Winston Liauw

Early- and Long-Term Outcome Data of Patients With Pseudomyxoma Peritonei From Appendiceal Origin Treated by a Strategy of Cytoreductive Surgery and Hyperthermic Intraperitoneal Chemotherapy

PURPOSE Pseudomyxoma peritonei (PMP) originating from an appendiceal mucinous neoplasm remains a biologically heterogeneous disease. The purpose of our study was to evaluate outcome and long-term survival after cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) consolidated through an international registry study. PATIENTS AND METHODS A retrospective multi-institutional registry was established through collaborative efforts of participating units affiliated with the Peritoneal Surface Oncology Group International. RESULTS Two thousand two hundred ninety-eight patients from 16 specialized units underwent CRS for PMP. Treatment-related mortality was 2% and major operative complications occurred in 24% of patients. The median survival rate was 196 months (16.3 years) and the median progression-free survival rate was 98 months (8.2 years), with 10- and 15-year survival rates of 63% and 59%, respectively. Multivariate analysis identified prior chemotherapy treatment (P < .001), peritoneal mucinous carcinomatosis (PMCA) histopathologic subtype (P < .001), major postoperative complications (P = .008), high peritoneal cancer index (P = .013), debulking surgery (completeness of cytoreduction [CCR], 2 or 3; P < .001), and not using HIPEC (P = .030) as independent predictors for a poorer progression-free survival. Older age (P = .006), major postoperative complications (P < .001), debulking surgery (CCR 2 or 3; P < .001), prior chemotherapy treatment (P = .001), and PMCA histopathologic subtype (P < .001) were independent predictors of a poorer overall survival. CONCLUSION The combined modality strategy for PMP may be performed safely with acceptable morbidity and mortality in a specialized unit setting with 63% of patients surviving beyond 10 years. Minimizing nondefinitive operative and systemic chemotherapy treatments before definitive cytoreduction may facilitate the feasibility and improve the outcome of this therapy to achieve long-term survival. Optimal cytoreduction achieves the best outcomes.

Pharmacodynamic interaction of warfarin with cranberry but not with garlic in healthy subjects

Patients commonly take complementary medicines in conjunction with warfarin yet evidence supporting the safety or the risk of a herb–drug interaction is lacking. The aim of this study was to investigate the possible impact of two commonly used herbal medicines, garlic and cranberry, on the pharmacokinetics and pharmacodynamics of warfarin in healthy male subjects.

Systematic Review of Randomized and Nonrandomized Trials of the Clinical Response and Outcomes of Neoadjuvant Systemic Chemotherapy for Resectable Colorectal Liver Metastases

BackgroundNeoadjuvant chemotherapy prior to hepatectomy in patients with resectable colorectal liver metastases (CLM) may facilitate the resectability of the liver lesions and treat occult metastasis but may also lead to hepatic parenchyma damage. There is argument over the oncologic benefit of this practice in patients who would already be suitable for a curative hepatectomy.MethodsExtensive literature search of databases (MEDLINE and PubMed) to identify published studies of preoperative systemic chemotherapy for resectable CLM was undertaken with clinical response to treatment and survival outcomes as the endpoints.ResultsTwenty-three studies were reviewed: 1 phase III randomized control trial, 3 phase II studies, and 19 observational studies, comprising 3,278 patients. Objective (complete/partial) radiological response was observed in 64% (range 44–100%) [complete 4% (range 0–38%), partial 52% (range 10–90%)] of patients after neoadjuvant chemotherapy. Pathologically, a median of 9% (range 2–24%) and 36% (range 20–60%) had complete and partial response, respectively. Of patients, 41% (range 0–65%) had stable or progressive disease whilst on neoadjuvant chemotherapy. Median disease-free survival (DFS) was 21 (range 11–40) months. Median overall survival (OS) was 46 (range 20–67) months.ConclusionCurrent evidence suggests that objective response to neoadjuvant chemotherapy may be achieved with improvement in DFS in patients with resectable CLM. A prospective randomized trial of neoadjuvant therapy versus adjuvant therapy after liver resection is required to determine the optimal perisurgical treatment regimen.Neoadjuvant chemotherapy prior to hepatectomy in patients with resectable colorectal liver metastases (CLM) may facilitate the resectability of the liver lesions and treat occult metastasis but may also lead to hepatic parenchyma damage. There is argument over the oncologic benefit of this practice in patients who would already be suitable for a curative hepatectomy. Extensive literature search of databases (MEDLINE and PubMed) to identify published studies of preoperative systemic chemotherapy for resectable CLM was undertaken with clinical response to treatment and survival outcomes as the endpoints. Twenty-three studies were reviewed: 1 phase III randomized control trial, 3 phase II studies, and 19 observational studies, comprising 3,278 patients. Objective (complete/partial) radiological response was observed in 64% (range 44–100%) [complete 4% (range 0–38%), partial 52% (range 10–90%)] of patients after neoadjuvant chemotherapy. Pathologically, a median of 9% (range 2–24%) and 36% (range 20–60%) had complete and partial response, respectively. Of patients, 41% (range 0–65%) had stable or progressive disease whilst on neoadjuvant chemotherapy. Median disease-free survival (DFS) was 21 (range 11–40) months. Median overall survival (OS) was 46 (range 20–67) months. Current evidence suggests that objective response to neoadjuvant chemotherapy may be achieved with improvement in DFS in patients with resectable CLM. A prospective randomized trial of neoadjuvant therapy versus adjuvant therapy after liver resection is required to determine the optimal perisurgical treatment regimen.

