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.

Radiation-induced proliferation of the human A431 squamous carcinoma cells is dependent on EGFR tyrosine phosphorylation.

Accelerated cellular repopulation has been described as a response of tumors to fractionated irradiation in both normal tissue and tumor systems. To identify the mechanisms by which cells enhance their proliferative rate in response to clinically used doses of ionizing radiation (IR) we have studied human mammary and squamous carcinoma cells which are autocrine growth regulated by the epidermal growth factor receptor (EGFR) and its ligands, transforming growth factor-alpha and EGF. Both EGF and IR induced EGFR autophosphorylation, comparable levels of phospholipase C gamma activation as measured by inositol-1,4,5-triphosphate production, and as a consequence oscillations in cytosolic [Ca2+]. Activities of Raf-1 and mitogen-activated protein kinase (MAPK) were also stimulated by EGF and IR by Ca(2+)-dependent mechanisms. All these responses to EGF and IR were dependent upon activation of EGFR as judged by the use of the specific inhibitor of EGFR autophosphorylation, tyrphostin AG1478. Importantly, IR-induced proliferation of A431 cells was also inhibited by AG1478. This is the first report which demonstrates a link between IR-induced activation of proliferative signal transduction pathways and enhanced proliferation. We propose that accelerated repopulation of tumors whose growth is regulated by EGFR is initiated by an IR-induced EGFR activation mechanism that mimics the effects of growth factors.

Radiation-induced enhanced proliferation of human squamous cancer cells in vitro: a release from inhibition by epidermal growth factor.

Ionizing radiation is believed to stimulate the repopulation of squamous carcinoma cells that survive the early portion of a fractionated course of radiotherapy. To characterize any intrinsic radiation-induced adaptive response and to examine whether epidermal growth factor (EGF) influences this response, A431 and 183A cells were irradiated with repeated daily exposures of 0.5-0.75 Gy and then grown in monolayer culture for 7 days with or without EGF at a 1 ng/ml concentration. Cell numbers were quantified using a microtiter dye-reduction assay. EGF alone caused approximately 70% and 30% growth inhibition of human SC A431 and 183A cells, respectively. Although radiation alone did not affect proliferative rates in these conditions, radiation eliminated the EGF-related growth inhibition in both cell lines. This effect was dose dependent in single radiation exposure experiments. Cell cycle analyses indicated that EGF initially promoted entry into S-phase 3 days after treatment but caused a G1-S block after 7 days. Treatment with radiation recruited cells into S-phase and G2-M, an effect which was sustained 7 days after treatment, overriding the influence of EGF. Radiation-induced modulation of the response of human squamous carcinoma cells to EGF in vitro after single and repeated radiation exposures suggests a proliferation response that may underlie enhanced repopulation of tumor clonogens in vivo.

Heuristically derived tumor burden score as a prognostic factor for stage IIIB carcinoma of the cervix.

PURPOSE: A retrospective analysis of radiotherapeutic management of locally advanced carcinoma of the uterine cervix was performed to evaluate the effect of various treatment parameters and disease extent upon treat outcome. METHODS AND MATERIALS: Between 1976 and 1989, 89 patients with Stage IIIB disease were treated with external beam radiotherapy and brachytherapy. Treatment outcomes were evaluated by dose to Point A, the proportion of Point A dose delivered by brachytherapy, clinical response at 3 months, and a newly developed tumor burden scoring system that quantifies the anatomical extent of disease. Kaplan-Meier estimates of tumor control and survival parameters were determined. RESULTS: Loco-regional control (LRC), disease-free survival (DFS), and overall survival (OVS) at 5 years were 52.9%, 45.5%, and 50.3%, respectively. Clinical response at 3 months was highly predictive of local and distant tumor control. There was no correlation between proportion of brachytherapy dose and treatment outcome. The tumor burden scoring system demonstrates that FIGO Stage IIIB disease can be clinically divided into two prognostic groups of low and high tumor burden. Five year LRC was 62.9% and 40.2% for the low and high tumor burden groups, respectively (p = 0.024). Within the high tumor burden group the LRC was 53.0% and 22.5% when the point A dose given was > 78 Gy and < or = 78 Gy, respectively (p = 0.047). This correlated with improved DFS and OVS. CONCLUSION: The tumor burden scoring system subdivides FIGO Stage IIIB cervical carcinoma into two prognostic groups, predicting for overall survival and demonstrating a dose response in the high tumor burden group. This system may serve to improve future comparison of treatment outcome and to guide selection of patients who may benefit from a more aggressive treatment approach.

