• Publikační typ
• abstrakt z konference MeSH

BACKGROUND: Vinorelbine constitutes effective chemotherapy for metastatic breast cancer (MBC) and acts synergistically with trastuzumab in HER-2/neu positive disease. The present study was set out to evaluate the efficacy and safety of vinorelbine when combined with lapatinib, an anti-HER2 tyrosine-kinase inhibitor, as late-line regimen administered beyond previous disease progression on prior lapatinib in patients with HER-2/neu- positive MBC. METHODS: The CECOG LaVie study was designed as open-labeled, single-arm, multicenter phase II trial. Patients had to be pretreated with lapatinib plus chemotherapy, and received lapatinib at a daily dose of 1250 mg in combination with vinorelbine 20 mg/m(2) i.v. on days 1 and 8 of a three-week cycle until disease progression, intolerable toxicity or withdrawal of consent. Progression-free survival (PFS) was defined as primary study endpoint; secondary endpoints included overall survival (OS), response rate according to RECIST 1.1, and safety. The study was terminated early due to poor accrual. RESULTS: A total number of nine patients were included; lapatinib administered beyond disease progression combined with vinorelbine resulted in a median PFS of 7.7 months (95% CI 0.56-14.91) and a median OS of 23.4 months (95% CI 16.61-30.13), respectively. Partial remission was seen in one of nine patients, three patients had stable disease of > six months, whereas the remaining five patients had primary disease progression. In two patients, modification of vinorelbine dose due to toxicity became necessary; no dose modification was needed for lapatinib. The majority of reported adverse events (AE) were grade 1 and 2 in severity with diarrhea being the most commonly observed AE CONCLUSION: In this heavily pretreated patient population, combination of vinorelbine plus lapatinib showed encouraging activity and was characterized by an acceptable safety profile. Despite the low patient number, lapatinib plus vinorelbine may constitute a potential treatment option in heavily pretreated patients with HER-2/neu-positive MBC previously exposed to lapatinib. TRIAL REGISTRATION: EudraCT number 2009-016826-15, (15. 10.2009).

• MeSH
• chinazoliny aplikace a dávkování   škodlivé účinky   terapeutické užití   MeSH
• dospělí MeSH
• kombinovaná farmakoterapie MeSH
• lidé středního věku MeSH
• lidé MeSH
• nádory prsu farmakoterapie   MeSH
• protinádorové látky aplikace a dávkování   škodlivé účinky   terapeutické užití   MeSH
• receptor erbB-2 MeSH
• senioři MeSH
• vinblastin aplikace a dávkování   škodlivé účinky   analogy a deriváty   terapeutické užití   MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• klinické zkoušky, fáze II MeSH
• multicentrická studie MeSH
• práce podpořená grantem MeSH

• MeSH
• deoxycytidin analogy a deriváty   aplikace a dávkování   MeSH
• fluoruracil analogy a deriváty   aplikace a dávkování   MeSH
• humanizované monoklonální protilátky aplikace a dávkování   MeSH
• kolorektální nádory * farmakoterapie   mortalita   patologie   MeSH
• lidé MeSH
• míra přežití MeSH
• nádory jater * farmakoterapie   mortalita   sekundární   MeSH
• nádory plic * farmakoterapie   mortalita   sekundární   MeSH
• následné studie MeSH
• prognóza MeSH
• protokoly protinádorové kombinované chemoterapie * terapeutické užití   MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• staging nádorů MeSH
• Check Tag
• lidé MeSH
• mužské pohlaví MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• klinické zkoušky, fáze III MeSH
• multicentrická studie MeSH
• práce podpořená grantem MeSH
• randomizované kontrolované studie MeSH
• srovnávací studie MeSH

Lapatinib is a HER1 and HER2 tyrosine kinase inhibitor (TKI) approved in second line treatment of advanced or metastatic breast cancer following progression on trastuzumab-containing therapy. Biomarkers for activity of lapatinib and other TKIs are lacking. Formalin-fixed, paraffin-embedded primary tumor samples were obtained from 189 HER2-positive patients treated with lapatinib plus capecitabine following progression on trastuzumab. The HERmark® Breast Cancer Assay was used to quantify HER2 protein expression. HER3 and p95HER2 protein expression was quantified using the VeraTag® technology. Overall survival (OS) was inversely correlated with HER2 (HR = 1.9/log; P = 0.009) for patients with tumors above the cut-off positivity level by the HERmark assay. OS was significantly shorter for those with above median HER2 levels (HR = 1.7; P = 0.015) and trended shorter for those below the cut-off level of positivity by the HERmark assay (HR = 1.7; P = 0.057) compared to cases with moderate HER2 overexpression. The relationship between HER2 protein expression and OS was best captured with a U-shaped parabolic function (P = 0.004), with the best prognosis at moderate levels of HER2 protein overexpression. In a multivariate model including HER2, increasing p95HER2 expression was associated with longer OS (HR = 0.35/log; P = 0.027). Continuous HER3 did not significantly correlate with OS. Patients with moderately overexpressed HER2 levels and high p95HER2 expression may have best outcomes while receiving lapatinib following progression on trastuzumab. Further study is warranted to explore the predictive utility of quantitative HER2 and p95HER2 in guiding HER2-directed therapies.

