Gastric Cancer: A Practical Review on Management of Individuals with Hereditary or Familial Risk for Gastric Cancer.

Gastric adenocarcinoma is one of the most frequent and deadly cancers worldwide. However, its incidence is variable, being higher in eastern countries where screening the general population is recommended. On the other hand, in low to intermediate-risk countries, screening the general population may not be cost-effective, and therefore, it is necessary to be aware of high-risk populations that may benefit from adequate screening and surveillance. It is not always easy to identify these individuals, leading to a late diagnosis of gastric adenocarcinoma. In this review, the authors intend to summarize the data required to identify the population at risk of sporadic or familial gastric adenocarcinoma and the beginning of screening and its surveillance, with the final aim of increasing early detection of gastric adenocarcinoma and decreasing morbimortality. The authors highlight the importance to be aware of the several hereditary syndromes and MAPS recommendations and apply screen and surveillance protocols. The high-risk syndromes to gastric adenocarcinoma are gastric adenocarcinoma and proximal polyposis of the stomach, hereditary diffuse gastric cancer, and familial intestinal gastric cancer.

O adenocarcinoma gástrico é um dos cancros mais frequentes e mortais em todo o mundo. No entanto, a sua incidência é variável, sendo maior nos países orientais, onde o rastreio da população geral está recomendado. Por outro lado, nos países de risco baixo a intermediário, o rastreio da população geral pode não ser custo-efetivo e, portanto, é necessário conhecer quais são as populações de alto risco que podem beneficiar de rastreio e vigilância adequados. Porém, nem sempre é fácil identificar esses indivíduos levando a um diagnóstico tardio de adenocarcinoma gástrico. Nesta revisão, os autores pretendem resumir a informação necessária à identificação da população em risco de adenocarcinoma gástrico esporádico ou familiar e o início do rastreio e sua vigilância, com o objetivo final de otimizar a deteção precoce do adenocarcinoma gástrico e diminuir a morbimortalidade. Os autores salientam a importância de conhecer as diversas síndromes hereditárias e recomendações MAPS e aplicar protocolos de rastreio e vigilância. As síndromes de maior risco para adenocarcinoma gástrico são GAPPS, HDGC e FIGC.

The Contribution of the Sheep and the Goat Model to the Study of Ovarian Ageing.

Ovarian ageing stands as the major contributor towards fertility loss. As such, there is an urge for studies addressing the mechanisms that promote ovarian ageing and new strategies aiming to delay it. Recently, the presence of a unique population of multinucleated giant cells has been identified in the ovaries of reproductively aged mice. These cells have been considered hallmarks of ovarian ageing. However, up to date multinucleated giant cells have only been described in the ovaries of the mice. Therefore, the aim of the present work was to evaluate and characterize the presence of such hallmarks of ovarian ageing in the sheep and the goat. In this study, ovaries from juvenile (6 months) and mature animals (18-24 months) were used. The hematoxylin and eosin technique was performed to describe the ovarian morphology and evaluate the ovarian follicle reserve pool. Sudan black B staining and the detection of autofluorescence emission were used to identify and characterize the presence of multinucleated giant cells. Statistical analyses were performed with GraphPad Prism 9.0.0. A decrease in the follicle reserve pool and the presence of multinucleated giant cells, with lipofuscin accumulation and the emission of autofluorescence, were observed in the ovaries of the mature animals of both species. Our results support the interest in the use of the ovine and the caprine model, that share physiological and pathophysiological characteristics with humans, in future studies addressing ovarian ageing.

Biallelic mismatch repair deficiency – A rare and troublesome genetic syndrome

Biallelic mismatch repair deficiency (BMMRD) is a rare autosomal recessive disorder characterized by numerous early-onset cancers, especially gastrointestinal tumors. Biallelic germline mutations in one of four mismatch repair (MMR) genes (MLH1, MSH2, MSH6, or PMS2) cause this devastating disease. Given the rarity of the syndrome, often-asymptomatic tumors, diagnosis is frequently unrecognized or delayed. A high degree of clinical awareness is needed to identify new cases. Immunohistochemical assessment of MMR protein expression and analysis of microsatellite instability are the first tools with which to initiate the study of this syndrome in solid malignancies. MMR immunohistochemical shows a hallmark pattern with absence of staining in both neoplastic and non-neoplastic cells for the biallelic mutated gene. We present a unique case of a young boy diagnosed with invasive colon adenocarcinoma and brain tumor, with classical BMMRD features, found to have biallelic pathogenic PMS2 mutations. (AU)

Mechanical circulatory support in children: Strategies, challenges and future directions.

