tbuckley/cabot-search huggingface dataset:
Augmentation of urothelial cancer cells' response to gemcitabine and cisplatin by a Smac mimetic.
Authors: Eugene K. Lee, Jinesh Gerald, Naomi Laing, Woonyoung Choi, David James McConkey, Ashish M. Kamat
Journal: Journal of Clinical Oncology (2013)

261 Background: Cisplatin-based chemotherapy is considered the gold standard for patients with advanced bladder cancer. Despite initial response, many patients will relapse; therefore, novel salvage treatment strategies are desperately needed. Herein, we studied a mechanism based treatment combination using a Smac mimetic with standard chemotherapy. Methods: A panel of 10 urothelial cancer cell lines was exposed to gemcitabine and cisplatin, a Smac mimetic, and the combination. Sensitivity was determined using a DNA fragmentation assay. Constitutive expression of select members of the IAP family (XIAP, cIAP-1, cIAP-2, Survivin), the BCL family (BCL-2, BCL XL , BAX) and Smac were evaluated by gene expression profiling and Western blotting. Changes in protein expression under treatment conditions were examined using Western blotting. TNF-a blocking antibody was used to explore the contribution of autocrine TNF-a in cellular death. Lastly, a mouse model of bladder cancer was used to determine the effectiveness of the drug combination. Results: UMUC-3, UMUC-13 and RT4v6 were considered sensitive to the combination of gemcitabine and cisplatin based on an apoptosis assay. Three additional cell lines were sensitized to gemcitabine and cisplatin with the addition of the Smac mimetic (UMUC-6, UMUC-12, UMUC-18). The constitutive RNA and protein expression of SMAC, select members of the IAP family, and members of the BCL family did not correlate to drug sensitivity. Autocrine TNF-a demonstrated a partial contribution to cell death in UMUC-12. In an in vivo mouse model, the Smac mimetic alone and in combination with gemcitabine and cisplatin resulted in decreased tumor volume and increased apoptosis compared to the chemotherapy treatment alone. The combination resulted in decreased cellular proliferation and decreased microvessel density. Conclusions: Smac mimetic is able to augment the activity of gemcitabine and cisplatin based chemotherapy in vitro and in vivo. This may be an effective treatment strategy in patients with urothelial carcinoma and warrants further investigation.
Symptom experiences and nonadherent medication-taking behaviors of breast cancer patients taking adjuvant hormone therapy.
Authors: R. A. Shelby, F. J. Keefe, S. N. Red, K. L. Blackwell, J. M. Peppercorn, P. K. Marcom, G. G. Kimmick
Journal: Journal of Clinical Oncology (2011)

