tbuckley/cabot-search huggingface dataset:
A phase II trial of dasatinib in patients with unresectable locally advanced or stage IV mucosal, acral, and vulvovaginal melanomas: A trial of the ECOG-ACRIN Cancer Research Group (E2607).
Authors: Kevin Kalinsky, Sandra J. Lee, Krista M. Rubin, Donald P. Lawrence, A. John Iafrate, Darrell R. Borger, Kim Allyson Margolin, Mario M. Leitao, Henry B. Koon, Ahmad A. Tarhini, Andrew Pecora, Gary Irvin Cohen, Timothy Kuzel, John M. Kirkwood
Journal: Journal of Clinical Oncology (2016)

9501 Background: Pre-clinical studies report a critical role of c-KIT mutations in some mucosal, acral, solar, and vulvovaginal melanomas. Clinical trials of KIT-directed therapy with imatinib and sunitinib demonstrated activity in these subtypes. Unlike other TKIs, dasatinib has activity in melanoma cell lines with the most common KIT mutation at exon 11L576P. E2607 assessed the efficacy of dasatinib in treatment-naïve or previously-treated patients (pts) with unresectable melanoma of these subtypes. Methods: Pts were assigned to receive dasatinib 70 mg PO twice daily with adjustment for toxicity. The primary objective for this two-stage phase II trial was response rate (RR: RECIST). Stage I was open to KIT mutated (KIT+) and wild-type (KIT-) tumors with mucosal, acral, and solar melanomas (n = 57). Depending upon the interim analysis, stage II would be for pts with KIT+ (n = 30) tumors; to enrich for KIT+, vulvovaginal was added and solar melanomas removed. Secondary objectives included progression-free survival (PFS), overall survival (OS), and safety. Results: From May 2009 to Dec 2010, 57 pts were accrued to stage I. These data were presented at ASCO 2012. Three pts had KIT+ tumors, with 13.2+ months (mo) as the longest OS. Stage II opened in Nov 2011, accrued 24 pts with KIT+ tumors, and closed in Dec 2015 due to slow accrual. Six pts had mucosal (25%), 9 acral (37.5%), and 9 vulvovaginal melanomas (37.5%). As of Jan 2016, 16/24 have progressed (median PFS: 4.0 mo, 95% CI: 1.3-25.0) and 14/24 died (median OS: 12.3 mo, 4.5-29.7). Among 10 surviving pts, median follow-up is 15.2 mo (0.5-36.1 mo). Of 17 pts from stage II with mature response data, 4 had partial response (PR: 23.5%), 6 stable disease (35%), 5 progression (29.5%), and 2 were unevaluable (12%). Grade III (11/23: 48%) treatment-related toxicities were fatigue, (5 pts), anemia (3 pts) and dyspnea (2 pts). One pt had grade IV dyspnea. Conclusions: E2607 is closed to accrual, and finalized results, including type of KIT mutation and durations of disease control from stages I and II will be presented. Among pts with these KIT+ melanoma subtypes, dasatinib is an active agent. Clinical trial information: NCT00700882.
Sipuleucel-T (sip-T) overall survival (OS) and clinical outcomes by baseline (BL) prostate-specific antigen (PSA) quartiles in patients (pts) with metastatic castration-resistant prostate cancer (mCRPC): PROCEED registry.
