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PURPOSE The classification of the International Germ Cell Cancer Collaborative Group (IGCCCG) plays a pivotal role in the management of metastatic germ cell tumors but relies on data of patients treated between 1975 and 1990. MATERIALS AND METHODS Data on 9,728 men with metastatic nonseminomatous germ cell tumors treated with cisplatin- and etoposide-based first-line chemotherapy between 1990 and 2013 were collected from 30 institutions or collaborative groups in Europe, North America, and Australia. Clinical trial and registry data were included. Primary end points were progression-free survival (PFS) and overall survival (OS). The survival estimates were updated for the current era. Additionally, a novel prognostic model for PFS was developed in 3,542 patients with complete information on potentially relevant variables. The results were validated in an independent data set. RESULTS Compared with the original IGCCCG publication, 5-year PFS remained similar in patients with good prognosis with 89% (87%-91%) versus 90% (95% CI, 89 to 91), but the 5-year OS increased from 92% (90%-94%) to 96% (95%-96%). In patients with intermediate prognosis, PFS remained similar with 75% (71%-79%) versus 78% (76%-80%) and the OS increased from 80% (76%-84%) to 89% (88%-91%). In patients with poor prognosis, the PFS increased from 41% (95% CI, 35 to 47) to 54% (95% CI, 52 to 56) and the OS from 48% (95% CI, 42 to 54) to 67% (95% CI, 65 to 69). A more granular prognostic model was developed and independently validated. This model identified a new cutoff of lactate dehydrogenase at a 2.5 upper limit of normal and increasing age and presence of lung metastases as additional adverse prognostic factors. An online calculator is provided ( https://www.eortc.org/IGCCCG-Update ). CONCLUSION The IGCCCG Update model improves individual prognostication in metastatic nonseminomatous germ cell tumors. Increasing age and lung metastases add granularity to the original IGCCCG classification as adverse prognostic factors.

BackgroundMetastatic germ cell cancer of the testis is characterized by favorable prognosis since effective treatment methods are available even in cases of extensive disease. Retroperitoneal masses frequently encroach major blood vessels requiring a vascular intervention usually performed in association with the post-chemotherapy retroperitoneal lymph node dissection (RPLND). Reported clinical case describes a successful pre-treatment endovascular surgery for abdominal aortic rupture allowing for full-dose systemic chemotherapy administration, and subsequent radical surgical intervention at primary tumor site as well as metastatic retroperitoneal lymph node dissection including the reconstruction of inferior caval vein.Case presentationPatient presented with left-sided testicular tumor and voluminous retroperitoneal mass with vascular involvement. Soon after the patient had been admitted for the first cycle of cisplatin-based chemotherapy, computed tomographic angiography (CTA) revealed a dorsal aortic wall rupture with active extravasation and irregular pseudoaneurysmatic dilatation of the aorta below the leak area. Retroperitoneal intratumoral hemorrhage associated with the bilateral iliac venous thrombosis required an endovascular repair procedure of infrarenal abdominal aorta.ConclusionsFollowing the successful endovascular aortic repair 3 cycles of BEP (bleomycin, etoposide, cisplatin) regimen were administered with subsequent delayed left radical orchiectomy and RPLND associated with vena cava inferior (VCI) resection. Reconstruction of VCI was originally not deemed necessary as collateral blood flow appeared sufficient, however, intraoperative complications resulted in the need for unilateral VCI reconstruction, using the interposed bypass between right common iliac vein and infrarenal segment of VCI. Histopathologic examination of the attained specimen detected no vital cancer structures. The patient remains disease-free 18 months after the RPLND.

PURPOSE Presence of teratoma in patients with metastatic testicular germ cell tumor (GCT) is of unknown prognostic significance. We report survival outcomes of patients with or without teratoma in primary tumor and postchemotherapy retroperitoneal lymph node dissection (PC-RPLND) specimen and assess impact on prognosis. PATIENTS AND METHODS Patients with metastatic nonseminomatous GCT (NSGCT) who were evaluated at Indiana University between 1990 and 2016 and had primary testicular tumor specimen from orchiectomy (ORCH) were included. All patients were treated with cisplatin-based combination chemotherapy. The cohort was divided into 2 groups according to presence or absence of teratoma in ORCH specimen. Survival data were correlated with histopathologic findings. Differences in progression-free (PFS) and overall survival (OS) were evaluated using log-rank tests and Cox proportional hazards models to adjust for known adverse prognostic factors. RESULTS We identified 1,224 consecutive patients evaluated at Indiana University between 1990 and 2016 who met inclusion criteria. Median age was 27 years (range, 13-71 years); 689 patients had teratoma in ORCH specimen, and 535 did not. With median follow-up of 2.3 years, 5-year PFS was 61.9% (95% CI, 57.1% to 66.2%) for those with teratoma versus 63.1% (95% CI, 58.0% to 67.8%) for those without ( P = .66); 5-year OS was 82.2% (95% CI, 77.9% to 85.8%) versus 81.4% (95% CI, 76.5% to 85.3%; P = .91), respectively. A total of 473 patients underwent PC-RPLND; 5-year PFS for patients with pure teratoma in PC-RPLND specimen versus necrosis only was 65.9% versus 79.1% ( P = .06), and 5-year OS was 90.3% versus 93.4% ( P = .21), respectively. CONCLUSION Presence of teratoma in ORCH and PC-RPLND specimens was not a prognostic factor in this large retrospective study of patients with NSGCT.

Testicular germ cell tumors (TGCTs) are an excellent example of chemosensitive disease. However, cisplatin-based chemotherapy has significant side effects, including myelosuppression. Previously, we found endogenous DNA damage level in peripheral blood mononuclear cells (PBMCs) to be an independent prognostic marker. In this study, we tested the hypothesis that patients with high endogenous DNA damage levels in PBMCs have an increased risk of developing hematological toxicity.One hundred twenty chemotherapy-naive TGCT patients treated in the National Cancer Institute and the St Elisabeth Cancer Institute in Bratislava, Slovakia, from 2012 to 2018 were enrolled. All patients received platinum-based chemotherapy with granulocyte colony stimulating factor support. On the day of starting treatment, we measured the DNA damage levels in PBMCs using the comet assay. We used the cutoff level of 5.25, a value previously reported to stratify patients on the basis of their prognosis. We monitored hematological toxicity during the first cycle of chemotherapy. The mean and standard error of the mean were calculated for all variables.Patients with high DNA damage levels (5.25) had more significant hematological toxicity with significantly lower nadir white blood cell count (P = .001), absolute neutrophil count (P = .013) and absolute lymphocyte count (ALC; P .001). ALCs on day 0 (P = .005) and day 22 (P = .046) were also significantly lower in patients with high DNA damage levels.This study shows that higher endogenous DNA damage levels correlate with increased risk of hematological toxicity in TGCT patients. Hence, the DNA damage levels can be used to select patients for closer monitoring because of a higher risk of acute chemotherapy-related complications.

textabstractGerm cell tumours predominantly of the testis ((T)GCTs) are remarkably chemotherapy sensitive. However, a small proportion of patients fail to be cured with cisplatin-based combination chemotherapy. miR-371a-3p is a new liquid biopsy biomarker for (T)GCTs. The aim of this study was to evaluate clinical utility of plasma miR-371a-3p level in patients starting systemic chemotherapy. Patients were included before the first cycle (N = 180) and second cycle (N = 101) of systemic first line chemotherapy, treated between July 2010 and May 2017. Plasma miR-371a-3p levels were measured with the ampTSmiR test and compared to disease characteristics and outcome. Pretreatment plasma miR-371a-3p levels were increased in 51.7% of cases and associated with number of metastatic sites, presence of lung, retroperitoneal, and mediastinal lymph node metastases, S – stage, IGCCCG risk group, and response to therapy. Patients with a negative pretreatment plasma level had better progression-free survival (PFS) and overall survival (OS) compared to patients being positive for miR-371a-3p (hazard ratio [HR] = 0.26, 95% confidence interval [CI] 0.09-0.71, P = 0.02 for PFS and HR = 0.21, 95% CI 0.07-0.67, P = 0.03 for OS, respectively). Patients negative for miR-371a-3p in both samples had a superior PFS (HR = 0.10, 95% CI 0.01-21.49, P = 0.02) and OS (HR = 0.08, 95% CI 0.01-27.81, P = 0.008) compared to patients with miR-371a-3p positive in both samples (multivariate analyses were non-significant). In total 68% of the patients were S0. This study demonstrates clinical value of plasma miR-371a-3p level in chemotherapy naive (T)GCT patients starting first line of chemotherapy to predict prognosis.

