Citations

Abstract Low dietary folate intake is associated with an increased risk for colon cancer; however, relevant genetic animal models are lacking. We therefore investigated the effect of targeted ablation of two folate transport genes, folate binding protein 1 (Folbp1) and reduced folate carrier 1 (RFC1), on folate homeostasis to elucidate the molecular mechanisms of folate action on colonocyte cell proliferation, gene expression, and colon carcinogenesis. Targeted deletion of Folbp1 (Folbp1+/− and Folbp1−/−) significantly reduced (P < 0.05) colonic Folbp1 mRNA, colonic mucosa, and plasma folate concentration. In contrast, subtle changes in folate homeostasis resulted from targeted deletion of RFC1 (RFC1+/−). These animals had reduced (P < 0.05) colonic RFC1 mRNA and exhibited a 2-fold reduction in the plasma S-adenosylmethionine/S-adenosylhomocysteine. Folbp1+/− and Folbp1−/− mice had larger crypts expressed as greater (P < 0.05) numbers of cells per crypt column relative to Folbp1+/+ mice. Colonic cell proliferation was increased in RFC1+/− mice relative to RFC1+/+ mice. Microarray analysis of colonic mucosa showed distinct changes in gene expression specific to Folbp1 or RFC1 ablation. The effect of folate transporter gene ablation on colon carcinogenesis was evaluated 8 and 38 weeks post-azoxymethane injection in wild-type and heterozygous mice. Relative to RFC1+/+ mice, RFC1+/− mice developed increased (P < 0.05) numbers of aberrant crypt foci at 8 weeks. At 38 weeks, RFC1+/− mice developed local inflammatory lesions with or without epithelial dysplasia as well as adenocarcinomas, which were larger relative to RFC1+/+ mice. In contrast, Folbp1+/− mice developed 4-fold (P < 0.05) more lesions relative to Folbp1+/+ mice. In conclusion, Folbp1 and RFC1 genetically modified mice exhibit distinct changes in colonocyte phenotype and therefore have utility as models to examine the role of folate homeostasis in colon cancer development.

Purpose: To characterize choroidal amyloid angiopathy (CAA) using late-phase indocyanine green angiography (ICGA). Methods: This was a multicenter retrospective observational case series on patients with transthyretin (ATTR) and AL amyloidosis who underwent ICGA. The timing of hyperfluorescence and longitudinal changes were analyzed. Results: Thirty-two patients (27 with ATTR and 5 with AL) with mean age of 58.9 ± 17.4 years were included. Hyperfluorescent spots in the very late phases of ICGA, corresponding to CAA, were observed in 49 of 55 eyes (89%). The median time to maximal staining was 672 (95% confidence interval, 644–752) seconds, which was significantly later than the initial staining (503 [95% confidence interval, 447–521], P < 0.0001; Wilcoxon signed rank test). In seven patients with ATTR amyloidosis who underwent follow-up of ICGA, the CAA was stable in two patients and improved in five patients during treatment. However, 3 patients (43%) had worsening vitreous opacities in both eyes, and 4 patients (57%) developed secondary open-angle glaucoma. Conclusion: Most patients with amyloidosis were found to have CAA on ICGA. Up to 12.5 minutes is required for maximal ICG staining. Choroidal amyloid angiopathy improved in most patients with systemic treatment and may serve as a marker of systemic disease status.

Background TAILOR‐PCI (Tailored Antiplatelet Initiation to Lessen Outcomes due to decreased Clopidogrel Response After Percutaneous Coronary Intervention) studied genotype‐guided selection of antiplatelet therapy after percutaneous coronary intervention versus conventional therapy with clopidogrel. The presence of CYP2C19 loss‐of‐function alleles in patients treated with clopidogrel may be associated with increased risk for ischemic events. We report a prespecified sex‐specific analysis of genotyping and associated cardiovascular outcomes from this study. Methods and Results Associations between sex and major adverse cardiac events (MACE: cardiovascular death, myocardial infarction, stroke, stent thrombosis, and severe recurrent ischemia) and Bleeding Academic Research Consortium (BARC) bleeding at 12 months were analyzed using Cox proportional‐hazards models. Among 5276 randomized patients, loss‐of‐function carriers were observed in ≈36% of both sexes, and >80% of carriers were heterozygotes. At 12 months, after adjustment for baseline differences, risks of MACE (HR , 1.28 [0.97 to 1.68]; P =0.088) and BARC bleeding (hazard ratio [HR], 1.36 [0.91 to 2.05]; P =0.14) were comparable among women and men. There were no significant interactions between sex and treatment strategy for MACE interaction P value ( P int =0.59) or BARC bleeding ( P int =0.47) nor for sex and genotype (MACE P int =0.15, and BARC bleeding P int =0.60). Conclusions CYP2C19 loss‐of‐function alleles were present in ≈1 in 3 women and men. Women had similar adjusted risks of MACE and bleeding as men following percutaneous coronary intervention. Genotype‐guided therapy did not significantly reduce the risk of MACE or bleeding relative to conventional therapy for both sexes. Registration URL: https://www.clinicaltrials.gov ; Unique identifier: NCT01742117.

