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  • 1
    In: Cancer Immunology, Immunotherapy, Springer Science and Business Media LLC, Vol. 72, No. 5 ( 2023-05), p. 1061-1073
    Abstract: Immune checkpoint inhibitors (ICI) such as anti-PD-L1 and anti-PD-1 agents have been proven to be effective in various cancers. However, the rate of non-responders is still high in all cancer entities. Therefore, the identification of biomarkers that could help to optimize therapeutic decision-making is of great clinical importance. Soluble PD-L1 (sPD-L1) and PD-1 (sPD-1) are emerging blood-based biomarkers and were previously shown to be prognostic in various clinical studies. Objective We aimed to evaluate the prognostic relevance of sPD-L1 and sPD-1 in patients with different tumor entities who underwent ICI therapy. Methods We searched for articles in PubMed via Medline, Embase, Scopus, and Cochrane databases. The primary outcome was overall survival (OS) and progression-free survival (PFS); furthermore, we analyzed on-treatment serum level changes of sPD-L1 and sPD-1 during ICI therapy. Results We synthesized the data of 1,054 patients with different cancer types from 15 articles. Pooled univariate analysis showed that elevated levels of sPD-L1 were significantly associated with inferior OS (HR = 1.67; CI:1.26–2.23, I 2  = 79%, p   〈  0.001). The strongest association was found in non-small cell lung cancer, whereas weaker or no association was observed in melanoma as well as in renal cell and esophageal cancers. Pooled multivariate analysis also showed that elevated levels of sPD-L1 correlated with worse OS (HR = 1.62; CI: 1.00–2.62, I 2  = 84%, p  = 0.05) and PFS (HR = 1.71; CI:1.00–2.94, I 2  = 82%, p  = 0.051). Furthermore, we observed that one or three months of anti-PD-L1 treatment caused a strong (27.67-fold) elevation of sPD-L1 levels in malignant mesothelioma and urothelial cancer. Conclusions We found significantly inferior OS in ICI-treated cancer patients with elevated pre-treatment sPD-L1 levels, but this association seems to be tumor type dependent. In addition, sPD-L1 increases during anti-PD-L1 therapy seems to be therapy specific.
    Type of Medium: Online Resource
    ISSN: 0340-7004 , 1432-0851
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2023
    detail.hit.zdb_id: 1458489-X
    detail.hit.zdb_id: 195342-4
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  • 2
    In: Prostate Cancer and Prostatic Diseases, Springer Science and Business Media LLC
    Abstract: Abiraterone (Abi) is an androgen receptor signaling inhibitor that significantly improves patients’ life expectancy in metastatic prostate cancer (PCa). Despite its beneficial effects, many patients have baseline or acquired resistance against Abi. The aim of this study was to identify predictive serum biomarkers for Abi treatment. Methods We performed a comparative proteome analysis on three Abi sensitive (LNCaPabl, LAPC4, DuCaP) and resistant (LNCaPabl-Abi, LAPC4-Abi, DuCaP-Abi) PCa cell lines using liquid chromatography tandem mass spectrometry (LC-MS/MS) technique. Two bioinformatic selection workflows were applied to select the most promising candidate serum markers. Serum levels of selected proteins were assessed in samples of 100 Abi-treated patients with metastatic castration-resistant disease (mCRPC) using ELISA. Moreover, FSCN1 serum concentrations were measured in samples of 69 Docetaxel (Doc) treated mCRPC patients. Results Our proteome analysis identified 68 significantly, at least two-fold upregulated proteins in Abi resistant cells. Using two filtering workflows four proteins (AMACR, KLK2, FSCN1 and CTAG1A) were selected for ELISA analyses. We found high baseline FSCN1 serum levels to be significantly associated with poor survival in Abi-treated mCRPC patients. Moreover, the multivariable analysis revealed that higher ECOG status ( 〉 1) and high baseline FSCN1 serum levels ( 〉 10.22 ng/ml by ROC cut-off) were independently associated with worse survival in Abi-treated patients ( p   〈  0.001 and p  = 0.021, respectively). In contrast, no association was found between serum FSCN1 concentrations and overall survival in Doc-treated patients. Conclusions Our analysis identified baseline FSCN1 serum levels to be independently associated with poor survival of Abi-treated, but not Doc-treated mCRPC patients, suggesting a therapy specific prognostic value for FSCN1.
