tbuckley/cabot-search huggingface dataset:
Study of tumor infiltrating immune CELLS and vasculature in human gliomas: Differences in IDH1/2 mutant versus IDH1/2WT tumors.
Authors: Maria Cruz Martin Soberón, Juan Manuel Manuel Sepulveda Sanchez, Ricardo Gargini, Berta Segura, Jacquelin Gutierrez, Yolanda Ruano, Diana Cantero, Aurelio Hernandez-Lain, Pilar Sanchez-Gomez, Angel Perez-Núñez, Luis Jimenez Roldan, Patricia Marín, Daniel E. Castellano, Guillermo De Velasco, Teresa Cejalvo
Journal: Journal of Clinical Oncology (2019)

2030 Background: Gliomas harboring mutations in IDH1/2 show a higher overall survival time than “wild type” (wt) tumors. Although the clinical aspects are well described, little is known about the underlying mechanisms by which these mutations generate such a difference in the clinical course. Our group has recently described that IDH1/2 mutations induce a distinct vascular phenotype in the tumors, with less blood-brain barrier (BBB) leakage than the IDH1/2 wt gliomas (In Press, DOI:10.1101/541326). Methods: Prospective study analyzing a cohort of 20 patients with primary gliomas resected in one institution. Samples were obtained in the first surgery and 12 IDHmut and 8 IDHwt gliomas were included. Immune infiltration was analysed by flow cytometry and vasculature by inmunohistochemistry. For molecular biology studies, western blots were performed with Mini-PROTEAN system. Proteins were visible by enhanced chemoluminescence. Results: We show that the immune component also differentiates these two pathologies. There is significantly less immune infiltration in IDH1/2 mutant gliomas. Within the CD45 subset, IDH1/2 mutant gliomas have a reduced proportion of T lymphocytes with a different T cell exhaustion profile and an increased proportion of CD11b + cells in comparison to IDH1/2 wt cases. Myeloid compartment distribution is also different in these two types of tumors, showing an augmented proportion of the M2 (CD206 + ) and the neutrophil subsets in IDH1/2 wt gliomas. Moreover, a higher proportion of CD45 PDL1 + was present in the IDH1/2 wt tumors samples. The analysis of the vasculature showed an increase density and the lumen size of the vessels of the IDH1/2 wt compared to the IDH1/2 mutant gliomas which correlate with changes in the immune profile. The biochemical analysis showed that there is an increment in EGFR and PDGFR activity in the IDH wt gliomas that is related with more vascular aberrations and higher CD45 infiltrate. This suggests that EGFR and PDGFR are the key regulators of the tumor microenvironment. Conclusions: To understand the matching between the immune infiltration and vasculogenesis is relevant for interpreting data coming from the clinical trials with checkpoints inhibitors. At the time abstract submission survival analysis is not yet available due to the short time of follow-up but in May 2019, the number of expected events for analysis will be reached.
Randomized phase II study of adjuvant afatinib for three months versus two years in patients with resected stage I-III <i>EGFR</i> mutant NSCLC.
Authors: Jamie E. Chaft, Daniel Botelho Costa, Alona Muzikansky, Joseph B Shrager, Michael Lanuti, James Huang, Kavitha Ramchandran, Deepa Rangachari, Mark Huberman, Zofia Piotrowska, Mark G. Kris, Christopher G. Azzoli, Lecia V. Sequist, Joel W. Neal
Journal: Journal of Clinical Oncology (2019)

