Citations

Abstract Ruxolitinib reduces spleen volume, improves symptoms, and increases survival in patients with intermediate- or high-risk myelofibrosis. However, suboptimal response may occur, potentially because of signaling via the phosphoinositide 3-kinase (PI3K)/protein kinase B pathway. This phase 2 study evaluated dosing, efficacy, and safety of add-on PI3Kδ inhibitor parsaclisib for patients with primary or secondary myelofibrosis with suboptimal response to ruxolitinib. Eligible patients remained on a stable ruxolitinib dose and received add-on parsaclisib 10 or 20 mg, once daily for 8 weeks, and once weekly thereafter (daily-to-weekly dosing; n = 32); or parsaclisib 5 or 20 mg, once daily for 8 weeks, then 5 mg once daily thereafter (all-daily dosing; n = 42). Proportion of patients achieving a ≥10% decrease in spleen volume at 12 weeks was 28% for daily-to-weekly dosing and 59.5% for all-daily dosing. Proportions of patients achieving ≥50% decrease at week 12 in Myelofibrosis Symptom Assessment Form and Myeloproliferative Neoplasms Symptom Assessment Form symptom scores were 14% and 18% for daily-to-weekly dosing, and 28% and 32% for all-daily dosing, respectively. Most common nonhematologic treatment-emergent adverse events were nausea (23%), diarrhea (22%), abdominal pain and fatigue (each 19%), and cough and dyspnea (each 18%). New-onset grade 3 and 4 thrombocytopenia were observed in 19% of patients, each dosed daily-to-weekly, and in 26% and 7% of patients dosed all-daily, respectively, managed with dose interruptions. Hemoglobin levels remained steady. The addition of parsaclisib to stable-dose ruxolitinib can reduce splenomegaly and improve symptoms, with manageable toxicity in patients with myelofibrosis with suboptimal response to ruxolitinib. This trial was registered at www.clinicaltrials.gov as #NCT02718300.

Background Analysis of the real-world data of low-dose spiral CT screening of healthy physical examination population in Southwest China from 2006 to 2017, discussed the standard of low-dose spiral CT screening for high-risk population of lung cancer in China. Methods Incorporate all team subjects who have undergone LDCT screenings at the Health Management Center of West China Hospital of Sichuan University between 2006 and 2017, and analyze the cumulative incidence and age-standardized (Segi population) incidence of lung cancer in the whole population; finally, analysis the age-specific, smoking and non-smokers’ lung cancer incidence. Results A total of 15,996 people who met the enrollment conditions and participated in the LDCT lung cancer screening were included. The average screening interval was 1.12±0.26 years, and the average follow-up time was 5.43±0.82 years; The cumulative number of lung cancer cases with negative baseline screening was 56 cases, and the cumulative incidence rate of lung cancer was 122.1/100,000 (the world standard rate is 60.6/100,000), of which males were 100.0/100,000 (the world standard rate is 45.3/100,000) and women were 156.6 /100,000 (the world standard rate is 94.7/100,000); the cumulative incidence of lung cancer in the smoking group is higher than that in the non-smoking group for both males and females, but the cumulative incidence of lung cancer in the non-smokers of the female population (146.3/100,000) is higher than that of the male population (86.5/10 Million). Conclusion In the real world study of lung cancer screening in Chinese population, we should consider setting different standards for high-risk groups of lung cancer by gender or smoking and non-smokers.

Mechanical valves in both aortic and mitral positions pose a challenge for left ventricular (LV) access during ventricular tachycardia (VT) ablation using the antegrade transseptal or the retrograde transaortic approach. A 57 year-old male with ischemic cardiomyopathy, mechanical aortic and mitral valves, and recurrent VT underwent a combined endocardial and epicardial ablation via direct ventricular puncture via mini-thoracotomy. Successful mapping with endocardial and epicardial ablation was performed, with no recurrent VT on follow up. We showcase the feasibility of VT ablation using an open transapical approach for patients with mechanical aortic and mitral valves.

Chromothripsis is characterized by shattering and subsequent reassembly of chromosomes by DNA repair processes, which can give rise to a variety of congenital abnormalities and cancer. Constitutional chromothripsis is a rare occurrence, reported in children presenting with a wide range of birth defects. We present a case of a female child born with multiple major congenital abnormalities including severe microcephaly, ocular dysgenesis, heart defect, and imperforate anus. Chromosomal microarray and mate pair sequencing identified a complex chromosomal rearrangement involving the terminal end of the long arm of chromosome 2, with two duplications (located at 2p25.3-p25.1 and 2q35-q37.2 regions) and two deletions (located at 2q37.2-q37.3 and 2q37.3 regions) along with structural changes including inverted segments. A review of the literature for complex rearrangements on chromosome 2 revealed overlapping features; however, our patient had a significantly more severe phenotype which resulted in early death at the age of 2 years. Breakpoints analysis did not reveal the involvement of any candidate genes. We concluded that the complexity of the genomic rearrangement and the combined dosage/structural effect of these copy number variants are likely explanations for the severe presentation in our patient.

