Hidden perils of automation and its effect on error reduction.
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Artificial Intelligence↗
Biomedical subjects
R M Macklis
Publications and source records attributed to R M Macklis.
Brief courses of palliative radiotherapy for metastatic bone pain: a pilot cost-minimization comparison with narcotic analgesics.
The use of radiotherapy to treat metastatic bone pain is being challenged by claims of high cost and by more readily available, noninvasive treatment approaches. The authors assessed the effectiveness of brief courses of radiotherapy in reducing pain and estimated cost data for a pilot comparison between radiotherapy and narcotic analgesics in patients with cancer. A representative group of outpatients undergoing brief courses of radiotherapy with Karnofsky scores above 70 and without serious comorbidities were recruited from 1995 through 1996. Patients indicated their pain at rest and with movement on a scale of from 1 to 10 both before and up to 12 months after radiotherapy. Radiotherapy costs were estimated from Medicare-allowable charges. Narcotic analgesia costs were estimated from published values. In 66 patients with 131 individually treated sites, median at rest pain score decreased by about 4 points after treatment (5.58 [-/+3.28] before treatment vs. 1.55 [-/+1.8] after treatment; p < 0.05). Median with movement pain score was about 5 points lower after treatment (7.32 [-/+2.72] before treatment vs. 1.94 [-/+2.07] after treatment; p < 0.05). No differences were found when stratifying by type of pain, tumor histologic type, or skeletal site. The estimated cost per patient ranged from $1,200 to $2,500 for radiotherapy. This compares with an estimated cost of $9,000 to $36,000 for 9 months of narcotics. In this pilot study, a brief course of radiotherapy significantly reduced pain and appeared to be cost effective when compared with narcotic analgesia. A full economic evaluation is warranted.
Aged↗
Error rates in clinical radiotherapy.
PURPOSE: Error rates in clinical oncology are undergoing increasing scrutiny. The purpose of this study was to understand error frequency, error patterns, underlying causal links, consequences, and possible prevention strategies in clinical radiotherapy. PATIENTS AND METHODS: Treatment information, self-reported error documentation, and retrospective analyses of electronic treatment verification transcripts for 1,925 consecutive patients treated with a total of 93,332 individual radiotherapy fields were reviewed and analyzed. RESULTS: A total of 59 separate errors that affected 168 individual treatment fields were detected, which yielded a crude radiation delivery error rate of 0.18%. All 59 errors were judged to be level I (negligible chance of adverse medical outcome) with the most common error category being a minor treatment field block misplacement. A comprehensive quality assurance program and an electronic record-and-verify linear accelerator interlock system seem to have prevented the occurrence of many additional errors. However, nine of the 59 errors were directly related to the use of this system and generally involved the transposition of similar numbers within series of treatment coordinate data-sets. Overall, radiotherapy error rates favorably compare with reported error rates for pharmaceutical administration in large tertiary care hospitals. CONCLUSION: When modern automated error-minimization methods are used along with nonpunitive error reporting systems, clinical radiotherapy seems to be highly safe. Formal error analysis studies may allow the rational design of prevention strategies that are attuned to the frequency, seriousness, and antecedent causes of many classes of potential radiotherapy errors.
Humans↗
Effective targeting of magnetic radioactive 90Y-microspheres to tumor cells by an externally applied magnetic field. Preliminary in vitro and in vivo results.
Magnetic biodegradable poly(lactic acid) microspheres that incorporate both magnetite and the beta-emitter 90Y were prepared. By applying a directional external magnetic field gradient in excess of 0.02 Tesla/cm across a 96-well plate containing neuroblastoma cells incubated with the 90Y magnetite loaded microspheres, the radiation dose to the cells could be enhanced or reduced relative to the dose from a uniform loading of the well with 90Y-DTPA. Using the MTT assay, cell survival was measured for the magnetic field directed from above (cell sparing) and from below (cell targeting) the well plate, resulting in 65 +/- 8% or 18 +/- 5% survival respectively. This method was then applied to an in vivo murine tumor model. The biodistribution of intraperitoneally injected magnetic radioactive microspheres, after 24 h in mice, showed that 73 +/- 32% of the radioactivity was found on the subcutaneous tumor that had a rare earth magnet fixed above it. In contrast, the tumor radioactivity with no attached magnet was 6 +/- 4%. Magnetically targeted radiopolymers such as 90Y-microspheres show great promise for regional or intracavitary radiotherapy.
Animals↗
The spatial accuracy of cellular dose estimates obtained from 3D reconstructed serial tissue autoradiographs.
