tbuckley/cabot-search huggingface dataset:
Impact of metformin use in the outcomes of multiple myeloma patients post stem cell transplant.
Authors: Narjust Duma, Jesus Vera Aguilera, Jonas Paludo, Yucai Wang, Theodora Anagnostou, Amie L. Fonder, Francis Buadi, Shaji Kumar, Martha Lacy, Suzanne R. Hayman, Angela Dispenzieri, Morie A. Gertz, David Dingli
Journal: Journal of Clinical Oncology (2017)

8034 Background: Multiple myeloma (MM), a monoclonal plasma cell disorder, is one of the most common hematologic malignancies in the US. In preclinical studies, metformin demonstrated plasma cells cytotoxicity. However, there is lack of studies translating the effect of metformin into the clinical setting. Therefore, we assessed the clinical effect of metformin in patients (pts) with MM. Methods: All MM pts who underwent stem cell transplant (SCT) at the Mayo Clinic Rochester from 2007 to 2012 were reviewed. Patients were grouped based on metformin use. Initial diagnosis at our institution and ≥12 months of follow up were required. Kaplan-Meier method and Cox regression were used for time-to-event and multivariate analysis. Results: Out of 687 pts, 78 (11.4%) were using metformin at the time of MM diagnosis. Baseline characteristics in the metformin (Mt) and no-metformin (NMt) groups were similar (Table). Median (M) metformin dose was 2000 mg daily and m duration of metformin use from MM diagnosis was 22 months. Pts on the Mt group achieved higher rates of CR after SCT (41% vs. 29%, p&lt;0.02). Median PFS after SCT was longer in the Mt group, 31.3 months (95% CI: 10.4-52.2) vs. 16.6 months in the NMt group (95%CI: 14.5-18.7) p&lt;0.04. There was a trend towards longer OS in the Mt group, but it was not statistically significant (170 vs. 106 months, p&lt;0.10). In a multivariate analysis of metformin use, age, ISS, LDH, and cytogenetics/FISH, the former was an independent predictor of PFS after SCT (OR: 0.38, 95%CI: 0.20-0.68, p&lt;0.001). Conclusions: Metformin use was associated with a better PFS and higher CR after SCT in our MM cohort. A trend towards better OS was also noted in the Mt group. Larger studies are needed to enhance our understanding of the clinic effect of metformin on MM. [Table: see text]
Correlation of survival outcomes with progression heterogeneity in patients (pts) treated with pembrolizumab (pembro).
Authors: Lawrence H. Schwartz, Seth Robey, David C. Turner, Yiwei Zhang, Eunhee Kim, Dinesh de Alwis, Robin Mogg, Andrea Marie Perrone, Geoffrey R. Oxnard
Journal: Journal of Clinical Oncology (2018)

