Variation in treatment modalities, costs and outcomes of rectal cancer patients in Poland

Aim of the study: To evaluate outcome, costs and treatment differences in rectal cancer patients between various regions in Poland. Material and methods: Data from the Polish National Health Fund of all patients with rectal cancer diagnosed and treated between 2005 and 2007 were analyzed. Overall, relative 5-year survival and the percentage of patients receiving chemotherapy, radiotherapy and surgery were analyzed. The possible influence of cost of treatment per patient and mean number of rectal cancer patients per surgical oncologist were analyzed as well. Results: In total 15,281 patients with rectal cancer were diagnosed and treated in Poland in 2005–2007 within the services of the National Health Fund. The overall, relative 5-year survival rate was 51.6%. Curative surgery was performed in 64.1% of patients. Radiotherapy and chemotherapy were used in 47.5% and 60.7% of patients, respectively. The mean cost of treatment of one rectal cancer patient was 32,800 PLN and there were 49.8 rectal cancer patients per specialist in surgical oncology. Important differences between regions were found in all these factors, but without a significant influence on survival. A correlation between numbers of patients per specialist in different voivodeships and survival rates was observed, as well as a correlation between percentage of surgical resection in voivodeships and survival rates (p = 0.07). Conclusions: Results of treatment of colorectal cancer in Poland improved significantly during the last decade. There exist however, important disparities between regions in terms of method of treatment, costs and outcomes

Perspektywy skojarzonego leczenia raka wątrobowokomórkowego

Rak wątrobowokomórkowy (HCC) stanowi około 80% pierwotnych nowotworów wątroby oraz jest 5. przyczynązgonów z powodu nowotworów na świecie. Dotychczasowe postępy w diagnostyce oraz leczeniu HCC nie przełożyłysię na istotną poprawę rokowania. W zależności od zaawansowania choroby, a także obecności nadciśnieniawrotnego oraz chorób współistniejących, pacjenci mogą być poddawani takim zabiegom jak resekcja wątroby,transplantacja wątroby, leczenie z wykorzystaniem metod miejscowych: przeztętniczej chemoembolizacji (TACE),ablacji falami o częstotliwości radiowej (RFA) czy przezskórnego wstrzyknięcia etanolu (PEI). W przypadku chorobyzaawansowanej i dyskwalifikacji od leczenia miejscowego stosuje się sorafenib.Obecnie prowadzi się badania kliniczne nad kojarzeniem wyżej wymienionych metod leczenia. W przypadkuleczenia radykalnego obejmują one łączenie resekcji lub ablacji z zastosowaniem sorafenibu. U pacjentówz chorobą o pośrednim stopniu zaawansowania wykonuje się zabiegi TACE. Kojarzenie TACE z leczeniemsystemowym w różnych sekwencjach jest oceniane w badaniach klinicznych. Aktualnie trwają również badanianad łączeniem sorafenibu z cytostatykami, z terapiami celowanymi, a także z inhibitorami deacetylaz histonów(faza badań przedklinicznych)

Fast-neutron induced pre-equilibrium reactions on 55Mn and 63,65Cu at energies up to 40 MeV

Excitation functions were measured for the $^{55}$Mn(n,2n)$^{54}$Mn, $^{55}$Mn(n,$\alpha$)$^{52}$V, $^{63}$Cu(n,$\alpha$)$^{60}$Co, $^{65}$Cu(n,2n)$^{64}$Cu, and $^{65}$Cu(n,p)$^{65}$Ni reactions from 13.47 to 14.83 MeV. The experimental cross sections are compared with the results of calculations including all activation channels for the stable isotopes of Mn and Cu, for neutron incident energies up to 50 MeV. Within the energy range up to 20 MeV the model calculations are most sensitive to the parameters related to nuclei in the early stages of the reaction, while the model assumptions are better established by analysis of the data in the energy range 20-40 MeV. While the present analysis has taken advantage of both a new set of accurate measured cross sections around 14 MeV and the larger data basis fortunately available between 20 and 40 MeV for the Mn and Cu isotopes, the need of additional measurements below as well as above 40 MeV is pointed out. Keywords: 55Mn, 63,65Cu, E$\leq$40 MeV, Neutron activation cross section measurements, Nuclear reactions, Model calculations, Manganese, CopperComment: 39 pages, 12 figure

Aberrant DNA Methylation Is Associated with Disease Progression, Resistance to Imatinib and Shortened Survival in Chronic Myelogenous Leukemia

