Global research landscape of Peutz-Jeghers syndrome and successful endoscopic management of intestinal intussusception in patients with recurrent laparotomies

Abstract

BACKGROUND

Peutz-Jeghers syndrome (PJS) has brought significant physical, psychological and economic burdens on the patients and their families due to its early onset, diagnostic and therapeutic challenges and increased recurrence risk.

AIM

To explore the current research status and emerging hotspots of PJS.

METHODS

Studies on PJS published during 1994-2023 were gathered based on Web of Science Core Collection. Additionally, a case of PJS-induced intestinal intussusception, successfully treated with endoscopic methods despite three laparotomies, was highlighted. Comprehensive bibliometric and visual analysis were conducted with VOSviewer, R and CiteSpace.

RESULTS

Altogether 1760 studies were identified, indicating a steady increase in the publication number. The United States had the highest influence, whereas the University of Helsinki emerged as the leading institution, and Aaltonen LA from the University of Helsinki was the most prolific author. Cancer Research, Oncogene and Endoscopy were the top three journals based on H-index. Keyword burst direction analysis revealed that "cancer risk", "management", "surveillance" and "familial pancreatic cancer" were the potential hotspots for investigation. Additionally, "early detection", "capsule endoscopy", "clinical management", "double-balloon endoscopy", "familial pancreatic cancer" and "molecular genetic basis" were identified as the key clusters of co-cited references. Endoscopic polypectomy remained effective on resolving intestinal intussusception in patients who underwent three previous laparotomies.

CONCLUSION

In the last three decades, global publications related to PJS show a steadily increasing trend in number. Endoscopic management is currently a research hotspot.

Key Words: Peutz-Jeghers syndrome; Endoscopy; Management; Cancer; Microbiota; Bibliometric

Core Tip: This study investigated the current situation of Peutz-Jeghers syndrome and identified "cancer risk" and "treatment management" as the research focuses. In addition, it also emphasized the significant therapeutic effect of endoscopic polypectomy, even in cases with intussusception after the first three abdominal surgeries. These findings provide valuable insights for diagnosing and treating such patients by clinical doctors, thereby improving patient life quality and prognosis.

INTRODUCTION

Peutz-Jeghers syndrome (PJS), a rare autosomal dominant genetic disease, has the primary features of hamartomatous polyp generation within gastrointestinal tract (GI)[1]. This syndrome first came to light in 1921 through the work by Peutz[2], and was later elaborated by JEGHERS et al[3] in 1949. The characteristic hallmark of PJS includes the manifestation of distinctive mucocutaneous pigmentation, predominantly affecting areas such as the lips, oral cavity and fingertips, alongside the widespread polyp proliferation in GI tract, except for esophagus[4].

It is predicted that PJS affects 1 in 50000-200000 people, underscoring its rarity. The disease typically results from STK11 gene mutations, following the autosomal dominant heredity pattern[5]. PJS patients probably have occult GI hemorrhage due to small intestinal hamartomatous polyps, while larger polyps may result in bowel obstruction and intussusception[6]. In addition, PJS patients are associated with a significantly higher risk of GI malignancies, as well as cancers in organs like the lungs, pancreas, breasts, ovaries and testes, than the general population[7,8]. Despite significant progress in understanding the nature of PJS, the high incidence of cancer and GI complications of the syndrome severely limit the quality of life of the affected people. These individuals often face significant physical discomfort, emotional turmoil and financial stress[9]. Early research on PJS mainly focused on the pathogenesis and clinical manifestations of the disease, while current research more focuses on management, with endoscopic polypectomy being the preferred option. This requires an ongoing commitment from researchers and clinicians to discover effective management strategies for PJS and to identify potential therapeutic targets. In fact, a number of novel therapeutic targets including gut microbiota and the corresponding metabolites are considered as candidate therapeutic targets in the future.

