Citations

Exposure to high altitude results in hypobaric hypoxia, leading to physiological changes in the cardiovascular system that may result in limiting symptoms, including dyspnea, fatigue, and exercise intolerance. However, it is still unclear why some patients are more susceptible to high-altitude symptoms than others. Hypoxic simulation testing (HST) simulates changes in physiology that occur at a specific altitude by asking the patients to breathe a mixture of gases with decreased oxygen content. This study aimed to determine whether the use of transthoracic echocardiography (TTE) during HST can detect the rise in right-sided pressures and the impact of hypoxia on right ventricle (RV) hemodynamics and right to left shunts, thus revealing the underlying causes of high-altitude signs and symptoms. A retrospective study was performed including consecutive patients with unexplained dyspnea at high altitude. HSTs were performed by administrating reduced FiO2 to simulate altitude levels specific to patients’ history. Echocardiography images were obtained at baseline and during hypoxia. The study included 27 patients, with a mean age of 65 years, 14 patients (51.9%) were female. RV systolic pressure increased at peak hypoxia, while RV systolic function declined as shown by a significant decrease in the tricuspid annular plane systolic excursion (TAPSE), the maximum velocity achieved by the lateral tricuspid annulus during systole (S’ wave), and the RV free wall longitudinal strain. Additionally, right-to-left shunt was present in 19 (70.4%) patients as identified by bubble contrast injections. Among these, the severity of the shunt increased at peak hypoxia in eight cases (42.1%), and the shunt was only evident during hypoxia in seven patients (36.8%). In conclusion, the use of TTE during HST provides valuable information by revealing the presence of symptomatic, sustained shunts and confirming the decline in RV hemodynamics, thus potentially explaining dyspnea at high altitude. Further studies are needed to establish the optimal clinical role of this physiologic method.

Germline 3q21 chromosome deletions result in a rare multi-system condition. Of the 14 cases of germline 3q21 deletion syndrome reported, 2 have been reported to develop myelodysplastic syndrome necessitating allogeneic HCT (our patient and one other). Our patient was treated with an allogeneic, matched sibling hematopoietic cell transplantation. Patients with 3q21 deletion have a predilection for myelodysplastic syndrome, likely due to GATA2 deletion. We recommend frequent complete blood count evaluation with annual bone marrow aspiration to monitor for development of MDS in patients with 3q21 deletion.

Background: The natural history of primary sclerosing cholangitis (PSC) among African Americans (AA) is not well understood. Methods: Transplant-free survival and hepatic decompensation–free survival were assessed using a retrospective research registry from 16 centers throughout North America. Patients with PSC alive without liver transplantation after 2008 were included. Diagnostic delay was defined from the first abnormal liver test to the first abnormal cholangiogram/liver biopsy. Socioeconomic status was imputed by the Zip code. Results: Among 850 patients, 661 (77.8%) were non-Hispanic Whites (NHWs), and 85 (10.0%) were AA. There were no significant differences by race in age at diagnosis, sex, or PSC type. Inflammatory bowel disease was more common in NHWs (75.8% vs. 51.8% p =0.0001). The baseline (median, IQR) Amsterdam-Oxford Model score was lower in NHWs (14.3, 13.4–15.2 vs. 15.1, 14.1–15.7, p =0.002), but Mayo risk score (0.03, −0.8 to 1.1 vs. 0.02, −0.7 to 1.0, p =0.83), Model for End-stage Liver Disease (5.9, 2.8–10.7 vs. 6.4, 2.6–10.4, p =0.95), and cirrhosis (27.4% vs. 27.1%, p =0.95) did not differ. Race was not associated with hepatic decompensation, and after adjusting for clinical variables, neither race nor socioeconomic status was associated with transplant-free survival. Variables independently associated with death/liver transplant (HR, 95% CI) included age at diagnosis (1.04, 1.02–1.06, p <0.0001), total bilirubin (1.06, 1.04–1.08, p <0.0001), and albumin (0.44, 0.33–0.61, p <0.0001). AA race did not affect the performance of prognostic models. Conclusions: AA patients with PSC have a lower rate of inflammatory bowel disease but similar progression to hepatic decompensation and liver transplant/death compared to NHWs.