The epigenetic impact of DNA methylation in chronic myelogenous leukemia (CML) is not completely understood. To elucidate its role we analyzed 120 patients with CML for methylation of promoter-associated CpG islands of 10 genes. Five genes were identified by DNA methylation screening in the K562 cell line and 3 genes in patients with myeloproliferative neoplasms. The CDKN2B gene was selected for its frequent methylation in myeloid malignancies and ABL1 as the target of BCR-ABL translocation. Thirty patients were imatinib-naïve (mostly treated by interferon-alpha before the imatinib era), 30 were imatinib-responsive, 50 were imatinib-resistant, and 10 were imatinib-intolerant. We quantified DNA methylation by bisulfite pyrosequencing. The average number of methylated genes was 4.5 per patient in the chronic phase, increasing significantly to 6.2 in the accelerated and 6.4 in the blastic phase. Higher numbers of methylated genes were also observed in patients resistant or intolerant to imatinib. These patients also showed almost exclusive methylation of a putative transporter OSCP1. Abnormal methylation of a Src suppressor gene PDLIM4 was associated with shortened survival independently of CML stage and imatinib responsiveness. We conclude that aberrant DNA methylation is associated with CML progression and that DNA methylation could be a marker associated with imatinib resistance. Finally, DNA methylation of PDLIM4 may help identify a subset of CML patients that would benefit from treatment with Src/Abl inhibitors

Environmental Levels of the Antiviral Oseltamivir Induce Development of Resistance Mutation H274Y in Influenza A/H1N1 Virus in Mallards

Oseltamivir (Tamiflu®) is the most widely used drug against influenza infections and is extensively stockpiled worldwide as part of pandemic preparedness plans. However, resistance is a growing problem and in 2008–2009, seasonal human influenza A/H1N1 virus strains in most parts of the world carried the mutation H274Y in the neuraminidase gene which causes resistance to the drug. The active metabolite of oseltamivir, oseltamivir carboxylate (OC), is poorly degraded in sewage treatment plants and surface water and has been detected in aquatic environments where the natural influenza reservoir, dabbling ducks, can be exposed to the substance. To assess if resistance can develop under these circumstances, we infected mallards with influenza A/H1N1 virus and exposed the birds to 80 ng/L, 1 µg/L and 80 µg/L of OC through their sole water source. By sequencing the neuraminidase gene from fecal samples, we found that H274Y occurred at 1 µg/L of OC and rapidly dominated the viral population at 80 µg/L. IC50 for OC was increased from 2–4 nM in wild-type viruses to 400–700 nM in H274Y mutants as measured by a neuraminidase inhibition assay. This is consistent with the decrease in sensitivity to OC that has been noted among human clinical isolates carrying H274Y. Environmental OC levels have been measured to 58–293 ng/L during seasonal outbreaks and are expected to reach µg/L-levels during pandemics. Thus, resistance could be induced in influenza viruses circulating among wild ducks. As influenza viruses can cross species barriers, oseltamivir resistance could spread to human-adapted strains with pandemic potential disabling oseltamivir, a cornerstone in pandemic preparedness planning. We propose surveillance in wild birds as a measure to understand the resistance situation in nature and to monitor it over time. Strategies to lower environmental levels of OC include improved sewage treatment and, more importantly, a prudent use of antivirals

Wnt signalling in human breast cancer: expression of the putative Wnt inhibitor Dickkopf-3 (DKK3) is frequently suppressed by promoter hypermethylation in mammary tumours

INTRODUCTION: Expression of the putative Wnt signalling inhibitor Dickkopf-3 (DKK3) is frequently lost in human cancer tissues because of aberrant 5'-cytosine methylation within the DKK3 gene promoter. Since other Wnt signalling inhibitors have been reported to be targets of epigenetic inactivation in human breast cancer, we questioned if DKK3 expression is also epigenetically silenced during breast carcinogenesis and therefore might contribute to oncogenic Wnt signalling commonly found in this disease. METHODS: DKK3 mRNA expression and DKK3 promoter methylation were determined by RT-PCR, realtime PCR and methylation-specific PCR in breast cell lines (n = 9), normal breast tissues (n = 19) and primary breast carcinomas (n = 150), respectively. In vitro DNA demethylation was performed by incubating breast cell lines with 5-aza-2'-deoxycytidine and trichostatin A. DKK3 protein expression was analysed by immunohistochemistry in breast carcinomas (n = 16) and normal breast tissues (n = 8). Methylation data were statistically correlated with clinical patient characteristics. All statistical evaluations were performed with SPSS 14.0 software. RESULTS: DKK3 mRNA was downregulated in 71% (five of seven) of breast cancer cell lines and in 68% of primary breast carcinomas (27 of 40) compared with benign cell lines and normal breast tissues, respectively. A DNA demethylating treatment of breast cell lines resulted in strong induction of DKK3 mRNA expression. In tumourous breast tissues, DKK3 mRNA downregulation was significantly associated with DKK3 promoter methylation (p < 0.001). Of the breast carcinomas, 61% (92 of 150) revealed a methylated DKK3 promoter, whereas 39% (58 of 150) retained an unmethylated promoter. Loss of DKK3 expression in association with DKK3 promoter methylation (p = 0.001) was also confirmed at the protein level (p < 0.001). In bivariate analysis, DKK3 promoter methylation was not associated with investigated clinicopathological parameters except patient age (p = 0.007). CONCLUSIONS: DKK3 mRNA expression and consequently DKK3 protein expression become frequently downregulated during human breast cancer development due to aberrant methylation of the DKK3 promoter. Since DKK3 is thought to negatively regulate oncogenic Wnt signalling, DKK3 may be a potential tumour suppressor gene in normal breast tissue

