scholarly journals Combined Ruxolitinib and Venetoclax Treatment in a Patient with a BCR-JAK2 Rearranged Myeloid Neoplasm

2021 ◽  
Vol 2021 ◽  
pp. 1-6
Author(s):  
Coen J. Lap ◽  
Samah Nassereddine ◽  
Min-Ling Liu ◽  
Victor E. Nava ◽  
Anita Aggarwal
Keyword(s):  
Combination Treatment ◽  
Treatment Options ◽  
Classification Systems ◽  
Rare Disorders ◽  
Future Studies ◽  
Jak2 Inhibitor ◽  
Downstream Target ◽  
Myeloid Neoplasm ◽  
Low Toxicity ◽  
Inhibitor Resistance

Hematological malignancies with a BCR-JAK2 rearrangement have been described only sporadically in the literature over the last three decades. Although most patients suffer from a chronic myeloid neoplasm with marked eosinophilia, the clinical presentation varies significantly and can even manifest as a lymphoid malignancy. In this case report, we present a patient with a therapy-related BCR-JAK2+ myeloid neoplasm with extensive extramedullary disease localizing in the lymph nodes. While treatment with a JAK2 inhibitor (ruxolitinib) was not able to stop disease progression, combination treatment with inhibitors of both JAK2 and BCL2 (venetoclax) resulted in disease control for over 1.5 years. Combining these two inhibitors might be strategic in these patients, not only because BCL2 is a downstream target of JAK/STAT signaling but also because BCL2 is crucial for JAK2 inhibitor resistance. The recent inclusion of JAK2-rearranged malignancies in major classification systems and guidelines emphasizes the importance of not only getting a better understanding of the clinical phenotype of these rare disorders but also of identifying alternative treatment options for patients ineligible for allogeneic stem cell transplantation. Considering the low toxicity of combination treatment with these two small molecule inhibitors, this regimen could be further explored in future studies.

scholarly journals The ‘wave sign’ in hip arthroscopy: a systematic review of epidemiological factors, current diagnostic methods and treatment options

2020 ◽  
Author(s):  
Jason Derry Onggo ◽  
James Randolph Onggo ◽  
Mithun Nambiar ◽  
Andrew Duong ◽  
Olufemi R Ayeni ◽  
...  
Keyword(s):  
Risk Factors ◽  
Systematic Review ◽  
Protective Factor ◽  
Treatment Options ◽  
Arthroscopic Surgery ◽  
Classification Systems ◽  
Diagnostic Methods ◽  
Suture Repair ◽  
Significant Heterogeneity ◽  
Epidemiological Factors

ABSTRACT This study aims to present a systematic review and synthesized evidence on the epidemiological factors, diagnostic methods and treatment options available for this phenomenon. A multi-database search (OVID Medline, EMBASE and PubMed) was performed according to PRISMA guidelines on 18 June 2019. All studies of any study design discussing on the epidemiological factors, diagnostic methods, classification systems and treatment options of the wave sign were included. The Newcastle–Ottawa quality assessment tool was used to appraise articles. No quantitative analysis could be performed due to heterogeneous data reported; 11 studies with a total of 501 patients with the wave sign were included. Three studies examined risk factors for wave sign and concluded that cam lesions were most common. Other risk factors include alpha angle >65° (OR=4.00, 95% CI: 1.26–12.71, P=0.02), male gender (OR 2.24, 95% CI: 1.09–4.62, P=0.03) and older age (OR=1.04, 95% CI: 1.01–1.07, P=0.03). Increased acetabular coverage in setting of concurrent cam lesions may be a protective factor. Wave signs most commonly occur at the anterior, superior and anterosuperior acetabulum. In terms of staging accuracy, the Haddad classification had the highest coefficients in intraclass correlation (k=0.81, 95% CI: 0.23–0.95, P=0.011), inter-observer reliability (k=0.88, 95% CI: 0.72–0.97, P<0.001) and internal validity (k=0.89). One study investigated the utility of quantitative magnetic imaging for wave sign, concluding that significant heterogeneity in T1ρ and T2 values (P<0.05) of acetabular cartilage is indicative of acetabular debonding. Four studies reported treatment techniques, including bridging suture repair, reverse microfracture with bubble decompression and microfracture with fibrin adhesive glue, with the latter reporting statistically significant improvements in modified Harris hip scores at 6-months (MD=19.2, P<0.05), 12-months (MD=22.0, P<0.05) and 28-months (MD=17.5, P<0.001). No clinical studies were available for other treatment options. There is a scarcity of literature on the wave sign. Identifying at risk symptomatic patients is important to provide prompt diagnosis and treatment. Diagnostic techniques and operative options are still in early developmental stages. More research is needed to understand the natural history of wave sign lesions after arthroscopic surgery and whether intervention can improve long-term outcomes. Level IV, Systematic review of non-homogeneous studies.

