Association of preoperative and postoperative circulating tumour DNA (ctDNA) with PIK3CA gene mutation with risk of recurrence in patients with non-metastatic breast cancer.

BACKGROUND: Circulating tumour DNA (ctDNA), contains tumour-specific gene mutation in blood circulation and could aid in postoperative risk stratification of non-metastatic breast cancer. In this study, we investigated the feasibility of detecting PIK3CA gene mutations in ctDNA in the preoperative (preop) and postoperative period (postop), and its prognostic significance in patients with breast cancer. METHODS: A cohort of patients with breast cancer undergoing curative surgery with available blood samples preoperatively and postoperatively (Post op) at either Post op time period; week 1-2, week 3-4 or weeks 5-12 were enrolled. PIK3CA gene mutations at exons 9 and 20 were detected in ctDNA with High resolution melting (HRM) PCR and Allele specific fluorescence probe-based PCR. RESULTS: A total of 62 patients (age, median (IQR), 51.50 (45.0-65.0) years), with a median follow-up of 90 months (interquartile range (IQR),60-120 months) were enrolled. In total, 25 (40.3%) and 22 (35%) patients with breast cancer had detectable PIK3CA gene mutations in ctDNA in preoperative and postoperative period, respectively. PIK3CA gene mutations in ctDNA in postoperative period (hazard ratio (H.R: 18.05, p = 0.001) were a negative prognostic factor for recurrencefree survival (RFS) and overall survival (OS) (H.R: 11.9, p = 0.01) in patients with breast cancer. Subgroup analysis of ctDNA indicate that positive ctDNA in both preoperative/postoperative period and post op period only were found to have prognostic effect on RFS and OS (RFS; p < 0.0001, O·S; p = 0.0007). Moreover, ctDNA-based detection preceded clinical detection of recurrence in patients with an average lead time of 12 months (IQR:20-28.5 months) across all the breast cancer subtypes. CONCLUSION: We highlighted the prognostic ability of ctDNA in patients with breast cancer in perioperative period. However, future prospective studies are needed to assess the utility of ctDNA in clinical practice.

Assessment of cell-free DNA (cfDNA) concentrations in the perioperative period can predict risk of recurrence in patients with non-metastatic breast cancer.

BACKGROUND: Circulating cell-free DNA (cfDNA) is a potential non-invasive biomarker of disease status in patients with cancer, and provides important diagnostic and prognostic information in breast cancer. The goal of this study was to quantify cfDNA concentrations during the perioperative period and investigate its potential utility to detect recurrence outcomes in patients with breast cancer. METHODS: Sixty-two (n = 62) patients with non-metastatic breast cancer, undergoing curative-intent surgery were screened for inclusion. Blood samples were collected from these patients: pre-operatively (Preop) and post-operatively (PO) at either of the following PO time points; PO week 1-2, PO week 3-4 and PO weeks 5-12 following surgery. cfDNA was extracted and quantified using nanodrop spectrophotometer. RESULTS: In a cohort of 62 patients (age, median (IQR), 51.5(45.0-65.0) years), with a median follow-up of 90 months (interquartile range (IQR),60-120 months), significant association was observed between cfDNA concentrations and risk of recurrence in patients with breast cancer. The group of patients who had disease recurrence during follow-up had significantly higher cfDNA concentrations (cutoff:400 ng/ml) compared to the group of patients who remain disease-free (Preop and PO period: p < 0.0001). The median Recurrence Free Survival (RFS) between the Disease Recurrence (DR) and the Disease Free (DF) groups of patients with breast cancer were 12(20-28.5) months and 72.00 (96-120) months; p < 0.0001). Univariate and multivariate cox regression analysis indicated that postoperative cfDNA concentration (Hazard ratio:5.0, 95% Confidence Interval:1.19-21.28, p = 0.028) was an independent negative prognostic factor for RFS in patients with non-metastatic breast cancer. CONCLUSION: Our study demonstrated that high postoperative cfDNA is associated with increased risk of future recurrence in patients with non-metastatic breast cancer. Further, prospective studies are warranted to validate its clinical utility in breast cancer.

The relevance of liquid biopsy in surgical oncology: The application of perioperative circulating nucleic acid dynamics in improving patient outcomes.

