Marco Montorsi

Diagnostic value of HSP70, glypican 3, and glutamine synthetase in hepatocellular nodules in cirrhosis

Hepatocellular nodules in cirrhosis include regenerative (large regenerative, LRN) and dysplastic (low and high grade, LGDN and HGDN) nodules, early and grade 1 HCC (eHCC‐G1), and overt HCC. The differential diagnosis may be particularly difficult when lesions such as HGDN and eHCC‐G1 are involved. We investigated the diagnostic yield of a panel of 3 putative markers of hepatocellular malignancy such as HSP70, glypican 3 (GPC3), and glutamine synthetase (GS). We selected 52 surgically removed nonmalignant nodules (15 LRNs, 15 LGDNs, 22 HGDNs) and 53 HCCs (10 early, 22 grade 1, and 21 grade 2‐3) and immunostained them for HSP70, GPC3, and GS. The sensitivity and specificity of the individual markers for the detection of eHCC‐G1 were 59% and 86% for GS, 69% and 91% for GPC3, and 78% and 95% for HSP70. We identified 2 main phenotypes: (1) all negative, seen in 100% LRN and LGDN, 73% HGDN and 3% eHCC‐G1; (2) all positive, a feature detected in less than half the eHCC‐G1. Using a 3‐marker panel, when at least 2 of them, regardless which, were positive, the sensitivity and specificity for the detection of eHCC‐G1 were respectively 72% and 100%; the most sensitive combination was HSP70+/GPC3+ (59%) when a 2‐marker panel was used. Conclusion: The adopted panel of 3 markers is very helpful in distinguishing eHCC‐G1 from dysplastic nodules arising in cirrhosis. (HEPATOLOGY 2007;45:725–734.)

Efficacy of octreotide in the prevention of pancreatic fistula after elective pancreatic resections: A prospective, controlled, randomized clinical trial

BACKGROUND A prospective, randomized controlled clinical trial was conducted in 33 Italian surgical departments with the aim of evaluating the efficacy of octreotide in the prevention of pancreatic fistula after elective pancreatic resections. METHODS Between July 1990 and May 1992, 278 patients were enrolled in the study. Fifty-four dropped out because of unresectable disease and six were excluded because of protocol violation; the remaining 218 were randomly assigned to the octreotide group (n = 111) or to the placebo group (n = 107). There were 131 men and 87 women with a mean age of 58.2 +/- 11.7 yrs. Pancreaticoduodenectomy was the most common operation performed (n = 143), sixty-four percent of patients had a pancreatic or periampullary cancer; chronic pancreatitis accounted for 8.2% of cases. RESULTS Mortality rate was 6.9%. A pancreatic fistula occurred in 31 patients (14.2%), 9% in the octreotide group and 19.6% in the placebo group (p < 0.05). Morbidity rate was significantly lower in the octreotide (21.6%) than in the placebo group (36.4%) (p < 0.05). When specific pancreatic complications were grouped together and evaluated, they occurred less frequently in the treated (15.3%) than in the placebo group (29.9%) (p < 0.05). CONCLUSIONS Octreotide was able to reduce significantly the incidence of pancreatic fistula after elective pancreatic resections.

Borderline resectable pancreatic cancer: A consensus statement by the International Study Group of Pancreatic Surgery (ISGPS)

BACKGROUND This position statement was developed to expedite a consensus on definition and treatment for borderline resectable pancreatic ductal adenocarcinoma (BRPC) that would have worldwide acceptability. METHODS An international panel of pancreatic surgeons from well-established, high-volume centers collaborated on a literature review and development of consensus on issues related to borderline resectable pancreatic cancer. RESULTS The International Study Group of Pancreatic Surgery (ISGPS) supports the National Comprehensive Cancer Network criteria for the definition of BRPC. Current evidence supports operative exploration and resection in the case of involvement of the mesentericoportal venous axis; in addition, a new classification of extrahepatic mesentericoportal venous resections is proposed by the ISGPS. Suspicion of arterial involvement should lead to exploration to confirm the imaging-based findings. Formal arterial resections are not recommended; however, in exceptional circumstances, individual therapeutic approaches may be evaluated under experimental protocols. The ISGPS endorses the recommendations for specimen examination and the definition of an R1 resection (tumor within 1 mm from the margin) used by the British Royal College of Pathologists. Standard preoperative diagnostics for BRPC may include: (1) serum levels of CA19-9, because CA19-9 levels predict survival in large retrospective series; and also (2) the modified Glasgow Prognostic Score and the neutrophil/lymphocyte ratio because of the prognostic relevance of the systemic inflammatory response. Various regimens of neoadjuvant therapy are recommended only in the setting of prospective trials at high-volume centers. CONCLUSION Current evidence justifies portomesenteric venous resection in patients with BRPC. Basic definitions were identified, that are currently lacking but that are needed to obtain further evidence and improvement for this important patient subgroup. A consensus for each topic is given.

