382 results on '"Daniel A. Laheru"'
Search Results
302. Impact of a Single-Day Multidisciplinary Clinic on the Management of Pancreatic Cancer: 3-Year Update
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Ralph H. Hruban, Amy Hacker-Prietz, Katherine Y. Fan, Joseph M. Herman, E K Fishman, Lei Zheng, Timothy M. Pawlik, Daniel A. Laheru, Mary Hodgin, and Christopher L. Wolfgang
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Cancer Research ,medicine.medical_specialty ,Radiation ,Oncology ,Multidisciplinary approach ,business.industry ,Pancreatic cancer ,Emergency medicine ,medicine ,Radiology, Nuclear Medicine and imaging ,medicine.disease ,business - Published
- 2013
303. Efficacy of Platinum Chemotherapy Agents in the Adjuvant Setting for Adenosquamous Carcinoma of the Pancreas
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Avani S. Dholakia, Matthew J. Weiss, Timothy M. Pawlik, Phuoc T. Tran, Aaron T. Wild, Amy Hacker-Prietz, Katherine Y. Fan, Dung T. Le, Lei Zheng, Daniel A. Laheru, John L. Cameron, Susannah G. Ellsworth, Christopher L. Wolfgang, Ana De Jesus-Acosta, Ralph H. Hruban, Luis A. Diaz, Khinh Ranh Voong, and Joseph M. Herman
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Oncology ,medicine.medical_specialty ,business.industry ,Adenosquamous carcinoma ,medicine.medical_treatment ,medicine.disease ,Pathology and Forensic Medicine ,medicine.anatomical_structure ,Internal medicine ,Platinum chemotherapy ,Medicine ,business ,Pancreas ,Adjuvant - Published
- 2013
304. Hemoglobin-A1c level to predict for clinical outcomes in patients with pancreatic cancer
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Dung T. Le, Zheng Su, Rachit Kumar, Phuoc T. Tran, Todd D. Brown, Ana De Jesus-Acosta, Katherine Y. Fan, Mary Hodgin, Amy Hacker-Prietz, Luis A. Diaz, Avani S. Dholakia, Ralph H. Hruban, Joseph M. Herman, Charles C. Hsu, Daniel A. Laheru, Timothy M. Pawlik, Christopher L. Wolfgang, Aaron T. Wild, and Elliot K. Fishman
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Oncology ,Cancer Research ,medicine.medical_specialty ,Pancreatic ductal adenocarcinoma ,business.industry ,education ,medicine.disease ,Pancreatic cancer ,Internal medicine ,Diabetes mellitus ,Medicine ,In patient ,Hemoglobin ,Risk factor ,business - Abstract
4039 Background: An association between diabetes mellitus (DM) and pancreatic ductal adenocarcinoma (PDA) has long been recognized. While long-standing DM may be a risk factor for developing PDA, new-onset DM may be a manifestation of the cancer. Here we assess the role of an objective and quantifiable measure of glucose intolerance, hemoglobin-A1c (HbA1c), in predicting clinical outcomes in PDA. Methods: HbA1c values were prospectively collected on 656 consecutive patients presenting to the Johns Hopkins Pancreas Multidisciplinary Cancer Clinic from 2009-2012. Patients were diagnosed with benign pancreatic disease (BPD) or biopsy-confirmed resectable (R), borderline/locally advanced (BL), or metastatic (M) PDA. Patients with prior treatment for PDA or a history of DM greater than a 1-year were excluded. Univariate Cox regression analyses and multivariable proportional hazards models were used to identify poor prognostic factors for overall survival. Results: Of 284 patients included, 44 had benign disease, 62 R-PDA, 115 BL-PDA, and 63 M-PDA. Patients with malignant disease (R-, BL-, and M-PDA) collectively had higher HbA1c values on average at presentation than patients with BPD (6.1% vs. 5.6%, p6.4%) increased with more advanced stage of disease. Among patients with PDA (n=240), univariate analyses showed HbA1c≥6.5, age≥65, ECOG≥1, CA19-9>90, tumor size >3cm, and advanced stage to be significantly associated with inferior survival (all HR>1, p3cm remained in the model for inferior survival. Conclusions: HbA1c level at presentation appears to correlate with disease stage and, moreover, to predict for survival among all stages of PDA. Patients with PDA have significantly higher HbA1c levels at presentation than patients with BPD. This study highlights the potential utility of HbA1c as a screening tool and prognostic factor.
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- 2013
305. Efficacy of platinum chemotherapy agents in the adjuvant setting for adenosquamous carcinoma of the pancreas
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K. Ranh Voong, Phuoc T. Tran, Ralph H. Hruban, Daniel A. Laheru, Rachit Kumar, John L. Cameron, Avani S. Dholakia, Dung T. Le, Ana De Jesus-Acosta, Joseph M. Herman, Katherine Y. Fan, Lei Zheng, Timothy M. Pawlik, Susannah G. Ellsworth, Christopher L. Wolfgang, Luis A. Diaz, Aaron T. Wild, Matthew J. Weiss, and Amy Hacker-Prietz
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Oncology ,Cancer Research ,medicine.medical_specialty ,Proportional hazards model ,business.industry ,Adenosquamous carcinoma ,Hazard ratio ,Retrospective cohort study ,Pancreatic Adenosquamous Carcinoma ,medicine.disease ,medicine.anatomical_structure ,Interquartile range ,Internal medicine ,medicine ,Adjuvant therapy ,Pancreas ,business - Abstract
e15028 Background: Pancreatic adenosquamous carcinoma (PASC) is a rare morphological subtype of pancreatic adenocarcinoma. PASC accounts for only 1-4% of exocrine pancreatic cancers and carries a particularly poor prognosis. Due to the rarity of PASC, studies of therapies specifically targeting this histopathologic entity are exceedingly limited. Based on efficacy exhibited by platinum agents against squamous carcinoma of other body sites, addition of these agents to adjuvant regimens may benefit patients with PASC. This retrospective study was performed among the largest series of patients with PASC identified to date in order to determine whether addition of platinum agents improves survival. Methods: Records of all patients who underwent pancreatic resection at our institution from 1986-2012 were reviewed to identify those with PASC. Demographic, surgical, pathologic, adjuvant therapy, and survival data were collected. Patients were divided into non-platinum (NPG) and platinum (PG) groups based on whether or not they received a platinum agent as part of adjuvant therapy. Results: In total, 62 patients with PASC were identified among 5,627 cases (1.1%). Fourteen patients received a platinum agent in the adjuvant setting (PG), while 48 did not (NPG). These two groups were comparable in regard to median age (65 vs. 69 yrs, p=0.34), gender (36 vs. 46% female, p=0.50), performance status (78 vs. 79% ECOG 0, p=0.98), histologic grade (86 vs. 77% grade 3, p=0.49), positive resection margins (14 vs. 29%, p=0.26), lymph node involvement (71 vs. 79%, p=0.54), median tumor diameter (4.0 vs. 4.3 cm, p=0.64), and proportion receiving radiotherapy (57 vs. 42%, p=0.31). PG patients received a median of 5.5 cycles (IQR, 3.3-6.0) of platinum chemotherapy, with 10 patients (71%) receiving cisplatin-based regimens and 4 (29%) receiving oxaliplatin-based regimens. PG patients experienced significantly longer median survival (19.1 months, 95% CI 12.8-25.4) compared to NPG patients (9.8 months, 95% CI 7.3-12.4) (p=0.024). Conclusions: Addition of a platinum agent to adjuvant regimens for resected PASC may improve survival among these high risk patients, though collaborative prospective investigation is needed.
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- 2013
306. Chemotherapy-induced diarrhea in older patients with colorectal cancer receiving fluoropyrimidines: A retrospective review
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Lei Zheng, Amanda L. Blackford, Luis A. Diaz, Ana De Jesus-Acosta, Daniel A. Laheru, Michael Purtell, Dung T. Le, Laxmi H Iyer, David Cosgrove, Nilofer S. Azad, Ilene Browner, Ross C. Donehower, Zeshaan A. Rasheed, and Maura Kadan
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Cancer Research ,medicine.medical_specialty ,Retrospective review ,business.industry ,Colorectal cancer ,Chemotherapy induced diarrhea ,medicine.disease ,Diarrhea ,Oncology ,Older patients ,Internal medicine ,Toxicity ,medicine ,medicine.symptom ,Intensive care medicine ,business - Abstract
e14647 Background: Chemotherapy-induced diarrhea (CID) is a common treatment-limiting toxicity of regimens used for colorectal cancer (CRC). Fluoropyrimidines, the backbone of CRC regimens, are associated with diarrhea, but the frequency and severity in older patients are less known due to under-representation of older patients in CRC trials. As life expectancy increases, the prevalence of older CRC patients will increase. We aimed to evaluate if older patients are vulnerable to CID. Methods: We retrospectively studied patients >70 years old who received fluoropyrimidines based therapy for stages II-IV CRC at Johns Hopkins and Bayview Medical Center from 1996-2007. Patient demographics and cancer-specific data were retrieved. Diarrhea was graded per National Cancer Institute Clinical Toxicity Criteria. Results: We included 150 patients > 70 years old. Median age was 75 (range 70-87). 65 (43%) were 70-74 years old, 52 (35%) were 75-79 years and 33 (22%) > 80. Diarrhea occurred in 48% (n=72) of patients. Presence of diarrhea was not significantly associated with increasing age (70-74, 75-79 or >80 years), gender, ECOG performance, number of comorbidities or medications. Severe grade 3-4 diarrhea occurred in 16% (n=24) and was associated with advanced stage (p=0.04). CID (all grades) was more common in cycle 1 than subsequent cycles (p=0.002). Conclusions: Fluoropyrimidines based therapy was tolerated in older patients with CRC. Incidence of CID was not associated with increasing age, gender, performance, comorbidities or polypharmacy. Severe diarrhea occurs in advanced stage and early during therapy. Larger prospective studies are needed to definitively evaluate the impact of age on CID.