The primary treatment modality for PJS is surgical intervention. Currently, the treatment involves routine surveillance with enteroscopy to detect and remove larger polyps[10,11]. In recent years, guidelines on PJS have been published, but they are largely based on expert consensus and a limited number of long-term follow-up cohorts. These guidelines provide a valuable resource[12,13]. However, case studies from a single institution, despite their expertise, do not provide the critical mass of patients who required effective care assessment. This highlights the challenge involved in getting more knowledge about rare diseases. To this end, we focused on conducting the comprehensive bibliometric analysis for capturing the latest advances in PJS research, predicting subsequent research directions and providing screening and management directions.

In this study, all PJS studies published between 1994 and 2023 were included. The analysis took into account several factors, including number of publications, authorship, geographical distribution, references and keywords. Through this methodology, we aimed to holistically understand research landscape in the area. Additionally, this study presented a case of intestinal intussusception caused by PJS, which was successfully managed with endoscopic techniques, despite the fact that the patient underwent three laparotomies. Our objective was to produce a structured statistical report, provide a comprehensive overview to help researchers make informed decisions about PJS, and contribute to the advancement in the realm.

MATERIALS AND METHODS

Data source and search strategy

The Web of Science Core Collection (WOSCC), which is extensively identified as an appropriate database for conducting bibliometric analysis, was comprehensively searched to identify articles focusing on PJS from 1994 to 2023[14] using search terms below, TS = (Peutz syndrome OR Peutz' syndrome OR Peutz's syndrome OR Peutz-Jeghers syndrome OR Peutz-Jeghers syndrome OR Peutz-Touraine-Jeghers syndrome OR the syndrome of Peutz and Jeghers OR PJS). Only English studies (including articles or reviews) published from January 1^st, 1994 to December 31^st, 2023 were enrolled. The retrieved literature was exported as "complete records with cited references" and saved as a text file for further analysis. Studies were searched and data were obtained in a single day for minimizing the bias resulting from database update. To ensure relevance to the study's main topic, two researchers (Sun Q and Wang XY) were responsible for independently screening and recording studies through title- and abstract-reviewing. Figure 1 displays exclusion criteria and detailed screening flowchart.

Figure 1 The Flowchart diagram showing search strategy.

Bibliometric analysis

The collected data for analysis encompassed the publication year, geographical distribution, affiliation, author, keywords and citation. Subsequently, we uploaded the texts in analysis software. Microsoft Office Excel 2021 software (Microsoft, Redmond, WA, United States) was adopted to conduct descriptive analyses on growth trends, annual outputs, keywords and journals for documents, and the creation of relevant tables. To assess the relative significance of journals within a specific field, the impact factors of the retrieved journals were obtained from the Journal Citation Report. Furthermore, quality and impact of the research documents were evaluated using the H-index, which is calculated based on the number of citations received in other publications[15].

We utilized VOSviewer software (version 1.6.19) for constructing the country, institution, author and keyword bibliometric visualization networks. In the VOSviewer map, nodes represent items such as countries, institutions, journals, or authors, with node size and color indicating item count and classification, separately. The thickness of the lines connecting nodes signifies the collaboration and co-citation level among items[16]. Additionally, CiteSpace software (version 6.1.6 R2) was employed to generate a visual map for analyzing the annual publication number, the overall publication number and the centrality of countries, institutions, authors and frequently occurring keywords over time. Furthermore, CiteSpace can identify references and keywords with greatest citation bursts, and visualize a network of co-citation clusters comprising the co-cited references. Noteworthily, diverse nodes in CiteSpace software visualization network stand for distinct entities under analysis, with a larger node indicating a higher frequency[17].

Study population

We introduced a case of PJS patient who previously underwent three laparotomies and subsequently received double-balloon enteroscopy treatment at the Air Force Medical Center in Beijing, China. The standard procedure involved the use of a double balloon-assisted enteroscopy (Fujifilm Inc., Tokyo, Japan). The patient successfully underwent piecemeal polypectomy. Before surgery, the patient offered informed consent. Preoperative laboratory tests and computed tomography (CT) imaging were performed. The study was conducted following the Declaration of Helsinki and was approved by Ethics Committee of Air Force Medical Center (2023-77-PJ01).

