HCV carriers with normal alanine aminotransferase levels: Healthy persons or severely ill patients?: Dealing with an everyday clinical problem

Approximately 30% of patients with chronic HCV infection show persistently normal ALT levels. Although formerly referred to as ‘healthy’ or ‘asymptomatic’ HCV carriers, and thus historically excluded from antiviral treatment, it has now become clear that the majority of these patients have some degree of histological liver damage that may be significant in up to 20% of patients and might progress toward a more severe degree of liver fibrosis. A significant proportion of patients (≥ 20%) experience periods of increased serum ALT (flare) associated with enhanced disease progression. However, controversies still exist in clinical practice regarding the definition of ‘persistent’ ALT normality, the virological and histological features of these subjects, the need for liver biopsy, the role of non invasive tools for the assessment of liver fibrosis (transient hepatic elastography, fibroscan), and the natural history and optimal management of chronic hepatitis C with normal ALT. The advent of new therapeutic options (pegylated interferons plus ribavirin) has shifted treatment targets toward eradication of underlying infection, with therapy decision based on age, severity of disease and likelihood of response rather than on aminotransferase levels. This review does approach the main unresolved issues on this topic in the form of a dialog between a hepatologist and a patient with HCV infection but normal alanine aminotransferase levels, trying to give evidence-based answers to the more frequently asked questions from patients and their physicians.     

A phase I trial of pemetrexed plus gemcitabine given biweekly with B-vitamin support in solid tumor malignancies or advanced epithelial ovarian cancer

PURPOSE: To determine the maximally tolerated dose (MTD) of biweekly pemetrexed with gemcitabine plus B(12) and folate supplementation in patients with advanced solid tumors and ovarian cancer. EXPERIMENTAL DESIGN: Patients with no prior pemetrexed or gemcitabine therapy enrolled in cohorts of three, expanding to six if dose-limiting toxicity (DLT) was observed. Pemetrexed, escalated from to 700 mg/m(2), was given before gemcitabine 1,500 mg/m(2) every 14 days. DLTs were grade 4 neutropenia lasting >7 days or febrile neutropenia, grade 4 or 3 thrombocytopenia (with bleeding), grade > or =3 nonhematologic toxicity, or treatment delay of > or =1 week due to unresolved toxicity. RESULTS: The ovarian cancer cohort enrolled 24 patients with unlimited prior cytotoxic chemotherapies. MTD was observed at pemetrexed 600 mg/m(2), with 2 of 9 patients experiencing DLT. Most common grade 3 to 4 toxicities per patient were neutropenia (83%), leukopenia (67%), lymphopenia (73%), and febrile neutropenia (12%). Median cycle per patient was 8 (range, 1-16). Six of 21 (28%) patients had confirmed partial responses. Study protocol was modified for the solid tumor cohort (n = 30) to enroll patients with two or more prior cytotoxic regimens. MTD was observed at pemetrexed 500 mg/m(2), with 1 of 9 patients experiencing DLT. Most common grade 3 to 4 toxicities per patient were neutropenia (63%), lymphopenia (43%), leukopenia (70%) and febrile neutropenia (6.6%). Median cycle per patient was 4 (range, 1-20). Three of 29 (10.3%) response-evaluable patients had confirmed partial responses: 2 squamous cell carcinomas of head and neck and 1 nasopharyngeal cancer. CONCLUSION: MTDs for the solid tumor and ovarian cancer cohorts were reached at pemetrexed 500 and 600 mg/m(2), respectively, given biweekly with gemcitabine 1,500 mg/m(2).     

Intrathecal drug therapy for long-term pain management.

