrie Nettles, Angeles Cinelli, Meghan Le, Joy Lawrence, Donna Liu, Jenelle Mock, Danica Klaus, Gina Crisafi, Regina Smith, Jeff Krings, Rachel Weaver, Daniel Nguyen, Kristin McIntire, Sara Baicker-McKee, Annabelle Charbit, John Trudeau, Heather Floerke, Susan Foster, Brian Rector, Huiqing Yin-Declue, Dr Patricia Noel, Dr Tom Croxton, Dr Robert Smith
Journal: Journal of Allergy and Clinical Immunology (2020)
Molecular characterization of a gastric cancer transmitted from an organ donor to four transplant recipients.
Authors: Chloe Evelyn Atreya, Meyeon Park, James P. Grenert, Spencer Behr, Amalia Gonzalez, Jonathan Chou, Samantha Maisel, Terence W. Friedlander, Chris E. Freise, Jun Shoji, Thomas John Semrad, Peter Chin-Hong, Eric A. Collisson, Jessica Van Ziffle
Journal: Journal of Clinical Oncology (2020)

414 Background: Donor-derived malignancy may occur even when not suspected based on donor or recipient factors, including age and time to cancer diagnosis. Early recognition of donor-derived malignancy has treatment implications. We describe the molecular characterization of a gastric cancer transmitted from an organ donor to heart, liver (LR), left kidney (LKR), and right kidney-pancreas (KPR) recipients. Methods: IRB approval for chart review was obtained; LR, LKR, and KPR also provided research consent for molecular profiling. Short Tandem Repeat (STR) genotyping was performed by polymerase chain reaction and gel electrophoresis. Tumor and germline DNA from patients and the organ donor were subjected to next generation sequencing (NGS) of 479 genes. Fluorescence in situ hybridization (FISH) was used to confirm MET amplification. Results: Donor origin was established by STR analysis, with the tumors showing high levels of donor alleles. Pathology revealed a poorly differentiated adenocarcinoma with signet ring features. Immunohistochemical staining and CA-19-9 elevation were most consistent with gastric or pancreas origin. Tumor sequencing was notable for somatic mutation of CDH1, MET amplification and wild-type KRAS genes. Tumors from LR and KPR were nearly identical based on pathogenic variants, allele frequency, and copy number variation. Insufficient tumor cellularity in all LKR specimens precluded NGS profiling, but clinical testing found that the cancer was mismatch repair proficient; ERBB2 equivocal; and PDL-1 positive. A circulating tumor DNA test did not uncover any genomic alterations; however, MET amplification was confirmed in this tumor using FISH probes. Conclusions: STR analysis and reporting should be standard immediately following diagnosis of cancer in an organ transplant recipient to ascertain donor derivation. Further molecular characterization, including NGS, may aid in defining primary tumor origin. Here, diagnosis with PDL1-positive gastric cancer enabled use of pembrolizumab. One patient remains alive and without evidence of cancer following prompt organ explant after cancer was reported in other recipients.
Bilirubin as a signaling molecule
Authors: Libor Vítek
Journal: Medicinal Research Reviews (2020)

Abstract For long time bilirubin was only considered as a potentially dangerous sign of liver diseases, but it now appears clear that it is also a powerful signaling molecule. Together with potent antioxidant activities that were only reported in the last few decades, many other biological effects have now been clearly described. These include especially profound inhibitory effects on almost all effectors of the immune system, with their clinical consequences in the bilirubin‐mediated protection against autoimmune and inflammatory diseases. Separate from these, bilirubin activates various nuclear and cytoplasmic receptors, resembling the endocrine activities of actual hormonal substances. This is true for the “classical” hepatic nuclear receptors, including the aryl hydrocarbon receptor, or the constitutive androstane receptor; and also for some lesser‐explored receptors such as peroxisome proliferator‐activated receptors α and γ; Mas‐related G protein‐coupled receptor; or other signaling molecules including fatty acid binding protein 1, apolipoprotein D, or reactive oxygen species. All of these targets have broad metabolic effects, which in turn may offer protection against obesity, diabetes mellitus, and other metabolic diseases. The (mostly experimental) data are also supported by clinical evidence. In fact, data from the last three decades have convincingly demonstrated the protective effects of mildly elevated serum bilirubin concentrations against various “diseases of civilization.” Additionally, even tiny, micromolar changes of serum bilirubin concentrations have been associated with substantial alteration in the risks of these diseases. It is highly likely that all of the biological activities of bilirubin have yet to be exhaustively explored, and thus we can expect further clinical discoveries about this evolutionarily old molecule into the future.
A prediction model for pathological findings after neoadjuvant chemoradiotherapy for resectable locally advanced esophageal cancer based on PET images using radiomics and machine-learning.
Authors: Yuji Murakami, Yasushi Nagata, Daisuke Kawahara
Journal: Journal of Clinical Oncology (2020)

