tbuckley/cabot-search huggingface dataset:
Bringing patient navigation to primary health care in Rio de Janeiro: Pilot project in the Andaraí community.
Authors: Sandra Gioia, Cristiane Torres, Renata Galdino, Lucia Brigagao, Alessandra Heringer, Marcelle Medeiros, Lindsay Krush, Paul E. Goss
Journal: Journal of Clinical Oncology (2019)

e13104 Background: This research project aims to study the increase of mammographic coverage rate with Patient Navigation Program (PNP) in a community of Rio de Janeiro. The general objective is to measure adherence to Ministry of Health’s recommendations for breast cancer screening with mammography, with the help of a patient navigator. Other objectives include: (1) establish the viability of the PNP in this context; 2) identify the barriers to mammography screening and; 3) ensure that at least 70% of women recruited between 50 and 69 years of age and asymptomatic update the biennial mammographic examination and annual clinical examination, increasing the mammographic coverage from 14% to at least 70% considered acceptable by the World Health Organization. Methods: From March to September 2018, women from the Andaraí Community were recruited in the Municipality of Rio de Janeiro. The follow-up was carried out by telephone, e-mail, and text messages. Of the 678 women (average age = 58), 12% of women refused to participate in the PNP for cultural reasons. Results: All 599 women participants reported barriers to obtaining breast health care with the number of barriers reported ranging from 1 to 6 barriers, (average = 3). The main barriers were system problems with health care programming (100%), financial problems (64%), communication concerns with the medical staff (58%), fear (44%), and social support (14%). We obtained 100% satisfaction with the PNP and exceeded our goal with 88% mammographic coverage rate. Conclusions: The PNP for breast cancer in the Andaraí Community has proven to be feasible in the context of local public health. The PNP promoted an increase in the mammographic coverage rate to 88%, assisted in the transmission of quality information, reduced the fear of mammography, and facilitated access to breast health care. Clinical trial information: 70832117.8.0000.5279.
EAGLE: A phase 3, randomized, open-label study of durvalumab (D) with or without tremelimumab (T) in patients (pts) with recurrent or metastatic head and neck squamous cell carcinoma (R/M HNSCC).
Authors: Lisa F. Licitra, Robert I. Haddad, Caroline Even, Makoto Tahara, Mikhail Dvorkin, Tudor-Eliade Ciuleanu, Paul M. Clement, Ricard Mesia, Svetlana I. Kutukova, Lyubov Zholudeva, Amaury Daste, Javier Daroqui Caballero, Bhumsuk Keam, Ihor Vynnychenko, Cedrik Lafond, Jagdish Shetty, Nassim Morsli, Helen Mann, Jerome Fayette, Robert L. Ferris
Journal: Journal of Clinical Oncology (2019)

