Initial clinical experience with a video-based patient positioning system.

PURPOSE: To report initial clinical experience with an interactive, video-based patient positioning system that is inexpensive, quick, accurate, and easy to use. METHODS AND MATERIALS: System hardware includes two black-and-white CCD cameras, zoom lenses, and a PC equipped with a frame grabber. Custom software is used to acquire and archive video images, as well as to display real-time subtraction images revealing patient misalignment in multiple views. Two studies are described. In the first study, video is used to document the daily setup histories of 5 head and neck patients. Time-lapse cine loops are generated for each patient and used to diagnose and correct common setup errors. In the second study, 6 twice-daily (BID) head and neck patients are positioned according to the following protocol: at AM setups conventional treatment room lasers are used; at PM setups lasers are used initially and then video is used for 1-2 minutes to fine-tune the patient position. Lateral video images and lateral verification films are registered off-line to compare the distribution of setup errors per patient, with and without video assistance. RESULTS: In the first study, video images were used to determine the accuracy of our conventional head and neck setup technique, i.e., alignment of lightcast marks and surface anatomy to treatment room lasers and the light field. For this initial cohort of patients, errors ranged from sigma = 5 to 7 mm and were patient-specific. Time-lapse cine loops of the images revealed sources of the error, and as a result, our localization techniques and immobilization device were modified to improve setup accuracy. After the improvements, conventional setup errors were reduced to sigma = 3 to 5 mm. In the second study, when a stereo pair of live subtraction images were introduced to perform daily "on-line" setup correction, errors were reduced to sigma = 1 to 3 mm. Results depended on patient health and cooperation and the length of time spent fine-tuning the position. CONCLUSION: An interactive, video-based patient positioning system was shown to reduce setup errors to within 1 to 3 mm in head and neck patients, without a significant increase in overall treatment time or labor-intensive procedures. Unlike retrospective portal image analysis, use of two live-video images provides the therapists with immediate feedback and allows for true 3-D positioning and correction of out-of-plane rotation before radiation is delivered. With significant improvement in head and neck alignment and the elimination of setup errors greater than 3 to 5 mm, margins associated with treatment volumes potentially can be reduced, thereby decreasing normal tissue irradiation.

Cognitive-behavioral group therapy with medication for depressed gay men with AIDS or symptomatic HIV infection.

OBJECTIVE: The feasibility and effectiveness of a combination of group cognitive-behavioral therapy and medication for the treatment of depression among gay men with AIDS or symptomatic HIV infection were evaluated. METHODS: Fifteen patients diagnosed with DSM-IV major depressive disorder or dysthymia were treated in one of two weekly therapy groups in which cognitive-behavioral therapy had been specially modified for the target population. The majority of these patients, including two who had been on medication before joining the groups, also received antidepressant medication. Thirteen of the 15 patients completed therapy, attending an average of 15 of the 20 therapy sessions. RESULTS: The group cognitive-behavioral therapy used in this project appeared to be attractive to most patients; retention, attendance, and therapy compliance were good. Depression scores showed substantial decreases from pre- to posttherapy, with further decreases at one-year follow-up. Patients' self-reports indicated that some aspects of the intervention, particularly the focus on cognitive restructuring, were especially valuable in alleviating their depression. CONCLUSIONS: The modified group cognitive-behavioral therapy described in this study report offers a reasonable option for treatment of this clinically challenging group of patients.

Confirmation of multiple tetracycline residues in milk and oxytetracycline in shrimp by liquid chromatography-particle beam mass spectrometry.

A confirmation procedure is described for detection of residues of six tetracyclines in bovine milk, and oxytetracycline in shrimp. Residues are extracted from milk or shrimp tissue using metal chelate affinity chromatography. The extracts are desalted, further concentrated using polymeric solid-phase extraction, and chromatographed on a polymeric reversed-phase column. Analysis is by methane negative ion chemical ionization on a quadrupole mass spectrometer using a particle beam interface. Data are acquired in partial scan mode, monitoring from m/z 378 to m/z 480. The procedure was validated with control milk and shrimp, fortified milk (30 ng/ml) and shrimp (100 ng/g), and milk and tissue from animals treated with the drugs.

Preparation and in vivo evaluation of an N-(p-[125I]iodophenethyl)maleimide-antibody conjugate.

