Lenalidomide for second-line treatment of advanced hepatocellular cancer: a Brown University oncology group phase II study.

PURPOSE: To assess the activity and toxicity of lenalidomide for patients with advanced hepatocellular cancer (HCC) previously treated with sorafenib. MATERIALS AND METHODS: Patients with advanced HCC who progressed on or were intolerant to sorafenib were eligible. Patients received lenalidomide 25 mg orally for 1 to 21 days in a 28-day cycle until disease progression or unacceptable toxicities. RESULTS: Forty patients were enrolled and were classified according to the Child-Pugh score: 19 were Child-Pugh A, 16 patients were Child-Pugh B, and 5 were Child-Pugh C. Seventeen patients had extrahepatic disease. Grade 4 neutropenia occurred in 1 of 40 patients (2.5%). Grade 3 fatigue (n=3) and rash (n=4) were the most common nonhematologic toxicities attributable to lenalidomide. Six of 40 patients (15%) had a partial response. Two patients (5%) have not progressed at 36 and 32 months. The median progression-free survival was 3.6 months and the median overall survival was 7.6 months. CONCLUSIONS: Lenalidomide can be administered to patients with advanced HCC and hepatic dysfunction. Promising, and in a small percentage of patients, durable activity has been demonstrated. Investigations are needed to explore the mechanism of action of lenalidomide in HCC.

Safety and efficacy of trans arterial chemoembolization with drug-eluting beads in hepatocellular cancer: a systematic review.

BACKGROUND/AIMS: The aim of this review was to compare current conventional TACE to the drug eluting beads loaded with doxorubicin (DEBDOX) device in the treatment of HCC. METHODOLOGY: A recent hepatocellular consensus discussion was convened to review all recent and past literature in the use of hepatic directed therapies to compare the safety, efficacy and overall survival of the available hepatic directed therapies in the management of hepatocellular cancer. A review of all publications in peer review journals in the English Language from 1995 to 2007 was performed. RESULTS: The DEBDOX are an effective therapy with a favorable pharmacokinetic profile with significantly less systemic doxorubicin exposure when compared to conventional TACE. The DEBDOX had a significant (p<0.05) advantage in objective response in the more advanced patients (defined as Child-Pugh B, ECOG 1, recurrent disease and bilobar disease; p=0.038) and overall disease control in the more advanced patients (p=0.026). The DEBDOX Bead was also found to have a highly significant (p<0.01) advantage in the reduction of doxorubicin associated side effects (p=0.0001) in all patients. CONCLUSIONS: The current collective data on the use of DEBDOX Bead in HCC patients provides sufficient evidence to support its use as a safe and effective chemo-embolic treatment in intermediate HCC patients. There is growing evidence to support the its use is superior to conventional doxorubicin TACE.

The international position on laparoscopic liver surgery: The Louisville Statement, 2008.

OBJECTIVE: To summarize the current world position on laparoscopic liver surgery. SUMMARY BACKGROUND DATA: Multiple series have reported on the safety and efficacy of laparoscopic liver surgery. Small and medium sized procedures have become commonplace in many centers, while major laparoscopic liver resections have been performed with efficacy and safety equaling open surgery in highly specialized centers. Although the field has begun to expand rapidly, no consensus meeting has been convened to discuss the evolving field of laparoscopic liver surgery. METHODS: On November 7 to 8, 2008, 45 experts in hepatobiliary surgery were invited to participate in a consensus conference convened in Louisville, KY, US. In addition, over 300 attendees were present from 5 continents. The conference was divided into sessions, with 2 moderators assigned to each, so as to stimulate discussion and highlight controversies. The format of the meeting varied from formal presentation of experiential data to expert opinion debates. Written and video records of the presentations were produced. Specific areas of discussion included indications for surgery, patient selection, surgical techniques, complications, patient safety, and surgeon training. RESULTS: The consensus conference used the terms pure laparoscopy, hand-assisted laparoscopy, and the hybrid technique to define laparoscopic liver procedures. Currently acceptable indications for laparoscopic liver resection are patients with solitary lesions, 5 cm or less, located in liver segments 2 to 6. The laparoscopic approach to left lateral sectionectomy should be considered standard practice. Although all types of liver resection can be performed laparoscopically, major liver resections (eg, right or left hepatectomies) should be reserved for experienced surgeons facile with more advanced laparoscopic hepatic resections. Conversion should be performed for difficult resections requiring extended operating times, and for patient safety, and should be considered prudent surgical practice rather than failure. In emergent situations, efforts should be made to control bleeding before converting to a formal open approach. Utilization of a hand assist or hybrid technique may be faster, safer, and more efficacious. Indications for surgery for benign hepatic lesions should not be widened simply because the surgery can be done laparoscopically. Although data presented on colorectal metastases did not reveal an adverse effect of the laparoscopic approach on oncological outcomes in terms of margins or survival, adequacy of margins and ability to detect occult lesions are concerns. The pure laparoscopic technique of left lateral sectionectomy was used for adult to child donation while the hybrid approach has been the only one reported to date in the case of adult to adult right lobe donation. Laparoscopic liver surgery has not been tested by controlled trials for efficacy or safety. A prospective randomized trial appears to be logistically prohibitive; however, an international registry should be initiated to document the role and safety of laparoscopic liver resection. CONCLUSIONS: Laparoscopic liver surgery is a safe and effective approach to the management of surgical liver disease in the hands of trained surgeons with experience in hepatobiliary and laparoscopic surgery. National and international societies, as well as governing boards, should become involved in the goal of establishing training standards and credentialing, to ensure consistent standards and clinical outcomes.

