Michael J. Zinner

Minimally invasive esophagectomy: outcomes in 222 patients.

Objective: To assess our outcomes after minimally invasive esophagectomy (MIE). Summary Background Data: Esophagectomy has traditionally been performed by open methods. Results from most series include mortality rates in excess of 5% and hospital stays frequently greater than 10 days. MIE has the potential to improve these results, but only a few small series have been reported. This report summarizes our experience of 222 cases. Methods: From 1996 to 2002, MIE was performed in 222 patients. Indications for operation included high-grade dysplasia (n = 47) and cancer (n = 175). Neoadjuvant chemotherapy was used in 78 (35.1%) and radiation in 36 (16.2%). Initially, a laparoscopic transhiatal approach was used (n = 8), but subsequently our approach evolved to include thoracoscopic mobilization (n = 214). Results: There were 186 men and 36 women. Median age was 66.5 years (range, 39–89). Nonemergent conversion to open procedure was required in 16 patients (7.2%). MIE was successfully completed in 206 (92.8%) patients. The median intensive care unit stay was 1 day (range, 1–30); hospital stay was 7 days (range, 3–75). Operative mortality was 1.4% (n = 3). Anastomotic leak rate was 11.7% (n = 26). At a mean follow-up of 19 months (range, 1–68), quality of life scores were similar to preoperative values and population norms. Stage specific survival was similar to open series Conclusions: MIE offers results as good as or better than open operation in our center with extensive minimally invasive and open experience. In this single institution experience, we observed a lower mortality rate (1.4%) and shorter hospital stay (7 days) than most open series. Given these results, we are now developing an intergroup trial (ECOG 2202) to assess MIE in a multicenter setting.

Relationship of necrosis to organ failure in severe acute pancreatitis.

BACKGROUND & AIMS Pancreatic necrosis and organ failure are principal determinants of severity in acute pancreatitis. The purpose of this study was to determine the relationship of necrosis to organ failure in severe acute pancreatitis. METHODS Patients with necrotizing pancreatitis from May 1992 to January 1996 were retrospectively studied. Pancreatic necrosis was identified by characteristic findings on dynamic contrast-enhanced computerized tomography scan and infected necrosis by computerized tomography-guided percutaneous aspiration. Organ dysfunction was defined in accordance with the Atlanta symposium. RESULTS Organ failure was present in only 26 of 51 patients (51%). There was no difference in the prevalence of organ failure in infected necrosis compared with sterile necrosis (approximately 50% in both groups). Patients with increased amounts of necrosis did not have an increased prevalence of organ failure or infected necrosis compared with those with lesser amounts of necrosis. Patients with organ failure had an increased morbidity and mortality compared with those without organ failure. CONCLUSIONS Organ failure occurred in only one half of patients with necrotizing pancreatitis. Because organ failure increases the severity of illness, studies of patients with necrotizing pancreatitis must stratify for organ failure to facilitate interpretation of results.

Open cholecystectomy. A contemporary analysis of 42,474 patients.

ObjectiveThis study evaluated, in a large, heterogeneous population, the outcome of open cholecystectomy as it is currently practiced. Summary Background and DataAlthough cholecystectomy has been the gold standard of treatment for cholelithiasis for more than 100 years, it has recently been challenged by the introduction of several new modalities including laparoscopic cholecystectomy. Efforts to define the role of these alternative treatments have been hampered by the lack of contemporary data regarding open cholecystectomy. MethodsA population-based study was performed examining all open cholecystectomies performed by surgeons in an eastern and western state during a recent 12-month period. Data compiled consisted of a computerized analysis of Uniformed Billing (UB-82) discharge analysis information from all non-Veterans Administration (VA), acute care hospitals in California (Office of Statewide Planning and Development [OSHPD]) and in Maryland (Health Services Cost Review Commission [HSCRC]) between January 1, 1989, and December 31, 1989. This data base was supplemented with a 5% random sample of Medicare UB-82 data from patients who were discharged between October 1,1988, and September 30, 1989. Patients undergoing cholecystectomy were identified based on diagnosis-related groups (DRG-197 and DRG-198), and then classified by Principal Diagnosis and divided into three clinically homogeneous subgroups: acute cholecystitis, chronic cholecystitis, and complicated cholecystitis. ResultsA total of 42,474 patients were analyzed, which represents approximately 8% of all patients undergoing cholecystectomy in the United States in any recent 12-month period. The overall mortality rate was 0.17% and the Incidence rate of bile duct injuries was approximately 0.2%. The mortality rate was 0.03% in patients younger than 65 years of age and 0.5% in those older than 65 years of age. Mortality rate, length of hospital stay, and charges were all significantly correlated (p < 0.001) with age, admission status (elective, urgent, or emergent), and disease status. ConclusionsThese data indicate that open cholecystectomy currently is a very safe, effective treatment for cholelithiasis and is being performed with near zero mortality. The ultimate role of laparoscopic

Relationship of perioperative hyperglycemia and postoperative infections in patients who undergo general and vascular surgery.

