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Biomedical subjects

L S Constine

Publications and source records attributed to L S Constine.

54 records · Page 3Linked to original sources
PubMed1990

Efficacy and toxicity of 12 courses of ABVD chemotherapy followed by low-dose regional radiation in advanced Hodgkin's disease in children: a report from the Children's Cancer Study Group.

Sixty-four patients aged 2 to 18 years with advanced-stage Hodgkin's disease (HD) were treated on a Children's Cancer Study Group (CCSG) pilot toxicity study (521-P). Therapy consisted of 12 courses of Adriamycin (doxorubicin; Adria Laboratories, Columbus, OH), bleomycin, vinblastine, and dacarbazine (ABVD), followed by low-dose (2,100 cGy in 12 fractions) regional irradiation (RT). All patients were monitored for toxicity with particular attention to the pulmonary system. Six patients (9%) developed grade 3 or 4 pulmonary toxicity. Three had grade 3 toxicity based solely on changes in carbon monoxide diffusing capacity (DLCO) and remained well for more than 3 years after diagnosis. There was one fatality among the three symptomatic cases. In five cases, toxicity occurred prior to RT. One occurred after seven courses of ABVD, one after nine courses, and three after 10 courses. In one of these five cases, ABVD was stopped. The patient was given nitrogen mustard (mechlorethamine), vincristine, prednisone, and procarbazine (MOPP). This patient subsequently developed recurrence of HD and died of overwhelming sepsis. The other four continued on study and completed their chemotherapy. Three patients had no further bleomycin, and one continued bleomycin at 50% of the assigned dose. They all received mantle RT following chemotherapy, one with a boost dose to the mediastinum to 3,800 cGy and one with added RT to both lungs (1,050 cGy). In the sixth case of pulmonary toxicity, symptoms were first noticed 2 weeks after mantle RT to 3,500 cGy. This patient died of progressive respiratory failure. The event-free survival (EFS) and overall survival is 87% at 3 years. These early results indicate that this therapy is effective in advanced HD in children but has a 9% incidence of acute pulmonary toxicity.

Adolescent↗
PubMed1989

Craniopharyngiomas: fluctuation in cyst size following surgery and radiation therapy.

Patients with craniopharyngiomas who demonstrate cyst enlargement after surgery and radiation are often presumed to be treatment failures. Therapeutic approaches in various centers include repetitive cyst aspirations, surgical reexcision, and installation of cytotoxic agents such as methotrexate, 32P, or 198Au. Each intervention has associated severe or even lethal side effects. Not all patients with craniopharyngioma who have cystic enlargement after primary therapy require an intervention, as demonstrated by 4 patients recently managed in the University of Rochester Medical Center. Since 1978, when computed tomography was routinely in use, we have managed 11 patients with craniopharyngiomas who were treated with surgery followed by radiation therapy. Three of these patients demonstrated post-irradiation enlargement of the residual cystic component followed by a decrease in size without surgical intervention. An additional patient showed cystic growth followed by stabilization of size. It is noteworthy that the cyst enlarged within the first 5 months after radiation therapy in the 3 patients who subsequently demonstrated a diminution in the size of their cysts. This suggests that the mechanism for cyst formation remained intact and subsequently abated because of a radiation-induced lesion. We conclude that after treatment with surgery and radiation therapy, the cystic component of craniopharyngiomas may increase and, without intervention, subsequently decrease in size. Thus, in the asymptomatic patient who demonstrates cystic growth soon after primary therapy, close observation alone may be warranted.

Adolescent↗
PubMed1988

Myelin basic protein and magnetic resonance imaging for diagnosing radiation myelopathy.

