Cabazitaxel versus abiraterone or enzalutamide in poor prognosis metastatic castration-resistant prostate cancer: a multicentre, randomised, open-label, phase II trial.

BACKGROUND: Treatment of poor prognosis metastatic castration-resistant prostate cancer (mCRPC) includes taxane chemotherapy and androgen receptor pathway inhibitors (ARPI). We sought to determine optimal treatment in this setting. PATIENTS AND METHODS: This multicentre, randomised, open-label, phase II trial recruited patients with ARPI-naive mCRPC and poor prognosis features (presence of liver metastases, progression to mCRPC after <12 months of androgen deprivation therapy, or ≥4 of 6 clinical criteria). Patients were randomly assigned 1 : 1 to receive cabazitaxel plus prednisone (group A) or physician's choice of enzalutamide or abiraterone plus prednisone (group B) at standard doses. Patients could cross over at progression. The primary endpoint was clinical benefit rate for first-line treatment (defined as prostate-specific antigen response ≥50%, radiographic response, or stable disease ≥12 weeks). RESULTS: Ninety-five patients were accrued (median follow-up 21.9 months). First-line clinical benefit rate was greater in group A versus group B (80% versus 62%, P = 0.039). Overall survival was not different between groups A and B (median 37.0 versus 15.5 months, hazard ratio (HR) = 0.58, P = 0.073) nor was time to progression (median 5.3 versus 2.8 months, HR = 0.87, P = 0.52). The most common first-line treatment-related grade ≥3 adverse events were neutropenia (cabazitaxel 32% versus ARPI 0%), diarrhoea (9% versus 0%), infection (9% versus 0%), and fatigue (7% versus 5%). Baseline circulating tumour DNA (ctDNA) fraction above the cohort median and on-treatment ctDNA increase were associated with shorter time to progression (HR = 2.38, P < 0.001; HR = 4.03, P < 0.001). Patients with >30% ctDNA fraction at baseline had markedly shorter overall survival than those with undetectable ctDNA (HR = 38.22, P < 0.001). CONCLUSIONS: Cabazitaxel was associated with a higher clinical benefit rate in patients with ARPI-naive poor prognosis mCRPC. ctDNA abundance was prognostic independent of clinical features, and holds promise as a stratification biomarker.

Outcome of dogs with intermediate grade low mitotic index high Ki67 mast cell tumours treated with surgery and single agent lomustine.

OBJECTIVES: The objective of this retrospective study was to evaluate the outcome of dogs when grade II mast cell tumour (MCT) with low mitotic index (MI) and high Ki67 were treated with adjuvant lomustine. ANIMALS: Client owned dogs with spontaneously occurring disease treated with adjuvant chemotherapy for grade II mast cell tumour with low MI (≤5/10HPF) and high Ki67 (>1.8%) with no evidence of metastatic disease at presentation. PROCEDURES: Lomustine was administered every 3 weeks with three or four planned cycles. Response to treatment was assessed by regular re-staging ultrasound with or without cytopathological examination of liver and spleen or through medical records from the referring veterinarian. Disease-free interval (DFI) and median survival time (MST) were calculated using Kaplan-Meier method. RESULTS: Twenty-one dogs were included. All dogs underwent surgical excision and two dogs received adjuvant radiotherapy. None of the patients developed local recurrence. Three dogs (14.3%) developed metastatic disease. The DFI of these dogs was 141, 186 and 223 days. Median follow-up period of the whole study population was 1112 days (358-2619). MST for patients with metastatic disease was 417 days. MST of the whole group was not reached. One-year and 2-year survivals were 95.2% and 90.5%, respectively. CONCLUSIONS AND CLINICAL RELEVANCE: This study population had low rates of tumour recurrence and improved survival compared to previously published data of similar population of dogs with low MI/high Ki67 MCT without adjuvant chemotherapy.

Nomogram Predicting Bladder Cancer-specific Mortality After Neoadjuvant Chemotherapy and Radical Cystectomy for Muscle-invasive Bladder Cancer: Results of an International Consortium.

