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Pancreatic Neoplasms: HELP
Articles by Bert H. O'Neil
Based on 10 articles published since 2008
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Between 2008 and 2019, B. O'Neil wrote the following 10 articles about Pancreatic Neoplasms.
 
+ Citations + Abstracts
1 Review Impact of Nab-Paclitaxel-based Second-line Chemotherapy in Metastatic Pancreatic Cancer. 2017

Dadi, Neelakanta / Stanley, Melissa / Shahda, Safi / O'Neil, Bert H / Sehdev, Amikar. ·Division of Hematology and Oncology, Department of Medicine, Indiana University School of Medicine, Indianapolis, IN, U.S.A. · Division of Hematology and Oncology, Department of Medicine, Indiana University School of Medicine, Indianapolis, IN, U.S.A. asehdev@iupui.edu. · Center for Health Services Research, Regenstrief Institute, Indianapolis, IN, U.S.A. · Richard M. Fairbanks School of Public Health, Indiana University, Indianapolis, IN, U.S.A. ·Anticancer Res · Pubmed #28982867.

ABSTRACT: BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) is a lethal malignancy with median survival of 20% at 1 year. We conducted a retrospective study to assess the efficacy and tolerability of nab-paclitaxel (NP)-based second-line chemotherapy in metastatic PDAC. PATIENTS AND METHODS: The Indiana University Simon Cancer Center pancreatic cancer program was used to identify patients with metastatic PDAC who received any second-line chemotherapy. Demographic, clinical and outcomes data were collected by manual chart abstraction. Patients were divided into two groups: a NP-based treatment group and a non- NP-based treatment group. Overall (OS) and progression-free (PFS) survival were estimated using Kaplan-Meier method. Cox proportional hazards regression was used for multivariate analyses. RESULTS: A total of 120 patients received second-line chemotherapy. There were 47 (39%) patients in the NP group and 73 (61%) in the non-NP group. As compared to the non-NP group, the NP group showed improved median PFS [2.8 vs. 2.1 months; hazard ratio (HR)=0.62, 95% confidence interval (CI)=0.38-1.02; p=0.06] and median OS (7.5 vs. 4.7 months; HR=0.67, 95% CI=0.45-1.00; p=0.05). Multivariate analyses adjusted for age showed a significantly improved PFS (adjusted HR=0.60, 95% CI=0.36-0.98; p=0.04) and a suggestion of improved OS (adjusted HR=0.67, 95% CI=0.44-1.01, p=0.05) in the NP group as compared to non-NP group. Serious adverse events were seen in 13.3% of patients in the non-NP group and 17.1% patients in the NP group. CONCLUSION: In a single-institution retrospective cohort study, we report a significant improvement in the PFS and suggestion of improvement in the OS with NP-based second-line chemotherapy with an acceptable toxicity rate.

2 Review A Multidisciplinary Approach to Pancreas Cancer in 2016: A Review. 2017

Fogel, Evan L / Shahda, Safi / Sandrasegaran, Kumar / DeWitt, John / Easler, Jeffrey J / Agarwal, David M / Eagleson, Mackenzie / Zyromski, Nicholas J / House, Michael G / Ellsworth, Susannah / El Hajj, Ihab / O'Neil, Bert H / Nakeeb, Attila / Sherman, Stuart. ·Department of Medicine, Division of Gastroenterology/Hepatology, Indiana University Health, Indiana University School of Medicine, University Hospital, Indianapolis, Indiana, USA. · Department of Radiology, Indiana University School of Medicine, Indianapolis, Indiana, USA. · Department of Surgery, Indiana University School of Medicine, Indianapolis, Indiana, USA. ·Am J Gastroenterol · Pubmed #28139655.

ABSTRACT: In this article, we review our multidisciplinary approach for patients with pancreatic cancer. Specifically, we review the epidemiology, diagnosis and staging, biliary drainage techniques, selection of patients for surgery, chemotherapy, radiation therapy, and discuss other palliative interventions. The areas of active research investigation and where our knowledge is limited are emphasized.