524 Background: Many breast cancer patients do not adhere to prescribed adjuvant hormone therapy. This pilot study explored symptom experiences and medication adherence behaviors. Methods: Eligible women were postmenopausal, had hormone receptor positive stage I-IIIA breast cancer, completed surgery, chemotherapy, and radiation, and were taking adjuvant hormonal therapy. Standardized instruments were used: Brief Fatigue Inventory, Brief Pain Inventory, Menopause Specific Quality of Life Questionnaire, Pain Catastrophizing Scale, Modified Morisky Medication Adherence Scale, and Beliefs about Medicines Questionnaire. T-tests were used to compare symptoms by type of medication. Pearson correlations examined associations between medication taking behaviors and symptoms. Results: 108 women enrolled: mean age 64 (SD 9) years, 81% white. Mean time from surgery was 46 (SD 29) months and on hormonal therapy, overall and current, was 41 (SD 30) and 26 (SD 20) months, respectively. 19% were taking tamoxifen and 81% an AI (30% anastrozole; 18% exemestane; 33% letrozole). 27% changed therapy. Reasons for change were pain (tamoxifen n=8 vs AI n=20), vasomotor symptoms (1 vs 1), osteoporosis (1 vs 3), and rash (1 vs 1). Significantly (p<.05) more fatigue, pain intensity, and pain interference were reported with AI compared to tamoxifen. Significant (p<.05) predictors of nonadherent medication taking behaviors were: greater fatigue (r=.28), pain intensity (r=.28), pain interference (r=.35), pain catastrophizing (r=.30), menopausal symptoms (r=.41), and medication concerns (r=.29). Type of medication and perceived medication necessity were not associated with nonadherent medication taking behaviors. Conclusions: Side effects and perceived side effect severity are associated with nonadherent medication taking behavior. Interventions to address perceived side effects may improve adherence to therapy. Patient-reported symptoms. Fatigue Pain intensity Pain interference Menopausal symptoms Tamoxifen 2.19 0.74 0.93 2.62 AI 3.72 1.90 1.88 2.97 t=2.54, p=.02 t=3.42, p=.001 t=2.38, p=.02 t=1.14, p=.26
Differences in terms of progression-free survival (PFS) and overall survival (OS) in patients treated with first-line sorafenib, sunitinib, and pazopanib for late relapsing (&gt;5 years) renal cell carcinoma.
Authors: Matteo Santoni, Camillo Porta, Giuseppe Procopio, Linda Cerbone, Umberto Basso, Ugo De Giorgi, Mimma Rizzo, Cinzia Ortega, Francesco Massari, Roberto Iacovelli, Giuseppe di Lorenzo, Michele Milella, Roberto Sabbatini, Francesco Atzori, Rocco De Vivo, Rossana Berardi, Daniele Santini, Stefano Cascinu
Journal: Journal of Clinical Oncology (2014)

421 Background: Aim of this retrospective study was to investigate the clinico-pathological features and the outcome of patients (pts) with late relapsing renal cell carcinoma (LateR-RCC) treated with vascular endothelial growth factor receptor (VEGFR) tyrosine kinase inhibitor (TKI) as first line therapy. Methods: Data were collected from 19 Italian centers involved in the treatment of metastatic RCC. Late relapse was defined as &gt;5 yr after initial radical nephrectomy. MSKCC prognostic categories were assessed before starting first-line treatment with VEGFR-TKI. Overall survival (OS) and progression free-survival (PFS) were estimated with the Kaplan-Meyer method with 95% CI and curves were compared with log-rank test. A Cox-regression model was applied to the data with a univariate and multivariate approach. Variables included in the univariate analysis were gender, age, time from surgery, MSKCC risk-group and targeted therapy employed at first line. Results: A total of 2,490 pts were screened and 269 pts (11%) were identified as LateR-RCC and treated with first-line VEGFR-TKI. Median age was 66 yr (range 29-87). Median time to recurrence was 7.9 yr. MSKCC prognostic category was good in 63% of pts, intermediate in 31% and poor in 6%. First-line therapy consisted of sunitinib in 190 pts (71%), sorafenib in 58 pts (21%) and pazopanib in 21 pts (8%). The median PFS was 20.0 months (95% CI 17.0−25.1) for sunitinib and 14.1 months for both sorafenib (95% CI 11.0−29.0) and pazopanib (95% CI 11.2−NR). At multivariate analysis, only MSKCC prognostic group was an independent prognostic factor for OS (HR: 2.07; 95% CI, 1.52–2.82 p &lt; 0.001) and PFS (HR 2.54; 95% CI, 1.93−3.36 p &lt; 0.001), whereas first line TKI was not significantly associated with OS (HR: 0.94; 95% CI, 0.38–1.82 p = 0.895) and PFS (HR 0.77; 95% CI, 0.43−1.99 p= 0.547). Conclusions: No significant differences were found in terms of OS and PFS in pts with LateR-RCC treated with first-line sorafenib, sunitinib or pazopanib. Our data may be considered in the long-term management of these patients.
The fibroblast growth factor receptor 4 Arg388 allele is associated with prognosis in head and neck squamous cell carcinoma
Authors: B. Garicochea, V. C. D. C. Andrade, C. P. Hors, P. C. D. M. Martins, A. P. Silva, O. Parise
Journal: Journal of Clinical Oncology (2005)

