Leandro Gennari

Liver Transplantation for the Treatment of Small Hepatocellular Carcinomas in Patients with Cirrhosis

BACKGROUND The role of orthotopic liver transplantation in the treatment of patients with cirrhosis and hepatocellular carcinoma is controversial, and determining which patients are likely to have a good outcome after liver transplantation is difficult. METHODS We studied 48 patients with cirrhosis who had small, unresectable hepatocellular carcinomas and who underwent liver transplantation. In 94 percent of the patients, the cirrhosis was related to infection with hepatitis B virus, hepatitis C virus, or both. The presence of tumor was confirmed by biopsy or serum alpha-fetoprotein assay. The criteria for eligibility for transplantation were the presence of a tumor 5 cm or less in diameter in patients with single hepatocellular carcinomas and no more than three tumor nodules, each 3 cm or less in diameter, in patients with multiple tumors. Thirty-three patients with sufficient hepatic function underwent treatment for the tumor, mainly chemoembolization, before transplantation. After liver transplantation, the patients were followed prospectively for a median of 26 months (range, 9 to 54). No anticancer treatment was given after transplantation. RESULTS The overall mortality rate was 17 percent. After four years, the actuarial survival rate was 75 percent and the rate of recurrence-free survival was 83 percent. Hepatocellular carcinoma recurred in four patients (8 percent). The overall and recurrence-free survival rates at four years among the 35 patients (73 percent of the total) who met the predetermined criteria for the selection of small hepatocellular carcinomas at pathological review of small hepatocellular carcinomas at pathological review of the explanted liver wer 85 percent and 92 percent, respectively, whereas the rates in the 13 patients (27 percent) whose tumors exceeded these limits were 50 percent and 59 percent, respectively (P=0.01 for overall survival; P=0.002 for recurrence-free survival). In this group of 48 patients with early-stage tumors, tumor-node-metastasis status, the number of tumors, the serum alphafetoprotein concentration, treatment received before transplantation, and 10 other variables were not significantly correlated with survival. CONCLUSIONS Liver transplantation is an effective treatment for small, unresectable hepatocellular carcinomas in patients with cirrhosis.

Subtotal Versus Total Gastrectomy for Gastric Cancer: Five-Year Survival Rates in a Multicenter Randomized Italian Trial

OBJECTIVE To evaluate the impact of subtotal (SG) versus total (TG) gastrectomy on the oncologic outcome of patients with cancer of the distal stomach from 28 Italian institutions. SUMMARY BACKGROUND DATA There is controversy over whether SG and TG have a different impact on the 5-year survival probability of patients with cancer of the distal half of the stomach. METHODS The present analysis involved 618 patients randomized during surgery to SG (315) or TG (303), provided there was at least 6 cm from the proximal edge of the tumor to the cardia, there was no intrapertoneal or distant spread, and it was possible to remove the tumor entirely. Both surgical treatments included regional lymphadenectomy. RESULTS Four patients died after SG and seven after TG. Median follow-up was 72 months after SG (range 2 to 125) and 75 months after TG (range 7 to 113). Five-year survival probability as computed by the Kaplan-Meier method was 65.3% for SG and 62.4% for TG. The test of equivalence led to the conclusion that the two procedures may be considered equivalent in terms of 5-year survival probability. The analysis of survival using a multivariate Cox regression model showed a statistically significant impact on survival of tumor site, tumor spread within the gastric wall, extent of resection to the spleen plus or minus neighboring organs or structures, and relative frequency of metastasis in resected lymph nodes. CONCLUSIONS Both procedures have a similar survival probability. The authors believe that SG, which has been reported to be associated with a better nutritional status and quality of life, should be the procedure of choice, provided that the proximal margin of the resection falls in healthy tissue.

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.

Total Versus Subtotal Gastrectomy: Surgical Morbidity and Mortality Rates in a Multicenter Italian Randomized Trial