3 Clinical Trial Phase 1 study of EUS-guided photodynamic therapy for locally advanced pancreatic cancer. 2019

DeWitt, John M / Sandrasegaran, Kumar / O'Neil, Bert / House, Michael G / Zyromski, Nicholas J / Sehdev, Amikar / Perkins, Susan M / Flynn, Janet / McCranor, Lynne / Shahda, Safi. ·Department of Gastroenterology, Indiana University Health Medical Center, Indianapolis, Indiana, USA. · Department of Radiology, Indiana University Health Medical Center, Indianapolis, Indiana, USA. · Department of Oncology, Indiana University Health Medical Center, Indianapolis, Indiana, USA. · Department of Surgery, Indiana University Health Medical Center, Indianapolis, Indiana, USA. · Department of Statistics, Indiana University Health Medical Center, Indianapolis, Indiana, USA. ·Gastrointest Endosc · Pubmed #30222972.

ABSTRACT: BACKGROUND AND AIMS: Locally advanced pancreatic cancer (LAPC) has a poor prognosis. There are limited data describing the use of photodynamic therapy (PDT) for pancreatic cancer in humans. We hypothesized that EUS-guided PDT for LAPC is safe, technically feasible, and produces a dose- and time-dependent increasing degree of image-defined tumor necrosis. METHODS: In a single-center, prospective, dose-escalation phase 1 study, patients with treatment-naïve LAPC received intravenous porfimer sodium (Concordia Laboratories Inc, St Michael, Barbados) followed 2 days later by EUS-PDT. EUS-PDT was performed by puncture with a 19-gauge needle and insertion of a 1.0-cm light diffuser (Pioneer Optics, Bloomfield, Conn) and illumination with a 630-nm light (Diomed Inc, Andover, Mass). A CT scan 18 days after PDT was done to assess for change in pancreatic necrosis. Nab-paclitaxel (125 mg/ m RESULTS: Twelve patients (mean age, 67 ± 6 years; 8 male) with tumors (mean diameter, 45.2 ± 12.9 mm) in the head and/or neck (8) or body and/or tail (4) underwent EUS-PDT. Compared with baseline imaging, increased volume and percentage of tumor necrosis were observed in 6 of 12 patients (50%) after EUS-PDT. The mean overall increases in volume and percentage necrosis were 10 ± 26 cm CONCLUSION: EUS-PDT for LAPC appears to be safe and produces measurable imaged-defined tumor necrosis. Phase 2 studies are warranted. (Clinical trial registration number: NCT01770132.).

4 Clinical Trial A phase 1b study of erlotinib in combination with gemcitabine and nab-paclitaxel in patients with previously untreated advanced pancreatic cancer: an Academic Oncology GI Cancer Consortium study. 2016

Cohen, Steven J / O'Neil, Bert H / Berlin, Jordan / Ames, Patricia / McKinley, Marti / Horan, Julie / Catalano, Patricia M / Davies, Angela / Weekes, Colin D / Leichman, Lawrence. ·Fox Chase Cancer Center, 333 Cottman Avenue, Philadelphia, PA, 19111-2497, USA. steven.cohen@fccc.edu. · Indiana University Simon Cancer Center, Indianapolis, IN, USA. · Vanderbilt-Ingram Cancer Center, Nashville, TN, USA. · Abrazo Community Health Network, Phoenix, AZ, USA. · Aptium Oncology, Criterium, Inc., Los Angeles, CA, USA. · Novella Clinical, Boulder, CO, USA. · Champions Oncology, Hackensack, NJ, USA. · University of Colorado School of Medicine, Aurora, CO, USA. · New York University, New York, NY, USA. ·Cancer Chemother Pharmacol · Pubmed #26886016.

