Highly specific reasons for nonadherence to antiretroviral therapy: results from the German adherence study.

BACKGROUND: Reasons for and frequency of nonadherence to antiretroviral therapy (ART) may have changed due to pharmacological improvements. In addition, the importance of known non-pharmacologic reasons for nonadherence is unclear. METHODS: We performed a cross-sectional, noninterventional, multicenter study to identify current reasons for nonadherence. Patients were categorized by physicians into the following adherence groups: good, unstable, or poor adherence. Co-variables of interest included age, sex, time since HIV diagnosis, ART duration, current ART regimen, HIV transmission route, comorbidity, HIV-1 RNA viral load (VL), and CD4 cell count. Patients self-reported the number of missed doses and provided their specific reasons for nonadherent behavior. Statistical analyses were performed using Fisher's extended exact test, Kruskal-Wallis test, and logistic regression models. RESULTS: Our study assessed 215 participants with good (n=162), unstable (n=36), and poor adherence (n=17). Compared to patients with good adherence, patients with unstable and poor adherence reported more often to have missed at least one dose during the last week (good 11% vs unstable 47% vs poor 63%, p<0.001). Physicians' adherence assessment was concordant with patients' self-reports of missed doses during the last week (no vs one or more) in 81% cases. Similarly, we found a strong association of physicians' assessment with viral suppression. Logistic regression analysis showed that "reduced adherence" - defined as unstable or poor - was significantly associated with patients <30 years old, intravenous drug use, history of acquired immune deficiency syndrome (AIDS), and psychiatric disorders (p<0.05). Univariate analyses showed that specific reasons, such as questioning the efficacy/dosing of ART, HIV stigma, interactive toxicity beliefs regarding alcohol and/or party drugs, and dissatisfaction with regimen complexity, correlated with unstable or poor adherence (p<0.05). CONCLUSION: Identification of factors associated with poor adherence helps in identifying patients with a higher risk for nonadherence. Reasons for nonadherence should be directly addressed in every patient, because they are common and constitute possible adherence intervention points.

Is the size of the pancreas useful in diagnosing chronic pancreatitis? An ultrasound based, retrospective study.

BACKGROUND/OBJECTIVES: According to the widely accepted "Cambridge Classification", one of the morphological criteria for chronic pancreatitis (CP) is enlargement of the pancreas. Increased size seems to be an obvious feature of an inflammatory disease. However, it has never been validated so far, if CP is indeed accompanied by significant enlargement of the pancreas. METHODS: In this retrospective study, reference values for the size of the pancreas (head, body and tail measured in the transverse plane by transabdominal ultrasound) were established from 921 patients without pancreatic disease. Measurements were performed by a single investigator. Subsequently, the size of the pancreas from 72 patients with CP was compared to age- and sex-matched controls. RESULTS: Calculating the 5th and 95th percentile, reference values of the pancreatic size were as follows: head 1.5-3.1 cm (mean: 2.2); body 0.6-1.6 cm (mean: 1.1); tail 1.4-3.0 cm (mean: 2.1). The size of the pancreas correlated significantly with body height, weight and body mass index. Patients with CP had only a slightly but statistically significantly larger pancreas than controls. Mean values from the CP group were still between the 5th and 95th percentile of matched controls. CONCLUSIONS: Although the pancreas from patients with CP was statistically significantly larger compared to controls, the difference was only marginally. According to these data, it is at least questionable if pancreatic size is a helpful parameter for sonographic evaluation to discriminate chronic pancreatitis from healthy pancreas.

Comparison of a pocket-size ultrasound device with a premium ultrasound machine: diagnostic value and time required in bedside ultrasound examination.

