Advancing early onset colorectal cancer research: research advocacy, health disparities, and scientific imperatives.

Early onset colorectal cancer (EOCRC) emerged as the fourth foremost contributor to cancer-related mortality among both genders in the late 1990s. Presently, EOCRC (<50) ranks as the leading cause of cancer mortality in men and the second leading cause in women within the United States. Similar trends are now also evident globally, particularly in developed countries. Furthermore, there is strong evidence confirming that health disparities persist in the diagnosis and treatment of EOCRC, with signs indicating that these gaps may worsen in specific cases. These alarming trends highlight the critical need for research to inform evidence-based interventions to reduce the burden of EOCRC globally. Fight Colorectal Cancer (Fight CRC) is the leading patient advocacy group in the United States providing information on colon and rectal cancer research, prevention, treatment, and policy. It is the opinion of Fight CRC that an international, coordinated effort with the medical, research, scientific, advocacy, industry and funding community is needed to advance impactful research. Fight CRC, in partnership with José Perea, MD, PhD, of the Institute of Biomedical Research of Salamanca (IBSAL) in Spain, and partners, are working together to address this global phenomenon and are presenting a multi-faceted research approach to move the field forward.

Early-onset cancer incidence in the United States by race/ethnicity between 2011 and 2020.

We characterized trends in early onset (aged 20-49) cancer incidence by race/ethnicity and sex using the 2011-2020 Surveillance, Epidemiology, and End Results (SEER) Program dataset. We estimated age-standardized cancer incidence rates, incidence rate ratios (IRR), and annual percentage changes (APC) with 95 % confidence intervals (CI). During the time period examined, cancer incidence increased for female breast (APC: 0.64; 95 % CI: 0.10, 1.20), female colorectal (APC: 2.16; 95 % CI: 1.22, 3.10), and male colorectal (APC: 2.49; 95 % CI: 1.81, 3.19) cancer. Among racial/ethnic groups examined, Hispanic individuals had the largest increases in female all sites (APC: 1.31; 95 % CI: 0.38, 2.25), female breast (APC: 1.04; 95 % CI: 0.29, 1.81), and female (APC: 4.67; 95 % Cl: 3.07, 6.30) and male (APC: 3.53; 95 % CI: 2.58, 4.49) colorectal cancer incidence. Further research is needed to clarify the causal mechanisms driving these patterns.

Age-specific colorectal cancer incidence trends in Canada, 1971-2021.

INTRODUCTION: Colorectal cancer (CRC) incidence among adults younger than 50 years has increased in recent decades, leading to some advocating for lowering the age to start CRC screening. Here, we estimate age-specific trends in CRC incidence in Canada and changes in risk by birth cohort. METHODS: CRC incidence data from 1971 to 2021 by province, sex, and five-year age group (35-64) were obtained from the National Cancer Incidence Reporting System and the Canadian Cancer Registry. Annual percent changes in age-specific or age-adjusted incidence rates were analyzed with joinpoint regression. Birth cohort effect was estimated with age-period-cohort models and reported as cohort incidence rate ratios (IRRs) with respect to the 1947-51 cohort. RESULTS: CRC incidence has increased among all age groups under 50 years, with the largest relative increases occurring in the youngest age group (35-39 years). Males and females had similar incidence trends, though males under age 50 had larger increases than females. The birth cohort analysis showed that males born since 1966 have a significantly higher risk than those born at any other time. CONCLUSIONS: These results up to 2021 confirm and update reports that CRC incidence is increasing among adults under age 50 in Canada and that the youngest birth cohorts carry the highest risk. Future studies should assess the effectiveness of CRC screening in younger populations.

Young-Onset Rectal Cancer: Is It for Real?

The incidence of early-onset colorectal cancer has been rising over the last two decades. Tumors in young patients have distinct features compared to older patients. They predominantly arise in the distal colon and rectum and have poor histological features. Patients tend to present at a more advanced stage and be exposed to more aggressive management approaches; however, this has not translated into a significant survival benefit compared to their older counterparts. This chapter will share current evidence on risk factors and management options for early onset colorectal cancer with a focus on rectal cancer.

Antibiotic Management for Early-Onset Sepsis in Neonates With Gestational Ages of ≥ 34 Weeks: The Kaiser Sepsis Calculator Versus the 2010 CDC Guidelines.

