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Study Objectives: This study examined the impact of central disorders of hypersomnolence (CDH) on family members of adult patients, the ways family members assist with managing CDH, and family members' utilization and satisfaction with information and support., Methods: Participants were adults (N=100) with an adult family member diagnosed with idiopathic hypersomnia or narcolepsy. They completed a survey which included the Family Reported Outcome Measure (FROM-16), checklists, satisfaction ratings, and open-response questions., Results: The FROM-16 sample mean (14.2, SD=6.8) corresponded to a moderate effect on quality of life. Compared to parents, partners reported a higher impact on the Personal and Social Life domain (p=.04, d=.44). The most frequently endorsed sources of support were family (60.0%) and friends (50.0%), whereas information was most commonly obtained from hypersomnia organizations (69.0%) and medical professionals (61.0%). Only 8.0% of participants were satisfied with support, and 9.0% were satisfied with information. Participants endorsed assisting with managing CDH, such as picking up prescriptions (61.0%), attending medical visits (50.0%), reminding to take medication (48.0%), and coordinating medical care (39.0%). Qualitative data indicated that relationships underwent a transformation from conflict and confusion (pre-diagnosis) to clarity (post-diagnosis), followed by adjusting expectations. Caregiving strain, effects on shared activities, and negative psychosocial impacts on family also emerged as themes., Conclusions: Family members play an important role in supporting adults with CDH in many ways, including tasks related to managing CDH. Family members experience many psychosocial impacts from CDH, and data from this study indicate unmet needs for support., (© 2024 American Academy of Sleep Medicine.)

Background/objectives: Narcolepsy is a chronic neurologic disorder associated with substantial challenges that affect the social, emotional, and financial quality-of-life domains. A social listening analysis and structured survey were conducted to better understand the candid perspective of people with narcolepsy (PWN) and their experience with twice-nightly sodium oxybate (SXB)., Methods: To characterize conversations and experiences in narcolepsy communities where SXB was mentioned, a social media analysis was conducted from August 2011 to October 2022. A structured survey was administered to PWN taking oxybate therapy from October 2022 to November 2022., Results: From the social media analysis, the largest topic was related to "cataplexy", with 537 posts/comments. The most frequent term was "xyrem", with 22,200 mentions. Of the 87 survey respondents, 85 respondents had narcolepsy, 75.3% (64/85) reported missing their second dose of immediate-release SXB or mixed-salt oxybates, and 58.8% (50/85) of respondents reported that they took their second dose of oxybate > 4 h after the first dose. Respondents reported poor sleep quality as the greatest effect or issue experienced after missing their second oxybate dose. When respondents were asked whether they had ever been injured after waking to take their second oxybate dose, 31.8% (27/85) of respondents reported an injury., Conclusions: PWN taking twice-nightly oxybates often report inconsistent adherence to the prescribed dosing, which results in negative consequences in their lives. This research provided an anonymized forum for PWN to voice challenges with middle-of-the-night awakenings that they may be reluctant to explain to their clinician., Competing Interests: The funding sponsor of this study did not have a role in the design of the study, collection, analysis, or interpretation of the data. The funder did have a role in the choice of research project, writing of the manuscript, and the decision to publish the results. M.P. is an owner of and owns stock options in TREND Community. Clients of TREND Community are pharmaceutical and biotechnology companies including, but not limited to, Horizon Therapeutics, Chiesi Global Rare Disease, Novartis, Harmony Biosciences, and Avadel Pharmaceuticals. F.A. has no disclosures to report. M.H. is a consultant to Avadel Pharmaceuticals; has received compensation or honoraria from Alkermes, Axsome Therapeutics, Centessa Pharmaceuticals, and Harmony Biosciences; and is a member of the Sleep Consortium Advisory Board. He was an employee of TREND when this study