Chemoresistance of germ cell tumors (GCTs) represents an intensively studied property of GCTs that is the result of a complicated multifactorial process. One of the driving factors in this process is the tumor microenvironment (TME). Intensive crosstalk between the DNA damage/DNA repair pathways and the TME has already been reported. This study aimed at evaluating the interplay between the immune TME and endogenous DNA damage levels in GCT patients. A cocultivation system consisting of peripheral blood mononuclear cells (PBMCs) from healthy donors and GCT cell lines was used in an in vitro study. The patient cohort included 74 chemotherapy-naïve GCT patients. Endogenous DNA damage levels were measured by comet assay. Immunophenotyping of leukocyte subpopulations was performed using flow cytometry. Statistical analysis included data assessing immunophenotypes, DNA damage levels and clinicopathological characteristics of enrolled patients. The DNA damage level in PBMCs cocultivated with cisplatin (CDDP)-resistant GCT cell lines was significantly higher than in PBMCs cocultivated with their sensitive counterparts. In GCT patients, endogenous DNA damage levels above the cutoff value were independently associated with increased percentages of natural killer cells, CD16-positive dendritic cells and regulatory T cells. The crosstalk between the endogenous DNA damage level and specific changes in the immune TME reflected in the blood of GCT patients was revealed. The obtained data contribute to a deeper understanding of ongoing interactions in the TME of GCTs.

Numerical models for the flow of blood and other fluids can be used to design and optimize microfluidic devices computationally and thus to save time and resources needed for production, testing, and redesigning of the physical microfluidic devices. Like biological experiments, computer simulations have their limitations. Data from both the biological and the computational experiments can be processed by machine learning methods to obtain new insights which then can be used for the optimization of the microfluidic devices and also for diagnostic purposes. In this work, we propose a method for identifying red blood cells in flow by their stiffness based on their movement data processed by neural networks. We describe the performed classification experiments and evaluate their accuracy in various modifications of the neural network model. We outline other uses of the model for processing data from video recordings of blood flow. The proposed model and neural network methodology classify healthy and more rigid (diseased) red blood cells with the accuracy of about 99.5% depending on the selected dataset that represents the flow of a suspension of blood cells of various levels of stiffness.

PURPOSE The classification of the International Germ-Cell Cancer Collaborative Group (IGCCCG) has been a major advance in the management of germ-cell tumors, but relies on data of only 660 patients with seminoma treated between 1975 and 1990. We re-evaluated this classification in a database from a large international consortium. MATERIALS AND METHODS Data on 2,451 men with metastatic seminoma treated with cisplatin- and etoposide-based first-line chemotherapy between 1990 and 2013 were collected from 30 institutions or collaborative groups in Australia, Europe, and North America. Clinical trial and registry data were included. Primary end points were progression-free survival (PFS) and overall survival (OS) calculated from day 1 of treatment. Variables at initial presentation were evaluated for their prognostic impact. Results were validated in an independent validation set of 764 additional patients. RESULTS Compared with the initial IGCCCG classification, in our modern series, 5-year PFS improved from 82% to 89% (95% CI, 87 to 90) and 5-year OS from 86% to 95% (95% CI, 94 to 96) in good prognosis, and from 67% to 79% (95% CI, 70 to 85) and 72% to 88% (95% CI, 80 to 93) in intermediate prognosis patients. Lactate dehydrogenase (LDH) proved to be an additional adverse prognostic factor. Good prognosis patients with LDH above 2.5× upper limit of normal had a 3-year PFS of 80% (95% CI, 75 to 84) and a 3-year OS of 92% (95% CI, 88 to 95) versus 92% (95% CI, 90 to 94) and 97% (95% CI, 96 to 98) in the group with lower LDH. CONCLUSION PFS and OS in metastatic seminoma significantly improved in our modern series compared with the original data. The original IGCCCG classification retains its relevance, but can be further refined by adding LDH at a cutoff of 2.5× upper limit of normal as an additional adverse prognostic factor.

Currently, ~95% of patients with testicular germ cell tumour (TGCT) are cured, resulting in an increasing number of TGCT survivors. Although cured, these men face potential late adverse effects and reduced quality of life. Survivors face a twofold increased risk of second malignant neoplasms after chemotherapy and radiotherapy, with evidence of dose-dependent associations. For survivors managed with surveillance or treated with radiotherapy, the risk of cardiovascular disease (CVD) is comparable to the risk in the general population, whereas treatment with chemotherapy increases the risk of life-threatening CVD, especially during treatment and after 10 years of follow-up. Other adverse effects are organ-related toxicities such as neuropathy and ototoxicity. Pulmonary and renal impairment in patients with TGCT treated with chemotherapy is limited. Survivors of TGCT might experience psychosocial distress including anxiety disorders, fear of cancer recurrence and TGCT-specific issues, such as sexual dysfunction. Late adverse effects can be avoided in most patients with stage I disease if followed on a surveillance programme. However, patients with disseminated disease can experience toxicities associated with radiotherapy and chemotherapy, and/or adverse effects related to surgery for residual disease. The severity of adverse effects increases with dose of both chemotherapy and radiotherapy. This Review discusses the most recent data concerning the late adverse effects of today’s standard treatments for TGCT. Currently, ~95% of patients with testicular germ cell tumour are cured. Although cured, these men face potential late adverse effects and reduced quality of life. This Review outlines these adverse effects with recommendations on how to minimize their severity.

Apoptosis is a strictly regulated process essential for preservation of tissue homeostasis. This study aimed to evaluate expression of apoptosis inducing factor (AIF) in testicular germ cell tumors (GCTs) and to correlate expression patterns with clinicopathological variables. Formalin-fixed and paraffin-embedded specimens of non-neoplastic testicular tissue and GCTs obtained from 216 patients were included in the study. AIF expression was detected by immunohistochemistry, scored by the multiplicative quickscore method (QS). Normal testicular tissue exhibits higher cytoplasmic granular expression of AIF compared to GCTs (mean QS = 12.77 vs. 4.80, p &lt, 0.0001). Among invasive GCTs, mean QS was the highest in embryonal carcinoma, yolk sac tumor and seminoma, lower in teratoma and the lowest in choriocarcinoma. No nuclear translocation of AIF was observed. Nonpulmonary visceral metastases were associated with lower AIF expression. Metastatic GCTs patients with high AIF expression had better overall survival compared to patients with low AIF expression (HR = 0.26, 95% CI 0.11–0.62, p = 0.048). We observed significantly lower AIF expression in GCTs compared to normal testicular tissue, which is an uncommon finding in malignant tumors. AIF downregulation might represent one of the mechanisms of inhibition of apoptosis and promotion of cell survival in GCTs.

Testicular germ cell tumors (GCTs) are malignancies with a unique biology, pathology, clinical appearance, and excellent outcomes. A correct radiographic assessment of GCTs is extremely important for the clinical management in several typical scenarios. Advancements in the field of diagnostic medicine bring an increasing number of sophisticated imaging methods to increase the performance of imaging studies. The conventional computed tomography (CT) remains the mainstay of diagnostic imaging in the management of GCTs. While certain improvements in the sensitivity and specificity are suggested with magnetic resonance (MR) imaging with lymphotrophic nanoparticles in evaluating retroperitoneal lymph nodes during the staging procedure, further exploration in larger prospective studies is needed. A common diagnostic dilemma is assessing the post-chemotherapy residual disease in GCTs. Several studies have consistently shown advantages in the utility of positron emission tomography (PET) scanning in post-chemotherapy residual retroperitoneal lymph nodes in patients with seminoma, but not with non-seminoma. Recommendations suggest that seminoma patients with a residual disease in the retroperitoneum larger than 3 cm should be subjected for PET scanning with 18-fluorodeoxyglucose. Relatively high sensitivity, specificity and a negative predictive value (80–95%) may guide clinical decision to spare these patients of high morbidity of an unnecessary surgery. However, a positive predictive value of around 50% renders PET scanning difficult to interpret in the case of positive finding. These patients often require extremely difficult surgical procedures with the high risk of post-operative morbidity. Therefore, seminoma patients with PET positive residual masses larger than 3 cm still remain a serious challenge in the decision making of nuclear medicine specialist, oncologists, and urologic surgeons. In this article, we aim to summarize data on controversial dilemmas in staging procedures, active surveillance, and post-chemotherapy assessment of GCTs based on the available published literature.

