Validation and responsiveness of the English version of the Chemotherapy-Induced Alopecia Distress Scale (CADS) in breast cancer patients.

PURPOSE: This study aimed to validate the Chemotherapy-Induced Alopecia Distress Scale (CADS) in a diverse English-speaking population and patients with endocrine treatment-induced alopecia (EIA). OBJECTIVE: Chemotherapy and endocrine therapy commonly cause alopecia in breast cancer patients, leading to significant psychological and social challenges. The CADS was developed to assess the psychosocial impact of alopecia, but its generalizability beyond Korean patients requires further investigation. METHODS: Data from the CHANCE study (NCT02530177), which focused on non-metastatic breast cancer, was used. The cohort included 256 patients, and CADS data were collected at baseline, 6 months after chemotherapy completion, or 12 months after initiating endocrine therapy. The CADS questionnaire comprised 17 items covering physical and emotional health, daily activities, and relationships. Reliability was assessed using Cronbach's alpha, and responsiveness was measured by effect size. RESULTS: The CADS exhibited good reliability, with Cronbach's alpha of 0.91 for the overall score, indicating acceptable internal consistency in both chemotherapy (0.89) and endocrine therapy (0.86) groups. Longitudinal responsiveness was supported by an effect size of 0.49 between decreasing satisfaction with hair growth and increasing emotional distress. Cross-sectional validity was confirmed, with effect sizes of 0.91 and 0.92 for satisfaction with hair growth and emotional and activity domains, respectively. CONCLUSION: The CADS is a valid and responsive tool for assessing the psychosocial impact of chemotherapy-induced alopecia and endocrine treatment-induced alopecia in a diverse Western patient population.

Predictors of Quality of Life Decline in Patients with Oligometastases treated with Stereotactic Ablative Radiotherapy: Analysis of the Population-Based SABR-5 Phase II Trial.

AIMS: Most patients experience stable quality of life (QoL) after stereotactic ablative radiotherapy (SABR) treatment for oligometastases. However, a subset of patients experience clinically relevant declines in QoL on post-treatment follow-up. This study aimed to identify risk factors for QoL decline. MATERIALS AND METHODS: The SABR-5 trial was a population-based single-arm phase II study of SABR to up to five sites of oligometastases. Prospective QoL was measured using treatment site-specific tools at pre-treatment baseline and 3, 6, 9, 12, 15, 18, 21, 24, 30 and 36 months after treatment. The time to persistent QoL decline was calculated as the time from SABR to the first decline in QoL score meeting minimum clinically important difference with no improvement to baseline score on subsequent assessments. Univariable and multivariable logistic regression analyses were carried out to determine factors associated with QoL decline. RESULTS: One hundred and thirty-three patients were included with a median follow-up of 32 months (interquartile range 25-43). Thirty-five patients (26%) experienced a persistent decline in QoL. The median time until persistent QoL decline was not reached. The cumulative incidence of QoL decline at 2 and 3 years were 22% (95% confidence interval 14.0-29.6) and 40% (95% confidence interval 28.0-51.2), respectively. In multivariable analysis, disease progression (odds ratio 5.23, 95% confidence interval 1.59-17.47, P = 0.007) and adrenal metastases (odds ratio 9.70, 95% confidence interval 1.41-66.93, P = 0.021) were associated with a higher risk of QoL decline. Grade 3 or higher (odds ratio 3.88, 95% confidence interval 0.92-16.31, P = 0.064) and grade 2 or higher SABR-associated toxicity (odds ratio 2.24, 95% confidence interval 0.85-5.91, P = 0.10) were associated with an increased risk of QoL decline but did not reach statistical significance. CONCLUSIONS: Disease progression and adrenal lesion site were associated with persistent QoL decline following SABR. The development of grade 3 or higher toxicities was also associated with an increased risk, albeit not statistically significant. Further studies are needed, focusing on the QoL impact of metastasis-directed therapies.

Prospective Longitudinal Assessment of Quality of Life After Stereotactic Ablative Radiotherapy for Oligometastases: Analysis of the Population-based SABR-5 Phase II Trial.

