Racial disparity in colorectal cancer:Gut microbiome and cancer stem cells

Over the past two decades there has been remarkable progress in cancer diagnosis, treatment and screening. The basic mechanisms leading to pathogenesis of various types of cancers are also understood better and some patients, if diagnosed at a particular stage go on to lead a normal pre-diagnosis life. Despite these achievements, racial disparity in some cancers remains a mystery. The higher incidence, aggressiveness and mortality of breast, prostate and colorectal cancers(CRCs) in AfricanAmericans as compared to Caucasian-Americans are now well documented. The polyp-carcinoma sequence in CRC and easy access to colonic epithelia or colonic epithelial cells through colonoscopy/colonic effluent provides the opportunity to study colonic stem cells early in course of natural history of the disease. With the advent of metagenomic sequencing, uncultivable organisms can now be identified in stool and their numbers correlated with the effects on colonic epithelia. It would be expected that these techniques would revolutionize our understanding of the racial disparity in CRC and pave a way for the same in other cancers as well. Unfortunately, this has not happened. Our understanding of the underlying factors responsible in African-Americans for higher incidence and mortality from colorectal carcinoma remains minimal. In this review, we aim to summarize the available data on role of microbiome and cancer stem cells in racial disparity in CRC. This will provide a platform for further research on this topic.     

Multiple mediation analysis of racial disparity in breast cancer survival

BackgroundRacial (Black vs. White) disparities in breast cancer survival have proven difficult to mitigate. Targeted strategies aimed at the primary factors driving the disparity offer the greatest potential for success. The purpose of this study was to use multiple mediation analysis to identify the most important mediators of the racial disparity in breast cancer survival.MethodsThis was a retrospective cohort study of non-Hispanic Black and non-Hispanic White women diagnosed with invasive breast cancer in Florida between 2004 and 2015. Cox regression was used to obtain unadjusted and adjusted hazard ratios (HR) with 95% confidence intervals (CI) for the association of race with 5- and 10-year breast cancer death. Multiple mediation analysis of tumor (advanced disease stage, tumor grade, hormone receptor status) and treatment-related factors (receipt of surgery, chemotherapy, radiotherapy, and hormone therapy) was used to determine the most important mediators of the survival disparity.ResultsThe study population consisted of 101,872 women of whom 87.0% (n = 88,617) were White and 13.0% were Black (n = 13,255). Black women experienced 2.3 times (HR, 2.27; 95% CI, 2.16–2.38) the rate of 5-year breast cancer death over the follow-up period, which decreased to a 38% increased rate (HR, 1.38; 95% CI, 1.31–1.45) after adjustment for age and the mediators of interest. Combined, all examined mediators explained 73% of the racial disparity in 5-year breast cancer survival. The most important mediators were: (1) advanced disease stage (44.8%), (2) nonreceipt of surgery (34.2%), and (3) tumor grade (18.2%) and hormone receptor status (17.6%). Similar results were obtained for 10-year breast cancer death.ConclusionThese results suggest that additional efforts to increase uptake of screening mammography in hard-to-reach women, and, following diagnosis, access to and receipt of surgery may offer the greatest potential to reduce racial disparities in breast cancer survival for women in Florida.     

Racial disparities in incidence of human papillomavirus-associated oropharyngeal cancer in an urban population

