tbuckley/cabot-search huggingface dataset:
Race, demographics, and socioeconomics as they relate to newly diagnosed metastatic prostate cancer in the United States.
Authors: Richard Matulewicz, Adam Benjamin Weiner, Jeffrey J. Tosoian, John Oliver Delancey, Joseph Feinglass, Scott E. Eggener, Edward M. Schaeffer
Journal: Journal of Clinical Oncology (2017)

195 Background: As screening practices evolve, understanding the influence race, demographics, and socioeconomic status have on the presentation of metastatic prostate cancer (mPCa) can lead to improved diagnostic strategies in high-risk populations. Methods: Men diagnosed with prostate cancer in the National Cancer Data Base from 2004-2013 were identified. Characteristics of men presenting with and without metastatic disease were compared. A four-level composite metric of SES was created using census-based income and education data. Multivariable logistic regression analysis evaluated the association of age, SES, race/ethnicity, insurance status and other relevant covariates with the likelihood of presenting with mPCa. Results: Of the 1,034,754 PCa patients identified, 4% presented with mPCa. Compared to the highest SES group, odds of mPCa increased continuously with decreasing SES. A total of 24% of White men were in the lowest SES while more than half of Black and Hispanic men were in lowest SES category. Black and Hispanic men had higher overall rates of metastases (5.9% and 6.2%; OR 1.47, 95% CI 1.43-1.51 and OR 1.22, 95% CI 1.17-1.28, respectively) compared to Whites (3.6%). Having Medicaid or no insurance increased the odds of being diagnosed with mPCa compared to having other insurance (13% vs 4%; OR 3.91, 95% 3.78-4.05) with all other variables held constant, including SES. Among men in the lowest SES, the effect of SES appeared to be additive to race: OR 1.34 (95% CI 1.29-1.39), OR 2.09 (95% CI 2.00-1.78), and OR 1.66 (95% CI 1.56-1.77), for White, Black, and Hispanic ethnicity all in the lowest SES group, respectively. Across each race, men aged 75 and older had the highest rates of mPCa. Overall, Black men over age 74 had a higher rate of mPCa (14%) relative to Whites (9%) and Hispanics (11%). Conclusions: There is an inverse relationship between SES and odds of presenting with mPCa. Having no insurance or Medicaid increased the odds of mPCa, even when accounting for SES. Black and Hispanic race was associated with increased odds of mPCa, and the effects of race and SES appeared to be additive.
Myocardial Viability
Authors: Henry Gewirtz, Vasken Dilsizian
Journal: Circulation Research (2017)

Myocardial responses to acute ischemia/reperfusion and to chronic ischemic conditions have been studied extensively at all levels of organization. These include subcellular (eg, mitochondria in vitro); intact, large animal models (eg, swine with chronic coronary stenosis); as well as human subjects. Investigations in humans have used positron emission tomographic metabolic and myocardial blood flow measurements, assessment of gene expression and anatomic description of myocardium obtained at the time of coronary artery revascularization, ventricular assist device placement, or heart transplantation. A multitude of genetic, molecular, and metabolic pathways have been identified, which may promote either myocyte survival or death or, most interestingly, both. Many of these potential mediators in both acute ischemia/reperfusion and adaptations to chronic ischemic conditions involve the mitochondria, which play a central role in cellular energy production and homeostasis. The present review is focused on operative survival mechanisms and potential myocardial viability molecular imaging targets in acute and chronic ischemia, especially those which impact mitochondrial function.
Phase II, Single Center Study of Oral Forodesine in Patients with Advanced, Fludarabine-Treated Chronic Lymphocytic Leukemia (CLL).
