Oncological outcomes of standard versus prolonged time to surgery after neoadjuvant chemoradiotherapy for oesophageal cancer in the multicentre, randomised, controlled NeoRes II trial.

BACKGROUND: The optimal time to surgery (TTS) after neoadjuvant chemoradiotherapy (nCRT) for oesophageal cancer is unknown and has traditionally been 4-6 weeks in clinical practice. Observational studies have suggested better outcomes, especially in terms of histological response, after prolonged delay of up to 3 months after nCRT. The NeoRes II trial is the first randomised trial to compare standard to prolonged TTS after nCRT for oesophageal cancer. PATIENTS AND METHODS: Patients with resectable, locally advanced oesophageal cancer were randomly assigned to standard delay of surgery of 4-6 weeks or prolonged delay of 10-12 weeks after nCRT. The primary endpoint was complete histological response of the primary tumour in patients with adenocarcinoma (AC). Secondary endpoints included histological tumour response, resection margins, overall and progression-free survival in all patients and stratified by histologic type. RESULTS: Between February 2015 and March 2019, 249 patients from 10 participating centres in Sweden, Norway and Germany were randomised: 125 to standard and 124 to prolonged TTS. There was no significant difference in complete histological response between AC patients allocated to standard (21%) compared to prolonged (26%) TTS (P = 0.429). Tumour regression, resection margins and number of resected lymph nodes, total and metastatic, did not differ between the allocated interventions. The first quartile overall survival in patients allocated to standard TTS was 26.5 months compared to 14.2 months after prolonged TTS (P = 0.003) and the overall risk of death during follow-up was 35% higher after prolonged delay (hazard ratio 1.35, 95% confidence interval 0.94-1.95, P = 0.107). CONCLUSION: Prolonged TTS did not improve histological complete response or other pathological endpoints, while there was a strong trend towards worse survival, suggesting caution in routinely delaying surgery for >6 weeks after nCRT.

Integrated twin-screw wet granulation, continuous vibrational fluid drying and milling: A fully continuous powder to granule line.

Highly homogeneous low-dose (50 µg) tablets were produced incorporating perfectly free-flowing granules prepared by a fully integrated Continuous Manufacturing (CM) line. The adopted CM equipment consisted of a Twin-Screw Wet Granulator (TSWG), a Continuous Fluid Bed Dryer (CFBD) and a Continuous Sieving (CS) unit. Throughout the experiments a pre-blend of lactose-monohydrate and corn starch was gravimetrically dosed with 1 kg/h into the TSWG, where they were successfully granulated with the drug containing water-based PVPK30 solution. The wet mass was subsequently dried in the CFBD on a vibratory conveyor belt and finally sieved in the milling unit. Granule production efficiency was maximized by determining the minimal Liquid-to-Solid (L/S) ratio (0.11). Design of Experiments (DoE) were carried out in order to evaluate the influence of the drying process parameters of the CFBD on the Loss-on-Drying (LOD) results. The manufactured granules were compressed into tablets by an industrial tablet rotary press with excellent API homogeneity (RSD < 3%). Significant scale-up was realized with the CM line by increasing the throughput rate to 10 kg/h. The manufactured granules yielded very similar results to the previous small-scale granulation runs. API homogeneity was demonstrated (RSD < 2%) with Blend Uniformity Analysis (BUA). The efficiency of TSWG granulation was compared to High-Shear Granulation (HSG) with the same L/S ratio. The final results have demonstrated that both the liquid distribution and more importantly API homogeneity was better in case of the TSWG granulation (RSD 1.3% vs. 4.5%).

Mid-Infrared Imaging Is Able to Characterize and Separate Cancer Cell Lines.