AIMS: To evaluate longitudinal patient-reported quality of life (QoL) in patients treated with stereotactic ablative radiotherapy (SABR) for oligometastases. MATERIALS AND METHODS: The SABR-5 trial was a population-based single-arm phase II study of SABR to up to five sites of oligometastases, conducted in six regional cancer centres in British Columbia, Canada from 2016 to 2020. Prospective QoL was measured using treatment site-specific QoL questionnaires at pre-treatment baseline and at 3, 6, 9, 12, 15, 18, 21, 24, 30 and 36 months after treatment. Patients with bone metastases were assessed with the Brief Pain Inventory (BPI). Patients with liver, adrenal and abdominopelvic lymph node metastases were assessed with the Functional Assessment of Chronic Illness Therapy-Abdominal Discomfort (FACIT-AD). Patients with lung and intrathoracic lymph node metastases were assessed with the Prospective Outcomes and Support Initiative (POSI) lung questionnaire. The two one-sided test procedure was used to assess equivalence between the worst QoL score and the baseline score of individual patients. The mean QoL at all time points was used to determine the trajectory of QoL response after SABR. The proportion of patients with 'stable', 'improved' or 'worsened' QoL was determined for all time points based on standard minimal clinically important differences (MCID; BPI worst pain = 2, BPI functional interference score [FIS] = 0.5, FACIT-AD Trial Outcome Index [TOI] = 8, POSI = 3). RESULTS: All enrolled patients with baseline QoL assessment and at least one follow-up assessment were analysed (n = 133). On equivalence testing, the patients' worst QoL scores were clinically different from baseline scores and met MCID (BPI worst pain mean difference: 1.8, 90% confidence interval 1.19 to 2.42]; BPI FIS mean difference: 1.68, 90% confidence interval 1.15 to 2.21; FACIT-AD TOI mean difference: -8.76, 90% confidence interval -11.29 to -6.24; POSI mean difference: -4.61, 90% confidence interval -6.09 to -3.14). However, the mean FIS transiently worsened at 9, 18 and 21 months but eventually returned to stable levels. The mean FACIT and POSI scores also worsened at 36 months, albeit with a limited number of responses (n = 4 and 8, respectively). Most patients reported stable QoL at all time points (range: BPI worst pain 71-82%, BPI FIS 45-78%, FACIT-AD TOI 50-100%, POSI 25-73%). Clinically significant stability, worsening and improvement were seen in 70%/13%/18% of patients at 3 months, 53%/28%/19% at 18 months and 63%/25%/13% at 36 months. CONCLUSIONS: Transient decreases in QoL that met MCID were seen between patients' worst QoL scores and baseline scores. However, most patients experienced stable QoL relative to pre-treatment levels on long-term follow-up. Further studies are needed to characterise patients at greatest risk for decreased QoL.

Validation and Responsiveness of the English version of the Chemotherapy-Induced Alopecia Distress Scale (CADS) in Breast Cancer Patients.

Purpose: This study aimed to validate the chemotherapy-induced alopecia distress scale (CADS) in a diverse English-speaking population and patients with endocrine treatment- induced alopecia (EIA). Objective: Chemotherapy and endocrine therapy commonly cause alopecia in breast cancer patients, leading to significant psychological and social challenges. The CADS was developed to assess the psychosocial impact of alopecia, but its generalizability beyond Korean patients requires further investigation. Methods: Data from the CHANCE study ( NCT02530177 ), which focused on non-metastatic breast cancer, was used. The cohort included 256 patients, and CADS data were collected at baseline, six months after chemotherapy completion, or 12 months after initiating endocrine therapy. The CADS questionnaire comprised 17 items covering physical and emotional health, daily activities, and relationships. Reliability was assessed using Cronbach's alpha, and responsiveness was measured by effect size. Results: The CADS exhibited good reliability, with a Cronbach's alpha of 0.91 for the overall score, indicating acceptable internal consistency in both chemotherapy (0.89) and endocrine therapy (0.86) groups. Longitudinal responsiveness was supported by an effect size of 0.49 between decreasing satisfaction with hair growth and increasing emotional distress. Cross-sectional validity was confirmed, with effect sizes of 0.91 and 0.92 for satisfaction with hair growth and emotional and activity domains, respectively. Conclusion: The CADS is a valid and responsive tool for assessing the psychosocial impact of chemotherapy-induced alopecia and endocrine treatment-induced alopecia in a diverse Western patient population.

Pituitary-testis axis dysfunction following adjuvant androgen deprivation therapy.

Men with high-risk, non-metastatic prostate cancer receive adjuvant androgen deprivation therapy (ADT) for at least 2 years according to Danish guidelines. It remains unclarified if patients regain the function of the pituitary-testis axis after cessation of ADT. Thus, we aimed to investigate the function of the pituitary-testis axis following adjuvant ADT. In this study, we included men who underwent external beam radiation therapy and ADT for high-risk prostate cancer. All patients underwent assessment of testosterone deficiency (TD) symptoms, full biochemical assessment of the pituitary-testis axis, and dynamic stimulatory tests of gonadotropin (gonadotropin-releasing hormone (GnRH) test) and testosterone production (human chorionic gonadotrophin (hCG) test). Patients were diagnosed with TD based on a combination of TD symptoms and testosterone below age-specific reference ranges. TD was characterized as primary, secondary, or mixed based on serum gonadotropins and stimulatory tests. We found that among the 51 patients included in the study, the median time on ADT was 3.2 years and median time since ADT cessation was 3.8 years. Twenty-eight patients were diagnosed with TD; 10 had primary TD (testicular dysfunction), 11 secondary TD (pituitary dysfunction), and 7 mixed TD (combined pituitary and testicular dysfunction). An inadequate testosterone response to hCG stimulation was shown in 42 patients, whereas only 11 patients had a subnormal gonadotropin response to GnRH. We conclude that persistent TD is a common long-term consequence of adjuvant ADT in prostate cancer survivors, equally distributed between pituitary and testicular dysfunction. The study emphasizes the necessity for systematic follow-up of full pituitary-testis axis function in patients receiving adjuvant ADT.

