Martin J Heslin

Publications of Martin J Heslin

• ErbB3 expression promotes tumorigenesis in pancreatic adenocarcinoma.

  Authors: J Spencer Liles, Juan Pablo Arnoletti, Ching-Wei D Tzeng, J Harrison Howard, Andrew V Kossenkov, Peter Kulesza, Martin J Heslin, Andrey Frolov

  Cancer biology & therapy. 09/2010; 10(6):555-63.

  Historically, ErbB3 has been overlooked within the ErbB receptor family due to its perceived lack of tyrosine kinase activity. We have previously demonstrated that in pancreatic cancer ErbB3 is theHistorically, ErbB3 has been overlooked within the ErbB receptor family due to its perceived lack of tyrosine kinase activity. We have previously demonstrated that in pancreatic cancer ErbB3 is the preferred dimerization partner of EGFR, ErbB3 protein expression level directly correlates with the anti-proliferative effect of erlotinib (an EGFR-specific tyrosine kinase inhibitor), and transient knockdown of ErbB3 expression results in acquired resistance to EGFR-targeted therapy. In this study, we develop a stable isogenic model of ErbB3 expression in an attempt to decipher ErbB3's true contribution to pancreatic cancer tumorigenesis and to examine how this receptor affects cellular sensitivity to EGFR-targeted therapy. Analysis of the EGFR-ErbB3 heterodimer demonstrates that ligand-induced PI3K-AKT signaling is limited to ErbB3-expressing cells and that this signaling cascade can be partially abrogated by inhibiting EGFR function with erlotinib. Using our model of exogenous ErbB3 expression we showed a direct relationship between ErbB3 protein levels and increased pancreatic cancer cell proliferation in vitro. In vivo, ErbB3(+)PANC-1 xenografts had a significantly larger tumor volume than PANC-1 control xenografts (ErbB3-PANC-1) and displayed increased sensitivity to EGFR-targeted therapy. In pancreatic cancer, ErbB3 appears to be critically involved in EGFR signaling as evidenced by its profound effect on cellular proliferation and its ability to influence response to EGFR-targeted therapy.

• Epidermal growth factor receptor (EGFR) intron 1 polymorphism and clinical outcome in pancreatic adenocarcinoma.

  Authors: Andrey Frolov, J Spencer Liles, Andrew V Kossenkov, Ching-Wei D Tzeng, Nirag Jhala, Peter Kulesza, Shyam Varadarajulu, Mohamad Eloubeidi, Martin J Heslin, J Pablo Arnoletti

  American journal of surgery. 09/2010; 200(3):398-405.

  Epidermal growth factor receptor (EGFR) intron 1 has a polymorphic region of CA repeats that is believed to be associated with increased EGFR expression, tumor aggressiveness, and worse survival inEpidermal growth factor receptor (EGFR) intron 1 has a polymorphic region of CA repeats that is believed to be associated with increased EGFR expression, tumor aggressiveness, and worse survival in cancer patients. A large population of pancreatic adenocarcinoma patients was investigated to evaluate this polymorphism as a potential prognostic marker of clinical outcome. Deoxyribonucleic acid obtained from 50 resected pancreatic adenocarcinomas and from 85 diagnostic endoscopic ultrasound-guided fine-needle aspiration procedures corresponding to patients with unresectable tumors was included. The correlation between CA repeat length and EGFR messenger ribonucleic acid levels was also examined. Analysis of the 135 patients revealed no correlation between EGFR intron 1 CA repeat length and tumor stage. There was no difference in overall patient survival when stratified by allele length. A correlation between EGFR intron 1 length and EGFR transcript and protein levels could not be established. The length of the EGFR intron 1 CA repeats does not correlate with levels of EGFR expression and cannot be used as marker of clinical prognosis in pancreatic cancer patients.

• Recurrent retroperitoneal sarcoma: impact of biology and therapy on outcomes.

  Authors: Stephen R Grobmyer, Jason P Wilson, Brooke Apel, Jacquelyn Knapik, Walter C Bell, Tad Kim, Kirby I Bland, Edward M Copeland, Steven N Hochwald, Martin J Heslin

  Journal of the American College of Surgeons. 05/2010; 210(5):602-8, 608-10.

