Tumor-associated mesenchymal stromal cells modulate macrophage phagocytosis in stromal-rich colorectal cancer via PD-1 signaling.

CMS4 colorectal cancer (CRC), based on the consensus molecular subtype (CMS), stratifies patients with the poorest disease-free survival rates. It is characterized by a strong mesenchymal stromal cell (MSC) signature, wound healing-like inflammation and therapy resistance. We utilized 2D and 3D in vitro, in vivo, and ex vivo models to assess the impact of inflammation and stromal cells on immunosuppression in CMS4 CRC. RNA sequencing data from untreated stage II/III CRC patients showed enriched TNF-α signatures in CMS1 and CMS4 tumors. Secretome from TNF-α treated cancer cells induced an immunomodulatory and chemotactic phenotype in MSC and cancer-associated fibroblasts (CAFs). Macrophages in CRC tumours migrate and preferentially localise in stromal compartment. Inflammatory CRC secretome enhances expression of PD-L1 and CD47 on both human and murine stromal cells. We demonstrate that TNF-α-induced inflammation in CRC suppresses macrophage phagocytosis via stromal cells. We show that stromal cell-mediated suppression of macrophage phagocytosis is mediated in part through PD-1 signaling. These data suggest that re-stratification of CRC by CMS may reveal patient subsets with microsatellite stable tumors, particularly CMS4-like tumors, that may respond to immunotherapies.

Surgical Handover Core Outcome Measures (SH-CORE): a protocol for the development of a core outcome set for trials in surgical handover.

BACKGROUND: Surgical handover is associated with a significant risk of care failures. Existing research displays methodological deficiencies and little consensus on the outcomes that should be used to evaluate interventions in this area. This paper reports a protocol to develop a core outcome set (COS) to support standardisation, comparability, and evidence synthesis in future studies of surgical handover between doctors. METHODS: This study adheres to the Core Outcome Measures in Effectiveness Trials (COMET) initiative guidance for COS development, including the COS-Standards for Development (COS-STAD) and Reporting (COS-STAR) recommendations. It has been registered prospectively on the COMET database and will be led by an international steering group that includes surgical healthcare professionals, researchers, and patient and public partners. An initial list of reported outcomes was generated through a systematic review of interventions to improve surgical handover (PROSPERO: CRD42022363198). Findings of a qualitative evidence synthesis of patient and public perspectives on handover will augment this list, followed by a real-time Delphi survey involving all stakeholder groups. Each Delphi participant will then be invited to take part in at least one online consensus meeting to finalise the COS. ETHICS AND DISSEMINATION: This study was approved by the Royal College of Surgeons in Ireland (RCSI) Research Ethics Committee (202309015, 7th November 2023). Results will be presented at surgical scientific meetings and submitted to a peer-reviewed journal. A plain English summary will be disseminated through national websites and social media. The authors aim to integrate the COS into the handover curriculum of the Irish national surgical training body and ensure it is shared internationally with other postgraduate surgical training programmes. Collaborators will be encouraged to share the findings with relevant national health service functions and national bodies. DISCUSSION: This study will represent the first published COS for interventions to improve surgical handover, the first use of a real-time Delphi survey in a surgical context, and will support the generation of better-quality evidence to inform best practice. TRIAL REGISTRATION: Core Outcome Measures in Effectiveness Trials (COMET) initiative 2675.  http://www.comet-initiative.org/Studies/Details/2675 .

Evaluating the oncological safety of neoadjuvant chemotherapy in locally advanced colon carcinoma: a systematic review and meta-analysis of randomised clinical trials and propensity-matched studies.

