Peutz-Jeghers Syndrome Polyps Research Articles

Single-cell landscape of the cellular microenvironment in three different colonic polyp subtypes in children.

The understanding of the heterogeneous cellular microenvironment of colonic polyps in paediatric patients with solitary juvenile polyps (SJPs), polyposis syndrome (PJS) and Peutz-Jeghers syndrome (PJS) remains limited. We conducted single-cell RNA sequencing and multiplexed immunohistochemistry (mIHC) analyses on both normal colonic tissue and different types of colonic polyps obtained from paediatric patients. We identified both shared and disease-specific cell subsets and expression patterns that played important roles in shaping the unique cellular microenvironments observed in each polyp subtype. As such, increased myeloid, endothelial and epithelial cells were the most prominent features of SJP, JPS and PJS polyps, respectively. Noticeably, memory B cells were increased, and a cluster of epithelial-mesenchymal transition (EMT)-like colonocytes existed across all polyp subtypes. Abundant neutrophil infiltration was observed in SJP polyps, while CX3CR1hi CD8+ T cells and regulatory T cells (Tregs) were predominant in SJP and JPS polyps, while GZMAhi natural killer T cells were predominant in PJS polyps. Compared with normal colonic tissues, myeloid cells exhibited specific induction of genes involved in chemotaxis and interferon-related pathways in SJP polyps, whereas fibroblasts in JPS polyps had upregulation of myofiber-associated genes and epithelial cells in PJS polyps exhibited induction of a series of nutrient absorption-related genes. In addition, the TNF-α response was uniformly upregulated in most cell subsets across all polyp subtypes, while endothelial cells and fibroblasts separately showed upregulated cell adhesion and EMT signalling in SJP and JPS polyps. Cell-cell interaction network analysis showed markedly enhanced intercellular communication, such as TNF, VEGF, CXCL and collagen signalling networks, among most cell subsets in polyps, especially SJP and JPS polyps. These findings strengthen our understanding of the heterogeneous cellular microenvironment of polyp subtypes and identify potential therapeutic approaches to reduce the recurrence of polyps in children.

Advancements in endoscopic management of small-bowel polyps in Peutz-Jeghers syndrome and familial adenomatous polyposis.

Before the development of double-balloon enteroscopy (DBE), the standard management of small-bowel polyposis was surgical resection. This is an invasive procedure that could lead to short bowel syndrome. In the 21st century, several new enteroscopy techniques were distributed worldwide, including DBE, single-balloon enteroscopy, spiral enteroscopy, and motorized spiral enteroscopy. These devices enable the diagnoses and endoscopic interventions in the entire small bowel, even in patients with a history of laparotomy. In patients with Peutz-Jeghers syndrome (PJS), endoscopic ischemic polypectomy with clips or a detachable snare is the preferred method for managing pedunculated polyps because it is less likely to cause adverse events than conventional polypectomy. Although polyps in patients with PJS always recur, repeat endoscopic resection can reduce the total number and mean size of polyps in the long-term clinical course. Endoscopic reduction of small-bowel intussusception caused by PJS polyps can be successfully performed using DBE without surgery. A transparent hood is useful for securing a visual field during the treatment of small-bowel polyps, and minimal water exchange method is recommended to facilitate deep insertion. Familial adenomatous polyposis (FAP) is a genetic disorder that increases the risk of developing colorectal cancer. Because jejunal and ileal polyps in patients with FAP have the potential to develop into cancer via the adenoma-carcinoma sequence, periodical surveillance, and endoscopic resection are needed for them, not only polyps in the duodenum. In cases of multiple small-bowel polyps in patients with FAP, cold snare polypectomy without retrieval is an acceptable treatment option for polyps that are 10 mm or smaller in size. Additional good pieces of evidence are necessary to confirm these findings because this narrative review mostly includes retrospective observational studies from single center, case reports, and expert reviews.

Cancer Risk of Peutz-Jeghers Syndrome and Treatment Experience: A Chinese Medical Center.