Objective:Evaluate the association of perioperative hyperglycemia and postoperative infections (POI) in patients who had undergone general surgery. Background:Intensive glucose control leads to less postoperative infections (POI) in critically ill surgical patients, but the relationship of hyperglycemia and POI in a general surgical population remains unknown. Methods:A retrospective study of 995 patients who had undergone general and vascular surgery investigated the association of perioperative acute hyperglycemia and risk of 30-day POI over an 18-month period. The primary predictor of interest was postoperative glucose (POG). Bivariate analyses determined the association of each independent variable with POI. Factors significant at P < 0.05 were used in multivariable logistic regression models. Results:In bivariate analyses, preoperative blood glucose (P = 0.012), POG (P = 0.009), age (P = 0.002), diabetes (P = 0.04), American Society of Anesthesia Classification (ASAC) (P < 0.0001), operation length (P = 0.02), and blood transfusions (P = 0.02) were significant predictors of POI. In multivariate analyses, only POG (OR = 1.3, (1.03–1.64)), ASAC (OR = 1.9, (1.31–2.83)), and emergency status (OR = 2.2, (1.21–3.80)) remained significant predictors of POI. Postoperative hyperglycemia increased the risk of POI by 30% with every 40-point increase from normoglycemia (<110 mg/dL). Longer hospitalization was also observed for patients with POG from 110 to 200 mg/dL (OR = 1.4, (1.1–1.7)) and >200 mg/dL (OR = 1.8, (1.4–2.5)). Conclusion:The increased risk of POI and length of hospitalization posed by postoperative hyperglycemia is independent of diabetic status and needs further evaluation to assess for possible benefits of postoperative glycemic control in patients who have undergone general surgery.

Necrotizing pancreatitis: Contemporary analysis of 99 consecutive cases

ObjectiveTo analyze the impact of a conservative strategy of management in patients with necrotizing pancreatitis, reserving intervention for patients with documented infection or the late complications of organized necrosis. Summary Background DataThe role of surgery in patients with sterile pancreatic necrosis remains controversial. Although a conservative approach is being increasingly used, few studies have evaluated this strategy when applied to the entire spectrum of patients with necrotizing pancreatitis. MethodsThe authors reviewed 1,110 consecutive patients with acute pancreatitis managed at Brigham and Women’s Hospital between January 1, 1995, and January 1, 2000, focusing on those with pancreatic necrosis documented by contrast-enhanced computed tomography. Fine-needle aspiration, the presence of extraintestinal gas on computed tomography, or both were used to identify infection. ResultsThere were 99 (9%) patients with necrotizing pancreatitis treated, with an overall death rate of 14%. In three patients with underlying medical problems, the decision was made initially not to intervene. Of the other 62 patients without documented infection, all but 3 were managed conservatively; this group’s death rate was 11%. Of these seven deaths, all were related to multiorgan failure. Five patients in this group eventually required surgery for organized necrosis, with no deaths. Of the 34 patients with infected necrosis, 31 underwent surgery and 3 underwent percutaneous drainage. Only four (12%) of these patients died, all of multiorgan failure. Of the total 11 patients who died, few if any would have been candidates for earlier surgical intervention. ConclusionsThese results suggest that conservative strategies can be applied successfully to manage most patients with necrotizing pancreatitis, although some will eventually require surgery for symptomatic organized necrosis. Few if any patients seem likely to benefit from a more aggressive strategy.

RNA interference targeting the M2 subunit of ribonucleotide reductase enhances pancreatic adenocarcinoma chemosensitivity to gemcitabine.

Ribonucleotide reductase is emerging as an important determinant of gemcitabine chemoresistance in human cancers. Activity of this enzyme, which catalyses conversion of ribonucleotide 5′-diphosphates to their 2′-deoxynucleotides, is modulated by levels of its M2 subunit (RRM2). Here we show that RRM2 overexpression is associated with gemcitabine chemoresistance in pancreatic adenocarcinoma cells, and that suppression of RRM2 expression using RNA interference mediated by small interfering RNA (siRNA) enhances gemcitabine-induced cytotoxicity in vitro. We demonstrate the ability of systemically administered RRM2 siRNA to suppress tumoral RRM2 expression in an orthotopic xenograft model of pancreatic adenocarcinoma. Synergism between RRM2 siRNA and gemcitabine results in markedly suppressed tumor growth, increased tumor apoptosis and inhibition of metastasis. Our findings confirm the importance of RRM2 in pancreatic adenocarcinoma gemcitabine chemoresistance. This is the first demonstration that systemic delivery of siRNA-based therapy can enhance the efficacy of an anticancer nucleoside analog.

