Borealis-1: a randomized, first-line, placebo-controlled, phase II study evaluating apatorsen and chemotherapy for patients with advanced urothelial cancer.

BACKGROUND: Five-year survival of patients with inoperable, advanced urothelial carcinoma treated with the first-line chemotherapy is 5%-15%. We assessed whether the Hsp27 inhibitor apatorsen combined with gemcitabine plus cisplatin (GC) could improve overall survival (OS) in these patients. PATIENTS AND METHODS: This placebo-controlled, double-blind, phase II trial randomized 183 untreated urothelial carcinoma patients (North America and Europe) to receive GC plus either placebo (N = 62), 600 mg apatorsen (N = 60), or 1000 mg apatorsen (N = 61). In the experimental arm, treatment included loading doses of apatorsen followed by up to six cycles of apatorsen plus GC. Patients receiving at least four cycles could continue apatorsen monotherapy as maintenance until progression or unacceptable toxicity. The primary end point was OS. RESULTS: OS was not significantly improved in the single or combined 600- or 1000-mg apatorsen arms versus placebo [hazard ratio (HR), 0.86 and 0.90, respectively]. Exploratory study of specific statistical modeling showed a trend for improved survival in patients with baseline poor prognostic features treated with 600 mg apatorsen compared with placebo (HR = 0.72). Landmark analysis of serum Hsp27 (sHsp27) levels showed a trend toward survival benefit for poor-prognosis patients in 600- and 1000-mg apatorsen arms who achieved lower area under the curve sHsp27 levels, compared with the placebo arm (HR = 0.45 and 0.62, respectively). Higher baseline circulating tumor cells (≥5 cells/7.5 ml) was observed in patients with poor prognosis in correlation with poor survival. Treatment-emergent adverse events were manageable and more common in both apatorsen-treatment arms. CONCLUSIONS: Even though apatorsen combined with standard chemotherapy did not demonstrate a survival benefit in the overall study population, patients with poor prognostic features might benefit from this combination. Serum Hsp27 levels may act as a biomarker to predict treatment outcome. Further exploration of apatorsen in poor-risk patients is warranted.

Vinflunine-gemcitabine versus vinflunine-carboplatin as first-line chemotherapy in cisplatin-unfit patients with advanced urothelial carcinoma: results of an international randomized phase II trial (JASINT1).

BACKGROUND: There is no standard first-line chemotherapy for advanced urothelial carcinoma (aUC) in cisplatin-ineligible (cisplatin-unfit) patients. The study assessed the efficacy and tolerability profile of two vinflunine-based cytotoxic regimens in this setting. PATIENTS AND METHODS: Patients with aUC a creatinine clearance (CrCl) of <60 but ≥30 ml/min, performance status 0 or 1 and no prior chemotherapy for advanced disease were randomized (1 : 1). They received vinflunine 250 or 280 mg/m(2) (based on baseline CrCl) on day 1, plus either gemcitabine [750 mg/m(2) escalated to 1000 mg/m(2) in cycle 2 if no toxicity grade (G) ≥2 on days 1 and 8 (VG) or plus carboplatin area under the curve 4.5 day 1 (VC) every 21 days]. To detect a 22% improvement in each arm compared with H0 (41%) in the primary end point, disease control rate (DCR = complete response + partial response + stable disease), 31 assessable patients per arm were required (α = 5%, ß = 20%). RESULTS: Sixty-nine patients were enrolled (34 VG, 35 VC). Less G3/4 haematological adverse events (AEs) were reported with VG: neutropaenia was seen in 38% (versus 68% with VC) and febrile neutropaenia in 3% (versus 14% with VC) of patients. No major differences were observed for non-haematological AEs. DCR was 77% in both groups; overall response rate (ORR) was 44.1% versus 28.6%, with a median progression-free survival of 5.9 versus 6.1 months and median OS of 14.0 versus 12.8 months with VG and VC, respectively. CONCLUSION: Both vinflunine-based doublets offer a similar DCR, ORR and OS. The better haematological tolerance favours the VG combination, which warrants further study. CLINICALTRIALS.GOV PROTOCOL IDENTIFIER: NCT 01599013.

