tbuckley/cabot-search huggingface dataset:
RUNX2 overexpression and PTEN haploinsufficiency cooperate to promote CXCR7 expression and cellular trafficking, AKT hyperactivation and prostate tumorigenesis
Authors: Yang Bai, Yinhui Yang, Yuqian Yan, Jian Zhong, Alexandra M. Blee, Yunqian Pan, Tao Ma, R. Jeffrey Karnes, Rafael Jimenez, Wanhai Xu, Haojie Huang
Journal: Theranostics (2019)

Rationale:The overall success rate of prostate cancer (PCa) diagnosis and therapy has been improved over the years.However, genomic and phenotypic heterogeneity remains a major challenge for effective detection and treatment of PCa.Efforts to better classify PCa into functional subtypes and elucidate the molecular mechanisms underlying prostate tumorigenesis and therapy resistance are warranted for further improvement of PCa outcomes.Methods: We generated Cre + ;Runx2-cTg;Pten p/+ (Runx2-Pten double mutant) mice by crossbreeding Cre + ;Runx2-cTg males with Pten conditional (Pten p/p ) females.By using Hematoxylin and Eosin (H&E) staining, SMA and Masson's Trichrome staining, we investigated the effect of PTEN haploinsufficiency in combination with Runx2 overexpression on prostate tumorigenesis.Moreover, we employed immunohistochemistry (IHC) to stain Ki67 for cell proliferation, cleaved caspase 3 for apoptosis and AKT phosphorylation for signaling pathway in prostate tissues.Chromatin immunoprecipitation coupled quantitative PCR (ChIP-qPCR), reverse transcription coupled quantitative PCR (RT-qPCR), western blot (WB) analyses and immunofluorescence (IF) were conducted to determine the underlying mechanism by which RUNX2 regulates CXCR7 and AKT phosphorylation in PCa cells.Results: We demonstrated that mice with prostate-specific Pten heterozygous deletion and Runx2 overexpression developed high-grade prostatic intraepithelial neoplasia (HGPIN) and cancerous lesions at age younger than one year, with concomitant high level expression of Akt phosphorylation and the chemokine receptor Cxcr7 in malignant glands.RUNX2 overexpression induced CXCR7 transcription and membrane location and AKT phosphorylation in PTEN-deficient human PCa cell lines.Increased expression of RUNX2 also promoted growth of PCa cells and this effect was largely mediated by CXCR7.CXCR7 expression also positively correlated with AKT phosphorylation in PCa patient specimens.Conclusions: Our results reveal a previously unidentified cooperative role of RUNX2 overexpression and PTEN haploinsufficiency in prostate tumorigenesis, suggesting that the defined RUNX2-CXCR7-AKT axis can be a viable target for effective treatment of PCa.
Meat consumption and BRAF mutation status in colorectal cancer.
Authors: Rosa L. Frias, Michael Lam, Michael J. Overman, Van K. Morris, David R. Fogelman, Bryan K. Kee, Arvind Dasari, Kanwal Pratap Singh Raghav, Imad Shureiqi, Zhi-Qin Jiang, Patricia A. Jensen-Loewe, Robert A. Wolff, Cathy Eng, David Menter, Scott Kopetz, Jennifer S. Davis
Journal: Journal of Clinical Oncology (2019)

e15135 Background: Consumption of red and processed meat has been associated with increased risk of developing colorectal cancers, but less is known about the association of meat consumption with tumor molecular features. In this study, we tested the association of total meat consumption with molecular features of colorectal cancer and overall survival in a local cohort of patients. Methods: Data on meat consumption were collected using self-directed environmental surveys from patients with stage IV/locally advanced, treatment refractory colorectal cancer who were enrolled on the Assessment of Targeted Therapies Against Colorectal Cancer clinical protocol. Data on tumor molecular features were collected through medical record review. Patients were categorized into low, medium or high meat consumption groups based on servings per day tertile. Associations between tumor molecular features and meat intake were evaluated by Chi-square and logistic regression. Potential effects of meat consumption on overall survival were assessed using Cox Proportional Hazards models. Analyses were conducted with IBM SPSS v25. Results: Patients consumed an average of 0.74, 1.57 and 3.32 servings of meat per day in the low, medium and high categories, respectively. Out of 593 patients with evaluable data, 27 were found to have a BRAF V600E mutation. Total meat consumption differed significantly by BRAF V600E mutation status (p value 0.02) and by sex (p value &lt; .01), but did not differ by tumor location, microsatellite instability, or RAS mutation status. Using logistic regression, we found that compared to patients with the highest level of meat consumption, those in the medium consumption group may be less likely to have a BRAF V600E mutation (OR 0.24; p value 0.08). Although meat consumption may be associated with BRAF mutation status, it was not predictive of overall survival in our analyses. Conclusions: Among patients in our study, meat consumption may be associated with tumor BRAF V600E mutation status but is not directly associated with survival. Additional work is needed to test this association in cohorts including more BRAF mutant cases. If confirmed, this finding may add further insight into the etiology and biology of these tumors.
Bone marrow donation perceptions among healthcare workers: A follow-up study at University of Cincinnati Medical Center.
Authors: Logan Roof, Rekha T. Chaudhary
Journal: Journal of Clinical Oncology (2019)

