{"paper_id":"d04cf5be-8000-4383-9a3f-580cb65aa963","body_text":"Supplemental Digital Content is available for this article. Direct URL citations are provided in the HTML and PDF versions of this article on the journal's website, journals.lww.com/ijsopen/default.aspx.\nAppendiceal intussusception (AI), an uncommon entity with significant clinical importance, various intrinsic pathologies could act as a lead point, with endometriosis being an uncommon etiological factor posing diagnostic challenges for clinicians.\nObjectives:\nThis systematic review aims to provide valuable insights into the clinical aspects and management of AI caused by endometriosis to better understand this rare condition.\nMaterials and Methods:\nA systematic search of the literature was conducted in EBSCO, PubMed, ScienceDirect, Scopus, and SpringerLink databases to identify case reports describing AI associated with endometriosis. Data were extracted and organized into categories. The extracted data was entered into standardized Google spreadsheets. The risk of bias was assessed using the JBI Critical Appraisal Checklist.\nMain Results:\nThe review identified a total of 38 cases with a mean age of 41.58-years-old between 1949 and 2022. Patient’s clinical findings were categorized into being asymptomatic (15.79%), presenting with lower abdominal pain/gastrointestinal complaints (60.53%), or gynecological symptoms (23.68%), often mimicking other abdominal and gynecological disorders, leading to a variety of differential diagnoses with appendicitis being the most common. Most cases were diagnosed postoperatively (44.74%), with colonoscopy and computed tomography playing pivotal roles in preoperative diagnosis. Type V intussusception was most prevalent, and surgical interventions varied, ranging from appendectomy to right hemicolectomy. Postoperative outcomes were generally favorable, with most patients experiencing symptom resolution.\nConclusions:\nClinicians should consider AI caused by endometriosis as a differential diagnosis in female patients with recurrent cyclic abdominal pain and a cecal mass.\nIntroduction\nHighlights\nAppendiceal intussusception (AI), a rare condition where the appendix invaginates into itself can lead to complications and pose diagnostic challenges especially when associated with endometriosis.\nThis systematic review explores the realm of intussusception caused by endometriosis shedding light on clinical presentations and treatment options.\nThe association between endometriosis and AI is rare, yet significant for healthcare providers to acknowledge. Symptoms such as pain and gastrointestinal issues are common in clinical cases often resembling other abdominal conditions. This similarity makes reaching a diagnosis challenging, thus clinical assessment imaging tests, and possibly surgery may be necessary.\nThe review identified 38 cases of AI caused by endometriosis, with patients primarily presenting with lower abdominal pain/gastrointestinal complaints (60.53%) or gynecological symptoms (23.68%). Most cases were diagnosed postoperatively (44.74%), with colonoscopy and computed tomography aiding in preoperative diagnosis. Surgical interventions varied, ranging from appendectomy to right hemicolectomy, with favorable postoperative outcomes observed in the majority of cases.\nAI resulting from endometriosis presents a rare yet clinically significant pathology. The study presents detailed insights and management approaches that can enhance clinician’s diagnostic skills and patient care practices. Understanding this condition is vital for providing appropriate treatment to affected individuals.\nEndometriosis is a medical condition characterized by the presence of endometrium-like tissue outside the normal boundaries of the uterus, often accompanied by inflammation1. These lesions can present in the form of superficial lesions or ovarian cysts, peritoneal lesions, or deep infiltrating disease2, with deep infiltrating extending at least 5 mm below the peritoneum affecting the uterosacral ligaments, adnexae, colon, and appendix most commonly3. It is estimated that ~10–15% of women in their reproductive years’ experience endometriosis4.\nAppendiceal endometriosis is an uncommon condition that has a low occurrence rate of ~0.4–1% in the overall population5,6 significantly rising to 4–22% in patients with endometriosis7,8. Endometriosis of the appendix can manifest as either asymptomatic or with symptoms resembling acute or chronic appendicitis9,10. It is also recognized as a common cause of cyclic and chronic right lower quadrant (RLQ) pain11, melena12, and appendiceal intussusception (AI) into the cecum.\nThe occurrence of AI was first documented by McKidd et al.13 in 1858. McSwain14 then followed with a classification where he classified AI into four basic types depending on the relationship between intussusceptum and intussuscipiens.