Effects of molecular markers on the treatment decision and prognosis of colorectal cancer: a narrative review

ObjectiveTo summarize the effects of molecular markers on the treatment decision and prognosis of colorectal cancer.BackgroundColorectal cancer is a highly heterogeneous disease. Even colorectal cancers of the same pathological type and clinical stage may have significant differences in treatment efficacy and prognosis. There are three main molecular mechanisms for the occurrence and development of colorectal cancer: chromosomal instability (CIN) pathway, microsatellite instability (MSI), and CpG island methylate phenotype (CIMP). There are multiple molecular markers distributed on each pathway.MethodsWe performed a literature search on the PubMed database for studies published in English (from the date of initiation of the database to the year of 2020) using the following subject terms: “colon cancer”, “rectal cancer”, “colorectal cancer”, “molecular markers”, “biomarkers”, “treatment strategies”, and “prognosis”.ConclusionsThe different expression states of molecular markers have a significant impact on the treatment decision and prognosis of colorectal cancer. Main colorectal cancer molecular markers include MSI and some important genes. Individualized treatments for tumors with different molecular phenotypes have improved the treatment effectiveness for colorectal cancer. The rational use of molecular markers is valuable for treatment decision-making and the prognosis of patients with colorectal cancer.     

Diet and supplements and their impact on colorectal cancer

Background

Colorectal cancer is the third commonest cancer and the third leading cause of cancer death among men and women. It has been proposed that dietary factors are responsible for 70-90% of colorectal cancer and diet optimization may prevent most cases.

Aim

To evaluate the role of dietary components and supplements in colorectal cancer.

Methods

Bibliographical searches were performed in Pubmed for the terms “diet and colorectal cancer”, “diet and colon cancer”, “diet and rectal cancer”, “nutrition and colorectal cancer”, “probiotics and colorectal cancer”, “prebiotics and colorectal cancer”, “alcohol and cancer” and “colorectal cancer epidemiology”.

Results

Consumption of processed or red meat, especially when cooked at high temperatures may be associated with increased risk of colorectal cancer. The evidence for dietary fibre is unclear but foods that contain high amounts of fibre are usually rich in polyphenols which have been shown to alter molecular processes that can encourage colorectal carcinogenesis. Meta-analyses provide evidence on the benefits of circulating, diet-derived and supplemented, vitamin D and Calcium. We also found that diets rich in Folate may prevent colorectal carcinoma. The evidence on dietary micronutrients such as Zinc and Selenium in association with colorectal cancer is not conclusive. It has been suggested that there may be a direct association between alcohol intake and colorectal cancer. In vitro and in vivo studies have highlighted a possible protective role of prebiotics and probiotics.

Conclusions

The lack of randomized trials and the presence of confounding factors including smoking, physical activity, obesity and diabetes may often yield inconclusive results. Carefully designed randomized trials are recommended.Key Words: Colorectal cancer, nutrition, diet, carcinogenesis     

The evolving treatment paradigm of locally advanced rectal cancer: a narrative review

Background and ObjectiveSurgery is still considered the mainstay of treatment of locally advanced rectal cancer (LARC). Nevertheless, “curable” disease may still pose a great risk for both local and distant relapses. Since the early eighties of the past century, we have witnessed mounting evidence supporting the multi-modality approach to tackle this disease effectively. The multi-modality approach is variable between different positive trials. In this review, we discuss the treatment evolution of LARC, highlighting the key differences between the different contemporary strategies utilized. Based on current evidence, we sought to define distinct patient subgroups and to propose a treatment algorithm that best fits patient’s risk.MethodsWe conducted a literature search through PubMed and Google scholar. Eligible papers were phase 2/3 trials [in organ preservation (OP), observational and retrospective studies were also acceptable] published in English. We used keywords such as “locally advanced rectal cancer”, “perioperative therapy in rectal cancer”, “short course radiotherapy”, “chemoradiation in rectal cancer”, “interval to surgery”, “Neoadjuvant therapy”, “Organ preservation” and “Total neoadjuvant treatment [TNT]”.Key Content and FindingsVarious trials consistently demonstrated the benefit of preoperative radiotherapy in LARC, the role of adjuvant chemotherapy is controversial based on published studies, TNT was associated with a risk reduction in distant metastasis, and more reassuring evidence is accumulating regarding OP.ConclusionsThe treatment landscape of LARC is rapidly changing. Clinicians should carefully tailor treatment strategy based on patient’s risk.     

