Interpreting outcome data in hematopoietic cell transplantation for leukemia: tackling common biases.

Although patient outcomes after allogeneic hematopoietic cell transplantation (allo-HCT) have significantly improved in recent years, complications and associated mortality remain substantial. Although many transplants are performed worldwide, the number of patients enrolled prospectively into clinical trials is small. Patient and physician preferences often override treatment assignments in randomized transplant trials, biasing the common intention-to-treat analyses. Large retrospective and observational database studies are likely to detect the real effect of allo-HCT. However, they may be subject to immortal time and other biases derived from heterogeneity of allo-HCT indications and approaches and differences in referral or institutional policies affecting patient selection. Timing of the transplant procedure may be fundamental but studies commencing at start of transplant may neglect the influence of pretransplant therapies. Conversely, a prolonged lag period between the decision and execution of transplant may artificially 'improve' the outcome by 'natural' selection weeding out patients relapsing or dying before transplant. Finally, comparative nonrandomized transplantation trials often suffer from unbalanced assignment for therapy arms. We herein present common clinical dilemmas discussing proper application of available evidence in daily clinical practice. Pitfalls and caveats frequent in clinical studies of allo-SCT are highlighted to promote a balanced interpretation of available data.

The place of corticosteroids in migraine attack management: A 65-year systematic review with pooled analysis and critical appraisal.

BACKGROUND AND OBJECTIVES: Headaches recur in up to 87% of migraine patients visiting the emergency department (ED), making ED recidivism a management challenge. We aimed herein to determine the role of corticosteroids in the acute management of migraine in the ED and outpatient care. METHODS: Advanced search strategies employing PubMed/MEDLINE, Web of Science, and Cochrane Library databases inclusive of a relevant gray literature search was employed for Clinical Studies and Systematic Reviews by combining the terms "migraine" and "corticosteroids" spanning all previous years since the production of synthetic corticosteroids ca. 1950 until August 30, 2014. Methods were in accordance with MOOSE guidelines. RESULTS: Twenty-five studies (n = 3989, median age 37.5 years, interquartile range or IQR 35-41 years; median male:female ratio 1:4.23, IQR 1:2.1-6.14; 52% ED-based, 56% randomized-controlled) and four systematic reviews were included. International Classification of Headache Disorders criteria were applied in 64%. Nineteen studies (76%) indicated observed outcome differences favoring benefits of corticosteroids, while six (24%) studies indicated non-inferior outcomes for corticosteroids. Median absolute risk reduction was 30% (range 6%-48.2%), and 11% (6%-48.6%) for 24-, and 72-hour headache recurrence, respectively. Parenteral dexamethasone was the most commonly (56%) administered steroid, at a median single dose of 10 mg (range 4-24 mg). All meta-analyses revealed efficacy of adjuvant corticosteroids to various abortive medications-indicating generalizability. Adverse effects were tolerable. Higher disability, status migrainosus, incomplete pain relief, and previous history of headache recurrence predicted outcome favorability. CONCLUSIONS: Our literature review suggests that with corticosteroid treatment, recurrent headaches become milder than pretreated headaches and later respond to nonsteroidal therapy. Single-dose intravenous dexamethasone is a reasonable option for managing resistant, severe, or prolonged migraine attacks.

What is the evidence for the use of corticosteroids in migraine?

Corticosteroids are widely prescribed for the management of migraine attacks. The earliest clinical studies examining the efficacy of corticosteroid monotherapy for managing migraine attacks date back to 1952. Since then, 26 heterogeneous clinical studies and four meta-analyses have been conducted to assess the efficacy of corticosteroids in either aborting acute migraine attacks, prolonged migraine attacks or recurrent headaches. Most of these (86 %) studies employed different comparator arms with corticosteroids monotherapy administration while some studies (14 %) evaluated adjunctive corticosteroid therapy. The majority of these clinical studies revealed the superior efficacy of corticosteroids as mono- or adjunctive-therapy both for recurrent and acute migraine attacks, while the remaining showed non-inferior efficacy. Different forms of oral and parenteral corticosteroids in either single-dose or short-tapering schedules are prescribed; there are clinical studies supporting the efficacy of both methods. Corticosteroids can be administered safely up to six times annually. Corticosteroids are also useful in managing patients who frequent emergency departments with "medication-seeking behavior." Migraine patients with refractory headaches, history of recurrent headaches, severe baseline disability, and status migrainosus were found to have the most beneficial response from corticosteroid therapy.