PURPOSE: The use, safety, and efficacy of intrathecal medication administration with implantable pumps for cancer and chronic pain management are reviewed. SUMMARY: Implanted intrathecal drug-delivery systems (IDDSs) are used for long-term management of persistent, severe pain despite a multimodal approach with conventional pain treatment options. Currently, consensus papers published in the literature are used as guidelines for determining patient selection and medication administration, because there is a lack of supporting evidence from randomized, controlled, clinical trials. Pharmacists have a critical role in the safe use of intrathecal medication. Most of the medication concentrations and combinations administered through IDDSs are not commercially available and therefore must be compounded in a pharmacy. Medications commonly administered through IDDSs include opioids, local anesthetics, clonidine, baclofen, and ziconotide. It is important for pharmacists who prepare products for IDDSs to understand the pharmacology, adverse effects, and concentration limitations of each medication in order to prevent adverse events related to postoperative subarachnoid hemorrhage, infection, catheter-tip inflammatory masses, withdrawal, and overdose. Pharmacists play an important role in maintaining quality assurance of intrathecal drug use, including the use of standard procedures for ordering and compounding medications, documentation of patient education, and monitoring of patient outcomes. CONCLUSION: The use of long-term intrathecal drug delivery for the treatment of intractable pain or intolerable medication adverse effects has expanded to include the treatment of patients with chronic or cancer-related pain. Important considerations for the use of intrathecal drug therapy include the appropriate selection of patients, delivery systems, and medications, as well as potential complications of therapy and quality-assurance measures necessary to ensure patient safety.     

Initial experience in Brazil with endoscopic submucosal dissection for early gastric cancer using insulation-tipped knife: a safety and feasibility study

Background  Endoscopic resection is an adequate treatment for subgroups of patients with early gastric cancer. Endoscopic submucosal dissection (ESD) represents a recent advance and leads to good results when adequately indicated. There is great experience with this technique in Japan and it is gaining acceptance among Western endoscopists. We present the first gastric ESD series performed in Brazil. Methods  Patients with well-differentiated adenocarcinomas macroscopically classified as early cancer, less than 30 mm with no ulcer or scar, were included. ESD was performed with an insulated-tip knife and electrosurgical unit with endocut mode. Clinicopathological aspects and morbidity were evaluated. The study was approved by the local ethics committee and informed consent was obtained from all participant subjects. Results  From October 2005 to July 2007, 160 patients received surgical treatment for gastric cancer; 44 patients (27.5%) had early gastric cancer. In this latter group, 15 procedures (ESD) were performed in 12 patients. The mean size of the lesions was 16.8 mm. Almost half of the lesions were located in the proximal third of the stomach and the mean elapsed time for the procedure was 140 min. In 80% of the cases resection was en bloc and 80% of the resections were considered curative. We had three perforations, which were managed clinically, and no bleeding. Conclusion  When adequately indicated, ESD is a safe and feasible technique.     

Antimalarial chemoprophylaxis in children

In early age, drugs without side effects are required for malaria chemoprophylaxis. Several regimens are available for drug-resistant plasmodium spp in many countries.     

Oral trimethoprim/sulfamethoxazole for prevention of bacterial infection during the induction phase of cancer chemotherapy in children

We conducted a randomized, double-blind, placebo-controlled study to evaluate the efficacy of oral trimethoprim/sulfamethoxazole (TMP/SMX) in the prevention of bacterial infections in children with cancer. Sixty-three patients with acute leukemia were studied during the induction phase of chemotherapy; 28 patients with solid tumors who were starting intensive chemotherapy were also enrolled and treated for 2 months. There was no significant difference in the frequency of febrile episodes between the 43 children receiving trimethoprim/sulfamethoxazole and the 48 receiving placebo. However, when the group of 74 children who experienced granulocytopenia (absolute granulocyte count less than 500/microL) was analyzed separately, significant reductions in the frequencies of confirmed bacteremia (2.6% v 20.0%, P = .02) and febrile episodes (35.9% v 65.7%, P = .01) were observed in the trimethoprim/sulfamethoxazole group. Furthermore, life table analysis showed that children with leukemia receiving trimethoprim/sulfamethoxazole had significantly more days without fever and without bacteremia. No benefits from prophylaxis were recognized in the subgroup with solid tumors. Although the frequency of oral thrush was greater (P = .02) in the trimethoprim/sulfamethoxazole group (25.6%) than in the placebo group (6.3%), invasive fungal infection did not occur. Although the mean duration of granulocytopenia was greater among those receiving trimethoprim/sulfamethoxazole (13.7 v 9.0 days, P = .05), this did not appear to increase the overall risk for bacterial infection. These data suggest that trimethoprim/sulfamethoxazole reduces the frequency of bacteremia and febrile episodes in granulocytopenic children undergoing induction chemotherapy for acute leukemia.     