Authors: Dushyant Verma, Kumudha Balakrishnan, Susan O'Brien, Deborah A. Thomas, Alessandra Ferrajoli, William G. Wierda, Amit Verma, Stefan Faderl, Susan M Bickel, Shanta Bantia, Hagop M Kantarjian, Michael J. Keating, Varsha Gandhi, Farhad Ravandi
Journal: Blood (2009)
Clinically Relevant Concentrations of Anticancer Drugs: A Guide for Nonclinical Studies
Authors: Dane R. Liston, Myrtle Davis
Journal: Clinical Cancer Research (2017)

Approved and marketed drugs are frequently studied in nonclinical models to evaluate the potential application to additional disease indications or to gain insight about molecular mechanisms of action. A survey of the literature reveals that nonclinical experimental designs (in vitro or in vivo) often include evaluation of drug concentrations or doses that are much higher than what can be achieved in patients (i.e., above the maximally tolerated dose or much higher than the clinically relevant exposures). The results obtained with these high concentrations may be particularly helpful in elucidating off-target effects and toxicities, but it is critical to have a dose-response curve that includes the minimally effective or clinically effective concentration for comparison. We have reviewed the clinical literature and drug product labels for all small molecules and biological agents approved by the FDA for use in oncology to identify and compile the available pharmacokinetic parameters. The data summarized here can serve as a guide for selection of in vitro concentrations and in vivo plasma exposures for evaluation of drug effects in nonclinical studies. Inclusion of drug concentrations or exposures that are relevant to those observed in clinical practice can improve translation of nonclinical mechanism of action findings into potentially relevant clinical effects. Clin Cancer Res; 23(14); 3489-98. ©2017 AACR.
Cognitive function and fatigue in colorectal cancer (CRC) patients: A prospective longitudinal controlled study.
Authors: Janette L. Vardy, Haryana M. Dhillon, Gregory Russell Pond, Sean Rourke, Wei Xu, Corrinne Renton, Anna Dodd, Philip James Beale, Stephen John Clarke, Ian Tannock
Journal: Journal of Clinical Oncology (2012)

9021 Background: A subset of cancer patients has cognitive impairment and fatigue after chemotherapy (CTh). We evaluated these symptoms and potential mechanisms in CRC patients and healthy controls (HC). Methods: Cognitive function was evaluated in CRC patients and HC at baseline (pre-CTh), 6 and 12 months. Group 1A (Stage II/III) received CTh and Gr 1B (Stage I/II) no CTh. Gr 2 had limited metastatic CRC. All subjects completed cognitive assessment and questionnaires for fatigue, QOL, anxiety/depression, and perceived cognitive function. Blood tests evaluated: 10 cytokines, clotting factors, sex hormones, CEA, CBC and apolipoprotein genotyping as potential causal factors. Primary endpoints: cognitive function and fatigue (Gr. 1A &amp; 1B) at 12 months. Associations between results and demographic and disease-related factors were sought. Results: 359 CRC patients (173 Gr 1A, 116 Gr 1B, 70 Gr. 2) and 72 HC were assessed. Median age 58 (23-75 years); 58% male. Cognitive impairment: baseline Gr 1A 34% vs 1B 32.5% (p=.9), Gr 1 33% vs HC 10% (p&lt;0.001); 12 months Gr 1A 21% vs 1B 16% (p=0.43), Gr 1 19% vs HC 2% (p=0.001). Cognitive domains most affected: verbal &amp; visual memory, processing speed. Men had greater impairment than women (p&lt;0.009). Cognitive decline from 0-12 months: Gr 1A 30%, Gr 1B 19%, Gr 2 24%, and HC 16%. Perceived cognitive impairment at 12 months: Gr 1A 19% vs 1B 7% (p=.04), Gr 1 14% vs HC 0% (p=.009). Fatigue was greatest in Gr 1A (70%) at 6 months; at 12 months Gr. 1A 46% vs 1B 31% (p=0.056), Gr 2 60%, HC 36%. Cytokines were elevated in CRC patients compared to HC. No association was found with cognitive function and: fatigue, QOL, anxiety/depression, cytokines, sex hormones, clotting factors, CEA or apoE genotype. Objective cognitive function was associated with perceived cognitive function at baseline only. Fatigue at baseline was associated with hemoglobin and at 12 months with neutrophil count. Conclusions: Compared to HC, CRC patients had more cognitive impairment at baseline, 6 and 12 months; but impairment was not significantly different between those who did and did not receive CTh. The mechanisms of cognitive impairment remain unknown. Fatigue improved with time.
