tbuckley/cabot-search huggingface dataset:
Effect of DNA hypermethylation on immune escape through downregulation of antigen presentation genes in breast cancer.
Authors: Balazs Gyorffy, Adam Nagy, Lorinc Pongor, Alberta Locatelli, Lucia Vigano', Anton Mikhailovich Safonov, Lajos Pusztai, Luca Gianni, Giampaolo Bianchini
Journal: Journal of Clinical Oncology (2016)

11547 Background: Downregulation/loss of HLA class I is a major mechanism of immune escape. Tumors with low MHC1 have higher risk of relapse in HER2+ and triple-negative breast cancer (BC). We investigated the contribution of methylation status to downregulation/loss of HLAs and B2M (β2 microglobulin) in different BC subtypes. Methods: Gene-expression and methylation data were retrieved for 970 breast cancer samples from TCGA. We defined tertiles of mRNA expression of HLAs (classical A, B, C and non-classical G) and B2M, and compared the methylation of 19,956 genes between the high and low tertile groups of each of the above genes in each breast cancer subtype [HER2+, n = 290; ER-HER2- (TN), n = 201; ER+HER2-; n = 479]. To minimize false discovery rate, results were considered significant if p < 1E-05. Results: B2M, HLA-A and HLA-B were significantly hypermethylated in the low compared to high tertile group in each BC subtype (p < 1E-05). HLA-C gene was also hypermethylated in the low tertile group (p = 3.7E-05, p = 1.5E-05 and p = 5.0E-12 in HER2+, TN and ER+HER2- groups respectively). Expression of HLA-G was not significantly correlated to methylation. Except for HLA-G, a plethora of genes had different methylation in low and high tertile groups. In particular, several genes involved in antigen presentation and immune function were co-hypermethylated. For instance, the 25 top-ranking hypermethylated genes in each BC subtype in the low HLA-A expressing group consistently included HLA-A, HLA-B, HLA-E, HLA-F, B2M, TAP1, PSMB8 (antigen presentation) and IFIT3, IRF1, IFNAR1 (interferon-signaling). Conclusions: The results suggest that epigenetic hypermethylation contributes significantly to HLAs and B2M loss/downregulation in all breast cancer subtypes. Several genes involved in antigen presentation were co-hypermethylated, partially due to co-localization on chromosome 6p21.3, but methylation also of B2M (chr 15q21.1) suggests a coordinate contribution to immune escape. Our data together with preclinical evidence that HLA expression can be restored by DNA methylation inhibitors, provide a rationale for testing DNA-demethylating agents in combination with immune checkpoint inhibitors in BC.
Mutations in multiple components of the nuclear pore complex cause nephrotic syndrome
Authors: Daniela A. Braun, Svjetlana Lovric, David Schapiro, Ronen Schneider, Jonathan Marquez, Maria Asif, Muhammad Sajid Hussain, Ankana Daga, Eugen Widmeier, Jia Rao, Shazia Ashraf, Weizhen Tan, C. Patrick Lusk, Amy Kolb, Tilman Jobst-Schwan, Johanna Magdalena Schmidt, Charlotte A. Hoogstraten, Kaitlyn Eddy, Thomas M. Kitzler, Shirlee Shril, Abubakar Moawia, Kathrin Schrage, Arwa Ishaq A. Khayyat, Jennifer A. Lawson, Heon Yung Gee, Jillian K. Warejko, Tobias Hermle, Amar J. Majmundar, Hannah Hugo, Birgit Budde, Susanne Motameny, Janine Altmüller, Angelika Anna Noegel, Hanan M. Fathy, Daniel P. Gale, Syeda Seema Waseem, Ayaz Khan, Larissa Kerecuk, Seema Hashmi, Nilufar Mohebbi, Robert Ettenger, Erkin Serdaroğlu, Khalid A. Alhasan, Mais Hashem, Sara Goncalves, Gema Ariceta, Mercedes Ubetagoyena, Wolfram Antonin, Shahid Mahmood Baig, Fowzan S. Alkuraya, Qian Shen, Hong Xu, Corinne Antignac, Richard P. Lifton, Shrikant Mane, Peter Nürnberg, Mustafa K. Khokha, Friedhelm Hildebrandt
Journal: Journal of Clinical Investigation (2018)

