Testicular Germ Cell Cancer Research Articles

Clinical outcome of postchemotherapy retroperitoneal lymph node dissection and predicting retroperitoneal histology in advanced nonseminomatous germ cell tumours of the testis

Objective: To explore the clinical outcome of advanced testicular nonseminomatous germ cell cancer patients undergoing post chemotherapy retroperitoneal lymph node dissection (PC-RPLND), and to analyze the relevant prognostic factors of lymph node pathological. Methods: A total of 43 consecutive testicular nonseminomatous germ cell cancer patients underwent PC-RPLND between March 2001 and December 2014 in Department of Urology at Sun Yat-sen University Cancer Center were retrospectively reviewed. The average age of the patients was (29.0±11.5) years (ranging from 12 to 58 years). Before PC-RPLND, 22 patients were classified as phase Ⅱ, while 21 were phase Ⅲ. Primary tumor histology revealed seminomatous elements in 19 cases, embryonal cell carcinoma in 22 cases, yolk sac tumor in 13 cases, chorionic carcinoma in 3 cases, mature teratomatous elements in 11 and immature teratomatous elements in 2 cases. Patients were treated with cisplatin-based chemotherapy after orchectomy and then underwent surgical resection of retroperitoneal lymph nodes.After PC-RPLND, all patients underwent a periodic review including the blood routine, biochemistry routine and computed tomography or ultrasonograph of the chest, the abdomen and the pelvis. The association of pathological data with patient's clinic features and the correlations between molecular features detected with each other were assessed by the t test, χ(2) and Fisher's exact test. Multivariate logistic regression were used to assess prognostic factors. Results: The median operative time was 278 minutes (ranging from 50 to 715 minutes). Median blood loss was 425 ml (ranging from 50 to 5 000 ml). Eight patients received blood transfusion intra-operatively, 2 patients underwent adjunctive surgical procedures, 4 patients developed ileus and 4 had an ascites chylosus following PC-RPLND, 1 patient had a postoperative hyperthermia and retrograde ejaculation was present in 10 patients. The transverse diameter of the residual tumor in patients ranged from 0.8 to 18.2 cm. Necrosis, teratoma and viable germ cell tumors were found in 15, 17 and 11 of all patients. The median follow-up time was 46 months (ranging from 6 to 169 months). There were 39 patients had no tumor recurrence, 7 patients were found recurrence after PC-RPLND, 5 died of malignant germ cell tumor. The normal serum lactate dehydrogenase (LDH) level before chemotherapy (HR=25.811, 95%CI: 0.678 to 982.624, P=0.017) and relative changes more than 50% in retroperitoneal lymph node size (HR=0.016, 95%CI: 0 to 0.698, P=0.032) were statistically significant prognostic factors of the presence of necrosis. Conclusions: Since most residual masses are not sensitive to chemotherapy, PC-RPLND is still an essential part of the treatment of metastatic testicular nonseminomatous germ cell cancer. Patients with the normal serum LDH level before chemotherapy and a shrinkage of 50% or more in retroperitoneal mass have a considerably chance of having necrosis in the retroperitoneum resection. This may help to refine the selection of candidates for PC-RPLND.

Postnatal risk factors for testicular cancer: The EPSAM case-control study.

Testicular cancer is considered to originate from an impaired differentiation of fetal germ cells, but puberty could represent another time window of susceptibility. Our study aimed at investigating the association between environmental exposures acting during puberty/adolescence (13-19 years of age) and the risk of testicular cancer. We used data of the EPSAM study, a case-control study on germ-cell testicular cancer conducted in the province of Turin, Italy, involving cases diagnosed between 1997 and 2008. Histologically confirmed cases (n = 255) and controls (n = 459) completed a postal questionnaire focusing in particular on the pubertal period (namely age 13 years) with questions on physical activity (competitive sports, gardening), lifestyle (alcohol consumption, smoking), occupational history and medical conditions. All analyses were adjusted for the matching variables, cryptorchidism and educational level. Having done at least one competitive sport during puberty (odds ratio [OR]: 0.72, 95% confidence interval: 0.52-1.00), gardening activities during puberty (OR: 0.62, 0.42-0.94) and having a lower weight than peers during puberty (OR: 0.64, 0.42-0.97) were all inversely associated with the risk of testicular cancer. No evidence of association between smoking or alcohol consumption during puberty and the risk of testicular cancer was observed. Regarding agriculture-related occupations, we found an association with the risk of testicular cancer both for occasional jobs during puberty (OR: 2.40, 95% CI: 1.08-5.29) and ever employment in adolescence (OR: 2.59, 95% CI: 0.83-8.10). Our results suggest that postnatal exposures could play a role in testicular cancer aetiology, at least when acting in puberty or adolescence.

