Metabolomic Pathway Activity with Genomic Single-Nucleotide Polymorphisms Associated with Colorectal Cancer Recurrence and 5-Year Overall Survival.

PURPOSE: Metabolomic analysis in colorectal cancer (CRC) is an emerging research area with both prognostic and therapeutic targeting potential. We aimed to identify metabolomic pathway activity prognostic for CRC recurrence and overall survival and cross-reference such metabolomic data with prognostic genomic single-nucleotide polymorphisms (SNPs). METHODS: A systematic search of PubMed, Embase and Cochrane Library was performed for studies reporting prognostic metabolomic pathway activity in CRC in keeping with PRISMA guidelines. The QUADOMICS tool was used to assess study quality. MetaboAnalyst software (version4.0) was used to map metabolites that were associated with recurrence and survival in CRC to recognise metabolic pathways and identify genomic SNPs associated with CRC prognosis, referencing the following databases: Human Metabolome Database (HMDB), the Small Molecule Pathway Database (SMPDB), PubChem and Kyoto Encyclopaedia of Genes and Genomes (KEGG) Pathway Database. RESULTS: Nine studies met the inclusion criteria, reporting on 1117 patients. Increased metabolic activity in the urea cycle (p = 0.002, FDR = 0.198), ammonia recycling (p = 0.004, FDR = 0.359) and glycine and serine metabolism (p = 0.004, FDR = 0.374) was prognostic of CRC recurrence. Increased activity in aspartate metabolism (p < 0.001, FDR = 0.079) and ammonia recycling (p = 0.004, FDR = 0.345) was prognostic of survival. Eight resulting SNPs were prognostic for CRC recurrence (rs2194980, rs1392880, rs2567397, rs715, rs169712, rs2300701, rs313408, rs7018169) and three for survival (rs2194980, rs169712, rs12106698) of which two overlapped with recurrence (rs2194980, rs169712). CONCLUSIONS: With a caveat on study heterogeneity, specific metabolites and metabolic pathway activity appear evident in the setting of poor prognostic colorectal cancers and such metabolic signatures are associated with specific genomic SNPs.

Perioperative cell-free DNA trends predict recurrence of non-metastatic colorectal cancer significantly earlier than CEA trends over the first 2 years post-operatively in stage II and stage III colon cancer.

PURPOSE: We aimed to compare the diagnostic accuracy of perioperative ΔcfDNA to ΔCEA (over the first 2 years post-operatively) for identifying disease recurrence in colon cancer. METHODS: Patients presenting for elective resection for colon cancer with curative intent were screened for inclusion. Perioperative cfDNA levels were measured at seven different times points(pre-operative and post-operative at 3 h, 6 h, 24 h, 48 h, POD3 and POD5). CEA levels were measured on the same patients up to 2 years post-operatively. Change in trend (Δ) was defined as the ß coefficient using a logistic regression model. Statistical analysis was performed using SPSS, version 23. RESULTS: Longitudinal data on twenty-two patients were analysed (n = 16 male, n = 6 female) for a median of 29 months (IQR 23 months) during which time three patients developed (distant) recurrence. Perioperative ΔcfDNA at 48Hrs, POD3 and POD5 were significantly associated with early recurrence. ΔCEA was significantly associated with early recurrence at 6 months, 1 year and 2 years post-operatively, only when disease recurrence was macroscopically established. ΔcfDNA was associated with an area under the curve (AUC) of 0.947 (95% CI 0.88-1.0, p < 0.001) and ΔCEA was associated with an AUC of 0.9382 (95%CI 0.88-0.99, p < 0.0001). This translated into a specificity of 97% (95%CI 86.51-99.87%) for ΔcfDNA and 77.5% sensitivity (95%CI 62.5-87.7%) in the immediate perioperative period and an 88.9% specificity (95%CI 56.5-99.4%) and 76.5% sensitivity (95%CI 63.24-86%) for ΔCEA over the first 2 years post-operatively. CONCLUSIONS: In this pilot study, following curative resection for colon cancer changing trends in perioperative cfDNA (ΔcfDNA) identify those at risk of recurrent disease before recurrence develops which is at least 6 months earlier than CEA changes (ΔCEA) which are only observed when recurrence is established.

Body Composition, Inflammation, and 5-Year Outcomes in Colon Cancer.