e18032 Background: It has been well-documented that there is a severe lack of participants enrolled in the National Bone Marrow Donor registry. Even those who are registered often decline to donate at a critical juncture in the donation process due to a wide variety of misconceptions. Health care professionals should be among the most educated about the bone marrow donation process as they will often be giving advice to potential donors. Methods: We conducted an anonymous online survey of medical students, residents, fellows, and attending physicians at the University of Cincinnati Medical Center to determine the common misconceptions surrounding bone marrow donation. Results: There were a total of 187 participants (73% medical students, 23% residents/fellows, 4% attending physicians). Fifty-one percent were already bone marrow donors, while 49% were not. Forty percent of respondents believe bone marrow biopsy is necessary for donation and 10% believe CT scans are done prior to donation. Twenty-eight percent responded that bone marrow is extracted under general anesthesia, 43% responded that it is extracted not under general anesthesia, 5% responded that it is extracted via central intravenous line, and 24% responded that it is extracted via peripheral intravenous line. Thirty percent responded that they are not bone marrow donors because bone marrow donation is painful, 12% because it involves surgery, 2% because it weakens the donor, 13% because it involves a lengthy recovery process, 3% because donors have to pay for donation, 1% because of ethnic/religious/cultural beliefs, while 39% have not had the opportunity to donate but would or are planning on it. Conclusions: The majority of allogeneic transplants are performed with peripherally collected bone marrow stem cells, however, most potential donors including health care professionals do not know this. We conclude that a great deal of education surrounding bone marrow donation is still needed among healthcare workers today. Educating health care workers is of the utmost importance as they will impart this knowledge to those considering donation. Future aims of this project are to develop an educational curriculum to address the most common misconceptions, particularly in medical students, as they are in the age group most targeted in bone marrow donation and they will be the future generation of physicians to educate patients on the process.
Primary analysis of phase 2 results of cemiplimab, a human monoclonal anti-PD-1, in patients (pts) with locally advanced cutaneous squamous cell carcinoma (laCSCC).
Authors: Michael Robert Migden, Nikhil I. Khushalani, Anne Lynn S. Chang, Danny Rischin, Chrysalyne D. Schmults, Leonel Fernando Hernandez-Aya, Friedegund Elke Meier, Dirk Schadendorf, Alexander David Guminski, Axel Hauschild, Deborah J.L. Wong, Gregory A. Daniels, Carola Berking, Vladimir Jankovic, Elizabeth Stankevich, Jocelyn Booth, Siyu Li, Israel Lowy, Matthew G. Fury, Karl D. Lewis
Journal: Journal of Clinical Oncology (2019)

