tbuckley/cabot-search huggingface dataset:
Breast cancer survivorship: A model for risk assessment and follow-up care.
Authors: Jodie Ann Barr, Anne O'Dea, Lori Ranallo, Carol J. Fabian, Jennifer R. Klemp
Journal: Journal of Clinical Oncology (2016)

e21576 Background: Over 3.1 million women in the U.S. have a history of invasive breast cancer. National accreditation standards require development and delivery of a survivorship care plan (SCP), but there is currently little evidence describing the impact of the SCP. There is an increase in the number of survivors receiving care by primary care physicians. We report prospective findings from a group of breast cancer survivors from 2007-2015 attending a continuity of care breast cancer survivorship clinic. Methods: Four- hundred twenty four BrCa survivors consented to participate in an IRB approved, longitudinal survivorship registry. SCP baseline variables on demographics, disease history, summary of cancer treatment, late effects, medications and health status were collected. Follow-up data collection included disease status or new primary cancer, changes in health status and late and long-term effects. Comparisons from SCP baseline to subsequent visits provided information on changes in key variables over time. Results: Participants were 57 years old and 49% were premenopausal at diagnosis. Increase in BMI from diagnosis 25.7 to SCP 27.0. Cardiovascular Risk Factors: 67% had > 3 cardiac risk factors (defined by tx, personal factors, and family hx). Family History of breast cancer, 55%; ovarian cancer, 15%; 33% (138) previously underwent BRCA1/2 testing, of those tested, 8% (11) were found to have a deleterious mutation; subsequently an additional 34 (8%) underwent testing with 3% (1) positive. Follow-up included, symptom management, lifestyle recommendations, referrals to specialists, (77% referred & completed colonoscopy; 92% referred & attended cardio-oncology screening visit; 100% referred health screenings). Conclusions: Comprehensive continuity of care implemented by a survivorship care model assessed and managed factors for lifestyle, cardiovascular health, bone health, and menopausal symptoms, update genetic testing and management of hereditary cancer risk, leading to increased compliance with recommended cancer follow up. Further evaluation of the impact of SCP is necessary to evaluate long-term health outcomes and cost of the health delivery system as well as the integration into electronic medical records.
Clinical anti-lymphoma activity and toxicity of T cells expressing a novel anti-CD19 chimeric antigen receptor with fully-human variable regions.
Authors: Jennifer N. Brudno, Steven D. Hartman, Stefania Pittaluga, David Stroncek, Norris Lam, Jennifer Ann Kanakry, Steven Zivko Pavletic, Lekha Mikkilineni, Mohammadhadi Bagheri, Mark J. Roschewski, Robert M. Dean, Jeremy J. Rose, Rashmika Patel, Brenna G. Hansen, Ronald Gress, James Kochenderfer
Journal: Journal of Clinical Oncology (2018)

3052 Background: T cells expressing chimeric antigen receptors (CARs) targeting CD19 have powerful activity against B-cell lymphoma. A limitation to CAR T-cell therapy for lymphoma is occurrence of toxicities, especially neurologic toxicities. Methods: We designed an anti-CD19 CAR with fully human variable regions (Hu19CAR). This CAR has CD8α hinge and transmembrane domains and a CD28 costimulatory domain; T cells expressing this CAR release relatively low levels of cytokines. A phase I dose-escalation trial was conducted to investigate the safety of Hu19CAR T cells and to assess efficacy for patients with previously treated B-cell lymphoma. Patients received cyclophosphamide and fludarabine chemotherapy to enhance CAR T-cell activity. Two days after the completion of chemotherapy, Hu19CAR T cells were infused. Results: Twenty patients have received Hu19CAR T-cell infusions. Of these patients, 75% had lymphoma that was chemotherapy-refractory or relapsed after autologous stem cell transplant. Patients received a median of 4 prior lines of therapy. The overall response rate is 75%, with 55% complete remissions (CRs). CRs were observed in patients with chemotherapy-refractory lymphomas and in patients with double-hit diffuse large B-cell lymphoma. Durations of response currently range from 1 to 17 months. Forty percent of patients are in ongoing remissions. Only one patient experienced greater than Grade 2 neurotoxicity (5%), which is a neurotoxicity rate lower than that of many anti-CD19 CAR trials. This patient had Grade 4 neurotoxicity which reversed in less than 24 hours with corticosteroid therapy. Three patients had Grade 3 cytokine release syndrome (CRS), and 1 patient had Grade 4 CRS; all other patients had Grade 2 or lower CRS. CRS and neurotoxicities resolved completely in all patients. Loss of CD19 expression by lymphoma cells was observed in 4 of the 8 patients who underwent biopsies of recurrent or residual lymphoma after Hu19CAR T-cell infusions. CAR T cells were detected in the blood of all patients at levels ranging from 4-2216 cells/µL. Conclusions: Hu19CAR T cells have substantial activity against advanced lymphoma with a low rate of neurotoxicity. Clinical trial information: NCT02659943.
Targeting epigenetic mechanisms in periodontal diseases
Authors: Silvana P. Barros, Eman Hefni, Rafael Nepomuceno, Steven Offenbacher, Kari North
Journal: Periodontology 2000 (2018)

