Metformin, initially prescribed as an oral hypoglycemic medication for type 2 diabetes, has recently gained attention for its potential anticancer effects. Its history dates to 1918, when guanidine, a component of the traditional European herb Galega officinalis, was found to reduce glycemia. This review precisely examines the mechanisms underlying Metformin's anticancer effects across various neoplastic conditions. This investigation explores the complex interactions between metformin and major signaling pathways associated with carcinogenesis, including AMP-activated protein kinase (AMPK), mTOR, and insulin-like growth factor (IGF) pathways. The review emphasizes Metformin's diverse effects on angiogenesis, inflammation, apoptosis, and cellular metabolism in cancer cells. Additionally, new data on metformin's capacity to alter the tumor microenvironment and enhance immune surveillance systems against cancer are examined. The review underscores Metformin's potential for repurposing in oncology, emphasizing its clinical relevance as an adjuvant therapy for various cancers. The review provides insightful information about the complex anticancer mechanisms of metformin by combining data from preclinical and clinical studies. These findings not only broaden our knowledge of the effects of metformin but also open new avenues for oncology research and treatment developments.

Introduction: Obesity is a chronic disease associated with increased risk for several cancers, including colorectal cancer (CRC), a leading cause of cancer-related mortality. The majority of CRC cases are associated with modifiable risk factors. Metabolic and bariatric surgery (MBS) is a proven, durable, and successful intervention for obesity. This study aimed to evaluate the impact of MBS on CRC risk through measures of association, such as relative risk (RR) and odds ratio (OR). Methods: A systematic search of PubMed, Scopus, Web of Science, ScienceDirect, and Embase was conducted to identify systematic reviews (SR) and meta-analyses examining the relationship between obesity treated with MBS and CRC incidence. The PICO framework guided inclusion criteria, and three independent reviewers screened articles using Rayyan software. Quality assessment was performed using AMSTAR2. Results: Of 1336 screened articles, 10 SR met inclusion criteria, encompassing 53,452,658 patients. Meta-analyses consistently showed a significant reduction in CRC risk following MBS in patients with severe obesity. Risk reductions were reported by Liu et al. (RR: 0.46, 95% CI: 0.32-0.67, p < 0.01), Chierici et al. (RR: 0.46, 95% CI: 0.28-0.75, p = 0.018), Wilson et al. (RR: 0.69, 95% CI: 0.53-0.88, p = 0.003), and Pararas et al. (RR: 0.56, 95% CI: 0.40-0.80, p < 0.001). Sensitivity analyses supported these findings. For colon cancer, Liu and Chierici both reported an RR of 0.75 (95% CI: 0.46-1.21, p = 0.2444) with significant heterogeneity (I2 = 89%). A trend towards reduced rectal cancer risk (RR: 0.74, 95% CI: 0.40-1.39, p = 0.3523) was noted but limited by fewer studies. Sex-specific analyses revealed protective effects in both sexes, with a more pronounced impact in females (RR: 0.54, 95% CI: 0.37-0.79, p = 0.0014). Conclusions: This umbrella review synthesizes current evidence on the impact of MBS on CRC risk, highlighting a consistent protective association. The findings also indicate a potential risk reduction for both colon and rectal cancer, with a more pronounced effect observed among females compared to males. Given the profound implications of MBS on cancer incidence, morbidity, and mortality, further high-quality, long-term studies are essential to deepen our understanding and optimize its role in cancer prevention and patient care.

Despite a reduction of both incidence and mortality from CRC, recent studies have shown an increase in the incidence of early-onset CRC (EO-CRC). Data on this setting are limited. The aim of our study was to evaluate the clinical and molecular profiles of metastatic EO-CRC patients in order to identify differences compared to a late-onset CRC (LO-CRC) control group.

We retrospectively collected data from 1272 metastatic colorectal cancers from 5 different Italian Institutions. The main objective was to the evaluate clinical outcome for EO-CRC patients in comparison to patients included in the control group.

In the overall population, mOS was 34,7 in EO-CRC pts vs 43,0 months (mo) (p < 0,0001). In the RAS/BRAF mutated subgroup mOS in EO-CRC pts was 30,3 vs 34,0 mo (p = 0,0156). In RAS/BRAF wild-type EO-CRC mOS was 43,0 vs 50,0 mo (p = 0,0290). mPFS was 11,0 in EO-CRC pts vs 14,0 mo (p < 0,0001).

Findings indicate a general worse prognosis for patients with early-onset colorectal cancer compared to late-onset patients. Interestingly this seems to occur regardless of the molecular status. These observations might have a considerable impact on clinical practice and research.

The proportion of early onset colorectal cancer (EOCRC) is alarming in adults, including in African Americans (AA).

To investigate differences between EOCRC compared to late-onset colorectal cancer (LOCRC) among AA patients.

This retrospective study reviewed demographic, clinical presentations, colonoscopy, and pathology reports of patients at Howard University Hospital from 1959 to 2023. The study included 176 EOCRC cases (< 45 years) and 2034 LOCRC cases (> 45 years).

Both EOCRC and LOCRC groups were predominantly AA (> 80%) with slightly more females (53%) than males. The mean age was 38 years for EOCRC and 66 years for LOCRC cases. EOCRC cases increased as a proportion of total detected CRC cases since 2010 (over 13%) after several decades of just above 6%. Family history of CRC in first degree relatives was higher among EOCRC (15.5% vs.3.4% in LOCRC patients, p < 0.01). Symptoms at presentation were prevalent in both EOCRC (93.8%) and LOCRC (92.6%). EOCRC patients exhibited higher incidence of abdominal pain (23.3% vs. 17.2%, p = 0.05) and changes in bowel habits (24.4% vs. 14%, p < 0.01) compared to LOCRC patients. Other symptoms such as melena, hematochezia, and weight loss were less prevalent in EOCRC patients. Comorbidities like hypertension (HTN), diabetes mellitus (DM), and inflammatory bowel disease (IBD) were less frequent among EOCRC patients. EOCRC was primarily observed in the sigmoid and rectosigmoid regions (p = 0.02). Metastasis at index colonoscopy was more prevalent with EOCRC compared to LOCRC (p = 0.04), with a higher proportion of patients at stage 3 cancer (p < 0.05). Significant differences were noted in the timeline for undergoing surgery after the diagnosis of colorectal cancer, with EOCRC patients taking longer than LOCRC patients (p = 0.03).