Let food be thy medicine: the role of diet in colorectal cancer: a narrative review

Background and ObjectiveColorectal cancer (CRC) is the third most common cancer worldwide, and the incidence and mortality rates continue to increase annually. Many factors, including genetic, immune, and environmental factors, influence the occurrence and development of CRC. Along with the economic development, changes in lifestyle, especially dietary factors, have been shown to greatly affect the progression of CRC. Increasing evidence showed that dietary patterns influence the risk of CRC and affect CRC treatment. The present review describes the role of diet in the prevention and treatment of CRC with the hope that doctors attach importance to dietary patterns in educating patients with CRC or at risk of CRC and that diet may be regarded as an auxiliary treatment strategy to improve patients’ outcomes.MethodsEnglish language articles published from 2000 to December 2021 in PubMed and Embase were identified by searching titles for keywords including “diet”, “colorectal cancer”, “dietary pattern”, and “dietary factor”; 101 articles were selected for review.Key Content and FindingsThe present review describes the role of different dietary patterns and factors in the prevention and treatment of CRC. We found that dietary intervention is closely related to the occurrence, development, and prognosis of CRC. Adherence to the Mediterranean diet (MD), the Dietary Approaches to Stop Hypertension (DASH) diet, fasting, vegetarian diets and the ketogenic diet (KD) were found to reduce the risk of CRC, prolong patient survival, and delay disease progression. Moderate intake of dietary fiber (DF), omega-3 fatty acids, micronutrients (e.g., calcium, iron, and selenium), and vitamins have been shown to be beneficial in the prevention and treatment of CRC. Conversely, diets high in fat or sugar and those rich in red meat or processed meat promote CRC.ConclusionsPeople at high risk of CRC and those with CRC are recommended to eat a plant-based diet rich in fruits, vegetables, and whole grains with appropriate DF intake and to avoid high levels of processed meat, red meat, and highly refined grains.     

Correlation of ulcerative colitis and colorectal cancer: a systematic review and meta-analysis

BackgroundA large number of studies have shown that ulcerative colitis (UC) can increase the risk of colorectal cancer (CRC). The purpose of the present study was to explore the specific mechanism of UC influence on CRC.MethodsWe searched PubMed for articles related to CRC and colitis since the establishment of the database until April 2021. Keywords, such as ulcerative colitis, colorectal cancer, and relevance, were used for the article search. Two investigators read through the full text according to the inclusion and exclusion criteria to screen the articles. Cochrane system review manual (version 5.3) was adopted to evaluate the quality of the selected articles. Then, data was extracted, and the overall risk of UC patients into CRC, the course of the disease, and the region were systematically analyzed.ResultsA total of 11 studies involving 26,765 patients with UC were included. The results showed that UC is one of the risk factors for CRC. we also found that geographical location also had an impact on the transition from UC to CRC, but the impact was not significant. Patients with colitis had a significantly higher rate of conversion to CRC after 10 to 20 years of disease.DiscussionA total of 11 articles were included to analyze the association between UC and CRC. The studies found that the location, duration, and geographical location of patients with UC directly affected the occurrence of CRC and are independent risk factors for the transformation of UC into CRC.     

Liquid biopsies for colorectal cancer: a narrative review of ongoing clinical trials and the current use of this technology at a comprehensive cancer center

ObjectiveIn this review, we summarize ongoing clinical trials involving liquid biopsies (LB) for colorectal cancer (CRC), outlining the current landscape and the future implementation of this technology. We also describe the current use of LB in CRC treatment at our institution, the Mayo Clinic Enterprise.BackgroundThe use of LB in CRC treatment merits close attention. Their role is being evaluated in the screening, non-intervention, intervention, and surveillance settings through many active trials. This, coupled with the technique’s rapid integration into clinical practice, creates constant evolution of care.MethodsReview of ClinicalTrials.gov was performed identifying relevant and active trials involving LB for CRC. “Colorectal cancer” plus other terms including “liquid biopsies” and “ctDNA” were used as search terms, identifying 35 active trials.ConclusionsLB use for the CRC is actively being investigated and requires close attention. Based on current evidence, Mayo Clinic Enterprise currently uses LB in the non-interventional, interventional and surveillance setting, but not for screening. Results of these trials may further establish the use of LB in the management of CRC.     

