Management of treatment-related sequelae following colorectal cancer.

AIM: Colorectal cancer survivors are one of the most rapidly growing groups of patients living with and beyond cancer. In a national multidisciplinary setting, we have examined the extent of late treatment-related sequelae in colorectal cancer survivors and present the scientific evidence for management of these conditions in this patient category with the aim of facilitating identification and treatment. METHOD: A systematic search for existing guidelines and relevant studies was performed across 16 and 4 databases, respectively, from inception to 2021. This yielded 13 guidelines and 886 abstracts, of which 188 were included in the finalized guideline (231 included for full text review). Secondarily, bibliographies were cross-referenced and 53 additional articles were included. RESULTS: Symptoms have been divided into overall categories including psychosocial, bowel-related, urinary, sexual (male and female), pain/neuropathy and fatigue symptoms or complaints that are examined individually. Merging and grading of data resulted in 22 recommendations and 42 management strategies across categories. Recommendations are of a more general character, whereas management strategies provide more practical advice suited for initiation on site before referral to specialized units. CONCLUSION: Treatment-related sequelae in colorectal cancer survivors are common and attention needs to be focused on identifying patients with unmet treatment needs and the development of evidence-based treatment algorithms.

Use of Bladder-Related Medication in Non-Muscle Invasive Bladder Cancer Patients.

Repeated transurethral bladder resections (TURBs) and instillation treatments in non-muscle invasive bladder cancer (NMIBC) might influence bladder function and, therefore, quality of life. Bladder-related medication is a surrogate marker of compromised bladder function. The objective was to investigate whether TURBs and adjuvant instillation therapy are associated with the use of anticholinergics, ß3-agonists, and cystitis-relevant antibiotics. We divided all Danish patients diagnosed with primary NMIBC during 2002-2017 registered in the Danish National Patient Registry (DNPR) based on TURB-load within the first five years from diagnosis (1 TURB, 2-4 TURBs, ≥5 TURBs). Instillation therapy with either mitomycin C (MMC) or bacillus Calmette-Guerin vaccine (BCG) was independent exposure (yes or no). We included 17,774 patients; 76% men, median age: 70 years (IQR: 63, 77). Patients exposed to ≥5 TURBs had a higher risk of using bladder-relaxing medication than patients exposed to 1 TURB, HR = 4.01 [3.33; 4.83], and higher risk of cystitis, HR = 2.27 [2.05; 2.51]. BCG-exposed patients had a higher risk of bladder-relaxing medication use compared to non-exposed, HR = 1.92 [1.69; 2.18], and a higher risk of cystitis, HR = 1.39 [1.31; 1.48]. Repeated TURBs have the highest impact on bladder function. Adjuvant instillation therapy is also associated with the use of bladder-related medication.

Bladder pain syndrome.

Bladder pain syndrome is rare and leads to increased morbidity and decreased quality of life. The patients are a heterogenous group with different clinical presentations, and little is known of the different aspects of the syndrome. A thorough patient history and specialised diagnostics are required to offer these patients the best possible treatment. This review suggests an algorithm to manage these patients at all levels of the Danish health-care system. It is recommended that final diagnosis and multidisciplinary treatment should be centered at large regional hospitals.

Treatment of benign prostatic hyperplasia.

The treatment of benign prostatic hyperplasia includes a variety of options ranging from medication to open prostatectomy. Several newer technologies have been developed. Transurethral resection of the prostate remains the gold standard among surgical procedures for prostates less than 80 cc whereas enucleation and simple open prostatectomy are most documented for larger prostates. This review has focus on the status of treatment available in Denmark at the moment. Thorough evaluation of the patients before treatment and shared decision-making with regard to treatment options is essential.

Urinary incontinence.

Around 500,000 Danes are suffering from urinary incontinence, and stress urinary incontinence and urgency urinary incontinence, alone or mixed, are the most common types. Diagnostic workup is similar for all types of urinary incontinence (men and women) and can be done by the GP. Most conservative interventions can be commenced by the GP. In complicated or treatment-resistant cases and when surgery is needed, referral to a urologic or gynaecological department can be necessary, as argued in this review.

Desmopressin, as a "designer-drug," in the treatment of overactive bladder syndrome.

AIMS: This study looked at whether oral desmopressin, by decreasing kidney urine production, would prolong bladder filling-time thereby increasing the time to reach maximum capacity, thus reducing overactive bladder (OAB) symptoms, and providing an alternative method of treatment to OAB sufferers. METHODS: An investigator-initiated, 2-week, multi-national, multi-centre, "proof-of-concept," phase IIb, double-blind, placebo-controlled, prospective, randomized, cross-over study was conducted using 0.2 mg of oral desmopressin in adults suffering with OAB. Patients were included in the trial period if they had >or=4 voids in the first 8-hr of the day after rising, excluding the first morning void. The primary endpoint was evaluation of effectiveness of desmopressin in increasing the time to the first OAB symptom episodes during the first 8-hr following treatment. RESULTS: Time to first void was 8-min later on the drug than on placebo (P = 0.27). However, the drug led to one less void (3.2 vs. 4.2) in the same period (P < 0.001). There was an increase in the time to first urgency episode with a decrease in the number of urgency episodes in the drug days compared to placebo (P < 0.003). There was a subjective improvement in frequency and urgency and overall quality-of-life as measured by the ICIQ-OAB. Twenty-seven people reported adverse events which were all mild, headache being the commonest and no hyponatremia was recorded. CONCLUSIONS: Antidiuresis, using oral desmopressin tablets, is a novel, feasible and safe (short-term basis) method of treatment for adults with OAB, and could be considered in the armamentarium of drugs available for the treatment of OAB.

Danish version of the National Institutes of Health-Chronic Prostatitis Symptom Index (NIH-CPSI) questionnaire: a linguistic translation, cross-cultural adaptation and test-re-test reliability study.

Objective: To translate and cross-culturally adapt the National Institutes of Health-Chronic Prostatitis Symptom Index (NIH-CPSI) into Danish and assess the reliability of the translated version. Methods: The NIH-CPSI was translated into Danish by a formalized translation procedure. Study participants suffering from Chronic Prostatitis/Chronic Pelvic Pain Syndrome (CP/CPPS) were recruited from a CP/CPPS newsletter email-list. The translated questionnaire was tested for face validity by interviewing men (n = 7) suffering from CP/CPPS. Relative reliability (interclass correlations coefficient, ICC) and absolute reliability (minimal detectable change, MDC; and standard error of measurement, SEM) were assessed on an electronic version of the Danish NIH-CPSI, including a general response assessment of symptom stability at the second assessment. Results: One hundred and twenty-nine men volunteered for the test-re-test study, 43 did not fit the eligibility criteria or had incomplete tests and 27 were excluded due to symptom changes between test and re-test, leaving 59 participants for the reliability study. The relative reliability for the total NIH-CPSI score was found to be an excellent ICC of 0.93 (95% CI = 0.91-0.96). The absolute reliability for the total NIH-CPSI score revealed an MDC of 5.0 and a SEM of 1.8, corresponding to 12% and 4%, respectively, of the maximal obtainable NIH-CPSI score. Conclusion: The NIH-CPSI questionnaire was successfully translated and cross-culturally adapted into a Danish version. An electronic version of the Danish NIH-CPSI showed excellent reliability. The questionnaire is suitable for use as an outcome measure in research studies and may also be a useful tool in the clinical setting.

The influence of high and low levels of estrogen on diurnal urine regulation in young women.

BACKGROUND: Sex hormones have a pronounced effect on arginine vasopressin (AVP), and therefore on the diurnal water homeostasis. Low and high levels of plasma-estradiol as seen in the follicular phase of the menstrual cycle may therefore alter the diurnal regulation of urine production. Furthermore the structural resemblance of oxytocin to vasopressin has led to speculations about the possible antidiuretic properties of oxytocin under normal physiological conditions. To elucidate the influence of high and low p-estradiol on the regulation of the diurnal urine production, 15 normal menstruating women (21-33 y) underwent two circadian in-patient investigations, both situated in follicular phase. METHODS: Admitting the participants solely in the follicular phase resulted in high and low plasma-estradiol whereas plasma-progesterone was similar. Urine and blood samples were taken at predetermined time points to determine plasma AVP, plasma oxytocin, plasma aldosterone, plasma natriuretic peptide (ANP), urinary solute excretions, and urinary excretions of prostaglandin E2 (PGE-2) and aquaporin-2 (AQP-2). Blood pressure was measured every hour. RESULTS: Plasma AVP, plasma aldosterone and plasma ANP were unaffected by the different levels of estradiol. All had marked circadian variations whereas oxytocin did not display any circadian rhythm. High estradiol resulted in lower p-osmolality and p-sodium reflecting the downward resetting of the osmoreceptors. Oxytocin did not correlate with either diuresis or urine osmolality. The diurnal urine production was similar in the two groups as were urine osmolality, excretion of PGE-2 and AQP-2. AQP-2 does not have a circadian rhythm and is not significantly correlated to either AVP or oxytocin under normal physiological conditions. CONCLUSION: High and low level of estradiol has no influence on the circadian rhythm of AVP or the subsequent urine production. High p-estradiol resets the osmoreceptors for AVP release. Furthermore it appears that oxytocin under normal physiological conditions do not contribute to the overall antidiuretic effect.

Long-term urodynamic findings following radical prostatectomy and salvage radiotherapy.

OBJECTIVE: Lower urinary tract symptoms (LUTS) are common following radical prostatectomy (RP) or intended curative radiotherapy in prostate cancer patients. One-quarter of those treated with RP experience biochemical failure and are subsequently offered salvage radiotherapy (SRT) to the prostatic bed. The aim of this study was to elucidate long-term LUTS after surgery and SRT. MATERIALS AND METHODS: Urodynamic parameters from 16 patients treated with RP and subsequent SRT in the period 2000-2010 were evaluated with uroflowmetry, filling cystometry, pressure-flow and urethral pressure profile (UPP). In conjunction with the urodynamic examination, all patients completed the Danish Prostatic Symptom Score (DAN-PSS) questionnaire, which evaluates the grade of LUTS. RESULTS: Median time from SRT to urodynamic examination was 7.7 years (range 5.8-10.0 years). The following urodynamic parameters were affected: bladder volume at maximal cystometric capacity, bladder compliance, bladder function, bladder outlet obstruction and UPP. The total DAN-PSS index combining all symptoms and their corresponding impact on patients was mild in six patients (≤ 7 points), moderate in seven patients (8-19 points) and severe in three patients (≥ 20 points). CONCLUSIONS: This urodynamic study is one of the first to evaluate long-term urodynamic characteristics in patients treated with SRT. Several urodynamic parameters were affected. This indicates that SRT primarily affects bladder compliance, maximal cystometric capacity and bladder outlet obstruction. LUTS were proven to be strongly related to urodynamic parameters.

Oral Contraceptives and Renal Water Handling: A diurnal study in young women.

To test the hypothesis that use of oral contraceptives (OC) changes diurnal variation in fluid balance mechanisms including blood pressure, secretion of vasopressin and oxytocin, and renal water and electrolyte excretion. Fifteen naturally cycling (NC) women in mid-follicular phase and 11 long-term OC users were included in a 24-h standardized inpatient study for measurements of vasopressin, oxytocin, sodium, and osmolality in plasma as well as urinary excretion of electrolytes, aquaporin-2, and prostaglandin E2. Blood pressure and heart rate were monitored noninvasively. Plasma vasopressin showed circadian rhythm (P = 0.02) and were similar in both groups (P = 0.18) including nighttime increases (P < 0.001). There was no circadian rhythm in plasma oxytocin within (P = 0.84) or between groups (P = 0.22). OC users had significantly lower plasma osmolality (Δosm: 3.05 ± 0.29 mosm/kg, P = 0.04) and lower plasma sodium (ΔNa+: 0.91 ± 0.09 mmol/l, P = 0.05). The two groups showed similar nighttime decreases in diuresis (1.08 ± 0.04 mL/(kg·h), P < 0.001) and increases in urine osmolality (109 ± 9 mosm/kg, P = 0.02), but similar rates of excretion of Aquaporin-2, prostaglandin E2 and sodium. Nighttime decreases in mean arterial pressure of approximately 13% were significant in both groups (P < 0.001), but 24-h average mean arterial pressure was significantly higher in OC users than in controls (+4.7 ± 0.4 mmHg, P = 0.02). Packed cell volumes were similar between groups (P = 0.54). OC does not change the diurnal patterns of renal fluid excretion, but resets the osmoreceptors for vasopressin release and leads to a significant increase in arterial blood pressure.

Urethral pressure profile 6 months after radical prostatectomy may be diagnostic of sphincteric incontinence: preliminary data after 12 months' follow-up.

OBJECTIVE: Male stress incontinence is mainly caused by sphincter lesions, representing the majority of incontinent patients after retropubic radical prostatectomy (RRP). Reflecting the sphincter activity, the urethral pressure profile (UPP) was used to evaluate 65 consecutive patients 6 months after retropubic RRP to identify patients with persistent sphincteric incontinence. MATERIAL AND METHODS: According to the history of continence, patients were divided into a continent group and three incontinent subgroups. Six months postoperatively, spontaneous flow and two cystometries were performed with a filling rate of 60 ml/min, immediately followed by pressure flow and two UPPs, flow rate 1 ml with a pulling rate of 2 mm/s, focusing on functional length (FL) and maximal urethral closure pressure (MUCP). At 6 and 12 months' follow-up, questionnaires were filled in concerning the present state of continence. RESULTS: After RRP, two-thirds were continent after 6 months, whereas one-third still suffered from incontinence. MUCP and FL in the stress incontinent group had decreased significantly compared with the continent group (66.2+/-26.4 vs 21.0+/-13.6 cmH(2)O, p< or =0.001; and 11.4+/-3.7 and 8.2+/-3.7 mm, p=0.05), accompanied by a characteristic UPP configuration. After 12 months subgroups of sphincter incontinence and bladder and sphincter combined experienced no change, whereas the group with bladder incontinence achieved satisfactory improvement. CONCLUSIONS: Postoperative urodynamics after 6 months may be predictive for persistent incontinence at the bladder, sphincter, and both, suggesting that immediate intervention is more appropriate than watchful waiting. Sphincter incontinence was diagnosed by stress incontinence with MUCP below 30 cmH(2)O, decreased FL and a distinctive profile.

Normal voiding patterns assessed by means of a frequency-volume chart.

OBJECTIVE: Voiding dysfunction is one of the commonest problems among the elderly. This study aimed to elucidate the mechanisms behind the diurnal and nocturnal urine output patterns in young and elderly male volunteers. Of particular interest was bladder reservoir function during the day and night. MATERIAL AND METHODS: Young males (n=25; median age 25.0 years; range 22-32 years) and elderly males (n=18; median age 61.1 years; range 55-73 years) were included in the study. Their voiding habits were assessed from a 3-day frequency-volume chart (FVC) detailing all fluid intake and urine output. Data on voided volume, voiding frequency, maximum voided volume (MVV) and average voided volume (AVV) were obtained from the FVC. RESULTS: The young males' average fluid intake was significantly higher than that of the elderly males. On average the elderly males had a slightly higher voiding frequency than the young males, although this was not statistically significant. There was no difference between the two groups regarding their AVVs at night (including the first morning void). The MVVs of the young and elderly males were significantly different, whereas the ratio between voided volume and MVV did not differ between the groups. CONCLUSIONS: The main finding was that young and elderly males void with equal average volumes of urine at night (first morning void inclusive), whereas the elderly void with smaller volumes than the young during the day-time. The elderly thus seem to have the capacity to adjust their AVV to night-time urine output size.

Nocturia and circadian blood pressure profile in healthy elderly male volunteers.

PURPOSE: Nocturia is attributed to nocturnal polyuria and/or decreased functional bladder capacity. In this study we elucidated the mechanisms behind circadian fluid regulation and the occurrence of nocturia in healthy elderly males, specifically to determine the role of urine output and regulating hormones, blood pressure, and average voided volumes. MATERIALS AND METHODS: A total of 18 males 55 to 73 years old (mean age 61.1) were included in the study. Voiding habits were assessed by completion of a 7-day frequency volume chart recording all fluid intake and voiding. The subjects subsequently underwent inpatient circadian studies measuring the diurnal rhythm of blood pressure, vasopressin, atrial natriuretic peptide, angiotensin II, aldosterone and urine volume. RESULTS: Of the nightly home recordings 25% showed nocturia, characterized by a higher 24-hour and nighttime urine volume. During the inpatient studies 12 of the 18 participants experienced a nocturnal void. Nocturia nights were characterized by significantly decreased day-to-night ratios in urine output and a higher nighttime mean arterial blood pressure. A circadian variation in plasma arginine vasopressin was seen only in the group without nocturia. The other hormones revealed a circadian rhythm similar in the 2 groups. CONCLUSIONS: In healthy males with occasional nocturia, the occurrence of nocturia seems to be associated with a blunting of the circadian rhythm of diuresis and increased arterial blood pressures during the night. These findings may implicate a role for a baroregulatory related mechanism in nocturia.

Pharmacokinetics and pharmacodynamics of desmopressin administered orally versus intravenously at daytime versus night-time in healthy men aged 55-70 years.

OBJECTIVE: To investigate (1) the pharmacokinetic and pharmacodynamic profiles of desmopressin in men from an age group with a high incidence of nocturia; and (2) circadian variation in the pharmacokinetic parameters. METHODS: The study had an open, randomised, four-way cross-over design. Desmopressin was administered orally (0.2 mg) and intravenously (2 microg), daytime and night-time, yielding four in-hospital sessions, separated by at least 2 days. Blood samples were taken before and at predetermined time points up to 12 h after dosing. Pharmacokinetic parameters were derived using a two-compartmental model except for AUC(0-->t), which was derived using non-compartmental analysis. Bioavailability was estimated using AUC(0-->t) for the oral and the intravenous periods. Urine, for measurements of volume and osmolality, was collected in predetermined intervals before and until 12 h after dosing. RESULTS: Fifteen healthy men aged 55-70 years were included in the analysis. The concentration-time curve after 2 microg intravenous desmopressin was best described using a biexponential term. The mean (95% CI) AUC at night was 302 (272-335) pg x h/ml and in the day was 281 (253-312) pg x h/ml. No statistically significant differences were detected between night and day except for terminal half-life, which was 3.1 h at night and 2.8 h in the daytime (P=0.02). After oral desmopressin, concentrations above the limit of quantification (2.5 pg/ml) were only detected in 51% of the samples. Peak plasma concentration (Cmax) was 6.2 (5.1-7.5) pg/ml at night and 6.6 (5.5-7.9) pg/ml in the daytime. Median time to reach Cmax (tmax) was 1.5 (range 1.0-4.1) h at night and 1.5 (range 0.5-3.0) h in the day. The bioavailability was 0.08%. The pharmacodynamic effects of oral and intravenous desmopressin given in the daytime were similar during the first 6 h after dosing. The night-time dosing and daytime intravenous dose resulted in antidiuresis throughout the measuring period, while the effect of the daytime peroral dose receded after 6 h. CONCLUSION: The pharmacokinetic profile of desmopressin is biexponential. Terminal half-life was longer at night than in the daytime, but the difference is considered too small to be of clinical importance. The plasma levels given by the intravenous dose resulted in a duration of action of 12 h or more. Despite low bioavailability, the pharmacodynamic effects of oral desmopressin were similar in magnitude to those after intravenous dose at night and during the first 6 h after daytime administration.