  Local recurrence remains the major cause of death in patients with retroperitoneal sarcoma (RPS). There is no consensus regarding management of patients with recurrent RPS. We performed aLocal recurrence remains the major cause of death in patients with retroperitoneal sarcoma (RPS). There is no consensus regarding management of patients with recurrent RPS. We performed a retrospective review of patients with recurrent RPS managed at 2 tertiary care centers between 1983 and 2008. Presentation, treatments, and outcomes were analyzed. Seventy-eight patients were identified and analyzed. Sixteen patients (22%) presented with concurrent metastatic disease; survival in this subset of patients was poor (median 12 months). Forty-eight patients underwent resection of the first local recurrence of RPS. Palliation of tumor-related symptoms was achieved in 79% with operation. Survival was significantly better in patients having complete (p = 0.001) and incomplete resection (p = 0.02) compared with patients having biopsy only. Among patients with first local recurrence, high grade tumor (p = 0.0001) and no resection (p = 0.007) were significantly associated with reduced survival. On multivariate analysis, radiation therapy, multifocality, histologic subtype, and time to local recurrence did not significantly correlate with survival. Second and third local recurrences occurred at shorter intervals compared with first local recurrence and were less likely to be completely resectable. Patients undergoing resection of second and third local recurrences had survival similar to that in patients undergoing resection of first local recurrence. Tumor biology (high grade) is a significant prognostic factor for patients with recurrent RPS. Resection should be considered in patients with first and subsequent local recurrences (even if multifocal) of RPS because it is associated with improved survival. Operation should also be considered for palliation of symptoms in patients in whom resection is not possible.

• Laparoscopic and open distal pancreatectomy: a comparison of outcomes.

  Authors: Kelly R Finan, Emily E Cannon, Eugenia J Kim, Mary M Wesley, Pablo J Arnoletti, Martin J Heslin, John D Christein

  The American surgeon. 08/2009; 75(8):671-9; discussion 679-80.

  Laparoscopic (lap) pancreatic surgery has been increasingly reported since its introduction in 1992. A retrospective analysis of consecutive patients undergoing elective lap and open distalLaparoscopic (lap) pancreatic surgery has been increasingly reported since its introduction in 1992. A retrospective analysis of consecutive patients undergoing elective lap and open distal pancreatectomy from 2002 to 2007 was performed. Univariate analysis was completed to evaluate perioperative variables. Logistic regression analysis was used to model predictors of postoperative pancreatic fistula. One hundred forty-eight subjects underwent distal pancreatectomy; 98 completed open, 44 lap, and six converted to open. There was no significant difference in the incidence of postoperative morbidity or mortality between the surgical approaches. Decreased operative time (156 vs 200 minutes, P < 0.01), blood loss (157 vs 719 mL, P < 0.01), and length of stay (5.9 vs 8.6 days, P < 0.01) were seen in the lap group. There was no significant difference in the rate of all pancreatic fistula formation (50 vs 46%, P = 0.94) or clinically significant leaks (18 vs 19%, P = 0.97) between techniques. A preoperative biopsy-proven cancer, increasing body mass index, history of pancreatitis, and male gender were significant predictors of having a pancreatic fistula. Lap and open distal pancreatectomy are performed safely at high-volume pancreatic surgery centers. This report provides ongoing support of the feasibility and safety of the lap approach with improved perioperative outcomes and equivalent pancreatic fistula rate.

• Retroperitoneal and intra-abdominal sarcoma.

  Authors: J Spencer Liles, Ching-Wei D Tzeng, Joshua J Short, Peter Kulesza, Martin J Heslin

  Current problems in surgery. 07/2009; 46(6):445-503.

• Radiofrequency ablation for unresectable tumors of the liver.

  Authors: J Harrison Howard, Ching-Wei D Tzeng, J Kevin Smith, Devon E Eckhoff, J Steve Bynon, Thomas Wang, J Pablo Arnoletti, Martin J Heslin

  The American surgeon. 07/2008; 74(7):594-600; discussion 600-1.

