Germ Cell Tumor Patients Research Articles

Improved outcomes in testicular germ cell tumor patients treated at the referral center in Slovakia in the last decade.

e16059 Background: Treatment at expert centers results in superior survival in patients with germ cell tumors (GCTs). This study evaluated outcomes in patients treated at National Cancer Institute in Slovakia before and after the year 2008 after refining the treatment strategies. Methods: Our institutional database was searched for GCT patients treated at National Cancer Institute in Slovakia between 1992 and 2016. A year of 2008 was selected for cutoff to compare changes in outcomes before and after this time-point due to refining treatment strategies such as centralization of post-chemotherapy surgery and incorporation of granulocyte-colony stimulating factor (G-CSF) for routine prophylaxis of febrile neutropenia. Kaplan-Meier product limit and log-rank test were used for statistical analysis. Results: This retrospective study included 485 patients treated for metastatic GCT. Two hundred and sixty-three patients (54%) were treated before 2008 (group 1) and 222 patients (46%) were treated after 2008, including (group 2). Progression-free survival (PFS) and overall survival (OS) was significantly improved in group 2 vs 1 (HR = 0.63, 95% CI 0.46-0.87; P= 0.0039 for PFS and HR = 0.44, 95% CI 0.30-0.65; P = 0.0003 for OS, respectively). In a subgroup analysis of International Germ Cell Cancer Collaborative Group criteria, favorable change in survival was observed in good-risk GCTs (HR = 0.40, 95% CI 0.24-0.67; P = 0.0009 for PFS, and HR = 0.20, 95% CI 0.10-0.38; P = 0.0002 for OS), but nor in intermediate or poor risk group. Conclusions: Treatment outcomes of GCTs have significantly improved in the last decade at our institution. We hypothesize that changes in treatment approach contributed to this improvement including centralization of post-chemotherapy retroperitoneal lymph-node dissections and routine use of granulocyte-colony stimulating factors that have been implemented in 2007. Referral bias for extremely poor risk patients in recent years may be an accounting factor for lack of improvement in this subgroup.

Is gynecomastia related to the disease characteristics and prognosis in testicular germ cell tumor patients?

We aimed to assess the relationship between gynecomastia and tumor markers, histologic subtypes, and prognosis in patients with testicular germ cell tumors. This study included 73 testicular germ cell cancer patients with pretreatment chest, abdomen and pelvis computed tomography (CT) scans and tumor markers (β-human chorionic gonadotropin [β-hCG], lactate dehydrogenase [LDH], α-fetoprotein [AFP]). The volumetric analysis of the breast glandular tissue, the presence of gynecomastia and metastatic disease were determined using CT scans. Patients were classified according to the International Germ Cell Cancer Collaborative Group (IGCCCG) prognostic classification. The association between gynecomastia, breast glandular tissue volume, tumor markers, metastatic disease, and disease prognosis were evaluated. Thirty-four of the patients (46.6%) had gynecomastia. A breast volume cutoff value of 0.78 cm3 to diagnose gynecomastia led to 85% sensitivity and 95% specificity. Serum β-hCG level correlated with the breast glandular tissue volume weakly (r=0.242, P = 0.039). Gynecomastia was more common in patients with elevated β-hCG levels (P = 0.047), and was not associated with pulmonary, nonpulmonary distant, or nodal metastases (P = 0.378, P = 0.884, P = 0.333, respectively). No significant association was found between the disease prognosis and gynecomastia (P = 0.556). Gynecomastia was common among testicular germ cell cancer patients with elevated β-hCG. However, it was not associated with metastatic disease and prognosis.

Noncaseating granulomatous diseases in germ cell cancer patients–A single-center experience

ObjectivesIn patients with testicular Germ Cell Tumors (GCT) noncaseating granulomatous diseases such as Sarcoid Like Lesions (SLL) or Sarcoidosis can mimic metastasis due to hilar or mediastinal lymphadenopathy. Due to the clinical and prognostic impact, exclusion of malignant diseases is mandatory. Material and methodsRetrospectively, data from 636 GCT patients, who were seen in the course of tumor surveillance/follow-up were collected. Focus was put on the detection of tumor relapse vs. noncaseating granulomatous reactions. For the differential diagnosis of thoracic lymphadenopathy or pulmonary infiltrates either bronchoscopy (e.g., endobronchial ultrasound-guided transbronchial needle aspiration, endobronchial ultrasound-guided transbronchial needle aspiration) or thoracic surgery was performed. Both GCT patients with either tumor relapse or coexisting SLL were compared to GCT patients without SLL and tumor relapse. ResultsTwenty-nine patients suffered from suspected tumor relapse. Whereas thoracic relapses were suspected in 15 patients on chest computed tomography, thoracic relapse was confirmed in 5 cases by open surgery. In 2 cases open surgery yielded reactive lymphadenitis, and in 8 cases SLL was diagnosed either via EBUS-TBNA (n = 7) or thoracoscopic wedge resection plus lymphadenectomy (n = 1). With focus on overall survival, no relevant difference was found between all tested subgroups (P = 0.265; logrank test). ConclusionsIn GCT patients, the coexistence of noncaseating granulomatous disease is common. Minimal invasive bronchoscopic techniques can serve for the cytopathologic exclusion of malignant thoracic manifestations. In our monocenter patient group the coexistence of SLL did not have any prognostic impact on overall survival.

