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Bone marrow transplantation (BMT) has considerable potential for the treatment of malignancies, hemoglobinopathies, and autoimmune diseases, as well as the induction of transplantation allograft tolerance. Toxicities associated with standard preparative regimens for bone marrow transplantation, however, make this approach unacceptable for all but the most severe of these clinical situations. Here, we demonstrate that stable mixed hematopoietic cell chimerism and donor-specific tolerance can be established in miniature swine, using a relatively mild, non-myeloablative preparative regimen. We conditioned recipient swine with whole-body and thymic irradiation, and we depleted their T-cells by CD3 immunotoxin-treatment. Infusion of either bone marrow cells or cytokine-mobilized peripheral blood stem cells from leukocyte antigen-matched animals resulted in stable mixed chimerism, as detected by flow cytometry in the peripheral blood, thymus, and bone marrow, without any clinical evidence of graft-versus-host disease (GvHD). Long-term acceptance of donor skin and consistent rejection of third-party skin indicated that the recipients had developed donor-specific tolerance.

Purpose: It is standard practice in our department to monitor weekly complete blood counts (CBCs) in patients receiving definitive radiation therapy for prostate cancer. The clinical utility and cost effectiveness of this practice has not been analyzed., Methods and Materials: The charts of all prostate cancer patients treated with radiation therapy between January 1994 and July 1996 at the Veterans Administration Hospital, Philadelphia, PA were reviewed. CBC values were available for 89 patients. Patients received a median dose of 68 Gy using a four-field box technique and megavoltage photons. Whole-pelvic radiotherapy followed by a conedown to the prostate was administered to 29 patients. Fifty-nine patients received radiation to the prostate alone or prostate and seminal vesicles. Fifty-seven patients received concurrent hormonal therapy which included luteinizing hormone-releasing hormone (LHRH) agonist, antiandrogens, or both., Results: No patient experienced a drop in their hemoglobin, white blood cells (WBCs), or platelets below critical nadirs (defined as WBC < 2 counts x 1000/mm(3), hemoglobin < 8 g/dl, platelet < 50 counts x 1000/mm(3) 2 in WBCs. In the urban area surrounding the Philadelphia Veterans Administration Medical Center, the cost of obtaining a CBC is approximately $30. However, if staff time is considered, the cost of obtaining a weekly CBC during prostate cancer radiotherapy approached $400 per patient., Conclusion: These results suggest that weekly monitoring of CBCs in prostate cancer patients undergoing definitive radiotherapy may not be necessary. We recommend a baseline CBC be performed, and if normal, no other monitoring unless clinically indicated. This strategy would result in a cost savings approaching $30,000 per 100 treated patients. Further research on the cost effectiveness and utility of serial blood tests in patients receiving partial body radiation therapy is needed.

In experiments with dogs the acute radiation sickness was caused by common relatively uniform 3.5 Gy dose gamma-irradiation. Reinfusion of UV-irradiated autologous blood induced undoubted curative effect, which manifested itself in increased mean life, reduced mortality, more full restoring of blood-formation.

The pathological changes of radiation on wound healing in rats were observed by macroscopic, microscopic, and electronmicroscopic examination and detection of collagen types. We found that the wound healing process was obviously delayed by irradiation. First, the early phase inflammatory response was severely inhibited. In particular, the number of infiltrating macrophages and neutrophils was decreased, blood vessels were injured, and hemorrhage was evident. Second, the formation and maturation of granulation tissue were slowed down, fibroblasts were injured, and transcription of types and collagen mRNAs and synthesis and secretion of collagen were reduced. Finally, the reepithelialization process was delayed and the healing time was prolonged.

