Purpose
A single-center study was conducted to investigate the impact of sarcopenia as a predictor for 90-day mortality (90 dM) and complications within 90 days after radical cystectomy for bladder ...cancer.
Methods
In total, 327 patients with preoperative available digital computed tomography (CT) scans of the abdomen and pelvis were identified. The lumbar skeletal muscle index was measured using preoperative abdominal CT to assess sarcopenia. Complications were recorded and graded according to Clavien–Dindo (CD). Predictors of 90 dM and complications within 90 days were analyzed by uni- and multivariable logistic regression.
Results
Of the 327 patients, 262 (80%) were male and 108 (33%) patients were classified as sarcopenic. Within 90 days, 28 (7.8%) patients died, of whom 15 patients were sarcopenic and 13 were not. In multivariable logistic regression analysis, sarcopenia (OR 2.59; 95% CI 1.13–5.95;
p
= 0.025), ASA 3–4 (OR 2.53; 95% CI 1.10–5.82;
p
= 0.029) and cM + (OR 7.43; 95% CI 2.34–23.64;
p
= 0.001) were independent predictors of 90-day mortality. Sarcopenic patients experienced significantly more complications, i.e., CD 4a–5 (
p
= 0.003), compared to non-sarcopenic patients. In multivariable logistic regression analysis, sarcopenia was independently associated with CD ≥ 3b complications corrected for age, BMI, ASA-Score and type of urinary diversion.
Conclusions
We reported that sarcopenia proved an independent predictor for 90 dM and complications in patients undergoing RC for bladder cancer.
Abstract Background Despite recent improvements, radical cystectomy (RC) is still associated with adverse rates for 90-d mortality. Objective To validate the performance of the Isbarn nomogram ...incorporating age and postoperative tumor characteristics for predicting 90-d RC mortality in a multicenter series and to generate a new nomogram based strictly on preoperative parameters. Design, setting, and participants Data of 679 bladder cancer (BCa) patients treated with RC at 18 institutions in 2011 were prospectively collected, from which 597 patients were eligible for final analysis. Intervention RC for BCa. Outcome measurements and statistical analysis An established prediction tool, the Isbarn nomogram, was applied to our cohort. For the purpose of external validation, model discrimination was measured using the receiver operating characteristics–derived area under the curve. Calibration plots examined the relationship between predicted and observed probabilities. Univariable and multivariable logistic regression models were fitted to assess the impact of preoperative characteristics on 90-d mortality. Results and limitations The 30-, 60-, and 90-d mortality rates in the development cohort ( n = 597) were 2.7%, 6.7%, and 9.0%, respectively. The Isbarn nomogram predicted individual 90-d mortality with an accuracy of 68.6%. Our preoperative multivariable model identified age (odds ratio OR:1.052), American Society of Anesthesiologists score (OR: 2.274), hospital volume (OR: 0.982), clinically lymphatic metastases (OR: 4.111), and clinically distant metastases (OR: 7.788) (all p < 0.05) as independent predictors of 90-d mortality (predictive accuracy: 78.8%). Our conclusions are limited by the lack of an external validation of the preoperative model. Conclusions The Isbarn nomogram was validated with moderate discrimination. Our newly developed model consisting of preoperative characteristics might outperform existing models. Our model might be particularly suitable for preoperative patient counseling. Patient summary The current report validated an established nomogram predicting 90-d mortality in patients with bladder cancer after radical cystectomy (RC). We developed a new prediction tool consisting of strictly preoperative parameters, thus allowing clinicians an optimal consultation for RC candidates.
Background
A multicentre study was conducted to investigate the impact of sarcopenia as an independent predictor of oncological outcome after radical cystectomy for bladder cancer.
Methods
In total, ...500 patients with available digital computed tomography scans of the abdomen obtained within 90 days before surgery were identified. The lumbar skeletal muscle index was measured using pre‐operative computed tomography. Cancer‐specific survival (CSS) and overall survival (OS) were estimated using Kaplan–Meier curves. Predictors of CSS and OS were analysed by univariable and multivariable Cox regression models.