Malignancies are still responsible for a large share of lethalities. Macroscopical evaluation of the surgical resection margins is uncertain. Big data based imaging approaches have emerged in the recent decade (mass spectrometry, two-photon microscopy, infrared and Raman spectroscopy). Indocianine green labelled MS is the most common approach, however, label free mid-infrared imaging is more promising for future practical application. We aimed to identify and separate different transformed (A-375, HT-29) and non-transformed (CCD986SK) cell lines by a label-free infrared spectroscopy method. Our approach applied a novel set-up for label-free mid-infrared range classification method. Transflection spectroscopy was used on aluminium coated glass slides. Both whole range spectra (4000-648 cm-1) and hypersensitive fingerprint regions (1800-648 cm-1) were tested on the imaged areas of cell lines fixed in ethanol. Non-cell spectra were possible to be excluded based on mean transmission values being above 90%. Feasibility of a mean transmission based spectra filtering method with principal component analysis and linear discriminant analysis was shown to separate cell lines representing different tissue types. Fingerprint region resulted the best separation of cell lines spectra with accuracy of 99.84% at 70-75 mean transmittance range. Our approach in vitro was able to separate unique cell lines representing different tissues of origin. Proper data handling and spectra processing are key steps to achieve the adaptation of this dye-free technique for intraoperative surgery. Further studies are urgently needed to test this novel, marker-free approach.

A multivariate approach to predict the volumetric and gravimetric feeding behavior of a low feed rate feeder based on raw material properties.

In this study, the volumetric and gravimetric feeding behavior of 15 pharmaceutical powders on a low feed rate feeder was correlated with their material properties through a multivariate approach. The powders under investigation differ substantially in terms of material properties, making the selected powders representative for powders typically used in pharmaceutical manufacturing. The material properties were described by 25 material property descriptors, obtained from a rational selection of critical characterization techniques that provided maximal information with minimal characterization effort. From volumetric feeding experiments (i.e., powder feed rate not controlled), the maximum feeding capacity (maximum feed factor (FFmax)) and optimal hopper fill level at which the feeder should be refilled during gravimetric feeding (feed factor decay (FFdecay)) were obtained. During gravimetric feeding experiments (i.e., powder feed rate controlled), the variability on the feed rate (relative standard deviation (RSD)) and the difference between the setpoint and mean feed rate (relative error (RE)) were determined. Partial least squares (PLS) regression was applied to correlate the volumetric and gravimetric feeding responses (Y) with the material property descriptors (X). The predictive ability of the developed PLS models was assessed by predicting the feeding responses of two new powders (i.e., validation set). Overall, the volumetric feeding responses (FFmax and FFdecay) were predicted better than the gravimetric feeding responses (RSD and RE), since in gravimetric mode the impact of material properties on the feeding behavior is reduced due to the control system of the feeder. Especially RE was weakly correlated with material properties as RE of most powders varied around zero with only a small numerical variation. Interestingly, this confirms that the control system is working properly and that the feeder is capable of feeding different powders accurately at low feed rates. The developed models allowed to predict the feeding behavior of new powders based on their material properties. Consequently the number of feeding experiments during process development can be greatly reduced, thereby leading to a more efficient and faster development of new drug products.

Retinoprotective Effects of TAT-Bound Vasoactive Intestinal Peptide and Pituitary Adenylate Cyclase Activating Polypeptide.

Vasoactive intestinal peptide (VIP) and pituitary adenylate cyclase activating polypeptide (PACAP) belong to the same peptide family and exert a variety of biological functions. Both PACAP and VIP have protective effects in several tissues. While PACAP is known to be a stronger retinoprotective peptide, VIP has very potent anti-inflammatory effects. The need for a non-invasive therapeutic approach has emerged and PACAP has been shown to be retinoprotective when administered in the form of eye drops as well. The cell penetrating peptide TAT is composed of 11 amino acids and tagging of TAT at the C-terminus of neuropeptides PACAP/VIP can enhance the traversing ability of the peptides through the biological barriers. We hypothesized that TAT-bound PACAP and VIP could be more effective in exerting retinoprotective effects when given in eye drops, by increasing the traversing efficacy and enhancing the activation of the PAC1 receptor. Rats were subjected to bilateral carotid artery occlusion (BCCAO), and retinas were processed for histological analysis 14 days later. The efficiency of the TAT-bound peptides to reach the retina was assessed as well as their cAMP increasing ability. Our present study provides evidence, for the first time, that topically administered PACAP and VIP derivatives (PACAP-TAT and VIP-TAT) attenuate ischemic retinal degeneration via the PAC1 receptor presumably due to a multifactorial protective mechanism.

PACAP deficiency as a model of aging.

