Search for Daily Modulation of MeV Dark Matter Signals with DAMIC-M.

Dark matter (DM) particles with sufficiently large cross sections may scatter as they travel through Earth's bulk. The corresponding changes in the DM flux give rise to a characteristic daily modulation signal in detectors sensitive to DM-electron interactions. Here, we report results obtained from the first underground operation of the DAMIC-M prototype detector searching for such a signal from DM with MeV-scale mass. A model-independent analysis finds no modulation in the rate of 1 e^{-} events with sidereal period, where a DM signal would appear. We then use these data to place exclusion limits on DM in the mass range [0.53,2.7] MeV/c^{2} interacting with electrons via a dark photon mediator. Taking advantage of the time-dependent signal we improve by ∼2 orders of magnitude on our previous limit obtained from the total rate of 1 e^{-} events, using the same dataset. This daily modulation search represents the current strongest limit on DM-electron scattering via ultralight mediators for DM masses around 1 MeV/c^{2}.

Disparities in disease presentation in the four screenable cancers according to health insurance status.

OBJECTIVES: Current guidelines support the use of screening for early detection in breast, prostate, colorectal and cervical cancer. The purpose of this study was to evaluate whether insurance status predicts for more advanced disease in these four currently screened cancers. STUDY DESIGN: The Surveillance, Epidemiology, and End Results (SEER) database was queried for breast, prostate, colorectal and cervix in patients aged 18-64 years. The database was queried from 2007 to 2011, with 425,614 patients with known insurance status included. METHODS: Multinomial logistic regression was used to evaluate insurance status and cancer presentation. RESULTS: Under multivariate analysis for breast cancer, uninsured patients more often had invasive disease (odds ratio [OR]: 1.55), T- (OR: 2.00), N- (OR: 1.59) stage, and metastatic disease (OR: 3.48), and were more often high-grade (OR: 1.21). For prostate cancer, uninsured patients again presented more commonly with higher T-stage (OR: 1.45), nodal (OR: 2.90) and metastatic (OR: 4.98) disease, in addition to higher prostate-specific antigen (OR: 2.85) and Gleason score (OR: 1.65). Colorectal cancer had similar findings with uninsured individuals presenting with more invasive disease (OR: 1.78), higher T (OR: 1.86), N (OR: 1.22), and M (OR: 1.58) stage, in addition to higher carcinoembryonic antigen levels (OR: 1.66). Similar results were seen for cervical cancer with uninsured having higher T (OR: 2.03), N (OR: 1.21), and M (OR: 1.45) stage. CONCLUSION: In the four cancers detected by screening exams, those without health insurance present with more advanced disease, with higher stage and grade, and more elevated tumour markers.

WE-G-217BCD-08: Image Quality Effects of Dynamic Iodine Concentrations for Contrast-Enhanced Cone-Beam CT.

PURPOSE: To study the image effects of the time-wise dynamic aspect of intravenous contrast agents to enable contrast-enhanced cone-beam CT (CE- CBCT) localization of liver lesions for stereotactic body radiation therapy (SBRT). METHODS: A model was developed to study dynamic IV contrast agents using static phantoms and to derive optimum parameters for CE- CBCT imaging. Ten samples containing iodine at 0-5 mg/mL were prepared in cylindrical tubes, corresponding roughly to 0-100 HU as measured by 120 kV helical CT imaging. Each sample was imaged separately in a tissue- equivalent phantom, yielding ten datasets (roughly 650 projections each) corresponding to these static CBCT images. To reconstruct images of dynamic contrast concentrations, the CBCT 2D projections were re- assembled to match the expected amount of contrast at different points in time. This model was applied to published hepatic contrast enhancement curves, and optimum imaging and contrast injection parameters were derived. RESULTS: A signal-to-noise ratio (SNR) decrease of 25%-75% in dynamic CE-CBCT images from ideal CT of samples with a 20-100 HU difference from water was observed in the un-optimized scans. This demonstrates the difficulty of CE-CBCT, and was noticed even in geometries that minimize or eliminate x-ray scatter, detector glare, and motion. Using our model, we found parameters for iodine injection, CBCT scanning, and injection/scanning timing which optimize contrast enhancement, and a 100% SNR increase with respect to the un-optimized scans was achieved. CONCLUSIONS: The effect of IV contrast is severely degraded in CBCT, and optimization of image and timing parameters is crucial for improved CE-CBCT imaging for target localization. CBCT has very low temporal resolution, and the pharmacokinetics of IV contrast must be carefully considered in order to apply this technique to localize liver lesions for SBRT. This model will be used to establish the feasibility of CE- CBCT for routine localization of liver lesions.

