K J Monahan

EUS-guided FNA for diagnosis of solid pancreatic neoplasms: a meta-analysis.

BACKGROUND Preoperative diagnosis of solid pancreatic lesions remains challenging despite advancement in imaging technologies. EUS has the benefit of being a minimally invasive, well-tolerated procedure, although results are operator-dependent. The addition of FNA (EUS-guided FNA) provides samples for cytopathologic analysis, a major advantage over other imaging techniques. OBJECTIVE To determine the diagnostic accuracy of EUS-FNA for pancreatic cancer. DESIGN This is a meta-analysis of published studies assessing the diagnostic capability of EUS-FNA. Relevant studies were identified via MEDLINE and were included if they used a reference standard of definitive surgical histology or clinical follow-up of at least 6 months. MAIN OUTCOME MEASUREMENTS Data from selected studies were analyzed by using test accuracy meta-analysis software, providing a pooled value for sensitivity, specificity, diagnostic odds ratio, and summary receiver operating characteristic curve. Cytology results were classified as inadequate, benign, atypical, suspicious, or malignant. Predefined subgroup analysis was performed. RESULTS Thirty-three studies published between 1997 and 2009 were included, with a total number of 4984 patients. The pooled sensitivity for malignant cytology was 85% (95% confidence interval [CI], 84-86), and pooled specificity was 98% (95% CI, 0.97-0.99). If atypical and suspicious cytology results were included to determine true neoplasms, the sensitivity increased to 91% (95% CI, 90-92); however, the specificity was reduced to 94% (95% CI, 93-96). The diagnostic accuracy of EUS-FNA was enhanced in prospective, multicenter studies. LIMITATION Publication bias was not a significant determinant of pooled accuracy. CONCLUSION This meta-analysis demonstrates that EUS-FNA is a highly accurate diagnostic test for solid neoplasms of the pancreas and should be considered when algorithms for investigating solid pancreatic lesions are being planned.

Endoscopic ultrasound guided fine needle aspiration for the diagnosis of pancreatic cystic neoplasms: a meta-analysis.

BACKGROUND AND OBJECTIVES Mucinous cystic neoplasms and intraductal papillary mucinous tumours have greater malignant potential than serous cystic neoplasms. EUS alone is inadequate for characterising these lesions but the addition of FNA may significantly improve diagnostic accuracy. The performance of EUS-FNA is highly variable in published studies. AIM To determine the diagnostic accuracy of EUS-FNA to differentiate mucinous versus non-mucinous cystic lesions with cyst fluid analysis for cytology and carcinoembryonic antigen (CEA) by performing a meta-analysis of published studies. METHODS Relevant studies were identified via structured database search and included if they used a reference standard of definitive surgical histology or clinical follow-up of at least 6 months. Data from selected studies were pooled to give summary sensitivity, specificity, positive and negative likelihood ratios, diagnostic odds ratio and Receiver Operating Characteristic (ROC) curve. Pre-defined subgroup analysis was performed. RESULTS Eighteen studies (published 2002-2011) were included, with a total of 1438 patients. For cytology, pooled sensitivity was 54(95%CI 49-59)% and specificity 93(90-95)%. The diagnostic odds ratio (DOR) was 13.3 (4.37-49.43), with I(2) of 77.1%. For CEA sensitivity was 63(59-67)% and specificity 88(83-91)%. The DOR was 10.76(6.29-18.41) with an I(2) of 25.4%. The diagnostic accuracy of EUS-FNA was enhanced in prospective studies and studies of <36 months duration. No impact of publication bias on our results was demonstrated. CONCLUSIONS Fine-needle aspiration has moderate sensitivity but high specificity for mucinous lesions. EUS-FNA, when used in conjunction with cross sectional imaging, is a useful diagnostic tool for the correct identification of mucinous cysts.

Critical research gaps and recommendations to inform research prioritisation for more effective prevention and improved outcomes in colorectal cancer

