Polymer carriers based on N-(2-hydroxypropyl)methacrylamide (HPMA) copolymers with incorporated organic nitrates as nitric oxide (NO) donors were designed with the aim to localise NO generation in solid tumours, thus highly increasing the enhanced permeability and retention (EPR) effect. The NO donors were coupled to the polymer carrier either through a stable bond or through a hydrolytically degradable, pH sensitive, bond. In vivo, the co-administration of the polymer NO donor and HPMA copolymer-bound cytotoxic drug (doxorubicin; Dox) resulted in an improvement in the treatment of murine EL4 T-cell lymphoma. The polymer NO donors neither potentiated the in vitro toxicity of the cytotoxic drug nor exerted any effect on in vivo model without the EPR effect, such as BCL1 leukaemia. Thus, an increase in passive accumulation of the nanomedicine carrying cytotoxic drug via NO-enhanced EPR effect was the operative mechanism of action. The most significant improvement in the therapy was observed in a combination treatment with such a polymer conjugate of Dox, which is characterised by increased circulation in the blood and efficient accumulation in solid tumours. Notably, the combination treatment enabled the development of an anti-tumour immune response, which was previously demonstrated as an important feature of HPMA-based polymer cytotoxic drugs.

• Klíčová slova
• Drug delivery, EL4 lymphoma, HPMA copolymers, anti-tumour immune response, enhanced EPR effect, polymer NO donor, polymer cytotoxic drugs, solid tumour treatment,
• MeSH
• antitumorózní látky aplikace a dávkování   metabolismus   MeSH
• donory oxidu dusnatého aplikace a dávkování   metabolismus   MeSH
• experimentální nádory farmakoterapie   metabolismus   patologie   MeSH
• myši inbrední BALB C MeSH
• myši inbrední C57BL MeSH
• myši MeSH
• nádorové buněčné linie MeSH
• nanočástice aplikace a dávkování   metabolismus   MeSH
• nosiče léků aplikace a dávkování   metabolismus   MeSH
• oxid dusnatý metabolismus   MeSH
• polymery aplikace a dávkování   metabolismus   MeSH
• tumor burden účinky léků   fyziologie   MeSH
• výsledek terapie MeSH
• zvířata MeSH
• Check Tag
• myši MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• antitumorózní látky MeSH
• donory oxidu dusnatého MeSH
• nosiče léků MeSH
• oxid dusnatý MeSH
• polymery MeSH

Tumors are not merely masses of neoplastic cells but complex tissues composed of cellular and noncellular elements. This review provides recent data on the main components of a dynamic system, such as carcinoma associated fibroblasts that change the extracellular matrix (ECM) topology, induce stemness and promote metastasis-initiating cells. Altered production and characteristics of collagen, hyaluronan and other ECM proteins induce increased matrix stiffness. Stiffness along with tumor growth-induced solid stress and increased interstitial fluid pressure contribute to tumor progression and therapy resistance. Second, the role of immune cells, cytokines and chemokines is outlined. We discuss other noncellular characteristics of the tumor microenvironment such as hypoxia and extracellular pH in relation to neoangiogenesis. Overall, full understanding of the events driving the interactions between tumor cells and their environment is of crucial importance in overcoming treatment resistance and improving patient outcome.

• Klíčová slova
• Cancer associated fibroblasts, Interstitial fluid pressure, Solid stress, Therapy resistance, Tumor microenvironment,
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH

BACKGROUND: Antibodies targeting programmed death-1 (PD-1) or programmed death-ligand 1 (PD-L1) have shown clinical activity in the treatment of metastatic renal cell carcinoma (mRCC). This phase Ib cohort of the JAVELIN Solid Tumor trial assessed the efficacy and safety of avelumab (anti-PD-L1) monotherapy in patients with mRCC as either first-line (1 L) or second-line (2 L) treatment. METHODS: Patients with mRCC with a clear-cell component who were treatment naive (1 L subgroup) or had disease progression after one prior line of therapy (2 L subgroup) received avelumab 10 mg/kg intravenous infusion every 2 weeks. Endpoints included confirmed best overall response, duration of response (DOR), progression-free survival (PFS), overall survival (OS), PD-L1 expression, and safety. RESULTS: A total of 62 patients were enrolled in the 1 L subgroup, and 20 patients were enrolled in the 2 L subgroup. In the 1 L and 2 L subgroups, confirmed objective response rates were 16.1 and 10.0%, median DOR was 9.9 months (95% confidence interval [CI], 2.8-not evaluable) and not evaluable (95% CI, 6.9-not evaluable), median PFS was 8.3 months (95% CI, 5.5-9.5) and 5.6 months (95% CI, 2.3-9.6), and median OS was not evaluable (95% CI, not evaluable) and 16.9 months (95% CI, 8.3-not evaluable), respectively. Treatment-related adverse events (TRAEs) of any grade occurred in 51 patients in the 1 L subgroup (82.3%) and 14 patients in the 2 L subgroup (70.0%). Grade ≥ 3 TRAEs occurred in eight patients in the 1 L subgroup (12.9%) and one patient in the 2 L subgroup (5.0%). No treatment-related deaths occurred. CONCLUSION: Avelumab showed clinical activity and a manageable safety profile in both the 1 L and 2 L treatment setting in patients with mRCC. These data support the use of avelumab in combination with other agents in mRCC. TRIAL REGISTRATION: ClinicalTrials.gov: NCT01772004 ; registered 21 January, 2013.

• Klíčová slova
• Avelumab, Metastatic, PD-L1, Phase I, Renal cell carcinoma,
• MeSH
• dospělí MeSH
• humanizované monoklonální protilátky aplikace a dávkování   škodlivé účinky   terapeutické užití   MeSH
• Kaplanův-Meierův odhad MeSH
• karcinom z renálních buněk farmakoterapie   mortalita   patologie   MeSH
• lidé středního věku MeSH
• lidé MeSH
• metastázy nádorů MeSH
• nádory ledvin farmakoterapie   mortalita   patologie   MeSH
• prognóza MeSH
• protinádorové látky imunologicky aktivní aplikace a dávkování   škodlivé účinky   terapeutické užití   MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• staging nádorů 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
• klinické zkoušky, fáze I MeSH
• multicentrická studie MeSH
• práce podpořená grantem MeSH
• Názvy látek
• avelumab MeSH Prohlížeč
• humanizované monoklonální protilátky MeSH
• protinádorové látky imunologicky aktivní MeSH

Magnetic and temperature-sensitive solid lipid particles (mag. SLPs) were prepared in the presence of oleic acid-coated iron oxide (IO-OA) nanoparticles with 1-tetradecanol and poly(ethylene oxide)-block-poly(ε-caprolactone) as lipid and stabilizing surfactant-like agents, respectively. The particles, typically ~850 nm in hydrodynamic size, showed heat dissipation under the applied alternating magnetic field. Cytotoxic activity of the mag.SLPs, non-magnetic SLPs, and iron oxide nanoparticles was compared concerning the mammalian cancer cell lines and their drug-resistant counterparts using trypan blue exclusion test and MTT assay. The mag.SLPs exhibited dose-dependent cytotoxicity against human leukemia cell lines growing in suspension (Jurkat and HL-60/wt), as well as the doxorubicin (Dox)- and vincristine-resistant HL-60 sublines. The mag.SLPs showed higher cytotoxicity toward drug-resistant sublines as compared to Dox. The human glioblastoma cell line U251 growing in a monolayer culture was also sensitive to mag.SLPs cytotoxicity. Staining of U251 cells with the fluorescent dyes Hoechst 33342 and propidium iodide (PI) revealed that mag.SLPs treatment resulted in an increased number of cells with condensed chromatin and/or fragmented nuclei as well as with blebbing of the plasma membranes. While the Hoechst 33342 staining of cell suggested the pro-apoptotic activity of the particles, the PI staining indicated the pro-necrotic changes in the target cells. These conclusions were confirmed by Western blot analysis of apoptosis-related proteins, study of DNA fragmentation (DNA laddering due to the inter-nucleosomal cleavage and DNA comets due to single strand breaks), as well as by FACS analysis of the patterns of cell cycle distribution (pre-G1 phase) and Annexin V/PI staining of the treated Jurkat cells. The induction of apoptosis or necrosis by the particles used to treat Jurkat cells depended on the dose of the particles. Production of the reactive oxygen species (ROS) was proposed as a potential mechanism of mag.SLPs-induced cytotoxicity. Accordingly, hydrogen peroxide and superoxide radical levels in mag.SLPs-treated Jurkat leukemic cells were increased by ~20-40 and ~70%, respectively. In contrast, the non-magnetic SLPs and neat iron oxides did not influence ROS levels significantly. Thus, the developed mag.SLPs can be used for effective killing of human tumor cells, including drug-resistant ones.

