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Background Germ cell tumors represent highly curable disease even in metastatic stage. However, poor-risk patients with an unfavorable serum tumor marker (STM) decline after the first cycle of chemotherapy represent a subgroup with dismal prognosis, with approximately 50% cure rate using bleomycin, etoposide, and cisplatin (BEP). Objective The aim of this study was to determine the efficacy and safety of paclitaxel, ifosfamide, and cisplatin (TIP) in this patient population. Design, setting, and participants This was an open-labeled, nonrandomized, single-center phase II trial to study the efficacy and toxicity of TIP in the first-line treatment of germ cell tumor patients with an unfavorable decline of STMs. Nineteen patients with a poor prognosis according to the International Germ Cell Cancer Collaboration Group classification and an unfavorable STM decline after the first cycle of chemotherapy were included in this phase II study (NCT02414685). The treatment regimen consisted of paclitaxel 250 mg/m2 on day 1, ifosfamide 1200 mg/m2 on days 1–5, and cisplatin 20 mg/m2 on days 1–5, totally for four cycles. Outcome measurements and statistical analysis The primary endpoint was complete response (CR) rate. An optimal Simon two-stage design was used with a type I error of 5% and study power of 80%. If fewer than six CRs to study therapy have been observed among the first 19 patients, the study was to be terminated. Results and limitations A CR was achieved in four (21.1%) patients; therefore, the study was terminated in the first stage. A favorable response rate (CR or partial remission with negative tumor markers) was observed in 14 (78.9%) patients. At a median follow-up period of 35.2 mo (range, 5.6–62.1 mo), ten (52.6%) patients experienced disease progression and eight patients (42.1%) died. The 2-yr progression-free and overall survival was 41.2% (95% confidence interval [CI] 16.8–65.7) and 72.7% (95% CI 48.9–96.4), respectively. TIP was well tolerated, and no unexpected toxicity was observed. No informative biomarkers, including miR-371a-3p was identified. Conclusions Treatment modification from the BEP to the TIP regimen in patients with an unfavorable STM decline after the first cycle of chemotherapy was not associated with improved outcome, and four cycles of BEP remain the standard treatment option in this patient population. Patient summary Poor-risk patients with an unfavorable serum tumor marker decline after the first cycle of chemotherapy represent a subgroup with dismal prognosis, with an approximately 50% cure rate using bleomycin, etoposide, and cisplatin (BEP). Treatment modification from the BEP regimen to the paclitaxel, ifosfamide, and cisplatin regimen in patients with an unfavorable serum tumor marker decline after the first cycle of chemotherapy was not associated with improved outcome, and four cycles of BEP remain the standard treatment option in this patient population., Take Home Message Poor-risk patients with an unfavorable serum tumor marker (STM) decline after the first cycle of chemotherapy represent a subgroup with dismal prognosis, with approximately 50% cure rate using bleomycin, etoposide, and cisplatin (BEP). The aim of this study was to determine the efficacy and safety of paclitaxel, ifosfamide, and cisplatin (TIP) in this patient population. Treatment modification from the BEP to the TIP regimen in this patient population was not associated with an improved outcome, and four cycles of BEP remain the standard treatment option in this group of patients.

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.

The treatment of testicular cancer includes unilateral orchiectomy and chemotherapy and is curative for most patients. However, observational studies revealed an association with depression, anxiety and cognitive impairment. It is unclear whether these side effects are caused by chemotherapy, hemicastration or the disease itself. The aim of our study was to analyse the behavioural effects of hemicastration and chemotherapy in adult male mice. The animals were randomly divided into four groups – control, chemotherapy, hemicastration and hemicastration with chemotherapy. After chemotherapy that included three cycles of bleomycin, etoposide, cisplatin mice underwent a battery of behavioural tests. To assess the long-term effects animals were tested also 3 months after the end of treatment. Chemotherapy led to lower locomotor- and exploratory activity, higher anxiety-like behaviour and worse spatial memory immediately after treatment. These behavioural effects were not present three months later. Hemicastration had no effect on most of the observed outcomes. In conclusion, adverse behavioural effects induced by chemotherapy in mice are transient and disappear later in life. Further studies are needed to elucidate the mechanisms responsible for the observed effects.

