Health-related quality of life prior to and 1 year after radical cystectomy evaluated with FACT-G and FACT-VCI questionnaires.

OBJECTIVE: The aim of this study was to investigate health-related quality of life (HRQoL) before and 1 year after radical cystectomy in relation to age and gender. METHODS: This prospective study involves 112 men and 40 women with bladder cancer treated with radical cystectomy between 2015 and 2018. HRQoL was assessed preoperatively and 1 year post-surgery through Functional Assessment of Cancer Therapy Scale - General (FACT-G) and Functional Assessment of Cancer Therapy Scale - Vanderbilt Cystectomy Index (FACT-VCI) questionnaires. The median age of the 152 patients was 71.5 years. RESULTS: Preoperatively, emotional and functional well-being were negatively affected. Physical, emotional and functional well-being presented higher values 1 year after surgery compared to before radical cystectomy, that is, better HRQoL. Social well-being showed a reduction, especially regarding closeness to partner and support from family. Men and women were equally satisfied with their sex life before radical cystectomy, but less so 1 year after, where men were less satisfied compared to women. Additionally, one out of five patients reported that they had to limit their physical activities, were afraid of being far from a toilet and were dissatisfied with their body appearance after surgery. CONCLUSIONS: Recovery regarding HRQoL was ongoing 1 year after radical cystectomy. Patients recovered in three out of four dimensions of HRQoL, but social well-being was still negatively affected 1 year after treatment. Sexual function after radical cystectomy was exceedingly limited for both men and women. An individual sexual rehabilitation plan involving the couple with special intention to encourage intimacy, might not only improve sexual life but also have a positive effect on social well-being as a consequence.

Swedish National Guidelines on Urothelial Carcinoma: 2021 update on non-muscle invasive bladder cancer and upper tract urothelial carcinoma.

OBJECTIVE: To overview the updated Swedish National Guidelines on Urothelial Carcinoma 2021, with emphasis on non-muscle-invasive bladder cancer (NMIBC) and upper tract urothelial carcinoma (UTUC). METHODS: A narrative review of the updated version of the Swedish National Guidelines on Urothelial Carcinoma 2021 and highlighting new treatment recommendations, with comparison to the European Association of Urology (EAU) guidelines and current literature. RESULTS: For NMIBC the new EAU 2021 risk group stratification has been introduced for non-muscle invasive bladder cancer to predict risk of progression and the web-based application has been translated to Swedish (https://nmibc.net.). For patients with non-BCG -responsive disease treatment recommendations have been pinpointed, to guide patient counselling in this clinical situation. A new recommendation in the current version of the guidelines is the introduction of four courses of adjuvant platinum-based chemotherapy to patients with advanced disease in the nephroureterectomy specimen (pT2 or higher and/or N+). Patients with papillary urothelial neoplasms with low malignant potential (PUNLMP) can be discharged from follow-up already after 3 years based on a very low subsequent risk of further recurrences. CONCLUSIONS: The current version of the Swedish national guidelines introduces a new risk-stratification model and follow-up recommendation for NMIBC and adjuvant chemotherapy after radical surgery for UTUC.

A double-blind randomized controlled trial investigating a time-lapse algorithm for selecting Day 5 blastocysts for transfer.