Body Mass Index and Outcomes in Germ-Cell Tumors.

Obesity at the time of diagnosis has been associated with better outcomes in some metastatic cancers such as renal-cell cancer. The association between body mass index (BMI) and germ-cell tumor (GCT) outcomes has not been reported. We sought to assess the association between BMI and outcomes in men with GCT in a large hospital registry. Electronic medical records for 1161 GCT patients treated at Dana-Farber Cancer Institute between 1997 and 2012 were reviewed. Information regarding BMI, histology, stage, treatment, and patient characteristics was obtained. We separately evaluated patients with clinical stage 1 and metastatic disease. Using logistic regression analysis, we investigated the association between BMI and clinical features, such as International Germ Cell Consensus Classification (IGCCC) and stage at diagnosis. We used Cox proportional hazards regression to assess the association between BMI and risk of relapse and GCT-specific death. Among men diagnosed with clinical stage 1 GCT, BMI≥ 25 kg/m2 was not associated with an increased risk of relapse (hazard ratio= 0.83; 95% confidence interval, 0.53-1.30) compared to those with BMI< 25 kg/m2. In the metastatic disease setting, men with BMI< 25 kg/m2 were less likely to present with good-risk disease; however, BMI was not associated with risk of relapse (hazard ratio= 1.00; 95% confidence interval, 0.63-1.59, P= .99). There was no evidence for an association between BMI and GCT outcomes. A lower BMI was associated with adverse prognostic variables at presentation per IGCCC risk groups for metastatic GCT, but this was not associated with relapse.

New insights into germ cell tumor genomics.

Testicular germ cell tumors (GCTs) represent the most common malignancy in young men. While GCTs represent a model for curable solid tumors due to exquisite chemosensitivity, mortality for patients with GCT comprises the most life years lost for non-pediatric malignancies. Given limited options for patients with platinum-resistant disease, improved insight into GCT biology could identify novel therapeutic options for patients with platinum-resistant disease. Recent studies into molecular characteristics of both early stage and advanced germ cell tumors suggest a role for rationally targeted agents and potentially immunotherapy. Recent GWAS meta-analyses have uncovered additional susceptibility loci for GCT and provide further evidence that GCT risk is polygenic. Chromosome arm level amplifications and reciprocal loss of heterozygosity have been described as significantly enriched in GCT compared to other cancer types. Contemporary analyses confirm ubiquitous gain of isochromosome 12 and mutations in addition to previously described GCT-associated genes such as KIT and KRAS. Alterations within the TP53-MDM2 signal transduction pathway appear to be enriched among patients with platinum-resistant disease. Potentially actionable targets, including alterations in TP53-MDM2, Wnt/β-catenin, PI3K, and MAPK signaling, are present in significant proportions of patients with platinum-resistant disease and may be exploited as therapeutic options. Pre-clinical and early clinical data also suggest a potential role for immunotherapy among patients with GCTs. Molecular characterization of GCT patients may provide biologic rationale for novel treatment options in patients with platinum-resistant disease.

Predicting vital retroperitoneal residual tumors of metastatic testicular tumor patients after chemotherapy using radiomics.