Authors: A. Oliver Sartor, Celestia S. Higano, Matthew R. Cooperberg, Nicholas J. Vogelzang, Shaker R. Dakhil, Christopher Michael Pieczonka, Jeff Vacirca, Raoul S Concepcion, Ronald F Tutrone, Luke T. Nordquist, Carl A Olsson, David F. Penson, Ian Schnadig, James L. Bailen, Bryan Mehlhaff, Nancy N. Chang, Nadeem Anwar Sheikh, Bruce Brown, Andrew J. Armstrong
Journal: Journal of Clinical Oncology (2018)

5041 Background: Sip-T is an autologous cellular immunotherapy for asymptomatic/minimally symptomatic mCRPC. IMPACT analyses suggested that OS was longer in treated and control pts with low baseline PSA, and OS benefit was greatest for sip-T vs control in the pts with the lowest PSA (Schellhammer Urol 2013). We analyzed the prognostic value of BL PSA in PROCEED (NCT01306890), a phase 4 registry study in mCRPC pts. Methods: Eligible mCRPC pts were scheduled to receive 3 sip-T infusions at ~2-weekly intervals. Objectives included cerebrovascular event risk (primary) and OS (secondary). Follow-up was every 3 months after sip-T for 3 years minimum or until death or withdrawal. This is a post-hoc analysis (see Table for tests) of outcomes by PSA quartile. Results: 1976 pts were enrolled between 2011–2017: median age 72 yrs; 87% Caucasians, 12% African Americans; 51% had a Gleason score ≥8; prior therapies 78% (local) & 99% (hormonal). 1255 pts died. Median (range) BL PSA was 15 (0–7497) ng/mL. All outcomes in Table were significantly worse in the 2nd, 3rd & 4th PSA quartiles vs the 1st (lowest PSA) quartile. Clinical trial information: NCT01306890. Conclusions: OS & time to first ACI are longer in sip-T treated pts in the lowest BL PSA quartile vs sip-T treated pts with higher PSA. Survival of nearly 5 years was seen in the lowest PSA quartile. Although PROCEED did not have a comparator arm, the trend for longer OS is concordant with that seen in IMPACT. BL PSA ng/mL ≤5.27 N = 472 > 5.27–≤15.08 N = 471 > 15.08–≤46 N = 472 >46 N = 471 Median time to event (months; 95% CI)a Hazard ratio (95% confidence interval) vs 1st quartile† OS 48 (44–51) 33 (31–36) 1.6 (1.3–1.9)† 27 (24–30) 2.0 (1.7–2.4)† 18 (16–21) 3.0 (2.6–3.6)† Time to 1st ACI 10 (9–12) 8 (7–9) 1.4 (1.2–1.6)† 7 (6–8) 1.5 (1.3–1.8)† 6 (6–7) 1.7 (1.5–2.0)† Time to death due to disease progressionb 57 (49–not estimable) 37 (34–42) 1.7 (1.4–2.1)† 34 (29–39) 2.0 (1.7–2.5)† 24 (21–27) 3.1 (2.5–3.7)† aKaplan Meier; bclinical or PSA progressionACI, anticancer intervention (abiraterone, enzalutamide, radium-223, docetaxel, cabazitaxel)†p < 0.001 (Cox regression model)
Abstract 17781: Single Measurement of Cardiac Troponin T With a High-Sensitivity Assay Provides Valuable Information in Unselected Chest Pain Patients
Authors: Sjur H Tveit, Peder L Myhre, Nils Jacob Hoff, Tri M Le, Tor-Arne Hagve, Torbjørn Omland, Helge Røsjø
Journal: Circulation (2017)

Introduction: Whether high-sensitivity cardiac troponin T (hs-cTnT) levels provide valuable diagnostic and prognostic information across the spectrum of patients with acute coronary syndrome (ACS) ...
The tissue microenvironment (TME) of colorectal cancer (CRC): Myeloid cells to display a combination of activatory and inhibitory markers and relation to mTOR induction.