Importance: Obesity, particularly visceral obesity and sarcopenia, are poor prognostic indicators in colon cancer. Objectives: To explore the association between body composition profiles and 5-year colon cancer outcomes and delineate the associated underlying inflammatory processes. Design, Setting, and Participants: This multicenter translational cohort study included patients with nonmetastatic colon cancer who did not have underlying chronic inflammatory disorders and were not receiving anti-inflammatory drugs referred to tertiary cancer centers from 2009 to 2015. Preoperative acute phase proteins (white cell count, C-reactive protein, and albumin), cytokines (interleukin [IL]-1b, IL-2, IL-6, IL-10, interferon γ, and tumor necrosis factor α), vascular endothelial growth factor (VEGF), and cell surface receptor expression levels (CD11b and CD14) were measured. All patients underwent follow-up for at least 5 years. Data were analyzed in December 2020. Exposure: Nonmetastatic colon cancer. Main Outcomes and Measures: The associations of body composition profiles with 5-year cancer recurrence and disease-specific mortality were analyzed using Mantel Cox log-rank test and Kaplan-Meier curves. Results: A total of 28 patients were included (median [interquartile range] age, 67 [58-72] years; 22 [78.6%] men). Low skeletal muscle area (SMA) and high visceral to total fat ratio were associated with poor clinical and oncological outcomes, including increased 5-year recurrence (low SMA: hazard ratio [HR], 2.30 [95% CI, 1.41-2.89]; P = .04; high visceral to total fat ratio: HR, 5.78 [95% CI, 3.66-7.95]; P = .02). High visceral to total fat ratio was associated with increased 5-year disease-specific mortality (HR, 5.92 [95% CI, 4.04-8.00]; P = .02). Patients with low SMA who developed a cancer recurrence, compared with those who did not, had higher C-reactive protein (mean [SD], 31.24 [6.95] mg/dL vs 8.11 [0.58] mg/dL; P = .003), IL-6 (mean [SD], 1.93 [1.16] ng/mL vs 0.88 [0.14] ng/mL; P = .004), VEGF (mean [SD], 310.03 [122.66] ng/mL vs 176.12 [22.94] ng/mL; P = .007), and CD14 (mean [SD], 521.23 [302.02] ng/mL vs 322.07 [98.35] ng/mL; P = .03) expression and lower albumin (mean [SD], 3.8 [0.6] g/dL vs 43.50 [3.69] g/dL; P = .01), IL-2 (mean [SD], 0.45 [0.25] ng/mL vs 0.94 [0.43] ng/mL; P < .001), IL-10 (mean [SD], 8.15 [1.09] ng/mL vs 16.32 [4.43] ng/mL; P = .004), and interferon γ (mean [SD], 2.61 [1.36] ng/mL vs 14.87 [3.43] ng/mL; P = .02) levels. Patients with high visceral to total fat ratio who developed recurrence had higher levels of IL-6 (mean [SD], 5.26 [7.05] ng/mL vs 2.76 [3.11] ng/mL; P = .03) and tumor necrosis factor α (mean [SD], 5.74 [4.53] ng/mL vs 4.50 [1.99] ng/mL; P = .03). Conclusions and Relevance: These findings suggest that low SMA and high visceral to total fat ratio were associated with worse colon cancer outcomes and with increased expression of proinflammatory cytokines and VEGF and inhibition of anti-inflammatory cytokines.

The LOCalizer Radiofrequency Identification System: An Effective New Technology for Localizing Non-Palpable Breast Lesions for Surgery.

Background. Breast screening has decreased morbidity and mortality due to detection of early, non-palpable breast cancers. One of the challenges of performing breast-conserving surgery on non-palpable breast tumours is accurate localization of the cancer. We aimed to perform a feasibility study to examine the outcomes associated with the introduction of a novel radiofrequency identification system (RFID) called LOCalizer as an alternative to traditional wire-guided localization. Methods. Data were prospectively collected on all patients undergoing breast-conserving surgery using the LOCalizer RFID system in a regional cancer centre between July 2019 and March 2020. Patients had a RFID tag placed preoperatively and underwent surgical removal of the tag with the index lesion guided by a handheld LOCalizer probe. The primary aim was successful placement and retrieval of the RFID tag. Re-excision rates, specimen size, specimen weight, cancer subtype and complication rate were all recorded. Results. Sixty-nine patients aged between 50 and 69 years had a LOCalizer tag inserted between July 2019 and March 2020. Of these, 6 (8.7%) were diagnostic and 63 (91.3%) were therapeutic. There was no migration of RFID tags, and all tags were retrieved with the index lesion. The overall re-excision of margin rate was 17.4% (12/69). All re-excision of margins was due to positive radial margins. The overall complication rate was 1.4% with one grade 1 Clavien-Dindo morbidity. Conclusion. The LOCalizer RFID is an effective and safe wire-free localization method for non-palpable breast lesions.

