Colorectal adenocarcinomas diagnosed following a negative faecal immunochemical test show high-risk pathological features in a colon screening programme.

AIMS: The faecal immunochemical test (FIT) is used every 2 years to screen average-risk British Columbians aged 50-74 years, with follow-up colonoscopy for positive results. Non-screen-detected colorectal adenocarcinomas are defined as those detected within 25 months following a negative FIT. We aimed to more clearly characterise these malignancies. METHODS AND RESULTS: A medical chart and focused pathology review of colorectal malignancies from 926 individuals who completed FIT in the British Columbia Colon Screening Program in 2014, and whose pathology reports were available for review, was conducted. This cohort was divided into two groups: individuals with colorectal adenocarcinomas diagnosed following a positive FIT (screen-detected) and individuals with colorectal adenocarcinoma diagnosed within 25 months of a negative FIT (FIT-interval cancers). Rates of clinically relevant pathological parameters, as outlined in the American Joint Committee on Cancer (AJCC), 8th edition, were compared between the screen-detected and FIT-interval cancer groups. A total of 876 screen-detected and 50 FIT-interval cancers were identified. FIT-interval cancers exhibited higher rates of high-grade differentiation (including poorly differentiated and undifferentiated cases; P < 0.01) and aggressive histotype (signet ring cell and mucinous carcinomas; P < 0.01) than did screen-detected cancers after Bonferroni correction. Colorectal adenocarcinoma diagnosed after a negative FIT may therefore be associated with worse prognostic determinants than screen-detected cancers. CONCLUSION: FIT-interval cancers are associated with high-risk pathological features; the possibility that more aggressive, fast-growing lesions which arise in the interval after truly negative FITs cannot be ruled out. Further study of a larger cohort of FIT-interval cancers controlling for interaction among the different pathologic parameters will be undertaken.

Should you repeat mismatch repair testing in cases of tumour recurrence? An evaluation of repeat mismatch repair testing by the use of immunohistochemistry in recurrent tumours of the gastrointestinal and gynaecological tracts.

AIMS: The role of mismatch repair (MMR) testing has evolved from identifying Lynch syndrome patients to predicting response to immune checkpoint inhibitors. This has led to requests from clinicians to retest recurrences of MMR-proficient primary tumours in the hope that the recurrence may show a different MMR status and qualify the patient for treatment. We aimed to determine whether repeat testing is warranted. METHODS AND RESULTS: We evaluated recurrent tumours (local recurrences or metastases) from 137 patients with MMR-proficient primary tumours of the gastrointestinal and gynaecological tracts. The local recurrences and metastases all occurred at least 30 days after resection of the primary tumour. We used a combination of a tissue microarray and whole slide staining to perform immunohistochemistry (IHC) for PMS2, MLH1, MSH2, and MSH6, and compared the results with the MMR status of the primary tumour. Three of 137 (2%) initially showed a discordant staining pattern. However, further investigation showed that these discordances were attributable to some of the known pitfalls associated with MMR IHC interpretation - post-radiotherapy loss of MSH6 expression and subclonal loss of MLH1 staining. We did not identify any cases with a genuine discordance in MMR status. CONCLUSION: We conclude that repeat MMR IHC testing of recurrences is not warranted, as MMR status does not change relative to that of the primary tumour.

Metastatic Gallbladder Adenocarcinoma to the Endometrium: A Case Report and Review of Literature.

Gallbladder carcinoma (GBC) metastasis to the uterine cervix is very rare, accounting for less than 10 reported cases. GBC is an uncommon neoplasm with a poor prognosis. Many patients remain asymptomatic until it reaches an advanced stage or discovered incidentally. Most metastatic diseases occur in the lung, liver, and bones. We report a case of a patient treated for GBC with a good clinical response, who presented with metastasis in the uterine cervix. Uterine cervix metastasis from any extragenital primary is rare and poses a radiologic, pathologic, and clinical diagnostic challenge. Here, we review and discuss the published literature on uterine cervix metastasis from extragenital sources. Gynecologic clinicians should be wary of these rare presentations of metastatic disease, as the diagnosis can alter the management.

Cytohistological diagnosis of pancreatic serous cystadenoma: a multimodal approach.

