Abstract Background Extracellular microRNAs (miRNAs) embedded in circulating exosomes may serves as prognostic biomarkers in cancer. Objective To identify and evaluate plasma exosomal miRNAs for ...prognosis in castration-resistant prostate cancer (CRPC). Design, setting, and participants RNA sequencing was performed to identify candidate exosomal miRNAs associated with overall survival in a screening cohort of 23 CRPC patients. Candidate miRNAs were further evaluated for prognosis using quantitative real-time polymerase chain reaction in a follow-up cohort of 100 CRPC patients. Outcome measurements and statistical analysis Cox regression and Kaplan-Meier survival analyses were used to evaluate survival association using candidate miRNAs along with clinical prognostic factors. Results and limitations RNA sequencing in screening cohort generated approximately 6.80 million mappable reads per patient. Of those with normalized read counts ≥5, 43% were mapped to miRNAs for a total of 375 known and 57 novel miRNAs. Cox regression analysis identified an association of miR-1290, -1246, and -375 with overall survival (false discover rate < 0.05). Of those, higher levels of miR-1290 and -375 were significantly associated with poor overall survival ( p < 0.004) in the follow-up cohort. Incorporation of miR-1290/-375 into putative clinical prognostic factors-based models in CRPC stage significantly improved predictive performance with a time-dependent area under the curve increase from 0.66 to 0.73 ( p = 6.57 × 10−6 ). Conclusions Plasma exosomal miR-1290 and miR-375 are promising prognostic biomarkers for CRPC patients. Prospective validation is needed for further evaluation of these candidate miRNAs. Patient summary In this study, we evaluated whether small RNAs circulating in blood could be used to predict clinical outcomes in late-stage prostate cancer patients. We identified two blood-based small RNAs whose levels showed significant association with survival. Our results warrant further investigation because the noninvasive blood-based test has great potential in the management of late-stage prostate cancer.
Background
Sodium‐glucose cotransporter 2 (SLGT2) inhibitors has been associated with an increased risk of genital infections secondary to increased glycosuria.
Case Report
We report a case of a ...41‐year‐old man with type 2 diabetes treated with empagliflozin and metformin who presented with scrotal swelling. He described multiple preceding episodes of genital thrush for which he self‐administered over‐the‐counter anti‐fungal treatment. On examination, he was afebrile and hemodynamically stable. Perineal examination revealed grossly swollen and indurated scrotum with bilateral inguinal lymphadenopathy. Investigations showed elevated inflammatory markers and HbA1c of 99 mmol/mol (11.2%). Computed tomography revealed features consistent with Fournier's gangrene. He underwent emergency exploration and debridement under anaesthetic with a later return to theatre for further exploration, washout and application of a vacuum dressing. He then received a split skin graft to his perineum. He required a 2‐week course of intravenous antibiotics and was discharged home on oral antibiotics. Empagliflozin was ceased on admission and he was commenced on a basal bolus insulin regimen for glycaemic optimisation.
Conclusion
There is a wide clinical spectrum of genital infections associated with SGLT2 inhibitors with most being generally mild and easily treated. However, risk factors such as diabetes, obesity, immunosuppressed states, smoking, alcohol abuse and end‐stage renal or liver failure may increase the risk of potentially more severe infections such as Fournier's gangrene. Timely cessation of SGLT2 inhibitors in individuals with multiple risk factors may help prevent progression to more severe genital infections.
Guidelines are presented for safe practice in the use of intravenous drug infusions for general anaesthesia. When maintenance of general anaesthesia is by intravenous infusion, this is referred to as ...total intravenous anaesthesia. Although total intravenous anaesthesia has advantages for some patients, the commonest technique used for maintenance of anaesthesia in the UK and Ireland remains the administration of an inhaled volatile anaesthetic. However, the use of an inhalational technique is sometimes not possible, and in some situations, inhalational anaesthesia is contraindicated. Therefore, all anaesthetists should be able to deliver total intravenous anaesthesia competently and safely. For the purposes of simplicity, these guidelines will use the term total intravenous anaesthesia but also encompass techniques involving a combination of intravenous infusion and inhalational anaesthesia. This document is intended as a guideline for safe practice when total intravenous anaesthesia is being used, and not as a review of the pros and cons of total intravenous anaesthesia vs. inhalational anaesthesia in situations where both techniques are possible.