In order to better predict and understand the effects of radiopharmaceuticals used for therapy, it is necessary to determine more accurately the radiation absorbed dose to cells in tissue. Using thin-section autoradiography, the spatial distribution of sources relative to the cells can be obtained from a single section with micrometre resolution. By collecting and analysing serial sections, the 3D microscopic distribution of radionuclide relative to the cellular histology, and therefore the dose rate distribution, can be established. In this paper, a method of 3D reconstruction of serial sections is proposed, and measurements are reported of (i) the accuracy and reproducibility of quantitative autoradiography and (ii) the spatial precision with which tissue features from one section can be related to adjacent sections. Uncertainties in the activity determination for the specimen result from activity losses during tissue processing (4-11%), and the variation of grain count per unit activity between batches of serial sections (6-25%). Correlation of the section activity to grain count densities showed deviations ranging from 6-34%. The spatial alignment uncertainties were assessed using nylon fibre fiduciary markers incorporated into the tissue block, and compared to those for alignment based on internal tissue landmarks. The standard deviation for the variation in nylon fibre fiduciary alignment was measured to be 41 microns cm-1, compared to 69 microns cm-1 when internal tissue histology landmarks were used. In addition, tissue shrinkage during histological processing of up to 10% was observed. The implications of these measured activity and spatial distribution uncertainties upon the estimate of cellular dose rate distribution depends upon the range of the radiation emissions. For long-range beta particles, uncertainties in both the activity and spatial distribution translate linearly to the uncertainty in dose rate of < 15%. For short-range emitters (< 100 microns), such as alpha particle sources, the magnitude of the uncertainty in serial section alignment is comparable with the particle track length. Under these circumstances, dosimetric errors are introduced in proportion to the serial section alignment inaccuracy.
Animals↗
The palliative role of radiotherapy in the management of the cancer patient.
Radiotherapy (RT) plays a major role in the palliation of cancer symptoms. Cancer-related bone pain, bronchial obstruction, superior vena cava syndrome, spinal cord compression, and central neurologic dysfunction due to brain metastases are all treated effectively and safely by RT. Although numerous techniques and radiation dose fractionation schemes are used in practice, substantial palliation often may be accomplished by just two to 10 appropriately targeted treatments. Thus, palliative RT regimens need not be highly protracted to be effective. Several new techniques, including strontium 89 radiopharmaceutical therapy, high-dose-rate endobronchial brachytherapy, and stereotactic radiosurgery, are now being evaluated in clinical trials to determine their efficacy in the relief of various oncologic symptoms. Palliative RT continues to be a mainstay of treatment in the management of cancer patients with advanced disease.
Bone Neoplasms↗
Modulation of radiation-induced apoptosis and G2/M block in murine T-lymphoma cells.
Radiation-induced apoptosis in lymphocyte-derived cell lines is characterized by endonucleolytic cleavage of cellular DNA within hours after radiation exposure. We have studied this phenomenon qualitatively (DNA gel electrophoresis) and quantitatively (diphenylamine reagent assay) in murine EL4 T-lymphoma cells exposed to 137Cs gamma irradiation. Fragmentation was discernible within 18-24 h after exposure. It increased with time and dose and reached a plateau after 8 Gy of gamma radiation. We studied the effect of several pharmacological agents on the radiation-induced G2/M block and DNA fragmentation. The agents which reduced the radiation-induced G2/M-phase arrest (caffeine, theobromine, theophylline and 2-aminopurine) enhanced the degree of DNA fragmentation at 24 h. In contrast, the agents which sustained the radiation-induced G2/M-phase arrest (TPA, DBcAMP, IBMX and 3-aminobenzamide) inhibited the DNA fragmentation at 24 h. These studies on EL4 lymphoma cells are consistent with the hypothesis that cells with radiation-induced genetic damage are eliminated by apoptosis subsequent to a G2/M block. Furthermore, it may be possible to modulate the process of radiation-induced apoptosis in lymphoma cells with pharmacological agents that modify the radiation-induced G2/M block, and to use this effect in the treatment of patients with malignant disease.
2-Aminopurine↗
Radiobiologic studies of low-dose-rate 90Y-lymphoma therapy.