Objective Colorectal cancer (CRC) leads to significant morbidity/mortality worldwide. Defining critical research gaps (RG), their prioritisation and resolution, could improve patient outcomes. Design RG analysis was conducted by a multidisciplinary panel of patients, clinicians and researchers (n=71). Eight working groups (WG) were constituted: discovery science; risk; prevention; early diagnosis and screening; pathology; curative treatment; stage IV disease; and living with and beyond CRC. A series of discussions led to development of draft papers by each WG, which were evaluated by a 20-strong patient panel. A final list of RGs and research recommendations (RR) was endorsed by all participants. Results Fifteen critical RGs are summarised below: RG1: Lack of realistic models that recapitulate tumour/tumour micro/macroenvironment; RG2: Insufficient evidence on precise contributions of genetic/environmental/lifestyle factors to CRC risk; RG3: Pressing need for prevention trials; RG4: Lack of integration of different prevention approaches; RG5: Lack of optimal strategies for CRC screening; RG6: Lack of effective triage systems for invasive investigations; RG7: Imprecise pathological assessment of CRC; RG8: Lack of qualified personnel in genomics, data sciences and digital pathology; RG9: Inadequate assessment/communication of risk, benefit and uncertainty of treatment choices; RG10: Need for novel technologies/interventions to improve curative outcomes; RG11: Lack of approaches that recognise molecular interplay between metastasising tumours and their microenvironment; RG12: Lack of reliable biomarkers to guide stage IV treatment; RG13: Need to increase understanding of health related quality of life (HRQOL) and promote residual symptom resolution; RG14: Lack of coordination of CRC research/funding; RG15: Lack of effective communication between relevant stakeholders. Conclusion Prioritising research activity and funding could have a significant impact on reducing CRC disease burden over the next 5 years.

Endoscopic ultrasound guided fine needle aspiration for the diagnosis of pancreatic cystic neoplasms: A meta-analysis

Introduction Pancreatic cystic neoplasms consist of mucinous cystic neoplasms (MCNs) and serous cystic neoplasms (SCNs). MCNs have significantly greater malignant potential, and if resected early the prognosis is excellent, although mortality is 2%–3%. Endoscopic ultrasound is a minimally invasive and well tolerated procedure. EUS with fine-needle aspiration (EUS-FNA) provides samples for cytology and fluid analysis, a major advantage over other techniques. However the diagnostic accuracy of EUS-FNA is highly variable in published studies. Aim To determine the diagnostic accuracy of EUS-FNA to differentiate mucinous vs non-mucinous cystic lesions with morphology, and cyst fluid analysis for cytology and carcinoembryonic antigen (CEA) via a meta-analysis of published studies. Methods Relevant studies were identified using MEDLINE and included if they used a reference standard of definitive surgical pathology or clinical follow-up (≥6 months). Study quality was assessed using the STARD (STAndards for the Reporting of Diagnostic Accuracy) initiative criteria. Data were analysed using Meta-DiSc© v.1.4, which generated pooled estimates for sensitivity, specificity and summary ROC curve. Subgroups, determined a priori, were used to assess heterogeneity: prospective vs retrospective, location, number of centres and patients, 19G or 22G needle and STARD score. Results 24 studies published between 2001 and 2011 were included, a total of 1703 patients. The median number of patients in each study was 53 (range 18–197) and the median study length was 54 (12–144) months. The pooled sensitivities (95% CI) and specificities (95% CI) and area under the sROC curve (SE), respectively, were: EUS morphology 55 (49–61)%, 65 (57–72)% and 0.74 (0.095); Cytology 54 (50–59)%, 93 (90–95)% and 0.95 (0.040); and CEA 63 (59–67)%, 88 (83–91)% and 0.79 (0.034). Subgroup analysis indicated that retrospective design, low STARD score and study location outside Europe were significant sources of heterogeneity. Conclusion Fine-needle aspiration has moderate sensitivity but high specificity resulting in good overall diagnostic accuracy for MCNs. Morphology alone is inadequate for distinguishing cystic lesions but may contribute to the assessment of more advanced lesions. The moderate sensitivity of FNA (54%) means a significant proportion of MCNs will not be detected. However, the high specificity (93%) means that a positive result is strongly indicative of a MCN. Thus, EUS-FNA is a useful diagnostic tool for correct identification of MCNs and may be the gold standard for pre-operative assessment. Competing interests None declared.

Urgent improvements needed to diagnose and manage Lynch syndrome

Lynch syndrome is currently under-recognised, underdiagnosed, and undermanaged, so opportunities to reduce cancer mortality are often missed. The new guideline from the National Institute for Health and Care Excellence recommends universal testing for Lynch syndrome in all people newly diagnosed as having colorectal cancer.1 This should prevent several hundred colorectal cancers annually, but several issues hinder good care …

The Association of Low-Penetrance Variants in DNA Repair Genes with Colorectal Cancer: A Systematic Review and Meta-Analysis