Validation of the Prognostic Utility of ESTRO/EORTC Oligometastatic Disease Classification: A Secondary Analysis From the Population-Based Phase II SABR-5 Trial.

PURPOSE: The recently developed European Society for Radiotherapy and Oncology (ESTRO)/European Organization for Research and Treatment of Cancer (EORTC) oligometastatic disease (OMD) classification has not been validated in terms of its prognostic significance. This study stratified patients from the phase II SABR-5 trial based on ESTRO/EORTC criteria and compared progression-free survival (PFS) and overall survival (OS) to determine the prognostic significance of the classification scheme. METHODS AND MATERIALS: The SABR-5 trial was a single arm phase II study conducted at the 6 regional cancer centers across British Columbia (BC), Canada, where SABR for oligometastases was only offered on trial. Patients with up to 5 oligometastases (total or not controlled by prior treatment and including induced OMD) underwent SABR to all lesions. Patients were 18 years of age or older, Eastern Cooperative Oncology Group 0 to 2, and life expectancy ≥6 months. PFS and OS were calculated using the Kaplan-Meier method and differences between OMD groups were assessed with log-rank tests. Univariable and multivariable analyses were performed using Cox regression modeling. RESULTS: Between November 2016 and July 2020, 381 patients underwent SABR on trial. Median follow-up was 27 months (interquartile range, 18-36). The most frequent OMD group was de novo OMD (69%), followed by repeat (16%) and induced (13%). OMD groups differed significantly in PFS (P < .001) but not OS (P = .069). The OMD classification was an independent predictor of both PFS (P = .005) and OS (P = .002). Of the 5 classification factors, only chronicity (synchronous, hazard ratio, 0.52; P = .027) and oligoprogression (hazard ratio, 2.05; P = .004) were independently prognostic for OS. CONCLUSIONS: In this large prospective cohort, the ESTRO/EORTC classification was an independent predictor of PFS and OS and should be used to identify specific patient groups for clinical trials. In this trial population, the prognostic power is largely attributable to chronicity and oligoprogression. Simplification of the framework may be possible in the future and allow for greater ease of use; however, further data on underrepresented OMD groups and histologies will be required.

Non-invasive, in vivo, characterization of cutaneous metastases using a novel multimodal RCM-OCT imaging device: a case-series.

BACKGROUND: Cutaneous metastases (CM) diagnosis is clinically challenging, requiring an invasive biopsy for confirmation. A novel, RCM-OCT device combines the advantage of horizontal high-resolution reflectance confocal microscopy (RCM) images and vertical deeper optical coherence tomography (OCT) images to aid in non-invasive diagnosis of CM from breast cancers. OBJECTIVE: Characterize CM from breast cancers using RCM-OCT device. METHODS: Seven patients suffering from breast cancers with suspicious CM were consented and imaged with RCM-OCT device. CM features were defined by comparing with histopathology. Tumour depths were measured on OCT and on H&E-images and correlated using statistical analysis Pearson test. 3D-OCT images were reconstructed to enhance tumour visualization. RESULTS: 6/7 lesions were CM from breast cancers, and one was vascular ectasia, on histopathology. CM appeared as greyish-darkish oval to round structures within the dermis on RCM and OCT-images. On RCM, individual tumour cells were seen, enabling identification of even small tumour foci; while, on OCT deeper tumours were detected. Inflammatory cells, dilated vessels and coarse collagen were identified in the dermis. Pearson correlation had an r2 of 0.38 and a significant P-value <0.004 for depth measurements. CM from breast cancers could be differentiated from ecstatic vessels on 3D-reconstructed OCT image. LIMITATION: Small sample size and lack of clinical mimickers. CONCLUSION: RCM-OCT can detect CM and has potential in aiding non-invasive diagnosis and management.

Combined Radiotherapy and New Systemic Therapies - Have We Moved Beyond Palliation?

The new systemic therapies for cancer are having major impacts on the prognosis of patients with advanced cancers, some achieving long-term survival with targeted therapy or immune checkpoint inhibitors. Interactions of radiotherapy with the new systemic therapies are reviewed. Many agents increase radiosensitivity and particular caution is required combining BRAF inhibitors and radiotherapy because of significant toxicity. Most new systemic therapies can be used safely with palliative doses of radiotherapy, but it is important to be aware of overlapping toxicities depending on the site treated. DNA damage response modulators increase radiosensitivity and may potentially increase radiation toxicity but are at an earlier stage of development. Stereotactic ablative radiotherapy may produce further survival gains in patients responding to targeted therapy and immunotherapy.

Bone mineral density is preserved in men with idiopathic infertility.

