Simon R. Bramhall

Imbalance of expression of matrix metalloproteinases (MMPs) and tissue inhibitors of the matrix metalloproteinases (TIMPs) in human pancreatic carcinoma.

Degradation of the extracellular matrix (ECM) is an essential step in tumour invasion and metastasis. The matrix metalloproteinases (MMPs) each have different substrate specificities within the ECM and are important in its degradation. MMP activity is dependent on the levels of activated MMP and tissue inhibitors of matrix metalloproteinases (TIMPs). The expression of MMPs and TIMPs in pancreatic carcinoma, normal pancreas, and pancreatic carcinoma cell lines has been determined by Northern analysis. The transcripts have been localized by in situ hybridization and the MMP2 protein by immunohistochemistry. Expression of MMP2, ‐7, and ‐11 was greater in pancreatic carcinoma than in normal pancreas (P<0·01). MMP7 expression in normal pancreas and MMP7 and ‐11 expression in tumours was always seen with TIMP1 expression. TIMP2 was expressed in only half of the tumours and a previously undescribed transcript size is reported for TIMP2. MTMMP was expressed concurrently with MMP2 in 64 per cent of tumours, but concurrent MMP2 and TIMP2 expression occurred in only half. MMP2 mRNA was found more often in the tumour stroma than with the other MMPs or TIMPs (P<0·02). It is concluded that while overexpression of MMP7 and ‐11 may be countered by TIMP1, the aggressive phenotype of pancreatic carcinoma may occur because of overexpression of MMP2, activated by MTMMP and associated with a reduced expression of TIMP2.

Hepatic artery thrombosis following orthotopic liver transplantation: a 10-year experience from a single centre in the United Kingdom.

Hepatic artery thrombosis (HAT) occurs in 3–9% of all liver transplants and acute graft loss is a possible sequelae. We present our experience in the management of HAT over a 10‐year period. Prospectively collected data from April 1994 to April 2004 were analyzed. There were 1,257 liver transplants, 669 males, median age 51 (16–73) years. There were 61 (4.9%) cases of HAT. Early HAT occurred in 21 (1.8%). Thirty six had graft dysfunction, 11 required a regraft, and 14 died. Positive CMV serology in the donor, cold ischemia time, duration of operation, transfusions of more than 6 units of blood, and 15 units of plasma, an aortic conduit for arterial reconstruction, Roux‐en‐Y biliary reconstructions, regrafts and relaparotomy were associated with HAT. At multivariate analysis, type of biliary anastomosis was the only significant factor associated with HAT. Split or reduced liver graft were not risk factors for HAT. Number of hepatic arteries requiring multiple arterial anastomosis was not a risk for HAT. HAT resulted in a reduction in overall survival post liver transplantation. The incidence of HAT was 4.9%; with 1.8% early HAT and HAT impacted on survival. Surgical technique was not an aetiological factor for HAT. In conclusion, while a Roux‐en‐Y biliary reconstruction was an independent risk factor for HAT, cold ischemia and operative times, the use of blood and plasma and the use of aortic conduits in arterial reconstruction were associated with HAT. Regrafts and reoperation were also identified risk factors. Liver Transpl 12:146–151, 2006.

A Randomized Phase 2 Trial of Neoadjuvant Chemotherapy in Resectable Pancreatic Cancer: Gemcitabine Alone Versus Gemcitabine Combined with Cisplatin

BackgroundSurvival after surgery for pancreas cancer remains low. This improves with adjuvant chemotherapy, but up to 30% patients do not receive the prescribed treatment. Neoadjuvant therapy may increase the proportion of patients who receive all treatment components, may downstage disease before surgery, and may provide early treatment of micrometastases. This randomized phase 2 study compares gemcitabine-based chemotherapy regimens to identify the most promising regimen for future study.MethodsFifty patients with potentially resectable pancreas lesions were enrolled onto the study. Twenty-four patients were randomized to gemcitabine (1000 mg/m2) every 7 days for 43 days; 26 patients were randomized to gemcitabine (1000 mg/m2) and cisplatin (25 mg/m2), 7 to the original schedule (omitting day 22) and 19 to a revised schedule due to neutropenia (omitting days 15 and 36). The primary outcome measure was resection rate.ResultsPatients who were allocated to gemcitabine received a median of 85% of the planned dose. Patients who were allocated to combination treatment received a median of 88% and 92% of the planned gemcitabine and cisplatin doses, respectively. There were 10 episodes of grade III/IV hematological toxicity in each group. Twenty-seven patients (54%) underwent pancreatic resection, 9 (38%) in the gemcitabine arm and 18 (70%) in the combination arm, with no increase in surgical complications. To date, 34 patients (68%) have died. Twelve-month survival for the gemcitabine and combination groups was 42% and 62%.ConclusionsChemotherapy can be safely administered before pancreatic surgery. Combination therapy with gemcitabine and cisplatin is associated with a high resection rate and an encouraging survival rate, suggesting that further study is warranted.