Laparoscopic liver resection for colorectal liver metastases — short- and long-term outcomes: A systematic review

BACKGROUNDFor well-selected patients and procedures, laparoscopic liver resection (LLR) has become the gold standard for the treatment of colorectal liver metastases (CRLM) when performed in specialized centers. However, little is currently known concerning patient-related and peri-operative factors that could play a role in survival outcomes associated with LLR for CRLM.AIMTo provide an extensive summary of reported outcomes and prognostic factors associated with LLR for CRLM.METHODSA systematic search was performed in PubMed, EMBASE, Web of Science and the Cochrane Library using the keywords “colorectal liver metastases”, “laparoscopy”, “liver resection”, “prognostic factors”, “outcomes” and “survival”. Only publications written in English and published until December 2019 were included. Furthermore, abstracts of which no accompanying full text was published, reviews, case reports, letters, protocols, comments, surveys and animal studies were excluded. All search results were saved to Endnote Online and imported in Rayyan for systematic selection. Data of interest were extracted from the included publications and tabulated for qualitative analysis.RESULTSOut of 1064 articles retrieved by means of a systematic and grey literature search, 77 were included for qualitative analysis. Seventy-two research papers provided data concerning outcomes of LLR for CRLM. Fourteen papers were eligible for extraction of data concerning prognostic factors affecting survival outcomes. Qualitative analysis of the collected data showed that LLR for CRLM is safe, feasible and provides oncological efficiency. Multiple research groups have reported on the short-term advantages of LLR compared to open procedures. The obtained results accounted for minor LLR, as well as major LLR, simultaneous laparoscopic colorectal and liver resection, LLR of posterosuperior segments, two-stage hepatectomy and repeat LLR for CRLM. Few research groups so far have studied prognostic factors affecting long-term outcomes of LLR for CRLM.CONCLUSIONIn experienced hands, LLR for CRLM provides good short- and long-term outcomes, independent of the complexity of the procedure.     

Robotic rectal surgery: State of the art

Laparoscopic rectal surgery has demonstrated its superiority over the open approach, however it still has some technical limitations that lead to the development of robotic platforms. Nevertheless the literature on this topic is rapidly expanding there is still no consensus about benefits of robotic rectal cancer surgery over the laparoscopic one. For this reason a review of all the literature examining robotic surgery for rectal cancer was performed. Two reviewers independently conducted a search of electronic databases (PubMed and EMBASE) using the key words “rectum”, “rectal”, “cancer”, “laparoscopy”, “robot”. After the initial screen of 266 articles, 43 papers were selected for review. A total of 3013 patients were included in the review. The most commonly performed intervention was low anterior resection (1450 patients, 48.1%), followed by anterior resections (997 patients, 33%), ultra-low anterior resections (393 patients, 13%) and abdominoperineal resections (173 patients, 5.7%). Robotic rectal surgery seems to offer potential advantages especially in low anterior resections with lower conversions rates and better preservation of the autonomic function. Quality of mesorectum and status of and circumferential resection margins are similar to those obtained with conventional laparoscopy even if robotic rectal surgery is undoubtedly associated with longer operative times. This review demonstrated that robotic rectal surgery is both safe and feasible but there is no evidence of its superiority over laparoscopy in terms of postoperative, clinical outcomes and incidence of complications. In conclusion robotic rectal surgery seems to overcome some of technical limitations of conventional laparoscopic surgery especially for tumors requiring low and ultra-low anterior resections but this technical improvement seems not to provide, until now, any significant clinical advantages to the patients.     

Methods of Sentinel Lymph Node Detection and Management in Urinary Bladder Cancer—A Narrative Review

