The identification of heterozygous neomorphic isocitrate dehydrogenase (IDH) mutations across multiple cancer types including both solid and hematologic malignancies has revolutionized our understanding of oncogenesis in these malignancies and the potential for targeted therapeutics using small molecule inhibitors. The neomorphic mutation in IDH generates an oncometabolite product, 2-hydroxyglutarate (2HG), which has been linked to the disruption of metabolic and epigenetic mechanisms responsible for cellular differentiation and is likely an early and critical contributor to oncogenesis. In the past 2 years, two mutant IDH (mutIDH) inhibitors, Enasidenib (AG-221), and Ivosidenib (AG-120), have been FDA-approved for IDH-mutant relapsed or refractory acute myeloid leukemia (AML) based on phase 1 safety and efficacy data and continue to be studied in trials in hematologic malignancies, as well as in glioma, cholangiocarcinoma, and chondrosarcoma. In this review, we will summarize the molecular pathways and oncogenic consequences associated with mutIDH with a particular emphasis on glioma and AML, and systematically review the development and preclinical testing of mutIDH inhibitors. Existing clinical data in both hematologic and solid tumors will likewise be reviewed followed by a discussion on the potential limitations of mutIDH inhibitor monotherapy and potential routes for treatment optimization using combination therapy.

clinicaltrials.gov Identifier: NCT01825798.

No abstract

Innovative technology and techniques have revolutionized minimally invasive spine surgery (MIS) within the past decade. The introduction of navigation and image-guided surgery has greatly affected spinal surgery and will continue to make surgery safer and more efficient. Eventually, it is conceivable that fluoroscopy will be completely replaced with image guidance. These advancements, among others such as robotics and virtual and augmented reality technology, will continue to drive the value of 3-dimensional navigation in MIS. In this review, we cover pertinent features of navigation in MIS and explore their evolution over time. Moreover, we aim to discuss the key features germane to surgical advancement, including technique and technology development, accuracy, overall health care costs, operating room time efficiency, and radiation exposure.

OBJECTIVES: To evaluate the impact of ICU surge on mortality and to explore clinical and sociodemographic predictors of mortality. DESIGN: Retrospective cohort analysis. SETTING: NYC Health + Hospitals ICUs. PATIENTS: Adult ICU patients with coronavirus disease 2019 admitted between March 24, and May 12, 2020. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Hospitals reported surge levels daily. Uni- and multivariable analyses were conducted to assess factors impacting in-hospital mortality. Mortality in Hispanic patients was higher for high/very high surge compared with low/medium surge (69.6% vs 56.4%; p = 0.0011). Patients 65 years old and older had similar mortality across surge levels. Mortality decreased from high/very high surge to low/medium surge in, patients 18–44 years old and 45–64 (18–44 yr: 46.4% vs 27.3%; p = 0.0017 and 45–64 yr: 64.9% vs 53.2%; p = 0.002), and for medium, high, and very high poverty neighborhoods (medium: 69.5% vs 60.7%; p = 0.019 and high: 71.2% vs 59.7%; p = 0.0078 and very high: 66.6% vs 50.7%; p = 0.0003). In the multivariable model high surge (high/very high vs low/medium odds ratio, 1.4; 95% CI, 1.2–1.8), race/ethnicity (Black vs White odds ratio, 1.5; 95% CI, 1.1–2.0 and Asian vs White odds ratio 1.5; 95% CI, 1.0–2.3; other vs White odds ratio 1.5, 95% CI, 1.0–2.3), age (45–64 vs 18–44 odds ratio, 2.0; 95% CI, 1.6–2.5 and 65–74 vs 18–44 odds ratio, 5.1; 95% CI, 3.3–8.0 and 75+ vs 18–44 odds ratio, 6.8; 95% CI, 4.7–10.1), payer type (uninsured vs commercial/other odds ratio, 1.7; 95% CI, 1.2–2.3; medicaid vs commercial/other odds ratio, 1.3; 95% CI, 1.1–1.5), neighborhood poverty (medium vs low odds ratio 1.6, 95% CI, 1.0–2.4 and high vs low odds ratio, 1.8; 95% CI, 1.3–2.5), comorbidities (diabetes odds ratio, 1.6; 95% CI, 1.2–2.0 and asthma odds ratio, 1.4; 95% CI, 1.1–1.8 and heart disease odds ratio, 2.5; 95% CI, 2.0–3.3), and interventions (mechanical ventilation odds ratio, 8.8; 95% CI, 6.1–12.9 and dialysis odds ratio, 3.0; 95% CI, 1.9–4.7) were significant predictors for mortality. CONCLUSIONS: Patients admitted to ICUs with higher surge scores were at greater risk of death. Impact of surge levels on mortality varied across sociodemographic groups.

