tbuckley/cabot-search huggingface dataset:
Inhibitory Receptors Induced by VSV Viroimmunotherapy Are Not Necessarily Targets for Improving Treatment Efficacy
Authors: Kevin G. Shim, Shane Zaidi, Jill Thompson, Tim Kottke, Laura Evgin, Karishma R. Rajani, Matthew Schuelke, Christopher B. Driscoll, Amanda Huff, Jose S. Pulido, Richard G. Vile
Journal: Molecular Therapy (2017)

Systemic viroimmunotherapy activates endogenous innate and adaptive immune responses against both viral and tumor antigens. We have shown that therapy with vesicular stomatitis virus (VSV) engineered to express a tumor-associated antigen activates antigen-specific adoptively transferred T cells (adoptive cell therapy, ACT) in vivo to generate effective therapy. The overall goal of this study was to phenotypically characterize the immune response to VSV+ACT therapy and use the information gained to rationally improve combination therapy. We observed rapid expansion of blood CD8+ effector cells acutely following VSV therapy with markedly high expression of the immune checkpoint molecules PD-1 and TIM-3. Using these data, we tested a treatment schedule incorporating mAb immune checkpoint inhibitors with VSV+ACT treatment. Unlike clinical scenarios, we delivered therapy at early time points following tumor establishment and treatment. Our goal was to potentiate the immune response generated by VSV therapy to achieve durable control of metastatic disease. Despite the high frequency of endogenous PD-1+ TIM-3+ CD8+ T cells following virus administration, antibody blockade did not improve survival. These findings provide highly significant information about response kinetics to viroimmunotherapy and juxtapose the clinical use of checkpoint inhibitors against chronically dysfunctional T cells and the acute T cell response to oncolytic viruses.Graphical abstract
Optimizing a risk stratification for local-regional failure after radical cystectomy using the SWOG 8710 cohort.
Authors: Brian C. Baumann, Jiwei He, Wei-Ting Hwang, Kai Tucker, Seth P. Lerner, Catherine M. Tangen, Harry W. Herr, Thomas J. Guzzo, S. Bruce Malkowicz, John Paul Christodouleas
Journal: Journal of Clinical Oncology (2014)

297 Background: Trials of adjuvant radiation (RT) after radical cystectomy + pelvic node dissection (RC) are in development, but patient selection criteria have not been clearly identified. We evaluated a published model predicting the risk of local-regional failure (LF) by applying the model to a multi-center patient cohort. We also assessed the model’s ability to stratify overall survival (OS) and isolated distant metastases (DM). Methods: The original LF risk model was derived from 442 patients who had a RC +/- chemotherapy at the University of Pennsylvania (PENN). Analysis identified 3 subgroups with significantly different LF risk based on pathologic stage (pT) and number of nodes dissected (&lt;10 vs ≥10). This risk rubric was then applied to 264 patients in the multi-center SWOG 8710 trial randomized to RC +/- neoadjuvant chemotherapy. SWOG patients differed significantly from PENN patients in mean age, pT stage, number of nodes removed, surgical margin status, and use of neoadjuvant chemotherapy. In both cohorts, LF was any pelvic failure detected before or within 3 months of DM. Secondary endpoints were OS and DM. Competing risk analysis was used. Results: The original risk stratification was not fully validated in the SWOG cohort. Regression analysis of the SWOG data found margin status was more predictive of LF than number of nodes dissected. A revised risk stratification model combining pT stage, margin status, and number of nodes removed identified 3 subgroups in both the SWOG and PENN cohorts with significantly different LF risks: low (≤pT2), intermediate (≥pT3 with negative margins AND ≥10 nodes removed), and high (≥pT3 with positive margins OR &lt;10 nodes removed) with 5 year LF rates of 8%, 20%, and 41% in the SWOG group and 8%, 19%, and 41% in the PENN cohort. The 3 subgroups also differed significantly in OS within both cohorts with 5 year OS of 62%, 39%, and 7% for SWOG and 60%, 31%, and 10% for PENN. The model did not stratify with respect to isolated DM. Conclusions: The revised risk model combining pT stage, margin status, and number of nodes excised provides a simple rubric to stratify LF risk in two significantly different bladder cancer populations and may inform the design of adjuvant RT trials.
