Surgical management of pelvic organ prolapse.

Despite pelvic organ prolapse being a universal problem experienced in nearly 50% of parous women, the surgical management of vaginal prolapse remains an enigma to many, with wide variation in the rates and types of intervention performed. As part of the 6th International Consultation on Incontinence (ICI) our committee, charged with producing an evidence-based report on the surgical management of prolapse, produced a pathway for the surgical management of prolapse. The 2017 ICI surgical management of prolapse evidence-based pathway will be presented and summarized. Weaknesses of the data and pathway will be discussed and avenues for future research proposed.

Ureterovaginal fistula: a case series.

INTRODUCTION AND HYPOTHESIS: We describe the presentation, diagnosis, and management of ureterovaginal fistula over a 7-year period at a tertiary care center. METHODS: A retrospective review of ureterovaginal fistula cases between 2003 and 2011 was performed. Demographic information, antecedent event, symptoms, diagnostic modalities, and management strategies were reviewed. RESULTS: Nineteen ureterovaginal fistulas were identified during the 7-year study period. One fistula followed a repeat cesarean section and 18 fistulas followed a hysterectomy (9 total abdominal, 6 total laparoscopic, 3 vaginal hysterectomies). Ureteral injuries were not recognized in any of the patients at the time of index surgery. Computed tomography (CT) urography was the most commonly utilized diagnostic modality (58%). Primary non-surgical management with ureteral stents was attempted and successful in 5 out of 7 cases (71%). There were 14 total surgical repairs, including 2 cases in which stents were successfully placed, but the fistula persisted, and 6 additional cases where attempted stent placement failed. Surgical repair consisted of 10 ureteroneocystostomies performed via laparotomy and 4 performed laparoscopically, 3 of which were robotically assisted. CONCLUSIONS: Despite being uncommon, ureterovaginal fistula should remain in the differential diagnosis of new post-operative urinary incontinence after gynecological surgery. Conservative management with ureteral stent appears to be the best initial approach in selected patients, with a success rate of 71%. Minimally invasive approaches to performing ureteroneocystostomy have high success rates, comparable to those of open surgical repair.

Outcomes following treatment for pelvic floor mesh complications.

INTRODUCTION AND HYPOTHESIS: Our aim was to determine symptoms and degree of improvement in a cohort of women who presented following treatment for vaginal mesh complications. METHODS: This study was a follow-up to a multicenter, retrospective study of women who presented to four tertiary referral centers for management of vaginal-mesh-related complications. Study participants completed a one-time follow-up survey regarding any additional treatment, current symptoms, and degree of improvement from initial presentation. RESULTS: Two hundred and sixty women received surveys; we had a response rate of 41.1 % (107/260). Complete data were available for 101 respondents. Survey respondents were more likely to be postmenopausal (p = 0.006), but otherwise did not differ from nonrespondents. Fifty-one percent (52/101) of women underwent surgery as the primary intervention for their mesh complication; 8 % (4/52) underwent a second surgery; 34 % (17/52) required a second nonsurgical intervention. Three patients required three or more surgeries. Of the 30 % (30/101) of respondents who reported pelvic pain prior to intervention, 63 % (19/30) reported improvement, 30 % (9/30) were worse, and 7 % (2/30) reported no change. Of the 33 % (33/101) who reported voiding dysfunction prior to intervention, 61 % (20/33) reported being at least somewhat bothered by these symptoms. CONCLUSIONS: About 50 % of women with mesh complications in this study underwent surgical management as treatment, and <10 % required a second surgery. Most patients with pain preintervention reported significant improvement after treatment; however, almost a third reported worsening pain or no change after surgical management. Less than half of patients with voiding dysfunction improved after intervention.

Bladder pain syndrome/interstitial cystitis in twin sisters.