Authors: Louise Ann Elliott, Kieran Sheahan, Glen Doherty, Raymond S. McDermott, David William Fennelly, Elizabeth Ryan
Journal: Journal of Clinical Oncology (2016)

e23106 Background: Tumor resident myeloid cells (MCs) are instrumental to cancer progression. Consequently, MCs are an emerging therapeutic target in many cancers. However, the mechanisms by which tumours regulate MCs remain poorly defined.Our aim was to investigate how the colorectal TME impacts on MCs recruitment and function. Methods: We analyzed the phenotype of tumor infiltrating MCs compared to those resident in uninvolved tissue employing multi-colour flow cytometry (n = 21, patients with Stage II/III CRC). We generated tumor (TCM) and normal (NCM) conditioned media from (n = 40) freshly cultured colorectal tumors and assessed levels of 16 cytokines using a multiplex assay. Finally, we designed a MC:Cell line co-culture model to investigate the molecular mechanisms that control MC function. Results: We found that two distinct MC subsets HLA-DRhiCD11chi and CD11bhiCD15hi, unique to the tumor tissue (n = 19), dominated the CD45+ compartment. Further analysis showed that the HLA-DRhiCD11chi and the CD11bhiCD15hi were of monocyte (CD14&CD64) and neutrophil (CD66b&CD16) origin, respectively. In support of their potential inhibitory and proangiogenic function, we showed that the HLA-DRhiCD11chi subset expressed ILT4, PDL1 and Tie-2. The CD11bhiCD15hi subset exhibited high levels of arginase, an enzyme involved in T cell suppression. Interestingly, both cell subsets displayed an altered chemokine receptor profile compared to their blood counterparts. Accordingly, we were able to confirm the upregulated expression of inflammatory mediators, CXCL1 (p < 0.0001), CXCL5 (p < 0.0198), CCL5 (p < 0.0001), CCL4 (p < 0.0074), IL-8 (p < 0.0127), and IL-1β (p < 0.0001) in TCM compared to NCM. Finally, using both the RT2 profiler PCR array and a kinome array we identified a number of key protumor genes and mTOR signaling as potential regulators of tumor associated MCs. Conclusions: This study identifies two MC subsets in patients with CRC. We demonstrate that the TME recruits these cells via a complex chemokine-chemokine receptor network subsequently transforming them into a highly activated but potentially suppressive cell that favors tumor growth.
Predictors of sexual function in women after treatment for breast cancer.
Authors: Robert Michal Kowalczyk, Ida Cedrych, Zbigniew Lew-Starowicz, Krzysztof Nowosielski, Krzysztof Krzemieniecki, Marek Krzystanek, Iwona Glogowska, Joanna Streb, Jakub Kucharz
Journal: Journal of Clinical Oncology (2016)

10071 Background: Due to a novel diagnostic and therapeutic options survival rate of breast cancer patients is constantly increasing. The therapy focuses not only on the removal of the primary disease, but also on improving the quality of life in breast cancer survivors, especially in the context of sexual well-being. Methods: A cohort of 121 women who underwent surgery for early stage breast cancer (stage I to IIB) were included in a retrospective cross-sectional questionnaire-based study. The questionnaire consisted of socio-epidemiological questions, medical and breast cancer diagnosis and treatment (chemo-, radio- and endocrine therapy) history and current relationship status. Sexual function was assessed by Changes in Sexual Function Questionnaire, depressive symptoms by Hospital Anxiety and Depression Scale, body image by Body Image after Breast Cancer Questionnaire and partner’s support by Provisions of Social Relation Scale. The investigated group was then divided according to sexual function evaluated by Changes in Sexual Function Questionnaire into cases (CSFQ ≤ 41, n = 53) and controls (CSFQ > 41; n = 75). Results: The mean age of the investigated group was 51.1±10.1 years. 64.8% were diagnosed with stage I breast cancer. The analysis of correlations revealed that the scores in CSFQ correlated with higher patient age, higher partner age, higher levels of anxiety and depression, lower levels of support from the partner, the more negative self-image, longer time for breast surgery and the more radical surgery. When logistic regression model was used 3 main predictors of sexual dysfunction were noted: lack of sexual partner (odd ratio – 0.1), lower levels of support from the partner (odd ratio – 1.2) and higher levels of anxiety (odd ratio - 0.8). Conclusions: Breast cancer surgery, regardless of type, has a negative impact on female sexual function. The presence of a sexual partner and the support they provide as well as the level of state anxiety are the predictors of sexual dysfunction in breast cancer survivors. These factors should be taken into account when consulting patients treated for breast cancer.
Functional status of neuroendocrine tumors among elderly patients: A large population-based study using SEER-Medicare data.