BACKGROUND: Cisplatin-based neoadjuvant chemotherapy (NAC) for muscle-invasive bladder cancer (MIBC) is associated with improved overall and cancer-specific survival. The post-NAC pathological stage has previously been reported to be a major determinant of outcome. OBJECTIVE: To develop a postoperative nomogram for survival based on pathological and clinical parameters from an international consortium. DESIGN, SETTING, AND PARTICIPANTS: Between 2000 and 2015, 1866 patients with MIBC were treated at 19 institutions in the USA, Canada, and Europe. Analysis was limited to 640 patients with adequate follow-up who had received three or more cycles of NAC. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: A nomogram for bladder cancer-specific mortality (BCSM) was developed by multivariable Cox regression analysis. Decision curve analysis was used to assess the model's clinical utility. RESULTS AND LIMITATIONS: A total of 640 patients were identified. Downstaging to non-MIBC (ypT1, ypTa, and ypTis) occurred in 271 patients (42 %), and 113 (17 %) achieved a complete response (ypT0N0). The 5-yr BCSM was 47.2 % (95 % confidence interval [CI]: 41.2-52.6 %). On multivariable analysis, covariates with a statistically significant association with BCSM were lymph node metastasis (hazard ratio [HR] 1.90 [95% CI: 1.4-2.6]; p < 0.001), positive surgical margins (HR 2.01 [95 % CI: 1.3-2.9]; p < 0.001), and pathological stage (with ypT0/Tis/Ta/T1 as reference: ypT2 [HR 2.77 {95 % CI: 1.7-4.6}; p < 0.001] and ypT3-4 [HR 5.9 {95 % CI: 3.8-9.3}; p < 0.001]). The area under the curve of the model predicting 5-yr BCSM after cross validation with 300 bootstraps was 75.4 % (95 % CI: 68.1-82.6 %). Decision curve analyses showed a modest net benefit for the use of the BCSM nomogram in the current cohort compared with the use of American Joint Committee on Cancer staging alone. Limitations include the retrospective study design and the lack of central pathology. CONCLUSIONS: We have developed and internally validated a nomogram predicting BCSM after NAC and radical cystectomy for MIBC. The nomogram will be useful for patient counseling and in the identification of patients at high risk for BCSM suitable for enrollment in clinical trials of adjuvant therapy. PATIENT SUMMARY: In this report, we looked at the outcomes of patients with muscle-invasive bladder cancer in a large multi-institutional population. We found that we can accurately predict death after radical surgical treatment in patients treated with chemotherapy before surgery. We conclude that the pathological report provides key factors for determining survival probability.

Anomalous Intensities in the 2+1 REMPI Spectrum of the E 1Π-X 1Σ+ Transition of CO.

We report on one-color experiments near 214 nm involving the photodissociation of jet-cooled OCS to produce high rotational states (40 < J < 80) of CO (X 1Σ+, v = 0, 1) which were then ionized by 2+1 resonance-enhanced multiphoton ionization via the E 1Π state. The nominally forbidden Q-branch of the two-photon E 1Π-X 1Σ+ transition is observed with intensity comparable to the allowed R-branch. The bright character of the high- J Q-branch lines can be described quantitatively as intensity borrowing due to mixing of the E 1Π and C 1Σ+ states, using J-dependent mixing coefficients extrapolated from the observed Λ-doubling in the lower rotational levels of the E state. In addition to the significant enhancement of Q-branch intensities above the values predicted by conventional two-photon line strengths for a 1Π-1Σ+ transition, the high- J lines of the R- and P-branches appear to be suppressed in intensity by approximately a factor of 3 compared to the unperturbed low- J line strengths, most likely due to perturbations associated with a 1Σ- state. The E-state rotational term values for J < 80, v = 0 derived from the present spectra agree within our measurement and calibration uncertainties with the extrapolations based on the molecular constants previously derived from rotational levels with J < 50. The E-X transition is attractive for future application to photodissociation dynamics and rotational polarization measurements of CO photofragments, with convenient access to state-selective probing on multiple rotational branches, which exhibit different sensitivity to fragment alignment.