Hematoxylin and eosin staining

Hematoxylin and eosin staining was performed according to conventional methods[18]. Briefly, after dewaxing and rehydration, 3-μm sections were stained with hematoxylin for 5 minutes. Subsequently, the sections were immersed five times with 1% acidified ethanol and rinsed with distilled water. After 3-minute staining with eosin dye, the sections were dehydrated with gradient alcohol and transparentized with xylene. Finally, observation and photographing of the sections were conducted using an Pannoramic MIDI II automatic digital slide scanner (3DHISTECH Ltd., Hungary).

RESULTS

Overview of publications on PJS

A comprehensive search in the WOSCC identified 1760 publications related to PJS. These publications were carefully selected based on pre-defined inclusion criteria. Collectively, altogether 85500 citations were obtained, and the mean citing frequency was 48.58 times for each study, underscoring the significant influence and impact of the research in this field. Furthermore, the H-index, a metric that measures scientific output and impact, was calculated to be 56.31 for all PJS-related publications, indicating the high level of recognition and scholarly contribution of the research in this area.

Years and countries of publications on PJS

PJS demonstrated a noticeable increase in research outputs and citations from 1994 to 2023 (Figure 2A). Before 2010, the publication number per year steadily increased, starting from 13 in 1994 and reaching 82 in 2010. Subsequently, it consistently maintained a relatively high level, with an average of 70.31 publications per year over the past thirteen years. Similarly, the annual citation number experienced substantial growth, increasing from 4 in 1994 to 4228 in 2023, with a peak of 5590 citations in 2022. Noteworthily, our analysis was conducted in December 2023, and some articles from that year were not included into Web of Science database at that time. This substantial volume of publications indicated that despite being a rare disease, PJS continued to garner significant attention from researchers.

Figure 2 The years and countries in which the articles on Peutz-Jeghers syndrome were published from 1994-2023. A: Annual publication and citation numbers; B: Geographical distribution of related countries; C: Cooperation of countries contributing to publications; D: Growth trends of the top 10 countries.

In terms of geographical distribution, the United States was the major contributor to research outputs, followed by China, as depicted in Figure 2B. Table 1 displays those 10 most significant contributing countries. Notably, the United States accounted for 37.9% of all publications. Centrality score, which serves as the measure to estimate the network node significance, revealed that the United States (0.37) held the highest position within the network, indicating its stronger cooperation and influence. However, the visualization map displayed a low density of national collaborations, suggesting that the research countries operated relatively independently and could benefit from deeper cooperation (Figure 2C). Additionally, citation frequency and total link strength, the key measures to evaluate paper quality, were also examined[19]. The published literature from the United States received the highest citation frequency of 49668, securing the top position among all countries/regions. Furthermore, the United States achieved the highest total link strength value of 338. The United Kingdom ranked as the second most-cited country with 16826 citations and a total link strength of 236, although it only published 186 articles, placing it third with regard to publication number (Table 1). Notably, since 2010, China made a particularly noteworthy contribution to the research. In 2023, it surpassed the United States in publication number, possibly due to advancements in medical expertise and endoscopic technology, as well as the improved hardware capabilities, leading to a deeper understanding of PJS (Figure 2D).

Table 1 The top 10 published countries in Peutz-Jeghers syndrome field from 1994 to 2023.

Rank	Country	Counts	Centrality	Citations	Total link strength
1	United States	667	0.37	49668	338
2	China	227	0.02	3153	56
3	United Kingdom	186	0.16	16826	236
4	Japan	164	0.07	7407	91
5	Italy	103	0.05	4967	119
6	Netherlands	96	0.02	10400	153
7	Germany	82	0.07	7011	139
8	Canada	82	0.03	5443	90
9	France	66	0.10	5835	134
10	Finland	65	0.04	8199	119

Contributions of institutions and authors

Figure 3A illustrates the PJS-centered institutional collaboration network. The University of Helsinki was most prolific (57) of those 10 institutions, followed by Harvard University (56) and Johns Hopkins University (40) (Table 2). Five of the 10 most prolific institutions were located in the United States, while two were in the United Kingdom. The remaining three were the University of Helsinki in Finland, the University of Amsterdam in the Netherlands and the Dana Farber Cancer Institute in New Zealand.