Peutz-Jeghers syndrome (PJS), also known as hereditary mucocutaneous pigmented gastrointestinal polyposis, is a clinically rare autosomal dominant genetic disease, which falls into the category of hereditary colorectal cancer. There are ∼7,000 new cases of PJS in China every year, and 170,000 PJS patients may survive for a long time in society. PJS polyps are characterized by an early age of onset, difficult diagnosis and treatment, and easy recurrence. With repeated growth, polyps can lead to serious complications such as intestinal obstruction, intussusception, gastrointestinal bleeding, and cancerization, which cause serious clinical problems. Due to repeated hospitalization and endoscopic follow-up, PJS patients and their families suffer from great physical and mental pain and economic burden. With the in-depth understanding of PJS and the development and popularization of endoscopic techniques in the past decade, an integrated treatment modality based on endoscopy plus surgery has gradually become the preferred treatment in most hospitals, which greatly improves the quality of life of PJS patients. However, there is still a lack of effective drug prevention and cure means. In this paper, the current clinical treatment means for PJS polyps were summarized by literature review combined with the treatment experience of our medical center, with a focus on their clinical diagnosis, treatment, and cancer risk.

Clinical features, diagnosis, and treatment of Peutz-Jeghers syndrome: Experience with 566 Chinese cases.

Peutz-Jeghers syndrome (PJS) is a clinically rare disease with pigmented spots on the lips and mucous membranes and extremities, scattered gastrointestinal polyps, and susceptibility to tumors as clinical manifestations. Effective preventive and curative methods are still lacking. Here we summarize our experience with 566 Chinese patients with PJS from a Chinese medical center with regard to the clinical features, diagnosis, and treatment. To explore the clinical features, diagnosis, and treatment of PJS in a Chinese medical center. The diagnosis and treatment information of 566 cases of PJS admitted to the Air Force Medical Center from January 1994 to October 2022 was summarized. A clinical database was established covering age, gender, ethnicity, family history, age at first treatment, time and sequence of appearance of mucocutaneous pigmentation, polyp distribution, quantity, and diameter, frequency of hospitalization, frequency of surgical operations, etc. The clinical data was retrospectively analyzed using SPSS 26.0 software, with P < 0.05 considered statistically significant. Of all the patients included, 55.3% were male and 44.7% were female. Median time to the appearance of mucocutaneous pigmentation was 2 years, and median time from the appearance of mucocutaneous pigmentation to the occurrence of abdominal symptoms was 10 years. The vast majority (92.2%) of patients underwent small bowel endoscopy and treatment, with 2.3% having serious complications. There was a statistically significant difference in the number of enteroscopies between patients with and without canceration (P = 0.004, Z = -2.882); 71.2% of patients underwent surgical operation, 75.6% of patients underwent surgical operation before the age of 35 years, and there was a statistically significant difference in the frequency of surgical operations between patients with and without cancer (P = 0.000, Z = -5.127). At 40 years of age, the cumulative risk of intussusception in PJS was approximately 72.0%, and at 50 years, the cumulative risk of intussusception in PJS was approximately 89.6%. At 50 years of age, the cumulative risk of cancer in PJS was approximately 49.3%, and at 60 years of age, the cumulative risk of cancer in PJS was approximately 71.7%. The risk of intussusception and cancer of PJS polyps increases with age. PJS patients ≥ 10 years old should undergo annual enteroscopy. Endoscopic treatment has a good safety profile and can reduce the occurrence of polyps intussusception and cancer. Surgery should be conducted to protect the gastrointestinal system by removing polyps.

Massive gastric polyposis in Peutz-Jeghers Syndrome – a case report

Peutz-Jeghers Syndrome (PJS) is a rare autosomal dominant disorder equally affecting males and females with an incidence of 1/25,000 – 1/300,000 births. It is characterised by the development of hamartomatous polyps of the digestive tract, a lifetime risk of colorectal cancer and other gastrointestinal malignancies, as well as non-gastrointestinal cancers such as breast and ovarian cancers. Intestinal polyposis is very common in PJS, however, gastric polyps occur in less than 20% of patients with massive polyposis rarely reported. We report a case of massive gastric polyposis in an elderly PJS patient with concurrent and prior intestinal polyps and multiple occurrences of intussusception. The gastric polyps were present in the fundus through to the gastro-eosophageal junction. Microscopy demonstrated arborising branches of smooth muscle covered by disorganised mucosa – consistent with PJS polyps. The largest gastric polyp showed architectural complexity and nuclear atypia suggestive of high-grade dysplasia. An intrapolyp adenocarcinoma had been biopsied from the gastric fundus two months prior but no residual invasion was present in the gastrectomy specimen. It is important for pathologists to be aware of the association between PJS and gastric polyps in which dysplasia and malignancy can develop.