Introduction: Detection of lymph node status in bladder cancer significantly impacts clinical decisions regarding its management. There is a wide range of detection modalities for this task, including lymphoscintigraphy, computed tomography, magnetic resonance imaging, single-photon emission computed tomography, positron emission tomography, and fluoroscopy. We aimed to study the pre- and intraoperative detection modalities of sentinel lymph nodes in urinary bladder cancer. Method: This narrative review was performed by searching the PubMed and EMBASE libraries using the following search terms: (“Transitional cell carcinoma of the bladder” OR “urothelial cancer” OR “urinary bladder cancer” OR “bladder cancer”) AND ((“sentinel lymph node”) OR (“lymphatic mapping”) OR (“lymphoscintigraphy”) OR (“lymphangiography”) OR (“lymph node metastases”)). Studies analysing the effectiveness and outcomes of sentinel lymph node detection in bladder cancer were included, while non-English language, duplicates, and non-article studies were excluded. After analysing the libraries and a further manual search of bibliographies, 31 studies were included in this paper. We followed the RAMESES publication standard for narrative reviews to produce this paper. Results: Of the 31 studies included, 7 studies included multiple detection methods; 5 studies included lymphoscintigraphy; 5 studies included computed tomography and/or single-photon emission computed tomography; 5 studies included fluoroscopy; 4 studies included magnetic resonance imaging; and 5 studies included positron emission tomography. Discussion: Anatomical, radioactive, and functional detection modalities have been studied independently and in combination. The consensus is that preoperative detection with imaging helps guide surgical management and intraoperative detection methods help capture any lymph nodes that may have been missed. Each of these types of detection represent their own set of benefits and drawbacks, but there is currently limited evidence to support any change in overall practice to replace conventional staging.     

Radiation costing methods: a systematic review

ObjectiveCosts for radiation therapy (rt) and the methods used to cost rt are highly diverse across the literature. To date, no study has compared various costing methods in detail. Our objective was to perform a thorough review of the radiation costing literature to identify sources of costs and methods used.MethodsA systematic review of Ovid medline, Ovid oldmedline, embase, Ovid HealthStar, and EconLit from 2005 to 23 March 2015 used search terms such as “radiation,” “radiotherapy,” “neoplasm,” “cost,” “ cost analysis,” and “cost benefit analysis” to locate relevant articles. Original papers were reviewed for detailed costing methods. Cost sources and methods were extracted for papers investigating rt modalities, including three-dimensional conformal rt (3D-crt), intensity-modulated rt (imrt), stereotactic body rt (sbrt), and brachytherapy (bt). All costs were translated into 2014 U.S. dollars.ResultsMost of the studies (91%) reported in the 33 articles retrieved provided rt costs from the health system perspective. The cost of rt ranged from US$2,687.87 to US$111,900.60 per treatment for imrt, followed by US$5,583.28 to US$90,055 for 3D-crt, US$10,544.22 to US$78,667.40 for bt, and US$6,520.58 to US$19,602.68 for sbrt. Cost drivers were professional or personnel costs and the cost of rt treatment. Most studies did not address the cost of rt equipment (85%) and institutional or facility costs (66%).ConclusionsCosting methods and sources were widely variable across studies, highlighting the need for consistency in the reporting of rt costs. More work to promote comparability and consistency across studies is needed.     

Frequent post-operative monitoring of colorectal cancer using individualised ctDNA validated by multiregional molecular profiling

Background Circulating tumour DNA (ctDNA) is known as a tumour-specific personalised biomarker, but the mutation-selection criteria from heterogeneous tumours remain a challenge.Methods We conducted multiregional sequencing of 42 specimens from 14 colorectal tumours of 12 patients, including two double-cancer cases, to identify mutational heterogeneity to develop personalised ctDNA assays using 175 plasma samples.Results “Founder” mutations, defined as a mutation that is present in all regions of the tumour in a binary manner (i.e., present or absent), were identified in 12/14 tumours. In contrast, “truncal” mutations, which are the first mutation that occurs prior to the divergence of branches in the phylogenetic tree using variant allele frequency (VAF) as continuous variables, were identified in 12/14 tumours. Two tumours without founder and truncal mutations were hypermutators. Most founder and truncal mutations exhibited higher VAFs than “non-founder” and “branch” mutations, resulting in a high chance to be detected in ctDNA. In post-operative long-term observation for 10/12 patients, early relapse prediction, treatment efficacy and non-relapse corroboration were achievable from frequent ctDNA monitoring.Conclusions A single biopsy is sufficient to develop custom dPCR probes for monitoring tumour burden in most CRC patients. However, it may not be effective for those with hypermutated tumours.Subject terms: Rectal cancer, Cancer genomics, Colon cancer, Tumour biomarkers     

Correlation between targeted RNAseq signature of breast cancer CTCs and onset of bone-only metastases