Concomitant CIS on TURBT does not impact oncological outcomes in patients treated with neoadjuvant or induction chemotherapy followed by radical cystectomy.

BACKGROUND: Cisplatin-based neoadjuvant chemotherapy (NAC) for muscle invasive bladder cancer improves all-cause and cancer specific survival. We aimed to evaluate whether the detection of carcinoma in situ (CIS) at the time of initial transurethral resection of bladder tumor (TURBT) has an oncological impact on the response to NAC prior to radical cystectomy. PATIENTS AND METHODS: Patients were identified retrospectively from 19 centers who received at least three cycles of NAC or induction chemotherapy for cT2-T4aN0-3M0 urothelial carcinoma of the bladder followed by radical cystectomy between 2000 and 2013. The primary and secondary outcomes were pathological response and overall survival, respectively. Multivariable analysis was performed to determine the independent predictive value of CIS on these outcomes. RESULTS: Of 1213 patients included in the analysis, 21.8% had concomitant CIS. Baseline clinical and pathologic characteristics of the 'CIS' versus 'no-CIS' groups were similar. The pathological response did not differ between the two arms when response was defined as pT0N0 (17.9% with CIS vs 21.9% without CIS; p = 0.16) which may indicate that patients with CIS may be less sensitive to NAC or ≤ pT1N0 (42.8% with CIS vs 37.8% without CIS; p = 0.15). On Cox regression model for overall survival for the cN0 cohort, the presence of CIS was not associated with survival (HR 0.86 (95% CI 0.63-1.18; p = 0.35). The presence of LVI (HR 1.41, 95% CI 1.01-1.96; p = 0.04), hydronephrosis (HR 1.63, 95% CI 1.23-2.16; p = 0.001) and use of chemotherapy other than ddMVAC (HR 0.57, 95% CI 0.34-0.94; p = 0.03) were associated with shorter overall survival. For the whole cohort, the presence of CIS was also not associated with survival (HR 1.05 (95% CI 0.82-1.35; p = 0.70). CONCLUSION: In this multicenter, real-world cohort, CIS status at TURBT did not affect pathologic response to neoadjuvant or induction chemotherapy. This study is limited by its retrospective nature as well as variability in chemotherapy regimens and surveillance regimens.

Adsorption of Small Cationic Nanoparticles onto Large Anionic Particles from Aqueous Solution: A Model System for Understanding Pigment Dispersion and the Problem of Effective Particle Density.

The present study focuses on the use of copolymer nanoparticles as a dispersant for a model pigment (silica). Reversible addition-fragmentation chain transfer (RAFT) alcoholic dispersion polymerization was used to synthesize sterically stabilized diblock copolymer nanoparticles. The steric stabilizer block was poly(2-(dimethylamino)ethyl methacrylate) (PDMA) and the core-forming block was poly(benzyl methacrylate) (PBzMA). The mean degrees of polymerization for the PDMA and PBzMA blocks were 71 and 100, respectively. Transmission electron microscopy (TEM) studies confirmed a near-monodisperse spherical morphology, while dynamic light scattering (DLS) studies indicated an intensity-average diameter of 30 nm. Small-angle X-ray scattering (SAXS) reported a volume-average diameter of 29 ± 0.5 nm and a mean aggregation number of 154. Aqueous electrophoresis measurements confirmed that these PDMA71-PBzMA100 nanoparticles acquired cationic character when transferred from ethanol to water as a result of protonation of the weakly basic PDMA chains. Electrostatic adsorption of these nanoparticles from aqueous solution onto 470 nm silica particles led to either flocculation at submonolayer coverage or steric stabilization at or above monolayer coverage, as judged by DLS. This technique indicated that saturation coverage was achieved on addition of approximately 465 copolymer nanoparticles per silica particle, which corresponds to a fractional surface coverage of around 0.42. These adsorption data were corroborated using thermogravimetry, UV spectroscopy and X-ray photoelectron spectroscopy. TEM studies indicated that the cationic nanoparticles remained intact on the silica surface after electrostatic adsorption, while aqueous electrophoresis confirmed that surface charge reversal occurred below pH 7. The relatively thick layer of adsorbed nanoparticles led to a significant reduction in the effective particle density of the silica particles from 1.99 g cm-3 to approximately 1.74 g cm-3, as judged by disk centrifuge photosedimentometry (DCP). Combining the DCP and SAXS data suggests that essentially no deformation of the PBzMA cores occurs during nanoparticle adsorption onto the silica particles.

