tbuckley/cabot-search huggingface dataset:
Tumor mutation burden in triple negative breast cancer patients in Japan.
Authors: Masayuki Nagahashi, Yiwei Ling, Tetsu Hayashida, Yuko Kitagawa, Manabu Futamura, Kazuhiro Yoshida, Takashi Kuwayama, Seigo Nakamura, Chie Toshikawa, Hideko Yamauchi, Teruo Yamauchi, Koji Kaneko, Chizuko Kanbayashi, Nobuaki Sato, Yasuo Miyoshi, Junko Tsuchida, Stephen Lyle, Kazuaki Takabe, Shujiro Okuda, Toshifumi Wakai
Journal: Journal of Clinical Oncology (2018)

e13111 Background: Breast cancer is the most frequent cancer among women both in US and Japan. Triple negative breast cancer (TNBC), a subset of breast cancers that are negative for estrogen receptor, progesterone receptor, and HER2, is associated with a poor prognosis. A high tumor mutation burden (TMB-H) is defined as a high rate of somatic mutation in tumor, which has recently been correlated with the generation of neo-antigens and clinical response to immunotherapy drugs. We have previously demonstrated that next-generation sequencing-based comprehensive genomic sequencing (CGS) with > 400 genes can reliably identify patients with TMB-H in colorectal (Genome Med 2016) and gastric cancer (Genome Med 2017), both of which were associated with microsatellite instability (MSI). However, TMB-H and MSI in Japanese TNBC patients have been unknown yet. The aim of the study is to examine the TMB-H and MSI in Japanese TNBC patients by CGS. Further, we compared the TMB data with the publicly available The Cancer Genome Atlas (TCGA) database. Methods: We examined all exons of 435 known cancer genes and determined TMB in Japanese TNBC patients (N = 53) by CGS. TMB-H was defined as ≥20 mutations/Mb of sequenced DNA. Mutations in DNA mismatch repair genes and microsatellite loci were analyzed to determine MSI. TCGA TNBC whole exome sequencing database (N = 123) was reanalyzed in silico with the 435 genes to determine TMB. Results: The median (range) mutation burden for 53 Japanese patients was 11.5 (3.9-56.2)/Mb, and three patients (5.7%) were identified as TMB-H. No MSI was observed in any of the 53 Japanese TNBC patients. The mutation burden of the TCGA TNBC cohort reanalyzed in silico revealed a comparable mutation burden between the Japanese cohort and the TCGA cohort, with six (4.9%) TMB-H patents identified in the TCGA cohort. Conclusions: We identified 5.7% TMB-H in Japanese TNBC patients without any MSI. The frequency of TMB-H was comparable between Japanese patients and TCGA cohort.
High neutrophil-to-lymphocyte ratio (NLR), myeloid-derived suppressor cells (MDSCs) and resistance to corticosteroid therapy (CST) in castration-resistant prostate cancer (CRPC).
