A randomised, phase II study of nintedanib or sunitinib in previously untreated patients with advanced renal cell cancer: 3-year results.

BACKGROUND: This exploratory study evaluated the safety/efficacy of nintedanib or sunitinib as first-line therapy in patients with advanced renal cell carcinoma (RCC). METHODS: Ninety-six patients were randomised (2:1) to either nintedanib (200 mg twice daily) or sunitinib (50 mg kg(-1) once daily (4 weeks on treatment; 2 weeks off)). Primary endpoint was progression-free survival (PFS) at 9 months. P-values reported are descriptive only; the study was not powered for such comparisons. RESULTS: Progression-free survival at 9 months was comparable between nintedanib and sunitinib (43.1% vs 45.2%, respectively; P=0.85). Median PFS was 8.4 months in each group (hazard ratio (HR), 1.12; 95% confidence interval (CI): 0.70-1.80; P=0.64). Median overall survival was 20.4 and 21.2 months for nintedanib and sunitinib, respectively (HR, 0.92; 95% CI: 0.54-1.56; P=0.76). Overall incidence of any grade adverse events (AEs) was comparable (90.6% vs 93.8%); AEs grade ⩾ 3 were lower with nintedanib than sunitinib (48.4% vs 59.4%). Nintedanib was associated with lower incidences of some AEs typical of antiangiogenic tyrosine kinase inhibitors (TKIs): hypertension, hypothyroidism, hand-foot syndrome, cardiac disorders and haematological abnormalities. CONCLUSIONS: In patients with advanced RCC, nintedanib has promising efficacy and similar tolerability to sunitinib, and a manageable safety profile with fewer TKI-associated AEs.

Different pathways of molecular pathophysiology underlie cognitive and motor tauopathy phenotypes in transgenic models for Alzheimer's disease and frontotemporal lobar degeneration.

A poorly understood feature of the tauopathies is their very different clinical presentations. The frontotemporal lobar degeneration (FTLD) spectrum is dominated by motor and emotional/psychiatric abnormalities, whereas cognitive and memory deficits are prominent in the early stages of Alzheimer's disease (AD). We report two novel mouse models overexpressing different human tau protein constructs. One is a full-length tau carrying a double mutation [P301S/G335D; line 66 (L66)] and the second is a truncated 3-repeat tau fragment which constitutes the bulk of the PHF core in AD corresponding to residues 296-390 fused with a signal sequence targeting it to the endoplasmic reticulum membrane (line 1; L1). L66 has abundant tau pathology widely distributed throughout the brain, with particularly high counts of affected neurons in hippocampus and entorhinal cortex. The pathology is neuroanatomically static and declines with age. Behaviourally, the model is devoid of a higher cognitive phenotype but presents with sensorimotor impairments and motor learning phenotypes. L1 displays a much weaker histopathological phenotype, but shows evidence of neuroanatomical spread and amplification with age that resembles the Braak staging of AD. Behaviourally, the model has minimal motor deficits but shows severe cognitive impairments affecting particularly the rodent equivalent of episodic memory which progresses with advancing age. In both models, tau aggregation can be dissociated from abnormal phosphorylation. The two models make possible the demonstration of two distinct but nevertheless convergent pathways of tau molecular pathogenesis. L1 appears to be useful for modelling the cognitive impairment of AD, whereas L66 appears to be more useful for modelling the motor features of the FTLD spectrum. Differences in clinical presentation of AD-like and FTLD syndromes are therefore likely to be inherent to the respective underlying tauopathy, and are not dependent on presence or absence of concomitant APP pathology.

Reliability of frozen section in the assessment of allograft steatosis in liver transplantation.

