What is the optimal systemic treatment of men with metastatic, hormone-naive prostate cancer? A STOPCAP systematic review and network meta-analysis.

Background: Our prior Systemic Treatment Options for Cancer of the Prostate systematic reviews showed improved survival for men with metastatic hormone-naive prostate cancer when abiraterone acetate plus prednisolone/prednisone (AAP) or docetaxel (Doc), but not zoledronic acid (ZA), were added to androgen-deprivation therapy (ADT). Trial evidence also suggests a benefit of combining celecoxib (Cel) with ZA and ADT. To establish the optimal treatments, a network meta-analysis (NMA) was carried out based on aggregate data (AD) from all available studies. Methods: Overall survival (OS) and failure-free survival data from completed Systemic Treatment Options for Cancer of the Prostate reviews of Doc, ZA and AAP and from recent trials of ZA and Cel contributed to this comprehensive AD-NMA. The primary outcome was OS. Correlations between treatment comparisons within one multi-arm, multi-stage trial were estimated from control-arm event counts. Network consistency and a common heterogeneity variance were assumed. Results: We identified 10 completed trials which had closed to recruitment, and one trial in which recruitment was ongoing, as eligible for inclusion. Results are based on six trials including 6204 men (97% of men randomised in all completed trials). Network estimates of effects on OS were consistent with reported comparisons with ADT alone for AAP [hazard ration (HR) = 0.61, 95% confidence interval (CI) 0.53-0.71], Doc (HR = 0.77, 95% CI 0.68-0.87), ZA + Cel (HR = 0.78, 95% CI 0.62-0.97), ZA + Doc (HR = 0.79, 95% CI 0.66-0.94), Cel (HR = 0.94 95% CI 0.75-1.17) and ZA (HR = 0.90 95% CI 0.79-1.03). The effect of ZA + Cel is consistent with the additive effects of the individual treatments. Results suggest that AAP has the highest probability of being the most effective treatment both for OS (94% probability) and failure-free survival (100% probability). Doc was the second-best treatment of OS (35% probability). Conclusions: Uniquely, we have included all available results and appropriately accounted for inclusion of multi-arm, multi-stage trials in this AD-NMA. Our results support the use of AAP or Doc with ADT in men with metastatic hormone-naive prostate cancer. AAP appears to be the most effective treatment, but it is not clear to what extent and whether this is due to a true increased benefit with AAP or the variable features of the individual trials. To fully account for patient variability across trials, changes in prognosis or treatment effects over time and the potential impact of treatment on progression, a network meta-analysis based on individual participant data is in development.

Effects of nicotine on visuospatial attentional orienting in non-smokers.

Nicotine is a highly addictive substance, suggested to be in part due to its cognitive enhancing effects in the attentional domain. Improvements in stimulus selection with nicotine have been reported but its effects on visual-spatial selective attention are unclear. This study utilized event-related potentials (ERPs) to examine the acute effects of nicotine on selective attention in non-smokers performing a Posner-type visuo-spatial task. The attentional processing of visual-spatial locations is reflected in the P1 ERP component, which represents earlier stages of visual analysis. 24 non-smokers received nicotine gum (6 mg) in a randomized, double-blind, placebo-controlled, repeated measures design. Behavioral performance and ERPs were assessed in response to target locations preceded by valid, invalid and neutral cues. Nicotine did not affect behavioral performance indices. P1 amplitudes were greater in valid and neutral cue trials compared to invalid cue trials and acute nicotine administration (vs. placebo) was found to increase P1 amplitudes in the right hemisphere, particularly in valid cue trials. In addition, in high symptomatic subjects (as indexed by greater increases in heart rate post-administration), nicotine (vs. placebo) produced greater P1 amplitudes in valid cue trials. The study concludes that nicotine enhanced visuospatial selective attention with regards to early visual encoding and analysis. These results demonstrate support in general for the attentional effects of nicotine and nicotinic agonists and they specifically extend these effects to include orienting of visual-spatial attention.

Differential effects of nicotine on P50 amplitude, its gating, and their neural sources in low and high suppressors.

