Chemotherapy-induced toxicity in patients with testicular germ cell tumors: The impact of physical fitness and regular exercise.

BACKGROUND: Testicular germ cell tumors (TGCTs) represent ∼95% of testicular malignancies and are the most common type of malignancy in young male adults. While the incidence of TGCTs has increased during the last decades, the advances in treatment, namely introducing cisplatin into the chemotherapy regimen, have made TGCTs highly curable with the 10-year survival rate exceeding 95%. However, in parallel with increased cure rates, survivors may experience acute and late adverse effects of treatment, which increase morbidity, reduce the quality of life, and can be potentially life-threatening. Chemotherapy-related toxicities include cardiovascular and metabolic diseases, secondary cancer, avascular necrosis, cognitive impairment, cancer-related fatigue, poor mental health-related quality of life, nephrotoxicity, hypogonadism, neurotoxicity, pulmonary toxicity, anxiety, and depression. These treatment-related adverse effects have emerged as important survivorship dilemmas in TGCT cancer survivors. Recently, regular physical exercise has increasingly attracted research and clinical attention as an adjunct therapy for cancer patients. PURPOSE: Herein, we review the most common chemotherapy-related adverse effects in TGCT survivors and clinical relevance of exercise and increased cardio-respiratory fitness in modulating chemotherapy-related toxicity and quality of life in this population. RESULTS AND CONCLUSION: Exercise has positive effects on a spectrum of physical and psychosocial outcomes during and after cancer treatment, and current guidelines on exercise prescription in chronic diseases define the recommended dose (volume and intensity) of regular exercise for cancer survivors, highlighting regular, sufficiently intensive physical activity as an essential part of patients' care.

Case Report: SARS-CoV-2 Infection in a Child With Suprasellar Tumor and Hypothalamic-Pituitary Failure.

In early 2020, a novel coronavirus leading to potentially death was discovered. Since then, the 2019 coronavirus disease (COVID-19) has spread to become a worldwide pandemic. Beyond the risks strictly related to the infection, concerns have been expressed for the endocrinological impact that COVID-19 may have, especially in vulnerable individuals with pre-existing endocrinological health conditions. To date new information is emerging regarding severe acute respiratory syndrome-related coronavirus 2 (SARS-CoV-2) in children but the literature is still scarce concerning this infection in patients with intracranial malignant neoplasms. We report a 9-year-old child infected with SARS-CoV-2 and recent diagnosis of suprasellar non-germinomatous germ cell tumor also suffering from diabetes insipidus and hypothalamic-pituitary failure (hypothyroidism, adrenal insufficiency, hypothalamic obesity and growth hormone deficiency) and its clinical course. The patient remained asymptomatic for the duration of the infection without requiring any change in the replacement therapeutic dosages taken before the infection. We then discuss the proposed approach to treat a pediatric patient with SARS-CoV-2 infection and hypothalamic-pituitary failure and we include a review of the literature. Our report suggests that SARS-CoV-2 infection is usually mild and self-limiting in children even those immunocompromised and with multiple endocrinological deficits. Patients are advised to keep any scheduled appointments unless informed otherwise.

What is the damage? Testicular germ cell tumour survivors deficient in testosterone at risk of metabolic syndrome and a need for medical intervention.

Testicular germ cell tumours (TGCT) survivors are coping with late treatment sequelae. Testosterone deficiency may contribute to earlier onset of metabolic syndrome. The study aimed to assess connections between serum testosterone concentrations and metabolic disorders as well as body composition in TGCT survivors. 336 TGCT patients with over two years of complete post-treatment remission were divided into three groups: definite testosterone deficiency (< 8 nmol/L), 'grey zone' (8-12 nmol/L) and normal testosterone (> 12 nmol/L; control group) to assess differences in metabolism. Univariate and multivariate analyses were performed. The multivariate analysis assessed the risk of metabolic disorders and changes in body composition with regard to testosterone concentrations adjusted for age, smoking history, clinical stage, type of treatment and follow-up period. 14% of patients presented with definite testosterone deficiency; 46% were in the 'grey zone'. On multivariate analysis, low testosterone levels were related to hyperglycemia, hypercholesterolemia, hypertriglyceridemia, inflammatory processes, procoagulant state and obesity. The odds ratio (OR) for the onset of metabolic syndrome was 2.87 (95% CI 1.74-4.73, p < 0.001) for the 'grey zone' patients and 7.92 (95% CI 3.76-16.70, p < 0.001) for those with definite testosterone deficiency. Testosterone concentrations were independently associated with metabolic disorders in TGCT survivors. Testicular cancer survivors often have lower testosterone and metabolic disorders. Apart from recurrence, follow-up should focus on promoting a healthy lifestyle, preventing and managing late effects.