  Surgical resection of primary or metastatic tumors of the liver offers patients the best long-term survival. Liver resections may not be appropriate in patients with bilobar metastases, liverSurgical resection of primary or metastatic tumors of the liver offers patients the best long-term survival. Liver resections may not be appropriate in patients with bilobar metastases, liver dysfunction, or severe comorbidities. Radiofrequency ablation (RFA) is a technique used to destroy unresectable hepatic tumors through thermocoagulation. We retrospectively reviewed a consecutive series of patients undergoing RFA with unresectable hepatic tumors for local recurrence and overall survival. Under an Institutional Review Board-approved protocol, all patients treated with RFA at the University of Alabama at Birmingham from September 1, 1998, to June 15, 2005, were identified. During this time period, 189 lesions in 107 patients were treated with RFA. Patients' charts were retrospectively reviewed. Data is presented as mean +/- SEM. Significance is defined as P < 0.05. Patient demographics revealed 62 per cent males and 38 per cent females with a mean age of 59 (+/- 1) years. Hepatocellular carcinoma (HCC) represented 54 per cent of the tumors treated. Metastatic colorectal cancer represented 22 per cent and the remaining 24 per cent were other metastatic tumors. Overall recurrence rates for all tumors after RFA was 53 per cent. Local recurrence rates for HCC, colorectal cancer, and other metastatic lesions were 27.6 per cent, 29.1 per cent, and 52 per cent, respectively. The morbidity rate for the procedure was 11 per cent. There was one mortality (0.9%) related to RFA. Laparoscopic RFA for HCC in Childs-Pugh Class C cirrhotics (n = 6) resulted in 50 per cent of patients being transplanted with no evidence of disease at a mean follow-up period of 14 months. RFA is a safe and effective way for treating HCC and other unresectable tumors in the liver that are not eligible for hepatic resection. More effective control of systemic recurrence will dictate survival in the majority of patients with metastatic cancers. Local ablation for HCC in cirrhotic patients may be an effective bridge to transplantation. Liver transplantation may still be the most effective long-term treatment for localized HCC.

• Durable improvements in efficiency, safety, and satisfaction in the operating room.

  Authors: Martin J Heslin, Barbara E Doster, Sandra L Daily, Michael R Waldrum, Arthur M Boudreaux, A Blair Smith, Glenn Peters, Debbie B Ragan, Scott Buchalter, Kirby I Bland, Loring W Rue

  Journal of the American College of Surgeons. 06/2008; 206(5):1083-9; discussion 1089-90.

  BACKGROUND: Enhanced productivity and efficiency in the operating room must be balanced with patient safety and staff satisfaction. In December 2004, transition to an expanded replacement hospitalBACKGROUND: Enhanced productivity and efficiency in the operating room must be balanced with patient safety and staff satisfaction. In December 2004, transition to an expanded replacement hospital resulted in mandatory overtime, unpredictable work hours, and poor morale among operating room (OR) staff. A staff-retention crisis resulted, which threatened the viability of the OR and the institution. We report the changes implemented to efficiently deliver safe patient care in a supportive environment for surgeons and OR staff. STUDY DESIGN: University of Alabama at Birmingham University Hospital OR data were evaluated for fiscal year 2004 and compared with fiscal years 2005 and 2006. Case volumes, number of operational ORs, and on-time case starts were evaluated. OR adverse events were tabulated. Percentage of registered nurse hires and staff departures served as a proxy for staff satisfaction. RESULTS: Short, intermediate, and longterm strategies were implemented by an engaged OR management committee with the guidance of surgical, anesthesia, and hospital leadership. These included new block time release policies; use of traveling nurses until new staff could be hired and trained; and incentive-based, voluntary, employee-scheduled overtime. Mandatory nursing education time was blocked weekly. Enforcement of the National Patient Safety Goals were implemented and adjudicated with a "surgeon-of-the-day" system providing backup for nurse management. We demonstrated an increase in operations per year, on-time starts, and registered nurse hires in fiscal years 2005 and 2006. During this same time, we were able to markedly decrease the number of adverse events, admitting delays, and staff departures. CONCLUSIONS: Change is difficult to accept but essential when vital clinical activities are impaired and at risk. To maintain important clinical environments like the OR in an academic center, we developed and implemented effective, data-driven changes. This allowed us to retain critical human resources and restore a supportive environment for the patients, the doctors, and the staff.

• Primary colonic lymphoma.

  Authors: Quintín H Gonzalez, Martin J Heslin, Andrea Dávila-Cervantes, Javier Alvarez-Tostado, Antonio Espinosa-de-los-Monteros, Gregg Shore, Selwyn M Vickers

  The American surgeon. 04/2008; 74(3):214-6.

