The Dimensional Yale-Brown Obsessive-Compulsive Scale (DY-BOCS): an instrument for assessing obsessive-compulsive symptom dimensions.

Obsessive-compulsive disorder (OCD) encompasses a broad range of symptoms representing multiple domains. This complex phenotype can be summarized using a few consistent and temporally stable symptom dimensions. The objective of this study was to assess the psychometric properties of the Dimensional Yale-Brown Obsessive-Compulsive Scale (DY-BOCS). This scale measures the presence and severity of obsessive-compulsive (OC) symptoms within six distinct dimensions that combine thematically related obsessions and compulsions. The DY-BOCS includes portions to be used as a self-report instrument and portions to be used by expert raters, including global ratings of OC symptom severity and overall impairment. We assessed 137 patients with a Diagnostic and Statistical Manual-IV diagnosis of OCD, aged 6-69 years, from sites in the USA, Canada and Brazil. Estimates of the reliability and validity of both the expert and self-report versions of the DY-BOCS were calculated and stratified according to age (pediatric vs. adult subjects). The internal consistency of each of the six symptom dimensions and the global severity score were excellent. The inter-rater agreement was also excellent for all component scores. Self-report and expert ratings were highly intercorrelated. The global DY-BOCS score was highly correlated with the total Yale-Brown Obsessive-Compulsive Scale score (Pearson r = 0.82, P<0.0001). Severity scores for individual symptom dimensions were largely independent of one another, only modestly correlated with the global ratings, and were also differentially related to ratings of depression, anxiety and tic severity. No major differences were observed when the results were stratified by age. These results indicate that the DY-BOCS is a reliable and valid instrument for assessing multiple aspects of OCD symptom severity in natural history, neuroimaging, treatment response and genetic studies when administered by expert clinicians or their highly trained staff.

Photopolymerized hydrogel carriers for live vaccine ballistic delivery.

Photopolymerized poly(ethylene glycol) (PEG)-crosslinked hydrogels were assessed for their ability to serve as a payload vehicle to deliver a viable bacterial vaccine (Brucella abortus strain RB51 (RB51) to bison in Yellowstone National Park) ballistically using thermoplastic degradable Biobullets. PEG modified with degradable glycolide or lactide oligomers capped with photopolymerizable methacrylate groups served to crosslink the hydrogel vaccine carrier inside commercial hydroxypropylcellulose Biobullets. Release of 1 microm diameter model fluorescent particles from hydrogels followed known degradation trends for glycolide- and lactide-modified PEG hydrogels. All particles were released from PEG-co-glycolide hydrogels after approximately 10 days and PEG-co-lactide hydrogels after approximately 45 days following gel degradation. Minimal particle release was observed from pure PEG dimethacrylate hydrogels over 40 days. P. aeruginosa (strain PAO1) and RB51 live vaccines exhibit excellent viability following exposure to photopolymerization encapsulation within these gel matrices. Hydrogels photopolymerized into the payload chamber of Biobullets exhibit similar ballistic properties to commercially available Biobullets and penetrate and remain intact when fired intramuscularly into live elk for release of their gel payload in the host.

Design and synthesis of a new polymer drug delivery conjugate.

This work describes the design and synthesis of a novel polymer conjugate to facilitate intracellular release of attached cargo. Water soluble poly[N(2-hydroxypropyl) methacrylamide] with derivatizable pendant side chains was used as the polymer carrier. The membrane active Tat peptide was masked with poly(ethylene glycol) to inhibit non-specific interactions with exterior cell membranes, and then covalently linked to poly[N-(2-hydroxypropyl) methacrylamide]. A novel heterobifunctional crosslinker was synthesized containing both maleimide and aldehyde functionality to allow attachment of peptides to the polymer backbone through a pH sensitive bond. Analysis of the proposed conjugate by gel permeation chromatography, nuclear absorbance spectroscopy, and absorbance measurements indicate that the desired compound has been synthesized.

Clinical implementation of a Monte Carlo treatment planning system.