BACKGROUND: Lower semen quality is associated with increased mortality and morbidity, which may include osteoporosis. OBJECTIVE: To assess whether infertile men have a lower bone mineral density (BMD) compared with fertile men at the time of fertility workup. METHODS: A total of 146 men from infertile couples with unexplained impaired semen quality, characterized by sperm concentration < 20 million/mL, progressive motility < 50% or < 12% morphologically normal spermatozoa. Men with infertility due to a genetic etiology or a condition that could cause testicular damage were excluded. A total of 271 men from couples with an ongoing naturally conceived pregnancy served as a control group. Lumbar, femoral, and total body BMD were measured by dual X-ray absorptiometry. RESULTS: Infertile men had similar BMD compared with fertile men (Beta coefficient (g/cm2 ) and 95% confidence interval for the difference between the two groups: -0.02 (-0.05; 0.01) for lumbar BMD, -0.02 (-0.05; 0.01) for femoral neck BMD, -0.01 (-0.04; 0.02) for total femur BMD, and -0.01 (-0.03; 0.01) for total body BMD). Semen parameters were not associated with BMD measurements. Furthermore, BMD did not differ between infertile men with the lowest semen quality vs. infertile men with better semen quality nor between infertile men with low testosterone vs. fertile men with normal testosterone levels. CONCLUSION: Bone mineral density is preserved in men with unexplained infertility at the time of fertility workup.

EAA clinical practice guidelines-gynecomastia evaluation and management.

BACKGROUND: Gynecomastia (GM) is a benign proliferation of the glandular tissue of the breast in men. It is a frequent condition with a reported prevalence of 32-65%, depending on the age and the criteria used for definition. GM of infancy and puberty are common, benign conditions resolving spontaneously in the majority of cases. GM of adulthood is more prevalent among the elderly and proper investigation may reveal an underlying pathology in 45-50% of cases. OBJECTIVES: The aim was to provide clinical practice guidelines for the evaluation and management of GM. MATERIALS AND METHODS: A literature search of articles in English for the term 'gynecomastia' was conducted. Evidence-based recommendations were developed using the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) system. RESULTS: A set of five statements and fifteen clinical recommendations was formulated. CONCLUSIONS: The purpose of GM assessment should be the detection of underlying pathological conditions, reversible causes (administration/abuse of aggravating substances), and the discrimination from other breast lumps, particularly breast cancer. Assessment should comprise a thorough medical history and physical examination of the breast and genitalia (including testicular ultrasound). A set of laboratory investigations may integrate the evaluation: testosterone (T), estradiol (E2), sex hormone-binding globulin (SHBG), luteinizing hormone (LH), follicular stimulating hormone (FSH), thyroid stimulating hormone (TSH), prolactin, human chorionic gonadotropin (hCG), alpha-fetal protein (AFP), liver and renal function tests. Breast imaging may be used whenever the clinical examination is equivocal. In suspicious lesions, core needle biopsy should be sought directly instead. Watchful waiting is recommended after treatment of underlying pathology or discontinuation of substances associated with GM. T treatment should be offered to men with proven T deficiency. The use of selective estrogen receptor modulators (SERMs), aromatase inhibitors (AIs) and non-aromatizable androgens is not justified in general. Surgical treatment is the therapy of choice for patients with long-lasting GM. SUMMARY OF STATEMENTS (S) AND RECOMMENDATIONS (R): S1. Gynecomastia (GM) is a benign proliferation of glandular tissue of the breast in males. S2. GM of infancy is a common condition that usually resolves spontaneously, typically within the first year of life. S3. GM of puberty is a common condition, affecting approximately 50% of mid-pubertal boys; in more than 90% of cases, it resolves spontaneously within 24 months. S4. The prevalence of GM in adulthood increases with increasing age; proper investigation may reveal an underlying pathology in approximately 45-50% of the cases. S5. Male breast cancer is rare; GM should not be considered a premalignant condition. The following recommendations are divided into 'strong', denoted by the number 1 and associated with the terminology 'we recommend', and 'weak' denoted by the number 2 and associated with the phrase 'we suggest'. The grading of the quality of evidence is denoted as follows: ⊕○○○ for very low-quality evidence; ⊕⊕○○ for low quality; ⊕⊕⊕○ for moderate quality; and ⊕⊕⊕⊕ for high quality. R1. The presence of an underlying pathology should be considered in GM of adulthood. We recommend that the identification of an apparent reason for GM in adulthood, including the use of medication known to be associated with GM, should not preclude a detailed investigation (1 ⊕⊕⊕○). R2. We suggest that the initial screening to rule out lipomastia, obvious breast cancer, or testicular cancer might be performed by a general practitioner or another non-specialist (2 ⊕○○○). R3. We recommend that in those cases where a thorough diagnostic workup is warranted, it should be performed by a specialist (1 ⊕○○○). R4. We recommend that the medical history should include information on the onset and duration of GM, sexual development and function, and administration or abuse of substances associated with GM (1 ⊕⊕⊕○). R5. We recommend that the physical examination should detect signs of under-virilization or systemic disease (1 ⊕⊕⊕⊕). R6. We recommend that breast examination should confirm the presence of palpable glandular tissue to discriminate GM from lipomastia (pseudo-gynecomastia) and rule out the suspicion of malignant breast tumor (1 ⊕⊕⊕⊕). R7. We recommend that the physical examination should include the examination of the genitalia to rule out the presence of a palpable testicular tumor and to detect testicular atrophy (1 ⊕⊕⊕⊕). R8. We recommend that genitalia examination is aided by a testicular ultrasound, as the detection of a testicular tumor by palpation has low sensitivity (1 ⊕⊕○○). R9. We suggest that a set of evaluations may include T, E2 , SHBG, LH, FSH, TSH, prolactin, hCG, AFP, and liver and renal function tests (2 ⊕⊕○○). R10. We suggest that breast imaging may offer assistance, where the clinical examination is equivocal (2 ⊕⊕○○). R11. We suggest that, if the clinical picture is suspicious for a malignant lesion, core needle biopsy should be performed (2 ⊕⊕○○). R12. We recommend watchful waiting after treatment of underlying pathology or discontinuation of the administration/abuse of substances associated with GM (1 ⊕⊕○○). R13. We recommend that T treatment should be offered only to men with proven testosterone deficiency (1 ⊕⊕⊕○). R14. We do not recommend the use of selective estrogen receptor modulators (SERMs), aromatase inhibitors (AIs), or non-aromatizable androgens in the treatment of GM in general (1 ⊕⊕○○). R15. We suggest surgical treatment only for patients with long-lasting GM, which does not regress spontaneously or following medical therapy. The extent and type of surgery depend on the size of breast enlargement, and the amount of adipose tissue (2 ⊕⊕○○).

