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Young oncologists around the globe face many challenges when it comes to their career and professional development. Aspects such as time management, work-life balance, career progression, and educational opportunities are only some of them. Professional societies have identified these challenges in this professional group and designed programs to tackle them specifically. The importance of this strategy cannot be overstated, as young oncologists, defined by most societies as oncologists under 40 years of age, compose almost 50% of the oncology workforce. On the other hand, recent surveys have shown that many young oncologists are considering alternative career paths due to burnout issues aggravated by the COVID-19 pandemic, on top of all other challenges. The virtual setting that has been forcedly introduced into our professional life has shortened distances between professionals and might have contributed to more accessible access to information and opportunities that some young oncologists could not profit from due to their traveling constraints. On the other hand, this virtual setting has shown us the asymmetries in opportunities for these professionals. Knowledgeable of all this, we summarize in this article some of the career and professional development offers available to all young oncologists, which we consider could help them deal with current and future challenges.

Zusammenfassung Hintergrund Keimzelltumoren des Hodens sind die häufigste maligne Tumorerkrankung bei Männern im Alter von 15–40 Jahren. Die Unterscheidung von Seminomen und Nichtseminomen hat prognostische Bedeutung und ist für Therapieplanung und Nachsorge essenziell. Durch interdisziplinäre, stadiengerechte Therapie haben Keimzelltumoren generell eine sehr gute Prognose. Eine Übertherapie sollte wegen möglicher Langzeitfolgen vermieden werden. Hierbei hilft die Risikobeurteilung anhand klinischer und pathologischer Faktoren. Ziel der Arbeit Darstellung der (histo-)pathologischen Charakteristika, die die uroonkologische Therapieplanung maßgeblich beeinflussen. Material und Methoden Nichtsystematischer Übersichtsartikel über die relevanten (histo-)pathologischen Befunde für die klinische Therapieplanung im interdisziplinären Kontext. Ergebnisse Zentrale Pathologiebefunde für Kliniker:Innen sind: (i) Identifikation eines Keimzelltumors, ggf. durch Nachweis eines Chromosom-12p-Zugewinns, (ii) Subtypenspezifizierung und (iii) Angabe von Risikofaktoren (insbesondere Invasion von Lymphgefäßen und/oder Rete testis und Tumorgröße). Molekularpathologische Untersuchungen i. S. von Mutationsanalysen sind angesichts einer sehr geringen Mutationslast und bislang fehlender prädiktiver Marker und zielgerichteter Therapieoptionen nicht Teil der Routinediagnostik. Diskussion Ein detaillierter, idealerweise synoptischer histopathologischer Befundbericht ist Grundlage der Planung und Durchführung einer leitlinienkonformen, risikoadaptierten Therapie und neben der bildgebenden Diagnostik und der Bestimmung der Serumtumormarker AFP und β‑HCG (letztere insbesondere bei Nichtseminomen) mitentscheidend, um die guten Heilungsaussichten zu wahren und eine Übertherapie zu vermeiden.

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

Context: Each year the European Association of Urology (EAU) produce a document based on the most recent evidence on the diagnosis, therapy, and follow-up of testicular cancer (TC). Objective: To represent a summarised version of the EAU guidelines on TC for 2023 with a focus on key changes in the 2023 update. Evidence acquisition: A multidisciplinary panel of TC experts, comprising urologists, medical and radiation oncologists, and pathologists, reviewed the results from a structured literature search to compile the guidelines document. Each recommendation in the guidelines was assigned a strength rating. Evidence synthesis: For the 2023 EAU guidelines on TC, a review and restructure were undertaken. The key changes incorporated in the 2023 update include: new supporting text regarding venous thromboembolism prophylaxis in males with metastatic germ cell tumours receiving chemotherapy; quality of life after treatment; an update of the histological classifications and inclusion of the World Health Organization 2022 pathological classification; inclusion of the revalidation of the 1997 International Germ Cell Cancer Collaborative Group prognostic risk factors; and a new section covering oncology treatment protocols. Conclusions: The 2023 version of the EAU guidelines on TC include the highest available scientific evidence to standardise the management of TC. Better stratification and optimisation of treatment modalities will continue to improve the high survival rates for patients with TC. Patient summary: This article presents a summary of the European Association of Urology guidelines on testicular cancer published in 2023 and includes the latest recommendations for management of this disease. The guidelines are a valuable resource that may help patients in understanding treatment recommendations.

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

High-dose chemotherapy (HD-Cx) in refractory germ cell cancer (GCC) is effective but limited data are available concerning the optimal approach for stem cell mobilization (SCM) in these patients. In this analysis 102 patients undergoing SCM during first (n = 25) or subsequent treatment lines (n = 77) were analyzed. Subcutaneous injections of granulocyte colony-stimulating factor (G-CSF) were given once daily (group 1) in 52 patients (51%), twice daily (group 2) in 39 patients (38%) or one injection Pegylated-G-CSF (PegG-CSF) (group 3) in eleven patients (11%) after one cycle of mobilization chemotherapy. Plerixafor was administered 13 times in group 1, seven times in group 2 and once in group 3. Overall, 77 (75%) patients achieved successful SCM defined as ≥8*106 CD34+ cells/kg body weight for three consecutive HD-Cx plus one backup dose. In group 1, 40 of 52 patients (77%) achieved successful SCM with a median of 11 G-CSF injections, in group 2, 27 of 39 patients (69%) with a median of 14 G-CSF injections and in group 3, 10 of 11 patients (91%) with one injection of PegG-CSF. SCM was more successful if conducted during first-line chemotherapy (p = 0.016) and associated with a beneficial outcome concerning overall survival (p = 0.02) if performed satisfactorily.