IMPORTANCE Alteration in lung microbes is associated with disease progression in idiopathic pulmonary fibrosis. OBJECTIVE To assess the effect of antimicrobial therapy on clinical outcomes. DESIGN, SETTING, AND PARTICIPANTS Pragmatic, randomized, unblinded clinical trial conducted across 35 US sites. A total of 513 patients older than 40 years were randomized from August 2017 to June 2019 (final follow-up was January 2020).INTERVENTIONS Patients were randomized in a 1:1 allocation ratio to receive antimicrobials (n = 254) or usual care alone (n = 259). Antimicrobials included co-trimoxazole (trimethoprim 160 mg/sulfamethoxazole 800 mg twice daily plus folic acid 5 mg daily, n = 128) or doxycycline (100 mg once daily if body weight <50 kg or 100 mg twice daily if Ն50 kg, n = 126). No placebo was administered in the usual care alone group. MAIN OUTCOMES AND MEASURESThe primary end point was time to first nonelective respiratory hospitalization or all-cause mortality. RESULTS Among the 513 patients who were randomized (mean age, 71 years; 23.6% women), all (100%) were included in the analysis. The study was terminated for futility on December 18, 2019. After a mean follow-up time of 13.1 months (median, 12.7 months), a total of 108 primary end point events occurred: 52 events (20.4 events per 100 patient-years [95% CI, 14.8-25.9]) in the usual care plus antimicrobial therapy group and 56 events (18.4 events per 100 patient-years [95% CI, 13.2-23.6]) in the usual care group, with no significant difference between groups (adjusted HR, 1.04 [95% CI, 0.71-1.53; P = .83]. There was no statistically significant interaction between the effect of the prespecified antimicrobial agent (co-trimoxazole vs doxycycline) on the primary end point (adjusted HR, 1.15 [95% CI 0.68-1.95] in the co-trimoxazole group vs 0.82 [95% CI, 0.46-1.47] in the doxycycline group; P = .66). Serious adverse events occurring at 5% or greater among those treated with usual care plus antimicrobials vs usual care alone included respiratory events (16.5% vs 10.0%) and infections (2.8% vs 6.6%); adverse events of special interest included diarrhea (10.2% vs 3.1%) and rash (6.7% vs 0%).CONCLUSIONS AND RELEVANCE Among adults with idiopathic pulmonary fibrosis, the addition of co-trimoxazole or doxycycline to usual care, compared with usual care alone, did not significantly improve time to nonelective respiratory hospitalization or death. These findings do not support treatment with these antibiotics for the underlying disease.

Background The prevalence of daily cigarette smoking has dropped to 10% in Hong Kong (HK) in 2017, however, smoking still kills 5700 persons per year. Studies suggest that abstinence rates are higher with combined NRT than single NRT, although local data on safety and benefits of combined NRT are lacking. The aim of this study is to compare the effectiveness of combined NRT with single NRT among HK Chinese. Methods This is a one-year, two-arm, parallel randomised trial. Five hundred sixty smokers, who smoked ≥10 cigarettes/day for ≥1 year, were randomized to combined and single NRT. Combined NRT group received counseling and nicotine patch & gum. Single NRT group received counselling and nicotine patch. Primary outcome was abstinence rate measured as self-reported 7-day point prevalence with CO validated at 52 weeks. Secondary outcomes included smoking abstinence rates at 4, 12, & 26 weeks. Crude odds ratio and p-value were reported from logistic regression without adjustment; for trend analysis, adjusted odds ratio (AOR) and p-value were reported from Generalized Estimating Equation (GEE) (controlling for time). All AORs were adjusted for age, sex, baseline CO and clusters. Results Abstinence rates at 4, 12, 26 and 52 weeks were all higher in the combined NRT group (35.8, 21.9, 16.8, 20.1%) compared with the single NRT group (28, 16.8, 11.2, 14.3%). At 4 weeks, combined NRT group was more likely to quit smoking (OR 1.43, 95% CI, 1.00 to 2.05) than the single NRT group. From GEE analysis, combined NRT group had a significantly higher abstinence rate (23.6%) than the single NRT group (17.6%) across repeated measures at all-time points. Combined NRT group was more likely to quit smoking (OR 1.43, 95% CI, 1.15 to 1.77). No significant difference in the side effect profile was detected between groups. Conclusions Smokers given 8 weeks of combined NRT were more likely to quit smoking at 4, 12, 26 and 52 weeks compared with single NRT. Combined NRT was as well tolerated as single NRT and it should be further promoted in our community. Trial registration NCT03836560 from ClinicalTrial.gov, 9 Feb 2019.

Background: In patients with symptomatic lumbar stenosis undergoing lateral transpsoas approach for lumbar interbody fusion (LLIF) surgery, it is not always clear when indirect decompression is sufficient in order to achieve symptom resolution. Indirect decompression failure (IDF), defined as “postoperative persistent symptoms of nerve compression with or without a second direct decompression surgery to reach adequate symptom resolution,” is not widely reported. This information, however, is critical to better understand the indications, the potential, and the limitations of indirect decompression. Objective: The purpose of this study was to systematically review the current literature on IDF after LLIF. Methods: A literature search was performed on PubMed. We included randomized controlled trials and prospective, retrospective, case-control studies, and case reports. Information on sample size, demographics, procedure, number and location of involved levels, follow-up time, and complications were extracted. Results: After applying the exclusion criteria, we included 9 of the 268 screened articles that reported failure. A total of 632 patients were screened in these articles and detailed information was provided. Average follow-up time was 21 months. Overall reported incidence of IDF was 9%. Conclusion: Failures of decompression via LLIF are inconsistently reported and the incidence is approximately 9%. IDF failure in LLIF may be underreported or misinterpreted as a complication. We propose to include the term “IDF” as described in this article to differentiate them from complications for future studies. A better understanding of why IDF occurs will allow surgeons to better plan surgical intervention and will avoid revision surgery.