BackgroundRecent studies suggest that rates of human papillomavirus related oropharyngeal cancer (HPVOPC) in the US are higher in Caucasians than minorities. We hypothesized that this disparity would be less marked in a racially and ethnically diverse population from New York City.MethodsThis is a retrospective chart review of 210 patients with biopsied or surgically treated OPC at the Icahn School of Medicine at Mount Sinai (ISMMS) between 1999 and 2013. Polymerase chain reaction (PCR) was used to detect the presence of HPV-DNA in paraffin-embedded tumor blocks. Incidence of HPV-positive cancers was compared between Caucasians and minorities (defined as African Americans, Asians, and Hispanics) using Fisher’s exact test.ResultsWe found a higher incidence of HPV-positive OPC in Caucasians than racial minorities within the ISMMS population (p = 0.002). HPV incidence detected by PCR was 139/165 [84.2%] for Caucasians and 28/45 [62.2%] for minorities. Specifically, there was a higher rate in Caucasians compared to African Americans (p = 0.017), but no significant difference between Caucasians and Hispanics (p = 0.087).ConclusionWe documented a disparity in incidence of HPVOPC amongst racial groups, consistent with previously reported trends from study populations in less urbanized areas. Thus we conclude that the factors underlying racial/ethnic disparities in HPVOPC incidence are likely to be similar across communities with different levels of urbanization and population diversity.     

Racial differences in body mass indices of men imprisoned in 19th Century Texas

A limited amount of research has been done on the body mass index values of 19th century Americans. This paper uses Texas prison records to demonstrate that, in contrast to today's distributions, most BMI values were in the normal range. Only 21.5% and 1.2% of the population was overweight or obese, while today comparable figures are 36% and 23%. There was also little change in BMI values between 1876 and 1919. Farmers were consistently heavier than non-farmers, while Southwestern men had lower BMI values than their counterparts from other regions of the US. BMI values indicate that 19th century African-Americans, and whites populations were well fed in spite of large expenditures on energy.     

Breast and colorectal cancer recurrence-free survival estimates in the US: Modeling versus active data collection

BackgroundA modeling method was developed to estimate recurrence-free survival using cancer registry survival data. This study aims to validate the modeled recurrence-free survival against “gold-standard” estimates from data collected by the National Program of Cancer Registries (NPCR) Patient-Centered Outcomes Research (PCOR) project.MethodsWe compared 5-year metastatic recurrence-free survival using modeling and empirical estimates from the PCOR project that collected disease-free status, tumor progression and recurrence for colorectal and female breast cancer cases diagnosed in 2011 in 5 U.S. state registries. To estimate empirical recurrence-free survival, we developed an algorithm that combined disease-free, recurrence, progression, and date information from NPCR-PCOR data. We applied the modeling method to relative survival for patients diagnosed with female breast and colorectal cancer in 2000–2015 in the SEER-18 areas.ResultsWhen grouping patients with stages I-III, the 5-year metastatic recurrence-free modeled and NPCR-PCOR estimates are very similar being respectively, 90.2 % and 88.6 % for female breast cancer, 74.6 % and 75.3 % for colon cancer, and 68.8 % and 68.5 % for rectum cancer. In general, the 5-year recurrence-free NPCR-PCOR and modeled estimates are still similar when controlling by stage. The modeled estimates, however, are not as accurate for recurrence-free survival in years 1–3 from diagnosis.ConclusionsThe alignment between NPCR-PCOR and modeled estimates supports their validity and provides robust population-based estimates of 5-year metastatic recurrence-free survival for female breast, colon, and rectum cancers. The modeling approach can in principle be extended to other cancer sites to provide provisional population-based estimates of 5-year recurrence free survival.     

Analysis of racial disparities in the treatment and outcomes of colorectal cancer in young adults