Regulation of fetal male germ cell development by members of the TGFβ superfamily

There is now substantial evidence that members of the transforming growth factor-β (TGFβ family) regulate germ cell development in the mouse fetal testis. Correct development of germ cells during fetal life is critical for establishment of effective spermatogenesis and for avoiding the formation of testicular germ cell cancer in later life. Here we consider the evidence for involvement of various TGFβ family members, attempt to reconcile discrepancies and clarify what we believe to be the likely in vivo roles of these factors.

MicroRNA-371a-3p as informative biomarker for the follow-up of testicular germ cell cancer patients

Purposeα-fetoprotein (AFP) and human chorionic gonadotropin subunit beta (B-HCG) are informative serum biomarkers for the primary diagnosis and follow-up of testicular germ cell cancer (TGCC) patients. About 20% of TGCC patients with a non-seminoma (NS) and about 80% with a seminoma (SE) are, however, negative for these biomarkers. Embryonic stem cell microRNAs (miRs) may serve as promising alternative serum biomarkers. Here we investigated a retrospective series of serum samples from selected TGCC patients who developed a relapse in time to test the possible additional value of the serum-based ampTSmiR test compared to the conventional serum-based protein biomarkers for follow-up.MethodsWe investigated 261 retrospective serum samples of six selected fully evaluated TGCC patients with a proven relapse using the ampTSmiR test for miR-371a-3p, miR-373-3p, and miR-367-3p and compared the results to those of the conventional protein biomarkers.ResultsAt primary diagnosis, elevated serum B-HCG, AFP and LDH levels were found to be informative in 4/6, 3/6 and 3/6 patients, respectively. At primary diagnosis the levels of miR-371a-3p and miR-373-3p were elevated in 4/4, and miR-367-3p in 3/4 patients. For two cases no starting serum sample was available for retrospective miR analysis. Residual disease (overlooked by histopathological examination) was detected in one case by miR-371a-3p only. The miR-371a-3p level was increased in one patient two months before detection of an intracranial metastasis. B-HCG was informative in 3/4 and the ampTSmiR test in 4/4 patients with a relapse or residual disease. None of the biomarkers were informative for the detection of residual mature teratoma.ConclusionsThe ampTSmiR test is more sensitive than the conventional TGCC protein biomarkers for the detection of residual disease and relapse, excluding mature teratoma.

Risk of low bone mineral density in testicular germ cell cancer survivors: association with hypogonadism and treatment modality.

The cure rate of testicular cancer exceeds 95%, but testicular cancer survivors (TCS) are at increased risk of hypogonadism (HG). It has been suggested that TCS have reduced bone mineral density (BMD), but it is unclear whether this is related to HG or a direct effect of cancer therapy. The aim of this study was to evaluate whether TCS have decreased BMD, and if BMD is related to HG and/or the cancer treatment given. We investigated 91 TCS (mean age at diagnosis: 31years; mean 9.3years follow-up) and equal number of age matched controls (mean age at inclusion 40.3years and 41.2years, respectively). Total testosterone and LH were measured. BMD was determined using dual-energy X-ray absorptiometry (DXA). Low BMD (LBD) was defined as Z-score <-1. Compared to eugonadal TCS, both TCS with untreated HG (mean difference: -0.063g/cm2 ; 95% CI: -0.122; -0.004 p=0.037) and TCS receiving androgen replacement (mean difference -0.085g/cm2 ; 95% CI: -0.168; -0.003; p=0.043) presented with statistically significantly 6-8% lower hip BMD. At the spine, L1-L4, an 8% difference reached the level of statistical significance only for those with untreated HG (mean difference: -0.097g/cm2 ; 95% CI: -0.179; -0.014; p=0.022). TCS with untreated HG had significantly increased OR for spine L1-L4 LBD (OR=4.1; 95% CI: 1.3; 13; p=0.020). The associations between the treatment given and BMD were statistically non-significant, both with and without adjustment for HG. In conclusion, TCS with HG are at increased risk of impaired bone health. Prevention of osteoporosis should be considered as an important part in future follow up of these men.

