Risk of Suicide After Cancer Diagnosis in England.

Importance: A diagnosis of cancer carries a substantial risk of psychological distress. There has not yet been a national population-based study in England of the risk of suicide after cancer diagnosis. Objectives: To quantify suicide risk in patients with cancers in England and identify risk factors that may assist in needs-based psychological assessment. Design, Setting, and Participants: Population-based study using data from the National Cancer Registration and Analysis Service in England linked to death certification data of 4 722 099 individuals (22 million person-years at risk). Patients (aged 18-99 years) with cancer diagnosed from January 1, 1995, to December 31, 2015, with follow-up until August 31, 2017, were included. Exposures: Diagnosis of malignant tumors, excluding nonmelanoma skin cancer. Main Outcomes and Measures: All deaths in patients that received a verdict of suicide or an open verdict at the inquest. Standardized mortality ratios (SMRs) and absolute excess risks (AERs) were calculated. Results: Of the 4 722 099 patients with cancer, 50.3% were men and 49.7% were women. A total of 3 509 392 patients in the cohort (74.3%) were aged 60 years or older when the diagnosis was made. A total of 2491 patients (1719 men and 772 women) with cancer died by suicide, representing 0.08% of all deaths during the follow-up period. The overall SMR for suicide was 1.20 (95% CI, 1.16-1.25) and the AER per 10 000 person-years was 0.19 (95% CI, 0.15-0.23). The risk was highest among patients with mesothelioma, with a 4.51-fold risk corresponding to 4.20 extra deaths per 10 000 person-years. This risk was followed by pancreatic (3.89-fold), esophageal (2.65-fold), lung (2.57-fold), and stomach (2.20-fold) cancer. Suicide risk was highest in the first 6 months following cancer diagnosis (SMR, 2.74; 95% CI, 2.52-2.98). Conclusions and Relevance: Despite low absolute numbers, the elevated risk of suicide in patients with certain cancers is a concern, representing potentially preventable deaths. The increased risk in the first 6 months after diagnosis may indicate an unmet need for psychological support. The findings of this study suggest a need for improved psychological support for all patients with cancer, and attention to modifiable risk factors, such as pain, particularly in specific cancer groups.

Mucosectomy with handsewn anastomosis reduces the risk of adenoma formation in the anorectal segment after restorative proctocolectomy for familial adenomatous polyposis.

OBJECTIVE: The study compared the risk of adenoma or carcinoma formation in the anorectal segment after either mucosectomy with manual anastomosis or stapled ileoanal anastomosis (IAA) following restorative proctocolectomy (RPC) for familial adenomatous polyposis (FAP). BACKGROUND: Few data exist on the risk of adenoma formation after either technique in FAP. METHODS: All endoscopy and histology reports for patients having RPC for FAP attending for annual pouchoscopy from 1978 to 2007 were reviewed. The incidence, timing, and histological characteristics of adenoma or carcinoma formation were recorded. RESULTS: Of the 206 patients, 140 attended for endoscopic follow-up for a median of 10.3 years after RPC. Fifty-two patients developed neoplastic transformation in the anorectal segment, with a cumulative risk at 10 years of 22.6% after mucosectomy with manual anastomosis and 51.1% after stapled IAA (P < 0.001). The median time to first adenoma was longer after mucosectomy with handsewn anastomosis than after stapled IAA (10.1 vs 6.5 years, P < 0.001). On multivariate analysis, stapled IAA (hazard ratio= 3.45, 95% confidence interval = 1.01­4.98) and age at RPC older than 40 years (hazard ratio = 2.20, 95% confidence interval = 1.01­4.89) were significantly associated with increased risk of adenoma formation. Nine patients developed a large (>10 mm) adenoma. One patient (handsewn ileoanal anastomosis) developed adenocarcinoma in the anorectal mucosa at 13 years and required pouch excision. CONCLUSIONS: Adenoma formation in the anorectal mucosa after RPC for FAP is common but carcinoma is rare. The risk is lower after mucosectomy with handsewn anastomosis than after stapled IAA. Regular endoscopic surveillance after either technique is mandatory.

