Skeletal Muscle-Derived Cell Implantation for the Treatment of Fecal Incontinence: A Randomized, Placebo-Controlled Study.

BACKGROUND AND AIMS: Fecal incontinence (FI) improvement following injection of autologous skeletal muscle-derived cells has been previously suggested. This study aimed to test the efficacy and safety of said cells through a multicenter, placebo-controlled study, to determine an appropriate cell dose, and to delineate the target patient population that can most benefit from cell therapy. METHODS: Patients experiencing FI for at least 6 months were randomized to receive a cell-free medium or low or high dose of cells. All patients received pelvic floor electrical stimulation before and after treatment. Incontinence episode frequency (IEF), FI quality of life, FI burden assessed on a visual analog scale, Wexner score, and parameters reflecting anorectal physiological function were all assessed for up to 12 months. RESULTS: Cell therapy improved IEF, FI quality of life, and FI burden, reaching a preset level of statistical significance in IEF change compared with the control treatment. Post hoc exploratory analyses indicated that patients with limited FI duration and high IEF at baseline are most responsive to cells. Effects prevailed or increased in the high cell count group from 6 to 12 months but plateaued or diminished in the low cell count and control groups. Most physiological parameters remained unaltered. No unexpected adverse events were observed. CONCLUSIONS: Injection of a high dose of autologous skeletal muscle-derived cells followed by electrical stimulation significantly improved FI, particularly in patients with limited FI duration and high IEF at baseline, and could become a valuable tool for treatment of FI, subject to confirmatory phase 3 trial(s). (ClinicalTrialRegister.eu; EudraCT Number: 2010-021463-32).

Sonographic postpartum anal sphincter defects and the association with pelvic floor pain and dyspareunia.

INTRODUCTION: Pelvic floor pain and dyspareunia are both important entities of postpartum pelvic pain, often concomitant and associated with perineal tears during vaginal delivery. The association between postpartum sonographic anal sphincter defects, pelvic floor pain, and dyspareunia has not been fully established. We aimed to determine the prevalence of postpartum anal sphincter defects using three-dimensional endoanal ultrasonography (3D-EAUS) and evaluate their association with symptoms of pelvic floor pain and dyspareunia. MATERIAL AND METHODS: This prospective cohort study followed 239 primiparas from birth to 12 months post delivery. Anal sphincters were assessed with 3D-EAUS 3 months postpartum, and self-reported pelvic floor function data were obtained using a web-based questionnaire distributed 1 year after delivery. Descriptive statistics were compared between the patients with and without sonographic defects, and the association between sonographic sphincter defects and outcomes were analyzed using logistic regression. RESULTS: At 3 months postpartum, 48/239 (20%) patients had anal sphincter defects on 3D-EAUS, of which 43 (18%) were not clinically diagnosed with obstetric anal sphincter injury at the time of delivery. Patients with sonographic defects had higher fetal weight than those without defects, and a perineum <2 cm before the suture was a risk factor for defects (odds ratio [OR], 6.9). Patients with sonographic defects had a higher frequency of dyspareunia (OR, 2.4), and pelvic floor pain (OR, 2.3) than those without defects. CONCLUSIONS: Our results suggest an association between postpartum sonographic anal sphincter defects, pelvic floor pain, and dyspareunia. A perineal height <2 cm, measured by bidigital palpation immediately postdelivery, was a risk factor for sonographic anal sphincter defect. We suggest offering pelvic floor sonography around 3 months postpartum to high- risk women to optimize diagnosis and treatment of perineal tears and include perineum <2 cm prior to primary repair as a proposed indication for postpartum follow-up sonography.

Use of endoanal ultrasound in detecting obstetric anal sphincter injury immediately after birth.

INTRODUCTION: Obstetric anal sphincter injury (OASI) complicates around 5% of deliveries in primiparas. The study objective was to assess the utility of three-dimensional endoanal ultrasonography (3D-EAUS) in the diagnosis of OASI. MATERIAL AND METHODS: The present study was designed to mirror screening settings with an unselected cohort of nulliparous women. All enrolled patients underwent clinical examination of the perineum by the caregiver, and 3D-EAUS was conducted. Post-processing of ultrasonography volume data was performed by an experienced colorectal surgeon who was blinded to all other data. The sensitivity, specificity, negative predictive value, and positive predictive value of 3D-EAUS in the diagnosis of OASI was evaluated. The trial is registered at ISCRTN: 18006769. RESULTS: A total of 680 scans were performed, of which 18.5% were judged as "non-assessable", resulting in 554 assessable recordings. Sphincter defects were observed in 12.8% of all assessable recordings on 3D-EAUS (n = 71). With clinical examination set as the reference standard, ultrasound sensitivity in the diagnosis of OASI was 30.4%, whereas its specificity was 87.9%. The negative predictive value was 96.7% and the positive predictive value was only 9.9%. Comments were left on 175 examinations, of which 74% referred to the management of the examination. CONCLUSIONS: Using 3D-EAUS in a maternity ward is demanding because staff generally have little experience in endoanal ultrasound, which contributes to difficulties in obtaining good image quality. When 3D-EAUS is performed to mirror screening settings, it adds no convincing diagnostic power to clinical examination in the diagnosis of OASI.