scholarly journals 1186. Cefazolin inoculum effect predicts reduced susceptibility to other antibiotics and patient outcomes in MSSA endovascular infections

2020 ◽  
Vol 7 (Supplement_1) ◽  
pp. S617-S617
Author(s):  
Dan Smelter ◽  
Sue McCrone ◽  
Warren Rose
Keyword(s):  
Infective Endocarditis ◽  
Mortality Rate ◽  
Patient Outcomes ◽  
Treatment Options ◽  
Fold Increase ◽  
Specific Mechanism ◽  
Research Support ◽  
High Burden ◽  
Low Toxicity ◽  
Inoculum Effect

Abstract Background MSSA Infective endocarditis (IE) is inherently a high-burden infection with up to a 30% mortality rate. Cefazolin is an appealing treatment option for IE with low toxicity and a favorable dosing scheme. However, cefazolin has been associated with treatment failure in IE, attributed to an inoculum effect. The specific mechanism underlying the cefazolin inoculum effect (CIE) remains undetermined, but CIE has been linked to both blaZ expression and agr dysfunction. This study aims to determine whether CIE is linked to reduced susceptibility to other antibiotics and worse outcomes regardless of therapy in MSSA endovascular infections. Methods Sixty-four MSSA strains were collected from patients with endovascular infections not treated with cefazolin. To determine CIE phenotype, strains were cultured and MICs assayed for cefazolin, nafcillin, and vancomycin at 107 CFU/mL for high-inocula (HI) and 105 CFU/mL for standard-inocula (SI). This study defined CIE as a ≥ 4-fold increase in MIC at HI compared to SI, with at least an MIC of 4 mg/L at HI. Nitrocefin disks identified blaZ expression, and beta lysin disks were used to determine hemolysin type and agr function. Patient outcomes of mortality and bacteremia duration were assessed across cohorts. Results Twenty-four strains exhibit a CIE (38%), with 10 strains having an MIC of ≥ 32mg/L at HI. Nafcillin and vancomycin also had an inoculum effect, uncoupled from the CIE and occurring at a lower frequency and amplitude at HI. Presence of CIE had a greater association with blaZ expression (71% vs 25%) than agr dysfunction (38% vs 20%). 50% (9/18) of CIE infections were cleared within 48 hours while 77% (20/26) of CIE-negative infections were cleared within 48 hours (P=0.106). However, presence of CIE was not associated with increased mortality (25% CIE-positive vs 35%; P=0.578) Conclusion Previous studies for CIE failed to enrich for isolates from endovascular sources, where inocula are known to be high. This study presents one of the largest endovascular source cohorts for CIE evaluation. It identifies that CIE prevalence (38%) is higher than reports from diverse infection sources (10-36%). CIE appears to predict bacteremia duration with other MSSA treatment options, suggesting mechanisms independent of blaZ and agr function for this phenomenon. Disclosures Warren Rose, PharmD, MPH, Merck (Grant/Research Support)Paratek (Grant/Research Support)

Sensorineural hearing loss in neurobrucellosis

1993 ◽  
Vol 107 (11) ◽  
pp. 1034-1036 ◽  
Author(s):  
Ratna Thomas ◽  
Mohan Kameswaran ◽  
Vel Murugan ◽  
B. C. Okafor
Keyword(s):  
Hearing Loss ◽  
Sensorineural Hearing Loss ◽  
Combination Treatment ◽  
Incidental Finding ◽  
Treatment Options ◽  
Sensorineural Hearing ◽  
Clinical Feature ◽  
Diagnostic Features ◽  
Diagnostic Screening

AbstractA case of neurobrucellosis presenting to the otologist with sensorineural hearing loss (SNHL) as the predominant clinical feature is reported. The diagnostic features and treatment options are discussed and the need for prolonged combination treatment to prevent relapse and further deterioration of hearing stressed. SNHL in neurobrucellosis has hitherto been reported principally in neurology literature as something of an incidental finding and so escapes the attention of otologists. It is hoped that this report will alert otologists in areas where brucellosis is endemic to the need to include tests for brucellosis in the routine diagnostic screening for SNHL. Practitioners in other locations should also consider this possibility when dealing with patients who have visited or lived in endemic regions.