Authors: Niven Mehra, Ricardo Marcelo Morilla, Adam Sharp, Alison Morilla, Mateus Crespo, Maryou B. Lambros, Karen Thomas, Daniel Nava Rodrigues, Diletta Bianchini, Penelope Flohr, David P. Dearnaley, Chris C. Parker, Johann S. De Bono
Journal: Journal of Clinical Oncology (2016)

5076 Background: Cancer-secreted cytokines drive inflammation, supporting tumour growth and increasing the NLR. A high NLR associates with poor prognosis and treatment resistance (TXR). MDSCs are are recruited by these same cytokines and also implicated with TXR. We correlated NLR with response to CST, also investigating whether higher NLR associates with increased MDSCs in men with CRPC. Methods: NLR was prospectively evaluated in 75 PTS recruited to a randomized phase II trial of CST in chemotherapy/abiraterone/enzalutamide-naïve CRPC (POD trial). Baseline (BL) NLR, and NLR changes during treatment were associated with PSA response and time to PSA progression (TTPSAPD). The relationship of NLR with MDSCs was then prospectively analysed in 55 progressing mCRPC PTS and in 14 male healthy volunteers (MHV) by flow cytometry, performed < 24-hours following blood draw. Data were acquired with a BD FACS Canto II with FACS-Diva software and analysed with Kaluza 1.3 software. Results: In the POD trial, BL-NLR (log10) was prognostic for OS (HR 5.99, p = 0.011). PTS with a BL-NLR > 3 had a lower likelihood of PSA > 50% fall (p = 0.014); lower magnitude of PSA fall (p = 0.05); and shorter TTPSAPD (3.0 vs 6.0 months, p = 0.011). During CST, median NLR increased slightly after 6 weeks from 2.60 to 2.94. After 6-weeks of CST an NLR > 3 was still associated with a shorter TTPSAPD (2.5 vs 8.5 months; HR 0.30, p = 0.001). These results indicated that high NLR associates with resistance to CST; we then evaluated if high NLR associates with MDSC count and analysed 67 BL samples from 55 PTS by flow cytometry. CD14+/CD33+/HLA-DRlow MDSCs were increased in PTS compared to MHV (0.24 vs 0.09, n = 75, p < 0.001), and specifically in PTS with an NLR > 3 (n = 60, p = 0.001; NLR > 3.0: median 0.31 [range: 0.07-0.64]; NLR < 3.0: median 0.15 [range: 0.04-0.49]). NLR correlated well with the presence of MDSCs (r = 0.50, p < 0.001, n = 60). Conclusions: CST resistance is associated with a high BL and elevated NLR after 6-weeks of CST in PTS treated on the POD trial, with high NLR associating with elevated numbers of MDSCs. This study warrants prospective validation and consideration of targeting MDSC in CRPC. Clinical trial information: 2005-006018-16.
Could less apatnib be better? an exploration study of dose-effect of apatnib in 41 stage IV solid tumors.
Authors: Yingying Huang, Yunbo Zhao, Xueqing Hu, Xiaonan Wu, Lin Li
Journal: Journal of Clinical Oncology (2018)

e24328 Background: Apatinib is an oral, highly potent tyrosine kinase inhibitor targeting vascular endothelial growth factor receptor 2(VEGFR-2).It can be used alone or combined with other chemotherapy. While in practise we found most of patients can not be good tolerated with 850mg. We observed carefully in 41solid tumors patients with different doses of Apatinib. Though many clinical trials of Apatinib could be effective at least over 250mg,we found many patients had objective response and manageable toxicity less than 250mg. Methods: We treated 41 stage IV solid tumors with Apatinib alone or combined with other treatment. According to patients' tolerance we adjusted the dose. We evaluated the best efficacy according to RESICT 1.1at least over 1 month and found lower dose Apatinib can also have the objective response Results: There were 41 solid tumors including gastric cancer, esophageal cancer , colon cancer ,lung cancer ,pancreatic cancer ,breast cancer ,prostate cancer, ovarian cancer, NEC.There were 3 patients who could not be evaluated because of adverse effects. The mean time of taking Apatinib was 5.2 months ( 0.3-16 months). Two of 4 patients with Apatinib 125mg got PR and two of 4 patients got SD, eight of 11 patients with 250mg got PR and three of 11 discontinued the treatment because of adverse effects. Ten of 12 PR patients just took Apatinib 250mg alone or combinationed. Conclusions: Apatinib is a novel VEGFR inhibitor. It is a good drug while we should use it at the optimal dose and right combination treatment. Whether there is a potent biomarker which can be used as an indication for doctors still are looking forward. For some patient with low dose Apatinib less than 250mg such as 125mg could also be effective and less toxic. We just wish this real world study can give us more information to look for the precision therapy for advanced cancer patients. Number Less than 250mg Over than 500mg gastric cancer 11 5( PR 1, SD 4) 5( PR 1, SD 4) esophageal cancer 1 1 ( SD 1) 0 colon cancer 10 7 (SD 7 ) 2 ( SD 2) lung cancer 8 6 ( PR 2, SD 3, PD 1) 1 (PR 1) pancreatic cancer 3 3 (PR 2, SD 1) 0 breast cancer 2 2 (PR 1, SD 1) 0 overian cancer 1 1(PD 1) 0 prostate cancer1 1 1 (PD) 0 NEC 4 4 (PR 4) 0
