Citations

INTRODUCTION: Gastroesophageal reflux plays a significant role in idiopathic pulmonary fibrosis (IPF). Given the morbidity and mortality associated with IPF, understanding the mechanisms responsible for reflux is essential if patients are to receive optimal treatment and management, especially given the lack of clear benefit of antireflux therapies. Our aim was to understand the inter-relationships between esophageal motility, lung mechanics and reflux (particularly proximal reflux—a prerequisite of aspiration), and pulmonary function in patients with IPF. METHODS: We prospectively recruited 35 patients with IPF (aged 53–75 years; 27 men) who underwent high-resolution impedance manometry and 24-hour pH-impedance, together with pulmonary function assessment. RESULTS: Twenty-two patients (63%) exhibited dysmotility, 16 (73%) exhibited ineffective esophageal motility (IEM), and 6 (27%) exhibited esophagogastric junction outflow obstruction. Patients with IEM had more severe pulmonary disease (% forced vital capacity: P = 0.032) and more proximal reflux ( P = 0.074) than patients with normal motility. In patients with IEM, intrathoracic pressure inversely correlated with the number of proximal events (r = −0.429; P = 0.098). Surprisingly, inspiratory lower esophageal sphincter pressure (LESP) positively correlated with the percentage of reflux events reaching the proximal esophagus (r = 0.583; P = 0.018), whereas in patients with normal motility, it inversely correlated with the bolus exposure time (r = −0.478; P = 0.098) and number of proximal events (r = −0.542; P = 0.056). % forced vital capacity in patients with IEM inversely correlated with the percentage of reflux events reaching the proximal esophagus (r = −0.520; P = 0.039) and inspiratory LESP (r = −0.477; P = 0.062) and positively correlated with intrathoracic pressure (r = 0.633; P = 0.008). DISCUSSION: We have shown that pulmonary function is worse in patients with IEM which is associated with more proximal reflux events, the latter correlating with lower intrathoracic pressures and higher LESPs.

Abstract It was not known whether the polygenic risk scores (PRSs) that predict colorectal cancer could predict colorectal cancer for people with inherited pathogenic variants in DNA mismatch repair genes—people with Lynch syndrome. We tested a PRS comprising 107 established single-nucleotide polymorphisms associated with colorectal cancer in European populations for 826 European-descent carriers of pathogenic variants in DNA mismatch repair genes (293 MLH1, 314 MSH2, 126 MSH6, 71 PMS2, and 22 EPCAM) from the Colon Cancer Family Registry, of whom 504 had colorectal cancer. There was no evidence of an association between the PRS and colorectal cancer risk, irrespective of which DNA mismatch repair gene was mutated, or sex (all 2-sided P > .05). The hazard ratio per standard deviation of the PRS for colorectal cancer was 0.97 (95% confidence interval = 0.88 to 1.06; 2-sided P = .51). Whereas PRSs are predictive of colorectal cancer in the general population, they do not predict Lynch syndrome colorectal cancer.

Summary: Vascularized omentum lymphatic transplant is frequently used for the treatment of lymphedema due to demonstrated efficacy, a reduced complication profile, and, in particular, negligible risk of donor site lymphedema. Historically harvested by open laparotomy, more recent techniques involve laparoscopic omental harvest. Although effective and reproducible, laparoscopy may be limited by reduced visualization, minimal tactile feedback, multiple port sites, and imprecise instrumentation. Therefore, we employed the da Vinci Single-Port (SP) surgical robot system for vascularized omentum lymphatic transplant. A 52-year-old man with a 3-year history of progressive left lower extremity swelling and lymphoscintigraphy and magnetic resonance lymphangiogram consistent with lymphedema of unknown etiology underwent vascularized omentum lymphatic transplant to the left groin. A 2.5-cm infraumbilical incision was used for placement of the primary trocar, through which the camera and operating instruments were passed. Following robotic harvest, the omental lymph node flap was transferred to the left groin for microsurgical anastomosis. The procedure was uneventful, and the patient was discharged on postoperative day 1. At 6 weeks, there were no complications. Here, we show for the first time the safety and feasibility of robotic omental lymph node flap harvest for extremity lymphedema using the da Vinci Single-Port robotic system. The benefits of this technology include a minimally-invasive approach that allows for flap dissection and removal through a single 2.5-cm incision. Further investigation is necessary to characterize the indications and limitations of this technique in plastic surgery.