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.

Background Translocation renal cell carcinoma (TRCC) is a rare form of RCC affecting mostly children and young adults with the occurrence of only 1-5% of all renal cell carcinomas. These carcinomas are associated with different translocations on a short arm of chromosome X in the region 11.2, which results in genetic modification of the p arm containing the transcription factor E3 gene. Methods Herein we report a case of a patient who was dia-gnosed with TRCC with c-Met overexpression and was treated with multiple targeted therapy agents and immunotherapy. Case A 28-year old woman without a significant past medical history underwent left sided total nephrectomy for TRCC. Seven months later, she developed systemic relapse and was treated with multiple lines of targeted therapy including sunitinib, everolimus, sorafenib, crizotinib, and pazopanib as well as with anti-PD-L1 antibody nivolumab, with stable disease as a best response. The most pronounced disease stabilization was achieved with sorafenib, which lasted 18 months. The patient died 81 months after initial dia-gnosis and 74 months from the dia-gnosis of metastatic disease. Conclusion Improved survival observed in our patient could be related to the effectivity of tyrosine-kinase inhibitors, but notm-TOR inhibitors, even though disease stabilisation was observed as a best response. Identification of new treatment targets are warranted in this rare disease.

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 The use of immune checkpoint inhibitors has dramatically improved the prognosis of many cancer patients. However, their increasing use has also revealed several unexpected side effects - including cardiovascular complications. Increased attention was paid to them in recent years only, especially due to their potentially fatal character. Checkpoint inhibitors cardiotoxicity includes myocarditis, rhythm disorders (atrioventricular blocks, atrial and ventricular arrhythmias), pericarditis, myocardial infarction, left ventricular dysfunction/heart failure, dilated cardiomyopathy, cardiogenic shock and sudden cardiac death. The risk of ICI-associated cardiotoxicity is increased in patients treated with dual immune therapy, in combination with other cardiotoxic drugs, with preexisting cardiac damage, diabetes mellitus, underlying autoimmune disease and some other factors. Currently, there are no guidelines for prediction and management of ICI-associated cardiotoxicity. Purpose Herein, we briefly summarize the findings regarding checkpoint inhibitor-induced cardiotoxicity and provide a new definition of anti-tumor-induced myocarditis together with a suitable design for immune- induced myocarditis management prepared by experts from the field of cardiooncology.

BACKGROUND Primary squamous cell carcinomas (SCC) of the colon are extremely rare and occur predominantly in the fifth decade of life, with a slight prevalence in men. The most common anatomical sites are the rectum and the proximal colon. Clinical signs and common dia-gnostic methods cannot clearly distinguish SCC from adenocarcinoma. METHODS In this case report, we present a case of a 68-year-old patient with SCC of the cecum and colon ascendens, who was treated with resection and systemic gemcitabine- and cisplatin-based chemotherapy. RESULTS A 68-year-old patient underwent right-sided hemicolectomy for cecal and colon ascendens tumor, histologically poorly differentiated epidermoid carcinoma, grade 3 with an initial stage of pT4aN1aM0. Due to local recurrence at the resection site with suspected infiltration of straight and oblique abdominal muscles, he was treated with systemic gemcitabine and cisplatin based chemotherapy with partial remission. Subsequently, the postchemotherapeutic residual tumor was radically resected, achieving complete remission of the disease, which persists for 10 months after the surgery. CONCLUSION The case emphasizes the need for a multidisciplinary treatment approach of this rare disease. Early surgery plays a key role. Although the standard chemotherapy regimen is not well defined, the use of a combination of cisplatin and gemcitabine resulted in partial remission in our patient, which in turn allowed a radical resection of the relapse and subsequently achieved complete remission of the disease.

