Steven N. Hochwald

Hilar Cholangiocarcinoma: patterns of spread, the importance of hepatic resection for curative operation, and a presurgical clinical staging system.

OBJECTIVES To determine the resectability rate for hilar cholangiocarcinoma, to analyze reasons for unresectability, and to devise a presurgical clinical T-staging system. METHODS Ninety patients with hilar cholangiocarcinomas seen between March 1, 1991, and April 1, 1997, were evaluated. Accurate patterns of disease progression and therapy were evaluable. Disease was staged in 87 patients using extent of ductal tumor involvement, portal vein compromise, and liver atrophy. RESULTS In 21 patients, disease was deemed unresectable for cure at presentation. In 39 patients, disease was found to be unresectable at laparotomy, 23 secondary to nodal (N2) or distant metastases. Unresectability was the result of metastases in 52% and of locally advanced disease in 28%. Thirty patients (33%) had resection of all gross disease, and 25 of these (83%) had negative histologic margins. Twenty-two patients underwent partial hepatectomy. The 30-day mortality rate was 7%. Projected survival is greater than 60 months in those with a negative histologic margin, with a median follow-up of 26 months. A presurgical T-staging system allows presurgical selection for therapy, predicts partial hepatectomy, and offers an index of prognosis. CONCLUSIONS In half the patients, unresectability is mainly the result of intraabdominal metastases. Presurgical imaging predicts unresectability based on local extension but is poor for assessing nodal metastases. In one third of patients, disease can be resected for cure with a long median survival. Curative resection depends on negative margins, and hepatic resection is necessary to achieve this. The T-staging system correlates with resectability, the need for hepatectomy, and overall survival.

Preoperative portal vein embolization for extended hepatectomy.

ObjectiveTo examine the authors’ experience with preoperative ipsilateral portal vein embolization (PVE) and assess its role in extended hepatectomy. Summary Background DataExtended hepatectomy (five or more liver segments) has been associated with higher complication rates and increased postoperative liver dysfunction than have standard hepatic resections involving lesser volumes. Recently, PVE has been used in patients who have a predicted (postresection) future liver remnant (FLR) volume less than 25% of total liver volume in an attempt to increase the FLR and reduce complications. MethodsSixty patients from 1996 to 2002 were reviewed. Thirty-nine patients had PVE preoperatively. Eight patients who had PVE were not resected either due to the discovery of additional unresectable disease after embolization but before surgery (n = 5) or due to unresectable disease at surgery (n = 3). Therefore, 31 patients who had PVE subsequently underwent extended hepatic lobectomy. A comparable cohort of 21 patients who had an extended hepatectomy without PVE were selected on the basis of demographic, tumor, and liver volume characteristics. Patients had colorectal liver metastases (n = 30), hepatocellular carcinoma (n = 15), Klatskin tumors (n = 9), peripheral cholangiocarcinoma (n = 3), and other tumors (n = 3). The 52 resections performed included 42 extended right hepatectomies, 6 extended left hepatectomies, and 4 right hepatectomies extended to include the middle hepatic vein and the caudate lobe but preserving the majority of segment 4. Concomitant vascular reconstruction of either the inferior vena cava or hepatic veins was performed in five patients. ResultsThere were no differences between PVE and non-PVE groups in terms of tumor number, tumor size, tumor type, surgical margin status, complexity of operation, or perioperative red cell transfusion requirements. The predicted FLR was similar between PVE and non-PVE groups at presentation. After PVE the FLR was higher than in the non-PVE group. No complications were observed after PVE before resection. There was no difference in postoperative mortality, with one death from liver failure in the non-PVE group and no operative mortality in the PVE group. Postoperative peak bilirubin was higher in the non-PVE than the PVE group, as were postoperative fresh-frozen plasma requirements. Liver failure (defined as the development of encephalopathy, ascites requiring sustained diuretics or paracentesis, or coagulopathy unresponsive to vitamin K requiring fresh-frozen plasma after the first 24 hours postresection) was higher in the non-PVE patients than the PVE patients. The hospital stay was longer in the non-PVE than the PVE group. ConclusionsPreoperative PVE is a safe and effective method of increasing the remnant liver volume before extended hepatectomy. Increasing the remnant liver volume in patients with estimated postresection volumes of less than 25% appears to reduce postoperative liver dysfunction.