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- 2013
307. Understanding the Role of 18Flurodeoxyglucose PET in Predicting Improved Survival in Locally Advanced Pancreatic Cancer
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Daniel A. Laheru, Richard L. Wahl, Luis A. Diaz, Jeffrey P. Leal, Aaron T. Wild, C.L. Wolfgang, Amy Hacker-Prietz, Avani S. Dholakia, Muhammad A. Chaudhry, and Joseph M. Herman
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Oncology ,medicine.medical_specialty ,business.industry ,Internal medicine ,medicine ,Improved survival ,Radiology, Nuclear Medicine and imaging ,business ,Locally advanced pancreatic cancer - Published
- 2013
308. Abstract 1242: The association between treatment-related lymphopenia and survival in patients with solid tumors
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Malcolm V. Brock, Daniel A. Laheru, Shanthi Marur, Jian Campian, Stuart A. Grossman, Susannah Yovino, Aaron T. Wild, Xiaobu Ye, Joseph M. Herman, and Ani Sarkis Balmanoukian
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Oncology ,Cancer Research ,Prognostic variable ,medicine.medical_specialty ,Chemotherapy ,business.industry ,medicine.medical_treatment ,Hazard ratio ,Head and neck cancer ,Cancer ,medicine.disease ,Surgery ,Tumor progression ,Internal medicine ,Pancreatic cancer ,medicine ,business ,Lung cancer - Abstract
Proceedings: AACR 104th Annual Meeting 2013; Apr 6-10, 2013; Washington, DC Background: This retrospective review was conducted to determine: 1) the frequency and severity of treatment related lymphopenia (TRL) in solid tumors, 2) its association with survival accounting for prognostic variables, and 3) its relationship to radiation or chemotherapy. Methods: Serial lymphocyte counts (pre-treatment and monthly for one year), prognostic factors, treatment details, and survival were retrospectively reviewed in 338 newly diagnosed patients with 1) high grade glioma, 2) resected pancreatic cancer, 3) unresectable pancreatic cancer, 4) stage III lung cancer, and 5) HPV- head and neck cancer in this IRB approved study. Severe TRL was defined as grade III-IV lymphopenia (
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- 2013
309. Quality of life in a multicenter phase II trial of neoadjuvant full-dose gemcitabine, oxaliplatin, and radiation in patients with resectable or borderline resectable pancreatic adenocarcinoma
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Mark M. Zalupski, Alice Chia-chi Wei, Joseph M. Herman, Christopher L. Wolfgang, Tanios Bekaii-Saab, Edgar Ben-Josef, Jolie Ringash, Edward J. Kim, Laura A. Dawson, Pablo Emilio Serrano Aybar, Malcolm J. Moore, and Daniel A. Laheru
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Oncology ,Cancer Research ,medicine.medical_specialty ,business.industry ,medicine.medical_treatment ,Pancreaticoduodenectomy ,medicine.disease ,humanities ,Gemcitabine ,Oxaliplatin ,Radiation therapy ,Quality of life ,Internal medicine ,Pancreatic cancer ,Pancreatectomy ,medicine ,Adenocarcinoma ,business ,medicine.drug - Abstract
226 Background: Pancreatic cancer remains incurable for the great majority of patients afflicted with the disease. The purpose of this study was to evaluate health related quality of life (HRQoL) following neoadjuvant full dose gemcitabine, oxaliplatin and radiation therapy (30 Gy) for pancreatic adenocarcinoma in a multi-institutional Phase-II trial. Methods: Fifty-seven patients were evaluable for the HRQoL component of this trial that consisted of two cycles of neoadjuvant chemoradiation with gemcitabine and oxaliplatin followed by pancreatectomy and two additional cycles of adjuvant chemotherapy. The effects of therapy on HRQoL were evaluated using: EORTC-C30, EORTC-PAN26 and FACT-HEP. Results: There were 20 patients (35%) with untreated resectable and 37 (65%) with borderline resectable pancreatic cancer. Thirty-nine patients (69%) completed two cycles of preoperative chemotherapy and surgery, 26 (40%) underwent a pancreaticoduodenectomy and 9 (14%) a distal pancreatectomy. Twenty-six patients completed postoperative adjuvant therapy. The median age was 64 (range 42-82); patients younger than 65 had a higher global HRQoL score at 6 months (p=0.046) following the initiation of treatment. There was no difference in the HRQoL according to type of operation performed. EORTC-C30 Global HRQoL remained statistically and clinically unchanged compared to baseline levels at all time-points. FACT-Hep Trial Outcome Index and Total score showed a statistically significant but not clinically meaningful decline following cycle 2 of neoadjuvant treatment (p=0.002 and p=0.004), returning back to baseline levels after 6 months. This may in part be explained by a decrease in the functional (p=0.004) and physical (p=0.001) wellbeing, an increase in diarrhea (p=0.044), digestive symptoms (p=0.037) and an increased fatigue (p
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- 2013
310. Phase II study of erlotinib combined with adjuvant chemoradiation and chemotherapy for resectable pancreatic cancer
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Daniel A. Laheru, John L. Cameron, Susannah G. Ellsworth, Zeshaan A. Rasheed, Aaron T. Wild, Timothy M. Pawlik, Phuoc T. Tran, Lei Zheng, E K Fishman, Avani S. Dholakia, Katherine Y. Fan, Ana De Jesus-Acosta, Rachit Kumar, Matthew J. Weiss, Christopher L. Wolfgang, Martin A. Makary, Joseph M. Herman, Amy Hacker-Prietz, Ralph H. Hruban, and D.T. Le
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Oncology ,Cancer Research ,Chemotherapy ,medicine.medical_specialty ,business.industry ,medicine.medical_treatment ,Phases of clinical research ,medicine.disease ,Gemcitabine ,Capecitabine ,Internal medicine ,medicine ,Adjuvant therapy ,Adenocarcinoma ,Erlotinib ,business ,Adjuvant ,medicine.drug - Abstract
269 Background: Amplification and overexpression of the EGFR gene and surface protein have been described in up to 80% of pancreatic tumors, making EGFR an attractive target in developing new adjuvant therapy for pancreatic adenocarcinoma (PDAC). Inhibition of EGFR has been suggested to provide additive activity when combined with capecitabine and radiation. Here we evaluate the antitumor activity and toxicity profile of erlotinib combined with adjuvant chemoradiotherapy (CRT) and chemotherapy. Methods: 50 patients with resected stage I/II PDAC were enrolled in a phase II trial of adjuvant erlotinib and capecitabine administered concurrently with IMRT (50.4 Gy), followed by 4 cycles of erlotinib and gemcitabine. Results: Median length of follow-up was 18.2 months (IQR, 13.8-27.1). Seventy-nine percent of tumors were of the pancreatic head, 85% had nodal involvement, and 17% had positive margins. Median RFS was 15.6 months (95% CI, 14.1-17.1), local RFS 21.1 months (95% CI, 17.1-25.1), and OS 24.4 months (95% CI, 17.1-31.6). Local recurrence was only observed in 19% patients and synchronous recurrence in 8%. Patients with maximum tumor diameter of ≤3 cm showed superior RFS (17.9 vs. 14.0 months; P=0.049), as did patients with cutaneous reaction to erlotinib (16.3 vs. 9.3 months, P=0.021). Superior OS was associated with less than median (32.3U/mL) pre-CRT CA19-9 values (28.2 vs. 19.0 months, P=0.012). During CRT, 31% patients experienced grade 3 toxicity and 2% grade 4, while 31% patients required a treatment break/stopped treatment early. During post-CRT chemotherapy, 35% patients experienced grade 3 toxicity and 8% grade 4, while 30% required a dose reduction. Conclusions: Results of this phase II trial suggest erlotinib combined with standard adjuvant CRT and chemotherapy provides excellent local disease control and reasonable tolerability compared with existing adjuvant regimens. Patients with maximum tumor diameter of ≤3 cm, cutaneous reaction to erlotinib, and less than median pre-CRT CA19-9 values appear to especially benefit from this new adjuvant regimen. Clinical trial information: NCT00962520.
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- 2013
311. Prognostic factors for achieving resection following neoadjuvant radiation therapy for borderline resectable pancreatic adenocarcinoma
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Timothy M. Pawlik, Rachit Kumar, Laura D. Wood, Daniel A. Laheru, Ana De Jesus-Acosta, Katherine Y. Fan, Susannah G. Ellsworth, Zeshaan A. Rasheed, Aaron T. Wild, Siva P. Raman, E K Fishman, Christopher L. Wolfgang, Ralph H. Hruban, Amy Hacker-Prietz, John L. Cameron, D.T. Le, Lei Zheng, Martin A. Makary, Joseph M. Herman, and Avani S. Dholakia
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Cancer Research ,medicine.medical_specialty ,business.industry ,medicine.medical_treatment ,medicine.disease ,Resection ,Surgery ,Radiation therapy ,Oncology ,Borderline resectable ,Pancreatic cancer ,Ascites ,Overall survival ,Medicine ,Adenocarcinoma ,medicine.symptom ,business ,Neoadjuvant chemoradiotherapy - Abstract
285 Background: Margin-negative (R0) surgical resection is the only potentially curative therapy for pancreatic cancer. For patients deemed borderline resectable (BL), neoadjuvant chemoradiotherapy (NCRT) increases the likelihood of subsequent R0 resection and improves overall survival. Prognostic factors for achieving resection following NCRT have yet to be clearly identified. Methods: 50 consecutive patients diagnosed with BL pancreatic cancer by a multidisciplinary tumor board from 2008-12 were retrospectively identified. Pre- and post-NCRT CT scans and surgical specimens were centrally reviewed by a blinded radiologist and pathologist, respectively. Results: 29 patients underwent resection following NCRT, while 21 remained unresectable. Between the two groups, age, gender, mean RT dose, and proportion of pancreatic head tumors were not significantly different. Lack of the following factors was favorably associated with resection: SMV/PV encasement (p=0.01), SMA involvement (p=0.02), ascites (p=0.01), and questionable/overt metastases (p=0.01). Notably, celiac artery involvement/encasement, common hepatic artery encasement, and percentage change in tumor volume were not significant predictors of resectability (all p>0.05). Additionally, tumor volume and degree of individual vessel involvement did not significantly change from scans before and after NCRT (all p>0.05). Median OS was 22.9 vs.13.0 months in resected and unresected patients, respectively (p
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- 2013
312. Abstract B27: IgE-independent hypersensitvity reactions are associated with prolonged survival in advanced pancreatic cancer patients receiving a GM-CSF cell-based vaccine plus cyclophosphamide (Cy) and cetuximab
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John T. Schroeder, Lei Zheng, Dung T. Le, Todd D. Armstrong, Elizabeth M. Jaffee, Elizabeth A. Sugar, Julie Ng, Daniel A. Laheru, Beth Onners, Sara Solt, Jennifer N. Uram, and Barbara A. Biedrzycki
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Oncology ,Cancer Research ,medicine.medical_specialty ,biology ,Cetuximab ,Cyclophosphamide ,business.industry ,medicine.medical_treatment ,Cancer ,Immunotherapy ,Immunoglobulin E ,medicine.disease ,Pancreatic tumor ,Internal medicine ,Pancreatic cancer ,Immunology ,biology.protein ,medicine ,Antibody ,business ,medicine.drug - Abstract
Background: Pre-clinical and clinical studies demonstrate that combining Cy with granulocyte-macrophage colony-stimulating factor (GM-CSF) secreting irradiated allogeneic pancreatic tumor cells (pancGVAX) enhances clinical and vaccine induced anti-tumor immune responses. The mechanism is thought to occur by inhibiting suppressor T-cell activity and promoting a type 1 cytotoxic immune response by promoting dendritic cell (DC) activation. Additional pre-clinical evidence support monoclonal antibodies such as Cetuximab that target growth factor receptors (GFRs) in synergistic anti-tumor immune responses. It is estimated that >70% of pancreatic cancers overexpress EGFR. This supports a role for combinatorial immunotherapies in advanced pancreatic cancer. Methods: Sixty patients with advanced pancreatic cancer who progressed on, or refused, first line standard therapy received six cycles of Cy (250 mg/m2) on day 0, pancGVAX (5x108 cells) on day 1, and Cetuximab on days 1, 8 and 15 (initial dose of 400 mg/m2 and subsequent doses of 250 mg/m2) every three weeks. Patients who experienced grade 3 Cetuximab hypersensitivity reactions continued to receive Cy and pancGVAX treatments without further Cetuximab. Serum cytokines and immunoglobulins were analyzed by ELISA and serum cell populations were evaluated using flow cytometry. Results: Twelve out of the 60 patients were hypersensitive to Cetuximab. Median survival was 4.5 months overall. Survival in the hypersensitivity group was 7.1 versus 4.1 months in the non-hypersensitivity group (p=0.026). Baseline characteristics were similar except for the increased number of metastatic disease sites in the hypersensitivity group (2 or more, 100% versus 69%, p=0.027). There was a significant difference in the association between serum IgE levels at enrollment and overall survival for hypersensitive as compared to non-hypersensitive patients (p=0.004). Among hypersensitive patients, higher serum IgE levels at enrollment was associated with increased risk of death (p=0.019, HR =1.05, 95% CI: 1.009 to 1.099). The baseline serum IgE level was not predictive of overall survival for non-hypersensitive patients (p=0.75); however, higher serum IgE levels following the first vaccine was associated with increased risk (p=0.010, HR = 1.026, 95% CI: 1.006 to 1.046). Lower levels of surface IgE bound to plasmacytoid DCs (pDCs), but not monocytoid DCs or basophils, correlated with overall survival both at baseline (p=0.019) and after vaccination (p=0.006). Overall survival also correlated with lower levels of serum IL-6 (p=0.031) and IL-8 (p=0.043). This suggests that a pDC-mediated skewing towards type 2 inflammatory responses is associated with poor prognosis in these patients. Conclusions: Prolonged survival in advanced pancreatic cancer patients correlated with IgE-independent hypersensitivity to Cetuximab. IgE mediated type 2 inflammatory responses are associated with poor prognosis in patients receiving immunotherapy. Blockade of IgE may enhance the efficacy of immunotherapy in pancreatic cancer patients. Citation Format: Julie Ng, Jennifer Uram, Beth Onners, Barbara Biedrzycki, Elizabeth Sugar, Sara Solt, Todd Armstrong, Dung Le, Lei Zheng, John Schroeder, Elizabeth Jaffee, Daniel Laheru. IgE-independent hypersensitvity reactions are associated with prolonged survival in advanced pancreatic cancer patients receiving a GM-CSF cell-based vaccine plus cyclophosphamide (Cy) and cetuximab. [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology: Multidisciplinary Science Driving Basic and Clinical Advances; Dec 2-5, 2012; Miami, FL. Philadelphia (PA): AACR; Cancer Res 2013;73(1 Suppl):Abstract nr B27.
