BACKGROUND: Hepatocellular carcinoma (HCC) is one of the most common and lethal malignant tumours worldwide. Sorafenib (SOR) is one of the most effective single-drug systemic therapy against advanced HCC, but the identification of novel combination regimens for a continued improvement in overall survival is a big challenge. Recent studies highlighted the crucial role of focal adhesion kinase (FAK) in HCC growth. The aim of this study was to investigate the antitumor effects of three different FAK inhibitors (FAKi), alone or in combination with SOR, using in vitro and in vivo models of HCC. METHODS: The effect of PND1186, PF431396, TAE226 on cell viability was compared to SOR. Among them TAE226, emerging as the most effective FAKi, was tested alone or in combination with SOR using 2D/3D human HCC cell line cultures and HCC xenograft murine models. The mechanisms of action were assessed by gene/protein expression and imaging approaches, combined with high-throughput methods. RESULTS: TAE226 was the more effective FAKi to be combined with SOR against HCC. Combined TAE226 and SOR treatment reduced HCC growth both in vitro and in vivo by affecting tumour-promoting gene expression and inducing epigenetic changes via dysregulation of FAK nuclear interactome. We characterized a novel nuclear functional interaction between FAK and the NuRD complex. TAE226-mediated FAK depletion and SOR-promoted MAPK down-modulation caused a decrease in the nuclear amount of HDAC1/2 and a consequent increase of the histone H3 lysine 27 acetylation, thus counteracting histone H3 lysine 27 trimethylation. CONCLUSIONS: Altogether, our findings provide the first evidence that TAE226 combined with SOR efficiently reduces HCC growth in vitro and in vivo. Also, our data highlight that deep analysis of FAK nuclear interactome may lead to the identification of new promising targets for HCC therapy.

• Klíčová slova
• Epigenetic, FAK, HCC, Sorafenib, Therapy,
• MeSH
• epigeneze genetická genetika   MeSH
• hepatocelulární karcinom farmakoterapie   MeSH
• lidé MeSH
• morfoliny farmakologie   terapeutické užití   MeSH
• myši inbrední NOD MeSH
• myši MeSH
• nádorové buněčné linie MeSH
• nádory jater farmakoterapie   MeSH
• proliferace buněk MeSH
• protokoly protinádorové kombinované chemoterapie farmakologie   terapeutické užití   MeSH
• sorafenib farmakologie   terapeutické užití   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• mužské pohlaví MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• morfoliny MeSH
• sorafenib MeSH
• TAE226 MeSH Prohlížeč

BACKGROUND: Translocation renal cell carcinoma (TRCC) is a rare form of RCC affecting mostly children and young adults with the occurrence of only 1-5% of all renal cell carcinomas. These carcinomas are associated with different translocations on a short arm of chromosome X in the region 11.2, which results in genetic modification of the p arm containing the transcription factor E3 gene. METHODS: Herein we report a case of a patient who was dia-gnosed with TRCC with c-Met overexpression and was treated with multiple targeted therapy agents and immunotherapy. CASE: A 28-year old woman without a significant past medical history underwent left sided total nephrectomy for TRCC. Seven months later, she developed systemic relapse and was treated with multiple lines of targeted therapy including sunitinib, everolimus, sorafenib, crizotinib, and pazopanib as well as with anti-PD-L1 antibody nivolumab, with stable disease as a best response. The most pronounced disease stabilization was achieved with sorafenib, which lasted 18 months. The patient died 81 months after initial dia-gnosis and 74 months from the dia-gnosis of metastatic disease. CONCLUSION: Improved survival observed in our patient could be related to the effectivity of tyrosine-kinase inhibitors, but notm-TOR inhibitors, even though disease stabilisation was observed as a best response. Identification of new treatment targets are warranted in this rare disease.