Most patients with follicular lymphoma (FL) experience multiple relapses necessitating subsequent lines of therapy. Ibrutinib, a Bruton tyrosine kinase (BTK) inhibitor approved for the treatment of ...several B-cell malignancies, showed promising activity in FL in a phase 1 study. We report the results of a phase 2 trial evaluating ibrutinib in recurrent FL. Forty patients with recurrent FL were treated with ibrutinib 560 mg/d until progression or intolerance. The primary end point was overall response rate (ORR). Exploratory analyses included correlations of outcome with recurrent mutations identified in a cancer gene panel that used next-generation sequencing in pretreatment biopsies from 31 patients and results of early interim positron emission tomography/computed tomography scans in 20 patients. ORR was 37.5% with a complete response rate of 12.5%, median progression-free survival (PFS) of 14 months, and 2-year PFS of 20.4%. Response rates were significantly higher among patients whose disease was sensitive to rituximab (52.6%) compared with those who were rituximab refractory (16.7%) (P = .04). CARD11 mutations were present in 16% of patients (5 of 31) and predicted resistance to ibrutinib with only wild-type patients responding (P = .002). Maximum standardized uptake value at cycle 1 day 8 correlated with response and PFS. Ibrutinib was well-tolerated with a toxicity profile similar to labeled indications. Ibrutinib is a well-tolerated treatment with modest activity in relapsed FL. Evaluation of BTK inhibitors in earlier lines of therapy may be warranted on the basis of improved response rates in rituximab-sensitive disease. Somatic mutations such as CARD11 may have an impact on response to ibrutinib, may inform clinical decisions, and should be evaluated in larger data sets. This trial was registered at www.clinicaltrials.gov as #NCT01849263.
•Ibrutinib has modest activity in FL with low response rates in rituximab-refractory patients.•CARD11 mutations predict for lack of response to ibrutinib.
Voice disorders affect patients profoundly, and acoustic tools can potentially measure voice function objectively. Disordered sustained vowels exhibit wide-ranging phenomena, from nearly periodic to ...highly complex, aperiodic vibrations, and increased "breathiness". Modelling and surrogate data studies have shown significant nonlinear and non-Gaussian random properties in these sounds. Nonetheless, existing tools are limited to analysing voices displaying near periodicity, and do not account for this inherent biophysical nonlinearity and non-Gaussian randomness, often using linear signal processing methods insensitive to these properties. They do not directly measure the two main biophysical symptoms of disorder: complex nonlinear aperiodicity, and turbulent, aeroacoustic, non-Gaussian randomness. Often these tools cannot be applied to more severe disordered voices, limiting their clinical usefulness.
This paper introduces two new tools to speech analysis: recurrence and fractal scaling, which overcome the range limitations of existing tools by addressing directly these two symptoms of disorder, together reproducing a "hoarseness" diagram. A simple bootstrapped classifier then uses these two features to distinguish normal from disordered voices.
On a large database of subjects with a wide variety of voice disorders, these new techniques can distinguish normal from disordered cases, using quadratic discriminant analysis, to overall correct classification performance of 91.8 +/- 2.0%. The true positive classification performance is 95.4 +/- 3.2%, and the true negative performance is 91.5 +/- 2.3% (95% confidence). This is shown to outperform all combinations of the most popular classical tools.
Given the very large number of arbitrary parameters and computational complexity of existing techniques, these new techniques are far simpler and yet achieve clinically useful classification performance using only a basic classification technique. They do so by exploiting the inherent nonlinearity and turbulent randomness in disordered voice signals. They are widely applicable to the whole range of disordered voice phenomena by design. These new measures could therefore be used for a variety of practical clinical purposes.
Abstract
This article interrogates the normative coherence of the label of ‘digital constitutionalism’. In particular, I argue that the use of the label ‘constitutionalism’ in digital contexts often ...conflates the practical realities of existing contractual governance models with the superficial appeal of constitutional structures. As a result, the label is misleading in both normative and qualitative terms as it obscures the true nature of the governance architectures to which it is applied, which are more appropriately understood as implementing a distinct genre of ‘private policy’.
While the probability of malignant versus benign histology based on renal tumor size has been described, this alone does not sufficiently inform decision-making in the modern era since indolent ...malignant tumors can be managed with active surveillance.
To characterize the probability of aggressive versus indolent histology based on radiographic tumor size.
We evaluated patients who underwent radical or partial nephrectomy at Mayo Clinic for a pT1-2, pNx/0, M0 solid renal tumor between 1990 and 2010. Pathology was reviewed by one genitourinary pathologist. High-grade clear-cell renal cell carcinoma (RCC), high-grade papillary RCC, collecting duct RCC, translocation-associated RCC, hereditary leiomyomatosis RCC, unclassified RCC, and malignant non-RCC tumors were all considered aggressive, as well as any tumors demonstrating coagulative necrosis (except low-grade papillary RCC) or sarcomatoid differentiation. The remaining benign and malignant tumors were considered indolent.
Cancer-specific survival (CSS) was estimated using the Kaplan-Meier method. Logistic regression models were used to estimate the probability of malignant and aggressive histology based on tumor size. Sex-stratified analyses were also performed.
Of the 2650 patients included, there were 1860 patients with indolent tumors (300 benign; 1560 malignant) and 790 with aggressive tumors. The 10-yr CSS was 96% for indolent malignant tumors and 81% for aggressive malignant tumors. The predicted percentages of any malignant histology as well as aggressive histology increased with tumor size. Specifically, 2cm, 3cm, and 4cm tumors have an estimated 84%, 87%, and 88% likelihood of malignancy, respectively, and an 18%, 24%, and 29% likelihood of aggressive histology, respectively. For any given tumor size, men had a greater chance of aggressive histology than women. Potential limitations of this observational surgical cohort include selection bias.
