The HELENA study: Hexvix®-TURB vs. white-light TURB followed by intravesical adjuvant chemotherapy-a prospective randomized controlled open-label multicenter non-inferiority study.

PURPOSE: Photodynamic diagnosis and white-light TURB with adjuvant intravesical chemotherapy (ICT) is widely used in treatment of bladder cancer. This non-inferiority trial is designed to demonstrate non-inferiority regarding recurrence-free survival (RFS) of Hexvix® TURB followed by immediate instillation compared to white-light TURB with immediate instillation followed by maintenance ICT. METHODS: Between 07/2010 and 12/2016, 129 patients with EORTC intermediate risk non-muscle invasive bladder cancer treated with TURB were included in this multicentre phase III study. Patients were randomized and received either white-light TURB with immediate ICT followed by maintenance ICT (n = 62, 20 mg Mitomycin weekly for 6 weeks as induction phase, afterwards 20 mg/month for 6 months) or Hexvix® TURB with immediate ICT only (n = 67, 40 mg Mitomycin). Primary study endpoint was RFS after 12 months. Hexvix® TURB was counted as non-inferior to white light alone if the upper limit of the one-sided 95% confidence interval of hazard ratio was lower than 1.676. Due to the non-inferiority design, the per-protocol population was used as the primary analysis population (n = 113) RESULTS: Median follow-up was 1.81 years. Hexvix® group showed more events (recurrence or death) than white-light group (19 vs. 10) resulting in a HR of 1.29 (upper limit of one-sided 95%-CI = 2.45; pnon-inferiority = 0.249). The ITT population yielded similar results (HR = 1.67); 3.18], pnon-inferiority = 0.493). There was no significant difference in overall survival between both groups (p = 0.257). CONCLUSION: Non-inferiority of Hexvix® TURB relative to white-light TURB with maintenance Mitomycin instillation in intermediate risk urothelial carcinoma of the bladder was not proven. Hence a higher effect of maintenance ICT is to assume compared to a Hexvix®-improved TURB only, confirming its important role in patient treatment.

Room temperature "optical nanodiamond hyperpolarizer": Physics, design, and operation.

Dynamic Nuclear Polarization (DNP) is a powerful suite of techniques that deliver multifold signal enhancements in nuclear magnetic resonance (NMR) and MRI. The generated athermal spin states can also be exploited for quantum sensing and as probes for many-body physics. Typical DNP methods require the use of cryogens, large magnetic fields, and high power microwave excitation, which are expensive and unwieldy. Nanodiamond particles, rich in Nitrogen-Vacancy (NV) centers, have attracted attention as alternative DNP agents because they can potentially be optically hyperpolarized at room temperature. Here, unraveling new physics underlying an optical DNP mechanism first introduced by Ajoy et al. [Sci. Adv. 4, eaar5492 (2018)], we report the realization of a miniature "optical nanodiamond hyperpolarizer," where 13C nuclei within the diamond particles are hyperpolarized via the NV centers. The device occupies a compact footprint and operates at room temperature. Instrumental requirements are very modest: low polarizing fields, low optical and microwave irradiation powers, and convenient frequency ranges that enable miniaturization. We obtain the best reported optical 13C hyperpolarization in diamond particles exceeding 720 times of the thermal 7 T value (0.86% bulk polarization), corresponding to a ten-million-fold gain in averaging time to detect them by NMR. In addition, the hyperpolarization signal can be background-suppressed by over two-orders of magnitude, retained for multiple-minute long periods at low fields, and deployed efficiently even to 13C enriched particles. Besides applications in quantum sensing and bright-contrast MRI imaging, this work opens possibilities for low-cost room-temperature DNP platforms that relay the 13C polarization to liquids in contact with the high surface-area particles.

Is there evidence for a close connection between side of intravesical tumor location and ipsilateral lymphatic spread in lymph node-positive bladder cancer patients at radical cystectomy? Results of the PROMETRICS 2011 database.

