Mutational analysis of hypoxia‐related genes HIF1α and CUL2 in common human cancers

Park SW, Chung NG, Hur SY, Kim HS, Yoo NJ, Lee SH. Mutational analysis of hypoxia‐related genes HIF1α and CUL2 in common human cancers. APMIS 2009; 117: 880–5. Hypoxia is a general feature of solid cancer tissues. Hypoxia upregulates hypoxia‐inducible factor 1α (HIF1α) that transactivates downstream genes and contributes to cancer pathogenesis. HIF1α is upregulated not only by hypoxia but also by genetic alterations in HIF1α‐related genes, including VHL. Cullin 2 (CUL2) interacts with the trimeric VHL‐elongin B‐elongin C complex and plays an essential role in the ubiquitinated degradation of HIF1α. The aim of this study was to explore whether HIF1α and CUL2 genes are somatically mutated, and contribute to HIF1α activation in common human cancers. For this, we have analyzed the coding region of oxygen‐dependent degradation domain of HIF1α in 47 colon, 47 gastric, 47 breast, 47 lung, and 47 hepatocellular carcinomas, and 47 acute leukemias by a single‐strand conformation polymorphism assay. In addition, we analyzed mononucleotide repeat sequences (A8) in CUL2 in 55 colorectal and 45 gastric carcinomas with microsatellite instability (MSI). We found one HIF1α mutation (p.Ala593Pro) in the hepatocellular carcinomas (1/47; 2.1%), but none in other cancers. We found two CUL2 frameshift mutations in colon cancers (p.Asn292MetfsX20), which were exclusively detected in high MSI cancers (4.9%; 2/41). Our data indicate that somatic mutation of HIF1α is rare in common cancers, and somatic mutation of CUL2 occurs in a fraction of colorectal cancers (colorectal cancers with high MSI). The data suggest that neither HIF1α nor CUL2 mutation may play a central role in HIF1α activation in gastric, colorectal, breast, lung and hepatocellular carcinomas, and acute leukemias.     

Persistence of heroin use despite methadone treatment: Poor coping self‐efficacy predicts continued heroin use

Aim. To evaluate the association between coping self‐efficacy and persistent use of heroin by patients enrolled in a methadone treatment program. Design and Methods. Cross‐sectional survey. One hundred and ninety‐one patients attending outpatient methadone clinics in South‐East England, United Kingdom. Validated questionnaires were used to assess drug use (Maudsley Addiction Profile), alcohol use (Alcohol Use Disorders Identification Test), mental health (Hospital Anxiety and Depression Scale) and coping self‐efficacy (brief 8‐item Drug Taking Confidence Questionnaire). Results. Half of the participants (95/191) reported heroin use in the preceding 14‐day period. Heroin use during methadone treatment was associated with financial problems (P = 0.008), spending time with other drug users (P < 0.001), cocaine use (P = 0.002), low mood (P = 0.002) and dissatisfaction with the daily methadone dose (P = 0.014). Compared with ‘Heroin‐abstinent’ patients, the ‘Heroin’ group reported significantly lower mean coping self‐efficacy scores (t = 9.8, d.f. = 182, P < 0.001, effect size 1.17). After correcting for the effects of co‐variants in a logistic regression model, the main determinants of persistent heroin use were ‘coping self‐efficacy’[B ?0.05; standard error (SE) 0.008; Wald 36.6; odds ratio (OR) 0.95, 95% confidence interval (CI) 0.94, 0.97; P < 0.001] and ‘dissatisfaction with methadone dose’ (B 0.93; SE 0.46; Wald 4.1; OR 2.5, 95% CI 1.03, 6.25; P = 0.042). Satisfaction with methadone dose showed no association with self‐efficacy. Discussion and Conclusions. While heroin use during methadone treatment can partly be explained by inadequate dosing, our data suggest a more complex picture with significant contribution from poor coping self‐efficacy. Efforts aimed at enhancing and maintaining the patients' self‐efficacy and social skills are likely to improve heroin and other drug use outcomes with added benefits for treatment completion rates and the throughput of methadone programs.[Senbanjo R, Wolff K, Marshall EJ, Strang J. Persistence of heroin use despite methadone treatment: Poor coping self‐efficacy predicts continued heroin use. Drug Alcohol Rev 2009]     

Control of Palmar Hyperhidrosis with a New "Dry-Type" Iontophoretic Device

BACKGROUND: Palmar hyperhidrosis is characterized by excessive sweating on the palm, and among the various treatment modalities, tap water iontophoresis has been widely used. OBJECTIVE: The objective of this study was to assess the effect of a new "dry-type" iontophoretic device that was locally manufactured and did not use tap water to control sweating. METHODS: Ten subjects with palmar hyperhidrosis were enrolled in this study. To be treated the patients were instructed that they only have to grasp the device. Only one palm was treated for 2 weeks, and then the treatment was discontinued the following next 2 weeks. The other palm was not treated as a control. At the end of second week, biopsy specimens were obtained from untreated and treated palm, respectively, and examined histologically. RESULTS: Nine of 10 patients were satisfied with this therapy reducing their sweat outputs from 33% to 51% of baseline at the end of 2 weeks' treatment, and after 2 weeks of discontinuation of treatment sweat productions returned to near baseline. The pathologic examinations showed some occlusions and destruction of intraepithelial eccrine ducts only in the treated palm. CONCLUSION: We suggest that dry-type iontophoresis could reduce palmar sweating more conveniently than other conventional methods.     

