tbuckley/cabot-search huggingface dataset:
Updated Overall Survival (OS) Analysis from a Phase III Study of Sunitinib vs Placebo in Patients (PTS) with Advanced, Unresectable Pancreatic Neuroendocrine Tumor (NET)
Authors: S. Faivre, P. Niccoli, J.L. Raoul, Y. Bang, I. Borbath, J.W. Valle, X. Huang, S. Patyna, R. Chao, E. Raymond
Journal: Annals of Oncology (2012)
Intermediate atypical carcinoma (IAC): A discrete subtype of metastatic castration-resistant prostate cancer (mCRPC) suggesting that treatment-associated small cell/neuroendocrine prostate cancer (t-SCNC) may evolve from mCRPC adenocarcinoma (adeno)—Results from the SU2C/PCF/AACR West Coast Prostate Cancer Dream Team (WCDT).
Authors: Eric Jay Small, Rahul Raj Aggarwal, Verena Friedl, Alana Weinstein, George V. Thomas, Lawrence D. True, Adam Foye, Tomasz M. Beer, Matthew Rettig, Martin Gleave, Christopher P. Evans, Joshi J. Alumkal, Robert Evan Reiter, Primo Lara, Kim N. Chi, Felix Y Feng, Adina Bailey, Josh Stuart, Jiaoti Huang
Journal: Journal of Clinical Oncology (2020)

158 Background: A subset of mCRPC patients (pts) that develop resistance to next-gen androgen signaling inhibitors are subsequently found to harbor t-SCNC. We have undertaken a longitudinal prospective biopsy (bx) study to clinically and molecularly characterize these pts. Methods: Eligible pts underwent an image-guided mCRPC bx at one of 5 WCDT centers. Tissue was both frozen and formalin fixed/paraffin embedded (FFPE). FFPE tissue was used for targeted next generation sequencing (NGS) and independent pathologic review by 3 pathologists. Frozen specimens underwent laser capture micro-dissection prior to RNA sequencing (seq). Machine learning was used to derive histology-specific expression signatures. Linear Discriminant Analysis (LDA) was applied to the RNA seq data from the first 131 bx using 3 observed histologic subtypes as labels to test for an intermediate subtype. Results: Of 391 mCRPC metastasis (53% bone, 26% node, 12% liver, 9% other soft tissue), 295(75%) yielded cancer. Overall, 89% of the bx contained a single histologic subtype: pure adeno in 156(53%); pure t-SCNC in 35(12%). A novel morphologically distinct subtype, IAC, with features of both tSCNC and adeno was seen in 72(24%). Samples comprised of two subtypes made up 32(11%) of all bx. Overall, 50(17%) of bx had a t-SCNC component. TP53 and/or RB1 loss of function variants were significantly more frequent in t-SCNC. NGS revealed no difference between adeno and IAC. LDA classified IAC as intermediate between adeno and t-SCNC 93% of the time, across 100 bootstrap replicates, significantly better than the 33% expected by chance (p &lt;10 −17 ). Conclusions: Nearly half of mCRPC bx exhibit non-adeno features with t-SCNC found in 17%. IAC is a reproducible mCRPC histologic subtype found in 24% of bx, with a gene expression signature that is intermediate to adeno and t-SCNC, and targeted NGS results similar to adeno. Understanding the role of IAC in disease evolution and resistance is critical for improving outcomes in mCRPC. Clinical trial information: NCT02432001.
DETERMINING COMPLETENESS OF CASE ASCERTAINMENT TO A LUNG CANCER REGISTRY: A SINGLE INSTITUTIONAL STUDY.
Authors: Robert Stirling, Peta Mclaughlin, Meera Senthuren, Sue Evans, Katherine Allnutt, Lise Hales, Annie Gilbert, Chris Bain, Catriona Mclean, Neil Watkins
Journal: Journal of Thoracic Oncology (2013)
Incorporating mpMRI and biomarkers in active surveillance protocols: The prospective Stockholm3 Active Surveillance trial (STHLM3AS).
