New insights on testicular cancer prevalence with novel diagnostic biomarkers and therapeutic approaches.

BACKGROUND: Testicular cancer (TC), comprising merely 1% of male neoplasms, holds the distinction of being the most commonly encountered neoplasm among young males. RECENT FINDINGS: Most cases of testicular neoplasms can be classified into two main groups, namely germ cell tumors representing approximately 95% of the cases, and sex cord-stromal tumors accounting for about 5% of the cases. Moreover, its prevalence is on the rise across the globe. TC is a neoplastic condition characterized by a favorable prognosis. The advent of cisplatin-based chemotherapeutic agents in the latter part of the 1970s has led to a significant enhancement in the 5-year survival rate, which presently surpasses 95%. Given that TC is commonly detected before reaching the age of 40, it can be anticipated that these individuals will enjoy an additional 40-50 years of life following successful treatment. The potential causes of TC are multifactorial and related to different pathologies. Accurate identification is imperative to guarantee the utmost efficacious and suitable therapy. To a certain degree, this can be accomplished through the utilization of blood examinations for neoplastic indicators; nonetheless, an unequivocal diagnosis necessitates an evaluation of the histological composition of a specimen via a pathologist. CONCLUSION: TC is multifactorial and has various pathologies, therefore this review aimed to revise the prenatal and postnatal causes as well as novel diagnostic biomarkers and the therapeutic strategies of TC.

PFOA and testis cancer in the Veneto Region (Italy).

The largest documented episode of human contamination by PFOA in the world (approximately 150,000 actual residents on 1 January 2020) has occurred in Italy's Veneto Region. In this large, mostly flat plain area, a cluster of testicular cancers has also been observed. Preliminary data are reported, and the most relevant and recent recommendations regarding the health surveillance of exposed individuals are emphasized.

Describing patterns of familial cancer risk in subfertile men using population pedigree data.

