Michael L. Kendrick

Do consensus indications for resection in branch duct intraductal papillary mucinous neoplasm predict malignancy? A study of 147 patients

BACKGROUND AND AIMS:Recent consensus guidelines suggest that presence of ≥1 of the following is an indication for resection (IR) of branch duct intraductal papillary mucinous neoplasm (IPMN-Br): cyst-related symptoms, main pancreatic duct diameter ≥10 mm, cyst size ≥30 mm, intramural nodules, or cyst fluid cytology suspicious/positive for malignancy. Among a cohort of patients with IPMN-Br we determined if the consensus IR (CIR), presence of multifocal IPMN-Br, or growth of cyst size on follow-up predict malignancy.METHODS:We identified 147 patients with IPMN-Br of whom 66 underwent surgical resection at diagnosis and 81 were followed conservatively, of whom 11 were resected during follow-up. Clinical, imaging, histological, and cyst fluid characteristics from all 147 patients with IPMN-Br were obtained from clinical records and/or by contacting the patients. In all cases, presence of CIR at baseline and during follow-up (N = 66), presence of multifocal cysts (N = 57), and increase in cyst size (N = 38) were noted.RESULTS:Among the 77 resected IPMN-Brs, at initial evaluation 61 had at least one CIR and 16 had none. Malignancy was present in 9/61 (15%) with CIR and 0/16 without IR (P = 0.1). When presence of any one of the CIR was taken as an indicator of malignancy, the CIR had a sensitivity, specificity, positive predictive value, and negative predictive value of 100%, 23%, 14%, and 100%, respectively. Prevalence of malignancy in those with single versus multifocal IPMN-Br was similar (13% vs 11%). No patient has developed malignancy after a median follow-up of 15 months. So far, none of the 38 patients with increase in cyst size on follow-up has developed malignancy related symptoms.CONCLUSIONS:Suggested consensus indications for resection identify all patients with malignancy; however, their specificity is low. In the short term it would be safe to follow patients without these features.

Total Laparoscopic Pancreaticoduodenectomy: Feasibility and Outcome in an Early Experience

HYPOTHESIS Total laparoscopic pancreaticoduodenectomy is a safe and effective therapeutic approach. DESIGN Single-institutional retrospective review. SETTING Tertiary referral center. PATIENTS All consecutive patients undergoing total laparoscopic pancreaticoduodenectomy from July 2007 through July 2009 at a single center (n = 62). MAIN OUTCOME MEASURES Blood loss, operative time, postoperative morbidity, length of hospital stay, and 30-day or in-hospital mortality. RESULTS Of 65 patients undergoing laparoscopic resection, 62 patients with a mean age of 66 years (SD, 12 years) underwent total laparoscopic pancreaticoduodenectomy. The pancreaticojejunostomy consisted of a duct-to-mucosa anastomosis with interrupted suture. Median operative time was 368 minutes (range, 258-608 minutes) and median blood loss was 240 mL (range, 30-1200 mL). Diagnosis was pancreatic adenocarcinoma (n = 31), intraductal papillary mucinous neoplasm (n = 12), periampullary adenocarcinoma (n = 8), neuroendocrine tumor (n = 4), chronic pancreatitis (n = 3), cholangiocarcinoma (n = 1), metastatic renal cell carcinoma (n = 1), cystadenoma (n = 1), and duodenal adenoma (n = 1). Median tumor size was 3 cm (range, 0.9-10.0 cm) and the median number of lymph nodes harvested was 15 (range, 6-31). Perioperative morbidity occurred in 26 patients and included pancreatic fistula (n = 11), delayed gastric emptying (n = 9), bleeding (n = 5), and deep vein thrombosis (n = 2). There was 1 postoperative mortality. Median length of hospital stay was 7 days (range, 4-69 days). CONCLUSIONS Laparoscopic pancreaticoduodenectomy is feasible, safe, and effective. Outcomes appear comparable with those via the open approach; however, controlled trials are needed. Despite this series representing experience within the learning curve, laparoscopic pancreaticoduodenectomy holds promise for providing advantages seen with minimally invasive approaches in other procedures.