527 Background: About 50% of patients undergoing post-chemotherapy retroperitoneal lymph node dissection (pcRPLND) are overtreated due to missing markers or valid prediction scores prior surgery. The potential of radiomics and machine learning applied on computed tomography (CT) imaging to predict the presence of viable tumor or teratoma in retroperitoneal lymph node metastases from germ cell tumor (GCT) patients prior to pcRPLND has not been explored. Therefore, we applied radiomics and machine learning to CT images of GCT patients prior to pcRPLND. Methods: Metastasized GCT patients who were treated with chemotherapy and received a contrast-enhanced CT prior to pcRPLND possessing complete clinical data were included in the study. Only lymph nodes which were identified in the CT images and correlated with the pathological findings (benign: necrosis / fibrosis vs. viable: viable tumor/ teratoma) were included. Lymph nodes identified in the CT images, were semiautomatically segmented and 93 radiographic features were analyzed. A linear support vector machine (SVM) algorithm was applied to analyze reproducible radiomics features. Additionally, a continuous reduction of the features analyzed was performed using Random Forest algorithms, as well as consecutive correlation and receiver operating curve analyzes. Results: Forty-two patients fulfilled the inclusion criteria and were included in the study. Total in these patients 96 lymph nodes were segmented on CT. Histologically, 41 lymph nodes were classified as viable tumors and 55 as benign. To train the SVM, 67 lymph nodes were randomly selected. Of the 93 radiomic features analyzed, 51 features were reproducible. Applying the trained algorithm to the remaining 29 lymph nodes resulted in a classification accuracy of 82% with a diagnostic sensitivity of 81% and a specificity of 83%. After multistep feature reduction, the three most important predictors for viable tumor achieved a sensitivity of 66% and a specificity of 78% when combined in a multivariate model. Conclusions: The applied radiomics model, solely based on CT images achieved a good sensitivity and specificity in predicting viable metastases.

Factors that impact the outcomes in testicular germ cell tumors in low–middle-income countries

Germ cell tumors (GCTs) are one of the most common tumors in adolescents and young adults. There is paucity of data on GCT from low-middle-income countries (LMIC). The present study was conducted to assess the demographic features, clinical manifestations, pathology, and outcomes of GCT patients treated at our center. Patients with testicular GCT above the age of 18 years, treated at our center from 2001 to 2015 were included in the study. Data were extracted retrospectively from the case records. Event-free survival (EFS) and overall survival (OS) were calculated using the Kaplan-Meier method and the variables were compared using the log-rank test. The study included 421 patients among whom 128 (30%) had a histological diagnosis of seminoma and 293 (70%) had non-seminomatous germ cell tumor (NSGCT). Metastatic disease at presentation was observed in 83/128 (65%) with seminoma and 254/293 (87%) with NSGCT. According to the International Germ Cell Cancer Collaborative Group (IGCCCG) risk stratification for metastatic disease, good- and intermediate-risk seminoma were observed in 55/83 (66%) and 28/83 (34%) patients, respectively, and good-, intermediate-, and poor-risk NSGCT were observed in 82/254 (32%), 76/254 (30%), and 96/254 (38%) patients, respectively. The median follow-up was 32.3months (range 0.03-200months). The 3-year OS for the entire cohort was 80.3%. The 3-year OS for seminoma was 91.4%, and for NSGCT was 75.3%. Factors significantly associated with inferior EFS and OS on multivariate analysis included poor performance status, scrotal orchidectomy, carboplatin-based regimen, NSGCT histology, and treatment default. Patients with testicular GCT in India present in an advanced stage and higher IGCCCG risk compared to Western data. Factors unique to LMIC like treatment default, bulky disease, dose compromise, and scrotal orchidectomy have a negative impact on the outcome.

Pulmonary Metastasectomy for Germ Cell Tumors.

Germ cell tumors (GCTs) are the most common malignancy among young men in the United States. Although prognosis is favorable and response to cisplatin-based chemotherapy regimens is good, 10%–20% of patients with thoracic metastases require surgical management following completion of chemotherapy. Pulmonary metastasectomy (PM) has been employed for GCT patients with lung metastases for several decades. Outcomes have been excellent thus far. However, there have been no randomized controlled trials of PM in GCT and, as new surgical techniques are developed, there is variability in management. This article reviews the existing data on current management of pulmonary metastases in GCT, with attention paid to timing of surgery, surgical approaches, and complications.

Hematologic Malignancies Arising in Patients with Germ Cell Tumors: Secondary Somatic Differentiation of Hematopoietic Malignancies from Germ Cell Precursors