8507 Background: EGFR tyrosine kinase inhibitors are superior to chemotherapy in patients with advanced EGFR + lung cancers. In the adjuvant setting, erlotinib for two years improves recurrence free survival (RFS) compared to historical controls. The optimal duration of adjuvant TKI is unknown. Methods: Patients with completely resected Stage I-III NSCLC with a sensitizing EGFR mutation were enrolled after standard adjuvant therapy. Pts were randomly assigned to 3 months (3m) or 2 years (2y) of adjuvant afatinib. Afatinib was started at 30 mg by mouth daily. Patients without toxicity after 28 days were allowed to escalate to 40 mg daily. Patients were imaged with CT every 6 months for 3 years and then annually or as clinically indicated. RFS was measured from the date of randomization. The primary study endpoint was recurrence rate at 2 years. 60 randomized patients would provide 82.5% power to detect a 26% difference in 2y-recurrence rate. Results: Patient characteristics are in the Table. The study was terminated for slow accrual after 46 of the planned 60 patients. Planned treatment was completed by 92% (22/24) pts in the 3m arm and 41% (9/22) of pt in the 2y arm. 22 patients required ≥1 dose modification due to toxicity including expected GI, mucosal, and skin AEs. With a median follow-up of ≥38 months there were 10 recurrences and 3 deaths in the 3m arm and there were 5 recurrences (2 on treatment) and 2 deaths in the 2y arm. Median RFS has not been reached in either arm, but recurrence was more common in the 3m arm at every landmark. 2y-recurrence rates were 29% for 3m and 15% for 2y. Conclusions: Recurrences at 2 years were 14% less common with 2y versus 3m of adjuvant afatinib. This difference did not meet the primary study endpoint. The RFS curves show a durable and clinically meaningful separation with substantial follow-up. Failure to meet significance was likely influenced by under-accrual and early drug discontinuation on the 2y arm. In the era of TKIs with improved tolerance, duration of adjuvant therapy remains an important question. Clinical trial information: NCT01746251. [Table: see text]
Circulating tumor DNA fraction (ctDNA) as a surrogate predictive biomarker in metastatic castration-resistant prostate cancer (mCRPC).
Authors: Vincenza Conteduca, Daniel Wetterskog, Emanuela Scarpi, Alessandro Romanel, Giorgia Gurioli, Anuradha Jayaram, Cristian Lolli, Giuseppe Schepisi, Chiara Casadei, Cecilia Menna, Anna Wingate, Francesca Demichelis, Ugo De Giorgi, Gerhardt Attard
Journal: Journal of Clinical Oncology (2019)

5039 Background: Plasma ctDNA is a promising minimally invasive biomarker in mCRPC. Pre-treatment high levels of ctDNA reflect poor prognosis (Romanel et al, Sci Transl Med 2015; Annala et al, Cancer Discov 2018). However, the role of plasma ctDNA in prostate tumour monitoring is largely unexplored. We aimed to determine if monitoring tumour response by quantifying ctDNA levels in plasma could enable early assessment of therapy efficacy for mCRPC. Methods: Between January 2011 and June 2016, 132 sequential plasma samples from 54 mCRPC patients (pts) (30 pre- and 24 post-chemotherapy) treated with abiraterone (abi) were collected. Targeted next-generation sequencing was performed on the PGM Ion Torrent using a 316 or 318 Chip to account for 1000X expected coverage per target. We estimated the global tumour content for each sequential plasma sample from study patients by using the approach developed in (Carreira et al, Sci Trasl Med 2014; Romanel et al, Sci Transl Med 2015 ), which extends the CLONET framework (Prandi et al, Genome Biol 2014). Prostate Cancer Working Group -3 (PCWG3) criteria were used to assess clinical, biochemical (PSA) and radiographic (RAD) progression disease (PD). We considered ctDNA PD any increase of ctDNA from baseline value. Results: In our cohort of 54 pts (median age: 75 years, range 70-78), we observed 17 (31.5%) PD, 14 (25.9%) stable disease, and 23 (42.6%) partial/complete response after the first 3 months (mo) abi therapy. The odds ratio (OR) for PD having any increase in ctDNA and a PSA decline &lt; 50% at ~3-mo therapy was 10.83, 95% CI 2.55-45.95, P = 0.001, and 3.27, 95% CI 0.89-12.3, P = 0.074, respectively. In addition, we assessed all 3 types of median PD time from starting abi treatment, suggesting the ability of ctDNA variation to predict overall PD [RAD PD = 6.8 mo, PSA PD = 4.4 mo, and ctDNA PD = 3.0 mo, P = 0.008). An increase of ctDNA levels during the first 3-mo abi treatment was significantly associated with a long-term androgen deprivation therapy (ADT) before plasma sample collection (previous ADT &gt; 24 mo vs 12 &gt; previous ADT ≤23 mo vs &lt; 12 mo: P = 0.036). Conclusions: In mCRPC, an early change in ctDNA fraction may be considered as a predictive biomarker playing a key role in individualized disease monitoring. Prospective evaluation of treatment decisions based on ctDNA is now required.
Genomic analysis of urothelial cancer and associations with treatment choice and outcome.
Authors: David Sarid, Raanan Berger, Meital Levartovsky, Moran Gadot, Corinne Maurice-Dror, Maya Collin, Avivit Peer, Ruth Perets, Ofer Purim, Michal Sarfaty, Eli Rosenbaum, Victoria Neiman, Hagai Ligumsky, Keren Rouvinov, Ialyzaveta Romanov, Wilmosh Mermershtain, Noa Shani Shrem, Gilad Wolf Vainer, Raya Leibowitz-Amit
Journal: Journal of Clinical Oncology (2019)