was conducted. E.Z. is an employee of and owns stock options in TREND Community. Clients of TREND Community are pharmaceutical and biotechnology companies including, but not limited to, Horizon Therapeutics, Chiesi Global Rare Disease, Novartis, Harmony Biosciences, and Avadel Pharmaceuticals. L.D. is an employee of and owns stock options in TREND Community. Clients of TREND Community are pharmaceutical and biotechnology companies including, but not limited to, Horizon Therapeutics, Chiesi Global Rare Disease, Novartis, Harmony Biosciences, and Avadel Pharmaceuticals. C.D. is an owner of and owns stock options in TREND Community. Clients of TREND Community are pharmaceutical and biotechnology companies including, but not limited to, Horizon Therapeutics, Chiesi Global Rare Disease, Novartis, Harmony Biosciences, and Avadel Pharmaceuticals. M.F. was an employee of TREND Community at the time of the study. Clients of TREND Community are pharmaceutical and biotechnology companies including, but not limited to, Horizon Therapeutics, Chiesi Global Rare Disease, Novartis, Harmony Biosciences, and Avadel Pharmaceuticals. R.C. was an employee of TREND Community at the time of the study. Clients of TREND Community are pharmaceutical and biotechnology companies including, but not limited to, Horizon Therapeutics, Chiesi Global Rare Disease, Novartis, Harmony Biosciences, and Avadel Pharmaceuticals. A.M.M. has served as a consultant, speaker, and/or on advisory boards for Avadel Pharmaceuticals, Eisai, Harmony Biosciences, Jazz Pharmaceuticals, Alkermes, and Takeda Pharmaceutical Co; has received grant funding from National Institutes of Health, UCB Pharmaceuticals, Jazz Pharmaceuticals, ResMed Foundation, Coverys Foundation, Harmony Biosciences and Geisinger Health Plan; is the CEO of DAMM Good Sleep, LLC; and serves as an advisor for Neura Health and Floraworks. L.E.O. is a consultant to Harmony Biosciences and has served on advisory boards for Avadel Pharmaceuticals and Jazz Pharmaceuticals. E.R.W. is an employee of and owns stock options in TREND Community. Clients of TREND Community are pharmaceutical and biotechnology companies including, but not limited to, Horizon Therapeutics, Chiesi Global Rare Disease, Novartis, Harmony Biosciences, and Avadel Pharmaceuticals. J.G. is an employee of Avadel Pharmaceuticals.

What Is This Summary About?: This is a plain language summary of a published article in the journal CNS Drugs . Narcolepsy is a rare sleep condition. Most people with narcolepsy experience disrupted nighttime sleep and have poor quality of sleep. Sometimes these symptoms are not easily diagnosed as a symptom of narcolepsy. Sodium oxybate is an approved treatment for narcolepsy. The only version of sodium oxybate that was available until 2023 required people to take their sodium oxybate at bedtime and then again in the middle of the night. The US Food and Drug Administration (FDA for short) has approved a once-nightly bedtime dose of sodium oxybate (ON-SXB for short, also known as FT218 or LUMRYZ ™ ) to treat symptoms of narcolepsy in adults. These symptoms are daytime sleepiness and cataplexy, which is an episode of sudden muscle weakness. The once-nightly bedtime dose of ON-SXB removes the need for a middle-of-the-night dose of sodium oxybate. The REST-ON clinical study compared ON-SXB to a placebo (a substance that contains no medicine) to determine if it was better at treating symptoms of disrupted nighttime sleep associated with narcolepsy. This summary looks at whether; ON-SXB was better than placebo at treating symptoms of disrupted nighttime sleep., What Were the Results?: Compared to people who took placebo, people who took ON-SXB had fewer number of changes from deeper to lighter sleep stages and woke up less during the night. They also reported that they slept better at night and felt more refreshed when waking up in the morning. People with narcolepsy sometimes take alerting agents to help with sleepiness during the day, but alerting agents can cause difficulty sleeping at night. This study showed that people who took ON-SXB had better nighttime sleep even if they were taking alerting agents during the day. The most common side effects of ON-SXB included dizziness, nausea (feeling sick to your stomach), vomiting, headache, and bedwetting., What Do the Results Mean?: A once-nightly bedtime dose of ON-SXB is a narcolepsy treatment option for people without the need for a middle-of-the-night dose of sodium oxybate.