PURPOSE: Time savings and clinical accuracy of a new miniature ultrasound device was investigated utilizing comparison with conventional high-end ultrasound instruments. Our objective was to determine appropriate usage and limitations of this diagnostic tool in internal medicine. METHODS: We investigated 28 patients from the internal-medicine department. Patients were examined with the Acuson P10 portable device and a Sonoline Antares instrument in a cross-over design. All investigations were carried out at the bedside; the results were entered on a standardized report form. The time for the ultrasound examination (transfer time, setting up and disassembly, switching on and off, and complete investigation time) was recorded separately. RESULTS: Mean time for overall examination per patient with the portable ultrasound device was shorter (25.0 ± 4.5 min) than with the high-end machine (29.4 ± 4.4 min; p < 0.001). When measuring the size of liver, spleen, and kidneys, the values obtained differed significantly between portable device and the high-end instrument. In our study, we identified 113 pathological ultrasound findings with the high-end ultrasound machine, while 82 pathological findings (73%) were concordantly detected with the portable ultrasound device. The main diagnostic strengths of the portable device were in the detection of ascites (sensitivity 80%), diagnosis of fatty liver, and identification of severe parenchymal liver damage. CONCLUSIONS: The clinical utility of portable ultrasound machines is limited. There will be clinical roles for distinct clinical questions such as detection of ascites or pleural effusion when used by experienced examiners. However, sensitivity in detecting multiple pathologies is not comparable to high-end ultrasound machines.

Endosonography For Right-sided and Acute Upper Intestinal Misery: the EFRAIM study: A prospective, randomized, controlled, blinded study.

BACKGROUND: Acute upper abdominal pain is a frequent symptom leading to hospital admission. OBJECTIVE: To determine whether a primary intra- and extraluminal diagnostic approach enabled by endoscopic ultrasound is as effective as a conventional diagnostic algorithm of transabdominal ultrasound followed by oesophagogastroduodenoscopy. METHODS: A total of 240 patients who presented with acute right-sided and/or upper abdominal pain were prospectively recruited. Exclusion criteria were chronic pain, malignancy, prior abdominal surgery, bleeding, peritonitis, and elevated liver enzymes or lipase as defined 3-times higher than upper reference value. All patients underwent first transabdominal ultrasound and were then randomized (1 : 1) to either endoscopy followed by endoscopic ultrasound or vice versa. Patients and respective examiners were blinded to prior findings. RESULTS: A total of 223 patients were included. Endoscopic ultrasound provided a higher diagnostic yield than the combination of transabdominal ultrasound and endoscopy (62.3 vs. 50.7%; p = 0.001). For mucosal/intraluminal lesions, we observed a very good agreement between both endoscopic modalities (kappa 0.89). The agreement for pancreatic and biliary causes was good between both ultrasound modalities (kappa 0.66). CONCLUSIONS: Due to its high diagnostic yield, endoscopic ultrasound as a primary diagnostic modality appears to be a valuable option in patients with acute upper abdominal pain.

Influence of calcaneus angle and muscle forces on strain distribution in the human Achilles tendon.

BACKGROUND: Heterogeneous distribution of tendon strain is considered to contribute to the development of the Achilles tendon overuse injuries. Force distribution between the three portions of the triceps surae muscle and position of the calcaneus might affect the extent of strain differences within the Achilles tendon. Purpose of this study was to determine the effect of changes in force distribution within the triceps muscle and changes in calcaneus position on intratendinous strain distribution of the Achilles tendon. METHODS: Five cadaveric Achilles tendons including complete triceps surae and calcaneus were dissected. Specimens were mounted in a loading simulator allowing independent force application for the three parts of triceps muscle and changes calcaneus eversion and inversion position. Strain was determined in different aspects of the Achilles tendon. FINDINGS: Changes of calcaneus position resulted in intratendinous strain differences up to 15%, changes in force distribution within the triceps muscle resulted in strain differences up to 2.5%. Calcaneal eversion was connected to a higher degree of strain in medial tendon portions, while inversion increased strain in lateral tendon portions. INTERPRETATION: Medio-lateral, proximo-distal and dorsal-ventral distribution of tendon strain is rather influenced by kinematics of the subtalar joint than by muscular imbalances within the triceps muscle. Clinical movement analyses should focus on motion pattern combining rearfoot eversion with high Achilles tendon load. The results indicate that twist of the Achilles tendon fascicles seems of paramount importance in balancing tendon strain. To get more insight into the Achilles tendon injuries pathogenesis future research should focus on methods monitoring heterogeneous distribution of strain in vivo.