What is the role of comorbidity, frailty, and functional status in the decision-making process for older adults with cancer and their family members, oncologists, and family physician?
Authors: Martine Puts, Schroder Sattar, Kara McWatters, Katharine Lee, Michael Kulik, Mary Ellen Macdonald, Raymond Woo-Jun Jang, Eitan Amir, Monika K. Krzyzanowska, Natasha B. Leighl, Margaret Fitch, Anthony M. Joshua, Padraig Richard Warde, Ann Tourangeau, Shabbir M.H. Alibhai
Journal: Journal of Clinical Oncology (2016)

92 Background: Little is known about the treatment decision making process (TDMP) in older adults (OA) with cancer. The objective of this study is to develop a theoretical framework with the aim to improve the TDMP for this population. Methods: This is a mixed methods multi-perspective longitudinal study. OAs aged &gt; 70 years with advanced prostate, breast, colorectal, or lung cancer, their family members, oncologists and family physicians are invited to participate in individual, semi-structured interviews. Each OA also completes a short survey to characterize their health, functional status, frailty level, decision-making preferences, and satisfaction with the TDMP. The sample is stratified on age (70-79 and 80+) to obtain data saturation for the oldest old. All interviews will be analyzed using the grounded-theory approach. Results: To date, 32 first interviews and 15 second interviews have been completed with 32 older adults, 21 family members and 12 family physicians and 7 cancer specialists. Interviews lasted between 10-60 minutes. Most older adults felt that they should have the final say in the treatment decision, but strongly valued their physician’s opinion. Most participants felt they received enough information, time and support from the oncologist to make their decision. About half the participants went to see their family physician to talk about the diagnosis and plan. Comorbidity and potential side-effects did not play a major role in the decision-making processes for patients and families but it did for oncologists. Family physicians reported they were not involved in treatment decisions, and they preferred more timely information about the patient. Conclusions: This study-in-progress is examining the TDMP from four different perspectives and examining changes over time in the TDMP. Patients and family members were generally satisfied with the treatment decision making process. Final results will be presented at the conference.
Ascorbic Acid Overcomes Drug Resistance in Myeloma and Significantly Increases the Anti-Myeloma Effects of both Arsenic Trioxide and Melphalan in Vitro and in Vivo.
Authors: Richard A. Campbell, Haiming Chen, Daocheng Zhu, Janice C. Santos, Benjamin Bonavida, Shen Pang, Jonathan Said, James R. Berenson
Journal: Blood (2004)
Patterns of palliative procedures and clinical outcome in advanced non-small cell lung cancer
Authors: Y. Kim, H. J. Kim, M. Seo, H. Yi, S. Lee, D. Kim, D. Heo
Journal: Journal of Clinical Oncology (2008)

20752 Background: Despite recent progress in palliative chemotherapy of advanced non-small cell lung cancer (NSCLC), the prognosis is still poor. Aside from multiple lines of chemotherapy, many patients need palliative procedures due to disease related events. The patterns of these palliative procedures and their impact on clinical course have not been well described. Methods: We evaluated 162 patients who were diagnosed as stage IIIB (with malignant pleural effusion) or IV NSCLC at Seoul National University Hospital in 2005. The patterns of disease related events requiring palliative procedures, the palliative procedures given, and clinical outcomes were retrospectively analyzed. Results: Of the 162 patients, 107 were male (66%) and 55 were female (34%) with a median age of 61 years (range, 31–90). Among these patients, 108 patients (66%) received palliative procedures due to disease related events. Forty-nine patients (30%) needed palliative procedure at the time of diagnosis, and 59 patients (36%) later during their treatment course. The events requiring palliative procedures were CNS event (brain metastasis or leptomeningeal carcinomatosis) in 37 (34%), thoracic event (malignant effusion or severe pneumonia requiring intensive care unit not related to chemotherapy) in 30 (28%), skeletal event (bone metastasis requiring radiation, spinal cord compression, hypercalcemia) in 29 (27%), and other event in 12 (11%). Patients who had events at the time of diagnosis showed comparable overall survival to the eventless patients at diagnosis (14.6 vs. 13.3 months, p=0.65). Patients who had later events during their treatment course had short median survival after palliative procedures (median 2.7months, 95% CI 2.19–3.21). Conclusion: Considerable proportion of advanced NSCLC patients receive palliative procedures apart from chemotherapy. These interventions should be taken into consideration for comprehensive care planning and timely cooperation with palliative care team. No significant financial relationships to disclose.