A prospective, randomized trial of early enteral feeding after resection of upper gastrointestinal malignancy

OBJECTIVE The purpose of the study was to determine whether early postoperative enteral feeding with an immune-enhancing formula (IEF) decreases morbidity, mortality, and length of hospital stay in patients with upper gastrointestinal (GI) cancer. SUMMARY BACKGROUND DATA Early enteral feeding with an IEF has been associated with improved outcome in trauma and critical care patients. Evaluable data documenting reduced complications after major upper GI surgery for malignancy with early enteral feeding are limited. METHODS Between March 1994 and August 1996, 195 patients with a preoperative diagnosis of esophageal (n = 23), gastric (n = 75), peripancreatic (n = 86), or bile duct (n = 11) cancer underwent resection and were randomized to IEF via jejunostomy tube or control (CNTL). Tube feedings were supplemented with arginine, RNA, and omega-3 fatty acids, begun on postoperative 1, and advanced to a goal of 25 kcal/kg per day. The CNTL involved intravenous crystalloid solutions. Statistical analysis was by t test, chi square, or logistic regression. RESULTS Patient demographics, nutritional status, and operative factors were similar between the groups. Caloric intake was 61% and 22% of goal for the IEF and CNTL groups, respectively. The IEF group received significantly more protein, carbohydrate, lipids and immune-enhancing nutrients than did the CNTL group. There were no significant differences in the number of minor, major, or infectious wound complications between the groups. There was one bowel necrosis associated with IEF requiring reoperation. Hospital mortality was 2.5% and median length of hospital stay was 11 days, which was not different between the groups. CONCLUSION Early enteral feeding with an IEF was not beneficial and should not be used in a routine fashion after surgery for upper GI malignancies.

Emerging implications of nanotechnology on cancer diagnostics and therapeutics

Nanotechnology is multidisciplinary field that involves the design and engineering of objects <500 nanometers (nm) in size. The National Cancer Institute has recognized that nanotechnology offers an extraordinary, paradigm‐changing opportunity to make significant advances in cancer diagnosis and treatment. In the last several decades, nanotechnology has been studied and developed primarily for use in novel drug‐delivery systems (e.g. liposomes, gelatin nanoparticles, micelles). A recent explosion in engineering and technology has led to 1) the development of many new nanoscale platforms, including quantum dots, nanoshells, gold nanoparticles, paramagnetic nanoparticles, and carbon nanotubes, and 2) improvements in traditional, lipid‐based nanoscale platforms. The emerging implications of these platforms for advances in cancer diagnostics and therapeutics form the basis of this review. A widespread understanding of these new technologies is important, because they currently are being integrated into the clinical practice of oncology. Cancer 2006.

Prognostic Factors in Pancreatic Endocrine Neoplasms: An Analysis of 136 Cases With a Proposal for Low-Grade and Intermediate-Grade Groups

