Age-dependent effects of the ß3 adrenoceptor agonist CL316,243 on human and rat detrusor muscle strips.

Motility of detrusor smooth muscle includes adrenergic relaxation and cholinergic contraction. Since the latter may be deregulated in overactive bladder (OAB) pathophysiology, anticholinergics are the standard therapy but occasionally less tolerated due to side effects such as dry mouth and constipation. ß3 adrenoceptor agonists also alleviate OAB symptoms by relaxing the detrusor muscle. Their age dependence, however, is far from understood. To address this issue, we induced contractions with KCl (60 mM) and carbachol (from 10 nM to 100 µM) in the presence of the ß3 adrenoceptor agonist CL316,243 (from 0.1 to 10 µM) in both human and rat muscle strips. Our results confirmed that both contractions were attenuated by ß3 adrenoceptor activation in both species, but with differing age dependence. In humans, specimens from mid-life subjects showed a significantly more pronounced effect of CL316,243 in attenuating carbachol-induced contractions than those from aged subjects (Cohen's d of maximal attenuation: 1.82 in mid-life versus 0.13 in aged) without altering EC50. Conversely, attenuation of KCl responses by CL316,243 increased during ageing (Spearman correlation coefficient = -0.584, P<0.01). In rats, both KCl- and carbachol-induced contractions were significantly more attenuated by CL316,243 in samples from adolescent as compared to aged samples. Immunohistochemistry in human detrusor sections proved ß3 adrenoreceptor abundance to remain unaltered during ageing. In conclusion, our findings suggest differential age-dependent changes in human ß3 adrenoceptor-dependent attenuation of detrusor contraction in terms of electromechanical versus pharmacomechanical coupling; they may help understand the differential responsiveness of OAB patients to ß3 agents.

A paired-kidney allocation study found superior survival with HLA-DR compatible kidney transplants in the Eurotransplant Senior Program.

The Eurotransplant Senior Program (ESP) has expedited the chance for elderly patients with kidney failure to receive a timely transplant. This current study evaluated survival parameters of kidneys donated after brain death with or without matching for HLA-DR antigens. This cohort study evaluated the period within ESP with paired allocation of 675 kidneys from donors 65 years and older to transplant candidates 65 years and older, the first kidney to 341 patients within the Eurotransplant Senior DR-compatible Program and 334 contralateral kidneys without (ESP) HLA-DR antigen matching. We used Kaplan-Meier estimates and competing risk analysis to assess all cause mortality and kidney graft failure, respectively. The log-rank test and Cox proportional hazards regression were used for comparisons. Within ESP, matching for HLA-DR antigens was associated with a significantly lower five-year risk of mortality (hazard ratio 0.71; 95% confidence interval 0.53-0.95) and significantly lower cause-specific hazards for kidney graft failure and return to dialysis at one year (0.55; 0.35-0.87) and five years (0.73; 0.53-0.99) post-transplant. Allocation based on HLA-DR matching resulted in longer cold ischemia (mean difference 1.00 hours; 95% confidence interval: 0.32-1.68) and kidney offers with a significantly shorter median dialysis vintage of 2.4 versus 4.1 yrs. in ESP without matching. Thus, our allocation based on HLA-DR matching improved five-year patient and kidney allograft survival. Hence, our paired allocation study suggests a superior outcome of HLA-DR matching in the context of old-for-old kidney transplantation.

Concomitant vs Staged Therapeutic Inguinal Lymphadenectomy in Clinically Node Positive Penile Squamous Cell Carcinoma: Does It Make a Difference?

