Chemoprevention in Patients with Peutz-Jeghers Syndrome: Lessons Learned.

LESSONS LEARNED: Motivating patients to enroll in chemopreventive studies is challenging.Chemoprevention with toxic drugs is not feasible. BACKGROUND: LKB1 mutations are the underlying genetic abnormality causing Peutz-Jeghers syndrome (PJS) and are a potential target for everolimus. In this phase II study, the efficacy of everolimus on polyp and tumor growth in PJS patients was investigated. METHODS: Adult patients with a proven LKB1 mutation and who were suitable for everolimus treatment were included in two different PJS cohorts: (a) patients with unresectable malignancies and (b) patients with high-risk polyps. Treatment in both groups was oral everolimus, 10 mg daily. Response rates were primary endpoints for both cohorts. RESULTS: Between October 2011 and April 2016, only two patients were enrolled, one in each cohort. A 49-year-old patient with advanced pancreatic cancer in cohort 1 was progressive after 2 months. A 52-year-old male patient in cohort 2 experienced severe toxicity and refused treatment after 4 months, even though endoscopy suggested stabilization of polyps. Adverse events included dental inflammations, mucositis, and rash. In 2016, the trial was aborted for lack of accrual, despite extensive accrual efforts in an area where PJS is highly prevalent and care is highly centralized. CONCLUSION: Due to accrual problems, no conclusions can be drawn about the value of everolimus in PJS treatment, questioning the feasibility of this agent for chemoprevention.

Hereditary breast cancer: an update on risk assessment and genetic testing in 2015.

The last 5 years have brought significant innovation and advancement in the genetics of breast cancer. This clinical opinion aims to summarize and update current approaches to the care of women at risk for a hereditary predisposition to breast cancer. Implications of the BRCA mutation and several other hereditary syndromes will be discussed. Risk assessment and criteria for referral to cancer genetic professionals as well as high-risk screening and prophylactic options will be reviewed. Finally, the newly available genetic cancer panels and implications of mutations in some of these lesser known genes will be discussed. As the field of cancer genetics continues to evolve, the education of medical students, residents, and faculty will be paramount to identify appropriate candidates for genetic counseling and testing in conjunction with cancer genetic professionals.

A rationale for mTOR inhibitors as chemoprevention agents in Peutz-Jeghers syndrome.

Peutz-Jeghers patients frequently develop clinically significant complications, namely hemorrhage and bowel obstruction, from small intestinal hamartomatous polyps that frequently require surgery. In addition, many PJS patients develop epithelial malignancies in a variety of organs. The vast majority of PJS is due to germline alterations in the STK11 gene that encodes a protein that modulates PI3-kinase signaling, a key regulator of cell survival and growth. One of the major downstream mediators of PI3-kinase signaling is mTOR, the mammalian target of rapamycin. Several drugs that inhibit the PI3-kinase signal transduction pathway are in development and one, RAD001 (everolimus), an mTOR inhibitor, was recently approved for the treatment of renal cell carcinoma. Effective chemoprevention of intestinal polyps would be a first step in simplifying and improving the management of PJS patients. We present here, the rationale for the first human PJS chemoprevention trial using an mTOR inhibitor.

Chemopreventive efficacy of rapamycin on Peutz-Jeghers syndrome in a mouse model.

Germline mutations in LKB1 cause Peutz-Jeghers syndrome (PJS), an autosomal dominant disorder with a predisposition to gastrointestinal polyposis and cancer. Hyperactivation of mTOR-signaling has been associated with PJS. We previously reported that rapamycin treatment of Lkb1(+/-) mice after the onset of polyposis reduced the polyp burden. Here we evaluated the preventive efficacy of rapamycin on Peutz-Jeghers polyposis. We found that rapamycin treatment of Lkb1(+/-) mice initiated before the onset of polyposis in Lkb1(+/-) mice led to a dramatic reduction in both polyp burden and polyp size and this reduction was associated with decreased phosphorylation levels of S6 and 4EBP1. Together, these findings support the use of rapamycin as an option for chemoprevention and treatment of PJS.

[Screening and surveillance for hereditary polyposis and non-polyposis syndromes with capsule endoscopy]. / Hereditaer intestinalis polyposis- és nem polyposisos szindrómák követése és szurése kapszulás endoszkópiával.