Background: Inflammation is integral in the pathogenesis and propagation of atrial fibrillation (AF). Peri-ablation administration of steroids has been shown to significantly reduce AF recurrence at 3 months. We sought to determine the effect of intraoperative dexamethasone on early recurrence at both 3 months and 12 months post-ablation. Methods: A cohort of 94 adult patients (>18 years) underwent catheter ablation at Mayo Clinic Rochester from January to March 2019. Only first-time ablation patients were included, with all re-do ablations excluded to minimize heterogeneity. Administration of intraoperative dexamethasone 4 mg or 8 mg was determined by chart review from the procedure. At our institution, intraoperative intravenous steroids are administered for postoperative nausea and vomiting (PONV) prophylaxis at the discretion of the anesthesiologist. AF recurrence was determined by ECG or cardiac monitoring at less than 3 months or between 3 months and 1 year with an in-person follow-up visit. Results: A total of 36.2% of patients received intravenous dexamethasone compared to 63.8% who did not (providing a 2:1 comparison group). The incidence of documented AF or flutter lasting greater than 30 seconds was 20.6% in the dexamethasone group versus 21.7% in the non-dexamethasone group, p value 1.00. AF or atrial flutter recurrence from 3 months to 1 year was 20.6% in the dexamethasone group compared to 21.7% in the non-dexamethasone group, p value 1.00. Conclusion: These data suggest that intraoperative intravenous dexamethasone administered during AF ablation for postoperative nausea and vomiting prophylaxis does not have a significant effect on AF recurrence rates.

Hepatocellular carcinoma (HCC) is the most prevalent form of primary liver cancer and ranks as the second leading cause of cancer-related mortality globally. Despite advances in current HCC treatment, it remains a malignancy with poor prognosis. Therefore, developing novel treatment options for patients with HCC is urgently needed. Chimeric antigen receptor (CAR)-modified natural killer (NK) cells have shown potent anti-tumor effects, making them as a promising immunotherapy strategy for cancer treatment. Glypican-3 (GPC3), a cell surface oncofetal glycoprotein, is highly expressed in most HCC tissues, but not in normal tissues, and functions as a key driver of carcinogenesis. Given its high expression level on the cell surface, GPC3 is considered as an attractive immunotherapy target for HCC. In this study, two GPC3-specific CAR-NK cells, NK92MI/NH3 and NK92MI/HS20, were established using NK92MI cells, a modified IL-2-independent NK cell line. These cell lines were engineered with third generation GPC3-specific CAR, and their activities were subsequently evaluated in the treatment of HCC. We found that NK92MI/NH3 cells, rather than NK92MI/HS20 cells, exhibited a significant cytotoxicity effect against GPC3 + HepG2 cells in vitro and efficiently suppressed tumor growth in a xenograft model using NSG mice. In addition, irradiated NK92MI/NH3 cells displayed similar anti-tumor efficacy to unirradiated NK92MI/NH3 cells. Furthermore, we observed that NK92MI/NH3 cells showed higher killing activity against the GPC3 isoform 2 overexpression cell line (SK-Hep1-v2) than those with GPC3 isoform 1 overexpression cell line (SK-Hep1-v1) both in vitro and in vivo. This suggest that the presence of different GPC3 isoforms in HCC may impact the cytotoxicity activity of NK92MI/NH3 cells and potentially influence therapeutic outcomes. These findings highlight the effective anti-HCC effects of NK92MI/HN3 cells, as well as the underlying therapy resistance, suggesting their potential as a promising therapy for HCC.

ABSTRACT The activity of a novel β-lactamase inhibitor combination, sulbactam-durlobactam (SUL-DUR), was tested against 87 colistin-resistant and/or cefiderocol-non-susceptible carbapenem-resistant Acinetobacter baumannii clinical isolates collected from U.S. hospitals between 2017 and 2019. Among them, 89% and 97% were susceptible to SUL-DUR and imipenem plus SUL-DUR, with MIC 50 /MIC 90 values of 2 µg/mL/8 µg/mL and 1 µg/mL/4 µg/mL, respectively. The presence of amino acid substitutions in penicillin-binding protein 3, including previously reported A515V or T526S, was associated with SUL-DUR non-susceptibility.