The identification of radiation myelopathy using biochemical assays and imaging techniques has not previously been accomplished but has clear clinical application. Measurement of myelin basic protein (MBP) in the cerebrospinal fluid (CSF) and visualization of the spinal cord using magnetic resonance imaging (MRI) gives a potentially accurate diagnosis of radiation myelopathy. Female New Zealand white rabbits were irradiated to the thoracic spinal cord with single doses of 15-45 Gy. Animals receiving higher doses (greater than or equal to 22 Gy) generally demonstrated an early paresis (4-8 weeks) that temporarily improved, and then progressed to complete paralysis by 14-18 weeks. MBP levels in the CSF became strikingly elevated to 100-1000 times the normal value. Subsequent, experiments in which rabbits were serially assessed for MBP levels demonstrated a transient elevation, which corresponded to the transient paresis, followed by dramatic elevations concurrent with the onset of paralysis. Magnetic resonance imaging (MRI) of the irradiated spinal cord showed a geographically distinct region of abnormality that corresponded to the radiation field. Histopathology demonstrated demyelination, focal astrocytosis, erythrodiapedesis, and perineuronal edema in the irradiated sections. It appears that MBP levels in the CSF reflect not only radiation-induced myelopathy but also transient demyelination, and that MRI may have the potential to indicate the region of damage.

Animals↗
PubMed1988

Adverse effects of brain irradiation correlated with MR and CT imaging.

Forty-one patients treated for primary malignancies of the brain at the University of Rochester Cancer Center since 1970 were assessed for adverse effects of irradiation clinically, and by computerized tomography (CT) and magnetic resonance (MR) imaging. At diagnosis, patients ranged in age from 1-65 years (median 19 years) and the most common tumor (in 30) was astrocytoma. Radiation doses ranged from 45 to 81.3 Gy (median 56.8 Gy). White matter changes visible on MR were graded on a scale of 1-4, with grades 1-2 known to occur in some normal patients. Areas of increased signal intensity not associated with the tumor or surgery were visible in all patients (gr 1 = 37%, gr 2 = 32%, gr 3 = 17%, gr 4 = 15%) whereas only 35% had regions of abnormality (hypodensity) on CT. Sulci enlargement and ventricular abnormalities (asymmetry or dilatation) were present in approximately 50% of patients by each technique. Higher grade MR lesions were associated with radiation to large volumes and high doses. For the 36 patients treated with 1.5-2.0 Gy daily fractions, the mean radiation dose by grade was as follows: gr 1 = 55.1 Gy, gr 2 = 58.8 Gy, gr 3 = 60.0 Gy, gr 4 = 63.5 Gy. All 5 patients treated on a hyperfractionated schedule had gr 1-2 changes despite receiving greater than 70 Gy. Fifty percent of patients treated to the whole brain (+/- boost) had gr 3-4 changes, compared with 14% treated with local fields (peak dose regions similar in both groups). Among the children (less than or equal to 13 years), 20% had gr 3-4 changes compared with 56% of adults (excluding hyperfractionated patients). This finding may be due entirely or in part to the lower radiation doses used for children (mean 54.4 Gy vs. 63.7 Gy in adults). Clinical abnormalities attributable to irradiation included an impairment in mental functioning in 7 adults, and learning disabilities in 5 children. Five of these adults (71%) had gr 3-4 changes on MR as compared to gr 3-4 changes in 29% of the remaining adult group. Five patients developed seizure disorders. We conclude that adverse effects of brain irradiation are more sensitively imaged by MR than CT and that these abnormalities are associated with larger treatment volumes and either (or both) higher doses or older age. Conversely, some patients treated with high radiation doses have unremarkable changes on MR, and others have severe white matter changes which are not clinically expressed.(ABSTRACT TRUNCATED AT 400 WORDS)

Astrocytoma↗
PubMed1987

Hyperprolactinemia and hypothyroidism following cytotoxic therapy for central nervous system malignancies.