• Klíčová slova
• FACS analysis, ROS production, doxorubicin- and vincristine-resistant sublines, fluorescent microscopy, human leukemia cells, magnetic, solid lipid particles, temperature sensitive,
• Publikační typ
• časopisecké články MeSH

AIM OF STUDY: Aim of the study was to assess the complications and long-term results in children operated on for solid pseudopapillary tumor of the pancreas (SPTP) between 1993-2008 at the authors' institution with a focus on a novel duodenum-sparing technique to treat tumors of the head of the pancreas. METHODS: Retrospective analysis was performed of patient data including demographics, diagnostic measures, the operative technique focusing on tumor of the head of the pancreas, complications and long-term results. RESULTS: There were 13 patients (12 girls and one boy) with an average age of 14 years (9-17.5 years) at operation. In 7 patients the tumor was localized in the head of the pancreas, in 4 patients in the tail, and in 2 patients both the body and tail were involved. Patients with body and tail involvement underwent distal pancreatic resection. In 6 patients with head involvement a duodenum-sparing resection of the head and end-to-end anastomosis of the excluded jejunal loop either to the corpus or tail of the pancreas were performed. One girl underwent a modified Whipple operation. She developed a biliary fistula which closed after three weeks with endoscopic stenting. One patient with head resection developed a biliary fistula which closed after two weeks of stenting. One patient who underwent resection of the pancreatic head complained of recurrent abdominal pain one year postoperatively. All patients are alive without tumor recurrence at 6 months to 16 years after operation. CONCLUSION: SPTP is a rare pancreatic tumor with a low degree of malignancy. No perioperative chemotherapy is necessary. Therefore duodenal resection in cases of SPTP in the head of the gland seems too invasive and mutilating. The authors consider the duodenum-sparing technique to be more appropriate for the developing organism of a child. Favorable short and long-term results support this opinion.

• MeSH
• biliární píštěl etiologie   chirurgie   MeSH
• dítě MeSH
• duodenum * chirurgie   MeSH
• lidé MeSH
• mladiství MeSH
• nádory slinivky břišní diagnóza   chirurgie   MeSH
• následné studie MeSH
• pankreatektomie škodlivé účinky   metody   MeSH
• papilární karcinom diagnóza   chirurgie   MeSH
• retrospektivní studie MeSH
• výsledek terapie MeSH
• Check Tag
• dítě MeSH
• lidé MeSH
• mladiství MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH

INTRODUCTION: Benign cystic tumors represent only 2% of all pancreatic tumors (pancreatic cancer - PC). In contrast to malignant cystic tumors, these tumors occur typically in young women. A solid pseudopapillary tumor is a relatively rare affliction representing less than 4% of cystic PC. Although the tumor is considered benign, metastasis, especially to the spleen, has been reported in approximately 0.5-4% patients. Despite R0 resection, vascular and perineural invasion is monitored in 20% of cases. Invasion is the cause of tumor relapse in up to one third of affected patients. Characteristic features of the disease are latent clinical indicators such as signs of pain and malfunction of intestinal passage. The diagnostics is based on MR, sometimes in combination with positron emission tomography. Medical treatment is specifically surgical. CASE HISTORY: Authors present a case of a 20-year-old female patient who was examined due to pain in the epigastrium, further exasperated by a voluminous expansion of the abdominal cavity. An initial ultra-sonographic examination was conducted to examine for possible nodular focal nodular hyperplasia of the liver; however, an MRI scan revealed the likelihood of a malignant tumor in the subhepatic region. During laparotomy, a tumor protruding from the head of the pancreas was discovered and removed. Histological examination showed it was a solid pseudopapillary pancreatic tumor. After a month of good post-operative progress, the patient was re-operated because of the presence of pancreatic fistula. Complete healing of the fistula was achieved after total parenteral nutrition and administration of sandostatin. At her last examination, the patient was without any problems. CONCLUSION: Solid pseudopapillary pancreatic tumors are rare, mainly benign lesions. It is essential to consider them in the differential diagnostics of afflictions of the subhepatic region, especially in young women. The only generally accepted cure nowadays is surgical resection. It is necessary to monitor patients consistently considering the rather high frequency of relapse of disease despite R0 resections. In the case of surgical removal, the 5-year survival rate is near 97%. Key words: solid pseudopapillary tumor of pancreas - diagnostics - therapy The authors declare they have no potential conflicts of interest concerning drugs, products, or services used in the study. The Editorial Board declares that the manuscript met the ICMJE recommendation for biomedical papers. Submitted: 17. 4. 2018 Accepted: 13. 8. 2018.

