Young Onset Research Articles

CXCR4 Expression and Cancer-associated Fibroblasts May Play an Important Role in the Invasion of Low-grade Endometrioid Carcinoma.

Well-differentiated endometrioid carcinoma (EC) is a low-grade cancer with relatively indolent behavior. However, even with well-differentiated histology, it sometimes tends to invade extensively and shows metastatic potential, suggesting that this is a group of cancers with heterogeneous behavior. In contrast, due to its tendency for younger onset, the treatment strategy for EC frequently considers fertility preservation, highlighting the need for a more accurate evaluation of myometrial invasion through biopsy and imaging diagnostics. We previously reported the involvement of the CXCR4-CXCL12 and CXCL14 axes in EC invasion. Accordingly, we investigated whether CXCR4 expression could reflect invasive potential and explored its interaction with cancer-associated fibroblasts that produce chemokines in the tumor microenvironment. Immunohistochemical expression of CXCR4 was assessed in 71 cases of EC (14 of EC confined to the endometrium and 57 of myoinvasive EC), 6 cases of endometrial intraepithelial neoplasia, and 42 cases of noncarcinomatous conditions. CXCR4 expression was significantly higher in myoinvasive EC than in noncancerous conditions, endometrial intraepithelial neoplasia, and endometrium-confined EC. By univariate and multivariate analysis, CXCR4 expression significantly reflected myometrial invasion. CXCR4 expression in the biopsied and resected specimens correlated weakly positively. Invasion and wound-healing assays were performed culturing an EC cell line in a cancer-associated fibroblast-conditioned medium. The invasion and wound-healing potentials were dependent on CXCR4 and cancer-associated fibroblast. Our study demonstrated that CXCR4 expression is an independent factor in myometrial invasion and can support diagnostic evaluation before treatment in the biopsy sample.

Role of behavioural problems in carer burden in young onset dementia.

Role of behavioural problems in carer burden in young onset dementia.

Sex-based differences in the transcriptomic metabolic profiling in young onset colorectal cancer (YOCRC).

155 Background: The incidence of YOCRC has been rising rapidly. We recently showed that the YOCRC population has significantly different transcriptional metabolic and immune profiles than their older counterparts. In a separate study, we found that the metabolic and immune environments are affected by the sex of the patient. Based on these findings, we hypothesize that significant differences in transcriptional metabolic and immune profiles of males and females exist within the YOCRC population. The primary objective of this study was to identify those differences and compare them with the average onset colorectal cancer (AOCRC) population. Methods: Using TCGA (YOCRC N=48) and ORIEN CRC (YOCRC N=96) datasets, patients were separated into younger onset (<50) and older (>60) patient populations, comparing male and female transcriptional programs within each of the age groups. Subsequently, their transcriptional profiles were compared and assessed via differential gene expression analysis (DESeq2), gene set enrichment analysis (GSEA), immune deconvolution (TIMER2.0), and metabolic pathway analysis (MetaPhOR). These pathways were then mapped to assess transcriptional dysregulation, and patterns of predicted metabolic flux. Results: Our analysis revealed different transcriptional, metabolic, and immune signatures between males and females in differing age groups. Amongst the young patients, females were enriched for lipid metabolism (cholesterol and steroid metabolism), decreased macrophage signatures, and a proliferative phenotype. Conversely, males were enriched for glucocorticoid metabolism, urea cycle metabolites, metastasis, and CD4+ T Cell populations. Further, CTLA4 and PD-L1 response signatures were decreased in young males compared to young females, with a notable increase in inflammatory pathways. Immune deconvolution revealed no difference in the predicted infiltration of immune cells between younger males and females. In older patients (>60), females were enriched for lipid metabolism (testosterone, linoleic acid metabolism), CD8+ T cell signatures, and a proliferative phenotype. In contrast, males were enriched for lipid metabolism (cortisol), epigenetic alterations, and decreased macrophages. Like the younger population, CTLA4 and PD-L1 response signatures were decreased in older males, compared to older females, with a notable increase in inflammatory pathways. Immune deconvolution revealed decreases in CD8+ T cells and neutrophils in the predicted infiltration of older males' immune cells compared to older females. Conclusions: Our research revealed that the sex of the patient is associated with the transcriptional metabolic and immune profiles in YOCRC and AOCRC. Further translational research is needed to understand the biology better and develop effective, personalized treatment options.

