Abstract
BACKGROUND
Current treatment modalities, including surgical resection, radiosurgery and immune checkpoint inhibitors, have improved local control rates of brain metastases, but overall ...prognosis is still poor. AIM: To investigate the immune microenvironment in brain metastases for better understanding of treatment failures.
METHODS
We identified 42 patients with melanoma (M), breast (B) and lung (L) brain metastases and performed multiplex immunofluorescent staining for immune markers (CD4, CD8, CD45, PD1, PD-L1) and quantitative analysis with HALO software. NanoString nCounter mRNA gene expression assay was used for identification of immune pathways. CyTOF and single cell RNA sequencing were done on 12 different brain metastases and their matched peripheral blood samples.
RESULTS
The median CD8, CD4 and PD1 density (as a total number of cells) was 0.24%, 0.13%, and 0.07% for M, 0.24%, 0.51% and 0.08% for B, and 0.87%, 1.36%, 0.67% for L. CD4 and CD8+PD1+ expression was significantly different between all groups (p=0.01), CD4+PD1+ in M vs. L (p=0.03) and PD1 in B vs. L (p=0.03). No significant difference was found in terms of CD45 positive cells (M 2.13%, B, 1.99%, L 4.95%). PD-L1 expression was significantly different between histologies; the highest expression was present in breast metastases (M: 1.51%, B: 49.98%, L: 31.90%, p=0.0002). Spatial distribution revealed a characteristic pattern with a peritumoral border infiltrate in M, and predominant intratumoral distribution in B and L (M 0.2%, B 2.6%, L 3.6%, p=0.02). CyTOF clustering demonstrated that macrophages are the most prevalent immune population overall (83.08%), with an inhibitory phenotype and gene expression pattern present in different histologies (S100A9, CCL20, IFI16, MARCO). T-cells (predominantly CD4+, 3.6%), and B-cells (1.5%) comprise the remaining immune cell populations.
CONCLUSION
Neoadjuvant targeted treatment approaches may be needed to alter predominance of inhibitory macrophages and recruit activated T lymphocytes in brain metastases.
There are 9 recombinant human growth hormone (rhGH) products currently available for 10 US Food and Drug Administration-approved indications; each rhGH product is approved for 1 or more indications. ...Adult and pediatric patients with the various conditions for which rhGH is indicated, from idiopathic short stature (ISS) and growth hormone (GH) deficiency to short bowel syndrome and HIV/AIDS wasting, may benefit from rhGH treatment. In clinical practice, pediatric patients with GH deficiency or ISS make up the majority of the population receiving treatment with rhGH. Most rhGH products are provided through specialty pharmacies that often have to balance the needs of the patient, their own utilization objectives, and the availability of the rhGH on formulary from a particular payer. Often, a payer will prefer only 2 or 3 rhGH products to cover all 10 indications. As such, managed care professionals need to be more informed about the options available and should be familiar with the different indications to help educate patients about treatment. Additionally, healthcare providers should endeavor to identify and manage the care of appropriate patients who would potentially benefit from rhGH therapy, and should be aware of formulary options. Because many of the patients are children and young adults, adherence to treatment is a concern; patient education on the importance of treatment adherence should be ongoing. Various mechanisms are in place (eg, prior authorization requirements and case manager follow-up) to help ensure that rhGH products are used, and used appropriately. This publication includes highlights from a roundtable discussion by key opinion leaders (clinicians and managed care professionals) on how managed care policies and clinical guidelines on appropriate use of rhGH translate into real-world practice. Also discussed are the efficacy and safety of rhGH therapy for its pediatric indications, and the role of specialty pharmacies in managing patient access to therapy.