7566 Background: Parenteral limited-duration BR chemoimmunotherapy and continuous orally administered Ibr, a Bruton tyrosine kinase inhibitor, dominate the treatment landscape of WM, a rare B cell lymphoma. No trials have assessed the comparative effectiveness of these 2 vastly different approaches. We conducted a multiinstitutional, international, collaborative study to compare BR and single-agent Ibr in patients (pts) with treatment naïve (TN) WM. Methods: Data from 347 pts with active TN WM, seen between 2011 and 2021 in the US and Europe, were analyzed. The pts on rituximab maintenance were excluded. The modified IWWM-6 criteria (based on IgM alone) were used for response assessment. All time-to-event analyses were performed from the frontline therapy initiation, using the Kaplan-Meier method. Results: The median age of the pts treated with BR (n=208) and Ibr (n=139) was 66 (range 40-86) years (y) and 69 (39-97) y, respectively, (p=0.005). With a median follow up of 4.2 y (95% CI 3.8-4.5), the 4-y progression free survival (PFS) was 73% in each group, p=0.6, and 4-y overall survival (OS) was 94% (95% CI 91-98) in the BR group versus ( v) 82% (95% CI 75-90) in the Ibr group, p=0.01. In a bivariate analysis adjusting for age and the treatment type, only age emerged as a predictor for OS (HR 7.2, p=0.0001). Therefore, a 1:1 age-matched analysis of 246 pts who received Ibr (n=123) or BR (n=123) was performed. Pts with a known MYD88WT status who had received Ibr and their age matched controls on BR were excluded. The international prognostic scoring system (IPSS) WM was comparable between the 2 groups (Table). A higher proportion of pts on BR attained very good partial or deeper response (≥VGPR) as the best response in comparison to the pts on Ibr (Table). The 4-y PFS for the BR and Ibr groups was similar [72% (95% CI 63-82) v 78% (95% CI 70-87), p=0.14] and 4-y OS was 95% (95% CI 91-99) with BR v 86% (95% CI 80-93) with Ibr (p=0.3). Premature discontinuation, during active treatment, due to adverse effects (AEs) or lack of response was noted in 13% and 33% of pts on BR and Ibr, respectively. A detailed assessment of the AEs will be presented at the meeting. Conclusions: Both BR and Ibr lead to comparable outcomes in pts with TN WM, although deeper responses are attained with BR. These findings require confirmation in prospective studies. For pts who harbor MYD 88L265P mutation, selection between the 2 approaches should be dictated by their potential toxicities, pt comorbidities, pt/clinician preference (parenteral fixed-duration v continuous oral) and access to therapies. [Table: see text]