Presentation of EOCRC over LOCRC increased proportionally in our cohort since 2010 and is associated with family history, and symptoms such as abdominal pain and change in bowel habits. Likely because of age at presentation, there are less comorbidities among EOCRC patients who predominantly present in the outpatient setting, and more likely diagnosed with advanced stage lesions that are predominantly sigmoid or rectosigmoid. These findings are similar to observations seen in the general population with EOCRC, albeit African American patients have commonly had earlier age presentation of CRC than White American patients.

The incidence of colorectal cancer (CRC) has been steadily rising, and obesity has been identified as a significant risk factor. Numerous studies suggest a strong correlation between excess body weight and increased risk of CRC, but comprehensive quantification through pooled analysis remains limited. This study aims to systematically review and meta-analyze the existing literature to evaluate the association between obesity and CRC risk, considering variations across sex and study designs. A systematic literature search was conducted in PubMed, Cochrane Central Register of Controlled Trials (CENTRAL), and Web of Science to identify randomized controlled trials and human clinical trials from 1992 to 2024. Statistical analysis was performed using the https://metaanalysisonline.com web application using a random effects model to estimate the pooled hazard rates (HR). Forest plots, funnel plots, and Z-score plots were utilized to visualize results. We identified 52 clinical trials and 14 case-control studies, encompassing a total of 83,251,050 and 236,877 subjects, respectively. The pooled analysis indicated that obesity significantly increased the prevalence of CRC (HR = 1.36, 95% CI = 1.24-1.48, p < 0.01). This effect was consistent across sexes, with HRs of 1.57 (95% CI = 1.38-1.78, p = 0.01) for males and 1.25 (95% CI = 1.14-1.38, p < 0.01) for females. Case-control studies specifically showed an effect, but with marginal significance only (HR = 1.27, 95% CI = 0.98-1.65, p = 0.07). The Z-score plot indicated the need for additional analysis in the case-control group. A significant heterogeneity was observed across studies in all four settings. This meta-analysis provides robust evidence that obesity is a significant risk factor for colorectal cancer, with an overall hazard rate indicating a 36% increased risk. The effect is pronounced across both sexes, with males showing a slightly higher risk compared to females. Although case-control studies showed a weaker association, the overall trend supports the link between obesity and CRC. These results underscore the importance of public health interventions aimed at reducing obesity to potentially lower the risk of colorectal cancer.

Evidence indicates that both vitamin D and the gut microbiome are involved in the process of colon carcinogenesis. However, it is unclear what effects supplemental vitamin D3 has on the gut microbiome and its metabolites in healthy adults. We conducted a double-blind, randomized, placebo-controlled trial to identify the acute and long-term microbiota structural and metabolite changes that occur in response to a moderate dose (4,000 IU) of vitamin D3 for 12 weeks in healthy adults. Our results demonstrated a significant increase in serum 25-hydroxy-vitamin D (25(OH)D) in the treatment group compared to placebo (P < 0.0001). Vitamin D3 significantly increased compositional similarity (P < 0.0001) in the treatment group, and enriched members of the Bifidobacteriaceae family. We also identified a significant inverse relationship between the percent change in serum 25(OH)D and microbial stability in the treatment group (R = -0.52, P < 0.019). Furthermore, vitamin D3 supplementation resulted in notable metabolic shifts, in addition to resulting in a drastic rewiring of key gut microbial-metabolic associations. In conclusion, we show that a moderate dose of vitamin D3 among healthy adults has unique acute and persistent effects on the fecal microbiota, and suggest novel mechanisms by which vitamin D may affect the host-microbiota relationship.

Preventative measures to reduce the rise in early-onset colorectal cancer are of critical need. Both vitamin D, dietary and serum levels, and the gut microbiome are implicated in the etiology of colorectal cancer. By understanding the intimate relationship between vitamin D, the gut microbiome, and its metabolites, we may be able to identify key mechanisms that can be targeted for intervention, including inflammation and metabolic dysfunction. Furthermore, the similarity of vitamin D to cholesterol, which is metabolized by the gut microbiome, gives precedence to its ability to produce metabolites that can be further studied and leveraged for controlling colorectal cancer incidence and mortality.

There has been a global increase in early-onset colorectal cancer (EOCRC), yet there has been very limited exploration of its impact in Indonesia. This study aimed to determine the clinicopathologic characteristics and the overall survival (OS) of EOCRC compared with those of average-onset colorectal cancer (AOCRC).

Medical records were retrospectively reviewed from all patients presenting with colorectal cancer (CRC) at Dr Sardjito General Hospital (Yogyakarta, Indonesia) between 2016 and 2019. Sociodemographic, clinicopathologic, and treatment variables were extracted. t Tests were used to compare characteristics of EOCRC and AOCRC patient groups. The Cox proportional hazards regression model was used to analyze age and other potential prognostic factors.

The total population (N = 1,276) comprised EOCRC (n = 149; 11.7%) and AOCRC (n = 1,127; 88.3%) patients. EOCRC patients were more likely to have a higher education level, be single, have out-of-pocket insurance, be underweight, and have signet ring histology (all P values <.05), compared with AOCRC patients. EOCRC and AOCRC groups had a comparable estimated 5-year OS of 34.2% and 36.9%, respectively. In multivariable analyses, performance status (Eastern Cooperative Oncology Group), hemoglobin level, cancer stage, and treatment intention were independent prognostic factors for OS (all P values <.05).

To our knowledge, this first major study of EOCRC in Indonesia highlights its role in the overall burden of CRC and its connection with social determinants of health. Patients with EOCRC are more commonly underweight and generally have a higher proportion of signet ring histology than AOCRC, yet OS in both groups is similar. Future research is required to identify risk factors to inform the content and focus of public health education activities, alongside delineating the biology and causes of early and average onset of the disease.

The incidence of early-onset colorectal cancer (EO-CRC) is rising in the United States, and is often diagnosed at advanced stages. Low serum ferritin is often incidentally discovered in young adults, however, the indication for endoscopy in EO-CRC is unclear.

