Young-onset Patients Research Articles

An unusual case of recurrent oral cancer in a young woman HPV-negative, non-smoker and non-drinker

An unusual case of recurrent oral cancer in a young woman HPV-negative, non-smoker and non-drinker

Association between adiponectin T94G polymorphism and resistant hypertension in young-onset Taiwanese patients

Young-onset hypertensives (YOHs) with resistant hypertension (RH) have a greater long-term cardiovascular risk. The present study examined whether a functional adiponectin T94G polymorphism (rs2241766) is associated with RH in YOHs. We analyzed data from the Academia Sinica Collaborative Study on Hypertension Genetics in Taiwanese subjects to compare rs2241766 between YOHs with and without RH (≤50 years of age). RH was defined as the need for at least 3 drugs, including a diuretic to control blood pressure. Genotyping of rs2241766 was performed using TaqMan allelic discrimination. A total of 861 YOHs were enrolled and 54 had RH in enrolled population. For the rs2241766 in the allelic model, the odds ratio (OR) of RH allele frequency was 2.45 (p = 0.008), and there was a linear relationship between allele numbers and the presence of RH (p = 0.005). In multivariate analysis, the rs2241766 (OR = 2.766, p = 0.002), age (OR = 1.103, p = 0.001), uric acid (OR = 1.322, p = 0.001), high-sensitivity C-reactive protein (OR = 2.769, p = 0.001) and aldosterone (OR = 1.004, p = 0.001) were independently associated with the presence of RH. In the Taiwanese population, the adiponectin T94G polymorphism (rs2241766) is associated with RH in YOHs.

Racial Disparities in Incidence of Young-Onset Colorectal Cancer and Patient Survival

Increasing rates of young-onset colorectal cancer (CRC) have attracted substantial research and media attention, but we know little about racial disparities among younger adults with CRC. We examined racial disparities in young-onset CRC by comparing CRC incidence and relative survival among younger (<50-year-old) adults in 2 time periods. Using data from the Surveillance, Epidemiology, and End Results program of cancer registries, we estimated CRC incidence rates (per 100,000 persons 20-49 years old) from 1992 through 2014 for different periods (1992-1996 vs 2010-2014) and races (white vs black). Relative survival was calculated as the ratio of observed survival to expected survival in a comparable cancer-free population. From 1992-1996 to 2010-2014, CRC incidence increased from 7.5 to 11.0 per 100,000 in white individuals and from 11.7 to 12.7 per 100,000 in black individuals. The increase in rectal cancer was larger in whites (from 2.7 to 4.5 per 100,000) than in blacks (from 3.4 to 4.0 per 100,000); in the 2010-2014 period, blacks and whites had similar rates of rectal cancer. Compared with whites, blacks had smaller increases in relative survival with proximal colon cancer but larger increases in survival with rectal cancer (from 55.3% to 70.8%). In an analysis of the Surveillance, Epidemiology, and End Results database, we found racial disparities in incidence of young-onset CRC and patient survival for cancer of the colon but minimal difference for rectal cancer. Well-documented and recent increases in young-onset CRC have largely been due to increases in rectal cancer, especially in whites.

Facebook Intervention for Young-Onset Melanoma Patients and Their Family Members: Pilot and Feasibility Study

Background: Despite their elevated melanoma risk, young-onset melanoma patients and their families exhibit low rates of engagement in skin cancer surveillance and sun protection behaviors. Interventions that improve skin cancer surveillance (total cutaneous exam [TCE] and skin self-exam [SSE]) and prevention (sun protection) practices among young-onset patients and their family members would likely have an impact on skin cancer morbidity and mortality; however, such interventions are lacking. Objective: The objective of our study was to examine the development, feasibility, and preliminary impact of a family-focused Facebook intervention to increase engagement in TCE, SSE, and sun protection among young-onset melanoma patients and their families. Methods: In this study, 48 young-onset melanoma patients and their 40 family members completed measures of knowledge; beliefs; and TCE, SSE, and sun protection intentions before and 1 month after participating in 1 of 5 separate “secret” (ie, private) Facebook groups. The intervention content consisted of daily postings about skin cancer, skin cancer risk factors, TCE, SSE, and sun protection. Results: Patient and family member participation rates differed by recruitment setting, with acceptance rates ranging from 24.6% to 39.0% among families recruited from a cancer center setting and from 12.7% to 61.5% among families recruited from a state registry. Among the 5 consecutive groups conducted, engagement, as measured by comments and likes in response to postings, increased across the groups. In addition, participants positively evaluated the intervention content and approach. Preliminary analyses indicated increases in TCE, SSE, and sun protection intentions. Conclusions: Our family-focused Facebook intervention showed promise as a potentially feasible and efficacious method to increase sun protection and skin cancer surveillance among individuals at increased risk for melanoma.