PURPOSE: We determined the genetic contribution of and associated factors for bladder pain syndrome using an identical twin model. MATERIALS AND METHODS: Multiple questionnaires were administered to adult identical twin sister pairs. The O'Leary-Sant Interstitial Cystitis Symptom and Problem Index was administered to identify individuals at risk for bladder pain syndrome. Potential associated factors were modeled against the bladder pain syndrome score with the twin pair as a random effect of the factor on the bladder pain syndrome score. Variables that showed a significant relationship with the bladder pain syndrome score were entered into a multivariable model. RESULTS: In this study 246 identical twin sister pairs (total 492) participated with a mean age (± SD) of 40.3 ± 17 years. Of these women 45 (9%) were identified as having a moderate or high risk of bladder pain syndrome (index score greater than 13). There were 5 twin sets (2%) in which both twins met the criteria. Correlation of bladder pain syndrome scores within twin pairs was estimated at 0.35, suggesting a genetic contribution to bladder pain syndrome. Multivariable analysis revealed that increasing age (estimate 0.46 [95% CI 0.2, 0.7]), irritable bowel syndrome (1.8 [0.6, 3.7]), physical abuse (2.5 [0.5, 4.1]), frequent headaches (1.6 [0.6, 2.8]), multiple drug allergies (1.5 [0.5, 2.7]) and number of self-reported urinary tract infections in the last year (8.2 [4.7, 10.9]) were significantly associated with bladder pain syndrome. CONCLUSIONS: Bladder pain syndrome scores within twin pairs were moderately correlated, implying some genetic component. Increasing age, irritable bowel syndrome, frequent headaches, drug allergies, self-reported urinary tract infections and physical abuse were factors associated with higher bladder pain syndrome scores.

[Eosinophilic esophagitis. A not so rare clinical case]. / Esofagitis eosinofílica. Un caso clínico no tan raro.

Eosinophilic esophagitis is a chronic disease of multifactorial aetiology locally mediated immune in which the form of presentation varies according to the age of the patient, being mainly signs of esophageal dysfunction. Diagnosis is made by histological criteria and treatment is based on diet and topical corticosteroid therapy and, in the event of stenosis, dilations are performed. An early diagnosis slows down the evolution, reduces complications and improves the prognosis.

The mammalian target of rapamycin inhibitor everolimus (RAD001) in early breast cancer: results of a pre-operative study.

mTOR plays a key role in tumor cell cycle control, proliferation, and survival. RAD001 (everolimus) is a novel macrolide that inhibits mTOR and thus downstream signaling pathways. 31 post-menopausal women with early breast cancer were given 5 mg RAD001 once daily for 14 days prior to surgery. Biopsies were taken at diagnosis and at surgery (post 14 days of treatment) and assessed for immunohistochemical changes in proliferation (Ki67), apoptosis (active caspase-3), p-AKT (s473), p-S6 (s235/236 and s240/244), p-mTOR (s2448), ER, and PR. Five patients did not complete the 2-week treatment period due to adverse events. All adverse events were grade 1 or 2 (NCIC-CTC scale). RAD001 treatment significantly decreased proliferation (geometric mean reduction 74% from baseline (p = 0.019)), particularly in HER-2 positive tumors. High Ki67 pre-treatment correlated with reduction in Ki67, an increase in apoptosis, a reduction in p-AKT (cytoplasmic) and reduction in p-mTOR following treatment. Nuclear expression of p-AKT was significantly reduced with treatment. Tumors that had a reduction in Ki67 with treatment exhibited a significant reduction in cytoplasmic p-AKT. p-S6 staining was significantly reduced independently of Ki67 (p < 0.001 for two sites of phosphorylation). RAD001 5 mg/daily is safe and tolerable in postmenopausal early breast cancer patients and inhibits the mTOR pathway and its downstream effectors, significantly reducing tumor cell proliferation. Tumors with high Ki67, high p-AKT, and HER-2 positivity may be more responsive to mTOR inhibition with RAD001. This is the first study to report results of RAD001 5 mg as a single agent in early breast cancer.

Randomised trial of laparoscopic Burch colposuspension versus tension-free vaginal tape: long-term follow up.

