Isthmoceles - Accuracy of imaging diagnosis and clinical correlation with histology: A prospective cohort study.

Background: Isthmoceles are a growing clinical concern. Objectives: To evaluate the accuracy of diagnosis of isthmoceles by imaging and to correlate the dimensions with clinical symptoms and histopathology. Materials and Methods: Prospective study of women (n=60) with ≥1 C-section undergoing hysterectomy. Isthmoceles were measured by imaging before surgery and macroscopically on the specimen after hysterectomy, followed by histological analysis. Main outcome measures: Accuracy of isthmocele diagnosis, correlation with clinical symptoms, and histopathological findings. Result: By imaging, isthmoceles were slightly deeper (P=0.0176) and shorter (P=0.0045) than macroscopic measurements. Differences were typically small (≤3mm). Defined as an indentation of ≥2 mm at site of C-section scar, imaging diagnosed 2 isthmoceles consequently not seen by histology and missed 3. Number of prior C-sections increased isthmocele severity but neither the incidence nor the remaining myometrial thickness (RMT) did. Severity correlated positively with symptoms and histology. However, clinical use was limited. Histological analysis revealed presence of thick wall vessels in 100%, elastosis in 40%, and adenomyosis in 38%. Isthmocele lining was asynchronous with the menstrual phase in 31%. Conclusions: Dimensions of isthmoceles by imaging were largely accurate with occasionally large differences observed. Number of C-sections did not increase isthmocele incidence, only severity. Indication for surgery remains clinical, considering dimensions and symptoms. What is new?: Dimensions of isthmoceles should be confirmed before surgery since uterine contractions might change those dimensions. Symptoms increase with dimensions of isthmoceles but are not specific. Endometrial lining within the isthmocele can be asynchronous with the menstrual phase.

Breast cancer screening in women taking hormone replacement therapy needs updating.

Breast cancer screening by mammography is widely used. The diagnostic accuracy is limited, with a positive predictive value of 16%. Therefore, a stepwise investigation, with repeat mammography and confirmation by pathology, is usually proposed. Although this stepwise investigation intends to avoid overtreatment, the many false positives result in unnecessary fear and diagnostic surgery in many women. The false negatives are not known since these women have not been investigated. Given the estimated low risk of missing breast cancer and the slow growth, repeating a screening mammography every two years is sufficient. The false positive screening results, increase with breast density, and breast density increases when hormone replacement therapy (HRT) is given. It, therefore, is suggested to use clinical judgment and stop HRT for 3 to 6 months before repeating the mammography instead of starting immediately a stepwise investigation in all women.

The importance of rotation to teach secure half-hitch sequences in surgery.

Background: Knot security of half-knot (H) sequences varies with rotation, but half-knots risk destabilisation. Objectives: To investigate the rotation of half-hitch (S) sequences on knot security. Materials and Methods: The loop and knot security of symmetrical and asymmetrical sliding and blocking half-hitch sequences was measured using a tensiometer. Results: Loop security of symmetrical sliding half-hitch sequences is much higher than asymmetrical sequences, increasing from 6+2 to 21+2 and from 27+6 to 48+5 Newton (N) for 2 and 4 half-hitches respectively (both P<0.0001). Symmetrical sliding sequences are more compact and remain in the same plane, squeezing the passive thread, while asymmetrical sequences rotate loosely around the passive end. Blocking sequences are superior when asymmetrical since changing the passive end acts like changing rotation, transforming the asymmetrical sliding into a symmetrical blocking half-hitch on the new passive thread. The knot security of 2 sliding and 1 blocking half-hitch doubles from 52+3 to 98+2 N for the worst (asymmetric sliding and symmetric blocking, SSaSsb) or best rotation sequences (SSsSab). Adding a second asymmetric blocking half-hitch (Sab) increases security further to 105+3 N. The overall knot security of four-throw, correctly rotated, half-hitch (SSsSabSab) or half-knot (H2H1sH1s, H2H2a and H2H2s) sequences is similar for four suture diameters. Conclusion: Rotation affects the security of half-hitch sequences, which should be symmetrical when sliding, and asymmetrical when blocking. What is new?: Half-hitch sequences are clinically superior to half-knot sequences. They do not risk destabilisation, and loop security improves approximation of tissues under traction, permitting tight knots.

A proof of concept that experience-based management of endometriosis can complement evidence-based guidelines.