  Surgical resection of primary colonic lymphoma can be an important therapeutic tool. We performed a nonrandomized retrospective descriptive study at the University hospital tertiary care center. FromSurgical resection of primary colonic lymphoma can be an important therapeutic tool. We performed a nonrandomized retrospective descriptive study at the University hospital tertiary care center. From January 1990 to June 2002, a total of 15 patients with primary colonic lymphoma were identified from the tumor registry at University of Alabama at Birmingham and retrospectively reviewed under Institutional Review Board approved protocol. Demographic data, clinical features, treatment method (surgery and/or chemotherapy), recurrence rate, and survival were analyzed. The results are presented as mean +/- standard deviation or median and range. Differences in survival were evaluated by the log-rank test and the interval of disease-free survival was calculated using the Kaplan-Meier method. A P value of <0.05 was considered statistically significant. Main outcome measures included surgical results, morbidity, mortality, and recurrence rate. Mean age was 51.5 years (standard deviation 16.4), 33 per cent were male and 67 per cent were female. Presenting symptoms were diarrhea (53.5%), lower gastrointestinal bleeding (13.3%), and nausea and vomiting (46.7%) secondary to low-grade obstruction. Concomitant colorectal disease was present in one patient with ulcerative colitis. Preoperative diagnosis of lymphoma was made in 13 patients (87%) with colonoscopy and biopsy. CT scan was performed in all patients; and none had radiographic evidence of systemic extension. Only one patient had a history of lymphoproliferative disease and exposure to radiation. The most common disease location was the cecum (60%), followed by the right colon (27%), and the sigmoid colon (13%). The mean lactic dehydrogenase (LDH) value was 214.9 u/L (range 129-309). Thirty-three per cent of the patients had an LDH value that was above the upper normal limit. LDH returned to normal after treatment in all patients. Operations performed consisted of right hemicolectomy (13), total proctocolectomy with ileal J J-pouch (1), and sigmoid colectomy (1). Eighty-seven per cent had negative margins at the time of operation. Twelve patients received postoperative chemotherapy (80%). According to the clinical classification of primary non-Hodgkin lymphoma (NHL) of the gastrointestinal tract (Lugano, 1993) all patients corresponded to stage IE. Mean hospital stay was 6.4 days (range 3-26). There was no surgical mortality and the morbidity rate was 20 per cent (3 patients). One patient had a systemic recurrence (7%) approximately 4 months after surgical resection. Mean follow-up was 31 months (median 2-73). Surgical resection of localized, primary colonic lymphoma provides excellent local disease control and should be considered a primary treatment option. The role of chemotherapy remains controversial depending on the grade, stage, and extension of residual disease.

• Prognostic factors and preoperative radiation therapy associated with sphincter preservation in patients with resectable rectal cancer.

  Authors: J Harrison Howard, Quintin Gonzalez, J Pablo Arnoletti, Suzanne Russo, John B Fiveash, Kirby I Bland, Martin J Heslin

  American journal of surgery. 03/2008; 195(2):239-43.

  BACKGROUND: This study evaluates the importance of patient and tumor factors, receipt of preoperative radiation therapy, and American Joint Committee on Cancer stage for sphincter preservation (SP)BACKGROUND: This study evaluates the importance of patient and tumor factors, receipt of preoperative radiation therapy, and American Joint Committee on Cancer stage for sphincter preservation (SP) in patients with rectal cancer. METHODS: Age, sex, race, body mass index, tumor size, distance from the anal verge (DAV), differentiation, American Joint Committee on Cancer stage, and preoperative radiation were evaluated. The end point was continence versus colostomy. Comparison was done by logistic regression; data were presented as mean +/- SEM; and significance was defined as P <.05. RESULTS: Factors independently associated with SP were greater DAV, body mass index (BMI) <30, smaller tumor, and preoperative radiation therapy (all P <.05). CONCLUSIONS: DAV remains the most important factor for prediction of SP in patients with rectal cancer. Preoperative tumor size and BMI were also independent factors. Preoperative radiation therapy may increase the chance of SP in patients with large tumors, increased BMI, or low rectal tumors.

• EGFR genomic gain and aberrant pathway signaling in pancreatic cancer patients.

  Authors: Ching-Wei D Tzeng, Andrey Frolov, Natalya Frolova, Nirag C Jhala, J Harrison Howard, Selwyn M Vickers, Donald J Buchsbaum, Martin J Heslin, J Pablo Arnoletti

  The Journal of surgical research. 12/2007; 143(1):20-6.

