Late Responses in Patients With Chronic Myeloid Leukemia Initially Refractory to Tyrosine Kinase Inhibitors.

BACKGROUND: The introduction of tyrosine kinase inhibitor (TKI) therapy has dramatically improved outcomes for patients with chronic myeloid leukemia (CML); however, the prognosis for those who do not meet treatment milestones remains guarded. Here, we report our experience of patients with CML treated at a single center who did not achieve a complete cytogenetic response (CCyR) at 24 months. METHODS: We retrospectively evaluated 305 patients who were diagnosed with CML at the University of Michigan between 2001 and 2014 and were treated with TKIs. We assessed rates of CCyR at 24 months correlated to clinical outcomes. RESULTS: The majority of patients (79%) achieved CCyR at 24 months and were classified as responders. At a median follow-up of 8.1 years from TKI initiation, overall survival among responders was significantly greater than nonresponders (93% vs. 85%, P < .001). Progression to blast phase was more common in nonresponders (1.9% vs. 10.4%, P = .004). However, 34% of nonresponders (at 24 months) went on to achieve CCyR with continued TKI therapy. CONCLUSION: Here, we re-demonstrate the importance of early CCyR in predicting survival and prevention of progression to blast phase. In addition, late CCyR appears to have prognostic implications, and continued TKI therapy with the goal of achieving a later CCyR may be a reasonable strategy in patients with limited alternate treatment options.

A provider's guide to primary myelofibrosis: pathophysiology, diagnosis, and management.

Although understanding of the pathogenesis and molecular biology of primary myelofibrosis continues to improve, treatment options are limited, and several biological features remain unexplained. With an appropriate clinical history, exam, laboratory evaluation, and bone marrow biopsy, the diagnosis can often be established. Recent studies have better characterized prognostic factors and driver mutations in myelofibrosis, facilitated by use of next-generation sequencing. These advances have facilitated development of a management strategy that is based on both risk factors and clinical phenotype. For low-risk patients, treatment will depend on symptom severity. For patients with higher-risk disease, several treatments are available including JAK inhibitors, allogeneic hematopoietic stem cell transplant, and clinical trials using novel molecularly targeted therapies and rational drug combinations. In this review, we outline what is known about the disease pathogenesis, discuss an approach to reaching the diagnosis, review the prognosis of myelofibrosis, and detail current therapeutic strategies.

Evaluating Acalabrutinib In The Treatment Of Mantle Cell Lymphoma: Design, Development, And Place In Therapy.

Mantle cell lymphoma (MCL) is an incurable intermediate-grade lymphoma representing 5-6% of non-Hodgkin's lymphomas diagnosed in the United States. The introduction of inhibitors of Bruton's tyrosine kinase (BTK) into targeted therapy for MCL has significantly improved outcomes in patients with relapsed/refractory (R/R) disease. Since the initial approval of the first-generation inhibitor, ibrutinib, several second-generation inhibitors have been explored. Acalabrutinib, a second-generation BTK inhibitor, has demonstrated impressive efficacy in clinical trials along with a safety profile that thus far appears improved compared to ibrutinib. The results of a Phase II trial in patients with R/R MCL led to the approval of acalabrutinib in this patient population while fueling further exploration of acalabrutinib in several ongoing clinical trials.

Predictive models for splenic response to JAK-inhibitor therapy in patients with myelofibrosis.

JAK inhibitors for myelofibrosis (MF) reduce spleen size, control constitutional symptoms, and may improve survival. We studied the clinical characteristics of 548 MF patients treated with JAK inhibitors from 2008 to 2016 to better understand predictors of splenic response. Response was defined as a 50% decrease in spleen size at early (3-4 months on therapy) and late (5-12 months) timepoints after therapy initiation. Early response positively correlated with higher doses of JAK inhibitor, baseline spleen size 5-10 cm, and hemoglobin. Early response negatively correlated with baseline spleen size >20 cm and high WBC. The strongest predictor of late response was whether a patient had a response at the earlier timepoint (OR 8.88). Our response models suggest that clinical factors can be used to predict which patients are more likely to respond to JAK inhibitors, and those who do not achieve an early response, i.e. within 3-4 months, should consider alternative treatments.