Peutz–Jeghers Syndrome which Develops into Descending Sigmoid Colon Adenocarcinoma

Introduction: Peutz–Jeghers Syndrome (PJS) is an autosomal dominant hereditary condition mainly characterized by hamartomatous gastrointestinal (GI) polyps. Medical treatment is often sought due to complications that arise from the polyps. PJS polyps tend to be accompanied by freckling or hyperpigmentation on the lips, buccal mucosa, vulva, fingers, and toes. PJS is also associated with an increased risk for colorectal or extraintestinal tumors. Case Presentation: A 24-year-old female complained about a lump in her abdomen and constipation. The physical examination found hyperpigmentation on the lips and a hard and mobile mass on the left quadrant abdomen. We found a descending-sigmoid colon tumor with multiple polyps on all colon mucous and performed total colectomy and ileorectal anastomosis on the laparotomy operation. Two months later, Esophagogastroduodenoscopy revealed multiple polyps on Duodenum 1, II, and gaster. The colon tumor pathology result showed welldifferentiated adenocarcinoma. Conclusions: Peutz–Jeghers Syndrome (PJS) can develop into malignant intestinal tumors that require surgery for resection of the tumor.

Solitary gastric Peutz-Jeghers polyp: a case report

Peutz-Jeghers syndrome is an inherited condition that is characterized by mucocutaneous pigmentation and hamartomatous polyposis in the gastrointestinal tract. It increases significantly the risk for developing of several cancers such as breast, colon, rectum, pancreas and stomach. Solitary Peutz-Jeghers polyp is defined as a unique hamartomatous polyp having the same histological features as Peutz-Jeghers syndrome polyps without associated intestinal polyposis, mucocutaneous pigmentation and family history of Peutz-Jeghers syndrome. Gastric solitary Peutz-Jeghers polyp is extremely rare. We found only 13 cases in the literature. We report a new case of solitary gastric Peutz-Jeghers polyp associated with a branch duct intraductal papillary mucinous neoplasm revealed by an acute pancreatitis. Computed tomography of the abdomen found a branch duct intraductal papillary mucinous neoplasm with a pedicled polypoid formation in the greater gastric curvature. Endoscopic resection was performed without complications. Histologic examination showed Peutz-Jeghers hamartomatous polyp. The risk of cancer remains unclear in this entity. Therefore, the follow-up of these patients is necessary because of the possible risk of malignancy.

Distinct promoter methylation patterns of LKB1 in the hamartomatous polyps of Peutz-Jeghers syndrome and its potential in gastrointestinal malignancy prediction

BackgroundPeutz-Jeghers Syndrome (PJS) is known as a rare inherited polyposis due to the malfunction of serine/threonine kinase gene LKB1. However, not all of PJS patients carry LKB1 germline mutation. Previous researches have observed the elevated DNA methylation level in PJS polyps. Nevertheless, the mechanism of such abnormal and its impact on PJS patients remains to be fully described.ResultsThe results proved a significant increase on the methylation level of LKB1 promoter in PJS polyps compared with normal colon biopsies through bisulfite PCR followed by Sanger sequencing. Moreover, the methylation pattern in PJS polyps could be further categorized as three different scenarios: hypermethylated, hemimethylated and hypomethylated pattern. Furthermore, immunohistochemistry of DNMT1/3a/3b suggested the up-regulation of DNMT1 and 3a might participate the epigenetic alternation of LKB1 in PJS polyps. Logistic regression suggested hypomethylated LKB1 promoter in PJS polyps as a risk factor for gastrointestinal malignancies in PJS patients.ConclusionsThe promoter methylation level of LKB1 gene in PJS polyps is generally elevated compared with normal colon mucosa. Yet not all of PJS polyps carry hypermethylated LKB1 promoter. Hypomethylation in this region has linked to malignant tumors in PJS patients. Given the rarity of PJS, this work together with previous researches, have proved the importance of LKB1 promoter methylation in PJS development and prognosis.

