tbuckley/cabot-search huggingface dataset:
Physical Activity and Risk of Coronary Heart Disease and Stroke in Older Adults
Authors: Luisa Soares-Miranda, David S. Siscovick, Bruce M. Psaty, W. T. Longstreth, Dariush Mozaffarian
Journal: Circulation (2015)

Background— Although guidelines suggest that older adults engage in regular physical activity (PA) to reduce cardiovascular disease (CVD), surprisingly few studies have evaluated this relationship, especially in those &gt;75 years. In addition, with advancing age the ability to perform some types of PA might decrease, making light-moderate exercise such as walking especially important to meet recommendations. Methods and Results— Prospective cohort analysis among 4207 US men and women of a mean age of 73 years (standard deviation=6) who were free of CVD at baseline in the Cardiovascular Health Study were followed from 1989 to 1999. PA was assessed and cumulatively updated over time to minimize misclassification and assess the long-term effects of habitual activity. Walking (pace, blocks, combined walking score) was updated annually from baseline through 1999. Leisure-time activity and exercise intensity were updated at baseline, 1992, and 1996. Incident CVD (fatal or nonfatal myocardial infarction, coronary death, or stroke) was adjudicated using medical records. During 41 995 person-years of follow-up, 1182 CVD events occurred. After multivariable adjustment, greater PA was inversely associated with coronary heart disease, stroke (especially ischemic stroke), and total CVD, even in those ≥75 years. Walking pace, distance, and overall walking score, leisure-time activity, and exercise intensity were each associated with lower risk. For example, in comparison with a walking pace &lt;2 mph, those that habitually walked at a pace &gt;3 mph had a lower risk of coronary heart disease (0.50; confidence interval, 0.38–0.67), stroke (0.47; confidence interval, 033–0.66), and CVD (0.50; confidence interval, 0.40–0.62). Conclusions— These data provide empirical evidence supporting PA recommendations, in particular, walking, to reduce the incidence of CVD among older adults.
Outcomes with second-line chemotherapy in castrate metastatic prostate cancer
Authors: K. W. Beekman, M. T. Fleming, H. I. Scher, M. Warren, N. Ishill, G. Heller, W. K. Kelly
Journal: Journal of Clinical Oncology (2005)

4659 Background: Docetaxel is the standard 1st-line chemotherapy for patients (pts) with progressive castrate metastatic prostate cancer (CMPC). We describe the outcomes of patients following first-line therapy in the contemporary era. Methods: The outcomes of 108 pts treated with a microtubule-targeting chemotherapy as 1st-line were evaluated for response to 2nd and 3rd line cytotoxic treatments. The subsequent treatments included a docetaxel/paclitaxel, mitoxantrone, doxorubicin, cyclophosphamide or investigational agents. Parameters evaluated were: the proportion who received a subsequent treatment, and the Karnofsky Performance Status (KPS), LDH, Alk, Hb, Alb, and PSA at the start of the therapy. Post-therapy PSA levels were also recorded. Survival estimates were performed using the Kaplan-Meier method. Results: Of the entire cohort, 83% (90 of 108) received 2nd and 40% (44 of 108) received 3rd line therapy. The median survival for 1st line treatment was 21 months (95% CI, 18–25), for 2nd line 13 months (95% CI, 10–15), and 12 months (95% CI, 9–19) for 3rd line therapy. Baseline characteristics showed similar Hgb, Alb, and LDH between those receiving 1st, 2nd and 3rd line treatment, with a trend to higher Alk and PSA values. The proportion showing post-therapy PSA declines were .72, .15 and .24. Conclusions: In this cohort, a significant proportion of pts with CMPC who receive 1st-line therapy go on to receive 2nd and 3rd line chemotherapy. Most baseline characteristics do not change and survival remains notable. The results have implications in the design of trials for 2nd and 3rd line chemotherapy. Support: Prostate Cancer Foundation Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Aventis Aventis
Anti-tumor activity of low-dose single agent CCI-779 for relapsed mantle celllLymphoma: A phase II trial in the North Central Cancer Treatment Group
Authors: T. E. Witzig, S. M. Ansell, S. M. Geyer, P. J. Kurtin, K. M. Rowland, P. J. Flynn, R. F. Morton, S. R. Dakhil, H. M. Gross, M. J. Maurer, S. H. Kaufmann
Journal: Journal of Clinical Oncology (2005)