Purpose To report on the clinical characteristics, outcome, and frequency of peritoneal carcinosis (PC) in patients with advanced germ cell tumors (GCT), a multicenter registry analysis was carried out. Methods A multicenter registry analysis was conducted by the German Testicular Cancer Study Group (GTCSG) with international collaborators. Data was collected and analyzed retrospectively. Patients were eligible for inclusion if PC was diagnosed either by radiologic or histopathologic finding during the course of disease. Descriptive and explorative statistical analysis was carried out with cancer-specific survival (CSS) as primary study endpoint. Results Collaborators from ten GCT expert centers identified 28 GCT (0.77%) patients with PC after screening approximately 3767 GCT patient files and one case was contributed from a cancer registry request. Patients were diagnosed from 1997 to 2019 at a median age of 37 years (interquartile range, 13). Two patients (7%) presented with stage I and 27 patients (93%) with synchronous metastatic disease at first diagnosis. The primary histology was seminoma in seven (27%) and non-seminoma in 21 patients (72%). PC was detected after a median of 15.3 months from primary diagnosis (range 0–177) and two consecutive treatment lines (range 0–5), respectively. The median CSS from the time of detection of PC was 10.5 months (95%Confidence Interval 0.47–1.30) associated with an overall 2-year CSS rate of 30%. Conclusion PC represents a rare tumor manifestation in GCT patients and was primarily associated with the occurrence of advanced cisplatin-refractory disease conferring to a dismal prognosis.

AIMS Primary mediastinal germ cell tumours (PMGCTs) are rare mediastinal neoplasms, and their diagnosis can be challenging, owing to small biopsy samples. The aim of this study was to develop a diagnostic algorithm using immunohistochemical staining, with a focus on novel markers, and molecular analysis of isochromosome 12p [i(12p)]. METHODS AND RESULTS Paraffin-embedded tissues of 32 mediastinal tumours were analysed with immunohistochemical staining for sal-like transcription factor 4 (SALL4), Lin-28 homologue A (LIN28), octamer-binding transcription factor 3/4 (OCT3/4), D2-40, cluster of differentiation 117 (CD117), sex-determining region Y-box 17, sex-determining region Y-box 2 (SOX2), cluster of differentiation 30, the β-subunit of human chorionic gonadotropin (β-hCG), GATA-binding protein 3 (GATA3), forkhead box protein A2 (FOXA2), glypican-3 (GPC3), α-fetoprotein (AFP), terminal deoxynucleotidyl transferase (TdT), nuclear protein of the testis (NUT), and pan-cytokeratin. Quantitative real-time polymerase chain reaction was performed to investigate the i(12p) status. Fifteen seminomas, seven teratomas, one yolk sac tumour, one choriocarcinoma and seven mixed PMGCTs were diagnosed. Each entity had different immunohistochemical staining patterns, which helped to distinguish them: OCT3/4, D2-40, CD117 and TdT for seminoma; OCT3/4 and SOX2 for embryonal carcinoma; FOXA2, GPC3 and AFP for yolk sac tumour; and β-hCG and GATA3 for choriocarcinoma. Mature teratomas stained positively for pan-cytokeratin in epithelial components and focally for SALL4, SOX2, GATA3, D2-40, and FOXA2. Furthermore, a NUT carcinoma mimicking a PMGCT was diagnosed, showing strong nuclear SOX2 staining and speckled nuclear NUT staining. i(12p) was detected in 24 of 27 PMGCTs (89%). CONCLUSION A diagnostic algorithm is of great importance for a reliable diagnosis of PMGCT in, usually small, tissue biopsy samples. Therefore, a combination of three to four antibodies to identify the correct histological subtype is usually necessary, in addition to morphological features. The i(12p) status serves as an additional option to indicate a germ cell origin in selected cases.

Purpose The prognostic significance of lactate dehydrogenase (LDH) in patients with metastatic seminoma is not defined. We investigated the prognostic impact of LDH levels prior to first-line systemic treatment and other clinical characteristics in this subset of patients. Methods Files from two registry studies and one single-institution database were analyzed retrospectively. Uni- and multivariate analyses were conducted to identify patient characteristics associated with recurrence free survival (RFS), overall survival (OS), and complete response rate (CRR). Results The dataset included 351 metastatic seminoma patients with a median follow-up of 5.36 years. Five-year RFS, OS and CRR were 82%, 89% and 52%, respectively. Explorative analysis revealed a cut-off LDH level of n = 228) vs. ≥ 2.5 ULN (n = 123) to be associated with a significant difference concerning OS associated with 5-years OS rates of 93% vs. 83% (p = 0.001) which was confirmed in multivariate analysis (HR 2.87; p = 0.004). Furthermore, the cut-off LDH p = 0.012) and 32% vs. 59% (p ≤ 0.001), respectively. Conclusions LDH levels correlate with treatment response and survival in metastatic seminoma patients and should be considered for their prognostic stratification.