Short anogenital distance is associated with testicular germ cell tumour development.

BACKGROUND: Testicular germ cell tumour is a multifactorial disease in which various genetic and environmental factors play a role. Testicular germ cell tumour is part of the testicular dysgenesis syndrome which includes also cryptorchidism, hypospadias, oligo/azoospermia and short anogenital distance. OBJECTIVES: The primary objective was to examine anogenital distance in testicular germ cell tumour cases and healthy fertile controls. The secondary objective was to assess the (CAG)n polymorphism of the Androgen Receptor gene in relationship with anogenital distances and testicular germ cell tumour development. MATERIAL AND METHODS: 156 testicular germ cell tumour patients and 110 tumour-free normozoospermic controls of Spanish origin. All subjects underwent full andrological workup (including semen and hormone analysis) and genetic analysis (Androgen Receptor (CAG)n). The main outcome measures were the anopenile distance (AGDap), the anoscrotal distance (AGDas) and AR(CAG)n. RESULT: We observed significantly shorter anogenital distances in the group of testicular germ cell tumour patients in respect to controls (P < .001) independently from sperm count and testis histology. Threshold values, applicable only to our cohort, were calculated for anogenital distances with the best sensitivity and specificity. Subjects with AGDap and AGDas below threshold showed a significantly increased risk for testicular germ cell tumour (OR = 4.97, 95% CI = 2.01-12.33, P = .001 and OR = 4.11, 95% CI = 1.89-8.92, P ≤ .001, respectively). No significant correlation was observed between AR(CAG)n polymorphism and anogenital distances. The median values of the AR(CAG)n were similar between cases and controls, excluding a major role for this polymorphism in the etiopathogenesis of these testicular dysgenesis syndrome components. CONCLUSIONS: Ours is the first study focusing on anogenital distances in testicular germ cell tumour patients. We identified short anogenital distances (which is a surrogate biomarker of androgen action during foetal life) as a significant risk factor for this disease. After further validation of our preliminary data, anogenital distance measurement could become part of testicular germ cell tumour screening in order to better define those individuals who would benefit from long-term active follow-up.

Reproductive outcomes following fertility-sparing surgery for malignant ovarian germ cell tumors: A systematic review of the literature.

OBJECTIVE: Investigate the reproductive outcomes of patients diagnosed with malignant ovarian germ cell tumors (MOGCTs) following fertility-sparing surgery (FSS). METHODS: A systematic review of the Pubmed/Medline, EMBASE and Web-of-Science databases between January 1st 1990 and February 28th 2020 was performed. Full articles reporting on at least 10 patients with MOGCT who underwent FSS and provided data on fertility or pregnancy outcomes were included. RESULTS: A total of 47 studies that included 2189 patients with MOGCT who underwent FSS were included. Rate of chemotherapy use was 79.9% while cumulative relapse rate was 8.7%. Based on 1110 patient from 27 studies rate of premature ovarian failure was 3.7%. Fecundity rate was 24.6% (n = 1980, from 42 studies), while 80.6% of patients attempting pregnancy had at least one pregnancy (n = 474, from 27 studies). Based on 294 live births, the rate of preterm delivery was 3% while among 261 live infants, only 3 (1.2%) malformations were reported. CONCLUSIONS: The majority of patients with MOGCTs have normal menstrual and reproductive function following FSS. Fecundity and pregnancy outcomes are comparable to the general population.

Polymetastatic testicular cancer turns out to be secondary syphilis: a case report.

Syphilis is a sexually transmissible infection, with increasing rates of infection worldwide. The differential diagnosis of syphilis should include various diseases, not excluding cancer. Making the right diagnosis can protect the patient against life-threatening complications and the repercussions of a misdiagnosis, as in the present case (orchidectomy).

CXCL12 expression is an adverse predictor for disease recurrence in patients with metastatic non-seminomatous testicular germ cell tumors.