Authors: Anna Lantz, Henrik Olsson, Tobias Nordström, Fredrik Jäderling, Lars Egevad, Magnus Annerstedt, Henrik Gronberg, Martin Eklund
Journal: Journal of Clinical Oncology (2020)

TPS379 Background: Level one evidence shows that men with low-risk prostate cancer undergoing active surveillance (AS) with repeated PSA tests and systematic biopsies have low mortality. However, monitoring sometimes misses significant cancer progression and causes patient morbidity. The objective of this study is to evaluate a new proposed protocol for AS using the combination of the Stockholm3 test and MRI targeted biopsies in comparison to conventional follow-up using PSA and systematic biopsies. Methods: A prospective multicenter study with paired design was used to evaluate our proposed protocol (Stockholm3, MRI, targeted biopsies) compared with the conventional protocol according to Swedish National Guidelines (PSA, systematic biopsies) for follow-up of men on AS. The STHLM3 study was performed between 2012-2014. In the study 1 374 men were diagnosed with ISUP grade 1 disease. Out of these, 541 men currently on AS were invited to the STHLM3AS study. Eligible individuals had to be alive without any severe comorbidity, without contraindications for MRI and without a history of initiating prostate cancer treatment. The primary endpoint ISUP grade ≥2 cancer and the secondary endpoint number of performed biopsies will be evaluated using relative sensitivity (RS). At baseline a blood test for PSA and Stockholm3 test as well as a bi-parametric MRI was performed. For men with PIRADS ≥ 3 targeted and systematic biopsies were performed. For men with PIRADS &lt; 3 only systematic biopsies were performed. The study is registered at ClinicalTrials.gov (NCTNCT03956108). Results: 301 men on AS have been included in the study. Since this is a trial in progress, no results will be presented. Conclusions: To our knowledge, this is the largest prospective multicenter study evaluating the performance of MRI for disease monitoring in an AS-cohort. Prediction models using biomarkers and MRI will likely both have an increasing role in the monitoring of AS patients in the future. We hypothesise that the sequential use of first Stockholm3 test followed by MRI will decrease the number of biopsies, while retaining the sensitivity to detect ISUP grade ≥2 cancer compared with using systematic biopsies in all men. Clinical trial information: NCTNCT03956108.
Recanalization of a complete coloanal anastomotic obstruction using a combined antegrade-retrograde rendezvous technique
Authors: Saowanee Ngamruengphong, Sonmoon Mohapatra, Thomas M. Runge, Eduardo Paredes, Sandy H. Fang
Journal: Endoscopy (2020)

A 66-year-old man with a history of lower rectal adenocarcinoma and robotic-assisted low anterior resection with creation of a diverting ileostomy, presented with complete stenosis of the coloanal anastomosis ([Fig. 1 a]). Rendezvous recanalization of the coloanal obstruction was planned ([Video 1]).
Molecular mechanism of FGFR activation and resulting differences in the tumor-immune environment of bladder cancer.
Authors: Takashi Kawahara, Takahiro Kojima, Masanobu Shiga, Ken Tanaka, Shuya Kandori, Hiromitsu Negoro, Koji Kawai, Hiroyuki Nishiyama
Journal: Journal of Clinical Oncology (2020)

432 Background: Activation of FGFR signals in bladder cancer is frequently observed. Previous study reported that infiltration of tumor immune cells is suppressed in FGFR3 mutated bladder cancer. In this study, we elucidate the relationship between molecular mechanism of FGFR activation and tumor immune environment in bladder cancer. Methods: We analyzed 103 tissues of bladder cancer patients. Detection of somatic mutations were performed by target sequencing and gene expressions were analyzed by RNA-seq. Immunohistochemical staining of CD8 was performed for evaluating tumor-infiltrating lymphocytes. We compared the relationship between molecular mechanism of FGFR activation and tumor immune environment. Results: FGFR3 activated mutation or fusion was found in 37 cases (36%). FGFR1 overexpression was found in 10 cases (10%). FGFR3 activated mutation or fusion and FGFR1 overexpression were mutually exclusive. Tumors harboring FGFR3 mutation showed less infiltration of CD8 positive cells ( p = 0.01) and low PD-L1 expression ( p = 0.08) compared to those without. On the other hand, tumors with FGFR1 overexpression showed more infiltration of CD8 positive cells ( p = 0.06) and high PD-L1 expression ( p = 0.02). Conclusions: Clinicopathological features and intratumor immune environment of bladder cancer is different depending on the molecular mechanism of FGFR activation. These results suggest a possible association between molecular mechanism of FGFR activation and sensitivity of immunotherapy.