Results
Based on skeletal muscle index, 189 patients (37.8%) were classified as sarcopenic. Patients with sarcopenia were older compared with their counterparts (P = 0.002), but both groups were comparable regarding to gender, comorbidity, tumor, node, metastasis (TNM) stage, and type of urinary diversion (all P > 0.05). In total, 234 (46.8%) patients died, and of these, 145 (29.0%) died because of urothelial carcinoma of the bladder. Sarcopenic patients had significantly worse 5 year OS (38.3% vs. 50.5%; P = 0.002) and 5 year CSS (49.5% vs. 62.3%; P = 0.016) rates compared with patients without sarcopenia. Moreover, sarcopenia was associated independently with both increased all‐cause mortality (hazard ratio, 1.43; 95% confidence interval 1.09–1.87; P = 0.01) and increased cancer‐specific mortality (hazard ratio, 1.42; 95% confidence interval, 1.00–2.02; P = 0.048). Our results are limited by the lack of prospective frailty assessment.
Conclusions
Sarcopenia has been shown to be an independent predictor for OS and CSS in a large multicentre study with patients undergoing radical cystectomy for bladder cancer.
Renal cell carcinoma (RCC) is frequently infiltrated by immune cells, a process which is governed by chemokines. CD8
T cells in the RCC tumor microenvironment (TME) may be exhausted which most ...likely influence therapy response and survival. The aim of this study was to evaluate chemokine-driven T cell recruitment, T cell exhaustion in the RCC TME, as well as metabolic processes leading to their functional anergy in RCC. Eight publicly available bulk RCC transcriptome collectives (n=1819) and a single cell RNAseq dataset (n=12) were analyzed. Immunodeconvolution, semi-supervised clustering, gene set variation analysis and Monte Carlo-based modeling of metabolic reaction activity were employed. Among 28 chemokine genes available,
mRNA expression were significantly increased in RCC compared to normal kidney tissue and also strongly associated with tumor-infiltrating effector memory and central memory CD8
T cells in all investigated collectives. M1 TAMs, T cells, NK cells as well as tumor cells were identified as the major sources of these chemokines, whereas T cells, B cells and dendritic cells were found to predominantly express the cognate receptors. The cluster of RCCs characterized by high chemokine expression and high CD8
T cell infiltration displayed a strong activation of IFN/JAK/STAT signaling with elevated expression of multiple T cell exhaustion-associated transcripts. Chemokine
RCCs were characterized by metabolic reprogramming, in particular by downregulated OXPHOS and increased IDO1-mediated tryptophan degradation. None of the investigated chemokine genes was significantly associated with survival or response to immunotherapy. We propose a chemokine network that mediates CD8
T cell recruitment and identify T cell exhaustion, altered energy metabolism and high IDO1 activity as key mechanisms of their suppression. Concomitant targeting of exhaustion pathways and metabolism may pose an effective approach to RCC therapy.
The available randomised controlled trials (RCTs) assessing the influence of peritoneal interposition flaps (PIF) on the reduction of symptomatic lymphoceles (sLCs) post robot-assisted radical ...prostatectomy (RARP) do not constitute a sufficient follow-up (FU) to assess the long-term effects. The PIANOFORTE trial was the first of these RCTs, showing no sLC reduction at the 3-month FU. Therefore, all 232 patients from the PIANOFORTE trial were invited for long-term FU. One hundred seventy-six patients (76%) presented themselves for FU and constituted the study group (SG). The median FU duration was 43 months. No significant differences in group allocation or LC endpoints at 90 days were observed between SG patients and patients not presenting themselves for the FU. During the FU period, four patients (2.3%) in the SG developed sLCs, and six patients (3.4%) developed asymptomatic lymphoceles (aLCs), which persisted in five patients (2.9%). There were no significant differences between PIF and non-PIF regarding sLC/aLC formation or persistence, newly developed complications, stress urinary incontinence or biochemical/clinical tumour recurrence. Therefore, this long-term FU confirms the primary outcomes of the PIANOFORTE trial that, while PIF does not impact complications or functionality, it does not reduce sLC/aLC rates. Furthermore, it shows the potential occurrence of LC after the third postoperative month.