Генетические факторы риска развития спорадических герминогенных опухолей яичка

Approximately 95% of all testicular cancers are testicular germ cell tumors (GCTTs), represented by seminoma and nonseminoma germ cell testicular cancer. There is a hypothesis that the formation of GCTTs begins in early embryogenesis being a part of testicular dysgenesis syndrome (TDS). To determine the role of genetic factors in the development of GCTTs. We studied the frequency of alleles and genotypes KITLG (rs995030, rs1508595), SPRY4 (rs4624820, rs6897876) and BAK1 (rs210138) in 97 fertile men (control), and 73 patients with GCTTs (34 seminoma and 39 nonseminoma). GCTTs were statistically significantly associated with KITLG rs1508595 gene (p=0.0003 for allele G, p=0.0014 for genotype GG), and with rs995030 gene (p=0.0031 for genotype GG). When comparing patients with seminoma and control group, statistically significant differences were found for SPRY4 rs4624820 (p=0.0226 for the A and p=0.04 for the AA), for KITLG rs995030 (p=0.0375 for the G and p=0.0282 for GG), rs1508595 (p=0.0306 for G), for BAK1 rs210138 (p=0.0329 for the G and p=0.0219 for the GG). When comparing patients with nonseminoma and fertile men, statistically significant differences were found only for KITLG rs1508595 (p=0.0005 for the G and p=0.0021 for the GG). There was no statistically significant difference between the allele and genotype frequencies of the investigated genes from seminoma and nonseminoma GCTTs patients. However, these groups differed statistically significantly when genotype combinations of the three genes were investigated (p=0,029; OR 3,709 [1.147-11.99]). The combination of genotypes of the three genes was found to increase the risk of GCTTs by 6.5 times (p=0.0005; OR 6.526 [2.078-20.5], and the risk for seminoma was over 12-fold (p<0.0001; OR 12,68 [3,731-43,11]. A comprehensive study of genotypes associated with GCTTs in patients with manifested TDS can be used for risk stratification to identify and follow-up high-risk patients, develop approaches to family counseling and treatment, which is the basis for predictive medicine.

Abstract B14: A novel role for BRD9 in regulating cellular growth and DNA damage response pathways

Abstract Bromodomain containing protein BRD9 has been identified as a component of the SWI/SNF chromatin remodeling complex. Next generation sequencing studies have revealed that SWI/SNF is the most highly perturbed chromatin remodeling complex in cancer with subunit mutations present in approximately 20% of all tumor types. SWI/SNF has been implicated as both tumor suppressor and oncogenic driver in diverse contexts. For example, the catalytic subunit SMARCA4 functions as an oncogenic driver, essential for the maintenance of hematologic malignancies such as leukemia. In contrast, loss of function of the ATPase subunit SMARCA4 and the ARID1a subunit precipitate loss of tumor suppressor activity and are apparent in lung and ovarian subtypes. However, the role of BRD9 has not been clearly delineated. Clinical data indicates that testicular germ cell cancer (66%) and esophageal cancer (18%) bear a hemizygous deletion of BRD9 conferring HETLOSS status. Loss of BRD9 heterozygosity leading to enhanced tumorigenic potential is a hallmark of tumor suppressors. This highlights a novel role for this bromodomain protein in regulating the process of oncogenesis. Here we demonstrate shRNA-mediated knockdown of BRD9 enhances clonogenic potential of solid tumor cancer cell lines, while expression of wild-type BRD9 in a HETLOSS cell line abrogates colony formation. Collectively, our data suggests BRD9 functions as a regulator of cellular growth. We examined if SWI/SNF chromatin remodeling activity was dependent on BRD9 status and how this correlated with the growth phenotype. Nucleosome accessibility was significantly decreased when BRD9 was depleted indicating chromatin exists in a more compacted conformation. However, BRD9 knockdown does not result in alterations in assembly or stability of the SWI/SNF complex. Though loss of BRD9 does not perturb SWI/SNF dynamics, it may be required for complex recruitment to chromatin directly or by tethering through protein-protein interactions. Identification of novel BRD9-interacting proteins that target recruitment was carried out by proteomic survey. Analysis of the study revealed enrichment of proteins involved in DNA damage repair pathways. Using a double strand break reporter, we examined if BRD9 depletion perturbed homology-directed or non-homologous end joining repair pathways. Knockdown of BRD9 increased NHEJ-associated reporter activity but had subtle effect on homology-directed repair events. BRD9 colocalizes with γH2AX foci upon damage but this colocalization is lost upon depletion of BRD9. We propose that BRD9 is necessary for recruitment of SWI/SNF to sites of damage, to permit chromatin expansion and assembly of homology-directed repair factors. However, knockdown of BRD9 may shift the balance and favor interactions of non-homologous end joining pathway players to sites of damage, resulting in enhanced error-prone repair and ultimately leading to oncogenic transformation. Collectively, this work highlights a novel and previously unidentified role for BRD9 in DNA damage pathways and identifies a potential vulnerability in NHEJ dependence that may be therapeutically targeted. Citation Format: Caroline Vallaster, Farzin Gharadaghi, Alexis Cocozaki, Kelly Jacques, Brendan Price, Sylvie Guichard. A novel role for BRD9 in regulating cellular growth and DNA damage response pathways [abstract]. In: Proceedings of the AACR Special Conference on DNA Repair: Tumor Development and Therapeutic Response; 2016 Nov 2-5; Montreal, QC, Canada. Philadelphia (PA): AACR; Mol Cancer Res 2017;15(4_Suppl):Abstract nr B14.