Targeting abnormal DNA double-strand break repair in tyrosine kinase inhibitor-resistant chronic myeloid leukemias.

Resistance to imatinib (IM) and other tyrosine kinase inhibitors (TKI)s is an increasing problem in leukemias caused by expression of BCR-ABL1. As chronic myeloid leukemia (CML) cell lines expressing BCR-ABL1 utilize an alternative non-homologous end-joining pathway (ALT NHEJ) to repair DNA double-strand breaks (DSB)s, we asked whether this repair pathway is a novel therapeutic target in TKI-resistant disease. Notably, the steady state levels of two ALT NHEJ proteins, poly-(ADP-ribose) polymerase 1 (PARP1) and DNA ligase IIIα, were increased in the BCR-ABL1-positive CML cell line K562 and, to a greater extent, in its imatinib-resistant (IMR) derivative. Incubation of these cell lines with a combination of DNA ligase and PARP inhibitors inhibited ALT NHEJ and selectively decreased survival with the effect being greater in the IMR derivative. Similar results were obtained with TKI-resistant derivatives of two hematopoietic cell lines that had been engineered to stably express BCR-ABL1. Together our results show that the sensitivity of cell lines expressing BCR-ABL1 to the combination of DNA ligase and PARP inhibitors correlates with the steady state levels of PARP1 and DNA ligase IIIα, and ALT NHEJ activity. Importantly, analysis of clinical samples from CML patients confirmed that the expression levels of PARP1 and DNA ligase IIIα correlated with the sensitivity to the DNA repair inhibitor combination. Thus, the expression levels of PARP1 and DNA ligase IIIα serve as biomarkers to identify a subgroup of CML patients who may be candidates for therapies that target the ALT NHEJ pathway when treatment with TKIs has failed.

New frontiers in headache therapy.

There are numerous headache therapies available for our patients, more for migraine than for any of the other primary headache disorders. Only four medications have been approved for migraine prevention in the last few decades in the US and onabotulinumtoxinA was recently approved in the UK and the US for chronic migraine. We have been more fortunate in the acute care arena where in the US we have had seven triptans and one nonsteroidal anti-inflammatory medication approved by the FDA and currently available. There are several other acute care medications in various stages of development and there are two new methods of administering a triptan and others under investigation. We are always looking for faster, easier and more efficient administration of medications with fewer adverse events, as optimal migraine therapy requires these characteristics. What follows is a brief review of the progress in development for four of the many new acute care medications being investigated: the CGRP antagonist tablet telcagepant, the sumatriptan iontophoretic patch, sumatriptan powder for use in the OptiNose apparatus and the dihydroergotamine oral inhaler. I will not include transcranial magnetic stimulation, a 5-HT(1F) agonist, large conductance calcium-activated potassium channel openers, glial modulators or other medications and devices in early stages of development [1].

Granulomatous amebic encephalitis: an under-recognized cause of infectious mortality after hematopoietic stem cell transplantation.

Granulomatous amebic encephalitis (GAE) is a rare, nearly always fatal form of encephalitis that occurs mostly in the setting of immune compromise or chronic disease. The prevalence and clinical characteristics of this Acanthamoeba infection in hematopoietic stem cell transplant (HSCT) recipients are not well described. We present an HSCT patient in whom the diagnosis of GAE was made at autopsy. A systematic review of previously reported cases is provided to highlight the clinical presentation and early diagnostic features of GAE in HSCT recipients. Amebic infection usually initially involves the skin or lungs over a period of months, and becomes rapidly fatal once it crosses the blood-brain barrier. GAE is usually discovered postmortem owing to lack of awareness of this deadly infection and delay in diagnosis. Subacute presentation of multiple recurrent panniculitis-like subcutaneous nodules associated with eosinophilia and a history of chronic rhinitis or sinusitis warrant investigation for a possible amebic infection. Prolonged corticosteroid use and a recent exposure to unhygienic water are potential risk factors for GAE. Successful outcomes may be achieved with early intensive treatment using a combination of effective drugs.

