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Purpose: Precision oncology requires biomarker testing from tumor tissue for clinical decision-making and selection of targeted therapies. We systematically evaluated the role of tissue biomarker testing within interventional clinical trials for locally advanced and metastatic urothelial carcinoma (UC). Methods: A systematic search within the publicly available ClinicalTrials.gov database was performed for the period 1995 to January 2020. We searched for all interventional studies on systemic treatments for advanced UC. Two investigators independently screened the records and extracted the data for statistical analyses. Results: We included 356 studies out of 827 initial records in the final analysis. The overall number of interventional trials in UC patients significantly increased during the past 25 years. Forty-three studies (12.1%) required specific biomarker testing as a prerequisite for inclusion. Of the remaining 313 trials, explorative biomarkers of interest were studied in 83 studies (23.3%). In trials with obligate biomarker testing as a precondition for study inclusion, only 3 studies (7%) required an actual fresh pretreatment biopsy, while the majority of studies did not state any tissue requirements (55.8%) or accepted archival tissue samples (37.3%). Among studies without biomarker prerequisites, freshly obtained tissue samples were required in 16.3% of studies evaluating immune checkpoint inhibition and 5.7% evaluating targeted therapy. The collection of archival tissue was allowed in 67.4% and 20% of studies evaluating immune checkpoint inhibitors and targeted therapies, respectively. Conclusion: There has been an increase in the number of studies using biomarker-guided interventions for the treatment of advanced UC over the past 25 years. Studies investigating druggable targets in actual UC biopsies immediately before treatment are still rare. Standardized criteria for tissue-based biomarker testing may further accelerate personalized treatment of patients with advanced UC.

O artigo objetiva conhecer as narrativas de profissionais de saúde que atuam no Centro de Atenção Psicossocial da Infância e Adolescência acerca da internação involuntária, assim como a relação da família no processo de cuidado e da judicialização da assistência em saúde mental. O estudo é de caráter descritivo e exploratório, com abordagem qualitativa. Aplicou-se uma entrevista semiestruturada com dois servidores, com questões referentes à rotina do serviço, perfil do usuário e participação da família. A análise dos dados produzidos foi dada a partir da Análise temática de Braun e Clarke. Os achados durante as entrevistas proporcionaram a criação de 3 eixos temáticos para discutir a questão: 1) Perfil dos pacientes internados, em que foi possível identificar que geralmente os usuários indicados para a internação são adolescentes infratores do gênero masculino; 2) Internação involuntária: punição ou salvação? em que buscamos compreender as condições que são aplicadas para tal prática e; 3) Judicialização como recurso de adesão das famílias e dos serviços de saúde, uma incursão nas falas para investigar a dualidade das ações judiciais em processos/tratamento por uso de drogas. Considerações finais: Observou-se que é necessário um alinhamento dos setores da saúde e do judiciário, priorizando igualmente a saúde e a segurança dos adolescentes. Ainda, o estabelecimento de uma rede de cuidados integral, que vise a reintegração do mesmo na sociedade, seguindo os princípios do Sistema Único de Saúde.

Purpose Testicular germ cell tumours (GCTs) represent the most common malignancy in young adult males with two thirds of all cases presenting with clinical stage I (CSI). Active surveillance is the management modality mostly favoured by current guidelines. This systematic review assesses the treatment results in CSI patients concerning recurrence rate and overall survival in non-seminoma (NS) and pure seminoma (SE) resulting from surveillance in comparison to adjuvant strategies. Methods/systematic review We performed a systematic literature review confining the search to most recent studies published 2010–2021 that reported direct comparisons of surveillance to adjuvant management. We searched Medline and the Cochrane Library with additional hand-searching of reference lists to identify relevant studies. Data extraction and quality assessment of included studies were performed with stratification for histology (NS vs. SE) and treatment modalities. The results were tabulated and evaluated with descriptive statistical methods. Results Thirty-four studies met the inclusion criteria. In NS patients relapse rates were 12 to 37%, 0 to 10%, and 0 to 11.8% for surveillance, chemotherapy and for retroperitoneal lymph node dissection (RPLND) while overall survival rates were 90.7−100%, 91.7−100%, and 97−99.1%, respectively. In SE CSI, relapse rates were 0−22.3%, 0−5%, and 0−12.5% for surveillance, radiotherapy, chemotherapy, while overall survival rates were 84.1−98.7%, 83.5−100%, and 92.3−100%, respectively. Conclusion In both histologic subgroups, active surveillance offers almost identical overall survival as adjuvant management strategies, however, at the expense of higher relapse rates. Each of the management strategies in CSI GCT patients have specific merits and shared-decision-making is advised to tailor treatment.