Investigating Equivalence of In-Person and Telehealth-Based Neuropsychological Assessment Performance for Individuals Being Investigated for Younger Onset Dementia.

Given the rapid shift to in-home teleneuropsychology models, more research is needed to investigate the equivalence of non-facilitator models of teleneuropsychology delivery for people with younger onset dementia (YOD). This study aimed to determine whether equivalent performances were observed on neuropsychological measures administered in-person and via teleneuropsychology in a sample of people being investigated for YOD. Using a randomized counterbalanced cross-over design, 43 participants (Mage = 60.26, SDage = 7.19) with a possible or probable YOD diagnosis completed 14 neuropsychological tests in-person and via teleneuropsychology, with a 2-week interval. Repeated measures t-tests, intraclass correlation coefficients (ICC), and Bland Altman analyses were used to investigate equivalence across the administration conditions. No statistical differences were found between in-person and teleneuropsychology conditions, except for the Hospital Anxiety and Depression Scale Anxiety subtest. Small to negligible effect sizes were observed (ranging from .01 to .20). ICC estimates ranged from .71 to .97 across the neuropsychological measures. Bland Altman analyses revealed that the Wechsler Adult Intelligence Scale-Fourth Edition Block Design subtest had slightly better overall performance in the in-person condition and participants reported higher levels of anxiety symptoms during the teleneuropsychology condition; however, average anxiety symptoms remained within the clinically normal range. Participants reported a high level of acceptability for teleneuropsychology assessments. These results suggest that performances are comparable between in-person and teleneuropsychology assessment modalities. Our findings support teleneuropsychology as a feasible alternative to in-person neuropsychological services for people under investigation of YOD, who face significant barriers in accessing timely diagnoses and treatment options.

Tumoral microbial and pathway alterations associated with young-onset rectal cancer and its response to therapy.

160 Background: Given the increasing incidence of young onset rectal cancer (YORC) in recent decades, we examined the potential of tumor and fecal microbiome pathways in YORCs as compared to late-onset rectal cancers (LORCs) while also exploring markers of response to neoadjuvant therapy (NAT). We hypothesize microbial markers reflect unique and potentially causative biology in YORC, and variability in response to NAT. Methods: Treatment-naïve patients with YO- (<50 years old) or LO- ≥50 years old) rectal cancers were prospectively enrolled. Tumor and tumor-adjacent normal tissues (TANs) were collected via endoscopic biopsy, as well as stool at baseline. After whole genome sequencing, metagenomic analysis was performed using MetaPhlAn4, VirMAP and HUMAnN3 for taxonomical and metabolomic profiling. Association of microbial and immune signatures were examined comparing tumors vs. TANs, and YO- vs. LORC tumors. Differential abundance analyses were performed using paired Wilcoxon test and MaAsLin2. Molecular subtype defined for tissues with whole transcriptomic sequencing available. Results: 162 tumors and paired normal tissues, 73 (45.1%) YO- and 89 (54.9%) LORC were analyzed. Additional whole transcriptomic sequencing was available for 88 patients. The majority 145 (89.5%) of patients received neoadjuvant therapy. Observed bacterial diversity was higher in tumors as compared to tumor associated normal (TAN) tissue (p<0.001). Moreover, bacterial diversity also increased linearly with age of diagnosis in tumors (p=0.01), but not TAN (p=NS). Oral bacteria previously associated with colorectal cancer were noted in these rectal cancers including Fusobacterium nucleatum (q<0.001) and Parvimonas micra (q<0.001). Escherichia coli, previously associated with colorectal cancer and development of metastatic disease was associated with YORC (q<0.001) but not LORC. For NAT treated patients, major pathologic response in YORC was associated with higher bacterial diversity (p=0.03) but not in LORC (p=NS). Similarly, no significant bacterial marker of response to neoadjuvant therapy was noted in LORC. While Butyricimonas virosa (q<0.001), Alistipes shahi (q=0.01), and Parabacteroides merdae (q=0.01) were all associated with a diminished pathologic response. Conclusions: Oral bacterial signatures previously associated with colorectal cancer were noted in both YORC and LORC when comparing matched tumor and TAN. Importantly, several unique bacterial associations were identified with YORC, including Escherichia Coli – previously associated with development of metastases in CRC. We also noted distinct microbial associations related to response to therapy in YORC suggesting the unique biology of these tumors. Functional bacterial pathway associations with response suggest a potential to augment NAT with existing or next-generation microbial modulation strategies.

