cGy Of Radiation Research Articles

Topical application of platelet supernatant gel in the management of radiotherapy-induced mucositis: a case report.

Radiotherapy is the treatment of cancer and other diseases with ionising radiation. Oral cancer is the sixth most common cancer in the world1–2. Surgery and radiotherapy have been the standard loco-regional treatment modalities employed in oral cancer with a high cure rate1. Radiotherapy, principally used with curative intent3, is indicated for the majority of patients with head and neck cancers1. Oral mucositis, inflammation and ulceration that occurs in the oral cavity, is a major complication associated with radiotherapy administered to the head and neck area. It is associated with significant morbidity characterised by pain, odynodysphagia, dysgeusia, malnutrition, dehydration, and also increases the risk of systemic infections in immunocompromised patients4,5. Its severity is dependent on the type of ionising radiation, the volume of irradiated tissue, the dose per day, and cumulative dose. Patients undergoing radiotherapy for head and neck cancer receive approximately 200 cGy of radiation per day, 5 days a week, for 5 to 7 consecutive weeks4,5. Often the mucositis is of such severity that it requires parental analgesia, interruption of radiotherapy, and hospitalisation. This is of marked concern because there is strong clinical and radiobiological evidence that protraction of overall time of radiotherapy has an adverse influence on the curability of certain human tumours, particularly squamous cell carcinoma of the head and neck region6. Interventions are an area of interest and are constantly evolving in order to identify new therapeutic solution able to improve the quality of life of patients7. Platelet supernatant gel is a product derived from blood and is intended for non-transfusional therapeutic purposes. It increases and enhances natural haemostasis as well as processes of tissue repair and regeneration. It is produced by collecting the supernatant obtained after the activation of coagulation of platelet concentrate. The ensuing supernatant is rich in platelet growth factors that stimulate tissues growth and regeneration8–10. Platelet supernatant gel acts in synergy with plasma-derived factors to activate a complex network of autocrine functions that modulate healing11–13. The properties of platelet supernatant have been exploited in several medical and surgical specialties14–18, and new uses for platelet gel are currently under investigation. Taking into account this background, we used platelet supernatant gel in the management of a patient with a severe radiation-induced oral mucositis.

Body mass index (BMI) and its impact on quality of life (QOL) in childhood leukemia survivors.

9606 Background: Obesity after childhood cancer carries implications for survivors’ future health risks; however little is known about the impact of weight after treatment on QOL. Methods: Adult survivors of childhood leukemia in remission (51% male) completed the Health Related QOL Short Form (SF-36) between 2006-2012. Standard BMI cut points were assessed at the time of survey completion. 97% received treatment with chemotherapy, 55.6% stem cell transplant (SCT), 27.8% were in remission from a second cancer. The impact of demographic (age at diagnosis, current age, gender), treatment [radiation therapy, SCT, total body irradiation (TBI), cranial radiation, disease characteristics, history of relapse] were explored. For each subscale, linear regression models were performed. All statistical tests were two-sided, P-values < 0.05 considered statistically significant. Results: 73 survivors diagnosed at a median age of 9.0 (1.0-27.0) years and surveyed at a median of 17.4 (2.5-34.7) years later completed SF-36. 75.6% had received a median dose of 1800 (800-8750) cGy of radiation. The distribution of BMI was underweight <18.5 (9.6%), normal 18.5-24.9 (42.5%), overweight 25-29.9 (27.4%), or obese >30 (20.6%). Consistent with previous studies, those who received whole brain radiation had greater BMI at the time of survey than those who did not receive radiation and those who received TBI (F=2.52, p=0.065). In analyses adjusted for age at diagnosis and time since diagnosis, the reported vitality (fatigue) for those who were obese (mean 45.0+/-8.9) or underweight (45.8+/-9.5) was significantly lower (p=0.002) than normal (55.7+/-10.4) or overweight (50.4+/-10.0), and those who were underweight (39.0+/-13.3) also reported poor physical functioning (endurance and strength) (p=0.038) compared with the others (52.3+/-8.1 normal weight, 49.5+/-11.7 overweight, 47.1+/-9.0 obese). Conclusions: Weight management in leukemia survivors is problematic with 48% of our sample being overweight or obese. Weight status is associated with QOL, impacting survivors’ fatigue and physical functioning. Interventions to help survivors achieve a healthy weight after cancer treatment are needed, and may lead to improvements in QOL.

