Citations

Scattered tubular-like cells (STCs), dedifferentiated renal tubular epithelial cells, contribute to renal self-healing, but severe injury might blunt their effectiveness. We hypothesized that ischemic renovascular disease (RVD) induces senescence in STC and impairs their reparative potency. CD24+/CD133+ STCs were isolated from swine kidneys after 16 weeks of RVD or healthy controls. To test their reparative capabilities in injured kidneys, control or RVD-STC (5×10 5 ) were prelabeled and injected into the aorta of 2 kidneys, 1-clip (2k,1c) mice 2 weeks after surgery. Murine renal function and oxygenation were studied in vivo 2 weeks after injection using micro-magnetic resonance imaging, and fibrosis, tubulointerstitial injury, capillary density, and expression of profibrotic and inflammatory genes ex vivo. STC isolated from swine RVD kidneys showed increased gene expression of senescence and senescence-associated secretory phenotype markers and positive SA-β-gal staining. Delivery of normal pig STCs in 2k,1c mice improved murine renal perfusion, blood flow, and glomerular filtration rate, and downregulated profibrotic and inflammatory gene expression. These renoprotective effects were blunted using STC harvested from RVD kidneys, which also failed to attenuate hypoxia, fibrosis, tubular injury, and capillary loss in injured mouse 2k,1c kidneys. Hence, RVD may induce senescence in endogenous STC and impair their reparative capacity. These observations implicate cellular senescence in the pathophysiology of ischemic kidney disease and support senolytic therapy to permit self-healing of senescent kidneys.

OBJECTIVE Radiation-induced meningiomas (RIMs) are associated with aggressive clinical behavior. Stereotactic radiosurgery (SRS) is sometimes considered for selected RIMs. The authors investigated the effectiveness and safety of SRS for the management of RIMs. METHODS From 12 institutions participating in the International Radiosurgery Research Foundation, the authors pooled patients who had prior cranial irradiation and were subsequently clinically diagnosed with WHO grade I meningiomas that were managed with SRS. RESULTS Fifty-two patients underwent 60 SRS procedures for histologically confirmed or radiologically suspected WHO grade I RIMs. The median ages at initial cranial radiation therapy and SRS for RIM were 5.5 years and 39 years, respectively. The most common reasons for cranial radiation therapy were leukemia (21%) and medulloblastoma (17%). There were 39 multiple RIMs (35%), the mean target volume was 8.61 ± 7.80 cm 3 , and the median prescription dose was 14 Gy. The median imaging follow-up duration was 48 months (range 4–195 months). RIM progressed in 9 patients (17%) at a median duration of 30 months (range 3–45 months) after SRS. Progression-free survival at 5 years post-SRS was 83%. Treatment volume ≥ 5 cm 3 predicted progression (HR 8.226, 95% CI 1.028–65.857, p = 0.047). Seven patients (14%) developed new neurological symptoms or experienced SRS-related complications or T2 signal change from 1 to 72 months after SRS. CONCLUSIONS SRS is associated with durable local control of RIMs in the majority of patients and has an acceptable safety profile. SRS can be considered for patients and tumors that are deemed suboptimal, poor surgical candidates, and those whose tumor again progresses after removal.

