tbuckley/cabot-search huggingface dataset:
The impact of a multi-epitope melanoma helper peptide vaccine on Th1 cytokine production by responding lymphocytes.
Authors: Patrick Michael Dillon, Walter C. Olson, Kimberly A. Chianese-Bullock, Andrea Czarkowski, Craig L. Slingluff
Journal: Journal of Clinical Oncology (2012)

e19028 Background: Melanomas produce soluble and cell-associated molecules that can suppress or alter antitumor immunity. Preclinical studies suggest the disease burden may alter the cytokine profile of helper T cell responses to cancer antigens. To describe the vaccine-induced production of Th2 or Th1 responses to helper peptides in the setting of advanced melanoma, we measured cytokine production of helper T cells responding to vaccination by 6 melanoma helper peptides (6MHP). We then analyzed results by measurable disease status. Methods: Thirty-nine patients with stage IIIB-IV melanoma received a 6MHP vaccine as a part of the UVA Mel41 clinical trial. For analysis of this correlative endpoint, antigen-reactive T cells were exposed to antigen, and supernatants (days 2 and 5) were assayed by cytokine bead arrays for Th1 and Th2 cytokines. Results: The dominant Th1 and Th2 cytokines detected were IFN-g and IL-5, respectively, though high levels of IL-2 were also produced early by sentinel lymph node lymphocytes. Th1 cytokine responses predominated both pre and post vaccine. Peripheral blood lymphocytes from patients with clinically measurable disease produced similar levels of total cytokine as patients with no evidence of disease (111pg/ml versus 174pg/ml respectively, p=0.44). For both disease statuses, the cytokine profile was Th1-dominant in most patients. Total cytokine production varied significantly among patients and varied over time but persisted up to nine months post-vaccine. Conclusions: The MHC class II-associated peptides used in this study induced helper T cells with a Th1-biased cytokine response in both PBMC and sentinel immunized nodes. However, both groups of patients can mount a Th1 dominant response to these peptides, which may persist long after the vaccination sequence. Future studies are needed to test newer vaccine adjuvants in combination with these peptides.
Age disparities in the trend of colorectal cancer incidence in California.
Authors: Jason A. Zell, Kathryn E. Singh, Thomas H. Taylor, Chuan-Ju G. Pan, Michael J. Stamos
Journal: Journal of Clinical Oncology (2013)

e12528 Background: Colorectal cancer (CRC) incidence has decreased over the past three decades, due in part to screening for pre-malignant polyps. Relatively little is known about CRC incidence among adults under age 50 (when screening recommendations commence for average-risk individuals). We examined CRC incidence trends with a focus on adults under age 50, in order to identify high-risk subgroups. Methods: 231,544 incident CRC cases (including 21,220 adults &lt;50) from the California Cancer Registry from 1988-2009 were analyzed. We assessed age-specific incidence rates by race/ethnic group, gender, and tumor location within the colorectum, and calculated annual percent change (APC) to monitor change in incidence over the 21-year study period. Results: We observed increased CRC incidence rates in the adult population under age 50 in all examined race/ethnic groups, especially in Hispanic males (APC=+7.5%/p=0.0001) and Caucasian females (APC=+6.5%/p&lt;0.0001). Young individuals were also more likely to present with metastatic disease at diagnosis. Overall, African Americans had the highest overall incidence rates and were most likely to present with metastatic disease compared to other groups. Conclusions: Incidence of CRC in adults under 50 is increasing across all race/ethnic groups. The high frequency of metastatic disease at initial presentation in this age group is particularly concerning. However, a considerable limitation of this analysis is the lack of data on family history of CRC. Our observations highlight the importance of identifying at-risk adults under age 50, especially those in higher-risk race/ethnic groups, with the overarching goal of decreasing the burden of CRC through screening and early detection.
Long-term outcomes by race/ethnicity in the Childhood Cancer Survivor Study (CCSS) cohort.
Authors: Smita Bhatia, Qi Liu, Wendy M. Leisenring, Kirsten K. Ness, Todd M. Gibson, Leslie L. Robison, Gregory T. Armstrong, Yutaka Yasui
Journal: Journal of Clinical Oncology (2015)