A case of jejunal solitary Peutz–Jeghers polyp with intussusception identified by double-balloon enteroscopy

Solitary Peutz-Jeghers polyp is a rare hamartomatous polyp that has similar histologic characteristics with those of polyps in Peutz-Jeghers syndrome, without associated mucocutaneous hyperpigmentation and a family history. Previous reports indicated that solitary Peutz-Jeghers polyp is rarely found in the small intestine. We experienced a rare case of jejunal solitary Peutz-Jeghers polyp. A 29-year-old man was admitted to our hospital with a 6-month history of upper abdominal pain. He had no hyperpigmentation or a family history of Peutz-Jeghers syndrome. Abdominal computed tomography showed a 3-cm tumor-like structure at the tip of a mildly intussuscepted jejunum. Per oral double-balloon enteroscopy revealed a 3-cm pedunculated polyp in the jejunum. The patient underwent partial jejunal resection under laparotomy. Macroscopically, the surgical specimen showed a pedunculated polyp, measuring 30 × 15 × 10mm in size, with lobulated head. Histopathologic examination revealed irregular aggregation of hyperplastic crypts with branching muscular bundles originating from the muscularis mucosae. Based on these histologic findings, we finally diagnosed the patient as a solitary Peutz-Jeghers polyp in the jejunum. The present case indicated that solitary Peutz-Jeghers polyp should be considered in a patient with solitary hamartomatous polyp in the gastrointestinal tract.

Abstract PR03: YAP/TAZ requirement in mesenchyme-originated intestinal hamartomatous polyposis

Abstract Hamartomatous polyposis syndromes (HPS) are rare genetic syndromes, including Peutz-Jeghers syndrome (PJS) and PTEN hamartoma tumor syndrome (Cowden and Bannayan-Riley-Ruvalcaba syndromes), which are caused by germline mutations of STK11 (LKB1) and PTEN genes, respectively. HPS is characterized by the development of hamartomatous polyps in the GI tract; however, the cellular origins and molecular mechanism underlying hamartomatous polyposis remain poorly understood. Here we demonstrate that specific disruption or deletion of Stk11 or Pten in mouse GI mesenchyme, but not in the epithelium, generates hamartomatous polyps histologically resembling GI polyps observed in PJS and Cowden syndrome patients. Genetically, we show that mTOR activity is essential for Pten but not Stk11 deletion-driven hamartomatous polyposis. Furthermore, we show that AMPK1/2 deletion is not able to initiate PJS polyp formation. However, we find significant upregulation of mesenchymal YAP/TAZ activity in PJS polyps and demonstrate that YAP/TAZ in gut mesenchyme are required for Stk11 deletion-induced PJS hamartomatous polyposis. Our studies suggest a mesenchymal origin of GI polyps in HPS and reveal the distinct roles of YAP/TAZ and mTOR in gut mesenchyme during hamartomatous polyposis, which likely have important therapeutic implication for treating these HPSs. This abstract is also being presented as Poster A06. Citation Format: Jennifer L. Cotton, Kyvan Dang, Qi Li, Randy L. Johnson, Y. Tony Ip, Xu Wu, Junhao Mao. YAP/TAZ requirement in mesenchyme-originated intestinal hamartomatous polyposis [abstract]. In: Proceedings of the AACR Special Conference on the Hippo Pathway: Signaling, Cancer, and Beyond; 2019 May 8-11; San Diego, CA. Philadelphia (PA): AACR; Mol Cancer Res 2020;18(8_Suppl):Abstract nr PR03.

Small bowel polyp resection using device-assisted enteroscopy in Peutz-Jeghers Syndrome: Results of a specialised tertiary care centre.