Abstract Epigenetic factors are heritable genome modifications that potentially impact gene transcription, contributing to disease states. Epigenetic marks play an important role in chronic inflammatory conditions, as observed in periodontal diseases, by allowing microbial persistence or by permitting microbial insult to play a role in the so‐called ‘hit‐and‐run’ infectious mechanism, leading to lasting pathogen interference with the host genome. Epigenetics also affects the health sciences by providing a dynamic mechanistic framework to explain the way in which environmental and behavioral factors interact with the genome to alter disease risk. In this article we review current knowledge of epigenome regulation in light of the multifactorial nature of periodontal diseases. We discuss epigenetic tagging in identified genes, and consider the potential implications of epigenetic changes on host–microbiome dynamics in chronic inflammatory states and in response to environmental stressors. The most recent advances in genomic technologies have placed us in a position to analyze interaction effects (eg, between periodontal disease and type 2 diabetes mellitus), which can be investigated through epigenome‐wide association analysis. Finally, because of the individualized traits of epigenetic biomarkers, pharmacoepigenomic perspectives are also considered as potentially novel therapeutic approaches for improving periodontal disease status.
Cost-related changes in medication use among cancer survivors by socioeconomic status.
Authors: Jingxuan Zhao, Zhiyuan Zheng, Xuesong Han, Matthew P. Banegas, Amy J. Davidoff, Ahmedin Jemal, K Robin Yabroff
Journal: Journal of Clinical Oncology (2018)

e18920 Background: Rising out-of-pocket (OOP) costs for medications is increasingly a critical issue for cancer survivors in the U.S., causing some to delay or forgo recommended medications. Little is known about how OOP costs affect medication use by socioeconomic status. This study aims to evaluate cost-related changes in medication use, both delaying or forgoing medications and shifting to lower-cost alternatives, by socioeconomic status, among adults with and without a cancer history. Methods: We identified 4,340 cancer survivors and 99,958 individuals without a cancer history aged 18-64 from the National Health Interview Survey (2013-2016). Cost-related changes were measured as 1) delaying or forgoing medications (skipping, taking less or delaying medication); 2) shifting to alternatives (asking for lower cost medication or using alternative therapies). Multivariable logistic regression analyses were conducted to examine the associations between cancer history and medication changes. Predictive margins were generated to compare cancer survivors to those without a cancer history, stratified by family income ( < 200% of the federal poverty line (FPL) 200%-399% of FPL, ≥400% of FPL). Results: Compared to adults without a cancer history, cancer survivors were more likely to report delaying or forgoing medication (15% vs 12%; p < .01) and shifting to alternatives (26% vs 24%; p = .06). Differences by cancer history were greatest for those in 200% to 399% of FPL. Moreover, higher cost-related medication change was associated with lower family income: for the three income groups delaying or forgoing medication (cancer survivors: 23%, 18.0%, 7.0%, respectively; adults without a cancer history: 21%, 14%, 5%, respectively. All p < .01) and shifting to alternatives (cancer survivors: 32%, 29%, 18%, respectively; adults without a cancer history: 29%, 27%, 18%, respectively. All p < .01). Conclusions: Cancer survivors are more likely to report delaying or forgoing medications than adults without a cancer history, with such cost-related medication change most prominent in low-income families. Policy interventions are warranted to improve medication adherence among cancer survivors.
PRUNE2 and PCA3 expression in paired non-malignant and tumor specimens from radical prostatectomy patients with gleason score 7 prostate cancer.
Authors: Richard C. Lauer, Marc Barry, Jin Wu, Ji-Hyun Lee, Dennis J. McCance, Ruofei Du, Arpit Rao, Andrey S. Dobroff, Emmanuel Dias-Neto, Isan Chen, Renata Pasqualini, Wadih Arap
Journal: Journal of Clinical Oncology (2017)