Endocrinologic dysfunction including hyperprolactinemia and hypothyroidism are recognized complications of irradiation to the hypothalamic-pituitary axis or thyroid gland in the course of treating CNS malignancies. However, the frequency of these adverse effects in both short- and long-term survivors may be underestimated. Sixty-five patients treated in the University of Rochester Cancer Center since 1968 with radiation with or without BCNU chemotherapy for CNS tumors not involving the hypothalamic-pituitary axis were evaluated for thyroid, prolactin, and gonadal disturbances regardless of clinical symptomatology. Prolactin values were elevated in 19 of 47 patients (40%). For males and females treated with greater than 55 Gy, abnormal values were present in nine of 11 (82%) and seven of 14 (50%), respectively. For males and females treated with less than or equal to 55 Gy, two of nine (22%) and one of 13 (8%), respectively, were abnormal (P = .0001). Six of six patients who also received BCNU chemotherapy were hyperprolactinemic, as compared with six of ten (60%) who did not receive BCNU. Seven of eight females with elevated prolactin levels had menstruation abnormalities, and five of seven adult males noted a decrease in libido. Mild abnormalities in testosterone concentration were found in three of nine men evaluated, all of whom had normal gonadotropins. Of 47 patients who did not receive irradiation to the spinal axis (and thus the thyroid gland), ten (21%) had a decreased thyroxin (T4) value. Only one of these patients had an elevated thyroid-stimulating hormone (TSH) value. Of 32 patients who received greater than 55 Gy, ten (31%) had a low T4, compared with zero of 15 who received less than or equal to 55 Gy (P = .0001). Four of eight patients (50%) who also received BCNU had low T4 values, as compared with three of 14 (21%) who did not receive BCNU. Of 15 patients who were treated with 4 to 10 MV photon irradiation to the spinal axis, five patients (33%) had elevated TSH values. The mean spinal axis dose in these patients was 33 Gy. Two euthyroid children in this group manifested the early onset of puberty. The complex of endocrinologic abnormalities observed in several patients receiving only cranial irradiation, that is elevated prolactin, decreased thyroid, and gonadal hormone secretion in the presence of otherwise normal pituitary hormone levels, suggests a radiation-induced insult to the hypothalamic regulation of pituitary function.

Adolescent↗
PubMed1987

The differential protection by WR2721 of skin versus growing cartilage following irradiation in weanling rats.

The potential for radioprotection of growing cartilage by the thiophosphate WR2721 was evaluated in weanling rats using single fractions of irradiation. Protection of acute skin toxicity was monitored simultaneously. Single doses of 600, 1200, 1800, or 2400 cGy were administered to the left tibia of CrL:CD(SD)BR female rats in groups of 12. Identically treated groups were injected with 310 mg/kg WR2721 (2/3 the determined LD50/30) in a concentration of 26 mg/ml intraperitoneally 15 min prior to irradiation. Rats untreated or given WR2721 without radiation served as control groups. Radiographs of the irradiated and unirradiated tibiae for each animal were obtained weekly to the date of sacrifice at 80 days following the initial treatment. Skin toxicity was assessed weekly starting on the second week using Moulder's scale (J.E. Moulder, J.J. Fischer, and A. Casey, Radiology 115, 465-470 (1975]. No significant difference in bone growth as measured by tibial lengths for the WR2721-treated or untreated animals was observed. Skin toxicity including moist desquamation occurred in irradiated limbs and was substantially less in rats treated with WR2721. As opposed to previous work with cysteamine, WR2721 as administered had no significant radioprotective effect on tibial growth in weanling rats but substantially reduced the accompanying skin toxicity.

Amifostine↗
PubMed1986

Protection by WR-2721 of human bone marrow function following irradiation.