Anogenital distance is associated with semen quality but not reproductive hormones in 1106 young men from the general population.

STUDY QUESTION: Is anogenital distance (AGD) associated with semen quality and reproductive hormones in men from the general population? SUMMARY ANSWER: Short AGD measured from the anus to the base of scrotum (AGDAS) was associated with reduced sperm counts and morphology but not with sperm motility or reproductive hormones. WHAT IS KNOWN ALREADY: AGD is longer in males than in females. In rodents, AGD is a well-established and sensitive marker of disruption during the masculinization programming window in utero and it has been suggested to be so in humans as well. Therefore, the average AGD would be expected to be shorter in men with poor semen quality, which some studies have confirmed while others have not. STUDY DESIGN, SIZE, DURATION: This cross-sectional population-based study was of 1106 men included between 2012 and 2016. PARTICIPANTS/MATERIALS, SETTING, METHODS: Men from the general Danish population (median age 19 years), unselected with regard to fertility status and semen quality, delivered a semen sample, had a blood sample drawn, which was analyzed for concentrations of reproductive hormones, and answered a comprehensive questionnaire. They also had a physical examination performed including determination of AGD measured as the distance between anus and scrotum (AGDAS) and penis (AGDAP). Odds ratios (OR) and 95% CI were estimated for a man having abnormal semen parameters according to the World Health Organization's reference values or a low/high concentration of reproductive hormones (defined as the lowest or highest 10%) depending on AGD. AGD was categorized in four strata: ≤10th percentile, 10th-30th percentile, 30th-50th percentile and >50th percentile. MAIN RESULTS AND THE ROLE OF CHANCE: Men with the 10% shortest AGDAS had a more than doubled risk (OR: 2.19, 95% CI: 1.40-3.42) of being in the subfertile range for either sperm concentration (<15 million/mL) or sperm morphology (<4%) compared to men with AGDAS above the median (reference). Men in the 10th-30th percentile also had an increased OR of 1.48 (95% CI: 1.06-2.08) but not men in the 30th-50th percentile (OR: 1.14, 95% CI: 0.81-1.62). AGDAP was only weakly related to semen quality. AGD was not associated with testicular volume or any of the reproductive hormones. LIMITATIONS, REASONS FOR CAUTION: Limitations include the potential non-differential misclassification of reproductive outcomes based on a single semen and blood sample and some between-examiner differences in AGD measurements which introduces noise and may result in an underestimation of observed associations. WIDER IMPLICATIONS OF THE FINDINGS: Our study of men from the general population confirmed associations between AGD and semen quality, supporting the hypothesis that AGD in humans could be a marker of fetal testicular development. This suggests that the low semen quality in Danish men may partly be explained by prenatal factors. STUDY FUNDING/COMPETING INTEREST(S): The study has received financial support from the ReproUnion (L.P.); the Research fund of Rigshospitalet, Copenhagen University Hospital (N.J.); Grants R01ES016863-04 and R01ES016863-02S4; National Institute of Environmental Health Sciences (NIEHS) and National Institute of Environmental Health Sciences grant (P30ES023515) (S.S.); the European Union (Contract numbers BMH4-CT96-0314, QLK4-CT-1999-01422, QLK4-CT-2002-00603, FP7/2007-2013, DEER Grant agreement no. 212844); the Danish Ministry of Health; the Danish Environmental Protection Agency; A.P. Møller and wife Chastine McKinney Møllers foundation; and Svend Andersens Foundation. None of the funders had any role in the study design, collection, analysis or interpretation of data, writing of the paper or publication decisions. The authors have nothing to declare. TRIAL REGISTRATION NUMBER: N/A.

An initial melanoma diagnosis may increase the subsequent risk of prostate cancer: Results from the New South Wales Cancer Registry.

