Transient Sideroblastic Anemia Post-COVID-19 Infection.

A 57-year-old gentleman presented to the hospital with progressive fatigue and dyspnea on exertion three months after recovering from COVID-19. He was noted to have severe anemia with reticulocytopenia. After excluding vitamin deficiencies and heavy metal toxicities, a bone marrow aspirate and biopsy were performed, which showed erythroid predominant trilineage maturing hematopoiesis with 79% ring sideroblasts and no dysplasia. SF3B1 mutation was negative. He was diagnosed with sideroblastic anemia and became transfusion-dependent. He was treated with an erythropoiesis-stimulating agent and luspatercept with transient improvement in anemia. After 12 months of treatment, anemia spontaneously improved. Repeat bone marrow biopsy showed hypercellular marrow with 39% ringed sideroblasts. We suspect that this possibly was a delayed manifestation of COVID-19 infection.

The Conundrum of "Warfarin Hypersensitivity": Prolonged Partial Thromboplastin Time From Factor IX Propeptide Mutation.

Carboxylation of glutamic acid residues of vitamin K dependent clotting factors (II, VII, IX, and X) is essential to their biological functioning. Binding of these factors to γ-glutamyl carboxylase enzyme for carboxylation reaction is mediated by wild-type propeptide, a small sequence of amino acids that precede the actual polypeptide. Missense mutations at certain residue severely decrease the affinity of mutated propeptide for the enzyme. Such mutations are reported to occur at codon-10 of factor IX propeptide, a clinically silent metabolic event in normal conditions. However in the presence of warfarin, such mutations and resultant decrease affinity of factor IX propeptide for the enzyme that causes severe selective decrease in factor IX activity. This can potentially leads to life-threatening bleeding complications and known as one of the causes of warfarin hypersensitivity. It is imperative to recognize such cases early on to avoid additional warfarin therapy. Recurrent bleeding episodes, subtherapeutic to therapeutic range international normalized ratio values with relatively prolong partial thromboplastin time should raise the suspicion of underlying factor IX propeptide mutations.

Chalazia Development in Multiple Myeloma: A New Complication Associated with Bortezomib Therapy.

Multiple myeloma (MM) is a neoplasm of plasma cells within the bone marrow. A major impact on improving survival in MM has been the use of the boronic acid-derived proteasome inhibitor bortezomib, a first-in-class selective inhibitor of the 26S proteasome. Ocular side effects of bortezomib are rare. In this report, we present 2 patients with active MM in whom persistent chalazia became a therapy-interfering complication of treatment with bortezomib. Both patients had relapsed ISS III B kappa light chain myeloma, and they were responding to treatment with bortezomib until chalazia - which caused intolerable discomfort - started. In both patients discontinuation of bortezomib was necessary for chalazia to heal, and restarting of bortezomib was associated with relapse of chalazia.

Improving resident morning sign-out by use of daily events reports.

OBJECTIVES: The clinician arriving at the hospital in the morning may not yet be aware of key overnight clinical activity. To address this situation at our facility, we modified our handoff software to permit continuous updating of clinical information and the automatic relay of important overnight clinical updates to relevant providers each morning. METHODS: Cross-covering residents electronically entered safety concerns and clinical issues within the reporting module of the handoff software between 5 PM and 7 AM. This updated their handoff-information at shift change and permitted the generation of reports that were emailed to primary providers and reviewed before 7 AM prerounds. At 7:30 sign-out, if a resident was already aware of an issue being signed out, he/she indicated this so that sign-out could quickly proceed to the next patient. Study sign-out duration was recorded, and residents were surveyed regarding the new communication system. RESULTS: Morning sign-out duration decreased from 25.5 to 22.7 minutes (P = 0.0338). All respondents agreed strongly (12/14, 86%) or somewhat (2/14, 14%) that daily morning events reports prevented "loss of key information between shifts" and enhanced safety greatly (10/14, 71%) or moderately (4/14, 29%).All agreed either strongly (10/14, 71%) or somewhat (4/14, 29%) that the daily report improved the quality of handoff information and strongly (12/14, 86%) or somewhat (2/14, 14%) that the report was convenient. CONCLUSIONS: The collection of key clinical handoff information and its automatic forwarding to incoming providers reduced the average duration of resident morning sign-out and significantly enhanced provider perceptions regarding patient safety and the quality of handoff information.

STAT inhibitors for cancer therapy.

Signal Transducer and Activator of Transcription (STAT) proteins are a family of cytoplasmic transcription factors consisting of 7 members, STAT1 to STAT6, including STAT5a and STAT5b. STAT proteins are thought to be ideal targets for anti-cancer therapy since cancer cells are more dependent on the STAT activity than their normal counterparts. Inhibitors targeting STAT3 and STAT5 have been developed. These included peptidomimetics, small molecule inhibitors and oligonucleotides. This review summarized advances in preclinical and clinical development of these compounds.