Advanced hemodynamic monitoring before and after transjugular intrahepatic portosystemic shunt: implications for selection of patients--a prospective study.

PURPOSE: To investigate immediate and short-term effects of transjugular intrahepatic portosystemic shunt (TIPS) on cardiocirculatory, hepatic, and renal function and characterize predictors for TIPS outcome in terms of organ function after TIPS. MATERIALS AND METHODS: This prospective study was approved by the ethics committee at a university hospital and was conducted in a medical intensive care unit. Informed consent was obtained. Twenty patients with indication for TIPS were enrolled. Monitoring of hemodynamic and hepatic function (transpulmonary thermodilution, indocyanine green plasma disappearance rate [ICG-PDR]) was performed. Biochemical markers of organ function were obtained. Statistical analysis (Wilcoxon test, Spearman correlation, multivariate linear regression analysis, receiver operating characteristic [ROC] analysis) was performed. RESULTS: After TIPS, central venous pressure (median, 11 vs 15 cm H(2)O; P < .001), cardiac index (3.4 vs 3.8 L/min/m(2); P = .001), and global end-diastolic volume index (GEDVI) (726 vs 775 mL/m(2); P = .003) increased significantly. Portosystemic pressure gradient (28 vs 11 cm H(2)O; P < .001) and systemic vascular resistance index (1610 vs 1384 dyn · sec · cm(-5) · m(2); P = .015) decreased significantly. Creatinine (1.1 vs 1.1 mg/dL; P = .008) and blood urea nitrogen (BUN) (27 vs 21 mg/dL; P = .006) decreased significantly. Bilirubin (1.8 vs 2.2 mg/dL; P = .032) and international normalized ratio (1.4 vs 1.5; P = .022) increased significantly. ICG-PDR significantly deteriorated after TIPS (P = .006). Higher baseline creatinine was independently associated with a decrease in creatinine after TIPS (R = 0.816, P < .001). ROC analysis identified baseline BUN (P = .026, area under ROC curve [AUC] = 0.818), cystatin C (P = .033, AUC = 0.805), and creatinine (P = .052, AUC = 0.779) as predictors of a decrease in creatinine of 0.5 mg/dL or greater and/or 25% or greater. An increase in bilirubin of 1 mg/dL or greater 1 week after TIPS was significantly associated with high baseline BUN (P = .007, AUC = 0.893) and high central venous pressure (P = .040, AUC = 0.800). Lower baseline alanine aminotransferase (P = .002, AUC = 1.000) and cardiac power index · GEDVI (P = .005, AUC = 0.960) predicted favorable TIPS outcome (creatinine decrease of ≥ 0.2 mg/dL without model for end-stage liver disease score increase of more than one point). CONCLUSION: Patients with renal insufficiency, compensated hepatocellular function, decreased cardiac preload, and decreased cardiac performance benefit most from TIPS.

Preoperative radiological characterization of hepatic angiomyolipoma using magnetic resonance imaging and contrast-enhanced ultrasonography: a case report.

INTRODUCTION: A hepatic angiomyolipoma is a rare benign tumor of the liver composed of a mixture of smooth muscle cells, blood vessels and a variable amount of adipose tissue. Differentiating them from malignant liver tumors can often be very difficult. CASE PRESENTATION: We report the case of a 43-year-old Caucasian man presenting with a large liver mass in the right lobe. The results of magnetic resonance imaging and contrast-enhanced ultrasonography were consistent with a well-demarcated adipose tissue- containing tumor, showing prolonged hyperperfusion in comparison with the surrounding liver tissue. Surgery was performed and the diagnosis of hepatic angiomyolipoma was made with histopathology. CONCLUSION: Preoperative radiological characterization using magnetic resonance imaging and contrast-enhanced ultrasonography may improve diagnostic accuracy of hepatic angiomyolipoma. Identification of smooth muscle cells, blood vessels and adipose tissue with a positive immunohistochemical reaction for HMB-45 is the final evidence for an angiomyolipoma.

Intraarticular pressure distribution in the talocrural joint is related to lower leg muscle forces.

