Survival outcomes used to validate version 9 of the American Joint Committee on Cancer staging system for appendiceal cancer.

The standard for cancer staging in the United States for all cancer sites, including primary carcinomas of the appendix, is the American Joint Committee on Cancer (AJCC) staging system. AJCC staging criteria undergo periodic revisions, led by a panel of site-specific experts, to maintain contemporary staging definitions through the evaluation of new evidence. Since its last revision, the AJCC has restructured its processes to include prospectively collected data because large data sets have become increasingly robust and available over time. Thus survival analyses using AJCC eighth edition staging criteria were used to inform stage group revisions in the version 9 AJCC staging system, including appendiceal cancer. Although the current AJCC staging definitions were maintained for appendiceal cancer, incorporating survival analysis into the version 9 staging system provided unique insight into the clinical challenges in staging rare malignancies. This article highlights the critical clinical components of the now published version 9 AJCC staging system for appendix cancer, which (1) justified the separation of three different histologies (non-mucinous, mucinous, signet-ring cell) in terms of prognostic variance, (2) demonstrated the clinical implications and challenges in staging heterogeneous and rare tumors, and (3) emphasized the influence of data limitations on survival analysis for low-grade appendiceal mucinous neoplasms.

Single-cell sequencing of the vermiform appendix during development identifies transcriptional relationships with appendicitis in preschool children.

BACKGROUND: The development of the human vermiform appendix at the cellular level, as well as its function, is not well understood. Appendicitis in preschool children, although uncommon, is associated with a high perforation rate and increased morbidity. METHODS: We performed single-cell RNA sequencing (scRNA-seq) on the human appendix during fetal and pediatric stages as well as preschool-age inflammatory appendices. Transcriptional features of each cell compartment were discussed in the developing appendix. Cellular interactions and differentiation trajectories were also investigated. We compared scRNA-seq profiles from preschool appendicitis to those of matched healthy controls to reveal disease-associated changes. Bulk transcriptomic data, immunohistochemistry, and real-time quantitative PCR were used to validate the findings. RESULTS: Our analysis identified 76 cell types in total and described the cellular atlas of the developing appendix. We discovered the potential role of the BMP signaling pathway in appendiceal epithelium development and identified HOXC8 and PITX2 as the specific regulons of appendix goblet cells. Higher pericyte coverage, endothelial angiogenesis, and goblet mucus scores together with lower epithelial and endothelial tight junction scores were found in the preschool appendix, which possibly contribute to the clinical features of preschool appendicitis. Preschool appendicitis scRNA-seq profiles revealed that the interleukin-17 signaling pathway may participate in the inflammation process. CONCLUSIONS: Our study provides new insights into the development of the appendix and deepens the understanding of appendicitis in preschool children.

Sufficient Regional Lymph Node Examination for Staging Adenocarcinoma of the Appendix.

BACKGROUND: The presence of lymph node (LN) metastasis is a known negative prognostic factor in appendix cancer (AC) patients. However, currently the minimum number of LNs required to adequately determine LN negativity is extrapolated from colorectal studies and data specific to AC is lacking. We aimed to define the lowest number of LNs required to adequately stage AC and assess its impact on oncologic outcomes. METHODS: Patients with stage II-III AC from the National Cancer Database (NCDB 2004-2019) undergoing surgical resection with complete information about LN examination were included. Multivariable logistic regression assessed the odds of LN positive (LNP) disease for different numbers of LNs examined. Multivariable Cox regressions were performed by LN status subgroups, adjusted by prognostic factors, including grade, histologic subtype, surgical approach, and documented adjuvant systemic chemotherapy. RESULTS: Overall, 3,602 patients were included, from which 1,026 (28.5%) were LNP. Harvesting ten LNs was the minimum number required without decreased odds of LNP compared with the reference category (≥ 20 LNs). Total LNs examined were < 10 in 466 (12.9%) patients. Median follow-up from diagnosis was 75.4 months. Failing to evaluate at least ten LNs was an independent negative prognostic factor for overall survival (adjusted hazard ratio 1.39, p < 0.01). CONCLUSIONS: In appendix adenocarcinoma, examining a minimum of ten LNs was necessary to minimize the risk of missing LNP disease and was associated with improved overall survival rates. To mitigate the risk of misclassification, an adequate number of regional LNs must be assessed to determine LN status.

