Tumour budding as a prognostic biomarker in biopsies and resections of neoadjuvant-treated rectal adenocarcinoma.

BACKGROUND: Tumour budding (TB) is a marker of tumour aggressiveness which, when measured in rectal cancer resection specimens, predicts worse outcomes and response to neoadjuvant therapy. We investigated the utility of TB assessment in the setting of neoadjuvant treatment. METHODS AND RESULTS: A single-centre, retrospective cohort study was conducted. TB was assessed using the hot-spot International Tumour Budding Consortium (ITBCC) method and classified by the revised ITBCC criteria. Haematoxylin and eosin (H&E) and AE1/AE3 cytokeratin (CK) stains for ITB (intratumoural budding) in biopsies with PTB (peritumoural budding) and ITB (intratumoural budding) in resection specimens were compared. Logistic regression assessed budding as predictors of lymph node metastasis (LNM). Cox regression and Kaplan-Meier analyses investigated their utility as a predictor of disease-free (DFS) and overall (OS) survival. A total of 146 patients were included; 91 were male (62.3%). Thirty-seven cases (25.3%) had ITB on H&E and 79 (54.1%) had ITB on CK assessment of biopsy tissue. In univariable analysis, H&E ITB [odds (OR) = 2.709, 95% confidence interval (CI) = 1.261-5.822, P = 0.011] and CK ITB (OR = 2.165, 95% CI = 1.076-4.357, P = 0.030) predicted LNM. Biopsy-assessed H&E ITB (OR = 2.749, 95% CI = 1.258-6.528, P = 0.022) was an independent predictor of LNM. In Kaplan-Meier analysis, ITB identified on biopsy was associated with worse OS (H&E, P = 0.003, CK: P = 0.009) and DFS (H&E, P = 0.012; CK, P = 0.045). In resection specimens, CK PTB was associated with worse OS (P = 0.047), and both CK PTB and ITB with worse DFS (PTB, P = 0.014; ITB: P = 0.019). In multivariable analysis H&E ITB predicted OS (HR = 2.930, 95% CI = 1.261-6.809) and DFS (HR = 2.072, 95% CI = 1.031-4.164). CK PTB grading on resection also independently predicted OS (HR = 3.417, 95% CI = 1.45-8.053, P = 0.005). CONCLUSION: Assessment of TB using H&E and CK may be feasible in rectal cancer biopsy and post-neoadjuvant therapy-treated resection specimens and is associated with LNM and worse survival outcomes. Future management strategies for rectal cancer might be tailored to incorporate these findings.

Relevance of shrinkage versus fragmented response patterns in rectal cancer.

AIMS: Partial response to neoadjuvant chemoradiotherapy (CRT) presents with one of two main response patterns: shrinkage or fragmentation. This study investigated the relevance of these response patterns in rectal cancer, correlation with other response indicators, and outcome. METHODS AND RESULTS: The study included a test (n = 197) and a validation cohort (n = 218) of post-CRT patients with rectal adenocarcinoma not otherwise specified and a partial response. Response patterns were scored by two independent observers using a previously developed three-step flowchart. Tumour regression grading (TRG) was established according to both the College of American Pathologists (CAP) and Dworak classifications. In both cohorts, the predominant response pattern was fragmentation (70% and 74%), and the scoring interobserver agreement was excellent (k = 0.85). Patients with a fragmented pattern presented with significantly higher pathological stage (ypTNM II-IV, 78% versus 35%; P < 0.001), less tumour regression with Dworak (P = 0.004), and CAP TRG (P = 0.005) compared to patients with a shrinkage pattern. As a predictor of prognosis, the shrinkage pattern outperformed the TRG classification and stratified patients better in overall (fragmented pattern, hazard ratio [HR] 2.04, 95% confidence interval [CI] 1.19-3.50, P = 0.008) and disease-free survival (DFS; fragmented pattern, HR 2.50, 95% CI 1.23-5.10, P = 0.011) in the combined cohorts. The multivariable regression analyses revealed pathological stage as the only independent predictor of DFS. CONCLUSIONS: The heterogeneous nature of tumour response following CRT is reflected in fragmentation and shrinkage. In rectal cancer there is a predominance of the fragmented pattern, which is associated with advanced stage and less tumour regression. While not independently associated with survival, these reproducible patterns give insights into the biology of tumour response.