STUDY QUESTION: Can we simultaneously assess risk for multiple cancers to identify familial multicancer patterns in families of azoospermic and severely oligozoospermic men? SUMMARY ANSWER: Distinct familial cancer patterns were observed in the azoospermia and severe oligozoospermia cohorts, suggesting heterogeneity in familial cancer risk by both type of subfertility and within subfertility type. WHAT IS KNOWN ALREADY: Subfertile men and their relatives show increased risk for certain cancers including testicular, thyroid, and pediatric. STUDY DESIGN, SIZE, DURATION: A retrospective cohort of subfertile men (N = 786) was identified and matched to fertile population controls (N = 5674). Family members out to third-degree relatives were identified for both subfertile men and fertile population controls (N = 337 754). The study period was 1966-2017. Individuals were censored at death or loss to follow-up, loss to follow-up occurred if they left Utah during the study period. PARTICIPANTS/MATERIALS, SETTING, METHODS: Azoospermic (0 × 106/mL) and severely oligozoospermic (<1.5 × 106/mL) men were identified in the Subfertility Health and Assisted Reproduction and the Environment cohort (SHARE). Subfertile men were age- and sex-matched 5:1 to fertile population controls and family members out to third-degree relatives were identified using the Utah Population Database (UPDB). Cancer diagnoses were identified through the Utah Cancer Registry. Families containing ≥10 members with ≥1 year of follow-up 1966-2017 were included (azoospermic: N = 426 families, 21 361 individuals; oligozoospermic: N = 360 families, 18 818 individuals). Unsupervised clustering based on standardized incidence ratios for 34 cancer phenotypes in the families was used to identify familial multicancer patterns; azoospermia and severe oligospermia families were assessed separately. MAIN RESULTS AND THE ROLE OF CHANCE: Compared to control families, significant increases in cancer risks were observed in the azoospermia cohort for five cancer types: bone and joint cancers hazard ratio (HR) = 2.56 (95% CI = 1.48-4.42), soft tissue cancers HR = 1.56 (95% CI = 1.01-2.39), uterine cancers HR = 1.27 (95% CI = 1.03-1.56), Hodgkin lymphomas HR = 1.60 (95% CI = 1.07-2.39), and thyroid cancer HR = 1.54 (95% CI = 1.21-1.97). Among severe oligozoospermia families, increased risk was seen for three cancer types: colon cancer HR = 1.16 (95% CI = 1.01-1.32), bone and joint cancers HR = 2.43 (95% CI = 1.30-4.54), and testis cancer HR = 2.34 (95% CI = 1.60-3.42) along with a significant decrease in esophageal cancer risk HR = 0.39 (95% CI = 0.16-0.97). Thirteen clusters of familial multicancer patterns were identified in families of azoospermic men, 66% of families in the azoospermia cohort showed population-level cancer risks, however, the remaining 12 clusters showed elevated risk for 2-7 cancer types. Several of the clusters with elevated cancer risks also showed increased odds of cancer diagnoses at young ages with six clusters showing increased odds of adolescent and young adult (AYA) diagnosis [odds ratio (OR) = 1.96-2.88] and two clusters showing increased odds of pediatric cancer diagnosis (OR = 3.64-12.63). Within the severe oligozoospermia cohort, 12 distinct familial multicancer clusters were identified. All 12 clusters showed elevated risk for 1-3 cancer types. An increase in odds of cancer diagnoses at young ages was also seen in five of the severe oligozoospermia familial multicancer clusters, three clusters showed increased odds of AYA diagnosis (OR = 2.19-2.78) with an additional two clusters showing increased odds of a pediatric diagnosis (OR = 3.84-9.32). LIMITATIONS, REASONS FOR CAUTION: Although this study has many strengths, including population data for family structure, cancer diagnoses and subfertility, there are limitations. First, semen measures are not available for the sample of fertile men. Second, there is no information on medical comorbidities or lifestyle risk factors such as smoking status, BMI, or environmental exposures. Third, all of the subfertile men included in this study were seen at a fertility clinic for evaluation. These men were therefore a subset of the overall population experiencing fertility problems and likely represent those with the socioeconomic means for evaluation by a physician. WIDER IMPLICATIONS OF THE FINDINGS: This analysis leveraged unique population-level data resources, SHARE and the UPDB, to describe novel multicancer clusters among the families of azoospermic and severely oligozoospermic men. Distinct overall multicancer risk and familial multicancer patterns were observed in the azoospermia and severe oligozoospermia cohorts, suggesting heterogeneity in cancer risk by type of subfertility and within subfertility type. Describing families with similar cancer risk patterns provides a new avenue to increase homogeneity for focused gene discovery and environmental risk factor studies. Such discoveries will lead to more accurate risk predictions and improved counseling for patients and their families. STUDY FUNDING/COMPETING INTEREST(S): This work was funded by GEMS: Genomic approach to connecting Elevated germline Mutation rates with male infertility and Somatic health (Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD): R01 HD106112). The authors have no conflicts of interest relevant to this work. TRIAL REGISTRATION NUMBER: N/A.

[No Differences in Testis Cancer Outcomes between urban and rural regions in the Canton of Berne].

INTRODUCTION: Testis cancer is highly curable. However, historical data point to differences between urban and rural areas with more advanced diseases at presentation and worse outcomes in the latter. In a cohort of 296 men with testis cancer diagnosed and treated at the Inselspital Berne between 2010 and 2020, we found no clinically relevant differences in presentation and outcomes depending on their residential area.

Twenty-two-year incidence trend of urological cancers in the Republic of Korea: 1999-2020.