6015 Background: Cemiplimab (REGN2810) produced substantial antitumor activity with durable responses in Phase 1 CSCC expansion cohorts and Phase 2 metastatic (m) CSCC cohort. We now present the primary analysis of the Phase 2 laCSCC cohort (NCT02760498; data cutoff date: Oct 10, 2018). Methods: Pts with laCSCC received cemiplimab 3 mg/kg IV every 2 weeks (Q2W). Tumor measurements were performed Q8W. The primary objective was to evaluate objective response rate (ORR; complete response [CR] + partial response [PR]) according to independent central review (per RECIST 1.1 for scans; modified WHO criteria for photos). Results: 78 pts were enrolled (59 M/ 19 F; median age: 74 years; ECOG PS: 0 in 38 pts, 1 in 40 pts; primary CSCC site: head/neck in 79.5%; prior systemic therapy: 15.4%; prior radiotherapy: 55.1%). Median duration of follow-up was 9.3 months (range: 0.8–27.9). ORR by central review was 43.6% (95% CI: 32.4–55.3; 10 CRs and 24 PRs); investigator-assessed (INV) ORR was 52.6% (95% CI: 40.9–64.0; 13 CRs and 28 PRs). Median duration of response (DOR) has not been reached. The longest DOR at data cut-off was 24.2 months and was still ongoing. Durable disease control rate (stable disease or response for ≥16 weeks) was 62.8% (95% CI: 51.1–73.5). Median observed time to response was 1.9 months (range: 1.8–8.8). Median progression-free and overall survival have not been reached. Tumor PD-L1 status is available for 48/78 pts, tumor mutational burden analysis (from targeted exome panel) is ongoing for ≥40/78 pts; response correlation analyses are planned. The most common treatment-emergent adverse events (AEs; all grades, Grade ≥3) were fatigue (42.3%, 1.3%), diarrhea and pruritus (both 26.9%, 0%), and nausea (21.8%, 0%). INV grade ≥3 immune-related AEs occurred in 10.3% of pts. One pt died due to an unknown cause that was assessed as treatment-related. Conclusions: Cemiplimab 3 mg/kg Q2W showed substantial antitumor activity, durable responses, and acceptable safety profile in pts with laCSCC. These data strongly support the recent FDA approval of cemiplimab-rwlc for pts with mCSCC or laCSCC who are not candidates for curative surgery or curative radiation. Clinical trial information: NCT02760498.
Improving time to initiation of bone modifying agents in patients with newly diagnosed multiple myeloma.
Authors: Nathaniel Rosko, Sarah Lee, Christy Joy Samaras, Alex V. Mejia, Faiz Anwer, Beth Faiman, Saveta Mathur, Kimberly Hamilton, Janice Reed, Mary Ann Karam, Jason Neil Valent
Journal: Journal of Clinical Oncology (2019)

6528 Background: Current ASCO and IMWG guidelines recommend that all patients (pts) on active anti-myeloma therapy receive concurrent supportive care treatment with a bone modifying agent (BMA) to decrease the risk of skeletal related events (SRE). Unfortunately, recent data shows only 51% of Medicare pts with myeloma received a BMA within 90 days of first chemotherapy. We implemented a quality improvement project to identify the average time to BMA initiation at all Cleveland Clinic affiliated sites, with the primary goal to improve time to initiation of BMA in newly diagnosed multiple myeloma (NDMM) pts by 4 weeks at Cleveland Clinic Main Campus (MC). Methods: Barriers with BMA initiation were identified using quality improvement tools developed at the ASCO Quality Training Program. The first PDSA cycle was implemented between September 2018 – January 2019 with an emphasis on education. This included review of updated guidelines, literature review of risks and toxicities associated with BMAs, and strategies for choosing BMA based on pt factors. Baseline data on time to start BMA and data to evaluate impact of PDSA intervention was completed via chart review. Results: 161 NDMM pts were evaluated between 2015 to 2018 at all sites. The average time difference between the start of anti-myeloma therapy and the start date of a BMA in NDMM pts was 10.5 weeks. Subset analysis based on whether pts were treated at MC vs affiliate sites was 10.6 weeks vs 9.1 weeks, respectively. During the first PDSA cycle, 14 NDMM pts were treated at MC. 86% (12/14) pts were treated with a BMA. The average time between cycle 1 day 1 of first line treatment and first dose BMA was 4.3 weeks (range 4-12 weeks). Conclusions: With increased physician education and awareness of internal baseline data, we achieved our initial goal and observed a significant improvement in time to initiation of BMA from 10.5 weeks to 4.3 weeks. Obstacles regarding effective communication with patients on the benefit of BMAs as well as need for dental clearance were barriers identified early on. We plan to incorporate BMA guidelines in our institutional care path with the goal to decrease time to initiation at all affiliated practices. Further mechanisms to ensure reinforcement of BMA initiation in NDMM patients is warranted to maintain therapeutic benefit.
Analysis of three models to predict pathohistology in patients undergoing postchemotherapy RPLND for (pcRPLND) advanced nonseminomatous germ cell tumors (NSGCT).
Authors: Axel Heidenreich, Pia Paffenholz, David Pfister, Martin Hellmich, Peter Albers, Andreas Hiester, Alessandro Nini, Tim Nestler
Journal: Journal of Clinical Oncology (2019)

