Evidence of Common Pathophysiology Between Stress and Urgency Urinary Incontinence in Women.

BACKGROUND/AIM: Urinary incontinence in women is commonly categorized as stress urinary incontinence (SUI) and urgency urinary incontinence (UUI). SUI occurs due to an increased intra-abdominal pressure caused by an unstable anatomical outlet of the bladder and can be successfully treated surgically. UUI, a combination of a symptom (urgency to void) and urinary incontinence, is considered to be caused by a neurological dysfunction of the bladder. Current treatment options can reduce the feeling of urgency, but effects on restoration of continence are less impressive. However, surgery for pelvic organ prolapse reduction leads to cure UUI, indicating a critical role of pelvic anatomy in the etiology of UUI. We hypothesized that incontinence in patients with UUI is caused by an anatomical instability at the bladder outlet leading to incontinence even under minor physical stress exerted on the bladder base. PATIENTS AND METHODS: Patients with UUI symptoms were asked to specify exactly when (in which body position) they involuntary lose urine after the feeling of urgency to void. RESULTS: In total, 569 patients were evaluated between 2012 and 2020. Overall, 96% of the patients lost urine when they got up from a sitting position on their way to the toilet. Of the total study patients 3% lost urine already in the sitting position when they felt the urgency to void. CONCLUSION: The current treatment options for UUI are based on the hypothesis that UUI is a neurological disorder. This study demonstrated that urinary incontinence in patients with UUI is dependent on an intact anatomical stability of the urethro-vesical junction under pressure. Therefore, treatment modalities should focus on the anatomical repair or support in that area.

Evaluation of Different 'Tensioning' of Apical Suspension in Women Undergoing Surgery for Prolapse and Urinary Incontinence.

BACKGROUND: According to the literature, restoration of pelvic organ prolapse also restores urinary continence. However, it is difficult to determine which exact surgical procedure actually led to urinary continence due to a lack of standardisation among these techniques. For example, an apical fixation is broadly defined in terms of type and shape of implanted material, anatomical fixation sides and tensioning. The aim of this study was to evaluate the effect of bilateral uterosacral ligament replacement with alloplastic tapes of defined lengths on symptoms of urinary incontinence. PATIENTS AND METHODS: Patients with urinary incontinence and pelvic organ prolapse underwent an apical suspension. Thereby, both uterosacral ligaments (USL) were replaced by alloplastic structures of defined length. These alloplastic tapes had defined lengths in all patients of 9, 10, or 11 cm in length. They were sutured on both sides of the cervix, placed in the left and right peritoneal fold of the USL, and were sutured laterally to the prevertebral fascial layer of the sacral vertebra at the level of S2. Furthermore, all patients received additional transobturator tape. Pelvic organ prolapse was classified according to the Baden-Walker system, and urinary incontinence symptoms according to validated questionnaires. RESULTS: Four months after bilateral USL replacement, apical suspension was restored in all 31 patients. In addition, urinary continence was re-established in 18 out of these 31 patients (58%). The highest continence rate was observed in patients in which both USL were replaced with alloplastic tapes of 9 cm in length. CONCLUSION: The findings indicated the importance of USL integrity for urinary continence. In particular, a defined length for both USL seems to be important for (re-)establishing urinary continence.

Comparison of Solifenacin and Bilateral Apical Fixation in the Treatment of Mixed and Urgency Urinary Incontinence in Women: URGE 1 Study, A Randomized Clinical Trial.