PURPOSE: Cancer is a disease with high social costs, and policymaking through accurate statistics is very important. This study presents the national cancer statistics on the incidence of urological cancers in the Republic of Korea over 22 years, from 1999 to 2020. MATERIALS AND METHODS: Through the Korean Statistical Information Service, data on the incidence of urological cancers by sex and age in each year was obtained. For each urological cancer, the number of cases, crude incidence rate (CIR), and age-standardized incidence rate (ASR) were calculated, and the statistical trends were confirmed by joinpoint regression analysis. RESULTS: Urological cancers, which have increased ASR over 22 years, are as follows: prostate cancer (average annual percent change [AAPC]=6.72%, p-trend<0.05), testicular cancer (AAPC=5.26%, p-trend<0.05), ureter cancer (AAPC=4.16%, p-trend<0.05), kidney cancer (AAPC=4.14%, p-trend<0.05), renal pelvis cancer (AAPC=3.86%, p-trend<0.05), and total urological cancer (AAPC=4.37%, p-trend<0.05). Urological cancers, which has decreased ASR over 22 years, are as follows: penile cancer (AAPC=-2.93%, p-trend<0.05) and bladder cancer (AAPC=-0.31%, p-trend<0.05). CONCLUSIONS: It was confirmed that the ASR of all urological cancers increased for 22 years, except for bladder and penile cancer. With the aging of the population, the CIR increased for all urological cancers. This study will serve as basic data for future research and policy decisions.

The increasing burden of testicular seminomas and non-seminomas in adolescents and young adults (AYAs): incidence, treatment, disease-specific survival and mortality trends in the Netherlands between 1989 and 2019.

BACKGROUND: Testicular cancer incidence among adolescents and young adults (AYAs, aged 18-39 years at diagnosis) is increasing worldwide and most patients will survive the initial disease. Still, detailed epidemiological information about testicular cancer among AYAs is scarce. This study aimed to provide a detailed overview of testicular cancer trends in incidence, treatment, long-term relative survival and mortality by histological subtype among AYAs diagnosed in the Netherlands between 1989 and 2019. MATERIALS AND METHODS: Data of all malignant testicular cancers (ICD-code C62) were extracted from the Netherlands Cancer Registry. Mortality data were retrieved from Statistics Netherlands. European age-standardized incidence and mortality rates with average annual percentage change statistics and relative survival estimates up to 20 years of follow-up were calculated. RESULTS: A total of 12 528 testicular cancers were diagnosed between 1989 and 2019. Comparing 1989-1999 to 2010-2019, the incidence increased from 4.4 to 11.4 for seminomas and from 5.7 to 11.1 per 100 000 person-years for non-seminomas. Rising trends were most prominent for localized disease. Radiotherapy use in localized testicular seminomas declined from 78% in 1989-1993 to 5% in 2015-2019. Meanwhile, there was a slight increase in chemotherapy use. Most AYAs with localized seminomas and non-seminomas received active surveillance only (>80%). Overall, relative survival estimates remained well above 90% even at 20 years of follow-up for both seminomas and non-seminomas. Mortality rates declined from 0.5 to 0.4 per 100 000 person-years between 1989-1999 and 2010-2019. CONCLUSIONS: The incidence of seminoma and non-seminoma testicular cancers significantly increased in AYAs in the Netherlands between 1989 and 2019. There was a shift towards less-aggressive treatment regimens without negative survival effects. Relative survival estimates remained well above 90% at 20 years of follow-up in most cases. Testicular cancer mortality was already low, but has improved further over time, which makes survivorship care an important issue for these young adults.

Testicular adrenal rest tumors - Epidemiology, diagnosis and treatment.