Testicular germ cell tumors (TGCTs) are malignancies with very high curative potential even in metastatic settings, mainly due to the introduction of cisplatin in the treatment of this disease. However, in a group of patients with cisplatin-refractory disease or with progressive disease despite high-dose salvage chemotherapy treatment, the prognosis is typically dismal. The triple combination of gemcitabine, oxaliplatin, and paclitaxel (GOP) has reasonable efficacy and is considered to be standard care for this group of patients. It remains to be seen, however, whether refractory TGCTs may represent a potential target for immune checkpoint inhibition. This review will focus on the rationale of the use of immunotherapy for platinum-refractory TGCTs and summarize data reporting experiences with immune checkpoint inhibitor treatment for this malignancy.

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.

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 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.

Cisplatin resistance in testicular germ cell tumors (TGCTs) is a clinical challenge. We investigated the underlying mechanisms associated with cancer stem cell (CSC) markers and modalities circumventing the chemoresistance. Chemoresistant models (designated as CisR) of human embryonal carcinoma cell lines NTERA-2 and NCCIT were derived and characterized using flow cytometry, gene expression, functional and protein arrays. Tumorigenicity was determined on immunodeficient mouse model. Disulfiram was used to examine chemosensitization of resistant cells. ALDH1A3 isoform expression was evaluated by immunohistochemistry in 216 patients&rsquo, tissue samples. Chemoresistant cells were significantly more resistant to cisplatin, carboplatin and oxaliplatin compared to parental cells. NTERA-2 CisR cells exhibited altered morphology and increased tumorigenicity. High ALDH1A3 expression and increased ALDH activity were detected in both refractory cell lines. Disulfiram in combination with cisplatin showed synergy for NTERA-2 CisR and NCCIT CisR cells and inhibited growth of NTERA-2 CisR xenografts. Significantly higher ALDH1A3 expression was detected in TGCTs patients&rsquo, tissue samples compared to normal testicular tissue. We characterized novel clinically relevant model of chemoresistant TGCTs, for the first time identified the ALDH1A3 as a therapeutic target in TGCTs and more importantly, showed that disulfiram represents a viable treatment option for refractory TGCTs.

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

BACKGROUND Growing teratoma syndrome (GTS) is an uncommon clinical finding in patients treated for testicular cancer. It is diagnosed during or after chemotherapy as an expanding tumour mass not responding to the treatment while the serum tumour markers are within the normal range. Pathological evaluation of resected tissue confirms the structures of benign mature teratoma. CASE Authors report a case of metastatic germ cell testicular cancer treated with 2 lines of chemotherapy and everolimus, that had finally been subjected for the resection of voluminous metastatic masses. We give a brief overview of current records concerning clinical management of GTS, and support the major role of surgical treatment in GTS. RESULTS Patient with metastatic mixed germ cell tumour of testis underwent a radical orchiectomy and completed the 1st line treatment with BEP (bleomycin, etoposide, cisplatin) regimen. Radiographic restaging showed considerable disease progression to the retroperitoneum and supraclavicular lymph nodes. Second-line treatment with VIP (etoposide, ifosfamide, cisplatin) did not reverse the progression and the patient was consulted at our institute. Following the enrolment to the clinical study with everolimus, the patient exhibited continual metastatic growth in contrast to serum markers decrease. GTS was confirmed after resection of enormous retroperitoneal tumour mass, as well as from the specimen obtained from the subsequent supraclavicular and hepatal metastasectomy. The patient attained complete remission and has been closely observed over the last 31 months since the last surgery. CONCLUSION GTS is resistant to chemotherapy and radiation and complete surgical resection results in excellent disease control. Clinicians should be aware of this infrequent presentation of testicular tumours, to ensure the timely diagnosis and the appropriate surgical removal without any delay. Despite the great extent and vital vasculature encasement, surgery may be feasible and successful, as we report in our case, consistently with the published data.