Targeting the NLRP3 inflammasome reduces inflammation in hidradenitis suppurativa skin.

BACKGROUND: Treatment for the debilitating disease hidradenitis suppurativa (HS) is inadequate in many patients. Despite an incidence of approximately 1%, HS is often under-recognized and underdiagnosed, and is associated with a high morbidity and poor quality of life. OBJECTIVES: To gain a better understanding of the pathogenesis of HS, in order to design new therapeutic strategies. METHODS: We employed single-cell RNA sequencing to analyse gene expression in immune cells isolated from involved HS skin vs. healthy skin. Flow cytometry was used to quantify the absolute numbers of the main immune populations. The secretion of inflammatory mediators from skin explant cultures was measured using multiplex and enzyme-linked immunosorbent assays. RESULTS: Single-cell RNA sequencing analysis identified a significant enrichment in the frequency of plasma cells, T helper (Th) 17 cells and dendritic cell subsets in HS skin, and the immune transcriptome was distinct and more heterogeneous than healthy skin. Flow cytometry revealed significantly increased numbers of T cells, B cells, neutrophils, dermal macrophages and dendritic cells in HS skin. Genes and pathways associated with Th17 cells, interleukin (IL)-17, IL-1ß and the NLRP3 inflammasome were enhanced in HS skin, particularly in samples with a high inflammatory load. Inflammasome constituent genes principally mapped to Langerhans cells and a subpopulation of dendritic cells. The secretome of HS skin explants contained significantly increased concentrations of inflammatory mediators, including IL-1ß and IL-17A, and culture with an NLRP3 inflammasome inhibitor significantly reduced the secretion of these, as well as other, key mediators of inflammation. CONCLUSIONS: These data provide a rationale for targeting the NLRP3 inflammasome in HS using small-molecule inhibitors that are currently being tested for other indications.

Rates and outcomes of testing for lynch syndrome in a national colorectal cancer screening programme.

BACKGROUND: Lynch Syndrome (LS), the most common cause of hereditary colorectal cancer (CRC), is characterised by pathogenic variants in mismatch repair (MMR) genes. Universal testing of all CRCs for LS can increase detection. Rates and outcomes of testing in Ireland's national CRC screening programme have not been examined previously. METHODS: CRCs diagnosed at two screening sites between 2015 and 2020 were identified. Patient records were used to determine if CRCs had been tested for MMR deficiency and if detected, what downstream testing to rule out LS or genetic testing to confirm LS was undertaken. RESULTS: Over five years, 206 CRCs were diagnosed. Testing for LS was carried out for 100% of CRCs at site A and 69% of CRCs at site B. Of CRCs tested for LS, 14 (8%) were MMR deficient. After downstream testing for BRAF mutation or hypermethylation of MLH1, three CRCs were identified as potentially LS-related. Of these two individuals declined genetic testing and one was lost to follow-up. CONCLUSIONS: By 2020 both sites had implemented universal testing of all CRCs for LS. A small number of individuals were identified as being eligible for genetic testing for LS, however those offered declined testing and one individual was lost to follow up. This highlights the importance of universal testing and the need for referral pathways to ensure all appropriate individuals are referred onwards to genetic services.

Updated systematic review of the approach to pelvic exenteration for locally advanced primary rectal cancer.

