Benjamin R Tan

Washington University in St. Louis, San Luis, Missouri, United States

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Publications (34)188.75 Total impact

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    ABSTRACT: Background Preoperative radiation therapy with 5-fluorouracil chemotherapy is a standard of care for cT3-4 rectal cancer. Studies incorporating additional cytotoxic agents demonstrate increased morbidity with little benefit. We evaluate a template that: (1) includes the benefits of preoperative radiation therapy on local response/control; (2) provides preoperative multidrug chemotherapy; and (3) avoids the morbidity of concurrent radiation therapy and multidrug chemotherapy. Methods and Materials Patients with cT3-4, any N, any M rectal cancer were eligible. Patients were confirmed to be candidates for pelvic surgery, provided response was sufficient. Preoperative treatment was 5 fractions radiation therapy (25 Gy to involved mesorectum, 20 Gy to elective nodes), followed by 4 cycles of FOLFOX [5-fluorouracil, oxaliplatin, leucovorin]. Extirpative surgery was performed 4 to 9 weeks after preoperative chemotherapy. Postoperative chemotherapy was at the discretion of the medical oncologist. The principal objectives were to achieve T stage downstaging (ypT < cT) and preoperative grade 3+ gastrointestinal morbidity equal to or better than that of historical controls. Results 76 evaluable cases included 7 cT4 and 69 cT3; 59 (78%) cN+, and 7 cM1. Grade 3 preoperative GI morbidity occurred in 7 cases (9%) (no grade 4 or 5). Sphincter-preserving surgery was performed on 57 (75%) patients. At surgery, 53 patients (70%) had ypT0-2 residual disease, including 21 (28%) ypT0 and 19 (25%) ypT0N0 (complete response); 24 (32%) were ypN+. At 30 months, local control for all evaluable cases and freedom from disease for M0 evaluable cases were, respectively, 95% (95% confidence interval [CI]: 89%-100%) and 87% (95% CI: 76%-98%). Cases were subanalyzed by whether disease met requirements for the recently activated PROSPECT trial for intermediate-risk rectal cancer. Thirty-eight patients met PROSPECT eligibility and achieved 16 ypT0 (42%), 15 ypT0N0 (39%), and 33 ypT0-2 (87%). Conclusion This regimen achieved response and morbidity rates that compare favorably with those of conventionally fractionated radiation therapy and concurrent chemotherapy.
    International journal of radiation oncology, biology, physics 01/2014; 88(4):829–836. · 4.59 Impact Factor
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    ABSTRACT: The prevalence of vitamin D deficiency among patients with cancer has been previously reported. Because vitamin D is fat soluble, patients with pancreatic adenocarcinoma may have an especially high risk of vitamin D deficiency in association with ongoing and varying degrees of malabsorption. However, little is known about the correlation between vitamin D status and prognosis in these patients. We conducted a retrospective review of vitamin D status in patients with pancreatic adenocarcinoma who were treated at Siteman Cancer Center. Patients' demographic information, clinical staging at the time of vitamin D assessment, vitamin D levels, and survival data were collected. Vitamin D deficiency was defined as a serum 25-hydroxyvitamin D (25[OH]D) level of less than 20 ng/mL, and vitamin D insufficiency was defined as a 25(OH)D level of between 20 ng/mL and 30 ng/mL. Between December 2007 and June 2011, 178 patients with pancreatic adenocarcinoma had their vitamin D levels checked at the time of initial visit at this center. Of these 178 patients, 87 (49%) had vitamin D deficiency, and 44 (25%) had vitamin D insufficiency. The median 25(OH)D level was significantly lower among nonwhite patients and among patients with stage I and II disease. A 25(OH)D level of less than 20 ng/mL was found to be associated with poor prognosis (p = 0.0019) in patients with stage III and IV disease. Vitamin D insufficiency and deficiency were prevalent among patients with pancreatic adenocarcinoma. The vitamin D level appears to be prognostic for patients with advanced pancreatic adenocarcinoma, and its effects should be further examined in a prospective study.
