In vivo assessment of antiangiogenic activity of SU6668 in an experimental colon carcinoma model.

PURPOSE: The purpose of this research was to assess in vivo by dynamic contrast enhanced magnetic resonance imaging (DCE-MRI) the antiangiogenic effect of SU6668, an oral, small molecule inhibitor of the angiogenic receptor tyrosine kinases vascular endothelial growth factor receptor 2 (Flk-1/KDR), platelet-derived growth factor receptor, and fibroblast growth factor receptor 1. EXPERIMENTAL DESIGN: A s.c. tumor model of HT29 human colon carcinoma in athymic mice was used. DCE-MRI with a macromolecular contrast agent was used to measure transendothelial permeability and fractional plasma volume, accepted surrogate markers of tumor angiogenesis. CD31 immunohistochemical staining was used for assessing microvessels density and vessels area. Experiments were performed after 24 h, and 3, 7, and 14 days of treatment. RESULTS: DCE-MRI clearly detected the early effect (after 24 h of treatment) of SU6668 on tumor vasculature as a 51% and 26% decrease in the average vessel permeability measured in the tumor rim and core (respectively). A substantial decrease was also observed in average fractional plasma volume in the rim (59%) and core (35%) of the tumor. Histological results confirmed magnetic resonance imaging findings. After 3, 7, and 14 days of treatment, postcontrast magnetic resonant images presented a thin strip of strongly enhanced tissue at the tumor periphery; histology examination showed that this hyperenhanced ring corresponded to strongly vascularized tissue adjacent but external to the tumor. Histology also revealed a strong decrease in the thickness of peripheral viable tissue, with a greatly reduced vessel count. SU6668 greatly inhibited tumor growth, with 60% inhibition at 14 days of treatment. CONCLUSIONS: DCE-MRI detected in vivo the antiangiogenic efficacy of SU6668.     

Scoring the short form ICSmaleSF questionnaire. International Continence Society

PURPOSE: The International Continence Society (ICS) ICSmale questionnaire was devised to provide a thorough evaluation of the occurrence and bothersomeness of lower urinary tract symptoms and their impact on the lives of men with benign prostatic disease. This report completes the developmental work on the questionnaire, producing the concise short form instrument, ICSmaleSF, with a valid, reliable and scientifically justified scoring system. MATERIALS AND METHODS: Two data sets were used. The short form version of the questionnaire was devised and initially evaluated using data on men with uncomplicated lower urinary tract symptoms who were involved in the CLasP randomized controlled trial comparing laser therapy with transurethral prostatic resection and conservative management or monitoring without active intervention. External validation of the scoring system was undertaken using data from phase II of the ICS benign prostatic hyperplasia (BPH) study, an observational study of outcome in men with lower urinary tract symptoms related to benign prostatic enlargement. All patients completed the developmental version of the ICSmale questionnaire. Parallel analysis on the CLasP data set identified items that were responsive to change or highly problematic, allowing other redundant and overlapping items to be eliminated. Factor analysis and Cronbach's alpha coefficients were used to examine the clustering of items. Regression models were used to investigate the validity of followup scores within and across treatment groups in the CLasP and ICS/BPH studies. RESULTS: The questionnaire, which originally comprised 22 items, was shortened to 11 items in the 2 distinct factors of voiding (ICSmaleVS) and incontinence (ICSmaleIS) symptoms. Cronbach's alpha coefficients were high at 0.76 for ICSmaleVS and 0.78 for ICSmaleIS. A simple additive score was calculated by adding the 5 items in ICSmaleVS and 6 in ICSmaleIS. ICSmaleVS and ICSmaleIS detected expected improvement in the laser therapy and transurethral prostatic resection groups, and stability in the conservative management group within CLasP. Similarly each subscore but particularly ICSmaleVS was sensitive to differences in the outcome of the range of treatments in the ICS/BPH study. While frequency and nocturia were highly problematic and sensitive to change individually, they did not load into the other main factors or correlate with each other. It is suggested that these symptoms should be evaluated separately with the additional inclusion of a single item measure of the impact of lower urinary tract symptoms on daily life. CONCLUSIONS: The ICSmaleSF represents a comprehensive, concise, valid and reliable instrument for evaluating men with lower urinary tract symptoms. Unlike other questionnaires in the field it contains subscores for the domains of voiding and incontinent symptoms as well as the separate consideration of frequency, nocturia and impact on daily life. We hope that it will become the tool of choice for the comprehensive evaluation of treatment of men with lower urinary tract symptoms associated with benign prostatic disease.     