Ano1 is a selective marker of interstitial cells of Cajal in the human and mouse gastrointestinal tract

Populations of interstitial cells of Cajal (ICC) are altered in several gastrointestinal neuromuscular disorders. ICC are identified typically by ultrastructure and expression of Kit (CD117), a protein that is also expressed on mast cells. No other molecular marker currently exists to independently identify ICC. The expression of ANO1 (DOG1, TMEM16A), a Ca(2+)-activated Cl(-) channel, in gastrointestinal stromal tumors suggests it may be useful as an ICC marker. The aims of this study were therefore to determine the distribution of Ano1 immunoreactivity compared with Kit and to establish whether Ano1 is a reliable marker for human and mouse ICC. Expression of Ano1 in human and mouse stomach, small intestine, and colon was investigated by immunofluorescence labeling using antibodies to Ano1 alone and in combination with antibodies to Kit. Colocalization of immunoreactivity was demonstrated by epifluorescence and confocal microscopy. In the muscularis propria, Ano1 immunoreactivity was restricted to cells with the morphology and distribution of ICC. All Ano1-positive cells in the muscularis propria were also Kit positive. Kit-expressing mast cells were not Ano1 positive. Some non-ICC in the mucosa and submucosa of human tissues were Ano1 positive but Kit negative. A few (3.2%) Ano1-positive cells in the human gastric muscularis propria were labeled weakly for Kit. Ano1 labels all classes of ICC and represents a highly specific marker for studying the distribution of ICC in mouse and human tissues with an advantage over Kit since it does not label mast cells.

Hepatic Resection of Hepatocellular Carcinoma in Patients With Cirrhosis: Model of End-Stage Liver Disease (MELD) Score Predicts Perioperative Mortality

Hepatic resection for hepatocellular carcinoma (HCC) in patients with cirrhosis is generally recommended for patients with Child-Turcotte-Pugh (CTP) Class A liver disease and early tumor stage. The Model for End-Stage Liver Disease (MELD) has been shown to accurately predict survival in patients with cirrhosis, but whether MELD is useful for selection of patients with cirrhosis for hepatic resection is unknown. We examined whether MELD was predictive of perioperative mortality and correlated MELD with other potential clinicopathologic factors to overall survival in patients with cirrhosis undergoing hepatic resection for HCC. A retrospective chart review was undertaken of patients with HCC and cirrhosis undergoing hepatic resection between 1993 and 2003. Eighty-two patients (62 men, 20 women; mean age, 62 years) were identified. Forty-five patients had MELD score ≥9 (range, 9–15) and CTP score ranged from 5 to 9 points. Fifty-nine patients underwent minor (<3 segments) hepatic resections (MELD ≤8, n = 29; MELD ≥9, n = 30) and 23 underwent major (≥3 segments) hepatic resections (MELD ≤8, n = 8; MELD ≥9, n = 15). Perioperative mortality rate was 16%. MELD score ≤8 was associated with no perioperative mortality versus 29% for patients with an MELD score ≥9 (P < 0.01). Multivariate analysis demonstrated that MELD score ≥9 (P < 0.01), clinical tumor symptoms (P < 0.01), and ASA score (P = 0.046) are independent predictors of perioperative mortality. Multivariate analysis showed MELD ≥9 (P < 0.01), tumor size >5 cm(P < 0.01), high tumor grade (P = 0.03), and absence of tumor capsule (P < 0.01) as independent predictors of decreased long-term survival. MELD score was a strong predictor of both perioperative mortality and long-term survival in patients with cirrhosis undergoing hepatic resection for HCC. In patients with cirrhosis, hepatic resection (minor or major) for HCC is recommended if the MELD score is ≤8. In patients with MELD score ≥9, other treatment modalities should be considered.

Total laparoscopic pancreaticoduodenectomy for pancreatic ductal adenocarcinoma: oncologic advantages over open approaches?

Objective:To directly compare the oncologic outcomes of TLPD and OPD in the setting of pancreatic ductal adenocarcinoma. Background:Total laparoscopic pancreaticoduodenectomy (TLPD) has been demonstrated to be feasible and may have several potential advantages over open pancreaticoduodenectomy (OPD), including lower blood loss and shorter hospital stay. Whether potential advantages could allow patients to recover in a timelier manner and pursue adjuvant treatment options remains to be answered. Methods:We reviewed data for all patients undergoing TLPD (N = 108) or OPD (N = 214) for pancreatic ductal adenocarcinoma at our institution between January 2008 and July 2013. Results:Neoadjuvant therapy, tumor size, node positivity, and margin-positive resection were not significantly different between the 2 groups. Median length of hospital stay was significantly longer in the OPD group (9 days; range, 5–73 days) than in the TLPD group (6 days; range, 4–118 days; P < 0.001). There was a significantly higher proportion of patients in the OPD group (12%) who had a delay of greater than 90 days or who did not receive adjuvant chemotherapy at all compared with that in the TLPD group (5%; P = 0.04). There was no significant difference in overall survival between the 2 groups (P = 0.22). A significantly longer progression-free survival was seen in the TLPD group than in the OPD group (P = 0.03). Conclusions:TLPD is not only feasible in the setting of pancreatic ductal adenocarcinoma but also has advantages such as shorter hospital stay and faster recovery, allowing patients to recover in a timelier manner and pursue adjuvant treatment options. This study also demonstrated a longer progression-free survival in patients undergoing TLPD than those undergoing OPD.

