Meta-analysis and trial sequential analysis of robotic versus laparoscopic total mesorectal excision in management of rectal cancer.

BACKGROUND: We aimed to evaluate comparative outcomes of robotic and laparoscopic total mesorectal excision (TME) in patients with rectal cancer. METHODS: We systematically searched electronic data sources with application of combination of free text and controlled vocabulary search adapted to thesaurus headings, search operators, and limits. Perioperative clinical and short-term oncological outcomes were evaluated. Trial Sequential Analysis of the outcomes was conducted. RESULTS: Nine randomised-controlled trials reporting 1463 patients evaluating outcomes of robotic TME (n = 728) and laparoscopic TME (n = 735) were included. Although the robotic approach was associated with significantly longer operative time (MD 31.64, P = 0.002), it was associated with significantly longer DRM (MD 0.8, P = 0.004) and shorter time to soft diet (MD - 0.50, P = 0.03) compared to the laparoscopic approach. Moreover, there was no significant difference in intraoperative (RR 1.07, P = 0.76)) and postoperative (RR 0.97, P = 0.81) complications, anastomotic leak (RR 0.93, P = 0.69), conversion to open rate (RR 0.46, P = 0.05), blood loss (MD 19.65, P = 0.74), time to first flatus (MD - 0.30, P = 0.37), LARS (RR 0.83, P = 0.41), ileus (RR 0.72, P = 0.39), positive CRM (RR 0.82, P = 0.49), PRM (MD - 0.5, P = 0.55), number of harvested lymph nodes (MD 0.33, P = 0.58), or length of stay (MD - 0.60, P = 0.12) between two groups. The Trial Sequential Analysis demonstrated that the risk of type 1 and type 2 errors was minimal in most outcomes. CONCLUSIONS: Moderate-quality evidence suggested that robotic and laparoscopic TME may be comparable in terms of clinical and short-term oncological profile but the robotic approach may be associated with longer procedure time. Future high-quality randomised studies are encouraged to compare the functional, long-term oncological, and cost-effectiveness outcomes of both approaches.

Circulating plasma microRNAs as a screening method for detection of colorectal adenomas.

BACKGROUND: MicroRNAs (miRNAs) are small non-coding RNA molecules. Reduced or increased levels of specific miRNAs are observed in colon and other cancers, supporting their role in carcinogenesis. Detection of colorectal polyps is the cornerstone of the Bowel Cancer Screening Programme in the UK. However, uptake of screening nationally remains under 60%. We aimed to see whether circulating plasma miRNAs can be used to screen for patients with colorectal polyps, adenomas, or both. METHODS: Blood samples were taken from patients from the Bowel Cancer Screening Programme (asymptomatic but faecal occult blood testing [FOBt] positive). Plasma RNA was extracted, target miRNAs (19a, 98, 146b, 186, 191, 222*, 331-5p, 452, 625, 664, 1247) were identified on pooled case miRNA assay cards, and miRNA fraction was quantified by quantitative RT-PCR assay. Results were compared with endoscopy reports and with histology of any polyps identified and removed. Analysis was done with Excel (2011) and SPSS (version 20) software. FINDINGS: 210 patients were included (117 with polyps, 12 with cancer, 81 healthy controls [FOBt positive]). The miRNA panel showed significant differences in expression (on t testing) for patients compared with controls for those with polyps, cancer, or both (miR-19a, p=0·0184; miR-98, p=0·0206; miR-146b, p=0·0029; miR-186, p=0·0006; miR-62,5 p=0·0008), polyps (miR-19a, p=0·0233; miR-98, p=0·0224; miR-146b, p=0·003; miR-186, p=0·0004; miR-625, p=0·001), adenomas (miR-19a, p=0·0339; miR-98, p=0·0266; miR-146b, p=0·0045; miR-186, p=0·0008; miR-625, p=0·0049), multiple adenomas (both sides of colon; miR-146b, p=0·0194; miR-186, p=0·0226; miR-625, p=0·0013), and right-sided adenomas (miR-98, p=0·031; miR-146b, p=0·0076; miR-186, p=0·0041; miR-331-5p, p=0·0142; miR-625, p=0·0049). Receiver operating characteristic analysis showed sensitivity of 60% or more, and specificity of 86% or more for men with polyps, men with adenomas, all patients with haemorrhoids or diverticulosis and polyps, and all patients with haemorrhoids or diverticulosis and adenomas. INTERPRETATION: The target miRNAs that we identified showed significant differences in expression levels for patients with polyps and patients with adenomas from controls. Use of this panel has potential as a screening test. FUNDING: Bowel Disease Research Foundation.

MicroRNA manipulation in colorectal cancer cells: from laboratory to clinical application.

