BACKGROUND: Pediatric low-grade glioma (pLGG) is essentially a single pathway disease, with most tumors driven by genomic alterations affecting the mitogen-activated protein kinase/ERK (MAPK) pathway, predominantly KIAA1549::BRAF fusions and BRAF V600E mutations. This makes pLGG an ideal candidate for MAPK pathway-targeted treatments. The type I BRAF inhibitor, dabrafenib, in combination with the MEK inhibitor, trametinib, has been approved by the United States Food and Drug Administration for the systemic treatment of BRAF V600E-mutated pLGG. However, this combination is not approved for the treatment of patients with tumors harboring BRAF fusions as type I RAF inhibitors are ineffective in this setting and may paradoxically enhance tumor growth. The type II RAF inhibitor, tovorafenib (formerly DAY101, TAK-580, MLN2480), has shown promising activity and good tolerability in patients with BRAF-altered pLGG in the phase 2 FIREFLY-1 study, with an objective response rate (ORR) per Response Assessment in Neuro-Oncology high-grade glioma (RANO-HGG) criteria of 67%. Tumor response was independent of histologic subtype, BRAF alteration type (fusion vs. mutation), number of prior lines of therapy, and prior MAPK-pathway inhibitor use. METHODS: LOGGIC/FIREFLY-2 is a two-arm, randomized, open-label, multicenter, global, phase 3 trial to evaluate the efficacy, safety, and tolerability of tovorafenib monotherapy vs. current standard of care (SoC) chemotherapy in patients < 25 years of age with pLGG harboring an activating RAF alteration who require first-line systemic therapy. Patients are randomized 1:1 to either tovorafenib, administered once weekly at 420 mg/m2 (not to exceed 600 mg), or investigator's choice of prespecified SoC chemotherapy regimens. The primary objective is to compare ORR between the two treatment arms, as assessed by independent review per RANO-LGG criteria. Secondary objectives include comparisons of progression-free survival, duration of response, safety, neurologic function, and clinical benefit rate. DISCUSSION: The promising tovorafenib activity data, CNS-penetration properties, strong scientific rationale combined with the manageable tolerability and safety profile seen in patients with pLGG led to the SIOPe-BTG-LGG working group to nominate tovorafenib for comparison with SoC chemotherapy in this first-line phase 3 trial. The efficacy, safety, and functional response data generated from the trial may define a new SoC treatment for newly diagnosed pLGG. TRIAL REGISTRATION: ClinicalTrials.gov: NCT05566795. Registered on October 4, 2022.
- MeSH
- dítě MeSH
- gliom * farmakoterapie genetika metabolismus MeSH
- lidé MeSH
- mitogenem aktivované proteinkinasy MeSH
- mladý dospělý MeSH
- mutace MeSH
- oximy MeSH
- protokoly antitumorózní kombinované chemoterapie terapeutické užití MeSH
- protoonkogenní proteiny B-Raf MeSH
- pyridony MeSH
- pyrimidinony terapeutické užití MeSH
- světluškovití * metabolismus MeSH
- výsledek terapie MeSH
- zvířata MeSH
- Check Tag
- dítě MeSH
- lidé MeSH
- mladý dospělý MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- klinické zkoušky, fáze III MeSH
- multicentrická studie MeSH
- randomizované kontrolované studie MeSH
BACKGROUND: The prognostic significance of mast cells and different phenotypes of macrophages in the microenvironment of hepatocellular carcinoma (HCC) following resection is unclear. We aimed in this study to assess the local distribution of infiltrating macrophages and mast cells of specific phenotypes in tissues of HCC and to evaluate their prognostic values for survival of post-surgical patients. METHODS: The clinicopathological and follow-up data of 70 patients with HCC, who underwent curative resection of tumor from 1997 to 2019, were collected. The infiltration of CD68+ and CD163+ macrophages and CD117+ mast cells was assessed immunohistochemically in representative resected specimens of HCC and adjacent tissues. The area fraction (AF) of positively stained cells was estimated automatically using QuPath image analysis software in several regions, such as tumor center (TC), inner margin (IM), outer margin (OM), and peritumor (PT) area. The prognostic significance of immune cells, individually and in associations, for time to recurrence (TTR), disease-free survival (DFS), and overall survival (OS) was evaluated using Kaplan-Meier and Cox regression analyses. RESULTS: High AF of CD68+ macrophages in TC and IM and high AF of mast cells in IM and PT area were associated with a longer DFS. High AF of CD163+ macrophages in PT area correlated with a shorter DFS. Patients from CD163TChigh & CD68TClow group had a shorter DFS compared to all the rest of the groups, and cases with CD163IMlow & CD68IMhigh demonstrated significantly longer DFS compared to low AF of both markers. Patients from CD68IMhigh & CD163PTlow group, CD117IMhigh & CD163PTlow group, and CD117PThigh & CD163PTlow group had a significantly longer DFS compared to all other combinations of respective cells. CONCLUSIONS: The individual prognostic impact of CD68+ and CD163+ macrophages and mast cells in the microenvironment of HCC after resection depends on their abundance and location, whereas the cumulative impact is built upon combination of different cell phenotypes within and between regions.
