tbuckley/cabot-search huggingface dataset:
Treatment evolution for metastatic castration-resistant prostate cancer (mCRPC) with recent introduction of new oral agents: Retrospective analysis of real world data.
Authors: Thomas W. Flaig, Ravi C. Potluri, Yvette Ng, Mary Beth Todd, Maneesha Mehra
Journal: Journal of Clinical Oncology (2014)

e16010 Background: Docetaxel has played a major role as the standard of care for mCRPC. We used real world data to better understand how treatment patterns for mCRPC have changed since the approval of newer agents. Methods: The US claims database Truven Health Analytics MarketScan (2000-2013) was used to identify patients (pts) with an index PC diagnosis (dx [ICD-9 codes 185X or 233.4X]). Prior to the index PC dx, pts had ≥ 180-day history available without any PC dx, and had no other primary malignancy within 5 yrs. Pts with mCRPC were defined based on exposure to docetaxel, abiraterone acetate, cabazitaxel, enzalutamide, sipuleucel-T, mitoxantrone, and estramustine based on NCCN guidelines or labelled indication. First line of therapy (LOT1) and second line of therapy and beyond (LOT2+) regimen analysis was carried out among pt cohorts based on the yr of first mCRPC drug usage. Results: Among 3,397 evaluable pts exposed to mCRPC drugs from 2000 to 2013, 66% were exposed to docetaxel; 62% and 10% received docetaxel as LOT1 (or primary) and LOT2+ mCRPC therapy, respectively. Among cohorts (Table), use of docetaxel steadily decreased since 2010, with only 15% of pts using docetaxel as LOT1 in 2013. A decline in chemotherapy paralleled increased use of abiraterone acetate, enzalutamide, and sipuleucel-t, with abiraterone acetate accounting for 67% of LOT1 use in 2013. In LOT2+, abiraterone acetate and enzalutamide were the most commonly used agents over cytotoxic agents. Median treatment duration of AA in LOT1 and LOT2+ was highest among mCRPC drugs. Conclusions: These results demonstrate a shift in the use of mCRPC treatments, with greater use of newer non-cytotoxic treatments over docetaxel. These real world data aid in understanding the changing role of chemotherapy in the management of mCRPC. Cohort Median duration (days) 2000-2013 2010 2011 2012 2013 LOT1, n 3397 292 465 566 531 % Use Docetaxel 62 91 61 44 15 100 Estramustine 5 4 1.5 0.5 0.4 70 Cabazitaxel 0.2 0 0.6 0.4 0.4 49 Abiraterone acetate 21 1 28 38 67 122 Enzalutamide 2 0 0 2 9 87 Sipuleucel-T 5 0 8 15 8 28 LOT2+, n 2,039 246 446 408 110 % Use Docetaxel 10 4 8 8 18 70 Abiraterone acetate 23 30 37 33 33 118 Enzalutamide 12 8 15 28 28 96
Evaluation of the Revised International Staging System in 400 Patients with Symptomatic Myeloma in a Japanese Clinical Setting
Authors: Yoshiaki Abe, Yamashita Takeshi, Ueda Mikio, Kazutaka Sunami, Kentaro Narita, Hiroki Kobayashi, Hiroyuki Takamatsu, Akihiro Kitadate, Masami Takeuchi, Kosei Matsue
Journal: Blood (2018)
Ischemia-reperfusion injury in renal transplantation: 3 key signaling pathways in tubular epithelial cells
Authors: Stephanie F. Smith, Sarah A. Hosgood, Michael L. Nicholson
Journal: Kidney International (2018)

Renal ischemia-reperfusion injury (IRI) is a significant clinical challenge faced by clinicians perioperatively in kidney transplantation. Recent work has demonstrated the key importance of transmembrane receptors in the injured tubular epithelial cell, most notably Toll-like receptors, activated by exogenous and endogenous ligands in response to external and internal stresses. Through sequential protein-protein interactions, the signal is relayed deep into the core physiological machinery of the cell, having numerous effects from upregulation of pro-inflammatory gene products through to modulating mitochondrial respiration. Inter-pathway cross talk facilitates a co-ordinated response at an individual cellular level, as well as modulating the surrounding tissue's microenvironment through close interactions with the endothelium and circulating leukocytes. Defining the underlying cellular cascades involved in IRI will assist the identification of novel interventional targets to attenuate IRI with the potential to improve transplantation outcomes. We present a focused review of 3 key cellular signalling pathways in the injured tubular epithelial cell that have been the focus of much research over the past 2 decades: toll-like receptors, sphingosine-1-phosphate receptors and hypoxia inducible factors. We provide a unique perspective on the potential clinical translations of this recent work in the transplant setting. This is particularly timely with the recent completion of phase I and ongoing phase 2 clinical trials of inhibitors targeting specific components of these signaling cascades.