• Klíčová slova
• or services used in the study. The Editorial Board declares that the manuscript met the ICMJE recommendation for biomedical papers. Submitted: 17. 4. 2018 Accepted: 13. 8. 2018, products, solid pseudopapillary tumor of pancreas - diagnostics - therapy The authors declare they have no potential conflicts of interest concerning drugs,
• MeSH
• dospělí MeSH
• gastrointestinální látky terapeutické užití   MeSH
• lidé MeSH
• magnetická rezonanční tomografie MeSH
• mladý dospělý MeSH
• nádory slinivky břišní diagnóza   chirurgie   MeSH
• oktreotid terapeutické užití   MeSH
• pankreatická píštěl diagnóza   terapie   MeSH
• parenterální výživa MeSH
• ultrasonografie MeSH
• vzácné nemoci diagnóza   chirurgie   MeSH
• Check Tag
• dospělí MeSH
• lidé MeSH
• mladý dospělý MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• kazuistiky MeSH
• Názvy látek
• gastrointestinální látky MeSH
• oktreotid MeSH

Nanoparticles (NPs) represent an emerging platform for diagnosis and treatment of various diseases such as cancer, where they can take advantage of enhanced permeability and retention (EPR) effect for solid tumor accumulation. To improve their colloidal stability, prolong their blood circulation time and avoid premature entrapment into reticuloendothelial system, coating with hydrophilic biocompatible polymers is often essential. Most studies, however, employ just one type of coating polymer. The main purpose of this study is to head-to-head compare biological behavior of three leading polymers commonly used as "stealth" coating materials for biocompatibilization of NPs poly(ethylene oxide), poly(2-ethyl-2-oxazoline) and poly[N-(2-hydroxypropyl)methacrylamide] in an in vivo animal solid tumor model. We used radiolabeled biodegradable hydroxyapatite NPs as a model nanoparticle core within this study and we anchored the polymers to the NPs core by hydroxybisphosphonate end groups. The general suitability of polymers for coating of NPs intended for solid tumor accumulation is that poly(2-ethyl-2-oxazoline) and poly(ethylene oxide) gave comparably similar very good results, while poly[N-(2-hydroxypropyl)methacrylamide] was significantly worse. We did not observe a strong effect of molecular weight of the coating polymers on tumor and organ accumulation, blood circulation time, biodistribution and biodegradation of the NPs.

• Klíčová slova
• animal model, hydroxyapatite, nanoparticles, poly(2-ethyl-2-oxazoline), poly(ethylene oxide), poly[N-(2-hydroxypropyl)methacrylamide], solid tumor,
• Publikační typ
• časopisecké články MeSH

The application of lipid-based nanoparticles for COVID-19 vaccines and transthyretin-mediated amyloidosis treatment have highlighted their potential for translation to cancer therapy. However, their use in delivering drugs to solid tumors is limited by ineffective targeting, heterogeneous organ distribution, systemic inflammatory responses, and insufficient drug accumulation at the tumor. Instead, the use of lipid-based nanoparticles to remotely activate immune system responses is an emerging effective strategy. Despite this approach showing potential for treating hematological cancers, its application to treat solid tumors is hampered by the selection of eligible targets, tumor heterogeneity, and ineffective penetration of activated T cells within the tumor. Notwithstanding, the use of lipid-based nanoparticles for immunotherapy is projected to revolutionize cancer therapy, with the ultimate goal of rendering cancer a chronic disease. However, the translational success is likely to depend on the use of predictive tumor models in preclinical studies, simulating the complexity of the tumor microenvironment (e.g., the fibrotic extracellular matrix that impairs therapeutic outcomes) and stimulating tumor progression. This review compiles recent advances in the field of antitumor lipid-based nanoparticles and highlights emerging therapeutic approaches (e.g., mechanotherapy) to modulate tumor stiffness and improve T cell infiltration, and the use of organoids to better guide therapeutic outcomes.