Genomic analyses have recently illuminated our understanding of therapy-associated myeloid neoplasms in patients receiving therapy for other cancers. One of the most intriguing relationships between solid tumors and myeloid neoplasms involves a unique clinical entity of patients with germ cell tumors (GCT) and myeloid neoplasms. One in 17 patients with primary mediastinal germ cell tumor (PMGCT) develops a hematologic malignancy (most commonly AML, MDS, or histiocytosis) and the median survival in such patients is poor at only 5 months. Intriguingly, the presence of isochromosome 12p [i(12p)], a clonal marker common to GCTs but absent in de novo myeloid neoplasms, has been demonstrated as shared across GCTs and myeloid neoplasms in such individuals. While these data suggest a clonal relationship between the two, the exact nature of the shared origin is unknown. There are two competing hypotheses to explain this: (1) an embryonic progenitor with the capacity to differentiate into germ cell and hematopoietic lineages harbors the initiating genetic alterations and drives development of both malignancies or (2) the leukemia is derived directly from GCTs with the capacity to differentiate into hematopoietic lineages. To trace the clonal evolution of these seemingly unrelated cancer types and identify recurrent genomic lesions in leukemias present in GCT patients, we applied whole exome sequencing (WES), targeted genomic analyses, and/or RNA-seq to leukemias, GCTs, and germline DNA in a series of patients with myeloid neoplasms and concurrent GCTs.We collected 12 patients with GCT and synchronously or metachronously occurring myeloid neoplasms (8 AML, 5 MDS/CMML, 2 histiocytic sarcoma (some had >1 hematologic malignancy)) with an average of 4 months between the two diagnoses. Consistent with prior reports, all were young men (median age 26) with PMGCT and nonseminomatous histology and a 3-month median survival from leukemia diagnosis (Fig. A). In each case, at least one copy number alteration or coding mutation was shared across the GCT and hematopoietic neoplasm, demonstrating the shared origin of both lesions. For example, half of the patients (6/12) carried i(12p) in both the GCT and hematopoietic neoplasm. In the i(12p) negative cases, somatic genetic alterations identified in the GCT were also found in the leukemia. The most common genomic alterations in leukemias beyond i(12p) included mutations activating RAS-PI3K-AKT signaling (including PTEN, RAS and PI3K isoform mutations) or inactivating TP53 (Fig. B). The only exception was a testicular-only GCT patient who developed clonally distinct acute promyelocytic leukemia; however, further analysis identified this as a chemotherapy-induced neoplasm with the PML-RARa breakpoint mapped to an etoposide sensitive area and this patient was not counted amongst the 12 cases.We next traced the evolutionary history of clonally related GCTs and leukemias based on cancer cell fraction of all coding mutations and copy number alterations using WES of DNA from each tumor type and finger nails. In each instance, we identified clonal evolution of the hematopoietic malignancies from antecedent precursors within the GCT. To illustrate this, a 19-year-old male developed successive diagnoses of histiocytic sarcoma, CMML, and AML within 18 months of GCT diagnosis. Lineage tracing by WES of each of these four individual cancers revealed that all four were clonally related, and the histiocytic sarcoma, CMML, and AML were all derived from the GCT with a common precursor giving rise to the three hematopoietic malignancies (Fig. C-D). Moreover, the histiocytic sarcoma evolved separately from CMML/AML in this patient, where the AML represented leukemic transformation from the CMML.These data conclusively demonstrate that myeloid neoplasms developing in patients with PMGCT represent secondary somatic differentiation of a hematologic progenitor from totipotent aberrant cells that are present in the GCT. Thus, GCT-associated leukemias have a unique ontogeny from de novo and/or secondary myeloid neoplasms, which originate from progenitors within the bone marrow. As such, GCT-associated leukemias have characteristic genomic alterations hallmarked by frequent i(12p) in combination with mutations activating RAS-PI3K-AKT signaling and inactivating TP53, and these patients do poorly even when treated with aggressive contemporary chemotherapy. DisclosuresRampal:Jazz: Consultancy, Honoraria; Celgene: Honoraria; Constellation: Research Funding; Incyte: Honoraria, Research Funding; Stemline: Research Funding. Tallman:ADC Therapeutics: Research Funding; Orsenix: Other: Advisory board; AROG: Research Funding; Cellerant: Research Funding; AbbVie: Research Funding; Daiichi-Sankyo: Other: Advisory board; BioSight: Other: Advisory board.

Emerging Prognostic Biomarkers in Testicular Germ Cell Tumors: Looking Beyond Established Practice.

Testicular germ cell tumors are unique among solid cancers. Historically, this disease was deadly if progressed beyond the stage I. The implementation of cisplatin-based chemotherapy regimens has drastically changed the clinical outcome of metastatic testicular cancer. Several biomarkers were established to refine the prognosis by International Germ Cell Collaborative Group in 1997. Among these, the most significant were primary tumor site; metastatic sites, such as non-pulmonary visceral metastases; and the amplitude of serum tumor markers α-fetoprotein, β-chorionic gonadotropin, and lactate dehydrogenase. Since then, oncology has experienced discoveries of various molecular biomarkers to further refine the prognosis and treatment of malignancies. However, the ability to predict the prognosis and treatment response in germ cell tumors did not improve for many years. Clinical trials with novel targeting agents that were conducted in refractory germ cell tumor patients have proven to have negative outcomes. With the recent advances and developments, novel biomarkers emerge in the field of germ cell tumor oncology. This review article aims to summarize the current knowledge in the research of novel prognostic biomarkers in testicular germ cell tumors.