WS12-1 - Front-Line Concurrent Chemoradiotherapy (CCRT) Followed Consolidation Chemotherapy in Localized NASAL NK/T-Cell Lymphoma

ABSTRACT Background Extranodal, nature killer/T-cell lymphoma of nasal type, the nasal NKTCL, is known for its close association with EBV infection and poor clinical outcome after chemotherapy (C/T). The aims of the study are to evaluate the therapeutic efficacy of front-line concomitant chemoradiotherapy (CCRT) plus consolidation C/T and the impact of EBV viral status on the clinical outcomes in patients with localized nasal NKTCL. Methods Patients with newly diagnosed, measurable stage I/II nasal NKTCL were eligible. The CCRT was comprised of two cycles of dexamethasone and etoposide D1-3, plus cisplatin D1, the DEP regimen, q 4 weeks with concurrent 5040 cGy radiation in 28 fractions/5 weeks. Tumor assessment was carried out 4 weeks after completion of CCRT. Patients without disease progression after CCRT were subjected for two cycles of consolidation C/T consisted of dexamethasone, etoposide, ifosphamide, mesna and cisplatin D1-4, the DVIP regimen, q 4 weeks. Serial blood samples were collected for EBV viral titer and IFN-γ determination. Results A total of 33 patients were enrolled. The best tumor response was complete response (CR) in 23, partial response (PR) in 5, with an overall response rate and CR rate of 84.8% and 69.7%, respectively. The 2- and 5-year progression-free survival (PFS) rate of intent-to-treat population was 63.1% (95% CI, 46.5–79.7%) and 56.1% (95% CI, 36.5–75.7%), respectively; while the corresponding overall survival (OS) rate was 72.0% (95% CI, 56.5–87.65%) and 61.7% (95% CI, 42.7–80.8%), respectively. The most common treatment-related grade 3/4 toxic effects were leucopenia (84.9%), febrile neutropenia (39.4%), nausea/vomiting (33.4%), anemia (30.3%) and mucositis (30.3%). Detectable baseline plasma EBV DNA level was an adversely prognostic factor for both PFS (log-rank test, P = 0.04) and OS (log-rank test, P = 0.01) of CR/PR patients. Conclusions Front-line CCRT plus consolidation chemotherapy is feasible and active in localized nasal NKTCL.

Effect of radiation therapy on permanent pacemaker and implantable cardioverter-defibrillator function

Radiation therapy's (RT's) effects on cardiac implantable electronic devices (CIEDs) such as implantable cardioverter-defibrillators (ICDs) and pacemakers (PMs) are not well established, leading to device removal or relocation in preparation for RT. To determine the effect of scattered RT on CIED performance. We analyzed 69 patients--50 (72%) with PMs and 19 (28%) with ICDs--receiving RT at the University of Michigan. Collected data included device model, anatomic location, and treatment beam energies, treatment type, and estimated dose to the device. Patients were treated with either high-energy (16-MV) and/or low-energy (6 MV) photon beams with or without electron beams (6-16 MeV). The devices were interrogated with pre- and post-RT and/or weekly with either in-treatment or home interrogation, depending on the patient's dependence on the device and the estimated or measured delivered dose. Outcomes analyzed were inappropriate ICD therapies, device malfunctions, or device-related clinical events. The PMs were exposed to 84.4 ± 99.7 cGy of radiation, and the ICDs were exposed to 92.1 ± 72.6 cGy of radiation. Two patients with ICDs experienced a partial reset of the ICD with the loss of historic diagnostic data after receiving 123 and 4 cGy, respectively. No device malfunction or premature battery depletion was observed at 6-month follow-up from RT completion. CIED malfunction due to indirect RT exposure is uncommon. Regular in-treatment or home interrogation should be done to detect and treat these events and to ensure that diagnostic data are preserved.

Marrow Stromal Cells (MSC) Rescue Hematopoiesis in Lethally Irradiated Mice Despite Rapid Clearance After Infusion,