  BACKGROUND: Epidermal growth factor receptor (EGFR) expression does not predict response to anti-EGFR therapy with erlotinib in pancreatic cancer patients. In the absence of known pancreatic cancerBACKGROUND: Epidermal growth factor receptor (EGFR) expression does not predict response to anti-EGFR therapy with erlotinib in pancreatic cancer patients. In the absence of known pancreatic cancer EGFR activating mutations, we sought to identify alternative factors, such as increased gene copy number (genomic gain) and ligand overexpression, which could be associated with aberrant EGFR pathway activation and improved response to targeted therapy. METHODS: EGFR gene copy number was analyzed by fluorescence in situ hybridization in nine pancreatic cancer cell lines and 31 pancreatic cancer surgical specimens. In vitro effects of erlotinib on tumor cell proliferation were tested. Tumor specimen EGFR expression levels were measured by reverse transcriptase-polymerase chain reaction. Expression of stimulating ligand (EGF), phosphorylated receptor (p-EGFR), and activated downstream adaptor proteins (p-Akt and p-ERK), were evaluated by immunohistochemistry and immunoblotting. RESULTS: Pancreatic cancer EGFR genomic gain, in the form of high polysomy, was present in four of nine cell lines and in 10/24 (42%) of patients. Twenty-four patients (77%) expressed EGFR transcript, and of those, half displayed p-EGFR (35% of all patients). A majority of patients demonstrated downstream EGFR pathway activation, with 65% expressing p-Akt and 84% expressing p-ERK. EGFR-expressing tumors also expressed EGF, with exclusive tumor cell localization, suggesting autocrine stimulation of the EGFR pathway. EGF expression level was significantly greater in patients with increased EGFR gene copy number (P = 0.016). CONCLUSIONS: Increased EGFR gene copy number and elevated EGF levels are present in a significant proportion of pancreatic cancer patients, and this may reflect increased EGFR pathway dependence with improved sensitivity to EGFR-targeted therapy.

• Brennan-isms and the process of mentoring.

  Authors: Martin J Heslin

  Journal of the American College of Surgeons. 11/2007; 205(4 Suppl):S22-5.

• A prospective evaluation of an algorithm incorporating routine preoperative endoscopic ultrasound-guided fine needle aspiration in suspected pancreatic cancer.

  Authors: Mohamad A Eloubeidi, Shyam Varadarajulu, Shilpa Desai, Rhett Shirley, Martin J Heslin, Mohit Mehra, Juan P Arnoletti, Isam Eltoum, Charles M Wilcox, Selwyn M Vickers

  Journal of gastrointestinal surgery : official journal of the Society for Surgery of the Alimentary Tract. 08/2007; 11(7):813-9.

  BACKGROUND: Whether tissue diagnosis is required in the preoperative evaluation of patients with suspected pancreatic cancer remains controversial. We prospectively evaluated the accuracy, safety,BACKGROUND: Whether tissue diagnosis is required in the preoperative evaluation of patients with suspected pancreatic cancer remains controversial. We prospectively evaluated the accuracy, safety, and potential impact on surgical intervention of endoscopic ultrasound-guided fine needle aspiration (EUS-FNA) in the preoperative evaluation of suspected pancreatic cancer. METHODS: All patients who underwent EUS-FNA at our institution (n = 547) over a 4.5-year period were enrolled. Patients underwent surgical exploration and resection based on their comorbidity status, evidence of resectability based on spiral computed tomography (CT) and EUS imaging reviewed in a multidisciplinary approach. RESULTS: Of 547 patients enrolled (median age 64 years, 60% male), 49% presented with obstructive jaundice. The operating characteristics of EUS-FNA of solid pancreatic masses were: sensitivity 95% (95% CI: 93.2-95.4), specificity 92% (95% CI: 86.6-95.7), positive predictive value 98% (95% CI: 97-99), negative predictive value 80% (95% CI: 74.9-82.7). The overall accuracy of EUS-FNA was 94.1% (95% CI: 92.0-94). Of the 414 true positive patients by EUS-FNA, 138 (33%) were explored. Of patients deemed operable by combined imaging, 42% had surgical resection. Eighty-two percent of true positive patients were ultimately found inoperable and received palliative therapy or chemotherapy. Of the 94 patients with true negative cytology based on extended follow-up, only 7 (7%) underwent surgical resection. Of those with false negative diagnoses (n = 24), 5 patients underwent exploration/resection based on detection of mass lesions by EUS. The remaining patients had unresectable disease. Mild self-limiting pancreatitis occurred in (0.91%). CONCLUSIONS: EUS-FNA is a safe and highly accurate method for tissue diagnosis in suspected pancreatic cancer. This approach allows for preoperative counseling of patients, minimizing surgeon's operative time in cases of unresectable disease, and avoids surgical biopsies in the majority of patients with inoperable disease. In addition, it allows for conservative management of patients with benign biopsies. We still, however, recommend exploration of patients with clinical scenario suspicious for pancreatic cancer, a mass found on EUS or CT, but inconclusive or negative cytology.