6012 Background: EAGLE is a phase 3 study evaluating efficacy of D (anti-PD-L1 mAb) monotherapy and D+T (anti-CTLA-4 mAb) vs standard of care (SOC) in pts with R/M HNSCC who progressed following platinum-based therapy (NCT02369874). Methods: Pts were randomized 1:1:1 to D 10 mg/kg IV every 2 weeks (Q2W), D+T (D 20 mg/kg IV Q4W + T 1 mg/kg IV Q4W for 4 doses, then D 10 mg/kg IV Q2W), or SOC (investigator’s choice: cetuximab, taxane, methotrexate, or fluoropyrimidine-based regimen). The primary endpoint was overall survival (OS) with dual primary objectives of D+T vs SOC and D vs SOC. Additional endpoints included objective response rate (ORR), duration of response (DoR), and adverse events (AEs). Results: 240 pts were randomized to D, 247 to D+T and 249 to SOC. An imbalance for Eastern Cooperative Oncology Group performance status (ECOG PS) was seen in favor of the SOC arm (D, PS 0 = 26%, PS 1 = 74%; D+T, PS 0 = 26%, PS 1 = 74%; SOC, PS 0 = 32%, PS 1 = 68%). The risk of death was not statistically significantly different for D compared with SOC (HR: 0.88; 95% CI: 0.72–1.08; P = 0.20) or D+T vs SOC (HR: 1.04; 95% CI: 0.85–1.26; P = 0.76). Efficacy data are provided in the table. Treatment-related AEs Grade ≥3 were reported in 10.1% of pts (regardless of causality Grade ≥3 AEs were 41.4%) in the D arm, 16.3% (51.2%) for D+T, and 24.2% (44.2%) for SOC. Following treatment, 2% of pts in D, 5% in D+T and 15% in SOC received immunotherapy. Conclusions: D and D+T did not demonstrate a statistically significant improvement in OS compared to standard chemotherapy in pts with R/M HNSCC. Median OS and ORR of D arm were similar to other studies with checkpoint inhibitors. The SOC arm outperformed what has been seen for SOC arms in previous studies; subsequent immunotherapy may have confounded the OS analyses. The safety profile for D and D + T in R/M HNSCC is consistent with previous trials. Clinical trial information: NCT02369874. [Table: see text]
H3B-6527 clinical biomarker assay development and characterization of HCC patient samples.
Authors: Pavan Kumar, Vicki Rimkunas, Kun Yu, Zhaojie Zhang, Crystal MacKenzie, Joanne Schindler, Peter Smith, Ping Zhu, Anand Selvaraj, Lihua Yu, Subhasree Das, Jaya Julie Joshi
Journal: Journal of Clinical Oncology (2019)

4121 Background: FGFR4/FGF19 signaling axis is a novel therapeutic target in HCC. Multiple covalent FGFR4 inhibitors, including H3B-6527, are under clinical development. Preclinical efficacy studies in mice (including PDX) have shown that FGF19 expression (FGF19 + ) is a predictive biomarker for FGFR4 inhibitor response. The mechanisms driving FGF19 expression in HCC is largely unknown however, in some cases, focal amplification of ch11q13.3 containing FGF19 gene is thought to drive the FGF19 expression. Consistent with the preclinical observations, clinical studies have also shown that FGF19 + is a predictive biomarker for FGFR4 inhibitor response. However, these trials have also reported a large number of FGF19 + patients failing to respond to FGFR4 inhibitors necessitating refinement of patient selection strategies. In an attempt to obtain deeper insights into the role of FGF19 + as a predictive biomarker and potentially uncover additional biomarkers that will enable improvement in patient selection strategies, we have characterized a set of 258 HCC patient samples Methods: Samples were acquired from biobanks and utilized to qualify clinical assays including FGF19 copy number (FISH), mRNA expression (qRT-PCR), FGF19 protein (IHC), and a focused NGS panel for assessing both mutations and copy number. A multiplexed protein and mRNA platform enabled assessment of p-ERK and Ki67 (protein) and Cyp7A1 (mRNA) amongst other exploratory PD biomarkers from two FFPE slides. Results: FGF19 positivity rates for IHC and qRT-PCR were 18% (41/225) and 42% (87/209), respectively. The overall correlation was 60%, with 63% (22/235) IHC positive cases also being positive by qRT-PCR. For IHC+/qRT-PCR (-) cases, RNA quality may have impacted assay sensitivity. 4% (9/244) of samples were positive for FGF19 copy number. Among samples with FGF19 copy number gains, 22% (2/9) did not show positive FGF19 expression. Conclusions: Based on our data, FGF19 mRNA is a more inclusive selection strategy and offers an approach to further refine thresholds for efficacy as determined in the clinic. Multiplexed protein-mRNA assays were also validated and implemented to enable a more comprehensive clinical biomarker program.
Efficacy of tyrosine kinase inhibitors (TKIs) based on the ALK resistance mutations on amplicon-based liquid biopsy in ALK positive non-small cell lung cancer (NSCLC) patients (pts).
Authors: Laura Mezquita, Aurélie Swalduz, Cecile Jovelet, Sandra Ortiz-Cuaran, David Planchard, Gonzalo Recondo, Jose Carlos Benitez, Karen Howarth, Clive D. Morris, Emma Green, Ludovic Lacroix, Luc Odier, Etienne Rouleau, Pierre Fournel, Caroline Caramella, Claire Tissot, Maurice Perol, Luc Friboulet, Benjamin Besse, Pierre Saintigny
Journal: Journal of Clinical Oncology (2019)