High and Variable Rates of Repeat-Mediated Mitochondrial Genome Rearrangement in a Genus of Plants
Authors: Logan W Cole, Wenhu Guo, Jeffrey P Mower, Jeffrey D Palmer
Journal: Molecular Biology and Evolution (2018)

For 30 years, it has been clear that angiosperm mitochondrial genomes evolve rapidly in sequence arrangement (i.e., synteny), yet absolute rates of rearrangement have not been measured in any plant group, nor is it known how much these rates vary. To investigate these issues, we sequenced and reconstructed the rearrangement history of seven mitochondrial genomes in Monsonia (Geraniaceae). We show that rearrangements (occurring mostly as inversions) not only take place at generally high rates in these genomes but also uncover significant variation in rearrangement rates. For example, the hyperactive mitochondrial genome of Monsonia ciliata has accumulated at least 30 rearrangements over the last million years, whereas the branch leading to M. ciliata and its sister species has sustained rearrangement at a rate that is at least ten times lower. Furthermore, our analysis of published data shows that rates of mitochondrial genome rearrangement in seed plants vary by at least 600-fold. We find that sites of rearrangement are highly preferentially located in very close proximity to repeated sequences in Monsonia. This provides strong support for the hypothesis that rearrangement in angiosperm mitochondrial genomes occurs largely through repeat-mediated recombination. Because there is little variation in the amount of repeat sequence among Monsonia genomes, the variable rates of rearrangement in Monsonia probably reflect variable rates of mitochondrial recombination itself. Finally, we show that mitochondrial synonymous substitutions occur in a clock-like manner in Monsonia; rates of mitochondrial substitutions and rearrangements are therefore highly uncoupled in this group.
Retrospective analysis of clinical outcomes of early stage ALK-positive (ALK+) non-small cell lung cancer (NSCLC).
Authors: Ibiayi Dagogo-Jack, Fernando Santini, Juliana Eng, Beow Y. Yeap, Benjamin Izar, Emily Chin, Anya Litvak, David Randolph Jones, Mark G. Kris, Alice Tsang Shaw, Justin F. Gainor, Jamie E. Chaft
Journal: Journal of Clinical Oncology (2017)

8536 Background: ALK rearrangements are important oncogenic drivers in NSCLC. However, the prognostic implications of these rearrangements are unclear due to 1) conflicting results from small series of patients (pts) with early-stage ALK+ NSCLC, and 2) use of highly effective ALK tyrosine kinase inhibitors (TKI) in the metastatic setting. To assess the prognostic significance of ALK rearrangements in resected NSCLC, we performed a retrospective analysis of survival outcomes among pts with resected ALK+, EGFR+, or KRAS+ NSCLC treated at two institutions. Methods: We reviewed charts of pts that underwent resection for stage 1-3 NSCLC at Massachusetts General Hospital or Memorial Sloan Kettering Cancer Center between 1/2009 and 12/2012. Recurrence-free survival (RFS) was estimated for each genotype. Results: Among 764 pts (480 KRAS+, 255 EGFR+, 29 ALK+), we identified 555 (73%), 101 (13%), and 108 (14%) pts with stage I, 2, and 3 NSCLC, respectively. ALK+ pts were distributed across all stages: 10 (34%) stage I, 6 (21%) stage 2, and 13 (45%) stage 3 NSCLCs. Chemotherapy was administered to 14 ALK+ ( 0% stage 1, 67% stage 2, 77% stage 3), 45 EGFR+ (3% stage 1, 44% stage 2, 81% stage 3), and 96 KRAS+ pts (4% stage 1, 56% stage 2, 71% stage 3), respectively, for early-stage NSCLC. Thirteen (7%) stage 1 EGFR+ patients received adjuvant EGFR TKI. Although median RFS was not reached for EGFR+ pts, it was 24.3 months (95%CI 11.4 to 65.3) for ALK+ pts and 72.9 months (95%CI 59.7 to undefined) for KRAS+ pts. RFS for ALK+ NSCLC was significantly shorter than the other groups (HR 2.9, 95%CI: 1.75-4.89 vs. EGFR and HR 1.8, 95%CI: 1.12-2.93 vs. KRAS). When adjusted for stage, ALK+ NSCLC remained associated with worse RFS compared to EGFR+ NSCLC (HR 1.8, 95%CI: 1.09-3.12), but not when compared to KRAS+ NSCLC (HR 1.30, 95%CI: 0.79-2.12). Conclusions: Early stage ALK+ NSCLC is associated with shorter RFS than EGFR+ NSCLC. The propensity for relapse and the significant anti-tumor activity of ALK TKIs in pts with metastatic NSCLC suggest that enrollment of patients on trials of adjuvant ALK TKIs should be prioritized.
