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Javle M.,University of Houston | Churi C.,University of Houston | Kang H.C.,University of Houston | Shroff R.,University of Houston | And 11 more authors.
Journal of Hematology and Oncology | Year: 2015

Background: Biliary cancers are highly aggressive tumors that are often diagnosed an advanced disease stage and have a poor outcome with systemic therapy. Recent efforts towards molecular characterization have identified a subset of biliary patients that have HER2/neu amplification or mutation. HER2/neu amplification is associated with response to HER2/neu-directed therapy in breast and gastric cancers. However, the efficacy of HER2/neu-targeted therapy in biliary cancers is unknown. Patients and methods: We retrospectively reviewed cases of advanced gallbladder cancer and cholangiocarcinoma with HER2/neu genetic aberrations or protein overexpression who received HER2/neu-directed therapy between 2007 and 2014. Clinical data were retrieved from medical records, and imaging studies were independently reviewed. Results: Nine patients with gallbladder cancer and five patients with cholangiocarcinoma had received HER2/neu-directed therapy (trastuzumab, lapatinib, or pertuzumab) during the study period. In the gallbladder cancer group, HER2/neu gene amplification or overexpression was detected in eight cases. These patients experienced disease stability (n = 3), partial response (n = 4), or complete response (n = 1) with HER2/neu-directed therapy. One patient had HER2/neu mutation and experienced a mixed response after lapatinib therapy. The duration of response varied from 8+ to 168 weeks (median 40 weeks), and three patients are still on therapy. One patient developed HER2/neu amplification as a secondary event after FGFR-directed therapy for FGF3-TACC3 gene fusion. The cholangiocarcinoma cases treated in this series had a higher proportion of HER2/neu mutations, and no radiological responses were seen in these patients despite HER2/neu-directed therapy. Conclusions: HER2/neu blockade is a promising treatment strategy for gallbladder cancer patients with gene amplification and deserves further exploration in a multi-center study. © 2015 Javle et al.

Bryant V.L.,University of South Florida | Bryant V.L.,Moffitt Cancer Center | Elias R.M.,Moffitt Cancer Center | McCarthy S.M.,Moffitt Cancer Center | And 3 more authors.
Molecular Cancer Research | Year: 2015

Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest forms of cancer and is very difficult to treat with conventional chemotherapeutic regimens. Gemcitabine and 5-fluorouracil are used in the management of PDAC and act by indirectly blocking replicative forks. However, these drugs are not highly effective at suppressing disease progression, indicating a need for the development of innovative therapeutic approaches. Recent studies indicate that suppression of the MCM helicase may provide a novel means to sensitize cancer cells to chemotherapeutic agents that inhibit replicative fork progression. Mammalian cells assemble more MCM complexes on DNA than are required to start S-phase. The excessMCMcomplexes function as backup initiation sites under conditions of replicative stress. The current study provides definitive evidence that cosuppression of the excess/backup MCM complexes sensitizes PDAC tumor lines to both gemcitabine and 5-FU, leading to increased loss of proliferative capacity compared with drugs alone. This occurs because reduced MCM levels prevent efficient recovery of DNA replication in tumor cells exposed to drug. PDAC tumor cells are more sensitive to MCM loss in the presence of gemcitabine than are nontumor, immortalized epithelial cells. Similarly, colon tumor cells are rendered less viable when cosuppression of MCM complexes occurs during exposure to the crosslinking agent oxaliplatin or topoisomerase inhibitor etoposide. Implications: These studies demonstrate that suppressing the backup complement of MCM complexes provides an effective sensitizing approach with the potential to increase the therapeutic index of drugs used in the clinical management of PDAC and other cancers. © 2015 American Association for Cancer Research.

Gersh J.A.,Gibbs Cancer Center and Research Institute | Gersh J.A.,Spectrum Medical Physics LLC. | Willett B.,Accuray
Journal of Applied Clinical Medical Physics | Year: 2015

Traditional CyberKnife (CK) calibration uses TG-51, which requires kQ to be defined using the standard reference condition of 100 cm SSD in a 10 cm × 10 cm field. Since the CK is calibrated using a 6 cm fixed-aperture collimating cone at 80 cm SAD, the BJR-25 method is commonly used to relate circular-field PDDs to square-field PDDs for kQ determination. Using the InCise MLC system, the CK is able to deliver rectangular fields, allowing a more direct measurement of %dd(10cm) using conventional reference conditions. We define the PDD correction factor (CPDD) as the ratio of %dd(10 cm) measured using CK reference conditions to that measured using standard TG-51 reference conditions. Using four ionization chambers (A1SL, CC08, CC13, and A19), %dd(10 cm) is measured using a 6 cm fixed cone at 80 cm SSD and at 100 cm SSD using an effective 10 cm × 10 cm MLC-collimated field. These values are used to calculate CPDD, while the latter is used to directly calculate a kQ value. This direct kQ value is then compared to values determined using the BJR-25 method. Using the MLC system, this study demonstrates conversion between the %dd(10 cm) measured using CyberKnife reference conditions and TG-51 reference conditions. These values provide the means for derivation of a kQ curve as a function of direct measurements of %dd(10cm) using a 6 cm fixed-aperture collimating cone at 80 cm SSD.