Emerging evidence suggests that a diagnosis of cutaneous melanoma (CM) may be associated with prostate cancer (PC) incidence. We examined if the incidence of CM was associated with an increased subsequent risk of PC. We used data from the New South Wales Cancer Registry for all CM and PC cases diagnosed between January 1972 and December 2008. We calculated the age standardized incidence ratio (SIR) and 95% confidence intervals (95% CI) for PC incidence following a CM diagnosis, applying age- and calendar- specific rates to the appropriate person years at risk. We determined rate ratio (RR) and 95% CI of PC incidence according to specified socio-demographic categories and disease related characteristics, using a negative binomial model. There were 143,594 men diagnosed with PC or CM in the study period and of these 101,198 and 42,396 were diagnosed with PC and CM, respectively, as first primary cancers. Risk of PC incidence increased following CM diagnosis (n = 2,114; SIR = 1.25; 95% CI:1.20.8-1.31: p < 0.0001), with the increased risk apparent in men diagnosed with localised CM (n = 1,862;SIR = 1.26; 95% CI:1.20-1.32). CM diagnosis increased the subsequent risk of PC incidence. This raises the potential for future PC risk to be discussed with newly diagnosed males with CM.

Average sperm count remains unchanged despite reduction in maternal smoking: results from a large cross-sectional study with annual investigations over 21 years.

STUDY QUESTION: How are temporal trends in lifestyle factors, including exposure to maternal smoking in utero, associated to semen quality in young men from the general population? SUMMARY ANSWER: Exposure to maternal smoking was associated with lower sperm counts but no overall increase in sperm counts was observed during the study period despite a decrease in this exposure. WHAT IS KNOWN ALREADY: Meta-analyses suggest a continuous decline in semen quality but few studies have investigated temporal trends in unselected populations recruited and analysed with the same protocol over a long period and none have studied simultaneous trends in lifestyle factors. STUDY DESIGN, SIZE, DURATION: Cross-sectional population-based study including ~300 participants per year (total number = 6386) between 1996 and 2016. PARTICIPANTS/MATERIALS, SETTING, METHODS: The study is based on men from the Greater Copenhagen area, Denmark, with a median age of 19 years, and unselected with regard to fertility status and semen quality. The men delivered a semen sample, had a blood sample drawn and a physical examination performed and answered a comprehensive questionnaire, including information on lifestyle and the mother's pregnancy. Temporal trends in semen quality and lifestyle were illustrated graphically, and trends in semen parameters and the impact of prenatal and current lifestyle factors were explored in multiple regression analyses. MAIN RESULTS AND THE ROLE OF CHANCE: Throughout the study period, 35% of the men had low semen quality. Overall, there were no persistent temporal trends in semen quality, testicular volume or levels of follicle-stimulating hormone over the 21 years studied. The men's alcohol intake was lowest between 2011 and 2016, whereas BMI, use of medication and smoking showed no clear temporal trends. Parental age increased, and exposure in utero to maternal smoking declined from 40% among men investigated in 1996-2000 to 18% among men investigated in 2011-2016. Exposure to maternal smoking was associated with lower sperm counts but no overall increase in sperm counts was observed despite the decrease in this exposure. LIMITATIONS, REASONS FOR CAUTION: Information of current and prenatal lifestyle was obtained by self-report, and the men delivered only one semen sample each. WIDER IMPLICATIONS OF THE FINDINGS: The significant decline in in utero exposure to maternal smoking, which was not reflected in an overall improvement of semen quality at the population level, suggest that other unknown adverse factors may maintain the low semen quality among Danish men. STUDY FUNDING/COMPETING INTEREST(S): The study has received financial support from the ReproUnion; the Research fund of Rigshospitalet, Copenhagen University Hospital; the European Union (Contract numbers BMH4-CT96-0314,QLK4-CT-1999-01422, QLK4-CT-2002-00603, FP7/2007-2013, DEER Grant agreement no. 212844); the Danish Ministry of Health; the Danish Environmental Protection Agency; A.P. Møller and wife Chastine McKinney Møllers foundation; and Svend Andersens Foundation. None of the funders had any role in the study design, collection, analysis or interpretation of data, writing of the paper or publication decisions. TRIAL REGISTRATION NUMBER: N/A.

Neurons derived from patients with bipolar disorder divide into intrinsically different sub-populations of neurons, predicting the patients' responsiveness to lithium.