OBJECTIVE: To compare the long-term efficacy of laparoscopic Burch colposuspension with tension-free vaginal tape (TVT) for the treatment of urodynamic stress urinary incontinence (SUI). DESIGN: Long-term follow up from a prospective randomised trial. SETTING: Academic tertiary referral centre. SAMPLE: Seventy-two women with urodynamic SUI from two institutions. METHODS: Subjects were randomised to either laparoscopic Burch or TVT from August 1999 to August 2002. Follow-up evaluations occurred 6 months, 1 year, 2 years, and 4-8 years after surgery. MAIN OUTCOME MEASURES: Subjects completed the Incontinence Severity Index, Urogenital Distress Inventory 6 (UDI-6), Incontinence Impact Questionnaire (IIQ-7), and Patient Global Impression of Improvement (PGI-I) scales. RESULTS: Median follow-up duration was 65 months (range 12-88 months) with 92% completing at least one follow-up visit. Seventy-four percent of subjects had long-term (4-8 years) follow up. Fifty-eight percent of subjects receiving laparoscopic Burch compared with 48% of TVT subjects reported any urinary incontinence 4-8 years after surgery (Relative Risk (RR):1.19; 95% CI: 0.71-2.0) with no significant difference between groups. Bothersome SUI symptoms were seen in 11 and 8%, respectively, 4-8 years after surgery (P = 0.26). There was significant improvement in the postoperative UDI-6 and IIQ-7 scores in both groups at 1-2 years that were maintained throughout follow up with no significant differences between the groups. CONCLUSIONS: TVT has similar long-term efficacy to laparoscopic Burch for the treatment of SUI. A substantial proportion of subjects have some degree of urinary incontinence 4-8 years after surgery; however, the majority of incontinence is not bothersome.

Esofagitis eosinofílica. Un caso clínico no tan raro / Eosinophilic esophagitis. A not so rare clinical case

La esofagitis eosinofílica es una enfermedad crónica de etiología multifactorial inmunomediada localmente en la cual la forma de presentación varía según la edad del paciente, siendo mayoritariamente signos de disfunción esofágica. El diagnóstico se realiza mediante criterio histológico y el tratamiento se fundamenta en dieta y corticoterapia tópica y en caso de presentar estenosis se realizan dilataciones. Un diagnóstico precoz frena la evolución, reduce complicaciones y mejora el pronóstico (AU)

Eosinophilic esophagitis is a chronic disease of multifactorial aetiology locally mediated immune in which the form of presentation varies according to the age of the patient, being mainly signs of esophageal dysfunction. Diagnosis is made by histological criteria and treatment is based on diet and topical corticosteroid therapy and, in the event of stenosis, dilations are performed. An early diagnosis slows down the evolution, reduces complications and improves the prognosis (AU)

Biological evaluation of a lipid-mobilizing factor isolated from the urine of cancer patients.

We have previously shown human lipid-mobilizing factor (LMF) to be homologous with the plasma protein Zn-alpha2-glycoprotein in amino acid sequence, electrophoretic mobility, and immunoreactivity. In this study, both LMF and Zn-alpha2-glycoprotein have been shown to stimulate glycerol release from isolated murine epididymal adipocytes with a comparable dose-response profile. Both LMF and Zn-alpha2-glycoprotein caused a stimulation of adenylate cyclase in murine adipocyte plasma membranes in a GTP-dependent process, with maximum stimulation at 0.1 microM GTP and with saturation at protein concentrations of >5 microg/assay. Administration of LMF to exbreeder male mice over a 89-h period produced a decrease in body weight without a change in food and water intake. Body composition analysis showed a 42% reduction in carcass lipid when compared with controls. Treatment of ob/ob mice with human LMF over a 160-h period also produced a decrease in body weight, with a 19% reduction in carcass fat, without a change in body water or nonfat mass. Serum levels of glycerol and 3-hydroxybutyrate were significantly increased, as was oxygen uptake by interscapular brown adipose tissue, providing evidence of increased lipid mobilization and utilization. Human white adipocytes responded to both LMF and isoprenaline to the same extent, although the maximal response was lower than that for murine white adipocytes. These results suggest that LMF not only has the capacity to induce lipid mobilization and catabolism in mice, but it also has the potential to exert similar effects in cachectic cancer patients.

Eicosapentaenoic acid modulates the immune response but has no effect on a mimic of antigen-specific responses.

