S.S. Noticewala

Direct inhibition of myosin II effectively blocks glioma invasion in the presence of multiple motogens

ETOC: Brain invasion by gliomas makes these tumors particularly malignant. In this paper, we demonstrate that these tumors need myosin II to drive this process and that the need for myosin II cannot be replaced by stimulating the upstream signal transduction cascades that are pathogenic in this disease.

De Novo Glioblastoma in the Territory of a Prior Middle Cerebral Artery Infarct

We report a case of a patient who developed glioblastoma in the territory of a previous infarction. Two years after an ischemic stroke, the patient presented with a cystic, necrotic, and heterogeneously enhancing mass. Open biopsy and debulking of the mass with histological analysis revealed the mass to be glioblastoma. Though several cases of posttraumatic GBM have been reported, this is the first proposed case of GBM after an ischemic stroke. From this case, we suggest that the ischemic stroke, like other forms of cortical injury, may predispose to glioblastoma formation.

Validated Competing Event Model for the Stage I-II Endometrial Cancer Population

PURPOSE/OBJECTIVES(S) Early-stage endometrial cancer patients are at higher risk of noncancer mortality than of cancer mortality. Competing event models incorporating comorbidity could help identify women most likely to benefit from treatment intensification. METHODS AND MATERIALS 67,397 women with stage I-II endometrioid adenocarcinoma after total hysterectomy diagnosed from 1988 to 2009 were identified in Surveillance, Epidemiology, and End Results (SEER) and linked SEER-Medicare databases. Using demographic and clinical information, including comorbidity, we sought to develop and validate a risk score to predict the incidence of competing mortality. RESULTS In the validation cohort, increasing competing mortality risk score was associated with increased risk of noncancer mortality (subdistribution hazard ratio [SDHR], 1.92; 95% confidence interval [CI], 1.60-2.30) and decreased risk of endometrial cancer mortality (SDHR, 0.61; 95% CI, 0.55-0.78). Controlling for other variables, Charlson Comorbidity Index (CCI) = 1 (SDHR, 1.62; 95% CI, 1.45-1.82) and CCI >1 (SDHR, 3.31; 95% CI, 2.74-4.01) were associated with increased risk of noncancer mortality. The 10-year cumulative incidences of competing mortality within low-, medium-, and high-risk strata were 27.3% (95% CI, 25.2%-29.4%), 34.6% (95% CI, 32.5%-36.7%), and 50.3% (95% CI, 48.2%-52.6%), respectively. With increasing competing mortality risk score, we observed a significant decline in omega (ω), indicating a diminishing likelihood of benefit from treatment intensification. CONCLUSION Comorbidity and other factors influence the risk of competing mortality among patients with early-stage endometrial cancer. Competing event models could improve our ability to identify patients likely to benefit from treatment intensification.

Survival in unresectable sinonasal undifferentiated carcinoma treated with concurrent intra-arterial cisplatin and radiation

We report the successful use of RADPLAT to treat a patient with an unresectable T4N0 sinonasal undifferentiated carcinoma. This patient received 4 cycles of weekly intra-arterial cisplatin together with thiosulfate infusion with concurrent radiation therapy. Radiation therapy was given in 28 daily fractions to 54 Gy using intensity-modulated radiation therapy followed by a hypofractionated stereotactic boost of 3 fractions to 13 Gy to a total dose of 67 Gy in 31 fractions to the nasal sinus and bilateral neck. Intra-arterial cisplatin was administered using a bilateral approach due to the midline site of this tumor. Within days of the first intra-arterial cisplatin, there was an obvious decrease in tumor size. She has been followed with magnetic resonance imaging and positron emission tomography, and remains disease-free 47 mo post-treatment. Centers with expertise in intra-arterial chemotherapy could consider the RADPLAT approach for patients with unresectable sinonasal undifferentiated carcinoma.