Dysregulation of neuropeptides may play an important role in aging-induced impairments. In the long list of neuropeptides, pituitary adenylate cyclase-activating polypeptide (PACAP) represents a highly effective cytoprotective peptide that provides an endogenous control against a variety of tissue-damaging stimuli. PACAP has neuro- and general cytoprotective effects due to anti-apoptotic, anti-inflammatory, and antioxidant actions. As PACAP is also a part of the endogenous protective machinery, it can be hypothesized that the decreased protective effects in lack of endogenous PACAP would accelerate age-related degeneration and PACAP knockout mice would display age-related degenerative signs earlier. Recent results support this hypothesis showing that PACAP deficiency mimics aspects of age-related pathophysiological changes including increased neuronal vulnerability and systemic degeneration accompanied by increased apoptosis, oxidative stress, and inflammation. Decrease in PACAP expression has been shown in different species from invertebrates to humans. PACAP-deficient mice display numerous pathological alterations mimicking early aging, such as retinal changes, corneal keratinization and blurring, and systemic amyloidosis. In the present review, we summarize these findings and propose that PACAP deficiency could be a good model of premature aging.

A novel vertebrate system for the examination and direct comparison of the relative biological effectiveness for different radiation qualities and sources.

PURPOSE: The recent rapid increase of hadron therapy applications requires the development of high performance, reliable in vivo models for preclinical research on the biological effects of high linear energy transfer (LET) particle radiation. AIM: The aim of this paper was to test the relative biological effectiveness (RBE) of the zebrafish embryo system at two neutron facilities. MATERIAL AND METHODS: Series of viable zebrafish embryos at 24-hour post-fertilization (hpf) were exposed to single fraction, whole-body, photon and neutron (reactor fission neutrons () and (p (18 MeV)+Be, = 3.5 MeV) fast neutron) irradiation. The survival and morphologic abnormalities of each embryo were assessed at 24-hour intervals from the point of fertilization up to 192 hpf and then compared to conventional 6 MV photon beam irradiation results. RESULTS: The higher energy of the fast neutron beams represents lower RBE (ref. source LINAC 6 MV photon). The lethality rate in the zebrafish embryo model was 10 times higher for 1 MeV fission neutrons and 2.5 times greater for p (18 MeV)+Be cyclotron generated fast neutron beam when compared to photon irradiation results. Dose-dependent organ perturbations (shortening of the body length, spine curvature, microcephaly, micro-ophthalmia, pericardial edema and inhibition of yolk sac resorption) and microscopic (marked cellular changes in eyes, brain, liver, muscle and the gastrointestinal system) changes scale together with the dose response. CONCLUSION: The zebrafish embryo system is a powerful and versatile model for assessing the effect of ionizing radiation with different LET values on viability, organ and tissue development.

Application of hydroxypropyl methylcellulose as a protective agent against magnesium stearate induced crystallization of amorphous itraconazole.

Itraconazole is a fungicide drug which has low bioavailability due to its poor water solubility. Amorphous solid dispersion (ASD) is a tool that has the potential to greatly increase the dissolution rate and extent of compounds. In this work, the dissolution of tablets containing the ASD of itraconazole with either hydroxypropyl methylcellulose (HPMC) or vinylpyrrolidone-vinyl acetate copolymer (PVPVA) was compared in order to find a formulation which can prevent the drug from the precipitation caused by magnesium stearate. Formulations containing the PVPVA-based ASD with HPMC included in various forms could reach 90% dissolution in 2 h, while HPMC-based ASDs could release 100% of the drug. However, HPMC-based ASD had remarkably poor grindability and low bulk density, which limited its processability and applicability. The latter issue could be resolved by roller compacting the ASD, which significantly increases the bulk density and the flowability of the powder blends used for tableting. This roller compaction step might be a base for the industrial application of HPMC-based, electrospun ASDs.

Protective effects of pituitary adenylate cyclase activating polypeptide against neurotoxic agents.

Pituitary adenylate cyclase activating polypeptide (PACAP) is a neuropeptide highly expressed in the central and peripheral nervous system, where it exerts several neuromodulatory functions and is an important trophic and protective factor. PACAP has been shown to activate several protective pathways, mainly through its specific PAC1 receptor and protein kinase A, C and MAP kinases downstream. It has been shown to have very potent neuroprotective actions against different neurotoxic agents both in vitro and in vivo. The aim of the present review is to provide an overview on the neurotoxic injuries against which PACAP exerts protection, and to give an insight into its protective mechanism. We give a summary of the neuroprotective effects against the most commonly used neurotoxic agents, such as 6-OHDA, MPTP, glutamate and some less well-known neurotoxic compounds. Also endogenous PACAP has neuroprotective effects, known from studies in PACAP knockout mice or from blocking endogenous effects by antagonists. Altogether, the vast amount of data for the neuroprotective effects of PACAP give a firm background for its endogenous role as part of the neuroprotective machinery and its possible future therapeutic use as a neuroprotective factor.