PURPOSE: Use of neoadjuvant chemotherapy (NAC) for locally advanced colon cancer (LACC) remains controversial. An integrated analysis of data from high-quality studies may inform the long-term safety of NAC for this cohort. Our aim was to perform a systematic review and meta-analysis of randomised clinical trials (RCTs) and propensity-matched studies to assess the oncological safety of NAC in patients with LACC. METHODS: A systematic review was performed as per preferred reporting items for systematic reviews and meta-analyses (PRISMA) guidelines. Survival was expressed as hazard ratios using time-to-effect generic inverse variance methodology, while surgical outcomes were expressed as odds ratios (ORs) using the Mantel-Haenszel method. Data analysis was performed using Review Manager version 5.4. RESULTS: Eight studies (4 RCTs and 4 retrospective studies) including 31,047 patients with LACC were included. Mean age was 61.0 years (range: 19-93 years) and mean follow-up was 47.6 months (range: 2-133 months). Of those receiving NAC, 4.6% achieved a pathological complete response and 90.6% achieved R0 resection (versus 85.9%, P < 0.001). At 3 years, patients receiving NAC had improved disease-free survival (DFS) (OR: 1.28, 95% confidence interval (CI): 1.02-1.60, P = 0.030) and overall survival (OS) (OR: 1.76, 95% CI: 1.10-2.81, P = 0.020). When using time-to-effect modelling, a non-significant difference was observed for DFS (HR: 0.79, 95% CI: 0.57-1.09, P = 0.150) while a significant difference in favour of NAC was observed for OS (HR: 0.75, 95% CI: 0.58-0.98, P = 0.030). CONCLUSION: This study highlights the oncological safety of NAC for patients being treated with curative intent for LACC using RCT and propensity-matched studies only. These results refute current management guidelines which do not advocate for NAC to improve surgical and oncological outcomes in patients with LACC. TRIAL REGISTRATION: International Prospective Register of Systematic Review (PROSPERO) registration: CRD4202341723.

Targeting stromal cell sialylation reverses T cell-mediated immunosuppression in the tumor microenvironment.

Immunosuppressive tumor microenvironments (TMEs) reduce the effectiveness of immune responses in cancer. Mesenchymal stromal cells (MSCs), precursors to cancer-associated fibroblasts (CAFs), promote tumor progression by enhancing immune cell suppression in colorectal cancer (CRC). Hyper-sialylation of glycans promotes immune evasion in cancer through binding of sialic acids to their receptors, Siglecs, expressed on immune cells, which results in inhibition of effector functions. The role of sialylation in shaping MSC/CAF immunosuppression in the TME is not well characterized. In this study, we show that tumor-conditioned stromal cells have increased sialyltransferase expression, α2,3/6-linked sialic acid, and Siglec ligands. Tumor-conditioned stromal cells and CAFs induce exhausted immunomodulatory CD8+ PD1+ and CD8+ Siglec-7+/Siglec-9+ T cell phenotypes. In vivo, targeting stromal cell sialylation reverses stromal cell-mediated immunosuppression, as shown by infiltration of CD25 and granzyme B-expressing CD8+ T cells in the tumor and draining lymph node. Targeting stromal cell sialylation may overcome immunosuppression in the CRC TME.

Impact of the 12-gene recurrence score in influencing adjuvant chemotherapy prescription in mismatch repair proficient stage II/III colonic carcinoma-a systematic review and meta-analysis.

INTRODUCTION: The 12-gene recurrence score (RS) is a clinically validated assay which predicts recurrence risk in patients with stage II/III colon cancer. Decisions regarding adjuvant chemotherapy may be guided using this assay or based on the judgement of tumour board. AIMS: To assess the concordance between the RS and MDT decisions regarding adjuvant chemotherapy in colon cancer. METHODS: A systematic review was performed in accordance with PRISMA guidelines. Meta-analyses were performed using the Mantel-Haenszel method using the Review Manager version 5.4 software. RESULTS: Four studies including 855 patients with a mean age of 68 years (range: 25-90 years) met inclusion criteria. Overall, 79.2% had stage II disease (677/855) and 20.8% had stage III disease (178/855). For the entire cohort, concordant results between the 12-gene assay and MDT were more likely than discordant (odds ratio (OR): 0.38, 95% confidence interval (CI): 0.25-0.56, P < 0.001). Patients were more likely to have chemotherapy omitted than escalated when using the RS (OR: 9.76, 95% CI: 6.72-14.18, P < 0.001). For those with stage II disease, concordant results between the 12-gene assay and MDT were more likely than discordant (OR: 0.30, 95% CI: 0.17-0.53, P < 0.001). In stage II disease, patients were more likely to have chemotherapy omitted than escalated when using the RS (OR: 7.39, 95% CI: 4.85-11.26, P < 0.001). CONCLUSIONS: The use of the 12-gene signature refutes the decision of tumour board in 25% of cases, with 75% of discordant decisions resulting in omission of adjuvant chemotherapy. Therefore, it is possible that a proportion of such patients are being overtreated when relying on tumour board decisions alone.

The use of radiomic analysis of magnetic resonance imaging in predicting distant metastases of rectal carcinoma following surgical resection: A systematic review and meta-analysis.