Liver transplantation as a cure for acute intermittent porphyria

Acute intermittent porphyria occasionally causes frequent and crippling acute neurovisceral attacks associated with increased hepatic production of porphyrin precursors, resulting in long-term damage, poor quality of life, and shortened life expectancy. There has been no cure for this condition, but replacement of deficient hepatic enzymes might restore excretion of porphyrin precursors to normal and prevent acute attacks. We aimed to treat severe acute intermittent porphyria in a 19-year-old woman by liver transplantation. After the transplant, concentrations of haem precursors in the patients urine returned to normal, and 1.5 years later her quality of life was good. Our report suggests some hope of cure for selected patients with severe forms of this disease.

The matrix metalloproteinases and their inhibitors in pancreatic cancer : From molecular science to a clinical application

SummaryThe matrix metalloproteinases (MMPs) and their tissue-specific inhibitors (TIMPs) are described and their roles in tumor invasion and metastasis are reviewed. The expression and activity of the MMPs and TIMPs in pancreatic cancer is reported and illustrated with immunohistochemistry andin situ hybridization. The role of MMP inhibitors (MMPIs) is reviewed in vivo and the use of novel MMPIs, e.g., BB94 (Batimastat) and BB2516 (Marimastat), in animal experiments are also described. Finally, the preliminary results from a phase 2 trial of BB2516 (Marimastat) in pancreatic cancer are reported.

Expression of collagenase (MMP2), stromelysin (MMP3) and tissue inhibitor of the metalloproteinases (TIMP1) in pancreatic and ampullary disease.

It is now recognised that epithelial-stromal interactions are important in a wide range of disease processes including neoplasia and inflammation. Metalloproteinases are central to matrix degradation and remodelling, which are key events in tumour invasion and metastasis and may also be involved in tissue changes occurring in chronic inflammation. Immunohistochemistry was performed on sections from 50 patients with pancreatic cancer (n = 27), ampullary cancer (n = 12), low bile duct cancer (n = 3), neuroendocrine tumours (n = 3) and chronic pancreatitis (n = 5), using antibodies raised against collagenase (MMP2), stromelysin (MMP3) and tissue inhibitor of metalloproteinase (TIMP1) and developed using the avidin-biotin complex method. Abundance of MMP2, MMP3 and TIMP1 was greater in pancreatic and ampullary cancer than any other pathology and immunoreactivity in the malignant epithelial cells in pancreatic and ampullary cancer was greater than in the stromal tissues (in pancreatic cancer: MMP2 100% vs 37%, MMP3 93% vs 15%, TIMP1 93% vs 4%, P < 0.0001). There were strong correlations between the immunoreactivity of the two antibodies for MMP2 (P < 0.0001), between MMP2 and TIMP1 (P < 0.0001) and between MMP3 and TIMP1 (P < 0.0001). The immunoreactivity for TIMP1 in pancreatic and ampullary cancers with lymph node metastases was significantly less compared with those cases without lymph node metastases (P < 0.02) and there was an association between increased immunoreactivity for MMP2 and the degree of tumour differentiation (P < 0.01). The results implicate MMP2, MMP3 and TIMP1 in the invasive phenotype of pancreatic and ampullary cancer.

Portal Vein Resection in Borderline Resectable Pancreatic Cancer: A United Kingdom Multicenter Study

BACKGROUND Until recently, in the United Kingdom, borderline resectable pancreatic cancer with invasion into the portomesenteric veins often resulted in surgical bypass because of the presumed high risk for complications and the uncertainty of a survival benefit associated with a vascular resection. Portomesenteric vein resection has therefore remained controversial. We present the second largest published cohort of patients undergoing portal vein resection for borderline resectable (T3) adenocarcinoma of the head of the pancreas. STUDY DESIGN This is a UK multicenter retrospective cohort study comparing pancreaticoduodenectomy with vein resection (PDVR), standard pancreaticoduodenectomy (PD), and surgical bypass (SB). Nine high-volume UK centers contributed. All consecutive patients with T3 (stage IIA to III) adenocarcinoma of the head of the pancreas undergoing surgery between December 1998 and June 2011 were included. The primary outcomes measures are overall survival and in-hospital mortality. Secondary outcomes measure is operative morbidity. RESULTS One thousand five hundred and eighty-eight patients underwent surgery for borderline resectable pancreatic cancer; 840 PD, 230 PDVR, and 518 SB. Of 230 PDVR patients, 129 had primary closure (56%), 65 had end to end anastomosis (28%), and 36 had interposition grafts (16%). Both resection groups had greater complication rates than the bypass group, but with no difference between PD and PDVR. In-hospital mortality was similar across all 3 surgical groups. Median survival was 18 months for PD, 18.2 months for PDVR, and 8 months for SB (p = 0.0001). CONCLUSIONS This study, the second largest to date on borderline resectable pancreatic cancer, demonstrates no significant difference in perioperative mortality in the 3 groups and a similar overall survival between PD and PDVR; significantly better compared with SB.