PURPOSE: To evaluate the possible association between bladder tumor location and the laterality of positive lymph nodes (LN) in a prospectively collected multi-institutional radical cystectomy (RC) series. METHODS: The study population included 148 node-positive bladder cancer (BC) patients undergoing RC and pelvic lymph node dissection in 2011 without neoadjuvant chemotherapy and without distant metastasis. Tumor location was classified as right, left or bilateral and compared to the laterality of positive pelvic LN. A logistic regression model was used to identify predictors of ipsilaterality of lymphatic spread. Using multivariate Cox regression analyses (median follow-up: 25 months), the effect of the laterality of positive LN on cancer-specific mortality (CSM) was estimated. RESULTS: Overall, median 18.5 LN [interquartile range (IQR), 11-27] were removed and 3 LN (IQR 1-5) were positive. There was concordance of tumor location and laterality of positive LN in 82% [95% confidence interval (CI), 76-89]. Patients with unilateral tumors (n = 78) harbored exclusively ipsilateral positive LN in 67% (95% CI 56-77). No criteria were found to predict ipsilateral positive LN in patients with unilateral tumors. CSM after 3 years in patients with ipsilateral, contralateral, and bilateral LN metastasis was 41, 67, and 100%, respectively (p = 0.042). However, no significant effect of the laterality of positive pelvic LN on CSM could be confirmed in multivariate analyses. CONCLUSIONS: Our prospective cohort showed a concordance of tumor location and laterality of LN metastasis in BC at RC without any predictive criteria and without any influence on CSM. It is debatable, whether these findings may contribute to a more individualized patient management.

[Anamnesis, Pathological Assessment, Therapeutic Features and Course of Disease: Retrospective Study on Clinical-Based Factors for Prediction of Cancer-Specific Survival of 378 Patients with Stage pT1 Urothelial Bladder Carcinoma]. / Anamnese, pathologische Originalbefunde, Therapie bezogene Parameter und Krankheitsverlauf: retrospektive Analyse von klinisch basierten Faktoren für die Prognose des tumorspezifischen Überlebens von 378 Patienten mit pT1-Harnblasenkarzinom.

BACKGROUND: Urothelial carcinoma of the bladder (UBC) at stage pT1 is a heterogenous disease. Established criteria for prognosis prediction are not suitable for every patient. Choosing the right therapeutic strategy for the individual patient thus remains a challenge. The aim of the present study was to identify clinical parameters regarding cancer-specific survival (CSS) in patients with pT1 UBC. MATERIALS AND METHODS: A retrospective analysis of clinical parameters of all patients with a pT1 UBC between 1989 and 2012 from a single centre was performed. Treatment consisted of transurethral resection, second resection followed by initially bladder sparing treatment. Anamnestic data, histopathological reports and clinical course were assessed with CSS being defined as primary endpoint. Kaplan-Meier analysis, uni- and multivariate analysis were performed using SPSS (Version 22, IBM). RESULTS: 378 patients (78% male, median age 72 years) were included, median follow-up was 35 months. Pathological stage pT1G3 (66 vs. 91%, p<0.001), lack of instillation therapy (66 vs. 83%, p<0.001), presence of a second malignoma (41 vs. 77%, p=0,004), diagnosis after 2000 (75 vs. 76%, p=0,018) and tumour progress (42 vs. 85%, p<0.001) were associated with a worse CSS in univariate and Kaplan-Meier analysis. Multivariate analysis revealed the presence of a second malignoma (HR 2.267; CI 95% 1.143-4.497, p=0.019), pathological stage pT1G3 at initial diagnosis (HR 4.567; CI 95% 2.040-10.22, p<0.001) and tumour progress (HR 3.742; CI 95% 1.544-9.069, p=0.003) as independent negative predictors of CSS. Instillation therapy was a prognostic factor for improved CSS (HR 0.368; CI 95% 0.212-0.638, p<0.001). CONCLUSION: The present study identified the presence of a second malignoma, pathological stage pT1G3 and tumour progress as negative predictive factors for CSS. Maintenance instillation therapy after reresection was associated with an improved CSS.

Management of rectourinary fistula after urological interventions using biodesigned mesh: first experiences of an innovative technique.