Clonality assessment and clonal ordering of individual neoplastic crypts shows polyclonality of colorectal adenomas.

BACKGROUND & AIMS: According to the somatic mutation theory, monoclonal colorectal lesions arise from sequential mutations in the progeny of a single stem cell. However, studies in a sex chromosome mixoploid mosaic (XO/XY) patient indicated that colorectal adenomas were polyclonal. We assessed adenoma clonality on an individual crypt basis and completed a genetic dependency analysis in carcinomas-in-adenomas to assess mutation order and timing. METHODS: Polyp samples were analyzed from the XO/XY individual, patients with familial adenomatous polyposis and attenuated familial adenomatous polyposis, patients with small sporadic adenomas, and patients with sporadic carcinoma-in-adenomas. Clonality was analyzed using X/Y chromosome fluorescence in situ hybridization, analysis of 5q loss of heterozygosity in XO/XY tissue, and sequencing of adenomatous polyposis coli. Individual crypts and different phenotypic areas of carcinoma-in-adenoma lesions were analyzed for mutations in adenomatous polyposis coli, p53, and K-RAS; loss of heterozygosity at 5q, 17p, and 18q; and aneuploidy. Phylogenetic trees were constructed. RESULTS: All familial adenomatous polyposis-associated adenomas and some sporadic lesions had polyclonal genetic defects. Some independent clones appeared to be maintained in advanced adenomas. No clear obligate order of genetic events was established. Top-down growth of dysplastic tissue into neighboring crypts was a possible mechanism of clonal competition. CONCLUSIONS: Human colorectal microadenomas are polyclonal and may arise from a combination of host genetic features, mucosal exposures, and active crypt interactions. Analyses of tumor phylogenies show that most lesions undergo intermittent genetic homogenization, but heterotypic mutation patterns indicate that independent clonal evolution can occur throughout adenoma development. Based on observations of clonal ordering the requirement and timing of genetic events during neoplastic progression may be more variable than previously thought.

RUNX3 inactivation in colorectal polyps arising through different pathways of colonic carcinogenesis.

OBJECTIVES: We hypothesized that RUNX3 inactivation by promoter hypermethylation in colorectal polyps is an early molecular event in colorectal carcinogenesis. METHODS: RUNX3 protein expression was analyzed immunohistochemically in 50 sporadic colorectal polyps comprising 19 hyperplastic polyps (HPs), 14 traditional serrated adenomas (TSAs), and 17 sporadic traditional adenomas (sTAs) as well as in 19 familial adenomatous polyposis (FAP) samples from 10 patients showing aberrant crypt foci (ACF) (n=91), small adenomas (SmAds) (n=40), and large adenomas (LAds) (n=13). In addition, we assessed the frequency of promoter hypermethylation of RUNX3 by methylation-specific PCR (MSP) in all the 50 sporadic polyps as well as 38 microdissected FAP polyps comprising ACF, SmAds, and LAds obtained from 7 FAP samples. A total of 12 normal colon samples were also included for RUNX3 MSP analysis. RESULTS: Compared to normal colon (2 of 12, 16%) and sTAs (3 of 17, 18%), HPs (15 of 19, 79%) and TSAs (8 of 14, 57%) displayed significant inactivation of RUNX3 (P<0.05). In FAP, RUNX3 inactivation was more frequently seen in ACF (78 of 91, 86%), SmAds (25 of 40, 62%), and LAds (6 of 13, 46%) compared to normal mucosa (0 of 19, 0%) in the same samples (all P<0.05). Promoter hypermethylation of RUNX3 was significantly higher in colorectal polyps (64 of 87, 74%) compared to normal colon (2 of 12, 16%) (P=0.001). Serrated polyps such as HPs (17 of 19, 89%) and TSAs (12 of 14, 86%) were significantly more methylated than sTAs (7 of 17, 44%) (P=0.004). RUNX3 hypermethylation was observed in 28 of the total 38 (74%) FAP polyps. Overall, RUNX3 promoter methylation correlated with inactivation of RUNX3 expression in sporadic (27 of 36, 75%) (P=0.022) and FAP (21 of 28, 75%) (P=0.021) polyps. CONCLUSIONS: Our data suggest that RUNX3 inactivation due to promoter hypermethylation in colorectal polyps represents an early event in colorectal cancer (CRC) progression. In addition, epigenetic RUNX3 inactivation is a frequent event in the serrated colonic polyps as well as in the ACF of FAP polyps.