STUDY QUESTION: Can use of a commercially available time-lapse algorithm for Day 5 blastocyst selection improve pregnancy rates compared with morphology alone? SUMMARY ANSWER: The use of a time-lapse selection model to choose blastocysts for fresh single embryo transfer on Day 5 did not improve ongoing pregnancy rate compared to morphology alone. WHAT IS KNOWN ALREADY: Evidence from time-lapse monitoring suggests correlations between timing of key developmental events and embryo viability. No good quality evidence exists to support improved pregnancy rates following time-lapse selection. STUDY DESIGN, SIZE, DURATION: A prospective multicenter randomized controlled trial including 776 randomized patients was performed between 2018 and 2021. Patients with at least two good quality blastocysts on Day 5 were allocated by a computer randomization program in a proportion of 1:1 into either the control group, whereby single blastocysts were selected for transfer by morphology alone, or the intervention group whereby final selection was decided by a commercially available time-lapse model. The embryologists at the time of blastocyst morphological scoring were blinded to which study group the patients would be randomized, and the physician and patients were blind to which group they were allocated until after the primary outcome was known. The primary outcome was number of ongoing pregnancies in the two groups. PARTICIPANTS/MATERIALS, SETTING, METHODS: From 10 Nordic IVF clinics, 776 patients with a minimum of two good quality blastocysts on Day 5 (D5) were randomized into one of the two study groups. A commercial time-lapse model decided the final selection of blastocysts for 387 patients in the intervention (time-lapse) group, and blastocysts with the highest morphological score were transferred for 389 patients in the control group. Only single embryo transfers in fresh cycles were performed. MAIN RESULTS AND THE ROLE OF CHANCE: In the full analysis set, the ongoing pregnancy rate for the time-lapse group was 47.4% (175/369) and 48.1% (181/376) in the control group. No statistically significant difference was found between the two groups: mean difference -0.7% (95% CI -8.2, 6.7, P = 0.90). Pregnancy rate (60.2% versus 59.0%, mean difference 1.1%, 95% CI -6.2, 8.4, P = 0.81) and early pregnancy loss (21.2% versus 18.5%, mean difference 2.7%, 95% CI -5.2, 10.6, P = 0.55) were the same for the time-lapse and the control group. Subgroup analyses showed that patient and treatment characteristics did not significantly affect the commercial time-lapse model D5 performance. In the time-lapse group, the choice of best blastocyst changed on 42% of occasions (154/369, 95% CI 36.9, 47.2) after the algorithm was applied, and this rate was similar for most treatment clinics. LIMITATIONS, REASONS FOR CAUTION: During 2020, the patient recruitment rate slowed down at participating clinics owing to coronavirus disease-19 restrictions, so the target sample size was not achieved as planned and it was decided to stop the trial prematurely. The study only investigated embryo selection at the blastocyst stage on D5 in fresh IVF transfer cycles. In addition, only blastocysts of good morphological quality were considered for transfer, limiting the number of embryos for selection in both groups: also, it could be argued that this manual preselection of blastocysts limits the theoretical selection power of time-lapse, as well as restricting the results mainly to a good prognosis patient group. Most patients were aimed for blastocyst stage transfer when a minimum of five zygotes were available for extended culture. Finally, the primary clinical outcome evaluated was pregnancy to only 6-8 weeks. WIDER IMPLICATIONS OF THE FINDINGS: The study suggests that time-lapse selection with a commercially available time-lapse model does not increase chance of ongoing pregnancy after single blastocyst transfer on Day 5 compared to morphology alone. STUDY FUNDING/COMPETING INTEREST(S): The study was financed by a grant from the Swedish state under the ALF-agreement between the Swedish government and the county councils (ALFGBG-723141). Vitrolife supported the study with embryo culture dishes and culture media. During the study period, T.H. changed his employment from Livio AB to Vitrolife AB. All other authors have no conflicts of interests to disclose. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov registration number NCT03445923. TRIAL REGISTRATION DATE: 26 February 2018. DATE OF FIRST PATIENT'S ENROLMENT: 11 June 2018.

Anorectal dysfunction after radical cystectomy for bladder cancer.