3017 Background: The relevance of RECIST v1.1 measures of progression in pts treated with immunotherapy is unclear. We conducted analyses of KEYNOTE-001 (KN; exploratory) and KN052 (confirmatory) to assess associations of progression heterogeneity by CT imaging with survival outcomes among pts treated with pembro. Methods: KN001 and KN052 enrolled pts with advanced melanoma and urothelial cancer, respectively. Blinded independent central review was performed per RECIST v1.1. Beyond RECIST v1.1, pts subgroups (SG) with progressive disease (PD) were defined as No Growth (NG; no individual target lesion [TL] Growth (G) ≥20% from baseline [BL]) with (NG+) and without (NG–) new metastatic lesions; Mixed Growth (MG; any individual TL G ≥20% from BL and not aggregate G [AG] ± new lesion G); and, AG (G ≥20% from BL ± new lesion G). SG were assigned at first documented PD. OS between SG was assessed using KM analysis. A Cox model with time-varying covariates related to PD SG and pembro treatment status was used to assess the relative mortality risk between SG on treatment and the effects of discontinuing treatment within each SG. KN001 findings were tested in KN052. Results: Of 511 KN001 (N = 655) pts with a post-BL scan, 301 (59%) had RECIST-PD on study, of which 42 (14%) were NG–, 78 (26%) NG+, 75 (25%) MG, and 106 (35%) AG. Median OS was 32.5, 23.2, 16.1, and 8.1 mo, respectively, and 43.6 mo for non-PD. Of 331 KN052 (N = 370) pts with a post-BL scan, 223 (67%) had PD on study, of which 29 (13%) were NG–, 66 (30%) NG+, 35 (16%) MG, and 93 (42%) AG. Median OS was 14.2, 10.2, 6.7, and 5.3 mo, respectively, and not reached for non-PD. Relative to non-PD and consistent with overall study KM estimates, model-derived “on-treatment” HRs were highest for AG, followed by MG, NG+, NG–. Treatment discontinuation was associated with increased mortality risk (HR > 1) in all PD SG, but with differing magnitude. All KN001 findings were confirmed in KN052. Similar analyses will be shown for pts with NSCLC in KN010 (pembro vs docetaxel). Conclusions: These analyses suggest there may be distinct populations of PD phenotypes with unique survival outcomes. RECIST v1.1 does not fully capture these PD phenotypes and may not accurately identify treatment failure. Clinical trial information: NCT01295827 for KEYNOTE-001, NCT02335424 for KEYNOTE-052.
Abstract 16659: What Contributes to the Difference in Cost Between the CICU and NICU in Neonates Undergoing Congenital Heart Surgery?
Authors: Joyce T Johnson, Kirsen Sullivan, Xiaoming Sheng, Tom Greene, David Bailly, Aaron Eckhauser, LuAnn Minich, Nelangi Pinto
Journal: Circulation (2016)

Introduction: The mechanisms for previously reported increased costs of care for neonatal congenital heart surgery (CHS) in a neonatal intensive care unit (NICU) compared to a cardiac (CICU) or ped...
Development and validation of a novel clinical-genomic risk group classification for prostate cancer incorporating genomic and clinicopathologic risk.
Authors: Daniel Eidelberg Spratt, Jingbin Zhang, Maria Santiago-Jimenez, John W. Davis, Robert Benjamin Den, Adam Dicker, Christopher J. Kane, Alan Pollack, Ashley Ross, Marguerite du Plessis, Voleak Choeurng, Kasra Yousefi, Zaid Haddad, Elai Davicioni, Sheila Weinmann, Edward M. Schaeffer, Eric A. Klein, R. Jeffrey Karnes, Felix Yi-Chung Feng, Paul L. Nguyen
Journal: Journal of Clinical Oncology (2017)

5000 Background: It is clinically challenging to integrate genomic classifier results that report a continuous numerical risk of recurrence into treatment decisions for prostate cancer (PCa). We aimed to develop a novel clinical-genomic risk system that can readily be incorporated into treatment guidelines for localized PCa. Methods: Four multi-center cohorts (n = 6928 men; 5937 prospective samples and 991 retrospective samples with long-term follow-up) were utilized to identify and validate our clinical-genomic risk system in radical prostatectomy (RP) samples and subsequently in pre-treatment biopsy samples. All patients’ FFPE tissue underwent microarray analysis, and the expression values for 22 prespecified biomarkers that constitute Decipher were extracted. Cumulative incidence curves were constructed to estimate metastasis risk. C-indices were calculated to compare NCCN and CAPRA score to our clinical-genomic system. Results: With a median follow-up of 8 years for men in our RP cohort, the 10-year distant metastasis rates for NCCN low, favorable-intermediate, unfavorable-intermediate, and high-risk were 7.8%, 9.4%, 40.1%, and 41.4%, respectively. Our 3-tier clinical-genomic risk groups had 10-year distant metastasis rates of 3.7%, 30.7%, and 57.7%, for low, intermediate, and high-risk, which were validated in our pre-treatment biopsy cohort with 10-year rate of distant metastasis of 0%, 30.3%, and 63.2%, respectively. C-indices for the clinical-genomic system (0.84, 95%CI 0.62-0.92) were significantly improved over NCCN (0.71, 95%CI 0.59-0.84) and CAPRA (0.71, 95%CI 0.60-0.81) score. A total of 33.4% of men would be reclassified by the clinical-genomic system, and specifically 17.1%, 41.3%, and 19.4% of men in NCCN low, intermediate and high risk groups would be reclassified by our new system. Conclusions: The use of a readily available genomic classifier in combination with clinicopathologic variables can generate a simple to use 3-tier clinical-genomic risk system that is highly prognostic for distant metastasis, is more accurate than clinical risk, and can be easily incorporated into NCCN guidelines to inform treatment decisions.
Risk of premature death from chronic conditions higher in UK than many other rich countries
Authors: Ingrid Torjesen
Journal: BMJ (2018)

