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Novel pyrazolyl-derived diazonium tetrafluoroborate salts were used in the palladium-catalyzed Heck–Matsuda reaction for the diastereoselective synthesis of highly substituted cyclopenten-ols/-amines.

Prophylactic administration of somatostatin analogues (SA) to reduce the incidence of post-operative pancreatic fistula (POPF) remains contentious. This meta-analysis evaluated its impact on outcomes following pancreaticoduodenectomy (PD). The EMBASE, MEDLINE and Cochrane databases were searched for randomised controlled trials (RCTs) investigating prophylactic SA following PD. Comparative effects were summarised as odds ratio and weighted mean difference based on an intention to treat. Quantitative pooling of the effect sizes was derived using the random-effects model. Twelve RCTs were included involving 1615 patients [SA-treated group (n = 820) and control group (n = 795)]. The SA used included somatostatin-14, pasireotide, vapreotide and octreotide. Pooling of the data showed no significant benefit of its use for the primary outcome measure of all grades of POPF, odds ratio (OR) 0.73 [95% confidence interval (CI), 0.51–1.05, p = 0.09] and clinically relevant POPF, OR 0.48 [95% CI, 0.22–1.06, p = 0.07]. There were no benefits in the secondary outcome measures of delayed gastric emptying, OR 0.98 [95% CI, 0.57–1.69, p = 0.94]; infected abdominal collections, OR 0.80 [95% CI, 0.44–1.43, p = 0.80]; reoperation rates, OR 1.24 [95% CI, 0.73–2.13, p = 0.42]; duration of hospital stay, − 0.23 [95% CI − .59 to 1.13, p = 0.74]; and mortality, 1.78 [95% CI, 0.94–3.39, p = 0.08]. SA did not improve the post-operative outcomes following PD, including reducing the incidence of POPF. The routine administration of SA cannot be recommended following PD.

BackgroundAVT02 is an investigational biosimilar to adalimumab. It is approved in Europe, Canada, and the UK. It is not approved by the US Food and Drug Administration (FDA).ObjectivesTo evaluate the pharmacokinetic similarity of 100 mg/mL AVT02, an investigational biosimilar of adalimumab, when administered either via a pre-filled syringe, or with a newly developed autoinjector in healthy adult subjects.MethodsThis was a Phase 1, randomized, open-label, parallel-group study in which 207 healthy adult subjects were randomized in a 1:1 ratio to receive 100 mg/mL AVT02 either via a pre-filled syringe, or with an autoinjector, stratified by body weight. Subjects received a single subcutaneous 40 mg dose on Day 1. Pharmacokinetics, immunogenicity, local injection site reactions, and adverse events were assessed prior to, and up to 64 days after, study drug administration.ResultsThe results observed supported the assessment of pharmacokinetic similarity of investigational AVT02 administered by pre-filled syringe or with an autoinjector. The 90% CIs for the ratios of geometric least square means for the primary pharmacokinetic parameters Cmax, AUC0-t, and AUC0-∞ were contained within prespecified margins 80% and 125%, based on an analysis of variance model with treatment as a fixed effect. The mean serum concentration-time profile of adalimumab by treatment group is shown in Figure 1.Figure 1.Mean Serum Concentration-Time Profile of Adalimumab by Treatment Group on Semilogarithmic Scale (Pharmacokinetic Population)Binding anti-drug antibodies were detectable at the end of study visit on Day 64 in 100% and 97.0% of subjects in the pre-filled syringe administration and the autoinjector groups, respectively. Of those subjects positive for anti-drug antibodies, 85.7% and 86.5% further tested positive for neutralizing antibodies in the pre-filled syringe administration and autoinjector groups, respectively. The frequency of local administration site reactions was 11.8% overall and similar between treatment groups. The most frequently reported treatment-emergent adverse events in both treatment groups were under the SOC: Infections and infestations (56.0% in the AVT02-pre-filled syringe group and 45.2% in the AVT02-autoinjector group). The safety profiles were generally similar between treatment groups.ConclusionThe results observed supported the assessment of pharmacokinetic similarity between the pre-filled syringe and autoinjector delivery systems after a single subcutaneous 40 mg dose. The autoinjector delivery system was generally well tolerated in healthy subjects, with a safety and immunogenicity profile similar to that observed with 100 mg/mL AVT02 administered using a pre-filled syringe.ClinicalTrials.gov Identifier: NCT03983876Disclosure of InterestsChristopher Wynne: None declared, Heimo Stroissnig Employee of: Alvotech, Roshan Dias Employee of: Alvotech, Joanna Sobierska Employee of: Alvotech, Eric Guenzi Employee of: Alvotech, Hendrik Otto Employee of: Alvotech, Abid Sattar Employee of: Alvotech, Halimu N. Haliduola Employee of: Alvotech, Elin Edwald Employee of: Alvotech, Fausto Berti Employee of: Alvotech

BackgroundAVT02 is an investigational biosimilar to adalimumab. It is approved in Europe, Canada, and the UK. It is not approved by the US Food and Drug Administration (FDA).ObjectivesTo assess the real-life patient handling of an autoinjector (AI) in adult patients with moderate-to-severe active rheumatoid arthritis (RA) who self-inject AVT02 subcutaneously (s.c.).MethodsThis open-label study enrolled 107 adalimumab-naïve subjects with moderate-to-severe active RA to self-inject AVT02 with the proposed AI 40 mg s.c. in Week 1, and every other week thereafter through Week 8. In an optional extension phase through Week 56, subjects were switched from AVT02 AI to pre-filled syringe and followed for safety and efficacy. The primary endpoint was the percentage of successful self-injections as reported by both the trial site and by subjects using standardized questionnaires at Week 8. Additional endpoints included ease of use and robustness of the AI at Week 8, and efficacy in RA, assessment of serum trough levels of AVT02, and detection of antidrug antibodies (ADA) throughout the study.ResultsThe AI success rate was 100% as reported by both the trial site and by subjects. No handling events were noted through Week 8. Approximately 80% (78.1–84.9%) of subjects found the AI ‘very easy’ to use and, in general, less difficulty was reported as the study progressed. The first 110 AIs used were inspected for robustness and none showed any sign of damage or malfunction.All subjects who completed Week 8 (n = 106) took part in and completed the optional extension phase through Week 56.At Week 8, 49.1%, 5.7% and 0.9% subjects achieved ACR20, -50 and -70 responses, respectively. Improvement was also reported for the SDAI, DAS28 CRP and HAQ, with scores consistently decreasing through Week 8. In the extension phase, 70.8%, 47.2% and 13.2% subjects achieved ACR20, -50 and -70 responses at Week 56. Improvement was also reported for the SDAI, DAS28 CRP and HAQ, with scores consistently decreasing through Week 56.From Baseline through Week 8 the mean serum concentrations of investigational AVT02 increased consistently at each visit, reaching a peak at Week 24. There was no significant difference in serum concentrations of AVT02 based on injection subsite (abdomen or thigh).ADAs were detected in 65.1% of subjects through Week 8, reducing to 49.1% by Week 56. Of ADA-positive subjects, most were also positive for neutralizing antibodies through Week 8 (62.3%) increasing through Week 56 (90.4%). Subjects who were ADA-positive had lower serum concentrations of study drug compared with the overall population at Week 8 and Week 56 as expected.There were no clinically relevant safety or tolerability issues. Overall, treatment-emergent adverse events reported in at least 5% of subjects at the PT level were anaemia and influenza (6 subjects [5.6%)] reported 6 events each), and no local ISRs were reported.ConclusionThe fully successful self-injection with the AI in this study supported the use of the device while administering AVT02. Furthermore, subjects typically found the AI easy to use, with ease of use increasing as time progressed.The ACR20, -50, and -70, SDAI, DAS28 CRP and HAQ results supported the use of AVT02 to treat adult patients with moderate-to-severe RA, with the treatment effect persisting beyond Week 8 and through Week 56.The safety and immunogenicity profiles were as expected for adalimumab.ClinicalTrials.gov Identifier: NCT04224194Disclosure of InterestsNemanja Damjanov: None declared, Heimo Stroissnig Employee of: Alvotech, Matjaz Steiger Employee of: Alvotech, Joanna Sobierska Employee of: Alvotech, Eric Guenzi Employee of: Alvotech, Hendrik Otto Employee of: Alvotech, Abid Sattar Employee of: Alvotech, Halimu N. Haliduola Employee of: Alvotech, Elin Edwald Employee of: Alvotech, Fausto Berti Employee of: Alvotech