BACKGROUND: Liquid biopsy is gaining increasing clinical utility in the management of cancer patients. The main components of a liquid biopsy are circulating nucleic acids, circulating tumour cells and extracellular vesicles such as exosomes. Circulating nucleic acids including cell free DNA (cfDNA) and circulating tumour DNA (ctDNA) in particular have been the focus of recent attention as they have demonstrated excellent potential in cancer screening, provision of prognostic information and in genomic profiling of a tumour without the need for repeated tissue biopsies. The aim of this review was to explore the current evidence in relation to the use of liquid biopsy in the perioperative setting and identify ways in which liquid biopsy may be applied in the future. METHODS: This narrative review is based on a comprehensive literature search up to the 1st of June 2020 for papers relevant to the application of liquid biopsy in surgical oncology, focusing particularly on the perioperative period. RESULTS: Recent evidence has demonstrated that perioperative liquid biopsy can accurately stratify patients' risk of recurrence compared to conventional biomarkers. Attention to the perioperative dynamics of liquid biopsy components can potentially provide new understanding of the complex relationship between surgery and cancer outcome. In addition, careful evaluation of liquid biopsy components in the perioperative window may provide important diagnostic and therapeutic information for cancer patients. CONCLUSION: The rapidly evolving concept of the liquid biopsy has the potential to become the cornerstone for decision making around surveillance and adjuvant therapies the era of personalised medicine.

Association of Circulating Tumor DNA With Disease-Free Survival in Breast Cancer: A Systematic Review and Meta-analysis.

Importance: Fragmented DNA is continuously released into the circulation following apoptosis and necrosis of both cancerous and noncancerous cells; when it is released by cancer cells, it is specifically known as circulating tumor DNA (ctDNA). Previous studies have suggested that ctDNA can reflect tumor burden and guide potential therapeutic targets. Objective: To determine the association of ctDNA with breast cancer disease-free survival (DFS) and progression-free survival in early, locally advanced, and metastatic breast cancer. Data Sources: An electronic search was conducted using the Cochrane Library, ScienceDirect, PubMed, and Embase from July 30, 2019, to October 31, 2019; all languages were included. The following search terms were used: ctDNA OR circulating tumor DNA OR liquid biopsy AND breast cancer OR breast carcinoma OR breast tumor AND prognosis OR survival. All titles were screened, and the appropriate abstracts were reviewed. If any data were missing, the authors contacted the study authors for permission to access data and extrapolate hazard ratios (HRs). Study Selection: To be included in the analysis, the studies had to meet the following prespecified inclusion criteria: (1) a ctDNA blood sample was measured; (2) DFS, progression-free survival, or relapse-free survival was reported as an HR; and (3) the patient population only had breast cancer. Retrospective and prospective observational cohort studies were included. Data Extraction and Synthesis: Two authors (C.C. and C.F.) independently reviewed the literature. All data were recorded independently by both authors and were compared at the end of the reviewing process to limit selection bias. Duplicates were removed and any disparities were clarified. Data were pooled using a fixed-effects or random-effects model according to the study heterogeneity. This study adhered to the guidelines of the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) and Meta-Analysis of Observational Studies in Epidemiology (MOOSE). Main Outcomes and Measures: The primary outcome was the association of ctDNA with DFS or relapse-free survival in breast cancer. Secondary outcomes focused on subgroup analysis in the setting of early breast cancer and metastatic breast cancer. Results: From a total of 263 publications found using the predefined search terms, data from 8 studies (3.0%) reporting on 739 patients in total were suitable for inclusion. Circulating tumor DNA gene variation detection (both before and after treatment) was statistically significantly associated with shorter DFS (HR, 4.44; 95% CI, 2.29-8.61; P < .001). Detection of ctDNA was statistically significantly associated with a reduction in DFS in both the early breast cancer subgroup (HR, 8.32; 95% CI, 3.01-22.99; P < .001) and the metastatic or locally advanced subgroup (HR, 1.91; 95% CI, 1.35-2.71; P < .001). Pretreatment and posttreatment plasma sample collection was analyzed in both early and metastatic groups. The posttreatment group encompassed both surgical and oncologic therapy. Pretreatment plasma detection of ctDNA was statistically significantly associated with reduced DFS (HR, 3.30; 95% CI, 1.98-5.52; P < .001). Posttreatment sampling of ctDNA failed to achieve statistical significance (HR, 8.17; 95% CI, 1.01-65.89; P = .05). Conclusions and Relevance: In this systematic review and meta-analysis, elevated plasma ctDNA was associated with a high risk of relapse. This finding suggests that plasma ctDNA may provide an excellent method to stratify risk and personalize patient follow-up.