BACKGROUND: The aetiology of urgency urinary incontinence is a matter of debate. Current treatment options are based on the hypothesis of a neurological disorder of bladder innervation. However, it has also been hypothesised that one main cause is the reduced function of the bladder-holding apparatus, that is, insufficient suspension of the vesico-urethral junction. This study compared the effects of surgical apical vaginal elevation with those of solifenacin on urgency urinary incontinence in women. PATIENTS AND METHODS: Women with mixed and urgency urinary incontinence were randomised to either an established pharmacological arm (10 mg/day solifenacin) or the surgical arm (bilateral uterosacral ligament replacement, cervicosacropexy, CESA; or vaginosacropexy, VASA. Clinical and objective outcomes were assessed at 4 months after each type of intervention. RESULTS: The study was terminated early; 55 patients were operated on and 41 patients received pharmacological treatment. After surgical treatment, 23 patients (42%, 95% confidence intervaI=29-55%) became continent compared to four patients (10%, 95% confidence intervaI=1-19%) during solifenacin treatment. CONCLUSION: Compared to pharmacological treatment, the surgical repair of the apical vaginal end restored urinary continence in significantly more patients.

Laparoscopic bilateral cervicosacropexy: introduction to a new tunneling technique.

INTRODUCTION AND HYPOTHESIS: To elevate and suspend the apical end of the vagina, the uterosacral ligaments (USL) were replaced by polyvinylidene fluoride (PVDF) structures. These PVDF structures were placed in the peritoneal folds of the USL at the pelvic wall to mimic the lateral and backward tension and to avoid rectal obstruction. A special tunneling device was used, which allowed the semi-circular placement of the structure without destroying the peritoneum. METHODS: A 59-year-old woman with mixed urinary incontinence and apical prolapse (pelvic organ prolapse quantification system, POP-Q, stage 2) of the uterus underwent laparoscopic bilateral USL replacement. USLs were replaced by PVDF structures by performing the cervicosacropexy (CESA) technique using a semi-circular tunneling device. RESULTS: Apical support was restored (POP-Q stage 0), and the patient was continent thereafter. The tunneling device was pulled through the peritoneal folds of the USLs toward the cervix. The new USL structures were brought to their physiological position. The new technique did not lead to any complications and did not cause any side effects during 1-year follow-up. CONCLUSIONS: Restoration of apical prolapse and urinary continence was achieved by bilateral USL replacement using a semi-circular tunneling device that was inserted through the lateral abdominal trocar incision.

TOT 8/4: A Way to Standardize the Surgical Procedure of a Transobturator Tape.

Suburethral tapes are placed "tension-free" below the urethra. Several studies reported considerable differences of the distance between urethra and tape. These distances ranged from 1 to 10 mm amongst different patients. This either caused urethral obstruction or had no effect on urinary incontinence. Therefore, we decided to standardize the procedure by placing a Hegar dilator of 8-millimeter diameter in the urethra and another Hegar dilator of 4-millimeter diameter between the urethra and the tape during transobturator tape placement. Using that simple technique, which we named "TOT 8/4," we observed that 83% of the tapes were placed in the desired distance between 3 and 5 millimeters below the urethra.

Surgical treatment of mixed and urge urinary incontinence in women.

BACKGROUND/AIMS: The etiology of urge urinary incontinence is unknown. Pharmacological treatments are disappointing, since they are only slightly more effective than a placebo. In this study, we analyzed whether the surgical replacement of the uterosacral ligaments by an alloplastic tape can cure patients with mixed and urge urinary incontinence. METHODS: This study was a nonrandomized clinical trial. The study was performed in the Department of Gynecology of a general hospital and a university clinic. 135 women with urge or mixed urinary incontinence were operated on. The utero-sacral ligaments as well as the pubo-urethral ligaments - if necessary - were replaced by alloplastic tapes. Clinical outcome was evaluated immediately after surgery, 3 months later and 1 year later. Outcome was classified as cure, improvement or failure and recurrences. RESULTS: 102 patients (77%) were cured and a further 24 patients (18%) showed improvement after surgery. 19 patients developed a recurrence between 5 and 33 months after surgery. CONCLUSION: We therefore conclude that most patients with urge and mixed urinary incontinence can be cured by surgery.

Prediction of axillary lymph node status of breast cancer patients by tumorbiological factors of the primary tumor.