OBJECTIVE The purpose of this study was to analyze postoperative morbidity and mortality of patients included in a randomized trial comparing total versus subtotal gastrectomy for gastric cancer. SUMMARY BACKGROUND DATA There is controversy as to whether the optimal surgery for gastric cancer in the distal half of the stomach is subtotal or total gastrectomy. Although only a randomized trial can resolve this oncologic dilemma, the first step is to demonstrate whether the two procedures are penalized by different postoperative morbidity and mortality rates. METHODS A total of 624 patients with cancer in the distal half of the stomach were randomized to subtotal gastrectomy (320) or total gastrectomy (304), both associated with a second-level lymphadenectomy, in a multicenter trial aimed at assessing the oncologic outcome after the two procedures. The end points considered were the occurrence of a postoperative event, complication, or death and length of postoperative stay. RESULTS Nonfatal complications and death occurred in 9% and 1% of subtotal gastrectomy patients and in 13% and 2% of total gastrectomy patients, respectively. Multivariate analysis of postoperative events showed that splenectomy or resection of adjacent organs was associated with a twofold risk of postoperative complications. Random surgery and extension of surgery influenced the length of stay. The mean length of stay, adjusted for extension of surgery, was 13.8 days for subtotal gastrectomy and 15.4 days for total gastrectomy. CONCLUSIONS Our data show that subtotal and total gastrectomies, with second-level lymphadenectomy, performed as an elective procedure have a similar postoperative complication rate and surgical outcome. A conclusive long-term evaluation of the two operations and an accurate estimate of the oncologic impact of surgery on long-term survival, not penalized by excess surgical risk of one of the two operations, are consequently feasible.

Surgical treatment of hepatic metastases from colorectal cancer.

From 1980 to 1984, 48 patients were subjected to liver resection for hepatic metastases from colorectal cancer. The disease was staged according to the original staging system proposed by the authors: stage I, single metastasis involving less than 25% of hepatic parenchyma (21 patients); stage II, multiple metastases involving less than 25% of hepatic parenchyma or single metastasis involving between 25-50% (9 patients); and stage III, multiple metastases involving between 25-50% or more than 50% of hepatic parenchyma, irrespective of the number of metastases (18 patients). The extent of hepatic resection was generally related to that of liver disease; a typical lobectomy was performed in 28 patients and segmentectomies in 20. One patient died after operation (mortality, 2.1%), and major complications occurred in seven patients (morbidity, 14.9%). Morbidity was related to operatory blood loss: 45% of patients with blood replacement of more than 2000 cc developed major complications versus 5.4% with blood replacement of less than 2000 cc (p less than 0.05). The actuarial 3-year survival for stages I, II, and III was 73%, 60%, and 29%, respectively (p less than 0.05). Twenty-two patients (45%) have had recurrences, all stage III patients within 2 years of resection versus 28% of stage I patients (30 months disease-free survival, 49%). The liver only was the site of recurrence in 10 patients, distant sites in seven, and both liver and distant in five. Analysis of the different features of the primary tumor, the interval between bowel resection and detection of hepatic metastases, and the number and extent of liver secondaries demonstrated that prognosis after surgery was mainly related to the latter; they are considered in the staging system adopted in this study. It is a simple system and shows a good prognostic correlation. The results reported here are in agreement with those of the literature; the low mortality and morbidity and the survival benefit support the growing acceptance of surgery in treatment of hepatic metastases from colorectal cancer, in particular stage I patients. For the other stages, surgery should represent, when applicable, only the first step of a multimodality treatment.

Adequacy of margins of resection in gastrectomy for cancer.

This study determines the infiltration rate of proximal and distal margins of resection in patients operated on for gastric cancer at the Istituto Nazionale Tumori of Milan. Two hundred and eighty-five proximal margins and 286 distal margins were reviewed, and the incidence of infiltration was related to the length of grossly tumor-free edge, the location, site, size, and gross appearance of the tumor, degree of invasion of the gastric wall, histologic type, and status of perigastric lymph nodes. Infiltration occurred in 7.3% of oral margins of transection and in 2.6% of aboral margins. Except for the degree of invasion of the gastric wall, no correlation was found among the infiltration rate and the above parameters. In fact, the incidence of infiltration of the proximal edge was significantly higher (6.4% vs. 0.8%, p < 0.01) when the tumor penetrated the serosa or spread beyond it than when the lesion was confined to the mucosa, submucosa, or muscular layer. With reference to the length of margin of resection, it is noteworthy that no involvement was found when cranial distance between the lesion and line of transection was equal to or greater than 6 cm. Proximal or distal infiltration for a distance greater than 3 cm did not occur in patients with lesions confined to the mucosa, submucosa, and muscularis. This data should provide the surgeon with a rational basis for assessing the extent of resection when performing gastrectomy for cancer.

