Faruk Zorlu

Salvage reirradiaton with stereotactic body radiotherapy for locally recurrent head-and-neck tumors.

PURPOSE In this study, we present our results of reirradiation of locally recurrent head-and-neck cancer with image-guided, fractionated, frameless stereotactic body radiotherapy technique. METHODS AND MATERIALS From July 2007 to February 2009, 46 patients were treated using the CyberKnife (Accuray, Sunnyvale, CA) at the Department of Radiation Oncology, Hacettepe University, Ankara, Turkey. All patients had recurrent, unresectable, and previously irradiated head-and-neck cancer. The most prominent site was the nasopharynx (32.6%), and the most common histopathology was epidermoid carcinoma. The planning target volume was defined as the gross tumor volume identified on magnetic resonance imaging and computed tomography. There were 22 female and 24 male patients. Median age was 53 years (range, 19-87 years). The median tumor dose with stereotactic body radiotherapy was 30 Gy (range, 18-35 Gy) in a median of five (range, one to five) fractions. RESULTS Of 37 patients whose response to therapy was evaluated, 10 patients (27%) had complete tumor regression, 11 (29.8%) had partial response, and 10 (27%) had stable disease. Ultimate local disease control was achieved in 31 patients (83.8%). The overall survival was 11.93 months in median (ranged, 11.4-17.4 months), and the median progression free survival was 10.5 months. One-year progression-free survival and overall survival were 41% and 46%, respectively. Grade II or greater long-term complications were observed in 6 (13.3%) patients. On follow-up, 8 (17.3%) patients had carotid blow-out syndrome, and 7 (15.2%) patients died of bleeding from carotid arteries. We discovered that this fatal syndrome occurred only in patients with tumor surrounding carotid arteries and carotid arteries receiving all prescribed dose. CONCLUSIONS Stereotactic body radiotherapy is an appealing treatment option for patients with recurrent head-and-neck cancer previously treated with radiation to high doses. Good local control with considerable 1-year survival is achieved with a relatively high rate of morbidity and related mortality.

Conventional external radiotherapy in the management of clivus chordomas with overt residual disease.

Abstract Cranial chordomas are uncommon tumors accounting for less than 1% of all intracranial neoplasms. Although they are slowly growing, rarely metastasising tumors, cranial chordomas are challenging to treat due to their critical location, invasive nature and aggressive recurrence. The aim of this retrospective study was to evaluate the role of conventional irradiation in the treatment of clival chordomas with overt residual disease after incomplete surgery.Between January 1979 and December 1997, 18 patients with histologically confirmed clival chordoma were treated with radiotherapy. Median age at the time of diagnosis was 32 years. The mean duration of the symptoms before diagnosis was 33.9 months. Median tumor diameter at initial presentation was 5 cm (range, 3–7 cm). The type of surgical procedure was subtotal excision in 11 patients and biopsy in 7. Radiation treatment was delivered with megavoltage units, and total doses between 50 Gy and 64 Gy (median, 60 Gy) were administered with conventional daily fractions. One patient received additional 12.50 Gy with linear accelerator-based stereotactic radiosurgery after subtotal excision and external irradiation.The mean follow-up time was 43.2 months. Overall survival at 5 years was 35%. Eleven patients showed progression after radiotherapy. The median time to progression after radiotherapy was 40.8 months (38.4–43.2) with a 5-year progression-free survival of 23%. Five patients (29.4%) showed symptomatic relief after radiotherapy while persistent symptoms were recorded for 6 patients. Incomplete surgery and conventional external radiotherapy with a dose of around 60 Gy seem to be inadequate in the treatment of clival chordomas.

Chronic hypoperfusion alters the content and structure of proteins and lipids of rat brain homogenates: a Fourier transform infrared spectroscopy study

Arteriovenous malformations (AVMs), masses of abnormal blood vessels which grow in the brain, produce high flow shunts that steal blood from surrounding brain tissue, which is chronically hypoperfused. Hypoperfusion is a condition of inadequate tissue perfusion and oxygenation, resulting in abnormal tissue metabolism. Fourier transform infrared (FTIR) spectroscopy is used in this study to investigate the effect of hypoperfusion on homogenized rat brain samples at the molecular level. The results suggest that the lipid content increases, the protein content decreases, the lipid-to-protein ratio increases, and the state of order of the lipids increases in the hypoperfused brain samples. FTIR results also revealed that, owing to hypoperfusion, not only the protein synthesis but also the protein secondary structure profile is altered in favor of β-sheets and random coils. These findings clearly demonstrate that, FTIR spectroscopy can be used to extract valuable information at the molecular level so as to have a better understanding of the effect of hypoperfusion on rat brain.