PBK/TOPK interacts with the DBD domain of tumor suppressor p53 and modulates expression of transcriptional targets including p21.

PBK/TOPK (PDZ-binding kinase, T-LAK-cell-originated protein kinase) is a serine-threonine kinase that is overexpressed in a variety of tumor cells but its role in oncogenesis remains unclear. Here we show, by co-immunoprecipitation experiments and yeast two-hybrid analysis, that PBK/TOPK physically interacts with the tumor suppressor p53 through its DNA-binding (DBD) domain in HCT116 colorectal carcinoma cells that express wild-type p53. PBK also binds to p53 mutants carrying five common point mutations in the DBD domain. The PBK-p53 interaction appears to downmodulate p53 transactivation function as indicated by PBK/TOPK knockdown experiments, which show upregulated expression of the key p53 target gene and cyclin-dependent kinase inhibitor p21 in HCT116 cells, particularly after genotoxic damage from doxorubicin. Furthermore, stable PBK/TOPK knockdown cell lines (derived from HCT116 and MCF-7 cells) showed increased apoptosis, G(2)/M arrest and slower growth as compared to stable empty vector-transfected control cell lines. Gene microarray studies identified additional p53 target genes involved in apoptosis or cell cycling, which were differentially regulated by PBK knockdown. Together, these data suggest that increased levels of PBK/TOPK may contribute to tumor cell development and progression through suppression of p53 function and consequent reductions in the cell-cycle regulatory proteins such as p21. PBK/TOPK may therefore be a valid target for antineoplastic kinase inhibitors to sensitize tumor cells to chemotherapy-induced apoptosis and growth suppression.

Anhydrobiosis in yeast: stabilization by exogenous lactose.

We have found that incubation in lactose solutions (0.75 M) of yeast culture Saccharomyces cerevisiae sensitive to dehydration damage increased the stability of the cells during dehydration. Simultaneously with this increase in viability, a decrease in plasma membrane permeability during rehydration was seen. Using Fourier transform infrared spectroscopy to measure lipid phase transitions, we observed that the lactose treatment depressed the membrane phospholipid phase transition temperature in a sensitive culture of dry yeast. As a result, it leads to the decrease in the damages of molecular organization of membranes during rehydration of dry yeast cells, thus reducing leakage from the cells.

Antimigraine drugs: new frontiers.

There are many acute care and preventive medications for the treatment of migraine. However, patients may often find that their headaches are not under optimal control. There are several targets that have been looked at and studied for the production of new, more effective medications. There are also effective devices for therapy of migraine. A list of targets will be put forth and a small number of them will be described in greater detail in this paper.

Chronic migraine and medication overuse headache: clarifying the current International Headache Society classification criteria.

Despite the recent advances in the understanding and classification of the chronic daily headaches, considerable controversy still exists regarding the classification of individual headaches, including chronic migraine (CM) and medication overuse headache (MOH). The original criteria, published in 2004, were difficult to apply to most patients with these disorders and were subsequently revised, resulting in broader clinical applicability. Nonetheless, they remain a topic of debate, and the revisions to the criteria have further added to the confusion. Even some prominent headache specialists are unsure which criteria to use. We aimed to explain the nature of the controversies surrounding the entities of CM and MOH. A clinical case will be used to illustrate some of the problems faced by clinicians in diagnosing patients with chronic daily headache.

New daily persistent headache in the paediatric population.

We conducted a clinic-based study focusing on the clinical features of new-onset chronic daily headaches (CDH) in children and adolescents. The clinical records and headache diaries of 306 children and adolescents were reviewed, to identify 187 with CDH. Relevant information was transferred to a standardized form that included operational criteria for the diagnoses of the headaches. Since we were interested in describing the clinical features of these headaches, we followed the criteria A and B of the 2nd edn of the International Classification of Headache Disorders (ICHD-2) and refer to them as new daily persistent headaches (NDPH) regardless of the presence of migraine features (therefore, this is a modified version of the ICHD-2 criteria). From the 56 adolescents with NDPH, most (91.8%) did not overuse medications. Nearly half (48.1%) reported they could recall the month when their headaches started. NDPH was more common than chronic tension-type headache in both adolescents overusing and not overusing medication. Individuals with NDPH had headaches fulfilling criteria for migraine on an average of 18.5 days per month. On most days, they had migraine-associated symptoms (one of nausea, photophobia or phonophobia)). NDPH is common in children and adolescents with CDH. Most subjects do not overuse medication. Migraine features are common.