BACKGROUND AND PURPOSE: The increasing use of systemic adjuvant therapy even in lymph node-negative breast cancer patients and breast cancer screening programs detecting smaller tumors with less probability of metastatic lymph nodes questions the need for routine axillary lymph node dissection. Since morbidity of breast cancer surgery is predominantly related to axillary lymph node dissection, predictive models for lymph node involvement may provide a way to avoid lymph node surgery and its side effects in subgroups of patients. PATIENTS AND METHODS: Using a multivariate logistic regression model, tumorbiological parameters such as expression of estrogen and progesterone receptors, Ki-67, p53, cathepsin D, HER2, S-phase fraction, and ploidy were analyzed regarding their ability to predict axillary lymph node involvement in 655 breast cancer patients. RESULTS: The model correctly predicted axillary lymph node metastases in 58% of the patients by including expression of progesterone receptor, HER2, and Ki-67. In a subgroup of 200 patients predicted to be at extremely high or extremely low risk for axillary lymph node metastases, the accuracy of the prediction was 70%. CONCLUSION: With a model just based on tumorbiological parameters obtained in the primary tumor it is possible to predict axillary lymph node status. By including additional parameters it appears to be feasible to further improve the model in order to avoid axillary lymph node surgery in low-risk women.

Evaluation of CA125, physical and radiological findings in follow-up of ovarian cancer patients.

The majority of ovarian cancer patients will suffer from intraabdominal relapse within the first five years after surgery. Today various diagnostic tools, including ultrasound or CT, are available to detect an ovarian cancer recurrence. Radiological examinations at regular time-intervals may lead to the detection of tumor relapse, however these procedures have limited sensitivity and specificity. Moreover, imaging procedures are costly. CA125 is a tumor marker with high sensitivity in ovarian cancer patients. Tumor marker determination is a simple, reproducible technique, and may therefore be useful in routine follow-up in ovarian cancer patients, supplemented with additional imaging procedures. In a retrospective analysis of 58 patients with recurrent ovarian cancer, the sensitivity of clinical examination and tumor marker analysis was compared to radiological findings. Physical interview and physical examination were performed for all patients. CA125 levels were determined in 54 out of 58 patients at the time of diagnosis of recurrence. Forty-seven out of 58 patients received a vaginal ultrasound and 42 were examined by CT scan. In 45 out of 54 (83%) patients, CA 125 was elevated at the time of recurrence. In 45 out of the 58 (78%) patients, a tumor was detected by physical examination. Forty-two out of the 58 patients had CT scans. Pathological findings were seen in 33 out of these patients (80%) Ultrasound revealed tumor recurrence in 33 out of 47 patients (70%). By a follow-up based on physical examination and CA125 determination, 53 out of 54 (98%) patients with recurrences could be identified. In patients with a pelvic recurrence, vaginal examination had the highest sensitivity in comparison to vaginal ultrasound and CT scan. Imaging techniques did not add clinically relevant information during follow-up and should therefore only be performed prior to surgical or therapeutical intervention.

Prognostic significance of serum HER2 and CA 15-3 at the time of diagnosis of metastatic breast cancer.

BACKGROUND: Serum HER2 testing allows the determination of real-time HER2 status during clinical course. The aim of this investigation was: (1) to study the prognostic significance of serum HER2 at the time of first diagnosis of metastatic breast cancer and (2) to evaluate its relationship to CA15-3 which is a surrogate marker for tumor load. MATERIALS AND METHODS: Serum samples of 120 breast cancer patients were assayed for HER2 and CA15-3 at the onset of metastatic disease. RESULTS: Forty-seven out of 120 (39%) metastatic breast cancer patients had elevated serum HER2 levels. The positivity rate of CA15-3 was 51%. The median survival after relapse (SAR) for HER2-positive patients was shorter (10 months, 95%-CI: 6-14 months) compared to the SAR of HER2-negative patients (19 months, 95%-CI:15-23 months) (p<0.01). The median survival of patients with increased CA15-3 was 13 months (95%-CI: 9-17 months) compared to 18 months (95%-CI: 15-21 months) for patients with normal CA15-3 concentrations (p<0.05). In the multivariate analysis serum HER2 was an independent prognostic marker for SAR even when adjusted for tumor load measured by CA15-3 levels. CONCLUSION: Serum HER2 is a strong independent prognostic factor for survival after relapse in metastatic breast cancer even when adjusted for tumor load. Therefore, the prognostic significance of serum HER2 may not only be related to the tumor load but also to the biological behavior of the tumor.