The development of Colorectal Cancer (CRC) follows a sequential progression from adenoma to the carcinoma. Therefore, opportunities exist to interfere with the natural course of disease development and progression. Dysregulation of microRNAs (miRNAs) in cancer cells indirectly results in higher levels of messenger RNA (mRNA) specific to tumour promoter genes or tumour suppressor genes. This narrative review aims to provide a comprehensive review of the literature about the manipulation of oncogenic or tumour suppressor miRNAs in colorectal cancer cells for the purpose of development of anticancer therapies. A literature search identified studies describing manipulation of miRNAs in colorectal cancer cells in vivo and in vitro. Studies were also included to provide an update on the role of miRNAs in CRC development, progression and diagnosis. Strategy based on restoration of silenced miRNAs or inhibition of over expressed miRNAs has opened a new area of research in cancer therapy. In this review article different techniques for miRNA manipulation are reviewed and their utility for colorectal cancer therapy has been discussed in detail. Restoration of normal equilibrium for cancer related miRNAs can result in inhibition of tumour growth, apoptosis, blocking of invasion, angiogenesis and metastasis. Furthermore, drug resistant cancer cells can be turned into drug sensitive cells on alteration of specific miRNAs in cancer cells. MiRNA modulation in cancer cells holds great potential to replace current anticancer therapies. However, further work is needed on tissue specific delivery systems and strategies to avoid side effects.

Triple Assessment of Breast Lump: Should We Perform Core Biopsy for Every Patient?

Introduction The triple assessment for a lump in the breast is standard practice and the robustness of assessment towards the diagnosis of breast cancer is crucial. The combination of the modalities, physical examination, imaging (mammogram and ultrasound), and fine-needle aspiration cytology (FNAC) is more accurate than any modality alone. Aim To examine the combined and individual predictive values of physical examination (P), mammography (M), ultrasound (U), FNAC (C), with core biopsy (B) - triple assessment in the diagnosis of breast cancer. Methods To obtain the results of physical examination (P), mammography (M), ultrasound (U), FNAC (C), and core biopsy (B), we examined the records of 124 breast cancer patients seen between April 1, 2009, and March 30, 2010. To assess the diagnostic potential of the combination of the modalities (P, U, and M), we considered all cases with a score of 4 (probably malignant) and 5 (malignant) as positive for malignancy. All cases with a score of 3 (equivocal), 2 (benign), and 1 (normal) were considered negative for malignancy. For FNAC, a score of 1 (insufficient sample), 2 (benign), and 3 (atypia/probably benign) were considered. All the patients were diagnosed with breast cancer on excision biopsy. Among 124 patients, 12 were excluded, as they were unfit for intervention. Results The accuracy of physical examination (P) as confirmed by core biopsy (B) is dependent on the experience of the surgeon. It has limitations in younger women and smaller lesions. In our study, P has a positive predictive value (PPV) of 58.9% when compared with surgical biopsy, which is comparable with other studies. Our results showed PPV 66.1% and after an ultrasound scan, the overall radiological grading (M & U) gives a PPV of 81.3%, reflecting the important role of ultrasound scans. Our results showed the sensitivity of FNAC to be 73.2%. Core biopsy was diagnostic in 107 (95.5%) patients, making it a reliable tool. Our results confirmed that a combination of the modalities (P, M, U, R, FNAC) is more accurate than any modality alone. Conclusion When all the three modalities are positive for a diagnosis of malignant breast disease, surgical biopsy confirms the breast cancer diagnosis with a PPV of 100% and a sensitivity of 95.5%.

Comparison of 'Excision and Primary Repair' with 'Bascom's Technique' in the Surgical Treatment of Pilonidal Sinus.

Introduction The management of the chronic pilonidal disease is variable and the principles of treatment are aimed to eradicate the sinus tract, promote wound healing, prevent disease recurrence, and improve the quality of life of the patient. This study aims to compare the effectiveness of excision and primary closure, and Bascom's technique in the management of pilonidal sinus disease. Methods  The study was performed at a tertiary hospital from April to October 2011. All patients with chronic pilonidal sinus were included in the study (n=60) and randomly allocated into Group A - undergoing excision and primary closure (n=30) and Group B - undergoing Bascom's repair. Comparative outcomes of interest were duration of hospital admission, post-operative pain, wound infection, wound-healing and disease recurrence.  Results The mean age of presentation was 24.18±5.6 years. A higher number of patients in Group A were discharged within 24 hours compared to Group B (p = 0.001). Group B had significantly less post-operative pain by the first postoperative week (p = 0.049). Group B had lower infection rates with clean wounds observed in 28 (93.3%) patients compared to 23 (76.7%) in Group A by the first postoperative week (p = 0.07). Recurrence rate during 12-week follow-up was observed in one (3.3%) patient in Group B, and five (16.7%) in Group A (p= 0.085). Conclusions Patients who underwent Bascom's operation had less postoperative pain, lower infection rates and disease recurrence, and better wound healing. Therefore, in our patient cohort, we conclude Bascom's repair appears to be superior to primary excision and repair in reducing patient morbidity.

