Intrathecal mafosfamide therapy for pediatric brain tumors with meningeal dissemination

The treatment of childhood brain tumors with cerebrospinal fluid (CSF) dissemination is limited by the relative inaccessibility of the CSF to drugs administered systemically and the paucity of available agents for intrathecal therapy. Mafosfamide is a cyclophosphamide derivative, which does not require hepatic activation and thus can be utilized for regional therapy. Between May 1994 and December 1996, 16 patients 2 to 19 (median 12) years old with various disseminated brain tumors were treated with intraventricular mafosfamide via an indwelling subcutaneous reservoir. The patients received mafosfamide at a dose of 20 mg once or twice weekly until remission was achieved, followed by weekly administrations as consolidation therapy, and every 3 to 4 weeks thereafter for maintenance therapy. Except for transient headaches, nausea and vomiting during and immediately after mafosfamide administration no toxicities were observed. Nine of the 16 patients were evaluable for response by CSF cytology. Eight had complete responses and one patient did not respond. In addition to mafosfamide all patients received systemic chemotherapy as well. However, 4 of the 8 responding patients had developed CSF dissemination under concurrent systemic therapy and cleared their CSF only after administration of intrathecal mafosfamide. At a median follow-up of 21 months, 7 patients are in complete and 4 in partial remission, 2 have stable disease and 3 died of tumor progression. We conclude that mafosfamide at a dose of 20 mg can be safely administered into the CSF and may produce responses and prolong remission of the leptomeningeal disease.     

Induction of apoptosis/necrosis in various human cell lineages by Haemophilus ducreyi cytolethal distending toxin.

We investigated the impact of highly purified Haemophilus ducreyi cytolethal distending toxin (HdCDT) on the apoptosis and necrosis of various human cells; including myeloid cells, epithelial cells, keratinocytes, and primary fibroblasts. The levels of apoptosis and necrosis induced in these cells were compared to those induced by HdCDT in human T cells and in the Jurkat T cell line. Levels of caspase-3 activity were measured, and membrane changes like phosphatidylserine (PS) translocation was evaluated after double-staining with the fluorescein isothiocyanate (FITC)-labeled annexin V and propidium iodide (PI) using flow cytometry. HdCDT induced various degrees of apoptosis and necrosis in dose- and time-dependent manners in cells of various lineages. Early and late apoptosis (annexin V-stained cells) were induced in more than 90% of T cells and monocytes after treatment with 100 ng/ml HdCDT for 24 and 48 h, respectively. The corresponding numbers for epithelial cells, keratinocytes, and fibroblasts were 26-32% after treatment with 100 ng/ml HdCDT for 48 h. HdCDT appears to eliminate effectively by inducing apoptosis those cells that are involved in immune responses. Epithelial cells, keratinocytes and fibroblasts, which are important for the healing of chancroid ulcers, are eliminated by apoptosis or necrosis after contact with HdCDT, albeit slower and to a lesser extent than T cells.     

Cholecystectomy: costs and health-related quality of life: a comparison of two techniques.

BACKGROUND: Outcomes of previous health economic evaluations comparing minilaparotomy cholecystectomy and laparoscopic cholecystectomy have been inconsistent. OBJECTIVE: To compare costs for minilaparotomy cholecystectomy and laparoscopic cholecystectomy and to study changes in quality of life induced by these operations. DESIGN: Single-blind, randomized controlled trial, run from 1 March 1997 to 30 April 1999. SETTING: One university hospital and four non-university hospitals in Sweden. MAIN MEASURE: : Cost and perceived health estimation according to the global quality of life instrument EuroQol-5D. RESULTS: Of 1719 cholecystectomy patients at five centres, 724 entered the trial and were treated with minilaparotomy cholecystectomy or laparoscopic cholecystectomy, 362 in each group. Total health care costs were less for minilaparotomy cholecystectomy than for laparoscopic cholecystectomy (median values US$2428 for minilaparotomy cholecystectomy versus US$2613 or US$3006 for laparoscopic cholecystectomy with 100 operations per year and reusable trocars or 50 operations per year and disposable trocars, respectively). There was no significant difference in total costs (including costs due to loss of production) between minilaparotomy cholecystectomy and laparoscopic cholecystectomy with 100 operations per year and reusable trocars in laparoscopic cholecystectomy (US$3731 versus US$3649, respectively). However, in calculations assuming 50 operations per year and disposable trocars in laparoscopic cholecystectomy, this technique was more expensive than minilaparotomy cholecystectomy (US$4042 versus US$3731). Health-related quality of life was slightly but significantly lower for the minilaparotomy cholecystectomy group 1 week after surgery. One month and 1 year postoperatively no difference between the randomized groups was found. CONCLUSION: Total costs did not differ between minilaparotomy cholecystectomy and laparoscopic cholecystectomy with high-volume surgery and disposable trocars, whereas laparoscopic cholecystectomy was more expensive with fewer operations and disposable trocars. The gain in health-related quality of life with laparoscopic cholecystectomy compared with minilaparotomy cholecystectomy was small and of limited duration.     