Enteroscopy resection of small bowel polyps in Peutz-Jeghers syndrome has only been described in small case series. Herein, we aimed to assess the efficacy of enteroscopy resection of small bowel polyps within a specialised tertiary care centre and the impact on intraoperative enteroscopy. This was an observational single-centre study. All adult Peutz-Jeghers syndrome patients followed in the Predisposition Digestive Ile-de-France network who underwent an endoscopic resection of at least one small bowel polyp ≥ 1 cm by enteroscopy between 2002-2015 were included. Small bowel polyps were detected under a dedicated screening programme by previous capsule endoscopy and/or magnetic resonance enterography, performed every 2-3 years. Complete treatment was defined as the absence of polyps ≥ 1 cm after conventional endoscopic resection. Intraoperative enteroscopy or surgical resection were indicated in incomplete treatments. The overall complete treatment rate including conventional enteroscopy and intraoperative enteroscopy was also considered. Endoscopic resection of 216 small bowel polyps (median: 8.6 per patient, size: 6-60 mm) was performed by 50 enteroscopies in 25 patients (mean age: 36 years, range: 18-71, 56% male) with small bowel polyp ≥ 1 cm. Twenty-three patients (92%) underwent 42 screening capsule endoscopies and 14 (57%) had 23 magnetic resonance enterographies during a median follow-up of 60 months. Complete treatment was achieved in 76%. Intraoperative enteroscopy and surgical resection were performed in four (16%) and two (8%) patients. Intraoperative enteroscopy improved by 16% the complete treatment rate and the overall rate was 92%. The complication rate was 6%. This long-term study confirmed the efficacy and safety of endoscopic resection of small bowel polyps in Peutz-Jeghers syndrome. Intraoperative enteroscopy can be a complementary approach in selected cases.

Primary experience of small bowel polypectomy with balloon-assisted enteroscopy in young pediatric Peutz–Jeghers syndrome patients

For Peutz-Jeghers syndrome (PJS) patients, small bowel polyps develop and result in symptoms at an early age. Balloon-assisted enteroscopy (BAE) is verified as a safe and efficient choice to evaluate and remove small intestinal polyps in adult PJS. But the safety of BAE, especially BAE-facilitated polypectomy for young pediatrics, is little known. This prospective study focused on the effectiveness and safety of BAE-facilitated polypectomy in small bowel for young pediatric PJS. PJS patients (aged 0-14years old) with BAE (including both single-balloon and double-balloon enteroscopies) were included from 1 September 2012 to 30 April 2018. The demographic data, medical history, and details of BAE were recorded. BAE-related complications and symptom relief after BAE were evaluated and compared between the PJS patients aged 5-10years old (the younger pediatric group) and those aged 11-14years old (the older pediatric group). A total of 41 pediatric PJS patients (5-14years old) subjected to 82 BAEs were included. BAE-facilitated polypectomy was performed for 33 children (80.5%), and 242 polyps in small bowel were removed. For 10 (24.4%) patients, one or more giant polyps (maximum diameter larger than 5cm) were removed. For eight patients, no polypectomy was done as no polyps were observed (six subjects) or not suitable for BAE-facilitated polypectomy (two subjects) because of high risk of perforation. The complication rates of BAE and BAE-facilitated polypectomy were 1.2% (1/82) and 1.8% (1/55), and the symptom relief rate was 70.8% (17/24). Compared with the older pediatric group, the younger pediatric group showed no increased BAE complication rate (0.0% vs. 5.0%, p = 0.488) and a comparable rate of symptom relief after BAE therapy (80.8% vs. 55.6%, p = 0.356).Conclusion: BAE-facilitated polypectomy in young pediatric PJS is safe and effective.What is known:• Small bowel evaluation and prophetic polypectomy are important for pediatric PJS patients to avoid polyp-related intussusception, obstruction, and bleeding.• BAE polypectomy was a recommended intervention for removing small bowel polyps in adult PJS patients.What is new:• BAE-facilitated small bowel polypectomy is safe and effective for young pediatric PJS, even for those aged less than 10years old.

HIGH-TECH DIAGNOSTIC METHODS AND AN ENTEROSCOPIC TREATMENT OF CHILDREN WITH PEUTZ-JEGHERS SYNDROME

Peutz-Jeghers syndrome (PJS) is an autosomal dominant hereditary hamartomatous polyposis with predominant localization in the jejunum and ileum. Because of PJS polyps differ from adenomatous ones, the performing polypectomy is associated with a high risk of bowel perforation. During 2015-2017 18 PJS children were comprehensively examined including esophagogastroduodenoscopy, colonoscopy, and video capsule endoscopy There was developed a step-by-step procedure for the removal of polyps common in all parts of the small intestine, including the creation of a “persistent pillow”; electroexcision of a polyp and application of a clip to the region of the womb of a removed polyp. Polyps more than 7 mm detected in the stomach and duodenum, were removed during endogastroduodenoscopy, and in the colon - under a colonoscopy. During video capsular endoscopy, polyps with a diameter of 2 mm to 2.5 cm were detected in the deep parts of the small intestine. For their surgical removal, during a therapeutic single-balloon enteroscopy, an electroscission of all polyps was performed. The postoperative period was uneventful. The combination of a single balloon enteroscopy with an electroexcision of polyps is suggested by the authors as the optimal method for the diagnosis and treatment of PJS in children, which allows avoiding delayed perforations of the small intestine in the postoperative period. Thanks to this technique, enteroscopy becomes the only possible alternative to bowel resection in PJS children.

