tbuckley/cabot-search huggingface dataset:
The Role of Lineage Plasticity in Prostate Cancer Therapy Resistance
Authors: Himisha Beltran, Andrew Hruszkewycz, Howard I. Scher, Jeffrey Hildesheim, Jennifer Isaacs, Evan Y. Yu, Kathleen Kelly, Daniel Lin, Adam Dicker, Julia Arnold, Toby Hecht, Max Wicha, Rosalie Sears, David Rowley, Richard White, James L. Gulley, John Lee, Maria Diaz Meco, Eric J. Small, Michael Shen, Karen Knudsen, David W. Goodrich, Tamara Lotan, Amina Zoubeidi, Charles L. Sawyers, Charles M. Rudin, Massimo Loda, Timothy Thompson, Mark A. Rubin, Abdul Tawab-Amiri, William Dahut, Peter S. Nelson
Journal: Clinical Cancer Research (2019)

Abstract Lineage plasticity has emerged as an important mechanism of treatment resistance in prostate cancer. Treatment-refractory prostate cancers are increasingly associated with loss of luminal prostate markers, and in many cases induction of developmental programs, stem cell–like phenotypes, and neuroendocrine/neuronal features. Clinically, lineage plasticity may manifest as low PSA progression, resistance to androgen receptor (AR) pathway inhibitors, and sometimes small cell/neuroendocrine pathologic features observed on metastatic biopsy. This mechanism is not restricted to prostate cancer as other malignancies also demonstrate lineage plasticity during resistance to targeted therapies. At present, there is no established therapeutic approach for patients with advanced prostate cancer developing lineage plasticity or small cell neuroendocrine prostate cancer (NEPC) due to knowledge gaps in the underlying biology. Few clinical trials address questions in this space, and the outlook for patients remains poor. To move forward, urgently needed are: (i) a fundamental understanding of how lineage plasticity occurs and how it can best be defined; (ii) the temporal contribution and cooperation of emerging drivers; (iii) preclinical models that recapitulate biology of the disease and the recognized phenotypes; (iv) identification of therapeutic targets; and (v) novel trial designs dedicated to the entity as it is defined. This Perspective represents a consensus arising from the NCI Workshop on Lineage Plasticity and Androgen Receptor-Independent Prostate Cancer. We focus on the critical questions underlying lineage plasticity and AR-independent prostate cancer, outline knowledge and resource gaps, and identify strategies to facilitate future collaborative clinical translational and basic studies in this space.
Energy‐Free, Singlet Oxygen‐Based Chemodynamic Therapy for Selective Tumor Treatment without Dark Toxicity
Authors: Yanrui Chen, Jian Deng, Fang Liu, Peipei Dai, Yang An, Zheng Wang, Yanjun Zhao
Journal: Advanced Healthcare Materials (2019)

Abstract Traditional singlet oxygen‐based antitumor therapies have been burdened with the necessity of external energy (e.g., light and ultrasound) and harmful dark toxicity. Ascorbate at the pharmacological concentration could accumulate hydrogen peroxide only in the tumor site. It is postulated that the concurrent delivery of ascorbate and nanoparticulate hypochlorous ion (ClO − ) could produce singlet oxygen at the tumor site as an energy‐free, tumor‐specific therapy. The ClO − is loaded in a hybrid core–shell nanocarrier consisting of a zeolitic imidazolate framework and amphiphilic poloxamer 188. Intracellular singlet oxygen production is verified in 4T1 cells by the cooperation between hybrid nanocarriers and ascorbate, which induces significant apoptotic cell death. Upon intravenous nanocarriers delivery plus intraperitoneal ascorbate administration to xenograft mice, the in vivo antitumor efficacy of this cooperative nanomedicine is demonstrated without noticeable side‐effects. This work demonstrates a proof‐of‐concept of singlet oxygen‐based chemodynamic therapy for selective tumor eradication, which produces a novel trigger‐free, singlet oxygen‐based cancer therapy without the side effects of traditional photodynamic and sonodynamic therapy.
SYK expression in metastatic retinoblastoma.
Authors: Rachel Christine Brennan, Matthew W. Wilson, Michael A. Dyer, Armita Bahrami
Journal: Journal of Clinical Oncology (2012)