Modelling prognostic factors in advanced pancreatic cancer.

Pancreatic cancer is the fifth most common cause of cancer death. Identification of defined patient groups based on a prognostic index may improve the prediction of survival and selection of therapy. Many prognostic factors have been identified often based on retrospective, underpowered studies with unclear analyses. Data from 653 patients were analysed. Continuous variables are often simplified assuming a linear relationship with log hazard or introducing a step function (dichotomising). Misspecification may lead to inappropriate conclusions but has not been previously investigated in pancreatic cancer studies. Models based on standard assumptions were compared with a novel approach using nonlinear fractional polynomial (FP) transformations. The model based on FP-transformed covariates was most appropriate and confirmed five previously reported prognostic factors: albumin, CA19-9, alkaline phosphatase, LDH and metastases, and identified three additional factors not previously reported: WBC, AST and BUN. The effects of CA19-9, alkaline phosphatase, AST and BUN may go unrecognised due to simplistic assumptions made in statistical modelling. We advocate a multivariable approach that uses information contained within continuous variables appropriately. The functional form of the relationship between continuous covariates and survival should always be assessed. Our model should aid individual patient risk stratification and the design and analysis of future trials in pancreatic cancer.

Donation After Cardiac Death Liver Transplant Recipients Have an Increased Frequency of Acute Kidney Injury

Donation after cardiac death (DCD) liver transplantation is associated with an increased frequency of hepato‐biliary complications. The implications for renal function have not been explored previously. The aims of this single‐center study of 88 consecutive DCD liver transplant recipients were (1) to compare renal outcomes with propensity‐risk‐matched donation after brain death (DBD) patients and (2) in the DCD patients specifically to examine the risk factors for acute kidney injury (AKI; peak creatinine ≥2 times baseline) and chronic kidney disease (CKD; eGFR <60 mL/min/1.73 m2). During the immediate postoperative period DCD liver transplantation was associated with an increased incidence of AKI (DCD, 53.4%; DBD 31.8%, p = 0.004). In DCD patients AKI was a risk factor for CKD (p = 0.035) and mortality (p = 0.017). The cumulative incidence of CKD by 3 years post‐transplant was 53.7% and 42.1% for DCD and DBD patients, respectively (p = 0.774). Importantly, increasing peak perioperative aspartate aminotransferase, a surrogate marker of hepatic ischemia reperfusion injury, was the only consistent predictor of renal dysfunction after DCD transplantation (AKI, p < 0.001; CKD, p = 0.032). In conclusion, DCD liver transplantation is associated with an increased frequency of AKI. The findings suggest that hepatic ischemia reperfusion injury may play a critical role in the pathogenesis of post‐transplant renal dysfunction.

Favourable prognostic factors in a large UK experience of adenocarcinoma of the head of the pancreas and periampullary region.

Aims: To present the surgical experience in a regional unit, analysing the post-operative outcome, and determining risk factors for survival after pancreaticoduodenectomy for periampullary and pancreatic head carcinoma. Methods: Data were collected on 251 patients with pancreatic head adenocarcinoma (133), ampullary carcinomas (88) and distal common bile duct (30), between 1987 and 2002. Survival was calculated using the Kaplan-Meier method. Clinical, surgical and histopathological records were examined by univariate and multivariate analysis to identify the independent prognostic predictors of survival. Results: Median actuarial survival for carcinoma of the pancreatic head, ampulla and distal bile duct were 13.4, 35.5 and 16 months, respectively; p < 0.0001. On univariate analysis for the whole series, the age ≤60, tumour of the head of the pancreas, lymph node positive, resection margin R1, poorly differentiated tumours, and portal vein invasion significantly decreased survival. On multivariate analysis, poor tumour differentiation, surgical margin, lymph node metastases, and age independently influence survival. Mortality and morbidity were 4.8 and 29.9%, respectively. Conclusions: Pancreaticoduodenectomy for pancreatic and periampullary tumours is the only therapy that may cure patients and can be performed safely in centres with significant experience.