Serial circulating tumour DNA analysis during multimodality treatment of locally advanced rectal cancer: a prospective biomarker study.

OBJECTIVE: For patients with locally advanced rectal cancer (LARC), adjuvant chemotherapy selection following surgery remains a major clinical dilemma. Here, we investigated the ability of circulating tumour DNA (ctDNA) to improve risk stratification in patients with LARC. DESIGN: We enrolled patients with LARC (T3/T4 and/or N+) planned for neoadjuvant chemoradiotherapy. Plasma samples were collected pretreatment, postchemoradiotherapy and 4-10 weeks after surgery. Somatic mutations in individual patient's tumour were identified via massively parallel sequencing of 15 genes commonly mutated in colorectal cancer. We then designed personalised assays to quantify ctDNA in plasma samples. Patients received adjuvant therapy at clinician discretion, blinded to the ctDNA results. RESULTS: We analysed 462 serial plasma samples from 159 patients. ctDNA was detectable in 77%, 8.3% and 12% of pretreatment, postchemoradiotherapy and postsurgery plasma samples. Significantly worse recurrence-free survival was seen if ctDNA was detectable after chemoradiotherapy (HR 6.6; P<0.001) or after surgery (HR 13.0; P<0.001). The estimated 3-year recurrence-free survival was 33% for the postoperative ctDNA-positive patients and 87% for the postoperative ctDNA-negative patients. Postoperative ctDNA detection was predictive of recurrence irrespective of adjuvant chemotherapy use (chemotherapy: HR 10.0; P<0.001; without chemotherapy: HR 22.0; P<0.001). Postoperative ctDNA status remained an independent predictor of recurrence-free survival after adjusting for known clinicopathological risk factors (HR 6.0; P<0.001). CONCLUSION: Postoperative ctDNA analysis stratifies patients with LARC into subsets that are either at very high or at low risk of recurrence, independent of conventional clinicopathological risk factors. ctDNA analysis could potentially be used to guide patient selection for adjuvant chemotherapy.

Morbidity and mortality with atrial fibrillation following colorectal surgery.

Post-operative atrial fibrillation (POAF) is a common, self-limiting complication following non-cardiac surgery. It is associated with other complications such as pneumonia and sepsis, increased hospital stay and in-hospital mortality. The aim of the study is to identify risk factors, morbidity and mortality associated with POAF. METHODS: Retrospective cohort study of 571 consecutive patients who presented for colorectal surgery at The Canberra Hospital. Seventy-four patients were excluded due to history of atrial fibrillation and a further 124 patients were lost to follow-up at 1 year. Patient characteristics, intraoperative factors and post-operative outcomes were retrospectively collected. One-year mortality data were collected for 373 patients in the cohort. RESULTS: A total of 497 patients were included, 33 (6.6%) developed POAF within 30 days of surgery. POAF is associated with ischaemic heart disease (24.2 versus 11.6%, P = 0.035), emergency (66.7 versus 34.1%, P = 0.0001) and open procedures (87.9 versus 70.9%, P = 0.036). There is a higher incidence of post-operative complications including pneumonia (24.2 versus 9.1%, P = 0.006), abdominal collection (21.2 versus 9.7%, P = 0.049) and sepsis (21.2 versus 7.5%, P < 0.0001). POAF had a higher in-hospital mortality (9.1 versus 2.6%, P = 0.035) and 1-year mortality (33.3 versus 8.8%, P < 0.0001). CONCLUSION: POAF is a common presentation following colorectal surgery and is associated with infective complications, reflecting an inflammatory process. Risk factors for POAF have been clearly identified in the literature; however, further studies need to be conducted on preventative strategies. There is a significantly higher 1-year mortality rate compared with the controls, the aetiology of which has not yet been widely reviewed.

Does chronomodulated radiotherapy improve pathological response in locally advanced rectal cancer?

The predominant mode of radiation-induced cell death for solid tumours is mitotic catastrophe, which is in part dependent on sublethal damage repair being complete at around 6 h. Circadian variation appears to play a role in normal cellular division, and this could influence tumour response of radiation treatment depending on the time of treatment delivery. We tested the hypothesis that radiation treatment later in the day may improve tumour response and nodal downstaging in rectal cancer patients treated neoadjuvantly with radiation therapy. Recruitment was by retrospective review of 267 rectal cancer patients treated neoadjuvantly in the Department of Radiation Oncology at the Canberra Hospital between January 2010 and November 2015. One hundred and fifty-five patients met the inclusion criteria for which demographic, pathological and imaging data were collected, as well as the time of day patients received treatment with each fraction of radiotherapy. Data analysis was performed using the Statistical Package R with nonparametric methods of significance for all tests set at p < 0.05. Of the 45 female and 110 male patients, the median age was 64. Seventy-three percent had cT3 disease and there was a mean tumour distance from the anal verge of 7 cm. Time to surgical resection following radiotherapy ranged from 4 to 162 days with a median of 50 days, with a complete pathological response seen in 21% of patients. Patients exhibiting a favourable pathological response had smaller median pre- and postradiotherapy tumour size and had a greater change in tumour size following treatment (p < 0.01). Patients who received the majority of their radiotherapy fractions after 12:00 pm were more likely to show a complete or moderate pathological response (p = 0.035) and improved nodal downstaging. There were also more favourable responses amongst patients with longer time to surgical resection postradiotherapy (p < 0.004), although no relationship was seen between response and tumour distance from the anal verge. Females were less likely to exhibit several of the above responses. Neoadjuvant radiotherapy for locally advanced rectal cancer performed later in the day coupled with a longer time period to surgical resection may improve pathological tumour response rates and nodal downstaging. A prospective study in chronomodulated radiotherapy in this disease is warranted.