To compare serum ferritin between patients with EO-CRC and healthy controls (HCs), and examine the association of serum ferritin in EO-CRC with patient- and disease-specific characteristics.

A retrospective study of patients < 50 years with newly-diagnosed EO-CRC was conducted from 1/2013-12/2023. Patients were included if serum ferritin was measured within 2 years prior to 1 year following CRC histologic diagnosis. To supplement the analysis, a cohort of HCs meeting similar inclusion and exclusion criteria were identified for comparison. A sensitivity analysis including only patients with serum ferritin obtained at or before diagnosis was separately performed to minimize risk of confounding.

Among 85 patients identified with EO-CRC (48 females), the median serum ferritin level was 26 ng/mL (range < 1-2759 ng/mL). Compared to HCs (n = 80211), there were a higher proportion of individuals with EO-CRC with serum ferritin < 20 ng/mL (female 65%, male 40%) versus HCs (female 32.1%, male 7.2%) age 29-39 years (P = 0.002 and P < 0.00001, respectively). Stage IV disease was associated with significantly higher serum ferritin compared to less advanced stages (P < 0.001). Serum ferritin obtained before or at the time of diagnosis was lower than levels obtained after diagnosis. Similar findings were confirmed in the sensitivity analysis.

Severe iron deficiency may indicate an increased risk of EO-CRC, particularly at earlier stages. Further studies defining the optimal serum ferritin threshold and routine incorporation of serum ferritin in screening algorithms is essential to develop more effective screening strategies for EO-CRC.

Prognostic assessment for colorectal cancer (CRC) displays substantial heterogeneity, as reliance solely on traditional TNM staging falls short of achieving precise individualized predictions. The integration of diverse biological information sources holds the potential to enhance prognostic accuracy.

To establish a comprehensive multi-tiered precision prognostic evaluation system for CRC by amalgamating gene expression profiles, clinical characteristics, and tumor microsatellite instability (MSI) status in CRC patients.

We integrated genomic data, clinical information, and survival follow-up data from 483 CRC patients obtained from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases. MSI-related gene modules were identified using differential expression analysis and Weighted Gene Co-expression Network Analysis (WGCNA). Three prognostic models were constructed: MSI-Related Gene Prognostic Model (Model I), Clinical Prognostic Model (Model II), and Integrated Multi-Layered Prognostic Model (Model III) by combining clinical features. Model performance was assessed and compared using Receiver Operating Characteristic (ROC) curves, Kaplan-Meier analysis, and other methods.

Six MSI-related genes were selected for constructing Model I (AUC = 0.724); Model II used two clinical features (AUC = 0.684). Compared to individual models, the integrated Model III exhibited superior performance (AUC = 0.825) and demonstrated good stability in an independent dataset (AUC = 0.767).

This study successfully developed and validated a comprehensive multi-tiered precision prognostic assessment model for CRC, providing an effective tool for personalized medical management of CRC.

There exists a link between irritable bowel syndrome (IBS) and depression. Similarly, chronic depression is known to increase the risk of cancer in general. In this population-based analysis, we investigated the prevalence and the odds of colorectal cancer (CRC) in young-depressed patients with IBS.

To investigate the relationship between IBS and CRC in young, depressed patients using a nationally representative United States inpatient sample.

The 2019 National Inpatient Sample was used to identify young (18-44 years) patients admitted with comorbid depression in the presence vs absence of IBS using relevant International Classification of Diseases, Tenth Revision, Clinical Modification codes. Primary endpoint was the prevalence and odds of CRC in age matched (1:1) young-depressed cohort hospitalized with IBS (IBS+) vs without IBS (IBS-). Multivariable regression analysis was performed adjusting for potential confounders.

Age-matched (1:1) young-depressed IBS+ (83.9% females, median age 36 years) and IBS- (65.8% females, median age 36 years) cohorts consisted of 14370 patients in each group. IBS+ cohort had higher rates of hypertension, uncomplicated diabetes, hyperlipidemia, obesity, peripheral vascular disease, chronic obstructive pulmonary disease, hypothyroidism, prior stroke, prior venous thromboembolism, anxiety, bipolar disorder, and borderline personality disorder (P < 0.005) vs the IBS- cohort. However, prior myocardial infarction, acquired immunodeficiency syndrome, dementia, smoking, alcohol abuse, and drug abuse (P < 0.005) are high in IBS- cohort. The rate of CRC was comparable in both cohorts [IBS+ n = 25 (0.17%) vs IBS- n = 35 (0.24%)]. Compared to the IBS- cohort, the odds ratio (OR) of developing CRC was not significantly higher [OR 0.71, 95% confidence interval (CI) 0.23-2.25)] in IBS+ cohort. Also, adjusting for baseline sociodemographic and hospital characteristics and relevant comorbidities, the OR was found to be non-significant (OR 0.89, 95%CI 0.21-3.83).

This nationwide propensity-matched analysis revealed comparable prevalence and risk of CRC in young-depressed patients with vs without IBS. Future large-scale prospective studies are needed to evaluate the long-term effects of depression and its treatment on CRC risk and outcomes in IBS patients.

Early-onset colorectal cancer (EOCRC), defined as a diagnosis at younger than age 50 years, is increasing, and so-called red flag signs and symptoms among these individuals are often missed, leading to diagnostic delays. Improved recognition of presenting signs and symptoms associated with EOCRC could facilitate more timely diagnosis and impact clinical outcomes.

To report the frequency of presenting red flag signs and symptoms among individuals with EOCRC, to examine their association with EOCRC risk, and to measure variation in time to diagnosis from sign or symptom presentation.

PubMed/MEDLINE, Embase, CINAHL, and Web of Science were searched from database inception through May 2023.

Studies that reported on sign and symptom presentation or time from sign and symptom presentation to diagnosis for patients younger than age 50 years diagnosed with nonhereditary CRC were included.

Data extraction and quality assessment were performed independently in duplicate for all included studies using Preferred Reporting Items for Systematic Reviews and Meta-analyses reporting guidelines. Joanna Briggs Institute Critical Appraisal tools were used to measure risk of bias. Data on frequency of signs and symptoms were pooled using a random-effects model.