BACKGROUND: It is of paramount importance to know the magnitude and the distribution of joint contact stress within the most heavily loaded structures of the human foot. In the talocrural joint role of external loading and loading applied by muscles on joint contact stress is not extensively studied. The purpose was to determine the distribution of joint contact stress of the talocrural joint with varying axial tibia loading and extrinsic tendon loading. METHODS: Five cadaveric feet were studied in the intact condition and following transsection of ligaments under seventeen different loading conditions. Joint contact stress was determined from capacitive pressure sensors implanted in the talocrural joint when the specimens were loaded in a specially designed loading simulator. Different axial tibia and extrinsic tendon loads were applied. Motions of the bony structures were assessed by an optical motion analysis system. FINDINGS: The anterior aspect of the joint is predominantly stressed in all loading conditions. The influence of muscle force on the internal joint contact stress distribution is higher than the axial shank loading. The biggest effect on joint contact stress was initiated by the tibialis posterior muscle. The flexor hallucis homogenizes the pressure distribution in intact joint conditions. Joint angles were not substantially changed by muscle force applications. INTERPRETATION: The functions of the muscles of the lower leg are important for maintaining physiologic joint contact stress. Reducing the force potentials of certain muscle tendon units through surgeries, immobilization, fatigue or inappropriate footwear should change the joint contact stress. Such information is helpful to understand the physiological function of the foot. It might also explain the development and manifestation of certain foot pathologies.

Effect of low-molecular-weight heparin on survival in patients with advanced pancreatic adenocarcinoma.

This retrospective analysis aimed to identify whether low-molecular-weight heparins (LMWH) might improve survival in patients receiving chemotherapeutic treatment for advanced pancreatic adenocarcinoma. Two hundred forty-three patients who had received chemotherapy for advanced pancreatic adenocarcinoma were identified from a prospectively maintained database. Of these, 30 patients had to be excluded from analysis due to insufficient documentation. Of the remaining 213 patients 94 patients had been treated with LMWH, whereas 119 patients served as controls. Outcome was assessed in relation to overall survival, which was calculated from the date of initiation of chemotherapy to the date of death. There was no significant difference (hazard ratio, 0.8; 95% confidence interval (CI), 0.6 to 1.1; P = 0,2) between the two groups in terms of overall survival. The median survival was 7.1 months (95% CI, 5.8-8.4 months) in the LMWH group and 5.9 months (95% CI, 5.1-6.7 months) in the non-LMWH group. A positive effect of LMWH was seen in patients with metastatic disease (hazard ratio for LMWH vs. non-LMWH, 0,6; 95% CI, 0,4 to 0,8; P = 0,006) in contrast to those without metastatic disease (hazard ratio for LMWH vs. non-LMWH, 1; 95% CI, 0.6 to 1.7; P = 0,96). The median survival of patients with metastatic disease was 6,6 months (95% CI, 5-8, 2 months) and 3.8 months (95% CI, 2.5-5.1 months) for the LMWH group and the non-LMWH group, respectively. In conclusion, we found for metastatic pancreatic adenocarcinoma a survival advantage for patients receiving LMWH. Nevertheless, our observations need confirmation by prospective randomized studies.

Role of meal carbohydrate content for the imbalance of plasma amino acids in patients with liver cirrhosis.