Pain is a major public health problem, causing heavy social and economic burdens to patients and society while consuming tremendous medical resources at the same time. Thus, there is a critical need to find low-cost, efficacious, and therapeutic approaches to help manage pain. While acupuncture is increasingly recognized as a promising pain-relieving method, less is known about a specific form of auricular acupuncture known as Battlefield Acupuncture (BFA). The BFA technique involves the sequential placement of semi-permanent, single-use, French ASP[Formula: see text] golden needles to five specific acupoints in one or both ears, where they are left in place for 3–4 days or longer [Niemtzow, R.C., Battlefield acupuncture. Med. Acupunct. 19: 225–228, 2007]. The BFA needles (more accurately described as tiny conical darts) pierce the ear in designated locations in a particular order [Levy, C.E., N. Casler and D.B. FitzGerald. Battlefield acupuncture: an emerging method for easing pain. Am. J. Phys. Med. Rehabil. 97: e18–e19, 2018.]. (Figs. 4 and 5) It was developed by Dr. Richard C. Niemtzow in 2001, as a subgroup form of an auricular acupuncture technique based on the somatotopic arrangement of an inverted fetus pattern on the external ear [Romoli, M. Ear acupuncture: historical abstract–differences of ear cartography between the east and the west. Dtsch. Z. Akupunkt. 53: 24–33, 2010.]. Currently, BFA is widely used in the US military, but to our knowledge, there is no review which comprehensively synthesizes the current publications surrounding pain management. This review aims to investigate the effects and safety of BFA in adults with pain. Electronic databases were searched for randomized controlled trials (RCTs) published in English evaluating efficacy and safety of BFA in adults with pain, from database inception to September 6, 2019. The primary outcome was pain intensity change, and the secondary outcome was safety. Nine RCTs were included in this review, and five trials involving 344 participants were analyzed quantitatively. Compared with no intervention, usual care, sham BFA, and delayed BFA interventions, BFA had no significant improvement in the pain intensity felt by adults suffering from pain. Few adverse effects (AEs) were reported with BFA therapy, but they were mild and transitory. BFA is a safe, rapid, and easily learned acupuncture technique, mainly used in acute pain management, but no significant efficacy was found in adult individuals with pain, compared with the control groups. Given the poor methodological quality of the included studies, high-quality RCTs with rigorous evaluation methods are needed in the future.

AbstractIgA nephropathy (IgAN), an immune complex‐mediated process and the most common primary glomerulonephritis, can progress to end‐stage renal disease in up to 40% of patients. Accordingly, a therapeutic strategy targeting a specific molecular pathway is urgently warranted. Aided by structure characterisation and target identification, we predicted that a novel ring‐fused 6‐(2,4‐difluorophenyl)‐3‐(3‐(trifluoromethyl)phenyl)‐2H‐benzo[e][1,3]oxazine‐2,4(3H)‐dione (LCC18) targets the NLRP3 inflammasome, which participates in IgAN pathogenesis. We further developed biomarkers for the disease. We used two complementary IgAN models in C57BL/6 mice, involving TEPC‐15 hybridoma‐derived IgA, and in gddY mice. Moreover, we created specific cell models to validate therapeutic effects of LCC18 on IgAN and to explain its underlying mechanisms. IgAN mice benefited significantly from treatment with LCC18, showing dramatically improved renal function, including greatly reduced proteinuria and renal pathology. Mechanistic studies showed that the mode of action specifically involved: (1) blocking of the MAPKs/COX‐2 axis‐mediated priming of the NLRP3 inflammasome; (2) inhibition of ASC oligomerisation and NLRP3 inflammasome assembly by inhibiting NLRP3 binding to PKR, NEK7 and ASC; and (3) activation of autophagy. LCC18 exerts therapeutic effects on murine IgAN by differentially regulating NLRP3 inflammasome activation and autophagy induction, suggesting this new compound as a promising drug candidate to treat IgAN. © 2020 The Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Abstract Context Active surveillance (AS) of thyroid cancer with serial ultrasounds is a newer management option in the United States. Objective This work aimed to understand factors associated with the adoption of AS. Methods We surveyed endocrinologists and surgeons in the American Medical Association Masterfile. To estimate adoption, respondents recommended treatment for 2 hypothetical cases appropriate for AS. Established models of guideline implementation guided questionnaire development. Outcome measures included adoption of AS (nonadopters vs adopters, who respectively did not recommend or recommended AS at least once; and partial vs full adopters, who respectively recommended AS for one or both cases). Results The 464 respondents (33.3% response) demographically represented specialties that treat thyroid cancer. Nonadopters (45.7%) were significantly (P < .001) less likely than adopters to practice in academic settings, see more than 25 thyroid cancer patients/year, be aware of AS, use applicable guidelines (P = .04), know how to determine whether a patient is appropriate for AS, have resources to perform AS, or be motivated to use AS. Nonadopters were also significantly more likely to be anxious or have reservations about AS, be concerned about poor outcomes, or believe AS places a psychological burden on patients. Among adopters, partial and full adopters were similar except partial adopters were less likely to discuss AS with patients (P = .03) and more likely to be anxious (P = .04), have reservations (P = .03), and have concerns about the psychological burden (P = .009) of AS. Few respondents (3.2%) believed patients were aware of AS. Conclusion Widespread adoption of AS will require increased patient and physician awareness, interest, and evaluation of outcomes.