Background: Leptomeningeal metastasis (LM) in breast cancer is associated with poor prognosis. Although no randomised trial has demonstrated that intrathecal chemotherapy prolongs survival this treatment is considered standard of care in this setting. Prognosis of patients with LM is poor, with median overall survival less than 6 months. Methods: Herein, we report a case of young woman with breast cancer presented with leptomeningeal metastasis at the time of relapse and subsequently treated with two lines of intrathecal chemotherapy with prolonged survival. Results: A 28-year old woman without significant past medical history was diagnosed with triple-negative invasive ductal carcinoma. Eight months after adjuvant treatment she developed multiple brain metastases and subsequently one months after finishing whole brain irradiation, LM developed. Initially, she was treated with combination of methotrexate, cytarabine and dexamethasone intrathecally but after 3 months the patient was presented with worsening of clinical status and increased of cancer cells in CSF. Subsequently, she received combination of thiotepa and methotrexate intrathecally with prolonged response lasting for 10 months. Patient died 32 months after initial diagnosis and 18 months from LM infiltration due to disease progression in the liver and lungs as well as in LM. Conclusions: Prognosis of patients with LM remains poor because of the limited effectiveness of the currently available agents used in intrathecal therapies, however, intrathecal chemotherapy could substantially prolong survival in selected patients Key words: Leptomeningeal metastasis, breast cancer, intrathecal treatment, thiotepa.

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 Epithelioid angiomyolipoma (EAML) of the kidney, in contrast to classic benign renal angiomyolipoma, is a rare mesenchymal neoplasm with malignant potential. Represent-ing a member of the perivascular epithelioid cells (PEComa) tumor family aris-ing from the perivascular epithelioid cells, its accurate dia-gnosis and therapeutic approach remains challenging. Methods We report a case of a patient with malignant EAML, initially treated as renal cell carcinoma (RCC) at our institution. In this paper, we briefly summarize current status of clinical and histopathological knowledge of renal PEComas with metastatic potential and reconsider the dia-gnostic and therapeutic approach in this particular case to highlight the risk of mis-dia-g----nosis, malignant potential of renal PEComas and to demonstrate an unexpected treatment response. Results The patient in our case was dia-gnosed with chromophobe RCC with sarcomatoid features. She underwent a radical nephrectomy and epinephrectomy with a satisfactory postoperative history. Local recurrence urged chemother-apy commencement with sunitinib in the first line, and shortly afterwards, the patient was enrolled in a clinical trial with everolimus, with an extraordinary favorable treatment response for 30 months. Follow-ing the extirpation of single abdominal nodularity after 36 months of treatment with mTOR inhibitor, and proceed-ing the everolimus administration, the dis-ease slowly progressed to the right liver lobe, result-ing in right hemihepatectomy in another 24 months. The immunoprofile of liver metastases with positive stain-ing of melanoma markers and smooth muscle markers induced the revaluation of the primary tumor and abdominal nodularity specimen to an invasive EAML of the kidney. Further dis-ease progression was unavoidable despite several chemother-apy regimens, and the patient died 104 months after primary dia-gnosis. Conclusions Renal tumors with adverse radiographic and histopathological features should become candidates for immunohistochemical stain-ing as its omission frequently leads to a misdia-gnosis, as showed in our case report. Atypical treatment response might suggest a possibility of a diagnostic mistake and should lead to reevaluation of the diagnostic and treatment process in the particular patient. Key words: renal PEComa - epithelioid angiomyolipoma - dia-gnosis - everolimus.

e17010 Background: Germ cell tumors (GCTs) represent a highly curable cancer. However, a small proportion of patients with super-high-risk characteristics can develop choriocarcinoma syndrome (CS) connected with acute respiratory distress syndrome (ARDS). CS is defined as a syndrome with hemorrhage from metastatic sites in patients with advanced GCTs with high-volume of choriocarcinoma elements, especially those with a choriogonadotropin level over 50,000 IU/l. CS typically develop shortly after the chemotherapy start with high mortality rate. Our retrospective study aimed to determine the risk factors of high-risk GCTs susceptible to CS development. Methods: Using a computerized database and a systematic chart review, we identified the records of 532 patients with GCTs treated in NCI through 2000 to 2018, and 90 eligible patients with high-risk GCTs relying on IGCCCG classification, were identified. All patients were treated with platinum-based induction chemotherapy. Clinicopathological variables were collected and analyzed in correlation to CS development. Results: Nine (10 %) of 90 patients developed CS in a median of 1 day (1- 9 days) after the chemotherapy administration. All patients died shortly after the chemotherapy start with median of 4 days (3-35 days) due to consecutive ARDS development. Predictive factors for CS development were metastatic lung involvement ≥50% of lung parenchyma, choriocarcinoma elements in histology specimen, dyspnea, cough, hemoptysis, ECOG PS ≥2, weight loss and hemoglobin ≤100 g/l at the time of presentation. In multivariate analysis, ECOG PS ≥2 and metastatic lung involvement ≥50% were independently associated with CS. All patients with these two characteristics developed CS compared to 0% with one or zero of these predictive factors (P < 0.000001). Conclusions: In our study we identified predictive factors for CS development. These factors might improve the risk stratification of the patients susceptible to CS development connected with ARDS as well as to find optimal treatment approach for them.