• Klíčová slova
• ECM, immunotherapy, lipid-based nanoparticles, mechanotherapy, tumor,
• MeSH
• familiární amyloidové neuropatie * MeSH
• imunoterapie MeSH
• lidé MeSH
• lipidy MeSH
• nádorové mikroprostředí MeSH
• nádory * terapie   MeSH
• vakcíny proti COVID-19 MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• přehledy MeSH
• Názvy látek
• lipidy MeSH
• vakcíny proti COVID-19 MeSH

Incorporation of doxorubicin into polyethylene glycol-coated (pegylated) liposomes increases the therapeutic index, prolongs circulation time and enhances tumor localization. Pegylated liposomal doxorubicin (PLD) is an established therapeutic agent in epithelial ovarian carcinoma (EOC), breast carcinoma or Kaposi's sarcoma, and PLD administration results in reduction of toxicity. Addition of regional hyperthermia increases liposome extravasation, induces the doxorubicin release from the liposomes, and the combination of hyperthermia and doxorubicin itself may be supra-additive, resulting in enhanced antitumor efficacy in the heated region. Encouraging results have been reported for the combination of PLD and hyperthermia in EOC, breast carcinoma and hepatocellular carcinoma.

• MeSH
• antibiotika antitumorózní aplikace a dávkování   MeSH
• doxorubicin aplikace a dávkování   MeSH
• indukovaná hypertermie * MeSH
• kombinovaná terapie MeSH
• lidé MeSH
• liposomy MeSH
• nádory jater terapie   MeSH
• nádory prsu terapie   MeSH
• nádory vaječníků terapie   MeSH
• nádory terapie   MeSH
• Check Tag
• lidé MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• antibiotika antitumorózní MeSH
• doxorubicin MeSH
• liposomy MeSH

PURPOSE: In the integrated analysis of phase III head-to-head trials in patients with advanced solid tumors, denosumab demonstrated superiority over zoledronic acid in preventing skeletal-related events (SREs). Regular and continued drug use (persistence) is a precondition of clinical efficacy; persistence in real-life is yet undetermined for denosumab. METHODS: This was a single-arm, prospective, observational, non-interventional study in 598 patients with bone metastases from breast, prostate, lung, or other solid tumors treated with denosumab every four weeks in real-world clinical practice in Austria, Czech Republic, Hungary, Slovakia, and Bulgaria. Persistence was defined as denosumab administration at ≤ 35-day intervals over 24 or 48 weeks, respectively. RESULTS: Previous SREs were found in 10.9% of patients. 62.6% were persistent over 24 weeks and 40.1% over 48 weeks. The Kaplan-Meier median (95% CI) time to non-persistence was 274.0 days (232.0, 316.0). The most frequent reason for non-persistence was delayed administration. There was a trend towards weaker analgesics over time, with approximately 60% of patients not requiring any analgesics. Serum calcium remained within the normal range throughout the study. Adjudicated osteonecrosis of the jaw was documented in three patients with an incidence per patient-year (95% CI) of 0.012 (0.004, 0.029). CONCLUSIONS: Most patients received denosumab regularly once every four weeks over 24 weeks of treatment. Non-persistence was mainly due to delayed administration. The incidence of adverse drug reactions, especially of osteonecrosis of the jaw, was in line with expectations from previous studies.

• Klíčová slova
• Bone metastases, Denosumab, Observational study, Persistence, Solid tumors,
• MeSH
• denosumab aplikace a dávkování   škodlivé účinky   MeSH
• dospělí MeSH
• inhibitory kostní resorpce aplikace a dávkování   škodlivé účinky   MeSH
• kohortové studie MeSH
• lidé středního věku MeSH
• lidé MeSH
• mladý dospělý MeSH
• nádory kostí farmakoterapie   sekundární   MeSH
• nádory farmakoterapie   patologie   MeSH
• osteonekróza chemicky indukované   MeSH
• prospektivní studie MeSH
• rozvrh dávkování léků MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mladý dospělý MeSH
• mužské pohlaví MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• multicentrická studie MeSH
• pozorovací studie MeSH
• Názvy látek
• denosumab MeSH
• inhibitory kostní resorpce MeSH