e16582 Background: PCA3 is an FDA-approved biomarker for prostate cancer. We have recently reported that PRUNE2 is a tumor suppressor gene in human prostate cancer that it is inactivated through a PCA3-mediated regulatory axis. Based upon this previous work, here we investigated if PRUNE2 and PCA3expression levels would be different in non-malignant versus tumor paired samples obtained from Gleason 7 Score prostate cancer patients undergoing radical prostatectomy. Methods: We examined Gleason Score 7 prostate cancer specimens, obtained from a cohort of patients (n=24) who have undergone radical prostatectomy at UNM Hospital. Paired non-malignant and tumor tissues were recovered from these specimens after tissue microdissection and processed for RNA extraction. PRUNE2 and PCA3transcripts were measured by qRT-PCR using three and two different primer sets, respectively, and normalized using appropriate internal controls. Each experiment was carried out in triplicates. The Wilcoxon signed rank test was used to test whether the differences between the paired tumor and non-malignant tissue samples were significant. Results: Gene expression analyses showed PRUNE2 levels to be consistently lower in tumor samples compared to non-malignant areas of the same gland (P&lt;0.0001). In contrast, the opposite trend was seen for PCA3, which has a marked upregulation in tumor areas (P&lt;0.0001). Conclusions: Both PRUNE2 and PCA3 expression levels were significantly different between matched non-malignant and malignant tissue pairs in Gleason Score 7 prostate cancer patients post radical prostatectomy. This retrospective dataset provides additional support for a mechanistic role for the molecular interplay between PRUNE2 and PCA3 in human prostate cancer, which may lead to the development of novel diagnostic and therapeutic approaches in this disease. Prospective studies targeting our original finding are either ongoing or planned. [Table: see text]
Prognostic factors of advanced Hodgkin’s lymphoma: multivariate analysis of 199 Chinese patients with long-term follow-up.
Authors: Qin Wang, Yan Qin, Suyi Kang, Xiaohui He, Peng Liu, Sheng Yang, Shengyu Zhou, Changgong Zhang, Lin Gui, Jianliang Yang, Yan Sun, Yuankai Shi
Journal: Journal of Clinical Oncology (2016)

e19021 Background: About 30% of advanced HL patients will suffer relapse and some may be overtreated. More accurate methods are needed to identify patients with different prognosis. The current International Prognostic Score (IPS) is imperfect and there is almost no data about prognostic factors of advanced HL in the Chinese population until now. Methods: We conducted a retrospective study involving 199 Chinese advanced HL patients admitted to Cancer Hospital Chinese Academy of Medical Sciences (CHCAMS) from 1999.1 to 2015.1. All patients received standard first-line therapy. Survival outcome and 18 parameters at diagnosis of the 199 patients were collected and analyzed to identify independent prognostic factors. Treatment regimen of cases with progressed or recurrent disease were not uniform, and some patients died of toxicity or other diseases, so we analyzed factors affecting progression-free survival (PFS), but not overal survival (OS). Results: The median follow-up time was 66.4 months (range 9.4-200.5 months).Three factors showed significant independent prognostic value for PFS in the multivariate analysis: lymphocyte/monocyte ratio (LMR) < 2.67 (HR = 1.976, 95%CI, 1.193-3.272, P = 0.008), serum albumin < 4g/dL (HR = 1.703, 95%CI, 1.034-2.805, P = 0.037), serum beta-2 macroglobulin (B2MG) ≥ normal (HR = 1.836,95%CI, 1.114-3.026,P = 0.017). Prognostic score was calculated by adding 1 point each for any of the independent prognostic factors. According to the prognostic scores, patients could be divided into low (0 points), intermediate (1-2 points) and high (3 points) risk groups with 5-year PFS rate of 88.4%, 62.8% , 27.5% (0 vs.1-2, P = 0.001; 1-2 vs.3, P = 0.019; 0 vs.3,P = 0.000) and 5-year OS of 95.4%, 79.8%, 43.9% ( 0 vs.1-2, P = 0.009; 1-2 vs.3, P = 0.001; 0 vs.3, P = 0.000) respectively. Conclusions: Three factors were recognized as independent prognostic factors for Chinese advanced HL patients and a prognostic scoring system was established, according to which patients with different prognosis will be identified and more appropriate therapies could be made to increase the cure rate of patients with high risk for replase and avoid overtreatment in patients with lower risk.
Downregulation of CPA4 to suppress NSCLC proliferation by inducing apoptosis and G1 arrest.
Authors: Yangyang Fu, Xiaoying Huang, Liangxing Wang
Journal: Journal of Clinical Oncology (2017)