Morbidity of cholecystectomy and gastric bypass in a national database.

BACKGROUND: There is a strong association between obesity and gallstones. However, there is no clear evidence regarding the optimal order of Roux-en-Y gastric bypass (RYGB) and cholecystectomy when both procedures are clinically indicated. METHODS: Based on cross-matched data from the Swedish Register for Cholecystectomy and Endoscopic Retrograde Cholangiopancreatography (GallRiks; 79 386 patients) and the Scandinavian Obesity Surgery Registry (SOReg; 36 098 patients) from 2007 to 2013, complication rates, reoperation rates and operation times related to the timing of RYGB and cholecystectomy were explored. RESULTS: There was a higher aggregate complication risk when cholecystectomy was performed after RYGB rather than before (odds ratio (OR) 1·35, 95 per cent c.i. 1·09 to 1·68; P = 0·006). A complication after the first procedure independently increased the complication risk of the following procedure (OR 2·02, 1·44 to 2·85; P < 0·001). Furthermore, there was an increased complication risk when cholecystectomy was performed at the same time as RYGB (OR 1·72, 1·14 to 2·60; P = 0·010). Simultaneous cholecystectomy added 61·7 (95 per cent c.i. 56·1 to 67·4) min (P < 0·001) to the duration of surgery. CONCLUSION: Cholecystectomy should be performed before, not during or after, RYGB.

Investigation of Deteriorated Dissolution of Amorphous Itraconazole: Description of Incompatibility with Magnesium Stearate and Possible Solutions.

Disadvantageous crystallization phenomenon of amorphous itraconazole (ITR) occurring in the course of dissolution process was investigated in this work. A perfectly amorphous form (solid dispersion) of the drug was generated by the electroblowing method (with vinylpyrrolidone-vinyl acetate copolymer), and the obtained fibers were formulated into tablets. Incomplete dissolution of the tablets was noticed under the circumstances of the standard dissolution test, after which a precipitated material could be filtered. The filtrate consisted of ITR and stearic acid since no magnesium content was detectable in it. In parallel with dissolution, ITR forms an insoluble associate, stabilized by hydrogen bonding, with stearic acid deriving from magnesium stearate. This is why dissolution curves do not have the plateaus at 100%. Two ways are viable to tackle this issue: change the lubricant (with sodium stearyl fumarate >95% dissolution can be accomplished) or alter the polymer in the solid dispersion to a type being able to form hydrogen bonds with ITR (e.g., hydroxypropyl methylcellulose). This work draws attention to one possible phenomenon that can lead to a deterioration of originally good dissolution of an amorphous solid dispersion.

Identification of a novel HLA-B allele, HLA-B*08:177, in a Hungarian patient and her HLA identical sibling.

The newly detected HLA-B*08:177 differs from HLA-B*08:01:01:01 by 1 single nucleotide substitution at position 365 of exon 3.

Outcomes of laparoscopic gastric bypass in a randomized clinical trial compared with a concurrent national database.

BACKGROUND: RCTs are the standard for assessing medical interventions, but they may not be feasible and their external validity is sometimes questioned. This study aimed to compare results from an RCT on mesenteric defect closure during laparoscopic gastric bypass with those from a national database containing data on the same procedure, to shed light on the external validity of the RCT. METHODS: Patients undergoing laparoscopic gastric bypass surgery within an RCT conducted between 1 May 2010 and 14 November 2011 were compared with those who underwent the same procedure in Sweden outside the RCT over the same time interval. Primary endpoints were severe complications within 30 days and surgery for small bowel obstruction within 4 years. RESULTS: Some 2507 patients in the RCT were compared with 8485 patients in the non-RCT group. There were no differences in severe complications within 30 days in the group without closure of the mesenteric defect (odds ratio (OR) for RCT versus non-RCT 0·94, 95 per cent c.i. 0·64 to 1·36; P = 0·728) or in the group with closure of the defect (OR 1·34, 0·96 to 1·86; P = 0·087). There were no differences between the RCT and non-RCT cohorts in reoperation rates for small bowel obstruction in the mesenteric defect non-closure (cumulative incidence 10·9 versus 9·4 per cent respectively; hazard ratio (HR) 1·20, 95 per cent c.i. 0·99 to 1·46; P = 0·065) and closure (cumulative incidence 5·7 versus 7·0 per cent; HR 0·82, 0·62 to 1·07; P = 0·137) groups. The relative risk for small bowel obstruction without mesenteric defect closure compared with closure was 1·91 in the RCT group and 1·39 in the non-RCT group. CONCLUSION: The efficacy of mesenteric defect closure was similar in the RCT and national registry, providing evidence for the external validity of the RCT.