Background: Management of endometriosis should be based on the best available evidence. The pyramid of evidence reflects unbiased observations analysed with traditional statistics. Evidence-based medicine (EBM) is the clinical interpretation of these data by experts. Unfortunately, traditional statistical inference can refute but cannot confirm a hypothesis and clinical experience is considered a personal opinion. Objectives: A proof of concept to document clinical experience by considering each diagnosis and treatment as an experiment with an outcome, which is used to update subsequent management. Materials and Methods: Experience and knowledge-based questions were answered on a 0 to 10 visual analogue scale (VAS) by surgery-oriented clinicians with experience of > 50 surgeries for endometriosis. Results: The answers reflect the collective clinical experience of managing >10.000 women with endometriosis. Experience-based management was overall comparable as approved by >75% of answers rated ≥ 8/10 VAS. Knowledge-based management was more variable, reflecting debated issues and differences between experts and non-experts. Conclusions: The collective experience-based management of those with endometriosis is similar for surgery-oriented clinicians. Results do not conflict with EBM and are a Bayesian prior, to be confirmed, refuted or updated by further observations. What is new?: Collective experience-based management can be measured and is more than a personal opinion. This might extend EBM trial results to the entire population and add data difficult to obtain in RCTs, such as many aspects of surgery.

Reconsidering evidence-based management of endometriosis.

Background: Without an adequate animal model permitting experiments the pathophysiology of endometriosis remains unclear and without a non-invasive diagnosis, information is limited to symptomatic women. Lesions are macroscopically and biochemically variable. Hormonal medical therapy cannot be blinded since recognised by the patient and the evidence of extensive surgery is limited because of the combination of low numbers of interventions of variable difficulty with variable surgical skills. Experience is spread among specialists in imaging, medical therapy, infertility, pain and surgery. In addition, the limitations of traditional statistics and p-values to interpret results and the complementarity of Bayesian inference should be realised. Objectives: To review and discuss evidence in endometriosis management. Materials and Methods: A PubMed search for blinded randomised controlled trials in endometriosis. Results: Good-quality evidence is limited in endometriosis. Conclusions: Clinical experience remains undervalued especially for surgery. What is new?: Evidence-based medicine should integrate traditional statistical analysis and the limitations of P-values, with the complementary Bayesian inference which is predictive and sequential and more like clinical medicine. Since clinical experience is important for grading evidence, specific experience in the different disciplines of endometriosis should be used to judge trial designs and results. Finally, clinical medicine can be considered as a series of experiments controlled by the outcome. Therefore, the clinical opinion of many has more value than an opinion.

The severity and frequency distribution of endometriosis subtypes at different ages: a model to understand the natural history of endometriosis based on single centre/single surgeon data.

Background and Objective: to study the natural history of endometriosis. Materials and methods: the analysis of all women (n=2086) undergoing laparoscopy for pelvic pain and endometriosis between 1988 and 2011 at University Hospital Gasthuisberg. Main outcome measures: the severity of subtle, typical, cystic and deep endometriosis in adult women, with or without a pregnancy, as estimated by their pelvic area and their volume. Results: the number of women undergoing a laparoscopy increased up to 28 years of age and decreased thereafter. Between 24 and 44 years, the severity and relative frequencies of subtle, typical, cystic and deep lesions did not vary significantly. The number of women younger than 20 years was too small to ascertain the impression of less severe lesions. The severity of endometriosis lesions was not less in women with 1 or more previous pregnancies or with previous surgery. There was no bias over time since the type and severity of endometriosis lesions remained constant between 1988 and 2011. Conclusions: severity of endometriosis does not increase between 24 and 44 years of age, suggesting that growth is limited by intrinsic or extrinsic factors. Severity was not lower in women with a previous pregnancy. What is new: considering the time needed for lesions to become symptomatic together with the diagnostic delay, the decreasing number of laparoscopies after age 28 is compatible with a progressively declining risk of initiating endometriosis lesions after menarche, the remaining women being progessively less susceptible.

Preoperative imaging of deep endometriosis: pitfalls of a diagnostic test before surgery.