OBJECTIVE: It has been suggested that the omega-3 polyunsaturated fatty acid eicosapentaenoic acid (EPA) has immunosuppressive effects and that these may be detrimental in some circumstances. Many studies have used high-fat diets or have concentrated on one aspect of immune function, such as mitogen-induced proliferation. In the present study we assessed the effect of high-purity EPA provided as a novel diester with propane-1,3-diol, which was delivered orally within the normal dietary fat content. METHODS: Mitogen-induced proliferation and a mimic of antigen-specific splenocyte proliferation were examined. Proinflammatory cytokine production in response to lipopolysaccharide ex vivo was also measured. Balb/c mice were fed a fat-free diet to which was added oil to make up 5% of the final diet weight by using corn oil or 95% pure EPA as a diester with propane-1,3-diol (4%, plus 1% corn oil). RESULTS: There was no difference in food consumption or weight gain between mice fed the control and EPA-enriched diets for 10 or 24 d. There was a significant decrease in the splenocyte proliferation index in animals fed the EPA-enriched diet after 10 and 24 d when stimulated by concanavalin A (P<0.05), but no difference when cells were stimulated with anti-CD3 and interleukin-2. There was a significant increase in the production of tumor necrosis factor by splenocytes of mice fed the EPA-enriched diet when stimulated by lipopolysaccharide (P<0.0005). However, there was no difference in ex vivo lipopolysaccharide-stimulated production of interleukin-6 between the two diets at either time point (P>0.05). CONCLUSIONS: The present study found that, rather than producing a generalized immunosuppression, the administration of approximately 10 g of EPA/kg of body weight has more subtle effects in modulating the immune system. The observed effects of EPA may explain some of its reported beneficial effects in inflammatory conditions without producing detrimental effects on antigen-specific immunosurveillance.

Outcome of the use of acellular-dermal matrix to assist implant-based breast reconstruction in a single centre.

INTRODUCTION: The use of acellular dermal matrix (ADM) has transformed the technique of implant-based breast reconstruction. It offers the option of a one-stage procedure and is felt to have benefits in cosmetic outcome but the medium and long-term outcomes are unknown. METHODS: All cases where ADM was used in a breast reconstructive procedure in the Edinburgh Breast Unit from its initial use on 7/7/2008 to 31/7/2012 were reviewed retrospectively. Follow up was completed to 30/11/2012. RESULTS: 147 patients received 232 sheets of ADM (156 Strattice, 73 Permacol and 3 Alloderm). Mean follow up was 687 days. In 40 cases unplanned implant explantation occurred (17.2% or 27.2% of patients). 7 of 27 (25.9%) patients requiring adjuvant therapy had this delayed due to problems with the reconstruction. 30 of 80 patients (37.5%) undergoing unilateral surgery have undergone contralateral surgery. Implant loss varied significantly with smoking (34.6% loss rate in smokers vs 13.2% in non-smokers, p = 0.001), with radiotherapy (28.1% loss rate vs 13.8% with no radiotherapy, p = 0.001) and with incision type. There was no statistically significant variation by operating surgeon, type of ADM used, chemotherapy use, patient weight, breast weight or nipple preservation. Patients underwent a mean of 1.54 further operations (range 0-7). CONCLUSIONS: While offering potential cosmetic and financial benefits, the use of ADM with implant-based reconstructions has a significant rate of implant loss, further surgery and potential delay in adjuvant therapy. These must be considered when planning treatment and consenting patients.

Site-directed mutagenesis of yeast phosphoglycerate kinase. Arginines 65, 121 and 168.