Can the Neutrophil to Lymphocyte Ratio Predict Complete Pathologic Response to Neoadjuvant Breast Cancer Treatment? A Systematic Review and Meta-analysis.

The systemic inflammatory response plays a role in tumor progression and development. The neutrophil to lymphocyte ratio (NLR) is a biochemical marker of systemic inflammation and is increasingly gaining appreciation for its prognostic role in predicting breast cancer outcomes. Previous research has demonstrated that patients who achieve a complete pathologic response (pCR) to neoadjuvant breast cancer treatment have a more favorable disease-free survival. This study aimed to assess whether the NLR can predict pCR to neoadjuvant therapy in breast cancer. A meta-analysis of 8 relevant studies was performed. The primary endpoint included pCR. Secondary endpoint included 5-year disease-free survival. Eight studies were included, reporting on 1586 patients. A total of 363 (22.88%) patients achieved pCR post neoadjuvant therapy. A lower NLR was associated with a greater rate of pCR (odds ratio, 1.83; 95% confidence interval, 1.15-2.91; P = .0003). Only 4 studies produced data on disease-free survival. A lower NLR was associated with a higher 5-year disease-free survival; however, this did not achieve statistical significance (hazard ratio, 1.38; 95% confidence interval, 0.82-2.31; P = .02). Sub-group analysis of sample size, NLR value, and geographic location proved statistically significant in determining an association between NLR and pCR. This meta-analysis found NLR to be a predictor for pCR in patients with breast cancer. All of the studies reviewed were retrospective cohort studies. Adequately sized, prospective clinical trials are needed to understand if NLR could become an important prognostic indicator of pCR.

Evolution of adrenal surgery in a tertiary referral centre.

BACKGROUND: Laparoscopic transperitoneal and retroperitoneoscopic adrenalectomy have largely replaced open adrenal surgery, particularly in benign disease. Laparoscopic surgery results in less post-operative pain, fewer surgical site complications and reduced length of hospital stay. The aim of this retrospective study was to analyse the characteristics of patients and evolution of surgical technique in adrenal surgery at Cork University Hospital over a 12-year period. METHODS: All cases of adrenalectomy between January 1st, 2007 and December 31st, 2018 were retrospectively reviewed. Patient demographics, diagnosis, surgical approach, length of hospital stay, histology and complications were evaluated. Comparisons were made between open, laparoscopic transperitoneal and retroperitoneoscopic adrenalectomy cases. RESULTS: There were 57 adrenalectomies performed on 55 patients over the 12-year period. Twenty-six patients (46%) were male, and the mean age was 49 years (range 14-84 years). Twenty-two (39%) right-sided adrenalectomies were performed, 33 (57%) left sided and 2 (4%) patients underwent bilateral surgery. Seventeen adrenalectomies were performed using an open transperitoneal approach, 30 via a laparoscopic transperitoneal approach and 10 using the retroperitoneoscopic technique. Adenoma and pheochromocytoma were the most common indications for surgery (42% and 40%, respectively). Seven percent were performed for malignancy and 5% for other benign indications. The complication rate for open adrenalectomy was 18% versus 10% in laparoscopic transperitoneal adrenalectomy and 0% for retroperitoneoscopic adrenalectomy. Two patients (7%) undergoing laparoscopic transperitoneal surgery required conversion to an open procedure. There were no 30-day mortalities and no disease recurrence within the study time frame. The mean length of hospital stay was 7.6 days in the open group, 5.8 days for the laparoscopic transperitoneal group and 3 days for the retroperitoneoscopic group (p = 0.03). CONCLUSIONS: Adrenalectomy is a safe procedure and in our setting was primarily performed for pheochromocytoma and non-functioning adenomas. Minimally invasive adrenalectomy has become the standard of care internationally and is associated with fewer complications, shorter hospital stay and a low conversion rate.