Sensory gating impairment in schizophrenia has been documented in the form of aberrant middle latency P50 event-related brain potential responses to S(1) and/or S(2) stimuli in a paired (S(1)-S(2)) auditory stimulus paradigm. Evidenced by a failure to suppress S(2) P50 or by attenuated S(1) P50s, these sensory deficits have been associated with increased smoking behaviour in this disorder, and may be related to the putative ameliorating effects of smoke-inhaled nicotine on neural mechanisms regulating gating. Comparison of healthy controls with low versus high gating efficiency has been forwarded as a model for investigating the actions of antipsychotic agents on aberrant gating functions. In the current study, the effect of a single dose (6 mg) of nicotine gum on P50, gating indices, and their cortical sources indexed with sLORETA (standardized low resolution electromagnetic tomography), was examined in healthy non-smokers (n=24) stratified for low and high gating levels. Scalp surface recordings revealed nicotine modulation of P50 and its gating to be differentially exhibited in high (decreasing gating) and low (increasing gating) suppressors while the underlying cortical sources influenced by nicotine (middle frontal gyrus, inferior/superior parietal lobules, pre- and post-central gyri) were seen only in low suppressors. These findings suggest that nicotine impacts sensory gating in healthy volunteers and as the gating enhancing effects were dependent on low baseline gating efficiency, nicotinic receptor agonists may be associated with unique P50 modulating actions in schizophrenia.

The enteric toxins of Clostridium perfringens.

The Gram-positive pathogen Clostridium perfringens is a major cause of human and veterinary enteric disease largely because this bacterium can produce several toxins when present inside the gastrointestinal tract. The enteric toxins of C. perfringens share two common features: (1) they are all single polypeptides of modest (approximately 25-35 kDa) size, although lacking in sequence homology, and (2) they generally act by forming pores or channels in plasma membranes of host cells. These enteric toxins include C. perfringens enterotoxin (CPE), which is responsible for the symptoms of a common human food poisoning and acts by forming pores after interacting with intestinal tight junction proteins. Two other C. perfringens enteric toxins, epsilon-toxin (a bioterrorism select agent) and beta-toxin, cause veterinary enterotoxemias when absorbed from the intestines; beta- and epsilon-toxins then apparently act by forming oligomeric pores in intestinal or extra-intestinal target tissues. The action of a newly discovered C. perfringens enteric toxin, beta2 toxin, has not yet been defined but precedent suggests it might also be a pore-former. Experience with other clostridial toxins certainly warrants continued research on these C. perfringens enteric toxins to develop their potential as therapeutic agents and tools for cellular biology.

Pathology of fathead minnows (Pimephales promelas) exposed to chlorine dioxide and chlorite.

Fathead minnows (Pimephales promelas) were exposed to the biocide chlorine dioxide (0.13 and 0.19 mg l-1) for up to 12 h and to its primary decomposition product, chlorite (177 and 304 mg l-1), for up to 96 h followed by recovery periods of up to 14 days. Chlorine dioxide exposure produced dose-dependent gill pathology including epithelial lifting, hypertrophy, hyperplasia, lamellar fusion, and necrosis. Complete recovery, even in fish with severe hypertrophy and lamellar fusion, was achieved within 4 days. Chlorite did not produce gill pathology even at a lethal exposure level (304 mg l-1 for 96 h) but did elicit a chronic inflammatory response with a marked increase in circulating and fixed phagocytes within hematopoietic and vascular tissues. This study indicates that chlorine dioxide is approximately 1000 times more toxic to fathead minnows than chlorite. Further, exposure of fathead minnows to these distinct but related compounds is consistently associated with very different pathologies.

Antigenic properties of recombinant glycosylated and nonglycosylated Pneumocystis carinii glycoprotein A polypeptides expressed in baculovirus-infected insect cells.

Since a continuous culture system is not yet available for the opportunistic fungal pathogen Pneumocystis carinii, obtaining suitable amounts of purified P. carinii antigens free of mammalian-host lung contaminants is difficult. Hence, production of recombinant antigen possessing epitopes found in native P. carinii antigens is critical for immunological studies. We utilized the baculovirus expression vector system (BEVS) in insect cells to determine whether B-cell epitopes present in the protein core of a native P. carinii surface glycoprotein were conserved in the recombinant polypeptide, and to investigate its glycosylation by insect cells. B-cell epitopes were retained, but the insect cells appeared to hyperglycosylate the recombinant protein.

Primary hyperparathyroidism caused by a functional parathyroid adenoma in a horse.