Deep venous thrombosis (DVT) is a severe complication of coronavirus disease 2019 (COVID-19). The purpose of this study was to study the prevalence, risk factors, anticoagulant therapy and sex differences of DVT in patients with COVID-19. The enrolled 121 hospitalized non-ventilator patients were confirmed positive for COVID-19. All suspected patients received color Doppler ultrasound (US) to screen for DVT in both lower extremities. Multivariate logistic regression was performed to identify risk factors related to DVT in COVID-19 patients. DVT was found in 48% of the asymptomatic COVID-19 patients with an increased PADUA or Caprini index using US scanning. The multivariate logistic regression determined that age (OR, 1.05; p = .0306), C-reactive protein (CRP) (OR, 1.02; p = .0040), and baseline D-dimer (OR, 1.42; p = .0010) were risk factors among COVID-19 patients. Although the most common DVT location was infrapopliteal (classes I and II), higher mortality in DVT-COVID-19 patients was confirmed. DVT-COVID-19 patients presented significant increases in CRP, neutrophil count, and D-dimer throughout the whole inpatient period compared to non-DVT-COVID-19 patients. Although anticoagulation therapy accelerated the recovery of lymphocytopenia in DVT patients, men DVT-COVID-19 patients with anticoagulant therapy showed significant higher CRP and neutrophil count vs. lymphocyte count (N/L) ratio, but showed lower lymphocyte counts compared to women DVT-COVID-19 patients. DVT is common in COVID-19 patients with high-risk factors, especially for older age and higher CRP and baseline D-dimer populations. It is important to consider sex differences in anticoagulant therapy among DVT-COVID-19 patients.

AbstractVenetoclax (Ven) is a selective small‐molecule inhibitor of BCL‐2 that exhibits antitumoral activity against MM cells with t(11;14) translocation. We evaluated the safety and efficacy of Ven and dexamethasone (VenDex) combination in patients with t(11;14) positive relapsed/refractory (R/R) multiple myeloma (MM). This open‐label, multicenter study had two distinct phases (phase one [P1], phase two [P2]). Patients in both phases received VenDex (oral Ven 800 mg/day + oral Dex 40 mg [20 mg for patients ≥75 years] on days 1, 8, and 15, per 21–day cycle). The primary objective of the P1 VenDex cohort was to assess safety and pharmacokinetics. Phase two further evaluated efficacy with objective response rate (ORR) and very good partial response or better. Correlative studies explored baseline BCL2 (BCL‐2) and BCL2L1 (BCL‐XL) gene expression, cytogenetics, and recurrent somatic mutations in MM. Twenty and 31 patients in P1 and P2 with t(11;14) positive translocation received VenDex. P1/P2 patients had received a median of 3/5 lines of prior therapy, and 20%/87% were refractory to daratumumab. Predominant grade 3/4 hematological adverse events (AEs) with ≥10% occurrence included lymphopenia (20%/19%), neutropenia (15%/7%), thrombocytopenia (10%/10%), and anemia (5%/16%). At a median follow‐up of 12.3/9.2 months, ORR was 60%/48%. The duration of response estimate at 12 months was 50%/61%, and the median time to progression was 12.4/10.8 months. In biomarker evaluable patients, response to VenDex was independent of concurrent del(17p) or gain(1q) and mutations in key oncogenic signaling pathways, including MAPK and NF‐kB. VenDex demonstrated efficacy and manageable safety in heavily‐pre‐treated patients with t(11;14) R/R MM.