OBJECTIVES: To review the evidence regarding surgical advances in the management of primary locally advanced rectal cancer. BACKGROUND: The management of rectal cancer has evolved significantly in recent decades, with improved (neo)adjuvant treatment strategies and enhanced perioperative protocols. Centralization of care for complex, advanced cases has enabled surgeons in these units to undertake more ambitious surgical procedures. METHODS: A Pubmed, Ovid, Embase and Cochrane database search was conducted according to the predetermined search strategy. The review protocol was prospectively registered with PROSPERO (CRD42021245582). RESULTS: 14 studies were identified which reported on the outcomes of 3,188 patients who underwent pelvic exenteration (PE) for primary rectal cancer. 50% of patients had neoadjuvant radiotherapy. 24.2% underwent flap reconstruction, 9.4% required a bony resection and 34 patients underwent a major vascular excision. 73.9% achieved R0 resection, with 33.1% experiencing a major complication. Median length of hospital stay ranged from 13 to 19 days. 1.6% of patients died within 30 days of their operation. Five-year overall survival (OS) rates ranged 29%-78%. LIMITATIONS: The studies included in our review were mostly single-centre observational studies published prior to the introduction of modern neoadjuvant treatment regimens. It was not possible to perform a meta-analysis on the basis that most were non-randomized, non-comparative studies. CONCLUSIONS: Pelvic exenteration offers patients with locally advanced rectal cancer the chance of long-term survival with acceptable levels of morbidity. Increased experience facilitates more radical procedures, with the introduction of new platforms and/or reconstructive options.

Conflicting Guidelines: A Systematic Review on the Proper Interval for Colorectal Cancer Treatment.

BACKGROUND: Timely treatment for colorectal cancer (CRC) is a quality indicator in oncological care. However, patients with CRC might benefit more from preoperative optimization rather than rapid treatment initiation. The objectives of this study are (1) to determine the definition of the CRC treatment interval, (2) to study international recommendations regarding this interval and (3) to study whether length of the interval is associated with outcome. METHODS: We performed a systematic search of the literature in June 2020 through MEDLINE, EMBASE and Cochrane databases, complemented with a web search and a survey among colorectal surgeons worldwide. Full-text papers including subjects with CRC and a description of the treatment interval were included. RESULTS: Definition of the treatment interval varies widely in published studies, especially due to different starting points of the interval. Date of diagnosis is often used as start of the interval, determined with date of pathological confirmation. The end of the interval is rather consistently determined with date of initiation of any primary treatment. Recommendations on the timeline of the treatment interval range between and within countries from two weeks between decision to treat and surgery, to treatment within seven weeks after pathological diagnosis. Finally, there is no decisive evidence that a longer treatment interval is associated with worse outcome. CONCLUSIONS: The interval from diagnosis to treatment for CRC treatment could be used for prehabilitation to benefit patient recovery. It may be that this strategy is more beneficial than urgently proceeding with treatment.

Colonisation of the colonic mucus gel layer with butyrogenic and hydrogenotropic bacteria in health and ulcerative colitis.

Butyrate is the primary energy source for colonocytes and is essential for mucosal integrity and repair. Butyrate deficiency as a result of colonic dysbiosis is a putative factor in ulcerative colitis (UC). Commensal microbes are butyrogenic, while others may inhibit butyrate, through hydrogenotropic activity. The aim of this study was to quantify butyrogenic and hydrogenotropic species and determine their relationship with inflammation within the colonic mucus gel layer (MGL). Mucosal brushings were obtained from 20 healthy controls (HC), 20 patients with active colitis (AC) and 14 with quiescent colitis (QUC). Abundance of each species was determined by RT-PCR. Inflammatory scores were available for each patient. Statistical analyses were performed using Mann-Whitney-U and Kruskall-Wallis tests. Butyrogenic R. hominis was more abundant in health than UC (p < 0.005), prior to normalisation against total bacteria. Hydrogenotropic B. wadsworthia was reduced in AC compared to HC and QUC (p < 0.005). An inverse correlation existed between inflammation and R. hominis (ρ - 0.460, p < 0.005) and B. wadsworthia (ρ - 0.646, p < 0.005). Other hydrogenotropic species did not widely colonise the MGL. These data support a role for butyrogenic bacteria in UC. Butyrate deficiency in UC may be related to reduced microbial production, rather than inhibition by microbial by-products.

A case-control study examining the association of smad7 and TLR single nucleotide polymorphisms on the risk of colorectal cancer in ulcerative colitis.