Homozygous PMS2 deletion causes a severe colorectal cancer and multiple adenoma phenotype without extraintestinal cancer.

BACKGROUND & AIMS: We report a patient of Indian descent with parental consanguinity, who developed 10 carcinomas and 35 adenomatous polyps at age 23 and duodenal adenocarcinoma at age 25. He also had dysmorphic features, mental retardation, and café-au-lait spots but no brain tumor. We aimed to establish his molecular diagnosis. METHODS: Germ-line screening for APC and MYH/MUTYH mutations was normal as was immunohistochemistry for MLH1 and MSH2 proteins. Investigation by array-comparative genomic hybridization revealed deletion of a small region on chromosome 7. Using polymerase chain reaction, this region was refined to a 400-kilobase deletion, which included exons 9-15 of the PMS2 gene, and all coding regions of oncomodulin, TRIAD3, and FSCN1. RESULTS: The deletion was confirmed as homozygous, and both parents were carriers. Immunohistochemistry showed absent PMS2 expression in all tumors and normal tissue. Most tumors showed microsatellite instability, more marked at dinucleotide than mononucleotide repeats. The tumors harbored no somatic mutations in APC, BRAF, AXIN2, or beta-catenin, but KRAS2 and TGFBR2 mutations were found. CONCLUSIONS: Our patient represents a novel phenotype for homozygous PMS2 mutation and perhaps the most severe colorectal cancer phenotype-in terms of numbers of malignancies at an early age-described to date. PMS2 mutations-and perhaps other homozygous mismatch repair mutations-should be considered in any patient presenting with multiple gastrointestinal tumors, since our patient could not be distinguished clinically from cases with attenuated familial adenomatous polyposis or MUTYH-associated polyposis.

Diagnostic precision of nanoparticle-enhanced MRI for lymph-node metastases: a meta-analysis.

BACKGROUND: At present, there is no accepted, ideal imaging modality or technique for diagnosis of lymph-node metastases. We aimed to assess the diagnostic precision of MRI with ferumoxtran-10-an ultrasmall superparamagnetic iron-oxide nanoparticle used as a contrast agent for diagnosis of lymph-node metastases, compared with that of unenhanced MRI and final histological diagnosis. METHODS: We did a meta-analysis of prospective studies that compared MRI, with and without ferumoxtran-10, with histological diagnosis after surgery or biopsy. Sensitivity, specificity, and diagnostic odds ratio (DOR) were calculated for every study; summary receiver operating characteristic (ROC) and subgroup analyses were done; and study quality and heterogeneity were assessed. Metaregression analysis was used to analyse the effect of ferumoxtran-10 in diagnostic precision of MRI. FINDINGS: Summary ROC curve analysis for per-lymph-node data showed an overall sensitivity of 0.88 (95% CI 0.85-0.91) and overall specificity of 0.96 (0.95-0.97) for ferumoxtran-10-enhanced MRI. Overall weighted area under the curve for ferumoxtran-10-enhanced MRI was 0.96 (SE 0.01), DOR 123.05 (95% CI 5.93-256.93). Unenhanced MRI had less overall sensitivity (0.63 [0.57-0.69]) and specificity (0.93 [0.91-0.94]), with an overall weighted area under the ROC curve of 0.84 (SE 0.11) and DOR of 26.75 (95% CI 8.48-84.42). Significant heterogeneity was noted for studies reporting enhanced MRI and unenhanced MRI. Metaregression analysis confirmed the significant effect of ferumoxtran-10 in the diagnostic precision of MRI (p=0.001). INTERPRETATION: Ferumoxtran-10-enhanced MRI is sensitive and specific in detection of lymph-node metastases for various tumours. It offers higher diagnostic precision than does unenhanced MRI for detection of lymph-node metastases, and allows functional and anatomical definition when used as an imaging modality.