Peutz-Jeghers Phenotype Caused by an Unknown Variant APC Gene

Peutz-Jeghers syndrome is an autosomal dominant condition, characterized by hamartomatous polyps, mucocutanous pigmentation, and increased predisposition to both Gastrointestinal (GI) and Non-Gastrointestinal malignancies. Most cases are due to a mutation of the STK11 tumor suppressor gene. Diagnosis is based on clinical findings, while genetic studies are used to confirm the diagnosis. We present a rare case of Peutz-Jeghers phenotype with an APC gene mutation variant of unknown significance. A 56-year old male with significant past medical history of prior sigmoidectomy for a benign colon mass and hemorrhoidectomy, was evaluated for intermittent rectal bleeding. He described vague abdominal pain, and intermittent dark stools with concurrent bright red blood per rectum. Laboratory findings were consistent with iron deficiency anemia. Esophagogastroduodenoscopy revealed gastritis and a duodenal polyp, which on histology showed hamartomatous polyp with features of a Peutz-Jeghers polyp. Colonoscopy findings showed internal hemorrhoids. Retrospectively, on detailed physical examination, the patient was found to have brown pigmented macular lesions on his buccal mucosa. Molecular studies were performed for common hereditary cancer syndromes and revealed no STK11 mutation but showed an APC gene variant of unknown significance. Specifically, a c.2297C>T (P.Ala766Val) mutation. With the presence of classic Peutz-Jeghers polyp histology and mucocutaneous pigmentation, the patient was treated as a Peutz-Jeghers phenotype. He was discharged home on iron supplementation and is currently on an intensive surveillance regimen for cancers involving the thyroid, pancreas, colon, and testes. Hamartomatous polyps in Peutz-Jeghers syndrome can occur anywhere in the GI tract, yet they tend to have a strong predilection for the small intestine. Patients with Peutz-Jeghers are at an increased risk for cancers manifesting both within the intestinal tract and externally. Routine surveillance with endoscopy and polypectomy is indicated to screen for malignancy, and to help prevent polyp related complications including; bowel obstructions, intussusception, and bleeding. Genetically, STK11 mutation is present in between 50 to 80 percent of Peutz-Jeghers cases. We present a case of Peutz-Jeghers phenotype in the presence of an APC gene variant of unknown significance.

Gastrointestinal diseases and their oro-dental manifestations: Part 4: Peutz-Jeghers syndrome.

Peutz-Jeghers syndrome (PJS) is a rare, autosomal dominant inherited disorder, caused by germline mutations in the LKB1 tumour suppressor gene. It is clinically characterised by distinct perioral mucocutaneous pigmentations, gastrointestinal polyposis and an increased cancer risk in adult life. Hamartomatous polyps can develop already in the first decade of life and may cause various complications, including abdominal pain, bleeding, anaemia, and acute intestinal obstruction. Furthermore, patients have an increased risk for developing cancer, both in the gastrointestinal tract as in other organs. The medical management of PJS mainly consists of surveillance and treatment of the hamartomatous polyps. Upper and lower endoscopies are recommended for surveillance and removal of PJS polyps in the stomach and the small and large intestine. Furthermore, the high risk for pancreatic cancer justifies surveillance of the pancreatic region by MRI or endoscopic ultrasound. In addition, breast and gynaecological surveillance is recommended for female patients. Although the genetic defect underlying PJS is known, the pathogenesis of hamartomas and carcinomas is unclear. More insight into the molecular background of PJS might lead to targeted therapies for patients with this syndrome.