New insights in the management of pseudomyxoma peritonei.

While a rare entity, peritoneal pseudomyxoma treatment evolves. Decision-making criteria improve with imaging development and exploratory laparoscopy. Surgery remains at the core of the therapeutic strategy whatever disease progression. Complete cytoreduction plus hyperthermic intraperitoneal chemotherapy (HIPEC) is standard of care. Iterative cytoreduction or debulking is sometimes justified. Intraperitoneal chemotherapy modalities change with early postoperative HIPEC or pressurized intraperitoneal aerosol chemotherapy. Systemic or local treatment such as new chemo/immuno-therapies or BromAc should improve outcomes. Expertise and multicentric cooperation are more than ever needed.

Beyond a vestigial organ: effects of the appendix on gut microbiome and colorectal cancer.

The role of appendectomy in the pathogenesis of colorectal cancer (CRC) is a recent topic of contention. Given that appendectomy remains one of the most commonly performed operations and a first-line management strategy of acute appendicitis, it is inherently crucial to elucidate the association between prior appendectomy and subsequent development of CRC, as there may be long-term health repercussions. In this review, we summarize the data behind the relationship of CRC in post-appendectomy patients, discuss the role of the microbiome in relation to appendectomy and CRC pathogenesis, and provide an appraisal of our current understanding of the function of the appendix. We seek to piece together the current landscape surrounding the microbiome and immunological changes in the colon post-appendectomy and suggest a direction for future research involving molecular, transcriptomic, and immunologic analysis to complement our current understanding of the alterations in gut microbiome.

Expression of Calretinin in the Cecal Muscularis Interna: Observation and Hypothetical Relevance to Appendicitis.

BACKGROUND: The unexpected observation of calretinin immunoreactivity in smooth muscle cells in the muscularis propria of the cecum led to a more detailed examination of calretinin expression and its possible relationship to propulsive contractile activity around the vermiform appendix. METHODS: Immunohistochemistry and RNA in situ hybridization were performed to analyze calretinin expression in intestinal samples from 33 patients at ages ranging from mid-gestation fetuses to adults, as well as in some potentially relevant animal models. Dual immunolabeling was done to compare calretinin localization with markers of smooth muscle and interstitial cells of Cajal. RESULTS: Calretinin expression was observed consistently in the innermost smooth muscle layers of the muscularis interna in the human cecum, appendiceal base, and proximal ascending colon, but not elsewhere in the intestinal tract. Calretinin-positive smooth muscle cells did not co-express markers located in adjacent interstitial cells of Cajal. Muscular calretinin immunoreactivity was not detected in the ceca of mice or macaques, species which lack appendices, nor in the rabbit cecum or appendix. CONCLUSIONS: Localized expression of calretinin in cecal smooth muscle cells may reduce the likelihood of retrograde, calcium-mediated propulsive contractions from the proximal colon and suppress pro-inflammatory fecal stasis in the appendix.

Occult appendix pathology in patients undergoing colorectal cancer resection and prophylactic appendectomy.