    Type of Medium: Online Resource
    ISSN: 1365-7852 , 1476-5608
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2023
    detail.hit.zdb_id: 2008886-3
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  • 3
    In: Food & Function, Royal Society of Chemistry (RSC), Vol. 9, No. 7 ( 2018), p. 4008-4016
    Type of Medium: Online Resource
    ISSN: 2042-6496 , 2042-650X
    Language: English
    Publisher: Royal Society of Chemistry (RSC)
    Publication Date: 2018
    detail.hit.zdb_id: 2578152-2
    SSG: 21
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  • 4
    In: International Journal of Molecular Sciences, MDPI AG, Vol. 24, No. 9 ( 2023-04-26), p. 7859-
    Abstract: Lymph node (LN) status is the most significant prognostic factor for invasive urothelial bladder cancer (UBC); however, the optimal extent of LN dissection (LND) is debated. We assessed circulating matrix metalloproteinase-7 (MMP-7) as a prognostic factor and decision-making marker for the extent of LND. Preoperative serum MMP-7 levels were determined in two independent UBC cohorts (n = 188; n = 68) and in one control cohort (n = 97) by using the ELISA method. A systematic review and meta-analysis on the prognostic role of circulating pretreatment MMP-7 levels were performed. Serum MMP-7 levels were higher in patients compared to controls (p 〈 0.001) with the highest levels in LN-positive cases. Half of LN-positive UBC patients had low MMP-7 levels, whereas the survival of LN-negative patients with high serum MMP-7 findings was poor. MMP-7 levels were independently associated with poor survival in both cohorts (p = 0.006, p 〈 0.001). Accordingly, our systematic review of six eligible publications revealed a 2.5-fold higher mortality risk in patients with high MMP-7 levels. In conclusion, preoperative MMP-7 level is a validated and independent prognostic factor in urothelial cancer. It cannot be used to decide between regional or extended LND but may be useful in identifying LN-negative high-risk patients with potentially undetected metastases.
    Type of Medium: Online Resource
    ISSN: 1422-0067
    Language: English
    Publisher: MDPI AG
    Publication Date: 2023
    detail.hit.zdb_id: 2019364-6
    SSG: 12
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  • 5
    In: Cancer Medicine, Wiley, Vol. 12, No. 7 ( 2023-04), p. 9041-9054
    Abstract: Administration of targeted therapies provides a promising treatment strategy for urachal adenocarcinoma (UrC) or primary bladder adenocarcinoma (PBAC); however, the selection of appropriate drugs remains difficult. Here, we aimed to establish a routine compatible methodological pipeline for the identification of the most important therapeutic targets and potentially effective drugs for UrC and PBAC. Methods Next‐generation sequencing, using a 161 cancer driver gene panel, was performed on 41 UrC and 13 PBAC samples. Clinically relevant alterations were filtered, and therapeutic interpretation was performed by in silico evaluation of drug‐gene interactions. Results After data processing, 45/54 samples passed the quality control. Sequencing analysis revealed 191 pathogenic mutations in 68 genes. The most frequent gain‐of‐function mutations in UrC were found in KRAS (33%), and MYC (15%), while in PBAC KRAS (25%), MYC (25%), FLT3 (17%) and TERT (17%) were recurrently affected. The most frequently affected pathways were the cell cycle regulation, and the DNA damage control pathway. Actionable mutations with at least one available approved drug were identified in 31/33 (94%) UrC and 8/12 (67%) PBAC patients. Conclusions In this study, we developed a data‐processing pipeline for the detection and therapeutic interpretation of genetic alterations in two rare cancers. Our analyses revealed actionable mutations in a high rate of cases, suggesting that this approach is a potentially feasible strategy for both UrC and PBAC treatments.