Determining the optimal block margin on the planning target volume for extracranial stereotactic radiotherapy.

PURPOSE: To determine the block margin that minimizes normal tissue irradiation outside of the planning target volume (PTV) for body stereotactic radiotherapy (Body-SRT) of lung and liver tumors. METHODS AND MATERIALS: Representative patient cases of lung and liver tumors were chosen for analysis. A PTV was constructed for each case and plans were generated which employed an array of block margins ranging from -2.5 mm to 10 mm at isocenter. Plans were generated for cerrobend blocks and for a multileaf collimator. The prescription isodose coverage was renormalized for each case and dose-volume histograms (DVH) and normal tissue complication probabilities (NTCP) were determined for each plan. RESULTS AND CONCLUSION: For the cases studied, the optimal block margin was in the 0.0 mm range. The ranking of plans was identical for both dose-volume based and biological based criteria. The method of blocking had no significant effect on treatment plans. The use of narrow margins for Body-SRT results in normal tissue sparing and creates significant target dose inhomogeneity which may be beneficial for tumor control.

Optimization of planar high-dose-rate implants.

PURPOSE: Brachytherapy has long been used to deliver localized radiation to the breast and other cancer sites. For interstitial implants, proper source positioning is critical in obtaining satisfactory dose distributions. The present work examines techniques for optimizing source guide placement in high-dose-rate (HDR) biplanar implants, and examines the effects of suboptimal catheter placement. METHODS AND MATERIALS: Control of individual dwell times in HDR implants allows a high degree of dose uniformity in planes parallel to the implant planes. Biplanar HDR implants can be considered optimized when the dose at the implant center is equal to the dose at the symmetric target boundaries. It is shown that this optimal dose uniformity is achieved when the interplanar separation is related to the target thickness T through the direct proportionality, s = T/square root2. To quantify the significance of source positioning, the average dose and a related quantity, equivalent uniform dose (EUD), were calculated inside the treatment volume for two conditions of suboptimal catheter geometry. In one case, the interplanar spacing was varied from 1 cm up to the target thickness T, while a second study examined the effects of off-center placement of the implant planes. RESULTS: Both the average dose and EUD were minimized when the interplanar spacing satisfied the relationship s = T/square root2. EUD, however, was significantly smaller than the average dose, indicating a reduced relative cell killing in the high dose regions near the dwell points. It was also noted that in contrast to the average dose, the EUD is a relatively weak function of catheter misplacement, suggesting that the biological consequences of suboptimal implant geometry may be less significant than is indicated by the increase in average dose. CONCLUSION: A concise formula can be used to determine the interplanar separation needed for optimal dose uniformity in Manchester-type implants. Deviations from optimal source geometry result in an increase in the average dose inside the treatment volume, but the weaker dependence of the EUD suggests that the surviving fraction of cells may not be not strongly affected by suboptimal source geometry.

Late complications of postoperative radiation therapy for cancer of the rectum and rectosigmoid.