PURPOSE: Inguinal lymph node dissection within 3 months of primary tumor resection in penile cancer has been associated with longer recurrence-free and cancer-specific survival. However, the optimal timing and effect of lymphadenectomy performed concurrently at the time of primary lesion management on oncologic outcomes in clinically lymph node positive penile squamous cell carcinoma remains unknown. MATERIALS AND METHODS: An international, multicenter cohort of 966 penile cancer cases was queried for penile squamous cell carcinoma management after the year 2000, clinically lymph node positive status, and performance of penile surgery and inguinal lymph node dissection. Cohorts were stratified as concomitant if inguinal lymph node dissection and penile surgery occurred on the same date or staged when inguinal lymph node dissection was performed after penile resection. Rates and patterns of penile squamous cell carcinoma recurrence were reported. Distant recurrence-free, cancer-specific, and overall survival were estimated using Kaplan-Meier analyses and groups compared with log-rank testing. RESULTS: Of 253 contemporary men with clinically lymph node positive penile squamous cell carcinoma, 96 (38%) underwent concomitant inguinal lymph node dissection and 157 (62%) had inguinal lymph node dissection performed in a staged manner. Penile cancer was most likely to recur distantly (19%) followed by in the groin (14%) or pelvis (5%). There were no differences in distant recurrence-free, cancer-specific, or overall survival between management strategies. Multivariable analysis adjusting for stage, treatment center, and perioperative chemoradiation also demonstrated no recurrence-free, cancer-specific, or overall survival benefit between management strategies. CONCLUSIONS: Inguinal lymph node dissection performed concurrently with excision of the penile tumor for clinically node positive penile squamous cell carcinoma is not associated with differences in recurrence-free, cancer-specific, or overall survival compared to staged lymph node dissection.

Lifestyle aspects in a contemporary middle-European cohort of patients undergoing androgen deprivation therapy for advanced prostate cancer: data from the non-interventional LEAN study.

Androgen deprivation therapy (ADT) in men with prostate cancer (PCa) is associated with significant side effects. With the transition of PCa from a foudroyant course to a chronic disease, managing these side effects has become increasingly important. There is growing evidence that nutritional changes and physical activity are beneficial in these patients. Here we examine the impact of written patient information on the physical activity and dietary habits of PCa patients receiving ADT and behaviour changes between baseline and 1 year, in the open-label, non-interventional LEAN study. In total, 959 patients with advanced hormone-sensitive PCa requiring ADT with the Leuprorelin Sandoz® implant were included from January 2014 to July 2015 and followed for ≥ 12 months. At the start of the study, urologists received a questionnaire concerning the written information provided to patients regarding their disease, patient advocacy groups, diet and physical activity. Patients received a questionnaire on their dietary habits and physical activity at the start and end of the study. Urologists from 147 study centres and 540 patients responded to the questionnaires. While 69 % of these patients received disease-specific information, only 30 % and 17 % received information regarding nutrition and physical activity, respectively. The majority of urologists estimate that their patients rarely or never follow guidance on nutrition or physical activity, yet > 90 % of patients indicate they would make use of this information, if provided. Few patients showed behavioural changes between baseline and 1 year without evident differences between patients that received information and those that did not.

Thirty-Year-Old Male Patient with Non-Seminoma and Coincidental Rectal Cancer.

We present the case of a 31-year-old male patient with non-seminoma (90% embryonal carcinoma, 10% teratoma) pT1b L1 V0 Pn0 R0 cN2 cM0, Clinical Stage IIb and "good prognosis group" according to IGCCCG of the left testis. According to EAU guidelines, he received three cycles of BEP. After the second cycle, he developed recurrent, clinically not significant rectal bleeding, which we associated with deep thrombocytopenia. Following chemotherapy, there was one lymph node in the CT scan left, with a diameter of 0.9 cm at the inferior mesenteric arteria and the rectal bleeding did not stop; so coloscopy and staging revealed rectal cancer (adenocarcinoma) with peritoneal carcinosis. The patient was scheduled for radio-chemotherapy. Next-generation sequencing of the adenocarcinoma showed two mutations in KRAS and TP53 genes. To our knowledge, this is the first case of non-seminoma and coincidental rectal cancer. Furthermore, this case underlines the significance of molecular biological studies for the development of individualized targeted therapies, especially in younger patients and in chemo- and/or platin-resistance.

Prospective Evaluation of Health-Related Quality of Life in Patients with Metastatic Urothelial Carcinoma Undergoing Immunotherapy with Pembrolizumab: Symptom Burden Can Predict Survival.