Muscle and Myotendinous Tissue Properties at the Distal Tibia as Assessed by High-Resolution Peripheral Quantitative Computed Tomography.

High-resolution peripheral quantitative computed tomography (HR-pQCT) quantifies bone microstructure and density at the distal tibia where there is also a sizable amount of myotendinous (muscle and tendon) tissue (MT); however, there is no method for the quantification of MT. This study aimed (1) to assess the feasibility of using HR-pQCT distal tibia scans to estimate MT properties using a custom algorithm, and (2) to determine the relationship between MT properties at the distal tibia and mid-leg muscle density (MD) obtained from pQCT. Postmenopausal women from the Hamilton cohort of the Canadian Multicenter Osteoporosis Study had a single-slice (2.3 ± 0.5 mm) 66% site pQCT scan measuring muscle cross-sectional area (MCSA) and MD. A standard HR-pQCT scan was acquired at the distal tibia. HR-pQCT-derived MT cross-sectional area (MTCSA) and MT density (MTD) were calculated using a custom algorithm in which thresholds (34.22-194.32 mg HA/cm3) identified muscle seed volumes and were iteratively expanded. Pearson and Bland-Altman plots were used to assess correlations and systematic differences between pQCT- and HR-pQCT-derived muscle properties. Among 45 women (mean age: 74.6 ± 8.5 years, body mass index: 25.9 ± 4.3 kg/m2), MTD was moderately correlated with mid-leg MD across the 2 modalities (r = 0.69-0.70, p < 0.01). Bland-Altman analyses revealed no evidence of directional bias for MTD-MD. HR-pQCT and pQCT measures of MTCSA and MCSA were moderately correlated (r = 0.44, p < 0.01). Bland-Altman plots for MTCSA revealed that larger MCSAs related to larger discrepancy between the distal and the mid-leg locations. This is the first study to assess the ability of HR-pQCT to measure MT size, density, and morphometry. HR-pQCT-derived MTD was moderately correlated with mid-leg MD from pQCT. This relationship suggests that distal MT may share common properties with muscle throughout the length of the leg. Future studies will assess the value of HR-pQCT-derived MT properties in the context of falls, mobility, and balance.

Cancer prevention in the era of precision oncology.

Cancer is a highly heterogeneous disease, both between and within different target organs. Precision cancer prevention requires understanding the molecular pathways leading to cancer on a "per-person" level, identification of individuals most at risk for developing cancer, and tailoring interventions to accommodate pathogenesis, risk, and individual responses to interventions. This commentary will discuss how an investment in precision prevention research can accelerate cancer prevention agent development-the key to reducing cancer incidence and mortality.

The Protective Role of PAC1-Receptor Agonist Maxadilan in BCCAO-Induced Retinal Degeneration.

A number of studies have proven that pituitary adenylate cyclase activating polypeptide (PACAP) is protective in neurodegenerative diseases. Permanent bilateral common carotid artery occlusion (BCCAO) causes severe degeneration in the rat retina. In our previous studies, protective effects were observed with PACAP1-38, PACAP1-27, and VIP but not with their related peptides, glucagon, or secretin in BCCAO. All three PACAP receptors (PAC1, VPAC1, VPAC2) appear in the retina. Molecular and immunohistochemical analysis demonstrated that the retinoprotective effects are most probably mainly mediated by the PAC1 receptor. The aim of the present study was to investigate the retinoprotective effects of a selective PAC1-receptor agonist maxadilan in BCCAO-induced retinopathy. Wistar rats were used in the experiment. After performing BCCAO, the right eye was treated with intravitreal maxadilan (0.1 or 1 µM), while the left eye was injected with vehicle. Sham-operated rats received the same treatment. Two weeks after the operation, retinas were processed for standard morphometric and molecular analysis. Intravitreal injection of 0.1 or 1 µM maxadilan caused significant protection in the thickness of most retinal layers and the number of cells in the GCL compared to the BCCAO-operated eyes. In addition, 1 µM maxadilan application was more effective than 0.1 µM maxadilan treatment in the ONL, INL, IPL, and the entire retina (OLM-ILM). Maxadilan treatment significantly decreased cytokine expression (CINC-1, IL-1α, and L-selectin) in ischemia. In summary, our histological and molecular analysis showed that maxadilan, a selective PAC1 receptor agonist, has a protective role in BCCAO-induced retinal degeneration, further supporting the role of PAC1 receptor conveying the retinoprotective effects of PACAP.