Emerging roles for phospholipase A2 enzymes in cancer

Phospholipase A(2) (PLA(2)) enzymes (EC3.1.4.4) regulate the release of biologically active fatty acids and lysophospholipids from membrane phospholipid pools. These lipids are also substrates for intracellular biochemical pathways that generate potent autocrine and paracrine lipid mediators such as the eicosanoids and platelet activating factor. These factors, in turn, regulate cell proliferation, survival, differentiation, motility, tissue vascularisation, and immune surveillance in virtually all tissues, functions that are subverted by cancer cells for tumour growth and metastasis. Thus the relevance of PLA(2)-dependent pathways to the genesis and progression of cancer has been of interest since their discovery and with recent technological advances, their role in tumourigenesis has become more tractable experimentally. Limited human genetic studies have not yet identified PLA(2) enzymes as classical mutated oncogenes or tumour suppressor genes. However, there is strong evidence that of the 22 identified human PLA(2) enzymes, ten of which have been studied in cancer to date, most are aberrantly expressed in a proportion of tumours derived from diverse organs. Correlative and functional studies implicate the expression of some secreted enzymes (sPLA(2)s), particularly the best studied enzyme Group IIA sPLA(2) in either tumour promotion or inhibition, depending on the organ involved and the biochemical microenvironment of tumours. As in immune-mediated inflammatory pathologies, genetic deletion studies in mice, supported by limited studies with human cells and tissues, have identified an important role for Group IVA PLA(2) in regulating certain cancers. Pharmacological intervention studies in prostate cancer suggest that hGIIA-dependent tumour growth is dependent on indirect regulation of Group IVA PLA(2). Group VI calcium-independent PLA(2) enzymes have also been recently implicated in tumourigenesis with in vitro studies suggesting multiple possible roles for these enzymes. Though apparently complex, further characterization of the regulatory relationships amongst PLA(2) enzymes, lipid mediator biosynthetic enzymes and the lipid mediators they produce during tumour progression is required to define the biochemical context in which the enzymes modulate cancer growth and development.

Cytochrome P450 2B6 activity as measured by bupropion hydroxylation: Effect of induction by rifampin and ethnicity

The aim of this study was to investigate the activity of the drug‐metabolizing enzyme cytochrome P450 (CYP) 2B6 before and after in vivo induction by rifampin (INN, rifampicin) in white subjects and Chinese subjects by use of the probe drug bupropion (INN, amfebutamone).

Radioembolization with yttrium microspheres for neuroendocrine tumour liver metastases

90Y microsphere radioembolization is performed by injecting the microspheres through a hepatic artery catheter placed percutaneously via the femoral or brachial artery. This study assessed the efficacy of 90Y microsphere therapy for patients with unresectable neuroendocrine tumour liver metastases (NETLMs). Potential prognostic factors were analysed for their impact on overall survival.

Phase III Randomized, Placebo-Controlled Study of Cetuximab Plus Brivanib Alaninate Versus Cetuximab Plus Placebo in Patients With Metastatic, Chemotherapy-Refractory, Wild-Type K-RAS Colorectal Carcinoma: The NCIC Clinical Trials Group and AGITG CO.20 Trial