Abstract 712: Mechanisms of stromal Lkb1 loss induced tumorigenesis in mouse models of Peutz-Jeghers syndrome

Abstract Germline mutations in tumor suppressor kinase Lkb1 predispose to Peutz-Jeghers syndrome (PJS), with highly penetrant gastrointestinal polyposis and increased cancer risk. PJS polyps display abnormal growth of both stromal and epithelial cells. We have identified clonally expanding fibroblasts as the drivers of tumorigenesis in PJS mouse models by using Fsp1-Cre and Twist2-Cre mice to restrict Lkb1 deletion to stromal cells (unpublished), highlighting the importance of stromal-epithelial signaling in PJS tumorigenesis. Here, we address the molecular mechanisms of the pathogenesis linked to stromal Lkb1 loss in PJS mouse models. Lkb1 is involved in tissue size control by inhibiting of mTORC1 pathway via AMPK (Shaw et al, Cancer Cell 2004) and by regulating Hippo pathway (Mohseni et al, Nat Cell Biol 2014). First, we investigated the involvement of Lkb1-AMPK-mTORC1 pathway in polyposis. We conditionally deleted both catalytic AMPKá subunits (á1 and á2) in mice using Fsp1-Cre. Surprisingly, Fsp1-Cre-AMPK mice did not develop any tumors by 17 months of age indicating that AMPK is not the critical mediator of Lkb1 tumor suppression in PJS. We next studied the Hippo pathway in polyps of PJS mouse models. Levels of Yap and Taz, the main downstream effectors of Hippo, were elevated in polyps as shown by Western blotting. Immunohistochemical staining revealed profound nuclear Yap/Taz localization indicating transcriptional activity in the stromal compartment throughout the polyps. In contrast, nuclear Yap/Taz staining in epithelial cells was only noted in a restricted polyp base stem cell zone. In addition, we performed RNA-seq analysis of the of Fsp1-Cre;Lkb1flox mouse polyps and noted shared gene expression changes with PJS patient polyps. RNA-seq also revealed significant enrichment of Yap signature, which was validated by qPCR. Finally, we used small intestinal epithelial organoid culture to study the potential of Yap/Taz induced secreted factors to stimulate growth of epithelial cells. We observed that Wnt5a and Epiregulin enhanced epithelial organoid growth, indicating them as candidates mediating the stromal-epithelial signaling and promoting tumorigenesis in PJS polyps. In conclusion, we show that stromal Lkb1 mutations lead to phenotypes identical to germline Lkb1 heterozygosity in mice and propose increased stromal Yap/Taz activity as a potential mechanism to drive PJS tumorigenes. Citation Format: Saara Ollila, Kari Vaahtomeri, Iris Wong, Kaisa Laajanen, Tomi P. Mäkelä. Mechanisms of stromal Lkb1 loss induced tumorigenesis in mouse models of Peutz-Jeghers syndrome. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 712.

Acute intussusception and polyp with malignant transformation in Peutz-Jeghers syndrome: A case report.

Intussusception is one of the most frequent complications of Peutz-Jeghers syndrome, and has been well described in previous studies. More attention has been paid to malignancy, which is another complication of Peutz-Jeghers syndrome and which leads to increased mortality. Few cases of intussusception combined with malignant polyps in Peutz-Jeghers syndrome have been reported to date. In the present study, we report a case of intussusception and malignant polyps occurring in various parts of the small intestine in a 43-year-old male. In addition to repair of the intussusception and partial resection of the small intestine with malignant polyps, we also simultaneously performed polypectomy of as many polyps as possible without resection of the small intestine. Our aim is to make clinicians aware of intussusception and malignant polyps coexisting in Peutz-Jeghers syndrome when performing emergency surgery. Prophylaxis and polypectomy of the entire small bowel is an effective way to reduce the frequency of laparotomies in patients with this disease.