6504 Purpose: Mantle Cell Lymphoma (MCL) is characterized by t(11;14) resulting in over expression of cyclin D1, a member of the phosphatidylinosital 3-kinase (PI3K) pathway. CCI-779 is a novel inhibitor of the mammalian target of rapamycin (mTOR) kinase. Previous studies with weekly CCI-779 at a dose of 250mg demonstrated a 38% overall response rate in 35 patients (Blood 104(11):abstract 129, 2004). Thrombocytopenia was frequently observed and was dose limiting. The current study tests whether low-doses (25mg) of CCI-779 produce a similar overall response rate. Patients and Methods: Eligible patients had biopsy proven cyclin D1 positive MCL and had relapsed or were refractory to therapy. Patients received CCI-779 25mg IV weekly as a single agent. Patients were restaged after 1 cycle (4 doses), after 3 cycles, and every 3 cycles thereafter. Patients with a tumor response after 6 cycles were eligible to continue drug for a total of 12 or 2 cycles after complete remission (CR) and then were observed without maintenance. Results: Eighteen of the target 27 patients have been enrolled. One major protocol violation on cycle-1 was excluded. The design-mandated interim analysis on the first 13 evaluable patients (in progress) has verified 4 PRs in the first 8 (50%; CI 16%–84%) and stable disease in the other 4. Four responses are sufficient to declare the treatment “active” at the final analysis. One patient died of infection without progression; 1 with stable disease went off to other therapy; and 5 patients currently have insufficient response information available. With toxicity data available for 8 patients, no grade-4 toxicities and 1 each grade-3 neutropenia and thrombocytopenia have been reported. Conclusions: Single agent CCI-779 at a dose of 25mg has anti-tumor activity in relapsed MCL. This study demonstrates that agents which selectively target cellular pathways dysregulated in MCL cells can produce therapeutic benefit. The study continues to accrue patients to further clarify the toxicity profile of the lower dose. If this response rate is maintained with a low toxicity profile, then CCI-779 could potentially be combined with other agents in future trials. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Wyeth Wyeth
The immune landscape of renal cell carcinoma and its association with intratumoral clonality.
Authors: Andrew G. Winer, Yasin Senbabaoglu, Ron Gejman, Irina Ostrovnaya, Samuel D. Kaffenberger, Martin Henner Voss, Jonathan A. Coleman, Paul Russo, James Hsieh, Chris Sander, A. Ari Hakimi
Journal: Journal of Clinical Oncology (2016)

605 Background: Clear cell renal cell carcinoma (ccRCC) is among the most highly infiltrated tumors despite a relatively low mutation burden. Despite success in treating subsets of these patients with immunotherapy, the high immune-infiltration of ccRCC remains a conundrum that has not been sufficiently addressed. Methods: We utilized an original RNAseq-based aggregate immune score (Senbabaoglu Y, bioRxiv, 2015) to compare immune infiltration levels across 20 tumor types profiled in The Cancer Genome Atlas (TCGA) and validated our results with an independent cohort of ccRCC patients (Sato Y, Nat Genet, 2013). We also evaluated the immunogenic effect of intratumoral heterogeneity (ITH) through an analysis of clonal architecture in ccRCC tumors from both of the aforementioned data sets using the SciClone (Miller C, PLoS Comput Biol, 2014) algorithm. Results: We identified ccRCC as an immunogenic outlier that is unique from other highly infiltrated tumors in its exceptional overexpression of antigen presentation machinery compared to normal tissue. In a focused decomposition of immune cell levels within the 415 ccRCC tumors from TCGA, three unique clusters of tumors emerged primarily separated by varying degrees of T cell infiltration; termed (1) T-cell-enriched, (2) heterogeneous, and (3) non-infiltrated groups. These clusters were validated in an independent ccRCC cohort of 101 patients. A comparison of the degree of clonality with immune infiltration levels revealed that tumors with less ITH (i.e. fewer subclones) had significantly higher immune infiltration in both the TCGA and the validation cohort . Conclusions: Our findings provide novel insight into the immune landscape of ccRCC tumors and explore a potential mechanism for the immunogenicity of these tumors. Such information can potentially be used to aid in predicting therapeutic response to immunomodulatory agents.