BACKGROUND: Salivary gland carcinomas (SGC) are extremely rare malignancies with only limited treatment options for the metastatic phase of the disease. Treatment with anti-CD47 antibodies could represent a potent therapy for SGCs by promoting the phagocytic clearance of tumor cells through various mechanisms. However, the efficacy of anti-CD47 therapy is largely dependent on the expression of CD47 within the tumor microenvironment (TME). MATERIALS AND METHODS: In 43 patients with SGC, we were the first to investigate the CD47 expression in both tumor cells and tumor-infiltrating immune cells (TIIC) in the center and periphery of primary tumors. We also correlated the data with the clinicopathological variables of the patients and offered novel insights into the potential effectiveness of anti-CD47 therapy in SGCs. RESULTS: We observed that the CD47+ tumor cells are outnumbered by CD47+ TIICs in mucoepidermoid carcinoma. In the tumor center, the proportion of CD47+ tumor cells was comparable to the proportion of CD47+ TIICs in most histological subtypes. In low-grade tumors, significantly higher expression of CD47 was observed in TIICs in the periphery of the tumor as compared to the center of the tumor. CONCLUSION: The reason for a high expression of 'don't eat me' signals in TIICs in the tumor periphery is unclear. However, we hypothesize that in the tumor periphery, upregulation of CD47 in TIICs could be a mechanism to protect newly recruited leukocytes from macrophage-mediated phagocytosis, while also allowing the removal of old or exhausted leukocytes in the tumor center.
BACKGROUND: Hepatocellular carcinoma (HCC) is a fatal disease characterized by early genetic alterations in telomerase reverse transcriptase promoter (TERTp) and β-catenin (CTNNB1) genes and immune cell activation in the tumor microenvironment. As a novel approach, we wanted to assess patient survival influenced by combined presence of mutations and densities of CD8+ cytotoxic T cells. METHODS: Tissue samples were obtained from 67 HCC patients who had undergone resection. We analysed CD8+ T cells density, TERTp mutations, rs2853669 polymorphism, and CTNNB1 mutations. These variables were evaluated for time to recurrence (TTR) and disease free survival (DFS). RESULTS: TERTp mutations were found in 75.8% and CTNNB1 mutations in 35.6% of the patients. TERTp mutations were not associated with survival but polymorphism rs2853669 in TERTp was associated with improved TTR and DFS. CTNNB1 mutations were associated with improving TTR. High density of CD8+ T-lymphocytes in tumor center and invasive margin correlated with longer TTR and DFS. Combined genetic and immune factors further improved survival showing higher predictive values. E.g., combining CTNNB1 mutations and high density of CD8+ T-lymphocytes in tumor center yielded HRs of 0.12 (0.03-0.52), p = 0.005 for TTR and 0.25 (0.09-0.74), p = 0.01 for DFS. CONCLUSION: The results outline a novel integrative approach for prognostication through combining independent predictive factors from genetic and immune cell profiles. However, larger studies are needed to explore multiple cell types in the tumor microenvironment.
