New horizons from novel therapies in malignant pleural mesothelioma

Malignant pleural mesothelioma (MPM) is a relatively rare, but highly lethal cancer of the pleural mesothelial cells. Its pathoge-nesis is integrally linked to asbestos exposure. In spite of recent developments providing a more detailed understanding of the pathogenesis, the outcomes continue to be poor. To date, trimodality therapy involving surgery coupled with chemotherapy and/or radiotherapy remains the standard of therapy. The development of resistance of the tumor cells to radiation and several che-motherapeutic agents poses even greater challenges in the management of this cancer. Ionizing radiation damages cancer cell DNA and aids in therapeutic response, but it also activates cell survival signaling pathways that helps the tumor cells to overcome radiation-induced cytotoxicity. A careful evaluation of the biology involved in mesothelioma with an emphasis on the workings of pro-survival signaling pathways might offer some guidance for treatment options. This review focuses on the existing treatment options for MPM, novel treatment approaches based on recent studies combining the use of inhibitors which target different pro-survival pathways, and radiotherapy to optimize treatment

Assessment of the Corelation Between the Effect of Radiotherapy and MDR1 Gene Polymorphism

The relation between the polymorphism of the gene encoding for p-glycoprotein (MDR1), responsible for the excretion of many drugs and endogenous substances found in the cell membrane, and cancer or chemotherapy (CT) has been previously studied. However, there is limited information about the mentioned polymorphism and the efficacy of radiotherapy (RT). In our study, we aimed to investigate the effect of MDR1 gene polymorphisms C3435T, G2677A/T and C1236T on the clinical efficacy of RT. Retrospectively, 139 cancer patients were included, the frequency and timing of local recurrence development and response assessment of applied RT according to RECIST criteria were examined. Polymorphism in MDR1 gene was detected by PCR-RFLP method. The difference in the frequency of RT response and local recurrence development among patients with wild-type homozygous, heterozygous and mutant homozygous alleles was assessed by chi-square method; Kaplan-Meier log rank was used to assess the difference in the time of local recurrence. When all patients were examined, there was no difference in the RT response between genotypes and genotype combinations, or the risk of developing local recurrence after RT (p> 0.05).  In the subgroup analysis of five cancers constituting our study group, local progression-free survival was found to be lower in gastrointestinal system carcinoma patients carrying the 1236TT homozygous variant, p = 0.013. The effect of the 1236TT variant on local progression-free survival was significant after multivariate analysis. In conclusion, in this retrospective series, in patients with gastrointestinal cancer (colorectal, stomach, pancreas) the MDR1 1236TT variant was associated with shorter local progression-free survival. There was no relationship between RT activity and MDR1 polymorphism in breast and lung cancer patients.TEŞEKKÜR iii ÖZET iv ABSTRACT v İÇİNDEKİLER vi SİMGELER VE KISALTMALAR viii ŞEKİLLER x TABLOLAR xiii 1 GİRİŞ 1 2 GENEL BİLGİLER 3 2.1 Hassas Tıp (“Precision Medicine”) 3 2.2 P-glikoprotein 4 2.2.1 P-glikoproteinin Transport Dışı Etkileri 7 2.2.2 İnsan MDR1 (P-glikoprotein/ ABCB1) Genindeki Polimorfizm ve Kanser 7 2.3 P-glikoprotein ve KT 9 2.4 P-glikoprotein ve RT 10 3 HASTALAR VE YÖNTEM 13 3.1 Genotipleme 14 3.1.1 Hardy-Weinberg dengesi 18 3.2 İstatistiksel Yöntem 18 4 BULGULAR 20 4.1 Meme kanserli hastalarda RT sonrası alt grup analizi 32 4.2 Akciğer kanserli hastalarda RT sonrası alt grup analizi 44 4.3 Gastrointestinal sistem (GİS) kanserli hastalarda RT sonrası analizi 56 4.4 MDR1 Genotiplerin progresyonsuz ve genel sağkalım üzerindeki etkisi 71 4.4.1 Tüm çalışma grubumuzda genotiplere göre progresyonsuz ve genel sağkalım analizi 71 4.4.2 Meme kanserli hastalarda genotiplere göre progresyonsuz ve genel sağkalım analizi 77 4.4.3 Akciğer kanserli hastalarda genotiplere göre progresyonsuz ve genel sağkalım analizi 83 4.4.4 GİS kanserli hastalarda genotiplere göre progresyonsuz ve genel sağkalım analizi 89 4.5 Lokal progresyonsuz, progresyonsuz ve genel sağkalımı etkileyen faktörler 95 4.5.1 Tüm çalışma grubumuzda lokal progresyonsuz, progresyonsuz ve genel sağkalımı etkileyen faktörler 95 4.5.2 Meme kanserli hastalarda lokal progresyonsuz, progresyonsuz ve genel sağkalımı etkileyen faktörler 98 4.5.3 Akciğer kanserli hastalarda lokal progresyonsuz, progresyonsuz ve genel sağkalımı etkileyen faktörler 100 4.5.4 GİS kanserli hastalarda lokal progresyonsuz, progresyonsuz ve genel sağkalımı etkileyen faktörler 102 5 TARTIŞMA 105 6 SONUÇ VE ÖNERİLER 115 7 KAYNAKLAR 116Hücre zarında bulunan, birçok ilaç ve endojen maddenin hücre dışına atılımından sorumlu olan p-glikoproteini (MDR1) kodlayan gendeki polimorfizm ile kanser ve kemoterapi (KT) etkinliği arasındaki ilişki yapılan çalışmalarda ortaya konmuştur. Söz konusu polimorfizm ve radyoterapinin (RT) etkinliği ile ilgili kısıtlı bilgi bulunmaktadır. Çalışmamızda MDR1 geninde C3435T, G2677A/T ve C1236T polimorfizmlerin RT’nin klinik etkinliği üzerindeki etkisinin incelenmesi amaçlanmaktadır. Retrospektif olarak çalışmaya 139 kanser hastası dahil edilmiştir. Uygulanan RT’nin RECİST kriterlerine göre yanıt değerlendirilmesi, lokal nüks geliştirme sıklığı ve zamanı incelenmiştir. Hastaların genindeki polimorfizm PCR-RFLP yöntemiyle tespit edilmiştir. Yabanıl tip (wild type) homozigot, heterozigot ve mutant homozigot alelleri taşıyan hastalar arasında RT yanıtı ve lokal nüks geliştirme sıklıklarındaki farkı ki-kare yöntemiyle; lokal nükse geçen zamandaki farkı log rank testi ile incelenmiştir. Tüm hastalar incelendiğinde, genotiplerin ve genotip kombinasyonların arasında RT yanıtı, RT sonrası lokal nüks gelişme riskinde veya zamanında fark bulunamamıştır (p>0.05). Çalışma grubumuzu oluşturan beş kanser üzerinde yapılan alt grup analizlerinde 1236TT homozigot varyantı taşıyan gastrointestinal sistem kanserli hastalarda lokal progresyonsuz sağkalım daha düşük bulunmuştur, p=0.013. 1236TT varyantın lokal sağkalım üzerindeki etkisi çoklu değişken analizden sonra da anlamlı bulunmuştur. Sonuç olarak, bu retrospektif çalışmada gastrointestinal kanserli (kolorektal, mide, pankreas) hastalarında 1236TT varyantı daha kısa lokal progresyonsuz sağkalım ile ilişkili bulunmuştur. Meme ve akciğer kanserli hastalarında RT etkinliği ile MDR1 geni polimorfizmi arasında ilişki bulunmamıştır