INTRODUCTION: The traditional approach to neonatal early-onset sepsis (NEOS) management, involving maternal risk factors and nonspecific neonatal symptoms, usually leads to unnecessary antibiotic use. This study addresses these concerns by evaluating the Kaiser sepsis calculator (KSC) in guiding antibiotic therapy for NEOS, especially in high-incidence facilities (over 4/1,000 live births), by comparing it against the 2010 Centers for Disease Control and Prevention (CDC) guidelines for neonates ≥34 weeks with suspected sepsis, thereby emphasizing its implications for personalized patient care. METHODS: This is a prospective observational study. All neonates of 34 gestational weeks or more, presenting with either maternal risk factors or sepsis symptoms within 12 hours of birth, were included in the study. The analysis focused on antibiotic recommendations by the 2010 CDC guidelines versus those by the KSC at presumed (0.5/1,000) and actual (16/1,000) sepsis incidence rates. RESULTS: NEOS was identified in 14 cases (14.1%). Compared to the KSC, at an incidence rate of 16 per 1,000, the KSC resulted in a significant 32.3% reduction in antibiotic treatment (74 cases (74.7%) vs. 42 cases (42.4%), respectively; p < 0.001). The calculator advised immediate antibiotic utilization for 13 out of 14 (92.9%) diagnosed cases, suggesting further evaluation for the remaining cases. When a presumed incidence of 0.5/1,000 was applied, the KSC indicated antibiotics less frequently than when using the actual rate of 16/1,000 (p<0.001) with two missed NEOS cases. CONCLUSIONS: Using the KSC led to a decrease of 32 cases (32.3%) in unnecessary antibiotic prescriptions compared to adherence to 2010 CDC guidelines. However, setting a presumed incidence below the actual rate risked missing NEOS. The calculator was effective when actual local incidence rates were used, ensuring no missed cases needing antibiotics.

Comparison of Characteristics Between Early-Onset and Late-Onset Severe Preeclampsia: A Retrospective Cohort Study from a Tertiary Hospital in China.

This study aimed to explore the different characteristics between early-onset severe preeclampsia (ESPE) and late-onset severe preeclampsia (LSPE) to improve pregnancy outcomes. We performed a retrospective cohort study between January 2016 and December 2021. Eligible hospitalized pregnant women with severe preeclampsia were assigned into the early-onset or late-onset group, depending on the gestational age at the time of severe preeclampsia onset (< or ≥ 34 gestational weeks, respectively). The clinical characteristics, laboratory results, maternal complications, and fetal and neonatal outcomes were recorded and compared between the two groups. A total of 1,238 pregnant women were included, with 525 in the early-onset group and 713 in the late-onset group. The late-onset group had more cases of gestational diabetes, whereas the early-onset group had a higher blood pressure, showed more proteinuria, had more liver and renal damage, exhibited more serious adverse maternal, fetal, and neonatal outcomes, was more likely to be admitted to the intensive care unit, and required longer hospital stays (all P < 0.05). In addition, the early-onset group had fewer prenatal care appointments and was more often transferred from a primary or secondary care hospital. The logistic regression analysis showed that a weekly weight gain of > 100 g was a risk factor for ESPE and that fewer prenatal care appointments were a risk factor for ESPE in pregnant women with female fetuses. Moreover, logistic regression analysis indicated that nulliparity and gestational diabetes during the current pregnancy were risk factors for LSPE. In conclusion, compared with the women with LSPE, those with ESPE usually had worse maternal, fetal, and neonatal outcomes. More frequent prenatal screening and care should be provided for pregnant women with high-risk factors.

The Utility of Long-Read Sequencing in Diagnosing Genetic Autosomal Recessive Parkinson's Disease: a genetic screening study.