A prospective randomized trial comparing transurethral resection of the prostate and laser therapy in men with chronic urinary retention: The CLasP study

PURPOSE: We assessed the effectiveness of laser therapy versus transurethral prostatic resection in men with symptomatic chronic urinary retention secondary to benign prostatic enlargement. MATERIALS AND METHODS: This trial was multicenter, pragmatic and randomized. Analysis was done by intent to treat. Laser therapy involved neodymium:YAG noncontact visual prostate ablation, while transurethral prostatic resection was performed by standard electroresection. Patients were included in our study if they reported moderate to severe lower urinary tract symptoms with an International Prostate Symptom Score (I-PSS) of 8 or more, benign prostatic enlargement and a persistent post-void residual urine volume of more than 300 ml. Followup was 7.5 months. Primary outcome measures included the I-PSS, I-PSS quality of life score, maximum urinary flow and post-void residual urine volume. Secondary outcome measures included treatment failure, complications, hospital stay and catheterization time. RESULTS: A total of 82 patients agreed to be randomized to receive laser therapy (38) or transurethral prostatic resection (44). There were significant improvements in all primary outcomes in each group from randomization to followup. Transurethral prostatic resection was significantly better than laser therapy for I-PSS and maximum urinary flow values (p = 0.035 and 0.029, respectively) but there were no differences in post-void residual urine volume and I-PSS quality of life score between the groups. We noted significantly more treatment failures with laser therapy than resection (8 versus 0, p = 0.0014), although only 3 patients required resection after laser therapy because of persistent symptoms. In addition, hospital stay after resection was 2-fold that after laser therapy (ratio of geometric means 2.01, 95% confidence interval 1.54 to 2.61, p <0.0001). However, time to catheter removal was 9 times longer in the laser therapy group (p <0. 0001). Complication rates were significantly higher for transurethral prostatic resection (chi-square 5.05, 1 df, p = 0.025). CONCLUSIONS: Transurethral prostatic resection is more effective than laser ablation in men with chronic urinary retention in terms of symptom score, maximum urinary flow and failure. However, men who underwent resection had significantly more treatment complications and were hospitalized longer than those who received laser therapy. This finding implies that laser ablation therapy may have a role in patients at higher risk who are willing to accept a lower level of effectiveness in exchange for decreased complication rates and hospital stay.     

Neurophysiologic correlates of side effects in normal subjects randomized to venlafaxine or placebo.

Adverse events reported in the context of medication administration may be due to pharmacodynamic and/or nonpharmacodynamic effects (eg, nocebo phenomena). Neurophysiological substrates of side effects may be examined in placebo-controlled antidepressant treatment trials. We explored the relationship between side effects and regional neurophysiologic changes in normal subjects receiving a 1-week placebo lead-in followed by 4 weeks randomized treatment with placebo (n = 15) or venlafaxine IR (n = 17). Quantitative electroencephalographic (QEEG) cordance measures were obtained before and during treatment, and side effects were assessed weekly using semistructured interviews. Side effect burden, characterized as the mean number of side effects per postrandomization visit, correlated significantly with neurophysiologic changes in the antidepressant group but not the placebo group. Medication group side effects were negatively correlated with changes in prefrontal cordance at end of placebo lead-in (r = -0.67, p < 0.003), at 2 weeks (r = -0.77, p < 0.002), and at 4 weeks (r = -0.77, p < 0.004) post randomization. After controlling for the prefrontal change at the end of placebo lead-in, postrandomization brain changes did not further explain side effect burden. Changes in prefrontal brain function associated with later antidepressant side effects were observed during placebo lead-in-prior to the administration of medication. Prefrontal brain function during brief placebo administration may help explain susceptibility to the development of antidepressant side effects. Results of these exploratory hypothesis-generating analyses should be considered tentative until replicated.     

