A proliferation saturation index to predict radiation response and personalize radiotherapy fractionation

BACKGROUND: Although altered protocols that challenge conventional radiation fractionation have been tested in prospective clinical trials, we still have limited understanding of how to select the most appropriate fractionation schedule for individual patients. Currently, the prescription of definitive radiotherapy is based on the primary site and stage, without regard to patient-specific tumor or host factors that may influence outcome. We hypothesize that the proportion of radiosensitive proliferating cells is dependent on the saturation of the tumor carrying capacity. This may serve as a prognostic factor for personalized radiotherapy (RT) fractionation. METHODS: We introduce a proliferation saturation index (PSI), which is defined as the ratio of tumor volume to the host-influenced tumor carrying capacity. Carrying capacity is as a conceptual measure of the maximum volume that can be supported by the current tumor environment including oxygen and nutrient availability, immune surveillance and acidity. PSI is estimated from two temporally separated routine pre-radiotherapy computed tomography scans and a deterministic logistic tumor growth model. We introduce the patient-specific pre-treatment PSI into a model of tumor growth and radiotherapy response, and fit the model to retrospective data of four non-small cell lung cancer patients treated exclusively with standard fractionation. We then simulate both a clinical trial hyperfractionation protocol and daily fractionations, with equal biologically effective dose, to compare tumor volume reduction as a function of pretreatment PSI. RESULTS: With tumor doubling time and radiosensitivity assumed constant across patients, a patient-specific pretreatment PSI is sufficient to fit individual patient response data (R(2) = 0.98). PSI varies greatly between patients (coefficient of variation >128 %) and correlates inversely with radiotherapy response. For this study, our simulations suggest that only patients with intermediate PSI (0.45–0.9) are likely to truly benefit from hyperfractionation. For up to 20 % uncertainties in tumor growth rate, radiosensitivity, and noise in radiological data, the absolute estimation error of pretreatment PSI is <10 % for more than 75 % of patients. CONCLUSIONS: Routine radiological images can be used to calculate individual PSI, which may serve as a prognostic factor for radiation response. This provides a new paradigm and rationale to select personalized RT dose-fractionation

Lattice anisotropy as microscopic origin of static stripes in cuprates

Structural distortions in cuprate materials offer a microscopic origin for anisotropies in electron transport in the basal plane. Using a real-space Hartree-Fock approach, we consider the ground states of the anisotropic Hubbard (t_x \ne t_y) and t-J (t_x \ne t_y, J_x \ne J_y) models. Symmetrical but inhomogeneous (``polaronic'') charge structures in the isotropic models are altered even by rather small anisotropies to one-dimensional, stripe-like features. We find two distinct types of stripe, namely uniformly filled, antiphase domain walls and non-uniform, half-filled, in-phase ones. We characterize their properties, energies and dependence on the model parameters, including filling and anisotropy in t (and J). We discuss the connections among these results, other theoretical studies and experimental observation.Comment: 18 pages, 16 figures, 8 table

Chemotherapeutic agents subvert tumor immunity by generating agonists of platelet-activating factor

Oxidative stress suppresses host immunity by generating oxidized lipid agonists of the platelet-activating factor receptor (PAF-R). Because many classical chemotherapeutic drugs induce reactive oxygen species (ROS), we investigated whether these drugs might subvert host immunity by activating PAF-R. Here, we show that PAF-R agonists are produced in melanoma cells by chemotherapy that is administered in vitro, in vivo, or in human subjects. Structural characterization of the PAF-R agonists induced revealed multiple oxidized glycerophosphocholines that are generated nonenzymatically. In a murine model of melanoma, chemotherapeutic administration could augment tumor growth by a PAF-R-dependent process that could be blocked by treatment with antioxidants or COX-2 inhibitors or by depletion of regulatory T cells. Our findings reveal how PAF-R agonists induced by chemotherapy treatment can promote treatment failure. Furthermore, they offer new insights into how to improve the efficacy of chemotherapy by blocking its heretofore unknown impact on PAF-R activation

Predictors of linkage to care following community-based HIV counseling and testing in rural Kenya

Despite innovations in HIV counseling and testing (HCT), important gaps remain in understanding linkage to care. We followed a cohort diagnosed with HIV through a community-based HCT campaign that trained persons living with HIV/AIDS (PLHA) as navigators. Individual, interpersonal, and institutional predictors of linkage were assessed using survival analysis of self-reported time to enrollment. Of 483 persons consenting to follow-up, 305 (63.2%) enrolled in HIV care within 3 months. Proportions linking to care were similar across sexes, barring a sub-sample of men aged 18–25 years who were highly unlikely to enroll. Men were more likely to enroll if they had disclosed to their spouse, and women if they had disclosed to family. Women who anticipated violence or relationship breakup were less likely to link to care. Enrolment rates were significantly higher among participants receiving a PLHA visit, suggesting that a navigator approach may improve linkage from community-based HCT campaigns.Vestergaard Frandse

Image guidance using 3D-ultrasound (3D-US) for daily positioning of lumpectomy cavity for boost irradiation