We present tumor size-based estimates of the probability of aggressive histology for renal masses. This information should be useful for initial patient counseling and management.
Active surveillance is an option for kidney masses, even if they are malignant. Beyond knowing whether the mass is benign or cancer, it is important to know whether or not it is an aggressive tumor. This study presents tumor size-specific and sex-specific estimates of the probability of cancer overall and aggressive cancer among patients with a kidney mass in order to aid with initial decision-making.
We herein present tumor size-specific and sex-specific estimates of the probability of malignant histology and aggressive histology among patients with an indeterminate renal mass in order to aid with initial decision-making.
The optimal sequence of cytoreductive nephrectomy and targeted therapy of metastatic renal cell carcinoma is unclear. We compared overall survival between patients with metastatic renal cell ...carcinoma treated with initial cytoreductive nephrectomy with or without subsequent targeted therapy vs initial targeted therapy with or without subsequent cytoreductive nephrectomy.
We evaluated the records of cases in the National Cancer Database diagnosed with metastatic renal cell carcinoma between 2006 and 2013 who were treated with cytoreductive nephrectomy and/or targeted therapy. Receipt of targeted therapy after initial cytoreductive nephrectomy and cytoreductive nephrectomy after initial targeted therapy were evaluated on competing risks analyses. To account for treatment selection bias, inverse probability of treatment weighting was performed based on the propensity to receive initial cytoreductive nephrectomy or initial targeted therapy. Overall survival was compared between the groups by Kaplan-Meier analysis and Cox proportional hazards regression.
Of the 15,068 patients included in study 6,731 underwent initial cytoreductive nephrectomy and 8,337 received initial targeted therapy. Six months after initial cytoreductive nephrectomy 48.0% of patients received targeted therapy, of whom 15.3% died after initial cytoreductive nephrectomy prior to targeted therapy. Six months after initial targeted therapy 4.7% of patients underwent cytoreductive nephrectomy, of whom 44.9% died after initial targeted therapy prior to cytoreductive nephrectomy. Initial cytoreductive nephrectomy (OR 2.02, 95% CI 1.69–2.43, p <0.001) and cytoreductive nephrectomy after initial targeted therapy (HR 2.6, 95% CI 1.69–4.01, p <0.001) were more likely to be performed at academic vs community institutions. On inverse probability of treatment weighting analysis initial cytoreductive nephrectomy was associated with improved overall survival compared to initial targeted therapy (median 16.5 vs 9.2 months, HR 0.61, 95% CI 0.59–0.64, p <0.001).
Given the greater likelihood of receiving multimodal therapy and the associated overall survival benefit, these data support cytoreductive nephrectomy as the initial approach to metastatic renal cell carcinoma in appropriate surgical candidates. Continued efforts are warranted to establish the optimal multimodal approach in these patients.
To evaluate the genetic relatedness and carbapenem resistance mechanisms among carbapenem-non-susceptible Pseudomonas aeruginosa collected during 2009-11 in 14 European and Mediterranean countries.
...Doripenem-non-susceptible (MIC >2 mg/L) isolates were tested for susceptibility to imipenem, meropenem, doripenem, aztreonam, ceftazidime and cefepime with and without phenyl-arginine-β-naphthylamide (PAβN) (efflux inhibitor) and/or cloxacillin (AmpC inhibitor). Carbapenemase screening was performed by PCR and sequencing. Expression of chromosomal ampC, mexA, mexC, mexE and mexX was determined by quantitative real-time PCR using P. aeruginosa PAO1 or a group of susceptible isolates as baseline. Clonality was evaluated by PFGE and multilocus sequence typing.
Among 529 (25.6% overall) carbapenem-non-susceptible P. aeruginosa, 106 were positive for metallo-β-lactamase (MβL) genes encoding VIM-2 (76 strains), VIM-4 (14), VIM-1 (7) and VIM-5 (5). IMP-15 and three new MβLs (IMP-33, VIM-36 and VIM-37) were detected in one strain each. An increasing prevalence of MβL producers was noted in 2011 (30.6%) compared with previous years (13.4% and 12.3% in 2009 and 2010, respectively). Isolates displayed high genetic diversity, with 401 unique profiles detected. CC235 and ST111 were detected among MβL-producing clusters. The PAβN/cloxacillin effect ranged from 90.0% to 56.5%/from 1.3% to 21.2%. OprD decrease/loss was the most prevalent intrinsic mechanism and was detected among 94.9% of the P. aeruginosa, followed by AmpC (44.4%) and MexAB-OprM (20.1%). When using the susceptible group of isolates as baseline, MexAB-OprM became as prevalent as OprD decrease/loss.
Increasing MβL prevalence is worrisome in various European countries; however, intrinsic resistance mechanisms in a highly genetically diverse population of carbapenem-non-susceptible P. aeruginosa are probably a matter for greater concern in these countries.
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