Pembrolizumab and nab-paclitaxel as salvage therapy for platinum-treated, locally advanced or metastatic urothelial carcinoma: interim results of the open-label, single-arm, phase II PEANUT study.

BACKGROUND: Pembrolizumab is a new standard of care for patients with platinum-treated, metastatic urothelial carcinoma (UC). Nab-paclitaxel is active in advanced UC. In the PEANUT study (NCT03464734) we investigated their combination in advanced UC. PATIENTS AND METHODS: PEANUT was an open-label, single-arm, phase II trial that included patients who had failed one or two chemotherapy regimens, including platinum chemotherapy. Biomarker analyses focused on programmed cell-death ligand-1 combined positive score (CPS) and comprehensive genomic profiling on tumor samples and circulating tumor DNA. Patients received 200 mg pembrolizumab on day 1 (D1), and 125 mg/m2 nab-paclitaxel on D1 and D8, every 3 weeks, until disease progression or unacceptable toxicity. The primary end point was progression-free survival (PFS) according to RECIST (v1.1). The assumption was to detect an improvement in the median PFS from ≤3.0 months (H0) to ≥5.0 months (H1). RESULTS: Between January 2019 and January 2020, the PEANUT study enrolled 70 patients: 24% had failed two prior systemic therapies; 31% had an Eastern Cooperative Oncology Group (ECOG) performance status of 1; and 28.6% had liver metastases. After a median follow-up of 9.8 months, 40 patients have relapsed (57.1%). The median PFS was 5.9 months [95% confidence interval (CI) 3.1-11.5]. The confirmed objective response rate (ORR) was 38.6% (95% CI 27-51) with 17 partial responses and 10 complete responses (14.3%). The median duration of response was not reached. Five patients (7.1%) had ongoing responses lasting >12 months. The most common any-grade treatment-related adverse events included alopecia (71.4%), neutropenia (32.9%), and peripheral neuropathy (34.3%). Neither tumor mutational burden nor CPS was significantly associated with PFS at univariable analyses. The single-arm design of the trial was the major limitation. CONCLUSIONS: Pembrolizumab combined with nab-paclitaxel, as second- and third-line chemoimmunotherapy for metastatic UC, showed a favorable safety profile, durable PFS, and a clinically meaningful ORR in these preliminary analyses. This combination warrants additional randomized studies in earlier disease stages. CLINICALTRIALS. GOV NUMBER: ClinicalTrials.govNCT03464734; https://clinicaltrials.gov/ct2/show/NCT03464734.

Does the administration of preoperative pembrolizumab lead to sustained remission post-cystectomy? First survival outcomes from the PURE-01 study☆.

BACKGROUND: Initial studies of preoperative checkpoint inhibition before radical cystectomy (RC) have shown promising pathologic complete responses. We aimed to analyze the survival outcomes of patients enrolled in the PURE-01 study (NCT02736266). PATIENTS AND METHODS: We report the results of the secondary end points of PURE-01 in the final population of 143 patients. In particular, we report the event-free survival (EFS) outcomes, defined as the time from the first cycle of pembrolizumab to radiographic disease progression precluding RC, initiation of neoadjuvant chemotherapy (NAC), recurrence after RC, or death from any cause. Other end points were recurrence-free survival (RFS) and overall survival (OS). Subgroup analyses were carried out, including pathological response category, clinical complete responses (CR) assessed via multiparametric magnetic resonance imaging (mpMRI), and molecular subtyping. Cox regression analyses for EFS were also carried out. RESULTS: After a median [interquartile range (IQR)] follow-up of 23 (15-29) months, 12- and 24-month EFS were 84.5% [95% confidence interval (CI): 78.5-90.9] and 71.7% (62.7-82). The prognosis was favorable across all the different pathological response subgroups, with the exception of ypN+ (N = 21), showing a 24-month RFS (95% CI) of 39.3% (19.2% to 80.5%). A statistically significant EFS benefit was observed in patients with a clinical CR (P = 0.002). Programmed cell-death-ligand-1 combined positive score was significantly associated with longer EFS in multivariable analyses. Four patients refused RC after clinical evidence of CR, and none of them have recurred after a median follow-up of 10 months (IQR: 11-15). The claudin-low subtype displayed a numerically longer EFS after pembrolizumab and RC compared with the other subtypes. CONCLUSIONS: The EFS results from PURE-01 revealed that the immunotherapy effect was maintained post-RC in most patients. Pembrolizumab compared favorably with neoadjuvant chemotherapy, irrespective of the biomarker status. Molecular subtyping may be a useful tool to select the patients who are predicted to benefit the most from neoadjuvant pembrolizumab.