10070 Background: Racial/ethnic differences in risk for long-term adverse outcomes in childhood cancer survivors are not well established. Methods: Hispanic (H: 750, 5.4%) and African American (AA: 694, 5%) survivors were compared to non-Hispanic whites (NHW: 12,397, 89.6%) for late mortality, subsequent malignant neoplasms (SMN), and CTCAE-graded chronic health conditions. Poisson regression models adjusted for demographic/clinical factors were used to calculate relative rate (RR) and 95% confidence intervals (CI). Results: AA and H survivors were younger at diagnosis, and had lower SES. Mortality: No racial/ethnic difference was observed (Table). SMN: Risk did not differ by race/ethnicity (cumulative incidence 30y from diagnosis: NHW: 9.0%, AA: 6.6%, H: 7.0%, p=0.3). However, risk for non-melanoma skin cancer (NMSC) was very low among irradiated AA and H survivors (Table). Chronic Health Conditions (grades 3-5): Compared to NHW, AA were more likely to report cardiac conditions and H endocrine conditions (Table). These differences were attenuated after adjusting for cardiovascular risk factors (CVRF: dyslipidemia, hypertension, smoking). Conclusions: By and large, when adjusted for SES and treatment, morbidity/mortality did not differ by race/ethnicity. However, specific morbidities (H: endocrine, AA: cardiac) were more prevalent, and were partially explained by CVRFs. Risk of NMSC was negligible among irradiated AA and H, relative to irradiated NHW. These findings inform targeted intervention opportunities. NHW AA H Late Mortality RR (95% CI)* All-cause Ref 1.0 (0.8 – 1.4) 0.9 (0.7 – 1.2) P = 0.9 P = 0.5 SN 1.3 (0.7–2.2) 0.9 (0.5-1.6) P = 0.4 P = 0.7 Cardiac 1.6 (0.5–4.6) 1.5 (0.7–3.5) P = 0.4 P = 0.3 SMNs RR (95% CI)* 1.3 (0.8-2.0) 1.2 (0.8-1.7) P = 0.2 P = 0.4 NMSC (irradiated cohort) 0.0 (0.0-0.2) 0.3 (0.1-0.8) P < 0.001 P = 0.01 Chronic Health Conditions (grade 3-5) RR (95% CI)* Any 1.1 (0.9-1.4) 1.2 (1.0-1.5) P = 0.5 P = 0.06 Cardiac 1.6 (1.0-2.4) 1.2 (0.8-1.7) P = 0.03 P = 0.5 CardiacΩ 1.4 (0.9-2.1) 1.1 (0.7-1.7) P = 0.1 P = 0.7 Endocrine 1.0 (0.6-1.5) 1.7 (1.2-2.3) P = 0.8 P = 0.001 EndocrineΩ 0.9 (0.6-1.4) 1.4 (1.0-1.9) P = 0.7 P = 0.08 *From Poisson models adjusted for treatment, SES. Ω Further adjusted for CVRF.
The role of statines in the treatment of esophageal cancer patients.
Authors: Sjoerd M Lagarde, Maarten CJ Anderegg, Wernard A Borstlap, Suzanne S Gisbertz, Sybren L. Meijer, Maarten Hulshof, Jacques Bergman, Hanneke W.M. Van Laarhoven, Mark van Berge Henegouwen
Journal: Journal of Clinical Oncology (2014)