Phase I study of karenitecin in the treatment of recurrent malignant gliomas (MG)
Authors: G. J. Lesser, S. A. Grossman, K. Carson, S. Phupanich, T. Batchelor, D. Peereboom, L. B. Nabors, J. Supko, F. Hausheer
Journal: Journal of Clinical Oncology (2005)

1527 Background: Karenitecin is a camptothecin with activity in solid tumors. The pharmacology of several camptothecins is affected by hepatic enzyme inducing antiepileptic drugs (EIAED). This study was conducted to determine the maximum tolerated dose (MTD) of karenitecin in adults with recurrent MG, the effects of EIAEDs on its pharmacokinetics, and preliminary evidence of activity. Methods: Karenitecin was administered intravenously over 60 minutes daily for 5 consecutive days, every 3 weeks. The starting dose was 1.00 mg/m2 per day. This was escalated using the continual reassessment method independently in cohorts stratified by EIAED use. Three patients were treated at each dose level. Intrapatient dose escalation was not permitted. Treatment was continued until disease progression or treatment-related dose-limiting toxicity. Pharmacokinetic samples were obtained following the first dose of drug. One prior chemotherapy was permitted. Results: 32 pts were accrued with a median age of 52 years (range: 34–72), median KPS of 90 (range: 60–100). 78% had glioblastoma multiforme. Dose levels evaluated in the +EIAED arm were 1.0, 1.5, 1.7, 1.9, and 2.1 mg/m2 and 1.0, 1.5, and 1.8 mg/m2 in the -EIAED cohort. Myelosuppression was the major toxicity with transient grade 3–4 neutropenia or thrombocytopenia in 28% and 16% of patients, respectively. The MTD was 2.0 mg/m2 in +EIAED patients and 1.5 mg/m2 in the -EIAED patients. At the 1.5 mg/m2 dose (7 +EIAED, 6 -EIAED) the -EIAED cohort had a maximum concentration of drug in plasma 36% lower (mean: 22.9 ± 12.1 vs 35.8 ± ng/mL) and a mean total body clearance 29% higher (13.5 ± 13.5 vs 10.5 ± 3.3 l/h/m2) than the +EIAED group. The median survival was 6.5 months (95% CI 4.0 - 9.7 months) and 25 of the 32 patients are deceased. No complete or partial responses were observed although 12 patients were treated at or above the MTD. Conclusions: As observed with other camptothecin analogues, karenitecin elimination is enhanced by EIAED administration. Single agent karenitecin does not appear very active in recurrent MG. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration BioNumerik BioNumerik
Assessment of early metabolic response to one-cycle chemotherapy by PET in locally advanced esophageal squamous cell carcinoma (ESCC) treated with chemoradiotherapy (CRT) followed by surgery-A pilot study
Authors: J. Lo, C. Lin, K. Tzen, J. C. Cheng, F. Hsu, Y. Tsai, T. Huang, K. Yeh, Y. Lee, C. Hsu
Journal: Journal of Clinical Oncology (2008)

15610 Background: Preoperative CRT may confer a small survival advantage, but at the risk of increased surgical complications, in patients (pts) with locally advanced ESCC. Early metabolic response defined by 18-fluorodeoxyglucose-positron emission tomography (PET) after neoadjuvant chemotherapy (C/T) was proved to predict histological response and survival in locally advanced esophagogastric adenocarcinoma (Ott K et al: J Clin Oncol 2006;24:4692). We aimed to assess whether the early metabolic response to one-cycle C/T predicted the outcome of locally advanced ESCC pts subsequently treated with CRT followed by radical esophagectomy (Op). Methods: Pts with locally advanced ESCC (T3 or N1 or M1a) defined by CT, endoscopic ultrasound, and PET were treated with one cycle C/T (weekly paclitaxel (T), cisplatin (P), and 5-fluorouacil/leucovorin, 2/3 weeks), then CRT with twice weekly TP for a total radiation (RT) dose of 40 Gy in 