• Pancreatic cancer epidermal growth factor receptor (EGFR) intron 1 polymorphism influences postoperative patient survival and in vitro erlotinib response.

  Authors: Ching-Wei D Tzeng, Andrey Frolov, Natalya Frolova, Nirag C Jhala, J Harrison Howard, Selwyn M Vickers, Donald J Buchsbaum, Martin J Heslin, J Pablo Arnoletti

  Annals of surgical oncology. 07/2007; 14(7):2150-8.

  BACKGROUND: Epidermal growth factor receptor (EGFR) has a highly polymorphic CA repeat region that affects transcription efficiency and anti-EGFR drug sensitivity in carcinomas. Erlotinib is an EGFRBACKGROUND: Epidermal growth factor receptor (EGFR) has a highly polymorphic CA repeat region that affects transcription efficiency and anti-EGFR drug sensitivity in carcinomas. Erlotinib is an EGFR tyrosine kinase inhibitor approved for pancreatic cancer treatment. We analyzed the impact of EGFR intron 1 CA repeat lengths in pancreatic cancer clinical outcome and in vitro response to erlotinib. METHODS: Allele-specific EGFR intron 1 lengths were analyzed in 30 microdissected pancreatic cancer surgical specimens, matched peripheral blood samples, and 9 pancreatic cancer cell lines treated with erlotinib. CA repeat lengths were correlated with survival, tumor parameters, molecular markers of EGFR pathway activation, and in vitro antiproliferative effects of erlotinib. RESULTS: Both patient samples and cell lines displayed the full spectrum of EGFR CA repeat lengths (14-22 per allele). Patients with shorter sum of total CA repeats (<36) had worse median survival than patients with >or=36 repeats (13.7 vs 30.6 months, P = .002). Shorter patient EGFR intron 1 length correlated with EGFR expression (P = .026). Tumor intron 1 length was identical to that of matched peripheral blood specimens. There was no correlation between EGFR intron 1 length and pancreatic cancer stage, nodal status, grade, or expression of p-EGFR, p-ERK and p-Akt. Shorter EGFR intron 1 length was associated with in vitro response to erlotinib treatment (P = .02). CONCLUSIONS: Shorter EGFR intron 1 CA repeat length is associated with worse pancreatic cancer clinical prognosis and in vitro response to erlotinib. EGFR intron 1 length can be reliably measured in peripheral blood and may translate into a quantitative predictive marker of both pancreatic cancer aggressiveness and erlotinib sensitivity.

• Epidermal growth factor receptor (EGFR) is highly conserved in pancreatic cancer.

  Authors: Ching-Wei D Tzeng, Andrey Frolov, Natalya Frolova, Nirag C Jhala, J Harrison Howard, Donald J Buchsbaum, Selwyn M Vickers, Martin J Heslin, J Pablo Arnoletti

  Surgery. 05/2007; 141(4):464-9.

  BACKGROUND: Pancreatic cancer remains a deadly disease, and the vast majority of pancreatic cancer patients are not candidates for treatment with curative intent. Erlotinib, an EGFR-specific tyrosineBACKGROUND: Pancreatic cancer remains a deadly disease, and the vast majority of pancreatic cancer patients are not candidates for treatment with curative intent. Erlotinib, an EGFR-specific tyrosine kinase inhibitor, was approved recently for use in patients with pancreatic cancer. Somatic mutations in the EGFR gene appear to predict survival and response to tyrosine kinase inhibitor therapy in a subset of patients with non-small-cell lung cancer (NSCLC). METHODS: The purpose of this study was to characterize EGFR mutations in pancreatic adenocarcinoma. EGFR TK mutations were analyzed in 9 pancreatic carcinoma cell lines and 31 clinical specimens from patients with pancreatic cancer who underwent resection. Using laser capture microdissection, tumor cells from patients were harvested selectively for genomic DNA extraction. Mutations were examined by direct sequencing of exons 18-21. RESULTS: Of 9 pancreatic cancer cell lines, 6 had either 2454G>A or 2361G>A mutations in exon 20. Of 31 patients, 25 patients had 2361G>A in exon 20, and 1 patient had 2508C>T in exon 21. All were silent mutations. CONCLUSIONS: The EGFR tyrosine kinase domain is highly conserved in pancreatic cancer. The association among EGFR mutation status, clinical prognosis, and response to anti-EGFR therapy described in NSCLC may not be applicable to pancreatic cancer. This observation does not diminish the possible role of anti-EGFR therapy in pancreatic cancer because there remains a need to explore alternative explanations for pancreatic cancer aberrant EGFR pathway activation such as ligand overexpression, gene amplification, and loss of inhibitory mechanisms.

