Li-Fraumeni Syndrome (LFS) is characterized by risk of multiple primary malignancies in diverse sites, pediatric onset, near complete penetrance by age 70 years, limited options for prevention, and ...substantial uncertainty regarding disease manifestation and prognosis. Forty-five families, including 117 individuals aged 13–81 years, enrolled in the US National Cancer Institute’s Li-Fraumeni Syndrome Study completed 66 interviews regarding their LFS experiences. An interdisciplinary team used modified grounded theory to examine family distress regarding expectations of loss and change due to likely cancer diagnoses, and the consequences of this likelihood across physical, social, and emotional domains. Disease-free periods were characterized by fearful anticipation of diagnosis or recurrence, uncertainty regarding post-treatment quality of life, and planning for shifts in family dynamics to enable caregiving. The chronicity of waiting for these changes incited dread and inhibited effective coping with the pragmatic, emotional, and existential challenges of the syndrome. Consequently, families reported high burden on roles and resources and limited guidance to prepare for, or achieve resolution with, grief. Anticipatory loss, the experience of bereavement prior to an expected change, distinguishes hereditary cancer risk from a sporadic diagnosis. Such grief is often incomplete in impact or meaning, subjected to rapid or profound change as conditions worsen, and poorly understood. In this study, losses were compounded by profound uncertainty, a chronic feature of LFS, which compromised mourning. Long-term engagement of mental health providers with bereavement training, in partnership with genetics providers, can provide invaluable educational and psychological support to families as they navigate these implacable challenges.
ABSTRACT
Introduction
In light of recent evidence indicating that cancer is part of the myotonic dystrophy (DM) phenotype, we assessed the prevalence of benign and malignant tumors among 220 patients ...enrolled in the UK Myotonic Dystrophy Patient Registry and evaluated factors associated with their development.
Methods
A survey was distributed to collect tumor history and lifestyle information. We used multinomial logistic regression for the analysis.
Results
Thirty‐nine benign (30 patients), and 16 malignant (15 patients) tumors were reported. Increasing age (odds ratio OR = 1.13, 95% confidence interval CI = 1.05–1.21, P = 0.001) and earlier age at DM diagnosis (OR = 1.06, 95% CI = 1.00–1.13, P = 0.04) were associated with benign and malignant tumors (OR = 1.20, 95% CI = 1.10–1.30, P < 0.001 and OR = 1.08, 95% CI = 1.01–1.15, P = 0.02, respectively). Female gender was associated with benign tumors only (OR = 6.43, 95% CI = 1.79–23.04, P = 0.004). No associations were observed between tumors and smoking (P = 0.24), alcohol consumption (P = 0.50), or body mass index (P = 0.21).
Discussion
Our results confirm previous findings suggesting a limited role for common lifestyle factors and a potential genetic contribution in DM tumor predisposition. Muscle Nerve 57: 316–320, 2018
Familial aggregations of testicular germ cell tumor (FTGCT) have been well described, suggesting the existence of a hereditary TGCT subset. Approximately 1.4% of newly diagnosed TGCT patients report ...a positive family history of TGCT. Sons and siblings of TGCT patients have four- to sixfold and eight- to tenfold increases in TGCT risk respectively. Segregation analyses suggest an autosomal recessive mode of inheritance. Linkage analyses have identified several genomic regions of modest interest, although no high-penetrance cancer susceptibility gene has been mapped yet. These data suggest that the combined effects of multiple common alleles, each conferring modest risk, might underlie familial testicular cancer. Families display a mild phenotype: the most common number of affected families is 2. Age at diagnosis is 2-3 years younger for familial versus sporadic cases. The ratio of familial seminoma to nonseminoma is 1.0. FTGCT is more likely to be bilateral than sporadic TGCT. This syndrome is cancer site specific. Testicular microlithiasis is a newly recognized FTGCT component. Candidate gene-association studies have implicated the Y chromosome gr/gr deletion and PDE11A gene mutations as genetic modifiers of FTGCT risk. Two genomewide association studies of predominantly sporadic but also familial cases of TGCT have implicated the KIT-ligand, SPRY4, and BAK1 genes as TGCT risk modifiers. All five loci are involved in normal testicular development and/or male infertility. These genetic data provide a novel insight into the genetic basis of FTGCT, and an invaluable guide to future TGCT research.