e13544 Background: Retinoblastoma is an aggressive childhood cancer of the retina. While more than 90% of patients are cured when tumor is confined to the globe, for up to half of children in developing countries with advanced tumor at diagnosis, retinoblastoma remains a lethal disease. Recent whole-genome sequencing demonstrated that the retinoblastoma genome is relatively stable (Zhang et al). However, RB1 loss is associated with epigenetic deregulation of several cancer pathways. Significantly, the proto-oncogene SYK, spleen tyrosine kinase, which has no role in normal eye development, is upregulated in retinoblastoma and required for tumor cell survival (Zhang et al). Immunohistochemical (IHC) studies showed that SYK is ubiquitously overexpressed in intraocular retinoblastoma, whereas it is absent in normal retina. The purpose of this study is to investigate whether SYK overexpression persists in metastatic retinoblastoma. Methods: From 1962-2011, seven metastatic retinoblastoma tumor specimens (excluding bone marrow or cerebrospinal fluid) from six retinoblastoma patients were retrieved from the Pathology Archives in our institution. Morphology and supportive IHC, to include immunopositivity for synaptophysin and immunonegativity for cytokeratins, confirmed the diagnosis of metastatic retinoblastoma in each case. IHC for SYK was performed according to the previously published technique (Zhang et al). Results: Tumors occurred in two male and four female patients with seven metastatic retinoblastoma samples in scalp, lymph node, neck, ovary and bone (femur). By IHC, all seven metastatic retinoblastoma tumor samples were positive for SYK. Conclusions: This is the first report of SYK overexpression in metastatic retinoblastoma. Drugs targeting SYK are already in clinical trials for adults with leukemia and rheumatoid arthritis, and preclinical efficacy in vitro and in vivo has been established. Moving from bench to bedside with this epigenetically targeted agent warrants further investigation.
Multicenter phase II study of chemo-immunotherapy in the treatment of metastatic breast cancer (MBC)
Authors: F. Recchia, G. Saggio, A. Di Blasio, G. Amiconi, G. Candeloro, S. Necozione, S. Rea
Journal: Journal of Clinical Oncology (2007)