Objective: To prospectively assess anorectal dysfunction using patient-reported outcomes using validated questionnaires, manovolumetry and endoanal ultrasound before and 12 months after RC.Patients and methods: From 2014 to 2019, we prospectively included 44 patients scheduled for RC. Preoperatively and 12 months after surgery, 41 patients filled in a low anterior resection syndrome score (LARS-score) to assess fecal incontinence, increased frequency, urgency and emptying difficulties and a St Mark's score to assess fecal incontinence in conjunction with manovolumetry and endoanal ultrasound examinations. Pre- and postoperative patient-reported anorectal dysfunction were assessed by LARS-score and St Marks's score. At the same time-points, anorectal function was evaluated by measuring mean anal resting and maximal squeeze pressures, volumes and pressures at first desire, urgency to defecate and maximum toleration during manovolumetry. Wilcoxon's signed rank test was used to compare pre- and postoperative outcomes by questionnaires.Results: Postoperatively 6/41 (15%) patients reported flatus incontinence assessed by the LARS-questionnaire, and correspondingly the St Mark's score increased postoperatively. The median anal resting pressure decreased from 57 mmHg preoperatively to 46 mmHg after RC, but without any postoperative anatomic defects detected by endoanal ultrasound. Volumes and pressures at first desire, urgency to defecate and maximum toleration during manovolumetry all increased after RC, indicating decreased postoperative rectal sensation, as rectal compliance was unaltered.Conclusions: Postoperative flatus incontinence is reported by one out of seven patients after RC, which corresponds to decreased anal resting pressures. The finding of decreased rectal sensation might also contribute to patient-reported symptoms and anorectal dysfunction after RC.

Fast-track access to urologic care for patients with macroscopic haematuria is efficient and cost-effective: results from a prospective intervention study.

BACKGROUND: The delay between onset of macroscopic haematuria and diagnosis of bladder cancer is often long. METHODS: We evaluated timely diagnosis and health-care costs for patients with macroscopic haematuria given fast-track access to diagnostics. During a 15-month period, a telephone hotline for fast-track diagnostics was provided in nine Swedish municipalities for patients aged ⩾50 years with macroscopic haematuria. The control group comprised 101 patients diagnosed with bladder cancer in the same catchment area with macroscopic haematuria who underwent regular diagnostic process. RESULTS: In all 275 patients who called 'the Red Phone' hotline were investigated, and 47 of them (17%) were diagnosed with cancer and 36 of those had bladder cancer. Median time from patient-reported haematuria to diagnosis was 29 (interquartile range (IQR) 14-104) days and 50 (IQR 27-165) days in the intervention and the control group, respectively (P=0.03). The median health-care costs were lower in the intervention group (655 (IQR 655-655) EUR) than in the control group (767 (IQR 490-1096) EUR) (P=0.002). CONCLUSIONS: Direct access to urologic expertise and fast-track diagnostics is motivated for patients with macroscopic haematuria to reduce diagnostic intervals and lower health-care expenditures.

Patient-reported outcome after radical cystectomy: translation and psychometric validation of the Swedish version of the Functional Assessment of Cancer Therapy Scale Vanderbilt Cystectomy Index.

OBJECTIVE: The aim of this study was to translate and validate the Swedish version of the Functional Assessment of Cancer Therapy Scale - Vanderbilt Cystectomy Index (FACT-VCI). MATERIALS AND METHODS: For adaptation into Swedish, a multiprofessional team was used for translation including cultural adjustment, followed by back-translation. Test and retest in 10 individuals was followed by assessing metric properties in 75 consecutive patients with bladder cancer treated with radical cystectomy. Reliability and internal consistency were measured by Cronbach's alpha. Face validity was tested with two laypersons and construct validity was tested by correlation to the dimensions in the Functional Assessment of Cancer Therapy Scale - General (FACT-G). RESULTS: The translated Swedish instrument showed validity and reliability similar to the original, and the results were comparable to published studies using FACT-VCI. The correlation between the VCI sum score and FACT-G dimensions was significant in all dimensions and the item-total correlation was over 0.3; therefore, the construct validity was acceptable. In addition, it was possible to detect differences in separate items in the translated version of FACT-VCI between age groups, type of diversion and those treated with chemotherapy, even though the samples were small. CONCLUSIONS: The Swedish version of FACT-VCI is a valid and reliable instrument for use in the follow-up of patients with bladder cancer treated with urinary diversion. To measure changes after surgery, preoperative assessment with the related FACT-G instrument is advisable.

Serum anti-Müllerian hormone and ovarian morphology assessed by magnetic resonance imaging in response to acupuncture and exercise in women with polycystic ovary syndrome: secondary analyses of a randomized controlled trial.