BackgroundThe incidence of colorectal cancer (CRC) in young adults is increasing. Minority populations with CRC are known to have worse survival outcomes. The aim of this study is to evaluate adults under age 50 years with CRC by race and ethnicity.MethodsData were obtained from all US hospitals that contributed to the National Cancer Database (NCDB) between 2004 and 2013. Univariate and multivariable testing was done to identify factors associated with patient outcome. Kaplan-Meier analysis and Cox proportional hazards models were used for association between patient characteristics and survival.ResultsA total of 83,449 patients between 18 and 50 years of age were identified. Median age was 45 years (SD ± 6), with male preponderance (53.9%). 72% were non-Hispanic Whites (NHW), Blacks (AA) were 15.1% and Hispanics (who did not identify as Blacks) were 8.3% of the study population. Distribution across stages IIV was 15.6%, 22.4%, 33.9% and 27% consecutively. 41.8% of NHW and 28.4% of AA had rectal cancers (p < 0.001). Despite equally receiving standard of care (SOC) as per national guidelines, AA had significantly lower 5-year survival rates (58.8%) compared to Hispanics (64.8%) and NHW (66.9%; HR 1.42; 1.38-1.46; p < 0.001). Furthermore, NHW (HR 0.85; 0.81-0.88; p < 0.001) and Hispanics (HR 0.75; 0.70-0.79; p < 0.001) were more likely to benefit from chemotherapy compared to AA. SOC utilization was associated with improved survival across all racial groups, especially in AA (HR 0.64; 0.60-0.69; p < 0.001).ConclusionDespite comparable rates of SOC utilization, AA young adults had worse survival outcomes compared to other races. More colon (compared to rectal) cancers in AA may have contributed to their worse outcomes.     

Racial disparities in treatment and survival from ovarian cancer

BackgroundBlack women with ovarian cancer in the U.S. have lower survival than whites. We aimed to identify factors associated with racial differences in ovarian cancer treatment and overall survival (OS).MethodsWe examined data from 365 white and 95 black ovarian cancer patients from the Hollings Cancer Center Cancer Registry in Charleston, S.C. between 2000 and 2015. We used unconditional logistic regression to estimate odds ratios (ORs) and 95% confidence intervals (CIs) between race and receipt of surgery and chemotherapy, and Cox proportional hazards regression to estimate hazard ratios (HRs) and 95% CIs between race and OS. Model variables included diagnosis center, stage, histology, insurance status, smoking, age-adjusted Charlson comorbidity index (AACI) and residual disease. Interactions between race and AACI were assessed using −2 log likelihood tests.ResultsBlacks vs. whites were over two-fold less likely to receive a surgery-chemotherapy sequence (multivariable-adjusted OR 2.46, 95% CI 1.43–4.21), particularly if they had a higher AACI (interaction p = 0.008). In multivariable-adjusted Cox models, black women were at higher risk of death (HR 1.81, 95% CI 1.35–2.43) than whites, even when restricted to patients who received a surgery-chemotherapy sequence (HR 1.79, 95% CI 1.10–2.89) and particularly for those with higher AACI (HR 4.70, 95% CI 2.00 − 11.02, interaction p = 0.01).ConclusionsAmong blacks, higher comorbidity associates with less chance of receiving guideline-based treatment and also modifies OS. Differences in receipt of guideline-based care do not completely explain survival differences between blacks and whites with ovarian cancer. These results highlight opportunities for further research.     

Toward a comprehensive and systematic methylome signature in colorectal cancers

CpG Island Methylator Phenotype (CIMP) is one of the underlying mechanisms in colorectal cancer (CRC). This study aimed to define a methylome signature in CRC through a methylation microarray analysis and a compilation of promising CIMP markers from the literature. Illumina HumanMethylation27 (IHM27) array data was generated and analyzed based on statistical differences in methylation data (1st approach) or based on overall differences in methylation percentages using lower 95% CI (2nd approach). Pyrosequencing was performed for the validation of nine genes. A meta-analysis was used to identify CIMP and non-CIMP markers that were hypermethylated in CRC but did not yet make it to the CIMP genes’ list. Our 1st approach for array data analysis demonstrated the limitations in selecting genes for further validation, highlighting the need for the 2nd bioinformatics approach to adequately select genes with differential aberrant methylation. A more comprehensive list, which included non-CIMP genes, such as APC, EVL, CD109, PTEN, TWIST1, DCC, PTPRD, SFRP1, ICAM5, RASSF1A, EYA4, 30ST2, LAMA1, KCNQ5, ADHEF1, and TFPI2, was established. Array data are useful to categorize and cluster colonic lesions based on their global methylation profiles; however, its usefulness in identifying robust methylation markers is limited and rely on the data analysis method. We have identified 16 non-CIMP-panel genes for which we provide rationale for inclusion in a more comprehensive characterization of CIMP+ CRCs. The identification of a definitive list for methylome specific genes in CRC will contribute to better clinical management of CRC patients.     