Clinical response of masitinib mesylate in the treatment of canine macroscopic mast cell tumours.

OBJECTIVES: To retrospectively evaluate the clinical response and toxicity associated with masitinib mesylate (Masivet®) treatment of macroscopic mast cell tumours in the dog. METHODS: Retrospective review of medical records of 39 dogs that had undergone treatment with masitinib for macroscopic mast cell tumours. Patient signalment, tumour location, tumour grade, tumour stage, previous treatments, concurrent medications, dose of masitinib, side effects, response, time to tumour progression, survival time and cause of death were documented. Response was assessed according to RECIST criteria. RESULTS: Clinical response was observed in 32 (82·1%) dogs receiving masitinib, with 15 dogs (38·5%) exhibiting a complete response and 17 dogs (43·6%) achieving a partial response. The median time to progression was 79 days (range: 14 to 667 days). Adverse effects were seen in 25 dogs (64·1%) with serum alanine aminotransferase elevation (n=9; 23·1%) and vomiting (n=6; 15·4%) being most common. Median survival time following initiation of masitinib was 159 days (range: 14 to 1339). CLINICAL SIGNIFICANCE: Masitinib appears to be a well-tolerated and effective drug against macroscopic mast cell tumours.

Evaluation of the factors contributing to long-term survival in canine tonsillar squamous cell carcinoma.

OBJECTIVES: To identify any prognostic factors that may be associated with the long-term survival of dogs diagnosed with tonsillar squamous cell carcinoma (TSCC). METHODS: The medical records of 15 dogs treated for TSCC were reviewed retrospectively. The signalment, presenting signs, clinical stage, treatments and outcome were documented. RESULTS: The overall median survival time (MST) of the dogs in the study was 243 days. There was a 1-and 2-year survival of 40% and 20%, respectively. The results of initial staging had a significant effect on survival, as dogs with only one tonsil affected and no evidence of metastatic disease had a longer MST (637.5 days) than the dogs with local (MST: 134 days) or distant (MST: 75 days) metastatic disease or bilateral tonsillar involvement at the time of initial presentation. Prolonged survival times were reported for dogs undergoing surgery and adjunctive chemotherapy (MST: 464.5 days) for treatment of their TSCC. CLINICAL SIGNIFICANCE: This is the first veterinary study demonstrating an association between prognosis of patients with TSCC and stage at the time of presentation, with long survival times demonstrated for dogs with early-stage disease following an initial treatment protocol that included surgery and chemotherapy. There was no clear association between long survival and additional surgeries for progressive disease; however; further investigation is warranted.

A method to analyze molecular tagging velocimetry data using the Hough transform.

The development of a method to analyze molecular tagging velocimetry data based on the Hough transform is presented. This method, based on line fitting, parameterizes the grid lines "written" into a flowfield. Initial proof-of-principle illustration of this method was performed to obtain two-component velocity measurements in the wake of a cylinder in a Mach 4.6 flow, using a data set derived from computational fluid dynamics simulations. The Hough transform is attractive for molecular tagging velocimetry applications since it is capable of discriminating spurious features that can have a biasing effect in the fitting process. Assessment of the precision and accuracy of the method were also performed to show the dependence on analysis window size and signal-to-noise levels. The accuracy of this Hough transform-based method to quantify intersection displacements was determined to be comparable to cross-correlation methods. The employed line parameterization avoids the assumption of linearity in the vicinity of each intersection, which is important in the limit of drastic grid deformations resulting from large velocity gradients common in high-speed flow applications. This Hough transform method has the potential to enable the direct and spatially accurate measurement of local vorticity, which is important in applications involving turbulent flowfields. Finally, two-component velocity determinations using the Hough transform from experimentally obtained images are presented, demonstrating the feasibility of the proposed analysis method.

