Researcher:
Sezen, Duygu

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Duygu

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Sezen

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Sezen, Duygu

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2015 - 2019132020 - 202329

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    High-dose irradiation in combination with non-ablative low-dose radiation to treat metastatic disease after progression on immunotherapy: results of a phase II trial
    (Elsevier, 2021) Patel, Roshal R.; He, Kewen; Barsoumian, Hampartsoum B.; Chang, Joe Y.; Tang, Chad; Verma, Vivek; Comeaux, Nathan; Chun, Stephen G.; Gandhi, Saumil; Truong, Mylene T.; Erasmus, Jeremy J.; Hong, David S.; Lee, Percy P.; Ning, Matthew S.; Quynh-Nhu Nguyen; Heymach, John, V; Altan, Mehmet; Blumenschein, George; Fossella, Frank, V; Chen, Dawei; Carter, Brett W.; Davies, Michael A.; Glitza, Isabella C.; Diab, Adi; Ferrarotto, Renata; Cabanillas, Maria E.; Yuan, Ying; Shah, Shalin J.; Parra, Edwin R.; Sun, Baohua; Cortez, Maria Angelica; Welsh, James W.; N/A; Sezen, Duygu; Faculty Member; School of Medicine; 170535
    Aim: To report early findings from a phase II trial of high-dose radiotherapy (HD-RT) with or without low-dose RT (LD-RT) for metastatic cancer. Methods: Eligible patients had metastatic disease that progressed on immunotherapy within 6 months. Patients were given either HD-RT (20-70 Gy total; 3-12.5 Gy/f), or HD-RT + LD-RT (0.5-2 Gy/f up to 1-10 Gy total) to separate lesions, with continued immunotherapy. Radiographic response was assessed per RECIST 1.1 and Immune-Related Response Criteria (irRC). Primary endpoints: (1) 4-month disease control (DCR, complete/partial response [CR/PR] or stable disease [SD]) or an overall response (ORR, CR/PR) at any point in >10% of patients, per RECIST 1.1; (2) dose-limiting toxicity within 3 months not exceeding 30%. Secondary endpoint was lesion-specific response. Results: Seventy-four patients (NSCLC, n = 38; melanoma n = 21) were analyzed (39 HD-RT and 35 HDRT + LD-RT). The median follow-up time was 13.6 months. The primary endpoint was met for 72 evaluable patients, with a 4-month DCR of 42% (47% [16/34] vs. 37% [14/38] in HD-RT + LD-RT vs. HD-RT, P = 0.38), and 19% ORR at any time (26% [9/34] vs. 13% [5/38] in HD-RT + LD-RT vs. HD-RT, P = 0.27). Three patients had toxicity >grade 3. LD-RT lesion response (53%) was improved compared to nonirradiated lesions in HD-RT + LD-RT (23%, P = 0.002) and HD-RT (11%, P < 0.001). T-and NK cell infiltration was enhanced in lesions treated with LD-RT. Conclusions: HD-RT plus LD-RT safely improved lesion-specific response in patients with immune resistant solid tumors by promoting infiltration of effector immune cells into the tumor microenvironment.
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    Design considerations for clinical trials of radiotherapy combined with immunotherapy
    (İstanbul Tıp Fakültesi, 2023) Welsh, James; Sezen, Duygu; Faculty Member; School of Medicine; 170535
    The discovery of synergistic effects between radiation and immunotherapy in pre-clinical studies has encouraged researchers to conduct clinical trials testing the effects of combined therapy in patients. The first step in conducting any clinical trial is to define the hypothesis and core objectives. The challenge while developing trials analyzing combinations of immunotherapy and radiation therapy (RT) is to select an appropriate hypothesis that can be tested in the future research, as well as raising new questions for investigation. Here, we review some of the concerns and challenges for designing clinical trials of RT combined with immunotherapy.
