Andrea Casadei Gardini

Liver resection for hepatocellular carcinoma on cirrhosis: univariate and multivariate analysis of risk factors for intrahepatic recurrence.

ObjectiveTo evaluate prognostic factors that could affect disease-free survival and recurrence after liver resection for hepatocellular carcinoma (HCC) on cirrhosis. Summary Background DataTumor recurrence is the main cause of poor survival after liver resection for HCC on cirrhosis. MethodsTwo hundred twenty-four liver resections for HCC on cirrhosis were retrospectively reviewed. Univariate and multivariate analyses were performed on several clinicopathologic variables to analyze factors affecting long-term outcome and intrahepatic recurrence. The relation between preoperative aminotransferase level and recurrence rate was evaluated in the overall group, and separately in HCV-positive and in HBsAg-positive patients. Median follow-up was 35.6 months. ResultsThe 1-, 3-, and 5-year overall survival rates were 83%, 62.8%, and 42.5%, respectively. The 1-, 3-, and 5-year disease-free survival rates were 70.3%, 43%, and 27.4%, respectively. The 1-, 3-, and 5-year recurrence rates were 20.8%, 38.6%, and 54.4% respectively. Tumor recurrence appeared in 93 patients (41.5%) and was the main cause of death in 51 patients (56%). Number of nodules, tumor capsule, microvascular portal vein thrombosis, and preoperative serum aspartate aminotransferase (AST) level significantly affected disease-free survival and recurrence rates. On multivariate analysis, single nodules and preoperative AST level less than twice normal (2N) were related to a better 5-year disease-free survival and lower tumor recurrence. In particular, among HCV-positive patients the recurrence rate was strongly affected by the preoperative AST level. ConclusionsChild A patients with single nodules are the best candidates for liver resection. Tumor recurrence is strictly linked to the status of the underlying liver disease, and a preoperative AST level equal to 2N seems to be a sensitive cutoff among patients with different risks of recurrence. HCV-positive patients with AST levels above 2N have the highest risk for intrahepatic recurrence and should be monitored carefully or offered alternative treatments.

Liver resection for hepatocellular carcinoma in cirrhotics and noncirrhotics. Evaluation of clinicopathologic features and comparison of risk factors for long‐term survival and tumour recurrence in a single centre

Background : Differences in risk factors for survival and recurrence after liver resection for hepatocellular carcinoma (HCC) in patients with or without cirrhosis are not fully clarified.

The Role of Lymphadenectomy for Liver Tumors: Further Considerations on the Appropriateness of Treatment Strategy

Objective:To evaluate the role of regional lymphadenectomy in patients with liver tumors. Background:Lymph node status is 1 of the most important prognostic factors in oncologic surgery; however, the role of lymph node dissection remains unclear for hepatic tumors. Methods:A total of 120 consecutive patients undergoing liver resections for primary and secondary hepatic tumors were prospectively enrolled in the study. “Regional” lymphadenectomy was carried out routinely after specimen removal. Incidence, site, and influence on survival of node metastases were analyzed. Results:Only 1 postoperative complication (intra-abdominal bleeding) was related to lymph node excision. Median number of dissected nodes was 6.8 ± 3.6. Periportal, pericholedochal, and common hepatic artery stations were always removed. Lymph node metastases were found in 17 (16.5%) patients. The percentage rises to 20.3% when considering only noncirrhotic patients. The incidence of lymph node metastases was 7.5% for hepatocellular carcinoma, 14% for colorectal metastases, 40% for noncolorectal metastases, and 40% for intrahepatic cholangiocarcinoma (P < 0.002). Median survival time was 486 ± 93.2 days among all patients with node metastases and 725 ± 29.7 among patients without node metastases. The 2-year survival was 37.1% and 86.7%, in the 2 groups (P < 0.05). The 2-year recurrence rate was 77.6% and 45.3%, respectively (P < 0.05). Conclusions:Regional lymphadenectomy is a safe procedure after liver resection, and it should be routinely applied in patients with primary and secondary hepatic tumors, particularly in those without chronic disease. A careful evaluation of node status is nevertheless advisable also in patients with hepatocellular carcinoma on cirrhosis.

Venous outflow reconstructions with the piggyback technique in liver transplantation: a single-center experience of 431 cases

The ideal method of venous outflow reconstruction with the piggyback technique (PB) in orthotopic liver transplantation (OLT) is not well‐established. The complications related to PB in 431 primary OLTs were analyzed comparing the orifices used for the anastomosis (cuff of the recipient left and middle hepatic veins [LM], LM with a >1 cm cavoplasty [LM+], or also including the right hepatic vein [LMR]). Treatment strategies and outcome were also evaluated. Twenty patients (4.6%) experienced complications: 13 of 120 (10.8%) with LM, four of 225 (1.8%) with LM+, and three of 86 (3.5%) with LMR (LM versus LM+: P < 0.0001; LM versus LMR: P = NS; LM+ versus LMR = NS). Balloon dilation was successful in 10 of 13 cases in which it was attempted (77%). Eight patients required retransplantation (40%). Three patients (0.7%) died from causes linked to stenosis. Five‐year survival of patients with and without complications was 75% and 79%, respectively (P =NS); 5‐year graft survival was 50% and 76%, respectively (P = 0.001). The stump formed by the recipient left and middle hepatic veins with a transversal incision >1 cm of the caval wall constantly provides an adequate width for the caval anastomosis with the PB.