A Comparison of Visual Field and Optic Disc Appearance Depending on the Peak Intraocular Pressure in Patients with Normal-tension Glaucoma

Purpose To review the outcome of surgery for strabismus due to ethmoid sinus surgery.Cases and Methods The series comprised 13 cases, 1 of inferior rectus paresis, 1 of superior oblique paresis, 6 of medial rectus paresis, and 5 of medial rectus muscle palsy due to third nerve palsy. In the cases of paresis of the rectus muscle, resection of the rectus muscles was mainly performed. In the cases of palsy of the rectus muscle, transposition of the extraocular muscle with simultaneous recession of the lateral rectus muscle was performed. The major aim of surgery was to bring both eyes into alignment and to eliminate diplopia in the primary position.Results The mean preoperative horizontal deviation of 18.1 degrees of exotropia in the paresis cases was reduced to 1.4 degrees of exotropia after surgery. The mean preoperative vertical deviation of 3.8 degrees of hypertropia was reduced to 1.4 degrees of hypertropia postoperatively. The mean preoperative horizontal deviation of 35.6 degrees of exotropia in the palsy cases was reduced to 9.4 degrees of exotropia after surgery. The mean preoperative vertical deviation of 2.0 degrees of hypertropia was increased to 2.6 degrees of hypertropia postoperatively. Postoperatively, diplopia was absent in 11 cases with a slightly compensatory head posture.Conclusions Surgery for strabismus due to sinus surgery induces improvements in eye position and diplopia. Nippon Ganka Gakkai Zasshi (J Jpn Ophthalmol Soc 107:425–432, 2003)     

Knowledge of reproduction in teenagers and young adults in Sweden.

OBJECTIVE: To investigate the knowledge of reproductive physiology and anatomy among adolescents and young adults in Sweden, and to evaluate the education obtained on these issues. METHODS: Two hundred and nine study specific questionnaires were distributed, of which 206 were answered by students in primary school, upper secondary school and at first year of university. A total knowledge score based on 21 out of the 35 questions in the questionnaire was calculated. As only 44 of the 206 respondents answered all the questions a revised score was also calculated, in which partial dropouts were interpreted as wrong answers. RESULTS: The mean of the total knowledge score was 28.7 out of 54 among the 44 respondents answering all questions, and the revised knowledge score was 24.0. The level of knowledge tended to be higher in older age groups, among women, as well as among respondents who had visited a Youth clinic. The time of ovulation was known by 21.4% of men compared to 63.4% of women. Almost 50% of the students knew one mechanism whereby oral contraceptives act to protect against pregnancy. Of the respondents, 77.2% knew of Chlamydia trachomatis but the knowledge of other STIs, like condyloma, was poorer (16.5%). Reasons for infertility were relatively well known among the respondents. Of the respondents, 57.5% stated that they had not received enough information on reproductive issues. CONCLUSIONS: The students have not achieved sufficient knowledge concerning sexual and reproductive matters that they, according to the national curriculum, should have attained by the end of the 9th grade. An improvement of the quality of the education, adapted to the students' age and pre-existing knowledge, and a review of the contents of the education is therefore needed.     

Fatal venous thromboembolism associated with different combined oral contraceptives: a study of incidences and potential biases in spontaneous reporting.

BACKGROUND: Fatal venous thromboembolism (VTE) is a rare complication of combined oral contraceptive (COC) treatment. This study aims to determine incidences of fatal VTE in relation to the type of COC and the percentage of cases reported to the Swedish Adverse Drug Reactions Advisory Committee (SADRAC). A further aim is to compare the characteristics of reported and not reported cases. METHODS: This retrospective study is a separate analysis using data from a larger study that included women aged 15-44 years between 1990 and 1999 with VTE coded as the underlying or contributory cause of death in the Swedish Cause of Death Register. COC use within 2 months of the date of symptom onset or death was identified in 28 cases. Sales data were obtained from the National Corporation of Swedish Pharmacies. Reported cases were identified in the SADRAC database. RESULTS: After excluding two cases where the type of COC was unknown, the crude incidences of fatal VTE were 5.1 (95% CI 2.3, 9.6), 8.6 (95% CI 4.3, 15.4) and 9.1 (95% CI 3.3, 19.8) cases per million women per year for levonorgestrel-, desogestrel- and norethisterone-containing COCs, respectively. Age-adjusted incidences were approximately twice as high for desogestrel- and norethisterone-containing COCs compared with levonorgestrel-containing COCs, although differences were not statistically significant. Thirty-six percent of cases were reported. Reporting was positively associated with information in medical records relevant to the VTE diagnosis that the patient was a COC user and was significantly higher in northern Sweden. CONCLUSION: Results from this study support a higher incidence of fatal VTE with desogestrel-containing COCs than with levonorgestrel-containing COCs.     