PURPOSE: We retrospectively examined the surgical, medical, radiotherapeutic and technical factors associated with late small bowel and nonsmall bowel morbidity. METHODS AND MATERIALS: The medical records of 224 patients with cancer of the rectum and rectosigmoid treated mainly with abdominoperineal resection or anterior resection and postoperative radiotherapy at the University of Texas M.D. Anderson Cancer Center from 1973 to 1990 were reviewed. The median dose was 54 Gy (range 34-66 Gy) at 1.8-2 Gy per fraction using various techniques (23 had extended fields to L1 or L2; pelvic fields were treated with anterior-posterior in 85, 83 had a 3-field plan and 33 had a 4-field "box"). A positioning technique that treats patients on an open table-top device was used in 78 patients to move the small intestine out of the pelvis. Bladder distension was used in eight. Forty-seven patients received concomitant 5-fluorouracil. Small bowel series were performed in 122 patients to assess the volume of small bowel inside the pelvis below the conjugate line. RESULTS: In 29 patients, the median time to the development of small bowel obstruction was 7 months (range 0-69 months); 18 patients required reoperations. The small bowel obstruction rate was 30% in patients treated with daily extended field radiotherapy, 21% in those with a single pelvic field and 9% with multiple pelvic fields. Small bowel obstruction was positively correlated with postsurgical adhesions prior to radiotherapy and absence of reperitonealization at the time of initial surgery (p < 0.05). There was no correlation of small bowel obstruction with a history of hypertension, diabetes, prior surgery, history of abdominal infections, postoperative infections, wound healing, pathologic tumor stage, types of surgical procedures, sites of primary tumor, age, or sex. Patients developing small bowel obstruction had larger amounts of small bowel assessed radiologically below the conjugate line than those without complications. With the open table-top device, the small bowel obstruction rate was 3%. In 47 patients treated with radiation and chemotherapy on the open table-top device, the small bowel obstruction rate was 15%, but these patients had more small bowel inside the pelvis than those without the complication. The median time to the development of nonsmall bowel obstruction in 29 patients was 8 months (range 0-85 months), and the nonsmall bowel obstruction complications were significantly correlated with postoperative infection. Most nonsmall bowel obstruction complications were in the genitourinary tract and occurred in patients who had abdominoperineal resection. CONCLUSION: The open table-top device, by moving the small bowel out of the treatment field, reduces small bowel obstruction in patients treated with radical surgery and postoperative radiotherapy for cancer of the rectum and rectosigmoid. This technique is facile, reproducible, and does not require patient compliance.

Clinical use of a digital simulator for rapid setup verification in high dose rate brachytherapy.

PURPOSE: Fractionated high dose rate (HDR) brachytherapy provides a number of technical advantages over conventional implant therapy in that (a) it can be carried out on an outpatient basis, (b) personnel exposure is reduced to insignificant levels, and (c) patient motion during irradiation is minimized, resulting in a more accurate delivery of the planned radiation dose distribution to the target and critical structures. The patient discomfort associated with the repeated applicator insertions and/or treatment setups can be alleviated to the extent that the setup time is held to a minimum. This work describes the use of a prototype digital simulator to obtain fast, high-quality digital images for rapid setup verification. METHODS AND MATERIALS: The digital imaging system of the prototype simulator consists of a charge-coupled device (CCD) camera, which views the x-ray image optically transmitted from a conventional phosphor screen. Treatment is carried out with a remote afterloading HDR unit immediately after setup verification with the patient on the simulator stretcher. The high-resolution digital images are processed and displayed in about 5 s, as opposed to a minimum of approximately 2 min for film. RESULTS: The imaging system has been evaluated for a variety of implant types, both intracavitary and interstitial. The digital radiographs provided permanent high-resolution images as required in most cases for precise applicator positioning. The gray scale manipulation capabilities were found to be useful for imaging in regions of different density, such as lung and soft tissue, in the same radiograph. The advantages of short image acquisition and display times were observed in all cases, but were most evident in the intraluminal procedures, which sometimes involved several pretreatment applicator adjustments at a time of considerable patient discomfort. CONCLUSION: Pretreatment imaging is necessary to fully exploit the technical advantages of HDR brachytherapy. High-quality digital radiography offers unique advantages in HDR setup and verification by providing fast high-resolution, undistorted images with software manipulation capabilities and permanent storage of images.

Patterns of failure following combined modality therapy for esophageal cancer, 1984-1990.