Mechanisms of Resistance to Decitabine in the Myelodysplastic Syndrome

Purpose: The DNA methylation inhibitor 5-aza-29-deoxycytidine (DAC) is approved for the treatment of myelodysplastic syndromes (MDS), but resistance to DAC develops during treatment and mechanisms of resistance remain unknown. Therefore, we investigated mechanisms of primary and secondary resistance to DAC in MDS. Patients and Methods: We performed Quantitative Real-Time PCR to examine expression of genes related to DAC metabolism prior to therapy in 32 responders and non-responders with MDS as well as 14 patients who achieved a complete remission and subsequently relapsed while on therapy (secondary resistance). We then performed quantitative methylation analyses by bisulfite pyrosequencing of 10 genes as well as Methylated CpG Island Amplification Microarray (MCAM) analysis of global methylation in secondary resistance. Results: Most genes showed no differences by response, but the CDA/DCK ratio was 3 fold higher in non-responders than responders (P,.05), suggesting that this could be a mechanism of primary resistance. There were no significant differences at relapse in DAC metabolism genes, and no DCK mutations were detected. Global methylation measured by the LINE1 assay was lower at relapse than at diagnosis (P,.05). On average, the methylation of 10 genes was lower at relapse (16.1%) compared to diagnosis (18.1%) (P,.05).MCAM analysis showed decreased methylation of an average of 4.5 % (range 0.6%– 9.7%) of the genes at relapse. By contrast, new cytogenetic changes were found in 20 % of patients

Intercomparison of NO2, O4, O3 and HCHO slant column measurements by MAX-DOAS and zenith-sky UV¿visible spectrometers during CINDI-2

