A lot of hope for high-risk cancers is being pinned on immunotherapy but the evidence in children is lacking due to the rarity and limited efficacy of single-agent approaches. Here, we aim to assess the effectiveness of multimodal therapy comprising a personalized dendritic cell (DC) vaccine in children with relapsed and/or high-risk solid tumors using the N-of-1 approach in real-world scenario. A total of 160 evaluable events occurred in 48 patients during the 4-year follow-up. Overall survival of the cohort was 7.03 years. Disease control after vaccination was achieved in 53.8% patients. Comparative survival analysis showed the beneficial effect of DC vaccine beyond 2 years from initial diagnosis (HR = 0.53, P = .048) or in patients with disease control (HR = 0.16, P = .00053). A trend for synergistic effect with metronomic cyclophosphamide and/or vinblastine was indicated (HR = 0.60 P = .225). A strong synergistic effect was found for immune check-point inhibitors (ICIs) after priming with the DC vaccine (HR = 0.40, P = .0047). In conclusion, the personalized DC vaccine was an effective component in the multimodal individualized treatment. Personalized DC vaccine was effective in less burdened or more indolent diseases with a favorable safety profile and synergized with metronomic and/or immunomodulating agents.
- MeSH
- cyklofosfamid * terapeutické užití aplikace a dávkování MeSH
- dendritické buňky * imunologie MeSH
- dítě MeSH
- imunoterapie metody MeSH
- individualizovaná medicína * metody MeSH
- inhibitory kontrolních bodů terapeutické užití MeSH
- kojenec MeSH
- kombinovaná terapie MeSH
- lidé MeSH
- metronomické podávání léků MeSH
- mladiství MeSH
- nádory * mortalita imunologie terapie farmakoterapie MeSH
- následné studie MeSH
- předškolní dítě MeSH
- protinádorové vakcíny * aplikace a dávkování terapeutické užití MeSH
- vinblastin aplikace a dávkování terapeutické užití MeSH
- Check Tag
- dítě MeSH
- kojenec MeSH
- lidé MeSH
- mladiství MeSH
- mužské pohlaví MeSH
- předškolní dítě MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
Diferenciální diagnostika patologické břišní masy je široká. Obvykle na prvním místě ošetřující lékař s obavami pomýšlí na nádorové onemocnění. Nejčastější nádory, které v břišní dutině můžeme nalézt, jsou neuroblastom, hepatoblastom, lymfomy, sarkomy, Wilmsův nádor ledviny či ovariální nádory. V rámci řádného diferenciálně diagnostického procesu je nutno mít na paměti i neonkologické příčiny, které mohou ukazovat na jiné závažné onemocnění. V této kazuistice je prezentován případ pacienta s náhodně nahmatanou břišní resistencí, který byl došetřován pro podezření na zhoubné onemocnění. U tohoto pacienta masa neměla nádorový původ, jednalo se o rozsáhlý hematom, což byl první příznak doposud nepoznané těžké hemofilie A. Hemofilie je vzácné vrozené krvácivé onemocnění. U téměř třetiny pacientů není pozitivní rodinná anamnéza, a tedy se s ním může setkat i neonatolog či praktický lékař ve své ordinaci. Vhledem k závažným krvácivým komplikacím, které mohou být s touto chorobou spojeny, je úkolem ošetřujícího lékaře nemoc včas rozpoznat a odeslat pacienta do péče specialistů.
The differential diagnosis of a pathological abdominal mass is broad. Usually, the first thing the attending physician is concerned of is a malignant disease. Neuroblastomas, hepatoblastomas, lymphomas, sarcomas, Wilms' or ovarian tumors can be palpated in the abdominal cavity. As part of the proper differential diagnostic process, it is also necessary to keep in mind non-malignant causes that may point to other serious diseases. This case report presents the patient with accidentally palpated abdominal resistance, who was in diagnostic process for suspected malignancy. In this patient, the mass did not have a malignant origin, it was a large hematoma, which was the first symptom of previously unrecognized severe hemophilia A. Hemophilia is a rare congenital bleeding disorder that accompanies the patient and his family throughout their life. In almost one third of patients, this is a sporadic occurrence of the disease, and therefore a neonatologist or a pediatrician may encounter it in their praxis. In context of the possible serious complications that this disease brings, it is the task of the attending pediatrician to recognize the disease in time and transfer the patients to the specialist care.