We assessed a wide array of body composition parameters to identify those most relevant as prognostic tools for patients undergoing radical cystectomy (RC) due to bladder cancer (BC).
In this ...retrospective, single-center study, preoperative computed tomography (CT) scans of 657 patients were measured at the level of the 3rd lumbar vertebra (L3) to determine common body composition indices including sarcopenia, myosteatosis, psoas muscle index (PMI), subcutaneous and visceral fat index (SFI and VFI), visceral-to-subcutaneous fat ratio (VSR), and visceral obesity. Predictors of overall survival (OS) and cancer-specific survival (CSS) were identified in univariate and multivariate survival analysis.
Sarcopenia and a low PMI were independently associated with shorter OS (Sarcopenia: HR 1.30; 95% CI 1.02-1.66;
= 0.04 and a low PMI: HR 1.32; 95% CI 1.02-1.70;
= 0.03) and CSS (Sarcopenia: HR 1.64; 95% CI 1.19-2.25;
< 0.01 and a low PMI: HR 1.41; 95% CI 1.02-1.96;
= 0.04). Myosteatosis, measured as decreasing average Hounsfield units of skeletal muscle, was an independent risk factor for OS (HR 0.98; 95% CI 0.97-1.00;
= 0.01) and CSS (HR 0.98; 95% CI 0.96-1.00;
< 0.05). The assessed adipose tissue indices were not significant predictors for OS and CSS.
Sarcopenia, a low PMI, and myosteatosis are independent predictors for OS and CSS in patients undergoing radical cystectomy for bladder cancer.
Transcutaneous tibial nerve stimulation (TTNS) has proven to be a valuable treatment option for various lower urinary tract conditions, such as overactive bladder syndrome and neurogenic detrusor ...overactivity. The aim of this study was to investigate acute changes in urodynamic parameters due to bilateral TTNS.
Fifty-one patients (18-87 years; 61% female) with various lower urinary tract symptoms were enrolled in this study. They were single-blinded and randomly assigned to receive simultaneous bilateral TTNS either during their first urodynamic examination, followed by a second round using a placebo stimulation technique, or vice versa.
For subjects without signs of anatomical pathologies, the filling volume at the first desire to void (FDV) increased significantly by 54 mL (interquartile range IQR, 26-81 mL; P<0.01) under the influence of TTNS compared to placebo. The maximum cystometric capacity increased by 41 mL (IQR, 10-65 mL; P=0.02). The median micturition volume of patients with pathological postvoid residual volumes (>100 mL) increased by 76 mL compared to patients without urinary retention (IQR, 6-166 mL; P=0.03).
Compared to placebo, simultaneous bilateral TTNS showed significant improvements in bladder functioning, such as delayed FDV, increased maximum cystometric capacity, and reduced urinary retention. Patients with signs of anatomical pathologies did not seem to benefit from TTNS. Further studies need to be conducted to compare the effectiveness of bilateral versus unilateral TTNS.
Radical nephroureterectomy (NUE) is the gold standard treatment for high-risk urothelial cancer of the upper urinary tract (UTUC). Besides sarcopenia and frailty, fat distribution is moving ...increasingly into focus. Components of body composition were assessed in patients undergoing NUE due to UTUC. The study cohort included 142 patients. By using CT-based measurements, the skeletal muscle index (SMI), subcutaneous adipose tissue index (SATI), and visceral adipose tissue index (VATI) were measured at the height of the third lumbar vertebra. Overall survival (OS) and cancer-specific survival (CSS) were estimated using univariable und multivariable Cox regression models. The prevalence of sarcopenia in the study population (
= 142) was 37%. OS and CSS were significantly reduced in sarcopenic patients. In the multivariable cox regression analysis, including age, ACE-27, T-stage, R-stage, LVI and necrosis, sarcopenia remained a significant risk factor of OS (HR, 1.77; 95% CI 1.02-3.07;
= 0.042) and CSS (HR, 2.17; 95% CI 1.18-3.99;
= 0.012). High visceral adipose tissue seems to be protective, although not statistically significant. Sarcopenia is a comorbidity-independent risk factor in patients who underwent NUE due to UTUC. Visceral fat represents a potentially protective factor. These results suggest that specific factors of body composition can be used for better risk stratification.
