Clostridium difficile is a Gram-positive spore-forming anaerobe and a major cause of antibiotic-associated diarrhoea. Disruption of the commensal microbiota, such as through treatment with ...broad-spectrum antibiotics, is a critical precursor for colonisation by C. difficile and subsequent disease. Furthermore, failure of the gut microbiota to recover colonisation resistance can result in recurrence of infection. An unusual characteristic of C. difficile among gut bacteria is its ability to produce the bacteriostatic compound para-cresol (p-cresol) through fermentation of tyrosine. Here, we demonstrate that the ability of C. difficile to produce p-cresol in vitro provides a competitive advantage over gut bacteria including Escherichia coli, Klebsiella oxytoca and Bacteroides thetaiotaomicron. Metabolic profiling of competitive co-cultures revealed that acetate, alanine, butyrate, isobutyrate, p-cresol and p-hydroxyphenylacetate were the main metabolites responsible for differentiating the parent strain C. difficile (630Δerm) from a defined mutant deficient in p-cresol production. Moreover, we show that the p-cresol mutant displays a fitness defect in a mouse relapse model of C. difficile infection (CDI). Analysis of the microbiome from this mouse model of CDI demonstrates that colonisation by the p-cresol mutant results in a distinctly altered intestinal microbiota, and metabolic profile, with a greater representation of Gammaproteobacteria, including the Pseudomonales and Enterobacteriales. We demonstrate that Gammaproteobacteria are susceptible to exogenous p-cresol in vitro and that there is a clear divide between bacterial Phyla and their susceptibility to p-cresol. In general, Gram-negative species were relatively sensitive to p-cresol, whereas Gram-positive species were more tolerant. This study demonstrates that production of p-cresol by C. difficile has an effect on the viability of intestinal bacteria as well as the major metabolites produced in vitro. These observations are upheld in a mouse model of CDI, in which p-cresol production affects the biodiversity of gut microbiota and faecal metabolite profiles, suggesting that p-cresol production contributes to C. difficile survival and pathogenesis.
The optimal treatment of urothelial bladder cancer (UBC) with micropapillary (MP) variant histology is not clear.
To review the current literature on disease characteristics and treatment outcomes of ...MP UBC.
A systematic search was performed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement and the Cochrane Handbook for Systematic Reviews of Interventions. The primary end points were recurrence-free survival (RFS), cancer-specific survival (CSS), and overall survival (OS).
We identified 758 reports comprising a total of 3154 patients, of which 28 and 15 articles were selected for qualitative and quantitative analysis, respectively. In patients with T1 MP UBC, the 5-yr CSS rates for early radical cystectomy (RC) ranged from 81% to 100%, while they were between 60% and 85% for transurethral resection of the bladder and Bacillus Calmette-Guérin (BCG). In studies reporting on neoadjuvant chemotherapy (NAC), the rates of complete pathological response (ypT0) ranged from 11% to 55%. Nevertheless, the use of NAC did not improve RFS (hazard ratio HR 1.23, 95% confidence interval CI 0.52–2.93, p=0.6), CSS (HR 0.9, 95% CI 0.48–1.7, p=0.8), or OS (HR 1.35, 95% CI 0.98–1.86, p=0.1). Fifty-three percent (95% CI 43–63%) of patients who underwent RC alone had locally advanced disease (≥pT3), and 43% (95% CI 33–52%) were harbouring lymph node metastases. MP component at RC was not significantly associated with worse RFS (HR 1.25, 95% CI 0.88–1.78, p=0.2), CSS (HR 0.96, 95% CI 0.57–1.6, p=0.9), or OS (HR 1.20, 95% CI 0.88–1.62, p=0.3) when adjusted for pathological features.
While MP UBC is associated with clinicopathological features of advanced disease, it is not associated with worse survival outcomes in patients undergoing RC. NAC results in pathological downstaging in a significant number of patients. Nevertheless, this does not translate into better survival outcomes. The optimal treatment of patients with cT1 remains controversial.
Our results suggest that micropapillary urothelial bladder cancer does not necessarily mandate different treatment algorithms. Nevertheless, each case should be discussed individually considering other clinicopathological factors.
Micropapillary urothelial carcinoma is associated with advanced pathological features but not necessarily worse outcomes. Accordingly, it does not necessarily mandate different treatment options. Nevertheless, each case should be discussed individually in a multidisciplinary approach.
