Wolfgang Otto

Gut microbiota disturbance during antibiotic therapy: a multi-omic approach

Objective Antibiotic (AB) usage strongly affects microbial intestinal metabolism and thereby impacts human health. Understanding this process and the underlying mechanisms remains a major research goal. Accordingly, we conducted the first comparative omic investigation of gut microbial communities in faecal samples taken at multiple time points from an individual subjected to β-lactam therapy. Methods The total (16S rDNA) and active (16S rRNA) microbiota, metagenome, metatranscriptome (mRNAs), metametabolome (high-performance liquid chromatography coupled to electrospray ionisation and quadrupole time-of-flight mass spectrometry) and metaproteome (ultra high performing liquid chromatography coupled to an Orbitrap MS2 instrument [UPLC-LTQ Orbitrap-MS/MS]) of a patient undergoing AB therapy for 14 days were evaluated. Results Apparently oscillatory population dynamics were observed, with an early reduction in Gram-negative organisms (day 6) and an overall collapse in diversity and possible further colonisation by ‘presumptive’ naturally resistant bacteria (day 11), followed by the re-growth of Gram-positive species (day 14). During this process, the maximum imbalance in the active microbial fraction occurred later (day 14) than the greatest change in the total microbial fraction, which reached a minimum biodiversity and richness on day 11; additionally, major metabolic changes occurred at day 6. Gut bacteria respond to ABs early by activating systems to avoid the antimicrobial effects of the drugs, while ‘presumptively’ attenuating their overall energetic metabolic status and the capacity to transport and metabolise bile acid, cholesterol, hormones and vitamins; host–microbial interactions significantly improved after treatment cessation. Conclusions This proof-of-concept study provides an extensive description of gut microbiota responses to follow-up β-lactam therapy. The results demonstrate that ABs targeting specific pathogenic infections and diseases may alter gut microbial ecology and interactions with host metabolism at a much higher level than previously assumed.

ICUD-EAU international consultation on bladder cancer 2012: Non-muscle-invasive urothelial carcinoma of the bladder

CONTEXT Our aim was to present a summary of the Second International Consultation on Bladder Cancer recommendations on the diagnosis and treatment options for non-muscle-invasive urothelial cancer of the bladder (NMIBC) using an evidence-based approach. OBJECTIVE To critically review the recent data on the management of NMIBC to arrive at a general consensus. EVIDENCE ACQUISITION A detailed Medline analysis was performed for original articles addressing the treatment of NMIBC with regard to diagnosis, surgery, intravesical chemotherapy, and follow-up. Proceedings from the last 5 yr of major conferences were also searched. EVIDENCE SYNTHESIS The major findings are presented in an evidence-based fashion. We analyzed large retrospective and prospective studies. CONCLUSIONS Urothelial cancer of the bladder staged Ta, T1, and carcinoma in situ (CIS), also indicated as NMIBC, poses greatly varying but uniformly demanding challenges to urologic care. On the one hand, the high recurrence rate and low progression rate with Ta low-grade demand risk-adapted treatment and surveillance to provide thorough care while minimizing treatment-related burden. On the other hand, the propensity of Ta high-grade, T1, and CIS to progress demands intense care and timely consideration of radical cystectomy.

Comorbidity and Performance Indices as Predictors of Cancer-Independent Mortality But Not of Cancer-Specific Mortality After Radical Cystectomy for Urothelial Carcinoma of the Bladder