Simultaneous stoma reinforcement and perineal reconstruction with biological mesh - A multicentre prospective observational study.

INTRODUCTION: The optimal method for perineal reconstruction after extralevator abdominoperineal excision (elAPE) for low rectal cancer remains controversial. This study aimed to assess whether simultaneous perineal reconstruction and parastomal reinforcement with Strattice™ Reconstructive Tissue Matrix after elAPE could prevent hernia formation. METHODS: In this prospective, multicentre, observational, non-comparative study of consecutive patients undergoing elAPE for low rectal cancer underwent simultaneous perineal reconstruction and colostomy site reinforcement with Strattice™ mesh. All patients underwent long course chemoradiotherapy prior to surgery and had excision of the coccyx. Patients were assessed for perineal wound healing at 7 day, 1, 3, 6 and 12 months, perineal and parastomal hernia defects on clinical and radiological assessment at 1 year following surgery. RESULTS: 19 patients (median age = 67 years, median BMI = 26, M:F = 11:8) were entered the study. 10 (52.6%) patients underwent laparoscopic elAPE. The median length of post-operative stay was 9 days. Complete wound healing was observed for 8(42%) patients at 1 month, 12(63%) at 3 months, and 19(100%) patients at 12 months. Median time for radiological and clinical assessment for hernias was 12 months. No perineal hernia was detected in 17 patients following CT assessment. Dynamic MRI was undertaken in 11 patients at 12 months and all showed no evidence of perineal hernia. 3 (16%) patients had a parastomal hernia detected radiologically. No mesh was removed during the 12 months follow up period. CONCLUSION: Perineal and parastomal reconstruction with biological mesh is a feasible approach for parastomal and perineal hernia prevention after laparoscopic and open elAPE.

Acardiac twins: a case series.

Acardiac twinning is a severe and rare complication of monochorionic placentation. The acardiac twin does not survive while mortality of the normal twin is about 50-70% as the normal twin has to provide circulation not only for itself but also for acardiac twin. Proper timing of the delivery is of prime importance to the survival of the normal fetus for which emphasis is placed on close sonographic monitoring for early antenatal diagnosis. This series describes three such cases, which are now termed Twin Reversed Arterial Perfusion (TRAP) sequence.

The "two-week wait" referral pathway is not associated with improved survival for patients with colorectal cancer.

AIM: To improve survival rates in patients diagnosed with cancer in the UK, a two-week wait (2ww) referral to first appointment target and a 62 day referral to treatment target were introduced in 2004. This study analyses survival rates for patients diagnosed with colorectal cancer (CRC) by mode of referral and referral to treatment time. METHOD: A prospectively maintained database of CRC outcomes at the University Hospitals of Leicester NHS Trust was analysed. Data for patients diagnosed with CRC was analysed for survival. Comparisons were made by mode of referral (2ww, urgent, routine, emergency, national bowel cancer screening programme (NBCSP) and other screening pathways). In addition, this study assessed referral to initial treatment times for patients undergoing cancer resection (<62days group vs. >62days group). Inter-group comparisons were made using the Mann-Whitney-U-test. Kaplan-Meier survival probability estimates were calculated for overall survival and the log-rank test was used to compare the survival distributions in different groups. RESULTS: Overall survival (median time) was significantly lower for patients referred by the '2ww' pathway (3.5 years, 95% CI: 2.7-4.30), in comparison to the 'routine' (5.4 years, 95% CI: 4.5-6.6) pathway (p < 0.001). Patients referred on the '2ww' pathway were 1.34 times more likely to have stage IV disease at presentation in comparison to patients referred by the 'routine' pathway. Comparison of referral to initial treatment times showed there was no significant difference in survival between the <62days group and the >62days group (7.1 vs. 6.54, p = 0.620). CONCLUSION: Patients diagnosed with CRC by the 2ww pathway had shorter survival times than those referred by a routine pathway.

MicroRNAs associated with initiation and progression of colonic polyp: a feasibility study.