Made available in DSpace on 2020-12-10T17:35:31Z (GMT). No. of bitstreams: 0 Previous issue date: 2020-07-01 Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP) The study evaluated the effect of gain rates during the growing phase and the possible interaction with finishing phase forage allowance in beef cattle. In Exp. 1, eighty Nellore cattle (386 +/- 7.90 kg; divided into 16 paddocks) were used in a randomized block design in a 2 x 2 factorial arrangement of treatments: (1) gain rate during the growing phase (low and high); (2) forage allowance during the finishing phase (low and high). In Exp. 2, twelve cannulated animals were used to evaluate ruminal parameters at the finishing phase. The animals were supplemented (2% of body weight [BW]) during 112 days. The average forage mass was 6507 and 2712 kg DM/ha, resulting in a forage allowance of 2.91 and 1.31 kg DM/kg BW, respectively, for high and low supply. In Exp. 1, there was interaction among factors (P = 0.01) for average daily gain (ADG): low gain rate animals that were finished on high forage allowance had an ADG 0.203 kg/day greater than average of other treatments (0.917 kg/day). Animals with a high gain rate in the growing phase started the finishing phase 51.5 kg heavier than low gain rate animals; this difference dropped to 35.5 kg in final BW (P < 0.01). In terms of the carcass, this difference was 27 kg at the beginning and dropped to 25 kg at the final carcass weight (P < 0.01). In Exp. 2, the acetate concentration at the end was higher for animals fed high forage allowance compared to low. However, propionate concentration was higher for animals fed low forage allowance compared to high (P = 0.01). Our results showed that the growing phase influences performance during the finishing phase; however, forage allowance with high supplementation at the finishing phase had negligible effects under these experimental conditions. Univ Estadual Paulista, Fac Ciencias Agr & Vet, Via Acesso, BR-14884900 Jaboticabal, SP, Brazil Agencia Paulista Tecnol Agronegocios APTA, Ave Rui Barbosa,Caixa Postal 35, BR-14770000 Colina, SP, Brazil Ctr Univ Fundacao Educ Barretos, Prof Roberto Frade Monte 389, BR-14783226 Barretos, SP, Brazil Univ Estadual Paulista, Fac Ciencias Agr & Vet, Via Acesso, BR-14884900 Jaboticabal, SP, Brazil FAPESP: 2017/50339-5 FAPESP: 2018/20176-0 FAPESP: 2014/05510-0

Anaplastic Astrocytoma(AA) is a malignant, diffusely infiltrating, primary brain tumor. According to the WHO 2016 classification of central-nervous-system tumors, AA has been described as a glial tumor with no co-deletion of 1p/19q, and is divided into IDH mutated tumor, characterized by better prognosis, and IDH wild-type form, with worse prognosis. The standard of care is maximal safe resection followed by radiotherapy and chemotherapy with temozolomide. Several efforts have been made to evaluate, according to molecular selection, which is the best post-surgical treatment. At recurrence, the treatment remains challenging and some trials are ongoing to evaluate new potential drugs, alone or in combination with chemotherapy. We performed a description of the status of the art on diagnosis, molecular characteristics and treatment of AA. In particular, we focused our details on new drugs; indeed, a deeper knowledge of the molecular characteristics of gliomas could lead to to development of active personalized treatments according with precision medicine.

The aim of this trial was to evaluate the effect of encapsulated calcium ammonium nitrate as a partial substitute for soybean meals in the concentrate dry matter intake, average daily gain and feed efficiency of Nellore young bulls under grazing conditions, during the dry season. Sixty-four weaned Nellore (initial BW = 177.46±3.77 kg and 9 mo old) were used in a completely randomized assay. The study lasted 84 days on the dry season. Animals were allotted into 16 paddocks of 1.0 ha each of Urochloa brizantha, randomly assigned into one of two treatments: (CTL) supplement with 25% CP, without nitrate inclusion and; (ENP): supplement with 25% CP, with a inclusion of 50 g of encapsulated calcium ammonium nitrate to each 100 kg of body weight. Animals were fed with concentrate at 1.0% of body weight. Concentrate offered was monitored daily as well as his refusals were collected and weighed to determine daily concentrate dry matter intake (DMI) and feed efficiency (F:G). Animals were weighed every 28 d for calculating average daily gain (ADG). Data were analyzed as a completely randomized design, using ANOVA (α = 0.05). No effects of treatments (P > 0.3487) were observed for final BW (246.69 kg). The same for concentrate dry matter intake (P > 0.0550). Animals consumed 2.34 kg of supplement per day. The average daily gain (0.832 kg, P > 0.2649) and feed efficiency (0.356 kg, P > 0.7315) were not affected by the inclusion of nitrate. The inclusion of encapsulated calcium ammonium nitrate in supplement to Nellore young bulls under grazing conditions during the growing phase did not affect the performance.