Abstract 3406Ionizing radiation causes dose dependent damages in many organs with most pronounced effects on those with high proliferative potential such as the hematopoietic system and gastrointestinal tract. Lympho-hematopoietic failure is often the cause of death following moderate to severe exposures to radiation. Effects of low to moderate (sub-lethal) doses of radiation can be mitigated by cytokines such as granuclocyte colony stimulating factor (GCSF) or Flt-3 ligand; higher doses of radiation require a new hematopoietic system by stem cell transplantation (SCT). As SCT for large numbers of radiation victims is not only costly but impractical following mass casualties (given the need for tissue matching prior to transplantation), there is considerable interest in cellular therapies that can be rapidly expanded, have a long shelf life and do not require tissue matching. Mesenchymal stromal cells (MSC, also referred to as mesenchymal stem cells) have been proposed as one such cellular therapy that could improve survival after moderate to high doses of radiation, but direct evidence for such a clinical benefit is scant in pre-clinical models. To determine if infusion of MSCs following ionizing radiation may rescue hematopoiesis after lethal irradiation in the murine model, we first determined the LD50 (lethal dose 50 or the dose at which 50% of animals survive without specific intervention) in C57/BL6 mice to be between 600 and 700 cGy when a X-Ray irradiator (RS2000) was used as the source of ionizing radiation. We then radiated adult female C57/Bl6 mice (age 6 to 8 weeks) with 700 cGy followed by infusion of either pooled immortalized MSC clones (henceforth referred to as cMSC, 1×106 cells each, n=19) or primary MSC (referred to as pMSC, 1×106 cells each, n=20) by tail vein injection 2 hours later. MSC were syngeneic to the recipients. Control mice received equal volume of PBS (n=21). Survival at the end of 7 weeks after radiation was determined using log-rank test which showed that animals that received either cMSC or pMSCs had significantly improved survival rates (p values of 0.017 and 0.041 respectively) when compared to the control animals that received only PBS (Figure 1). [Display omitted] The precise mechanism of action of MSCs after systemic infusion in various tissue injury models is currently undefined. Although trans-differentiation to host tissues has been proposed as one potential mechanism, recent reports have suggested that there is little evidence of persistence of infused MSC after the initial few days in the target tissues making trans-differentiation unlikely. Hence we determined the in vivo distribution kinetics of infused MSC by three techniques: whole-body bioluminescent imaging. (BLI), immune histochemistry (IHC) and quantitative real time polymerase chain reaction (q RT PCR). MSC were labeled with firefly luciferase (ffLuc) using a lentiviral vector and infused to adult female recipients after they were administered 700 cGy radiation (1×106 cells each, n=7). In all mice, strong bioluminescent signals were detected from the chest region at 4 hours after infusion, suggesting an accumulation of infused MSCs in the lungs. The signals rapidly decreased during the first 24 hours, and no bioluminescent signal was detected at 72 hours after infusion. No signals were detectable from other organs (liver, spleen or long bones) at any time point. Ffluc could not be reliably detected in tissues by IHC. Detection of luciferase transcripts in different tissues (lungs, hearts, spleens, livers, guts, muscles, and bone marrow) was performed by quantitative RT PCR at days 1, 4 and 7 (n = 6 each) following infusion. Ffluc transcripts were reliably detected in all animals only in the lungs at 24 hours after MSC infusion, confirming the BLI results. At subsequent time points, ffluc transcripts were detectable at very low levels in a variable proportion of animals from various tissues. In the absence of reliable BLI signals from these extra-pulmonary tissues, we interpret the presence of low levels of ffluc transcripts in these tissues as to have arisen from unviable cells or circulating RNA. Together, these results show that both immortalized MSCs and primary MSCs improve hematopoietic recovery after lethal ionizing radiation, but the infused cells are mostly filtered out by the lungs and their beneficial effect is likely mediated by indirect mechanisms (secondary effector cells in the lungs or secreted cytokines). Disclosures:No relevant conflicts of interest to declare.

Induction Chemotherapy With Gemcitabine, Oxaliplatin, and 5-Fluorouracil/Leucovorin Followed by Concomitant Chemoradiotherapy in Patients With Locally Advanced Pancreatic Cancer: A Taiwan Cooperative Oncology Group Phase II Study

To evaluate the therapeutic efficacy of 3-month triplet induction chemotherapy (ICT) followed by concomitant chemoradiotherapy (CCRT) in patients with locally advanced pancreatic cancer (LAPC). Chemonaïve patients with measurable, histologically confirmed LAPC were eligible. The ICT consisted of biweekly gemcitabine (800 mg/m2) infusion at a fixed dose rate (10 mg/m2/min), followed by 85 mg/m2 oxaliplatin and 48-h infusion of 5-fluorouracil/leucovorin (3000/150 mg/m2) for 6 cycles. Patients without disease progression 4 weeks after ICT would receive weekly 400 mg/m2 gemcitabine and 5040 cGy radiation in 28 fractions. After CCRT, patients were subjected for surgical intervention and/or maintenance chemotherapy until progression or intolerable toxicity. Between December 2004 and August 2008, 50 patients were enrolled. The best responses after ICT were partial response (PR) in 9, stable disease in 26, and progressive disease or not evaluable in 15. Among the former 35 patients, 2 had disease progression before CCRT, and 3 declined to have CCRT. Of the 30 patients receiving CCRT, an additional 4 and 1 patient(s) achieved PR at the end of CCRT and during maintenance chemotherapy, respectively. On intent-to-treat analysis, the overall best response was PR in 14 patients and stable disease in 21. The overall response rate and disease control rate were 28% (95% confidence interval [CI], 16.2-42.5%) and 70% (95% CI, 44.4-99.2%), respectively. The median time to progression and overall survival of the intent-to-treat population was 9.3 (95% CI, 5.8-12.8) months and 14.5 (95% CI, 11.9-17.1) months, respectively. One- and two-year survival rates were 68% (95% CI, 55.1-80.9%) and 20.6% (95% CI, 8.7-32.5%), respectively. Neutropenia was the most common Grade 3-4 toxicity of both ICT and CCRT, with a frequency of 28% and 26.7%, respectively. Significant sensory neuropathy occurred in 9 patients (18%). Three months of triplet ICT followed by gemcitabine-based CCRT is feasible, moderately active, and associated with encouraging survival in patients with LAPC.