People in the UK have a greater risk of dying early from chronic conditions such as cancer, cardiovascular disease, chronic respiratory disease, and diabetes than those in many other high income countries, an analysis published in the Lancet shows.1

The global analysis of deaths from non-communicable diseases (NCDs) found that a 30 year old man living in the UK has a 12.9% chance of dying from these four key NCDs before age 70, whereas a man living in Iceland has a 9.9% chance, and a man living in Switzerland, Sweden, or Norway a less than 11% chance. …
The Interstitial Space Takes Shape
Authors: Prodromos Hytiroglou, Ian R. Wanless
Journal: Hepatology (2018)

Hytiroglou, Prodromos M.D.; Wanless, Ian R. M.D., C.M., F.R.C.P.C.Editor(s): Corey, Kathleen E.3; Malhi, Harmeet4 Author Information
Human capital costs of obtaining oral anticancer medications.
Authors: Yu-Ning Wong, Caitlin Meeker, Jamie Doyle, Elizabeth Handorf, Marijo Bilusic, Elizabeth R. Plimack, Daniel M. Geynisman
Journal: Journal of Clinical Oncology (2016)

6506 Background: Oral anticancer medications (OAMs) are commonly prescribed for various cancers. Initiating OAMs can involve extensive effort from clinic staff, including obtaining prior authorization and copayment assistance and coordinating with specialty pharmacies. We conducted a retrospective review to characterize potential delays in treatment (Tx). Methods: We included prostate and kidney cancer patients (pts) prescribed on-label OAMs at an academic center between 8/1/2014 and 8/31/2015. The following was extracted from nursing notes and pt charts: demographics, date of OAM prescription (Rx), date of first dose, number and reason for staff phone calls required to obtain OAM, copay amount and whether financial assistance was requested. We used Fisher’s exact and Kruskal-Wallis tests to compare differences between OAMs. Results: In 116 pts (55% kidney cancer, 45% prostate cancer) with 149 unique Rx, median age 65 (27-88), 85% male, 89% white, 78% had Rx drug coverage. See Table for results by drug. In pts with information available (56 unique Rx), quoted average/median copay/month was $1,224/$175 ($0-9453), but dropped to $42/$3 per month ($0-$1056) after copayment assistance program utilization. Conclusions: The initiation of on-label OAMs was a labor intensive process and on average it took 2 weeks to obtain a drug. The significant OAM dependent differences found may be related to specific drug plans, assistance programs or unmeasured variables and needs to be further validated in a larger sample. Out-of-pocket costs were variable and required considerable staff effort to mitigate via financial assistance. The process of initiating OAMs can be a barrier to care and should be a focus of quality improvement initiatives. Abiraterone Enzalutamide Sunitinib Pazopanib Everolimus Axitinib Total P-Value # Rx 26 28 26 22 10 37 149 Rx transferred to a different pharmacy (%) 35 32 50 50 10 11 32 0.003 Avg days from Rx – Tx Start 20 15 19 14 7 10 14 0.001 Rx requiring 2-4 calls by staff to obtain drug (%) 62 57 42 73 20 32 49 0.009 Rx requiring 5-8 calls by staff to obtain drug (%) 12 18 15 14 20 14 15 0.974 Reason for calls: Prior Authorization (%) 43 33 40 26 38 41 36 0.884 Reason for calls: Instructions (%) 45 51 38 46 54 50 47 0.96 Copay assistance utilized (%) 38 46 35 27 40 27 35 0.632
SOX2 as a target for immunotherapy of pediatric gliomas.
Authors: Juan Vasquez, Anita Huttner, Lin Zhang, Asher Marks, Amy Chan, Joachim M. Baehring, Kristopher Kahle, Kavita M. Dhodapkar
Journal: Journal of Clinical Oncology (2017)