Authors: Chan Shen, A. Dasari, Shouhao Zhou, Yiyi Chu, Ying Xu, Ya-Chen T. Shih, James C. Yao, Daniel M. Halperin
Journal: Journal of Clinical Oncology (2016)

4097 Background: Functional neuroendocrine tumors (NETs) secrete bioactive amines and cause carcinoid syndrome, with its incumbent symptom burden of flushing and diarrhea. However, the frequency of carcinoid syndrome in the NET population has never been rigorously evaluated, nor has the relationship between patient characteristics and tumor function. The objective of our study was to assess the proportion of NETs patients with carcinoid syndrome, and identify clinical factors associated with tumor function. Methods: We identified NET patients diagnosed between 1/2000 and 12/2011 from the SEER-Medicare database, excluding those under age 65, enrolled in HMOs or without continuous enrollment in Medicare Parts A and B 3 months before and 3 months after the NET diagnosis. We identified patients with functional NETs by requiring that they had at least two claims indicative of carcinoid syndrome during the 6-month time window described above. We compared the demographic and clinical characteristics between patients with and without functional NETs using Chi-squared tests. We used the Cochran-Armitage trend test to test the trend in the proportion of patients with functional NETs. Results: Among the study cohort of 10,226 NET patients aged 65 and over, 1922 (19%) had carcinoid syndrome. The proportion of functional NETs reported increased significantly during the study period, growing from 10.7% in 2000 to 18% in 2011 (p < 0.001). Compared to patients without syndrome, patients with functional NETs were more likely to have regional/distant stage than localized stage (p < 0.001), grade 1 or 2 than grade 3 or 4 histology (p < 0.001), and have primary tumors in the small bowel or cecum as opposed to the lung or colorectum (p < 0.001). We also found that female patients and non-Hispanic white patients were more likely to report carcinoid syndromes (p < 0.001). Conclusions: This first population-based study identified a potential upward trend in the proportion of US Medicare patients over 65 years old reported to have functional NET. The study also demonstrated tumor functionality to be significantly associated with histology grade, stage, and primary site.
Randomized trial assessing the impact of survivorship care plans on the quality of care for childhood cancer survivors.
Authors: Cary Philip Gross, Wilhelmenia Lee Ross, Jaime L. Rotatori, Hannah-Rose Mitchell, Xiaomei Ma, Nina S. Kadan-Lottick
Journal: Journal of Clinical Oncology (2016)

10007 Background: The American College of Surgeons will soon mandate that all cancer survivors receive a survivorship care plan (SCP) to guide surveillance for late effects of therapy. However, the impact of care plans on the care of childhood cancer survivors is unclear. In this randomized trial we assessed the impact of SCPs on quality of care as defined by surveillance adherence and newly identified late effects. Methods: Patients were randomized to either receiving a customized SCP and being advised to follow up with their primary care physician, or attending a regional specialty survivor clinic (the often-cited gold standard). Eligibility included diagnosis with cancer at age <18 years in Connecticut during 2000-2012, ≥ 1 year off-therapy, currently cancer-free, fluent in English or Spanish, and no prior attendance at a specialty survivor clinic. Randomization was stratified by gender, age at evaluation, and radiation history. After the 12-month intervention period, research staff abstracted patient medical records for surveillance adherence and late effects. Results: Overall, 96 childhood cancer survivors (47% female; mean age at evaluation 15.9±6.1 years) were enrolled; 74% had chemotherapy and 36% radiation. Surveillance adherence was significantly worse in the SCP group for each test evaluated (Table). While only 1 late effect (grade 1) was identified in the SCP group, twenty-one late effects (Common Terminology for Adverse Events grades 1-3) were identified in the survivor clinic group. Conclusions: Based on surveillance adherence and newly identified late effects, our randomized trial suggests that solely delivering a SCP to patients is not sufficient to achieve high quality survivorship care. Surveillance Adherence n (%) Survivorship Care Plan Specialty Survivor Clinic p-value Echo 3/20 (15) 19/19 (100) <0.05 EKG 0/20 (0) 15/19 (80) <0.05 Pulmonary Function Test 0/7 (0) 6/6 (100) <0.05 Bone Density 1/14 (7) 14/15 (93) <0.05 Urinalysis 11/23 (48) 19/21 (90) <0.05 Blood Tests: Liver 2/11 (18) 12/12 (100) <0.05 Renal 8/21 (38) 20/20 (100) <0.05 Thyroid 4/10 (40) 11/11 (100) <0.05 Newly Identified Late Effects Grade 1 1 13 <0.05 Grade 2 0 7 <0.05 Grade 3 0 1 0.51 Total 1 21 <0.05
Type 2 diabetes genetic loci informed by multi-trait associations point to disease mechanisms and subtypes: A soft clustering analysis
Authors: Miriam S. Udler, Jaegil Kim, Marcin von Grotthuss, Sílvia Bonàs-Guarch, Joanne B. Cole, Joshua Chiou, Michael Boehnke, Markku Laakso, Gil Atzmon, Benjamin Glaser, Josep M. Mercader, Kyle Gaulton, Jason Flannick, Gad Getz, Jose C. Florez