AIM: Ulcerative colitis (UC) is characterized by chronic mucosal inflammation and an increased risk of colorectal cancer. smad7, TLR2 and TLR4 modulate intestinal inflammation and their polymorphisms affect the risk of development of sporadic colorectal cancer. The aim of the current study was to examine the association between single nucleotide polymorphisms (SNPs) in smad7, TLR2 and TLR4 and the development of colorectal cancer in patients with UC. METHOD: DNA was extracted from formalin-fixed, paraffin-embedded tissue from 90 patients with UC who had undergone panproctocolectomy between 1985 and 2013 (30 with UC-associated colorectal cancer and 60 control UC patients). Control cases were matched 2:1 for age at diagnosis of colitis, duration of disease and gender. Genotyping was performed for the smad7 rs4464148, rs11874392, rs12953717 and rs4939827 SNPs, the TLR2 rs5743704 and rs5743708 SNPs and the TLR4 rs4986790 and rs4986791 SNPs. RESULTS: Sixty three of the 90 patients (70%) were men and the mean age at diagnosis of UC was 38.6 ± 1.6 years. The mean time to the diagnosis of UC-associated colorectal cancer was 13.5 ± 1.9 years. The 5-year recurrence-free and cancer-specific survival rates were 76% and 88%, respectively. All eight SNPs were in Hardy-Weinberg equilibrium. None of the eight SNPs assessed in smad7, TLR2 or TLR4 were associated with the development of UC-associated colorectal cancer at an allelic or genotypic level. CONCLUSIONS: These data do not support an association between polymorphisms in smad7, TLR2 or TLR4 and the development of UC-associated colorectal cancer.

Segmental versus extended colectomy for tumours of the transverse colon: a systematic review and meta-analysis.

AIM: There is no consensus on the appropriate extent of oncological resection for tumours of the transverse colon. Concerns regarding tumour factors such as pattern of lymph node spread and technical factors such as anastomotic perfusion lead to a variety of procedures being performed. METHODS: A comprehensive search for published studies examining outcomes following segmental versus extended colectomy for transverse colon tumours was performed adhering to PRISMA (Preferred Reporting Items in Systematic Reviews and Meta-analyses) guidelines. Random effects methods were used to combine data. RESULTS: Seven comparative series examining outcomes in 3395 patients were identified. Segmental colectomy results in shorter operating times (mean difference 15.80 min, 95% CI -20.98 to -10.62, P < 0.001) and less ileus (OR 0.52, 95% CI 0.33-0.81, P = 0.004). There was no difference in length of hospital stay (mean difference 1.53 days, 95% CI -3.79 to 0.73, P = 0.18). Extended colectomy results in a lower rate of anastomotic leak (OR 0.62, 95% CI 0.40-0.97, P = 0.04). There are fewer nodes retrieved in segmental colectomy (mean difference 7.60 nodes, 95% CI -9.60 to -5.61, P < 0.001) but no difference in disease recurrence (OR 0.88, 95% CI 0.59-1.34, P = 0.56) or overall survival (OR 0.98, 95% CI 0.68-1.4, P = 0.9). CONCLUSIONS: Available data are limited due to a lack of randomized controlled trials. However, based on current evidence, segmental resection for transverse colon tumours is associated with less ileus but lower lymph node yields and higher anastomotic leak rates. Length of stay is similar. Oncological outcomes are equivalent.

Salcaprozate sodium (SNAC) enhances permeability of octreotide across isolated rat and human intestinal epithelial mucosae in Ussing chambers.