MiR-371a-3p Serum Levels Are Increased in Recurrence of Testicular Germ Cell Tumor Patients.

Metastatic testicular germ cell tumors (TGCTs) are a potentially curable disease by administration of risk-adapted cytotoxic chemotherapy. Nevertheless, a disease-relapse after curative chemotherapy needs more intensive salvage chemotherapy and significantly worsens the prognosis of TGCT patients. Circulating tumor markers (β-subunit of human chorionic gonadotropin (β-HCG), alpha-Fetoprotein (AFP), and Lactate Dehydrogenase (LDH)) are frequently used for monitoring disease recurrence in TGCT patients, though they lack diagnostic sensitivity and specificity. Increasing evidence suggests that serum levels of stem cell-associated microRNAs (miR-371a-3p and miR-302/367 cluster) are outperforming the traditional tumor markers in terms of sensitivity to detect newly diagnosed TGCT patients. The aim of this study was to investigate whether these miRNAs are also informative in detection of disease recurrence in TGCT patients after curative first line therapy. For this purpose, we measured the serum levels of miR-371a-3p and miR-367 in 52 samples of ten TGCT patients at different time points during disease relapse and during salvage chemotherapy. In our study, miR-371a-3p levels in serum samples with proven disease recurrence were 13.65 fold higher than levels from the same patients without evidence of disease (p = 0.014). In contrast, miR-367 levels were not different in these patient groups (p = 0.985). In conclusion, miR-371a-3p is a sensitive and potentially novel biomarker for detecting disease relapse in TGCT patients. This promising biomarker should be investigated in further large prospective trials.

Surgical Management of Patients with Advanced Germ Cell Tumors Following Salvage Chemotherapy: Memorial Sloan Kettering Cancer Center (MSKCC) Experience.

ObjectiveTo characterize clinical and pathologic outcomes of cisplatin-refractory or relapsed germ cell tumor (GCT) patients who underwent retroperitoneal lymph node dissection (RPLND) following salvage chemotherapy with either conventional or high dose regimens. MethodsData were reviewed to identify all patients treated with TIP or TICE salvage chemotherapy between 1994 and 2011(n = 184) at our institution. We report clinicopathologic and outcomes data on 131 patients who were further managed with surgical resection. Using Cox-proportional hazards models, predictors of disease-specific survival (DSS) were analyzed. ResultsMedian follow-up was 7.3 years. Of the 112 patients who underwent postsalvage chemotherapy RPLND, histology was reported as viable GCT in 30 (27%), teratoma only in 26 (23%) and fibrosis in 56 (50%). 5-year DSS for the entire cohort was 74% (95% confidence interval 63%-80%). On multivariable analysis, viable GCT histology at RPLND or extra-RPLND resection predicted for worse DSS (hazard ratio 7.37, P = .003). ConclusionsOur data suggest that approximately half of the patient with cisplatin-refractory or relapsed GCT salvaged with TIP or TICE chemotherapy and evidence of residual disease are at risk of harboring either viable GCT or teratoma. This finding underlines the critical role of surgery in the multimodality approach to the management of this advanced disease entity. If retroperitoneal disease exists prior to salvage chemotherapy, we recommend postchemotherapy resection in all eligible patients.

913P - The prognostic value of DNA damage level in peripheral blood lymphocytes in germ cell cancer patients