Testicular germ cell tumours (GCTs) are the most frequent solid malignancy in younger males aged 15-40. The differentiation between seminomas and non-seminomas impacts prognosis, clinical management and follow-up procedures. With stage- and risk-adapted multimodal treatment approaches, GCTs have an exceptionally good prognosis. Therefore, avoiding overtreatment to reduce treatment-related long-term side effects is of utmost importance. Clinical and histopathological risk factors aid in treatment decision-making.Discussion of (histo-)pathological characteristics that directly influence treatment decision-making by urologists and oncologists.Non-systematic literature review to describe histopathological features for interdisciplinary treatment planning.Key histopathological characteristics for clinicians are: (i) identification of a GCT, if necessary by 12p aberration analysis, (ii) description of the different subtypes, and (iii) risk factors, including lymphovascular invasion and/or rete testis infiltration and size of the primary tumour. Molecular pathological analyses, that is, genomic sequencing, is not part of routine diagnostics due to the lack of prognostic/predictive markers and effective targeted treatment approaches.Detailed histopathology reporting, ideally with a synoptic template, is the basis for planning and conducting guideline-endorsed, risk-adapted, multi-disciplinary management of GCTs. Along with radiographic imaging and assessment of the serum tumour markers AFP and β‑HCG (especially in non-seminomas), histopathology is crucial to maintain success and reduce the burden of GCT treatment.HINTERGRUND: Keimzelltumoren des Hodens sind die häufigste maligne Tumorerkrankung bei Männern im Alter von 15–40 Jahren. Die Unterscheidung von Seminomen und Nichtseminomen hat prognostische Bedeutung und ist für Therapieplanung und Nachsorge essenziell. Durch interdisziplinäre, stadiengerechte Therapie haben Keimzelltumoren generell eine sehr gute Prognose. Eine Übertherapie sollte wegen möglicher Langzeitfolgen vermieden werden. Hierbei hilft die Risikobeurteilung anhand klinischer und pathologischer Faktoren.Darstellung der (histo-)pathologischen Charakteristika, die die uroonkologische Therapieplanung maßgeblich beeinflussen.Nichtsystematischer Übersichtsartikel über die relevanten (histo-)pathologischen Befunde für die klinische Therapieplanung im interdisziplinären Kontext.Zentrale Pathologiebefunde für Kliniker:Innen sind: (i) Identifikation eines Keimzelltumors, ggf. durch Nachweis eines Chromosom-12p-Zugewinns, (ii) Subtypenspezifizierung und (iii) Angabe von Risikofaktoren (insbesondere Invasion von Lymphgefäßen und/oder Rete testis und Tumorgröße). Molekularpathologische Untersuchungen i. S. von Mutationsanalysen sind angesichts einer sehr geringen Mutationslast und bislang fehlender prädiktiver Marker und zielgerichteter Therapieoptionen nicht Teil der Routinediagnostik.Ein detaillierter, idealerweise synoptischer histopathologischer Befundbericht ist Grundlage der Planung und Durchführung einer leitlinienkonformen, risikoadaptierten Therapie und neben der bildgebenden Diagnostik und der Bestimmung der Serumtumormarker AFP und β‑HCG (letztere insbesondere bei Nichtseminomen) mitentscheidend, um die guten Heilungsaussichten zu wahren und eine Übertherapie zu vermeiden.

Purpose: Radiation therapy is a possible treatment strategy for patients with testicular seminoma after orchiectomy in clinical stage I or II disease. Little is known about the outcome of patients who experience a relapse after radiation therapy. ----- Methods and materials: Data from 61 patients who relapsed after adjuvant or curative radiation therapy from 17 centers in 11 countries were collected and retrospectively analyzed. Primary outcomes were disease-free and overall survival. Secondary outcomes were time to relapse, stage at relapse, treatment for relapse, and rate of febrile neutropenia during chemotherapy for relapse. ----- Results: With a median follow-up of 9.9 years (95% confidence interval [CI], 7.5-10.9), we found a 5-year disease-free survival of 90% (95% CI, 79-95) and a 5-year overall survival of 98% (95% CI, 89-100). Sixty-six percent of patients had stage III disease at time of relapse and 93% of patients fell into the good prognosis group per the International Germ Cell Cancer Collaborative Group classification. The median time to relapse after radiation therapy was 15.6 months (95% CI, 12-23). Twenty-two (36%) patients relapsed more than 2 years after radiation therapy and 7 (11.5%) patients relapsed more than 5 years after radiation therapy. One-third of relapses was detected owing to patients' symptoms, whereas two-thirds of relapses were detected during routine follow-up. The majority (93%) of cases were treated with cisplatin-based chemotherapy. The rate of febrile neutropenia during chemotherapy was 35%. Five patients experienced a second relapse. At last follow-up, 55 patients (90%) were alive without disease. Only 1 patient died owing to disease progression. ----- Conclusions: Cisplatin-based chemotherapy for patients with seminoma who have relapsed after treatment with radiation therapy alone leads to excellent outcomes. Patients and physicians should be aware of possible late relapses after radiation therapy.

Keimzelltumoren des Hodens sind die haufigste bosartige solide Tumorerkrankung bei Mannern bis zu 40 Jahren. Mit cisplatinbasierten Kombinationschemotherapien werden selbst bei metastasierter Erkrankung hohe Heilungsraten erreicht. Verbesserte Therapieoptionen im Rezidivfall haben die Heilungsaussichten weiter verbessert. Eine leitlinienkonforme, stadienadaptierte Therapiedurchfuhrung ist Grundvoraussetzung, um die exzellenten Heilungsaussichten zu wahren und Spatfolgen bei Keimzelltumoruberlebenden zu minimieren. Langzeitfolgen der Chemotherapie, insbesondere Sekundarmalignome, das metabolische Syndrom, Polyneuropathie, Nierenfunktionseinschrankungen, Hypogonadismus und psychosoziale Aspekte, mussen in der Nachsorge unbedingt beachtet werden. Zielgerichtete Therapiestrategien spielen bisher keine Rolle bei Hodentumoren. Insbesondere fortgeschrittene Erkrankungsstadien und Erkrankungsruckfalle sollten an Zentren mit Erfahrung im Management von Keimzelltumoren behandelt werden.