INTRODUCTION: Despite the fact that guidelines recommend monitoring of quality of life during all phases of treatment in urothelial carcinoma, prospective data about health-related quality of life (HRQoL) in metastatic urothelial carcinoma undergoing immunotherapy are sparse. Consequently, we performed a prospective clinical pilot study about HRQoL using the Functional Assessment of Cancer Therapy - Immune Checkpoint Modulator (FACT-ICM) questionnaire. MATERIALS AND METHODS: Formally, this study is a prospective uni-centric noninterventional observation from January 2021 to December 2021. RESULTS: Fourteen patients with a mean age of 73.9 years (SD 8.8) participated in the study. The physical well-being subscale of FACT-G is most impaired during therapy with mean scores of 7.5, 6.2, and 4.0 followed by the emotional well-being. The FACT-G total score is stable during therapy with mean scores of 51.1, 50.4, and 48.0 and it is not significantly decreasing during therapy (p = 0.317). Furthermore, the symptom burden of these patients is low and not significantly changing over time (p = 0.500), but survival decreases significantly if symptom burden is high (FACT-ICM score over 40; p < 0.001). CONCLUSION: Physical and emotional needs have a strong impact on HRQoL and should be dealt with during treatment. If symptom burden is high, survival decreases. This needs further evaluation.

Prediction of Treatment Response and Survival with Chemotherapy for Metastatic Penile Cancer by the Modified Glasgow Prognostic Score.

PURPOSE: There is increasing evidence that a persistent systemic inflammatory response predicts lower survival in patients with malignant disease. The modified Glasgow Prognostic Score (mGPS) is defined by a combination of elevated C-reactive protein (CRP) (>10 mg/L) and hypoalbuminemia (<35 g/L). It is considered as an independent prognostic marker in several organ malignancies. The aim of this study was to investigate the value of mGPS in metastatic penile carcinoma in predicting treatment response and survival. METHODS: One hundred and fifty-six patients with penile carcinoma treated with chemotherapy were included in this retrospective study. The mGPS before chemotherapy was classified into 3 groups (mGPS 0 [CRP <10, any albumin], mGPS 1 [CRP >10 mg/L, albumin >35 g/L], and mGPS 2 [CRP >10 mg/L, albumin <35 g/L]). Overall survival and disease-free survival were calculated by Kaplan-Meier analysis and chemotherapy toxicity by CTC criteria. Univariate Cox proportional hazards models were calculated to estimate the effect of each predictor on OS and DFS. RESULTS: Survival was significantly different in the 3 mGPS classes, with mGPS 0 patients showing the best treatment response and survival. Univariate analysis showed that mGPS (p < 0.0001), tumor stage (p = 0.004), and venous and lymphatic invasion (p = 0.011) were factors independently associated with prognosis. The response to chemotherapy differed significantly between mGPS groups (mGPS 0, 36/51 [71%]; mGPS 1, 24/70 [34%]; mGPS 2, 9/35 [26%], p = 0.03 and p = 0.37, respectively). mGPS was significantly associated with chemotherapy-associated toxicity, with treatment adaptation (p < 0.01) and toxicity-related deaths (p = 0.028). CONCLUSIONS: Systemic inflammatory response and nutritional status as expressed by the mGPS are independent predictors of treatment response, chemotherapy-associated toxicity, and survival in metastatic penile carcinoma. In addition to other known pathological markers of tumor aggressiveness, the mGPS can be used as a clinical predictor of prognosis.

Therapy of clinical stage IIA and IIB seminoma: a systematic review.

PURPOSE: The optimal treatment for clinical stage (CS) IIA/IIB seminomas is still controversial. We evaluated current treatment options. METHODS: A systematic review was performed. Only randomized clinical trials and comparative studies published from January 2010 until February 2021 were included. Search items included: seminoma, CS IIA, CS IIB and therapy. Outcome parameters were relapse rate (RR), relapse-free (RFS), overall and cancer-specific survival (OS, CSS). Additionally, acute and long-term side effects including secondary malignancies (SMs) were analyzed. RESULTS: Seven comparative studies (one prospective and six retrospective) were identified with a total of 5049 patients (CS IIA: 2840, CS IIB: 2209). The applied treatment modalities were radiotherapy (RT) (n = 3049; CS IIA: 1888, CSIIB: 1006, unknown: 155) and chemotherapy (CT) or no RT (n = 2000; CS IIA: 797, CS IIB: 1074, unknown: 129). In CS IIA, RRs ranged from 0% to 4.8% for RT and 0% for CT. Concerning CS IIB RRs of 9.5%-21.1% for RT and of 0%-14.2% for CT have been reported. 5-year OS ranged from 90 to 100%. Only two studies reported on treatment-related toxicities. CONCLUSIONS: RT and CT are the most commonly applied treatments in CS IIA/B seminoma. In CS IIA seminomas, RRs after RT and CT are similar. However, in CS IIB, CT seems to be more effective. Survival rates of CS IIA/B seminomas are excellent. Consequently, long-term toxicities and SMs are important survivorship issues. Alternative treatment approaches, e.g., retroperitoneal lymph node dissection (RPLND) or dose-reduced sequential CT/RT are currently under prospective investigation.