Association of a compact 13-gene VEGF signature with OS in E2100.
Authors: Scooter Willis, Kathy Miller, Brandon F Young, Charles M. Perou, Zhiyuan Hu, Joseph Sparano, Robert James Gray, George W. Sledge, Nancy E. Davidson, Brian Leyland-Jones
Journal: Journal of Clinical Oncology (2012)

1027 Background: E2100, an open-label, randomized, phase III trial, demonstrated a significant improvement in progression free survival and overall response rate with paclitaxel plus bevacizumab compared with paclitaxel alone as initial chemotherapy for patients with HER2-negative metastatic breast cancer. Genentech completed additional clinical trials and submitted these data to the FDA. On 18 Nov, 2011, the FDA Commissioner revoked the agency’s approval of bevacizumab for the breast cancer indication because of the lack of evidence of an improvement in overall survival or a clinical benefit to patients sufficient to outweigh the risks. However, the Commissioner “encouraged Genentech to consider additional studies to identify if there are select subgroups of women who might benefit from this drug”. Hu et al. (BMC Medicine 2009) published a compact 13 gene VEGF-signature associated with distant metastases and poor outcomes. Supervised analyses comparing patients with distant metastases versus primary tumors or regional metastases showed that the distant metastases were distinct and distinguished by the lack of expression of fibroblast/mesenchymal genes, and by the high expression of a 13 gene profile that included VEGF, ANGPTL4, ADM and the monocarboxylic acid transporter SLC16A3. Methods: We have investigated the VEGF signature in silico on Illumina DASL analysis of 122 FFPE samples remaining from E2100. Results: PFS benefit is seen for pacli + bev vs pacli in both treatment arms with the low VEGF signature (HR 0.45 95% CI .27-.77 p .009 n 67) and with the high VEGF signature (HR 0.57 95% CI .32-1.0 p .015 n 55). However, OS benefit is only seen for pacli + bev vs pacli in the high VEGF group (HR 0.56 95% CI .30-1.05 p .02 n 52) and not in patients with the low VEGF signature (HR 1.12 95% CI .66-1.90 p .81 n 67). Conclusions: Hence, this signature, which suggests that the response to hypoxia includes the ability to promote new blood and lymphatic vessel formation, shows great potential as a predictive biomarker of those patients to whom bevacizumab would convey an OS advantage benefit. We note with great caution that this exploratory analysis of trial subset is underpowered, hence, this compact VEGF signature is being pursued in other bevacizumab trial sets.
Survival and outcomes of critically ill sarcoma patients admitted to the intensive care unit.