Hospital surgical volume and colorectal cancer survival in Norway: A nationwide cohort study

BackgroundStudies of hospital surgical volume and colorectal cancer survival are inconclusive. We investigated whether surgical volume was associated with survival of patients operated for colorectal cancer in Norway.MethodsUsing Cancer Registry of Norway data, we compared excess mortality from colorectal cancer by hospital surgical volume among 26,989 colon and 9779 rectal cancer patients diagnosed 2009–2020 and followed-up to 31.12.2021. Hospitals were divided into terciles according to their three-year average annual surgical volume; colon: low (< 22), middle (22–73), high (> 73); rectal: low (< 17), middle (17–38), high (> 38). We estimated excess hazard ratios (EHR) with flexible parametric models adjusted for age, year, stage, surgical urgency and surgery location (within/outside patient’s residential health trust).ResultsLow-volume hospitals had the highest proportion of late-stage or acutely operated colon cancer patients. Colon cancer patients operated at low- versus high-volume hospitals had significantly increased crude excess mortality (EHR = 1.30; 95 % CI = 1.14–1.48) but no difference after adjustment for age, year, and stage (EHR = 0.97; 0.85–1.11). High-volume hospitals had the highest proportion of late-stage rectal cancer patients and patients operated outside their residential area. Rectal cancer patients operated at low- versus high-volume hospitals did not have significantly different excess mortality before (EHR = 0.84; 0.64–1.10) or after (EHR = 1.03; 0.79–1.35) adjustment for age, year, stage, surgical urgency and surgery location. After accounting for case-mix, hospital surgical volume was not associated with excess mortality from colon (P = 0.40) or rectal cancer (P = 0.22).ConclusionLow hospital surgical volume was not associated with poorer colorectal cancer survival.     

Relative impact of earlier diagnosis and improved treatment on survival for colorectal cancer: A US database study among elderly patients

PurposesTo estimate what proportion of improvement in relative survival was attributable to smaller stage/size due to early detection and what proportion was attributable to cancer chemotherapy in patients with colorectal cancer (CRC).MethodsWe studied 69,718 patients with CRC aged ≥66 years in 1992–2009 from Surveillance, Epidemiology, and End Results registries. Study periods were categorized into three periods according to the major changes or advances in screening and chemotherapy regimens: (1) Period-1 (1992–1995), during which there was no evidence-based recommendation for routine CRC screening and 5-fluorouracil was the mainstay for chemotherapy; (2) Period-2 (1996–2000), during which evidences and guidelines supported the use of fecal occult blood test (FOBT) and sigmoidoscopy for routine CRC screening; and (3) Period-3 (2001–2009), during which Medicare Program added the full coverage for colonoscopy screening to average-risk individuals, and several newly developed chemotherapy regimens were approved. Outcome variables included the likelihood of being diagnosed at an early stage or with a small tumor size, and improvement in relative survival.ResultsCompared to period-1, likelihood of being diagnosed with early stage CRC increased by 20% in period-2 (odds ratio = 1.2, 95%CI: 1.1–1.2) and 30% in period-3 (1.3, 1.2–1.4); and likelihood of being diagnosed with small-size CRC increased by 60% in period-2 and 110% in period-3. Similarly, 5-year overall relative survival increased from 51% in period-1 to 56% in period-2 and 60% in period-3. Increase in survival attributable to migration in stage/size was 9% in period-2 and 20% in period-3, while the remaining survival improvement during period-2 and period-3 were largely attributable to more effective chemotherapy regimens (≥71.6%) and other treatment factors (≤25%).ConclusionsImprovements in CRC screening resulted in a migration of CRC toward earlier tumor stage and smaller size, which contributed to ≤20% of survival increase. Survival improvement over the past 2 decades was largely explained by more effective chemotherapy regimens (≥71.6%).     

