Clinical Significance Of DNA Repair Genes Expressions In Neurofibromatosis Type 1 Cases

AMAÇ: Nörofibromatozis Tip 1 (NF1), çeşitli fenotiplere sahip, sık görülen otozomal dominant genetik bir hastalıktır. NF1 hastalarının klinik çeşitliliğinin genetik nedeni sorgulanmaktadır. DNA onarım genleri DNA' daki hataların onarımından sorumludur. Bu çalışmada DNA onarım genlerinin ekspresyonunu ve onların NF1 hastalarındaki klinik önemini nörofibrom, hamartomatöz lezyon, diğer tümörler ya da ailesel NF1 varlığı ile karşılaştırarak analiz etmek ve gen ekspresyonları ile klinik bulgular arasında ilişki olup olmadığını belirlemek amaçlandı. YÖNTEMLER: NF1' li hastalar ve NF1 ile birlikte malignitesi olan hastalar çalışmaya alındı. Kontrol grubu olarak da benzer yaş grubundaki her hangi bir hastalığı olmayan çocuklar ve NF1 ile ilgisi olmayan maligniteli olgular oluşturdu. Çalışma toplam 46 olgu içermekteydi: 36 NF1 hastası (30 çocuk; 6 ebeveyn), hiç bir hastalığı olmayan 8 kontrol olgusu, rabdomiyosarkomlu NF1 olmayan 2 kontrol olgusu çalışmaya alındı. Her bir hasta ve kontrol grubundan periferik kandan mononükleer hücre izolasyonu yapıldı. RNA izolasyonu ve cDNA dönüşümünden sonra, her bir olguda Real-Time PCR ile DNA onarımı ile ilişkili 84 genin ekspresyonu (standart array, SABiosciences) belirlendi. Ekspresyonların kontrol grubuna göre kat değişiklikleri ve T test ile p değeri karşılaştırmalı gruplarda değerlendirildi. BULGULAR: Araştırma grubunu 36 NF1 hastası, kontrol grubunu ise 8 sağlam çocuk ve 2 adet de NF1 ile ilişkisi olmayan maligniteli olgu (rabdomiyosarkom) oluşturmaktadır. 8 kontrol olgusunun yaş ortalaması 17±7,03 (10-30 yaş) (ortanca 13 yaş) idi. NF1 olgularının 17' si kadın 19' u erkekti. NF1' li olgularımız için tanı anındaki yaş ortalaması 10,08±8,86 (9 ay- 38 yaş) (ortanca 8 yaş) iken hastalarımızın çalışmaya alınan ebeveynlerinin yaş ortalaması 40,50±1,22 (39-42 yaş) (ortanca40 yaş) idi. 36 hastanın, 17' si nörofibromlu, 17' si hamartomatöz lezyonluydu. 1 hastada rabdomiyosarkom (RMS) gözlenmiş, 1 hasta meme kanseri ve 4 hasta da optik gliomluydu. NF1 olgularında, PNKP, RAD18, XAB2, XRCC3, XRCC4 ve XRCC5 genlerinin ekspresyonu kontrol grup ile karşılaştırıldığında azaldı (p<0.05, T test). Nörofibromlu NF 1 olgularında, nörofibromsuz NF 1 olgularıyla karşılaştırıldığında POLB ekspresyonu artarken; ERCC3,LIG1,MGMT, MRE11A, MPG, MSH6, PARP2, PRKDC, RAD51B, RAD52, RPA3, SMUG1, TREX1, UNG ekspresyonu azaldı. RAD18 ailesel NF 1 varlığında ekspresyonu azalmış ve istatistiksel olarak önemli olduğu saptandı. Malign tümör olgularında NF 1' li ya da NF 1' siz gruplar karşılaştırıldığında gen ekspresyonunda kat değişiklikleri vardı. Maligniteli olgularda DDB2, MGMT, MLH1, POLB UNG, XPA ekspresyonları arttı. NF 1'li RMS olgusu ile NF 1' siz RMS olguları karşılaştırıldığında DDB2, MGMT, MLH1, POLB, UNG, XPA olmak üzere 6 genin ekspresyonu 10 kattan fazla artmış saptandı. SONUÇ: Bulgularımız NF 1 olgularındaki klinik bulgulardan tümör gelişimini öngörmek için DNA onarım sistemi ilişkili gen ekspresyon değişikliklerinin rolü olabileceğini göstermiştir. POLB nörofibrom varlığı belirteci, DDB2, MGMT, MLH1, POLB UNG, XPA malign tümör gözlenme belirteci olmaya aday genler olarak saptandı. Bu genlerin ekspresyonlarının daha geniş seri NF1li ve maligniteli olgularda çalışılması uygundur. OBJECTIVE: Neurofibromatosis Type 1 (NF1) is a a common autosomal dominant genetic disorder that has a variable phenotype. The genetical causes of clinical variability of NF1 patients is questioned. DNA repair genes are responsible for proofreading the missing in the DNA. We aimed to analyze expression of DNA repair genes and their clinical significance in NF1 patients; comparing exsistance of neurofibroma or hamartomatous lesions or other tumours or existance of NF1 in the family. The other aim of this study was to determine whether any relationship between gene expressions and clinical findings. METHODS: NF1 patients and malignancy with NF1 pateints were included and in this study. In the control gruop children that they are in the similar age group and they have no disease and no malignacy group were included. This study included total 46 cases. 36 NF1 patients (30 children; 6 parents), 8 control cases without any disease, two control cases with rhabdomyosarcoma without NF1 were included in this study. The mean age of control group was 17±7,03 (10-30 age) (median 13 age). In the NF1 pateints gruop 17 of them are female, and 19 are male. The mean age at diagnosis is 10,08±8,86 (9 months- 38 age)(median age 8) for children and 40,50±1,22 (39-42 age) (median age 40) for parents. Among 36 patients, 17 had neurofibromas, 17 had hamartomatous lesions. Rhabdomyosarcoma (RMS) was observed in one patient, breast cancer in one patient and four patients suffered optic glioma. Peripheral blood was obtained from each cases and mononuclear cells were separated. After RNA isolation and cDNA converting, expressions of 84 genes related with DNA Repair in standard array (SABiosciences) were determined by Real-Time PCR for each case. Fold changes and p values compared with control groups and fold changes evaluated with T test and p value in the comperative groups. RESULTS: 36 NF1 patients, 8 healthy children as a control and 2 cases no NF1 relationship with malignancy (rhabdomyosarcoma) were included in the study group. In NF1 cases PNKP, RAD18, XAB2, XRCC3, XRCC4 and XRCC5 genes were downregulated compared with control group. In NF1 cases having neurofibromas, POLB was over expressed; while ERCC3, LIG1, MGMT, MRE11A, MPG, MSH6, PARP2, PRKDC, RAD51B, RAD52, RPA3, SMUG1, TREX1, UNG were downregulated compared with the NF1 cases without neurofibromas (p<0.05, T test). RAD18 is the downregulated and statistical significant gene for existence of NF1 in the family. There are gene expression fold change differences determined when malign tumor cases with/without NF1 were compared. DDB2, MGMT, MLH1, POLB UNG, XPA are increased.   CONCLUSION: Our results may point toward a role of gene expression changes of DNA repair system to be predictive for clinical manifestations in NF1 cases