Randomised controlled trials: important but overrated?

Practising physicians individualise treatments, hoping to achieve optimal outcomes by tackling relevant patient variables. The randomised controlled trial (RCT) is universally accepted as the best means of comparison. Yet doctors sometimes wonder if particular patients might benefit more from treatments that fared worse in the RCT comparisons. Such clinicians may even feel ostracised by their peers for stepping outside treatments based on RCTs and guidelines. Are RCTs the only acceptable evaluations of how patient care can be assessed and delivered? In this controversy we explore the interpretation of RCT data for practising clinicians facing individualised patient choices. First, critical care anaesthetists John Boylan and Brian Kavanagh emphasise the dangers of bias and show how Bayesian approaches utilise prior probabilities to improve posterior (combined) probability estimates. Secondly, Jane Armitage, of the Clinical Trial Service Unit in Oxford, argues why RCTs remain essential and explores how the quality of randomisation can be improved through systematic reviews and by avoiding selective reporting.

Microscopic and macroscopic tumor and parenchymal effects of liver stereotactic body radiotherapy.

PURPOSE: To describe the histologic and volumetric changes in normal liver tissue after stereotactic body radiotherapy (SBRT) for liver metastases. METHODS AND MATERIALS: Pre- and post-SBRT imaging studies were analyzed to evaluate the effect of SBRT on normal liver volume (NLV) in 15 patients treated in a prospective clinical trial. Two other patients underwent exploratory surgery after SBRT and histologic analyses of the irradiated liver were performed to characterize the pathologic effects of SBRT. RESULTS: In the 15 patients studied quantitatively, the total NLV had decreased transiently at 2-3 months after SBRT and then began to regenerate at 3-8 months after SBRT. The median NLV reduction at the maximal observed effect was 315 cm(3) (range, 125-600) or 19% (range, 13-33%). Among the several dosimetric parameters evaluated, the strongest linear correlation was noted for the NLV percentage receiving 30 Gy as a predictor of maximal NLV reduction (r(2) = 0.72). The histologic changes observed 2 and 8 months after SBRT demonstrated distinct zones of tissue injury consistent with localized veno-occlusive disease. CONCLUSION: The well-demarcated focal parenchymal changes after liver SBRT (demonstrated both radiographically and histologically) within the high-dose zone are consistent with a threshold dose-induced set of phenomena. In contrast, the more global effect of NLV reduction, which is roughly proportional to whole organ dose parameters, resembles more closely an effect determined from radiobiologically parallel architecture. These observations suggest that modeling of normal tissue effects after liver SBRT might require different governing equations for different classes of effects.

Feasibility, limits and problems of clinical studies in Intensive Care Unit.

In critical care medicine there is still a paucity of evidence on how to manage most of the clinical problems commonly encountered in critically ill patients. Randomized controlled trials (RCTs) are the most powerful instruments to evaluate the efficacy of a therapeutic intervention and to generate evidence for clinical practice. Unfortunately, the design and conduct of RCTs in our field are particularly complicated, because of some intrinsic and structural problems (e.g. lack of reliable nosography, concomitant use of different therapies, problems in the definition of end-points besides mortality) that will be discussed in this review. Further challenges are represented by the lack of tradition of large ICU networks, difficulties in linking or integrating physiologic and therapeutic objectives in designing clinical protocols, scarcity of independent or non-profit funds. A particularly stimulating opportunity of development is represented also by the relationship of critical care to EBM. Because of the above problems, metanalyses could be less informative than in other areas of medicine, as they are based on few trials which are often contradictory and of unsatisfactory quality. Few suggestions are formulated which could help looking forwards.

Hypercapnia: permissive and therapeutic.