Background Bone is the most frequent site of metastases from breast cancer (BC), but no biomarkers are yet available to predict skeletal dissemination.Methods We attempted to identify a gene signature correlated with bone metastasis (BM) onset in circulating tumour cells (CTCs), isolated by a DEPArray-based protocol from 40 metastatic BC patients and grouped according to metastasis sites, namely “BM” (bone-only), “ES” (extra-skeletal) or BM + ES (bone + extra-skeletal).Results A 134-gene panel was first validated through targeted RNA sequencing (RNAseq) on sub-clones of the MDA-MB-231 BC cell line with variable organotropism, which successfully shaped their clustering. The panel was then applied to CTC groups and, in particular, the “BM” vs “ES” CTC comparison revealed 31 differentially expressed genes, including MAF, CAPG, GIPC1 and IL1B, playing key prognostic roles in BC.Conclusion Such evidence confirms that CTCs are suitable biological sources for organotropism investigation through targeted RNAseq and might deserve future applications in wide-scale prospective studies.Subject terms: Breast cancer, Molecular medicine     

Frequent low dose alcohol intake increases gastric cancer risk: the Health Examinees-Gem (HEXA-G) study

Objective:Epidemiological studies indicate that alcohol increases gastric cancer (GC) risk, yet most studies have focused on heavy alcohol intake, leaving other factors understudied. A comprehensive investigation of the effects of the frequency and amount of alcohol intake may help elucidate the GC risk associated with drinking behavior.Methods:The Health Examinees-Gem (HEXA-G) study, a community-based large-scale prospective cohort study, enrolled Korean adults 40–69 years of age between the years 2004 and 2013. Incident GC cases were identified through linkage to Korea Central Cancer Registry data until December 31, 2017. Self-reported questionnaires were used to survey alcohol consumption-related factors (duration, frequency, amount, and type of alcoholic beverages). The frequency and amount of alcohol consumption were combined to explore GC risk according to 4 drinking patterns: “infrequent-light”, “frequent-light”, “infrequent-heavy”, and “frequent-heavy”. We used Cox proportional hazard models to estimate the adjusted hazard ratios (HRs) and 95% confidence intervals (CIs), and investigate the relationship between alcohol intake and GC incidence.Results:A total of 128,218 participants were included in the analysis. During an average follow-up period of 8.6 years, 462 men and 385 women were diagnosed with GC. In men, current drinkers showed a 31% greater risk of GC than non-drinkers (HR 1.31, 95% CI 1.03–1.66), whereas no significant association was observed in women. In men, GC risk was associated with a higher frequency (P trend 0.02) and dose of ethanol intake in grams (P trend 0.03). In men, the “frequent-light” (≥5 times/week and <40 g ethanol/day) drinking pattern was associated with a 46% greater risk of GC (HR 1.46, 95% CI 1.02–2.07) than the “infrequent-light” pattern (<5 times/week and <40 g ethanol/day).Conclusions:This study suggests that frequent intake of alcohol, even in low quantities per session, increases GC risk. Further research is warranted to evaluate the relationship between alcohol and GC in detail.     

Delayed Effect of Dendritic Cells Vaccination on Survival in Glioblastoma: A Systematic Review and Meta-Analysis

Background: Dendritic cell vaccination (DCV) strategies, thanks to a complex immune response, may flare tumor regression and improve patients’ long-term survival. This meta-analysis aims to assess the efficacy of DCV for newly diagnosed glioblastoma patients in clinical trials. Methods: The study databases, including PubMed, Web of Knowledge, Google Scholar, Scopus, and Cochrane, were searched by two blinded investigators considering eligible studies based on the following keywords: “glioblastoma multiforme”, “dendritic cell”, “vaccination”, “immunotherapy”, “immune system”, “immune response”, “chemotherapy”, “recurrence”, and “temozolomide”. Among the 157 screened, only 15 articles were eligible for the final analysis. Results: Regimens including DCV showed no effect on 6-month progression-free survival (PFS, HR = 1.385, 95% CI: 0.822–2.335, p = 0.673) or on 6-month overall survival (OS, HR = 1.408, 95% CI: 0.882–2.248, p = 0.754). In contrast, DCV led to significantly longer 1-year OS (HR = 1.936, 95% CI: 1.396–2.85, p = 0.001) and longer 2-year OS (HR = 3.670, 95% CI: 2.291–5.879, p = 0.001) versus control groups. Hence, introducing DCV could lead to increased 1 and 2-year survival of patients by 1.9 and 3.6 times, respectively. Conclusion: Antitumor regimens including DCV can effectively improve mid-term survival in patients suffering glioblastoma multiforme (GBM), but its impact emerges only after one year from vaccination. These data indicate the need for more time to achieve an anti-GBM immune response and suggest additional therapeutics, such as checkpoint inhibitors, to empower an earlier DCV action in patients affected by a very poor prognosis.     