• ErbB3 expression and dimerization with EGFR influence pancreatic cancer cell sensitivity to erlotinib.

  Authors: Andrey Frolov, Kyle Schuller, Ching-Wei D Tzeng, Emily E Cannon, Brandon C Ku, J Harrison Howard, Selwyn M Vickers, Martin J Heslin, Donald J Buchsbaum, J Pablo Arnoletti

  Cancer biology & therapy. 05/2007; 6(4):548-54.

  Abnormal expression and signaling of ErbB receptors has been implicated in multiple epithelial malignancies, including pancreatic cancer. Erlotinib, an epidermal growth factor receptor tyrosineAbnormal expression and signaling of ErbB receptors has been implicated in multiple epithelial malignancies, including pancreatic cancer. Erlotinib, an epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI), has been recently approved for pancreatic cancer treatment, but there are no reliable predictors of patient response. Expression of additional ErbB receptors seems to influence tumor response to EGFR-targeted therapy. We analyzed the influence of ErbB3 expression on pancreatic cancer cell response to erlotinib treatment. Proliferation assays of five human pancreatic cancer cell lines were performed following treatment with erlotinib. Expression and phosphorylation profiles of ErbB receptors and downstream adaptor protein (Akt, ERK1/2, STAT3, mTOR) were evaluated following stimulation with EGF or neuregulin-beta. The formation of EGFR homodimers and EGFR-ErbB3 heterodimers, necessary to enable ErbB3 downstream signaling, was demonstrated by chemical cross-linking assays. The effects of RNA inhibition of ErbB3 on sensitivity to erlotinib treatment were evaluated in AsPC-1 pancreatic cancer cells. Erlotinib inhibited Akt phosphorylation and proliferation of all the ErbB3-expressing cell lines but did not affect mTOR activation. Cross-linking studies confirmed the presence of EGFR-ErbB3 heterodimers in pancreatic cancer cells. Only the ErbB3-deficient MIA PaCa-2 cells displayed persistent Akt activation and ongoing proliferation in spite of erlotinib treatment. siRNA-mediated inhibition of ErbB3 expression in AsPC-1 cells resulted in acquired resistance to erlotinib treatment. Pancreatic cancer cells which lack ErbB3 do not display activation of the ErbB3-PI3K-Akt cascade induced by EGFR/ErbB3 heterodimers and become less critically dependent on EGFR signaling and therefore resistant to erlotinib. Pancreatic cancer expression of ErbB3 may be useful for EGFR-targeted therapy patient selection.

• Surgical treatment of pancreatic endocrine neoplasms.

  Authors: Fernando Gomez-Rivera, Ashley E Stewart, J Pablo Arnoletti, Selwyn Vickers, Kirby I Bland, Martin J Heslin

  American journal of surgery. 05/2007; 193(4):460-5.

  BACKGROUND: Pancreatic endocrine neoplasia (PEN) is an entity with an indolent course and prolonged survival. The aim of the current study was to review the prognostic factors and outcome of patientsBACKGROUND: Pancreatic endocrine neoplasia (PEN) is an entity with an indolent course and prolonged survival. The aim of the current study was to review the prognostic factors and outcome of patients with PEN at 1 institution. METHODS: Records of patients with the diagnosis of PEN in the period of 1980 to 2001 were reviewed. Descriptive statistics and log-rank test were used; significance was defined as P < .05. RESULTS: Of 49 patients, 25 had functional and 24 nonfunctional tumors. Surgery was performed in 43 patients, 36 with curative intent. With a median follow-up of 31 months, there were 5 deaths. Symptoms were controlled with surgical resection in 86%. Median disease-free survival (DFS) was 46 months; actuarial 5-year disease-specific (DSS) was 72%. Factors associated with better DFS and DSS were absence of liver involvement (P = .02) and resection of the primary tumor (P = .04). CONCLUSIONS: Surgical resection and absence of liver metastases are associated with better DFS and DSS in patients with PEN.

• Soft tissue sarcoma: preoperative and postoperative imaging for staging.

  Authors: Ching-Wei D Tzeng, J Kevin Smith, Martin J Heslin

  Surgical oncology clinics of North America. 05/2007; 16(2):389-402.

