Saving bladders with brachytherapy: implantation technique and results

PURPOSE: To analyze and report the treatment results of brachytherapy for solitary bladder cancer in the Arnhem Radiotherapy Institute. METHODS AND MATERIALS: Between January 1983 and October 1998, 63 patients with a solitary bladder tumor were treated with a combination of transurethral resection, external beam radiotherapy (EBRT), and interstitial radiotherapy. The indications for bladder-conserving treatment were tumor < or =5 cm, T1G3 (n = 14), T2G2 (n = 8), T2G3 (n = 37), and T3a (n = 4). The prescribed implant dose was either 55 Gy (range 50-65 Gy) in combination with small pelvis external beam RT, 3-4 fractions of 3.5 Gy (n = 58), or 30 Gy in combination with 20 fractions of 2 Gy external beam radiotherapy (n = 5). Brachytherapy was performed with 2-8 137Cs needles until 1995 (n = 48) and 2-5 afterloading catheters (192Ir) since 1996 (n = 15). Follow-up cystoscopies were performed at 3-month intervals during the first 2 years, then every 6 months for 3 years, and annually after the fifth year. The median follow-up was 4.9 years. RESULTS: Twenty patients developed local recurrences, of which 6 were "true in-implant recurrences," 12 were in second bladder locations, and 2 were urethral recurrences. All recurrences developed within 2.5 years after treatment. Of these 20 patients, 13 underwent cystectomy: 6 stayed disease-free, 1 died of postoperative complications, 2 developed regional metastases, and 4 developed distant metastases. The 5-year disease-specific survival rate was 80% for patients with Stage T1 and 60% for those with Stage T2 disease. The local control rate was 70% in the whole patient population and 80% after salvage cystectomy. Forty-four bladders were saved. Acute complications were seen in 14 patients, and no significant late complications occurred. CONCLUSION: Using this treatment technique, a high cure rate with conservation of the bladder and only minor toxicity can be obtained in a selected patient population having a solitary tumor < or =5 cm.     

Correction of Murine Rag2 Severe Combined Immunodeficiency by Lentiviral Gene Therapy Using a Codon-optimized RAG2 Therapeutic Transgene

Recombination activating gene 2 (RAG2) deficiency results in severe combined immunodeficiency (SCID) with complete lack of T and B lymphocytes. Initial gammaretroviral gene therapy trials for other types of SCID proved effective, but also revealed the necessity of safe vector design. We report the development of lentiviral vectors with the spleen focus forming virus (SF) promoter driving codon-optimized human RAG2 (RAG2co), which improved phenotype amelioration compared to native RAG2 in Rag2^−/− mice. With the RAG2co therapeutic transgene, T-cell receptor (TCR) and immunoglobulin repertoire, T-cell mitogen responses, plasma immunoglobulin levels and T-cell dependent and independent specific antibody responses were restored. However, the thymus double positive T-cell population remained subnormal, possibly due to the SF virus derived element being sensitive to methylation/silencing in the thymus, which was prevented by replacing the SF promoter by the previously reported silencing resistant element (ubiquitous chromatin opening element (UCOE)), and also improved B-cell reconstitution to eventually near normal levels. Weak cellular promoters were effective in T-cell reconstitution, but deficient in B-cell reconstitution. We conclude that immune functions are corrected in Rag2^−/− mice by genetic modification of stem cells using the UCOE driven codon-optimized RAG2, providing a valid optional vector for clinical implementation.     

Clinical course of occupational irritant contact dermatitis of the hands in relation to filaggrin genotype status and atopy

Background Filaggrin loss‐of‐function mutations and atopy may alter the clinical course of irritant contact dermatitis (ICD). Objective To investigate the clinical course of patients with occupational ICD according to loss‐of‐function mutations in the filaggrin gene (FLG) and atopy. Methods In a prospective cohort study, the clinical course, use of topical corticosteroids, sick leave, recovery rate and job continuation were investigated in 459 inpatients treated for occupational ICD of the hands. Patients were genotyped for four FLG mutations, examined for atopy and followed for up to 3 years after discharge. Results Our study included 327 (71·2%) atopic individuals and 132 nonatopic individuals. Overall, 68 patients showed a mutation in the FLG alleles R501X, R2447X, S3247X and 2282del4 (60 atopic and eight nonatopic). Nonatopic patients with ICD responded well to therapeutic approaches, while atopy status made subjects more resistant to therapy, resulting in lower rates of recovery and job continuation and higher use of topical corticosteroids. Carriage of FLG loss‐of‐function mutations in combination with atopy worsened the course. The risk of abandoning one’s profession in this group was significantly increased when compared with ‘pure’ ICD (odds ratio 3·1) after 3 years. Conclusions Patients with atopy are a special risk population for ICD. In the presence of atopy, FLG mutations seem to be a modifier of the severity of the clinical course in ICD. Early‐stage identification of this subgroup may result in additional emphasis to these patients regarding the importance of adherence to specific therapeutic interventions.     