Reduction of Perioperative Antibiotic Prophylaxis in Open Radical Cystectomy with Ileal Conduit Is Feasible: Results of a Prospective Clinical Trial.

INTRODUCTION: The aim of this study is to perform a prospective clinical trial in antibiotic prophylaxis, infectious complication, and colonization of ileal conduit (IC) following radical cystectomy (RC) since urinary tract infections (UTIs) and surgical site infections (SSIs) contribute significantly to the morbidity associated with RC and IC. Moreover, an optimal regimen of antibiotic prophylaxis has not been established, yet. MATERIAL AND METHODS: After a positive vote of ethical review committee and the registration at the German Clinical Trials Register (DKRS 00020406), we started a prospective clinical unicentric not interventional study. The urine samples were collected by sterile catheterization of the IC. All patients received an antibiotic prophylaxis with 3 × 500 mg metronidazole and 3 × 1.5 g cefuroxime intravenously for 3 days starting on the day before RC. Ureteral stents got removed on days 9 and 10 after surgery without prior antibiotic administration. The student t test and the χ2 test or the Fisher exact test were used. For risk factor assessment, the univariate Cox regression method was applied. RESULTS: Nineteen male (63.3%) and 11 female patients (36.7%) with a median age of 70.5 years were included. Three patients developed complicated UTI (10%) on day 12 after RC with E. faecium and needed antibiotic treatment with meropenem (Clavien-Dindo II). Two patients (6.7%) developed SSI with E. faecium and needed surgery (Clavien-Dindo IIIb). Palliative RC (p < 0.0001), prior radiation therapy (p < 0.0001), and timeframe >3 months from diagnosis to RC (p = 0.036) are significantly associated with the development of complicated UTI. Interestingly, the IC got colonized with Staph. haemolyticus at day 12 after RC (n = 12; 40.0%). We must assume that our data have some limitations like a unicentric study population. CONCLUSION: Further evaluation of reduction to single-shot antibiotic prophylaxis in nonpalliative RC with IC could be feasible.

Predictors of Delayed Graft Function in Renal Transplantation.

PURPOSE: This study aimed to analyze our data on delayed graft function (DGF) and to identify associated factors. METHODS: This is a retrospective case-control study of all patients transplanted in our center over a period of 11 years (January 1, 2003, to December 31, 2014) comparing patients with immediate graft function (n = 332) to those with DGF (n = 165). DGF was defined as the need for hemodialysis within the first 7 days after transplantation. Donor and recipient characteristics as well as procedural factors were compared by univariate and multivariate logistic regression analyses. RESULTS: Overall, 33% of patients had DGF. The rate of DGF declined from 2003 to 2011. In cases with DGF, donors and recipients were significantly older (p = 0.004 and p = 0.005, respectively), had longer cold ischemia times (p = 0.039), more revision surgeries (p < 0.001), and more HLA mismatches (p = 0.001), especially in the DR locus (p = 0.002). Neither donor nor recipient gender, waiting time, nor CMV status had any influence. In multivariable analysis, significant risk factors were ischemia time and mismatches at the HLA-DR loci. CONCLUSIONS: DGF is a common complication in renal transplantation which occurred in 33% of our cases. Important factors identified were donor and recipient age, ischemia time, HLA mismatching, and revision surgery.

German S3 Evidence-Based Guidelines on Focal Therapy in Localized Prostate Cancer: The First Evidence-Based Guidelines on Focal Therapy.