Young versus Older-Onset Colorectal Cancer in a Safety Net Hospital

Introduction: To better understand recent increases in colorectal cancer (CRC) among younger adults (age <50 years), we compared demographic, clinicopathologic, and molecular characteristics of youngvs. older-onset CRC. Methods: We identified patients newly diagnosed with CRC at a large, integrated safety-net system between January 2009 and December 2017. We manually reviewed electronic medical records for patient demographics, tumor characteristics (e.g., stage, grade, histology), mutation testing, and treatment (e.g., surgery, chemotherapy, radiation). Results: Of 1,224 patients, 319 (26.1%) were diagnosed before age 50 years (median age 44.0), and 905 were diagnosed after age 50 years (median age 60.3). A higher proportion of younger patients were Hispanic (50.6% vs. 32.9%), had a family history of CRC (25.1% vs. 15.2%), were diagnosed with poorly differentiated tumors (24.3% vs. 14.2%), and had mucinous histology (11.3% vs. 7.2%). Of those with a family history of CRC (n=218), more young-onset patients reported CRC in a second- (50.0% vs. 23.9%) or third-degree (12.5% vs. 4.4%) relative. Distribution of CRC by anatomic subsite and stage at diagnosis was similar between the two groups, with 24.6% and 32.1% having stage I/II CRC, respectively. Receipt of surgery (77.7% vs 71.2%) and radiation therapy (24.8% vs 22.9%) was similar, compared to receipt of chemotherapy (75.6% vs 60.0%). More young patients underwent testing for BRAF (17.9% vs 13.7%), KRAS (49.2% vs 39.0%) and MMR deficiency (79.0% vs 61.6%). Of those who received MMR deficiency testing (n=809), 45 younger and 56 older patients were MMR deficient; 2 younger and 12 older patients had hypermethylation of the MLH1 promoter. About half (52.0%, n=166) of younger patients were referred to genetic counseling, and of those who received genetic testing (n=102), 43 had a germline mutation. Survival was similar between younger (mean 52.5 months) and older (mean 61.4 months) patients, after adjusting for stage at diagnosis (HR 0.82, 95% CI 0.64 - 1.02). Conclusion: We found few differences in anatomic subsite, stage at diagnosis, treatment, and survival between young- and older-onset CRC. Younger CRC patients more frequently reported second- or thirddegree relatives with CRC, which may provide clues for understanding mechanisms, beyond inherited syndromes (e.g., Lynch), that contribute to increasing incidence in this population.206 Figure 1 No Caption available.

P5371Gender differences in sympathetic nervous system activity and 24-hour ambulatory blood pressure in young-onset hypertension patients

P5371Gender differences in sympathetic nervous system activity and 24-hour ambulatory blood pressure in young-onset hypertension patients

Crossing barriers: a multidisciplinary approach to children and adults with young-onset movement disorders