Insulin-like Growth Factor 1 Supports a Pulmonary Niche that Promotes Type 3 Innate Lymphoid Cell Development in Newborn Lungs
Authors: Katherine Oherle, Elizabeth Acker, Madeline Bonfield, Timothy Wang, Jerilyn Gray, Ian Lang, James Bridges, Ian Lewkowich, Yan Xu, Shawn Ahlfeld, William Zacharias, Theresa Alenghat, Hitesh Deshmukh
Journal: Immunity (2020)
The impact of the expression of the transcription factor MYBL2 on outcomes of patients with localized and advanced prostate cancer.
Authors: Yuki Yoshikawa, Xin Victoria Wang, Yu-Hui Chen, Ying Zhang Mazzu, Goutam Chakraborty, Lina E. Jehane, Sai Harisha Rajanala, Rahim Hirani, Subhiksha Nandakumar, Konrad H. Stopsack, Gwo-Shu Mary Lee, Elai Davicioni, Glenn Liu, Robert S. DiPaola, Michael Anthony Carducci, Philip W. Kantoff, Christopher Sweeney
Journal: Journal of Clinical Oncology (2020)

149 Background: Patients with metastatic hormone-sensitive prostate cancer (mHSPC) have a variable response to ADT and some benefit from the addition of docetaxel or an androgen signaling pathway inhibitor. We found that loss of the epigenetic regulator KDM5D is associated with more aggressive prostate cancer (PC). We sought to determine whether MYBL2 which is regulated by KDM5D mediates this effect. MYBL2 is a transcription factor which controls key genes (e.g. FOXM1) and increases cell cycle progression and survival. Methods: AR expressing hormone-sensitive cell lines, LNCaP and LAPC4 were used. Motif analysis and CHiPseq of LNCaP with and without siKDM5D was performed and impact of modulation of KDM5D and MYBL2 in both cells on cell survival was assessed. Gene expression profiling (GEP) data assessed MYBL2’s association with KDM5D levels in localized disease (publicly available data) and mHSPC (Decipher whole Affymetrix platform on CHAARTED samples). Results: Silencing KDM5D increased H3K4me3 and increased MYBL2 expression. GEP showed a strong negative correlation between KDM5D and MYBL2 in patients with localized PC (-0.66; TCGA) but not from primary prostate cancer tissue with mHSPC (-0.03; CHAARTED). Cells with low KDM5D and high MYBL2 were androgen independent and more resistant to docetaxel. In TCGA, patients with high MYBL2 had a higher rate of relapse from localized disease. In patients with metastatic disease (CHAARTED) low MYBL2 was associated with a better overall survival (OS) on multivariable analysis when treated with ADT or ADT + docetaxel. Conclusions: Low MYBL2 is associated with a longer OS with ADT alone and ADT and docetaxel independent of clinical variables. Patients with high MYBL2 expression had better OS with ADT plus docetaxel compared with patients with high MYBL2 treated with ADT alone.[Table: see text]
Comprehensive analysis for immune profiles of tumor microenvironment in lung adenocarcinomas: Prognostic effect of immunomodulatory molecules
Authors: K. Takamochi, M. Hosoya, K. Mogushi, T. Hayashi, M. Ito, H. Kawaji, Y. Hayashizaki, K. Suzuki
Journal: Annals of Oncology (2018)

Background: Therapies targeting immune checkpoints have recently shown promising activity in patients with lung adenocarcinoma (LAD). T-cell activation is controlled by the balance of co-stimulatory molecules and co-inhibitory molecules (immune checkpoint molecules). Methods: A comprehensive analysis was performed for immune profiles of tumor microenvironment in LADs using cap analysis of gene expression (CAGE). CAGE is a method used to quantify promoter activities across the whole genome by determining the 5' ends of capped RNA molecules with next-generation sequencing. Gene expressions of PD-L1, PD-L2, co-inhibitory molecules (CTLA-4, PD-1, TIM-3, BTLA, VISTA, and LAG-3), co-stimulatory molecules (CD28, OX40, GITR, CD317, CD27, and HVEM), and markers of immune cells (CD4, CD8, CD25, Foxp3, CD68, and CD204) were quantified using RNA extracted from frozen tumor tissue samples of 71 surgically resected LADs. The correlations between the expression of immunomodulatory molecules and the clinicopathologic features (histological grade, EGFR mutation status, smoking status, and overall survival) were analyzed. Results: LADs in this study were classified into two groups: