Thomas J. Hugh

Proteomic profiling of cholangiocarcinoma: diagnostic potential of SELDI-TOF MS in malignant bile duct stricture.

Proteomic techniques promise to improve the diagnosis of cholangiocarcinoma (CC) in both tissue and serum as histological diagnosis and existing serum markers exhibit poor sensitivities. We explored the use of surface‐enhanced laser desorption/ionization time‐of‐flight mass spectrometry (SELDI‐TOF MS) to identify potential protein biomarkers of CC. Twenty‐two resected CC samples were compared with adjacent noninvolved bile duct tissue. Serum from patients with CC (n = 20) was compared with patients with benign disease (n = 20), and healthy volunteers (n = 25). Samples were analyzed on hydrophobic protein chips via SELDI‐TOF MS, and classification models were developed using logistic regression and cross‐validation analysis. Univariate analysis revealed 14 individual peaks differentially expressed between CC and bile duct tissue, 4 peaks between CC and benign disease, and 12 peaks between CC and sera of healthy volunteers. The 4,462 mass‐to‐charge serum peak had superior discriminatory ability to carbohydrate antigen 19.9 (CA19.9) and carcinoembryonic antigen (CEA) (P = .004; receiver operating characteristic [ROC] area under the curve [AUC] = 0.76, 0.73, and 0.70, respectively). The training models developed panels of peaks that distinguished CC from bile duct tissue (92.5% sensitivity, 92.3% specificity; ROC AUC = 0.96), CC from benign serum (65.0% sensitivity, 70.0% specificity; ROC AUC = 0.83), and CC from sera of healthy volunteers (75.0% sensitivity, 100% specificity; ROC AUC = 0.92). Serum results were further improved with the inclusion of CA19.9 and CEA (ROC AUC = 0.86 and 0.99 for CC vs benign and healthy volunteer serum, respectively). In conclusion, biomarker panels are capable of distinguishing CC from nonmalignant tissue; serum markers have important diagnostic implications for unknown bile duct stricture. (HEPATOLOGY 2006;44:658–666.)

Succinate dehydrogenase-deficient GISTs are characterized by IGF1R overexpression

Succinate dehydrogenase-deficient gastrointestinal stromal tumors (GISTs) demonstrate unique pathological and clinical features, including the absence of activating mutations of KIT and PDGFRA, and primary resistance to imatinib. They arise exclusively in the stomach and account for 5–7.5% of all adult stomach GISTs and the great majority of these tumors in childhood. Insulin-like growth factor 1 receptor (IGF1R) overexpression has been associated with wild-type and pediatric GISTs. We propose that IGF1R overexpression is a feature of succinate dehydrogenase-deficient GISTs as a group. We assessed succinate dehydrogenase complex subunit B (SDHB) and IGF1R expression by immunohistochemistry in eight known succinate dehydrogenase-deficient GISTs, three GISTs arising in the setting of neurofibromatosis type 1 syndrome and 40 unselected GISTs. Selected KIT and PDGFRA exons were amplified and sequenced from formalin-fixed paraffin-embedded tumor samples. All eight succinate dehydrogenase-deficient tumors were wild-type for KIT and PDGFRA, succinate dehydrogenase B negative and demonstrated IGF1R overexpression. The three neurofibromatosis-related tumors were succinate dehydrogenase B positive and IGF1R negative. Of the 40 unselected upper GISTs, five were wild-type for KIT and PDGFRA in the selected exons. Two of the wild-type GISTs were succinate dehydrogenase B negative and showed IGF1R overexpression and three were succinate dehydrogenase B positive and IGF1R negative. We conclude that IGF1R overexpression is a feature of succinate dehydrogenase deficient GIST as a group, rather than pediatric or wild-type GIST per se. Therefore, IGF1R inhibition represents a potential rational therapeutic approach in this recently recognized subgroup of GIST.

High expression of plasminogen activator inhibitor-2 (PAI-2) is a predictor of improved survival in patients with pancreatic adenocarcinoma.

ObjectiveRecent findings suggest that the urokinase-type plasminogen activator (uPA), its receptor (uPAR), plasminogen activator inhibitor-1 (PAI-1), and -2 (PAI-2) play key roles in cancer invasion.Summary Background DataThe prognostic value of components of this system is well established in breast cancer. However, little is known of its involvement in pancreatic cancer (PC).MethodsQuantitative real-time polymerase chain reaction (Q-RT-PCR) was used on tissue-banked specimens and immunohistochemistry (IHC) on paraffin specimens was used to measure expression of uPA, uPAR, PAI-1, and PAI-2 proteins in 46 PC and 12 cystadenoma specimens. Results were related to survival using Cox’s proportional hazards testing.ResultsIncreased expression of uPA, uPAR, and PAI-1 in PC tissue were independently associated with a higher Union Internationale Contre le Cancer [International Union Against Cancer (UICC)] tumor stage (P < 0.001) and were intercorrelated (P < 0.001). Overexpression of uPAR indicated reduced survival (P = 0.03). Conversely, PAI-2 messenger ribonucleic acid (mRNA) overexpression, which occurred in 21 of 46 tumors, negatively correlated with tumor size (P = 0.008) and survival (P < 0.007) but not with uPA, uPAR, or tumor stage. There was good agreement between PAI-2 mRNA value and IHC score (P < 0.001). Using Cox’s stepwise analysis, PAI-2 mRNA value (HR = 0.24; P = 0.001) and UICC tumor stage (HR = 2.014; P = 0.001) independently predicted survival. An IHC score for PAI-2 of 3+ or 4+ also independently predicted improved survival (HR = 2.72; P = 0.025).ConclusionsThe uPA/uPAR/PAI-1 system is activated in advanced pancreatic cancer and may account for the tumor’s aggressive behavior, whereas PAI-2 expression appears to be independent of uPA/uPAR/PAI-1 and is associated with improved prognosis. Because of its intercorrelation with mRNA expression, PAI-2 IHC may be used as an indicator of survival.