The insulin‐like growth factor (IGF) signaling pathway is involved in cell proliferation and differentiation. Elevated serum IGF1 levels have been associated with increased colorectal cancer risk; ...however, studies of this association with colorectal adenoma are inconclusive. We examined serum IGF1, IGF2 and IGFBP3 levels in relation to risk of advanced colorectal adenoma in a case‐control study within the prostate, lung, colorectal and ovarian cancer screening trial. A total of 764 advanced, left‐sided colorectal adenoma cases and 775 controls frequency‐matched on gender and ethnicity, without evidence of a left‐sided polyp on sigmoidoscopy were included in the current study. Serum levels of IGF1, IGF2 and IGFBP3 were measured using an enzyme linked immunosorbent assay in serum samples collected at baseline. Logistic regression was used to estimate the odds ratios (OR) and 95% confidence intervals (CI) for the associations adjusting for age, race, sex, year of blood draw, body mass index, smoking and education. Higher IGF1 levels were associated with increased adenoma risk: ORs = 1.58 (95% CI = 1.16–2.16), 1.42 (95% CI = 1.04–1.93), and 1.80 (95% CI = 1.30–2.47) for the second, third and fourth quartiles, respectively (ptrend = 0.002). Elevated IGF2 levels were also associated with increased adenoma risk (OR = 1.43, 95% CI = 1.05–1.96 for the fourth vs. first quartile, ptrend = 0.02), but the association was no longer significant after adjustment for IGF1 (ptrend = 0.28). IGFBP3 levels were not associated with adenoma risk. Our analysis showed a significant positive association between circulating IGF1 levels and risk of advanced colorectal adenoma, suggesting that IGF1 is associated with the pivotal precursor to colorectal cancer.
The prevalence of burnout and depressive symptoms is high among physician trainees.
What is the burden of burnout and depressive symptoms among fellows training in pulmonary and critical care ...medicine (PCCM) and what are associated individual fellow, program, and institutional characteristics?
We conducted a cross-sectional electronic survey of fellows enrolled in pulmonary, PCCM, and critical care medicine training programs in the United States to assess burnout and depressive symptoms. Burnout symptoms were measured using the Maslach Burnout Index two-item measure. The two-item Primary Care Evaluation of Mental Disorders Procedure was used to screen for depressive symptoms. For each of the two outcomes (burnout and depressive symptoms), we constructed three multivariate logistic regression models to assess individual fellow characteristics, program structure, and institutional polices associated with either burnout or depressive symptoms.
Five hundred two of the 976 fellows who received the survey completed it-including both outcome measures-giving a response rate of 51%. Fifty percent of fellows showed positive results for either burnout or depressive symptoms, with 41% showing positive results for depressive symptoms, 32% showing positive results for burnout, and 23% showing positive results for both. Reporting a coverage system in the case of personal illness or emergency (adjusted OR aOR, 0.44; 95% CI, 0.26-0.73) and access to mental health services (aOR, 0.14; 95% CI, 0.04-0.47) were associated with lower odds of burnout. Financial concern was associated with higher odds of depressive symptoms (aOR, 1.13; 95% CI, 1.05-1.22). Working more than 70 hours in an average clinical week and the burdens of electronic health record (EHR) documentation were associated with a higher odds of both burnout and depressive symptoms.
Given the high prevalence of burnout and depressive symptoms among fellows training in PCCM, an urgent need exists to identify solutions that address this public health crisis. Strategies such as providing an easily accessible coverage system, access to mental health resources, reducing EHR burden, addressing work hours, and addressing financial concerns among trainees may help to reduce burnout or depressive symptoms and should be studied further by the graduate medical education community.
Familial testicular germ cell tumours (TGCTs) and bilateral TGCTs comprise 1-2% and 5% of all TGCTs, respectively, but their genetic basis remains largely unknown.
To investigate the contribution of ...known testicular cancer risk variants in familial and bilateral TGCTs.
The study genotyped 106 single nucleotide polymorphisms (SNPs) in four regions (BAK1, DMRT1, KITLG, TERT-CLPTM1L) previously identified from genome-wide association studies of TGCT, including risk single nucleotide polymorphisms (SNPs) rs210138 (BAK1), rs755383 (DMRT1), rs4635969 (TERT-CLPTM1L) in 97 cases with familial TGCT and 22 affected individuals with sporadic bilateral TGCT as well as 871 controls. Using a generalised estimating equations method that takes into account blood relationships among cases, the associations with familial and bilateral TGCT were analysed. Three previously identified risk SNPs were found to be associated with familial and bilateral TGCT (rs210138: OR 1.80, CI 1.35 to 2.41, p=7.03×10(-5); rs755383: OR 1.67, CI 1.23 to 2.22, p=6.70×10(-4); rs4635969: OR 1.59, CI 1.16 to 2.19, p=4.07×10(-3)). Evidence for a second independent association was found for an SNP in TERT (rs4975605: OR 1.68, CI 1.23 to 2.29, p=1.24×10(-3)). Another association with an SNP was identified in KITLG (rs2046971: OR 2.33, p=1.28×10(-3)); this SNP is in high linkage disequilibrium (LD) with reported risk variant rs995030.