// 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

e17056 Background: Testicular germ cell tumors (GCTs) represent only one percent of all solid tumors; however, they are the most common solid malignancy in men 15-35 years old. Febrile neutropenia (FN) is a grievous complication of chemotherapy, frequently occurring in GCT patients. The aim of this retrospective study was to assess the effect of primary granulocyte-colony stimulating factor (G-CSF) prophylaxis on the incidence of FN in GCT patients. Methods: This study was conducted using the National Cancer Institute medical records database. Patients diagnosed with germ cell tumors treated with first line/adjuvant chemotherapy at the National Cancer Institute, Bratislava, Slovakia from January 2000 to December 2017 were eligible. Starting in January 2006, patients received G-CSF prophylaxis after every cycle of chemotherapy. Results: Out of 393 patients, 265 patients received primary G-CSF prophylaxis and 128 patients did not receive prophylaxis. The majority of patients (69.97%) were treated with bleomycin, etoposide and cisplatin chemotherapy. There were 61 deaths (15.5%) in our study population. 2- and 5-year OS of the study group was 86.8% and 83.1%, respectively. During the study period, 71 patients (18.1%) suffered FN events. Out of 128 patients who did not receive primary prophylaxis, 42 (32.8%) patients suffered FN, while only 29 (10.9%) patients with primary prophylaxis suffered FN ( P = 0.0000001). On subgroup analysis, FN incidence decreased in all groups with primary prophylaxis, except for patients with stage I GCT receiving adjuvant chemotherapy. Patients receiving G-CSF prophylaxis had significantly longer overall survival when compared to patients without prophylaxis. (HR = 0.44, 95% CI 0.26-0.75; P = 0.0009). Conclusions: Primary G-CSF prophylaxis was associated with significantly decreased FN incidence and longer overall survival in patients treated with first line chemotherapy and should be consider in all patients except stage I disease.

e17062 Background: Treatment for testicular germ cell tumors (GCTs) results in late chemotherapy-induced peripheral neuropathy (CIPN). This study aimed to evaluate impact of curative treatments on different subtypes of self-reported peripheral nerve damage. Methods: GCT survivors (N = 186) followed-up annually at National Cancer Institute in Slovakia have prospectively completed European Organisation for Research and Treatment of Cancer (EORTC) CIPN20 questionnaire at 10 years of median follow-up (range 4-25). EORTC CIPN20 scoring allowed to obtain subscales on sensory function, motor function and autonomy function as well as an overall score. Study groups consisted of survivors treated with chemotherapy (N = 141) and radiotherapy to the retroperitoneum (N = 15). The control group consisted of survivors cured with orchiectomy alone (N = 30) Results: GCT survivors cured with chemotherapy reported higher impairment in overall peripheral neurological function compared to controls (mean score ± SEM: 24.2 ± 0.5 vs. 22.3 ± 1.1, P = 0.03). CIPN20 subscales have shown greater impairment in motor function (P = 0.04), but not in sensory/autonomy functions (both P > 0.05) in chemotherapy group versus controls. Survivors treated with BEPx3 or EPx4 reported similar CIPN in all subscales (all P > 0.05). Motor function was worse in survivors who received ³400mg/m2 of cisplatin compared to ones who received < 400mg/m2 (mean score ± SEM: 9.5 ± 0.2 vs. 8.9 ± 0.3, P = 0.04). Interestingly, patients treated with radiotherapy to the retroperitoneum (but not with chemotherapy) suffered from significantly more peripheral neuropathy in all measured domains compared to the controls (all P < 0.02) Conclusions: Evaluation of long-term perceived peripheral neuropathy after treatment for GCT has shown primarily motor function impairment after chemotherapy. Moreover, significant peripheral neuropathy in all observed CIPN20 subscales after radiotherapy to the retroperitoneum suggests this symptom is not exclusive to cisplatin-based chemotherapy.

