Editorial:Identification, risk stratification, and optimized management for Lynch Syndrome

Non peer reviewe

Clinical characteristics of pancreatic and biliary tract cancers in Lynch syndrome : A retrospective analysis from the Finnish National Lynch Syndrome Research Registry

IntroductionPatients with Lynch syndrome (LS) have an increased lifetime risk of pancreatic cancer (PC) and biliary tract cancer (BTC). These cancers have a notoriously pessimistic prognosis due to late diagnosis and limited therapeutic options. There are limited data based on small cohorts reviewing PC and BTC in LS patients. MethodsIn this retrospective study of the Lynch Syndrome Registry of Finland (LSRFi), records of genetically verified LS patients diagnosed with PC or BTC between 1982 and 2020 were analyzed. ResultsThirty-nine patients were included: tumor(s) were in the pancreas in 26 patients, in the biliary tract in 10, and in the ampulla of Vater in three. A pathogenic germline variant was found in MLH1 in 33 of 39 patients. Twenty-six patients with 28 tumors located in the pancreas were identified: 23 pancreatic ductal adenocarcinomas (PDACs) and five neuroendocrine tumors (NETs). The median age at diagnosis of PC was 64 years (range of 38-81). In PC, the 5-year overall survival (OS) rate was 20%, and in PDAC, it was 13.6%. Ten patients with BTC were diagnosed: two intrahepatic, five perihilar, two distal extrahepatic cholangiocarcinomas, and one gallbladder carcinoma. Eight patients were male, and the median age at diagnosis was 54 years (range of 34-82). The 5-year OS rate for BTC was 30%. Metachronous tumors were diagnosed in 28 patients (70%). Colorectal cancer was the most common metachronous tumor, diagnosed in 20 patients (51%), and diagnosed prior to PC or BTC in all cases. Curative surgery was attempted on 17 of 39 patients. For 30 patients (91%), the cause of death was PC or BTC; two patients died from another LS-associated cancer, and one died from a stroke. ConclusionAlthough the survival of LS patients with PC or BTC is better than in sporadic cancers, it is still poor and may be reflected by the relatively higher surgical resectability accounted for by the earlier age of onset. More studies on analyses of the molecular and immune profile, screening, and management of LS-associated pancreaticobiliary cancers are warranted.Peer reviewe

Vanhemmat pelikasvattajina Kärsämäellä:fenomenografinen tutkimus pelikasvatukseen liittyvistä käsityksistä

Tiivistelmä. Pro gradu -tutkielmamme tavoitteena on selvittää kärsämäkisten vanhempien käsityksiä liittyen digitaalisiin peleihin, pelaamiseen ja pelikasvatukseen. Tämän avulla pyrimme saamaan myös käsityksiä siitä, miten kärsämäkiset vanhemmat toteuttavat pelikasvatusta. Tutkimus on toteutettu laadullisena tutkimuksena, jossa hyödynnetään fenomenografista tutkimusotetta. Fenomenografialla voidaan saada esiin vallalla olevien käsitysten varianssi käsiteltävästä ilmiöstä, eli pelikasvatuksesta ja sen toteutumisesta kodin kontekstissa. Tutkimuksessa perustamme pelikasvatuksen käsitteen dialogiseen kasvatuskäsitykseen ja rakentamamme teoreettinen viitekehys pohjautuu aiheesta aiemmin tehtyyn niin ulkomaiseen kuin kotimaiseen tutkimukseen. Aineistomme koostuu helmikuussa 2022 sähköisellä kyselylomakkeella kerätyistä vastauksista. Aineisto kerättiin Kärsämäen Frosteruksen koulun huoltajilta ja vastauksia saatiin yhteensä 23 kappaletta. Kyselyn vastaukset analysoitiin fenomenografisella analyysimenetelmällä. Analyysin tuloksena syntyi kolme kuvauskategoriaa: vanhempien käsitykset lastensa digitaalisista peleistä ja pelaamisesta, vanhempien käsitykset pelikasvatuksesta ja vanhempien käsitykset kodin pelikasvatuksesta. Kärsämäkiset vanhemmat käsittivät niin pelaamisen kuin pelikasvatuksen monipuolisena toimintana. Vanhempien käsitysten mukaan lasten peliharrastus ei rajoitu ainoastaan pelaamiseen, vaan siihen liittyy myös esimerkiksi videoiden katselua. Vanhemmat tunnistivat myös monipuolisesti peleihin ja pelaamiseen liittyviä hyötyjä ja haittoja. Vanhempien vastauksista välittyi aikaisemman tutkimuksen mukaisia rajoittavia, aktiivisia ja yhteisöllisiä tapoja toteuttaa pelikasvatusta. Yksittäisistä pelikasvatuksellisista käsittelytavoista esiin nousi erityisesti pelaamisen rajoittaminen. Yleisimpänä pelaamisen rajoittamista edustavana työkaluna on ruutuajan rajoittaminen. Vanhempien käsitykset peleistä, pelaamisesta ja pelikasvatuksesta antavat teoreettisesti pätevän pohjan toimivalle pelikasvatukselle