The usefulness of a test is determined by the clinical interpretation of its sensitivity and specificity. The pitfalls of a test with a surgical endpoint are described in this article, taking the diagnosis of deep endometriosis by imaging as an example, without discussing the management of deep endometriosis. Laparoscopy is not a 100% accurate "gold standard". Since it is not performed in women without symptoms, results are valid only for the group of women as specified in the indication for surgery. The confidence limits of accuracy estimations widen when accuracy is lower and when observations are less. Since positive and negative predictive values are inaccurate when prevalence of the disease is low, prevalence figures in the group of women investigated should be available. The accuracy of imaging should be stratified by clinically important aspects such as localisation and size of the lesion. The use of other variables as soft markers during ultrasonographic examination should be specified. It should be clear whether the accuracy of the test reflects symptoms and clinical examination and imaging combined, or whether the accuracy of the added value of imaging which requires Bayesian analysis. When imaging is used as an indication for surgery, circular reasoning should be avoided and the number of symptomatic women not undergoing surgery because of negative imaging should be reported. In conclusion, imaging reports should permit the clinician to judge the validity of the accuracy estimations of a diagnostic test, especially when used as an indication for surgery and when surgery is the gold standard to diagnose a disease.

Correction: Heterogeneity of endometriosis lesions requires individualisation of diagnosis and treatment and a different approach to research and evidence based medicine.

Statistical significance is used to analyse research findings and is together with biased free trials the cornerstone of evidence based medicine. However traditional statistics are based on the assumption that the population investigated is homogeneous without smaller hidden subgroups. The clinical, inflammatory, immunological, biochemical, histochemical and genetic-epigenetic heterogeneity of similar looking endometriosis lesions is a challenge for research and for diagnosis and treatment of endometriosis. The conclusions obtained by statistical testing of the entire group are not necessarily valid for subgroups. The importance is illustrated by the fact that a treatment with a beneficial effect in 80% of women but with exactly the same but opposite effect, worsening the disease in 20%, remains statistically highly significant. Since traditional statistics are unable to detect hidden subgroups, new approaches are mandatory. For diagnosis and treatment it is suggested to visualise individual data and to pay specific attention to the extremes of an analysis. For research it is important to integrate clinical, biochemical and histochemical data with molecular biological pathways and genetic-epigenetic analysis of the lesions.

Heterogeneity of endometriosis lesions requires individualisation of diagnosis and treatment and a different approach to research and evidence based medicine.

Statistical significance is used to analyse research findings and is together with biased free trials the cornerstone of evidence based medicine. However traditional statistics are based on the assumption that the population investigated is homogeneous without smaller hidden subgroups. The clinical, inflammatory, immunological, biochemical, histochemical and genetic-epigenetic heterogeneity of similar looking endometriosis lesions is a challenge for research and for diagnosis and treatment of endometriosis. The conclusions obtained by statistical testing of the entire group are not necessarily valid for subgroups. The importance is illustrated by the fact that a treatment with a beneficial effect in 80% of women but with exactly the same but opposite effect, worsening the disease in 20%, remains statistically highly significant. Since traditional statistics are unable to detect hidden subgroups, new approaches are mandatory. For diagnosis and treatment it is suggested to visualise individual data and to pay specific attention to the extremes of an analysis. For research it is important to integrate clinical, biochemical and histochemical data with molecular biological pathways and genetic-epigenetic analysis of the lesions.

Infection as a potential cofactor in the genetic-epigenetic pathophysiology of endometriosis: a systematic review.

BACKGROUND: The genetic-epigenetic theory postulates that endometriosis is triggered by a cumulative set of genetic-epigenetic (GE) incidents. Pelvic and upper genital tract infection might induce GE incidents and thus play a role in the pathogenesis of endometriosis. Thus, this article aims to review the association of endometriosis with upper genital tract and pelvic infections. METHODS: Pubmed, Scopus and Google Scholar were searched for 'endometriosis AND (infection OR PID OR bacteria OR viruses OR microbiome OR microbiota)', for 'reproductive microbiome' and for 'reproductive microbiome AND endometriosis', respectively. All 384 articles, the first 120 'best match' articles in PubMed for 'reproductive microbiome' and the first 160 hits in Google Scholar for 'reproductive microbiome AND endomytriosis' were hand searched for data describing an association between endometriosis and bacterial, viral or other infections. All 31 articles found were included in this manuscript. RESULTS: Women with endometriosis have a significantly increased risk of lower genital tract infection, chronic endometritis, severe PID and surgical site infections after hysterectomy. They have more colony forming units of Gardnerella, Streptococcus, Enterococci and Escherichia coli in the endometrium. In the cervix Atopobium is absent, but Gardnerella, Streptococcus, Escherichia, Shigella, and Ureoplasma are increased. They have higher concentrations of Escherichia Coli and higher concentrations of bacterial endotoxins in menstrual blood. A Shigella/Escherichia dominant stool microbiome is more frequent. The peritoneal fluid of women with endometriosis contains higher concentrations of bacterial endotoxins and an increased incidence of mollicutes and of HPV viruses. Endometriosis lesions have a specific bacterial colonisation with more frequently mollicutes (54%) and both high and medium-risk HPV infections (11%). They contain DNA with 96% homology with Shigella. In mice transplanted endometrium changes the gut microbiome while the gut microbiome influences the growth of these endometriosis lesions. CONCLUSIONS: Endometriosis is associated with more upper genital tract and peritoneal infections. These infections might be co-factors causing GE incidents and influencing endometriosis growth.