Protection by WR-2721 of bone marrow (BM) from depression following hemibody irradiation (HBI) was assessed in patients receiving palliative therapy for widespread symptomatic metastasis on a Phase I/II Radiation Therapy Oncology Group (RTOG) protocol. Twenty-five patients are currently evaluable for the assessment of hematologic toxicity. HBI (600 or 700 cGy) was delivered starting 15-30 min after WR-2721 (600-900 mg/m2) intravenous infusion. Twenty patients from previous RTOG HBI studies were comparable in terms of radiation dose, hematologic data, and previous cytotoxic therapy. The WBC and platelet count nadirs at any time within 6 wk following HBI were used for data analysis, and toxicity was rated according to RTOG criteria. For the patients treated with WR-2721, moderate, severe, or life-threatening toxicity were seen in 16%, 12%, and 0% of the patients, respectively, compared to 30%, 15%, and 10% of patients in the group not treated with WR-2721. For the subpopulation of patients treated with the higher irradiation dose (700 cGy), differences in toxicity appeared to be greater. Conversely, for the sub-population of patients treated only to the upper hemibody, the difference in toxicity was less apparent. The percentage change from the median pre-treatment white blood cell (WBC) and platelet counts (PC) was not different between the WR-2721 treated and non-treated group; however, the median WBC count for the WR-2721 group returned to the pre-treatment value by the fourth week following HBI, whereas, it remained at 61% of the pre-HBI value for the control group. Within the group of patients treated with WR-2721, 5 of 17 (29%) receiving 600 mg/m2 demonstrated a greater than 75% decline in either WBC or platelets, compared to 0/8 patients treated with 750-900 mg/m2. These preliminary data support a protective effect by WR-2721 on radiation-induced bone marrow depression in humans, which may become more apparent with the use of higher radiation and WR-2721 doses.

Amifostine↗
PubMed1986

A monoclonal anti-neuroblastoma antibody that discriminates between human nonhematopoietic and hematopoietic cell types.

A murine IgG2a monoclonal antibody, termed 6-19, was characterized in terms of its ability to bind to human cell lines and tissues. The hybridoma was selected for antibody binding to multiple human neuroblastoma cultured cell lines but not to peripheral blood mononuclear cells. 6-19 binds to the cell surface of all cultured human nonhematopoietic tumor cell lines tested, to cultured human fibroblasts and endothelial cells, and to nonhematopoietic tumors of many types. It does not bind detectably to any hematopoietic cells, leukemia cells, or lymphomas. In the presence of complement, 6-19 is very cytotoxic to cultured human neuroblastoma cells but not to bone marrow granulocyte-macrophage colony-forming cells. The 6-19 monoclonal antibody may prove useful in the identification or destruction of tumor and stromal cells in bone marrow.

Animals↗
PubMed1985

Systemic hemibody irradiation for overt and occult metastases.

Hemibody irradiation was initially employed as a palliative technique to treat diffuse metastatic disease in one session as opposed to multiple fields over an extended period. It provides a radiation treatment for disseminated cancer and therefore has been termed "systemic" therapy. Since it is possible to treat both halves of the body sequentially, it allows radiation treatment to the whole body in larger doses than could be accomplished with total-body irradiation. Because of the success in terms of dramatic rapid pain relief and the objective response on metastatic disease, it has been explored in the treatment of occult disease and as consolidation therapy in patients with tumors that have responded to chemotherapy. When hemibody irradiation is combined with chemotherapy, responses have been shown in metastases for several primaries, particularly small cell carcinoma, which is perhaps the most encouraging, and supports further research in the treatment of micrometastatic disease for this tumor type. As the technique moves from its current research phase into more general clinical use, radiation oncologists should become more familiar with the treatment, and the hospitalization originally required may be able to be avoided. An intensive premedication program has been developed to facilitate this. Innovative approaches using radiosensitizers, radioprotectors, hyperthermia, and hyperfractionation are ideas that are starting to be tested and will be further explored in the near future.

Amifostine↗
PubMed1985

Birth defects in three common pediatric malignancies; Wilms' tumor, neuroblastoma and Ewing's sarcoma.

During the period 1965-1980, 84 patients with Wilms' tumor, neuroblastoma and Ewing's sarcoma were treated at the University of Rochester Medical Center. All patients were evaluated for the presence of congenital abnormalities. Ten of 34 (29%) patients with Wilms' tumor, 3 of 32 (9%) patients with neuroblastoma, and 0 of 18 patients with Ewing's sarcoma were so effected. In the patients with Wilms' tumor, 5 children had more than one abnormality. In this group, types of defects included genitourinary in 10 patients, central nervous system in 3, and other structural defects in 7. In the patients with neuroblastoma, the abnormalities were dissimilar. As expected, most of the 13 patients with congenital malformations were detected as having defects prior to the diagnosis of malignancy. For the patients with Wilms' tumor, median age at diagnosis for the entire group and for the subgroup with defects was 3 years, with age ranges similar. Male to female ratios were 1.3:1 and 1:1, respectively. Seventy percent of each group survived more than 5 years. For the patients with neuroblastoma, median age (range) for the entire group was 16 months (0-12 years). The patients with defects had ages of 5 days, 1 month and 9 months at diagnosis. Male to female ratio for the entire group was 0.6:1 and survival was 63% at 3 years (range 3-23 years). Those with defects are alive 3-8 years from diagnosis.