Testicular germ cell tumors are among the most common malignancies seen in children and young adults. Genomic studies have identified characteristic molecular profiles in testicular cancer, which are associated with histologic subtypes and may predict clinical behavior including treatment responses. Emerging molecular technologies analyzing tumor genomics, transcriptomics, and proteomics may now guide precision management of testicular tumors. Laser-assisted microdissection methods such as laser capture microdissection efficiently isolate selected tumor cells from routine pathology specimens, avoiding contamination from nontarget cell populations. Laser capture microdissection in combination with next generation sequencing makes precise high throughput genetic evaluation effective and efficient. The use of laser capture microdissection (LCM) for molecular testing may translate into great benefits for the clinical management of patients with testicular cancers. This review discusses application protocols for laser-assisted microdissection to investigate testicular germ cell tumors.

Simple Summary While lifesaving achievements have allowed cancer to be cured in many patients, survivors cured of cancer may suffer from long-term adverse treatment sequelae, substantially altering their quality of life and reintegration into normal life. Increasing evidence suggests the emerging role of the microbiome in chemotherapy-induced late effects affecting cognitive functions and the cardiovascular system. Moreover, existing data from animal models and patients with neurocognitive disorders and cardiovascular diseases outline the possibility that microbiota modulation might potentially prevent or mitigate the psycho-physiological deficits following chemotherapy and help to improve the behavioral comorbidities, cognitive functions, and quality of life in cancer survivors. Abstract Chemotherapy, targeting not only malignant but also healthy cells, causes many undesirable side effects in cancer patients. Due to this fact, long-term cancer survivors often suffer from late effects, including cognitive impairment and cardiovascular toxicity. Chemotherapy damages the intestinal mucosa and heavily disrupts the gut ecosystem, leading to gastrointestinal toxicity. Animal models and clinical studies have revealed the associations between intestinal dysbiosis and depression, anxiety, pain, impaired cognitive functions, and cardiovascular diseases. Recently, a possible link between chemotherapy-induced gut microbiota disruption and late effects in cancer survivors has been proposed. In this review, we summarize the current understanding of preclinical and clinical findings regarding the emerging role of the microbiome and the microbiota–gut–brain axis in chemotherapy-related late effects affecting the central nervous system (CNS) and heart functions. Importantly, we provide an overview of clinical trials evaluating the relationship between the gut microbiome and cancer survivorship. Moreover, the beneficial effects of probiotics in experimental models and non-cancer patients with neurocognitive disorders and cardiovascular diseases as well as several studies on microbiota modulations via probiotics or fecal microbiota transplantation in cancer patients are discussed.

Germ cell tumors (GCTs) are the most common solid malignancies in young men. The overall cure rate of GCT patients in metastatic stage is excellent, however; patients with relapsed or refractory disease have poor prognosis. Attempts to treat refractory disease with novel effective treatment to improve prognosis have been historically dismal and the ability to predict prognosis and treatment response in GCTs did not sufficiently improve in the last three decades.We performed a comprehensive literature search of PubMed/MEDLINE to identify original and review articles (years 1964-2020) reporting on current improvement salvage treatment in GCTs and novel treatment options including molecularly targeted therapy and epigenetic approach. Review articles were further searched for additional original articles.Despite multimodal treatment approaches the treatment of relapsed or platinum-refractory GCTs remains a challenge. High-dose chemotherapy (HDCT) regimens with autologous stem-cell transplant (ASCT) from peripheral blood showed promising results in larger retrospective studies. Promising results from in vitro studies raised high expectations in molecular targets. So far, the lacking efficacy in small and unselected trials do not shed a light on targeted therapy. Currently, wide inclusion of patients into clinical trials is highly advised.

Background Survivors of germ-cell tumors (GCT) may suffer from long-term adverse consequences. Our study was conducted to assess a long-term sexual functioning in GCT survivors. Methods GCT survivors (N = 170) from the National Cancer Institute in Slovakia completed a Sexual Function Questionnaire that was modified from PROMIS Sexual Function and Satisfaction Questionnaire 9-year median follow up (range 5–32) as a primary exploratory aim. Study groups consisted of 17 survivors (10%) who had active surveillance (AS, controls), and 153 (90%) survivors who received treatment beyond orchiectomy (Tx), including cisplatin-based chemotherapy (CT, N = 132; 78%), radiotherapy to the retroperitoneal lymph nodes (RT, N = 12; 7%) or both (CTRT, N = 9; 5%). Results In univariate analysis, treatment of any type resulted in difficulty to maintain erection during sexual intercourse compared to patients treated with AS (P = 0.04). Survivors who received CTRT had lower ability to achieve orgasm during sexual activities (P = 0.04) and they reported disappointment with their overall quality of sex life (P = 0.002). The number of attempts to initiate sexual intercourse did not differ. Sexual relationships caused none or mild anxiety and the desire to be sexually active was higher after CTRT (P = 0.05). Multivariable analysis confirmed that orgasmic dysfunction after ≥400 mg/m2 of cisplatin and issues in maintaining erection after Tx were independent of retroperitoneal lymph-node dissection (P = 0.03 and P = 0.04, respectively). Survivors were disappointed with the quality of sex life and had stronger desire to be sexually active independent of age, (P = 0.01 and P = 0.05, respectively). Conclusions This study identified an impairment in sexual function may represent an issue for long-term GCT survivors. Treatment with chemotherapy plus radiotherapy were associated with disappointment and stronger sexual desire, while a higher cumulative dose of cisplatin may be responsible for orgasmic dysfunction.

Background For optimization of microfluidic devices for the analysis of blood samples, it is useful to simulate blood cells as elastic objects in flow of blood plasma. In such numerical models, we primarily need to take into consideration the movement and behavior of the dominant component of the blood, the red blood cells. This can be done quite precisely in small channels and within a short timeframe. However, larger volumes or timescales require different approaches. Instead of simplifying the simulation, we use a neural network to predict the movement of the red blood cells. Results The neural network uses data from the numerical simulation for learning, however, the simulation needs only be run once. Alternatively, the data could come from video processing of a recording of a biological experiment. Afterwards, the network is able to predict the movement of the red blood cells because it is a system of bases that gives an approximate cell velocity at each point of the simulation channel as a linear combination of bases.In a simple box geometry, the neural network gives results comparable to predictions using fluid streamlines, however in a channel with obstacles forming slits, the neural network is about five times more accurate.The network can also be used as a discriminator between different situations. We observe about two-fold increase in mean relative error when a network trained on one geometry is used to predict trajectories in a modified geometry. Even larger increase was observed when it was used to predict trajectories of cells with different elastic properties. Conclusions While for uncomplicated box channels there is no advantage in using a system of bases instead of a simple prediction using fluid streamlines, in a more complicated geometry, the neural network is significantly more accurate. Another application of this system of bases is using it as a comparison tool for different modeled situations. This has a significant future potential when applied to processing data from videos of microfluidic flows.

Testicular germ cell tumors (TGCT) are the most common solid malignant tumors in young men. Their incidence increases after puberty and peaks at the 3rd decade of life, following a bell-shaped age ...

High-dose chemotherapy (HDCT) has curative potential in relapsed/refractory germ cell tumors (GCT). Due to the complexity of this population and the toxicity of HDCT, we evaluated the association between blood-based systemic inflammatory indexes and the outcome of GCT patients undergoing salvage treatment with HDCT in order to define additional prognostic factors able to orient clinical decision. Baseline characteristics, neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), and the systemic immune-inflammation index (SII) of 62 patients undergoing HDCT for GCT were retrospectively collected. The aim is to evaluate the correlation between each inflammatory marker (NLR, PLR, and SII) and response to HDCT, overall survival (OS), and progression-free survival (PFS). Using the receiver operating curve to identify the best cutoff values, it was found that patients with GCT with NLR ≥3.3 and SII ≥844,000 had shorter PFS and inferior OS. In the multivariable analysis including inflammatory markers, the International Prognostic Factor Study Group (IPFSG) risk group, age, and previous line of treatment, NLR ≥3.3 and SII ≥844,000 were identified to be independently associated with shorter PFS and OS. Moreover, NLR, PLR, and SII significantly correlate with overall response to HDCT. Associating IPFSG prognostic score to inflammatory markers at baseline of HDCT may improve prognostic information and could help physicians to make more personalized treatment decisions.