tumors with high expression of almost all immunomodulatory targets (immunoreactive) and tumors with intermediate or low expression (non-immunoreactive). Co-stimulatory and co-inhibitory molecules were simultaneously highly expressed in immunoreactive tumors. The proportion of histologically high grade (acinar, papillary, solid or invasive mucinous) or EGFR mutation negative tumors was significantly higher than that of histologically low grade (AIS, MIA or lepidic) or EGFR mutation positive tumors in immunoreactive tumors. The prognosis of immunoreactive LADs was worse than that of non-immunoreactive LADs regardless of histological grade or EGFR mutation status (P = 0.002). High expression of CD137, TIM-3, and HVEM was an unfavorable prognostic factor. Legal entity responsible for the study: Juntendo University School of Medicine. Conclusions: LADs can be classified into immunogenic and non-immunogenic tumors. The prognosis of immunoreactive tumors was worse than that of non-immunoreactive tumors. Funding: Grant-in-Aid for Scientific Research (C), Research Grant for RIKEN Omics Science Center from MEXT, and Research Grant to RIKEN Preventive Medicine and Diagnosis Innovation Program from MEXT. Disclosure: All authors have declared no conflicts of interest.
Response to systemic therapy and survival outcomes in <i>de-novo</i> (D1) metastatic castration-sensitive prostate cancer (mCSPC) versus mCSPC with prior local therapy (D0).
Authors: Andrew W Hahn, Adam Kessel, Taylor Ryan McFarland, Umang Swami, Roberto Nussenzveig, John Esther, Divyam Goel, Deepika Sirohi, Benjamin Louis Maughan, Neeraj Agarwal
Journal: Journal of Clinical Oncology (2020)

46 Background: A real-world study (n= 436, PMID: 29707790) suggest that D1 mCSPC has worse outcomes than D0 mCSPC. The objective of our study is to validate these findings in a real-world setting, and compare clinical and tumor genomic characteristics associated with D1 vs. D0 mCSPC. Methods: In this retrospective study, eligible patients had mCSPC, received androgen deprivation therapy (ADT) +/- intensification with docetaxel or novel hormonal therapy. D1 mCSPC was diagnosed as those with distant metastasis at the first diagnosis of prostate cancer. Progression-free survival (PFS) was per PCWG2 criteria or clinical progression, and overall survival (OS) was date of death or last follow up from start of ADT for mCSPC. Baseline clinical characteristics were compared using the t test. Survival was compared using the log-rank test with Kaplan-Meier methods. Results: Of 396 eligible patients, 242 had D1 mCSPC. Men with D1 mCSPC were younger, had significantly higher median PSA, Gleason score, and alkaline phosphatase at diagnosis of mCSPC, and had significantly shorter PFS and OS with standard ADT, as well as intensified ADT, compared to men with D0 mCSPC (Table). Conclusions: These findings validate data from a previous real-world study that D1 CSPC is associated with inferior prognosis and outcomes on systemic therapy compared to D0 mCSPC. These data may aid with counseling and treatment selection, as well as patient stratification in future trials in mCSPC. Comparison of comprehensive genomic profiling data, obtained through CLIA certified labs, will be presented at the meeting.[Table: see text]
The gift of a lifetime: analysis of HIV at autopsy
Authors: Frank Maldarelli
Journal: Journal of Clinical Investigation (2020)

Currently, the incidence of HIV infection exceeds the death rate from HIV, and as a result, the prevalence of individuals living with the infection continues to increase. A critical limitation preventing the development of curative strategies is the lack of knowledge regarding mechanisms that allow HIV-infected cells to persist in individuals during combination antiviral therapy (ART). In this issue of the JCI, Chaillon and coworkers assessed HIV-infected cells from various anatomic compartments obtained through a rapid autopsy program of individuals undergoing long-term ART. This study, made possible with strong community collaboration, provides new insights on the potential locations of reservoirs of HIV-infected cells that persist during therapy.