Long-term prognosis and its associated predictive factors in patients with eosinophilic gastroenteritis.

Eosinophilic gastroenteritis (EGE) is a chronic recurrent disease with abnormal eosinophilic infiltration in the gastrointestinal tract. Glucocorticoids remain the most common treatment method. However, disease relapse and glucocorticoid dependence remain notable problems. To date, few studies have illuminated the prognosis of EGE and risk factors for disease relapse. To describe the clinical characteristics of EGE and possible predictive factors for disease relapse based on long-term follow-up. This was a retrospective cohort study of 55 patients diagnosed with EGE admitted to one medical center between 2013 and 2022. Clinical records were collected and analyzed. Kaplan-Meier curves and log-rank tests were conducted to reveal the risk factors for long-term relapse-free survival (RFS). EGE showed a median onset age of 38 years and a slight female predominance (56.4%). The main clinical symptoms were abdominal pain (89.1%), diarrhea (61.8%), nausea (52.7%), distension (49.1%) and vomiting (47.3%). Forty-three (78.2%) patients received glucocorticoid treatment, and compared with patients without glucocorticoid treatments, they were more likely to have elevated serum immunoglobin E (IgE) (86.8% vs 50.0%, P = 0.022) and descending duodenal involvement (62.8% vs 27.3%, P = 0.046) at diagnosis. With a median follow-up of 67 mo, all patients survived, and 56.4% had at least one relapse. Six variables at baseline might have been associated with the overall RFS rate, including age at diagnosis < 40 years [hazard ratio (HR) 2.0408, 95% confidence interval (CI): 1.0082-4.1312, P = 0.044], body mass index (BMI) > 24 kg/m2 (HR 0.3922, 95%CI: 0.1916-0.8027, P = 0.014), disease duration from symptom onset to diagnosis > 3.5 mo (HR 2.4725, 95%CI: 1.220-5.0110, P = 0.011), vomiting (HR 3.1259, 95%CI: 1.5246-6.4093, P = 0.001), total serum IgE > 300 KU/L at diagnosis (HR 0.2773, 95%CI: 0.1204-0.6384, P = 0.022) and glucocorticoid treatment (HR 6.1434, 95%CI: 2.8446-13.2676, P = 0.003). In patients with EGE, younger onset age, longer disease course, vomiting and glucocorticoid treatment were risk factors for disease relapse, whereas higher BMI and total IgE level at baseline were protective.

Diverticular disease and risk of dementia: a Danish population-based cohort study.

Patients with diverticular disease (DD) have ongoing chronic inflammation associated with changes in the gut microbiome, which might contribute to the development of dementia. Using Danish medical and administrative registries from 1980 to 2013, we conducted a nationwide population-based cohort study including all DD patients and a matched (5:1) general population comparison cohort without DD. A nested case-control analysis was then conducted using a risk set sampling, matching four DD controls without dementia to each DD patient with dementia. Clinical severity was categorized as uncomplicated DD (outpatient), conservatively treated DD (inpatient), and surgically treated DD. 149 527 DD patients and 747 635 general population comparators were identified. The 30-year cumulative incidence of dementia among DD patients and general population comparators were 12.4 (95% confidence interval [CI] 12.1-12.7) and 13.73% (95% CI 13.6-13.9), respectively. This corresponded to a 30-year hazard ratio (HR) of 1.10 (95% CI 1.1-1.1). The highest HRs were found in the conservatively treated DD group (1.15 95% CI 1.1-1.2) and the group with young onset of DD (1.52 95% CI 1.2-2.0). In the nested case-control analysis, we identified 8875 dementia cases and 35 491 matched controls. The adjusted odds ratio (OR) for conservatively treated DD was increased (1.08, 95% CI; 1.0-1.2) compared to the reference of uncomplicated DD. We observed a slight increased risk of dementia in patients with young onset DD and conservatively treated DD. Findings suggest an association between disease duration, perhaps reflecting the duration of gut inflammation, and the risk of developing dementia.