    Journal of Translational Medicine 09/2013; 11(1):206. · 3.46 Impact Factor
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    ABSTRACT: Our purpose was to determine whether geriatric assessments are associated with completion of a chemotherapy course, grade III/IV toxicity or survival in older adults with cancer. In this prospective cohort study, patients aged 65 years and older with colorectal, lung, or breast cancer or lymphoma completed a brief geriatric assessment prior to chemotherapy. Endpoints included completion of the planned number of chemotherapy cycles, grade III/IV toxicity and survival. Multivariate logistic regression determined which factors were independently associated with completion of therapy, grade III/IV toxicity or death. Sixty-five patients were enrolled in the study. The median age was 73 years (range 65-89). Geriatric syndromes were common, including depression (21.5%), dependence on others to carry out instrumental activities of daily living (38.5%) and activities of daily living (10.8%), and comorbidities (mild 47.7%, moderate 20%, severe 15.4%). Of the 65 participants, 67.6% completed the planned number of chemotherapy cycles. Curative intent therapy [OR 4.97 (95% CI 1.21-18.81)], Eastern Cooperative Oncology Group (ECOG) performance status 2-3 [OR 0.089 (0.015-0.53)] and renal function [OR 1.03 (1.00-1.06) per ml/min] were significantly associated with therapy completion. Furthermore, 31.1% experienced grade III/IV non-hematologic toxicity. Moderate to severe comorbidities significantly increased the risk of grade III/IV non-hematologic toxicity [OR 6.13 (1.65-22.74)]. Patients who received chemotherapy with curative intent had lower mortality [HR 0.15 (0.06-0.42)], while patients who reported a fall in the month prior to chemotherapy had an increased risk of death [HR 3.20 (1.13-9.11)]. Geriatric assessment is associated with completion of a planned number of cycles of chemotherapy, grade III/IV non-hematologic toxicity and mortality.
    Journal of Geriatric Oncology 07/2013; 4(3):227-234. · 1.12 Impact Factor
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    ABSTRACT: : Delayed repeated intraperitoneal chemotherapy after cytoreductive surgery for carcinomatosis may be an alternative to intraoperative hyperthermic infusion. : The aim of this study was to evaluate the safety and feasibility of delayed repeated intraperitoneal chemotherapy after cytoreduction of colorectal and appendiceal carcinomatosis and pseudomyxoma peritonei. : This study constitutes a retrospective case series. : This study was conducted at a single institution. : A total of 31 patients with peritoneal carcinomatosis (23) and pseudomyxoma peritonei (8) were included. : Cytoreduction was followed by placement of an adhesion barrier and intraperitoneal catheters. Peritoneal scintigraphy preceded biweekly intraperitoneal 5-fluorouracil and systemic combination chemotherapy with leucovorin, fluorouracil, and oxaliplatin (FOLFOX). : The primary outcomes measured are safety, feasibility, and short-term survival. : Cytoreduction to a score of 0 to 1 was possible in 25 patients (80%). Complications occurred in 16 patients (51.6%) and were confined to grades I to III. There were no deaths, and no digestive fistulae occurred. Port malfunction or complication resulted in removal in 5 patients (16.1%). Intraperitoneal chemotherapy was possible in 83.8% of patients; 55% completed the full course. Peritoneal scintigraphy demonstrated free diffusion of tracer in 18 patients (58%), 4 (12.9%) had diffusion in each gutter with limited communication, 5 (16.1%) had limited diffusion around each catheter without communication, and 2 (6.5%) had no diffusion on scintigraphy. Overall survival for peritoneal carcinomatosis was 44.5% at 3 years (95% CI = 23%-65%). : The nonrandomized nature of this study and the early experience are limitations. : Delayed repeated intraperitoneal and systemic chemotherapy after cytoreduction is feasible and has acceptable morbidity rates. Delayed intraperitoneal chemotherapy is possible in 83% of patients.
    Diseases of the Colon & Rectum 10/2012; 55(10):1044-52. · 3.34 Impact Factor
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    ABSTRACT: Purpose This phase I study was conducted to determine the safety profile and maximum tolerated dose (MTD) of IMP321, a soluble lymphocyte activation gene-3 (LAG-3) Ig fusion protein and MHC Class II agonist, combined with gemcitabine in patients with advanced pancreatic adenocarcinoma. Patients and methods Patients with advanced pancreatic adenocarcinoma were treated with gemcitabine (1,000 mg/m(2))(level 1), gemcitabine (1,000 mg/m(2)) plus IMP 321 at 0.5 mg (level 2) and 2.0 mg (level 3), respectively. Safety, toxicity, and immunological markers at baseline and post treatment were assessed. Results A total of 18 patients were enrolled to the study, and 17 were evaluable for toxicity. None of the 6 patients who received 0.5 mg IMP321 experienced IMP321-related adverse events. Of the 5 patients who received IMP321 at the 2 mg dose level, 1 experienced rash, 1 reported hot flashes and 2 had mild pain at the injection sites. No severe adverse events previously attributed to IMP321 were observed. No significant differences were observed when comparing pre- and post-treatment levels of monocytes (CD11b+CD14+), conventional dendritic cells (CD11c+) or T cell subsets (CD4, CD8). Conclusions IMP321 in combination with gemcitabine is a well-tolerated regimen. IMP321 did not result in any severe adverse events. No incremental activity observed for the additional IMP 321 to gemcitabine at the dose levels evaluated, likely due to sub-optimal dosing. Immunological markers suggested that higher dose levels of IMP321 are needed for future clinical studies.