BACKGROUND: Focal therapy (FT) is an option to treat localized prostate cancer (PCa) and preserve healthy prostate tissue in order to reduce known side effects from primary whole-gland treatment. The available FT modalities are manifold. Until now, national and international PCa guidelines have been cautious to propose recommendations regarding FT treatment since data from prospective controlled trials are lacking for most FT modalities. Moreover, none of the international guidelines provides a separate section on FT. In this purpose, we provide a synopsis of the consensus-based German S3 guidelines for a possible international use. SUMMARY: The recently published update of the German S3 guidelines, an evidence- and consensus-based guideline, provides a section on FT with recommendations for diagnostic work-up, indications, modalities, and follow-up. This section consists of 12 statements and recommendations for FT in the treatment of localized PCa. KEY MESSAGE: The German S3 guidelines on PCa are the first to incorporate recommendations for FT based on evidence and expert consensus including indication criteria for FT, pretreatment, and follow-up diagnostic pathways as well as an extended overview of FT techniques and the current supportive evidence.

Patterns of Recurrence following Inguinal Lymph Node Dissection for Penile Cancer: Optimizing Surveillance Strategies.

PURPOSE: Our primary objective is to detail the incidence, site, and timing of penile squamous cell carcinoma (pSCC) recurrence after inguinal lymph node dissection (ILND). MATERIALS AND METHODS: We performed a retrospective analysis of 551 patients who underwent ILND for pSCC from 2000 to 2017. The primary outcome was pSCC recurrence after ILND. Recurrences were identified and stratified by site. Timing of recurrence was determined. Multivariable logistic regression analysis determined associations with recurrence. Multivariable Cox regression analysis determined associations with overall survival (OS). Sub-group analysis of the distant recurrences analyzed timing and OS by site of distant recurrence. RESULTS: After ILND pSCC recurred in 176 (31.9%) patients. Median time to recurrence was 10 months for distant recurrences, 12 for inguinal, 10.5 for pelvic, and 44.5 for local. Greater than 95% of distant, inguinal, and pelvic recurrences occurred within 48 months of ILND, versus 127 months for local recurrences. Post-ILND recurrence was associated with pN2 (OR 1.99, 95% CI 1.0-4.1), and pN3 (OR 7.2, 95% CI 4.0-13.7). Patients who had local recurrence had similar OS to those without (HR 1.5, 95% CI 0.6-3.8), and worse OS was identified in patients with inguinal (HR 4.5, 95% CI 2.8-7.1), pelvic (HR 2.6, 95% CI 1.5-4.5), or distant (HR 4.0, 95% CI 2.7-5.8) recurrences. Patients with lung recurrences had worse OS than other sites (HR 2.2, 95% CI 1.1-4.3). CONCLUSIONS: Of the patients 31.9% had post-ILND recurrence associated with high pN staging. Greater than 95% of distant, inguinal, and pelvic recurrences occurred within 48 months, suggesting surveillance beyond this is low yield. Local recurrences occurred over a longer timeline, emphasizing necessity of long-term surveillance of the primary site.

Flow-dependent differentiation of cultured adrenal cells under different stimuli.

It still remains unclear how the functional organisation of the adrenal cortex arises. One aim of this study was to create a setup which allows for the establishment of a concentration gradient in vitro. This was achieved by a continuous flow of medium through the culture flask which caused differences in glucose and cortisol concentrations as well as in pH values between the sites of inflow and outflow of medium. Using real-time polymerase chain reaction, we found that a continuous supply of 1 ml medium per hour significantly increased the expression of MC2R, CYP11B1 and CYP17A1 genes of NCI-H295R cells in the distal area of the flask as compared with the proximal part. The expression of the AT1R showed a reverse regulation. The addition of dexamethasone to the medium led to an increase in gene expression of MC2R while AT1R was downregulated. Moreover, we detected a higher expression of CYP11B2 and a decreased expression of CYP11B1 when endothelial cell-conditioned medium (ECCM) was added to the inflow. Our experiments show that a directed medium delivery system creates different gradients and affects the functional differentiation of the NCI-H295R cells. Also, our results emphasise that products of endothelial cells have additional effects on the differentiation of the cultured adrenal cortical cells. Our results are in support that the regulation of the adrenal zonation is possible through different concentration gradients.