3055 Background: Acquired ALK resistance mutations (mut.) are the main mechanism of tyrosine kinase inhibitor (TKI) resistance (30-50%). While next-generation TKIs are more active on mut. than earlier TKIs, compound ALK resistance are associated with failure to next-generation TKIs. We evaluated the clinical utility of detecting ALK resistance mutations in blood to predict TKI efficacy. Methods: ALK positive advanced NSCLC pts were prospectively enrolled between Oct. 2015 and Aug. 2018 in 8 French institutions. Prospective samples were collected; ctDNA was analyzed by amplicon-based Inivata InVisionFirst-Lung. Results: A total of 101 pts with advanced ALK positive NSCLC were enrolled and 328 samples collected. In samples collected at TKI failure (N=74), we detected 9 single and 7 complex (≥2) ALK resistance mut. (22%), associated with EML4-ALK variant 3 (38%) vs. variant 2 (13%) vs. variant 1 (none); 30% had other somatic mut. (mainly TP53 and KRAS, PI3KCA, MET, etc.). No mutations were detected in 48% of samples (ctDNA neg ). ALK mut. were more frequent after 2nd/3rd generation TKI (43% post-lorlatinib (7), 29% post-2nd gen. (31), 11% post-crizotinib (36)). ALKG1202R was the most common, as single (n=3) or complex mut. (n=4). The median overall survival (mOS) was 100.4 mo. (95% CI 41.9-158.9) and the median progression free-survival (mPFS) to subsequent line was 2.8 mo. (0.7-4.9). Patients with ctDNA neg had mOS of 105 mo. (39.3-172.1) vs. 58.5 mo. (33.1-84.0) if ≥1 ALK mut. vs. 44.1 mo. (20.0-68.2) if others ( P=0.001). Pts with the complex ALK mut. had worse OS compared to singles ALK mut. (mOS 26.9 mo. vs. 58.5 mo., P=0.001); ALK complex mut. were associated with poor efficacy to subsequent therapy (PFS &lt;3 mo. in 57%; no cases with PFS &gt;6 mo.) vs. single mut., with longer PFS (PFS &gt;6 mo. in 56%). Detectable ALKG1202R mut. were associated with shorter median OS (58.3 mo.; 7.9-109.1) vs. overall population; 86% of cases developed rapid PD (PFS &lt;3mo.) to subsequent therapy with only one durable response to lorlatinib (PFS &gt;6mo.). Conclusions: The absence of ctDNA mutations at TKI failure was associated with prolonged OS, whereas complex ALK mutations at TKI failure may predict resistance to subsequent therapy. Larger and specifically designed studies should be performed to validate these findings.
A randomized noncomparative phase II study of maintenance therapy with multiepitope vaccine Tedopi (OSE2101) ± nivolumab or FOLFIRI after induction chemotherapy (CT) with FOLFIRINOX in patients (Pts) with advanced pancreatic ductal adenocarcinoma (aPDAC) (TEDOPaM–PRODIGE 63 GERCOR D17-01 study).
Authors: Cindy Neuzillet, Vincent Hautefeuille, Aurélien Lambert, Marie-Line Garcia-Larnicol, Dewi Vernerey
Journal: Journal of Clinical Oncology (2019)