ABSTRACT: PURPOSE: Addition of either nab-paclitaxel or erlotinib to gemcitabine to treat advanced pancreatic cancer has demonstrated overall survival benefit. This study was conducted to evaluate the tolerability and safety of combining all three drugs and assess preliminary evidence of efficacy. METHODS: In this open-label, phase 1b study, patients with previously untreated, advanced pancreatic cancer were treated in 28-day cycles with intravenous gemcitabine/nab-paclitaxel on days 1, 8, and 15, and once daily oral erlotinib. A standard "3 + 3" design was used. Dose level 1 (DL1) for gemcitabine (mg/m(2))/nab-paclitaxel (mg/m(2))/erlotinib (mg) was 1000/125/100, respectively, with de-escalation to DL-1 (1000/100/100), DL-2b (1000/75/100), and DL-3 (1000/75/75). The maximum tolerated dose (MTD) was defined by occurrence of dose-limiting toxicity (DLT) in ≤1 of six patients within the first cycle. Efficacy was assessed with CT scans performed at two-cycle intervals. RESULTS: Nineteen patients were enrolled. DLTs occurred in two patients at DL1, three patients at DL-1, two patients at DL-2b, and one patient at DL-3. The MTD for the combination of gemcitabine/nab-paclitaxel/erlotinib was DL-3 (1000/75/75). In analyses of efficacy among 14 evaluable patients, partial responses were observed in four of six patients at DL1, one of two patients at DL-2b, and two of six patients at DL-3. CONCLUSION: The addition of erlotinib to gemcitabine and nab-paclitaxel is not tolerable at standard single-agent dosing of all drugs. However, significant clinical activity was noted, even at DL-3. Further study of the combination will need to incorporate reduced dosing.

5 Clinical Trial (90)Y-clivatuzumab tetraxetan with or without low-dose gemcitabine: A phase Ib study in patients with metastatic pancreatic cancer after two or more prior therapies. 2015

Picozzi, Vincent J / Ramanathan, Ramesh K / Lowery, Maeve A / Ocean, Allyson J / Mitchel, Edith P / O'Neil, Bert H / Guarino, Michael J / Conkling, Paul R / Cohen, Steven J / Bahary, Nathan / Frank, Richard C / Dragovich, Tomislav / Bridges, Benjamin B / Braiteh, Fadi S / Starodub, Alexander N / Lee, Fa-Chyi / Gribbin, Thomas E / Richards, Donald A / Lee, Marie / Korn, Ronald L / Pandit-Taskar, Neeta / Goldsmith, Stanley J / Intenzo, Charles M / Sheikh, Arif / Manzone, Timothy C / Horne, Heather / Sharkey, Robert M / Wegener, William A / O'Reilly, Eileen M / Goldenberg, David M / Von Hoff, Daniel D. ·Virginia Mason Medical Center, Seattle, WA, United States. · Virginia G. Piper Cancer Center at Scottsdale Healthcare/TGen, Scottsdale, AZ, United States. · Memorial Sloan-Kettering Cancer Center, New York, NY, United States. · Weill Cornell Medical College, New York, NY, United States. · Kimmel Cancer Center of Thomas Jefferson University, Philadelphia, PA, United States. · UNC Lineberger Comprehensive Cancer Center, Chapel Hill, NC, United States. · Helen F. Graham Cancer Center at Christiana Care Health System, Newark, DE, United States. · US Oncology Phase II Group, Virginia Oncology Associates, Norfolk, VA, United States. · Fox Chase Cancer Center, Philadelphia, PA, United States. · University of Pittsburgh Medical Center, Pittsburgh, PA, United States. · Whittingham Cancer Center at Norwalk Hospital, Norwalk, CT, United States. · Banner MD Anderson Cancer Center, Gilbert, AZ, United States. · St Luke's Mountain States Tumor Institute, Meridian, ID, United States. · Comprehensive Cancer Centers of Nevada, Las Vegas, NV, United States. · Indiana University Health Center for Cancer Care, Goshen, IN, United States. · University of New Mexico Health Science Center, Albuquerque, NM, United States. · Lacks Cancer Center, Saint Mary's Health Care, Grand Rapids, MI, United States. · Tyler Cancer Center, US Oncology Research, Tyler, TX, United States. · Immunomedics, Inc., Morris Plains, NJ, United States. · Immunomedics, Inc., Morris Plains, NJ, United States; Center for Molecular Medicine and Immunology/Garden State Cancer Center, Morris Plains, NJ, United States. Electronic address: dmg.gscancer@att.net. ·Eur J Cancer · Pubmed #26187510.