Output factors of ionization chambers and solid state detectors for mobile intraoperative radiotherapy (IORT) accelerator electron beams

WOS: 000458309000003PubMed ID: 30632271Purpose The electron energy characteristics of mobile intraoperative radiotherapy (IORT) accelerator LIAC((R)) differ from commonly used linear accelerators, thus some of the frequently used detectors can give less accurate results. The aim of this study is to evaluate the output factors (OFs) of several ionization chambers (IC) and solid state detectors (SS) for electron beam energies generated by LIAC((R)) and compare with the output factor of Monte Carlo model (MC) in order to determine the adequate detectors for LIAC((R)). Methods The OFs were measured for 6, 8, 10, and 12 MeV electron energies with PTW 23343 Markus, PTW 34045 Advanced Markus, PTW 34001 Roos, IBA PPC05, IBA PPC40, IBA NACP-02, PTW 31010 Semiflex, PTW 31021 Semiflex 3D, PTW 31014 Pinpoint, PTW 60017 Diode E, PTW 60018 Diode SRS, SNC Diode EDGE, and PTW 60019 micro Diamond detectors. Ion recombination factors (k(sat)) of IC were measured for all applicator sizes and OFs were corrected according to k(sat). The measured OFs were compared with Monte Carlo output factors (OFMC). Results The measured OFs of IBA PPC05, PTW Advanced Markus, PTW Pinpoint, PTW microDiamond, and PTW Diode E detectors are in good agreement with OFMC. The maximum deviations of IBA PPC05 OFs to OFMC are-1.6%, +1.5%, +1.5%, and +2.0%; for PTW Advanced Markus +1.0%, +1.5%, +2.0%, and +2.0%; for PTW Pinpoint +2.0%, +1.6%, +4.0%, and +2.0%; for PTW microDiamond-1.6%, +2%, +1.1%, and +1.0%; and for PTW Diode E-+1.7%, +1.7%, +1.3%, and +2.5% for 6, 8, 10, and 12 MeV, respectively. PTW Roos, PTW Markus, IBA PPC40, PTW Semiflex, PTW Semiflex 3D, SNC Diode Edge measured OFs with a maximum deviation of +5.6%, +4.5%, +5.6%, +8.1%, +4.8%, and +9.6% with respect to OFMC, while PTW Diode SRS and IBA NACP-02 were the least accurate (with highest deviations-37.1% and-18.0%, respectively). Conclusion The OFs results of solid state detectors PTW microDiamond and PTW Diode E as well as the ICs with small electrode spacing distance such as IBA PPC05, PTW Advanced Markus and PTW Pinpoint are in excellent agreement with OFMC. The measurements of the other detectors evaluated in this study are less accurate, thus they should be used with caution. Particularly, PTW Diode SRS and IBA NACP-02 are not suitable and their use should be avoided in relative dosimetry measurements under high dose per pulsed (DPP) electron beams