13501 Background: Several maintenance chemotherapy (CT) strategies have failed to improve the outcome of MBC. With the aim of enhancing the immune function that could eradicate minimal residual disease, we have previously shown that low dose inteterleukin-2 (IL-2) and 13-cis- retinoic acid (RA) restored the immune function of advanced cancer patients that had a clinical benefit (CB) from CT (Clin Cancer Res, 2001). In this study we report on 100 consecutive patients with MBC treated with sequential CT and immunotherapy. Methods: Patients with MBC were eligible if they had no evidence of progression after 6–8 courses of an anthracycline-paclitaxel induction CT. Treatment consisted of IL-2, 1.8 X 10 6 IU and oral RA, 0.5 mg/Kg for 5 days/week for 2 cycles of 3 weeks, with a 1- week rest, with intermittent schedules, until progression. Hormonal therapy was given to estrogen receptor (ER) + patients. In order to increase ER expression, beta interferon (1 X 10 6 IU) was added, subcutaneously, twice a week, to 10 patients with low ER content. Primary endpoint was progression-free survival (PFS); secondary endpoints were toxicity, overall survival (OS) and the evaluation of immunological parameters. Results: From 9/1996 to 9/2001, 100 consecutive patients (median age of 59 years), exhibiting a CB from CT were entered into the study. Grade 2 cutaneous toxicity and fever occurred in 19% and 16% of patients, respectively, while grade 2 autoimmune reaction was observed in 10% of patients. After a median follow-up of 49 months, overall median PFS and OS were 37.1 months and 57.5 months, respectively. Patients with ER+ tumors had a similar response rate to that of patients with ER- tumors but had significantly longer PFS (medians of 44.7 and 32.7 months, respectively) and OS (medians of 64.5 and 51.4 months, respectively). With respect to baseline values, a statistically significant decrease of vascular endothelial growth factor (VEGF) and an improvement in lymphocyte, natural killer cell count and CD4 + /CD8 + ratio were observed. Conclusions: IL-2 and RA treatment of women with MBC who achieve a CB after 6–8 courses of anthracycline-paclitaxel based CT, is well tolerated, decreases VEGF, improves the immunological parameters, and seems to delay disease recurrence. A randomized trial is warranted. No significant financial relationships to disclose.
FDG-PET predicted unfavorable tumor histology in living donor liver transplant recipients; a retrospective cohort study
Authors: Louis Leong-Liung Ling, Chien-Chin Hsu, Chee-Chien Yong, Ahmed M. Elsarawy, Yi-Chia Chan, Chih-Chi Wang, Wei-Feng Li, Ting-Lung Lin, Fang-Ying Kuo, Yu-Fan Cheng, Li-Man Lin, Chao-Long Chen, Chih-Che Lin
Journal: International Journal of Surgery (2019)
Changes in Hepatic Venous Pressure Gradient Predict Hepatic Decompensation in Patients Who Achieved Sustained Virologic Response to Interferon‐Free Therapy
Authors: Mattias Mandorfer, Karin Kozbial, Philipp Schwabl, David Chromy, Georg Semmler, Albert F. Stättermayer, Matthias Pinter, Virginia Hernández‐Gea, Monika Fritzer‐Szekeres, Petra Steindl‐Munda, Michael Trauner, Markus Peck‐Radosavljevic, Juan C. García‐Pagán, Peter Ferenci, Thomas Reiberger
Journal: Hepatology (2019)

Sustained virologic response (SVR) to interferon (IFN)-free therapies ameliorates portal hypertension (PH); however, it remains unclear whether a decrease in hepatic venous pressure gradient (HVPG) after cure of hepatitis C translates into a clinical benefit. We assessed the impact of pretreatment HVPG, changes in HVPG, and posttreatment HVPG on the development of hepatic decompensation in patients with PH who achieved SVR to IFN-free therapy. Moreover, we evaluated transient elastography (TE) and von Willebrand factor to platelet count ratio (VITRO) as noninvasive methods for monitoring the evolution of PH.
HUPAN: a pan-genome analysis pipeline for human genomes
Authors: Zhongqu Duan, Yuyang Qiao, Jinyuan Lu, Huimin Lu, Wenmin Zhang, Fazhe Yan, Chen Sun, Zhiqiang Hu, Zhen Zhang, Guichao Li, Hongzhuan Chen, Zhen Xiang, Zhenggang Zhu, Hongyu Zhao, Yingyan Yu, Chaochun Wei
Journal: Genome biology (2019)

The human reference genome is still incomplete, especially for those population-specific or individual-specific regions, which may have important functions. Here, we developed a HUman Pan-genome ANalysis (HUPAN) system to build the human pan-genome. We applied it to 185 deep sequencing and 90 assembled Han Chinese genomes and detected 29.5 Mb novel genomic sequences and at least 188 novel protein-coding genes missing in the human reference genome (GRCh38). It can be an important resource for the human genome-related biomedical studies, such as cancer genome analysis. HUPAN is freely available at http://cgm.sjtu.edu.cn/hupan/ and https://github.com/SJTU-CGM/HUPAN .
Response to trans-arterial chemoembolization prior to orthotopic liver transplantation or hepatic resection in patients with hepatocellular carcinoma
Authors: K. Almhanna, A. Golshayan, M. Sands, A. Levitin, R. Kim, R. Pelley, S. Kalmadi
Journal: Journal of Clinical Oncology (2007)