New tools for old problems - comparing drone- and field-based assessments of a problematic plant species.

Plant species that negatively affect their environment by encroachment require constant management and monitoring through field surveys. Drones have been suggested to support field surveyors allowing more accurate mapping with just-in-time aerial imagery. Furthermore, object-based image analysis tools could increase the accuracy of species maps. However, only few studies compare species distribution maps resulting from traditional field surveys and object-based image analysis using drone imagery. We acquired drone imagery for a saltmarsh area (18 ha) on the Hallig Nordstrandischmoor (Germany) with patches of Elymus athericus, a tall grass which encroaches higher parts of saltmarshes. A field survey was conducted afterwards using the drone orthoimagery as a baseline. We used object-based image analysis (OBIA) to segment CIR imagery into polygons which were classified into eight land cover classes. Finally, we compared polygons of the field-based and OBIA-based maps visually and for location, area, and overlap before and after post-processing. OBIA-based classification yielded good results (kappa = 0.937) and agreed in general with the field-based maps (field = 6.29 ha, drone = 6.22 ha with E. athericus dominance). Post-processing revealed 0.31 ha of misclassified polygons, which were often related to water runnels or shadows, leaving 5.91 ha of E. athericus cover. Overlap of both polygon maps was only 70% resulting from many small patches identified where E. athericus was absent. In sum, drones can greatly support field surveys in monitoring of plant species by allowing for accurate species maps and just-in-time captured very-high-resolution imagery.

Piwil 2 expression is correlated with disease-specific and progression-free survival of chemotherapy-treated bladder cancer patients.

Piwi-like 2 (Piwil 2) belongs to the family of Argonaute genes/proteins. The expression of Piwil 2 is associated with stem cells. A role in tumorigenesis and/or tumor progression is proposed for different cancers but not yet for bladder cancer (BCa). We investigated the Piwil 2 expression by immunohistochemistry in a cohort of 202 BCa patients treated by cystectomy and adjuvant chemotherapy. The association between Piwil 2 expression and disease-specific (DSS) or progression-free survival (PFS) was calculated using Kaplan Meier analyses and univariate/multivariate Cox's regression hazard models.In a multivariate Cox's regression, Piwil 2 expression, either in the cytoplasm or the nucleus, was significantly associated with DSS and PFS. A weak cytoplasmic staining pattern was associated with poor DSS and tumor progression (RR=2.7; P=0.004 and RR=2.4; P=0.027). Likewise,, absent nuclear Piwil 2 immunoreactivity was associated with poor DSS and tumor progression (RR=2.3; P=0.023 and RR=2.2; P=0.022). BCa patients whose tumors exhibited a combination of weak cytoplasmic and absent nuclear immunoreactivity had a 6-fold increased risk of tumor-related death (P=0.005) compared to patients with strong expression. Considering only patients with high grade G3 tumors, a 7.8-fold risk of tumor-associated death and a 3.6-fold risk of tumor progression were detected independently of the histologic tumor subtype or the chemotherapy regimen. In summary, a combination of weak cytoplasmic and absent nuclear expression of Piwil 2 is significantly associated with an increased risk of DSS and tumor progression. This implicates that Piwil 2 could be a valuable prognostic marker for high-risk BCa patients.

Loss of MTUS1/ATIP expression is associated with adverse outcome in advanced bladder carcinomas: data from a retrospective study.