Preoperative mannan-binding lectin pathway and prognosis in colorectal cancer

Purpose: Deficiency of the mannan-binding lectin (MBL) pathway of innate immunity is associated with increased susceptibility to infections. In patients with colorectal cancer (CRC), postoperative infection is associated with poor prognosis. The aim of the present study was to evaluate (1) the relation between the MBL pathway and postoperative infectious complications and survival of patients resected for CRC, and (2) the role of MBL in acute phase response compared to C-reactive protein (CRP). Methods: Preoperative MBL concentration, MBL-associated serine protease (MBL/MASP) activity and CRP were determined in serum from 611 patients and 150 healthy controls. The patients were observed for 8 years. Postoperative infections, recurrence and survival were recorded. Results: The MBL pathway components were increased in the patients compared with the healthy controls (p<0.0001). Low MBL levels were predictive of pneumonia (p=0.01), and pneumonia (n=87) was associated with poor survival (p=0.003; HR=1.5; 95% CI, 1.1 to 1.9). MBL and MBL/MASP activity showed no correlation with CRP (Spearmans =0.02; 95% CI, –0.06 to 0.10). Conclusion: Low preoperative MBL levels are predictive of pneumonia, which is associated with poorer survival. MBL concentration and MBL/MASP activity was not predictive of other postoperative infections or long-term prognosis, and showed no correlation with CRP.     

Diabetes,metformin use,and colorectal cancer survival in postmenopausal women

Background: Observational studies have associated metformin use with lower colorectal cancer (CRC) incidence but few studies have examined metformin's influence on CRC survival. We examined the relationships among metformin use, diabetes, and survival in postmenopausal women with CRC in the Women's Health Initiative (WHI) clinical trials and observational study. Methods: 2066 postmenopausal women with CRC were followed for a median of 4.1 years, with 589 deaths after CRC diagnosis from all causes and 414 deaths directly attributed to CRC. CRC-specific survival was compared among women with diabetes with metformin use (n = 84); women with diabetes with no metformin use (n = 128); and women without diabetes (n = 1854). Cox proportional hazard models were used to estimate associations among metformin use, diabetes and survival after CRC. Strategies to adjust for potential confounders included: multivariate adjustment with known predictors of colorectal cancer survival and construction of a propensity score for the likelihood of receiving metformin, with model stratification by propensity score quintile. Results: After adjusting for age and stage, CRC specific survival in women with diabetes with metformin use was not significantly different compared to that in women with diabetes with no metformin use (HR 0.75; 95% CI 0.40–1.38, p = 0.67) and to women without diabetes (HR 1.00; 95% CI 0.61–1.66, p = 0.99). Following propensity score adjustment, the HR for CRC-specific survival in women with diabetes with metformin use compared to non-users was 0.78 (95% CI 0.38–1.55, p = 0.47) and for overall survival was 0.86 (95% CI 0.49–1.52; p = 0.60). Conclusions: In postmenopausal women with CRC and DM, no statistically significant difference was seen in CRC specific survival in those who used metformin compared to non-users. Analyses in larger populations of colorectal cancer patients are warranted.     