Glycoconjugate vaccines play an enormous role in preventing infectious diseases. The main carrier proteins used in commercial conjugate vaccines are the non-toxic mutant of diphtheria toxin (CRM197), diphtheria toxoid (DT) and tetanus toxoid (TT). Modern childhood routine vaccination schedules include the administration of several vaccines simultaneously or in close sequence, increasing the concern that the repeated exposure to conjugates based on these carrier proteins might interfere with the anti-polysaccharide response. Extending previous observations we show here that priming mice with CRM197 or DT does not suppress the response to the carbohydrate moiety of CRM197 meningococcal serogroup A (MenA) conjugates, while priming with DT can suppress the response to DT-MenA conjugates. To explain these findings we made use of biophysical and immunochemical techniques applied mainly to MenA conjugates. Differential scanning calorimetry and circular dichroism data revealed that the CRM197 structure was altered by the chemical conjugation, while DT and the formaldehyde-treated form of CRM197 were less impacted, depending on the degree of glycosylation. Investigating the binding and avidity properties of IgGs induced in mice by non-conjugated carriers, we found that CRM197 induced low levels of anti-carrier antibodies, with decreased avidity for its MenA conjugates and poor binding to DT and respective MenA conjugates. In contrast, DT induced high antibody titers able to bind with comparable avidity both the protein and its conjugates but showing very low avidity for CRM197 and related conjugates. The low intrinsic immunogenicity of CRM197 as compared to DT, the structural modifications induced by glycoconjugation and detoxification processes, resulting in conformational changes in CRM197 and DT epitopes with consequent alteration of the antibody recognition and avidity, might explain the different behavior of CRM197 and DT in a carrier priming context.

The objective was to evaluate the effects of Bacillus toyonensis on performance, carcass traits and its influence on ruminal and intestinal mucosa development of Nellore bulls fed tropical grass pasture on dry season supplemented with concentrate at 2.0% BW for 133 d. Four animals were slaughtered at the beginning of the experiment so that the initial carcass yield could be estimated. Eighty Nellore bulls (initial BW 354.02 ± 3.38 kg) were blocked according to body weight and assigned to one of two treatments: concentrate with Bacillus toyonensis (animals fed 1.6 x 109 UFC/day) or without (control group). Then, the remaining animals were allocated in 16 paddocks of Urochloa brizantha with 1.0 ha each (eight paddocks/treatment and five animals/paddock). At the end of the trial, bulls were slaughtered and carcass traits such as HCW, dressing percentage, 12th-rib fat thickness, carcass gain and carcass ADG were obtained. Tissue from the ventral sac and jejunum were collected and fixed in buffered formalin for evaluation of rumen papillae and intestine villi morphology. Data were analyzed using the GLM procedure of SAS. Paddock was the experimental unit for all analyses. Results indicated there were no significant difference (P > 0.05) between treatments for final BW (528.2 kg), ADG (1.333 kg) and G:F (0.165). No significant differences were detected between treatments for HCW (299.8 kg), dressing percentage (56.82%), and carcass ADG (0.885 kg). Conversely, control group showed a significant (P < 0.025) higher 12th-rib fat thickness (4.06 vs 2.97 mm). No significant effect on the development of the ruminal and intestinal epithelium was observed with the use of probiotic. Probiotic based on Bacillus toyonensis did not improve growth performance and carcass characteristics on finishing Nellore bulls fed tropical grass pasture on dry season.

Patient engagement in a patient–physician decision-making process has been correlated with satisfaction and clinical outcomes. Aim of this study is to evaluate if patient control preference may also influence TKA results. One hundred and seventy-six patients (120w–56m, age 66 ± 9 years, BMI 28 ± 4) underwent TKA and were prospectively evaluated, before surgery and at 6 and 12 months. The preoperative assessment included the Control Preference Scale (CPS) and other scales measuring psychological aspects (STAI, BDI, TSK), as well as SF12 (physical and mental subscales) and the assessment of pain and function. Pain, function, and SF12 subscales were then used to evaluate the improvement at 6- and 12-month follow-up. Pain, function, and SF12 scores improved at 6 and 12 months. CPS correlated with the outcome: pain and functional improvement at 6 months (p = 0.014; p = 0.003, respectively), patient function at 6 months (p = 0.022), improvement of SF12 physical subscale at 6 and 12 months (p = 0.027; p = 0.037, respectively), and satisfaction at 6 months (p = 0.033). Moreover, the multivariate analysis confirmed the importance of CPS regardless of other demographic, physical or psychological characteristics. In contrast with previous literature findings, this study shows that patients with more propensity for control presented lower improvements of pain and function than those more prone to rely on the physician making the decision. Physicians should be aware that the patient control preference may influence the treatment outcome and undertake measurements to optimize patient participation in the shared process to optimize the chances of TKA success. IV.

A 72-year-old woman who developed a left temporal protrusion was referred to our center. An MRI showed a heterogeneous mass in the left temple with T2 signal hyperintensity within the intradiploic space of the greater wing of the sphenoid bone, measuring 2.4 x 2.1 cm. The patient underwent a surgical removal of the mass through the pterional approach. Pathology showed an epidermoid cyst. Intradiploic epidermoid cysts of the skull are rare benign tumors of the skull. These lesions grow slowly and are composed of epidermoid cells debris rich in cholesterol. The prophylactic removal of these tumors with the goal of preventing recurrences is recommended.

Medulloblastoma in adulthood is uncommon but not rare; annual incidence is 2-20/1,000,000. Some peculiarities characterize medulloblastoma in adult patients compared with the child type: lateral cerebellar location, heterogeneous signal intensity on magnetic resonance imaging, desmoplastic histological variant, and more favourable prognosis. Preoperative diagnosis is crucial for correct management of these patients. However, because of the low incidence of medulloblastoma in the adult population, preoperative diagnosis remains challenging and prognostic factors and best treatment options are still controversial. In this setting, some unusual findings, for example multifocal presentation and extra-axial location, can confound diagnosis and make treatment difficult. We present a short case-illustrated review on these remarkable issues.

Prevalence of symptomatic central nervous system (CNS) metastases among patients with breast cancer ranges from 5% to 16%, although autoptic studies have reported prevalence rates of up to 30%. Solid brain tumours are the most common presentation in the CNS (85-95%), and they tend to arise at the grey-white matter junction with a distribution that is proportional to the regional cerebral blood flow. Descriptions of solitary intra-ventricular metastasis are very rare; to date no cases from breast cancer have been reported in the literature. We present the unusual case of a breast cancer patient who developed a solitary choroid plexus metastasis in the left lateral ventricle.

PURPOSE A morphofunctional approach to the management of brain tumours has been claimed to increase diagnostic accuracy. Among the proposed single-photon emission tomography (SPET) tracers, (99m)Tc-sestamibi is able to distinguish recurrent tumour from radio-necrosis and to identify early response or resistance to chemotherapy. Major drawbacks of sestamibi, that is, poor morphological resolution and the sites of physiological uptake, could be overcome by dual-modality, integrated systems. The purpose of this study was to investigate the real usefulness of (99m)Tc-sestamibi SPET/computed tomography (CT) and to establish a semiquantitative index. METHODS Charts from 33 consecutive patients selected for surgery, who underwent preoperative SPET/CT and magnetic resonance imaging (MRI), were reviewed. Tumours were confirmed histologically after the surgery in all patients and classified according to WHO recommendations. Semiquantitative indexes were obtained on images (maximum likelihood expectation maximization reconstructed) with and without attenuation correction and visual analysis of SPET versus SPET/CT was performed. RESULTS A significant statistical difference was shown between SPET and SPET/CT in terms of the delineation of medial shift, oedema and the ability to distinguish tumour from the skull-meninges complex and plexus. With regard to semiquantitative indexes, a ratio obtained comparing counts/pixel derived from a region of interest in the tumour area with mirrored region of interest in the contralateral site revealed a sensitivity of 90.9% and specificity of 71.45% in discriminating WHO grade 4 gliomas from a lower grade. CONCLUSION SPET/CT can distinguish tumour from the skull and other sites of physiological uptake better than SPET alone (as confirmed by MRI in all cases) and affords a morphological map. The proposed semiquantitative index also seems promising in identifying higher-grade disease. SPET/CT thus seems a useful additional tool in brain tumour management, especially when MRI is not feasible or PET/CT is not available.