Dueck A.C.,Mayo Medical School | Mendoza T.R.,University of Houston | Mitchell S.A.,National Cancer Institute | Reeve B.B.,University of North Carolina at Chapel Hill | And 21 more authors.
JAMA oncology | Year: 2015

IMPORTANCE: To integrate the patient perspective into adverse event reporting, the National Cancer Institute developed a patient-reported outcomes version of the Common Terminology Criteria for Adverse Events (PRO-CTCAE).OBJECTIVE: To assess the construct validity, test-retest reliability, and responsiveness of PRO-CTCAE items.DESIGN, SETTING, AND PARTICIPANTS: A total of 975 adults with cancer undergoing outpatient chemotherapy and/or radiation therapy enrolled in this questionnaire-based study between January 2011 and February 2012. Eligible participants could read English and had no clinically significant cognitive impairment. They completed PRO-CTCAE items on tablet computers in clinic waiting rooms at 9 US cancer centers and community oncology practices at 2 visits 1 to 6 weeks apart. A subset completed PRO-CTCAE items during an additional visit 1 business day after the first visit.MAIN OUTCOMES AND MEASURES: Primary comparators were clinician-reported Eastern Cooperative Oncology Group Performance Status (ECOG PS) and the European Organisation for Research and Treatment of Cancer Core Quality of Life Questionnaire (QLQ-C30).RESULTS: A total of 940 of 975 (96.4%) and 852 of 940 (90.6%) participants completed PRO-CTCAE items at visits 1 and 2, respectively. At least 1 symptom was reported by 938 of 940 (99.8%) participants. Participants' median age was 59 years; 57.3% were female, 32.4% had a high school education or less, and 17.1% had an ECOG PS of 2 to 4. All PRO-CTCAE items had at least 1 correlation in the expected direction with a QLQ-C30 scale (111 of 124, P<.05 for all). Stronger correlations were seen between PRO-CTCAE items and conceptually related QLQ-C30 domains. Scores for 94 of 124 PRO-CTCAE items were higher in the ECOG PS 2 to 4 vs 0 to 1 group (58 of 124, P<.05 for all). Overall, 119 of 124 items met at least 1 construct validity criterion. Test-retest reliability was 0.7 or greater for 36 of 49 prespecified items (median [range] intraclass correlation coefficient, 0.76 [0.53-.96]). Correlations between PRO-CTCAE item changes and corresponding QLQ-C30 scale changes were statistically significant for 27 prespecified items (median [range] r=0.43 [0.10-.56]; all P≤.006).CONCLUSIONS AND RELEVANCE: Evidence demonstrates favorable validity, reliability, and responsiveness of PRO-CTCAE in a large, heterogeneous US sample of patients undergoing cancer treatment. Studies evaluating other measurement properties of PRO-CTCAE are under way to inform further development of PRO-CTCAE and its inclusion in cancer trials.

Kothari N.,H. Lee Moffitt Cancer Center and Research Institute | Schell M.J.,H. Lee Moffitt Cancer Center and Research Institute | Teer J.K.,H. Lee Moffitt Cancer Center and Research Institute | Yeatman T.,Gibbs Cancer Center and Research Institute | And 2 more authors.
Journal of Clinical Pathology | Year: 2014

Aims: Based on KRAS testing, the subset of patients with metastatic colorectal cancer (CRC) that could benefit from anti-EGFR therapy can be better delineated. Though KRAS testing has become significantly more prevalent over the last few years, methods for testing remain heterogeneous and discordance has been reported between methods. Methods: In this study, we examined a CRC patient population and compared KRAS testing done in Clinical Laboratory Improvement Amendments (CLIA) approved laboratories as part of standard clinical care and by next-generation sequencing (NGS) using the Illumina platform. Discordances were further evaluated with manual review of the NGS testing. Results: Out of 468 CRC patient samples, 77 had KRAS testing done by both CLIA assay and NGS. There were concordant results between testing methodologies in 74 out of 77 patients, or 96% (95% CI 89% to 99%). There were three patient samples that showed discordant results between the two methods of testing. Upon further investigation of the NGS results for the three discordant cases, one sample showed a low level of the mutation seen in the standard testing, one sample showed low tumour fraction and a third did not show any evidence of the mutation that was found with the standard assay. Five patients had KRAS mutations not typically tested with standard testing. Conclusions: Overall there was a high concordance rate between NGS and standard testing for KRAS. However, NGS revealed mutations that are not tested for with standard KRAS assays that might have clinical impact with regards to the role for anti-EGFR therapy.

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