Steroid-resistant nephrotic syndrome (SRNS) almost invariably progresses to end-stage renal disease. Although more than 50 monogenic causes of SRNS have been described, a large proportion of SRNS remains unexplained. Recently, it was discovered that mutations of NUP93 and NUP205, encoding 2 proteins of the inner ring subunit of the nuclear pore complex (NPC), cause SRNS. Here, we describe mutations in genes encoding 4 components of the outer rings of the NPC, namely NUP107, NUP85, NUP133, and NUP160, in 13 families with SRNS. Using coimmunoprecipitation experiments, we showed that certain pathogenic alleles weakened the interaction between neighboring NPC subunits. We demonstrated that morpholino knockdown of nup107, nup85, or nup133 in Xenopus disrupted glomerulogenesis. Re-expression of WT mRNA, but not of mRNA reflecting mutations from SRNS patients, mitigated this phenotype. We furthermore found that CRISPR/Cas9 knockout of NUP107, NUP85, or NUP133 in podocytes activated Cdc42, an important effector of SRNS pathogenesis. CRISPR/Cas9 knockout of nup107 or nup85 in zebrafish caused developmental anomalies and early lethality. In contrast, an in-frame mutation of nup107 did not affect survival, thus mimicking the allelic effects seen in humans. In conclusion, we discovered here that mutations in 4 genes encoding components of the outer ring subunits of the NPC cause SRNS and thereby provide further evidence that specific hypomorphic mutations in these essential genes cause a distinct, organ-specific phenotype.
Apatinib plus SOX regimen as neoadjuvant chemotherapy for locally advanced gastric cancer: A phase II study.
Authors: Ya'nan Zheng, Xiao Yang, Hongpeng Shi, Zhongyin Yang, Chao Yan, Zhentian Ni, Mengjiao Li, Birendra Kumar Sah, Wentao Liu, Wei Xu, Xuexin Yao, Zhenglun Zhu, Min Yan, Zhenggang Zhu, Chen Li
Journal: Journal of Clinical Oncology (2018)

e16014 Background: Locally advanced gastric cancer (LAGC) occupies a relatively large proportion of gastric cancer and has a low 5-year survival rate. Neoadjuvant chemotherapy is an important part in the treatment of LAGC. We aimed to preliminarily evaluate the efficacy and safety of apatinib, an oral tyrosine kinase inhibitor targeting VEFGR-2, combined with SOX regimen in patients (pts) with LAGC as neoadjuvant chemotherapy. Methods: This is a prospective, single-arm phase II study. LAGC pts with pathologically and/or cytologically confirmed adenocarcinoma were eligible. Prior anti-cancer strategies were not allowed, including radiotherapy, chemotherapy, targeted therapy, and immunotherapy. Pts received 3 cycles (21 days a cycle) of neoadjuvant chemotherapy with apatinib (po, 500 mg qd), S-1 (po, 40-60 mg bid, day1-day14), and oxaliplatin (iv, 130 mg/m2, day1). Apatinib was prohibited in the last cycle. The operation should be performed 4 weeks later of the neoadjuvant chemotherapy. The primary outcome was safety of the neoadjuvant chemotherapy. The secondary outcomes included R0 resection rate, objective response rate (ORR), and disease control rate (DCR). Results: As of 25 January 2018,a total of 20 eligible pts including 15 males and 5 females were recruited. The median age was 60.0 years (range 43-73 years). Poorly differentiated adenocarcinoma was the main histological type (50.0%). All pts completed the neoadjuvant chemotherapy: one pts achieved complete response, 14 had partial response, four had stable disease, and one had progressive disease (PD). The ORR and DCR were 75.0% (15/20) and 95.0% (19/20), respectively. 19 pts received gastric surgery except the one who had PD, and the R0 resection rate was 100%. All pts were included for safety analysis. The incidence of adverse events (AEs) and grade 3/4 AEs were 100.0% and 30.0%, respectively. The most common AEs were hypertension (70.0%), anemia (65.0%), leucopenia (65.0%), and nausea (50.0%). Conclusions: Neoadjuvant chemotherapy with apatinib plus SOX brings clinical benefit to LAGC with a high disease control rate and tolerable adverse reactions. Clinical trial information: ChiCTR-OPC-16010061.