The increase in soybean productivity has contributed to a greater use of agrochemicals, which cause major problems, such as soil and water pollution and reduction of biodiversity, and have a negative impact on non-target species. The development of microbial biocontrol agents for soybean diseases can help to reduce pesticide abuse. Bacillus amyloliquefaciens BNM122 is a potential microbial biocontrol agent able to control the damping-off caused by Rhizoctonia solani when inoculated in soybean seeds, both in a plant growth chamber and in a greenhouse. In this study, we report the effect of soybean seed treatments with strain BNM122 or with two fungicides (thiram and carbendazim) on the structure and function of the bacterial community that colonizes the soybean rhizosphere. Also, soybean root nodulation by Bradyrhizobium japonicum , mycorrhization by arbuscular mycorrhizal fungi and plant growth were evaluated. We used the r - and K -strategist concept to evaluate the ecophysiological structure of the culturable bacterial community, community-level physiological profiles (CLPP) in Biolog™ EcoPlates to study bacterial functionality, and the patterns of 16S RNA genes amplified by PCR and separated by denaturing gradient gel electrophoresis (PCR–DGGE) to assess the genetic structure of the bacterial community. Neither the ecophysiological structure nor the physiological profiles of the soybean rhizosphere bacterial community showed important changes after seed inoculation with strain BNM122. On the contrary, seed treatment with fungicides increased the proportions of r -strategists and altered the metabolic profiles of the rhizosphere culturable bacterial community. The genetic structure of the rhizosphere bacterial community did not show perceptible changes between treated and non-treated seeds. Regarding the bacterial and fungal symbioses, seed treatments did not affect soybean nodulation, whereas soybean mycorrhization significantly decreased ( P It can be concluded that soybean seed treatment with B. amyloliquefaciens BNM122 had a lesser effect on soil microbial community than that with the fungicides, and that these differences may be attributed to the less environmental persistence and toxic effects of the strain, which deserve further studies in order to develop commercial formulations.

We present the case of a 57 year-old-right handed man with a history of alopecia presented with a visual loss, and an acute stroke of the left anterior cerebral artery and middle cerebral after scalp injection of platelet rich plasma (PRP) and stem cells for hair restoration.

The efficacy of temozolomide (TMZ) plus radiation therapy (RT) in elderly patients with glioblastoma is unclear. We performed a large multicenter retrospective study to analyze prognostic factors and clinical outcome in these patients. Inclusion criteria were age ≥65 years, newly histologically confirmed glioblastoma, ECOG PS 0-2, adjuvant treatment with RT plus TMZ. We enrolled 237 patients; the average age was 71 and ECOG PS was 0-1 in 196 patients; gross total resection was performed in 174 cases. MGMT was analyzed in 151 persons and was methylated in 56 %. IDH1 was assessed in 100 patients and was mutated in 6 %. Seventy-one patients were treated with RT 40 Gy and 166 with RT 60 Gy. Progression-free survival and overall survival (OS) were 11.3 and 17.3 months, respectively. Overall survival was 19.4 vs 13.8 months for patients treated with RT 60 Gy and 40 Gy (p = 0.02); OS was 17.7 versus 16.1 months for patients treated with gross total resection vs partial surgery (p = 0.02); OS was 21.2 versus 13.6 months for methylated and unmethylated MGMT (p < 0.001). On multivariate analysis, gross total resection, RT 60 Gy, methylated MGMT and ECOG PS 0-1 were independent predictors of longer survival. Twenty-five patients (10 %) had grade 3-4 haematological toxicity during the concomitant treatment. We showed that, in elderly patients in good clinical condition treated with concomitant treatment, standard-course irradiation might be more effective than short-course irradiation. Methylated MGMT remains the most important prognostic factor.

Background: various prospective clinical trials on high-grade gliomas were performed in the last years but patient (PTS) characteristics and outcome may be different in real clinical practice. We performed a retrospective analysis to evaluate the real-life experience in Padua Neuro-Oncology center. Matherials and Methods: retrospectively, we reviewed the medical records of PTS admitted to our observation from June 2010 to June 2015 with a diagnosis of AA or GBM. We analyzed clinical outcome with prognostic factors. Results: we analyzed 592 PTS with a diagnosis of CNS primary tumor. Among these, we enrolled 395 PTS: 33 (8.4%) with a histological diagnosis of AA, 293 (74%) with a histological diagnosis of GBM and 69 (17.4%) with a radiological diagnosis of GBM. At diagnosis, median age was 63.2 (range 24-88), 61.8% were male; 80% of PTS had an ECOG PS 0-2. Among PTS who underwent surgery, 48% had a radical surgery; 279 PTS (70.6%) performed RT in association to chemotherapy. 17% of PTS performed a second surgery at relapse and 45% a second-line treatment. MGMT was analyzed in all PTS who underwent surgery: it was methylated in 38.7% of PTS, IDH1 was mutated in 6%. GBM PTS with ECOG PS 0-2 and >2 had a median OS of 21.1 and 7.2 ms, respectively. GBM PTS with met and unmet MGMT had a mOS of 22.7 and 13.7 ms (p=0.005). AA PTS with met and unmet MGMT had a mOS of 29.5 and 16.6 ms (p=0.03). Considering all high-grade gliomas, PTS with met MGMT + mutIDH1 reported a mOS of 23.1ms, PTS with metMGMT + wtIDH1 had a mOS of 20.9 ms and PTS with unmetMGMT + wtIDH1 showed a mOS of 12.6ms (p