Treatment of status epilepticus and acute repetitive seizures with i.v. valproic acid vs phenytoin.

OBJECTIVE: To evaluate the efficacy and tolerability of the treatment with valproic acid (VPA) in patients with status epilepticus (SE) or acute repetitive seizures (ARS) comparing it with phenytoin (PHT) treatment. MATERIALS AND METHODS: Patients with SE or ARS were treated in a consecutive manner with either VPA or PHT intravenously. The primary endpoint was defined as clinical seizure cessation; the secondary endpoint was evaluation of drug tolerability. RESULTS: Seventy-four adult patients with SE or ARS participated in the study, 49 with VPA i.v. and 25 PHT i.v. In 43 (87.8%) of the VPA patients, the seizures discontinued, and no rescue medication was needed. Similar results were found in the PHT group in which seizures of 22 (88%) patients were well controlled. Side effects were found in 12% of the PHT group, and in none of the VPA group. CONCLUSIONS: VPA i.v. seems to be effective and well tolerated in adult patients with SE or ARS.

Chaotic scattering by steep repelling potentials.

Consider a classical two-dimensional scattering problem: a ray is scattered by a potential composed of several tall, repelling, steep mountains of arbitrary shape. We study when the traditional approximation of this nonlinear far-from-integrable problem by the corresponding simpler billiard problem, of scattering by hard-wall obstacles of similar shape, is justified. For one class of chaotic scatterers, named here regular Sinai scatterers, the scattering properties of the smooth system indeed limit to those of the billiards. For another class, the singular Sinai scatterers, these two scattering problems have essential differences: though the invariant set of such singular scatterers is hyperbolic (possibly with singularities), that of the smooth flow may have stable periodic orbits, even when the potential is arbitrarily steep. It follows that the fractal dimension of the scattering function of the smooth flow may be significantly altered by changing the ratio between the steepness parameter and a parameter which measures the billiards' deviation from a singular scatterer. Thus, even in this singular case, the billiard scattering problem is utilized as a skeleton for studying the properties of the smooth flow. Finally, we see that corners have nontrivial and significant impact on the scattering functions.

Randomized controlled trial of an oral CGRP receptor antagonist, MK-0974, in acute treatment of migraine.

OBJECTIVE: To determine an effective and tolerable dose of a novel oral calcitonin gene-related peptide (CGRP) receptor antagonist, MK-0974, for the acute treatment of migraine. METHODS: Randomized, double-blind, parallel-group, clinical trial with a two-stage, adaptive, dose-ranging design. Patients were allocated to treat a moderate or severe migraine attack with MK-0974 (25, 50, 100, 200, 300, 400, or 600 mg), rizatriptan 10 mg, or placebo taken orally. The primary endpoint was pain relief (reduction to mild or none) 2 hours after dosing. Secondary endpoints included pain freedom at 2 hours and sustained pain relief at 24 hours. A prespecified, blinded, automated interim analysis was used to discontinue randomization to less effective doses. RESULTS: Per the adaptive study design, the four lowest MK-0974 groups (25, 50, 100, 200 mg) were discontinued due to insufficient efficacy. For the remaining treatment groups, the estimated pain relief proportions at 2 hours were 300 mg (n = 38) 68.1%, 400 mg (n = 45) 48.2%, 600 mg (n = 40) 67.5%, rizatriptan 10 mg (n = 34) 69.5%, and placebo (n = 115) 46.3%. The prespecified primary efficacy hypothesis test, which compared the average 2-hour pain relief response proportion of the combined 300, 400, and 600 mg MK-0974 groups to placebo, was significant (P = 0.015). A generally similar efficacy pattern was seen for other endpoints. MK-0974 was generally well tolerated and there did not appear to be an increase in adverse events with increasing dose. CONCLUSIONS: The novel, orally administered calcitonin gene-related peptide (CGRP) receptor antagonist, MK-0974, was effective and generally well tolerated for the acute treatment of migraine.