Treatment of mCRPC in the AR-axis-targeted therapy-resistant state.

BACKGROUND: The increased use of the androgen receptor axis-targeted (ARAT) agents abiraterone and enzalutamide in first- and second-line treatment of metastatic castration-resistant prostate cancer (mCRPC) has improved patient outcomes, but resistance to these agents is inevitable. Early identification of patients with primary or secondary resistance to ARAT therapy is of increasing clinical concern. DESIGN: PubMed and conference proceedings were searched for studies of agents used after progression on abiraterone or enzalutamide. The key search terms (or aliases) used a combination of mCRPC and abiraterone or enzalutamide, and results were limited to clinical trials and comparative or validation studies. RESULTS AND CONCLUSION: This systematic review assembles current evidence and provides an approach to treatment using available clinical factors. Issues of patient selection, use of laboratory and clinical biomarkers to identify patients at risk of poor outcomes, and the timing and sequencing of available treatment options are addressed. Our findings reveal a lack of high-level evidence regarding predictive factors and treatment of patients with resistance to ARAT therapy, and a need for further research in this area. In the meantime, we suggest practical strategies to guide management of ARAT treatment-resistant patients based on available data.

Effects of resistance training frequency on physical functioning and quality of life in prostate cancer survivors: a pilot randomized controlled trial.

BACKGROUND: Resistance training (RT) improves muscular strength, physical functioning and quality of life in prostate cancer survivors, but the optimal frequency of RT is unknown. We conducted a pilot randomized controlled trial to compare the effects of 3 versus 2 days per week of RT in prostate cancer survivors diagnosed within the past 2 years. METHODS: Prostate cancer survivors (N=30) were randomized to 12 weeks of supervised RT performed either 3 days per week (n=16) or 2 days per week (n=14). The primary outcome was muscular strength assessed by a multiple repetition maximum test at baseline and postintervention. Secondary outcomes were objective physical functioning, quality of life and psychosocial functioning. RESULTS: A trend (P<0.10) and/or potentially meaningful effects (standardized effect size d⩾0.20) were found favoring 3 days per week over 2 days per week for the primary outcome of lower body strength (mean difference=27.8 kg; 95% confidence interval=-0.9 to 56.5; P=0.057; d=0.72) and for the secondary outcomes of 30-s chair stand (d=0.29; P=0.31), sit and reach (d=0.24; P=0.33), 6 -min walk (d=0.21; P=0.42) and the physical component summary (d=0.21; P=0.41). Conversely, a trend and/or potentially meaningful effects were found favoring 2 days per week over 3 days per week for the mental component summary (d=-0.38; P=0.10), mental health (d=-0.44; P=0.11), vitality (d=-0.31; P=0.28), role-emotional (d=-0.23; P=0.43), anxiety (d=0.32; P=0.29), happiness (d=-0.31; P=0.36) and perceived stress (d=0.23; P=0.39). CONCLUSIONS: This pilot randomized dose-comparison trial provides preliminary data to suggest that RT 3 days per week compared with 2 days per week may improve the strength and physical functioning in prostate cancer survivors, but may also blunt improvements in psychosocial functioning. Larger and more targeted phase II and III trials are needed to confirm the potentially complex effects of RT frequency in prostate cancer survivors.

A phase II study of the HDAC inhibitor SB939 in patients with castration resistant prostate cancer: NCIC clinical trials group study IND195.

