Quadratus Lumborum Block as a Cornerstone for Neonatal Intestinal Surgery Enhanced Recovery (ERAS): A Case Series.

Purpose: Neonates present unique challenges for pediatric surgical teams. To optimize outcomes, it is imperative to standardize perioperative care by using early extubation and multimodal analgesic techniques. The quadratus lumborum (QL) block provides longer duration and superior pain relief than other single-injection abdominal fascial plane techniques. The purpose of this case series was to report our initial experience with QL blocks in neonatal patients treated with intestinal ERAS. Patients and Methods: Ten neonates requiring intestinal surgery at a single tertiary care center who received QL blocks between December 2019 and April 2022 for enhanced recovery were studied. Bilateral QL blocks were performed with 0.5 mL/kg of 0.25% ropivacaine per side with an adjuvant of 1 mcg/kg of dexmedetomidine. Results: Gestational age at birth ranged from 32.2 to 41 weeks. The median age, weight, and American Society of Anesthesiologists (ASA) score at the time of surgery was 5 days [range 7.5 hours, 60 days], 2.84 kg [range 1.5, 4.5], and 3, respectively. Bilateral QL blocks were performed without complications in all patients. Two patients were outside the neonatal range from birth to surgery, but were under 42 weeks gestational age when corrected for prematurity. All patients were extubated with well-controlled pain, and no patient required reintubation within the first 24 hours. Postoperatively, median cumulative morphine equivalents were 0.16 mg/kg [range 0, 0.79] and six patients received scheduled acetaminophen. Morphine (0.1 mg/kg) was administered to patients with a modified neonatal infant pain scale (NIPS) score greater than or equal to 4, and pain was reassessed 1 hour after administration (Appendix). Conclusion: When developing intestinal ERAS protocols, Bilateral QL blocks may be considered for postoperative analgesia in the neonatal population. Further prospective studies are required to validate this approach in neonates.

Comprehensive evaluation and efficient classification of BRCA1 RING domain missense substitutions.

BRCA1 is a high-risk susceptibility gene for breast and ovarian cancer. Pathogenic protein-truncating variants are scattered across the open reading frame, but all known missense substitutions that are pathogenic because of missense dysfunction are located in either the amino-terminal RING domain or the carboxy-terminal BRCT domain. Heterodimerization of the BRCA1 and BARD1 RING domains is a molecularly defined obligate activity. Hence, we tested every BRCA1 RING domain missense substitution that can be created by a single nucleotide change for heterodimerization with BARD1 in a mammalian two-hybrid assay. Downstream of the laboratory assay, we addressed three additional challenges: assay calibration, validation thereof, and integration of the calibrated results with other available data, such as computational evidence and patient/population observational data to achieve clinically applicable classification. Overall, we found that 15%-20% of BRCA1 RING domain missense substitutions are pathogenic. Using a Bayesian point system for data integration and variant classification, we achieved clinical classification of 89% of observed missense substitutions. Moreover, among missense substitutions not present in the human observational data used here, we find an additional 45 with concordant computational and functional assay evidence in favor of pathogenicity plus 223 with concordant evidence in favor of benignity; these are particularly likely to be classified as likely pathogenic and likely benign, respectively, once human observational data become available.

Differential methylation of G-protein coupled receptor signaling genes in gastrointestinal neuroendocrine tumors.