One hundred and fourteen patients with painful bone metastases participated in this randomised, dose-controlled study of the efficacy and safety of 153Sm-ethylenediaminetetramethylenephosphonate (EDTMP), a systemically administered radiopharmaceutical. Fifty-five patients received single doses of 0.5 mCi/kg and 59 patients received single doses of 1.0 mCi/kg. Treatment with 153-Sm-EDTMP produced improvement from baseline in all patient-rated efficacy assessments, including degree of pain, level of daytime discomfort, quality of sleep and pain relief. During the first 4 weeks after dose administration, when the patients evaluated efficacy daily, there were statistically significant changes from baseline with the 1.0 mCi/kg dose but not with the 0.5 mCi/kg dose. The difference between doses in visual analogue pain scores was statistically significant at week 4 (P = 0.0476). Among subsets of patients examined, female patients with breast cancer receiving 1.0 mCi/kg had the most noticeable improvement. The physicians judged that approximately half of the patients in each dose group were experiencing some degree of pain relief by week 2. This value increased to 55% for the 0.5 mCi/kg group and 70% for the 1.0 mCi/kg group at week 4. More patients in the higher dose group (54%) than in the lower dose group (44%) completed the 16-week study. A predictable level of dose-related marrow suppression was the only toxicity associated with 153Sm-EDTMP treatment. Values for platelets and WBCs reached nadirs at 3 or 4 weeks with both doses and recovered by 8 weeks. Even at their lowest point, the values were generally higher than those associated with infectious or haemorrhagic complications. Myelotoxicity was no greater in female patients than in male patients. Long-term follow-up revealed longer survival among breast cancer patients who had received the higher dose than among those who had received the lower dose. The results suggest that the 1.0 mCi/kg dose of 153Sm-EDTMP is safe and effective for the treatment of painful bone metastases.

Purpose: The efficacy of radiation therapy for Kasabach-Merritt syndrome, which is characterized by a huge hemangioma with consumption coagulopathy, remains controversial. In this study, we retrospectively investigated the treatment outcome of radiation therapy for seven neonates with Kasabach-Merritt syndrome., Methods and Materials: During the past 25 years we have seen seven children with Kasabach-Merritt syndrome who were treated with radiation therapy. Their ages ranged from 1 day to 5 months, with a median age of 1 month. The hemangioma was located in the extremities in four of seven children. Tumor sizes ranged from 70 cm to more than 150 cm in greatest diameter. Initial platelet counts were all less than 40,000/mm3 except for one patient. In principle, the total dose applied to the hemangioma was 8-10 Gy, with a daily dose of 1 Gy five times a week., Results: Four of seven hemangiomas responded dramatically, with a concomitant rise of the platelet count to radiation therapy. Although the remaining three hemangiomas, all of which were ill circumscribed by widespread overlying shiny, dusky purple skin, became less tense during radiation therapy. Disseminated intravascular coagulopathy was not improved, but they have responded favorably to two or three courses of radiation therapy with an extended radiation field by 1.5 years of age. As a result, all seven patients are now surviving with no evidence of hemangioma or hematological abnormalities. Shortening of the extremity was observed in three patients who received multiple courses of radiation therapy., Conclusions: Radiation therapy appears to be one of the effective treatment options for Kasabach-Merritt syndrome despite the risk of growth delay and malignancy.

Graft-versus-host disease in solid organ transplantation is very rare, but the prognosis is poor when the condition causes pancytopenia. We report a case of graft-versus-host disease in a heart-lung transplant recipient who at 2 weeks after transplantation had development of features of graft-versus-host disease, including bone marrow aplasia, that could not be attributed to drugs or viral infections. The diagnosis was confirmed by skin biopsy and demonstration of chimerism of peripheral lymphocytes. Augmentation of immunosuppression with intravenous methylprednisolone resulted in improvement in liver function but had no effect on the pancytopenia. Mediastinal irradiation was given with increase in both white blood cell and platelet counts. Unfortunately the patient eventually died of gastrointestinal bleeding and fungemia.

Fifty consecutive patients undergoing cyclophosphamide/G-CSF mobilization were studied for indicators predictive for adequate harvest (CD34+ cells > 2 x 10(6)/kg, CFU-GM > 1 x 10(5)/kg). Target yields following a single leukopheresis were achieved for 66% of patients (89% with no previous alkylation chemotherapy or radiotherapy). Previous alkylation therapy, radiotherapy and low collection day platelet count were predictive of poor collection yields. Following reinfusion, the median time to platelets > 20 x 10(9)/l (PLT > 20) was 10 days and to neutrophils > 500 x 10(6)/l (ANC > 500) was 13 days. Total CD34+ cells infused was predictive of early platelet engraftment. Previous radiotherapy was inversely predictive of neutrophil engraftment. For the majority of patients not exposed to alkylation therapy or radiotherapy, adequate progenitor cells can be collected following a single leukopheresis. In patients suitable for future autologous bone marrow transplantation it would seem appropriate to avoid or minimize radiotherapy and alkylation therapy exposure in the pre-collection period.

