Opportunistic Salpingectomy Research Articles

Opportunistic salpingectomy during gynecologic and non-gynecologic abdominopelvic procedures for ovarian cancer primary prevention: A cost-effectiveness analysis

Opportunistic salpingectomy during gynecologic and non-gynecologic abdominopelvic procedures for ovarian cancer primary prevention: A cost-effectiveness analysis

Opportunistic salpingectomy during non-gynecologic ambulatory surgery in the United States, 2016–2020 12

Opportunistic salpingectomy during non-gynecologic ambulatory surgery in the United States, 2016–2020 12

Rates of Opportunistic Salpingectomy During Minimally-Invasive Benign Hysterectomy By Race/Ethnicity from 2016 to 2021

Rates of Opportunistic Salpingectomy During Minimally-Invasive Benign Hysterectomy By Race/Ethnicity from 2016 to 2021

FIGO position statement on opportunistic salpingectomy as an ovarian cancer prevention strategy.

Epithelial ovarian cancer, with the highest mortality rate among gynecologic malignancies, often goes undetected until advanced stages due to non-specific symptoms. Traditional prevention strategies such as bilateral salpingo-oophorectomy (BSO) are limited to high-risk women and induce surgical menopause, often leading to significant health concerns. Recent findings suggest that many serous epithelial ovarian cancers originate in the fallopian tubes rather than the ovaries. This has led to the hypothesis that salpingectomy, with preservation of the ovaries, may reduce the risk of ovarian cancer while avoiding the adverse effects of early menopause. Studies show that bilateral salpingectomy (BS) significantly reduces ovarian cancer incidence even in average-risk women. Bilateral salpingectomy has been demonstrated to be safe with minimal added operative time, no adverse effects on ovarian function and is also cost effective. Opportunistic salpingectomy (OS), at the time of non-gynecologic surgeries, is a promising strategy for reducing ovarian cancer risk, especially among average-risk women who have completed childbearing. It offers a safe and cost-effective alternative to traditional methods. Emerging data supports incorporating OS into standard surgical practices for benign gynecologic conditions and considering it during unrelated abdominal/pelvic surgeries after adequate patient counseling and informed consent. Further training of non-gynecologic surgeons in OS is recommended to expand its preventive benefits.

Prevention of Ovarian Cancer: Where are We Now and Where are We Going?

To describe current and future strategies to reduce the burden of ovarian cancer through prevention. Current strategies in genetic testing are missing a substantial number of individuals at risk, representing a missed opportunity for ovarian cancer prevention. Past efforts at screening and early detection have thus far failed to improve ovarian cancer mortality, and novel techniques are needed. Surgical prevention is highly effective, but surgical menopause from oophorectomy has significant side effects. Novel surgical strategies aimed at reducing risk while minimizing these harms are currently being studied. To maximize ovarian cancer prevention, a multi-pronged approach is needed. We propose that more inclusive and accurate genetic testing to identify more individuals at risk, novel molecular screening and early detection, surgical prevention that maximizes quality of life while reducing risk, and broader adoption of targeted and opportunistic salpingectomy will together reduce the burden of ovarian cancer.

Opportunistic salpingectomy to decrease the risk of ovarian cancer.

Opportunistic salpingectomy to decrease the risk of ovarian cancer.

The Impact of Opportunistic Salpingectomy on Ovarian Reserve: A Systematic Review.

Background: In the last decade, increasing evidence has suggested that high-grade serous ovarian cancers may have their origin in the fallopian tube rather than the ovary. This emerging theory presents an opportunity to prevent epithelial ovarian cancer by incorporating prophylactic bilateral salpingectomy into all surgical procedures for average-risk women. The aim of this review is to investigate the hypothesis that bilateral salpingectomy (BS) may have a negative impact on ovarian reserve, not only following hysterectomy for benign uterine pathologies but also when performed during cesarean sections as a method of sterilization or as a treatment for hydrosalpinx in Assisted Reproductive Technology interventions. Methods: PubMed, Medline, Google Scholar, and Cochrane were searched for original studies, meta-analyses, and opinion articles published between 2014 and 2024. Results: Out of 114 records from the database search, after the removal of duplicates, 102 articles were considered relevant for the current study. Conclusions: Performing opportunistic salpingectomy seems to have no adverse impact on ovarian function in the short term. However, because there is an existing risk of damaging ovarian blood supply during salpingectomy, there are concerns about potential long-term adverse effects on the ovarian reserve, which need further investigation.