Proton and photon radiotherapy in stage III NSCLC:Effects on hematological toxicity and adjuvant immune therapy

Background and purpose: Concurrent chemo-radiotherapy (CCRT) followed by adjuvant durvalumab is standard-of-care for fit patients with unresectable stage III NSCLC. Intensity modulated proton therapy (IMPT) results in different doses to organs than intensity modulated photon therapy (IMRT). We investigated whether IMPT compared to IMRT reduce hematological toxicity and whether it affects durvalumab treatment. Materials and methods: Prospectively collected series of consecutive patients with stage III NSCLC receiving CCRT between 06.16 and 12.22 (staged with FDG-PET-CT and brain imaging) were retrospectively analyzed. The primary endpoint was the incidence of lymphopenia grade ≥ 3 in IMPT vs IMRT treated patients. Results: 271 patients were enrolled (IMPT: n = 71, IMRT: n = 200) in four centers. All patients received platinum-based chemotherapy. Median age: 66 years, 58 % were male, 36 % had squamous NSCLC. The incidence of lymphopenia grade ≥ 3 during CCRT was 67 % and 47 % in the IMRT and IMPT group, respectively (OR 2.2, 95 % CI: 1.0–4.9, P = 0.03). The incidence of anemia grade ≥ 3 during CCRT was 26 % and 9 % in the IMRT and IMPT group respectively (OR = 4.9, 95 % CI: 1.9–12.6, P = 0.001). IMPT was associated with a lower rate of Performance Status (PS) ≥ 2 at day 21 and 42 after CCRT (13 % vs. 26 %, P = 0.04, and 24 % vs. 39 %, P = 0.02). Patients treated with IMPT had a higher probability of receiving adjuvant durvalumab (74 % vs. 52 %, OR 0.35, 95 % CI: 0.16–0.79, P = 0.01). Conclusion: IMPT was associated with a lower incidence of severe lymphopenia and anemia, better PS after CCRT and a higher probability of receiving adjuvant durvalumab.</p