Splenic irradiation has been used in patients with HIV-related thrombocytopenia. This retrospective review deals with four patients treated with low dose splenic irradiation. All patients had an increase in platelet count and tolerated the treatment without side effects. However, the treatment response lasted for several months only.

To determine the frequencies and differential counts of megakaryocytes after cytoreductive treatment in nucleated low-density (1.060 g/ml) bone marrow cells (BMNC) of dogs an immunogold-silver staining (IGSS) technique with the lineage specific monoclonal antibody 2F9 was established. This antibody recognizes the glycoprotein IIb/IIIa complex expressed on the surface of canine megakaryocytes and platelets. The IGSS technique enables not only the detection of megakaryocytes occurring at a low frequency (0.1-0.2%), but also the discrimination between the different maturation stages of megakaryocytes due to cell size, nuclear morphology and cytoplasmic staining. By the use of this technique, small lymphoid megakaryocytic cells were identified. Comparable numbers of megakaryocyte colony-forming cells in 2F9-depleted and nondepleted BMNC suspensions (25.7 +/- 5.0 vs. 25.3 +/- 5.1 Meg-CFC/10(5) BMNC) indicate that these small 2F9 positive cells are nonclonogenic precursors of megakaryoblasts. To prove the applicability of IGSS, serial examinations of bone marrow samples from dogs treated with recombinant human interleukin-6 (IL-6) after exposure to 2.4 Gy total body irradiation (TBI) were performed. The results of the microscopic evaluation indicate that, in the recovery phase after TBI, IL-6 induced an earlier and stronger increase in megakaryocyte frequency in comparison to the control. Interestingly, all maturation stages of the megakaryocytic lineage took part in this IL-6 induced improvement of megakaryocyte recovery.

Strontium-89 chloride (Metastron) is an FDA-approved treatment for palliation of cancer pain. We evaluated blood count changes and pain relief in 28 patients with widespread painful bony metastasis treated with strontium-89 at the University of Minnesota Hospital and Clinics. Eighteen patients had prostate cancer (all hormone-refractory cancer), seven patients had breast cancer, and three patients had lung cancer, all previously treated with either radiation, chemotherapy, or a combination of the two. Serial blood counts were performed weekly up to 8 weeks and at 12 weeks after administering Metastron. Pain scale and blood values were monitored simultaneously. The mean baselines of hemoglobin (Hgb), white blood count (WBC), and platelets (Plts) were 11.4, 5900, and 258,000, respectively. The mean dose of Metastron was 3 mCi (range 2.2-4.4). The median time (range) to nadir was about 6 weeks. The percentage reductions relative to baseline were 32% (range 0-72%) for WBC; 14% (range 0-50%) for Hgb; 15% (range 0-47%) for the red blood cell (RBC) count; and 40% (range 0-85%)for Plts. We did not find a close relationship among the baseline blood count, reduction of subsequent blood counts, or previously irradiated active bone marrow volume. The median time of survival was 23 weeks (range 2-66 weeks). At 12 weeks, 29% of patients had moderate to dramatic improvement of pain, 32% had some relief of pain, and 50% had no improvement in pain. Thirty-two percent of the treated patients required additional palliative external beam radiation to their bony lesions within the study period. Our results show that Metastron for palliation for bony metastases should be used with caution because of moderate to severe bone marrow toxicity, especially in platelets, associated with its use. Careful evaluation of patients given Metastron is needed to assess accurately its full benefit.