BACKGROUND AND AIM: Imbalance of circulating branched chain amino acids (BCAA) versus aromatic amino acids (AAA) and hyperinsulinemia are common metabolic alterations in patients with liver cirrhosis. The aim of this study was to characterize the effect of the carbohydrate component of a protein-rich mixed meal on postprandial plasma concentrations of 21 amino acids, insulin and C-peptide in patients with compensated liver cirrhosis. Furthermore, the effect of a dietary intervention on the metabolic alterations in cirrhotic patients was examined. METHODS: Eighteen patients with cirrhosis and 12 healthy volunteers received a protein-rich meal (pork filet 200 g) with or without carbohydrates (bread 50 g, glucose 20 g). A subgroup of four cirrhotic patients received an isoenergetic (117 kJ/kg bw) carbohydrate-enriched (60%) and -restricted (20%) diet for 7 days each. RESULTS: In the cirrhotic patients, basal plasma insulin and C-peptide concentrations were significantly elevated. The ingestion of a protein-rich meal without additional carbohydrates led to a significantly greater increase of insulin and C-peptide in the cirrhotic patients compared to controls. Postprandial increases of leucine and isoleucine were reduced, whereas those of phenylalanine were higher in cirrhotic patients. The addition of carbohydrates led to higher insulin and C-peptide plasma concentrations in cirrhotic patients. Postprandial BCAA increases were more impaired in the cirrhotic group after additional carbohydrate ingestion (46%vs 82%). After the carbohydrate-restricted diet for 7 days BCAA plasma levels increased but the BCAA/AAA ratio remained unaltered. CONCLUSIONS: The carbohydrate content of a meal enhances reduction of BCAA plasma concentrations in clinically stable cirrhotic patients. An imbalanced BCAA/AAA ratio cannot be avoided by a carbohydrate-reduced diet alone, supporting mandatory BCAA supplementation.

Carbamazepine for prevention of oxaliplatin-related neurotoxicity in patients with advanced colorectal cancer: final results of a randomised, controlled, multicenter phase II study.

BACKGROUND: Oxaliplatin-induced neurotoxicity is a growing, relevant clinical problem. In this study we evaluated the efficacy and safety of carbamazepine for prevention of oxaliplatin-associated neuropathy in patients with advanced colorectal cancer. METHODS: Chemotherapeutic treatment consisted of oxaliplatin 85 mg/m(2) given biweekly and weekly folinic acid 500 mg/m(2) followed by a 24-h infusion of 5-FU 2000 mg/m(2) (FUFOX). One cycle consisted of six consecutive weeks of treatment followed by two weeks of rest (=Treatment B). For Treatment A carbamazepine was added in a dosage for targeted plasma levels of 4-6 mg/L. Neurotoxicity was regularly assessed using a specific scale. Moreover, an evaluation of chronic sensory symptoms and a neurologic examination including tests for vibrational sense, strength and deep tendon reflexes were added creating a peripheral neuropathy (PNP) score. RESULTS: The prospectively defined adequate number of patients needed to provide power for the primary outcome could not be achieved. 19 patients were assigned to Treatment A and 17 to Treatment B. At baseline, the distribution of all clinicopathologic variables was comparable between the two groups. Overall response rates were 16% and 24% and overall survival 15.1 months and 17.4 months for Treatment A and Treatment B, respectively. Between Treatment A and Treatment B there were no major differences when considering worst neurotoxicity during the study period (p=0.46). Grade 3/4 neurotoxicity occured in 4 patients with Treatment A vs. 6 patients with Treatment B. There were no major differences between both groups in each category of the PNP score. CONCLUSIONS: Based on the small number of patients and low statistical power of our study definite conclusions regarding efficacy and safety of carbamazepine for prevention of oxaliplatin-associated neuropathy in patients with advanced colorectal cancer cannot be drawn.

Phase II trial of weekly 24-hour infusion of gemcitabine in patients with advanced gallbladder and biliary tract carcinoma.

BACKGROUND: Patients with advanced gallbladder and biliary tract carcinoma face a dismal prognosis, as no effective palliative chemotherapy exists. The antitumor effect of gemcitabine is schedule-dependent rather than dose-dependent. We evaluated the activity of a prolonged infusion of gemcitabine in advanced gallbladder and biliary tract carcinomas. METHODS: Nineteen consecutive eligible patients were enrolled. All patients were required to have histologically confirmed diagnosis and measurable disease. Gemcitabine was infused over 24 hours at a dose of 100 mg/m2 on days 1, 8, and 15. Treatment was repeated every 28 days until progression of disease or limiting toxicity. Tumor response was evaluated every second course by computed tomography (CT) scans. RESULTS: Eighteen patients were evaluable for response. A total of 89 cycles of therapy were administered. One partial response was observed (6%; 95% confidence interval (CI): 0-27%) and ten additional patients had stable disease for at least two months (disease control rate 61%; 95% CI: 36-83%). The therapy was well tolerated, with moderate myelosuppression as the main toxicity. The median time to tumor progression and median overall survival was 3.6 months (95% CI 2.6-4.6 months) and 7.5 months (95% CI 6.5-8.5 months), respectively. CONCLUSION: Weekly 24-hour gemcitabine at a dose of 100 mg/m2 is well tolerated. There was a relatively high rate of disease control for a median duration of 5.3 months (range 2.8-18.8 months). However, the objective response rate of this regimen in gallbladder and biliary tract carcinomas was limited.