Primar mediastinale Keimzelltumoren entstehen im vorderen Mediastinum. Sie sind histologisch mit mannlichen Keimzelltumoren des Hodens identisch, weisen aber eine distinkte Biologie und eine schlechtere Prognose auf. Es wird ein Uberblick uber die biologischen Besonderheiten, prognostische Faktoren und das interdisziplinare Management mediastinaler Keimzelltumoren gegeben. Die vorliegende Ubersichtsarbeit beruht auf einer selektiven Datenbankrecherche in PubMed, MEDLINE und aktuellen Leitlinien. Primar mediastinale Seminome unterscheiden sich prognostisch und therapeutisch nicht von anderen fortgeschrittenen Seminomen mit intermediarem Risikoprofil gemas International Germ Cell Cancer Collaborative Group (IGCCCG). Nichtseminome im Mediastinum hingegen sind oft chemotherapieresistent und haben eine ungunstige Prognose. Zur Vermeidung pulmonaler Komplikationen wird fur die Erstlinie ein Verzicht auf Bleomycin zugunsten der Kombinationstherapie mit Cisplatin, Etoposid und Ifosfamid (PEI) empfohlen. Die deutsche S3-Leitlinie empfiehlt zudem den Einsatz einer primaren Hochdosischemotherapie (HD-PEI). Ferner sollten alle sichtbaren postchemotherapeutischen Residualtumoren reseziert werden. Histologisch finden sich in diesen Resektaten gehauft vitale Keimzelltumoranteile sowie reife Teratome, teils mit maligner somatischer Transformation. Bei einem Rezidiv trotz adaquater multimodaler Erstlinienbehandlung ist die Prognose sehr schlecht. Die Behandlung primar mediastinaler Keimzelltumoren ist eine klinische Herausforderung, und sollte ausschlieslich an Zentren mit ausgewiesener Keimzelltumorexpertise erfolgen.

Keimzelltumoren des Hodens sind auserordentlich gut heilbar und betreffen meist junge Manner im Alter ≤35 Jahren. Selbst metastasierte Patienten konnen durch multimodale, Cisplatin-basierte Therapiekonzepte zu ca. 70 % geheilt werden. Patienten, bei denen die Standardtherapie versagt, haben eine sehr ungunstige Prognose, weshalb neue Biomarker und Therapieoptionen dringend benotigt werden. Diskussion histopathologischer Informationen, die fur die Entscheidungsfindung der mit der Therapie von Keimzelltumoren befassten Urologen und Onkologen masgeblich sind. Narrative Ubersichtsarbeit zu Schlusselinformationen mannlicher Keimzelltumoren fur die klinische Entscheidungsfindung. Zentrale histopathologische Informationen sind insbesondere (i) die Zuordnung eines unklaren Tumorleidens zu einem Keimzelltumorursprung uber das Isochromosom 12p, (ii) die klare Benennung der verschiedenen Histologien und (iii) die Beurteilung von Risikofaktoren wie die Lymphangioinvasion oder Rete-testis-Infiltration. Der histopathologische Befund ist masgeblich fur die leitlinienkonforme, risikobasierte Therapieplanung und erfolgreiche -durchfuhrung und hilft die therapeutische Belastung und Langzeitfolgen zu reduzieren. Fur refraktare Keimzelltumoren sind bisher keine pradiktiven oder prognostischen Biomarker oder zielgerichtete Therapien verfugbar. Eine enge Interaktion und interdisziplinare Diskussion histopathologischer und radiologischer Befunde sowie etablierter Risikofaktoren wie Serumtumormarker ist entscheidend fur den Behandlungserfolg und eine Therapieintensivierung (sofern erforderlich) oder -deeskalation zur Vermeidung einer Ubertherapie (sofern moglich).

PURPOSE Cisplatin is the main systemic treatment modality for male type II germ cell tumors (GCTs). Although generally very effective, 5%-10% of patients suffer from cisplatin-resistant disease. Identification of the driving mechanisms of resistance will enable improved risk stratification and development of alternative treatments. METHODS We developed and characterized cisplatin-resistant GCT cell line models and compared their molecular characteristics with patient samples with cisplatin resistance and/or a poor clinical outcome. Subsequently, the association between the overlapping genetic features and clinical data was assessed. Finally, we used Cox regression to determine the prognostic relevance of these features within the currently used risk classification. RESULTS Gain of chromosome 3p25.3 was detected in all cisplatin-resistant cell lines, and copy number of this region correlated with the level of resistance (R = 0.96, P = 1.5e-04). Gain of this region was detected at low frequencies in primary tumors and at higher frequencies in relapsed and/or cisplatin-resistant tumors. Chromosome 3p25.3 gain was associated with shorter progression-free survival and overall survival, with the strongest association observed in nonseminomas excluding pure teratomas. 3p25.3 gain was more frequently observed in tumors with yolk sac tumor histology and predicted adverse outcome independent of the International Germ Cell Cancer Collaborative Group risk classification and the presence of TP53/ MDM2 alterations. CONCLUSION On the basis of both in vitro analyses and clinical data, we found 3p25.3 to be strongly associated with cisplatin resistance and poor clinical outcome in male type II GCTs. Using genomic profiling, 3p25.3 status could help to improve risk stratification in male patients with type II GCT. Further characterization of this locus and underlying mechanisms of resistance is warranted to guide development of novel treatment approaches for cisplatin-resistant disease.