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- 2013
313. Patient retention and costs associated with a pancreatic multidisciplinary clinic
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Terry S. Langbaum, Ralph H. Hruban, Christopher L. Wolfgang, Deann Gavney, Tammy Snyder, Shereef M. Elnahal, Timothy M. Pawlik, Hao Wang, Richard D. Schulick, E K Fishman, Martin A. Makary, Joseph M. Herman, Barbara A. Biedrzycki, Aaron T. Wild, Elizabeth M. Jaffee, Amy Hacker-Prietz, Barish H. Edil, and Daniel A. Laheru
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Cancer Research ,medicine.medical_specialty ,business.industry ,Disease ,Patient retention ,medicine.disease ,Surgery ,Oncology ,Multidisciplinary approach ,Internal medicine ,Pancreatic cancer ,medicine ,Continuity of care ,Stage (cooking) ,business ,Clinical risk factor - Abstract
96 Background: Multidisciplinary clinics (MDC) are a burgeoning method of administering timely and comprehensive oncologic care. The continuity of care achievable with MDCs, in addition to their costs, are not well-described. We compared retention rates and charges for MDC patients to patients with individual referrals at the same academic center. Methods: The geographic origins of 482 MDC patients and 3,766 non-MDC patients, all referred for pancreatic cancer treatment between 2008-2010, were defined as “local,” “adjacent states,” and “non-adjacent states.” Proportions of patients in each group who presented initially and subsequently returned were compared using chi-squared tests. Multivariate adjustment was performed for disease stage and other clinical risk factors. Gross charges per patient were determined using billing data. Results: Overall, the MDC retained a higher percentage of patients for subsequent treatment than the non-MDC group (60.8% vs. 53.6%; p=0.003), as well as all three individual regions. Multivariate adjustment results are not yet available, but will be at the time of the meeting. Mean charges per patient were 11% higher for the non-MDC group. Conclusions: The MDC achieved higher patient retention, suggesting improved continuity of care. Total charges were higher for the non-MDC group, suggesting that MDCs may be more cost-effective. [Table: see text] [Table: see text]
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- 2012
314. SBRT as a Novel Treatment Option for Locally Recurrent Pancreatic Cancer After Failure of Definitive Multimodality Therapy: A Multi-institutional Case Series
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Christopher L. Wolfgang, Albert C. Koong, Susan M. Hiniker, Maneesha Limaye, Aaron T. Wild, Phuoc T. Tran, Timothy M. Pawlik, Joseph M. Herman, Daniel A. Laheru, and Daniel T. Chang
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Cancer Research ,medicine.medical_specialty ,Series (stratigraphy) ,Radiation ,business.industry ,Recurrent pancreatic cancer ,Treatment options ,Multimodality Therapy ,Surgery ,Oncology ,Medicine ,Radiology, Nuclear Medicine and imaging ,Radiology ,business - Published
- 2012
315. Association of low total lymphocyte count with overall and disease-free survival in patients with resected pancreatic adenocarcinoma receiving the GM-CSF secreting pancreatic tumor vaccine in combination with adjuvant chemoradiation
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Elizabeth M. Jaffee, Elaine Bigelow, Daniel A. Laheru, Barish H. Edil, Elizabeth A. Sugar, Lei Zheng, Jennifer N. Uram, Aaron J. Schueneman, and Joseph M. Herman
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Oncology ,Cancer Research ,medicine.medical_specialty ,Disease free survival ,business.industry ,medicine.medical_treatment ,Lymphocyte ,Immune dysregulation ,medicine.disease ,medicine.disease_cause ,medicine.anatomical_structure ,Pancreatic tumor ,Internal medicine ,Pancreatectomy ,medicine ,Adenocarcinoma ,In patient ,business ,Adjuvant - Abstract
e14585 Background: Pancreatectomy, though necessary for potential cure of pancreatic ductal carcinoma (PDA), can be associated with immune dysregulation. Low total lymphocyte count (TLC) has been found to be a poor prognostic indicator in several different tumor types. The goal of this study was to determine whether low TLC could affect response to therapy and survival in resected pancreatic cancer patients who received a GMCSF-secreting cell-based tumor vaccine (GVAX) in addition to standard adjuvant therapy. Methods: Retrospective analysis of 60 patients enrolled in a phase II trial evaluating the safety, efficacy and immune activation of GVAX tumor vaccine administered in an adjuvant setting in resected PDA. Blood counts were analyzed from 8 weeks after surgery and then monthly after the completion of adjuvant chemoradiation. Results: The TLC just prior to the first vaccine was 1977 (range: 700-3890) and 10 patients had TLC < 1500. After adjusting for the prognostic factors identified in the original study (lymph node + and margin status), OS was significantly lower for those patients with TLC < 1500 (median 18.4 mos., 95% CI: 8.63 to infinity) as compared to those with TLC > 1500 (median 28.4 mos., 95% CI: 23.9 to 32.6, hazard ratio [HR] = 2.43, 95% CI: 1.09 to 5.41, p = 0.03). TLC < 1500 prior to first vaccine was also associated with shorter disease free survival (HR: 3.18 p < 0.01). Adjuvant chemoradiation consistently decreased TLC with a mean reduction of 1224 (range 450 to 2740). After adjuvant therapy, TLC < 500 was associated with reduced OS (HR: 4.86, 95% CI: 1.70 to 13.87, p < 0.01). Conclusions: Low TLC after surgery and after adjuvant chemoradiation is associated with poor survival in patients who receive pancreatic GVAX. This result suggests that immune suppressive conditions associated with current standard pancreatectomy and chemoradiation significantly compromise the efficacy of immunotherapy. Less invasive laparoscopic surgical approaches that result in less immune dysregulation and chemotherapy regimens that have lower immunosuppression should be considered.
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- 2012
316. Treating patients with colorectal liver metastasis: A national decision-making analysis to understand choice of therapy
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Daniel A. Laheru, Hari Nathan, Christopher L. Wolfgang, David Cosgrove, Timothy M. Pawlik, Michael A. Choti, Joseph M. Herman, Luis A. Diaz, Barish H. Edil, Kenzo Hirose, and Richard D. Schulick
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Oncology ,Cancer Research ,medicine.medical_specialty ,business.industry ,Colorectal cancer ,medicine.disease ,Metastasis ,Surgery ,Internal medicine ,medicine ,Decision making analysis ,business ,Therapeutic strategy - Abstract
3596 Background: Criteria for resectability of colon cancer liver metastases (CLM) are evolving, yet little is known about how physicians choose a therapeutic strategy for potentially resectable CLM. Methods: Physicians completed a national web-based survey that consisted of varied CLM case scenarios. Respondents choose among 3 treatment strategies: immediate liver resection(LR), preoperative chemotherapy followed by surgery(C→LR), or palliative chemotherapy (PC). Data were analyzed using multinomial logistic regression, yielding relative risk ratios (RRR). Results: Of 219 respondents, 79% practiced at academic centers and 63% were in practice ≥10 years. Median number of cases evaluated was 4/month. Surgical training varied: 51% surgical oncology (SO), 44% hepatobiliary/transplant (HB/LT), 5% no fellowship. While each factor impacted choice of CLM therapy, the relative impact differed (p
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- 2012
317. Abstract LB-61: Targeting cancer cell metabolism in pancreatic cancer: p53, a key regulator of glycolysis and a major factor deciding the outcome of targeting the Warburg effect
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Prasanta Dutta, Daniel A. Laheru, Elizabeth De Oliveira, Nathaniel R. Campbell, Roeland F. de Wilde, Jurre J. Kamphorst, Shinichi Yabuuchi, Craig B. Thompson, Daniel D. Von Hoff, Manuel Hidalgo, Joshua D. Rabinowitz, Anne Le, N. V. Rajeshkumar, Sanjay K. Jain, Robert J. Gillies, Chi V. Dang, Ana De Jesus-Acosta, and Anirban Maitra
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Cancer Research ,medicine.medical_specialty ,education.field_of_study ,Lactate dehydrogenase A ,Cancer ,Tumor initiation ,Biology ,medicine.disease ,Warburg effect ,Endocrinology ,Oncology ,Tumor progression ,Internal medicine ,Pancreatic cancer ,Cancer cell ,medicine ,Cancer research ,Glycolysis ,education - Abstract
Background and Aim: Tumor cells depend on metabolic alterations for their continued growth and survival, and such changes make cancer cells peculiarly addicted to the rapacious uptake of glucose. The Warburg effect is such a metabolic feature of cancers that helps to preferentially metabolize pyruvate via glycolytic pathway to lactate by lactate dehydrogenase A (LDHA). Our recent findings indicated that LDHA is required not only for tumor initiation but for tumor maintenance and progression (Le et al., PNAS, 2010). Here, we investigated the therapeutic potential of LDHA inhibition in pancreatic cancer, and attempt to delineate the factors responsible for tumor response. Methods: We evaluated the in vivo efficacy of FX11, a small molecule inhibitor of LDHA, in a panel of pancreatic cancer xenografts with annotated mutational status. Non-invasive quantitative assessment of lactate production was measured by real-time hyperpolarization experiments with 1-13C-labeled pyruvate using a DNP polarizer (HyperSense). [18F]-fluorodeoxyglucose (FDG) positron emission tomography-computed tomography (PET) combined with computed tomography (CT) imaging was conducted to evaluate the effect of FX11 treatment on glucose metabolism. Liquid chromatography - mass spectrometry (LC-MS) was used to quantify the tumor metabolites. Ki-67 and TUNEL staining were performed to determine the effect of FX11 treatment on apoptosis and tumor cell proliferation. Results: p53-deficient pancreatic cancer xenografts showed higher baseline metabolic activity and FX11 treatment down-regulated the tumor metabolic activity. Real-time imaging of pyruvate to lactate conversion using nuclear magnetic resonance (NMR) spectroscopy revealed that FX11 treatment inhibits pyruvate to lactate conversion in p53-deficient pancreatic cancer xenografts. Importantly, p53 promotes the expression of TP53-induced glycolysis regulator (TIGAR) and loss of p53 in tumors results in reduced TIGAR levels. The metabolic profiles of p53-deficient versus p53-proficient pancreatic cancer xenografts were remarkably different. FX11 treatment attenuates tumor progression, induces apoptosis and reduces tumor cell proliferation, preferentially in p53-deficient pancreatic cancer xenografts. Conclusions: Because the Warburg effect is characteristic of virtually all cancers and p53 is frequently mutated in vast majority of human cancers, our finding that p53, a key regulator of glycolysis and a major factor deciding the therapeutic outcome of targeting the Warburg effect may have broad clinical implications. Our findings may help to identify patient subsets that may be particularly responsive to LDHA targeted agents in clinical trials. Acknowledgement: Stand Up To Cancer-AACR Dream Team Translational Cancer Research Grant No. SU2C-AACR DT0509. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr LB-61. doi:1538-7445.AM2012-LB-61
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- 2012
318. Abstract 3494: Liver X receptor activation represents a novel strategy to block Hedgehog signaling in pancreatic adenocarcinoma and enhance the antitumor effect of gemcitabine
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Anirban Maitra, William Matsui, Ana DeJesus-Acosta, Daniel A. Laheru, Farhad Parhami, Ming Zhao, Elizabeth Oliviero, Clinton Jung, Michelle A. Rudek, Ally Huang, Jasmin Roya Agarwal, Zeshaan A. Rasheed, N. V. Rajeshkumar, and Ping He
- Subjects
Cancer Research ,medicine.medical_specialty ,Stromal cell ,biology ,medicine.disease ,Gemcitabine ,Hedgehog signaling pathway ,Endocrinology ,Oncology ,GLI1 ,Internal medicine ,Pancreatic cancer ,medicine ,biology.protein ,Cancer research ,Signal transduction ,Liver X receptor ,Smoothened ,medicine.drug - Abstract
Background: The Hedgehog (Hh) signaling pathway plays a pathogenic role in many human cancers, including pancreatic adenocarcinoma, and several pathway antagonists have begun clinical testing. All of these novel agents target Smoothened (Smo), a key regulator of Hh signaling, but reported emergence of resistance mutations questions the durability of this approach. Oxysterols, oxidized derivatives of cholesterol, can modulate Hh signaling either through direct interaction with Smo or via cross-talk with liver X receptors (LXR) that serve as their natural receptors. Thus, oxysterols may represent mechanistically novel Hh inhibitors, especially if they involve LXRs. Methods: We examined the effects of LXR activation on the in vivo growth of pancreatic cancer. Nude mice bearing pancreatic cancer xenografts derived from primary clinical specimens were treated with a vehicle control, gemcitabine, the non-steroidal LXR agonist TO901317, or the combination of gemcitabine and TO901317 for 4-6 weeks. The LXR agonist TO901317 was used since it lacks the ability to directly bind to Smo. Tumor volumes were measured to assess response, and LXR and Hh pathway activities were quantified by real-time RT-PCR for Hh (GLI1, PTCH1) and LXR (ABCA1) target gene expression. Human specific primers were used to detect changes in tumor cells, whereas mouse-specific primers were used to study stroma. Intratumoral levels of gemcitabine triphosphate were quantified by LC-MS-MS. Results: Administration of TO901317 alone did not impact tumor growth compared to control treated animals similar to previous findings with Smo antagonists. Treatment with gemcitabine alone decreased tumor growth, However the addition of TO901317 to gemcitabine significantly enhanced this effect to promote tumor regression. In vivo treatment with TO901317 successfully activated LXR in both human tumor cells and murine stromal cells as evidenced by increased expression of ABCA1. Moreover, TO901317 inhibited expression of the Hh targets GLI1 and PTCH1 5- and 2-fold, respectively, in stromal cells and 5-fold in tumor cells. Previous studies (Olive et al, Science, 2009) demonstrated that Hh pathway inhibition improves drug delivery in vivo. Therefore, we quantified intratumoral levels of gemcitabine triphosphate, the active metabolite of gemcitabine, and found that it was significantly elevated in tumors exposed to TO901317 (P Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3494. doi:1538-7445.AM2012-3494
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- 2012
319. Phase Ib study of ipilimumab alone or in combination with allogeneic pancreatic tumor cells transfected with a GM-CSF gene (vaccine) in pancreatic cancer
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D.T. Le, Elizabeth M. Jaffee, Lei Zheng, Elizabeth A. Sugar, Eric R. Lutz, Daniel A. Laheru, Jennifer N. Uram, Lanqing Huang, Sara Solt, and Beth Onners
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Oncology ,Cancer Research ,medicine.medical_specialty ,biology ,business.industry ,Melanoma ,medicine.medical_treatment ,Cell ,Ipilimumab ,Transfection ,Immunotherapy ,medicine.disease ,medicine.anatomical_structure ,Pancreatic tumor ,Internal medicine ,Pancreatic cancer ,Immunology ,medicine ,biology.protein ,Antibody ,business ,medicine.drug - Abstract
211 Background: Ipilimumab (IPI) at 3mg/kg has been tested in pancreatic ductal adenocarcinoma (PDA) with a low but detectable response rate. This supports a role for immunotherapy in PDA. Melanoma (MEL) studies demonstrate a dose-response relationship with IPI. Preclinical studies show synergy between anti-CTLA-4 antibodies and GM-CSF cell-based vaccines. This study evaluated IPI 10mg/kg alone (Arm 1) versus IPI 10mg/kg + vaccine (Arm 2) in PDA. Methods: 30 subjects with previously treated, locally advanced or metastatic PDA were randomized (1:1) to Arm 1 or 2. Induction treatments were administered every 3 weeks (wk) X 4 doses. Subjects with stable disease (SD) or better between wk 14 and 22 were eligible for maintenance doses every 12 wks. Activity was assessed by response and overall survival (OS). IFN-g Elispots and ELISAs were used to detect induction of mesothelin-specific T cells and galectin-3 antibodies (Abs), respectively. Results: Baseline characteristics were similar (87% metastatic, 100% gemcitabine-treated) with the exception that Arm 1 had a lower % of subjects with > 1 prior therapies (60 vs 100%). Arm 1 had 2 SD (7 and 22 wks). Arm 2 had 3 SD (1 delayed regression starting at wk 14 and maintained until wk 31, 1 delayed stabilization starting at wk 22 and ongoing at wk 57, 1 SD ongoing at wk 64). Transient CA19-9 declines were seen only in Arm 2 (7/15). Median OS was 3.3 vs 5.5 months in Arm 1 vs Arm 2 (p=0.12) with a 12 month OS of 7 vs 27%. 73% (Arm 1) and 80% (Arm 2) of subjects experienced immune related adverse events (IRAE). 20% of subjects on both arms had Grade 3-4 IRAEs including rash (1), colitis (2), Guillain-Barre (1), nephritis (1), and pneumonitis (1). Rash was less frequent in Arm 1 (53 vs 73%). IRAEs (p=0.037), mesothelin T cell responses (p=0.012), and enhancement of the T cell repertoire (p=0.026) were associated with OS in both arms. Galectin-3 Ab responses were associated with OS in Arm 2 (p=0.002). Conclusions: Immunotherapy has potential even in advanced PDA. IRAEs in PDA are similar to IRAEs in MEL. Delayed responses suggest that standard RECIST criteria will underestimate activity and targeting a population with a longer life expectancy may improve efficacy.