e16026 Background: The use of next generation sequencing (NGS) is in a constant rise, without clear evidence to its utility in guiding treatment choices in urologic malignancies. While platinum-based chemotherapy (chemo) is still the mainstay of treatment, anti-PD1/L1 antibodies (IO) and FGFR3 inhibitors are emerging therapeutic options. Here our aim was to retrospectively assess the utility of next-generation sequencing (NGS) in selecting advanced treatment lines and define the response rates (RR) to chemo and IO in a real-life cohort. Methods: Metastatic urothelial carcinoma (UC) patients (pts) receiving first-line chemo were included. Paraffin-embedded pathological samples were subjected to FoundationOne genomic analysis (Roche) and to PD-L1 IHC staining using the FDA-approved Ventana's companion diagnostic test. Reports were anonymized and analysis was performed using Excel (Microsoft Office). Response was defined as either a clinically or radiologically-significant improvement. Results: 60 pts were included in this analysis with a median age of 69, of which 87.7% were men and 70% were current or past-smokers. RR to first line chemo or IO was 66% (95% CI 50-82) and 33% (95% CI 12-64), respectively. RR to second-line IO was 14% ((95% CI 4-40). Median TMB was 10 Mut/Mb (range 1-62) with no difference between smokers and non-smokers. 31% pts had tumor PD-L1 staining of &gt; 5% and 3.7% were MSI-high. 107 genes were altered across all pts. The median number of genomic alterations (mutations (muts), amplifications (amps), deletions (dels) and re-arrangements) was 7 (range 2-17). The most frequent were TERT promotor and TP53 mutations, occurring in in 39 (69.6%) and 30 (53.6%) pts, respectively. FGFR3 alterations were found in 9 (15%) pts (7 mut and 2 fusions), 12 pts (20%) had alterations in ERBB2/Her2 (6 amps, 3 muts, 3 equivocal amps), BRCA1 mutations were found in 6 (10%) pts, and TSC1 alterations were found in 6 (10%) pts (4 muts and 2 dels). Altogether, about 40% of patients had potentially actionable alterations; of these, to date, the treatment of 8 patients (13%) was consequently altered. The RR to IO was non-significantly higher in pts with TMB &gt; 10 (29% VS 20%, p = 0.1) across all pts in this cohort. Conclusions: RR to first-line chemo is higher than to first-line IO, and the association between TMB and response to IO is still debatable in UC. NGS can yield potentially 'actionable' alterations in about 40% of UC pts, and can change the treatment paradigm in the third of them.
Impact of enzalutamide and sequential flutamide and enzalutamide therapy for castration-resistant prostate cancer after bicalutamide-combined androgen blockade therapy onoverall survival: A follow-up study of randomized phase 2 trial (OCCU-CRPC study).
Authors: Taro Iguchi, Satoshi Tamada, Minoru Kato, Sayaka Yasuda, Taiyo Otoshi, Yuichi Machida, Tetsuji Ohmachi, Keiichi Ishii, Hiroyuki Iwata, Shinji Yamamoto, Tomohiro Kanamaru, Kazuya Morimoto, Taro Hase, Koichiro Tashiro, Koji Harimoto, Takashi Deguchi, Takahisa Adachi, Katsuki Iwamoto, Yoshinori Takegaki, Tatsuya Nakatani
Journal: Journal of Clinical Oncology (2019)