Figure 3 Joint mapping of contributions to publications on Peutz-Jeghers syndrome from 1994-2023. A: Institutions; B: Authors.

Table 2 The top 10 most published institutions regarding Peutz-Jeghers syndrome.

Rank	Article counts	Centrality	Institutions	Country
1	57	0.16	University of Helsinki	Finland
2	56	0.06	Harvard University	United States
3	40	0.05	Johns Hopkins University	United States
4	37	0.06	St Mark's Hospital	United Kingdom
5	33	0.03	University of Amsterdam	Netherlands
6	32	0.05	The Institute Cancer Research	United Kingdom
7	30	0.02	Mayo Clin	United States
8	29	0.02	Dana Farber Cancer Institute	New Zealand
9	27	0.01	Massachusetts General Hospital	United States
10	26	0.03	University of Pennsylvania	United States

VOSviewer was used to visualize authors (Figure 3B), which revealed altogether 312 authors published articles on PJS during 1994-2023, with 112 authors having more than five publications. Notably, Giardiello FM exhibited a more cohesive collaborative capability. Table 3 displayed the 10 most prolific researchers. Authors published more studies included Aaltonen LA from the University of Helsinki (25 articles, 2925 citations) and Stratakis CA from the Harvard University (25 articles, 1189 citations), followed by Giardiello FM from the Johns Hopkins University (23 articles, 2358 citations). We utilized H-index for assessing the researchers’ academic output quality, with Aaltonen LA achieving the highest H-index of 20. More detailed values are presented in Table 3.

Table 3 The top 10 published authors in this area.

Author	Articles counts	Centrality	Total citations	Total strength	H-index
Aaltonen LA	25	0.02	2925	113	20
Stratakis CA	25	0.01	1189	25	18
Giardiello FM	23	0.35	2358	103	18
Tomlinson I	18	0.02	2130	65	17
Alessi DR	16	0.01	2670	59	16
Westerman AM	15	0.06	908	86	13
Offerhaus G	15	0.03	774	85	18
Tomlinson IPM	14	0.01	816	74	13
Van leerdam ME	14	0.17	487	60	11
Mccluggage WG	12	0.2	410	19	10

Journals publishing studies

From 1994 to 2023, a total of 262 journals contributed to the field of PJS (Figure 4A). Table 4 provides an overview of the 10 most active journals in this area, with the majority being located in the Figure 3A illustrates the PJS-centered institutional collaboration network. The University of Helsinki was most prolific (57) of those 10 institutions, followed by Harvard University (56) and Johns Hopkins University (40) (Table 2). Of these, five belonged to Q1 and three belonged to Q2. In terms of publication number, the top 3 journals were Familial Cancer (IF = 2.2), World Journal of Gastroenterology (IF = 4.3) and Oncogene (IF = 8.0). As for H-index, the top 3 journals were Cancer Research (IF = 11.2; mean, 97.29 citations for each study), Oncogene (IF = 8.0; mean, 81.8 citations for each study) and Endoscopy (IF = 9.3; mean, 95.86 citations for each study). We also quantified publication numbers in various journals per year and detected the consistently increasing publication number in the Journal of Pediatric Gastroenterology and Nutrition over the past 10 years. More detailed data are presented in Figure 4B.

Figure 4 Journals publishing papers on Peutz-Jeghers syndrome from 1994-2023. A: Cooperation of journals contributing to publications; B: Publications in different journals annually.

Table 4 The top 10 most active journals in the area.