Outcomes of interest were pooled proportions of signs and symptoms in patients with EOCRC, estimates for association of signs and symptoms with EOCRC risk, and time from sign or symptom presentation to EOCRC diagnosis.

Of the 12 859 unique articles initially retrieved, 81 studies with 24 908 126 patients younger than 50 years were included. The most common presenting signs and symptoms, reported by 78 included studies, were hematochezia (pooled prevalence, 45% [95% CI, 40%-50%]), abdominal pain (pooled prevalence, 40% [95% CI, 35%-45%]), and altered bowel habits (pooled prevalence, 27% [95% CI, 22%-33%]). Hematochezia (estimate range, 5.2-54.0), abdominal pain (estimate range, 1.3-6.0), and anemia (estimate range, 2.1-10.8) were associated with higher EOCRC likelihood. Time from signs and symptoms presentation to EOCRC diagnosis was a mean (range) of 6.4 (1.8-13.7) months (23 studies) and a median (range) of 4 (2.0-8.7) months (16 studies).

In this systematic review and meta-analysis of patients with EOCRC, nearly half of individuals presented with hematochezia and abdominal pain and one-quarter with altered bowel habits. Hematochezia was associated with at least 5-fold increased EOCRC risk. Delays in diagnosis of 4 to 6 months were common. These findings highlight the need to identify concerning EOCRC signs and symptoms and complete timely diagnostic workup, particularly for individuals without an alternative diagnosis or sign or symptom resolution.

Colorectal cancer (CRC) is the third most common cancer worldwide. Although the overall incidence of CRC has been decreasing over the past 40 y, early-onset colorectal cancer (EOCRC), which is defined as a CRC diagnosis in patients aged >50 y has increased. In this Perspective, we highlight and summarize the association between diet quality and excess adiposity, and EOCRC. We also explore chronic psychosocial stress (CPS), a less investigated modifiable risk factor, and EOCRC. We were able to show that a poor-quality diet, characterized by a high intake of sugary beverages and a Western diet pattern (high intake of red and processed meats, refined grains, and foods with added sugars) can promote risk factors associated with EOCRC development, such as an imbalance in the composition and function of the gut microbiome, presence of chronic inflammation, and insulin resistance. Excess adiposity, particularly obesity onset in early adulthood, is a likely contributor of EOCRC. Although the research is sparse examining CPS and CRC/EOCRC, we describe likely pathways linking CPS to tumorigenesis. Although additional research is needed to understand what factors are driving the uptick in EOCRC, managing body weight, improving diet quality, and mitigating psychosocial stress, may play an important role in reducing an individual's risk of EOCRC.

Colorectal cancer (CRC) epidemiology is changing due to a birth cohort effect, first recognized by increasing incidence of early onset CRC (EOCRC, age <50 years). In this paper, we define "birth cohort CRC" as the observed phenomenon, among individuals born 1960 and later, of increasing CRC risk across successive birth cohorts, rising EOCRC incidence, increasing incidence among individuals aged 50 to 54 years, and flattening of prior decreasing incidence among individuals aged 55 to 74 years. We demonstrate birth cohort CRC is associated with unique features, including increasing rectal cancer (greater than colon) and distant (greater than local) stage CRC diagnosis, and increasing EOCRC across all racial/ethnic groups. We review potential risk factors, etiologies, and mechanisms for birth cohort CRC, using EOCRC as a starting point and describing importance of viewing these through the lens of birth cohort. We also outline implications of birth cohort CRC for epidemiologic and translational research, as well as current clinical practice. We postulate that recognition of birth cohort CRC as an entity-including and extending beyond rising EOCRC-can advance understanding of risk factors, etiologies, and mechanisms, and address the public health consequences of changing CRC epidemiology.

We aim to present incidence rates and geographical distribution of most common early-onset gastrointestinal cancers (EOGICs), including early-onset esophageal cancer (EOEC), gastric cancer (EOGC) and colorectal cancer (EOCRC) in Iran, 2014-2018.

Data on new cases of EOEC, EOGC and EOCRC were obtained from publicly available annual reports of the Iranian National Population-based Cancer Registry (INPCR). Incidence rates were calculated using the population data available from the Statistical center of Iran. We considered the World standard population for calculation of age-standardized incidence rates (ASR). We also calculated 95% confidence intervals (CIs) for ASR. All rates are presented per 100000 person-years.

Overall, 19,679 new cases of EOGIC were registered by the INPCR between 2014 and 2018. The ASRs (95% CI) of EOEC, EOGC and EOCRC were 0.49 (95% CI: 0.47-0.51), 1.67 (1.63-1.71), and 3.07 (3.01-3.13) per 100,000 person-years, respectively. Our findings indicate decreasing and constant trends in the ASR of EOEC and EOGC during the study period, 2014-2018. There was an increasing trend in the ASR of EOCRC. We also found geographical disparities in the incidence rates of EOGICs across provinces of Iran, suggesting the highest ASRs of EOEC in Golestan (1.3), EOGC in Ilam (2.99) and EOCRC in Ilam (4.49).

Our findings suggested that the incidence rate of EOCRC is consistently increasing. We also found variations in the incidence of EOGICs among different provinces. Further investigations are recommended to clarify the time trends and risk factors of EOGICs in Iran.

Colorectal cancer (CRC) ranks as the third leading cause of cancer-related mortality worldwide. Recent years have witnessed an increase in the incidence of CRC among adults <50 years old on a global scale. The increased incidence is associated with several modifiable risk factors, including obesity, type II diabetes, physical inactivity and frequent antibiotic use. In younger individuals, haematochezia and abdominal pain are the most common symptoms, predominantly affecting the left-side colon. While certain cases of early-onset CRC (eoCRC) are associated with a genetic predisposition, the majority result from sporadic mutations in the genes APC, KRAS, BRAF and TP53, which trigger uncontrolled cell proliferation and tumour formation. Colorectal carcinogenesis involves three major pathways: The chromosomal instability (CIN), microsatellite instability and CpG island methylator phenotype pathways. Dysregulation of the CIN pathway accounts for 85% of sporadic cases of eoCRC. Notably, eoCRC exhibits a distinctive molecular profile, characterized by a decreased prevalence of BRAF mutations, an increased prevalence of KRAS mutations and LINE-1 hypomethylation, and involvement of the Microsatellite and Chromosomal Stable pathway. Prevention strategies for eoCRC primarily centre on lifestyle modifications and the development of screening programs targeting younger populations. Further exploration into the molecular mechanisms involved in the identification of novel risk factors associated with eoCRC is imperative. These efforts, in conjunction with the development of specific screening strategies, hold the potential to reduce morbidity and mortality in the future.