5523 Background: The fibroblast growth factor receptor 4 gene Arg388 allele (FGFR4 Arg388) has been recently associated as an prognostic factor for cancer of the breast, colorectal carcinoma, high-grade soft tissue sarcoma and head and neck squamous cell carcinoma (HNSCC), whereas its FGFR4 Gly388 wild-type allele had no relevant on prediction of clinical prognosis. In the current study, we investigated the relation between FGFR4 Arg388allele and clinical outcome in patients with HNSCC. Methods: The study included sections from 75 paraffin-embedded tumors of the patients with head and neck squamous cell carcinoma diagnosed between 1996 and 2001 in the Sírio Libanês Hospital. The FGFR4 Arg388 allele was detected by PCR-RFLP and sequencing. Its presence was correlated with clinical data and outcome. Survival curves were plotted according Kaplan-Meier and a log-rank test was used for comparisons between groups. Results: The FGFR4 Arg388 allele was evaluated in 73 patients and was detected in 31 tumors, 27 (37%) of them were heterozygous carriers and 4 (5,5%) homozygous carriers. Its presence was correlated significantly with reduced overall survival, mainly after 24 months follow-up (P= 0,0213). Conclusions: Ours results suggest that the FGFR4 Arg388 allele is relevant for HNSCC prognosis and is associated with poor clinical outcome, supporting the significance of FGFR4 gene as a useful marker for head and neck squamous cell carcinoma. FGFR4 Arg388 allele carriers had an increase risk of dying of 2,2 if compared with noncarriers. No significant financial relationships to disclose.
Quality of life and acute radiation toxicity following hypofractionated stereotactic body radiation therapy with concurrent full-dose gemcitabine for unresectable pancreatic adenocarcinoma.
Authors: Marie Kate Gurka, Gary Tse, Keith Robert Unger, Nadim G Haddad, John Marshall, Colin Johnson, Lisa Ley, Rebecca Slack, Michael J. Pishvaian, Sean Patrick Collins
Journal: Journal of Clinical Oncology (2012)

336 Background: Quality of life (QoL) is of paramount importance when cure is not obtainable. The aim of this study is to report QoL outcomes and acute radiation toxicity in patients with pancreatic cancer treated with stereotactic body radiation therapy (SBRT) and concurrent gemcitabine. Methods: This prospective study reviewed the charts of 10 patients with locally advanced, unresectable pancreatic cancer treated with SBRT and 6 cycles of gemcitabine. The primary tumor and adjacent para-aortic nodes received a total dose of 2500 cGy in 500 cGy fractions on consecutive days between cycles 1 and 2 of gemcitabine. QoL was assessed on the 1st day of each cycle using the EORTC QLQ-C30 and EORTC QLQ-PAN26 questionnaires. Wilcoxon rank sum test was used to determine statistical significance between QoL scores. Toxicity was graded by NCI Common Terminology Criteria for Adverse Events, Version 3.0. Results: The median age was 62.5 years. All patients completed the prescribed SBRT. Median overall survival was 13 months (range 5- 17). QoL scores at baseline compared to immediately after SBRT showed an increase in the following symptoms: fatigue, nausea/vomiting (N/V) and anorexia, which were statistically significant (P &lt; 0.05). These were not statistically different from baseline by cycle 3 except N/V. No symptoms were significantly improved after radiation therapy; however, there was a trend towards improvement in back pain, night pain and abdominal discomfort. Functional scales declined after treatment, but not significantly. Global QoL did not significantly change from baseline. There were no grade 3 or 4 acute toxicities related to SBRT. Conclusions: Hypofractionated SBRT with concurrent gemcitabine is feasible for locally advanced, unresectable pancreatic cancer. There is a temporary increase in selected symptoms due to radiation which resolve within one month. This may be an improvement compared to conventional fractionated radiation due to shorter duration of symptoms related to radiation treatment.
Outcomes of allogeneic hematopoietic cell transplantation (alloHCT) among older patients with non-Hodgkin lymphoma (NHL).
Authors: P. Muthukrishnan, V. Bachanova, L. J. Burns, R. Shanley, D. J. Weisdorf, A. H. Blaes
Journal: Journal of Clinical Oncology (2011)