5042 Background: In Asia, bicalutamide-combined androgen blockade (CAB) is widely used to treat metastatic or locally advanced prostate cancer. Enzalutamide (ENZA) shows benefits in men with metastatic and nonmetastatic castration-resistant prostate cancer (CRPC), although flutamide (FLU) is still used as an alternative anti-androgen therapy after bicalutamide-CAB. Methods: The multicenter open-label phase 2 trial OCUU-CRPC (NCT02346578) randomized patients (1:1) with CRPC after bicalutamide-CAB to ENZA (160 mg/day) or FLU (375 mg/day). Patients were stratified according to distant metastases. The primary endpoint was the prostate-specific antigen (PSA) response rate (≥50% decrease) at 3 months. The endpoints of this follow-up observational study include PSA progression-free survival of ENZA therapy (PSA-PFS-ENZA), time to treatment failure of ENZA therapy (TTF-ENZA), and overall survival (OS). Results: In total, 103 patients were randomized to ENZA (n = 52) and FLU (n = 51). Overall, 67% had distant metastases and 10% had prior radical therapy. Twenty-five (48%) and 38 (75%) patients, respectively, discontinued their assigned treatment because of progressive disease or adverse events (AEs) and were treated by standard of care. Of the 38 patients that discontinued FLU, 34 (89%) received ENZA as subsequent therapy. The median follow-up time was 14 months (ENZA, interquartile range (IQR): 9.5-24.8) and 17.2 months (FLU, IQR: 9.8-24.9). PSA-PFS-ENZA was longer in patients not treated with FLU (hazard ratio (HR), 0.29; 95% confidence interval (CI), 0.14 to 0.63; p &lt; 0.001), but there was no significant difference in TTF-ENZA (HR, 1.27; 95% CI, 0.73 to 2.19; p = 0.397)and OS (HR, 0.77; 95% CI, 0.31 to 1.89; p = 0.567) between the two groups. The AEs of ENZA were consistent with those observed in prior phase 3 trials. Conclusions: ENZA after bicalutamide-CAB resulted in greater PSA-PFS than sequential FLU and ENZA therapy. No differences were observed in TTF-ENZA and OS between ENZA after bicalutamide-CAB and sequential FLU and ENZA therapy. Clinical trial information: NCT02346578. [Table: see text]
Dynamic changes in the immune infiltrate within hepatocellular carcinoma tumor correlate with response to PD-1 blockade.
Authors: Thomas Urban Marron, Fiona Desland, Yonit Lavin, Myron E. Schwartz, Parissa Tabrizian, Nicholas Fernandez, Joel Kim, Alexandra Tabachnikova, Alice O. Kamphorst, Alessandra Soares Schanoski, Brian Brown, Effi Kenigsberg, Max W. Sung, Bachir Taouli, Adeeb Rahman, Miriam Merad
Journal: Journal of Clinical Oncology (2019)

e15644 Background: Hepatocellular carcinoma (HCC) is the second leading cause of cancer deaths in men worldwide, and is the most rapidly rising cause of cancer mortality in the US. Patients with resectable disease experience high rates of locoregional recurrence, and there are few effective systemic treatment options available. PD-1 blockade was recently approved for 2 nd line therapy, and there are promising response rates seen in the 1 st -line setting. However, only 20% of patients achieve significant response, thus we must investigate further the tumor-immune microenvironment to understand how to better modulate the immune system in this highly immunosuppressive organ. Methods: We used mass cytometry (CyTOF) and cellular indexing of transcriptomes and epitopes by sequencing (CITE-seq) to study protein and transcriptomics of untreated tumor and tumor adjacent tissue, on a single-cell level. Results: Paired CyTOF analysis of 10 tumor lesions/adjacent tissues identified a significant increase in frequency of CD4 + T cells and T regulatory cells, a significant decrease in NK cells and neutrophils, and no difference in CD8 + T cells, macrophages, or dendritic cells (DCs) in the tumor microenvironment compared to the adjacent liver tissue. We also analyzed four patients who received nivolumab and subsequently went on to have their liver tumors resected; two out of the four patients treated had near-complete necrosis of their tumors (radiographically and histologically). Of note, the tumors of the two patients with significant pathologic response contained a significantly higher number of CD103 + tissue resident CD8 + and CD4 + T cells, compared to adjacent tissue. Moreover, activated CD8 + T cells (TIGIT + , PD-1 + , TIM3 + , and/or CD38 + ) were significantly higher in the tumor of nivolumab responders, indicating a tumor-specific response. We will also present single cell transcriptomic analyses of T cell and myeloid populations in responders and non-responders. Interestingly, high levels of nivolumab were detected on PD-1 + T cells in the tumor in all 4 patients; we will discuss transcriptional differences between nivolumab-targeted T cells in responders and non-responder patients. Conclusions: Based on this preliminary data we will be opening a clinical trial of neoadjuvant PD-1 blockade in HCC (NCT# pending) in March 2019.
Complex multimorbidity, perceived life expectancy, and routine cancer screening receipt: Differences between older women and men.
Authors: Siran M. Koroukian, David F Warner
Journal: Journal of Clinical Oncology (2019)