Background: MGMT gene promoter methylation status is acknowledged as a prognostic factor and predictive marker for temozolomide (TMZ) treatment. Although MGMT status determined by pyrosequencing was showed to correlate with progression free survival (PFS) and overall survival (OS), it is still unclear a cut-off value that discriminates between methylated and unmethylated patient (pts) and its correlation with the patient clinical outcome. Matherials and Methods: We analyzed the tissue samples from 128 PTS diagnosed with GBM from November 2009 to December 2015. All PTS underwent treatment with RT + TMZ and had an ECOG-PS 0-2. Methylation percentage for each sample was obtained by calculating the average methylation of all 10CpG sites (75-84) of MGMT promoter by pyrosequencing analysis. PTS with 0-6% of methylation were classified as unmethylated (UM), PTS with 7-24% as low methylated (LM) and PTS with ≥ 25% as high methylated (HM). 25% was the median value of methylation of our PTS having >6% of methylation. Results: Median age was 60 yrs (range 25-84), 60.9% were male, 74.2% had an ECOG PS 0-1, 50.8% underwent radical surgery, 85 PTS were dead at the time of analysis. 75 PTS were UM, 26 PTS were LM and 27 PTS were HM. On univariate analysis HM, LM and UM showed a PFS of 15.8, 10 and 9.1 ms, respectively (p=0.1). OS was 38.7, 21 and 18.8ms (p= 0.06). On multivariate analysis UM and LM PTS had a statistically lower PFS vs HM PTS (HR=2.57; p=0.001; HR= 2.5; p=0.007, respectively) and statistically lower OS (HR=3.47; p

Summary Background To investigate the efficacy of temozolomide in relation to response rate, toxicity, time to progression, and median survival time, a phase II study was conducted in patients with recurrent high-grade glioma following surgery plus radiotherapy and first-line chemotherapy based on nitrosourea, procarbazine and vincristine. Patients and methods Forty-one patients with high-grade glioma, at second recurrence or progression, of which twenty-two (54%) had glioblastoma multiforme, ten (24%) anaplastic astrocytoma, and nine (22%) anaplastic oligodendroglioma were administered temozolomide, 150 mg/m2/daily for five days every four weeks. Results Response was assessed in 40 patients. The overall response rate (complete + partial response) was 22.5% (95% confidence interval (CI): 9.5%–35%). The median time to progression for all 41 patients was 22.3 weeks; progression-free survival at 6 and 12 months was 48.5% and 34.7%, respectively. Median survival time was 37.1 weeks with 80.2% at 6 and 34.9% survival at 12 months. Conclusions On multivariate analysis, response to previous treatment was significant (P = 0.03) for time to progression and Karnofsky performance score for overall survivall (P = 0.002). Temozolomide gave a moderate response rate with acceptable toxicity as second-line chemotherapy in patients with recurrent high-grade glioma.

OBJECTIVE: IGF-I possesses specific myocardial receptors and is able to promote cardiac remodelling and even inotropic effects in both humans and other animals. In fact, reduced cardiac mass and performance are present in GH deficiency and these alterations are counteracted by recombinant human (rh) GH replacement, restoring IGF-I levels. Recently, the acute administration of 60 microg/kg rhIGF-I has also been reported to be able to improve cardiac performance evaluated by echocardiography or impedance cardiography in normal subjects. The aim of our study was to verify the effects of a subcutaneous low dose of rhIGF-I (20 microg/kg) on cardiac performance in humans. METHODS: In six healthy male adults (mean+/-S. e.m.: 35.7+/-4.3 years of age), the effects of rhIGF-I on left ventricular function evaluated by radionuclide angiocardiography and on circulating IGF-I, GH, insulin, glucose and catecholamines levels were studied. RESULTS: Administration of rhIGF-I increased circulating IGF-I (peak at +150 min vs baseline: 330.2+/- 9.6 vs 199. 7+/-8.7 microg/l, P

Vitiligo represents a selective destruction of the melanocytes. It is a relatively common, probably autoimmune disorder that affects people of all backgrounds and both genders. No particular group seems to be preferentially affected. Half of vitiligo patients have an onset before the age of 18 years. In regions where leprosy is endemic, individuals with vitiligo are often stigmatized due to similarities in appearance between the two diseases. We will review this important subject, emphasizing the latest therapeutic advances.

High-grade gliomas (HGG) are aggressive and highly vascularized brain tumours. Despite multimodality therapy including surgery, radiation therapy and in many cases temozolomide chemotherapy, the prognosis is dismal. Salvage therapies following progression after radiation therapy and chemotherapy have historically yielded disappointing results. Bevacizumab is an interesting antiangiogenic drug used as a second-line treatment but although most patients benefit, essentially all patients ultimately progress. Moreover, some clinical studies have documented low activity of a second attempt at vascular endothelial growth factor pathway inhibition after failure of a first. The use of another drug with a different angiogenic pathway inhibition may probably result in a higher activity. Here, we describe, to our knowledge for the first time, the activity and safety of cilengitide, an agent with a different antiangiogenic and anti-invasive activity, administered in two bevacizumab-refractory patients with HGG. In addition, we present a rapid review of the activity of cilengitide in HGG.

Summary The present work reports the synthesis of a series of compounds structurally related to the antiinflammatory and antihistaminic agent nimesulide (I), in which the p-nitrophenyl moiety has been replaced by pyridine (1a-c) and pyridine N-oxide (2a-c). In addition, two compounds (3a, 4a) have been synthesized in which the p-nitro group of I was substituted by a cyano and a iH-tetrazol-5-yl group, respectively. Representative 1a and 2a were also modified by replacing the methanesulfonamido group with an acetamido group (5a, 6a). The pharmacological evaluation of compounds 1-6 in comparison to I, indicates that such modifications are detrimental to the activity. Moreover 3a and 4a caused bronchoconstriction and hypotension, thus behaving as histaminic-like rather then antihistaminic agents.

OBJECTIVE: To investigate the pattern of care and outcomes for newly diagnosed glioblastoma in Italy and compare our results with the previous Italian Patterns of Care study to determine whether significant changes occurred in clinical practice during the past 10 years. METHODS: Clinical, pathological, therapeutic, and survival data regarding 1059 patients treated in 18 radiotherapy centers between 2002 and 2007 were collected and retrospectively reviewed. RESULTS:Most patients underwent both computed tomography and magnetic resonance imaging either preoperatively (62.7%) or postoperatively (35.5%). Only 123 patients (11.6%) underwent a biopsy. Radiochemotherapy with temozolomide was the most frequent adjuvant treatment (70.7%). Most patients (88.2%) received 3-dimensional conformal radiotherapy. Median survival was 9.5 months. Two- and 5-year survival rates were 24.8% and 3.9%, respectively. Multivariate analysis showed the statistical significance of age, postoperative Karnofsky Performance Status scale score, surgical extent, use of 3-dimensional conformal radiotherapy, and use of chemotherapy. Use of a more aggressive approach was associated with longer survival in elderly patients. Comparing our results with those of the subgroup of patients included in our previous study who were treated between 1997 and 2001, relevant differences were found: more frequent use of magnetic resonance imaging, surgical removal more common than biopsy, and widespread use of 3-dimensional conformal radiotherapy + temozolomide. Furthermore, a significant improvement in terms of survival was noted (P < .001). CONCLUSION: Changes in the care of glioblastoma over the past few years are documented. Prognosis of glioblastoma patients has slightly but significantly improved with a small but noteworthy number of relatively long-term survivors.