411 Background: Germ cell tumors (GCTs) represent a highly curable disease; however, a small proportion of patients with super-high-risk characteristics (choriocarcinoma, massive lung metastases, choriogonadotropin > 50 000 mIU/ml) can develop choriocarcinoma syndrome (CS) and consecutive acute respiratory distress syndrome (ARDS) shortly after the chemotherapy start with high mortality rate. This study aimed to evaluate biomarkers of lung damage as predictive biomarkers for ARDS development within CS in poor-risk GCTs patients. Methods: This study included 23 poor-risk GCTs treated from November 2000 to May 2018 in National Cancer Institute in Slovakia for whom plasma samples before chemotherapy initiation were available. Plasma levels of lung damage biomarkers (surfactant protein (D-SPD), receptor of advanced glycation end-products (sRAGE), and club cell secretory protein – (CC16)) were evaluated by ELISA assays. Results: Five (22%) of 23 patients developed CS, and all of them died shortly after the chemotherapy start. with median of 7 days (4 - 35 days). Four of them developed ARDS within CS, while one patient died due to massive abdominal hemorrhage. Pre-treatment levels of s-RAGE and SPD but not CC-16 were significantly associated with CS development ( P = 0.03 and P = 0.04). Level of sRAGE and SPD correlated significantly with dyspnea, weight loss, extent of metastatic lung involvement and need of mechanical ventilation after chemotherapy start, as well as with PFS and OS, while CC-16 did not correlate with any of these factors. Conclusions: In this study we identified new predictive biomarkers for CS development in poor-risk GCTs. Abovementioned factors might help to improve the risk stratification of these patients with GCTs as well as discover new treatment approaches preventing ARDS development within CS which may result in enhanced treatment outcome.

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.

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.

e16020 Background: Cisplatin-based combination chemotherapy is used as a standard neoadjuvant treatment of patients with muscle-infiltrating urothelial bladder carcinoma (MIUBC). DNA damage represents one of the most important factors contributing to its toxicity. The objective of this prospective study is to evaluate the prognostic value of the endogenous DNA damage level in peripheral blood mononuclear cells (PBMCs) from MIUBC patients before treatment with neoadjuvant chemotherapy. Methods: PBMCs isolated from 25 consecutive MIUBC patients (16 men, 64%) were included into this study. Karnofsky index < 80% was present in 1 patient (4%). DNA damage levels in PBMCs were evaluated by the Comet assay and scored as percentage of DNA in tail by the Metafer-MetaCyte analyzing software. Cut-off of 5.25 was used to dichotomize DNA damage level as “high” or “low” based on the previous study. Results: At the median follow-up 12.1 months, 13 patients progressed (52%) and 8 patients (32%) died. The median and IQR (interquartile range) of endogenous DNA damage level was 7.52 (4.07-27.9). Patients with low DNA damage levels had non-significantly better progression free survival (HR = 0.33, 95% CI: 0.09-1.29) and overall survival (HR = 0.64, 95% CI: 0.11-3.87) compared to patients with high DNA damage levels. Conclusions: These data suggest that endogenous DNA damage levels in PBMCs from MIUBC patients may serve as a prognostic marker early identifying patients with poor outcome. This study is supported by VEGA 2/0053/19 and APVV-17-0384.

There is a new era of treatment options since introduction of new biological targeted therapies (tyrosine kinase inhibitors (TKIs) and mammalian target of rapamycin (mTOR) inhibitors) in renal cell cancer. However, in patients who developed brain metastases, there is still treatment dilemma about an optimal therapeutic scenario, particularly in the subgroup of patients with-out disease progression outside the central nervous system. The objective of this case report is to present that it is possible to continue the same targeted therapy after development of brain metastasis after application of local whole brain irradiation with meaningful overall survival.