Activation of immediate-early gene expression by peroxisome proliferators in vitro

The hepatocarcinogenicity of peroxisome proliferators (PPs) in rodents has been attributed both to oxidative DNA damage resulting from excessive leakage of peroxisomal H₂O₂ and to increased hepatocellular replication that may be independent of peroxisome proliferation. Because of the growing association between tumor promotion and alterations in growth-regulatory signal transduction pathways, we investigated whether PPs can modulate these pathways in a mouse liver epithelial cell line, BNL-CL.2. We tested two PPs that differ markedly in rodent tumorigenicity for their ability to activate immediate-early proto-oncogene expression. 4-Chloro-6-(2,3-xylidino)-2-pyrimidinylthioacetic acid (Wy-14643), a highly tumorigenic PP, was an exceptionally strong inducer of c-fos expression. In contrast, diethylhexyl phthalate (DEHP), a weakly tumorigenic PP, was a very poor inducer of c-fos expression. Wy-14643 was also stronger than DEHP in stimulating c-jun expression, whereas both PPs were fairly strong inducers of jun-B and jun-D. The induction of fos and jun expression by Wy-14643 was specifically inhibited by the protein kinase C inhibitor 1-(5-isoquinolinesulfonyl)-2-methylpiperizine dihydrochloride (H-7). DEHP-induced gene expression was strongly inhibited by H-7, but was also partially inhibited by an inhibitor of protein kinase A. The activation of fos and jun gene expression by PPs was independent of peroxisome proliferation since it was an immediately-early response not requiring protein synthesis and since the cell lines used in this study do not undergo peroxisome proliferation. Our results raise the possibility that the carcinogenicity of PPs may be due, in part, to epigenetic modulation of growth-regulatory signal transduction pathways. © 1993 Wiley-Liss, Inc.     

Use of a pedicled rectus abdominis muscle flap sling in the treatment of complicated stress urinary incontinence

OBJECTIVE: A pedicled rectus muscle flap sling in the treatment of complicated stress urinary incontinence was evaluated. STUDY DESIGN: Thirty-two women underwent a combined vaginal and abdominal sling operation for stress incontinence with a pedicled muscle flap developed from the rectus abdominis muscle. All operations were performed jointly by the same two surgeons. The procedure involved transecting one rectus abdominis muscle just above its first tendinous intersection and isolating the muscle as a flap on its inferior vascular pedicle. The muscle flap was then swung beneath the urethra and bladder neck, pulled into the retropubic space on the contralateral side, and sewn to the obturator internus fascia or to Cooper's ligament. All patients undergoing the procedure had demonstrable stress incontinence on physical examination and underwent preoperative fluoroscopic video urodynamics. The diagnosis of complicated stress incontinence was based on the presence of one or more of the following factors: previous failed antiincontinence surgery (33 operations in 22 patients, average 1.5 operations), open vesical neck on fluoroscopy (14 patients), urethral closure pressure ≤30 cm H₂O by the Brown-Wickham technique (16 patients), or massive vaginal prolapse and demonstrable stress incontinence with the prolapse reduced and the urethra supported in a normal position (16 patients). Follow-up ranged from 2 to 13 months (average 6 months). Surgical outcome was assessed by physical examination and a detailed telephone interview conducted by a physician who was not involved in the operations. RESULTS: Twenty-eight patients (87.5%) were satisfied with the results of the operation. There were four surgical failures (12.5%). Stress incontinence persisted in three patients after surgery, and one patient who had mixed incontinence before surgery was cured of stress incontinence but continued to have significant urinary leakage as a result of detrusor overactivity. There appears to be less voiding dysfunction with this technique than with other sling procedures for stress incontinence. CONCLUSIONS: The sling procedure with a rectus abdominis muscle flap appears to be a viable surgical technique in the treatment of complicated stress incontinence. Further study is needed to assess the long-term results of this operation and to evaluate its proper place in reconstructive pelvic surgery. (Am J Obstet Gynecol 1996;175:1460-6.)     

Urinary morbidity with a modified peripheral loading technique of transperineal (125)i prostate implantation