20 fractions (Lin CC et al: Ann Oncol 2007;18:93), followed by Op 4 weeks later. The early metabolic response was defined as a decrease of tumor glucose standard uptake values (SUVs) > 35% from baseline, evaluated on day 14. Results: Between Aug 2006 and Dec 2007, 11 ESCC pts (M/F 11/0; median age 56 [range 46∼79]; clinical stage T3N0/T3N1/M1a 1/6/4) were studied. All pts completed one-cycle C/T, with 8 early metabolic responders and 3 non-responders. Subsequently, 7 pts received CRT followed by Op, 1 completed CRT and prepared for Op, 2 refused Op and received additional CRT to RT 60Gy, and 1 developed progressive disease (PD) during CRT. Among 7 pts receiving Op, 5 had pathologic complete response (pCR) and 2 had residual disease in lymph nodes. As for 6 metabolic responders who received Op, 4 had pCR (66%). As for 3 metabolic non-responders, 1 had early PD, 1 developed recurrence within 4 months after completing definitive CRT, and 1 had pCR (33%). Conclusions: Early metabolic response to one-cycle C/T may be helpful in distinguishing locally advanced ESCC pts with different outcomes. No significant financial relationships to disclose.
The natural history and role of surgical cytoreduction and systemic chemotherapy in high-grade mucinous adenocarcinomas of the appendix.
Authors: Michael J. Overman, Binsah George, Melissa W. Taggart, Cathy Eng, Richard E. Royal, Robert A. Wolff, Paul F. Mansfield, Keith F. Fournier
Journal: Journal of Clinical Oncology (2013)

199 Background: The natural history, clinical presentation, and impact of cytoreductive surgery (CRS) or systemic chemotherapy for high grade MAA has been poorly studied. Methods: A retrospective chart review of patients (pts) with moderate or poorly differentiated AA was completed from 1994-2010. Radiographic response was assessed semi-quantitatively form physician records and complete cytoreductive surgery (CRS) was defined as a completeness of cytoreduction score of 0 or 1. For CRS and chemotherapy subgroups efficacy endpoints were calculated from date of CRS or first chemotherapy dose, respectively. Results: 288 (136 moderate and 152 poor grade) pts were identified with a median age of 52 years (range: 25-82). Mucinous histology was present in 110 pts (38%) and differed by grade: 55% of moderate and 23% of poor. Stage IV presentation (n=163) occurred in 76% of poor grade but only 35% of moderate grade. Both median OS (4.5 vs. 2.7 yrs, P=0.04) and median OS for the stage IV subgroup (3 vs 1.9yrs, P=0.005) were improved for MAA vs. non-MAA. Moderate compared to poor grade had improved median OS (3.7 vs 1.9 yrs, P=0.002) for Stage IV disease, but this differed by mucinous histology (moderate mucinous 6.2yr vs. poor mucinous 1.6yr, P=0.001; moderate nonmucinous 1.4yr, poor nonmucinous 2yr). 39 MAA pts underwent a complete CRS (30 moderate and 9 poor) with a median time to recurrence of 1.5yrs and median OS of 9.2yrs. Improved OS was seen for pts with a complete CRS compared to pts with an incomplete CRS, P&lt;0.001. 55 MAA pts received systemic chemotherapy (fluoropyrimidine/oxaliplatin in 30, irinotecan-based in 8, fluoropyrimidine-based in 16, and other in 1): median OS of 2.1yr, median TTP of 7.2 months, and radiographic response of 36%. No statistical differences were seen between chemotherapy groups. Conclusions: High-grade MAA represents a heterogenous disease with a statistically worse OS for poor as opposed to moderate histological differentiation. This data does not support the AJCC 7 th edition use of a single mucinous high-grade category. The use of systemic chemotherapy appears to be a viable treatment option for these pts and a complete CRS is associated with improved OS.