BackgroundDiagnosis of less common young-onset movement disorders is often challenging, requiring a broad spectrum of skills of clinicians regarding phenotyping, normal and abnormal development and the wide range of possible acquired and genetic etiologies. This complexity often leads to considerable diagnostic delays, paralleled by uncertainty for patients and their families. Therefore, we hypothesized that these patients might benefit from a multidisciplinary approach. We report on the first 100 young-onset movement disorders patients who visited our multidisciplinary outpatient clinic.MethodsClinical data were obtained from the medical records of patients with disease-onset before age 18 years. We investigated whether the multidisciplinary team, consisting of a movement disorder specialist, pediatric neurologist, pediatrician for inborn errors of metabolism and clinical geneticist, revised the movement disorder classification, etiological diagnosis, and/or treatment.ResultsThe 100 referred patients (56 males) had a mean age of 12.5 ± 6.3 years and mean disease duration of 9.2 ± 6.3 years. Movement disorder classification was revised in 58/100 patients. Particularly dystonia and myoclonus were recognized frequently and supported by neurophysiological testing in 24/29 patients. Etiological diagnoses were made in 24/71 (34%) formerly undiagnosed patients, predominantly in the genetic domain. Treatment strategy was adjusted in 60 patients, of whom 43 (72%) reported a subjective positive effect.ConclusionsThis exploratory study demonstrates that a dedicated tertiary multidisciplinary approach to complex young-onset movement disorders may facilitate phenotyping and improve recognition of rare disorders, with a high diagnostic yield and minimal diagnostic delay. Future studies are needed to investigate the cost-benefit ratio of a multidisciplinary approach in comparison to regular subspecialty care.

Abstract P1-06-05: Clinical practice and mortality in patients with oncotype DX intermediate score: What do we know about the gray zone?

Abstract BACKGROUND: The 21 gene expression signature Oncotype DX (ODX) is a powerful predictor of disease outcome in early stage hormone receptor positive breast cancer. ODX can be used for better risk stratification of patients who may benefit from chemotherapy. ODX testing increases confidence in treatment decisions especially when ODX recurrence score (RS) is low or high. However, for the intermediate RS, decisions on receiving chemotherapy or not is a joint decision made by the physician and patient, in part because results from the TAILORx and RxPONDER randomized clinical trials addressing this very important clinical question has yet to be published. OBJECTIVE: To examine “real world” oncology practice and survival outcome for breast cancer patients with ODX RS score in the intermediate range. METHODS: A retrospective cohort of women diagnosed with early stage, hormone receptor positive breast cancer whose ODX score was in the intermediate range was established using the National Cancer Data Base (NCDB), 2009-2013. We assessed the relationship of overall survival with chemotherapy receipt and RS score using Cox proportional hazards models adjusted for patient characteristics, including age, race/ethnicity, grade, year of diagnosis, Charlson Co-morbidity Index, lymphovascular invasion, nodal involvement, tumor size, and histology. Intermediate RS score was analyzed as both continuous variable and categorical variables (18-20, 21-23, 24-26, and 27-30). RESULTS: Of 24,945 females reported to have intermediate ODX score, 10,179 (41.4%) received chemotherapy. Receipt of chemotherapy depended on ODX score monotonically, ranging from 19.1% in patients with RS = 19 to 76.1% in patients with RS = 30. In total, 426 patients have died from all causes. Overall, chemotherapy receipt was associated with a statistically significant reduction in the risk of death (hazard ratio=0.77; 95% confidence interval [CI]: 0.62-0.96, p=0.02) in multivariable Cox model. RS score was statistically positively associated with increased risk of death, with one unit increment in RS corresponding to 6.2% increased mortality risk (95% CI 3.2%- 9.2%, p&amp;lt;0.0001). Using a categorical scale, we found patients with intermediate ODX scores in RS 27-30 range had 1.64-fold increased risk of death (95% CI: 1.13-2.37) compared to patients with ODX scores in RS 18-20 range.. The association between ODX score and overall survival was more pronounced in women younger than 50 (hazard ratio per 1 unit increment = 1.28, 95% CI: 1.17-1.40) than in women 50 years or older (hazard ratio per 1 unit increment = 1.04, 95% CI: 1.01-1.07). CONCLUSION: Our analysis revealed the ODX score in the intermediate range still has prognostic value for overall survival especially for young-onset breast cancer patients, which is independent of other clinopathologic factors. As we eagerly await results from randomized clinical trials, young women with intermediate RS should be counseled to consider more aggressive treatment including chemotherapy, ovarian function suppression or participation in ongoing clinical trials of CDK inhibitors to improve overall survival outcomes. Citation Format: Ibraheem AF, Press D, Dezheng H, Olopade F. Clinical practice and mortality in patients with oncotype DX intermediate score: What do we know about the gray zone? [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P1-06-05.