A 14-year-old Arabian gelding had weight loss and anorexia of 3 weeks' duration. Results of repeated laboratory tests revealed persistent hypercalcemia and serum phosphorus concentration that was within or less than the reference range. Parathyroid hormone concentration was high. Histologic examination of specimens obtained at necropsy revealed parathyroid adenoma. A diagnosis of primary hyperparathyroidism attributable to a functional parathyroid adenoma was made. Abnormalities in calcium and phosphorus concentrations were similar to those seen with primary hyperparathyroidism in dogs, in which this syndrome is best described. Primary hyperparathyroidism should be considered to be a potential cause of hypercalcemia in horses in which other more common causes of hypercalcemia, such as humoral hypercalcemia of malignancy, nutritional secondary hyperparathyroidism, chronic renal failure, vitamin D toxicosis, and bony or granulomatous disease, are ruled out.

Balloon pulmonary valvuloplasty and stent implantation. For peripheral pulmonary artery stenosis in Alagille syndrome.

We report the case of a patient with Alagille syndrome and severe pulmonary valve and bilateral pulmonary artery branch stenosis. In this patient, transcatheter balloon pulmonary valvuloplasty combined with bilateral pulmonary artery angioplasty and stent placement provided excellent immediate results and long-term improvement.

Biotic factors modifying acute toxicity of aqueous cadmium to estuarine amphipod Leptocheirus plumulosus.

A 96-h exposure to aqueous cadmium (Cd) is the recommended reference toxicity test for 10-day sediment bioassays with the estuarine amphipod, Leptocheirus plumulosus (US EPA 1994). This water-only test was used to assess the influence of organism size, sex, and nutritional status on the sensitivity of laboratory-cultured L. plumulosus to Cd. In addition, the response of field-collected amphipods was compared to similarly sized laboratory animals to assess potential seasonal changes in Cd sensitivity. Lipid content of test organisms was measured in these seasonal experiments and those evaluating effects of nutritional status because of its potential as an indicator of physiological condition. LC50 values of laboratory animals size-sorted on nested 500-, 710-, and 1000-micron mesh sieves, increased with size class: 0.36, 0.65, and 0.88 mg Cd/L, respectively. Gravid females were less sensitive than males or mature females to aqueous Cd. Studies on the influence of the molt cycle on Cd toxicity indicated enhanced sensitivity of immediate postmolt animals that may explain some of the observed differences in Cd tolerance. Nutritional effects were investigated by comparing the sensitivity of fed and starved laboratory-reared amphipods. Starved juveniles and adults were significantly smaller than their fed counterparts and exhibited a 28-43% reduction in lipid content, respectively. However, comparison of LC50 values indicated no significant differences in sensitivity to Cd between starved and fed juveniles (0.23 vs 0.30 mg Cd/L) or adults (0.37 vs 0.52 mg Cd/L). Field-collected amphipods were typically more sensitive to Cd than laboratory animals, regardless of the season, although their lipid content varied, ranging from 6.6% in August to 13.7% in November. Results are discussed with respect to the use and interpretation of toxicity tests with this species.

Clinical experience with the video-assisted saphenectomy procedure for coronary bypass operations.

BACKGROUND: Leg wound complications after saphenectomy are frequent after coronary bypass operations and have a detrimental effect on postoperative quality of life and treatment cost. To reduce morbidity, we evaluated a new technique of video-assisted vein harvest. METHODS: Between March 1996 and October 1996, 50 patients had video-assisted saphenectomy (VAS) and 40 patients had the standard open technique (control group). An additional 13 patients had both procedures (hybrid group). Level of pain, edema, and wound complications were evaluated at discharge and at 2, 4, and 6 weeks postoperatively. RESULTS: The mean operating time for VAS patients was slightly higher than for control (60.6+/-24.7 minutes versus 53.2+/-21.1 minutes; p > 0.05). The average incision length in VAS patients was 13.8+/-8.8 cm for an average of 3.3 grafts per patient. Three VAS procedures were aborted, two because of time constraints, and one because of bleeding, and a segment of vein was lost to injury. The VAS group had considerably less early postoperative pain than the control group (1.7+/-1.2 versus 4.1+/-1.4 [1 = mild, 10 = severe]; p < 0.005) and edema was similar for both groups. Patients in the hybrid group reported less pain in the VAS-operated leg. Serious wound infection occurred in 4 patients, with 2 patients in the control group requiring reoperation for drainage and flap reconstruction. CONCLUSIONS: Based on this initial experience, VAS harvesting, although initially more time consuming, is a rapidly mastered technique, results in shorter overall incision length, and is associated with considerably less postoperative pain than the standard open technique.