Hypercapnia has traditionally been avoided in the quest to keep parameters normal. Recent understanding of the role of excessive tidal stretch has prompted clinicians to avoid high tidal volumes or plateau pressures, and the resulting permissive hypercapnia has been increasingly tolerated by clinicians. Newer data point to the potential for elevated CO2 to be protective, and in some experimental situations, to cause harm. The protective effects of so called therapeutic hypercapnia' remain experimental at present, but promising laboratory studies suggest potential roles for the eventual selective application at the bedside.

How should we describe the radioblologic effect of extracranial stereotactic radlosurgery: equivalent uniform dose or tumor control probability?

Extracranial stereotactic radiosurgery (ESR) is now undergoing clinical investigation at numerous institutions as a treatment for solitary malignant lesions. Because there is no standard ESR technique, the same minimum dose might be applied through widely variable target dose-volume histograms. For multicenter trials of ESR or interinstitutional comparisons, a reliable index of radiobiological dose equivalency might facilitate the evaluation of dose-response relationships. Equivalent uniform dose (EUD) and tumor control probability (TCP) were considered for this application. While EUD appears more robust for the prospective description of ESR, TCP is expected to remain more valuable for a post hoc estimation of radiosensitivity parameters.

Normocapnia vs hypercapnia.

Initial Implementation of Mechanical Ventilation was focused on providing adequate oxygenation and relief of work of breathing. Over the last few decades it has become apparent that stretch-induced lung injury, associated with normocapnia or hypocapnia, is a real phenomenon. Attempts to reduce stretch-induced injury led to development of permissive hypercapnia in the neonatal population, and later to its acceptance as a standard of care in adult patients with ARDS. Here, the elevated CO2 was a result of reduced minute ventilation, and was considered to be a by-product of the technique that could be tolerated in most instances. It is now apparent that hypercapnia by itself can be protective. In addition, hypocapnia can be harmful. These observations led to the hypothesis of therapeutic hypercapnia, i.e., deliberate production of high CO2 as a goal in the care of critically ill patients.

The effect of setup uncertainty on normal tissue sparing with IMRT for head-and-neck cancer.

PURPOSE: Intensity-modulated radiotherapy (IMRT) is being evaluated in the management of head-and-neck cancers at several institutions, and a Radiation Therapy Oncology Group study of its utility in parotid sparing is under development. There is an inherent risk that the sharper dose gradients generated by IMRT amplify the potentially detrimental impact of setup uncertainty. The International Commission on Radiation Units and Measurements Report 62 (ICRU-62) defined planning organ-at-risk volume (PRV) to account for positional uncertainties for normal tissues. The purpose of this study is to quantify the dosimetric effect of employing PRV for the parotid gland and to evaluate the use of PRV on normal-tissue sparing in the setting of small clinical setup errors. METHODS AND MATERIALS: The optimized nine-beam IMRT plans for three head-and-neck cancer patients participating in an institutional review board approved parotid-sparing protocol were used as reference plans. A second optimized plan was generated for each patient by adding a PRV of 5 mm for the contralateral parotid gland. The effect of these additions on the quality of the plans was quantified, in terms of both target coverage and normal-tissue sparing. To test the value of PRV in a worst-case scenario, systematic translational setup uncertainties were simulated by shifting the treatment isocenter 5 mm superiorly, inferiorly, left, right, anteriorly, and posteriorly, without altering optimized beam profiles. At each shifted isocenter, dose distributions were recalculated, producing a total of six shifted plans without PRV and six shifted plans with PRV for each patient. The effect of setup uncertainty on parotid sparing and the value of PRV in compensating for the uncertainty were evaluated. RESULTS: The addition of the PRV and reoptimization did not significantly affect the dose to gross tumor volume, spinal cord, or brainstem. In contrast, without any shift, the PRV did increase parotid sparing and reduce coverage of the nodal region adjacent to the parotid gland. As expected, when the plans were shifted, the greatest increase in contralateral parotid irradiation was noted with shifts toward the contralateral parotid gland. With these shifts, the average volume of contralateral parotid receiving greater than 30 Gy was reduced from 22% to 4% when a PRV was used. This correlated with a reduction in the average normal-tissue complication probability (NTCP) from 22% to 7%. CONCLUSIONS: The use of PRV may limit the volume of normal tissue structures, such as the parotid gland, exceeding tolerance dose as a result of setup errors. Consequently, it will be important to incorporate the nomenclature of ICRU-62 into the design of future IMRT studies, if the clinical gains of increased normal-tissue sparing are to be realized.