Testicular germ cell tumors (TGCTs) represent the most common neoplasia among young men. Management of TGCTs is an excellent example of curative outcomes in clinical oncology. The unique sensitivity to cisplatin-based chemotherapy regimens has led to establishing TGCTs as a “model of cancer cure.” However, mechanisms and factors underlying pervasive growth of TGCTs are still poorly understood. It is suggested that unique cancer stem cell (CSC) niche exists in the testicular tumor microenvironment. CSC niche potentially contributes to the progression of germ cell tumors. Furthermore, rich infiltration of TGCTs with immune cells indicates involvement of immune system in biology of this cancer type. This review summarizes current knowledge regarding specific cancer microenvironment in TGCTs and discusses the role of cancer stem cells as well as immune mechanisms in these tumors.

Background Cisplatin resistance of ovarian yolk sac tumors (oYST) is a clinical challenge due to dismal patient prognosis, even though the disease is extremely rare. We investigated potential association between cisplatin resistance and cancer stem cell (CSC) markers in chemoresistant oYST cells and targeting strategies to overcome resistance in oYST. Methods Chemoresistant cells were derived from chemosensitive human oYST cells by cultivation in cisplatin in vitro. Derivative cells were characterized by chemoresistance, functional assays, flow cytometry, gene expression and protein arrays focused on CSC markers. RNAseq, methylation and microRNA profiling were performed. Quail chorioallantoic membranes (CAM) with implanted oYST cells were used to analyze the micro-tumor extent and interconnection with the CAM. Tumorigenicity in vivo was determined on immunodeficient mouse model. Chemoresistant cells were treated by inhibitors intefering with the CSC properties to examine the chemosensitization to cisplatin. Results Long-term cisplatin exposure resulted in seven-fold higher IC50 value in resistant cells, cross-resistance to oxaliplatin and carboplatin, and increased migratory capacity, invasiveness and tumorigenicity, associated with hypomethylation of differentially methylated genes/promotors. Resistant cells exhibited increased expression of prominin-1 (CD133), ATP binding cassette subfamily G member 2 (ABCG2), aldehyde dehydrogenase 3 isoform A1 (ALDH3A1), correlating with reduced gene and promoter methylation, as well as increased expression of ALDH1A3 and higher overall ALDH enzymatic activity, rendering them cross-resistant to DEAB, disulfiram and napabucasin. Salinomycin and tunicamycin were significantly more toxic to resistant cells. Pretreatment with napabucasin resensitized the cells to cisplatin and reduced their tumorigenicity in vivo. Conclusions The novel chemoresistant cells represent unique model of refractory oYST. CSC markers are associated with cisplatin resistance being possible targets in chemorefractory oYST.

Background: We evaluated systemic immune-inflammation index (SII) and its association with patient outcome in germ-cell tumours (GCTs). Methods: Two independent cohorts of patients were analysed; the discovery set (n=171) from a single institution and the validation set (n=181) previously included in a study evaluating PD-L1 in GCTs. The SII was calculated using platelet (P), neutrophil (N) and lymphocyte (L) counts before chemotherapy and correlated with survival using regression analyses and Kaplan–Meier method. Results: In the discovery cohort, the SII was associated with poor risk clinical features. Patients with low SII had significantly longer progression-free survival (HR=0.22, 95% CI 0.12–0.41, P

Background To report our experience utilizing a multidisciplinary clinic (MDC) at Indiana University (IU) since the publication of the International Germ Cell Cancer Collaborative Group (IGCCCG), and to compare our overall survival (OS) to that of the National Cancer Institute (NCI) Surveillance, Epidemiology, and End Results (SEER) Program. Patients and methods We conducted a retrospective analysis of all patients with metastatic germ-cell tumor (GCT) seen at IU from 1998 to 2014. A total of 1611 consecutive patients were identified, of whom 704 patients received an initial evaluation by our MDC (including medical oncology, pathology, urology and thoracic surgery) and started first-line chemotherapy at IU. These 704 patients were eligible for analysis. All patients in this cohort were treated with cisplatin–etoposide-based combination chemotherapy. We compared the progression-free survival (PFS) and OS of patients treated at IU with that of the published IGCCCG cohort. OS of the IU testis cancer primary cohort (n = 622) was further compared with the SEER data of 1283 patients labeled with ‘distant' disease. The Kaplan–Meier method was used to estimate PFS and OS. Results With a median follow-up of 4.4 years, patients with good, intermediate, and poor risk disease by IGCCCG criteria treated at IU had 5-year PFS of 90%, 84%, and 54% and 5-year OS of 97%, 92%, and 73%, respectively. The 5-year PFS for all patients in the IU cohort was 79% [95% confidence interval (CI) 76% to 82%]. The 5-year OS for the IU cohort was 90% (95% CI 87% to 92%). IU testis cohort had 5-year OS 94% (95% CI 91% to 96%) versus 75% (95% CI 73% to 78%) for the SEER ‘distant' cohort between 2000 and 2014, P-value Conclusion The MDC approach to GCT at high-volume cancer center associated with improved OS outcomes in this contemporary dataset. OS is significantly higher in the IU cohort compared with the IGCCCG and SEER ‘distant' cohort.

Germ-cell tumors (GCTs) are highly curable with chemotherapy. Salvage chemotherapy or surgery can cure a proportion of patients, but the ones failing these treatments will die of their disease in the young age. Immune checkpoint pathways are emerging as powerful targetable biomarkers, and a significant preclinical and clinical research is underway to widen our knowledge and expand the treatment possibilities with immune therapy. The concept of immune modulation that was currently adopted in many solid tumors is understudied in GCTs. Herein, we summarize the current knowledge of published literature discussing the immune mechanisms and immune therapy in GCTs.

Introduction: Liquid biopsy is an increasingly studied approach for optimal and minimally invasive diagnostics of malignant tumors. The aim of this review is to provide evidence and discuss the utility of liquid biopsy in the management of germ cell tumors (GCTs).Areas covered: Herein, we summarize the evidence on liquid biopsy in GCTs including serum tumor markers, circulating tumor cells, microRNA and cell-free DNA. The search of literature was conducted from Pubmed/Medline, ASCO-meeting library searching for terms 'liquid biopsy', 'germ cell tumors', 'circulating tumor cells', 'microRNA', 'cell-free DNA'. Obtained original studies were included. Reference lists of review articles and key original articles were searched for additional original studies. We included articles published between1990 and 2019.Expert opinion: Liquid biopsy is a minimally invasive tool using body fluids for diagnostic purposes in cancer. The established value of serum tumor markers may be already considered a liquid biopsy technique in diagnosis of GCTs. Possible near-future refinements in diagnosis of GCTs are emerging. Further information on diagnosis, prognosis and resistance is added with recently described microRNAs, circulating tumor cells and cell-free DNA. While great promise is shown, further large-scale validation is needed to incorporate these novel liquid biopsies into clinical practice.

Introduction: The use of liquid biopsy on the blood from solid malignancies provides a convenient way of detecting actionable mutations, monitoring treatment response, detecting early recurrence and prognosticating outcomes. The aim of this review is to discuss the current status and future direction of serum biomarkers in the clinical management of urinary bladder cancer.Areas covered: This review provides an overview of blood liquid biopsy and bladder cancer using methods of circulating tumors cells, circulating RNA, serum metabolites and cell-free DNA. Recent clinical studies and advances in methodology are emphasized. We performed a literature search using PMC/PubMed with keywords including 'liquid biopsy', 'circulating tumor DNA', 'cell-free DNA', 'biomarkers', 'bladder cancer' 'precision medicine'. Additional articles were obtained from the cited references of key articles. An emphasis was placed on recent studies published since 2018.Expert opinion: Liquid biopsies represent a potential biomarker using cell-free DNA, metabolomic profiles of altered cellular metabolism, circulating cancer cells and RNA. Despite displaying tremendous clinical promise, the current status of the blood liquid biopsies has not reached fruition. However, future investigations should lead the evolution of liquid biomarker into clinical utility for the management of bladder cancer.