Background: Mutations within the genes PRKN and PINK1 are the leading cause of early onset autosomal recessive Parkinson's disease (PD). However, the genetic cause of most early-onset PD (EOPD) cases still remains unresolved. Long-read sequencing has successfully identified many pathogenic structural variants that cause disease, but this technology has not been widely applied to PD. We recently identified the genetic cause of EOPD in a pair of monozygotic twins by uncovering a complex structural variant that spans over 7 Mb, utilizing Oxford Nanopore Technologies (ONT) long-read sequencing. In this study, we aimed to expand on this and assess whether a second variant could be detected with ONT long-read sequencing in other unresolved EOPD cases reported to carry one heterozygous variant in PRKN or PINK1. Methods: ONT long-read sequencing was performed on patients with one reported PRKN/PINK1 pathogenic variant. EOPD patients with an age at onset younger than 50 were included in this study. As a positive control, we also included EOPD patients who had already been identified to carry two known PRKN pathogenic variants. Initial genetic testing was performed using either short-read targeted panel sequencing for single nucleotide variants and multiplex ligation-dependent probe amplification (MLPA) for copy number variants. Results: 48 patients were included in this study (PRKN "one-variant" n = 24, PINK1 "one-variant" n = 12, PRKN "two-variants" n = 12). Using ONT long-read sequencing, we detected a second pathogenic variant in six PRKN "one-variant" patients (26%, 6/23) but none in the PINK1 "one-variant" patients (0%, 0/12). Long-read sequencing identified one case with a complex inversion, two instances of structural variant overlap, and three cases of duplication. In addition, in the positive control PRKN "two-variants" group, we were able to identify both pathogenic variants in PRKN in all the patients (100%, 12/12). Conclusions: This data highlights that ONT long-read sequencing is a powerful tool to identify a pathogenic structural variant at the PRKN locus that is often missed by conventional methods. Therefore, for cases where conventional methods fail to detect a second variant for EOPD, long-read sequencing should be considered as an alternative and complementary approach.

Hsp90aa1/JUN/Ccl2 regulatory axis mediates migration and differentiation of NSPCs, promoting the onset and progression of early post-ischemic stroke epilepsy.

Early-onset epilepsy following ischemic stroke is a severe neurological condition, the pathogenesis of which remains incompletely understood. Recent studies suggest that Neural stem/progenitor cells (NSPCs) play a crucial role in the disease process, yet the precise molecular mechanisms regulating NSPCs have not been thoroughly investigated. This study utilized single-cell transcriptome sequencing and bioinformatics analysis to identify disease-related genes, which were subsequently validated in both in vitro and in vivo experiments. The findings revealed that Hsp90aa1 (heat shock protein 90 kDa alpha, class A member 1), Jun proto-oncogene (JUN), and CC Motif Ligation 2 (Ccl2) constitute an important regulatory axis influencing the migration and differentiation of NSPCs, potentially impacting the onset and progression of early-onset epilepsy post-ischemic stroke. Additionally, the expression of Hsp90aa1 was found to influence the likelihood of seizure occurrence and the severity of brain ischemia.

Early Onset Inflammatory Bowel Disease Due to Immunodeficiency as a Result of ICOS Gene Homozygous Mutation.

INTRODUCTION: Inflammatory bowel disease (IBD) is classified as very early-onset IBD (VEO-IBD) if it occurs before age six. VEO-IBD may progress with more severe and resistant inflammation findings in the gastrointestinal and non-gastrointestinal systems. CASE REPORT: We describe the clinical presentation of a 4-year-old female presenting with recurring episodes of bloody diarrhea, vomiting, abdominal pain, fever, arthritis, erysipelas, and bilateral ankle pain. Monogenic primary immunodeficiency (PID) was suspected due to her age, different clinical findings and the presence of atypical gastroscopic findings and deep transmural ulcerations resembling Crohn's disease. The gene analysis showed a homozygous mutation in the inducible T cell co-stimulator (ICOS) deficiency genes. DISCUSSION/CONCLUSION: This case presentation shares our clinical experience and demonstrates the link between IBD progression and ICOS deficiency.

Immunological Profiling of CD8+ and CD8- NK Cell Subpopulations and Immune Checkpoint Alterations in Early-Onset Preeclampsia and Healthy Pregnancy.