Psoas abscess following spine surgery is a rare condition that can be overlooked or delayed as a result of its vague clinical manifestations. Gone unchecked, it can lead to severe morbidity and even death. We present a 71-year-old female patient who developed bilateral psoas abscess immediately following L2 through S1 posterior instrumented fusion. The patient underwent CT-guided percutaneous drainage of the bilateral psoas abscess and blood cultures revealed methicillin-resistant Staphylococcus aureus (MRSA) sensitive to vancomycin. Following surgical re-exploration, debridement and removal of part of the instrumentation, the patient received antibiotic treatment for 12 weeks and at 1-year follow-up the patient continues asymptomatic.

In three general medical settings (general practice, hospital medical wards and emergency rooms) about 20% of the adult attenders had a DSM-III mental disorder, mainly in the area of affective and anxious disorders. Some of these disorders were quite severe. Of those cases reassessed 1 year and 2 years after the first interview, less than a quarter reached a "no-diagnosis status". The chronicity of most cases dependent on the interplay not only of either relapse or duration of the main disorder but also of comorbidity and incidence of new disorders. A high incidence of more transient disorders in subjects who were well at first assessment was also found.

Hydrogen sulphide (H(2)S) is an endogenous gaseous mediator active in the multilevel regulation of pathophysiological functions in mammalian cardiovascular tissues.This study investigated the pharmacological activity of a new H(2)S-releasing derivative of diclofenac, S-diclofenac (2-[(2,6-dichlorophenyl)amino]benzeneacetic acid 4-(3H-1,2-dithiole-3-thione-5-yl)-phenyl ester) in the isolated rabbit heart submitted to low-flow ischaemia-reperfusion damage.S-diclofenac (3, 10 and 30 microM), despite inhibiting prostacyclin generation by cardiac tissues, achieved dose-dependent normalization of coronary perfusion pressure, reducing left ventricular contracture during ischaemia and improving left ventricular developed pressure and +/-dP/dt(max) at reperfusion. Creatine kinase and lactate dehydrogenase activities in heart perfusates were significantly reduced during reperfusion. These effects were accompanied by substantial release of reduced glutathione (GSH), indicating that the H(2)S moiety may have up-regulated cysteine transport. The anti-ischaemic activities of S-diclofenac and the H(2)S-donor sodium hydro sulphide (NaHS) were partially prevented by the K(ATP) channel antagonist glibenclamide, suggesting a mechanism similar to H(2)S-induced cardioprotection in metabolic ischaemic preconditioning. Perfusion with the nitric oxide (NO) synthase inhibitor N(G)-monomethyl-L-arginine worsened the myocardial ischaemia-reperfusion damage, but this was dose-dependently prevented by S-diclofenac and NaHS, suggesting that the released H(2)S may have overcome NO deficiency.These data show that S-diclofenac had marked anti-ischaemic activity in ischaemic-reperfused rabbit hearts despite inhibition of prostaglandin generation. Increased GSH formation leading to activation of K(ATP) channels may have contributed to this beneficial effect. The pharmacological profile of S-diclofenac and its anti-inflammatory activity, with diminished gastrointestinal side effects, offer therapeutic applications in cardiovascular disease.

Phosphodiesterase-5 inhibitors are beneficial in pulmonary hypertension and congestive heart failure, the two conditions associated with coronary heart disease and ischaemia. We investigated whether sildenafil counteracts the cardiovascular alterations induced by N -nitro-L-arginine methyl ester (L-NAME) in the rat.Sildenafil was given orally to rats at doses of 0.37, 0.75 or 1.5 mg kg-1day-1 for four weeks, either alone or with L-NAME (35-40 mg kg-1 day-1 in the drinking water). Systolic blood pressure and urinary parameters (6-keto-prostaglandin F1alpha, thromboxane B2, 8-isoprostane-prostaglandin F2 and nitrite/nitrate) were measured in conscious rats. Isolated hearts were subjected to low flow ischaemia-reperfusion, and myocardial levels of guanosine 3', 5'cyclic monophosphate (cGMP) were determined. Endothelial vascular dysfunction was examined in aortic rings.Sildenafil dose-dependently prevented the rise in systolic blood pressure in L-NAME-treated rats. This activity was associated with a normalization of urinary 8-isoprostane-prostaglandin F2alpha and other biochemical parameters. In perfused hearts, the post-ischaemic ventricular dysfunction was worse in preparations from L-NAME-treated rats than in controls. Sildenafil dose-dependently reduced this effect, and creatine kinase and lactate dehydrogenase release were lower too. cGMP levels, which were low in myocardial tissue from L-NAME-treated rats, were restored by sildenafil. In noradrenaline-precontracted aortic rings from L-NAME-treated rats acetylcholine lost its vasorelaxant effect, and sildenafil restored it.In a rat model of chronic nitric oxide deprivation, where hypertension and aggravation of post-ischaemic ventricular dysfunction are associated with loss of vascular endothelium-relaxant function, sildenafil provided significant cardiovascular protection, primarily by maintaining tissue cGMP levels.

Since the early 1970s, increasing evidence has suggested that the consumption of moderate amounts of alcohol is inversely correlated with mortality from myocardial infarction. There is also some evidence that the protective effects of wine might be more pronounced than those of other alcoholic beverages. These observations prompted us to investigate the cardioprotective activity of Vitis vinifera seeds in experimental ischemia-reperfusion injury. An isolated rabbit heart preparation paced electrically was used to evaluate the effects of a highly purified, high molecular weight fraction of oligomeric procyanidins isolated from Vitis vinifera seeds on myocardial reperfusion injury after 40 min of low-flow (1 ml/min) ischemia. Infusion of the heart with 100 or 200 microg/ml procyanidins dose-dependently reduced left ventricular end-diastolic pressure during ischemia, decreased coronary perfusion pressure, improved cardiac mechanical performance upon reperfusion, increased the release of 6-Keto-prostaglandin F1alpha into the perfusate in both the preischemic and the reperfusion periods and suppressed rhythm irregularity. Procyanidins dose-dependently relaxed human internal mammary aortic (IMA) rings (with intact endothelium) precontracted with norepinephrine. This effect was completely abolished in IMA-rings without functional endothelium or when this vascular tissue was pretreated with nitric oxide synthase inhibitor (NG-monomethyl-L-arginine) or with guanylate cyclase inhibitor (1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one). In conclusion, these results indicate that procyanidins could be of therapeutical potential in cardiovascular diseases. However, further investigations are required for a better definition of the mode of action of these oligomers.

Background: The initial studies on nitrosoureas were performed >30 years ago. These drugs remain the standard chemotherapy for glioblastoma. However, because the criteria used to evaluate the activity of nitrosoureas in a neuro-oncologic setting have changed, new data on their activity are needed. Methods: The authors conducted a phase II study on 40 patients with recurrent glioblastoma following surgery and standard radiotherapy. They analyzed progression-free survival at 6 months (PFS-6), time to progression (TTP), response rate, and toxicity. Patients were treated with 80 mg/m 2 carmustine on days 1 to 3, every 8 weeks for a maximum of six cycles. Results: Median TTP was 13.3 weeks (95% CI, 10.26 to 16.86 weeks), and PFS-6 was 17.5% (95% CI, 8.9 to 34.3). Response to chemotherapy, age ≤40 years, and performance status ≥90 were significant prognostic factors for TTP; however, with multivariate analysis, only response to chemotherapy was significant. The major side effects were reversible hematologic and long-lasting hepatic and pulmonary toxicity. Conclusion: The activity of this BCNU regimen is comparable with that reported in the past and with the newest therapies, such as temozolomide. However, BCNU toxicity is high and recovery is slow, thus compromising the administration of further drugs in patients with progressive disease.