- MeSH
- beta-katenin genetika MeSH
- CD8-pozitivní T-lymfocyty patologie MeSH
- hepatocelulární karcinom * genetika patologie chirurgie MeSH
- jednonukleotidový polymorfismus MeSH
- lidé MeSH
- mutace MeSH
- nádorové mikroprostředí genetika MeSH
- nádory jater * genetika patologie chirurgie MeSH
- počet buněk MeSH
- telomerasa * genetika MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
BACKGROUND: Incidence of cervical cancer has been reduced by organized screening while for vaginal and vulvar cancers no systematic screening has been implemented. All these cancers are associated with human papilloma virus (HPV) infection. We wanted to analyze incidence trends and relative survival in these cancers with specific questions about the possible covariation of incidence, survival changes coinciding with incidence changes and the role of treatment in survival. We used nationwide cancer registry data for Denmark (DK), Finland (FI), Norway (NO) and Sweden (SE) to address these questions. METHODS: We use the NORDCAN database for the analyses: incidence data were available from 1943 in DK, 1953 in FI and NO and 1960 in SE, through 2016. Survival data were available from 1967 through 2016. World standard population was used in age standardization. RESULTS: In each country the incidence of cervical cancer declined subsequent to rolling out of screening activities. The attained plateau incidence was lowest at 4/100,000 in FI and highest at 10/100,000 in DK and NO. The incidence of vaginal and vulvar cancer remained relatively constant at about 2/100,000. Relative 1-year survival in cervical cancer improved in all countries from low 80%s to high 80%s in the 50-year period, and 5-year survival improved also but at 20% units lower level. Survival gains were found only in patients diagnosed before age 60 years. Survival in vaginal and vulvar cancer followed the same patterns but at a few % units lower level. CONCLUSION: Cervical cancer screening appeared to have reached its limits in the Nordic countries by year 2000. Novel treatments, such as immunotherapy, would be needed to improve survival until HPV vaccination will reach population coverage and boost the global fight against these cancers.
- MeSH
- časná detekce nádoru MeSH
- incidence MeSH
- infekce papilomavirem * MeSH
- lidé středního věku MeSH
- lidé MeSH
- nádory děložního čípku * prevence a kontrola terapie MeSH
- nádory vulvy * epidemiologie terapie MeSH
- Check Tag
- lidé středního věku MeSH
- lidé MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- Geografické názvy
- Dánsko MeSH
- Finsko MeSH
- Norsko MeSH
- Švédsko MeSH
BACKGROUND: Cancers of the oral cavity and pharynx encompass a heterogeneous group of cancers for which known risk factors include smoking, alcohol consumption and human papilloma virus (HPV) infection but their influence is site-specific with HPV mainly influencing oropharyngeal cancer. Their incidence and survival rates are not well known over extended periods of time. PATIENTS/METHODS: Data were obtained for Finnish (FI) and Swedish (SE) patients from the Nordcan database recently updated through 2019. Age-adjusted incidence trends (FI from 1953, SE from 1960) and relative survival rates for years 1970 through 2019 were calculated. RESULTS: We observed a prominent increase in oral and oropharyngeal cancers in FI and SE men and women but the trend for oral cancer was interrupted for SE men in 1985 and possibly also for FI and SE women in 2015. The trend changes in male and female oral cancer was confirmed in data for Denmark and Norway. Relative survival for these cancers has improved overall but they differed for one cluster of oral, oropharyngeal and nasopharyngeal cancers with 60-70% 5-year survival in the last period and hypopharyngeal cancer with 25% male survival. In all these cancers, survival for old patients was unfavorable. DISCUSSION/CONCLUSION: We hypothesize that reduction in smoking prevalence helped to stop the increase in oral cancer especially in men. As the prevalence of smoking is decreasing, HPV is becoming a dominant risk factor, particularly for the increasing oropharyngeal cancer. Prevention needs to emphasize sexual hygiene and HPV vaccination.