e15083 Background: Recently, there has been an increasing interest in the potential role of statins on pCR rates and survival in different types of cancer. However, no studies explored the role of statins in the curative treatment of esophageal cancer. The aim of the present study is to investigate the effect of statins on pathologic CR (pCR) and disease free survival in patients who are treated with after neoadjuvant chemo(radiation) therapy followed by esophagectomy. Methods: Between March 1994 and September 2013 all consecutive patients with cancer of the esophagus or gastroesophageal junction who underwent esophageal resection after neoadjuvant chemo (radio) therapy were included in the present study. Baseline demographic and clinical characteristics were compared between statin users nonusers. Results: 463 patients were included, 93 (20.1%) used statines at the time of diagnosis. 88 (19%) underwent preoperative chemotherapy and 375 (81%) underwent neoadjuvant chemoradiation therapy. 85 (18%) patients had a pCR (pyT0N0M0R0). pCR was not significantly different between statin users and nonstatin users (23% vs 17%, p=0.239). Median disease free survival was not significantly different between statin users and nonstatin users (44 (95% CI 32.2-55.9) vs 41 (95% CI 30.0-53.7) months, p=0.509). Conclusions: Statin users did not experience different outcomes compared with non-users and statin use did not affect the efficacy of neoadjuvant therapy. These data do not support modification or discontinuation of statin therapy for patients with esophageal cancer.
Genomic testing enhances treatment choices and clinical trial accrual in metastatic colorectal cancer (CRC): Results of a prospective clinical study.
Authors: Davendra Sohal, Brian I. Rini, Robert James Pelley, Bassam N. Estfan, Dale Randall Shepard, Timmy Q. Nguyen, Robert Dreicer, Brian James Bolwell, Alok A. Khorana
Journal: Journal of Clinical Oncology (2015)

e14631 Background: Tumor genome sequencing is being used in clinical settings but its value to individual patients has not been well-studied. We conducted a prospective study of outpatient genomic testing to evaluate this systematically. Methods: Patients provided written informed consent for this prospective cohort study approved by the Cleveland Clinic (CC) Institutional Review Board. Eligibility requirements included pathologic diagnosis of select solid tumor malignancies without a known curative option, age ≥ 18 years, and ECOG PS 0-2. Data for the CRC subgroup are presented here. Tumor samples were sequenced for up to 315 candidate genes using FoundationOne (Cambridge, MA). Results were discussed at the CC Genomics Tumor Board (GTB) that made therapeutic recommendations. Results: From Aug 2013 to Oct 2014, samples from 63 patients with CRC were analyzed. Median age was 59 years; 35 (56%) were female; 55 (87%) were white. Median time from consent to result was 26 days (range, 7-80); 4 (6%) samples had inadequate tissue. In 59 resulted samples, a median of 5 alterations (range, 2-19) were detected per sample; APC (90%), TP53 (80%) and KRAS (59%) were most common. A therapy targeting an actionable alteration was recommended in 27 (46%) patients; 90% of these recommendations were for clinical trials. To date, 6 (32%) of 19 patients who received new cancer-directed therapy after test results received genomics-driven therapies (Table). Previously unknown RASmutations were seen in 4 other patients, influencing EGFR antibody use decisions. The commonest reason for non-receipt of therapy based on the test result was non-availability of clinical trials. Conclusions: Routine tumor genome profiling in CRC patients is feasible and influenced treatment decisions in a third of patients. A GTB for the interpretation of rapidly evolving information, and improved access to clinical trials of targeted agents are critical to the success of precision oncology. Target Therapy N Clinical Trials FLT3 Dovitinib 2 PTCH1 SMO inhibitor 1 Off-label use PIK3R1 Everolimus 1 FLT3 Sunitinib 1 HER2 Trastuzumab 1 Non-genomics-based Systemic therapy 9 Local therapy 4
Racial/ethnic variations in lung cancer incidence and mortality, adjusted for smoking behavior: Results from the Women's Health Initiative.
Authors: Manali I. Patel, Ange Wang, Kristopher Kapphahn, Jessica Kubo, Manisha Desai, Rowan T. Chlebowski, Michael S. Simon, Chloe E. Bird, Giselle Corbie-Smith, Scarlett Lin Gomez, Lucile L. Adams-Campbell, Michele L Cote, Marcia L Stefanick, Heather A. Wakelee
Journal: Journal of Clinical Oncology (2014)