Incidental Serous Tubal Intraepithelial Carcinoma Finding in a Nepalese Patient Undergoing Opportunistic Salpingectomy and the Discovery of a BRCA1 Pathogenic Variant

BACKGROUND: Serous tubal intraepithelial carcinoma lesions are the precursor to high-grade serous ovarian carcinomas, which have the highest mortality rate among gynecologic malignancies. In women diagnosed with high-grade serous ovarian carcinoma, 20% of the carcinomas are found to be secondary to hereditary causes, with the majority being associated with germline pathogenic variants in BRCA1 and BRCA2 genes. Patients with a pathogenic variant are at high risk for developing high-grade serous ovarian carcinoma, so it is recommended that they undergo risk-reducing salpingo-oophorectomy in their 30s–40s. Opportunistic salpingectomy is the only ovarian cancer prevention method available for patients at average risk. Although serous tubal intraepithelial carcinoma lesions are rare in women at average risk, studies quote incidental serous tubal intraepithelial carcinoma lesion findings in 1–7% of patients undergoing opportunistic salpingectomy. CASE: A 38-year-old woman, gravida 2 para 2, of Nepalese ethnicity had an incidental finding of a serous tubal intraepithelial carcinoma lesion at the time of opportunistic salpingectomy for permanent sterilization at cesarean delivery. The serous tubal intraepithelial carcinoma lesion was found with representative sampling of the fallopian tubes because the patient was considered to be at average risk for ovarian cancer. This method is much less sensitive than the Sectioning and Extensively Examining the Fimbriated End (SEE-FIM) protocol, which is used with women known to be at high risk. This ultimately led to discovery of a BRCA1 mutation in the patient. CONCLUSION: The SEE-FIM protocol is used to identify serous tubal intraepithelial carcinoma lesions, but it is not routinely used on fallopian tubes of patients at average risk. Using the SEE-FIM protocol would lead to fewer missed serous tubal intraepithelial carcinoma lesions, but it is unclear how much extra cost and effort would be required to implement this protocol. There are knowledge gaps when it comes to understudied populations and hereditary breast and ovarian cancer gene prevalence. Studies show that current BRCA prediction models underestimate hereditary breast and ovarian cancer gene prevalence in Asian populations. Diagnosing serous tubal intraepithelial carcinoma lesions in understudied populations could lead to the discovery of a hereditary breast and ovarian cancer pathogenic variant that the patient may not have discovered until after a cancer diagnosis. Identification of a serous tubal intraepithelial carcinoma in a patient at average risk should lead to a referral for genetic counseling and screening.

Opportunistic Salpingectomy at the Time of General Surgery Procedures: A Systematic Review and Narrative Synthesis of Current Knowledge

Opportunistic salpingectomy (OS) for the primary prevention of ovarian cancer is performed by gynecologists. Advocates have suggested expanding its use to other surgical specialties. General surgeons are the other group to routinely perform intraperitoneal operations in women and could play a role in ovarian cancer prevention. Herein, we review the current evidence and perioperative factors requiring consideration prior to OS implementation in select general surgery cases. A systematic search was conducted for English-language studies evaluating OS during general surgery. The primary outcomes of this study were the feasibility and safety of OS during general surgery procedures. Secondary outcomes included pre-operative considerations (patient selection and the consent process), operative factors (technique and surgical specialty involvement), and post-operative factors (follow-up and management of operative complications). We evaluated 3977 studies, with 9 meeting the eligibility criteria. Few studies exist but preliminary evidence suggests relative safety, with no complication attributable to OS among 140 patients. Feasibility was reported in one study, which showed the capacity to perform OS in 98 out of 105 cholecystectomies (93.3%), while another study reported quick visualization of the fallopian tubes in >80% of cases. All patients in the included studies were undergoing elective procedures, including cholecystectomy, interval appendectomy, colorectal resection, bariatric surgery, and laparoscopic hernia repair. Studies only included patients ≥ 45 years old, and the mean age ranged from 49 to 67.5 years. Gynecologists were frequently involved during the consent and surgical procedures. OS represents a potential intervention to reduce the risk of ovarian cancer. Ongoing studies evaluating the general surgeon’s understanding; the consent process; the feasibility, operative outcomes, and risks of OS; and surgeon training are required prior to consideration.