Enhanced risk stratification in young and elderly patients treated with induction chemotherapy as well as in frail patients with AML.
Authors: S. Wilop, T. H. Brummendorf, M. M. Crysandt
Journal: Journal of Clinical Oncology (2011)

6582 Background: Cytogenetic aberrations represent the main risk factor in AML. The recently published Muenster AML score ameliorated risk stratification in elderly patients treated with induction chemotherapy in a large trial using additional clinical factors. A second score for prediction of complete remission (CR), overall survival (OS) and early death was established for cases, where cytogenetic information is not available. Methods: We first retrospectively applied these two scores in 59 elderly patients with newly diagnosed AML treated with induction chemotherapy. Although the score was not designed to, we then tested these scores in a cohort of young (n=73) patients who received induction therapy and additionally in frail (n=118) patients with cytoreductive therapy or best-supportive care only. Results: For the proposed patient-cohort of elderly patients treated with induction chemotherapy, the AML Score including cytogenetic information was, as expected, highly predictive for achieving CR (100% vs. 42.9%, p<0.001) and for OS (44.6 vs. 2.6 months, p<0.001). Using the score without cytogenetic information, prediction of OS was also possible (16.2 vs. 5.9 months, p=0.02) whereas prediction of CR lost statistical significance. Interestingly, in the not intended cohort of young patients, both scores achieved a very good discrimination of risk groups, even without using cytogenetic information (OS: 88.6 vs. 24.4 months, p<0.01; achieving CR: 94.4% vs. 59.1%, p=0.02). In our cohort of frail patients not suitable for induction therapy, using the score with cytogenetics also clearly discriminated risk groups for short OS (20.7 vs. 3.8 months, p<0.001). Discrimination using the score without cytogenetic information was not statistically significant (15.0 vs. 5.2 months, n.s.). However, prediction of early death showed no statistically significance in all of our three patient cohorts. Conclusions: The Muenster AML Scores may enhance selective risk stratification in young and elderly patients treated with induction chemotherapy as well as in frail patients without intensive treatment also in cases, where cytogenetic information is not available.
Randomized phase II study of PEP02, irinotecan, or docetaxel as a second-line therapy in gastric or gastroesophageal junction adenocarcinoma.