Prospective evaluation of the International Study Group for Liver Surgery definition of bile leak after a liver resection and the role of routine operative drainage: An international multicentre study

BACKGROUND The International Study Group for Liver Surgery (ISGLS) proposed a definition for bile leak after liver surgery. A multicentre international prospective study was designed to evaluate this definition. METHODS Data collected prospectively from 949 consecutive patients on specific datasheets from 11 international centres were collated centrally. RESULTS Bile leak occurred in 69 (7.3%) of patients, with 31 (3.3%), 32 (3.4%) and 6 (0.6%) classified as grade A, B and C, respectively. The grading system of severity correlated with the Dindo complication classification system (P < 0.001). Hospital length of stay was increased when bile leak occurred, from a median of 7 to 15 days (P < 0.001), as was intensive care stay (P < 0.001), and both correlated with increased severity grading of bile leak (P < 0.001). 96% of bile leaks occurred in patients with intra-operative drains. Drain placement did not prevent subsequent intervention in the bile leak group with a 5-15 times greater risk of intervention required in this group (P < 0.001). CONCLUSION The ISGLS definition of bile leak after liver surgery appears robust and intra-operative drain usage did not prevent the need for subsequent drain placement.

LEARNING THE SURGICAL CRAFT: A REVIEW OF SKILLS TRAINING OPTIONS

Surgical practice is undergoing fundamental changes, and this is having a significant effect on the training of surgeons. Learning the craft of surgery is threatened by reduced elective operative exposure and general service cuts within public teaching hospitals, safer working hour legislation and pressures to accelerate the training of young surgeons. Rapid technological changes mean that ‘old dogs’ have to teach ‘young dogs’ many new tricks in a relatively adverse environment. This review outlines the great variety of resources available for skills‐based training outside the operating room. These resources are ready to be used as a necessary adjunct to the training of competent surgeons in Australasia.

Grafts for Mesenterico-Portal Vein Resections Can Be Avoided during Pancreatoduodenectomy

BACKGROUND The aim of this study was to assess whether pancreatoduodenectomy (PD) and en bloc mesenterico-portal resection (PD+VR) could be performed with primary venous reconstruction, avoiding a vascular graft. In addition, the short-term surgical outcomes of this approach were compared with a standard PD (PD-VR). STUDY DESIGN Two hundred twelve patients underwent PD between January 2004 and June 2011. Clinical data, operative results, pathologic findings, and postoperative outcomes were collected prospectively and analyzed. RESULTS One hundred fifty patients (71%) had PD-VR and 62 patients underwent PD+VR. The majority (82%) of the venous reconstructions were performed with primary end-to-end anastomosis. Only 1 patient had synthetic interposition graft repair. The volume of intraoperative blood loss and the perioperative blood transfusion requirements were significantly greater, and the duration of the operation was significantly longer in the PD+VR group compared with the PD-VR group. There were no significant differences in the length of hospitalization, postoperative morbidity, or grades of complications between the 2 groups. Multivariate logistic regression identified American Society of Anesthesiologists score as the only predictor of postoperative morbidity. Fifty percent of patients with pancreatic adenocarcinoma (n = 101) required VR. A significantly higher rate of positive resection margins (p < 0.001) was noted in the PD+VR subgroup compared with PD-VR subgroup. Furthermore, high intraoperative blood loss and neural invasion were predictive of a positive resection margin. CONCLUSIONS Pancreatoduodenectomy with VR and primary venous anastomosis avoids the need for a graft and has comparable postoperative morbidity with PD-VR. However, it is associated with an increased operative time, higher intraoperative blood loss, and, for pancreatic ductal adenocarcinoma, a higher rate of positive resection margins compared with PD-VR.

Loss of BAP1 Expression Occurs Frequently in Intrahepatic Cholangiocarcinoma.