Background The coronavirus disease 2019 (COVID-19) pandemic has become a public health emergency affecting frail populations, including patients with cancer. This poses the question of whether cancer treatments can be postponed or modified without compromising their efficacy, especially for highly curable cancers such as germ cell tumors (GCTs). Materials and Methods To depict the state-of-the-art management of GCTs during the COVID-19 pandemic, a survey including 26 questions was circulated by e-mail among the physicians belonging to three cooperative groups: (a) Italian Germ Cell Cancer Group; (b) European Reference Network–Rare Adult Solid Cancers, Domain G3 (rare male genitourinary cancers); and (c) Genitourinary Medical Oncologists of Canada. Percentages of agreement between Italian respondents (I) versus Canadian respondents (C), I versus European respondents (E), and E versus C were compared by using Fisher's exact tests for dichotomous answers and chi square test for trends for the questions with three or more options. Results Fifty-three GCT experts responded to the survey: 20 Italian, 6 in other European countries, and 27 from Canada. Telemedicine was broadly used; there was high consensus to interrupt chemotherapy in COVID-19–positive patients (I = 75%, C = 55%, and E = 83.3%) and for use of granulocyte colony-stimulating factor primary prophylaxis for neutropenia (I = 65%, C = 62.9%, and E = 50%). The main differences emerged regarding the management of stage I and stage IIA disease, likely because of cultural and geographical differences. Conclusion Our study highlights the common efforts of GCT experts in Europe and Canada to maintain high standards of treatment for patients with GCT with few changes in their management during the COVID-19 pandemic.

Background Germ cell tumors (GCTs) are developmental cancers, tightly linked to embryogenesis and germ cell development. The recent and expanding field of RNA modifications is being increasingly implicated in such molecular events, as well as in tumor progression and resistance to therapy, but still rarely explored in GCTs. In this work, and as a follow-up of our recent study on this topic in TGCT tissue samples, we aim to investigate the role of N6-methyladenosine (m6A), the most abundant of such modifications in mRNA, in in vitro and in vivo models representative of such tumors. Methods Four cell lines representative of GCTs (three testicular and one mediastinal), including an isogenic cisplatin resistant subline, were used. CRISPR/Cas9-mediated knockdown of VIRMA was established and the chorioallantoic membrane assay was used to study its phenotypic effect in vivo. Results We demonstrated the differential expression of the various m6A writers, readers and erasers in GCT cell lines representative of the major classes of these tumors, seminomas and non-seminomas, and we evidenced changes occurring upon differentiation with all-trans retinoic acid treatment. We showed differential expression also among cells sensitive and resistant to cisplatin treatment, implicating these players in acquisition of cisplatin resistant phenotype. Knockdown of VIRMA led to disruption of the remaining methyltransferase complex and decrease in m6A abundance, as well as overall reduced tumor aggressiveness (with decreased cell viability, tumor cell proliferation, migration, and invasion) and increased sensitivity to cisplatin treatment, both in vitro and confirmed in vivo. Enhanced response to cisplatin after VIRMA knockdown was related to significant increase in DNA damage (with higher γH2AX and GADD45B levels) and downregulation of XLF and MRE11. Conclusions VIRMA has an oncogenic role in GCTs confirming our previous tissue-based study and is further involved in response to cisplatin by interfering with DNA repair. These data contribute to our better understanding of the emergence of cisplatin resistance in GCTs and support recent attempts to therapeutically target elements of the m6A writer complex.

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

Background The microRNAs of the miR-371-3 cluster are novel serum markers for testicular germ cell tumors. Sporadic reports suggested the expression of this miRNA in semen. Objectives To verify the expression of miR-371a-3p in seminal plasma and unprocessed ejaculate; to compare seminal plasma miRNA levels in germ cell tumors patients with those of controls; to look for an association of miRNA levels with semen quality. Materials and methods The miR-371a-3p expression was analyzed with qPCR. The study population consisted of 100 participants: seminal plasma samples from 20 germ cell tumors patients and 30 controls, serum samples from 12 healthy men, ejaculate samples from 38 men undergoing fertility testing. Results The seminal plasma miR-371a-3p levels of germ cell tumors patients were not different from controls. The miRNA expression was very low in serum but much higher in seminal plasma. In ejaculate samples, the miRNA expression significantly correlated with sperm concentration and the total sperm count. Discussion miR-371-a-3p is present in sperm-containing fluids. Seminal plasma levels cannot be used to distinguish germ cell tumors from controls. The correlation with sperm concentration in ejaculate samples suggests the spermatozoa as possible source of miR-371a-3p production. Conclusion The miR-371a-3p levels in ejaculate could represent a novel biomarker for the non-invasive evaluation of male infertility.