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    Case presentation: the effect of volumetric image guidance and adaptive radiotherapy on cardiac dose in a patient with esophageal cancer
    (Kare Publ, 2018) Sağlam, Yücel; Alpan, Vildan; N/A; N/A; N/A; N/A; N/A; Sezen, Duygu; Bölükbaşı, Yasemin; Durankuş, Nilüfer Kılıç; Atasoy, Ali İhsan; Selek, Uğur; Faculty Member; Faculty Member; Teaching Faculty; Other; Faculty Member; School of Medicine; School of Medicine; School of Medicine; School of Medicine; School of Medicine; 170535; 216814; 148139; N/A; N/A; N/A; 27211
    We present the case of a patient with esophageal cancer whose tumor size regression prompted re-planning to decrease the cardiac dose. A 68-year-old male presented at our outpatient clinic with dysphagia. He was diagnosed with clinical T3N1 M0 adenocarcinoma located at the distal esophagus-esophagogastric junction. He was decided to have surgery after receiving neoadjuvant chemoradiotherapy. Following 4-D CT simulation, IG-IMRT with SIB technique was planned as 50 Gy in 25 fractions to iGTV and as 45 Gy to the area identified as the CIV. Daily kV and weekly CBCI were planned at the beginning of the treatment. Concurrent CT with weekly paclitaxel-carboplatin was administered. At the simulation and start of the treatment, the heart was pushed anteriorly due to the mass effect and dilatation in the mid-lower esophagus. The mass and dilatation regressed at the weekly CBCT of the patient. The third-week CBCT evaluation revealed the movement of the heart posteriorly into the PTV. Re-simulation was performed to continue with the adaptive planning for the last 10 treatment fractions. The cumulative dose received by the heart was reduced from 96% to 93% for V5Gy, from 79% to 60.8% for V10Gy, from 60% to 43.2% for V15Gy, from 35% to 21% for V20Gy, and from 29.6 to 28 Gy for the mean cardiac dose with the volumetric image-guided adaptive planning. If tumor regression is predicted during radiotherapy to possibly change doses of organs at risk, volumetric image guidance should be encouraged once per week, at least, to consider adaptive treatment when required to ensure the critical organ doses within safe limits.
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    Inhibition of STAT6 with antisense oligonucleotides enhances the systemic antitumor effects of radiotherapy and anti-PD-1 in metastatic non-small cell lung cancer
    (American Association for Cancer Research, 2023) He, Kewen; Barsoumian, Hampartsoum B.; Puebla-Osorio, Nahum; Hu, Yun; Wasley, Mark D.; Bertolet, Genevieve; Zhang, Jie; Leuschner, Carola; Yang, Liangpeng; Kettlun Leyton, Claudia S.; Fowlkes, Natalie Wall; Green, Morgan Maureen; Hettrick, Lisa; Chen, Dawei; Masrorpour, Fatemeh; Gu, Meidi; Maazi, Hadi; Revenko, Alexey S.; Cortez, Maria Angelica; Welsh, James W.; N/A; Sezen, Duygu; Faculty Member; School of Medicine; 170535
    Diverse factors contribute to the limited clinical response to radiotherapy (RT) and immunotherapy in metastatic non-small cell lung cancer (NSCLC), among which is the ability of these tumors to recruit a retinue of suppressive immune cells-such as M2 tumor-associated macrophages (TAM)-thereby establishing an immunosuppressive tumor microenvironment that contributes to tumor progression and radio resistance. M2 TAMs are activated by the STAT6 signaling pathway. Therefore, we targeted STAT6 using an antisense oligonucleotide (ASO) along with hypofractionated RT (hRT; 3 fractions of 12 Gy each) to primary tumors in three bilateral murine NSCLC models (Lewis lung carcinoma, 344SQ-parental, and anti-PD-1-resistant 344SQ lung adenocarcinomas). We found that STAT6 ASO plus hRT slowed growth of both primary and abscopal tumors, decreased lung metastases, and extended survival. Interrogating the mechanism of action showed reduced M2 macrophage tumor infiltration, enhanced TH1 polarization, improved T-cell and macrophage function, and decreased TGFβ levels. The addition of anti-PD-1 further enhanced systemic antitumor responses. These results provide a preclinical rationale for the pursuit of an alternative therapeutic approach for patients with immune-resistant NSCLC.
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    Radiation therapy modulates tumor physical characteristics to reduce intratumoral pressure and enhance intratumoral drug delivery and retention
    (Elsevier, 2023) Barsoumian, Hampartsoum B.; Sheth, Rahul A.; Ramapriyan, Rishab; Hsu, Ethan; Gagea, Mihai; Crowley, Kaitlyn; Williams, Malea; Welsh, James W.; Sezen, Duygu; Faculty Member; School of Medicine; 170535
    Purpose: High intratumoral pressure, caused by tumor cell-to-cell interactions, interstitial fluid pressure, and surrounding stromal composition, plays a substantial role in resistance to intratumoral drug delivery and distribution. Radiation therapy (XRT) is commonly administered in conjunction with different intratumoral drugs, but assessing how radiation can reduce pressure locally and help intratumoral drug administration and retention is important. Methods and Materials: 344SQ-parental or 344SQ-anti-programmed cell death protein 1-resistant lung adenocarcinoma cells were established in 129Sv/Ev mice, and irradiated with either 1 Gy × 2, 5 Gy × 3, 8 Gy × 3, 12 Gy × 3, or 20 Gy × 1. Intratumoral pressure was measured every 3 to 4 days after XRT. Contrast dye was injected into the tumors 3- and 6-days after XRT, and imaged to measure drug retention. Results: In the 344SQ-parental model, low-dose radiation (1 Gy × 2) created an early window of reduced intratumoral pressure 1 to 3 days after XRT compared with untreated control. High-dose stereotactic radiation (12 Gy × 3) reduced intratumoral pressure 3 to 12 days after XRT, and 20 Gy × 1 showed a delayed pressure reduction on day 12. Intermediate doses of radiation did not significantly affect intratumoral pressure. In the more aggressive 344SQ-anti-programmed cell death protein 1-resistant model, low-dose radiation reduced pressure 1 to 5 days after XRT, and 12 Gy × 3 reduced pressure 1 to 3 days after XRT. Moreover, both 1 Gy × 2 and 12 Gy × 3 significantly improved drug retention 3 days after XRT; however, there was no significance detected 6 days after XRT. Lastly, a histopathologic evaluation showed that 1 Gy × 2 reduced collagen deposition within the tumor, and 12 Gy × 3 led to more necrotic core and higher extracellular matrix formation in the tumor periphery. Conclusions: Optimized low-dose XRT, as well as higher stereotactic XRT regimen led to a reduction in intratumoral pressure and increased drug retention. The findings from this work can be readily translated into the clinic to enhance intratumoral injections of various anticancer agents.