Background: Germ cell tumors (GCTs) are extraordinarily sensitive to cisplatin (CDDP)-based chemotherapy. DNA damage represents one of the most important factors contributing to the toxic effects of CDDP-based chemotherapy. Previously, in a pilot study, we observed prognostic value of the DNA damage level in peripheral blood lymphocytes (PBLs) from chemo-naïve GCT patients. This study was aimed to validate the prognostic value of the DNA damage level in PBL in chemo-naïve, as well as chemotherapy pre-treated GCT patients. Methods: PBLs isolated from 123 GCT patients (101 chemotherapy-naïve and 22 chemotherapy pre-treated) baseline and before 2nd cycle of chemotherapy were included into this prospective study. The DNA damage levels in PBLs were evaluated by the Comet assay and scored as percentage of DNA in tail by the Metafer-MetaCyte analyzing software. The DNA damage level in PBL was categorized as ‘low’ or ‘high’ according to the cut-off level of the mean. Results: The mean ± SEM (standard error of the mean) of the endogenous DNA damage level was 5.25 ± 0.64. Chemotherapy-naïve patients with “low” DNA damage levels at baseline had significantly better progression-free survival (PFS) (hazard ratio [HR] = 0.05 95%CI (0.02 – 0.17), P = 0.0001) and overall survival (OS) (HR = 0.00, P = 0.0002, no death occurred in patients with “low” DNA damage level) compared to patients with “high” DNA damage levels. In multivariate analysis, prognostic value of the DNA damage level in PBL was significantly associated with PFS and OS independently of IGCCCG risk group. Moreover, there was significant correlation between the DNA damage level and response to treatment, non-pulmonary visceral metastases, number of metastatic sites, presence of mediastinal lymph nodes metastases and serum tumor markers level. There was no prognostic value of DNA damage level in PBL before 2nd cycle of chemotherapy and/or in pre-treated GCTs. Conclusions: These data suggest that the DNA damage levels in PBLs of GCT patients are a novel prognostic marker timely identifying patients with poor outcome. We hypothesize that altered DNA damage level in PBLs could be induced by GCTs similarly to cancer-related immunosuppression and is abolished by administration of chemotherapy. Legal entity responsible for the study: Michal Mego. Funding: VEGA 1/0043/18, APVV-15-0086. Disclosure: All authors have declared no conflicts of interest.

914P - Intermediate prognosis in metastatic germ cell tumors (IPGCT): Outcome and prognostic stratification

Background: Germ cell tumor patients with intermediate prognosis (IPGCT) according to the IGCCCG classification represent a heterogeneous group exhibiting a variety of clinical features. We established a registry to identify prognostic markers to further characterize IPGCT. Methods: A retrospective observational study was performed. Eligibility criteria were intermediate prognosis according to IGCCCG criteria, male sex, age ≥16 years. Patients were diagnosed from 1979 to 2014. Clinical characteristics were evaluated with uni- and multivariate analyses to detect new prognosticators. AFP and HCG were available in 85% and LDH levels in 72% of the cases, respectively. Overall survival (OS) was the primary endpoint. Results: The database included n = 707 IPGCT with a median follow-up of 8.6 years (IQR: 14.4). First line cisplatin-based chemotherapy was administered to 701 patients (99%) and the 5-year OS rate was 87%. First diagnosis in the 1980s (n = 115), the 1990s (n = 158), and after 2000 (n = 434) were associated with 5-year OS rates of 81%, 85%, and 89%, respectively. Statistical analyses revealed AFP and LDH, but not HCG levels prior chemotherapy as prognosticators. A patient stratification according to AFP levels 2000 to 5000 IU/ml (n = 93) and >5000 (n = 74) IU/ml prior first course of chemotherapy, revealed a significant correlation between AFP levels and OS, associated with 5-year OS rates of 89%, 87%, 86% and 82%, respectively (p = 0.037). LDH levels prior chemotherapy also correlated with outcome, associated with five-year OS rates of 92% for 3 to 4 ULN (n = 37), and 78% for >4 ULN (n = 89), respectively (p = 0.011). In multivariate analysis cut-off values of AFP levels >6000 IU/ml (p = 0.036; HR 2.096) and LHD levels >2 ULN (p = 0.02; HR 2.121) or > 3 ULN (p = <0.001; HR 2.305) were independent prognosticators for OS. Conclusions: Prognostication according to LDH and AFP levels prior chemotherapy could offer a new approach to stratify IPGCT. The largest fraction of patients had AFP levels <2000 IU/ml and LDH <2 ULN associated with an outcome similar to the good prognosis category. These results need to be confirmed in the upcoming IGCCCG reclassification. (Less)

The study of the correlation between 37 single nucleotide polymorphisms and testicular germ cell tumor

Objective To study associated single nucleotide polymorphisms (SNPs) with testicular germ cell tumors (TGCTs) patients in China, expect to find the different risk SNPs of domestic TGCTs. Methods Selecting 37 SNPs from foreign genome-wide association study about TGCTs as candidate SNPs in this experiment.76 TGCTs patients and 148 healthy men blood samples from three hospitals of China are genotyping in iMLDR™ for case-control. Results rs4624820, rs6897876, rs4324715, rs12699477, rs10463352, rs4888262, rs4617646, rs210138, rs8046148, rs2839186, rs3805663, rs4635969 are associated with TGCTs in China. rs10463352, rs12699477, rs755383, rs6897876, rs4624820, rs2900333, rs4617646, rs4324715 are related to seminoma. And rs10463352, rs12699477, rs210138, rs6897876, rs4617646, rs4624820, rs4324715 are related to non-seminoma. Conclusion The positive SNPs sites of TGCTs patients in the studied area of China are different from that of foreign TGCTs patients. There are also differences of positive SNPs sites between seminoma and non-seminoma. Key words: Testicular germ cell tumors; Susceptibility gene; Single nucleotide polymorphisms; Genetic susceptibility

Intermediate and long-term complications associated with adjuvant chemotherapy for stage I germ cell tumor patients.