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- 2012
320. A phase I study of MEK inhibitor MEK162 (ARRY-438162) in patients with biliary tract cancer
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Amita Patnaik, Emma Barrett, Daniel A. Laheru, Johanna C. Bendell, Colin D. Weekes, Benjamin R. Tan, Gazala Khan, Richard S. Finn, Lisa Anderson, Janna Christy-Bittel, Kevin Litwiler, Milind Javle, Kari Guthrie, and Tanios Bekaii-Saab
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MAPK/ERK pathway ,Cancer Research ,medicine.medical_specialty ,Pathology ,Biliary tract cancer ,business.industry ,Gallbladder ,MEK inhibitor ,Gastroenterology ,Gemcitabine ,medicine.anatomical_structure ,Oncology ,Pharmacokinetics ,Pharmacodynamics ,Internal medicine ,Medicine ,In patient ,business ,medicine.drug - Abstract
220 Background: The RAS/RAF/MEK/ERK pathway plays a major role in cell growth and survival and is aberrantly activated in many cancers. MEK162 (ARRY-438162) is a potent, selective, ATP-uncompetitive inhibitor of MEK1/2. The objectives of this Phase 1 expansion study were to characterize the safety, pharmacokinetics (PK), pharmacodynamics (PD) and preliminary efficacy of MEK162 in patients (pts) with biliary tract cancer (BTC). Methods: Pts with unresectable, locally advanced or metastatic BTC who had received ≤ 1 prior systemic therapy received oral MEK162 at 60 mg twice daily (BID). Mutation status of RAS, BRAF and other relevant genes were assessed from tumor samples. Tumor response was assessed every 6 weeks. Results: Twenty-eight pts, median age 64 years (range 30-86) with gallbladder (7), intrahepatic (14) or extrahepatic (7) cholangiocarcinoma (CC) were enrolled. All pts were ECOG 0-1 and 43% received previous first-line therapy (primarily gemcitabine combinations). Of the 23 tumors assessed, 17 were wild type (WT) on all loci tested and 6 had mutations (1 MET, 1 PIK3CA, 2 KRAS, 2 PTEN null). The most common treatment-related AEs were rash, nausea, vomiting, diarrhea, peripheral edema, fatigue and central serous-like retinopathy, and most were Grade (G) 1 or 2. G3/4 treatment-related AEs were anasarca, hypokalemia, hyponatremia, upper/lower gastrointestinal hemorrhage and mucositis (1 each). Thirteen pts were dose reduced for AEs, of which, G1/2 central serous-like retinopathy was the most frequently reported event (6). Three pts were discontinued for treatment-related AEs (G2 central serous-like retinopathy, G1 nausea, G4 anasarca). Of the 26 pts evaluable for response, 1 CR, 1 PR and 11 SD (≥ 6 weeks) were observed. Of note, both responders were WT on all loci tested and had extrahepatic CC. The PK in this population was equivalent to that observed in prior studies. A consistent mean reduction (40-60%) of circulating TNFα was observed. Conclusions: MEK162 has an acceptable safety profile and desirable PK properties at 60 mg BID and RECIST responses were observed in pts with BTC. Additional expansion cohorts are ongoing in pts with KRAS- or BRAF-mutant metastatic colorectal cancer.
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- 2012
321. Radiation in the management of pancreatic neuroendocrine tumors
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William F. Regine, Trevor A. Ellison, Richard D. Schulick, Michael A. Choti, Joseph M. Herman, Lei Zheng, Navesh K. Sharma, Nader Hanna, Kelly Olino, Petr F. Hausner, Ralph H. Hruban, Daniel A. Laheru, Bertram W. Maidment, Barish H. Edil, Aaron T. Wild, H. Richard Alexander, John L. Cameron, and Christopher L. Wolfgang
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Cancer Research ,medicine.medical_specialty ,medicine.diagnostic_test ,business.industry ,medicine.medical_treatment ,Radiography ,Patient demographics ,Neuroendocrine tumors ,medicine.disease ,Primary tumor ,Surgery ,Radiation therapy ,Oncology ,Cohort ,Biopsy ,medicine ,Disease characteristics ,Radiology ,business - Abstract
335 Background: Radiation therapy (RT) has not historically been incorporated into multidisciplinary management of pancreatic neuroendocrine tumors (PNTs). We provide a two-institution series of patients with PNTs who were treated with external beam RT either neoadjuvantly to attempt down-staging for surgery, or in the setting of post-surgical recurrence. Our objective was to assess treatment response and outcomes in this cohort of patients. Methods: We identified eleven patients with a pathologic diagnosis of PNT from 2006-2011 who received external beam RT to the primary tumor or resection bed. Each institution’s electronic medical record was used to evaluate patient demographics, disease characteristics, treatment regimens and tolerance, radiographic response, and survival. Results: Our series consists of eleven patients (6 men, 5 women) with a mean age of 57 years (range 37-72 years). All had biopsy proven PNT and were clinically T3 (n=3) or T4 (n=8), M0. Five patients were clinically node positive. All patients received RT to the primary tumor or resection bed to a median dose of 50.4 Gy. Seven patients received concurrent chemotherapy with capecitabine at a median dose of 1000mg/m2 bid. Nine patients were treated definitively for locally advanced disease, two of whom subsequently underwent surgical resection. Two patients were treated to palliate post-resection recurrence. Initial radiographic response to RT included 2 complete responses (CR), 2 partial responses (PR), 4 stable disease, 3 progressive disease (PD). Two patients were classified as PD due to the development of distant metastases less than 2 months after completing RT. Two grade 3 toxicities were documented (one early, one late). At a median follow-up of 30.4 months, three patients had died with evidence of PD, two had died without evidence of PD, three were alive with metastases, and three were alive without evidence of disease progression (1 stable, 1 PR, 1 CR). From the start of RT, median overall survival was 32.1 months; progression free survival was 14.6 months. Conclusions: RT may have the potential to convert PNTs from locally-advanced to resectable. RT may also increase local control of PNTs. Consideration should be given to the use of RT in prospective trials of PNT treatment.
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- 2012
322. Effect of treatment-related lymphopenia on survival in newly diagnosed patients with resected adenocarcinoma of the pancreas
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Joseph M. Herman, Daniel A. Laheru, Ani Sarkis Balmanoukian, Stuart A. Grossman, and Xiaobu Ye
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Cancer Research ,Chemotherapy ,medicine.medical_specialty ,business.industry ,Lymphocyte ,medicine.medical_treatment ,medicine.disease ,Pancreaticoduodenectomy ,Gastroenterology ,Gemcitabine ,Surgery ,medicine.anatomical_structure ,Oncology ,Concomitant ,Internal medicine ,Pancreatic cancer ,medicine ,Adenocarcinoma ,Pancreas ,business ,medicine.drug - Abstract
270 Background: Severe treatment-related lymphopenia is associated with shorter survival in patients with high grade gliomas. This study was performed to determine if patients with resected pancreatic adenocarcinoma treated with post-operative radiation and chemotherapy develop significant lymphopenia and if this affects overall survival. Methods: Patients selected for this retrospective analysis underwent pancreatic cancer resection between 1997 and 2008, and received post-operative radiation with gemcitabine or 5-FU based chemotherapy at Johns Hopkins Hospital. Serial lymphocyte counts were recorded and survival was analyzed as a function of lymphopenia and known prognostic factors. Results: Fifty-three adults met the eligibility criteria. Their median age was 64, median tumor size was 3 centimeters, 83% underwent a pancreaticoduodenectomy, 47% had positive margins, and 92% had positive nodes. Total lymphocyte counts were normal in 91% of patients prior to receiving radiation and concomitant chemotherapy with 5FU(59%) or gemcitabine (41%). Total lymphocyte counts fell to 3 in 45% of patients two months after initiating therapy with a median reduction of 63% from the baseline (p3 at 2 months was 14 months versus 20 months in patients with more lymphocytes (p=0.0485). Univariate analysis revealed no significant association between pre-treatment patient characteristics and survival. Multivariate analysis revealed a significant association between survival and lymphocyte count (3) at 2 months (HR 2.2, p = 0.014). Conclusions: Adjuvant radiation and chemotherapy induced lymphopenia is frequent, severe, and an independent predictor for survival in patients with resected pancreatic adenocarcinoma.
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- 2012
323. Effect of chemoradiation-related lymphopenia on survival in patients with unresectable, locally advanced pancreatic adenocarcinoma
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Phuoc T. Tran, Lei Zheng, Amy Hacker-Prietz, Susannah Yovino, Stuart A. Grossman, Timothy M. Pawlik, Joseph M. Herman, Daniel A. Laheru, Christopher L. Wolfgang, Rachit Kumar, Mark A. Ziegler, Ani Sarkis Balmanoukian, and Aaron T. Wild
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Cancer Research ,Immune system ,Pancreatic ductal adenocarcinoma ,Oncology ,business.industry ,Cancer research ,Locally advanced ,Medicine ,Adenocarcinoma ,In patient ,business ,medicine.disease - Abstract
307 Background: Pancreatic ductal adenocarcinoma (PDA) has been shown to elicit antitumor cell-mediated immune responses. In high grade gliomas, treatment-related lymphopenia has been associated with shorter survival. This study was performed to determine if patients with locally advanced PDA treated with definitive chemoradiation therapy (CRT) develop significant lymphopenia and if this affects overall survival (OS). Methods: A retrospective analysis of patients with locally advanced PDA treated at a single institution with CRT from 1997-2009 was performed. Serial lymphocyte counts were recorded and OS was analyzed as a function of lymphopenia and known prognostic factors. Results: 99 patients met eligibility criteria (≥18 years of age, ECOG performance status 0-2, and had baseline/follow-up lab values measured at our institution). Mean age was 61.6 years (SD, 11.6), 55% were male, mean tumor size 4.1 cm (SD, 1.6), and 97 had stage III disease. Median pre/post-CRT CA19-9 values were 241.5 and 105.2 U/mL, respectively. Total lymphocyte counts were normal in 87% of patients prior to RT. Mean RT dose was 47.3 Gy (SD, 8.2) and concurrent chemotherapy was 5-FU (67%), gemcitabine (20%), taxotere (7%), or none (6%). Chemotherapy dose reduction was necessary in 9%, and 39% required a RT break. Total lymphocyte counts fell to ≤500 cells/mm3 in 51% two months after initiating CRT with a median reduction of 66% from baseline (p3 at 2 months was 7.7 months (95% CI, 6.8-8.7) versus 15.4 (95% CI, 11.9-19.0) for patients with >500 cells/mm3 (p3) at 2 months post-CRT (HR 3.8, p Conclusions: Definitive CRT induced lymphopenia is frequent, severe, and appears to be an independent predictor for OS in patients with locally advanced PDA.