15114 Background: Trans-arterial chemoembolization (TACE) is often used as pre-operative therapy for patients with hepatocellular carcinoma (HCC) prior to orthotopic liver transplantation (OLT) or hepatic resection (HR). However, the benefit of response to TACE on overall survival (OS) and progression free survival (PFS) remains unclear. Methods: Complete data was available for 24 patients with HCC who underwent TACE prior to either OLT or HR from 1998–2006. Known prognostic factors including tumor size, histology, number of nodules, Child-Pugh class, Okuda stage, MELD score, CLIP score were recorded. Clinical features before and after TACE were identified and tested by univariate analysis. Results: The mean patient age was age 51 years (range 31–65). Underlying diagnoses included: HBV (17%), HCV (54%), alcohol abuse (63%), cryptogenic (8%), nonalcoholic steotohepatitis (4%). The mean maximum tumor diameter was 6.2 cm (range 1.6–16.1 cm), with 13 tumors (54%) measuring &gt;5 cm. The median number of lesions were 2 (range 1 - 7). The Milan criteria was met in 15 patients (63%). Eighteen subjects underwent OLT, while 6 had HR. Median PFS was 35 months (m) (95% C.I. 17–58 m). One- and three-year OS were 95.8% and 73%, respectively. TACE was performed within a mean time of 2.5 months from diagnosis (range 0.5–9 m). Post-TACE, eleven subjects demonstrated a biologic response, defined as decrease in serum alfa-fetoprotein (AFP) by &gt;50%, or reduction in AFP level to &lt;10 ng/mL. However, biologic response did not predict for improved PFS (p =0.41). Additionally, nine patients had a radiographic response to TACE as measured by RECIST criteria, but this also did not predict for improved PFS (p = 0.79). Only tumor size &gt;5 cm (p = 0.04) and CLIP score (p = 0.01) were found to be independent predictors of improved PFS. Conclusions: Neither radiographic nor biologic responses to TACE appear to serve as selection criteria for OLT or HR. Those patients who fail to demonstrate response to TACE should not necessarily be denied surgical therapy. Larger, prospective trials are needed to better evaluate which patients will benefit most from TACE prior to OLT or HR. No significant financial relationships to disclose.
Abstract 12697: Predictors of In-Hospital Mortality for Acute Myocardial Infarction Requiring Mechanical Support Devices
Authors: Takashi Morita, Masatake Fukunami, Takahisa Yamada, Koichi Nakao, Yukio Ozaki, Kazuo Kimura, Junya Ako, Teruo Noguchi, Satoshi Yasuda, Satoru Suwa, Kazuteru Fujimoto, Yasuharu Nakama, Wataru Shimizu, Yoshihiko Saito, Atsushi Hirohata, Yasuhiro Morita, Teruo Inoue, Atsunori Okamura, Toshiaki Mano, Kunihiro Nishimura, Yoshihiro Miyamoto, Hisao Ogawa, Masaharu Ishihara
Journal: Circulation (2018)

Introduction: Mechanical support (MS) devices such as intra-aortic balloon pumping (IABP) and veno-arterial extra corporeal membrane oxygenation (VA-ECMO) are essential for AMI patients complicated...
Impact of multidisciplinary cancer care on the postoperative mortality and survival of patients with esophageal and esophagogastric junction cancer.
Authors: Maica Galán, Leandre Farran, Luisa Aliste, Gloria Hormigo, Mariona Calvo, Humberto Aranda, Ana Maria Boladeras, Josep Maria Botargues, Eugenia de Lama, Maria Jose Paúles, Javier Robles, Olbia Serra, Núria Virgili, Josep Maria Borràs
Journal: Journal of Clinical Oncology (2013)

