Matteo Donadon

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.

One-stage ultrasonographically guided hepatectomy for multiple bilobar colorectal metastases: A feasible and effective alternative to the 2-stage approach

BACKGROUND Two-stage hepatectomy with or without portal vein embolization allows treatment of multiple bilobar metastases, thereby expanding operative indications for these patients. Two operations are needed, however, and some patients are not able to complete the treatment strategy because of disease progression. Using experience gained from our policy of ultrasonographically guided resection, we explored the safety and effectiveness of 1-stage operative procedures in patients otherwise recommended for the 2-stage approach. METHODS A total of 29 patients with multiple (>or=4) bilobar colorectal liver metastases (CLM) were selected from 100 consecutive patients submitted to surgical resection. The total number of preoperative CLM was 163 (median, 5; range, 2-20). The operative strategy was based on tumor-vessel relationships at intraoperative ultrasonography (IOUS) and on findings at color Doppler IOUS. RESULTS There was no in-hospital mortality. Tumor removal was feasible with 1-stage operative procedures in all but 3 patients who underwent laparotomy. The overall morbidity rate was 23% (6/26); none of the patients required reoperation. Major morbidity occurred in 1 patient (4%). Blood transfusions were administered in 4 patients (15%). After a mean follow-up of 17 months (median, 14; range, 6-54), 3 patients had died from systemic recurrence, 12 patients were alive without disease, and 11 were alive with disease. No local recurrences were observed at the resection margin. CONCLUSION IOUS-guided resection based on strict criteria allows a 1-stage operative treatment in selected patients with multiple bilobar CLM. This strategy decreases the need for a two-stage hepatectomy, thereby avoiding the disadvantages of a 2-stage approach.

Contrast-enhanced intraoperative ultrasonography during hepatectomies for colorectal cancer liver metastases

Preliminary reports showed that contrast-enhanced intraoperative ultrasonography (CEIOUS) provides information on primary or metastatic tumors of the liver that is not obtainable with conventional intraoperative ultrasonography (IOUS). This study validates the impact of CEIOUS, focusing on resective surgery for colorectal cancer (CRC) liver metastases. Twenty-four consecutive patients underwent liver resection using IOUS and CEIOUS for CRC liver metastases. CEIOUS was accomplished with intravenous injection of 4.8 mL of sulphur-hexafluoride microbubbles. CEIOUS found lesions missed at preoperative imaging and at IOUS in four patients and confirmed all of the new findings of IOUS in four patients. In addition, CEIOUS helped to define the tumor margins of the main lesion in 29% of patients with CRC liver metastases. No adverse effects were observed in relation with CEIOUS. In conclusion, CEIOUS improves IOUS accuracy with a significant impact on surgical strategy and radicality in patients who undergo surgery for CRC liver metastases.

Ultrasonographically guided surgical approach to liver tumours involving the hepatic veins close to the caval confluence

Intraoperative ultrasonography (IOUS) may allow a more conservative procedure in patients with liver tumours involving a hepatic vein at the caval confluence. The aim of this study was to determine whether IOUS and colour Doppler IOUS might reduce the rate of major hepatectomy and vascular reconstruction in patients with such tumours.

Human liver-resident CD56bright/CD16neg NK cells are retained within hepatic sinusoids via the engagement of CCR5 and CXCR6 pathways

RATIONALE The liver-specific natural killer (NK) cell population is critical for local innate immune responses, but the mechanisms that lead to their selective homing and the definition of their functionally relevance remain enigmatic. OBJECTIVES We took advantage of the availability of healthy human liver to rigorously define the mechanisms regulating the homing of NK cells to liver and the repertoire of receptors that distinguish liver-resident NK (lr-NK) cells from circulating counterparts. FINDINGS Nearly 50% of the entire liver NK cell population is composed of functionally relevant CD56(bright) lr-NK cells that localize within hepatic sinusoids. CD56(bright) lr-NK cells express CD69, CCR5 and CXCR6 and this unique repertoire of chemokine receptors is functionally critical as it determines selective migration in response to the chemotactic stimuli exerted by CCL3, CCL5 and CXCL16. Here, we also show that hepatic sinusoids express CCL3(pos) Kupffer cells, CXCL16(pos) endothelial cells and CCL5(pos) T and NK lymphocytes. The selective presence of these chemokines in sinusoidal spaces creates a unique tissue niche for lr-CD56(bright) NK cells that constitutively express CCR5 and CXCR6. CD56(bright) lr-NK cells co-exist with CD56(dim) conventional NK (c-NK) cells that are, interestingly, transcriptionally and phenotypically similar to their peripheral circulating counterparts. Indeed, CD56(dim) c-NK cells lack expression of CD69, CCR5, and CXCR6 but express selectins, integrins and CX3CR1. CONCLUSION Our findings disclosing the phenotypic and functional differences between lr-Nk cells and c-NK cells are critical to distinguish liver-specific innate immune responses. Hence, any therapeutic attempts at modifying the large population of CD56(bright) lr-NK cells will require modification of hepatic CCR5 and CXCR6.