BACKGROUND: Seventy percent of all bladder tumours tend to recur and need intensive surveillance, and a subset of tumours progress to muscle-invasive and metastatic disease. However, it is still difficult to find the adequate treatment for every individual patient as it is a very heterogeneous disease and reliable biomarkers are still missing. In our study we searched for new target genes in the critical chromosomal region 8p and investigated the potential tumour suppressor gene candidate MTUS1/ATIP in bladder cancer. METHODS: MTUS1 was identified to be the most promising deleted target gene at 8p in aCGH analysis with 19 papillary bladder tumours. A correlation with bladder cancer was further validated using immunohistochemistry of 85 papillary and 236 advanced bladder tumours and in functional experiments. Kaplan-Meier analysis and multivariate Cox-regression addressed overall survival (OS) and disease-specific survival (DSS) as a function of MTUS1/ATIP expression. Bivariate correlations investigated associations between MTUS1/ATIP expression, patient characteristics and histopathology. MTUS1 expression was analysed in cell lines and overexpressed in RT112, where impact on viability, proliferation and migration was measured. RESULTS: MTUS1 protein expression was lost in almost 50% of all papillary and advanced bladder cancers. Survival, however, was only influenced in advanced carcinomas, where loss of MTUS1 was associated with adverse OS and DSS. In this cohort, there was also a significant correlation of MTUS1 expression and histological subtype: positive expression was detected in all micropapillary tumours and aberrant nuclear staining was detected in a subset of plasmocytoid urothelial carcinomas. MTUS1 was expressed in all investigated bladder cell lines and overexpression in RT112 led to significantly decreased viability. CONCLUSIONS: MTUS1 is a tumour suppressor gene in cultured bladder cancer cells and in advanced bladder tumours. It might represent one new target gene at chromosome 8p and can be used as an independent prognostic factor for advanced bladder cancer patients. The limitation of the study is the retrospective data analysis. Thus, findings should be validated with a prospective advanced bladder tumour cohort.

Long-term quality of life of testicular cancer survivors differs according to applied adjuvant treatment and tumour type.

PURPOSE: To evaluate the quality of life (QoL) in long-term testicular cancer (TC) survivors. METHODS: QoL was assessed in TC survivors treated between March 1976 and December 2004 (n = 625) using the EORTC-QLQ-C30 questionnaire, including a TC module. The assessment was performed at two time points (2006: response rate: n = 201/625 (32.2%), median follow-up (FU): 12.9 years (range 1.1-30.9); 2017: response rate: n = 95/201 (47.3%), median FU: 26.2 years (range: 13.0-41.2)). TC survivors were grouped according to treatment strategy, tumour entity, clinical stage and prognosis group. Linear and multiple linear regression analyses were performed, with age and time of follow-up as possible confounders. RESULTS: Radiation therapy (RT) compared to retroperitoneal lymph node dissection (RPLND) was associated with a higher impairment of physical function (2017: ß = - 9.038; t(84) = - 2.03; p = 0.045), role function (2017: ß = - 12.764; t(84) = - 2.00; p = 0.048), emotional function (2006: ß = - 9.501; t(183) = - 2.09; p = 0.038) and nausea (2006: ß = 6.679; t(185) = 2.70; p = 0.008). However, RT was associated with a lower impairment of sexual enjoyment (2017: symptoms: ß = 26.831; t(64) = 2.66; p = 0.010; functional: ß = 22.983; t(65) = 2.36; p = 0.021). Chemotherapy (CT), compared to RPLND was associated with a higher impairment of role (2017: ß = - 16.944; t(84) = - 2.62; p = 0.011) and social function (2017: ß = - 19.160; t(79) = - 2.56; p = 0.012), more insomnia (2017: ß = 19.595; t(84) = 2.25; p = 0.027) and greater concerns about infertility (2017: ß = 19.830; t(80) = 2.30; p = 0.024). In terms of tumour type, nonseminomatous germ cell tumour (NSGCT) compared to seminoma survivors had significantly lower impairment of nausea (2006: ß = - 4.659; t(187) = - 2.17; p = 0.031), appetite loss (2006: ß = - 7.554; t(188) = - 2.77; p = 0.006) and future perspective (2006: ß = - 12.146; t(175) = - 2.08; p = 0.039). On the other hand, surviving NSGCT was associated with higher impairment in terms of sexual problems (2006: ß = 16.759; t(145) = 3.51; p < 0.001; 2017: ß = 21.207; t(63) = 2.73; p = 0.008) and sexual enjoyment (2017: ß = - 24.224; t(66) = - 2.76; p = 0.008). CONCLUSIONS: The applied adjuvant treatment and the tumour entity had a significant impact on the long-term QoL of TC survivors, even more than 25 years after the completion of therapy. Both RT and CT had a negative impact compared to survivors treated with RPLND, except for sexual concerns. NSGCT survivors had a lower impairment of QoL compared to seminoma survivors, except in terms of sexual concerns. IMPLICATIONS FOR CANCER SURVIVORS: Implications for cancer survivors are to raise awareness of aspects of long-term and late effects on QoL in TC survivors; offer supportive care, such as psycho-oncological support or lifestyle modification, if a deterioration in QoL is noticed; and avoid toxic treatment without compromising a cure whenever possible.

Proposal for a Novel Histological Scoring System as a Potential Grading Approach for Muscle-invasive Urothelial Bladder Cancer Correlating with Disease Aggressiveness and Patient Outcomes.

