Circulating microRNAs can predict chemotherapy-induced toxicities in patients being treated for primary breast cancer.

PURPOSE: Prescribing NAC for breast cancer is a pragmatic treatment strategy for several reasons; however, certain patients suffer chemotherapy-induced toxicities. Unfortunately, identifying patients at risk of toxicity often proves challenging. MiRNAs are small non-coding RNA molecules which modulate genetic expression. The aim of this study was to determine whether circulating miRNAs are sensitive biomarkers that can identify the patients likely to suffer treatment-related toxicities to neoadjuvant chemotherapy (NAC) for primary breast cancer. METHODS: This secondary exploratory from the prospective, multicentre translational research trial (CTRIAL ICORG10/11-NCT01722851) recruited 101 patients treated with NAC for breast cancer, from eight treatment sites across Ireland. A predetermined five miRNAs panel was quantified using RQ-PCR from patient bloods at diagnosis. MiRNA expression was correlated with chemotherapy-induced toxicities. Regression analyses was performed using SPSS v26.0. RESULTS: One hundred and one patients with median age of 55 years were recruited (range: 25-76). The mean tumour size was 36 mm and 60.4% had nodal involvement (n = 61) Overall, 33.7% of patients developed peripheral neuropathies (n = 34), 28.7% developed neutropenia (n = 29), and 5.9% developed anaemia (n = 6). Reduced miR-195 predicted patients likely to develop neutropenia (P = 0.048), while increased miR-10b predicted those likely to develop anaemia (P = 0.049). Increased miR-145 predicted those experiencing nausea and vomiting (P = 0.019), while decreased miR-21 predicted the development of mucositis (P = 0.008). CONCLUSION: This is the first study which illustrates the value of measuring circulatory miRNA to predict patient-specific toxicities to NAC. These results support the ideology that circulatory miRNAs are biomarkers with utility in predicting chemotherapy toxicity as well as treatment response.

Evaluating the Role of Circulating MicroRNAs in Predicting Long-Term Survival Outcomes in Breast Cancer: A Prospective, Multicenter Clinical Trial.

BACKGROUND: While long-term outcomes have improved for patients with breast cancer, 20% to 30% will still develop recurrence, and identifying these patients remains a challenge. MicroRNAs (miRNAs) are small, noncoding molecules that modulate genetic expression and affect oncogenesis. STUDY DESIGN: This prospective, multicenter trial (ICORG10/11-NCT01722851) recruited patients undergoing neoadjuvant chemotherapy across 8 Irish centers. Predetermined miRNAs were quantified from patient whole blood using quantitative reverse transcriptase polymerase chain reaction. Venous sampling was performed at diagnosis (timepoint 1) and midway during neoadjuvant chemotherapy (timepoint 2 [T2]). miRNA expression profiles were correlated with recurrence-free survival (RFS), disease-free survival (DFS), and overall survival. Data analysis was performed using R v3.2.3. RESULTS: A total of 124 patients were recruited with a median age of 55.0 years. The median follow-up was 103.1 months. Increased miR-145 expression at T2 was associated with improved RFS (hazard ratio 0.00; 95% confidence interval [CI] 0.00 to 0.99; p = 0.050). Using survival regression tree analysis, a relative cutoff of increased miR-145 expression greater than 0.222 was associated with improved RFS (p = 0.041). Increased miR-145 expression at T2 trended towards significance in predicting improved DFS (hazard ratio 0.00; 95% CI 0.00 to 1.42; p = 0.067). Using survival regression tree analysis, a relative cutoff of increased miR-145 expression greater than 0.222 was associated with improved DFS (p = 0.012). No miRNAs correlated with overall survival. CONCLUSIONS: ICORG10/11 is the first Irish multicenter, translational research trial evaluating circulatory miRNAs as biomarkers predictive of long-term survival and correlated increased miR-145 expression with enhanced outcomes in early-stage breast cancer. Validation of these findings is required in the next generation of translational research trials.

Evaluating the Role of Circulating MicroRNAs to Aid Therapeutic Decision Making for Neoadjuvant Chemotherapy in Breast Cancer: A Prospective, Multicenter Clinical Trial.