Recurrent or persistent neuroblastoma in stages III and IV is usually fatal despite modern therapies. Metaiodobenzylguanidine labeled with 131-I (131-I MIBG) concentrates in most neuroblastoma and when given in doses that impart therapeutic radiation, has produced remissions in patients with these tumors. However, success with 131-I MIBG has been limited. The physical characteristics of radiation imparted by 125-I MIBG theoretically could overcome some of the limitations that restrain the therapeutic effects of 131-I MIBG in patients with neuroblastoma. Thereby, 125-I MIBG may offer advantages over 131-I MIBG in the treatment of neuroblastoma. Ten children who manifested persistent/recurrent stage III or IV neuroblastoma were given 8.3 to 30.1 GBq or 224 to 814 mCi of 125-I MIBG in a phase I-II trial. Five of the patients had progression-free survivals > 1 year (continuing in three patients), and four of these subjects are surviving 17 to 52 months after treatment with 125-I MIBG. With appropriate doses of 125-I MIBG, life-threatening toxicity can be avoided. Thus, survivals after 125-I MIBG appear to be as long or longer than those historically observed following other treatments for patients similarly afflicted with refractory neuroblastoma.

The relative impact of age, sex, nucleated cell dose, prior chemotherapy, prior cranio-spinal irradiation (CSI) and bone marrow harvest (BMH) site on hematological recovery after ABMT were analyzed in a multivariate model. The study population comprised 100 patients with a median age of 9 years who underwent ABMT for malignant brain tumors. Two engraftment parameters were evaluated: number of days post ABMT before (1) an absolute neutrophil count (ANC) > or = 0.5 x 10(9)/l and (2) a platelet count > or = 50 x 10(9)/I were achieved for the third consecutive day without transfusions. Increasing cell dose correlated significantly with a more prompt recovery of platelet counts and ANC. Previous chemotherapy significantly delayed both neutrophil and platelet engraftment. The group of patients who also received CSI had a very delayed platelet recovery with a median time to engraftment of 72 days. Neutrophil engraftment was also significantly delayed and occurred at a median of 23 days. This effect of CSI was independent of cell dose or prior chemotherapy. In 20 of these patients, marrow was harvested at least partially from the posterior iliac crests, which might have received significant doses of irradiation. We conclude that engraftment is significantly faster if bone marrow is harvested prior to any chemotherapy administration, and that patients who receive prior CSI may have significant engraftment delay, particularly of the platelet lineage. In this latter group of patients, marrow should not be harvested from the posterior iliac crests. Strategies that might enhance both neutrophil and platelet count recovery should be considered in patients with irradiation damage to a substantial proportion of the total hematopoietic tissue.

Unlabelled: Rhenium-186(Sn)-1,1-hydroxyethylidene diphosphonate (186Re-HEDP) has been used for palliation of metastatic bone pain. The purpose of this study was to find a relationship between the bone marrow absorbed dose and the toxicity, expressed as the percentage decrease in the peripheral blood platelet count., Methods: The bone marrow absorbed dose was calculated according to the MIRD model using data obtained from ten treatments of patients suffering from metastatic prostate cancer; noninvasive and pharmacokinetic methods were used. The bone marrow doses were related to toxicity using the pharmacodynamic sigmoid Emax model., Results: The mean bone marrow absorbed doses using the noninvasive and pharmacokinetic methods were in a close range to each other (1.07 mGy/MBq and 1.02 mGy/MBq, respectively). There was a good relationship between the toxicity and the bone marrow absorbed dose (r = 0.80). Furthermore, the EDrm50 (i.e., the bone marrow absorbed dose producing a 50% platelet decrease) to bone marrow for 186Re-HEDP was on the order of 2 Gy., Conclusion: Although the function of normal bone marrow is affected by metastases in patients with metastatic bone disease, the MIRD model can be used to relate toxicity to the bone marrow absorbed dose after a therapeutic dosage of 186Re-HEDP.