A pre-specified statistical model based on four kallikrein markers in blood to predict advanced pathology on radical prostatectomy.
Authors: Thomas Steuber, Alexander Haese, Amy Tin, Daniel D Sjoberg, Dirk Pehrke, Hartwig Huland, Markus Graefen, Thorsten Schlomm, Andrew J. Vickers, Hans Lilja, Guido Sauter
Journal: Journal of Clinical Oncology (2018)

5073 Background: Four kallikrein markers in blood – commercially available as the 4Kscore – has been shown to be highly predictive of Gleason Grade Group (GGG) 2 or higher prostate cancer at biopsy. However, tissue sampling and grading at biopsy is an imperfect gold standard and may miss aggressive disease. We measured the kallikrein in cryopreserved blood in patients undergoing radical prostatectomy at a tertiary referral center during 2000 - 2010, during which it was common to treat GGG1 prostate cancer. Methods: Aggressive disease was defined as primary Gleason grade 4, any grade 5, seminal vesicle invasion, extra-capsular extension (ECE) or lymph node invasion. ECE was excluded in a sensitivity analysis. A second sensitivity analysis excluded patients with low scores from the kallikrein panel, who may never have been biopsied had they received a 4Kscore. We assessed improvement in discrimination when the kallikrein panel was added to a base model using established clinical predictors: age, prostate specific antigen, clinical stage and grade. We also examined a model that included number of positive cores and mm of cancer. We pre-specified that we would separately assess men with GGG1 – where the decision concerns confirmatory biopsy – and GGG2 – where the decision would concern treatment vs. active surveillance. Results: The cohort included 2284 men with data on cores for 1294. The kallikrein panel was significantly associated with advanced pathology after adjusting for clinical variables (P < 0.001). Overall, the panel added 0.014 to the AUC of clinical model, with larger effects within GGG1 (0.047) and GGG2 (0.017). Results were similar when cores data were included and not sensitive to alternative definitions of advanced disease, or exclusion of patients with low panel risks. Decision curve analysis confirmed the additional value of the panel in appropriate ranges for decision thresholds: 5 – 20% for confirmatory biopsy and 20 – 60% for treatment. Conclusions: The kallikrein panel is strongly associated with pathologic outcome, and can be used to make subsequent management decisions for patients found with GGG1 or GGG2-cancer at biopsy and the need for confirmatory biopsy and treatment.
Papillary Thyroid Microcarcinoma: Reclassification to Non-Invasive Follicular Thyroid Neoplasm with Papillary-Like Nuclear Features (NIFTP): a Retrospective Clinicopathologic Study
Authors: Khurram Shafique, Virginia A. LiVolsi, Kathleen Montone, Zubair W. Baloch
Journal: Endocrine Pathology (2018)
The effect of corticosteroid (Cs) use during docetaxel (D) treatment on overall survival (OS) in metastatic castration-resistant prostate cancer (mCRPC).