AbstractBRCA1-associated protein 1 (BAP1) is a deubiquitinating enzyme that functions as a tumor suppressor gene. Double hit BAP1 inactivation has been reported in a range of tumor types, including intrahepatic cholangiocarcinoma (ICC), sometimes in association with germline mutation.We performed immunohistochemistry for BAP1 on a well-characterized cohort of 211 ICC patients undergoing surgical resection with curative intent at 3 institutions based in 3 different countries. The median age at diagnosis was 65 years (range, 36.5–86) and 108 (51%) were men. Negative staining for BAP1 (defined as completely absent nuclear staining in the presence of positive internal controls in nonneoplastic cells) occurred in 55 ICCs (26%). BAP1 loss predicted a strong trend toward improved median survival of 40.80 months (95% CI, 28.14–53.46) versus 24.87 months (95% CI, 18.73–31.01), P = 0.059). In a multivariate model including age, sex, BAP1 status, tumor stage, tumor grade, lymphovascular invasion, and tumor size, female sex was associated with improved survival (hazard ratio [HR] 0.54; 95% CI, 0.34–0.85), while advanced tumor stage and lymphovascular invasion (HR 1.89; 95% CI, 1.09–3.28) correlated with decreased survival. In a multivariate analysis, high grade tumors were associated with BAP1 loss (odds ratio [OR] 3.32; 95% CI, 1.29–8.55), while lymphatic invasion was inversely associated with BAP1 loss (OR 0.36; 95% CI, 0.13–0.99).In conclusion, we observed a trend toward improved prognosis in ICC associated with absent expression of BAP1 and an association of BAP1 loss with higher histological grade and absent lymphatic invasion. Female sex was associated with improved survival while advanced tumor stage and lymphatic invasion were associated with decreased survival.

Focal nodular hyperplasia--a review of myths and truths.

BackgroundFocal nodular hyperplasia (FNH) is a benign hyperplastic lesion of the liver with no known malignant potential. It has generated much interest due to the frequency with which it presents with atypical features on radiological imaging. Often resulting in misdiagnosis. Moreover, the understanding of particular subtypes of this lesion at a molecular level has changed in recent years. This may have implications on how certain subtypes should be managed.PurposeThis review aims to analyse current literature pertaining to FNH and to provide clinically relevant advice regarding diagnosis and management.

Clinical care and technical recommendations for 90yttrium microsphere treatment of liver cancer

Selective internal radiation therapy (SIRT) with 90yttrium microspheres is a relatively new clinical modality for treating non‐resectable malignant liver tumours. This interventional radiology technique employs percutaneous microcatheterisation of the hepatic arterial vasculature to selectively deliver radioembolic microspheres into neoplastic tissue. SIRT results in measurable tumour responses or delayed disease progression in the majority of eligible patients with hepatocellular carcinoma or hepatic metastases arising from colorectal cancer. It has also been successfully used as palliative therapy for non‐colorectal malignancies metastatic to the liver. Although most adverse events are mild and transient, SIRT also carries some risks for serious and – rarely – fatal outcomes. In particular, entry of microspheres into non‐target vessels may result in radiation‐induced tissue damage, such as severe gastric ulceration or radiation cholecystitis. Radiation‐induced liver disease poses another significant risk. By careful case selection, considered dose calculation and meticulous angiographic technique, it is possible to minimise the incidence of such complications to less than 10% of all treatments. As the number of physicians employing SIRT expands, there is an increasing need to consolidate clinical experience and expertise to optimise patient outcomes. Authored by a panel of clinicians experienced in treating liver tumours via SIRT, this paper collates experience in vessel mapping, embolisation, dosimetry, microsphere delivery and minimisation of non‐target delivery. In addition to these clinical recommendations, the authors propose institutional criteria for introducing SIRT at new centres and for incorporating the technique into multidisciplinary care plans for patients with hepatic neoplasms.

One hundred and seventy-eight consecutive pancreatoduodenectomies without mortality: role of the multidisciplinary approach

BACKGROUND Pancreatoduodenectomy offers the only chance of cure for patients with periampullary cancers. This, however, is a major undertaking in most patients and is associated with a significant morbidity and mortality. A multidisciplinary approach to the workup and follow-up of patients undergoing pancreatoduodenectomy was initiated at our institution to improve the diagnosis, resection rate, mortality and morbidity. We undertook the study to assess the effect of this approach on diagnosis, resection rates and short-term outcomes such as morbidity and mortality. METHODS A prospective database of patients presenting with periampullary cancers to a single surgeon between April 2004 and April 2010 was reviewed. All cases were discussed at a multidisciplinary meeting comprising surgeons, gastroenterologists, radiologists, oncologists, radiation oncologists, pathologists and nursing staff. A standardized investigation and management algorithm was followed. Complications were graded according to the Clavien-Dindo classification. RESULTS A total of 295 patients with a periampullary lesion were discussed and 178 underwent pancreatoduodenectomy (resection rate 60%). Sixty-one patients (34%) required either a vascular or an additional organ resection. Eighty-nine patients experienced complications, of which the commonest was blood transfusion (12%). Thirty-four patients (19%) had major complications, i.e. grade 3 or above. There was no in-hospital, 30-day or 60-day mortality. CONCLUSIONS Pancreatoduodenectomy can safely be performed in high-volume centers with very low mortality. The surgeons role should be careful patient selection, intensive preoperative investigations, use of a team approach, and an unbiased discussion at a multidisciplinary meeting to optimize the outcome in these patients.