\nThe incidence of AI was found to be 0.01% in a large, monumental study done by Collins15, with a 4:1 male-to-female ratio usually in the first decade of life16. AI can present with a variety of symptoms mimicking several acute and chronic abdominal diseases and could be misdiagnosed as a mass or cecal polyp colonoscopically17,18. The coexistence of endometriosis and AI is exceedingly uncommon, with a limited number of cases documented in medical literature19.\nAlthough AI due to endometriosis is a rare phenomenon, it presents a significant clinical challenge. This review aims to enhance our understanding, shed light on this rare but clinically important pathology, and identify its clinical presentation, diagnostic modalities, and optimal management strategies to address the existing gaps in current medical literature on endometriosis-induced AI.\nMethods\nThis review is reported in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-analysis (PRISMA, Supplemental Digital Content 1, https://links.lww.com/IJSOPEN/A16, Supplemental Digital Content 2, https://links.lww.com/IJSOPEN/A17) and AMSTAR, Supplemental Digital Content 3, https://links.lww.com/IJSOPEN/A18 (Assessing the methodological quality of systematic reviews).20,21 Also, it was registered in the International Prospective Register of Systematic Reviews (PROSPERO).\nSearch strategy and study selection\nWe conducted an extensive and advanced search of case reports/series in five major databases, including (EBSCO, PubMed, ScienceDirect, Scopus, and SpringerLink) regarding AI due to endometriosis published between 1949 and 2022. Two authors (M.A. and A.A.) conducted all the searches and stored them in EndNote version 20 for Windows. We used a combination of keywords and medical subject headings (MeSH) that includes: (‘appendix’ OR ‘appendiceal intussusception’ OR ‘invagination’ AND ‘endometriosis’ OR ‘appendiceal endometriosis’). To ensure a thorough review of the literature, we also looked over references from bibliographies of the included studies. After screening titles and abstracts, duplicates were removed using EndNote. Studies that met our inclusion criteria were retrieved, and full-text screening was done. Any conflicts between the authors were resolved after a thorough discussion among them.\nInclusion and exclusion criteria\nThe eligibility criteria for study selection were: (1) Occurrence of AI. (2) Histological testing to confirm the presence of endometriosis in the appendix. (3) Raw data were provided on clinical symptoms, diagnosis, treatment, and outcome of AI due to endometriosis. (4) Studies are in the English language. Nonclinical articles such as Letters to the Editor were also included due to fulfilling the criteria. Articles were excluded if they were not written in English, were unavailable in full-text and lacked histological confirmation of endometriosis in the appendix or reported malignancy.\nData extraction\nData extraction was performed by five independent authors (‘M.A., A.A., Z.S., A.Z. and M.B.’) who read the full articles and then extracted data from the eligible ones. All data were entered into standardized Google spreadsheets. Three authors (‘M.A., A.A. and A.Z.’) reviewed the extracted data to ensure its validity. The following data were extracted from each study: the first author’s name, year, country, study type, age, medical history, surgical history, presenting symptoms, gynecological symptoms, diagnosis at presentation or differential diagnosis, investigations, and their findings [computed tomography (CT), colonoscopy, or any incidental findings], gross and microscopic findings (histology), intervention, time of intussusception diagnosis (before, during, after surgery), and outcome (patient’s postsurgery condition and any complications).\nAssessment of risk of bias\nThe included studies’ methodological quality and risk of bias were rigorously assessed using the Joanna Briggs Institute (JBI) Critical Appraisal Checklist for case reports. This comprehensive appraisal allowed for the systematic evaluation of each case report’s quality, risk of bias, and contribution to the overall evidence base. Additionally, it is important to note that we classified publications with three or fewer cases as a case report, in accordance with established criteria in the literature.\nResults\nSearching published literature\nAfter performing a comprehensive search in our literature, the initial results revealed (n=976) potential articles. Only (n=799) were retrieved after removing (n=177) duplicate records. Two independent researchers screened titles and abstracts in which (n=638) were irrelevant and excluded, leaving us with a total of (n=161) records for the full-text screening. Among these, (n=38) records were not retrievable, (n=87) failed to fulfill the inclusion criteria and were excluded. Finally, a total of (n=36) articles were included in our review. Our selections were based on the PRISMA flow methodology Figure 1.