• Klíčová slova
• Xp11.2 translocation, c-Met, crizotinib, immunotherapy, sorafenib, targeted therapy, translocation renal cell carcinoma,
• MeSH
• cílená molekulární terapie MeSH
• dospělí MeSH
• everolimus terapeutické užití   MeSH
• fatální výsledek MeSH
• indazoly terapeutické užití   MeSH
• inhibitory proteinkinas terapeutické užití   MeSH
• karcinom z renálních buněk diagnostické zobrazování   farmakoterapie   genetika   patologie   MeSH
• krizotinib terapeutické užití   MeSH
• lidé MeSH
• lidské chromozomy X * MeSH
• nádory ledvin diagnostické zobrazování   farmakoterapie   genetika   patologie   MeSH
• nivolumab terapeutické užití   MeSH
• počítačová rentgenová tomografie MeSH
• progrese nemoci MeSH
• protinádorové látky terapeutické užití   MeSH
• protoonkogenní proteiny c-met antagonisté a inhibitory   genetika   MeSH
• pyrimidiny terapeutické užití   MeSH
• sorafenib terapeutické užití   MeSH
• sulfonamidy terapeutické užití   MeSH
• sunitinib terapeutické užití   MeSH
• transkripční faktory BHLH-Zip genetika   MeSH
• Check Tag
• dospělí MeSH
• lidé MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• kazuistiky MeSH
• Názvy látek
• everolimus MeSH
• indazoly MeSH
• inhibitory proteinkinas MeSH
• krizotinib MeSH
• nivolumab MeSH
• pazopanib MeSH Prohlížeč
• protinádorové látky MeSH
• protoonkogenní proteiny c-met MeSH
• pyrimidiny MeSH
• sorafenib MeSH
• sulfonamidy MeSH
• sunitinib MeSH
• TFE3 protein, human MeSH Prohlížeč
• transkripční faktory BHLH-Zip MeSH

BACKGROUND: Predictive markers can help tailor treatment to the individual in metastatic renal cell carcinoma (mRCC). De Ritis ratio (DRR) is associated with oncologic outcomes in various solid tumors. OBJECTIVE: To assess the value of DRR in prognosticating survival in mRCC patients treated with tyrosine-kinase inhibitors (TKI). METHODS: Overall, 220 mRCC patients treated with TKI first-line therapy were analyzed. An optimal cut-off point for DRR was determined with Youden's J. We used multiple strata for DRR, performed descriptive, Kaplan-Meier and multivariable Cox-regression analyses to assess associations of DRR with progression-free (PFS) and overall survival (OS). RESULTS: Patients above the optimal cut-off point for DRR of ≥ 1.58 had fewer liver metastases (p = 0.01). There was no difference in PFS (p > 0.05) between DRR groups. DRR above the median of 1.08 (HR 1.42; p = 0.03), DRR ≥ 1.1(HR 1.44; p = 0.02), ≥ 1.8 (HR 1.56; p = 0.03), ≥ 1.9 (HR 1.59; p = 0.02) and ≥ 2.0 (HR 1.63; p = 0.047) were associated with worse OS. These associations did not remain after multivariable adjustment. In the intermediate MSKCC group, DRR was associated with inferior OS at cut-offs ≥ 1.0 (HR 1.78; p = 0.02), ≥ 1.1 (HR 1.81; p = 0.01) and above median (HR 1.88; p = 0.007) in multivariable analyses. In patients with clear-cell histology, DRR above median (HR 1.54; p = 0.029) and DRR ≥ 1.1 (HR 1.53; p = 0.029) were associated with OS in multivariable analyses. CONCLUSION: There was no independent association between DRR and survival of mRCC patients treated with TKI in the entire cohort. However, OS of patients with intermediate risk and clear-cell histology were affected by DRR. DRR could be used for tailored decision-making in these subgroups.

• Klíčová slova
• De ritis ratio, Metastatic renal cell carcinoma, Prognostic marker, Tumor markers, Tyrosine-kinase inhibitors,
• MeSH
• alanintransaminasa analýza   krev   MeSH
• analýza přežití MeSH
• aspartátaminotransferasy analýza   krev   MeSH
• cytoredukční chirurgie metody   MeSH
• indazoly * aplikace a dávkování   škodlivé účinky   MeSH
• inhibitory proteinkinas aplikace a dávkování   škodlivé účinky   MeSH
• karcinom z renálních buněk * krev   farmakoterapie   patologie   chirurgie   MeSH
• Karnofského skóre MeSH
• lidé středního věku MeSH
• lidé MeSH
• nádory ledvin * krev   farmakoterapie   patologie   chirurgie   MeSH
• nefrektomie metody   MeSH
• prediktivní hodnota testů MeSH
• prognóza MeSH
• pyrimidiny * aplikace a dávkování   škodlivé účinky   MeSH
• sorafenib aplikace a dávkování   škodlivé účinky   MeSH
• staging nádorů MeSH
• stupeň nádoru MeSH
• sulfonamidy * aplikace a dávkování   škodlivé účinky   MeSH
• sunitinib * aplikace a dávkování   škodlivé účinky   MeSH
• Check Tag
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• alanintransaminasa MeSH
• aspartátaminotransferasy MeSH
• indazoly * MeSH
• inhibitory proteinkinas MeSH
• pazopanib MeSH Prohlížeč
• pyrimidiny * MeSH
• sorafenib MeSH
• sulfonamidy * MeSH
• sunitinib * MeSH

