Third-line hormonal treatment with exemestane in postmenopausal patients with advanced breast cancer progressing on letrozole or anastrozole. A phase II trial conducted by the Hellenic Group of Oncology (HELGO)

AIMS AND BACKGROUND: The understanding of hormonal therapies in postmenopausal women with metastatic breast cancer has advanced greatly in the past several decades. With the introduction of orally active, potent and selective third-generation aromatase inhibitors (anastrozole, letrozole and exemestane), approaches to the treatment of hormone-sensitive advanced breast cancer are undergoing reevaluation. For treatment of advanced or metastatic disease that has progressed on tamoxifen, all three agents are active. The purpose of the study was to assess the antitumor efficacy and tolerance of exemestane administered as third-line hormonal therapy to postmenopausal women with metastatic breast cancer refractory to letrozole and anastrozole. STUDY DESIGN: Sixty postmenopausal women with stage IV hormone receptor-positive carcinoma of the breast were enrolled in the study. All patients had received two prior hormonal manipulations and had measurable or assessable disease. All adverse events were monitored. RESULTS: Objective tumor response was achieved in 12 (20%) patients (95% CI, 9.6-30.4). The overall clinical benefit was 38.3% (95% CI, 21.2-49.3), and the median duration of objective tumor response was 20 months (range, 9-26). The median time to death was 17.4 months (95% CI, 16.14-18.66). CONCLUSIONS: Exemestane represents an active and well-tolerated treatment option in pretreated patients with advanced breast cancer who have received standard first- and second line hormonal therapies. By extending the sequence of hormonal therapy, disease progression and the need for chemotherapy may be significantly delayed.     

Laparoscopic Versus Open Surgery for Rectal Cancer: A Meta-Analysis

Background Laparoscopic rectal cancer surgery aims to provide patients with curative resection while minimizing postoperative morbidity and mortality. This study used meta-analytical techniques to compare laparoscopic and open surgery as the primary treatment for patients with rectal cancer with regard to short-term and long-term outcomes. Methods A literature search was performed on all studies between 1993 and 2004 comparing laparoscopic and open surgery for rectal cancer. Subgroup analysis was performed on patients undergoing abdominoperineal excision of the rectum. The following end points were evaluated: operative outcomes, postoperative recovery, and early and late adverse events. Results Twenty studies matched the selection criteria and reported on 2071 subjects, of whom 909 (44%) underwent laparoscopic and 1162 (56%) underwent open surgery for rectal cancer. Time to stomal function (weighted mean difference [WMD], −1.52; 95% confidence interval [95% CI], −2.20, −1.01), first bowel movement (WMD, −.72; 95% CI, −1.21, −.22), feeding solids (WMD, −.92; 95% CI, −1.35, −.50), and length of hospital stay (WMD, −2.67; 95% CI, −3.81, −1.54) were all significantly reduced after laparoscopic surgery. In patients who underwent abdominoperineal excision of the rectum, wound infection (odds ratio, .15; 95% CI, .03, .73) and requirement for postoperative parenteral analgesia (WMD, −.63; 95% CI, −1.22, −.04) were also significantly reduced. There was no difference between groups in the extent of oncological clearance. Conclusions Laparoscopic rectal cancer surgery results in an earlier postoperative recovery and a resected specimen that is oncologically comparable to open surgery. Results from randomized trials reporting long-term outcomes such as cancer recurrence (local and metastatic) and 5-year survival are eagerly awaited.     

