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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 < 2.5 upper limit of normal (ULN) (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 < 2.5 ULN vs. ≥ 2.5 ULN correlated with RFS and CRR associated with a 5-years RFS rate and CRR of 76% vs. 86% (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. [ABSTRACT FROM AUTHOR]

Background: Metastatic germ cell tumor (mGCT) patients receiving chemotherapy have increased risk of life‐threatening venous thromboembolism (VTE). Identifying VTE risk factors may guide thromboprophylaxis in this highly curable population. Methods: Data were collected from mGCT patients receiving first‐line platinum‐based chemotherapy at 22 centers. Predefined variables included International Germ Cell Cancer Collaborative Group (IGCCCG) risk classification, long‐axis diameter of largest retroperitoneal lymph node (RPLN), Khorana score, and use of indwelling vascular access device (VAD). VTE occurring at baseline, during chemotherapy and within 90 days, was analyzed. Results: Data from 1135 patients were collected. Median age was 31 years (range 10‐74). IGCCCG risk was 64% good, 20% intermediate, and 16% poor. VTE occurred in 150 (13%) patients. RPLN >3.5 cm demonstrated highest discriminatory accuracy for VTE (AUC 0.632, P <.001) and was associated with significantly higher risk of VTE in univariable analysis (22% vs 8%, OR 3.0, P <.001) and multivariable analysis (OR 1.8, P =.02). Other significant risk factors included, Khorana score ≥3 (OR 2.6, P =.008) and VAD use (OR 2.7, P <.001). Conclusions: Large RPLN and VAD use are independent risk factors for VTE in mGCT patients receiving chemotherapy. VAD use should be minimized in this population and thromboprophylaxis might be considered for large RPLN. [ABSTRACT FROM AUTHOR]

Background: Aberrant overexpression of PIWI/piRNA pathway proteins is shown for many types of tumors. Interestingly, these proteins are downregulated in testicular germ cell tumors (TGCTs) compared to normal testis tissues. Here, we used germline and TGCT markers to assess the piRNA biogenesis and function in TGCTs and their precursor germ cell neoplasia in situ (GCNIS).Methods: We used small RNA deep sequencing, qRT-PCR, and mining public RNAseq/small RNA-seq datasets to examine PIWI/piRNA gene expression and piRNA biogenesis at four stages of TGCT development: (i) germ cells in healthy testis tissues, (ii) germ cells in testis tissues adjacent to TGCTs, (iii) GCNIS cells and (iv) TGCT cells. To this end, we studied three types of samples: (a) healthy testis, (b) testis tissues adjacent to two types of TGCTs (seminomas and nonseminomas) and containing both germ cells and GCNIS cells, as well as (c) matching TGCT samples.Results: Based on our analyses of small RNA-seq data as well as the presence/absence of expression correlation between PIWI/piRNA pathway genes and germline or TGCT markers, we can suggest that piRNA biogenesis is intact in germ cells present in healthy adult testes, and adjacent to TGCTs. Conversely, GCNIS and TGCT cells were found to lack PIWI/piRNA pathway gene expression and germline-like piRNA biogenesis. However, using an in vitro cell line model, we revealed a possible role for a short PIWIL2/HILI isoform expressed in TGCTs in posttranscriptional regulation of the youngest members of LINE and SINE classes of transposable elements. Importantly, this regulation is also implemented without involvement of germline-like biogenesis of piRNAs.Conclusions: Though further studies are warranted, these findings suggest that the conventional germline-like PIWI/piRNA pathway is lost in transition from germ cells to GCNIS cells. [ABSTRACT FROM AUTHOR]

