tbuckley/cabot-search huggingface dataset:
A phase I trial of ALKS 4230, an engineered cytokine activator of NK and effector T cells, in patients with advanced solid tumors.
Authors: Ulka N. Vaishampayan, Marc S. Ernstoff, Vamsidhar Velcheti, Christopher J. Hoimes, Mayer N. Fishman, Daniel C. Cho, David F. McDermott, Michael R. Kurman, Juan Alvarez, Lei Sun, William Slichenmyer, Sean Rossi
Journal: Journal of Clinical Oncology (2017)

TPS3111 Background: ALKS 4230 is an engineered fusion protein comprised of a circularly permuted interleukin-2 (IL-2) and IL-2 Receptor (IL-2R) α designed to selectively activate the intermediate-affinity (ia) IL-2R, comprised of IL-2Rβ and γ c . The iaIL-2R is expressed predominantly on effector lymphocytes, which play an important role in driving antitumor immune responses. In contrast, unmodified IL-2 activates high-affinity (ha) IL-2R, driving the expansion of haIL-2R-expressing cell types including immunosuppressive CD4 + regulatory T (T reg ) cells at concentrations below those at which iaIL-2R bearing effector cells are activated. Also, the haIL-2R is expressed on endothelial cells and may contribute to IL-2 mediated toxicity via capillary leak syndrome. Thus, selective activation of the iaIL-2R by ALKS 4230 has the potential to provide enhanced tumor killing as well as improved tolerability. Methods: ALKS 4230 is being studied in a phase 1 first-in-human trial in patients with advanced solid tumors. Key study objectives are to determine a recommended phase 2 dose and characterize the safety profile, pharmacokinetics (PK), pharmacodynamics (PD) and evidence of antitumor activity. A dose-escalation phase in patients with refractory solid tumors (Part A) will be followed by expansion cohorts in defined populations (Part B). ALKS 4230 is administered as a 30-minute intravenous infusion once daily for five days each cycle. Eligibility requires age 18, ECOG PS 0-1 and adequate bone marrow, liver and kidney function. The dose will be escalated until reaching MTD or an Optimal Biologic Dose. The first two dose cohorts will use a 3+3 design. Subsequent cohorts in Part A will enroll a minimum of 6 subjects. In Part B up to 21 patients will be enrolled into each of four tumor-specific cohorts. Peripheral blood samples will be collected for PK, immunogenicity and PD assessments. The primary PD endpoint is change-from-baseline in CD8 + T, NK and T reg cell counts. Other PD measures include serum concentrations of multiple proinflammatory cytokines and immunohistochemical assessment of markers of immune activation in tumor tissue from selected patients. Recruitment for Part A is ongoing. Clinical trial information: NCT02799095.
Chronic Pain Among Suicide Decedents, 2003 to 2014: Findings From the National Violent Death Reporting System
Authors: Emiko Petrosky, Rafael Harpaz, Katherine A. Fowler, Michele K. Bohm, Charles G. Helmick, Keming Yuan, Carter J. Betz
Journal: Annals of Internal Medicine (2018)

More than 25 million adults in the United States have chronic pain. Chronic pain has been associated with suicidality, but previous studies primarily examined nonfatal suicidal behaviors rather than suicide deaths associated with chronic pain or the characteristics of such deaths.
Efficacy of dabrafenib (D) and trametinib (T) in patients (pts) with <i>BRAF</i> V600E–mutated anaplastic thyroid cancer (ATC).
Authors: Vivek Subbiah, Robert J. Kreitman, Zev A. Wainberg, Jae Yong Cho, Jan H.M. Schellens, Jean-Charles Soria, Patrick Y. Wen, Christoph Zielinski, Gladys Urbanowitz, Bijoyesh Mookerjee, Dazhe Wang, Fatima A. Rangwala, Bhumsuk Keam
Journal: Journal of Clinical Oncology (2017)

