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Colony-forming ability after exposure to ionizing irradiation was compared for proliferating hormone response MCF-7 breast carcinoma cells and cells whose growth was inhibited by tamoxifen or 17B-estradiol. As compared with controls (Do = 1.20 Gy, n = 3.1), cells in 1 microM or 5 microM tamoxifen were less radiosensitive (Do = 1.20 Gy, n = 7.0; Do = 1.22 Gy, n = 7.0, respectively) with the predominant effect being a widened shoulder on the survival curve. This protective effect could be abolished by co-incubation of 5 microM tamoxifen with 100 nM 17B-estradiol (Do = 1.30 Gy, n = 2.6; Do = 1.20 Gy, n = 2.6, respectively). The decrease in radiosensitivity induced by tamoxifen was similar to that seen when replating of irradiated plateau-phase cultures was delayed for 24 h (Do = 1.30 Gy, n = 6.0). In contrast, when proliferation of MCF-7 cultures was inhibited by 10 microM 17B-estradiol, radiosensitivity was increased with a markedly diminished survival curve shoulder (Do = 1.40 Gy, n = 1.0). Different hormonal manipulations of cycling human breast carcinoma cells may have profound but disparate effects on radiosensitivity such that tamoxifen and estrogens may serve as useful agents with which to study the biochemical mechanisms of repair.

The approach to these lesions is being reexamined in light of results with conservative surgery for invasive breast cancers. According to available data, the invasive potential of in situ lesions varies. Mammographic and pathologic findings may differentiate patients who will benefit from lumpectomy (with or without radiotherapy) from those requiring mastectomy.

The dopaminergic properties of metoclopramide and four of its metabolites were determined in a series of in vivo and in vitro tests. In vivo measures included changes in dopamine turnover, serum prolactin levels and antagonism of apomorphine-induced stereotyped behavior. In each of these tests the four metabolites were either completely inactive or significantly less potent than the parent compound. The potency of metoclopramide and its metabolites in in vitro dopamine/neuroleptic receptor models was compared to the potency of standard reference compounds. In vitro results indicate that none of the four metabolites tested had antagonist activity in any of the receptor models in which they were evaluated. These findings will be discussed in light of the current understanding of receptor models as they relate to antipsychotic efficacy.

Metoclopramide is a dopamine (DA) antagonist with a potency and pharmacologic profile similar to chlorpromazine, but is paradoxical insofar as it is virtually inactive as an antagonist of DA-stimulated adenylate cyclase and has an extremely low affinity for DA/neuroleptic binding sites in membranes prepared from DA-rich brain regions. Chronic administration of metoclopramide to rats induced behavioral supersensitivity to apomorphine which was associated with enhanced specific binding of 3 H-spiroperidol to striatal membranes. These changes were seen when metoclopramide was administered to rats in their drinking water for 39 days, but not when it was given i.p. once daily for 14 days. These findings are discussed in terms of their implications regarding the validity of currently used receptor models as predictors of DA antagonism as well as the implicit assumption that DA/neuroleptic binding sites truly represent functionally relevant DA receptors.

Background Two randomized intraoperative radiation therapy trials for early-stage breast cancer were recently published. The ELIOT Trial used electrons (IOERT), and the TARGIT-A Trial Update used 50-kV X-rays (IORT). These studies were compared for similarities and differences. The results were analyzed and used to determine which patients might be suitable for single-dose treatment. Methods The primary sources of data were the ELIOT Trial and TARGIT-A Trial, as well as a comprehensive analysis of the peer-reviewed literature of accelerated partial breast irradiation (APBI) using 50-kV X-rays or electrons. Studies published or presented prior to March 2014 were analyzed for efficacy, patient restrictions, complications, and outcome. Results With a median follow-up of 5.8 years, the 5-year recurrence rates for ELIOT versus EBRT patients were 4.4 and 0.4 %, respectively, p = 0.0001. A low-risk ELIOT group was identified with a 5-year recurrence rate of 1.5 %. With a median follow-up of 29 months, the 5-year recurrence rates for the TARGIT-A versus EBRT patients were 3.3 and 1.3 %, respectively, p = 0.042. Conclusions With 5.8 years of median follow-up, IOERT appears to have a subset of low risk women for whom IOERT is acceptable. With 29 months of median follow-up the results of IORT with 50-kV devices are promising, but longer follow-up data are required. At the current time, single-fraction IOERT or IORT patients should be treated under strict institutional protocols.