PURPOSE: Rectourinary fistula (RUF) is an uncommon but devastating condition that usually occurs as a complication of surgical treatment or radiotherapy of prostate cancer. Although operative fistula repair remains the most successful treatment, there still is no consensus concerning the management of RUF. We present first experiences and transanal surgical technique using biological mesh for fistula repair after urological intervention. MATERIAL AND METHODS: From January 2009 to December 2013, four cases of RUF were reported at our university hospital. Fistula occurred after extraperitoneal laparoscopic radical prostatectomy, open radical prostatectomy, and high-intensity focused ultrasound, respectively. All patients were initially treated with transanal Cook Biodesign™ mesh, whereas two patients received reoperation with rectal mucosa advancement flap and gracilis muscle flap interposition, respectively. Mean follow-up was 36 months (range 9-62). RESULTS: Fistula diameters ranged from 0.6 to 3.0 cm and were located 5 to 6 cm of anocutaneous line. The time from diagnosis to fistula repair was 3 to 7 weeks. The median operative time for Cook Biodesing™ mesh procedure was 79 min (IQR 60, 98). The initial success rate for biological mesh was 50 % (2/4 patients). Larger fistulae were minimalized successfully and finally closed with reoperation mentioned above. No deterioration of continence was documented. CONCLUSIONS: Management of rectourinary fistula is still challenging. Using biomaterials for fistula closure seems to be a promising and minimally invasive transanal technique in future. Further analysis including more patients is needed to clarify its exact role in comparison to traditional surgical techniques.

Preoperative anemia is associated with adverse outcome in patients with urothelial carcinoma of the bladder following radical cystectomy.

PURPOSE: Radical cystectomy (RC) can be associated with significant blood loss, whereas many patients are presenting with anemia preoperatively. To date, there is a lack of data addressing the impact of preoperative anemia (PA) on survival of patients undergoing RC for urothelial carcinoma of the bladder (UCB). METHODS: This retrospective multicenter study includes 684 patients with UCB undergoing RC with pelvic lymph node dissection. The median follow-up was 50 (IQR 29,78) months. Anemia was defined in line with the WHO classification (hemoglobin (Hb): male ≤13 g/dL, female ≤12 g/dL) and based on contemporary gender- and age-adjusted classification (Hb: white male aged <60 years: ≤13.7 g/dL; ≥60 years: ≤13.2 g/dL; white female of all ages ≤12.2 g/dL). Univariable and multivariable Cox regression analyses were used to assess the effects of PA on oncological outcomes. RESULTS: A total of 269 (39.3 %) and 302 (44.2 %) patients were anemic according to the WHO classification versus contemporary classification. Age, increased ECOG performance status, advanced tumor stages, lymph node metastasis, positive surgical margin and anemia were associated with disease recurrence (DR), cancer-specific mortality (CSM) and all-cause mortality (ACM). In multivariable analysis, anemia was an independent predictor of DR, CSM and ACM (WHO and/or contemporary classification). Blood transfusion was significantly associated with ACM in both classifications of anemia. CONCLUSIONS: PA is significantly associated with worse oncological outcome in patients undergoing RC. Based on the additional unfavorable influence of blood transfusion, this emphasizes the importance of early diagnosis and correction of anemia and implementation of alternative methods of blood volume management.

The effect of intra- and postoperative allogenic blood transfusion on patients' survival undergoing radical cystectomy for urothelial carcinoma of the bladder.

PURPOSE: Radical cystectomy (RC) can be associated with significant blood loss. Allogenic blood transfusion (ABT) may alter disease outcome because of a theoretical immunomodulatory effect. We evaluated the effects of ABT on overall survival (OS) and progression-free survival (PFS) of patients undergoing RC for urothelial carcinoma of the bladder (UCB). MATERIALS AND METHODS: This is a retrospective single-center study of 350 consecutive patients of a university health center with a median follow-up of 70.1 month. All patients underwent RC and pelvic lymph node dissection. The effect of ABT on OS and PFS was analyzed using univariable and multivariable Cox proportional hazards models. RESULTS: The overall ABT rate was 63 % (n = 219), with intraoperative blood transfusion and postoperative blood transfusion being performed in 183 patients (52 %) and 99 patients (28 %), respectively. Preoperative anemia was detected in 156 patients (45 %) with median estimated blood loss of 800 ml (IQR: 500-1,200). ABT was associated with significant decrease of OS and PFS in multivariable analyses (p < 0.001), whereas patients' prognosis worsened the more packed red blood cells (PRBC) were transfused (p < 0.001). The study is limited in part due to its retrospective design. CONCLUSIONS: We found that ABT and the number of PRBC transfused are associated with poor prognosis for UCB patients undergoing RC, whereas preoperative anemia had no influence on survival. This emphasizes the importance of surgeon's awareness for a strict indication for ABT. A prospective study will be necessary to evaluate the independent risks associated with ABT during surgical treatments.