This study provides evidence for replication of recent genome-wide association studies results and shows that variants in or near BAK1, DMRT1, TERT-CLPTM1L, and KITLG predispose to familial and bilateral TGCT. These findings imply that familial TGCT and sporadic TGCT share a common genetic basis.
Women who are genetically predisposed to ovarian cancer are at very high risk of developing this disease. Although risk-reducing salpingo-oophorectomy (RRSO) and various screening regimens are ...currently recommended to reduce ovarian cancer risk, the optimal management strategy has not been established nor have multiple additional issues been adequately addressed. We developed a collaboration among the Clinical Genetics Branch (National Cancer Institute's Intramural Research Program), the Gynecologic Oncology Group (GOG), and the Cancer Genetics Network to address these issues.
This is a prospective, international, two-cohort, nonrandomized study of women at genetic risk of ovarian cancer, who chose either to undergo RRSO or screening, at study enrollment. Primary study objectives include quantifying and comparing ovarian and breast cancer incidence in the two study groups, assessing feasibility and selected performance characteristics of a novel ovarian cancer screening strategy (the Risk of Ovarian Cancer Algorithm), evaluating various aspects of quality of life and nononcologic morbidity related to various interventions in at-risk women, and creating a biospecimen repository for subsequent translational research.
Study accrual is complete as of November 2006; 2,605 participants enrolled: 1,030 (40%) into the surgical cohort and 1,575 (60%) into the screening cohort. Five years of prospective follow-up ends in November 2011. Verification of BRCA mutation carrier status is under way, either through patient-provided reports from clinical genetic testing done before enrollment or through research-based genetic testing being conducted as part of the protocol. Patient eligibility is currently under evaluation and baseline, surgical, pathology, and outcome data are still being collected. The study design and selected baseline characteristics of cohort members are summarized.
This National Cancer Institute intramural/extramural collaboration will provide invaluable prospectively collected observational data on women at high familial ovarian cancer risk, including substantial numbers of women carrying BRCA1/2 mutations. These data will aid in elucidating the effect of RRSO on breast/ovarian cancer risk and the effects of two management strategies, on quality of life and other issues that may influence patient care, as well as providing preliminary estimates of test specificity and positive predictive value of a novel ovarian cancer screening strategy.
Li‐Fraumeni Syndrome (LFS) is a hereditary disorder that confers an approximately 90% lifetime risk of cancer and requires comprehensive lifetime cancer screening. We explored healthcare roles for ...managing LFS‐related cancer risks and treatments that were assumed by parents, adolescents, and adult children. Semi‐structured interviews were conducted with 23 families. Family groupings were comprised of 2–5 members, with the younger generation in each family ranging in age from 7 to 40 years. Using grounded theory methods, we conducted open and focused coding of interview transcript content. Family members described how the role of health leader was implemented in their family, as well as factors such as maturation of a child or death of a member that determined who assumed particular roles and how these roles shifted over time. They often expressed collective responsibility for helping relatives understand LFS and implement appropriate cancer risk management. Members demonstrated their health role by attending others’ medical appointments for support or information gathering. The health leader role was intergenerational and provided the family necessary support in navigating complicated healthcare decisions. Our findings provide insight into healthcare providers regarding how LFS patients and their relatives develop unique medical decision‐making and caring roles influenced by the hereditary nature of LFS, and how these roles change over time. Providers who are attuned to family role dynamics may be better able to meet relatives’ psychosocial and medical needs by understanding how living with LFS influences the family system’s functioning and facilitating members’ support for each other.