Screening of Protective Effect of Amifostine on Radiation-Induced Structural and Functional Variations in Rat Liver Microsomal Membranes by FT-IR Spectroscopy

In this study, the protective effect of amifostine, which is the only FDA-approved radioprotective agent, was investigated against the deleterious effects of ionizing radiation on rat liver microsomal membranes at molecular level. Sprague-Dawley rats, which were either administered amifostine or not, were whole-body irradiated with a single dose of 800 cGy and decapitated after 24 h. The microsomal membranes isolated from the livers of these rats were investigated using FT-IR spectroscopy. The results revealed that radiation caused a significant decrease in the lipid-to-protein ratio and the degradation of lipids into smaller fragments that contain less CH(2) and more carbonyl esters, olefinic═CH and CH(3) groups, which could be interpreted as a result of lipid peroxidation. Radiation altered the secondary structure of proteins by inducing a decrease in the β-sheet structures and an increase in the turns and random coil structures. Moreover, a dramatic increase in lipid order and a significant decrease in the membrane dynamics were observed in the irradiated group. The administration of amifostine before ionizing radiation inhibited all the radiation induced compositional, structural, and functional damages. In addition, these results suggest that FT-IR spectroscopy provides a novel approach to monitoring radiation-induced damage on biological membranes.

Effect of stereotactic radiosurgery on lipids and proteins of normal and hypoperfused rat brain homogenates: A Fourier transform infrared spectroscopy study

Purpose: The effect of stereotactic radiosurgery on lipids and proteins of normal and hypoperfused rat brain was investigated to see if hypoxic areas are really more resistant to radiation effects or not. Materials and methods: Rat brain samples from contol, stereotactically irradiated and chronically hypoperfused plus stereotactically irradiated groups were homogenized separately with saline phosphate buffer, and centrifuged at 125,000 g for 15 min. Membrane rich parts (pellet) of these homogenates were used for Fourier Transform Infrared (FTIR) spectroscopy studies. Mann-Whitney U tests were performed on the groups, two by two, to test the significance of the differences between the control group and stereotactically irradiated group as well as the control group and chronically hypoperfused plus stereotactically irradiated group. Results: After a single high dose of X-rays to healthy rat brain, the lipid concentration increased slightly, protein content decreased significantly (p < 0.05) and protein-to-lipid ratio decreased slightly. The secondary structure of the proteins was altered in the irradiated brain samples such that the content of α-helical structure decreased significantly (p < 0.01) and random coil increased dramatically (p < 0.05). The effect of radiation on the content of α-helical structure was not found to be significant in the hypoperfused group, but the decrease in the content of random coil was significant (p < 0.01). Conclusion: Stereotactic radiosurgery of the brain increased the lipid concentration, decreased the protein concentration and consequently resulted in a decrease in the protein to lipid ratio compared to unirratiated brain. Radiation also altered the secondary structure of protein. The variations in lipid and protein content and the resulting lipid to protein ratio imply that chronically hypoperfused brain is more vulnerable to radiation than non-hypoperfused brain and suggests chronic hypoperfusion does not prevent cerebral damage caused by irradiation. However, irradiation of hypoperfused brain resulted in less alteration in protein structure than in non-hypperfused brain, suggesting higher resistance to irradiation using this endpoint.

Reduced incidence of the somnolence syndrome after prophylactic cranial irradiation in children with acute lymphoblastic leukemia

A prospective double blind randomized trial comparing two different dose schedules of continuous steroid coverage during prophylactic cranial radiotherapy (CRT) in leukemic children was conducted to find out the optimum dose to be prescribed to reduce the incidence of Somnolence Syndrome (SS). Between April 1994 and February 1996, 32 patients with acute lymphoblastic leukemia received CRT of 18 Gy in 10 fractions. Patients were randomized to receive oral dexamethasone of 2 or 4 mg/m2 during radiotherapy. The diagnosis of SS was made clinically based on symptoms of somnolence. All patients were followed for a minimum of 8 months. The overall incidence of SS was 40%. The development of SS was steroid dose dependent. In low dose steroid arm the incidence of SS was 64.3% (9/14), compared to 17.6% (3/17) in high dose arm with statistically significant difference (P = 0.008). The median time to development of SS was 4 weeks. The most common symptom of SS was drowsiness followed by anorexia, headache, nausea, vomiting, decreased activity, irritability, fever and ataxia, respectively. The duration of symptoms ranged from 2 to 14 days. The development of SS was not related to the presence of acute reactions, age at the time of CRT and sex. In all cases the symptoms subsided completely and spontaneously. Our results suggest that steroid coverage at a dose of 4 mg/m2 during CRT reduces the incidence of SS. However, a multicentric prospective randomized trial is needed to determine the role and the optimal dose of steroid.

Tamoxifen increases membrane fluidity at high concentrations.

There are contradictory results in the literature relating to the effect oftamoxifen on membrane fluidity. The present work investigates the effect oftamoxifen on membrane dynamics to find out whether the concentration oftamoxifen can be one of the factors in this discrepancy. Turbidity(absorbance at 440 nm) and Fourier transform infrared spectroscopicstudies reveal that tamoxifen causes opposite effects on membranefluidity at low (1 mol.%) and high (30 mol.%) tamoxifen concentrations. Lowtamoxifen concentrations increase the absorbance in the gel and liquidcrystalline phase, whereas high tamoxifen concentrations decrease theabsorbance in gel and liquid crystalline phase, whereas tamoxifenconcentrations decrease the absorbance. Observations on both phasesshow that the bandwidth of the CH2 stretching bands decreases with1 mol.% tamoxifen and increases with 30 mol.% tamoxifen present, indicatinga decrease in membrane fluidity at low tamoxifen concentrations and anincrease in fluidity at high tamoxifen concentrations. It is seen that theapparent discrepancy in the literature on the effect of tamoxifen onmembrane fluidity mainly arises from the tamoxifen concentration used andthe confusion on the concept of lipid fluidity and lipid order.