Neutrophil to lymphocyte ratios and pathologic response to neoadjuvant therapy in esophageal cancer.
Authors: Nathan W. Bronson, Renato Luna, Lisa M. Bloker, Miriam A. Douthit, Brian S. Diggs, James P. Dolan, John G. Hunter
Journal: Journal of Clinical Oncology (2012)

44 Background: Esophageal cancer (EC) is increasing in incidence dramatically, and is associated with suboptimal outcomes despite the widespread adoption of neoadjuvant multimodality therapy (NAT) as a de-facto standard-of-care for clinically resectable disease. Between one-quarter and one-third of patients (pts) are found to have no evidence of tumor (pCR) at the time of surgical resection, a prognostic indicator of superior survival benefit. However, we currently lack a method to prospectively identify pts who will respond to (NAT). Identifying complete responders could reduce the number of patients requiring esophagectomy. The specific aim of this study was to determine if the pre-operative neutrophil to lymphocyte ratio (NLR), which has been reported as a prognosticator of mortality, is prognostic of pCR to NAT. Methods: A prospectively collected database was queried for all pts that have undergone esophagectomy for EC, including both squamous cell carcinoma and adenocarcinoma. Records were evaluated for preoperative complete blood count (CBC) with differential from which a NLR was calculated as the absolute neutrophil count divided by the absolute lymphocyte count. A NLR greater than 5 was considered elevated. Pts were classified as pCR if they had no residual tumor on final pathology, partial responders (PR) if they demonstrated down staging after neoadjuvant therapy, or non-responders (NR) if they did not show any improvement in their stage on final pathology. Results: Of 114 pts who underwent both NAT and esophagectomy for EC, 41 had a pre-operative CBC with differential from which a NLR could be calculated. There were 19 NR, 14 PR and 8 CR. These groups were demographically similar. The average NLR was 5.92 for NR, 6.56 for PR, and 4.89 among CR, with no statistically significant difference between groups. Overall survival at 5 years was 33%. By multivariate analysis NLR&gt;5 did not correlate with pathologic response (p=0.78), and NLR &gt;5 did not correlate with survival (p=0.33). Conclusions: Elevated neutrophil to lymphocyte ratios are not predictive of pathologic response to NAT in esophageal cancer.
Micropapillary bladder cancer: Stage at presentation and treatment outcome—Analysis of 121 patients from a cancer database.