Mitä ovat pakohuoneet ja millaisia oppimistehtäviä niiden avulla voidaan toteuttaa?

Tiivistelmä. Tämän kandidaatintutkielman tavoitteena on selvittää mitä ovat pakohuoneet, millaisia oppimistehtäviä niiden avulla voidaan toteuttaa ja kuinka ne tukevat oppimista. Tutkielma on toteutettu kirjallisuuskatsauksena, jossa on hyödynnetty pääosin kansainvälisiä, mutta myös kotimaisia julkaisuja. Luvussa kolme määritellään pelillistämisen ja pelioppimisen käsitteet sekä tarkastellaan pakopelejä ja pakohuoneita niiden kontekstissa. Tutkielmassa eritellään pakohuoneiden eri rakenteita ja niiden ratkaisemiseen vaadittavia taitoja. Luvussa neljä esitellään erilaisia opetuskäytössä toteutettuja pakohuoneiden sovelluksia. Pakohuoneita on tutkittu etenkin lääketieteen opetuksen yhteydessä. Lisäksi tutkielmassa tarkastellaan pakohuoneita käsitteleviä kokoavia tutkimuksia. Aiemman tutkimuksen perusteella voidaan todeta pakohuoneilla olevan potentiaalia opetuskäytössä. Niiden selkeänä vahvuutena on monipuolisuus ja soveltuvuus erilaisille oppijoille. Pakohuoneet voivat vaatia paljon erilaisia taitoja, joita oppijat pääsevät harjoittamaan ryhmätyötilanteissa. Erilaiset tehtävätyypit ja ryhmässä toimiminen mahdollistavat osallistumisen oppijan omien vahvuuksien ehdoilla. Pakohuoneilla on usein pyritty harjoittelemaan etenkin ryhmätyöskentelytaitoja, ja aineiston perusteella pakohuoneilla on ollut myönteinen vaikutus niiden kehittymiselle. Haasteena pakohuoneiden oppimiskäytössä on oppimisen mittaaminen ja arviointi. Tutkimustulokset perustuvat pitkälti oppijoiden omiin kokemuksiin oppimisesta. Lisäksi pakohuoneiden järjestäminen vaatii aikaa ja tilaa, joita opetusta järjestettäessä on usein rajallisesti. Haasteita ajankäyttöön tuo pakohuoneen rajattu pelaajamäärä. Opetuskontekstissa pakohuoneita on vielä tämän tutkielman julkaisuhetkellä tutkittu vähän. Tähän mennessä tutkimus on keskittynyt korkeakouluihin, eikä sitä ole toteutettu vielä peruskouluissa huomattavissa määrin

Prospective observational data informs understanding and future management of Lynch syndrome: insights from the Prospective Lynch Syndrome Database (PLSD)

The Prospective Lynch Syndrome Database (PLSD) has been developed as an international, multicentre, prospective, obser- vational study that aims to provide age and organ-specific cancer risks according to gene and gender, estimates of survival after cancer and information on the effects of interventions. Recent reports from PLSD provided improved estimates of cancer risks and survival and showed that different time intervals between surveillance colonoscopies did not affect the incidence, stage or prognosis of colorectal cancer. The PLSD reports suggest that current management guidelines for Lynch syndrome should be revised in light of the different gene and gender-specific cancer risks and the good prognosis for the most commonly associated cancers. In this review, we describe the discrepancies between the current management guidelines for Lynch Syndrome and the most recent prospective observational studies, indicating the areas of further research.Peer reviewe