INTRODUCTION: Testicular adrenal rest tumors (TART) are common in males suffering from congenital adrenal hyperplasia (CAH). Correct and timely diagnosis is important for differential diagnosis with malignant testis tumors, related infertility and as TART may worsen in time, especially in the absence of adequate and continuous hormonal control. The rarity of the disease, predominance of small cohorts and case reports and research heterogeneity (concerning type of CAH, patients' age and specific focus of the paper) complicate the understanding of this condition. OBJECTIVES: To review epidemiological and clinical aspects of TART, including treatment and prognosis. METHODS: Non-systematic review of CAH-related TART research. RESULTS: TART's prevalence grows progressively over time, predominating after puberty, affecting a mean of 20-40 % of CAH males. There is no proof of more frequent proportional affection of specific CAH phenotypes or types of enzyme deficiency, but cases of TART among non-classic CAH patients have been rarely reported. Chronic undertreated are more frequently affected and present larger tumors. Systematic ultrasound screening of CAH males is the state-of-the art for diagnosis, but TART are still often diagnosed in CAH adults seeking infertility treatment. TART are usually asymptomatic and present normal testicular volume. Biopsies are not recommended, except when the differential diagnosis between TART and testicular tumors cannot be guaranteed. Abnormal semen analysis is common. Leydig cell tumors are the main differential diagnosis, due to histological similarities to TART. Misdiagnosis may lead to unnecessary orchiectomies. Preservation of gonadal functions is inversely proportional to the total tumor volume. Tumors tend to regress under adequate adrenal suppression with steroids. Surgery in not indicated to treat TART. DISCUSSION: The reported prevalence of TART depends on age, usage of systematic follow-up ultrasound, and adequate CAH control. Timely detection of the disease is important to avoid irreversible gonadal dysfunction (not clinically apparent, due to high serum levels of androgen) and infertility. The relationship between TART and specific CAH phenotypes/genotypes has not been proved, and some cases do not present abnormal serum ACTH levels. Knowledge about TART should be disseminated among non-experts, to avoid unnecessary orchiectomies and false diagnosis of malignant testis tumors. Infertility is frequent, but has not been not satisfactorily addressed by physicians, even among experts. Sperm cryopreservation should be early offered to CAH adult males, but there are offer problems related to high cost.

Higher prevalence of benign tumors in men with testicular tumors and history of treated cryptorchidism.

OBJECTIVES: To identify if surgically treated cryptorchidism correlated with testicular tumor pathology at presentation. MATERIALS AND METHODS: An institutional database of patients treated for testicular cancer between 2003 and 2020 was reviewed. Inclusion criteria included orchiectomy patients. Exclusion criteria included unknown cryptorchidism history or pathology or laterality of orchiectomy. Data collection included demographics, surgical history, and tumor marker status. RESULTS: A total of 435 patients were included. Thirty-three of these patients had a history of UDT. There was no statistical difference in age at orchiectomy, laterality of orchiectomy, or lymphovascular invasion with regard to UDT history. There was a statistical difference in tumor pathology after orchiectomy, P = 0.03. On secondary analysis, benign pathology was significantly more common in patients with a history of UDT (15.2%) than without (4.7%), P = 0.01. Mixed GCT was also found at a significantly lower rate in patients with a history of UDT (18.2%) compared to those with no history of UDT (37.3%), P = 0.03. There were no statistically significant differences in other pathology. CONCLUSION: Previous studies have shown that there is a greater rate of seminoma in patients with testicular cancer in an undescended testis. This study shows that in patients with a history of UDT compared to those without a history of UDT, there is a greater percentage of patients with benign testicular masses after orchiectomy. Guideline based practices including monthly self-examination and testis-sparing surgery for appropriate patients may reduce rates of radical orchiectomy for benign tumors.

Adolescent and Young Adult Germ Cell Tumors: Epidemiology, Genomics, Treatment, and Survivorship.