Role of Imaging in Testicular Cancer

Testicular malignancy is the most common nonhematologic malignancy in young men. Around 95% of them are germ cell tumors (GCTs), and with correct assessment of the disease and application of chemotherapy and radiotherapy survival rates of more than 90% can be achieved. Imaging studies not only aid in the diagnosis of testicular cancer but also help determine the tumor extent and site of metastatic disease, in monitoring treatment response, surgical planning and detecting sites of relapse and residual disease. Scrotal sonography combined with clinical examination has a high sensitivity for diagnosing testicular cancer and thus is often the first imaging modality to be performed on patients presenting with testicular mass. Abdominal and pelvic CT and chest CT remain the preferred techniques for staging, monitoring of treatment response, and detecting relapse and residual disease in patients with testicular cancer but MRI, PET with 18F-FDG (fluorodeoxyglucose) and sonography also show promises in certain situations. This article reviews the literatures on the role of imaging in the management of testicular germ cell cancer. Keywords: Testicular cancer, Testicular mass, CT, MRI, Diagnosis, Staging, Imaging.

Epigenetic and risk factors of testicular germ cell tumors: a brief review.

Testicular germ cell cancer (TGCT) is the most common malignancy among young adult males, which has become important due to its increased incidence and mortality in the population worldwide. The etiology is multifactorial. Recent studies have shown some associations between the development of isolated TGCT and certain risk factors, such as exposure to endocrine disruptors, cryptorchidism, and family history of cancer, in order to identify the key pieces in carcinogenesis. Some of the most important findings in recent years is the association of different genes, such as c-KIT/KITLG, expression of the miR-371-373 cluster and protein expression as c-KIT and POU5F1 in the development of this neoplasia, and the identification of new molecular markers as TGFBR3 gene, identifying aberrant methylation patterns in promoter regions of several genes, expression of miR-1297 which regulates PTEN and protein expression as DMTR1. In the future, a multidisciplinary research strategy could provide valuable new insights into the etiology of TGCTs, which support clinical diagnosis of TGCT in the next years to increase survival in this kind of patients.

Leydig cell clustering and Reinke crystal distribution in relation to hormonal function in adult patients with testicular dysgenesis syndrome (TDS) including cryptorchidism.