    Type of Medium: Online Resource
    ISSN: 2045-7634 , 2045-7634
    URL: Issue
    Language: English
    Publisher: Wiley
    Publication Date: 2023
    detail.hit.zdb_id: 2659751-2
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  • 6
    In: Cancer Medicine, Wiley, Vol. 12, No. 5 ( 2023-03), p. 5222-5232
    Abstract: Although targeted approaches have become available in second‐ and third‐line settings, platinum‐based chemotherapy remains the standard first‐line treatment for advanced muscle‐invasive bladder cancer (MIBC). Therefore, the prediction of platinum resistance is of utmost clinical importance. Methods In this study, we established a routine compatible method for the molecular classification of MIBC samples according to various classification systems and applied this method to evaluate the impact of subtypes on survival after adjuvant chemotherapy. This retrospective study included 191 patients with advanced MIBC (pT≥3 or pN+) who underwent radical cystectomy, with or without adjuvant chemotherapy. A 48‐gene panel and classifier rule set were established to determine molecular subtypes according to TCGA, MDA, LundTax, and Consensus classifications. Additionally, 12 single platinum‐predictive candidate genes were assessed. The results were correlated with patients' clinicopathological and follow‐up data and were validated using independent data sets. Results Our final evaluation of 159 patients demonstrated better survival in the luminal groups for those who received chemotherapy compared with those who did not. In contrast, no such differences were observed in basal subtypes. The use of chemotherapy was associated with better survival in patients with high APOBEC3G expression ( p   〈  0.002). This association was confirmed using an independent data set of patients who received neoadjuvant platinum therapy. Conclusions The proposed method robustly replicates the most commonly used transcriptome‐based subtype classifications from paraffin‐embedded tissue samples. The luminal, but not basal, molecular subtypes had the greatest benefit from adjuvant platinum therapy. We identified and validated APOBEC3G as a novel predictive marker for platinum‐treated patients.
    Type of Medium: Online Resource
    ISSN: 2045-7634 , 2045-7634
    URL: Issue
    Language: English
    Publisher: Wiley
    Publication Date: 2023
    detail.hit.zdb_id: 2659751-2
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  • 7
    In: Pharmacological Reports, Springer Science and Business Media LLC, Vol. 63, No. 1 ( 2011-01), p. 244-
    Type of Medium: Online Resource
    ISSN: 1734-1140
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2011
    detail.hit.zdb_id: 2129019-2
    SSG: 15,3
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  • 8
    In: Orvosi Hetilap, Akademiai Kiado Zrt., Vol. 161, No. 20 ( 2020-05), p. 813-820
    Abstract: A metasztatikus kasztrációrezisztens prosztatarák kezelésére az elmúlt években számos új, különböző hatásmechanizmusú gyógyszeres kezelés vált elérhetővé. Ez a fejlődés a terápiás döntéshozatalt egyre nehezebbé teszi. Az újabb kezelésekkel szemben is megfigyelhető az alapvonali, a szerzett és a keresztrezisztencia jelensége is. Ezért tehát az elsődleges terápia helyes megválasztása mellett, az azt követő vonalakban alkalmazott kezelések sorrendje és alkalmazásuk ideje is optimalizálásra szorul. Az újabb kezelésekkel kapcsolatos rezisztenciamechanizmusok egyre nagyobb mértékben válnak ismertté. Ezzel a terápiatervezés az eddigi empirikus – főleg a kipróbálásra építő – irányából egyre inkább a racionális – az adott daganat molekuláris sajátságait is figyelembe vevő –, személyre szabott kezelés irányába mozdul el. Ebben az összefoglaló közleményben ismertetjük azokat a rezisztenciamechanizmusokat, amelyek a metasztatikus kasztrációrezisztens prosztatarák kezelésében leggyakrabban használt három gyógyszerrel – docetaxel, abirateron és enzalutamid – kapcsolatosak. Többek között áttekintést nyújtunk a MDR- (multidrogrezisztens) fehérjéken keresztül megvalósuló, az androgénreceptor-, a Wnt-, a p53-szignálút, valamint a DNS hibajavító mechanizmusában részt vevő gének (mint például a BRCA és ATM ) sérüléseivel összefüggésben kialakuló és a neuroendokrin differenciá ció által kiváltott rezisztenciamechanizmusokról. Orv Hetil. 2020; 161(20): 813–820.