Allogeneic bone marrow transplantation (BMT) has become the treatment of choice for patients of appropriate age with chronic myeloid leukemia (CML). In an attempt to enhance tumor cytoreduction, splenic radiation therapy (RT) has been done before the allogeneic transplant, but the role of splenic RT in this setting remains controversial. The purpose of this study is to evaluate the role of splenic RT before allogeneic BMT in patients with CML. Thirty-seven patients with chronic (n=33) or accelerated (n=4) phase CML underwent BMT from April 1990 to January 1998. All patients received splenic RT consisting of 500 cGy in five daily fractions (n=36) or 250 cGy in five daily fractions (n=1) completed within 10 days before BMT. The conditioning regimen included total-body irradiation and cyclophosphamide; etoposide was added to the regimen of patients in the accelerated phase. Continuous-infusion cyclosporine and pulse methotrexate were administered to all patients for prophylaxis of graft-vs.-host disease (GVHD). All patients achieved hematologic and cytogenetic remission. At a median follow-up of 37 months, the freedom from progression (FFP) and overall survival (OS) were 90 and 82%, respectively. None of the patients in accelerated phase have relapsed. Five patients have died of late transplant-related complications while in complete remission. Acute GVHD of grade > or=II was observed in 20% (14% grade II, 6% grade III). Fifty-one percent of patients developed limited chronic GVHD. The median posttransplant creatinine level was 1.2 mg/dL (range 0.6-4.2). Renal dysfunction, manifested as a persistent elevation in serum creatinine level (> 1.2 mg/dL), was observed in 40% of the patients. Only 8.5% had a creatinine level > 2.0 mg/dL, and no patient required dialysis as a result of renal dysfunction. Seven patients (18.9%) developed pulmonary complications, which included idiopathic interstitial pneumonitis (two), biopsy-proven interstitial fibrosis (four), and alveolar hemorrhage (one). The low relapse rate observed in this study may reflect the use of splenic RT as a part of the cytoreductive regimen before BMT. The fractionation schedule of 500 cGy in five daily fractions was well tolerated and did not appear to increase the toxicity of the preparative regimen. These favorable results indicate that splenic RT deserves further investigation and may be of benefit as a part of the conditioning regimen for patients receiving allogeneic BMT for CML. Biol Blood Marrow Transplant 1999;5(3):173-9.

Plasma samples from individuals treated with equivalent doses of metoclopramide or thioridazine were tested for their potency in the radioreceptor assay. Samples of plasma from patients treated with thioridazine actively displaced 3H-spiroperidol from striatal membranes, while plasma from patients treated with metoclopramide were virtually inactive. The lack of activity in the radioreceptor assay is of particular interest as the concentration of metoclopramide determined by gas chromatography, in the same plasma samples, indicates a mean value of 1,102 ng/ml.

Irregularly shaped tumors of the nasopharynx require the capacity to design flexible and reproducible treatment plans for high-dose boost irradiation. We use a variety of external beam techniques which may be combined with an afterloading intracavitary implant. Careful planning of such treatment is crucial and requires an accurate assessment of tumor volume and regional anatomy as defined by lateral simulator films, computed tomography, and magnetic resonance imaging scans. External beam irradiation is performed using a variety of arc rotations or fixed-beam cross-fire techniques in order to maximize the dose to an irregular tumor volume while minimizing irradiation of sensitive neighboring structures. Intracavitary implantation is achieved by constructing a mold of the nasopharynx with a silastic polymer and fitting it with hollow plastic catheters for afterloading with iridium-192.

Synaptosomes from rat cerebral cortex incubated with 3H-S-adenosyl-L-methionine (3H-SAM) displayed an increase in chloroform- extractable tritium when norepinephrine was added to the reaction mixture. The products of this mixture were maximally generated from intact synaptosomes, only partially inhibited by propranolol, and not enhanced by exogenous phospholipids. Thin layer chromatographic analysis of these chloroform extracts in three solvent systems yielded large norepinephrine- stimulated peaks of radioactivity that did not consistently co-chromatograph with authentic methylated phospholipid standards: phosphatidylmonomethylethanolamine (PME), phosphatidyldimethylethanolamine (PDE), and phosphatidylcholine (PC). Further, attempts to identify these peaks of radio-activity using as standards several putative methylated products of varied chemical classes, failed to elucidate likely candidates. It appears that while norepinephrine markedly stimulates the amount of tritium extracted into the chloroform phase, careful and positive structural elucidation of formed products is required before it can be concluded that these are indeed methylated phospholipids.

