tbuckley/cabot-search huggingface dataset:
Patient-derived organoids for personalized drug screening in intrahepatic cholangiocarcinoma.
Authors: Ricardo J. Antonia, Kan Toriguchi, Eveliina Karelehto, Dania Annuar, Luika Timmerman, Noura Tbeileh, Aras N. Mattis, Carlos U. Corvera, Kenzo Hirose, Eric K. Nakakura, David B. Donner, Robert S. Warren
Journal: Journal of Clinical Oncology (2020)

581 Background: Despite standard treatment with gemcitabine and cisplatin, median survival for unresectable Intrahepatic Cholangiocarcinoma (ICC) is &lt; 1 year. Clearly, novel therapeutic strategies are urgently needed. The paucity of targetable mutations in ICC and the as yet unproven benefit of genetically targeted drugs led us to ask whether a reliable clinical benefit may be revealed by patient-specific therapeutic testing in novel models of ICC. Here we describe our ability to establish patient-derived three-dimensional organoid cultures (PDO) that enable individualized identification of active single agents or drug combinations in surrogate models of ICC. Methods: To model patient-specific drug responses, we used the freshly resected ICCs from small samples of single patient tumors to generate PDXs and PDOs, small spheroidal clusters of tumor cells grown in vitro. We have employed a high-throughput drug screening platform using AI-enhanced robotics (Yamaha Motor Corporation) to identify and distribute single, uniformly sized PDOs into 384-well ultra-low adherent plates. This is coupled with a TECAN D300e drug dispenser that rapidly delivers nanoliter volumes of a 34-drug panel, thereby facilitating rapid, reliable drug response analyses. Results: Our data show that PDOs retain characteristic genomic and histological features of the patients’ tumors. Drug responses were specific to each patient tumor, but PDOs from all patients responded to a greater or lesser degree to mTOR inhibition, suggesting that this pathway is important in ICC. The responses of PDO to the mTOR inhibitor Sapanisertib (INK128), was recapitulated in the same patient’s PDX. Further, INK128 was synergistic with gemcitabine in patient 970 PDOs as well as in vivo in PDX also from patient 970. Conclusions: As it is believed that PDX can predict patient responses to drugs, our results suggest that PDO may also predict patient drug responses. The establishment of PDO may allow economical patient-specific, high throughput drug screens that could ultimately inform clinical practice. [Table: see text]
Comparison of efficacy of aspirin plus epirubicin, oxaliplatin, and capecitabine versus epirubicin, oxaliplatin, and capecitabine alone in patients with locally advanced and metastatic gastric cancer: A randomized clinical trial.
Authors: Esha Jafa, Biswajit Dubashi, Smita Kayal, Vikram Kate, Rajesh Nachiappa Ganesh, Sunitha V. C., Charles L., Yadav Nisha
Journal: Journal of Clinical Oncology (2020)

384 Background: Aspirin was long known to prevent cancer, the last decade revealed its therapeutic role via varied mechanisms like inhibition of platelet activation, COX and PI3K pathway. Since PI3K/AKT/mTOR is one of the pathways activated in gastric cancer and Giampieri et al (2016) showed improved response rates, PFS and OS with addition of aspirin to capecitabine in heavily pretreated metastatic colorectal cancer,a cancer in which efficacy of aspirin is related to presence of PI3K mutations,we aimed to compare the efficacy of aspirin added to a standard regime EOX with EOX alone in locally advanced and metastatic gastric cancer. Methods: All patients with advanced gastric cancer coming to JIPMER,Department of Medical oncology between march 2017 to may 2019 were screened for eligibility in the trial.Those eligible were randomly assigned to standard EOX or standard EOX plus 150 mg of daily aspirin.Tumor measurements were performed at baseline,then after 3-4 cycles (interim response) and the response to treatment was assessed by the radiologist who was blinded to treatment arms according to RECIST1.1 criteria.Toxicity profiles were recorded as per CTCAE v 4.03.In per protocol analysis,response rates, PFS(progression free survival) and OS (overall analysis) were analysed for patients who received ≥3 cycles and had an evaluable interim response. Results: 95 patients were randomised.In per protocol analysis, 70 patients were included. The results are shown in table. Conclusions: No statistically significant difference was seen with respect to response rates, PFS, OS and toxicity, although there was a higher ORR (overall response rate=complete response,CR +partial response, PR) and OS seen in EOX plus aspirin arm. Clinical trial information: CTRI/2017/11/010651. JIPMER,Puducherry,India [Table: see text]
Cis- and Trans-Regulatory Variations in the Domestication of the Chili Pepper Fruit
Authors: Erik Díaz-Valenzuela, Ruairidh H Sawers, Angélica Cibrián-Jaramillo
Journal: Molecular Biology and Evolution (2020)