BACKGROUND: SB939 is a potent oral inhibitor of class 1, 2, and 4 histone deacetylases (HDACs). These three HDAC classes are highly expressed in castration resistant prostate cancer (CRPC) and associated with poor clinical outcomes. We designed a phase II study of SB939 in men with metastatic CRPC. METHODS: Patients received SB939 60 mg on alternate days three times per week for 3 weeks on a 4-week cycle. Primary endpoints were PSA response rate (RR) and progression-free survival (PFS). Secondary endpoints included objective response rate and duration; overall survival; circulating tumor cell (CTC) enumeration and safety. Exploratory correlative studies of the TMPRSS2-ERG fusion and PTEN biomarkers were also performed. RESULTS: Thirty-two patients were enrolled of whom 88 % had received no prior chemotherapy. The median number of SB939 cycles administered was three (range 1-8). Adverse events were generally grade 1-2, with five pts experiencing one or more grade three event. One patient died due to myocardial infarction. A confirmed PSA response was noted in two pts (6 %), lasting 3.0 and 21.6 months. In patients with measurable disease there were no objective responses. Six patients had stable disease lasting 1.7 to 8.0 months. CTC response (from ≥5 at baseline to <5 at 6 or 12 weeks) occurred in 9/14 evaluable patients (64 %). CONCLUSION: Although SB939 was tolerable at the dose/schedule given, and showed declines in CTC in the majority of evaluable patients, it did not show sufficient activity based on PSA RR to warrant further study as a single agent in unselected patients with CRPC.

Low-temperature collisional quenching of NO A(2)Σ(+)(v' = 0) by NO(X(2)Π) and O2 between 34 and 109 K.

We present measurements of collisional fluorescence quenching cross sections of NO(A(2)Σ(+), v' = 0) by NO(X(2)Π) and O2 between 34 and 109 K using a pulsed converging-diverging nozzle gas expansion, extending the temperature range of previous measurements. The thermally averaged fluorescence quenching cross sections for both species show a monotonic increase as temperature decreases in this temperature range, consistent with earlier observations. These new measurements, however, allow discrimination between predictions obtained by extrapolating fits of previous data using different functional forms that show discrepancies exceeding 120% for NO and 160% for O2 at 34 K. The measured self-quenching cross section is 52.9 Å(2) near 112 K and increases to 64.1 Å(2) at 35 K, whereas the O2 fluorescence quenching cross section is 42.9 Å(2) at 109 K and increases to 58.3 Å(2) at 34 K. Global fits of the quenching cross section temperature dependence show that, when including our current measurements, the low temperature behavior of the quenching cross sections for NO and O2 is better described by a parameterization that accounts for the long-range interactions leading to the collisional deactivation via an inverse power law model.

Anti-VEGF therapy in mRCC: differences between Asian and non-Asian patients.

BACKGROUND: Several reports suggest that vascular endothelial growth factor (VEGF)-targeted therapy in metastatic renal cell carcinoma (mRCC) may be more toxic in Asian vs non-Asian populations. Comparative efficacy of these agents with respect to ethnicity is not well characterised. METHODS: A multicentre, retrospective, cohort study using Asian and non-Asian centres which collected data on ethnicity, dose reductions and outcomes using the International mRCC Database Consortium. RESULTS: This study included 1024 (464 Asian, 560 non-Asian) patients with a 29.4 months median follow-up. The percentage of dose modifications/reductions between non-Asians and Asians was similar (55% vs 61% P=0.1197). When adjusted for risk groups, there was no difference in overall or progression-free survival between non-Asians and Asians. Patients with dose reductions due to toxicity had longer treatment durations and overall survival than those who did not in both non-Asian (10.6 vs 5.0 months, P<0.0001; 22.6 vs 16.1 months, P=0.0016, respectively) and Asian populations (8.9 vs 5.4 months, P=0.0028; 28.0 vs 18.7 months, P=0.0069, respectively). CONCLUSIONS: Adjusting for risk groups, there appears to be no difference in outcome between Asian vs non-Asian patients with mRCC treated with VEGF-targeted therapy. Judicious dose reductions may allow for better outcomes in both populations due to longer treatment durations, but direct comparisons are needed.