Reduced likelihood of metastases in patients with microsatellite-unstable colorectal cancer

Purpose: The outcome of patients with colorectal cancer is more favorable when the tumor exhibits high-frequency microsatellite instability (MSI). Although associated with earlier-stage tumors, MSI has been proposed as an independent predictor of survival. We tested the prognostic value of MSI in a large series of patients diagnosed with colorectal cancer in the last decade. Experimental Design: The survival of 893 consecutive patients with colorectal cancer characterized by microsatellite status was analyzed. The 89 (10%) patients with MSI cancer were classified according to tumor mismatch repair (MMR) defect, MMR germ-line mutation, hMLH1 and p16 promoter methylation, BRAF and K-ras mutations, and frameshifts of target genes. Results: The colorectal cancer–specific survival was significantly (P = 0.02) better in patients with MSI cancer than in those with stable tumor (MSS). MSI did not predict a significantly lower risk of cancer-related death if tumor stage was included in the multivariate analysis [hazard ratio, 0.72; 95% confidence interval (95% CI), 0.40-1.29; P = 0.27]. Instead, MSI was strongly associated with a decreased likelihood of lymph node (odds ratio, 0.31; 95% CI, 0.17-0.56; P < 0.001) and distant organ (odds ratio, 0.13; 95% CI, 0.05-0.33; P < 0.001) metastases at diagnosis, independently of tumor pathologic features. Molecular predictors of reduced metastatic risk, and then of more favorable prognosis, included TGFβRII mutation for all MSI tumors, hMSH2 deficiency for hereditary non-polyposis colorectal cancer, and absence of p16 methylation for sporadic hMLH1-deficient cancers. Conclusions: Tumor MSI is a stage-dependent predictor of survival in patients with colorectal cancer. The decreased likelihood of metastases in patients with MSI cancer is associated with specific genetic and epigenetic changes of the primary tumor.

Definition of a standard lymphadenectomy in surgery for pancreatic ductal adenocarcinoma: A consensus statement by the International Study Group on Pancreatic Surgery (ISGPS)

BACKGROUND The lymph node (Ln) status of patients with resectable pancreatic ductal adenocarcinoma is an important predictor of survival. The survival benefit of extended lymphadenectomy during pancreatectomy is, however, disputed, and there is no true definition of the optimal extent of the lymphadenectomy. The aim of this study was to formulate a definition for standard lymphadenectomy during pancreatectomy. METHODS During a consensus meeting of the International Study Group on Pancreatic Surgery, pancreatic surgeons formulated a consensus statement based on available literature and their experience. RESULTS The nomenclature of the Japanese Pancreas Society was accepted by all participants. Extended lymphadenectomy during pancreatoduodenectomy with resection of Lns along the left side of the superior mesenteric artery (SMA) and around the celiac trunk, splenic artery, or left gastric artery showed no survival benefit compared with a standard lymphadenectomy. No level I evidence was available on prognostic impact of positive para-aortic Lns. Consensus was reached on selectively removing suspected Lns outside the resection area for frozen section. No consensus was reached on continuing or terminating resection in cases where these nodes were positive. CONCLUSION Extended lymphadenectomy cannot be recommended. Standard lymphadenectomy for pancreatoduodenectomy should strive to resect Ln stations no. 5, 6, 8a, 12b1, 12b2, 12c, 13a, 13b, 14a, 14b, 17a, and 17b. For cancers of the body and tail of the pancreas, removal of stations 10, 11, and 18 is standard. Furthermore, lymphadenectomy is important for adequate nodal staging. Both pancreatic resection in relatively fit patients or nonresectional palliative treatment were accepted as acceptable treatment in cases of positive Lns outside the resection plane. This consensus statement could serve as a guide for surgeons and researchers in future directives and new clinical studies.