Colorectal cancer (CRC) incidence in young adults is rising. Identifying genetic risk factors is fundamental for the clinical management of patients and their families. This study aimed to identify clinically significant germline variants among young adults with CRC. Whole-exome sequencing data of blood-derived DNA from 133 unrelated young CRC patients (<55 years of age) underwent a comprehensive analysis of 133 cancer-predisposition/implicated genes. All patient tumors were evaluated for mismatch repair deficiency (dMMR). Among 133 patients (aged 16-54 years), 15% (20/133) had clinically actionable pathogenic or likely pathogenic (P/LP) variants in at least 1 well established cancer-predisposing gene: dMMR genes (6), MUTYH [bi-allelic (2), mono-allelic (3)], RNF43 (1), BMPR1A (1), BRCA2 (4), ATM (1), RAD51C (1), and BRIP1 (1). Five patients (4%) had variants in genes implicated in cancer but where the significance of germline variants in CRC risk is uncertain: GATA2 (1), ERCC2 (mono-allelic) (1), ERCC4 (mono-allelic) (1), CFTR (2). Fourteen (11%) had dMMR tumors. Eighteen (14%) reported a first-degree relative with CRC, but only three of these carried P/LP variants. Three patients with variants in polyposis-associated genes showed no polyposis (one each in MUTYH [bi-allelic], RNF43, and BMPR1A). Approximately one in five young adults in our series carried at least one P/LP variant in a cancer-predisposing/implicated gene; 80% of these variants are currently considered clinically actionable in a familial cancer setting. Family history and phenotype have limitations for genetic risk prediction; therefore multigene panel testing and genetic counseling are warranted for all young adults with CRC regardless of those two factors., (© 2021 Wiley Periodicals LLC.)

The role of RNF43 as a cause of an inherited predisposition to colorectal cancer (CRC) is yet to be fully explored. This report presents our findings of two individuals with CRC from a single family carrying a likely-pathogenic inherited germline variant in RNF43. The proband (III:1) and the proband's mother (II:2) were diagnosed with mismatch repair proficient CRCs at the age of 50 years and 65 years, respectively. Both patients had BRAF V600E mutated colon tumours, indicating that the CRCs arose in sessile serrated lesions. The germline variant RNF43:c.375+1G>A was identified in both patients. RNA studies showed that this variant resulted in an aberrantly spliced transcript, which was predicted to encode RNF43:p.Ala126Ilefs*50 resulting in premature termination of protein synthesis and was classified as a likely-pathogenic variant. Our report adds further evidence to the hereditary role of RNF43 as a tumour suppressor gene in colorectal tumorigenesis and supports the inclusion of RNF43 as a gene of interest in the investigation of CRC predispositions outside the setting of serrated polyposis., (© 2021 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Primary appendiceal neoplasms (ANs) comprise a heterogeneous group of tumors. The pathology and classification of ANs have been controversial, and thus, a new classification of these neoplasms was published in the World Health Organization (WHO) classification of tumors (5th edition, 2019). However, immunohistochemistry (IHC) features of epithelial ANs are not explained in this edition and the limited data on the molecular pathology of these tumors shows inconsistent findings in various studies. It would be useful to identify biomarkers appropriate for each subtype to better aid in treatment selection. Therefore, we reviewed the literature to investigate what is known of the molecular pathology and IHC features of the most frequently diagnosed pathological subtypes of epithelial ANs based on the recent classification. The inconsistencies in research findings regarding the IHC features and molecular pathology of ANs could be due to differences in the number of samples and their collection and preparation as well as to the lack of a universally accepted classification system for these neoplasms. However, the literature shows that epithelial ANs typically stain positive for MUC2, CK20, and CDX2 and that the expression of SATB2 protein could be used as a biomarker for appendix tumor origin. Low-grade appendiceal mucinous neoplasms tend to have mutations in KRAS and GNAS but are usually wild-type for BRAF , APC , and P53 . Conversely, appendiceal adenocarcinomas are frequently found with mutations in KRAS , GNAS , P53 , PIK3CA , and APC , and have significant nuclear expression of β-catenin, loss of nuclear or nuclear and cytoplasmic expression of SMAD4, and loss of cytoplasmic membranous expression of E-cadherin. Goblet cell carcinomas (GCCs) typically stain positive for keratin and mucin markers and are frequently mutated in P53 and chromatin-modifier genes, but they tend to be wild-type for KRAS , GNAS , APC , and PIK3CA. The expression of CK7 and SATB2 proteins is usually negative in appendiceal neuroendocrine neoplasms and they lack the mutations in common cancer-associated genes including APC , BRAF , SMAD4 , and PIK3C. The available data suggest that GCCs have distinct molecular and immunohistochemical features and that they have characteristics more in common with adenocarcinoma than classical neuroendocrine tumors. In addition, MSI does not seem to have a role in the pathogenesis of epithelial ANs because they are rarely detected in these tumors. Finally, hereditary predisposition may have a role in the development of ANs because heterozygous CTNNβ1 , NOTCH1, and NOTCH4 germline mutations have recently been identified in low and high grades ANs.