BACKGROUND: Because liver allograft steatosis is an important risk factor of graft dysfunction after liver transplantation, it must be taken into consideration during graft acceptance. The aim of this study was to evaluate the reliability of frozen section in the assessment of liver steatosis before transplantation. METHODS: The retrospective analysis was based on data of 112 liver allograft procurements performed between 2003 and 2012. Hepatic steatosis was assessed in frozen and routine sections. Sensitivity, specificity, and positive and negative predictive values of the frozen section were evaluated with respect to detection of >30% and >50% steatosis. RESULTS: According to routine section assessment, there were 32 (28.6%) cases of steatosis >30% and 16 (14.3%) of >50%. The results of frozen section assessment were underestimated and overestimated in a similar low number of cases, both for the >30% (0.0% and 0.9%, respectively, P < 1.000) and the >50% (4.5% and 0.9%, respectively, P = .221) cutoff. Sensitivity, specificity, positive and negative predictive values of frozen section assessment were 100.0%, 98.8%, 97.0%, and 100.0%, respectively, for detection of >30% steatosis, and 68.8%, 99.0%, 91.7%, and 95.0%, respectively, for >50% steatosis. CONCLUSIONS: Considering high positive predictive value of frozen section assessment in detection of >50% steatosis, it may serve as a base to discard the use of graft for transplantation. However, according to the relatively moderate sensitivity of this method, decision of graft acceptance must also be made on consideration of other well-known factors for poor posttransplant function.

Genetic comparison of Campylobacter jejuni isolated from different cattle farms.

To compare the genotypes of Campylobacter jejuni, isolates of cattle origin were collected from 9 Polish farms and genotyped by ERIC-PCR. We identified 28 genotypes among the 43 C. jejuni isolates, and demonstrated high genomic diversity. The highest level of diversity was observed in strains isolated from stanchion-barn animals in opposition to those from the loose-housing system.

A survey of anti-Ostertagia ostertagii antibody levels in bulk tank milk samples (BTM) in dairy herds in Lower Silesia Region (Poland).

This work presents serological evidence of cattle ostertagiosis in the Lower Silesia Region (Poland), based on the measurement of antibodies in bulk tank milk (BTM) samples. It represents the first evidence of this parasite examined with the use of the ELISA test and milk samples in Poland. The prevalence of Ostertagia ostertagii antibodies was determined in BTM from 32 dairy cattle herds. Antibodies to O. ostertagii were demonstrated in all herds. The optical density ratio (ODR) varied from -0.088 to 1.024. The mean ODR value in the examined region was 0.53.

The effect of undecanones and their derivatives on tumor angiogenesis and VEGF content.

The in vivo effects of some derivatives of aliphatic ketones (2-undecanone, 3-undecanone, 4-undecanone and their derivatives) on L-1 sarcoma tumor angiogenesis and VEGF content were studied in Balb/c mice. Mice that inhaled 10% solution of 3-undecanone(3-on) or 1% solution of 2-undecanone propylene acetal (Acpr2) for 3 days after tumor cells implantation, presented lower neovascular response measured by tumor-induced cutaneous angiogenesis test (TIA) and lower tumor VEGF content in 5-days tumors, than non-inhaled controls. Other substances presented various effects on tumor VEGF concentration and angiogenesis. Histological examination of lesions collected from mice inhaled Acpr2, or non-inhaled controls, revealed small diffused areas of necrosis in the former group. In both groups, slight to moderate inflammatory infiltrations were seen at the tumor's margin. In Acpr2 group, there were less small blood vessels at tumor's margin than in the control group.

The influence of Rhodiola quadrifida 50% hydro-alcoholic extract and salidroside on tumor-induced angiogenesis in mice.

UNLABELLED: The genus Rhodiola (Crassulaceae) consists of more than 100 species. They grow mainly in Tibet, China and Mongolia and are traditionally used as tonic, adaptogen, antidepressant and anti-inflammatory drugs. The best known is Rhodiola rosea (R. rosea) now cultivated also in Europe and North America, and present on the market as dietary supplement. Some authors reported anti-tumor activity of R. rosea extracts. Recently, we have published some data on immunomodulatory and antiangiogenic properties of R. rosea. Rhodiola quadrifida (R. quadrifida) belongs to the same family, but is almost not known in Europe, and there is no information about its possible anti-tumor as well as immunotropic and angiotropic activity. The aim of this study was to determine the influence of 50% hydro-alcoholic extract from rhizomes of R. quadrifida (Mongolian origin) and its main biologically active compound salidroside on tumor-induced angiogenesis. Angiogenesis was induced in the skin of Balb/c mice by grafting of syngeneic L-1 sarcoma cells. Mice were fed R. quadrifida extract or salidroside in daily doses 40, 200 and 400 microg, or 0.5, 1, 2, and 4 microg, respectively. After 72 hours, mice were sacrificed with lethal dose of Morbital. All newly formed blood vessels were identified and counted in dissection microscope. RESULTS: It was found that R. quadrifida extract and salidroside highly significantly decreased neovascular reaction in all doses applied.

