Cytoreductive surgery and hyperthermic intraperitoneal chemotherapy in peritoneal carcinomatosis from ovarian cancer

BACKGROUND: In selected patients with peritoneal carcinomatosis from ovarian cancer prognosis can be improved by cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (HIPEC). METHODS: Between September 1995 and February 1999, 19 patients (mean age 52 years, range 30–72 years) with peritoneal carcinomatosis from primary or recurrent epithelial ovarian carcinoma were operated with the aim of complete macroscopical cytoreduction. Surgery was followed by intraoperative HIPEC. The data was analyzed retrospectively. RESULTS: Eleven patients had recurrent and 8 primary ovarian cancer. The median progression free interval was 18 months (range 6–36 months). Macroscopically complete cytoreduction was achieved in 9 patients. Cisplatin (n = 16) or mitoxantrone (n = 3) were used for the intraoperative chemotherapy. The median intraabdominal inflow temperature was 41.5°C. Complications occurred in seven patients. Most frequent complications were anastomotic leakage (2/19) and intraabdominal abscess formation (2/19). One patient died postoperatively. The mean (± SD) overall survival time was 33(± 6) months with a 5-year survival rate of 15%. The survival was found to be influenced by the completeness of cytoreduction (44 ± 11 vs. 25 ± 6 months, p = 0.40), tumor volume (54 ± 10 versus 16 ± 4, p = 0.002) and presence of lymph node (38 ± 8 vs. 20 ± 8 months, p= 0.2) or liver metastases (51 ± 9 vs. 21 ± 6 months, p = 0.06). CONCLUSIONS: Cytoreductive surgery combined with HIPEC is feasible and is associated with a reasonable morbidity and mortality. Complete cytoreduction may improve survival in select group of patients with low tumor volume and no organ metastases

Further evaluation of plasma sphingomyelin levels as a risk factor for coronary artery disease

BACKGROUND: Sphingomyelin (SM) is the major phospholipid in cell membranes and in lipoproteins. In human plasma, SM is mainly found in atherogenic lipoproteins; thus, high levels of SM may promote atherogenesis. METHODS: We investigated in a median follow up of 6.0 years the association of SM with the incidence of a combined endpoint (myocardial infarction and cardiovascular death) in stable and unstable patients, and its relation to other marker of atherosclerosis in 1,102 patients with angiographically documented CAD and 444 healthy controls. RESULTS AND DISCUSSION: Logistic regression analysis showed that SM categorized by median was associated with an elevated risk for CAD (HR 3.2, 95%CI 2.5–4.0, p < 0.05). SM levels were correlated with apoB (r = 0.34) and triglyceride levels (r = 0.31). In patients with stable angina (n = 614), SM categorized by median was not related to incidence of a combined endpoint (cardiovascular death and myocardial infarction) (p = 0.844 by Log-rank test). However, in patients with acute coronary syndrome (n = 488), elevated SM was related to the combined endpoint (p < 0.05 by Log-rank test), also in a multivariate Cox regression analysis including potential confounders (HR 1.8, 95%CI 1.0–3.3, p < 0.05). CONCLUSION: The results of our study reveal that 1) human plasma SM levels are a risk factor for CAD; 2) the pro-atherogenic property of plasma SM might be related to metabolism of apoB-containing or triglyceride-rich lipoproteins; and 3) plasma SM levels are a predictor for outcome of patients with acute coronary syndrome

Sirolimus Use in Liver Transplant Recipients With Hepatocellular Carcinoma : A Randomized, Multicenter, Open-Label Phase 3 Trial

Background We investigated whether sirolimus-based immunosuppression improves outcomes in liver transplantation (LTx) candidates with hepatocellular carcinoma (HCC). Methods In a prospective-randomized open-label international trial, 525 LTx recipients with HCC initially receiving mammalian target of rapamycin inhibitor-free immunosuppression were randomized 4 to 6 weeks after transplantation into a group on mammalian target of rapamycin inhibitor-free immunosuppression (group A: 264 patients) or a group incorporating sirolimus (group B: 261). The primary endpoint was recurrence-free survival (RFS); intention-to-treat (ITT) analysis was conducted after 8 years. Overall survival (OS) was a secondary endpoint. Results Recurrence-free survival was 64.5% in group A and 70.2% in group B at study end, this difference was not significant (P = 0.28; hazard ratio [HR], 0.84; 95% confidence interval [95% CI], 0.62; 1.15). In a planned analysis of RFS rates at yearly intervals, group B showed better outcomes 3 years after transplantation (HR, 0.7; 95% CI, 0.48-1.00). Similarly, OS (P = 0.21; HR, 0.81; 95% CI, 0.58-1.13) was not statistically better in group B at study end, but yearly analyses showed improvement out to 5 years (HR, 0.7; 95% CI, 0.49-1.00). Interestingly, subgroup (Milan Criteria-based) analyses revealed that low-risk, rather than high-risk, patients benefited most from sirolimus; furthermore, younger recipients (age 60) also benefited, as well sirolimus monotherapy patients. Serious adverse event numbers were alike in groups A (860) and B (874). Conclusions Sirolimus in LTx recipients with HCC does not improve long-term RFS beyond 5 years. However, a RFS and OS benefit is evident in the first 3 to 5 years, especially in low-risk patients. This trial provides the first high-level evidence base for selecting immunosuppression in LTx recipients with HCC.Peer reviewe