e18508
Evaluation of plasma insulin-like growth factor binding protein 2 (IGFBP-2) as a biomarker for 17-allylamino-17-demethoxygeldanamycin (17-AAG) treatment of adult patients (pts) with advanced solid tumors
Authors: J. L. Eiseman, J. Guo, B. Weinbaum, R. K. Ramanathan, C. P. Belani, D. B. Solit, H. I. Scher, S. P. Ivy, E. G. Zuhowski, M. J. Egorin
Journal: Journal of Clinical Oncology (2005)

2083 Background: 17-AAG, which is currently in phase I/II clinical trials, binds to heat shock protein 90 and results in proteasomal degradation of many proteins, including IGFBP-2. Recently, concentrations of IGFBP-2 and Her-2 extracellular domain in serum of mice bearing BT474 human breast tumor xenografts were reported as being decreased by 17-AAG treatment (Proc. AACR, 45:894, 2004). We investigated whether the same phenomenon occurred in plasma of pts treated with 17-AAG. Methods: 8–15 serial plasma samples were obtained between 0 and 72 h from 27 pts treated with single-agent 17-AAG at doses of 10 to 307 mg/m2 and 18 pts treated with 17-AAG doses of 220 to 450 mg/m2 combined with 70 mg/m2 of docetaxel. Single plasma samples were also obtained from 12 healthy volunteers. Plasma samples were analyzed in duplicate, and IGFBP-2 concentrations were quantitated by ELISA (R&D Systems, Minneapolis, MN). Results: Pretreatment plasma IGFBP-2 concentrations in cancer pts (172 ± 122 ng/ml) were 2-fold higher those in healthy volunteers (85 ± 44 ng/ml) (P<0.05). Following 17-AAG treatment, there were no consistent dose-dependent or time-dependent changes in plasma IGFBP-2 concentrations. IGFBP-2 concentrations decreased by 40% in 10 pts, increased 2- to 5-fold in 6 pts and remained essentially unchanged in 29 pts. There was no obvious relationship between pretreatment IGFBP-2 concentration and the change in IGFBP-2 after 17-AAG treatment. Conclusions: As previously reported, IGFBP-2 concentrations in plasma of cancer pts are significantly higher than those in plasma of healthy volunteers. In contrast to results from a mouse model, change in plasma IGFBP-2 concentration was not a clinically useful biomarker for 17-AAG treatment. Support: 1 UO1-CA099168, NIH/NCCR/GCRC #5MO1 RR 00056, NIH P50-CA93629, CaPCURE, and a subcontract from the CTEP Translational Research Initiative. No significant financial relationships to disclose.
Tumor response assessment by measuring the single largest lesion per organ in patients with advanced gastric cancer or colorectal cancer.
Authors: Jung Han Kim, Hyun Joo Jang, Hyeong Su Kim, Hun Ho Song, Dae Young Zang
Journal: Journal of Clinical Oncology (2015)