The U.S. Preventive Services Task Force does not recommend routine screening for testicular cancer (TC) in asymptomatic men, essentially because serological testicular cancer (TC) biomarkers are not reliable. The main reason is that two of the most important TC biomarkers, α-fetoprotein (AFP) and human chorionic gonadotropin (hCG), are not produced solely due to TC. Moreover, up to 40% of patients with TC do not have elevated serological biomarkers, which is why serial imaging with CT is the chief means of monitoring progress. On the other hand, exposure to radiation can lead to an increased risk of secondary malignancies. This review provides the first comprehensive account of the applicability of protein glycoprofiling as a promising biomarker for TC with applications in disease diagnostics, monitoring and recurrence evaluation. The review first deals with the description and classification of TC. Secondly, the limitations of current TC biomarkers such as hCG, AFP and lactate dehydrogenase are provided together with an extensive overview of the glycosylation of hCG and AFP related to TC. The final part of the review summarises the potential of glycan changes on either hCG and AFP as TC biomarkers for diagnostics and prognostics purposes, and for disease recurrence evaluation. Finally, an analysis of glycans in serum and tissues as TC biomarkers is also provided.

Testicular cancer is the most common tumor in young males aged 15–40 years. The overall cure rate for men with testicular cancer is >90%, so a huge number of these patients will become testicular cancer survivors. These people may feel some stress in the experience of diagnosis, treatment, and consequences that affects the quality of life, and during follow-up, especially when new issues and emotional distresses appear over time, such as late side-effects of treatments and emotional challenges including fear of tumor relapse, fertility and sexuality concerns, and social and workplace issues. The cancer experience has an impact not only on patients, but also on their relatives (e.g., spouses, parents, or siblings), who often have to assume a caregiving role for the duration of and following treatment for cancer. Moreover, the caregiver plays an important role in supporting a man with a testicular cancer, providing physical and emotional care. This review presents a summary of existing knowledge regarding the impact and the burden of testicular cancer on caregivers.

Background Germ cell tumors (GCTs) are highly curable diseases; however, not all patients can be cured. Patients in their second relapse have especially poor prognoses. PD-L1 expression is significantly higher in GCTs than in normal testicular tissue, and high PD-L1 expression is associated with a poor prognosis. This study aimed to determine the efficacy and safety of avelumab, a PD-L1 inhibitor, in patients with GCTs. Methods In this phase 2 study, patients with multiple relapsed and/or refractory GCTs were treated with avelumab at a dose of 10 mg/kg administered biweekly until progression or unacceptable toxicity. The primary endpoint was 12-week progression-free survival (PFS). Fifteen evaluable patients had to be enrolled in the first cohort, and if

Germ cell tumors represent 11% of the cancers diagnosed in adolescent males and are the most common solid tumors in adult men between the ages of 20 and 35. Pure seminoma accounts for around 50% of all testicular germ cell tumors. The prognostic classification of the International Germ Cell Cancer Collaborative Group for good-prognosis seminoma includes both nodal disease and pulmonary visceral metastases. In this article, we analyzed recent data on prognosis and outcome of good-prognosis seminoma to revise the traditional classification of the disease and improve tailored treatment.

Background Germ cell tumours (GCTs) represent a highly curable malignity as they respond well to cisplatin (CDDP)-based chemotherapy. Nevertheless, a small proportion of GCT patients relapse or do not respond to therapy. As this might be caused by an increased capacity to repair CDDP-induced DNA damage, identification of DNA repair biomarkers predicting inadequate or aberrant response to CDDP, and thus poor prognosis for GCT patients, poses a challenge. The objective of this study is to examine the expression levels of the key nucleotide excision repair (NER) factors, XPA, ERCC1 and XPF, in GCT patients and cell lines. Methods Two hundred seven GCT patients’ specimens with sufficient follow-up clinical-pathological data and pairwise combinations of CDDP-resistant and -sensitive GCT cell lines were included. Immunohistochemistry was used to detect the ERCC1, XPF and XPA protein expression levels in GCT patients’ specimen and Western blot and qRT-PCR examined the protein and mRNA expression levels in GCT cell lines. Results GCT patients with low XPA expression had significantly better overall survival than patients with high expression (hazard ratio = 0.38, 95% confidence interval: 0.12–1.23, p = 0.0228). In addition, XPA expression was increased in the non-seminomatous histological subtype, IGCCCG poor prognosis group, increasing S stage, as well as the presence of lung, liver and non-pulmonary visceral metastases. Importantly, a correlation between inadequate or aberrant CDDP response and XPA expression found in GCT patients was also seen in GCT cell lines. Conclusions XPA expression is an additional independent prognostic biomarker for stratifying GCT patients, allowing for improvements in decision-making on treatment for those at high risk of refractoriness or relapse. In addition, it could represent a novel therapeutic target in GCTs.

// Zuzana Sestakova 1, * , Katarina Kalavska 1, 2, * , Lenka Hurbanova 1 , Dana Jurkovicova 1 , Jan Gursky 1 , Michal Chovanec 3, 4 , Daniela Svetlovska 2 , Vera Miskovska 5 , Jana Obertova 3, 4 , Patrik Palacka 3, 4 , Katarina Rejlekova 3, 4 , Zuzana Sycova-Mila 4 , Silvia Cingelova 4 , Stanislav Spanik 5, 6 , Jozef Mardiak 3, 4 , Miroslav Chovanec 1, # , Michal Mego 2, 3, 4, # 1 Department of Genetics Cancer Research Institute, Biomedical Research Center, Slovak Academy of Sciences, Bratislava, Slovakia 2 Translational Research Unit, Faculty of Medicine, Comenius University, National Cancer Institute, Bratislava, Slovakia 3 2nd Department of Oncology, Faculty of Medicine, Comenius University and National Cancer Institute, Bratislava, Slovakia 4 Department of Oncology, National Cancer Institute, Bratislava, Slovakia 5 1st Department of Oncology, Faculty of Medicine, Comenius University and St. Elisabeth Cancer Institute, Bratislava, Slovakia 6 Department of Oncology, St. Elizabeth Cancer Institute, Bratislava, Slovakia * K-K and Z-S share the first authorship # M-CH and M-M share the last authorship Correspondence to: Miroslav Chovanec, email: miroslav.chovanec@savba.sk Michal Mego, email: misomego@gmail.com Keywords: DNA damage, DNA repair, cisplatin, germ cell tumors, prognostic marker Received: July 04, 2016 Accepted: September 29, 2016 Published: October 07, 2016 ABSTRACT Germ cell tumors (GCTs) are extraordinarily sensitive to cisplatin (CDDP)-based chemotherapy. DNA damage represents one of the most important factors contributing to toxic effects of CDDP-based chemotherapy. This study was aimed to evaluate the prognostic value of DNA damage level in peripheral blood lymphocytes (PBLs) from chemo-naive GCT patients. PBLs isolated from 59 chemotherapy-naive GCT patients were included into this prospective study. DNA damage levels in PBLs were evaluated by the Comet assay and scored as percentage tail DNA by the Metafer-MetaCyte analyzing software. The mean ± SEM (standard error of the mean) of endogenous DNA damage level was 5.25 ± 0.64. Patients with DNA damage levels lower than mean had significantly better progression free survival (hazard ratio [HR] = 0.19, 95% CI (0.04 – 0.96), P = 0.01) and overall survival (HR = 0.00, 95% CI (0.00 – 0.0), P < 0.001) compared to patients with DNA damage levels higher than mean. Moreover, there was significant correlation between the DNA damage level and presence of mediastinal lymph nodes metastases, IGCCCG (International Germ Cell Cancer Collaborative Group) risk group, and serum tumor markers level. These data suggest that DNA damage levels in PBLs of GCT patients may serve as an important prognostic marker early identifying patients with poor outcome.