The worldwide approval of the combination maintenance therapy of olaparib and bevacizumab in advanced high-grade serous ovarian cancer requires complex molecular diagnostic assays that are sufficiently robust for the routine detection of driver mutations in homologous recombination repair (HRR) genes and genomic instability (GI), employing formalin-fixed (FFPE) paraffin-embedded tumor samples without matched normal tissue. We therefore established a DNA-based hybrid capture NGS assay and an associated bioinformatic pipeline that fulfils our institution’s specific needs. The assay´s target regions cover the full exonic territory of relevant cancer-related genes and HRR genes and more than 20,000 evenly distributed single nucleotide polymorphism (SNP) loci to allow for the detection of genome-wide allele specific copy number alterations (CNA). To determine GI status, we implemented an %CNA score that is robust across a broad range of tumor cell content (25–85%) often found in routine FFPE samples. The assay was established using high-grade serous ovarian cancer samples for which BRCA1 and BRCA2 mutation status as well as Myriad MyChoice homologous repair deficiency (HRD) status was known. The NOGGO (Northeastern German Society for Gynecologic Oncology) GIS (GI-Score) v1 assay was clinically validated on more than 400 samples of the ENGOT PAOLA-1 clinical trial as part of the European Network for Gynaecological Oncological Trial groups (ENGOT) HRD European Initiative. The “NOGGO GIS v1 assay” performed using highly robust hazard ratios for progression-free survival (PFS) and overall survival (OS), as well a significantly lower dropout rate than the Myriad MyChoice clinical trial assay supporting the clinical utility of the assay. We also provide proof of a modular and scalable routine diagnostic method, that can be flexibly adapted and adjusted to meet future clinical needs, emerging biomarkers, and further tumor entities.

Objective To systematically evaluate evidence on prognostic factors for tumor recurrence in clinical stage I nonseminoma patients other than lymphovascular invasion (LVI). Methods We performed a systematic literature search in the biomedical databases Medline (via Ovid) and Cochrane Central Register of Controlled Trials (search period January 2010 to February 2021) for full text publications in English and German language, reporting on retro- or prospectively assessed prognostic factors for tumor recurrence in patients with stage I nonseminomatous germ cell tumors. Results Our literature search yielded eleven studies reporting on 20 potential prognostic factors. Results are based on cohort studies of mostly moderate to low quality. Five out of eight studies found a significant association of embryonal carcinoma (EC) in the primary tumor with relapse. Among the different risk definitions of embryonal carcinoma (presence, predominance, pure), presence of EC alone seems to be sufficient for prognostification. Interesting results were found for rete testis invasion, predominant yolk sac tumor, T-stage and history of cryptorchidism, but the sparse data situation does not justify their clinical use. Conclusions No additional factors that meet the prognostic value of LVI, especially when determined by immunohistochemistry, could be identified through our systematic search. The presence of EC might serve as a second, subordinate prognostic factor for clinical use as the data situation is less abundant than the one of LVI. Further efforts are necessary to optimize the use of these two prognostic factors and to evaluate and validate further potential factors with promising preliminary data.