The effects of the alveolar recruitment maneuver and positive end-expiratory pressure on arterial oxygenation during laparoscopic bariatric surgery.

Abnormalities in gas exchange that occur during anesthesia are mostly caused by atelectasis, and these alterations are more pronounced in morbidly obese than in normal weight subjects. Sustained lung insufflation is capable of recruiting the collapsed areas and improving oxygenation in healthy patients of normal weight. We tested the effect of this ventilatory strategy on arterial oxygenation (Pao2) in patients undergoing laparoscopic bariatric surgery. After pneumoperitoneum was accomplished, the recruitment group received up to 4 sustained lung inflations with peak inspiratory pressures up to 50 cm H2O, which was followed by ventilation with 12 cm H2O positive end-expiratory pressure (PEEP). The patients lungs in the control group were ventilated in a standard fashion with PEEP of 4 cm H2O. Variables related to gas exchange, respiratory mechanics, and hemodynamics were compared between recruitment and control groups. We found that alveolar recruitment effectively increased intraoperative Pao2 and temporarily increased respiratory system dynamic compliance (both P < 0.01). The effects of alveolar recruitment on oxygenation lasted as long as the trachea was intubated, and lungs were ventilated with high PEEP, but soon after tracheal extubation, all the beneficial effects on oxygenation disappeared. The mean number of vasopressor treatments given during surgery was larger in the recruitment group compared with the control group (3.0 versus 0.8; P = 0.04). In conclusion, our data suggest that the use of alveolar recruitment may be an effective mode of improving intraoperative oxygenation in morbidly obese patients. Our results showed the effect to be short lived and associated with more frequent intraoperative use of vasopressors.

Laparoscopic vs open distal pancreatectomy: a single-institution comparative study.

HYPOTHESIS Laparoscopic distal pancreatectomy (LDP) provides outcome advantages compared with open distal pancreatectomy (ODP). DESIGN Single-institutional, retrospective review from January 1, 2004, to May 1, 2009. SETTING Tertiary referral center. PATIENTS Patients undergoing LDP (n = 100) were matched by age, pathologic diagnosis, and pancreatic specimen length to a cohort undergoing ODP (n = 100). MAIN OUTCOME MEASURES Perioperative outcomes and overall 30-day morbidity and mortality. Univariate and multivariate analyses were performed using logistic or linear regression as appropriate. RESULTS Patients in the LDP group did not differ from those in the ODP group in age (mean, 59.0 vs 58.6 years; P = .85), sex (60% vs 50% female; P = .16), body mass index (calculated as weight in kilograms divided by height in meters squared) (mean, 27.4 vs 27.9; P = .44), or American Society of Anesthesiologists score of 3 or higher (58% vs 52%; P = .39). Tumor size was greater in the ODP group than in the LDP group (mean, 4.0 vs 3.3 cm; P = .02). The LDP group as compared with the ODP group demonstrated decreased blood loss (mean, 171 vs 519 mL; P < .001) and shorter duration of hospital stay (mean, 6.1 vs 8.6 days; P < .001). There were no differences between the LDP and ODP groups in operative time (mean, 214 vs 208 minutes; P = .50), pancreatic leak rate (17% vs 17%; P > .99), overall 30-day morbidity (34% vs 29%; P = .45), and 30-day mortality (3% vs 1%; P = .62). CONCLUSIONS The laparoscopic approach to distal pancreatectomy appears to provide advantages of reduced blood loss and length of hospital stay in selected patients compared with the open approach. Overall complication rates appear similar. Patient selection bias and limits of a retrospective analysis warrant prospective validation.

CYSTIC NEOPLASMS OF THE PANCREAS: Benign to Malignant Epithelial Neoplasms

Clinical presentation and state-of-the-art imaging permit the differentiation of most cystic pancreatic neoplasms not only from other cystic pancreatic disorders but also from one another. The differentiation of serous cystic lesions from the mucinous neoplasms (cystadenoma or carcinoma and IPMT) is crucial because of the radically different biological characteristics of these two neoplasms. Although mucinous cystic neoplasms should be resected because of their premalignant or overtly malignant tendency, most patients with serous neoplasms require no operative intervention unless they are symptomatic. IPMT is best treated by a total pancreatectomy, although lesser subtotal resections should be strongly considered depending on patient age, medical comorbidity, and psychosocial situations.