Subsite- and stage-specific colorectal cancer trends in Estonia prior to implementation of screening

BackgroundThe occurrence of colorectal cancer (CRC) in Estonia has been characterised by increasing incidence, low survival and no screening. The study aimed to examine long-term incidence and survival trends of CRC in Estonia with specific focus on subsite and stage.MethodsWe analysed CRC incidence and relative survival using Estonian Cancer Registry data on all cases of colorectal cancer (ICD-10 C18–21) diagnosed in 1995–2014. TNM classification was used to categorise stage.ResultsAge-standardized incidence of colon cancer increased both in men and women at a rate of approximately 1% per year. Significant increase was seen for right-sided tumours, but not for left-sided tumours. Rectal cancer incidence increased significantly only in men and anal cancer incidence only in women. Age-standardized five-year relative survival for colon cancer increased from 50% in 1995–1999 to 59% in 2010–2014; for rectal cancer, from 38% to 56%. Colon cancer survival improved significantly for left-sided tumours (from 51% to 62%) and stage IV disease (from 6% to 15%). For rectal cancer, significant survival gain was seen for stage II (from 58% to 75%), stage III (from 34% to 70%) and stage IV (from 1% to 12%).ConclusionIn the pre-screening era in Estonia, increase in colon cancer incidence was limited to right-sided tumours. Large stage-specific survival gain, particularly for rectal cancer, was probably due to better staging and advances in multimodality treatment. Nonetheless, more than one quarter of new CRC cases are diagnosed at stage IV, emphasising the need for an efficient screening program.     

Survival pattern of colorectal cancer in Sub-Saharan Africa: A systematic review and meta-analysis

Cancer incidence is relatively low in sub-Saharan Africa (SSA), however, prognosis is expected to be poor in comparison with high-income countries. Comprehensive evidence is limited on the survival pattern of colorectal cancer patients in the region. We conducted a systematic review and meta-analysis to investigate the pattern of colorectal cancer survival in the region and to identify variation across countries and over time. We searched international databases MEDLINE, Scopus, Embase, Web of Science, ProQuest, CINAHL, and Google Scholar to retrieve studies that estimated survival from colorectal cancer in SSA countries from inception to December 31, 2021 without language restriction. Due to between-study heterogeneity, we performed a random-effects meta-analysis to pool survival rates. To identify study-level sources of variation, we performed subgroup analysis and meta-regression. Results are reported in line with the Preferred Reporting Items for Systematic Review and Meta-Analyses (PRISMA) 2020 guideline and the protocol was registered in PROSPERO database (CRD42021246935). 23 studies involving 10,031 patients were included in the review, of which, 20 were included in the meta-analysis. The meta-analysis results showed that the pooled 1-, 2-, 3-, 4-, and 5-year survival rates in SSA were 0.74 (95% CI, 0.66–0.81), 0.50 (95% CI, 0.41–0.58), 0.36 (95% CI, 0.27–0.47), 0.31 (95% CI, 0.22–0.42), and 0.28 (95% CI, 0.19–0.38) respectively. Subgroup analyses indicated that the survival rate varied according to year of study, in which those conducted in recent decades showed relatively better survival. The 5-year survival was higher in middle-income SSA countries (0.31; 95%CI: 0.17–0.49) than low-income countries (0.20; 95%CI: 0.11–0.35), however, the difference was not statistically significant. In conclusion, survival from colorectal cancer is low in sub-Saharan Africa compared to other regions. Thus, intervention strategies to improve screening, early diagnosis and treatment of colorectal cancer should be developed and implemented to improve survival in the region.     

Social disparities in survival after diagnosis with colorectal cancer: Contribution of race and insurance status