OBJECTIVE: To evaluate whether circulating micro ribonucleic acids (miRNAs) predict response to neoadjuvant chemotherapy (NAC) and inform decision-making in breast cancer patients. INTRODUCTION: Deciphering response to NAC remains a challenge. Those unlikely to respond may benefit from NAC de-escalation before completion, while "responders" should complete treatment. Establishing biomarkers which identify response to NAC is imperative to personalize treatment strategies. miRNAs are small noncoding RNA molecules which modulate genetic expression. miRNAs are believed to inform response to NAC. METHODS: This prospective, multicenter trial (NCT01722851) recruited 120 patients treated with NAC across 8 Irish treatment sites. Predetermined miRNAs were quantified from patient whole bloods using relative quantification polymerase chain reactiond. Venous sampling was performed at diagnosis and midway during NAC. Trends in miRNA expression between timepoints were correlated with treatment response. Data analysis was performed using R 3.2.3. RESULTS: A total of 120 patients were included (median age: 55 years). Overall, 49.2% had luminal breast cancers (59/120), 17.5% luminal B (L/HER2) (21/120), 12.5% human epidermal growth factor receptor-2 positive (HER2+) (15/120), and 20.8% triple negative disease (25/120). In total, 46.7% of patients responded to NAC (56/125) and 26.7% achieved a pathological complete response (pCR) (32/120). For patients with L/HER2, increased Let-7a predicted response to NAC ( P =0.049), while decreased miR-145 predicted response to NAC in HER2+ ( P =0.033). For patients with luminal breast cancers, reduced Let-7a predicted achieving a pCR ( P =0.037) and reduced miR-145 predicted achieving a pCR to NAC in HER2+ ( P =0.027). CONCLUSIONS: This study illustrates the potential value of circulatory miRNA measurement in predicting response to NAC. Further interrogation of these findings may see miRNAs personalize therapeutic decision-making for patients undergoing NAC for early breast cancer.

The Impact of Preoperative Breast Magnetic Resonance Imaging on Surgical Management in Symptomatic Patients With Invasive Lobular Carcinoma.

OBJECTIVE: Due to an insidious proliferative pattern, invasive lobular breast cancer (ILC) often fails to form a defined radiological or palpable lesion and accurate diagnosis remains challenging. This study aimed to determine the value of preoperative magnetic resonance imaging (MRI) for ILC and its impact on surgical outcomes. METHODS: Consecutive symptomatic patients diagnosed with ILC in a tertiary centre over a 9-year period were reviewed. The time from diagnosis until surgery, initial type of surgery/index operation (breast-conserving surgery [BCS]/mastectomy) and the rates of reoperation (re-excision/completion mastectomy) were recorded. Patients were grouped into those who received conventional imaging and preoperative MRI (MR+) and those who received conventional imaging alone (MR-). RESULTS: There were 218 cases of ILC, and 32.1% (n = 70) had preoperative MRI. Time from diagnosis to surgery was longer in the MR+ than the MR- group (32.5 vs 21.1 days, P < .001) even when adjusting for age and breast density. Initial BCS was performed on 71.4% (n = 50) of MR+ patients and 72.3% (n = 107) of the MR- group. While the rate of completion mastectomy following initial BCS was higher in the MR+ group (30.0%, n = 15 vs 14.0%, n = 15; χ2 = 5.63; P = .018), this association was not maintained in multivariable analysis. No difference was recorded in overall (initial and completion) mastectomy rate between the MR+ and MR- group (50.0%, n = 35 vs 37.8%, n = 56; χ2 = 2.89; P = .089). Margin re-excision following BCS was comparable between groups (8.0%, n =4, vs 9.3%, n = 10; χ2 = 0.076, P = .783) despite the selection bias for borderline conservable cases in the MR+ group. The rate of usage of MRI for ILC cases declined over the study period. CONCLUSION: While MRI was associated with minor delays in treatment and did not reduce overall rates of margin re-excision or completion mastectomy, it altered the choice of surgical procedure in almost a quarter of MR+ cases. The benefit of preoperative breast MRI appears to be confined to select (younger, dense breast, borderline conservable) cases in symptomatic ILC.

Prospective Assessment of Systemic MicroRNAs as Markers of Response to Neoadjuvant Chemotherapy in Breast Cancer.