Authors: D. Cunningham, S. Park, Y. Kang, Y. Chao, L. Chen, C. Rees, H. Lim, J. Tabernero, G. Yeh, A. De Gramont
Journal: Journal of Clinical Oncology (2011)

6 Background: PEP02 is a novel nanoparticle liposome formulation of irinotecan (CPT-11). In phase I studies, PEP02 has improved pharmacokinetics (PK) of CPT-11 and its active metabolite-SN38 with encouraging safety and tumor response in several cancer types including gastric cancer. This study evaluated the efficacy and safety of PEP02 (P), irinotecan (I) or docetaxel (D) as a single agent in gastric or gastroesophageal junction (GEJ) adenocarcinoma. Methods: A randomized, 3 arms (1:1:1), Simon's 2-stage (2/21, 5/41 based on tumor response) study was conducted in Europe and Asia. Patients (pts) with locally advanced or metastatic disease, failed to one prior chemotherapy, ECOG PS ≤ 2, at least 1 measurable lesion, no prior CPT-11 or taxane, were treated with P - 120 mg/m 2 , I - 300 mg/m 2 , or D - 75 mg/m 2 every 3 weeks. PK and pharmacogenetics (PGx) samples were collected for pts in P and I arms. Results: A total of 135 pts were randomized with 132 (44 per arm) treated between Jan 2008 and Jun 2010. Pts demographics (P/I/D): median age: 56/62/58, male (%): 79.5/77.3/77.3, Pts from Europe (%): 54.6/52.3/56.8, metastatic (%): 97.7/90.9/97.7, gastric adenocarcinoma (%): 84.1/79.6/68.2, and ECOG 0 + 1 (%): 93.2/93.2/90.9. The confirmed responders of P/I/D were 6 (13.6%)/3 (6.8%)/7 (15.9%) and disease control were 27 (61.4%)/27 (61.4%)/24 (54.6%). These three arms have similar progression free survival and overall survival. If stratified by region, Asian pts had longer survival than European pts. Toxicities of P/I/D were: grade 3/4 neutropenia (%): 9.1/13.6/15.9. grade 3/4 diarrhea (%): 27.3/18.2/2.3, hand-foot syndromes (%): 0.0/6.8/18.2. It was notable that symptoms related to acute cholinergic syndrome were less reported in P arm than in I arm. The PK data showed the mean T 1/2 , C max and AUC 0→∞ of SN-38 in P/I arms were 88.8/22.8 hr, 8.79/44.1 ng/mL and 879/440 hr x ng/mL. Conclusions: This randomized phase II study suggests that PEP02 improves the PK profile and tumor response over irinotecan, and it is as efficacious as docetaxel in the 2nd-line treatment for gastric or GEJ adenocarcinoma. PEP02 is worthy of further evaluation as either 1st- or 2nd-line setting in future gastric cancer studies. [Table: see text]
A randomized multicenter phase II trial of capecitabine versus S-1 as first-line treatment in unresectable or recurrent breast cancer patients.
Authors: D. Yamamoto, S. Iwase, H. Odagiri, Y. Kuroda, K. Akazawa, K. Kitamura, T. Kawaguchi, C. Yamamoto, Y. Nagumo, N. Sakata
Journal: Journal of Clinical Oncology (2010)

TPS136 Background: S-1 is a novel oral anticancer drug, composed of tegafur, gimestat, and otastat potassium in a molar ratio of 1:0.4:1, based on the biochemical modulation of 5-fluorouracil. Especially, in Japan, S-1 is popular and widely used for breast cancer treatment. Therefore, we reported that S-1 achieved a high tumor control rate in patients with metastatic breast cancer (ASCO, 2009). On the other hand, capecitabine has been well known to be useful and effective. Therefore, the randomized multicenter phase II study was conducted to investigate the activity and safety of two oral fluoropyrimidines, capecitabine or S-1, in patients with MBC. Methods: This study was an open-label, multicenter, randomized phase II trial with two treatment arms. Patients are required to be between 25 and 75 years of age, with ECOG performance status <3. Patients are randomly assigned to receive either capecitabine or S-1. Random assignment (1:1 ratio) is centralized and performed by Japan Breast Cancer Research Network. Oral capecitabine is administered at a dose of 1,657 mg/m2 twice daily on days 1–21 every 4 weeks. S-1 is 40–60 mg two times daily according to body surface area on days 1–28 every 6 weeks. Three dosage levels of S-1 were defined according to body surface area (BSA) as follows: BSA less than 1.25 m2, 40 mg two times daily; BSA, 1.25 to 1.5 m2, 50 mg two times daily; and BSA more than 1.5 m2, 60 mg two times daily. Tumor response is assessed every two cycles in the capecitabine arm and every cycle for S-1 according to the RECIST criteria. National Cancer Institute Common Toxicity Criteria, version 3.0, are used to assess toxicity. The primary endpoint is TTP. The secondary endpoint is response and OS. Kaplan–Meier estimates and the Cox proportional hazard model are used in the analysis of time-event variables. Sample size calculations for this trial estimated that 110 randomly assigned patients per treatment group would be required for primary endpoint. No significant financial relationships to disclose.