Oncology education in Canadian undergraduate and postgraduate medical programs: a survey of educators and learners.

BACKGROUND: The oncology education framework currently in use in Canadian medical training programs is unknown, and the needs of learners have not been fully assessed to determine whether they are adequately prepared to manage patients with cancer. METHODS: To assess the oncology education framework currently in use at Canadian medical schools and residency training programs for family (fm) and internal medicine (im), and to evaluate opinions about the content and utility of standard oncology education objectives, a Web survey was designed and sent to educators and learners. The survey recipients included undergraduate medical education curriculum committee members (umeccms), directors of fm and im programs, oncologists, medical students, and fm and im residents. RESULTS: Survey responses were received from 677 educators and learners. Oncology education was felt to be inadequate in their respective programs by 58% of umeccms, 57% of fm program directors, and 50% of im program directors. For learners, oncology education was thought to be inadequate by 67% of medical students, 86% of fm residents, and 63% of im residents. When comparing teaching of medical subspecialty-related diseases, all groups agreed that their trainees were least prepared to manage patients with cancer. A standard set of oncology objectives was thought to be possibly or definitely useful for undergraduate learners by 59% of respondents overall and by 61% of postgraduate learners. CONCLUSIONS: Oncology education in Canadian undergraduate and postgraduate fm and im training programs are currently thought to be inadequate by a majority of educators and learners. Developing a standard set of oncology objectives might address the needs of learners.

Development of a real-time PCR to detect Streptococcus equi subspecies equi.

REASONS FOR PERFORMING STUDY: Infection with Streptococcus equi subspecies equi (S. equi) is endemic in the UK. A proportion of horses serve as long-term carriers and act as a reservoir of infection. Detection of these persistently infected horses is difficult using standard culture techniques owing to a lack of sensitivity and overgrowth by contaminating bacteria. In addition, differentiation of this causative bacterium from the closely related S. equi zooepidemicus has made the development of reliable and accurate diagnostic tests difficult. OBJECTIVE: To develop and validate a sensitive and specific real-time PCR assay to detect S. equi and to compare the results with traditional culture techniques. STUDY DESIGN: Retrospective cross-sectional study. METHODS: The assay was validated using a panel of 92 samples from suspected clinical cases of strangles. These were cultured using microbial techniques and tested using the S. equi real-time PCR. The results of the 2 methods were compared, and the diagnostic sensitivity and specificity of the real-time PCR were calculated. The real-time PCR was tested for cross-reactivity with horse commensal bacteria, and the efficiencies and limits of detection were established. RESULTS: The assay had a diagnostic sensitivity of 95% and specificity of 86%. No cross-reactivity was observed with any of the bacterial species tested, including S. equi zooepidemicus. The assay detected as few as 3 gene copies. CONCLUSION: The assay is fast, sensitive and specific and will detect S. equi DNA directly from a crude extract of clinical material on a swab. POTENTIAL RELEVANCE: This assay could aid in the rapid detection of subclinical shedders of S. equi, enabling quicker treatment and helping to limit the spread of strangles in equine populations.

Outcomes of patients with metastatic renal cell carcinoma that do not meet eligibility criteria for clinical trials.