1528 Background: It is unclear whether there are racial/ethnic disparities in lung cancer incidence and mortality among women. Therefore, we examined lung cancer incidence and mortality in the Women’s Health Initiative (WHI), a prospective cohort of post-menopausal women. Methods: Lung cancer diagnoses were centrally adjudicated by pathology review. Logistic regression models estimated odds of incidence and mortality by race/ethnicity adjusted for age, education, calcium/vitamin D, BMI, smoking (status, age at start, duration and pack-years), alcohol, family history, oral contraceptive, hormones, physical activity, and diet. Results: The analytic cohort included 129,951 women -108,487 (83%) white (47.5% current/ past smoker); 10,892 (8%) Black (47.7% current/ past smoker); 4,882 (4%) Hispanic (33.7% current/past smoker); 3,696 (3%) Asian/Pacific Islander (A/PI) (26.2 % current/past smoker); 534 American Indian/Alaskan Native (48.3% current/past smoker) and 1994 (1.4%) other (41.6% current/past smoker). In unadjusted models Hispanics had 66% lower odds of lung cancer compared with whites (OR 0.34 95% CI (0.2-0.5)), followed by A/PI (OR 0.45 95% CI (0.27-0.75)) and blacks (OR 0.75 95% CI (0.59-0.95). In fully adjusted multivariable models, decreased risk of lung cancer for blacks, Hispanics, and A/PI compared to whites was no longer statistically significant. In unadjusted models Hispanics and A/PI had decreased risk of death from compared to whites (OR 0.3 95% CI (0.15-0.62), OR (0.3 95% (0.16-0.75)), respectively); however, no significant racial/ethnic differences were found in risk of death from lung cancer in fully adjusted models. Conclusions: We found no racial/ethnic disparities in lung cancer incidence or mortality in a population of post-menopausal women after adjusting for socio-demographic, clinical, and behavioral factors. Clinical trial information: 1757.
Dose-dense paclitaxel with cisplatin as perioperative chemotherapy for locally advanced cervical cancer: Early efficacy results of a multicenter phase II study.
Authors: Takuma Onoe, Maki Tanioka, Satoshi Yamaguchi, Shinya Sato, Muneaki Shimada, Masato Nishimura, Shinichi Okame, Atsumi Kojima, Junzo Kigawa, Kiyoshi Fujiwara
Journal: Journal of Clinical Oncology (2015)

e16515 Background: To develop a treatment strategy with better survival and less toxicity than conventional chemoradiotherapy, we conducted a phase II study of dose-dense paclitaxel with cisplatin (ddTP) chemotherapy, followed by radical hysterectomy with stratified adjuvant treatments, for locally advanced cervical cancer. Methods: From August 2012 to August 2014, 52 patients were enrolled. They received three cycles of ddTP (80 mg/m2 paclitaxel on days 1, 8, and 15; 75 mg/m2cisplatin on day 1, every 3 weeks) before surgery. Two cycles of ddTP were added after surgery, if patient pathological findings showed one of the following: pelvic lymph node metastases, parametrial invasion, or intrauterine lymphovascular invasion. Other patients received no adjuvant therapies. The primary endpoint was 2-year recurrence-free survival (RFS), and secondary end points included response rate (RR) and pathological complete response (pCR) rate. Results: The median age of enrolled patients was 48.5 years; International FIGO stages were IB2 (n = 14), IIA (n = 5), and IIB (n = 33) and histological types were squamous cell carcinoma (n = 39), adenocarcinoma (n = 11), adenosquamous (n = 1), and undifferentiated carcinoma (n = 1). RR was 96% (complete response: n = 14; partial response: 36) and pCR rate was 21% (squamous cell carcinoma: n = 10, adenosquamous: n = 1). Seventeen patients (33%) received adjuvant ddTP, while 35 (67%) did not receive any adjuvant treatments. Grade 3–4 toxicities were neutropenia (21%), anemia (6%), nausea (4%), fatigue (4%), peripheral sensory neuropathy (2%), and hyponatremia (2%). One patient experienced Grade 5 cardiac arrest, unlikely to be related to the treatment protocol (suspected fetal arrhythmia) during neoadjuvant chemotherapy. Conclusions: Perioperative ddTP was feasible and effective in terms of RR and pCR compared with prior studies. Clinical trial information: UMIN000009643.
Asian and non-Asian disparities in outcomes of head and neck cancer (HNC).
Authors: Jason D. Kim, Tian Yang Darren Liu, Ali Moghaddamjou, Winson Y. Cheung
Journal: Journal of Clinical Oncology (2014)