BACKGROUND: Radioimmunotherapy and other forms of biologically targeted radiopharmaceutic treatment appear to show unexpected efficacy in many patients with lymphoma, neuroblastoma, and several other types of nonepithelial malignancies. The radiobiologic mechanisms responsible for this high clinical radioresponsiveness are unclear, but must involve some sort of cytotoxic enhancement or sensitization to protracted courses of low-dose-rate radiation exposure. MATERIALS AND METHODS: A series of in vitro experiments was performed with malignant lymphoma cell lines exposed under various conditions to high-dose-rate external beam radiotherapy or low-dose-rate 90Y radiation. Data were collected on cell cycle effects, DNA fragmentation, and modulation of cytotoxicity by caffeine and treatment sequence alterations. RESULTS: The data showed that some malignant lymphoma lines are highly sensitive to low-dose-rate radiation and that a portion of the cytotoxicity appears to be mediated by the induction of radiation-associated apoptosis (programmed cell death). Cell cycle effects of low-dose-rate radiation (such as G2M block) appear to be relatively minor in this experimental system. Agents that modulate apoptosis (such as the calcium-releasing agent caffeine) significantly enhance cell kill and DNA fragmentation after 90Y treatment. CONCLUSIONS: These results suggest that radiation-associated apoptosis may be important in the radiobiology of targeted radiopharmaceutical therapy.
Animals↗
Magnetically directed poly(lactic acid) 90Y-microspheres: novel agents for targeted intracavitary radiotherapy.
High energy beta-emitting radioisotopes like Yttrium-90 have a radiotoxic range of about one centimeter. For cancer treatment they must be brought near the tumor cells and kept there for as long as they are radioactive. We developed as carriers for the ionic form of 90Y a matrix-type polymeric drug delivery system, poly(lactic acid) (PLA) microspheres. This radiopharmaceutical could be selectively delivered to the target site after incorporating 10% Fe3O4 (magnetite) which made the magnetic microspheres (MMS) responsive to an external magnetic field. Furthermore, MMS are biodegradable and slowly hydrolyze into physiologic lactic acid after the radioactivity is completely decayed. Previously prepared 10-40 microns MMS were radiochemically loaded to high specific activity with 90Y at a pH of 5.7. Stability studies showed that approximately 95% of added 90Y is retained within the PLA matrix after 28 days (> 10 half-lives) at 37 degrees C in serum, and electron microscopy showed that the microspheres retained their characteristic morphologic appearance for the same time period. Cytotoxicity studies with SK-N-SH neuroblastoma cells growing in monolayer showed that the radiocytotoxicity of the microspheres could be directed magnetically to either kill or spare specific cell populations, thus making them of great interest for targeted intracavitary tumor therapy. We are currently optimizing this system for use in the treatment of neoplastic meningitis.
Animals↗
Recent experience with Wilms' tumor: 1978-1991.
BACKGROUND: The treatment of Wilms' tumor has undergone major advances in the past four decades. Current therapy is based on both the stage and pathology of the tumor. We have reviewed our recent experience with this tumor to assess the results of treatment on protocols that generally avoid the use of doxorubicin. METHODS: Between January 1978 and December 1991 we treated 114 children with renal tumors. Ninety-one (80%) had favorable histology Wilms' tumor and 23 (20%), unfavorable histology tumors (13 anaplastic Wilms' tumors, four clear cell tumors of the kidney, and six sarcomatous tumors with rhabdoid elements). Chemotherapy was divided into two eras: 1978-1982 (vincristine and actinomycin-D) and 1983-1991 [vincristine and actinomycin-D for all patients, and cyclophosphamide for those with favorable histology and metastatic disease (n = 13) and all patients with anaplastic histology (n = 13)]. Four patients with clear cell or rhabdoid/sarcomatous tumor, three of whom are disease-free, were treated with a five-drug regimen (vincristine, doxorubin, cyclophosphamide, platinum, and VP-16). Approximately two thirds of the patients received megavoltage radiotherapy to the tumor bed. Mean abdominal radiation doses from 1978 to 1982 were slightly higher than those used from 1983 to 1991 (2,597 +/- 782 cGy vs. 2,039 +/- 524 cGy, respectively). RESULTS: No isolated local failures were observed in any favorable histology patient who received radiotherapy. Among the 91 patients with favorable histology, there was no statistically significant difference in event-free survival irrespective of stage. Outcome for patients with anaplastic or clear cell variants was not different from that for those patients with favorable histology, but there were only small numbers in these groups for comparison. Only children with a rhabdoid/sarcomatous variant demonstrated survival that was different from all others (p = 0.00). Our previously reported patients with stage I tumors (< 550 g) (n = 11) who were treated by nephrectomy only continue to have an excellent outcome (survival 100%). CONCLUSIONS: Wilms' tumors remain highly curable. Some unfavorable histology tumors require intensive therapy. Others such as our stage I tumors may be best observed without adjuvant therapy to avoid the toxicity of treatment.