TPS4160 Background: FOLFIRINOX (5-fluorouracil [5FU], folinic acid [FA], irinotecan [Iri], and oxaliplatin [Ox]) is a standard 1 st -line treatment in fit Pts with aPDAC. Anti-PD-1/PD-L1 as single agents have failed in PDAC so far and new combination immunotherapies are needed. Tedopi (OSE2101) is a multiple neoepitope vaccine restricted to HLA-A2 positive Pts, targeting 5 tumor-associated antigens (CEA, HER2, MAGE2, MAGE3, TP53) that are frequently expressed in PDAC. This study aims to assess the efficacy and safety of Tedopi alone and in combination with anti-PD-1 nivolumab, or FOLFIRI as maintenance therapy in Pts with aPDAC after FOLFIRINOX induction CT. Methods: TEDOPaM - PRODIGE 63 is a 3-arm, Fleming 2-stage, open-label, randomized, non-comparative phase II study. 156 Pts with locally advanced or metastatic, pathologically proven PDAC; ECOG performance status 0-1; HLA-A2 genotype; controlled disease (objective response or stable disease) after 8 cycles of (modified) FOLFIRINOX; and adequate organ functions, are randomized (1:1:1, stratified on center, tumor stage, and best response to FOLFIRINOX) into 3 arms: Clinical trial information: NCT03806309. In Arms B and C, FOLFIRI is reintroduced at disease progression or unacceptable toxicity. Primary endpoint: overall survival rate at M12. Secondary endpoints: progression-free survival (CT-scan Q8W), duration of disease control, safety, objective response rate, RECIST v1.1/iRECIST comparison, HRQoL (EORTC QLQ-C30), Q-TWiST. An interim analysis is planned after inclusion of 20 Pts in each arm. Translational research will be performed on tumor tissue (initial FFPE biopsy and optional re-biopsy at inclusion): RNAseq (cancer and stroma), mutation burden, MMR status, immune infiltrates; and in blood (before and on-treatment): cytokine panel, PBMC phenotyping, vaccine-antigen specific T-cells, TCR repertoire, and extracellular vesicles, to explore biomarkers and pharmacodynamics effects of Tedopi ± nivolumab. Enrollment (12 th Feb 2019): 1. ClinicalTrials Registration: NCT03806309.[Table: see text]
A novel therapeutic peptide targeting myocardial reperfusion injury
Authors: Prisca Boisguérin, Aurélie Covinhes, Laura Gallot, Christian Barrère, Anne Vincent, Muriel Busson, Christophe Piot, Joël Nargeot, Bernard Lebleu, Stéphanie Barrère-Lemaire
Journal: Cardiovascular Research (2019)

Regulated cell death is a main contributor of myocardial ischaemia-reperfusion (IR) injury during acute myocardial infarction. In this context, targeting apoptosis could be a potent therapeutical strategy. In a previous study, we showed that DAXX (death-associated protein) was essential for transducing the FAS-dependent apoptotic signal during IR injury. The present study aims at evaluating the cardioprotective effects of a synthetic peptide inhibiting FAS:DAXX interaction.An interfering peptide was engineered and then coupled to the Tat cell penetrating peptide (Tat-DAXXp). Its internalization and anti-apoptotic properties were demonstrated in primary cardiomyocytes. Importantly, an intravenous bolus injection of Tat-DAXXp (1 mg/kg) 5 min before reperfusion in a murine myocardial IR model decreased infarct size by 48% after 24 h of reperfusion. In addition, Tat-DAXXp was still efficient after a 30-min delayed administration, and was completely degraded and eliminated within 24 h thereby reducing risks of potential side effects. Importantly, Tat-DAXXp reduced mouse early post-infarction mortality by 67%. Mechanistically, cardioprotection was supported by both anti-apoptotic and pro-survival effects, and an improvement of myocardial functional recovery as evidenced in ex vivo experiments.Our study demonstrates that a single dose of Tat-DAXXp injected intravenously at the onset of reperfusion leads to a strong cardioprotection in vivo by inhibiting IR injury validating Tat-DAXXp as a promising candidate for therapeutic application.
Development of a prognostic risk model for small cell lung cancer: Identification of high-, intermediate-, and low-risk cohorts based on clinical-genomic data.
Authors: Fatemeh Ardeshir-Larijani, Gary Wildey, Pingfu Fu, Afshin Dowlati
Journal: Journal of Clinical Oncology (2019)