To evaluate the relative utility of interstitial implant as a technique for tumor bed dose escalation and assess technical factors related to outcome.From 1982-1994, a prospectively applied institutional policy of margin-directed boost dose escalation to the tumor bed was followed whereby interstitial implantation was commonly employed for a final margin status (FMS)or = 2 mm. There were 509 treated breasts, of which 127 received an implant boost. For purposes of comparison, cases were broadly classed as "implant" (all FMSor = 2 mm) and "nonimplant" (FMSor = 2 mm or FMS2 mm). The implant target volume was determined at completion of whole breast irradiation by clinical assessment. All implants were constructed in accordance with a preplanning algorithm designed to maximize dose homogeneity within a prescription isodose goal of 0.50 Gy/h for 40 h. Local control and cosmetic outcome were evaluated with respect to extent of tumor, histopathology, FMS, extent of surgery, and systemic adjuvant therapy. Implant quality was assessed using four calculated parameters: strand separation quotient (SSQ), planar separation quotient (PSQ), global separation quotient (GSQ), and dose homogeneity index (DHI). The mean implant volume was 48.3 +/- 20 cc, the mean prescribed dose rate was 0.46 +/- 0.08 Gy/h, and the mean total implant dose was 19.94 +/- 1.52 Gy.Cosmetic outcome was good/excellent in 90% of implant and 83% of all nonimplant cases, which was not statistically different. Cosmesis was significantly superior with implant when compared to nonimplant cases receiving an external boost of 20 Gy. Logistic regression analyses of implant cases revealed that reexcision volume and decreased DHI were associated with adverse cosmesis. There were 10 local failures in the implanted patients (4 within the prescribed isodose volume, 5 at the periphery, and 1 elsewhere in the breast). The local failure rate at 5 and 7 years in the implanted group was 3.9 and 9.0%, respectively, compared to nonimplant cases with a marginor = 2 mm of 3.2 and 3.2%, respectively. These differences were not significant. The crude local failure rate in patients with an associated DCIS component was 12% a compared to 3% in patients with pure invasive histology (p = 0.06). A proportional hazards survival model revealed a significant association of local failure with the performance of a reexcision and young age.We conclude that interstitial implant boost for breast conserving irradiation is associated with cosmesis that is superior than the same nominal dose of external beam boost, although this is highly dependent upon the technical quality of the source position and the relative uniformity of dose deposition. Breast implantation results in a rate of local control no better than dose-matched external beam boost in patients with a final marginor = 2 mm. Local control with implantation might be further enhanced by increasing implant volume and/or improved target localization.

[3H]Quinuclidinyl benzilate and [3H]spiperone binding to murine lymphocytes is displaceable but differs from binding to brain receptor sites for these ligands: (1) binding to intact lymphocyte preparations was not saturable; (2) disruption of intact lymphocytes was associated with a marked loss of displaceable ligand binding; (3) drugs differentially displace these ligands in lymphocytes compared to brain. Displaceable binding was increased following incubation of lymphocytes under phospholipid methylating conditions; however, marked effects on cell viability and cell recovery make it difficult to interpret these binding changes. If dopaminergic and cholinergic receptors do exist on lymphocytes, their binding characteristics are profoundly different from comparable ens receptors.

When quaternary-chlorpromazine (Q-CPZ) was administered intraventricularly (ICV) to rats, it induced a lateralized dystonic reaction, which progressed to head-to-tail barrel rolling. The syndrome persisted for approximately 10 minutes, was not antagonized by pretreatment with drugs used to treat extrapyramidal movement disorders, and could not be mimicked by ICV administration of dopamine antagonists. Unlike known dopamine antagonists, Q-CPZ does not alter dopamine turnover, cause prolactin release in vivo, or bind to dopamine/neuroleptic receptors in vitro. These data suggest that Q-CPZ differs substantially from CPZ in pharmacologic action, and that it elicits a behavioral syndrome of potential use for studying dystonias.

Biol Blood Marrow Transplant 2000;6(2A):213.