    Type of Medium: Online Resource
    ISSN: 0030-6002 , 1788-6120
    Language: Unknown
    Publisher: Akademiai Kiado Zrt.
    Publication Date: 2020
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  • 9
    In: Orvosi Hetilap, Akademiai Kiado Zrt., Vol. 162, No. 48 ( 2021-11-28), p. 1931-1939
    Abstract: Összefoglaló. Bevezetés: A neonatalis intenzív centrumokban kezelt betegek naponta számos fájdalmas beavatkozáson eshetnek át. A kezeletlen fájdalom következményeinek ismerete ellenére, fájdalmuk csillapítása még messze nem ideális. Célkitűzés: Obszervációs tanulmányunk célja az osztályunkon kezelt koraszülötteket és beteg újszülötteket ért fájdalmas beavatkozások gyakoriságának és természetének meghatározása volt. Vizsgáltuk a procedurális fájdalom esetén alkalmazott gyógyszeres és nonfarmakológiai fájdalomcsillapítók használatát, valamint a beavatkozások számát és a fájdalomcsillapítás alkalmazását befolyásoló tényezőket. Módszerek: A vizsgálatba az osztályunkon 2019. 09. 01. és 2019. 12. 31. között kezelt betegeket vontuk be. Prospektív adatgyűjtést végeztünk a hospitalizáció első 14 napján, egy erre a célra kialakított kérdőíven, amelyet az egészségügyi személyzet valós időben töltött ki. Eredmények: Kutatásunkba 143 gyermeket tudtunk bevonni. A vizsgálati időszak alatt 43-féle fájdalmas beavatkozás történt, összesen 13 314 alkalommal, amiből 12 953 első, 361 többszöri kísérlet volt. Gyermekenként átlagosan 93,1 beavatkozást végeztünk a hospitalizáció első 2 hetében, ami átlagosan 8,2 fájdalmas procedúrát jelentett naponta és gyermekenként. Fájdalomcsillapítás összesen 4190 alkalommal, a beavatkozások 31,5%-ában történt. Ennek 55,5%-a folyamatos gyógyszeres, 40,7%-a nem gyógyszeres, 2,5%-a alkalmi gyógyszeres, 1,3%-a kombinált terápia volt. A legkisebb születési súlyú, legrövidebb gestatiós időre született és a lélegeztetett koraszülöttek szenvedték el a legtöbb fájdalmas beavatkozást. Következtetés: Betegeink nagyszámú fájdalmas beavatkozáson esnek át, és ezek nagyobb részénél nem történik fájdalomcsillapítás. A beavatkozások tervezésével, összehangolásával, a gyógyszeres és nem gyógyszeres fájdalomcsillapítás kiterjedtebb alkalmazásával jobb fájdalommenedzsment lenne elérhető. Orv Hetil. 2021; 162(48): 1931–1939. Summary. Introduction: Preterm infants and sick neonates treated in neonatal intensive care units may undergo numerous painful interventions. Despite rapidly growing knowledge about consequences of untreated pain, pain management of neonates is far from ideal. Objective: To determine the frequency and nature of painful procedures and corresponding analgesic therapies in neonates treated in a neonatal intensive care unit of a university teaching hospital in Hungary. Methods: A prospective observational study was performed between September and December 2019. We collected data of all painful procedures, pharmacological and non-pharmacological analgesic therapy performed on neonates during the first 14 days of hospitalization. For data collection, we used a questionnaire designed for this purpose, which was completed in real time by the medical staff. Results: 143 children were enrolled. 43 types of painful interventions were performed, a total of 13,314 times, of which 12,953 were the first, 361 multiple attempts. Each neonate was subjected to a mean of 93.1 interventions in the first 2 weeks of hospitalization, representing an average of 8.2 painful procedures per day per child. Pain relief was performed a total of 4190 times, in 31.5% of the interventions. Of this, 55.5% were continuous pharmacological, 40.7% non-pharmacological, 2.5% occasional drug, and 1.3% combination therapy. Ventilated neonates and preterm infants with shorter gestational age and lower birth weight had the most painful procedures. Conclusion: Patients treated in our unit undergo a large number of painful interventions, most of which are not accompanied by analgesia. Increased efforts are needed to promote our better pain management. Orv Hetil. 2021; 162(48): 1931–1939.