e22012 Background: New treatments are needed to improve outcomes for pediatric gliomas. Immune checkpoint inhibitors are effective therapies in tumors with a high mutation burden that express multiple neo-antigens. However, for pediatric tumors that carry few mutations, there is a need to identify new antigenic targets of anti-tumor immunity. SOX2 is an embryonal stem cell antigen implicated in the biology of glioma initiating cells. Expression of SOX2 by pediatric glial tumors, and the capacity of the immune system in these patients to recognize SOX2, has not been studied. Methods: We examined the expression of SOX2 on paraffin-embedded tissue from pediatric glial tumors (n = 30). The presence of T cell immunity to SOX2 was examined in both blood and tumor-infiltrating T cells using antigen-dependent cytokine and T cell proliferation assays (n = 15). The nature of tumor-infiltrating immune cells in glial tumors (n = 4) was analyzed using single cell mass cytometry. Results: SOX2 is expressed by tumor cells but not surrounding normal tissue in all low grade gliomas (n = 15), high grade gliomas (n = 7), ependymomas (n = 3) and in 60% of oligodendrogliomas (n = 5). T cells against SOX2 can be detected in blood and tumor tissue in 33% of patients. CD4 and CD8 tumor infiltrating T-cells display a higher proportion of PD-1 expression compared to circulating T cells (p &lt; 0.05). Glial CD4 and CD8 T cells are enriched for tissue resident memory phenotype (T RM ; CD45RO + , CD69 + , CCR7 - ) and the expression of PD-1 is primarily on these T RM cells (p &lt; 0.05). A subset of CD4 and CD8 T RM cells also co-express multiple inhibitory checkpoints including PD-L1 and TIGIT. Glial tumors also contain NK cells with reduced expression of lytic granzyme (p &lt; 0.05). Conclusions: Our data demonstrate in vivo immunogenicity of SOX2, which is specifically overexpressed on pediatric glial tumor cells. Our data also suggest that the T RM subset of tumor-infiltrating T cells may be key targets for immune checkpoint blockade, and harnessing tumor immunity will likely require the combined targeting of multiple inhibitory checkpoints. Future efforts to target SOX2 with dendritic cell vaccines combined with immune checkpoint blockade could provide effective tumor immunity and improve outcomes in pediatric brain tumors.
A multicenter randomized phase III trial of neo-adjuvant chemotherapy followed by surgery and chemotherapy or by surgery and chemoradiotherapy in resectable gastric cancer: First results from the CRITICS study.
Authors: Marcel Verheij, Edwin PM Jansen, Annemieke Cats, Nicole C.T. van Grieken, Neil K Aaronson, Henk Boot, Pehr A. Lind, Elma Meershoek – Klein Kranenbarg, Marianne Nordsmark, Hein Putter, Anouk Kirsten Trip, Johanna W. van Sandick, Karolina Sikorska, Harm van Tinteren, Cornelis J. H. Van De Velde
Journal: Journal of Clinical Oncology (2016)