BACKGROUND: Grading of muscle-invasive bladder cancer (MIBC) according to the current World Health Organization (WHO) criteria is controversial due to its limited prognostic value. All MIBC cases except a tiny minority are of high grade. OBJECTIVE: To develop a prognostic histological scoring system for MIBC integrating histomorphological phenotype, stromal tumor-infiltrating lymphocytes (sTILs), tumor budding, and growth and spreading patterns. DESIGN, SETTING, AND PARTICIPANTS: Tissue specimens and clinical data of 484 patients receiving cystectomy and lymphadenectomy with curative intent with or without adjuvant chemotherapy. Histomorphological phenotypes, sTILs, tumor budding, and growth and spreading patterns were evaluated and categorized into four grade groups (GGs). GGs were correlated with molecular subtypes, immune infiltration, immune checkpoint expression, extracellular matrix (ECM) remodeling, and epithelial-mesenchymal transition (EMT) activity. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: GGs were associated with overall (OS), disease-specific (DSS), and progression-free (PFS) survival in univariable and multivariable analyses. Association with biological features was analyzed with descriptive statistics. RESULTS AND LIMITATIONS: Integration of two histomorphological tumor groups, three sTILs groups, three tumor budding groups, and four growth/spread patterns yielded four novel GGs that had high significance in the univariable survival analysis (OS, DSS, and PFS). GGs were confirmed as independent prognostic predictors with the greatest effect in the multivariable Cox regression analysis. Correlation with molecular data showed a gradual transition from basal to luminal subtypes from GG1 to GG4; a gradual decrease in survival, immune infiltration, and immune checkpoint activity; and a gradual increase in ECM remodeling and EMT activity. CONCLUSIONS: We propose a novel, prognostically relevant, and biologically based scoring system for MIBC in cystectomies applicable to routine pathological sections. PATIENT SUMMARY: We developed a novel approach to assess the aggressiveness of advanced bladder cancer, which allows improved risk stratification compared with the method currently proposed by the World Health Organization.

Nuclear E-cadherin expression is associated with the loss of membranous E-cadherin, plasmacytoid differentiation and reduced overall survival in urothelial carcinoma of the bladder.

BACKGROUND: Loss of E-cadherin represents a hallmark of plasmacytoid differentiation. We analyzed the effect of membranous E-cadherin loss and its nuclear accumulation in patients with locally advanced conventional urothelial carcinoma (UC) who were treated with radical cystectomy and adjuvant chemotherapy. METHODS: A total of 247 formalin-fixed, paraffin-embedded tumor samples were reviewed to detect histological variants of UC. Immunohistochemical staining of E-cadherin was performed and analyzed for membranous and nuclear expression. The correlation between E-cadherin expression and histology was assessed, and overall survival (OS) was analyzed with univariate and multivariate Cox regression and Kaplan-Meier analyses. Correlation of nuclear E-cadherin to tumor stage (pT), lymph node metastasis (pN), histologic subtype, and chemotherapy was performed by Fisher's exact test. RESULTS: Membranous and nuclear E-cadherin expression was strongly correlated to plasmacytoid urothelial carcinoma (PUC) (p < 0.001). Complete loss of membranous E-cadherin expression was observed in 76.2 % of PUCs, 11.1 % of conventional UCs, and 0 % of micropapillary urothelial carcinoma (MPCs). Nuclear accumulation was found in 47.6 % of PUCs, 10 % of MPCs, and 1.8 % of UCs. Sixty-two percent of all tumors with negative membranous E-cadherin expression and nuclear accumulation were PUCs (p = 0.035). In a Kaplan-Meier analysis, mean survival with nuclear E-cadherin expression was 31.9 months [95 % confidence interval (CI) 16.1-47.6] of patients without nuclear staining 61 months (95 % CI 53.5-67.7; p = 0.045). A univariate Cox regression analysis showed that nuclear E-cadherin accumulation was associated with a 2-fold increase in risk of death (95 % CI 1.03-4.06; p = 0.04). In multivariate Cox regression analysis adjusted to type of chemotherapy, tumor stage, and tumor grade, the hazard ratio for patients with nuclear E-cadherin was 2.03 (95 % CI 1.00-4.121; p = 0.050). CONCLUSIONS: Nuclear E-cadherin is associated with PUCs and is suggested to be an independent prognostic factor in advanced UC.

SNAI1 protein expression is an independent negative prognosticator in muscle-invasive bladder cancer.