Treatment with a Toll-like Receptor 7 ligand evokes protective immunity against atherosclerosis in hypercholesterolaemic mice.

BACKGROUND: The interplay between innate and adaptive immunity is central in life-threatening clinical complications of atherosclerosis such as myocardial infarction and stroke. The specific mechanisms involved and their protective versus detrimental effects in the disease process remain poorly understood. We have previously shown that higher levels of Toll-like receptor 7 (TLR7) expression in human atherosclerotic lesions are correlated with better patient outcome. OBJECTIVE: In this study, we explored whether TLR7 activation can ameliorate disease in experimental atherosclerosis in mice. METHODS: Apolipoprotein E deficient mice (Apoe-/- ) with established disease were injected for five weeks intraperitoneally with the TLR7 ligand R848. Local effects were evaluated by characterization of the lesion. Systemic effects of the treatment were investigated by immune composition analysis in the spleen and plasma measurements. RESULTS: The in vivo treatment arrested lesion progression in the aorta. We also detected expansion of marginal zone B cells and Treg in the spleen together with increased plasma IgM antibodies against oxidized low-density lipoprotein (oxLDL) and reduced plasma cholesterol levels. These changes were accompanied by increased accumulation of IgM antibodies, decreased necrosis and fewer apoptotic cells in atherosclerotic lesions. CONCLUSIONS: Our findings show that TLR7 stimulation could ameliorate atherosclerotic lesion burden and reduce plasma cholesterol in Apoe-/- mice. TLR7 stimulation was associated with an atheroprotective B-cell and Treg response, which may have systemic and local effects within lesions that could prevent arterial lipid accumulation and inflammation.

Regional modulation of the ankle plantarflexor muscles associated with standing external perturbations across different directions.

Maintenance of upright standing posture has often been explained using the inverted pendulum model. This model considers the ankle plantarflexors to act as a single synergistic group. There are differences in muscle properties among the medial and lateral gastrocnemius (MG and LG, respectively) and the soleus that may affect their activation. Twelve volunteers participated in an investigation to determine whether the activation of the ankle plantarflexor muscles was modulated according to perturbation direction during unilateral standing perturbations of 1% body mass. High-density surface electromyography (HDS-EMG) was used to determine the amplitude and barycenter of the muscle activation and kinematic analysis was used to evaluate ankle, knee, and hip joint movement. The HDS-EMG amplitude and barycenter of MG and LG were modulated with the perturbation direction (MG p < 0.05; LG p < 0.01; one-way repeated-measures ANOVA). In soleus, the HDS-EMG barycenter modulated across the perturbation direction (p < 0.01 for X&Y coordinates), but the HDS-EMG amplitude did not change. A repeated-measures correlation was used to interpret the HDS-EMG pattern in the context of the kinematics. The relative contribution of MG activation compared to the total gastrocnemii activation was significantly associated with ankle dorsi/plantarflexion (rrm = 0.620), knee flexion/extension and abduction/adduction (rrm = 0.622 and rrm = 0.547, respectively), and hip flexion/extension and abduction/adduction (rrm = 0.653 and rrm = 0.432, respectively). The findings suggest that the central nervous system activates motor units within different regions of MG, LG and SOL in response to standing perturbations in different directions.

Effect of standing posture on inhibitory postsynaptic potentials in gastrocnemius motoneurons.