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- 2012
324. A multivariate model for identifying risk of early death after Pancreaticoduodenectomy(PDD) and adjuvant therapy for periampullary Adenocarcinoma(PA): importance for understanding post treatment outcomes
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Larry T. Korman, John L. Cameron, Charles J. Yeo, Keith D. Lillemoe, Daniel A. Laheru, Marianna Zahurak, Ross A. Abrams, Ralph H. Hruban, Elizabeth M. Jaffee, Ross C. Donehower, and T. A. Sohn
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Oncology ,Cancer Research ,medicine.medical_specialty ,Multivariate statistics ,Radiation ,business.industry ,General surgery ,medicine.medical_treatment ,Early death ,Pancreaticoduodenectomy ,Periampullary Adenocarcinoma ,Internal medicine ,medicine ,Adjuvant therapy ,Radiology, Nuclear Medicine and imaging ,Post treatment ,business - Published
- 2002
325. Abstract A87: Preliminary results of a phase II study of erlotinib combined with adjuvant chemoradiation and chemotherapy in patients with resectable pancreatic cancer
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Richard D. Schulick, Aaron T. Wild, Manuel Hidalgo, Dung T. Le, Christopher L. Wolfgang, Joseph M. Herman, Daniel A. Laheru, Phuoc T. Tran, Mark A. Ziegler, Amy Hacker-Prietz, Barish H. Edil, Lei Zheng, Timothy M. Pawlik, and Ariel E. Marciscano
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Cancer Research ,medicine.medical_specialty ,Chemotherapy ,business.industry ,medicine.medical_treatment ,Phases of clinical research ,Neutropenia ,medicine.disease ,Gastroenterology ,Gemcitabine ,Oncology ,Internal medicine ,Immunology ,medicine ,Adjuvant therapy ,Progression-free survival ,Erlotinib ,business ,Survival rate ,medicine.drug - Abstract
Background: Both local and systemic recurrences are common after surgical resection of pancreatic ductal adenocarcinoma (PDA). This pattern of failure suggests that a combination of systemic and local adjuvant therapy may positively impact survival. The epidermal growth factor receptor (EGFR) gene is overexpressed in up to 80% of PDA specimens. Thus, EGFR is an attractive target for improving efficacy of adjuvant therapy for PDA. Purpose: (1) To evaluate the antitumor activity of erlotinib (E) combined with standard adjuvant chemoradiotherapy (CRT) and chemotherapy as measured by progression free survival (PFS) and overall survival (OS). (2) To characterize the toxicity profile of E combined with adjuvant therapy. Methods: 43 patients with resected stage I/II PDA were enrolled in a phase II trial of E (100 mg daily) and capecitabine (800 mg/m2 twice daily Monday-Friday) administered concurrently with IMRT delivered at 1.8 Gy daily in 28 fractions (50.4 Gy total). 4–8 weeks following CRT, patients continued treatment with 4 cycles of gemcitabine (1000 mg/m2 on days 1, 8, and 15 every 28 days) and E (100 mg daily). OS and PFS were calculated as time from surgery to death and to disease progression, respectively. Toxicity was assessed using the NCI CTCAE Version 3.0. Results: Mean age was 61.7 years (SD, 8.7) and 44% were male. 72% had tumors of the pancreatic head, while 28% had tumors of the body/tail. 86% had regional nodal involvement and 33% had positive resection margins. Median follow-up was 16.7 months (interquartile range, 7.4–22.8). Median OS was 24.7 months (95% CI, 18.5–30.9). Median PFS was 15.4 months (95% CI, 9.4–21.3). Survival rate at 1 year was 90.3%. Median CA19–9 prior to CRT was 30.6 U/mL; CRT combined with E resulted in CA19–9 reduction or stabilization in 84.8%. No difference in OS was observed between patients with tumors of the pancreatic head versus body/tail (p=0.64). Of 27 patients who progressed, first recurrence developed distantly in 16 (59.3%) and locally in 11 (40.7%). A trend towards greater OS (25.1 vs. 19.0 months) was observed among patients who first recurred locally (p=0.10). CRT was stopped early due to toxicity in 5 patients (11.6%); 11 (25.6%) required a treatment break; and 3 (6.7%) required discontinuation of chemotherapy before completion of CRT. Acute grade 2 toxicity included weight loss (27.9%), abdominal pain/nausea/vomiting (27.9%), anorexia (25.6%), fatigue (23.3%), dermatitis (20.9%), diarrhea (9.3%), and transaminitis (4.7%), but none of these were dose-limiting. Acute grade 3 toxicity included neutropenia (11.6%), transaminitis (7.0%), dermatitis (4.7%), and weight loss (2.3%). 1 patient experienced grade 4 neutropenia during chemotherapy. 3 patients (7.0%) experienced grade ≥3 late toxicity in the form of small bowel obstruction. Conclusions: Preliminary analysis of this phase II trial provides encouraging evidence that E combined with standard adjuvant therapy may improve PFS in patients with resected PDA. Longer follow-up is needed to establish whether the addition of E provides a survival advantage over current standard of care regimens. Acute grade 2 toxicity is considerable, but does not preclude patients from receiving the full dose of RT. Grade ≥3 acute and late toxicities are uncommon, though longer follow-up may be necessary to adequately assess late toxicity. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr A87.
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- 2011
326. Prognostic Value of DPC4 Status for Resected Pancreatic Adenocarcinoma Patients Receiving Adjuvant Chemoradiation
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Joseph M. Herman, E K Fishman, Amy Hacker-Prietz, Daniel A. Laheru, Amol Narang, Christine A. Iacobuzio-Donahue, Charles C. Hsu, John L. Cameron, Christopher L. Wolfgang, and S.H. Lin
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Oncology ,Cancer Research ,medicine.medical_specialty ,Radiation ,business.industry ,medicine.medical_treatment ,medicine.disease ,Internal medicine ,medicine ,Adenocarcinoma ,Radiology, Nuclear Medicine and imaging ,business ,Adjuvant ,Value (mathematics) - Published
- 2011
327. Evaluation of adjuvant chemoradiation therapy for ampullary adenocarcinoma: the Johns Hopkins Hospital - Mayo Clinic collaborative study
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John L. Cameron, Richard D. Schulick, Jessica Zhou, Jordan M. Winter, Sumita Bhatia, Amol Narang, Charles C. Hsu, Michael G. Haddock, Christopher L. Wolfgang, Robert C. Miller, Daniel A. Laheru, Joseph M. Herman, Timothy M. Pawlik, John H. Donohue, and Ralph H. Hruban
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Male ,medicine.medical_treatment ,carcinoma ,Gastroenterology ,Risk Factors ,Stage (cooking) ,Neoplasm Metastasis ,chemoradiation ,Aged, 80 and over ,Univariate analysis ,ampullary ,Chemoradiotherapy ,Middle Aged ,lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,Treatment Outcome ,Oncology ,Radiology Nuclear Medicine and imaging ,Chemotherapy, Adjuvant ,resectable ,Adenocarcinoma ,Female ,Fluorouracil ,lcsh:Medical physics. Medical radiology. Nuclear medicine ,Adult ,medicine.medical_specialty ,Ampulla of Vater ,lcsh:R895-920 ,Minnesota ,Common Bile Duct Neoplasms ,Antineoplastic Agents ,lcsh:RC254-282 ,adjuvant ,Internal medicine ,medicine ,Carcinoma ,Humans ,Radiology, Nuclear Medicine and imaging ,Survival analysis ,Aged ,Proportional Hazards Models ,Retrospective Studies ,Maryland ,Proportional hazards model ,business.industry ,Research ,medicine.disease ,Surgery ,Radiation therapy ,Radiotherapy, Conformal ,business - Abstract
Background The role of adjuvant chemoradiation therapy for ampullary carcinoma is unknown. Previous literature suggests that certain populations with high risk factors for recurrence may benefit from adjuvant chemoradiation. We combined the experience of two institutions to better delineate which patients may benefit from adjuvant chemoradiation. Methods Patients who underwent curative surgery for ampullary carcinoma at the Johns Hopkins Hospital (n = 290; 1992-2007) and at the Mayo Clinic (n = 130; 1977-2005) were reviewed. Patients with Results Median overall-survival was 39.9 months with 2- and 5-year survival rates of 62.4% and 39.1%. On univariate analysis, adverse prognostic factors for overall survival included T3/T4 stage disease (RR = 1.86, p = 0.002), node positive status (RR = 3.18, p < 0.001), and poor histological grade (RR = 1.69, p = 0.011). Patients who received adjuvant chemoradiation (n = 66) vs. surgery alone (n = 120) showed a higher rate of T3/T4 stage disease (57.6% vs. 30.8%, P < 0.001), lymph node involvement (72.7% vs. 30.0%, P < 0.001), and close or positive margins (4.6% vs. 0.0%, P = 0.019). Five year survival rates among node negative and node positive patients were 58.7% and 18.4% respectively. When compared with surgery alone, use of adjuvant chemoradiation improved survival among node positive patients (mOS 32.1 vs. 15.7 mos, 5 yr OS: 27.5% vs. 5.9%; RR = 0.47, P = 0.004). After adjusting for adverse prognostic factors on multivariate analysis, patients treated with adjuvant chemoradiation demonstrated a significant survival benefit (RR = 0.40, P < 0.001). Disease relapse occurred in 37.1% of all patients, most commonly metastatic disease in the liver or peritoneum. Conclusions Node-positive patients with resected ampullary adenocarcinoma may benefit from 5-FU based adjuvant chemoradiation. Since a significant proportion of patients develop metastatic disease, there is a need for more effective systemic treatment.
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- 2011
328. Tolerance of full-dose sorafenib (S) combined with irinotecan (I; weekly, two on, one off) and cetuximab (C) in previously treated patients with advanced colorectal cancer (CRC)
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Wells A. Messersmith, John J. Arcaroli, Nilofer S. Azad, Arvind Dasari, Rebecca W. Powell, Michael A. Carducci, Manuel Hidalgo, John Wright, Michelle A. Rudek, and Daniel A. Laheru
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Oncology ,Sorafenib ,Cancer Research ,medicine.medical_specialty ,Cetuximab ,biology ,business.industry ,Pharmacology ,medicine.disease ,Irinotecan ,Advanced colorectal cancer ,Vascular endothelial growth factor ,chemistry.chemical_compound ,chemistry ,Internal medicine ,Toxicity ,medicine ,biology.protein ,Epidermal growth factor receptor ,business ,Febrile neutropenia ,medicine.drug - Abstract
522 Background: The epidermal growth factor receptor (EGFR) and vascular endothelial growth factor (VEGF) pathways are qualified targets in CRC, and are both inhibited by S. Preclinical evidence suggests S may also overcome cetuximab resistance. We previously reported (2008 GI Symposium, abstr#435) excessive toxicity of this combination with I 120 mg/m2 days (d) 1,8,15,22 every 42 d; the study was amended with an alternative I dose/schedule and the phase I results are presented. Methods: Patients (pts) with advanced, pretreated CRC irrespective of KRAS mutation status with ECOG PS 0-2 and good organ function were eligible. The original dose/schedule of I was combined with C 400 mg/m2 IV d1 and 250 mg/m2 weekly; and S PO daily with dose level (DL) 1 = 200mg QD, DL2=200 mg BID and DL 3=400 mg BID. 2/4 pts had DLTs: grade (g) 3 fatigue and febrile neutropenia. The dose/schedule were amended to I 100 mg/m2 d1, 8 of 21d cycles (c) without changing S or C. As with the original design, there was a C/S lead-in for 2 weeks in c1, thus c1 (DLT window) was 5 weeks (w). Results: In the original design, 5 subjects were recruited; after the study amendment, 13 additional pts were recruited (3, 3 and 7 pts respectively at amended DL1, DL2 and DL3). Overall, median age was 56.5 yrs, M: F 12:6 and colon: rectal cancer 16:2. All patients are evaluable and 3 are still on treatment (10+ - 20+ w). At the amended I dose/schedule, there were no further DLTs. Any c g3 toxicities included constitutional (fatigue:2, dehydration:1), gastrointestinal (nausea:1, vomiting:2, diarrhea:1), metabolic (hypomagnesemia:2 including one with tetany; hypokalemia:3), elevated ALT:1 and neutropenia:1. G 4 toxicities included neutropenia:1, thrombocytopenia:1. Two pts (one KRAS MT) had partial response with one pt (KRAS WT) on treatment for >44 w. 10 pts had stable disease (5–20+ w). PK/PD analysis is ongoing. Conclusions: The recommended phase II dose is I 100 mg/m2d1,8; C 400 mg/m2 IV d1 and 250 mg/m2 weekly; and S 400 mg PO BID. The regimen is tolerable in advanced, pretreated CRC. Due to the limited responses and current phase III studies with S in CRC, there are no plans to open the phase II portion at this time. No significant financial relationships to disclose.
- Published
- 2011
329. Resectable pancreatic small cell carcinoma: The experience of two institutions and review of the literature
- Author
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Daniel A. Laheru, D. K. Andersen, Jordan M. Winter, Joseph M. Herman, John L. Cameron, Robert C. Miller, Frederic E. Eckhauser, Aaron S. Mansfield, Matthew T. Olson, and Amol Narang
- Subjects
Surgical resection ,Cancer Research ,medicine.medical_specialty ,Oncology ,business.industry ,General surgery ,Medicine ,business ,medicine.disease ,Small-cell carcinoma ,Surgery - Abstract
333 Background: Primary pancreatic small cell carcinoma (SCC) is rare, with just over 30 cases reported in the literature. Only 7 of these patients underwent surgical resection with a median survival of 6 months. Prognosis of SCC is therefore considered to be poor, and the role of adjuvant therapy is uncertain. Here we report two institutions' experience with resectable pancreatic SCC. Methods: Six patients with pancreatic SCC at the Johns Hopkins Hospital (4 patients) and the Mayo Clinic (2 patients) were identified from prospectively collected pancreatic cancer databases and re-reviewed by pathology. All six patients underwent a pancreaticoduodenectomy. Clinicopathologic data was analyzed, and the literature on pancreatic SCC was reviewed. Results: Median age at diagnosis was 50 years (range 27-60). Half of the patients were male, and half were known smokers. All six masses were limited to the pancreatic head. Median tumor size was 3 cm, and all cases had positive lymph nodes except for one patient who only had five nodes sampled. There was no perioperative mortality, although three patients had postoperative complications. All six patients received adjuvant chemotherapy therapy, five of whom were given cisplatin and etoposide. Of these five patients, three were known to have received radiation, while the remaining two had a plan for radiation at an outside facility. Median survival was 20 months with a range of 9-173 months. The patient who lived for 9 months received chemotherapy only, while the patient who lived for 173 months was given chemoradiation with cisplatin and etoposide and represents the longest reported survival time from pancreatic SCC to date. Conclusions: Pancreatic SCC is an extremely rare form of cancer with a poor prognosis. Patients in this surgical series showed improved survival rates when compared to prior experiences with both resected and unresectable cases. Cisplatin and etoposide appears to be the preferred chemotherapy regimen, although its efficacy remains uncertain, as does the role of combined modality treatment with radiation. No significant financial relationships to disclose.