AIM: Estimating prognosis in rectal carcinoma (RC) is challenging, with distant recurrence (DR) occurring in up to 30% of cases. Radiomics is a novel field using diagnostic imaging to investigate the tumour heterogeneity of cancers and may have the potential to predict DR. The aim of the study was to perform a systematic review of the current literature evaluating the use of radiomics in predicting DR in patients with resected RC. METHODS: A systematic review was performed as per PRISMA guidelines to identify studies reporting radiomic analysis of magnetic resonance imaging (MRI) to predict DR in patients diagnosed with RC. Sensitivity and specificity of radiomic analyses were included for meta-analysis. RESULTS: A total of seven studies including 1497 patients (998 males) were included, seven, five and one of whom reported radiomics, respectively. The overall pooled rate of DR from all included studies was 17.1% (256/1497), with 15.6% (236/1497), 1.3% (19/1497) and 0.2% (3/1497) of patients having hepatic, pulmonary and peritoneal metastases. Meta-analysis demonstrated that radiomics correctly predicted DR with pooled sensitivities and specificities of MRI 0.76 (95% CI: 0.73, 0.78) and 0.85 (95% CI: 0.83, 0.88), respectively. CONCLUSION: This systematic review suggests the benefit of radiomic analysis of preoperative MRI in identifying patients with resected RC at an increased risk of DR. Our findings warrant validation in larger prospective studies as modalities to predict DR is a significant unmet need in RC. Radiomics may allow for tailored therapeutic strategies for high-risk groups.

Role of nerve block as a diagnostic tool in pudendal nerve entrapment.

BACKGROUND: Pudendal nerve entrapment is a disabling condition which is difficult to diagnose and treat. Nantes criteria include the requirement of positive anaesthetic pudendal nerve block that is widely used to allow identification of patients likely to benefit from the definitive but invasive pudendal nerve release. This study aimed to determine if pudendal nerve blockade under general anaesthesia could diagnose and temporarily treat pudendal nerve entrapment in patients suffering from chronic pelvic/perineal pain and/or organ dysfunction. METHODS: This retrospective analysis of a prospectively maintained database examined the outcomes of all recipients of diagnostic pudendal nerve block in a quaternary referral centre between 2012 and 2017. Primary outcome was relief of perineal pain (transient or permanent). Secondary outcomes were demographics, referral patterns for definitive procedure and complication rates. Statistical analysis was performed using SPSS v 24. RESULTS: A total of 77 patients were included in the study. Mean age was 57.27 ± 13.55 years. Majority were females (n = 62, 80.5%). Relief of pain was experienced by 47 of 76 (68.1%) patients after initial injection. Complication rate of injection was 3.9% (n = 3) which in all cases was unilateral lower limb paraesthesia. Of the 37 patients (52.9%) referred, 20 underwent surgical decompression with 12 (60%) being successful. CONCLUSION: Pudendal nerve injection is a safe and simple procedure that can provide accurate diagnosis and transient relief from this chronic and debilitating problem. This technique helps to isolate patients suitable for pudendal nerve decompression which offers high success rates.

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.

Awareness and uptake of family screening in patients diagnosed with colorectal cancer at a young age.

Background. One-fifth of people who develop colorectal cancer (CRC) have a first-degree relative (FDR) also affected. There is a large disparity in guidelines for screening of relatives of patients with CRC. Herein we address awareness and uptake of family screening amongst patients diagnosed with CRC under age 60 and compare guidelines for screening. Study Design. Patients under age 60 who received surgical management for CRC between June 2009 and May 2012 were identified using pathology records and theatre logbooks. A telephone questionnaire was carried out to investigate family history and screening uptake among FDRs. Results. Of 317 patients surgically managed for CRC over the study period, 65 were under age 60 at diagnosis (8 deceased). The mean age was 51 (30-59). 66% had node positive disease. 25% had a family history of colorectal cancer in a FDR. While American and Canadian guidelines identified 100% of these patients as requiring screening, British guidelines advocated screening for only 40%. Of 324 FDRs, only 40.9% had been screened as a result of patient's diagnosis. Conclusions. Uptake of screening in FDRs of young patients with CRC is low. Increased education and uniformity of guidelines may improve screening uptake in this high-risk population.

Isolated cutaneous metastasis of uterine leiomyosarcoma: case report and review of literature.