Cure of Interstitial Cystitis and Non-Ulcerating Hunner's Ulcer by Cardinal/Uterosacral Ligament Repair.

A serendipitous cure in a 73-year-old woman of Hunner's ulcer, urge, nocturia, apical prolapse by a tissue fixation system tensioned minisling (TFS) which reinforced the cardinal, and uterosacral ligaments (USLs) led us to analyse the relationship between Hunner's ulcer and known pain conditions associated with USL laxity. The original intention was to cure the "posterior fornix syndrome" (PFS), uterine prolapse, and associated pain and bladder symptoms by USL repair. A speculum inserted preoperatively into the posterior fornix alleviated pain and urge symptoms, by mechanically supporting USLs. Hunner's ulcer, along with pain and other PFS symptoms were cured by USL repair. The concept of USL laxity causing chronic pelvic pain and bladder problems is not new. It was published in the German literature by Heinrich Martius in 1938 and by Petros in the English literature in 1993. These findings raise important questions. As PFS symptoms are identical with those of interstitial cystitis (IC), are PFS and IC similar conditions? If so, then patients with IC who have a positive speculum test are at least theoretically, potentially curable by USL repair. These questions need to be explored.

Effectiveness and Distribution of Testosterone Levels within First Year of Androgen Deprivation Therapy in a Real-World Setting: Results from the Non-Interventional German Cohort LEAN Study.

BACKGROUND: Observational studies generate information on real-world therapy and complement data from prospective randomized trials. LEAN is an open-label, non-interventional, multi-centre, German cohort study on leuprorelin in routine clinical practice. OBJECTIVES: To extend knowledge on the use, effectiveness, and tolerability of HEXAL/Sandoz leuprorelin (in this article, the term Leuprone® HEXAL® covers Leuprorelin Sandoz® as well) solid implant in patients with prostate cancer (PCa) in a real-world setting. METHODS: 959 PCa patients scheduled for androgen deprivation therapy (ADT) received leuprorelin acetate implant. Metabolism, serum prostate-specific antigen (PSA), and testosterone data, if available, were collected at baseline and follow-up visits for ≥12 months. RESULTS: Of 694 patients in the modified full analysis set, 26.4% received GnRH analogues ≤6 months before enrolment. Fifty-one percent of patients were treated for locally advanced or metastatic PCa. In 19.6% of patients, ADT was used in neoadjuvant or adjuvant settings and in 28.5% with rising PSA after definite therapy. Testosterone levels <0.5 ng/mL were achieved in >90% of patients. Safety profile was in line with the summary of product characteristics. Therapy was well tolerated, with patient-triggered therapy discontinuation in 3.6%. CONCLUSIONS: This interim analysis confirmed previous efficacy findings for leuprorelin implant in a real-world setting. This contemporary cohort showed a shift in the use of ADT to non-metastatic PCa stages.

Management of Germ Cell Tumours of the Testes in Adult Patients: German Clinical Practice Guideline, PART II - Recommendations for the Treatment of Advanced, Recurrent, and Refractory Disease and Extragonadal and Sex Cord/Stromal Tumours and for the Management of Follow-Up, Toxicity, Quality of Life, Palliative Care, and Supportive Therapy.

OBJECTIVES: We developed the first German evidence- and consensus-based clinical guideline on diagnosis, treatment, and follow-up of germ cell tumours (GCT) of the testes in adult patients. We present the guideline content in 2 separate publications. The present second part summarizes therecommendations for the treatment of advanced disease stages and for the management of follow-up and late effects. MATERIALS AND METHODS: An interdisciplinary panel of 42 experts including 1 patient representative developed the guideline content. Clinical recommendations and statements were based on scientific evidence and expert consensus. For this purpose, evidence tables for several review questions, which were based on systematic literature searches (last search in March 2018), were provided. Thirty-one experts, who were entitled to vote, rated the final clinical recommendations and statements. RESULTS: Here we present the treatment recommendations separately for patients with metastatic seminoma and non-seminomatous GCT (stages IIA/B and IIC/III), for restaging and treatment of residual masses, and for relapsed and refractory disease stages. The recommendations also cover extragonadal and sex cord/stromal tumours, the management of follow-up and toxicity, quality-of-life aspects, palliative care, and supportive therapy. CONCLUSION: Physicians and other medical service providers who are involved in the diagnostics, treatment, and follow-up of GCT (all stages, outpatient and inpatient care as well as rehabilitation) are the users of the present guideline. The guideline also comprises quality indicators for measuring the implementation of the guideline recommendations in routine clinical care; these data will be presented in a future publication.