TCT-385 Diagnostic Performance of Noninvasive Fractional Flow Reserve derived from Computed Tomography in Diabetic Patients
Authors: Shinichiro Sakurai, Hiroaki Takashima, Akihiro Suzuki, HIroaki Sawada, Hirohiko Ando, Yuki Saka, Katsuhisa Waseda
Journal: Journal of the American College of Cardiology (2018)
Circulating tumor DNA (ctDNA) burden and actionable mutations in treatment-naïve metastatic castration-resistant prostate cancer (mCRPC).
Authors: Alexander William Wyatt, Matti Annala, Sunil Parimi, Muhammad Zulfiqar, Daygen L. Finch, Conrad D. Oja, Joanna Vergidis, Arun Azad, Martin Gleave, Kim N. Chi
Journal: Journal of Clinical Oncology (2016)

5034 Background: The molecular landscape underpinning response to therapy in mCRPC patients is undefined. The analysis of plasma cell-free DNA (cfDNA) has recently emerged as a minimally-invasive method to explore tumor characteristics and therefore has potential utility as a predictive biomarker. However, the broad applicability of cfDNA remains unclear, especially in treatment-naïve mCRPC where tumor burden is typically lower. Methods: To dissect the landscape of tumor-derived cfDNA we collected baseline cfDNA samples from 36 chemotherapy-naïve mCRPC patients enrolled in an ongoing randomized phase II cross-over trial of abiraterone vs enzalutamide (NCT02125357) and performed deep targeted sequencing using a custom NimbleGen SeqCap EZ Choice panel of 72 mCRPC-related genes. 10ng of cfDNA was used for library construction and minimum read depth was ~500X. Results: Using a conservative detection threshold of > 2% allelic frequency, we identified a total of 53 somatic coding mutations in 36 baseline cfDNA samples, with 22/36 samples harboring at least one mutation. Mutations were highly consistent with advanced prostate cancer, falling for example in the AR (n = 5), SPOP (n = 3), PTEN (n = 3) and TP53 (n = 9). The median allelic frequency of coding mutation was 15.8% (range 2.0-74.9), with 10 patients harboring at least one mutation at greater than 25% frequency. Assuming heterozygosity, this suggests that circulating tumor DNA (ctDNA) comprises a majority of the total cfDNA fraction in almost a third of the cohort. Known activating mutations in PIK3CA (E545K, H1074R) were detected in in two patients, and several DNA damage repair genes, including BRCA2, ATM and FANCD2, harbored deleterious mutations and evidence of bi-allelic loss. Conclusions: Our data suggests that a high ctDNA fraction amenable to next-generation sequencing is present in the majority of chemotherapy-naïve mCRPC patients starting 1st line abiraterone or enzalutamide. The readiness of detection of clinically-actionable and informative mutations suggests that targeted cfDNA sequencing can form the basis of a practical biomarker for clinical trial enrichment.
Prognostic role of HMG proteins in a series of 301 advanced soft tissue sarcoma patients: A Spanish Group for Sarcoma Research Study (GEIS).