From 1984-1990, 143 patients with squamous cell or adenocarcinoma of the esophagus were enrolled in a Phase I/II study of neoadjuvant chemotherapy followed by concurrent chemotherapy plus radiotherapy with or without subsequent esophagectomy. Patients received one cycle of Cisplatin or Carboplatin plus Etoposide for squamous cell carcinoma, or Cisplatin or Carboplatin plus 5FU for adenocarcinoma, followed by two cycles of the same chemotherapy given concurrently with 44-46 Gy over 5 weeks. Operable patients then underwent esophagectomy. Inoperable patients and those with positive surgical margins received additional irradiation (16-18 Gy). Twelve percent of the surgical group received preoperative radiotherapy doses > or = 50 Gy. Seventy-two percent (103) had clinical Stage I-III tumors and 28% (40) were clinical Stage IV (1983 American Joint Committee on Cancer criteria). Only clinical Stage I-III patients were analyzed with respect to patterns of failure. Isolated local failure occurred in 19/103 (18%) of clinical Stage I-III patients. Both local and distant relapse occurred in 15/103 (15%), and distant metastases alone occurred in 25/103 (24%). The 3-year actuarial rates of local and distant failures were 45% and 60%, respectively. Among the clinical Stage I-III patients who underwent surgery (n = 58) versus those who did not (n = 45), the 3-year actuarial local and distant failure rates were 30% versus 60% and 45% versus 45%, respectively. Multivariate analysis was performed to identify significant predictors of local control. For all clinical Stage I-III patients, treatment with surgery (p = 0.001) and with three or more cycles of chemotherapy (p = 0.02) were significant predictors of improved local control. Patients who underwent surgery were significantly younger and had a better performance status than those who did not. The improvement in local control with surgery did not translate into better survival, likely on account of a high operative mortality rate in older patients and those receiving > or = 50 Gy preoperatively. We conclude that local control remains poor with concurrent chemotherapy + radiotherapy for esophageal cancer. The addition of surgery improved local control, but distant metastases remain a problem both in this group of patients as well as those treated without esophagectomy. Efforts to improve local control appear warranted, but it remains to be demonstrated that improved local control translates into improved survival in esophageal cancer because of a high rate of distant metastases in patients whose disease is controlled in the esophagus.

A pilot study of concomitant boost accelerated superfractionated radiotherapy for stage III cancer of the uterine cervix.

PURPOSE: Retrospective studies suggest that prolonged treatment time adversely affects control rates of squamous carcinomas managed by radiotherapy. From 1989 to 1994 a prospective clinical trial was conducted to assess the feasibility and efficacy of concomitant boost accelerated superfractionated (CBASF) radiotherapy for advanced uterine cervical carcinoma. METHODS AND MATERIALS: Twenty newly diagnosed patients with FIGO stage III squamous cell carcinoma of the cervix were irradiated using a CBASF regimen. Patients received 45 Gy administered to the whole pelvis in 25 fractions in 5 weeks. On Monday, Wednesday, and Friday of the last 3 weeks, an additional 1.6 Gy boost was given 6 hours after the whole pelvis treatment. The 9 boost treatments, totaling 14.4 Gy, were given via lateral fields encompassing the parametria and primary tumor for a cumulative tumor dose of 59.4 Gy. A single low-dose rate brachytherapy procedure was performed within 1 week after the external beam radiotherapy to raise the point A dose to 85-90 Gy in 42 days. Primary endpoints of analysis were local control, complications, and patterns of failure. Results are compared with the outcomes of 21 patients treated with conventionally fractionated (CF) radiotherapy during the same years. RESULTS: Median total treatment time was 46 days in the CBASF group (range 37-62). Median follow-up interval among surviving CBASF patients is 3.8 years. The four-year actuarial local control rates are 78% and 70% in the CBASF and CF groups, respectively (p = ns). Only 2 CBASF patients required a treatment break because of acute toxicity, but severe late complications occurred in 8/20 CBASF patients for a crude rate of 40%. Distant failure was more common than local failure in the CBASF group, and para-aortic node failure occurred in six of the eight CBASF patients with distant failure. CONCLUSIONS: In the management of stage III cervix cancer, the CBASF regimen produced a trend toward improved local control when compared with the CF regimen, shifting the patterns of failure toward a higher rate of isolated distant failures. The high frequency of para-aortic node failure warrants consideration of elective treatment to this region in stage III patients treated with curative intent. Although the high local control rate of the CBASF regimen supports further investigation of accelerated treatment regimens for locally advanced cervix cancer, the unacceptable risk of late complications necessitates refinement in technique and scheduling to improve the therapeutic ratio.