40 pags., 22 figs., 13 tabs.In September 2016, 36 spectrometers from 24 institutes measured a number of key atmospheric pollutants for a period of 17¿d during the Second Cabauw Intercomparison campaign for Nitrogen Dioxide measuring Instruments (CINDI-2) that took place at Cabauw, the Netherlands (51.97¿¿N, 4.93¿¿E). We report on the outcome of the formal semi-blind intercomparison exercise, which was held under the umbrella of the Network for the Detection of Atmospheric Composition Change (NDACC) and the European Space Agency (ESA). The three major goals of CINDI-2 were (1) to characterise and better understand the differences between a large number of multi-axis differential optical absorption spectroscopy (MAX-DOAS) and zenith-sky DOAS instruments and analysis methods, (2) to define a robust methodology for performance assessment of all participating instruments, and (3) to contribute to a harmonisation of the measurement settings and retrieval methods. This, in turn, creates the capability to produce consistent high-quality ground-based data sets, which are an essential requirement to generate reliable long-term measurement time series suitable for trend analysis and satellite data validation. The data products investigated during the semi-blind intercomparison are slant columns of nitrogen dioxide (NO2), the oxygen collision complex (O4) and ozone (O3) measured in the UV and visible wavelength region, formaldehyde (HCHO) in the UV spectral region, and NO2 in an additional (smaller) wavelength range in the visible region. The campaign design and implementation processes are discussed in detail including the measurement protocol, calibration procedures and slant column retrieval settings. Strong emphasis was put on the careful alignment and synchronisation of the measurement systems, resulting in a unique set of measurements made under highly comparable air mass conditions. The CINDI-2 data sets were investigated using a regression analysis of the slant columns measured by each instrument and for each of the target data products. The slope and intercept of the regression analysis respectively quantify the mean systematic bias and offset of the individual data sets against the selected reference (which is obtained from the median of either all data sets or a subset), and the rms error provides an estimate of the measurement noise or dispersion. These three criteria are examined and for each of the parameters and each of the data products, performance thresholds are set and applied to all the measurements. The approach presented here has been developed based on heritage from previous intercomparison exercises. It introduces a quantitative assessment of the consistency between all the participating instruments for the MAX-DOAS and zenith-sky DOAS techniques.CINDI-2 received funding from the Netherlands Space Office (NSO). Funding for this study was provided by ESA through the CINDI-2 (ESA contract no. 4000118533/16/ISbo) and FRM4DOAS (ESA contract no. 4000118181/16/I-EF) projects and partly within the EU 7th Framework Programme QA4ECV project (grant agreement no. 607405). The BOKU MAX-DOAS instrument was funded and the participation of Stefan F. Schreier was supported by the Austrian Science Fund (FWF): I 2296-N29. The participation of the University of Toronto team was supported by the Canadian Space Agency (through the AVATARS project) and the Natural Sciences and Engineering Research Council (through the PAHA project). The instrument was primarily funded by the Canada Foundation for Innovation and is usually operated at the Polar Environment Atmospheric Research Laboratory (PEARL) by the Canadian Network for the Detection of Atmospheric Change (CANDAC). Funding for CISC was provided by the UVAS (“Ultraviolet and Visible Atmospheric Sounder”) projects SEOSAT/INGENIO, ESP2015-71299- R, MINECO-FEDER and UE. The activities of the IUP-Heidelberg were supported by the DFG project RAPSODI (grant no. PL 193/17-1). SAOZ and Mini-SAOZ instruments are supported by the Centre National de la Recherche Scientifique (CNRS) and the Centre National d’Etudes Spatiales (CNES). INTA recognises support from the National funding projects HELADO (CTM2013-41311-P) and AVATAR (CGL2014-55230-R). AMOIAP recognises support from the Russian Science Foundation (grant no. 16-17-10275) and the Russian Foundation for Basic Research (grant nos. 16-05- 01062 and 18-35-00682). Ka L. Chan received transnational access funding from ACTRIS-2 (H2020 grant agreement no. 654109). Rainer Volkamer recognises funding from NASA’s Atmospheric Composition Program (NASA-16-NUP2016-0001) and the US National Science Foundation (award AGS-1620530). Henning Finkenzeller is the recipient of a NASA graduate fellowship. Mihalis Vrekoussis recognises support from the University of Bremen and the DFG Research Center/Cluster of Excellence “The Ocean in the Earth System-MARUM”. Financial support through the University of Bremen Institutional Strategy in the framework of the DFG Excellence Initiative is gratefully appreciated for Anja Schönhardt. Pandora instrument deployment was supported by Luftblick through the ESA Pandonia Project and NASA Pandora Project at the Goddard Space Flight Center under NASA Headquarters’ Tropospheric Composition Program. The article processing charges for this open-access publication were covered by BK Scientific

Impact of the HIV-1 env Genetic Context outside HR1–HR2 on Resistance to the Fusion Inhibitor Enfuvirtide and Viral Infectivity in Clinical Isolates

Resistance mutations to the HIV-1 fusion inhibitor enfuvirtide emerge mainly within the drug's target region, HR1, and compensatory mutations have been described within HR2. The surrounding envelope (env) genetic context might also contribute to resistance, although to what extent and through which determinants remains elusive. To quantify the direct role of the env context in resistance to enfuvirtide and in viral infectivity, we compared enfuvirtide susceptibility and infectivity of recombinant viral pairs harboring the HR1–HR2 region or the full Env ectodomain of longitudinal env clones from 5 heavily treated patients failing enfuvirtide therapy. Prior to enfuvirtide treatment onset, no env carried known resistance mutations and full Env viruses were on average less susceptible than HR1–HR2 recombinants. All escape clones carried at least one of G36D, V38A, N42D and/or N43D/S in HR1, and accordingly, resistance increased 11- to 2800-fold relative to baseline. Resistance of full Env recombinant viruses was similar to resistance of their HR1–HR2 counterpart, indicating that HR1 and HR2 are the main contributors to resistance. Strictly X4 viruses were more resistant than strictly R5 viruses, while dual-tropic Envs featured similar resistance levels irrespective of the coreceptor expressed by the cell line used. Full Env recombinants from all patients gained infectivity under prolonged drug pressure; for HR1–HR2 viruses, infectivity remained steady for 3/5 patients, while for 2/5 patients, gains in infectivity paralleled those of the corresponding full Env recombinants, indicating that the env genetic context accounts mainly for infectivity adjustments. Phylogenetic analyses revealed that quasispecies selection is a step-wise process where selection of enfuvirtide resistance is a dominant factor early during therapy, while increased infectivity is the prominent driver under prolonged therapy