BACKGROUND: The prognosis of muscle-invasive bladder cancer is poor. Molecular prognosticators have gained increasing attention for individualized therapeutic options because they can identify patients with different prognoses. METHODS: Tissue microarrays of formalin-fixed and paraffin-embedded tumor samples from 206 bladder cancer patients treated with cystectomy and chemotherapy were studied for SNAI1 protein expression by immunohistochemistry. SNAI1 expression was evaluated using an immunoreactive score (IRS). For statistical analysis, the patients were separated into two groups: those with tumor specimens negative for SNAI1 expression (IRS = 0), and the other positive for SNAI1 expression (IRS ≥1). RESULTS: Tumor samples from 42 patients showed negative SNAI1 expression, whereas the nuclei of tumor cells from 164 patients showed detectable nuclear staining of SNAI1. A Kaplan-Meier analysis of the bladder cancer patients with negative SNAI1 expression showed significantly reduced disease-specific survival (DSS) and progression-free survival (PFS) compared to the patients with positive expression (p = 0.010 and 0.013). A multivariate Cox regression analysis (adjusted for gender, age, tumor stage, tumor grade, lymph node metastasis, chemotherapy, and histologic subtype) again showed a significant correlation between patients lacking SNAI1 expression and DSS (p = 0.005; relative risk 2.31; 95 % confidence interval 1.28-4.17) or PFS (p = 0.004; relative risk 2.20; 95 % confidence interval 1.29-3.78) compared to patients with positive SNAI1 staining. CONCLUSIONS: Loss of SNAI1 protein expression is an independent prognosticator for PFS and DSS in bladder cancer patients treated by radical cystectomy and adjuvant chemotherapy. Its prognostic value for neoadjuvant or adjuvant chemotherapy must be evaluated in further prospective randomized controlled trials.

Plasmacytoid variant of bladder cancer defines patients with poor prognosis if treated with cystectomy and adjuvant cisplatin-based chemotherapy.

BACKGROUND: Since the definition of different histologic subtypes of urothelial carcinomas by the World Health Organization (WHO) 2004 classification, description of molecular features and clinical behavior of these variants has gained more attention. METHODS: We reviewed 205 tumor samples of patients with locally advanced bladder cancer mainly treated within the randomized AUO-AB05/95 trial with radical cystectomy and adjuvant cisplatin-based chemotherapy for histologic subtypes. 178 UC, 18 plasmacytoid (PUC) and 9 micropapillary (MPC) carcinomas of the bladder were identified. Kaplan Meier analysis and backward multivariate Cox's proportional hazards regression analysis were performed to compare overall survival between the three histologic subtypes. RESULTS: Patients suffering from PUC have the worst clinical outcome regarding overall survival compared to conventional UC and MPC of the bladder that in turn seem have to best clinical outcome (27.4 months, 62.6 months, and 64.2 months, respectively; p=0.013 by Kaplan Meier analysis). Backward multivariate Cox´s proportional hazards regression analysis (adjusted to relevant clinicopathological parameters) showed a hazard ratio of 3.2 (p=0.045) for PUC in contrast to patients suffering from MPC. CONCLUSIONS: Histopathological diagnosis of rare variants of urothelial carcinoma can identify patients with poor prognosis.

Fast-track rehabilitation after robot-assisted laparoscopic cystectomy accelerates postoperative recovery.

UNLABELLED: WHAT'S KNOWN ON THE SUBJECT? AND WHAT DOES THE STUDY ADD?: There is evidence from large abdominal surgeries and some open cystectomy series that multifactorial fast-track regimens shorten postoperative convalescence without any effect on morbidity and mortality. Such a regimen is of particular interest in combination with minimally invasive techniques, as early patient recovery demands for more rapid nutrition and mobilisation schemes. The present study, in a single institution, reports on the design, application and results of a fast-track protocol in patients undergoing robot-assisted laparoscopic cystectomy. There was no evidence of a higher incidence of complications with the fast-track regimen and postoperative recovery was faster. OBJECTIVES: To evaluate the feasibility and effectiveness of a multifactorial fast-track (FT) regimen on perioperative outcomes in patients undergoing robot-assisted laparoscopic cystectomy (RALC) with extracorporeal urinary diversion. To point out that morbidity and mortality of radical cystectomy have improved markedly over the last decades and RALC is an emerging technique showing further advances in postoperative recovery, thus demanding for more rapid nutrition and mobilisation schemes. PATIENTS AND METHODS: A non-randomised cohort study of 63 patients who underwent RALC at one institution between January 2007 and March 2010. In all, 31 patients underwent RALC without FT and 31 RALC with FT. One patient required conversion to open surgery and was therefore excluded from the study. The FT regimen included early nutrition and the quickest possible mobilisation, while mechanical bowel preparation before surgery, as well as preoperative fasting and nasogastric or abdominal drains after surgery, were omitted. Demographics, perioperative and complication data (according to modified Clavien system), as well as required opioid pain medication were documented prospectively and compared between RALC patients with and without FT. RESULTS: Groups were comparable for demographics, risk factors and clinical stage as well as operative parameters, e.g. mean operating room time, estimated blood loss, lymph nodes removed and postoperative haemoglobin level. In the FT group, abdominal drains were mostly omitted and nasogastric tubes were removed immediately after surgery. There were significant differences in the mobilisation within the room (17.5 vs 31.2 h), the time to a regular diet (4.0 vs 6.6 days) and a remarkably lower use of postoperative morphine equivalents (57.3 vs 92.4 mg) for patients receiving FT. There were no significant differences in the overall complication rates or major complications based on Clavien classification. The informative value of the study is limited by its single-centre, non-randomised design, a relatively small sample size and a possible learning curve bias. CONCLUSIONS: Combining RALC with FT is feasible in the perioperative treatment of these patients. Multifactorial postoperative regimens seem to quicken postoperative recovery of RALC patients without increasing their risk of postoperative complications.