Neoadjuvant chemotherapy (NACT) is used in locally advanced breast cancer to reduce tumour burden prior to surgical resection. However, only a subset of NACT treated patients will respond to treatment or achieve a pathologic complete response (pCR). This multicenter, prospective study (CTRIAL-IE (ICORG) 10-11 study) evaluated circulating microRNA as novel non-invasive prognostic biomarkers of NACT response in breast cancer. Selected circulating microRNAs (Let-7a, miR-21, miR-145, miR-155, miR-195) were quantified from patients undergoing standard of care NACT treatment (n = 114) from whole blood at collected at diagnosis, and the association with NACT response and clinicopathological features evaluated. NACT responders had significantly lower levels of miR-21 (p = 0.036) and miR-195 (p = 0.017), compared to non-responders. Evaluating all breast cancer cases miR-21 was found to be an independent predictor of response (OR 0.538, 95% CI 0.308-0.943, p < 0.05). Luminal cancer NACT responders were found to have significantly decreased levels of miR-145 (p = 0.033) and miR-21 (p = 0.048), compared to non-responders. This study demonstrates the prognostic ability of miR-21, miR-195 and miR-145 as circulating biomarkers stratifying breast cancer patients by NACT response, identifying patients that will derive the maximum benefit from chemotherapy.

Investigating the Potential and Pitfalls of EV-Encapsulated MicroRNAs as Circulating Biomarkers of Breast Cancer.

Extracellular vesicles (EVs) shuttle microRNA (miRNA) throughout the circulation and are believed to represent a fingerprint of the releasing cell. We isolated and characterized serum EVs of breast tumour-bearing animals, breast cancer (BC) patients, and healthy controls. EVs were characterized using transmission electron microscopy (TEM), protein quantification, western blotting, and nanoparticle tracking analysis (NTA). Absolute quantitative (AQ)-PCR was employed to analyse EV-miR-451a expression. Isolated EVs had the appropriate morphology and size. Patient sera contained significantly more EVs than did healthy controls. In tumour-bearing animals, a correlation between serum EV number and tumour burden was observed. There was no significant relationship between EV protein yield and EV quantity determined by NTA, highlighting the requirement for direct quantification. Using AQ-PCR to relate miRNA copy number to EV yield, a significant increase in miRNA-451a copies/EV was detected in BC patient sera, suggesting potential as a novel biomarker of breast cancer.

The clinical utility of pre-operative neutrophil-to-lymphocyte ratio as a predictor of outcomes in patients undergoing elective laparoscopic cholecystectomy.

BACKGROUND: In recent years, there has been an increasing trend towards day-case surgery for patients undergoing laparoscopic cholecystectomy (LC). We investigated the predictive value that pre-operative neutrophil-to-lymphocyte ratio (PNLR) had on surgical outcomes. METHODS: A review of all patients who underwent LC during a 6-year period in a single institution was performed and PNLR recorded. A PNLR cutoff value of 3 was utilised. We compared operation time, length of stay (LOS), and conversion to open between those with PNLR less and greater than 3. RESULTS: A total of 567 patients underwent elective LC. Those with PNLR>3 had associated prolonged operation time (p < 0.005), prolonged LOS (p < 0.005), and higher rates of conversion to open surgery (p < 0.005). CONCLUSIONS: PNLR correlates with outcomes following LC. It is useful in delineating patients that have higher risk of conversion or prolonged length of hospital stay and is helpful in assessing suitability of day-case surgery.

The prognostic value of neutrophil-to-lymphocyte ratio in colorectal cancer: A systematic review.

BACKGROUND AND OBJECTIVES: The detection of a simple and reliable prognostic biomarker for colorectal cancer (CRC) outcomes remains a significant challenge. The use of neutrophil-to-lymphocyte ratio (NLR), has been reported to predict surgical and survival outcomes. The aim of our review was to assess the predictive value of pre-operative NLR in predicting post-operative outcomes in CRC. METHODS: A systematic review of the available studies on NLR in CRC was performed. Primarily, we assessed its ability to predict survival outcomes, and highlight values that would help adjuvant therapy choices. RESULTS: 19 studies comprising 10 259 patients were included. Eleven and eight studies reported on patients with localized CRC and colorectal liver metastasis, respectively. Five-year survival for those with localized CRC was 77.2% in patients with a "low" pre-operative NLR versus 50.8% in those with a "high" pre-operative NLR value. Alternatively, for patients with colorectal liver metastasis, patients with a "high" pre-operative NLR value had a 5-year survival of 27%. CONCLUSION: Elevated pre-operative NLR>5 is associated with poorer long-term survival in both patients with localized CRC and those with liver metastasis. NLR is a useful biomarker in delineating those patients with poorer prognosis and whom may benefit from adjuvant therapies.