6567 Background: Racial differences in cancer outcomes are frequently observed for specific tumor types, including nasopharyngeal cancers, but prior research has mainly focused on disparities between Black and White races. Our aim was to evaluate the impact of Asian and non-Asian races on overall survival (OS) in a large population-based cohort of HNC. Methods: All patients diagnosed with non-nasopharyngeal HNC from 2001 to 2010 and referred to any 1 of 5 regional comprehensive cancer centers in British Columbia, Canada were reviewed. Using specialized software (Onomap, Inc.) that recognized common and distinctive surnames based on race, patients were classified as Asians vs. non-Asians. Using Kaplan-Meier methods and Cox regression, we examined the relationship between race and OS while controlling for confounders that consisted of additional socio-demographics and other tumor and treatment-related characteristics. Results: We identified a total of 3,036 patients: median age was 64 years (range 20-100), 74% were men, 32% were ECOG 0/1, and 7% and 93% were Asian and non-Asian, respectively. Comparing baseline characteristics between racial groups, Asians tended to exhibit worse prognostic features in that they had poorer functional status (ECOG 2+, 29% vs. 23%, p=0.07) and were more frequently affected by larger tumors (>4 cm, 33% vs 21%, p=0.02) and by oral cavity cancers (38% vs. 25%, p<0.001) than non-Asians. With respect to treatment, Asians were less likely to receive multimodality therapy than non-Asians (90% vs. 95%, p=0.02). Upon adjusting for prognostic factors, multivariate models showed that non-Asians actually had significantly higher odds of death when compared to Asians (HR 2.46, 95%CI 1.25-4.87, p=0.009). Advanced age, worse ECOG, greater tumor size, and lack of treatment also correlated with inferior OS. Conclusions: In addition to the racial differences reported in the literature for nasopharyngeal carcinoma, we observed variations in non-nasopharyngeal HNC outcomes between Asians and non-Asians. Despite worse prognostic features and less treatment, Asians exhibited better survival than non-Asians, suggesting a potential difference in tumor biology, pharmacogenetics, or predisposition to HPV exposure.
Digoxin exposure and prostate cancer mortality: A matched cohort study.
Authors: Evelyn Flahavan, Kathleen Bennett, Linda Sharp, Thomas Ian Barron
Journal: Journal of Clinical Oncology (2012)

e13096 Background: Digoxin (DIG) exposure has been associated with reduced prostate cancer (PC) incidence in epidemiological studies. Preclinical data suggests that this anti-cancer effect is mediated through the inhibition of hypoxia-inducible factor 1-α by DIG. This retrospective cohort study examines associations between DIG exposure and mortality in men with PC. Methods: Men diagnosed with PC during 2001–2006 were identified from National Cancer Registry Ireland records and linked prescription claims data. Propensity scores for DIG exposure in the 90 days prior to PC diagnosis were estimated. DIG exposed and unexposed men were matched (1:1) within a calliper of 0.2 standard deviations of the propensity score logit, using greedy matching without replacement. Standardized differences were used to assess covariate balance (z-score &lt;0.1) between matched cohorts. Hazard ratios (HR) for associations between DIG exposure and all-cause (ACM) or PC-specific (PCM) mortality were estimated using Cox proportional hazards models adjusted for age, comorbidity, tumour stage and grade. Categorical exposure-response analyses were carried out using tertiles of exposure (low, intermediate, high) in the 90 days pre-diagnosis. Results: 5734 PC cases were identified from the linked database. 395 cases received DIG in the 90 days pre-diagnosis, of which 391 were matched to unexposed controls. Matched covariate balance was acceptable. In adjusted analyses, DIG exposure was not associated with ACM (HR 1.06, 95% CI 0.88-1.27) but was associated with a small but non-significant reduction in the risk of PCM (HR 0.89, 95% CI 0.68-1.17). In the exposure-response analysis, DIG exposure in the highest tertile, but not in the intermediate or lower tertiles, was associated with a reduced risk of PCM approaching statistical significance (HR 0.69, 95% CI 0.47-1.01, p=0.059). Men in the high DIG exposure group received a supply of DIG for 98% of their eligible follow up in the year post diagnosis. Post diagnostic DIG exposure in the intermediate and lower tertiles was 94% and 80% respectively. Conclusions: DIG exposure was associated with a non-significant decrease in PCM. Stratification by exposure suggests the presence of an exposure-response relationship.
Safety, tolerability, pharmacokinetics, and activity of the novel long-acting antimalarial DSM265: a two-part first-in-human phase 1a/1b randomised study
Authors: James S McCarthy, Julie Lotharius, Thomas Rückle, Stephan Chalon, Margaret A Phillips, Suzanne Elliott, Silvana Sekuloski, Paul Griffin, Caroline L Ng, David A Fidock, Louise Marquart, Noelle S Williams, Nathalie Gobeau, Lidiya Bebrevska, Maria Rosario, Kennan Marsh, Jörg J Möhrle
Journal: The Lancet Infectious Diseases (2017)