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    Impact of prolonged neoadjuvant treatment-surgery interval on histopathologic and operative outcomes in patients undergoing total mesorectal excision for locally advanced rectal cancer
    (Lippincott Williams and Wilkins (LWW), 2020) Akbaba, Ata C.; Aytac, Erman; Yozgatlı, Tahir K.; Bengür, Fuat B.; Esen, Eren; Bilgin, İsmail A.; Şahin, Bilgehan; Atalar, Banu; Erdamar, Sibel; Özben, Volkan; Baca, Bilgi; Hamzaoğlu, İsmail; Karahasanoğlu, Tayfun; Zenger, Serkan; Buğra, Dursun; Sezen, Duygu; Kapran, Yersu; Balık, Emre; Buğra, Dursun; Faculty Member; Faculty Member; Faculty Member; Faculty Member; Faculty Member; School of Medicine; School of Medicine; School of Medicine; School of Medicine; American Hospital; 170535; 168101; 18758; 1758
    Background: This study primarily aimed to assess the impact of prolonged neoadjuvant treatment-surgery interval (PNSI) on histopathologic and postoperative outcomes. Impacts of the mode of neoadjuvant treatment (NT) and surgery on the outcomes were also evaluated in the same patient population. Patients and Methods: Between February 2011 and December 2017, patients who underwent NT and total mesorectal excision for locally advanced rectal cancer were included. PNSI was defined as >4 and >8 weeks after short-course and long-course NT modalities, respectively. Results: A total of 44 (27%) patients received short-course NT (standard interval: n=28; PNSI: n=16) and 122 (73%) patients received long-course NT (standard interval: n=39; PNSI: n=83). Postoperative morbidity was similar between the standard interval and PNSI in patients undergoing short-course [n=3 (11%) vs. n=3 (19%), P=0.455] and long-course [n=6 (15%) vs. n=16 (19%), P=0.602] NT. PNSI was associated with increased complete pathologic response in patients receiving short-course NT [0 vs. n=5 (31%), P=0.002]. Compared with short-course NT, long-course NT was superior in terms of tumor response based on the Mandard [Mandard 1 to 2: n=6 (21%) vs. 6 (38%), P=0.012] and the College of American Pathologists (CAP) [CAP 0 to 1: n=13 (46%) vs. n=8 (50%), P=0.009] scores. Postoperative morbidity was similar after open, laparoscopic, and robotic total mesorectal excision [n=1 (14.2%) vs. n=21 (21%) vs. n=6 (12.5%), P=0.455] irrespective of the interval time to surgery and the type of NT. Conclusions: PNSI can be considered in patients undergoing short-course NT due to its potential oncological benefits. The mode of surgery performed at tertiary centers has no impact on postoperative morbidity after both NT modalities.
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    In Regard to Hammer et al.