Profiling of 1,350 neuroendocrine tumors for identification of multiple potential drug targets.
Authors: Igor A. Astsaturov, Steven J. Cohen, Paul F. Engstrom, Sherri Z. Millis
Journal: Journal of Clinical Oncology (2014)

4113 Background: Identification of new drug targets may extend treatment options for neuroendocrine tumors (NET) regardless of histologic classification or primary organ site. Methods: 1,350 cases of infradiaphragmatic neuroendocrine tumors (all grades and sites) were identified among >60,000 cases profiled in a CLIA-certified laboratory. Biomarker profiling utilized multiple platforms: gene sequencing (next generation sequencing [NGS], Sanger or pyrosequencing), gene copy number (in-situhybridization), and protein expression (immunohistochemistry [IHC]). The results are shown relative to the total number of tests performed. Results: Overall, drug therapy-relevant alterations were identified in 1255 of 1350 (93%) of cases. Low or absent (0 or 1+ by IHC) expression of MGMT a biomarker of sensitivity to alkylating agents, was found in 149/243 pancreatic cases (61%), and in 488/1015 (48%) of non-pancreatic NET. Low or absent (0 or 1+ by IHC) expression of RRM1, a biomarker of gemcitabine sensitivity, was found in 927/1193 of NET (78%) and low or absent thymidine synthase, TS, a biomarker of fluoropyrimidines sensitivity, was shown for 950/1187 (80%) of NET by IHC. Sequencing of tumors showed oncogenic mutations in BRAF (6/446 (V600E in 4, and G596R in 2), CTNNB1 (3/223), KIT (4/357), EGFR (1/245), FGFR2 (2/224), GNAS (1/224), HRAS (2/192), PIK3CA (10/418), RB1 (4/222) VHL (2/203), KRAS (23/472), NRAS (2/349), and APC (14/224) and amplifications of EGFR (46/688) and MET (4/306. Therapies guided by mechanism-based biomarkers produced durable responses in documented cases: partial response (PR) >1 year to imatinib in a patient with KIT-mutant metastatic NET, and in cases of MGMTlow/TSlowtreated with streptozocin or temozolomide plus fluoropyrimidine chemotherapy, thus supporting the clinical relevance of target profiling in NET. Conclusions: Comprehensive multiplatform profiling of a large series (n=1350) of NET, despite low frequency of individual biomarkers, identified clinically relevant targets in >90% of patients.Given the increasing utilization of chemotherapy for NET, our results provide the basis for future clinical trials to assess the efficacy of biomarker-based therapy for NET.
Survival results of hepatectomy followed by adjuvant chemotherapy with three months of capecitabine plus oxaliplatin for colorectal cancer liver metastases: A multicenter phase II study.