PURPOSE: Analysis of urinary morbidity within the first 12 months following a modified peripheral loading technique for permanent transperineal transrectal ultrasound (TRUS) guided (125)I prostate implantation and comparison of urinary morbidity with various clinical and implant parameters. MATERIALS AND METHODS: Between October 1, 1996, and March 11, 1998, 87 patients with favorable, early stage prostate cancer were treated with permanent transperineal TRUS guided (125)I prostate implantation. A peripheral loading technique was utilized for source placement with 75-80% source distribution in the periphery and 20-25% source distribution centrally. A mean total activity of 38 mCi of (125)I was implanted (range, 19-66 mCi). The mean source activity was 0.43 mCi/source (range, 0.26-0.61 mCi/source) and the mean number of sources implanted was 88 (range, 56-134). The minimum prescribed dose to the prostate was 145 Gy. The median D(90), V(100), and V(150) were 152 Gy (range, 104-211 Gy), 92% (range, 71-99%), and 61% (range, 11-89%), respectively. The median follow-up time was 19 months (range, 12-29 months). Urinary morbidity was scored at 3 weeks and then at 3-month intervals for the first 2 years using a modified Radiation Therapy Oncology Group (RTOG) grading system (scale 0-5). RESULTS: Most patients developed at least minor urinary symptoms with frequency or nocturia being the most common. Overall, 79% (69/87) of patients experienced urinary morbidity with 21% (18/87) reporting no symptoms. The incidence of overall Grade 1 urinary morbidity was 37% (32/87); Grade 2 morbidity was 37% (32/87); and Grade 3 morbidity was 6% (5/87). There was no Grade 4 or 5 morbidity. The incidence of Grade 0 frequency/nocturia was 36% (31/87); Grade 1 was 33% (29/87); Grade 2 was 30% (26/87); and Grade 3 was 1% (1/87). Grade 0 dysuria was seen in 56% (49/87) of patients; 32% (28/87) had Grade 1; 10% (9/87) Grade 2; and 1% (1/87) Grade 3 dysuria. Most urinary symptoms started a few weeks after implantation and began to subside by 6 months. At 12 months, 22% (19/87) of patients had persistent urinary symptoms (78% Grade 0, 15% Grade 1, 3% Grade 2, and 3% Grade 3). The mean urethral point dose was 174 Gy (range, 99-315 Gy). The mean number of sources implanted correlated significantly with the likelihood of developing acute urinary morbidity (p = 0.03). The total activity implanted also correlated with the morbidity outcome dysuria (p = 0.01) with a threshold seen at 37 mCi. Urethral point dose, source activity, intraoperative TRUS prostate volume, D(90), V(100), V(150), patient age, pretreatment PSA, Gleason score, and T stage did not correlate with morbidity. CONCLUSIONS: Permanent transperineal TRUS guided (125)I prostate implantation using a modified peripheral loading technique is associated with mild urinary morbidity that resolves in 78% of patients by 12 months. Grade 3 urinary morbidity was encountered in only 6% (5/87) of patients. Urinary morbidity may be related to the total number of sources implanted and/or the total activity implanted. Overall urinary morbidity was not correlated with urethral point dose, source activity, intraoperative TRUS prostate volume, D(90), V(100), V(150), patient age, pretreatment PSA, Gleason score, and T stage. The low incidence of urinary morbidity may be a consequence of our modified peripheral loading technique and/or the selection of patients with good-to-excellent preimplant urological parameters. Longer follow-up is necessary to assess biochemical control rates and long-term morbidity.     

High dose ifosfamide in combination with etoposide and epirubicin followed by autologous stem cell transplantation in the treatment of relapsed/refractory Hodgkin's disease: a report on toxicity and efficacy

Patients with Hodgkin's disease (HD) refractory to first line chemotherapy and those who have rapid or multiple relapses have a very poor prognosis. With the increasing use of hybrid chemotherapy these patients will have been exposed to many of the drugs active in HD so it is important to develop salvage regimens that are novel and demonstrate activity in this group of patients. We report the use of a continuous high dose infusion of ?fosfamide at a dose of 9g/m(2) over 3 days in combination with etoposide and epirubicin followed by autologous stem cell transplant with either BEAM or Melphalan/VP16 conditioning in this difficult group. Forty six patients (28M:18F) with a median age of 28 years (range 13-45) were treated. Overall 39 out of 46 (85%) patients responded to treatment, with 17 achieving complete remission and 11 a good partial remission; 28 proceeded to autologous bone marrow/stem cell transplantation. In total, 23 patients are alive and in continuous remission with a follow up of between 12 and 61 months. Median overall survival for the whole group is 36 months. Haematological toxicity, particularly neutropenia (WHO grade IV), was observed in all cases but improved over the 3 courses of treatment in all patients. Non-haematological toxicity was not a major problem; no significant cardiac, hepatic, renal, pulmonary or neuro toxicity was observed and there were no deaths on treatment. This regime shows promise in patients with difficult Hodgkin's disease and warrants further study.     

Multiple valve operation for advanced valvular heart disease: results and risk factors in 513 patients.

To assess the results and incremental risk factors affecting outcome after multiple-valve operation in the early blood cardioplegia era of cardiac surgery, follow-up data (mean +/- SD 3.1 +/- 2 years) were obtained on 97% of 513 patients (mean age +/- SD 58.8 +/- 10.5 years) who underwent a multiple-valve procedure between June 1976 and August 1985. Preoperatively 41% of patients were in New York Heart Association functional class III and 54% in class IV. Three groups accounted for 98.6% of the patients: 57.7% had an aortic and mitral valve procedure, 29% had a mitral and tricuspid valve procedure and 11.9% had a triple-valve procedure. The overall hospital mortality rate was 12.5% and overall 5-year survival rate was 67.1%. Hazard function analysis for all deaths revealed systolic pulmonary artery pressure (p less than 0.0001), age (p = 0.005), triple valve procedure (p less than 0.005), concomitant coronary bypass operation (p less than 0.005) and prior cardiac surgery (p less than 0.002) as the significant incremental risk factors predicting decreased survival in the early hazard phase; diabetes (p less than 0.005) predicted decreased survival in the late hazard phase. Postoperatively the condition of 80% of the patients improved to functional class I or II; only 0.6% remained in functional class IV. The 5-year rate of freedom from late combined valve-related morbidity was 81.7% and that of freedom from late combined valve-related morbidity and mortality was 71.7%. These results demonstrate excellent clinical improvement and late survival after multiple valve operation in patients with advanced valvular heart disease, justifying aggressive surgical therapy in these patients.(ABSTRACT TRUNCATED AT 250 WORDS)     

Serum MBP immunoreactivity and immunoglobulin level as markers of tumour type

Summary Forty three patients, admitted to the department of Neurological Surgery for management of central nervous system tumours, were studied pre-operatively for serum myelin basic protein immunoreactivity as a marker of central nervous system lesion and for circulating immunoglobulins and complement (C₃) levels. Myelin basic protein concentration did not appear to correlate with tumour type or grade. Serum immunoglobulin levels were found to be within the normal range but the mean IgM level was significantly higher in the glioma group when compared with meningiomas.