Protein sulfhydryl reactive N-(4-[125I]iodophenethyl)maleimide (IPEM, 5) was obtained from N-[4-(tri-n-butylstannyl)phenethyl]maleimide in 59-100% radiochemical yield. Conjugation of 5 to NR-ML-05 Fab, a murine anti-melanoma antibody Fab fragment that had been previously reduced with dithiothreitol (DTT), was effected in an average of 85% yield. Results from in vitro chemical challenges and serum stability studies on the IPEM conjugate of NR-ML-05 Fab (6) indicated a stable covalent attachment of the radioiodine. A biodistribution study of the IPEM conjugate in tumor-bearing athymic nude mice showed lack of significant accumulation of radioiodine in the thyroid and stomach which was an indication of in vivo stability. The observed uptake in tumor was consistent with that obtained for Chloramine-T- or p-iodobenzoate-labeled NR-ML-05 Fab conjugates.

Astatine-211 labeling of an antimelanoma antibody and its Fab fragment using N-succinimidyl p-astatobenzoate: comparisons in vivo with the p-[125I]iodobenzoyl conjugate.

Astatine-211 labeling of an antimelanoma antibody, NR-ML-05, and its Fab fragment with N-succinimidyl p-[211At]astatobenzoate (2a) has been described. Preparation of the astatinated intermediate 2a was accomplished by distilling astatine-211 from an irradiated bismuth target directly into a reaction mixture containing an organometallic compound, N-succinimidyl p-(tri-n-butylstannyl)benzoate (1), and an oxidant, N-chlorosuccinimide, in 5% HOAc/MeOH. Trapping of distilled astatine as 2a was found to be efficient, resulting in 70-90% yields based on the amount of astatine-211 in the reaction mixture. The dry distillation technique employed gave recoveries of astatine-211 which ranged from 20% to 75%. Conjugation of 2a to NR-ML-05 and its Fab fragment was accomplished in 40-60% yields. The [211At]astatobenzoyl-conjugated antibodies were found to be stable in vitro when challenged by strong denaturants and nucleophilic reagents. Coinjected dual-labeled studies of the 2a astatinated antibodies and the same antibodies labeled with N-succinimidyl p-[125I]iodobenzoate (2b) in athymic mice bearing the human tumor xenograft A375 Met/Mix demonstrated that both radiolabeled antibodies had equivalent tumor localization. Data from the dual-labeled biodistribution of the intact antibody suggests that the astatine is stably attached. Data from the dual-labeled Fab fragment suggests that a portion of the astatine label is released as astatide, either from the astatinated Fab or from a catabolite.

Radioiodinated iodobenzoyl conjugates of a monoclonal antibody Fab fragment. In vivo comparisons with chloramine-T-labeled Fab.

A comparative investigation of the biodistributions of radioiodinated p- and m-iodobenzoyl conjugates of a monoclonal antibody Fab fragment, NR-LU-10 Fab, and the same antibody Fab fragment radioiodinated by the chloramine-T (ChT) method has been carried out in mice. Coinjected, dual-isotope studies in athymic mice with tumor xenografts have demonstrated that there are only minor differences in the in vivo distributions of the iodobenzoyl-labeled Fabs, except in the excretory organs, kidneys, and intestines, where major differences were observed. Similarly, coinjection of either the p-iodobenzoyl or m-iodobenzoyl conjugate of NR-LU-10 Fab with the Fab radioiodinated with ChT/radioiodide into BALB/c mice provided additional data that indicated that the two iodobenzoyl conjugates distributed similar in a number of selected tissues. The tissue-distribution differences of the regioisomeric iodobenzoyl conjugates in relation to the ChT-radioiodinated Fab were large for the stomach and neck, consistent with previous studies. The most notable difference between the two iodobenzoyl conjugates was the kidney activity, where the m-iodobenzoyl conjugate was similar to the directly labeled Fab, but the p-iodobenzoyl-conjugated Fab was higher by nearly a factor of 2.

Evaluation of iodovinyl antibody conjugates: comparison with a p-iodobenzoyl conjugate and direct radioiodination.

The preparations and conjugations of 2,3,5,6-tetrafluorophenyl 5-[125I/131I]iodo-4-pentenoate (7a) and 2,3,5,6-tetrafluorophenyl 3,3-dimethyl-5-[125I/131I]iodo-4-pentenoate (7b) to monoclonal antibodies are reported. Reagents 7a and 7b were prepared in high radiochemical yield by iododestannylation of their corresponding 5-tri-n-butylstannyl precursors. Radioiodinated antibody conjugates were prepared by reaction of 7a or 7b with the protein at basic pH. Evaluation of these conjugates by several in vitro procedures demonstrated that the radiolabel was attached to the antibody in a stable manner and that the conjugates maintained immunoreactivity. Comparative dual-isotope biodistribution studies of a monoclonal antibody Fab fragment conjugate of 7a and 7b with the same Fab fragment labeled with N-succinimidyl p-[131I]iodobenzoate (PIB, p-iodobenzoate, 2) or directly radioiodinated have been carried out in tumor-bearing nude mice. Coinjection of the Fab conjugate of 7a with the Fab conjugate of 2 demonstrated that the biodistributions were similar in most organs, except the neck tissue (thyroid-containing) and the stomach, which contained substantially increased levels of the 7a label. Coinjection of the Fab conjugate of 7a with the Fab fragment radioiodinated by using the chloramine-T method demonstrated that the biodistributions were remarkably similar, suggesting roughly equivalent in vivo deiodination of these labeled antibody fragments. Coinjection of the Fab conjugate of 7a with the Fab conjugate of 7b indicated that there was approximately a 2-fold reduction in the amount of in vivo deiodination of the 7b conjugate as compared to the 7a conjugate.