Abstract Background More than a decade since its inception, the benefits and cost efficiency of robot-assisted radical prostatectomy (RARP) continue to elicit controversy. Objective To compare ...outcomes and costs between RARP and open RP (ORP). Design, setting, and participants A cohort study of 629 593 men who underwent RP for localized prostate cancer at 449 hospitals in the USA from 2003 to 2013, using the Premier Hospital Database. Intervention RARP was ascertained through a review of the hospital charge description master for robotic supplies. Outcome measures and statistical analysis Outcomes were 90-d postoperative complications (Clavien), blood product transfusions, operating room time (ORT), length of stay (LOS), and direct hospital costs. Propensity-weighted regression analyses accounting for clustering by hospitals and survey weighting ensured nationally representative estimates. Results and limitations RARP utilization rapidly increased from 1.8% in 2003 to 85% in 2013 ( p < 0.001). RARP patients ( n = 311 135) were less likely to experience any complications (odds ratio OR 0.68, p < 0.001) or prolonged LOS (OR 0.28, p < 0.001), or to receive blood products (OR 0.33, p = 0.002) compared to ORP patients ( n = 318 458). The adjusted mean ORT was 131 min longer for RARP ( p = 0.002). The 90-d direct hospital costs were higher for RARP (+$4528, p < 0.001), primarily attributed to operating room and supplies costs. Costs were no longer signficantly different between ORP and RARP among the highest-volume surgeons (≥104 cases/yr; +$1990, p = 0.40) and highest-volume hospitals (≥318 cases/yr; +$1225, p = 0.39). Limitations include the lack of oncologic characteristics and the retrospective nature of the study. Conclusions Our contemporary analysis reveals that RARP confers a perioperative morbidity advantage at higher cost. In the absence of large randomized trials because of the widespread adoption of RARP, this retrospective study represents the best available evidence for the morbidity and cost profile of RARP versus ORP. Patient summary In this large study of men with prostate cancer who underwent either open or robotic radical prostatectomy, we found that robotic surgery has a better morbidity profile but costs more.
Abstract Given the lack of randomized evidence comparing trimodal therapy (TMT) to radical cystectomy (RC) for muscle-invasive urothelial carcinoma of the bladder (UCB), we performed an observational ...cohort study to examine the comparative effectiveness of these two definitive treatments. Within the National Cancer Data Base (2004–2011),we identified 1257 (9.8%) and 11 586 (90.2%) patients who received TMT and RC, respectively. Inverse probability of treatment weighting (IPTW)–adjusted Kaplan-Meier analysis showed that median overall survival (OS) was similar between the TMT (40 mo, 95% confidence interval CI 34–46) and RC groups (43 mo 95% CI 41–45; p = 0.3). In IPTW-adjusted Cox regression analysis with a time-varying covariate, TMT was associated with a significant adverse impact on long-term OS (hazard ratio 1.37, 95% CI 1.16–1.59; p < 0.001). Interaction terms indicated that the adverse treatment effect of TMT versus RC decreased with age ( p = 0.004), while there was no significant interaction with gender ( p = 0.6), Charlson comorbidity index ( p = 0.09) or cT stage ( p = 0.8). In conclusion, we found that TMT was generally associated with worse long-term OS compared to RC for muscle-invasive UCB. However, the survival benefit of RC should be weighed against the risks of surgery, especially in older patients. These results are preliminary and emphasize the need for a randomized controlled trial to compare TMT versus RC. Patient summary We examined the comparative effectiveness of trimodal therapy versus radical cystectomy for muscle-invasive urothelial carcinoma of the bladder. We found that trimodal therapy was generally associated with worse long-term overall survival, although there may be no difference with radical cystectomy in older individuals.
Purpose There is limited evidence to support the use of adjuvant chemotherapy (AC) after radical nephroureterectomy (RNU) for upper tract urothelial carcinoma (UTUC). Against this backdrop, we ...hypothesized that such treatment is associated with overall survival (OS) benefit in patients with locally advanced and/or positive regional lymph node disease. Patients and Methods Within the National Cancer Database (2004 to 2012), we identified 3,253 individuals who received AC or observation after RNU for pT3/T4 and/or pN+ UTUC. Inverse probability of treatment weighting (IPTW) -adjusted Kaplan-Meier curves and Cox proportional hazards regression analyses were used to compare OS of patients in the two treatment groups. In addition, we performed exploratory analyses of treatment effect according to age, gender, Charlson comorbidity index, pathologic stage (pT3/T4N0, pT3/T4Nx and pTanyN+), and surgical margin status. Results Overall, 762 (23.42%) and 2,491 (76.58%) patients with pT3/T4 and/or pN+ UTUC received AC and observation, respectively, after RNU. IPTW-adjusted Kaplan-Meier curves showed that median OS was significantly longer for AC versus observation (47.41 interquartile range,19.88 to 112.39 v 35.78 interquartile range, 14.09 to 99.22 months; P < .001). The 5-year IPTW-adjusted rates of OS for AC versus observation were 43.90% and 35.85%, respectively. In IPTW-adjusted Cox proportional hazards regression analysis, AC was associated with a significant OS benefit (hazard ratio, 0.77 95% CI, 0.68 to 0.88; P < .001). This benefit was consistent across all subgroups examined (all P < .05), and no significant heterogeneity of treatment effect was observed (all P
> .05). Conclusion We report an OS benefit in patients who received AC versus observation after RNU for pT3/T4 and/or pN+ UTUC. Although our results are limited by the usual biases related to the observational study design, we believe that the present findings should be considered when advising post-RNU management of advanced UTUC, pending level I evidence.