This study examined the task dependence of sensory inputs on motoneuron excitability by comparing the inhibitory postsynaptic potential (IPSP) evoked by stimulation of the sural nerve between a standing postural task (Free Standing) and a comparable voluntary isometric contraction performed in a supine position (Lying Supine). We hypothesized that there would be a smaller IPSP in standing than in the supine position, based on the task dependence of the ankle plantarflexor activity on the standing task. Ten healthy participants participated in a total of 15 experiments. Single motor unit (MU) firings were recorded with both intramuscular fine-wire electrodes and high-density surface electromyography. Participants maintained the MU discharge at 6-8 Hz in Free Standing or Lying Supine while the right sural nerve was stimulated at random intervals between 1 and 3 s. To evaluate the reflex response, the firing times of the discriminated MUs were used to construct peristimulus time histograms and peristimulus frequencygrams. The sural nerve stimulation resulted in weaker inhibition in Free Standing than in Lying Supine. This finding is discussed in relation to the putative activation of persistent inward currents in standing posture and the task-dependent advantages of overriding inhibitory synaptic inputs to the plantarflexors to maintain the standing posture. NEW & NOTEWORTHY The task-dependent modulation of sensory inputs on motoneuron excitability in standing is not well understood. Evoking an inhibitory postsynaptic potential (IPSP) resulted in a smaller IPSP in gastrocnemius motoneurons in standing than in the supine position. Mildly painful sensory inputs produced weaker motoneuron inhibition in standing, suggesting an imperative to maintain ankle plantarflexion activity for the task of upright stance.

Fifteen-year single-centre experience with three different surgical procedures of nerve-sparing cystectomy in selected organ-confined bladder cancer patients.

OBJECTIVES: To evaluate technical feasibility and oncologic and functional outcomes of three different surgical procedures of nerve-sparing radical cystectomy (NS-RC) for the treatment of organ-confined bladder cancer at a single referral centre. MATERIALS AND METHODS: All consecutive cases of NS-RC carried out between 1997 and 2012 were retrospectively analysed. NS-RC included nerve-sparing cysto-vesicleprostatectomy (NS-CVP), capsule-sparing cystectomy (CS-C) and seminal-sparing cysto-prostatectomy (SS-CP). Peri-operative parameters and post-operative outcomes were analysed. RESULTS: Overall, 90 patients underwent NS-RC, 35 (38.9 %) of whom received a NS-CVP, while 36 (40 %) and 19 (21.1 %) underwent capsule CS-C and SS-CP, respectively. No difference was registered comparing oncologic outcomes of the three different techniques; however, two local recurrences after CS-C were attributed to the surgical technique. Complete post-operative daytime and night-time urinary continence (UC) at 24 and 48 months was achieved in 94.4 and 74.4 % and in 88.8 and 84.4 % of cases, respectively. CS-C showed both the best UC and sexual function preservation rate at early follow-up (24 months). Overall, a satisfactory post-operative erectile function (IIEF-5 ≥ 22) was proved in 57 (68.6 %) and 54 (65.0 %) patients at 24 and 48 months, respectively. Significant difference was found when comparing sexual function preservation rate of NS-CVP (28.5 %) to that of CS-C (91.6 %) and SS-CP (84.2 %). CONCLUSION: NS-RC for male patients accounted for 7.4 % of overall radical cystectomy. To a limited extent of the selected organ-confined bladder cancers treated, the three different procedures analysed showed comparable results in terms of local recurrence and cancer-specific survival. Both CS-C and SS-CP procedures provided excellent functional outcomes when compared to original NS-CVP.

Extended pelvic lymph node dissection in prostate cancer: a 20-year audit in a single center.

BACKGROUND: We set to assess the impact of stage migration in prostate cancer (PCa) on the evolution of the pN1 rate and tumor characteristics in pN1 patients over the last two decades. PATIENTS AND METHODS: We evaluated 5274 PCa patients treated with radical prostatectomy and anatomically extended pelvic lymph node dissection (ePLND) between 1990 and 2010. Year-per-year trends of clinical and pathological characteristics were examined. Logistic regression analyses addressed predictors of pN1. RESULTS: The median number of lymph nodes (LNs) removed was 16.0. Overall, the pN1 rate was 13.8% and it decreased from 26.1% to 15.6% between 1990 and 2010 (P < 0.001). For the same period, the pN1 rate changed from 0% to 3% in the low-risk PCa, from 20% to 7% in the intermediate-risk PCa, and from 33% to 44% in the high-risk PCa (P ≤ 0.01). In pN1 patients, pre-operative cancer characteristics and the median number of positive LNs (three in 1990 versus two in 2010) did not significantly change overtime (all P ≥ 0.1). Year of surgery was not an independent predictor of pN1 (all P ≥ 0.06). CONCLUSION: Based on ePLND outcomes, contemporary patients with intermediate- and high-risk PCa's still harbor a significant LNI risk. In consequence, stage migration does not justify omitting or limiting the extent of PLND in these individuals.