BACKGROUND Testicular germ cell tumors (TGCTs) belong to the most chemosensitive solid tumors; however, a small proportion of patients fail to be cured with cisplatin-based chemotherapy. Inhibitors of PD-1/PD-L1 pathways represent a new class of promising drugs in anticancer therapy. The aim of this study was to evaluate expression and prognostic value of PD-1 and PD-L1 in TGCTs. PATIENTS AND METHODS Surgical specimens from 140 patients with TGCTs (131 with primary testicular tumor and 9 with extragonadal GCTs) were included into the translational study. PD-1 and PD-L1 expression was detected in the tumor tissue by immunohistochemistry using monoclonal antibodies, scored by the multiplicative quickscore (QS) method, compared with their expression in normal testicular tissue and correlated with clinicopathological characteristics and clinical outcome. RESULTS None of the GCTs exhibited PD-1 protein, although expression of PD-L1 was significantly higher in GCTs in comparison with normal testicular tissue (mean QS = 5.29 versus 0.32, P < 0.0001). Choriocarcinomas exhibit the highest level of PD-L1 with decreasing positivity in embryonal carcinoma, teratoma, yolk sac tumor and seminoma. PD-L1 expression was associated with poor prognostic features, including ≥3 metastatic sites, increased serum tumor markers and/or non-pulmonary visceral metastases. Patients with low PD-L1 expression had significantly better progression-free survival [hazard ratio (HR) = 0.40, 95% confidence interval (CI) 0.16-1.01, P = 0.008] and overall survival (HR = 0.43, 95% CI 0.15-1.23, P = 0.040) compared with patients with high PD-L1 expression. CONCLUSIONS In this translational study, we showed, for the first time, the prognostic value of PD-L1 expression in TGCTs and our data imply that the PD-1/PD-L1 pathway could be a novel therapeutic target in TGCTs.

Germ cell tumour (GCT) patients who fail to respond to chemotherapy or who relapse have a poor prognosis. Timely and accurately stratifying such patients could optimise their therapy. We identified endogenous DNA damage levels as a prognostic marker for progression-free (PFS) and overall (OS) survival in chemotherapy-naïve GCT patients. In the present study, we have extended our previous results and reviewed the prognostic power of DNA damage level in GCTs. Endogenous DNA damage levels were measured with the comet assay. Receiver operator characteristic analysis was applied to determine the optimal cut-off value and to evaluate its prognostic accuracy. PFS and OS were estimated by the Kaplan-Meier method and compared using the log-rank test. Hazard ratio (HR) estimates were calculated by Cox regression analysis. A cut-off value of 6.34 provided the highest sensitivity and specificity, with area under curve values of 0.813 and 0.814 for disease progression and mortality, respectively. A % DNA in tail6.34 was significantly associated with shorter PFS (HR = 9.54, 95 % confidence interval [CI]: 3.43-26.55, p 0.001) and OS (HR = 14.62, 95 % CI: 3.14-67.95, p = 0.001) by univariate analysis. The prognostic value of DNA damage measurement was confirmed by multivariate models (HR = 6.45, 95 % CI: 2.22-18.75, p = 0.001 for PFS and HR = 9.40, 95 % CI: 1.70-52.09, p = 0.010 for OS), when HR was adjusted for relevant clinical categories. The added prognostic value of DNA damage in combination with International Germ Cell Cancer Collaborative Group (IGCCCG) risk groups has been revealed. Endogenous DNA damage is an independent prognosticator for PFS and OS in GCT patients and its clinical use, particularly in combination with IGCCCG risk groups, may help in stratifying these patients.

e17063 Background: Chemotherapy-induced peripheral neuropathy (CIPN20) after curative treatment for testicular germ cell tumors (GCTs) has been previously reported. The impact of CIPN on long-term quality of life (QOL) in GCT survivors remains unclear. Herein, we aimed to evaluate chemotherapy-induced peripheral neuropathy (CIPN20) in association with QOL in GCT survivors. Methods: European Organisation for Research and Treatment of Cancer (EORTC) CIPN20, QLQ-C30 and Functional Assessment of Cancer Therapy-Cognitive Function (FACT-Cog) questionnaires were prospectively completed by GCT survivors (N = 153) at National Cancer Institute in Slovakia during their annual follow-up. The median follow-up was 10 years (range 4-25). Upon obtaining the scores from each questionnaire per recommended guidelines, each score from QLQ-C30 and FACT-Cog was correlated with CIPN defined as high or low (above and below median) as obtained from CIPN20. Results: GCT survivors with CIPN high reported impairment in quality of life in QLQ-C30. The global health status was lower in survivors with high vs low CIPN (mean score ± SEM: 66.5 ± 1.9 vs. 86.2 ± 1.8, P < 0.00001). Survivors with CIPN high reported substantially worse physical, role, emotional, cognitive and social functioning compared to CIPN low (all P < 0.00001). CIPN high survivors perceived more fatigue, nausea, pain, dyspnoea, appetite loss and more sleeping disorders compared to CIPN low (all P < 0.0001). Higher burden of CIPN was associated with more financial problems vs CIPN low (mean score ± SEM: 19.6 ± 2.6 vs. 6.67 ± 2.3, P = 0.0002). Cognitive impairment was higher in all FACT-Cog domains including the overall cognitive function score (all P < 0.001) for CIPN high. Spearman analysis has confirmed negative correlations of CIPN20 overall score with QLQ-C30 global health status (R = -0.54, P < 0.0001) and with FACT-Cog overall cognitive function score (R = -0.52, P < 0.0001). Conclusions: CIPN is a powerful predictor of disturbances in QOL and cognitive functioning among GCT survivors. Physicians should never over-treat patients unnecessarily and novel therapies with lower burden of late toxicity should be researched

Background WNT/βcatenin (WNTβ) pathway is activated in early stages of embryonic development. We aimed to evaluate the significance of βcatenin in germ cell tumors (GCTs) and explore associations with the inflamed environment. Methods Surgical specimens from 247 patients were analyzed. Βcatenin expression was detected in the tumor tissue by immunohistochemistry and correlated with clinical characteristics, outcome, PD-L1 expression and systemic immune-inflammation index (SII). The Ingenuity Pathway Analysis (IPA) was used to investigate the immune-cell related effects of βcatenin and PD-L1 encoding genes. Results βcatenin was expressed in 86.2% of GCTs. The expression in seminomas was significantly lower compared to all subtypes of non-seminoma (all P 150) was associated with primary mediastinal non-seminoma (P = 0.035), intermediate/poor risk disease (P = 0.033) and high tumor markers (P = 0.035). We observed a positive correlation with the PD-L1 in tumor and an inverse correlation with the SII. IPA uncovered relationships of CTNNB (βcatenin) and CD274 (PD-L1) genes and their effects on differentiation, proliferation and activation of lymphocyte subtypes. Conclusion Herein, we showed that βcatenin is associated with male adult GCT characteristics as well as supressed immune environment. Electronic supplementary material The online version of this article (10.1186/s12885-018-4929-x) contains supplementary material, which is available to authorized users.

Testicular germ cell tumors (TGCTs) are highly sensitive to cisplatin‑based chemotherapy. Nevertheless, there are metastatic tumors that do not completely respond to front‑line chemotherapy. For these tumors, surgical resection of residual masses is necessary to achieve long‑term disease control. Resected tissues represent valuable clinical material, which may be used for the engraftment into immunocompromised mice to produce patient‑derived xenografts (PDXs). They typically maintain similarities to the parental tumors and therefore serve as more realistic preclinical models. Moreover, a correlation between PDX treatment outcomes and clinical response to chemotherapy has been previously described. The aim of the present study was to establish and characterize TGCT patient‑derived xenografts. These originated from retroperitoneal lymph node metastases infiltrated with TGCTs following previous cisplatin‑based chemotherapy, in order to analyze novel treatment options for cisplatin‑resistant testicular tumors. We generated two testicular patient‑derived xenograft models in SCID beige male mice. Immunohistochemical analyses demonstrated that histological characteristics of the primary tumor were not retained, and transformation into lymphoma, and eventually plasmocytoma, was observed. A potential explanation for the lymphoma transformation observed in PDXs may include tumor‑infiltrating lymphocytes (TILs) in xenografted samples of patients, which are transformed following engraftment into immunodeficient recipient mice. Based on these data, we indicated that lymphomagenesis prevention and terminal differentiation represent new challenges in the establishment of PDX models derived from patients with germ cell tumors.