The Efficacy of Prophylactic Negative Pressure Wound Therapy for Closed Incisions in Breast Surgery: A Systematic Review and Meta-Analysis.

BACKGROUND: Negative pressure wound therapy (NPWT) is a promising advance in the management of closed surgical incisions. NPWT application induces several effects locally within the wound including reduced lateral tension and improving lymphatic drainage. As a result, NPWT may improve wound healing and reduce surgical site complications. We aim to evaluate the efficacy of prophylactic application of NPWT in preventing surgical site complications for closed incisions in breast surgery. METHODS: This systematic review was reported according to PRISMA guidelines. The protocol was published in PROSPERO (CRD42018114625). Medline, Embase, CINAHL and Cochrane Library databases were searched for studies which compare the efficacy of NPWT versus non-NPWT dressings for closed incisions in breast surgery. Specific outcomes of interest were total wound complications, surgical site infection (SSI), seroma, haematoma, wound dehiscence and necrosis. RESULTS: Seven studies (1500 breast incisions in 904 patients) met the inclusion criteria. NPWT was associated with a significantly lower rate of total wound complications [odds ratio (OR) 0.36; 95% CI 0.19-069; P = 0.002], SSI (OR 0.45; 95% CI 0.24-0.86; P = 0.015), seroma (OR 0.28; 95% CI 0.13-0.59; P = 0.001), wound dehiscence (OR 0.49; 95% CI 0.32-0.72; P < 0.001) and wound necrosis (OR 0.38; 95% CI 0.19-0.78; P = 0.008). There was no significant difference in haematoma rate (OR 0.8; 95% CI 0.19-3.2; P = 0.75). Statistically significant heterogeneity existed for total wound complications, but no other outcomes. CONCLUSION: Compared with conventional non-NPWT dressings, prophylactic application of NPWT is associated with significantly fewer surgical site complications including SSI, seroma, wound dehiscence and wound necrosis for closed breast incisions.

Abdominal compartment syndrome secondary to megarectum and megasigmoid.

A 31-year-old male patient with chronic constipation of unknown aetiology presented emergently with worsening nausea, vomiting and abdominal distension of one week duration. On examination, his abdomen was distended with minimal tenderness. A plain film of the abdomen demonstrated severe faecal loading. The patient was haemodynamically unstable on admission and appeared sick. An urgent CT abdomen and pelvis was conducted showing extensive rectal dilatation and associated proximal colonic stercoral perforation. The patient proceeded straight to theatre for laparotomy as his general condition was deteriorating rapidly. On transfer to the operating table, the patient suffered cardiopulmonary arrest. Resuscitation was immediately commenced. Abdominal compartment syndrome was suspected. Cardiac output was re-established following a midline laparotomy which acted relieve the abdominal pressure. The rectosigmoid faecal content was decompressed via an enterotomy. The perforated segment of transverse colon was resected and an end colostomy fashioned. A year later, the continuity of the bowel was re-established.

Incidental small cell carcinoma of the gallbladder-an unexpected finding at elective cholecystectomy.

A 69-year-old woman was admitted electively for a laparoscopic cholecystectomy. Pre-operatively she had an ultrasound abdomen which demonstrated a large gallbladder (GB) stone. Intraoperatively, a nodule was noted on the liver supero-lateral to GB. The procedure was subsequently converted to open and the lesion was resected en-bloc with GB. The histology result showed small cell carcinoma (SCC) of the gallbladder with invasion into the liver parenchyma. A staging computerized tomographic of the thorax, abdomen and pelvis was performed. This demonstrated enlarged adenopathy locally and systemically with metastasis to medial segment of the left hepatic lobe and right lung. Following multi-disciplinary team meeting she was referred to Oncology for chemotherapy. The patient has survived for 7 months after the initial diagnosis of SCC.

Prophylactic Negative Pressure Dressing Use in Closed Laparotomy Wounds Following Abdominal Operations: A Randomized, Controlled, Open-label Trial: The P.I.C.O. Trial.