456 Background: The pathologic complete response (PCR) rate by neoadjuvant chemoradiotherapy (NCRT) for resectable locally advanced esophageal squamous cell carcinoma (ESCC) is about 40%. If we could predict a PCR from pre-treatment image data, it might be possible to select patients who can be cured by organ-preserving CRT. The purpose of this study is to construct a predictive model for PCR by NCRT in patients with locally advanced ESCC using radiomics and machine-learning. Methods: We used data of 98 ESCC patients who underwent NCRT and surgery from 2003 to 2016. Firstly, we fused the radiotherapy treatment planning CT images and PET images scanned before treatment. Then using target delineations on planning CT images, we created eight kinds of target regions on PET images. Secondly, we generated a total of 6968 features per patient using the PET image data within these target regions that were preprocessed by radiomics technique. Among them, we extracted the optimal features for machine-learning using the least absolute shrinkage and selection operator (LASSO) logistic regression. Thirdly, artificial neural networks were used as a machine-learning method to create a predictive model. The extracted radiomics features were used as input values, and the information of ‘PCR’ or ‘not PCR’ was used as output values. We used data of randomly selected 58 patients for training and constructed a predictive model. Then we used data of 15 patients to validate the models and created the optimal model. Finally, we evaluated the predictive model using the test data of 25 patients. Results: By the LASSO analysis, 32 radiomics features were extracted for machine-learning classification. This predictive model predicted pathological findings after NCRT in 24 of 25 test data. The accuracy, specificity and sensitivity in the prediction of PCR after NCRT by this predictive model were 96.0%, 93.8%, and 100%, respectively. Conclusions: A prediction model based on PET images using radiomics and machine-learning could predict pathological findings after NCRT for resectable locally advanced ESCC.
Postoperative adjuvant transarterial infusion chemotherapy with FOLFOX could improve outcomes of hepatocellular carcinoma patients with microvascular invasion: A preliminary report of a phase III, randomized, controlled clinical trial.
Authors: Shaohua Li, Wei Wei, Qiaoxuan Wang, Zhixing Guo, Jie Mei, Lianghe Lu, Yihong Ling, Li Xu, Minshan Chen, Wenping Lin, Jingwen Zou, Yuhua Wen, Rongping Guo
Journal: Journal of Clinical Oncology (2020)

527 Background: Microvascular invasion (MVI) is a risk factor for recurrence after hepatectomy for hepatocellular carcinoma (HCC) patients. This study aimed to investigate to efficacy and safety of postoperative adjuvant transarterial infusion chemotherapy (TAI) with FOLFOX regimen for HCC patients with MVI. Methods: In this prospective, phase III, randomized, open-labeled, controlled clinical trial, HCC patients with histologically confirmed MVI were randomly assigned (1:1) after hepatectomy to receive either 1-2 cycles adjuvant TAI (AT group) or follow-up without any adjuvant treatment (FU group). The primary endpoint was disease-free survival (DFS), the secondary endpoints are overall survival (OS) and safety. Results: Between June, 2016 and April 2019, 127 patients were randomly assigned to AT group (n=63) or FU group (n=64). Clinicopathological characteristics were balanced between the two groups. The 6-, 12-, and 18-month OS rates for AT group were 100.0%, 97.7%, and 97.7%, and were 94.5%, 89.6%, and 78.5% for FU group, respectively. The 6-, 12-, and 18-month DFS rates for AT group were 84.7%, 61.8%, and 58.7%, and were 62.9%, 48.1%, and 38.6% for FU group, respectively. The OS and DFS were significantly better in AT group than in FU group (p=0.037 and 0.023, respectively). No patients in AT group experienced grade 3 or more severe adverse events (AEs). Conclusions: Adjuvant TAI after hepatectomy may bring survival benefits of OS and DFS for HCC patients with MVI. Clinical trial information: NCT03192618.
Effect of previous chemotherapy treatments on circulating tumor-associated cells in colorectal cancer.
Authors: Sewanti Limaye, Timothy Crook, Raymond Page, Darshana Patil, Dadasaheb Akolkar, Vineet Datta, Stefan Schuster, Cynthe Sims, Revati Patil, Sanket Patil, Vishakha Mhase, Sachin Apurwa, Shabista Khan, Ajay Srinivasan, Rajan Datar
Journal: Journal of Clinical Oncology (2020)