BACKGROUND: Hepatocellular carcinoma (HCC) is one of the most common types of cancer with increasing incidence. It accounts for approximately 90% of primary liver cancers and it is a significant global health problem. Globally, it represents the 5th most common disease and it is considered to be the third most common cause of cancer related deaths. The occurrence of HCC is related to environmental factors, eating habits and lifestyle. It is more common in men than in women. The highest incidence of HCC is in Southeast Asia, China, West and Central Africa, and among immigrants from high-risk areas in the United States. In North America, Europe and Japan, hepatitis C virus infection is its major risk factor along with alcohol consumption. Modern therapeutic methods improved the results of the treatment in patients with HCC. In early stages of HCC, curative treatment, surgical resection, liver transplantation, and radiofrequency ablation are possible. In advanced disease, local chemotherapy and systemic targeted therapy have prolonged survival. PURPOSE: The aim of the article is to present the possibilities of systemic treatment of HCC in first and second lines of the treatment. Sorafenib was the first drug to be approved by the U. S. Food and Drug Administration for the treatment of advanced HCC and is a standard first-line drug. The first choice in the second line treatment of patients with progressive disease (after the treatment with sorafenib) is regorafenib. Nowadays, immunotherapy is also an adequate treatment option. Cabozantinib and ramucirumab represent additional treatment.

• Klíčová slova
• cabozantinib, hepatocellular carcinoma, ramucirumab, regorafenib, sorafenib, treatment,
• MeSH
• anilidy terapeutické užití   MeSH
• fenylmočovinové sloučeniny terapeutické užití   MeSH
• hepatocelulární karcinom mortalita   patologie   terapie   MeSH
• humanizované monoklonální protilátky terapeutické užití   MeSH
• imunoterapie metody   MeSH
• lidé MeSH
• nádory jater mortalita   patologie   terapie   MeSH
• protinádorové látky terapeutické užití   MeSH
• pyridiny terapeutické užití   MeSH
• ramucirumab MeSH
• sorafenib terapeutické užití   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• anilidy MeSH
• cabozantinib MeSH Prohlížeč
• fenylmočovinové sloučeniny MeSH
• humanizované monoklonální protilátky MeSH
• protinádorové látky MeSH
• pyridiny MeSH
• regorafenib MeSH Prohlížeč
• sorafenib MeSH

BACKGROUND: Tyrosine kinase inhibitor therapy (TKI) has changed the treatment paradigm of metastatic renal cell carcinoma (mRCC). The recent CARMENA and SURTIME trials challenged the role of the cytoreductive nephrectomy (CN). OBJECTIVE: To assess the impact of CN prior to TKI therapy in patients with mRCC in a real-world setting. METHODS: Overall, 262 consecutive patients with mRCC were treated with CN plus TKI or TKI only at our institution between 2000 and 2016. Patients with prior immunotherapy or metastasectomy were excluded. Multiple imputation and inverse probability of treatment weighting (IPTW) were performed to account for missing values and imbalances between the treatment groups, respectively. Unadjusted and adjusted Kaplan-Meier estimates were used to determine differences in progression-free (PFS), overall (OS), and cancer-specific survival (CSS). RESULTS: Overall, 104 (40%) patients received CN before TKI treatment. Most frequent first line therapy was Sunitinib (66%), followed by Sorafenib (20%) and Pazopanib (10%). After adjustment with IPTW, there was no difference in PFS, CSS, and OS (all P > 0.05) between the treatment groups. In subgroup analyses, CSS was improved when CN was performed in patients with sarcomatoid features and clear cell histology (P = 0.04 and P = 0.03) and PFS was improved in patients with clear cell histology when CN was performed [0.04]). CN did not improve OS in any subgroup analysis. CONCLUSION: The role of CN remains controversial. We found no difference in survival outcomes between patients treated with and without CN before TKI therapy. However, CN was associated with improved survival in specific patient subgroups. Tailored, individualized treatment is key to further improve oncological outcomes for mRCC.