Ribosomal biogenesis and protein synthesis are deregulated in most cancers, suggesting that interfering with translation machinery may hold significant therapeutic potential. Here, we show that loss of the tumor suppressor adenomatous polyposis coli (APC), which constitutes the initiating event in the adenoma carcinoma sequence for colorectal cancer (CRC), induces the expression of RNA polymerase I (RNAPOL1) transcription machinery, and subsequently upregulates ribosomal DNA (rDNA) transcription. Targeting RNAPOL1 with a specific inhibitor, CX5461, disrupts nucleolar integrity, and induces a disbalance of ribosomal proteins. Surprisingly, CX5461-induced growth arrest is irreversible and exhibits features of senescence and terminal differentiation. Mechanistically, CX5461 promotes differentiation in an MYC-interacting zinc-finger protein 1 (MIZ1)- and retinoblastoma protein (Rb)-dependent manner. In addition, the inhibition of RNAPOL1 renders CRC cells vulnerable towards senolytic agents. We validated this therapeutic effect of CX5461 in murine- and patient-derived organoids, and in a xenograft mouse model. These results show that targeting ribosomal biogenesis together with targeting the consecutive, senescent phenotype using approved drugs is a new therapeutic approach, which can rapidly be transferred from bench to bedside.

Summary Background Systematic reviews indicated that home treatment is an effective and cost-saving alternative to conventional acute psychiatric treatment options. Treatment success has often been defined as a reduction of hospital admissions. In the current study, symptoms and well-being are assessed regularly during treatment as an indicator for treatment success. Patients’ characteristics such as diagnosis, age, substance use, and motivation for treatment were discussed as predictors for treatment success. A second focal point of the study lies in the examination of the therapeutic relationship in terms of the outcome, which has not yet been systematically investigated in home treatment. Methods This is an observational study with a prospective naturalistic design. Measurements are carried out at baseline, during and at the end of treatment as well as at the 3‑month follow-up. Patients’ characteristics as potential predictors for treatment success will be assessed at baseline. In addition, the perceived relationship between the patients and the team will be measured daily and weekly throughout the treatment. Treatment success is by the changes in symptoms and general well-being assessed weekly. We aim to include 82 participants assigned to home treatment. Variance analyses with repeated measurements will be conducted to evaluate treatment success. Conclusion By examining potential patient- and relationship-related predictors of treatment success, insights into relevant determining variables of treatment success in this setting are expected. The results might help to better identify who benefits the most from home treatment.

Purpose In this review, we summarize and discuss contemporary treatment standards and possible selection criteria for decision making after failure of adjuvant or first-line cisplatin-based chemotherapy for primarily localized or metastatic germ cell tumors. Methods This work is based on a systematic literature search conducted for the elaboration of the first German clinical practice guideline to identify prospective clinical trials and retrospective comparative studies published between Jan 2010 and Feb 2021. Study end points of interest were progression-free (PFS) and overall survival (OS), relapse rate (RR), and/or safety. Results Relapses of clinical stage I (CS I) patients irrespective of prior adjuvant treatment after orchiectomy are treated stage adapted in accordance for primary metastatic patients. Surgical approaches for sole retroperitoneal relapses are investigated in ongoing clinical trials. The appropriate salvage chemotherapy for metastatic patients progressing or relapsing after first-line cisplatin-based chemotherapy is still a matter of controversy. Conventional cisplatin-based chemotherapy is the international guideline-endorsed standard of care, but based on retrospective data high-dose chemotherapy and subsequent autologous stem cell transplantation may offer a 10–15% survival benefit for all patients. Secondary complete surgical resection of all visible residual masses irrespective of size is paramount for treatment success. Conclusions Patients relapsing after definite treatment of locoregional disease are to be treated by stage-adapted first-line standard therapy for metastatic disease. Patients with primary advanced/metastatic disease failing one line of cisplatin-based combination chemotherapy should be referred to GCT expert centers. Dose intensity is a matter of ongoing debate, but sequential high-dose chemotherapy seems to improve patients’ survival.

Introduction: As part of the development of the evidence-based (S3) clinical practice guidelines for kidney and bladder cancer by the German Guideline Program in Oncology, quality indicators (QIs) were defined to measure the quality of care. Based on these guidelines and QIs, the German Cancer Society (DKG) developed two new certification systems. The aim of this article is to show the process of development and implementation of QIs in certified cancer centres. Methods: Based on strong recommendations of each guideline and an additional systematic literature review for national and international QIs, two sets of QIs were derived in a multistep standardized approach. These QIs were implemented in the centres in certification data sheets to measure their outcomes. First results of treatment years 2018 and 2019 are available. Results: The final sets include 9 QIs for kidney cancer and 12 QIs for bladder cancer. Two-thirds of the QIs were transferred to the data sheets. In 2018 and 2019, the results of all but one QI are within the plausibility limits. From 2020 on, they are replaced by stricter target values that will challenge centres to improve their outcomes. Conclusions: Guideline-derived QIs make relevant aspects of patient care measurable and consequently improvable. The first QI results are encouraging. However, the DKG certification system and the methods of measuring quality are under ongoing development. Systematic QI implementation and evaluation may help to generate broader databases and thus expand knowledge.

