Surveillance of Individuals with a Family History of Pancreatic Cancer and Inherited Cancer Syndromes: A Strategy for Detecting Early Pancreatic Cancers

Matsubayashi, Hiroyuki; Kiyozumi, Yoshimi; Ishiwatari, Hirotoshi; Uesaka, Katsuhiko; Kikuyama, Masataka; Ono, Hiroyuki

doi:10.3390/diagnostics9040169

Cited by 8 publications

(6 citation statements)

References 114 publications

(166 reference statements)

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“…Although more challenging to demonstrate in a clinical trial, mebendazole may have promise as a chemoprevention either alone or in combination with anti-inflammatories in those patients at high risk for developing pancreatic cancer, including mucinous lesions and certain inherited cancer syndromes that account for 5-10% of PDAC [35][36][37]. A starting point for future studies is to generate additional evidence and to optimize mebendazole for use as an adjuvant therapy to prevent metastasis and slow tumor progression after surgery in patients diagnosed with non-metastatic pancreatic cancer.…”

Section: Discussionmentioning

confidence: 99%

Mebendazole disrupts stromal desmoplasia and tumorigenesis in two models of pancreatic cancer

et al. 2021

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The five-year survival rate for metastatic pancreatic cancer is currently only 3%, which increases to 13% with local invasion only and to 39% with localized disease at diagnosis. Here we evaluated repurposed mebendazole, an approved anthelminthic drug, to determine how mebendazole might work at the different stages of pancreatic cancer formation and progression. We asked if mebendazole could prevent initiation of pancreatic intraepithelial neoplasia precursor lesions, interfere with stromal desmoplasia, or suppress tumor growth and liver metastasis. In both the Kras LSL.G12D/+ ; Pdx1-Cre (KC) mouse model of caerulein-induced inflammatory pancreatitis and the Kras LSL.G12D/+ ; Tp53 R172H/+ ; Pdx1-Cre (KPC) mouse model of advanced pancreatic cancer, mebendazole significantly reduced pancreas weight, dysplasia and intraepithelial neoplasia formation, compared to controls. Mebendazole significantly reduced trichrome-positive fibrotic connective tissue and α-SMA-positive activated pancreatic stellate cells that heralds fibrogenesis. In the aggressive KPC model, mebendazole significantly suppressed pancreatic tumor growth, both as an early and late intervention. Mebendazole reduced the overall incidence of pancreatic cancer and severity of liver metastasis in KPC mice. Using early models of pancreatic cancer, treatment with mebendazole resulted in less inflammation, decreased dysplasia, with the later stage model additionally showing a decreased tumor burden, less advanced tumors, and a reduction of metastasis. We conclude that mebendazole should be investigated further as a component of adjuvant therapy to slow progression and prevent metastasis, and well as for primary prevention in the highest risk patients.

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Section: Discussionmentioning

confidence: 99%

Mebendazole disrupts stromal desmoplasia and tumorigenesis in two models of pancreatic cancer

et al. 2021

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“…Repeated small intestinal resections can result in short bowel syndrome [61,64,65,66 & ,67,68]. Patients with Peutz-Jeghers syndrome are exposed to a higher risk of malignancy, both gastrointestinal and extra-gastrointestinal [11,69,70]. A review of 20 studies (with 1644 patients) reported lifetime risk for any cancer between 37 and 93% [13].…”

Section: Complicationsmentioning

confidence: 99%

Peutz-Jeghers syndrome

Tachecí

Kopáčová²,

Bureš³

2021

Current Opinion in Gastroenterology

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Purpose of review Peutz-Jeghers syndrome is a rare, autosomal dominant, hereditary polyposis syndrome defined by gastrointestinal hamartomas and mucocutaneous pigmentations, caused by a germline mutation in the serine/ threonine kinase 11 or liver kinase B1 (STK11/LKB1) genes. Hamartomatous polyps located throughout the gastrointestinal tract can be complicated by bleeding and small bowel intussusception, potentially leading to the need for emergency surgery. Individuals suffering from Peutz-Jeghers syndrome have an increased lifetime risk of various forms of cancer (gastrointestinal, pancreatic, lung, breast, uterine, ovarian and testicular). Surveillance should lead to the prevention of complications and thus a reduction in mortality and morbidity of patients. Recent findings A combined approach based on wireless capsule endoscopy, magnetic resonance enterography and device-assisted enteroscopy is effective in reduction of the polyp burden and thus decreasing the risk of bleeding and intussusception. Current guidelines for screening and surveillance are mostly based on expert opinion rather than evidence. Summary Peutz-Jeghers syndrome is an emerging disease that significantly affects the quality of life enjoyed by patients. Despite of all the progress in improved early diagnostics, options for advanced endoscopic therapy and elaborate surveillance, acute and chronic complications decrease the life expectancy of patients suffering from Peutz-Jeghers syndrome.

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“…Associations with ovarian SCTAT and uterine cervical LEGH and MDA have been highlighted in the field of gynecology, and an association with endometrial cancer has recently gained interest based on case reports and genetic studies [33][34][35][36] .…”

Section: Clinical Characteristics Of Pjsmentioning

confidence: 99%

Role of the Serine/Threonine Kinase 11 (STK11) or Liver Kinase B1 (LKB1) Gene in Peutz-Jeghers Syndrome

Altamish

Dahiya

Singh

et al. 2020

Crit Rev Eukaryot Gene Expr

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Peutz-Jeghers syndrome (PJS) is a well-described inherited syndrome, characterized by the development of gastrointestinal polyps, and characteristic mucocutaneous freckling. PJS, an autosomal prevailing disease due to genetic mutation on chromosome 19p, manifested by restricted mucocutaneous melanosis in association with gastrointestinal (GI) polyposis. The gene for PJS has recently been shown to be a serine/threonine kinase, known as LKB1 or STK11, which maps to chromosome subband 19p13.3. This gene has a putative coding region of 1302 bp, divided into nine exons, and acts as a tumour suppressor in the hamartomatous polyps of PJS patients and in the other neoplasms which develop in PJS patients. It is probable that these neoplasms develop from hamartomas, but remains possible that the LKB1 or STK11 locus plays a role in a different genetic pathway of tumour growth in the cancers of PJS patients. This article has focused on role of LKB1 or STK11 gene expression in PJS and related cancers.

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Surveillance of Individuals with a Family History of Pancreatic Cancer and Inherited Cancer Syndromes: A Strategy for Detecting Early Pancreatic Cancers

Cited by 8 publications

References 114 publications

Mebendazole disrupts stromal desmoplasia and tumorigenesis in two models of pancreatic cancer

Mebendazole disrupts stromal desmoplasia and tumorigenesis in two models of pancreatic cancer

Peutz-Jeghers syndrome

Role of the Serine/Threonine Kinase 11 (STK11) or Liver Kinase B1 (LKB1) Gene in Peutz-Jeghers Syndrome

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