Incidence and risk factors of renal hematoma: a prospective study of 1,300 SWL treatments.

Shock wave lithotripsy (SWL) is the gold standard for the treatment of upper urinary tract stones. Despite being relatively non-invasive, SWL can cause renal hematoma (RHT). The aim of this study was to determine incidence and risk factors for RHT following SWL. 857 patients were included in a prospectively maintained database. The observation period spans from 2007 to 2012. 1,324 procedures were performed due to kidney stones. Treatment protocol included power ramping and shock wave frequency of 60-90 per minute as well as an ultrasound check within 3 days of SWL for all patients. Patients with RHT were analyzed, and treatment characteristics were compared with the complete population in a non-statistical manner due to the low event count. RHTs after SWL, sized between 2.6 × 0.6 cm and 17 × 15 cm, were verified in seven patients (0.53%). In four patients, the RHT was asymptomatic. Three patients developed pain after SWL treatment due to a RHT. In one patient surgical intervention was necessary due to a symptomatic RHT, the kidney was preserved. The risk of RHT following SWL treatment of kidney stones is about 0.5%. Clinically relevant or symptomatic RHTs occur in 0.23%, RHTs requiring surgical intervention are extremely rare. Older age and vascular comorbidities appear to be risk factors for the development of RHT. The technical characteristics of SWL treatment and intake of low-dose acetylsalicylic acid due to an imperative cardiologic indication do not appear to influence the risk. Prospective studies are warranted.

Clinical and pathological nodal staging score for urothelial carcinoma of the bladder: an external validation.

PURPOSE: Radical cystectomy (RC) and pelvic lymph node dissection (LND) are standard treatments for muscle-invasive urothelial carcinoma of the bladder. Lymph node staging is a prerequisite for clinical decision-making regarding adjuvant chemotherapy and follow-up regimens. Recently, the clinical and pathological nodal staging scores (cNSS and pNSS) were developed. Prior to RC, cNSS determines the minimum number of lymph nodes required to be dissected; pNSS quantifies the accuracy of negative nodal staging based on pT stage and dissected LNs. cNSS and pNSS have not been externally validated, and their relevance for prediction of cancer-specific mortality (CSM) has not been assessed. METHODS: In this retrospective study of 2,483 RC patients from eight German centers, we externally validated cNSS and pNSS and determined their prediction of CSM. All patients underwent RC and LND. Median follow-up was 44 months. cNSS and pNSS sensitivities were evaluated using the original beta-binominal models. Adjusted proportional hazards models were calculated for pN0 patients to assess the predictive value of cNSS and pNSS for CSM. RESULTS: cNSS and pNSS both pass external validation. Adjusted for other clinical parameters, cNSS can predict outcome after RC. pNSS has no independent impact on prediction of CSM. The retrospective design is the major limitation of the study. CONCLUSIONS: In the present external validation, we confirm the validity of both cNSS and pNSS. cNSS is an independent predictor of CSM, thus rendering it useful as a tool for planning the extent of LND.

Oncological outcome of primary versus secondary muscle-invasive bladder cancer is comparable after radical cystectomy.

BACKGROUND: High-risk non-muscle-invasive bladder cancer (NMIBC) progressing to muscle-invasive bladder cancer (MIBC) is associated with adverse tumour biology. It is unclear, however, whether outcome of NMIBC progressing to MIBC is adverse compared to primary MIBC and whether NMIBC of higher risk of progression to MIBC is adverse compared to NMIBC of lower risk. OBJECTIVE: Our objective was to assess cancer-specific survival (CSS) following radical cystectomy (RC) for primary MIBC and for NMIBC progressing to MIBC in dependence of EORTC risk score. MATERIALS AND METHODS: Clinical and histopathological characteristics and CSS of 150 patients were assessed. Secondary MIBCs were stratified by EORTC risk score at the last transurethral resection of bladder tumour for NMIBC. RESULTS: CSS did not differ significantly between primary and secondary MIBC (p = 0.521). Secondary MIBC with high EORTC score had significantly shorter CSS compared to secondary MIBC with intermediate EORTC score (p = 0.029). In multivariable analysis, pathological tumour stage (HR = 3.77; p = 0.020) and lymph node stage (HR = 2.34; p = 0.022) were significantly correlated with CSS. CONCLUSION: While the outcome of secondary MIBC is not generally adverse compared to primary MIBC, the EORTC risk score not only reflects high risk of progression of NMIBC to MIBC, but also worse outcome following RC for secondary MIBC. Timely RC should thus be debated in high-risk NMIBC.