The Netherlands protocol for standardisation and quantification of FDG whole body PET studies in multi-centre trials

Introduction  Several studies have shown the usefulness of positron emission tomography (PET) quantification using standardised uptake values (SUV) for diagnosis and staging, prognosis and response monitoring. Many factors affect SUV, such as patient preparation procedures, scan acquisition, image reconstruction and data analysis settings, and the variability in methodology across centres prohibits exchange of SUV data. Therefore, standardisation of 2-[¹⁸F] fluoro-2-deoxy-D-glucose (FDG) PET whole body procedures is required in multi-centre trials. Methods  A protocol for standardisation of quantitative FDG whole body PET studies in the Netherlands (NL) was defined. This protocol is based on standardisation of: (1) patient preparation; (2) matching of scan statistics by prescribing dosage as function of patient weight, scan time per bed position, percentage of bed overlap and image acquisition mode (2D or 3D); (3) matching of image resolution by prescribing reconstruction settings for each type of scanner; (4) matching of data analysis procedure by defining volume of interest methods and SUV calculations and; (5) finally, a multi-centre QC procedure is defined using a 20-cm diameter phantom for verification of scanner calibration and the NEMA NU 2 2001 Image Quality phantom for verification of activity concentration recoveries (i.e., verification of image resolution and reconstruction convergence). Discussion  This paper describes a protocol for standardization of quantitative FDG whole body multi-centre PET studies. Conclusion  The protocol was successfully implemented in the Netherlands and has been approved by the Netherlands Society of Nuclear Medicine. An erratum to this article can be found at     

Effect of postpartum lifestyle interventions on weight loss, smoking cessation, and prevention of smoking relapse: a systematic review

Postpartum lifestyle interventions are recommended for women after pregnancies complicated by preeclampsia, intrauterine growth restriction, and/or gestational diabetes, since they are at increased cardiovascular risk. To identify potential intervention strategies to reduce this risk, a systematic review of the literature is presented on the effectiveness of postpartum lifestyle interventions aimed at weight loss, smoking cessation, and smoking relapse prevention. The main characteristics of these postpartum lifestyle interventions are briefly described. The PubMed, Embase, Web of Science, PsychInfo, and Cinahl databases were searched for studies on the effects of postpartum lifestyle interventions on weight loss, and smoking cessation or prevention of smoking relapse, initiated for up to 1 year postpartum. No studies on the effectiveness of postpartum lifestyle interventions after the aforementioned specific pregnancy complications were found. However, 21 studies are included that describe existing postpartum lifestyle interventions, which were applied to unselected (on the basis of pregnancy complications) postpartum women. Six of 8 weight loss interventions, 4 of 5 smoking cessation interventions, and 4 of 8 smoking relapse prevention interventions were effective. Individually tailored counseling, group counseling sessions, and use of diaries or other correspondence materials were shown to be effective. Currently, postpartum lifestyle interventions tailored specifically for women who experienced the pregnancy complications are lacking. While awaiting their development, it seems reasonable to utilize existing lifestyle interventions shown to be effective in unselected postpartum women. LEARNING OBJECTIVES: After completion of this educational activity, the obstetrician/gynecologist should be better able to: counsel patients on how to apply existing postpartum lifestyle intervention strategies aimed at weight loss, smoking cessation, and smoking relapse prevention to lower future cardiovascular risk; and educate postpartum women who have experienced preeclampsia, intra-uterine growth restriction, and/or gestational diabetes about their increased cardiovascular risk later in life. TARGET AUDIENCE: Obstetricians & Gynecologists, Family Physicians.     

Amino-terminal pro-brain natriuretic peptide (NT-proBNP) is a biomarker of cardiac filling pressures in pre-eclampsia

Objective

To evaluate if amino-terminal pro-brain natriuretic peptide (NT-proBNP) plasma levels reflect intracardiac filling pressures in pre-eclamptic patients.

Study design

In a cross-sectional study we investigated 22 untreated critically ill pre-eclamptic women between 22 and 34 weeks gestation. All patients underwent intra-arterial blood pressure and central hemodynamic measurements and NT-proBNP was determined in stored plasma. Baseline characteristics, plasma NT-proBNP concentrations and relevant laboratory variables were investigated for correlations with hemodynamic values using Spearman's rank correlation test.

Results

No significant correlations were demonstrated between NT-proBNP concentrations and variables associated with the severity of the pre-eclampsia. We found significant positive correlations between NT-proBNP and diastolic pulmonary pressure (r = 0.59; p = 0.005) and pulmonary capillary wedge pressure (PCWP) (r = 0.51; p = 0.015). Multiple linear regression analysis showed that the association between NT-proBNP and PCWP was not affected by creatinine level.

Conclusion

NT-proBNP is a biomarker of left ventricular cardiac filling pressures in untreated pre-eclamptic patients.