Usefulness of turbo spin-echo MR imaging in the evaluation of meniscal tears: comparison with a conventional spin-echo sequence.

OBJECTIVE: Fast (turbo) spin-echo imaging techniques have replaced conventional spin-echo protocols in a large proportion of MR applications, with the principle advantage of decreased imaging time. The choice of echo train length is a key determinant of time savings realized, but the echo train length can also adversely affect image quality if too many echoes are incorporated into an image. Several recent studies have shown conflicting results regarding the usefulness of turbo spin-echo imaging in the evaluation of meniscal tears. We compare a turbo spin-echo sequence that has an echo train length of five with a conventional spin-echo sequence for evaluating meniscal tears. SUBJECTS AND METHODS: Forty knees in 39 consecutive patients referred for MR study of the knee were imaged using both conventional spin-echo and turbo spin-echo sequences. The turbo spin-echo sequence provided both proton density-weighted and T2-weighted images (dual echo technique) with an effective echo-train length of five. Nineteen knees (38 menisci) were studied arthroscopically. The arthroscopic findings were considered the reference standard. Spin-echo and turbo spin-echo images were reviewed retrospectively, and results were compared statistically. RESULTS: Of the 80 menisci evaluated with MR imaging, spin-echo and turbo spin-echo images provided concordant results in 95% of cases, with no statistically significant difference found between the two techniques (p < .05). Seventeen tears were found at arthroscopy in 38 menisci studied. Spin-echo and turbo spin-echo imaging had identical specificities (90%) and similar sensitivities (88% and 82%, respectively). CONCLUSION: This study shows that proton density-weighted sequences with an echo train length of five preserve sufficient high-spatial-frequency information to provide performance similar to that of conventional spin-echo sequences. Our data support the conclusion that fast spin-echo imaging with short echo train length is a reasonable substitute for conventional spin-echo imaging in the evaluation of the knee.

Echo-planar FLAIR imaging in evaluation of intracranial lesions.

Fluid-attenuated inversion-recovery (FLAIR) imaging is a magnetic resonance imaging technique that improves lesion detection in the brain. This technique suppresses signal from free water in cerebrospinal fluid and maintains the hyperintense lesion contrast of T2-weighted spin-echo imaging. Unfortunately, conventional FLAIR imaging requires a long acquisition time and provides a limited number of sections. A combination of echo-planar imaging and FLAIR imaging offers the image contrast effects of FLAIR imaging and the speed of echo-planar imaging. Clinically, the echo-planar FLAIR technique is most helpful in detecting subtle, early lesions that do not enhance, such as early infarct, demyelinating disease, early infection, and trauma. The increased magnetic susceptibility effect associated with the echo-planar technique can be clinically useful in detecting subtle hemorrhage and cavernous angioma. Echo-planar FLAIR imaging is a practical and efficient means of screening the entire brain in a short time.

Regulation of SERCA 2 expression by thyroid hormone in cultured chick embryo cardiomyocytes.

We investigated the role of thyroid hormone in the physiological perinatal increase in cardiac sarcoplasmic reticulum (SR) Ca(2+)-adenosinetriphosphatase (ATPase) expression. We isolated and cultured the cardiomyocytes in 10(-8) M triiodothyronine (T3) for 48 h and then measured SR Ca(2+)-ATPase mRNA and immunodetectable protein contents as well as SR-dependent 45Ca2+ uptake rate. We also examined the effect of T3 on expression of the same gene in monkey kidney CV-1 cells, which do not express thyroid hormone receptors. T3 increased cardiomyocyte SR Ca2+ pump mRNA content by 289 +/- 35%, and immunodetectable SR Ca2+ pump protein content by 255 +/- 44%, and SR-specific 45Ca2+ uptake rate by 189 +/- 22% (P < 0.01 for each). In contrast, T3 had no significant effect on the total cellular RNA or protein contents in the cardiomyocyte, and there was no effect of T3 on Ca(2+)-ATPase mRNA content in the thyroid hormone receptor-negative CV-1 cells. These data demonstrate that T3 increases expression of the cardiac SR Ca2+ pump, that the effect can be localized to the cardiomyocyte, and that the effect is dependent on thyroid hormone receptors. These data are consistent with pretranslational and possibly transcriptional level effect of thyroid hormone on the cardiac SR Ca2+ pump gene (SERCA 2). The gestation-associated increase in thyroid hormone may be at least partially responsible for the previously demonstrated perinatal increase in cardiac SR Ca2+ pump expression.