OBJECTIVE: A randomized controlled trial was undertaken to investigate the effect of prophylactic negative pressure dressings on postoperative surgical site infection (SSI) rates in closed laparotomy wounds. SUMMARY OF BACKGROUND DATA: Laparotomy wounds are associated with high rates of SSI. The effect of prophylactic negative pressure dressing of closed incisional wounds on SSI rate is unknown. METHODS: A randomized, controlled, open-label trial was conducted (clinicaltrials.gov registration number NCT02780453). Fifty patients undergoing open abdominal surgery were included, with 25 patients randomized to the negative pressure dressing group and 25 to the standard dressing group. The primary endpoint was SSI incidence at 30 days postoperatively. Secondary endpoints included SSI incidence at 4 days, length of stay, cosmetic outcome, and patient satisfaction. Statistical analysis was performed on a per-protocol basis using SPSS version 23.0. RESULTS: The incidence of SSI at 30 days postoperatively was significantly reduced in the treatment group compared with the control group [8.3% vs 32.0%, P = 0.043 (1-sided), P = 0.074 (2-sided)]. There was no difference in SSIs at 4 days postoperatively [4.1% vs 8.0%, P = 0.516 (1-sided), P = 1.0 (2-sided)]. Analysis of predictors of wound infection identified standard wound dressings as the only significant predictor of SSI development. Length of stay was significantly reduced in the negative pressure dressing group [6.1 vs 14.7 days, P = 0.019 (2-sided)]. Cosmetic outcome and patient satisfaction did not show any difference between the 2 groups. CONCLUSIONS: Prophylactic use of negative pressure dressings for closed laparotomy wounds significantly reduces the incidence of SSI at 30 days postoperatively.

The mesentery in Crohn's disease: friend or foe?

PURPOSE OF REVIEW: This article assesses the role of the mesentery in Crohn's disease. RECENT FINDINGS: The mesentery is centrally positioned both anatomically and physiologically. Overlapping mesenteric and submucosal mesenchymal contributions are important in the pathobiology of Crohn's disease. Mesenteric contributions explain the topographic distribution of Crohn's disease in general and mucosal disease in particular. Operative strategies that are mesenteric based (i.e. mesocolic excision) may reduce rates of postoperative recurrence. SUMMARY: The net effect of mesenteric events in Crohn's disease is pathologic. This can be targeted by operative means. VIDEO ABSTRACT: http://links.lww.com/COG/A18.

An Appraisal of Inflammatory Markers in Distinguishing Acute Uncomplicated and Complicated Appendicitis.

BACKGROUND: It remains difficult to distinguish between complicated appendicitis (CAP) and uncomplicated appendicitis (UAP). There is a paucity of studies utilizing inflammatory markers to stratify the severity of acute appendicitis. This study aimed to evaluate and demonstrate the potential clinical utility of inflammatory markers as adjuncts in distinguishing CAP and UAP. METHODS: A comparative observational study was performed. Patients diagnosed with acute appendicitis were categorized as (a) complicated (necrosis, perforation, abscess) and (b) uncomplicated (inflamed, edematous). Hematological indices were combined to generate the following ratios: white cell lymphocyte ratio (WLR), white cell neutrophil ratio (WNR) and neutrophil lymphocyte ratio (NLR). Parameter accuracy was assessed using summary receiver operating characteristic (sROC) curves, classification and regression tree analysis and confusion matrix generation. RESULTS: On sROC analysis, neutrophils (area under the curve (AUC) 0.79, p < 0.001), WLR (AUC 0.79, p < 0.001) and NLR (AUC 0.79, p < 0.001) were the most accurate parameters in distinguishing CAP and UAP. White cell count (WCC; AUC 0.76, p < 0.001) and C-reactive protein (AUC 0.75, p < 0.001) were less accurate. WCC >12.25 (sensitivity 70%, specificity 68%) and NLR >5.47 (sensitivity 78%, specificity 70%) were the most accurate in identifying CAP. CONCLUSION: Inflammatory marker cutoff points can be generated and utilized to differentiate between UAP and CAP. This may be useful when deciding between conservative and operative management.

Diagnostic dilemmas due to fish bone ingestion: Case report & literature review.

