Incidence of Invasive Fungal Infections in Patients Initiating Ibrutinib and Other Small Molecule Kinase Inhibitors-United States, July 2016-June 2019.

We analyzed administrative data to determine the 1-year incidence of invasive fungal infections (IFIs) in patients beginning small molecule kinase inhibitor (SMKI) therapy. The incidence of IFIs by small molecule kinase inhibitor ranged from 0.0% to 10.6%, with patients taking midostaurin having the highest incidence. An IFI developed in 38 of 1286 patients taking ibrutinib (3.0%).

Hydroxyurea and fetal hemoglobin effect on leg ulcers in patients with sickle cell disease.

The presence of leg ulcers in individuals with sickle cell disease often represents an early sign of vasculopathy and future end organ damage. Pathophysiological mechanisms of formation and evolution of leg ulcers are poorly understood; nevertheless, HbF has been associated with lower incidence of leg ulcers, while hydroxyurea has been correlated with high risk of leg ulcers. As a result, there is hesitation regarding hydroxyurea use in patients with SCD and leg ulcers. In this study, we aim to define (1) a target of HbF that offers protection against leg ulcer development and (2) the impact of hydroxyurea therapy on leg ulcer prevalence. Our study demonstrated that in order to reduce leg ulcer incidence by one-third, a HbF > 25% is needed, a threshold not commonly reached and maintained in the adult SCD population. Importantly, leg ulcer incidence appears to be independent of HU use (p = 0.50). Our interpretation of this data is that the use of HU in a patient with SCD and leg ulcers should be guided by a careful assessment of risks and benefits of this therapeutic modality.

Acute and chronic pain management in patients with sickle cell disease in the modern era: a comprehensive review.

Sickle cell disease (SCD) is the most common inherited red blood cell (RBC) disorder worldwide, resulting in chronic hemolytic anemia, vaso-occlusion, tissue hypoxia, and ultimately end organ damage. The hallmark of the disease is manifested by vaso-occlusive crisis (VOC) resulting in acute on chronic pain, and the most common cause for presentation to the emergency department and hospital admission. The management of pain for patients with SCD in the U.S. has historically been socially and politically complex with most patients experiencing pain on a daily basis but not seeking immediate medical attention. The pathophysiology of acute and chronic pain in SCD is multifactorial and complex. Here, we describe factors contributing to acute and chronic pain in SCD and management strategies.

First Report of Compound Heterozygosity for Hb S (HBB: c.20A>T) and Hb Haringey (HBB: c.131A>G).

Sickle cell disease variants include hemoglobinopathies that result from inheritance of the sickle cell globin mutation with another globin mutation. The most common variants include the homozygous disease state (Hb SS disease), Hb S (HBB: c.20A>T)/Hb C (HBB: c.19G>A) disease and Hb S/ß-thalassemia (Hb S/ß-thal). Other rare/less common variants such as Hb S/Hb E (HBB: c.79G>A) and Hb S/HPFH [hereditary persistence of fetal hemoglobin (Hb)] disease exist. We report the first case of compound heterozygosity for Hb S and Hb Haringey (HBB: c.131A>G) in a 35-year-old male following a positive sickle screen test on hospital admission for pancreatitis. Ion exchange high performance liquid chromatography (HPLC), Hb electrophoresis and genetic sequencing were utilized to identify a new sickle Hb variant: Hb S/Hb Haringey. Hb S/Hb Haringey is a newly discovered sickle cell variant which seems to portray a mild/benign clinical phenotype of sickle cell disease.

Effectiveness of Biologic Agents Among Hispanic Patients With Metastatic Colorectal Cancer.

BACKGROUND: Randomized clinical trials have defined the survival advantage with the addition of biologic drugs to chemotherapy in patients with metastatic colorectal cancer (mCRC). Under representation of Hispanics contributes to poorly defined outcomes in this group. We aim to determine whether the real-world benefit of biologics extends to Hispanics using a comparative effectiveness research approach. METHODS: This retrospective cohort study included all treatment centers contributing to SEER registry with available claims in the SEER-Medicare linked database (2001-2011) and 2 hospitals (2004-2016) catering to minorities. Metastatic CRC patients were classified as receiving chemotherapy or biochemotherapy (CT plus biologics; if initiated within 3 months of chemotherapy). The primary outcome was overall survival (OS) among the Hispanic patients calculated from time of administration of first dose of chemotherapy to death or last follow-up. A weighted Cox regression model was used to assess differences in survival. RESULTS: We identified 182 Hispanic patients with mCRC from the Patient Entitlement and Diagnosis Summary (PEDSF) file (n = 101) and hospital database (n = 81). Overall, 52% were women and 72% received biologics. The median OS was 11.3 and 17.0 months in chemotherapy and biochemotherapy group, respectively. Biochemotherapy offered a survival benefit compared with chemotherapy alone, with an average hazard rate reduction of 39% (95% CI 6%-60%, p = .0236) using inverse probability of treatment weighting (IPTW) based analysis. CONCLUSION: In this cohort of Hispanic patients with mCRC, biochemotherapy was associated with longer survival. Clinicians may offer biochemotherapy therapy to all patients regardless of race/ethnicity to maximize clinical benefit.