Rank	Journal	Articles counts	Country	Journal citation report (2022)	Impact factor (2022)	Total cites	H-index
1	Familial Cancer	30	Netherlands	Q3	2.2	687	15
2	World Journal of Gastroenterology	30	United States	Q2	4.3	1418	15
3	Oncogene	25	England	Q1	8.0	2045	23
4	Cancer Research	24	United States	Q1	11.2	2335	24
5	Gastrointestinal Endoscopy	24	United States	Q1	7.7	1283	15
6	Endoscopy	22	Germany	Q1	9.3	2109	18
7	Best Practice & Research Clinical Gastroenterology	19	England	Q3	3.2	367	11
8	American Journal of Surgical Pathology	19	United States	Q1	5.6	1250	16
9	Journal of Medical Genetics	17	England	Q2	4.0	1692	16
10	Journal of Pediatric Gastroenterology and Nutrition	17	United States	Q2	2.9	388	10

Keywords co-occurrence and keywords bursts

VOSviewer software was utilized for title and keyword analyses from 1760 studies. The distribution of the top 18 keywords out of all the 632 keywords over time is depicted in Figure 5A. Keywords with the highest occurrence frequency included "PJS" (685), "cancer" (307), "gene" (163), "mutations" (161), "LKB1" (152) and "familial adenomatous polyposis" (149), indicating that initial studies on PJS mainly focused on the pathogenesis and clinical manifestations of the disease. Subsequently, we identified the top 25 keyword bursts from 1994 to 2023 (Figure 5B). The timeline was represented by a straight line including red and/or blue, with the red section indicating the burst period and its length representing the burst starting, ending years, and duration. During this period, "management" (18.41) was the top keyword burst, followed by "Lynch syndrome" (17.28), "increased risk" (14.11), "locus" (10.97), "somatic mutation" (10.9), "tumor suppressor gene" (10.72) and "recommendation" (10.15). The analysis of keyword burst direction indicated that "cancer risk" (2016-2023), "management" (2017-2023), "surveillance" (2017-2023) and "familial pancreatic cancer" (2017-2023) were the potential hotspots for investigation.

Figure 5 Co-occurrence analysis on global studies regarding Peutz-Jeghers syndrome. A: Distribution of keywords over time; B: Keywords of greatest citation bursts.

Co-cited references and research hotspots

In this study, we analyzed co-citation correlation among 85500 cited references contained in 1760 studies. Table 5 displays the 10 studies with highest co-citation frequencies. The study published by Hemminki A in Nature had most citations (537), followed by the one conducted by Jenne DE and published in Nature Genetics (490) and the one conducted by Giardiello FM and published in Gastroenterology (379 citations). The higher citation frequency indicated the higher quality and stronger references of the publications. Citation burst refers to the references receiving more attention from scholars in the particular area during the specific time period. Figure 6A shows those 25 studies with most citations. Among them, the paper “ACG Clinical Guideline: Genetic Testing and Management of Hereditary Gastrointestinal Cancer Syndromes” by Syngal et al[5] had the most recent greatest burst (33.19), with the citation burst lasting from 2016 to 2020. Noteworthily, most studies with frequent citations were published in top-tier journals. To determine the research hotspots of PJS, we ranked the co-cited studies based on the analysis results. "Carney complex", "multi-society task force", "tumor suppressor", "early detection", "PJS", " PJS kinase LKB1", "genetic testing", "nonpolyposis syndrome", "somatic mutation", "capsule endoscopy", "clinical management", "double-balloon endoscopy", "recent progress", "familial pancreatic cancer" and "molecular genetic basis" represented the 15 key co-cited reference clusters (Figure 6B).

Figure 6 Co-cited references and research hotspots. A: Those top 25 references of greatest citation bursts; B: Cluster network map of co-cited references.

Table 5 The top 10 most co-cited references.

