John A. Chabot

An aggressive resectional approach to cystic neoplasms of the pancreas

BACKGROUND Prognosis is good after curative resection for serous and mucinous cystic neoplasms of the pancreas. There has been a recent trend to resect all cystic neoplasms, without attempts to preoperatively determine the exact histologic subtype. Our purpose is to report on the results of such an aggressive surgical approach to all cystic neoplasms of the pancreas. METHODS This is a retrospective cohort analysis of 25 patients with cystic neoplasms of the pancreas treated between July 1991 and July 1998. Data include patient demographics, presenting symptom, operative procedure, pathologic diagnosis, periop morbidity and mortality, survival, and symptomatic follow-up data. RESULTS Twenty-one patients were women, with a mean age of 60 for the entire cohort. Mean follow-up was 24 months (range 6 months to 4.3 years) with complete follow-up possible in 92%. Twenty-three patients had curative resections and 2 had palliative resections. One patient with an uncinate mass had a partial pancreatectomy; 4 patients underwent distal pancreatectomy and 9 had distal pancreatectomy with splenectomy; 11 patients required a pancreatoduodenectomy, and of these, 4 had tumors involving the portal vein, necessitating a portal vein resection. Pathologic analysis revealed 12 serous cystadenomas, 4 mucinous cystadenomas, 3 mucinous cystadenocarcinomas, 5 intraductal papillary cystic neoplasms, and 1 serous cystadenocarcinoma. The overall perioperative complication rate was 40% with 5 major and 5 minor complications. In the 11 pancreatoduodenectomy patients alone, there were 1 major and 4 minor complications. There were no pancreatic fistulas or portal vein thromboses and no operative mortalities. Two patients, both with mucinous cystadenocarcinomas, died of their disease at 6 and 16 months postoperatively. All 11 pancreatoduodenectomy patients have only mild pancreatic insufficiency relieved by daily enzyme replacement. CONCLUSIONS The good outcomes in this study support an aggressive surgical approach to all patients diagnosed with a cystic neoplasm of the pancreas, if medically fit to tolerate surgery. This approach is justified for the following reasons: (1) preoperative differentiation of a benign versus malignant tumor is unreliable and routine testing for this purpose is of questionable utility; (2) potential adverse consequences of nonresectional therapy are significant; (3) perioperative morbidity and mortality of pancreatic surgery is low; and (4) prognosis with curative resection is good.

Pancreatic Cancer Screening in a Prospective Cohort of High-Risk Patients: A Comprehensive Strategy of Imaging and Genetics

Purpose: Pancreatic cancer is a virtually uniformly fatal disease. We aimed to determine if screening to identify curable neoplasms is effective when offered to patients at high risk. Experimental Design: Patients at high risk of pancreatic cancer were prospectively enrolled into a screening program. Endoscopic ultrasound (EUS), magnetic resonance imaging (MRI), and genetic testing were offered by a multidisciplinary team according to each patients risk. Results: Fifty-one patients in 43 families were enrolled, with mean age of 52 years, 35% of whom were male. Of these patients, 31 underwent EUS and 33 MRI. EUS revealed two patients with pancreatic cancer (one resectable, one metastatic), five with intraductal papillary mucinous neoplasms (IPMN), seven with cysts, and six with parenchymal changes. Five had pancreatic surgery (one total pancreatectomy for pancreatic cancer, three distal and one central pancreatectomy for pancreatic intraepithelial neoplasia 2 and IPMN). A total of 24 (47%) had genetic testing (19 for BRCA1/2 mutations, 4 for CDKN2A, 1 for MLH1/MSH2) and 7 were positive for BRCA1/2 mutations. Four extrapancreatic neoplasms were found: two ovarian cancers on prophylactic total abdominal hysterectomy and bilateral salpingo-oophorectomy, one carcinoid, and one papillary thyroid carcinoma. Overall, 6 (12%) of the 51 patients had neoplastic lesions in the pancreas and 9 (18%) had neoplasms in any location. All were on the initial round of screening. All patients remain alive and without complications of screening. Conclusions: Pancreatic cancer screening for high-risk patients with a comprehensive strategy of imaging and genetics is effective and identifies curable neoplasms that can be resected. Ongoing study will better define who will benefit from screening and what screening strategy will be the most effective. Clin Cancer Res; 16(20); 5028–37. ©2010 AACR.