Inhibition of DNA methyltransferases (DNMTs) has emerged as a novel treatment strategy in solid tumors. Aberrant hyperme-thylation in promoters of critical tumor suppressor genes is the basis for the idea that treatment with hypomethylating agents may lead to the restoration of a “normal” epigenome and produce clinically meaningful therapeutic outcomes. The aim of this review article is to summarize the current state of knowledge of DNMT inhibitors in the treatment of genitourinary malignancies. The efficacy of these agents in genitourinary malignancies was reported in a number of studies and suggests a role of induced DNA hypomethylation in overcoming resistance to conventional cytotoxic treatments. The clinical significance of these findings should be further investigated.

Context Testicular germ-cell tumors (GCT) are highly curable. A multidisciplinary approach, including cisplatin-based chemotherapy has resulted in cure in the majority of patients with GCT. Thus, the life expectancy of survivors will extend to many decades post-diagnosis. Late treatment toxicities associated with cisplatin-based chemotherapy may impact their future health. Objective To systematically evaluate evidence regarding the long-term toxicity of cisplatin in GCT survivors. Evidence acquisition We carried out a critical review of PubMed/Medline in February 2017 according to the Preferred Reporting Items for Systematic Review and Meta-analysis (PRISMA) statement. Identified reports were reviewed according to the Consolidated Standards of Reporting Trials (CONSORT) criteria. Eighty-three publications were selected for inclusion in this analysis. Evidence synthesis Included reports evaluated long-term toxicities of cisplatin-based chemotherapy in GCT survivors. Studies reporting neuro- and ototoxicity, secondary malignancies, cardiovascular, renal and pulmonary toxicities, hypogonadism and infertility were found. Seven studies (8%) reported genetic underpinnings of long-term toxicities and 3 (4%) and 14 (19%) studies correlated long-term toxicities with circulating platinum levels and cumulative dose of cisplatin, respectively. Significant risks for long-term toxicities associated with cisplatin and platinum-based regimens were reported. The cumulative dose of cisplatin and circulating platinum were reported as risk factors. Several single-nucleotide polymorphisms identified patients susceptible to cisplatin compared with wild-type individuals. Conclusions GCT survivors cured with cisplatin-based chemotherapy are at risk for long-term side-effects. Detection of single-nucleotide polymorphisms could be a valuable tool for predicting long-term toxicities. Patient summary Herein, this article summarizes the available evidence of long-term toxicity of cisplatin-based chemotherapy in GCT survivors and provide insights from Indiana University.

Background Treatment for cancer may lead to development of cognitive difficulties in cancer survivors. This study aimed to evaluate long-term cognitive functioning (CogF) in germ-cell tumor (GCT) survivors. Subjects, Materials, and Methods GCT survivors (n = 155) from the National Cancer Institute of Slovakia completed the Functional Assessment of Cancer Therapy Cognitive Function at a median of 10 years of follow-up (range: 5–32). The study group consisted of survivors receiving a cisplatin-based chemotherapy, radiotherapy to the retroperitoneal lymph nodes, or both, whereas the control group included survivors treated with orchiectomy only. Results Of the total survivors, 138 received treatment beyond orchiectomy and 17 controls had orchiectomy alone. Any treatment resulted in significantly greater cognitive difficulties on the overall cognitive function score. Treatment with radiotherapy was associated with cognitive declines in overall cognitive functioning and in subscales for perceived cognitive impairment and cognitive impairment perceived by others (both p Conclusion This prospective study shows that GCT survivors suffer from a long-term CogF impairment. These results may help guide clinicians’ decisions in treatment and follow-up of GCTs. Implications for Practice In this study, long-term survivors of germ-cell tumors have reported cognitive impairment after curative treatment with radiotherapy and chemotherapy compared with controls who had treatment with orchiectomy only. These data provide an argument against the use of adjuvant radiotherapy for stage I seminoma. Unnecessary overtreatment with chemotherapy and additional radiotherapy after chemotherapy should be avoided.

Endogenous and exogenous factors can severely affect the integrity of genetic information by inducing DNA damage and impairing genome stability. The protection of genome integrity is ensured by the so-called “DNA damage response” (DDR), a set of evolutionary-conserved events that, triggered upon DNA damage detection, arrests the cell cycle, and attempts DNA repair. Here, we review the role of the DDR proteins as post-transcriptional regulators of gene expression, in addition to their roles in DNA damage recognition, signaling, and repair. At the same time, we discuss recent insights into how pre-mRNA splicing factors go beyond their splicing activities and play direct functions in detecting, signaling, and repairing DNA damage. The importance of extensive two-way crosstalk and interaction between the RNA processing and the DDR stems from growing evidence that the defects of their communication lead to genomic instability.

Application areas of Wireless Sensor Network are spread in so many fields that the creation of an universal WSN is a big and challenging problem. But what unites almost all major solutions is the need for communication at some certain time slot or the need for communication between the nodes. Nodes usually have to make measurements, in some cases process the data and send them. Because of the mentioned reasons the synchronization of nodes in network, as well as use of real time communication in network is highly desirable. The detailed explanation of the node level of Firefly-based Universal Synchronization Algorithm and the network level is supported by the simulation results along with the implementation remarks. Then the real-time scheduler for real time operating system in small mobile robotics or WSN with strong modularity is described with features as advanced sleep modes and event driven programming. At the end we represent the basic concept of WSN with use of proposed methods on each node.

e16045 Background: Testicular germ cell tumors (TGCTs) represent a highly curable disease; however, a small proportion of patients develop disease recurrence. PD-L1 expression is significantly higher in germ cell tumors (GCTs) in comparison to normal testicular tissue and high PD-L1 expression is associated with inferior progression-free and overall survival compared to patients with low PD-L1 expression. This study aimed to determine the efficacy and toxicity of PD-L1 antagonist, Avelumab, in patients with refractory GCTs. Methods: From November 2017 to January 2018, 8 patients with refractory GCTs were enrolled in the phase II study. All patients were pretreated with at least 2 cisplatin-based therapies (median 5, range 2 – 6); 5 tumors (62.5%) were absolutely refractory to cisplatin and 5 patients (62.5%) had visceral non-pulmonary metastases. Avelumab was administered at a dose of 10mg/kg biweekly until progression or unacceptable toxicity. The primary end point was 12-weeks progression-free survival (PFS). If < 8 responses to study therapy will be observed among the first 15 patients, the study will be terminated. Results: Median age was 29 years (range: 22 – 52 years). During a median follow-up period of 2.6 months (range: 0.3 - 14.4), 7 (87.5%) patients experienced disease progression and 6 patients (80.0%) died. Twelve-week PFS was 0%, median PFS was 1.4 months, 95%CI (0.9 – 1.4) and median OS was 2.7 months, 95% CI (1.0 – 3.3). No objective response was observed. Avelumab was well tolerated, no severe adverse event was observed. Conclusions: This study failed to achieve its primary end point and our data suggest lack of Avelumab efficacy in unselected multiple relapsed/refractory TGCTs. Clinical trial information: NCT03403777.

Clinical stage I testicular germ cell tumours (TGCT) are highly curable neoplasms. The treatment of stage I testicular cancer is complex and requires a multidisciplinary approach. Standard options after radical orchiectomy for seminoma include active surveillance, radiation therapy or 1-2 cycles of carboplatin, and options for nonseminoma include active surveillance, retroperitoneal lymph node dissection (RPLND) or 1-2 cycles of bleomycin plus etoposide plus cisplatin (BEP). All the options should be discussed with each patient and treatment choices should be made by shared decision making as virtually all patients with clinical stage I TGCT can be cured of their disease. Long-term survival of men with stage I disease is ∼99% and care must be taken to limit the long-term risks of treatment. Orchiectomy is curative in the majority of patients. The management of clinical stage I TGCT remains controversial among experts at high-volume centres throughout the world. The main controversy is whether to overtreat a substantial number of patients with stage I disease to prevent relapse, or to observe and treat only patients who experience disease relapse as adjuvant treatment and surveillance strategy both bring curative outcome. Thus, a summary of the available evidence in stage I disease and recommendations for disease management from a high-volume centre such as Indiana University might be of interest to treating clinicians.