Abstract Background Microsurgery is being increasingly utilized across surgical specialties, including plastic surgery. Microsurgical techniques require greater time and financial investment compared with traditional methods. This study aimed to evaluate 20-year trends in Medicare reimbursement and utilization for commonly billed reconstructive microsurgery procedures from 2000 to 2019. Methods Microsurgical procedures commonly billed by plastic surgeons were identified. Reimbursement data were extracted from The Physician Fee Schedule Look-Up Tool from the Centers for Medicare and Medicaid Services for each current procedural terminology (CPT) code. All monetary data were adjusted for inflation to 2019 U.S. dollars. The average annual and total percentage changes in reimbursement were calculated based on these adjusted trends. To assess utilization trends, CMS physician/supplier procedure summary files were queried for the number of procedures billed by plastic surgeons from 2010 to 2018. Results After adjusting for inflation, the average reimbursement for all procedures decreased by 26.92% from 2000 to 2019. The greatest mean decrease was observed in CPT 20969 free osteocutaneous flaps with microvascular anastomosis (−36.93%). The smallest mean decrease was observed in repair of blood vessels with vein graft (−9.28%). None of the included procedures saw an increase in reimbursement rate over the study period. From 2000 to 2019, the adjusted reimbursement rate for all procedures decreased by an average of 1.35% annually. Meanwhile, the number of services billed to Medicare by plastic surgeons across the included CPT codes increased by 42.17% from 2010 to 2018. Conclusion This is the first study evaluating 20-year trends in inflation-adjusted Medicare reimbursement and utilization in reconstructive microsurgery. Reimbursement for all included procedures decreased over 20% during the study period, while number of services increased. Increased consideration of these trends will be important for U.S. policymakers, hospitals, and surgeons to assure continued access and reconstructive options for patients.

Objective An understanding of the etiologic heterogeneity of colorectal cancer (CRC) is critical for improving precision prevention, including individualized screening recommendations and the discovery of novel drug targets and repurposable drug candidates for chemoprevention. Known differences in molecular characteristics and environmental risk factors among tumors arising in different locations of the colorectum suggest partly distinct mechanisms of carcinogenesis. The extent to which the contribution of inherited genetic risk factors for CRC differs by anatomical subsite of the primary tumor has not been examined. Design To identify new anatomical subsite-specific risk loci, we performed genome-wide association study (GWAS) meta-analyses including data of 48 214 CRC cases and 64 159 controls of European ancestry. We characterised effect heterogeneity at CRC risk loci using multinomial modelling. Results We identified 13 loci that reached genome-wide significance (p<5×10 −8 ) and that were not reported by previous GWASs for overall CRC risk. Multiple lines of evidence support candidate genes at several of these loci. We detected substantial heterogeneity between anatomical subsites. Just over half (61) of 109 known and new risk variants showed no evidence for heterogeneity. In contrast, 22 variants showed association with distal CRC (including rectal cancer), but no evidence for association or an attenuated association with proximal CRC. For two loci, there was strong evidence for effects confined to proximal colon cancer. Conclusion Genetic architectures of proximal and distal CRC are partly distinct. Studies of risk factors and mechanisms of carcinogenesis, and precision prevention strategies should take into consideration the anatomical subsite of the tumour.