ABSTRACT: BACKGROUND: For patients with metastatic pancreatic adenocarcinoma, there are no approved or established treatments beyond the 2nd line. A Phase Ib study of fractionated radioimmunotherapy was undertaken in this setting, administering (90)Y-clivatuzumab tetraxetan (yttrium-90-radiolabelled humanised antibody targeting pancreatic adenocarcinoma mucin) with or without low radiosensitising doses of gemcitabine. METHODS: Fifty-eight patients with three (2-7) median prior treatments were treated on Arm A (N=29, (90)Y-clivatuzumab tetraxetan, weekly 6.5 mCi/m(2)doses×3, plus gemcitabine, weekly 200 mg/m(2) doses×4 starting 1 week earlier) or Arm B (N=29, (90)Y-clivatuzumab tetraxetan alone, weekly 6.5 mCi/m(2)doses×3), repeating cycles after 4-week delays. Safety was the primary endpoint; efficacy was also evaluated. RESULTS: Cytopaenias (predominantly transient thrombocytopenia) were the only significant toxicities. Fifty-three patients (27 Arm A, 26 Arm B, 91% overall) completed ⩾1 full treatment cycles, with 23 (12 Arm A, 11 Arm B; 40%) receiving multiple cycles, including seven (6 Arm A, 1 Arm B; 12%) given 3-9 cycles. Two patients in Arm A had partial responses by RECIST criteria. Kaplan-Meier overall survival (OS) appeared improved in Arm A versus B (hazard ratio [HR] 0.55, 95% CI: 0.29-0.86; P=0.017, log-rank) and the median OS for Arm A versus Arm B increased to 7.9 versus 3.4 months with multiple cycles (HR 0.32, P=0.004), including three patients in Arm A surviving >1 year. CONCLUSIONS: Clinical studies of (90)Y-clivatuzumab tetraxetan combined with low-dose gemcitabine appear feasible in metastatic pancreatic cancer patients beyond 2nd line and a Phase III trial of this combination is now underway in this setting.

6 Clinical Trial A phase II/III randomized study to compare the efficacy and safety of rigosertib plus gemcitabine versus gemcitabine alone in patients with previously untreated metastatic pancreatic cancer. 2015

O'Neil, B H / Scott, A J / Ma, W W / Cohen, S J / Leichman, L / Aisner, D L / Menter, A R / Tejani, M A / Cho, J K / Granfortuna, J / Coveler, A L / Olowokure, O O / Baranda, J C / Cusnir, M / Phillip, P / Boles, J / Nazemzadeh, R / Rarick, M / Cohen, D J / Radford, J / Fehrenbacher, L / Bajaj, R / Bathini, V / Fanta, P / Berlin, J / McRee, A J / Maguire, R / Wilhelm, F / Maniar, M / Jimeno, A / Gomes, C L / Messersmith, W A. ·Simon Cancer Center, Indiana University School of Medicine, Indianapolis. · University of Colorado, Denver, Aurora. · Roswell Park Cancer Institute, Buffalo. · Fox Chase Cancer Center, Philadelphia. · Kaiser Permanente, Lone Tree. · University of Rochester Medical Center, Rochester. · Oncare Hawaii, Honolulu. · Cone Health Cancer Center, Greensboro. · University of Washington, Seattle. · University of Cincinnati Cancer Institute, Cincinnati. · University of Kansas Medical Center, Westwood. · Mount Sinai Medical Center, Miami Beach. · Karmanos Cancer Institute, Detroit. · Rex Cancer Center UNC Healthcare, Raleigh. · Carolinas Health Care, Charlotte. · Kaiser Permanante Northwest, Portland. · NYU Clinical Cancer Center, New York. · Hendersonville Hematology and Oncology at Pardee, Hendersonville. · Kaiser Permanante Medical Center, Vallejo. · McLeod Regional Medical Center, Florence. · University of Massachusetts Memorial, Worcester. · UCSD Moores Cancer Center, La Jolla. · Vanderbilt-Ingram Cancer Center, Nashville. · UNC Lineberger Comprehensive Cancer Center, Chapel Hill. · Onconova Therapeutics Inc., Newtown. · Oncology Consortia of Criterium Inc., Saratoga Springs, USA. · University of Colorado, Denver, Aurora wells.messersmith@ucdenver.edu. ·Ann Oncol · Pubmed #26091808.

