IMRT reduces acute hematologic and GI toxicity compared with standard treatment, with promising therapeutic outcomes. Positron emission tomography IG-IMRT reduces the incidence of acute neutropenia.

Mutations in PROM1 have been described to cause a severe form of autosomal recessive RP in two families of Indian and Pakistani descent. The results of this study have demonstrated that a distinct redundant PROM1 mutation (R373C) can also produce an autosomal dominant, fully penetrant retinopathy, characterized by BEM with little inter- and intrafamilial variability, and retinal dystrophy with variable rod or rod-cone dysfunction and marked intra- and interfamilial variability, ranging from isolated maculopathy without generalized photoreceptor dysfunction to maculopathy associated with very severe rod-cone dysfunction.

Purpose Radiation-induced cognitive deficits may be mediated by tissue damage to cortical regions. Volumetric changes in cortex can be reliably measured using high-resolution magnetic resonance imaging (MRI). We used these methods to study the association between radiation therapy (RT) dose and change in cortical thickness in high-grade glioma (HGG) patients. Methods and Materials We performed a voxel-wise analysis of MR imaging from 15 HGG patients who underwent fractionated partial brain RT. Three-dimensional MRI was acquired pre- and 1-year post-RT. Cortex was parcellated with well-validated segmentation software (Freesufer). Surgical cavities were censored. Each cortical voxel was assigned a change in cortical thickness between time points, RT dose value, and neuroanatomic label by lobe. Effect of dose, neuroanatomic location, age, and chemotherapy on cortical thickness was tested using linear mixed effects (LME) modeling. Results Cortical atrophy was seen after 1-year post RT, with greater effects at higher doses. Estimates from LME modeling showed that cortical thickness decreased by −0.0033 mm (p<0.001) for every 1 Gy increase in RT dose. Temporal and limbic cortex exhibited the largest change in cortical thickness per Gy, compared to other regions (p<0.001). Age and chemotherapy were not significantly associated with cortical thickness change. Conclusions We found dose-dependent thinning of the cerebral cortex, with varying neuroanatomical regional sensitivity, one year after fractionated partial brain RT. The magnitude of thinning parallels one-year atrophy rates seen in neurodegenerative diseases, and may contribute to cognitive decline following high-dose RT.

Purpose To demonstrate an efficient method for training and validation of a knowledge-based planning (KBP) system as a radiotherapy clinical trial plan quality control (QC) system. Methods We analyzed 86 stage IB-IVA cervical cancer patients treated with intensity modulated radiotherapy (IMRT) at two institutions according to XXXXX multi-institutional protocol standards. The protocol utilized a planning target volume (PTV) and two primary organs-at-risk (OARs): pelvic bone marrow (PBM) and bowel. Secondary OARs were rectum and bladder. Initial UNFILTERED dose-volume histogram (DVH) estimation models were trained using all 86 plans. REFINED training sets and DVH-estimation models were constructed by identifying 30/86 plans emphasizing PBM-sparing (comparing protocol-specified V10 and V20 with UNFILTERED predictions), and another 30/86 plans emphasizing bowel sparing (comparing V40 and V45, 9 in common with PBM set). To obtain deliverable KBP plans, REFINED models must inform patient-specific optimization objectives/priorities (an auto-planning “routine”). Four candidate routines emphasizing different tradeoffs were composed and a script was developed to automatically re-plan multiple patients with each routine. After selection of the routine best meeting protocol objectives in the 51-patient training sample (KBPFINAL), protocol-specific DVH metrics and normal tissue complication probability (NTCP) were compared for original vs. KBPFINAL plans across the 35-patient validation set. Paired t-tests tested differences between planning sets. Results KBPFINAL plans outperformed manual planning across the validation set in all protocol-specific DVH cutpoints. The mean NTCP for GI toxicity was lower for KBPFINAL vs. validation-set plans (48.7% vs. 53.8%, p<.001). Similarly, the estimated mean white blood cell count (WBC) nadir was higher (2.77 vs 2.49, p<.001) with KBPFINAL plans, indicating lowered probability of hematologic toxicity. Conclusions This work demonstrates that a KBP system can be efficiently trained and refined for use in radiotherapy clinical trials with minimal effort. This patient-specific plan QC resulted in improvements on protocol-specific dosimetric endpoints.

Compared with standard modeling approaches, GCE models improve stratification of elderly patients with cancer according to their risk of dying from cancer relative to overall mortality.

A common haplotype on 10q26 influences the risk of age-related macular degeneration (AMD) and encompasses two genes, LOC387715 and HTRA1. Recent data have suggested that loss of LOC387715, mediated by an insertion/deletion (in/del) that destabilizes its message, is causally related with the disorder. Here we show that loss of LOC387715 is insufficient to explain AMD susceptibility, since a nonsense mutation (R38X) in this gene that leads to loss of its message resides in a protective haplotype. At the same time, the common disease haplotype tagged by the in/del and rs11200638 has an effect on the transcriptional upregulation of the adjacent gene, HTRA1. These data implicate increased HTRA1 expression in the pathogenesis of AMD and highlight the importance of exploring multiple functional consequences of alleles in haplotypes that confer susceptibility to complex traits.

Purpose/Objectives(s) To quantify changes in bone marrow fat fraction and determine associations with peripheral blood cell counts. Methods and Materials In this prospective study, 19 patients received either highly myelotoxic (radiotherapy plus cisplatin, 5FU/MMC or cisplatin/5FU/cetuximab) or less myelotoxic treatment (capacitabine-radiotherapy or no concurrent chemotherapy). Patients underwent MR imaging and venipuncture at baseline, mid-treatment, and post-treatment visits. We performed mixed effects modeling of the mean proton density fat fraction (PDFF(%)) by linear-time, treatment, and vertebral column region (L4-S2 vs. T10-L3 vs. C3-T9), while controlling for cumulative mean dose and other confounders. Spearman rank correlations were performed by blood cell counts versus the difference in PDFF(%) pre- and post-treatment. Results Cumulative mean dose was associated with a 0.43% per Gy (p=.004) increase in PDFF(%). In the highly myelotoxic group, we observed significant changes in PDFF(%) per visit within L4-S2 (10.1%,p<.001) and within T10-L3 (3.93%,p=.01), relative to the reference C3-T9. In the less myelotoxic group, we did not observe significant changes in PDFF(%) per visit according to region. Within L4-S2, we observed a significant difference between treatment groups in the change in PDFF(%) per visit (5.36%,p=.04). Rank correlations of the inverse log difference in WBC versus the difference in PDFF(%) overall and within T10-S2 ranged from 0.69-0.78 (p<0.05). Rank correlations of the inverse log difference in ANC versus the difference in PDFF(%) overall and within L4-S2 ranged from 0.79-0.81 (p<0.05). Conclusion MRI fat quantification is sensitive to marrow composition changes that result from (chemo)radiotherapy. These changes are associated with peripheral blood cell counts. This study supports a rationale for bone marrow sparing treatment planning to reduce the risk of hematologic toxicity.

Background Stereotactic radiosurgery is a well-accepted treatment for patients with intracranial metastases, but outcomes with volumetric modulated arc radiosurgery (VMAR) are poorly described. Objective To report our initial clinical experience applying a novel single-isocenter technique to frameless VMAR for simultaneous treatment of multiple intracranial metastases. Methods We performed a retrospective analysis of 15 patients undergoing frameless VMAR for multiple intracranial metastases using a single, centrally-located isocenter between 2009 and 2011. Among these, 3 patients were treated for progressive or recurrent intracranial disease. A total of 62 metastases (median 3 per patient, range 2-13) were treated to a median dose of 20 Gy (range, 15-30 Gy). 3 patients were treated with fractionated SRS. Follow-up including clinical examination and magnetic resonance imaging (MRI) occurred every 3 months. Results Median follow-up for all patients was 7.1 months (range, 1.1-24.3), with 11 patients (73.3%) followed until death. For the remaining 4 patients alive at the time of analysis, median follow-up was 19.6 months (range, 9.2-24.3). Local control at 6 and 12 months was 91.7 (95% Confidence Interval [C.I.], 84.6-100.0%) and 81.5 (95% C.I., 67.9-100.0%), respectively. Regional failure was observed in 9 patients (60.0%), and 7 patients (46.7%) received salvage therapy. Overall survival at 6 months was 60.0% (95% C.I., 40.3-88.2%). Grade 3 or greater treatment-related toxicity was not observed. Median total treatment time was 7.2 minutes (range, 2.8-13.2 minutes). Conclusion Single-isocenter, frameless VMAR for multiple intracranial metastases is a promising technique that may provide similar clinical outcomes compared to conventional radiosurgery.