- Published
- 2011
330. NPC-1C: A novel, therapeutic antibody to treat pancreas and colorectal cancers
- Author
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Daniel A. Laheru, David O. Cosgrove, Philip M. Arlen, L. Zheng, D.T. Le, Nilofer S. Azad, C. E. Devoe, J. A. Bristol, and Luis A. Diaz
- Subjects
Cancer Research ,Pathology ,medicine.medical_specialty ,biology ,Colorectal cancer ,medicine.drug_class ,business.industry ,medicine.disease ,Monoclonal antibody ,Epitope ,medicine.anatomical_structure ,Oncology ,Pancreatic tumor ,medicine ,biology.protein ,Cancer research ,CA19-9 ,Antibody ,Ensituximab ,Pancreas ,business ,medicine.drug - Abstract
235 Background: NPC-1C (ensituximab) is a chimeric monoclonal antibody being developed as a novel biologic treatment for pancreatic and colorectal cancers. This antibody was selected from a panel of hybridomas generated from mice immunized with semi-purified membrane-associated proteins derived from biologically screened, pooled human allogeneic colon cancer tissues. The NPC-1C epitope appears to be expressed specifically by human colon and pancreatic tumor tissues and cell lines. Methods: Antitumor activity was established in vitro by measuring ADCC with a standard 4-hour 111-Indium release assay on pancreatic and colorectal cancer cell lines. In vivo antitumor efficacy of NPC-1C was tested using pre-established subcutaneous human pancreatic tumor xenograft models. Results: In vitro, the NPC-1C antibody exhibits ADCC activity specifically against human colon and pancreatic tumor cells, but not against control tumor cell lines. The in vivo data showed significant, and reproducible, antitumor action, including some complete tumor regressions. The clinical application for this antibody was bolstered by several examples of human tumor tissues stained with biotin-conjugated NPC-1C that showed a strong correlation of NPC-1C staining against pancreatic and colon tumors. Approximately 45% of tumors stained strongly positive. The staining pattern was typical of elaborated mucin expression, but also showed cytoplasmic and cell membrane staining. Conclusions: A phase I open label, multicenter dose escalation clinical trial with NPC-1C is currently accruing patients with advanced pancreatic and colorectal cancer who are refractory to standard therapy. The primary objectives of the phase I clinical trial are to determine the safety and tolerability of escalating doses of NPC-1C monoclonal antibody therapy and to assess pharmacokinetics and select immune responses to the antibody at each dose level. Secondary objectives are to evaluate evidence of clinical benefit and to explore the immunologic correlates associated with administration of NPC-1C. Results from this trial will determine the minimum standard dosage levels to be used in further trials. [Table: see text]
- Published
- 2011
331. Correlation between pancreatic tumor size as measured on 3D CT scan versus pathologic specimen: Impact on radiation treatment volume
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Daniel A. Laheru, H. Qiu, Christopher L. Wolfgang, Barish H. Edil, Joseph M. Herman, R. Tuli, Charles C. Hsu, L. Zheng, E K Fishman, and Ralph H. Hruban
- Subjects
Cancer Research ,medicine.medical_specialty ,Tumor size ,business.industry ,Planning target volume ,medicine.disease ,Resection ,Oncology ,Pancreatic tumor ,Pancreatic cancer ,Chart review ,medicine ,3d ct scan ,Radiology ,business ,Pathological - Abstract
276 Background: Definition of the target volume for irradiation of pancreatic cancer (PCA) must balance coverage of micrometastatic disease with toxicity. To determine differences between radiographically defined tumors and true pathologic tumor specimens, we correlated the maximum tumor diameter (TD) of preoperatively imaged tumors with resected tumor specimens. Methods: With IRB approval, a retrospective chart review of patients who underwent resection of PCA between 2006 and 2010 was conducted. 73 patients were identified with preoperative CT imaging and pathologic analysis of tumors. 70 of 73 patients had a preoperative 3D CT performed. The TD as measured by a radiologist (EF) on contrast CT and 3D CT reconstruction was compared with that measured by pathological analysis of the resected specimen. Results: 70 patients underwent resection with preoperative CT imaging; 14.1% of these patients had CT performed >6 weeks prior to surgery. The mean (SD) pathologic maximum TD was 31.3 mm (11.3) with range 3 mm to 60 mm. Whereas TD was underestimated by 1.9 mm (1.7 SE) with CT relative to pathologic analysis, this difference was not statistically significant (paired t-test, p=0.27) with a correlation coefficient of 0.265. 3D CT imaging had a smaller mean difference with a mean 3D CT diameter 0.4 mm (1.76 SE) larger than the pathologic specimen (p=0.82) with correlation coefficient 0.222. However, the max TD on 3D CT imaging was on average 2.3 mm larger than on CT (p=0.016) with correlation coefficient 0.798. Of patients with R0 resections (N=48), CT underestimated path size by 3.1 mm (p=0.020), whereas 3D CT was slightly larger (0.1 mm, p=0.949). For R1 resections (n=22), both CT and 3D CT overestimated size (0.8 mm and 1.1 mm, respectively, p>0.5). Conclusions: PCA TD is generally underestimated on CT imaging, yet better approximated with 3D CT. Improved correlation was seen between CT and pathologic specimens following R0 resection. Alternatively, R1 resection specimens were slightly overestimated by CT/3D CT imaging. As a result, clinical target volumes should be expanded accordingly during radiotherapy planning to properly account for these discrepancies in the gross tumor. No significant financial relationships to disclose.
- Published
- 2011
332. Correlation of DPC4 status with outcomes in pancreatic adenocarcinoma patients receiving adjuvant chemoradiation
- Author
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Joseph M. Herman, Christopher L. Wolfgang, Daniel A. Laheru, E K Fishman, Christine A. Iacobuzio-Donahue, Ralph H. Hruban, S.H. Lin, John L. Cameron, Amy Hacker-Prietz, and Charles C. Hsu
- Subjects
Oncology ,Cancer Research ,medicine.medical_specialty ,Pathology ,business.industry ,Proportional hazards model ,medicine.medical_treatment ,medicine.disease ,Tumor tissue ,Gemcitabine ,Metastasis ,Correlation ,Internal medicine ,Pancreatic cancer ,Medicine ,Adenocarcinoma ,business ,Adjuvant ,medicine.drug - Abstract
168 Background: In an autopsy series of patients with advanced pancreatic cancer (PCA), loss of DPC4 was highly correlated with disseminated metastasis. The purpose of this study was to determine if DPC4 gene status predicts for survival and patterns of recurrence following adjuvant (adj) chemoradiation (CRT). Methods: 101 patients who underwent surgery followed by adjuvant 5-FU or gemcitabine-based CRT were studied. Imaging studies were reviewed to assess patterns of recurrence and tumor tissue obtained to determine DPC4 immunolabeling status. DPC4 status was graded as intact or lost/mutated. Kaplan-Meier estimates were used to compute survival and Cox proportional hazards were used to compare risk factors. Results: Median overall (mOS) and progression-free survival (PFS) was 22.6 mos (95% CI 18.8 to 31.6) and 14.0 mos (95% CI 11.5 to 18.4). The mOS and 1-yr OS for patients with DPC4 intact vs. lost status was 21.9 mos (95% CI 16.8-32.4) and 78.4% vs. 22.6 mos (95% CI 18.4-32.6) and 78.2%, respectively (HR: 1.05, p=0.82). After adjusting for node, margin status, tumor grade, tumor size, and age, DPC4 status did not predict for mOS (RR 1.04, 95% CI: 0.62-1.74, p=0.89). Time to first progression at any site for PCA with DPC4 intact vs. lost status was 13.8 vs. 14.0 mos (p=0.79). Local recurrence was more common in PCA with DPC4 loss than with intact status (34.4% vs. 13.7%, p=0.012). There was no difference in the rates of distant recurrence in PCA with intact vs. loss of DPC4 expression (62.8% vs. 55.7%, p=0.45); however, DPC4 loss was more commonly associated with liver recurrence (27.9% vs. 19.6%, p=0.31). Conclusions: In pancreatic cancer patients receiving adj CRT, loss of DPC4 labeling in their resected PCA indicates a greater likelihood of developing local recurrence despite having received adj CRT. Efforts to improve loco-regional control are therefore needed for these patients following surgery and adj CRT. No significant financial relationships to disclose.
- Published
- 2011
333. Probing the determinants of disulfide stability in native pancreatic trypsin inhibitor
- Author
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Daniel A. Laheru, Jia Dong Zhou, David M. Goldenberg, and Lynne S. Bekeart
- Subjects
Models, Molecular ,Stereochemistry ,Protein Conformation ,Trypsin inhibitor ,Molecular Sequence Data ,Peptide ,Calorimetry ,Biochemistry ,Dithiothreitol ,chemistry.chemical_compound ,Aprotinin ,Drug Stability ,medicine ,Amino Acid Sequence ,Disulfides ,Site-directed mutagenesis ,Protein disulfide-isomerase ,chemistry.chemical_classification ,Chemistry ,Trypsin ,Recombinant Proteins ,Kinetics ,Enzyme ,Mutagenesis, Site-Directed ,Chemical stability ,Mathematics ,medicine.drug - Abstract
The effects of single amino acid replacements on the stability of the 14-38 disulfide bond in the native form of bovine pancreatic trypsin inhibitor (BPTI) were measured. A total of 17 mutant proteins, with substitutions at one of 7 residues located 5-15 A from the disulfide in the native wild-type protein, were examined. The replacements were found to decrease the thermodynamic stability of the disulfide, as measured by exchange with thiol-disulfide reagents, by 0.6-5 kcal/mol, corresponding to a range of nearly 100 mV in redox potentials. The effects of the substitutions on disulfide stability were roughly correlated with the changes in side-chain volume, suggesting that optimal packing is a major factor in determining the stability of the disulfide in the wild-type protein. With only one exception, the substitutions also led to increases, as large as 50-fold, in the rates of disulfide reduction by dithiothreitol. The increased rates of reduction suggest that at least a fraction of the mutational destabilization of the disulfide is due to strain in the native protein that is relieved in the transition state for reduction. The stability of the disulfide in a peptide corresponding to the segments that are linked together by the 14-38 disulfide in native BPTI was found to be about 5 kcal/mol less than that of the disulfide in the intact wild-type protein. Together, the results with the mutant proteins and the peptide indicate that the stability of the disulfide in the native protein depends on both the local environment of the disulfide and on the ability of the rest of the protein to favor a conformation that promotes disulfide formation.
- Published
- 1993
334. Low Dose Upper Abdominal Radiation Therapy (LD-UART) Potentiates Gemcitabine in Patients with Advanced, Unresectable Pancreatic Cancer (PC): Final Results from a Phase II Multi-Institutional Study
- Author
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William F. Regine, Naimish Pandya, Joseph M. Herman, N.L. Kennedy, Raimond Wong, H.R. Alexander, Navesh K. Sharma, Daniel A. Laheru, Nader Hanna, and Pierre Major
- Subjects
Unresectable Pancreatic Cancer ,Oncology ,Cancer Research ,medicine.medical_specialty ,Radiation ,business.industry ,medicine.medical_treatment ,Low dose ,Gemcitabine ,Radiation therapy ,Internal medicine ,medicine ,Radiology, Nuclear Medicine and imaging ,In patient ,Radiology ,business ,medicine.drug - Published
- 2010
335. A multicenter review of gemcitabine, docetaxel, and capecitabine (GTX) in patients with advanced pancreatic adenocarcinoma
- Author
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D.T. Le, Luis A. Diaz, A. De Jesus-Acosta, David O. Cosgrove, L. Zheng, Lalan S. Wilfong, E. Flores, Ross C. Donehower, Daniel A. Laheru, and George R. Oliver
- Subjects
Oncology ,Cancer Research ,medicine.medical_specialty ,business.industry ,Combination chemotherapy ,medicine.disease ,Gemcitabine ,Capecitabine ,Regimen ,Docetaxel ,Internal medicine ,medicine ,Adenocarcinoma ,Single agent ,In patient ,business ,medicine.drug - Abstract
e14580 Background: Combination chemotherapy provides modest benefit in patients with advanced pancreatic adenocarcinoma over single agent gemcitabine. Recent studies have suggested that new regimen...