ABSTRACT: BACKGROUND: Rigosertib (ON 01910.Na), a first-in-class Ras mimetic and small-molecule inhibitor of multiple signaling pathways including polo-like kinase 1 (PLK1) and phosphoinositide 3-kinase (PI3K), has shown efficacy in preclinical pancreatic cancer models. In this study, rigosertib was assessed in combination with gemcitabine in patients with treatment-naïve metastatic pancreatic adenocarcinoma. MATERIALS AND METHODS: Patients with metastatic pancreatic adenocarcinoma were randomized in a 2:1 fashion to gemcitabine 1000 mg/m(2) weekly for 3 weeks of a 4-week cycle plus rigosertib 1800 mg/m(2) via 2-h continuous IV infusions given twice weekly for 3 weeks of a 4-week cycle (RIG + GEM) versus gemcitabine 1000 mg/m(2) weekly for 3 weeks in a 4-week cycle (GEM). RESULTS: A total of 160 patients were enrolled globally and randomly assigned to RIG + GEM (106 patients) or GEM (54). The most common grade 3 or higher adverse events were neutropenia (8% in the RIG + GEM group versus 6% in the GEM group), hyponatremia (17% versus 4%), and anemia (8% versus 4%). The median overall survival was 6.1 months for RIG + GEM versus 6.4 months for GEM [hazard ratio (HR), 1.24; 95% confidence interval (CI) 0.85-1.81]. The median progression-free survival was 3.4 months for both groups (HR = 0.96; 95% CI 0.68-1.36). The partial response rate was 19% versus 13% for RIG + GEM versus GEM, respectively. Of 64 tumor samples sent for molecular analysis, 47 were adequate for multiplex genetic testing and 41 were positive for mutations. The majority of cases had KRAS gene mutations (40 cases). Other mutations detected included TP53 (13 cases) and PIK3CA (1 case). No correlation between mutational status and efficacy was detected. CONCLUSIONS: The combination of RIG + GEM failed to demonstrate an improvement in survival or response compared with GEM in patients with metastatic pancreatic adenocarcinoma. Rigosertib showed a similar safety profile to that seen in previous trials using the IV formulation.

7 Clinical Trial A two-cohort phase I study of weekly oxaliplatin and gemcitabine, then oxaliplatin, gemcitabine, and erlotinib during radiotherapy for unresectable pancreatic carcinoma. 2013

Raftery, Laura / Tepper, Joel E / Goldberg, Richard M / Blackstock, A William / Aklilu, Mebea / Bernard, Stephen A / Ivanova, Anastasia / Davies, Janine M / O'Neil, Bert H. ·Division of Hematology and Oncology, Ohio State University, Columbus, OH, USA. ·Am J Clin Oncol · Pubmed #22547007.

ABSTRACT: OBJECTIVES: Gemcitabine is a potent radiosensitizer. When combined with standard radiotherapy (XRT) the gemcitabine dose must be reduced to about 10% of its conventional dose. Oxaliplatin and erlotinib also have radiosensitizing properties. Oxaliplatin and gemcitabine have demonstrated synergy in vitro. We aimed to determine the maximum tolerated dose of oxaliplatin and gemcitabine with concurrent XRT, then oxaliplatin, gemcitaibine, and erlotinib with XRT in the treatment of locally advanced and low-volume metastatic pancreatic or biliary cancer. METHODS: A modified 3+3 dose-escalation design was used for testing 4 dose levels of oxaliplatin and gemcitabine given once weekly for a maximum of 6 weeks with daily XRT in fractions of 1.8 Gy to a total dose of 50.4 Gy. Dose-limiting toxicity (DLT) was defined as any grade 4 toxicity or grade 3 toxicity resulting in a treatment delay of >1 week. In addition, dose reduction in 2 of the 3 patients in a given cohort was counted as a DLT in dose escalation-deescalation rule in the modified 3+3 design. RESULTS: Eighteen patients were enrolled, all with pancreatic cancer. Grade 4 transaminitis in a patient in cohort 3 resulted in cohort expansion. Cohort 4, the highest planned dose cohort, had no DLTs. The recommended phase II dose is oxaliplatin 50 mg/m(2)/wk with gemcitabine 200 mg/m(2)/wk and 50.4 Gy XRT. The most prevalent grade 3 toxicities were nausea (22%), elevated transaminases (17%), leucopenia (17%), and hyperglycemia (17%). Median progression-free survival was 7.1 months (95% confidence interval, 4.6-11.1 mo) and median overall survival was 10.8 months (95% confidence interval, 7.1-16.7 mo). The addition of erlotinib was poorly tolerated at the first planned dose level, but full study of the combination was hindered by early closure of the study. CONCLUSIONS: Weekly oxaliplatin 50 mg/m/wk combined with gemcitabine 200 mg/m/wk and XRT for pancreatic cancer has acceptable toxicity and interesting activity.