BACKGROUND: Targeted therapies in metastatic renal cell carcinoma (mRCC) have been approved based on registration clinical trials that have strict eligibility criteria. The clinical outcomes of patients treated with targeted agents but are ineligible for trials are unknown. PATIENTS AND METHODS: mRCC patients treated with vascular endothelial growth factor-targeted therapy were retrospectively deemed ineligible for clinical trials (according to commonly used inclusion/exclusion criteria) if they had a Karnofsky performance status (KPS) <70%, nonclear-cell histology, brain metastases, hemoglobin ≤9 g/dl, creatinine >2× the upper limit of normal, corrected calcium ≥12 mg/dl, platelet count of <100 × 10(3)/uL, or neutrophil count <1500/mm(3). RESULTS: Overall, 768 of 2210 (35%) patients in the International Metastatic RCC Database Consortium (IMDC) were deemed ineligible for clinical trials by the above criteria. Between ineligible versus eligible patients, the response rate, median progression-free survival (PFS) and median overall survival of first-line targeted therapy were 22% versus 29% (P = 0.0005), 5.2 versus 8.6 months, and 12.5 versus 28.4 months (both P < 0.0001), respectively. Second-line PFS (if applicable) was 2.8 months in the trial ineligible versus 4.3 months in the trial eligible patients (P = 0.0039). When adjusted by the IMDC prognostic categories, the HR for death between trial ineligible and trial eligible patients was 1.55 (95% confidence interval 1.378-1.751, P < 0.0001). CONCLUSIONS: The number of patients that are ineligible for clinical trials is substantial and their outcomes are inferior. Specific trials addressing the unmet needs of protocol ineligible patients are warranted.

Isolation and detection of extended spectrum ß-lactamase (ESBL)-producing enterobacteriaceae from meat using chromogenic agars and isothermal loop-mediated amplification (LAMP) assays.

The aim of this work was to develop a molecular method using loop-mediated isothermal amplification (LAMP) for detection of extended spectrum ß-lactamase (ESBL)-producing Enterobacteriaceae from meat, and to compare it with different isolation agars and microarrays. LAMP assays were developed for CTX-M groups 1, 2, and 9 and OXA-10-like genes. Chicken, lamb, beef, pork, and turkey samples were spiked with 10, 100, and 1,000 cfu/gram using 8 strains of ESBL-producing Enterobacteriaceae (CTX-M sequence types 1, 2, 3, 14, 15, OXA-11, SHV-2, TEM-52) +/- a mix of competitor organisms. Samples were enriched overnight in buffered peptone water (BPW) +/- antibacterials before plating to CHROMagar CTX, OXOID ESBL Brilliance agar, and MacConkey agar with 1 mg/L cefotaxime. Selected BPW broths were also tested using LAMP assays, microarrays and using cefpodoxime discs on agar. For isolation/detection of ESBL producers from beef, pork, lamb, and turkey spiked with 10 or 100 cfu/gram ESBL (natural flora only), all agars and the LAMP assays showed 100% sensitivity and specificity for ESBL spike strains. For chicken samples, both LAMP and chromogenic agars showed improved sensitivity and specificity for isolation of ESBLs compared with MacConkey agar, particularly with competitor bacteria added. In comparison, the cefpodoxime disc method and microarray showed reduced sensitivity.

Genitourinary small-cell carcinoma: a single-institution experience.

BACKGROUND: Small-cell carcinomas (sccs) of the genitourinary (gu) tract are rare systemic diseases, and there is no standard treatment strategy for patients with this malignancy. The objectives of the present study were to report the management and outcome of patients with scc of the gu tract treated at a tertiary-care institution from 1982 to 2009. METHODS: In a chart review of all patients diagnosed with scc of the gu tract between 1982 and 2009, data on demographics, clinical and pathologic characteristics, treatment, and patient outcomes were collected. RESULTS: The 58 patients identified had scc in the following primary sites: urinary bladder (n = 35), prostate (n = 17), and upper urinary tract (n = 6). In 38 patients (66%), the scc was of pure histology; in the remainder, histology was mixed. Overall, 28 patients had limited-stage disease; 24 had extensive-stage disease; and staging was unknown in 6 patients. Median survival for the entire cohort was 7.5 months, with extensive-stage disease being identified as a poor prognostic factor (survival was 22.0 months for limited-stage patients and 4.1 months for extensive-stage patients, p < 0.001). Based on site, prostate patients fared worst, with a median survival of only 5.1 months. Compared with best supportive care, treatment was associated with better outcomes (median survival: 12.3 months vs. 2.3 months, p < 0.0001). CONCLUSIONS: Small-cell cancer of the gu tract is an aggressive cancer, with a poor prognosis overall. Although there is no standard of care, patients should be treated using a multimodality approach analogous to that used in the treatment of small-cell lung cancer.