Rank	Title	First author	Year	Journal	Cited frequency
1	A serine/threonine kinase gene defective in Peutz-Jeghers syndrome	Hemminki A	1998	Nature	537
2	Peutz-Jeghers syndrome is caused by mutations in a novel serine threonine kinase	Jenne DE	1998	Nature Genetics	490
3	Very high risk of cancer in familial Peutz-Jeghers syndrome	Giardiello FM	2000	Gastroenterology	379
4	Increased risk of cancer in the Peutz-Jeghers syndrome	Giardiello FM	1987	New England Journal of Medicine	331
5	Frequency and spectrum of cancers in the Peutz-Jeghers syndrome	Hearle N	2006	Clinical Cancer Research	242
6	Localization of a susceptibility locus for Peutz-Jeghers syndrome to 19p using comparative genomic hybridization and targeted linkage analysis	Hemminki A	1997	Nature Genetics	238
7	Peutz-Jeghers syndrome: a systematic review and recommendations for management	Beggs AD	2010	Gut	209
8	Increased risk for cancer in patients with the Peutz-Jeghers syndrome	Boardman LA	1998	Annals of Internal Medicine	287
9	High cancer risk in Peutz-Jeghers syndrome: a systematic review and surveillance recommendations	M G F van Lier	2010	American Journal of Gastroenterology	178
10	Cancer and the Peutz-Jeghers syndrome	Spigelman AD	1989	Gut	163

Successful endoscopic reduction of intestinal intussusception in a patient with previous abdominal surgery

A 36-year-old male patient had PJS when he was 8 years old, with lower abdominal pain and an inability to eat. He underwent three surgical laparotomies for intestinal intussusception previously. Laboratory tests revealed severe malnutrition. The CT scan revealed multiple intussusceptions in the duodenum and small intestine, along with anomalous course of the common bile duct and several visible polyps (3.5 cm × 3.5 cm) (Figure 7A). The patient strongly refused further surgical intervention, therefore, endoscopic treatment was considered prior to laparotomy. During enteroscopy, a polyp larger than 5.0 cm was found, obscuring the full view (Figure 7B). Piecemeal polypectomy technique was adopted under retroflexed endoscopic visualization (Figure 7C). Following the procedure, the patient's symptoms significantly improved, and his nutritional status markedly ameliorated. At a three-month postoperative follow-up, no complications or recurrence were reported. The resected polyp sample was histopathologically examined, which suggested hamartomatous hyperplasia of mucosal epithelium and dendritic growth of smooth muscle fiber bundle from muscularis mucosae, characteristic of PJS polyps (Figure 7D).

Figure 7 Imaging, endoscopic and histopathological findings of multiple intussusceptions and polypectomy in Peutz-Jeghers syndrome. A: Computed tomography imaging revealed multiple intussusceptions, along with anomalous course of the common bile duct and several visible polyps; B: Enteroscopy imaging showed a polyp obscuring the full view; C: Piecemeal polypectomy; D: Histopathological image of the polyp.

DISCUSSION

Principal findings

This study performed bibliometric analysis of 1760 original articles and reviews regarding PJS during 1994-2023 based on Web of Science database. We focused on exploring research hotspots and developmental trends in PJS over the past 30 years. Collaboration network analysis revealed that the most influential entities in this field were the United States (country), the University of Helsinki (institution) and Aaltonen LA (investigator). Keyword burst detection identified "cancer risk", "management", "surveillance" and "familial pancreatic cancer" as the potential hotspots for investigation. This bibliometric analysis provides valuable insights for researchers who are interested in this field to quickly understand the research status.

Interpretation of findings

The annual publication number and citation frequency serve as the indicators of the developmental pace and research status within the specific realm. The PJS-related publication number demonstrated a modest fluctuation annually, with a steadily increasing trend over the last three decades, signifying the sustained attention to this rare disease. Collaborative network analysis facilitated to evaluate country, institution and author collaborations. In the last three decades, the United States was the core of international collaboration with prolific countries. Five among those top 10 institutions, with regard to publication number, were based in the United States. The United States also ranked first with regard to mean citations, followed by the United Kingdom and the Netherlands, indicating that publications from the three countries were high-quality. The University of Helsinki in Finland had the highest number of published articles, underscoring its significant contribution to the field of PJS. Continued enhancements of collaboration among institutions and countries might further propel advancements in the realm.