Cost analysis of erythropoietin versus blood transfusions for cervical cancer patients receiving chemoradiotherapy.

PURPOSE: Red blood cell (RBC) transfusions or erythropoietin (EPO) can be used to evade the detrimental effects of anemia during radiotherapy, but the economic consequences of selecting either intervention are not well defined. The RBC transfusion needs during chemoradiotherapy for cervix cancer were quantified to allow comparison of RBC transfusion costs with the projected cost of EPO in this setting. METHODS AND MATERIALS: For patients receiving pelvic radiotherapy, weekly cisplatin, and brachytherapy, the RBC units transfused during treatment were tallied. RBC transfusion costs per unit included the blood itself, laboratory fees, and expected value (risk multiplied by cost) of transfusion-related viral illness. EPO costs included the drug itself and supplemental RBC transfusions when hemoglobin was not adequately maintained. An EPO dosage based on reported usage in cervix cancer patients was applied. RESULTS: Transfusions were given for hemoglobin <10 g/dL. Among 12 consecutive patients, 10 needed at least 1 U of RBC before or during treatment, most commonly after the fifth week. A total of 37 U was given during treatment, for an average of 3.1 U/patient. The sum total of the projected average transfusion-related costs was $990, compared with the total projected EPO-related costs of $3869. CONCLUSIONS: Because no proven clinical advantage has been documented for EPO compared with RBC transfusions to maintain hemoglobin during cervix cancer treatment, for most patients, transfusions are an appropriate and appealingly less expensive option.

Long-term local control and survival after concomitant boost accelerated radiotherapy for locally advanced cervix cancer.

Between 1989 and 1994, a prospective clinical trial tested the safety and efficacy of concomitant boost accelerated superfractionated (CBASF) radiotherapy for patients with locally advanced cervix cancer. CBASF radiotherapy included 45 Gy/25 fractions to the pelvis and a 14.4 Gy/9 fraction concomitant boost to the primary tumor, followed by brachytherapy for a total point A dose of 85 Gy to 90 Gy. The 22 patients of International Federation of Gynecology and Obstetrics stages IIIA-IVA who received CBASF radiotherapy now have a median follow-up time of more than 8 years. The 7-year actuarial rates of local control and overall survival are 81% and 36%, respectively. Serious late toxicity included bowel injury requiring colostomy in eight patients within 2.5 years after treatment, but no other severe toxicity was observed after longer follow-up intervals. The local control and survival rates achieved with CBASF radiotherapy were higher than those observed within a matched contemporaneous cohort of patients treated with standard radiotherapy alone at the same institution (p = 0.1 for local control, 0.09 for survival). The encouraging trend toward improved tumor control, tempered by the complication rate, suggests an opportunity to apply more sophisticated radiotherapy techniques that might sustain the favorable effects of dose intensification while mitigating the normal tissue toxicity.

A phase I study of RSR13, a radiation-enhancing hemoglobin modifier: tolerance of repeated intravenous doses and correlation of pharmacokinetics with pharmacodynamics.