• Klíčová slova
• Cytoreductive nephrectomy, Metastatic renal cell carcinoma, Tyrosine-kinase inhibitor,
• MeSH
• cytoredukční chirurgie * MeSH
• inhibitory proteinkinas terapeutické užití   MeSH
• karcinom z renálních buněk mortalita   sekundární   terapie   MeSH
• kohortové studie MeSH
• kombinovaná terapie MeSH
• lidé středního věku MeSH
• lidé MeSH
• míra přežití MeSH
• nádory ledvin mortalita   patologie   terapie   MeSH
• nefrektomie metody   MeSH
• retrospektivní studie MeSH
• senioři MeSH
• sorafenib terapeutické užití   MeSH
• sunitinib terapeutické užití   MeSH
• tyrosinkinasy antagonisté a inhibitory   MeSH
• výsledek terapie MeSH
• Check Tag
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• inhibitory proteinkinas MeSH
• sorafenib MeSH
• sunitinib MeSH
• tyrosinkinasy MeSH

BACKGROUND & AIMS: Limited data on treatment of elderly patients with hepatocellular carcinoma (HCC) increase the unmet need. REACH and REACH-2 were global phase III studies of ramucirumab in patients with HCC after prior sorafenib, where patients with alpha-fetoprotein (AFP) ≥400 ng/mL showed an overall ssurvival (OS) benefit for ramucirumab. These post-hoc analyses examined efficacy and safety of ramucirumab in patients with HCC and baseline AFP ≥ 400 ng/mL by three prespecified age subgroups (<65, ≥65 to <75 and ≥75 years). METHODS: Individual patient data were pooled from REACH (baseline AFP ≥400 ng/mL) and REACH-2. Kaplan-Meier and Cox proportional hazards regression methods (stratified by study) assessed OS, progression-free survival (PFS), time to progression (TTP) and patient-reported outcomes (Functional Hepatobiliary System Index-8 [FHSI-8] score). RESULTS: A total of 542 patients (<65 years: n = 302; ≥65 to <75 years: n = 160; ≥75 years: n = 80) showed similar baseline characteristics between ramucirumab and placebo. Older subgroups had higher hepatitis C and steatohepatitis incidences, and lower AFP levels, than the <65 years subgroup. Ramucirumab prolonged OS in patients <65 years (hazard ratio [HR], 0.753; 95% CI 0.581-0.975), ≥65 to <75 years (0.602; 0.419-0.866) and ≥75 years (0.709; 0.420-1.199), PFS and TTP irrespective of age. Ramucirumab showed similar overall safety profiles across subgroups, with a consistent median relative dose intensity ≥97.8%. A trend towards a delay in symptom deterioration in FHSI-8 with ramucirumab was observed in all subgroups. CONCLUSIONS: In this post-hoc analysis, ramucirumab showed a survival benefit across age subgroups with a tolerable safety profile, supporting its use in advanced HCC with elevated AFP, irrespective of age, including ≥75 years.

• Klíčová slova
• VEGFR2, alpha-fetoprotein (AFP), elderly, hepatocellular carcinoma, ramucirumab, sorafenib intolerance,
• MeSH
• alfa-fetoproteiny MeSH
• hepatocelulární karcinom * farmakoterapie   MeSH
• humanizované monoklonální protilátky MeSH
• lidé MeSH
• nádory jater * farmakoterapie   MeSH
• ramucirumab MeSH
• senioři MeSH
• sorafenib MeSH
• výsledek terapie MeSH
• Check Tag
• lidé MeSH
• senioři MeSH
• Publikační typ
• časopisecké články MeSH
• klinické zkoušky, fáze III MeSH
• práce podpořená grantem MeSH
• randomizované kontrolované studie MeSH
• Názvy látek
• alfa-fetoproteiny MeSH
• humanizované monoklonální protilátky MeSH
• sorafenib MeSH