Are Caucasian-European men delaying fatherhood? Results of a 7 year observational study of infertile couples with male factor infertility.

This study was aimed at assessing presence and predictors of a trend towards more advanced paternal age at presentation in a cohort of 1283 Caucasian-European infertile couples with male factor infertility (MFI) over a short time frame. Multivariate linear regression analysis tested the association between predictors [namely, partners' age, length of infertility at first presentation, patients' comorbidities as scored with the Charlson Comorbidity Index (CCI) and educational status] and patient's age at presentation. Using anova, patient's age at presentation (F ratio: 2.43; p = 0.024) and patients' educational status (χ(2) trend: 142.38; p < 0.001) significantly increased over time. In contrast, length of infertility at first presentation, CCI and partners' age did not significantly change over time (all p ≥ 0.05). Linear regression analyses showed that CCI, educational status and year of presentation were not correlated with patients' age at presentation (all p ≥ 0.05), whereas partners' age (ß = 0.170; p < 0.001) and length of infertility (ß = 0.123; p = 0.004) were independent predictors of delayed fatherhood. These results showed a significant shift towards advanced paternal age, but a non-significant increase of maternal age at first presentation among Caucasian-European infertile couples with MFI over a short time frame.

Availability of HLA-allele-matched unrelated donors and registry size: Estimation from haplotype frequency in the Italian population.

In Italy, an HLA-matched unrelated donor is currently the primary donor when a HLA matched sibling is not found for allogeneic haematopoietic stem cell transplantation (HSCT). Better outcomes for transplantation require optimal matching between donor and recipient at least at the HLA-A, -B, -C, and -DRB1 loci; therefore, the availability of HLA-matched unrelated donors is important. The enormous HLA polymorphism has always necessitated registries with a large number of individuals in order to be able to provide well-matched donors to a substantial percentage of patients. In order to increase the efficiency of the Italian Bone Marrow Donor Registry (IBMDR) in providing Italian patients with a suitable donor, the probability of finding an HLA-A, -B, -C, and -DRB1 allele-matched (8/8) or a single mismatch unrelated donor (7/8) was estimated in this study according to IBMDR size. Using a biostatistical approach based on HLA haplotype frequencies of more than 100,000 Italian donors enrolled in the IBMDR and HLA-typed at high-resolution level, the probability of finding an 8/8 HLA-matched donor was 23.8%; 33.4%; and 41.4% in simulated registry sizes of 200,000; 500,000; and 1,000,000 donors; respectively. More than 2 million recruited donors are needed to increase the likelihood of identifying an HLA 8/8 matched donor for 50% of Italian patients. If one single mismatch at HLA I class loci was accepted, the probability of finding a 7/8 HLA-matched donor was 62.8%; 73.7%; and 80.3% in 200,000 donors; 500,000; and 1,000,000 donors; respectively. Using the regional haplotype frequencies of IBMDR donors, the probability of recruiting a donor with a new HLA phenotype, in the different Italian regions, was also calculated. Our findings are highly relevant in estimating the optimal size of the national registry, in planning a cost-effective strategy for donor recruitment in Italy, and determining the regional priority setting of recruitment activity in order to increase the phenotypic variability of IBMDR as well as its efficiency.

ESX1 gene expression as a robust marker of residual spermatogenesis in azoospermic men.