PURPOSE: Preclinical studies indicate that RSR13 oxygenates and radiosensitizes hypoxic solid tumors by decreasing the oxygen (O(2))-binding affinity of hemoglobin (Hb). A Phase I open-label, multicenter dose and frequency escalation study was conducted to assess the safety, tolerance, pharmacokinetics, and pharmacodynamic effect of daily RSR13 administration to cancer patients receiving concurrent palliative radiotherapy (RT). METHODS AND MATERIALS: Eligibility criteria included the following: ECOG performance status < or =2; resting and exercise arterial oxygen saturation (SaO(2)) > or =90%; an indication for palliative RT, 20-40 Gy in 10-15 fractions. RSR13 was administered i.v. via central vein over 60 min immediately before RT. Patients received supplemental O(2) via nasal cannula at 4 L/min during RSR13 infusion and RT. Plasma, red blood cell (RBC), and urine RSR13 concentrations were assayed. The pharmacodynamic effect of RSR13 on Hb-O(2) binding affinity was quantified by multipoint tonometry and expressed as an increase in p50, defined as the partial pressure of O(2) that results in 50% SaO(2). The RSR13 dose in the first cohort was 75 mg/kg once a week for two doses; successive cohorts received higher, more frequent doses up to 100 mg/kg/day for 10 days during RT. RESULTS: Twenty patients were enrolled in the study. Repeated daily doses of RSR13 were generally well tolerated. Two adverse events of note occurred: (1) A patient with pre-existing restrictive lung disease had transient persistent hypoxemia after the sixth RSR13 dose; (2) a patient with a recurrent glioma receiving high-dose corticosteroids had edema after the seventh RSR13 dose, likely due to the daily high-volume fluid infusions. Both patients recovered to baseline status with conservative management. Maximum pharmacodynamic effect occurred at the end of RSR13 infusion and was proportional to the RBC RSR13 concentration. After an RSR13 dose of 100 mg/kg, the peak increase in p50 averaged 8.1 mm Hg, consistent with the targeted physiologic effect, and then diminished with a half-life of approximately 5 h. CONCLUSIONS: RSR13 was well tolerated in daily doses up to 100 mg/kg administered for 10 days during RT. The combined administration of RSR13 with 4 L/min supplemental O(2) yielded pharmacodynamic conditions in which hypoxic tumor radiosensitization can occur. Ongoing Phase II and Phase III studies are evaluating the combination of RT and RSR13 for selected indications, including primary brain tumors, brain metastases, and non-small-cell lung cancer.

Therapeutic hypercapnia reduces pulmonary and systemic injury following in vivo lung reperfusion.

Permissive hypercapnia, involving tolerance to elevated Pa(CO(2)), is associated with reduced acute lung injury (ALI), thought to result from reduced mechanical stretch, and improved outcome in ARDS. However, deliberately elevating inspired CO(2) concentration alone (therapeutic hypercapnia, TH) protects against ALI in ex vivo models. We investigated whether TH would protect against ALI in an in vivo model of lung ischemia-reperfusion (IR). Anesthetized open chest rabbits were ventilated (standard eucapnic settings), and were randomized to TH (FI(CO(2)) 0.12) versus control (FI(CO(2)) 0.00). Pa(CO(2)) and arterial pH values achieved in the TH versus CON groups were 101 +/- 3 versus 44.4 +/- 4 mm Hg and 7.10 +/- 0.03 versus 7.37 +/- 0.03, respectively. Following left lung ischemia and reperfusion, TH versus control was associated with preservation of lung mechanics, attenuation of protein leakage, reduction in pulmonary edema, and improved oxygenation. Indices of systemic protection included improved acid-base and lactate profile, in the absence of systemic hypoxemia. In the TH group, mean BALF TNF-alpha levels were 3.5% of CON levels (p < 0.01), and mean 8-isoprostane levels were 30% of CON levels (p = 0.02). Western blot analysis demonstrated reduced lung tissue nitrotyrosine in TH, indicating attenuation of tissue nitration. Finally, preliminary data suggest that TH may attenuate apoptosis following lung IR. We conclude that in the current model TH is protective versus IR lung injury and mechanisms of protection include preservation of lung mechanics, attenuation of pulmonary inflammation, and reduction of free radical mediated injury. If these findings are confirmed in additional models, TH may become a candidate for clinical testing in critical care.

Extracorporeal irradiation of tumorous calvaria. Case report.

This patient with recurrent meningioma grossly involving the frontal bone underwent craniotomy and tumor resection. During the procedure a bone flap was irradiated extracorporeally at a very high dose (120 Gy) sufficient to sterilize residual tumor cells, and the bone was then successfully replaced orthotopically for reconstruction. The use of autologous irradiated bone in this setting offers advantages over cadaveric transplantation and prosthetic implants. Radiation might cause less disruption of the bone's architecture than other techniques of tumor cell eradication.