Major publications in the critical care pharmacotherapy literature: January-December 2017.

PURPOSE: To summarize selected meta-analyses and trials related to critical care pharmacotherapy published in 2017. The Critical Care Pharmacotherapy Literature Update (CCPLU) Group screened 32 journals monthly for impactful articles and reviewed 115 during 2017. Two meta-analyses and eight original research trials were reviewed here from those included in the monthly CCPLU. Meta-analyses on early, goal-directed therapy for septic shock and statin therapy for acute respiratory distress syndrome were summarized. Original research trials that were included evaluate thrombolytic therapy in severe stroke, hyperoxia and hypertonic saline in septic shock, intraoperative ketamine for prevention of post-operative delirium, intravenous ketorolac dosing regimens for acute pain, angiotensin II for vasodilatory shock, dabigatran reversal with idarucizumab, bivalirudin versus heparin monotherapy for myocardial infarction, and balanced crystalloids versus saline fluid resuscitation. CONCLUSION: This clinical review provides perspectives on impactful critical care pharmacotherapy publications in 2017.

Surveillance Scans in Lymphoma: Friend or Foe?

OPINION STATEMENT: Advancements in the treatment of lymphoma over the last few decades have allowed more patients to achieve a remission after the completion of therapy. Due to the improvement in response rates, methods to detect recurrence early and accurately during follow-up, especially in patients with potential curable aggressive lymphomas, are a key. Observation has always involved close clinical follow-up with the use of physical exams and routine labs, but rapid changes in technology have allowed CT scans, PET scans, and MRIs to become an integral part of managing patients with lymphoma. While the utility of scans in initial staging and immediately after completion of therapy is well established, the use of these imaging modalities for monitoring recurrence in lymphoma patients is still controversial. Patient advocacy groups and other regulatory committees have questioned the frequency and in some cases even the need for these tests in patients without evidence of active disease given the concern for radiation-associated health risks. Additionally, the extent to which this form of testing impacts the psyche of our patients is not completely known. Given the numerous questions raised about the benefits, safety, and cost-effectiveness of CT imaging, firm guidelines are needed at this time in standard practice and within our clinical trials to limit the use of surveillance imaging. Such efforts are expected to improve the utility of these scans in asymptomatic patients, reduce healthcare costs, and reduce patient exposure to radiation.

Induction of p53 suppresses chronic myeloid leukemia.

Chronic myeloid leukemia (CML) is characterized by the chromosomal translocation 9;22, known as the Philadelphia chromosome (Ph), which produces the BCR-ABL fusion tyrosine kinase. Although well-managed by BCR-ABL tyrosine kinase inhibitors (TKIs), treatment fails to eliminate Ph + primitive progenitors, and cessation of therapy frequently results in relapse. The p53 protein is an important regulator of cell cycle and apoptosis. The small molecules MI-219 target the interaction between p53 and its negative regulator HDM2, leading to its stabilization and activation. We show that treatment with MI-219 reduced the number of CML cells in both in vitro and in vivo settings but not that of normal primitive progenitors, and activated different gene signatures in CML potentially explaining the differential impact of this agent on each population. Our data suggest that a p53-activating agent may be an effective approach in the management and potential operational cure of CML.

Major publications in the critical care pharmacotherapy literature in 2015.