Die radikale Zystektomie ist Goldstandard in der Behandlung des muskelinvasiven Harnblasen-karzinoms, jedoch erleiden 50 % der Patienten ein Rezidiv. Eine neoadjuvante Cisplatin-basierte Chemotherapie verbessert das Uberleben signifikant, bleibt jedoch weiterhin vielen Patienten vorenthalten. Die Evidenz fur die haufiger eingesetzte adjuvante Chemotherapie ist schwacher, aber auch hier scheint ein Uberlebensvorteil gegeben. Fur Cisplatin-ungeeignete Patienten gab es bislang keine Empfehlung zur perioperativen Systemtherapie. Neue Substanzen, inbesondere Checkpointinhibitoren, eroffnen zukunftig auch in dieser Situation perioperative Therapie-optionen.

Cisplatin-based chemotherapy has been used for more than four decades as a standard therapeutic option in several tumor entities. However, being a multifaceted and heterogeneous phenomenon, inherent or acquired resistance to cisplatin remains a major obstacle during the treatment of several solid malignancies and inevitably results in disease progression. Hence, we felt there was an urgent need to evaluate common mechanisms between multifarious cancer entities to identify patient-specific therapeutic strategies. We found joint molecular and (epi)genetic resistance mechanisms and specific cisplatin-induced mutational signatures that depended on the developmental origin (endo-, meso-, ectoderm) of the tumor tissue. Based on the findings of thirteen tumor entities, we identified three resistance groups, where Group 1 (endodermal origin) prominently indicates NRF2-pathway activation, Group 2 (mesodermal origin, primordial germ cells) shares elevated DNA repair mechanisms and decreased apoptosis induction, and Group 3 (ectodermal and paraxial mesodermal origin) commonly presents deregulated apoptosis induction and alternating pathways as the main cisplatin-induced resistance mechanisms. This review further proposes potential and novel therapeutic strategies to improve the outcome of cisplatin-based chemotherapy.

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.

Prostate cancer is a complex disease that affects millions of men globally, predominantly in high human development index regions. Patients with localized disease at a low to intermediate risk of recurrence generally have a favourable outcome of 99% overall survival for 10 years if the disease is detected and treated at an early stage. Key genetic alterations include fusions of TMPRSS2 with ETS family genes, amplification of the MYC oncogene, deletion and/or mutation of PTEN and TP53 and, in advanced disease, amplification and/or mutation of the androgen receptor (AR). Prostate cancer is usually diagnosed by prostate biopsy prompted by a blood test to measure prostate-specific antigen levels and/or digital rectal examination. Treatment for localized disease includes active surveillance, radical prostatectomy or ablative radiotherapy as curative approaches. Men whose disease relapses after prostatectomy are treated with salvage radiotherapy and/or androgen deprivation therapy (ADT) for local relapse, or with ADT combined with chemotherapy or novel androgen signalling-targeted agents for systemic relapse. Advanced prostate cancer often progresses despite androgen ablation and is then considered castration-resistant and incurable. Current treatment options include AR-targeted agents, chemotherapy, radionuclides and the poly(ADP-ribose) inhibitor olaparib. Current research aims to improve prostate cancer detection, management and outcomes, including understanding the fundamental biology at all stages of the disease.

Background: The ESMO Resilience Task Force has investigated wellbeing since COVID-19 in relation to work, lifestyle and support factors in oncology professionals globally. We reported on the significant impact of the initial surge of the pandemic on wellbeing and job performance (Banerjee et al. 2021). As the pandemic continues, it is imperative to understand experiences and concerns to better inform support measures for the oncology workforce. Methods: Three anonymous online surveys were conducted during the COVID-19 pandemic (S1, Apr/May 2020;S2, Jul/Aug 2020;S3, Feb/Mar 2021). Longitudinal analysis of responses at these timepoints were conducted. Here, we present responses to questions on job demands and resources, and perceived job performance since COVID-19 (JP-CV). Results: We analysed 3894 individual responses (S1, n=1520;S2, n=942;S3, n=1432): 53% (n=1961/3731) female, 45% (n=1679/3731) =/ 100 countries. There has been significant increases from S1 to S3 (p

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

Background The COVID-19 pandemic has resulted in significant changes to professional and personal lives of oncology professionals globally. The European Society for Medical Oncology (ESMO) Resilience Task Force collaboration aimed to provide contemporaneous reports on the impact of COVID-19 on the lived experiences and well-being in oncology. Methods This online anonymous survey (July-August 2020) is the second of a series of global surveys launched during the course of the pandemic. Longitudinal key outcome measures including well-being/distress (expanded Well-being Index—9 items), burnout (1 item from expanded Well-being Index), and job performance since COVID-19 were tracked. Results A total of 942 participants from 99 countries were included for final analysis: 58% (n = 544) from Europe, 52% (n = 485) female, 43% (n = 409) ≤40 years old, and 36% (n = 343) of non-white ethnicity. In July/August 2020, 60% (n = 525) continued to report a change in professional duties compared with the pre-COVID-19 era. The proportion of participants at risk of poor well-being (33%, n = 310) and who reported feeling burnout (49%, n = 460) had increased significantly compared with April/May 2020 (25% and 38%, respectively; P < 0.001), despite improved job performance since COVID-19 (34% versus 51%; P < 0.001). Of those who had been tested for COVID-19, 8% (n = 39/484) tested positive; 18% (n = 7/39) felt they had not been given adequate time to recover before return to work. Since the pandemic, 39% (n = 353/908) had expressed concerns that COVID-19 would have a negative impact on their career development or training and 40% (n = 366/917) felt that their job security had been compromised. More than two-thirds (n = 608/879) revealed that COVID-19 has changed their outlook on their work-personal life balance. Conclusion The COVID-19 pandemic continues to impact the well-being of oncology professionals globally, with significantly more in distress and feeling burnout compared with the first wave. Collective efforts from both national and international communities addressing support and coping strategies will be crucial as we recover from the COVID-19 crisis. In particular, an action plan should also be devised to tackle concerns raised regarding the negative impact of COVID-19 on career development, training, and job security., Highlights • Compared with survey I, more oncology professionals were at risk of poor well-being (33% versus 25%) and burnout (49% versus 38%). • Job performance since COVID-19 (JP-CV) has improved from 34% to 51%. • About 1 in 5 who tested positive for COVID-19 felt they had not been given adequate time to recover before return to work. • Some 39% expressed concerns that COVID-19 would have a negative impact on their career development or training. • More than two-thirds revealed that COVID-19 had changed their outlook on work-personal life balance.