Innovations in the care of adolescent and young adult (AYA) germ cell tumors (GCTs) are needed for one of the most common AYA cancers for which treatment has not significantly changed for several decades. Testicular GCTs (TGCTs) are the most common cancers in 15- to 39-year-old men, and ovarian GCTs (OvGCTs) are the leading gynecologic malignancies in women younger than 25 years. Excellent outcomes, even in widely metastatic disease using cisplatin-based chemotherapy, can be achieved since Einhorn and Donohue's landmark 1977 study in TGCT. However, as the severity of accompanying late effects (ototoxicity, neurotoxicity, cardiovascular disease, second malignant neoplasms, nephrotoxicity, and others) has emerged, efforts to deintensity treatment and find alternatives to cisplatin have taken on new urgency. Current innovations include the collaborative design of clinical trials that accrue GCTs across all ages and both sexes, including adolescents (previously on pediatric trials), and OvGCT (previously on gynecologic-only trials). Joint trials accrue larger sample sizes at a faster rate and therefore evaluate new approaches more rapidly. These joint trials also allow for biospecimen collection to further probe GCT etiology and underlying mechanisms of tumor growth, thus providing new therapeutic options. This AYA approach has been fostered by The Malignant Germ Cell International Consortium, which includes over 115 GCT disease experts from pediatric, gynecologic, and genitourinary oncologies in 16 countries. Trials in development incorporate, to our knowledge, for the first time, molecular risk stratification and precision oncology approaches on the basis of specific GCT biology. This collaborative AYA approach pioneering successfully in GCT could serve as a model for impactful research for other AYA cancer types.

Occurrence of mammary gland tumours in male dogs and its weak association with development of testicular tumours: a review.

Mammary gland tumours (MGTs) are commonly occurring neoplasms in female dogs. However, rare cases of MGTs in male dogs have been reported for years. Due to the low incidence of MGTs in male dogs in comparison to female dogs, veterinary oncology is mainly focused on mammary neoplasms diagnosed in female dogs and extensive research is conducted in this scientific area. Therefore, there are no sufficient epidemiological data on male dogs and the aetiology of their tumour development is still poorly understood.The aim of this literature review was to present cases of MGTs in male dogs for better understanding the scale of the problem over the years. The analyses of 74 affected male dogs with 92 tumours showed that the majority of MGTs in male dogs were benign tumours (54.3%), especially in form of adenomas, often developed in posterior canine mammary glands (58.1%).The increased number of canine MGTs in male dogs aged 7 -13 years with an age peak at 11 years was noted. The age of affected animals was not related to breed. Mammary gland neoplasms were diagnosed predominately in Crossbreeds (20.2%) followed by Cocker Spaniels (18.9%) and German Shepherds (10.8%).The association between MGT development in male dogs and co-occurrence of testicular tumours (TTs) has been discussed for years. Thus, cases of development of both tumours were included in this study. As a result, only in 12.7% cases of MGTs also history of TTs was described. Therefore, no general association between these tumours should be assumed.

Prevalence of neoplasia at colonoscopy among testicular cancer survivors treated with platinum-based chemotherapy.

Testicular cancer survivors (TCS) treated with platinum-based chemotherapy have an increased risk of colorectal cancer (CRC). We determined the yield of colonoscopy in TCS to assess its potential in reducing CRC incidence and mortality. We conducted a colonoscopy screening study among TCS in four Dutch hospitals to assess the yield of colorectal neoplasia. Neoplasia was defined as adenomas, serrated polyps (SPs), advanced adenomas (AAs: ≥10 mm diameter, high-grade dysplasia or ≥25% villous component), advanced serrated polyps (ASPs: ≥10 mm diameter or dysplasia) or CRC. Advanced neoplasia (AN) was defined as AA, ASP or CRC. Colonoscopy yield was compared to average-risk American males who underwent screening colonoscopy (n = 24,193) using a propensity score matched analysis, adjusted for age, smoking status, alcohol consumption and body mass index. A total of 137 TCS underwent colonoscopy. Median age was 50 years among TCS (IQR 43-57) vs 55 years (IQR 51-62) among American controls. A total of 126 TCS were matched to 602 controls. The prevalence of AN was higher in TCS than in controls (8.7% vs 1.7%; P = .0002). Nonadvanced adenomas and SPs were detected in 45.2% of TCS vs 5.5% of controls (P < .0001). No lesions were detected in 46.0% of TCS vs 92.9% of controls (P < .0001). TCS treated with platinum-based chemotherapy have a higher prevalence of neoplasia and AN than matched controls. These results support our hypothesis that platinum-based chemotherapy increases the risk of colorectal neoplasia in TCS. Cost-effectiveness studies are warranted to ascertain the threshold of AN prevalence that justifies the recommendation of colonoscopy for TCS.