PURPOSE: Recently published practice guidelines and research reports on pharmacotherapy in critical care patient populations are summarized. SUMMARY: The Critical Care Pharmacotherapy Literature Update (CCPLU) Group is composed of over 50 experienced critical care pharmacists who evaluate 31 peer-reviewed journals monthly to identify literature pertaining to pharmacotherapy in critical care populations. Articles are chosen for summarization in a monthly CCPLU Group publication on the basis of applicability and relevance to clinical practice and strength of study design. From January to December 2015, a total of 121 articles were summarized; of these, 3 articles presenting clinical practice guidelines and 12 articles presenting original research findings were objectively selected for inclusion in this review based on their potential to change or reinforce current evidence-based practice. The reviewed guidelines address the management of intracranial hemorrhage (ICH), adult advanced cardiac life support (ACLS) and post-cardiac arrest care, and the management of supraventricular tachycardia (SVT). The reviewed research reports address topics such as nutrition in critically ill adults, administration of ß-lactams for severe sepsis, anticoagulant selection in the context of continuous renal replacement therapy, early goal-directed therapy in septic shock, magnesium use for neuroprotection in acute stroke, and progesterone use in patients with traumatic brain injury. CONCLUSION: Important recent additions to the critical care pharmacy literature include updated joint clinical practice guidelines on the management of spontaneous ICH, ACLS, and SVT.

Successful management of angiolymphoid hyperplasia with eosinophilia in a split-face trial of topical tacrolimus and timolol solution.

Angiolymphoid hyperplasia with eosinophilia (ALHE) is an uncommon, benign condition characterized by multiple benign angiomatous nodules or plaques. Cutaneous lesions can be painful, pruritic, pulsatile, or potentially disfiguring resulting in significant morbidity. ALHE is a pathologic diagnosis featuring proliferations of capillary-sized vessels with epithelioid endothelial cells surrounded by larger, thick-walled vessels and accompanying eosinophils and lymphocytes. Surgery is generally required, however the skin lesions often recur after excision. ALHE is notoriously difficult to treat and many physicians would prefer a non-invasive treatment of choice. We report a case of ALHE that was successfully treated with the novel use of topical tacrolimus in a split-face trial with topical timolol solution.

The interferon-alpha revival in CML.

Interferon-alpha (IFNα) was once the standard of frontline treatment for chronic myeloid leukemia (CML). Its pleiotropic mechanism of action in CML includes immune activation and specific targeting of CML stem cells. Early studies of IFNα in CML demonstrated that patients in chronic phase could attain extremely stable remissions, which correlated with long-term survival. Some patients even sustained their remission after discontinuing therapy, but the mechanism underlying this phenomenon is not well understood. Today, BCR-ABL tyrosine kinase inhibitors (TKIs), such as imatinib, induce remarkable responses in CML patients and have become the mainstay of CML therapy. Although TKIs target the pathogenic BCR-ABL protein in CML, they cannot fully eradicate CML stem cells. Some of the clinical trials testing IFNα plus imatinib combination therapy suggest that addition of IFNα increases the speed and rate of responses with imatinib therapy. However, the undesirable side effects of IFNα can make this therapy difficult to deliver, and the optimal therapeutic window for using IFNα in combination therapy is unknown. Further studies are needed to clarify the best niche for IFNα use in CML.

Nation-building policies in Timor-Leste: disaster risk reduction, including climate change adaptation.

Few studies have explored the relationships between nation-building, disaster risk reduction and climate change adaptation. Focusing on small island developing states, this paper examines nation-building in Timor-Leste, a small island developing state that recently achieved independence. Nation-building in Timor-Leste is explored in the context of disaster risk reduction, which necessarily includes climate change adaptation. The study presents a synopsis of Timor-Leste's history and its nation-building efforts as well as an overview of the state of knowledge of disaster risk reduction including climate change adaptation. It also offers an analysis of significant gaps and challenges in terms of vertical and horizontal governance, large donor presence, data availability and the integration of disaster risk reduction and climate change adaptation for nation-building in Timor-Leste. Relevant and applicable lessons are provided from other small island developing states to assist Timor-Leste in identifying its own trajectory out of underdevelopment while it builds on existing strengths.

Major publications in the critical care pharmacotherapy literature: February 2012 through February 2013.