Aims Malignant germ cell tumours (GCTs) of the testis are rare neoplasms, but the most common solid malignancies in young men. World Health Organization guidelines divide GCTs into five types, for which numerous immunohistochemical markers allow exact histological subtyping in the majority of cases. In contrast, a germ cell origin is often hard to prove in metastatic GCTs that have developed so-called somatic malignant transformation. A high percentage, up to 89%, of GCTs are characterised by the appearance of isochromosome 12p [i(12p)]. Fluorescence in-situ hybridisation has been the most common diagnostic method for the detection of i(12p) so far, but has the disadvantages of being time-consuming, demanding, and not being a stand-alone method. The aim of the present study was to establish a quantitative real-time polymerase chain reaction assay as an independent method for detecting i(12p) and regional amplifications of the short arm of chromosome 12 by using DNA extracted from formalin-fixed paraffin-embedded tissue. Methods and results A cut-off value to distinguish between the presence and absence of i(12p) was established in a control set consisting of 36 tumour-free samples. In a training set of 149 GCT samples, i(12p) was detectable in 133 tumours (89%), but not in 16 tumours (11%). In a test set containing 27 primary and metastatic GCTs, all 16 tumours with metastatic spread and/or somatic malignant transformation were successfully identified by the detection of i(12p). Conclusion In summary, the qPCR assay presented here can help to identify, further characterise and assign a large proportion of histologically inconclusive malignancies to a GCT origin.

Background The impact of the coronavirus disease 2019 (COVID-19) pandemic on well-being has the potential for serious negative consequences on work, home life, and patient care. The European Society for Medical Oncology (ESMO) Resilience Task Force collaboration set out to investigate well-being in oncology over time since COVID-19. Methods Two online anonymous surveys were conducted (survey I: April/May 2020; survey II: July/August 2020). Statistical analyses were performed to examine group differences, associations, and predictors of key outcomes: (i) well-being/distress [expanded Well-being Index (eWBI; 9 items)]; (ii) burnout (1 item from eWBI); (iii) job performance since COVID-19 (JP-CV; 2 items). Results Responses from survey I (1520 participants from 101 countries) indicate that COVID-19 is impacting oncology professionals; in particular, 25% of participants indicated being at risk of distress (poor well-being, eWBI ≥ 4), 38% reported feeling burnout, and 66% reported not being able to perform their job compared with the pre-COVID-19 period. Higher JP-CV was associated with better well-being and not feeling burnout (P < 0.01). Differences were seen in well-being and JP-CV between countries (P < 0.001) and were related to country COVID-19 crude mortality rate (P < 0.05). Consistent predictors of well-being, burnout, and JP-CV were psychological resilience and changes to work hours. In survey II, among 272 participants who completed both surveys, while JP-CV improved (38% versus 54%, P < 0.001), eWBI scores ≥4 and burnout rates were significantly higher compared with survey I (22% versus 31%, P = 0.01; and 35% versus 49%, P = 0.001, respectively), suggesting well-being and burnout have worsened over a 3-month period during the COVID-19 pandemic. Conclusion In the first and largest global survey series, COVID-19 is impacting well-being and job performance of oncology professionals. JP-CV has improved but risk of distress and burnout has increased over time. Urgent measures to address well-being and improve resilience are essential., Highlights • This is the first global report of well-being in oncology professionals since the coronavirus disease 2019 (COVID-19) pandemic. • In this survey of 1520 oncology professionals, 67% reported a change in professional duties since COVID-19. • About 25% had risk of distress (poor well-being), 38% felt burnout, and 66% were not able to perform their job compared with the pre-COVID-19 period. • Well-being and job performance since COVID-19 (JP-CV) were correlated with COVID-19 crude mortality rate in the country of practice. • The main predictors of well-being, burnout, and JP-CV were resilience and changes to work hours. • JP-CV has improved but risk of distress and burnout has increased over time.