The effect of Rhodiola quadrifida extracts on cellular immunity in mice and rats.

Rhodiola quadrifida (Rq) roots and rhizomes are traditionally used in Asia as a tonic, adaptogen, antidepressant and anti-inflammatory drug. The aim of this work was to study the in vivo effect of aqueous and 50% hydro-alcoholic extracts of Rq rhizomes on some parameters of cellular immunity in mice and rats. The metabolic activity of blood phagocyting cells was determined based on the measurement of intracellular respiratory burst after stimulation by PMA in RBA test. Potential bactericidal activity of phagocyting cells was determined in isolated blood leukocytes stimulated with killed microorganisms, according to the PKA test. Proliferative response of lymphocytes stimulated by mitogen concanavaline A (ConA) or lipopolysaccharide (LPS) were determined by MTT assay. Both extracts stimulated granulocytes activity in vitro and increased lymphocyte response to mitogens. The ability of parental strain mice lymphocytes to induce local cutaneous graft-versus-host reaction (GVH) in F1 hybrids was stimulated by 50% hydro-alcoholic extract only.

Impact of food advertising on food purchases by students in primary and secondary schools in south-eastern Poland.

AIM: The aim of the present study was to determine the impact of food advertising in primary and secondary schools on the food purchasing habits of children. METHODS: All forty-four primary and secondary schools in Rzeszow, Poland were included in the investigation; 15000 children attend primary and secondary schools in the region. Schools were visited by members of the research team, who filled in a questionnaire regarding the type of food products displayed or advertised in the school shop window and recorded the presence of direct corporate advertising in the proximity of the school shop. Shop owners were asked to fill in a form describing food purchases by students within the week preceding the visit. The school principal (or one of teachers) completed a form describing the school's policy regarding food advertising and the sponsorship of school activities by food companies. RESULTS: Recommended foods like milk, yogurts and fruit were offered by only 40.9 % of shops. There was a correlation between foods offered in the shop and foods purchased by students. In schools, 40.9% (95% CI 25.8, 56.0%) of shop windows displayed or advertised 'healthy' foods while 9.1% (95% CI 0.0, 17.9%) of shops displayed advertisements of food companies. The difference between display of 'healthy' food in shop windows and display of food on company advertisements was significant (likelihood ratio chi2 test, P < 0.04). Type of school (primary v. secondary) was not significant factor in advertising or purchasing pattern. CONCLUSIONS: Educational programmes should be introduced in schools with the aim of improving the understanding of nutritional principles among pupils, teachers and parents.

Intracellular distribution of Photofrin in malignant and normal endothelial cell lines.

Compared to current treatments including surgery, radiation therapy, and chemotherapy, PDT offers the advantage of an effective and selective method of destroying diseased tissues without damaging surrounding healthy tissues. One of the aspects of antitumour effectiveness of PDT is related to the distribution of photosensitizing drugs. The localization of photosensitizers in cytoplasmic organelles during PDT plays a major role in the cell destruction; therefore, intracellular localization of Ph in malignant and normal cells was investigated. The cell lines used throughout the study were: human malignant A549, MCF-7, Me45 and normal endothelial cell line HUV-EC-C. After incubation with Ph cells were examined using fluorescence and confocal microscopy to visualize the photosensitizer accumulation. For cytoplasm and mitochondria identification, cells were stained with CellTracker Green and MitoTracker Green, respectively. Distribution of Ph was different in malignant and normal cells and dependent on the incubation time. The maximal concentration of Ph in two malignant cell lines (A549 and MCF-7) was observed after 4 hours of incubation, and the most intensive signal was observed around the nuclear envelope. Intracellular distribution of Ph in the Me45 cell line showed that the fluorescence emitted by Ph overlaid that from MitoTracker. This indicates preferential accumulation of the sensitizer in mitochondria. Our results based on the mitochondrial localization support the idea that PDT can contribute to elimination of malignant cells by inducing apoptosis, which is of physiological significance.