PURPOSE The antiepidermal growth factor receptor monoclonal antibody cetuximab has improved survival in patients with metastatic, chemotherapy-refractory, wild-type K-RAS colorectal cancer. The addition of brivanib, a tyrosine kinase inhibitor targeting vascular endothelial growth factor receptor and fibroblast growth factor receptor, to cetuximab has shown encouraging early clinical activity. PATIENTS AND METHODS Patients with metastatic colorectal cancer previously treated with combination chemotherapy were randomly assigned 1:1 to receive cetuximab 400 mg/m(2) intravenous loading dose followed by weekly maintenance of 250 mg/m(2) plus either brivanib 800 mg orally daily (arm A) or placebo (arm B). The primary end point was overall survival (OS). RESULTS A total of 750 patients were randomly assigned (376 in arm A and 374 in arm B). Median OS in the intent-to-treat population was 8.8 months in arm A and 8.1 months in arm B (hazard ratio [HR], 0.88; 95% CI, 0.74 to 1.03; P = .12). Median progression-free survival (PFS) was 5.0 months in arm A and 3.4 months in arm B (HR, 0.72; 95% CI, 0.62 to 0.84; P < .001). Partial responses observed (13.6% v 7.2%; P = .004) were higher in arm A. Incidence of any grade ≥ 3 adverse events was 78% in arm A and 53% in arm B. Fewer patients received ≥ 90% dose-intensity of both cetuximab (57% v 83%) and brivanib/placebo (48% v 87%) in arm A versus arm B, respectively. CONCLUSION Despite positive effects on PFS and objective response, cetuximab plus brivanib increased toxicity and did not significantly improve OS in patients with metastatic, chemotherapy-refractory, wild-type K-RAS colorectal cancer.

Effects of St John's wort and CYP2C9 genotype on the pharmacokinetics and pharmacodynamics of gliclazide

Patients commonly take complementary medicines in conjunction with conventional drugs without clear evidence of safety or the risk of herb–drug interactions. The aim of this study was to assess potential pharmacokinetic (PK) and pharmacodynamic (PD) interactions between St Johns wort and gliclazide in healthy subjects with different cytochrome P450 2C9 (CYP2C9) genotypes.

Hepatic resection for metastatic breast cancer: A systematic review

BACKGROUND Systemic chemotherapy is the mainstay of treatment for metastatic breast cancer with the role of surgery being strictly limited for palliation of metastatic complications or locoregional relapse. An increasing number of studies examining the role of therapeutic hepatic metastasectomy show encouraging survival results. A systematic review was undertaken to define its safety, efficacy and to identify prognostic factors associated with survival. METHODS Electronic search of the MEDLINE and PubMed databases (January 2000-January 2011) to identify studies reporting outcomes of hepatectomy for breast cancer liver metastases (BCLM) with hepatectomy was undertaken. Two reviewers independently appraised each study using a predetermined protocol. Safety and clinical efficacy was synthesised through a narrative review with full tabulation of results of all included studies. RESULTS Nineteen studies were examined. This comprised of 553 patients. Hepatectomy for BCLM was performed at a rate of 1.8 (range, 0.7-7.7) cases per year in reported series. The median time to liver metastases occurred at a median of 40 (range, 23-77) months. The median mortality and complication rate were 0% (range, 0-6%) and 21% (range, 0-44%), respectively. The median overall survival was 40 (range, 15-74) months and median 5-year survival rate was 40% (range, 21-80%). Potential prognostic factors associated with a poorer overall survival include a positive liver surgical margin and hormone refractory disease. CONCLUSION Hepatectomy is rarely performed for BCLM but the studies described in this review indicate consistent results with superior 5-year survival for selected patients with isolated liver metastases and in those with well controlled minimal extrahepatic disease. To evaluate its efficacy and control for selection bias, a randomised trial of standard chemotherapy with or without hepatectomy for BCLM is warranted.

Systematic review of neoadjuvant transarterial chemoembolization for resectable hepatocellular carcinoma.

Resection of hepatocellular carcinoma (HCC) offers the only hope for cure. However, in patients undergoing resection, recurrences, in particular, intrahepatic recurrence are common. The effectiveness of transarterial chemoembolization (TACE) as a neoadjuvant therapy for unresectable HCC was exploited by numerous liver units and employed preoperatively in the setting of resectable HCC with an aim to prevent recurrence and prolong survival. A systematic literature search of databases (Medline and PubMed) to identify published studies of TACE administered preoperatively as a neoadjuvant treatment for resectable HCC was undertaken. A systematic review by tabulation of the results was performed with disease‐free survival (DFS) as the primary endpoint. Overall survival (OS), rate of pathological response, impact on surgical morbidity and mortality and pattern of recurrences were secondary endpoints of this review. Eighteen studies; three randomized trials and 15 observational studies were evaluated. This comprised of 3927 patients, of which, 1293 underwent neoadjuvant TACE. The median DFS in the TACE and non‐TACE group ranged from 10 to 46 and 8 to 52 months, respectively, with 67% of studies reporting similar DFS between groups despite higher extent of tumour necrosis from the resected specimens indicating a higher rate of pathological response (partial TACE 27–72% vs. non‐TACE 23–52%; complete TACE 0–28% vs. non‐TACE zero), with no difference in surgical morbidity and mortality outcome. No conclusion could be drawn with respect to OS. Both randomized and non‐randomized trials suggest the use of TACE preoperatively as a neoadjuvant treatment in resectable HCC is a safe and efficacious procedure with high rates of pathological responses. However, it does not appear to improve DFS.