\nThis review includes 36 Studies, consisting of 36 case reports that were published between 1949 and 2022 with (27) articles from the 21st century. Basic publication information and patient demographics are presented in Table 1. A total of 38 patients were included; all of them are female in sex, and their ages range from 29 to 63 years (41.58±8.12). These studies were conducted in numerous countries, including The United States (n=14), United Kingdom (n=4), Australia (n=2), Belgium (n=2), Germany (n=2), Japan (n=2), Republic of Korea (n=2), Turkey (n=2), Colombia (n=1), Ireland (n=1), Philippines (n=1), Portugal (n=1), Spain (n=1), and Taiwan (n=1).\nTable 1 -\nPatient’s characteristics and medical history\nAcute cholecystitis, symptomatic uterine fibroids, and endometriosis\nLaparoscopic cholecystectomy, and supracervical hysterectomy with bilateral salpingectomy\n5 days of intermittent throbbing abdominal pain, started peri-umbilically, migrating to the RLQ, which was associated with nausea and increased stool frequency\nFIT, fecal immunohistochemical test; LLQ, left lower quadrant; LSO, left Salpingo-Oophorectomy; RIF, right iliac fossa; RLQ, right lower quadrant; RSO, right Salpingo-Oophorectomy; RUQ, right upper quadrant.\nPatient’s presenting symptoms\nIn Table 1, the clinical characteristics of the patients included in this review are well-described. We classified the patients according to their presentations into three distinct categories. The first category deals with cases where patients are asymptomatic, accounting for 15.79% of the total cases. The second category includes most cases (60.53%) in which patients presented with abdominal pain and other gastrointestinal symptoms such as nausea, vomiting, diarrhea, constipation, loss of appetite, melena, hematochezia, and others; of these cases, 13.04% were related to menses. The description of pain varied among patients; for instance, the site of pain was reported as none specified, RUQ, RLQ, Epigastric, Periumbilical, and LLQ pain with prevalence rates of (30.77%), (3.85%), (50%), (7.69%), (3.85%), (3.85%), respectively. Moreover, the character of pain ranged from dull and throbbing to colicky and crampy pain. Finally, 23.68% of patients presented with gynecological symptoms (e.g. menorrhagia, dysmenorrhea, intermenstrual bleeding, dysfunctional uterine bleeding, and secondary infertility).\nColonoscopy and CT scan findings\nColonoscopy and CT scan findings proved to be helpful in diagnosing AI in these cases Table 2. Twenty-one patients underwent colonoscopy. Two of them had normal results22,37. Among the remaining patients, five exhibited a frank appearance of AI in the cecum17,27,35,42,49, while the other 13 cases showed various abnormalities. These 13 cases revealed either a multilobed or polypoid mass or a lesion originating from the appendiceal orifice or the cecum causing compression in the surrounding structures29,30,34,38,39,41,43,46,48,49,53,55,56. Additionally, one case revealed the presence of lesions inside the lumen of the appendix45.\nPhysical examination, laboratory tests, abdominal ultrasound, contrast-enhanced CT, and colonoscopy\nConfirmed the diagnosis of appendiceal intussusception\nMucosal enhancement in the cecal lumen lesion which was continuous with the cecal mucosa, which appeared axially as a ‘target’ and sagittally as a ‘sausage’\nA tubular structure lying medially to the cecum, which is either a swollen appendix or the terminal ileum. No associated inflammation, or fluid collections\nEnhancing mass with the surrounding mesenteric fat was shown to invaginate into the cecum at the level of the appendiceal opening. No appendix was identified\nRegarding CT scan findings, among the 38 patients, 21 had an ordinary CT scan for the abdomen and pelvis without contrast, while only one patient (according to Marc Paul Jose Lopez 2021’s case report29) had a CT scan with triple contrast enhancement. Four patients had normal CT scan results without significant findings17,38,43,49. On the other hand, the CT scan results of 18 patients varied. Eight of them failed to detect the appendix and revealed a tubular structure adjacent to or inside the cecum, suggesting AI28,30,33,42,45,47,51,56. Seven patients showed polypoid masses or filling defect lesions of varying sizes inside the cecum, suggesting neoplasms19,22,27,29,32,39,55. Two cases revealed space-occupying lesions in the ovaries34,50, and one patient had a dilated, fluid-filled appendix49 (second case).