8 Clinical Trial Fractionated radioimmunotherapy with (90) Y-clivatuzumab tetraxetan and low-dose gemcitabine is active in advanced pancreatic cancer: A phase 1 trial. 2012

Ocean, Allyson J / Pennington, Kenneth L / Guarino, Michael J / Sheikh, Arif / Bekaii-Saab, Tanios / Serafini, Aldo N / Lee, Daniel / Sung, Max W / Gulec, Seza A / Goldsmith, Stanley J / Manzone, Timothy / Holt, Michael / O'Neil, Bert H / Hall, Nathan / Montero, Alberto J / Kauh, John / Gold, David V / Horne, Heather / Wegener, William A / Goldenberg, David M. ·Department of Medicine, Division of Hematology and Medical Oncology, New York Presbyterian Hospital, Weill Medical College of Cornell University, New York, New York 10021, USA. ajo9001@med.cornell.edu ·Cancer · Pubmed #22569804.

ABSTRACT: BACKGROUND: It has been demonstrated that the humanized clivatuzumab tetraxetan (hPAM4) antibody targets pancreatic ductal carcinoma selectively. After a trial of radioimmunotherapy that determined the maximum tolerated dose of single-dose yttrium-90-labeled hPAM4 ((90) Y-hPAM4) and produced objective responses in patients with advanced pancreatic ductal carcinoma, the authors studied fractionated radioimmunotherapy combined with low-dose gemcitabine in this disease. METHODS: Thirty-eight previously untreated patients (33 patients with stage IV disease and 5 patients with stage III disease) received gemcitabine 200 mg/m(2) weekly for 4 weeks with (90) Y-hPAM4 given weekly in Weeks 2, 3, and 4 (cycle 1), and the same cycle was repeated in 13 patients (cycles 2-4). In the first part of the study, 19 patients received escalating weekly (90) Y doses of 6.5 mCi/m(2) , 9.0 mCi/m(2) , 12.0 mCi/m(2) , and 15.0 mCi/m(2) . In the second portion, 19 additional patients received weekly doses of 9.0 mCi/m(2) or 12.0 mCi/m(2) . RESULTS: Grade 3/4 thrombocytopenia or neutropenia (according to version 3.0 of the National Cancer Institute's Common Terminology Criteria for Adverse Events) developed in 28 of 38 patients after cycle 1 and in all retreated patients; no grade >3 nonhematologic toxicities occurred. Fractionated dosing of cycle 1 allowed almost twice the radiation dose compared with single-dose radioimmunotherapy. The maximum tolerated dose of (90) Y-hPAM4 was 12.0 mCi/m(2) weekly for 3 weeks for cycle 1, with ≤9.0 mCi/m(2) weekly for 3 weeks for subsequent cycles, and that dose will be used in future trials. Six patients (16%) had partial responses according to computed tomography-based Response Evaluation Criteria in Solid Tumors, and 16 patients (42%) had stabilization as their best response (58% disease control). The median overall survival was 7.7 months for all 38 patients, including 11.8 months for those who received repeated cycles (46% [6 of 13 patients] ≥1 year), with improved efficacy at the higher radioimmunotherapy doses. CONCLUSIONS: Fractionated radioimmunotherapy with (90) Y-hPAM4 and low-dose gemcitabine demonstrated promising therapeutic activity and manageable myelosuppression in patients with advanced pancreatic ductal carcinoma.

9 Article Clinical benefit of a precision medicine based approach for guiding treatment of refractory cancers. 2016

Radovich, Milan / Kiel, Patrick J / Nance, Stacy M / Niland, Erin E / Parsley, Megan E / Ferguson, Meagan E / Jiang, Guanglong / Ammakkanavar, Natraj R / Einhorn, Lawrence H / Cheng, Liang / Nassiri, Mehdi / Davidson, Darrell D / Rushing, Daniel A / Loehrer, Patrick J / Pili, Roberto / Hanna, Nasser / Callaghan, J Thomas / Skaar, Todd C / Helft, Paul R / Shahda, Safi / O'Neil, Bert H / Schneider, Bryan P. ·Indiana University Health Precision Genomics Program, Indianapolis, IN, USA. · Indiana University Melvin and Bren Simon Cancer Center, Indianapolis, IN, USA. ·Oncotarget · Pubmed #27447854.