Adolescent↗
PubMed1985

Anti-neuroblastoma monoclonal antibodies which do not bind to bone marrow cells.

Three previously unreported mouse monoclonal antibodies are described. All three bind to cultured human neuroblastoma cells from six of six cell lines, but do not detectably bind to human bone marrow cells. The two IgG2a monoclonal antibodies bind to greater than 98% of the cultured cells from each cell line, bind to six of six human neuroblastoma tumors by immunoperoxidase histochemistry, and are cytotoxic with complement to cultured human neuroblastoma cells but not to human bone marrow granulocyte-macrophage colony-forming cells.

Animals↗
PubMed1984

Thyroid dysfunction after radiotherapy in children with Hodgkin's disease.

Thyroid function was measured in 119 children, 16 years of age or less, after radiotherapy (XRT) for Hodgkin's disease. Thyroid abnormalities developed in 4 of 24 children (17%) who received 2600 rad or less, and in 74 of 95 children (78%) who received greater than 2600 rad to the cervical area, including the thyroid. The abnormality in all but three (one with hyperthyroidism and two with thyroid nodules) included the development of elevated levels of thyroid stimulating hormone (TSH). Age, sex, and administration of chemotherapy were not significant factors in the development of thyroid dysfunction. All children had lymphangiograms (LAG) and no time relationship was noted between thyroid dysfunction and LAG-XRT interval. The mean interval from radiotherapy to documented thyroid dysfunction was 18 months in the low-dose group and 31 months in the high-dose group, with most patients becoming abnormal within 3 to 5 years. Of interest was a spontaneous return of TSH to within normal limits in 20 children and substantial improvement in another 7. This study confirms the occurrence of dose-related occult hypothyroidism in children following external irradiation of the neck.

Adolescent↗
PubMed1984

Characterization of the biophysical properties of human tumor and bone marrow cells as a preliminary step to the use of centrifugal elutriation in autologous bone marrow transplantation.

The principle of centrifugal elutriation (CE) depends on a balance of an outwardly directed centrifugal force and inwardly directed fluid flow and buoyant forces. This method (CE) can be used effectively to separate cells on the basis of size. In the murine model, neoplastic cells from different tumors are generally larger than bone marrow cells and can be removed from bone marrow almost completely with centrifugal elutriation. In order to determine if CE is capable of eliminating human tumor cells from harvested bone marrow (BM), the biophysical characteristics of a variety of human tumor cells and bone marrow cells were determined. Human tumor cells were dispersed into single cell suspensions by several enzymatic digestion and mechanical dissociation methods. The size and density characteristics of these cells were determined with an electronic particle counter and channelyzer and density gradients. Of 40 solid tumors studied, 29 tumors had cell size distributions distinctively larger than BM, as was found in the experimental animal model. The cell size distributions of tumor cells from 11 solid tumors and 7 leukemias were not substantially different from that of BM. Mixtures of BM and cultured human hypernephroma, ovarian, and neuroblastoma cells, were separated into BM and tumor fractions by CE. The separation results as indicated by the labeling index and colony forming efficiency of tumor cells in each fraction showed that a BM fraction virtually free of tumor cells could be obtained. Thus, CE should be able to separate BM cells from most tumor cells metastatic to BM.

Bone Marrow↗
PubMed1984

The paradoxes in patterns and mechanism of bone marrow regeneration after irradiation. 1. Different volumes and doses.