4000 Background: The mainstay of potentially curative treatment of gastric cancer is radical surgical resection. Because most patients in the Western world present with advanced stages long-term survival remains poor at about 25%, with local recurrences as part of treatment failure in up to 80% of cases. Postoperative chemoradiotherapy (CRT) and perioperative chemotherapy (CT) have demonstrated a survival benefit over surgery alone. The current randomized phase III CRITICS-study (NCT00407186) investigated whether chemoradiotherapy after neo-adjuvant chemotherapy and adequate (D2) surgery leads to improved overall survival (OS) in comparison with postoperative chemotherapy. Furthermore, toxicity of both treatment regimens was explored. Methods: Patients with stage Ib-IVa resectable gastric cancer were randomized after diagnosis. Neo-adjuvant CT was prescribed in both arms and consisted of 3 courses of epirubicin, cisplatin/oxaliplatin and capecitabine (ECC/EOC). After gastric cancer resection, patients received another 3 courses of ECC/EOC or CRT (45 Gy in 25 fractions combined with weekly cisplatin and daily capecitabine). Primary endpoint is OS; secondary endpoints are: disease free survival, toxicity profile and quality of life. Results: Between January 2007 and April 2015, 788 patients from The Netherlands, Sweden and Denmark were randomized (393 CT; 395 CRT). Baseline characteristics were well balanced with 70% males and a median age of 61 years. 84% completed 3 cycles before surgery. In the CT arm 46% and in the CRT arm 55% completed treatment according to protocol. After a median follow-up of 50 months, 405 patients have died. The 5-year survival is 41.3% for CT and 40.9% for CRT (p=0.99). Toxicity was mainly hematological (grade III or higher: 44% vs 34%; p=0.01) and gastrointestinal (grade III or higher: 37% vs 42%; p=0.14) for CT and CRT, respectively. Conclusion: No significant difference in overall survival was found between postoperative chemotherapy and chemoradiotherapy. Clinical trial information: NCT00407186.
TCT-92 Randomized Comparison of Ridaforolimus- and Zotarolimus-Eluting Coronary Stents: 2-Year Clinical Outcomes of the Pooled BIONICS and NIREUS Trials
Authors: Maayan Konigstein, Pieter Smits, Ori Ben-Yehuda, M. Ozgu Ozan, Mengdan Liu, Yoram Richter, Martin Leon, Gregg Stone, David Kandzari
Journal: Journal of the American College of Cardiology (2018)
TCT-847 Ultrasound-guided versus Palpation-guided Radial Artery Catheterization in Adult Population: Updated Meta-analysis and Systematic Review of Randomized Controlled Trials
Authors: Homam Moussa Pacha, Yasser Al-khadra, Mohamad Soud, Fahed Darmoch, Fares Alahdab, Amr Idris, Ziad SayedAhmad, Zaher Fanari, Anwar Zaitoun, Amir Kaki, M Chadi Alraies
Journal: Journal of the American College of Cardiology (2018)
Mir-506-3p synergistically represses breast cancer progression through altering cell cycle regulators
Authors: G. Saad El Din, R.A. Youness, R.A. Assal, M.Z. Gad
Journal: Annals of Oncology (2018)