Abstract MYC oncoproteins regulate transcription of genes directing cell proliferation, metabolism, and tumorigenesis. A variety of alterations drive MYC expression in acute myeloid leukemia (AML), and enforced MYC expression in hematopoietic progenitors is sufficient to induce AML. Here we report that AML and myeloid progenitor cell growth and survival rely on MYC-directed suppression of Transcription Factor EB (TFEB), a master regulator of the autophagy–lysosome pathway. Notably, although originally identified as an oncogene, TFEB functions as a tumor suppressor in AML, where it provokes AML cell differentiation and death. These responses reflect TFEB control of myeloid epigenetic programs by inducing expression of isocitrate dehydrogenase-1 (IDH1) and IDH2, resulting in global hydroxylation of 5-methycytosine. Finally, activating the TFEB–IDH1/IDH2–TET2 axis is revealed as a targetable vulnerability in AML. Thus, epigenetic control by an MYC–TFEB circuit dictates myeloid cell fate and is essential for maintenance of AML. Significance: Alterations in epigenetic control are a hallmark of AML. This study establishes that a MYC–TFEB circuit controls AML differentiation and epigenetic programs by inducing IDH1/IDH2 and hydroxylation of 5-methylcytosine, that TFEB functions as a tumor suppressor in AML, and that this circuit is a targetable vulnerability in AML. See related commentary by Wu and Eisenman, p. 116.

Abstract BackgroundAcute respiratory failure associated with sepsis contributes to higher in-hospital mortality. Intubation and invasive mechanical ventilation is a common rescue procedure. However, the 2016 International Guidelines for Management of Sepsis and Septic Shock does not provide any recommendation on indication nor timing of intubation. Timely intubation may improve outcome. The decision to intubate those patients is often hampered by the fear of further hemodynamic deterioration following intubation. MethodsThis study aimed at evaluating the impact of timely intubation on outcome in sepsis associated respiratory failure. We conducted an ancillary analysis of a prospective registry od adult ICU patients with septic shock admitted to the medical ICU in a tertiary medical center, between April 30th, 2014 and December 31st, 2017. All cases of sepsis with lactate >4 mmol/L, mean arterial pressure <65 mmHg, or vasopressor use after 30 mL/kg fluid boluses and suspected or confirmed infection. Patients who remained hospitalized at 24 hours following sepsis onset were separated into intubated and non-intubated groups. The primary outcome was hospital mortality. Univariate and multivariable analyses were used, adjusted for admission characteristics and stabilization of shock within 6 hours. In a secondary analysis, time-dependent propensity score matching was used to match intubated and non-intubated patients.ResultsWe identified 345 (33%) patients intubated within 24 hours and 707 (67%) not intubated. Intubated patients were younger, transferred more often from an outside facility, had higher severity of illness scores, more lung infection, achieved blood pressure goals more often but less often lactate normalization within 6 hours. The crude in-hospital mortality was higher, 89 (26%) vs. 82 (12%), p<0.001, as were ICU mortality, and ICU and hospital length of stay. After adjustment, intubation showed no effect on hospital mortality but fewer hospital-free days through day 28. After 1:1 propensity score matching, there was no difference in hospital mortality, but fewer hospital-free days in the intubated group. ConclusionsIntubation within 24 hours of sepsis onset was safe and not associated with hospital mortality, but was associated with less 28-day hospital-free days. Intubation should not be discouraged in appropriate patients with septic shock.

Abstract Background Chordomas are the most common primary spinal column malignancy in the United States. The aim of this study was to determine whether chordomas may be detected by evaluating mutations in circulating tumor DNA (ctDNA). Methods Thirty-two patients with a biopsy-confirmed diagnosis of chordoma had blood drawn pre-operatively and/or at follow-up appointments. Mutations in the primary tumor were identified by whole exome sequencing and liquid biopsy by ddPCR and/or RACE-Seq was used to detect one or more of these mutations in plasma ctDNA at concurrent or later time points. Results At the time of initial blood draw, 87.1% of patients were ctDNA positive (P &lt;.001). Follow-up blood draws in twenty of the patients suggest that ctDNA levels may reflect the clinical status of the disease. Patients with positive ctDNA levels were more likely to have greater mutant allele frequencies in their primary tumors (P = .004) and undergo radiotherapy (P = .02), and the presence of ctDNA may correlate with response to systemic chemotherapy and/or disease recurrence. Conclusions Detection of ctDNA mutations may allow for the detection and monitoring of disease progression for chordomas.