Authors: Hironaga Satake, Hiroki Hashida, Hiroaki Tanioka, Yasuhiro Miyake, Shinichi Yoshioka, Takanori Watanabe, Masato Matsuura, Takahisa Kyogoku, Michio Inukai, Takeshi Kotake, Yoshihiro Okita, Yukimasa Hatachi, Hisateru Yasui, Masahito Kotaka, Takeshi Kato, Satoshi Kaihara, Akihito Tsuji
Journal: Journal of Clinical Oncology (2018)

866 Background: Hepatic resection is one of the treatment strategies for resectable colorectal cancer liver metastases (CLM). The role of neoadjuvant and adjuvant chemotherapy in the management of initially resectable CLM is still unclear. Adjuvant chemotherapy consisting of capecitabine plus oxaliplatin (CapeOx) appears to be equivalent to FOLFOX in patients with stage III colon cancer. Furthermore, the IDEA collaboration reported that adjuvant chemotherapy with the three months of CapeOx after curative resection for stage III colon cancer has equivalent efficacy to adjuvant chemotherapy for 6 months. We conducted a multi-institutional, single-arm, phase II trial to confirm the feasibility of the three months of adjuvant CapeOx for post curative resection of CLM. Methods: Patients received one course of capecitabine followed by four courses of CapeOx for a total five courses (15 weeks) as adjuvant chemotherapy after curative resection of CLM. Oral capecitabine was given with 1,000 mg/m 2 twice daily for 2 weeks in a 3-week cycle, and CapeOx consisted of oral capecitabine plus oxaliplatin 130 mg/m 2 on day 1 in a 3-week cycle. The primary endpoint was completion rate of adjuvant chemotherapy. We set a threshold completion rate of protocol treatment of 45% and an expected completion rate of 70%. Given a one-sided α of 0.1 and statistical power of 80%, a minimum of 25 patients was required. Results: From May 2013 to November 2015, Twenty-eight patients were enrolled from six institutions: median age 69.5y, 54% male, 78.5% left-sided primary. Of the patients, 15 were synchronous metastases and 13 were metachronous. The locations of the metastases were unilobar in 20 patients and bilobar in 8. The mean number of lesions resected was two (range, 1 to 4). Among the 28 patients, 20 (71.4%: 95% CI, 53.6 to 89.3%) completed the protocol treatment. The most common grade 3/4 toxicities were neutropenia (29%). No treatment related death was observed. With a median follow-up period of 36 months (range 15-53months), 3 year-relapse free survival was 75.3%. Conclusions: The three months of adjuvant CapeOx is tolerable for post curative resection of CLM. Clinical trial information: 000011164.
A next-generation statistical tool for designing phase I trials.
Authors: Yuan Ji, Shengjie Yang
Journal: Journal of Clinical Oncology (2014)

e14022 Background: The three main-stream statistical methods for designing dose-finding phase I trials are the 3+3 (Storer, Biometrics 1989), CRM (O’Quigley et al., Biometrics 1990), and mTPI designs (Ji and Wang, Journal of Clinical Oncology 2013). Currently, no consensus is reached on the performance of these three methods due to lack of tools for comparison and implementation. The 3+3 design is the most popular method in practice due to its simplicity, although statisticians have been advocating against it for over two decades. Methods: We propose a web-based statistical tool, Next-GenDF, for designing phase I dose-finding trials. The tool incorporates all three main-stream methods and focus on the implementation of mTPI in practice. The tool is available at http://health.bsd.uchicago.edu/yji/dosefinding.htm Results: Next-GenDF is fully web-based that does not require any software download or installation, and allows users to design dose-finding trials on any internet web browser, such as Internet Exporere or Safari. Nexg-GENDF works on almost any electronic devices including laptops, tablets, and even smart phones, thus allowing clinicians to generate, discuss, and review designs anywhere and at anytime. More importantly, Next-GenDF provides real-time and head-to-head comparison of the three popular designs, with intuitive graphical and tabular display of comparison results. Conclusions: We believe that Next-GenDF will change the way phase I dose-finding trials are designed and conducted in practice. Specifically, we expect that mTPI will be the optimal design among the three in most cases, due to its superior performance over 3+3 (Ji and Wang, 2013) and more intuitive and less burdensome implementation than CRM (Ji et al. 2010). However, there could be cases where other two designs are more desirable, and Next-GenDF will greatly facilitate the evaluations in these cases.