Understanding Important Issues in Young-Onset Dementia Care: the Perspective of Healthcare Professionals

Psychosocial research on the lived experiences of young-onset dementia patients and caregivers has identified salient issues about their care, however, views on care from the perspective of young-onset dementia healthcare professionals is less well known. The aim of this study was to investigate and identify important issues in young-onset dementia care provision from a healthcare provider perspective. The design was an exploratory qualitative interview study. In-depth semistructured interviews were conducted with healthcare professionals with clinical expertise in young-onset dementia drawn from medicine, nursing and allied health. Thematic analysis was applied to interview transcripts to identify themes representing important underlying issues in care across the dementia clinical pathway (i.e., prediagnosis, diagnosis and postdiagnosis). In prediagnosis, it is important for healthcare professionals to recognize symptoms as organic and degenerative and more than psychological, and to refer patients to an appropriate clinical facility for assessment. During diagnosis, it may be challenging to determine dementia, and methods are employed to manage diagnostic uncertainty. Following diagnosis, optimizing routine clinical care is important and can include the provision of practical informational guidance, empathic concern and psychoeducational support. Meeting service-user requirements in the community is an important aspect of care, and may be facilitated by the involvement of clinical nurse specialists. The findings are presented as a paradigm for holistic young-onset dementia care. The paradigm offers a framework for contemplating and evaluating the criteria and quality of young-onset dementia care.

Predicting therapeutic response in IgG4-related disease based on cluster analysis

To bring the clinical practice of immunoglobulin (Ig)G4-related disease (IgG4-RD) close to personalized medicine, we classified the patient groups and clarified the therapeutic responses of each group. A total of 147 patients enrolled in our registry were classified into four groups by cluster analysis with the software. The therapeutic responses and prognosis of each group were examined. The cluster analysis classified the subjects into four groups: Cluster 1, patients who presented with prominent hypergammaglobulinemia, elevated levels of serum IgG4, and hypocomplementemia; Cluster 2, patients who presented with eosinophilia, elevated concentrations of serum IgG, IgG4, and IgE, and in whom CRP tended to be positive; Cluster 3, patients with younger onset and serum levels of IgG, IgG4, and IgE and peripheral eosinophil counts lower than the other clusters; and Cluster 4, patients with elder onset and low peripheral eosinophil counts. The amounts of glucocorticoid for maintenance treatment were from 5 to 7 mg/d in all groups, but the amounts were significantly greater in Cluster 1 (patients with hypergammaglobulinemia, elevated levels of serum IgG4, and hypocomplementemia) than in Cluster 4 (elder onset patients, relatively low concentrations of peripheral eosinophils). With regard to the use of immunosuppressants and the relapse rate, there were high frequencies in Cluster 1 and Cluster 3 (younger onset patients who presented with mild elevations of serum IgG and IgG4). On the other hand, Cluster 4 showed a low rate of relapse and often could discontinue steroids. The present results suggest that personalized medicine could be provided in IgG4-RD by classifying patients based on their clinical features.

Particulate matter and markers of glycemic control and insulin resistance in type 2 diabetic patients: result from Wellcome Trust Genetic study.

There is growing evidence that air pollution is associated with increased risk of type 2 diabetes (T2DM). However, information related to whether particulate matter (PM) contributing to worsened metabolic control in T2DM patients is inconsistent. We examined the association of PM10 exposure with glucose-function parameters in young-onset T2DM patients. We investigated the association between a year ambient concentration of PM10 at residential places, using AERMOD dispersion model, with fasting plasma glucose (FPG), hemoglobin A1c (HbA1c), 2 h post meal plasma glucose (2hPG), homeostasis model assessment of insulin resistance (HOMA-IR), β-cell function (HOMA-β) and disposition index (DI) in 1213 diabetic patients from the Wellcome Trust Genetic study at the Diabetes Unit, KEM Hospital Research Center, Pune, India. We used linear regression models and adjusted for a variety of individual and environmental confounding variables. Possible effect modification by age, gender, waist-to-hip ratio (WHR) and smoking status were investigated. Sensitivity analysis assessed the impact of relative humidity (RH) and temperature a day before examination and anti-diabetic and HHR medication (Hydralazine, Hydrochlorothiazide and Reserpine). We found that 1 SD increment in background concentration of PM10 at residential places (43.83 µg/m3) was significantly associated with 2.25 mmol/mol and 0.38 mmol/l increase in arithmetic means of HbA1c and 2hPG, respectively. A similar increase in PM10 was also associated with 4.89% increase in geometric mean of HOMA-IR. The associations remained significant after adjustment to RH and temperature, and WHR and smoking enhanced the size of the effect. Our study suggests that long-term exposure to PM10 is associated with higher glycaemia and insulin resistance. In context of our previous demonstration of association of SO2 and NO x and plasma C-reactive protein, we suggest that air pollution could influence progression of diabetes complications. Prospective studies and interventions are required to define mechanism and confirm causality.

