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The New England Journal of Medicine Dec 2020Adult-onset inflammatory syndromes often manifest with overlapping clinical features. Variants in ubiquitin-related genes, previously implicated in autoinflammatory...
BACKGROUND
Adult-onset inflammatory syndromes often manifest with overlapping clinical features. Variants in ubiquitin-related genes, previously implicated in autoinflammatory disease, may define new disorders.
METHODS
We analyzed peripheral-blood exome sequence data independent of clinical phenotype and inheritance pattern to identify deleterious mutations in ubiquitin-related genes. Sanger sequencing, immunoblotting, immunohistochemical testing, flow cytometry, and transcriptome and cytokine profiling were performed. CRISPR-Cas9-edited zebrafish were used as an in vivo model to assess gene function.
RESULTS
We identified 25 men with somatic mutations affecting methionine-41 (p.Met41) in UBA1, the major E1 enzyme that initiates ubiquitylation. (The gene lies on the X chromosome.) In such patients, an often fatal, treatment-refractory inflammatory syndrome develops in late adulthood, with fevers, cytopenias, characteristic vacuoles in myeloid and erythroid precursor cells, dysplastic bone marrow, neutrophilic cutaneous and pulmonary inflammation, chondritis, and vasculitis. Most of these 25 patients met clinical criteria for an inflammatory syndrome (relapsing polychondritis, Sweet's syndrome, polyarteritis nodosa, or giant-cell arteritis) or a hematologic condition (myelodysplastic syndrome or multiple myeloma) or both. Mutations were found in more than half the hematopoietic stem cells, including peripheral-blood myeloid cells but not lymphocytes or fibroblasts. Mutations affecting p.Met41 resulted in loss of the canonical cytoplasmic isoform of UBA1 and in expression of a novel, catalytically impaired isoform initiated at p.Met67. Mutant peripheral-blood cells showed decreased ubiquitylation and activated innate immune pathways. Knockout of the cytoplasmic UBA1 isoform homologue in zebrafish caused systemic inflammation.
CONCLUSIONS
Using a genotype-driven approach, we identified a disorder that connects seemingly unrelated adult-onset inflammatory syndromes. We named this disorder the VEXAS (vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic) syndrome. (Funded by the NIH Intramural Research Programs and the EU Horizon 2020 Research and Innovation Program.).
Topics: Age of Onset; Aged; Aged, 80 and over; Autoimmune Diseases; Cytokines; Exome; Genetic Diseases, X-Linked; Genotype; Giant Cell Arteritis; Humans; Immunoblotting; Inflammation; Male; Middle Aged; Multiple Myeloma; Mutation, Missense; Myelodysplastic Syndromes; Polyarteritis Nodosa; Polychondritis, Relapsing; Sequence Analysis, DNA; Sweet Syndrome; Syndrome; Ubiquitin-Activating Enzymes
PubMed: 33108101
DOI: 10.1056/NEJMoa2026834 -
Current Oncology (Toronto, Ont.) Feb 2023Multiple myeloma remains an incurable disease with the usual disease course requiring induction therapy, autologous stem cell transplantation for eligible patients, and... (Review)
Review
Multiple myeloma remains an incurable disease with the usual disease course requiring induction therapy, autologous stem cell transplantation for eligible patients, and long-term maintenance. Risk stratification tools and cytogenetic alterations help inform individualized therapeutic choices for patients in hopes of achieving long-term remissions with preserved quality of life. Unfortunately, relapses occur at different stages of the course of the disease owing to the biological heterogeneity of the disease. Addressing relapse can be complex and challenging as there are both therapy- and patient-related factors to consider. In this broad scoping review of available therapies in relapsed/refractory multiple myeloma (RRMM), we cover the pharmacologic mechanisms underlying active therapies such as immunomodulatory agents (IMiDs), proteasome inhibitors (PIs), monoclonal antibodies (mAbs), traditional chemotherapy, and Venetoclax. We then review the clinical data supporting the use of these therapies, organized based on drug resistance/refractoriness, and the role of autologous stem cell transplant (ASCT). Approaches to special situations during relapse such as renal impairment and extramedullary disease are also covered. Lastly, we look towards the future by briefly reviewing the clinical data supporting the use of chimeric antigen receptor (CAR-T) therapy, bispecific T cell engagers (BITE), and Cereblon E3 Ligase Modulators (CELMoDs).