Authors: Fruzsina Gyergyay, Barna Budai, Krisztina Biro, Zsofia Kuronya, Krisztian Nagyivanyi, Timea Vajdics, Anna Oreskovich, Lajos Geczi
Journal: Journal of Clinical Oncology (2017)

e16522 Background: Cs are commonly used in the treatment of mCRPC, because of their inhibitory effects on the secretion of ACTH and their palliative effects. Inhibition of ACTH results in downregulation of adrenal androgens. Cs may have a cytotoxic effect on prostate cancer cells, mediated in part by the downregulation of androgen receptors and the activation of glucocorticoid receptor-mediated signaling and downstream antiangiogenic activity. The rationale for adding Cs to D chemotherapy is for the management of symptoms and adverse events rather than for improving responses. D (without Cs) + ADT (androgen-deprivation therapy) vs ADT alone in castration-sensitive prostate cancer has resulted in significant increase in survival (NEJM, 2015). Cs has been reported to adversely influence OS during enzalutamide (NEJM, 2012). In the COU-AA-301 trial Cs use at baseline was an independent prognostic factor in multivariate analysis, but not in a stepwise selection model (JCO, 2013). Methods: We performed a retrospective analysis of 117 mCRPC pts treated with D. All pts had standard Cs premedication before D and 74 pts received prednisone 5 mg po BID, but 43 pts didn’t get continuous Cs therapy. Kaplan-Meier estimates and Cox regression model were used. Results: Pts characteristics were as follows: median age 66 yrs (range 48-81), Gleason score ≤6: 22pts, ≥7: 61pts. (34 NA). Altogether 1015 cycles of D were given, median 8 (range 2-27). Subsequent therapies were as follows: Abiraterone Acetate (AA) (75), Mitoxantrone (46), Xofigo (5), other chemotherapies (7), none (21). Pts receiving Cs had an inferior OS in all subgroups, although none was significant (Table). Only the Gleason score was an independent prognostic factor in multivariate analysis. Conclusions: Our data suggest, that D therapy withouth Cs is at least as effective as the combination. More data is neccesary to support the suspicion of negative influence of Cs on OS. Thus unnecesarry Cs treatment might be ommited. [Table: see text]
P01.106 Impact of intraoperative magnetic resonance imaging on the extent of resection and functional outcome in awake surgery for eloquent gliomas - a single center retrospective study
Authors: C Jungk, M Scherer, H DaoTrong, C Schramm, S Haehnel, C Herold-Mende, A Unterberg
Journal: Neuro-Oncology (2018)

Maximizing the extent of resection (EOR) while preserving functional integrity is a mainstay of modern glioma surgery. Resection guidance tools such as intraoperative MRI (iMRI) help to augment the EOR. However, in eloquently located gliomas the significance of iMRI is controversial since the EOR is limited by functional rather than image-based boundaries. Thus, we set out to determine the impact of iMRI in our series of awake glioma resections. Our institutional database was searched for all awake glioma resections within or adjacent to eloquent (language, motor, sensory) areas since the implementation of a 1.5 Tesla iMRI in 2009. Demographic, tumor- and procedure-related data and functional outcome were assessed through medical charts review. The EOR was determined volumetrically on pre-, intra- and early postoperative T1 contrast-enhanced (CE) and FLAIR MR images. In a 7-year period, awake surgery was performed in 104 glioma patients of whom 86 had iMRI-guided surgery with concurrent language (n=72) and/or motor (n=50) mapping. The iMRI group consisted of 53 lower-grade gliomas and 33 glioblastomas with a median age of 47 years (range 12–74), mainly located in left-sided language or motor areas (n=73; 85%). iMRI was well tolerated by all patients and was done when functional boundaries were reached (n=26; 30%), for resection control (n=53; 62%) or for other reasons (n=7). Additional resection after iMRI (AR) was performed in 63 cases (73%); otherwise resection was terminated because either the targeted EOR or functional boundaries were reached. New or deteriorated neurological deficits occurred in 20 patients prior (23%) and 15 patients post (17%) iMRI; however, all but 3 resolved within 6 months (3%). Median EOR significantly increased after AR from 92.6% to 98.4% (∆5.8%; p<0.0001) when CE was the target volume and from 64.5% to 85.8% (∆21.3%; p<0.0001) in non-enhancing tumors. Remarkably, the reason to perform iMRI, either for resection control or because of functional limitations, did not affect the frequency of AR, deficits acquired post iMRI or the increase in EOR after AR. Also, AR did not increase the rate of neurological deficits in the early or late postoperative course. IMRI is feasible in awake surgery of eloquently located gliomas and is a valuable adjunct to maximize the EOR without increasing the risk for functional impairment, particularly in non-enhancing tumors. Importantly, iMRI contributes to a maximized EOR even in cases where the resection has to be stopped because functional boundaries were reached.
Biomarker-driven access to crizotinib in ALK, MET, or ROS1 positive (+) malignancies in adults and children: The French National AcSé Program.