Randomized trial to compare the dosage of darbepoetin alfa by administration route in haemodialysis patients

Aim:   The doses of darbepoetin alfa required to maintain target haemoglobin levels after s.c. or i.v. administration when recombinant human erythropoietin (rHuEpo) treatment was replaced by darbepoetin alfa treatment in haemodialysis (HD) patients were compared.
Methods:   In this prospective, randomized, open-label study, 65 HD patients who were receiving stable SC doses of rHuEpo were switched to an equivalent dose of darbepoetin alfa at a reduced frequency by s.c. or i.v. administration. Patients were randomly assigned to the s.c. group ( n  = 32) or the i.v. group ( n  = 33). Darbepoetin alfa doses were titrated to maintain target haemoglobin levels of 8.0–11.0 g/dL for up to 24 weeks. A period of 20 weeks was used for dose titration and haemoglobin stabilization. This was followed by a 4 week evaluation period.
Results:   The mean haemoglobin concentration during the evaluation period was similar in the s.c. and i.v. groups. The mean dose and mean weight-standardized dose of darbepoetin alfa during the evaluation period tended to be lower in the s.c. group than the i.v. group, although these differences were not statistically significant. The mean weekly darbepoetin alfa dose requirements during the evaluation period significantly decreased in both groups compared to the dose requirements at randomization.
Conclusion:   There is a possibility that s.c. administration of darbepoetin alfa is more efficacious than i.v. administration, but a definite benefit cannot be demonstrated with the current sample size. A bigger sample size is needed to confirm the result.     

Initial Experience with Transvenous Implantable Cardioverter Defibrillator Lead Systems: Operative Morbidity and Mortality

Introduction of non-thoracotomy lead systems™ (Medtronic, Inc.) for the implantable cardioverter defibrillator (ICD) has expanded the indications for use of this mode of therapy. Patients previously considered "too ill" to undergo a thoracotomy as well as patients who are at a high risk for developing sudden death but without previous cardiac arrest, are now considered candidates. The initial experience with the non-thoracotomy lead system at our institution was analyzed for morbidity and mortality. Thirty-four patients underwent attempted intravascular lead implantation, with 30 having initial successful implantation (88.2%). There were 23 males; average ejection fraction (EF) was 38.6%. Three patients developed pulmonary edema and low output immediately after the procedure. Three patients developed electromechanical dissociation during defibrillation threshold testing. A prolonged testing time for the non-thoracotomy lead system was noted when compared to the thoracotomy system (57.39 vs 32.30 min; P < 0.0000). There were more intraoperative morbidities with the non-thoracotomy leads than with the thoracotomy system. There were no perioperative deaths. The potential consequences of prolonged anesthesia time and extensive defibrillation threshold testing should be considered when choosing the route of ICD implant, the type of anesthesia, and the intraoperative testing protocol for each patient.     

Outcome of mid-urethral sling procedures in Korean women with stress urinary incontinence according to body mass index

BACKGROUND: The objective of this study was to determine whether the outcome of mid-urethral sling procedures is influenced by the body mass index of Korean women suffering from stress urinary incontinence (SUI). METHODS: A total of 285 women, ranging in age from 28 to 80 years (mean 55.4), all of whom were followed up for at least 6 months, were ultimately included in this study. The patients were classified as follows: normal weight, 18.5-23 kg/m2; overweight, 23-27.5 kg/m2; obesity, 27.5 kg/m2 or higher. RESULTS: We noted bladder perforations in 11 cases (4.9%, 3.8% and 2.2% in the normal weight, overweight, and obesity groups, respectively; P = 0.449). We determined there to be no significant differences among the three groups with regard to cure rate (P = 0.173). The rates of postoperative urinary retention were 9.9% in the normal weight group, 10.1% in the overweight group, and 15.6% in the obesity group (P = 0.396). We determined there to be no significant differences among the three groups with regard to the persistence of urgency (P = 0.312). Seventy-nine patients (27.7%) exhibited symptoms indicative of voiding disorder (hesitancy, poor flow, or sensations of incomplete emptying). The postoperative development of these voiding symptoms was not significantly different among the three groups (P = 0.106). CONCLUSION: Our results demonstrate both the feasibility and the safety of mid-urethral sling procedures for obese Korean women who suffer from SUI. Additional studies, including prospective randomized trials with longer follow-up periods, will be required in order to confirm these findings.