Testicular dysgenesis syndrome (TDS) comprises testicular germ cell cancer, cryptorchidism and some cases of male infertility and hypospadias, which can be linked to impairment of intrauterine gonadal development. Among histological signs of TDS, large Leydig cell (LC) clusters (micronodules) are frequently present. This study aimed to investigate possible associations of LC micronodules with the presence of Reinke crystals and hormonal function of LCs, the latter primarily reflected by serum concentrations of luteinising hormone (LH) and testosterone, in patients with TDS. A retrospective study of 101 andrological patients with TDS (infertility with and without a history of cryptorchidism or presence of germ cell neoplasia in situ) and 20 controls with normal testis histology and LC-function. Archived testicular biopsies were re-evaluated for the presence of LC micronodules and Reinke crystals and the findings were correlated with testis size and serum concentrations of LH, follicle-stimulating hormone (FSH), testosterone, inhibin B, estradiol and sex hormone binding globulin (SHBG). TDS patients with bilateral LC micronodules had significantly lower concentrations of LH, FSH and inhibin B, a lower testosterone/LH-ratio and smaller testis sizes compared to TDS-patients lacking this feature. Presence of LC micronodules was correlated with a lower number of Reinke crystals, while cryptorchid testes had a significantly higher number of crystals than normally descended TDS testes. LC micronodules appear to be a compensatory mechanism caused by androgenic failure and are presumably driven by high concentrations of LH. A relative paucity of Reinke crystals in LCs within micronodules in normally descended TDS testes may be a feature of recently renewed immature Leydig cells. The increased number of Reinke crystals in LCs in testes that were either undescended at birth or are persistently undescended could indicate an impairment of LC renewal in cryptorchidism.

The bromodomain inhibitor JQ1 triggers growth arrest and apoptosis in testicular germ cell tumours in vitro and in vivo.

Type II testicular germ cell cancers (TGCT) are the most frequently diagnosed tumours in young men (20–40 years) and are classified as seminoma or non‐seminoma. TGCTs are commonly treated by orchiectomy and chemo‐ or radiotherapy. However, a subset of metastatic non‐seminomas (embryonal carcinomas) displays only incomplete remission or relapse and requires novel treatment options. Recent studies have shown effective application of the small‐molecule inhibitor JQ1 in tumour therapy, which interferes with the function of ‘bromodomain and extraterminal (BET)’ proteins. JQ1‐treated TGCT cell lines display up‐regulation of genes indicative for DNA damage and cellular stress response and induce cell cycle arrest. Embryonal carcinoma (EC) cell lines, which presented as JQ1 sensitive, display down‐regulation of pluripotency factors and induction of mesodermal differentiation. In contrast, seminoma‐like TCam‐2 cells tolerated higher JQ1 concentrations and were resistant to differentiation. ECs xenografted in vivo showed a reduction in tumour size, proliferation rate and angiogenesis in response to JQ1. Finally, the combination of JQ1 and the histone deacetylase inhibitor romidepsin allowed for lower doses and less frequent application, compared with monotherapy. Thus, we propose that JQ1 in combination with romidepsin may serve as a novel therapeutic option for (mixed) TGCTs.

Heat Sensing Receptor TRPV1 Is a Mediator of Thermotaxis in Human Spermatozoa.

The molecular bases of sperm thermotaxis, the temperature-oriented cell motility, are currently under investigation. Thermal perception relies on a subclass of the transient receptor potential [TRP] channels, whose member TRPV1 is acknowledged as the heat sensing receptor. Here we investigated the involvement of TRPV1 in human sperm thermotaxis. We obtained semen samples from 16 normozoospermic subjects attending an infertility survey programme, testis biopsies from 6 patients with testicular germ cell cancer and testis fine needle aspirates from 6 patients with obstructive azoospermia undergoing assisted reproductive technologies. Expression of TRPV1 mRNA was assessed by RT-PCR. Protein expression of TRPV1 was determined by western blot, flow cytometry and immunofluorescence. Sperm motility was assessed by Sperm Class Analyser. Acrosome reaction, apoptosis and intracellular-Ca2+ content were assessed by flow cytometry. We found that TRPV1 mRNA and protein were highly expressed in the testis, in both Sertoli cells and germ-line cells. Moreover, compared to no-gradient controls at 31°C or 37°C (Ctrl 31°C and Ctrl 37°C respectively), sperm migration towards a temperature gradient of 31–37°C (T gradient) in non-capacitated conditions selected a higher number of cells (14,9 ± 4,2×106 cells T gradient vs 5,1± 0,3×106 cells Ctrl 31°C and 5,71±0,74×106 cells Ctrl 37°C; P = 0,039). Capacitation amplified the migrating capability towards the T gradient. Sperms migrated towards the T gradient showed enriched levels of both TRPV1 protein and mRNA. In addition, sperm cells were able to migrate toward a gradient of capsaicin, a specific agonist of TRPV1, whilst capsazepine, a specific agonist of TRPV1, blocked this effect. Finally, capsazepine severely blunted migration towards T gradient without abolishing. These results suggest that TRPV1 may represent a facilitating mediator of sperm thermotaxis.