Hypofractionated stereotactic radiotherapy as an alternative to radiosurgery for the treatment of patients with brain metastases.

PURPOSE: Modeling studies have demonstrated a potential biologic advantage of fractionated stereotactic radiotherapy for malignant brain tumors as compared to radiosurgery (SRS), even when only a few fractions are utilized. We prospectively evaluated the feasibility, toxicity, efficacy and cost of hypofractionated stereotactic radiotherapy (HSRT) in the treatment of selected radiosurgery-eligible patients with brain metastases. METHODS AND MATERIALS: Patients with a limited number of brain metastases not involving the brainstem or optic chiasm underwent linac-based HSRT delivered in 3 fractions using a relocatable stereotactic frame. Depth-helmet and reference point measurements were recorded to address treatment accuracy. All patients underwent whole brain radiotherapy to a dose of 30 Gy. Toxicity, response, and survival duration were recorded for each patient. Prognostic factors were assessed by Cox regression analysis. Cost comparisons with a cohort of SRS treated patients were performed. RESULTS: Thirty-two patients with 57 brain metastases were treated with HSRT. Twenty-three and 9 patients underwent HSRT for upfront and salvage treatment, respectively. The median dose delivered was 27 Gy, given in 3 fractions of 9 Gy. From 3328 depth-helmet measurements, the absolute median setup deviation in AP, lateral, and vertical orientations was approximately 1.0 mm. No significant acute toxicity was seen. Late toxicities included seizures in four patients, and radionecrosis in two patients. The median survival duration from treatment was 12 months. KPS (p = 0.039) and RTOG-RPA class (p = 0.039) were identified as significant prognostic factors for survival. HSRT was $4119 less costly than SRS. CONCLUSION: HSRT, as delivered in this study, is more comfortable for patients and less costly than SRS in the treatment of selected patients with brain metastases. Proper dose selection and radiobiologic/toxicity trade-offs with SRS await further study.

A retrospective quality of life analysis using the Lung Cancer Symptom Scale in patients treated with palliative radiotherapy for advanced nonsmall cell lung cancer.

PURPOSE: To measure symptom palliation in patients treated with radiation therapy for advanced nonsmall cell lung cancer (NSCLC). METHODS AND MATERIALS: Five hundred thirty patients with NSCLC were treated at the Medical College of Virginia between 1988 and 1993. Sixty-three patients with the least favorable prognostic features received palliative radiation to 30 Gy in 10 or 12 fractions for symptoms related to the presence of intrathoracic tumor. The observer portion of the Lung Cancer Symptom Scale (LCSS) was employed in a retrospective chart review, scoring measures of appetite, fatigue, cough, dyspnea, hemoptysis, and pain. RESULTS: In 54 evaluable patients, median survival was 4 months and was independent of age, stage, performance status, or histology. Ninety-six percent of the patients had at least one LCSS symptom at presentation. Fatigue was unaffected by therapy. Improvements in appetite (p = 0.68) and pain (p = 0.61) were not statistically significant. There was, however, a statistically significant reduction in cough (p = 0.01), hemoptysis (p = 0.001), and dyspnea (p = 0.0003). Self-limiting acute side effects included transient esophagitis in 37% of patients, though no severe toxicities were noted. CONCLUSIONS: These results suggest symptomatic benefit from radiotherapy even in those NSCLC patients with advanced disease and a limited life expectancy. Treatment should be given to patients whose symptoms are most amenable to palliation. A site-specific quality of life instrument such as the LCSS should be included within any future clinical trial of NSCLC management so that symptom control may be scored as a treatment outcome in addition to disease-free survival.

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.

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.

Simplified enrollment for autologous transfusion: automatic referral of presurgical patients for assessment for autologous blood collections.