The process of domestication requires the rapid transformation of the wild morphology into the cultivated forms that humans select for. This process often takes place through changes in the regulation of genes, yet, there is no definite pattern on the role of cis- and trans-acting regulatory variations in the domestication of the fruit among crops. Using allele-specific expression and network analyses, we characterized the regulatory patterns and the inheritance of gene expression in wild and cultivated accessions of chili pepper, a crop with remarkable fruit morphological variation. We propose that gene expression differences associated to the cultivated form are best explained by cis-regulatory hubs acting through trans-regulatory cascades. We show that in cultivated chili, the expression of genes associated with fruit morphology is partially recessive with respect to those in the wild relative, consistent with the hybrid fruit phenotype. Decreased expression of fruit maturation and growth genes in cultivated chili suggest that selection for loss-of-function took place in its domestication. Trans-regulatory changes underlie the majority of the genes showing regulatory divergence and had larger effect sizes on gene expression than cis-regulatory variants. Network analysis of selected cis-regulated genes, including ARP9 and MED25, indicated their interaction with many transcription factors involved in organ growth and fruit ripening. Differentially expressed genes linked to cis-regulatory variants and their interactions with downstream trans-acting genes have the potential to drive the morphological differences observed between wild and cultivated fruits and provide an attractive mechanism of morphological transformation during the domestication of the chili pepper.
A tumor-intrinsic PD-L1/NLRP3 inflammasome signaling pathway drives resistance to anti–PD-1 immunotherapy
Authors: Balamayoora Theivanthiran, Kathy S. Evans, Nicholas C. DeVito, Michael Plebanek, Michael Sturdivant, Luke P. Wachsmuth, April K.S. Salama, Yubin Kang, David Hsu, Justin M. Balko, Douglas B. Johnson, Mark Starr, Andrew Nixon, Alisha Holtzhausen, Brent A. Hanks
Journal: Journal of Clinical Investigation (2020)

An in-depth understanding of immune escape mechanisms in cancer is likely to lead to innovative advances in immunotherapeutic strategies. However, much remains unknown regarding these mechanisms and how they impact immunotherapy resistance. Using several preclinical tumor models as well as clinical specimens, we identified a mechanism whereby CD8+ T cell activation in response to programmed cell death 1 (PD-1) blockade induced a programmed death ligand 1/NOD-, LRR-, and pyrin domain-containing protein 3 (PD-L1/NLRP3) inflammasome signaling cascade that ultimately led to the recruitment of granulocytic myeloid-derived suppressor cells (PMN-MDSCs) into tumor tissues, thereby dampening the resulting antitumor immune response. The genetic and pharmacologic inhibition of NLRP3 suppressed PMN-MDSC tumor infiltration and significantly augmented the efficacy of anti-PD-1 antibody immunotherapy. This pathway therefore represents a tumor-intrinsic mechanism of adaptive resistance to anti-PD-1 checkpoint inhibitor immunotherapy and is a promising target for future translational research.
Predicting 10-Year Risk of End-Organ Complications of Type 2 Diabetes With and Without Metabolic Surgery: A Machine Learning Approach
Authors: Ali Aminian, Alexander Zajichek, David E. Arterburn, Kathy E. Wolski, Stacy A. Brethauer, Philip R. Schauer, Steven E. Nissen, Michael W. Kattan
Journal: Diabetes Care (2020)

