Adding abiraterone or docetaxel to long-term hormone therapy for prostate cancer: directly randomised data from the STAMPEDE multi-arm, multi-stage platform protocol.

Background: Adding abiraterone acetate with prednisolone (AAP) or docetaxel with prednisolone (DocP) to standard-of-care (SOC) each improved survival in systemic therapy for advanced or metastatic prostate cancer: evaluation of drug efficacy: a multi-arm multi-stage platform randomised controlled protocol recruiting patients with high-risk locally advanced or metastatic PCa starting long-term androgen deprivation therapy (ADT). The protocol provides the only direct, randomised comparative data of SOC + AAP versus SOC + DocP. Method: Recruitment to SOC + DocP and SOC + AAP overlapped November 2011 to March 2013. SOC was long-term ADT or, for most non-metastatic cases, ADT for ≥2 years and RT to the primary tumour. Stratified randomisation allocated pts 2 : 1 : 2 to SOC; SOC + docetaxel 75 mg/m2 3-weekly×6 + prednisolone 10 mg daily; or SOC + abiraterone acetate 1000 mg + prednisolone 5 mg daily. AAP duration depended on stage and intent to give radical RT. The primary outcome measure was death from any cause. Analyses used Cox proportional hazards and flexible parametric models, adjusted for stratification factors. This was not a formally powered comparison. A hazard ratio (HR) <1 favours SOC + AAP, and HR > 1 favours SOC + DocP. Results: A total of 566 consenting patients were contemporaneously randomised: 189 SOC + DocP and 377 SOC + AAP. The patients, balanced by allocated treatment were: 342 (60%) M1; 429 (76%) Gleason 8-10; 449 (79%) WHO performance status 0; median age 66 years and median PSA 56 ng/ml. With median follow-up 4 years, 149 deaths were reported. For overall survival, HR = 1.16 (95% CI 0.82-1.65); failure-free survival HR = 0.51 (95% CI 0.39-0.67); progression-free survival HR = 0.65 (95% CI 0.48-0.88); metastasis-free survival HR = 0.77 (95% CI 0.57-1.03); prostate cancer-specific survival HR = 1.02 (0.70-1.49); and symptomatic skeletal events HR = 0.83 (95% CI 0.55-1.25). In the safety population, the proportion reporting ≥1 grade 3, 4 or 5 adverse events ever was 36%, 13% and 1% SOC + DocP, and 40%, 7% and 1% SOC + AAP; prevalence 11% at 1 and 2 years on both arms. Relapse treatment patterns varied by arm. Conclusions: This direct, randomised comparative analysis of two new treatment standards for hormone-naïve prostate cancer showed no evidence of a difference in overall or prostate cancer-specific survival, nor in other important outcomes such as symptomatic skeletal events. Worst toxicity grade over entire time on trial was similar but comprised different toxicities in line with the known properties of the drugs. Trial registration: Clinicaltrials.gov: NCT00268476.

A new "keyhole" approach for multilevel anterior lumbar interbody fusion: the perinavel approach-technical note and literature review.

PURPOSE: The purpose of this study is to evaluate the feasibility and the safety of a new skin incision for minimally invasive anterior lumbar interbody fusion (ALIF): the perinavel incision. METHODS: Demographic and clinical data from patients who underwent ALIF with the perinavel incision were collected. Indications to surgery, preoperative symptoms, radiological data, number of treated levels, intraoperative and early postoperative complications and wound-related problems were analysed. RESULT: Ninety-seven patients underwent ALIF with this new skin incision. One hundred fifty-seven levels were treated (mean 1.7 level per patient) being L4-L5 the most frequently treated. Intraoperative complications were represented only by the venous injury with a rate of 3.09% (3 cases). Postoperative complications were all linked to skin incision issues: a case of wound dehiscence and a case of superficial infection. No case of skin necrosis occurs at 3-month follow-up. CONCLUSIONS: In this paper, the perinavel skin incision was demonstrated to be as safe as traditional approaches for ALIF. Furthermore, with this incision it is possible to perform multilevel (L3-S1) ALIF, which means a good option in minimally invasive surgery as well as revision surgery. These slides can be retrieved under Electronic Supplementary Material.

