Sex hormones influence survival of patients with metastatic urothelial carcinoma undergoing immune checkpoint therapy.

INTRODUCTION: Clinical trials investigating efficacy of immune checkpoint inhibitors (ICI) revealed sex-specific divergent outcomes in urothelial cancer (UC), suggesting that sex hormones might play an important role in gender-specific dimorphisms of response upon ICI. However, further clinical investigations are still needed to understand the influence of sex hormones in UC. The aim of this study was to get further insights on the prognostic and predictive value of sex hormone levels in patients with metastatic UC (mUC) who underwent ICI. MATERIAL AND METHODS: Sex hormone levels of patients with mUC including luteinizing hormone (LH), follicle-stimulating hormone (FSH), LH/FSH ratio, prolactin, testosterone and 17ß-estradiol (E2) were evaluated at baseline and during ICI at 6/8 weeks and 12/14 weeks. RESULTS: Twenty-eight patients (10 women, 18 men) with a median age of 70 years were included. Metastatic disease was confirmed in 21 patients (75%) after radical cystectomy while seven patients showed mUC at first diagnosis. Twelve patients (42.8%) received first line and 16 patients second line pembrolizumab. The objective response rate (ORR) was 39% (CR in 7%). The median progression-free survival (PFS) and overall survival (OS) was 5.5 and 20 months. Focusing on changes of sex hormone levels during ICI, a significant increase in FSH levels and decrease of the LH/FSH ratio was noticed in responders (p = 0.035), yet without sex-specific significance. When adjusted for sex and treatment line, a significant increase of FSH levels was confirmed in men during second line pembrolizumab. Focusing on baseline levels, LH/FSH ratio was significantly higher in female responders (p = 0.043) compared to non-responders. In women, increased LH levels and LH/FSH ratio were associated with better PFS (p = 0.014 for LH, p = 0.016 for LH/FSH ratio) and OS (p = 0.026 and p = 0.018). In male patients, increased E2 levels were linked with improved PFS (p < 0.001) and OS (p = 0.039). CONCLUSION: Increased LH and LH/FSH values in women as well as high E2 levels in men were significant predictors of better survival. Elevated LH/FSH ratio was predictive of better response to ICI in women. These results show first clinical evidence of the potential role of sex hormones as prognostic and predictive biomarker in mUC. Further prospective analyses are needed to corroborate our findings.

Urothelial carcinoma (UC) presents as aggressive disease with a greater incidence in men, yet a more aggressive course of disease in women. Patients with metastatic UC receive a chemotherapy regimen as the gold standard, based on an included platin substance. In the case of having contraindications to chemotherapy, checkpoint immunotherapy, priming the immune system to the tumor, is the treatment of choice. Furthermore, immunotherapy is used as second line therapy in progressive disease after chemotherapy and as maintenance therapy in stable tumor conditions after completing the chemotherapy regimen.Evidence shows that sex hormones of the hypothalamus­hypophysis axis influence development and course of UC. The sex hormones luteinizing hormone (LH) and follicle-stimulating hormone (FSH) stimulate estrogen (E2) production with a negative feedback function on the LH and FSH secretion. High levels of E2 present with a protective effect against UC. Sex has furthermore shown to predict potential response to immunotherapy. This study therefore focused on monitoring and correlating changes of sex hormone levels in 28 patients during therapy with checkpoint inhibitors.This first study assessing changes in sex hormones and the influence of baseline sex hormone values on survival in UC shows that responders to immunotherapy had significantly increased FSH levels. FSH furthermore increased in male patients receiving second line immunotherapy. High values of LH and a high LH/FSH ratio at baseline correlated with better overall survival in female patients. High E2 levels were indicative of better survival in male patients. The study results represent first suggestive prognostic and predictive results to the response of immunotherapy in UC.

Acceptance of female urologists among patients with suspected prostate disease.

BACKGROUNDS: The number of practicing female urologists is rising. The aim of this study is to evaluate the acceptance of female urologists by male patients and their partners. METHODS: Men who underwent a prostate MRI or a prostate biopsy between January and December 2018 and their partners, were sent questionnaires prior to the examination. Two types of questionnaires were used. One questionnaire asked "I want to be seen by: (I) a male urologist or (II) a female urologist or (III) no preference" (Groupnp), the other questionnaire only offered two possible answers: "I want to be seen by: (I) a male urologist or (II) a female urologist" (Groupm,f). All other questions were on prostate MRI and prostate biopsies. RESULTS: Overall, 377 questionnaires were sent to patients. One hundred and ninety-six questionnaires (52.0%) were returned. In Groupnp, 34.7% wanted to be seen by a male urologist, 60.8% of patients chose "no preference". The answers of the patients' female partners in Groupnp did not differ statistically significant (57.3% chose "no preference", 0% chose a female urologist). In Groupm,f, 54.5% of patients preferred a male urologist, one patient wanted to be seen by a female urologist, 44.3% did not answer the question. In Groupm,f, there was no statistically significant difference in preference in regard to the doctor's gender between the patients and their female partners (57% of partners wanted a male urologist, 0% wanted a female urologist). CONCLUSIONS: A large number of patients with prostate disease and their partners prefer male urologists rather than female urologists.

Sex differences in disease presentation, surgical and oncological outcome of liver resection for primary and metastatic liver tumors-A retrospective multicenter study.