The prognostic effect of tumour-infiltrating lymphocytic subpopulations in bladder cancer.

BACKGROUND: Intratumoural lymphocytic infiltration is strongly associated with the outcome of many human epithelial cancers. The current paper investigated whether subpopulations of tumour-infiltrating T lymphocytes are associated with certain clinicopathological parameters and the prognosis of patients with invasive bladder cancer (BCa). PATIENTS AND METHODS: The infiltration densities of the adaptive immune markers CD3 (the whole T cell population), FOXP3 (regulatory T cells; Tregs), CD8 (T effector cells) and CD45R0 (T effector memory cells) were analysed by immunohistochemistry and image analysis with tissue microarrays of tumour tissues from 149 patients with invasive BCa treated with radical cystectomy. The findings were correlated with certain clinicopathological parameters. RESULTS: Higher FOXP3/CD3 [OS: p = 0.016, HR 1.29, 95% confidence intervals (95% CIs 1.05-1.59)] and FOXP3/CD8 (OS: p = 0.013, HR 1.32, 95% CIs 1.06-1.65) ratios were significantly associated with briefer overall survival and time to cancer-specific death; the latter ratio represented an independent prognostic factor according to a multivariate analysis adjusted for pathological T and N stages (HR 1.32, 95% CIs 1.05-1.67, p = 0.018). The infiltration densities of individual markers (CD3, CD8, FOXP3 and CD45R0) were not significantly associated with clinicopathological parameters or survival; however, a trend towards a better outcome was observed for higher log-transformed CD8 (p = 0.070, HR 0.80, 95% CIs 0.63-1.02) and CD3 (p = 0.113, HR 0.84, 95% CIs 0.68-1.04) infiltration values. CONCLUSIONS: A high fraction of Tregs amongst CD3- and CD8-positive lymphocytes indicated a poor prognosis, thereby emphasising the important role that Tregs play in the suppression of the anti-tumour immune response. No single lymphocytic marker was significantly correlated with clinical outcomes, but high CD3 and CD8 infiltration showed trends towards better prognosis.

Mutant PIK3CA controls DUSP1-dependent ERK 1/2 activity to confer response to AKT target therapy.

BACKGROUND: Alterations in the phosphoinositide 3-kinase/AKT/mammalian target of rapamycin (PI3K/AKT/mTOR) signalling pathway are frequent in urothelial bladder cancer (BLCA) and thus provide a potential target for novel therapeutic strategies. We investigated the efficacy of the AKT inhibitor MK-2206 in BLCA and the molecular determinants that predict therapy response. METHODS: Biochemical and functional effects of the AKT inhibitor MK-2206 were analysed on a panel of 11 BLCA cell lines possessing different genetic alterations. Cell viability (CellTiter-Blue, cell counts), apoptosis (caspase 3/7 activity) and cell cycle progression (EdU incorporation) were analysed to determine effects on cell growth and proliferation. cDNA or siRNA transfections were used to manipulate the expression of specific proteins such as wild-type or mutant PIK3CA, DUSP1 or CREB. For in vivo analysis, the chicken chorioallantoic membrane model was utilised and tumours were characterised by weight and biochemically for the expression of Ki-67 and AKT phosphorylation. RESULTS: Treatment with MK-2206 suppressed AKT and S6K1 but not 4E-BP1 phosphorylation in all cell lines. Functionally, only cell lines bearing mutations in the hotspot helical domain of PIK3CA were sensitive to the drug, independent of other genetic alterations in the PI3K or MAPK signalling pathway. Following MK-2206 treatment, the presence of mutant PIK3CA resulted in an increase in DUSP1 expression that induced a decrease in ERK 1/2 phosphorylation. Manipulating the expression of mutant or wild-type PIK3CA or DUSP1 confirmed that this mechanism is responsible for the induction of apoptosis and the inhibition of tumour proliferation in vitro and in vivo, to sensitise cells to AKT target therapy.Conclusion or interpretation:PIK3CA mutations confer sensitivity to AKT target therapy in BLCA by regulating DUSP1 expression and subsequent ERK1/2 dephosphorylation and can potentially serve as a stratifying biomarker for treatment.

