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    Comparison of response and survival of first-line crizotinib therapy according to EML-4 ALK fusion variants in advanced non-small cell lung cancer patients: A Turkish Oncology Group study
    (Zerbinis Publications, 2021) Tatlı, Ali Murat; Yumuk, Perran Fulden; Öz, Büge; Bilici, Ahmet; Gürsoy, Pınar; Göker, Erdem; Sezer, Ahmet; Özet, Ahmet; Demirci, Umut; Bozkurtlar, Emine; Özbudak, İrem Hicran; Nart, Deniz; Canpolat, Tuğba; Akyürek, Nalan; Kılıçkap, Saadettin
    Purpose: In the literature there are conflicting data about the treatment efficacy of anaplastic lymphoma kinase (ALK) translocation positive non-small cell lung cancer (NSCLC) patients according to ALK fusion variants. We aimed to study the impact of ALK fusion variants on the survival of first-line crizotinib-treated NSCLC patients. Methods: 101 locally advanced or metastatic ALK positive NSCLC patients treated with first-line crizotinib between January 2013 and December 2019 were retrospectively evaluated. We studied ALK fusion variants in 38 of those patients with adequate tumor tissue with reverse transcription polymerase chain reaction (RT PCR). Patients having ALK fusion variant 1 (v1) and non-variant 1 (non-v1) were compared for survival and response to crizotinib. Results: Median age was 52.5 years (range 35-74), and 22 of 38 patients were male (57.9%). EML-4 ALK v1 was seen in 26 patients (68.4%) and 12 were non-v1 (variant 3a/b in 6, and non-EML-4 ALK variants in 6 patients). Objective response rate was 60.5% in all patients, whereas it was 61.5% in v1 and 58.3% in non-v1 group. Median progression-free survival (PFS) and overall survival (OS) were similar. Median PFS was 13.1 months in v1, and 12.4 months in non-v1 (p=0.232). Median OS was 23.2 months in v1, and 19.4 months non-v1 (p=0.493). Conclusion: ALK v1 and non-v1 patients had the same OS and PFS after first-line crizotinib treatment, however there was a trend for v1 group for better OS.
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    Concordance of PD-L1 expression and CD8+ TIL intensity between NSCLC and synchronous brain metastases
    (2020) Batur, Şebnem; Dülger, Onur; Durak, Şermin; Yumuk, Perran Fulden; Çağlar, Hale Başak; Bozkurtlar, Emine; Bozkurt, Süheyla; Taştekin, Ebru; Çiçin, İrfan; Ahiskalı, Rengin; Çakır, Aslı; Öz, Büge
    Programmed death-ligand 1 (PD-L1) is suggested to be a predictive biomarker in non-small-cell lung carcinoma (NSCLC). However, the differential expression of PD-L1 in primary lung tumor vs. synchronous metastases, especially brain metastasis (BM), remains unclear. This study assessed the concordance of PD-L1 expression on tumor cells and tumor-infiltrating lymphocytes (TILs) and CD8+ TIL intensity between primary lung tumors and synchronous BMs from 24 NSCLC patients. PD-L1, CD3, and CD8 positivity was determined by immunohistochemistry (IHC). PD-L1 scoring was based on the proportion of tumor cells with membranous expression of PD-L1 and the cutoff values <1%, 1–49%, and ?50%. CD3 and CD8 positivity in TILs was evaluated semi-quantitatively and the proportion of CD3+/CD8+ TILs was determined. PD-L1 expression on tumor cells and TILs was evaluated in relation to CD3+/CD8+ TIL proportions and the intensity of CD8+ TILs between the paired primary lung and BM tissues. In the primary lung tumors, PD-L1 positivity was observed in 25%, 37.5%, and 37.5% cases for the cutoff values <1%, 1–49%, and ?50%, respectively. PD-L1 expression on tumor cells was strongly correlated between the paired primary lung and BM tissues, in all cutoff groups. However, PD-L1 expression on TILs and the proportion of CD3+/CD8+ TILs were not strongly correlated in all three groups between the paired primary lung tumors and BMs. The intensity of CD8+ TILs was concordant in only 54.16% of the paired primary lung tumors and BMs. This study showed a high concordance of PD-L1 expression in neoplastic cells between primary NSCLC and synchronous BMs.