The purpose of this study was to implement the Monte Carlo method for clinical radiotherapy dose calculations. We used the EGS4/BEAM code to obtain the phase-space data for 6-20 MeV electron beams and 4, 6, and 15 MV photon beams for Varian Clinac 1800, 2100C, and 2300CD accelerators. A multiple-source model was used to reconstruct the phase-space data for both electron and photon beams, which retained the accuracy of the Monte Carlo beam data. The multiple-source model reduced the phase-space data storage requirement by a factor of 1000 and the accelerator simulation time by a factor of 10 or more. Agreement within 2% was achieved between the Monte Carlo calculations and measurements of the dose distributions in homogeneous and heterogeneous phantoms for various field sizes, source-surface distances, and beam modulations. The Monte Carlo calculated electron output factors were within 2% of the measured values for various treatment fields while the heterogeneity correction factors for various lung and bone phantoms were within 1% for photon beams and within 2% for electron beams. The EGS4/DOSXYZ Monte Carlo code was used for phantom and patient dose calculations. The results were compared to the dose distributions produced by a conventional treatment planning system and an intensity-modulated radiotherapy inverse-planning system. Significant differences (>5% in dose and >5 mm shift in isodose lines) were found between Monte Carlo calculations and the analytical calculations implemented in the commercial systems. Treatment sites showing the largest dose differences were for head and neck, lung, and breast cases.

Physical characteristics of a miniature multileaf collimator.

A preliminary study of the physical characteristics of a miniature multileaf collimator (mMLC) used with 4 MV x rays is reported. The mMLC attached to the accessory mount of a class C or D Varian linear accelerator (Varian Oncology Systems, Palo Alto, CA) with a source to aperture distance of 65 cm. The field penumbra using the small leaves was found to be consistent with the anticipated field penumbra using photon jaws at the same source to aperture distance as the mMLC. The percentage depth dose values of square fields were found to be consistent with the fields collimated with the upper and lower jaws. Output factors for the very small fields were found to vary rapidly. Circular fields could be produced with depth dose characteristics similar to those produced using conical tertiary collimators, commonly used for radiosurgery, but with a broader penumbra.

Monte Carlo calculations of electron beam output factors for a medical linear accelerator.

The purpose of this study was to investigate the application of the Monte Carlo technique to the calculation and analysis of output factors for electron beams used in radiotherapy. The code EGS4/BEAM was used to obtain phase-space files for 6, 12 and 20 MeV clinical electron beams from a scattering-foil linac (Varian Clinac 2100C) for a clinically representative range of applicator and square or rectangular insert combinations. The source-to-surface distance used was 100 cm. The field sizes ranged from 1 x 1 cm2 to 20 x 20 cm2. These phase-space files were analysed to study the intrinsic beam characteristics and used as source input for relative dose and output factor computations in homogeneous water phantoms using the code EGS4/DOSXYZ. The calculated relative central-axis depth-dose and transverse dose profiles at various depths of clinical interest agreed with the corresponding measured dose profiles to within 2% of the maximum dose. Calculated output factors for the fields studied agreed with measured output factors to about 2%. This demonstrated that for the Varian Clinac 2100C linear accelerator, electron beam dose calculations in homogeneous water phantoms can be performed accurately at the 2% level using Monte Carlo simulations.

Application of a video-optical beam imaging system for quality assurance of medical accelerators.

Method validation techniques were developed and experiments were carried out using a beam imaging system (BIS, Wellhöfer Dosimetrie, Schwarzenbruck, Germany) for routine quality assurance of medical accelerators. The routine quality assurance tasks include x-ray beam flatness and symmetry check, light/radiation field congruence test, beam energy constancy for electrons and mechanical checks for couch and collimator rotations. Comparisons were made between the BIS application and conventional quality assurance methods that use radiographic films or detector arrays. In this work, we have demonstrated efficiency and accuracy of the BIS to perform some of the routine quality assurance tasks for medical linear accelerators.

Differential response of buddleia (Buddleia davidii Franch.) to ozone.

Five cultivars of buddleia, Buddleia davidii Franch., were exposed to sub-ambient, ambient, and twice-ambient levels of ozone in open-top chambers for 8 weeks (June-August) during 1995: Plants were evaluated for foliar injury, growth index, and inflorescence characteristics during and following exposure. Destructive harvests were conducted at the end of the exposure period to determine dry weights of both above- and below-ground plant components. All cultivars had symptoms of visible injury in the twice-ambient treatment at both three and eight weeks after exposures began. No visible symptoms were observed at ambient ozone concentrations. At three weeks of exposure, 'Pink Delight' had the highest percentage of the leaves injured (PLI), 46.2%, followed by 'Opera' with a PLI of 23.3%. The other three cultivars had similar PLIs of less than 15%. After eight weeks of exposure, visible injury was equally severe on all cultivars with a mean PLI of 50.2% and mean Horsfall-Barratt rating of 5.4, indicating 12 to 25% of the leaf area was injured. No ozone x cultivar interaction was found for any growth variable measured. Across cultivars, growth index was reduced by 6%, total dry weight by 35%, and the number of developing floral buds and inflorescences by 29% for plants in twice-ambient ozone concentrations compared to ambient ozone concentrations. Percent biomass allocated to inflorescences was significantly greater for plants exposed to sub-ambient levels compared to those exposed to ozone at either ambient or twice-ambient concentrations. Results indicate that ozone levels similar to those in large urban areas in the southeastern United States have the potential to reduce growth and flowering of this important landscape plant.