Background: Mounting evidence demonstrated the potential of miR-506-3p to be employed in the diagnosis and treatment of a wide range of human malignancies due to its differential expression pattern and distinct biological roles. Despite the pivotal tumor suppressor role miR-506-3p plays in breast cancer (BC), it is frequently downregulated. Moreover, its role in governing cell cycle progression was not extensively studied in BC. Myc, E2F and Rb proteins are key players in cell cycle regulation. In BC, the CDK-RB-E2F axis is extensively deregulated by several genetic mutations. Additionally, the potent proto-oncogene Myc is highly expressed in BC. Thus, we aimed at uncovering the role miR-506-3p plays in cell cycle regulation in BC. Methods: pMyc-TA-Luc, pE2F-TA-Luc and pRb-TA-Luc vectors have response elements or enhancer elements of cMyc, Rb, and E2F cell cycle regulatory proteins, respectively. MDA-MB-231 cells were transfected with the aforementioned cell cycle vectors as well as an empty pLuc vector containing an unspecific binding site (used as a control) (Clontech, Germany). After 24 hrs, cells were co-transfected with miR-506-3p. Some cells were exposed to the transfection reagent only (mock cells). Relative luciferase activity was measured after 48 hrs by Steady-Glo® Luciferase Reporter Assay. Unspecific (baseline) luminescence detected for empty pTAL-Luc vector was subtracted from all values. Functional characterization of miR-506-3p was performed in MDA-MB-231 triple-negative breast cancer (BC) cells and MCF-7 HR+ cells to investigate its impact on several hallmarks of cancer using MTT and wound-healing assays. Results: Ectopic expression of miR-506-3p led to a significant decrease in cMyc and E2F proteins with a concomitant increase in RB protein compared to mock cells. Since miR-506-3p has seldomly been investigated in BC, the performed functional analysis of miRNA-506-3p revealed a significant decrease in the cellular viability and migration capacity of both MDA-MB-231TNBC cells and in MCF-7 HR+ BC cells. Conclusions: This study highlights a novel underlying mechanism of miR-506-3p as a tumor suppressor in BC through inhibiting cell cycle progression. This suggests its potential use in personalized BC therapy. Legal entity responsible for the study: German University in Cairo (GUC). Funding: Has not received any funding. Disclosure: All authors have declared no conflicts of interest.
Associations between mutations of DNA damage response and prognosis in microsatellite instability prevalent tumors.
Authors: Zhijie Wang, Jing Zhao, Guoqiang Wang, Yuzi Zhang, Hao Qin, Shangli Cai, Jianchun Duan, Hua Bai, Jie Wang
Journal: Journal of Clinical Oncology (2018)

e24257 Background: DNA damage response (DDR) system is necessary for genomic stability, whose mutations may be associated with improved sensitivity to DNA breaks agents, including platinum. Uterine Corpus Endometrial Carcinoma (UCEC), Colorectal Adenocarcinoma (COAD-READ) and Stomach Adenocarcinoma (STAD) are characterized as high prevalence of microsatellite instability (MSI) which indicates genomic instability, whose standard adjuvant treatment contains platinum. We hypothesize that DDR genes alterations are associated with MSI and prognosis in resected UCEC, STAD and COAD-READ. Methods: Whole-exome sequencing (WES) data of 530 UCEC, 437 STAD and 536 COAD-READ from The Cancer Genome Atlas were analyzed to explore the associations between 29 DDR mutations and MSI or prognosis. Results: The frequency of at least one deleterious DDR mutation was 45.9%, 26.5%, 37.9% in UCEC, STAD and COAD-READ, respectively. The mostly frequently mutated genes in UCEC, STAD and COAD-READ were ATM (17, 9, 14%), BRCA2 (15, 9, 8%), PRKDC (17, 10, 10%) and POLE (15, 6, 6%). DDR mutations were significantly associated with MSI-H (Mutation frequency in MSI-H/MSS: 85.2/28.3% in UCEC, 92.9/9.1% in STAD, 93.5/28.1% in COAD-READ, all P < 0.001). In UCEC, higher DDR mutations burden (at least 3 DDR mutations) was significantly associated with both disease free survival (DFS) and overall survival (OS) after adjusted for age (Hazard ratio (HR) = 0.28, 95% CI = 0.14-0.56 for DFS, HR = 0.24, 95% CI = 0.10-0.56 for OS). Besides, the HRs of DDR mutations with DFS or OS decreased with the increased counts of DDR mutations (P trend < 0.001 for DFS, < 0.001 for OS). In STAD, higher DDR mutations burden were significantly associated with both DFS and OS after adjusted for age, sex and pathological stage (HR = 0.51, 95% CI = 0.26-0.99 for DFS, HR = 0.58, 95% CI = 0.34-0.91 for OS). The HRs of DDR mutations with OS also decreased with the increased DDR mutations burden (P trend = 0.006). No associations were observed in COAD-READ. Conclusions: Deleterious DDR genes mutations were potential predictive biomarker for resected MSI prevalent tumors. Further studies are needed to validate their predictive roles in various adjuvant treatments.