<p>Abstract</p> <p>Purpose</p> <p>The goal of this study was to evaluate the use of 3D ultrasound (3DUS) breast IGRT for electron and photon lumpectomy site boost treatments.</p> <p>Materials and methods</p> <p>20 patients with a prescribed photon or electron boost were enrolled in this study. 3DUS images were acquired both at time of simulation, to form a coregistered CT/3DUS dataset, and at the time of daily treatment delivery. Intrafractional motion between treatment and simulation 3DUS datasets were calculated to determine IGRT shifts. Photon shifts were evaluated isocentrically, while electron shifts were evaluated in the beam's-eye-view. Volume differences between simulation and first boost fraction were calculated. Further, to control for the effect of change in seroma/cavity volume due to time lapse between the 2 sets of images, interfraction IGRT shifts using the first boost fraction as reference for all subsequent treatment fractions were also calculated.</p> <p>Results</p> <p>For photon boosts, IGRT shifts were 1.1 ± 0.5 cm and 50% of fractions required a shift >1.0 cm. Volume change between simulation and boost was 49 ± 31%. Shifts when using the first boost fraction as reference were 0.8 ± 0.4 cm and 24% required a shift >1.0 cm. For electron boosts, shifts were 1.0 ± 0.5 cm and 52% fell outside the dosimetric penumbra. Interfraction analysis relative to the first fraction noted the shifts to be 0.8 ± 0.4 cm and 36% fell outside the penumbra.</p> <p>Conclusion</p> <p>The lumpectomy cavity can shift significantly during fractionated radiation therapy. 3DUS can be used to image the cavity and correct for interfractional motion. Further studies to better define the protocol for clinical application of IGRT in breast cancer is needed.</p

The Impact of Economic Recession on the Incidence and Treatment of Cancer

Purpose: The impact of economic recessions on the incidence and treatment of cancer is unknown. We test the hypothesis that cancer incidence and treatment rates decrease during a recession, and that this relationship is more pronounced in cancers that present with mild, more easily ignored symptoms. Methods and Materials: Data on incidence and treatment for all cancers, and breast and pancreatic cancers specifically, from 1973-2008, were collected using Surveillance Epidemiology and End Results (SEER). The data was adjusted for race, income, and education. Unemployment rate was used as the measure of economic recession. Data was log-transformed, and multivariate linear mixed regression was used. Results: Adjusting for socioeconomic factors, the data revealed a significant inverse correlation between unemployment and rates of cancer incidence and treatment. Every 1% increase in unemployment was associated with a 2.2% (95% CI: 1.6-2.8%, p<0.001) reduction in cancer incidence, a 2.0% (1.2-2.8%, p=0.0157) decrease in surgery, and a 9.1% (8.2-10.0% p<0.001) decrease in radiation therapy (RT). Breast cancer incidence and treatment had a dramatic inverse relationship - 7.2% (6.3-8.1%), 6.7% (5.7-7.6%), and 19.0% (18.1-19.8%), respectively (p<0.001 for all). The decrease in incidence was only significant for in situ and localized tumors, but not in regional or distant breast cancer. Compared to breast cancer, pancreatic cancer had a weaker relationship between unemployment and incidence: 2.6% (1.8-3.3%, p=0.0005), surgery: 2.4% (2.0-2.7%, p<0.001), and RT: 1.9% (1.5-2.2% p<0.001). Conclusions: Increasing unemployment rates are associated with a decrease in the incidence and treatment of all cancers. This effect is exaggerated in breast cancer, where symptoms can more easily be ignored and where there are widely used screening tests relative to pancreatic cancer

Ser ou não ser Mãe/Pai? Eis a questão –Motivações para a parentalidade

Background Local and/or regional recurrence and metachronous primary tumor arising in a previously irradiated area are rather frequent events in patients with head and neck squamous cell carcinoma (HNSCC). Re‐treatment is associated with an increased risk of serious toxicity and impaired quality of life (QOL) with an uncertain survival advantage. Methods We analyzed the literature on the efficacy and toxicity of photon/electron‐based external beam reirradiation for previously irradiated patients with HNSCC of non‐nasopharyngeal origin. Studies were grouped according to the radiotherapy technique used for reirradiation. Patient selection criteria, target volume identification method, tumor dose, fractionation schedule, systemic therapy administration, and toxicities were reviewed. Results In addition to disease‐related factors, current comorbidities and preexisting organ dysfunction must be considered when selecting patients for reirradiation. As morbidity from re‐treatment may be considerable and differ depending on which mode of re‐treatment is used, it is important to give patients information on potential morbidity outcomes so that an informed choice can be made within a shared decision‐making context. With improved dose distribution and adequate imaging support, including positron emission tomography‐CT, modern radiotherapy techniques may improve local control and reduce toxicity of reirradiation. A reirradiation dose of ≥60 Gy and a volume encompassing the gross tumor with up to a 5‐mm margin are recommended. Concomitant administration of systemic therapeutics and reirradiation is likely to be of similar benefit as observed in large randomized studies of upfront therapy. Conclusion Reirradiation, administered either with or without concurrent systemic therapy, is feasible and tolerable in properly selected patients with recurrent or a new primary tumor in a previously irradiated area of the head and neck, offering a meaningful survival (in the range of 10% to 30% at 2 years). Whenever feasible, salvage surgery is the method of choice for curative intent; patients at high‐risk for local recurrence should be advised that postoperative reirradiation is expected to increase locoregional control at the expense of higher toxicity and without survival advantage compared to salvage surgery without reirradiation. © 2014 Wiley Periodicals, Inc. Head Neck 37 : 134–150, 2015Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/110100/1/hed23542.pd