Quantitative analysis of animal model lens anatomy: accommodative range is related to fiber structure and organization.

PURPOSE: The results of a recent study on accommodation in humans and baboons has revealed that lens fiber structure and organization are key components of the mechanism of accommodation. Dynamic focusing involves the controlled displacement and replacement, or realignment, of cortical fiber-ends at sutures as the mechanism of accommodation at the fiber level. This emended explanation of the mechanism of accommodation raises the following question: as the structure of crystalline lenses are only similar, not identical between species, is accommodative amplitude related to differences in the structure and organization of fibers between species? To address this question, we have quantitatively examined the structure and organization of fibers in a number of the more commonly used animal models (mice, cattle, frogs, rabbits and chickens) for lens research. MATERIALS AND METHODS: Lenses (a minimum of 12-18 lenses/species) from mice, cattle, frogs and rabbits were used for this study. Prior to fixation for structural analysis, measurements of the gross shape of the lenses (equatorial diameter, anterior and posterior minor radii [anterior + posterior minor radius = polar axis]) were taken directly through a stereo surgical dissecting microscope equipped with an ocular reticle. Lenses were then prepared for and examined by light (LM), transmission (TEM) and scanning electron microscopy (SEM). Scale computer-assisted drawings (CADs) of lenses and lens fibers were then constructed from quantitative data as described above and from quantitative data contained in micrographs. RESULTS: The differences in fiber structure and organization that effect accommodative range arise early in development and are continued throughout lifelong lens growth. In umbilical suture lenses (avian) secondary fibers develop with almost completely tapered anterior ends (85-90% reduction of their measures of width and thickness at the equator). By comparison, in lenses with line sutures (e.g. frogs and rabbits) secondary fibers develop with just a 50-60% reduction in anterior fiber taper. In lenses with Y sutures (mice and cattle), fiber width taper is only 25-40%. However, in all cases, while the taper of the posterior end width of fibers is just slightly less (approx. 15-20%) than that of anterior ends, posterior end thickness is only reduced by one half that of anterior thickness. CONCLUSIONS: In humans, the mechanism of accommodation at the fiber level involves the controlled realignment of very flattened and flared, rather than tapered fiber-ends at sutures. In this manner, the simultaneous increase in lens thickness and surface curvature in the accommodated state is the result of fiber-ends being overlapped along multiple (9-12) suture branches covering the majority of the anterior and posterior surfaces. The results of this animal study strongly suggest that accommodative range is directly related to quantitative differences in fiber structure and organization in the different suture types. The very broad accommodative range in birds is made possible, at least in part, by the almost complete tapering of fiber-ends at umbilical sutures. In contrast, the essentially negligible accommodative range of animals that have line- and Y-suture lenses is at least partially the result of the fact that these lenses have fibers with very little end taper. Thus, the blunt ends of fibers in line- and Y-suture lenses precludes any significant overlap of end segments to effect accommodation.

The clinical course of the Infectious Laryngotracheitis (ILT) field case in hens and estimation of immunoprophylaxis efficiency.

The ILT case was observed in laying hen farm where birds of different age (from 40 to 107 weeks) were kept in 10 flocks. A rapid spread of the disease, the decrease in egg production (in flock No. 1 it reached 58%) and higher mortality (the highest in 76 and 77 week-old birds, accounting for 0.11% and 0.36%, respectively ) was recorded during first 2 weeks of disease. Antibodies against ILT virus were detected in serum of the examined birds during the whole observation period (50 weeks after the disease outbreak). The laying hens were vaccinated at 8 weeks of age and boosted after 5 weeks. The vaccine was applied in drinking water, in a dose twice as high as usually recommended per one bird. Immunopropylaxis efficiency was estimated on the basis of immunological response in birds (serum samples, ILT ELISA kit, Guildhay Ltd.) and general health status of hens in flocks. Postvaccinal immunity, the presence of specific antibodies against ILT, was observed in all birds during the observation period (51 weeks). During that time GMT value ranged from 8261,3 (week 10) to 5196 (week 51) after the second vaccination, and CV amounted in this period to 41.1% and 51%, respectively. Subsequently, clinical symptoms of the disease disappeared and the egg production, as well as mortality, returned to the level of technological norms for laying hens.