\nPreliminary diagnosis or differential diagnosis\nDiagnosing AI due to endometriosis based solely on the patient’s history and physical examination is challenging. This is due to the variety of chief complaints and presenting symptoms encountered. The time of diagnosis of most cases was reported to be after performing surgery, which was about (44.74%), while diagnosing before surgery accounts for (36.84%), and during surgery was (18.42%). Various differential diagnoses were identified in these case reports, all of them were related to inflammation of the appendix (Appendicitis) due to the similarity in the presentation between them or the presence of a mass in the colon, which was suspected to be: an abscess, tumor, lymphoma, mucocele or cecal polyp, and an inverted appendix. In addition to other unrelated differentials which depends on the patient’s specific clinical presentation, (e.g. cholelithiasis and ovarian cyst) Table 3.\nTable 3 -\nInterventions and pathology characteristics\nAuthor and year\nDiagnosis at presentation or differential diagnosis\nTotal hysterectomy and BSO, excision of the distal cecum by the ‘no-touch’ technic\nType II\nEndometrial-like glands and stroma were found on the left ovary and fallopian tube, serosa of the uterus, the excised part of the uterovesical fold, and in the hemorrhagic tip of the appendix\nThe polyps were removed During Colonoscopy. A partial cecectomy was carried-out maintaining the ileocecal valve together with the intussuscepted appendix\nType II\nExtensive adherent appendiceal endometriosis extending toward the mesoappendix\n12 months postsurgery, the patient is doing well and free of symptoms\nBroad-spectrum antibiotics, and laparoscopic ileocecectomy with primary anastomosis\nN/A\nThe colonic wall was extensively involved by Endometriosis, endosalpingiosis and endocervicosis\nThe patient improved after a period of short ileus and was discharged from the hospital on postsurgical day 7 from the 2nd surgery tolerating regular diet\nTotal abdominal hysterectomy, simple appendicectomy, and BSO\nN/A\nThe appendiceal wall had diffuse endometrial foci and with no signs of malignancy, multiple follicular cysts and germinal inclusion cysts were seen on both ovaries, and leiomyomas within the myometrium\nAmong a total of 38 cases, Type I intussusception was identified in 1 case, accounting for ~2.63% of the analyzed cases. Type II intussusception was observed in two cases, constituting ~5.26% of the cases. Type III intussusception was identified in two cases, representing another 5.26% of the total cases. Interestingly, no cases of Type IV intussusception were encountered in this study. This was suspected due to a lack of documentation of grades of intussusception in all the included studies and not solely to the inherent nature of the study population. The most prevalent grade of intussusception among the cases was Type V, which was observed in 19 cases, constituting a majority share of ~50%.\nType V intussusception was often associated with various clinical symptoms. One case reported an intermediate stage between Type I and Type V. Furthermore, a notable portion of the cases, totaling 13 cases (34.21%), remained unidentified or unreported regarding their specific grade of intussusception Table 3.\nInterventions\nThe study examined a wide spectrum of surgical interventions and procedures applied in response to intussusception cases. Most cases were managed by appendectomy, which was done in 13 cases, reflecting its efficacy in managing AIs. The ileocecectomy approach was employed in eight cases, while seven cases required partial cecectomy. Additionally, two cases underwent cecal cuff wedge resection, and one case involved the use of a ‘no-touch’ technique for distal cecal amputation.\nA distinctive surgical approach was employed in one instance, involving limited cecal resection with a linear stapler cutter. Cecectomy, involving the complete removal of the cecum, was conducted in three cases. A total of four patients underwent hysterectomy, and two of them also had bilateral salpingo-oophorectomy concurrently. Meanwhile, four cases underwent right hemicolectomy, with one case including a concomitant cholecystectomy. Notably, a laparoscopic right colectomy was performed due to the identification of a mass at the base of the appendix in one patient. Furthermore, another case reported the excision of a 4 cm endometrioma of the left ovary Table 3.\nOutcome\nIt was observed that 23 cases presented a favorable and uneventful recovery. These patients demonstrated significant improvement, with a successful resolution of their initial symptoms following surgery. One case reported a brief postoperative short ileus, which was followed by the patient’s successful recovery and subsequent discharge, resuming a regular diet. Another case, characterized by 3 days of recurring dyspnea attacks, also exhibited a generally positive recovery. In 13 cases, clear information about the postoperative status of the patients was not documented Table 3.