• Publikační typ
• časopisecké články MeSH

• MeSH
• chemoprofylaxe MeSH
• lidé MeSH
• nádory prsu * epidemiologie   metabolismus   patologie   MeSH
• profylaktické chirurgické výkony MeSH
• rizikové faktory MeSH
• selektivní modulátory estrogenních receptorů terapeutické užití   MeSH
• strategie hodnocení a snižování rizika (USA) MeSH
• Check Tag
• lidé MeSH
• ženské pohlaví MeSH
• Publikační typ
• přehledy MeSH

• MeSH
• analýza podle původního léčebného záměru MeSH
• aplikace orální MeSH
• časové faktory MeSH
• cílená molekulární terapie MeSH
• cyklin D1 genetika   MeSH
• cyklin-dependentní kinasa 4 antagonisté a inhibitory   metabolismus   MeSH
• cyklin-dependentní kinasa 6 antagonisté a inhibitory   metabolismus   MeSH
• inhibitor p16 cyklin-dependentní kinasy genetika   MeSH
• inhibitory aromatasy aplikace a dávkování   MeSH
• inhibitory proteinkinas aplikace a dávkování   MeSH
• lidé středního věku MeSH
• lidé MeSH
• nádorové biomarkery MeSH
• nádory prsu enzymologie   farmakoterapie   genetika   patologie   MeSH
• nitrily aplikace a dávkování   MeSH
• piperaziny MeSH
• postmenopauza MeSH
• přežití bez známek nemoci MeSH
• proporcionální rizikové modely MeSH
• protokoly protinádorové kombinované chemoterapie škodlivé účinky   terapeutické užití   MeSH
• pyridiny aplikace a dávkování   MeSH
• randomizované kontrolované studie jako téma MeSH
• receptor erbB-2 analýza   genetika   MeSH
• receptory pro estrogeny analýza   MeSH
• rozvrh dávkování léků MeSH
• senioři MeSH
• triazoly aplikace a dávkování   MeSH
• výsledek terapie MeSH
• Check Tag
• lidé středního věku MeSH
• lidé MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Geografické názvy
• Evropa MeSH
• Jihoafrická republika MeSH
• Korejská republika MeSH
• Severní Amerika MeSH

Barley chromosome 5H, carrying important QTLs for plant adaptation and tolerance to abiotic stresses, is extremely instable in the wheat genetic background and is eliminated in the early generations of wheat-barley crosses. A spontaneous wheat-barley 5HS-7DS.7DL translocation was previously obtained among the progenies of the Mv9kr1 x Igri hybrid. The present work reports on the transfer of the 5HS-7DS.7DL translocation into a modern wheat cultivar, Mv Bodri, in order to use it in the wheat breeding program. The comparison of the hybridization bands of DNA repeats HvT01, pTa71, (GAA)n and the barley centromere-specific (AGGGAG)n in Igri barley and the 5HS-7DS.7DL translocation, together with the visualization of the barley chromatin made it possible to determine the size of the introgressed barley segment, which was approximately 74% of the whole 5HS. Of the 29 newly developed PCR markers, whose source ESTs were selected from the Genome Zipper of barley chromosome 5H, 23 were mapped in the introgressed 1-0.26 FL 5HS bin, three were located in the missing C-0.26 FL region, while three markers were specific for 5HL. The translocation breakpoint was flanked by markers Hv7502 and Hv3949. A comparison of the parental wheat cultivars and the wheat-barley introgression lines indicated that the presence of the translocation improved tillering ability in the Mv9kr1 and Mv Bodri genetic background. The similar or better yield components under high- or low-input cultivation environments, respectively, indicated that the 5HS-7DS.7DL translocation had little or no negative effect on yield components, making it a promising genotype to improve wheat genetic diversity. These results promise to accelerate functional genomic studies on barley chromosome 5H and to support pre-breeding and breeding research on wheat.

• MeSH
• chromatin genetika   metabolismus   MeSH
• chromozomy rostlin MeSH
• exprimované sekvenční adresy MeSH
• genetická vazba MeSH
• genetické markery MeSH
• genotyp MeSH
• hybridizace genetická MeSH
• ječmen (rod) genetika   MeSH
• mapování chromozomů MeSH
• pšenice genetika   MeSH
• translokace genetická * MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

• MeSH
• chemorezistence účinky léků   MeSH
• dospělí MeSH
• dvojitá slepá metoda MeSH
• everolimus MeSH
• geny erbB-2 MeSH
• humanizované monoklonální protilátky aplikace a dávkování   MeSH
• Kaplanův-Meierův odhad MeSH
• lidé středního věku MeSH
• lidé MeSH
• nádory prsu farmakoterapie   genetika   mortalita   MeSH
• přežití bez známek nemoci MeSH
• proporcionální rizikové modely MeSH
• protokoly protinádorové kombinované chemoterapie terapeutické užití   MeSH
• randomizované kontrolované studie jako téma MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• sirolimus analogy a deriváty   terapeutické užití   MeSH
• výsledek terapie MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• ženské pohlaví MeSH