The expression of hCG receptor mRNA in four human ovarian cancer cell lines varies considerably under different experimental conditions.

In the present study, expression and regulation of hCG receptor mRNA were analyzed in four established human ovarian cancer cell lines using different concentrations of hCG, EGF, and 8-bromo-cAMP for different periods between 6 and 72 h. The cells were examined for the hCG receptor using the reverse-transcriptase polymerase chain reaction with specific primers amplifying the hCG receptor gene. Receptor mRNA was found in all cell lines. In the line OVCAR-3, it was expressed in all samples independent of kind and concentration of the receptor agonist and incubation period. In the line COLO-704, the hCG receptor gene was expressed only in unstimulated samples, but not in the samples incubated with a receptor agonist. The cell line EFO-21 showed a downregulation of receptor mRNA after 24 h of treatment with 25 IU/ml hCG and after 6 h of treatment with 250 IU/ml hCG or 100 ng/ml EGF. The mRNA reappeared within 24-48 h. The cell line EFO-27 showed a downregulation of receptor mRNA after 6 h of incubation with 250 IU/ml hCG. Agarose gel electrophoresis and sequencing of the polymerase chain reaction products revealed four cDNA fragments resulting from an alternative splicing of the primary transcript. The results of the study demonstrate that the expression of hCG receptor mRNA in ovarian cancer cell lines varies considerably under different experimental conditions. We showed that ovarian cancer cells can produce hCG receptors when needed or wanted. The inherent mechanisms which rule this phenomenon need further evaluation.

Clinical evaluation of the Elecsys CA 15-3 test in breast cancer patients.

The aim of the present study was to evaluate the clinical performance of the CA 15-3 assay on Elecsys systems in an international multicenter study (11 centers). A total of 1326 single samples (272 apparently healthy individuals, 34 pregnant women, 308 benign diseases, 273 cancers other than breast, 439 breast cancer) and 538 serial samples of 98 breast cancer patients during follow-up were analyzed. 95% of values in healthy individuals were below 25 kU/L, and 88% in benign breast diseases, respectively. In malignant breast disease at primary diagnosis the value distribution of Elecsys CA 15-3, sensitivity at 95% specificity, as well as the areas under the curve in ROC analysis were clearly correlated to tumor stages: UICC I to IV 88 to 25% of values < 25 kU/L, sensitivity 7 to 78%, areas under the curve 0.53 to 0.94. During follow-up, sensitivity/specificity for detection of recurrences were 90%/71%. In metastatic disease clinical progression/response to therapy were indicated in 91%/78% of patients at a specificity of 92%/78%. The findings indicate that the Elecsys CA 15-3 assay is very suitable in routine work for detection of recurrences as well as for therapy control in metastatic breast cancer.

Cytotoxic effect of conjugates of doxorubicin and human chorionic gonadotropin (hCG) in breast cancer cells.