BACKGROUND: It would be of value to identify ongoing spermatogenesis molecular markers which can predict successful sperm recovery in patients with non-obstructive azoospermia undergoing conventional or microsurgical testicular sperm extraction (TESE/microTESE). ESX1 is an X-linked homeobox gene expressed in testis, placenta, brain and lung in humans and specifically in pre- and post-meiotic germ cells of the testis in mice. METHODS: We investigated the sequence, expression (by RT-PCR) and epigenetic status (by promoter pyrosequencing) of ESX1 in testicular tissue samples, obtained from 81 azoospermic subjects in the context of surgical sperm extraction, to check a possible association between ESX1 alterations and impaired spermatogenesis, as determined by histological analysis. RESULTS: The ESX1 transcript was detected in 100% of cases diagnosed as obstructive azoospermia (33), hypospermatogenesis (18) and incomplete maturation arrest (MA) (2), and sperm recovery was also successful in 100% of these cases. ESX1 mRNA was also detected in 5 of 6 patients with incomplete Sertoli cell-only syndrome, in 4 of 6 subjects with complete MA but in only 3 of 16 cases of complete Sertoli cell-only syndrome (cSCOS), whereas sperm recovery was successful in 4 of 6, 2 of 6 and 5 of 16 of these patients, respectively. In cases of focal spermatogenesis, ESX1 expression and sperm retrieval were concordant in 14 of 19 (74%) cases subjected to TESE, but in only 3 of 11 (27%) men who underwent microTESE. With TESE, but not with microTESE, both samples originated from adjacent testicular areas. The pyrosequencing of the ESX1 CpG island revealed methylation levels that were significantly lower in ESX1 expressors when compared with non-expressors. CONCLUSIONS: ESX1 emerges as a potentially reliable spermatogenesis molecular marker, whose clinical value as a predictor of successful sperm retrieval warrants further studies.

Sudden deaths and colony population decline in Greek honey bee colonies.

During June and July of 2009, sudden deaths, tremulous movements and population declines of adult honey bees were reported by the beekeepers in the region of Peloponnesus (Mt. Mainalo), Greece. A preliminary study was carried out to investigate these unexplained phenomena in this region. In total, 37 bee samples, two brood frames containing honey bee brood of various ages, eight sugar samples and four sugar patties were collected from the affected colonies. The samples were tested for a range of pests, pathogens and pesticides. Symptomatic adult honey bees tested positive for Varroa destructor, Nosema ceranae, Chronic bee paralysis virus (CBPV), Acute paralysis virus (ABPV), Deformed wing virus (DWV), Sacbrood virus (SBV) and Black queen cell virus (BQCV), but negative for Acarapis woodi. American Foulbrood was absent from the brood samples. Chemical analysis revealed that amitraz, thiametoxan, clothianidin and acetamiprid were all absent from symptomatic adult bees, sugar and sugar patty samples. However, some bee samples, were contaminated with imidacloprid in concentrations between 14 ng/g and 39 ng/g tissue. We present: the infection of Greek honey bees by multiple viruses; the presence of N. ceranae in Greek honey bees and the first record of imidacloprid (neonicotonoid) residues in Greek honey bee tissues. The presence of multiple pathogens and pesticides made it difficult to associate a single specific cause to the depopulation phenomena observed in Greece, although we believe that viruses and N. ceranae synergistically played the most important role. A follow-up in-depth survey across all Greek regions is required to provide context to these preliminary findings.

Neural reflex control of vascular inflammation.

Atherosclerosis is a multifactorial chronic inflammatory disease that underlies myocardial infarction and stroke. Efficacious treatment for hyperlipidemia and hypertension has significantly reduced morbidity and mortality in cardiovascular disease. However, atherosclerosis still confers a considerable risk of adverse cardiovascular events. In the current mechanistic understanding of the pathogenesis of atherosclerosis, inflammation is pivotal both in disease development and progression. Recent clinical data provided support for this notion and treatment targeting inflammation is currently being explored. Interestingly, neural reflexes regulate cytokine production and inflammation. Hence, new technology utilizing implantable devices to deliver electrical impulses to activate neural circuits are currently being investigated in treatment of inflammation. Hopefully, it may become possible to target vascular inflammation in cardiovascular disease using bioelectronic medicine. In this review, we discuss neural control of inflammation and the potential implications of new therapeutic strategies to treat cardiovascular disease.