Journal: PLoS Medicine (2018)

Type 2 diabetes (T2D) is a heterogeneous disease for which (1) disease-causing pathways are incompletely understood and (2) subclassification may improve patient management. Unlike other biomarkers, germline genetic markers do not change with disease progression or treatment. In this paper, we test whether a germline genetic approach informed by physiology can be used to deconstruct T2D heterogeneity. First, we aimed to categorize genetic loci into groups representing likely disease mechanistic pathways. Second, we asked whether the novel clusters of genetic loci we identified have any broad clinical consequence, as assessed in four separate subsets of individuals with T2D.In an effort to identify mechanistic pathways driven by established T2D genetic loci, we applied Bayesian nonnegative matrix factorization (bNMF) clustering to genome-wide association study (GWAS) results for 94 independent T2D genetic variants and 47 diabetes-related traits. We identified five robust clusters of T2D loci and traits, each with distinct tissue-specific enhancer enrichment based on analysis of epigenomic data from 28 cell types. Two clusters contained variant-trait associations indicative of reduced beta cell function, differing from each other by high versus low proinsulin levels. The three other clusters displayed features of insulin resistance: obesity mediated (high body mass index [BMI] and waist circumference [WC]), "lipodystrophy-like" fat distribution (low BMI, adiponectin, and high-density lipoprotein [HDL] cholesterol, and high triglycerides), and disrupted liver lipid metabolism (low triglycerides). Increased cluster genetic risk scores were associated with distinct clinical outcomes, including increased blood pressure, coronary artery disease (CAD), and stroke. We evaluated the potential for clinical impact of these clusters in four studies containing individuals with T2D (Metabolic Syndrome in Men Study [METSIM], N = 487; Ashkenazi, N = 509; Partners Biobank, N = 2,065; UK Biobank [UKBB], N = 14,813). Individuals with T2D in the top genetic risk score decile for each cluster reproducibly exhibited the predicted cluster-associated phenotypes, with approximately 30% of all individuals assigned to just one cluster top decile. Limitations of this study include that the genetic variants used in the cluster analysis were restricted to those associated with T2D in populations of European ancestry.Our approach identifies salient T2D genetically anchored and physiologically informed pathways, and supports the use of genetics to deconstruct T2D heterogeneity. Classification of patients by these genetic pathways may offer a step toward genetically informed T2D patient management.
ChemoQuant: A novel approach to address the current chemotherapy supply problems in low resource countries.
Authors: Thomas Eggebraaten, Alexandra Urman, Joel Mangan, Ching-Kun Wang, Fernando Jose Suarez Saiz
Journal: Journal of Clinical Oncology (2018)

e18593 Background: Access to chemotherapy in low resource such as Sub-Saharan Africa is a growing problem. It is estimated that more than half a million people die of cancer in 2015 alone and the trend is rising every year. According to the World Health Organization this number will double by 2030. One of the factors driving this number is the limited and untimely access to chemotherapy. Less than 10% of patients have access to treatment. Methods: To address the problem of supply and cost, IBM Health Corps in collaboration with the American Cancer Society (ACS) and the Clinton Health Access Initiative developed a tool called ChemoQuant. ChemoQuant is a cloud based software solution designed to forecast chemotherapy needs. The tool is intended to guide and facilitate the forecasting process for a group of users who need to understand the future demand needs for cancer-based therapies (drugs?). To achieve this it combines cancer prevalence data with standard and local cancer guidelines and then makes predictions on future drug quantities needed for a region or hospital by combining the predictions with cancer characteristic distributions, regimen components and dosing details. Reports are available from the tool that highlight drug quantity needs, total cost by drug, cancer and supplier, and a way for users to optimize their procurement when there is limited budget. Results: The tool is intended to allow health officials in these regions to track cancer case loads and with this information be able to place chemotherapy orders that are adequate in volume and at the same time allow them to negotiate bulk discounts with distributors. The tool allows for adequate sourcing of chemotherapy, planning and forecasting for health ministries. The tool is currently has support for the 15 most prevalent cancer types and is being tested by the ACS and local health authorities in 2 countries (Uganda and Ethiopia). Conclusions: With initiatives like ChemoQuant it is possible to address some of the most basic needs for cancer patients in resource poor communities. The types of tools will help increase access to more affordable treatment in order to help improve the quality of care for patients with cancer.