PURPOSE: Recent impactful additions to the professional literature on the role of pharmacotherapy in treating the critically ill are summarized. SUMMARY: An unusually large number of updated practice guidelines and other publications with broad critical care pharmacotherapy ramifications appeared in the primary biomedical literature during the designated review period (February 2012-February 2013). Hundreds of relevant articles were evaluated by the Critical Care Pharmacotherapy Literature Update group (CCPLU), a national group of pharmacists who routinely monitor 25 peer-reviewed journals for emerging evidence that pertains to rational medication use in the intensive care unit (ICU) setting. From among those articles, 64 were summarized for dissemination to CCPLU members; the 8 publications deemed to have the greatest utility for critical care practitioners, as determined by CCPLU through a voting process, were selected for inclusion in this review, with preference given to evidence meeting high standards of methodological quality. The summaries presented here include (1) important new recommendations on management of pain, agitation, and delirium in critically ill patients, (2) a comprehensive update of a practice guideline issued in 2008 by the Surviving Sepsis Campaign, (3) novel strategies for the prevention and/or treatment of hyperglycemia in critical care, and (4) reports on clinical trials of promising alternative methods of sedation for use in weaning patients from mechanical ventilation. CONCLUSION: This review provides synopses of practice guidelines and other recent additions to the professional literature pertaining to rational medication use in the ICU practice setting.

Acute care clinical pharmacy practice: unit- versus service-based models.

This commentary from the 2010 Task Force on Acute Care Practice Model of the American College of Clinical Pharmacy was developed to compare and contrast the "unit-based" and "service-based" orientation of the clinical pharmacist within an acute care pharmacy practice model and to offer an informed opinion concerning which should be preferred. The clinical pharmacy practice model must facilitate patient-centered care and therefore must position the pharmacist to be an active member of the interprofessional team focused on providing high-quality pharmaceutical care to the patient. Although both models may have advantages and disadvantages, the most important distinction pertains to the patient care role of the clinical pharmacist. The unit-based pharmacist is often in a position of reacting to an established order or decision and frequently is focused on task-oriented clinical services. By definition, the service-based clinical pharmacist functions as a member of the interprofessional team. As a team member, the pharmacist proactively contributes to the decision-making process and the development of patient-centered care plans. The service-based orientation of the pharmacist is consistent with both the practice vision embraced by ACCP and its definition of clinical pharmacy. The task force strongly recommends that institutions pursue a service-based pharmacy practice model to optimally deploy their clinical pharmacists. Those who elect to adopt this recommendation will face challenges in overcoming several resource, technologic, regulatory, and accreditation barriers. However, such challenges must be confronted if clinical pharmacists are to contribute fully to achieving optimal patient outcomes.

Acrodynia and hypertension in a young girl secondary to elemental mercury toxicity acquired in the home.

Acrodynia, also known as pink disease, erythredema polyneuropathy, Feer syndrome, and raw-beef hands and feet, is thought to be a toxic reaction to elemental mercury and less commonly to organic and inorganic forms. Occurring commonly in the early 20th century, acrodynia is now a seemingly extinct disease in the modern world because of regulations to eliminate mercury from personal care products, household items, medications, and vaccinations. We present a case of a 3-year-old girl with acrodynia secondary to toxic exposure to elemental mercury in the home environment.

CCAAT/enhancer binding protein ß expression is increased in the brain during HIV-1-infection and contributes to regulation of astrocyte tissue inhibitor of metalloproteinase-1.

