Alternating R‐CHOP and R‐cytarabine is a safe and effective regimen for transplant‐ineligible patients with a newly diagnosed mantle cell lymphoma

Implementation of cytarabine into induction therapy became standard of care for younger patients with mantle cell lymphoma (MCL). On the basis of its beneficial impact, many centers incorporated cytarabine at lower doses also into first‐line treatments of elderly patients. We conducted a multicenter observational study that prospectively analyzed safety and efficacy of alternating 3 + 3 cycles of R‐CHOP and R‐cytarabine for newly diagnosed transplant‐ineligible MCL patients. A total of 73 patients were enrolled with median age 70 years. Most patients had intermediate (39.7%) and high‐risk (50.7%) disease according to MCL international prognostic index. Rituximab maintenance was initiated in 58 patients. Overall response rate reached 89% by positron emission tomography–computed tomography, including 75.3% complete remissions. Two patients (2.7%) did not complete the induction therapy because of toxicity. Three patients (4.1%) were considered nonresponders, which led to therapy change before completion of induction. Estimated progression‐free survival and overall survival were 51.3% and 68.6% at 4 years, respectively. Mantle cell lymphoma international prognostic index, bulky disease (≥ 5 cm), and achievement of positron emission tomography–negativity independently correlated with progression‐free survival. Grade 3 to 4 hematologic and nonhematologic toxicity was documented in 48% and 20.5% patients, respectively. Alternation of R‐CHOP and R‐cytarabine represents feasible and very effective regimen for elderly/comorbid MCL patients. This study was registered at GovTrial ( clinicaltrials.gov ) NCT03054883.     

Allogeneic cartilage used for skull base plasty in children with primary intranasal encephalomeningocele associated with cerebrospinal fluid rhinorrhea

Three children with primary intranasal encephalomeningocele associated with cerebrospinal fluid rhinorrhea were operated on at the Department of Neurosurgery, Hradec Králové. In two children, aged 4 and 9.5 years, freeze-dried allogeneic costal cartilage was glued into the skull base defect. This plugging was covered up with deepfrozen allogeneic fascia lata. In the third child, an only 1-year-old boy, after transection of the neck of the encephalomeningocele freeze-dried allogeneic dura mater was glued on extradurally and deep-frozen allogeneic fascia lata applied intradurally. The cerebrospinal fluid rhinorrhea ceased immediately after surgery. Spontaneous atrophy of the intranasal portion of the encephalomeningocele was demonstrated respectively 11, 1, and 7 years postoperatively on computed tomography. To evaluate cartilage healing histologically, the extracted allogeneic cartilage used for orbital roof plasty after 4 months was examined. The extent of spotty regressions represented about 7% of the tissue volume. It is stressed that, once diagnosed, intranasal encephalomeningocele associated with cerebrospinal fluid rhinorrhea should be operated on for prevention of meningitis as soon as possible.     

A rapid and simple method for the analysis of 1-hydroxypyrene glucuronide: a potential biomarker for poly cyclic aromatic hydrocarbon exposure

The present study describes a simple method of analyzing metabolitesof pyrene in urine. This method is capable of detecting theglucuronic acid and sulfate conjugates of pyrene as well asfree 1-hydroxypyrene in a single analysis. In comparison toother analytical methods for detecting pyrene metabolites, thisnew method does not require an overnight enzymatic hydrolosisstep and is a much more rapid method of analysis. The newlydeveloped procedure involves solid phase extraction of pyrenemetabolites followed by separation using HPLC with a phenylmodified reverse phase column and an acidic buffer and acetonitrilegradient elution system. Metabolites were detected using a fluorescencedetector with wavelength conditions optimized for each metabolite.This method resulted in baseline separation of the glucuronicacid (1-OH P-GlcUA) and sulfate conjugate (1-OH P-Sul) of 1-hydroxypyreneand free 1-hydroxypyrene (1-OH P). The potential of this methodfor use in monitoring human exposure to mixtures of PAHs wasevaluated by analyzing urine obtained from five individualsworking in a coal gasification plant. 1-OH P-GlcUA was detectedas the major metabolite in the urine of all the five workers.This metabolite accounted for 80–100% of the total pyrenemetabolites excreted in urine. 1-OH P-GlcUA levels ranged from0.31–0.94 µg/g creatinine. Low levels of the sulfateconjugate (0.002–0.06 µg/g creatinine) were detectedin four of the samples while free 1-hydroxypyrene (0.07–0.2.µg/g creatinine) was detected in two of the five urinesamples. Urine from occupationally exposed workers was alsoanalyzed for 1-hydroxypyrene following enzymatic hydrolysisusing the standard approach. Levels of 1-hydroxypyrene rangedfrom 0.51–1.17 µg/g creatinine. Comparison of thefluorescence intensities of 1-OH P-GlcUA and 1-OH P-Sul to 1-hydroxypyrenedemonstrated that the glucuronide conjugate is 3-fold more fluorescentand the sulfate conjugate is 4-fold more fluorescent than 1-hydroxypyrene.These results indicate that conjugates of pyrene, specifically,1-OH P-GlcUA can potentially be used as a more sensitive biomarkerof exposure to PAHs.     

Factors related to poor asthma control in Latvian asthma patients between 2013 and 2015

Objectives: To investigate whether beliefs about asthma medication, cognitive and emotional factors are related to poor asthma control in a sample of Latvian asthma patients in 2015.

Design: Cross-sectional, self-administered survey.

Subjects: Three hundred and fifty two asthma patients (mean age 57.5 years) attending outpatient pulmonologist consultations in Riga, Latvia during September 2013 to December 2015. The sample size was calculated to detect a prevalence of poor asthma control of 50% with a margin of error of 5% and a power of 95%.