Objectives:Approximately 35% of colorectal cancer (CRC) risk is attributable to heritable factors known hereditary syndromes, accounting for 6%. The remainder may be due to lower penetrance polymorphisms particularly of DNA repair genes. DNA repair pathways, including base excision repair (BER), nucleotide excision repair (NER), mismatch repair (MMR), direct reversal repair (DRR), and double-strand break repair are complex, evolutionarily conserved, and critical in carcinogenesis. Germline mutations in these genes are associated with high-penetrance CRC syndromes such as Lynch syndrome. However, the association of low-penetrance polymorphisms of DNA repair genes with CRC risk remains unclear.Methods:A systematic literature review of PubMed, Embase, and HuGENet databases was conducted. Pre-specified criteria determined study inclusion/exclusion. Per-allele, pooled odds ratios disclosed the risk attributed to each variant. Heterogeneity was investigated by subgroup analyses for ethnicity and tumor location; funnel plots and Egger’s test assessed publication bias.Results:Sixty-one polymorphisms in 26 different DNA repair genes were identified. Meta-analyses for 22 polymorphisms in 17 genes revealed that six polymorphisms were significantly associated with CRC risk within BER (APE1, PARP1), NER (ERCC5, XPC), double-strand break (RAD18), and DRR (MGMT), but none within MMR. Subgroup analyses revealed significant association of OGG1 rs1052133 with rectal cancer risk. Egger’s test revealed no publication bias.Conclusions:Low-penetrance polymorphisms in DNA repair genes alter susceptibility to CRC. Future studies should therefore analyze whole-genome polymorphisms and any synergistic effects on CRC risk.Translational impact:This knowledge may enhance CRC risk assessment and facilitate a more personalized approach to cancer prevention.

The association of low penetrance genetic risk modifiers with colorectal cancer in lynch syndrome patients: a systematic review and meta-analysis

Lynch syndrome (LS) is a highly penetrant inherited cancer predisposition syndrome accounting for approximately 1000 cases of colorectal cancer (CRC) in the UK annually. LS is characterised by autosomal dominant inheritance and germline mutations in DNA mismatch repair genes. The penetrance is highly variable and the reasons for this have not been fully elucidated. This study investigates whether low penetrance genetic risk factors may result in phenotype modification in LS patients. To conduct a systematic literature review and meta-analysis to assess the association between low penetrance genetic risk modifiers and CRC in LS patients. A systematic review was conducted of the PubMed and HuGENet databases. Eligibility of studies was determined by pre-defined criteria. Included studies were analysed via the per-allele model and assessed by pooled odds ratios and establishing 95% confidence intervals. Study heterogeneity was assessed via Cochrane’s Q statistic and I2 values. Publication bias was evaluated with funnel plots. Subgroup analysis was conducted on gender. Statistical software used was the Metafor package for the R programme version 3.1.3. Sixty-four polymorphisms were identified and sufficient data was available for analysis of ten polymorphisms, with between 279 and 1768 CRC cases per polymorphism. None demonstrated association with CRC risk in LS patients. However in sub-group analysis the polymorphism rs16892766 (8q23.3) was significant in males (OR 1.53, 95% CI 1.12–2.10). The variable phenotype presentation of the disease still remains largely unexplained, and further investigation is warranted. Other factors may also be influencing the high variability of the disease, such as environmental factors, copy number variants and epigenetic alterations. Investigation into these areas is needed as well as larger and more definitive studies of the polymorphisms analysed in this study.

PWE-170 A Dedicated Colorectal Cancer Genetics Service Improves Adherence with Molecular Testing for Lynch Syndrome

Introduction Lynch Syndrome (LS) accounts for 2–3% of colorectal cancer (CRC); ~1000 cases of CRC in the United Kingdom annually. It occurs as a result of mutations in DNA repair genes; limiting DNA repair and causing Microsatellite Instability (MSI). Previous studies have demonstrated that in current practise less than 10% of these cases are identified as LS due to a lack of appropriate testing with immunohistochemistry or MSI analysis. The international Revised Bethesda Criteria were devised in 2004 to help identify such cases; these criteria include all individuals diagnosed < 50 years of age, those with synchronous or metachronous CRC or LS-related cancer, those with significant family history of CRC or a LS-related cancer, or individuals diagnosed < 60 years of age with MSI-type histology. Methods We identified all new cases of colorectal cancer over a 1 year period prior to and subsequent to the establishment of a dedicated ‘Family History of Bowel Cancer Service’. Adherence to the Revised Bethesda Criteria was determined by examination of medical records and UK National Bowel Cancer Audit Programme (NBOCAP) data. Pathology reports were studied in patients aged under 60 years of age at diagnosis looking for features consistent with MSI-H histology. We used Chi-squared testing to calculate significance for binary variables. Results Over the two year period 198 cases of colorectal cancer were discussed at the CRC multidisciplinary meeting. 41 patients fulfilled the Revised Bethesda Criteria for screening for Lynch Syndrome; 12 individuals were diagnosed under the age of 50 years (~6%); 4 patients were diagnosed under 60 years of age and had MSI-H type histology and 25 patients had a significant family history of CRC or a LS-related cancer. In the year prior to the introduction of the clinic, we identified 18 cases meeting the Revised Bethesda Criteria for screening for LS; however, only 1 patient had been tested (5.6%). In contrast following the introduction of the clinic 19 of 23 identified cases (82.6%) were tested. Chi-squared testing demonstrated clinical significance when comparing the screening prior to and subsequent to the introduction of the clinic, p value = 9.7x 10–7 (Chi = 23.9956). 6 of the screened cases demonstrated molecular features with MSI and abnormal Immunohistochemistry, and are undergoing further germline genetic testing. Conclusion The establishment of a dedicated ‘Family History of Bowel Cancer Service’ resulted in a significant improvement in the screening for Lynch Syndrome in accordance with the Revised Bethesda Criteria, 2004. We would recommend that this service should be extended throughout the United Kingdom to help aid early diagnoses and improve long-term outcomes. Disclosure of Interest None Declared.