Colorectal cancer (CRC) is the commonest cancer in Saudi males and the third most common in Saudi females. Although CRC represents a major public health challenge, the resources to evaluate its burden are inadequate. This study aims to elucidate the magnitude of CRC incidence trends in the Saudi population by age, gender, and administrative region. Data for multiple incidence measures were analyzed from the Saudi Cancer Registry (SCR) retrospectively from 2001 to 2018. Temporal trends were further analyzed by age group, gender, administrative region, and globally using joinpoint regression analysis. The number of CRC cases climbed by 335.6% and the disease increased by 56.4% to comprise 12.2% of all cancers cases. The age-standardized incidence rate (ASR) increased by 152% overall, and the median age at diagnosis peaked at 60 and 58 years for males and females, respectively. Riyadh and the Eastern Region had the highest ASR for both genders, peaking at 21.8 and 19.2 for males and 17.4 and 16.5 for females per 100 K population. Our prediction model identified growing trends with annual percentage changes (APCs) of 4.59% in males (CI: 3.1-6.1) and 3.91% among females (CI: 2.4-5.5). Males above 75 years had the highest APC (7.9%, CI: 5.3-10.7), whereas the highest APC among females was found in the age group 70-74 (5.4%, CI: 2.8-8). Globally, APC was the highest for both genders compared to selected countries. CRC incidence is increasing alarmingly in Saudi Arabia and is projected to continue. There is a need for better screening strategies, preventative measures, and awareness-building.

Advances in stroke treatment have greatly improved outcomes; however, disparities in access to treatment might increase. Achieving equitable access to stroke treatment is a health policy challenge, as rapid treatment is essential for positive outcomes. This ecological cross-sectional study aimed to determine the relationship between the disparities in spatial accessibility to mechanical thrombectomy (SAMT) and stroke mortality rates in Japan, hypothesizing that disparities in SAMT may increase the differences in stroke mortality between regions.

We used the average number of ischemic stroke (IS) deaths between 2020 and 2021 as the response variable; and SAMT, medical resources, and socioeconomic characteristics of each municipality as explanatory variables. A conditional autoregressive model was used to examine the association between the risk of stroke mortality and SAMT. The standardized mortality ratio (SMR) was mapped to understand the nationwide disparities in stroke mortality risk.

The median number of IS deaths was 17.5 persons per year in the municipalities (2020 to 2021). The study also found that municipalities with low SAMT were located in the northern part of Japan. The non-spatial regression model results indicated that poor accessibility, a small proportion of bachelor's degrees or higher, and a high proportion of workers in secondary industries were related to high IS mortality. Three models were evaluated using spatial analysis; Model 1 with accessibility indicators alone, Model 2 with medical resources added to Model 1, and Model 3 with socioeconomic characteristics added to Model 2. In Models 1 and 2, the population-weighted spatial accessibility index (PWSAI) showed a significant negative relationship with stroke mortality. However, this was not evident in Model 3. Mapping using Model 3 showed that the high-risk areas were predominantly located in northern Japan, excluding Hokkaido.

Access to mechanical thrombectomy was estimated, and regional differences were observed. The relationship between accessibility and IS mortality is unknown; however, regardless of accessibility, municipalities with a high proportion of workers in secondary industries and a small proportion with bachelor's degrees or above are at risk of death from stroke.

Prompt detection of colorectal cancer (CRC) among individuals younger than age 50 years (early-onset CRC) is a clinical priority because of its alarming rise.

We conducted a matched case-control study of 5075 incident early-onset CRC among US commercial insurance beneficiaries (113 million adults aged 18-64 years) with 2 or more years of continuous enrollment (2006-2015) to identify red-flag signs and symptoms between 3 months to 2 years before the index date among 17 prespecified signs and symptoms. We assessed diagnostic intervals according to the presence of these signs and symptoms before and within 3 months of diagnosis.

Between 3 months and 2 years before the index date, 4 red-flag signs and symptoms (abdominal pain, rectal bleeding, diarrhea, and iron deficiency anemia) were associated with an increased risk of early-onset CRC, with odds ratios (ORs) ranging from 1.34 to 5.13. Having 1, 2, or at least 3 of these signs and symptoms were associated with a 1.94-fold (95% confidence interval [CI] = 1.76 to 2.14), 3.59-fold (95% CI = 2.89 to 4.44), and 6.52-fold (95% CI = 3.78 to 11.23) risk (Ptrend < .001), respectively, with stronger associations for younger ages (Pinteraction < .001) and rectal cancer (Pheterogenity = .012). The number of different signs and symptoms was predictive of early-onset CRC beginning 18 months before diagnosis. Approximately 19.3% of patients had their first sign or symptom occur between 3 months and 2 years before diagnosis (median diagnostic interval = 8.7 months), and approximately 49.3% had the first sign or symptom within 3 months of diagnosis (median diagnostic interval = 0.53 month).

Early recognition of red-flag signs and symptoms (abdominal pain, rectal bleeding, diarrhea, and iron-deficiency anemia) may improve early detection and timely diagnosis of early-onset CRC.

Over the past decade, the incidence of colorectal cancer has increased in individuals under the age of 50 years. Meanwhile, the incidence has gradually decreased in the older population. As described herein, we reviewed the available literature to summarize the current landscape of early-onset colorectal cancer, including risk factors, clinicopathological presentation, genetic makeup of patients, and management. Currently, early-onset colorectal cancer is treated similarly as late-onset colorectal cancer, yet the available literature shows that early-onset colorectal cancer is more aggressive and different, and this remains a significant unmet need. A detailed understanding of early-onset colorectal cancer is needed to identify risk factors for the increased incidence and tailor treatments accordingly.