- Published
- 2010
336. Abstract C246: nab®-paclitaxel targets tumor stroma and results, combined with gemcitabine, in high efficacy against pancreatic cancer models
- Author
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N. V. Rajeshkumar, Michelle A. Rudek, Ignacio Garrido-Laguna, Neil P. Desai, Anirban Maitra, Jose Iglesias, Daniel D. Von Hoff, Manuel Hidalgo, and Daniel A. Laheru
- Subjects
Cancer Research ,business.industry ,medicine.disease ,Gemcitabine ,Clinical trial ,chemistry.chemical_compound ,Oncology ,Stroma ,Paclitaxel ,chemistry ,Pancreatic cancer ,Immunology ,medicine ,Cancer research ,In patient ,Tumor stroma ,business ,medicine.drug ,Nab-paclitaxel - Abstract
nab®-paclitaxel (Abraxane ™, Abraxis Bioscience, Los Angeles, CA) is an albumin-bound nano particle formulation of paclitaxel that may target SPARC (secreted protein acid-rich in cysteine). In a phase I/II study in patients with advanced pancreatic cancer, the combination of nab®-paclitaxel and gemcitabine resulted in impressive clinical activity with an objective response rate of 40%, 10.3 months median survival and 78 % of patients having a decrement of CA199 > 50 % (Von Hoff et al, ASCO 2009). To gain insight into the mechanisms underlying the high efficacy of this combination, we treated 11 freshly generated pancreatic cancer xenografts from the Johns Hopkins PancXenoBank collection. nab®-paclitaxel, in combination with gemcitabine, doubled the response rate of either agent alone and resulted in a 57% response rate, mimicking the results obtained in the clinical trial. Tumors treated with nab®-paclitaxel showed a marked decrement in the otherwise abundant fibrotic stroma characteristic of pancreatic cancer and present in control and gemcitabine only treated animals. The elimination of the stroma resulted in marked cellular tumors and increased tumor vascularization and cell-vessel proximity. Consequently, the intratumoral concentration of gemcitabine increased by 3.7 fold in mice treated with nabR-paclitaxel and gemcitabine versus those receiving gemcitabine alone. We conclude that nab®-paclitaxel effectively eliminates pancreatic cancer stroma resulting in increased delivery of gemcitabine and high antitumor effects. Targeting tumor stroma appears a promising strategy in pancreatic cancer. Citation Information: Mol Cancer Ther 2009;8(12 Suppl):C246.
- Published
- 2009
337. Abstract C31: Phase 1 study of AV-412, a novel irreversible EGFR inhibitor, administered daily in patients with advanced solid tumors
- Author
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Maximiliano Van Kooten, Marc Credi, Monica Varela, Carmen Pupareli, Daniel A. Laheru, Debra L. Wood, Justina L. Martinez, Manuel Hidalgo, Pankaj Bhargava, Monette M. Cotreau, and M. Al-Adhami
- Subjects
Cancer Research ,medicine.medical_specialty ,business.industry ,Colorectal cancer ,Nausea ,Cancer ,medicine.disease ,Gastroenterology ,T790M ,Oncology ,Internal medicine ,medicine ,Vomiting ,Erlotinib ,medicine.symptom ,business ,Adverse effect ,medicine.drug ,EGFR inhibitors - Abstract
Background: Acquired resistance to EGFR tyrosine kinase inhibitors (TKIs) such as erlotinib is a frequent clinical phenomenon in non-small cell lung cancer (NSCLC). Approximately 50% patients (pts) with acquired resistance to EGFR TKIs demonstrate the T790M mutation in EGFR gene. AV-412, an irreversible EGFR TKI, has demonstrated activity in chimeric mouse models with acquired resistance to EGFR TKIs (bearing the T790M mutation), and is being developed for treatment of NSCLC. Methods: Pts with advanced, incurable solid tumors were enrolled in a phase 1 study and administered AV-412 orally once-a-day. Doses evaluated were: 50mg, 100mg, 150mg and 200mg. The goals of the study were to determine the maximum tolerated dose (MTD), safety, dose limiting toxicity (DLT), pharmacokinetics (PK) and activity of AV-412. Results: 24 pts were treated: 13 males/11 females, median age 61 yrs (range 32–73). ECOG PS 0 (17 pts) or 1 (7 pts). Tumor types (No. of pts) were colorectal (5), NSCLC (3), pancreatic (3), uterine (3), melanoma (2), ovarian (2), hepatocellular (1), breast (1), head and neck (1) and other (3). Mean number of prior treatments were 6 (range 1–15). Five (20.8%) pts had received prior therapy with an EGFR inhibitor. The median duration of treatment was 32.5 days (range 7 – 214 days). Two pts experienced DLT at 200mg (grade 3 nausea and vomiting, and grade 3 diarrhea), following which anti-emetic premedications were instituted in the study. The MTD of AV-412 was 150mg; 11 pts were treated at this dose. The most common treatment-related adverse events (all grades) were nausea (54.2%), diarrhea (45.8%), and vomiting (41.7%); hematologic abnormalities included lymphopenia, increased INR, anemia, and leucopenia (12.5% each), hepatic and renal abnormalities included increased ALT, increased AST, and proteinuria (12.5% each). Drug-related laboratory abnormalities were generally mild to moderate in severity. Preliminary PK data indicate dose proportional exposure. Three patients had disease stabilization > 16 weeks: 2 pts with colorectal cancer (116 days, 170 days) and a pt with ovarian cancer (172 days). Conclusions: AV-412 is well tolerated at a dose of 150 mg/day. The most frequent toxicities were nausea and diarrhea, which could be controlled with standard medications. This study is currently enrolling a cohort of patients with NSCLC to evaluate clinical activity of AV-412 in patients with EGFR mutations, and updated results will be available for presentation. A phase 1 study of intermittent dosing of AV-412 is also being conducted. Citation Information: Mol Cancer Ther 2009;8(12 Suppl):C31.
- Published
- 2009
338. Evaluation of Pancreatic Disease Status, CA 19-9, Performance Status, Quality of Life Indices, and Treatment Choice: The Johns Hopkins Pancreas Multidisciplinary Cancer Clinic Quality of Life Study
- Author
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Timothy M. Pawlik, Jane Wang, Daniel A. Laheru, Joseph M. Herman, Charles C. Hsu, Edwin Lam, and Christopher L. Wolfgang
- Subjects
Gerontology ,Cancer Research ,medicine.medical_specialty ,Radiation ,Pancreatic disease ,Performance status ,business.industry ,Cancer ,medicine.disease ,Quality of life (healthcare) ,medicine.anatomical_structure ,Oncology ,Multidisciplinary approach ,Medicine ,Radiology, Nuclear Medicine and imaging ,CA19-9 ,business ,Intensive care medicine ,Pancreas - Published
- 2009
339. Comparison of Two Adjuvant Chemoradiotherapy Protocols after Resection of Primary Pancreatic Carcinoma: A 10 Year Experience
- Author
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Raymond Robinson, Daniel A. Laheru, Jane Wang, Timothy M. Pawlik, Marianna Zahurak, Ross A. Abrams, John L. Cameron, K.M. Jaques-Robinson, Christopher L. Wolfgang, and Joseph M. Herman
- Subjects
Oncology ,Cancer Research ,medicine.medical_specialty ,Radiation ,business.industry ,Internal medicine ,medicine ,Radiology, Nuclear Medicine and imaging ,Pancreatic carcinoma ,business ,Adjuvant chemoradiotherapy ,Resection - Published
- 2009
340. Adjuvant Chemoradiation for Adenocarcinoma of the Body and Tail of the Pancreas: The Johns Hopkins Experience
- Author
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K.J. Redmond, Timothy M. Pawlik, Michael A. Choti, Daniel A. Laheru, Elizabeth A. Sugar, Barish H. Edil, Christopher L. Wolfgang, Hari Nathan, Joseph M. Herman, and John L. Cameron
- Subjects
Oncology ,Cancer Research ,medicine.medical_specialty ,Radiation ,business.industry ,medicine.medical_treatment ,medicine.disease ,medicine.anatomical_structure ,Internal medicine ,medicine ,Adenocarcinoma ,Radiology, Nuclear Medicine and imaging ,Pancreas ,business ,Adjuvant - Published
- 2009
341. Outcomes and Long-term Survival with Adjuvant Chemoradiation Therapy for Duodenal Adenocarcinoma
- Author
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Elizabeth A. Sugar, Daniel A. Laheru, R. Tuli, John L. Cameron, Joseph M. Herman, Christopher L. Wolfgang, George A. Poultsides, Jane Wang, and Richard D. Schulick
- Subjects
Oncology ,Cancer Research ,medicine.medical_specialty ,Radiation ,business.industry ,medicine.medical_treatment ,Internal medicine ,Long term survival ,medicine ,Radiology, Nuclear Medicine and imaging ,Duodenal adenocarcinoma ,business ,Adjuvant - Published
- 2009
342. Integrated development of s-trans, trans-farnesylthiosalicyclic acid (FTS, salirasib) in advanced pancreatic cancer
- Author
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Michelle A. Rudek, Dung T. Le, Daniel A. Laheru, M. Angenendt, N. V. Rajeshkumar, Sheila Linden, Gretchen E. Taylor, Manuel Hidalgo, Ross C. Donehower, H. Goldsweig, and Antonio Jimeno
- Subjects
Cancer Research ,medicine.medical_specialty ,biology ,Cell growth ,business.industry ,Farnesyltransferase ,Cancer ,medicine.disease ,Gemcitabine ,Endocrinology ,medicine.anatomical_structure ,Oncology ,Ras Signaling Pathway ,Prenylation ,Pancreatic cancer ,Internal medicine ,biology.protein ,medicine ,Cancer research ,Pancreas ,business ,medicine.drug - Abstract
4529 Background: The Ras signaling pathway stands as a strategic target in pancreatic cancer. S-trans,trans-farnesylthiosalicyclic acid (FTS) inhibits Ras dependent cell growth by dislodging all of the isoforms of Ras from membrane binding sites. Here we studied the activity of this agent in patients with advanced pancreatic cancer. Methods: Patients with treatment naïve advanced peri-ampullary cancer were treated with gemcitabine (Gem) administered at standard dose and schedule + FTS administered orally at doses of 200–800 mg bid 21 days of a 28 day cycle. Patients were treated until progression or protocol defined DLT. Plasma samples were collected when FTS was administered alone (C1D7 or C1D22) and in combination (C1D15 or C1D8) to characterize FTS pharmacokinetics. Plasma samples were collected when Gem was administered alone (C1D1) and in combination (C1D15 or C1D8) to characterize Gem pharmacokinetics. PBMCs and tissue biopsies pre treatment and during cycle 1 were collected to characterize the effect of Gem + FTS on levels of activated Ras protein. Treatment efficacy was assessed every other cycle. Results: Thirteen patients (8 male, 5 female, ages 40 to 80, ECOG 0–1) are enrolled to date. The most common adverse events were neutropenia, anemia, abdominal cramping, elevated liver function tests and diarrhea. At the time of this analysis, the progression free survival for these 13 patients is 4.7 months with median survival of >10.8 months and 1 year survival of 50%. Conclusions: 1. Salirasib in combination with gemcitabine appears to be safe with no PK interaction. 2. Salirasib in combination with gemcitabine at doses to 800 mg b.i.d. did not reach conventional MTD, although dose related diarrhea suggests better tolerance at doses up to 600 mg b.i.d. 3. Salirasib at doses of 400 to 800 mg b.i.d. in combination with gemcitabine demonstrated a PFS, MS and 1 year survival of 4.7 months, >10.8 months and 50% respectively. 4. Salirasib mechanism of Ras inhibition is confirmed by reduction of tumor Ras in pancreatic cancer patients. 5. Salirasib warrants evaluation in a controlled study with gemcitabine in pancreatic cancer; doses of 600 or 400 mg b.i.d. are recommended. No significant financial relationships to disclose.