Cytokines are the communicators of immune system and are involved in all immune responses. The aim of this study was to assess the correlation among plasma cytokines, patient and tumor characteristics, and clinical outcome in chemonaive testicular germ-cell tumor (TGCT) patients.This study included 92 metastatic chemotherapy-naive TGCT patients treated with platinum-based chemotherapy from July 2010 to March 2014. Plasma was isolated before first administration of chemotherapy, and the concentration of 51 plasma cytokines were analyzed using multiplex bead arrays.At a median follow-up of 33.2 months (range, 0.1-54.8 months), 10.9% of patients experienced disease progression, and 7.6% died. Several cytokines were associated with different baseline clinicopathologic features. Elevated plasma levels of interferon (IFN)-α2, interleukin (IL)-2Rα, IL-16, hepatocyte growth factor (HGF), and monocyte chemotactic protein (MCP)-3 were significantly associated with worse progression-free survival and overall survival (OS). Moreover, elevated levels of stem-cell growth factor (SCGF)-β were also associated with worse OS. Patients with elevated levels of all 6 cytokines experienced significantly worse outcomes compared to patients who had fewer than 6 cytokines elevated (hazard ratio = 12.06; 95% confidence interval, 7.39-19.49; P = .002 for progression-free survival, and hazard ratio = 39.65; 95% confidence interval, 25.03-62.18; P .00001 for OS, respectively). Results were independent of International Germ Cell Cancer Collaborative Group criteria.We found a correlation among progression free-survival, OS, and circulating cytokines in TGCT. This suggests the existence an association between plasma cytokines and baseline clinicopathologic features in TGCT. Plasma cytokines could be used for identification of high-risk patients who are candidates for new therapeutic approaches.

// Michal Chovanec 1, 2, 7, * , Zuzana Cierna 3, * , Viera Miskovska 4 , Katarina Machalekova 5 , Daniela Svetlovska 2, 6 , Katarina Kalavska 2, 7, 8 , Katarina Rejlekova 1, 7 , Stanislav Spanik 4 , Karol Kajo 5 , Pavel Babal 3, 9 , Jozef Mardiak 1, 7 , Michal Mego 1, 2, 7 1 2nd Department of Oncology, Comenius University, Faculty of Medicine & National Cancer Institute, Bratislava, Slovak Republic 2 Translational Research Unit, 2nd Department of Oncology, Comenius University, Faculty of Medicine & National Cancer Institute, Bratislava, Slovak Republic 3 Department of Pathology, Comenius University, Faculty of Medicine, Bratislava, Slovak Republic 4 1st Department of Oncology, Comenius University, Faculty of Medicine & St. Elisabeth Cancer Institute, Bratislava, Slovak Republic 5 Department of Pathology, Slovak Medical University St. Elisabeth Cancer Institute, Bratislava, Slovak Republic 6 Department of Clinical Trials, National Cancer Institute, Bratislava, Slovak Republic 7 Department of Medical Oncology, National Cancer Institute, Bratislava, Slovak Republic 8 Cancer Research Institute, Slovak Academy of Sciences, Bratislava, Slovak Republic 9 Faculty Hospital with Policlinics Skalica, a.s., Skalica, Slovak Republic * M-CH and Z-C share the first authorship Correspondence to: Michal Mego, email: misomego@gmail.com Keywords: programmed death-ligand 1, programmed cell death protein 1, tumor infiltrating lymphocytes, prognostic factor, testicular germ cell tumors Received: August 12, 2016 Accepted: January 10, 2017 Published: February 21, 2017 ABSTRACT Purpose: Testicular germ cell tumors (TGCTs) are nearly universally curable malignancies. Nevertheless, standard cisplatin-based chemotherapy is not curative in a small subgroup of patients. Previously, we showed that PD-L1 overexpression is associated with worse prognosis in TGCTs, while tumor infiltrating lymphocytes (TILs) are prognostic in different types of cancer. This study aimed to evaluate the prognostic value of PD-1 and PD-L1 expressing TILs in TGCTs. Results: PD-L1 positive TILs were found significantly more often in seminomas (95.9% of patients) and embryonal carcinomas (91.0%) compared to yolk sac tumors (60.0%), choriocarcinomas (54.5%) or teratomas (35.7%) (All p < 0.05). TGCTs patients with high infiltration of PD-L1 positive TILs (HS ≥ 160) had significantly better progression-free survival (HR = 0.17, 95% CI 0.09 – 0.31, p = 0.0006) and overall survival (HR = 0.08, 95% CI 0.04 – 0.16, p = 0.001) opposite to patients with lower expression of PD-L1 (HS < 150). PD-1 expressing TILs were not prognostic in TGCTs. Materials and Methods: Surgical specimens from 240 patients with primary TGCTs were included into this translational study. The PD-1 and PD-L1 expression on tumor and TILs were detected by immunohistochemistry using anti-PD-1 and anti-PD-L1 monoclonal antibody. Scoring was performed semiquantitatively by weighted histoscore (HS) method. Conclusions: The prognostic value of PD-L1 expressing TILs in TGCTs was demonstrated for the first time.

Background Germ cell neoplasia in situ (GCNIS), is preinvasive stage of testicular germ cell tumours (TGCTs). Fibrillins, which are integral components of microfibrils are suggested to be involved in cancer pathogenesis and maintenance of embryonic stem cells pluripotency. The aim of this study was to examine fibrillin-1 (FBN-1) expression in TGCTs patients. Methods Surgical specimens from 203 patients with TGCTs were included into the translational study. FBN-1 expression was evaluated in the tumour tissue, in GCNIS and in adjacent non-neoplastic testicular tissue in all available cases. Tissue samples were processed by the tissue microarray method. FBN-1 was detected by immunohistochemistry using goat polyclonal antibody and the expression was evaluated by the multiplicative quickscore (QS). Results The highest FBN-1 positivity was detected in GCNIS (mean QS = 11.30), with overexpression of FBN-1 (QS >9) in the majority (77.1 %) of cases. Expression of FBN-1 in all subtypes of TGCTs was significantly lower in comparison to expression in GCNIS (all p

Testicular germ cell tumors (TGCTs) represent a highly curable malignancy, however a small proportion of patients fails to be cured with cisplatin-based chemotherapy. Carbonic anhydrase IX (CA IX) is upregulated by hypoxia in several cancer types and correlates with a poor prognosis. The present translational study evaluated expression and prognostic value of CA IX in TGCTs. Surgical specimens from 228 patients with TGCTs were processed by the tissue microarray method and subjected to immunohistochemistry with the M75 monoclonal antibody. CA IX expression was evaluated in tumors vs. adjacent normal testicular tissues and correlated with clinicopathological characteristics and clinical outcome. CA IX expression was detected in 62 (30.2%) of TGCTs compared to 0 (0%) of normal tissue adjacent to testicular tumor (P

Despite the fact that testicular germ cell tumors (TGCTs) are one of the most chemosensitive solid tumors, a small proportion of patients fail to be cured following cisplatin-based first line chemotherapy. Upregulation of carbonic anhydrase IX (CA IX) in various solid tumors is associated with poor outcome. The current prospective study investigated the prognostic value of serum CA IX level in TGCTs. In total, 83 patients (16 non-metastatic following orchiectomy with no evidence of disease, 57 metastatic chemotherapy-naive and 10 metastatic relapsed chemotherapy-pretreated) starting adjuvant and/or new line of chemotherapy and 35 healthy controls were enrolled in the study. Serum CA IX values were determined using an enzyme-linked immunosorbent assay, and intratumoral CA IX was analyzed by immunohistochemistry. Metastatic chemotherapy-naive patients had significantly higher mean CA IX serum levels than healthy controls (490.6 vs. 249.6 pg/ml, P=0.005), while there was no difference in serum CA IX levels in non-metastatic or relapsed TGCT patients compared with healthy controls. There was no significant difference in the mean serum CA IX levels between different groups of patients and between the first and second cycle of chemotherapy, nor association with patients/tumor characteristics. Serum CA IX was not prognostic for progression-free survival [hazard ratio (HR)=0.81, P=0.730] or overall survival (HR=0.64, P=0.480). However, there was a significant association between intratumoral CA IX expression and serum CA IX concentration (rho=0.51, P=0.040). These results suggest that serum CA IX level correlates with tumor CA IX expression in TGCT patients, but fails to exhibit either a prognostic value or an association with patients/tumor characteristics.