INTRODUCTION: The use of mechanical circulatory support (MCS) in the pediatric population has evolved significantly in the past 20 years, but its management still poses several challenges. We aim to describe patient characteristics, outcomes, and morbidity associated with different modalities of MCS, in a tertiary center. METHODS: Retrospective analysis of data from all the children who underwent MCS between 2002 and 2018 at a pediatric cardiology unit. RESULTS: Between 2002 and 2018, 22 devices were implanted in 20 patients. Patients were divided into three groups: Group A (n=11) extracorporeal membrane oxygenator (ECMO); Group B (n=8) pulsatile paracorporeal ventricular assist device (VAD) and group C (n=3) paracorporeal continuous flow VAD. The median age was similar in groups A and B (18 and 23 months, respectively), and higher in group C (13 years). ECMO patients were cannulated mainly as a bridge to recovery (post cardiotomy- 8) while group B and C patients were bridged to transplantation. The most frequent complications were bleeding (group A - 36%, group C - 66.6%) and thromboembolic events (group B - 50%, group C - 33.3%). As for outcomes, in group A the majority of patients (54.5%) were weaned and 27.3% died. Half of group B and all of group C patients underwent transplantation. CONCLUSION: Bleeding and thromboembolic events were the main complications observed. Group B showed the highest mortality, probably related to the low weight of the patients. Overall, outcomes and complications are related to the type of device and patient status and characteristics.

Risk factors for gastric cancer in patients with Lynch syndrome.

INTRODUCTION: The cumulative lifetime risk of gastric cancer (GC) in patients with Lynch syndrome (LS) is reported to be 8%. There is limited evidence on specific risk factors for GC and no agreement among guidelines on gastric endoscopic surveillance schedule in LS patients. AIMS AND METHODS: We conducted a retrospective cohort study to identify risk factors for gastric precancerous conditions (chronic atrophic gastritis and intestinal metaplasia) and GC in patients with LS and a case-control study to compare the prevalence of these conditions with a control group. RESULTS: We included 385 LS patients (40.5% male, mean age 49.0 years). During a median follow-up period of 48 months (interquartile range, 24-84 months), precancerous conditions were identified in 110 patients (34%) and the prevalence of advanced stages of atrophic gastritis was 3% for OLGA III/IV and 0.6% OLGIM III/IV. Family history of GC was significantly associated with OLGA III/IV ( P = 0.020). Among LS patients, 10 patients (2.6%) were diagnosed with GC (incidence rate of 5/1000 persons-year). Older age and OLGA III/IV were identified as risk factors for GC ( P < 0.001). When compared with controls, patients with LS had significantly higher rates of Hp infection ( P = 0.035) and lower OLGA and OLGIM stages ( P < 0.001 and P = 0.026, respectively). CONCLUSION: In our cohort, the incidence of GC and advanced stages of atrophic gastritis was low. Older age and OLGA III/IV were associated with a higher risk of GC. Identification of risk factors for GC in LS patients can help tailoring endoscopic surveillance.

Biallelic mismatch repair deficiency - A rare and troublesome genetic syndrome.

Biallelic mismatch repair deficiency (BMMRD) is a rare autosomal recessive disorder characterized by numerous early-onset cancers, especially gastrointestinal tumors. Biallelic germline mutations in one of four mismatch repair (MMR) genes (MLH1, MSH2, MSH6, or PMS2) cause this devastating disease. Given the rarity of the syndrome, often-asymptomatic tumors, diagnosis is frequently unrecognized or delayed. A high degree of clinical awareness is needed to identify new cases. Immunohistochemical assessment of MMR protein expression and analysis of microsatellite instability are the first tools with which to initiate the study of this syndrome in solid malignancies. MMR immunohistochemical shows a hallmark pattern with absence of staining in both neoplastic and non-neoplastic cells for the biallelic mutated gene. We present a unique case of a young boy diagnosed with invasive colon adenocarcinoma and brain tumor, with classical BMMRD features, found to have biallelic pathogenic PMS2 mutations.