Dose escalation of concurrent hypofractionated radiotherapy and continuous infusion 5-FU-chemotherapy in advanced adenocarcinoma of the pancreas.

BACKGROUND/AIMS: To investigate the advantages and palliative effectiveness of concurrent hypofractionated radiotherapy (RT) and chemotherapy (5-FU) in patients with locally advanced and metastatic adenocarcinoma of the pancreas. METHODOLOGY: A total of 26 patients were enrolled in this study. Twenty patients had locally advanced (M0) and 6 patients had metastatic (M1) disease. They were treated with hypofractionated radiation therapy (RT) (4x3 Gy per week) and concurrent continuous infusion (300mg/sqm/24h) of 5-fluorouracil. The RT doses were escalated in 6-Gy increments starting from 24 Gy in 8 fractions in 2 weeks to 30 Gy in 10 fractions in 2.5 weeks and finally to 36 Gy in 12 fractions in 3 weeks. RESULTS: Only 1 (4%) patient experienced grade 3 mucositis, while 12 (46%) patients experienced grade 2 nausea and 1 (4%) patient experienced grade 2 weakness. No patient experienced treatment interruption or dose reduction. Late high-grade (>3) toxicity was not observed, but few patients experienced prolonged hematological toxicity, due to administration of chemotherapy after radiochemotherapy. Pain improved in 70% of the patients. The median survival time for all 26 patients is 8 months, 9 months for locally advanced cancer patients and 5 months for metastatic cancer patients. CONCLUSIONS: Dose escalation to 36 Gy in a hypofractionated manner proved to be feasible with low toxicity in patients with locally advanced and metastatic adenocarcinoma of the pancreas and warrants further investigation aiming at optimal tailoring in these two subgroups of patients.

Phase II trial of a 24-hour infusion of gemcitabine in previously untreated patients with advanced pancreatic adenocarcinoma.

The antitumor effect of gemcitabine is not dose-response related but schedule dependent. Here we report a phase II trial of a weekly 24-hour infusion of gemcitabine in previously untreated patients with advanced pancreatic cancer. Patients with histologically proven, measurable, and irresectable pancreatic adenocarcinoma were treated with gemcitabine at a dose of 100 mg/m2 infused over 24 hr on days 1, 8, and 15. Treatment was repeated every 28 days until progression of disease or limiting toxicity. All 18 patients enrolled were evaluable for response. Neutropenia and thrombocytopenia grade 3 occurred in 1 patient each. One partial response and two minor responses were observed. Median time to progression of disease was 4.4 months. Improvement of the European Organization for Research and Treatment of Cancer C30 scores was observed in 6 patients (pain and overall symptom score, respectively) and in 3 patients (overall functioning score and global quality of life, respectively). Weekly 24-hr gemcitabine was well tolerated in previously untreated patients with advanced pancreatic cancer. It shows marginal antitumor activity in terms of response rate. However, the 24-hr infusion at a dose of 100 mg/m2 seems to be as active as the standard 30-min gemcitabine at a dose of 1000 mg/m2. Relatively long median time to progression of disease and improvement of symptom and quality-of-life scores suggest, that patients may benefit from 24-hr gemcitabine.

High incidence of angina pectoris in patients treated with 5-fluorouracil. A planned surveillance study with 102 patients.