KRAS, BRAF and PIK3CA Status in Squamous Cell Anal Carcinoma (SCAC)

Anti-EGFR therapy appears to be a potential treatment option for squamous cell anal carcinoma (SCAC). KRAS mutation is a rare event in SCAC, indicating the absence of the principal mechanism of resistance to this type of therapy. However, no information is available from the literature regarding the status of BRAF or PIK3CA in this cancer type. We analysed KRAS, BRAF and PIK3CA status in SCAC patients in relation to the clinical-pathological characteristics of patients and to the presence of the human papilloma virus (HPV). One hundred and three patients were treated with the Nigro scheme for anal cancer from March 2001 to August 2012. Fifty patients were considered for the study as there was insufficient paraffin-embedded tumour tissue to perform molecular analysis the remaining 53. DNA was extracted from paraffin-embedded sections. KRAS, BRAF and PIK3CA gene status and HPV genotype were evaluated by pyrosequencing. KRAS and BRAF genes were wild-type in all cases. Conversely, PIK3CA gene was found to be mutated in 11 (22%) cases. In particular, 8 mutations occurred in exon 9 and 3 in exon 20 of the PIK3CA gene. These findings suggest that SCAC could potentially respond to an anti-EGFR drug. PIK3CA mutation may be involved in the process of carcinogenesis in some cases of SCAC.

Predictive role of multiple gene alterations in response to cetuximab in metastatic colorectal cancer: a single center study.

BackgroundKRAS mutations negatively affect outcome after treatment with cetuximab in metastatic colorectal cancer (mCRC) patients. As only 20% of KRAS wild type (WT) patients respond to cetuximab it is possible that other mutations, constitutively activating the EGFR pathway, are present in the non-responding KRAS WT patients. We retrospectively analyzed objective tumor response rate, (ORR) progression-free (PFS) and overall survival (OS) with respect to the mutational status of KRAS, BRAF, PIK3CA and PTEN expression in mCRC patients treated with a cetuximab-based regimen.Methods67 mCRC patients were enrolled onto the study. DNA was extracted from paraffin-embedded sections derived from primary or metastatic lesions. Exon 2 of KRAS and exon 15 of BRAF were analyzed by direct sequencing, PIK3CA was evaluated by pyrosequencing and PTEN expression by immunohistochemistry.ResultsBRAF and PIK3CA mutations were independently associated with worse PFS (p = 0.006 and p = 0.028, respectively) and OS (p = 0.008 and p = 0.029, respectively). No differences in clinical outcome were found between patients who were positive or negative for PTEN expression. Conversely, patients negative for KRAS, BRAF and PIK3CA mutations were characterized by significantly better ORR, PFS and OS than patients with at least one of these mutations.ConclusionsBRAF and PIK3CA mutations would seem to be independent predictors of anti-EGFR therapy effectiveness and could be taken into consideration during treatment decision making.

Adjuvant adoptive immunotherapy with tumour-infiltrating lymphocytes and modulated doses of interleukin-2 in 22 patients with melanoma, colorectal and renal cancer, after radical metastasectomy, and in 12 advanced patients

Abstract Adoptive tumour infiltrating lymphocytes (TIL) in combination with a modulated dosage of interleukin-2 (IL-2) can be used with acceptable toxicity in the treatment of immunogenic tumours. Following an experience of reinfusion in advanced melanoma, colorectal and renal cancer patients, treatment was given to disease-free patients after metastasectomy. The high risk of relapse and favourable ratio between reinfused TIL and possible microscopic residual disease determined this choice of adjuvant treatment. A group of 12 patients with advanced disease (7 melanoma, 4 colorectal carcinoma, 1 kidney carcinoma) were treated with TIL (median 5.8×1010 cells) and IL-2 (West’s schedule) modulated towards a lower dosage (from 12 to 6 MIU/day) in order to maintain an acceptable level of toxicity. As treatment was well tolerated, it was offered to another 22 patients in an adjuvant setting after metastasectomy (11 melanoma, 10 colorectal carcinoma, 1 renal cancer), the median dose of TIL reinfused being 4.95×1010 cells. No objective response was observed in advanced patients: all patients progressed after a median of 1.5 months (0–8 months) and median survival was 8 months (3–22+ months). Thirteen patients from the second group are still disease-free after a median of 23+ months (9+–47+ months). The remaining 9 patients relapsed after a median of 5 months (3–18 months). Toxicity was moderate as clinical and hepatic/renal function parameters were used to assess the need for dose reductions. Consequently, there was great diversity in IL-2 dosages administered. In particular, there seemed to be a difference in IL-2 doses administered between disease-free cases and those who progressed (17.5 MIU/day versus 7 MIU/day in melanoma patients; 11.2 MIU/day versus 7.1 MIU/day in colorectal cancer patients). By contrast, no differences were observed between number of TIL reinfused and clinical response. Phenotypical characteristics of reinfused TIL were similar to those reported in the literature: 97% were CD3 and 92% were CD8. Aspecific cytolytic activity was evaluated on 12 cases whereas, in 2 melanoma cases, autologous tumour tissue was available for the specific cytotoxicity test. Perforin levels in TIL measured at the end of culture were generally high or very high. Cytokine levels were measured on the supernatant at the end of culture, with an estreme variability in results. Finally, ζ chain and p56lck were histologically assessed on the resected tissue from which TIL were cultivated. There were virtually none of the former and a complete absence of the latter, which concurs with data reported in the literature. The same immunocytochemical analysis was carried out on TIL at the end of culture. This time an almost complete restoration of both functions was seen, especially in melanoma patients, who are still free from disease. The study is on-going and it has been decided to focus on disease-free patients after metastasectomy in order to increase the number and possibility of clinical and histological correlations.