BACKGROUND: The risk-benefit balance of prophylactic appendectomy in patients undergoing left colorectal cancer resection is unclear. The aim of this report is to assess the proportion of histologically abnormal appendices in patients undergoing colorectal cancer resection in a unit where standard of care is appendectomy, with consent, when left-sided resection is performed. METHODS: A retrospective study on a prospectively collected database was conducted in a single tertiary-care center. Overall, 717 consecutive patients undergoing colorectal cancer resection between January 2015 and June 2021 were analyzed. The primary outcome was the proportion of histologically abnormal appendix specimens at prophylactic appendectomy. The secondary outcome was complications from prophylactic appendectomy. RESULTS: Overall, 576/717 (80%) patients had appendectomy at colorectal cancer surgery. In total, 234/576 (41%) had a right-/extended-right hemicolectomy or subtotal colectomy which incorporates appendectomy, and 342/576 (59%) had left-sided resection (left-hemicolectomy, anterior resection or abdominoperineal excision) with prophylactic appendectomy. At definitive histology, 534/576 (92.7%) had a normal appendix. The remaining 42/576 (7.3%) showed abnormal findings, including: 14/576 (2.4%) inflammatory appendix pathology, 2/576 (0.3%) endometriosis, 8/576 (1.4%) hyperplastic polyp, and 18/576 (3.1%) appendix tumors, which encompassed six low-grade appendiceal mucinous neoplasms (LAMNs), three carcinoids, and nine serrated polyps. In the 342 patients who had prophylactic appendectomy, 10 (2.9%) had a neoplasm (two LAMN, three carcinoids, and five serrated polyps). There were no complications attributable to appendectomy. CONCLUSION: Occult appendix pathology in patients undergoing colorectal cancer resection is uncommon when prophylactic appendectomy was performed. However, approximately 3% of patients had a synchronous appendix neoplasm.

Exploring the mysterious mucinous appendiceal neoplasm.

Mucinous neoplasms of the appendix comprise a group of diagnostically challenging lesions that have generated significant controversy and confusion throughout the years, given their potential for aggressive behavior despite very bland cytologic features. Numerous classification schemes have been proposed to characterize and stage these lesions, but confusion remains among pathologists, surgeons, and oncologists regarding diagnostic criteria, therapeutic implications, and overall prognosis. This review summaries the current recommended nomenclature, histologic characteristics of each entity, and helpful features to distinguish neoplasia from benign mimics.

Well-differentiated neuroendocrine tumors of the appendix: Diagnosis, differentials, and disease progression.

Well-differentiated neuroendocrine tumors are the most common neoplasm of the appendix. They are graded and staged using World Health Organization and American Joint Committee on Cancer criteria, respectively. They may be invisible grossly or form rounded yellow nodules, sometimes in the appendiceal tip. They show classic neuroendocrine tumor features microscopically, forming nests and cords of monotonous cells with salt-and-pepper chromatin and amphophilic cytoplasm. They are positive for neuroendocrine markers by immunohistochemistry, but their molecular characteristics are not well defined. pT-category staging relies primarily on tumor size, though higher-stage cases may involve the subserosa or mesoappendix. Few entities enter the differential diagnosis, but lesions such as goblet cell adenocarcinoma, poorly differentiated neuroendocrine carcinoma, and mixed neuroendocrine-non-neuroendocrine neoplasm may be considered. Appendiceal neuroendocrine tumors may metastasize to regional lymph nodes, but farther spread is rare. The most consistently proven risk factor for such spread is tumor size, though different studies have proposed different cutoffs. Other potential risk factors include lymphovascular invasion and margin positivity. Tumors smaller than 1 cm can be treated by appendectomy, while hemicolectomy is recommended for tumors larger than 2 cm. Proper treatment for cases measuring 1-2 cm remains a matter of debate.

A practical guide to serrated appendiceal lesions.