Healthcare Resource Utilization and Cost Burden of BCG-Treated Non-Muscle Invasive Bladder Cancer Patients in Germany: A Retrospective Claims Analysis.

Background: Intermediate and high-risk non-muscle-invasive bladder cancer (NMIBC) is typically managed with transurethral resection of the bladder tumour (TURBT) followed by intravesical Bacillus Calmette-Guérin (BCG) immunotherapy; however, NMIBC patients can become refractory or unresponsive to BCG treatment, and/or progress to muscle-invasive bladder cancer (MIBC). Healthcare resource utilization (HCRU) and costs in these patient populations are high. Methods: A retrospective longitudinal cohort design of adult (≥18 years) patients with bladder cancer and BCG treatment (01/01/2012-31/12/2017) was conducted using data from a representative subset of the German statutory health insurance database. During the follow-up period after last BCG, patients were categorized into subgroups of No further NMIBC treatment, Continuous treatment for NMIBC, or MIBC evidence; HCRU and costs were tabulated for each subgroup and for the entire cohort. Results: A total of 1049 patients met the study inclusion criteria (mean age, 70.9 years; 84.8% male). Across the different subgroups, patients showing MIBC evidence had more than two times higher hospitalization rates compared to the other subgroups. Overall, the entire BCG-treated cohort's total direct medical cost including hospitalizations, outpatient care and drugs was €33.9 million and €9250 per patient-year. Cost for patients with MIBC evidence was much higher, at €17,983 per patient-year, than patients with No further NMIBC treatment (€6617) and patients with Continuous treatment for NMIBC (€7786). Across the subgroups, hospitalization was the largest driver of cost and contributed the most to cost for those with MIBC evidence. Conclusion: The overall cost burden of this BCG-treated cohort of 1049 patients is high (€38 million whereof 4.1 million are indirect costs) over a mean follow-up of 3.9 years; economic burden is especially substantial for patients who fail BCG treatment and those who progress.

Adjuvant vs. progression-triggered treatment with gemcitabine in platinum-ineligible high-risk bladder cancer patients: Long-term follow-up of a randomized phase 3 trial.

BACKGROUND: Cisplatin-based chemotherapy (ChT) is the preferred perioperative treatment in muscle-invasive urothelial carcinoma of the urinary bladder (UCUB). Nevertheless, a certain number of patients are ineligible for platinum-based ChT. This trial compared immediate adjuvant vs. delayed gemcitabine ChT at progression in platinum-ineligible patients with high-risk UCUB. METHODS: High-risk platinum-ineligible UCUB patients (n = 115) were randomized 1:1 to adjuvant gemcitabine (n = 59) or gemcitabine at progression (n = 56). Overall survival was analyzed. Additionally, we analyzed progression-free survival (PFS), toxicity and quality of life (QoL). RESULTS: After a median follow-up of 3.0 years (inter quartile range [IQR]: 1.3-11.6), adjuvant ChT did not significantly prolong overall survival (OS) (HR: 0.84; 95% CI: 0.57-1.24; P = 0.375), with 5-year OS of 44.1% (95% CI: 31.2-56.2) and 30.4% (95% CI: 19.0-42.5), respectively. We noted no significant difference in PFS (HR: 0.76; 95% CI: 0.49-1.18; P = 0.218), with 5-year PFS of 36.2% (95% CI: 22.8-49.7) in the adjuvant group and 22.2% (95% CI: 11.5%-35.1%) when treated at progression. Patients with adjuvant treatment showed a significantly worse QoL. The trial was prematurely closed after recruitment of 115 of the planned 178 patients. CONCLUSIONS: There was no statistically significant difference in terms of OS and PFS for patients with platinum-ineligible high-risk UCUB receiving adjuvant gemcitabine compared to patients treated at progression. These findings underline the importance of implementing and developing new perioperative treatments for platinum-ineligible UCUB patients.