Authors: Rohan Gupta, Naveen Ramesh, Erfe Jean Rose, Kristen Carter, Dejka M. Araujo, Robert S. Benjamin, Shreyaskumar Patel, Joseph L. Nates, Vinod Ravi
Journal: Journal of Clinical Oncology (2014)

10576 Background: Survival and long-term outcomes of the critically ill patients with sarcoma who are admitted to the intensive care unit (ICU) are unknown. As a result, oncologists are often unsure of the utility of aggressive treatment measures in critically ill patients with these rare tumors. Methods: Objective: To determine factors that impact survival. We performed a retrospective chart review of all sarcoma patients admitted to the ICU at MD Anderson. Covariates such as histological diagnosis, site, stage, chemotherapy utilization, Charlson comorbidities index, Sequential organ failure assessment (SOFA) scores and reason for admission were reviewed and analyzed for impact on survival. Results: 212 ICU admissions were identified between 2005 and 2012. 23 patients had multiple ICU admissions. Of the remainder 191 patients, 17 surgical ICU patients were excluded, leaving a sample size of 172 patients (45.9% males) with the median age of 52 (17-89). Most common histological diagnoses were high grade unclassified sarcoma (25%), osteosarcoma (11%) and angiosarcoma (7.6%). Advanced metastatic disease was present in 73.3% patients. 25% of the patients were untreated at the time of admission to the ICU. Among patients on treatment, 34.3 % received doxorubicin based therapy and 11.6% received gemcitabine based therapy. 76.7% were alive after their first ICU admission. Post hospital, 30 days and 60 days survival were 70.3%, 60.5% and 55.2% respectively. Non-survivor group had maximum SOFA score of 16 (0-24) compared to survivor group 7 (0-22). 42.5% of the non survivors had > 2 organ dysfunctions compared to 6.82% of survivors. Reasons for admission to ICU that predicted poor outcome were acute kidney injury (70% in non-survivors vs 34.8 % in survivors), acute respiratory failure (90% vs 31.8%), septic shock (40% vs 25%), cardiac arrest (17.5% vs 2.3%) and pneumonia (47.5% vs 23.5%). Conclusions: Significant numbers of critically ill sarcoma patients with advanced disease survive the initial ICU stay. Organ dysfunction can be predictive of survival of sarcoma patients being admitted to the ICU. Patients with disseminated disease with predictors of poor survival should be considered for early transition to supportive care or hospice.
Pharmacodynamic biomarker-driven trial of MK-2206, an AKT inhibitor, with AZD6244 (selumetinib), a MEK inhibitor, in patients with advanced colorectal carcinoma (CRC).
Authors: Giovanna Speranza, Robert J. Kinders, Sonny Khin, Marcie K. Weil, Khanh Tu Do, Yvonne Horneffer, Lamin Juwara, Deborah Allen, P. Mickey Williams, Chih Jian Lih, Larry Rubinstein, Laurence A Doyle, James H. Doroshow, Shivaani Kummar
Journal: Journal of Clinical Oncology (2012)

3529 Background: The RAF/MEK/ERK and PI3K/AKT signaling pathways are commonly deregulated in CRC. Each can serve as a compensatory mechanism mediating resistance to single pathway blockade. Combined inhibition with MK-2206 and selumetinib (AZD6244) could enhance antitumor activity. Tolerable doses for the combination in solid tumors (ASCO 2011, abstr 3004) are less than single agent MTDs. We conducted a biomarker driven trial of MK-2206 and selumetinib at the established combination doses to determine extent of pERK and pAKT inhibition in tumor biopsies (bx), using new, clinically validated immunoassays for pERK and pAKT. Methods: Patients (pts) with advanced CRC, refractory to standard therapy, ECOG ≤ 2, adequate organ function, and disease amenable to bx were treated with oral MK-2206, 90 mg QW and selumetinib, 75 mg daily, stratified for KRAS mutation status (+ or WT). For each strata, pAKT and pERK levels from paired tumor bx, baseline and 3-6 hrs post-dose in 3 pts each on C1D1 or C1D22, were measured using a quantitative, chemiluminescence immunoassay (dilution linearity R 2 = 0.985 pERK, 0.995 pAKT; % CV at 0 &lt; 6). 70% inhibition was considered biologically significant based on levels observed in preclinical models that demonstrated antitumor activity. Results: 11 pts enrolled to date (KRAS +, 6 pts; WT, 5 pts). 2/9 pts had SD after 2 cycles. Gr 1/ 2 toxicities: rash, reversible retinal detachment, liver abnormalities, hypoalbuminemia, lymphopenia. Target protein inhibition data are available for 8 paired bx samples (Table). Conclusions: Although 4/8 pts demonstrated biologically significant inhibition in one marker, at the MTD for this combination no pt had ≥ 70% inhibition of both targets. If repeated dosing does not produce the desired inhibition of pERK and pAKT, we will conclude that the dose reductions for each agent necessitated by the toxicity of the agents used in combination preclude the possibility of providing adequate dual pathway inhibition. Loss of PTEN and DNA mutation analyses (KRAS, BRAF, PIK3Ca, AKT) are planned. [Table: see text]
The clinicopathologic significance of FOXC1 in <i>BRCA</i>-mutant breast cancer.