Voice Treatment Techniques

1998 ◽  
Vol 7 (3) ◽  
pp. 49-64 ◽  
Author(s):  
Mary Pannbacker
Keyword(s):  
Treatment Outcomes ◽  
Treatment Options ◽  
Limited Data ◽  
Future Studies ◽  
Treatment Practices ◽  
Breathing Exercises ◽  
Treatment Techniques ◽  
Voice Treatment

Clinicians are confronted with several treatment options for which there are limited data about efficacy. Some voice treatment practices have broad acceptance, whereas others, such as breathing exercises and optimum pitch, are controversial. This paper reviews what is currently known about the efficacy of voice treatment and makes recommendations for future studies of voice treatment outcomes and efficacy.

Thoracolumbar Burst Fractures

2018 ◽  
pp. 123-132
Author(s):  
Omaditya Khanna ◽  
Geoffrey P. Stricsek ◽  
James S. Harrop
Keyword(s):  
Treatment Options ◽  
Thoracolumbar Spine ◽  
Axial Loading ◽  
Classification Systems ◽  
Surgical Approaches ◽  
Thoracolumbar Burst Fractures ◽  
Burst Fractures ◽  
Thoracolumbar Injury ◽  
Fall From Height ◽  
Thoracolumbar Spine Fractures

Ten to twenty percent of all thoracolumbar spine fractures are burst fractures. Burst fractures are typically a result of an axial-loading mechanism, such as from jumping or a fall from height. In this chapter, the authors provide an overview of the different classification systems for thoracolumbar fractures, including the Arbeitsgemeinschaft für Osteosynthesefragen (AO) classification system and Thoracolumbar Injury Classification and Severity (TLICS) score. The various treatment options, both surgical and nonsurgical, are discussed, including criteria for when surgical intervention is warranted. The authors discuss the various surgical approaches for treatment of these fractures and their relative efficacies and outcomes. Finally, the authors review the evidence, outcomes, and potential complications of the various treatment options in order to aid the surgeon in their decision-making when these fractures are encountered in their practice.

Pulmonary Langerhans Cell Histiocytosis

2020 ◽  
Vol 41 (02) ◽  
pp. 269-279
Author(s):  
Brian Shaw ◽  
Michael Borchers ◽  
Dani Zander ◽  
Nishant Gupta
Keyword(s):  
Langerhans Cell Histiocytosis ◽  
Treatment Options ◽  
Skin Lesions ◽  
Langerhans Cell ◽  
Mitogen Activated Protein Kinase ◽  
Myeloid Neoplasm ◽  
Cystic Lung ◽  
Pulmonary Langerhans Cell Histiocytosis ◽  
Mitogen Activated Protein ◽  
The Central Nervous System

AbstractPulmonary Langerhans cell histiocytosis (PLCH) is a diffuse cystic lung disease that is strongly associated with exposure to cigarette smoke. Recently, activating pathogenic mutations in the mitogen-activated protein kinase pathway have been described in the dendritic cells in patients with PLCH and have firmly established PLCH to be an inflammatory myeloid neoplasm. Disease course and prognosis in PLCH are highly variable among individual patients, ranging from spontaneous resolution to development of pulmonary hypertension and progression to terminal respiratory failure. A subset of patients with PLCH may have extrapulmonary involvement, typically involving the skeletal system in the form of lytic lesions, skin lesions, or the central nervous system most commonly manifesting in the form of diabetes insipidus. Smoking cessation is the cornerstone of treatment in patients with PLCH and can lead to disease regression or stabilization in a substantial proportion of patients. Further insight into the underlying molecular pathogenesis of PLCH has paved the way for the future development of disease-specific biomarkers and targeted treatment options directed against the central disease-driving mutations.