The hereditary polyposis syndromes and non-polyposis colorectal carcinoma have been considered as scarcely occurring but inheritable dominant autosomal syndromes. The increasing risk of small bowel carcinoma and prevention of obstruction and intussusception have been making frequent and acute surgical interventions unavoidably led to the necessity of screening and surveillance the patients. Earlier the diagnosis of these symptoms was difficult to establish because traditional radiological methods have a low yield for small polyps. Furthermore, small bowel is only partially accessible with traditional endoscopic techniques such as upper endoscopy, colonoscopy and push-enteroscopy. The "wireless" capsule endoscopy has opened the way then for the non-invasive and painless test of the entire small intestine. - Test results have been cumulated to justify the efficiency and safety of capsule endoscopy concerning the syndromes above. This method can be applied safely even consequently to repeatedly performed surgical interventions by low risk of capsule retention. As the results compared of the diagnosed familial adenomatous polyposis and of Peutz-Jeghers syndrome reflect on capsule endoscopy, its diagnostic sensitiveness is stated as significantly higher than the Barium-contrast X-Ray and MR-enterography. Nevertheless, determination of size and location of polyps has become more problematic when evaluating the test results.

LKB1 signaling in mesenchymal cells required for suppression of gastrointestinal polyposis.

Germline mutations in STK11 (also known as LKB1) are found in individuals with Peutz-Jeghers syndrome (PJS) manifesting with gastrointestinal polyps that contain a prominent stromal component. Epithelia in polyps of Stk11(+/-) mice can retain a functional copy of Stk11 (refs. 2,3), and loss of heterozygosity is not an obligate feature of human polyps, raising the possibility of non-epithelial origins in tumorigenesis. Here we show that either monoallelic or biallelic loss of murine Stk11 limited to Tagln-expressing mesenchymal cells results in premature postnatal death as a result of gastrointestinal polyps indistinguishable from those in PJS. Stk11-deficient mesenchymal cells produced less TGFbeta, and defective TGFbeta signaling to epithelial cells coincided with epithelial proliferation. We also noted TGFbeta signaling defects in polyps of individuals with PJS, suggesting that the identified stromal-derived mechanism of tumor suppression is also relevant in PJS.

Consecuencias dentales después del tratamiento quirúrgico en un paciente con síndrome de Peutz-Jeghers / Dental consequences after surgical treatment in a patient with Peutz-Jeghers syndrome

El síndrome de Peutz-Jeghers, aunque clásico, es una entidad poco conocida que se transmite hereditariamente como un rasgo autonómico dominante caracterizado por pólipos intestinales hamartomatosos, depósitos mucocutáneos de melanina, y un elevado riesgo de cáncer. En este artículo presentamos el caso de un joven de 18 años, sin antecedentes familiares del síndrome, que fue tratado de urgencia por obstrucción intestinal. Le fue practicada una enterectomía que dio origen a un síndrome de intestino corto, que condujo aparentemente a caries rampante. Dos años después el paciente perdió todos sus dientes y actualmente usa dentaduras. El diagnóstico temprano del síndrome puede ser realizado por el dentista antes de la obstrucción intestinal para que el tratamiento quirúrgico sea conservador y así evitar el síndrome de intestino corto y sus consecuencias.

Peutz-Jeghers syndrome, although a classic, but not widely known entity, is a hereditary condition, with an autosomal dominant condition characterized by intestinal hamartomatous polyps, mucocutaneous melanin depositis, and increased risk of cancer. This paper reports an 18-year-old patient with no family history of the disease, who underwent surgery for treatment of an intestinal occlusion. Enterectomy was performed and the outcome was short bowel syndrome and rampant caries. Two years later the patient lost all his teeth and actually uses dentures. Early diagnosis can be done by dentist prior to intestinal occlusion for the conservative surgical treatment that prevents small short bowel syndrome and its consequences.

[Sporadic and hereditary colorectal cancer. Pathogenetically different with different therapeutic indications]. / Sporadisches und hereditäres Karzinom von Kolon und Rektum. Pathogenetisch different mit unterschiedlicher Therapieindikation.