Authors: Michael Phillip Choi, Xiaojiang Cui, Farnaz Dadmanesh, Georgia Liles, Xiao Zhang, Beth Karlan, Armando E. Giuliano, Farin F. Amersi
Journal: Journal of Clinical Oncology (2014)

1556 Background: BRCA1 breast cancer (BC) has been associated with the basal molecular subtype and BRCA2 with the luminal subtype but the biological basis for this is unknown. The forkhead box C1 (FOXC1) transcription factor has been identified as a marker of sporadic basal-like BC which correlates with a poor prognosis. Furthermore, loss of BRCA1 function has been shown to increase FOXC1 expression in BC cell lines resulting in aggressive cellular behavior. We investigated the clinicopathologic associations of FOXC1 expression in BRCA1/2 mutant BC. Methods: Review of our institutional database identified 37 BRCA1 and 35 BRCA2 mutation carriers treated for BC from 1995 to 2013. Immunohistochemical (IHC) staining of paraffin-embedded tissue sections was performed using a monoclonal FOXC1 antibody against nuclear FOXC1 protein and evaluated by two independent, blinded pathologists. The association of FOXC1 expression with clinical and pathologic variables was analyzed. Results: FOXC1 expression was identified in 21/37 BRCA1 mutant BC and 6/35 BRCA2 mutant BC on IHC (Table 1). Univariate analysis showed FOXC1 expression to be associated with younger age, higher tumor grade, higher Ki67%, triple negative/basal molecular subtype, and a lower number of positive lymph nodes. FOXC1 expression correlated with increased locoregional recurrence rates (p = 0.05) however there was no significant difference in overall survival between FOXC1 positive and negative BC. Conclusions: FOXC1 expression is more commonly seen in BRCA1 mutant BC than in BRCA2 mutant BC and is associated with aggressive pathological tumor characteristics and a higher rate of locoregional recurrence. FOXC1 + n FOXC1 - n P-value No. of patients 27 45 Age at diagnosis (mean years ± SD) 42.9 ± 13.3 50.7 ± 11.7 0.006 BRCA mutation 0.0007 BRCA1 21 16 BRCA2 6 29 Tumor Grade <0.0001 1 0 4 2 1 18 3 26 23 ER status <0.0001 ER + 4 41 ER - 23 4 PR status <0.0001 PR + 2 38 PR - 25 7 Ki67 % (mean ± SD) 50.9 ± 21.9 19.9 ± 13.6 <0.0001 Molecular subtype <0.0001 Luminal A 1 16 Luminal B 1 26 Basal 25 3 Number of positive lymph nodes (mean ± SD) 0.1 ± 0.5 2.6 ± 5.6 0.009 Locoregional recurrence 0.0512 No 24 45 Yes 3 0 Disease-free survival (mean months ± SD) 80 ± 74 67 ± 48 0.948 Overall survival (mean months ± SD) 102 ± 94 78 ± 58 0.958
Phase II study of Hyper-CVAD with pegylated liposomal doxorubicin alternating with methotrexate and cytarabine (HCVIDD/MA) in patients with newly diagnosed T- and NK-cell lymphoma (T/NKCL).
