Impact of 2016 WHO diagnosis of early and overt primary myelofibrosis on presentation and outcome of 232 patients treated with ruxolitinib

The 2016 WHO criteria identified early primary myelofibrosis (PMF) as an individual entity with milder clinical features and better outcome compared with overt PMF. Here, we compared early and overt PMF patients treated with ruxolitinib in terms of baseline clinical/laboratory characteristics, response, and toxicity to treatment. We observed that early‐PMF patients achieve better and more stable spleen and symptoms responses, with significantly lower rates of hematological toxicities. No differences in overall and leukemia‐free survival were detected between the two cohorts. The application of 2016 WHO criteria is crucial to identify those PMF patients who deserve a stricter monitoring during treatment.     

Closed-chamber inhalation pharmacokinetic studies with hexamethyldisiloxane in the rat

Gas uptake methods together with physiologically based pharmacokinetic (PBPK) modeling have been used to assess metabolic parameters and oral absorption rates for a wide variety of volatile organic compounds. We applied these techniques to study the in vivo metabolism of hexamethyldisiloxane (HMDS), a volatile siloxane with low blood/air (partition coefficient PB approximately 1.00) and high fat/blood partitioning (partition coefficient PF approximately 300). In contrast to other classes of metabolized volatiles, metabolic parameters could only be estimated from closed-chamber results with confidence by evaluating both closed-chamber disappearance curves and constant concentration inhalation studies. The constant-concentration inhalation results refine the estimate of the blood/air partition coefficient and constrain model structure for storage of the lipophilic compound in blood and tissues. The gas uptake results, from Fischer 344 rats (male, 8-9 wk old) exposed to initial HMDS air concentrations from 500 to 5000 ppm, were modeled with a 5-tissue PBPK model. Excellent fits were obtained with diffusion-limited uptake of HMDS in fat and a lipid storage pool in the blood. Metabolism, restricted to the liver, was described as a single saturable process (V(max) = 113.6 micro mol/h/kg; K(m) = 42.6 micro mol/L) and was affected by inhibitors (diethyldithiocarbamate) or inducers (phenobarbital) of cytochrome P-450s. Exhalation kinetics of HMDS after oral/intraperitoneal administration showed low bioavailability and significant lag times, also quite different from results of other classes of volatile hydrocarbons. In general, estimates of metabolic clearance by gas uptake studies were improved by simultaneous examination of time-course results from constant concentration inhalation studies. This conclusion is likely to hold for any volatile lipophilic compound with low blood/air partitioning.     

Combining Ibrutinib with Chk1 Inhibitors Synergistically Targets Mantle Cell Lymphoma Cell Lines

Background

Mantle cell lymphoma (MCL) is an aggressive B cell lymphoma with an unfavorable clinical course. Besides deregulation of the cell cycle, B cell receptor (BCR) signaling, essential for MCL proliferation and survival, is also often deregulated due to constitutive activation of Bruton’s tyrosine kinase (BTK). The BTK inhibitor ibrutinib has been approved as a therapy for refractory MCL, and while it shows some clinical activity, patients frequently develop primary or secondary ibrutinib resistance and have very poor outcomes after relapsing following ibrutinib treatment.

Objective

To overcome ibrutinib resistance, new therapeutic approaches are needed. As checkpoint kinase 1 (Chk1) inhibitors have recently been shown to be effective as single agents in MCL, we assessed the combination of ibrutinib with Chk1 inhibitors.

Methods

We examined the activity of ibrutinib combined with the Chk1 inhibitor PF-00477736 in eight MCL cell lines and analyzed underlying cellular and molecular effects.

Results

The combination was synergistic in all tested cell lines through different mechanisms. The treatment induced apoptosis in ibrutinib-sensitive cell lines, while in ibrutinib-resistant cells the effect was mainly cytostatic and occurred at micromolar concentrations of ibrutinib.

Conclusions

The pharmacological approach of simultaneously targeting cell cycle checkpoints (by Chk1 inhibitors) and pro-survival pathways (by ibrutinib) might offer a promising new therapeutic strategy for MCL patients.

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Adenosine A2A receptor agonists increase Fos-like immunoreactivity in mesolimbic areas

Expression of the early-gene c-fos is an useful method for studying potential sites of action of drugs active in the CNS. Stimulation of adenosine A_2A receptors by CGS 21680 (5 mg/kg) induced an increase in Fos-like immunoreactivity in the rat nucleus accumbens shell, while in the rostral pole and core CGS 21680 induced Fos-like immunoreactivity only after a high dose. CGS 21680 (5 mg/kg) stimulated c-fos expression also in the lateral septal nucleus and dorso-medial striatum, but not in the dorso-lateral striatum. A similar pattern of Fos-like immunoreactivity was obtained after administration of the A_2A agonist HENECA (5 mg/kg) which displays higher selectivity for A_2A receptors than CGS 21680. Administration of the selective A_2A antagonist SCH 58261 counteracted CGS 21680-induced Fos-like immunoreactivity. Lesions of the dopaminergic mesostriatal projection by 6-hydroxydopamine and stimulation of dopamine D₂/D₃ receptors by quinpirole, prevented CGS 21680-induced Fos-like immunoreactivity in the nucleus accumbens shell. The present results show that stimulation of A_2A receptors induces a profile of c-fos expression similar to that of atypical neuroleptics. A_2A receptor stimulation has been reported to have dopamine antagonistic actions, it is therefore suggested that A_2A agonists might have antipsychotic activity without producing extrapyramidal side effects.     

Perioperative and long-term results after left pancreatectomy: a single-institution, non-randomized, comparative study between open and laparoscopic approach

Background  

Laparoscopic left pancreatic resections are being increasingly performed. In this study, we provide a nonrandomized comparison between laparoscopic and open left pancreatectomy (OLP) for benign and borderline tumors, focusing on both perioperative and long-term results.     

Lesions of substantia nigra by kainic acid: Effects on apomorphine-induced stereotyped behaviour

Fifteen days after bilateral lesions of the substantia nigra by local infusion of kainic acid (0.75 μg) or after intranigral injection of vehicle, rats were administered 0.1, 0.25, 1.0 and 2.5 mg/kg s.c. of apomorphine and the stereotyped items (locomotion, sniffing and gnawing) were recorded on an event-recorder and motility was measured by a photocell apparatus. After low doses of apomorphine (0.1, 0.2 mg/kg), rats lesioned in the substantia nigra with kainic acid showed a degree of stimulation of motility and of sniffing similar to controls; on the other hand, in rats lesioned with kainic acid in the nigra, a dramatic reduction of gnawing and its replacement by sniffing was observed after administration of higher doses of apomorphine (1.0, 2.5 mg/kg). Bilateral infusion of kainic acid (0.75 μg) into the reticular information, 2.0 mm dorsal to the substantia nigra, had no effect on apomorphine-induced stereotyped behaviour.These results are in agreement with the concept that the substantia nigra, through non-DA pars reticulata neurons, mediates motor and behavioural syndromes of striatal origin.