Isocitrate Dehydrogenase-1 (IDH1) is commonly mutated in lower-grade diffuse gliomas. The IDH1R132H mutation is an important diagnostic tool for tumor diagnosis and prognosis; however, its role in glioma development, and its impact on response to therapy, is not fully understood. We developed a murine model of proneural IDH1R132H-mutated glioma that shows elevated production of 2-hydroxyglutarate (2-HG) and increased trimethylation of lysine residue K27 on histone H3 (H3K27me3) compared to IDH1 wild-type tumors. We found that using Tazemetostat to inhibit the methyltransferase for H3K27, Enhancer of Zeste 2 (EZH2), reduced H3K27me3 levels and increased acetylation on H3K27. We also found that, although the histone deacetylase inhibitor (HDACi) Panobinostat was less cytotoxic in IDH1R132H-mutated cells (either isolated from murine glioma or oligodendrocyte progenitor cells infected in vitro with a retrovirus expressing IDH1R132H) compared to IDH1-wild-type cells, combination treatment with Tazemetostat is synergistic in both mutant and wild-type models. These findings indicate a novel therapeutic strategy for IDH1-mutated gliomas that targets the specific epigenetic alteration in these tumors.

Abstract Background: The genotoxin colibactin causes a tumor single-base substitution (SBS) mutational signature, SBS88. It is unknown whether epidemiologic factors’ association with colorectal cancer risk and survival differs by SBS88. Methods: Within the Genetic Epidemiology of Colorectal Cancer Consortium and Colon Cancer Family Registry, we measured SBS88 in 4,308 microsatellite stable/microsatellite instability low tumors. Associations of epidemiologic factors with colorectal cancer risk by SBS88 were assessed using multinomial regression (N = 4,308 cases, 14,192 controls; cohort-only cases N = 1,911), and with colorectal cancer–specific survival using Cox proportional hazards regression (N = 3,465 cases). Results: 392 (9%) tumors were SBS88 positive. Among all cases, the highest quartile of fruit intake was associated with lower risk of SBS88-positive colorectal cancer than SBS88-negative colorectal cancer [odds ratio (OR) = 0.53, 95% confidence interval (CI) 0.37-0.76; OR = 0.75, 95% CI 0.66–0.85, respectively, Pheterogeneity = 0.047]. Among cohort studies, associations of body mass index (BMI), alcohol, and fruit intake with colorectal cancer risk differed by SBS88. BMI ≥30 kg/m2 was associated with worse colorectal cancer–specific survival among those SBS88-positive [hazard ratio (HR) = 3.40, 95% CI 1.47–7.84], but not among those SBS88-negative (HR = 0.97, 95% CI 0.78–1.21, Pheterogeneity = 0.066). Conclusions: Most epidemiologic factors did not differ by SBS88 for colorectal cancer risk or survival. Higher BMI may be associated with worse colorectal cancer–specific survival among those SBS88-positive; however, validation is needed in samples with whole-genome or whole-exome sequencing available. Impact: This study highlights the importance of identification of tumor phenotypes related to colorectal cancer and understanding potential heterogeneity for risk and survival.

Purpose To systematically review the existing literature on the functional performance of athletes at the time of return‐to‐sport (RTS) clearance after anterior cruciate ligament reconstruction (ACLR). Methods A systematic literature search of the MEDLINE, EMBASE, Scopus, and Web of Science databases was performed. The inclusion criteria were original research reports with study populations of athletes who had undergone ACLR and had undergone objective functional testing immediately after clearance to RTS. Functional testing was stratified by hop tests, strength tests, kinetic assessment, and kinematic assessment, and data were extracted from each study using a standardized template. Results Of the 937 unique studies identified, 46 met the inclusion criteria. The average time between ACLR and functional testing was 7.9 months among the included studies. In 10 of 17 studies, patients were found to have an average quadriceps strength limb symmetry index of less than 90%. However, only 2 of 12 studies found the average hop test limb symmetry index to be less than 90%. Kinematics included reduced knee flexion angle and increased trunk flexion on landing in ACLR patients compared with matched controls. On evaluation of kinetics, ACLR patients showed reduced peak vertical ground reaction force, lower peak knee extension and knee flexion moments, and altered energy absorption contribution compared with matched controls. Conclusions This systematic review suggests that athletes show functional deficits at the time of RTS at an average of 7.9 months after ACLR. Traditional functional tests, such as strength and hop tests, are not able to accurately identify patients who continue to show deficits. The most common biomechanical deficits that persist after RTS clearance include diminished peak knee extension moment, decreased knee flexion angle, increased trunk flexion angle, reduced vertical ground reaction force, and increased hamstring central activation ratio during various functional gait and landing tasks. Level of Evidence Level III, systematic review of Level I to III studies.