Retrospective analysis of 55 patients with gallbladder carcinoma.
Authors: Sener Cihan, Nurgul Yasar, Nalan Babacan, Hatice Odabas, Serkan Keskin, Cumhur Demir
Journal: Journal of Clinical Oncology (2014)

e15135 Background: Gallbladder cancer (GBC) is the most common malignant tumour of the biliary system. Due to the rarity of GBC, there exist few studies examining factors such as, histopathological features, stage at diagnosis, or treatments. The aim of this study was to identify prognostic factors in long-term survival. In this study, we retrospectively evaluated fifty-five patients with histologically proven gallbladder cancer. Methods: Between 2005 and 2013, medical records of all patients were reviewed. Fifty-five patients with gallbladder cancer were identified. There were 38 females (69%) and 17 (31%) males. The mean age at diagnosis was 63 (range 36–90) years. The diagnosis was achieved either post-operatively (n=43) or following the histological analysis of the gallbladder (n = 12), following gallbladder or liver biopsy. Presenting symptoms included upper abdominal pain, weight loss, nausea, vomiting, fever, painless jaundice, upper abdominal mass. Survival was calculated using Kaplan Meier method. Results: Histological examination revealed 53 adenocarcinomas (96.4%), 1 squamous cell carcinomas (1.8%) and one adenoacanthoma (1.8%). At presentation, 21 (38.2%) gallbladder cancers were stage IV, 15 (27.3%) were stage III, 12 (21.8%) were stage II and 7 (12.7%) were stage I. Three-year survival rates for stage I, II, III and IV were 83%, 46%, 26%, and 4%, respectively. These differences were significant (p<0.0001). Patients with metastases showed poorer survival rates. The survival was significantly better in patients with metastatic disease who receive palliative chemotherapy (p<0.0001). In contrast adjuvan chemotherapy had no significant effect on survival (p=0.065). Survival of patients diagnosed with surgical was beter than those diagnosed with biopsy (p<0.0001). Sex, age and calculous cholecystitis had no significant effect. Conclusions: Staging is the strongest prognostic factor for GBC. The majority of patients presented with advanced stage disease (stage IV) which carries a dismal prognosis. Patients who received chemotherapy with stage IV disease had better survival than those who did not. In contrast adjuvan chemotherapy had no significant effect on survival. This is probably a reflection of patient selection.
Association of MHC Class I Chain-Related Gene a (MICA) Polymorphisms with Allogeneic Hematopoietic Cell Transplantation Outcomes in Acute Myeloid Leukemia
Authors: Sagar S. Patel, Betty K. Hamilton, Lisa Rybicki, Dawn Thomas, Arden Emrick, Aziz Nazha, Sudipto Mukherjee, Anjali S. Advani, Hetty E. Carraway, Brad Pohlman, Brian J. Bolwell, Robert M. Dean, Aaron T. Gerds, Rabi Hanna, Matt Kalaycio, Aiwen Zhang, Mikkael A. Sekeres, Jaroslaw P. Maciejewski, Navneet S. Majhail, Medhat Askar, Ronald Sobecks
Journal: Blood (2018)
Radiation-induced astrocyte senescence is rescued by Δ133p53
Authors: Casmir Turnquist, Jessica A Beck, Izumi Horikawa, Ifeyinwa E Obiorah, Natalia Von Muhlinen, Borivoj Vojtesek, David P Lane, Christopher Grunseich, Joeffrey J Chahine, Heather M Ames, Dee Dee Smart, Brent T Harris, Curtis C Harris
Journal: Neuro-Oncology (2019)