Purpose: Hematopoiesis is among the most sensitive systems in the body to radiation. Routine complete blood counts (CBCs) are common in clinical radiotherapy practice. Only a few studies have attempted to characterize the behavior of peripheral blood levels during partial body radiation therapy with field sizes smaller than those used in hemibody or total nodal irradiation. Such information is needed to identify which patients are at risk for cytopenia and require close monitoring., Methods and Materials: In 1993, 412 new patients were seen at Michael Reese Hospital for radiotherapy. A total of 972 weekly CBCs were identified for 155 patients receiving a minimum of 5 weeks of treatment for breast, prostate, lung, gynecological, or head and neck malignancies. Linear regression models were fitted to the weekly CBC values for those patients who had pretreatment CBC values recorded. Factors affecting starting levels, rates of decline, and nadirs during treatment were determined for leukocytes, platelets, and hemoglobin., Results: Leukocytes declined most dramatically during the first week of treatment (16% from pretreatment to Week 1 levels) and then at a rate of 3.3% per week from Week 1 to Week 7 (p < 0.001). Total mean leukocyte decrease over 7 weeks of therapy was 30%. Platelets declined 9% on average during the first week of therapy and then at a mean rate of 1.4% per week (p < 0.02). A statistically significant decrease in hemoglobin levels could not be detected. No difference in the rate of decrease could be found for different disease sites, age groups, or amount of marrow irradiated. The effects of chemotherapy were variable, depending on blood element and whether therapy was sequential or concomitant. The odds of a nadir < 2000 counts/mm3 for white blood count (WBC), < 50,000 counts/mm3 for platelets, and < 8.0 g/dl for hemoglobin were all well below 5%. A strong correlation existed between starting CBC values and nadirs; patients with lower Week 1 CBC levels were most likely to have the lowest nadirs., Conclusions: Low CBC levels during radiation therapy are likely to be the result of other medical problems that cancer patients face. Regional irradiation with small field sizes (< 40% of total body marrow) typically used in clinical radiotherapy is unlikely to be the cause of marrow depression significant enough to warrant medical intervention. Blood levels taken during the first week of treatment (Week 1) can be used to determine risks of developing critical nadirs. Localized breast and prostate cancer patients are unlikely to require routine CBCs if initial levels are normal. Routine CBC levels on all radiation oncology patients without other reasons for hematopoietic depression requires reevaluation, as millions of dollars are spent on unnecessary testing. If weekly CBC blood levels are avoided in localized breast and prostate cancer patients, this alone could potentially result in a savings of as much as $40 million a year nationally.

The effects of recombinant human interleukin-11 (rhIL-11) were studied in normal dogs and dogs given otherwise sublethal total-body irradiation (TBI) without marrow transplantation. Ten normal dogs were given rhIL-11 subcutaneously, twice daily for 14 days at varying doses, two dogs at 30 micrograms/kg/day, four dogs at 60 micrograms/kg/day, two dogs at 120 micrograms/kg/day, and two dogs at 240 micrograms/kg/day. Peripheral blood platelet counts increased in all dogs. The increase in platelet counts ranged from 1.4 to 3.1 times the pre-treatment level. The greater increases of platelets were associated with higher doses (p = 0.01). No change in platelet size was evident except at the dose of 240 micrograms/kg/day. There were no changes in the total white blood cell (WBC) count or differential. A higher proportion of megakaryocytes with a DNA content of 32N/64N was observed in dogs treated with rhIL-11 at day 7 (n = 6) than for control dogs that did not receive rhIL-11 (n = 7; p = 0.01). In both peripheral blood and marrow, significantly increased hematopoietic progenitors (i.e, colony-forming unit granulocyte/macrophage [CFU-GM]) were present 7 and 14 days after the start of treatment. Concentrations of serum fibrinogen increased by a median of 155 mg/dL at day 7 of rhIL-11 (p < 0.01). Cholesterol also increased by a median of 52 mg/dL at day 14 (p < 0.01). There was a single death of a non-irradiated dog from pneumonitis on day 15 after the start of rhIL-11 administration at a dose of 120 micrograms/kg/day. All other non-irradiated dogs tolerated rhIL-11 without any significant adverse effects. Five dogs were given 200 cGy TBI without marrow grafting, followed by 240 micrograms/kg/day rhIL-11 subcutaneously in two divided doses for 28 days starting within 2 hours of TBI. The results in this group were compared with 10 dogs that had previously or concurrently been given 200 cGy without marrow grafting or hematopoietic growth factors. Two of the five treatment dogs died of pneumonitis on day 13 compared to one death among 10 control dogs on day 24. Among dogs that survived to hematologic recovery, the rhIL-11 dogs had decreased platelet counts (< 150,000) for a median of 24 days (range = 24 to 41) compared to a median of 28 days (range = 21-40) for the control group. Treatment with rhIL-11 increased platelet counts, platelet size, ploidy number of megakaryocytes, and marrow and peripheral blood CFU-GM in normal dogs.(ABSTRACT TRUNCATED AT 400 WORDS)