766 Background: The Response Evaluation Criteria in Solid Tumors Guidelines version 1.1 (RECIST 1.1) adopted a total of five target lesions to be measured, with a maximum of two lesions per organ. To the best of our knowledge, the criterion of two target lesions per organ in the RECIST 1.1 is arbitrary and has not been supported by any objective evidence. We hypothesized that measuring the single largest lesion in each organ (modified RECIST 1.1; mRECIST 1.1) might show almost the same response classification as measuring two target lesions per organ (RECIST 1.1). Methods: We compared tumor responses according to the modified RECIST 1.1 and RECIST 1.1 using computed tomography in patients with advanced gastric cancer (GC) or colorectal cancer (CRC) who received a first-line chemotherapy. Results: A total of 89 patients who had at least two target lesions in any organ according to the RECIST 1.1 were included: 51 with GC and 38 with CRC. Regardless of the primary sites, the number of target lesions according to the modified RECIST 1.1 was significantly lower than that according to the RECIST 1.1 (p &lt; 0.001). The assessment of tumor responses showed a high concordance between the two criteria, with a kappa value of 0.906 (95% CI, 0.826-0.986). Only five patients (5.6%) showed disagreement in the tumor response assessment between the two criteria: 3 in GC and 2 in CRC. Four patients showed disagreement between PR and SD, and one showed disagreement between SD and PD. The overall response rates of chemotherapy, which were calculated regardless of the primary sites and anti-cancer treatment, were not significantly different between the two criteria (42.7% versus 42.7%, p = 1.0) (Table). Conclusions: The modified RECIST 1.1, with a decreased number of target lesions, was comparable to the original RECIST 1.1 in the assessment of tumor response in patients with advanced GC or CRC. Our results suggest that it may be possible to measure the single largest lesion per organ for assessing tumor response. [Table: see text]
FPA144-001: A first in human study of FPA 144, an ADCC-enhanced, FGFR2b isoform-selective monoclonal antibody in patients with advanced solid tumors.
Authors: Johanna C. Bendell, Seema Rogers, Hong Xiang, Kristen L. Pierce, Kartik Krishnan, Robert S. Sikorski, Julie Hambleton, Drew W. Rasco
Journal: Journal of Clinical Oncology (2016)

140 Background: FPA144 is a humanized monoclonal IgG1 antibody directed against the 2b Isoform of thefibroblast growth factor receptor (FGFR2b) that has been glycoengineered to enhance ADCC. Amplification of FGFR2 is found in a number of tumors, including 3 – 9% of gastric cancer, and is associated with poor prognosis. FPA144-001 is a phase 1 study in two parts: Part 1 will evaluate the safety and pharmacokinetics (PK) of FPA144 in patients with solid tumors; Part 2 will evaluate efficacy in gastric cancer patients whose tumors overexpress FGFR2b, as determined by a proprietary test. Here we present early safety and PK results from solid tumor patients treated with FPA144. Methods: A standard 3+3 design was used to assess safety, tolerability and PK of escalating doses of FPA144 in patients with advanced solid tumors (Part 1A) or recurrent/metastatic gastric cancer (Part 1B). Tumor testing for FGFR2gene amplification or FGFR2b overexpression was conducted centrally by a proprietary assay consisting of both FISH and IHC. Results: At the time of data analysis, enrollment of FPA144-001 through the 6mg/kg q2w cohort had been completed. In Part 1A, 13 patients with 8 different tumor types have been enrolled. Patients have been treated for an average of 4 cycles (range 1 – 10, median 2) or 101 days (range 28 – 287, median 43). Nine patients have discontinued the study for progressive disease or lack of clinical benefit; all others continue on study treatment. No dose-limiting toxicities have been observed, and no patients have withdrawn due to an adverse drug reaction. Upper respiratory infection, alopecia and fatigue are the AEs reported in more than one patient; one SAE of dyspnea and pyrexia not related to drug has been reported. PK analysis demonstrates non-linear clearance in doses up to 3mg/kg, likely due to receptor-mediated clearance. Conclusions: FPA144 is a glycoengineered monoclonal antibody directed against FGFR2b that is being developed for the treatment of patients with tumors that overexpress FGFR2b. FPA144 has been safely administered at doses up to 6mg/kg q2w; dose escalation continues. Updated safety, PK and anti-tumor activity will be presented. Clinical trial information: NCT02318329.
Armed Oncolytic Adenovirus–Expressing PD-L1 Mini-Body Enhances Antitumor Effects of Chimeric Antigen Receptor T Cells in Solid Tumors
Authors: Kiyonori Tanoue, Amanda Rosewell Shaw, Norihiro Watanabe, Caroline Porter, Bhakti Rana, Stephen Gottschalk, Malcolm Brenner, Masataka Suzuki
Journal: Cancer Research (2017)