Cellular senescence and the senescence-associated secretory phenotype (SASP) may contribute to the development of radiation therapy–associated side effects in the lung and blood vessels by promoting chronic inflammation. In the brain, inflammation contributes to the development of neurologic disease, including Alzheimer's disease. In this study, we investigated the roles of cellular senescence and Δ133p53, an inhibitory isoform of p53, in radiation-induced brain injury. Senescent cell types in irradiated human brain were identified with immunohistochemical labeling of senescence-associated proteins p16INK4A and heterochromatin protein Hp1γ in 13 patient cases, including 7 irradiated samples. To investigate the impact of radiation on astrocytes specifically, primary human astrocytes were irradiated and examined for expression of Δ133p53 and induction of SASP. Lentiviral expression of ∆133p53 was performed to investigate its role in regulating radiation-induced cellular senescence and astrocyte-mediated neuroinflammation. Astrocytes expressing p16INK4A and Hp1γ were identified in all irradiated tissues, were increased in number in irradiated compared with untreated cancer patient tissues, and had higher labeling intensity in irradiated tissues compared with age-matched controls. Human astrocytes irradiated in vitro also experience induction of cellular senescence, have diminished Δ133p53, and adopt a neurotoxic phenotype as demonstrated by increased senescence-associated beta-galactosidase activity, p16INK4A, and interleukin (IL)-6. In human astrocytes, Δ133p53 inhibits radiation-induced senescence, promotes DNA double-strand break repair, and prevents astrocyte-mediated neuroinflammation and neurotoxicity. Restoring expression of the endogenous p53 isoform, ∆133p53, protects astrocytes from radiation-induced senescence, promotes DNA repair, and inhibits astrocyte-mediated neuroinflammation.
Targetable signaling pathway mutations and progression of <i>IDH</i>-mutant glioma.
Authors: Hiroaki Wakimoto, Shota Tanaka, William T. Curry, Franziska Loebel, Dan Zhao, Kensuke Tateishi, Juxiang Chen, Lindsay K. Klofas, Nina Lelic, James C. Kim, Dora Dias-Santagata, Leif W. Ellisen, Darrell R. Borger, Sarah-Maria Fendt, Matthew Vander Heiden, Tracy Batchelor, A. John Iafrate, Daniel P. Cahill, Andrew S. Chi
Journal: Journal of Clinical Oncology (2014)

2061 Background: Isocitrate dehydrogenase (IDH) gene mutations occur in low-grade and high-grade gliomas. We sought to identify the genetic basis of malignant phenotype heterogeneity in IDH-mutant gliomas. Methods: We prospectively implanted tumor specimens from 20 consecutive IDH1-mutant glioma resections into mouse brains and genotyped all resection specimens using a CLIA-certified molecular panel. Gliomas with cancer driver mutations were tested for sensitivity to targeted inhibitors in vitro. Associations between genomic alterations and outcomes were analyzed in patients. Results: By 10 months, 8 of 20 IDH1-mutant gliomas developed intracerebral xenografts. All xenografts maintained mutant IDH1 and high levels of 2-hydroxyglutarate on serial transplantation. All xenograft-producing gliomas harbored “lineage-defining” mutations in CIC (oligodendroglioma) or TP53 (astrocytoma), and 6 of 8 additionally had activating mutations in PIK3CA or amplification of PDGFRA, MET, or N-MYC. Only IDH1 and CIC/TP53 mutations were detected in non-xenograft-forming gliomas (P = 0.0007). Targeted inhibition of the additional alterations decreased proliferation in vitro. Moreover, we detected alterations in known cancer driver genes in 13.4% of IDH-mutant glioma patients, including PIK3CA, KRAS, AKT or PTEN mutation or PDGFRA, MET or N-MYC amplification. IDH/CIC mutant tumors were associated with PIK3CA/KRAS mutations while IDH/TP53 tumors correlated with PDGFRA/MET amplification. Presence of driver alterations at progression was associated with shorter subsequent progression-free survival (median 9.0 vs. 36.1 months, P=0.0011). Conclusions: A subset of IDH-mutant gliomas with mutations in driver oncogenes has a more malignant phenotype in patients. Identification of these alterations may provide an opportunity for use of targeted therapies in these patients.