Identification of potential prognostic biomarkers for hepatocellular carcinoma

BackgroundThe incidence of liver cancer is increasing every year. Hepatocellular carcinoma (HCC) accounts for nearly 90% of liver cancer, and the overall 5-year survival rate of become of Hepatocellular carcinoma patients less than 20%. However, the molecular mechanism of HCC progression and prognosis still requires further exploration.MethodsIn this study, we downloaded the gene expression data from the Cancer Genome Atlas (TCGA) Genomic Data and the official website of GEO database. Weighted gene co-expression network analysis (WGCNA) and Pearson’s correlation coefficient were utilized to detect the gene modules. The shared differentially-expressed genes (DEGs) were screened out by a Venn diagram, and the hub genes were identified through protein-protein interaction (PPI) network analyses. GO and KEGG enrichment analyses were constructed for these hub genes. Overall survival (OS) and correlation analysis were conducted to investigate the relationship between the hub genes and clinical features.ResultsWe screened out 27 shared DEGs, and the mainly enriched GO terms were mitotic nuclear division, chromosomal region, and tubulin binding. Furthermore, the top three enriched KEGG pathways were “cell cycle”, “oocyte meiosis”, and “p53 signaling pathway”. According to the Maximal Clique Centrality (MCC) algorithm, the top 10 candidate hub genes were MYC, MCM3, CDC20, CCNB1, BIRC5, UBE2C, TOP2A, RRM2, TK1, and PTTG1, among which BIRC5, CDC20, and UBE2C showed a strong correlation with the OS.ConclusionsThree hub genes (BIRC5, CDC20, and UBE2C) were identified and found to be correlated to the progression and prognosis of HCC. These may become potential targets for HCC therapy.     

Evaluation of quality of life and anxiety and depression levels in patients receiving chemotherapy for colorectal cancer: impact of patient education before treatment initiation

Background

As a consequence of the improved survival due to the availability of several treatment option cost-effectiveness and health-related quality of life (HRQoL) issues have gained increasing attention in colorectal cancer (CRC). In the present study, we aimed to evaluate quality of life, level of anxiety and depression before and after a 6-month follow-up period in chemotherapy receiving patients with CRC.

Methods

The study was conducted in 50 patients with colon or rectal cancer. All patients were informed and educated about their disease and treatment before getting the treatment and were followed for 6 months, during which they received chemotherapy. A “Questionnaire Form” to collect patient demographic characteristics; the “EORTC QLQ-C30 Scale” and “EQ-5D Scale” to evaluate patient’s quality of life; and the “Hospital Anxiety and Depression (HAD) Scale” to evaluate the level of anxiety and depression status of patients, were used as data collecting tools.

Results

Quality of life scores in all functional fields were high in the sixth course when compared to the first according to EORTC QLQ-C30 Scale, reaching to statistically significant level in emotional function score compared to the initial ones (P<0.05). Moreover quality of life score measured in the sixth month with EQ-5D was statistically significantly higher than the initial.

Conclusions

These data, shows that with proper patient management, quality of life score, and the anxiety and depression levels improve during the course of treatment.     

MLH1 promoter hypermethylation predicts poorer prognosis in mismatch repair deficiency endometrial carcinomas

ObjectiveThe antitumor effects of anti-PD-1 antibody against mismatch repair deficiency (MMR-D)-associated cancers have been reported. MMR-D is found in approximately 20%–30% of endometrial carcinomas (ECs) and frequently occurs due to MLH1 promoter hypermethylation (MLH1-PHM). ECs with MLH1-PHM are classified according to the molecular screening of Lynch syndrome (LS), but few detailed reports are available. The purpose of this study was to clarify the clinical features of EC with MLH1-PHM.MethodsImmunohistochemistry of MMR proteins (MLH1, MSH2, MSH6, and PMS2) was performed on specimens from 527 ECs treated at our university hospital from 2003 to 2018. MLH1 methylation analysis was added to cases with MLH1/PMS2 loss. ECs were classified as follows: cases that retained MMR proteins as “MMR-proficient;” cases with MLH1/PMS2 loss and MLH1-PHM as “met-EC;” and cases with other MMR protein loss and MLH1/PMS2 loss without MLH1-PHM as “suspected-LS.” The clinical features, including long-term prognosis, of each group, were analyzed.ResultsAccordingly, 419 (79.5%), 65 (12.3%), and 43 (8.2%) cases were categorized as “MMR-proficient,” “suspected-LS,” and “met-EC,” respectively. Significantly, “met-EC” had a lower proportion of grade 1 tumors (37.5%) and a higher proportion of stage III/IV tumors (37.2%) than the other groups. The overall and progression-free survival of “met-EC” were significantly worse than those of “suspected-LS” in all cases.ConclusionIn ECs with MMR-D, “met-ECs” were a subgroup with a poorer prognosis than “suspected-LS.” “Met-ECs” would be the main target for anti-PD-1 antibody treatment, and its clinical susceptibility should be verified individually.     