Progression of untreated gastric and pulmonary metastasis in a patient with resected acral melanoma.

We report a man in his 80s who presents with epigastric abdominal pain and fatigue for 2 weeks. His medical history was significant for left toe acral melanoma (excised 6 years prior) and a lung mass, further workup for which was declined at the time by the patient. On presentation, he had iron deficiency anaemia and esophagogastroduodenoscopy revealed a gastric mass. Histopathological analysis of gastric and subsequently, pulmonary, lesions were consistent with metastatic melanoma. This case demonstrates the unique slow progression of untreated pulmonary metastasis in metastatic melanoma.

HbF Levels in Sickle Cell Disease Are Associated with Proportion of Circulating Hematopoietic Stem and Progenitor Cells and CC-Chemokines.

The concentration of circulating hematopoietic stem and progenitor cells has not been studied longitudinally. Here, we report that the proportions of Lin-CD34+38- hematopoietic multipotent cells (HMCs) and of Lin-CD34+CD38+ hematopoietic progenitors cells (HPCs) are highly variable between individuals but stable over long periods of time, in both healthy individuals and sickle cell disease (SCD) patients. This suggests that these proportions are regulated by genetic polymorphisms or by epigenetic mechanisms. We also report that in SCD patients treated with hydroxyurea, the proportions of circulating HMCs and HPCs show a strong positive and negative correlation with fetal hemoglobin (HbF) levels, respectively. Titration of 65 cytokines revealed that the plasma concentration of chemokines CCL2, CCL11, CCL17, CCL24, CCL27, and PDGF-BB were highly correlated with the proportion of HMCs and HPCs and that a subset of these cytokines were also correlated with HbF levels. A linear model based on four of these chemokines could explain 80% of the variability in the proportion of circulating HMCs between individuals. The proportion of circulating HMCs and HPCs and the concentration of these chemokines might therefore become useful biomarkers for HbF response to HU in SCD patients. Such markers might become increasingly clinically relevant, as alternative treatment modalities for SCD are becoming available.

Characterization of Hematopoiesis in Sickle Cell Disease by Prospective Isolation of Stem and Progenitor Cells.

The consequences of sickle cell disease (SCD) include ongoing hematopoietic stress, hemolysis, vascular damage, and effect of chronic therapies, such as blood transfusions and hydroxyurea, on hematopoietic stem and progenitor cell (HSPC) have been poorly characterized. We have quantified the frequencies of nine HSPC populations by flow cytometry in the peripheral blood of pediatric and adult patients, stratified by treatment and control cohorts. We observed broad differences between SCD patients and healthy controls. SCD is associated with 10 to 20-fold increase in CD34dim cells, a two to five-fold increase in CD34bright cells, a depletion in Megakaryocyte-Erythroid Progenitors, and an increase in hematopoietic stem cells, when compared to controls. SCD is also associated with abnormal expression of CD235a as well as high levels CD49f antigen expression. These findings were present to varying degrees in all patients with SCD, including those on chronic therapy and those who were therapy naive. HU treatment appeared to normalize many of these parameters. Chronic stress erythropoiesis and inflammation incited by SCD and HU therapy have long been suspected of causing premature aging of the hematopoietic system, and potentially increasing the risk of hematological malignancies. An important finding of this study was that the observed concentration of CD34bright cells and of all the HSPCs decreased logarithmically with time of treatment with HU. This correlation was independent of age and specific to HU treatment. Although the number of circulating HSPCs is influenced by many parameters, our findings suggest that HU treatment may decrease premature aging and hematologic malignancy risk compared to the other therapeutic modalities in SCD.

Agranulocytosis from Outpatient Antimicrobial Treatment with Ceftriaxone: A Case Report.

INTRODUCTION: Agranulocytosis from antimicrobial therapy with ceftriaxone is rare. We report a case of agranulocytosis resulting from ceftriaxone noted more than 3 weeks into therapy. CASE PRESENTATION: A 72-year-old woman who was started on ceftriaxone for septic arthritis of the left knee 3 weeks before presentation was admitted to the hospital after being found to be neutropenic on outpatient laboratory analysis. Her absolute neutrophil count on admission was 0/µL. The cause of the agranulocytosis was suspected to be ceftriaxone. The drug was stopped, and she was started on granulocyte colony-stimulating factor with gradual resolution of the neutropenia. DISCUSSION: Serious adverse effects of ceftriaxone therapy, such as agranulocytosis, must be monitored for, especially in patients who are receiving prolonged therapy or high doses. Once this cause of agranulocytosis is identified, ceftriaxone therapy should be stopped; if the patient is febrile, an infectious disease workup should be performed and antibiotics should be started; and granulocyte colony-stimulating factor should be administered with daily monitoring of the absolute neutrophil count.

Negative allosteric modulation of the mGluR5 receptor reduces repetitive behaviors and rescues social deficits in mouse models of autism.