Cytotoxic activity of drug conjugates of human chorionic gonadotropin (hCG) and doxorubicin alone was investigated compared to doxorubicin in breast cancer cells with and without expression of hCG receptors. Expression of hCG receptor was determined in MCF-7 and MB231 breast cancer cell line using a multiplex nested rt-PCR approach. The entire sequence of mRNA encoding for hCG receptor was detected in MCF-7 but not in MB231 breast cancer cell line. Cytostatic effect of doxorubicin-hCG conjugates was investigated in these cell lines in comparison to unconjugated doxorubicin. The number of viable cells was determined after 24, 48, 72, 96, and 120h. To exclude non-specific uptake of the carrier hCG from the culture media, a similar experiment was performed with albumin-doxorubicin conjugates. The number of viable cells decreased in a concentration depending manner after doxorubicin and hCG-doxorubicin conjugate treatment. However, the cytotoxic effect of hCG-doxorubicin conjugate was 10-fold increased compared to unconjugated doxorubin in hCG-receptor positive MCF-7 but not in hCG-receptor negative MB231 cells. Albumin-doxorubicin conjugates showed no increased toxicity compared to doxorubicin. We conclude that the cytotoxic effect of hCG-doxorubicin conjugates is mediated specifically via the hCG receptor. By using hCG conjugates, the development of more selective cytostatics can be achieved.

Tumor size, axillary lymph node status and steroid receptor expression in breast cancer: prognostic relevance 5 years after surgery.

Tumor size, axillary lymph node status and expression of steroid receptors are well-established prognostic factors in breast cancer. However, it is not clear if these prognostic factors are time-dependent variables and lose their significance after several years of disease-free survival. To analyse how long these factors keep their prognostic relevance survival of 1162 breast cancer patients was analysed retrospectively. The post-operative follow-up period was split into consecutive 2-year intervals and each interval was analysed for rate of recurrence and rate of tumor depending deaths. Furthermore, a multivariate analysis was performed for the total follow-up time and for the follow-up period starting 5 years after surgery. Multivariate analysis revealed tumor size, axillary lymph node status and estrogen receptor status as independent prognostic parameters. Analysing separately the rate of recurrences and tumor-related deaths during consecutive 2-year intervals, only the tumor size was a constant prognostic parameter, whereas prognostic relevance of lymph node status decreased. Estrogen receptor status associated with favourable prognosis during the first years after surgery changed to an unfavourable prognostic factor 4 years after surgery. To summarize, prognostic factors obtained at the time of surgery can lose their significance with increasing disease-free survival.

Clinical utility of serial serum c-erbB-2 determinations in the follow-up of breast cancer patients.

To evaluate the ability of serum c-erbB-2 protein to (1) indicate occult and manifest metastases and (2) reflect response to first-line therapy, serial serum c-erbB-2 measurements were performed in a retrospective series of 52 primary breast cancer patients who had developed metastatic disease during follow-up. The results were compared with CA 15-3. Preoperatively, 31% (16/52) of the primary breast cancer patients had elevated c-erbB-2 concentrations. The CA 15-3 positivity rate was 13% (7/52). After surgery, 10 of the 52 patients showed either stable but highly elevated or rising c-erbB-2 serum levels indicating serum c-erbB-2 producing minimal residual disease. Increasing CA 15-3 concentrations were seen in only three patients. Elevated serum c-erbB-2 levels predicted manifest metastases in 27 and 50% of the patients at 6 and 3 months, respectively, prior to clinical diagnosis. CA 15-3 was less sensitive. Only 16 and 32% of the patients had increased CA 15-3 serum concentrations at 6 and 3 months, respectively, prior to clinical detection. The positivity rates of c-erbB-2 and CA 15-3 were similar when metastases were clinically diagnosed. Elevated c-erbB-2 concentrations were found in 62% (32/52). The sensitivity of CA 15-3 was 56% (29/52). The association between serum profiles and response to first-line therapy was evaluated in detail for 45 patients. Serial c-erbB-2 and CA 15-3 measurements reflected disease course in 24 and 27 patients, respectively. The serum profiles of c-erbB-2 and CA 15-3 were similar in 17 patients. In summary, our results suggest that serial determinations of serum c-erbB-2 are useful to monitor breast cancer patients.