Ospemifene 12-month safety and efficacy in postmenopausal women with vulvar and vaginal atrophy.

OBJECTIVE: Assessment of 12-month safety of ospemifene 60 mg/day for treatment of postmenopausal women with vulvar and vaginal atrophy (VVA). METHODS: In this 52-week, randomized, double-blind, placebo-controlled, parallel-group study, women 40-80 years with VVA and an intact uterus were randomized 6 : 1 to ospemifene 60 mg/day or placebo. The primary objective was 12-month safety, particularly endometrial; 12-week efficacy was assessed. Safety assessments included endometrial histology and thickness, and breast and gynecological examinations. Efficacy evaluations included changes from baseline to week 12 in percentage of superficial and parabasal cells and vaginal pH. RESULTS: Of 426 randomized subjects, 81.9% (n = 349) completed the study with adverse events the most common reason for discontinuation (ospemifene 9.5%; placebo 3.9%). Most (88%) treatment-emergent adverse events with ospemifene were considered mild or moderate. Three cases (1.0%) of active proliferation were observed in the ospemifene group. For one, active proliferation was seen at end of study week 52, and diagnosed as simple hyperplasia without atypia on follow-up biopsy 3 months after the last dose. This subsequently resolved with progestogen treatment and dilatation and curettage. In six subjects (five ospemifene (1.4%), one placebo (1.6%)) endometrial polyps were found (histopathology); however, only one (ospemifene) was confirmed as a true polyp during additional expert review. Endometrial histology showed no evidence of carcinoma. Statistically significant improvements were seen for all primary and secondary efficacy measures and were sustained through week 52 with ospemifene vs. placebo. CONCLUSIONS: The findings of this 52-week study confirm the tolerance and efficacy of oral ospemifene previously reported in short- and long-term studies.

Adhesion formation after laparoscopic surgery: what do we know about the role of the peritoneal environment?

In spite of the approaches that have been proposed to reduce postoperative peritoneal adhesions, they remain a major clinical problem because of the associated intestinal obstruction, chronic pelvic pain, female infertility and difficulties at the time of reoperation. The pathogenesis of the process have been focused almost exclusively on the local events induced by the surgical trauma, and the strategies for adhesion prevention thus focused on barriers to separate surgically denuded areas. The important role of the peritoneal cavity environment only recently became apparent and is not yet incorporated in adhesion reducing strategies. Recent data demonstrate that, in the presence of a direct surgical trauma, the entire peritoneal environment is quantitatively the most important factor in adhesion formation and hence adhesion prevention after both open and laparoscopic surgery. Indeed mesothelial hypoxia (CO2 pneumoperitoneum) or hyperoxia (open surgery), desiccation and surgical manipulation have been identified as factors cumulatively enhancing adhesions--. The clinical implication is especially relevant for laparoscopic surgery because the pneumoperitoneum, being a closed environment, can be easily conditioned. Although human studies are lacking, animal data indicate that peritoneal adhesions can be reduced by over 80% with a good surgical technique, with adequate pneumoperitoneum conditioning as adding 3-4% of oxygen to the CO2 pneumoperitoneum, prevention of desiccation and slight cooling. Adhesion prevention barriers remain additionally effective, although quantitatively less important. The relevance of all these strategies for adhesion prevention still have to be confirmed in humans, but since it seems that the peritoneal environment is quantitatively much more important than the surgical trauma, adhesion prevention research and strategies should be directed more to conditioning the peritoneal cavity than to the use of agents.

Hyperoxia and prevention of adhesion formation: a laparoscopic mouse model for open surgery.