Detection of circulating thyroid cells in peripheral blood

BACKGROUND Detection of circulating malignant thyroid cells may provide a method to identify postoperative patients at risk for metastatic thyroid cancer. METHODS On the basis of tissue specificity of thyroglobulin gene expression and the sensitivity of the reverse transcriptase-polymerase chain reaction (RT-PCR) analysis, we performed RT-PCR using primers for thyroglobulin on blood samples from patients with thyroid disease to detect thyroglobulin RNA transcripts. Postoperative peripheral blood samples from 100 patients, including patients with known metastatic thyroid cancer (six papillary and three follicular), thyroid cancer and no evidence of current metastases (63 papillary, 10 follicular, and five patients with both papillary and follicular), benign thyroid disease (six nontoxic nodular goiters), and normal volunteers (seven). RESULTS Thyroglobulin transcripts were detected in nine of nine patients with metastatic thyroid cancer, seven of 78 patients with thyroid cancer and no current metastases (although of these seven patients, five had a history of metastatic disease that had been previously treated by surgery, one had a coexisting parathyroid cancer, and one had both papillary and follicular thyroid cancers), zero of six patients with benign thyroid disease, and zero of seven normal volunteers. Identity of amplicons was confirmed by restriction enzyme digestion and by cloning and sequencing of RT-PCR amplified thyroglobulin fragment (the latter in a limited number of cases). CONCLUSIONS These data indicate that RT-PCR can be used to detect thyroglobulin mRNA in peripheral blood. The presence of these transcripts correlates with the existence of extrathyroidal disease.

Risk factors for biliary tract cancers

Abstract Objective: Little is known regarding risk factors for biliary tract cancer, i.e., gallbladder carcinoma and extrahepatic bile duct carcinoma. This is the first case-control study conducted in the U.S. regarding risk factors for these cancers. Methods: In this hospital-based case-control study, we reviewed the medical records of 69 patients with primary biliary tract cancer who were admitted to Columbia-Presbyterian Medical Center for surgery between January 1, 1980, and April 4, 1994, and of 138 controls, consisting of patients admitted for surgery for benign conditions. Results: We found a significant association between cholelithiasis and biliary tract cancers (odds ratio, 19.5; 95% confidence interval, 6.4–59.4). Risk factors associated with gallbladder cancer included female gender, age, cigarette smoking, and postmenopausal status in women. Risk factors associated with extrahepatic bile duct cancer included history of cholecystectomy and hysterectomy in women. Conclusion: The risk factors for biliary tract cancers that have been identified in our study delineate a high-risk population, which in the future may be targeted for preventive measures.

Thyroidectomy using monitored local or conventional general anesthesia: an analysis of outpatient surgery, outcome and cost in 1,194 consecutive cases.

BackgroundCritical appraisal of safety, feasibility, and economic impact of thyroidectomy procedures using local (LA) or general anesthesia (GA) is performed.MethodsConsecutive patients undergoing thyroidectomy procedures were selected from a prospective database from January 1996 to June 2003 of a single-surgeon practice at a tertiary center. Statistical analyses determined differences in patient characteristics, outcomes, operative data, and length of stay (LOS) between groups. A cohort of consecutive patients treated in 2002–2003 by all endocrine surgeons at the institution was selected for cost analysis.ResultsA total of 1,194 patients underwent thyroidectomy, the majority using LA (n = 939) and outpatient surgery (65%). Female gender (76%), body mass index ≥30 kg/m2 (29%), median age (49 years), and cancer diagnosis (45%) were similar between groups. Extent of thyroidectomy (59% total) and concomitant parathyroidectomy (13%) were similarly performed. GA was more commonly utilized for patients with comorbidity [15% vs. 10%, Anesthesia Society of America (ASA) ≥3; P < 0.001], symptomatic goiter (13% vs. 7%; P = 0.004), reoperative cases (10% vs. 6%; P = 0.01), and concomitant lymphadenectomy procedures (15% vs. 3%; P < 0.001). GA was associated with significant increase in LOS ≥24 hours (17 % vs. 4%) or overnight observation (49 % vs. 14%), P < 0.001. Operative room utilization was significantly associated with type of anesthesia (180 min vs. 120 min, GA vs. LA, P < .001) and impacted to a lesser degree by surgeon operative time (89 minutes vs. 76 minutes, GA vs. LA; P = .089). Overall morbidity rates were similar between groups (GA 5.8 % vs. LA 3.2%). The actual total cost (ATC) per case for GA was 48% higher than for LA and 30% higher than the ATC for all procedures (P = 0.006), with the combined weighted average impacted by more LA cases (n = 217 vs. 85).ConclusionThese data from a large, unselected group of thyroidectomy patients suggest LA results in similar outcomes and morbidity rates to GA. It is likely that associated LA costs are lower.