Global epidemiology of epithelial ovarian cancer.

Globally, ovarian cancer is the eighth most common cancer in women, accounting for an estimated 3.7% of cases and 4.7% of cancer deaths in 2020. Until the early 2000s, age-standardized incidence was highest in northern Europe and North America, but this trend has changed; incidence is now declining in these regions and increasing in parts of eastern Europe and Asia. Ovarian cancer is a very heterogeneous disease and, even among the most common type, namely epithelial ovarian cancer, five major clinically and genetically distinct histotypes exist. Most high-grade serous ovarian carcinomas are now recognized to originate in the fimbrial ends of the fallopian tube. This knowledge has led to more cancers being coded as fallopian tube in origin, which probably explains some of the apparent declines in ovarian cancer incidence, particularly in high-income countries; however, it also suggests that opportunistic salpingectomy offers an important opportunity for prevention. The five histotypes share several reproductive and hormonal risk factors, although differences also exist. In this Review, we summarize the epidemiology of this complex disease, comparing the different histotypes, and consider the potential for prevention. We also discuss how changes in the prevalence of risk and protective factors might have contributed to the observed changes in incidence and what this might mean for incidence in the future.

Screening and prevention of ovarian cancer.

Ovarian cancer remains the most lethal gynaecological malignancy with 314 000 cases and 207 000 deaths annually worldwide. Ovarian cancer cases and deaths are predicted to increase in Australia by 42% and 55% respectively by 2040. Earlier detection and significant downstaging of ovarian cancer have been demonstrated with multimodal screening in the largest randomised controlled trial of ovarian cancer screening in women at average population risk. However, none of the randomised trials have demonstrated a mortality benefit. Therefore, ovarian cancer screening is not currently recommended in women at average population risk. More frequent surveillance for ovarian cancer every three to four months in women at high risk has shown good performance characteristics and significant downstaging, but there is no available information on a survival benefit. Population testing offers an emerging novel strategy to identify women at high risk who can benefit from ovarian cancer prevention. Novel multicancer early detection biomarker, longitudinal multiple marker strategies, and new biomarkers are being investigated and evaluated for ovarian cancer screening. Risk-reducing salpingo-oophorectomy (RRSO) decreases ovarian cancer incidence and mortality and is recommended for women at over a 4-5% lifetime risk of ovarian cancer. Pre-menopausal women without contraindications to hormone replacement therapy (HRT) undergoing RRSO should be offered HRT until 51 years of age to minimise the detrimental consequences of premature menopause. Currently risk-reducing early salpingectomy and delayed oophorectomy (RRESDO) should only be offered to women at increased risk of ovarian cancer within the context of a research trial. Pre-menopausal early salpingectomy is associated with fewer menopausal symptoms and better sexual function than bilateral salpingo-oophorectomy. A Sectioning and Extensively Examining the Fimbria (SEE-FIM) protocol should be used for histopathological assessment in women at high risk of ovarian cancer who are undergoing surgical prevention. Opportunistic salpingectomy may be offered at routine gynaecological surgery to all women who have completed their family. Long term prospective opportunistic salpingectomy studies are needed to determine the effect size of ovarian cancer risk reduction and the impact on menopause.

Opportunistic Salpingectomy: A New Scope of Preventing a Deadly Disease

Background: Symptoms of ovarian cancer are non-specific and often do not arise until the cancer is in a late stage. Such late onset of symptoms and the lack of an effective screening test result in diagnosis at an advanced-stage for most patients of ovarian cancer. The fimbrial end of the fallopian tube has recently been suggested as the site of origin for epithelial ovarian cancers (EOC). Therefore, a change in practice with opportunistic salpingectomy (OS) at the time of hysterectomy has been advocated for prevention of ovarian cancer. Different gynaecological societies have published statements in favour of opportunistic salpingectomy in women at average population risk for ovarian cancer prevention. In recent years, salpingectomy has been increasingly performed for tubal sterilization also. We have gone through the available scientific publications and international guidelines in preparing this brief review in an attempt tobe familiar with the recent updated views regarding this issue. Delta Med Col J. Jan 2021;9(1):37-57

Morphologic and Molecular Heterogeneity of High-grade Serous Carcinoma Precursor Lesions.