Purpose To assess in a prospective trial the value of prognostic factors and the outcome of medulloblastoma in adults. Methods and materials Patients (≥18 years) with a histologic diagnosis of medulloblastoma were staged according to Chang et al. 's classification (low risk: T1, T2, T3a, M0, and no residual disease after surgery; high risk: T3b–T4, any M+ or postoperative presence of residual tumor). In low-risk patients, treatment consisted of 36 Gy to the craniospinal axis, supplemented by a local tumor dose of 18.8 Gy (total dose of 54.8 Gy). In high-risk patients, 2 cycles of “up-front chemotherapy” were delivered before the same radiation therapy, followed by maintenance chemotherapy if M1, M2, or M3 disease was present. Results Over a 12-year period, 36 evaluable patients were enrolled. Progression-free survival (PFS) at 5 years was higher in low-risk patients compared to the high-risk group: 76% ± 14% (95% confidence interval [CI] = 52%–100%) vs. 61% ± 11% (95% CI = 42%–87%). Patients with M− disease showed a significantly better outcome than M+ patients, with 75% showing PFS at 5 years vs. 45% ( p = 0.01). Conclusions The overall PFS observed is comparable to that obtained in pediatric series and suggests that a more effective therapy must be developed for high-risk patients.

Aim: The efficacy of temozolomide(TMZ) plus radiation therapy(RT) in elderly patients(EP) with glioblastoma(GBM) is unclear. We describe our experience of combining RT with concurrent TMZ in EP. Methods: Medical records of patients ≥65 years old with newly GBM, histologically confirmed and treated at Venetian Institute of Oncology – Padua, were reviewed. Concomitant TMZ was 75mg/m2/die. The adjuvant treatment consisted of TMZ 150-200mg/m2/die for six cycles. Results: We analyzed 67 consecutive patients(PTS), 35 males and 32 females; the average age was 71 (range 65-86); ECOG PS was 0-1 in 37 PTS and 2-3 in 30 PTS; complete surgery was performed in 41 PTS, partial surgery in 24 PTS. MGMT was analyzed in 46 PTS: methylated(met) MGMT in 21 PTS (46%). 36 PTS were treated with RT 40Gy in 15 fractions, 23 PTS with RT 60Gy in 30 fractions, 8 PTS with only TMZ. For all PTS, PFS and OS was 7 and 12.4 ms, respectively. PFS was 7.2 vs 6.7 ms (p = 0.5), OS was 11.9 vs 13.8 ms (p = 0.3), for PTS treated with RT 40Gy and 60Gy, respectively. PFS was 7.2 vs 4.5 ms (p = 0.04), OS was 13 vs 7.3 ms (p Conclusions: RT plus TMZ is effective and safe in EP with GBM. RT + TMZ treatment seems more effective than only TMZ. PFS and OS were not statistically different between RT 40Gy or 60Gy. RT + TMZ treatment and met MGMT were independent predictors of longer survival. In contrast, severe haematological toxicity was higher in PTS with RT + TMZ compared to TMZ alone. Disclosure: All authors have declared no conflicts of interest.

NCX 4016, a nitro-ester of aspirin endowed with antithrombotic activity, appears to have clinical potential in treating cardiac complications related to coronary insufficiency. This compound has been shown to improve postischemic ventricular dysfunction and to reduce myocardial infarct size in the rabbit. The cardioprotection conferred by NCX 4016 (10, 30, and 100 mg/kg) and aspirin (ASA, 54 mg/kg) was evaluated in anesthetized rats subjected to 30 min of myocardial ischemia followed by 120 min of reperfusion (MI/R). Drugs were given orally for 5 consecutive days. NCX 4016 displayed remarkable cardioprotection in rats subjected to MI/R as was evident in the reduction of ventricular premature beats and in the incidence of ventricular tachycardia and fibrillation; they were reduced dose dependently and correlated with survival of all rats treated with the higher dose of NCX 4016. In these animals, infarct size was restricted proportionally to the dose of NCX 4016 associated with diminution of both plasma creatine phosphokinase and cardiac myeloperoxidase activities. ASA showed only a minor degree of protection against MI/R damage. Rats treated with N(G)-nitro-L-arginine methyl ester (L-NAME, 10 mg/kg) demonstrated aggravated myocardial damage in terms of arrhythmias, mortality, and infarct size. Supplementation of nitric oxide (NO) with NCX 4016 (100 mg/kg) greatly reduced the worsening effect caused by L-NAME. The beneficial effects of NCX 4016 appear to derive in large part from the NO moiety, which modulates a number of cellular events leading to inflammation, obstruction of the coronary microcirculation, arrhythmias, and myocardial necrosis.

A new family of nitroderivatives of conventional non-steroidal anti-inflammatory drugs capable of releasing nitric oxide has been synthesized. Among these compounds, a nitroderivative of aspirin (NCX 4016), which displays antiplatelet and vasodilating activities, appears to have clinical potential in cardiac pathology related to coronary insufficiency.In this study the beneficial effects of NCX 4016 and aspirin were evaluated in vitro in a model of myocardial ischemia-reperfusion of the rabbit and in vivo in a model of acute myocardial infarction of the same animal species.The NCX 4016 (from 1 x 10(-5) M to 3 x 10(-4) M) caused dose-dependent cardiac protection in isolated rabbit hearts subjected to low flow ischemia-reperfusion. Inhibition of 6-keto-prostaglandin F1alpha (6-keto-PGF1alpha) generation and proportional reduction of creatine kinase (CK) activity at reperfusion was observed. Aspirin (1 x 10(-4)M) markedly worsened the post-ischemic ventricular dysfunction and this event was paralleled by a 63% increase in CK activity and abolition of 6-keto-PGF1alpha formation. Perfusion of the hearts with NG-monomethyl-L-arginine (1 x 10(-5) M) worsened the ischemia-reperfusion damage in perfused hearts. This event was prevented by prior treatment with NCX 4016 (1 x 10(-4) M) but not with aspirin (1 x 10(-4) M). Ligation of the first antero-lateral branch of the left coronary artery in rabbits resulted in acute myocardial infarction with a mortality rate of 60% at 24 hours. NCX 4016 (0.5 mg/kg/min for 2 hours) significantly reduced the mortality rate by 10%, protected the rabbits against electrocardiogram derangement and almost abolished CK activity in plasma and myeloperoxidase activity in cardiac tissue. Aspirin was devoid of any protective activity.In the rabbit NCX 4016 appears to exert a relevant cardioprotection likely mediated by nitric oxide donation. These results suggest that this nitroderivative of aspirin may lead to innovative therapy in myocardial ischemia and infarction.