INTRODUCTION The two main subtypes of pediatric glioblastoma (GBM) are marked by highly conserved somatic H3-3A gene mutations. The H3.3G34R/V GBM occurs in children and young adults, typically ...lobar, and frequently harbor concurrent TP53, ATRX/DAXX, and PDGFRA alterations. H3.3G34 alterations appear to affect K36 residue methylation, which regulates alternative splicing, synchronizing gene regulation through intron retention. We hypothesize that dendritic cell vaccination (DCV) against H3.3G34R GBM stimulates adaptive immunity driven by neoantigen-specific cytotoxic T lymphocytes. METHODS We developed an H3.3G34R GBM genetically-engineered mouse model by injecting DF-1 avian cells transfected to produce recombinant replication-competent avian sarcoma (RCAS) viruses intraventricular in neonatal C57/Bl-6J transgenic mice harboring homozygous floxed Trp53 and the RCAS virus tv-a receptor under the transcriptional control of the nestin gene promoter. The RCAS viral plasmids used encoded the PDGF receptor a, Cre recombinase, and H3.3G34R cDNAs. Mouse DC’s were produced per standard protocol, and pulsed with tumor lysate. Five animals were treated with DC vaccine on days 7 and 22 post-implantation, with six doses of monoclonal PD-1 antibody over 40 days; five animals were untreated. Bioluminescence was used to monitor tumor growth. RESULTS Three independent glioma lines were generated with G34R mutations confirmed by PCR and DNA sequencing. Tumor generation was 100% in three repeated experiments of five mice each, and mice died or became moribund at 30.5 days on average. All three isogenic cell lines grow as neurospheres in serum free media with supplemental FGF, EGF, and PDGFA/B. Preliminary analyses indicate that gene expression profiles and H3K36me3 landscapes show mild heterogeneity among the three RCAS/tv-a-derived cell lines. Bioluminescence shows three complete responses in the five treated mice, with one mouse in the treated group dying unexpectedly without significant tumor burden. Kaplan-Meier survival analysis suggests a significant survival benefit with treatment. Characterization of the adaptive immune response is ongoing. CONCLUSION We have created a genetically-representative syngeneic immunocompetent murine model of H3.3G34R GBM where DCV is effectively increasing survival.
Current knowledge of yield potential and best agronomic management practices for perennial bioenergy grasses is primarily derived from small‐scale and short‐term studies, yet these studies inform ...policy at the national scale. In an effort to learn more about how bioenergy grasses perform across multiple locations and years, the U.S. Department of Energy (US DOE)/Sun Grant Initiative Regional Feedstock Partnership was initiated in 2008. The objectives of the Feedstock Partnership were to (1) provide a wide range of information for feedstock selection (species choice) and management practice options for a variety of regions and (2) develop national maps of potential feedstock yield for each of the herbaceous species evaluated. The Feedstock Partnership expands our previous understanding of the bioenergy potential of switchgrass, Miscanthus, sorghum, energycane, and prairie mixtures on Conservation Reserve Program land by conducting long‐term, replicated trials of each species at diverse environments in the U.S. Trials were initiated between 2008 and 2010 and completed between 2012 and 2015 depending on species. Field‐scale plots were utilized for switchgrass and Conservation Reserve Program trials to use traditional agricultural machinery. This is important as we know that the smaller scale studies often overestimated yield potential of some of these species. Insufficient vegetative propagules of energycane and Miscanthus prohibited farm‐scale trials of these species. The Feedstock Partnership studies also confirmed that environmental differences across years and across sites had a large impact on biomass production. Nitrogen application had variable effects across feedstocks, but some nitrogen fertilizer generally had a positive effect. National yield potential maps were developed using PRISM‐ELM for each species in the Feedstock Partnership. This manuscript, with the accompanying supplemental data, will be useful in making decisions about feedstock selection as well as agronomic practices across a wide region of the country.
Maximum average annual yield potential of herbaceous feedstocks (switchgrass, Miscanthus, sorghum, energycane, and Conservation Reserve Program mixtures) across the continental United States. Yield potential shown on this map is that of the highest of all species evaluated at a given location in the United States. This map was generated using the PRISM‐ELM model and is based in part on data from Feedstock Partnership Field Trials.
Venous thromboembolism is a common condition affecting 7.1 persons per 10,000 person-years among community residents. Incidence rates for venous thromboembolism are higher in men and African ...Americans and increase substantially with age. It is critical to treat deep venous thrombosis at an early stage to avoid development of further complications, such as pulmonary embolism or recurrent deep venous thrombosis. The target audience for this guideline is all clinicians caring for patients who have been given a diagnosis of deep venous thrombosis or pulmonary embolism. The target patient population is patients receiving a diagnosis of pulmonary embolism or lower-extremity deep venous thrombosis.