Bevacizumab monotherapy as salvage therapy for patients with advanced clear cell renal cell carcinoma pretreated with targeted drugs.
Authors: Chung-Han Lee, Andreas M Hoetker, Martin Henner Voss, Darren Richard Feldman, Kaitlin Woo, Sujata Patil, Devyn Taylor Coskey, Oguz Akin, James Hsieh, Robert J. Motzer
Journal: Journal of Clinical Oncology (2015)

468 Background: Bevacizumab targets vascular endothelial growth factor (VEGF) and has showed benefit in first-line treatment of metastatic clear cell renal cell carcinoma (ccRCC) in combination with interferon α (Lancet 370: 2103). This retrospective analysis assessed the efficacy of bevacizumab monotherapy after progression on targeted drugs such as VEGFr tyrosine kinase inhibitors (TKI), and/or mTOR inhibitors. Methods: A retrospective analysis was performed on patients with metastatic ccRCC who received bevacizumab monotherapy at MSKCC after progression on prior targeted therapies. Primary end point is overall survival and secondary endpoints include progression free survival, time on therapy, and toxicity analysis. Results: 71 patients were treated with bevacizumab monotherapy in the salvage setting. Patients were heavily pretreated with 36 (51%) patients receiving bevacizumab as a fourth-line agent or later and 33 (46%) patients received at least 2 prior VEGF targeted agents. Seventeen (24%) patients had a KPS &lt;80% and 20 (28%) patients were in the poor prognosis MSKCC risk group. Overall median OS was 11.5 months (95% CI, 6.4-17.4 months) and overall median PFS was 1.9 months (95% CI, 1.7-4.1). Nine (13%) patients had a prolonged time on therapy of &gt;12 months. At last analysis, 8 (11%) patients remained on therapy. Therapy was discontinued for progression of disease (n=56, 89%), adverse events (n=4, 6%), or unknown/unrelated reasons (n=3, 5%). Univariate analysis showed KPS (&lt;80% vs. ≥80%) and MSKCC Risk Factor Classification (poor vs. favorable) as prognostic for poor outcome with hazard ratios of 3.97 (95% CI, 2.09-7.52, p&lt;0.001) and 2.84 (95% CI, 1.17-6.89, p=0.021), respectively. No significant differences in OS were seen when comparing number of lines of prior therapy or lines of prior VEGF targeted therapy. Conclusions: Bevacizumab monotherapy resulted in prolonged disease control in a subset of patients with few discontinuations for adverse events in patients after progression on other targeted therapies, including those who were heavily pretreated. The number of prior VEGF targeted TKI therapies did not correlate with response to bevacizumab, which may reflect a difference in targeting the receptor vs. ligand.
Staging of advanced hepatocellular carcinoma patients in the targeted therapy era.