Open prostatectomy and the evolution of HoLEP in the management of benign prostatic hyperplasia.

Trans-urethral resection of the prostate (TURP) and other minimally invasive therapies are the most common surgical procedures used to treat benign prostatic hyperplasia today. However, many patients with a markedly enlarged prostate are often not amenable to these treatment options. In these patients open prostatectomy has been representing a viable and preferred treatment. Despite the morbidity of open enucleation is substantial, until recently no other options were available when the size of the prostate approached 100 g and beyond. The use of holmium laser for the treatment of benign prostatic hyperplasia was first reported in 1996. Holmium laser enucleation of the prostate (HoLEP) has been proposed as an alternative to TURP and to open prostatectomy for patients with lower urinary tract symptoms (LUTS) due to large benign prostatic enlargement. In this manuscript, the development of HoLEP from the initial reports to the long-term follow-up data which demonstrate the effectiveness of the technique in treating patients affected by LUTS secondary to large adenomas has been reviewed. HoLEP seems to represent a valid alternative to both TURP and OP, with valid long-term functional results, a low rate of short-term and long-term complications, and very low rates of reintervention. In conclusion, HoLEP can be offered as the size-independent gold standard treatment of patients with LUTS due to benign prostatic enlargement.

Microbiological, chemical and physical quality of drinking water for commercial turkeys: a cross-sectional study.

Drinking water for poultry is not subject to particular microbiological, chemical and physical requirements, thereby representing a potential transmission route for pathogenic microorganisms and contaminants and/or becoming unsuitable for water-administered medications. This study assessed the microbiological, chemical and physical drinking water quality of 28 turkey farms in North-Eastern Italy: 14 supplied with tap water (TW) and 14 with well water (WW). Water salinity, hardness, pH, ammonia, sulphate, phosphate, nitrate, chromium, copper and iron levels were also assessed. Moreover, total bacterial count at 22°C, presence and enumeration of Enterococcus spp. and E. coli, presence of Salmonella spp. and Campylobacter spp. were quantified. A water sample was collected in winter and in summer at 3 sampling sites: the water source (A), the beginning (B) and the end (C) of the nipple line (168 samples in total). Chemical and physical quality of both TW and WW sources was mostly within the limits of TW for humans. However, high levels of hardness and iron were evidenced in both sources. In WW vs. TW, sulphate and salinity levels were significantly higher, whilst pH and nitrate levels were significantly lower. At site A, microbiological quality of WW and TW was mostly within the limit of TW for humans. However, both sources had a significantly lower microbiological quality at sites B and C. Salmonella enterica subsp. enterica serotype Kentucky was isolated only twice from WW. Campylobacter spp. were rarely isolated (3.6% of farms); however, Campylobacter spp. farm-level prevalence by real-time PCR was up to 43% for both water sources. Winter posed at higher risk than summer for Campylobacter spp. presence in water, whereas no significant associations were found with water source, site, recirculation system, and turkey age. Low salinity and high hardness were significant risk factors for C. coli and C. jejuni presence, respectively. These results show the need of improving sanitization of drinking water pipelines for commercial turkeys.

How to obtain Pt(iv) complexes suitable for conjugation to nanovectors from the oxidation of [PtCl(terpyridine)].