RESUMEN
El síndrome de Li‐Fraumeni (LFS) es un trastorno hereditario que concede aproximadamente un 90 % de riesgo durante toda la vida de contraer cáncer y exige exámenes completos para la detección del cáncer de por vida. Analizamos los roles sanitarios a la hora de manejar los riesgos y los tratamientos de cáncer relacionados con el LFS que asumieron los padres, los adolescentes y los hijos adultos. Se realizaron entrevistas semiestructuradas con 23 familias. Los agrupamientos familiares estaban compuestos por entre 2 y 5 familiares, donde la edad de la generación más joven de cada familia oscilaba entre 7 y 40 años. Utilizando los métodos de la teoría fundamentada, realizamos una codificación abierta y centrada del contenido de la transcripción de la entrevista. Los miembros de la familia describieron cómo se implementó el rol de jefe de la salud en su familia, así como factores como la maduración de un niño o la muerte de un miembro que determinaron quiénes asumieron roles particulares y cómo estos roles cambiaron con el tiempo. Con frecuencia ellos expresaron la responsabilidad colectiva de ayudar a los familiares a comprender el LFS y a implementar el manejo adecuado del riesgo de contraer cáncer. Los familiares demostraron sus roles sanitarios asistiendo a citas médicas de los demás para recibir apoyo u obtener información. El rol de jefe sanitario fue intergeneracional y proporcionó a la familia el apoyo necesario para manejarse ante decisiones complicadas sobre la asistencia sanitaria. Nuestros resultados brindan información para los prestadores de servicios médicos con respecto a cómo los pacientes de LFS y sus familiares desarrollan roles únicos para la toma de decisiones médicas y el cuidado influenciados por la índole hereditaria del LFS, y cómo estos roles cambian con el tiempo. Es posible que los prestadores que estén acostumbrados a la dinámica de roles familiares sean más capaces de satisfacer las necesidades psicosociales y médicas de los familiares si comprenden cómo vivir con LFS influye en el funcionamiento del sistema familiar y si facilitan el apoyo mutuo de los familiares.
摘要
李‐佛美尼综合症是一种遗传性的疾病，大概一生中有90%的患癌几率，它要求家庭成员终身接受综合性癌症筛查。本文研究医疗保健对管理李‐佛美尼综合症风险和治疗过程中所起的作用，这些风险和治疗均由家长，青少年和成年孩子们来承担着。参与研究的家庭有23个，采用半结构化的访谈。家庭的组成有2‐5个家庭成员，每个家庭的较年轻一代人年龄跨度7‐40岁。使用草根理论方法，我们针对访谈文稿进行了开放式和集中式解码。家庭成员描述了健康领袖的作用在家庭内如何实现的，还有孩子的成熟，某家庭成员的去世等因素，这些因素都决定了谁承担了什么角色，这些角色在一段时间范围内如何发生变化。他们通常会表达集体性的共同责任，帮助亲戚理解LFS症和实施合适的癌症风险管理。家庭成员通过陪同一起去就医来给与支持以及信息搜集的方式来实现他们的健康作用。健康领袖的作用是代际间的，提供了必要的支持给家庭，特别是在复杂的医疗保健方面的决定。我们的研究结果提供了健康医疗供给方的看法，主要是关于LFS病人和他们的亲戚如何作出特殊的医疗决策和发挥照料者的角色，这些都深受LFS遗传性特性的影响，和这些角色如何随着时间而发生变化。那些可以适应家庭角色动态变化的供给方可以较好地实现亲戚的社会心理和医疗的需要，主要是通过尽力理解承受LFS影响的家庭系统的功能，促进家庭成员们彼此的支持。
Young women with BRCA1/2 mutations face difficult health-care decisions regarding family formation, fertility, breastfeeding, and whether/when to undergo cancer risk-reducing surgery. This ...longitudinal qualitative study investigated these life choices during the reproductive years. We conducted two semistructured interviews over three years with 12 reproductive-age BRCA1/2-positive women. Researchers coded transcripts to examine the evolution of risk perceptions, risk management, and family planning decisions. To cope with the conflict between cancer risk reduction versus plans for pregnancy, breastfeeding, and child rearing, participants deliberately prioritized either risk reducing surgery or family formation goals. Implications for mutation carriers and health-care providers are outlined.
Objective: Li-Fraumeni syndrome (LFS) is a rare hereditary cancer predisposition syndrome that significantly increases one’s lifetime cancer risk from infancy to late adulthood. LFS is primarily ...caused by pathogenic autosomal dominant germline TP53 variants. Consequently, each naturally conceived biological child of an individual with a pathogenic variant has a 50% chance of inheriting it. This study examines the connections between family cancer history and reproductive beliefs within multigenerational family units including at least one member with TP53-positive LFS. Method: Forty-five families enrolled in a protocol-specific cancer screening study completed 66 group interviews. An interdisciplinary team constructed a thematic codebook of inductive and deductive codes using interpretive description and modified ground theory to analyze data and then implemented a framework method to organize themes. Results: The following major themes were related to reproductive beliefs in the context of LFS: (a) tension between morality and generational cancer experiences, (b) discriminating between multiple moral frames (i.e., religion and risk reduction), and (c) impossible choices between one’s own health and future children. Conclusions: Reproductive beliefs associated with LFS are distinct from other well-studied hereditary cancer syndromes. Families with LFS experience novel reproductive beliefs that may trigger moral distress. Reproductive LFS-tailored psychoeducational interventions and clinician awareness are needed.
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