Despite the numerous studies on the clinical aspects of early-onset preeclampsia, our understanding of the immunological consequences of inadequate placenta development remains incomplete. The Th1-predominance characteristic of early-onset preeclampsia significantly impacts maternal immunotolerance, and the role of immune checkpoint molecules in these mechanisms is yet to be fully elucidated. Our study aims to fill these crucial knowledge gaps. A total of 34 pregnant women diagnosed with early-onset preeclampsia and 34 healthy pregnant women were enrolled in this study. A mononuclear cell fragment from the venous blood was separated and frozen. The CD8+ and CD8- NK cell subpopulations were identified and compared to their immune checkpoint molecule expressions using multicolor flow cytometry. The serum CD226 levels were measured by ELISA. Based on our measures, the frequency of the CD8- subpopulation was significantly higher than that of the CD8+ counterpart in both the NKdim and NKbright subsets. Significantly lower CD226 surface expressions were detected in the preeclamptic group compared to healthy women in all the investigated subpopulations. However, while no difference was observed in the level of the soluble CD226 molecule between the two groups, the CD112 and CD155 surface expressions were significantly different. Our study's findings underscore the significant role of the CD8+ and CD8- NK subpopulations in the Th1-dominated immune environment. This deepens our understanding of early-onset preeclampsia and suggests that each subpopulation could contribute to the compensation mechanisms and the restoration of the immunological balance in this condition, a crucial step toward developing effective interventions.

Automated Method for Growing Rod Length Measurement on Ultrasound Images in Children With Early Onset Scoliosis.

OBJECTIVE: To develop and validate machine learning algorithms to automatically extract the rod length of the magnetically controlled growing rod from ultrasound images (US) in a pilot study. METHODS: Two machine-learning (ML) models, called the "Boundary model" and "Rod model," were developed to identify specific rod segments on ultrasound images. The models were developed utilizing Mask Regional Convolutional Neural Networks (Mask RCNN). Ninety US images were acquired from 23 participants who had early onset scoliosis (EOS) surgeries; among those, 70 were used for model development, including training and validation, and 20 were used for testing by comparing the AI-based vs. manual measurements. RESULTS: The average precision (AP) of the ML models was 88.5% and 60.2%, respectively. The inter-method correlation coefficient (ICC) was 0.98, and the mean absolute difference ± standard deviation (MAD ± SD) between AI and manual measurements was 0.86 ± 1.0 mm. The Bland-Altman analysis showed no bias, and 90% of the data were within the 95% confidence interval. The automated method was reliable, accurate, and fast. Measurements were displayed in 4.6 seconds after the US image was inputted. CONCLUSION: This was the first AI-based method to measure the MCGR rod length on US images automatically.

Primary Cilia Elongation in Early-Onset Polycystic Kidney Disease with 2 Hypomorphic PKD1 Alleles: A Case Report.

Recent studies have described several children with very early-onset polycystic kidney disease (PKD) that mimicked autosomal recessive polycystic kidney disease because of 2 hypomorphic PKD1 gene variants. However, no reports have described pathological changes in the primary cilia in these cases. We analyzed the primary cilia in the kidney tubules of an early elementary school child who had very early-onset PKD and a history of large, echogenic kidneys in utero. There was no family history of autosomal dominant PKD. The patient developed kidney failure and received a living-donor kidney transplant from his father. Genetic analysis revealed compound heterozygous variants in the PKD1 gene: c.3876C>A (p. Phe1292Leu) and c.5957C>T (p. Thr1986Met). These variants were likely pathogenic based on in silico analysis. The absence of kidney cysts in the parents suggested that these variants were hypomorphic alleles. Pathological examination of the patient's excised kidney showed prominent dilatation of the proximal and distal tubules. Immunofluorescence staining for α-tubulin showed pronounced elongation of the primary cilia. These findings suggest that the hypomorphic PKD1 variants expressed in this patient with very early-onset PKD were pathogenic.

Dysfunction of thalamocortical circuits in early-onset schizophrenia.

Previous studies have demonstrated that the thalamus is involved in multiple functional circuits in participants with schizophrenia. However, less is known about the thalamocortical circuit in the rare subtype of early-onset schizophrenia. A total of 110 participants with early-onset schizophrenia (47 antipsychotic-naive patients) and 70 matched healthy controls were recruited and underwent resting-state functional and diffusion-weighted magnetic resonance imaging scans. A data-driven parcellation method that combined the high spatial resolution of diffusion magnetic resonance imaging and the high sensitivity of functional magnetic resonance imaging was used to divide the thalamus. Next, the functional connectivity between each thalamic subdivision and the cortex/cerebellum was investigated. Compared to healthy controls, individuals with early-onset schizophrenia exhibited hypoconnectivity between subdivisions of the thalamus and the frontoparietal network, visual network, ventral attention network, somatomotor network and cerebellum, and hyperconnectivity between subdivisions of thalamus and the parahippocampal and temporal gyrus, which were included in limbic network. The functional connectivity between the right posterior cingulate cortex and 1 subdivision of the thalamus (region of interest 1) was positively correlated with the general psychopathology scale score. This study showed that the specific thalamocortical dysconnection in individuals with early-onset schizophrenia involves the prefrontal, auditory and visual cortices, and cerebellum. This study identified thalamocortical connectivity as a potential biomarker and treatment target for early-onset schizophrenia.