Parathyroid hormone-related protein and serum calcium in patients with renal cell carcinoma.

OBJECTIVE: To evaluate serum parathyroid hormone-related protein (PTHrP) in relation to serum calcium and clinical outcome of patients with renal cell carcinoma. METHODS: Sera from 243 patients with renal cell carcinoma were collected prior to therapy. Serum PTHrP was analyzed using an immunoradiometric assay. Tumour stage, nuclear grade, corrected serum calcium, and survival were assessed. RESULTS: Serum PTHrP was detectable in 37/243 sera (15%) and hypercalcaemia (> or =2.60 mmol/l) in 32/220 (15%). A positive correlation between serum PTHrP and serum calcium was found (r = 0.326; p < 0.01). Following subdivision of the material, based on storage time, the frequency of detectable serum PTHrP seemed to decrease with time. Serum calcium, but not serum PTHrP, was correlated to tumour stage (p < 0.001). Survival was similar for patients with detectable and undetectable PTHrP, but those with hypercalcaemia had a significantly shorter survival time compared to those with normal serum calcium (p < 0.001). A multivariate analysis showed that tumour stage and serum calcium were independent prognostic factors, but not grade or PTHrP. CONCLUSIONS: A positive relation of serum PTHrP to serum calcium was demonstrated in patients with renal cell carcinoma. Hypercalcaemia but not serum PTHrP predicted a worse prognosis.     

Cigarette smoking and risk of non-Hodgkin's lymphoma--a population-based case-control study.

BACKGROUND: Epidemiologic evidence of an association between tobacco smoking and non-Hodgkin's lymphoma has been conflicting. This may reflect that non-Hodgkin's lymphoma comprises several distinct disease entities with different etiologies, as some studies have indicated an association between smoking and follicular lymphoma. OBJECTIVE: To investigate the association between cigarette smoking and non-Hodgkin's lymphoma risk, overall and by subtype. METHODS: As part of a nationwide Danish-Swedish population-based case-control study, we interviewed 3,055 incident non-Hodgkin's lymphoma patients and 3,187 population controls. All lymphomas were uniformly classified according to the WHO classification. We used unconditional logistic regression to estimate adjusted odds ratios (OR) and 95% confidence intervals (95% CI) for the association between cigarette smoking and risk of non-Hodgkin's lymphoma. RESULTS: Cigarette smoking was not associated with the risk of non-Hodgkin's lymphoma overall (OR, 0.97; 95% CI, 0.87-1.08) nor with the major subgroups such as diffuse large B-cell lymphoma (OR, 0.94; 95% CI, 0.79-1.10), chronic lymphocytic leukemia (OR, 0.86; 95% CI, 0.72-1.02), or follicular lymphoma (OR, 1.03; 95% CI, 0.85-1.24). Female smokers were at a marginally increased risk of follicular lymphoma (OR, 1.41; 95% CI, 1.04-1.92). Men who had ever smoked had a significantly increased risk of T-cell lymphoma (OR, 1.67; 95% CI, 1.11-2.51). No dose-response association with cigarette smoking could be established for any lymphoma subgroup. CONCLUSION: We found little evidence of an association between cigarette smoking and non-Hodgkin's lymphoma risk overall. Although increased risks of follicular lymphoma in female smokers and of T-cell lymphoma in male smokers were suggested, no dose-response relationship was observed, leaving limited support for causality.     

Immunogenicity of meningococcal PorA formulations encapsulated in biodegradable microspheres.

The purpose of our study was to investigate the possibility to microencapsulate liposomes and meningococcal outer membrane vesicles (OMV), both containing neisserial pore protein A (PorA), in biodegradable dextran- and mannan-based microspheres and to study the immunogenicity of the encapsulated PorA formulations. PorA-liposomes and OMV were encapsulated in dextran- or mannan-based microspheres by using an aqueous two-phase system consisting of a polyethylene glycol solution and a methacrylated dextran or mannan solution. The formulations were characterized for size distribution, PorA structure and antigen recovery after release. Calcein-containing model liposomes were used to establish the encapsulation efficiency and release profiles from both types of microspheres. The immunogenicity of the PorA-containing formulations was determined in mice after subcutaneous immunization. Liposomes were encapsulated in dextran and mannan microspheres with a high efficiency (70-90%). Calcein liposomes, after a 5-day lag period, exhibited apparent zero-order release kinetics from both types of microspheres between Days 5 and 10 of incubation in vitro. The total release was 80 and 100% from mannan and dextran microspheres, respectively. The trimeric PorA conformation was preserved in the released liposomes and OMV and the antigen was partly recovered. The immunogenicity of PorA-liposomes and OMV encapsulated in dextran or mannan microspheres was preserved. In conclusion, PorA-liposomes and OMV could be encapsulated in dextran- and mannan-based microspheres with high efficiency. The immunogenicity of encapsulated antigen was preserved.