8554 Background: Although many clinical prognostic factors for SCLC outcome have been described, there are no models that incorporate the combination of clinical and genomic details into a risk model defining high and low risk patients. Methods: From a total of 791 SCLC patients seen between 2013-2018, 91 were evaluated by exome sequencing. Using the univariate Cox regression model, 19 genes were prognostic for survival and included RET, ERBB4 MAP3K1, ABL1, CCND1, TSC1, PRKCI, FGFR3, JAK3, ZNF217, BRCA1, GPR124, LRP1B, GNAS, TAF1, FGF3, STAT3, CD79A and FLT. LASSO, elastic-net Cox and traditional Cox model with stepwise selection along with traditional clinical factors (age and stage) were further used to build the final model. The final risk groups were defined based upon the prognostic index from multivariable Cox model involving age, stage (extensive/limited) and 6 genes ( MAP3K1, ABL1, CCND1, PRKCI, BRCA1, GNAS). Results: The overall survival (OS) for the entire cohort was 11.2 (95% CI: 9 – 13.4) months and the median age was 65 (range: 39 - 90) years. Eighty percent (N = 74) of evaluated patients had extensive stage (ES) disease. The HR for death of age and stage (ES/LS) was 1.06 (CI: 1.03-1.08, p &lt; 0.0001) and 4.33 (CI: 2.23-8.41, p &lt; 0.0001) respectively. ABL1 demonstrated the highest HR of 10.14 (2.81-36.6, p = 0.0004) followed by PRKCI (HR: 5.05, CI: 1.43-17.8 , p &lt; 0.012), CCND1 (HR: 4.52, CI: 1.23-16.57, p &lt; 0.023), MAP3K1 (HR: 3.38, CI: 1.37- 8.33, p = 0.008) and GNAS (HR: 2.21, CI: 1.11-4.43, p &lt; 0.025). Interestingly, BRACA1 mutation was protective as patients with BRACA1 mutation had significantly better overall survival (HR: 0.3, CI: 0.1- 0.85, p &lt; 0.023). Our model categorized patients into three groups of low risk ( N= 31), intermediate risk ( N= 30) and high risk ( N= 30) with significantly different survival outcomes ( p &lt; 0.0001). Those with low risk had the median OS of 27.4 (95% CI: 16.8-55.5) months, intermediate risk with median OS of 10.8 (95% CI: 7 – 14.7) months and high risk with median OS of 5.4 (95% CI: 3.9- 9) months. Conclusions: This clinical-genomic risk group stratification represents a useful model to estimate SCLC survival outcome and may have value in future clinical trials.
Case 43-1983
Authors: Richard C. Cabot, Robert E. Scully, Eugene J. Mark, Betty U. McNeely, Gary E. Friedlaender, Alan L. Schiller
Journal: New England Journal of Medicine (1983)

Presentation of CaseA 76-year-old man was admitted to the hospital because of pain and swelling in the left knee.There was a 35-year history of pain in the left knee after an athletic injury. Twelve years before admission the pain worsened; indomethacin was prescribed, with relief. Six years before entry the patient collapsed abruptly and was taken to another hospital, where a ruptured abdominal aortic aneurysm was found. An aortoiliac graft was inserted. The hospital course was complicated by hypotension, persistent renal failure that required hemodialysis, a respiratory-distress syndrome for which respiratory assistance was necessary, episodes of complete heart . . .
Nano-drug System Based on Hierarchical Drug Release for Deep Localized/Systematic Cascade Tumor Therapy Stimulating Antitumor Immune Responses
Authors: Yuchu He, Cong Cong, Xiaoling Li, Ruiyan Zhu, Anshuo Li, Shuxian Zhao, Xiaowei Li, Xin Cheng, Mengxue Yang, Dawei Gao
Journal: Theranostics (2019)