[Ocular Cicatricial Pemphigoid - a Retrospective Study]. / Ocní jizevnatý pemfigoid - retrospektivní studie.

INTRODUCTION: Ocular cicatricial pemphigoid (OCP) is rare, severe, sight threatening autoimmune disease of the conjunctiva, which affects elderly patients, more often women. AIM: To evaluate the success rate of stabilisation of ocular findings in patients with OCP. METHODS: Retrospective study of patients from Centre of Conjunctival and Corneal Diseases at Department of Ophthalmology, General University Hospital and 1st Medical Faculty of Charles University in Prague in 1992-2013 was performed. Frequency of OCP clinical stages, visual acuity (VA), disease activity and ocular complications of referred patients were monitored. Moreover, type of immunosuppressive (IS) therapy, the number of relapses of the disease and progress of OCP clinical stages were evaluated. Especially, we evaluated effects and side effects of mycophenolate mofetil (MM) therapy. In addition to that, type and frequency of ocular surgery that was carried out to the patients before and after the referral were recorded. Furthermore, we evaluated percentage of patients with mucous membranous pemphigoid (MMP). Also, the positive yield of diagnostic methods was assessed. RESULTS: The OCP was diagnosed and monitored in 51 patients (21 men and 30 women) during 21 years, the average age on the day of diagnosis was 68,4 years, the average period of observation was 57 months. 55 % of eyes were referred to our department at clinical stage 3, 27 % at stage 4. VA was maintained in 76 % of eyes, improved in 5 % of eyes and in 19 % of eyes deteriorated. Activity of OCP was detected during the first examination in 96 % of patients, the most common complications at that time was corneal ulcer or perforation. Patients were treated by immunosuppressive therapy, most often in combination: corticosteroids (47 patients), azathioprine (28 patients), cyclophosphamide (25 patients), MM (16 patients), sulphasalazine (5 patients), dapsone (5 patients). We ascertained relapses in 40 % of patients. The progression to the next stage of OCP were found in 7 eyes (6,9 %) and 95 eyes (93,1 %) remained stable. Activity of disease was well controlled in 11 patients out of 16 (69 %) by MM, IS therapy of remain 5 patients (31 %) had to be changed. Side effects of MM such as lymphopenia were present in 1 patient. Before OCP was diagnosed, patients underwent cataract surgery with the intraocular lens implantation, cryoepilation of eyelashes and eyelid plastic surgery, especially entropion. The most common indicated surgery in our clinic was amniotic membrane transplantation and retro position of muscular cutaneous leaf. 31 % of patients were diagnosed with MMP. Positive results of conjunctival biopsy were detected in 48 % from 42 examined samples and 22 % from 32 examined samples had positive results of indirect immunofluorescence (anti-desmosoms). CONCLUSION: OCP diagnosis is established on the basis of patient´s ophthalmic history and clinical findings. Positive results of direct and indirect immunofluorescence support the diagnosis. Activity of the disease and progression of OCP is effectively suppressed by systemic immunosuppressive therapy (for example MM), mainly if started at early stage of the disease. KEY WORDS: ocular cicatricial pemphigoid, immunosuppressive therapy, direct and indirect immunofluorescence, mycophenolate mofetil.

Selumetinib with and without erlotinib in KRAS mutant and KRAS wild-type advanced nonsmall-cell lung cancer.