Late effects of hematopoietic cell transplantation among 10-year adult survivors compared with case-matched controls.

PURPOSE: To determine late effects of hematopoietic cell transplantation (HCT) on health problems and health-related quality of life for 10-year survivors. PATIENTS AND METHODS: Four hundred five adults consented to the study before HCT. Medical records and standardized self-report measures were maintained prospectively. After 10 years, 137 survivors and nontransplant controls, case-matched on age, sex, and race, completed self-report of medical problems, symptoms, and health-related quality of life. RESULTS: Survivors and controls had similar rates of hospitalization and most diseases, but survivors reported an average of 3.5 medical problems versus 1.7 for controls (P < .001). Survivors reported more musculoskeletal stiffness, cramps, weakness and joint swelling (P < .001), cataract surgery (P < .001), hepatitis C (P = .004), sexual problems for men (P = .01) and women (P < .001), restrictions in social function (P = .002), memory and attention concerns (P = .003), urinary frequency or leaking (P = .006), use of psychotropic medication (P = .009), and denial of life and health insurance (P < .001). Survivors and controls did not differ in self-reported rates of osteoporosis, hypothyroidism, employment, marital satisfaction, divorce, or psychological health. CONCLUSION: Although indistinguishable in many respects, survivors had more medical needs than controls. Health problems were not focused on specific diseases or limited to survivors with readily identifiable risk factors. Musculoskeletal problems require both screening and research into etiologies and effective treatments. Osteoporosis and hypothyroidism may be underdiagnosed. Survivors require screening for sexual problems, urinary frequency, mood and need for antidepressants or benzodiazepines.     

Perisilicone proliferation after vitrectomy for proliferative vitreoretinopathy

From 1983 to 1986, silicone oil injections were used to treat 31 patients with retinal detachment (RD) and advanced proliferative vitreoretinopathy (PVR). In 19 eyes (61%), perisilicone proliferation (PSP) developed causing recurrent RDs in 15 eyes (49%). At an average of 5 weeks after surgery, PSP occurred and was characterized by extensive transparent preretinal membranes with denser focal areas. Microscopic examination of five preretinal membranes showed droplets of silicone oil and necrotic cells on the silicone side and glial or retinal pigment epithelial cells, or both, on the retinal side, often in layers separated by extracellular matrix. Silicone oil was present in periretinal membranes removed several months after the intraocular silicone had been evacuated indicating that silicone within cells may persist despite the removal of silicone. The use of silicone oil to provide tamponade in eyes with recurrent PVR is associated with a high incidence of periretinal proliferation that frequently leads to recurrent RD and visual failure.     

Clinicopathologic findings in anterior hyaloidal fibrovascular proliferation after diabetic vitrectomy

Two young patients (27 and 30 years old, respectively) with long-standing diabetes mellitus underwent vitreoretinal surgery for traction retinal detachment and vitreous hemorrhage. The postoperative course in each was characterized by early recurrence of the hemorrhage into the vitreous cavity, hypotony, and severe visual loss. Histopathologic examination of both operated on eyes showed anterior extraretinal fibrovascular proliferation extending along the anterior hyaloid to the posterior lens surface, causing traction detachments of the peripheral retina and ciliary body. The vessels originated from the anterior retina. There was no evidence of excess fibrous tissue at the well-healed sclerotomy wounds.