Effects of omega-3 fatty acids on components of the transforming growth factor beta-1 pathway: implication for dietary modification and prevention in ovarian cancer.

OBJECTIVE: We previously demonstrated that omega-3 fatty acids (OM-3FAs) have definitive inhibitory effects on ovarian cancer cell lines. We sought to determine whether the inhibitory effects of OM-3FAs were mediated by the transforming growth factor (TGF)-beta1 signaling pathway. STUDY DESIGN: Ovarian cancer cell lines were grown at 37 degrees C in 5% CO(2) and treated with OM-3FAs, omega-6 fatty acids, and control at different concentrations for 24-72 hours. Enzyme-linked immunosorbent assay (ELISA) assay and Western blot analysis were used to measure TGF-beta1, phosphorylated mothers against decapentaplegic (Smad)-3 and p21 protein levels. RESULTS: An ELISA assay demonstrated that OM-3FA treatment increased TGF-beta1 in all 3 Hey cell lines (P < .05). In both SKOV-3 and OVCAR-3 cells, TGF-beta1 levels were not significantly increased. Western blots confirmed increases in TGF-beta1, Smad-3 and p21 protein levels in Hey and HeyC2 but not SKOV-3 and OVCAR-3 cells. CONCLUSION: OM-3FAs increased the level of TGF-beta1, Smad-3, and p21 protein in ovarian cancer cells known to be more sensitive to their inhibitory effect.

Recommendations for radioembolization of hepatic malignancies using yttrium-90 microsphere brachytherapy: a consensus panel report from the radioembolization brachytherapy oncology consortium.

PURPOSE: To standardize the indications, techniques, multimodality treatment approaches, and dosimetry to be used for yttrium-90 (Y90) microsphere hepatic brachytherapy. METHODS AND MATERIALS: Members of the Radioembolization Brachytherapy Oncology Consortium met as an independent group of experts in interventional radiology, radiation oncology, nuclear medicine, medical oncology, and surgical oncology to identify areas of consensus and controversy and to issue clinical guidelines for Y90 microsphere brachytherapy. RESULTS: A total of 14 recommendations are made with category 2A consensus. Key findings include the following. Sufficient evidence exists to support the safety and effectiveness of Y90 microsphere therapy. A meticulous angiographic technique is required to prevent complications. Resin microsphere prescribed activity is best estimated by the body surface area method. By virtue of their training, certification, and contribution to Y90 microsphere treatment programs, the disciplines of radiation oncology, nuclear medicine, and interventional radiology are all qualified to use Y90 microspheres. The panel strongly advocates the creation of a treatment registry with uniform reporting criteria. Initiation of clinical trials is essential to further define the safety and role of Y90 microspheres in the context of currently available therapies. CONCLUSIONS: Yttrium-90 microsphere therapy is a complex procedure that requires multidisciplinary management for safety and success. Practitioners and cooperative groups are encouraged to use these guidelines to formulate their treatment and dose-reporting policies.

Outcome of coronary artery bypass operations in patients with renal insufficiency with and without renal transplantation.