Management of Proximal cholangiocarcinomas by surgical resection and radiotherapy

Ninety-six patients with proximal cholangiocarcinomas were managed surgically. Fifty-three patients (55 percent) were resected, 39 curatively (41 percent), and 43 (45 percent) underwent palliative stenting. The preoperative placement of Ring catheters and the operative use of silastic transhepatic biliary stents greatly facilitated the surgical management of these lesions. Sixty-three patients (66 percent) also received postoperative radiotherapy. Hospital mortality was 4 percent (four deaths). Hospital mortality was 2 percent after resection (1 of 53 patients) and 7 percent after palliative stenting (3 of 43 patients). All deaths resulted from sepsis. One, 3, 5, and 10-year survivals for the entire group were 49 percent, 12 percent, 5 percent, and 2 percent, respectively. One, 3, 5, and 10-year survivals in the resected group (66 percent, 21 percent, 8 percent, and 4 percent, respectively) were superior to those in the stented group (27 percent, 6 percent, 0 percent, and 0 percent, respectively). Radiotherapy appeared to significantly extend survival in those patients undergoing palliative stenting, but not in those undergoing resection. We conclude that surgical resection of proximal cholangiocarcinomas can be performed safely and that it significantly prolongs survival. Further improvement in long-term survival will depend on advances in adjuvant therapy.

The application of positron emission tomographic imaging with fluorodeoxyglucose to the evaluation of breast disease.

Positron emission tomography (PET) is a computer-aided tomographic imaging technique that uses positron-emitting compounds to trace biochemical processes of tissue, and construct images based on them. The authors applied a whole-body PET imaging technique to patients with breast masses or mammographic abnormalities using the isotope 2-[F-18]-fluoro-2-deoxy-D-glucose (FDG), in a clinical trial to evaluate the feasibility of using PET to identify primary breast cancer, axillary lymph node involvement, and systemic metastases, before surgical resection. Fourteen patients have been entered on this study, 10 of whom proved to have breast cancer. Positron emission tomography correctly predicted the nature of 12 of the 14 primary breast lesions, and correctly determined the lymph node status of 11 of the 14 patients. The authors conclude that PET with FDG has potential as a diagnostic modality for detection of primary breast cancer, particularly in the patient with radiodense breasts by conventional mammography, and that it has potential for the preoperative identification of axillary lymph node metastases.

EphA2: a determinant of malignant cellular behavior and a potential therapeutic target in pancreatic adenocarcinoma

The EphA2 receptor tyrosine kinase is overexpressed in a variety of human cancers. We sought to characterize the role of EphA2 in pancreatic adenocarcinoma and, using RNA interference (RNAi) mediated by small interfering RNA (siRNA), we determined the effects of suppressing EphA2 expression in vitro and in vivo. EphA2 expression in PANC1, MIAPaCa2, BxPC3 and Capan2 cells was assessed by Northern and Western blot. We artificially overexpressed EphA2 by transient transfection and suppressed EphA2 expression using RNAi. Cellular invasiveness was quantified by modified Boyden chamber assay. Anoikis was induced by anchorage-independent polyHEMA culture and caspase 3 activity was quantified fluorometrically. Focal adhesion kinase (FAK) phosphorylation was assessed by immunoprecipitation. EphA2 siRNA treatment was assessed in a nude mouse xenograft model. Pancreatic adenocarcinoma cells differentially express EphA2. Inherent and induced EphA2 overexpression is associated with increased cellular invasiveness and anoikis resistance. EphA2 siRNA suppresses EphA2 expression, cellular invasiveness, anoikis resistance and FAK phosphorylation in vitro and retards tumor growth and inhibits metastasis in vivo. EphA2 is both a determinant of malignant cellular behavior and a potential therapeutic target in pancreatic adenocarcinoma.

Is severity of necrotizing pancreatitis increased in extended necrosis and infected necrosis

Introduction We previously reported that organ failure occurs in 50% of patients with necrotizing pancreatitis, that extended pancreatic necrosis (greater than 50% necrosis) is not associated with an increased prevalence of organ failure or infected necrosis, and that the prevalence of organ failure is similar in sterile necrosis and infected necrosis. Aims To analyze these relations in a larger group of patients and to evaluate other factors that might have prognostic significance. Methodology We reviewed 1,110 consecutive cases of acute pancreatitis between January 1, 1995, and January 1, 2000. Necrosis was documented by contrast-enhanced CT. A p value less than 0.05 was considered significant. Results Ninety-nine patients (9%) had necrotizing pancreatitis; 52% had organ failure. Patients with extended pancreatic necrosis did not have increased prevalence of organ failure or infected necrosis but did have an increased need for intubation and an increased mortality rate associated with multiple organ failure. Patients with infected necrosis did not have an increased prevalence of organ failure but did have a marginally increased prevalence of multiple organ failure and increased need for intubation. Overall mortality was 14% and was markedly increased among patients with organ failure at admission (47%) and among patients who had multiple organ failure during the hospitalization (49%). Conclusion Although severity of necrotizing pancreatitis was somewhat increased in extended pancreatic necrosis and infected necrosis, mortality was more strongly linked to organ failure at admission and multiple organ failure during hospitalization.