Impact of neoadjuvant chemoradiotherapy followed by surgical resection on node-negative T3 and T4 non–small cell lung cancer

This study examined the impact of neoadjuvant chemotherapy and concurrent high-dose radiation therapy on survival in patients with node-negative T3 and T4 non-small cell lung cancer. A total of 110 consecutive patients underwent surgical resection for invasive T3N0M0 (94 patients) and T4N0M0 (16 patients) non-small cell lung cancer between 1979 and 2008. Forty-seven patients received neoadjuvant chemotherapy and concurrent high-dose (5940 cGy) radiation therapy before resection (Chemo-RT group). Sixty-three patients underwent surgical resection without receiving induction chemoradiotherapy (Surg group), of whom 21 received neoadjuvant radiation, 19 received adjuvant radiation, 17 received surgery alone, 2 received adjuvant chemotherapy, 2 received adjuvant chemoradiotherapy, and 2 received brachytherapy. Survival of the Chemo-RT and Surg groups was compared using both crude and adjusted Cox proportional hazards models. The 5-year, 10-year, and median survivals were 61%, 50%, and 90 months, respectively, in the Chemo-RT group versus 22%, 14%, and 22 months, respectively, in the Surg group. Subjects in the Surg group had an increased risk of death (hazard ratio, 2.60; 95% confidence interval, 1.62-4.18; P=.0001) compared with the Chemo-RT group. After adjustment for potential confounding variables of age, sex, tumor size, tumor location, type of operation, and decade of care, subjects in the Surg group remained at increased risk of death (hazard ratio, 2.81; 95% confidence interval, 1.45-5.44, P=.002) compared with the Chemo-RT group. Aggressive treatment of node-negative invasive T3 and T4 NSCLC with induction chemoradiotherapy may significantly prolong survival. This approach should be evaluated in a prospective multicenter national trial.

Pathologic femur fractures after limb-sparing treatment of soft-tissue sarcomas

Local control for sarcomas of the long bones includes limb sparing surgery and radiotherapy. While effective, there are potential complications. Patients treated for a soft tissue sarcoma of the thigh with limb-sparing surgery and radiation therapy between 1986 and 2000 at the University of Minnesota Masonic Cancer Center (n=89) were identified. Demographic, tumor, and treatment characteristics were abstracted from the medical record. Univariate analysis was conducted to identify significant risk factors for fracture. Survivors (58% male), median age of 50 (7-88) years, reported 8 (9%) fractures at a median of 7.3 (0.8-21.9) years from diagnosis after a median of 6300 (2000-7020) cGy of radiation. All fractures occurred within the previous radiation field, after no trauma. Three of the 8 (37.5%) had delayed union, 2 (25%) nonunion healing. Significant risk factors included periosteal stripping (p=0.006), anterior compartment location (p=0.022), and having 100% of the femoral circumference irradiated (p=0.018). Taking into account time to fracture using Kaplan Meier and log rank tests, these same predictors were identified. Older age, female sex, use of chemotherapy, and timing of radiation were not predictive of femoral fracture. Anterior tumor location, periosteal stripping, and radiation to 100% of the femur circumference are associated with femoral fracture. These patients require long-term monitoring and may warrant prophylactic intramedullary pinning or other protective measures. Survivors of soft tissue sarcomas of the femur may be at risk for the development of femur fractures and warrant close observation.

The effects of lazaroid U-74389G in a rat sepsis model

To examine the protective effects of a lazaroid, 21-aminosteroid U-74389G, in a rat septic shock model. Male Sprague-Dawley rats (n = 60) aged 6-8 months. Groups were exposed to 500 cGy radiation followed by E. coli inoculation, and either placebo or lazaroid injection (10 mg/kg intraperitoneal) 5 days after irradiation. Hemodynamic measurements, arterial blood gases, serum lactate, total antioxidative capacity, and cytokine levels were measured at specific time intervals. Treatment with the lazaroid U-74389G maintained cardiac output and mean aortic pressure. Lazaroid treatment also prevented the increase in serum lactate seen in placebo-treated rats. Cytokine serum levels in lazaroid-treated rats were not significantly different from those in placebo-treated rats at any time point. Lazaroid treatment of E. coli-inoculated septic animals lessens the hemodynamic deterioration seen in sepsis.

Femur fractures after limb-sparing treatment of soft-tissue sarcomas: One institution's experience.