    Investigational New Drugs 08/2012; · 3.50 Impact Factor
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    ABSTRACT: Combination chemotherapy with FOLFIRINOX (oxaliplatin, irinotecan, fluorouracil, and leucovorin) was shown to be effective in a large phase III trial. The purpose of this study was to examine the tolerance and effectiveness of FOLFIRINOX as practiced outside of the confines of a clinical trial and to document any dose modifications used by practicing oncologists. Data on patients with all stages of pancreatic adenocarcinoma treated with FOLFIRINOX at three institutions was analyzed for efficacy, tolerance, and use of any dose modifications. Total of 61 patients was included in this review. Median age was 58 years (range: 37 to 72 years), 33 were male (54.1%) and majority had ECOG performance of 0 or 1 (86.9%, 53 patients). Thirty-eight (62.3%) had metastatic disease, while 23 (37.7%) were treated for locally advanced or borderline resectable disease. Patients were treated with a median number of four cycles of FOLFIRINOX, with dose modifications in 58.3% (176/302) of all cycles. Ten patients had stable disease (16.4%), four had a partial response (6.6%) while eight had progressive disease (13.1%) on best imaging following therapy. Median progression-free survival and overall survival were 7.5 months and 13.5 months, respectively. The most common grade 3-4 adverse event was neutropenia at 19.7% (12 cases), with 4.9% (3 cases) rate of febrile neutropenia. Twenty-one patients (34.4%) were hospitalized as a result of therapy but there were no therapy-related deaths. Twenty-three (37.7%) had therapy eventually discontinued as a result of adverse events. Despite substantial rates of adverse events and use of dose modifications, FOLFIRINOX was found to be clinically effective in both metastatic and non-metastatic patients. Regimen toxicity did not detract from overall response and survival.
    JOP: Journal of the pancreas 01/2012; 13(5):497-501.
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    ABSTRACT: There is a large degree of variation in tumour response and host toxicities associated with neoadjuvant chemoradiation for rectal cancer patients. We performed a complimentary pharmacogenetic study to investigate germline polymorphisms of genes involved in 5-fluorouracil (5-FU) and irinotecan pathways and their potential association with clinical outcomes and toxicities from neoadjuvant chemoradiation in patients with rectal cancer treated in a prospective genotype-directed study. The germline DNA of 131 patients was genotyped for 10 variants in TYMS, MTHFR, DPYD, UGT1A1, ABCC1 and SLCO1B1 genes. Ninety-six patients were treated with 5-FU/radiotherapy (RT) and 35 received 5-FU/RT/irinotecan. Relationships between genetic variants and adverse events, tumour response, overall and disease-free survivals were assessed. MTHFR 1298A>C and MTHFR diplotypes (for 677C>T and 1298A>C) were associated with chemoradiation-related toxicity when 5-FU was used alone. MTHFR haplotypes (677C-1298C) and diplotypes (CA-TA and TA-TA) showed, respectively, a protective and a negative effect on the incidence of severe diarrhoea or mucositis. No association was observed between genetic markers and drug response. MTHFR polymorphisms can potentially predict toxicity in patients treated with 5-FU as a single chemotherapeutic drug.