Amifostine, a radioprotectant agent, protects rat brain tissue lipids against ionizing radiation induced damage: An FTIR microspectroscopic imaging study

Amifostine is the only approved radioprotective agent by FDA for reducing the damaging effects of radiation on healthy tissues. In this study, the protective effect of amifostine against the damaging effects of ionizing radiation on the white matter (WM) and grey matter (GM) regions of the rat brain were investigated at molecular level. Sprague-Dawley rats, which were administered amifostine or not, were whole-body irradiated at a single dose of 800 cGy, decapitated after 24 h and the brain tissues of these rats were analyzed using Fourier transform infrared microspectroscopy (FTIRM). The results revealed that the total lipid content and CH(2) groups of lipids decreased significantly and the carbonyl esters, olefinic=CH and CH(3) groups of lipids increased significantly in the WM and GM after exposure to ionizing radiation, which could be interpreted as a result of lipid peroxidation. These changes were more prominent in the WM of the brain. The administration of amifostine before ionizing radiation inhibited the radiation-induced lipid peroxidation in the brain. In addition, this study indicated that FTIRM provides a novel approach for monitoring ionizing radiation induced-lipid peroxidation and obtaining different molecular ratio images can be used as biomarkers to detect lipid peroxidation in biological systems.

A Retrospective Comparison of Robotic Stereotactic Body Radiotherapy and Three-Dimensional Conformal Radiotherapy for the Reirradiation of Locally Recurrent Nasopharyngeal Carcinoma

PURPOSE We assessed therapeutic outcomes of reirradiation with robotic stereotactic radiotherapy (SBRT) for locally recurrent nasopharyngeal carcinoma (LRNPC) patients and compared those results with three-dimensional conformal radiotherapy (CRT) with or without brachytherapy (BRT). METHODS AND MATERIALS Treatment outcomes were evaluated retrospectively in 51 LRNPC patients receiving either robotic SBRT (24 patients) or CRT with or without BRT (27 patients) in our department. CRT was delivered with a 6-MV linear accelerator, and a median total reirradiation dose of 57 Gy in 2 Gy/day was given. Robotic SBRT was delivered with CyberKnife (Accuray, Sunnyvale, CA). Patients in the SBRT arm received 30 Gy over 5 consecutive days. We calculated actuarial local control and cancer-specific survival rates for the comparison of treatment outcomes in SBRT and CRT arms. The Common Terminology Criteria for Adverse Events v3.0 was used for toxicity evaluation. RESULTS The median follow-up was 24 months for all patients. Two-year actuarial local control rates were 82% and 80% for SBRT and CRT arms, respectively (p = 0.6). Two-year cancer-specific survival rates were 64% and 47% for the SBRT and CRT arms, respectively (p = 0.4). Serious late toxicities (Grade 3 and above) were observed in 21% of patients in the SBRT arm, whereas 48% of patients had serious toxicity in the CRT arm (p = 0.04). Fatal complications occurred in three patients (12.5%) of the SBRT arm, and four patients (14.8%) of the CRT arm (p = 0.8). T stage at recurrence was the only independent predictor for local control and survival. CONCLUSION Our robotic SBRT protocol seems to be feasible and less toxic in terms of late effects compared with CRT arm for the reirradiation of LRNPC patients.

Characteristics of Breast Cancer Patients with Central Nervous System Metastases: A Single-Center Experience

The aim of this study was to assess the characteristics of breast cancer patients with central nervous system (CNS) metastases and factors associated with survival after development of CNS metastasis. One-hundred-forty-four patients with brain metastases were retrospectively analyzed. Median age at the time of brain metastasis diagnosis was 48.9. Median time between initial diagnosis and development of brain metastasis was 36 months. Fourteen cases had leptomeningeal involvement. Twenty-two patients (15.3%) had single metastasis. Ten percent of the patients had surgery, 94% had radiotherapy and 63% had chemotherapy. Median survival after development of brain metastasis was 7.4 months. Survival of patients with single metastasis was significantly longer than those with multiple metastases (33.5 vs. 6.5 months, p = 0.0006). Survival of patients who received chemotherapy was significantly longer than those who received radiotherapy alone (9.9 vs. 2 months, p < 0.0001). In multivariate Cox regression analyses, presence of single metastasis and application of chemotherapy were the only significant factors associated with better survival (p = 0.047 and p < 0.0001, respectively). Age at initial diagnosis or at the time of brain metastasis, time from initial diagnosis to development of brain metastasis, menopausal status, tumor stage, grade, hormone receptor or HER2 status individually were not associated with survival. In this study, survival after the diagnosis of CNS metastases appeared to be affected by patient characteristics rather than biologic characteristics of the tumor. This is probably secondary to the lack of effective treatment options in these patients and overall poor prognosis.