A modified perineal approach for the management of strangulated rectal prolapse: A case report.

INTRODUCTION: Conditions associated with increased intraabdominal pressure may lead to rectal prolapse. Like any pathological herniation, rectal prolapse can strangulate if incarcerated. When a patient presents with signs and symptoms of strangulation, emergent surgical intervention is warranted. This report strives to strengthen existing evidence for the use of an Altemeier-type perineal approach as a viable choice for the management of strangulated rectal prolapse in healthy individuals. PRESENTATION OF CASE: A healthy 70-year-old female presents with worsening rectal pain and an irreducible strangulated rectal prolapse. She is brought to the operating suite for an emergent exploration under anesthesia followed by an Altemeier-type procedure without diverting colostomy. The postoperative course is uneventful, and the patient is discharged on postoperative day three. Upon follow up, the patient reports having normal bowel function, and there is no evidence of recurrence. DISCUSSION: Rectal prolapse is traditionally managed through either a perineal or transabdominal approach depending on the patient's clinical disposition. Incarcerated prolapse is a precursor to strangulation, and recent case reports have demonstrated the efficacy of the Altemeier procedure (perineal rectosigmoidectomy) to treat strangulated prolapse. Our initial exploration under anesthesia revealed a small section of ischemic rectal mucosa that was proximal to the rectosigmoid junction. As a result, we decided to remain within perineal parameters and perform the resection in an Altemeier-type fashion based on the boundary of ischemia. CONCLUSION: An Altemeier approach was a reasonable option for emergent surgical management of strangulated rectal prolapse in an otherwise relatively healthy individual. This case has been reported in line with the SCARE criteria (Agha et al. [1]).

Strained ruthenium complexes are potent light-activated anticancer agents.

Strained ruthenium (Ru) complexes have been synthesized and characterized as novel agents for photodynamic therapy (PDT). The complexes are inert until triggered by visible light, which induces ligand loss and covalent modification of DNA. An increase in cytotoxicity of 2 orders of magnitude is observed with light activation in cancer cells, and the compounds display potencies superior to cisplatin against 3D tumor spheroids. The use of intramolecular strain may be applied as a general paradigm to develop light-activated ruthenium complexes for PDT applications.

Structure-activity relationships of anticancer ruthenium(II) complexes with substituted hydroxyquinolines.

8-Hydroxyquinolines (HQ), including clioquinol, possess cytotoxic properties and are widely used as ligands for metal-based anticancer drug research. The number and identity of substituents on the HQ can have a profound effect on activity for a variety of inorganic compounds. Ruthenium complexes of HQ exhibit radically improved potencies, and operate by a new, currently unknown, mechanism of action. To define structure-activity relationships (SAR), a family of 22 Ru(II) coordination complexes containing mono-, di- and tri-substituted hydroxyquinoline ligands were synthesized and their biological activity evaluated. The complexes exhibited promising cytotoxic activity against a cancer cell line, and the SAR data revealed the 2- and 7-positions as key sites for the incorporation of halogens to improve potency. The Ru(II) complexes potently inhibited translation, as demonstrated by an in-cell translation assay. The effects were seen at 2-15-fold higher concentrations than those required to observe cytotoxicity, suggesting that prevention of protein synthesis may be a primary, but not the exclusive mechanism for the observed cytotoxic activity.

Genetic and structural determinants of virus neutralizing antibodies.