Serous tubal intraepithelial carcinoma (STIC) is the fallopian tube precursor lesion for most cases of pelvic high-grade serous carcinoma (HGSC). To date, the morphologic, molecular, and clinical heterogeneity of STIC and a less atypical putative precursor lesion, termed serous tubal intraepithelial lesion, has not been well characterized. Better understanding of precursor heterogeneity could impact the clinical management of women with incidental STICs (without concurrent carcinoma) identified in cases of prophylactic or opportunistic salpingectomy. This study analyzed morphologic and molecular features of 171 STICs and 21 serous tubal intraepithelial lesions. We assessed their histologic features, Ki-67 and p53 staining patterns, and genome-wide DNA copy number alterations. We classified all precursor lesions into 2 morphologic subtypes, one with a flat surface (Flat) and the other characterized by budding, loosely adherent, or detached (BLAD) morphology. On the basis of pathology review by a panel of 8 gynecologic pathologists, we found 87 BLAD, 96 Flat, and 9 indeterminate lesions. As compared with Flat lesions, BLAD lesions were more frequently diagnostic of STIC ( P <0.0001) and were found concurrently with HGSC ( P <0.0001). BLAD morphology was also characterized by higher Ki-67 proliferation index ( P <0.0001), presence of epithelial stratification ( P <0.0001), and increased lymphocyte density ( P <0.0001). BLAD lesions also exhibited more frequent DNA copy number gain/amplification at the CCNE1 or CMYC loci canonical to HGSCs ( P <0.0001). Both BLAD morphology and STIC diagnoses are independent risk factors for an elevated Ki-67 proliferation index. No correlation was observed between BLAD and Flat lesions with respect to patient age, presence of germline BRCA1/2 mutation, or p53 staining pattern. These findings suggest that tubal precursor lesions are morphologically and molecularly heterogeneous, laying the foundation for further studies on the pathogenesis of HGSC initiation and identifying histologic features predictive of poor patient outcomes.

Prophylactic and opportunistic salpingectomy in a central-eastern European country – Club 35 young gynaecologists survey study results

Prophylactic and opportunistic salpingectomy in a central-eastern European country – Club 35 young gynaecologists survey study results

Opportunistic salpingectomy at the time of vaginal hysterectomy: A systematic review and meta-analysis.

Despite the rising rates of opportunistic salpingectomy at the time of surgery for non-malignant conditions, salpingectomy is not widely adopted during vaginal hysterectomy (VH) and has not been extensively investigated. The aim of the primary study was to determine the feasibility of bilateral opportunistic salpingectomy at the time of VH. Secondary aims included surgical outcomes, factors associated with patient selection, and the prevalence of incidental tubal malignancies. In this systematic review and meta-analysis we searched Pubmed, Embase and ClinicalTrials.gov databases from inception to September 1, 2023, using relevant keywords. Original articles with no language restriction reporting outcomes of women undergoing planned VH with opportunistic salpingectomy, were considered eligible. Studies including patients undergoing VH with and without opportunistic salpingectomy were also included. The Newcastle-Ottawa scale was used to assess quality of observational studies. DerSimonian-Laird random effects meta-analysis was performed and pooled effect estimates and proportions with corresponding 95% confidence intervals were computed. Heterogeneity was assessed using the I2 statistic. Seven observational cohort studies including 4808 women undergoing opportunistic salpingectomy at the time of VH and 10 295 patients undergoing VH alone were selected. The pooled proportion of success was 81.83 per 100 observations (95% CI: 75.35-87.54). Opportunistic salpingectomy at the time of VH, when feasible, was associated with a significant reduction in intraoperative complications (OR 0.06, 95% CI: 0.01, -0.37, P = 0.03) and total operative time (95% CI: -17.80, -1.07, P = 0.03) compared to those where it failed. Successful salpingectomy was significantly hindered by nulliparity (OR 0.12, 95% CI: -17.69, -1.21, P < 0.001) and favored by pelvic organ prolapse (OR 3.20, 95% CI: 1.35, 7.55, P = 0.008). Immunohistochemical tubal abnormalities were found in 13/579 (2.1%) patients. The overall quality of the evidence, according to the GRADE assessment, was low. Opportunistic salpingectomy is safe, effective, and feasible at the time of VH. Nulliparity and pelvic organ prolapse are factors potentially influencing surgical outcomes.