Sexual dysfunction in men with young onset Parkinson's disease.

Sexual dysfunction (SD) is a common, yet under-reported non-motor symptom of PD. Common sexual symptoms among male PD patients include erectile dysfunction, premature ejaculation, and decreased sexual desire. Few research papers have examined sexual dysfunction in PD, especially in YOPD male patients, and there is no Indian research study on sexual dysfunction in YOPD. In this study, we determined the frequency of sexual dysfunction in men with YOPD, and its correlation with other motor and NMS. This prospective cross-sectional study was conducted on YOPD males who presented to the Department of Neurology, NIMHANS, Bangalore, India, from May 2021 to April 2023. The diagnosis of YOPD was made based on MDS criteria for IPD 2015. Sexual functions were evaluated by ASEX, PEDT, QUIP-RS, and sex hormone assay. The patients also underwent other motor and non-motor assessments. Statistical analysis was done using SPSS version 22.0. The study was funded by the PDMD fund. This study included 62 male YOPD patients. The mean age of cases was 44.74 ± 8.54years. The mean duration of symptoms was 8.45 ± 6.23years. 43.5% of the cases of PD were Akinetic rigid type. By ASEX Score grading, 46.8% of the cases had erectile dysfunction and 71% of the cases of YOPD had premature ejaculation by PEDT Score grading. 9.7% of the cases had hypersexuality by QUIP-RS.Duration of YOPD was a better predictor of Erectile Dysfunction and premature ejaculation when compared with other variables. SD was related to anxiety and depression and it had a negative impact on the patient's health-related quality of life (HR-QoL). SD should be investigated and treated as an integral part of the neurological assessment in YOPD.

Optimising Online Peer Support for People with Young Onset Dementia.

People with Young Onset Dementia (YOD) can be hesitant to engage with online peer support. This work aims to explore (1) why people are hesitant to engage in online peer support, (2) how to get more people involved in online peer support, and (3) what makes online peer support work well. Nine interviews with people with YOD were conducted on MS Teams. Participants were recruited through purposive sampling. Data were analysed thematically. Reasons for being hesitant to engage with online peer support include being unsure what to expect and concerns about seeing others in more advanced stages of dementia. Additionally, it can be difficult to identify groups that suit one's needs and interests. Group facilitators of online peer support groups should provide a detailed description of their group so that people can better assess whether the group would suit them. The insights obtained from this study will be used to develop a Best Practice Guidance on online peer support for people with YOD. Moreover, the findings can be useful for further research exploring how to support people with dementia in general in accessing online health and social care services.

General and sex-specific effects of vitamin D against atrial fibrillation and young-onset ischemic stroke: a Mendelian randomization series.

Whether vitamin D deficiency causes atrial fibrillation and ischemic stroke of young onset was unknown. We derived a Genetic Risk Score for vitamin D from 3,922 subjects in Hong Kong and applied it in an independent sample (n = 1,297) for clinical outcomes. Primary endpoint was a composite of atrial fibrillation and/or ischemic stroke. A second study was performed in the UK Biobank (n = 392,010; 46% men; 14,878 atrial fibrillation and 4,050 ischemic stroke cases, vs 374,102 controls). After 76 ± 46 months, 240 primary endpoints (18.5%) were adjudicated. Higher genetically-predicted vitamin D independently predicted reduced primary endpoint [odds ratio = 0.83 (0.72 to 0.95), p = 0.008]. Mendelian randomization analyses indicated vitamin D was causally protective against the primary endpoint [odds ratio = 0.81 (95% CI: 0.65 to 0.98)]. Independent analyses in the UK Biobank revealed that vitamin D was protective against young-onset ischemic stroke <50 years and atrial fibrillation combined [odds ratio = 0.36 (95% CI 0.14 to 0.94)], with predominant effect amongst men [odds ratio = 0.28 (95% CI 0.09 to 0.91)] compared to women [odds ratio = 0.60 (95% CI: 0.11 to 3.22)]. In conclusion, vitamin D may protect against young-onset ischemic stroke through preventing atrial fibrillation. Investigating the sex-specifc effects of vitamin D deficiency may elucidate sex disparities of atrial fibrillation in the young.