Several neoplastic and non-neoplastic proliferations of the appendix can show varying degrees of serrated epithelial architecture. Of these, diffuse mucosal hyperplasia is most common, followed in frequency by low-grade mucinous and serrated neoplasms. It is important to distinguish serrated appendiceal neoplasms from their potential mimics because these entities may be managed differently. Diffuse mucosal hyperplasia is a non-neoplastic change that usually develops in the setting of resolving appendicitis and requires no further therapy or surveillance, and serrated neoplasms confined to the mucosa are adequately treated by appendectomy alone. On the other hand, low-grade appendiceal mucinous neoplasms may require surveillance, and those with extra-appendiceal spread differ from adenocarcinomas arising from serrated neoplasms with respect to both treatment and prognosis. Low-grade mucinous neoplasms in the peritoneum are frequently amenable to peritoneum-directed therapies alone, while adenocarcinomas derived from serrated neoplasms often spread to both regional lymph nodes and the peritoneum, potentially requiring right colectomy and systemic chemotherapy. The purpose of this review is to summarize the literature regarding the clinical and pathologic features of appendiceal lesions that show epithelial serration and provide the reader with helpful tips to distinguish serrated neoplasms from their mimics.

Appendiceal adenocarcinoma: Current concepts & challenges.

Appendiceal adenocarcinoma (ApAC) is a rare malignancy, comprising less than 1 % of all gastrointestinal tumors. The current World Health Organization classifies ApAC as mucinous or nonmucinous. Mucinous ApAC are composed of pools of mucin lined by cells with low- and high-grade cytology and areas of infiltrative invasion. Nonmucinous ApAC histologically resemble conventional colorectal adenocarcinomas and have a worse prognosis than their mucinous counterpart. Unfortunately, the nomenclature and histologic classification of ApAC, specifically the mucinous subtype, has changed several times throughout the years, contributing to diagnostic confusion for pathologists. The treatment for mucinous ApAC differs from that of other appendiceal mucinous neoplasms, thus accurate diagnosis is key to patient management and outcome. This review discusses the current classification and staging of ApAC with a particular emphasis on the mucinous subtype and peritoneal disease, as these areas are the most challenging for practicing surgical pathologists.

Development and assessment of a loop ligation simulator for laparoscopic appendectomy.

OBJECTIVE: Loop ligation of the appendix is a challenging surgical skill and well suited to be trained in a simulator. We aimed to develop an affordable and easy-to-build simulator and test its training effect. DESIGN AND PARTICIPANTS: Different materials were tested, and the best training modality was identified by researching the literature. The developed simulator training was tested on 20 surgical novices. RESULTS: A video was produced including an instruction on how to build the simulator and a step-by-step tuition on how to ligate the appendix. The Peyton approach was utilized to guide learners. Training with the simulator leads to reliable skill acquisition. All participants improved significantly in completing the task successfully during the structured learning. CONCLUSION: We succeeded in developing a simulator for loop ligation of the appendix during laparoscopic appendectomy. Participants significantly improve in handling the loops. The transferability of the skill learned during simulation to the operating room will be subject of a follow-up study.

Finding Waldo: Sonographic systematic approach to localize the appendix in children.

OBJECTIVES: To describe a systematic scanning approach using anatomical landmarks followed by an assessment of radiology trainees' ability to identify the normal appendix in healthy children. METHODS: Uncontrolled pre and post study assessing radiology residents' sonographic skills in detecting the normal appendix in healthy children. Initial questionnaire for the trainees' demographics, perceptions and experiences in detecting the appendix with ultrasound in children followed by a precourse test on healthy volunteers. Hands-on training was conducted by describing a systematic sonographic approach to identify the appendix using anatomical landmarks, and then a postcourse test was carried out. The primary outcome was unprompted ability to identify the appendix. Subjective self-scoring of confidence was also recorded. RESULTS: A three-hour hands-on workshop was conducted. Sixteen radiology trainees participated and were randomly distributed to four stations, each with different ultrasound machines and healthy volunteers. Fifteen had a precourse assessment, and 12 completed the postcourse assessment. Before the course, 3/15 (20%) identified the appendix, while 10/12 (83%) identified the appendix afterward. After the course, participants perceived finding the appendix easier than before. There was no statistically significant difference in the participants' perceived confidence in detecting the appendix. CONCLUSIONS: With the described scanning technique, most of the participants were able to identify the normal appendix after receiving short hands-on training. This highlights the importance of targeted training of radiology trainees and nonradiologists.