We implemented a pilot program at our institution for automatic referral of patients for presurgical assessment for preoperative and intraoperative collection of autologous blood. Although patients and clinicians support the use of autologous transfusion, often a request for collection of autologous blood is not initiated. During 11 months, 269 patients (82%) of three orthopedic surgeons entered the program, and 218 underwent operation and were dismissed from the hospital. A total of 940 units of autologous blood (675 preoperatively and 265 intraoperatively) was collected from these 218 patients, and 84% of the units were transfused. Throughout hospitalization, 86% of the patients received only autologous blood, whereas 14% received various proportions of homologous and autologous blood. In contrast, only 26% of a concomitant control group of 220 consecutive orthopedic surgical patients not participating in the automatic-referral program received only autologous blood. Thus, the automatic-referral program increased the percentage of elective orthopedic surgical patients who received only autologous blood from 26% to 86% (P less than 0.001). This study also showed that the same amount of blood was used for autologous transfusions as was routinely used for homologous transfusions in similar cases. The automatic-referral system was convenient for physicians and patients and offered the benefits of reduction of transfusion-associated risks and amelioration of patient anxieties.

Calcium-dependent stimulation of mitogen-activated protein kinase activity in A431 cells by low doses of ionizing radiation.

Ionizing radiation at 2 Gy activates the epidermal growth factor receptor (EGFR) kinase activity in A431 squamous carcinoma cells and as a consequence transiently activates a downstream effector, mitogen-activated protein kinase (MAPK). A dose-response analysis shows fourfold activation 3-5 min after irradiation at 0.5 Gy with no additional activation after doses up to 4 Gy. Activation is independent of protein kinase C as defined by marginal effects of protein kinase C down-regulation and the protein kinase C inhibitor, chelerythrine. In contrast, an intracellular Ca2+ chelator (BAPTA/AM), a Ca2+ antagonist (TMB-8) and a phospholipase C inhibitor (U73223), which inhibits radiation-induced Ca2+ oscillations, all block MAPK stimulation. The upstream component, Raf-1, is also activated through a mechanism that is dependent on EGFR and Ca2+. Activation of Raf-1, monitored by tyrosine phosphorylation and co-immunoprecipitation with Ras, was inhibited by BAPTA/AM and TMB-8, indicating that the Ca2+-dependent step occurs at or before the interaction of Ras and Raf-1. Neither the Ras guanosine triphosphate exchange protein, SOS, nor Ca2+-activated tyrosine kinases linked to the MAPK pathway, focal adhesion kinase and PYK2, were stimulated by radiation. In contrast, EGF activated SOS as shown by the enhanced association of SOS with EGFR in co-immunoprecipitation experiments. These results suggest that activation of EGFR-dependent downstream signaling induced by radiation differs from that induced by the natural ligands of EGFR.

Effects of the calcium channel blocker flunarizine on the hemodynamics and oxygenation of tumor microvasculature.

Flunarizine is a diphenylpiperazine calcium entry blocker that has been shown previously to increase tumor blood flow and sensitivity to radiotherapy via reduction in the radiobiologically significant hypoxic fraction. Two mechanisms of action have been proposed previously (vasodilation, altered blood viscosity), but no studies have been performed to examine its mechanisms of action in vivo. Such information would be invaluable in determining the role of flunarizine in multimodality approaches to reduce tumor hypoxia. Fisher-344 rats bearing R3230Ac tumors transplanted into dorsal flap window chambers were used to examine microcirculatory changes after administration of flunarizine (1.0 mg/kg, iv). The drug increased the diameters of the microvasculature and red cell velocities specifically in central tumor regions (producing an average increase in vessel flow by a factor of 1.96), which was accompanied by an increase in perivascular pO2 of 12 mm Hg, on the average. The drug did not change the diameters of tumor "feeding" vessels, nor did it change vascular length densities. Thus the improvement in central tumor blood flow and oxygenation could not be attributed to dilation of feeding vessels. The oxygen-carrying capacity of the blood was not altered either since hemoglobin saturation (measured in vitro) and the hematocrits of the microvasculature were unchanged after drug administration. Therefore, by a process of elimination, the most likely explanation for the effect of the drug is modification of blood viscosity. Additional studies are under way in this laboratory to examine whether changes in viscosity occur after flunarizine administration.