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    Histopathologic infiltration pattern predicts metastasis and progression better than pT-stage and grade in well-differentiated pancreatic neuroendocrine tumors: A proposal for an infiltration-based morphologic grading system
    (Springer Nature, 2021) Taşkın, Orhun; Reid, Michelle; Bağcı Çulçi, Pelin; Balcı, Serdar; Armutlu, Ayşe; Demirtaş, Deniz; Pehlivanoğlu, Burçin; Saka, Burcu; Memiş, Bahar; Bozkurtlar, Emine; Leblebici, Can Berk; Corobea, Adelina Birceanu; Xue, Yue; Erkan, Mert; Kapran, Yersu; Sökmensüer, Cenk; Scarpa, Aldo; Luchini, Claudio; Baştürk, Olca; Adsay, Nazmi Volkan
    [Abstract Not Available]
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    Histopathologic infiltration pattern predicts metastasis and progression better than pT-stage and grade in well-differentiated pancreatic neuroendocrine tumors: A proposal for an infiltration-based morphologic grading system
    (Springer Nature, 2021) Taşkın, Orhun; Reid, Michelle; Bağcı Çulçi, Pelin; Balcı, Serdar; Armutlu, Ayşe; Demirtaş, Deniz; Pehlivanoğlu, Burçin; Saka, Burcu; Memiş, Bahar; Bozkurtlar, Emine; Leblebici, Can Berk; Corobea, Adelina Birceanu; Xue, Yue; Erkan, Mert; Kapran, Yersu; Sökmensüer, Cenk; Scarpa, Aldo; Luchini, Claudio; Baştürk, Olca; Adsay, Nazmi Volkan
    [Abstract Not Available]
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    Macroscopic complete resection is not associated with improved survival in patients with malignant pleural mesothelioma
    (Mosby-Elsevier, 2018) Batırel, Hasan Fevzi; Metintaş, Muzaffer; Çağlar, Hale Başak; Ak, Güntülü; Yumuk, Perran Fulden; Ahıskalı, Rengin; Bozkurtlar, Emine; Bekiroğlu, Nural; Laçin, Tunç; Yıldızeli, Bedrettin; Yüksel, Mustafa
    Objective: Macroscopic complete resection (MCR) is the recommended surgical strategy in malignant pleural mesothelioma. Our objective was to analyze whether MCR influences survival in malignant pleural mesothelioma. Methods: Between 2002 and 2016, 154 patients underwent pleurectomy decortication (n = 90), extrapleural pneumonectomy (n = 42), or exploratory/diagnostic procedures (n = 22) in a single institution. Patient data were recorded in a prospective database. Patients who underwent surgical resection (n = 132) were analyzed according to MCR as a whole group and after propensity score matching based on gender, age, histology, clinical T and N status, adjuvant chemotherapy, and trimodality treatment. Kaplan-Meier survival and univariate and multivariate analyses were performed. Results: Median age was 56 years (range, 26 to 80 years) and 62 were women. One hundred ten had epithelioid histology. MCR was achieved in 75 patients (49%). In-hospital mortality was seen in 7 patients (4.5%). Preoperative chemotherapy was applied in 32 patients. One hundred thirty-three patients underwent adjuvant treatment (45 had chemoradiation). Mean follow-up was 21 +/- 19 months. Overall median survival, 2-year, and 5-year survivals were 18.1 months, 36%, and 16%, respectively. There was no difference in median survival between patients who underwent MCR (21.4 months) and who did not (16.3 months) (P = .6). Following propensity score matching (23 patients in each group), median survivals were similar (13.3 vs 14.2 months; P = .63). Conclusions: MCR was not associated with improved survival in malignant pleural mesothelioma. We need to clearly define MCR and identify subgroups of patients who would benefit from this principle because minimal versus extensive and location of gross residual disease may have different influences on survival.
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    PPP2R3C gene variants cause syndromic 46,XY gonadal dysgenesis and impaired spermatogenesis in humans
    (Bioscientifica Ltd, 2019) Güran, Tülay; Yeşil, Gözde; Turan, Serap; Atay, Zeynep; Bozkurtlar, Emine; Aghayev, AghaRza; Gül, Sinem; Tinay, İlker; Aru, Başak; Arslan, Sema; Köroğlu, Mustafa Kutay; Ercan, Feriha; Yanıkkaya Demirel, Gülderen; Tanay Eren, Funda; Karademir, Betül; Bereket, Abdullah
    Context: Most of the knowledge on the factors involved in human sexual development stems from studies of rare cases with disorders of sex development. Here, we have described a novel 46, XY complete gonadal dysgenesis syndrome caused by homozygous variants in PPP2R3C gene. This gene encodes B '' gamma regulatory subunit of the protein phosphatase 2A (PP2A), which is a serine/threonine phosphatase involved in the phospho-regulation processes of most mammalian cell types. PPP2R3C gene is most abundantly expressed in testis in humans, while its function was hitherto unknown. Patients and methods: Four girls from four unrelated families with 46, XY complete gonadal dysgenesis were studied using exome or Sanger sequencing of PPP2R3C gene. In total, four patients and their heterozygous parents were investigated for clinical, laboratory, immunohistochemical and molecular characteristics. Results: We have identified three different homozygous PPP2R3C variants, c.308T>C (pL103P), c.578T>C (pL193S) and c.1049T>C (pF350S), in four girls with 46, XY complete gonadal dysgenesis. Patients also manifested a unique syndrome of extragonadal anomalies, including typical facial gestalt, low birth weight, myopathy, rod and cone dystrophy, anal atresia, omphalocele, sensorineural hearing loss, dry and scaly skin, skeletal abnormalities, renal agenesis and neuromotor delay. We have shown a decreased SOX9-Phospho protein expression in the dysgenetic gonads of the patients with homozygous PPP2R3C variants suggesting impaired SOX9 signaling in the pathogenesis of gonadal dysgenesis. Heterozygous males presented with abnormal sperm morphology and impaired fertility. Conclusion: Our findings suggest that PPP2R3C protein is involved in the ontogeny of multiple organs, especially critical for testis development and spermatogenesis. PPPR3C provides insight into pathophysiology, as well as emerging as a potential therapeutic target for male infertility.