Evaluating the dose to the contralateral breast when using a dynamic wedge versus a regular wedge.

The incidence of secondary cancers in the contralateral breast after primary breast irradiation is several times higher than the incidence of first time breast cancer. Studies have shown that the scatter radiation to the contralateral breast may play a large part in the induction of secondary breast cancers. Factors that may contribute to the contralateral breast dose may include the use of blocks, the orientation of the field, and wedges. Reports have shown that the use of regular wedges, particularly for the medial tangential field, gives a significantly higher dose to the contralateral breast compared to an open field. This paper compares the peripheral dose outside the field using a regular wedge, a dynamic wedge, and an open field technique. The data collected consisted of measurements taken with patients, solid water and a Rando phantom using a Varian 2300CD linear accelerator. Ion chambers, thermoluminescent dosimeters (TLD), diodes, and films were the primary means for collecting the data. The measurements show that the peripheral dose outside the field using a dynamic wedge is close to that of open fields, and significantly lower than that of regular wedges. This information indicates that when using a medial wedge, a dynamic wedge should be used.

Measurement of dose rate from exposure-calibrated 125I seeds.

Dose rate in water 1 cm transverse to an 125I seed calibrated for air kerma strength is not well established; 125I dosimetry calculations are, however, based on this constant. The specific dose constant was obtained from a series of dose rate measurements using thermoluminescent dosimetry (TLD) in a rigid geometry, full scatter acrylic phantom for individual model 6711 seeds. With a statistical precision of approximately +/- .5%, the dose rate to an infinitesimal mass of water located in acrylic at a perpendicular distance of 1 cm from the seed was found to be 0.977 cGy/h per microGy-m2/h of air kerma strength. Dose rate in a water phantom was calculated using a model that takes into account differences in both attenuation and scatter between water and acrylic. The specific dose constant in water was determined to be 0.932 (1.184 cGy-cm2/mCi-h, for the conventional exposure rate constant of 1.45 R cm2/mCi-h). This value is 7.5% less than dose rate in water from an unattenuated point source, and 9.7% less than the value commonly used for dosimetry calculations. The results suggest that most clinical 125I dosimetry estimates to date should be reconsidered for a possible reduction by about 10%. Relative scatter attenuation factors at 3 and 5 mm are also presented.

Measurement and estimation of organ Bremsstrahlung radiation dose.

Bremsstrahlung radiation doses were measured in an anthropomorphic phantom using thermoluminescent dosimeters. A single source of 90Y (beta-ray range less than or equal to 1.0 cm) was inserted in the bladder region and dosimeters were placed at distances greater than or equal to 3 cm to preclude detection of decay betas. Doses were corrected so as to represent the case of no biologic clearance. By comparing dosimeter location with the standard MIRD human geometry, sample organ doses could be determined. Representative results were 432 +/- 76 mrad/mCi at 3 cm (bladder), 260 +/- 60 mrad/mCi (uterus), 71 +/- 4 mrad/mCi (lower large intestine), and 1.4 +/- 0.7 mrad/mCi (liver). An estimation method, based on absorbed fraction tables, gave organ doses that were within the errors of measurement for all tissues with the exception of the bladder site. We conclude that organ bremsstrahlung radiation doses are not negligible and that they can be estimated using an integration over both the brake and beta-ray spectra.

Total skin electron irradiation for mycosis fungoides: relationship between acute toxicities and measured dose at different anatomic sites.