OBJECTIVE To construct and internally validate prediction models to estimate the risk of long-term end-organ complications and mortality in patients with type 2 diabetes and obesity that can be used to inform treatment decisions for patients and practitioners who are considering metabolic surgery. RESEARCH DESIGN AND METHODS A total of 2,287 patients with type 2 diabetes who underwent metabolic surgery between 1998 and 2017 in the Cleveland Clinic Health System were propensity-matched 1:5 to 11,435 nonsurgical patients with BMI ≥30 kg/m2 and type 2 diabetes who received usual care with follow-up through December 2018. Multivariable time-to-event regression and random forest machine learning models were built and internally validated using fivefold cross-validation to predict the 10-year risk for four outcomes of interest. The prediction models were programmed to construct user-friendly web-based and smartphone applications of Individualized Diabetes Complications (IDC) Risk Scores for clinical use. RESULTS The prediction tools demonstrated the following discrimination ability based on the area under the receiver operating characteristic curve (1 = perfect discrimination and 0.5 = chance) at 10 years in the surgical and nonsurgical groups, respectively: all-cause mortality (0.79 and 0.81), coronary artery events (0.66 and 0.67), heart failure (0.73 and 0.75), and nephropathy (0.73 and 0.76). When a patient’s data are entered into the IDC application, it estimates the individualized 10-year morbidity and mortality risks with and without undergoing metabolic surgery. CONCLUSIONS The IDC Risk Scores can provide personalized evidence-based risk information for patients with type 2 diabetes and obesity about future cardiovascular outcomes and mortality with and without metabolic surgery based on their current status of obesity, diabetes, and related cardiometabolic conditions.
Harnessing the immune system after allogeneic stem cell transplant in acute myeloid leukemia
Authors: Cole Sterling, Jonathan Webster
Journal: American Journal of Hematology (2020)

Allogeneic stem cell transplantation (allo-SCT) is the most successful and widely used immunotherapy for the treatment of acute myeloid leukemia (AML), as a result of its anti-leukemic properties driven by T cells and natural killer (NK) cells, leading to a graft-vs-leukemia (GVL) effect. Despite its essential role in AML treatment, relapse after allo-SCT is common and associated with a poor prognosis. There is longstanding interest in developing immunologic strategies to augment the GVL effect post-transplant to prevent relapse and improve outcomes. In addition to prophylactic maintenance strategies, the GVL effect can also be used in relapsed patients to reinduce remission. While immune checkpoint inhibitors and other novel immune-targeted agents have been successfully used in the post-transplant setting to augment the GVL effect and induce remission in small clinical trials of relapsed patients, exacerbations of graft-vs-host disease (GVHD) have limited their broader use. Here we review advances in three areas of immunotherapy that have been studied in post-transplant AML: donor lymphocyte infusion (DLI), immune checkpoint inhibitors, and other monoclonal antibodies (mAbs), including antibody-drug conjugates (ADCs) and ligand receptor antagonists. We also discuss additional therapies with proposed immunologic mechanisms, such as hypomethylating agents, histone deacetylase inhibitors, and the FLT3 inhibitor sorafenib.
A clinical scoring system for survival prediction in advanced gastric cancer.
Authors: Jinchul Kim, Ja Hyun Yeo, Jung Yong Hong, Seung Tae Kim, Se Hoon Park, Joon Oh Park, Young Suk Park, Ho Yeong Lim, Won Ki Kang, Jeeyun Lee
Journal: Journal of Clinical Oncology (2020)

436 Background: We established a scoring system using easily approachable clinical characteristics at the timing of initiating palliative chemotherapy to achieve accurate overall survival prediction to first-line treatment consisting of fluoropyrimidines in patients with advanced gastric cancer. Methods: A total of 1,733 patients were included in the study. The dataset was split into a training (n=1156, 67%) and validation set (n=577, 33%). Top-ranked variables were identified using the Random Forest for Survival algorithm and analyzed into a Cox regression model, thereby constructing the scoring system for predicting overall survival of advanced gastric cancer. Results: Five variables were finally included in the scoring system: serum neutrophil-lymphocyte ratio, alkaline phosphatase, albumin level, performance status, and histologic differentiation. The scoring system determined four distinct risk groups in validation dataset with median overall survival of 17.1 month (95% confidence interval [CI] = 14.9 to 20.5 month), 12.9 month (95% CI = 11.4 to 14.6 month), 8.1 month (95% CI = 5.3 to 12.3 month), and 3.9 month (95% CI = 1.5 to 8.2 month), respectively. AUC to estimate discrimination performance of the scoring system was 66.1 for one-year overall survival. Conclusions: We developed a simple and clinically useful predictive scoring model in a relatively homogenous population who initiate fluoropyrimidine-containing chemotherapy in advanced gastric cancer. Generalized application of the scoring model will require additional independent validation. [Table: see text]
Change of clinical features and outcomes of adolescents and young adults (AYA) with colorectal cancer over time: Pooled analysis of 26,768 patients in the National Cancer Database (NCDB).
Authors: Sally Jeanne Trufan, William Mills Worrilow, Kunal C. Kadakia, Reza Nazemzadeh, Laura W. Musselwhite, Seungjean Chai, Stuart Salmon, Joshua Hill, Jonathan C. Salo, Edward S. Kim, Jimmy J. Hwang, Mohamed E. Salem
Journal: Journal of Clinical Oncology (2020)