Comparative dynamics of microglial and glioma cell motility at the infiltrative margin of brain tumours

Microglia are a major cellular component of gliomas, and abundant in the centre of the tumour and at the infiltrative margins. While glioma is a notoriously infiltrative disease, the dynamics of microglia and glioma migratory patterns have not been well characterized. To investigate the migratory behaviour of microglia and glioma cells at the infiltrative edge, we performed two-colour time-lapse fluorescence microscopy of brain slices generated from a platelet-derived growth factor-B (PDGFB)-driven rat model of glioma, in which glioma cells and microglia were each labelled with one of two different fluorescent markers. We used mathematical techniques to analyse glioma cells and microglia motility with both single cell tracking and particle image velocimetry (PIV). Our results show microglia motility is strongly correlated with the presence of glioma, while the correlation of the speeds of glioma cells and microglia was variable and weak. Additionally, we showed that microglia and glioma cells exhibit different types of diffusive migratory behaviour. Microglia movement fit a simple random walk, while glioma cell movement fits a super diffusion pattern. These results show that glioma cells stimulate microglia motility at the infiltrative margins, creating a correlation between the spatial distribution of glioma cells and the pattern of microglia motility.

Prospective Validation of a High-Dimensional Shape Model for Organ Motion in Intact Cervical Cancer.

PURPOSE Validated models are needed to justify strategies to define planning target volumes (PTVs) for intact cervical cancer used in clinical practice. Our objective was to independently validate a previously published shape model, using data collected prospectively from clinical trials. METHODS AND MATERIALS We analyzed 42 patients with intact cervical cancer treated with daily fractionated pelvic intensity modulated radiation therapy and concurrent chemotherapy in one of 2 prospective clinical trials. We collected online cone beam computed tomography (CBCT) scans before each fraction. Clinical target volume (CTV) structures from the planning computed tomography scan were cast onto each CBCT scan after rigid registration and manually redrawn to account for organ motion and deformation. We applied the 95% isodose cloud from the planning computed tomography scan to each CBCT scan and computed any CTV outside the 95% isodose cloud. The primary aim was to determine the proportion of CTVs that were encompassed within the 95% isodose volume. A 1-sample t test was used to test the hypothesis that the probability of complete coverage was different from 95%. We used mixed-effects logistic regression to assess effects of time and patient variability. RESULTS The 95% isodose line completely encompassed 92.3% of all CTVs (95% confidence interval, 88.3%-96.4%), not significantly different from the 95% probability anticipated a priori (P=.19). The overall proportion of missed CTVs was small: the grand mean of covered CTVs was 99.9%, and 95.2% of misses were located in the anterior body of the uterus. Time did not affect coverage probability (P=.71). CONCLUSIONS With the clinical implementation of a previously proposed PTV definition strategy based on a shape model for intact cervical cancer, the probability of CTV coverage was high and the volume of CTV missed was low. This PTV expansion strategy is acceptable for clinical trials and practice; however, we recommend daily image guidance to avoid systematic large misses in select patients.

Feasibility of atlas-based active bone marrow sparing intensity modulated radiation therapy for cervical cancer

BACKGROUND To test the hypothesis that atlas-based active bone marrow (ABM)-sparing intensity modulated radiation therapy (IMRT) yields similar dosimetric results compared to custom ABM-sparing IMRT for cervical cancer patients. METHODS We sampled 62 cervical cancer patients with pre-treatment FDG-PET/CT in training (n=32) or test (n=30) sets. ABM was defined as the subvolume of the pelvic bone marrow (PBM) with standardized uptake value (SUV) above the mean on the average FDG-PET image (ABMAtlas) vs. the individuals PET (ABMCustom). Both were deformed to the planning CT. Overlap between the two subvolumes was measured using the Dice coefficient. Three IMRT plans designed to spare PBM, ABMAtlas, or ABMCustom were compared for 30 test patients. Dosimetric parameters were used to evaluate plan quality. RESULTS ABMAtlas and ABMCustom volumes were not significantly different (p=0.90), with a mean Dice coefficient of 0.75, indicating good agreement. Compared to IMRT plans designed to spare PBM and ABMCustom, ABMAtlas-sparing IMRT plans achieved excellent target coverage and normal tissue sparing, without reducing dose to ABMCustom (mean ABMCustom dose 29.4Gy vs. 27.1Gyvs. 26.9Gy, respectively; p=0.10); however, PTV coverage and bowel sparing were slightly reduced. CONCLUSIONS Atlas-based ABM sparing IMRT is clinically feasible and may obviate the need for customized ABM-sparing as a strategy to reduce hematologic toxicity.