Hormonal control during infancy and testicular adrenal rest tumor development in males with congenital adrenal hyperplasia: a retrospective multicenter cohort study.

IMPORTANCE: Testicular adrenal rest tumors (TARTs), often found in male patients with congenital adrenal hyperplasia (CAH), are benign lesions causing testicular damage and infertility. We hypothesize that chronically elevated adrenocorticotropic hormone exposure during early life may promote TART development. OBJECTIVE: This study aimed to examine the association between commencing adequate glucocorticoid treatment early after birth and TART development. DESIGN AND PARTICIPANTS: This retrospective multicenter (n = 22) open cohort study collected longitudinal clinical and biochemical data of the first 4 years of life using the I-CAH registry and included 188 male patients (median age 13 years; interquartile range: 10-17) with 21-hydroxylase deficiency (n = 181) or 11-hydroxylase deficiency (n = 7). All patients underwent at least 1 testicular ultrasound. RESULTS: TART was detected in 72 (38%) of the patients. Prevalence varied between centers. When adjusted for CAH phenotype, a delayed CAH diagnosis of >1 year, compared with a diagnosis within 1 month of life, was associated with a 2.6 times higher risk of TART diagnosis. TART onset was not predicted by biochemical disease control or bone age advancement in the first 4 years of life, but increased height standard deviation scores at the end of the 4-year study period were associated with a 27% higher risk of TART diagnosis. CONCLUSIONS AND RELEVANCE: A delayed CAH diagnosis of >1 year vs CAH diagnosis within 1 month after birth was associated with a higher risk of TART development, which may be attributed to poor disease control in early life.

Testicular cancer mortality in Latin America and the Caribbean: trend analysis from 1997 to 2019.

BACKGROUND: In the last decades, an increasing incidence of testicular cancer has been observed in several countries worldwide. Although mortality rates have been variable in many countries, little information is available from Latin America and the Caribbean (LAC). Therefore, we examined mortality trends of testicular cancer in the last two decades. METHODS: Age-standardized mortality rates (ASMR) of testicular cancer per 100,000 men-years were estimated using the World Health Organization mortality database from 1997 to 2019. We examined the mortality trends and computed annual percent change (APC) for all ages and the following age groups, 15-29, 30-44, 15-44, and ≥ 45 years. RESULTS: Ten countries had mortality rates greater than 0.43 per 100,000 men, with the highest rates for Chile, Mexico, and Argentina. Significant increases in mortality rates were observed in Argentina, Brazil Colombia, and Mexico in all ages, and < 45 years, while Colombia, Ecuador, Mexico, and Peru reported significant downward trends in males aged ≥ 45 years. Only Chile showed significant decreases for all ages and age groups studied. CONCLUSION: Mortality by testicular cancer increased among LAC countries in males of all ages and across age groups. A reduction in mortality rates was observed only in Chilean males of all ages and in men ≥ 45 years in several countries. Strengthening of early detection among symptomatic males may decrease the mortality by this neoplasm.

Per- and Poly-fluoroalkyl Substances (PFAS) Exposure and Risk of Kidney, Liver, and Testicular Cancers: A Systematic Review and Meta-Analysis.

