Long-read DNA and cDNA sequencing identify cancer-predisposing deep intronic variation in tumor-suppressor genes.

The vast majority of deeply intronic genomic variants are benign, but some extremely rare or private deep intronic variants lead to exonification of intronic sequence with abnormal transcriptional consequences. Damaging variants of this class are likely underreported as causes of disease for several reasons: Most clinical DNA and RNA testing does not include full intronic sequences; many of these variants lie in complex repetitive regions that cannot be aligned from short-read whole-genome sequence; and, until recently, consequences of deep intronic variants were not accurately predicted by in silico tools. We evaluated the frequency and consequences of rare deep intronic variants for families severely affected with breast, ovarian, pancreatic, and/or metastatic prostate cancer, but with no causal variant identified by any previous genomic or cDNA-based approach. For 10 tumor-suppressor genes, we used multiplexed adaptive sampling long-read DNA sequencing and cDNA sequencing, based on patient-derived DNA and RNA, to systematically evaluate deep intronic variation. We identified all variants across the full genomic loci of targeted genes, applied the in silico tools SpliceAI and Pangolin to predict variants of functional consequence, and then carried out long-read cDNA sequencing to identify aberrant transcripts. For eight of the 120 (6%) previously unsolved families, rare deep intronic variants in BRCA1, PALB2, and ATM create intronic pseudoexons that are spliced into transcripts, leading to premature truncations. These results suggest that long-read DNA and cDNA sequencing can be integrated into variant discovery, with strategies for accurately characterizing pathogenic variants.

Evaluating variation in enhanced recovery for colorectal surgery: a report from the Surgical Care Outcomes Assessment Program.

AIM: Robust data demonstrate that enhanced recovery protocols (ERPs) decrease length of stay, complications and cost. However, little is known about the reasons for variation in compliance with ERPs. The aim of this work was to confirm the efficacy of ERPs in a regional network, and to determine factors that are associated with ERP delivery in diverse hospital settings. METHOD: A prospective cohort of patients was created by recording all elective colorectal operations at hospitals in the Surgical Care Outcomes Assessment Program (SCOAP). The delivery of 12 ERP components was tracked at all sites, and factors associated with ERP component delivery and affecting outcomes were reported. RESULTS: From 2016 to 2019, 9274 elective colorectal operations were performed at 36 hospitals. Indications were 48% cancer, 23% diverticulitis and 8% inflammatory bowel disease. Minimally invasive surgery was used in 71%. The proportion of cases with six or more ERP components received increased from 23% in 2016 to 50% in 2019. An increase in components was associated with a shorter length of stay and fewer combined adverse events and reinterventions. Further, increasing numbers of ERP components provided an incremental benefit to patients even when delivered in a low-volume centre or by a low-volume surgeon, and regardless of patient presentation. CONCLUSION: At SCOAP hospitals, the delivery of increasing numbers of ERP components was associated with improved perioperative outcomes and decreased complications after elective colorectal surgery. The variation in delivery of these evidence-based components in subsets of our cohort indicates an important opportunity for quality improvement initiatives.

Evaluating the Regional Uptake of Minimally Invasive Colorectal Surgery: a Report from the Surgical Care Outcomes Assessment Program.

BACKGROUND: Minimally invasive surgery (MIS) for colorectal disease has well-known benefits, but many patients undergo open operations. When choosing an MIS approach, robotic technology may have benefits over traditional laparoscopy and is increasingly used. However, the broad adoption of MIS, and specifically robotics, across colorectal operations has not been well described. Our primary hypothesis is that rates of MIS in colorectal surgery are increasing, with different contributions of robotics to abdominal and pelvic colorectal operations. METHODS: Rates of MIS colorectal operations are described using a prospective cohort of elective colorectal operations at hospitals in the Surgical Care Outcomes Assessment Program (SCOAP) from 2011 to 2018. The main outcome was proportion of cases approached using open, laparoscopic, and robotic surgery. Factors associated with increased use of MIS approaches were described. RESULTS: Across 21,423 elective colorectal operations, rates for MIS (laparoscopic or robotic surgery) increased from 44% in 2011 to 75% in 2018 (p < 0.001). Approaches for abdominal operations (n = 12,493) changed from 2 to 11% robotic, 43 to 63% laparoscopic, and 56 to 26% open (p < 0.001). Approaches for pelvic operations (n = 8930) changed from 3 to 33% robotic, 40 to 42% laparoscopic, and 57 to 24% open(p < 0.001). These trends were similar for high-(100 + operations/year) and low-volume hospitals and surgeons. CONCLUSIONS: At SCOAP hospitals, the majority of elective colorectal operations is now performed minimally invasively. The increase in the MIS approach is primarily driven by laparoscopy in abdominal procedures and robotics in pelvic procedures.

Other Surgeries in Patients with Inflammatory Bowel Disease.

Patients with inflammatory bowel disease (IBD) will often require abdominal surgical intervention for indications not directly related to their IBD. Because these patients often have a history of multiple previous abdominal operations and/or ostomies, they are at increased risk for incisional and parastomal hernias. They may also have develop symptomatic cholelithiasis, chronic pain, or desmoid disease. All of these potentially surgical issues may require special consideration in the IBD population.