- MeSH
- incidence MeSH
- infekce papilomavirem komplikace epidemiologie MeSH
- kouření škodlivé účinky epidemiologie MeSH
- lidé středního věku MeSH
- lidé MeSH
- nádory hltanu epidemiologie etiologie MeSH
- nádory orofaryngu epidemiologie etiologie MeSH
- nádory úst epidemiologie etiologie MeSH
- pití alkoholu škodlivé účinky epidemiologie MeSH
- registrace MeSH
- rizikové faktory MeSH
- senioři MeSH
- Check Tag
- lidé středního věku MeSH
- lidé MeSH
- mužské pohlaví MeSH
- senioři MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- Geografické názvy
- Finsko MeSH
- Švédsko MeSH
BACKGROUND: Telomeres are protective structures at chromosome ends which shorten gradually with increasing age. In chronic lymphocytic leukemia (CLL), short telomeres have been associated with unfavorable disease outcome, but the link between clonal evolution and telomere shortening remains unresolved. METHODS: We investigated relative telomere length (RTL) in a well-characterized cohort of 198 CLL patients by qPCR and focused in detail on a subgroup 26 patients who underwent clonal evolution of TP53 mutations (evolTP53). In the evolTP53 subgroup we explored factors influencing clonal evolution and corresponding changes in telomere length through measurements of telomerase expression, lymphocyte doubling time, and BCR signaling activity. RESULTS: At baseline, RTL of the evolTP53 patients was scattered across the entire RTL spectrum observed in our CLL cohort. RTL changed in the follow-up samples of 16/26 (62%) evolTP53 cases, inclining to reach intermediate RTL values, i.e., longer telomeres shortened compared to baseline while shorter ones prolonged. For the first time we show that TP53 clonal shifts are linked to RTL change, including unexpected RTL prolongation. We further investigated parameters associated with RTL changes. Unstable telomeres were significantly more frequent among younger patients (P = 0.032). Shorter telomeres were associated with decreased activity of the B-cell receptor signaling components p-ERK1/2, p-ZAP-70/SYK, and p-NFκB (P = 0.04, P = 0.01, and P = 0.02, respectively). CONCLUSIONS: Our study revealed that changes of telomere length reflect evolution in leukemic subclone proportion, and are associated with specific clinico-biological features of the explored cohort.
- MeSH
- chronická lymfatická leukemie genetika MeSH
- klonální evoluce genetika MeSH
- lidé středního věku MeSH
- lidé MeSH
- mutace MeSH
- nádorový supresorový protein p53 genetika MeSH
- protoonkogenní proteiny c-bcr metabolismus MeSH
- signální transdukce MeSH
- telomerasa genetika MeSH
- telomery ultrastruktura MeSH
- Check Tag
- lidé středního věku MeSH
- lidé MeSH
- mužské pohlaví MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
BACKGROUND: Malignant pleural mesothelioma (MPM) is a rare but fatal cancer, which is largely caused by exposure to asbestos. Reliable information about the incidence of MPM prior the influence of asbestos is lacking. The nationwide regional incidence trends for MPM remain poorly characterized. We use nationwide MPM data for Denmark (DK), Finland (FI), Norway (NO) and Sweden (SE) to assess incidence, mortality and survival trends for MPM in these countries. METHODS: We use the NORDCAN database for the analyses: incidence data were available from 1943 in DK, 1953 in FI and NO and 1958 in SE, through 2016. Survival data were available from 1967 through 2016. World standard population was used in age standardization. RESULTS: The lowest incidence that we recorded for MPM was 0.02/100,000 for NO women and 0.05/100,000 for FI men in 1953-57, marking the incidence before the influence of asbestos. The highest rate of 1.9/100,000 was recorded for DK in 1997. Female incidence was much lower than male incidence. In each country, the male incidence trend for MPM culminated, first in SE around 1990. The regional incidence trends matched with earlier asbestos-related industrial activity, shipbuilding in FI and SE, cement manufacturing and shipbuilding in DK and seafaring in NO. Relative 1-year survival increased from about 20 to 50% but 5-year survival remained at or below 10%. CONCLUSION: In the Nordic countries, the male incidence trends for MPM climaxed and started to decrease, indicating that the prevention of exposure was beneficial. Survival in MPM has improved for both sexes but long-term survival remains dismal.