AIMS: Serous cystadenomata (SCAs) are benign pancreatic cystic neoplasms that present a diagnostic challenge despite many investigational approaches. Notwithstanding the promise of molecular diagnostics, these tests have limited accessibility in day-to-day surgical pathology practices. We aim to corroborate and build on recent evidence which suggests that positive α-inhibin immunohistochemistry (IHC) is a helpful adjunct in the biopsy confirmation of pancreatic SCA. METHODS: We retrospectively reviewed 22 fine-needle aspirates/biopsies from 14 patients (mean age 65 years, 47-83 years) with pancreatic multicystic lesions radiologically suspicious for SCA (location: 6 body, 2 head, 4 tail, 1 neck, 1 uncinate; cyst size: mean 3.7 cm, 2.0-7.6 cm), as well as an additional 10 pancreatic resection specimens with confirmed SCA; α-inhibin IHC was performed on all cell blocks, biopsy slides and representative resection specimen sections. Where available, associated cyst fluid was analysed for correlative vascular endothelial growth factor A (VEGF-A) and carcinoembryonic antigen levels. RESULTS: An α-inhibin IHC sensitivity of 80% was observed in the cases with resection confirmed SCA. Of the fine-needle aspirate/biopsy specimens, 59% (13/22) contained epithelial cells strongly positive for α-inhibin. When selecting for specimens that exhibited distinct strips of epithelium, the α-inhibin strong positivity rate increased to 73% (8/11). VEGF-A values were supportive of false-negative α-inhibin IHC in three cases and true-negative α-inhibin IHC in one case. CONCLUSION: This study postulates a diagnostic algorithm to confirm pancreatic SCA which may help to decrease unnecessary follow-up endoscopy/surgical resection and would decrease the associated morbidity, mortality and financial costs in patients with this otherwise benign condition.

Genomic characterization of a well-differentiated grade 3 pancreatic neuroendocrine tumor.

Pancreatic neuroendocrine neoplasms (PanNENs) represent a minority of pancreatic neoplasms that exhibit variability in prognosis. Ongoing mutational analyses of PanNENs have found recurrent abnormalities in chromatin remodeling genes (e.g., DAXX and ATRX), and mTOR pathway genes (e.g., TSC2, PTEN PIK3CA, and MEN1), some of which have relevance to patients with related familial syndromes. Most recently, grade 3 PanNENs have been divided into two groups based on differentiation, creating a new group of well-differentiated grade 3 neuroendocrine tumors (PanNETs) that have had a limited whole-genome level characterization to date. In a patient with a metastatic well-differentiated grade 3 PanNET, our study utilized whole-genome sequencing of liver metastases for the comparative analysis and detection of single-nucleotide variants, insertions and deletions, structural variants, and copy-number variants, with their biologic relevance confirmed by RNA sequencing. We found that this tumor most notably exhibited a TSC1-disrupting fusion, showed a novel CHD7-BEND2 fusion, and lacked any somatic variants in ATRX, DAXX, and MEN1.

PGE2 production at sites of tissue injury promotes an anti-inflammatory neutrophil phenotype and determines the outcome of inflammation resolution in vivo.

Neutrophils are the first immune cells recruited to a site of injury or infection, where they perform many functions. Having completed their role, neutrophils must be removed from the inflammatory site-either by apoptosis and efferocytosis or by reverse migration away from the wound-for restoration of normal tissue homeostasis. Disruption of these tightly controlled physiological processes of neutrophil removal can lead to a range of inflammatory diseases. We used an in vivo zebrafish model to understand the role of lipid mediator production in neutrophil removal. Following tailfin amputation in the absence of macrophages, neutrophillic inflammation does not resolve, due to loss of macrophage-dependent handling of eicosanoid prostaglandin E2 (PGE2) that drives neutrophil removal via promotion of reverse migration. Knockdown of endogenous PGE synthase gene reveals PGE2 as essential for neutrophil inflammation resolution. Furthermore, PGE2 is able to signal through EP4 receptors during injury, causing an increase in Alox12 production and switching toward anti-inflammatory eicosanoid signaling. Our data confirm regulation of neutrophil migration by PGE2 and LXA4 (lipoxin A4) in an in vivo model of inflammation resolution. This pathway may contain therapeutic targets for driving inflammation resolution in chronic inflammatory disease.

Why do women not return family history forms when referred to breast cancer genetics services? A mixed-method study.