HYPOTHESIS: Renal insufficiency (RI) is associated with an increased risk of morbidity and mortality following coronary artery bypass graft (CABG) operations, particularly among patients who are dependent on dialysis. DESIGN AND SETTING: A retrospective analysis of data collected at a tertiary care center. PATIENTS: One hundred eighty-four consecutive patients with RI who underwent CABG surgery between 1992 and 2004. This group consisted of 152 patients with serum creatinine levels of > or = 1.7 mg/dL (group I) and 32 kidney transplant recipients (group II). Of the patients in group I, 90 were dialysis-free (subgroup IA) and 62 were dialysis-dependent (subgroup IB). MAIN OUTCOME MEASURES: Demographics, perioperative data, and outcomes for each of the three groups were evaluated and compared. RESULTS: Fifty-four percent of the patients were in New York Heart Association classes III and IV, 36% had unstable angina, and 21% had left main coronary disease. The mean ejection fraction was 38%. The median postoperative length of stay in the hospital was 10 days. Of the patients in group IB, 8% required reexploration for bleeding compared to 3% in groups IA and II (p < 0.05). Dialysis was needed postoperatively in five patients in group IA and two patients in group II (5.7%). The raw operative mortality rate was 7.6% and was higher in group IB (9.7%) compared to groups IA and II (6.7% and 6.2%, respectively; p < 0.05). The actuarial 5-year survival rate was higher in group II compared to group I (79% vs 59%, respectively; p < 0.05). The difference in survival rates was more apparent between groups II and IB (79% vs 57%, respectively; p < 0.005). CONCLUSIONS: CABG is associated with an increased rate of perioperative complications and mortality in patients with RI. Dialysis dependence is a major risk factor for patients undergoing CABG surgery. However, with acceptable surgical results, dialysis patients should not be denied CABG surgery. A survival advantage is demonstrated among patients with previous kidney transplants compared to those patients who are dependent on dialysis.

The effects of Omega-3 fatty acids on growth regulation of epithelial ovarian cancer cell lines.

OBJECTIVE: Omega-3 fatty acids (OM-3FAs) have been shown to possess anti-carcinogenic properties. We investigated the effect of OM-3FAs on epithelial ovarian cancer cell lines to determine if a growth suppressive effect existed and to gain a better insight on the potential molecular mechanisms that may be involved. METHODS: Three epithelial ovarian cancer cell lines (SKOV-3 [p53 null], TOV-21G [wt p53] and OVCAR-3 [mutant p53]) and one immortalized ovarian surface epithelial cell line (IOSE-29 [wt p53]) were treated with OM-3FAs and evaluated for cellular proliferation (WST-1 assay), apoptosis (Annexin V-FITC/PI method) and VEGF expression (VEGF ELISA assay). RESULTS: A statistically significant inhibitory effect under the influence of OM-3FAs was detected in all four cell lines. Apoptosis and VEGF down-regulation were either limited or not detected in the p53 null and mutant cell lines, SKOV-3 and OVCAR-3 respectively. Apoptosis and/or VEGF down-regulation was strongly evident in the wt p53 cell lines TOV-21G and IOSE-29. CONCLUSION: These data suggest that, under the influence of OM-3FAs, there are definitive growth suppressive mechanisms at work and that the biologic effects of OM-3FAs may in part be mediated by the p53 status.

Technical complications and durability of hepatic artery infusion pumps for unresectable colorectal liver metastases: an institutional experience of 544 consecutive cases.

BACKGROUND: Hepatic arterial infusion pump chemotherapy is an important component in the treatment of patients with hepatic metastases. Successful use of a hepatic arterial infusion pump requires a low technical complication rate. We evaluated the complications and longterm durability of these devices at our institution. STUDY DESIGN: Between April 1986 and March 2001, 544 patients underwent hepatic arterial infusion pump placement for treatment of unresectable colorectal liver metastases. Patient- and pump-related data were collected by chart review. Pump-related complications, duration of pump function, and overall patient survival were recorded. RESULTS: Median patient survival was 24 months after pump placement. The incidences of pump failure were 9% at 1 year and 16% at 2 years. Pump complications occurred in 120 (22%) of the patients. Complications that occurred early after operation (< 30 days) were more likely to be salvaged than those occurring late (70% versus 30%, p < 0.001). Increased pump complication rates occurred in the setting of variant arterial anatomy (28% versus 19%, p = 0.02), when the catheter was inserted into a vessel other than the gastroduodenal artery (42% versus 21%, p = 0.004), if the pump was placed during the first half of the study period (1986 to 1993, 25% versus 1994 to 2001, 18%; p = 0.05), and if the surgeon had performed fewer than 25 earlier procedures (< 25, 31% versus > or = 25, 19%; p < 0.002). CONCLUSIONS: In this large single institution experience, pump-related complications were low, the majority of early pump complications were salvaged, and pump complication rates improved as institutional experience accumulated. Longterm durability of pump function was excellent.