Main outcome measures: The validated Beliefs about Medication Questionnaire (BMQ) and the Brief Illness Perception Questionnaire (brief IPQ) were used. Good asthma control was assessed using the asthma control test (ACT), a validated five-item scale that reliably assesses asthma control over a recall period of four weeks. Logistic regression models were used to predict poor asthma control.

Results: Patients who had a good control of asthma medication (OR 0.70; 95% CI 0.61–0.79) or were confident that their asthma medication improves illness (OR 0.84; 95% CI 0.74–0.95) had a reduced risk of poor asthma control. The more symptoms (OR 1.63; 95% CI 1.44–1.84) the asthma patients perceived or the more their illness affects their life, the higher the probability of poor asthma control (OR 1.47; 95% CI 1.31–1.65). Some beliefs of necessity and concerns of asthma medication were also statistically significantly related to poor asthma control.

Conclusions: Beliefs of necessity of asthma medication, cognitive and emotional illness perception factors correlate well with poor asthma control in Latvian patients.     

Effect of early allograft dysfunction on outcomes following liver transplantation

Early allograft dysfunction (EAD) following liver transplantation (LT) remains a challenge for patients and clinicians. We retrospectively analyzed the effect of pre‐defined EAD on outcomes in a 10‐year cohort of deceased‐donor LT recipients with clearly defined exclusion criteria. EAD was defined by at least one of the following: AST or ALT >2000 IU/L within first‐week post‐LT, total bilirubin ≥10 mg/dL, and/or INR ≥1.6 on post‐operative day 7. Ten patients developed primary graft failure and were analyzed separately. EAD occurred in 86 (36%) recipients in a final cohort of 239 patients. In univariate and multivariate analyses, EAD was significantly associated with mechanical ventilation ≥2 days or death on days 0, 1, PACU/SICU stay >2 days or death on days 0‐2 and renal failure (RF) at time of hospital discharge (all P<.05). EAD was also significantly associated with higher one‐year graft loss in both uni‐ and multivariate Cox hazard analyses (P=.0203 and .0248, respectively). There was no difference in patient mortality between groups in either of the Cox proportional hazard models. In conclusion, we observed significant effects of EAD on short‐term post‐LT outcomes and lower graft survival.     

Isoprenoids responsible for protein prenylation modulate the biological effects of statins on pancreatic cancer cells

Background

Statin treatment of hypercholesterolemia is accompanied also with depletion of the mevalonate intermediates, including farnesyl pyrophosphate (FPP) and geranylgeranyl pyrophosphate (GGPP) necessary for proper function of small GTPases. These include Ras proteins, prevalently mutated in pancreatic cancer. In our study, we evaluated the effect of three key intermediates of the mevalonate pathway on GFP-K-Ras protein localization and the gene expression profile in pancreatic cancer cells after exposure to individual statins.

Methods

These effects were tested on MiaPaCa-2 human pancreatic cancer cells carrying a K-Ras activating mutation (G12C) after exposure to individual statins (20 μM). The effect of statins (atorvastatin, lovastatin, simvastatin, fluvastatin, cerivastatin, rosuvastatin, and pitavastatin) and mevalonate intermediates on GFP-K-Ras protein translocation was analyzed using fluorescence microscopy. The changes in gene expression induced in MiaPaCa-2 cells treated with simvastatin, FPP, GGPP, and their combinations with simvastatin were examined by whole genome DNA microarray analysis.

Results

All tested statins efficiently inhibited K-Ras protein trafficking from cytoplasm to the cell membrane of the MiaPaCa-2 cells. The inhibitory effect of statins on GFP-K-Ras protein trafficking was partially prevented by addition of any of the mevalonate pathway’s intermediates tested. Expressions of genes involved in metabolic and signaling pathways modulated by simvastatin treatment was normalized by the concurrent addition of FPP or GGPP. K-Ras protein trafficking within the pancreatic cancer cells is effectively inhibited by the majority of statins; the inhibition is eliminated by isoprenoid intermediates of the mevalonate pathway.

Conclusions

Our data indicate that the anticancer effects of statins observed in numerous studies to a large extent are mediated through isoprenoid intermediates of the mevalonate pathway, as they influence expression of genes involved in multiple intracellular pathways.

     

Novel leukotriene biosynthesis inhibitors (2012-2016) as anti-inflammatory agents

Introduction: Leukotrienes (LTs) are lipid mediators produced from arachidonic acid with a broad variety of bioactivities in allergy and inflammation. The biosynthesis of LTs mainly involves 5-lipoxygenase (5-LO) and its 5-lipoxygenase-activating protein (FLAP), LTA₄ hydrolase and LTC₄ synthase that all may represent potential targets for LT biosynthesis inhibitors.

Areas covered: We introduce the LT biosynthetic pathway and its cellular regulation, the diverse biological actions of LTs and their receptors, and we briefly describe the pharmacological strategies for suppression of LT formation as well as the classes of current LT biosynthesis inhibitors. The main focus is placed on the comprehensive discussion of recently reported inhibitors of 5-LO, FLAP, LTA₄ hydrolase and LTC₄ synthase, based on literature search (PubMed and Thomson Innovation Patents Searches), covering 2012–2016.

Expert opinion: Although many new series of 5-LO inhibitors have been presented without patenting, essentially by academia, novel FLAP inhibitors (many patented) are most advanced in clinical development and are apparently the focus of pharmaceutical companies. Only few novel inhibitors of LTA₄ hydrolase and LTC₄ synthase were reported. Major issues in the development of LT synthesis inhibitors are related to loss of potency in biological relevant environment, poor pharmacokinetics, lack of oral efficacy, and side effects.