Thoracic aortic aneurysm and dissection are complex diagnoses that require management by multidisciplinary providers using a variety of medical therapies, surgical interventions, and lifestyle ...modifications. Pharmacological agents, such as β-blockers (atenolol) and angiotensin II type 1 receptor blockers (losartan), have been mainstay treatments for several years, and research from the past decade has continued to evaluate these and other medication classes to further improve patient morbidity and mortality. Combination β- and renin–aldosterone–angiotensin blockade, statins, metformin, antioxidants, and vitamins have been evaluated as therapeutics in both thoracic and abdominal aortic aneurysms, as well as the effects of various antibiotics (ie, fluoroquinolones and tetracyclines) and benefits of lifestyle modifications (eg, diet and exercise) and enhanced patient-centered care and treatment adherence. In addition, as our understanding of the genetic, biochemical, and pathophysiological mechanisms behind these diseases expands, so do potential targets for future therapeutic research (eg, interleukins, matrix metalloproteases, and mast cells). This review incorporates the major meta-analyses, systematic and generalized reviews, and clinical trials published from 2010 through 2021 that focus on these topics in thoracic aortic aneurysms (and abdominal aneurysms when thoracic literature is scarce). Several key ongoing clinical trials, case studies, and in vivo/in vitro studies are also mentioned. Furthermore, we discuss current gaps in the literature and the abundance of clinical evidence for some interventions in abdominal aneurysms with few thoracic correlates, thus indicating a need for investigation of these subjects in the latter.
Medical errors play a large role in preventable harms within our health care system. Medications administered in the ICU can be numerous, complex and subject to daily changes. We describe a method to ...identify medication errors with the potential to improve patient safety.
A quality improvement intervention featuring a daily medication time out for each patient was performed during rounds.
A 12-bed Cardiac Surgical ICU at a single academic institution with approximately 180 beds.
After each patient encounter, the current medication list for the patient was read aloud from the electronic medical record, and the team would determine if any were erroneous or missing. Medication changes were recorded and graded post-hoc according to perceived significance.
This intervention resulted in 285 medication changes in 347 patient encounters. 179 of the 347 encounters (51.6%) resulted in at least one change. Of the changes observed, 40.4% were categorized as trivial, 50.5% as minor and 9.1% were considered to have significant potential impact on patient care. The average time spent per patient for this intervention was 1.24 (SD 0.65) minutes.
A daily medication time out should be considered as an additional mechanism for patient safety in the ICU.
•Medication errors are an important source of preventable patient harm.•Structured checklist-style interventions may help prevent errors.•A daily team-based “time out” intervention is a low-cost method to decrease errors.•In this study, a large number of medication changes were prompted by a “time out” intervention.
The Joint Panel of the American Academy of Family Physicians and the American College of Physicians, in collaboration with the Johns Hopkins Evidence-based Practice Center, systematically reviewed ...the available evidence on the management of newly detected atrial fibrillation and developed recommendations for adult patients with first-detected atrial fibrillation. The recommendations do not apply to patients with postoperative or post-myocardial infarction atrial fibrillation, patients with class IV heart failure, patients already taking antiarrhythmic drugs, or patients with valvular disease. The target physician audience is internists and family physicians dedicated to primary care. The recommendations are as follows: RECOMMENDATION 1: Rate control with chronic anticoagulation is the recommended strategy for the majority of patients with atrial fibrillation. Rhythm control has not been shown to be superior to rate control (with chronic anticoagulation) in reducing morbidity and mortality and may be inferior in some patient subgroups to rate control. Rhythm control is appropriate when based on other special considerations, such as patient symptoms, exercise tolerance, and patient preference. Grade: 2A. RECOMMENDATION 2: Patients with atrial fibrillation should receive chronic anticoagulation with adjusted-dose warfarin, unless they are at low risk of stroke or have a specific contraindication to the use of warfarin (thrombocytopenia, recent trauma or surgery, alcoholism). Grade: 1A. RECOMMENDATION 3: For patients with atrial fibrillation, the following drugs are recommended for their demonstrated efficacy in rate control during exercise and while at rest: atenolol, metoprolol, diltiazem, and verapamil (drugs listed alphabetically by class). Digoxin is only effective for rate control at rest and therefore should only be used as a second-line agent for rate control in atrial fibrillation. Grade: 1B. RECOMMENDATION 4: For those patients who elect to undergo acute cardioversion to achieve sinus rhythm in atrial fibrillation, both direct-current cardioversion (Grade: 1C+) and pharmacological conversion (Grade: 2A) are appropriate options. RECOMMENDATION 5: Both transesophageal echocardiography with short-term prior anticoagulation followed by early acute cardioversion (in the absence of intracardiac thrombus) with postcardioversion anticoagulation versus delayed cardioversion with pre- and postanticoagulation are appropriate management strategies for those patients who elect to undergo cardioversion. Grade: 2A. RECOMMENDATION 6: Most patients converted to sinus rhythm from atrial fibrillation should not be placed on rhythm maintenance therapy since the risks outweigh the benefits. In a selected group of patients whose quality of life is compromised by atrial fibrillation, the recommended pharmacologic agents for rhythm maintenance are amiodarone, disopyramide, propafenone, and sotalol (drugs listed in alphabetical order). The choice of agent predominantly depends on specific risk of side effects based on patient characteristics. Grade: 2A.