Authors: Dai Chihara, Barbara Pro, Sanam Loghavi, Roberto N. Miranda, L Jeffrey Medeiros, Michelle A. Fanale, Frederick B. Hagemeister, Luis Fayad, Jorge Enrique Romaguera, Felipe Samaniego, Sattva Swarup Neelapu, Anas Younes, Nathan Hale Fowler, Maria Alma Rodriguez, Michael Wang, Larry W. Kwak, Peter McLaughlin, Nam H. Dang, Yasuhiro Oki
Journal: Journal of Clinical Oncology (2015)

8538 Background: Prognosis of T/NKCL is poor after standard CHOP therapy. To prospectively evaluate the role of dose intensified chemotherapy, we conducted a phase II trial of HCVIDD/MA in patients with newly diagnosed T/NKCL. Methods: Eligible patients were adults with newly diagnosed untreated T/NKCL excluding ALK positive ALCL. Patients received HCVIDD/MA every 21 days for up to eight cycles. In this trial, pegylated liposomal doxorubicin at 25mg/m2was used instead of conventional doxorubicin. Results: Fifty-three patients were enrolled (PTCL-NOS: 24, AITL: 7, Systemic ALK negative ALCL: 7, HSTL: 7, extranodal NKCL: 5, Others: 3). The median age of patients was 54 (range 20-72). Eighty-five percent of the patients were in advanced stage, 32% had bone marrow involvement and 43% had IPI score > 2. The median cycle number of treatment given was five. Only 5 of 53 patients (9%) received seven or more cycles primarily due to prolonged cytopenias. Of 47 patients who were eligible for response evaluation, the overall response rate was 66% with complete response rate of 57%. Six patients (11%) underwent consolidative autologous stem cell transplant at treating physician's discretion. Median progression free survival (PFS) of all patients was 8.1 months. With the median follow-up time of 83 months, five-year PFS and overall survival (OS) rates were 22% and 49%, respectively. The patients with extranodal NKCL had shorter PFS (all 5 progressed < 13 months) than other types. Patients with HSTL had slightly longer PFS (median 49 months) than other types. There was no significant difference in PFS or OS by treatment cycles beyond five and by consolidative ASCT. Grade3/4 anemia, neutropenia and thrombocytopenia were observed in 66%, 74% and 79%, respectively. Of note, 11 patients (21%) were taken off study due to thrombocytopenia with median of 5 cycles. Conclusions: HCVIDD/MA for the first line treatment of T/NKCL showed response rate and survival outcome similar to previously reported those with conventional CHOP, and was associated with higher hematologic toxicities. (clinicaltrials.gov identifier: NCT00290433) Clinical trial information: NCT00290433.
Toremifene citrate increases bone mineral density in men receiving androgen deprivation therapy for prostate cancer
Authors: M. R. Smith, F. Chu, J. Forrest, S. B. Malkowicz, D. Price, P. Sieber, K. G. Barnette, S. Segal, M. S. Steiner
Journal: Journal of Clinical Oncology (2006)

4553 Background: In men with prostate cancer, androgen deprivation therapy by either surgical orchiectomy or treatment with a gonadotropin releasing hormone agonist decreases bone mineral density (BMD) and increases clinical fracture risk. In postmenopausal women, selective estrogen receptor modulators (SERMs) increase BMD and decrease fracture incidence. We conducted a multicenter randomized controlled trial to evaluate the efficacy of the SERM toremifene citrate in men with prostate cancer. Methods: In a 24-month prospective study, 1392 men with prostate cancer who have been treated with ADT for at least 6 months and are at increased risk of fracture based on either being older than 70 years of age or having evidence of osteopenia by baseline dual energy X-ray absorptiometry (DEXA) scan were assigned randomly (1:1) to receive either toremifene citrate 80mg or placebo (by mouth daily). The primary study endpoint is proportion of men with one or more fracture at 24 months. Secondary endpoints include changes in BMD of the hip and spine. Here we report the results of a planned interim analysis of 12-month changes in BMD for the first 200 subjects. Results: As summarized in the table below, toremifene citrate significantly increased BMD of the lumbar spine, total hip, and femoral neck compared to placebo. Conclusions: In men receiving ADT for prostate cancer, toremifene citrate significantly increased BMD of the hip and spine. In randomized controlled trials of SERMs in postmenopausal women, similar BMD improvements translated into statistically and clinically significant decreases in fractures risk. These interim results of BMD effects suggest toremifene citrate has the potential to provide a fracture reduction benefit in men with prostate cancer, the hypothesis being tested in the ongoing study. [Table: see text] [Table: see text]