    British Journal of Cancer 11/2011; 105(11):1654-62. · 5.08 Impact Factor
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    ABSTRACT: The purpose of this study was to assess the efficacy and safety of 5-fluorouracil (5FU) and gemcitabine administered concurrently with radiation in patients with locally advanced, nonmetastatic pancreatic cancer. Eligible patients had histologically confirmed pancreatic adenocarcinoma deemed locally unresectable without evidence of metastatic disease. In addition, all patients underwent laparoscopy or laparotomy before study entry to rule out peritoneal carcinomatosis. Patients received radiation therapy (50.4 Gy) with concurrent infusional 5FU (200 mg/m(2) 5 days/week) and weekly gemcitabine (200 mg/m(2) ). After a 3-week break, patients received weekly gemcitabine at 1000 mg/m(2) for 3 of 4 weeks, for 4 cycles. The primary endpoint of the trial was the proportion of patients surviving 9 months from study entry. Secondary endpoints included objective tumor response, CA19-9 response, overall survival (OS) time to progression (TTP), and toxicity. Between November 2001 and October 2004, 81 patients were enrolled, 78 of whom were eligible for analysis. With a median follow-up of 55.2 months, the median OS was 12.2 months (95% confidence interval [CI], 10.9-14.9) and the median TTP was 10 months (95% CI, 6.4-12.0). An objective tumor response was seen in 19 patients (25%), and among 56 patients with an elevated CA19-9 at baseline, 29 (52%) had a sustained CA19-9 response. Overall, 41% of patients had grade 3 or greater treatment-related gastrointestinal adverse events. The combination of 5FU, gemcitabine, and radiation is well tolerated. Survival is comparable with the best results of other recent studies of 5FU and radiation or gemcitabine and radiation.
    Cancer 06/2011; 117(12):2620-8. · 5.20 Impact Factor
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    ABSTRACT: UCN-01 (7-hydroxystaurosporine) is a multi-targeted protein kinase inhibitor that exhibits synergistic activity with DNA-damaging agents in preclinical studies. We conducted a Phase I study to determine the maximum-tolerated dose (MTD), dose-limiting toxicity (DLT), pharmacokinetic, and pharmacodynamic effects of UCN-01 and irinotecan in patients with resistant solid tumors. Patients received irinotecan (75-125 mg/m(2) IV on days 1, 8, 15, 22) and UCN-01 (50-90 mg/m(2) IV on day 2 and 25-45 mg/m(2) on day 23 and subsequent doses) every 42 days. Blood for pharmacokinetics of UCN-01 and irinotecan, and blood, normal rectal mucosa, and tumor biopsies for pharmacodynamic studies were obtained. Twenty-five patients enrolled to 5 dose levels. The MTD was irinotecan 125 mg/m(2) on days 1, 8, 15, 22 and UCN-01 70 mg/m(2) on day 2 and 35 mg/m(2) on day 23. DLTs included grade 3 diarrhea/dehydration and dyspnea. UCN-01 had a prolonged half-life and a low clearance rate. There was a significant reduction in SN-38 C(max) and aminopentanocarboxylic acid (APC) and SN-38 glucuronide half-lives. Phosphorylated ribosomal protein S6 was reduced in blood, normal rectal mucosa, and tumor biopsies at 24 h post-UCN-01. Two partial responses were observed in women with ER, PgR, and HER2-negative breast cancers (TBNC). Both tumors were defective for p53. Twelve patients had stable disease (mean duration 18 weeks, range 7-30 weeks). UCN-01 and irinotecan demonstrated acceptable toxicity and target inhibition. Anti-tumor activity was observed and a study of this combination in women with TNBC is underway.
    Cancer Chemotherapy and Pharmacology 06/2011; 67(6):1225-37. · 2.80 Impact Factor
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    ABSTRACT: Downstaging (DS) of rectal cancers is achieved in approximately 45% of patients with neoadjuvant fluorouracil (FU) -based chemoradiotherapy (CRT). Polymorphisms in the thymidylate synthase gene (TYMS) had previously defined two risk groups associated with disparate tumor DS rates (60% v 22%). We conducted a prospective single-institution phase II study using TYMS genotyping to direct neoadjuvant CRT for patients with rectal cancer. Patients with T3/T4, N0-2, M0-1 rectal adenocarcinoma were evaluated for germline TYMS genotyping. Patients with TYMS *2/*2, *2/*3, or *2/*4 (good risk) were treated with standard chemoradiotherapy using infusional FU at 225 mg/m²/d. Patients with TYMS *3/*3 or *3/*4 (poor risk) were treated with FU/RT plus weekly intravenous irinotecan at 50 mg/m². The primary end point was pathologic DS. Secondary end points included complete tumor response (ypT0), toxicity, recurrence rates, and overall survival. Overall, 135 patients were enrolled, of whom 27.4% (37 of 135) were considered poor risk. The prespecified statistical goals were achieved, with DS and ypT0 rates reaching 64.4% and 20% for good-risk and 64.5% and 42% for poor-risk patients, respectively. To our knowledge, this is the first study to prospectively use TYMS genotyping to direct neoadjuvant CRT in patients with rectal cancer. High rates of DS and ypT0 were achieved among both risk groups when personalized treatment was based on TYMS genotype. These results are encouraging, and further evaluation of this genotype-based strategy using a randomized study design for locally advanced rectal cancer is warranted.