Phase I study of BP1001 (Liposomal Grb2 Antisense) in patients with hematologic malignancies.
Authors: Maro Ohanian, Farhad Ravandi, Gautam Borthakur, Guillermo Garcia-Manero, Michael Andreeff, Elias Jabbour, Yesid Alvarado, Marina Konopleva, Miranda Lim, Sherry Pierce, Susan Mary O'Brien, Ana Tari Ashizawa, Srdan Verstovsek, William G. Wierda, Jorge E. Cortes
Journal: Journal of Clinical Oncology (2016)

7010 Background: Essential to cancer cell signaling, the Growth factor Receptor Bound protein-2 (Grb2) is utilized by oncogenic tyrosine kinases to activate Ras and ERK. BP1001is a liposome-incorporated antisense which inhibits Grb2 expression. The study aimed to define safety, maximum tolerated dose (MTD), pharmacokinetics, and anti-leukemic activity of BP1001 in patients (pts) with hematologic malignancies. Methods: This is a standard 3+3 phase I dose-finding study in pts with relapsed/refractory acute myeloid leukemia (AML), chronic myeloid leukemia in blast phase (CML-BP), and myelodysplastic syndrome (MDS). BP1001 was given twice weekly, IV over 2-3 hours for 28 days. Dose escalation proceeded through 5, 10, 20, 40, 60, and 90 mg/m2. Upon completion of single agent phase I cohorts 1-6, the combination of cytarabine 20 mg SubQ BID x 10 days + 60 mg/m2 BP1001 (cohort 7) or 90 mg/m2 BP1001 (cohort 8) was studied. Results: A total of 38 pts were treated: AML (n = 29), CML-BP (n = 5) and MDS (n = 4). Cytogenetic / molecular abnormalities included: t(9;22) (n = 2), diploid (n = 11), complex (n = 7), BCR-ABL (n = 5; including T315I in 2), FLT3D835 (n = 1), FLT3ITD (n = 1), CEBPA (n = 1), NPM1 (n = 2), TP53 (n = 3), IDH1 (n = 1), IDH2 (n = 3), NRAS (n = 1), JAK2 (n = 2), GATA2 (n = 1), TET2 (n = 1), DNMT3A (n = 1). Of 38 pts, 26 were evaluable; 12 failed completion of a full cycle due to disease progression and were replaced per protocol. Only one pt on 5 mg/m2 experienced a dose limiting toxicity (DLT), grade 3 mucositis and hand-foot syndrome, while on high-dose hydroxyurea for proliferative CML-BP. Among 26 evaluable pts, a median of 1 cycle was administered (1-5): 6 received 2 cycles, 4 received 5 cycles, and all others received 1 cycle. Among the 21 evaluable pts on single agent cohorts, 11 experienced ≥ 50% reduction in peripheral or bone marrow blasts; 2 had improvement of leukemia cutis; 6 had transient decline in blasts (n = 3) and/or stable disease (n = 3). Among the 5 evaluable pts on combination therapy, 2 achieved CR and 2 achieved PR. Conclusions: BP1001 at 5-90 mg/m2 is well tolerated with no MTD identified. Results demonstrate the novel BP1001 + cytarabine combination is well tolerated with early evidence of anti-leukemic activity including CR in 2 relapsed AML pts. Clinical trial information: NCT01159028.