6023 Background: ATC is a rare, aggressive malignancy with a dismal prognosis. Median overall survival (OS) is &lt; 6 mo. Combined BRAF and MEK inhibition is efficacious in BRAF V600–mutated melanoma and lung cancer. One-fourth of ATCs harbor activating BRAF V600E mutations; thus, D (BRAF inhibitor) + T (MEK inhibitor) was evaluated as a treatment for pts with BRAF V600E–mutated ATC. Methods: In this phase 2, open-label trial (NCT02034110), pts with BRAF V600E mutations in 9 rare tumor types, including ATC, received continuous D (150 mg BID) + T (2 mg QD) until unacceptable toxicity, disease progression, or death. Eligible pts had advanced or metastatic cancer with no standard-of-care treatment options. The primary endpoint was investigator-assessed overall response rate (ORR). Secondary endpoints included duration of response (DOR), progression-free survival (PFS), OS, and safety. We report data from the ATC cohort. Results: 16 pts with BRAF V600E–mutated ATC had evaluable data with a median follow-up time of 47 wk (range 4-120 wk). BRAF V600E mutations were centrally confirmed in 15/16 pts. Median age was 72 y; all 16 pts had undergone prior tumor radiation and/or surgery and 6/16 pts (38%) had received ≥1 prior line of systemic therapy. Investigator-assessed confirmed ORR was 69% (11/16; 95% CI, 41%-89%), with 7/11 responses ongoing at the time of data cut. The Bayesian estimate of ORR was 69% (95% credible interval, 47%-87%) with a 100% probability that this ORR exceeded the 15% historical RR. Median DOR, PFS, and OS were not estimable due to insufficient progression and death events. Kaplan-Meier estimates of DOR, PFS, and OS at 12 mo were 90%, 79%, and 80%, respectively. The safety population comprised 100 pts enrolled in 7/9 histologies. Among all pts, 92% had an AE. Common AEs of any grade for all histologies were fatigue (38%), pyrexia (37%), and nausea (35%). In the ATC cohort, the most common grade 3/4 events were hyponatremia (19%), pneumonia (13%), and anemia (13%). Conclusions: D+T combination therapy significantly improved outcomes in ATC with a favorable safety profile. This regimen represents a clinically meaningful therapeutic advance for pts with advanced/metastatic BRAF V600–mutated ATC. Clinical trial information: NCT02034110.
Lowering the <i>P</i> Value Threshold—Reply
Authors: John P. A. Ioannidis
Journal: JAMA (2018)

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Association of insurance status and race with overall survival among patients with cutaneous T-cell lymphoma: A National Cancer DataBase analysis.
Authors: Pamela Blair Allen, Christopher Flowers, Mary Jo Lechowicz, Jordan Goldstein
Journal: Journal of Clinical Oncology (2018)

e18624 Background: Previous studies have demonstrated outcome disparities among certain groups of patients with cutaneous T-cell lymphoma (CTCL) This study examined disparities in overall survival (OS) by insurance status in a large national cohort of patients with CTCL Methods: We used prospectively collected data from the National Cancer DataBase (NCDB) to evaluate clinical features and outcomes among patients diagnosed with Cutaneous T-cell lymphoma from 2004 - 2014. We identified patients with a histologically confirmed first primary diagnosis of CTCL using International Classification of Diseases for Oncology, 3rd Edition (ICD-O-3) histology codes. Patient age, race, sex, disease stage, Charlson comorbidity index, treatment, region (Northeast, Midwest, South, or West), income, and insurance status were assessed in multivariable Cox proportional hazards models examining OS. Results: Among 11,099 patients with CTCLs, subtypes included: mycosis fungoides (MF), Sezary syndrome (SS), mature T-cell lymphoma NOS, angioimmunoblastic T-cell lymphoma, and subcutaneous panniculitis-like. The insurance status was as follows: 5,633 (54.1%) private; uninsured 382 (4.2%); Medicaid 539 (4.9%); Medicare 4,545 (36.8%). When adjusting for covariates, the following factors were significantly associated with inferior survival: African American (AA) race (HR = 1.31; 95% CI 1.04-1.66, p = 0.02); Medicaid (HR = 2.5; 95% CI 1.81-3.43, p < 0.01), and Medicare (HR = 2.12; 95% CI 1.86-2.42, p < 0.01). Additional risk factors included age > 60 years, male gender, comorbidities, and advanced stage disease. For patients with MF and SS, there was decreased survival in the South and Midwest regions compared to the North. Conclusions: Our study reveals that CTCL patients with the following risk factors have been associated with inferior outcomes: AA race, Medicaid or Medicare insurance status, male gender, and presence of co-morbidities. These data supports prior studies demonstrating the role of insurance status, race, and other pre-treatment factors on survival for patients with CTCL and identifies populations in need of future interventional studies.
Fish oil supplementation and inflammatory response during neoadjuvant chemoradiation for rectal cancer: Results from a prospective, randomized, controlled trial.
Authors: Juliana De Aguiar Pastore Silva, Mariane Messias Reis Lima Silva, Celso Lopes Mello, Maria D. Begnami, Maria Leticia Gobo Silva, Samuel Aguiar Junior
Journal: Journal of Clinical Oncology (2018)