e19601 Background: Local control for soft tissue sarcomas of the long bones often includes limb sparing surgery with the addition of radiation therapy. While effective, there are potential complications including poor wound healing and late-onset fractures. Methods: This analysis includes patients treated for a soft tissue sarcoma of the thigh with limb-sparing surgery and radiation therapy between 1986 and 2000 at the University of Minnesota Masonic Cancer Center (n=89). Demographic, tumor, and treatment characteristics including age, sex, histology, location (anterior, posterior, medial, buttock, popliteal fossa), use of adjuvant chemotherapy (yes/no), use of periosteal stripping (yes/no), timing of radiation (pre-/post-operative, both), radiation dose [high (>60 Gy), low (</+60 Gy), radiation field length [> 30 centimeters (cm), </= 30 cm], circumference of radiation field (100%/< 100% of femur) were abstracted from the medical record. Univariate analysis was conducted to identify significant risk factors for fracture. Given the small numbers of patients with a femoral fracture, multivariate analysis was unable to be performed. Results: Survivors (58 % male) with a median age of 50 (7-88) years reported_8 (9%) fractures at a median of 7.3 (0.8 – 21.9) years from diagnosis after a median of 6300 (2000-7020) cGy of radiation. All fractures occurred within the previous radiation field, after minimal or no trauma. Three of the 8 (37.5%) had delayed union, 2 (25%) nonunion healing. Significant risk factors included periosteal stripping (p=0.006), anterior location (p=0.022), and having 100% of the femoral circumference irradiated (p=0.018). Taking into account time to fracture using Kaplan Meier and log rank tests, these same predictors were identified. Older age, female sex, use of chemotherapy, and timing of radiation were not predictive of femoral fracture. Conclusions: Anterior tumor location, the presence of periosteal stripping, and radiation to 100% of the femur circumference are significantly associated with femoral fracture. These patients require long-term monitoring and may warrant prophylactic intramedullary pinning or other protective measures. No significant financial relationships to disclose.

Effect of hypothalamic/pituitary radiation exposure in low doses on fertility in female childhood cancer survivor study (CCSS) participants.

9542 Background: Female childhood cancer survivors (CCS) are less likely to report having been pregnant when compared with females within the CCSS sibling cohort (Sibs) as the result of direct damage to the ovaries produced by radiation therapy (XRT) and/or chemotherapy. High-dose hypothalamic/pituitary (HPT) XRT, which causes central or secondary hypogonadism, may result in infertility due to failure to stimulate ovulation. Recently, another possible central mechanism has been postulated, luteal phase deficiency, resulting from low-dose HPT XRT. Methods: We evaluated the occurrence of pregnancy in 3,666 female CCS who participated in the CCSS and 2,082 Sibs. The association between low- dose HPT XRT and fertility was studied by restricting analyses to those female CCS who received no/scatter (≤10 cGy) radiation to the ovaries and comparing their fertility rates with those of Sibs using Cox-proportional hazards models. Specific treatment effects were studied by further limiting analyses to only CCS. Results: These CCS who received no/scatter (≤ 10 cGy) ovarian radiation were more likely to report being pregnant (hazard ratio [HR]:1.5, 95% confidence interval [95%CI]: 1.3, 1.7) when adjusted for race/ethnicity, smoking, marital status, and education than Sibs. Multivariable models showed a significant decrease in the risk of reporting pregnancy with HPT XRT doses of ≥ 2,200 cGy when compared with those CCS receiving no HPT XRT when adjusted for race/ethnicity, smoking, marital status, education, age at diagnosis, and treatment with VP16 (Table) (137 had missing HPT radiation doses). Conclusions: The results of this study support the hypothesis that low-dose HPT XRT may be a contributing factor to infertility among female CCS. HPT radiation dose (cGy) Number of CCSS participants HR ever pregnant 95% CI ever pregnant 0 1,996 1.0 > 0 to < 1500 371 0.8 0.7-1.1 ≥ 1500 to < 2200 599 0.9 0.7-1.1 ≥ 2200 to < 2700 316 0.6 0.5-0.8 ≥ 2700 247 0.7 0.5-0.9 No significant financial relationships to disclose.

Short-Term Effects of Whole-Body Exposure to56Fe Ions in Combination with Musculoskeletal Disuse on Bone Cells

Space travel and prolonged bed rest cause bone loss due to musculoskeletal disuse. In space, radiation fields may also have detrimental consequences because charged particles traversing the tissues of the body can elicit a wide range of cytotoxic and genotoxic lesions. The effects of heavy-ion radiation exposure in combination with musculoskeletal disuse on bone cells and tissue are not known. To explore this, normally loaded 16-week-old male C57BL/6 mice were exposed to (56)Fe ions (1 GeV/nucleon) at doses of 0 cGy (sham), 10 cGy, 50 cGy or 2 Gy 3 days before tissue harvest. Additional mice were hindlimb unloaded by tail traction continuously for 1 week to simulate weightlessness and exposed to (56)Fe-ion radiation (0 cGy, 50 cGy, 2 Gy) 3 days before tissue harvest. Despite the short duration of this study, low-dose (10, 50 cGy) irradiation of normally loaded mice reduced trabecular volume fraction (BV/TV) in the proximal tibiae by 18% relative to sham-irradiated controls. Hindlimb unloading together with 50 cGy radiation caused a 126% increase in the number of TRAP(+) osteoclasts on cancellous bone surfaces relative to normally loaded, sham-irradiated controls. Together, radiation and hindlimb unloading had a greater effect on suppressing osteoblastogenesis ex vivo than either treatment alone. In sum, low-dose exposure to heavy ions (50 cGy) caused rapid cancellous bone loss in normally loaded mice and increased osteoclast numbers in hindlimb unloaded mice. In vitro irradiation also was more detrimental to osteoblastogenesis in bone marrow cells that were recovered from hindlimb unloaded mice compared to cells from normally loaded mice. Furthermore, irradiation in vitro stimulated osteoclast formation in a macrophage cell line (RAW264.7) in the presence of RANKL (25 ng/ml), showing that heavy-ion radiation can stimulate osteoclast differentiation even in the absence of osteoblasts. Thus heavy-ion radiation can acutely increase osteoclast numbers in cancellous tissue and, under conditions of musculoskeletal disuse, can enhance the sensitivity of bone cells, in particular osteoprogenitors, to the effects of radiation.