Chimeric antigen receptor-modified T cells (CAR T cells) produce proinflammatory cytokines that increase expression of T-cell checkpoint signals such as PD-L1, which may inhibit their functionality against solid tumors. In this study, we evaluated in human tumor xenograft models the proinflammatory properties of an oncolytic adenovirus (Onc.Ad) with a helper-dependent Ad (HDAd) that expresses a PD-L1 blocking mini-antibody (mini-body; HDPDL1) as a strategy to enhance CAR T-cell killing. Coadministration of these agents (CAd-VECPDL1) exhibited oncolytic effects with production of PD-L1 mini-body locally at the tumor site. On their own, HDPDL1 exhibited no antitumor effect and CAd-VECPDL1 alone reduced tumors only to volumes comparable to Onc.Ad treatment. However, combining CAd-VECPDL1 with HER2.CAR T cells enhanced antitumor activity compared with treatment with either HER2.CAR T cells alone or HER2.CAR T cells plus Onc.Ad. The benefits of locally produced PD-L1 mini-body by CAd-VECPDL1 could not be replicated by infusion of anti-PD-L1 IgG plus HER2.CAR T cells and coadministration of Onc.Ad in an HER2+ prostate cancer xenograft model. Overall, our data document the superiority of local production of PD-L1 mini-body by CAd-VECPDL1 combined with administration of tumor-directed CAR T cells to control the growth of solid tumors. Cancer Res; 77(8); 2040-51. ©2017 AACR.
SMART chemotherapy: A comprehensive cancer center’s journey to shared medical appointments.
Authors: Lauren S. Prescott, Andrea S. Dickens, Sandra L. Guerra, Jila Tanha, Desiree G. Phillips, Kathryn B. Lowe, Miguel A. Lozano Garcia, Pamela T. Soliman, Elizabeth A. Garcia, Kai E. Lang, Paula A. Lewis-Patterson, Charles F. Levenback, Diane C. Bodurka
Journal: Journal of Clinical Oncology (2014)

135 Background: Shared medical appointments (SMA) offer a novel approach to improve efficiency and quality of care consistent with the goals of the Institute of Medicine. To our knowledge, there are no established SMA models for oncology patients undergoing treatment. Our objective was to develop and implement a SMA for chemotherapy education and clearance for women with gynecologic cancer. Methods: We first assessed the level of interest in SMAs among our patients and providers through qualitative interviews. We subsequently created a multidisciplinary team comprised of physicians, mid-level providers, nurses, pharmacists, administrators, health education specialists and members of the QI Department. Our project consisted of several phases: 1) provider buy-in, 2) program development, 3) staff education, 4) implementation; and 5) patient recruitment. A plan-do-study-act cycle was performed following each SMA, using patient and provider feedback. Appropriate modifications were made before the subsequent SMA. Results: Both patients and providers identified pre-chemotherapy as an optimal area to pilot SMAs. We established a multidisciplinary Shared Medical Appointment and Readiness Teaching (SMART) clinic for all gynecologic oncology patients initiating chemotherapy with platinum- and taxane-based regimens. This model of care provides patient education within a framework of social support that empowers patients. We developed a standardized chemotherapy education presentation, and also provided patients with a tool kit that consisted of chemotherapy drug education, a guide to managing side effects, advanced directives and center contact information. Surveyed patients reported being highly satisfied with the group visit and would recommend SMA to other patients. Our preliminary data analysis revealed that SMART visits decreased wait time and increased value-added time for patients. Conclusions: SMAs for oncology patients initiating chemotherapy is both novel and feasible. A patient centric model, collaboration of multidisciplinary team members, and timely responsiveness to constructive feedback are essential to the successful integration of SMAs in an academic center.