[Value of immunotherapy in the perioperative treatment of localized muscle invasive bladder cancer]. / Stellenwert der Immuntherapie in der perioperativen Behandlung des lokalisierten muskelinvasiven Harnblasenkarzinoms.

Immune checkpoint inhibitors are standard of care in the treatment of metastatic and locally advanced urothelial cancer. Their use in perioperative treatment is currently under investigation as monotherapy as well as in combination with chemotherapy or radiation regimens. This article provides an overview of recent trials, current data as well as an outlook on future developments in the perioperative management of urothelial cancer.

["Surgery only" is not enough: potential of multimodal therapy in urothelial bladder carcinoma]. / "Surgery only" reicht nicht aus: Potenziale einer multimodalen Therapie beim Urothelkarzinom der Harnblase.

Radical cystectomy is the standard treatment for muscle invasive bladder cancer. Using perioperative cisplatin-based chemotherapy, 5­year overall survival rates are 5% higher with neoadjuvant chemotherapy compared to local therapy alone. New multimodal concepts have been developed to improve oncologic efficacy and to reduce treatment-related morbidity. Perioperative use of checkpoint inhibitors aims at improving efficacy, while bladder-preserving concepts try to avoid cystectomy in good responders. This article reviews new developments in radioimmunotherapy and perioperative combination therapies as well as bladder-preserving concepts like trimodal bladder therapy.

[Quality assurance for the treatment of muscle-invasive and metastasized bladder carcinoma in Germany : An initiative of the Working Groups Urological Oncology (AUO) and Internal Oncology (AIO) in the German Cancer Society (DKG)]. / Qualitätssicherung zur Therapie des muskelinvasiven und metastasierten Harnblasenkarzinoms in Deutschland : Eine Initiative der Arbeitsgemeinschaften Urologische Onkologie (AUO) und Internistische Onkologie (AIO) in der Deutschen Krebsgesellschaft (DKG).

BACKGROUND: The S3-guideline on bladder cancer recommends radical cystectomy and cisplatin-based perioperative chemotherapy (POC) for muscle-invasive bladder cancer (MIBC). Recommendation for metastatic urothelial cancer (mUC) is cisplatin-based or immuno-oncological (IO) treatment in platinum-ineligible patients (pts) or as 2nd-line therapy. OBJECTIVES: Aim of the study was to obtain representative data on clinical routine treatment of MIBC and mUC in Germany. MATERIALS AND METHODS: A nationwide survey was performed to obtain data on stage-related patient volume in hospitals and office-based physicians. Based on these results, a representative sample of treatment data was collected retrospectively from pts with MIBC and mUC. RESULTS: Data from 956 pts (MIBC 576; mUC: 380) were collected. Of the MIBC pts, 49.8% received a systemic therapy (80.4% of them received cisplatin/gemcitabine) and 50.2% were treated with a cystectomy without POC. Significant factors for cystectomy without POC were higher age > 75 years (odds ratio [OR] 4.91, 95% confidence interval [CI] 3.01-8.11, p < 0.001) and platinum-ineligible pts (OR 2.15, 95% CI 1.30-3.59; p = 0.003). Treatment decision without interdisciplinary tumor board was also correlated with no POC (OR 2.43, 95% CI 1.65-3.61, p < 0.001). In mUC platinum-pretreated pts generally receive IO therapy (OR 12.07, 95% CI 6.94-21.82, p < 0.001). Other significant factors are positive PD-L1 status (OR 3.72, 95% CI 1.30-5.71, p < 0.001), higher age > 75 years (OR 2.83, 95% CI 1.43-5.73, p = 0.003) and platinum-ineligible pts (OR 2.57, 95% CI 1.30-5.71, p = 0.007). CONCLUSIONS: The "gold standard" cisplatin/gemcitabine is established in Germany if pts are treated with POC. Nonetheless half of the MIBC pts did not receive a POC, especially if the treatment decision is not discussed in a tumor board. In mUC IO therapy is established as 2nd-line therapy after a platinum-based treatment. Although the guideline recommendations are largely implemented, there is potential for optimization, especially in the establishment of interdisciplinary tumor boards.