Biodistribution of p-iodobenzoyl (PIP) labeled antibodies in a murine lymphoma model.

A monoclonal antibody against the murine T-cell antigen Thy 1.1 was radioiodinated using N-succinimidyl p-iodobenzoate (PIP) in an attempt to decrease deiodination of the labeled antibody. The biodistribution of the PIP labeled antibody was compared to Iodogen labeled antibody in Thy 1.1+ lymphoma bearing AKR/Cum mice, where the antibody was tumor specific, and AKR/J mice where the antibody reacted with both tumor and normal T-cells. PIP labeling resulted in decreased iodine concentrations in stomach and salivary gland as compared to Iodogen labeling. There was little difference in radioiodine concentrations between the two preparations in tumor, lymphoid tissues or other organs. These results suggest deiodination of intact antibody plays little role in the clearance of radioiodinated anti-Thy 1.1 antibody from tissues.

Development of a stable radioiodinating reagent to label monoclonal antibodies for radiotherapy of cancer.

A method of radioiodinating monoclonal antibodies such that the labeled antibodies do not undergo in vivo deiodination has been studied. The method utilizes conjugation of succinimidyl para-iodobenzoate to the antibody. The iodobenzoate was radiolabeled by using an organometallic intermediate to facilitate the reaction. Thus, succinimidyl para-tri-n-butylstannylbenzoate was radiolabeled in 60-90% radiochemical yield and subsequently conjugated to the antibody in 80-90% yield. Animal biodistribution studies were carried out with two separate anti-melanoma antibodies (9.2.27 and NR-M1-05) labeled by this method, and examined in nude mice bearing human melanoma tumor xenografts. Very large differences in the localization of radioactivity were observed in the thyroids and stomachs of mice when the iodobenzoyl-labeled antibodies were compared with the same antibodies labeled using the chloramine-T method of radioiodination. Few other significant differences in the tissue distribution of the radioiodinated antibodies were seen.

Approaches to radiolabeling of antibodies for diagnosis and therapy of cancer.

The development of monoclonal antibodies of high affinity and selectivity for tumor antigens has supported the development of radiolabeled antibodies for diagnostic localization and targeted delivery of therapeutic radionuclides. Several radionuclide chelating agent systems have been developed for indium-111 and technetium-99m that have shown good sensitivity and specificity for tumor detection in patients. Feasibility for therapy has been shown in animal models and a few patient studies with iodine-131 and yttrium-90. This review covers selection of radionuclides and chemistry of antibody radiolabeling.

NIMH Treatment of Depression Collaborative Research Program. Background and research plan.

The National Institute of Mental Health (NIMH) Treatment of Depression Collaborative Research Program (TDCRP) is the first multisite coordinated study initiated by the NIMH in the field of psychotherapy research. Three research sites, using an identical research protocol, are investigating the effectiveness of two forms of brief psychotherapy (cognitive behavior therapy and interpersonal psychotherapy) in the treatment of outpatient depression. Three training sites have trained experienced therapists in a standard fashion for each of the psychotherapies and the comparison pharmacotherapy conditions. This report presents the background of the TDCRP, the rationale for the choice of patient population and treatment conditions, and the research plan for both the training/pilot phase and the outcome study currently in progress, and discusses the potential contributions of the program to the field of psychotherapy research.

Specific vs nonspecific factors in psychotherapy. A controlled study of outcome.

This study explored the relative contribution of the therapist's technical skills and the qualities inherent in any good human relationship to outcome in time-limited individual psychotherapy. Highly experienced psychotherapists treated 15 patients drawn from a relatively homogeneous patient population (male college students, selected primarily on the basis of elevations on the depression, anxiety, and social introversion scales of the Minnesota Multiphasic Personality Inventory). By traditional diagnostic categories, they would be classified as neurotic depression or anxiety reactions. Obsessional trends and borderline personalities were common. A comparable patient group was treated by college professors chosen for their ability to form understanding relationships. Patients treated by professors showed, on the average, as much improvement as patients treated by professional therapists. Treated groups slightly exceeded the controls. Group means, however, obscured considerable individual variability.