From June 1978 to June 1986, 50 patients with primary and recurrent mycosis fungoides were treated with total skin electron irradiation (TSEI), using the Stanford technique, to a total dose of 3600 cGy. TSEI was used alone, or in combination with low dose total body photon irradiation, or MOPP. Thermoluminescent dosimeter (TLD) measurements of the prescribed skin dose were obtained on twenty patients. The dorsum of the foot was 24% higher. The axillae, the bottom, and the arch of the foot were significantly underdosed. Frequencies of acute toxicities noted at 2000 cGy were: Skin, Grade I-II (RTOG) 80%. Partial epilation: scalp, 100%; eyebrows and at eyelashes, 20%. Nail dystrophy, 48%. Edema: hands and feet, 44%. Bullae: dorsum of feet, 8%; hands, 4%; and 3600 cGy: Skin, grade III 22%. Total epilation: scalp, 66%; eyebrows and eyelashes, 56%. Nail loss, 38%. Edema: hands and feet, 76%. Bullae: dorsum of feet, 34%; hands, 12%. Conjunctivitis, 4%. Large bullae, were more significant on the dorsum of the feet. Severe moist desquamation occurred in eight patients who had ulcerated lesions on initial presentation. Three patients were hospitalized due to ulceration and skin infection. All patients completed treatment after a short to moderate break. No patient developed skin necrosis, or corneal ulceration. No correlation exists between dose level, degree and onset of toxicity with previous chemotherapy or TBI. We conclude that the overall toxicity of TSEI is well tolerated.

Fractionated total body irradiation and high dose cyclophosphamide: a preparative regimen for bone marrow transplantation for patients with hematologic malignancies in first complete remission.

We treated 73 patients with hematologic malignancies in first complete remission (acute lymphoblastic leukemia = 23 patients; acute non-lymphoblastic leukemia = 25 patients; chronic myelogenous leukemia in first chronic phase = 20 patients, and high grade lymphoma = five patients) with a uniform preparative regimen consisting of fractionated total body irradiation (1,320 cGy) and high dose cyclophosphamide (100 mg/kg), followed by allogeneic bone marrow transplantation. By radiation dosimetry we demonstrated that the calculated doses were delivered accurately and reproducibly. Actuarial survival rates (+/- SEM) in complete remission were as follows: Acute lymphoblastic leukemia = 74 +/- 9%; acute nonlymphoblastic leukemia = 50 +/- 11%; and chronic myelogenous leukemia = 55 +/- 11%. Actuarial relapse rates for these three diagnoses were 19 +/- 9%, 17 +/- 11%, and 0% respectively. Three of the five lymphoma patients are alive in complete remission at 22+, 28+, and 54+ months. Overall probability of survival for the 73 patients was 59 +/- 7%. Interstitial pneumonia, usually associated with cytomegalovirus infection and graft-versus-host disease, and relapse of the underlying malignancy were the major causes of death.

Intracatheter hyperthermia and iridium-192 radiotherapy in the treatment of bile duct carcinoma.

We report a case of a patient with locally advanced bile duct carcinoma treated with 4500 cGy external beam radiotherapy, followed 3 weeks later by intracatheter 915 MHz microwave hyperthermia and radiotherapy delivered through a biliary U-tube placed at the time of surgery. Heating was to 43-45 degrees C for 1 hour followed immediately by intracatheter Iridium-192 seeds to deliver 5000 cGy over a 72 hour period. Prior to treatment, a thermal dosimetry study in phanton was conducted, using the same type of U-tube catheter tubing as in the patient. Orthogonal X rays of the patient's porta hepatis region were used to reconstruct the catheter geometry in the phantom. Proper insertion depth was determined thermographically to obtain maximum heating at the center of the tumor. The maximum SAR was 8.8 watts per kilogram per watt input. During the treatment, the average power applied was 30 W. Six months after therapy, the patient is asymptomatic. Although alkaline phosphatase, SGOT and SGPT have remained elevated, bilirubin has returned to normal and computerized tomographic scans and cholangiograms remain stable. A duodenal ulcer developed after therapy and is healing well with conservative medical management. This case demonstrates that hyperthermia applied through biliary drainage catheters is technically feasible and clinically tolerated. We believe the use of intracatheter hyperthermia in conjunction with external and/or intracatheter radiotherapy in selected patients with unresectable bile duct carcinomas warrants further study.

Bone marrow transplantation for acute nonlymphoblastic leukemia during first complete remission. An analysis of prognostic factors.