BACKGROUND Comorbidity and performance indices allow assessment of preoperative health status. However, the optimal tool for use in patients with urothelial carcinoma of the bladder (UCB) who are undergoing radical cystectomy (RC) has not yet been established. OBJECTIVE To evaluate correlation of Adult Comorbidity Evaluation-27 (ACE27), Charlson Comorbidity Index, Age-Adjusted Charlson Comorbidity Index, Eastern Cooperative Oncology Group performance status, and American Society of Anesthesiologists (ASA) score with survival. DESIGN, SETTING, AND PARTICIPANTS A retrospective multicenter study was carried out on 555 unselected consecutive patients who underwent RC for UCB from 2000 to 2010. INTERVENTION RC with pelvic lymph node dissection in patients with UCB without neoadjuvant chemotherapy. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS Cox regression models were calculated with established variables to assess predictive capacity for cancer-specific mortality (CSM) and cancer-independent mortality (CIM). RESULTS AND LIMITATIONS All indices were independent predictors for CIM but not for CSM. The ASA score was the only index that significantly increased the predictive accuracy of the predefined CIM model (+2.3%; p=0.045). To create a clinically valuable tool, we devised a weighted prognostic model including age and the best prognosticators within the performance and comorbidity scores (ASA/ACE27 0-1/2-3). A 3-yr CIM rate of 8%, 26%, and 47% was calculated for the low-, intermediate-, and high-risk groups, respectively. Patients >75 yr of age with ASA 3/4 and ACE27 >1 exhibited a CIM risk seven times greater than patients ≤75 yr with ASA 1/2 and ACE27 0/1. This study is limited by the short follow-up and its retrospective nature. CONCLUSIONS Comorbidity and performance assessment is mandatory in the preoperative prediction of CIM for patients undergoing RC for UCB. The present results indicate that the ASA score is the tool of choice. External and prospective validation is warranted.

The WHO classification of 1973 is more suitable than the WHO classification of 2004 for predicting survival in pT1 urothelial bladder cancer

Study Type – Prognosis (systematic review)
 Level of Evidence 2a

Combination of CK20 and Ki-67 Immunostaining Analysis Predicts Recurrence, Progression, and Cancer-Specific Survival in pT1 Urothelial Bladder Cancer

BACKGROUND The prognostic value of CK20, Ki-67, and p53 has been investigated for non-muscle-invasive urothelial bladder cancers but not for the distinct and clinically challenging subset of pT1 bladder cancers. OBJECTIVE To evaluate the prognostic value of CK20, Ki-67, and p53 within the largest series of pT1 urothelial bladder cancers. DESIGN, SETTING, AND PARTICIPANTS Data from 309 patients with pT1 urothelial bladder cancer from one single urologic centre were collected. INTERVENTION Adjuvant instillation of bacillus Calmette-Guérin was performed in each patient. A second resection was performed after 4-8 wk. A total of 76 patients underwent cystectomy. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS We conducted histomorphologic analysis; immunohistochemistry for CK20, Ki-67, and p53; and univariate and multivariate Cox regression models including recurrence-free survival (RFS), progression-free survival (PFS), and cancer-specific survival (CSS). RESULTS AND LIMITATIONS At a median follow-up of 49 mo, we found recurrence and progression and disease-specific mortality rates of 22.7%, 20.1%, and 15.9%, respectively. CK20 expression was significantly correlated with RFS in multivariate analysis (hazard ratio [HR]: 5.89; 95% confidence interval [CI], 1.44-24.15; p=0.014). In multivariate analysis, Ki-67 was the only marker significantly correlated with PFS (HR: 2.80; 95% CI, 1.45-5.43, p=0.002). Ki-67 (HR: 3.83; 95% CI, 1.59-9.26; p=0.003), and CK20 (HR: 8.44; 95% CI,1.16-61.34; p=0.035) were significantly correlated with CSS in multivariate analysis. The combination of CK20 and Ki-67 showed significantly worse RFS (p=0.026), PFS (p=0.003), and CSS (p<0.001) in tumours with a high proliferation index and abnormal CK20 expression. A retrospective study design was the major limitation of this study. CONCLUSIONS Our present analysis of the largest series of patients with pT1 urothelial bladder cancer published to date found Ki-67 and CK20 to be potential prognostic markers improving the risk stratification of pT1 bladder tumours. They are reliable indicators of biologic aggressiveness and may contribute to decision making on therapeutic strategy for pT1 bladder carcinomas.

Does photodynamic transurethral resection of bladder tumour improve the outcome of initial T1 high-grade bladder cancer? A long-term follow-up of a randomized study

To evaluate, in a long‐term follow‐up of T1 high‐grade bladder cancer treated in a prospective, randomized trial, whether fluorescence diagnosis (FD) increases recurrence‐free survival (RFS) or reduces progression to muscle‐invasive stages.