L-kynurenine is a tryptophan-derived immunosuppressive metabolite and precursor to neurotoxic anthranilate and quinolinate. We evaluated the stereoisomer D-kynurenine as an immunosuppressive ...therapeutic which is hypothesized to produce less neurotoxic metabolites than L-kynurenine.
L-/D-kynurenine effects on human and murine T cell function were examined in vitro and in vivo (homeostatic proliferation, colitis, cardiac transplant). Kynurenine effects on T cell metabolism were interrogated using 13C glucose, glutamine and palmitate tracing. Kynurenine was measured in tissues from human and murine tumours and kynurenine-fed mice.
We observed that 1 mM D-kynurenine inhibits T cell proliferation through apoptosis similar to L-kynurenine. Mechanistically, 13C-tracing revealed that co-stimulated CD4+ T cells exposed to L-/D-kynurenine undergo increased β-oxidation depleting fatty acids. Replenishing oleate/palmitate restored effector T cell viability. We administered dietary D-kynurenine reaching tissue kynurenine concentrations of 19 μM, which is close to human kidney (6 μM) and head and neck cancer (14 μM) but well below the 1 mM required for apoptosis. D-kynurenine protected Rag1–/– mice from autoimmune colitis in an aryl-hydrocarbon receptor dependent manner but did not attenuate more stringent immunological challenges such as antigen mismatched cardiac allograft rejection.
Our dietary kynurenine model achieved tissue concentrations at or above human cancer kynurenine and exhibited only limited immunosuppression. Sub-suppressive kynurenine concentrations in human cancers may limit the responsiveness to indoleamine 2,3-dioxygenase inhibition evaluated in clinical trials.
The study was supported by the NIH, the Else Kröner-Fresenius-Foundation, Laffey McHugh foundation, and American Society of Nephrology.
Objectives
To investigate established prognostic factors and relatively new histopathological tumor characteristics including metric substage and lamina propria invasion patterns in a large series of ...T1 high‐grade non‐muscle‐invasive bladder cancer.
Methods
Between 1989 and 2012, 322 patients with initial stage T1 high‐grade bladder cancer underwent transurethral resection, followed by re‐transurethral resection and a conservative approach with follow‐up regime alone or instillation treatment. Transurethral resection specimens were reassessed by two experienced urological pathologists for tumor grade according to the World Health Organization 1973 classification, metric T1 substage, lamina propria invasion pattern and associated carcinoma in situ. The median follow‐up period was 42 months (interquartile range 25–72 months). In addition to Kaplan–Meier analyses, uni‐ and multivariable Cox regression analyses were used to compare progression‐free survival, cancer‐specific survival and overall survival for the studied parameters comparing two subcohorts.
Results
While in patients after instillation treatment no examined feature was shown as an independent predictor for prognosis, there were predictive histopathological features in multivariable Cox regression analyses in instillation treatment‐naïve patients: associated carcinoma in situ (hazard ratio 2.278, 95% confidence interval 1.119–4.634, P = 0.023) and World Health Organization 1973 grade 3 (hazard ratio 2.950, 95% confidence interval 1.021–8.536, P = 0.046) for worse progression‐free survival, infiltrative lamina propria tumor pattern for worse cancer‐specific survival (hazard ratio 2.369, 95% confidence interval 1.034–5.429, P = 0.042) and overall survival (hazard ratio 1.049, 95% confidence interval 1.024–1.075, P = 0.001).
Conclusions
The results of the present T1 high‐grade bladder cancer series suggest that lamina propria invasion pattern is a promising parameter to predict the prognosis of T1 high‐grade bladder cancer in an instillation treatment‐naïve subcohort. Prospective multicenter evaluations are warranted. The need for instillation treatment in T1 high‐grade bladder cancer is clearly demanded.
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