256 Background: The incidence of colorectal cancer (CRC) in younger patients (pts) is rising. The underlying etiology is unknown, and it is uncertain if disease biology and clinical features are changing over time. Methods: A retrospective study of pts data in the NCDB was performed to compare the clinicopathological features and outcomes of AYA with CRC over a 12-year period. Pts diagnosis period was dichotomized into older (2004 – 2009) and newer (2010 – 2015) eras. Uni- and multi-variable chi-square, logistic regression, and survival analyses were used for comparisons. Survival differences were assessed using Kaplan-Meier curves. Results: In total, 26,768 AYA (18-40yrs) with CRC were identified and included in the analysis: 45.8% (n = 12,268) from the older and 54.2% (n = 14,500) from the newer era. There were no differences between the 2 groups in gender distribution or levels of income and education. However, in the newer vs. older era, there was a greater proportion of non-white, non-black pts (7.2% vs. 6%; p = 0.0005) and pts diagnosed between the ages of 18-30 (21.1% vs. 18.8%; p &lt; .0001). Pts in the newer era tended to have more comorbidities (8.6 vs 7.5%; p = 0.0012), left-sided tumors (77.5% vs. 76.1%; p = 0.04), and well-differentiated histology (12.0% vs. 8.3%; p &lt; 0.0001). Newer era pts also had lower rates of metastatic disease at presentation (15.3% vs. 18.2%; p &lt; 0.001%) and nodal involvement (54.9 vs. 58.4%; p &lt; 0.001%). Median OS of pts with stage IV disease appears to have improved over time (24.1 vs. 22.5 mos; p = 0.014). After controlling for age, race, primary tumor site and grade, presence of comorbidities, and health insurance status, older era pts with stage IV CRC were at a 15.1% greater risk of all-cause death by year 5 compared to newer era pts (HR adj = 1.15 (1.07-1.24, p = 0.0001). Conclusions: Our data suggest that AYA with CRC in more recent years tend to present at a younger age and have a lower rate of metastatic disease. They also have improved survival. Further investigation of AYA disease etiology and biology are warranted. Continued efforts to increase awareness, promote early detection, and improve treatment options are essential.
Herd Protection Against Oral HPV Infection—Reply
Authors: Anil K. Chaturvedi, Barry I. Graubard, Maura L. Gillison
Journal: JAMA (2020)

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Inflammation and cell proliferation signatures: Implications for response to immune checkpoint inhibition therapies.
Authors: Sean Glenn, Sarabjot Pabla, Shumei Kato, Erik Van Roey, Jeffrey M. Conroy, Yirong Wang, Mary Nesline, Blake Burgher, Vincent Giamo, Jonathan Andreas, Felicia L. Lenzo, Razelle Kurzrock, Carl Morrison
Journal: Journal of Clinical Oncology (2020)

67 Background: Progress in unraveling the complex tumor immune microenvironment (TIME) has aided our understanding of the host immune response to ICI therapies. To gain further insight, we associate a 160-gene tumor inflammation signature (TIS) with cell proliferation status and response to ICI. Methods: 242 FFPE tumor samples from lung, RCC and melanoma were evaluated by RNA-seq to measure expression levels of 394 immune related genes. TIS (weak, moderate, strong) and cell proliferation status (poor, moderate, high) were determined by algorithmic analysis of selected gene pathways. All cases were evaluated for association with ORR to ICIs using RECIST criterion. Furthermore, 13 pre-post ICI treated biopsy pairs were studied to understand the dynamics of these signatures following treatment. Results: In both weakly and moderately inflamed tumors, ORR was highest in moderately proliferative tumors 32.6% (15/46) and 37.8% (14/37), respectively (Table). Surprisingly, in strongly inflamed tumors, both highly and moderately proliferative tumors had a high response rate of 55% (11/20) and 43.2% (16/37), whereas poorly proliferative tumors have a significantly lower response rate of 12.5% (3/24; p= 0.03). 6 of 13 pre-post ICI treated cases demonstrated increased inflammation post treatment, with 83% (5/6) demonstrating concurrent decrease in cell proliferation. Conclusions: Together, TIS and cell proliferation predict response to ICI in NSCLC, RCC and melanoma. The data suggests that in strongly inflamed and highly proliferative tumors, the cell proliferation signal could be attributed to antigen stimulated T-cell proliferation, whereas in other categories of inflammation, moderately proliferative tumors contain signal from both immune cells and tumor cells. Further studies are required to determine the relationship between these signatures in hot and cold tumors. [Table: see text]
Phase I trial evaluating safety and efficacy of intratumorally administered allogeneic monocyte-derived cells (ilixadencel) in advanced gastrointestinal stromal tumors.
Authors: Alex Karlsson-Parra, Robin Fröbom, Erik Berglund, David Berglund, Inga-Lena Nilsson, Christina Linder-Stragliotto, Peter Suenaert, Robert Branstrom
Journal: Journal of Clinical Oncology (2020)