Population-Based Assessment of a Biomarker-Based Screening Pathway to Aid Diagnosis of Monogenic Diabetes in Young-Onset Patients.

Monogenic diabetes, a young-onset form of diabetes, is often misdiagnosed as type 1 diabetes, resulting in unnecessary treatment with insulin. A screening approach for monogenic diabetes is needed to accurately select suitable patients for expensive diagnostic genetic testing. We used C-peptide and islet autoantibodies, highly sensitive and specific biomarkers for discriminating type 1 from non-type 1 diabetes, in a biomarker screening pathway for monogenic diabetes. We studied patients diagnosed at age 30 years or younger, currently younger than 50 years, in two U.K. regions with existing high detection of monogenic diabetes. The biomarker screening pathway comprised three stages: 1) assessment of endogenous insulin secretion using urinary C-peptide/creatinine ratio (UCPCR); 2) if UCPCR was ≥0.2 nmol/mmol, measurement of GAD and IA2 islet autoantibodies; and 3) if negative for both autoantibodies, molecular genetic diagnostic testing for 35 monogenic diabetes subtypes. A total of 1,407 patients participated (1,365 with no known genetic cause, 34 with monogenic diabetes, and 8 with cystic fibrosis-related diabetes). A total of 386 out of 1,365 (28%) patients had a UCPCR ≥0.2 nmol/mmol, and 216 out of 386 (56%) were negative for GAD and IA2 and underwent molecular genetic testing. Seventeen new cases of monogenic diabetes were diagnosed (8 common Maturity Onset Diabetes of the Young [Sanger sequencing] and 9 rarer causes [next-generation sequencing]) in addition to the 34 known cases (estimated prevalence of 3.6% [51/1,407] [95% CI 2.7-4.7%]). The positive predictive value was 20%, suggesting a 1-in-5 detection rate for the pathway. The negative predictive value was 99.9%. The biomarker screening pathway for monogenic diabetes is an effective, cheap, and easily implemented approach to systematically screening all young-onset patients. The minimum prevalence of monogenic diabetes is 3.6% of patients diagnosed at age 30 years or younger.

Inflammatory Bowel Disease is Similar in Patients with Older Onset and Younger Onset

As the American population is aging, the number of older people with inflammatory bowel disease is increasing. We used clinical data from the Sinai-Helmsley Alliance for Research Excellence (SHARE), a prospective cohort, to examine disease and treatment differences in older adults. We performed a cross-sectional study assessing demographics and disease behavior by age at diagnosis with univariate, bivariate, and multivariate analyses. "Older-onset" patients were diagnosed after age 60, "younger-onset" patients were diagnosed before age 60 but are older than 60 years, and the remainder were "young." There were 91 older-onset, 389 younger-onset, and 3431 young patients with Crohn's disease. Older-onset patients had more ileal (37%) and colonic (27%) disease compared with younger-onset and young patients. There were no differences in disease behavior, location, or surgeries between older-onset and young patients with Crohn's disease within 5 years of diagnosis. Older-onset patients with inflammatory disease had a higher odds of being in remission. Young patients reported more anti-tumor necrosis factor and thiopurine use compared with younger-onset and older-onset patients (P < 0.01). There were 98 older-onset, 218 younger-onset, and 1702 young patients with ulcerative colitis. There were no differences in disease extent, activity index, or surgeries. Young patients with ulcerative colitis reported more anti-tumor necrosis factor use (26%) compared with younger-onset patients (17%, P < 0.01). Disease behavior or location was not different between younger and older adults with inflammatory bowel disease. Older patients were less likely to be treated with immunosuppression. If older patients have similar disease behavior, less frequent treatment with immunosuppressives may risk suboptimally controlled disease.