OBJECTIVE: To investigate whether electro-acupuncture or physical exercise influence serum anti-Müllerian hormone (AMH), antral follicle count (AFC) or ovarian volume in women with polycystic ovary syndrome (PCOS). DESIGN: Secondary analyses of a prospective, randomized controlled clinical trial. SETTING: University Hospital, Sweden. PATIENTS: Seventy-four women with PCOS recruited from the general population. INTERVENTIONS: Women with PCOS were randomized to 16 weeks of electro-acupuncture (14 treatments), exercise (at least three times/week), or no intervention. MAIN OUTCOME MEASURES: Serum AMH recorded at baseline, after 16 weeks of intervention, and at follow up at 32 weeks. AFC, and ovarian volume assessed by magnetic resonance imaging at baseline and at follow up at 32 weeks. RESULTS: After 16 weeks of intervention, serum levels of AMH were significantly decreased in the electro-acupuncture group by 17.5% (p < 0.001), and differed from the change in the exercise group. AMH remained decreased by 15% (p = 0.004) also at follow up at 32 weeks, but did not differ from the exercise or the no intervention groups. There was a decrease by 8.5% (p = 0.015) in ovarian volume between baseline and follow up in the electro-acupuncture group, and by 11.7% (p = 0.01) in AFC in the physical exercise group. No other variables were affected. CONCLUSIONS: This study is the first to demonstrate that acupuncture reduces serum AMH levels and ovarian volume. Physical exercise did not influence circulating AMH or ovarian volume. Despite a within-group decrease in AFC, exercise did not lead to a between-group difference.

Ovarian morphology assessed by magnetic resonance imaging in women with and without polycystic ovary syndrome and associations with antimüllerian hormone, free testosterone, and glucose disposal rate.

OBJECTIVE: To characterize ovarian morphology and perfusion by magnetic resonance imaging (MRI) in women with and without polycystic ovary syndrome (PCOS) and to investigate associations with antimüllerian hormone (AMH), free T, and glucose disposal rate (GDR). DESIGN: Explorative cross-sectional study. SETTING: University hospital. PATIENT(S): Fifty-eight women with PCOS and 31 controls from the general population. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Antral follicle count (AFC), ovarian/stromal volume, perfusion, AMH, free T, and GDR. RESULT(S): Antral follicles of 1-3 and 4-6 mm, but not 7-9 mm, were more numerous, and total AFC (1-9 mm) was higher in women with PCOS. Ovarian volume was larger in women with PCOS. AMH and free T were higher and GDR was lower in women with PCOS. All values were more deranged in classic compared with nonclassic PCOS. There was a positive correlation between AMH and AFC, 1-3 mm (r = 0.81), and between AMH and total AFC (r = 0.87). In receiver operating characteristic analyses, the area under the curve was 0.89 for total AFC, 0.86 for AMH, and 0.90 for free T. PCOS was independently associated with AFC and free T but not with AMH or GDR when adjusted for age and body mass index. CONCLUSION(S): Counting antral follicles down to 1 mm in size by MRI yielded higher AFCs than previously reported. AFC, AMH, and free T discriminated with high accuracy between women with PCOS and controls, but AMH was not independently associated with PCOS. CLINICAL TRIAL REGISTRATION NUMBER: NCT00484705.

The water permeability channels aquaporins 1-4 are differentially expressed in granulosa and theca cells of the preovulatory follicle during precise stages of human ovulation.