Abstract Background: Inherited susceptibility is an important contributor to colorectal cancer risk, and rare variants in key genes or pathways could account in part for the missing proportion of colorectal cancer heritability. Methods: We conducted an exome-wide association study including 2,327 cases and 2,966 controls of European ancestry from three large epidemiologic studies. Single variant associations were tested using logistic regression models, adjusting for appropriate study-specific covariates. In addition, we examined the aggregate effects of rare coding variation at the gene and pathway levels using Bayesian model uncertainty techniques. Results: In an exome-wide gene-level analysis, we identified ST6GALNAC2 as the top associated gene based on the Bayesian risk index (BRI) method [summary Bayes factor (BF)BRI = 2604.23]. A rare coding variant in this gene, rs139401613, was the top associated variant (P = 1.01 × 10–6) in an exome-wide single variant analysis. Pathway-level association analyses based on the integrative BRI (iBRI) method found extreme evidence of association with the DNA repair pathway (BFiBRI = 17852.4), specifically with the nonhomologous end joining (BFiBRI = 437.95) and nucleotide excision repair (BFiBRI = 36.96) subpathways. The iBRI method also identified RPA2, PRKDC, ERCC5, and ERCC8 as the top associated DNA repair genes (summary BFiBRI ≥ 10), with rs28988897, rs8178232, rs141369732, and rs201642761 being the most likely associated variants in these genes, respectively. Conclusions: We identified novel variants and genes associated with colorectal cancer risk and provided additional evidence for a role of DNA repair in colorectal cancer tumorigenesis. Impact: This study provides new insights into the genetic predisposition to colorectal cancer, which has potential for translation into improved risk prediction.

Abstract Background A chimerically configured gracilis and profunda artery perforator (PAP) flap is highly prevalent based on recent computed tomography (CT)-imaging data. The purpose of this study is to further characterize the vascular anatomy of this novel flap configuration and determine the feasibility of flap dissection. Methods To characterize flap arterial anatomy, lower extremity CT angiograms performed from 2011 to 2018 were retrospectively reviewed. To characterize venous anatomy and determine the feasibility of flap harvest, the lower extremities of cadavers were evaluated. Results A total of 974 lower extremity CT angiograms and 32 cadavers were included for the assessment. Of the 974 CT angiograms, majority (966, 99%) were bilateral studies, yielding a total of 1,940 lower extremities (right-lower-extremity = 970 and left-lower-extremity = 970) for radiographic evaluation. On CT angiography, a chimerically configured gracilis and PAP flap was found in 51% of patients (n = 494/974). By laterality, chimeric anatomy was present in 26% of right lower extremities (n = 254/970) and 25% of left lower extremities (n = 240/970); bilateral chimeric anatomy was found in 12% (n = 112/966) of patients. Average length of the common arterial pedicle feeding both gracilis and PAP flap perforasomes was 31.1 ± 16.5 mm (range = 2.0–95.0 mm) with an average diameter of 2.8 ± 0.7 mm (range = 1.3–8.8 mm).A total of 15 cadavers exhibited chimeric anatomy with intact, conjoined arteries and veins allowing for anatomical tracing from the profunda femoris to the distal branches within the tissues of the medial thigh. Dissection and isolation of the common pedicle and distal vessels was feasible with minimal disruption of adjacent tissues. Chimeric flap venous anatomy was favorable, with vena commitante adjacent to the common pedicle in all specimens. Conclusion Dissection of a chimeric medial thigh flap consisting of both gracilis and PAP flap tissues is feasible in a cadaveric model. The vascular anatomy of this potential flap appears suitable for future utilization in a clinical setting.