Abstract 2942: Immunophenotypes in young-onset colorectal cancer

Abstract Colorectal cancer accounts for ten percent of new cancer cases and is the fourth most frequent cause of cancer-related deaths worldwide. In recent years, mainly due to screening programs, more patients are diagnosed in early stages of tumor progression, leading to a higher survival rate. However, the incidence of young (&amp;lt;50) patients diagnosed with colorectal cancer has been on the rise. These patients often have a poor prognosis due to the fact that tumors are diagnosed at advanced stages of tumor progression. To our knowledge, no study has yet characterized immunophenotypes and immune evasive mechanisms specifically in young-onset colorectal cancers. To that end we have investigated the expression of HLA class I and PD-L1 in over 200 colorectal cancers derived from young-onset (&amp;lt; 50 years-old) patients. Furthermore, we applied a novel multispectral immunofluorescence technology to perform multiparameter immunophenotyping with CD3, CD8, PD-1, PD-L1, CD163, and Ki-67 in the same cohort. We describe that HLA class I expression is maintained in the large majority of tumors allowing thus the development of neo-antigen targeted therapies. Interestingly, reduced expression of HLA class I but not total loss was associated with liver metastases, which suggests a specific selective pressure at this organ that might warrant tailored immune therapeutic interventions. As previous studies on colorectal cancer demonstrated, PD-L1 expression is limited and often restricted to immune cell compartments. The presence of immune cell infiltrates was related to the mutation background of tumors but also to their HLA class I phenotype: tumors with altered HLA class I expression were more likely to present traces of lymphocyte-mediated anti-tumor immunity. Retained HLA class I expression in the majority of colorectal cancers associated with low infiltration by effector immune cells suggests the therapeutic induction of anti-tumor immune responses in young-onset colorectal cancers, for instance, by means of neo-antigen-targeted therapies. We are currently assessing the frequency of natural recognition of neo-antigens in an autologous setting in young-onset, late-stage colorectal cancers. This work was supported by the Fight Colorectal Cancer-Michael’s Mission-AACR Fellowship in Young-Onset, Late-Stage Colorectal Cancer Research awarded to N.F.C.C. de Miranda (15-40-1645-DEMI) Citation Format: M E. van Herk, M Lee, M Rytterdahl, M E. Kop, A F. Ramalheiro, R van der Breggen, T van Wezel, H Morreau, E S. Jordanova, N F. de Miranda. Immunophenotypes in young-onset colorectal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2942. doi:10.1158/1538-7445.AM2017-2942

Screening for TMEM230 mutations in young-onset Parkinson's disease

TMEM230 gene mutations have been reported to be linked with Parkinson's disease (PD) recently. To investigate the prevalence of this gene in southeastern Chinese patients with PD, whole exome sequencing was performed in young-onset and familial PD patients and healthy controls in our Asian population. One heterozygous missense p.Phe121Ser mutation was detected in a healthy 76-year-old control subject and no other TMEM230 mutations were found in PD patients and controls. These data suggest that TMEM230 mutation might be a rare cause of Chinese familial and sporadic PD patients and a larger sample size will be needed to evaluate the association of TMEM230 polymorphic variants with PD.

Racial Disparities in Clinical Presentation and Survival Times Among Young-Onset Colorectal Adenocarcinoma.