•NMZL is most commonly an indolent disease with a probability of remaining untreated at five years of 25%.•Transformation of NMZL to large B-cell lymphoma is rare, with a cumulative incidence of 15% ...at 10 years.
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Nodal marginal zone lymphoma (NMZL) is a rare non-Hodgkin B-cell lymphoma that has historically been difficult to define, though is now formally recognized by the World Health Organization Classification. To better characterize the clinical outcomes of patients with NMZL, we reviewed a sequential cohort of 187 patients with NMZL to describe baseline characteristics, survival outcomes, and time-to-event data. Initial management strategies were classified into five categories: observation, radiation, anti-CD20 monoclonal antibody therapy, chemoimmunotherapy, or other. Baseline Follicular Lymphoma International Prognostic Index scores were calculated to evaluate prognosis. A total of 187 patients were analyzed. The five-year overall survival was 91% (95% confidence interval CI, 87-95), with a median follow-up time of 71 months (range, 8-253) among survivors. A total of 139 patients received active treatment at any point, with a median follow-up time of 56 months (range, 13-253) among survivors who were never treated. The probability of remaining untreated at five years was 25% (95% CI, 19-33). For those initially observed, the median time to active treatment was 72 months (95% CI, 49-not reached). For those who received at least one active treatment, the cumulative incidence of receiving a second active treatment at 60 months was 37%. Transformation to large B-cell lymphoma was rare, with a cumulative incidence of 15% at 10 years. In summary, our series is a large cohort of uniformly diagnosed NMZL with detailed analyses of survival and time to event analyses. We showed that NMZL commonly presents as an indolent lymphoma for which initial observation is often a reasonable strategy.
IMPORTANCE: Because of the similarity in clinical outcomes after elective open and endovascular repair of abdominal aortic aneurysm (AAA), cost may be an important factor in choosing a procedure. ...OBJECTIVE: To compare total and AAA-related use of health care services, costs, and cost-effectiveness between groups randomized to open or endovascular repair. DESIGN, SETTING, AND PARTICIPANTS: This unblinded randomized clinical trial enrolled 881 patients undergoing planned elective repair of AAA who were candidates for open and endovascular repair procedures. Patients were randomized from October 15, 2002, to April 15, 2008, at 42 Veterans Affairs medical centers. Follow-up was completed on October 15, 2011, and data were analyzed from April 15, 2013, to April 15, 2016, based on intention to treat. MAIN OUTCOMES AND MEASURES: Mean total and AAA-related health care cost per life-year and per quality-adjusted life-year (QALY). RESULTS: A total of 881 patients (876 men 99.4%; 5 women 0.6%; mean SD age, 70 7.8 years) were included in the analysis. After a mean of 5.2 years of follow-up, mean life-years were 4.89 in the endovascular group and 4.84 in the open repair group (P = .68), and mean QALYs were 3.72 in the endovascular group and 3.70 in the open repair group (P = .82). Total mean health care costs did not differ significantly between the 2 groups (endovascular group, $142 745; open repair group, $153 533; difference, −$10 788; 95% CI, −$29 796 to $5825; P = .25). Costs related to AAA, including the initial repair, constituted nearly 40% of total costs and did not differ significantly between the 2 groups (endovascular group, $57 501; open repair group, $57 893; difference, −$393; 95% CI, −$12 071 to $7928; P = .94). Lower costs due to shorter hospitalization for initial endovascular repair were offset by increased costs from AAA-related secondary procedures and imaging studies. The probability of endovascular repair being less costly and more effective was 56.8% when effectiveness was measured in life-years and 55.4% when effectiveness was measured in QALYs for total costs and 31.3% and 34.3%, respectively, for AAA-related costs. CONCLUSIONS AND RELEVANCE: In this multicenter randomized clinical trial with follow-up to 9 years, survival, quality of life, costs, and cost-effectiveness did not differ between elective open and endovascular repair of AAA. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00094575
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