Objectives: The study aimed to examine the incidence and mortality rates of appendiceal neoplasms (ANs) in Australia., Methods: A retrospective analysis was performed on national data obtained from the Australian Institute of Health and Welfare (AIHW) from 1982 to 2013. Changes to the incidence, and the cancer-specific mortality following the diagnosis of ANs were analyzed over this time period, with stratification performed for histological subtype, gender, and age groups (<50y and ≥50y)., Results: Incidence and mortality rates of ANs increased significantly across both genders and age groups. Incidence rates increased by 415%, from 0.40/100 000 population in 1982 to 2.06/100 000 in 2013. Overall mortality rates increased by 130%, from 0.057/100 000 during 1982-1985 to 0.131/100 000 during 2010-2013. Controlling for age group and gender, the incidence rates increased by 20% every four years (Incidence rate ratio (IRR) = 1.20, 95% confidence interval (CI): 1.17, 1.23, global P value<0.0001), and controlling for age, the mortality rates increased by 8% every four years (IRR = 1.08, 95% CI: 1.00, 1.17, global P-value = 0.0401)., Conclusion: The increasing use of CT scanning, improvements in pathological assessment of the appendix, and the growing aging population may have contributed in part to the apparent rise in the incidence of ANs.

Background: Colorectal cancer (CRC) is rising in incidence in young adults, and this observation is currently unexplained. We investigated whether having a personal history of type 2 diabetes mellitus (T2D) was a potential risk factor for young-onset colorectal cancer (YOCRC)., Methods: The South Australian Young Onset (SAYO) CRC study is a series of young adults with CRC below age 55. Ninety unrelated YOCRC cases were recruited to the study. Personal history and detailed family history of T2D were obtained at face-to-face interview and confirmed from medical records. Whole exome sequencing was conducted on germline DNA from each CRC case. Controls for personal history studies of T2D were 240 patients with proven clear colonoscopies and no known CRC predispositions., Results: The median age of YOCRC cases was 44 years (18-54) and of controls was 45 years (18-54), and 53% of both cases and controls were females (P = 0.99). Left-sided (distal) CRC was seen in 67/89 (75%) of cases. A personal history of T2D was confirmed in 17/90 (19%) YOCRC patients compared with controls (12/240, 5%; P < 0.001; odds ratio = 4.4; 95% confidence interval, 2.0-9.7). YOCRC patients frequently reported at least one first-degree relative with T2D (32/85, 38%). Ten of 87 (12%) of YOCRC cases had CRC-related pathogenic germline variants, however, no pathogenic variants in familial diabetes-associated genes were seen., Conclusions: Though the mechanism remains unclear, our observations suggest that there is enrichment for personal history of T2D in YOCRC patients., Impact: A diagnosis of T2D could therefore potentially identify a subset of young adults at increased risk for CRC and in whom early screening might be appropriate., (© 2020 John Wiley & Sons Australia, Ltd.)