- Klíčová slova
- emicizumab,
- MeSH
- břicho patologie MeSH
- dědičné koagulopatie diagnóza terapie MeSH
- hematom etiologie MeSH
- hemofilie A * diagnóza farmakoterapie komplikace MeSH
- humanizované monoklonální protilátky terapeutické užití MeSH
- koagulační faktory terapeutické užití MeSH
- kojenec MeSH
- krvácení etiologie MeSH
- lidé MeSH
- Check Tag
- kojenec MeSH
- lidé MeSH
- mužské pohlaví MeSH
- Publikační typ
- kazuistiky MeSH
Diseminovaná intravaskulární koagulace (DIK) je závažnou formou konsumpční koagulopatie. Jedná se o syndrom charakterizovaný nadměrnou intravaskulární aktivací koagulační kaskády, která vede jak ke krvácení, tak i tvorbě krevních sraženin. DIK je vždy sekundární proces způsobený celou řadu chorobných stavů (např. sepse, trauma, maligní onemocnění...), které zapříčiní prokoagulační nastavení organismu a následně i spuštění koagulační kaskády. Klinický obraz syndromu DIK je charakterizovaný krvácivou diatézou doprovázenou mikrovaskulární trombotizací a poškozením vnitřních orgánů, které může velmi rychle vyústit do multiorgánového selhání a smrti pacienta. Diagnóza probíhajícího syndromu DIK je založena na kombinaci klinických nálezů a abnormálních koagulačních testů. Vždy je nutné hodnotit dynamiku změn v laboratorních nálezech společně s měnícím se klinickým obrazem. Základem úspěšné léčby syndromu DIK je především včasné odhalení a odstranění primárního onemocnění, které dokázalo syndrom diseminované intravaskulární koagulace vyvolat. Podpůrná léčba při syndromu DIK se soustředí především na dodávku spotřebovaných krevních destiček a faktorů krevního srážení.
Disseminated intravascular coagulation (DIC) is an acquired syndrome characterized by excessive systemic activation of coagulation, resulting in both hemorrhage and thrombosis. DIC can progress rapidly into life-threatening multiorgan failure. The diagnosis of overt DIC is based upon a combination of clinical findings and abnormal coagulation studies. The most important principle in managing a child with DIC is to identify and treat the underlying cause. DIC supportive therapy is focused on replacement of consumpted platelets and clotting factors.
- Klíčová slova
- mikrotrombotizace,
- MeSH
- diseminovaná intravaskulární koagulace * diagnóza etiologie terapie MeSH
- dítě MeSH
- krvácení etiologie terapie MeSH
- lidé MeSH
- multiorgánové selhání MeSH
- novorozenec MeSH
- trombocytopenie komplikace MeSH
- Check Tag
- dítě MeSH
- lidé MeSH
- novorozenec MeSH
- Publikační typ
- přehledy MeSH
Metronomická terapie je léčebnou metodou u vybraných onkologických onemocnění, využívající dlouhodobého podávání nízkých dávek léků s přímým či nepřímým protinádorovým účinkem. Mimo přímou cytotoxickou eradikaci nádorových buněk dokáže metronomická terapie velmi silně ovlivnit nádorové mikroprostředí, má i účinek imunomodulační a antiangiogenní. Její minimální toxický profil umožňuje nasazení u pacientů s těžkými orgánovými dysfunkcemi a má i přímý vliv na kvalitu života a společenské uplatnění onkologicky nemocných pacientů.
Metronomic therapy is a therapeutic method in selected oncological diseases, using long-term administration of low doses of drugs with direct or indirect antitumor effect. In addition, to direct cytotoxic eradication of tumor cells, metronomic therapy can very strongly affect the tumor microenvironment; it also has an immunomodulatory and antiangiogenic effect. Its minimal toxic profile allows for use in patients with severe organ dysfunctions and directly impacts the quality of life and social inclusion of oncological patients.
- Publikační typ
- abstrakt z konference MeSH
- Publikační typ
- abstrakt z konference MeSH
In order to identify reasons for treatment failures when using targeted therapies, we have analyzed the comprehensive molecular profiles of three relapsed, poor-prognosis Burkitt lymphoma cases. All three cases had resembling clinical presentation and histology and all three patients relapsed, but their outcomes differed significantly. The samples of their tumor tissue were analyzed using whole-exome sequencing, gene expression profiling, phosphoproteomic assays, and single-cell phosphoflow cytometry. These results explain different treatment responses of the three histologically identical but molecularly different tumors. Our findings support a personalized approach for patient with high risk, refractory, and rare diseases and may contribute to personalized and customized treatment efforts for patients with limited treatment options like relapsed/refractory Burkitt lymphoma. Summary: The main aim of this study is to analyze three relapsed Burkitt lymphoma patients using a comprehensive molecular profiling, in order to explain their different outcomes and to propose a biomarker-based targeted treatment. In cases 1 and 3, the tumor tissue and the host were analyzed prospectively and appropriate target for the treatment was successfully implemented; however, in case 2, analyses become available only retrospectively and his empirically based rescue treatment did not hit the right target of his disease.
