Evaluation the effects of Her-2 gene polymorphism and p21 gene mutation on overall survival, locoregional and distant control in patients treated with postoperatively adjuvant chemoradiotherapy

Tıpta Uzmanlık TeziBu çalışma ile postoperatif adjuvan kemoradyoterapi uygulanan mide adenokarsinomu tanılı hastalarda Her-2 gen polimorfizmi ve p21 gen mutasyonunun sağkalım, lokal-bölgesel ve uzak kontrole etkilerinin değerlendirilmesi amaçlandı. Kırk dört olgunun patoloji preapartları incelenerek immünohistokimyasal boyama yöntemi ile Her-2 ve p21 protein ekspresyonu pozitifliği ve polimeraz zincir reaksiyon yöntemi ile p21 gen mutasyonu ve Her-2 gen polimorfizmi varlığı araştırılmıştır. p21 ve Her-2 ekspresyon pozitifliği sırası ile %61,4 ve %9,1 olarak saptanmıştır. p21 mutasyonu her beş olgudan birinde mevcut iken Her-2 gen polimorfizmi %2,3 oranında II fenotipinde idi. p21 ekspresyonunun negatif olduğu olgularda diffüz tip adenokarsinom, vasküler/nöral invazyon varlığı ve indiferansiye histoloji p21 ekspresyonu pozitif olgulara göre anlamlı olarak daha yüksek oranlarda gözlenmiştir. p21 mutasyon varlığında ise diffüz tip ve indiferansiye histoloji anlamlı olarak yüksek bulunmuştur. p21 ekspresyonunun negatif olduğu olgularda genel sağkalım p21 ekspresyonu pozitif olgulara göre anlamlı olarak daha kısa bulunmuştur (Cox regresyon, p=0.014). Hastalıksız sağkalım ile p21 ekspresyonu arasında ilişki saptanamamıştır. Her-2 gen ekspresyon pozitifliği ve polimorfizmi ile histopatolojik parametreler ve genel ve hastalıksız sağkalım arasında anlamlı bir ilişki bulunamamıştır. Sonuç olarak; p21 ekspresyonu negatifliği kötü prognostik faktörler olduğu bilinen vasküler/nöral invazyon, indiferansiye ve diffüz tip histoloji ile ilişkili olup mide adenokarsinom tanılı hastalarda genel sağkalımı olumsuz etkilemektedir. Anahtar kelimerler: Mide kanseri, p21, Her-2AbstractIn this study it was aimed to evaluate the effects of Her-2 gene polymorphism and p21 gene mutation on overall survival, locoregional and distant control in patients treated with postoperatively adjuvant chemoradiotherapy. Immunohistochemical staining (IHC) and polymerase chain reaction (PCR) was performed in 44 patients who were treated with adjuvant chemoradiotherapy in 1999-2008. The expression of p21 and Her-2 was found in 61.4% and 9.1% patients respectively. p21 gene mutation was positive in one of every five patients and Her-2 polymorphism was II phenotype in 2.3% patient. In the patients with the negative expression of p21, diffuse type histology, whole gastric involvement and positive vascular and neural invasion, undifferential histology rate was significantly higher than in the patients with positive expression of p21. p21 mutation was significantly higher in diffuse and undifferential type histology. In the patients with the negative expression of p21, overall survival was significantly shorter than in the patients with positive expression of p21 (Cox regression, p=0.014). There was no association between any parameters with disease free survival. There was no significant association between histopathological parameters with Her-2 expression and Her-2 gene polymorphism. Consequently, negative p21 staining with IHC is associated with undifferantial and diffuse type histology which are known as a worse prognostic factors and it effects negatively overall survival in patients with gastric adenocarcinoma who were treated with postoperatively adjuvant chemoradiotherapy. Key words: Gastric cancer, p21, Her-2

Radyasyon kaynaklı proktitte amifostinin koruyucu etkinliği: Sistemik ile topikal uygulamaların karşılaştırılması