Octreotide is approved as a one-month injectable for treatment of acromegaly and neuroendocrine tumours. Oral delivery of the octapeptide is a challenge due mainly to low intestinal epithelial permeability. The intestinal permeation enhancer (PE) salcaprozate sodium (SNAC) has Generally Regarded As Safe (GRAS) status and is a component of an approved oral peptide formulation. The purpose of the study was to examine the capacity of salcaprozate sodium (SNAC), to increase its permeability across isolated rat intestinal mucosae from five regions and across human colonic mucosae mounted in Ussing chambers. Apical-side buffers were Kreb's-Henseleit (KH), fasted simulated intestinal fluid (FaSSIF-V2), rat simulated intestinal fluid (rSIF), and colonic simulated intestinal fluid (FaSSCoF). The basal apparent permeability coefficient (Papp) of [3H]-octreotide was equally low across rat intestinal regional mucosae in KH, rSIF, and FaSSIF-V2. Apical addition of 20 mM SNAC increased the Papp across rat tissue in KH: colon (by 3.2-fold) > ileum (3.4-fold) > upper jejunum (2.3-fold) > duodenum (1.4-fold) > stomach (1.4-fold). 20 mM and 40 mM SNAC also increased the Papp by 1.5-fold and 2.1-fold respectively across human colonic mucosae in KH. Transepithelial electrical resistance (TEER) values were reduced in the presence in SNAC especially in colonic regions. LC-MS/MS analysis of permeated unlabelled octreotide across human colonic mucosae in the presence of SNAC indicated that [3H]-octreotide remained intact. No gross damage was caused to rat or human mucosae by SNAC. Attenuation of the effects of SNAC was seen in rat jejunal mucosae incubated with FaSSIF-V2 and rSIF, and also to some extent in human colonic mucosae using FaSSCoF, suggesting interaction between SNAC with buffer components. In conclusion, SNAC showed potential as an intestinal permeation enhancer for octreotide, but in vivo efficacy may be attenuated by interactions with GI luminal fluid contents.

Personalised mapping of tumour development in synchronous colorectal cancer patients.

Synchronous colorectal cancers (syCRCs) are two or more primary tumours identified simultaneously in a patient. Previous studies report high inter-tumour heterogeneity between syCRCs, suggesting independent origin and different treatment response, making their management particularly challenging, with no specific guidelines currently in place. Here, we performed in-depth bioinformatic analyses of genomic and transcriptomic data of a total of eleven syCRCs and one metachronous CRC collected from three patients. We found mixed microsatellite status between and within patients. Overlap of mutations between synchronous tumours was consistently low (<0.5%) and heterogeneity of driver events across syCRCs was high in all patients. Microbial analysis revealed the presence of Fusobacterium nucleatum species in patients with MSI tumours, while quantification of tumour immune infiltration showed varying immune responses between syCRCs. Our results suggest high heterogeneity of syCRCs within patients but find clinically actionable biomarkers that help predict responses to currently available targeted therapies. Our study highlights the importance of personalised genome and transcriptome sequencing of all synchronous lesions to aid therapy decision and improve management of syCRC patients.

The abundance of Akkermansia muciniphila and its relationship with sulphated colonic mucins in health and ulcerative colitis.

Akkermansia muciniphila utilises colonic mucin as its substrate. Abundance is reduced in ulcerative colitis (UC), as is the relative proportion of sulphated mucin in the mucus gel layer (MGL). It is unknown if these phenomena are related, however reduced sulphated mucins could contribute to reduced abundance, owing to a lack of substrate. The aim of this study was to quantify A. muciniphila within the MGL and to relate these findings with markers of inflammation and the relative proportion of sulphomucin present. Colonic biopsies and mucus brushings were obtained from 20 patients with active UC (AC), 14 with quiescent UC (QUC) and 20 healthy controls (HC). A. muciniphila abundance was determined by RT-PCR. High iron diamine alcian-blue staining was performed for histological analysis. Patients with AC had reduced abundance of A. muciniphila compared to HC and QUC. A positive association was found between A. muciniphila abundance and higher percentage of sulphated mucin (ρ 0.546, p = 0.000). Lower abundances of A. muciniphila correlated with higher inflammatory scores (ρ = 0.294 (p = 0.001)). This study confirms an inverse relationship between A. muciniphila and inflammation and a positive association between A. muciniphila abundance and percentage of sulfated mucin in the MGL.