    Journal of Clinical Oncology 01/2011; 29(7):875-83. · 18.04 Impact Factor
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    ABSTRACT: Polymorphisms in the 5' regulatory region of the thymidylate synthase gene (TYMS) have been shown to modulate thymidylate synthase expression and are associated with resistance to fluoropyrimidine-based therapies. These polymorphisms include a two repeat (2R) or three repeat (3R) of a 28-bp sequence and a G>C SNP in the second repeat of the 3R allele (TSER*3 G>C). Genotyping methods for the TYMS 5'-UTR polymorphisms have typically involved visualizing PCR and RFLP products on agarose gels. This article describes the use of a robust capillary electrophoresis assay for TYMS 5'-UTR genotyping. As part of pharmacogenetic studies, we performed TYMS genotyping for the 5'-UTR polymorphisms in 314 colorectal cancer patients. A gel-based capillary electrophoresis method, employing a high-resolution gel cartridge on a QIAxcel(®) system, was developed to detect PCR products and RFLP fragment sizes. The high resolution of the capillary electrophoresis technique allowed identification of a 6-bp insertion in the second repeat of the 3R allele in three patients. The frequency of the insertion allele was 0.4% in Caucasians and 1.3% in African-Americans. We also found 3.3% of Caucasian patients were heterozygous for a G>C SNP in the first repeat of the 2R allele, but this allele was not observed in the African-American patients. We describe a robust RFLP genotyping technique that employs size discrimination by capillary electrophoresis to genotype the TYMS TSER*3 G>C SNP. The technique also allows identification of a 6-bp insertion in the 3R allele, and we report the allelic frequencies for two uncommon TSER alleles.
    Pharmacogenomics 12/2010; 11(12):1751-6. · 3.86 Impact Factor
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    ABSTRACT: OBJECTIVES: To determine the combined effect of age and comorbidity on receipt of chemotherapy and its impact on survival in elderly patients with stage III colorectal cancer (CRC). MATERIALS AND METHODS: All patients over age 65 with Stage III CRC diagnosed 1996-2006 were identified from the Barnes-Jewish Hospital Oncology Data Services registry. An age/comorbidity staging system was created using the ACE-27 comorbidity index and data from both Stage II and III CRC. The staging system was then applied to patients with Stage III CRC. Odds of receiving chemotherapy were calculated, and survival analyses determined the impact of chemotherapy on overall survival in each age/comorbidity stage. RESULTS: 435 patients with Stage III CRC were evaluated [median age 75 years (range 65-99)]. Advancing age/comorbidity stage (Alpha, Beta, Gamma) was associated with decreasing odds of receiving chemotherapy for Stage III CRC [Odds Ratio 0.83 (95% CI, 0.51-1.35) for Beta and 0.14 (95% CI, 0.08-0.24) for Gamma, compared to Alpha]. Chemotherapy was associated with lower risk of death in each of the age/comorbidity stages, compared to those who underwent surgery only. The hazard ratio for death in patients who did not receive chemotherapy, relative to those who did, within each age/comorbidity stage was 1.8 [95%CI 1.06-3.06] for Alpha, 2.24 [95%CI 1.38-3.63] for Beta and 2.10 [95% CI 1.23-3.57] for Gamma. CONCLUSION: While stage III CRC patients with increasing age and comorbidity are less likely to receive chemotherapy, receipt of chemotherapy is associated with a lower risk of death.