Human immunodeficiency virus (HIV)-1-associated neurocognitive disorders (HAND) associated with infection and activation of mononuclear phagocytes (MP) in the brain, occur late in disease. Infected/activated MP initiate neuroinflammation activating glial cells and ultimately disrupting neuronal function. Astrocytes secrete tissue inhibitor of metalloproteinase (TIMP)-1 in response to neural injury. Altered TIMP-1 levels are implicated in several CNS diseases. CCAAT enhancer-binding protein ß (C/EBPß), a transcription factor, is expressed in rodent brains in response to neuroinflammation, implicating it in Alzheimer's, Parkinson's, and HAND. Here, we report that C/EBPß mRNA levels are elevated and its isoforms differentially expressed in total brain tissue lysates of HIV-1-infected and HIV-1 encephalitis patients. In vitro, HAND-relevant stimuli additively induce C/EBPß nuclear expression in human astrocytes through 7 days of treatment. Over-expression of C/EBPß increases TIMP-1 promoter activity, mRNA, and protein levels in human astrocytes activated with interleukin-1ß. Knockdown of C/EBPß with siRNA decreases TIMP-1 mRNA and protein levels. These data suggest that C/EBPß isoforms are involved in complex regulation of astrocyte TIMP-1 production during HIV-1 infection; however, further studies are required to completely understand their role during disease progression.

Aminoglycoside pharmacokinetic parameters in neurocritical care patients undergoing induced hypothermia.

STUDY OBJECTIVE: To determine the effects of mild-to-moderate induced hypothermia-a neuroprotectant and/or therapeutic strategy for the management of intracranial hypertension in neurologically injured patients-on the pharmacokinetics of aminoglycoside therapy. DESIGN: Pharmacokinetic analysis. SETTING: Critical care unit at a university-affiliated hospital. PATIENTS: Three patients, aged 22, 24, and 47 years, who received tobramycin and had documented tobramycin levels while undergoing induced hypothermia for more than 24 hours for intracranial hypertension. MEASUREMENTS AND MAIN RESULTS: For each of the three patients, predicted pharmacokinetic parameters (volume of distribution, first-order elimination rate constant, half-life, and renal drug clearance) based on population data were compared with their actual pharmacokinetic parameters that were calculated based on observed tobramycin serum levels. All three patients had a normal creatinine clearance, estimated according to established methods. When pharmacokinetic parameters were calculated after the first tobramycin dose using a one-compartment method, all patients had a slower first-order elimination rate and a larger volume of distribution compared with predicted population estimates. CONCLUSION: These findings suggest that induced hypothermia may result in impaired elimination of aminoglycosides. Caution should be exercised when attempting to use predicted pharmacokinetic parameters to dose aminoglycosides in this patient population, and first-dose pharmacokinetics should be considered to optimize the dose and dosing interval early in the course of therapy. Further investigation of this phenomenon with greater numbers of patients are needed to confirm these findings and to determine optimal dosing strategies of aminoglycosides in patients undergoing induced hypothermia.

Framework for integrating indigenous and scientific knowledge for disaster risk reduction.

A growing awareness of the value of indigenous knowledge has prompted calls for its use within disaster risk reduction. The use of indigenous knowledge alongside scientific knowledge is increasingly advocated but there is as yet no clearly developed framework demonstrating how the two may be integrated to reduce community vulnerability to environmental hazards. This paper presents such a framework, using a participatory approach in which relevant indigenous and scientific knowledge may be integrated to reduce a community's vulnerability to environmental hazards. Focusing on small island developing states it presents an analysis of the need for such a framework alongside the difficulties of incorporating indigenous knowledge. This is followed by an explanation of the various processes within the framework, drawing on research completed in Papua New Guinea. This framework is an important first step in identifying how indigenous and scientific knowledge may be integrated to reduce community vulnerability to environmental hazards.

Dynamic O-GlcNAc modification of nucleocytoplasmic proteins in response to stress. A survival response of mammalian cells.

Cellular response to environmental, physiological, or chemical stress is key to survival following injury or disease. Here we describe a unique signaling mechanism by which cells detect and respond to stress in order to survive. A wide variety of stress stimuli rapidly increase nucleocytoplasmic protein modification by O-linked beta-N-acetylglucosamine (O-GlcNAc), an essential post-translational modification of Ser and Thr residues of metazoans. Blocking this post-translational modification, or reducing it, renders cells more sensitive to stress and results in decreased cell survival; and increasing O-GlcNAc levels protects cells. O-GlcNAc regulates both the rates and extent of the stress-induced induction of heat shock proteins, providing a molecular basis for these findings.