Management of Germ Cell Tumours of the Testis in Adult Patients. German Clinical Practice Guideline Part I: Epidemiology, Classification, Diagnosis, Prognosis, Fertility Preservation, and Treatment Recommendations for Localized Stages.

INTRODUCTION: This is the first German evidence- and consensus-based clinical guideline on diagnosis, treatment, and follow-up on germ cell tumours (GCTs) of the testis in adult patients. We present the guideline content in two publications. Part I covers the topic's background, methods, epidemiology, classification systems, diagnostics, prognosis, and treatment recommendations for the localized stages. METHODS: An interdisciplinary panel of 42 experts including 1 patient representative developed the guideline content. Clinical recommendations and statements were based on scientific evidence and expert consensus. For this purpose, evidence tables for several review questions, which were based on systematic literature searches (last search was in March 2018) were provided. Thirty-one experts entitled to vote, rated the final clinical recommendations and statements. RESULTS: We provide 161 clinical recommendations and statements. We present information on the quality of cancer care and epidemiology and give recommendations for staging and classification as well as for diagnostic procedures. The diagnostic recommendations encompass measures for assessing the primary tumour as well as procedures for the detection of metastases. One chapter addresses prognostic factors. In part I, we separately present the treatment recommendations for germ cell neoplasia in situ, and the organ-confined stages (clinical stage I) of both seminoma and nonseminoma. CONCLUSION: Although GCT is a rare tumour entity with excellent survival rates for the localized stages, its management requires an interdisciplinary approach, including several clinical experts. Quality of care is highly related to institutional expertise and can be reassured by established online-based second-opinion boards. There are very few studies on diagnostics with good level of evidence. Treatment of metastatic GCTs must be tailored to the risk according to the International Germ Cell Cancer Collaboration Group classification after careful diagnostic evaluation. An interdisciplinary approach as well as the referral of selected patients to centres with proven experience can help achieve favourable clinical outcomes.

Targeting IL-11 in the treatment of BK virus-associated haemorrhagic cystitis-A promising new approach.

The BK polyomavirus (BKPyV) has pathogenic relevance especially in immunocompromised patients. No causal therapy has been established yet. Therefore, new therapeutic targets need to be identified in experimental studies. A 3D organotypic cell culture model with primary urothelial cells and fibroblasts was used as infection model. The detection of virus replication was performed with quantitative polymerase chain reaction (qPCR), and immunohistochemistry (IHC) was also used for analysis. Interleukin levels were measured by enzyme-linked immunosorbent assay (ELISA). Interestingly, the signal transducer and activator of transcription 3 (STAT3) pathway seems to be activated during infection with BKPyV, for example phosphorylated STAT3 is significantly (P < 0.0001) elevated on day 6 following infection. Therefore, we performed ELISAs for involved interleukins in STAT3 pathway. Interleukin 11 (IL-11) was significantly (P = 0.026) elevated at day 9. Subsequently, 3D cultures were treated with IL-11 neutralizing antibody. At day 9 following infection, the median virus replication rate is 4.4 × 106 copies/ml. The difference to replication rate without treatment was significantly lower at day 6 (P < 0.0001) and at day 9 (P < 0.0001), respectively. STAT3 pathways seem to be involved during BKPyV infection and need further investigation in experimental studies. A very promising target for treatment might be IL-11.

First-in-human dosimetry of gastrin-releasing peptide receptor antagonist [177Lu]Lu-RM2: a radiopharmaceutical for the treatment of metastatic castration-resistant prostate cancer.