PREVENTION OF OVARIAN, FALLOPIAN TUBE, AND PERITONEAL SEROUS CANCERS (LITERATURE REVIEW)

This literature review presents an analysis of the incidence and state of prevention of highly malignant tumors that are difficult to diagnose: serous ovarian cancer, primary fallopian tube cancer, and primary peritoneal cancer. In this group of patients, ovarian cancer amounts to 82.0%, fallopian tube cancer – 6.4%, and peritoneal cancer – 10.7%. The problem is very urgent, since, according to the International Agency for Research on Cancer (IARC), more than 225,000 new cases of ovarian cancer alone are registered annually in the world, and more than half of the patients die during the year. No more than 30% of the treated patients survive for up to 10 years. Such poor results are due to the lack of effective methods of prevention and the difficulties of diagnosing this group of diseases. Methods. The author selected from the world literature more than 45 scientific works on the problems of incidence and prevention of ovarian cancer, primary fallopian tube cancer, and peritoneal cancer and carried out a detailed analysis of them. Results and Discussion. At the beginning of the 21st century, after a number of morphological, immunohistochemical, and molecular genetic examinations, the global scientific community clearly proved that the root cause of serous ovarian, fallopian tube, and peritoneal cancers is the pathology of the fallopian tube mucosa. Practical observations revealed that women who underwent salpingectomy or tubal sterilization had a much lower risk of serous pelvic cancers. As a result of these examinations and observations, clinical recommendations were made: in order to prevent ovarian cancer, women should be suggested opportunistic bilateral salpingectomy during their operations in the post-reproductive age. Sterilization should be done by removing the fallopian tubes, not by ligation, because of the lower efficiency of the latter. According to the reports of some authors, this method can reduce the risk of ovarian cancer by 90–98%. There is a lack of reports on the prevention of fallopian tube and peritoneal cancers in the periodical scientific literature, but we can assume that they will not be worse than those for ovarian cancer.

Vaginal hysterectomy and transvaginal natural orifice transluminal endoscopic surgery for uterosacral ligament suspension for pelvic organ prolapse: 53 cases of single-surgeon experience.

The objective of this study was to describe the single-surgeon experience on transvaginal natural orifice transluminal endoscopic surgery for uterosacral ligament suspension in patients with severe prolapse who had concomitant vaginal hysterectomy. A total of 53 patients with severe uterine prolapse who underwent vaginal hysterectomy and transvaginal natural orifice transluminal endoscopic surgery for uterosacral ligament suspension between January 2021 and March 2023 were included in the study. Operation time, intraoperative and postoperative complications, de novo urinary continence, and duration of hospitalization were obtained from the patient records. Initial postoperative follow-up visits were scheduled for the first week of the month. Patients were followed up yearly, and they had the opportunity to reach the surgical team at any time. Symptomatic prolapse beyond the hymen is defined as recurrence. Patients had a mean age of 61.7 years ±7.7 SD. All patients received bilateral opportunistic salpingectomy and salpingo-oophorectomy. The total operation time was 162±31 min, with transvaginal natural orifice transluminal endoscopic surgery taking 32.3±5.37 min. There were no intraoperative complications. 12 patients had recurrence; 8 anterior, 3 apical, and 1 posterior prolapse. The mean recurrence time was 11.5 months (range 5-23 months). The reoperation rate was 13.2% (n:7). Three of the patients had obliterative vaginal surgery, three of the patients had anterior, and one patient had posterior repair. Overall failure of apical surgical procedure was 5.6%. Two patients had de novo incontinence postoperatively. Transvaginal natural orifice transluminal endoscopic surgery uterosacral ligament suspension is a feasible technique to treat severe pelvic organ prolapse with promising results for short-term efficacy and safety in patients who had concomitant vaginal hysterectomy. Longer follow-up periods are needed to evaluate the long-term efficacy profile of transvaginal natural orifice transluminal endoscopic surgery for uterosacral ligament suspension.