Purpose To present the current evidence and the development of studies in recent years on the management of extragonadal germ cell tumors (EGCT). Methods A systematic literature search was conducted in Medline and the Cochrane Library. Studies within the search period (January 2010 to February 2021) that addressed the classification, diagnosis, prognosis, treatment, and follow-up of extragonadal tumors were included. Risk of bias was assessed and relevant data were extracted in evidence tables. Results The systematic search identified nine studies. Germ cell tumors (GCT) arise predominantly from within the testis, but about 5% of the tumors are primarily located extragonadal. EGCT are localized primarily mediastinal or retroperitoneal in the midline of the body. EGCT patients are classified according to the IGCCCG classification. Consecutively, all mediastinal non-seminomatous EGCT patients belong to the “poor prognosis” group. In contrast mediastinal seminoma and both retroperitoneal seminoma and non-seminoma patients seem to have a similar prognosis as patients with gonadal GCTs and metastasis at theses respective sites. The standard chemotherapy regimen for patients with a EGCT consists of 3–4 cycles (good vs intermediate prognosis) of bleomycin, etoposid, cisplatin (BEP); however, due to their very poor prognosis patients with non-seminomatous mediastinal GCT should receive a dose-intensified or high-dose chemotherapy approach upfront on an individual basis and should thus be referred to expert centers Ifosfamide may be exchanged for bleomycin in cases of additional pulmonary metastasis due to subsequently planned resections. In general patients with non-seminomatous EGCT, residual tumor resection (RTR) should be performed after chemotherapy. Conclusion In general, non-seminomatous EGCT have a poorer prognosis compared to testicular GCT, while seminomatous EGGCT seem to have a similar prognosis to patients with metastatic testicular seminoma. The current insights on EGCT are limited, since all data are mainly based on case series and studies with small patient numbers and non-comparative studies. In general, systemic treatment should be performed like in testicular metastatic GCTs but upfront dose intensification of chemotherapy should be considered for mediastinal non-seminoma patients. Thus, EGCT should be referred to interdisciplinary centers with utmost experience in the treatment of germ cell tumors.

A saúde mental da população foi impactada pela pandemia da COVID-19, exigindo a criação de estratégias de cuidado, como a crescente utilização da telepsicoterapia. Desta forma, o presente artigo tem como objetivo analisar a adesão à telepsicoterapia oferecida no período pandêmico, considerando o perfil sociodemográfico do público atendido, a participação no estudo pelas sessões de psicoterapia e pelo preenchimento dos questionários disponibilizados através da plataforma de atendimento online. O estudo teve caráter quantitativo e descritivo, cuja amostra incluiu pessoas maiores de 18 anos e que morassem nas regiões do Vale do Rio Pardo e Vale do Taquari -RS. As informações sociodemográficas foram coletadas por meio de questionários, que posteriormente geraram um banco de dados, no qual também foi registrada a frequência dos participantes em quatro sessões de telepsicoterapia. A análise dos dados foi realizada no Microsoft Office Excel e apresentada de modo descritivo. O período de coleta dos dados foi de janeiro a dezembro de 2021. A amostra foi composta por 153 indivíduos de 19 municípios. O perfil predominante encontrado foi de 75,51% mulheres (n=114), 71,9% adultos de 25-60 anos (n=110), 69,28% residentes de centros urbanos (n=110). A taxa de adesão à telepsicoterapia foi de 91,5% na quarta sessão (n=140). Os resultados encontrados demonstram que esta é uma ferramenta potente para populações que não acessam a saúde mental pública devido a sobrecarga no sistema ou por aqueles que se encontram impossibilitados de serem atendidos de forma presencial.