Public child welfare agencies are legally responsible for the safety, permanency, and well-being of millions of vulnerable children and youth. Fulfilling this critical societal function occurs in an ...occupational environment consisting of large caseloads and immense time pressures. Research demonstrates that exposure to high work demands can negatively impact employees' affective well-being. Despite this well-documented finding, no known published quantitative research study has investigated if workplace resources, such as job control, can help buffer work demands' adverse effects on the affective well-being of public child welfare case managers. This study addressed this issue by testing a recently introduced nonlinear demand by linear control model on a sample of 349 county-based public child welfare case managers from the state of New York. As expected, the moderated nonlinear model was statistically and significantly associated with job-related affective well-being in the expected direction. This finding is the first-of-its-kind and, therefore, adds to both the child welfare and DC model literatures.
•Karasek's seminal linear multiplicative model has yielded inconsistent findings.•This study surveyed 419 public child welfare case managers from the state of New York were surveyed.•A significant and positive nonlinear demand by linear control interaction on affective wellbeing was observed.•High-control jobs decreased case managers' affective wellbeing at lower and intermediate levels of work demands.•High-control jobs buffered high work demands' detrimental impact on case managers' affective wellbeing.
Radiation-associated muscle-invasive bladder cancers arising after prostate cancer radiotherapy have mutational evidence of radiation exposure but share many driver alterations with ...non–radiation-associated muscle-invasive bladder cancers.
Muscle-invasive bladder cancer (MIBC) is a rare but serious event following definitive radiation for prostate cancer. Radiation-associated MIBC (RA-MIBC) can be difficult to manage given the challenges of delivering definitive therapy to a previously irradiated pelvis. The genomic landscape of RA-MIBC and whether it is distinct from non–RA-MIBC are unknown.
To define mutational features of RA-MIBC and compare the genomic landscape of RA-MIBC with that of non–RA-MIBC.
We identified patients from our institution who received radiotherapy for prostate cancer and subsequently developed MIBC.
We performed whole exome sequencing of bladder tumors from RA-MIBC patients. Tumor genetic alterations including mutations, copy number alterations, and mutational signatures were identified and were compared with genetic features of non–RA-MIBC. We used the Kaplan-Meier method to estimate recurrence-free (RFS) and overall (OS) survival.
We identified 19 RA-MIBC patients with available tumor tissue (n = 22 tumors) and clinical data. The median age was 76 yr, and the median time from prostate cancer radiation to RA-MIBC was 12 yr. The median RFS was 14.5 mo and the median OS was 22.0 mo. Compared with a cohort of non–RA-MIBC analyzed in parallel, there was no difference in tumor mutational burden, but RA-MIBCs had a significantly increased number of short insertions and deletions (indels) consistent with previous radiation exposure. We identified mutation signatures characteristic of APOBEC-mediated mutagenesis, aging, and homologous recombination deficiency. The frequency of mutations in many known bladder cancer genes, including TP53, KDM6A, and RB1, as well as copy number alterations such as CDKN2A loss was similar in RA-MIBC and non-RA-MIBC.
We identified unique mutational properties that likely contribute to the distinct biological and clinical features of RA-MIBC.
Bladder cancer is a rare but serious diagnosis following radiation for prostate cancer. We characterized genetic features of bladder tumors arising after prostate radiotherapy, and identify similarities with and differences from bladder tumors from patients without previous radiation.
In metastatic urothelial carcinoma (mUC), predictive biomarkers that correlate with response to immune checkpoint inhibitors (ICIs) are lacking. Here, we interrogated genomic and clinical features ...associated with response to ICIs in mUC.
Sixty two mUC patients treated with ICI who had targeted tumour sequencing were studied. We examined associations between candidate biomarkers and clinical benefit (CB, any objective reduction in tumour size) versus no clinical benefit (NCB, no change or objective increase in tumour size). Both univariable and multivariable analyses for associations were conducted. A comparator cohort of 39 mUC patients treated with taxanes was analysed by using the same methodology.
Nine clinical and seven genomic factors correlated with clinical outcomes in univariable analysis in the ICI cohort. Among the 16 factors, neutrophil-to-lymphocyte ratio (NLR) ≥5 (OR = 0.12, 95% CI, 0.01-1.15), visceral metastasis (OR = 0.05, 95% CI, 0.01-0.43) and single-nucleotide variant (SNV) count < 10 (OR = 0.04, 95% CI, 0.006-0.27) were identified as independent predictors of NCB to ICI in multivariable analysis (c-statistic = 0.90). None of the 16 variables were associated with clinical benefit in the taxane cohort.
This three-factor model includes genomic (SNV count >9) and clinical (NLR <5, lack of visceral metastasis) variables predictive for benefit to ICI but not taxane therapy for mUC. External validation of these hypothesis-generating results is warranted to enable use in routine clinical care.
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