Authors: Nadia Hindi, Rafael Ramos, Javier Martinez-Trufero, Rosa Maria Alvarez Alvarez, Magda Cordeiro, Luis Miguel Gonzalez de Sande, Gloria Marquina, Juana Maria Cano, Josefina Cruz, Claudia Maria Valverde Morales, María Ángeles Vaz Salgado, Javier Lavernia, Antonio Lopez-Pousa, Robert Diaz Beveridge, Isabel Sevilla, Antonio Gutierrez, David Marcilla, Miquel Taron, David Silva Moura, Javier Martin Broto
Journal: Journal of Clinical Oncology (2018)

11573 Background: High Mobility Group (HMG) proteins act as architectural transcription factors and can influence the expression of many genes. The role of promoting an undifferentiated pluripotent stem-like cell state makes HMGA proteins attractive for sarcoma research. Overexpression of HMGA1 and HMGA2 have been correlated with poor prognosis in some epithelial tumors but there is hardly any data on the prognostic role of HMGA in soft tissue sarcoma (STS). We present the analyses of protein expression of HMGA1/2 and B1 as prognostic factor in STS. Methods: Selection criteria were: advanced STS (at diagnosis or at any time from then on), paraffin block available, treated with at least 2 lines in advanced disease (one of them with trabectedin) and ethic committee’s approval. A TMA was set up for nuclear expression of HMGA1 (Abcam), HMGA2 (Sigma-Aldrich) and HMGB1 (Abcam) with block from diagnostic time. An expert blinded pathologist reviewed and classified the intensity staining into negative, weak or strong and the extension as high (at least 50% of stained cells) or low ( < 50%) for each protein. Kaplan–Meier was used for time-to-event variables and the log-rank test was used to compare groups. Results: A series of 301 patients was studied, median age 52, 53% females and median follow-up from metastasis (M1) of 42 m. Strong and high expression were distributed as follows: HMGA1 24% and 18%, HMGA2 58% and 63%, HMGB1 69% and 75%, respectively. Strong expression of HMGA1 showed significant worse prognosis for OS from M1 time (31 vs 22 m; p = 0.007) and for PFS of trabectedin line (3.8 vs 2.6 m; p = 0.002). Similar results were obtained with high HMGA1 expression. In multivariate analyses, age ( > 60y) HR 1.52 (1.10-2.09) p = 0.009, short lapse to metastases ( < 10 months) HR 1.44 (1.08-1.92) p = 0.013, and strong expression of HMGA1 HR 1.45 (1.06-1.48) p = 0.018 showed to be independent prognostic factors for worse survival from M1. Conclusions: Protein expression of HMGA1 exhibited a significant prognostic role in a series of advanced STS. Validation studies are ongoing to confirm its prognostic and potential predictive role. These results could open new target in STS.
Smad7 Promotes Healing of Radiotherapy-Induced Oral Mucositis without Compromising Oral Cancer Therapy in a Xenograft Mouse Model
Authors: Jingjing Luo, Li Bian, Melanie A. Blevins, Dongyan Wang, Chao Liang, Danfeng Du, Fanglong Wu, Barry Holwerda, Rui Zhao, David Raben, Hongmei Zhou, Christian D. Young, Xiao-Jing Wang
Journal: Clinical Cancer Research (2018)

Abstract Purpose: We previously reported preventive and therapeutic effects of Smad7, a multifunctional protein, on radiotherapy (RT)-induced mucositis in mice without promoting human oral cancer cell survival or migration in vitro. The current study aims to determine whether a Smad7-based biologic can treat existing oral mucositis during radiotherapy for oral cancer and whether this treatment compromises RT-induced cancer cell killing in neighboring oral cancer. Experimental Design: We transplanted human oral cancer cells into the tongues of mice and applied craniofacial irradiation to simultaneously kill tumor cells and induce oral mucositis, thus modeling RT and mucositis in oral cancer patients. We topically applied a recombinant human Smad7 protein fused with the cell-penetrating Tat tag (Tat-Smad7) to the oral mucosa of tumor-bearing mice post RT when oral mucositis began to develop. Results: Topically applied Tat-Smad7 penetrated cells in both the oral mucosa and oral cancer, attenuating TGFβ and NF-κB signaling as well as inflammation at both sites. Tat-Smad7 treatment alleviated oral mucositis with reductions in DNA damage and apoptosis in keratinocytes, but increased keratinocyte proliferation compared with vehicle-treated mucositis lesions. In contrast, adjacent oral cancer exposed to Tat-Smad7 did not show alterations in proliferation or direct DNA damage, but showed increased oxidative stress damage and apoptosis compared with tumors treated with vehicle. Conclusions: Our results suggest that short-course Tat-Smad7 application to oral mucositis promotes its healing but does not compromise the cytotoxic effect of RT on oral cancer and has context-specific effects on oral mucosa versus oral cancer.