Contrast-Enhanced Intraoperative Ultrasonography During Surgery for Hepatocellular Carcinoma in Liver Cirrhosis: Is It Useful or Useless? A Prospective Cohort Study of Our Experience

BackgroundPreliminary results showed that contrast-enhanced intraoperative ultrasonography (CEIOUS) could provide information not obtainable with conventional IOUS during surgery for hepatocellular carcinoma (HCC). The aim of the study was to prospectively validate the role of CEIOUS on the basis of a larger experience and to establish a new classification that takes into account its findings.MethodsEighty-seven consecutive patients underwent hepatecomies for HCC. Those patients with new lesions at IOUS underwent CEIOUS: for that patients received intravenously 4.8 mL sulphurhexafluoride microbubbles. Pattern of enhancement was classified in 4 categories: A1 (full enhancement in the arterial phase and wash-out in the delayed phases), A2 (intralesional signs of neovascularization during all phases), A3 (no nodular enhancement but detectability during the liver enhancement), and B (undetectability during the liver enhancement). Resection was recommended for A1-3 nodules and no treatment for B nodules.ResultsTwenty-nine patients (33%) had 59 new lesions at IOUS and underwent CEIOUS. Twenty-seven nodules showed a B pattern at CEIOUS and were not removed; 32 nodules were classified as A1 in 5 patients, A2 in 11 patients, and A3 in 16 patients. The nodules were removed, and by histology, five A1, nine A2, and six A3 nodules were confirmed to be HCC. CEIOUS modified the operative decision making in 79% of these patients.ConclusionsCEIOUS is useful during surgery for HCC; it complements the accuracy of IOUS and affects the radicalness of the surgical. Specificity of CEIOUS has to be further improved, although intrinsic drawbacks exist in the diagnostic criterion of tumor vascularity.

Anatomical segmental and subsegmental resection of the liver for hepatocellular carcinoma: a new approach by means of ultrasound-guided vessel compression.

Background:Anatomic resection is considered the gold standard approach for liver resection in patients with hepatocellular carcinoma. The use of intraoperative ultrasound (IOUS) as guidance is indispensable in this sense but methods available up to now were rather complex and for that reason of limited use. We herein describe a novel technique for the demarcation of the resection area by means of IOUS-guided finger compression to systematically accomplish anatomic segmental and subsegmental resections. Methods:Thirty-three patients met the eligibility criteria. This technique consisted in the demarcation of the resection area by IOUS-guided finger compression of the vascular pedicle feeding the tumor at the level closest to the tumor but oncologically suitable. Median age was 65 years (range, 36–81). There were 25 men and 8 women. Median tumor number was 1 (range, 1–2); median tumor size was 2 cm (range, 1–10). Twenty-five (76%) patients had cirrhosis or chronic hepatitis, and 8 (24%) had steatosis (ClinicalTrials.Gov ID: NCT00829335). Results:Procedure resulted feasible in all eligible patients, and demarcation area was obtained in all patients within 1 minute of bimanual IOUS-guided compression. There was no mortality or major morbidity: only 7 (21%) patients experienced minor morbidity. No blood transfusions were administered. Conclusions:Systematic segmentectomy and subsegmentectomy by IOUS-guided finger compression is a feasible, safe, and effective technique, which could be considered as a simpler alternative to those up to now proposed.

Systematic extended right posterior sectionectomy: a safe and effective alternative to right hepatectomy.

Background:A surgical approach based on ultrasound-guided hepatectomy might minimize the need for major resection, whose rates of morbidity and mortality are not negligible. Right hepatectomy (RH) is traditionally performed in cases of vascular invasion of the right hepatic vein with multiple tumors in the right posterior section, and/or of the right posterior portal branch (P6-7) with tumor in contact with right anterior portal branch (P5-8). We herein describe an alternative approach to RH consisting in ultrasound-guided systematic extended right posterior hepatic sectionectomy (SERPS). Methods:Among 207 consecutive patients who underwent hepatectomies, 21 (10%) underwent SERPS. Median age was 67 years (range, 48–79). There were 13 men and 8 women. Ten (48%) patients had hepatocellular carcinoma; 11 (52%) had colorectal liver metastases. Median tumor number was 2 (range, 1–15); median tumor size was 4.5 cm (range, 2.5–20). Ten (48%) patients had cirrhosis, 8 (38%) had steatosis, and 3 (16%) had normal liver. Surgical strategy was based on tumor-vessels relationship at intraoperative ultrasonography (IOUS) and on findings at color-Doppler IOUS. Results:In-hospital and 90-days mortality were nil. Major and minor morbidity occurred in 3 (14%) and 2 (9.5%) patients, respectively. No patients were reoperated because of complications. Blood transfusions were given to 2 (9.5%) patients. After a median follow-up of 21 months, no local recurrence was observed. Conclusions:IOUS-guided SERPS is feasible, safe, and effective. It should be applied whenever possible as alternative resection to RH to maximize liver parenchymal sparing.