Neurodevelopmental disorders such as autism and fragile X syndrome were long thought to be medically untreatable, on the assumption that brain dysfunctions were immutably hardwired before diagnosis. Recent revelations that many cases of autism are caused by mutations in genes that control the ongoing formation and maturation of synapses have challenged this dogma. Antagonists of metabotropic glutamate receptor subtype 5 (mGluR5), which modulate excitatory neurotransmission, are in clinical trials for fragile X syndrome, a major genetic cause of intellectual disabilities. About 30% of patients with fragile X syndrome meet the diagnostic criteria for autism. Reasoning by analogy, we considered the mGluR5 receptor as a potential target for intervention in autism. We used BTBR T+tf/J (BTBR) mice, an established model with robust behavioral phenotypes relevant to the three diagnostic behavioral symptoms of autism--unusual social interactions, impaired communication, and repetitive behaviors--to probe the efficacy of a selective negative allosteric modulator of the mGluR5 receptor, GRN-529. GRN-529 reduced repetitive behaviors in three cohorts of BTBR mice at doses that did not induce sedation in control assays of open field locomotion. In addition, the same nonsedating doses reduced the spontaneous stereotyped jumping that characterizes a second inbred strain of mice, C58/J. Further, GRN-529 partially reversed the striking lack of sociability in BTBR mice on some parameters of social approach and reciprocal social interactions. These findings raise the possibility that a single targeted pharmacological intervention may alleviate multiple diagnostic behavioral symptoms of autism.

Sociability and motor functions in Shank1 mutant mice.

Autism is a neurodevelopmental disorder characterized by aberrant reciprocal social interactions, impaired communication, and repetitive behaviors. While the etiology remains unclear, strong evidence exists for a genetic component, and several synaptic genes have been implicated. SHANK genes encode a family of synaptic scaffolding proteins located postsynaptically on excitatory synapses. Mutations in SHANK genes have been detected in several autistic individuals. To understand the consequences of SHANK mutations relevant to the diagnostic and associated symptoms of autism, comprehensive behavioral phenotyping on a line of Shank1 mutant mice was conducted on multiple measures of social interactions, social olfaction, repetitive behaviors, anxiety-related behaviors, motor functions, and a series of control measures for physical abilities. Results from our comprehensive behavioral phenotyping battery indicated that adult Shank1 null mutant mice were similar to their wildtype and heterozygous littermates on standardized measures of general health, neurological reflexes and sensory skills. Motor functions were reduced in the null mutants on open field activity, rotarod, and wire hang, replicating and extending previous findings (Hung et al., 2008). A partial anxiety-like phenotype was detected in the null mutants in some components of the light ↔ dark task, as previously reported (Hung et al., 2008) but not in the elevated plus-maze. Juvenile reciprocal social interactions did not differ across genotypes. Interpretation of adult social approach was confounded by a lack of normal sociability in wildtype and heterozygous littermates. All genotypes were able to discriminate social odors on an olfactory habituation/dishabituation task. All genotypes displayed relatively high levels of repetitive self-grooming. Our findings support the interpretation that Shank1 null mice do not demonstrate autism-relevant social interaction deficits, but confirm and extend a role for Shank1 in motor functions.

Repetitive self-grooming behavior in the BTBR mouse model of autism is blocked by the mGluR5 antagonist MPEP.

Autism is a neurodevelopmental disorder characterized by abnormal reciprocal social interactions, communication deficits, and repetitive behaviors with restricted interests. BTBR T+tf/J (BTBR) is an inbred mouse strain that shows robust behavioral phenotypes with analogies to all three of the diagnostic symptoms of autism, including well-replicated deficits in reciprocal social interactions and social approach, unusual patterns of ultrasonic vocalization, and high levels of repetitive self-grooming. These phenotypes offer straightforward behavioral assays for translational investigations of pharmacological compounds. Two suggested treatments for autism were evaluated in the BTBR mouse model. Methyl-6-phenylethynyl-pyridine (MPEP), an antagonist of the mGluR5 metabotropic glutamate receptor, blocks aberrant phenotypes in the Fmr1 mouse model of Fragile X, a comorbid neurodevelopmental disorder with autistic features. Risperidone has been approved by the United States Food and Drug Administration for the treatment of irritability, tantrums, and self-injurious behavior in autistic individuals. We evaluated the actions of MPEP and risperidone on two BTBR phenotypes, low sociability and high repetitive self-grooming. Open field activity served as an independent control for non-social exploratory activity and motor functions. C57BL/6J (B6), an inbred strain with high sociability and low self-grooming, served as the strain control. MPEP significantly reduced repetitive self-grooming in BTBR, at doses that had no sedating effects on open field activity. Risperidone reduced repetitive self-grooming in BTBR, but only at doses that induced sedation in both strains. No overall improvements in sociability were detected in BTBR after treatment with either MPEP or risperidone. Our findings suggest that antagonists of mGluR5 receptors may have selective therapeutic efficacy in treating repetitive behaviors in autism.