BACKGROUND: To validate the utility of the chemokine ligand 12 (CXCL12) as prognostic marker in patients with localized and metastatic germ cell tumors (GCT). METHODS: CXCL12 expression was analyzed on a tissue microarray consisting of 750 tissue cores of different histological tumor components, Germ cell neoplasia in situ (GCNIS) and adjacent normal tissue of 263 testicular cancer patients using a semi-quantitative score. The association between CXCL12 expression and recurrence-free survival (RFS) as well as overall survival (OS) was assessed using Kaplan-Meier curves with log-rank tests. RESULTS: CXCL12 expression was absent in all seminomas but was found in 52 of 99 (52.5%) non-seminomas. Follow-up was available for 260 patients of which 36 (13.8%) recurred. In patients with stage 1 non-seminoma GCT, CXCL12 expression was not associated with higher risk of disease recurrence (p = 0.270). In contrast, post chemotherapy RFS of patients with metastatic non-seminoma and positive CXCL12 expression was significantly shorter compared to CXCL12 negative patients (p = 0.003). OS differences were not statistically different between patients with CXCL12 positive or negative tumors for either localized or metastatic disease. CONCLUSIONS: CXCL12 is almost exclusively expressed in non-seminoma. Pure seminoma, GCNIS and adjacent normal testicular tissue are CXCL12 negative. Our analysis suggests that patients with metastatic disease and a CXCL12-positive non-seminoma are at higher risk for disease recurrence after first-line chemotherapy and might thus be candidates for more intensive treatment and/or closer follow-up.

What Is the Significance of Rete Testis Invasion by Malign Germ Cell Tumor and Does Hilum Predict Metastasis?

BACKGROUND: The significance of hilar soft tissue invasion of rete testis in malign germ cell tumors is still controversial on current guidelines. OBJECTIVES: We aimed to investigate the importance of hilar soft tissue involvement in germ cell tumors and evaluated the possibility of a risk factor such as rete testis. METHOD: Totally, 59 radical orchiectomy specimens operated between 2007 and 2015 at our clinics. All records were retrospectively researched. Patients' age, level of tumor markers, tumor size, histological subtype, clinical stage, presence or absence of carcinoma in situ, vascular/lymphatic and/or hilar soft tissue invasion, tumoral necrosis, number, site and diameter of metastasis, type of further treatment (radiotherapy or chemotheraphy) and follow-up period were recorded and evaluated for all patients. RESULTS: Twenty-six of totally 59 malign germ cell tumors were seminomatous and 33 were nonseminomatous (NS). Mean patients age was 38.54 years (range 17-89 years). Mean follow-up duration was 39.84 months (range 3-96). Serum tumor marker levels were found associated with rete testis invasion (p = 0.035). Hilar soft tissue invasion was significantly associated with vascular invasion (p = 0.001). As it was expected, vascular invasion was significantly associated with metastasis (p = 0.024). CONCLUSIONS: We concluded that there is a strong association between hilar soft tissue invasion and vascular invasion. Especially in NS germ cell tumors, hilar soft tissue involvement a risk factor for prognosis and to determine the need for additional treatment. According to our study, hilar soft tissue status should be reported on routine pathology report.

Health-related quality of life of Brazilian children and adolescents with benign and malignant solid tumours: A prospective cohort study during the first year after hospital admission.

INTRODUCTION: This study aims to assess the impact of paediatric benign and malignant solid tumours and its treatment on the health-related quality of life of children and adolescents who were followed up in a Reference Center in Pediatric Oncology in Rio de Janeiro. METHODS: It is a prospective cohort study. Quality of life assessment was performed using the PedsQL™ 4.0 Generic Core Scales and PedsQL™ 3.0 Cancer Module protocols three times: during hospital admission (T1), 6 months after admission (T2) and 1 year after admission (T3). RESULTS: We evaluated 132 patients, 59 men and 73 women, aged 2-17 years. In PedsQL™4.0, the Emotional Functioning scale was the one with the worst scores, while the scores on the Social Functioning scale was the best. In PedsQL™ 3.0, the worst domains were Procedural Anxiety and Worry. Patients with malignant bone tumours had the worst health-related quality of life. The group who received only surgery had better results. Total scores of PedsQL™4.0 and PedsQL™ 3.0 improved between T1 and T3. CONCLUSION: Children and adolescents with malignant and benign neoplasms undergo changes in quality of life as a result of the disease and treatment, but an improvement has been observed over time.

Different Clinical Presentations and Management in Complete Androgen Insensitivity Syndrome (CAIS).