Extended versus conventional thromboprophylaxis after major abdominal and pelvic surgery: Systematic review and meta-analysis of randomized clinical trials.

BACKGROUND: Venous thromboembolism, presenting as deep vein thrombosis or pulmonary embolism, can be associated with considerable morbidity after major abdominal and pelvic surgery. Perioperative thromboprophylaxis with low-molecular-weight heparin is well established, but the duration of treatment remains debated. We aimed to assess the efficacy and safety of extended (4-week) versus conventional (1-week) thromboprophylaxis with low-molecular-weight heparin in patients undergoing abdominopelvic surgery. METHODS: Using MEDLINE databases (PubMed, EMBASE, and Web of Science), we conducted an electronic, systematic search of randomized controlled trials comparing post-operative extended versus conventional low-molecular-weight heparin on venous thromboembolism, deep vein thrombosis, and pulmonary embolism rates. RESULTS: Four randomized controlled trials met the predefined criteria. Extended prophylaxis with low-molecular-weight heparin after major abdominal and pelvic surgery decreased rates of postoperative venous thromboembolism, deep vein thrombosis, and proximal deep vein thrombosis without increased postoperative bleeding. Numbers needed to treat to prevent venous thromboembolism, overall deep vein thrombosis, and proximal deep vein thrombosis were 14, 14, and 44, respectively. Rates of postoperative symptomatic PE were rare, and the incidence was similar in both groups. CONCLUSION: Extended prophylaxis with low-molecular-weight heparin is associated with a decrease in asymptomatic venous thromboembolism. There remains sparse evidence regarding its impact on pulmonary embolism because of the overall low incidence. Extended prophylaxis should be considered in high-risk patients.

Isolation and gene expression profiling of intestinal epithelial cells: crypt isolation by calcium chelation from in vivo samples.

AIM: The epithelial layer within the colon represents a physical barrier between the luminal contents and its underlying mucosa. It plays a pivotal role in mucosal homeostasis, and both tolerance and anti-pathogenic immune responses. Identifying signals of inflammation initiation and responses to stimuli from within the epithelial layer is critical to understanding the molecular pathways underlying disease pathology. This study validated a method to isolate and analyze epithelial populations, enabling investigations of epithelial function and response in a variety of disease setting. MATERIALS AND METHODS: Epithelial cells were isolated from whole mucosal biopsies harvested from healthy controls and patients with active ulcerative colitis by calcium chelation. The purity of isolated cells was assessed by flow cytometry. The expression profiles of a panel of epithelial functional genes were investigated by reverse transcription-polymerase chain reaction (PCR) in isolated epithelial cells and corresponding mucosal biopsies. The expression profiles of isolated cells and corresponding mucosal biopsies were evaluated and compared between healthy and inflamed colonic tissue. RESULTS: Flow cytometry identified 97% of cells isolated as intestinal epithelial cells (IECs). Comparisons of gene expression profiles between the mucosal biopsies and isolated IECs demonstrated clear differences in the gene expression signatures. Sixty percent of the examined genes showed contrasting trends of expression between sample types. CONCLUSION: The calcium chelation isolation method provided a reliable method for the isolation of a pure population of cells with preservation of epithelial cell-specific gene expression. This demonstrates the importance of sample choice when investigating functions directly affecting the colonic epithelial layer.

Tumor Budding and PDC Grade Are Stage Independent Predictors of Clinical Outcome in Mismatch Repair Deficient Colorectal Cancer.

