• MeSH
• farmakoterapie * trendy   MeSH
• lidé MeSH
• melanom * farmakoterapie   MeSH
• metastázy nádorů farmakoterapie   MeSH
• Check Tag
• lidé MeSH

• MeSH
• lékařská onkologie * MeSH
• lidé MeSH
• významné osobnosti * MeSH
• Check Tag
• lidé MeSH

• O autorovi
• Melichar, Bohuslav, 1965- Autorita

• Publikační typ
• zprávy MeSH

PURPOSE: There are limited treatment options for advanced melanoma that have progressed during or after immune checkpoint inhibitor therapy. Intratumoral (IT) immunotherapy may improve tumor-specific immune activation by promoting local tumor antigen presentation while avoiding systemic toxicities. The phase 3 ILLUMINATE-301 study (ClinicalTrials.gov identifier: NCT03445533) evaluated tilsotolimod, a Toll-like receptor-9 agonist, with or without ipilimumab in patients with anti-PD-1 advanced refractory melanoma. METHODS: Patients with unresectable stage III-IV melanoma that progressed during or after anti-PD-1 therapy were randomly assigned 1:1 to receive 24 weeks of tilsotolimod plus ipilimumab or 10 weeks of ipilimumab alone. Nine IT injections of tilsotolimod were administered to a single designated lesion over 24 weeks. Intravenous ipilimumab 3 mg/kg was administered once every 3 weeks from week 2 in the tilsotolimod arm and week 1 in the ipilimumab arm. The primary end point was efficacy measured using objective response rate (ORR; independent review) and overall survival (OS). RESULTS: A total of 481 patients received tilsotolimod plus ipilimumab (n = 238) or ipilimumab alone (n = 243). ORRs were 8.8% in the tilsotolimod arm and 8.6% in the ipilimumab arm, with disease control rates of 34.5% and 27.2%, respectively. Median OS was 11.6 months in the tilsotolimod arm and 10 months in the ipilimumab arm (hazard ratio, 0.96 [95% CI, 0.77 to 1.19]; P = .7). Grade ≥3 treatment-emergent adverse events occurred in 61.1% and 55.5% of patients in the tilsotolimod and ipilimumab arms, respectively. CONCLUSION: Combining IT tilsotolimod with ipilimumab did not significantly improve the ORR or OS compared with ipilimumab alone in patients with anti-PD-1 advanced refractory melanoma.

• MeSH
• dospělí MeSH
• ipilimumab * aplikace a dávkování   škodlivé účinky   MeSH
• lidé středního věku MeSH
• lidé MeSH
• melanom * farmakoterapie   patologie   imunologie   mortalita   MeSH
• nádory kůže * farmakoterapie   patologie   imunologie   MeSH
• oligonukleotidy MeSH
• protokoly protinádorové kombinované chemoterapie * terapeutické užití   škodlivé účinky   MeSH
• senioři nad 80 let MeSH
• senioři 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 III MeSH
• multicentrická studie MeSH
• randomizované kontrolované studie MeSH

OBJECTIVE: Dementia with Lewy bodies (DLB) and Parkinson's disease (PD) share clinical, pathological, and genetic risk factors, including GBA1 and APOEε4 mutations. Biomarkers associated with the pathways of these mutations, such as glucocerebrosidase enzyme (GCase) activity and amyloid-beta 42 (Aβ42) levels, may hold potential as predictive indicators, providing valuable insights into the likelihood of cognitive decline within these diagnoses. Our objective was to determine their association with cognitive decline in DLB and PD. METHODS: A total of 121 DLB patients from the European-DLB Consortium and 117 PD patients from the Norwegian ParkWest Study were included in this study. The four most commonly associated variants of GBA1 mutations (E326K, T369M, N370S, L444P), APOEε4 status, and cerebrospinal fluid (CSF) Aβ42 levels and GCase activity were assessed, as well as global cognition using the Mini-Mental State Examination. Linear mixed-effects regression models were used to evaluate the association of CSF biomarkers with cognitive decline in each diagnostic group, adjusted for age, sex, education, and genetic mutation profile. RESULTS: Low CSF Aβ42 levels were associated with accelerated cognitive decline in DLB, whereas reduced CSF GCase activity predicted faster cognitive decline in PD. These associations were independent of GBA1 gene mutations or APOEε4 status. INTERPRETATION: Our study provides important evidence on the relationship between brain Aβ deposition and GCase activity in the Lewy body disease spectrum independent of their genetic mutation profile. This information could be relevant for designing future clinical trials targeting these pathways.