Recently published data indicate increasing incidence of colorectal adenocarcinoma (CRC) in young-onset (<50years) patients. This study examines racial disparities in presentation and survival times among non-Hispanic Blacks (NHB) and Hispanics compared with non-Hispanic Whites (NHW). A retrospective single-center cohort study was conducted from 2004 through 2014 using 96 patient medical charts with a diagnosis of young-onset CRC. Age, gender, primary site, and histological stage at the time of diagnosis were assessed for survival probabilities by racial group over a minimum follow-up period of 5years. Among subjects with CRC diagnosis before 50years of age, the majority of subjects were between 40 and 50years, with CRC presentation occurring among this age group for 51 (79.7%) of NHW, 18 (81.8%) of NHB, and 5 (50.0%) of Hispanics. The majority of all patients presented with advanced stages of CRC (31.3% with stage III and 27.1% with stage IV). NHB exhibited statistically significantly worse survival compared to NHW (adjusted hazard ratio for death=2.09; 95% confidence interval 1.14-3.84; P=0.02). A possible trend of worse survival was identified for Hispanics compared to NHW, but this group was low in numbers and results were not statistically significant. Disparities between racial groups among young-onset CRC cases were identified in overall survival and reflect growing concern in rising incidence and differentiated care management.

Genomic analysis of inherited breast cancer among Palestinian women: Genetic heterogeneity and a founder mutation in TP53.

Breast cancer among Palestinian women has lower incidence than in Europe or North America, yet is very frequently familial. We studied genetic causes of this familial clustering in a consecutive hospital-based series of 875 Palestinian patients with invasive breast cancer, including 453 women with diagnosis by age 40, or with breast or ovarian cancer in a mother, sister, grandmother or aunt ("discovery series"); and 422 women diagnosed after age 40 and with negative family history ("older-onset sporadic patient series"). Genomic DNA from women in the discovery series was sequenced for all known breast cancer genes, revealing a pathogenic mutation in 13% (61/453) of patients. These mutations were screened in all patients and in 300 Palestinian female controls, revealing 1.0% (4/422) carriers among older, nonfamilial patients and two carriers among controls. The mutational spectrum was highly heterogeneous, including pathogenic mutations in 11 different genes: BRCA1, BRCA2, TP53, ATM, CHEK2, BARD1, BRIP1, PALB2, MRE11A, PTEN and XRCC2. BRCA1 carriers were significantly more likely than other patients to have triple negative tumors (p = 0.03). The single most frequent mutation was TP53 p.R181C, which was significantly enriched in the discovery series compared to controls (p = 0.01) and was responsible for 15% of breast cancers among young onset or familial patients. TP53 p.R181C predisposed specifically to breast cancer with incomplete penetrance, and not to other Li-Fraumeni cancers. Palestinian women with young onset or familial breast cancer and their families would benefit from genetic analysis and counseling.

Characteristics and cardiovascular complications of a large cohort of adults diagnosed with type 2 diabetes\xa0

BackgroundThe aim was to evaluate the characteristics and cardiovascular complications of a large Belgian cohort of adults diagnosed with type 2 diabetes (T2DM) <45 years.MethodsRetrospective analysis of 886 patients diagnosed with T2DM <45 years and 933 T2DM patients diagnosed at the age between 60 and 70 years. To compare variables between groups, the independent t test or paired t test was used for normally distributed continuous variables, the Mann–Whitney’s U-test for non-normally distributed continuous variables and the Chi squared test or McNemar test for categorical variables. Multivariable logistic regression was used to adjust for confounders.ResultsIn the young-onset T2DM cohort, the age at diagnosis was 37.3 ± 6.4 years, 44.1% of patients were female and 12.1% were from an ethnic minority (EM) background. At last visit, age of patients was 57.3 ± 12.5 years with a diabetes duration of 20.5 ± 11.8 years and a mean HbA1c of 7.3% ± 1.3 (56 mmol/mol ± 14). Of all patients, 56.8% were obese, 49.9% were hypertensive, 34.1% did not reach the LDL cholesterol target and 20.1% had a cardiac event by time of last visit. Compared to women, men had a higher HbA1c [7.3% ± 1.4 (56 mmol/mol ± 15) vs. 7.1% ± 1.2 (54 mmol/mol ± 13), p = 0.021] and a significantly higher rate of cardiac events, even after adjustment for confounders (24.3 vs. 14.8%, p = 0.010). Compared to Caucasians, EM patients were younger at diagnosis (35.4 ± 6.8 years vs. 37.6 ± 6.2 years, p = 0.001) and were less often obese (43.3 vs. 55.6%, p = 0.007). Compared to the first visit, glycemic control improved [7.3% ± 1.3 (56 mmol/mol ± 14) vs. 7.9% ± 1.7 (62 mmol/mol ± 19), p < 0.0001] by the time of the last visit. Compared to the older-onset T2DM cohort, young-onset T2DM patients showed a higher HbA1c [7.3 ± 1.3% (56 mmol/mol ± 14) vs. 6.9 ± 1.0% (51 mmol/mol ± 11), p = <0.0001] and a higher BMI (31.2 ± 5.8 vs. 29.6 ± 5.5 kg/m2, p = <0.0001) at last contact. When adjusted for age, diabetes duration, HbA1c and cardiovascular risk factors, there was no difference in cardiovascular events between the two cohorts.ConclusionsA diagnosis of T2DM <45 years has an important impact on patients’ lives. Prevention measures are essential, but also specific attention to this high-risk group is needed for them to better achieve their therapeutic targets.