Low probability of disease cure in advanced ovarian carcinomas before the PARP inhibitor era

Background In ovarian carcinomas, the likelihood of disease cure following first-line medical-surgical treatment has been poorly addressed. The objective was to: (a) assess the likelihood of long-term disease-free (LDF) > 5 years; and (b) evaluate the impact of the tumour primary chemosensitivity (assessed with the modelled CA-125 KELIM) with respect to disease stage, and completeness of debulking surgery.Methods Three Phase III trial datasets (AGO-OVAR 9; AGO-OVAR 7; ICON-7) were retrospectively investigated in an “adjuvant dataset”, whilst the Netherlands Cancer Registry was used in a “neoadjuvant dataset”. The prognostic values of KELIM, disease stage and surgery outcomes regarding the likelihood of LDF were assessed using univariate/multivariate analyses.Results Of 2029 patients in the “adjuvant dataset”, 82 (4.0%) experienced LDF (Stage I–II: 25.9%; III: 2.1%; IV: 0.5%). Multivariate analyses identified disease stage and KELIM (OR = 4.24) as independent prognostic factors. Among the 1452 patients from the “neoadjuvant dataset”, 36 (2.4%) had LDF (Stage II–III: 3.3%; IV: 1.3%). Using multivariate tests, high-risk diseases (OR = 0.18) and KELIM (OR = 2.96) were significant.Conclusion The probability of LDF > 5 years after first-line treatment in 3486 patients (<4%) was lower than thought. These data could represent a reference for future studies meant to assess progress related to PARP inhibitors.Subject terms: Medical research, Ovarian cancer     

Inflammatory bowel disease in Ashkenazi Jews: implications for familial colorectal cancer

Inflammatory bowel disease (IBD) has a multifactorial etiology and includes ulcerative colitis (UC) and Crohn's disease (CD). Powerful epidemiologic and genetic studies have provided ample evidence that a subset of both CD and UC are attributable to a likely primary genetic etiology. This is evidenced by the recent identification of the IBD1 gene (NOD2) mutations which show an association with susceptibility to CD. The IBD complex shows a significant increased frequency in Jews when compared to non-Jews. While there is an increased incidence of colorectal cancer (CRC) in patients with IBD, it nevertheless is important to realize that IBD likely accounts for no more than 1–3% of all cases of CRC in Ashkenazi Jews. Importantly, however, awareness of the increased CRC risk in IBD may aid immeasurably in preventive interventions. The molecular pathway leading to CRC in IBD appears to differ from the well-known adenoma-to-CRC sequence, given the fact that these cancers appear to arise from either flat, dysplastic tissue or dysplasia-associated lesions or masses (DALMs). An important model, but by no means an absolute one, for colon carcinogenesis in IBD follows progression from an absence of dysplasia, to indefinite dysplasia, to low-grade dysplasia, on to high-grade dysplasia, and ultimately to invasive CRC. This carcinogenic process relates to the disease duration with respect to the extent of colonic involvement and may also involve primary sclerosing cholangitis. Given this knowledge of an increased risk for CRC in UC and CD, surveillance colonoscopy should initially be performed 8–10 years after onset of symptoms as opposed to diagnosis, and it should be performed 1–2 years after 8 years of disease in patients with pancolitis or after 15 years in those with left-sided colitis. A search for dysplasia of colonic mucosa with biopsies performed in all four quadrants every 10 cm throughout the colon is exceedingly important. Additional biopsies should be taken of any flat lesions, masses, or strictures. Prophylactic colectomy may then be indicated when severe dysplasia is confirmed by knowledgeable pathologists.