Comparison of ITS profiling, REP- and ERIC-PCR of Salmonella Enteritidis isolates from Poland.

Thirty-one Salmonella Enteritidis strains isolated from chickens, broilers and hens were analysed by genotypic typing including REP-PCR. ERIC-PCR and ITS profiling (PCR-ribotyping). Analysis of DNA banding patterns generated by REP-PCR revealed the presence of 22 different genotypes, which were grouped by dendrogram analysis into three distinct lineages (maximum similarity approx. 50%). Each isolate of S. Enteritidis analysed by ERIC-PCR generated an individual DNA pattern. Again, these isolates could be divided into three distinct genomic groups (maximum similarity approx. 60%) by their ERIC-PCR fingerprints. REP- and ERIC-PCR were found to be more discriminatory for typing of S. Enteritidis than ITS profiling. Amplification of the 16S-23S rDNA spacer region gave nine different profiles of DNA, subdivided into two closely related groups by dendrogram analysis. In summary, data obtained by genotyping methods for S. Enteritidis isolates from regions located in the south-west and the central parts of Poland revealed an enormous heterogeneity among analysed samples, and proved that REP- and ERIC-PCR are highly discriminatory techniques, which can be used, in addition to conventional methods, in epidemiological studies of S. Enteritidis infections.

A multicentre randomized/controlled trial of a conventional versus modestly accelerated radiotherapy in the laryngeal cancer: influence of a 1 week shortening overall time.

BACKGROUND AND PURPOSE: To compare in a phase III study the loco-regional control, disease-free survival and overall survival induced by an accelerated regimen (AF) as compared with conventional regimen (CF) and to analyze the early and late post-radiation morbidity in both arms. MATERIALS AND METHODS: Patients with age < or = 75, WHO 0-1, suitable for a radical course of radiotherapy T1-T3, N0, M0, stage of glottic and supraglottic laryngeal cancer were randomized to either CF: 66Gy given in 33 fractions over 45 days or AF: 66Gy given in 33 fractions over 38 days (2 fractions every Thursday). A total of 395 patients were included from 05.1995 to 12.1998. RESULTS: Early toxicity: At the end of radiotherapy patients treated with AF complained for more severe reactions than patients treated with CF. In 8 weeks after treatment completion patients treated with AF complained only for more severe pain on swallowing (P=0.027). In 4 months after treatment completion all types of toxicity except for skin teleangiectasia (P=0.001) were similar in the two groups. Loco-regional control: comparison between CF and AF showed no difference in terms of loco-regional control (P=0.37). CONCLUSIONS: The improvement in AF in terms of loco-regional control is estimated to be 3-5% in comparison with conventional regimen and is not significant. The intensity of reactions after 4 months was similar in both arms, what suggests the possibility of further shortening of the overall time by few days or enhancing the total dose within the limits of acceptable morbidity.

[Cisplatin and vinorelbine therapy of previously treated advanced breast cancer (preliminary studies)]. / Cisplatyna i winorelbina jako kolejny rzut leczenia w zaawansowanym raku piersi (doniesienie wstepne).

In this work it was investigated the efficacy of second and third line chemotherapy (vinorelbine, cisplatin/carboplatin) in patients with metastases breast cancer. The twenty pre-treated women with metastases to the liver, lung, lymph nodules and subcutaneous tissue were treated the regiment including navelbine 30 mg day 1 and 5 and cisplatin 100 mg/m2 day 1 every 3 weeks. The patients had been early received CMF and/or FAC. The total response rate was 40%. The median time to progression was 8 months. The stabilisation disease was at 20% patients. The tolerance of treatment was good and the frequent complication was leucopenia (WHO 2 and 3) and thrombocytopenia (WHO 1). The women received from 6 to 10 courses.