Purpose: This study aimed to identify cancer incidence trends in the United States and globally in adolescents and young adults (AYAs) 15-39 years of age, by sex, and to speculate on causes for trend changes. Methods: For the United States, SEER*Stat was used to obtain average annual percent change (AAPC) trends in cancer incidence during the period 2000-2019 among 395,163 AYAs. For global data, the source was the Institute of Health Metrics and Evaluation and its sociodemographic index (SDI) classification system. Results: In the United States, the invasive cancer incidence increased during the period 2000-2019 in both females (AAPC: 1.05, 95% CI: 0.90-1.20, p << 0.001) and males (AAPC: 0.56, 95% CI: 0.43-0.69, p << 0.001). A total of 25 and 20 types of cancers increased statistically significantly in female and male AYAs, respectively. Among potential causes for the increases, the obesity epidemic in the United States strongly correlates with the overall cancer increase in both its female (Pearson correlation coefficient R2 = 0.88, p = 0.0007) and male (R2 = 0.83, p = 0.003) AYAs, as does the most common malignancy in American AYAs, breast cancer (R2 = 0.83, p = 0.003). Worldwide, cancer incidence in the age group increased steadily during the period 2000-2019 among high-middle, middle, and low-middle SDI countries, but not in low SDI countries and with slowing of increase in high SDI countries. Conclusions: The increases and their age-dependent profiles implicate several causations that are preventable, including obesity, overdiagnosis, unnecessary diagnostic radiation, human papilloma virus infection, and cannabis avoidance. The United States is beginning to reverse the increasing incidence, and prevention efforts should be augmented accordingly.

In the past decades the incidence of colorectal cancer (CRC) in people under the age of 50 years has increased, which is referred to as early-onset CRC or young-onset CRC (YO-CRC). YO-CRC is expected to account for 11% of colon cancers and 23% of rectal cancers by 2030. This trend is observed in different parts of the world and in both men and women. In 20% of patients with YO-CRC, a hereditary cancer syndrome is found as the underlying cause; however, in the majority of patients no genetic predisposition is present. Beginning in the 1950s, major changes in lifestyle such as antibiotic use, low physical activity and obesity have affected the gut microbiome and may be an important factor in YO-CRC development. Owing to a lack of screening, patients with YO-CRC are often diagnosed with advanced-stage disease. Long-term treatment-related complications should be taken into account in these younger patients, making the more traditional sequential approaches of drug therapy not always the most appropriate option. To better understand the underlying mechanism and define relationships between environmental factors and YO-CRC development, long-term prospective studies are needed with lifestyle data collected from childhood.

Patients with early-onset colorectal cancer (eoCRC) are managed according to guidelines that are not age-specific. A multidisciplinary international group (DIRECt), composed of 69 experts, was convened to develop the first evidence-based consensus recommendations for eoCRC.

After reviewing the published literature, a Delphi methodology was used to draft and respond to clinically relevant questions. Each statement underwent 3 rounds of voting and reached a consensus level of agreement of ≥80%.

The DIRECt group produced 31 statements in 7 areas of interest: diagnosis, risk factors, genetics, pathology-oncology, endoscopy, therapy, and supportive care. There was strong consensus that all individuals younger than 50 should undergo CRC risk stratification and prompt symptom assessment. All newly diagnosed eoCRC patients should receive germline genetic testing, ideally before surgery. On the basis of current evidence, endoscopic, surgical, and oncologic treatment of eoCRC should not differ from later-onset CRC, except for individuals with pathogenic or likely pathogenic germline variants. The evidence on chemotherapy is not sufficient to recommend changes to established therapeutic protocols. Fertility preservation and sexual health are important to address in eoCRC survivors. The DIRECt group highlighted areas with knowledge gaps that should be prioritized in future research efforts, including age at first screening for the general population, use of fecal immunochemical tests, chemotherapy, endoscopic therapy, and post-treatment surveillance for eoCRC patients.

The DIRECt group produced the first consensus recommendations on eoCRC. All statements should be considered together with the accompanying comments and literature reviews. We highlighted areas where research should be prioritized. These guidelines represent a useful tool for clinicians caring for patients with eoCRC.

Epidemiologic data indicate a significant increase in the incidence of colorectal cancer in younger populations in the past three decades. Moreover, recent evidence also demonstrates a similar trend in gastric, pancreatic, and biliary tract cancers. A majority of these early-onset cases are sporadic and lack hereditary or familial background, implying a potential key role for behavioral, lifestyle, nutritional, microbial, and environmental factors. This review explores the current data on early-onset gastrointestinal cancer, exploring the etiology, unique treatment considerations for this population, future challenges, as well as implications for research and practice.

The worrisome trend of an increasing incidence of early-onset gastrointestinal cancers appears to be correlated with nonhereditary etiologies in which behavioral, lifestyle, nutritional, microbial, and environmental factors, as well as host mechanisms, may play a key role. Further epidemiologic and pathogenetic research is urgently needed to better understand the underlying mechanisms and to develop preventive strategies and tailored early detection. Young patients with gastrointestinal cancer face unique challenges and unmet needs. These must be addressed in the future management of the disease to minimize treatment-related somatic morbidity and prevent psychosocial sequelae.

Colorectal cancer (CRC) is one of the most prevalent malignancies worldwide. Although most prevalent among older people, its incidence above 50 years old has been decreasing globally in the last decades, probably as a result of better screening. Paradoxically, its incidence in patients below 50 years old [early-onset CRC (EO-CRC)] has been increasing, for reasons not yet fully understood. EO-CRC's increasing incidence is genre independent but shows racial disparities and has been described to occur worldwide. It follows a birth-cohort effect which probably reflects a change in exposure to CRC risk factors. Its incidence is predicted to double until 2030, which makes EO-CRC a serious public health issue. Both modifiable and non-modifiable risk factors have been identified - some are potential targets for preventive measures. EO-CRC is often diagnosed at advanced stages and histological features associated with poor prognosis have been described. EO-CRC presents some distinctive features: Microsatellite in-stability is common, but another subtype of tumours, both microsatellite and chromosome stable also seems relevant. There are no age-specific treatment protocols and studies on EO-CRC survival rates have shown conflicting data. Due to the higher germline pathological mutations found in EO-CRC patients, an accurate genetic risk evaluation should be performed. In this review, we summarize the current evidence on epidemiological, clinical, histopathological and molecular features of EO-CRC and discuss the contribution of genetics and lifestyle risk factors. We further comment on screening strategies and specific dimensions to consider when dealing with a younger cancer patient.