Rare forms of autosomal recessive spinocerebellar ataxia associated with mutations in the ANO10 (ATX-ANO10) and SYNE1 (ATX-SYNE1) genes

To analyze clinical and genetic characteristics of patients with the verified rare forms of autosomal recessive spinocerebellar ataxias, ATX-ANO10 and ATX-SYNE1. Six unrelated patients with established diagnoses were examined: 4 patients with ATX-ANO10 and 2 patients with ATX-SYNE1. Brain MRI and nerve conduction study were performed. To screen for cognitive impairment, the scale for the Assessment and Rating of Ataxia (SARA), and the Montreal Cognitive Assessment Scale (MoCA) were used. Mutation screening included panel sequencing on the Illumina MiSeq platform. Six variants were found in the ANO10 gene: the previously described pathogenic nonsense mutations c.G1025A (p.W342X) and c.C1244G (p.S415X), as well as novel probably pathogenic variants c.1477-2A>G and c.G101T (p.W34L) and missense mutations c.A110C (p.N37T) and c.T104C (p.L35P) of undetermined significance. A novel nonsense mutation c.C8911T (p.Q2971X) and a previously described pathogenic variant c.C4939T (p.Q1647X) were found in the SYNE1 gene. The clinical presentation of the ATX-ANO10 and ATX-SYNE1 was typical presenting with slowly progressive cerebellar ataxia with pyramidal signs, with young onset and cerebellar atrophy according to brain MRI study. We provided first-ever data on clinical features and mutation spectrum In Russian patients with ATX-ANO10 and ATX-SYNE1. The phenotype of these ataxias is nonspecific, so the method of choice for molecular diagnostics is massive parallel sequencing.

Pramipexole induced syndrome of inappropriate antidiuretic hormone secretion in a patient with young onset Parkinson’s disease

Abstract Pramipexole, a dopaminergic agonist, has rarely been implicated as a cause of hyponatremia in patients with Parkinson’s disease (PD). Pramipexole-induced stimulation of anti-diuretic hormone results in euvolemic hyponatremia. This is often neglected, and hyponatremia may lead to worsening of the motor symptoms with PD and an unnecessary increase in dopaminergic medications, causing disabling dyskinesias. This case report describes a patient with young-onset PD who developed new-onset hyponatremia due to pramipexole-induced syndrome of inappropriate anti-diuretic hormone within 3 months of starting the drug.

Impulse control and related behavioral disorders (ICRD) in Idiopathic Parkinson’s Disease treated with different dopamine agonists in Hong Kong: Is any dopamine agonist better?

ObjectiveTo assess the incidence of Impulse control and related behavioral disorders (ICRD) in Chinese Idiopathic Parkinson Disease (IPD) patients treated with different dopamine agonists (DA), and their clinical characteristics and associated risk factors. MethodsThis was an observational cohort study based on clinical interviews and medical records of IPD patients treated with DA for >6 months in three hospitals in Hong Kong. The short version of Questionnaire for Impulsive-Compulsive Disorders in Parkinson’s Disease (QUIP-S) was used to screen for ICRD. ICRD incidence among different DA, clinical characteristics and risk factors were examined. ResultsIncidence of ICRD was analyzed in 311 patients taking their first, single DA. 43 patients (13.8 %) developed ICRD. The mean duration of IPD was 8.5 ± 5.6 years and median HY stage was 2.5. Bromocriptine and rotigotine users had lower ICRD incidence rate. Both pramipexole [adjusted HR 7.28 (2.46–21.54), p < 0.001] and ropinirole [adjusted HR 6.53 (2.67–15.99), p < 0.001] were independently associated with higher risk of ICRD compared to bromocriptine in multivariate analysis. Similarly, pramipexole and ropinirole appeared to carry higher risk compared to rotigotine but did not reach statistical significance. Male [adjusted HR 2.24 (1.07–4.72), p = 0.033], younger IPD onset [adjusted HR 2.99 (1.44–6.19) for onset < 50 year, p = 0.003] and history of psychiatric disorders [adjusted HR 2.80 (1.39–5.62), p = 0.004] were other independent risk factors. ConclusionBromocriptine and probably rotigotine carried a lower ICRD risk compared to pramipexole and ropinirole.