ABSTRACT: PATIENTS AND METHODS: Patients with metastatic solid tumors who had progressed on at least one line of standard of care therapy were referred to the Indiana University Health Precision Genomics Program. Tumor samples were submitted for DNA & RNA next-generation sequencing, fluorescence in situ hybridization, and immunohistochemistry for actionable targets. A multi-disciplinary tumor board reviewed all results. For each patient, the ratio of progression-free survival (PFS) of the genomically guided line of therapy divided by the PFS of their prior line was calculated. Patients whose PFS ratio was ≥ 1.3 were deemed to have a meaningful improvement in PFS. RESULTS: From April 2014-October 2015, 168 patients were evaluated and 101 patients achieved adequate clinical follow-up for analysis. 19 of 44 (43.2%) patients treated with genomically guided therapy attained a PFS ratio ≥ 1.3 vs. 3 of 57 (5.3%) treated with non-genomically guided therapy (p < 0.0001). Similarly, overall PFS ratios (irrespective of cutoff) were higher for patients with genomically guided therapy vs non-genomically guided therapy (p = 0.05). Further, patients treated with genomically guided therapy had a superior median PFS compared to those treated with non-genomically guided therapy (86 days vs. 49 days, p = 0.005, H.R. = 0.55, 95% C.I.:0.37-0.84). CONCLUSION: Patients with refractory metastatic cancer who receive genomically guided therapy have improved PFS ratios and longer median PFS compared to patients who do not receive genomically guided therapy.

10 Article Metformin Treatment Does Not Inhibit Growth of Pancreatic Cancer Patient-Derived Xenografts. 2016

Lipner, Matthew B / Marayati, Raoud / Deng, Yangmei / Wang, Xianxi / Raftery, Laura / O'Neil, Bert H / Yeh, Jen Jen. ·Department of Pharmacology, School of Medicine, The University of North Carolina, Chapel Hill, NC, United States of America. · Lineberger Comprehensive Cancer Center, The University of North Carolina, Chapel Hill, NC, United States of America. · ProHealth Care Regional Cancer Center, Waukesha, WI, United States of America. · Department of Medicine, Division of Medical Oncology, University of Indiana, Indianapolis, IN, United States of America. · Department of Surgery, Division of Surgical Oncology and Endocrinology, The University of North Carolina, Chapel Hill, NC, United States of America. ·PLoS One · Pubmed #26760500.

ABSTRACT: There is currently tremendous interest in developing anti-cancer therapeutics targeting cell signaling pathways important for both cancer cell metabolism and growth. Several epidemiological studies have shown that diabetic patients taking metformin have a decreased incidence of pancreatic cancer. This has prompted efforts to evaluate metformin, a drug with negligible toxicity, as a therapeutic modality in pancreatic cancer. Preclinical studies in cell line xenografts and one study in patient-derived xenograft (PDX) models were promising, while recently published clinical trials showed no benefit to adding metformin to combination therapy regimens for locally advanced and metastatic pancreatic cancer. PDX models in which patient tumors are directly engrafted into immunocompromised mice have been shown to be excellent preclinical models for biomarker discovery and therapeutic development. We evaluated the response of four PDX tumor lines to metformin treatment and found that all four of our PDX lines were resistant to metformin. We found that the mechanisms of resistance may occur through lack of sustained activation of adenosine monophosphate-activated protein kinase (AMPK) or downstream reactivation of the mammalian target of rapamycin (mTOR). Moreover, combined treatment with metformin and mTOR inhibitors failed to improve responses in cell lines, which further indicates that metformin alone or in combination with mTOR inhibitors will be ineffective in patients, and that resistance to metformin may occur through multiple pathways. Further studies are required to better understand these mechanisms of resistance and inform potential combination therapies with metformin and existing or novel therapeutics.