Comparison of ultrasound assisted and intraoperative diameter measurement in acute appendicitis.

Detailed anamnesis and systematic physical examination are often relevant in the diagnostic routine of acute appendicitis. However, physicians are increasingly motivated to obtain radiological approval. Inherent limitations due to radiologists' experience and the presenting anatomy may result in contradictory outcomes between the described and intraoperative findings. In this study, a comparison of anthropometric measurements of the appendix vermiformis obtained by radiologists and surgeons in children with acute appendicitis is discussed. The external appendiceal diameter in 53 patients who underwent surgery between April 2022 and January 2024 was measured at three different anatomical locations during preoperative ultrasound and intraoperatively with the help of Vernier calipers. Appendectomy materials were classified into negative, acute, and complicated appendicitis subgroups on the basis of histopathological results. The widest median diameter, expressed in millimeters, was analyzed statistically in terms of diagnostic accuracy. Histopathological analysis revealed negative appendectomy in 15.1%, acute appendicitis in 66%, and complicated appendicitis in 18.8% of the patients. The median age at presentation was 11.4 years (4-17.3 years), and 45.3% of the patients were females. The average median appendiceal diameter was 7.8 ± 2.4 mm according to the caliper and 7.9 ± 2.7 mm according to ultrasound (p > 0.05). The evaluation by the caliper revealed a much smaller diameter in 19 patients than did ultrasound. The appendiceal diameter of eight documented negative appendectomy samples was 7 mm or greater. US failed to identify the presence of an appendicolith in 11 cases (20.8%), all of which were disclosed during histopathological evaluation. It is possible to conclude that ultrasound and intraoperative anthropometric measurements correlate according to our study. Diagnostic accuracy, however, which is individually based on ultrasound appendix diameter values greater than 6 mm, is controversial. It is clear that comparison and further reinterpretation of such anthropometric measurements in light of histopathological consequences may help diminish the frequency of negative and perforated appendectomies.

Is LigaSure Alone Sufficient for the Closure of the Appendix Stump?

PURPOSES: Closure of the appendix stump is necessary for laparoscopic appendectomy. Problems that occur during the appendix stump closure can cause severe morbidity. Several methods of stump closure have been described. This study aimed to investigate the adequacy of LigaSure alone in closing the appendix stump. METHODS: Patients who were operated on with the diagnosis of acute appendicitis between October 2021 and January 2022 were evaluated retrospectively. The patients were divided into two groups according to the closure technique of the appendix stump hemoclip(group I) and LigaSure only(group II). In addition, demographic data (age, gender), body mass index (BMI), presence of comorbid disease, perioperative appendicitis classification, operation time, postoperative hospital stay, radiological and pathological appendix size of the patients included in the study were recorded. Clavien Dindo was used for postoperative complication assessment. RESULT: The study included 77 patients. 48(62.3%) of the patients were in group I, and 29(37.7%) were in group II. There was no statistical difference between the groups regarding age, gender distribution, BMI, presence of comorbid disease (P > .05). The operation time of group I was longer than group II (P < .001). There was no difference between the groups in terms of both radiological and pathological appendix size. There was no statistical difference between the groups regarding postoperative complications and severity of complications (P = .76, P = .99, respectively). CONCLUSION: Appendiceal stump closure can be performed with Ligasure, but it should be noted that this procedure can be performed on selected patients, as in the study group, not on all patients.

Histomorphometric and developmental analysis of human fetal caecum and appendix with its embryological significance.