Neutralizing antibodies (Abs) are the principal protective mechanism against disease caused by reinfection with viruses. Ab-mediated neutralization of viruses is a complex process comprising multiple mechanisms. Every structural aspect of Abs is potentially capable of modulating the level of neutralizing activity or the mechanisms of neutralization. The focus of our laboratory is to understand the genetic and structural basis of Ab-mediated neutralization of human viral pathogens. We demonstrated the unexpected finding that virus antigen-binding fragments of Abs (Fabs) mediate potent virus neutralizing effects in vivo. This work has led to a broad investigation of the importance of the genetics, chemistry, and structure of the combining site to the neutralizing activity of antiviral Abs. Ongoing work in our laboratory reveals that effect or functions specified by the Ab isotype such as polymer formation, interactions with complement, interactions with Fc receptors, and the ability to transcytose mucosal epithelia, also modulate the mechanism and level of neutralizing effects mediated by antiviral Abs.

Radioimmunotherapy of cancer: using monoclonal antibodies to target radiotherapy.

After years of pre-clinical and clinical testing monoclonal antibodies (mAbs) finally offer new therapeutic choices for patients with haematological and solid malignancies both as unconjugated antibody and as vectors to target radionuclides in radioimmunotherapy (RIT). In recent years some of the most exciting clinical data have come from the use of RIT in the treatment of lymphoma and haematological malignancies and it would now appear highly likely that RIT will play a major role in the treatment strategies for these diseases. For the solid tumours there has also been considerable progress with RIT and mAbs have become a component of treatment protocols for breast cancer. This review highlights the important recent clinical progress that has been made with clinical RIT and provides some new insights into the important mechanisms of action of RIT in haematological malignancies.

GDNF improves dopamine function in the substantia nigra but not the putamen of unilateral MPTP-lesioned rhesus monkeys.

Microdialysis measurements of dopamine (DA) and DA metabolites were carried out in the putamen and substantia nigra of unilateral 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-lesioned rhesus monkeys that received intraventricular injections of vehicle or glial-derived neurotrophic factor (GDNF, 300 microg) 3 weeks prior to the microdialysis studies. Following behavioral measures in the MPTP-lesioned monkeys, they were anesthetized with isoflurane and placed in a stereotaxic apparatus. Magnetic resonance imaging (MRI)-guided sterile stereotaxic procedures were used for implantations of the microdialysis probes. Basal extracellular levels of DA and the DA metabolites, 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA), were found to be decreased by >95% in the right putamen of the MPTP-lesioned monkeys as compared to normal animals. In contrast, basal DA levels were not significantly decreased, and DOPAC and HVA levels were decreased by only 65% and 30%, respectively, in the MPTP-lesioned substantia nigra. Significant reductions in d-amphetamine-evoked DA release were also observed in the MPTP-lesioned substantia nigra and putamen of the monkeys as compared to normal animals. A single intraventricular administration of GDNF into one group of MPTP-lesioned monkeys elicited improvements in the parkinsonian symptoms in these animals at 2-3 weeks post-administration. In addition, d-amphetamine-evoked overflow of DA was significantly increased in the substantia nigra but not the putamen of MPTP-lesioned monkeys that had received GDNF. Moreover, post-mortem brain tissue studies showed increases in whole tissue levels of DA and DA metabolite levels primarily within the substantia nigra in MPTP-lesioned monkeys that had received GDNF. Taken together, these data support that single ventricular infusions of GDNF produce improvements in motoric behavior in MPTP-lesioned monkeys that correlate with increases in DA neuronal function that are localized to the substantia nigra and not the putamen.

Correlation of apomorphine- and amphetamine-induced turning with nigrostriatal dopamine content in unilateral 6-hydroxydopamine lesioned rats.