3605 Background: It has been proposed that omega-3 fatty acids can modulate inflammatory response and contribute to improve anti-cancer therapies. Methods: Patients clinically staged as T3,4 and / or N + rectal carcinoma were randomized to receive oral ingestion of encapsulated fish oil during neoadjuvant conventional chemoradiation (intervention group – IG) or chemoradiation without supplement (control group – CG). All patients were operated about 8 weeks after chemoradiation. Glasgow Prognostic Score (GPS) was the primary endpoint. Other inflammatory and nutritional parameters and quality of life (QOL) measurements were also collected at 4 moments: M1: at diagnosis; M2: at the end of chemoradiation; M3: at 4 weeks after end of chemoradiation; and M4: preoperatively. Eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) were quantified in blood samples by gas chromatography. Results: 179 patients were referred for neoadjuvant treatment between January, 2013 and July, 2017. 120 met eligibility criteria. 114 were randomized (IG: 55 and CG: 59). Mean age were 59.5 years, ranging from 30-86 years. There was no difference between groups in M1. In M2 and M3 there were differences between the supplemented group (IG) and the CG in systemic inflammatory response measured by Glasgow Prognostic Score (M2:P = 0.001; M3:P = 0.027), serum protein C reactive (PCR)(M2: P = 0.001; M3: P = 0.045) and ratio CRP / Albumin (M2:P = 0.00; M3: P = 0.005) - the lowest values in the IG. About QOL, CG presented more symptoms in M2 for dysuria (P = 0.031), M3 for pain (P = 0.023), buttock pain (P = 0.005) and dyspareunia (P = 0.041); IG presented less anxiety (P = 0.040). In M4 the differences between the groups were about recent lost weight (P = 0.025), with lowest values in IG, and CG present more symptoms for appetite loss (P = 0.016), buttock pain (P = 0.044) and bloating (P = 0.007). There were no differences in food intake, body composition, global subjective assessment and classification of nutritional status at any study moment. Conclusions: This dietary intervention was able to modulate inflammatory response, has impact on some nutritional markers and some components of quality of life. Clinical trial information: NCT02534389.
TCT-315 Correlation between fractional flow reserve and non-invasive myocardial perfusion imaging in patients with severe aortic stenosis and coronary artery disease.
Authors: Roberto Scarsini, Rosaria Cantone, Gabriele Venturi, Giovanni Luigi De Maria, Mattia Lunardi, Mauro Feola, Rajesh Kharbanda, Adrian Banning, Flavio Ribichini, Flavio Ribichini
Journal: Journal of the American College of Cardiology (2018)
Pan-cancer mesenchymal assay to predict response to MEK inhibitors.
Authors: Nuala McCabe, Laura A Knight, Lara Dura Perez, Bethanie Price, Andrena McCavigan, Aya El-Helali, Sharon Eddie, Charlie Gourley, Denis P Harkin, Richard D. Kennedy
Journal: Journal of Clinical Oncology (2018)