Mismatch repair deficient (dMMR) colorectal cancer (CRC) despite its association with poor histologic grade often has improved prognosis compared with MMR proficient CRC. Tumor budding and poorly differentiated clusters (PDCs) may predict metastatic potential of colorectal adenocarcinoma (CRC). In addition, their assessment may be more reproducible than the evaluation of other histopathologic parameters. Therefore, we wished to determine their potential as prognostic indicators in a cohort of dMMR CRC patients relative to histologic grade. We investigated the predictive value of conventional WHO grade, budding, PDC grade and other histopathologic parameters on the presence of lymph node metastasis (LNM) and clinical outcome in 238 dMMR CRCs. MMR status was determined by immunohistochemistry for the mismatch repair proteins hMLH1, hMSH2, hMSH6, and hPMS2. Tumor budding and PDCs were highly correlated (r=0.701; P<0.000). Both budding and PDC grade were associated with WHO grade, perineural invasion, lympho-vascular invasion, and extramural vascular invasion, and the presence of LNM in dMMR CRC (P<0.009). Independent predictors of LNM were PDC grade (odds ratio, 4.12; 95% confidence interval [CI], 1.69-10.04; P=0.011) and EMVI (odds ratio, 3.81; 95% CI, 1.56-9.19; P<0.000). Only pTstage (hazard ratio [HR], 4.11; 95% CI, 1.48-11.36; P=0.007) and tumor budding (HR, 2.99; 95% CI, 1.72-5.19; P<0.000) were independently associated with worse disease-free survival (DFS). If tumor budding was excluded from the model, PDC grade became significant for DFS (HR, 2.34; 95% CI, 1.34-4.09; P=0.003). WHO Grade does not independently correlate with clinical outcome in dMMR CRC. PDC grade and extramural vascular invasion are independent predictors of LNM. Tumor budding and pTstage are the best predictors of DFS. If tumor budding cannot be assessed, PDC grade may be used as a prognostic surrogate.

Changing the Rules of the Game: How Do We Measure Success in Social Media?

Ours will be the generation proud to say we shifted the sands of educational deserts by open access and proliferation, seeding of data sharing, and watering grassroots research in resource-compromised environments. Universal "social" media is defining features of modern professional life that provide powerful modes of knowledge acquisition/sharing to that end. Altmetric and other measurements stratify academic communications according to this alternate, online media presence (not academic penetrance). Are they meaningless, self-absorbed integers, or reliable yardsticks of scientific and educational prowess? Far beyond this trite, patronizing question from the minds of outdated, terrified technophobes, the real impact of "social" media is not narcissistic solipsism. Instant dissemination of contemporary surgical controversies on a truly global level drives improved (or at least reflective) health care for all. While a numerical assignment of value according to views, "likes," impressions, or "retweets" may seem meaningless to cynical, established academics, the impetus for universal improvement is self-evident. Electronic data and opinion sharing may not balance the inequity between low- and high-income countries, but it keeps it in perspective. The best way to shift desert sands is to blow on them constantly.

Screening for mismatch repair deficiency in colorectal cancer: data from three academic medical centers.

Reflex immunohistochemistry (rIHC) for mismatch repair (MMR) protein expression can be used as a screening tool to detect Lynch Syndrome (LS). Increasingly the mismatch repair-deficient (dMMR) phenotype has therapeutic implications. We investigated the pattern and consequence of testing for dMMR in three Irish Cancer Centres (CCs). CRC databases were analyzed from January 2005-December 2013. CC1 performs IHC upon physician request, CC2 implemented rIHC in November 2008, and CC3 has been performing rIHC since 2004. The number of eligible patients referred to clinical genetic services (CGS), and the number of LS patients per center was determined. 3906 patients were included over a 9-year period. dMMR CRCs were found in 32/153 (21%) of patients at CC1 and 55/536 (10%) at CC2, accounting for 3% and 5% of the CRC population, respectively. At CC3, 182/1737 patients (10%) had dMMR CRCs (P < 0.001). Additional testing for the BRAF V600E mutation, was performed in 49 patients at CC3 prior to CGS referral, of which 29 were positive and considered sporadic CRC. Referrals to CGS were made in 66%, 33%, and 30% of eligible patients at CC1, CC2, and CC3, respectively. LS accounted for CRC in eight patients (0.8%) at CC1, eight patients (0.7%) at CC2, and 20 patients (1.2%) at CC3. Cascade testing of patients with dMMR CRC was not completed in 56%. Universal screening increases the detection of dMMR tumors and LS kindreds. Successful implementation of this approach requires adequate resources for appropriate downstream management of these patients.