[The usefulness of combined gynecologic and endocrinologic consultation in pediatrics: a retrospective study of the reasons for consultation and the practical approach]. / De l'utilité d'une consultation conjointe de gynécologie- endocrinologie pédiatrique: etude rétrospective des motifs de consultation et approche pratique.

The gynaecological issues encountered in children and teenagers lay at the intersection of paediatric endocrinology and gynaecology. More than ten years ago, an outpatient clinic in paediatric endocrinology and gynaecology has been created. Here, we review the last 6 years. 214 girls were included, considering only the first visit for each patient. Collected data are initial concern for this consultation, age at first consultation and confirmed or suspected diagnosis. A classification is done according to the initial concern of patients in six categories. Principal queries concern pubertal development, precocious pilosity or abnormalities in menstrual cycles. Vulvovaginitis and morphologic abnormalities are also frequently encountered. This consultation suggests a paediatric approach with a child feeling confident and a gynaecological examination with a specialist knowing the anatomy particularities and the development of the children. This article focuses on the importance of specific gynaecological examination in children and reviews the main diseases encountered.

[EMMPRIN (CD147). A prognostic and potentially therapeutic marker in urothelial cancer]. / EMMPRIN (CD147). Ein prognostischer und potenzieller therapeutischer Marker im Urothelkarzinom.

In 50% of all cases, bladder cancer patients develop tumor progression despite modern surgical methods such as radical cystectomy. A solution to the problem might be the identification and understanding of molecular biomarkers which could result in the development of advanced methods with better preventive, diagnostic, and therapeutic potential. One suitable approach is the identification of a bladder cancer-specific molecular marker in order to enhance patients' outcome. We and others have identified EMMPRIN as a prognostic biomarker in a variety of tumor diseases. EMMPRIN (CD147, extracellular matrix metalloproteinase inducer) is a cell surface protein that is expressed among other cell types, in particular in tumor cells. Since its first description in 1982 it is established that overexpression of EMMPRIN correlates with tumor progression and patient outcome. EMMPRIN expression levels can be used as an independent prognostic factor for survival. Recently, EMMPRIN has been defined as a potential target for tumor therapy in preclinical studies.

[EMMPRIN (CD147). A new key protein during tumor progression in bladder cancer]. / EMMPRIN (CD147). Ein neues Schlüsselprotein in der Tumorprogression des Harnblasenkarzinoms.

EMMPRIN (CD147) is a cell surface protein that is highly expressed on tumor cells. Elevated EMMPRIN levels have been detected in a variety of malignant tumors and have been associated with tumor progression in experimental and clinical conditions. Recent studies have shown that EMMPRIN is an independent prognostic factor for overall survival in bladder cancer patients. In a multicenter phase II trial, antibodies against EMMPRIN were shown to be successful in hepatocellular cancer therapy. We are characterizing the functional importance of EMMPRIN in bladder cancer in order to evaluate this protein as a new target molecule for therapy.

[Muscle-invasive urothelial carcinoma of the bladder. Detection and topography of micrometastases in lymph nodes]. / Muskelinvasives Urothelkarzinom der Harnblase. Detektion und Topographie von Mikrometastasen in Lymphknoten.

Detection of metastases in lymph nodes is an important prognostic factor for progression-free survival in bladder cancer patients. Patients undergoing radical cystectomy with pelvic lymphadenectomy are randomized in the LEA study (AUO AB 25/02) into two groups receiving standard (obturator and external nodes) or extended lymphadenectomy (complete pelvic nodes up to the inferior mesenteric artery).The aim of this study is the detection of lymph node metastases that are not identified with classic pathological methods using RT-PCR as a highly sensitive and specific method. For detection of occult disseminated tumor cells we analyze the expression of the tumor markers cytokeratin 20 (CK-20), uroplakin II (UP II), mucin 2 (MUC2), and mucin 7 (MUC7).We examined 315 lymph nodes from 19 cystectomy patients for the expression of CK-20. In 93 lymph nodes CK-20 expression was detected whereas only 18 lymph nodes were histopathologically positive. More than one third of CK-20-positive lymph node metastases were located outside the standard lymphadenectomy field. We did not detect any skip lesions. Follow-up data will validate if there is a correlation between detection of occult disseminated tumor cells and progression-free survival.