e20074 Background: Carboxypepidase A4 (CPA4) is a member of the metallocarboxypeptidase family. Previous study discovered that CPA4 may participate in cell growth and differentiation of prostate epithelial cells. Meanwhile, CPA4 is a printed gene and thought to be involved in prostate cancer aggressiveness. As is reported, CPA4 was increased in NSCLC tissues compared to normal lung tissues and high expression of CPA4 was correlated with poor prognosis of NSCLC patients. However, the role of CPA4 play in lung tumorigenesis is still unclear. Methods: We examined the mRNA and protein expression level of CPA4 via real-time PCR and immunohistochemistry in NSCLC tissues and adjacent tissues. Growth assays both in vitro and in vivo were performed to elucidate the role of CPA4 may play in lung cancer and Fluorescence Activated Cell Sorter was conducted to uncover the putative mechanism. Results: CPA4 expression was increased both in mRNA and protein levels in NSCLC tissues compared to adjacent tissues. MTT and colony formation assays showed that downregulation of CPA4 in H1299 and A549 cells inhibited lung cancer cells proliferation. We further confirmed this result by using cellomics and celligo. Depleting CPA4 also suppressed tumor growth in mice. Mechanically, we found that suppressing CPA4 expression in lung cancer cells could induce apoptosis and G1 arrest. We supposed that CPA4 expression may be associated with caspase family and it needs further studies. Conclusions: Collectively, we demonstrate that decreased CPA4 inhibits NSCLC proliferation via inducing apoptosis and G1 arrest.
TEAPOT, a quantitative approach to address intra-tumor heterogeneity by identifying driver mutations in cancer cell subpopulations.
Authors: Jianshu Zhang, Helaman Escobar, Yang Wei, Mickey Miller, Harshmi Shah, Michelle Knirr, Baoli Yang, Eric Devor, Kristina Thiel, Lincoln Nadauld, Donghai Dai
Journal: Journal of Clinical Oncology (2018)

e24215 Background: Therapeutic efficacy is often impeded by drug resistance arising from ubiquitous intra-tumor genetic heterogeneity. However, commonly used tests for identification of driver mutations, defined as mutations in cancer genes, report only the presence of driver mutations in a tumor, largely ignoring the mutation’s distribution in cancer cell subpopulations. The most effective cancer treatments today should rely upon a personalized and precision approach that take into account of intra-tumor heterogeneity. Methods: We have developed a novel approach, TEAPOT (Tumor Evolution Assay for Personalized Oncology Therapy), to reconstruct a tumor’s evolutionary history through combination of whole exome sequencing data from a bulk primary tumor and 16-24 microsamples taken from the bulk tumor. The evolutionary history for an individual tumor is expressed as a rooted tree representing the mitotic process of tumor development starting from an ancestral cancer cell. Individual mutations are assigned to the cells in which they first present. The size of each offspring carrying a specific mutation is estimated based on tumor purity, variant allele frequency, and the variant’s copy number. Results: By re-building a tumor’s evolutionary history, TEAPOT depicts the occurrence of driver mutations in the most recent common ancestor cells for a subpopulation. The size of offspring carrying a driver mutation can thus be estimated. Studies in melanoma, ovarian, and lung tumors revealed that driver mutations are often present in minority clones. Most tumors do not have a driver mutation at the ancestor of the entire cancer cell population. More than 50% of tumors have two or more driver mutations and > 50% of driver mutations are present only in a subpopulation with a size of less than 50% of the total cancer cell population. Conclusions: We developed a novel approach, TEAPOT, to define intra-tumor heterogeneity by estimating the intra-tumor prevalence of individual driver mutations. Such information may assist in selection of an effective targeted agent and provide the rationale for cocktail treatments targeting multiple driver mutations simultaneously.
High Prevalence of Claudin 18.2 Expression in Japanese Patients with Gastric Cancer.
Authors: Özlem Tureci, Kyogo Itoh, Rin Yamaguchi, Svetlana Mukhina, Ugur Sahin, Christoph Rohde
Journal: Journal of Clinical Oncology (2017)