High immune cell infiltration predicts improved survival in cholangiocarcinoma

BackgroundAntitumoral immune response has a crucial role in constraining cancer. However, previous studies on cholangiocarcinoma (CCA), a rare and aggressive cancer, have reported contradictory findings on the prognostic impact of tumor-infiltrating T-lymphocytes. We aimed to clarify the effect of tumor-infiltrating CD3+ and CD8+ lymphocytes and PD-1/PD-L1 expression on CCA prognosis.MethodsCD3+, CD8+, and PD-1+ lymphocyte densities, as well as PD-L1 expression rate were analyzed from stained tissue microarray samples from the tumor center and invasive margin of 47 cholangiocarcinomas. The association of CD3+ and CD8+ based Immune cell score (ICS) and its components with overall survival was evaluated, adjusting for age, sex, TNM stage, radicality of surgery, tumor location, and PD-L1 expression on immune cells.ResultsLow ICS was a strong independent prognostic factor for worse overall survival (Hazard ratio 9.27, 95% confidence interval 2.72-31.64, P<0.001). Among the ICS components, high CD8+ lymphocyte infiltration at the tumor center had the most evident impact on patient outcome. PD-1 and PD-L1 expression on immune cells did not have a significant impact on overall survival alone; however, PD-L1 positivity seemed to impair survival for ICSlow subgroup.ConclusionIdentifying patient subgroups that could benefit from immunotherapy with PD-1/PD-L1 pathway blockade may help improve treatment strategies for this aggressive cancer. Our findings highlight the importance of evaluating the immune contexture in cholangiocarcinoma, as ICS serves as a strong independent prognostic and selective factor for patients who might benefit from immunotherapy

Variation in the risk of colorectal cancer in families with Lynch syndrome: a retrospective cohort study

doi: 10.1016/S1470-2045(21)00189-3Findings 5585 families with Lynch syndrome from 22 countries were eligible for the analysis. Of these, there were insufficient numbers to estimate penetrance for Asia and South America, and for those with EPCAM variants. Therefore, we used data (collected between July 11, 2014, and Dec 31, 2018) from 5255 families (1829 MLH1, 2179 MSH2, 798 MSH6, and 449 PMS2), comprising 79 809 relatives, recruited in 15 countries in North America, Europe, and Australasia. There was strong evidence of the existence of unknown familial risk factors modifying colorectal cancer risk for Lynch syndrome carriers (p 0 center dot 0001 for each of the three three continents). These familial risk factors resulted in a wide within-gene variation in the risk of colorectal cancer for men and women from each continent who all carried pathogenic variants in the same gene or the MSH2 c.942+3A T variant. The variation was especially prominent for MLH1 and MSH2 variant carriers, depending on gene, sex and continent, with 7-56% of carriers having a colorectal cancer penetrance of less than 20%, 9-44% having a penetrance of more than 80%, and only Background Existing clinical practice guidelines for carriers of pathogenic variants of DNA mismatch repair genes (Lynch syndrome) are based on the mean age-specific cumulative risk (penetrance) of colorectal cancer for all carriers of pathogenic variants in the same gene. We aimed to estimate the variation in the penetrance of colorectal cancer between carriers of pathogenic variants in the same gene by sex and continent of residence. Methods In this retrospective cohort study, we sourced data from the International Mismatch Repair Consortium, which comprises 273 members from 122 research centres or clinics in 32 countries from six continents who are involved in Lynch syndrome research. Families with at least three members and at least one confirmed carrier of a pathogenic or likely pathogenic variant in a DNA mismatch repair gene (MLH1, MSH2, MSH6, or PMS2) were included. The families of probands with known de-novo pathogenic variants were excluded. Data were collected on the method of ascertainment of the family, sex, carrier status, cancer diagnoses, and ages at the time of pedigree collection and at last contact or death. We used a segregation analysis conditioned on ascertainment to estimate the mean penetrance of colorectal cancer and modelled unmeasured polygenic factors to estimate the variation in penetrance. The existence of unknown familial risk factors modifying colorectal cancer risk for Lynch syndrome carriers was tested by use of a Wald p value for the null hypothesis that the polygenic SD is zero. Findings 5585 families with Lynch syndrome from 22 countries were eligible for the analysis. Of these, there were insufficient numbers to estimate penetrance for Asia and South America, and for those with EPCAM variants. Therefore, we used data (collected between July 11, 2014, and Dec 31, 2018) from 5255 families (1829 MLH1, 2179 MSH2, 798 MSH6, and 449 PMS2), comprising 79 809 relatives, recruited in 15 countries in North America, Europe, and Australasia. There was strong evidence of the existence of unknown familial risk factors modifying colorectal cancer risk for Lynch syndrome carriers (pT variant. The variation was especially prominent for MLH1 and MSH2 variant carriers, depending on gene, sex and continent, with 7-56% of carriers having a colorectal cancer penetrance of less than 20%, 9-44% having a penetrance of more than 80%, and only 10-19% having a penetrance of 40-60%. Interpretation Our study findings highlight the important role of risk modifiers, which could lead to personalised risk assessments for precision prevention and early detection of colorectal cancer for people with Lynch syndrome. Funding National Health and Medical Research Council, Australia. Copyright (c) 2021 Elsevier Ltd. All rights reserved. Methods In this retrospective cohort study, we sourced data from the International Mismatch Repair Consortium, which comprises 273 members from 122 research centres or clinics in 32 countries from six continents who are involved in Lynch syndrome research. Families with at least three members and at least one confirmed carrier of a pathogenic or likely pathogenic variant in a DNA mismatch repair gene (MLH1, MSH2, MSH6, or PMS2) were included. The families of probands with known de-novo pathogenic variants were excluded. Data were collected on the method of ascertainment of the family, sex, carrier status, cancer diagnoses, and ages at the time of pedigree collection and at last contact or death. We used a segregation analysis conditioned on ascertainment to estimate the mean penetrance of colorectal cancer and modelled unmeasured polygenic factors to estimate the variation in penetrance. The existence of unknown familial risk factors modifying colorectal cancer risk for Lynch syndrome carriers was tested by use of a Wald p value for the null hypothesis that the polygenic SD is zero.Peer reviewe