INTRODUCTION: Indeterminate acute liver failure (IND-ALF) is a rare clinical syndrome with a high mortality rate. Lacking a known etiology makes rapid evaluation and treatment difficult, with liver transplantation often considered as the only therapeutic option. Our aim was to identify genetic variants from whole exome sequencing data that might be associated with IND-ALF clinical outcomes. METHODS: Bioinformatics analysis was performed on whole exome sequencing data for 22 patients with IND-ALF. A 2-tier approach was used to identify significant single-nucleotide polymorphisms (SNPs) associated with IND-ALF clinical outcomes. Tier 1 identified the SNPs with a higher relative risk in the IND-ALF population compared with those identified in control populations. Tier 2 determined the SNPs connected to transplant-free survival and associated with model for end-stage liver disease serum sodium and Acute Liver Failure Study Group prognostic scores. RESULTS: Thirty-one SNPs were found associated with a higher relative risk in the IND-ALF population compared with those in controls, of which 11 belong to the human leukocyte antigen (HLA) class II genes but none for the class I. Further analysis showed that 5 SNPs: rs796202376, rs139189937, and rs113473719 of HLA-DRB5; rs9272712 of HLA-DQA1; and rs747397929 of IDO1 were associated with a higher probability of IND-ALF transplant-free survival. Using 3 selected SNPs, a model for the polygenic risk score was developed to predict IND-ALF prognoses, which are comparable with those by model for end-stage liver disease serum sodium and Acute Liver Failure Study Group prognostic scores. DISCUSSION: Certain gene variants in HLA-DRB5, HLA-DQA1, and IDO1 were found associated with IND-ALF transplant-free survival. Once validated, these identified SNPs may help elucidate the mechanism of IND-ALF and assist in its diagnosis and management.

The use of flow diverters is a rapidly growing endovascular approach for the treatment of intracranial aneurysms. All FDA-approved flow diverters are composed of nitinol or cobalt-chromium, which will remain in the patient for the duration of their life. Bioresorbable flow diverters have been proposed by several independent investigators as the next generation of flow diverting devices. These devices aim to serve their transient function of occluding and healing the aneurysm prior to being safely resorbed by the body, eliminating complications associated with the permanent presence of conventional flow diverters. Theoretical advantages of bioresorbable flow diverters include (1) reduction in device-induced thrombosis; (2) reduction in chronic inflammation and device-induced stenosis; (3) reduction in side branch occlusion; (4) restoration of physiological vasomotor function; (5) reduction in imaging artifacts; and (6) use in pediatric applications. Advances made in the similar bioresorbable coronary stenting field highlight some of these advantages and demonstrate the feasibility and safety of bioresorbable endovascular devices in the clinic. The current work aims to review the progress of bioresorbable flow diverters, identify opportunities for further investigation, and ultimately stimulate the advancement of this technology.

Abstract Background Postmastectomy breast reconstruction (PMR) increases patient satisfaction, quality of life, and psychosocial well-being. There is scarce data regarding the safety of PMR in chronic anticoagulated patients. Perioperative complications can reduce patient satisfaction; therefore, it is important to elucidate the safety of PMR in these patients. Methods A retrospective case–control study of patients who underwent PMR with implants and were on chronic anticoagulation was performed at our institution. Inclusion criteria were women ≥ 18 years old. Exclusion criteria included autologous reconstructions, lumpectomy, and oncoplastic procedures. Two controls for every one patient on anticoagulation were matched by age, body mass index, radiotherapy, smoking history, type of reconstruction, time of reconstruction, and laterality. Results From 2009 to 2020, 37 breasts (20 patients) underwent PMR with implant-based reconstruction and were on chronic anticoagulation. A total of 74 breasts (40 patients) who had similar demographic characteristics to the cases were defined as the control group. Mean age for the case group was 53.6 years (standard deviation [SD] = 16.1), mean body mass index was 28.6 kg/m2 (SD = 5.1), and 2.7% of breasts had radiotherapy before reconstruction and 5.4% after reconstruction. Nine patients were on long-term warfarin, six on apixaban, three on rivaroxaban, one on low-molecular-weight heparin, and one on dabigatran. The indications for anticoagulation were prior thromboembolic events in 50%. Anticoagulated patients had a higher risk of capsular contracture (10.8% vs. 0%, p = 0.005). There were no differences regarding incidence of hematoma (2.7% vs. 1.4%, p = 0.63), thromboembolism (5% vs. 0%, p = 0.16), reconstructive-related complications, or length of hospitalization (1.6 days [SD = 24.2] vs. 1.4 days [SD = 24.2], p = 0.85). Conclusion Postmastectomy implant-based breast reconstruction can be safely performed in patients on chronic anticoagulation with appropriate perioperative management of anticoagulation. This information can be useful for preoperative counseling on these patients.