    Journal of Geriatric Oncology 10/2010; 1(2):48-56. · 1.12 Impact Factor
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    ABSTRACT: Only recently has a standard chemotherapy regimen, gemcitabine plus cisplatin, been established for advanced biliary tract cancers (BTCs) based on a phase III randomized study. The aim of this phase II single-institution trial was to assess the efficacy and safety of gemcitabine combined with carboplatin in the first-line treatment of patients with advanced BTCs. Patients with histologically proven BTCs, including cholangiocarcinoma or gallbladder and ampullary carcinomas, were treated with a maximum of nine cycles of intravenous (i.v.) gemcitabine at 1000 mg/m(2) over 30 min on days 1 and 8 with i.v. carboplatin dosed at an area-under-the-curve (AUC) of 5 over 60 min on day 1 of a 21-day cycle. A total of 48 patients with advanced BTCs (35 cholangiocarcinoma, 12 gallbladder and 1 ampullary cancer) were enrolled. A median of four cycles were administered (range: 1-9). The overall response rate for evaluable patients was 31.1%. Median progression-free survival, overall survival and 6-month survival rates are 7.8 months, 10.6 months and 85.4%, respectively. The most common grade 3-4 toxicities include neutropenia and thrombocytopenia. Grade 3 or 4 non-haematological toxicities were rare. Gemcitabine combined with carboplatin has activity against advanced BTCs. Our results are comparable to other gemcitabine-platinum or gemcitabine-fluoropyrimidine combinations in advanced BTCs.
    HPB 08/2010; 12(6):418-26. · 1.94 Impact Factor
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    ABSTRACT: Preclinical studies have shown synergism between topoisomerase I and II inhibitors. We conducted a phase I study evaluating the combination of pegylated liposomal doxorubicin and irinotecan in patients with previously treated solid tumors. Twelve patients were enrolled. The median age was 62 years (range 19-72). The most common grade 3/4 toxicities were neutropenia (dose-limiting toxicity), diarrhea and nausea/vomiting. The maximal tolerated dose and recommended schedule were pegylated liposomal doxorubicin 20 mg/m(2) over 60 min on day 1, followed by irinotecan 100 mg/m(2) over 90 min on days 1 and 8 of a 21-day cycle. There were no objective clinical responses, but 5 patients achieved stable disease lasting a median of 11 weeks duration (range 2-35). This regimen should be further studied in patients with tumors known to have a sensitivity to both topoisomerase I and II inhibitors such as ovarian and small cell carcinoma.
    Chemotherapy 12/2009; 55(6):441-5. · 2.07 Impact Factor
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    ABSTRACT: Mesothelin is a glycoprotein expressed on normal mesothelial cells and is overexpressed in several histologic types of tumors including pancreatic adenocarcinomas. A soluble form of mesothelin has been detected in patients with ovarian cancer and malignant mesothelioma, and has prognostic value. Mesothelin has also been considered as a target for immune-based therapies. We conducted a study on the potential clinical utility of mesothelin as a biomarker for pancreatic disease and therapeutic target pancreatic cancer. Tumor cell-bound and soluble mesothelin in patients was evaluated by immunohistochemistry and ELISA, respectively. The in vitro cellular immune response to mesothelin was evaluated by INF gamma ELISA and intracellular cytokine staining for IFN gamma in CD4(+) and CD8(+) T cells. The level of circulating antibodies to mesothelin was measured by ELISA. All tumor tissue from patients with pancreatic adenocarcinoma expressed mesothelin (n = 10). Circulating mesothelin protein was detected in patients with pancreatic adenocarcinoma (73 of 74 patients) and benign pancreatic disease (5 of 5) but not in healthy individuals. Mesothelin-specific CD4(+) and CD8(+) T cells were generated from peripheral blood lymphocytes of patients with pancreatic cancer in 50% of patients compared with only 20% of healthy individuals. Antibodies reactive to mesothelin were detected in <3% of either patients or healthy individuals. Circulating mesothelin is a useful biomarker for pancreatic disease. Furthermore, mesothelin-specific T cells can be induced in patients with pancreatic cancer. This suggests that mesothelin is a potential target for immune-based intervention strategies in pancreatic cancer.