e15111 Background: Modern management of Oesophageal and oesophagogastric junction (OGJ) cancers requires a multidisciplinary approach, which was implemented at our health centre in 2005. This study aimed to assess the impact of this change on clinical outcomes. Methods: A retrospective cohort study was conducted, covering all patients treated for oesophageal and OGJ cancer at the cancer centre established by the Bellvitge University Hospital and Catalonian Institute of Oncology, over two time periods, i.e., 2000-2004 and 2005-2008. Descriptive and multivariate analyses were performed using survival at 1 and 3 years as dependent variables. Results: Between 1 January 2000 and 31 December 2008, 586 patients were included. Number of patients with unknown stage at diagnosis was significantly reduced. Neoadjuvant strategies at the oesophageal location clearly increased in the recent period. A multidisciplinary approach resulted in a significant reduction in surgical mortality (11.8% vs. 2%) in the period 2005-2008. Analysis restricted to patients undergoing surgery with curative intent indicated a significant increase in 1- and 3-year survival in the latter period (68.4% vs. 89.8% and 38.2% vs. 57.1% respectively). Multivariate analysis showed that variables associated with improved survival were: age; tumour stage; radical intent of treatment (surgery and radical combined chemoradiotherapy); and therapeutic strategy. Conclusions: Better selection of patients for therapy together with improved staging resulted in a significant improvement in 1- and 3-year survival in cases undergoing surgery with curative intent. These changes would support the adoption of a multidisciplinary approach to clinical decision-making in cases of oesophageal and OGJ cancer.
Progressive multifocal leucoencephalopathy (PML): A novel complication of brentuximab vedotin from the Southern Network on Adverse Reactions (SONAR) project.
Authors: Charles L. Bennett, Kenneth Robert Carson, Scott D. Newsome, Ellen J. Kim, LeAnn B. Norris, Pankaj Jalan, Dennis W. Raisch, Gene Major
Journal: Journal of Clinical Oncology (2013)

e22181 Background: BV is FDA approved for angio-immunoblastic large cell lymphoma and refractory Hodgkin’s lymphoma (HL). BV-linked PML cases reviewed. Methods: Case 1—Age:47/HIV negative male relapsed stage IIIB mixed cellularity undergoing treatment with BV. Prior therapies: 8 cycles of ABVD, ESHAP, BEAM, autologous stem cell transplant, involved field radiotherapy to the neck and mediastinum in 2008 and GVD ending in 2009. A 2011 relapse treated with BV q 3 weeks. Patient complained of impaired coordination and left greater than right dysdiadokinesis after 2 BV doses. Third BV cycle administered. Patient formed dysarthria, left-sided hemianopsia, hemiparesis. CSF analysis for JC virus DNA by PCR positive. Patient died shortly after. Case 2—Age:38/female revealed cutaneous anaplastic T-cell lymphoma refractory started on BV in mid-2011 led to loss of cutaneous tumors. A day after 2 nd BV dose, difficulty finding words and unsteady gait. MRI revealed multifocal white matter lesions in bilateral cerebral hemispheres. Brain biopsy revealed PML. Prednisone initiated. Patient continued mixed non-fluent aphasia, quadriparesis, gait ataxia. MRI showed white matter lesions and contrast enhancement consistent with IRIS. High dose oral corticosteroids continued. Repeat MRI shows decreased lesion load, resolution of enhancement. Patient improving. Case 3—Age:72/female stage IB mycosis fungoides (MF) controlled with topical steroids and nitrogen mustard, phototherapy and interferon alpha, developed painful ulcerated plaques and tumors 4 years after diagnosis. BV administered, clinical response of skin tumors, decreased pain. Two weeks after 3 rd BV dose: disoriented, poor short term memory. MRI revealed right frontal white matter. CSF sent for JC virus DNA was negative. Patient died 2 months after last BV dose. Autopsy: demyelination associated JC virus positive cells. Results: Shown. Conclusions: Unexpected PML occurrences after 2 or more BV doses, with IRIS and survival in 1 patient.
Hospital variation in bronchoscopy and esophagoscopy rates during head and neck cancer diagnostic evaluation.
Authors: Gordon H. Sun, Oluseyi Aliu, Nicholas M. Moloci, Joshua Keith Mondschein, James F. Burke, Rodney A. Hayward
Journal: Journal of Clinical Oncology (2013)