The role of plastidial glucose-6-phosphate/phosphate translocators in vegetative tissues of Arabidopsis thaliana mutants impaired in starch biosynthesis.

Arabidopsis thaliana mutants impaired in starch biosynthesis due to defects in either ADP glucose pyrophosphorylase (adg1-1), plastidic phosphoglucose mutase (pgm) or a new allele of plastidic phosphoglucose isomerase (pgi1-2) exhibit substantial activity of glucose-6-phosphate (Glc6P) transport in leaves that is mediated by a Glc6P/phosphate translocator (GPT) of the inner plastid envelope membrane. In contrast to the wild type, GPT2, one of two functional GPT genes of A. thaliana, is strongly induced in these mutants during the light period. The proposed function of the GPT in plastids of non-green tissues is the provision of Glc6P for starch biosynthesis and/or the oxidative pentose phosphate pathway. The function of GPT in photosynthetic tissues, however, remains obscure. The adg1-1 and pgi1-2 mutants were crossed with the gpt2-1 mutant defective in GPT2. Whereas adg1-1/gpt2-1 was starch-free, residual starch could be detected in pgi1-2/gpt2-1 and was confined to stomatal guard cells, bundle sheath cells and root tips, which parallels the reported spatial expression profile of AtGPT1. Glucose content in the cytosolic heteroglycan increased substantially in adg1-1 but decreased in pgi1-2, suggesting that the plastidic Glc6P pool contributes to its biosynthesis. The abundance of GPT2 mRNA correlates with increased levels of soluble sugars, in particular of glucose in leaves, suggesting induction by the sugar-sensing pathway. The possible function of GPT2 in starch-free mutants is discussed in the background of carbon requirement in leaves during the light-dark cycle.

Analytical electron microscopical investigations on the apoplastic pathways of lanthanum transport in barley roots.

In transmission electron microscopy studies, lanthanum ions have been used as electron-opaque tracers to delineate the apoplastic pathways for ion transport in barley (Hordeum vulgare L.) roots. To localize La3+ on the subcellular level, e.g. in cell walls and on the surface of membranes, electron-energy-loss spectroscopy and electron-spectroscopic imaging were used. Seminal and nodal roots were exposed for 30 min to 1 mM LaCl3 and 10 mM LaCl3, respectively. In seminal roots, possessing no exodermis, La3+ diffusion through the apoplast was stopped by the Casparian bands of the endodermis. In nodal roots with an exodermis, however, La3+ diffusion through the cortical apoplast had already stopped at the tight junctions of the exodermal cell walls resembling the Casparian bands of the endodermis. Therefore, we conclude that in some specialized roots such as the nodal roots of barley, the physiological role of the endodermis is largely performed by the exodermis.

[Small intestinal absorption in cancer patients--basis for enteral feeding therapy in oncology]. / Dünndarmresorption bei Krebskranken--Grundlagen für die enterale Ernährungstherapie in der Onkologie.

A deteriorating nutritional condition combined with the loss of body mass is one of the most noticeable symptoms of cancer. In order to answer the question to what extent absorption disorders in the small intestine are responsible for the malnutrition which develops, we studied 54 oncologic patients using modified D-xylose absorption tests. After the oral and intravenous administration of 10 g D-xylose at different times, the degree of absorption dependent on time was determined on the basis of a biophysical model. When accompanied by general nonspecific tumor symptoms, the frequency of absorption restrictions was increased. An established relation was found between the extent of small intestinal absorption, on the one hand, and the degree of spreading (staging) and the degree of histological differentiation of the carcinoma, on the other hand. Enteral absorption disorders represent a partial cause for the development of malnutrition in cancer patients and must be viewed as a result of a metabolic situation which is distinctly catabolic.