CONTEXT: Changes in vascular permeability and expansion of the fluid-filled antrum are major events in the LH-induced ovulatory process. OBJECTIVES: Our objective was to investigate the presence and expression levels of aquaporins (AQPs) in the granulosa and theca cell compartments of the follicle during defined phases of human ovulation. DESIGN AND SETTING: We conducted a prospective experimental study at the Department of Obstetrics and Gynaecology at a university hospital. PARTICIPANTS: Twenty-eight women underwent laparoscopic sterilization and at the same time follicle retrieval at four periovulatory phases. MAIN OUTCOME MEASURES: mRNA levels of AQP1-4 were measured in separated granulosa and theca cells from preovulatory phase, early ovulatory (EO) phase, late ovulatory phase, and postovulatory phase. Immunohistochemistry was done for AQP1-4 in intact human follicles. RESULTS: All four AQPs were expressed in both the theca and granulosa cells during ovulation. In granulosa cells, AQP1 levels increased in the late ovulatory and postovulatory phases. Expression of AQP2-3 followed a similar pattern with a marked increase in the EO phase, whereas AQP4 levels decreased from preovulatory to the EO phase. The presence of AQP1-4 in the human follicle was verified by immunohistochemistry. CONCLUSIONS: The results show for the first time the presence of AQP1-4 in human follicles during ovulation. The marked early rise in expression of AQP2 and AQP3 suggests a role during the process leading to follicular rupture, and the late rise of AQP1 suggests a role in corpus luteum formation.

Impact of electro-acupuncture and physical exercise on hyperandrogenism and oligo/amenorrhea in women with polycystic ovary syndrome: a randomized controlled trial.

Polycystic ovary syndrome (PCOS), the most common endocrine disorder in women of reproductive age, is characterized by hyperandrogenism, oligo/amenorrhea, and polycystic ovaries. We aimed to determine whether low-frequency electro-acupuncture (EA) would decrease hyperandrogenism and improve oligo/amenorrhea more effectively than physical exercise or no intervention. We randomized 84 women with PCOS, aged 18-37 yr, to 16 wk of low-frequency EA, physical exercise, or no intervention. The primary outcome measure changes in the concentration of total testosterone (T) at week 16 determined by gas and liquid chromatography-mass spectrometry was analyzed by intention to treat. Secondary outcome measures were changes in menstrual frequency; concentrations of androgens, estrogens, androgen precursors, and glucuronidated androgen metabolites; and acne and hirsutism. Outcomes were assessed at baseline, after 16 wk of intervention, and after a 16-wk follow-up. After 16 wk of intervention, circulating T decreased by -25%, androsterone glucuronide by -30%, and androstane-3α,17ß-diol-3-glucuronide by -28% in the EA group (P = 0.038, 0.030, and 0.047, respectively vs. exercise); menstrual frequency increased to 0.69/month from 0.28 at baseline in the EA group (P = 0.018 vs. exercise). After the 16-wk follow-up, the acne score decreased by -32% in the EA group (P = 0.006 vs. exercise). Both EA and exercise improved menstrual frequency and decreased the levels of several sex steroids at week 16 and at the 16-wk follow-up compared with no intervention. Low-frequency EA and physical exercise improved hyperandrogenism and menstrual frequency more effectively than no intervention in women with PCOS. Low-frequency EA was superior to physical exercise and may be useful for treating hyperandrogenism and oligo/amenorrhea.

RUNX2 transcription factor regulates gene expression in luteinizing granulosa cells of rat ovaries.

The LH surge promotes terminal differentiation of follicular cells to become luteal cells. RUNX2 has been shown to play an important role in cell differentiation, but the regulation of Runx2 expression and its function in the ovary remain to be determined. The present study examined 1) the expression profile of Runx2 and its partner CBFbeta during the periovulatory period, 2) regulatory mechanisms of Runx2 expression, and 3) its potential function in the ovary. Runx2 expression was induced in periovulatory granulosa cells of human and rodent ovaries. RUNX2 and core binding factor-beta (CBFbeta) proteins in nuclear extracts and RUNX2 binding to a consensus binding sequence increased after human chorionic gonadotropin (hCG) administration. This in vivo up-regulation of Runx2 expression was recapitulated in vitro in preovulatory granulosa cells by stimulation with hCG. The hCG-induced Runx2 expression was reduced by antiprogestin (RU486) and EGF-receptor tyrosine kinase inhibitor (AG1478), indicating the involvement of EGF-signaling and progesterone-mediated pathways. We also found that in the C/EBPbeta knockout mouse ovary, Runx2 expression was reduced, indicating C/EBPbeta-mediated expression. Next, the function of RUNX2 was investigated by suppressing Runx2 expression by small interfering RNA in vitro. Runx2 knockdown resulted in reduced levels of mRNA for Rgc32, Ptgds, Fabp6, Mmp13, and Abcb1a genes. Chromatin immunoprecipitation analysis demonstrated the binding of RUNX2 in the promoter region of these genes, suggesting that these genes are direct downstream targets of RUNX2. Collectively, the present data indicate that the LH surge-induced RUNX2 is involved in various aspects of luteal function by directly regulating the expression of diverse luteal genes.