[Muscle pain in myositis in a young female patient: what is behind this?] / Muskelschmerzen bei Myositis bei einer jungen Patientin ­ was steckt dahinter?

Myositis is a connective tissue disease which is most frequently diagnosed in women aged 40-60 years. Due to a clear association with underlying malignant diseases, general tumor screening is recommended whenever it is diagnosed. Colorectal carcinoma (CRC) is a common malignant disease, and the typical at-risk group comprised, to date, patients older than 55 years. However, with the rising incidence of so-called early-onset colorectal carcinoma (EO-CRC), an increasingly important patient population is emerging in the 20- to 50-year age range. One reason for the rising incidence is suggested to be an increase in classic risk factors at younger ages. Here, the case of a 34-year-old female patient who presented with the leading paraneoplastic syndrome of myositis and was diagnosed with a sporadic form of CRC is reported. Monitoring of known risk factors as early on as in young adulthood and greater attention in the presence of symptoms such as gastrointestinal hemorrhage or paraneoplastic syndromes seem necessary to compensate for the time delay in diagnosis that currently still exists and the associated worse oncologic outcome.

Body Surface Area-Based Dosing of Infliximab is Superior to Standard Weight-Based Dosing in Children With Very Early Onset Inflammatory Bowel Disease.

Background and Aims: Children with very early onset inflammatory bowel disease (VEO-IBD) are uniquely at risk of inadequate infliximab (IFX) exposure. We studied the association between standard body weight (BW)-based and body surface area (BSA)-based dosing strategies and outcomes. Methods: We identified VEO-IBD patients treated with IFX before 9 years at a single center. Patients were separated into those that received a BSA-based dose (200 mg/m2) and standard BW dosing (5 mg/kg). IFX drug levels, dose intensification, time on steroids, and long-term outcomes were compared. Receiver operator characteristic curves determined the optimal BW- and BSA-based dose to achieve a trough ≥10 µg/ml at dose 4 (IFX#4). Results: Forty-three children with VEO-IBD were identified. Receiver operator characteristic curves demonstrated optimal BW- and BSA-based doses to achieve IFX trough ≥10 µg/ml at IFX#4 were 7.5 mg/kg and 180mg/m2. Children were classified to standard BW dosing (22/43) and BSA dosing (10/43). IFX#4 trough was significantly higher in those who received BSA dosing (BSA 18.6 µg/ml [interquartile range 10.8-28.1] vs BW 5.1 µg/ml [interquartile range 2.6-10.7], P = .04). BSA dosing was more likely to achieve a target drug level >10 µg/ml at IFX#4 (BSA 70% vs BW 18%, P = .02). BW dosing was associated with a greater likelihood of dose escalation (BW 82% vs BSA 30%, P < .01) and a shorter time to first escalation. BSA dosing was associated with shorter time spent on steroids (P = .02). Conclusion: Young children require higher IFX dosing to achieve adequate drug exposure. Our data support the use of a BSA-based dose of 200 mg/m2 or, if a BW-based approach is used, 7.5 mg/kg. BSA dosing allows the use of a consistent dose over the age and weight spectrum.

Clinical application of whole genome sequencing in young onset dementia: challenges and opportunities.