Authors: Gilles Vassal, Nathalie Cozic, Gilbert Ferretti, Sophie Taieb, Roch Houot, Laurence Brugieres, Thomas Aparicio, Jean-Yves Blay, Ivan Bieche, Sylvie Lantuejoul, Celine Mahier - Ait Oukhatar, Natalie Hoog Labouret, Denis Moro-Sibilot
Journal: Journal of Clinical Oncology (2018)

2504 Background: Crizotinib (czb) is registered for the treatment of patients (pts) with ALK+ or ROS1+ lung cancer. Czb targets (ALK, MET, ROS1) are also altered (translocation [tlc], amplification [amp], mutation [mut]) in a wide range of malignancies (malg.) in adults and children. To generate high evidenced-based knowledge and to prevent off-label use, the French National Cancer Institute (INCa) launched the AcSé Program: equal access to tumor molecular diagnosis along with an exploratory phase II trial, to allow for a nationwide safe and controlled access to czb outside its indication. Methods: Biomarker identification was proposed to pts ≥ 1 year old (yo) with an advanced disease among more than 15 malg. known to harbor a czb target alteration. If not eligible for any other trial, pts may enter one of the 22 cohorts defined by the type of tumor and target. Tumor response was evaluated every 2 months (mo) using RECIST criteria v1.1. The primary endpoint is the objective response rate (ORR) at 2 mo [complete + partial response]. A two-stage Simon design is applied to each cohort. Results: From 08/2013 to 12/2017, 12836 pts from 186 centers have entered the biomarker program. Alterations found in pts were: ALK tlc, mut, amp in 14/2053, 8/306, 10/1846; MET amp ( > 6 copies/diploid genome) in 392/7847 [250/4127 NSCLC, 60/1232 glioblastomas, 28/939 colon, 33/546 esogastric, 7/635 ovarian, 3/82 kidney cancers]; MET mut in 98/2697; ROS1 tlc in 80/4625 [NSCLC, cholangiocarcinoma, inflammatory myofibroblastic tumor (IMT)]. Clinical trial information: NCT02034981. Overall, 235 pts (median age, 58 yo [1–92]) received czb (adult 250 mg bid; child 280 mg/m² bid). Conclusions: Czb displayed a wide antitumor activity in several MET, ALK and ROS1+ malg. Equal and safe access across France to molecular testing and targeted therapies outside their approved indication is feasible. Positive cohorts Pts analyzed CR/PR ORR % [IC95%] ALCL ALK tlc 22 12 54 [34-75] NSCLC MET amp 25 6 24 [7-40] ROS1 tlc 37 20 54 [40-70] MET mut 27 6 22 [7-38] Esogastric MET amp 8 3 37 [10-74] IMT ALK tlc / ROS1 tlc 7 1 28 [5-70]
A randomized phase III trial comparing adjuvant chemotherapy with S-1 vs. surgery alone in patients with resectable biliary tract cancer (JCOG1202: ASCOT).
Authors: Masafumi Ikeda, Kohei Nakachi, Masaru Konishi, Shuichi Mitsunaga, Junki Mizusawa, Katsuhiko Uesaka, Akio Saiura, Hiroaki Yanagimoto, Soichiro Morinaga, Junko Eba, Hiroshi Katayama, Haruhiko Fukuda, Hiroshi Ishii, Takuji Okusaka, Junji Furuse
Journal: Journal of Clinical Oncology (2017)

TPS4144 Background: No standard adjuvant treatment has been established for patients with curatively resected biliary tract cancer (BTC). S-1, which is one of the oral fluoropyrimidine derivatives, showed promising efficacy with a mild toxicity profiles in patients with advanced BTC, and the survival benefit of adjuvant S-1 therapy has been demonstrated in patients with resected gastric cancer and pancreatic cancer. The aim of this open-label, multicenter, randomized phase III trial is to assess whether adjuvant S-1 would prolong the overall survival in patients with resected BTC. Methods: The main eligibility criteria are as follows: 1) curatively resected carcinoma of the extrahepatic bile duct, gallbladder or ampulla of Vater (T2-4, N0, M0 or T1-4, N1, M0), or carcinoma of the intrahepatic bile duct (T1-4, N0-1, M0) (7 th UICC classification), 2) histologically confirmed adeno (squamous) carcinoma, 3) R0 or R1 residual disease, 4) age 20 to 80 years, 5) ECOG performance status 