e15584 Background: Expression of the gastric mucosal tight junction protein, Claudin-18.2 (CLDN18.2), is altered in gastric cancer (GC). In a phase 2 clinical trial (NCT01630083; FAST), a monoclonal antibody against CLDN18.2 (IMAB362) significantly increased overall survival in European patients with CLDN18.2-positive (CLDN18.2 + ) gastric and gastroesophageal junction adenocarcinomas when added to an EOX chemotherapy regimen. As the GC occurrence is high in Japan, this study evaluated the prevalence of CLDN18.2 expression in Japanese patients with GC. Methods: CLDN18.2 expression was assessed in primary GC tumors and corresponding lymph node metastases (LNM) by cell membrane staining intensity using a validated, semi-quantitative, immunohistochemical assay for CLDN18.2 expression. Samples showing any positivity for specific staining with at least 1+ intensity were defined as CLDN18.2 + . Correlation between percentage of CLDN18.2 + cells in primary tumors and corresponding LNM was determined with Spearman’s rank correlation. Results: A total of 263 samples, including tissues from 134 primary GC tumor/LNM matched pairs, 128 primary GC tumors only, and 1 LNM only were collected at Kurume University Medical Center, Japan, between 2000 and 2012. Overall, CLDN18.2 was detected in 87% (n = 228/262) of all primary tumors and 80% (n = 108/135) of LNM. Strong CLDN18.2 expression (≥2+ membrane staining intensity in ≥40% of tumor cells; eligibility criterion in FAST) was observed in 52% (n = 135/262) of primary tumors and 45% (n = 61/135) of LNM. Individual tumor samples consisted of a mixture of tumor cells expressing CLDN18.2 at different staining intensities; samples with a high fraction of CLDN18.2 reactivity had a large proportion of tumor cells staining with 3+ intensity (Spearman r = .8413, P&lt; .0001). In matched pairs, 72% of samples were CLDN18.2 + (n = 96/134) and 9% were CLDN18.2 – (n = 12/134). The fraction of CLDN18.2 + tumor cells at any staining intensity strongly correlated in matched paired samples (Spearman r = .6942; P&lt; .0001). Conclusions: CLDN18.2 expression is highly prevalent in Japanese GC patients, making it a targetable alteration and supporting development of IMAB362 as a therapeutic agent for this patient population.
The benefit of combining docetaxel to androgen deprivation therapy in localized and metastatic castration-sensitive prostate cancer as predicted by ERG status: An analysis of two GETUG phase III trials.
Authors: Shanna Rajpar, Alexandra Carmel, Zahira Merabet, Philippe Vielh, StÃ©phanie Foulon, Francois Lesaunier, Remy Delva, Frederic Rolland, Frank Priou, Jean-Marc Ferrero, Nadine Houede, Loic Mourey, Christine Theodore, Ivan Krakowski, Laura Faivre, Muriel Habibian, Stephane Culine, Anne Chauchereau, Gwenaelle Gravis, Karim Fizazi
Journal: Journal of Clinical Oncology (2017)

5012 Background: Combining docetaxel to androgen deprivation therapy (ADT) improves survival in metastatic castration-sensitive prostate cancer (CSPC) (Vale C, Lancet Oncol 2016; 17: 243-56) and it also improves relapse-free survival (RFS) in high-risk localized CSPC (Fizazi K, Lancet Oncol 2015; 16: 787-94). However it is unlikely that all patients (pts) derive a benefit from docetaxel treatment and identifying predictive biomarkers remains a major unmet need. A subset of prostate cancers contains TMPRSS2-ERG gene fusions leading to ERG overexpression. Methods: Pre-treatment prostate core biopsies were collected from 255/413 pts and 79/385 pts enrolled respectively in the GETUG 12 and GETUG 15 (Gravis G, Eur Urol 2016; 70: 256-62) phase 3 trials testing early docetaxel in high-risk localized and metastatic CSPC. ERG, PTEN, Ki67 and Rb expression was assessed using immunohistochemistry. RFS curves were compared using the Logrank test. Results: The median age was 63 years (46-77) and 62 years (49-76) in GETUG 12 and GETUG 15. ERG staining was positive in 88/191 (46%) and 33/79 (42%) pts with available tissue, respectively. In GETUG 12, docetaxel-based chemotherapy was associated with improved RFS in pts with ERG+ expression (HR = 0.55 [0.29-1.03]; 6-year RFS : 80% ADT+docetaxel vs 68% ADT alone), but not in pts with ERG- (HR = 1.10 [0.66-1.85]; 6-year RFS 55% ADT+docetaxel vs 60% ADT alone), interaction test: p = 0.02. Similar findings were observed in GETUG 15, which was used as a validation set: the median RFS was 10.7 (6.5-14.3) and 18.8 (9.8-41) months in pts with ERG+ cancers receiving ADT alone and ADT+docetaxel, and 10.6 (4.8-25.3) and 13.2 (9.4-24) months in pts with ERG- cancers. In contrast, no difference in patient outcome by docetaxel treatment was observed by PTEN, Ki67 and Rb expression. Conclusions: Docetaxel-related benefit in men with CSPC is predicted by ERG expression. This biomarker may help better select pts for docetaxel treatment.