Effects of metformin on clinical outcome in diabetic patients with advanced HCC receiving sorafenib

Background and objective: Several studies have reported an association between type 2 diabetes mellitus and hepatocellular carcinoma (HCC). Data from several retrospective studies and meta-analyses have highlighted a reduction of about 50% in the risk of developing HCC in cirrhotic patients treated with metformin for diabetes. The aim of this study was to evaluate the different outcomes of patients who received or did not receive metformin during treatment with sorafenib. Methods: We analyzed 93 patients consecutively treated with sorafenib. Forty-two (45.2%) patients were diabetic, of whom 31 were on metformin. Progression-free survival (PFS) and overall survival (OS) were estimated with the Kaplan-Meier method and compared with the log-rank test. Results: The concomitant use of sorafenib and metformin was associated with a median PFS of 2.6 months (95% CI 1.9–3.3) compared to 5.0 months (95% CI 2.5–8.2) for patients receiving sorafenib alone (p = 0.029). The median OS of patients treated with the combination was 10.4 months (95% CI 3.9–14.4) compared to 15.1 months (95% CI 11.7–17.8) for those who were not given metformin (p = 0.014). Conclusions: Our findings could be the result of increased tumor aggressiveness and resistance to sorafenib in metformin-treated patients.

Immunotherapy for colorectal cancer: where are we heading?

ABSTRACT Introduction: In the last few years, significant advances in molecular biology have provided new therapeutic options for colorectal cancer (CRC). The development of new drugs that target the immune response to cancer cells seems very promising and has already been established for other tumor types. In particular, the use of immune checkpoint inhibitors seems to be an encouraging immunotherapeutic strategy. Areas covered: In this review, the authors provide an update of the current evidence related to this topic, though most immunotherapies are still in early-phase clinical trials for CRC. To understand the key role of immunotherapy in CRC, the authors discuss the delicate balance between immune-stimulating and immune-suppressive networks that occur in the tumor microenvironment. Expert opinion: Modulation of the immune system through checkpoint inhibition is an emerging approach in CRC therapy. Nevertheless, selection criteria that could enable the identification of patients who may benefit from these agents are necessary. Furthermore, potential prognostic and predictive immune biomarkers based on immune and molecular classifications have been proposed. As expected, additional studies are required to develop biomarkers, effective therapeutic strategies and novel combinations to overcome immune escape resistance and enhance effector response.

Fecal DNA for Noninvasive Diagnosis of Colorectal Cancer in Immunochemical Fecal Occult Blood Test–Positive Individuals

Background: We aimed to define the potential of the fecal DNA assay as an alternative or in addition to the currently used immunochemical fecal occult blood test (iFOBT) for the early diagnosis of colorectal cancer. Methods: A total of 560 individuals aged 50 to 69 years with a positive iFOBT were recruited from an Italian FOBT regional screening program. Twenty-six were diagnosed with adenocarcinoma, 264 with high-risk adenoma, and 54 with low-risk adenoma, whereas 216 subjects did not have premalignant or malignant lesions. Fecal DNA integrity was analyzed blindly by the fluorescence long DNA (FL-DNA) test. Results: iFOBT and FL-DNA were largely independent variables (rs = 0.036, P = 0.42), with values ranging from 101 to 5,826 ng/mL and from 0 to 515 ng, respectively. Median values of both variables were significantly higher in cancer patients than in patients with noncancerous lesions or in healthy individuals. Moreover, iFOBT and FL-DNA values were individually associated with a number of pathologic parameters. Sequential use of the diagnostic iFOBT and FL-DNA methods showed that fecal DNA provided more accurate diagnostic information and was able to identify subgroups at different risk of cancer in iFOBT-positive individuals. Conclusions: A combined approach based on FL-DNA and iFOBT evaluation could help to better identify colorectal cancers and to determine a patients risk of harboring a preneoplastic or neoplastic lesion. Further evaluation in a screening setting is needed to confirm this hypothesis. Impact: Fecal DNA could be a useful tool to better predict cancer risk in FOBT-positive individuals. Cancer Epidemiol Biomarkers Prev; 19(10); 2647–54. ©2010 AACR.