Inhibitors of apoptosis proteins (IAPs) expression and their prognostic significance in hepatocellular carcinoma

BackgroundSimilarly to other tumor types, an imbalance between unrestrained cell proliferation and impaired apoptosis appears to be a major unfavorable feature of hepatocellular carcinoma (HCC). The members of IAP family are key regulators of apoptosis, cytokinesis and signal transduction. IAP survival action is antagonized by specific binding of Smac/DIABLO and XAF1. This study aimed to investigate the gene and protein expression pattern of IAP family members and their antagonists in a series of human HCCs and to assess their clinical significance.MethodsRelative quantification of IAPs and their antagonist genes was assessed by quantitative Real Time RT-PCR (qPCR) in 80 patients who underwent surgical resection for HCC. The expression ratios of XIAP/XAF1 and of XIAP/Smac were also evaluated. Survivin, XIAP and XAF1 protein expression were investigated by immunohistochemistry. Correlations between mRNA levels, protein expression and clinicopathological features were assessed. Follow-up data were available for 69 HCC patients. The overall survival analysis was estimated according to the Kaplan-Meier method.ResultsSurvivin and Livin/ML-IAP mRNAs were significantly over-expressed in cancer tissues compared to non-neoplastic counterparts. Although Survivin immunoreactivity did not correlate with qPCR data, a significant relation was found between higher Survivin mRNA level and tumor stage, tumor grade and vascular invasion.The mRNA ratio XIAP/XAF1 was significantly higher in HCCs than in cirrhotic tissues. Moreover, high XIAP/XAF1 ratio was an indicator of poor prognosis when overall survival was estimated and elevated XIAP immunoreactivity was significantly associated with shorter survival.ConclusionOur study demonstrates that alterations in the expression of IAP family members, including Survivin and Livin/ML-IAP, are frequent in HCCs. Of interest, we could determine that an imbalance in XIAP/XAF1 mRNA expression levels correlated to overall patient survival, and that high XIAP immunoreactivity was a poor prognostic factor.

Survival and recurrences after hepatic resection or radiofrequency for hepatocellular carcinoma in cirrhotic patients: a multivariate analysis

Hepatic resection is still considered the treatment of choice for hepatocellular carcinoma in patients with liver cirrhosis. Radiofrequency ablation is a new emerging modality. The aim of this study was to compare two homogeneous groups of patients who underwent either surgical resection or laparoscopic radiofrequency, analyzing the factors predicting survival and intrahepatic recurrences with use of a multivariate analysis. From February 1997 to April 2003, 98 patients were enrolled in this prospective study. Inclusion criteria were a single nodule of less than 5 cm, Child A-B class of liver function, and no previous treatment: 40 patients were in the surgical group and 58 patients were in the radiofrequency group. The two groups were homogeneous as far as preoperative characteristics were concerned. Operative mortality was zero, and the rates of operative morbidity were similar. Actuarial survival at 4 years was not significantly different (61% after resection and 45% after radiofrequency). There was a significant higher incidence of intrahepatic recurrences after radiofrequency than after resection (53% versus 30%; P = 0.018). This was mainly due to local recurrences, whereas those appearing in other liver segments were similar in both groups. A multivariate analysis showed that the significant factors predictive of an intrahepatic recurrence were the level of α-fetoprotein, the etiology of cirrhosis, and the type of the treatment. On the other hand, multivariate analysis of the survival showed that only the level of α-fetoprotein was an independent predictor of survival. The results of our study showed a significant lower incidence of intrahepatic recurrences after resection compared with after radiofrequency. This seems not to significantly influence the overall survival, probably because of a prompt and effective treatment of the recurrences themselves.