A randomized phase II study of erdafitinib (ERDA) versus intravesical chemotherapy (IC) in patients with high-risk nonmuscle invasive bladder cancer (HR-NMIBC) with FGFR mutations or fusions, who recurred after Bacillus Calmette-Guérin (BCG) therapy.
Authors: Gary D. Steinberg, Joan Palou-Redorta, Juergen E. Gschwend, Ben Tran, Yohann Loriot, Siamak Daneshmand, Morgan Roupret, Ademi E. Santiago-Walker, Julie C. Switzky, Christopher Major, Mahadi Baig, Qi Xia, James WF Catto
Journal: Journal of Clinical Oncology (2020)

TPS603 Background: ERDA, an oral pan-FGFR inhibitor, is approved by the US FDA for metastatic urothelial carcinoma (mUC) with susceptible FGFR3 or FGFR2 gene alterations and progressed on/ or after at least 1 line of prior platinum-containing chemotherapy (PCC) including within 12 months of neoadjuvant/adjuvant PCC. 1 Around 40% of patients with bladder cancer present with HR-NMIBC. First-line BCG therapy fails in 30-40% of patients and subsequent treatment options are limited. This study is designed to evaluate recurrence-free survival (RFS) following treatment with ERDA vs IC in patients with FGFR positive HR-NMIBC who recurred after BCG therapy. Methods: This is an open-label, multicenter, randomized, phase 2, safety and efficacy study of ERDA in adults with histologically confirmed HR-NMIBC and FGFR mutations or fusions. Inclusion criteria: ECOG status ≤1, adequate bone marrow, liver, renal function, and ineligibility for or declining cystectomy, with no history of prior FGFR inhibitors. Patients will be enrolled into 1 of 3 cohorts. Cohort 1 (n=240): high-grade disease Ta/T1 lesion (papillary only) with disease recurrence after BCG therapy will be randomized to ERDA or IC (investigator choice: gemcitabine or mitomycin C); Cohort 2 (n=20): carcinoma in situ (CIS) with/without papillary disease to receive ERDA monotherapy; Cohort 3 (n=20): marker lesion study in patients with intermediate-risk papillary disease only to receive ERDA monotherapy. Dose will be maintained at 8 mg, up-titrated to 9 mg, or withheld based on phosphate levels. Primary endpoint: Cohort 1- RFS; Secondary endpoints: Cohort 1 - time to progression and disease worsening, disease-specific survival (invasive bladder cancer), overall survival, RFS rate at 6, 12, 24 months, and RFS on subsequent anticancer therapy (RFS2). An IDMC will be commissioned for Cohort 1. Exploratory endpoints: Cohort 2- complete response (CR) rate at 6 months; Cohort 3- CR in marker lesion. Patients will be enrolled at sites in ~14 countries. EudraCT: 2019-002449-39. Loriot Y et al. N Engl J Med. 2019;381:338-48. Clinical trial information: 2019-002449-39.