This study investigates the microvascular permeability changes in tracheal tissue of rats exposed to hyperbaric oxygen (HBO). Rats, following exposure to HBO or ambient air (control animals) for 1.5, 3 and 6 h, were prepared for recording of nitric oxide exhaled (FENO) in air using a chemiluminescence analyser. The level of FENO was not statistically different in the two groups. Plasma exudation, evaluated by measuring the leakage of Evans blue (EB) dye into the tracheal tissue, was significantly elevated (48, 86 and 105% at 1.5, 3 and 6 h, respectively) in HBO-treated rats. Plasma exudation in the trachea of control rats was significantly increased (42%, P0.05) by NG-nitro-L-arginine methyl ester (L-NAME), whereas it was significantly reduced (31%, P0.05) in rats exposed to HBO for 3 h. N-acetylcysteine (NAC) and flunisolide significantly prevented the increase in plasma leakage in HBO-treated rats. In contrast, indomethacin was devoid of anti-exudative activity in these experiments. Western immunoblot showed a significant increase in the level of inducible nitric oxide synthase (iNOS) protein in the tracheal homogenates of HBO-treated rats, as compared to basal levels. These results indicate that nitric oxide (NO) is involved in the maintenance of microvascular permeability in tracheal tissue of rats. The protective effect observed with the steroid seems to support this hypothesis. Furthermore, the beneficial action of NAC underlines that reactive oxygen species participate in the microvascular permeability changes observed in tracheal tissue of rats exposed to HBO.

PURPOSE: A phase II study was conducted in patients with high-grade gliomas that recurred after surgery plus radiotherapy and a first-line nitrosourea-based regimen. Our aim was to investigate the efficacy of procarbazine (PCB) combined with high-dose tamoxifen in relation to tumor control, toxicity, and time to progression (TTP). PATIENTS AND METHODS: Fifty-three patients were treated with procarbazine in repeated 30-day courses at 100 mg/m2/d plus tamoxifen 100 mg/d, with a 30-day interval between courses. Thirty-four patients had been pretreated with a first-line nitrosourea-based chemotherapy regimen (group A), and 19 patients had also been pretreated with a second-line chemotherapy regimen consisting of carboplatin and teniposide (group B). Twenty-one of the patients had also been procarbazine pretreated, whereas the remaining 32 patients were not procarbazine pretreated. RESULTS: The response was assessed in 51 patients, 28 of whom had glioblastoma multiforme (GBM) and 23 of whom had anaplastic astrocytoma (AA). There were two complete responses (CR) (4%) and 13 partial responses (PR) (25.5%). The overall response rate (CR + PR) was 29.5% (SE, 6.4; 95% confidence interval [CI], 23 to 35.8). Seventeen patients (32%) had stable disease (SE, 6.2; 95% CI, 21 to 33.6). The median TTP was 13 weeks for patients with GBM and 33 weeks for patients with AA (P = .006). The median survival time (MST) was 27 weeks for patients with GBM and 57 weeks for those with AA (P = .006). CONCLUSION: Combined PCB and tamoxifen as a second-line regimen gave a reasonably high response rate in patients with heavily pretreated high-grade gliomas. However, although it resulted in an improvement in the patients' quality of life and/or performance status, it was not followed by an increased TTP or MST.

1. Starting from the structure of an old 4-oxystilbene derivate with ganglioplegic activity (MG624), we synthesized two further derivates (F2 and F3) and two stereoisomers of F3 (F3A and F3B), and studied their selective effect on neuronal nicotinic acetylcholine receptor (AChR) subtypes. 2. MG 624, F3, F3A and F3B inhibited of 125I-alphaBungarotoxin (alphaBgtx) binding to neuronal chick optic lobe (COL) membranes, with nM affinity, but inhibited 125I-alphaBgtx binding to TE671 cell-expressed muscle-type AChR only at much higher concentrations. 3. We immobilized the alpha7, beta2 and beta4 containing chick neuronal nicotinic AChR subtypes using anti-subunit specific antibodies. MG 624, F3, F3A and F3B inhibited 125I-alphaBgtx binding to the alpha7-containing receptors with nM affinity, but inhibited 3H-Epi binding to beta2-containing receptors only at very high concentrations (more than 35 microM); their affinity for the beta4-containing receptors was ten times more than for the beta2-containing subtype. 4. Both MG624 and F3 compounds inhibited the ACh evoked currents in homomeric oocyte-expressed chick alpha7 receptors with an IC50 of respectively 94 and 119 nM. 5. High doses of both MG 624 and F3 depressed the contractile response to vagus nerve stimulation in guinea pig nerve-stomach preparations although at different IC50s (49.4 vs 166.2 microM) The effect of MG624 on rat nerve-hemidiaphragm preparations was 33 times less potent than that of F3 (IC50 486 vs 14.5 microM). 6. In conclusion, MG624 and F3 have a high degree of antagonist selectivity for neuronal nicotinic alphaBgtx receptors containing the alpha7 subunit.

The ability of hexarelin, a recently synthesized hexapeptide with a remarkable growth hormone (GH)-releasing activity, to reverse signs of cardiovascular dysfunction in GH-deficient animals was studied in young male rats made GH deficient by the administration of an anti-GH-releasing hormone serum (GHRH-Ab) for 20 days. Heart preparations from GHRH-Ab treated rats, subjected to low-flow ischemia and reperfusion, showed: a progressive increase of left ventricular end-diastolic pressure during the ischemic period and a poor recovery of contractility at reperfusion as compared to control hearts; a decreased rate of formation of 6-keto-PGF1 alpha, the stable metabolite of prostacyclin, in perfusates of both preischemic and reperfusion period; an increased vasopressor activity of angiotensin II on the coronary vasculature. The endothelium-dependent relaxing function in GH-deficient rats was also evaluated in aortic ring preparations, which showed: a decreased rate of formation of 6-keto-PGF1 alpha, an hyperreactivity to endothelin-1, a markedly reduced vasopressor response to NG-monomethyl-L-arginine (the nitric oxide synthase inhibitor) and a decreased vasodilator response to acetylcholine of precontracted aortic tissue. Hexarelin (80 micrograms/kg, s.c. twice daily), administered for 15 days to GHRH-Ab-treated rats, fully restored the somatotropic function and reversed all the signs of cardiac and endothelial dysfunction. In fact, in heart preparations from rats treated with hexarelin the trend of the ischemic damage was similar to that observed in control rats and both the rate of formation of 6-keto-PGF1 alpha and the vasopressor activity of angiotensin II were reverted to control levels. Furthermore, all the parameters of endothelial function were in the normal range. These results indicate that GH deficiency in rats is responsible for an impairment of cardiac function that is associated with a damage of the endothelium-dependent relaxing function not limited to coronary vessels but widespread in the circulation. These alterations are fully reverted by an in vivo treatment with hexarelin.