A 20-gene model for molecular nodal staging of bladder cancer: development and prospective assessment.

BACKGROUND: Neoadjuvant chemotherapy before cystectomy confers a survival benefit in bladder cancer, but it has not been widely adopted since most patients do not benefit and we are at present unable to predict those that do. Since the most important predictor of recurrence after cystectomy is pathologically positive nodes, our aim was to assess techniques that define this stage for the selection of patients for neoadjuvant chemotherapy. METHODS: We developed a gene expression model (GEM) to predict the pathological node status in primary tumour tissue from three independent cohorts of patients who were clinically node negative. From a subset of transcripts detected faithfully by microarrays from both paired frozen and formalin-fixed tissues (32 pairs), we developed both the GEM and cutoffs that identified patient strata with raised risk of nodal involvement by use of two separate training cohorts (90 and 66 patients). We then assessed the GEM and cutoffs to predict node-positive disease in tissues from a phase 3 trial cohort (AUO-AB-05/95; 185 patients). FINDINGS: We developed a 20-gene GEM with an area under the curve of 0·67 (95% CI 0·60-0·75) for prediction of nodal disease at cystectomy in AUO-AB-05/95. The cutoff system identified patients with high relative risk (1·74, 95% CI 1·03-2·93) and low relative risk (0·70, 95% CI 0·51-0·96) of node-positive disease. Multivariate logistic regression showed the GEM predictor was independent of age, sex, pathological stage, and lymphovascular space invasion (coefficient 9·81, 95% CI 1·64-18·00; p=0·019). INTERPRETATION: Selecting patients for neoadjuvant chemotherapy on the basis of risk of node-positive disease has the potential to benefit high-risk patients while sparing other patients toxic effects and delay to cystectomy. FUNDING: US National Cancer Institute (R01CA143971).

[CARD study: relevance for the treatment of advanced prostate cancer]. / CARD-Studie ­ Bedeutung für die Therapie des fortgeschrittenen Prostatakarzinoms.

BACKGROUND: Various life-prolonging therapy options are available for the treatment of metastatic castration-resistant prostate cancer (mCRPC). OBJECTIVE: The optimal therapy sequence for mCRPC has been discussed for years. With the final results of the CARD study, important prospective data are available to enlighten the discussion about the therapy sequence. MATERIAL AND METHOD: CARD is a randomised phase IV trial in patients with mCRPC who were previously treated with docetaxel and an anti-androgen receptor (ARTA). The study showed significant efficacy benefits in favour of further treatment with cabazitaxel versus a second ARTA therapy. The study results are presented and discussed in the context of previous study data with regard to their importance for everyday clinical practice. RESULTS: The CARD study data confirm cabazitaxel as an effective therapy option for mCRPC patients previously treated with docetaxel and an ARTA. Cabazitaxel was safe to apply. The study results confirm the cross resistance between the two ARTAs Abiraterone and Enzalutamide. CONCLUSION: In mCRPC patients eligible for chemotherapy, the therapy sequence should be chosen so that the patients also receive cabazitaxel. A direct therapy sequence with two ARTAs should be avoided or, at least, only considered if other substances are contraindicated.

The plasmacytoid carcinoma of the bladder--rare variant of aggressive urothelial carcinoma.

The WHO 2004 classification defines new histological and molecular variants of urothelial carcinoma. However, there are limited data available on the clinicopathological characteristics or prognosis of these variants. We present histopathological, molecular and clinical data of 32 plasmacytoid carcinomas of the bladder (PUC) showing that PUC is a high-grade tumor with molecular features of aggressive urothelial carcinoma, usually diagnosed in advanced pathological stage (64% pT3, 23% pT4) showing metastases in 60% of the patients. Average survival of our cohort of PUC treated with radical cystectomy and adjuvant chemotherapy was lower than what is typically seen for comparable conventional urothelial carcinomas. Eighty-seven percent of the PUCs showed a negative or strongly reduced membranous staining of E-cadherin. ß-Catenin staining was negative in 22.5%, and 16.7% of the remaining tumors showed nuclear accumulation. Aberrant CK20 expression (negative or >10% of cells stained) and negative CK7 staining was found in 100% and 22.6%, respectively. Ninety-seven percent revealed positive staining for PAN-CK. CD138 was positive in 78%, whereas MUM-1 expression was negative in all cases. Multitarget fluorescence in situ hybridization showed all PUCs to be highly aneuploid and polysomic. Deletions on chromosome 9p21 seem to play an important role in this variant. FGFR3 and PIK3CA mutation analyses yielded no mutations in any of the PUCs analyzed. TP53 mutation analysis showed mutations in 29%. In summary, PUC is an aggressive variant of bladder cancer with molecular features of advanced bladder cancer and evidence of WNT pathway activation in some of the cases.