Intercellular cytoplasm transport during oogenesis of the moth midge, Tinearia alternata Say (Diptera: Psychodidae).

Polytrophic ovaries of the nematocerous dipteran, Tinearia alternata Say consists of several developmentally synchronized ovarioles each housing only one functional egg chamber with 15 nurse cells and an oocyte. At the early stages of previtellogenesis the nurse cells become polyploid and synthetically active. Their nuclei contain polytene chromosomes and prominent nucleoli. With the advance of previtellogenic growth the nurse cell cytoplasm is loaded with the growing number of ribosomes and contain perinuclear nuage material, mitochondria, electron dense bodies and aggregations of endoplasmic reticulum. All these organelles are transported into the oocyte thanks to the massive and rapid flow of the nurse cell cytoplasmic contents. Nurse cell-oocyte transport is mediated by actin cytoskeleton. Prior to the rapid cytoplasm transfer, F-actin network is associated with the nurse cell membranes while tiny bundles of microfilaments form actin baskets connected with ring canals. Nurse cells in Tinearia lack an extensive scaffold of radially oriented, F-actin bundles (cables) that would tether their nuclei in place, thus preventing ring canals from plugging. The way the nuclei are anchored to their central positions within the cells remains unclear. Towards the final stages of oogenesis nurse cells are almost devoid of cytoplasm and degenerate. Although their nuclei undergo dramatic morphological transformations, typical hallmarks of apoptotic pathway could not be clearly observed. Rapid ooplasmic streaming does not occur.

[Induction chemotherapy and radiotherapy in locally advanced head and neck carcinoma]. / Wartosc chemioterapii indukcyjnej w leczeniu napromienianiem zaawansowanych nowotworów glowy i szyi.

The value of inductive chemotherapy preceding the radical irradiation of locally advanced neoplasms of head and neck has been estimated. The following have been applied: cisplatin, adriamycin, bleomycin, or cyclophosphamide, adriamycin, 5-fluorouracil, or cisplatin 5-fluorouracil. A reaction to treatment in the form of CR and PR has been achieved in 71.5% of the treated patients. Irradiation was started in two to four weeks after chemotherapy had been stopped. After combined treatment the proportion of 69.5% CR and PR was achieved. The average length of time of CR and PR was 8.7 months. Treatment was well tolerated.

[Operations of parotid malignant tumors]. / Operacje nowotworów zlosliwych slinianek przyusznych.

In a group of 64 patients with malignant tumours of the parotid gland the most common type was adenoid cystic carcinoma (20%) and malignant pleomorphic adenoma (14%). A group of 33 patients with follow-up from 4 months to 18 years was analyzed. The overall 5-year survival rate was 45%.

The role of GABA-ergic system in human mammary gland pathology and in growth of transplantable murine mammary cancer.

In this paper we described the results of our studies on the baclophen (gamma aminobutyric acid (GABA)-B receptor agonist) inhibitory effect on the growth of experimental mammary cancer 16/C in mice and on the estimation of GABA level and GAD (glutamine acid decarboxylase--the key enzyme in GABA synthesis) activity after this treatment in mice. The experimental data are confronted with the estimation of GABA level and GAD activity in human mammary gland material taken from the patients with benign breast tumors of different pathological and age related hormonal stages. A significant inhibition of 16/C tumor growth in treated with baclophen mice was observed. Mean GABA level and GAD activity were significantly higher both in tumor and in normal tissue of baclophen treated mice in comparison to control animals. The results of clinical studies have shown that the lowest GABA level and GAD activity in tumor and normal mammary gland tissue was detected in patients in peri-menopausal stage. Both, in human and mouse material, the GABA level and GAD activity were higher in tumor than in normal tissue and there was a clear positive correlation between GABA level and GAD activity in both tissues studied. GABA level and GAD activity in tumor and in normal tissue were lower in patients with dysplasia than in patients with fibroadenoma. Considering our results, namely an inhibitory effect of GABA receptor agonist on mammary cancer growth and the correlation between GABA level and the stage of breast pathology and/or hormonal activity, it seems probable that GABA-ergic system is involved in hormonal regulation and pathogenesis of breast cancer.