Intrahepatic chemotherapy for unresectable hepatocellular carcinoma

From 1976 to 1983, 28 patients (24 male and four female) with unresectable hepatocellular carcinoma (HCC) were treated by intraarterial chemotherapy at the Istituto Nazionale Tumori of Milan, Milan, Italy. Tumors were retrospectively classified by a previously proposed staging system. Two patients were classified as Stage I and 26 as Stage II. Liver cirrhosis was present only in the males (in 50% of them). Nineteen patients were treated with doxorubicin (Adriamycin [Adria Laboratories, Columbus, OH]) and nine with 5‐fluorouraciI. Systemic toxicity was mild, but the treatment induced hepatic toxicity (ascites, clinical jaundice, or biochemical impairment) in 18% of noncirrhotic and 66% of cirrhotic patients. Clinical reduction of hepatomegaly was observed in 50% of noncirrhotic versus 16% of cirrhotic patients. Doxorubicin was effective in 66% of noncirrhotic patients and 20% of cirrhotic patients, with an overall response rate of 42%. 5‐fluorouracil was effective only in patients without cirrhosis, with an overall response rate of 22%. Overall median actuarial survival was 3.5 months, with a significant difference between noncirrhotic and cirrhotic patients (6 versus 2 months, respectively). Overall median survival of patients who responded to the treatment was 13 versus 2 months for nonresponders (P < 0.001). Liver cirrhosis was the most important prognostic factor in terms of liver toxicity, response rate, and survival. This study emphasized the negative impact of the treatment on cirrhotic patients. Also, the real value of intraarterial administration of doxorubicin was investigated.

A Clinicopathologic Study of Primary Hepatic Carcinoid Tumors

Six cases of primary hepatic carcinoid tumors were studied with combined immunocytochemical and electron microscopic techniques. Positive tumor immunostaining with PHE5, LK2H10, neuron‐specific enolase (NSE), serotonin, gastrin, and insulin antibodies was observed. At the ultrastructural level, cytoplasmic dense granules were seen in all the cases tested. This finding supports a putative origin of these carcinoids found in the liver from a pluripotential stem cell. The clinical course and follow‐up of these cases suggests that this unusual hepatic neoplasm has a more favorable prognosis than other forms of hepatic cancer.

Surgical treatment of locally recurrent rectal carcinoma

PURPOSE: This study was performed to analyze the outcomes of patients with local (pelvic) recurrence (following radical surgery for rectal cancer) who subsequently underwent a new operation. METHODS: Forty-five patients (19 percent of 213 local recurrences) were explored surgically because the disease was deemed to be confined to the pelvis with a limited extension and, therefore, amenable to surgical cure. RESULTS: Only 21 of the 45 patients who underwent surgical exploration had an oncologically radical operation (RO). In the remaining 24 patients, either a simple exploration or palliation or a nonradical procedure (R1-R2) was performed. In the RO group, there was a 19 percent five-year survival ratevs.a 0 percent rate in the R1-R2 group (median survival, 4 months). Site of recurrence (anastomosisvs.other sites) was statistically associated with a higher chance of long-term survival for those who underwent an RO operation. CONCLUSIONS: The prognosis of locally recurrent rectal cancer is dismal; less than 10 percent of all patients who underwent surgical treatment benefit from reoperation with an overall survival for five years. On the basis of these results, we no longer consider the surgical approach as the primary option for treating locally recurrent rectal cancer.

Genetic and epigenetic changes in primary metastatic and nonmetastatic colorectal cancer

Colorectal cancer (CRC) develops as multistep process, which involves genetic and epigenetic alterations. K-Ras, p53 and B-Raf mutations and RASSF1A, E-Cadherin and p16INK4A promoter methylation were investigated in 202 CRCs with and without lymph node and/or liver metastasis, to assess whether gene abnormalities are related to a metastogenic phenotype. K-Ras, B-Raf and p53 mutations were detected in 27, 3 and 32% of the cases, with K-Ras mutations significantly associated with metastatic tumour (P=0.019). RASSF1A, E-Cadherin and p16INK4A methylation was documented in 20, 44 and 33% of the cases with p16INK4A significantly associated with metastatic tumours (P=0.001). Overall, out of 202 tumours, 34 (17%) did not show any molecular change, 125 (62%) had one or two and 43 (21%) three or more. Primary but yet metastatic CRCs were prevalent in the latter group (P=0.023) where the most frequent combination was one genetic (K-Ras in particular) and two epigenetic alterations. In conclusion, this analysis provided to detect some molecular differences between primary metastatic and nonmetastatic CRCs, with K-Ras and p16INK4A statistically altered in metastatic tumours; particular gene combinations, such as coincidental K-Ras mutation with two methylated genes are associated to a metastogenic phenotype.