Hepatocellular carcinoma (HCC) is the most common type of primary liver cancer and the fourth most frequent cause of cancer-related death worldwide. Sorafenib is the first line recommended therapy for patients with locally advanced/metastatic HCC. The low response rate is attributed to intrinsic resistance of HCC cells to Sorafenib. The potential resistance to Sorafenib-induced cell death is multifactorial and involves all hallmarks of cancer. However, the presence of sub-therapeutic dose can negatively influence the antitumoral properties of the drug. In this sense, the present study showed that the sub-optimal Sorafenib concentration (10 nM) was associated with activation of caspase-9, AMP-activated protein kinase (AMPK), sustained autophagy, peroxisome proliferator-activated receptor-coactivator 1α (PGC-1α) and mitochondrial function in HepG2 cells. The increased mitochondrial respiration by Sorafenib (10 nM) was also observed in permeabilized HepG2 cells, but not in isolated rat mitochondria, which suggests the involvement of an upstream component in this regulatory mechanism. The basal glycolysis was dose dependently increased at early time point studied (6 h). Interestingly, Sorafenib increased nitric oxide (NO) generation that played an inhibitory role in mitochondrial respiration in sub-therapeutic dose of Sorafenib. The administration of sustained therapeutic dose of Sorafenib (10 µM, 24 h) induced mitochondrial dysfunction and dropped basal glycolysis derived acidification, as well as increased oxidative stress and apoptosis in HepG2. In conclusion, the accurate control of the administered dose of Sorafenib is relevant for the potential prosurvival or proapoptotic properties induced by the drug in liver cancer cells.

• Klíčová slova
• AMPK, Apoptosis, Autophagy, Mitochondria, Reactive oxygen species,
• MeSH
• autofagie účinky léků   MeSH
• buněčná smrt účinky léků   MeSH
• buňky Hep G2 MeSH
• chemorezistence účinky léků   MeSH
• hepatocelulární karcinom metabolismus   patologie   MeSH
• jaterní mitochondrie účinky léků   metabolismus   MeSH
• kaspasa 9 metabolismus   MeSH
• lidé MeSH
• nádory jater metabolismus   patologie   MeSH
• oxid dusnatý metabolismus   MeSH
• potkani Wistar MeSH
• PPARGC1A metabolismus   MeSH
• proteinkinasy aktivované AMP metabolismus   MeSH
• protinádorové látky farmakologie   MeSH
• signální transdukce účinky léků   MeSH
• sorafenib farmakologie   MeSH
• vztah mezi dávkou a účinkem léčiva MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• mužské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• kaspasa 9 MeSH
• oxid dusnatý MeSH
• PPARGC1A protein, human MeSH Prohlížeč
• PPARGC1A MeSH
• proteinkinasy aktivované AMP MeSH
• protinádorové látky MeSH
• sorafenib MeSH

Hepatocellular carcinoma (HCC) has a poor outcome. Most HCCs develop in the context of liver fibrosis and cirrhosis caused by chronic inflammation. Short-term fasting approaches enhance the activity of chemotherapy in preclinical cancer models, other than HCC. Multi-tyrosine kinase inhibitor Sorafenib is the mainstay of treatment in HCC. However, its benefit is frequently short-lived. Whether fasting can alleviate liver fibrosis and whether combining fasting with Sorafenib is beneficial remains unknown. A 24 hr fasting (2% serum, 0.1% glucose)-induced changes on human hepatic stellate cells (HSC) LX-2 proliferation/viability/cell cycle were assessed by MTT and flow cytometry. Expression of lypolysaccharide (LPS)-induced activation markers (vimentin, αSMA) was evaluated by qPCR and immunoblotting. Liver fibrosis and inflammation were evaluated in a mouse model of steatohepatitis exposed to cycles of fasting, by histological and biochemical analyses. A 24 hr fasting-induced changes were also analyzed on the proliferation/viability/glucose uptake of human HCC cells exposed to Sorafenib. An expression panel of genes involved in survival, inflammation, and metabolism was examined by qPCR in HCC cells exposed to fasting and/or Sorafenib. Fasting decreased the proliferation and the activation of HSC. Repeated cycles of short term starvation were safe in mice but did not improve fibrosis. Fasting synergized with Sorafenib in hampering HCC cell growth and glucose uptake. Finally, fasting normalized the expression levels of genes which are commonly altered by Sorafenib in HCC cells. Fasting or fasting-mimicking diet diets should be evaluated in preclinical studies as a mean to potentiate the activity of Sorafenib in clinical use.