PURPOSE In some organs (eg, the lung), endocrine tumors are classified on the basis of mitotic rate and necrosis. The purpose of this study was to evaluate prognostic factors in pancreatic endocrine neoplasms recently treated at a single institution. PATIENTS AND METHODS In 136 patients undergoing surgery from 1979 to 1998, the influence on disease-free survival (DFS) and disease-specific survival (DSS) of tumor size, mitotic rate, vascular invasion, necrosis, metastases, and nuclear grade was determined. Cases were further grouped according to an existing proposed classification system and then regrouped on the basis of mitotic rate (< 2 mitoses per 50 high-power fields v higher) and necrosis (present or absent) into low- and intermediate-grade groups. RESULTS Correlations with DFS and DSS in univariate analysis included < or = 2 mitoses per 50 high-power fields (P =.001, P =.002), vascular invasion (P =.02, P =.04), size < or = 2 cm (P =.01, P =.05), metastases (P =.0002, P =.07), necrosis (P =.002, P =.16), and nuclear grade (P =.04, P =.33), respectively. By multivariate analysis, for DFS, tumor necrosis and presence of metastases retained significance (P =.01, P =.04, respectively). For DSS, only mitotic rate was a prognostic factor (P =.02). Among the 18 macroadenomas, eight borderline tumors, and 48 low-grade carcinomas, there was no significant difference in DSS between any groups (P =.3). However, in evaluating our newly proposed groups, the differences in DFS and DSS between low- and intermediate-grade groups were highly significant (P =.0007, P =.006, respectively). CONCLUSION Pancreatic endocrine neoplasms exhibit a spectrum of biologic behavior, and the proposed benign (macroadenoma) and borderline groups contain potentially aggressive tumors. An alternative system based on mitotic rate and necrosis correlates strongly with survival without specifically designating any group as benign.

Determining Prognosis in Patients With Pancreatic Endocrine Neoplasms: Can the WHO Classification System Be Simplified?

PURPOSE The WHO classification for well-differentiated pancreatic endocrine neoplasms (PENs) incorporates both stage and grade. This study compares the prognostic value of a simplified staging and grading system with the WHO system in a large single-institution study. PATIENTS AND METHODS A prospective database (1982 to 2005) identified 183 patients who underwent operative treatment for PENs. Tumors were staged (< 2 cm primary, >/= 2 cm primary, or metastases) and graded (low grade: no necrosis and < two mitoses/50 high-powered fields [HPF]; or intermediate grade: necrosis and/or >/= two mitoses/50 HPF) with a simplified schema. Influence of stage and grade on recurrence and disease-specific survival (DSS) was determined. Prognostic strength was assessed with the concordance index (CI). RESULTS Median age of the 183 patients was 56 years, and 53% were women. Median follow-up time was 44 months (range, 1 to 226 months). Classification identified 28 patients (15%) with WHO 1.1 disease, 74 (41%) with 1.2 disease, and 81 (44%) with 2.0 disease. Classification by stage identified 35 patients (19%) with tumors less than 2 cm, 96 (52%) with tumors >/= 2 cm, and 52 (29%) with nodal or distant metastases. Tumors were low grade in 102 patients (56%). Earlier stage tumors were more likely to be low grade (< 2 cm, 83%; >/= 2 cm, 61%; metastases, 28%; P < .001). The WHO classification, tumor stage, and grade were associated with 5-year DSS (P < .001). Tumors >/= 2 cm or metastases are stratified by grade (5-year DSS rate for low v intermediate grade: >/= 2 cm, 97% v 80%, respectively; P < .001; metastases, 93% v 62%, respectively; P = .05). The CI was 0.72 for WHO, 0.71 for stage, 0.66 for grade, and 0.76 for stage combined with grade. CONCLUSION Accurate prognostic information can be obtained by combining tumor size and metastases with simple grading information based on necrosis and mitotic rate.

Malignant peripheral nerve sheath tumor: Molecular pathogenesis and current management considerations

Malignant Peripheral Nerve Sheath Tumors (MPNSTs) are rare tumors that often occur in patients with neurofibromatosis 1. Surgical resection represents the mainstay of treatment. Radiation and chemotherapy have a role in selected patients with MPNST. Accurate pathologic diagnosis remains a challenge in many cases of MPNST. There are many recent advances in the understanding of the molecular pathogenesis of MPNST which represent the best opportunities to develop new strategies for management of patients with MPNST. J. Surg. Oncol. 2008;97:340–349.

Role of endoscopic ultrasound (EUS) and EUS-guided fine needle aspiration in the diagnosis and treatment of cystic lesions of the pancreas.