Hepatectomy for Stage B and Stage C Hepatocellular Carcinoma in the Barcelona Clinic Liver Cancer Classification: Results of a Prospective Analysis

HYPOTHESIS Using an algorithm for selection of patients with hepatocellular carcinoma (HCC) for surgery, Barcelona Clinic Liver Cancer (BCLC) classification stage B and stage C disease is not a contraindication. DESIGN Prospective cohort study. SETTING University tertiary care hospital. PATIENTS Among 163 consecutive patients with HCC, 120 (73.6%) underwent surgery; 113 of 120 (94.2%) underwent resection. Of 113 patients, 61 (54.0%) had BCLC stage 0 or A disease, 24 (21.2%) had stage B disease, and 28 (24.8%) had stage C disease. INTERVENTIONS Surgical strategy was based on the relationship of the tumor to the intrahepatic vascular structures on intraoperative ultrasonography. MAIN OUTCOME MEASURES Mortality, morbidity, rate of cut edge local recurrences, and long-term outcome were evaluated. P < .05 was considered statistically significant. RESULTS Hospital mortality was 0.9%. The overall morbidity was 27.4%, and major morbidity was 3.5%. After a median follow-up of 24 months (range, 1-65 months), there was no cut edge recurrence. For patients with BCLC stages 0 or A, B, and C disease, the 3-year overall survival rates were 81%, 67%, and 74%, respectively (P =.24); the 3-year disease-free survival rates were 30%, 35%, and 15%, respectively (P =.85); and the 3-year hepatic disease-free survival rates were 39%, 44%, and 17%, respectively (P =.79). CONCLUSIONS Patients with BCLC stage B and stage C HCC can tolerate hepatic resection with low mortality, acceptable morbidity, and survival benefits if resection is performed under strict intraoperative ultrasonographic guidance. These results should prompt revision of the BCLC recommendations.

Intraoperative ultrasound during thoracoscopic procedures for solitary pulmonary nodules

BACKGROUND Traditional nonoperative diagnostic approaches to the solitary pulmonary nodule (bronchoscopy and percutaneous needle biopsy) can be inconclusive. Video-assisted thoracic surgery (VATS) provides a minimally invasive way to diagnose and treat these nodules. We evaluated the use of a dedicated intraoperative ultrasound probe as an aid in localization of small pulmonary nodules during VATS. METHODS An intraoperative ultrasound examination during a thoracoscopic procedure was performed on 18 patients to localize deep pulmonary nodules less than 20 mm in diameter without a definitive diagnosis by preoperative imaging techniques. RESULTS In the 18 patients, all nodules were successfully identified by intraoperative ultrasound. A definitive pathologic diagnosis was obtained from thoracoscopic biopsy or resection. The final diagnoses were primary lung cancer in 5 patients, metastatic lesions in 4 patients, hamartoma or chondroma in 4, granuloma in 3, and interstitial fibrosis in 2 patients. CONCLUSIONS In our experience, intraoperative ultrasound can safely and effectively localize invisible or nonpalpable pulmonary nodules at the time of thoracoscopy. This may help surgeons perform minimally invasive lung resections with clear surgical margins.

Coenzyme Q10 in Neuromuscular and Neurodegenerative Disorders

Coenzyme Q10 (CoQ10, or ubiquinone) is an electron carrier of the mitochondrial respiratory chain (electron transport chain) with antioxidant properties. In view of the involvement of CoQ10 in oxidative phosphorylation and cellular antioxidant protection a deficiency in this quinone would be expected to contribute to disease pathophysiology by causing a failure in energy metabolism and antioxidant status. Indeed, a deficit in CoQ10 status has been determined in a number of neuromuscular and neurodegenerative disorders. Primary disorders of CoQ10 biosynthesis are potentially treatable conditions and therefore a high degree of clinical awareness about this condition is essential. A secondary loss of CoQ10 status following HMG-Coa reductase inhibitor (statins) treatment has be implicated in the pathophysiology of the myotoxicity associated with this pharmacotherapy. CoQ10 and its analogue, idebenone, have been widely used in the treatment of neurodegenerative and neuromuscular disorders. These compounds could potentially play a role in the treatment of mitochondrial disorders, Parkinsons disease, Huntingtons disease, amyotrophic lateral sclerosis, Friedreichs ataxia, and other conditions which have been linked to mitochondrial dysfunction. This article reviews the physiological roles of CoQ10, as well as the rationale and the role in clinical practice of CoQ10 supplementation in different neurological and muscular diseases, from primary CoQ10 deficiency to neurodegenerative disorders. We also briefly report a case of the myopathic form of CoQ10 deficiency.