Emerging roles of RAC1 in treating lung cancer patients.

The Ras-related C3 botulinum toxin substrate 1 (RAC1), a member of the Rho family of small guanosine triphosphatases, is critical for many cellular activities, such as phagocytosis, adhesion, migration, motility, cell proliferation, and axonal growth. In addition, RAC1 plays an important role in cancer angiogenesis, invasion, and migration, and it has been reported to be related to most cancers, such as breast cancer, gastric cancer, testicular germ cell cancer, and lung cancer. Recently, the therapeutic target of RAC1 in cancer has been investigated. In addition, some investigations have shown that inhibition of RAC1 can reverse drug-resistance in non-small cell lung cancer. In this review, we summarize the recent advances in understanding the role of RAC1 in lung cancer and the underlying mechanisms and discuss its value in clinical therapy.

The biology of germ cell tumors in disorders of sex development.

Development of a malignant germ cell tumor, i.e., germ cell cancer (GCC) in individuals with disorders of sex development (DSD) depends on a number of (epi-)genetic factors related to early gonadal- and germ cell development, possibly related to genetic susceptibility. Fetal development of germ cells is orchestrated by strict processes involving specification, migration and the development of a proper gonadal niche. In this review we will discuss the early (epi-)genetic events in normal and aberrant germ cell and gonadal development. Focus will be on the formation of the precursor lesions of GCC in individuals who have DSD. In our view, expression of the different embryonic markers in, and epigenetic profile of the precursor lesions reflects the developmental stage in which these cells are blocked in their maturation. Therefore, these are not a primary pathogenetic driving force. Progression later in life towards a full blown cancer likely depends on additional factors such as a changed endocrine environment in a susceptible individual. Genetic susceptibility is, as evidenced by the presence of specific risk genetic variants (SNPs) in patients with a testicular GCC, related to genes involved in early germ cell and gonadal development.

Androgen receptor gene CAG and GGN repeat lengths as predictors of recovery of spermatogenesis following testicular germ cell cancer treatment.

Spermatogenesis is an androgen-regulated process that depends on the action of androgen receptor (AR). Sperm production may be affected in men treated for testicular cancer (TC), and it is important to identify the factors influencing the timing of spermatogenesis recovery following cancer treatment. It is known that the CAG and GGN repeat numbers affect the activity of the AR; therefore, the aim of this study is to investigate if the CAG and GGN polymorphisms in the AR gene predict recovery of sperm production after TC treatment. TC patients (n = 130) delivered ejaculates at the following time points: postorchiectomy and at 6, 12, 24, 36, and 60 months posttherapy (T0, T6, T12, T24, T36, and T60). The CAG lengths were categorized into three groups, <22 CAG, 22–23 CAG, and >23 CAG, and the GGN tracts were also categorized into three groups, <23 GGN, 23 GGN, and >23 GGN. At T12, men with 22–23 CAG presented with a statistically significantly (P = 0.045) lower sperm concentration than those with other CAG numbers (8.4 × 106 ml−1 vs 16 × 106 ml−1; 95% CI: 1.01–2.65). This association was robust to omitting adjustment for treatment type and sperm concentration at T0 (P = 0.021; 3.7 × 106 ml−1 vs 10 × 106 ml−1; 95% CI: 1.13–4.90). The same trends were observed for total sperm number. The least active AR variant seems to be associated with a more rapid recovery of spermatogenesis. This finding adds to our understanding of the biology of postcancer therapy recovery of fertility in males and has clinical implications.

SEOM clinical guidelines for the management of germ cell testicular cancer (2016).