194 Background: Resistance to combination regimens of fluorouracil, oxaliplatin and irinotecan are commonly observed in Colorectal cancers (CRC). There are presently no viable approaches for ‘real-time’ monitoring of innate and acquired chemoresistance. We used a novel method for chemo-interrogation (CI) by harvesting from peripheral blood sufficient numbers of Circulating-Tumor Associated Cells (CTACs) which are defined as apoptosis-resistant cells of tumorigenic origin which are positive for Epithelial Cell Adhesion Molecule (EpCAM) and pan-cytokeratins (pan-CK) irrespective of CD45 status. Methods: Peripheral blood was collected from 110 patients with confirmed diagnosis of CRC, among whom 56 were recently diagnosed and therapy naïve while 54 were pre-treated. Peripheral blood mononuclear cells (PBMCs) were harvested by centrifugation and treated with commercially available stabilizing agents by a proprietary protocol to stabilize apoptosis resistant C-TACs. Surviving C-TACs were confirmed by immunostaining for EpCAM and pan-CK. Harvested C-TACs were treated in vitro with 5-fluorouracil, irinotecan and oxaliplatin and the fraction of surviving cells estimated to determine resistance profiles. Results: Among the 56 cases of recently diagnosed therapy naïve CRC, innate chemoresistance was observed in 37.5%, 47.3% and 41.8% of samples (unique patient-drug combinations) towards 5-fluorouracil, irinotecan and oxaliplatin respectively. Among the 54 cases of previously treated CRC, acquired chemoresistance was observed in 92.6%, 92.6% and 95.5% of samples towards 5-fluorouracil, irinotecan and oxaliplatin respectively. Conclusions: We show for the first time that sufficient C-TACs can be harvested for meaningful CI in newly diagnosed treatment naïve CRC as well as refractory CRCs. Post-treatment chemoresistance being an order of magnitude higher than the untreated cohort indicates that C-TACs in CRC are resistance-educated by previous treatments and can guide treatment strategy.
Immune-related adverse events (irAE) to cancer immune checkpoint inhibitors (CPI) and survival outcomes: To rechallenge or not—An Appalachian experience.
Authors: Heidar Albandar, Salah Ud Din Safi, Jacob Lane Fuqua, Samuel Merrill, Patrick C. Ma
Journal: Journal of Clinical Oncology (2020)

81 Background: The adoption of immunotherapy has led to a paradigm shift in the treatment of many advanced stage malignancies. Patients with durable long term survival under cancer immunotherapy have begun to emerge. Circulating memory immune T and B-cells play a key role in the anamnestic response to future similar antigen exposure and may contribute to durable cancer immunotherapy response and benefits in patients with irAE. We hypothesized that there is increased median overall survival (mOS) in patients who had irAE under CPI therapy. Methods: We conducted a retrospective analysis with an IRB-approved study protocol of adults treated between 2011-2019 at the West Virginia University Cancer Institute, with a histopathologic diagnosis of melanoma or lung cancer, who had received CPI therapy. We collected data on demographics, histology, stage at diagnosis, immunotherapy type used, irAE and its grade, and days from immunotherapy initiation to death. Patients were stratified by irAE status and CPI rechallenge status following irAE. Results: Demographics were similar between the irAE and non-irAE groups within both cancer types. A total of 229 lung and 114 melanoma cancer patients had received CPI. Overall, there were 105/343 (30.6%) cases of irAE found of any grades: 27.5% of lung and 37.7% of melanoma patients developed irAE. The mOS for the non-irAE cohort group was 299 days, which was significantly worse than the irAE cohort (mOS not met, Log-rank, p &lt; 0.0001). Within the irAE cohort, there was no significant survival difference between the non-rechallenged and rechallenged groups (Log-rank p = 0.6150). Conclusions: Our findings identified significantly improved survival outcomes among lung cancer/melanoma patients treated with CPI who developed irAE, including those who were rechallenged after irAE, compared to those who had no irAE. Patients who were CPI-rechallenged after irAE had comparable survival outcomes compared to those without rechallenge. Further multi-center validation studies and prospective studies are warranted to further confirm these findings and help guide clinical management in patients who experience CPI irAE.
Judge issues guidance after “troubling” case of woman with reduced capacity whose treatment was delayed
Authors: Clare Dyer
Journal: BMJ (2020)

The vice president of the Court of Protection has issued new guidance on medical treatment for patients who cannot take treatment decisions for themselves, warning that delays in applying to the court can turn a treatable condition into a fatal one.1

Mr Justice Hayden attached the guidance to his judgment in the case of a woman with squamous cell carcinoma who was referred to Sherwood Forest Hospitals NHS Foundation Trust by her GP in October 2018. She was assessed as lacking capacity to decide on treatment in May 2019, but an application to the Court of Protection was not made until 20 December. That date was the end of the legal term, and the case could not be heard until the start of the new term, on 14 January this year.

The 71 year old patient, referred to as Mrs H, had bipolar disorder and a history of being sectioned under the Mental Health …