Purpose: Patients (pts) with mediastinal nonseminomatous germ cell tumors (MNGCT) are belonged to poor prognostic group by IGCCCG. We retrospectively studied the prognostic factors and efficacy of different chemotherapeutic regimen in pts with MNGCT. Methods: We analyzed data on 61 pts with MNGCT. Conditional induction chemotherapy BEP was performed in 38 %, TBEP-in 28 %, CBOP-in 28 %, accelerated (two weekly) version of BEP-in 6 % pts. Based on similar efficacy of CBOP and TBEP regimens, we combines pts with CPOB and TBEP regimen in one group-55.8 % and different variants of BEP regimen in the second group-44.2 %. Multivariate Cox regression analysis was performed to determine independent factors, which influenced on overall survival. Results: We revealed the following independent negative prognostic factors: age ≥24 years ( p = 0.07), size of the primary mediastinal tumor ≥19 cm ( p = 0.03). Median overall survival (OS) has not been reached, and 2-year OS was 66 % in pts with good prognosis (age <24 years and/or size of mediastinal tumor <19 cm) versus 15 months and 40 % in pts with poor prognosis ( p = 0.03). Objective marker negative response was revealed more often in pts with CPOB/TBEP group: 26/34 (76.5 %) versus 14/27 (52 %), p = 0.08. Median OS was also higher in pts with CPOB/TBEP group: nonreached versus 15 months ( p = 0.01). Conclusion: CPOB and TBEP regimen were significantly associated with better outcome in pts with MNGCT. Age ≥24 years and size of the primary mediastinal tumor ≥19 cm were found as independent negative prognostic factors. [ABSTRACT FROM AUTHOR]

Abstract: Objectives: Late relapses (>2 years) after completion of chemotherapy are rare and often platinum-resistant. There are limited data concerning late relapses in chemotherapy-naïve patients with stage I germ cell tumors. This retrospective analysis was performed to compare the outcome between patients with stage I germ cell tumors, who had late (≥2 years) and early (≥3 months and <2 years) relapse after orchiectomy. Methods and materials: We analyzed data of 1,069 chemotherapy-naïve patients with advanced germ cell tumors of testis treated in our department from 1986 to 2008. All patients had cisplatin- and etoposide-based chemotherapy. We identified 169 (15.8%) patients with prior stage I disease, who had not received adjuvant treatment: 140 and 29 patients had early and late relapse, respectively. Among patients with late relapse, pure seminoma was revealed in 14 patients, and nonseminoma in 15 patients. Median follow-up time for 169 patients was 35 (range, 2–218) months. Results: Patients with late relapse were older, 35 years (23–57) and had more frequent pure seminoma in primary tumor, 14/29 (48.3%), than patients with early relapse, 30 years (16–63) (P = 0.0008) and 46/140 (32,8%, P = 0.08), respectively. At the time of disease progression, both groups were very similar according to well-known prognostic factors including IGCCCG classification. The only difference was larger size of retroperitoneal lymph nodes in late (9 cm) than in early relapse (4 cm, P < 0.0001). The outcome in patients with late relapse was significantly worse than in patients with early relapse: complete response rate after induction chemotherapy was 20.7% (6/29) vs. 42.1% (59/140) (P = 0.01), 3-year progression-free survival 66% vs. 84% (P = 0.02, HR = 2.4, 95% CI 1.2–8.8) and 3-year overall survival, 72% vs. 88% (P = 0.04, HR = 2.4, 95% CI 1.05–10.25), respectively. In patients with pure seminoma, this difference in overall survival was even more significant: 65% vs. 91% (P = 0.04, HR = 3.8, 95% CI 1.06–32.4). Conclusions: Late relapses following stage I germ cell tumors were associated with seminoma, older age, and worse outcome after induction chemotherapy. [Copyright &y& Elsevier]