Oxidation of [Pt(II)Cl(terpy)]+ (terpy = 2,2':6',2''-terpyridine) has been attempted with several oxidizing agents and under different experimental conditions in order to obtain a Pt(iv) complex suitable for the conjugation to nanovectors to be used in drug delivery targeting for anticancer therapy. The best compromise in terms of yield and purity of the final complex was obtained by microwave-assisted reaction at 70 °C in 50% aqueous H2O2 for 2 h. Under these conditions the quantitative formation of [Pt(IV)Cl(OH)2(terpy)]+ was observed. The subsequent synthetic steps were, (i) functionalization of [Pt(IV)Cl(OH)2(terpy)]+ in the axial position with succinic anhydride to obtain [Pt(IV)Cl(OH)(succinato)(terpy)]+ and (ii) reaction of the latter with nonporous silica nanoparticles (SNPs) with an external shell containing primary amino groups to obtain a nanovector able to transport the Pt(iv) antitumor prodrug in the form of a conjugate Pt-SNP. Finally, the antiproliferative activity and cell accumulation of [Pt(II)Cl(terpy)]+, [Pt(IV)Cl(OH)2(terpy)]+, and the Pt-SNP conjugate were measured on three cancer cell lines. Despite highly effective accumulation of Pt-SNP in cells, a modest increase in activity was observed with respect to the molecular species. Further experiments showed that the Pt-SNP conjugate can release [Pt(II)Cl(terpy)]+ upon reduction, but this metabolite may undergo hydrolysis, and the resulting aquo complex could coordinate once again the free amino groups of the SNPs. In the resulting tetraamine form, the Pt(ii) complex conjugated to the SNPs cannot completely perform its antiproliferative activity.

Cisplatin and valproate released from the bifunctional [Pt(IV)Cl2(NH3)2(valproato)2] antitumor prodrug or from liposome formulations: who does what?

The cisplatin-sensitive human ovarian cancer cells A2780 have been challenged with cationic liposomes containing the single drug cisplatin or valproate or their combination with an approximate 1 : 2 molar ratio, i.e. the same ratio present in preformed (OC-6-33)-diamminedichloridobis(valproato)platinum(iv), that releases such metabolites by intracellular Pt(iv) → Pt(ii) reduction. The results of this comparison confirm that valproate barely penetrates cells unless it is transported by liposomes or it is coordinated to a lipophilic Pt(iv) assembly. The two drugs have a synergistic action, cisplatin being the more potent antiproliferative agent. Even if the preformed (OC-6-33)-diamminedichloridobis(valproato)platinum(iv) releases cisplatin and valproate in the same amount as the liposome formulation, the Pt(iv) derivative is more active. This important feature, common to all Pt(iv) complexes having very lipophilic carboxylates, is attributable to their propensity to remain in cells and to continuously bind DNA, unlike cisplatin that is partially removed from cells by efficient efflux pathways.

Differentiation of motor evoked potentials elicited from multiple forearm muscles: An investigation with high-density surface electromyography.

Transcranial magnetic stimulation (TMS) is a non-invasive method to measure corticospinal excitability of the primary motor cortex. However, motor evoked potentials (MEPs) elicited by TMS in a target muscle are variable; inconsistent MEPs may be due to overlapping cortical muscle representations and/or volume conduction from neighbouring muscles. The source of variable muscle responses may not be apparent using conventional bipolar electromyography (EMG), particularly over areas with several distinct neighbouring muscles (e.g. the forearm). High-density surface EMG (HDsEMG) may provide a useful means to investigate the underlying variability in amplitude and spatial distribution of MEPs. Here, we investigated the spatial distribution of MEPs in the forearm extensors using HDsEMG. HDsEMG consisted of a 16×5 grid of surface electrodes placed on the right (dominant) dorsal forearm over the extensor carpi radialis (ECR), ulnaris (ECU) and extensor digitorum communis finger extensors (EDC). MEP amplitude and distribution were recorded from 100 to 170% of resting (RMT) and active motor threshold (AMT). The distribution of MEPs was correlated to the activity recorded during selective, isometric contractions of the ECR, ECU, middle (EDC-D3) and ring (EDC-D4) finger extensors to determine the spatial distribution of MEPs in the forearm extensors. Although ECR was the hotspot, resting MEP spatial distribution was primarily correlated to that of EDC-D4 and ECU. With background ECR activation, the spatial distribution of MEPs correlated strongly with ECR. Further, while holding a background ECR contraction, EDC-D4 and ECU MEPs increased with greater stimulation intensity. Our results suggest that HDsEMG provides a useful way to differentiate which wrist extensor muscles are activated by TMS.

Physiological arousal accompanying postural responses to external perturbations after stroke.