e16053 Background: We aim to validate the two best performing prediction models (Vergouwe and Leao) for final pathohistology in NSGCT patients undergoing pcRPLND and we introduce a new radiomics approach. Methods: A cohort of 496 patients treated between 2008 and 2018 was used to validate the 2 prediction modelsusing published formulas and thresholds.For group comparisons, we used t-test or chi-square test. ROC were plotted (sensitivity against 1-specificity) and AUC was calculated. We determined the optimal cut point and used bootstrapping (1,000 replications) to estimate its variability. A p-value of &lt; 0.05 was considered statistically significant. For radiomics, lymph nodes identified on CT images, were semiautomatically segmented with 93 radiographic features (pyRadiomics package). A linear support vector machine algorithm was applied to analyze reproducible radiomics features. A continuous reduction of features analyzed was performed using Random Forest algorithms and ROC analysis. Results: The Vergouwe model had a significantly better AUC compared to Leao model (0.749 [CI 0.706-0.792] vs. 0.689 [0.642-0.736], p = 0.004) to predict benign histology. At a threshold of &gt; 70% for the probability of benign disease, the Leao model would have avoided RLND in 8.6% with benign disease with an error rate of 5.6% for viable tumor. The Vergouwe model would avoid pcRPLND in 23.4% with benign disease with an error rate of 12.7% for viable tumor/teratoma. Of the 93 radiomic features analyzed, 51 features were reproducible. Applying the trained algorithm resulted in a AUC of 82% with a diagnostic sensitivity of 81% and a specificity of 83%. Conclusions: The discriminatory accuracy of both models is not sufficient to safely select patients for surveillance strategy instead of pcRPLND. The radiomics model is promising but needs prospective validation. Further studies including new biomarkers are needed to optimize the accuracy of potential prediction models.
Cardioprotection in patients with cancer undergoing chemotherapy: A network meta-analysis.
Authors: Pragnan Kancharla, Alexander Ivanov
Journal: Journal of Clinical Oncology (2019)

e12008 Background: Introduction of anthracycline or trastuzumab based regimen for various types of cancer during the past two decades led to substantial improvement in life expectancy, yet resulting in increased prevalence of unintended side effects. Left ventricular systolic dysfunction is a known complication of the currently employed chemotherapy regimens with anthracycline or trastuzumab which not only affects patient’s cardiac outcome but also limits their therapeutic opportunities, especially continuation or reintroduction of chemotherapy treatment. We aimed to perform comprehensive network meta analysis to synthesize data from randomized clinical trials (RCT) comparing all modern regimens to prevent cardiotoxicity in such patients. Methods: We performed a comprehensive search of pubmed, embase, google scholar and TRIP database for all RCT comparing cardioprotective effects of medication in patients with various types of cancer on chemotherapy with either an anthracycline or trastuzumab based regimen from 1997 to 2019. Left ventricular ejection fraction (LVEF) was measured by transthoracic echocardiogram or cardiac magnetic resonance imaging. Patients treated with either Angiotensin Converting Enzyme-Inhibitor(ACE) or Angiotensin receptor blocker(ARB) were combined into one group. Primary outcome was change in LVEF between start and end of the chemotherapy. Network meta-analyses were conducted using consistency and inconsistency models. Results: A total of 16 studies with 1459 patients were included in the analysis where either an Anthracycline or Trastuzumab based chemotherapy regimen was administered. 369 patients received beta blockers(BB), 351 received either an ACE or ARB, 61 received a combination of BB and either an ACE or ARB, 20 received a statin and 657 were given a placebo. The primary cancer was breast cancer in 8 studies, one each of lymphoma, blood cancers and remaining 6 being mixed. Mean age was 48.81 years. Compared to patients on placebo there was a significant cardioprotective effect (smaller reduction in LVEF) noted with ACE/ARB (beta coef 5.2 (1.5-8.9), p&lt;0.01), BB(beta coef 4.62 (0.8-7.8), p&lt;0.02), and spironolactone beta coef 12.9 (1.9-23.4), p&lt;0.03) There was an evidence of inconsistency with all p&gt;0.3, other than in spironolactone arm as there were suggestion of inconsistency with p&lt;0.01 likely due to the presence of single study. Conclusions: BB and ACE/ARB are associated with reduction in cardiotoxicity in patients with cancer undergoing cancer chemotherapy with an anthracycline or trastuzumab based regimen.
Functional personalized oncology to determine drug sensitivity in cholangiocarcinoma.
Authors: Ali Zarrinpar, Un Bi Kim, Carla Grandori, Franz Schaub, Rachele Rosati
Journal: Journal of Clinical Oncology (2019)