    (Elsevier Ltd, 2023) Önal, Cem; Oymak, Ezgi; Bölükbaşı, Yasemin; Spratt, Daniel E.; Ward, Matthew C.; Fasola, Carolina E.; White, Richard L.; Bentzen, Søren M.; Khan, Atif J.; Vicini, Frank; Shah, Chirag; Vaidya, Jayant S.; Bulsara, Max; Wenz, Frederik; Sperk, Elena; Massarut, Samuele; Alvarado, Michael; Williams, Norman R.; Brew-Graves, Chris; Bernstein, Marcelle; Holmes, Dennis; Vinante, Lorenzo; Pigorsch, Steffi; Lundgren, Steiner; Uhl, Valery; Joseph, David; Tobias, Jeffrey S.; Sezen, Duygu; Faculty Member; School of Medicine; 170535
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    Selection criteria for definitive treatment approach in thoracic malignancies: radiation oncology perspective
    (Springer, 2016) Topkan, Erkan; Sezen, Duygu; Bölükbaşı, Yasemin; Selek, Uğur; Faculty Member; Faculty Member; Faculty Member; School of Medicine; School of Medicine; School of Medicine; 170535; 216814; 27211
    Although surgical resection is directly related with anatomic boundaries and as a summary an all-or-none modality, even surgical prognosticators to define post-resection functional status could remain suboptimal. Radiotherapy, on the other site, is not an anatomical dissection, not a straightforward modality, and cannot be easily defined in numbers because of lack of correlation of effected anatomic units and heterogeneity of the effect on each unit. So evaluation before radiotherapy is overall a risk assessment with the baseline functional status and radiotherapy-induced expected loss in the function. Radiotherapy-triggered changes are gradual over time, sometimes as unusual reactions or hypersensitivity pneumonitis, and the compensation by the unirradiated lung is unpredictable. Overall, a radiation oncologist is expected to minimize the potential toxicity risks in an environment of various combinations of medical inoperability, poor pulmonary functionality, riskily localized or large parenchyma endangering bulky tumors, etc. and is mostly asked to be prepared to accept potential morbidities in this referred population with great expectations who will face a certain death if not treated.
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    The prognostic significance of novel pancreas cancer prognostic index in unresectable locally advanced pancreas cancers treated with definitive concurrent chemoradiotherapy
    (Dove Medical Press, 2021) Topkan, Erkan; Pehlivan, Berrin; Kucuk, Ahmet; Haksoyler, Veysel; Bölükbaşı, Yasemin; Selek, Uğur; Sezen, Duygu; Durankuş, Nilüfer Kılıç; Faculty Member; Faculty Member; Faculty Member; Teaching Faculty; School of Medicine; School of Medicine; School of Medicine; School of Medicine; 216814; 27211; 170535; 148139
    Purpose: We evaluated the prognostic quality of the novel pancreas cancer prognostic index (PCPI), a combination of CA 19-9 and systemic inflammation response index (SIRI), on the outcomes of locally advanced pancreas adenocarcinoma (LAPAC) patients who received concurrent chemoradiotherapy (C-CRT). Methods: This retrospective analysis covered 152 unresectable LAPAC patients treated from 2007 to 2019. Receiver operating characteristic (ROC) curve analysis was used to define ideal cutoff thresholds for the pretreatment CA 19-9 and SIRI measurements, indivi-dually. The associations between the PCPI groups and progression -free-(PFS) and overall survival (OS) comprised the respective primary and secondary endpoints. Results: The ROC curve analysis distinguished the respective rounded optimal cutoffs at 91 U/m/ L (< versus >= 90) and 1.8 (< versus >= 1.8) for CA 19-9 and SIRI, arranging the study cohort into two significantly different survival groups for each, with resultant four likely groups: Group-1: CA 19-9<90 U/m/L and SIRI<1.8, Group-2: CA 19-9<90 U/m/L but SIRI >= 1.8, Group-3: CA 19-9 >= 90 U/ m/L but SIRI<1.8, and Group-4: CA 19-9 >= 90 U/m/L and SIRI >= 1.8. Since the PFS (P=0.79) and OS (P=0.86) estimates of the groups 2 and 3 were statistically indistinct, we merged them as one group and created the novel three-tiered PCPI: PCPI-1: CA 19-9<90 U/m/L and SIRI<1.8, PCPI-2: CA 19-9<90 U/m/L but SIRI >= 1.8 or CA 19-9 >= 90 U/m/L but SIRI<1.8, and PCPI-3: CA 19-9 >= 90 U/m/L and SIRI >= 1.8, respectively. Comparative analyses unveiled that the PCPI-1 and PCPI-3 groups had the respective best and worst PFS (17.0 versus 7.5 versus 4.4 months; P<0.001) and OS (26.1 versus 15.1 versus 7.4 months; P<0.001) outcomes, while the PCPI-2 group posed in between. The multivariate analysis outcomes confirmed the novel three tired PCPI's independent prognostic significance on either of the PFS [HR: 5.38 (95% confidence interval (CI): 4.96-5.80); P<0.001)] and OS [HR: 5.67 (95% CI: 5.19-6.15); P<0.001] endpoints, separately. Conclusion: The new PCPI introduced here can be used as an independent and reliable prog-nostic indicator to divide LAPAC patients into three subgroups with discrete survival results.
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    Hypofractionated radiation therapy (HFRT) of breast/chest wall and regional nodes in locally advanced breast cancer: toxicity profile and survival outcomes in retrospective mono-institutional study: in regard to de matteis et al
    (Cig Media Group, Lp, 2022) Oymak, Ezgi; Onal, Cem; N/A; Bölükbaşı, Yasemin; Sezen, Duygu; Faculty Member; Faculty Member; School of Medicine; School of Medicine; 216814; 170535
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