In recent years, there have been major advances regarding the understanding of the pathogenesis of sporadic and hereditary colorectal cancer on the basis of molecular research. The clinical implications of this knowledge differ for the sporadic and hereditary forms. In sporadic colorectal cancer, gene mutations occur in colorectal cells but not as germline mutations. Even though molecular data currently do not influence the clinical management of this form of colorectal cancer, promising molecular approaches exist for the assessment of prognosis, early detection, prevention, and therapy. Germline mutations are the cause of hereditary colorectal cancers, in which molecular methods have a major impact on diagnosis and therapy. Prophylactic surgery is accepted for patients with familial adenomatous polyposis (FAP), but not for patients with hereditary non-polyposis colorectal cancer (HNPCC), the second main form of hereditary colorectal cancer. Further studies will have to clarity this issue.

Heritable colorectal cancer syndromes: recognition and preventive management.

Familial CRC syndromes account for a small yet important portion of colorectal malignancies. HNPCC, FAP, JPS, and Peutz-Jeghers syndrome are the four major conditions to r to consider if an hereditary condition is suspected in an individual with CRC. A multidisciplinary team comprised of a medical geneticist, gastroenterologist, pathologist, radiologist, and colorectal surgeon with expertise in recognizing and establishing the diagnosis of a specific familial cancer condition is crucial to implementing the proper management and prevention strategies unique to each of these syndromes. Genetic testing for each of these coniditions is available and useful for presymptomatic diagnosis and for indicated surveillance regimens. Vigilant endoscopic surveillance and careful timing of surgery are the mainstays of prevention for gastrointestinal malignancies. But with the advancement of genetic evaluation, improved cancer surveillance for intestinal as well as extraintestinal cancer, and chemopreventive strategies, the management of patients with a familial CRC syndrome will continue to evolve and, hopefully, significantly reduce their cancer burden.

Preventive measures in Peutz-Jeghers syndrome.

Peutz-Jeghers syndrome is a rare genetic disorder characterized by mucocutaneous melanin deposition, intestinal polyposis and an increased risk of cancer, both intestinal and extra-intestinal. We describe the current status of diagnosis and the methods by which the consequences of this condition can be minimized. A surveillance program for those diagnosed is also included.

[Strategies for genetic counseling and examination of families with hereditary tumor diseases]. / Strategien für die genetische Beratung und Untersuchung von Familien mit erblichen Tumorerkrankungen.

Although everybody is at some risk of developing cancer, individuals whose families show certain characteristics might be at high risk. The existence of families with hereditary cancers have been known for a long time. Meanwhile several genes for these dispositions have been identified, which gives high-risk individuals the opportunity to choose presymptomatic testing. This leads to a new group of "patients", the healthy gene carriers. Genetic counselling is a process which includes verification of diagnosis, pedigree analysis, individual risk assessment, explanation of complex medical and genetic facts and the choice of possible options to deal with the genetic burden (e.g. coping strategies, prevention). Presently cancer gene testing has 2 clinical applications. In affected individuals it is part of the diagnostic procedure, in at risk individuals it segregates gene carriers from non-carriers. With regard to the healthy carriers of highly penetrant mutated genes and to some extend also with regard to the non-carriers this means new medical, psychological, social and ethical tasks. Genetic counselling should be offered to any family with a history of cancer or cancer-linked conditions. It has to be considered that not only patients and their families are laymen with regard to medicine, but that we all are laymen with regard to the leading a life with the knowledge of once own deleterious heritage.

Genetics of colonic cancer.

Research in hereditary forms of colorectal cancer (CRC) has increased almost logarithmically thanks in a major way to momentous discoveries in molecular genetics during the past decade. Between 10 and 20% of the total CRC burden is due to Mendelian-inherited CRC syndromes. The paradigm for hereditary CRC is familial adenomatous polyposis (FAP), wherein the APC germ-line mutation has been identified. This has contributed to the elucidation of genomic and clinical heterogeneity within the syndrome, wherein an attenuated form of FAP has been identified as a result of intragenic mutations within this large APC gene. The most common form of hereditary CRC is hereditary nonpolyposis colorectal cancer (HNPCC). Several mutator genes, namely hMSH2, hMLH1, hPMS1, hPMS2 and, more recently, hMSH6/GTBP, have been identified. These molecular genetic discoveries are providing new insights into the pathogenesis of CRC. Individuals within these kindreds who are harbingers of these germ-line mutations will benefit from screening and, one day, chemoprevention.