"I have always lived with the disease in the family": family adaptation to hereditary cancer-risk.

BACKGROUND: Hereditary cancer syndromes have been conceptualized as a family level process. The present study explores the complexity and challenges of family adaptation to the hereditary cancer syndrome, in the context of genetic counseling and long-term cancer risk management and follow-up surveillance. METHODS: We performed semi-structured interviews with 13 participants with one of the following hereditary cancer syndromes: Lynch Syndrome, Hereditary Diffuse Gastric Cancer Syndrome, Hereditary Breast and Ovarian Cancer Syndrome, or Familial Adenomatous Polyposis. The interview was developed through a participatory approach with the involvement of healthcare professionals and individuals with first-hand experience of living with the hereditary cancer syndromes. RESULTS: The family is the main source of information and emotional support to deal with hereditary cancer syndromes. Multiple individual adaptation processes and communal coping networks interact, influencing the emotional and health-related behavior of family members. This is affected and affects the family's communication and its' members reactions to disclosure, with consequent changes in relationships. CONCLUSIONS: The systemic interdependent dynamics of family adaptation calls for family-centered care of genetic cancer syndromes.

Diagnosis of MALT Lymphoma from Surveillance Endoscopy of a Patient with a CDH1 Gene Germline Mutation.

Carriers of the mutated CDH1 gene have an increased risk of developing early-onset signet-ring cell (diffuse) gastric cancer. We present a case of a young patient with a confirmed mutation of the CDH1 gene, who was diagnosed with a gastric marginal zone B-cell lymphoma (MZL) of mucosa-associated lymphoid tissue (MALT lymphoma) from surveillance endoscopy. He underwent Helicobacter pylori eradication treatment and was subsequently submitted to a total prophylactic gastrectomy. The surgical specimen only revealed foci of signet-ring cell carcinoma (SRCC) in situ without lymphoma signs. We highlight here the occurrence of other pathology in high-risk patients as well as its possible influence on the decision to perform gastrectomy.

A mutação do gene CDH1 determina um risco aumentado de desenvolvimento precoce de cancro gástrico de células em anel de sinete (tipo difuso). Apresentamos um caso de um doente jovem portador de uma mutação no gene CDH1 que foi diagnosticado com linfoma de MALT gástrico numa endoscopia de vigilância. O doente foi submetido a terapêutica de erradicação da Helicobacter pylori e subsequentemente realizou uma gastrectomia total profilática. A avaliação histológica da peça cirúrgica identificou focos de carcinoma in situ de células de anel em sinete, sem evidência de linfoma. O nosso objetivo é salientar a ocorrência de outras patologias em doentes de alto risco assim como a sua possível influência na decisão cirúrgica.

Multi-Gene Panel Testing in Gastroenterology: Are We Ready for the Results?

Genetic testing aims to identify patients at risk for inherited cancer susceptibility. In the last decade, there was a significant increase in the request of broader panels of genes as multi-gene panel testing became widely available. However, physicians may be faced with genetic findings for which there is lack of management evidence, despite some progress in understanding their clinical relevance. In this short review, we discuss the advantages and the drawbacks related to multi-gene panel testing in the setting of a Gastrointestinal Familial Cancer Risk clinic. We also summarize the available recommendations on management of pathogenic variant carriers.

O estudo genético tem como objetivo identificar indivíduos em risco de cancro hereditário. Na última década, verificou-se um aumento significativo do número de genes analisados devido ao surgimento de painéis de sequenciação multi-gene. Neste sentido, os médicos podem ser confrontados com resultados genéticos para os quais não há orientações de manejo ou seguimento, apesar de progressos na compreensão da relevância clínica dessas variantes genéticas. Nesta revisão de literatura, discutimos as vantagens e desvantagens dos testes de sequenciação multi-gene e apresentamos um resumo das recomendações disponíveis relativas à orientação dos portadores de variantes genéticas patogénicas.