Amaç: Bu çalışmanın amacı ışınlama ile oluşturulan proktitte amifostinin radyoprotektif etkinliğinin intrarektal ve intraperitoneal uygulama yapılarak karşılaştırılmasıdır. Hastalar ve Yöntemler: Otuz iki Sprague-Dawley sıçan randomize olarak 4 gruba ayrıldı: Kontrol (CONT), sadece ışınlama (RT), intraperitoneal amifostin ve ışınlama (IPAMI) ile intrarektal amifostin ve ışınlama (IRAMI). RT, IPAMI ve IRAMI gruplarındaki sıçanların her birinin pelvis bölgesi tek fraksiyonda 17,5 Gy ışınlandı. Amifostin ışınlamadan önce intraperitoneal (200 mg/kg) veya intrarektal (2000 mg/kg) yoldan uygulandı. Rektumun histopatolojik incelemesi ışınlamadan 14 gün sonra yapıldı. Bulgular: Bütün histopatolojik parametrelerde ışınlamanın istatistiksel olarak anlamlı hasar oluşturduğu ve bu hasarın amifostin uygulaması ile azaldığı gözlendi. Işınlamadan önce IPAMI uygulaması lamina propria inflamasyonunu (p=0.021), kriptiti (p=0.002), kript absesini (p=0.015) anlamlı olarak azalttı. Buna karşın IRAMI ile koruyucu etki eozinofil lökosit sayısı (p=0.02), kript distorsiyonu (p=0.013) ve rejeneratif/reperatif atipi (p=0.013) dahil tüm parametreler için anlamlı oldu ve anlamlılıkları IPAMI’ya göre eşit veya daha yüksekti. Sonuç: Amifostinin yüksek doz intrarektal topikal uygulaması ışınlamanın oluşturduğu proktitin önlenmesinde intraperitoneal sistemik uygulamasına göre daha etkindir. Anahtar sözcükler: Amifostin, proktit, ışınlama, radyoproteksiyon.Objective: The aim of the study was to evaluate the radioprotective efficacy of intrarectal administration of amifostine in radiation-induced proctitis compared to intraperitoneal administration. Materials and Methods: Thirty-two Sprague-Dawley rats were randomly divided into four groups: Control (CONT), irradiation alone (RT), intraperitoneal amifostine plus irradiation (IPAMI), and intrarectal amifostine plus irradiation (IRAMI). The rats in the RT, IPAMI and IRAMI groups were irradiated individually with a single dose of 17.5 Gy to the pelvis. Amifostine was administered by the intraperitoneal (200 mg/kg) or intrarectal (2000 mg/kg) route before irradiation. Histopathologic analysis of the rectum was performed 14 days after irradiation. Results: Significant radiation damage appeared in all histopathologic parameters and was reduced by amifostine. Pretreatment with IPAMI significantly reduced the inflammatory infiltrate in the lamina propria (p=0.021), cryptitis (p=0.002) and crypt abscess (p=0.015). However, the protective effect of IRAMI was significant for all parameters with equal or higher significance than IPAMI, including the eosinophil leucocytes count (p=0.02), and distortion of the crypts (p=0.008), and was also significant for regenerative/reparative atypia (p=0.013). Conclusion: Intrarectal high dose topical administration of amifostine is more effective in the prevention of radiation-induced proctitis compared to its intraperitoneal systemic administration

The Protective Effect of Amifostine on Radiation-Induced Proctitis: Systemic Versus Topical Application