Predictive factors for colonic resection in patients less than 49 years with symptomatic diverticular disease.

BACKGROUND: Diverticular disease is a condition strongly associated with low-fiber intake and obesity. There have been reports of an increasing incidence in younger individuals ranging from 12% to 21% of all cases. The aim of this study was to evaluate the management of complicated diverticular disease in patients less than 49 years and attempt to identify factors predictive of a more virulent course. METHODS: An analysis of a prospectively updated database of all patients admitted with a primary diagnosis of acute diverticulitis from 2005 to 2013 was performed. Data collected included age, length of stay, inflammatory markers on admission, use of computed tomography (CT), and Hinchey Classification. SPSS version 22 was used for statistical analysis, and a P value of .05 or less was considered significant. RESULTS: A total of 120 (54 female and 66 male) patients less than 49 (28 to 49, 42.1) years were noted to have a diagnosis of acute diverticulitis. Twelve patients (10%) required colonic resection for complicated diverticulitis. Histological evaluation revealed 5 cases of stricture, 2 obstruction, and 5 perforations. On multivariate analysis, predictors of operative intervention and/or colonic resection included, (hazard ratio [95% confidence interval]) patients aged 40 to 49 years (.92 [.9 to .95]) and elevated C-reactive protein on index admission (1.4 [1.32 to 1.54]). Females were less likely to undergo colonic resection compared with males (1.18 [1.15 to 1.2]). Median length of stay was 4 days (1 to 48) for patients managed nonoperatively and 13 days (5 to 27) for those who underwent surgery. CONCLUSIONS: Most younger patients with acute diverticulitis can be treated successfully by conservative means. However, a proportion of patients require aggressive surgical management.

A National Evaluation of the Conservative Management of Uncomplicated Acute Appendicitis: How Common Is This and What Are the Issues.

INTRODUCTION: The management approach for acute appendicitis has been challenged in recent years, with numerous randomized controlled trials demonstrating that antibiotics/conservative management is an efficacious treatment, with lower complication rates. METHODS: A national survey of all consultant general surgeons evaluating their practices was performed. Reasons for changed practices, choice of antibiotics and follow-up investigations were evaluated. In addition, the role of interval appendicectomy and conservative management in the pediatric population was also assessed. RESULTS: The response rate for this survey was 74.7% (n = 74/99). Over one-fifth (n = 17, 22.9%) routinely treat acute appendicitis conservatively, while another 14.8% (n = 11) consider this approach in selected cases. Main reasons for modified practices included the presence of inflammatory phlegmon (75%), delayed presentation (64%), and recent evidence-based medicine developments (46%). Co-amoxiclav/clavulanic acid was the most popular antibiotic for conservative management (53%). Alternatively, combinations of antibiotics were also utilized. One-third felt interval appendicectomy was warranted, while one-fifth supported conservative management in the paediatric setting. The overwhelming majority (>95%) advocate follow-up colonoscopy ± computed tomography in any patient aged >40 years managed conservatively. CONCLUSION: Considerable variation in management of uncomplicated appendicitis remains in Ireland despite growing evidence suggesting that the non-operative approach is safe. Reasons for adopting a conservative management practice have been identified and reflect the expanding literature on this subject.

Efficacy of a Laparoscopically Delivered Transversus Abdominis Plane Block Technique during Elective Laparoscopic Cholecystectomy: A Prospective, Double-Blind Randomized Trial.

