Circumferential resection margin positivity due to direct or indirect tumour involvement in rectal cancer - a call for better stratification.

BACKGROUND: A positive circumferential resection margin (CRM) after rectal cancer surgery, which can be the result of direct or indirect tumour involvement, has consistently been associated with increased local recurrence and poorer survival. However, little is known of the differential impact of the mode of tumour involvement on outcomes. METHODS: 1460 consecutive patients undergoing rectal cancer resection between 2003 and 2018 were retrospectively assessed. Histopathology reports for patients with a positive CRM were reviewed to determine cases of direct (R1-tumour) or indirect tumour involvement (R1-other). Disease-free survival (DFS) and overall survival (OS) were assessed by Kaplan-Meier analysis. The role of the mode of CRM positivity was examined by univariate and multivariate Cox proportional hazards models. RESULTS: Eighty-five patients had an R1 resection due to CRM involvement (5.8%). Of those, 69 were due to direct tumour involvement, while 16 were from indirect causes. Kaplan-Meier analysis revealed that R1-other was associated with increased OS (hazard ratio 0.40, log-rank P = 0.006) and DFS (P = 0.043). Multivariate regression confirmed that the mode of CRM positivity was an independent predictor of OS. More interestingly, the patterns of recurrence were different between the two groups, with R1-tumour leading to significantly more local recurrence (P = 0.04). CONCLUSIONS: Our data strongly suggests that direct tumour involvement of the CRM confers worse prognosis after rectal cancer surgery. Importantly, differences in the site and frequency of recurrences make a case for better stratification of patients with a positive CRM to guide treatment decisions.

Temporal recording of mammalian development and precancer.

Key to understanding many biological phenomena is knowing the temporal ordering of cellular events, which often require continuous direct observations [1, 2]. An alternative solution involves the utilization of irreversible genetic changes, such as naturally occurring mutations, to create indelible markers that enables retrospective temporal ordering [3-8]. Using NSC-seq, a newly designed and validated multi-purpose single-cell CRISPR platform, we developed a molecular clock approach to record the timing of cellular events and clonality in vivo , while incorporating assigned cell state and lineage information. Using this approach, we uncovered precise timing of tissue-specific cell expansion during murine embryonic development and identified new intestinal epithelial progenitor states by their unique genetic histories. NSC-seq analysis of murine adenomas and single-cell multi-omic profiling of human precancers as part of the Human Tumor Atlas Network (HTAN), including 116 scRNA-seq datasets and clonal analysis of 418 human polyps, demonstrated the occurrence of polyancestral initiation in 15-30% of colonic precancers, revealing their origins from multiple normal founders. Thus, our multimodal framework augments existing single-cell analyses and lays the foundation for in vivo multimodal recording, enabling the tracking of lineage and temporal events during development and tumorigenesis.

Changes in the Emergency General Surgery Operations in the Setting of COVID-19 and Impact of Strategy of Non-Operative Management on Outcomes in Acute Appendicitis.

BACKGROUND: Coronavirus disease 2019 (COVID-19) has posed significant challenges to the provision of elective and emergency general surgical care. Patterns of presentation have changed and management pathways have also been adapted, moving to more non-operative management (NOM) for some conditions. We investigated how COVID-19 changed the volume of emergency general surgery operating in our district general hospital (DGH). We aimed to evaluate the impact of NOM on outcomes in acute appendicitis. METHODS: A retrospective case review of operating lists, patient handover lists, and patient notes was undertaken for patients presented between 1st January 2020 and 3rd June 2020. The study period was divided into two, with the period between 1st January 2020 and 23rd March 2020 representing the pre-COVID cohort. RESULTS: Some 393 emergency general surgery operations were performed in the study period. There was a clear reduction in operating volume after 23rd March 2020. During that same period, 325 patients were assessed with right iliac fossa (RIF) pain. Median age was 21 (range 5-87) and 201 patients were female (61.8%). The rate of NOM for suspected acute appendicitis was 8.8% in the pre-COVID group, which increased to 36.4% in the COVID group. The incidence of normal histology following appendicectomy did not change with this difference in management (16.1% compared to 17.9%, p = 0.78). CONCLUSIONS: This study summarizes the changes brought to the provision of emergency general surgery in the setting of a DGH by the COVID-19 pandemic. In particular, NOM was the preferred option for acute appendicitis but this did not alter the negative appendicectomy rate.

The management of asymptomatic radiological anastomotic leakage following anterior resection.

BACKGROUND: The evidence to guide the management of asymptomatic radiologically-detected anastomotic leakages (ARAL) following anterior resection (AR) with diverting ileostomy is deficient. This study describes the outcomes of managing ARAL one of the UK teaching hospitals. METHOD: The study included all patients diagnosed with ARAL following AR during 8 years period (2012-2020). The following data were retrospectively collected: patient demographics, surgical indication, anastomotic technique, tumour staging, neoadjuvant therapy, how ARAL was managed, the outcomes and duration to heal and ileostomy reversal. RESULTS: A total of 35 patients (M = 24) who developed ARAL during the study period were included. In 32 patients, AR was performed for rectal cancer. All patients with ARAL were treated conservatively and in 31 (89%) patients, there was complete resolution of the leakage within a median duration of 6 months. Covering loop ileostomies were reversed in 26 (74%) patients with a median interval to reversal of 10 months. CONCLUSION: Most asymptomatic radiologically-detected anastomotic leakages after anterior resection heal with conservative treatment in the presence of a covering loop ileostomy with an expected average delay of 6 months for the leakage to heal before covering ileostomies can be reversed.

Sex-specific outcomes with addition of defibrillation to resynchronisation therapy in patients with heart failure.

OBJECTIVE: Among primary prevention patients with heart failure receiving cardiac resynchronisation therapy (CRT), the impact of additional implantable cardioverter defibrillator (ICD) treatment on outcomes and its interaction with sex remains uncertain. We aim to assess whether the addition of the ICD functionality to CRT devices offers a more pronounced survival benefit in men compared with women, as previous research has suggested. METHODS: Observational multicentre cohort study of 5307 consecutive patients with ischaemic or non-ischaemic dilated cardiomyopathy and no history of sustained ventricular arrhythmias having CRT implantation with (cardiac resynchronisation therapy defibrillator (CRT-D), n=4037) or without (cardiac resynchronisation therapy pacemaker (CRT-P), n=1270) defibrillator functionality. Using propensity score (PS) matching and weighting and cause-of-death data, we assessed and compared the outcome of patients with CRT-D versus CRT-P. This analysis was stratified according to sex. RESULTS: After a median follow-up of 34 months (interquartile range 22-60 months) no survival advantage, of CRT-D versus CRT-P was observed in both men and women after PS matching (HR=0.95, 95% CI 0.77 to 1.16, p=0.61, and HR=1.30, 95% CI 0.83 to 2.04, p=0.25, respectively). With inverse-probability weighting, a benefit of CRT-D was seen in male patients (HR 0.78, 95% CI 0.65 to 0.94, p=0.012) but not in women (HR 0.87, 95% CI 0.63 to 1.19, p=0.43). The excess unadjusted mortality of patients with CRT-P compared with CRT-D was related to sudden cardiac death in 7.4% of cases in men but only 2.2% in women. CONCLUSIONS: In primary prevention patients with CRT indication, the addition of a defibrillator might convey additional benefit only in well-selected male patients.