Background For metastatic germ cell tumour patients with intermediate prognosis (IPGCT) according to the IGCCCG classification 5-year overall survival (OS) rates of 79% were described, but recent data suggest significant changes. Patients and methods To compare the outcome of current IPGCT with former patients and to find new prognosticators a retrospective observational study was performed. Eligibility criteria were: age ≥16 years, diagnosed between 1979 and 2014. Primary end-point was the 5-year OS rate. Results This database includes 707 IPGCT: group 1 was diagnosed 1979–1996 ( n = 237), and group 2 1997–2014 ( n = 470). Median follow-up was 8.6 years (IQR: 14.4). Group 1 and 2 received first-line treatment with BEP (median 4 cycles; range 1–6) in 99% (group 1) and 95% (group 2), respectively. The proportion of first-line chemotherapy responders (CR and marker negative PR) was similar: 94% (group 1) and 96% (group 2), respectively ( P = 0.290), but OS was superior in group 2 with a 5-year OS rate of 89% compared with 83% in group 1 ( P = 0.035). In refractory disease, high-dose chemotherapy and treatment beyond second line was performed more often in group 2. A lactate dehydrogenase (LDH) cut-off value of 2 ULN ( P = 0.002; HR 2.121) and alpha-fetoprotein (AFP) levels of 6200 IU/ml ( P = 0.032; HR 2.155) pre-chemotherapy were independent prognosticators for OS in a multivariate analysis. Conclusion Outcome of IPGCT has improved and is now closer to the good prognosis category. LDH and AFP levels represent potential markers to stratify IPGCT before treatment initiation. [ABSTRACT FROM AUTHOR]

Abstract: Objectives: Classically, orchiectomy (OE) is the first step of treatment in patients with metastatic germ cell tumors (mGCTs) of testis. However, some patients have severe symptoms of disease, which require immediate beginning of chemotherapy (CT) followed by OE. This retrospective analysis was performed to find the effect of time constraints of delayed OE on survival in patients with mGCT. Methods and materials: We analyzed the data of 1,483 CT-naive patients with advanced mGCT of the testis treated in our Department from 1986 to 2009. Delayed OE was performed on 71 (4.8%) patients: seminoma in 8 patients (11.2%), nonseminomatous tumor in 50 patients (70.4%), and unknown tumor histology in 13 patients (18.4%). Twenty percent, 40%, and 40% of patients belonged to good, intermediate, and poor International Germ Cell Cancer Consensus Group prognostic groups, respectively. Median time from the beginning of the CT to OE was 18 (range, 1–250) days. OE was performed on 39 (55%), 21 (29.5%), and 11 (15.5%) patients during cycle 1, cycle 2 to completion of CT, and after the finishing of induction CT, respectively. Median follow-up time was 156 (range, 3–241) months. Etoposide and cisplatin-based CTs were received by 66 patients (93%). Results: Three-year overall survival (OS) of all 1,483 patients was 75%. An excellent primary tumor response to CT was observed among the patients, who had delayed OE after completion of CT (n = 11): only mature teratoma (n = 4) and tumor necrosis (n = 7) were found. The 3-year OS in patients with delayed OE was 63%. OE performed after completion of CT was associated with better prognosis. The 3-year OS in patients with delayed OE performed during the cycle 1 (group 1) was 67%, cycle 2 to completion of CT (group 2) was 39%, and after finishing of CT (group 3) was 88% (groups 1 vs. 3: hazard ratio 3.7, 95% confidence interval 0.69–10.1, P = 0.15; groups 2 vs. 3: P = 0.01, hazard ratio 8.1, 95% confidence interval 1.32–18.,72). It seems that if OE had been performed during CT, the beginning of the successive cycle was delayed and dose intensity of CT was decreased. Conclusions: In case of severe symptoms of disease, which require an immediate start of CT, performing OE simultaneously with other surgeries after completion of induction CT was associated with better OS, when compared with performing OE during induction CT. [Copyright &y& Elsevier]