\nQuality assessment\nBased on the JBI Critical Appraisal Checklist, our included studies had varying degrees of methodological quality, with most studies meeting the criteria related to patient demographics, current clinical conditions, and takeaway lessons. However, the presentation of patient history, diagnostic tests, interventions, and postintervention clinical condition had some discrepancies (Fig. 2, Supplementary: Table 1, Supplemental Digital Content 4, https://links.lww.com/IJSOPEN/A19).\nAI is one of the many complications caused by endometriosis. Our systematic review aimed to highlight and analyze the various clinical presentations, types, findings, and outcomes of endometriosis-induced AI, thereby providing valuable insights into this rare pathology. As far as we are aware, no prior systematic reviews have been conducted on this subject. Our review of case reports presented a diversity of clinical symptoms that patients may complain of, including lower abdominal pain, dysmenorrhea, gastrointestinal-complaints, and gynecological symptoms, all of which may be caused by various other abdominal and gynecological disorders leading to a diagnostic challenge. In some instances, the pain was closely related to the menstrual cycle, which suggests a hormonal factor in the pathogenesis of this condition. Patients might report a history of gynecological symptoms, with dysmenorrhea and menorrhagia being the most common, often associated with endometriosis. Diagnostic modalities played a vital role in confirming the diagnosis, especially colonoscopy and CT imaging, which often confirmed the presence of a mass at the site of the appendiceal orifice. The vague symptoms that patients present with, in addition to the presence of a mass, may mimic a wide range of differential diagnoses, with neoplasia and acute appendicitis being the most frequently encountered. The type of intussusception may influence the patient’s clinical presentation and management, with type V being the most common, with the appendix fully invaginating into the cecum. Interventions were usually surgical, ranging from basic appendectomy to more extensive procedures such as a right hemicolectomy, determined based on the severity and the presence of associated pathologies.\nMost operations went on without any complications with the resolution of the initial symptoms and an uneventful recovery postoperatively.\nEndometrial implants of the appendix are a rare entity that was initially described in 1860 by von Rokitansky8. Multiple theories have emerged in an attempt to explain the pathogenesis, the oldest principle being retrograde menstruation. This theory claims that during menstruation, shed endometrial cells travel backwards through the fallopian tubes and enter the pelvic cavity, resulting in the development of endometriosis57. However, retrograde menstruation is not so uncommon, occurring in about 76–90% of women with healthy fallopian tubes without necessarily experiencing endometriosis58.\nThis led to the emergence of other theories, including ① coelomic metaplasia theory, which suggests that specialized cells within the peritoneum undergo metaplasia resulting in endometriosis59, ② embryonic rest theory, which states that appropriate stimuli could induce formation of endometrial tissue originating from Mullerian origin60,61, ③ cellular immunity theory, which states that regurgitation of the endometrial cells triggers an inflammatory response, which may lead to defective immunity and prevention of menstrual debris elimination that promotes endometrial cells growth in ectopic sites62,63. Although many more theories are trying to explain the etiology, the pathophysiology of appendiceal and all extragenital endometriosis is still unknown64.\nSome pathological intrinsic conditions could act as a lead point resulting in AI, which includes carcinoid tumors, adenocarcinoma, Endometriosis, mucocele, polyps, lymphoid hyperplasia, and parasites22,65,66, with endometriosis being the most common cause in adults followed by mucocele22. This review focused on endometriosis as the causative agent of AI. Fink et al.67 have classified the symptoms caused by AI into four groups, in the first one, the symptoms are sudden and can mimic those of acute appendicitis; in the second group, there are intussusception symptoms with constipation or bloody diarrhea and signs of obstruction, the third group takes more of a chronic course with repeated and intermittent attacks of RLQ pain, with the fourth group being completely asymptomatic.