Topics: Humans; Multiple Myeloma; Hematopoietic Stem Cell Transplantation; Quality of Life; Transplantation, Autologous; Neoplasm Recurrence, Local
PubMed: 36826140
DOI: 10.3390/curroncol30020179 -
Anaesthesia Jul 2007The clinical features of propofol infusion syndrome (PRIS) are acute refractory bradycardia leading to asystole, in the presence of one or more of the following:... (Review)
Review
The clinical features of propofol infusion syndrome (PRIS) are acute refractory bradycardia leading to asystole, in the presence of one or more of the following: metabolic acidosis (base deficit > 10 mmol.l(-1)), rhabdomyolysis, hyperlipidaemia, and enlarged or fatty liver. There is an association between PRIS and propofol infusions at doses higher than 4 mg.kg(-1).h(-1) for greater than 48 h duration. Sixty-one patients with PRIS have been recorded in the literature, with deaths in 20 paediatric and 18 adult patients. Seven of these patients (four paediatric and three adult patients) developed PRIS during anaesthesia. It is proposed that the syndrome may be caused by either a direct mitochondrial respiratory chain inhibition or impaired mitochondrial fatty acid metabolism mediated by propofol. An early sign of cardiac instability associated with the syndrome is the development of right bundle branch block with convex-curved ('coved type') ST elevation in the right praecordial leads (V1 to V3) of the electrocardiogram. Predisposing factors include young age, severe critical illness of central nervous system or respiratory origin, exogenous catecholamine or glucocorticoid administration, inadequate carbohydrate intake and subclinical mitochondrial disease. Treatment options are limited. Haemodialysis or haemoperfusion with cardiorespiratory support has been the most successful treatment.
Topics: Acidosis; Adolescent; Adult; Anesthetics, Intravenous; Biomarkers; Bradycardia; Child; Child, Preschool; Death, Sudden; Female; Humans; Hypnotics and Sedatives; Infant; Male; Mitochondrial Diseases; Propofol; Risk Factors; Syndrome
PubMed: 17567345
DOI: 10.1111/j.1365-2044.2007.05055.x -
Current Gastroenterology Reports Aug 2020Low anterior resection syndrome is a highly prevalent condition that can develop after anal sphincter-sparing surgery for rectal cancer and impair quality of life. In... (Review)
Review
PURPOSE OF REVIEW
Low anterior resection syndrome is a highly prevalent condition that can develop after anal sphincter-sparing surgery for rectal cancer and impair quality of life. In this review, we summarize the major features and pathophysiology of this syndrome and discuss treatment approaches.
RECENT FINDINGS
Quality of life correlates significantly with severity of low anterior resection syndrome. Prompt assessment and initiation of therapy are essential to rehabilitating damaged mechanical and neural structures. Anorectal manometry demonstrates a global decrease in sphincteric function postoperatively, though in many patients, function does recover. Transanal irrigation, pelvic floor rehabilitation, and biofeedback are the mainstays of the treatment of major LARS. Definitive stoma can be considered in therapy refractory LARS > 2 years. The development of low anterior resection syndrome likely involves an interplay between mechanical and neural pathways. Clinically, patients present at varying levels of severity, and scoring systems are available to help assess patient symptoms and guide therapy. Treatment approaches range from conservative therapies to biofeedback and sacral nerve stimulation. Future randomized controlled trials aimed at risk stratification of patients and development of severity-based treatment algorithms are warranted.
Topics: Anal Canal; Biofeedback, Psychology; Constipation; Diet; Fecal Incontinence; Humans; Manometry; Organ Sparing Treatments; Postoperative Complications; Quality of Life; Rectal Neoplasms; Risk Factors; Syndrome; Therapeutic Irrigation
PubMed: 32749603
DOI: 10.1007/s11894-020-00785-z -
Developmental Medicine and Child... Mar 2021Sunflower syndrome is a rare photosensitive epilepsy which has received little attention in recent medical literature. The historical cases documenting the epilepsy's... (Review)
Review
Sunflower syndrome is a rare photosensitive epilepsy which has received little attention in recent medical literature. The historical cases documenting the epilepsy's stereotyped handwaving motion in front of light characterized the behavior as self-inducing seizures via mimic of stroboscopic effect. However, the relationship between handwaving episodes and attendant generalized electroencephalogram abnormalities, and an appreciation of the compulsive attraction the sun and other light sources hold for these patients, suggest the handwaving motion may be a part of the seizure rather than a mechanism of self-induction. The lack of awareness of Sunflower syndrome often leads to misdiagnosis. The seizures are often refractory to traditional anticonvulsant medication, and patients resort to behavioral intervention, such as hats and sunglasses, to reduce handwaving episodes. Further study is required to determine the syndrome's natural history and to identify more effective treatment options. WHAT THIS PAPER ADDS: Sunflower syndrome is a rare condition that is often misdiagnosed. Awareness of the clinical and electroencephalogram characteristics of Sunflower syndromemay reduce the prevalence of misdiagnosis.
Topics: Anticonvulsants; Epilepsy, Reflex; Humans; Photic Stimulation; Syndrome
PubMed: 33135153
DOI: 10.1111/dmcn.14723 -
Technology in Cancer Research &... 2022Multiple myeloma (MM) is a hematologic malignancy characterized by the proliferation of clonal plasma cells. Although advances in treatment have markedly improved... (Review)
Review
Multiple myeloma (MM) is a hematologic malignancy characterized by the proliferation of clonal plasma cells. Although advances in treatment have markedly improved survival outcomes for patients with MM, this disease is still considered incurable owing to its high incidence of relapse and refractoriness. Isatuximab is an anti-CD38 monoclonal antibody that can induce apoptosis in myeloma cells through a variety of mechanisms. Many clinical studies have demonstrated the efficacy and efficiency of isatuximab in both relapsed/refractory multiple myeloma (RRMM) and newly diagnosed multiple myeloma, leading to its approval for the treatment of adults with RRMM in combination therapies. In this review, the structure, mechanisms of action, pharmacokinetics, pharmacogenetics, and safety profile of isatuximab in MM are summarized. Additionally, isatuximab is compared with daratumumab in terms of mechanism and efficacy.
Topics: Adult; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Humans; Multiple Myeloma; Neoplasm Recurrence, Local
PubMed: 35903924
DOI: 10.1177/15330338221106563 -
Internal and Emergency Medicine Jan 2021Acute aortic syndromes (AASs) are deadly cardiovascular emergencies involving the thoracic aorta. AASs are relatively rare conditions, have unspecific signs and symptoms... (Review)
Review
Acute aortic syndromes (AASs) are deadly cardiovascular emergencies involving the thoracic aorta. AASs are relatively rare conditions, have unspecific signs and symptoms (including truncal pain, syncope, neurologic deficit and limb ischemia) and require contrast-enhanced tomography angiography (CTA) of the chest and abdomen for conclusive diagnosis and subsequent therapeutic planning. In the Emergency Department (ED), most patients with potential signs/symptoms of AASs are finally found affected by other alternative diagnoses. Hence, misdiagnosis and delayed diagnosis of AASs are major concerns. In critically ill patients, decision to perform CTA is usually straightforward, as exam benefits largely outweigh risks. In patients with ST-tract elevation on ECG, suspected primary ischemic stroke and in stable patients (representing the most prevalent ED scenarios), proper selection of patients necessitating CTA is cumbersome, due to concurrent risks of misdiagnosis and over-testing. Available studies support an algorithm integrating clinical probability assessment, bedside echocardiography and D-dimer (if the clinical probability is not high). Therapeutic management includes medical therapy for all patients including an opioid and anti-impulse drugs (a beta-blocker and a vasodilator), targeting a heart rate of 60 bpm and systolic blood pressure of 100-120 mmHg. Patients with AASs involving the ascending aorta are likely candidate for urgent surgery, and complicated type B AASs (severe aortic dilatation, impending or frank rupture, organ malperfusion, refractory pain, severe hypertension) necessitate evaluation for urgent endovascular treatment. For uncomplicated type B AASs, optimal medical therapy is the current standard of care.
Topics: Acute Disease; Algorithms; Aorta, Thoracic; Aortic Diseases; Computed Tomography Angiography; Contrast Media; Diagnosis, Differential; Echocardiography; Emergency Service, Hospital; Humans; Patient Selection; Syndrome
PubMed: 32358680
DOI: 10.1007/s11739-020-02354-8 -
Annals of Oncology : Official Journal... Jun 2022Compared with adult cancers, pediatric cancers are uniquely characterized by a genomically stable landscape and lower tumor mutational burden. Alternative splicing,... (Review)
Review
BACKGROUND
Compared with adult cancers, pediatric cancers are uniquely characterized by a genomically stable landscape and lower tumor mutational burden. Alternative splicing, however, a global cellular process that produces different messenger RNA/protein isoforms from a single messenger RNA transcript, has been increasingly implicated in the development of pediatric cancers.
DESIGN
We review the current literature on the role of alternative splicing in adult cancer, cancer predisposition syndromes, and pediatric cancers. We also describe multiple splice variants identified in adult cancers and confirmed through comprehensive genomic profiling in our institutional cohort of rare, refractory, and relapsed pediatric and adolescent young adult cancer patients. Finally, we summarize the contributions of alternative splicing events to neoantigens and chemoresistance and prospects for splicing-based therapies.
RESULTS
Published dysregulated splicing events can be categorized as exon inclusion, exon exclusion, splicing factor up-regulation, or splice site alterations. We observe these phenomena in cancer predisposition syndromes (Lynch syndrome, Li-Fraumeni syndrome, CHEK2) and pediatric leukemia (B-cell acute lymphoblastic leukemia), sarcomas (Ewing sarcoma, rhabdomyosarcoma, osteosarcoma), retinoblastoma, Wilms' tumor, and neuroblastoma. Within our institutional cohort, we demonstrate splice variants in key regulatory genes (CHEK2, TP53, PIK3R1, MDM2, KDM6A, NF1) that resulted in exon exclusion or splice site alterations, which were predicted to impact functional protein expression and promote tumorigenesis. Differentially spliced isoforms and splicing proteins also impact neoantigen creation and treatment resistance, such as imatinib or glucocorticoid regimens. Additionally, splice-altering strategies with the potential to change the therapeutic landscape of pediatric cancers include antisense oligonucleotides, adeno-associated virus gene transfers, and small molecule inhibitors.
CONCLUSIONS
Alternative splicing plays a critical role in the formation and growth of pediatric cancers, and our institutional cohort confirms and highlights the broad spectrum of affected genes in a variety of cancers. Further studies that elucidate the mechanisms of disease-inducing splicing events will contribute toward the development of novel therapeutics.
Topics: Adolescent; Alternative Splicing; Carcinogenesis; Cell Transformation, Neoplastic; Child; Humans; Neoplasms; RNA, Messenger; Syndrome; Young Adult
PubMed: 35339647
DOI: 10.1016/j.annonc.2022.03.011 -
CAR T cell-induced cytokine release syndrome is mediated by macrophages and abated by IL-1 blockade.Nature Medicine Jun 2018Chimeric antigen receptor (CAR) therapy targeting CD19 is an effective treatment for refractory B cell malignancies, especially acute lymphoblastic leukemia (ALL) ....
Chimeric antigen receptor (CAR) therapy targeting CD19 is an effective treatment for refractory B cell malignancies, especially acute lymphoblastic leukemia (ALL) . Although a majority of patients will achieve a complete response following a single infusion of CD19-targeted CAR-modified T cells (CD19 CAR T cells), the broad applicability of this treatment is hampered by severe cytokine release syndrome (CRS), which is characterized by fever, hypotension and respiratory insufficiency associated with elevated serum cytokines, including interleukin-6 (IL-6). CRS usually occurs within days of T cell infusion at the peak of CAR T cell expansion. In ALL, it is most frequent and more severe in patients with high tumor burden. CRS may respond to IL-6 receptor blockade but can require further treatment with high dose corticosteroids to curb potentially lethal severity. Improved therapeutic and preventive treatments require a better understanding of CRS physiopathology, which has so far remained elusive. Here we report a murine model of CRS that develops within 2-3 d of CAR T cell infusion and that is potentially lethal and responsive to IL-6 receptor blockade. We show that its severity is mediated not by CAR T cell-derived cytokines, but by IL-6, IL-1 and nitric oxide (NO) produced by recipient macrophages, which enables new therapeutic interventions.
Topics: Animals; Cytokines; Humans; Immunotherapy, Adoptive; Interleukin 1 Receptor Antagonist Protein; Interleukin-1; Macrophages; Mice; Myeloid Cells; Neoplasms; Syndrome
PubMed: 29808005
DOI: 10.1038/s41591-018-0041-7 -
Allergy Aug 2015Chronic rhinosinusitis (CRS) can be classified into CRS with nasal polyps (CRSwNP) and CRS without nasal polyps (CRSsNP). CRSwNP displays more intense eosinophilic... (Comparative Study)
Comparative Study
BACKGROUND
Chronic rhinosinusitis (CRS) can be classified into CRS with nasal polyps (CRSwNP) and CRS without nasal polyps (CRSsNP). CRSwNP displays more intense eosinophilic infiltration and the presence of Th2 cytokines. Mucosal eosinophilia is associated with more severe symptoms and often requires multiple surgeries because of recurrence; however, even in eosinophilic CRS (ECRS), clinical course is variable. In this study, we wanted to set objective clinical criteria for the diagnosis of refractory CRS.
METHODS
This was a retrospective study conducted by 15 institutions participating in the Japanese Epidemiological Survey of Refractory Eosinophilic Chronic Rhinosinusitis (JESREC). We evaluated patients with CRS treated with endoscopic sinus surgery (ESS), and risk of recurrence was estimated using Cox proportional hazard models. Multiple logistic regression models and receiver operating characteristics curves were constructed to create the diagnostic criterion for ECRS.
RESULTS
We analyzed 1716 patients treated with ESS. To diagnose ECRS, the JESREC scoring system assessed unilateral or bilateral disease, the presence of nasal polyps, blood eosinophilia, and dominant shadow of ethmoid sinuses in computed tomography (CT) scans. The cutoff value of the score was 11 points (sensitivity: 83%, specificity: 66%). Blood eosinophilia (>5%), ethmoid sinus disease detected by CT scan, bronchial asthma, aspirin, and nonsteroidal anti-inflammatory drugs intolerance were associated significantly with recurrence.
CONCLUSION
We subdivided CRSwNP in non-ECRS, mild, moderate, and severe ECRS according to our algorithm. This classification was significantly correlated with prognosis. It is notable that this algorithm may give useful information to clinicians in the refractoriness of CRS before ESS or biopsy.
Topics: Adult; Age Distribution; Age of Onset; Aged; Algorithms; Chronic Disease; Cohort Studies; Eosinophilia; Female; Humans; Incidence; Japan; Male; Middle Aged; Multivariate Analysis; Prognosis; Proportional Hazards Models; Retrospective Studies; Rhinitis; Risk Assessment; Severity of Illness Index; Sex Distribution; Sinusitis; Young Adult
PubMed: 25945591
DOI: 10.1111/all.12644