Authors: Joshua D. Holyoak, Zachary Panfili, Ravi P. Kiran, Naveen Pokala
Journal: Journal of Clinical Oncology (2013)

289 Background: The micropapillary variant of transitional cell cancer(MPTCC) is an aggressive pathological subtype of bladder cancer and radical cystectomy is recommended for patients with non−muscle invasive disease. This study compares the treatment patterns and survival outcome in 121 patients. Methods: Patients with MPTCC (code 8131) were identified from the Surveillance Epidemiology and End Results (SEER 17) database. Data was analyzed for demographics, stage, treatment, overall (OS) and cancer specific survival (CSS). Appropriate statistical tests were used. Results: 121 patients were identified (2001−08). Mean age was 73.3 years, 76.9% were male (76.9%, n=93), 82.7% were Caucasian. 40.5% (n=49) had non−muscle invasive (NMI) disease and 59.5% had muscle−invasive disease (MI) at diagnosis. The T stage was Ta or Tis (n=17), T1 (n=32), T2 (n=38) T3 (n=20) and T4 (n=14). 23 patients had node positive disease, the nodal status was not known in 4 patients. 10 patients had distant metastasis. Surgical procedures performed include, TURBT (n=83), Radical cystectomy (n=34), pelvic exenteration (n=1) and partial cystectomy (n=3). 8 patients received post−operative radiotherapy. The mean OS was 64.9, 42.9, 16.1 and 50.2 months and the mean CSS was 81.2, 56.3, 15.7 and 64.4 months for NMI, MI, distant and the whole group respectively. The 5−year OS was 40%, 54% and 34% and the 5 year CSS was 62%, 53% and 82% for the whole group, MI and NMI respectively. All patients with distant disease were dead by 28 months. On analysis of CSS by treatment type the 5−yr CSS for NMI was 81% (n=36) after TURBT and 100% (n=3) after Radical surgery. For MI disease the 3−yr CSS was 66% after TURBT (n=18) and the 5−yr CSS was 54% after radical surgery (n=29). On multivariate analysis, higher stage and age were associated with worse survival. TURBT was associated with better survival. Conclusions: MPTCC is a rare variant of TCC. 81% survival can be achieved with TURBT for non-muscle invasive MPTCC.
A phase 0 microdosing trial to identify chemoresistance in bladder cancer.
Authors: C. Pan, S. Wang, M. He, R. de Vere White, P. Lara, D. R. Gandara, P. C. Mack, K. Turteltaub, P. T. Henderson
Journal: Journal of Clinical Oncology (2011)

264 Background: DNA damage is the critical step in cancer cell response to platinum (Pt) chemotherapy. We hypothesize that low levels of Pt-induced DNA damage are predictive of chemoresistance. Accelerator mass spectrometry (AMS) is an ultrasensitive method for measuring radiocarbon. By measuring 14 C bound to DNA, AMS can detect carboplatin-induced DNA damage after patients receive one subtoxic microdose of 14 C-labeled carboplatin. Methods: Cancer cells and mice bearing tumor xenografts were treated with one microdose (1/100th of the therapeutic dose) or one therapeutic dose of [ 14 C]carboplatin. Carboplatin-DNA adducts and other relevant parameters such as drug influx/efflux, intracellular drug inactivation, and repair of DNA damage, were measured and correlated with response to chemotherapy. Results: AMS detected Pt-DNA damage when cancer cells and mice with tumor xenografts were exposed to one microdose of [ 14 C]carboplatin. The levels of microdose-induced DNA damage were linearly proportional to the DNA damage caused by the therapeutic drug dose (R 2 =0.92, p&lt;0.001); and these levels of DNA damage correlated with chemoresistance. Low DNA damage predicts chemoresistance. Measuring drug uptake/efflux, intracellular inactivation and DNA repair allowed insight into some resistance mechanisms. We have opened a phase 0 microdosing trial to study patients with bladder cancer who are scheduled to receive Pt-based chemotherapy. One subtoxic microdose of 14 C-carboplatin will be administered to these patients before biopsy. Pt-induced DNA damage and repair in left-over tumor biopsy specimens and other relevant parameters will be measured and correlated with the response and toxicity of chemotherapy. Molecular analysis of genes such as ERCC1 and RRM1 will be analyzed and compared with this phase 0 results. We have opened a similar phase 0 trial in dog patients with bladder cancer. Conclusions: The levels of DNA damage induced by nontoxic microdosing carboplatin can potentially predict chemoresistance in cancer cell lines. The clinical data of the phase 0 trial will be presented. No significant financial relationships to disclose.