Although platinum-based chemotherapy (CHT) remains the cornerstone of clinical stage I testicular germ cell tumor (GCT) treatment, its long-term toxicity and complications in cancer survivors are unclear. Cardiovascular disease and secondary malignancies represent the most life-threatening long-term complications and typically occur 10 years after treatment. Other potential intermediate deleterious effects include pulmonary toxicity, ototoxicity, neurotoxicity, hypogonadism and infertility. The incidence and time to onset vary according to patients' genetic susceptibility, CHT regimen and cumulative dosage. Genetic variability may play an important role as a harbinger of future disease and the development of biomarkers may help predict organ damage. Efforts should be concentrated in developing individualized strategies to identify patients who are at high risk of developing long-term complications after CHT for testicular GCTs. The treatment of clinical stage I testicular GCTs represents the paradigm of a curable malignancy and one of the greatest oncological advances of the twentieth century. Since the introduction of platinum-based CHT in the late 1970s, the 10-year survival rates exceed 95% today and patients can expect to live decades after being successfully treated. The curative nature of GCT treatment, however, is a double-edged sword and is hindered by an increased risk of potential intermediate and long-term complications. The recent focus of clinical research has thus shifted into the prevention of treatment-related long-term effects.

Retroperitoneal lymph node dissection in the setting of elevated markers.

The management of residual tumor masses in patients with metastatic germ cell tumor and persistently elevated tumor marker levels after first- and second-line chemotherapy usually excludes surgical resection. The lack of benefit of salvage chemotherapy in patients with persistently elevated markers implies a degree of chemotherapy resistance. However, previous studies demonstrated therapeutic efficacy for a surgical approach in these very particular patients. Therefore, we evaluated pre and postoperative factors, which help to identify suitable candidates, who could potentially benefit from tumor resection. Preoperative parameters, which predict favorable outcomes, include good prognosis according to the International Germ Cell Cancer Collaborative group, a high preoperative level of alpha-fetoprotein in contrast to a high level of β-HCG, stable or decreasing preoperative tumor markers and teratomatous elements in the initial testicular tumor. Retroperitoneal and mediastinal lymph nodes as target lesions are predictive for good long-term outcome due to the higher chance of complete tumor resection. Teratoma or necrosis in the resected residual tissue and postoperative marker normalization additionally represent a favorable prognosis. Even in advanced chemorefractory germ cell tumor patients with elevated tumor markers the disease remains curative with radical surgery as a salvage option, if a complete resection can be achieved. Thus, a surgical approach should always be considered in the management of selected patients to avoid unnecessary salvage chemotherapy.

Reproductive outcomes of 105 malignant ovarian germ cell tumor survivors: a multicenter study

Malignant ovarian germ cell tumors usually occur in young women. Until the 1970s, before establishment of systemic chemotherapy, malignant ovarian germ cell tumors had a very poor prognosis. Recently, prognosis has improved, and fertility-sparing treatment is being adopted in patients who desire to become pregnant. However, the number of malignant ovarian germ cell tumor survivors who actually became pregnant remains unknown. The present study aimed to clarify the reproductive outcomes in malignant ovarian germ cell tumor survivors by using data from a multicenter database and an additional survey on reproductive outcomes. The study used the Tokai Ovarian Tumor Study Group database on ovarian cancer patients. We assessed the database from 1986 through 2016 and selected malignant ovarian germ cell tumor patients <40 years of age who received fertility-sparing treatment. Questionnaires on reproductive outcomes were sent to the registered facilities. The following data were collected and used in this study: age, date of onset, surgical procedure, chemotherapy regimen, tumor type, International Federation of Gynecology and Obstetrics stage, survival outcome and period, number of pregnancies and childbirths, marital status, childbearing desire, method of pregnancy, gestational weeks at delivery, birthweight of the baby, obstetric complications, and menstrual status after fertility-sparing treatment. A total of 110 malignant ovarian germ cell tumor patients who received fertility-sparing treatment were identified. The median follow-up period was 10.4 years. Five patients were excluded because of death or loss of fertility after treatment for recurrence. Thus, 105 patients were finally included. The additional survey revealed that 42 of 45 patients who desired childbirth became pregnant. The total number of pregnancies was 65, and 56 babies were born to 40 malignant ovarian germ cell tumor survivors. The reproductive outcomes of malignant ovarian germ cell tumor survivor are promising with fertility-sparing treatment. Malignant ovarian germ cell tumor survivors can become pregnant and give birth if they desire.