PURPOSE: The variable positions of the appendix can mislead surgeons and physicians to a wrong diagnosis. When appendicitis happens in subhepatic caecum, it can be misdiagnosed and can lead to severe complications during surgical procedures. Therefore, this study aimed to understand the histomorphometric development of the appendix and caecum and to identify when lymphoid follicles appear in the appendix during fetal life. METHODS: The study was conducted on a total of 50 fetuses. The caecum and appendix were carefully dissected. Their position and various measurements were observed. Afterwards, the appendix was taken out for histological processing. All three layers, mucosa, submucosa, and muscularis externa were measured using Image Analyzer Software Image Pro Premiere 9.1, and the appearance of lymphoid follicles was also examined. Results were analyzed using SPSS statistical software. RESULTS: During the 1st, 2nd, and 3rd trimesters the most common caecum type was type 1: as a lengthy tube, type 3: The lateral wall expanded more, thus it has an asymmetric saccule, and type 4: adult-like caecum. The caecum was mostly situated in the right lumbar region in the 2nd and 3rd trimesters. In the 1st trimester, it was subhepatic in position. The most common position of the appendix was 11 o'clock in 1st and 3rd trimesters. 2nd trimester's most common position of the appendix was 12 o'clock. The thickness of the mucosa, submucosa, and the muscularis externa increases as the trimester increases. The lymphoid follicles have appeared during the 2nd trimester. CONCLUSION: The knowledge from this study will be useful in the diagnosis and treatment of malformations, pathology, and anomalies of the caecum and appendix due to congenital causes.

[Appendiceal goblet cell adenocarcinoma: Has the controversy come to an end?] / Adénocarcinome à cellules caliciformes appendiculaire : la fin de la controverse ?

In 2019, the 5th edition of the WHO classification of digestive tumours has retained the terminology "goblet cell adenocarcinoma" (GCA) to designate a tumour whose amphicrine nature owed it more than ten denominations since its initial description among which the most tenacious "goblet cell carcinoid" is no longer recommended today. This rare tumour represents 15-19% of appendicular tumours. Its incidence is rising. The positive diagnosis is based on morphological examination and mandatory identification of a low-grade component of glands comprising goblet cells stained by PAS and Alcian blue. The appendix must be entirely examined. Global tumour grade (low, intermediate, high) is based on the proportions of low-grade and high-grade components. This tumour's immunohistochemical profile is particular because of expression of CK20 and often CK7 as well as neuroendocrine markers. It is often an incidental finding on a surgical specimen, among individuals aged 50 or more years, presenting with a locally advanced stage with vascular and perineural invasion. Lymph node metastases are present in a third of cases. Non-specific mutations of ARID1A and genes of the Wnt pathway may be identified. GCA is not associated with microsatellite instability or Lynch syndrome. Its prognosis is intermediate. Surgery is the reference therapy based on the stage. The main differential diagnoses are colorectal adenocarcinoma NOS, mucinous adenocarcinoma and signet ring cell adenocarcinoma. Patients are referred to the RENAPE expert network.

Conspiring simplification strategies of [Obstruent+Liquid] clusters in a case study of child Greek: emergence of the marked.

This paper addresses the idiosyncratic cluster simplification patterns observed in a child with disordered phonological development, who is acquiring Greek. The child has mastered word-internal and word-final codas and clusters of reversed sonority. However, the child does not realise the target well-formed tautosyllabic [Obstruent+Liquid] clusters with rising sonority. The child's system requires a single onset with maximum sonority dispersion between the onset and the syllable nucleus. As a result, cluster simplification occurs, via reduction to the less sonorous Obstruent - the most prevalent reduction pattern cross-linguistically. However, at the same time, the grammar requires faithful realisation of the target segment number. This requirement is fulfiled through two distinct conspiring metathesis patterns, distributed complementarily, resulting in the realisation of marked structures. The patterns depend on the position of the cluster within the target word. In word internal position, a compensatory metathesis of the Liquid takes place in the preceding syllable coda. In word initial position, the Manner of Articulation of the metathesised Liquid is delinked, while its Coronal Place of Articulation is faithfully preserved, and is realised by default as a Coronal Sibilant [s]. The latter Sibilant is attached as an appendix to the syllable node at the word left-edge. We argue that, in the grammar of this child, there is a-synchronisation between the development of the prosodic word layer and the development of syllable layer. Specifically, a-synchronisation is evident in the development of the (branching) onset syllabic subconstituent.