AbstractBackgroundPatient‐reported outcomes (PROs) are a better tool for evaluating the experiences of patients who have symptomatic, treatment‐associated adverse events (AEs) compared with clinician‐rated AEs. The authors present PROs assessing health‐related quality of life (HRQoL) and treatment‐related neurotoxicity for adjuvant capecitabine versus platinum on the Eastern Cooperative Oncology Group‐American College of Radiology Imaging Network (ECOG‐ACRIN) EA1131 trial (ClinicalTrials.gov identifier NCT02445391).MethodsParticipants completed the National Comprehensive Cancer Network Functional Assessment of Cancer Therapy–Breast Cancer Symptom Index (NFBSI‐16) and the Functional Assessment of Cancer Therapy–Gynecologic Oncology Group neurotoxicity subscale (platinum arm only) at baseline, cycle 3 day 1 (C3D1), 6 months, and 15 months. Because of early termination, power was insufficient to test the hypothesis that HRQoL, as assessed by the NFBSI‐16 treatment side‐effect (TSE) subscale, would be better at 6 and 15 months in the capecitabine arm; all analyses were exploratory. Means were compared by using t‐tests or the Wilcoxon rank‐sum test, and proportions were compared by using the χ2 test.ResultsTwo hundred ninety‐six of 330 eligible patients provided PROs. The mean NFBSI‐16 TSE subscale score was lower for the platinum arm at baseline (p = .02; absolute difference, 0.6 points) and for the capecitabine arm at C3D1 (p = .04; absolute difference, 0.5 points), but it did not differ at other times. The mean change in TSE subscale scores differed between the arms from baseline to C3D1 (platinum arm, 0.15; capecitabine arm, −0.72; p = .03), but not from baseline to later time points. The mean decline in Functional Assessment of Cancer Therapy–Gynecologic Oncology Group neurotoxicity subscale scores exceeded the minimal meaningful change (1.38 points) from baseline to each subsequent time point (all p < .05).ConclusionsDespite the similar frequency of clinician‐rated AEs, PROs identified greater on‐treatment symptom burden with capecitabine and complemented clinician‐rated AEs by characterizing patients’ experiences during chemotherapy.