PURPOSE: Besides PSMA, prostate cancer cells also express gastrin-releasing peptide receptor (GRPr) which is therefore a promising target for theranostic approaches. The high affinity GRPr antagonist RM2 can be labeled with beta-emitting radiometals for therapeutic purposes. The aim of this study was to calculate absorbed doses for critical organs and tumor lesions for [177Lu]Lu-RM2 therapy administered in a group of metastatic castration-resistant prostate cancer (mCRPC) patients who had insufficient PSMA expression or showed lower PSMA accumulation after previous cycles of [177Lu]Lu-PSMA-617 therapy. METHODS: Thirty-five patients suffering from mCRPC without further treatment options for approved therapies were examined with [68Ga]Ga-RM2-PET/CT. Out of these, 4 patients (mean age 68 years) were treated with [177Lu]Lu-RM2; two of these also received a 2nd therapy cycle. Mean activity was 4.5 ± 0.9 GBq. For dosimetry, patients underwent planar WB-scintigraphy and SPECT/CT imaging of the upper and lower abdomen at approximately 1, 24, 48, and 72 h p.i. along with blood sampling. Absorbed doses for kidneys, pancreas, liver, spleen, gallbladder wall, and tumor lesions were derived based on quantitative SPECT/CT according to RADAR dosimetry scheme; individual organ masses were extracted from CT. Absorbed dose to bone marrow was calculated based on serial whole-body images and blood sampling according to the EANM guideline. RESULTS: Therapy was well tolerated by all patients and no side effects were observed. An increased uptake in tumor lesions and the pancreas was seen within the first 1 h. Mean absorbed organ doses were 1.08 ± 0.44 Gy/GBq in the pancreas, 0.35 ± 0.14 Gy/GBq in the kidneys, 0.05 ± 0.02 Gy/GBq in the liver, 0.07 ± 0.02 Gy/GBq in the gallbladder wall, 0.10 ± 0.06 Gy/GBq in the spleen, and 0.02 ± 0.01 Gy/GBq for the red bone marrow. The mean dose for tumor lesions was 6.20 ± 3.00 Gy/GBq. CONCLUSIONS: Application of GRPr antagonist [177Lu]Lu-RM2 is suitable for targeted radiotherapy of mCRPC as it shows high tumor uptake and rapid clearance from normal organs. Absorbed doses in tumor lesions are therapeutically relevant. The critical organ receiving the highest absorbed dose was the pancreas. Results suggest that the activity administered for each cycle could be increased to maximize the absorbed dose of tumors and metastases.

Identifying an optimal lymph node yield for penile squamous cell carcinoma: prognostic impact of surgical dissection.

OBJECTIVE: To evaluate the prognostic impact of lymph node yield (LNY) on survival outcomes for penile squamous cell carcinoma (SCC). PATIENTS AND METHODS: In all, 532 patients who underwent inguinal LN dissection (ILND) across tertiary referral centres from Europe, China, Brazil and North America were retrospectively evaluated. From this cohort, 198 patients received pelvic LND (PLND).We identified threshold values for ILND and PLND using receiver operating characteristic curves. We tested prognostic value of LNY for recurrence-free survival (RFS), disease-specific survival (DSS), and overall survival (OS) using the Kaplan-Meir method and Cox proportional hazard regression models. RESULTS: The median (interquartile [IQR]) age was 59 (49-68) years and the median (IQR) follow-up after ILND was 28 (12-68.2) months. Overall, 85% of the patients had bilateral dissections. The median (IQR) number of inguinal LNs removed was 15 (10-22). Of those receiving PLND, The median (IQR) number of LNs was 13 (8-19). A LNY of ≥15 was used for dichotomisation of ILND patients, and a LNY of ≥9 was used in the PLND cohort. Patients with a LNY ≥15 had significantly better 5-year OS vs patients with a LNY <15 (70.1% vs 58.7%). On multivariable analyses, a LNY ≥15 was a predictor of OS (hazard ratio [HR] 0.68, P = 0.029). For cN0 patients, a LNY ≥15 was an independent predictor of RFS (HR 0.52, P = 0.043) and OS (HR 0.53, P = 0.021). In the PLND cohort, a LNY ≥9 was a predictor of RFS (HR 0.53, P = 0.032). CONCLUSIONS: Using one of the largest LND datasets to date, we found LNY to be a significant predictor of outcomes after lymphatic staging for penile SCC. Prospective validation is warranted.