BACKGROUND: Sex differences are becoming of rising interest in many fields of medicine. It remains unknown whether sex has a role in postoperative and long-term outcome after hepatic resection (HR). The aim of this study was to investigate sex differences in disease presentation, surgical and oncological outcome after curative HR. METHODS: Retrospective analysis of 1010 patients who underwent HR between 2005 and 2018 at two tertiary hospitals in Austria. Demographics and survival data were obtained from a prospectively maintained database. Univariate analysis was used to identify sex differences for the entire cohort and for sub-cohorts. Disease-free- and overall survival was assessed by the Kaplan-Meier estimate and results were compared by log-rank tests. RESULTS: 436 females and 574 males were analyzed. Women were younger (p<0.001), had less liver cirrhosis (p<0.001), cardiac comorbidities (p<0.001), diabetes (28 (p<0.001) and obesity (p<0.001). Type of HR and surgical management did not vary by sex. Ninety-day morbidity (p = 0.179) and -mortality (p = 0.888) were comparable. In patients with malignant disease, no differences in disease-free- and overall survival was observed, neither for the entire cohort nor for the subgroups according to tumor entity or type of resection. Only in HCC patients, females showed an inferior OS (p = 0.029). CONCLUSION: This study delivers new insights on the impact of sex differences in liver surgery. Despite the fact that male patients have a higher incidence of preoperative morbidities, we did not observe specific disparities in terms of immediate postoperative as well as long term oncological outcome between sexes.

Gender-related Outcome in Bladder Cancer Patients undergoing Radical Cystectomy.

Background: The impact of gender on oncological outcome after radical cystectomy (RC) is not fully understood yet. The aim of the study was to evaluate gender-related differences in histopathological parameters and prognosis of patients with bladder cancer undergoing RC. Methods: A retrospective analysis of a 10-year single-center cystectomy database was performed. Kaplan-Meier survival and Cox-regression analyses with sex-specific interactions were performed to determine the impact of gender on recurrence-free survival (RFS), cancer-specific survival (CSS), and overall survival (OS), in addition to established clinicopathological factors. Results: 259 patients (212 [81.8%] men and 47 [18.2%] women) were enrolled. Although women had a greater propensity for extravesical (≥pT3) disease (53.2% vs. 33.9%, p=0.03) and heterotopic urinary diversion (72.3% vs. 49.5%, p=0.006), gender did not independently predict RFS, CSS or OS on multivariate analysis. Extravesical tumor disease was the sole independent predictor concerning RFS (hazard ratio [HR]=4.70; p<0.001), CCS (HR=2.77; p=0.013), and OS (HR=1.93; p=0.041). Orthotopic urinary diversion (HR=0.36; p=0.002) had an independent effect only on RFS. Rates of 5-year RFS (73.7% vs. 48.3%; p=0.001), CSS (72.5% vs. 44.9%; p<0.001) and OS (62.6% vs. 37.8%; p<0.001) were higher in orthotopic versus heterotopic diversions. Conclusion: In our series, women presented with more advanced tumors and higher rates of heterotopic urinary diversions, but their survival outcome was not significantly inferior to that of men. Extravesical disease was independently related to poorer survival after RC.

Mediation analysis of the relationship between sex, cardiovascular risk factors and mortality from coronary heart disease: Findings from the population-based VHM&PP cohort.

BACKGROUND: In Europe, annually about 77,000 women, but 253,000 men die prematurely from coronary heart disease (CHD) before the age of 65 years. This gap narrows with increasing age and disappears after the eighth life decade. However, little is known regarding the contribution of cardiovascular risk factors to this sex difference. OBJECTIVE: We investigated to what extent men's higher risk of dying from CHD is explained through a different risk factor profile, as compared to women. METHODS: Mediation analysis technique was used to assess the specific contributions of blood pressure, cholesterol, glucose, and smoking to the difference between men and women regarding CHD mortality in a large Austrian cohort consisting of 117,264 individuals younger than 50 years (as a proxy for pre-menopausal status) and 54,998 older ones, with 3892 deaths due to CHD during a median follow-up of 14.6 years. RESULTS: Adjusting for age and year of examination, we observed a male versus female CHD mortality hazard ratio (HR) of 4.7 (95% CI: 3.4-5.9) in individuals younger than 50 years, of which 40.9% (95% CI: 27.1%-54.7%) was explained through risk factor pathways, mainly through blood pressure. In older participants, there was a HR of 1.9 (95% CI: 1.8-2.0) of which 8.2% (95% CI: 4.6%-11.7%) was mediated through the risk factors. CONCLUSION: The extent to which major risk factors contribute to the sex difference regarding CHD mortality decreases with age. The female survival advantage was explained to a substantial part through the pathways of major risk factors only in younger individuals.

[Gender differences in cardiology]. / Geschlechtsunterschiede in der Kardiologie.

Frequent reports of gender differences in cardiology prompted us to study the cardiological situation in Tyrol, Austria, from 1995 to 2000. Mortality statistics for heart deaths 1995: women 1008 (53.5%), men 875 (46.5%); 2000: women 1104 (58.2%), men 792 (41.8%). Coronary heart deaths 1995: women 572 (50.0%), men 571 (50.0%); 2000: women 634 (54.4%), men 531 (45.6%). Angiograms 1995: women 332 (33.9%), men 646 (66.1%); 2000: women 688 (32.5%), men 1429 (67.5%). Bypass surgery 1995: women 54 (33.0%), men 156 (67.0%); 2000: women 42 (27.5%), men 157 (72.5%). Heart deaths 1995-2000: women +9.5%, men -9.5%; coronary heart deaths 1995-2000: women +10.8%, men -7.0%. By (welcome) contrast, coronary angiograms 1995-2000: women +107.2%, men +121.2%. Bypass operations 1995-2000: women -22.2%, men +0.6%. Life expectancy 1995-2000: women +0.6%, men +0.6%. Patient age at heart death 1995-2000: women +1.8%, men +2.5%. In aggregate, we see that for decades more women than men have died a heart death, but that cardiac mortalities remain a typically "male bastion" with persistent gender differences in access to clinical cardiology. The worsening trend for women begs for awareness programs and corresponding preventive measures.