0 or 1, 6) no prior chemotherapy or radiotherapy, 7) adequate organ functions, 8) written informed consent. Patients are randomly assigned to the surgery alone arm (arm A) or the adjuvant S-1 arm (arm B) by the minimization method for balancing institution, primary site of cancer and lymph node metastasis between the arms. Patients in arm A do not receive any anti-cancer treatment, while patients in arm B receive 4 cycles of oral S-1 chemotherapy at the dose of 40 mg/m 2 twice daily for 4 weeks followed by 2 weeks of rest. The primary endpoint is overall survival, while the secondary endpoints are relapse-free survival, incidence of (serious) adverse events, and proportion of treatment completion. We assumed a 3-year survival in arm A of 47% and a 10% increase in the 3-year survival in arm B. The sample size was calculated as a total of 350, with a one-side alpha of 5% and power of 70%; planned accrual period is 4 years, and follow-up period, 3 years. Primary analysis will be conducted at 3 years and updated analysis will be conducted at 5 years after closing of accrual. As of Jan 31, 2016, a total of 285 patients have already been enrolled in this trial from Sep 2013. Clinical trial information: UMIN000011688.
A retrospective analysis comparing efficacy of filgastrim-sndz versus filgastrim for autologous, peripheral stem cell mobilization in patients with multiple myeloma and lymphoma.
Authors: Derek Young, Pavan S. Reddy, Bassam Ibrahim Mattar, Phu Van Truong, Seth Joel Page, Quoc Van Truong, Nassim H. Nabbout, Chris Dakhil, Michael W. Cannon, Shaker R. Dakhil, Jeremy Michael Deutsch, Patricia Bluml
Journal: Journal of Clinical Oncology (2018)

e19505 Background: Filgrastim-sndz was the first biosimilar granulocyte colony stimulating factor to be approved by the FDA for the same indications, including peripheral blood stem cell mobilization, as the originator G-CSF filgrastim. Pharmacodynamic studies in healthy volunteers were used to show biosimilarity in CD34+ mobilization. This study adds to the small literature base comparing use of biosimilar G-CSF to originator G-CSF for autologous stem cell mobilization. Methods: A retrospective analysis was performed on all patients with MM, NHL and HD undergoing auto-HSCT at a single center from the years 2015-2017. All patients had peripheral blood stem cell mobilization with filgrastim-sndz or filgrastim given as 10 µg/kg/day s.c. injections on days 1-5 with plerixafor 0.24 mg/kg s.c. given on day 4. Apheresis was performed on day 5. The primary endpoint was to compare day 5 collection of CD34+ cell/kg. Secondary endpoints were day 4 peripheral CD34+ cells/µL, and number of days to neutrophil (ANC > 500 cells/µL) and platelet ( > 20,000 platelets/µL) engraftment. Results: A total of 80 patients were included in the review (filgrastim-sndz, n = 25; filgrastim, n = 55). The yield of CD34+ cells/kg on day 5 was not significantly different between patients receiving filgrastim-sndz and filgrastim. There were significant differences in the engraftment times of both neutrophils and platelets in favor of filgrastim-sndz. Conclusions: In this single-institution study, filgrastim-sndz for peripheral stem cell mobilization showed no difference in yield of CD34+ cells compared to filgrastim but did result in a significantly shorter time to neutrophil and platelet engraftment. This finding should be confirmed by a large, randomized controlled trial, as time to engraftment is an important factor in patient morbidity and mortality. Primary and secondary endpoints Filgrastim-sndz Filgrastim P value Day 5 CD34+ cells/kg, mean ± SD 5.19 ± 3.02 4.58 ± 2.43 0.34 Day 4 PB CD34+ cells/µL, mean ± SD 18.9 ± 16.1 16.9 ± 13.6 0.57 Days to neutrophil engraftment, median ± SD 10.8 ± 1.78 12 ± 2.83 0.05 Days to platelet engraftment, median ± SD 16.8 ± 4.13 19.7 ± 5.09 0.02