A review of clinical and oncological outcomes following the introduction of the first robotic colorectal surgery programme to a university teaching hospital in Ireland using a dual console training platform.

Robotic-assisted surgery is evolving, with improving clinical and cancer outcomes. The aim of this study was to present the clinical and cancer outcomes of patients undergoing robotic-assisted colorectal surgery (RAS-CR) at University Hospital Limerick (UHL) since its introduction to the 100th case, using the daVinci Xi dual-console surgical system. The RAS-CR programme at UHL commenced in June 2016 and the 100th case was performed in July 2019. All patient-related data were recorded prospectively during the perioperative period by the RAS-CR team. Statistical analysis was performed using SPSS, version 22. One hundred patients were operated on, comprising of 47 males and 53 females. The median age was 65 years (IQR 13.0; range 25-84) with 69% of cases performed for cancer [N = 39 rectal cancer, N = 30 colon cancer], 20% for benign disease and 11% for dysplasia. Median length of stay for cancer operations was 6.5 days for colon cancer cases (5.0 days when cases with complications were excluded) and 7.0 days for rectal cancer cases. Median operative time was 255 mins (IQR 130 min; all cases), median docking time was 33 mins (IQR 20 mins) and median intra-operative blood loss was 80 ml (IQR 70 ml). Thirty-one patients developed a post-operative complication (5% anastomotic leak; 13% SSI). In cancer cases, median nodal harvest was 14 nodes (IQR10) and an R0 resection was achieved in 98.6% (n = 68) of cancer cases. Three patients (4.3%) developed metastatic disease at a median interval of 16.5 months. Clinical and operative outcomes remained stable over time from case 1 to 100. Structured introduction of a RAS-CR programme with appropriate governance and continuous audit results in favourable clinical and cancer outcomes and provides an excellent training opportunity for surgical residents.

Six-year review of traumatic brain injury in a regional trauma unit: demographics, contributing factors and service provision in Ireland.

BACKGROUND: Traumatic brain injury (TBI) represents a significant burden of care for acute surgical services, particularly in the absence of on-site neurosurgical cover or sufficient post-acute rehabilitation facilities. We examine factors contributing to TBI, prolonged lengths of stay (LoS) and implications for hospital resources. Long-term outcomes are assessed. METHODS: This is a retrospective cohort study of patients admitted to a regional trauma unit with TBI from 2008 to 2013. Patients with LoS > 48 h were assessed. Demographic, clinical and longitudinal mortality data were collected using electronic clinical and radiological systems and chart review. RESULTS: A total of 690 patients presented with TBI from 2008 to 2013; 213 patients with LoS > 48 h were assessed. One hundred and thirty (61%) were male. Mean age was 56 years (±SD 24). Mechanical fall was the most frequent injury mechanism (n = 120/213, 56%). Twenty-five per cent were associated with alcohol consumption; these were more likely to be male, involved in an Road Traffic Accident (RTA) or assault and necessitate transfer to a neurosurgical unit (p < 0.001, p = 0.029, p < 0.001, p = 0.05). A total of 112 patients(53%) had a prolonged LoS (>2 weeks). Mean LoS was 20 days (±SD 35), increasing to 39 days for patients requiring neurosurgical intervention. The 12-month all-cause mortality rate was 12%. CONCLUSIONS: TBIs result in significant utilisation of acute inpatient bed days. Improved rehabilitation services and strategies to reduce acute hospital LoS are warranted.

Focused Versus Bilateral Parathyroid Exploration for Primary Hyperparathyroidism: A Systematic Review and Meta-analysis.