Among those significant contributing authors to the realm, Aaltonen LA, Stratakis CA and Giardiello FM were identified as the three most productive authors. Aaltonen LA, a distinguished Finnish medical researcher, serves as a professor of medicine at the University of Helsinki and has been a leading figure in multiple international research projects. He is renowned for his pioneering work in hereditary cancer syndromes, particularly his substantial contributions to the study of PJS[20]. In 1998, his research team achieved a major breakthrough by identifying the STK11 gene as the primary causative gene of PJS through genetic linkage analysis, marking a significant milestone in the molecular genetic research of this disease[21]. Professor Stratakis CA, affiliated with the National Institute of Child Health and Human Development in the Aaltonen LA, Stratakis CA and Giardiello FM were identified as the three most productive authors. Aaltonen LA, a distinguished Finnish medical researcher, serves as a professor of medicine at the University of Helsinki and has been a leading figure in multiple international research projects., is dedicated to the research of endocrine-related tumors caused by PJS[22]. Professor Giardiello FM, from the Johns Hopkins University School of Medicine, has made noteworthy contributions to the clinical characterization, diagnostic criteria and monitoring strategies for patients with PJS[23].

Source journals were analyzed, which assisted in identifying core journals of respective research areas. Of those 10 active journals, Cancer Research was most frequently cited, followed by Endoscopy and Oncogene. Articles published in Cancer Research also had the greatest mean citations for each study, indicating its global recognition and authoritative status. Furthermore, the Journal of Pediatric Gastroenterology and Nutrition had consistently increasing publications over the past decade, suggesting that the present research topics on PJS were primarily related to early intervention and endoscopic management.

Keyword bursts are indicative of the extensively cited keywords in published studies, which can assist in identifying hotspots and trends of the research area[24]. Figure 5B illustrates the 25 keywords with greatest citation bursts in PJS. During this period, "management" emerged as the strongest keyword burst, signifying that research on management was a significant hotspot. Cluster analysis of co-citations was conducted for identifying main research topics. From Figure 6B, "capsule endoscopy", "clinical management" and "double-balloon endoscopy" were the primary research themes, aligning with the keyword burst analysis. Prior to the advent of double-balloon enteroscopy, surgical resection was the standard way to manage PJS, but its invasiveness might result in short bowel syndrome[25,26]. Some novel enteroscopic technologies emerged in 21^st century, like spiral enteroscopy, double-balloon endoscopy, motorized spiral enteroscopy, and single-balloon enteroscopy, enabling diagnosis and endoscopic treatment throughout the whole small intestine[27-29]. Due to small-intestine endoscopic advancement, endoscopic polypectomy has been widely adopted to be the standard treatment for PJS, avoiding a need for invasive surgical resection and reconstruction, even for patients who received laparotomy previously[30]. This was confirmed in a case at our center and underscored the significant impact of endoscopic resolution of all obstructions due to intussusception, providing valuable insights for the treatment of such patients.

The identification of "cancer risk" and "familial pancreatic cancer" represented other potential areas of interest for further investigation. A meta-analysis encompassing 210 patients with PJS revealed that, the risk of cancer increased by 15.2 times in these patients; to be specific, the risks of oesophageal, small intestinal and gastric cancers increased by 57, 520 and 213 times, respectively[31]. Broadly defined familial pancreatic cancer refers to the condition where at least two first-degree relatives have pancreatic cancer, while the narrowly defined familial pancreatic cancer excludes patients with hereditary tumor syndromes. As highlighted in 2015 by The American College of Gastroenterology, PJS was the hereditary GI cancer syndrome closely associated with pancreatic cancer occurrence[5]. Pathologically, intraductal papillary mucinous neoplasms may be seen in some PJS patients as the precancerous lesions of pancreatic ductal adenocarcinoma. The meta-analysis also showed that the pancreatic cancer risk in PJS patients elevated by 132 times. Despite the recent medical advances that improve survival rates of cancer patients, the prognosis for pancreatic cancer is still dismal, and the 5-year survival rate is < 10%. In addition, pancreatic cancer is difficult to diagnose in its early stages, and many patients present with symptoms in the late stages, highlighting the need for surveillance. Research has shown that cases with STK11 mutations do not have a significant difference in cumulative risk of all cancers compared with cases without STK11 mutations[32]. However, the reasons for the higher cancer incidence among PJS patients remain unclear, which require further investigation in the future.