Dietary Supplements Reduce the Cataractogenic Potential of Proton and HZE-Particle Radiation in Mice

Abstract The present study was undertaken to investigate the ability of dietary supplements to reduce the formation and severity of cataracts in mice irradiated with high-energy protons or iron ions, which are important components of the radiation encountered by astronauts during space travel. The mice were exposed to proton or iron-ion radiation and fed with a control diet or diets supplemented with the soybean-derived protease inhibitor, Bowman-Birk inhibitor (BBI), in the form of BBI Concentrate (BBIC) or an antioxidant formulation [containing l-selenomethionine (SeM), N-acetyl cysteine (NAC), ascorbic acid, co-enzyme Q10, alpha-lipoic acid and vitamin E succinate] both before and after the radiation exposure. At approximately 2 years after the radiation exposure, the animals were killed humanely and lenses were harvested and characterized using an established classification system that assigns discrete scores based on the severity of the lens opacifications. The results showed that exposure to 1 GeV/nucleon proton (3 Gy) or iron-ion (50 cGy) radiation significantly increased the cataract prevalence and severity in CBA/J mice to levels above the baseline levels of age-induced cataract formation in this mouse strain. Treatment with BBIC or the antioxidant formulation significantly reduced the prevalence and severity of the lens opacifications in the mice exposed to iron-ion radiation. Treatment with BBIC or the antioxidant formulation also decreased the severity of the lens opacifications in the mice exposed to proton radiation; however, the decrease did not reach statistical significance. These results indicate that BBIC and the antioxidant formulation evaluated in this study could be useful for protecting astronauts against space radiation-induced cataracts during or after long-term manned space missions.

Pneumonectomy After Neoadjuvant Chemotherapy and Radiation for Advanced-Stage Lung Cancer

Intergroup 0139 Trial suggests an increase in mortality after pneumonectomy in patients receiving preoperative chemotherapy and radiation. We evaluate our outcomes with pneumonectomy after neoadjuvant chemotherapy and radiation. Neoadjuvant chemotherapy and radiation consisted of cisplatin 50 mg/m2 on days 1, 8, 29, and 36 and etoposide 50 mg/m2 on days 1-5 and 29-33 given concurrently with 5,040 cGy radiation. From a prospective database, results after pneumonectomy were compared between patients receiving and not receiving neoadjuvant chemotherapy and radiation during the same time period. Over 7 years, 50 pneumonectomies were performed for non-small-cell carcinoma; 18 received neoadjuvant chemotherapy and radiation (group A) and 32 did not (group B). Comparing group A with group B, there was no significant difference in patient demographics, blood loss, transfusion requirements or pneumonectomy side. Group A had more patients with stage III disease [17/ 18 (94%) versus 15/32 (47%), P = 0.001] and also more often had vascularized flap for bronchial stump coverage [17/18 (94%) versus 4/32 (13%), P < 0.001]. There was no significant difference in operative morbidity or mortality. Mortality for group A was 0/18 and for group B was 2/32 (6.3%) (P = 0.530). Group A patients with IIIA(N2) disease (n = 13) had median recurrence-free survival of 12.4 months, median overall survival of 25 months, and 3- year overall survival of 22.2%. Using a multidisciplinary team approach at a tertiary care center, pneumonectomy can be performed successfully after neoadjuvant chemotherapy and radiation for advanced-stage lung cancer. Vascularized flap for bronchial stump coverage may be important in this regard.

GATA3 is a master regulator of the transcriptional response to low-dose ionizing radiation in human keratinocytes