12111 Background: Unsupervised hierarchical clustering of gene expression data from 265 high grade serous ovarian cancer (HGSOC) patients identified 3 major molecular subgroups. One subgroup is driven by activation of the MAPK-pathway and is associated with a mesenchymal phenotype, poor prognosis and resistance to platinum.The MAPK pathway is currently being targeted by novel therapeutics and hence an assay to detect activation of the pathway across cancers would be highly valuable as a clinical trial enrichment tool. Methods: Using TCGA data we show the existence of the mesenchymal subgroup across a range of solid tumours including stomach, bladder colon, lung, melanoma and prostate cancer. Further to this, a common gene list was generated to include only transcripts with high variability and expression across diseases, and used as a starting list for the development of a 15 transcript assay which can be used to prospectively identify the mesenchymal subgroup from archived tissue. The 15 gene expression assay was tested in preclinical model systems to assess its utility at predicting response to MEK inhibitors. Results: The 15 gene expression mesenchymal assay was a poor prognostic marker in 13 different solid tumours: overall HR = 1.78 [95% CI:1.65-1.92]) p < 0.0001. Additionally the assay was associated with a mesenchymal phenotype (migration, invasion) and activated MAPK (phospho-MAPK) signalling in preclinical cell line models. The assay also predicted phospho-MEK expression in clinical samples (p < 0.05). The assay score was reduced by MEK inhibition (p < 0.05) and elevated by KRAS, NRAS and MEK1 overexpression (p < 0.05). The assay predicted response to the MEK inhibitors Trametinib and Selumetinib across cell line models from multiple diseases (p < 0.001) and to Trametinib in mouse xenograft studies of lung cancer cell lines. Conclusions: A 15 gene expression assay has been developed from FFPE samples across multiple diseases to detect a mesenchymal molecular subgroup associated with MAPK signalling. The assay predicted sensitivity to MEK inhibitors in pre-clinical cell line and mouse model systems. Further work aims to validate the assay as a predictive biomarker in clinical samples from patients treated with MEK targeted therapies.
Pilot analysis exploring the potential value of an integrated electronic patient reported outcome (PRO) application specifically designed for use in oncology practice.
Authors: Thomas Hopkins
Journal: Journal of Clinical Oncology (2017)

e18246 Background: PROs may soon be used as indicators of the quality of care provided and to support comparative effectiveness research (CER). Many oncology practices are developing tools to deploy PRO tools electronically to improve effectiveness of data capture, enhance the clinical utility of the data for providers and integrate PRO data with local and national registries. Here we describe our preliminary experience with developing software for this purpose. Methods: We created a software application and a HIPAA compliant cloud-based data architecture to obtain, store, clean and normalize PRO data and infusion system data needed to define, create, measure and analyze clinical and operational key performance indicators, which are then integrated into reports and displayed to end-users on a dashboard in an actionable format. The application supports efficient data collection and interfaces with patients via secure text message or email link. The dashboard component of the application is a legible, single-page, real-time interface, depicting a tabular and graphical presentation of current and historical key performance indicators that enable instantaneous and informed decisions. Results: Figure I depicts the application patient demographics page, which allows clinicians and clinical support staff to enter patient data and enroll the patient in customized templates, which allow flexible delivery of content on a customized predetermined timeline. Figure II illustrates the PRO patient-facing interface, as displayed on a mobile device. Figure III illustrates the analytics function of the application, which displays patient-specific summary or population aggregate data and has the capacity to combine PRO data with objective data obtained from infusion systems. Conclusions: In this abstract, we describe our experience with creating an application that will collect and deliver accurate, reliable and ultimately actionable clinical and operational data to clinicians and operational leaders in oncology practices. The application is currently being evaluated for clinical and research use at our institution.
Determining the sensitivity of primary acute myeloid leukemia (AML) samples with FLT3-ITD or FLT3-D835 mutations to FLT3 inhibitors using an ex vivo drug sensitivity screen.
Authors: Mara Rosenberg, Guang Fan, Kevin Watanabe-Smith, Cristina Tognon, Brian J. Druker, Jeffrey Tyner, Marc Loriaux
Journal: Journal of Clinical Oncology (2018)