Patients without hepatocellular carcinoma progression after transarterial chemoembolization benefit from liver transplantation

AIM: To assess the outcome of patients, who underwent transarterial chemoembolization (TACE) for hepatocellular carcinoma (HCC) and subsequently liver transplantation (OLT) irrespective of tumor size when no tumor progression was observed. METHODS: Records, imaging studies and pathology of 84 patients with HCC were reviewed. Ten patients were not treated at all, 67 patients had TACE and 35 of them were listed for OLT. Tumor progression was monitored by ultrasound and AFP level every 6 wk. Fifteen patients showed signs of tumor progression without transplantation. The remaining 20 patients underwent OLT. Further records of 7 patients with HCC seen in histological examination after OLT were included. RESULTS: The patients after TACE without tumor progression underwent transplantation and had a median survival of 92.3 mo. Patients, who did not qualify for liver transplantation or had signs of tumor progression had a median survival of 8.4 mo. The patients without treatment had a median survival of 3.8 mo. Independent of International Union Against Cancer (UICC) stages, the patients without tumor progression and subsequent OLT had longer median survival. No significant difference was seen in the OLT treated patients if they did not fulfill the Milan criteria. CONCLUSION: Selection of patients for OLT based on tumor progression results in good survival. The evaluation of HCC patients should not only be based on tumor size and number of foci but also on tumor progression and growth behavior under therapy. (c) 2007 The WJG Press. All rights reserved

Outcome of patients with ischemic-like cholangiopathy with secondary sclerosing cholangitis after liver transplantation

Sclerosing cholangitis in critically ill patients (SC-CIP) with sepsis and acute respiratory distress syndrome (ARDS) is a cholestatic liver disease with a rapid progression to liver cirrhosis and hepatic failure. Data on outcome of these patients after liver transplantation (LT) are sparse

Dual inhibition of Raf and VEGFR2 reduces growth and vascularization of hepatocellular carcinoma in an experimental model.

BACKGROUND AND AIMS: Activation of the mitogen-activated protein kinase-extracellular-signal-regulated kinase (ERK) pathways plays an important role in the progression of hepatocellular carcinoma (HCC). Importantly, Raf kinases are principal effectors within this oncogenic signaling cascade. We hypothesized that concomitant inhibition of Raf and vascular endothelial growth factor receptor 2 (VEGFR2) will affect tumor growth and angiogenesis of HCC. MATERIALS AND METHODS: Human HCC cell lines, endothelial cells (EC), and vascular smooth muscle cells (VSMC) were used. For blocking Raf kinase and VEGFR2, the small molecule inhibitor NVP-AAL881 (Novartis, USA) was used. Activation of signaling intermediates was assessed by Western blotting, and changes in cell motility were evaluated in migration assays. Effects of NVP-AAL881 on HCC growth were determined in a subcutaneous tumor model. RESULTS: NVP-AAL881 disrupted activation of ERK and STAT3 in HCC cells and reduced cancer cell motility. In addition, the migration of ECs and VSMC was also significantly impaired. In ECs, HCC-conditioned media-induced activation of STAT3 was diminished by NVP-AAL881 treatment. In vivo, NVP-AAL881 significantly reduced tumor growth, CD31-vessel area, and numbers of BrdU-positive proliferating tumor cells. CONCLUSIONS: Combined inhibition of Raf and VEGFR2 disrupts oncogenic signaling and efficiently reduces tumor growth and vascularization of HCC. Hence, this strategy could prove valuable for therapy of HCC

Liver transplantation in a subject with familial hypercholesterolemia carrying the homozygous p.W577R LDL-receptor gene mutation

Mutations within the low density lipoprotein (LDL)-receptor gene result in familial hypercholesterolemia, an autosomal dominant inherited disease. Clinical homozygous affected subjects die of premature coronary artery disease as early as in early childhood. We identified a girl at the age of five yr with clinical homozygous familial hypercholesterolemia presenting with achilles tendon xanthomas and arcus lipoides. Her total cholesterol reached up to 1050 mg/dL. Molecular characterization of the LDL-receptor gene revealed a homozygous p.W577R mutation. Despite intensive treatment interventions with the combination of diet, statins, colestipol, and LDL-apheresis, the patient developed symptomatic coronary artery disease at the age of 16 yr. Subsequently, orthotopic liver transplantation was performed to cure the defective LDL-receptor gene. Clinical follow-up for almost nine yr post-transplantation revealed excellent liver function, normal liver enzymes, normal LDL-cholesterol, and regression of both tendon xanthomas and symptomatic coronary artery disease. In conclusion, liver transplantation can effectively reduce LDL-cholesterol in a familial hypercholesterolemia recipient with subsequent regression of xanthomas and atherosclerosis. Timing is extremely important in these exceptional cases to exclude the demand for heart transplantation due to severe coronary artery disease. In addition, the identification of the LDL-receptor as etiology of clinical homozygous hypercholesterolemia is a prerequisite once liver transplantation is considered as therapeutic option