BACKGROUNDThere is considerable interest in the molecular evaluation of solid tumors in pediatric cases. Although clinical trials are in progress for targeted therapies against neuroblastoma (NB), ...novel therapeutic strategies are needed for high-risk cases that are resistant to therapy. The aim of the present study was to document the specific gene mutations related to targeted therapy in relapsed or refractory NB patients by using next generation sequencing (NGS). METHODSThe study included 57 NB patients from amongst 1965 neuroblastic cases in Turkey who experienced a recurrence after multi-model therapy. The cases were diagnosed, risk-stratified, and treated according to the classification system from the International Neuroblastoma Risk Group. Single nucleotide variations in 60 genes were investigated using the Pillar Onco/Reveal Multicancer v4 panel and Pillar RNA fusion panel on the Illumina Miniseq platform. RESULTSERBB2 I655V was the most frequent mutation and was found in 39.65% of cases. Anaplastic Lymphoma Kinase (ALK) mutations (F1174L, R1275Q, and rare mutations in the tyrosine kinase domain) were detected in 29.3% of cases. Fusion mutations in NTRK1, NTRK3, ROS1, RET, FGFR3, ALK and BRAF were observed in 19.6% of cases. CONCLUSIONSThis study presents valuable mutation data for relapsed and refractory NB patients. The high frequency of the ERBB2 I655V mutation may allow further exploration of this mutation as a potential therapeutic target. Rare BRAF mutations may also provide opportunities for targeted therapy. The role of ABL1 mutations in NB should also be explored further.
Abstract
Objectives
In our study, we aimed to (1) create a peritoneal metastasis (PM) model in nude mice, administer intraperitoneal chemotherapy using the peritoneal infusion pump we developed in ...this model, and (2) compare the efficacy of intraperitoneal chemotherapy using various drugs at different temperatures.
Methods
The peritoneal metastasis model was established in nude mice using the CC531 colon carcinoma cell line. Models with peritoneal metastasis (PM) were randomized into four groups of seven animals each: Group 1, control group (n=7); Group 2, normothermic intraperitoneal chemotherapy (NIPEC) with mitomycin C(MMC) (n=7); Group 3, hyperthermic intraperitoneal chemotherapy (HIPEC) with mitomycin C (n=7), and Group 4, NIPEC with 5-fluorouracil (5-FU).
Results
Tumor development was achieved in all animals. While the tumor burden decreased significantly in the treatment Group 3 (p=0.034), no significant difference was found in the other groups. In the PM mouse model, hyperthermic intraperitoneal administration of MMC had the highest tumoricidal effect.
Conclusions
Our PM model provided a good opportunity to examine the efficacy of HIPEC and intraperitoneal infusion pump (IPIP). In future studies, we plan to evaluate efficacies of different drugs in the PM models we have created.
Objective: Tumor heterogeneity describes the differences between cancer cells in the same tumor sample. Neuroblastoma (NB) is a type of cancer where tumor heterogeneity complicates its treatment. ...This study aims to explore the role of molecular heterogeneity detected by routine molecular tests in NB. Method: Seventy-one patients were included in the study. NB samples were chosen among 1,300 NB samples that were evaluated using molecular tests between 2012-2020 according to the guidelines of Turkish Pediatric Oncology Group Protocol. Molecular investigations were performed (total 142 samples) obtained from two different areas of the tumor (synchronous) or at two different times (metachronous). Heterogeneity was questioned for five tests: MYCN amplification, 1p36LOH, 11q23 deletion and 17q25 gain (identified with real-time polymerase chain reaction) and DNA ploidy (identified with flow cytometry). Results: Heterogeneity was observed for MYCN in 22.53%, for 1p36LOH in 36.62%, for 11q23del in 29.58%, and for 17q25 gain in 40.85% of cases, while DNA ploidy was heterogeneous in 36.4% of cases. Molecular heterogeneity did not show statistical difference among metachronous and synchronous cases. High-risk cases more frequently displayed molecular heterogeneity without any statistically significant difference between both groups. Conclusions: Our findings support the fact that molecular heterogeneity either exists in different areas of a tumor or seen in the same tumor at different times. It will be beneficial to perform more than one molecular analysis on the tumor tissue specimens. In addition, recurrences or re-biopsy specimens from metachronous metastases shall be re-evaluated using molecular tests in cases of NB.
Neuroblastoma-targeted Anticancer Drug Delivery Safiye Aktaş; Özde Elif Gökbayrak; Aylin Erol ...