BACKGROUND: KRAS mutations in NSCLC are associated with a lack of response to epidermal growth factor receptor inhibitors. Selumetinib (AZD6244; ARRY-142886) is an oral selective MEK kinase inhibitor of the Ras/Raf/MEK/ERK pathway. PATIENTS AND METHODS: Advanced nonsmall-cell lung cancer (NSCLC) patients failing one to two prior regimens underwent KRAS profiling. KRAS wild-type patients were randomized to erlotinib (150 mg daily) or a combination of selumetinib (150 mg daily) with erlotinib (100 mg daily). KRAS mutant patients were randomized to selumetinib (75 mg b.i.d.) or the combination. The primary end points were progression-free survival (PFS) for the KRAS wild-type cohort and objective response rate (ORR) for the KRAS mutant cohort. Biomarker studies of ERK phosphorylation and immune subsets were carried out. RESULTS: From March 2010 to May 2013, 89 patients were screened; 41 KRAS mutant and 38 KRAS wild-type patients were enrolled. Median PFS in the KRAS wild-type arm was 2.4 months [95% confidence interval (CI) 1.3-3.7] for erlotinib alone and 2.1 months (95% CI 1.8-5.1) for the combination. The ORR in the KRAS mutant group was 0% (95% CI 0.0% to 33.6%) for selumetinib alone and 10% (95% CI 2.1% to 26.3%) for the combination. Combination therapy resulted in increased toxicities, requiring dose reductions (56%) and discontinuation (8%). Programmed cell death-1 expression on regulatory T cells (Tregs), Tim-3 on CD8+ T cells and Th17 levels were associated with PFS and overall survival in patients receiving selumetinib. CONCLUSIONS: This study failed to show improvement in ORR or PFS with combination therapy of selumetinib and erlotinib over monotherapy in KRAS mutant and KRAS wild-type advanced NSCLC. The association of immune subsets and immune checkpoint receptor expression with selumetinib may warrant further studies.

A comparative study of the physical development and motor performance of mentally non-handicapped children and children with intellectual and development disabilities.

Several studies state that there might be a difference in the physical development and the motor performance of the mentally non-handicapped children and those with intellectual and development disabilities. The aim of our research was to compare the two groups from these aspects. The study included the assessment of the physical development and motor performance of altogether 225 primary school pupils (mentally non-handicapped and with intellectual and development disabilities) aged 8-11. The following indicators of physical development and build were examined: body height, body weight and body mass index (BMI), musculoskeletal plasticity index, biceps and triceps skinfold thickness. The motor tests included: 20 m dash, standing long jump, medicine-ball throwing, six minutes continuous running, obstacle race-test and a match test. We also examined the children's chronological (decimal) and morphological age. Data were analysed with SPSS programme. The differences between the averages were calculated with ANOVA and Fisher's LSD tests. The results show that the children with intellectual and development disabilities are in general less developed physically than non-handicapped children of the same age and sex. It is also concluded that in most motor tests the children with intellectual and development disabilities fall behind the non-handicapped ones.

Identification of autonomic neuronal chains innervating gingiva and lip.

The major goals of this present study were 1) to further clarify which parasympathetic ganglion sends postganglionic fibers to the lower gingiva and lip that may be involved in the inflammatory processes besides the local factors; 2) to separately examine the central pathways regulating sympathetic and parasympathetic innervation; and 3) to examine the distribution of central premotor neurons on both sides. A retrogradely transported green fluorescent protein conjugated pseudorabies virus was injected into the lower gingiva and lip of intact and sympathectomized adult female rats. Some animals received virus in the adrenal medulla which receive only preganglionic sympathetic fibers to separately clarify the sympathetic nature of premotor neurons. After 72-120h of survival and perfusion, the corresponding thoracic part of the spinal cord, brainstem, hypothalamus, cervical, otic, submandibular and trigeminal ganglia were harvested. Frozen sections were investigated under a confocal microscope. Green fluorescence indicated the presence of the virus. The postganglionic sympathetic neurons related to both organs are located in the three cervical ganglia, the preganglionic neurons in the lateral horn of the spinal cord on ipsilateral side; premotor neurons were found in the ventrolateral medulla, locus ceruleus, gigantocellular and paraventricular nucleus and perifornical region in nearly the same number on both sides. The parasympathetic postganglionic neurons related to the gingiva are present in the otic and related to the lip are present in the otic and submandibular ganglia and the preganglionic neurons are in the salivatory nuclei. Third order neurons were found in the gigantocellular reticular and hypothalamic paraventricular nuclei and perifornical area.