Monocyte chemotactic protein-1 (MCP-1), its receptor, and macrophages in the perifollicular stroma during the human ovulatory process.

OBJECTIVE: To evaluate the expression and localization of the macrophage-specific chemokine monocyte chemotactic protein-1 (MCP-1), CC chemokine receptor 2 (CCR2), and macrophages (CD68) in the perifollicular stroma of different phases of the human ovulatory process and its relation to macrophage influx. DESIGN: Experimental study on patient-controlled material. SETTING: University hospital. PATIENT(S): Twenty-eight women planned to undergo laparoscopic sterilization. INTERVENTION(S): Surgery was performed at either of four distinct ovulatory phases, and a biopsy sample was obtained from the perifollicular stroma of the ovulatory follicle. MAIN OUTCOME MEASURE(S): Real-time polymerase chain reaction, immunoblotting, and immunohistochemistry were used for measurements of MCP-1, CCR2, and macrophages. RESULT(S): The messenger RNA levels of MCP-1 in the perifollicular stroma increased from the preovulatory to the late ovulatory phase and declined during the postovulatory phase. A higher density of macrophages was found in the preovulatory and early ovulatory phases compared with late and postovulatory phases. Monocyte chemotactic protein-1 and CCR2 were present in the stroma. Protein expression of CD68 and CCR2 were identified in the four ovulatory phases. CONCLUSION(S): This study demonstrates an upregulation of MCP-1 in the stroma compartment around the human follicle during the ovulatory process, and a high density of macrophages was found at earlier phases. Thus, inflammation-like reactions are integral in the ovulatory process and may be targeted to stimulate or inhibit this process.

Monocyte chemotactic protein-1 in the follicle of the menstrual and IVF cycle.

Ovulation constitutes an inflammatory-like process, with macrophages migrating into the follicle. This study evaluates the production of two macrophage-specific chemokines, monocyte chemotactic protein-1 (MCP-1) and macrophage inflammatory protein-1alpha (MIP-1alpha), in the human follicle at ovulation. Blood samples, follicular fluids and follicular cells were collected during menstrual and IVF cycles. Levels of MCP-1 and MIP-1alpha were measured in follicular fluid, blood plasma and cultured media (granulosa, theca and granulosa-lutein cells [GLCs]). Cells were cultured with or without LH, FSH, interleukin (IL)-1alpha, IL-1beta, tumour necrosis factor (TNF) alpha, progesterone or estradiol. The levels of MCP-1 were markedly higher in follicular fluid as compared with blood plasma in both menstrual and IVF cycles. The difference in MCP-1 levels between follicular fluid and plasma in menstrual cycles increased from the follicular phase (three-fold difference) to the late ovulatory phase (25-fold). Levels of MIP-1alpha were low in plasma and follicular fluid of both menstrual and IVF cycles. Theca cells from follicles of menstrual cycles secreted both MCP-1 and MIP-1alpha under basal conditions, and the secretion was increased by addition of IL-1beta (MCP-1 and MIP-1alpha) and IL-1alpha (MCP-1). GLCs secreted MCP-1 under basal conditions and also MIP-1alpha after IL-1beta stimulation. The macrophage-specific chemokine MCP-1 is highly expressed and is induced by IL-1 in the theca layer of the human follicle at ovulation.