A case of death after the severing three appendiceal arteries during appendectomy.

INTRODUCTION: Acute appendicitis is one of the most common acute abdominal issues requiring surgery and is usually treated by appendectomy. During the process of removing the appendix, the appendiceal artery is severed. In most individuals, the appendix is supplied by only one appendiceal artery. CASE PRESENTATION: A 50-year-old man underwent appendectomy. During the surgical procedure, the appendix artery and two accessory arteries of the appendix were severed, leading to massive hemorrhaging in the abdominal cavity, which ultimately resulted in the patient's unfortunate demise. CONCLUSION: Through this case, we hope that surgeons can learn more about the anatomy of the appendiceal artery and understand the possibility of accessory arteries to the appendix. During surgery, the blood vessels supplying the appendix should be carefully explored, and the "one-size-fits-all approach" should be avoided. Moreover, attention should be given to complications after appendectomy, and timely symptomatic treatment should be provided. Key points 1. Rare typing: The case of death due to improper handling of the accessory appendicular artery during appendectomy in patients with three appendiceal arteries is currently unreported. 2. Detailed anatomical knowledge: Surgeons performing an appendectomy need to make a detailed exploration of the blood vessel supply of the appendix to avoid ignoring anatomically different blood vessels. 3. Avoid a one-size-fits-all approach: In the surgical process, a "one-size-fits-all" approach should be avoided, that is, the same surgical approach should not be used in all cases, but should be adjusted according to the anatomical characteristics of the individual. 4. Observation of postoperative bleeding: In the perioperative period, peritoneal drainage should be closely observed. If a large amount of bloody fluid is found, timely surgical treatment should be carried out. 5. Attention to complications: Surgeons should pay.

Gastrointestinal syndromes preceding a diagnosis of Parkinson's disease: testing Braak's hypothesis using a nationwide database for comparison with Alzheimer's disease and cerebrovascular diseases.

OBJECTIVE: Braak's hypothesis states that Parkinson's disease (PD) originates in the gastrointestinal (GI) tract, and similar associations have been established for Alzheimer's disease (AD) and cerebrovascular diseases (CVD). We aimed to determine the incidence of GI syndromes and interventions preceding PD compared with negative controls (NCs), AD and CVD. DESIGN: We performed a combined case-control and cohort study using TriNetX, a US based nationwide medical record network. Firstly, we compared subjects with new onset idiopathic PD with matched NCs and patients with contemporary diagnoses of AD and CVD, to investigate preceding GI syndromes, appendectomy and vagotomy. Secondly, we compared cohorts with these exposures to matched NCs for the development of PD, AD and CVD within 5 years. RESULTS: We identified 24 624 PD patients in the case-control analysis and matched 18 cohorts with each exposure to their NCs. Gastroparesis, dysphagia, irritable bowel syndrome (IBS) without diarrhoea and constipation showed specific associations with PD (vs NCs, AD and CVD) in both the case-control (odds ratios (ORs) vs NCs 4.64, 3.58, 3.53 and 3.32, respectively, all p<0.0001) and cohort analyses (relative risks (RRs) vs NCs 2.43, 2.27, 1.17 and 2.38, respectively, all p<0.05). While functional dyspepsia, IBS with diarrhoea, diarrhoea and faecal incontinence were not PD specific, IBS with constipation and intestinal pseudo-obstruction showed PD specificity in the case-control (OR 4.11) and cohort analysis (RR 1.84), respectively. Appendectomy decreased the risk of PD in the cohort analysis (RR 0.48). Neither inflammatory bowel disease nor vagotomy were associated with PD. CONCLUSION: Dysphagia, gastroparesis, IBS without diarrhoea and constipation might specifically predict Parkinson's disease.