• Klíčová slova
• Sorafenib, fasting, hepatic stellate cells, hepatocellular carcinoma,
• MeSH
• buňky Hep G2 MeSH
• časové faktory MeSH
• experimentální cirhóza jater metabolismus   patologie   MeSH
• fenylmočovinové sloučeniny farmakologie   MeSH
• glukosa metabolismus   MeSH
• hepatocelulární karcinom farmakoterapie   genetika   metabolismus   patologie   MeSH
• jaterní hvězdicovité buňky účinky léků   metabolismus   patologie   MeSH
• lidé MeSH
• lipopolysacharidy farmakologie   MeSH
• myši inbrední C57BL MeSH
• nádory jater farmakoterapie   genetika   metabolismus   patologie   MeSH
• nealkoholová steatóza jater metabolismus   patologie   MeSH
• niacinamid analogy a deriváty   farmakologie   MeSH
• omezení příjmu potravy metabolismus   MeSH
• proliferace buněk účinky léků   MeSH
• protinádorové látky farmakologie   MeSH
• regulace genové exprese u nádorů účinky léků   MeSH
• sorafenib MeSH
• vztah mezi dávkou a účinkem léčiva MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• fenylmočovinové sloučeniny MeSH
• glukosa MeSH
• lipopolysacharidy MeSH
• niacinamid MeSH
• protinádorové látky MeSH
• sorafenib MeSH

INTRODUCTION: Sorafenib is a multikinase inhibitor with antiangiogenic/antiproliferative activity. In this randomized, double-blind, placebo-controlled phase III trial, we assessed first- or second-line capecitabine with sorafenib or placebo in patients with locally advanced/metastatic HER2-negative breast cancer resistant to a taxane and anthracycline and with known estrogen/progesterone receptor status. PATIENTS AND METHODS: A total of 537 patients were randomized to capecitabine 1000 mg/m2 orally twice per day for days 1 to 14 every 21 days with oral sorafenib 600 mg/d or placebo. The primary end point was progression-free survival (PFS). Patients were stratified according to hormone receptor status, previous chemotherapies for metastatic breast cancer, and geographic region. RESULTS: Treatment with sorafenib with capecitabine, compared with capecitabine with placebo, did not prolong median PFS (5.5 vs. 5.4 months; hazard ratio [HR], 0.973; 95% confidence interval [CI], 0.779-1.217; P = .811) or overall survival (OS; 18.9 vs. 20.3 months; HR, 1.195; 95% CI, 0.943-1.513; P = .140); or enhance overall response rate (ORR; 13.5% vs. 15.5%; P = .515). Any grade toxicities (sorafenib vs. placebo) included palmar-plantar erythrodysesthesia syndrome (PPES; 79.2% vs. 59.6%), diarrhea (47.3% vs. 37.8%), mucosal inflammation (15.4% vs. 6.7%), and hypertension (26.2% vs. 5.6%). Grade 3/4 toxicities included PPES (15.4% vs. 7.1%), diarrhea (4.2% vs. 6.4%), and vomiting (3.5% vs. 0.7%). CONCLUSION: The combination of sorafenib with capecitabine did not improve PFS, OS, or ORR in patients with HER2-negative advanced breast cancer. Rates of Grade 3 toxicities were higher in the sorafenib arm.