Better preservation of endocrine function after central versus distal pancreatectomy for mid-gland lesions.

BACKGROUND Traditional resections for benign and low-grade malignant neoplasms of the mid pancreas result in loss of normal parenchyma that can cause pancreatic endocrine and exocrine insufficiency. Central pancreatectomy (CP) is a parenchyma-sparing option for such lesions. This study evaluates a single institutions experience with CP and compares outcomes with distal pancreatectomy (DP). METHODS We retrospectively collected data on CP patients from 1997 through 2009 and evaluated outcomes. In a subset of 50 patients, we performed a matched-pairs analysis to directly compare the short- and long-term outcomes of CP and DP. RESULTS Seventy-three patients underwent CP with a median operating room time of 254 minutes. Overall morbidity was 41.1% with pancreatic fistula in 20.5%. Mortality was 0%. There were no differences in fistula, morbidity, and mortality rates between the CP and DP groups. The CP group had resected for smaller lesions. CP patients had a lower rate of new-onset and worsening diabetes than DP patients (14% vs 46%; P = .003). Of new-onset and worsening diabetics, only 1 CP patient required insulin compared with 14 DP patients (P = .002). CONCLUSION CP is safe and effective for select neoplasms of the mid pancreas. Patients undergoing CP have markedly decreased insulin requirements compared with DP patients.

Soluble Ig-Like Transcript 3 Inhibits Tumor Allograft Rejection in Humanized SCID Mice and T Cell Responses in Cancer Patients

Attempts to enhance patients’ immune responses to malignancies have been largely unsuccessful. We now describe an immune-escape mechanism mediated by the inhibitory receptor Ig-like transcript 3 (ILT3) that may be responsible for such failures. Using a humanized SCID mouse model, we demonstrate that soluble and membrane ILT3 induce CD8+ T suppressor cells and prevent rejection of allogeneic tumor transplants. Furthermore, we found that patients with melanoma, and carcinomas of the colon, rectum, and pancreas produce the soluble ILT3 protein, which induces the differentiation of CD8+ T suppressor cells and impairs T cell responses in MLC. These responses are restored by anti-ILT3 mAb or by depletion of soluble ILT3 from the serum. Immunohistochemical staining of biopsies from the tumors and metastatic lymph nodes suggests that CD68+ tumor-associated macrophages represent the major source of soluble ILT3. Alternative splicing, resulting in the loss of the ILT3 transmembrane domain, may contribute to the release of ILT3 in the circulation. These data suggest that ILT3 depletion or blockade is crucial to the success of immunotherapy in cancer. In contrast, the inhibitory activity of soluble ILT3 on T cell alloreactivity in vitro and in vivo suggests the potential usefulness of rILT3 for immunosuppressive treatment of allograft recipients or patients with autoimmune diseases.