A multicenter retrospective analysis of patients with nasopharyngeal carcinoma treated in IMRT era from a nonendemic population: Turkish Society for Radiation Oncology Head and Neck Cancer Group Study (TROD 01-001)

BackgroundWe aimed to evaluate patients with nasopharyngeal carcinoma (NPC) in a nonendemic population. MethodsIn a national, retrospective, multicenteric study, 563 patients treated with intensity modulated radiotherapy at 22 centers between 2015 and 2020 were analyzed. ResultsMedian age was 48 (9-83), age distribution was bimodal, 74.1% were male, and 78.7% were stage III-IVA. Keratinizing and undifferentiated carcinoma rates were 3.9% and 81.2%. Patients were treated with concomitant chemoradiotherapy (48.9%), or radiotherapy combined with induction chemotherapy (25%) or adjuvant chemotherapy (19.5%). After 34 (6-78) months follow-up, 8.2% locoregional and 8% distant relapse were observed. Three-year overall survival was 89.5% and was lower in patients with age >= 50, male sex, keratinizing histology, T4, N3 and advanced stage (III-IVA). ConclusionsPatients with NPC in Turkey have mixed clinical features of both east and west. Survival outcomes are comparable to other reported series; however, the rate of distant metastases seems to be lower.The author, Ashok K. Pathak, acknowledges financial assistance from the University Grants Commission (UGC), New Delhi (8- 4(57)/2015(MRP/NRCB)). Author, V. K. Singh is very thankful to UGC-DAE CSR Kolkata Centre for partial financial support.University Grants Commission (UGC), New Delhi [8- 4(57)/2015(MRP/NRCB]; UGC-DAE CSR Kolkata Centr

Long-term toxicity and survival outcomes after stereotactic ablative radiotherapy for patients with centrally located thoracic tumors

Stereotactic ablative radiotherapy (SABR) is effective for thoracic cancer and metastases; however, adverse effects are greater for central tumors. We evaluated factors affecting outcomes and toxicities after SABR for patients with primary lung and oligometastatic tumors

Nowe perspektywy leczenia złośliwego międzybłoniaka opłucnej

Złośliwy międzybłoniak opłucnej to stosunkowo rzadko występująca choroba rozrostowa komórek mezotelialnych opłucnej, cechująca się dużą śmiertelnością. Jej patogeneza nieodłącznie wiąże się z ekspozycją na działanie azbestu. I chociaż coraz więcej wiadomo na ten temat, nadal wiele zagadnień dotyczących mechanizmu powstawania i rozwoju złośliwego międzybłoniaka opłucnej pozostaje niejasnych. Terapia trójmodalna, składająca się z leczenia chirurgicznego skojarzonego z chemioterapią i/lub radioterapią, nadal pozostaje terapią standardową. Rozwój oporności komórek guza na radioterapię oraz niektóre środki chemioterapeutyczne bardzo utrudniają leczenie tego nowotworu. Promieniowanie jonizujące uszkadza DNA komórek nowotworowych i zwiększa odpowiedź na leczenie, lecz uaktywnia także szlaki sygnałowe przeżycia komórki, co pozwala komórkom nowotworowym pokonać cytotoksyczność wywołaną promieniowaniem. Uważna ocena międzybłoniaka na poziomie biologicznym, z naciskiem na mechanizmy działania szlaków sygnałowych prowadzących komórkę na drogę przeżycia, może być pomocna przy wyborze opcji terapeutycznej. Niniejsza praca skupia się na dostępnych metodach leczenia złośliwego międzybłoniaka opłucnej, nowym podejściu terapeutycznym opartym na najnowszych badaniach, wykorzystującym inhibitory ukierunkowane na różne szlaki sprzyjające przeżyciu i radioterapii stosowanej w celu optymalizacji metod leczenia

New Horizons from Novel Therapies in Malignant Pleural Mesothelioma

Malignant pleural mesothelioma (MPM) is a relatively rare, but highly lethal cancer of the pleural mesothelial cells. Its pathoge-nesis is integrally linked to asbestos exposure. In spite of recent developments providing a more detailed understanding of the pathogenesis, the outcomes continue to be poor. To date, trimodality therapy involving surgery coupled with chemotherapy and/or radiotherapy remains the standard of therapy. The development of resistance of the tumor cells to radiation and several che-motherapeutic agents poses even greater challenges in the management of this cancer. Ionizing radiation damages cancer cell DNA and aids in therapeutic response, but it also activates cell survival signaling pathways that helps the tumor cells to overcome radiation-induced cytotoxicity. A careful evaluation of the biology involved in mesothelioma with an emphasis on the workings of pro-survival signaling pathways might offer some guidance for treatment options. This review focuses on the existing treatment options for MPM, novel treatment approaches based on recent studies combining the use of inhibitors which target different pro-survival pathways, and radiotherapy to optimize treatment