Objective: The aim of the study was to evaluate the radioprotective efficacy of intrarectal administration of amifostine in radiation-induced proctitis compared to intraperitoneal administration.Materials and Methods: Thirty-two Sprague-Dawley rats were randomly divided into four groups: Control (CONT), irradiation alone (RT), intraperitoneal amifostine plus irradiation (IPAMI), and intrarectal amifostine plus irradiation (IRAMI). The rats in the RT, IPAMI and IRAMI groups were irradiated individually with a single dose of 17.5 Gy to the pelvis. Amifostine was administered by the intraperitoneal (200 mg/kg) or intrarectal (2000 mg/kg) route before irradiation. Histopathologic analysis of the rectum was performed 14 days after irradiation. Results: Significant radiation damage appeared in all histopathologic parameters and was reduced by amifostine. Pretreatment with IPAMI significantly reduced the inflammatory infiltrate in the lamina propria (p=0.021), cryptitis (p=0.002) and crypt abscess (p=0.015). However, the protective effect of IRAMI was significant for all parameters with equal or higher significance than IPAMI, including the eosinophil leucocytes count (p=0.02), and distortion of the crypts (p=0.008), and was also significant for regenerative/reparative atypia (p=0.013). Conclusion: Intrarectal high dose topical administration of amifostine is more effective in the prevention of radiation-induced proctitis compared to its intraperitoneal systemic administration

Diagnostic delay in rare diseases

OBJECTIVE Post-operative radiotherapy (PORT) in non-small cell lung cancer (NSCLC), especially after complete resection, has long been an unresolved dilemma and debated among therapeutic disciplines. We aimed to evaluate the effects of different radiotherapy volumes and techniques on local-regional recurrence patterns and PORT results in patients with NSCLC. METHODS The results of 389 patients who underwent surgery and received PORT at 11 centers were analyzed retrospectively. The surgical margin was positive or closes in 100 (26%) patients. The PORT dose was a median of 50 Gy (36-60 Gy). Intensity-modulated RT methods were used in 68 (17.5%) patients. RESULTS The first recurrence of the patients who developed relapse, local recurrence was found in 77 (19.8%) patients, distant recurrence was found in 95 (24%) patients, and both recurrences was found in 30 (8%) patients. The median time to locoregional relapse was 14 months (1.84-59.7 months). Local-regional recurrence was not significantly higher in patients with positive surgical margins than in negative pa-tients (39% vs. 29%, p=0.1), but the dose administered to these patients was also higher. Mediastinal recurrence occurred in 28 (19%) patients who did not receive radiotherapy to the mediastinum; 25 of these recurrences (89%) were just near or outside the field. Cardiac events became 7% in all groups and did not change according to chosen mediastinal radiotherapy volume. CONCLUSION A clear description of the PORT volumes according to the localization of the primary tumor and the involved lymph nodes would be beneficial in terms of establishing the recurrence/toxicity balance better

Diagnostic delay in rare diseases

OBJECTIVE Post-operative radiotherapy (PORT) in non-small cell lung cancer (NSCLC), especially after complete resection, has long been an unresolved dilemma and debated among therapeutic disciplines. We aimed to evaluate the effects of different radiotherapy volumes and techniques on local-regional recurrence patterns and PORT results in patients with NSCLC. METHODS The results of 389 patients who underwent surgery and received PORT at 11 centers were analyzed retrospectively. The surgical margin was positive or closes in 100 (26%) patients. The PORT dose was a median of 50 Gy (36-60 Gy). Intensity-modulated RT methods were used in 68 (17.5%) patients. RESULTS The first recurrence of the patients who developed relapse, local recurrence was found in 77 (19.8%) patients, distant recurrence was found in 95 (24%) patients, and both recurrences was found in 30 (8%) patients. The median time to locoregional relapse was 14 months (1.84-59.7 months). Local-regional recurrence was not significantly higher in patients with positive surgical margins than in negative pa-tients (39% vs. 29%, p=0.1), but the dose administered to these patients was also higher. Mediastinal recurrence occurred in 28 (19%) patients who did not receive radiotherapy to the mediastinum; 25 of these recurrences (89%) were just near or outside the field. Cardiac events became 7% in all groups and did not change according to chosen mediastinal radiotherapy volume. CONCLUSION A clear description of the PORT volumes according to the localization of the primary tumor and the involved lymph nodes would be beneficial in terms of establishing the recurrence/toxicity balance better