A new assay was developed to measure the concentration of remimazolam besylate (CNS7056B) and its major carboxylic acid metabolite (CNS7054X) in human plasma. For this new assay method, midazolam-d4 maleate was used as an internal standard. After setting up a previously described assay method, using CNS7056-d4 and CNS7054-d4 as internal standards, analytical results of both methods were compared. For the new analytical method, ultra-high-performance liquid chromatography (UHPLC) with tandem mass spectrometry was applied. A purification method, using solid phase extraction, was developed and validated. The chromatographic separation of the analytes was achieved with a mobile phase gradient using a Water Acquity™ UHPLC-System. The Kinetex™ biphenyl 50 × 2.1 mm UHPLC column was used with a particle diameter of 1.7 μm (Phenomenex, Germany). A measuring range of 0.6–2,000 ng/mL for CNS7056B and of 6–20,000 ng/mL for CNS7054X could be achieved with this new assay. The lower limit of quantification was 0.6 ng/mL for CNS7056B and 6 ng/mL for CNS7054X. The assay was validated according to US Food and Drug Administration guidelines. The new method showed an accuracy of 96.9–110.4% and a precision of 2.1–6.7% for both analytes.

Contains fulltext : 237261.pdf (Publisher’s version ) (Closed access) Adherence to national and international clinical practice guidelines is suboptimal throughout Europe. The European Association of Urology Guidelines Office project "IMAGINE" (IMpact Assessment of Guidelines Implementation and Education) has been developed to measure baseline adherence to urological guideline recommendations across Europe and to identify issues that drive nonadherence.

While there have been significant advances in the understanding of drought in the surface water domain, little knowledge is available for groundwater and the interactions with surface water. In particular, few studies have been run to understand the short-term transient changes in groundwater quality since the early onset of a hydrological drought period. This contribution presents data and information on the groundwater hydrochemical and hydrodynamics changes occurring in an aquifer following the onset of an early dry season in Spring 2021 and developed in a hydrological drought period lasted until December 2021 in the alluvial plain of the Cornia River in coastal Tuscany (Italy).The Cornia plain hosts a Holocene coastal aquifer constituted, in the investigated area, mainly by gravel in silty matrix. We monitored groundwater chemical quality and hydrodynamics in a series of multi-depth piezometers in a recharge area covering three different depths from the soil surface (i.e., 8m, 12m, and 18m) in the near of a Managed Aquifer Recharge (MAR) scheme (Caligaris et al. 2022). We monitored these piezometers alongside with the existing network of piezometers and the relations with Cornia River surface water for nine months from April 2021 (when the max groundwater head was recorded) until December 2021 (when the minimum was recorded).Ten sampling campaigns were performed in this period, covering the early end of the annual MAR operation period in May 2021, and monitoring every fifteen days in the initial phase of the dry season. The last effective rainfall occurred on 11 May 2021. A total of about 130 water samples were collected. The concentrations of the main ions in the water samples were determined using an Ion Chromatography (IC) instrument. The concentrations of trace elements were determined using an Inductively Coupled Plasma Mass Spectrometer (ICP). The concentration of Boron in water was determined using a Microwave Plasma Atomic Emission Spectrometer (MP-AES). Physico-chemical parameters were measured in the field with a multiparametric probe. This resulted on the measurement of the spatiotemporal variation of 49 different parameters at each of the study point.An important groundwater table decline, ranging from 6 to 10 m, was observed in this period, which brought to relevant water stress even in trees at the end of October 2021. The statistical behavior of the different parameters as well as their relationships are studied and presented to define a robust conceptual model unifying hydrochemistry and hydrodynamics in order to describe the evolution of the aquifer.AcknowledgementThis paper is presented within the framework of the project MARSoluT (www.marsolut-itn.eu), a four-year Marie Skłodowska-Curie Actions (MSCA) Innovative Training Network (ITN) funded by the European Commission (Grant Agreement 814066).ReferencesCaligaris, E.; Agostini, M.; Rossetto, R. Using Heat as a Tracer to Detect the Development of the Recharge Bulb in Managed Aquifer Recharge Schemes. Hydrology 2022, 9, 14. https://doi.org/10.3390/hydrology9010014