In the absence of a structure of the closed form of phosphoglycerate kinase we have modified by site directed mutagenesis several of the residues which, on the basis of the open form structure, are likely to be involved in substrate binding and catalysis. Here we report on the kinetic and anion activation properties of the yeast enzyme modified at positions 65, 121 and 168. In each case an arginine, thought to be involved in the binding of the sugar substrate's non-transferable phosphate group, has been replaced by lysine (same charge) and by methionine (no charge). Km values for 3-phosphoglycerate of all six mutant enzymes are only marginally higher than that of the wild-type enzyme. Removing the charge associated with two of the three arginine residues appears to influence (as judged by the measured Km's) the binding of ATP. Although binding affinity is not necessarily coupled to turnover the substitutions which have the greatest effect on the Km's do correlate with the reduction in enzymes maximum velocity. The one exception to this generalisation is the R65K mutant which, surprisingly, has a significantly higher kcat than the wild-type enzyme. In the open form structure of the pig muscle enzyme each of the three substituted arginines residues are seen to make two hydrogen bonds to the sugar substrate's non-transferable phosphate. From this it might be expected that anion activation would be similarly affected by the substitution of any one of these three residues. Although the interpretation of such effects are complicated by the fact that one of the mutants (R65M) unfolds at low salt concentrations, this appears not to be the case. Replacing Arg121 and Arg168 with methionine reduces the anion activation whereas a lysine in either of these two positions practically destroys the effect. With the substitutions at residue 65 the opposite is observed in that the lysine mutant shows anion activation whereas the methionine mutant does not.

Interferon-gamma polymorphisms correlate with duration of survival in pancreatic cancer.

Despite progress in diagnosis and staging, pancreatic cancer still has a poor prognosis and it remains difficult to predict duration of survival in advanced pancreatic cancer. Nutritional decline, or cachexia, is a contributory factor to decreased survival in advanced pancreatic carcinoma, and it has been demonstrated that proinflammatory cytokines give rise to cachexia. Interferon (IFN)-gamma is a proinflammatory cytokine whose administration increases survival outcomes in a variety of cancers. The human IFN-gamma gene has a variable length CA-repeat sequence, the length that has been shown to influence IFN-gamma production. The current study was performed to ascertain whether polymorphisms of the IFN-gamma gene would influence survival of individuals with advanced pancreatic cancer. The study demonstrated that the presence of allele 2 (12 CA repeats) was consistently associated with increased duration of survival after confirmation of nonresectable pancreatic carcinoma. We therefore propose that the presence of allele 2 may be a useful marker for patient outcome.

Effect of patient position on clinical evaluation of pelvic organ prolapse.

OBJECTIVE: To compare the severity of pelvic organ prolapse between examinations performed in dorsal lithotomy position and examinations performed upright in a birthing chair using the Pelvic Organ Prolapse Quantification System (POPQ). METHODS: One hundred eighty-nine consecutive women were evaluated between April 1997 and September 1998. All women were examined in the dorsal lithotomy position and in a birthing chair at a 45 degrees angle. Degree of pelvic organ prolapse was assessed using the POPQ. RESULTS: When examined upright, 133 patients (70%) had the same stage of prolapse, whereas 49 (26%) had a higher stage and seven (4%) had a lower stage. Of patients who were stage 0 or I when examined in lithotomy position, 23 (36%) were stage II or greater when examined upright. Similarly, of patients who were stage II in lithotomy, 17 (23%) were stage III or higher when examined upright. There was a statistically significant increase in the degree of prolapse at all the POPQ measurements (P <.05 for each point), except for measurement of total vaginal length. Forty-eight percent of patients had at least one measurement increase by 2 cm or more when examined upright. Logistic regression identified no patient characteristics that were independently associated with a significant increase in stage or POPQ values with change in examination position. CONCLUSION: The degree of pelvic organ prolapse assessed with the patient in the lithotomy position correlates well with assessment performed upright; however, overall there is a higher degree of prolapse with upright examination.

Cost-effectiveness of universal cystoscopy to identify ureteral injury at hysterectomy.