BackgroundBoth minority race and lack of health insurance are risk factors for lower survival in colorectal cancer (CRC) but the interaction between the two factors has not been explored in detail.MethodsOne to 5-year survival by race/ethnic group and insurance type for patients with CRC diagnosed in 2007-13 and registered in the Surveillance Epidemiology, and EndResultsdatabase were explored. Shared frailty models were computed to further explore the association between CRC specific survival and insurance status after adjustment for demographic and treatment variables.ResultsAge-adjusted 5-year survival estimates were 70.4% for non-Hispanic whites (nHW), 62.7% for non-Hispanic blacks (nHB), 70.2% for Hispanics, 64.7% for Native Americans, and 73.1% for Asian/Pacific Islanders (API). Survival was greater for patients with insurance other than Medicaid for all races, but the differential in survival varied with race, with the greatest difference being seen for nHW at +25.0% and +20.2%, respectively, for Medicaid and uninsured versus other insurance. Similar results were observed for stage- and age-specific analyses, with survival being consistently higher for nHW and API compared to other groups. After confounder adjustment, hazard ratios of 1.53 and 1.50 for CRC-specific survival were observed for Medicaid and uninsured. Racial/ethnic differences remained significant only for nHB compared to nHW.ConclusionsRace/ethnic group and insurance type are partially independent factors affecting survival expectations for patients diagnosed with CRC. NHB had lower than expected survival for all insurance types.     

Statin use and survival in colorectal cancer: Results from a population-based cohort study and an updated systematic review and meta-analysis

BackgroundThe aim of this study was to investigate the association between statin use and survival in a population-based colorectal cancer (CRC) cohort and perform an updated meta-analysis to quantify the magnitude of any association.MethodsA cohort of 8391 patients with newly diagnosed Dukes’ A-C CRC (2009–2012) was identified from the Scottish Cancer Registry. This cohort was linked to the Prescribing Information System and the National Records of Scotland Death Records (until January 2015) to identify 1064 colorectal cancer-specific deaths. Adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) for cancer-specific mortality by statin use were calculated using time dependent Cox regression models. The systematic review included relevant studies published before January 2016. Meta-analysis techniques were used to derive combined HRs for associations between statin use and cancer-specific and overall mortality.ResultsIn the Scottish cohort, statin use before diagnosis (HR = 0.84, 95% CI 0.75–0.94), but not after (HR = 0.90, 95% CI 0.77–1.05), was associated with significantly improved cancer-specific mortality. The systematic review identified 15 relevant studies. In the meta-analysis, there was consistent (I² = 0%,heterogeneity P = 0.57) evidence of a reduction in cancer-specific mortality with statin use before diagnosis in 6 studies (n = 86,622, pooled HR = 0.82, 95% CI 0.79–0.86) but this association was less apparent and more heterogeneous (I² = 67%,heterogeneity P = 0.03) with statin use after diagnosis in 4 studies (n = 19,152, pooled HR = 0.84, 95% CI 0.68–1.04).ConclusionIn a Scottish CRC cohort and updated meta-analysis there was some evidence that statin use was associated with improved survival. However, these associations were weak in magnitude and, particularly for post-diagnosis use, varied markedly between studies.     

Lessons learnt from the implementation of a colorectal cancer screening programme for lynch syndrome in a tertiary public hospital

BackgroundLynch syndrome (LS) is the first cause of inherited colorectal cancer (CRC), being responsible for 2–4% of all diagnoses. Identification of affected individuals is important as they have an increased lifetime risk of multiple CRC and other neoplasms, however, LS is consistently underdiagnosed at the population level. We aimed to evaluate the yield of LS screening in CRC in a single-referral centre and to identify the barriers to its effective implementation.MethodsLS screening programme included individuals with CRC < 70 years, multiple CRC, or endometrial cancer at any age. Mismatch repair (MMR) protein immunohistochemistry (IHC) analysis was performed in routine practice on the surgical specimen and, if MLH1 IHC was altered, MLH1 gene promoter methylation was analysed. Results were collected in the CRC multidisciplinary board database. LS suspected individuals (altered MMR IHC without MLH1 promoter methylation) were referred to the Cancer Genetic Counselling Unit (CGCU). If accepted, a genetic study was performed. Two checkpoints were included: review of the pathology data and verification of patient referral by a genetic counsellor.ResultsBetween 2016 and 2019, 381 individuals were included. MMR IHC analysis was performed in 374/381 (98.2 %) CRC cases and MLH1 promoter methylation in 18/21 (85.7 %). Seventeen of the 20 LS suspected individuals were invited for referral at the CGCU. Two cases were not invited and the remaining patient died of cancer before completion of tumour screening. Fifteen individuals attended and a genetic analysis was performed in 15/20 (75 %) LS suspected individuals. Ten individuals were diagnosed with LS, in concordance with the IHC profile (2.7 % of the total cohort). This led to cascade testing in 58/75 (77.3 %) of the available adult relatives at risk, identifying 26 individuals with LS.ConclusionsEstablishing a standardized institutional LS screening programme with checkpoints in the workflow is key to increasing the yield of LS identification.     