Cognitive-Linguistic Profiling in Young Onset Dementia: A case Study

The onset of dementia is after 65 years. Though there are evidence reported in the past regarding the onset of dementia before this age, it is very rare. Studies carried out in the past have concentrated on the site of lesion, genetic base for the young onset dementia and the studies focusing on cognitive linguistic profiling are extremely rare. The current study focussed on the cognitive linguistic profiling and profiling the effect of dementia on the activities of daily living. The findings suggested that the cognitive linguistic deficit was very severe and had a note-worthy impact on the activities of daily living. This is pivotal in designing the plan of intervention and deciding the course of treatment.

Renal Transplantation in Rare Monogenic Urinary Stone Disease – A Single-center Experience

Introduction: Monogenic urinary stone disease (MUSD) tends to be more severe with early onset of symptoms and a higher risk of chronic kidney disease than sporadic USD. The literature on the outcome after renal transplant in patients with certain MUSD is scarce. Materials and Methods: This is a retrospective single-center observational study conducted in a tertiary care renal transplant unit in North India between 2018 and 2021. The renal transplant recipients who developed an end-stage renal disease (ESRD) due to renal calculus disease/nephrocalcinosis were included in the study. All the patients presented to us in an anuric state, and hence, a 24-h urine metabolic profile could not be performed. Ear, nose, and throat and ophthalmological evaluations were done to rule out extrarenal manifestations. These patients were subjected to genetic analysis, i.e., clinical exome sequencing using next-generation sequencing. Results: Out of 283 live renal transplants, 11 patients developed ESRD due to nephrocalcinosis/renal calculus disease. Out of 11, only 4 had genetic mutations and the rest did not have any identifiable genetic mutations. The gene mutations were identified in ADCY10, CLDN16, CaSR, and SLC3A4. The patient with ADCY10 mutation had a strong family history. The clinical phenotype and in silico parameters analysis predicted the variant to be damaging except the one with CaSR mutation which causes Hypocalciuric hypercalcemia syndrome, type 1. Three of four underwent surgical intervention at younger age. All underwent successful live-related renal transplantation, with good graft function on follow-up, without any recurrence of calculus in the allograft. Conclusion: Renal transplantation can be safely proceeded in patients with the above monogenic mutations. Genetic analysis should be a part of pretransplant evaluation in young onset nephrolithiasis and end-stage kidney disease patients to look for a monogenic cause, to assess the risk of recurrence postrenal transplant.

Unusual Case of Young Age Onset Stroke Suspected to Be Associated with Pseudoxanthoma Elasticum Gene Mutation in ABCC6: A Case Report

Ischemic stroke in young adults can pose diagnostic challenges, particularly when the clinical features deviate from the common presentation. Here, we present the case of a 31-year-old female with transient left-sided hemiparesis. Brain magnetic resonance imaging and angiography revealed right frontoparietal lobe infarction and stenosis of the right internal carotid arteries. Genetic testing revealed a heterozygous variant of unknown significance in the ATP-binding cassette subfamily C member 6 gene NM_001171.6:c.3739C&gt;A (p.Pro1247Thr) that is associated with pseudoxanthoma elasticum, which is a rare disorder characterized by abnormal mineralization of elastic tissues. Although variants of unknown significance can only be classified as causative conditions if all other possible causes are ruled out, this report suggests the importance of considering unusual genetic conditions in young patients with ischemic stroke. Further genetic research, functional studies, and genetic counseling are vital for a comprehensive understanding of these cases.

Prognostic and relapsing factors of primary autoimmune cerebellar ataxia: a prospective cohort study.