OBJECTIVE: To evaluate the cost-effectiveness of routine cystoscopy at the time of abdominal, vaginal, and laparoscopically assisted vaginal hysterectomy in terms of cost per ureteral injury identified and treated. METHODS: Using a hospital-based perspective, a decision-analysis model was constructed to estimate the outcomes and costs of cystoscopy or no cystoscopy at the time of abdominal hysterectomy. A similar model was constructed for vaginal and laparoscopically assisted vaginal hysterectomy to account for the cost of conversion to laparotomy. Cost estimates were based on estimated costs of Duke University Medical Center and from average Medicare reimbursements for similar Diagnostic Related Groups from the Health Care Financing Administration. The incidence of ureteral injury was obtained from a review of the literature. Sensitivity analyses were performed for the following variables: ureteral injury rate, silent ureteral injury rate, cost of cystoscopy, and cost of therapeutic interventions. We assumed a silent renal death rate of 0%. RESULTS: Routine cystoscopy at abdominal hysterectomy was cost-saving above a threshold ureteral injury rate of 1.5%. At a ureteral injury rate of 0.2%, the marginal increase in the cost of routine intraoperative cystoscopy was $108 per abdominal hysterectomy, with an associated cost of $54,000 per ureteral injury identified. In comparison, at a ureteral injury rate of 2%, routine cystoscopy gave a marginal cost savings of $44 per hysterectomy, with a cost savings of $2200 per ureteral injury identified intraoperatively. At the baseline ureteral injury rate of 0.5%, routine cystoscopy had a marginally increased cost of $83 per hysterectomy, with an incremental cost-effectiveness of $16,600 spent per ureteral injury identified. The model constructed for vaginal hysterectomy and laparoscopically assisted vaginal hysterectomy yielded a threshold ureteral injury rate of 2%, above which routine cystoscopy was cost-saving. In both models, the incidence of ureteral injury and the cost of readmission were the two variables with the greatest influence on cost-effectiveness. CONCLUSION: The cost-effectiveness of routine intraoperative cystoscopy depends on the rate of ureteral injury independent of the route of hysterectomy. If that rate exceeds 1.5% for abdominal hysterectomy and 2% for vaginal or laparoscopically assisted vaginal hysterectomy, then routine cystoscopy is cost-effective.

Cancer cachexia.

Cachexia is a common cause of morbidity and mortality in patients with advanced cancer. It is characterised by numerous metabolic abnormalities including inefficient substrate utilisation, alterations in the balance of energy intake and expenditure and the acute-phase protein response. These changes seem to be driven by pro-inflammatory cytokines, alterations of the neuro-endocrine axis and tumour-derived catabolic factors. This results in the loss of both fat and lean tissue. Trials of conventional nutritional supplements in patients with cancer cachexia have failed to show any benefit in terms of weight gain or quality of life and this may be because the ongoing metabolic abnormalities prevent the efficient use of additional calories supplied. A variety of pharmacological agents have been studied in an attempt to normalise these metabolic changes with only limited success. However, it is possible that the combination of an agent to normalise the metabolic milieu along with the provision of additional nutritional support may have the potential to reverse cachexia in advanced cancer.

Cancer cachexia and its treatment with fish-oil-enriched nutritional supplementation.

OBJECTIVE: Cachexia is a common condition affecting those with advanced cancer. This review explores mechanisms of cachexia and possible treatments devised with these mechanisms in mind. METHODS: Selective review of the relevant scientific literature was performed with particular emphasis on studies performed by our group over the past 10 y involving patients with advanced pancreatic cancer. RESULTS: Cancer cachexia adversely affects patient quality of life and survival. It is characterized by a lack of a normal anabolic response to the provision of apparently adequate nutrition. It appears to result from a persistent response to illness stimulated by the cancer resulting in a proinflammatory cytokine and catabolic hormonal environment. Interventions that ignore this inflammatory milieu have had little success. More promising interventions have a broad antiinflammatory component such as nonsteroidal antiinflammatory drugs or fish oil. Preliminary studies of a combination of fish oil as an antiinflammatory agent with nutritional supplementation show promise in reversing weight loss with apparent gains in lean tissue and performance status in association with normalization of the metabolic environment in patients with advanced pancreatic cancer. CONCLUSIONS: Cancer cachexia produces a metabolic environment that prevents the appropriate use of supplied nutrition. Antiinflammatory agents such as fish oil in combination with nutritional supplementation may reverse aspects of cachexia.

The cancer cachexia syndrome.

The provision of additional calories and protein alone has not been shown to be efficacious in patients with cancer cachexia. Although primary research continues to unravel the complex metabolic derangements and diverse mediator pathways underlying cancer cachexia, the future lies in drugs and neutracenticals that may modulate this altered metabolism and enable conventional nutritional support to effectively replenish vital lean tissue.