BackgroundThe general population is constantly exposed to low levels of radiation through natural, occupational or medical irradiation. Even if the biological effects of low-level radiation have been intensely debated and investigated, the molecular mechanisms underlying the cellular response to low doses remain largely unknown.ResultsThe present study investigated the role of GATA3 protein in the control of the cellular and molecular response of human keratinocytes exposed to a 1 cGy dose of X-rays. Chromatin immunoprecipitation showed GATA3 to be able to bind the promoter of 4 genes responding to a 1 cGy exposure. To go further into the role of GATA3 after ionizing radiation exposure, we studied the cellular and molecular consequences of radiation in GATA3 knock-down cells. Knock-down was obtained by lentiviral-mediated expression of an shRNA targeting the GATA3 transcript in differentiated keratinocytes. First, radiosensitivity was assessed: the toxicity, in terms of immediate survival (with XTT test), associated with 1 cGy radiation was found to be increased in GATA3 knock-down cells. The impact of GATA3 knock-down on the transcriptome of X-ray irradiated cells was also investigated, using oligonucleotide microarrays to assess changes between 3 h and 72 h post-irradiation in normal vs GATA3 knock-down backgrounds; transcriptome response was found to be completely altered in GATA3 knock-down cells, with a strong induction/repression peak 48 h after irradiation. Functional annotation revealed enrichment in genes known to be involved in chaperone activity, TGFβ signalling and stress response.ConclusionTaken together, these data indicate that GATA3 is an important regulator of the cellular and molecular response of epidermal cells to very low doses of radiation.

Clinical significance of NQO1 C609T polymorphisms after postoperative radiation therapy in completely resected non-small cell lung cancer

Purpose To investigate the clinical significance of NQO1 C609T polymorphisms to treatment outcome after postoperative radiation therapy in completely resected non-small cell lung cancer (NSCLC). Methods One hundred and sixteen, Korean-ethnic, patients who were treated with surgery and postoperative radiation therapy from February 2000 to September 2005 in Asan Medical Center (Seoul, South Korea) were analyzed. All patients received 5040 cGy radiation to surgical stump, mediastinum and ipsilateral supraclavicular node. NQO1 C609T polymorphisms were examined from a peripheral blood sample in all patients. Three types of NQO1 C609T polymorphisms were designated as C/C, C/T and T/T. Chest computed tomography was routinely checked after radiation therapy at every 3 or 6 months and locoregional tumor control, distant metastasis and survival by NQO1 C609T genotype were analyzed. Results The proportion of NQO1 C609T polymorphisms was 27.6% for C/C, 53.4% for C/T and 19.0% for T/T. Most patients were men and had squamous cell carcinoma or adenocarcinoma. Median age of patients was 61 years. Major failure pattern was distant metastasis and 13 (11.2%) patients showed locoregional recurrence within the field of previous radiation therapy. Crude locoregional recurrence rate was significantly different by NQO1 genotype; 6.3% in C/C, 8.1% in C/T, and 27.3% in T/T ( p = 0.03), but distant metastasis was not different. Median follow-up time was 49.2 months (range: 3.4–103.5 months). Locoregional recurrence-free survival (LRRFS) was affected in T/T genotype compared with C/C or C/T genotype ( p = 0.01, Kaplan–Meier method), but distant metastasis-free survival (DMFS) or overall survival (OS) was not different by NQO1 genotype in univariate analysis. NQO1 genotype was also a significant factor for LRRFS ( p = 0.01) in multivariate analysis. Radiation-induced pneumonitis or esophagitis was tolerable in all patients and the difference by NQO1 genotype was not observed. Conclusions NQO1 C609T polymorphisms could be a predictive factor for the locoregional tumor control after postoperative radiation therapy in completely resected NSCLC.

TH‐D‐BRD‐04: Increased Tumor Radioresistance by Imaging Doses From Volumetric Image Guided Radiation Therapy

Purpose: The radiation dose delivered from volumetric imaging guidance is normally between 1–10 cGy, depending on the imaging modalities, tumor sites and patient thickness. To correctly compensate for such doses, their biological effects on tumor and endothelial cells are investigated. Methods and materials: A lung carcinoma cell line (H460), a breast cancer cell line (MCF‐7) and a prostate cancer cell line (PC3) and a human umbilical vein endothelial cell line (HUVEC) were studied for their responses to small doses of radiation ranging from 5 cGy to 50 cGy. Specifically, a MTT assay was used to quantify their proliferation over time. To measure the impact of image guidance doses on cell survival, 5 cGy or 10 cGy were delivered to H460 cells before a 200 cGy therapeutic dose. The tumor cell survival was measured by clonogenic assay and compared with cells that received 200 cGy only. Results: Accelerated proliferation was observed among all tumor cell lines but not the HUVEC to low dose irradiation. The acceleration was statistically significant (p&lt;0.05) for H460 and MFC7 cells but not for the PC3 cells. A 12.6% increase in the H460 cell survival was observed for cells receiving 5cGy before 200 cGy radiation compared to those that received 200 cGy alone (p&lt;0.02), while cells receiving 10 cGy prior to 200 cGy had the same survival as cells receiving 200 cGy alone. Conclusions: Small pre‐treatment doses of radiation may increase the radioresistance of tumor cells. In this study, we demonstrated that the imaging dose from image guided radiation therapy is sufficient to trigger accelerated proliferation when delivered alone and increased tumor survival when delivered prior to a therapeutic dose. Our results suggest that subtracting the imaging dose from the therapeutic dose may adversely affect the tumor control probability.