OBJECTIVE: CO(2) pneumoperitoneum with more than 10% oxygen enhances adhesions. As during open surgery the peritoneum is exposed to air (20% oxygen), in this hyperoxia-enhanced adhesion model we evaluated the effect of hypothermia and products with known effectiveness in hypoxia (pure CO(2) pneumoperitoneum) and normoxia (CO(2) pneumoperitoneum plus 3-4% oxygen) models. Results were expected to be important for adhesion prevention in open surgery, and, moreover, similarities and differences between the three models would be important to identify differences in pathways of adhesion formation between laparoscopy and laparotomy. DESIGN: Two experiments were performed in which the effect of hypothermia (32 degrees C), a surfactant (phospholipids), a barrier (Hyalobarrier gel), reactive oxygen species scavengers (superoxide dismutase, SOD, and ascorbic acid, AA), anti-inflammatory agents (dexamethasone and nimesulide), a calcium channel blocker (diltiazem) and recombinant plasminogen activator (r-PA) were evaluated upon adhesions. SETTING: University Hospital. POPULATION: BALB/c mice. METHODS: Hyperoxia-enhanced adhesions were induced by performing laparoscopically bipolar lesions during 60 minutes of CO(2) pneumoperitoneum plus 12% oxygen at 37 degrees C body temperature. MAIN OUTCOME MEASURES: Adhesions were scored after 7 days. RESULTS: In this model, adhesions were reduced by hypothermia (P < 0.02; Wilcoxon), phospholipids (P = 0.03), Hyalobarrier gel (P < 0.004), dexamethasone (P < 0.005) and diltiazem (P < 0.01). A significant but quantitatively borderline effect was seen for AA (P < 0.002) and r-PA (P = 0.0005), whereas SOD and nimesulide did not have any effect. CONCLUSIONS: Hyperoxia-enhanced adhesions were prevented by hypothermia, dexamethasone, phospholipids, Hyalobarrier gel, diltiazem, r-PA and AA. All effects were similar to those in the hypoxia-enhanced adhesion model, suggesting that the underlying mechanisms are similar.

Prevention of adhesion formation in a laparoscopic mouse model should combine local treatment with peritoneal cavity conditioning.

BACKGROUND: Adhesion formation results from a series of local events at the trauma site. This process can be enhanced by factors derived from the peritoneal cavity such as mesothelial cell hypoxia (pneumoperitoneum with pure CO(2)), reactive oxygen species (pneumoperitoneum with more than 4% oxygen), desiccation and mesothelial trauma produced through manipulation. Adhesion prevention, therefore, should combine local treatment while minimizing adverse peritoneal factors through conditioning of the pneumoperitoneum. METHODS: In a laparoscopic mouse model, adhesion induction comprised a mechanical lesion together with a humidified pneumoperitoneum for 60 min with pure CO(2) at 37 degrees C. Adhesion prevention consisted of a combination of treatments known to reduce adhesions, i.e. pneumoperitoneum with CO(2) with the addition of 3-4% O(2), reduction of body temperature (BT) to 32 degrees C and application of antiadhesion products such as anti-inflammatory drugs (dexamethasone, nimesulide), calcium-channel blockers (diltiem), surfactants (phospholipids), barriers (Hyalobarrier gel), reactive oxygen species scavengers (superoxide dismutase and ascorbic acid) and recombinant plasminogen activator. RESULTS: The addition of 3% O(2) to the pneumoperitoneum or a lower BT decreased adhesions by 32% or 48%, respectively (P < 0.05, Wilcoxon), but were without additional effects when combined. In addition, if dexamethasone or Hyalobarrier((R)) gel were administrated, the total reduction was 76% (P = 0.04) or 85% (P < 0.02), respectively. CONCLUSIONS: Combining pneumoperitoneum conditioning together with dexamethasone or a barrier resulted in significant adhesion reduction in a laparoscopic mouse model.

Accident analysis: factors contributing to a ureteric injury during deep endometriosis surgery.

OBJECTIVE: To analyse factors associated with a ureteric injury. DESIGN: Retrospective accident analysis. SETTING: Deep endometriosis surgery in a tertiary referral centre. SAMPLE: Video recording of a surgical accident was analysed by six gynaecologists. METHODS: A 26-year-old woman underwent laparoscopy for deep endometriosis that involves the rectosigmoid and left ureter. Post operatively left ureter transection was identified and corrected by laparoscopy. Interventions were recorded and reviewed independently. MAIN OUTCOME MEASURES: Changes in surgical behaviour that could be measured were identified using the video recording. Results During the intervention, the periods of uncontrolled bleeding (P < 0.0001) and the duration of laser activation (P = 0.013) increased progressively. Simultaneous laser activation and bipolar coagulation only occurred at the end of surgery (seven episodes). Fatigue could not be measured. CONCLUSION: Unconscious acceleration of surgery, possibly as a consequence of fatigue, is suggested as a contributing factor for an error of judgement.