BACKGROUND: Focused exploration (FE) and bilateral parathyroid exploration (BE) are the standard surgical options for patients with primary hyperparathyroidism. However, the relative risk of recurrence, persistence, overall failure, reoperation, and any complications associated with either surgical approach is unclear. This study compared the outcomes and complication rates after FE and BE for patients with primary hyperparathyroidism. METHODS: PubMed and Embase were searched for studies comparing these outcomes between FE and BE. A meta-analysis was performed using RevMan 5.3 software. Published data were pooled using the DerSimonian random-effect model, and results were presented as odds ratio (OR) or mean difference with 95% confidence interval (CI). RESULTS: A total of 12,743 patients from 19 studies were included in this meta-analysis. In comparison with BE, the FE arm had comparable rates of recurrence (OR 1.08; 95% CI 0.59-2.00; p = 0.80; n = 9 studies), persistence (OR 0.89; 95% CI 0.58-1.35; p = 0.58; n = 13), overall failure (OR 0.88; 95% CI 0.58-1.34; p = 0.56; n = 13), and reoperation (OR 1.05; 95% CI 0.25-4.32; p = 0.95, n = 4). The operative time was significantly shorter (mean difference = -39.86; 95% CI -53.05 to -26.84; p < 0.01, n = 9), with a lower overall complication rate in the FE arm (OR  0.35; 95% CI 0.15-0.84; p = 0.02; n = 12). The latter was attributed predominantly to a lower risk of transient hypocalcemia (OR  0.36; 95% CI 0.14-0.90; p = 0.03; n = 9). There was a significant heterogeneity among these studies for all outcomes except for disease recurrence. CONCLUSIONS: Compared with BE, FE has similar recurrence, persistence, and reoperation rates but significantly lower overall complication rates and shorter operative time.

The significance of BRAF V600E mutation status discordance between primary cutaneous melanoma and brain metastases: The implications for BRAF inhibitor therapy.

To compare BRAF V600E status of primary melanoma and brain metastases to assess for discordance by cross-sectional study, and to evaluate clinical implications on BRAF inhibitor therapy.Brain metastases are common in patients with advanced melanoma. Between 40% and 60% of melanomas demonstrate BRAF mutations, BRAF V600E being most common. Selective BRAF inhibitor therapy has shown improvement in outcome in patients with melanoma. It has been demonstrated that not all metastatic lesions carry the same BRAF mutation status as the primary, but the frequency in which discordance occurs remains unclear. Establishing this may have implications in the use of BRAF inhibitors in patients with melanoma brain metastases.Patients who underwent metastectomy for melanoma brain metastases were identified using our local histopathology database. A review of histology of the primary lesion and the metastasis was performed for each patient, assessing for BRAF mutation status discordance.Fourty-two patients who underwent a brain metastectomy following excision of a melanoma primary were identified over a 7-year period. Median survival was 9 months. The median Breslow thickness for the primary lesion was 3.4 mm. Six patients (14%) had discrepancy between the BRAF status of a melanoma primary and metastatic lesion. Of these 6 patients, 3 had a BRAF mutation positive primary with a BRAF mutation negative metastatic lesion, while the other 3 had a BRAF mutation negative primary with BRAF mutation positive metastasis.There is an important discordance rate in the BRAF mutation status of melanoma primaries versus brain metastases.

Predictors and patterns of melanoma recurrence following a negative sentinel lymph node biopsy.

To analyse the patient demographics, tumour characteristics and follow-up data of patients with recurrence of melanoma following a negative sentinel lymph node biopsy. A retrospective review of a prospectively maintained melanoma database was conducted. Melanoma patients who had a negative sentinel lymph node were identified and we performed statistical analysis on their respective demographics, tumour histology characteristics and follow-up data. Of 164 patients studied, 40 (24%) had a recurrence of melanoma at a median of 39.5 months following diagnosis (range 1-92 months). Distant metastases were the most common form of disease recurrence (40% of all recurrences). Increasing tumour thickness was an independent predictor of recurrence on multivariate analysis while nodular histology approached significance. Median survival of 6 months was seen following disease recurrence (range 1-126 months). In the setting of a negative sentinel lymph node biopsy, there remains a risk of melanoma recurrence. Distant metastases were the most common form of recurrence. Disease recurrence occurred more frequently in those with thick primary tumours. Recurrences occurred at long intervals from diagnosis indicating the need to consider prolonged patient follow-up.

Case report of recurrent acute appendicitis in a residual tip.

INTRODUCTION: Residual appendicitis involving the stump of the appendix has been well described in the literature in the past. CASE REPORT: We report the case of a 43 year old male with acute onset of abdominal pain who had undergone an appendicectomy ten years previously. Ultrasound revealed the presence of an inflamed tubular structure. Subsequent laparotomy and histology confirmed that this structure was an inflamed residual appendiceal tip. CONCLUSION: Residual tip appendicitis has not been reported in the literature previously and should be considered in the differential diagnosis of localised peritonitis in a patient with a history of a previous open appendicectomy.