Abstract 591: LKB1 regulates COX-2 transcription via CRTCs dependent pathway

Abstract Inactivation of the liver kinase B1 (LKB1) gene by somatic mutation is a common event in lung adenocarcinoma. LKB1 was first identified as a tumor suppressor responsible for Peutz-Jeghers syndrome (PJS) and up regulation of cyclooxygenase-2 (COX-2) was detected in a significant percentage of human PJS polyps. In addition, COX-2 has been proposed as a therapeutic target for lung cancer although clinical trial using COX-2 inhibitors have been disappointing. In the current study, we identified a novel LKB1/CRTC/COX-2 molecular pathway in human lung cancer cells and provided new information for clinical use of COX-2 inhibitors. The Kaye lab cloned the CREB-regulated transcription co-activators (CRTCs) and showed aberrant phosphorylation and activation of CRTC1 exclusively in non-small cell lung cancer (NSCLC) samples carrying LKB1 null mutations. We have now demonstrated that CRTC directly regulates COX-2 expression via evolutionarily conserved CRE sites within the promoter. In addition, we observed that ectopic expression of LKB1 resulted in nuclear export of phosphorylated CRTC with attenuation of COX-2 expression. Alternatively, LKB1 knock-down results in CRTC activation and promotes COX-2 expression in NSCLC cells. Importantly, LKB1 null lung cancer cells were preferentially sensitive to COX-2 inhibitors. In summary, our data defines a CRTCs-mediated transcriptional regulatory mechanism for COX-2 activity in cancer and proposes a possible clinical application of COX-2 inhibitors in patients with lung tumors carrying somatic LKB1 null mutations. Citation Format: Chunxia Cao, Ruli Gao, Min Zhang, Zirong Chen, Lizi Wu, Maria Zajac Kaye, Frederic Kaye. LKB1 regulates COX-2 transcription via CRTCs dependent pathway. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 591. doi:10.1158/1538-7445.AM2014-591

Jejunoduodenal intussusception caused by a solitary polyp in a woman with Peutz-Jeghers syndrome: a case report

IntroductionPeutz-Jeghers syndrome is a rare autosomal dominant disorder characterized by hamartomatous polyps and characteristic mucocutaneous pigmentation. The hamartomatous polyps of Peutz-Jeghers syndrome can cause intestinal occlusion, especially in the small intestine. Intussusception is seen frequently in children, but rarely in adults.Case presentationWe present the case of a 21-year-old female patient who was admitted to our emergency service with symptoms of ileus as a result of intussusception due to duodenal polyps. Radiological and endoscopic findings determined a jejunoduedonal intussusception. After an unsuccessful endoscopic attempt, a laparotomy was performed that revealed a polypoid mass originating from the fourth part of her duodenum, with intussusception of her proximal jejunum.ConclusionIntussusception caused by Peutz-Jeghers syndrome is a rare diagnosis and is mostly jejunojejunal or jejunoileal. Despite the fact that a few duodenojejunal cases have been reported, this is to the best of our knowledge the first case of jejunoduedonal intussusception in a patient with Peutz-Jeghers syndrome to be described in the literature.

Double-balloon enteroscopy in the management of patients with Peutz-Jeghers syndrome: a retrospective cohort multicenter study

Little is known about the clinical impact of double-balloon enteroscopy (DBE) in patients with Peutz- Jeghers syndrome (PJS).The aim of this study was to assess the efficacy and safety of DBE in the management of small-bowel polyps in PJS patients. We conducted a multicentre, retrospective cohort study, which included all consecutive patients diagnosed with PJS who underwent DBE for polypectomy between January 2006 and August 2012. In all cases, previous videocapsule enteroscopy had shown at least one polyp ≥ 10 mm in size. Twenty-five patients (13 men; median age 36 years; 14 with prior laparotomy) underwent 46 DBE procedures (1 to 5 per patient, 44 via oral route). Polypectomy was performed in 39/46 DBEs. A total of 214 polyps were removed (median-size 30 mm), with a median number of polypectomies per procedure of 5.0 (range 1-18). The estimated maximum-sizes of resected polyps significantly decreased at each session: 30.0, 25.0, 20.0, 15.0, and 17.5 mm (p = 0.02). In 7 DBEs no polypectomy was performed (4-only minor polyps detected; 3-endoscopic irresecability). Complications occurred in 3/39 of therapeutic procedures (2-minor delayed bleeding; 1-mucosal tear), all of them dealt with conservative or endoscopic therapy. Six patients underwent elective surgery post DBE due to polyps not amenable for endoscopic resection. There were no small-bowel polyp related complications during a median follow-up of 56.5 months. DBE showed to be a safe and effective technique in the management of small-bowel polyps in PJS patients, allowing a presymptomatic and non-surgical approach.