In the unilateral 6-hydroxydopamine (6-OHDA)-lesioned rat model of Parkinson's disease, controversy exists concerning the use of apomorphine- or D-amphetamine-induced rotations as reliable indicators of nigrostriatal dopamine depletion. Our objective was to evaluate which, if either, drug-induced behavior is more predictive of the extent of nigrostriatal dopamine depletion. Fischer 344 and Sprague-Dawley rats were unilaterally injected with 9 micrograms/4 microliters/4 min 6-hydroxydopamine into the medial forebrain bundle. The animals were behaviorally tested with apomorphine (0.05 mg/kg, s.c.) and D-amphetamine (5.0 mg/kg, s.c.). Following testing, the brains were removed and the right and left striata, substantia nigra and ventral tegmental area were dissected free and quickly frozen at -70 degrees C for analysis of catecholamine content by high performance liquid chromatography coupled with electrochemical detection. Our results indicate that an animal which has greater than a 90% depletion of dopamine in the striatum might not rotate substantially on apomorphine, without a concomitant depletion of > 50% of the DA content in the corresponding substantia nigra. No correlations were seen involving depletions of the ventral tegmental area and the extent of the lesions to the striatum. Submaximally lesioned (75-90% depleted) rats were found to rotate on D-amphetamine but not on apomorphine. In addition, control rats that did not receive lesions were often seen to rotate extensively on D-amphetamine. We therefore conclude that maximal lesions of the striatum and substantia nigra are required to generate rotations demonstrable with low dose apomorphine but not with D-amphetamine.(ABSTRACT TRUNCATED AT 250 WORDS)

Evidence for mitochondrial metabolism of 7,12-dimethylbenz(a)anthracene in porcine ovaries: comparison with microsomal metabolism.

7,12-dimethylbenz(a)anthracene (DMBA) causes necrosis in endocrine organs. DMBA metabolism in follicles and corpora lutea from porcine ovaries was demonstrated not only in the microsomal but also in the mitochondrial fraction, in contrast to what has been found in the rat ovary. Maximal activities were present in these fractions of the corpus luteum, with specific activities of 5.9 and 2.2 pmol/min x mg protein, respectively. DMBA metabolism in mitoplasts, i.e. mitochondrial inner membranes, proved to be more than 10-fold higher than the corresponding activity in the mitochondrial fraction. The purities of the subcellular fractions were assessed by measurements of marker enzymes. 17-42% of the mitochondrial DMBA metabolism was concluded to be due to microsomal contamination. In the mitoplast fraction such contamination was only 0.18-2.8%. Ellipticine and alpha-naphthoflavone reduced the metabolism of DMBA in the luteal microsomal fraction by 95 and 77%, respectively. In mitochondria the inhibition by these agents was 63 and 30%, respectively. Indomethacine and estradiol decreased microsomal DMBA metabolism by 53 and 52%, respectively. In mitochondria the inhibition was 52 and 23%, respectively. None of these inhibitors affected the DMBA metabolism by the mitoplast fraction.

Pulmonary tumour emboli: a difficult ante-mortem diagnosis.

A woman with known metastatic breast cancer presented with subacute dyspnoea. Investigations were non-conclusive; provisional diagnoses of pulmonary thromboemboli and carcinomatous lymphangitis were made. Despite treatment the patient died 10 days after admission. Post-mortem examination showed extensive tumour emboli within the pulmonary arteries. The appropriate investigation and management of such patients is discussed.

Anti-Yo antibody-positive cerebellar degeneration associated with endometrial carcinoma: case report and review of the literature.

Paraneoplastic cerebellar degeneration (PCD) is a rare, severely debilitating disease, often with a rapid onset and progression, which predate the diagnosis of malignancy. Despite characteristic features, diagnosis is commonly difficult and successful therapy, which relies on early instigation of treatment, is rare. Here we present a patient in whom anti-Yo antibody-positive PCD was associated with endometrial carcinoma and an extensive review of the literature outlining the clinical features, pathogenesis and treatment of PCD.

The treatment of spasticity by intrathecal administration of baclofen: a preliminary personal experience.

The administration of baclofen, a GABAb agonist, by direct infusion into the CSF by means of a programmable device, may avoid the undesired side effects of the oral administration of both the same and other antispastic drugs while giving a marked reduction of spasticity. The preliminary results on 12 patients show the total efficacy of this procedure in reducing spasticity markedly.

Chemical precipitation of heavy metals from acid mine drainage.