Growth hormone-stimulated insulin-like growth factor-1 expression in rainbow trout (Oncorhynchus mykiss) hepatocytes is mediated by ERK, PI3K-AKT, and JAK-STAT

2011 ◽  
Vol 301 (1) ◽  
pp. R236-R243 ◽  
Author(s):  
Katie M. Reindl ◽  
Jeffrey D. Kittilson ◽  
Heather E. Bergan ◽  
Mark A. Sheridan
Keyword(s):  
Growth Hormone ◽  
Rainbow Trout ◽  
Growth Factor ◽  
Insulin Like Growth Factor ◽  
Molecular Signaling ◽  
Pi3k Inhibitor Ly294002 ◽  
Hepatic Expression ◽  
Jak2 Inhibitor ◽  
Downstream Target

Growth hormone (GH) initiates many of its growth-promoting actions by binding to GH receptors (GHR) and stimulating the synthesis and secretion of insulin-like growth factor-1 (IGF-1) from the liver and other sites. In this study, we used hepatocytes isolated from rainbow trout as a model system in which to determine the molecular signaling events of GH in fish. GH directly stimulated the phosphorylation of ERK, protein kinase B (Akt), a downstream target of phosphatidylinositol 3-kinase (PI3K), JAK2, and STAT5 in hepatocytes incubated in vitro. Activation of ERK, Akt, JAK2, and STAT5 was rapid, occurring within 5–10 min, and was concentration dependent. GH-induced ERK activation was completely blocked by the ERK pathway inhibitor, U0126, and the JAK2 inhibitor, 1,2,3,4,5,6-hexabromocyclohexane (Hex), and was partially blocked by the PI3K inhibitor LY294002. GH-stimulated Akt activation was completely blocked by LY294002 and Hex, but was not affected by U0126; whereas, STAT5 activation by GH was blocked only by Hex, and was not affected by either U0126 or LY294002. GH stimulated hepatic expression of IGF-1 mRNA as well as the secretion of IGF-1, effects that were partially or completely blocked by U0126, LY294002, and Hex. These results indicate that GHR linkage to the ERK, PI3K/Akt, or STAT pathways in trout liver cells requires activation of JAK2, and that GH-stimulated IGF-1 synthesis and secretion is mediated through the ERK, PI3K/Akt, and JAK-STAT pathways.

The human α-defensin-derived peptide HD5(1-9) inhibits cellular attachment and entry of human cytomegalovirus

2019 ◽  
Author(s):  
Rebecca Böffert ◽  
Ramona Businger ◽  
Hannes Preiß ◽  
Dirk Ehmann ◽  
Vincent Truffault ◽  
...  
Keyword(s):  
Antiviral Activity ◽  
Human Cytomegalovirus ◽  
Treatment Options ◽  
Unmet Need ◽  
Severe Illness ◽  
Natural Occurrence ◽  
Natural Defense ◽  
Cellular Attachment ◽  
Arginine Residues ◽  
Low Toxicity

ABSTRACTHuman cytomegalovirus (HCMV) infection causes severe illness in newborns and immunocompromised patients. Since treatment options are limited there is an unmet need for new therapeutic approaches. Defensins are cationic peptides, produced by various human tissues, which serve as antimicrobial effectors of the immune system. Furthermore, some defensins are proteolytically cleaved, resulting in the generation of smaller fragments with increased activity. Together, this led us to hypothesize that defensin-derived peptides are natural human inhibitors of virus infection with low toxicity. We screened several human defensin HNP4- and HD5-derived peptides and found HD5(1-9) to be antiviral without toxicity at high concentrations. HD5(1-9) inhibited HCMV cellular attachment and thereby entry and was active against primary as well as a multiresistant HCMV isolate. Moreover, cysteine and arginine residues were identified to mediate the antiviral activity of HD5(1-9). Altogether, defensin-derived peptides, in particular HD5(1-9), qualify as promising candidates for further development as a novel class of HCMV entry inhibitors.AUTHOR SUMMARYDefensins are peptides produced by various human organs which take part in the natural defense against pathogens. Recently, it has been shown that defensins are further cleaved to smaller peptides that have high intrinsic anti-microbial activity. We here challenged the hypothesis that these peptides might have antiviral activity, and due to their presumably natural occurrence, low toxicity. Indeed, we found one peptide fragment that turned out to block the attachment of the human cytomegalovirus (HCMV) to cells. Furthermore, this peptide did not show toxicity in various cellular assays or impede the embryonic development of zebrafish at the concentrations used to block HCMV. This is important, since HCMV is one of the most important viral congenital infections. Altogether, our results hold promise for the development of a new class of antivirals against HCMV.

scholarly journals Where does transplant fit in the age of targeted therapies?