Cancer Prevention with Resistant Starch in Lynch Syndrome Patients in the CAPP2-Randomized Placebo Controlled Trial : Planned 10-Year Follow-up

The CAPP2 trial investigated the long-term effects of aspirin and resistant starch on cancer incidence in patients with Lynch syndrome (LS). Participants with LS were randomized double-blind to 30 g resistant starch (RS) daily or placebo for up to 4 years. We present long-term cancer outcomes based on the planned 10-year follow-up from recruitment, supplemented by National Cancer Registry data to 20 years in England, Wales, and Finland. Overall, 463 participants received RS and 455 participants received placebo. After up to 20 years follow-up, there was no difference in colorectal cancer incidence (n = 52 diagnosed with colorectal cancer among those randomized to RS against n = 53 on placebo) but fewer participants had non-colorectal LS cancers in those randomized to RS (n = 27) compared with placebo (n = 48); intention-to-treat (ITT) analysis [HR, 0.54; 95% confidence interval (CI), 0.33-0.86; P = 0.010]. In ITT analysis, allowing for multiple primary cancer diagnoses among participants by calculating incidence rate ratios (IRR) confirmed the protective effect of RS against non-colorectal cancer LS cancers (IRR, 0.52; 95% CI, 0.32-0.84; P= 0.0075). These effects are particularly pronounced for cancers of the upper GI tract; 5 diagnoses in those on RS versus 21 diagnoses on placebo. The reduction in non-colorectal cancer LS cancers was detectable in the first 10 years and continued in the next decade. For colorectal cancer, ITT analysis showed no effect of RS on colorectal cancer risk (HR, 0.92; 95% CI, 0.62-1.34; P = 0.63). There was no interaction between aspirin and RS treatments. In conclusion, 30 g daily RS appears to have a substantial protective effect against non-colorectal cancer cancers for patients with LS. Prevention Relevance: Regular bowel screening and aspirin reduce colorectal cancer among patients with LS but extracolonic cancers are difficult to detect and manage. This study suggests that RS reduces morbidity associated with extracolonic cancers.Peer reviewe