DSM265 is a novel antimalarial that inhibits plasmodial dihydroorotate dehydrogenase, an enzyme essential for pyrimidine biosynthesis. We investigated the safety, tolerability, and pharmacokinetics of DSM265, and tested its antimalarial activity.
Association of a DNA damage response deficiency (DDRD) assay and prognosis in early-stage esophageal adenocarcinoma.
Authors: Richard C. Turkington, Laura A. Hill, Damian McManus, Stephen McQuaid, Ken Arthur, Jacqueline James, Manuel Salto-Tellez, Timothy S. Davison, Claire Harrison, Colin Purcell, Richard H. Wilson, Thomas P. MacGregor, Ricky A. Sharma, Rebecca C. Fitzgerald, Patrick Johnston, Paul D Harkin, Martin McKinlay Eatock, Richard D. Kennedy
Journal: Journal of Clinical Oncology (2014)

4015 Background: The incidence of esophageal adenocarcinoma (EAC) has increased 6-fold in the last 30 years and in early stage EAC 5-year survival remains poor at 25-35%. Neoadjuvant therapy confers a significant improvement in outcomes but the optimal approach for individual patients remains unclear. We assessed a 44 gene DNA Damage Response Deficient (DDRD) assay, previously developed to detect loss of the Fanconi Anaemia (FA)/BRCA pathway in breast cancer, as a predictor of prognosis following DNA damaging chemotherapy in EAC. Methods: This study was conducted using 63 formalin fixed paraffin embedded (FFPE) pre-treatment endoscopic biopsy specimens from early stage EAC patients treated with cisplatin-based neoadjuvant chemotherapy followed by surgical resection between 2004 and 2010 at the NI Cancer Centre. EAC biopsies were profiled using the Xcel array, a cDNA microarray-based technology optimized for archival FFPE tissue (Almac/Affymetrix), and scored for the DDRD assay. The association between the DDRD score and prognosis was assessed by Kaplan-Meier analysis and Cox Proportional Hazards regression. Results: Sufficient quality RNA for analysis was obtained for 62 out of 63 samples (98.4%). A total of 13 samples (21%) were characterised as DDRD positive with the remaining 49 samples (79%) DDRD negative. With a median follow up of 65 months, DDRD assay positivity demonstrated a statistically significant association with disease-free (HR 0.33; 95% CI 0.13-0.87; p=0.024) and overall survival (HR 0.32; 95% CI 0.12-0.82; p=0.017; median DDRD+ve 94.3 months vs DDRD-ve 32.2 months). The assay was not predictive of survival in patients who did not receive chemotherapy. Conclusions: The DDRD assay is the first array-based biomarker using pre-treatment FFPE biopsies to be validated as predictive of prognosis following DNA damaging chemotherapy in early stage EAC. Multivariable analysis of disease-free survival. Hazard ratio Lower 95% CI Upper 95% CI p value DDRD-positive 0.310 0.110 0.877 0.027 Surgical T stage 2 vs 0 & 1 0.343 0.078 1.519 0.159 Surgical T stage 3+ vs 0 & 1 0.470 0.126 1.751 0.261 N stage 1 vs 0 4.793 1.590 14.447 0.005 N stage 2 & 3 vs 0 7.822 2.777 22.034 <0.001