Simultaneous measurement of seminal L-carnitine, alpha,1-4-glucosidase, and glycerylphosphorylcholine in azoospermic and oligozoospermic patients

L-carnitine, alpha,1-4-glucosidase, and glycerylphosphorylcholine were measured in seminal plasma of a selected group of azoospermic men and in an unselected group of oligozoospermic men. In vasectomized subjects the epididymal indices (mean +/- standard error: L-carnitine, 276.9 +/- 27.5 nmol/ejaculate; alpha-glucosidase, 1.2 +/- 0.1 U/ejaculate; and glycerylphosphorylcholine, 1.5 +/- 0.2 mumol/ejaculate) were always below the normal range of fertile subjects (1757.4 +/- 76.7 nmol/ejaculate; 16.4 +/- 0.9 U/ejaculate; and 17.3 +/- 0.7 mumol/ejaculate, respectively). On the contrary in a large number of patients affected by azoospermia because of seminiferous tubular damage (750.4 +/- 83.6 nmol/ejaculate; 6.8 +/- 0.9 U/ejaculate; and 6.1 +/- 0.6 mumol/ejaculate; respectively) and in a few oligozoospermic subjects (1193.7 +/- 72.3 nmol/ejaculate; 10.3 +/- 0.7 U/ejaculate; and 10.8 +/- 0.7 mumol/ejaculate; respectively) the epididymal indices were found in the range of vasectomized subjects, showing an association between seminiferous tubular lesion and epididymal dysfunction. In conclusion, in spite of the low levels of epididymal indices found in patients with obstructive azoospermia, the presence of a large number of subjects with seminiferous tubular lesions without obstruction with similar low values of L-carnitine, alpha-glucosidase, and glycerylphosphorylcholine reduces the usefulness of these indices in differential diagnosis of azoospermia.     

Temporin A as a prophylactic agent against methicillin sodium-susceptible and methicillin sodium-resistant Staphylococcus epidermidis vascular graft infection

OBJECTIVE: The purpose of this study was to investigate the efficacy of temporin A as a prophylactic agent in a rat model of vascular graft infection from methicillin sodium-susceptible and methicillin sodium-resistant Staphylococcus epidermidis. METHODS: The prospective, randomized, controlled animal study set in a research laboratory in a university hospital used 280 adult male Wistar rats (weight range, 280 to 350 g). Graft infections were established in the back subcutaneous tissue of rats with implantation of 1-cm(2) sterile Dacron grafts followed by topical inoculation with 2 x 10(7) colony-forming units of S epidermidis. The study for each staphylococcal strain included: one control group (no graft contamination), one contaminated group that did not receive any antibiotic prophylaxis, one contaminated group that received temporin A-soaked graft, two contaminated groups that received perioperative intraperitoneal cefazolin (30 mg/kg) or vancomycin hydrochloride prophylaxis (10 mg/kg), and two contaminated groups that received temporin A-soaked graft and perioperative intraperitoneal cefazolin (30 mg/kg) or vancomycin hydrochloride (10 mg/kg) prophylaxis. All grafts were explanted at 7 days after implantation. The main outcome measure was quantification of bacterial contamination. RESULTS: Overall, the perioperative prophylaxis based on soaked grafts was not significantly different to that of parenteral vancomycin hydrochloride. Only the combination between temporin A and vancomycin hydrochloride produced a complete bacterial inhibition for both strains. CONCLUSION: Temporin A showed a similar antibacterial in vitro activity against the two different strains. The in vivo results suggest its potential use in providing prophylaxis to direct graft contamination when used in combination with parenteral vancomycin hydrochloride.     

Urinary hydroxyproline as a biomarker of effect after exposure to nitrogen dioxide

A cross-sectional study was carried out on two groups of subjects differently exposed to nitrogen dioxide in order to test the urinary hydroxyproline ratio (UHP/mg/24 h/m(2)) as a biomarker of effect after exposure to this pollutant. UHP was determined in samples of 58 subjects divided into two groups comparable to as lifestyle and training. The first group was composed of 29 subjects who used to do jogging in urban areas polluted by nitrogen dioxide. The second group was made up of 29 subjects who used to do jogging in non-polluted countryside areas. The mean concentration of UHP of urban joggers was 25.02+/-9.21 mg/24 h/m(2), whereas in those training in the countryside it was 13.78+/-6.68 mg/24 h/m(2). Thus, UHP was higher in subjects training in areas polluted by nitrogen dioxide than in the subjects training in non-polluted areas.