    Clinical Cancer Research 11/2009; 15(21):6511-8. · 7.84 Impact Factor
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    ABSTRACT: Gastrointestinal stromal tumour is the most common sarcoma of the intestinal tract. Imatinib mesylate is a small molecule that inhibits activation of the KIT and platelet-derived growth factor receptor alpha proteins, and is effective in first-line treatment of metastatic gastrointestinal stromal tumour. We postulated that adjuvant treatment with imatinib would improve recurrence-free survival compared with placebo after resection of localised, primary gastrointestinal stromal tumour. We undertook a randomised phase III, double-blind, placebo-controlled, multicentre trial. Eligible patients had complete gross resection of a primary gastrointestinal stromal tumour at least 3 cm in size and positive for the KIT protein by immunohistochemistry. Patients were randomly assigned, by a stratified biased coin design, to imatinib 400 mg (n=359) or to placebo (n=354) daily for 1 year after surgical resection. Patients and investigators were blinded to the treatment group. Patients assigned to placebo were eligible to crossover to imatinib treatment in the event of tumour recurrence. The primary endpoint was recurrence-free survival, and analysis was by intention to treat. Accrual was stopped early because the trial results crossed the interim analysis efficacy boundary for recurrence-free survival. This study is registered with ClinicalTrials.gov, number NCT00041197. All randomised patients were included in the analysis. At median follow-up of 19.7 months (minimum-maximum 0-56.4), 30 (8%) patients in the imatinib group and 70 (20%) in the placebo group had had tumour recurrence or had died. Imatinib significantly improved recurrence-free survival compared with placebo (98% [95% CI 96-100] vs 83% [78-88] at 1 year; hazard ratio [HR] 0.35 [0.22-0.53]; one-sided p<0.0001). Adjuvant imatinib was well tolerated, with the most common serious events being dermatitis (11 [3%] vs 0), abdominal pain (12 [3%] vs six [1%]), and diarrhoea (ten [2%] vs five [1%]) in the imatinib group and hyperglycaemia (two [<1%] vs seven [2%]) in the placebo group. Adjuvant imatinib therapy is safe and seems to improve recurrence-free survival compared with placebo after the resection of primary gastrointestinal stromal tumour. US National Institutes of Health and Novartis Pharmaceuticals.
    The Lancet 03/2009; 373(9669):1097-104. · 39.06 Impact Factor
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    ABSTRACT: To evaluate the factors associated with disease control and morbidity after radiotherapy for anal carcinoma. Between 1975 and 2005, 194 patients with localized epidermoid anal carcinoma underwent radiotherapy. Treatment evolved from radiotherapy with or without surgery, to preoperative chemoradiotherapy, to definitive chemoradiotherapy (CRT). The radiotherapy techniques also evolved. With a median follow-up of 61 months, 57 patients had persistence or recurrence, 9 of whom were successfully salvaged, resulting in 146 (75%) ultimately free of disease (UNED). Univariate analysis for UNED survival showed a strong association with the T and N stage (5-year UNED rate, 88.5% +/- 3.4% for those with Stage T1-T2N0; 70.1% +/- 4.2% for Stage T3N0; and 52.7% +/- 6.6% for Stage III; p > .001) and mobility on palpation (5-year UNED rate, 89.2% +/- 4.6% for those with mobile tumors vs. 59.3% +/- 6.1% for those with tethered/fixed tumor; p > .001). No association was found with gender, age, preoperative vs. definitive CRT, or human immunodeficiency virus status. The 20 human immunodeficiency virus+ patients all received CRT. The radiotherapy factors associated with Grade 3 or greater late morbidity included anorectal morbidity with tumor dose (29% with a dose > or =55 Gy vs. 9% otherwise), small bowel injury with technique (9% with anteroposterior-posteroanterior supine vs. 0.7% with multiple fields prone), and bone injury with femoral head dose (9% with a dose of > or =44 Gy vs. 0.7% otherwise). Of the 194 patients, 56 had 68 additional malignancies, mainly either antedating the anal cancer or outside the radiation fields. Our results have confirmed that CRT is an effective approach. Patients with human immunodeficiency virus can be treated with CRT. Tumor mobility significantly predicts the outcome; the implications for management are discussed. We also discuss the treatment planning implications of the late morbidity findings. The substantial incidence of additional malignancies underscores the importance of full oncologic screening during follow-up.
    International journal of radiation oncology, biology, physics 02/2009; 75(2):428-35. · 4.59 Impact Factor
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    ABSTRACT: The use of radioembolization of hepatic metastases with yttrium-90 ((90)Y) microspheres is increasing. The present report describes the outcomes in a cohort of patients with metastatic liver tumors treated with a resin-based microsphere agent. Thirty patients with colon (n = 13), breast (n = 7), and other primary cancers (n = 10) were treated after the failure of first- and second-line therapy. Overall survival (OS), time to progression (TTP), and time to treatment failure (TTTF) were calculated from the first treatment. Response was measured according to Response Evaluation Criteria In Solid Tumors at interval follow-up imaging. Thirty patients underwent 56 infusions of (90)Y, and 18 remained alive at the end of the study. Fourteen patients (47%) had a partial response or stable disease. OS (604 vs 251 days), TTP (223 vs 87 days), and TTTF (363 vs 87 days) were all significantly longer for patients who had a partial response or stable disease (P < .05). Median OS, TTP, and TTTF for patients with colorectal carcinoma were 357, 112, and 107 days, respectively, versus 638, 118, and 363 days in patients with other metastatic sources. Median survival was not reached for patients with breast carcinoma, and the TTP and TTTF were each 282 days. One patient (3%) experienced grade 3 toxicity (gastrointestinal ulceration). (90)Y microsphere therapy produced promising survival rates compared with systemic salvage options, with minimal toxicity.