Complete androgen insensitivity syndrome (CAIS) is an X-linked recessive genetic disorder resulting from maternally inherited or de novo mutations involving the androgen receptor gene, situated in the Xq11-q12 region. The diagnosis is based on the presence of female external genitalia in a 46, XY human individual, with normally developed but undescended testes and complete unresponsiveness of target tissues to androgens. Subsequently, pelvic ultrasound or magnetic resonance imaging (MRI) could be helpful in confirming the absence of Mullerian structures, revealing the presence of a blind-ending vagina and identifying testes. CAIS management still represents a unique challenge throughout childhood and adolescence, particularly regarding timing of gonadectomy, type of hormonal therapy, and psychological concerns. Indeed this condition is associated with an increased risk of testicular germ cell tumour (TGCT), although TGCT results less frequently than in other disorders of sex development (DSD). Furthermore, the majority of detected tumoral lesions are non-invasive and with a low probability of progression into aggressive forms. Therefore, histological, epidemiological, and prognostic features of testicular cancer in CAIS allow postponing of the gonadectomy until after pubertal age in order to guarantee the initial spontaneous pubertal development and avoid the necessity of hormonal replacement therapy (HRT) induction. However, HRT is necessary after gonadectomy in order to prevent symptoms of hypoestrogenism and to maintain secondary sexual features. This article presents differential clinical presentations and management in patients with CAIS to emphasize the continued importance of standardizing the clinical and surgical approach to this disorder.

Germ cell neoplasia in situ complicating 17ß-hydroxysteroid dehydrogenase type 3 deficiency.

17ß-hydroxysteroid dehydrogenase type 3 (17ßHSD3) deficiency is an autosomal recessive disorder of male sex development that results in defective testosterone biosynthesis. Although mutations in the cognate HSD17B3 gene cause a spectrum of phenotypic manifestations, the majority of affected patients are genetic males having female external genitalia. Many cases do not present until puberty, at which time peripheral conversion of androgen precursors causes progressive virilization. Measurement of the testosterone-to-androstenedione ratio is useful to screen for 17ßHSD3 deficiency, and genetic analysis can confirm the diagnosis. As some individuals with 17ßHSD3 deficiency transition from a female sex assignment to identifying as males, providers should ensure stable gender identity prior to recommending irreversible treatments. Gonadectomy is indicated to prevent further virilization if a female gender identity is established. The risk of testicular neoplasia is unknown, a point which should be discussed if patients elect to transition into a male gender role.

Development of a best-practice clinical guideline for the use of bleomycin in the treatment of germ cell tumours in the UK.

Bleomycin, a cytotoxic chemotherapy agent, forms a key component of curative regimens for lymphoma and germ cell tumours. It can be associated with severe toxicity, long-term complications and even death in extreme cases. There is a lack of evidence or consensus on how to prevent and monitor bleomycin toxicity. We surveyed 63 germ cell cancer physicians from 32 cancer centres across the UK to understand their approach to using bleomycin. Subsequent guideline development was based upon current practice, best available published evidence and expert consensus. We observed heterogeneity in practice in the following areas: monitoring; route of administration; contraindications to use; baseline and follow-up investigations performed, and advice given to patients. A best-practice clinical guideline for the use of bleomycin in the treatment of germ cell tumours has been developed and includes recommendations regarding baseline investigations, the use of pulmonary function tests, route of administration, monitoring and patient advice. It is likely that existing heterogeneity in clinical practice of bleomycin prescribing has significant economic, safety and patient experience implications. The development of an evidence-based consensus guideline was supported by 93% of survey participants and aims to address these issues and homogenise practice across the UK.

Synchronous adrenocortical carcinoma and ovarian malignant mixed germ cell tumor: A case report and literature review.

RATIONALE: Adrenocortical carcinoma (ACC) is an endocrine malignancy with poor prognosis, which commonly arises in a sporadic manner, but may also become a part of a familial syndrome. ACC rarely arises simultaneously with other malignant tumors. PATIENT CONCERNS: We report a case of a 29-year-old woman with ACC synchronously followed by an ovarian malignant mixed germ cell tumor. We describe the clinical, histopathological, and immunohistochemical findings and review the English literatures. So far, as we know, the patient presented here is the first case with synchronous malignant tumors of the adrenal gland and ovary. DIAGNOSES: She was diagnosed with ovarian malignant mixed germ cell tumor with admixture of dysgerminoma and yolk sac tumor after ACC. INTERVENTIONS: The left adrenal tumor was resected laparoscopically on April 28, 2017. A total laparoscopic hysterectomy with unilateral (right) adnexectomy was performed on November 11, 2017. OUTCOMES: Up to now, illness condition has not progressed. Patient is free of disease at 3 months of follow-up. LESSONS: This is the first report in English literature about coexistence of ACC with ovarian malignant mixed germ cell tumor and the sixteenth case that presents a synchronous tumor associated with a sporadic ACC. This case reminds us that a comprehensive examination of patients with ACC is necessary to identify a possible synchronous tumor.