Early-onset colorectal cancer (EOCRC) incidence is increasing worldwide. Efforts are directed to understand the biological and clinical signatures of EOCRC compared to late-onset colorectal cancer (LOCRC). EOCRC is thought to present differently across different ethnic groups and geographical regions. This study was an attempt to contribute with data from the Arab world toward the understanding of the clinicopathological parameters of EOCRC compared to LOCRC. Data from 254 CRC patients diagnosed at Sultan Qaboos University Hospital from the period 2015-2020 were studied. About 32.6% of all diagnosed CRC patients are below 50 years old, with no differences in gender distribution between EOCRC and LOCRC (p-value 0.417). Rectal involvement and tumor laterality were comparable among the two groups. Adenocarcinoma accounts for 83.3% and 94.2% of EOCRC and LOCRC, respectively. More mucinous and signet ring adenocarcinoma (8.3% each) were reported in EOCRC than LOCRC (2.9% and 2.2%, respectively). MLH1 and PMS2 loss are more common among LOCRC, but MSH6 loss is more frequent in EOCRC. The overall survival of EOCRC and LOCRC was comparable (median survival 64.88 and 67.24 months, respectively). This study showed comparable clinicopathological parameters between EOCRC and LOCRC from Arabs, which adds to the bigger picture of understand the disease.

Experiencing pain and insufficient relief can be devastating and negatively affect a patient's quality of life. Developments in oncology such as new treatments and adjusted pain management guidelines may have influenced the prevalence of cancer pain and severity in patients. This review aims to provide an overview of the prevalence and severity of pain in cancer patients in the 2014-2021 literature period. A systematic literature search was performed using the databases PubMed, Embase, CINAHL, and Cochrane. Titles and abstracts were screened, and full texts were evaluated and assessed on methodological quality. A meta-analysis was performed on the pooled prevalence and severity rates. A meta-regression analysis was used to explore differences between treatment groups. We identified 10,637 studies, of which 444 studies were included. The overall prevalence of pain was 44.5%. Moderate to severe pain was experienced by 30.6% of the patients, a lower proportion compared to previous research. Pain experienced by cancer survivors was significantly lower compared to most treatment groups. Our results imply that both the prevalence of pain and pain severity declined in the past decade. Increased attention to the assessment and management of pain might have fostered the decline in the prevalence and severity of pain.

The incidence of early-onset colorectal cancer (EOCRC), which means colorectal cancer diagnosed in patients under 50 years, has been increasing around the world. However, the etiology remains unclear. This study aims to identify risk factors for EOCRC.

This systematic review was conducted in PubMed, Embase, Scopus, and Cochrane Library databases from inception to November 25, 2022. We examined risk factors for EOCRC, including demographic factors, chronic conditions, and lifestyle behaviors or environmental factors. Random-effects/fixed-effects meta-analysis was adopted to combine effect estimates from published data. Study quality was evaluated with the Newcastle-Ottawa Scale (NOS). Statistical analysis was performed Revman5.3. Studies not suitable for the meta-analysis were analyzed by a systematic review.

A total of 36 studies were identified for this review, and 30 studies were included in the meta-analysis. Significant risk factors for EOCRC included male (OR=1.20; 95% CI, 1.08-1.33), Caucasian (OR=1.44; 95% CI, 1.15-1.80), a family history of CRC (OR=5.90; 95% CI, 3.67-9.48), inflammatory bowel disease (OR=4.43; 95% CI, 4.05-4.84), obesity (OR=1.52; 95%CI, 1.20-1.91), overweight (OR=1.18; 95% CI, 1.12-1.25), triglycerides (OR=1.12; 95% CI, 1, 08-1.18), hypertension (OR=1.16; 95% CI, 1.12-1.21), metabolic syndrome (OR=1.29; 95% CI, 1.15-1.45), smoking (OR=1.44; 95% CI, 1.10-1.88), alcohol consumption (OR=1.41; 95% CI, 1.22-1.62), a sedentary lifestyle (OR=1.24; 95% CI, 1.05-1.46), red meat (OR=1.10; 95% CI, 1.04-1.16), processed meat (OR=1.53; 95% CI, 1.13-2.06), Western dietary patterns (OR=1.43; 95% CI, 1.18-1.73) and sugar-sweetened beverages (OR=1.55; 95% CI, 1.23-1.95). However, no statistical differences were found for hyperlipidemia and hyperglycemia. Vitamin D may be a protective factor (OR=0.72; 95% CI, 0.56-0.92). There was considerable heterogeneity among studies (I²>60%).

The study provides an overview of the etiology and risk factors of EOCRC. Current evidence can provide baseline data for risk prediction models specific to EOCRC and risk-tailored screening strategies.

The incidence of early-onset (EO) GI cancers occurring in individuals younger than age 50 years has been rising at an alarming rate over the past two decades. Although this rise in incidence among young patients correlates with increased rates of obesity, changes in diet, and alterations in the environment, the effects of these environmental factors on carcinogenesis, metastasis, and treatment response are unknown. Although several unique clinical trends exist among EO-GI cancers and their average-onset GI cancer counterparts, GI cancers are molecularly indistinct between younger and older patients, and no data support distinct treatment paradigms for patients with EO disease. The majority of EO-GI cancers are not explained by germline changes. There remains a critical need for further research to understand the pathogenesis and optimal management of EO-GI cancers. In addition, current screening strategies are not adequate to identify EO-GI cancers, and early biomarkers are needed. Specialized centers, with a focus on psychosocial aspects of cancer management, can address the unique care needs of patients with EO-GI cancers.

Human immunodeficiency virus (HIV) infection is associated with several immune-mediated disorders. However, the risk of inflammatory bowel disease (IBD) in people living with HIV (PLWH) remains unclear. We aimed to assess the risk of IBD among PLWH using a nationwide, population-based Danish cohort and to validate findings in a large American insurance-based database.