Complications after opportunistic salpingectomy compared with tubal ligation at cesarean section: a retrospective cohort study

To compare perioperative and postoperative complications in patients who underwent opportunistic salpingectomy (OS) (removal of the fallopian tubes for ovarian cancer risk reduction during another surgery) at the time of cesarean section (C-section) with those in patients who underwent tubal ligation. A population-based, retrospective cohort study. British Columbia, Canada. A total of 18,184 patients were included in this study, of whom 8,440 and 9,744 underwent OS and tubal ligation, respectively. Patients who underwent OS during a C-section were compared with those who underwent tubal ligation during a C-section. We examined the perioperative outcomes, including operating room time, length of hospital stay, surgical complications such as infections, anemia, incision complications, injury to a pelvic organ, or operating room return; postoperative complications, including physician visits for a postoperative infection or visits that resulted in ultrasound or laboratory examinations and hospital readmissions in the 6 weeks after discharge; and likelihood to fill a prescription for antibiotics or analgesics. The OS group had decreased odds of perioperative complications compared with the tubal ligation group (adjusted odds ratio [aOR], 0.77; 95% confidence interval [CI], 0.61-0.99). Patients who underwent OS did not have increased risks of physician visits for surgical complications, such as infection, or hospital readmissions in the 6 weeks after hospital discharge. In addition, these patients had 18% and 23% increased odds of filling prescriptions for nonsteroidal anti-inflammatory drugs (aOR, 1.18; 95% CI, 1.07-1.28) and opioids (aOR, 1.23%; 95% CI, 1.12-1.35), respectively. In this population-based, real-world study of OS at C-section, we report decreased perioperative complications and no difference in postoperative complications between patients who underwent OS and those who underwent tubal ligation. Patients who underwent OS had an increased likelihood of filling a prescription for nonsteroidal anti-inflammatory drugs and opioids in the 6 weeks after hospital discharge. This result should be interpreted with caution because we did not have data on over-the-counter medication use and, thus, not all prescription analgesics were captured in our data. Our data suggest that OS after C-section is a safe way to provide effective contraception and ovarian cancer risk reduction.

Ovarian Cancer: From Precursor Lesion Identification to Population-Based Prevention Programs.

Epithelial ovarian cancer (EOC) is a heterogeneous group of malignancies, including high-grade serous ovarian cancer (HGSC). HGSC is often diagnosed at advanced stages and is linked to TP53 variants. While BRCA variants elevate risk, most HGSC cases occur in individuals without known genetic variants, necessitating prevention strategies for people without known high-risk genetic variants. Effective prevention programs are also needed due to the lack of traditional screening options. An emerging primary prevention strategy is opportunistic salpingectomy, which involves removing fallopian tubes during another planned pelvic surgery. Opportunistic salpingectomy offers a safe and cost-effective preventative option that is gaining global adoption. With the publication of the first cohort study of patients who underwent salpingectomy, specifically for cancer prevention, attention has turned to broadening opportunities for salpingectomy in addition to more targeted approaches. Prevention opportunities are promising with increasing adoption of salpingectomy and the increased understanding of the etiology of the distinct histotypes of ovarian cancer. Yet, further research on targeted risk-reducing salpingectomy with thoughtful consideration of equity is necessary to reduce death and suffering from ovarian cancer.

Beyond Sterilization: A Comprehensive Review on the Safety and Efficacy of Opportunistic Salpingectomy as a Preventative Strategy for Ovarian Cancer.

Ovarian cancer (OC) is Canada's third most common gynecological cancer, with an estimated 3000 new cases and 1950 deaths projected in 2022. No effective screening has been found to identify OC, especially the most common subtype, high-grade serous carcinoma (HGSC), at an earlier, curable stage. In patients with hereditary predispositions such as BRCA mutations, the rates of HGSC are significantly elevated, leading to the use of risk-reducing salpingo-oophorectomy as the key preventative intervention. Although surgery has been shown to prevent HGSC in high-risk women, the associated premature menopause has adverse long-term sequelae and mortality due to non-cancer causes. The fact that 75% of HGSCs are sporadic means that most women diagnosed with HGSC will not have had the option to avail of either screening or prevention. Recent research suggests that the fimbrial distal fallopian tube is the most likely origin of HGSC. This has led to the development of a prevention plan for the general population: opportunistic salpingectomy, the removal of both fallopian tubes. This article aims to compile and review the studies evaluating the effect of opportunistic salpingectomy on surgical-related complications, ovarian reserve, cost, and OC incidence when performed along with hysterectomy or instead of tubal ligation in the general population.