UNLABELLED: Molecular mechanisms of lapatinib resistance in breast cancer are not well understood. The aim of this study was to correlate expression of selected proteins involved in ErbB family signaling pathways with clinical efficacy of lapatinib. Study group included 270 HER2-positive advanced breast cancer patients treated with lapatinib and capecitabine. Immunohistochemical expression of phosphorylated adenosine monophosphate-activated protein (p-AMPK), mitogen-activated protein kinase (p-MAPK), phospho (p)-p70S6K, cyclin E, phosphatase and tensin homolog were analyzed in primary breast cancer samples. The best discriminative value for progression-free survival (PFS) was established for each biomarker and subjected to multivariate analysis. At least one biomarker was determined in 199 patients. Expression of p-p70S6K was independently associated with longer (HR 0.45; 95% CI: 0.25-0.81; p = 0.009), and cyclin E with shorter PFS (HR 1.83; 95% CI: 1.06-3.14; p = 0.029). Expression of p-MAPK (HR 1.61; 95% CI 1.13-2.29; p = 0.009) and cyclin E (HR 2.99; 95% CI: 1.29-6.94; p = 0.011) was correlated with shorter, and expression of estrogen receptor (HR 0.65; 95% CI 0.43-0.98; p = 0.041) with longer overall survival. Expression of p-AMPK negatively impacted response to treatment (HR 3.31; 95% CI 1.48-7.44; p = 0.004) and disease control (HR 3.07; 95% CI 1.25-7.58; p = 0.015). IN CONCLUSION: the efficacy of lapatinib seems to be associated with the activity of downstream signaling pathways - AMPK/mTOR and Ras/Raf/MAPK. Further research is warranted to assess the clinical utility of these data and to determine a potential role of combining lapatinib with MAPK pathway inhibitors.

• MeSH
• chinazoliny terapeutické užití   MeSH
• cyklin E metabolismus   MeSH
• dospělí MeSH
• fosforylace účinky léků   MeSH
• hodnocení výsledků zdravotní péče metody   statistika a číselné údaje   MeSH
• imunohistochemie metody   MeSH
• inhibitory proteinkinas farmakologie   MeSH
• Kaplanův-Meierův odhad MeSH
• kinasy ribozomálního proteinu S6, 70-kDa metabolismus   MeSH
• lidé středního věku MeSH
• lidé MeSH
• mitogenem aktivované proteinkinasy metabolismus   MeSH
• mladý dospělý MeSH
• nádory prsu farmakoterapie   metabolismus   patologie   MeSH
• prediktivní hodnota testů MeSH
• prognóza MeSH
• proporcionální rizikové modely MeSH
• receptor erbB-2 antagonisté a inhibitory   metabolismus   MeSH
• receptory pro estrogeny metabolismus   MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mladý dospělý MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

BACKGROUND AND AIMS: Aegilops markgrafii (CC) and its natural hybrids Ae. triuncialis (U(t)U(t)C(t)C(t)) and Ae. cylindrica (D(c)D(c)C(c)C(c)) represent a rich reservoir of useful genes for improvement of bread wheat (Triticum aestivum), but the limited information available on their genome structure and the shortage of molecular (cyto-) genetic tools hamper the utilization of the extant genetic diversity. This study provides the complete karyotypes in the three species obtained after fluorescent in situ hybridization (FISH) with repetitive DNA probes, and evaluates the potential of flow cytometric chromosome sorting. METHODS: The flow karyotypes obtained after the analysis of 4',6-diamidino-2-phenylindole (DAPI)-stained chromosomes were characterized and the chromosome content of the peaks on the flow karyotypes was determined by FISH. Twenty-nine conserved orthologous set (COS) markers covering all seven wheat homoeologous chromosome groups were used for PCR with DNA amplified from flow-sorted chromosomes and genomic DNA. KEY RESULTS: FISH with repetitive DNA probes revealed that chromosomes 4C, 5C, 7C(t), T6U(t)S.6U(t)L-5C(t)L, 1C(c) and 5D(c) could be sorted with purities ranging from 66 to 91 %, while the remaining chromosomes could be sorted in groups of 2-5. This identified a partial wheat-C-genome homology for group 4 and 5 chromosomes. In addition, 1C chromosomes were homologous with group 1 of wheat; a small segment from group 2 indicated 1C-2C rearrangement. An extensively rearranged structure of chromosome 7C relative to wheat was also detected. CONCLUSIONS: The possibility of purifying Aegilops chromosomes provides an attractive opportunity to investigate the structure and evolution of the Aegilops C genome and to develop molecular tools to facilitate the identification of alien chromatin and support alien introgression breeding in bread wheat.

• MeSH
• chromozomy rostlin genetika   MeSH
• genom rostlinný * MeSH
• hybridizace in situ fluorescenční MeSH
• indoly MeSH
• karyotyp MeSH
• karyotypizace MeSH
• konzervovaná sekvence genetika   MeSH
• lipnicovité genetika   MeSH
• metafáze MeSH
• průtoková cytometrie metody   MeSH
• pšenice genetika   MeSH
• sekvenční homologie nukleových kyselin MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH