Mindi TenNapel

SIRT6 Minor Allele Genotype Is Associated with >5-Year Decrease in Lifespan in an Aged Cohort

Aging is a natural process involving complex interplay between environment, metabolism, and genes. Sirtuin genes and their downstream targets have been associated with lifespan in numerous organisms from nematodes to humans. Several target proteins of the sirtuin genes are key sensors and/or effectors of oxidative stress pathways including FOXO3, SOD3, and AKT1. To examine the relationship between single nucleotide polymorphisms (SNP) at candidate genes in these pathways and human lifespan, we performed a molecular epidemiologic study of an elderly cohort (≥65 years old.). Using age at death as a continuous outcome variable and assuming a co-dominant genetic model within the framework of multi-variable linear regression analysis, the genotype-specific adjusted mean age at death was estimated for individual SNP genotypes while controlling for age-related risk factors including smoking, body mass index, alcohol consumption and co-morbidity. Significant associations were detected between human lifespan and SNPs in genes SIRT3, SIRT5, SIRT6, FOXO3 and SOD3. Individuals with either the CC or CT genotype at rs107251 within SIRT6 displayed >5-year mean survival advantages compared to the TT genotype (5.5 and 5.9 years, respectively; q-value  = 0.012). Other SNPs revealed genotype-specific mean survival advantages ranging from 0.5 to 1.6 years. Gender also modified the effect of SNPs in SIRT3, SIRT5 and AKT1 on lifespan. Our novel findings highlight the impact of sirtuins and sirtuin-related genotypes on lifespan, the importance of evaluating gender and the advantage of using age as a continuous variable in analyses to report mean age at death.

Spatial mapping of functional pelvic bone marrow using FLT PET

The purpose of this study was to determine the ability of regions identified with bony landmarks on CT imaging to accurately represent active bone marrow when compared to FLT PET imaging. These surrogate regions could then be used to create a bone marrow sparing radiation therapy plan when FLT PET imaging is not available. Whole body (WB) FLT PET images were obtained of 18 subjects prior to chemoradiation therapy. The FLT image of each subject was registered to a CT image acquired for that subject to obtain anatomic information of the pelvis. Seventeen regions were identified based on features of the pelvic bones, sacrum, and femoral heads. The probability of FLT uptake being located in each of 17 different CT‐based regions of the bony pelvis was calculated using Tukeys multiple comparison test. Statistical analysis of FLT uptake in the pelvis indicated four distinct groups within the 17 regions that had similar levels of activity. Regions located in the central part of the pelvis, including the superior part of the sacrum, the inner halves of the iliac crests, and the L5 vertebral body, had greater FLT uptake than those in the peripheral regions (p‐value < 0.05). We have developed a method to use CT‐defined pelvic bone regions to represent FLT PET‐identified functional bone marrow. Individual regions that have a statistically significant probability of containing functional bone marrow can be used as avoidance regions to reduce radiation dose to functional bone marrow in radiation therapy planning. However, because likely active bone marrow regions and pelvic targets typically overlap, patient‐specific spatial detail may be advantageous in IMRT planning scenarios and may best be provided using FLT PET imaging. PACS number: 87.57.ukThe purpose of this study was to determine the ability of regions identified with bony landmarks on CT imaging to accurately represent active bone marrow when compared to FLT PET imaging. These surrogate regions could then be used to create a bone marrow sparing radiation therapy plan when FLT PET imaging is not available. Whole body (WB) FLT PET images were obtained of 18 subjects prior to chemoradiation therapy. The FLT image of each subject was registered to a CT image acquired for that subject to obtain anatomic information of the pelvis. Seventeen regions were identified based on features of the pelvic bones, sacrum, and femoral heads. The probability of FLT uptake being located in each of 17 different CT-based regions of the bony pelvis was calculated using Tukeys multiple comparison test. Statistical analysis of FLT uptake in the pelvis indicated four distinct groups within the 17 regions that had similar levels of activity. Regions located in the central part of the pelvis, including the superior part of the sacrum, the inner halves of the iliac crests, and the L5 vertebral body, had greater FLT uptake than those in the peripheral regions (p-value < 0.05). We have developed a method to use CT-defined pelvic bone regions to represent FLT PET-identified functional bone marrow. Individual regions that have a statistically significant probability of containing functional bone marrow can be used as avoidance regions to reduce radiation dose to functional bone marrow in radiation therapy planning. However, because likely active bone marrow regions and pelvic targets typically overlap, patient-specific spatial detail may be advantageous in IMRT planning scenarios and may best be provided using FLT PET imaging. PACS number: 87.57.uk.

Impact of spot size on plan quality of spot scanning proton radiosurgery for peripheral brain lesions.

PURPOSE To determine the plan quality of proton spot scanning (SS) radiosurgery as a function of spot size (in-air sigma) in comparison to x-ray radiosurgery for treating peripheral brain lesions. METHODS Single-field optimized (SFO) proton SS plans with sigma ranging from 1 to 8 mm, cone-based x-ray radiosurgery (Cone), and x-ray volumetric modulated arc therapy (VMAT) plans were generated for 11 patients. Plans were evaluated using secondary cancer risk and brain necrosis normal tissue complication probability (NTCP). RESULTS For all patients, secondary cancer is a negligible risk compared to brain necrosis NTCP. Secondary cancer risk was lower in proton SS plans than in photon plans regardless of spot size (p = 0.001). Brain necrosis NTCP increased monotonically from an average of 2.34/100 (range 0.42/100-4.49/100) to 6.05/100 (range 1.38/100-11.6/100) as sigma increased from 1 to 8 mm, compared to the average of 6.01/100 (range 0.82/100-11.5/100) for Cone and 5.22/100 (range 1.37/100-8.00/100) for VMAT. An in-air sigma less than 4.3 mm was required for proton SS plans to reduce NTCP over photon techniques for the cohort of patients studied with statistical significance (p = 0.0186). Proton SS plans with in-air sigma larger than 7.1 mm had significantly greater brain necrosis NTCP than photon techniques (p = 0.0322). CONCLUSIONS For treating peripheral brain lesions--where proton therapy would be expected to have the greatest depth-dose advantage over photon therapy--the lateral penumbra strongly impacts the SS plan quality relative to photon techniques: proton beamlet sigma at patient surface must be small (<7.1 mm for three-beam single-field optimized SS plans) in order to achieve comparable or smaller brain necrosis NTCP relative to photon radiosurgery techniques. Achieving such small in-air sigma values at low energy (<70 MeV) is a major technological challenge in commercially available proton therapy systems.

Risk of Radiation-Induced Malignancy With Heterotopic Ossification Prophylaxis: A Case–Control Analysis

PURPOSE To determine the risk of radiation-induced malignancy after prophylactic treatment for heterotopic ossification (HO). METHODS AND MATERIALS A matched case-control study was conducted within a population-based cohort of 3489 patients treated either for acetabular fractures with acetabular open reduction internal fixation or who underwent total hip arthroplasty from 1990 to 2009. Record-linkage techniques identified patients who were diagnosed with a malignancy from our state health registry. Patients with a prior history of malignancy were excluded from the cohort. For each documented case of cancer, 2 controls were selected by stratified random sampling from the cohort that did not develop a malignancy. Matching factors were sex, age at time of hip treatment, and duration of follow-up. RESULTS A total of 243 patients were diagnosed with a malignancy after hip treatment. Five patients were excluded owing to inadequate follow-up time in the corresponding control cohort. A cohort of 238 cases (control, 476 patients) was included. Mean follow-up was 10 years, 12 years in the control group. In the cancer cohort, 4% of patients had radiation therapy (RT), compared with 7% in the control group. Of the 9 patients diagnosed with cancer after RT, none occurred within the field. The mean latency period was 5.9 years in the patients who received RT and 6.6 years in the patients who did not. Median (range) age at time of cancer diagnosis in patients who received RT was 62 (43-75) years, compared with 70 (32-92) years in the non-RT patients. An ad hoc analysis was subsequently performed in all 2749 patients who were not matched and found neither an increased incidence of malignancy nor a difference in distribution of type of malignancy. CONCLUSION We were unable to demonstrate an increased risk of malignancy in patients who were treated with RT for HO prophylaxis compared with those who were not.

SU-E-T-690: Radiosurgery of Peripheral Brain Lesions by Spot Scanning Proton Therapy

PURPOSE To determine how small the lateral width in air of proton spots must be in order for proton spot scanning (SS) plan quality to be superior to x-ray radiosurgery for peripheral brain lesions. METHODS Single-beam proton SS plans with sigma (lateral spot intensity standard deviation) values ranging from 1 to 14 mm, x-ray volumetric modulated arc therapy (VMAT) utilizing a 0.5 cm leaf thickness, and cone-based x-ray radiosurgery plans were generated for eleven patients with clinical target volumes ranging from 0.5 cm3 to 25 cm3. Plans were evaluated using brain necrosis normal tissue complication probability (NTCP), high dose conformity index, and integral dose metrics. RESULTS For proton SS plans, as sigma increased from 1 to 14 mm, integral dose relative to the cone plan increased from an average of 0.10 (range 0.05 to 0.17) to 0.63 (range 0.26 to 0.85) compared an average of 1.49 (range 0.90 to 3.00) for VMAT. As SS sigma increased from 1 mm to 14 mm, NTCP for healthy brain necrosis increased from an average of 0.02 (range 0.01 to 0.07) to 0.08 (range 0.01 to 0.18) compared to the averages of 0.06 (range 0.01 to 0.15) for cone and 0.05 (range 0.01 to 0.11) for VMAT plans. An in-air sigma of less than 6 mm was required for the SS plans to have a statistically significant (p < 0.05) NTCP reduction relative to the x-ray techniques. CONCLUSION When treating peripheral brain lesions, which are ideal cases for SS since only a single proton beam direction is needed, SS only provides a superior NTCP to x-ray radiosurgery techniques if the proton therapy system can produce an in-air sigma of 6 mm or less.

Uterine Carcinosarcoma Confined to the Pelvis: A Retrospective Review and Outcome Analysis

Objective. We compared the treatments of uterine carcinosarcoma at our institution and evaluated their impact on survival. Methods. A retrospective analysis was performed on 60 eligible patients with carcinosarcoma limited to the pelvis. Subjects were divided into four categories: surgery, surgery plus chemotherapy, surgery plus radiation therapy, and a combination of surgery, chemotherapy, and RT. The most commonly used chemotherapy was cisplatin and/or carboplatin and taxol. Radiotherapy included external beam radiation therapy (EBRT) alone or with high dose rate (HDR) brachytherapy or HDR brachytherapy alone. Survival probability data were computed using the Kaplan-Meier method. The differences between groups were compared using the log-rank test. Results. The combination of surgery and radiation therapy with or without chemotherapy is seen to improve overall survival (OS) compared to surgery alone and , resp.). Brachytherapy involving three HDR vaginal cylinder fractions shows an equally effective reduction in local recurrence compared to EBRT. Conclusion. Our study of a relatively large number of carcinosarcoma patients suggests that adjuvant radiation therapy improves OS compared to surgery alone. Brachytherapy with 3 HDR vaginal cylinder fractions is preferred because of its time-saving, better tolerance, low toxicity and equivalent OS, and local control compared to EBRT.