Fenofibrate: metabolic and pleiotropic effects

Disturbances of lipoprotein metabolism represent one of the most important risk factors for vascular events. However, dyslipidaemic patients often have a number of additional abnormalities (such as endothelial dysfunction, hypertension, low-grade inflammation, haemostatic abnormalities and hyperuricaemia) that may accelerate the atherosclerotic process. Thus, the ideal lipid-modifying drug, along with exerting beneficial effects on lipoprotein metabolism, should also improve these coexisting disturbances. Fibric acid derivatives (fibrates) are a class of lipid-modifying drugs mainly used in patients with elevated triglyceride levels. These drugs mainly exert their actions via the activation of specific nuclear receptors called peroxisome proliferator-activated receptors alpha (PPARalpha). In this review, we summarize the current evidence suggesting that fenofibrate, one of the most widely used fibric acid derivatives, along with its well established actions on lipids also exerts several other antiatherogenic actions. Based on recently published studies, fenofibrate is a useful option for patients with primary combined dyslipidaemias or secondary dyslipidaemias, such as those associated with diabetes mellitus, metabolic syndrome or HIV infection. Additionally, in cases of refractory dyslipidaemia, the combination of fenofibrate with statins is a therapeutic option.     

Surgery insight: Current advances in percutaneous heart valve replacement and repair

Several advances have been made in interventional cardiology, particularly in the field of valvular heart disease. Among the procedures for which technologies are available, percutaneous replacement of the pulmonary and aortic valves, and percutaneous repair of the mitral valve, via annuloplasty or the Alfieri method, are the best known. Along with the excitement generated by these new subspecialties, however, there has also been skepticism. In this article we focus on the current innovations that have been applied to the procedures in humans, and discuss the advantages and disadvantages of the different strategies.     

Management of a ruptured bile duct cyst

A case of a ruptured bile duct cyst in a 25-year-old male patient is presented. The initial management of the clinical presentation of acute abdomen consisted of an exploratory laparotomy and a T-tube cystostomy of a choledochal cyst. Two months later, he was admitted to our surgical department. Preoperative evaluation showed a type IV-A choledochal cyst. The patient underwent excision of the choledochal cyst, cholecystectomy, and the construction of a Roux-en-Y end-to-side hepaticojejunostomy.     

Surgical Techniques and Treatment for Hepatic Hydatid Cysts

Purpose Hepatic hydatid cysts (HHCs) are a parasitic infestation caused by several species of Echinococcus. We examined the clinical features of HHCs and evaluated the results of various surgical procedures. Methods One hundred and sixty-nine patients aged between 17 and 84 years underwent surgery for HHCs within a 12-year period. We recorded the demographic data, location of the cysts, surgical procedures used, morbidity, recurrences, and hospital stay. Results Most (90.5%) of the patients presented with symptoms, but 16 (9.5%) patients reported no symptoms. The most common symptom was abdominal pain. The overall number of cysts was 216 HHCs and 9 concomitant hydatid cysts in other abdominal organs. The surgical treatments consisted of hepatic resection in 8 (4.7%) patients, cystostomy with drainage in 43 (25.5%), cystostomy with capitonnage in 22 (13%), cystostomy with omentoplasty in 72 (42.6%), and cystectomy in 24 (14.2%). Splenectomy or nephrectomy was also performed in nine patients. Postoperative complications developed in 36 (21.3%) patients, and three suffered recurrences. The postoperative mortality rate was 1.2%. Postoperative complications were more frequent after cystostomy with capitonnage than after cystostomy with omentoplasty (P < 0.001) or cystectomy (P = 0.0037). The additional procedures prolonged the hospital stay. Conclusions Current surgical techniques combined with antiscolicidal therapy using albendazole are effective and safe treatments for HHCs, associated with low morbidity, mortality, and recurrence rates.     

Primary Resection With Anastomosis vs. Hartmann’s Procedure in Nonelective Surgery for Acute Colonic Diverticulitis: A Systematic Review