    Journal of vascular and interventional radiology: JVIR 09/2008; 19(10):1427-33. · 1.81 Impact Factor
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    ABSTRACT: This is a phase II, single-center, single-arm study of patients with resectable adenocarcinoma of the pancreas who were treated with adjuvant interferon-based chemoradiation followed by gemcitabine. The primary end point was 2-year overall survival, with secondary endpoints being 2-year disease-free survival, and the frequency of grade 3 or 4 toxicity. From April 2002 to September 2005, 53 patients with adenocarcinoma of the pancreas underwent curative resection at a single institution, and subsequently received interferon- and gemcitabine-based adjuvant therapy consisting of external-beam irradiation at a dose of 5040 cGy (25 fractions per 5 weeks) and simultaneous 3-drug chemotherapy consisting of (1) continuous infusion 5-fluorouracil (175 mg/m2); (2) weekly intravenous bolus cisplatin (25 mg/m2); and (3) interferon-alpha (3 million units subcutaneously 3 times per week) during the 6 weeks of radiation. This was followed by two 4-week courses of weekly intravenous infusion of gemcitabine (1000 mg/m2, 3 of 4 weeks). Median follow-up is 38 months. Seventy-seven percent of patients had node-positive disease. Sixteen patients (30%) failed to complete adjuvant therapy, due to disease progression (7 patients), toxicity (7 patients), and consent withdrawal (2 patients). No patients completed planned therapy without dose modification. Median overall survival was 25 months (confidence interval [CI] = 21.5-48.5 months). Actuarial overall survival for the 1-, 2- and 3-year periods were 75% (CI = 61-85%), 56% (CI = 41-69%), and 41% (26-55%), respectively. This phase II trial demonstrated increased patient survival compared with historical controls, and equivalent survival compared with the regimen combining interferon-alpha with 5-fluorouracil-based chemoradiation. Despite these encouraging results, significant concerns regarding dose- and treatment-limiting toxicities remain.
    Annals of surgery 08/2008; 248(2):145-51. · 7.90 Impact Factor
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    ABSTRACT: Oxaliplatin, gemcitabine and capecitabine are all active agents against upper gastrointestinal and pancreaticobiliary cancers. Patients with upper gastrointestinal malignancies treated with 0-2 prior chemotherapy regimens received oxaliplatin (85-100 mg/m(2)) as a 2-h i.v. infusion with gemcitabine (800-1000 mg/m(2)) at a constant rate i.v. infusion (CI) of 10 mg/m(2)/min on days 1 and 15 of a 28-day cycle. Capecitabine (600-800 mg/m(2)) was administered orally twice a day on days 1-7 and 15-21. A three per cohort dose escalation schema was used to determine the maximum tolerated dose (MTD) and the dose-limiting toxic effects (DLTs) of this combination regimen. Thirty patients with advanced upper gastrointestinal malignancies were enrolled. The MTD was defined as oxaliplatin 100 mg/m(2) i.v. over 2 h plus gemcitabine 800 mg/m(2) i.v. at a CI of 10 mg/m(2)/min on days 1 and 15 with capecitabine 800 mg/m(2) p.o. b.i.d. days 1-7 and 15-21 of a 29-day cycle. DLTs include grade 3 fatigue and grade 3 dyspnea. One complete and two partial responses were observed. This biweekly schedule of oxaliplatin, gemcitabine and capecitabine is tolerable and warrants further investigation in biliary and pancreatic malignancies.
    Annals of Oncology 07/2008; 19(10):1742-8. · 7.38 Impact Factor

Publication Stats

620 Citations
188.75 Total Impact Points

Institutions

  • 2005–2014
    • Washington University in St. Louis
      • Department of Pathology and Immunology
      San Luis, Missouri, United States
  • 2010–2011
    • University of North Carolina at Chapel Hill
      • Institute of Pharmacogenomics and Individualized Therapy
      Chapel Hill, NC, United States
  • 2009
    • University of Washington Seattle
      • Department of Radiation Oncology
      Seattle, WA, United States