7025 Background: AML has high molecular complexity and certain markers are predictors of overall survival. Mutations in FLT3-ITD, for example, lead to a poor prognosis with outcomes further worsened by co-occurring mutations in DNMT3A. Small molecule inhibitors have been developed to target a select number of these mutations such as Midostaurin on FLT3-ITD and FLT3-D835. However, the impact of the specific FLT3 mutation or the effect of co-occurring mutations in DNMT3A and NPM1 on drug sensitivity is not fully known. Methods: We identified 503 primary AML samples tested with an ex-vivo drug sensitivity screen that includes 130 small-molecule inhibitors and over 10 FLT3 inhibitors. Mononuclear cells were screened, metabolic viability assessed, and drug response summarized by area under the curve (AUC). Results: FLT3-ITD was the strongest indicator for response to FLT3 inhibitors (Table 1). Sensitivities were similar with DNMT3A and/or NPM1 co-mutations. Further, FLT3-D835 mutant samples showed no increased sensitivity to FLT3 inhibitors compared to non-FLT3 mutated samples. Conclusions: The similar ex-vivo drug sensitivity profiles inFLT3-ITD AML with or without DNMT3A and/or NPM1 mutations suggest co-treatment with FLT3 inhibitors will allow for improved overall survival in these cohorts. Additional clinical testing may further characterize the effect of FLT3-D835 mutations on targeted therapies and the impact of co-mutations. Some FLT3-ITD inhibitors showed increased potency compared to Midostaurin suggesting alternative treatment choices for select AML patients. Mean AUC values (± confidence interval) for each drug by sample classification. Classification Quizartinib KW-2449 Cabozantinib Sorafenib Sunitinib Midostaurin ITD+ 37(±3)* 55(±5) 45(±4)* 52(±4) 55(±4) 56(±4) ITD+ / DNMT3A+ 36(±5)* 55(±6) 41(±7)* 48(±7) 54(±7) 60(±7) ITD+ / NPM1+ 35(±4)* 52(±6) 39(±5)* 48(±5) 53(±4) 53(±6) D835+ 46(±8)* 70(±8) 53(±11) 59(±8) 61(±8) 69(±9) FLT3- 57(±2)* 77(±2) 67(±2)* 73(±2) 74(±2) 75(±2) *Drug AUC differs from Midostaurin (p < 0.001). Sample classification differs from FLT3 Negative cohort (p < 0.001).
Treatment trends and outcomes in early-stage Hodgkin lymphoma in elderly: A National Cancer Data Base analysis.
Authors: Gaurav Goyal, Arun Kanmanthareddy, Ronald S. Go, Peter T. Silberstein, James O. Armitage
Journal: Journal of Clinical Oncology (2016)

7536 Background: The outcomes for early stage (I-II) Hodgkin lymphoma (HL) have improved significantly over the past few decades. However, old age (≥60 years) continues to be associated with poor outcomes. There is a paucity of data defining optimal treatment regimens in this age group. In this study, we aim to identify the practice patterns and outcomes in elderly with early stage HL using the National Cancer Data Base (NCDB). Methods: This is a retrospective study of patients aged ≥ 60 years diagnosed with early stage HL from 2004 to 2012 utilizing NCDB. Outcomes of patients undergoing chemotherapy (CT), radiation therapy (RT) or CT+RT were compared. Kaplan-Meier curves of survival for individual therapy were constructed and compared using log-rank test. Multivariate analysis for predictors of mortality was conducted using Cox-proportional hazard method. Results: A total of 3,795 patients were included in the analysis. At baseline, 51% of the patients were male and 41% had stage I disease. Out of the 3,795 patients, 51% underwent CT, 16% underwent RT, and 33% underwent CT+RT. The utilization of all treatment modalities did not vary significantly from 2004 to 2012 (CT 48% vs. 52%; RT 20% vs. 15%; CT+RT 32% vs. 34%; P=0.227). With a median follow up duration of 40.4 months, the unadjusted survival rates for patients receiving CT, RT or CT+RT were 58.1%, 54% and 77.7%, respectively (P<0.0001). On multivariate analysis, CT+RT improved the overall mortality as compared to monotherapy (Table 1). Conclusions: In older patients (≥60 years) with stage I-II HL, combination of chemotherapy and consolidative radiation results in improved survival as compared to monotherapy. However, utilization of combination therapy in this age group appears low. It could be partly secondary to comorbidities limiting the use of CT+RT in elderly. Patient characteristics and multivariate analysis. Baseline characteristics P value Radiation therapy (RT) Chemotherapy (CT) CT+RT Age (years) 75.5 ± 8.9 70.9 ±7.6 69.4 ±7.1 <0.001 Charlson Deyo Score <0.001 0 79% 74% 80% 1 15% 20% 15% 2 6% 6% 5% Multivariate analysis Charlson Deyo Score HR CI 0 0.59 0.48 - 0.72 1 0.83 0.66 - 1.03 2 1 Treatment type CT 2.39 2.08 - 2.74 RT 2.63 2.22 - 3.12 CT+RT 1