Baseline characteristics and patterns of care in testicular cancer patients: first data from the Swiss Austrian German Testicular Cancer Cohort Study (SAG TCCS)

The majority of germ cell tumour (GCT) patients can be cured by orchiectomy followed by active surveillance or subsequent systemic and/or local treatments. There are various guidelines for a structured follow-up including radiographic and clinical examinations. The Swiss Austrian German Testicular Cancer Cohort Study (SAG TCCS) prospectively evaluates follow-up, indicator of relapse and late toxicities. This is a descriptive analysis; we present baseline characteristics and treatment strategies for the first 299 patients with primary GCT or relapsed GCT after completion of treatment. Of the patients included in this study, 192 (64.2%) had seminoma and 107 (35.8%) non-seminoma. Mean age was 41 years (standard deviation [SD] 11.7) for seminoma and 31 (SD 9.3) years for non-seminoma patients. Median tumour size was 3.5 cm (interquartile range 2.5¬‒5.0 and 2.3‒4.5 in seminoma and non-seminoma, respectively) in both histological groups. Among seminoma patients, 81 (42.2%) had primary tumours >4cm; 154 (80.2%) seminoma patients had stage I, 26 (13.5%) stage II and 12 (6.3%) stage III disease. Fifty-seven (53.3%) non-seminoma tumours were stage I, 29 (27.1%) stage II and 21 (19.6%) stage III. Marker-positive disease was present in 58 (30.2%) seminoma patients and 78 (72.9%) non-seminoma patients. Of 154 stage I seminoma patients, 89 (57.8%) chose active surveillance and 65 (42.2%) adjuvant chemotherapy. Twenty-six (45.6%) stage I non-seminoma patients had high-risk disease; 23 of these were treated with adjuvant chemotherapy and 3 chose active surveillance. Among the 30 (52.6%) low risk stage I patients, all opted for active surveillance. Twelve (46.2%) stage II seminoma patients had radiotherapy, 14 (53.8%) were treated with three to four cycles of chemotherapy. All stage III seminoma patients, and all stage II and III non-seminoma patients were treated with three to four cycles of chemotherapy. Treatment decisions were made at the respective centre. Eleven patients did not receive therapy that conformed with guidelines. It is important to enrol GCT patients in prospective studies in general, but also in follow-up studies to assess baseline characteristics, oncological outcome, and long-term toxicity and to validate the performance of follow-up schedules. This is the first time that the distribution of disease, detailed baseline characteristics and the respective treatment of men with GCT is collected in a prospective manner in German speaking countries (Switzerland, Austria and Germany) and therefore patterns of care have been evaluated. SAG TCCS results will inform on future modifications of surveillance schedules and follow-up procedures. NCT02229916 (Clinicaltrials.gov).

Dose-reduced first cycle of chemotherapy for prevention of life-threatening acute complications in nonseminomatous germ cell tumor patients with ultra high tumor markers and/or poor performance status.

Patients with metastatic nonseminomatous germ cell tumors (mNSGCT) and a high tumor burden or a poor performance status at initial diagnosis are at risk from potentially life-threatening early complications during or after the first chemotherapy cycle. The outcomes with dose-reduced first cycle of chemotherapy in this population of patients are not well established. We performed a retrospective analysis of patients with mNSGCT and International Germ Cell Cancer Collaborative Group (IGCCCG) poor risk features. All patients received cisplatin and etoposide-based combinations as first-line treatment. Ultra high tumor marker levels were defined as α-fetoprotein ≥ 100,000ng/ml or human chorionic gonadotropin ≥ 200,000mIU/ml. Before 2005, the first treatment cycle was administered at a full dose in our center. After 2005, we used an abbreviated course of cisplatin and etoposide (EP) for the first cycle, followed by subsequent full-dose administration. From 1987 to 2012, 265 patients with poor risk features according to IGCCCG received first-line chemotherapy. Among them, 63 out of 265 (24%) patients had ultra high tumor marker levels and/or ECOG performance status of 3-4. Dose reduction of the first chemotherapy cycle was associated with a significant decrease of life-threatening complications from 76 to 44% (p = 0.01), but not with the overall survival (HR 0.99, 95% CI 0.44-2.26). Dose reduction of the first EP cycle by 40-60% in the subgroup of poor risk patients with ultra high tumor marker levels and/or ECOG performance status 3-4 is associated with significantly lowered acute complication rates but not with overall survival.