15 Background: Ilixadencel is a cell-based, off-the-shelf product based on allogeneic monocyte-derived inflammatory cells aimed to prime an anti-cancer immune response when injected intratumorally. The present single arm Phase I trial (ClinicalTrials.gov Identifier: NCT02686944) assessed the safety and efficacy of ilixadencel in subjects with progressing advanced/metastatic GIST despite ongoing treatment with second or later lines of tyrosine kinase inhibitors (TKI). Methods: Three GIST patients were progressing while on sunitinib (second-line), one on regorafenib (third-line), and two on pazopanib (fifth-line). Treatment consisted of two intratumoral injections of ilixadencel two weeks apart. If further tumor progression was observed at the 3-month follow up, the TKI was withdrawn and the subject performed an end of study visit. If stable disease or objective response was observed, the subject continued with the TKI until progression of disease. Results: No severe adverse events were found to be related to ilixadencel administration. Four patients showed continued tumor progression at 3 months per RECIST 1.1 and Choi criteria. Two patients had stable disease as best response; one of these patients (on third-line regorafenib) progressed at 12 months and the other (a patient on second-line sunitinib) showed continued stable disease at end of study (12 months) as per RECIST 1.1. These two patients also developed a partial response as per Choi criteria with a duration of 3 and 6 months, respectively. No serious adverse events were found to be possibly or probably related to ilixadencel administrtion. Conclusions: Ilixadencel treatment presented an acceptable safety profile among advanced GIST patients who developed resistance to TKI. Encouraging radiological tumor responses were detected in 33% of treated patients, supporting further investigation. Clinical trial information: 02686944.
Prognostic value (PV) of pathologic response (PR) to neoadjuvant chemotherapy (NC) alone in resected pancreatic cancer (PDAC): Initial analysis.
Authors: Vincent J. Picozzi, Margaret T. Mandelson, Bruce Shih-Li Lin, Thomas R Biehl, Adnan Alseidi, Flavio G. Rocha, Scott Helton
Journal: Journal of Clinical Oncology (2020)

771 Background: As neoadjuvant Rx for resected PDAC often includes chemoradiation, the PV of PR includes its impact. We began analysis of the impact of NC alone in this setting. Methods: Patients (pts) were identified from the Virginia Mason Pancreaticobiliary Cancer Database. Inclusion criteria: 1) Dx 1/2010 - 3/2019; 2) Path dx PDAC stage I-III; 3) NC ( any type) as sole neoadjuvant Rx; 4) complete surg path data; 5) longitudinal OS known. Exclusion criteria: 1) neoadjuvant chemoradiation; 2) unknown NC (outside providers only). Histologic response was scored as follows: ( 0=complete response, 1 ≥95% response, 2=50-95% response, 3&lt;50% response). Results: Results for 134 pts are in Table. Median (med) f/u was 33 months (mo). In univariate analysis, all path features examined were statistically significant re med/5-yr OS. In multivariate analysis, risk increased with tumor size (HR 1.9, 95% CI 1.1-3.2) and tumor differentiation (HR 1.8, 95% CI 1.1-3.1 ) independent of other variables. Conclusions: 1) In univariate analysis, all PR features after NC had PV for med/5-yr OS, especially tumor size and histologic response score. NC type was not significant. 2) In multivariate analysis, risk increased with tumor size and tumor differentiation.3) This data needs extension to a bigger pt base/correlation with other variables (Ca 19.9, postop Rx, recurrence pattern etc.) for greater utility ( now underway). 4) This approach may aid postop Rx decision -making in this setting. [Table: see text]