Izmir Dr. Behçet Uz Çocuk Hastanesi dergisi,
01/2021, Letnik:
11, Številka:
3
Journal Article
Recenzirano
Odprti dostop
Neuroblastoma (NB) is the most common solid tumor in pediatric cases. NB accounts for about 8% of malignancies in patients younger than 15 years, and since 50% of newly diagnosed cases metastasize to ...regional lymph nodes, bone marrow, bone, liver, and skin, the disease is usually diagnosed in its late stages. Overexpression of N-MYC, which is characterized by poor prognosis in NB, changes the progression of the disease and the course of the treatment. Targeting these pathways may be a treatment option in NB, since the mTOR and AURKA pathways interact with N-MYC and directly cause protein stabilization. The widespread use of conventional chemotherapeutics has some limitations associated with their common side effects and the bioavailability of the drugs. New therapeutic approaches have focused on nanoparticle (NP) -based therapies, and chemoimmunoagents in the form of many NPs are being tried in NB. Here, we review new therapeutic approaches that would help to treat NB.
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•Electrochemical determination of Bendamustine was performed.•Interaction of Bendamustine and dsDNA was investigated.•The interaction was determined by electrochemically in the ...absence and presence of Quercetin.•QRCT prevents the interaction of DNA with BND as it interacts with DNA.
Studies based on drug-DNA interactions, especially anticancer drug-DNA interactions, are of great importance for the method development. It is thought that single-use electrodes, which give fast, cheap and reproducible results, will make a great contribution to the chip technology for the development of individual patient analysis in the future. It is known that antioxidants reduce carcinogenesis caused by oxidative stress with their radical scavenging effects. Literature shows that quercetin (QRCT) exhibits anticancer activity by preventing oxidative cell damage as an effective radical scavenger. In this study, Bendamustine (BND), an anticancer drug, which is used in different blood cancer types, was electrochemically determined and the toxicity degree was calculated by examining the interaction of the drug with DNA in the absence and presence of QRCT, which is the first examination in the literature. Limit of detection and quantification for BND was calculated as 6.0 and 20.0 μg/mL respectively by using the equation I = 0.029 × CBND+ 1.197, (R2 = 0.997). We found that QRCT prevents the interaction between BND and DNA because of its strong interaction with DNA.
The aim of the study was to demonstrate the most common genetic alterations and evaluate possible targets involving phosphatidylinositol-3-OH kinase (PIK3)/AKT/mammalian target of rapamycin (mTOR) ...signaling and DNA damage repair (DDR) pathways for personalized treatment in patients with non-muscle invasive bladder cancer (NMIBC). Alterations of these pathways were observed in 89.5% and 100% of patients, respectively. Among them, BARD1 was more frequently altered in low/intermediate-risk cases, but PARP4 was more frequently affected in intermediate/high-risk patients. The possible target feasibility of BARD1 and PARP4 alterations should be evaluated for personalized treatment using PARP-inhibitors in NMIBC. It is important to detect high tumor mutation burden (TMB) in patients in terms of immunotherapy.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
Giriş: Çocukluk çağı kanserleri, tedavi ve sağkalım oranlarında ilerleme görülmesine karşın, yeni tedavi stratejilerine gereksinim duyulan bir kanser grubudur.Seskiterpen laktonlar (SL) 100'den fazla ...çiçekli bitki familyasında bulunan çeşitli doğal ürünler grubudur. SL’lar geleneksel olarak kullanılan birçok tıbbi bitkinin aktif bileşenleridir. SL’lerin değişik kanser gruplarında anti-kanser etkisi kanıtlanmış olup, çocukluk çağı kanserlerinde bu konuyla ilgili yapılmış çalışma bulunmamaktadır. Bu çalışmanın amacı ; dehydroleucodine(DhL) ve yapısında bir çok aktif SL bulunduğu bilinen Inula viscosa(Yapışkan Andız Otu) bitkisinin ekstraktlarının etkisinin sisplatin (CDDP) ile karşılaştırılmalı olarak çocukluk çağı kanserlerinde araştırılmasıdır.In vitro çalışmada, nöroblastom hücre hattı olan KELLY, Ewing sarkom hücre hattı olan SKES ve çocukluk çağı karaciğer kanseri hücre hattı olan Hep-G2 hücreleri kullanılmıştır. DhL ve CDDP ticari olarak satın alınmıştır. Inula viscosaAğustos 2018’ de Manisa Spil Dağı’ndan toplanmıştır. Tür tayini Ege Üniversitesi Botanik Bahçesinde yapılmıştır. Bitkinin ekstraktı, Ege Üniversitesi Eczacılık Fakültesi’nde katı-sıvı ekstraksiyon yöntemiyle elde edilmiştir. Ekstraktlardan DPPH yöntemi ile antioksidan aktivite , alüminyum