• MeSH
• amyloidní beta-protein * mozkomíšní mok   MeSH
• biologické markery mozkomíšní mok   MeSH
• demence s Lewyho tělísky * mozkomíšní mok   genetika   komplikace   MeSH
• glukosylceramidasa * genetika   metabolismus   mozkomíšní mok   MeSH
• kognitivní dysfunkce * mozkomíšní mok   genetika   etiologie   MeSH
• lidé středního věku MeSH
• lidé MeSH
• Parkinsonova nemoc * mozkomíšní mok   genetika   komplikace   MeSH
• peptidové fragmenty * mozkomíšní mok   MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• Check Tag
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH

of the original article, 'Efficacy of Trastuzumab Deruxtecan in HER2-Expressing Solid Tumors by Enrollment HER2 IHC Status: Post Hoc Analysis of DESTINY-PanTumor02'. Trastuzumab deruxtecan (T-DXd) is an antibody-drug conjugate, which is a chemotherapy with a linker (deruxtecan) joined to an antibody (trastuzumab). Trastuzumab binds to the human epidermal growth factor receptor 2 (HER2) protein on cancer cells, where it releases the chemotherapy to kill these cells. The DESTINY-PanTumor02 clinical study tested the effectiveness of T-DXd for people with various HER2-expressing cancers and the safety of treatment. Previous results from DESTINY-PanTumor02 showed that T-DXd had antitumor activity, and the greatest effects were seen in people with the highest tumor level of HER2 [defined as immunohistochemistry (IHC) 3+]. In this previous analysis, the HER2 expression was measured at a central laboratory. In clinical practice, HER2 expression will likely be measured at a local laboratory, so understanding whether T-DXd has similar effects regardless of how HER2 expression is measured is important. Here, we looked at the effects of T-DXd based on the HER2 test result used to determine a person's eligibility for the study, which could be measured using a local or central laboratory. In people with IHC 3+ tumors (where HER2 was measured at a local or central laboratory), 51% had a decrease in the size or number of tumors, according to established criteria (referred to as an objective response), while, in people with IHC 2+ tumors, 26% had an objective response. Side effects with T-DXd were consistent with previous studies. These results confirm T-DXd has antitumor effects in HER2-expressing cancers where the HER2 expression is measured by a local or central laboratory.

• MeSH
• imunohistochemie MeSH
• imunokonjugáty * terapeutické užití   škodlivé účinky   MeSH
• kamptothecin * analogy a deriváty   terapeutické užití   aplikace a dávkování   škodlivé účinky   MeSH
• klinické zkoušky, fáze II jako téma MeSH
• lidé MeSH
• nádory * farmakoterapie   metabolismus   patologie   MeSH
• protinádorové látky imunologicky aktivní * terapeutické užití   MeSH
• receptor erbB-2 * metabolismus   MeSH
• sekundární analýza dat MeSH
• trastuzumab * terapeutické užití   škodlivé účinky   MeSH
• výsledek terapie MeSH
• Check Tag
• lidé MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH

Developing methodological approaches for discovering novel pathways is a key challenge in the life science research. Biological pathways are regulated-in higher eukaryotes-by a vast diversity of linear peptide motifs that mediate combinatorial specificity in signal transduction pathways. The E3 ubiquitin ligase component (MDM2) is such a protein that interacts with target proteins containing linear motifs such as p53. Drug leads, such as Nutlin-3, that bind to the MDM2 hydrophobic pocket mimic p53 and can release p53 from MDM2 control and this can lead to cell death. However, these drug leads act allosterically, having agonist effects on MDM2's functions and there are other proteins whose steady state levels can be altered by Nutlin-3. As cell density can alter the proliferation state of cell populations, we examined the impact of Nutlin-3 on levels of newly synthesized proteins using pulse-SILAC mass spectrometry. The data demonstrate that at differing cell densities or population-wide proliferation rates, different newly synthesized proteins dominate the proteome landscape in a Nutlin-3 dependent manner. These data further confirm that the cell state in a population of cells can in turn impact on the MDM2 signalling landscape. This methodology forms a blueprint for biomarker discovery using clinical samples that can detect changes in the synthesis rate of proteins in cell populations treated with specific agents. Broader implications highlight tools that can be used to study allosteric regulation of protein-drug combinations.

• MeSH
• imidazoly * farmakologie   MeSH
• lidé MeSH
• nádorový supresorový protein p53 metabolismus   MeSH
• piperaziny * farmakologie   MeSH
• proliferace buněk účinky léků   MeSH
• proteom * metabolismus   MeSH
• proteomika metody   MeSH
• protoonkogenní proteiny c-mdm2 metabolismus   MeSH
• signální transdukce účinky léků   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH

For many hematological malignancies (HMs) survival among older patients is compromised. We want to test the most up-to-date age-group-specific survival differences in five hematological malignancies, Hodgkin lymphoma (HL), multiple myeloma (MM), chronic lymphocytic leukemia (CLL), acute myeloid leukemia (AML) and myeloproliferative diseases (MPD) in Sweden (SE) and compared these to Denmark, Finland and Norway. For analysis we apply a recently published metric for comparing and visualizing age-group-specific relative survival differences using data from the NORDCAN database between 1972 and 2021. Periodic changes in age-related deviation in SE survival showed increasing differences for AML and MM while for the other HMs the differences declined in the course of time. Country-specific differences were observed, for Finnish male CLL and female MPD deviations were larger than those for the other countries, both of which were explained by the deviant survival of the oldest patients. Age-related deviations in 5-year survival increased for AML and MM for which survival improvements have been achieved through intense treatment regimens but these are not offered to old patients because of risk of complications. Paradoxically, improving overall survival in AML and MM has contributed to the widening of the age gaps. For the remaining HMs, age-related deviations declined with time as even old patients benefitted from the survival improvements; most notably female MPD and CLL patients had hardly any age gaps. Age disparities are an issue in hematological malignancies, and an intense search for novel treatments also includes old patients with an example of success as a novel drug venetoclax.

• MeSH
• dospělí MeSH
• hematologické nádory * mortalita   diagnóza   epidemiologie   MeSH
• lidé středního věku MeSH
• lidé MeSH
• míra přežití trendy   MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• věkové faktory 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
• srovnávací studie MeSH
• Geografické názvy
• Dánsko MeSH
• Finsko MeSH
• Norsko MeSH
• Švédsko MeSH

The Bonebridge (BB) was the first active transcutaneous implantation system for bone conduction. The main indications are conductive or mixed hearing loss and single-sided deafness. Treacher-Collins syndrome (TCS) is a rare genetic disease that affects craniofacial development. The disorder results in deformations of facial structure including ear malformations, especially microtia and ear canal atresia. These patients suffer from conductive hearing loss. CT scans often show unfavorable temporal bone anatomy making placement of an implant difficult. For implantable hearing rehabilitation, patients may decide for conduction implants, such as a BAHA, a Ponto, a Vibrant Soundbridge, or a Bonebridge. In this case report, we present 2 patients with TCS implanted with the Bonebridge system, their audiological results, and quality of life.

• MeSH
• implantace protézy * metody   MeSH
• kostní vedení zvuku MeSH
• kvalita života MeSH
• lidé MeSH
• mandibulofaciální dysostóza * komplikace   MeSH
• převodní nedoslýchavost * chirurgie   etiologie   rehabilitace   MeSH
• sluchové pomůcky * MeSH
• výsledek terapie MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• kazuistiky MeSH

• Publikační typ
• úvodníky MeSH