BACKGROUND: The management of postoperative pain is paramount to facilitate the delivery of day case surgical programs. In recent years, the complexity of procedures carried out has increased to include laparoscopic cholecystectomy. The aim of this study was to evaluate the impact of laparoscopic-assisted 4-quadrant transversus abdominis plane (TAP) block vs periportal local anesthetic wound infiltration in managing postoperative pain. STUDY DESIGN: A prospective, randomized, double-blinded trial was conducted with patients undergoing elective laparoscopic cholecystectomy. Patients were randomized using computerized "random number table" into a test group that received laparoscopic-assisted TAP block with bupivacaine with periportal saline injection and a control group that received a laparoscopic-assisted TAP block with saline and periportal bupivacaine. All patients received intraperitoneal instillation of bupivacaine in the gallbladder bed. Postoperative pain scores were recorded using numerical rating scores at rest and coughing at dedicated time points. Statistical analysis was carried out using GraphPad Prism software, version 5 (GraphPad Software) and p < 0.05 was considered significant. RESULTS: Eighty patients (70 female and 10 male) were enrolled; 40 patients were randomized to each group. Age, American Society of Anesthesiologists score, operative time, and BMI were comparable between the groups. No adverse events were encountered with the administration of TAP blocks. Numerical rating scores were significantly reduced in the test group at 1, 3, and 6 hours at rest (p = 0.025, p = 0.03, and p = 0.007, respectively). Numerical rating score was significantly reduced at 1, 3, and 6 hours during coughing (p = 0.026, p = 0.02, and p = 0.03, respectively). Difference in postoperative analgesic requirements between both groups was statistically insignificant (p = 0.17). CONCLUSIONS: This analysis has confirmed the therapeutic benefit of laparoscopically delivered TAP blocks in elective laparoscopic cholecystectomy.

Recurrent adult jejuno-jejunal intussusception due to inflammatory fibroid polyp - Vanek's tumour: a case report.

BACKGROUND: Adult intussusception is a rare but challenging condition. Preoperative diagnosis is frequently missed or delayed because of nonspecific or sub-acute symptoms. CASE PRESENTATION: We present the case of a sixty-two year old gentleman who initially presented with pseudo-obstruction. Computerised tomography displayed a jejuno-jejunal intussusception, which was treated by primary laparoscopic reduction. The patient re-presented with acute small bowel obstruction two weeks later. He underwent a laparotomy showing recurrent intussusception and required a small bowel resection with primary anastomosis. Histological examination of the specimen revealed that the intussusception lead point was due to an inflammatory fibroid polyp (Vanek's tumour) causing double invagination. CONCLUSIONS: Adult intussusception presents with a variety of acute, intermittent, and chronic symptoms, thus making its preoperative diagnosis difficult. Although computed tomography is useful in confirming an anatomical abnormality, final diagnosis requires histopathological analysis. Vanek's tumours arising within the small bowel rarely present with obstruction or intussusception. The optimal surgical management of adult small bowel intussusception varies between reduction and resection. Reduction can be attempted in small bowel intussusceptions provided that the segment involved is viable and malignancy is not suspected. VIRTUAL SLIDES: The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/7292185123639943.

Assessing awareness of colorectal cancer symptoms and screening in a peripheral colorectal surgical unit: a survey based study.

BACKGROUND: The National Screening Program for colorectal cancer is scheduled to commence in the near future. Previous studies on the topic of colorectal cancer and screening have highlighted paucity in public awareness of epidemiology, symptoms and signs of colorectal cancer. The aim of this study was to assess understanding of colorectal cancer and screening in a representative sample of the local catchment population of Mayo General Hospital. METHODS: A prospective cohort study was instituted utilising an anonymous survey, which was distributed at consecutive general surgical out-patient clinics over a one month period prior to initiation of the screening program. Data collected included demographics, presenting complaint type and duration, and general knowledge of colorectal cancer facts. Attitudes towards screening were also evaluated. RESULTS: Eighty-eight of the one hundred and thirty six patients sampled were female (65%). Thirty-six per cent of the sample was within the screening target age-group (55-74), with mean age 53 years (+/-18). Most respondents recognised bleeding per rectum as a possible symptom of colorectal cancer. A significant proportion, however, incorrectly selected less sinister symptoms as concerning, while only fifty per cent correctly cited weight loss. Family history was acknowledged as a risk factor by fifty-seven per cent with age and gender cited less often (29%, 4%), while forty-seven per cent incorrectly cited stress as a risk. Screening was defined as testing of symptomatic patients or those with a positive family history by eighty-one per cent of respondents, with only nineteen per cent associating screening with an asymptomatic cohort. Strikingly, twenty-five per cent of patients would decline screening. CONCLUSIONS: There remains poverty of awareness regarding colorectal cancer. More public health initiatives are required to help improve understanding of the disease process, and to improve public compliance with the screening initiative.