OBJECTIVE: The purpose of this study was to examine simultaneously the level of physiological arousal and the postural response to external perturbations in people post-stroke compared to age-matched controls to build a more comprehensive understanding of the effect of stroke on postural control and balance self-efficacy. METHODS: Participants stood with each foot on separate force platforms. Ten applications of loads of 2% body weight at the hips perturbed the participant anteriorly under two conditions: investigator-triggered or self-triggered (total 20). Electrodermal activity (EDA; measurement of physiological arousal), electromyography (EMG) of the ankle plantarflexor muscles and anterior-posterior center of pressure measurements were taken pre-perturbation (anticipatory) and post-perturbation (response) and compared between the initial (first two) and final (last two) perturbations. RESULTS: Participants post-stroke demonstrated significantly higher levels of anticipatory EDA and anticipatory paretic plantarflexor EMG during both self- and investigator-triggered conditions compared to controls. Anticipatory EDA levels were higher in the final perturbations in participants post-stroke in both conditions, but not in controls. Habituation of the EDA responses post-perturbation was exhibited in the self-triggered perturbations in controls, but not in participants post-stroke. CONCLUSIONS: Physiological arousal and postural control strategies of controls revealed habituation in response to self-triggered perturbations, whereas this was not seen in participants post-stroke. SIGNIFICANCE: Understanding the physiological arousal response to challenges to standing balance post-stroke furthers our understanding of postural control mechanisms post-stroke.

The surgical management of patients with clinical stage T4 bladder cancer: A single institution experience.

INTRODUCTION: Patients with clinical T4 (cT4) bladder cancer (BCa) infrequently undergo radical cystectomy (RC). We investigated the reliability of preoperative clinical staging, perioperative and survival outcomes in patients treated with RC due to cT4a-b BCa disease at a single tertiary care institution. METHODS: The study relied on 917 BCa patients treated with RC and pelvic lymph node dissection (PLND) at a single institution between January 1995 and December 2012. We compared the accuracy of the clinical assessment with final pathology results. Moreover, we evaluated perioperative outcomes, complication rates and survival after surgery. RESULTS: The median follow-up was 62 months. Overall, 74 (8.1%) patients presented cT4 stage at preoperative evaluation. Conversely, a pathological T4 disease was confirmed only in 68.9% patients staged initially as cT4. No differences were recorded in complications, 30 days readmission or 30 days death rates between cT1-T3 vs. cT4a vs. cT4b (p > 0.1). At multivariable Cox regression analyses predicting cancer specific mortality, clinical T4 stage vs. clinical T1-2, clinical T3 stage vs. clinical T1-2 and age were predictors of worst survival after RC (all p < 0.04). CONCLUSIONS: We recorded poor concordance between preoperative imaging and pathology in cT4 patients. No differences in major perioperative outcomes and acceptable survival expectancies were reported in patients treated for cT4 disease.

Between-day reliability of triceps surae responses to standing perturbations in people post-stroke and healthy controls: A high-density surface EMG investigation.

The reliability of triceps surae electromyographic responses to standing perturbations in people after stroke and healthy controls is unknown. High-Density surface Electromyography (HDsEMG) is a technique that records electromyographic signals from different locations over a muscle, overcoming limitations of traditional surface EMG such as between-day differences in electrode placement. In this study, HDsEMG was used to measure responses from soleus (SOL, 18 channels) and medial and lateral gastrocnemius (MG and LG, 16 channels each) in 10 people after stroke and 10 controls. Timing and amplitude of the response were estimated for each channel of the grids. Intraclass Correlation Coefficient (ICC) and normalized Standard Error of Measurement (SEM%) were calculated for each channel individually (single-channel configuration) and on the median of each grid (all-channels configuration). Both timing (single-channel: ICC=0.75-0.96, SEM%=5.0-9.1; all-channels: ICC=0.85-0.97; SEM%=3.5-6.2%) and amplitude (single-channel: ICC=0.60-0.91, SEM%=25.1-46.6; ICC=0.73-0.95, SEM%=19.3-42.1) showed good-to-excellent reliability. HDsEMG provides reliable estimates of EMG responses to perturbations both in individuals after stroke and in healthy controls; reliability was marginally better for the all-channels compared to the single-channel configuration.