Inaccessibility of deep-seated malignant cells in the central region of tumors and uncontrollable tumor recurrence represent a significant challenge for conventional synergistic cancer therapy. Herein, we designed a novel nanoplatform based on hierarchical drug release for deep cascade cancer therapy including localized photothermal therapy, systematic chemotherapy, and elicited immune responses. Methods: The first-step chemotherapy could be carried out by polydopamine (PDA) releasing doxorubicin (DOX) in the specific microenvironment of lysosomes (pH 5.5). The branched gold nanoshells and PDA converted the light to heat efficiently to accomplish the second-step photothermal therapy and collapsed biomimetic vesicles (BVs) to release paclitaxel (PTX), which promoted the third-step of chemotherapy and triggered immune responses. Results: After 10 days of treatment, there were no obvious residual tumors in tumor-bearing mice. Significantly, 10 days after stopping treatment, mice in the drug immune-therapeutic group showed little tumor recurrence (1.5 times) compared to substantial recurrence (20 times) in the conventional treatment group. Conclusion: The hierarchical drug release and cascade therapeutic modality enhance the penetration of drugs deep into the tumor tissue and effectively inhibit recurrence. This cascade therapeutic modality provides a novel approach for more effective cancer therapy.
Racial disparities in setting of care in women with breast cancer in South Carolina.
Authors: McKenzie Sorrell, Karen Wickersham, Swann Arp Adams, Sue P. Heiney
Journal: Journal of Clinical Oncology (2019)

e18146 Background: African American (AA) women with breast cancer (BrCa) suffer a 40% higher mortality burden than White women despite having about equal incidence nationally and lower incidence in South Carolina. Our aim was to describe inpatient and emergency department visits by race and geographic location among BrCa survivors. Methods: We analyzed data from a study (1R15CA179355-01A1; Adams, PI) that combined administrative claims data from South Carolina’s Medicaid Program and a state-based, private-payor health plan to matching BrCA cases from the SC Central Cancer Registry. Race was determined by patient self-report. Geographic location was assigned using designations from the Rural-Urban Commuting Area Codes (RUCA). We used descriptive statistics to characterize the study sample and Chi-square test of independence to compare the descriptive statistics by race and rural/urban continuum. Results: The sample (N = 2723) was 33.6% AA, 91.8% non-Hispanic, primarily married 48.8%, and ranged in age from 14 to 64 years. Most women in the sample lived in an urban area (74.9 %). Most women had Stage I (16.9%), IIA (13.9%), or IIB (7.5%) disease. Women were primarily treated in an outpatient setting; 1.3% (n = 36) were seen in an emergency room and 1.2% (n = 34) were hospitalized. When comparing women living in a rural versus urban area, there were significant differences in TNM stage of disease (by pathology), marital status, race, and setting of care (all p’s ≤ 0.001). When comparing women by race, there were significant differences in age, ethnicity, marital status, stage of disease, and setting of care (all p’s ≤ 0.001). Conclusions: Women with BrCA in SC continue to experience disparities with regard to stage of disease at diagnosis and setting of care. Future research should focus on specific predictors of hospitalization and the relationship of rurality and race with setting of care.
Abstract 13180: Dmp1 Overexpression Prevents Bone Alterations, Fgf23 Elevations and Cardiac Hypertrophy in Mice With Chronic Kidney Disease
Authors: Corey Dussold, Claire Gerber, Samantha White, Xueyan Wang, Connor Francis, Lixin Qi, Ying Liu, Chaoyuan Li, Jian Q Feng, Myles Wolf, Valentin David, Aline Martin
Journal: Circulation (2018)

Introduction: Disordered bone and mineral metabolism is a common complication of chronic kidney disease (CKD), including an exponential increase in production and secretion of the osteocyte-derived...