INTRODUCTION: Per- and poly-fluoroalkyl substances (PFASs) are a large, complex group of synthetic chemicals humans can be exposed to from occupational or environmental sources. In this systematic review and meta-analysis, we examined the association between PFAS exposure, particularly Perfluorooctanoic Acid (PFOA), and Perfluorooctane Sulfonic Acid (PFOS), and risk of kidney, liver, and testicular cancer. METHODS: We systematically searched PubMed to identify cohort and case-control studies reported after the Monograph of the International Agency for Research on Cancer and the Toxicological Profile of the Agency for Toxic Substances and Disease Registry. We assessed the quality of the studies by using a modified version of the Newcastle-Ottawa Scale (NOS). Forest relative risk (RR) plots were constructed for liver, kidney, and testicular cancer. We conducted stratified analyses by geographic region, study design, quality score, outcome, years of publication, exposure source, and PFAS type. A random-effects model was used to address heterogeneity between studies. RESULTS: Fifteen studies, including ten cohort studies, three case-control studies nested in a cohort, and two case-control studies were included after removing duplicate and irrelevant reports. We found an association between overall PFAS exposure and the risk of kidney cancers (RR=1.18, 95% CI =1.05-1.32; I =52.8%, 11 studies). Also, we showed an association between high-level exposure to PFAS and kidney cancer (RR=1.74, 95% CI =1.23-2.47; p=0.005) and testicular cancer (RR=2.22, 95% CI =1.12-4.39; p=0.057). There was no association with liver cancer. We found no heterogeneity by geographical region, PFAS type, study design, outcome, quality score, year of publication, or exposure source. Only two studies reported results among women. CONCLUSIONS: We detected an association between overall PFAS exposure and kidney cancer and high doses of PFAS with testicular cancer. However, bias and confounding cannot be excluded, precluding a conclusion in terms of causality.

Adverse health outcomes and global quality of life in long-term testicular cancer survivors: a longitudinal 30-year perspective.

BACKGROUND: The aim of this study was to characterize the prevalence of self-reported adverse health outcomes (AHOs), track changes in AHOs, and examine their impact on health-related quality of life (HrQoL) in testicular cancer survivors (TCSs) who were diagnosed between 1980 and 1994. These assessments were conducted during two survey waves (SWs), with the first occurring ∼12 years after surgery-only or platinum-based chemotherapy (PBCT), and the second ∼28 years after initial treatment. The study primarily focused on 'typical AHOs', which included Peripheral Sensory Neuropathy (PSN), Raynaud's phenomenon, Tinnitus, and Hearing loss. PATIENTS AND METHODS: A total of 427 TCSs were included in the evaluation, distributed as follows: surgery-only group (n = 155), PBCT-standard group with ≤850 mg cisplatin (n = 222), and PBCT-high group with >850 mg cisplatin (n = 50). For comparison of HrQoL, men from the general population served as a control group (referred to as 'Norms'). The statistical significance level was set at P < 0.05, and clinical importance, in terms of testing HrQoL differences, was defined as Δ ≥2.5 points. RESULTS: A higher number of TCSs who underwent PBCT reported experiencing typical AHOs compared with those who had surgery only. The highest prevalence rates were observed among TCSs who had undergone PBCT-high. Further, the number of TCSs describing typical AHOs, except Raynaud's phenomenon, increased during the observation period of 16 years. At the last SW, a median of 4 AHOs (any type) were reported after PBCT-high compared with a median of 2 AHOs after Surgery-only or after PBCT-standard. With Surgery-only as reference, PBCT-high, but not PBCT-standard, was associated with decreasing physical HrQoL in the last SW (A2 Regression coefficient: -4.3; P = 0.008). When comparing all TCSs with Norms no clinically important difference in physical and mental HrQoL was observed at either SW. However, at the last SW, TCSs after PBCT-high therapy represented a subgroup of TCSs with clinically important impairment of HRQoL. Of the typical AHOs, only PSN reduced HrQoL. Chronic fatigue, pain, anxiety/depression, sexual dysfunction, unemployment, being single, and low education were additional covariates. CONCLUSIONS: After a median of 28 years since their treatment, HrQoL in TCSs was found to be comparable to that of Norms. This similarity held true even though AHOs, especially after PBCT-high, were becoming more prevalent among TCSs. The study revealed that individuals with a history of PBCT-high are at a high risk of experiencing a significantly increased prevalence of long-term AHOs, which subsequently leads to diminished HrQoL. It is crucial to recognize and provide specialized attention to these TCSs during lifelong follow-up care.