\nDiagnosing AI is a challenging task. In fact, very few cases have been diagnosed preoperatively, while a large portion of cases are diagnosed shortly after or during surgery68. Radiological imaging may prove helpful in the preoperative diagnosis of AI. The intussuscepted appendix has been described as a ‘spiral shell’ or a ‘coiled spring’ when visualized with contrast enema or abdominal ultrasound69. On CT scan, the intussuscepted appendix may appear as a ‘target’ or as concentric rings with the cecum17.\nThe management of AI depends on the pathology, with surgery being the definitive procedure in endometriosis-induced cases, a variety of surgical procedures could be done, with appendectomy being the most common for adults, with a rate of 42%, and in children, with a rate of 71%, alternatively, ileocecectomy, right colectomy, and subtotal colectomy may be considered22. Misdiagnosis of AI can lead to ill-advised attempts at endoscopic excision or unnecessary surgery. There are cases of misdiagnosing AI as a polyp or a malignancy with the patient undergoing colonoscopic polypectomy resulting in perforation and subsequent peritonitis70. On the other hand, patients have undergone inappropriate surgeries, with malignancy being the diagnosis instead of AI44,71,72.\nTo the best of our knowledge, our systematic review is the first comprehensive systematic review studying all the published cases of AI in the literature from the forties of the last century. However, certain limitations have been recognized in this review. First, although our search process was extensive, the possibility of overlooking some relevant articles cannot be fully ruled out. Second, limited papers published on this topic only included case reports; therefore, caution should be exercised when interpreting the results due to the limited evidence available from case reports.\nAdditionally, some poor-quality reports have been included with some data missing, leading to some skewness in the dataset; thus, publication bias may be present. Third, diagnosing endometriosis based on histological tests alone without reporting the method of confirmation may affect the prevalence of appendiceal endometriosis since the diagnosis may differ between patients with endometrial epithelium, stroma, or both. Fourth, we limited our search to papers published in English; thus, some relevant papers were excluded.\nConclusion\nEven though AI due to endometriosis is a rare diagnosis, this systematic review summarized this pathology’s clinical presentation, management, and outcome. Female patients with recurrent abdominal pain and/or a cecal mass on colonoscopy should be investigated for AI as a differential diagnosis. Misdiagnosis could result in serious complications for the patients, leading to morbidity or mortality. This systematic review could prove useful for physicians in clinical practice.\nEthical approval\nNot required.\nConsent\nNot required.\nSources of funding\nNot required.\nAuthor contribution\nM.A.-B., A.Q.A.-S., and Z.S.: study concept, data collection, and writing the paper; A.Z., M.B.-Y.: writing the paper and data collection; R.M.O., D.N., and A.J.N.: writing the paper, editing, and leading.\nConflicts of interest disclosure\nThe authors declare no competing financial interests.\nResearch registration unique identifying number (UIN)\nName of the registry: Prospero.\nUnique identifying number or registration ID: CRD42023453354.\n1. Tomassetti C, et alInternational working group of AAGL E, ESHRE, WES. 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Lauwers GY, Prendergast NC, Wahl SJ, et al. Invagination of vermiform appendix. Dig Dis Sci 1993;38:565–568.\n61. Von Recklinghausen F. Adenomyomas and cystadenomas of the wall of the uterus and tube: their origin as remnants of the wolffian body. Wien Klin Wochenschr 1896;8:897–903.\n62. Kyama CM, Mihalyi A, Simsa P, et al. Role of cytokines in the endometrial-peritoneal cross-talk and development of endometriosis. Front Biosci-Elite 2009;1:444–454.\n63. Christodoulakos G, Augoulea A, Lambrinoudaki I, et al. Pathogenesis of endometriosis: the role of defective ‘immunosurveillance’. Eur J Contracept Reprod Health Care 2007;12:194–202.\n66. Takahashi M, Sawada T, Fukuda T, et al. Complete appendiceal intussusception induced by primary appendiceal adenocarcinoma in tubular adenoma: a case report. Jpn J Clin Oncol 2003;33:413–415.\n68. Ozuner G, Davidson P, Church J. Intussusception of the vermiform appendix: preoperative colonoscopic diagnosis of two cases and review of the literature. Int J Colorectal Dis 2000;15:185–187.\n69. Pumberger W, Hörmann M, Pomberger G, et al. Sonographic diagnosis of intussusception of the appendix vermiformis. J Clin Ultrasound 2000;28:492–496.\n70. Fazio RA, Wickremesinghe PC, Arsura EL, et al. Endoscopic removal of an intussuscepted appendix mimicking a polyp–an endoscopic hazard. Am J Gastroenterol (Springer Nature) 1982;77:556–558.","source_license":"CC0","license_restricted":false}