Response to letter to editor regarding published article—metachronous colorectal cancer following segmental or extended colectomy in Lynch syndrome: a systematic review and meta-analysis

We would like to thanks Anele and colleagues for their valued comments regarding our recently published article [1]. We feel it is first of all important to acknowledge them as the authors of Anele CC et al. Risk of metachronous colorectal cancer following colectomy in Lynch syndrome: a systematic review and meta-analysis. Color Dis. 2017;19(6):528–36 referenced in our article (reference 27) [2]. We are thankful for Anele and colleagues for undertaking a re-analysis of their data excluding the study performed by Aronson et al. [3]. This was an important omission in the original study and we are glad they have acknowledged and corrected this, and we feel this also underlines the importance of access to this unpublished data from the paper by Aronson et al., in order to perform a robust meta-analysis. We also accept the point raised in their letter about two rectal metachronous colorectal cancer in the Stupart study [4]. We also appreciate that the results of our analyses are similar, however feels that the differences identified by this re-analysis are important to publish as more definitive result, better informing future studies. With regard to the other points raised we agree that the statement ‘In LS, segmental colectomy results in a significant increased risk of developing MCC’ could be misleading, and should have included more context. We would disagree that there is little mention of complications and poorer functional outcomes. Despite not being the primary outcome of this study we feel we have addressed this in both the discussion and conclusion—indeed we have emphasised the need for an individualised approach to surgical decision making in Lynch Syndrome patients. As reported by other studies (including the study by Anele and colleagues) data on morbidity, bowel function and quality of life is often not reported making further subanalysis challenging. We have reported the results as relative risk, reflecting both included studies and similar systematic reviews and meta-analysis. The addition of number need to treat was considered for the analysis, however was problematic to calculate (using the baseline studies) and has not been included in similar systematic reviews and meta-analysis (including the study by Anele and colleagues) however would be a useful addition in future studies. We agree with the final comments by Anele and colleagues that management decisions are highly personalised and need to consider a plethora of factors. However we feel that analyses such as this study provide valuable information and insight to both clinicians and patients allowing them to make a more informed choice.

PWE-003 Mdm2 t309g polymorphism and risk of colorectal cancer

Introduction Murine double minute 2 (MDM2) is an E3 ubiquitin-protein ligase that mediates cell cycle arrest by negatively regulating the tumour suppressor gene p53. Polymorphisms have been thought to be associated with colorectal cancer (CRC), however results have been largely inconclusive. A meta-analysis of MDM2 T309G (rs2279744) was conducted to clarify and assess whether any association could be found. Method A systematic literature review of the Pubmed and HuGENet databases was conducted and studies were included/excluded based on pre-specified criteria. The per allele model was used to assess risk by calculating pooled odds ratios with 95% confidence intervals. Publication bias was investigated using a funnel plot. Statistical analysis was conducted using the R program (version 3.2.4). Results A total of 135 studies were screened and 6 case control studies were included with 3553 cases and 5781 controls. No association was found between MDM2 T309G and CRC (OR=1.25; 95% CI 0.97–1.62). The funnel plot showed that publication bias was present. Abstract PWE-003 Figure 1 Conclusion This meta-analysis suggests that MDM2 T309G polymorphism is not associated with risk of CRC and should not be evaluated as part of a patient risk assessment. Future studies with larger and more varied ethnicities would allow more accurate assessment of the association between MDM2 T390G and CRC risk. Disclosure of Interest None Declared