Current guidelines recommend surveillance in metastatic non-seminomatous germ cell tumour patients treated with first-line-chemotherapy and a complete clinical response (normalisation of serum tumour markers and residual masses <1 cm). However, this recommendation is based on a series including patients with good prognosis according to International Germ Cell Cancer Cooperative Group prognostic group (IGCCCG-PG). The aim of this study was to analyse the proportion of residual teratoma and survival among patients with intermediate/poor IGCCCG-PG and a complete clinical response after first-line-chemotherapy. This is a retrospective study of men with intermediate/poor IGCCCG-PG, who had a complete clinical response after first-line chemotherapy. Patients were either followed by surveillance or treated with post-chemotherapy retroperitoneal lymph node dissection (pcRPLND). Between 2009 and 2018, 143 men with intermediate (n = 83) or poor (n = 60) IGCCCG-PG were treated at 11 international centres. Among 33 patients treated with pcRPLND, the specimen showed teratoma and viable cancer in 16 (48%) and 4 (12%). During a median a 7-year follow-up, 20/110 (18%) patients managed with surveillance relapsed, of whom seven (6%) had a retroperitoneal-only relapse versus 2/33 patients managed with pcRPLND relapsed. No difference was observed regarding overall survival (OS) among men treated with pcRPLND or surveillance (5-year OS, 93% and 89%, p -value = 0.35). The median time-to-recurrence among men on surveillance was 1.3 years (range: 0.3–9.1), and the most common sites of relapses included retroperitoneum (11%), chest (5%), and bones (4%). While most men with intermediate/poor IGCCCG-PG harbour teratoma/cancer in the retroperitoneum despite a complete response to first-line-chemotherapy, only 6% managed with surveillance relapsed in the retroperitoneum. There was no significant difference in OS between the two groups. • >95% long-term survival if intermediate/poor risk metastatic NSGCT and remission. • Most men with intermediate/poor IGCCCG have residual cancer in the retroperitoneum. • 6% of those men managed with surveillance relapse in the retroperitoneum only. [ABSTRACT FROM AUTHOR]

Background: Germ cell tumor patients with intermediate prognosis (IPGCT) according to the International Germ Cell Cancer Collaborative Group (IGCCCG) classification represent a heterogeneous group with different clinical features. This analysis was performed to investigate the prognostic impact of different tumor marker levels prior to first line chemotherapy within IPGCT.Methods: For this study an international registry for IPGCT was established. Eligibility criteria were intermediate prognosis according to IGCCCG criteria, nonseminomatous histology, male sex, and age ≥ 16 years. Uni- and multivariate analysis were conducted to identify characteristics associated with survival outcomes. Receiver-Operating-Characteristic curve analysis was applied to find cut-off parameters. Five-year overall survival (OS) rate was the primary and 5-year progression-free survival rate the secondary endpoint.Results: This database included 634 IPGCT with a median follow-up of 9.0 years (interquartile range: 14.35). Patients received first line treatment with platinum based chemotherapy, associated with a 5-year OS rate of 87%. The stratification of patients according to AFP levels revealed a correlation between AFP levels and outcome, associated with 5-year OS rates of 88% for AFP levels <1,000 IU/ml (n = 303), 89% for 1,000 to 2,000 IU/ml (n = 82), 87% for >2,000 to 6,000 IU/ml (n = 121), and 82% for >6,000 IU/ml (n = 57) prior first course of chemotherapy, respectively (P= 0.013). LDH levels prior fist course of chemotherapy also correlated with outcome associated with 5-year OS rates of 92% for <2 UNL (n = 271), 89% for ≥2 to 3 UNL (n = 85), 78% for >3 to 4 UNL (n = 34), and 77% for >4 UNL (n = 79), respectively (P= 0.03). Different HCG levels prior chemotherapy were not associated with outcome. In multivariable analysis AFP levels >6,000 IU/ml (P= 0.023; hazard ratio HR 2.263) or >1,982 IU/ml (P= 0.031; HR 1.722), and LDH levels >3 UNL (P< 0.001; HR 2.616) were independent prognosticators for OS.Conclusions: Prognostication according to LDH and AFP levels prior chemotherapy could offer a new approach to stratify patients within the intermediate prognosis cohort. According to our findings, patients with AFP values above 6,000 IU/ml or/and LDH > 3 UNL represent an independent high risk cohort. Our results need to be confirmed in the upcoming IGCCCG reclassification. [ABSTRACT FROM AUTHOR]