INTRODUCTION: Young onset dementia (YOD) by its nature is difficult to diagnose. Despite involvement of multidisciplinary neurogenetics services, patients with YOD and their families face significant diagnostic delays. Genetic testing for people with YOD currently involves a staggered, iterative approach. There is currently no optimal single genetic investigation that simultaneously identifies the different genetic variants resulting in YOD. AREAS COVERED: This review discusses the advances in clinical genomic testing for people with YOD. Whole genome sequencing (WGS) can be employed as a 'one stop shop' genomic test for YOD. In addition to single nucleotide variants, WGS can reliably detect structural variants, short tandem repeat expansions, mitochondrial genetic variants as well as capture single nucleotide polymorphisms for the calculation of polygenic risk scores. EXPERT OPINION: WGS, when used as the initial genetic test, can enhance the likelihood of a precision diagnosis and curtail the time taken to reach this. Finding a clinical diagnosis using WGS can reduce invasive and expensive investigations and could be cost effective. These advances need to be balanced against the limitations of the technology and the genetic counseling needs for these vulnerable patients and their families.

Current Concepts in the Treatment of Early Onset Scoliosis.

Despite many surgical advances in the treatment of early onset scoliosis (EOS) over the past two decades, this condition remains a challenge to address. While otherwise healthy children can have EOS, many of these patients have complicated comorbidities making proper treatment algorithms extraordinarily difficult. Non-operative measures can be successful when initiated early, but are many times utilized as a delay tactic until growth-friendly operative procedures can be safely performed. This article will summarize the current concepts in the treatment of EOS with a focus on the surgical advances that have recently been made.

Burden of gastrointestinal cancers among people younger than 50 years in China, 1990 to 2019.

OBJECTIVES: This study aimed to assess the burden of early-onset gastrointestinal (GI) cancers in China over three decades. STUDY DESIGN: A comprehensive analysis was performed using data from the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2019. METHODS: Data on early-onset GI cancers in 2020 and from 1990 to 2019 were extracted from GLOBOCAN 2020 database and GBD 2019, respectively. The average annual percent change (AAPC) was calculated to analyze the temporal trends using the Joinpoint Regression Program. The Bayesian age-period-cohort (BAPC) model was used to predict future trends up to 2030. RESULTS: In China, there were 185,980 incident cases and 119,116 deaths of early-onset GI cancer in 2020, with the highest incidence and mortality observed in liver cancer (new cases: 71,662; deaths: 62,412). The spectrum of early-onset GI cancers in China has transitioned over the last 30 years. The age-standardized rates of incidence, mortality, and disability-adjusted life years for colorectal and pancreatic cancers exhibited rapid increases (AAPC >0, P ≤ 0.001). The fastest-growing incidence rate was found in colorectal cancer (AAPC: 3.06, P < 0.001). Despite the decreases in liver, gastric, and esophageal cancers, these trends have been reversed or flattened in recent years. High body mass index was found to be the fastest-growing risk factor for early-onset GI cancers (estimated annual percentage change: 2.75-4.19, P < 0.05). Projection analyses showed an increasing trend in age-standardized incidence rates for almost all early-onset GI cancers during 2020-2030. CONCLUSIONS: The transitioning pattern of early-onset GI cancers in China emphasizes the urgency of addressing this public health challenge.

Contemporary Review of the Management and Treatment of Young Breast Cancer Patients.

Approximately 11% of all new breast cancer cases annually are diagnosed in young women, and this continues to be the leading cause of death in women age 20 to 49. Young, premenopausal breast cancer patients present with more advanced stages and with a higher proportion of aggressive subtypes such as triple negative and HER2-enriched tumors. Recently, the United States Preventive Services Task Force (USPSTF) lowered the age threshold to initiate screening mammograms to age 40 to aid in earlier detection. Young age at diagnosis increases the likelihood for a pathogenic mutation, and genetic testing is recommended for all patients age 50 and younger. This population is often underrepresented in landmark clinical trials, and data is extrapolated for the treatment of young women with breast cancer. Despite there being no survival benefit to more extensive surgical treatments, such as mastectomy or contralateral prophylactic mastectomy, many patients opt against breast conservation. Young patients with breast cancer face issues related to treatment toxicities, potential overtreatment of their disease, mental health, sexual health, and fertility preservation. This unique population requires a multidisciplinary care team of physicians, surgeons, genetic counselors, fertility specialists, mental health professionals, physical therapists, and dieticians to provide individualized, comprehensive care. Our aim is to (1) provide a narrative review of retrospective studies, relevant society guidelines, and clinical trials focused on the contemporary treatment and management of YBC patients and (2) discuss important nuances in their care as a guide for members of their multidisciplinary treatment team.