[German Association for Bladder Cancer Research]. / Deutscher Forschungsverbund Blasenkarzinom e.V.

The "German Association for Bladder Cancer Research" was founded in May 2008 by urologists, scientists, and pathologists. The purpose of this association is to concentrate research activities on a national level, to facilitate collaborations with an interdisciplinary background, and to define standard methodology for a higher quality of scientific results. Additionally, a national database for bladder cancer specimens will be initiated. The website http://www.forschungsverbund-blasenkarzinom.de will provide further information about the German Association for Bladder Cancer Research.

[Efficacy of a ketogenic diet in urological cancers patients : A systematic review]. / Wirksamkeit der ketogenen Diät bei urologischen Tumorerkrankungen : Ein systematischer Review.

BACKGROUND: Beside the classical anticancer treatment tumor patients try to find proactive alternative therapies to fight their disease. Lifestyle changes such as introducing a ketogenic diet is one of the most popular among them. The German Association of Urological Oncology (AUO, Arbeitsgemeinschaft Urologische Onkologie) presents a systematic review investigating the evidence of ketogenic diet in cancer patients. MATERIALS AND METHODS: A systematic literature research was conducted in the databases Medline, Livivo, and the Cochrane Library. Only clinical studies of tumor patients receiving chemotherapy while on a ketogenic diet were included. The assessment of the results was performed according to the predefined primary endpoints overall survival and progression-free survival and secondary endpoints quality of life and reduction of adverse effects induced by cytostatics. RESULTS: Nine studies met the inclusion criteria: eight prospective and one retrospective study case series respectively cohort-studies, with a total of 107 patients. Currently there is no evidence of a therapeutic effect of a ketogenic diet in patients with malignant tumors regarding the clinical outcome or quality of life. CONCLUSION: Based on the current data, a ketogenic diet can not be recommended to cancer patients because prospective, randomized trials are missing.

[Chemotherapy-induced nausea and vomiting : Current recommendations for prophylaxis]. / Chemotherapieinduzierte Nausea und Emesis : Aktuelle Empfehlungen zur Prophylaxe.

The chemotherapy-induced nausea and vomiting (CINV) is one of the most frequent side effects in cytostatic therapy and a profound challenge during the therapy of cancer patients. Therefore, standardized guideline-orientated prophylaxis is essential and a fundamental contribution for the success of treatment. This review summarizes the current recommendations for CINV of the Multinational Association of Supportive Care in Cancer (MASCC) and European Society of Medical Oncology (ESMO), the American Society for Clinical Oncology (ASCO), the National Comprehensive Cancer Network (NCCN) and the S3-guideline Supportive Therapie of the Leitlinienprogramm Onkologie and shall facilitate its use in the daily routine.

[Advanced bladder cancer : From chemo- to immunotherapy]. / Fortgeschrittenes Urothelkarzinom : Von der Chemotherapie zur Immuntherapie.

In November 2016, the results of a phase III clinical trial with the protein cell death (PD)-1 inhibitor pembrolizumab for second-line treatment of metastatic urothelial carcinoma were published and showed an overall survival benefit in comparison with conventional chemotherapy with vinflunine, docetaxel, or paclitaxel. In a similar trial the PD-L1 antibody atezolizumab showed no significant benefit in comparison to chemotherapy in the subgroup of PD-L1-positive patients and, thus, missed its primary endpoint. For other PD-1/PD-L1 directed substances, large phase I/II trials reported data concerning response rates and overall survival. This substance class will most likely become the new treatment standard in second-line treatment of metastatic urothelial cancer. Currently, PD-1/PD-L1 inhibitors are also being tested within randomized phase III trials for first-line treatment using different approaches either as a monotherapy or a combination with conventional chemotherapy or cytotoxic T­lymphocyte-associated protein (CTLA)-4 inhibitors. Whereas data from single-arm phase II clinical trials have already been published, preliminary phase III data are expected in 2018.