A 54 year old lady presented for routine excision of a scalp lesion thought clinically to represent a sebaceous cyst of the right occiput. 4 years earlier she underwent total abdominal hysterectomy and right salpingo-oophorectomy for 3 large uterine fibroids. Histo-pathological examination of the hysterectomy specimen revealed an incidental low-grade leiomyosarcoma. Staging imaging was negative for metastatic disease. She made an uneventful recovery and was treated further by adjuvant pelvic radiotherapy.She noticed an uncomfortable and unsightly cystic swelling on her occiput four years after hysterectomy and was referred for routine excision of what was believed to be a benign lesion. The lesion was excised and sent for histopathological examination. Microscopic analysis including immuno-histochemistry demonstrated an ER and PR positive metastatic deposit of leiomyosarcoma. The margins of excision were histologically clear of disease.At Multi-Disciplinary Team (MDT) discussion a diagnosis of metastatic scalp deposit from previous uterine leiomyosarcoma was made. Re-staging CT brain, thorax, abdomen and pelvis and MRI brain were negative for local recurrence or distant metastases. She is currently undergoing radiotherapy to the scalp and surrounding tissues and will be followed up closely by the involved teams.To the best of our knowledge, this is the first case described in the worldwide literature of isolated cutaneous metastasis to the scalp of uterine leiomyosarcoma without evidence of disseminated disease at other sites. VIRTUAL SLIDES: The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/1311834987345566.

The flavonone naringenin inhibits chloride secretion in isolated colonic epithelia.

Studies investigating the activating and inhibitory actions of bioflavonoids on colonic function have yielded conflicting results. At low concentrations, flavonoids may stimulate chloride secretion while at higher concentrations they may have antisecretory actions in the colon. Naringenin (4',5,7-trihydroxyflavanone), found predominantly in citrus fruits, confers a protective effect against colorectal cancer and is purported to modulate secretory function in colonic cell lines. The aim of this study was to investigate the effects of naringenin on ion transport in rat and human colonic mucosae. Naringenin inhibited basal and stimulated chloride secretion in rat and human colonic mucosae mounted in Ussing chambers (IC(50) 330 µMol/L and 360 µMol/L respectively) and did not alter intracellular cAMP generation. Naringenin inhibited chloride secretion in MQAE (N-(ethoxycarbonylmethyl)-6-methoxyquinolinium bromide) loaded crypts stimulated with forskolin. In BCECF (2',7'-bis-(2-carboxyethyl)-5-(and 6)-carboxyfluorescein acetoxymethyl ester) loaded crypts, naringenin caused an intracellular acidification (ΔpH/min=0.05 ± 0.004) which was sensitive to the Na-K-Cl co-transporter (NKCC) inhibitor bumetanide. In addition, the antisecretory effect of naringenin was not inhibited by blockade of barium sensitive basolateral K(+) transporters or by inhibition of Na+/H(+) exchange by amiloride. We propose that the antisecretory action of naringenin is due to inhibition of basolateral NKCC1 in rat and human colon.

Microbial and viral pathogens in colorectal cancer.

The heterogenetic and sporadic nature of colorectal cancer has led to many epidemiological associations with causes of this disease. As our understanding of the underlying molecular processes in colorectal-cancer develops, the concept of microbial-epithelial interactions as an oncogenic trigger might provide a plausible hypothesis for the pathogenesis of colorectal cancer. By contrast with other cancers of the gastrointestinal tract (gastric carcinoma, mucosa-associated lymphoid-tissue lymphoma), a direct causal link between microbial infection (bacteria and viruses) and colorectal carcinoma has not been established. Studies support the involvement of these organisms in oncogenesis, however, in colorectal cancer, clinical data are lacking. Here, we discuss current evidence (both in vitro and clinical studies), and focus on a putative role for bacterial and viral pathogens as a cause of colorectal cancer.

Estrogen and its role in gastrointestinal health and disease.

INTRODUCTION: While the concept of a role of estrogen in gastrointestinal (in particular, colonic) malignancy has generated excitement in recent years, no review has examined the role of this potent and omnipresent steroid hormone in physiological states or its contribution to the development of benign pathological processes. Understanding these effects (and mechanisms therein) may provide a platform for a deeper understanding of more complex disease processes. METHODS: A literature search was conducted using the PubMed database and the search terms were "estrogen," "estrogen AND gastrointestinal tract," "estrogen AND colon," "estrogen AND esophagus," "estrogen AND small intestine," "estrogen AND stomach," "estrogen AND gallbladder," and "estrogen AND motility." Bibliographies of extracted studies were further cross-referenced. In all, 136 full-text articles were selected for review. A logical organ-based approach was taken to enable extraction of data of clinical relevance and meaningful interpretation thereof. Insight is provided into the hypotheses, theories, controversies, and contradictions generated over the last five decades by extensive investigation of estrogen in human, animal, and cell models using techniques as diverse as autoradiographic studies of baboons to human population analysis. CONCLUSIONS: Effects from esophagus through to the colon and rectum are summarized in this first concise collection of data pertaining to estrogenic actions in gastrointestinal health and disease. Mechanisms of these actions are discussed where possible. Undoubtedly, this hormone exerts many actions yet to be elucidated, and its potential therapeutic applications remain, as yet, largely unexplored.