- MeSH
- analýza přežití MeSH
- azbest škodlivé účinky normy MeSH
- dějiny 20. století MeSH
- dějiny 21. století MeSH
- dospělí MeSH
- incidence MeSH
- lidé středního věku MeSH
- lidé MeSH
- maligní mezoteliom epidemiologie etiologie MeSH
- mladý dospělý MeSH
- mortalita dějiny trendy MeSH
- nádory pleury epidemiologie etiologie MeSH
- senioři nad 80 let MeSH
- senioři MeSH
- sexuální faktory MeSH
- věkové rozložení MeSH
- vystavení vlivu životního prostředí škodlivé účinky normy MeSH
- Check Tag
- dějiny 20. století MeSH
- dějiny 21. století MeSH
- 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
- historické články MeSH
- Geografické názvy
- Dánsko MeSH
- Finsko MeSH
- Norsko MeSH
- Švédsko MeSH
BACKGROUND: Favorable survival in malignant cutaneous melanoma (melanoma) has increased the likelihood of second primary cancer (SPC). We assess the influence of patient characteristics at diagnosis of first melanoma and the type of SPC (second melanoma and other SPC) on overall survival. METHODS: We used the Swedish Cancer Registry data to assess overall survival in melanoma for the period 1990 to 2015. Kaplan-Meier curves were plotted and hazard ratios (HRs) were estimated with Cox regression models by considering SPC diagnosis as a time-dependent variable. RESULTS: A total of 46,726 patients were diagnosed with melanoma, and 15.3% of them developed SPC, among which, two thirds were other SPCs. Second melanomas were diagnosed early (31% during the first year) compared to non-melanoma SPCs (9.5%). Survival for women with second melanoma or other SPC (56 and 21% alive after 25 years of follow-up, respectively) exceeded the male rates (21 and 10%, respectively) but all these figures were lower than for females (60% alive) or males (48%) without SPC. Time dependent analysis showed vastly increased HRs for cancer types that are fatal also as first cancers, but SPC-specific HRs remained relatively uniform, irrespective of SPC diagnosed soon or late after first melanoma. In early-onset melanoma, SPC diagnosis after 10 years may not negatively influence overall survival. CONCLUSIONS: As the overall survival of patients with many types of SPCs is unfavorable, advice about health lifestyle should benefit smoking patients and early detection methods may be recommended for SPCs of the breast, prostate and colorectum.
- MeSH
- časové faktory MeSH
- Kaplanův-Meierův odhad MeSH
- kouření MeSH
- lidé středního věku MeSH
- lidé MeSH
- melanom mortalita MeSH
- nádory kůže mortalita MeSH
- přežívající onkologičtí pacienti statistika a číselné údaje MeSH
- proporcionální rizikové modely MeSH
- registrace MeSH
- sekundární malignity mortalita MeSH
- senioři nad 80 let MeSH
- senioři MeSH
- sexuální faktory MeSH
- věkové faktory 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
- Geografické názvy
- Švédsko MeSH
BACKGROUND: Prostate cancer is caused by genomic aberrations in normal epithelial cells, however clinical translation of findings from analyses of cancer cells alone has been very limited. A deeper understanding of the tumour microenvironment is needed to identify the key drivers of disease progression and reveal novel therapeutic opportunities. RESULTS: In this study, the experimental enrichment of selected cell-types, the development of a Bayesian inference model for continuous differential transcript abundance, and multiplex immunohistochemistry permitted us to define the transcriptional landscape of the prostate cancer microenvironment along the disease progression axis. An important role of monocytes and macrophages in prostate cancer progression and disease recurrence was uncovered, supported by both transcriptional landscape findings and by differential tissue composition analyses. These findings were corroborated and validated by spatial analyses at the single-cell level using multiplex immunohistochemistry. CONCLUSIONS: This study advances our knowledge concerning the role of monocyte-derived recruitment in primary prostate cancer, and supports their key role in disease progression, patient survival and prostate microenvironment immune modulation.
- MeSH
- anotace sekvence MeSH
- imunofenotypizace MeSH
- imunohistochemie MeSH
- Kaplanův-Meierův odhad MeSH
- lidé MeSH
- monocyty metabolismus patologie MeSH
- nádorové mikroprostředí genetika MeSH
- nádory prostaty diagnóza genetika metabolismus mortalita MeSH
- prognóza MeSH
- progrese nemoci MeSH
- stanovení celkové genové exprese * metody MeSH
- transkriptom * MeSH
- výpočetní biologie metody MeSH
- vysoce účinné nukleotidové sekvenování MeSH
- Check Tag
- lidé MeSH
- mužské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