Testicular cancer represents the most common malignancy in males aged 15–34 years and is considered a model of curable neoplasm. Maintaining success, reducing treatment burden, and focusing on survivorship are then key objectives. Inguinal orchiectomy is the first recommended maneuver that has both diagnostic and therapeutic aims. Most patients are diagnosed with stage I disease (confined to the testicle). Close surveillance and selective, short-course adjuvant chemotherapy are accepted alternatives for these cases. In patients with more advanced disease (stages II and III), 3–4 courses of cisplatin-based chemotherapy (according to IGCCCG risk classification) followed by the judicious surgical removal of residual masses represent the cornerstone of therapy. Poor-risk patients and those failing a first-line therapy should be referred to specialized tertiary centers. Paclitaxel-based conventional chemotherapy and high-dose chemotherapy plus autologous hematopoietic support can cure a proportion of patients with relapsing or refractory disease.

Role of DNA repair machinery and p53 in the testicular germ cell cancer: a review.

Notwithstanding the peculiar sensitivity to cisplatin-based treatment, resulting in a very high percentage of cures even in advanced stages of the disease, still we do not know the biological mechanisms that make Testicular Germ Cell Tumor (TGCT) “unique” in the oncology scene. p53 and MDM2 seem to play a pivotal role, according to several in vitro observations, but no correlation has been found between their mutational or expression status in tissue samples and patients clinical outcome. Furthermore, other players seem to be on stage: DNA Damage Repair Machinery (DDR) , especially Homologous Recombination (HR) proteins, above all Ataxia Telangiectasia Mutated (ATM), cooperates with p53 in response to DNA damage, activating apoptotic cascade and contributing to cell “fate”. Homologous Recombination deficiency has been assumed to be a Germ Cell Tumor characteristic underlying platinum-sensitivity, whereby Poly(ADP-ribose) polymerase (PARP), an enzyme involved in HR DNA repair, is an intriguing target: PARP inhibitors have already entered in clinical practice of other malignancies and trials are recruiting TGCT patients in order to validate their role in this disease. This paper aims to summarize evidence, trying to outline an overview of DDR implications not only in TGCT curability, but also in resistance to chemotherapy.

Association between abdominal adiposity, muscle mass, and metabolic syndrome in survivors of testicular germ cell cancer.

250 Background: Testicular germ cell tumor survivors (TGCTSs) contend with treatment side effects for decades after cure, and many have metabolic syndrome (MTS), a modifiable cardiometabolic risk factor. Because reliably predicting MTS could prompt interventionreducing risk, we analyzed clinical data and body composition in computed tomography (CT) scans to identify associations. Methods: In a retrospective review of 196 TGCTSs treated at a single institution from 1970 to 2007, we collected patient (pt) demographics, clinical data, body fat composition measures, and evidence from CT scans from baseline through posttreatment. NIH Image J was used to analyze cross-sectional CT images and measured subcutaneous adipose tissue, visceral adipose tissue, and skeletal muscle. Visceral fat-to-muscle ratio (VMR), visceral-to-subcutaneous fat ratio (VSR), and change in VMR and VSR from baseline to 3 to 5 years posttreatment (ΔVMR and ΔVSR) were calculated. We also gathered posttreatment glucose, blood pressure, lipid data, and body weight and height measured at time of scans. The 2001 U.S. National Cholesterol Education Program Adult Treatment Panel III guideline defined MTS. Univariate and multivariate logistic regression analyses identified associations. Results: Of the 167 pts included in the final analysis, 37.7% had MTS, 76.6% were white, and 68.9% had chemotherapy. Pts with MTS had significantly higher VMRs (p = .007) and VSRs (p = .021) than those without. Pts receiving chemotherapy and radiotherapy were significantly more likely to have MTS (p = .044 and p = .037). A multinomial logistic regression model including year of diagnosis, age, race, tumor histology, treatment, VSR, and VMR identified the association of high VMR and VSR with MTS; ΔVMR and ΔVSR were not statistically significant predictors. Conclusions: Body composition analyses identified VMR and VSR as significant predictors of MTS.