Fertility preservation in testicular cancer - predictors of spermatogenesis.

OBJECTIVES: To determine the frequency of spermatogenesis in patients with testicular cancer and to assess for any predictors of spermatogenesis. PATIENTS AND METHODS: We retrospectively reviewed 103 testicular germ cell tumours (TGCTs) in men who underwent radical orchidectomy conducted at Guy's Hospital, London, between 2011 and 2015. Primary outcome measures included: the presence and characteristics of spermatogenesis (widespread/focal/proximity to tumour). Secondary outcome measures included: the presence of testicular microlithiasis, tumour characteristics (size, stage, and type), and tumour markers. Secondary outcome measures as potential predictors of spermatogenesis were assessed using univariate and multivariate logistic regression analyses. RESULTS: Spermatogenesis was present in 70% (72/103) of the patients; it was widespread in 63% (45/72) and focal in 38% (27/72). Neither tumour type, stage, presence of microcalcification nor tumour markers predicted spermatogenesis. Men with a percentage testis tumour occupation (PTTO) of >50% of their testis were 82% (95% confidence interval 73.2-98.4) less likely to have spermatogenesis than a PTTO of <50%. CONCLUSIONS: Spermatogenesis is present in most testes affected by TGCTs; it is widespread in two-thirds of patients, and located away from the tumour in 94%. These findings can help predict and guide successful surgical sperm retrieval in testes with TGCTs. The finding of focal spermatogenesis in a third of patients would support a microsurgical approach to sperm retrieval at the time of orchidectomy to maximise success.

Update on the Pathophysiology and Risk Factors for the Development of Malignant Testicular Germ Cell Tumors in Complete Androgen Insensitivity Syndrome.

Prophylactic gonadectomy in young adult women with complete androgen insensitivity syndrome (CAIS) to avoid development of an invasive testicular germ cell tumor (TGCT) is currently advised in most centers. However, women with CAIS increasingly question the need of this procedure. In order to provide optimal counseling and follow-up of these women, insight in the mechanisms underlying TGCT development in androgen insensitivity syndrome (AIS), data regarding the incidence of TGCT in AIS adults specifically, and an overview of existing and novel screening tools for in situ and invasive neoplastic lesions are crucial. The current knowledge regarding these topics is revised in this paper.

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: 31 years; mean 9.3 years follow-up) and equal number of age matched controls (mean age at inclusion 40.3 years and 41.2 years, 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: -0.063 g/cm2 ; 95% CI: -0.122; -0.004 p = 0.037) and TCS receiving androgen replacement (mean difference -0.085 g/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: -0.097 g/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.

A practical guide for evaluating gonadal germ cell tumor predisposition in differences of sex development.

Differences of Sex Development (DSD) includes a wide spectrum of etiologies and phenotypes. A subset of individuals with DSDs are predisposed to gonadal germ cell tumor (GCT). In this setting, GCT risk varies widely, depending on the DSD molecular etiology and penetrance. Prognostication based on molecular diagnosis remains challenging, as natural history data specific to recently identified molecular causes of DSD is lacking. In this review, we provide a framework for the clinical geneticist to consider GCT tumor risk in the patient with DSD. We discuss germ cell development and etiology of GCT growth, along with parameters to consider when recommending prophylactic gonadectomy including fertility, hormonal output, and malignant GTC treatment outcomes. Shortly after the 2006 reorganization of DSD nomenclature, literature reviews of natural history publications stratified GCT risk by a chromosomal, pathological, and hormonal taxonomy. Our 2017 literature review reveals a larger body of publications. However, the broad DSD GCT risk stratification within the 2006 taxonomy remains stable. We discuss precise GCT risk assessment for specific diagnoses, including androgen insensitivity, Smith-Lemli-Opitz, and 46,XY with MAP3K1 mutations and gonadal dysgenesis, as examples. We also examine the GCT risk in non-DSD syndromes, in addition to the cancer risks in DSD patients with dimorphic gonads and genitalia. This review is intended to provide a nuanced assessment of relative germ cell tumor risk in the DSD patient, including modern precise molecular diagnosis, for use by the clinical geneticist.