Increased expression of transcription factor TFAP2α correlates with chemosensitivity in advanced bladder cancer.

BACKGROUND: The standard treatment for patients with advanced transitional cell carcinoma of the bladder is platin based chemotherapy. Only approximately 50% of the patients respond to chemotherapy. Therefore, molecular predictive markers for identification of chemotherapy sensitive subgroups of patients are highly needed. We selected the transcription factor TFAP2α from a previously identified gene expression signature for chemotherapy response. METHODS: TFAP2α expression and localization was assessed by immunohistochemistry using a tissue microarray (TMA) containing 282 bladder cancer tumors from patients with locally advanced (pT2-T4(b) and N(1-3)) or metastatic (M(1)) disease. All patients had received cisplatin containing chemotherapy. Furthermore, QPCR analysis of three TFAP2α isoforms was performed on tumor specimens of advanced muscle invasive bladder cancers (T2-4). Using the bladder cell lines T24 and SW780 the relation of TFAP2α and cisplatin and gemcitabine sensitivity as well as cell proliferation was examined using siRNA directed TFAP2α knockdown. RESULTS: TFAP2α protein expression was analyzed on a TMA with cores from 282 advanced bladder cancer tumors from patients treated with cisplatin based combinational chemotherapy. TFAP2α was identified as a strong independent predictive marker for a good response and survival after cisplatin-containing chemotherapy in patients with advanced bladder cancer. Strong TFAP2α nuclear and cytoplasmic staining predicted good response to chemotherapy in patients with lymph node metastasis, whereas weak TFAP2α nuclear staining predicted good response in patients without lymph node metastasis. In vitro studies showed that siRNA mediated knockdown of TFAP2α increased the proliferation of SW780 cells and rendered the cells less sensitive to cisplatin and gemcitabine. In contrast to that T24 bladder cells with mutated p53 showed to be more drug sensitive upon TFAP2α depletion. CONCLUSIONS: High levels of nuclear and cytoplasmic TFAP2α protein were a predictor of increased overall survival and progression free survival in patients with advanced bladder cancer treated with cisplatin based chemotherapy. TFAP2α knockdown increased the proliferation of the SW780 bladder cells and reduced cisplatin and gemcitabine induced cell death. The inverse effect was observed in the TP53 mutated T24 cell line where TFAP2α silencing augmented cisplatin and gemcitabine sensitivity and did not stimulate proliferation.

Are recently deglaciated areas at both poles colonised by the same bacteria?

Polar glacier forefields offer an unprecedented framework for studying community assembly processes in regions that are geographically and climatically isolated. Through amplicon sequence variant (ASV) inference, we compared the composition and structure of soil bacterial communities from glacier forefields in Iceland and Antarctica to assess overlap between communities and the impact of established cryptogamic covers on the uniqueness of their taxa. These pioneer microbial communities were found to share only 8% of ASVs and each taxonomic group's contribution to the shared ASV data subset was heterogeneous and independent of their relative abundance. Although the presence of ASVs specific to one glacier forefield and/or different cryptogam cover values confirms the existence of habitat specialist bacteria, our data show that the influence of cryptogams on the edaphic bacterial community structure also varied also depending on the taxonomic group. Hence, the establishment of distinct cryptogamic covers is probably not the only factor driving the uniqueness of bacterial communities at both poles. The structure of bacterial communities colonising deglaciated areas seems also conditioned by lineage-specific limitations in their dispersal capacity and/or their establishment and persistence in these isolated and hostile regions.

Cryptogamic cover determines soil attributes and functioning in polar terrestrial ecosystems.

We still lack studies that provide evidence for direct links between the development of soil surface cryptogamic communities and soil attributes and functioning. This is particularly true in areas free of potentially confounding factors such as different soil types, land uses, or anthropogenic disturbances. Despite the ecological importance of polar ecosystems and their sensitivity to climate change, we are far from understanding how their soils function and will respond to climate change-driven alterations in above- and belowground features. We used two complementary approaches (i.e. cover gradients in the forefront of retreating glaciers as well as long-time deglaciated areas with well-developed cryptogamic cover types) to evaluate the role of cryptogams driving multiple soil biotic and abiotic attributes and functioning rates in polar terrestrial ecosystems. Increases in cryptogamic cover were consistently related to increases in organic matter accumulation, soil fertility, and bacterial diversity, but also in enhanced soil functioning rates in both sampling areas. However, we also show that the ability to influence soil attributes varies among different polar cryptogamic covers, indicating that their differential ability to thrive under climate-change scenarios will largely determine the fate of polar soils in coming decades.