Testicular type II germ cell tumours (GCTs) are an exemplar of a curable cancer and the most common malignancy in males aged ≤35 years. Even in metastatic stages, about 70% of patients can be cured by cisplatin-based chemotherapy and multimodal treatments. For patients failing platinum-based standard therapy, prognosis is poor and novel biomarkers and therapeutic options are urgently needed.Discussion of desired histopathological information to guide urologists' and oncologists' decision making in the treatment of male GCTs.A narrative review of histopathological key features of male GCT tissue samples for clinical decision making.Histopathological workup is crucial to identify (i) a GCT origin in cancers of unknown primary based on isochromosome 12p (i(12p)) detection, (ii) the different type II GCT subtypes, and (iii) risk factors, i.e. lymphovascular or rete testis invasion, among others. Proper histopathological diagnosis is indispensable for guideline-endorsed, histology-driven, and risk-adapted treatment decisions, hereby helping to maintain treatment success while reducing the therapeutic burden and potential long-term sequelae of multimodal treatments. For refractory patients failing standard treatment options, prognosis remains poor and, so far, neither predictive or prognostic biomarkers nor novel therapeutic targets have been established.Close interaction and interdisciplinary discussion of histopathologic and radiologic findings and established risk factors including serum tumour markers is crucial for successful treatment including intensified strategies, where necessary, or prevention of overtreatment, where possible.HINTERGRUND: Keimzelltumoren des Hodens sind außerordentlich gut heilbar und betreffen meist junge Männer im Alter ≤35 Jahren. Selbst metastasierte Patienten können durch multimodale, Cisplatin-basierte Therapiekonzepte zu ca. 70 % geheilt werden. Patienten, bei denen die Standardtherapie versagt, haben eine sehr ungünstige Prognose, weshalb neue Biomarker und Therapieoptionen dringend benötigt werden.Diskussion histopathologischer Informationen, die für die Entscheidungsfindung der mit der Therapie von Keimzelltumoren befassten Urologen und Onkologen maßgeblich sind.Narrative Übersichtsarbeit zu Schlüsselinformationen männlicher Keimzelltumoren für die klinische Entscheidungsfindung.Zentrale histopathologische Informationen sind insbesondere (i) die Zuordnung eines unklaren Tumorleidens zu einem Keimzelltumorursprung über das Isochromosom 12p, (ii) die klare Benennung der verschiedenen Histologien und (iii) die Beurteilung von Risikofaktoren wie die Lymphangioinvasion oder Rete-testis-Infiltration. Der histopathologische Befund ist maßgeblich für die leitlinienkonforme, risikobasierte Therapieplanung und erfolgreiche -durchführung und hilft die therapeutische Belastung und Langzeitfolgen zu reduzieren. Für refraktäre Keimzelltumoren sind bisher keine prädiktiven oder prognostischen Biomarker oder zielgerichtete Therapien verfügbar.Eine enge Interaktion und interdisziplinäre Diskussion histopathologischer und radiologischer Befunde sowie etablierter Risikofaktoren wie Serumtumormarker ist entscheidend für den Behandlungserfolg und eine Therapieintensivierung (sofern erforderlich) oder -deeskalation zur Vermeidung einer Übertherapie (sofern möglich).

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

Structured abstract: Introduction: Loss of skeletal muscle (SM) and gain of subcutaneous fat (SCF) are known side-effects of androgen-deprivation in treatment of prostate cancer. Scarce data is available concerning the effects of abiraterone/pred (ABI) on body composition and no published data regarding enzalutamide (ENZA). Our objective was to analyse the effects of ENZA on SM/SCF and to compare the results with ABI in patients with metastatic castration-resistant prostate-cancer (mCRPC). Patients and Methods: 54 patients starting ABI (n = 17) or ENZA (n = 37) at a single-centre between 2012 and 2018 were retrospectively identified. SM and SCF were assessed using CT-scans at baseline and after a median of 10.8 months on treatment. A deep learning image-segmentation software was used to quantify SM and SCF. In a subgroup of patients receiving ENZA within a trial, we investigated change of SM using serial timepoints. Results: Median time of treatment with ABI/ENZA was 14.6 months. A significant loss of SM compared to baseline was observed for ENZA (mean loss 5.2%, p

Simple Summary There is a need for novel treatment options for patients with testicular germ cell tumors, especially for those that are resistant to standard chemotherapy, who show poor prognosis. In this work, we test two compounds that inhibit epigenetic enzymes called histone deacetylases—belinostat and panobinostat. We show that these enzymes are expressed at different levels in different germ cell tumor subtypes (seminomas and non-seminomas) and that both drugs are effective in reducing tumor cell viability, by decreasing cell proliferation and increasing cell death. These results are promising and should prompt further works with these compounds, envisioning the improvement of care of germ cell tumor patients. Abstract Novel treatment options are needed for testicular germ cell tumor (TGCT) patients, particularly important for those showing or developing cisplatin resistance, the major cause of cancer-related deaths. As TGCTs pathobiology is highly related to epigenetic (de)regulation, epidrugs are potentially effective therapies. Hence, we sought to explore, for the first time, the effect of the two most recently FDA-approved HDAC inhibitors (HDACis), belinostat and panobinostat, in (T)GCT cell lines including those resistant to cisplatin. In silico results were validated in 261 patient samples and differential expression of HDACs was also observed across cell lines. Belinostat and panobinostat reduced cell viability in both cisplatin-sensitive cells (NCCIT-P, 2102Ep-P, and NT2-P) and, importantly, also in matched cisplatin-resistant subclones (NCCIT-R, 2102Ep-R, and NT2-R), with IC50s in the low nanomolar range for all cell lines. Treatment of NCCIT-R with both drugs increased acetylation, induced cell cycle arrest, reduced proliferation, decreased Ki67 index, and increased p21, while increasing cell death by apoptosis, with upregulation of cleaved caspase 3. These findings support the effectiveness of HDACis for treating TGCT patients in general, including those developing cisplatin resistance. Future studies should explore them as single or combination agents.