Organizational and Job Resources on Employees' Job Insecurity During the First Wave of COVID-19: The Mediating Effect of Work Engagement.

The world of work has been severely affected by the COVID-19 pandemic due to the high instability observed in the labor market, bringing several new challenges for leaders and employees. The present study aims to analyze the role of organizational and job resources in predicting employees' job insecurity during the first wave of the COVID-19 outbreak, through the mediating role of work engagement. A sample of 207 Portuguese employees participated (Mean age = 45 years old, SD = 9.92), of which 64.7% were women. Data was collected using an online survey, including self-report measures of organizational resources (perceived organizational support), job resources (performance feedback and job autonomy), job insecurity, and work engagement. Data showed that job and organizational resources negatively influenced job insecurity. Moreover, work engagement was a significant mediator of the relation between performance feedback (facet of job resources) and job insecurity. Findings suggest that investing in job and organizational resources can act as protective factors to minimize feelings of job insecurity. Likewise, leaders should foster work engagement among employees to help them balance the relation between these resources and job insecurity, especially in crisis situations. Overall, this study takes a new, underexplored perspective, theoretically bridging organizational and job resources with job insecurity and work engagement during a time of great uncertainty, such as the COVID-19 pandemic.

Daily life attitudes of women with moderate or severe chronic pelvic pain. A qualitative study.

OBJECTIVE: How a woman copes with the pain might play a significant role in the management of chronic pelvic pain. This study aimed to understand the attitudes adopted by women with chronic pelvic pain (CPP) to deal with daily life problems caused by the illness. STUDY DESIGN: We conducted a qualitative study including 58 women diagnosed with chronic pelvic pain regardless of the cause. To collect the data, we used semi-structured interviews with the key question: "How do you handle the pain in your daily life?". The interviews were audio-recorded and transcribed. We conducted a qualitative thematic analysis of transcribed texts following the sequence: 1) initial reading; 2) preliminary identification of codes; 3) identification of themes; 4) review of themes; 5) nominating the themes in categories; 6) final study synthesis. The analysis was performed with the aid of the RQDA package in the R environment. RESULTS: Daily life attitudes varied from submission to the pain to positive coping. We identified five major categories: 1) shaping life by pain; 2) isolating from social contact; 3) avoiding sexual relationship; 4) seeking pain relief; 5) seeking positive strategies. Positive strategies were more frequent in older women. CONCLUSION: Women with chronic pelvic pain adopted a broad spectrum of attitudes to deal with the pain in daily life. The depth understanding of patient perspectives has the potential to improve the multidisciplinary care of this debilitating condition.

Cancer-risk by family history and mismatch-repair mutation in Lynch syndrome.

Introduction: Surveillance of Lynch syndrome (LS) is recommended to reduce cancer-risk. There is an increased awareness that cancer-risk may vary with mismatch-repair mutation and family history. However, gene-specific and family-specific surveillance are not recommended. Therefore, we aimed to estimate the cumulative incidence of lesions and to assess the cancer-risk by family history and mismatch-repair mutation (MMR).Methods: Single-centre retrospective cohort of all individuals (n = 241) in a specialized institution was conducted.Results: Forty-eight percent of individuals inherited MSH2 mutations, 32% MLH1, 15% MSH6 and 5% PMS2. The calculated cumulative incidence for any cancer increased with age. By age 70, the cumulative incidence for low-risk, high-risk adenomas and CRC was estimated at 66.6%, 57.7% and 25.7%, respectively. By age 70, the cumulative incidence of endometrial cancer (EC), gastric cancer and urinary tract cancer was estimated at 17.3%, 3.3% and 12.6%, respectively. MLH1 and MSH2 mutation carriers had lower mean age of CRC diagnosis than MSH6 and PMS2 [MLH1:44(CI95% 38-50); MSH2:43(CI95% 40-47); MSH6:52(CI95% 45-59); PMS2:46(CI95% 35-57)]. The risk of EC was higher when family history was present (RR = 2.39, CI95%[1.3;4.6]). MSH6 mutation carriers had higher risk of EC comparative to other MMR mutation carriers (RR = 1.9, p = .09). The risk of urinary tract cancer was higher with MSH2 (RR = 8.4, CI95%[2.7;25.9]) and positive family history (RR = 10.8, CI95%[1.4;82.8]).Conclusion: This cohort demonstrates the effectiveness of LS surveillance and suggests possible tailored surveillance strategies by gene mutation and family history.