Comparison of the efficacy of once- and twice-daily colchicine dosage in pediatric patients with familial Mediterranean fever - a randomized controlled noninferiority trial

Background: In this study, we examined the efficacy and safety of a once-daily dosage schema of colchicine compared with a twice-daily dosage schema in pediatric patients with familial Mediterranean fever (FMF). Methods: In this 24-week, multicenter, randomized controlled noninferiority trial, pediatric patients newly diagnosed with FMF carrying a homozygous or compound heterozygous mutation and not receiving any treatment were included. Patients were randomly assigned using a block randomization method to receive treatment with a once- or twice-daily dosage. Clinical and laboratory characteristics and medication side effects were recorded and compared between groups. The study was carried out in compliance with Good Clinical Practice and the Consolidated Standards for Reporting of Trials (CONSORT) statement. Results: A total of 92 patients were selected, and 79 patients completed the study. There were 42 patients in the once-daily dosage group and 37 in the twice-daily dosage group. The results indicated that the once-daily dosage was not inferior to the twice-daily dosage regarding decrease in attack frequency and duration as well as improvement in clinical findings and Mor severity scores. Alterations in laboratory findings indicating inflammation, such as erythrocyte sedimentation rate, C-reactive protein, and serum amyloid A, were similar in both groups. The rates of drug side effects were similar between the once- and twice-daily dosage groups, implying comparable safety of colchicine, with the exception of diarrhea, which was slightly higher in the once-daily dosage group. Conclusions: Using colchicine with either a once- or twice-daily dosage provides similar clinical and laboratory improvements. Considering both efficacy and safety, colchicine can be prescribed with a once-daily dosage. Trial Registration ID: ClinicalTrials.gov identifier NCT02602028. Registered 5 November 2015

Exploring the impact of patient-specific clinical features on osimertinib effectiveness in a real-world cohort of patients with EGFR mutated non-small cell lung cancer

Osimertinib is prescribed to patients with metastatic non-small cell lung cancer (NSCLC) and a sensitizing EGFR mutation. Limited data exists on the impact of patient characteristics or osimertinib exposure on effectiveness outcomes. This was a Dutch, multicenter cohort study. Eligible patients were ≥18 years, with metastatic EGFRm+ NSCLC, receiving osimertinib. Primary endpoint was progression-free survival (PFS). Secondary endpoints included overall survival (OS) and safety. Kaplan-Meier analyses and multivariate Cox proportional hazard models were performed. In total, 294 patients were included. Primary EGFR-mutations were mainly exon 19 deletions (54%) and p.L858R point mutations (30%). Osimertinib was given in first-line (40%), second-line (46%) or beyond (14%), with median PFS 14.4 (95% CI: 9.4-19.3), 13.9 (95% CI: 11.3-16.1) and 8.7 months (95% CI: 4.6-12.7), respectively. Patients with low BMI (&lt;20.0 kg/m2) had significantly shorter PFS/OS compared to all other subgroups. Patients with a high plasma trough concentration in steady state (Cmin,SS; &gt;271 ng/mL) had shorter PFS compared to a low Cmin,SS (&lt;163 ng/mL; aHR 2.29; 95% CI: 1.13-4.63). A significant longer PFS was seen in females (aHR = 0.61, 95% CI: 0.45-0.82) and patients with the exon 19 deletion (aHR = 0.58, 95% CI: 0.36-0.92). A trend towards longer PFS was seen for TP53 wild-type patients, while age did not impact PFS. Patients with a primary EGFR exon 19 deletion had longer PFS, while a low BMI, male sex and a high Cmin,SS were indicative for shorter PFS and/or OS. Age was not associated with effectiveness outcomes of osimertinib.</p

Bilateral Breast Cancer with Neurofibromatosis Type 1 Patient: Case Report

Neurofibromatosis type 1 (NF1) is autosomal dominant and it is the most common hereditary disease. This case report is about a woman and her daughter. Both of them are NF1 and mother also has metachronous bilateral breast carcinoma. We analyzed expressions of 84 genes related with DNA Repair by Real Time PCR (AB Applied Biosystem 7000 Sequence Detection System

The anti-inflammatory and antioxidant effects of pravastatin and nebivolol in rat aorta

Objective: The aim of this study was to investigate the effects of pravastatin and nebivolol in the atherosclerotic process including inflammation and oxidative stress in rat aorta

The anti-inflammatory and antioxidant effects of pravastatin and nebivolol in rat aorta

Objective: The aim of this study was to investigate the effects of pravastatin and nebivolol in the atherosclerotic process including inflammation and oxidative stress in rat aorta