- Published
- 2009
343. Plasma IL-6 level and survival of pancreatic cancer patients treated with a VEGFR inhibitor, vatalanib (PTK/ZK)
- Author
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Tomislav Dragovich, Manuel Hidalgo, A. Cui, Amanda F. Baker, D. D. Von Hoff, Daniel A. Laheru, and Christopher J Campen
- Subjects
Cancer Research ,Vatalanib ,Pathology ,medicine.medical_specialty ,biology ,business.industry ,VEGFR Inhibitor ,medicine.disease ,Oncology ,Pancreatic cancer ,Cancer research ,biology.protein ,Medicine ,business ,Interleukin 6 - Abstract
e15514 Background: Use of anti-angiogenesis drugs in pancreatic cancer has not yet resulted in significant clinical improvements and it is unknown if there are subsets of patients with pancreatic cancer that may benefit from this therapeutic approach. We have reported on a phase II trial of PTK/ZK (VEGFR inhibitor) in patients (n=65) who have failed or progressed on gemcitabine. The 6- month OS met the primary endpoint of 29 % and there were 2 partial responses. We investigated some of the plasma proteins relevant for angiogenesis in correlation with clinical outcomes on this trial. Methods: Plasma samples were obtained prior to and after 4 weeks of therapy with PTK/ZK, aliquoted and frozen until assayed. Patient plasma was assayed for: VEGFA, VEGFC, VEGFR1, VEGFR2, FGFb, PDGFBB, OPN, ANG2, IL-6, and sIL-6R (SearchLight, Pierce Biotechnology Multiplex ELISA and IL-6 and sIL-6R using R&D Systems).The Spearmen correlation was utilized to look for correlations and changes from baseline compared to post-treatment levels. The correlation of baseline levels with survival were analyzed using the Cox proportional hazard model. Results: Thirty eight paired patient samples were assayed. A significant correlation of baseline values was found between VEGF-C and VEGFR1 (p=0.0496), VEGF-C and VEGF (0.0092), PDGFB and ANG2 (p=0.0003), IL-6 and ANG2 (p=0.0089), and FGFb and OPN (p=0.0281). A correlation in post-treatment change was observed between VEGF-C and PDGFB (p=0.0008), FGFb and OPN (p=0.0374), PDGFB and ANG2 (p=0.0005), IL-6 and ANG-2 (p=0.0464), and VEGF and IL-6 (p=0.0546). Lower baseline IL-6 levels correlated with longer survival (p=0.0227). A post-treatment decrease in plasma IL-6 levels was significantly associated with improvement in survival (p=0.0457). IL-6 mediates multiple effects including angiogenic and pro-survival signaling and has been proposed as a potential prognostic factor in different malignancies. Conclusions: Of all angiogenesis markers analyzed only a post-treatment decrease in plasma IL-6 correlated with improved survival on study. IL-6 warrants further investigation as a potential marker of sensitivity to anti-angiogenesis therapy, especially in patients with pancreatic cancer. Supported by: 1P50 CA95060; 1PO1CA109552–01A1 [Table: see text]
- Published
- 2009
344. Single nucleotide polymorphisms of TSER, ATM, RecQ1 genes association with survival in pancrease cancer
- Author
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Kathleen M. Murphy, Antonio Jimeno, Colin D. Weekes, Sharyn D. Baker, C. Redlinger, Manuel Hidalgo, Wells A. Messersmith, Daniel A. Laheru, Sujatha Nallapareddy, and Michelle A. Rudek
- Subjects
Cancer Research ,DNA damage ,Colorectal cancer ,business.industry ,Single-nucleotide polymorphism ,Bioinformatics ,medicine.disease ,Gemcitabine ,Capecitabine ,Oncology ,Pancreatic cancer ,medicine ,Cancer research ,Gene polymorphism ,business ,Gene ,medicine.drug - Abstract
e14590 Background: Pancreatic cancer (PaCa) is the 4th leading cause of cancer-related mortality in the U.S . We tried to determine whether ATM, RecQ1 gene polymorphisms correlate with gemcitabine (G) and TSER gene polymorphism with capecitabine (C) response and over all survival(OS). We also tested the hypothesis that PaCa pts homozygous for the S/S variant of the TSER will have a higher 6-month survival with C compared to historical controls. TS expression is regulated by a polymorphism in the TSER and has been shown that pts with S/S variant have high response rate and increased toxicity in colon cancer pts. ATM and recQ1 genes are involved with DNA damage response and repair and correlate with G response. Methods: DNA isolated from peripheral blood samples in 82 pts with Stage IV pancreatic cancer was tested for the TSER, ATM and RecQ1 gene polymorphisms. All patients were treated with G 1,000mg/m2 wkly for 3/4 wks. Pts homozygous for the S/S variant were treated with C, 2,000 mg/m2/day for 14 /21days. Pts were evaluated for response to therapy according to the RECIST. Results: 16 pts (19.5%) were positive for S/S variant of TSER, but only 4 (4.8%) were treated. The reasons for declining treatment were geographic, logistic or progression issues. Only 1 pt was evaluable, receiving at least 3 cycles of C . All pts needed dose reductions due to toxicities. Grade 3 hand foot syndrome, diarrhea and vomiting were dose limiting toxicities. No complete or partial responses were seen. The pt who received 3 cycles came off study due to progressive disease and the other 3 pts came of the study due to toxicities. TSER polymorphism was correlated to OS and only S/S variant was significant with a trend towards improved OS by log rank test and Kaplan Meier plot. ATM and RecQ1 gene polymorphisms subtypes did not correlate with G response and OS ( not statistically significant). Conclusions: Our study represents an initial effort to apply pharmacogenetics to PaCa therapy. 19.5% of pts had the S/S variant of the TSER polymorphism, but only 4.8% enrolled. C administration was associated with excess toxicity. The toxicities observed in this study appear to outweigh the benefit of using C in this pt population. There is no correlation between ATM and RecQ1 genotypes with OS. However the sample size is too small to draw conclusions. [Table: see text]
- Published
- 2009
345. SPARC correlation with response to gemcitabine (G) plus nab-paclitaxel (nab-P) in patients with advanced metastatic pancreatic cancer: A phase I/II study
- Author
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Daniel A. Laheru, T. E. Wood, Lon Smith, Mitesh J. Borad, Manuel Hidalgo, Neil P. Desai, R. K. Ramanathan, Jose Iglesias, D. D. Von Hoff, and Ronald L. Korn
- Subjects
Oncology ,Cancer Research ,medicine.medical_specialty ,business.industry ,medicine.disease ,Gemcitabine ,Phase i ii ,Stroma ,Internal medicine ,Pancreatic cancer ,Metastatic pancreatic cancer ,medicine ,In patient ,business ,Cysteine ,medicine.drug ,Nab-paclitaxel - Abstract
4525 Background: Pancreatic cancer cells and surrounding stroma are known to overexpress SPARC (secreted protein acid rich in cysteine), which is associated with poor clinical outcomes. nab-P, an albumin-bound nanoparticle form of paclitaxel increased tumor accumulation of paclitaxel through binding of albumin to SPARC. This disease specific phase 1 study was designed to evaluate the safety and efficacy of G + nab-P and the correlation of response with tumor SPARC and serum CA19–9 levels. Methods: nab-P doses (100–150 mg/m2) + (G) (1000 mg/m2) were given on days 1, 8, and 15 of a 28-day cycle to pts with metastatic pancreatic adenocarcinoma and with no prior chemotherapy for their metastatic disease. Level 3 SPARC staining by immunohistochemistry was considered positive. Results: 63 pts received treatment. The most common grade 3 and 4 adverse event that occurred in >20% of pts was neutropenia. Nine (18%) pts and 4 (8%) pts had a grade 3/4 event, respectively. Neuropathy was also observed. One combination-associated death due to sepsis occurred at the 150 mg/m2 nab-P level. Serial PET scans of 53 pts with outside adjudication to date showed 12 (23%) complete responses, 29 (55%) partial responses (PRs) and 4 (8%) stable disease (SD). By RECIST criteria, of the 49 pts evaluable to date, 1(2%) had CR, 12 (24%) had PR, and 20 (41%) had SD. The median survival was 9 months to date. SPARC data were available for 35 pts, of which 10 (29%) were SPARC+ and 25 (71%) were SPARC-. Of these, 27 pts had evaluable response data. Pts that were SPARC+ (8/27) were more likely to be responders (6/8, 75%) than pts who were SPARC- (5/19, 26%), P = 0.03, Fisher's exact test. Median progression-free survival (PFS) increased from 4.8 months for SPARC- pts (22 pts) to 6.2 months for SPARC+ pts (9 pts); however, these data are still immature. Of 45 pts with elevated CA19–9 at baseline, 42 (93%) had maximum decrease of >40% with a median maximum decrease of 92%. Conclusions: The combination of nab-P and G was generally well tolerated and had substantial enough antitumor activity in patients with pancreatic cancer to warrant a phase III clinical trial. SPARC+ status in these patients was associated with higher response rate and longer PFS. [Table: see text]
- Published
- 2009
346. Current Cancer Therapeutics
- Author
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Daniel A. Laheru
- Subjects
Oncology ,Cancer Research ,medicine.medical_specialty ,business.industry ,Internal medicine ,medicine ,Cancer ,Current (fluid) ,business ,medicine.disease - Published
- 1999
347. A Phase I Tolerability and Pharmacokinetic Study of Adjuvant Erlotinib (E) and Capecitabine (Cap) with Concurrent Radiation (RT) in Resected Pancreatic Cancer (PanCa)
- Author
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W. Ma, A. Howard, Joseph M. Herman, Ross C. Donehower, Yasmin Khan, Wells A. Messersmith, Michelle A. Rudek, Manuel Hidalgo, Daniel A. Laheru, and Antonio Jimeno
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Oncology ,Cancer Research ,medicine.medical_specialty ,Radiation ,biology ,business.industry ,Panca ,medicine.medical_treatment ,biology.organism_classification ,medicine.disease ,Capecitabine ,Pharmacokinetics ,Tolerability ,Internal medicine ,Pancreatic cancer ,medicine ,Radiology, Nuclear Medicine and imaging ,Erlotinib ,business ,Adjuvant ,medicine.drug - Published
- 2008
348. Phase II trial of vatalinib in patients with advanced or metastatic pancreatic adenocarcinoma who failed gemcitabine therapy
- Author
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Vanessa Bolejack, Lon Smith, H. A. Burris, John Crowley, P. J. Rosen, Daniel A. Laheru, Tomislav Dragovich, D. D. Von Hoff, Manuel Hidalgo, and John E. Seng
- Subjects
Oncology ,Cancer Research ,medicine.medical_specialty ,biology ,business.industry ,VEGF receptors ,Metastatic Pancreatic Adenocarcinoma ,Receptor tyrosine kinase ,Gemcitabine ,medicine.anatomical_structure ,Internal medicine ,biology.protein ,medicine ,In patient ,Receptor ,Pancreas ,business ,Platelet-derived growth factor receptor ,medicine.drug - Abstract
4615 Background: Adenocarcinomas of the pancreas overexpress VEGF and PDGF receptors, both targeted by vatalinib, a small molecule inhibitor of receptor tyrosine kinases. We have examined the ramp-...
- Published
- 2008
349. A phase I study of MORab-009, a monoclonal antibody against mesothelin, in mesothelioma, pancreatic and ovarian cancer
- Author
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Raffit Hassan, Julie R. Brahmer, M. Phillips, Susan C. Weil, Steven J. Cohen, Daniel A. Laheru, Deborah K. Armstrong, Ira Pastan, and Elizabeth M. Jaffee
- Subjects
Cancer Research ,Pathology ,medicine.medical_specialty ,endocrine system diseases ,biology ,medicine.drug_class ,business.industry ,Cell ,Monoclonal antibody ,medicine.disease ,respiratory tract diseases ,Phase i study ,medicine.anatomical_structure ,Oncology ,Pancreatic cancer ,biology.protein ,medicine ,CA19-9 ,Mesothelin ,Mesothelioma ,Ovarian cancer ,business - Abstract
3578 Background: MORAb-009 is a monoclonal antibody that targets mesothelin, a cell surface adhesion protein over-expressed in pancreatic cancer, mesothelioma and other malignancies, with minimal e...
- Published
- 2008
350. Abstract 5000: The functional stem cell marker aldehyde dehydrogenase enhances pancreatic cancer stem cell isolation and correlates with clinical prognosis
- Author
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William Matsui, Zeshaan A. Rasheed, Anirban Maitra, Seung-Mo Hong, Antonio Jimeno, David M. Berman, Jan-Bart Koorstra, Irwin Freed, Manuel Hidalgo, Qiuju Wang, Jie Yang, Daniel A. Laheru, and Xiaobing He
- Subjects
Cancer Research ,education.field_of_study ,Pathology ,medicine.medical_specialty ,biology ,business.industry ,CD44 ,Population ,Cell ,Aldehyde dehydrogenase ,Stem cell marker ,medicine.disease ,medicine.anatomical_structure ,Oncology ,Cancer stem cell ,Pancreatic cancer ,biology.protein ,medicine ,Cancer research ,education ,Clonogenic assay ,business - Abstract
Pancreatic adenocarcinoma is a highly aggressive cancer that is largely resistant to current therapies and portends a median survival for patients of 9-12 months. Resistance may be due to a subpopulation of cells that are chemoresistant and able to support tumor propagation, such as cancer stem cells (CSCs). CSCs have emerged as attractive therapeutic targets, but the development of effective therapies requires the isolation of highly purified cell populations. Surface antigen expression has been used to identify CSC in most systems, however, methods based on functional properties, such as Hoechst dye exclusion or aldehyde dehydrogenase (ALDH) activity, can enhance stem cell isolation from normal and malignant tissues. We compared CSCs from pancreatic adenocarcinomas isolated by cell surface phenotype, ALDH activity, or both. Initially, we studied ALDH expression in human pancreatic cancer cell lines (CAPAN-1, DAN-G, CFPAC-1) using the Aldefluor assay. We found that each line contained a small population of ALDH+ cells (0.9-6.5% of total cells) that demonstrated increased clonogenic growth potential both in vitro and in vivo compared to ALDH- cells. Next, we compared ALDH expression with the published pancreatic CSC phenotype (CD24+CD44+) in cell lines and low-passage xenografts derived from primary human tumor specimens. Interestingly, we found that the putative CSC populations were only partially overlapping since 7-18.2% of the ALDH+ cells were CD44+CD24+ and only 4.2-36.2% of the CD44+CD24+ cells expressed ALDH. We compared CD44+CD24+ and CD44+CD24+ALDH+ cells isolated from 5 unique human pancreatic cancer xenografts and found that the CD44+CD24+ALDH+ cells were more tumorgenic in NOD/SCID mice. We also evaluated ALDH expression in primary pathologic specimen from 268 patients with pancreatic cancer by immunohistochemistry and found small, intensely positive cells with round or oval nuclei near the base of cancerous glands or at the invasive front in 90 (34%) of those patients. Furthermore, the presence of these cells was significantly associated with poorer overall survival (14 vs. 18 mos, p=0.02). We have begun to evaluate the mechanism by which pancreatic CSCs may be involved in more aggressive disease and found that CD44+CD24+ALDH+ cells isolated from tumor xenografts have significantly lower expression of E-cadherin and higher expression of Slug, a transcriptional repressor of E-cadherin, compared to ALDH+ or ALDH- cells. Therefore, ALDH appears to mark highly clonogenic pancreatic CSCs. Moreover, increased features associated with epithelial-to-mesenchymal transition may play a role in the correlation of ALDH+ cells with long-term outcomes.
- Published
- 2008
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