Random biopsies in patients harboring a CDH1 mutation: time to change the approach?

INTRODUCTION AND AIM: hereditary diffuse gastric cancer (HDGC) can be caused by a CDH1 mutation. It often presents as multiple foci of signet ring cell carcinoma (SRCC) that is rarely detected by gastroscopy. Prophylactic total gastrectomy is recommended at a young age. The aim of this study was to determine the adequacy of gastroscopy according to the Cambridge protocol in patients with a CDH1 mutation. METHODS: patients with a CDH1 mutation admitted to our department between September 2016 and October 2018 were evaluated. All patients underwent a baseline gastroscopy according to the Cambridge protocol, followed by a recommended total gastrectomy. Endoscopic findings, the number of biopsies and histological evaluation of biopsy samples were registered. Postoperative histopathological assessment was compared with endoscopic findings in patients that underwent a total gastrectomy (n = 13). RESULTS: twenty-five patients were included and 35 gastroscopies performed. On these, 996 gastric biopsies were performed, which included 952 random and 44 targeted. Only three patients had SRCC foci in random biopsies and one also had SRCC lesions in two targeted biopsies. In our cohort, 332 random and 22 targeted biopsies were needed to identify a single SRCC focus. Total gastrectomy was performed in 13 patients and SRCC foci were identified in 12 surgical specimens, the remaining specimen had a precursor lesion of HDGC. DISCUSSION: gastroscopy has a poor sensitivity to detect SRCC. Even with Cambridge protocol, gastroscopy has a very limited role in the surveillance of patients with a CDH1 mutation and prophylactic total gastrectomy is the most advisable option. Nevertheless, endoscopic protocols should be optimized to favor targeted biopsies over a high number of random biopsies

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Random biopsies in patients harboring a CDH1 mutation: time to change the approach?

INTRODUCTION AND AIM: hereditary diffuse gastric cancer (HDGC) can be caused by a CDH1 mutation. It often presents as multiple foci of signet ring cell carcinoma (SRCC) that is rarely detected by gastroscopy. Prophylactic total gastrectomy is recommended at a young age. The aim of this study was to determine the adequacy of gastroscopy according to the Cambridge protocol in patients with a CDH1 mutation. METHODS: patients with a CDH1 mutation admitted to our department between September 2016 and October 2018 were evaluated. All patients underwent a baseline gastroscopy according to the Cambridge protocol, followed by a recommended total gastrectomy. Endoscopic findings, the number of biopsies and histological evaluation of biopsy samples were registered. Postoperative histopathological assessment was compared with endoscopic findings in patients that underwent a total gastrectomy (n = 13). RESULTS: twenty-five patients were included and 35 gastroscopies performed. On these, 996 gastric biopsies were performed, which included 952 random and 44 targeted. Only three patients had SRCC foci in random biopsies and one also had SRCC lesions in two targeted biopsies. In our cohort, 332 random and 22 targeted biopsies were needed to identify a single SRCC focus. Total gastrectomy was performed in 13 patients and SRCC foci were identified in 12 surgical specimens, the remaining specimen had a precursor lesion of HDGC. DISCUSSION: gastroscopy has a poor sensitivity to detect SRCC. Even with Cambridge protocol, gastroscopy has a very limited role in the surveillance of patients with a CDH1 mutation and prophylactic total gastrectomy is the most advisable option. Nevertheless, endoscopic protocols should be optimized to favor targeted biopsies over a high number of random biopsies.