A deleterious RNF43 germline mutation in a severely affected serrated polyposis kindred.

We report a germline nonsense mutation within the extracellular domain of the RING finger ubiquitin ligase RNF43, segregating with a severe form of serrated polyposis within a kindred. The finding provides evidence that inherited RNF43 mutations define a familial cancer syndrome.

Multicenter randomized trial of centralized nurse-led telephone-based care coordination to improve outcomes after surgical resection for colorectal cancer: the CONNECT intervention.

PURPOSE: To investigate the effectiveness of a centralized, nurse-delivered telephone-based service to improve care coordination and patient-reported outcomes after surgery for colorectal cancer. PATIENTS AND METHODS: Patients with a newly diagnosed colorectal cancer were randomly assigned to the CONNECT intervention or usual care. Intervention-group patients received standardized calls from the centrally based nurse 3 and 10 days and 1, 3, and 6 months after discharge from hospital. Unmet supportive care needs, experience of care coordination, unplanned readmissions, emergency department presentations, distress, and quality of life (QOL) were assessed by questionnaire at 1, 3, and 6 months. RESULTS: Of 775 patients treated at 23 public and private hospitals in Australia, 387 were randomly assigned to the intervention group and 369 to the control group. There were no significant differences between groups in unmet supportive care needs, but these were consistently low in both groups at both follow-up time points. There were no differences between the groups in emergency department presentations (10.8% v 13.8%; P = .2) or unplanned hospital readmissions (8.6% v 10.5%; P = .4) at 1 month. By 6 months, 25.6% of intervention-group patients had reported an unplanned readmission compared with 27.9% of controls (P = .5). There were no significant differences in experience of care coordination, distress, or QOL between groups at any follow-up time point. CONCLUSION: This trial failed to demonstrate substantial benefit of a centralized system to provide standardized, telephone follow-up for postoperative patients with colorectal cancer. Future interventions could investigate a more tailored approach.

Small bowel tumours: a 10 year experience in four Sydney teaching hospitals.

BACKGROUND: Small bowel tumours are uncommon and can have a long delay prior to diagnosis. The present study aims to compare the use of computed tomography (CT) and contrast small bowel series (SBS) in their diagnosis and to outline the clinical features of small bowel tumours. METHODS: A retrospective, case note study was conducted between 1990 and 2000 in four Sydney teaching hospitals. The data collected included clinical features, investigations and tumour characteristics. RESULTS: One hundred and sixty-six people with small bowel tumours were identified (91 malignant; 75 benign). Malignant tumours consisted of adenocarcinomas (31%), carcinoid tumours (12%), lymphomas (7%) and leiomyosarcomas (5%). Benign tumours consisted of adenomas (22%), hamartomas (13%), leiomyomas (4%), inflammatory polyps (4%) and hyperplastic polyps (2%) and a benign schwannoma (1%). Adenocarcinomas were mainly located in the duodenum (P < 0.001) and carcinoid tumours in the ileum (P < 0.001). Malignant tumours were associated with a higher proportion of symptoms (P < 0.01), signs (P < 0.001) and episodes of small bowel obstruction (P < 0.01). Abdominal CT scans demonstrated a greater sensitivity (87.7%) than SBS (72.9%) with a slightly improved sensitivity when both investigations were used (89.3%). Abdominal ultrasound had a lower sensitivity than both of the above investigations of 65%. Gastroduodenoscopy had a sensitivity of 90% for diagnosing duodenal tumours. Operative procedures were performed on 92 patients with a preoperative diagnosis made in 77%. Metastatic spread of malignant tumours was evident in 46%. The sites of spread were to lymph nodes (23%), liver (21%) and distant locations (2%) at diagnosis. CONCLUSIONS: Malignant small bowel tumours are more likely to produce symptoms and signs than benign tumours, particularly caused by small bowel obstruction. Abdominal CT is the best radiological investigation for small bowel tumours and has a slight complimentary effect with SBS in improving the chances of detection. Gastroduodenoscopy remains the best investigation of duodenal tumours.