Comparing Clinical Characteristics and Outcomes of Young-onset and Late-onset Colorectal Cancer: An International Collaborative Study

BackgroundCompared with the general population, the incidence of young-onset (YO) colorectal cancer (CRC) is increasing. However, a significant knowledge gap exists in the clinical characteristics, treatment patterns, and outcomes for these patients. Materials and MethodsSix international tertiary cancer centers conducted a retrospective study. Patients with YO CRC (aged 18-44 years) and LO CRC (aged > 44 years) diagnosed with histologically proven colorectal adenocarcinoma from June 2003 to June 2014 were enrolled. Patients were randomly chosen from each center's database, and the patient demographics and treatment information were collected. The data were then centralized, and the final analysis was performed at a single institution. Cox proportional hazards models were used to estimate the crude and adjusted hazard ratios (HRs) with 95% confidence intervals (CIs) for progression-free survival and mortality, and YO was compared with LO. Site-specific HRs were pooled using a random-effects meta-analysis. ResultsOverall, 498 patients, including 224 with YO (129 men; mean age, 37 ± 5.5 years) and 274 with LO (167 men; mean age, 64.8 ± 9.5 years) CRC, were included. At the diagnosis, 137 patients (61.2%) and 122 patients (44.5%) with YO and LO CRC had metastatic disease, respectively. For both cohorts, the 3 most common presenting symptoms were pain, hematochezia, and weight loss. Surgery was performed in 141 YO (63.0%) and 219 LO (79.9%) patients. The longitudinal noncurative treatment patterns were similar, but more biologic therapy was used for these YO patients. The pooled progression-free survival analysis results for first-line noncurative treatment favored LO (HR, 1.96; 95% CI, 1.04-3.68). The mortality analysis showed no significant differences between the 2 groups (YO: HR, 1.53; 95% CI, 0.91-2.58). ConclusionDespite similar treatment patterns and survival outcomes, YO disease might be clinically more aggressive.

New insights into mechanisms of small vessel disease stroke from genetics.

Cerebral small vessel disease (SVD) is a common cause of lacunar strokes, vascular cognitive impairment (VCI) and vascular dementia. SVD is thought to result in reduced cerebral blood flow, impaired cerebral autoregulation and increased blood-brain barrier (BBB) permeability. However, the molecular mechanisms underlying SVD are incompletely understood. Recent studies in monogenic forms of SVD, such as cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), and 'sporadic' SVD have shed light on possible disease mechanisms in SVD. Proteomic and biochemical studies in post-mortem monogenic SVD patients, as well as in animal models of monogenic disease have suggested that disease pathways are shared between different types of monogenic disease, often involving the impairment of extracellular matrix (ECM) function. In addition, genetic studies in 'sporadic' SVD have also shown that the disease is highly heritable, particularly among young-onset stroke patients, and that common variants in monogenic disease genes may contribute to disease processes in some SVD subtypes. Genetic studies in sporadic lacunar stroke patients have also suggested distinct genetic mechanisms between subtypes of SVD. Genome-wide association studies (GWAS) have also shed light on other potential disease mechanisms that may be shared with other diseases involving the white matter, or with pathways implicated in monogenic disease. This review brings together recent data from studies in monogenic SVD and genetic studies in 'sporadic' SVD. It aims to show how these provide new insights into the pathogenesis of SVD, and highlights the possible convergence of disease mechanisms in monogenic and sporadic SVD.