Introduction and Aims Cystic neoplasms of the pancreas may be inadvertently treated as benign pseudocysts in clinical practice, often without the use of cytology, cyst tumor markers, or histopathology. We assessed the utility of EUS-guided fine-needle aspiration (EUS-FNA) to assist in the diagnosis and management of pancreatic cysts. Methodology All patients who had pancreatic cysts detected by EUS over a 24-month period were analyzed. Preoperative diagnosis was derived from an algorithm combining clinical history and endosonographic features. In selected cases, EUS-FNA was performed and cyst fluid aspirates were analyzed. Surgical specimens served as diagnostic standard. Results A total of 43 patients with pancreatic cysts underwent 45 EUS examinations. Surgical specimens were obtained from 9 patients (mucinous cystadenocarcinoma, 3; adenocarcinoma, 3; pancreatic endocrine tumor, 2; and benign cyst, 1); diagnostic EUS correctly predicted malignant cysts in 8/9 (88.9%). One case inaccurately interpreted by EUS as cystic neoplasm turned out to be a benign cyst on resection. Twenty-one patients underwent EUS-FNA. The cytologic interpretation was adenocarcinoma in 9.5% (2/21); suspicious for malignancy or atypical cells in 19.0% (4/21); benign in 66.6% (14/21); and insufficient cells in 4.8% (1/21). Conclusion The information gathered from clinical history and EUS, complemented by fluid analysis after EUS-guided FNA, predicts neoplastic pancreatic cysts and assists in decision-making for medical or surgical approach.

Is intra-abdominal drainage necessary after pancreaticoduodenectomy?☆

Closed suction drains after pancreaticoduodenectomy are theoretically used to drain potential collections and anastomotic leaks. It is unknown whether such drains are effective, harmful, or affect the outcome after this operation. Eighty-nine consecutive patients underwent pancreaticoduodenectomy for presumed periampullary malignancy and were retrospectively reviewed. Thirty-eight had no intraabdominal drains and 51 had drains placed at the conclusion of the operation. We analyzed patient, nutritional, laboratory, and operating room factors with end points being complications and length of hospital stay. Intra-abdominal complications were defined as intra-abdominal abscess and pancreatic or biliary fistula. Postoperative interventions were defined as CT-guided drainage and reoperation. Analysis was by Student’s t test and chi-square test. Two of eight surgeons contributed 92% of the patients without drains. The groups were equivalent with respect to demographic, nutritional, and operative factors. Time under anesthesia was significantly shorter in the group without drains (P = 0.0001). There was no statistical difference in the rate of fistula, abscess, CT drainage, or length of hospital stay. Intra-abdominal drainage did not significantly alter the risk of fistula, abscess, or reoperation or the necessity for CT-guided intervention after pancreaticoduodenectomy. Routine use of drains after pancreaticoduodenectomy may not be necessary and should be subjected to a randomized trial.

A novel small molecule inhibitor of FAK decreases growth of human pancreatic cancer

Focal adhesion kinase (FAK) is a cytoplasmic tyrosine kinase that is overexpressed in many types of tumors, including pancreatic cancer, and plays an important role in cell adhesion and survival signaling. Pancreatic cancer is a lethal disease and is very resistant to chemotherapy, and FAK has been shown recently to assist in tumor cell survival. Therefore, FAK is an excellent potential target for anti-cancer therapy. We identified a novel small molecule inhibitor (1,2,4,5-Benzenetetraamine tetrahydrochloride, that we called Y15) targeting the main autophosphorylation site of FAK and hypothesized that it would be an effective treatment strategy against human pancreatic cancer. Y15 specifically blocked phosphorylation of Y397-FAK and total phosphorylation of FAK. It directly inhibited FAK autophosphorylation in a dose- and time-dependent manner. Furthermore, Y15 increased pancreatic cancer cell detachment and inhibited cell adhesion in a dose-dependent manner. Y15 effectively caused human pancreatic tumor regression in vivo, when administered alone and its effects were synergistic with gemcitabine chemotherapy. This was accompanied by a decrease in Y397-phosphorylation of FAK in the tumors treated with Y15. Thus, targeting the Y397 site of FAK in pancreatic cancer with the small molecule inhibitor, 1,2,4,5-Benzenetetraamine tetrahydrochloride, is a potentially effective treatment strategy in this deadly disease.