Child↗
Image analysis for the study of radionuclide distribution in tissue sections.
UNLABELLED: Tissue section autoradiographs are often prepared to review the precise spatial locations of a radiolabeled molecule relative to cells, such as in the study of radiolabeled antibody distribution. The objective of this work was to develop and evaluate a method to automatically detect both grains and cell nuclei from stained tissue autoradiographs using a microscope and an image analyzer. METHOD: Using a sequence of morphological image operations, the densely stained regions of the section, representing the cell nuclei are identified first, and then subtracted from the original image. This enables the identification of autoradiographic grains under conditions of variable contrast, by separation of the grains overlapping the cell nuclei from the extracellular spaces, permitting a more accurate and robust automatic segmentation routine. RESULTS: The accuracy of the method to detect grains has been evaluated at different threshold levels. The highest accuracy obtained was approximately 90%. The accuracy in the detection of cell nuclei was histology-dependent. As examples, we have estimated accuracies of approximately: 86%, 81% and 77% for kidney, EL-4 lymphoma and pneumonocyte sections, respectively. CONCLUSION: This method was tested using specimens designed to study radiolabeled antibody distribution, but it should be applicable with comparable accuracy to other radiolabeled compounds for which quantitative information on the heterogeneity of distribution is required.
Animals↗
Cell cycle alterations, apoptosis, and response to low-dose-rate radioimmunotherapy in lymphoma cells.
PURPOSE: In an attempt to elucidate some aspects of the radiobiological basis of radioimmunotherapy, we have evaluated the in vitro cellular response patterns for malignant lymphoma cell lines exposed to high- and low-dose-rate radiation administered within the physiological context of antibody cell-surface binding. METHODS AND MATERIALS: We used two different malignant lymphoma cell lines, a Thy1.2+ murine T-lymphoma line called EL-4 and a CD20+ human B-lymphoma line called Raji. Cells were grown in suspension cultures and exposed to high-dose-rate gamma radiation from an external 137Cs source or low-dose-rate beta radiation from DTPA-solubilized 90Y in solution. In some experiments, cells were pre-incubated with an excess of nonradioactive antibody in order to assess the effects of immunoglobulin surface binding during radiation exposure. Irradiated cells were evaluated for viability, cell-cycle changes, patterns of post-radiation morphologic changes, and biochemical hallmarks of radiation-associated necrosis and programmed cell death. RESULTS: The EL-4 line was sensitive to both high-dose-rate and low-dose-rate irradiation, while the Raji showed efficient cell kill only after high-dose-rate irradiation. Studies of radiation-induced cell cycle changes demonstrated that both cell lines were efficiently blocked at the G2/M interface by high-dose-rate irradiation, with the Raji cells appearing somewhat more susceptible than the EL-4 cells to low-dose-rate radiation-induced G2/M block. Electron microscopy and DNA gel electrophoresis studies showed that a significant proportion of the EL-4 cells appeared to be dying by radiation-induced programmed cell death (apoptosis) while the Raji cells appeared to be dying primarily by classical radiation-induced cellular necrosis. CONCLUSION: We propose that the unusual clinical responsiveness of some high and low grade lymphomas to modest doses of low-dose-rate radioimmunotherapy may be explained in part by the induction of apoptosis. The unusual dose-response characteristics observed in some experimental models of radiation-induced apoptosis may require a reappraisal of standard linear quadratic and alpha/beta algorithms used to predict target tissue cytoreduction after radioimmunotherapy.
Animals↗
Magnetic healing, quackery, and the debate about the health effects of electromagnetic fields.
Although the biological effects of low-frequency electromagnetic radiation have been studied since the time of Paracelsus, there is still no consensus on whether these effects are physiologically significant. The recent discovery of deposits of magnetite within the human brain as well as recent, highly publicized tort litigation charging adverse effects after exposure to magnetic fields has rekindled the debate. New data suggest that electromagnetic radiation generated from power lines may lead to physiologic effects with potentially dangerous results. Whether these effects are important enough to produce major epidemiologic consequences remains to be established. The assumption of quackery that has attended this subject since the time of Mesmer's original "animal magnetism" investigations continues to hamper efforts to compile a reliable data base on the health effects of electromagnetic fields.
Adult↗
G2M arrest and apoptosis in murine T lymphoma cells following exposure to 212Bi alpha particle irradiation.