BACKGROUND: Personal and family data forms, completed by women referred to breast cancer genetics clinics, are valuable tools for verification and extension of family history, crucial steps in accurate risk evaluation. A significant minority of women do not complete and return these forms, despite reminders, even when completion is a pre-requisite for a clinic appointment. OBJECTIVE: To facilitate access of women at increased familial risk of breast cancer to screening and counselling services by investigating reasons for non-return of the forms. PARTICIPANTS AND DESIGN: Based on a single regional 'breast cancer family' service in the UK, Analysis of quantitative data comparing women who did not return forms (n = 55) with those who had done so (n = 59), together with qualitative evaluation of potential barriers to form-completion through semi-structured telephone interviews with a random subset of 'non-returners' (n = 23). RESULTS: Non-returners have higher proportions of the very young (below the age at which surveillance could be offered) and of women from lower social deprivation categories. Interviews revealed that the majority of non-returners are anxious, rather than unconcerned about their breast cancer risk and circumstances and attitudes contributed to non-compliance. Twenty-one participants confirmed that they would welcome an appointment at a 'breast cancer family' clinic, but nine did not attend for the appointment. They were significantly younger than those who attend, but were not at lower familial risk. DISCUSSION AND CONCLUSIONS: Many women who fail to complete and return a family history form would benefit from risk assessment and genetic counselling. Several steps are suggested that might help them access the relevant services.

Oral contraceptive use and BRCA penetrance: a case-only study.

BACKGROUND: Women with deleterious mutations in BRCA genes are at increased risk of breast cancer. However, the penetrance of the genetic trait may be regulated through environmental factors. This multinational case-only study tested the interaction between oral contraceptive use and genetic susceptibility in the occurrence of breast cancer. METHODS: We recruited 3,123 patients diagnosed with breast cancer before the age of 45 years. Participants were classified according to their probability of carrying a BRCA mutation on the basis of their family history of breast and ovarian cancer. According to a case-only approach, the frequency of relevant exposures among breast cancer cases with high probability of BRCA mutation ("genetic cases") was compared with the frequency of the same exposures among breast cancer cases with a low probability of BRCA mutation ("sporadic cases"). The interaction odds ratios (OR) and 95% confidence intervals (CI) for oral contraceptive use were estimated by unconditional logistic regression, after controlling for potentially confounding variables. RESULTS: The analysis was carried out comparing 382 "genetic" and 1,333 "sporadic" cases. We found a borderline significant interaction between genetic breast cancer and oral contraceptive use for ever users compared with never users (OR, 1.3; 95% CI, 1.0-1.7). The greatest interaction OR was found for women who started using pill at 18 to 20 years (OR, 1.6; 95% CI, 1.1-2.3). CONCLUSION: These results suggest that BRCA mutation carriers, as well as women with a significant family history of breast and ovarian cancer are more vulnerable to exogenous hormones in oral contraceptives.

Predicting breast cancer risk: implications of a "weak" family history.

Published guidelines adopted in many countries recommend that women whose family history of breast cancer places them at a risk>or=1.7 times that of the age-matched general population, should be considered for inclusion in special surveillance programmes. However validation of risk assessment models has been called for as a matter of urgency. The databases of the four Scottish Familial Breast Cancer clinics and the Scottish Cancer Registry have been searched to identify breast cancers occurring among 1,125 women aged 40-56, with family histories placing them below the "moderate" level of genetic risk. The observed incidence over 6 years was compared with age-specific data for the Scottish population. Our findings confirm that when there are two affected relatives (one first degree) the relative risk (RR) exceeds 1.7 regardless of their ages at diagnosis. When only one (first degree) relative was affected at any age from 40 to 55, the RR does not reach 1.7 if that relative was a mother but exceeds it if the relative was a sister. The probable explanation is that sisters are more likely than mother/daughter pairs to share homozygosity for a risk allele. Surveillance programmes might therefore accommodate sisters of women affected before age 55. Evidence that "low penetrance" alleles contributing to breast cancer risk may be recessive should be taken into account in strategies for identifying them.

Evaluation of the current knowledge limitations in breast cancer research: a gap analysis.