- Publikační typ
- časopisecké články MeSH
Monocyte-derived dendritic cell (DC)-based vaccines loaded with tumor self-antigens represent a novel approach in anticancer therapy. We evaluated DC-based anticancer immunotherapy (ITx) in an academic Phase I/II clinical trial for children, adolescent, and young adults with progressive, recurrent, or primarily metastatic high-risk tumors. The primary endpoint was safety of intradermal administration of manufactured DCs. Here, we focused on relapsing high-risk sarcoma subgroup representing a major diagnosis in DC clinical trial. As a part of peripheral blood immunomonitoring, we evaluated quantitative association between basic cell-based immune parameters. Furthermore, we describe the pattern of these parameters and their time-dependent variations during the DC vaccination in the peripheral blood immunograms. The peripheral blood immunograms revealed distinct patterns in particular patients in the study group. As a functional testing, we evaluated immune response of patient T-cells to the tumor antigens presented by DCs in the autoMLR proliferation assay. This analysis was performed with T-cells obtained prior to DC ITx initiation and with T-cells collected after the fifth dose of DCs, demonstrating that the anticancer DC-based vaccine stimulates a preexisting immune response against self-tumor antigens. Finally, we present clinical and immunological findings in a Ewing's sarcoma patient with an interesting clinical course. Prior to DC therapy, we observed prevailing CD8+ T-cell stimulation and low immunosuppressive monocytic myeloid-derived suppressor cells (M-MDSC) and regulatory T-cells (Tregs). This patient was subsequently treated with 19 doses of DCs and experienced substantial regression of metastatic lesions after second disease relapse and was further rechallenged with DCs. In this patient, functional ex vivo testing of autologous T-cell activation by manufactured DC medicinal product during the course of DC ITx revealed that personalized anticancer DC-based vaccine stimulates a preexisting immune response against self-tumor antigens and that the T-cell reactivity persisted for the period without DC treatment and was further boosted by DC rechallenge. Trial Registration Number: EudraCT 2014-003388-39.
- Publikační typ
- časopisecké články MeSH
The survival rate for patients with high-risk neuroblastomas remains poor despite new improvements in available therapeutic modalities. A detailed understanding of the mechanisms underlying clinical responses to multimodal treatment is one of the important aspects that may provide precision in the prediction of a patient's clinical outcome. Our study was designed as a detailed comparative analysis of five selected proteins (DDX39A, HMGA1, HOXC9, NF1, and PBX1) in one cohort of patients using the same methodical approaches. These proteins were already reported separately as related to the resistance or sensitivity to retinoids and as useful prognostic markers of survival probability. In the cohort of 19 patients suffering from high-risk neuroblastomas, we analyzed initial immunohistochemistry samples obtained by diagnostic biopsy and post-induction samples taken after the end of induction therapy. The expression of DDX39A, HMGA1, HOXC9, and NF1 showed varied patterns with almost no differences between responders and non-responders. Nevertheless, we found very interesting results for PBX1: non-responders had significantly higher expression levels of this protein in the initial tumor samples when compared with responders; this expression pattern changed inversely in the post-induction samples, and this change was also statistically significant. Moreover, our results from survival analyses reveal the prognostic value of PBX1, NF1, and HOXC9 expression in neuroblastoma tissue. In addition to the prognostic importance of PBX1, NF1, and HOXC9 proteins, our results demonstrated that PBX1 could be used for the prediction of the clinical response to induction chemotherapy in patients suffering from high-risk neuroblastoma.
- Publikační typ
- časopisecké články MeSH
Despite efforts to develop novel treatment strategies, refractory and relapsing sarcoma, and high-risk neuroblastoma continue to have poor prognoses and limited overall survival. Monocyte-derived dendritic cell (DC)-based anti-cancer immunotherapy represents a promising treatment modality in these neoplasias. A DC-based anti-cancer vaccine was evaluated for safety in an academic phase-I/II clinical trial for children, adolescents, and young adults with progressive, recurrent, or primarily metastatic high-risk tumors, mainly sarcomas and neuroblastomas. The DC vaccine was loaded with self-tumor antigens obtained from patient tumor tissue. DC vaccine quality was assessed in terms of DC yield, viability, immunophenotype, production of IL-12 and IL-10, and stimulation of allogenic donor T-cells and autologous T-cells in allo-MLR and auto-MLR, respectively. Here, we show that the outcome of the manufacture of DC-based vaccine is highly variable in terms of both DC yield and DC immunostimulatory properties. In 30% of cases, manufacturing resulted in a product that failed to meet medicinal product specifications and therefore was not released for administration to a patient. Focusing on the isolation of monocytes and the pharmacotherapy preceding monocyte harvest, we show that isolation of monocytes by elutriation is not superior to adherence on plastic in terms of DC yield, viability, or immunostimulatory capacity. Trial patients having undergone monocyte-interfering pharmacotherapy prior to monocyte harvest was associated with an impaired DC-based immunotherapy product outcome. Certain combinations of anti-cancer treatment resulted in a similar pattern of inadequate DC parameters, namely, a combination of temozolomide with irinotecan was associated with DCs showing poor maturation and decreased immunostimulatory features, and a combination of pazopanib, topotecan, and MTD-based cyclophosphamide was associated with poor monocyte differentiation and decreased DC immunostimulatory parameters. Searching for a surrogate marker predicting an adverse outcome of DC manufacture in the peripheral blood complete blood count prior to monocyte harvest, we observed an association between an increased number of immature granulocytes in peripheral blood and decreased potency of the DC-based product as quantified by allo-MLR. We conclude that the DC-manufacturing yield and the immunostimulatory quality of anti-cancer DC-based vaccines generated from the monocytes of patients were not influenced by the monocyte isolation modality but were detrimentally affected by the specific combination of anti-cancer agents used prior to monocyte harvest.
- Publikační typ
- časopisecké články MeSH