    Type of Medium: Online Resource
    ISSN: 0030-6002 , 1788-6120
    Language: Unknown
    Publisher: Akademiai Kiado Zrt.
    Publication Date: 2021
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  • 10
    In: BMC Cancer, Springer Science and Business Media LLC, Vol. 13, No. 1 ( 2013-12)
    Abstract: Targeting signaling pathways is an attractive approach in many malignancies. The PI3K/Akt/mTOR pathway is activated in a number of human neoplasms, accompanied by lower overall and/or disease free survival. mTOR kinase inhibitors have been introduced in the therapy of renal cell carcinoma and mantle cell lymphoma, and several trials are currently underway. However, the pathological characterization of mTOR activity in lymphomas is still incomplete. Methods mTOR activity and the elements of mTOR complexes were investigated by immunohistochemistry on tissue microarrays representing different human non-Hodgkin-lymphomas (81 cases) and Hodgkin-lymphomas (87 cases). The expression of phospho-mTOR, phospho-4EBP1, phospho-p70S6K, phospho-S6, Rictor, Raptor and Bcl-2, Bcl-xL, Survivin and NF-kappaB-p50 were evaluated, and mTOR activity was statistically analyzed along with 5-year survival data. The in vitro and in vivo effect of the mTOR inhibitor rapamycin was also examined in human Hodgkin-lymphoma cell lines. Results The majority ( 〉 50%) of mantle cell lymphoma, Burkitt lymphoma, diffuse large B-cell lymphoma, anaplastic large-cell lymphoma and Hodgkin-lymphoma cases showed higher mTOR activity compared to normal lymphoid tissues. Hodgkin-lymphoma was characterized by high mTOR activity in 93% of the cases, and Bcl-xL and NF-kappaB expression correlated with this mTOR activity. High mTOR activity was observed in the case of both favorable and unfavorable clinical response. Low mTOR activity was accompanied by complete remission and at least 5-year disease free survival in Hodgkin-lymphoma patients. However, statistical analysis did not identify correlation beetween mTOR activity and different clinical data of HL patients, such as survival. We also found that Rictor (mTORC2) was not overexpressed in Hodgkin-lymphoma biopsies and cell lines. Rapamycin inhibited proliferation and induced apoptosis in Hodgkin-lymphoma cells both in vitro and in vivo, moreover, it increased the apoptotic effect of chemotherapeutic agents. Conclusions Targeting mTOR activity may be a potential therapeutic tool in lymphomas. The presence of mTOR activity probably indicates that the inclusion of mTOR inhibition in the therapy of Hodgkin-lymphomas may be feasible and beneficial, especially when standard protocols are ineffective, and it may also allow dose reduction in order to decrease late treatment toxicity. Most likely, the combination of mTOR inhibitors with other agents will offer the highest efficiency for achieving the best clinical response.
    Type of Medium: Online Resource
    ISSN: 1471-2407
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2013
    detail.hit.zdb_id: 2041352-X
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