INTRODUCTION: The diagnosis of abdominal complications due to fish bone ingestion is particularly difficult as the presentation may mimic common abdominal pathologies. PRESENTATION OF CASE: 65 year-old male presented with a two day history of right iliac fossa pain. He denied any nausea and vomiting. He had no systemic systems including fever, change in bowel habit. He had tenderness and guarding localized to the right iliac fossa. He had raised inflammatory markers. A CT scan of the abdomen was performed which showed fat standing in proximity to the terminal ileum, with the appearance of Crohn's disease. The clinical picture did not match the imaging and so the patient underwent a diagnostic laparoscopy. Findings included an acutely inflamed terminal ileum. A foreign body was identified piercing through at the small bowel wall at the terminal ileum. The foreign body was removed and revealed a fish bone. Intracorporeal sutures were inserted at the site of the microperforation. The patient was discharged well two days post operatively. DISCUSSION: Fish bone perforation is not a common cause of gastrointestinal perforation. Unfortunately the history is often non-specific and these people can be misdiagnosed with acute appendicitis & other pathologies. CT scans can be useful to aid diagnostics. It is not however fully sensitive in detecting complications arising from fishbone ingestion. CONCLUSION: Management therefore, should be based taking into account primarily the clinical picture & may necessitate diagnostic laparoscopy.

Metastatic ovarian carcinoma presenting as an incarcerated femoral hernia.

INTRODUCTION: Incarcerated femoral hernias usually contain a simple loop of bowel. Occasionally other abdominal structures may be found within the hernial sac. Rarely femoral hernias may contain metastatic tumour deposits. PRESENTATION OF CASE: We report the case of an 82 year old lady with a background of ovarian carcinoma, who presented with acute small bowel obstruction and an irreducible right groin mass. CT imaging revealed an incarcerated loop of small bowel within a femoral hernia sac. The patient proceeded to theatre for hernia repair. Upon opening the hernial sac an adherent incarcerated small bowel loop was discovered. Interestingly, the sac itself was lined with metastatic deposits, which were later histologically proven to be ovarian in origin. The sac was reduced and the hernia was repaired. The patient's post-operative course was uneventful. DISCUSSION: As abdominal wall hernias communicate with the abdominal cavity there is the potential for malignant cells to seed the peritoneal lining of the hernia sac. If the sac also contains bowel wall, this may become involved in the tumour mass. This may result in small bowel incarceration & obstruction. CONCLUSION: In cases, where there is a known intra-abdominal malignancy & the presence of an incarcerated hernia, there should be a high index of suspicion for the presence of tumour within the hernial contents.

Hospital tests and patient related factors influencing time-to-theatre in 1000 cases of suspected appendicitis: a cohort study.

BACKGROUND: Acute appendicitis is increasingly being managed in the setting of a dedicated emergency theatre. However understanding of hospital factors that influence time-to-theatre (TTT) is poor. Thus, the aim of this study is to identify factors that influence TTT and to observe the effect of prolonged TTT on patient outcome. METHODS: A retrospective review of an electronic prospectively maintained database was performed over a 2 year period. Factors thought to influence TTT were highlighted. A delay was defined as TTT >8 hours. Data analysis was performed using SPSS 20. RESULTS: 1,000 cases of suspected acute appendicitis were identified. Median age was 19 years. Appendicectomy was performed in 90.7%. 68.1% underwent laparoscopic appendicectomy. Overall mean TTT was 12 hours, 27 minutes. There was a significant association between delayed TTT and female gender (p = 0.017), older age (p = 0.001), pre-operative radiology (<0.001), normal WCC (p < 0.001), normal neutrophils (p < 0.001) and histological non-perforated appendix (p < 0.001). However, on multivariate analysis, younger age, a neutrophilia and presence of a perforation had a shorter TTT. Delayed TTT did not affect outcome variables including post-operative collection (3.59% v 4.38%, p = 0.528), readmission rate (6.54% v 5.72%, p = 0.403) and length of stay (3.1 days v 3.34 days, p = 0.823). CONCLUSIONS: This study highlights key hospital factors that influence TTT in patients with suspected appendicitis. Identification of these influential factors adds greatly to our understanding of patient prioritisation. Finally, TTT delays greater than 8 hour do not appear to affect short-term patient outcomes.