e13071 Background: Complex multimorbidity (MM) predicts poor health outcomes. How MM predicts preventive health services receipt, such as cancer screening, is less clear. Yet cancer screening decision making involves not only clinical presentation (MM) and age, but also patients’ perceptions about need. We hypothesize that patients’ perceived life expectancy (PLE) moderates the effect of MM and age on cancer screening receipt (mammography for women and prostate screening for men). Methods: Data came from 20,705 women and men, ages 52-90, from the 2002-2012 waves of the U.S. Health and Retirement Study. Receipt of screening mammogram (women) or “examination of [the] prostate to screen for cancer” (men) in the last two years were binary (0/1) measures. MM was an ordinal count (0-3) of the co-occurrence of any chronic conditions, functional limitations, and geriatric syndromes. Age was measured in years. PLE was the chance respondents’ thought they would live 10-15 more years (0 = 0% - 10 = &gt; 90%). Additional control variables included self-rated health, race/ethnicity, socioeconomic status, marital status, smoking, BMI, and other preventive services (e.g., flu shot) receipt. We used survey-adjusted repeated measures logistic regression to predict screening receipt separately by gender. Results: Women reported higher MM and PLE than men. Greater MM reduced the likelihood of mammography receipt. However, women with MM who had greater PLE had an increased likelihood of mammography receipt. Furthermore, mammography receipt decreased more slowly with age for women with high PLE. For men, greater MM did not lead to reduced prostate screening. Men’s PLE was not associated with screening nor did it modify the effects of MM or age. Conclusions: Greater PLE increases likelihood of cancer screening for women even when MM and advanced age would recommend against. Men’s clinical presentation and subjective perceptions of longevity are not associated with prostate screening receipt. We speculate that the differences in the nature of the screening tests combined with greater public awareness of breast cancer create conditions where subjective perceptions are more likely to affect mammography decision-making.
Cardiomyopathy in Children: Classification and Diagnosis: A Scientific Statement From the American Heart Association
Authors: Steven E. Lipshultz, Yuk M. Law, Alfred Asante-Korang, Eric D. Austin, Anne I. Dipchand, Melanie D. Everitt, Daphne T. Hsu, Kimberly Y. Lin, Jack F. Price, James D. Wilkinson, Steven D. Colan
Journal: Circulation (2019)

In this scientific statement from the American Heart Association, experts in the field of cardiomyopathy (heart muscle disease) in children address 2 issues: the most current understanding of the causes of cardiomyopathy in children and the optimal approaches to diagnosis cardiomyopathy in children. Cardiomyopathies result in some of the worst pediatric cardiology outcomes; nearly 40% of children who present with symptomatic cardiomyopathy undergo a heart transplantation or die within the first 2 years after diagnosis. The percentage of children with cardiomyopathy who underwent a heart transplantation has not declined over the past 10 years, and cardiomyopathy remains the leading cause of transplantation for children &gt;1 year of age. Studies from the National Heart, Lung, and Blood Institute–funded Pediatric Cardiomyopathy Registry have shown that causes are established in very few children with cardiomyopathy, yet genetic causes are likely to be present in most. The incidence of pediatric cardiomyopathy is ≈1 per 100 000 children. This is comparable to the incidence of such childhood cancers as lymphoma, Wilms tumor, and neuroblastoma. However, the published research and scientific conferences focused on pediatric cardiomyopathy are sparcer than for those cancers. The aim of the statement is to focus on the diagnosis and classification of cardiomyopathy. We anticipate that this report will help shape the future research priorities in this set of diseases to achieve earlier diagnosis, improved clinical outcomes, and better quality of life for these children and their families.
RERG involvement in the RAS pathway and ER-dependent transcription in breast cancer.
Authors: Pei-Chen Hsu, Jar-Yi Ho, Cheng-Ping Yu
Journal: Journal of Clinical Oncology (2019)

e14638 Background: Breast cancer is the highest incidence malignancies in women worldwide. Luminal breast cancers are typically estrogen receptor–positive with better prognosis. However, the rapid disease progression and the high relapse rate of this subtype of breast cancer have become a puzzle in breast cancer treatment. It gave us the motivation to figure out the anomalous molecular mechanism which devoted in. It has been well-documented that the RAS pathway is overloadly activated in more than half of human breast tumors. RAS genes encode a superfamily of small GTPases that contribute to cell growth signals. Methods: Gene expression level were measured by qPCR and Western Blot.Biological effects of each condition were evaluated in cell viability and migration. Results: In this study, we investigated one member of the RAS family, RERG, which was related to the ER pathway and contributed to inhibit Ras activated pathway. Our results showed that knockdown of RERG concomitantly promoted two major oncogenic pathways, Ras and Stat3 signaling pathways, in luminal type breast cancer cell lines. Moreover, ectopic RERG expression significantly inhibited Ras expression. It implicated that RERG mediated in RAS-driven biological effects. Our findings indicated that knockdown of RERG enhanced mobility of the breast cancer cells and made cells more intractable under SERM treatment. Conclusions: We elucidated the tumor-suppressor role of RERG in breast cancer cells though inhibition of the Ras and Stat3 signaling pathways. Therefore, this study might shed light on the important mechanistic insight into the tumorigenesis of ER-positive luminal type cancer and provided the prognostic and therapeutic improved roles of RERG.