Purpose This study compares primary resection with anastomosis and Hartmann's procedure in an adult population with acute colonic diverticulitis. Methods Comparative studies published between 1984 and 2004 of primary resection with anastomosis vs. Hartmann's procedure were included. The primary end point was postoperative mortality. Secondary end points included surgical and medical morbidity, operative time, and length of postoperative hospitalization. Random effects model was used and sensitivity analysis was performed. Results Fifteen studies, including 963 patients (57 percent primary resection with anastomoses, 43 percent Hartmann's procedures), were analyzed. Overall mortality was significantly reduced with primary resection and anastomosis (4.9 vs. 15.1 percent; odds ratio = 0.41). Subgroup analysis of trials matched for emergency operations showed significantly decreased mortality with primary resection and anastomosis (7.4 vs. 15.6 percent; odds ratio = 0.44). No significant difference in mortality was observed in trials matched for severity of peritonitis Hinchey > 2 (14.1 vs. 14.4 percent; odds ratio = 0.85). Sensitivity analysis did not reveal significant heterogeneity between the studies for the primary outcome. Conclusions Patients selected for primary resection and anastomosis have a lower mortality than those treated by Hartmann's procedure in the emergency setting and comparable mortality under conditions of generalized peritonitis (Hinchey > 2). The retrospective nature of the included studies allows for a considerable degree of selection bias that limits robust and clinically sound conclusions. This analysis highlights the need for high-quality randomized trials comparing the two techniques.     

Enzymatic mechanisms of ethanol oxidation in the brain

BACKGROUND: The exact enzymatic mechanisms of ethanol oxidation in the brain are still unclear. The catalase-mediated oxidation of ethanol was demonstrated in rat brain using incubation of brain homogenates with catalase inhibitors. The role of the alcohol dehydrogenase (ADH) or cytochrome P450-dependent system in this process is possible, but has not been confirmed. The objective of the study was to determine the contribution of the different enzymatic pathways to ethanol oxidation in brain homogenates from mice and rats. METHODS: Three approaches were used to investigate the enzymatic mechanisms of ethanol oxidation in the brain of rats and mice: (1) preincubation of brain homogenates with inhibitors of the ethanol-metabolizing enzymes (catalase, CYP2E1, ADH, and ALDH); (2) utilization of mice with genetic deficiency in ethanol-metabolizing enzymes (catalase, CYP2E1, or both enzymes); and (3) determination of ethanol oxidation in brain subcellular fractions known to have differential activity of ethanol-metabolizing enzymes. The ethanol-derived acetaldehyde (AC) and acetate were determined in brain samples by gas chromatography. RESULTS: The catalase inhibitors sodium azide (5 mM) and aminotriazole (5 mM) as well as CYP2E1 inhibitors diallyl sulfide (2 mM) and beta-phenethyl isothiocyanate (0.1 mM) lowered significantly the accumulation of the ethanol-derived AC and acetate in brain homogenates. The ADH inhibitor 4-methyl pyrazole (5 mM) significantly decreased the acetate but not the AC accumulation. Ethanol-derived AC accumulation in brain homogenates of acatalasemic mice was 47% of the control value, 91% in CYP2E1-null mice, and 24% in double mutants (with deficiency of both catalase and CYP2E1). The highest levels of ethanol oxidation were found in microsomal and peroxisomal subcellular brain fractions, where CYP2E1 and catalase are located, respectively. CONCLUSIONS: Catalase is the key enzyme of ethanol oxidation in the brain of rodents: it may be responsible for about 60% of the process. CYP2E1 plays an important role in ethanol oxidation in the rodent brains. Alcohol dehydrogenase plays a minor role, if any, in this process. Aldehyde dehydrogenase plays the crucial role in the further oxidation of ethanol-derived AC in the brain homogenates.     

Drug-based optical agents: infiltrating clinics at lower risk

Fluorescent agents with specificity to cellular and subcellular moieties present promise for enhancing diagnostics and theranostics, yet challenges associated with regulatory approvals of experimental agents stifle the clinical translation. As a result, targeted fluorescent agents have remained predominantly as preclinical imaging tools. We discuss the potential of using optically labeled drugs to accelerate the clinical acceptance of optical and optoacoustic agents, in analogy to nuclear medicine approaches. This strategy, corroborated with microdosing studies, outlines a promising approach for overcoming bottlenecks and advancing photonic clinical imaging.