During our search, we also uncovered an intriguing topic regarding effect of intestinal microbiota on PJS pathogenesis[33,34]. The intestinal microbiota constitutes a complex ecosystem, and is affected by many factors such as environment, genetics, diet, medication and lifestyle[35]. Recently, advances in sequencing technologies have increased the attention paid to the intestinal microbiota, often referred to as the "forgotten organ". Intestinal microbiota and the corresponding metabolites is tightly associated with the immune and enteric nervous systems, collectively maintaining intestinal homeostasis[36,37]. Dysbiosis of intestinal microbiota may be related to occurrence of diseases like irritable bowel syndrome, inflammatory bowel disease or colorectal cancer[38-40]. Interestingly, several studies have found significant alterations of intestinal microbial composition among PJS cases, and fungal microbiota remains relatively stable[41]. Wang et al[42] have identified unique bacterial compositions and metabolic pathway alterations in the mucosa-associated microbiota that influence intestinal inflammation and tumor development. Bacteroides shows a high abundance among PJS patients, which is positively related to the greatest polyp size, suggesting the potential role in exacerbating intestinal inflammation and promoting polyp growth. Conversely, Agathobacter exhibits the negative relation to the onset age. Additionally, acetic acid, butyric acid, and propionic acid have positive relation to the onset age and negative relation to polyp number[43]. Previous research has suggested that onset age probably affects the development and management of inflammatory bowel disease and colorectal cancer[44,45]. Based on these results, it is hypothesized that intestinal microbiota along with the corresponding metabolites is potentially related to onset age of PJS patients, and early targeted microbiota-based interventions may help improve patient prognosis and enhance their quality of life. Therefore, further clinical research is warranted to validate these findings.

Strengths and limitations

This study has the strength that it comprehensively included PJS-related research from 1994 to 2023, and utilized bibliometric analysis to assess the developmental trends and research themes of this realm. Additionally, the introduction of a case study on PJS-induced intestinal intussusception at our center reaffirmed the significant clinical value of endoscopic polypectomy in resolving intussusception, thereby avoiding the need for further surgical interventions. The study results were accurate and objective. However, this study has certain limitations. Firstly, our selection was limited to the WOSCC, overlooking other search engines like PubMed and Scopus. Secondly, inclusion of only English-language articles might have reduced the number of retrievable papers. Lastly, bibliometric analysis may be subjected to temporal bias, potentially constraining the comprehensiveness of our conclusions. In future research, we focus on comprehensively summarizing and analyzing outcomes in the field, thus further exploring the research hotspot.

CONCLUSION

To conclude, this study represents the first bibliometric and visual analysis on PJS. In the last three decades, publications related to PJS steadily elevate, indicating that sustained attention is paid to this rare disease by researchers. The United States has been most active in international research collaborations. Earlier research on PJS primarily focuses on the pathogenesis and clinical manifestations of the disease, while current research is more centered on management, with endoscopic polypectomy being a preferred choice. Additionally, the intestinal microbiota and its metabolites may serve as potential future therapeutic targets. Hopefully, the present bibliometric analysis can shed valuable lights on future studies on PJS.

ACKNOWLEDGEMENTS

We express our gratitude to Professor Teng Li for his patient guidance in histopathology.