Cancer predisposing germline mutations in patients (pts) with urothelial cancer (UC) of the renal pelvis (R-P), ureter (U) and bladder (B).
Authors: Maria Isabel Carlo, Liying Zhang, Diana Mandelker, Joseph Vijai, Catharine Kline Cipolla, Mark E. Robson, Samuel Funt, A. Ari Hakimi, Gopa Iyer, Jonathan E. Rosenberg, Jonathan Coleman, David B. Solit, Kenneth Offit, Dean F. Bajorin
Journal: Journal of Clinical Oncology (2017)

4510 Background: Urothelial cancers (UC) are suspected to have a substantial hereditary component, but other than highly penetrant genes such as those in mismatch-repair pathway (e.g. MSH2) typically associated with R-P/U primaries, heritable gene mutations have not been systematically studied. We sought to investigate the prevalence of known cancer pre-disposing germline mutations in pts with UC originating from all sites within the urinary tract. Methods: Pts with R-P, U and B primaries, unselected for suspicion of inherited cancer syndrome, were prospectively enrolled from medical oncology and urology clinics to a germline sequencing protocol from June 2016 to January 2017. Germline gene analysis was performed in a CLIA-certified lab using a next generation sequencing (NGS) platform (MSK-IMPACT) that analyzes tumor-normal DNA pairs. The germline gene panel consisted of 76 genes associated with hereditary cancer predisposition. Results: As of January 24, 2017, 101 pts have NGS results available, with median age 63 (31-87), 76% male, 24% female. Primary sites were B (67%), R-P/U (31%), or both (3%). 73% had organ-confined disease and 27% had metastases. 8% had early onset (≤45 yrs at diagnosis), 10% had a family history of UC, 25% had documented non-UC cancers. 25 pathogenic or likely pathogenic (P-LP) mutations were identified in 22 patients. P-LP mutations were present in 29% of pts with R-P/U primaries and 18% of pts with B primaries. 12 DNA damage response gene alterations were found (4 CHEK2, 3 BRCA1, 2 BRCA2, 1 ATM, 1 BRIP1, 1 NBN) and 8 in Lynch syndrome associated genes (5 MSH2, 2 MSH6, 1 MLH1). Other mutations include 2 APC, 1 TP53, and 1 FH. Notably 3 pts had 2 alterations each ( MSH6/ APC, BRCA2/ APC, BRCA1/ CHEK2). 9/22 pts with P-LP mutations did not meet American College of Medical Genetics criteria for genetic screening. Conclusions: 22% of UC pts had a germline mutation in a cancer-associated gene. There was an unexpectedly high frequency of pts with DNA-repair pathway mutations. Active accrual is ongoing to define the full spectrum of alterations. These results have profound implications for genetic counseling and screening and further studies are warranted.
TCT-635 Unmasking Myocardial Bridge Related Ischemia by Intracoronary Functional Evaluation
Authors: Alberto Barioli, Luca Nai Fovino, Chiara Fraccaro, Giulia Masiero, Gianpiero D'Amico, Daisuke Ueshima, Mostafa Badawy, Alessandro Schiavo, Benedetta Schiavon, Tommaso Fabris, Andrea Pavei, Massimo Napodano, Giuseppe Tarantini
Journal: Journal of the American College of Cardiology (2018)