Repeat hepatectomy justified in patients with early recurrence of colorectal cancer liver metastases: A systematic review and meta-analysis

BackgroundThe benefit of repeat hepatectomy in patients with early recurrence of colorectal cancer liver metastases (CRLM) is questioned, in particular in those suffering from recurrence within three to six months following initial hepatectomy. The aim of this review was therefore to assess whether disease-free interval was associated with overall survival in patients undergoing repeat hepatectomy for recurrent CRLM.MethodsA systematic review and meta-analysis was conducted, according to PRISMA guidelines. PubMed, Embase and Cochrane Library databases were searched from database inception to 6th June 2020. Observational studies describing results of repeat hepatectomy for recurrent CRLM, including (disease-free) interval between hepatic resections and overall survival were included. Patients undergoing repeat hepatectomy within three months or additional resection of extrahepatic disease were excluded from meta-analysis.ResultsThe initial search identified 2159 records, of which 28 were included for qualitative synthesis. A meta-analysis of 15 cohort studies was performed, comprising 1039 eligible patients. Median overall survival of 54.0 months [95 %-CI: 38.6–69.4] was observed after repeat hepatectomy in patients suffering from recurrent CRLM between three to six months compared to 53.0 months [95 %-CI: 44.3–61.6] for patients with recurrent CRLM between seven to twelve months (adjusted HR = 0.89, 95 %-CI: 0.66–1.18; p = 0.410), and 60.0 months [95 %-CI: 52.7–67.3] for patients with recurrent CRLM after twelve months (adjusted HR = 0.70, 95 %-CI: 0.53−0.92; p = 0.012).ConclusionsDisease-free interval is considered a prognostic factor for overall survival, but should not be used as selection criterion per se for repeat hepatectomy in patients suffering from recurrent CRLM.     

Claudins upregulation in human colorectal cancer

In colorectal cancer tight junction molecular and morphological alterations are poorly understood. In this study, adenocarcinoma tissues and their paired normal mucosa (n = 12) were analyzed for tight junction alterations molecular. The expression of claudin-1, -3 and -4 was upregulated 5.7-, 1.5- and 2.4-fold, respectively, in colorectal tumor tissues in comparison to the normal ones. Although tight junction remains in the cancerous epithelium, its barrier function was altered. Despite claudins overexpression, paracellular permeability to ruthenium red was increased and a significant disorganization of tight junction strands was observed in freeze fracture replicas. Whereas the functional significance of claudin overexpression in colorectal cancer is unclear, these proteins can become potential markers and targets in colorectal cancer.     

Progress in the identification of plasma biomarkers of colorectal cancer

Proteomic analysis of human tissue and plasma samples has been a useful tool in recent years for the identification of potential biomarkers to aid in the early diagnosis of colorectal cancer. However, biomarkers relating to the crucial transition between adenomatous lesions and invasive colorectal malignancy have not previously been described. The work of Choi et al. (Proteomics 2013, 13, 2361–2374) attempts to address this issue. Using plasma samples from age‐matched patients with colorectal adenomas or invasive disease this group identified a range of plasma proteins and cytokines that were differentially expressed. This information not only provides insights into the biology of the adenoma to carcinoma progression sequence but it also represents a step towards the goal of achieving diagnostically accurate and clinically acceptable biomarkers in early colorectal cancer.