klorit yöntemi ile total flavonoid miktarı ve Folin Coicalteu yöntemi ile total fenolik madde tayinleri yapılmıştır. İnce tabaka kromatografi yöntemi ile ekstraktların analiz ve görüntülenmesi yapılmıştır. Hücre hatları kültüre edilip, 96 well platede dört farklı çözücü ile hazırlanmış ekstrakt, DhL ve CDDP’in LD50 dozları MTT hücre canlılık testi ile saptanmıştır. Etkin bulunan LD50 dozları 6 well platede tüm hücre hatlarına uygulanmış, canlılık ve sonra akım sitometride Annexin V+PI testi ile apoptoz ve nekroz yüzdeleri saptanmıştır.Toluidin mavisi boyaması ile hücrelerdeki morfolojik değişiklikler incelenmiştir. Bu kapsamda proliferasyon indeksi olarak Ki67, apoptoz mekanizmasını belirleme amacıyla Kaspaz 3,8,9 ile immünohistokimyasal incelemeler yapılmıştır.Bulgularımız Mann Whitney U testi ile p<0,05 düzeyinde karşılaştırılmıştır. Nöroblastom hücre hattı Kelly için CDDP proliferasyon ve apoptoz üzerinde beklenen güçlü etkiyi göstermiştir. DhL ve Metanol çözücülü bitki ekstraktı (MBE) ‘nin ise CDDP ‘ye göre proliferasyonu daha az azalttığı halde hücreleri apoptoza sürüklediği görülmüştür. Çocukluk çağı karaciğer kanseri hücre hattı HEP-G2 için CDDP, MBE, DhL ‘nin proliferasyonda benzer miktarda azalmaya sebep olduğu , her üç ajanında hücreleri apoptoza sürüklediği ve apoptotik intrinsik yolağı daha çok kullandığı görülmüştür. Ewing sarkom hücre hattı SK-ES için DhL ve MBE ‘nin proliferasyonu CDDP’ e göre daha az azalttığı fakat hücreleri bariz biçimde apoptoza sürüklediği görülmüştür.Klinikte tedavide kullanılan bir ajan olan CDDP kıyasla bakıldığında her iki madde benzer ve istatistiksel olarak anlamlı şekilde anti-kanser aktivite göstermiştir. Ve bu etkiyi apoptoz ve nekroptoz üzerinden yapmıştır. Bu ajanlarla ilgili in vivo deneylerin de planlanması gerekmektedir. In vivodeneylerinin tamamlanması ve moleküler mekanizmalarının tam olarak açıklanması sonrasında ülkemizde doğal olarak bulunan bu bitki klinikte işlevsel olarak kullanılan bir, pediatrik anti-kanser ajan olma adayıdır.
Background and Aim
In neuroblastoma, anaplastic lymphoma kinase mutations have recently received attention as molecular targets for the treatment of neuroblastoma, as 6% to 10% of patients with ...neuroblastoma have anaplastic lymphoma kinase mutations. There are little data from the cases in Turkey. We aimed to detect anaplastic lymphoma kinase mutations and molecular heterogeneity in neuroblastoma using next-generation sequencing. This study is the first one with this many cases in Turkey.
Methods
Next-generation sequencing analysis was performed using an Illumina MiniSeq custom gene panel. Clinically important mutations were selected for the analysis. We also gathered clinical data of the patients from Turkish Pediatric Oncology Group cohorts to associate them with anaplastic lymphoma kinase mutations. This study is a retrospective cross-sectional study. We followed STROBE guideline (https://www.equator-network.org/reporting-guidelines/strobe/) on this study.
Results
We analyzed anaplastic lymphoma kinase in 108 patients with neuroblastoma, with a mean age of 43.76 months. Pathogenic anaplastic lymphoma kinase mutations were detected in 13 patients (12.04%). We noted that anaplastic lymphoma kinase mutations were primarily observed in intermediate- and high-risk patients (P = .028). R1275Q and F1174-related mutations were predominant; I1171T, L1226F, S1189F, V1135A, and G1125S mutations were rare. Duplicate samples did not exhibit any heterogeneity.
Conclusions
We found that F1174 and R1275Q-related anaplastic lymphoma kinase mutations are the most common pathogenic mutations in neuroblastoma. Anaplastic lymphoma kinase mutation status did not show any heterogeneity, and the mutations were correlated with intermediate- or high-risk groups.
To evaluate the
efficacy of chemotherapy, immunotherapy and targeted agents with the oncogram method in patients with bladder cancer and determine the most appropriate personalized treatment agent ...using immune markers.
Bladder cancer tissues were obtained from each patient. After cultivation, cell cultures were divided into 12 groups for each patient and 11 drugs were administered. Cell viability and immunohistochemistry expression were examined.
A good response rate was determined to be a 23% viability drop. The nivolumab good response rate was slightly better in PD-L1-positive patients and the ipilimumab good response rate was slightly better in tumoral CTLA-4-positive cases. Interestingly, the cetuximab response was worse in EGFR-positive cases.
Although good responses of drug groups after their
application by using oncogram were found to be higher than control group, this outcome differed on a per patient basis.
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