The polyethoxylated castor oil, Cremophor EL (Cremophor) is approved for human use as a vehicle for oral and intravenous administration of water-insoluble compounds. Cremophor has also previously been shown to reverse the multidrug resistance phenotype at clinically acceptable doses. This study demonstrates that doses of Cremophor in the range of 25-50 microliters/kg intravenously (i.v.) administered 1 day prior to near-lethal irradiation protected the regenerative capacity of the marrow, resulting in haematopoietic radioprotection and long-term survival of near-lethally-irradiated mice. In normal mice, Cremophor administration (1) markedly reduced the level of serum haematopoietic inhibitory activity 4-8 h following injection; (2) resulted in a transient decrease in femoral bone marrow cellularity and upregulated B220 (B cells), and 7/4 (neutrophils and activated macrophages), but not Thy-1 (T-cells) surface antigen expression in bone marrow cells within 24 h of injection; and (3) transiently elevated the incidence of both primitive and committed haematopoietic progenitor cells detected in clonal agar culture within 48 h of injection. Bone marrow progenitor cell content, and peripheral blood white cell, platelet and reticulocyte counts were unaffected. This suggests that the haematopoietic radioprotection and recovery observed in irradiated mice pretreated with Cremophor may be the result of accessory cell activation and/or modulation of accessory factors regulating haematopoietic progenitor cells. Our data suggest a potential clinical use of Cremophor as an adjunct to, or as a substitute for, cytokines to minimize myelosuppression following cytotoxic therapy.

Background: Forty patients with Stage II-III breast cancer with 10 or more positive axillary nodes were treated with mastectomy followed by four cycles of standard dose CAF (cytoxan, Adriamycin, 5-FU), followed by high dose cytoxan, cisplatin, carmustine (HDCT) with autologous bone marrow transplant support (ABMT), and local-regional radiotherapy (LR XRT). During LR XRT, the hematologic toxicity experienced by these patients appeared more severe than that usually seen in patients not heavily pretreated with chemotherapy. Radiation therapy was interrupted in four patients (10%) because of thrombocytopenia and leukopenia. This observation prompted a comparison of the hematologic changes seen in this group with those seen in patients not treated previously with chemotherapy., Methods: A detailed analysis of changes in hematologic parameters during LR XRT was performed in 33 evaluable patients who received CAF-HDCT/ABMT and compared with a "control" group of 17 women who did not receive prior chemotherapy., Results: The mean pretreatment leukocyte, platelet, and hematocrit counts were lower in the CAF-HDCT/ABMT group than in the control group, with the differences indicating statistical significance for the latter two (P = 0.17, P < 0.001, and P = 0.001, respectively). None of the control patients required a treatment interruption because of hematologic toxicity, whereas four of the CAF-HDCT/ABMT patients did. Among the CAF-HDCT/ABMT patients, a leukocyte count nadir of less than 2.0, a platelet nadir of less than 50,000, and a hematocrit nadir of less than 25 occurred in 12%, 19%, and 9%, respectively. The corresponding rates of control patients were 6%, 0%, and 0%, respectively. Relative to their pretreatment levels, however, both groups experienced similar declines in platelet and leukocyte counts., Conclusion: The higher rate of hematologic toxicity observed in the patients who previously received conventional chemotherapy plus HDCT/ABMT appears to have been due primarily to lower preradiotherapy blood counts.

Unlabelled: A potential limitation of rhenium-186-1,1-hydroxyethylidene diphosphonate (186Re-HEDP) therapy in patients with painful bone metastases is thrombocytopenia. Given the palliative character of this therapy, it is essential to be able to predict the degree of thrombocytopenia before therapy., Methods: Thus far, 39 prostatic cancer patients with multiple painful bone metastases were treated. Twenty-one patients underwent the therapy twice, resulting in 60 therapies. From the pre-therapy 99mTc-HDP scintigram, the bone scan index (BSI) was determined as an index of the extent of bone involvement., Results: The administered activity ranged from 1104 to 3479 MBq 186Re-HEDP. The platelet count was lowest 4 wk following therapy. From this value and the pretreatment level, the percentage decrease in the platelet count was determined (47% +/- 19%, range 14%-89%). The BSI ranged from 8 to 93. Regression analysis showed a functional relation (R = 0.78; p < 0.001) of the percentage of platelet decrease with BSI and administered activity normalized to standard body surface area., Conclusion: Using this relation, it is possible to predict thrombocytopenia by pretreatment bone scintigraphy and to adjust the dosage to each patient to avoid unacceptable toxicity.