BACKGROUND: A gap analysis was conducted to determine which areas of breast cancer research, if targeted by researchers and funding bodies, could produce the greatest impact on patients. METHODS: Fifty-six Breast Cancer Campaign grant holders and prominent UK breast cancer researchers participated in a gap analysis of current breast cancer research. Before, during and following the meeting, groups in seven key research areas participated in cycles of presentation, literature review and discussion. Summary papers were prepared by each group and collated into this position paper highlighting the research gaps, with recommendations for action. RESULTS: Gaps were identified in all seven themes. General barriers to progress were lack of financial and practical resources, and poor collaboration between disciplines. Critical gaps in each theme included: (1) genetics (knowledge of genetic changes, their effects and interactions); (2) initiation of breast cancer (how developmental signalling pathways cause ductal elongation and branching at the cellular level and influence stem cell dynamics, and how their disruption initiates tumour formation); (3) progression of breast cancer (deciphering the intracellular and extracellular regulators of early progression, tumour growth, angiogenesis and metastasis); (4) therapies and targets (understanding who develops advanced disease); (5) disease markers (incorporating intelligent trial design into all studies to ensure new treatments are tested in patient groups stratified using biomarkers); (6) prevention (strategies to prevent oestrogen-receptor negative tumours and the long-term effects of chemoprevention for oestrogen-receptor positive tumours); (7) psychosocial aspects of cancer (the use of appropriate psychosocial interventions, and the personal impact of all stages of the disease among patients from a range of ethnic and demographic backgrounds). CONCLUSION: Through recommendations to address these gaps with future research, the long-term benefits to patients will include: better estimation of risk in families with breast cancer and strategies to reduce risk; better prediction of drug response and patient prognosis; improved tailoring of treatments to patient subgroups and development of new therapeutic approaches; earlier initiation of treatment; more effective use of resources for screening populations; and an enhanced experience for people with or at risk of breast cancer and their families. The challenge to funding bodies and researchers in all disciplines is to focus on these gaps and to drive advances in knowledge into improvements in patient care.

Long-term attendance at follow-up of women assessed as being at increased risk of developing breast cancer in south-east Scotland.

BACKGROUND: Women with a family history of breast cancer increasingly seek genetic advice and screening. In the present study we investigated referral rates and factors associated with long-term attendance for screening in Scotland. METHODS: We investigated referral rates to the genetic service over a 21-month period and long-term attendance for screening amongst the 226 women at increased risk of developing breast cancer. RESULTS: The overall annual referral rate was 0.31 per 1,000 patients on general practitioners' lists. Some 98% of women for whom it was appropriate attended at least one screening appointment and 88% were continuing to attend appointments for surveillance up to 5 years later. Attendance was significantly lower among more socially deprived patients (p < 0.01). CONCLUSIONS: These results suggest that as increasing numbers of women with a positive family history seek risk assessment and screening, current facilities may be inadequate.

Provision of breast cancer risk information to women at the lower end of the familial risk spectrum.

BACKGROUND: Breast cancer family clinics provide risk information as one of their key functions. Many referrals to these clinics are 'low-risk' women. OBJECTIVE: It was the aim of this study to report on the generic risk status letters and printed materials (in the form of leaflets) provided to this category of counselees by UK cancer genetics centres. METHODS: A postal survey was conducted requesting information materials from genetic centres. RESULTS: Personalized risk letters and/or printed materials were received from 16 of 22 familial cancer centres in the UK. Personalized risk letters and printed materials currently provided to these counselees display inconsistencies and over-simplification that may lead to misunderstanding. CONCLUSION: There is a need for collaboration among cancer genetics centres to design more helpful and consistent literature.

Analysis of referrals to a multi-disciplinary breast cancer genetics clinic: practical and economic considerations.

Analysis of activity was undertaken in an established regional clinic providing risk assessment, counselling, screening and management for women with a family history of breast or ovarian cancer. The objectives were to determine: (1) how closely the route and pattern of referrals matched official guidelines (2) whether the previously recorded socio-economic imbalance among clinic clientele persisted and (3) the economic and practical consequences of committing resources to verification and extension of reported family histories. The findings were: (1) after some years of operation, the proportion of referrals direct from primary care had increased from less than 50% to over 75%, with a concomitant slight decrease in overall referral rate; (2) the socio-economic distribution of patients referred had become less selective and (3) extension and verification of reported family histories led to a redistribution of risk categories, increasing the proportion of referrals judged to be in the "low risk" category, from 25% (based on referral letter alone) to 41% (at the end of the process). The costs associated with this approach are offset by the savings generated and it allows specialised counselling and screening services to be targeted more efficiently.