Processo de transição para uma posição de liderança: um estudo com mulheres / Transitioning process to an organizational leardership position: a study with women

Parecem ser vários os desafios, emoções e constrangimentos com os quais as mulheres se deparam para alcançarem posições de liderança nas organizações. Nesse seguimento, este estudo tem como objetivos descrever o processo de transição de mulheres para uma posição de liderança em contexto organizacional e as representações de jovens mulheres sobre o mesmo. De forma a concretizar os objetivos definidos foram realizados dois estudos. O estudo 1 recorreu a entrevistas semiestruturadas a mulheres que viveram recentemente o processo de transição. No estudo 2 aplicou-se um questionário com perguntas abertas a 30 jovens mulheres universitárias. Os dados foram sujeitos a análise de conteúdo categorial. Os resultados permitiram identificar três fases no processo de transição para uma posição de liderança - Aprendizagem, Autonomização e Consolidação. Permitiu ainda identificar que ao longo do processo de transição as mulheres experienciam dificuldades a nível do assumir as novas funções, obter reconhecimento do papel de líder e mudanças nas relações. As representações das jovens mulheres vão ao encontro das vivências das mulheres, revelando-se conscientes do papel dos estereótipos de gênero na liderança feminina.

Women face challenges and constraints in reaching leadership positions in organizations. This research aims to describe the process of transition of women to a leadership position in an organizational context and the representations of young women regarding that process. In order to achieve this, two studies were conducted. Study 1 used semi-structured interviews with women who recently experienced the transition process. In study 2, a questionnaire with open questions was applied to 30 young university women. Data were subjected to categorical content analysis. The results allowed us to identify three phases in the process of transition to a leadership position - Learning, Empowerment and Consolidation. It was also identified that throughout the transition process women experience difficulties assuming the new role, gaining recognition of the leading role and changes in relationships. Representations of young women meet these women's experiences and we see they are aware of the role of gender stereotypes in female leadership.

Transcatheter closure of a rare coronary artery fistula using a modified mother-child technique.

Coronary artery fistulas (CAFs) are rare abnormal communications between a normal coronary artery and a cardiac chamber or great vessel, such as the pulmonary artery, bypassing the myocardial capillary network. We report the case of a 17-year-old male with a medical history of pulmonary valve stenosis, who presented with progressive dyspnea and fatigue. Transthoracic Doppler echocardiography showed multiple continuous flows both on the apical interventricular septum and entering the left atrium. A tortuous CAF arising from the left main coronary artery to the left atrium was revealed by coronary angiography. The lesion was successfully closed percutaneously using an off-label Amplatzer™ Duct Occluder II Additional Sizes with a backup support of a modified "mother-child" system. This case highlights the effort of both pediatric and adult cardiology teams to come up with new potential strategies and combined techniques to overcome the difficulties of managing complicated CAFs, such as the use of percutaneous coronary intervention techniques and the selection of the most adequate occlusion devices, even when used off-label.

The nonsense mutation MSH2 c.2152C>T shows a founder effect in Portuguese Lynch syndrome families.

The mutational spectrum of the MMR genes is highly heterogeneous, but specific mutations are observed at high frequencies in well-defined populations or ethnic groups, due to founder effects. The MSH2 mutation c.2152C>T, p.(Gln718*), has occasionally been described in Lynch families worldwide, including in Portuguese Lynch syndrome families. During genetic testing for Lynch syndrome at the Portuguese Oncology Institutes of Porto and Lisbon, this mutation was identified in 28 seemingly unrelated families. In order to evaluate if this alteration is a founder mutation, haplotype analysis using microsatellite and SNP markers flanking the MSH2 gene was performed in the 28 probands and 87 family members. Additionally, the geographic origin of these families was evaluated and the age of the mutation estimated. Twelve different haplotypes were phased for 13 out of the 28 families and shared a conserved region of ∼3.6 Mb. Based on the mutation and recombination events observed in the microsatellite haplotypes and assuming a generation time of 25 years, the age estimate for the MSH2 mutation was 273 ± 64 years. The geographic origins of these families were mostly from the Northern region of Portugal. Concluding, these results suggest that the MSH2 c.2152C>T alteration is a founder mutation in Portugal with a relatively recent origin. Furthermore, its high proportion indicates that screening for this mutation as a first step, together with the previously reported Portuguese founder mutations, may be cost-effective in genetic testing of Lynch syndrome suspects of Portuguese ancestry.