Second Malignant Neoplasms and Cause of Death in Patients With Germ Cell Cancer

ImportancePatients given systemic treatment for testicular germ cell cancer (GCC) are at increased risk for a second malignant neoplasm (SMN). Previous studies on SMN and causes of death lacked information on the exact treatment applied or were based on patients receiving former treatment options.ObjectiveTo evaluate the treatment-specific risks for SMN and death in a nationwide population-based cohort of patients with GCC treated with current standard regimens.Design, Setting, and ParticipantsThis study examined a Danish nationwide cohort of 5190 men with GCC who entered the Danish Testicular Cancer database between January 1, 1984, and December 31, 2007. Treatment results were compared with a randomly sampled, age-stratified, population-based control group. Cases of gonadal and extragonadal primary were included in the nationwide cohort. The treatments were surveillance only; retroperitoneal radiotherapy (RT); bleomycin, etoposide, and cisplatin (BEP); or more than 1 line of treatment (MTOL).Main Outcomes and MeasuresCumulative incidence and hazard ratios (HRs) for SMN and death calculated by the Cox proportional hazards model were compared with those of age-matched controls.ResultsThe study population comprised 2804 patients with seminoma and 2386 with nonseminoma. The median follow-up was 14.4 years (interquartile range, 8.6-20.5 years). The 20-year cumulative incidence of SMN with death as a competing risk was 7.8% (surveillance), 7.6% (BEP), 13.5% (RT), 9.2% (MTOL), and 7.0% (controls). We found no increased risk for SMN after surveillance, while the HRs were 1.7 (95% CI, 1.4-2.0), 1.8 (95% CI, 1.5-2.3), and 3.7 (95% CI, 2.5-5.5), respectively, after BEP, RT, and MTOL. Mortality owing to non-GCC causes was decreased after surveillance, but increased by 1.3 times after BEP and RT and by 2.6 times after MTOL. Excess mortality due to SMN was found after BEP (HR, 1.6; 95% CI, 1.2-2.2), RT (HR, 2.1; 95% CI, 1.5-2.9), and MTOL (HR, 5.8; 95% CI, 3.6-9.6).Conclusions and RelevanceWe found no increased risk for SMN or death among patients undergoing surveillance only. The risks for SMN and death due to SMN were increased after BEP alone, RT alone, and MTOL. Approaches to define patients who might benefit from less intensive treatment are needed.

Metastatic Testicular Choriocarcinoma Leading to Upper GI Bleed

Introduction: Testicular cancer is the most common neoplasia in men between the ages of 15 to 35 years. Choriocarcinoma represent less than 1% of testicular tumors. It usually characterized by early hematogenous spread to the lungs and brain (seen in 80% of the cases). Metastasis to the gastrointestinal tract is extremely rare. Most metastatic lesions in the GI tract are seen in the small bowel. Metastasis to the stomach is rarely seen and only reported in few case reports. Clinical Case: We present a 30 year-old African American male with a past medical history significant for non-seminomatous germ cell testicular cancer. Diagnosis was made via inguinal lymph node biopsy followed by right orchiectomy in April 2015. The patient was initially put on chemotherapy; however, he was not compliant with his treatment. In February 2016, he presented to the hospital with shortness of breath and chest pain. A CT angiography of the chest was done which showed multiple masses scattered in all lung fields. Those lesions were believed to be metastatic in nature. Laboraptory testing showed a human chorionic gonadotropin beta of 40,453 IU/L, LDH 258 IUnits/L and alfa-fetoprotein 8.9 ng/mL. His hospital stay was complicated with melena and a fall of his hemoglobin from a baseline of 12 to 7 gm/dL. He was given 2 units of packed red cells and started on pantoprazole drip. An EGD showed three erythematous friable nodules in the gastric body (figure 1). Biopsy results came back showing cytotrophoblast and syncytiotrophoblast which represent hallmark findings for metastatic choriocarcinoma (figure 2). The patient was offered salvage chemotherapy however he refused treatment and was discharged home.Figure 1Figure 2Discussion: Choriocarcinomas are the most aggressive and rapidly arising germ cell tumors. By the time they are diagnosed nearly half of the cases have already metastasized. Patients usually present with symptoms of hemorrhage in metastatic sites due to the high level of vascularization of those lesions. Gastrointestinal metastases from choriocarcinomas are very rare which account for 5% of all metastatic lesions. Of those less than 1% affect the stomach. The presenting symptoms of stomach metastases is melena and/or hematemesis along with anemia. Conclusion: Although extremely rare, gastric metastasis of choriocarcinoma should be kept in mind as part of the differential diagnosis for young patients with upper gastrointestinal bleeding.