Using Danish registries (1983-2018), we identified 8995 PLWH and age- and sex-matched them to 449,750 HIV-negative individuals. Cox regression analysis was undertaken to calculate hazard ratios (HRs) with 95% confidence intervals (CIs) for IBD diagnosis. Results were stratified by sex, age, and year of HIV diagnosis. Using an American insurance-based cohort, Explorys (1999-2018), we assessed the prevalence odds ratio (OR) and 95% CI of IBD diagnosis in PLWH compared with HIV-negative individuals.

IBD diagnosis among PLWH in Denmark was increased (HR: 2.25, 95% CI: 1.78-2.83) compared with matched HIV-negative individuals. This was seen for both Crohn's disease (HR: 2.25, 95% CI: 1.47-3.44) and ulcerative colitis (HR: 2.24, 95% CI: 1.70-2.96) and in male (HR: 2.75, 95% CI: 2.15-3.52) but not female (HR: 0.93, 95% CI: 0.48-1.79) PLWH. Explorys analysis also showed an increased odds of IBD diagnoses among PLWH (OR: 1.41; 95% CI: 1.35-1.49).

This study finds an increased risk of IBD diagnosis among PLWH in both a Danish and US cohort, highlighting a need to consider IBD in PLWH with new-onset gastrointestinal symptoms. Further research into the role of antiretroviral therapy in this relationship is required.

Asian developing countries share the burden of colorectal cancer (CRC) with rising mortality rates. This prospective study aims to apprehend the clinical relevance of age, gender, lifestyle choices (dietary habits and addiction) and body mass index (BMI) to the occurrence and progression of colon cancer (CC).

A cohort of non-cancer (NC) and CC patients of South-Central Asian origin registered for screening colonoscopy or surgery at Shaukat Khanum Memorial Cancer Hospital and Research Centre (SKMCH and RC), Lahore, Pakistan, from 2015 to 2020 was identified. BMI (Kg/m2) was classified according to the World Health Organization criteria as underweight (<18.5 Kg/m2), normal weight (18.5-24.9 Kg/m2) and overweight (≥25 Kg/m2).

Among 236 participants, 99 (41.9%) belonged to the NC group, and 137 (58.1 %) participants had CC Overall, participants included 74 women and 162 men aged 20-85 years (mean ± SD; 49.9 ± 14.9). Notably, 46.0% of cancer patients had a family history of cancer. There was a direct relationship between CC with abnormal BMI (underweight and overweight), positive smoking history and positive family history of cancer.

Being underweight or overweight is a potential risk factor for CC patients. The overall survival in patients with CC is clinically associated with lifestyle choices before CC diagnosis. A balanced diet, walking and other forms of exercise should be strongly recommended to the community and those undergoing screening colonoscopy.

Asian developing countries share the burden of colorectal cancer (CRC) with rising mortality rates. This prospective study aims to apprehend the clinical relevance of age, gender, lifestyle choices (dietary habits and addiction) and body mass index (BMI) to the occurrence and progression of colon cancer (CC).

A cohort of non-cancer (NC) and CC patients of South-Central Asian origin registered for screening colonoscopy or surgery at Shaukat Khanum Memorial Cancer Hospital and Research Centre (SKMCH and RC), Lahore, Pakistan, from 2015 to 2020 was identified. BMI (Kg/m2) was classified according to the World Health Organization criteria as underweight (<18.5 Kg/m2), normal weight (18.5-24.9 Kg/m2) and overweight (≥25 Kg/m2).

Among 236 participants, 99 (41.9%) belonged to the NC group, and 137 (58.1 %) participants had CC Overall, participants included 74 women and 162 men aged 20-85 years (mean ± SD; 49.9 ± 14.9). Notably, 46.0% of cancer patients had a family history of cancer. There was a direct relationship between CC with abnormal BMI (underweight and overweight), positive smoking history and positive family history of cancer.

Being underweight or overweight is a potential risk factor for CC patients. The overall survival in patients with CC is clinically associated with lifestyle choices before CC diagnosis. A balanced diet, walking and other forms of exercise should be strongly recommended to the community and those undergoing screening colonoscopy.

Contrary to decreasing incidence rate of colorectal cancer (CRC) in older adults, incidence rates have nearly doubled in younger adults (age <50 years) in the United States since the early 1990s. A similar increase has been observed across the globe. Despite overall population trends in aging, about 15% of CRCs will be diagnosed in younger adults by 2030. The mechanisms and factors contributing to early-onset CRC (EOCRC) remain puzzling, especially because most young adults diagnosed with CRC have no known risk factors or predisposing conditions, such as family history of CRC or polyps or a hereditary syndrome (eg, Lynch syndrome, polyposis). In this up-to-date review, we discuss the current knowledge of EOCRC, including epidemiology, risk factors, clinical and molecular features, treatment and survival, and recognition and screening strategies.

Incidence of colorectal cancer (CRC) in younger adults is increasing in many countries. Given the established association of body mass index (BMI) with CRC risk and the increasing obesity prevalence among younger generations, we aimed to evaluate the association of BMI at different ages during early adulthood with early-onset CRC.

Among 6602 patients with CRC and 7950 matched controls who were recruited in 2003-2020 in the Darmkrebs: Chancen der Verhütung durch Screening study, a population-based case-control study from Germany, 747 patients and 621 controls were younger than 55 years and included in this analysis. Self-reported height and weight at ages 20 years and 30 years and at approximately 10 years before diagnosis or interview were recorded in personal interviews. Associations of BMI with early-onset CRC were estimated using multiple logistic regression.

Compared with participants with BMI <25 kg/m², those with BMI ≥30 kg/m² (obesity) at ages 20 years and 30 years and approximately 10 years before diagnosis or interview had 2.56- (95% confidence interval, 1.20-5.44), 2.06- (confidence interval, 1.25-3.40), and 1.88- (95% confidence interval, 1.30-2.73) fold risk of early-onset CRC. The association of BMI with early-onset CRC risk was particularly pronounced among, and essentially restricted to, the majority of participants with no previous colonoscopy.

Obesity at early adulthood is strongly associated with increased risk of early-onset CRC. German Clinical Trials Register ID: DRKS00011793.