Bipolar disorder (BD) is a progressive psychiatric disorder with more than 3% prevalence worldwide. Affected individuals experience recurrent episodes of depression and mania, disrupting normal life and increasing the risk of suicide greatly. The complexity and genetic heterogeneity of psychiatric disorders have challenged the development of animal and cellular models. We recently reported that hippocampal dentate gyrus (DG) neurons differentiated from induced pluripotent stem cell (iPSC)-derived fibroblasts of BD patients are electrophysiologically hyperexcitable. Here we used iPSCs derived from Epstein-Barr virus-immortalized B-lymphocytes to verify that the hyperexcitability of DG-like neurons is reproduced in this different cohort of patients and cells. Lymphocytes are readily available for research with a large number of banked lines with associated patient clinical description. We used whole-cell patch-clamp recordings of over 460 neurons to characterize neurons derived from control individuals and BD patients. Extensive functional analysis showed that intrinsic cell parameters are very different between the two groups of BD neurons, those derived from lithium (Li)-responsive (LR) patients and those derived from Li-non-responsive (NR) patients, which led us to partition our BD neurons into two sub-populations of cells and suggested two different subdisorders. Training a Naïve Bayes classifier with the electrophysiological features of patients whose responses to Li are known allows for accurate classification with more than 92% success rate for a new patient whose response to Li is unknown. Despite their very different functional profiles, both populations of neurons share a large, fast after-hyperpolarization (AHP). We therefore suggest that the large, fast AHP is a key feature of BD and a main contributor to the fast, sustained spiking abilities of BD neurons. Confirming our previous report with fibroblast-derived DG neurons, chronic Li treatment reduced the hyperexcitability in the lymphoblast-derived LR group but not in the NR group, strengthening the validity and utility of this new human cellular model of BD.

Is the FSHR 2039A>G variant associated with susceptibility to testicular germ cell cancer?

Testicular germ cell cancer (TGCC) is derived from germ cell neoplasia in situ (GCNIS), which arises due to niche disturbances affecting the Sertoli cells. It is believed that exogenous endocrine factors have a crucial role in governing neoplastic transformation but on a strong hereditary background. Follicle-stimulating hormone (FSH) is the major regulatory hormone of the Sertoli cells. FSH signalling-related single-nucleotide polymorphisms (SNPs) have previously been shown to affect FSH action in men at different levels. We aimed to investigate whether three FSH-related SNPs (FSHR 2039A>G, FSHR -29G>A and FSHB -211G>T) are associated with development of TGCC. A total of 752 Danish and German patients with TGCC from two tertiary andrological referral centres were included. Three control groups comprising 2020 men from the general population, 679 fertile men and 417 infertile men, were also included. Chi-squared test was performed to compare genotype- and allele frequencies. Kruskal-Wallis test was performed to compare age at diagnosis. Patients with TGCC had a higher frequency of the A-allele of FSHR 2039A>G compared to the group of fertile men with an AA-genotype frequency of 30.2% vs. 22.0%, respectively, p = 0.002. This variant is associated with higher FSH receptor activity. The distribution of the FSHR 2039A>G did not differ significantly between the patients with TGCC and the infertile or the general population. The frequency of the two other SNPs did not differ between patient with TGCC and any of the control groups. No differences were detected between genotypes and age distribution or histological subtype of the tumours. In conclusion, we observed that a genetic variant associated with FSHR activity may modulate the susceptibility to TGCC.

Possible involvement of the glucocorticoid receptor (NR3C1) and selected NR3C1 gene variants in regulation of human testicular function.

Perceived stress has been associated with decreased semen quality but the mechanisms have not been elucidated. It is not known whether cortisol, the major stress hormone in humans, can act directly via receptors in the testis, and whether variants in the gene encoding the glucocorticoid receptor (NR3C1) can possibly modulate the effect. To address these questions, we investigated the expression of the glucocorticoid receptor in human testicular tissue, including adult and fetal samples (n = 20) by immunohistochemical staining, and in silico analysis of publicly available datasets. In the adult testis NR3C1 protein was detected in peritubular cells, a subset of Leydig cells, Sertoli cells (weak), and spermatogonia, but not in spermatids. The NR3C1 expression pattern in fetal testis samples differed by a notably stronger reaction in Sertoli cells, lack of staining in gonocytes but the presence in a subset of pro-spermatogonia, and the almost absent reaction in nascent peritubular cells. In parallel, we explored the association between adult testicular function and three single nucleotide NR3C1 polymorphisms (BcII [rs41423247], 9ß [rs6198], and Tth111I [rs10052957]) affecting glucocorticoid sensitivity. Testicular function was determined by semen analysis and reproductive hormone profiling in 893 men from the general population. The NR3C1 SNP BclI was associated with semen quality in an over-dominant manner with heterozygotes having better semen parameters compared to both homozygote constellations, and with sperm motility showing the strongest association. This association was supported by a higher inhibin B and inhibin B/FSH ratio, as well as a lower FSH in BclI heterozygotes. The SNPs 9ß and Tth111I were not associated with semen parameters. Although the clinical impact of the findings is limited, the results substantiate a suggested link between stress and testicular function. Hence this investigation should be regarded as a discovery study generating hypotheses for future studies.

Gynaecomastia in 786 adult men: clinical and biochemical findings.

OBJECTIVE: Gynaecomastia is a benign proliferation of glandular tissue of the breast; however, it is an important clinical observation because it can be the first symptom of an underlying disease. Some controversy exists concerning the clinical importance of an in-depth investigation of men who develop gynaecomastia. We hypothesise that a thorough work-up is required in adult men with gynaecomastia. DESIGN: All adult men (n = 818) referred to a secondary level andrological department at Rigshospitalet in Copenhagen, Denmark during a four-year period (2008-2011) under the diagnosis of gynaecomastia (ICD-10: N62) were included. METHODS: Thirty-two men who did not have gynaecomastia when examined were excluded; leaving 786 men for final analyses. They underwent an andrological examination, ultrasound of the testicles and analysis of endogenous serum hormones levels. RESULTS: In 43% of men with adult onset of gynaecomastia (≥18 years) an underlying, and often treatable, cause could be detected. In men younger at onset an underlying cause for gynaecomastia could be detected in merely 7.7%. The study is limited by the fact that we did not have access to investigate men who were referred directly by their GP to private clinics for plastic surgery or who sought cosmetic correction without consulting their GP first. CONCLUSIONS: Our study demonstrates the importance of a thorough examination and provides a comprehensible examination strategy to disclose the underlying pathology leading to the development of gynaecomastia in adulthood.