The 1,3-benzenediamidoethanethiol dianion (BDET, known commercially as MetX) has been developed to selectively and irreversibly bind soft heavy metals from aqueous solution. In the present study BDET was found to remove > 90% of several toxic or problematic metals from AMD samples taken from an abandoned mine in Pikeville, Kentucky. The concentrations of metals such as iron, may be reduced at pH 4.5 from 194 ppm to below 0.009 ppm. The formation of stoichiomietric BDET-metal precipitates in this process was confirmed using X-ray powder diffraction (XRD), proton nuclear magnetic resonance (1H NMR), and infrared spectroscopy (IR).

Soft metal preferences of 1,3-benzenediamidoethanethiol.

Recent studies indicate that the sodium salt of 1,3-benzenediamidoethanethiol (BDET) is both economical and effective in precipitating mercury and other heavy metals from water. Because wastewaters and contaminated natural waters may contain a variety of heavy metals, it is important to determine how different heavy metals may interact with BDET, and whether free metals may displace those that are bound. To explore this possibility, Cd-, Cu-, Pb-, Mn-, Hg- and Zn-BDET were leached separately under a nitrogen purge for up to 240 h in pH 3 aqueous solutions containing 0.100 mmol of all five heavy metals. The leaching studies indicate that dissolved Hg has a strong tendency to displace Cd, Cu, Mn, Pb, and Zn from the BDET structure.

Neurophysiological monitoring of cranial nerves during posterior fossa surgery.

Intraoperative neurophysiological monitoring of cranial nerve functions in surgery for microvascular decompression and tumors of the posterior fossa is important for minimizing risk of permanent damage to the nerves. In particular, intraoperative BAEP and the EMG function of muscle innervated by trigeminal and facial muscle have been found useful. We report here our experiences with intraoperative monitoring of brainstem auditory evoked potentials (BAEP) and EMG recorded from muscles supplied by the trigeminal and facial nerves.

Influence of the National Curriculum for Physical Education on inner-city teachers' behaviours associated with pupils' psychosocial development.

This study examined the quality of instruction provided by a sample of teachers working in a depressed urban setting and within the confines of the National Curriculum for Physical Education in terms of use of behaviours related to pupils' psychosocial development. Subjects were 18 specialist physical education teachers working in seven mixed-sex secondary schools in one large city in southeastern England. Two lessons of each teacher's choice, in which they taught any activity to pupils in Years 7, 8, or 9, were videotaped during the summer term of 1996. Lessons were coded with the Coaching Behavior Assessment System, an observational procedure designed to record the rate at which teachers use behaviours positively and negatively associated with pupils' psychosocial development. Descriptive statistics indicated that teachers used behaviours linked with pupils' positive psychosocial development much more frequently than they used behaviours associated with pupils' negative psychosocial development. A comparison of the data collected at these seven urban schools with those collected previously in a rural setting (Curtner-Smith, Kerr, & Hencken, 1995) suggested that, in general, British physical education teachers' behaviours are similar across the locations.

Tailoring the message.

Health care practitioners can learn how to recognize and respond to patient differences. Applying the techniques outlined in this article can improve the kind and depth of information a patient shares, patient satisfaction, patient follow-through, and actual health outcomes.

Coordination of hydroxyquinolines to a ruthenium bis-dimethyl-phenanthroline scaffold radically improves potency for potential as antineoplastic agents.

A series of ruthenium coordination complexes containing hydroxyquinoline ligands were synthesized that exhibited radically improved potencies up to 86-fold greater than clioquinol, a known cytotoxic compound. The complexes were also >100-fold more potent than clioquinol in a tumor spheroid model, with values similar to currently used chemotherapeutics for the treatment of solid tumors. Cytotoxicity occurs through rapid processes that induce apoptosis but appear to be mediated by cell-cycle independent mechanisms. The ruthenium complexes do not inhibit the proteasome at concentrations relevant for cell death, and contrary to previous reports, clioquinol and other hydroxyquinoline compounds do not act as direct proteasome inhibitors to induce cell death.