INTRODUCTION: Colorectal cancer is the third most common neoplasm worldwide. The sequential progression of colorectal cancer from adenoma to carcinoma highlights that opportunities exist to alter the natural course of disease progression. The aim of this study was to characterize the expression levels of microRNAs linked to development and progression of colorectal neoplasia. Patient, Design, Patients & Methods: MicroRNA expression signature was developed for RNA extracted from freshly frozen tumour and adjacent normal tissue (n = 5). Based on differential expression and literature search, hsa-miR-135b was selected for further characterisation in different types of colonic polyps and cancer tissue. Formalin Fixed Paraffin Embedded tissue were studied for miRNA expression, KRAS, BRAF, PIK3CA mutations, and immuno-histochemistry for APC and p53 proteins for normal colon (n=11), hyperplastic polyps (n=11), high grade adenomas (n=10), low grade adenomas (n=34) and adenocarcinoma (n=13). RESULTS: CRC tissue had significantly higher expression levels of hsa-miR-135b (p=0.0017) than their adjacent paired normal tissues (mean increase=8.90 fold, 95% CI=2.98-26.50). Linear trend analysis showed a progressive increase in expression level of hsa-miR-135b across normal epithelium, low grade adenomas, high grade adenomas and carcinomas (p=0.0007, R squared 0.16, slope -0.35). KRAS mutant colonic polyps and cancer tissue had significantly higher (3.04 fold, 95% CI=1.23-7.46) expression levels of hsa-miR-135b compared to polyps and cancers with non mutant KRAS gene (p=0.001). Whereas, hsa-miR-135b expression levels were significantly lower in colonic polyp and cancer tissue stained positively for APC proteins (p<0.001). CONCLUSION: There is a progressive increase in expression levels of hsa-miR-135b correlating with the sequential progression of normal epithelium to adenoma and carcinoma. Expression levels of hsa-miR-135b correlate with expression of APC proteins in colorectal tissue suggesting its role in tumour initiation. HIGHLIGHTS: This study highlights the role of tissue microRNAs for their role in the development of colorectal carcinoma. Identification of tissue specific microRNAs will help is designing microRNAs based gene therapies to control the development and progression of colonic neoplasia.

Ten years experience of managing the primary tumours in patients with stage IV colorectal cancers.

INTRODUCTION: Approximately 20% of patients with colorectal cancer have metastases at the time of presentation. Such patients are often offered systemic chemotherapy but debate continues as to whether these patients benefit from resection of the primary tumour. We describe our ten years experience of managing the primary tumours in patients with stage IV colorectal cancer. The aim of this study was to describe the overall survival of patients undergoing surgery in these circumstances and to determine whether any prognostic indicators could be identified. PATIENTS & METHODS: 920 consecutive patients presenting with stage IV colorectal cancer disease were identified from the Leicester Colorectal Cancer database. Patients undergoing resection of the primary tumour (Resection Group) with the residual metastatic disease were compared to those patients who had not their primary tumour excised (Non-Resection Group). Various different variables in two groups were compared by using Mann-Whitney U test. Kaplan-Meier survival analysis and log-rank test were used to compare the overall survivals. Univariate analysis was performed for each group to elicit the significant prognostic factors whereas Cox regression model was used to identify the independent predictors of overall survival. RESULTS: The Kaplan-Meier survival analysis of two groups showed prolonged survival for Resection Group compared to the Non-Resection Group (median; 14.5 Vs 5.83 months, p = <0.005). The multivariate analysis of different survival predicting variables, revealed the resection of the primary tumour as an independent predictor of overall survival (p < 0.001). The univariate analysis of resection group identified age at presentation, tumour site, tumour stage (pT), lymph nodal stage (pN), complete histological resection, tumour fixity, ASA grade, mode of surgery, post-operative chemotherapy and sites of metastasis as significant factors (p < 0.05) for survival prediction. When these factors were used in Cox-Regression model, only the age at presentation (p = 0.001), tumour fixity (p = 0.012) and lymph nodal involvement (p = 0.042) were independent predictors for overall survival. Treatment with post-operative chemotherapy and a smaller volume of liver metastases were associated with prolonged survival (p < 0.05). CONCLUSIONS: Surgical resection of primary tumour for stage IV colorectal cancers is associated with prolonged survival for selected patients. Age at presentation, extent of liver involvement, tumour fixity and ASA grade can help to decide the patients who will benefit from surgery.

Synchronous ileal carcinoid and primary colonic neoplasms: a case report.

Primary colonic tumours with synchronous ileal carcinoid tumours are rare in occurrence and are mainly found incidentally on autopsies or pathological examination of resected surgical specimens. This article describes a case of adenomatous colonic polyps, adenocarcinoma of sigmoid colon and concurrent malignant carcinoid tumour of ileocaecal junction, detected on colonoscopic examination. The radiological staging investigations revealed no distant spread of disease. The patient was effectively treated with subtotal colectomy, resection of terminal ileum, excision of locoregional lymph nodes and the bowel continuity was restored with stapled ileo-rectal anastomosis. This article is as an example of concomitant presence of two types of malignant tumours, effectively managed surgically.