Neuroendocrine tumors (NETs) of the small intestine undergo large chromosomal and methylation changes. The objective of this study was to identify methylation differences in NETs and consider how the differentially methylated genes may impact patient survival. Genome-wide methylation and chromosomal copy number variation (CNV) of NETs from the small intestine and appendix were measured. Tumors were divided into three molecular subtypes according to CNV results: chromosome 18 loss (18LOH), Multiple CNV, and No CNV. Comparison of 18LOH tumors with MultiCNV and NoCNV tumors identified 901 differentially methylated genes. Genes from the G-protein coupled receptor (GPCR) pathways are statistically overrepresented in the differentially methylated genes. One of the highlighted genes from the GPCR pathway is somatostatin (SST), a clinical target for NETs. Patient survival based on low versus high methylation in all samples identified four significant genes (p < 0.05) OR2S2, SMILR, RNU6-653P, and AC010543.1. Within the 18LOH molecular subtype tumors, survival differences were identified in high versus low methylation of 24 genes. The most significant is TRHR (p < 0.01), a GPCR with multiple FDA-approved drugs. By separating NETs into different molecular subtypes based on chromosomal changes, we find that multiple GPCRs and their ligands appear to be regulated through methylation and correlated with survival. These results suggest opportunities for better treatment strategies for NETs based on molecular features.

FANCM c5791C>T stopgain mutation (rs144567652) is a familial colorectal cancer risk factor.

PURPOSE: While familial aggregation of colorectal cancer (CRC) is recognized, the majority of the germline predisposition factors remain unidentified, and many high-risk CRC pedigrees remain unexplained by known risk variants. Fanconi Anemia genes have been recognized to be associated with cancer risk. Notably, FANCM (OMIM 609644) variants have been reported to confer risk for CRC and breast cancer. METHODS: Exome sequencing of CRC-affected cousins in a set of 47 independent extended high-risk CRC pedigrees identified a candidate set of rare, shared variants. Variants were tested for association with risk in 744 Utah CRC cases and 1525 controls, and for segregation with CRC in affected relatives. RESULTS: A FANCM stopgain variant was observed in two CRC-affected cousin pairs, each from an independent Utah high-risk pedigree, and yielded a nonsignificant, but elevated OR = 2.05 in a set of Utah cases and controls. Segregation of the variant to other related CRC-affected cases was observed in the two extended pedigrees. CONCLUSION: A rare stopgain variant in FANCM (rs144567652) that is recognized as a breast cancer predisposition variant, and that has previously been proposed, but not confirmed, as a CRC predisposition variant, is validated here as a risk factor for familial CRC.

Clinical and Molecular Features of Post-Colonoscopy Colorectal Cancers.

BACKGROUND & AIMS: Post-colonoscopy colorectal cancers (PCCRCs) may arise from missed lesions or due to molecular features of tumors that allow them to grow rapidly. We aimed to compare clinical, pathology, and molecular features of PCCRCs (those detected within 6-60 months of colonoscopy) and detected CRCs (those detected within 6 months of a colonoscopy). METHODS: Within a population-based cross-sectional study of incident CRC cases in Utah (from 1995 through 2009), we identified PCCRCs (those cancers that developed within 5 years of a colonoscopy) and matched the patients by age, sex, and hospital site to patients with detected CRC. Archived specimens were retrieved and tested for microsatellite instability (MSI), CpG island methylation, and mutations in KRAS and BRAF. There were 2659 cases of CRC diagnosed within the study window; 6% of these (n = 159) were defined as PCCRCs; 84 of these cases had tissue available and were matched to 84 subjects with detected CRC. RESULTS: Higher proportions of PCCRCs than detected CRCs formed in the proximal colon (64% vs 44%; P = .016) and were of an early stage (86% vs 69%; P = .040). MSI was observed in 32% of PCCRCs compared with 13% of detected CRCs (P = .005). The other molecular features were found in similar proportions of PCCRCs and detected CRCs. In a multivariable logistic regression, MSI (odds ratio, 4.20; 95% CI, 1.58-11.14) was associated with PCCRC. There was no difference in 5-year survival between patients with PCCRCs vs detected CRCs. CONCLUSION: In this population-based cross-sectional study of incident CRC cases in Utah, we found PCCRCs to be more likely to arise in the proximal colon and demonstrate MSI, so PCCRCs and detected CRC appear to have different features or processes of tumorigenesis. Additional studies are needed to determine if post-colonoscopy cancers arise through a specific genetic pathway.

Soma-germ line interactions and a role for muscle in the regulation of C. elegans sperm motility.