Authors: Neeraj Nailesh Shah, Manal Hassan, Lianchun Xiao, James L. Abbruzzese, Jeffrey Morris, Ahmed Omar Kaseb
Journal: Journal of Clinical Oncology (2012)

209 Background: Several hepatocellular carcinoma (HCC) staging systems are currently available. However, they were all developed before the targeted therapy era prevailed in the last decade which has changed the natural history of the disease. Our study goal was to test the performance of different HCC staging systems in patients with HCC who were treated at our institution during the last decade. Methods: We prospectively enrolled 438 patients from early 2000 to late 2009. Baseline clinicopathologic parameters and staging were available, including the TNM, Cancer of the Liver Italian Program (CLIP), Barcelona Clinic Liver Cancer (BCLC), Okuda, and Chinese University Prognostic Index (CUPI). We performed survival and cox-regression analyses, and compared the staging systems’ predictive ability using Harrell's C-index. Finally, we performed a subgroup analysis of 3 independent cohorts based on whether or not they received sorafenib, whether or not they had hepatitis, and whether or not they had cirrhosis. Results: The overall survival was 13.9 months. Overall, CLIP score was the most predictive staging system with a C-index of 0.71. 187 patients were treated with targeted therapies and 138 were treated with sorafenib after it was approved in 2007. CLIP score was the most predictive staging system with a C-index of 0.71 in the no sorafenib group, and 0.74 in the sorafenib group. In hepatitis patients, CLIP topped amongst all staging systems with a C-index of 0.75, and in patients without hepatitis, despite all staging systems having a poor predictive ability, CLIP score still had the highest C-index of 0.67. Similarly, CLIP score had the best predictive ability in patients with and without pre-existing liver cirrhosis, with C-indices of 0.73 and 0.68 respectively. There was no statistically significant interaction between CLIP score and hepatitis status, and CLIP score and liver cirrhosis. Thus, overall the CLIP score was the best predictive system in all cohorts. Conclusions: Our results suggest that the CLIP score has the highest stratification ability in our advanced HCC patient population, including several subgroups. Our study confirms the utility of the CLIP score to stratify advanced HCC patients in clinical trials.
Assessing the relationship between accrual and operational efficiency in investigator initiated trials.
Authors: A. Malankar, Y. Novik, A. Martocci, L. Gaynes
Journal: Journal of Clinical Oncology (2011)

e16561 Background: Investigator initiated clinical trials (IITs) are a critical component of the clinical program at the NYU Cancer Institute. Since 2007 the administrative processes has been restructured to open trials in a timely manner and increase accruals. This research investigates the impact of the restructuring upon accrual to adult therapeutic IITs and conducts a preliminary assessment of operational efficiency. Methods: Analyzed accrual data for 2007-2009 and compared 5 factors for each year. Number of new initiated protocols (NP); NPs that accrued > 1 subject (NPa); total number of ongoing trials (TO), number of TOs that accrued >1 subject (TOa) and TOs that accrued 0 subjects (TO-0). Results: There has been a positive impact upon accrual to IITs. There was a 10% increase from ‘07 (n=251) to ‘08 (n=276) and a 12% increase to ‘09 (n=310). There was an ascending trend among TOa ‘07(14) ‘08(18) ‘09(20). The number of TO-0 remained stable in ‘07(22) and ‘08(22) but then increased by 77% in ‘09(39). There was a notable increase in TO ‘07(36), ‘08(40), and ‘09(59). %TOa ’07(38%), vs ‘08(45%) and ‘09(33%) indicated no improvement in overall efficiency despite increase in empirical numbers of TOa. There was however an indication of increased efficiency among NP. NP doubled in 09(13) vs 07(7) and 08(6) and had a better rate of accrual: %NPa ’09 (85%), vs. 08(66%) and 07(57%). Conclusions: The reorganization has had a positive impact upon the absolute number of accruals to IITs, increased number of newly initiated and accruing new trials. However increase in overall accrual and successful new trials aren’t directly correlated with increased efficiency considering the time and resources expended upon supporting non performing trials. Our research is limited to preliminary parameters which aren’t adjusted for success in meeting target accrual in individual trials or select non performing protocols (e.g. rare tumors, stringent molecular eligibility) which require special consideration. Further research into refining metrics will facilitate a more accurate assessment of efficiency and help researchers optimize resources. 2007 2008 2009 Subject accrual 253 276 310 NP 7 6 13 NP-a 4 4 11 TO-a 14 18 20 TO-0 22 22 39 TO 36 40 59