Abstract Background: Cyclin dependent 4/6 kinase inhibitors (CDK4/6i) and endocrine therapy (ET) have improved progression-free survival (PFS) and overall survival in hormone-receptor (HR)-positive metastatic breast cancer (MBC), but progression of disease is inevitable. Serum thymidine kinase-1 (TK1) is a secreted marker of proliferation that is prognostic in patients (pts) with HR-positive, HER2-negative MBC and may be predictive of ET and CDK 4/6i response. PROMISE (NCT0281902) is a prospective study enrolling women with HR-positive MBC starting palbociclib (Pb) + letrozole (L) (1st line) or Pb + fulvestrant (2nd line). We undertook a comprehensive “omic” assessment of blood, tumor, urine and the fecal microbiome in order to identify novel genomic variants and pathways associated with an early decline in TK1 (measured after 2 months) and PFS. Additionally, patient derived xenografts/organoids were generated at baseline and progression to test new therapeutic approaches to overcome resistance to CDK4/6i and ET. We report the initial association between the baseline genomic landscape and baseline TK1 levels. Methods: FFPE tumor biopsies were obtained for DNA/RNA sequencing (TempusTM) and blood samples for TK1 (Divitum® assay, Biovica) were collected pretreatment (pre-Pb) and after 2 cycles of Pb + ET (post-Pb2). Both whole-exome (exome capture) sequencing (WES) and RNA-Seq used the Integrated DNA Technologies xGen Exome Research Panel v1.0 capture kit. TK1+ disease was defined as &gt; 200 Du/L and TK1- disease as below limit of detection up to 200 Du/L. We tested the association between genomic and transcriptomic characteristics with baseline TK1 data in pretreatment samples where both WES and RNA-seq and TK1 was available. The data were analyzed using bioinformatics pipelines for somatic and germline mutations and copy number alterations. The current analysis focuses on baseline 1st-line pre-Pb omics data in conjunction with baseline TK1 levels. The database was locked for analysis on 5/29/2020. Results: Thirty-three pts (median age: 59 yrs.) were evaluable, with paired samples for TK1 in 32. Six pts had TK1+ disease pre-Pb and post-Pb2. Twenty-two pts had TK1- disease pre-Pb and post-Pb2. Four pts had a decrease in TK1 after 2 cycles of treatment that altered the classification from TK1+ to TK1-. Both baseline RNA seq and serum TK1 (n=16) were available for 4 TK1+ and 12 TK1- pts. In this group, 476 genes were differentially regulated (398 upregulated; 78 downregulated). Pathway analysis demonstrated enrichment in complement and coagulation cascade pathway, PPAR signaling pathway, and metabolism-related pathways related to up-regulation of CYP and UGT gene families. Further testing for the association of WES data with baseline TK1+ (n=8) and TK1- (n=16) disease demonstrated somatic copy number variations on chromosomes 6, 11, 12 and 15. CDK4 copy number gains were observed in 3/8 TK1+ pts and 0/16 TK1- pts. We also observed that somatic mutations (LOH, copy number and/or SNV/INDELs) were more prevalent in the TK1+ compared to the TK1- pre-Pb group in several cancer-associated genes (FAS [p=0.06] PTEN, PIK3CB, NAB2, SOX9 and FAT1 [p=0.08], TP53, and MAP2K4 [p=0.22]). Conversely, we also noted that 6/7 pts with GATA3 mutations had TK1- disease (p=0.23). Conclusions: Using a comprehensive “omics” approach, our data suggest that a secreted biomarker of proliferation (TK1) obtained prior to initiating CDK4/6i and ET for the first line treatment of HR+ MBC is associated with established and novel genes and pathways associated with prognosis of pts receiving ET and CDK 4/6i. Analysis of on-treatment (after 2 cycles) tumor RNA seq and its association with change in TK1 as well as data from the 2nd-line cohort will be presented at the meeting. Citation Format: Ciara C O Sullivan, Krishna R Kalari, Vera J Suman, Peter T Vedell, Ann Moyer, Abraham D Eyman Casey, Jason Sinnwell, Xiaojia Tang, Kevin Thompson, Alvaro Moreno-Aspitia, Donald W Northfelt, Minetta C Liu, Tufia C Haddad, Saranya Chumsri, Prema Peethambaram, Kathryn J Ruddy, Karthik V Giridhar, Roberto A Leon-Ferre, Adrian Nordmark, Mattias Bergqvist, Brendan P McMenomy, Richard M Weinshilboum, Liewei Wang, Matthew P Goetz. Novel genomic variants and pathways associated with baseline serum thymidine kinase 1 levels in HR-positive HER2-negative MBC patients commencing palbociclib and letrozole [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS5-24.