Bone marrow regeneration (BMR) following irradiation has been largely studied as a dose-effect phenomenon, however, a large literature has simultaneously developed utilizing a wide variety of volumes, both in clinical studies and in experimental studies. In human situations radiation treatment fields and the amount of bone marrow organ exposed have ranged from total body irradiation (small daily and total doses) to large field (half-body) single high doses encompassing 50% of the bone marrow, to segmental or localized field (50-25%). Volume factors, more than dose, determine patterns of suppression and regeneration which have been documented by a variety of assay systems. Experimental evidence is presented which indicates that high dose irradiation (500-1000 cGy) to large volumes of bone marrow (50%) does not completely suppress bone marrow regeneration but results in a rapid compensatory response. The nadir response of bone marrow CFUc-GM stem cell compartment was directly proportional to increasing doses of irradiation (200-2000 cGy) delivered to a single limb. Immediate depression of CFUc-GM was followed by an increase proliferative phase with the most notable difference observed in doses less than or greater than 1000 rad. Following doses of 500 and 1000 rad to large field (half-body), an immediate depression was again observed followed by an immediate and greater compensatory response particularly after the 1000 rad dose. Comparisons ae made between the small and larger volumes at similar doses and indicate a greater overall compensatory response after the larger field irradiation, being more rapid in onset particularly after the 1000 rad dose. Although in-field regeneration of bone marrow occurs after single dose radiation to different volumes of bone marrow, experimental and clinical evidence from protracted conventional doses of irradiation to different volumes of bone marrow (greater or less than 50%) indicate significantly different response mechanisms. From our laboratory and clinical investigations it can be determined that bone marrow is extremely sensitive to radiation insult and has different compensatory mechanisms to "fine tune" its response in proportion to the volume insulted.

Animals↗
PubMed1984

The paradoxes in patterns and mechanism of bone marrow regeneration after irradiation. 2. Total body irradiation.

Low dose total body irradiation (TBI) administered in small fractional doses (5-10 cGy) for the treatment of disseminated malignancies such as chronic lymphocytic leukemia (CLL) and non-Hodgkin's lymphoma can be extremely toxic with substantial bone marrow depression. We elected to study bone marrow suppression following fractionated TBI in the rabbit. New Zealand white/female rabbits were thus treated with one of the following three schedules: (1) 3 fractions of 10 cGy per week; (2) 5 fractions of 10 cGy per week; and (3) 5 fractions of 25 cGy per week. Total doses ranged from 1050 to 2625 cGy and animals were sacrificed immediately, 4 weeks, or 8 weeks following completion of therapy. With the 10 cGy/day schedules, slight depression of total WBC counts and lymphocyte numbers occurred during and to the completion of irradiation followed by a rebound to greater than normal levels. With the 25 cGy schedule, a significant WBC and lymphocyte depression occurred at an accumulated dose of 1000 cGy and continued to decrease up to 2500 cGy, followed again by a rebound to greater than normal levels. The depression with the 25 cGy fractions was significantly greater than with the 10 cGy daily fractions. Thus, the severe and persistent peripheral blood count depression observed in CLL patients treated with TBI in small fractional doses was not reproduced in the normal rabbits. Possible explanations for this paradox are offered.

Animals↗
PubMedDate not supplied

The development of an oral prodrug, SR-2545, of the 2-nitroimidazole radiosensitizer SR-2508.

SR-2508, a 2-nitroimidazole radiosensitizer, is expected to be clinically superior to desmethylmisonidazole or misonidazole because of its lower lipophilicity with subsequent lower drug levels in neural tissue and more rapid plasma elimination. The intravenous route of administration will be optimal but oral drugs may be necessary. Since decreased lipophilicity will decrease oral absorption we have synthesized, and tested in mice, SR-2545, an acetate ester prodrug of SR-2508. In the liver there is complete first pass metabolism to parent drug with no prodrug detectable in the blood. Compared to an equal dose of oral SR-2508, the prodrug yields a more rapid, reproducible, plasma peak with twice the bioavailability, peak plasma concentration and radiosensitization. If oral preparations of SR-2508 are to be used in the clinic the prodrug, SR-2545, is likely to be superior to oral SR-2508.

Administration, Oral↗