Rome IV Functional Gastrointestinal Disorders and Health Impairment in Subjects With Hypermobility Spectrum Disorders or Hypermobile Ehlers-Danlos Syndrome
Authors: Ching Y. Lam, Olafur S. Palsson, William E. Whitehead, Ami D. Sperber, Hans Tornblom, Magnus Simren, Imran Aziz
Journal: Clinical Gastroenterology and Hepatology (2020)
Abstract 215: Allogeneic MSCs Improve Endothelial Function in Patients with Dilated Cardiomyopathy via an SDF-1α-mediated Mechanism and the Suppression of Pathologic Cytokines
Authors: Courtney Premer, Ivonne H Schulman, Wayne Balkan, Valeria Porras, Michael A Bellio, Joshua M Hare
Journal: Circulation Research (2017)

Endothelial dysfunction is central to the pathophysiology of heart failure, including dilated cardiomyopathy (DCM). Current drug therapies are unable to halt the progression of DCM, compelling the emergence of novel stem cell therapy approaches. Mesenchymal stem cells (MSCs) are pro-angiogenic, immunomodulatory, antifibrotic, and stimulate endogenous endothelial progenitor (EPC) proliferation and function, thus having the potential to ameliorate endothelial dysfunction. We demonstrated that patients with DCM who received allogeneic MSCs had a significant improvement in endothelial function 3-months post treatment, whereas patients who received autologous MSCs had no improvement. Therefore, we hypothesized that allogeneic MSCs preferentially improve endothelial function via a mechanism involving the suppression of pathologic levels of vascular endothelial growth factor (VEGF), stromal derived factor-1 alpha (SDF-1α), and tumor necrosis factor alpha (TNFα). Accordingly, patient serum VEGF and TNFα were measured at baseline and 3 months post MSC treatment. In vitro, MSC secretion of SDF-1α and TNFα was also measured. Our results show that patients with DCM had elevated levels of VEGF (n=21, 581.2±812.2 pg/mL) and TNFα (n=15, 22±9.4 pg/mL) at baseline, and that only allogeneic MSCs were able to restore these levels toward normal (VEGF: n=10, Δ-267.1±252.1, P=0.01; TNFα: n=8, Δ-7.1±3.1 pg/mL, P=0.0005). While there was no difference in TNFα secretion by autologous or allogeneic MSCs (0.01±0.14 vs. 0.4±0.6 pg/mL), autologous MSCs secreted significantly higher levels of SDF-1α compared to allogeneic MSCs (n=12, 79.3±16.7 vs. 14.2±9.4 pg/mL, P=0.0001). In vitro secreted SDF-1α and serum VEGF and TNFα levels correlated with EPC bioactivity (ΔSDF-1α to ΔEPC-CFUs, R=-0.9, P&lt;0.0001; ΔVEGF to ΔEPC-CFUs, R=-0.7, P=0.001; ΔTNFα to ΔEPC-CFUs, R=-0.6, P=0.01). These findings reveal a novel mechanism by which allogeneic MSCs secrete physiologic levels of SDF-1α resulting in physiologic levels of VEGF signaling, reduced TNFα, increased EPC bioactivity, and improved endothelial function. These findings have important clinical and biological implications for the use of MSCs in patients with DCM.
Severe Immune-Related Hepatitis Treated With Plasma Exchange
Authors: Hiroaki Kanemura, Hidetoshi Hayashi, Satoru Hagiwara, Tomoyuki Otani, Koji Haratani, Kimio Yonesaka, Akihiko Ito, Masatoshi Kudo, Kazuhiko Nakagawa
Journal: Journal of Thoracic Oncology (2020)
Tolerability of carbapenems (meropenem and imipenem/cilastatin) in children with IgE-mediated hypersensitivity to penicillins
Authors: F. Gaeta, Marina Atanasković-Marković, R. Valluzzi, Marija Gavrović-Jankulović, Tanja Ćirković-Veličković, A. Romano
Journal: Allergy (2009)
Simultaneous kinase inhibition with ibrutinib and BCL2 inhibition with venetoclax offers a therapeutic strategy for acute myeloid leukemia
Authors: Christopher A. Eide, Stephen E. Kurtz, Andy Kaempf, Nicola Long, Anupriya Agarwal, Cristina E. Tognon, Motomi Mori, Brian J. Druker, Bill H. Chang, Alexey V. Danilov, Jeffrey W. Tyner
Journal: Leukemia (2020)
The Influence of MUC5AC SNPs on expression of MUC5AC and mucus hypersecretion genes during asthma exacerbations
Authors: Daniel Jackson, Kaitlin Flynn, Mario Rosasco, Michelle Gill, Andrew Liu, Rebecca Gruchalla, George O, Jacqueline Pongracic, Carolyn Kercsmar, Gurjit Khurana Hershey, Edward Zoratti, Stephen Teach, Meyer Kattan, Leonard Bacharier, Peter Gergen, Lisa Wheatley, Scott Presnell, Alkis Togias, William Busse, Matthew Altman
Journal: Journal of Allergy and Clinical Immunology (2020)