Myeloid-Specific Deletion of Epsins 1 and 2 Reduces Atherosclerosis by Preventing LRP-1 Downregulation
Authors: Megan L. Brophy, Yunzhou Dong, Huan Tao, Patricia G. Yancey, Kai Song, Kun Zhang, Aiyun Wen, Hao Wu, Yang Lee, Marina V. Malovichko, Srinivas D. Sithu, Scott Wong, Lili Yu, Olivier Kocher, Joyce Bischoff, Sanjay Srivastava, MacRae F. Linton, Klaus Ley, Hong Chen
Journal: Circulation Research (2018)

Atherosclerosis is, in part, caused by immune and inflammatory cell infiltration into the vascular wall, leading to enhanced inflammation and lipid accumulation in the aortic endothelium. Understanding the molecular mechanisms underlying this disease is critical for the development of new therapies. Our recent studies demonstrate that epsins, a family of ubiquitin-binding endocytic adaptors, are critical regulators of atherogenicity. Given the fundamental contribution lesion macrophages make to fuel atherosclerosis, whether and how myeloid-specific epsins promote atherogenesis is an open and significant question.
Distinct biomarkers as prognostic in chronic lymphocytic leukemia patients treated with alvocidib and lenalidomide as single agents or combination regimens thereof.
Authors: William E. Pierceall, Kami J. Maddocks, Ellen N Wei, Christine Chen, Steven Warner, Camille Doykan, Ryan Lena, Noel Blake, Michael H. Cardone, Leslie A. Andritsos, Michael R. Grever, John C. Byrd, Suzanne Trudel, Amy J. Johnson
Journal: Journal of Clinical Oncology (2014)

7087 Background: Chronic lymphocytic leukemia (CLL) patient outcomes may benefit from targeting therapies alone or in combination to individuals with favorable molecular profiles. Whether such personalized medicine approaches are best tailored to patients treated with single agent therapies or regimens using those agents in combination is an underexplored question. Here, we assessed mitochondrial apoptosis signaling in CLL patients treated with lenalidomide, alvocidib, or lenalidomide + alvocidib. Methods: Pretreatment blood mononuclear cell (PBMC) specimens were assessed measuring mitochondrial outer membrane permeabilization following incubation with BH3 peptides as a surrogate for Bcl-2 family proteins function. The study comprised 106 patients: 62 alvocidib-treated patients, 20 lenalidomide-treated patients, and 24 patients treated with combinational lenalidomide + alvocidib. Results: In alvocidib-treated patients assessment of biomarker and clinical response association, Bim AUC=.73 (p=.0004) and Hrk (indicating Bcl-xL-dependence) AUC=.73 (p=.0002). Hrk benefitted from trisomy12 inclusion (AUC=.83; p<.0001). In single agent lenalidomide-treated patients, no biomarkers were associated with response, however, priming of Mcl-1, determined by response to the Noxa peptide, was associated with progression-free survival (p=.032). In lenalidomide + alvocidib-treated patients, the prognostic significance was different from either of the two agents independently as Puma (pan-antiapoptoic modulator of Mcl-1, Bcl-xL, and Bcl-2) was associated with clinical response (AUC=.73; P=.027) that improved with addition of bulky adenopathy (AUC=0.84 p=.0063). Conclusions: Alvocidib (cyclin-dependent kinase inhibition) and lenalidomide (immunomodulation) have distinct mechanisms of action and offer separate molecular profiles associated with clinical outcomes. Although the importance of Bcl-2 family regulated apoptosis is consistent, biomarker associated outcomes in combination regimen patients differ from those associated with single agent therapies.