One Hundred Thirty Resections for Pancreatic Neuroendocrine Tumor: Evaluating the Impact of Minimally Invasive and Parenchyma-Sparing Techniques

BackgroundIncreasingly, surgeons apply minimally invasive and parenchyma-sparing techniques to the management of pancreatic neuroendocrine tumor (PNET). The aim of this study was to evaluate the impact of these approaches on patient outcomes.MethodsWe retrospectively collected data on patients with PNET and compared perioperative and pathologic variables. Survival was analyzed using the Kaplan–Meier method. Factors influencing survival were evaluated using a Cox proportional hazards model.ResultsOne hundred thirty patients underwent resection for PNET. Traditional resections included 43 pancreaticoduodenectomies (PD), 38 open distal pancreatectomies (DP), and four total pancreatectomies. Minimally invasive and parenchyma-sparing resections included 25 laparoscopic DP, 11 central pancreatectomies, five enucleations, three partial pancreatectomies, and one laparoscopic-assisted PD. Compared to traditional resections, the minimally invasive and parenchyma-sparing resections had shorter hospital stays. By univariate analysis of neuroendocrine carcinoma, liver metastases and positive resection margins correlated with poor survival. There was an increase in minimally invasive or parenchyma-sparing resections over the study period with no differences in morbidity, mortality, or survival.ConclusionIn this series, there has been a significant increase in minimally invasive and parenchyma-sparing techniques for PNET. This shift did not increase morbidity or compromise survival. In addition, minimally invasive and parenchyma-sparing operations yielded shorter hospital stays.

P16 Loss and Mitotic Activity Predict Poor Survival in Patients with Peritoneal Malignant Mesothelioma

Purpose: Peritoneal malignant mesothelioma is an aggressive neoplasm for which intensive therapy improves survival in a subset of patients. We hypothesized that pathologic variables would stratify patients into favorable and unfavorable survival subgroups. Experimental Design: Fifty-four patients with peritoneal malignant mesothelioma were evaluated for trimodal therapy from 1995 to 2003. Two pathologists evaluated pathologic variables independently, and p16 status was analyzed by immunohistochemistry. Results: Patients not receiving trimodal therapy had a significantly increased risk of death [hazard ratio (HR), 9.6; 4.3-21.6; P < 0.0001]. Biphasic histology was also associated with increased risk of death (HR, 8.5; 3.4-21.8; P < 0.0001). In multivariate analysis adjusting for treatment modality and histologic type, high mitotic rate and p16 loss were associated with increased risk of death (HR, 3.074; 1.05-9.0; P < 0.04 and HR, 3.65; 1.3-10.2; P < 0.014, respectively). Conclusions: Biphasic histology, increased mitotic rate, and p16 loss were independently associated with poorer survival in peritoneal malignant mesothelioma. Among the trimodal treated patients, increased mitotic rate was associated with increased risk of death.

Combined Resection, Intraperitoneal Chemotherapy, and Whole Abdominal Radiation for the Treatment of Malignant Peritoneal Mesothelioma

Objective:We report a single-institution Phase I or II trial of surgical debulking, intraperitoneal chemotherapy, and immunotherapy followed by whole abdominal radiotherapy in patients with malignant peritoneal mesothelioma. Methods:Between 1997 and 2000, 27 patients with malignant peritoneal mesothelioma were enrolled: 23 with epithelial subtype and 4 with sarcomatoid or mixed subtype. The treatment regimen consisted of surgical debulking followed by 4 intraperitoneal courses of cisplatin alternating with 4 courses of doxorubicin, 4 doses of intraperitoneal gamma interferon, a second laparotomy with resection of residual disease plus intraoperative intraperitoneal mitomycin and cisplatin heated to 41°C, and finally whole abdominal radiotherapy. Results:The median overall survival was 70 months with a 3-year survival of 67% (95% confidence interval, 46%–81%). Fourteen patients have died of their disease with a median time to death of 17 months (range, 0.4–71 months) after consenting to treatment. Seven patients are alive without evidence of disease with a median follow-up of 90 months (range, 71–110 months), and 6 are alive with disease with a median follow-up of 86 months (range, 70–106 months). The regimen was well tolerated. There were no patients with Grade III or IV hematological toxicities, 2 patients with Grade III ototoxicity, and 3 patients with Grade III gastrointestinal toxicity. Conclusion:Based on the results of this study, intensive multimodality therapy appears feasible and effective in this group of patients.