6044 Background: Hospital variation in bronchoscopy and esophagoscopy rates while diagnosing head and neck cancer may reflect professional uncertainty about the effectiveness of these procedures and a lack of clinical guidelines on best practices. Furthermore, high-volume hospitals have demonstrated better outcomes for select oncologic procedures. We examined the association between hospital case volume and diagnostic bronchoscopy and esophagoscopy rates. Methods: This retrospective cohort study used the 2006-2010 Michigan State Ambulatory Surgery Databases, capturing all outpatient surgical cases in Michigan. Eligible cases included head and neck cancer patients who underwent laryngoscopy, bronchoscopy, and/or esophagoscopy. The primary outcome measure was the likelihood that a patient who underwent laryngoscopy during head and neck cancer diagnostic workup also underwent either bronchoscopy or esophagoscopy. We used hierarchical, mixed-effect logistic regression to measure the association between the primary outcome and hospital case volume (&lt;100, 100-999, or ≥1,000 cases/hospital) while adjusting for patient-level variables such as age, sex, race, insurance status, and household income. Results: Of 17,828 head and neck cancer patients, 9,218 underwent diagnostic laryngoscopy. The 50 low-volume and 40 medium-volume hospitals performed significantly more concurrent bronchoscopies and esophagoscopies compared to the 2 high-volume hospitals (both p&lt;0.001). After adjusting for patient characteristics, medium-volume and low-volume hospitals respectively had 9.3-fold and 7.8-fold higher odds of performing esophagoscopy relative to high-volume hospitals (p=0.003), although the association with bronchoscopy was no longer statistically significant. Conclusions: The proportion of head and neck cancer patients undergoing diagnostic laryngoscopy with concurrent esophagoscopy, but not bronchoscopy, varies significantly by hospital volume. A robust discussion of the comparative effectiveness of comprehensive and selective endoscopy will require further research into whether endoscopic volume correlates with tumor staging, survival, and other outcomes data.
Abstract 3698: Conditionally reprogrammed cells from patient-derived xenograft to model neuroendocrine prostate cancer development
Authors: Xinpei Ci, Jun Hao, Xin Dong, Hui Xue, Rebecca Wu, Anne M. Haegert, Colin C. Collins, Dong Lin, Yuzhuo Wang
Journal: Cancer Research (2019)

Abstract Treatment-emergent neuroendocrine prostate cancer (t-NEPC) is a lethal subtype of advanced prostate cancer that occurs via NE transdifferentiation of prostate adenocarcinomas in response to androgen receptor (AR)-inhibition therapy. Study of t-NEPC has been hampered by a lack of clinically relevant models. We previously established a unique and first-in-field patient-derived xenograft (PDX) model of adenocarcinoma (LTL331)-to-NEPC (LTL331R) transdifferentiation. In this study, we established conditionally reprogrammed (CR) cells from the adenocarcinoma PDX tumor line LTL331. These LTL331-derived CR (LTL331-CR) cells retained the same genomic mutations of the parental tumor and, can be genetically manipulated and continuously propagated in vitro. Further androgen deprivation treatment on LTL331-CR cells showed no effect on cell proliferation. Transcriptomic analyses of the LTL331-CR cells revealed profound downregulation of androgen response pathway, and enrichment of stem/progenitor-like marker genes, compared with the parental tumor LTL331. Notably, when grafted back into the subrenal capsule of male NOD/SCID mice, these LTL331-CR cells gave rise to NEPC tumors directly as manifested by histological expression of NE markers. Transcriptomic analyses of the newly developed NEPC tumors also demonstrated marked enrichment of NEPC signature genes and loss of AR signaling genes. This study provides a novel strategy to investigate the mechanisms underlying t-NEPC development with a unique PDX by enabling gene manipulation ex vivo and subsequent functional evaluation in vivo. Citation Format: Xinpei Ci, Jun Hao, Xin Dong, Hui Xue, Rebecca Wu, Anne M. Haegert, Colin C. Collins, Dong Lin, Yuzhuo Wang. Conditionally reprogrammed cells from patient-derived xenograft to model neuroendocrine prostate cancer development [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3698.