e15672 Background: Rare tumors, such as cholangiocarcinoma (CC), have no established treatment protocols, forcing clinicians to select therapies based on educated guesses or small case series. Genomic tumor analyses fail to identify options for most patients. Here, we show the feasibility of using a high-throughput functional assay to test targeted drug libraries on individual patient-derived tumor organoids from CC to yield experimentally-validated therapeutic options. Methods: Three consecutive patients with CC who were undergoing a standard of care biopsy or resection were enrolled in an IRB-approved study. Patient characteristics, demographics, tumor pathology, including Next Generation Sequencing (NGS) data and organoid-derived drug recommendations are shown in the Table. Specimen (~ 200 mg of tumor) was shipped on ice overnight to SEngine Precision Medicine for tumor-derived organoid culture and sensitivity analysis. Organoids were evaluated using a multi-dose response to each drug in a library of 120 FDA-approved and investigational drugs and compared those responses to all prior patients. This established both functional sensitivity and the uniqueness of each patient’s response. Results: We tested operational logistics, tumor growth rates, and chemosensitivity reporting timelines. This has allowed us to: 1) operationalize the expansion process, 2) quantify turn-around time, and 3) identify any technical or logistic barriers. All specimens resulted in adequate growth for sensitivity characterization. None of the NGS studies resulted in recommendations for sensitivity to targeted chemotherapy. Conversely, tumor organoid assays rapidly identified selective, personalized drugs. Conclusions: We have shown the feasibility of this approach in CC. Our preliminary results will inform the design of a future prospective clinical trial to establish and validate this method to select personalized cancer treatments for rare malignancies.[Table: see text]
Utility of somatic mutation panel testing in patients with advanced cancer receiving treatment in an Irish teaching hospital.
Authors: Hadia Khan, Louise O' Callaghan, Gul Ahmed, Brian Richard Bird, Derbrenn O'Connor, Conleth G. Murphy
Journal: Journal of Clinical Oncology (2019)

3076 Background: Tumor testing for potentially actionable somatic mutations via commercially available panel tests has entered routine clinical practice in many countries. In Ireland the cost of these tests is not covered by insurance companies and must be paid for by patients. Use of these tests is sporadic and depends on patient and clinician factors (including ability to pay). Existing data suggest that such testing results in a direct impact on patient therapy in a minority of patients only. We reviewed the impact of somatic mutation testing on treatment selection and outcomes in patients attending a medical oncology service in a teaching hospital in Ireland. Methods: We performed a retrospective study of patients who had commercial panel testing performed as part of routine oncology care. All patients opportunistically tested between 2013 and 2018 were included. Patients having focused molecular tests for approved therapies (e.g. RAS mutations in colon cancer, EGFR and ALK mutations in non-small cell lung cancer) were excluded.We reviewed medical records to assess the frequency and utility of mutations detected, the impact of testing on next and subsequent lines of therapy, and the effectiveness of therapy. Results: 74 panel tests were performed in 71 patients. 39 tests (53%) detected mutations, of which 21 (28%) were potentially actionable. 36 patients (51%) had further treatment after testing was performed. 9 tests (12%) led to test-based treatment. The mean duration of test-based treatment was 34 days (range 1-90 days). No patients had benefit from test based treatment, defined as tumour response or disease stabilisation on restaging scans. 23 patients died within 90 days of panel tests being requested. Among patients starting and completing a subsequent line of therapy after testing, the mean duration of therapy with test-based treatment was 39 days (range 6-90) and for standard of care treatment was 56 days (range 1-262 days). Conclusions: While testing for tumor-specific somatic mutations with proven predictive benefit is very useful, somatic mutation panel testing for non standard of care genetic alterations is not of utility in this real world setting. Its role in Ireland should be limited to identification of suitable early phase clinical trials. Discussions of panel testing should include frank discussion of expected benefits, and should also address factors such as patient ability to travel for clinical trials. [Table: see text]