Dysregulation of JAK-STAT pathway in hematological malignancies and JAK inhibitors for clinical application.

JAK-STAT (Janus associated kinase-signal transducer and activator of transcription) pathway plays a critical role in transduction of extracellular signals from cytokines and growth factors involved in hematopoiesis, immune regulation, fertility, lactation, growth and embryogenesis. JAK family contains four cytoplasmic tyrosine kinases, JAK1-3 and Tyk2. Seven STAT proteins have been identified in human cells, STAT1-6, including STAT5a and STAT5b. Negative regulators of JAK-STAT pathways include tyrosine phosphatases (SHP1 and 2, CD45), protein inhibitors of activated STATs (PIAS), suppressors of cytokine signaling (SOCS) proteins, and cytokine-inducible SH2-containing protein (CIS). Dysregulation of JAK-STAT pathway have been found to be key events in a variety of hematological malignancies. JAK inhibitors are among the first successful agents reaching clinical application. Ruxolitinib (Jakafi), a non-selective inhibitor of JAK1 & 2, has been approved by FDA for patients with intermediate to high risk primary or secondary myelofibrosis. This review will also summarize early data on selective JAK inhibitors, including SAR302503 (TG101348), lestaurtinib (CEP701), CYT387, SB1518 (pacritinib), LY2784544, XL019, BMS-911543, NS-018, and AZD1480.

Ibrutinib and novel BTK inhibitors in clinical development.

Small molecule inhibitors targeting dysregulated pathways (RAS/RAF/MEK, PI3K/AKT/mTOR, JAK/STAT) have significantly improved clinical outcomes in cancer patients. Recently Bruton's tyrosine kinase (BTK), a crucial terminal kinase enzyme in the B-cell antigen receptor (BCR) signaling pathway, has emerged as an attractive target for therapeutic intervention in human malignancies and autoimmune disorders. Ibrutinib, a novel first-in-human BTK-inhibitor, has demonstrated clinical effectiveness and tolerability in early clinical trials and has progressed into phase III trials. However, additional research is necessary to identify the optimal dosing schedule, as well as patients most likely to benefit from BTK inhibition. This review summarizes preclinical and clinical development of ibrutinib and other novel BTK inhibitors (GDC-0834, CGI-560, CGI-1746, HM-71224, CC-292, and ONO-4059, CNX-774, LFM-A13) in the treatment of B-cell malignancies and autoimmune disorders.

MEK and the inhibitors: from bench to bedside.

Four distinct MAP kinase signaling pathways involving 7 MEK enzymes have been identified. MEK1 and MEK2 are the prototype members of MEK family proteins. Several MEK inhibitors are in clinical trials. Trametinib is being evaluated by FDA for the treatment of metastatic melanoma with BRAF V600 mutation. Selumetinib has been studied in combination with docetaxel in phase II randomized trial in previously treated patients with advanced lung cancer. Selumetinib group had better response rate and progression-free survival. This review also summarized new MEK inhibitors in clinical development, including pimasertib, refametinib, PD-0325901, TAK733, MEK162 (ARRY 438162), RO5126766, WX-554, RO4987655 (CH4987655), GDC-0973 (XL518), and AZD8330.

Novel CD20 monoclonal antibodies for lymphoma therapy.

Rituximab (RTX), a monoclonal antibody (mAb) against CD20, has been widely used for lymphoma therapy. RTX in combination with cyclophosphamide /doxorubicin /vincristine /prednisone (R-CHOP) remains the standard frontline regimen for diffuse large B-cell lymphoma. However, suboptimal response and /or resistance to rituximab have remained a challenge in the therapy of B-cell non-Hodgkin's lymphoma (NHL). Novel agents are under active clinical trials. This review will summarize the latest development in new mAbs against CD20, which include second-generation mAbs, ofatumumab, veltuzumab (IMMU-106), ocrelizumab (PRO70769), and third-generation mAbs, AME-133v (ocaratuzumab), PRO131921 and GA101 (obinutumumab).

Current management and novel agents for malignant melanoma.

Advanced malignant melanoma remains a challenging cancer. Over the past year, there have been 3 agents approved for treatment of melanoma by Food and Drug Administration. These include pegylated interferon alpha-2b for stage III melanoma, vemurafenib for unresectable or metastatic melanoma with BRAF V600E mutation, and ipilimumab for treatment of unresectable or metastatic melanoma. This review will also update on the development of novel agents, including tyrosine kinase inhibitors and adoptive cellular therapy.