Hematology ◽  
2019 ◽  
Vol 2019 (1) ◽  
pp. 287-293 ◽  
Author(s):  
Victor A. Chow ◽  
Ajay K. Gopal
Keyword(s):  
Follicular Lymphoma ◽  
Hematopoietic Cell Transplantation ◽  
Treatment Options ◽  
Progression Free Survival ◽  
Free Survival ◽  
Non Hodgkin Lymphoma ◽  
Low Toxicity ◽  
First Recurrence ◽  
Autologous Hct

Abstract The role of hematopoietic cell transplantation (HCT) for indolent lymphoma has evolved over the last 5 years with the availability of novel low-toxicity therapies and a better understanding of the prognosis of these entities. However, despite numerous treatment options for patients with follicular lymphoma, none are thought to be curative, and many require ongoing therapy with chronic toxicity. Historical trials indicate that autologous HCT as initial consolidation leads to improved progression-free survival, but not overall survival (OS) and, thus, is not typically recommended. However, autologous HCT for chemosensitive relapse can be carried out with ∼1% early mortality risk, affording disease control lasting a median of 3 to 5 years and the potential to improve OS. These results may compare favorably in efficacy, toxicity, and cost vs multiple sequential novel therapies with shorter durations of benefit. Recent data indicate that autologous HCT in follicular lymphoma patients with early initial progression will result in more than one third being alive and without relapse at 5 years, leading to improved OS when used within a year of the first recurrence. Unlike other available therapies, allogeneic HCT has the potential to cure up to one half of those transplanted with indolent B-cell non-Hodgkin lymphoma, although the risks need to be recognized and appropriate patient and donor selection is critical to ensure the best outcomes. HCT continues to remain a viable option in the current era of multiple targeted agents.

Hypoxia and STAT3 signalling interactions regulate pro-inflammatory pathways in rheumatoid arthritis

2014 ◽  
Vol 74 (6) ◽  
pp. 1275-1283 ◽  
Author(s):  
Wei Gao ◽  
Jennifer McCormick ◽  
Mary Connolly ◽  
Emese Balogh ◽  
Douglas J Veale ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Target Genes ◽  
Ex Vivo ◽  
Notch 1 ◽  
Functional Link ◽  
Jak2 Inhibitor ◽  
Downstream Target ◽  
Inflammatory Pathways ◽  
And Migration ◽  
Spontaneous Secretion

ObjectiveTo examine the effect of hypoxia on Signal Transducer and Activator of Transcription 3 (STAT3)-induced pro-inflammatory pathways in rheumatoid arthritis (RA).MethodsDetection of phospho-STAT3 was assessed in RA synovial tissue and fibroblasts (RASFC) by immunohistology/immunofluorescence. Primary RASFCs and a normal synoviocyte cell line (K4IM) were cultured under hypoxic and normoxic conditions±Stat3-siRNA, HIF-siRNA or WP1066 (JAK2-inhibitor). HIF1α, p-STAT3, p-STAT1 and Notch-1IC protein expression were analysed by western blot. Functional mechanisms were quantified by invasion chamber, matrigel and migration assays. IL-6, IL-8, IL-10 and matrixmetalloproteinases (MMP)-3 were quantified by ELISA. Notch-1 receptor, its DLL-4 ligand and downstream target genes (hrt-1, hrt-2) were quantified by real-time PCR. The effect of WP1066 on spontaneous secretion of pro/anti-inflammatory cytokines and Notch signalling was examined in RA synovial explants ex vivo.Resultsp-STAT3 was increased in RA synovium compared with control (p<0.05). Hypoxia induced p-STAT3, p-STAT1 and HIF1α expression, an effect blocked by Stat3-siRNA and WP1066. Hypoxia-induced cell invasion, migration and cytokine production were inhibited by Stat3-siRNA (p<0.05) and WP1066 (p<0.05). While HIF1α siRNA inhibited hypoxia-induced p-STAT3 detection, Stat3-siRNA also inhibited hypoxia-induced HIF1α. Furthermore, hypoxia-induced Notch-1IC, DLL4, hrt-1 and -2 expression were significantly inhibited by WP1066 (p<0.05). Finally, in RA synovial explant cultures ex vivo, WP1066 decreased spontaneous secretion of IL-6, IL-8 and MMP3 (p<0.05), Notch-1 mRNA (p<0.05) and induced IL-10 (p<0.05).ConclusionsThis is the first study to provide evidence of a functional link between HIF1α, STAT3 and Notch-1 signalling in the regulation of pro-inflammatory mechanisms in RA, and further supports a role for STAT blockade in the treatment of RA.

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