Importance Adding fulvestrant to anastrozole (A+F) improved survival in postmenopausal women with advanced estrogen receptor (ER)–positive/ERBB2 (formerly HER2)–negative breast cancer. However, the combination has not been tested in early-stage disease. Objective To determine whether neoadjuvant fulvestrant or A+F increases the rate of pathologic complete response or ypT1-2N0/N1mic/Ki67 2.7% or less residual disease (referred to as endocrine-sensitive disease) over anastrozole alone. Design, Setting, and Participants A phase 3 randomized clinical trial assessing differences in clinical and correlative outcomes between each of the fulvestrant-containing arms and the anastrozole arm. Postmenopausal women with clinical stage II to III, ER-rich (Allred score 6-8 or &amp;gt;66%)/ERBB2-negative breast cancer were included. All analyses were based on data frozen on March 2, 2023. Interventions Patients received anastrozole, fulvestrant, or a combination for 6 months preoperatively. Tumor Ki67 was assessed at week 4 and optionally at week 12, and if greater than 10% at either time point, the patient switched to neoadjuvant chemotherapy or immediate surgery. Main Outcomes and Measures The primary outcome was the endocrine-sensitive disease rate (ESDR). A secondary outcome was the percentage change in Ki67 after 4 weeks of neoadjuvant endocrine therapy (NET) (week 4 Ki67 suppression). Results Between February 2014 and November 2018, 1362 female patients (mean [SD] age, 65.0 [8.2] years) were enrolled. Among the 1298 evaluable patients, ESDRs were 18.7% (95% CI, 15.1%-22.7%), 22.8% (95% CI, 18.9%-27.1%), and 20.5% (95% CI, 16.8%-24.6%) with anastrozole, fulvestrant, and A+F, respectively. Compared to anastrozole, neither fulvestrant-containing regimen significantly improved ESDR or week 4 Ki67 suppression. The rate of week 4 or week 12 Ki67 greater than 10% was 25.1%, 24.2%, and 15.7% with anastrozole, fulvestrant, and A+F, respectively. Pathologic complete response/residual cancer burden class I occurred in 8 of 167 patients and 17 of 167 patients, respectively (15.0%; 95% CI, 9.9%-21.3%), after switching to neoadjuvant chemotherapy due to week 4 or week 12 Ki67 greater than 10%. PAM50 subtyping derived from RNA sequencing of baseline biopsies available for 753 patients (58%) identified 394 luminal A, 304 luminal B, and 55 nonluminal tumors. A+F led to a greater week 4 Ki67 suppression than anastrozole alone in luminal B tumors (median [IQR], −90.4% [−95.2 to −81.9%] vs −76.7% [−89.0 to −55.6%]; P &amp;lt; .001), but not luminal A tumors. Thirty-six nonluminal tumors (65.5%) had a week 4 or week 12 Ki67 greater than 10%. Conclusions and Relevance In this randomized clinical trial, neither fulvestrant nor A+F significantly improved the 6-month ESDR over anastrozole in ER-rich/ERBB2-negative breast cancer. Aromatase inhibition remains the standard-of-care NET. Differential NET response by PAM50 subtype in exploratory analyses warrants further investigation. Trial Registration ClinicalTrials.gov Identifier: NCT01953588

AbstractAxenfeld‐Rieger Syndrome (ARS) type 1 is a rare autosomal dominant condition characterized by anterior chamber anomalies, umbilical defects, dental hypoplasia, and craniofacial anomalies, with Meckel's diverticulum in some individuals. Here, we describe a clinically ascertained female of childbearing age with ARS for whom clinical targeted sequencing and deletion/duplication analysis followed by clinical exome and genome sequencing resulted in no pathogenic variants or variants of unknown significance in PITX2 or FOXC1. Advanced bioinformatic analysis of the genome data identified a complex, balanced rearrangement disrupting PITX2. This case is the first reported intrachromosomal rearrangement leading to ARS, illustrating that for patients with compelling clinical phenotypes but negative genomic testing, additional bioinformatic analysis are essential to identify subtle genomic abnormalities in target genes.

Platelet activation and the complement system are mutually dependent. Here, we investigated the effects of storage time on complement activation and platelet function in routinely produced platelet concentrates. The platelet concentrates (n = 10) were stored at 22 °C for seven days and assessed daily for complement and platelet activation markers. Additionally, platelet function was analyzed in terms of their responsiveness to protease-activated receptor-1 (PAR-1) and thromboxane A2 receptor (TXA2R) activation and their capacity to adhere to collagen. Complement activation increased over the storage period for all analyzed markers, including the C1rs/C1-INH complex (fold change (FC) = 1.9; p < 0.001), MASP-1/C1-INH complex (FC = 2.0; p < 0.001), C4c (FC = 1.8, p < 0.001), C3bc (FC = 4.0; p < 0.01), and soluble C5b-9 (FC = 1.7, p < 0.001). Furthermore, the levels of soluble platelet activation markers increased in the concentrates over the seven-day period, including neutrophil-activating peptide-2 (FC = 2.5; p < 0.0001), transforming growth factor beta 1 (FC = 1.9; p < 0.001) and platelet factor 4 (FC = 2.1; p < 0.0001). The ability of platelets to respond to activation, as measured by surface expression of CD62P and CD63, decreased by 19% and 24% (p < 0.05) for PAR-1 and 69–72% (p < 0.05) for TXA2R activation, respectively, on Day 7 compared to Day 1. The extent of platelet binding to collagen was not significantly impaired during storage. In conclusion, we demonstrated that complement activation increased during the storage of platelets, and this correlated with increased platelet activation and a reduced ability of the platelets to respond to, primarily, TXA2R activation.