OBJECTIVE: Angina pectoris, arrhythmic sudden death and myocardial infarction, all these cardiac events have occasionally been reported during 5-fluorouracil (5-FU) chemotherapy. Underlying mechanisms leading to these events are unknown; damage to the myocytes or vasospasms have been discussed. METHODS: 102 consecutive and unselected patients were monitored with 12-lead ECG, echocardiography and radionuclide ventriculography prior to the first cycle of 5-FU chemotherapy and 3 months from baseline. RESULTS: 19% of the patients developed reversible symptoms of angina pectoris during treatment which lasted up to 12 h after cessation of the infusion. Most of the 19 patients showed corresponding ECG changes. 6 out of the 19 patients with severe angina pectoris had subsequent coronary angiography. In none of these patients the coronary angiography showed coronary artery disease, but it showed low ventricular function (ejection fraction <50%) in 2 patients. The ejection fraction did not increase over time. Arrhythmias were screened for with Holter monitoring during 5-FU chemotherapy. The frequency of bradycardia and ventricular extrasystoles increased significantly (p < 0.05) during treatment compared to arrhythmias in Holter monitoring 3 months later. Furthermore the Qtc time in the ECG 3 months later was significantly prolonged (p < 0.05) compared to baseline values. CONCLUSIONS: The incidence of angina pectoris in patients during 5-FU treatment seems higher than previously suspected. As myocardial ischemia can be fatal, attentiveness to these symptoms and immediate treatment are crucial.

Prevention of oxaliplatin-induced peripheral sensory neuropathy by carbamazepine in patients with advanced colorectal cancer.

Oxaliplatin plays a key role in the treatment of advanced colorectal cancer. The dose-limiting side effect of this platinum analogue is neurotoxicity. Significant efforts have been undertaken in an attempt to prevent and/or circumvent the development of neurotoxicity. Sodium channel inactivation kinetics on rat sensory sural nerve preparations are altered after exposure to oxaliplatin. Carbamazepine antagonizes this effect in vitro. Results from preliminary clinical studies indicate that the sodium channel blockers carbamazepine and gabapentin may be effective in preventing neurotoxicity. The role of amifostine is not yet clear. Randomized clinical studies are necessary to confirm the potential benefit of carbamazepine and other sodium channel blockers in preventing and/or overcoming the development of oxaliplatin-induced neurotoxicity.

Different activities of type I interferons on hepatitis B virus core promoter regulated transcription.

The type I interferons (IFNs) are a group of closely related cytokines which have different signal transduction pathways and different biological activities. Using transient transfection of human hepatoma cells with reporter plasmids containing the firefly/renilla luciferase genes under the control of the HBV-Enhancer (Enh) I, Enh II and core promoter we have investigated the biological activities of 10 recombinant (r) type I IFNs on transcription. Low concentrations of IFN (0.025 ng/ml) had a significant and specific inhibitory effect but the potencies of the different recombinant type I IFNs differed markedly with IFNalpha8 and IFNbeta being six-fold more potent than the least effective subtype (IFNalpha1). However, the addition of IFNalpha5-the subtype produced predominantly in the human liver-did not cause any synergistic effects.The non-natural consensus IFN displayed a more pronounced inhibition of HBV-regulated transcription than IFNalpha8 or IFNalpha2 but not IFNbeta. The INF-induced inhibitory effect was not dependent on the presence of the HBV-Enh1 and in particular of an interferon stimulated response element (ISRE)-like sequence. The characterization of different effects among type I interferons on HBV-regulatory elements may implicate an IFN-subtype-specific role for the pathogenesis and treatment of HBV-infection.

Toxicity of a 24-hour infusion of gemcitabine in biliary tract and pancreatic cancer: a pilot study.

The antitumor activity of gemcitabine is not dose-response related but schedule-dependent. Based on the results of a published phase I study in patients with nonsmall-cell lung cancer we started a pilot study of a 24-hr infusion of gemcitabine in patients with adenocarcinoma of the pancreas and biliary tract cancer. Twenty-five patients were enrolled and received a 24-hr infusion of gemcitabine once weekly on three consecutive out of 4 weeks. Dose levels of gemcitabine ranged from 100 to 150 mg/m2. One of 13 chemotherapy-naive patients had a partial response. Dose-limiting toxicity (DLT) was thrombocytopenia in pretreated patients and neutropenia in chemotherapy-naive patients. Other toxicities were oral mucositis, fever, flu-like symptoms, and asthenia. Maximum tolerated dose (MTD), especially in pretreated patients, was 100 mg/m2.