The objective of this study was to investigate the factors influencing relapse and prognosis in patients with primary autoimmune cerebellar ataxia (PACA), an area previously not well understood. This prospective cohort study included patients who satisfied the modified diagnostic criteria of PACA. A modified Rankin scale score ≤ 2 at the last follow-up was defined as a favorable prognosis. Cox and Logistic regression were utilized to identify relapsing and prognostic factors, respectively. A total of 68 patients were included and 35.3% were male. The median onset age was 42.9years (IQR 22.1-54.0). Neuronal autoantibodies were detected in 33 (50.8%) patients. Of the 65 patients who received first-line immunotherapy, 55 (84.6%) were responsive and 10 (15.4%) were not. Responsiveness to first-line immunotherapy emerged as an independent factor for favorable prognosis (HR 16.762; 95% CI 2.877-97.655; p = 0.002), as did the absence of peripheral neuropathy/radiculopathy (HR 14.286; 95% CI 2.41-83.333; p = 0.003). Relapses occurred in 19 (27.9%) patients. Onset age ≤ 43years (HR 5.245; 95% CI 1.499-18.35; p = 0.009), presence of peripheral neuropathy/radiculopathy (HR 4.280; 95% CI 1.622-11.298; p = 0.003) and elevated cerebrospinal fluid (CSF) protein concentration (HR 3.443; 95% CI 1.083-10.951; p = 0.036) were statistically significant relapsing factors. This study identified younger onset age, presence of peripheral neuropathy/radiculopathy and elevated CSF protein concentration as relapsing factors, and absence of peripheral neuropathy/radiculopathy and responsiveness to first-line immunotherapy as independent factors for favorable prognosis in PACA patients. These findings may guide individualized treatment strategies and potentially improve patient outcomes.

CAREGIVER EXPERIENCE WITH FRONTOTEMPORAL DEGENERATION (FTD)

Abstract Frontotemporal degeneration (FTD) is the umbrella term for a group of young onset neurodegenerative disorders affecting the frontal and temporal lobes of the brain. Symptoms include changes in cognition, language, behavior, motor functioning, and personality. The FTD Insights Survey was designed to learn more about the lived experience of this often misunderstood set of disorders. A total of 1,246 past and current caregivers of people with FTD responded to questions regarding their and their loved one’s experiences with FTD. Caregivers most often provided care for more than 80 hours per week and 10% of respondents provided care for more than one person diagnosed with FTD. The majority were caring for someone or had cared for someone who was diagnosed between ages 50 and 69. Only 36% of caregivers reported the person diagnosed was aware or mostly aware of their symptoms and they noted being most distressed by changes in the diagnosed person’s language, personality, mood, and behavior. The caregivers described the impact of their loved one’s symptoms on activities of daily living at home, in the community, and on interpersonal functioning. The caregivers also provided insight into issues such as the length of time they have provided care, the level of functioning of the person diagnosed, and the impact of FTD symptoms on quality of life. It is critical that healthcare professionals and policy makers understand FTD caregiver strain in order to provide wraparound support and make policy decisions with these features in mind.

Comprehensive genomic profiling of breast cancers characterizes germline-somatic mutation interactions mediating therapeutic vulnerabilities

Germline-somatic mutation interactions are universal and associated with tumorigenesis, but their role in breast cancer, especially in non-Caucasians, remains poorly characterized. We performed large-scale prospective targeted sequencing of matched tumor-blood samples from 4079 Chinese females, coupled with detailed clinical annotation, to map interactions between germline and somatic alterations. We discovered 368 pathogenic germline variants and identified 5 breast cancer DNA repair-associated genes (BCDGs; BRCA1/BRCA2/CHEK2/PALB2/TP53). BCDG mutation carriers, especially those with two-hit inactivation, demonstrated younger onset, higher tumor mutation burden, and greater clinical benefits from platinum drugs, PARP inhibitors, and immune checkpoint inhibitors. Furthermore, we leveraged a multiomics cohort to reveal that clinical benefits derived from two-hit events are associated with increased genome instability and an immune-activated tumor microenvironment. We also established an ethnicity-specific tool to predict BCDG mutation and two-hit status for genetic evaluation and therapeutic decisions. Overall, this study leveraged the large sequencing cohort of Chinese breast cancers, optimizing genomics-guided selection of DNA damaging-targeted therapy and immunotherapy within a broader population.

Demographic characteristics and survival in young onset colorectal neuroendocrine tumors

Demographic characteristics and survival in young onset colorectal neuroendocrine tumors