The effect of contrast dose, imaging time, and lesion size in the MR detection of intracerebral metastasis.

PURPOSE: To evaluate the effect of MR contrast dose versus delayed imaging time on the detection of metastatic brain lesions based on lesion size. METHODS: Contrast MR examinations with gadoteridol were obtained in 45 patients with brain metastases. The patients were divided into two groups: 16 received cumulative standard dose (0.1 mmol/kg) and 29 received cumulative triple dose (0.3 mmol/kg). Both groups were evaluated at two dose levels (lower dose and higher dose) with two separate injections. Each patient received an initial bolus injection of either 0.05 (cumulative standard dose) or 0.1 (cumulative triple dose) mmol/kg of gadoteridol to reach the lower-dose level and underwent imaging immediately and 10 and 20 minutes later. Thirty minutes after injection, an additional bolus injection of 0.05 (cumulative standard dose) or 0.2 (cumulative triple dose) mmol/kg was administered to reach the cumulative higher-dose level (cumulative standard dose, 0.1 mmol/kg; cumulative triple dose, 0.3 mmol). Images were acquired immediately. RESULTS: There was no difference in the detection rate for lesions larger than 10 mm among T2-weighted, lower-dose immediate and delayed, or immediate higher-dose images in both study groups. Lesions smaller than 10 mm had improved detection with delayed imaging in both study groups; however, the immediate higher-dose studies still had the highest detection rate. CONCLUSION: In the evaluation of small central nervous system metastases, either delayed imaging after the injection of standard contrast dose or higher contrast dose may improve their detection, and therefore affect clinical management. Higher contrast dose (cumulative triple dose) studies appear to be more effective than delayed imaging with standard dose.

MR evaluation of acoustic schwannoma with fractional contrast doses.

OBJECTIVE: To investigate the utility of lower contrast medium doses for the detection and conspicuity of acoustic schwannomas. MATERIALS AND METHODS: The L/B (L, lesion; B, background) ratios or lesion contrast of 17 pathologically proven acoustic schwannomas studied with a standard dose (0.1 mmol/kg) of gadopentetate dimeglumine was measured. In addition, 22 patients with acoustic schwannomas were studied prospectively with fractional doses using the incremental dose technique. Each patient received an initial bolus injection of one-eight the standard dose (0.0125 mmol/kg) followed by an injection of one-eighth, one-fourth, and one-half the standard dose at 5 min intervals to achieve a cumulative dose of one-fourth, one-half and full dose, respectively. Imaging was performed immediately after each injection. RESULTS: Standard dose--The L/B ratios of pathologically proven acoustic schwannomas to mastoid air cells ranged from 14.8 to 41.2 (mean +/- SEM, 28.0 +/- 1.95), which were approximately 17 times more than those of intraparenchymal lesions. Fractional cumulative dose--Qualitative visual analysis demonstrated that all acoustic schwannomas showed apparent enhancement at one-fourth dose. Intense enhancement was noted at one-half and full dose. Quantitative analysis demonstrated the mean L/B ratios between the acoustic schwannomas and mastoid air cells of the precontrast and one-eighth, one-fourth, one-half, and full dose studies were 8.33 +/- 0.52, 11.21 +/- 0.75, 13.02 +/- 0.83, 15.38 +/- 0.98, and 18.03 +/- 1.36, respectively. CONCLUSION: The L/B ratios or lesion contrast of acoustic schwannomas at various fractional contrast medium doses was significantly higher compared with that of intraparenchymal lesions. Thus, the standard contrast medium dose may not be necessary for detection of acoustic schwannomas, and a fractional dose may be sufficient. Although the optimal fractional dose remains to be determined, one-half of the standard dose (0.05 mmol/kg) appears to be sufficient because of intense enhancement at this dose.