The omentum: anatomical, metabolic, and surgical aspects.

INTRODUCTION: The omentum is acknowledged to have diverse functions in the pathophysiology of intra-abdominal disease. Its angiogenic properties act as a natural defense mechanism in peritonitis and intra-abdominal sepsis. With advancing technology the omentum is revealing itself as a new player in the field of molecular surgery with special reference to cancer, obesity and tissue reconstruction. MATERIALS AND METHODS: This article reviews the existing and potential surgical applications of the omentum.

Quality of life after iatrogenic bile duct injury: a case control study.

OBJECTIVE: To compare quality of life (QOL) of patients following iatrogenic bile duct injuries (BDI) to matched controls. SUMMARY BACKGROUND DATA: BDI complicate approximately 0.3% of all cholecystectomy procedures. The literature regarding impact on quality of life is conflicted as assessment using clinical determinants alone is insufficient. METHODS: The medical outcomes study short form 36 (SF-36), a sensitive tool for quantification of life quality outcome, was used. The study group of iatrogenic BDI was compared with an age- and sex-matched group who underwent uncomplicated cholecystectomy. Telephone questionnaire using the SF-36 quality of life tool was administered to both groups at a median postoperative time of 12 years 8 months (range, 2 months -20 years). RESULTS: Seventy-eight patients were referred with BDI but due to mortality (n = 10) and unavailability (n = 6) 62 participated. The age- and sex-matched control cohort had undergone uncomplicated cholecystectomy (n = 62). Comparison between groups revealed that 7 of 8 variables examined were statistically similar to those of the control group (physical functioning, role physical, bodily pain, general health perceptions, vitality and social functioning, and mental health index). Mean role emotional scores were slightly worse in the BDI group (46 vs. 50) but the significance was borderline (P = 0.045). Subgroup analysis by method of intervention for BDI did not demonstrate significant differences. CONCLUSION: Quality of life of surviving patients following BDI compares favorably to that after uncomplicated laparoscopic cholecystectomy.

A case-control study of visual acuity in onychocryptosis.

BACKGROUND: There are many theories surrounding the etiology of ingrown toenails (IGTN). Few factors have been formally assessed, but it is widely accepted that a poor nail cutting technique has a causative role. AIM: To investigate the hypothesis that decreased visual acuity may lead to inadequate nail cutting and the formation of IGTN. METHODS: A prospective case-control study was performed. Near and distance visual acuity were tested on a population with IGTN (n = 19) and compared with that of an age- and sex-matched control cohort (n = 24) who underwent epidermal cyst excision in the same tertiary referral center. Comparisons of visual acuity were made between groups by Mann-Whitney U-test. Differences were taken to be significant if P < 0.05. Institutional Review Board approval was sought and granted. RESULTS: No significant difference in visual acuity (near or distance) was demonstrated between patients with IGTN and the control group (P = 0.33). CONCLUSION: Visual acuity does not appear to play a significant role in the development of IGTN.

Oestrogen and the colon: potential mechanisms for cancer prevention.

The role of oestrogen in oncogenesis has been examined extensively, especially in the context of breast cancer, and receptor modulators are an integral part of targeted treatment in this disease. The role of oestrogen signalling in colonic carcinoma is poorly understood. Men are more susceptible than women to colon cancer. Furthermore, hormone-replacement therapy affords an additive protective effect for postmenopausal women, and when these women do develop cancer, they typically have less aggressive disease. The discovery of a second oestrogen receptor (ERbeta) and its over expression in healthy human colon coupled with reduced expression in colon cancer suggests that this receptor might be involved. The underlying mechanism, however, remains largely unknown. In this Review, we discuss the various hypotheses presented in the published literature. We examine the cellular and molecular mechanisms through which oestrogen is purported to exert its protective influence, and we review the evidence available to support these claims.