• Klíčová slova
• Hormone-receptor status, Multikinase inhibitor, Overall survival, Progression-free survival, Raf kinases,
• MeSH
• antracykliny farmakologie   terapeutické užití   MeSH
• aplikace orální MeSH
• capecitabinum terapeutické užití   MeSH
• chemorezistence MeSH
• dvojitá slepá metoda MeSH
• fenylmočovinové sloučeniny terapeutické užití   MeSH
• hypertenze chemicky indukované   epidemiologie   MeSH
• Kaplanův-Meierův odhad MeSH
• lidé středního věku MeSH
• lidé MeSH
• nádory prsu farmakoterapie   patologie   MeSH
• niacinamid analogy a deriváty   terapeutické užití   MeSH
• placebo MeSH
• přemostěné cyklické sloučeniny farmakologie   terapeutické užití   MeSH
• přežití bez známek nemoci MeSH
• protokoly protinádorové kombinované chemoterapie terapeutické užití   MeSH
• průjem chemicky indukované   epidemiologie   MeSH
• receptor erbB-2 metabolismus   MeSH
• rozvrh dávkování léků MeSH
• senioři MeSH
• sorafenib MeSH
• syndrom ruka-noha epidemiologie   etiologie   MeSH
• taxoidy farmakologie   terapeutické užití   MeSH
• výsledek terapie MeSH
• Check Tag
• lidé středního věku MeSH
• lidé MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• klinické zkoušky, fáze III MeSH
• randomizované kontrolované studie MeSH
• srovnávací studie MeSH
• Názvy látek
• antracykliny MeSH
• capecitabinum MeSH
• ERBB2 protein, human MeSH Prohlížeč
• fenylmočovinové sloučeniny MeSH
• niacinamid MeSH
• placebo MeSH
• přemostěné cyklické sloučeniny MeSH
• receptor erbB-2 MeSH
• sorafenib MeSH
• taxane MeSH Prohlížeč
• taxoidy MeSH

BACKGROUND: Although targeted therapies with inhibitors of the vascular endothelial growth factor (VEGF) are the mainstay of treatment for metastatic renal cell carcinoma, there are limited data on the outcome of patients with long-term response to this treatment. PATIENTS AND METHODS: In a retrospective, registry-based study, patients continuously treated with first-line anti-VEGF agents for at least 24 months were included. In total, 219 patients had evaluable data and were included in the outcome analysis. RESULTS: Median progression-free survival (PFS) after initiation of first-line targeted therapy was 39.7 months (95% confidence interval [CI], 35.9-43.5 months), with 5-year PFS of 34.2% (95% CI, 27.2%-41.2%). Median overall survival (OS) reached 79.1 months (95% CI, 65.2-93.0 months) with the 5-year OS of 62.1% (95% CI, 54.5%-69.7%). In this cohort, 28, 103, and 88 patients achieved complete response (CR), partial response (PR), or stable disease (SD) as the best response, respectively. Median PFS and OS were comparable in patients with PR and SD, but significantly longer in patients with CR (log rank test P value for PFS difference < .001 and .009 for OS difference). CONCLUSION: There are marked differences in PFS and OS between patients who receive long-term anti-VEGF treatment, achieving CR and non-CR as the best clinical response. Patients with non-CR experienced a relatively high progression rate shortly after the landmark time point of 2 years.

• Klíčová slova
• Pazopanib, Renal cell carcinoma, Sorafenib, Sunitinib, Survival,
• MeSH
• analýza přežití MeSH
• bevacizumab terapeutické užití   MeSH
• cílená molekulární terapie MeSH
• dospělí MeSH
• fenylmočovinové sloučeniny terapeutické užití   MeSH
• indazoly MeSH
• indoly terapeutické užití   MeSH
• inhibitory angiogeneze terapeutické užití   MeSH
• karcinom z renálních buněk farmakoterapie   MeSH
• lidé středního věku MeSH
• lidé MeSH
• metastázy nádorů MeSH
• nádory ledvin farmakoterapie   MeSH
• niacinamid analogy a deriváty   terapeutické užití   MeSH
• přežití bez známek nemoci MeSH
• pyrimidiny terapeutické užití   MeSH
• pyrroly terapeutické užití   MeSH
• registrace MeSH
• retrospektivní studie MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• sorafenib MeSH
• sulfonamidy terapeutické užití   MeSH
• sunitinib MeSH
• vaskulární endoteliální růstový faktor A antagonisté a inhibitory   MeSH
• výsledek terapie MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• bevacizumab MeSH
• fenylmočovinové sloučeniny MeSH
• indazoly MeSH
• indoly MeSH
• inhibitory angiogeneze MeSH
• niacinamid MeSH
• pazopanib MeSH Prohlížeč
• pyrimidiny MeSH
• pyrroly MeSH
• sorafenib MeSH
• sulfonamidy MeSH
• sunitinib MeSH
• vaskulární endoteliální růstový faktor A MeSH
• VEGFA protein, human MeSH Prohlížeč