The NCCN Guidelines for Acute Myeloid Leukemia (AML) provide recommendations for the diagnosis and treatment of adults with AML based on clinical trials that have led to significant improvements in treatment, or have yielded new information regarding factors with prognostic importance, and are intended to aid physicians with clinical decision-making. These NCCN Guidelines Insights focus on recent select updates to the NCCN Guidelines, including familial genetic alterations in AML, postinduction or postremission treatment strategies in low-risk acute promyelocytic leukemia or favorable-risk AML, principles surrounding the use of venetoclax-based therapies, and considerations for patients who prefer not to receive blood transfusions during treatment.
We assessed the performance characteristics of an RNA sequencing (RNA-Seq) assay designed to detect gene fusions in 571 genes to help manage patients with cancer. Polyadenylated RNA was converted to cDNA, which was then used to prepare next-generation sequencing libraries that were sequenced on an Illumina HiSeq 2500 instrument and analyzed with an in-house developed bioinformatic pipeline. The assay identified 38 of 41 gene fusions detected by another method, such as fluorescence in situ hybridization or RT-PCR, for a sensitivity of 93%. No false-positive gene fusions were identified in 15 normal tissue specimens and 10 tumor specimens that were negative for fusions by RNA sequencing or Mate Pair NGS (100% specificity). The assay also identified 22 fusions in 17 tumor specimens that had not been detected by other methods. Eighteen of the 22 fusions had not previously been described. Good intra-assay and interassay reproducibility was observed with complete concordance for the presence or absence of gene fusions in replicates. The analytical sensitivity of the assay was tested by diluting RNA isolated from gene fusion-positive cases with fusion-negative RNA. Gene fusions were generally detectable down to 12.5% dilutions for most fusions and as little as 3% for some fusions. This assay can help identify fusions in patients with cancer; these patients may in turn benefit from both US Food and Drug Administration-approved and investigational targeted therapies.
A 57-year-old woman with common variable immune deficiency and liver failure of unknown etiology presented with recurrent fevers over a 5-month period. She was found to have Helicobacter canis bacteremia. Immunocompromised hosts with exposure to cats or dogs may be at risk for infection with this organism, which may be challenging to diagnose. CASE REPORTA 57-year-old woman from Montana was referred to our institution for Infectious Diseases consultation for recurrent fever and chills for 3 months. She had common variable immunodeficiency (for which she received intermittent intravenous immune globulin infusions), and presumed pulmonary sarcoidosis (treated intermittently with prednisone), and had undergone prior splenectomy. She had a 2-year history of elevated alkaline phosphatase. She had developed intermittent fever 3 months prior to consultation and had been previously hospitalized locally for fever and clinical sepsis with negative blood cultures. Laparoscopic liver biopsy had shown mildly active steatohepatitis with periportal fibrosis, and had been procedurally complicated by intra-abdominal hemorrhage. She had been hospitalized for fever on several subsequent occasions and had received multiple courses of empirical antibacterial therapy despite negative blood cultures and no clear definition of an infectious process.Upon presentation for initial Infectious Diseases consultation, fevers were described as low grade and intermittent and were accompanied by chills and sweats. She had taken prednisone (20 mg daily) for the previous 3 months for abdominal pain ascribed to possible gastrointestinal sarcoidosis. She reported a 1-year history of diarrhea and a 2-year 160-pound weight loss. A colonoscopic biopsy 5 months prior had shown findings consistent with common variable immunodeficiency. Stool studies showed no evidence of enteric infection. She had two dogs and three cats. The patient's blood cultures, serologic testing for HIV, blood PCR for cytomegalovirus, and chest X-ray were negative. Serum IgG was 408 mg/dl (767 to 1,590 mg/dl), and IgA was 2 mg/dl (61 to 356 mg/dl). Total bilirubin was 0.4 mg/dl (0.1 to 1 mg/dl), alkaline phosphatase 566 units/liter (46 to 118 units/liter), and alanine transaminase 155 units/liter (7 to 45 units/liter). Computed tomography of the chest, abdomen, and pelvis was notable only for a fluid collection around the liver. Aspiration of this collection was attempted, but no fluid was obtained, and the finding was ascribed to a resolving hematoma. A positron emission tomography scan was unremarkable. She was empirically treated with ciprofloxacin and metronidazole for 5 days. Fever resolved and she was discharged home.She was admitted to a local hospital 2 months later for recurring fevers and worsening cholestasis. Total bilirubin was 21.6 mg/dl (0.1 to 1 mg/dl), alkaline phosphatase 359 units/liter (46 to 118 units/liter), and alanine transaminase 384 units/liter (7 to 45 units/liter). She was subsequently transferred to our hospital, at which time she was afebrile in the a...
2B4 is a member of the SLAM receptor family capable of activating NK cell cytotoxicity in the context of EBV infection. SAP (SLAM Associated Protein) deficiency causes defective signaling downstream of SLAM family receptors and high susceptibility to EBV. 2B4 costimulates natural cytotoxicity receptor (NCR) and TCR initiated signals to induce cellular cytotoxicity and cytokine release. The 2B4-SAP signal transduction pathway is not predicted to overlap with the TCR-ITAM pathway, although SAP is required for some TCR-induced signals. We therefore examined the functional relationship between SLAM family receptor 2B4 and ITAM-containing adaptor complexes. Removal of FcεRIγ or CD3ζ-containing complexes, using genetically manipulated cell lines or siRNA specific suppression, significantly reduces 2B4-initiated functions in T and NK cells, respectively. Consistent with this relationship, Syk and ZAP-70 are capable of transducing 2B4 signals for calcium mobilization and cytolysis. Furthermore, ITAM-containing molecules constitutively associate with SAP. These results suggest a potential physical association between 2B4 and the ITAM receptor complexes that is required for 2B4-initiated signaling and cell-mediated killing.
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