Distal pancreatectomy for resectable adenocarcinoma of the body and tail of the pancreas

The study goal was to analyze outcome after distal pancreatectomy for three subtypes of adenocarcinoma to determine the role of en bloc resection in surgical management. A secondary aim was to identify those clinicopathologic factors correlating with survival in an analysis limited to ductal adenocarcinoma. Medical records of consecutive patients undergoing distal pancreatectomy for adenocarcinoma between 1987 and 2003 were reviewed. A comparative analysis was undertaken of the safety and outcome of patients undergoing standard and en bloc resections. Clinicopathologic factors for patients undergoing distal pancreatectomy for ductal adenocarcinoma were subjected to both univariate and multivariate survival analyses. Ninety-three patients underwent resection for ductal adenocarcinoma (66, 71%), mucinous cystadenocarcinoma (18, 19%), or adenocarcinoma associated with intraductal papillary mucinous neoplasm (IPMN) (9, 10%). En bloc resection was required in 33 (35%) patients. There was no operative mortality. Median survival was 15.5 months, 30.2 months, and 50.7 months for ductal adenocarcinoma, mucinous cystadenocarcinoma, and adenocarcinoma associated with IPMN, respectively. Patients undergoing en bloc resection had a higher overall complication rate, required more transfusions and more intensive care unit admissions, and had a higher rate of positive margins; however, there were no deaths. For ductal adenocarcinoma, tumor size greater than 3.5 cm, age greater than 60 years, and stage were factors that correlated with survival on a univariate analysis. None were significant on multivariate analysis. Four patients with ductal adenocarcinoma were actual 5-year survivors. While en bloc resections are associated with a higher rate of complications, the majority are self-limited and mortality is low. Resection, including adjacent organs, should be performed when appropriate. Long-term survival for patients with cystadenocarcinoma or IPMN-associated adenocarcinoma can be anticipated. While rare, long-term survival for patients with ductal adenocarcinoma after distal pancreatectomy can be achieved.

Differential expression of lumican and fatty acid binding protein-1: New insights into the histologic spectrum of nonalcoholic fatty liver disease†

The basis of hepatocellular injury and progressive fibrosis in a subset of patients with nonalcoholic fatty liver disease (NAFLD) is poorly understood. We sought to identify hepatic proteins that are differentially abundant across the histologic spectrum of NAFLD. Hepatic protein abundance was measured in liver samples from four groups (n = 10 each) of obese (body mass index >30 kg/m2) patients: (1) obese normal group (normal liver histology), (2) simple steatosis (SS), (3) nonalcoholic steatohepatitis (NASH)‐mild (steatohepatitis with fibrosis stage 0‐1), and (4) NASH‐progressive (steatohepatitis with fibrosis stage 2‐4). Hepatic peptides were analyzed on an API Qstar XL quadrupole time‐of‐flight mass spectrometer using Analyst QS software. Linear trends tests were performed and used to screen for differential abundance. Nine known proteins were expressed with differential abundance between study groups. For seven proteins differential abundance is likely to have been on the basis increased hepatic lipid content and/or inflammation. Lumican, a 40‐kDa keratin sulfate proteoglycan that regulates collagen fibril assembly and activates transforming growth factor‐beta and smooth muscle actin, was expressed similarly in obese normal and SS but was overexpressed in a progressive manner in NASH‐mild versus SS (124%, P < 0.001), NASH‐progressive versus NASH‐mild (156%, P < 0.001) and NASH‐progressive versus obese normal (178%, P < 0.001). Fatty acid binding protein‐1 (FABP‐1), which is protective against the detergent effects of excess free fatty acids, facilitates intracellular free fatty acid transport and is an important ligand for peroxisome proliferator‐activated receptor–mediated transcription, was overexpressed in SS when compared to the obese normal group (128%, P < 0.001), but was paradoxically underexpressed in NASH‐mild versus SS (73%, P < 0.001), NASH‐progressive versus NASH‐mild (81%, P < 0.001), and NASH‐progressive versus obese normal (59%, P < 0.001). Conclusion: Histologically progressive NAFLD is associated with overexpression of lumican, an important mediator of fibrosis in nonhepatic tissues, whereas FABP‐1 is paradoxically underexpressed in NASH, suggesting a new potential mechanism of lipotoxicity in NAFLD. Further studies are needed to determine the biologic basis of lumican and/or FABP‐1 dysregulation in NAFLD. (HEPATOLOGY 2009;49:1375–1384.)