Asynchronous exponentially growing EL4 murine T lymphoma cells were exposed either to high LET alpha-radiation from 212Bi-DTPA or to gamma-radiation from a 137Cs source. Radiation-induced cell cycle perturbation was studied by flow cytometry. Alpha irradiation, like gamma, transiently arrested cells in the G2M phase in a dose-dependent manner. The maximum percentages of cells accumulated in G2M 18 h after alpha- and gamma-irradiation were comparable, though the dose-response relationships differed. The "RBE" value for G2M block for alpha- versus gamma-radiation was approx. 4. Electron microscopic studies of the cell samples where a large proportion of cells were arrested in G2M showed subcellular changes in nuclear membrane and the presence of morphologically apoptotic cells. Biochemical analysis of DNA from irradiated cells by agarose gel electrophoresis revealed more extensive DNA fragmentation for alpha- vs gamma-irradiation, even at relatively low total doses. We conclude that the high LET radiation is more efficient in inducing G2M block and apoptosis in EL4 lymphoma cells. The overall radiosensitivity of some high and low grade malignant lymphoma cells to radiation may correlate with these processes. The clinical implications of 212Bi-induced G2M delay may be particularly important for biologically targeted high LET radiopharmaceutical therapy.
Alpha Particles↗
Posterior mediastinal masses.
Solid mediastinal masses in infancy and childhood occur most frequently in the posterior mediastinum. From 1972 to 1989, 63 patients presented with a posterior mediastinal mass. The median age at diagnosis was 6 years (range, 1 day to 26 years). Thirty patients were female. Forty-five percent of the patients presented with respiratory symptoms or chest pain; 13% had neurologic symptoms, one half of which were related to spinal cord compression; and 5% had a palpable mass. In 32% of patients the mass was an incidental finding. The tumors were of neurogenic origin in 89% of patients, of which neuroblastoma was the most common. Of all patients with posterior mediastinal masses, 60% had malignant tumors. Median follow-up for 62 of 63 evaluable patients was 45 months (range, 1 to 289 months). One patient was lost to follow-up. Of the 62 patients followed, 84% are alive and free of disease. All but 4 of the 32 patients with neuroblastoma are alive and free of disease with a median follow-up of 73 months (range, 7 to 289 months). Patients with neuroblastoma who were diagnosed in the first year of life had a significantly better survival pattern than those presenting after the first year. There were seven deaths in the series: four from neuroblastoma, two from primitive neuroectodermal tumor, and one from malignant schwannoma. Preoperative diagnostic evaluation of a posterior mediastinal mass should include posteroanterior and lateral chest roentgenograms, and either CT or MRI of the chest and abdomen to assess the extent of the mass.(ABSTRACT TRUNCATED AT 250 WORDS)
Adolescent↗
The great radium scandal.
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History, 20th Century↗
Stage III neuroblastoma over 1 year of age at diagnosis: improved survival with intensive multimodality therapy including multiple alkylating agents.
PURPOSE: A nonrandomized, single-arm trial was conducted to assess the efficacy of multimodality therapy including intensive chemotherapy with multiple alkylating agents in the treatment of children with Evans stage III neuroblastoma older than 1 year at diagnosis. PATIENTS AND METHODS: Twenty-five patients with a median age of 18 months at diagnosis were treated with multimodality therapy including surgery and chemotherapy using either nitrogen mustard (mechlorethamine), doxorubicin, cisplatin, dacarbazine (DTIC), vincristine, and cyclophosphamide (MADDOC) or cisplatin and cyclophosphamide induction followed by maintenance MADDOC (induction MADDOC) protocols. Sixteen of 25 patients also received radiotherapy to the tumor bed and primary lymph nodes. Event-free survival (EFS) was compared with that reported previously in the literature. N-myc amplification was evaluated prospectively and the Shimada classification was evaluated retrospectively as potential prognostic factors. RESULTS: We report a 72% EFS (95% confidence interval +/- 18%) with a median follow-up of 85 months. EFS was significantly worse for patients with tumors demonstrating N-myc amplification (P = .018). Patients classified as favorable according to the Shimada system experienced a significantly better EFS (P = .04), but unfavorable patients still maintained a 60% EFS. CONCLUSION: Intensive multimodality treatment including MADDOC and induction MADDOC chemotherapy provides a very good EFS for children older than 1 year who have stage III neuroblastoma. Children classified as favorable according to the Shimada system have a better prognosis. Patients whose tumors demonstrate N-myc amplification have a poor prognosis despite therapy.
Alkylating Agents↗
An update of pediatric radiation oncology.
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Chemotherapy, Adjuvant↗