Dynamic GnRH and hCG testing: establishment of new diagnostic reference levels.

OBJECTIVE: Gonadotropin-releasing hormone (GnRH) and human chorionic gonadotropin (hCG) stimulation tests may be used to evaluate the pituitary and testicular capacity. Our aim was to evaluate changes in follicular-stimulating hormone (FSH), luteinizing hormone (LH) and testosterone after GnRH and hCG stimulation in healthy men and assess the impact of six single nucleotide polymorphisms on the responses. DESIGN: GnRH and hCG stimulation tests were performed on 77 healthy men, 18-40 years (reference group) at a specialized andrology referral center at a university hospital. The potential influence of the tests was illustrated by results from 45 patients suspected of disordered hypothalamic-pituitary-gonadal axis. METHODS: Baseline, stimulated, relative and absolute changes in serum FSH and LH were determined by ultrasensitive TRIFMA, and testosterone was determined by LC-MS/MS. RESULTS: For the reference group, LH and FSH increased almost 400% and 40% during GnRH testing, stimulated levels varied from 4.4 to 58.8 U/L and 0.2 to 11.8 U/L and FSH decreased in nine men. Testosterone increased approximately 110% (range: 18.7-67.6 nmol/L) during hCG testing. None of the polymorphisms had any major impact on the test results. Results from GnRH and hCG tests in patients compared with the reference group showed that the stimulated level and absolute increase in LH showed superior identification of patients compared with the relative increase, and the absolute change in testosterone was superior in identifying men with Leydig cell insufficiency, compared with the relative increase. CONCLUSIONS: We provide novel reference ranges for GnRH and hCG test in healthy men, which allows future diagnostic evaluation of hypothalamic-pituitary-gonadal disorders in men.

An examination of prostate cancer trends in Australia, England, Canada and USA: Is the Australian death rate too high?

PURPOSE: To compare prostate cancer incidence and mortality rates in Australia, USA, Canada and England and quantify the gap between observed prostate cancer deaths in Australia and expected deaths, using US mortality rates. METHODS: Analysis of age-standardised prostate cancer incidence and mortality rates, using routinely available data, in four similarly developed countries and joinpoint regression to quantify the changing rates (annual percentage change: APC) and test statistical significance. Expected prostate cancer deaths, using US mortality rates, were calculated and compared with observed deaths in Australia (1994-2010). RESULTS: In all four countries, incidence rates initially peaked between 1992 and 1994, but a second, higher peak occurred in Australia in 2009 (188.9/100,000), rising at a rate of 5.8 % (1998-2008). Mortality rates in the USA (APC: -2.9 %; 2004-2010), Canada (APC: -2.9 %; 2006-2011) and England (APC: -2.6 %; 2003-2008) decreased at a faster rate compared with Australia (APC: -1.7 %; 1997-2011). In 2010, mortality rates were highest in England and Australia (23.8/100,000 in both countries). The mortality gap between Australia and USA grew from 1994 to 2010, with a total of 10,895 excess prostate cancer deaths in Australia compared with US rates over 17 preceding years. CONCLUSIONS: Prostate cancer incidence rates are likely heavily influenced by prostate-specific antigen testing, but the fall in mortality occurred too soon to be solely a result of testing. Greater emphasis should be placed on addressing system-wide differences in the management of prostate cancer to reduce the number of men dying from this disease.

A study of finger lengths, semen quality and sex hormones in 360 young men from the general Danish population.

BACKGROUND: It has been suggested that finger length may correlate with function or disorders of the male reproductive system. This is based on the HOXA and HOXD genes' common embryological control of finger development and differentiation of the genital bud. The objective of this study was to explore the association between the ratio of 2nd to 4th finger length (2D:4D ratio) and testis function in a sample of young Danish men from the general population. METHODS: Semen samples and finger measurements were obtained from a total of 360 young Danish men in addition to blood samples for sex hormone analysis to describe the possible association between 2D:4D and semen and sex-hormone parameters. RESULTS: A statistically significant inverse association with the 2D:4D was found only in relation to hormone levels of FSH in the group of young men with a 2D:4D >1 (P = 0.036) and a direct association with the total sperm count in the group of young men with a 2D:4D < or = 1 (P = 0.045). CONCLUSION: The statistically significant results may be 'false positives' (type I error) rather than representing true associations. This relatively large study of young, normal Danish men shows no reliable association between 2D:4D finger ratio and testicular function. Measurements of finger lengths do not have the power to predict the testicular function of adult men.