Sixty-nine patients with acute nonlymphocytic leukemia in first remission received total-body irradiation and chemotherapy followed by allogeneic bone marrow transplantation from histocompatible sibling donors. Patient age was between 1 and 41 years: 20 patients 1-19 years (group 1); 27 patients 20-29 years (group 2); and 22 patients 30-41 years (group 3). Two pretransplant radiochemotherapy regimens were employed: The first 45 patients received total-body irradiation (in a single dose) with cytosine arabinoside and cyclophosphamide; the next 24 patients received total-body irradiation (in a fractionated schedule) with cyclophosphamide alone. For all patients, actuarial disease-free survival is 51% (37 of 69 patients are alive and in continuous remission between 5 months and 9.3 years, median 3.7 years). For group 1 actuarial survival is 56%, group 2 48%, and group 3 48%. When analyzed for pretransplant factors that might predict disease-free survival after bone marrow transplantation neither patient age, white cell count at the time of diagnosis, FAB leukemic subtype, length of time before achieving remission, nor length of time between remission and bone marrow transplantation were established as prognostic.

Allogeneic bone marrow transplantation for acute lymphoblastic leukemia during first complete remission.

Patients with acute lymphoblastic leukemia who have poor prognostic features at diagnosis usually have a short disease-free survival in spite of successful remission induction. Those poor risk features are: age over 30 years, a white blood cell count over 25,000/microliter, certain translocations of chromosomes, and requirement for more than six weeks of induction chemotherapy to attain a complete remission. We have used high-dose radiochemotherapy to prepare 39 patients with acute lymphoblastic leukemia in first complete remission (1 infant and 38 adults; median age 23 years) for bone marrow transplantation from histocompatible sibling donors. Thirty-one of the 39 patients in this study had one (n = 23) or more (n = 8) poor risk features: age (n = 7); high white blood cell count (n = 19); translocations (n = 4), or resistance to initial induction therapy (n = 11). Currently, 26 patients are surviving for 4-72 months (median 18 months) following marrow grafting and are in complete remission. One of the surviving patients had two marrow transplant procedures because of recurrent leukemia. Actuarial survival in complete remission is 63% for the entire group of 39 patients and is 60% if the eight patients who had no poor risk features are excluded from analysis. The following causes for failure were observed: leukemic relapse was encountered in four patients between 3 and 17 months after BMT for an actuarial relapse rate of 16%; bacterial sepsis was the cause of death in two patients; graft-versus-host disease and/or interstitial pneumonia led to the demise of seven patients, and one patient died with leukoencephalopathy. It appears that high-dose radiochemotherapy followed by bone marrow transplantation from a histocompatible sibling donor during first complete remission can result in a high disease-free survival rate for younger adults with poor-risk acute lymphoblastic leukemia. This concept needs to be tested in prospective trials comparing bone marrow transplantation with chemotherapy.

Dosimetry of a dual photon energy linear accelerator.

We describe the dosimetric characteristics of a newly introduced dual photon energy linear accelerator, the Varian Clinac 1800. Depth doses are compared with other accelerators of the same nominal accelerating potentials (6 and 10 MV). Field flatness at dmax and at 10 cm depth, depth of dmax, wedge characteristics, output factors, and doses in the buildup region are presented.

Bone marrow transplantation for hematologic malignancies in patients aged 30 years or older.

During the past 10 years, 86 patients 30 to 54 years of age with hematologic malignancies were prepared with high-dose radiochemotherapy and received histocompatible bone marrow grafts. Thirty-four of these patients are surviving for 4 months to 9 years (median, 26 months) following marrow transplantation and 32 of them are in continuing complete remission (CR). Disease-free survival is 44% for 37 patients who were in first remission of acute leukemia or in the chronic phase of chronic granulocytic leukemia (CGL), 23% for 39 patients whose leukemia had relapsed at least once before transplantation or who had advanced stages of CGL, and 60% for ten patients who had hematologic malignancies other than leukemia. The median age of the surviving 34 patients is 36 years (range, 30 to 43 years). The incidence of moderate to severe acute graft-v-host disease (GVHD) was 48% and of chronic GVHD, 26%. The major causes of failure were interstitial pneumonia in 31 patients (24 of whom had antecedent acute GVHD) and recurrent leukemia in 12 patients (11 of whom had either never entered a CR or had relapsed at least once with acute leukemia or had progressive CGL before transplantation). Our data warrant further prospective studies in patients with hematologic malignancies who are older than 30 years.

Routine quality control of Ir-192 sources: results of 46 months of surveillance.

Documented problems with loose and inert Ir-192 seeds in nylon ribbons prompted us to develop a quality control program. Several problem cases are illustrated. A sample of ribbons from each shipment is measured in a radioisotope dose calibrator. Results of the measurements over a 46-month period are presented.