[Palliative and supportive treatment options in patients with advanced prostate cancer]. / Palliative und supportive Therapie bei Patienten mit fortgeschrittenem Prostatakarzinom.

In patients with advanced prostate cancer, quality of life and prevention of complications come to the fore. Besides handling local complications such as obstruction, hematuria and lymphedema, treatment of bone metastases and their complications is of great importance. Analgesic measures, bisphosphonates, radiation therapy, radionuclide therapy and neurosurgical procedures are available. Spinal cord compression with acute motor and sensory deficiency requires immediate neurosurgical and/or radiation therapy. Tumor anemia should be treated appropriately.

[The latest news on bladder cancer]. / Was gibt's Neues beim Harnblasenkarzinom?

A review of the current literature provides new scientific insights into the diagnosis, prognosis and novel molecular targets for bladder cancer. The new WHO classification refines our staging system and influences treatment options. International clinical databases provide new tools for calculating the individual risk for bladder cancer recurrence and progression. Systematic gene cluster analysis defines multimarker panels that can serve as robust predictors of outcome. Discoveries of new signaling pathways in bladder cancer are leading to novel molecular targets for innovative therapies.

[Is there an indication for adjuvant or neoadjuvant systemic chemotherapy in bladder cancer?]. / Gibt es eine Indikation für eine adjuvante oder neoadjuvante Systemtherapie beim Blasenkarzinom?

Two recent meta-analyses demonstrated a significant influence of adjuvant as well as neoadjuvant cisplatin-based chemotherapy regimens on survival of patients undergoing radical cystectomy for bladder cancer. Therefore, the introductory question can be answered with "yes". However, while providing the best evidence available to date on the subject, both analyses are based on clinical trials of dubious quality. Thus, the question today is not whether perioperative chemotherapy is advantageous in some patients undergoing radical cystectomy, but rather which subgroups will actually benefit from additional systemic treatment. Instead of a detailed literature overview, this article discusses potential advantages and disadvantages of perioperative chemotherapy and outlines basic principles for the design of future studies investigating both strategies in bladder cancer.

[Side effects of chemotherapy]. / Nebenwirkungen der Chemotherapie.

Urologic tumors are frequently treated by multimodal therapeutic strategies with the consequence of an increasing number of adverse events. The most common chemotherapy-induced side effects are neutropenia, stomatitis, mucositis, diarrhea, and emesis. The efficacy of tumor therapy can be improved by good prophylaxis and standardized management of side effects.

[PSMA-targeted radioligand therapy in prostate cancer]. / Radionuklidtherapie des Prostatakarzinoms mittels PSMA-Lutetium.

Radioligand therapy (RLT) directed against prostate-specific membrane antigen (PSMA) enables tumor-specific treatment directed against PSMA-overexpressing prostate cancer cells. Several PSMA ligands such as PSMA-617 or PSMA-I&T have been developed that can be labeled with ß­radiating lutetium-177. These are currently applied in compassionate use programs to treat metastatic castration-resistant prostate cancer (mCRPC). PSMA-directed RLT is currently being offered in several nuclear medicine departments throughout Germany. Several retrospective case series demonstrate its activity with a prostate-specific antigen (PSA) decrease >50% in 30-60% of mCRPC patients. The toxicity seems to be low. Hematologic grade 4 toxicity has not been observed and grade 3 toxicities rarely occur. The main nonhematologic adverse events are intermittent dry mouth because of unspecific PSMA expression in the salivary glands as well as fatigue and nausea. Currently there are no prospective studies available for evaluation of PSMA-targeted RLT and a survival benefit over approved standard therapies such as abiraterone, enzalutamide, radium-223-dichloride, docetaxel or cabazitaxel has not been shown. PSMA-targeted RLT should therefore currently only be offered after critical evaluation in patients who exhausted the approved standard therapies.