Predictive capacity of four comorbidity indices estimating perioperative mortality after radical cystectomy for urothelial carcinoma of the bladder

Study Type – Prognosis (case series)

Macroscopic sessile tumor architecture is a pathologic feature of biologically aggressive upper tract urothelial carcinoma

OBJECTIVE Macroscopic sessile tumor architecture was associated with adverse outcomes after radical nephroureterectomy (RNU) for upper tract urothelial carcinoma (UTUC). Before inclusion in daily clinical decision-making, the prognostic value of tumor architecture needs to be validated in an independent, external dataset. We tested whether macroscopic tumor architecture improves outcome prediction in an international cohort of patients. MATERIAL AND METHODS We retrospectively studied 754 patients treated with RNU for UTUC without neoadjuvant chemotherapy at 9 centers located in Asia, Canada, and Europe. Tumor architecture was macroscopically categorized as either papillary or sessile. Univariable and multivariable Cox regression analyses were used to address recurrence-free (RFS) and cancer-specific survival (CSS) estimates. RESULTS Macroscopic sessile architecture was present in 20% of the patients. Its prevalence increased with advancing pathologic stage and it was significantly associated with established features of biologically aggressive UTUC, such as tumor grade, lymph node metastasis, lymphovascular invasion, and concomitant CIS (all P values < 0.02). The median follow-up for patients who were alive at last follow-up was 40 months (IQR: 18-75 months, range: 1-271 months). Two-year RFS and CSS for tumors with papillary architecture were 85% and 90%, compared with 58% and 66% for those with macroscopic sessile architecture, respectively (P values < 0.0001). On multivariable Cox regression analyses, macroscopic sessile architecture was an independent predictor of both RFS (hazard ratio {HR}: 1.5; P = 0.036) and CSS (HR: 1.5; P = 0.03). CONCLUSION We confirmed the independent prognostic value of macroscopic tumor architecture in a large, independent, multicenter UTUC cohort. It should be reported in every pathology report and included in post-RNU predictive models in order to refine current clinical decision making regarding follow-up protocol and adjuvant therapy.

Hexaminolevulinate Is Equal to 5-Aminolevulinic Acid Concerning Residual Tumor and Recurrence Rate Following Photodynamic Diagnostic Assisted Transurethral Resection of Bladder Tumors

OBJECTIVES To compare the outcomes of 5-aminolaevulinic acid (ALA) vs hexaminolaevulinate (HEX) vs white light (WL) transurethral resection of bladder tumors (TURB) to assess transferability of ALA findings to HEX. Extending WL-TURB with photodynamic diagnostic improves outcome. Two fluorescent agents have been commonly used for this. Although numerous and specific data exist on the older substance ALA, considerably less are available on hex, the only agent approved however. To date no such report has been published. METHODS By random generator, each 200 patients with non-muscle-invasive bladder cancer having undergone TURB with WL, ALA or HEX were selected from our institutional data bank. Residual tumor in control TURB (RT) and recurrence-free survival (RFS) were assessed. RESULTS Complete follow-up data were available on 142 WL, 139 ALA, and 135 HEX patients. Median duration of follow-up was 24 months. RT was 33% in WL, 15% in ALA, and 9% in hex, respectively. RFS at 3 years was 67% in WL, 80% in ALA, and 82% in hex, respectively. RT was significantly reduced in ALA and HEX vs WL (P < .001) and RFS prolonged (P < .01). There were no significant differences between ALA and HEX in RT and RFS, respectively (RT: P = .37; RFS: P = .72). CONCLUSIONS In the present retrospective series, ALA and HEX were found to be significantly superior to WL. No differences between ALA and HEX were demonstrated. Even from a careful perspective both fluorescent agents seem to be comparable. Thus, ALA-based findings seem to be transferable on the approved agent HEX.

Predicting individual outcomes after radical cystectomy: an external validation of current nomograms

Study Type – Prognosis (outcomes research)
Level of Evidence 2c