  Soft tissue sarcoma (STS) management requires accurate tumor imaging for staging, treatment planning, and clinical follow-up. Careful preoperative planning may prevent poor primary resections thatSoft tissue sarcoma (STS) management requires accurate tumor imaging for staging, treatment planning, and clinical follow-up. Careful preoperative planning may prevent poor primary resections that place the patient at risk for more operations, local recurrence, and worse survival. Although MRI may be preferred for extremity STS, contrast-enhanced CT is an excellent alternative, with no decrease in ability to plan the operative strategy for limb-sparing resection. In retroperitoneal and other intra-abdominal STS, double (oral/intravenous) contrast-enhanced CT evaluates for liver metastases, defines surrounding vital structures that might be resected en bloc, identifies margins at risk for local recurrence, and shows surrounding organs at risk for toxicity during radiation therapy. Postoperative clinical follow-up and imaging must continue even beyond 5 years because of the continued risk of long-term relapse.

• Regionalization versus competition in complex cancer surgery

  Authors: Vivian Ho, Robert J Town, Martin J Heslin

  Cambridge University Press, Health Economics, Policy and Law. 01/2007; 2(01):51-71.

  This chapter presents the econometric methods that are used in health economics to model individuals health care costs. These methods are used for prediction, projection and forecasting, in theThis chapter presents the econometric methods that are used in health economics to model individuals health care costs. These methods are used for prediction, projection and forecasting, in the context of risk adjustment, resource allocation, technology assessment and policy evaluation. The chapter reviews the literature on the comparative performance of the methods, especially in the context of forecasting individual health care costs, and concludes with an empirical case study.

• Regionalization versus competition in complex cancer surgery.

  Authors: Vivian Ho, Robert J Town, Martin J Heslin

  Health economics, policy, and law. 01/2007; 2(Pt 1):51-71.

  The empirical association between high hospital procedure volume and lower mortality rates has led to recommendations for the regionalization of complex surgical procedures. While regionalization mayThe empirical association between high hospital procedure volume and lower mortality rates has led to recommendations for the regionalization of complex surgical procedures. While regionalization may improve outcomes, it also reduces market competition, which has been found to lower prices and improve health care quality. This study estimates the potential net benefits of regionalizing the Whipple surgery for pancreatic cancer patients. We confirm that increased hospital volume and surgeon volume are associated with lower inpatient mortality rates. We then predict the price and outcome consequences of concentrating Whipple surgery at hospitals that perform at least two, four, and six procedures respectively per year. Our consumer surplus calculations suggest that regionalization can increase consumer surplus, but potential price increases extract over half of the value of reduced deaths from regionalization. We reach three conclusions. First, regionalization can increase consumer surplus, but the benefits may be substantially less than implied by examining only the outcome side of the equation. Second, modest changes in outcomes due to regionalization may lead to decreases in consumer surplus. Third, before any regionalization policy is implemented, a deep and precise understanding of the nature of both outcome/volume and price/competition relationships is needed.

• Radiation therapy for retroperitoneal sarcoma.

  Authors: Ching-Wei D Tzeng, John B Fiveash, Martin J Heslin

  Expert review of anticancer therapy. 09/2006; 6(8):1251-60.

  Retroperitoneal soft-tissue sarcoma is an uncommon cancer of mesodermal origin, which is difficult to treat owing to its location and proximity to vital structures. Complete gross resection, oftenRetroperitoneal soft-tissue sarcoma is an uncommon cancer of mesodermal origin, which is difficult to treat owing to its location and proximity to vital structures. Complete gross resection, often involving en bloc resection, is the standard of care as it represents the only treatment that improves overall survival. Unlike extremity sarcoma, retroperitoneal soft-tissue sarcoma tumor mortality is from local recurrence. Radiation therapy is the only adjuvant treatment that has improved local control in several institutional series. However, there remains no definitive prospective, randomized trial that establishes the role of adjuvant radiation versus no radiation. Owing to significant radiation morbidity with adjacent organs, especially the small bowel, there exists no consensus on radiation timing, delivery method or dosing. Recent and current protocols use preoperative external-beam radiation with or without a method of focal boost dosing. Methods of boost dosing include brachytherapy, intraoperative radiation therapy and intensity-modulated radiation therapy. Further studies are needed to definitively include radiation therapy in the standard treatment of retroperitoneal soft-tissue sarcoma and to find the optimal balance between acceptable radiation toxicity and effective local control in treatment protocols.