The development of highly differentiated sperm cells that are specialized for navigating to and fusing with an oocyte is essential for sexual reproduction. As a major part of differentiation, sperm undergo extensive post-meiotic maturation en route to the oocyte. This is regulated largely by soma-derived cues. In Caenorhabditiselegans, this process is called sperm activation, and it transforms immotile spermatids into migratory fertilization-competent cells. Here, we show that the negative regulator of sperm activation, SWM-1, is produced in an unexpected cell type: body wall muscle. SWM-1 is secreted into the body cavity and enters the gonad; there, it is present with its likely target, TRY-5, a spermiogenesis activator. We show that, in addition to SWM-1, the somatic gonad and body fluid can exchange other factors, suggesting that soma-germ line transfer could affect other reproductive processes. In addition, we show that SWM-1 may have a separate role in the sperm migratory environment, to which it is contributed by both males and hermaphrodites. These findings reveal that late stages in gamete differentiation can be regulated at the whole-organism level by broadly secreted factors.This article has an associated 'The people behind the papers' interview.

Chemoprevention with Cyclooxygenase and Epidermal Growth Factor Receptor Inhibitors in Familial Adenomatous Polyposis Patients: mRNA Signatures of Duodenal Neoplasia.

To identify gene expression biomarkers and pathways targeted by sulindac and erlotinib given in a chemoprevention trial with a significant decrease in duodenal polyp burden at 6 months (P < 0.001) in familial adenomatous polyposis (FAP) patients, we biopsied normal and polyp duodenal tissues from patients on drug versus placebo and analyzed the RNA expression. RNA sequencing was performed on biopsies from the duodenum of FAP patients obtained at baseline and 6-month endpoint endoscopy. Ten FAP patients on placebo and 10 on sulindac and erlotinib were selected for analysis. Purity of biopsied polyp tissue was calculated from RNA expression data. RNAs differentially expressed between endpoint polyp and paired baseline normal were determined for each group and mapped to biological pathways. Key genes in candidate pathways were further validated by quantitative RT-PCR. RNA expression analyses of endpoint polyp compared with paired baseline normal for patients on placebo and drug show that pathways activated in polyp growth and proliferation are blocked by this drug combination. Directly comparing polyp gene expression between patients on drug and placebo also identified innate immune response genes (IL12 and IFNγ) preferentially expressed in patients on drug. Gene expression analyses from tissue obtained at endpoint of the trial demonstrated inhibition of the cancer pathways COX2/PGE2, EGFR, and WNT. These findings provide molecular evidence that the drug combination of sulindac and erlotinib reached the intended tissue and was on target for the predicted pathways. Furthermore, activation of innate immune pathways from patients on drug may have contributed to polyp regression. Cancer Prev Res; 11(1); 4-15. ©2017 AACRSee related editorial by Shureiqi, p. 1.

Characterization of an APC Promoter 1B deletion in a Patient Diagnosed with Familial Adenomatous Polyposis via Whole Genome Shotgun Sequencing.

Recently, deletions have been identified and published as causal for Familial Adenomatous Polyposis in the 1B promoter region of the APC gene.  Those deletions were measured using multiplex ligation-dependent probe amplification.  Here, we present and characterize an ~11kb deletion identified by whole genome shotgun sequencing.  The deletion occurred in a patient diagnosed with Familial Adenomatous Polyposis, and was located on chr5, between bases 112,034,824 and 112,045,845, fully encompassing the 1B promoter region of the APC gene.   Results are presented here that include the sequence evidence supporting the presence of the deletion as well as base level characterization of the deletion site.  These results demonstrate the capacity of whole genome sequencing for the detection of large structural variants in single individuals.

Role implications for nurses caring for gunshot wound victims.

Emergency department registered nurses treat victims of violent acts because the emergency department is usually the initial area of treatment. The nursing care of gunshot wound victims includes not only physical and immediate needs but also forensic and anticipated needs. The purpose of this article is to describe 3 types of gunshot wound forensic evidence and the nurses' roles when treating victims of gunshot wounds.