Desmoids: A Revelation in Biology and Treatment

Using a preoperative neoadjuvant chemoradiation protocol, followed by complete excision, we have achieved local control rates exceeding that found in most large series. From October 1990 through May 2008, resectable desmoids were initially treated with a preoperative protocol using Adriamycin 30 mg x 3 days continuous intravenous infusion followed by 3,000 cGy of radiation (300 cGy fractions over 10 days). Resection was performed 4-6 weeks later. After 2001, all patients were initially offered Tamoxifen 120 mg/day and Celebrex 400 mg/day for 1 year. Patients who progressed on Tamox/Celeb were treated with protocol and those with stabilization or regression were observed. Patient demographics, tumor size, history of previous recurrences, and follow-up status were recorded prospectively. There were 40 females and 12 males with a mean follow-up of 45 months. Forty patients presented with primary tumors and eight presented with recurrent disease. Thirty-nine patients had surgical resection and 13 were observed. Thirty patients underwent the neoadjuvant protocol. Tamoxifen and Celebrex were used in 16 patients, 6 had stabilization in growth, 1 had a 50% reduction in the size of the tumor, there was 1 complete regression, and 8 progressed. Of the patients who had resectable disease Tamoxifen and Celebrex obviated surgery in 30%. Overall 13% (5) of patients developed a recurrence. There were three recurrences among the protocol group for a local control rate of 90%. Although our neoadjuvant protocol demonstrates the best results to date in eradication of disease, an initial conservative approach is reasonable to determine who would most benefit from surgery.

Persistent Phenotypic Responses of Human Mammary Epithelial Cells Induced by Ionizing Radiation

Ionizing radiation (IR) is a known human breast carcinogen. Although the mutagenic capacity of IR is widely acknowledged as the basis for its action as a carcinogen, we and others have shown that IR can also induce growth factors and extracellular matrix remodeling. We have shown that irradiating human mammary epithelial cells (HMEC) cultured with that transforming growth factor β1 (TGFβ) can generate a persistent phenotype in daughter cells characterized by spindle cell morphology, increased mesenchymal markers, decreased epithelial markers and increased cellular motility and invasion, which are hallmarks of epithelial to mesenchymal transition (EMT). Neither radiation nor TGFβ alone elicited EMT, although IR increased chronic TGFβ signaling and activity. Gene expression profiling revealed that double-treated cells exhibit a specific 10-gene signature associated with Erk/MAPK signaling. We hypothesized that IR-induced MAPK activation primes nonmalignant HMEC to undergo TGFβ-mediated EMT. Consistent with this, Erk phosphorylation was transiently induced by irradiation and persisted in irradiated cells treated with TGFβ, and inhibition of Erk activation, blocked the EMT phenotype. Preliminary studies suggest that eqi-toxic doses of sparsely and densely ionizing radiation resulted in comparable EMT when cells were cultivated in the presence of TGFβ, Furthermore radiation dose response studies show that this effect has a very low threshold in that a single exposure of 3-200 cGy radiation elicits the ‘same’ phenotypic switch, which is consistent with non-targeted effects. Together, these data show that the interactions between radiation-induced signaling pathways elicit heritable phenotypes that could contribute to radiation carcinogenesis.

Induction Chemotherapy and Chemoradiation Therapy for Inoperable Locally Advanced Non–Small-Cell Lung Cancer: A Single-Institution Review of Two Different Regimens

Purpose We compared 2 different chemotherapeutic agents in combination with cisplatin as induction chemotherapy (ICT) followed by chemoradiation therapy (CHRT) in patients with inoperable locally advanced non–small-cell lung cancer (NSCLC). Patients and Methods A total of 90 patients with inoperable locally advanced NSCLC received 3 courses of ICT consisting of gemcitabine 1200 mg/m 2 on day 1 and day 8 every 3 weeks and cisplatin 75 mg/m 2 on day 1 every 3 weeks (group 1; n = 39) or docetaxel 75 mg/m 2 on day 1 every 3 weeks and cisplatin 75 mg/m 2 on day 1 every 3 weeks (group 2; n = 51) followed by CHRT (docetaxel 30 mg/m 2 every week and cisplatin 20 mg/m 2 every week with 6600 cGy radiation therapy). Results After the ICT, the response rate for group 2 (88.2%) was significantly higher than that of the gemcitabine-cisplatin arm (64.1%; P = .017). The response assessment performed on first month after CHRT revealed statistical difference for objective response rate in group 2 when compared with group 1 ( P = .04). At the median follow-up of 15.7 months (range, 5-36 months), median overall survival (OS) was 12 months in group 1 (95% CI, 9.1-14.8) and 29.9 months in group 2 (95% CI, 16-43). Median progression-free survival (PFS) was 8 months in group 1 and 15 months in group 2. There was statistically significant difference between the 2 groups regarding OS and PFS ( P = .043). Conclusion Our results suggest that OS, PFS, and local control rate are significantly improved with ICT consisting of docetaxel and cisplatin when compared with gemcitabine-cisplatin in inoperable locally advanced NSCLC.