Prediagnostic Hormone Levels and Risk of Testicular Germ Cell Tumors: A Nested Case-Control Study in the Janus Serum Bank.

BACKGROUND: It has been hypothesized that poorly functioning Leydig and/or Sertoli cells of the testes, indicated by higher levels of serum gonadotropins and lower levels of androgens, are related to the development of testicular germ cell tumors (TGCT). To investigate this hypothesis, we conducted a nested case-control study within the Janus Serum Bank cohort. METHODS: Men who developed TGCT (n = 182) were matched to men who did not (n = 364). Sex steroid hormones were measured using LC/MS. Sex hormone binding globulin, follicle-stimulating hormone (FSH), and luteinizing hormone (LH) were quantified by direct immunoassay. Multivariable logistic regression was used to calculate ORs and 95% confidence intervals (CI) for associations between hormone levels and TGCT risk. RESULTS: Higher FSH levels [tertile (T) 3 vs. T2: OR = 2.89, 95% CI = 1.83-4.57] were associated with TGCT risk, but higher LH levels were not (OR = 1.26, 95% CI = 0.81-1.96). The only sex steroid hormone associated with risk was androstane-3α, 17ß-diol-3G (3α-diol-3G; OR = 2.37, 95% CI = 1.46-3.83). Analysis by histology found that increased FSH levels were related to seminoma (OR = 3.55, 95% CI = 2.12-5.95) but not nonseminoma (OR = 1.19, 95% CI = 0.38-3.13). Increased levels of 3α-diol-3G were related to seminoma (OR = 2.29, 95% CI = 1.35-3.89) and nonsignificantly related to nonseminoma (OR = 2.71, 95% CI = 0.82-8.92). CONCLUSIONS: Higher FSH levels are consistent with the hypothesis that poorly functioning Sertoli cells are related to the development of TGCT. In contrast, higher levels of 3α-diol-3G do not support the hypothesis that insufficient androgenicity is related to risk of TGCT. IMPACT: Clarifying the role of sex hormones in the development of TGCT may stimulate new research hypotheses.

Disparities in testicular cancer incidence, mortality, and place of death trends from 1999 to 2020: A comprehensive cohort study.

BACKGROUND: Testicular cancer (TC) mortality rates have decreased over time, however it is unclear whether these improvements are consistent across all communities. AIMS: The aim of this study was to analyze trends in TC incidence, mortality, and place of death (PoD) in the United States between 1999-2020 and identify disparities across race, ethnicity, and geographic location. METHODS AND RESULTS: This cross-sectional study used CDC WONDER and NAACCR, to calculate age-adjusted rates of TC incidence and mortality, respectively. PoD data for individuals who died of TC were collected from CDC WONDER. Using Joinpoint analysis, longitudinal mortality trends were evaluated by age, race, ethnicity, US census region, and urbanization category. TC stage (localized vs metastatic) trends were also evaluated. Univariate and multivariate regression analysis identified demographic disparities for PoD. A total of 8,456 patients died of TC from 1999-2020. Average annual percent change (AAPC) of testicular cancer-specific mortality (TCSM) remained largely stable (AAPC, 0.4; 95% CI -0.2 to 0.9; p = 0.215). Men ages 25-29 experienced a significant increase in TCSM (AAPC, 1.3, p = 0.003), consistent with increased metastatic testicular cancer-specific incidence (TCSI) trend for this age group (AAPC, 1.6; p < 0.01). Mortality increased for Hispanic men (AAPC, 1.7, p < 0.001), with increased metastatic TCSI (AAPC, 2.5; p < 0.001). Finally, younger (<45), single, and Hispanic or Black men were more likely to die in medical facilities (all p < 0.001). The retrospective study design is a limitation. CONCLUSION: Significant increases in metastatic TC were found for Hispanic men and men aged 25-29 potentially driving increasing testicular cancer specific mortality in these groups. Evidence of racial and ethnic differences in place of death may also highlight treatment disparities.