Background: Increased attention has been directed toward the acetabular morphology in the management of patients with femoroacetabular impingement syndrome (FAIS). Whether acetabular version influences patient-reported outcomes remains poorly understood. Purpose: To use computed tomography (CT)–based 3-dimensional (3D) bone models to (1) quantify acetabular version in patients with FAIS, (2) compare acetabular version on 3D bone models with current plain radiographic parameters, and (3) explore the relationship between the magnitude of acetabular version and minimum 2-year clinical outcomes after hip arthroscopy. Study Design: Cohort study; Level of evidence, 3. Methods: Three-dimensional models of the pelvis and femur were generated by semiautomated segmentation and aligned to a standard coordinate system. Acetabular version was quantified at the 3-o’clock position, and 3 groups were identified: acetabular retroversion (AR; <15°), normal acetabular version (NV; 15°-25°), and acetabular anteversion (AA; >25°). Patient demographic characteristics, plain radiographic parameters, and clinical outcomes were analyzed, including the Hip Outcome Score–Activities of Daily Living, Hip Outcome Score–Sports Subscale, modified Harris Hip Score (mHHS), International Hip Outcome Tool (iHOT-12), and visual analog scale (VAS) for pain and satisfaction. Results: Preoperative CT scans were acquired in 105 consecutive patients before hip arthroscopy for FAIS, of which 84 (80.0%) completed minimum 2-year patient-reported outcomes. The mean ± SD age and body mass index of patients were 33.9 ± 12.6 years and 26.0 ± 5.4, respectively; 70.2% were female. The number of patients and the mean central acetabular version within each group were as follows: AR (n = 12; 11.3°± 2.7°), NV (n = 56; 20.7°± 2.9°), and AA (n = 16; 28.5°± 2.7°). Posterior wall sign was the only plain radiographic parameter that was significantly more observed in the AR group than in the other 2 groups. At minimum 2-year follow-up, significant between-group differences in the mHHS, iHOT-12, and VAS for pain and satisfaction ( P < .05) were appreciated, while post hoc analysis with Bonferroni correction ( P < .0167) found lower scores on the mHHS, iHOT-12, and VAS for pain and satisfaction in patients with AR as compared with NV. Lower scores on the VAS for satisfaction were reported in patients with AR when compared with AA ( P = .006) but not on the mHHS ( P = .023), iHOT-12 ( P = .032), or VAS for pain ( P = .072). Conclusion: Traditional plain radiographic indices to describe AR, including crossover sign and ischial spine sign, were not reliable in defining AR according to 3D models derived from CT scans. Only the posterior wall sign was observed in a higher proportion in the AR group. Patients with AR demonstrated inferior outcomes when compared with patients with NV and AA after hip arthroscopy for FAIS.

Background Although successful recanalization (modified Thrombolysis in Cerebral Infarction score 2b–3) can be achieved in >80% of patients experiencing stroke attributable to large‐vessel occlusion, up to 50% of patients may develop poor clinical outcomes (modified Rankin scale score at 90 days of 3–6), termed as futile recanalization (FR). The meta‐analysis aims to determine various risk factors associated with FR. Methods In February 2021, a comprehensive literature search on risk factors associated with FR was performed with keywords, including “stroke,” “thrombectomy,” “treatment outcome,” and “risk factors.” Their correlations with FR were evaluated using the random effect size meta‐analysis model. Results Twenty studies with 3037 patients were included with an FR rate of 51.0%. Our meta‐analyses showed that age (mean difference [MD], 5.6; 95% CI, 4.7–6.6), National Institutes of Health Stroke Scale score (MD, 4.2; 95% CI, 3.2–5.1), Alberta Stroke Program Early Computed Tomography (CT) Score (MD, −0.5; 95% CI, 0.8–0.3), hypertension (odds ratio [OR], 1.5; 95% CI, 1.3–1.9), systolic blood pressure (MD, 6.9; 95% CI, 3.6–8.7), atrial fibrillation (OR, 1.5; 95% CI, 1.2–1.8), IV tPA (tissue‐type plasminogen activator) (OR, 0.7; 95% CI, 0.5–0.8), puncture to recanalization time (MD, 9.6; 95% CI, 5.3–13.8), and time of onset to recanalization (MD, 32.1; 95% CI, 6.5–47.7) were significantly associated with FR ( P <0.001). Conclusions Age, admission National Institutes of Health Stroke Scale score, Alberta Stroke Program Early CT Score, comorbidities, including hypertension, systolic blood pressure, atrial fibrillation, and use of IV tPA, as well as time frames, including onset to recanalization and onset to arrival, were significant influencing factors for FR after mechanical thrombectomy. Future research on the mechanism underlying FR is warranted.