Immunophenotyping lymphomas in dogs: a comparison of results from fine needle aspirate and needle biopsy samples.

The reliability of utilizing cytologic samples for immunophenotyping canine lymphomas was evaluated by a systematic comparison of results from fine needle aspirate (FNA) to needle biopsy specimens stained by immunochemical methods. The specific reactivity of a selected panel of 12 antibodies to cell surface markers and intermediate filaments was assessed in 11 dogs by comparing cytologic to histologic samples. There was excellent correlation of results between immunostained cytologic and histologic samples. FNA sampling is a simple, noninvasive method for determining the lymphoid phenotype in canine lymphoma. In addition, this technique may be useful as a cytodiagnostic aid in differentiating lymphoid from non-lymphoid tumors and in assessing neoplastic vs. reactive or hyperplastic processes.

Phase III multicenter trial of high-dose gadoteridol in MR evaluation of brain metastases.

PURPOSE: To assess the efficacy and safety profile of high-dose (0.3 mmol/kg cumulative dose) gadoteridol in patients with suspected central nervous system metastatic disease. METHODS: We studied 67 patients using an incremental-dose technique. Patient monitoring included a medical history, physical examination, vital signs, and extensive laboratory tests within 24 hours before and after the MR examination. Precontrast T1- and T2-weighted spin-echo studies were performed, followed by intravenous injection of 0.1 mmol/kg of gadoteridol. T1-weighted images were acquired immediately after and at 10 and 20 minutes after injection. At 30 minutes an additional 0.2 mmol/kg of gadoteridol was administered (0.3-mmol/kg cumulative dose), and T1-weighted images were acquired. Cases demonstrating abnormal MR findings were assessed for efficacy by unblinded and blinded reviewers and were analyzed quantitatively. RESULTS: Three adverse effects in two patients were considered to be related to gadoteridol administration. No adverse effects were serious; all self-resolved. Forty-nine cases showed abnormal MR findings and were included in the efficacy analysis. A significantly greater number of lesions was seen on the high-dose as opposed to the standard-dose images. Blinded and unblinded readers identified 5 and 8 patients, respectively, with solitary lesions on standard-dose examination and multiple lesions on high-dose examination. Two patients who had normal standard-dose findings had lesions identified on high-dose studies. Quantitative analysis of 133 lesions in 45 patients demonstrated significant increases in lesion signal intensity on high-dose studies when compared with standard-dose studies. CONCLUSION: Gadoteridol can be safely administered up to a cumulative dose of 0.3 mmol/kg. High-dose contrast studies provide improved lesion detectability and additional diagnostic information over studies performed in the same patients with a 0.1-mmol/kg dose and aid in patient diagnosis and treatment. High-dose gadoteridol study may facilitate the care of patients with suspected central nervous system metastasis.

Cost-effectiveness of high-dose MR contrast studies in the evaluation of brain metastases.

PURPOSE: To investigate the cost-effectiveness of high-dose MR contrast studies in the management of brain metastases. METHODS: During the phase III clinical trial of high-dose contrast studies (0.3 mmol/kg), 11 of 27 patients were judged by the reviewers to have potential treatment changes based on the additional information provided by the high-dose studies. We retrospectively evaluated how many of these 27 patients had actual treatment changes because of the results of the high-dose study. Using the fee schedule at our institution, the cost-effectiveness was analyzed based on the cost savings from treatment changes and the additional expense of implementing the high-dose studies. RESULTS: A total of 3 craniotomies ($22,800 each) and 2 aggressive courses of radiation therapy ($1122 each) were avoided in 4 patients because of the additional lesions detected by the high-dose studies. This resulted in a treatment cost savings of $70,644. The extra expense for implementing the high-dose study is $9126 for a single injection in all 27 patients, $9295 for 2 separate injections completed in 1 visit in the 11 patients, and $11,154 for 2 separate injections completed in 2 separate visits. The cost savings in management (diagnosis and treatment) therefore ranged from $59,490 to $61,518 for all patients and from $2203 to $2278 per patient. CONCLUSION: Based on our limited data, the high-dose study seems to impact positively on the cost-effectiveness in the management of brain metastases. However, because our study had limitations, our results need to be confirmed with a larger patient population and a more standardized treatment approach and fee schedule.