Protracted, low-daily-dose gamma-ray exposure (3.8-7.5 cGy/day) segregates canines into separate survival- and pathology-based subgroups by the early elicitation of distinct, repair-mediated hemopathological response pathways. In this study, we verified the blood and marrow responses of two major subgroups prone to either aplastic anemia or myeloproliferative disease, along with two variants, and extended our analyses of hematopoietic repair to include studies of DNA repair in bone marrow blasts using an autoradiographically based unscheduled DNA synthesis (UDS) assay. The myeloproliferative disease-prone subgroup exhibited extended survival (> 200 days), related to partial, gradual restoration of blood leukocyte, platelet, and marrow progenitor levels following an initial phase of acute suppression. Marrow blasts taken during the restoration phase showed expanded and qualitatively modified UDS relative to marrow blasts of age-matched control animals. The amount of UDS per blast (signal strength) increased significantly, as did the number of UDS-positive cells and their sensitivities to high-dose UV induction and 1-beta-D-arabinofuranosylcytosine chemical inhibition. A nonevolving myeloproliferative disease-prone variant having prolonged survival (> 200 days) and restored blood cells and marrow progenitor levels also had marrow blasts with expanded UDS responses, but these were uniquely evoked by low (but not high) doses of UV inducer. The aplastic anemia-prone subgroup was characterized by short survival (< 200 days), progressive decline (without restoration) in all measured blood and marrow compartments, and largely nonsignificant changes in UDS responses of marrow blasts. A variant of this aplastic anemia-prone subgroup (with comparable short survival due to markedly ineffective hematopoiesis, but expressing select preleukemic features) exhibited reduced numbers (relative to age-matched controls) of highly responsive, UDS-positive marrow blasts (in terms of UDS signal strength and increased to sensitivity 1-beta-D-arabinofuranosylcytosine-induced UDS inhibition). From these observations we conclude that: (a) the UDS response of marrow blasts, a correlate of hematopoietic progenitorial repair, is altered differentially within selected subgroups of animals under chronic radiation exposure; and (b) the nature of altered UDS repair response patterns appears to be largely related to the preclinical status/predisposition of the individual animal and thus may provide prognostically useful information in the clinical monitoring of chronically irradiated individuals with minimal but evolving hematological disease.

Administration of interleukin-1 beta (IL-1 beta) before a lethal irradiation with or without allogeneic bone marrow transplantation (BMT) protects greater than 90% of the irradiated mice. To approach the mechanisms responsible for the radioprotective effect of IL-1, we examined the effects of IL-1 pretreatment on engraftment and kinetics of peripheral blood, spleen, and marrow cell reconstitution after irradiation and BMT. Although the BMT was not necessary for the survival of the IL-1-pretreated lethally irradiated mice, allogeneic marrow did engraft in these mice as evaluated in the spleen and marrow 2 months after BMT. IL-1 pretreatment significantly accelerated hematopoietic recovery versus transplanted saline-treated controls with a pronounced enhancement of peripheral leukocyte, platelet, and erythrocyte recovery. Leukocyte recovery in IL-1-pretreated mice was unique in that IL-1 first induced an early transient (maximum at day 7) increase of peripheral granulocytes before accelerating leukocyte recovery after day 11. IL-1 pretreatment also significantly enhanced marrow cell recovery after allogeneic BMT with an eightfold increase in marrow cellularity from day 4 to 11 versus control transplanted mice. When lethal irradiation was not followed by allogeneic BMT. IL-1 pretreatment also affected the peripheral reconstitution of leukocytes, platelets, and erythrocytes. Interestingly, in the absence of BMT, IL-1 also induced an early circulation of peripheral granulocytes. Overall, our data demonstrate that a single administration of IL-1 before lethal irradiation and allogeneic BMT can induce an early transient increase of circulating granulocytes, followed by an accelerated multilineage recovery and long-term allogeneic engraftment.

Ultraviolet-B (UV-B) irradiation of platelet concentrates (PCs) may prevent the development of posttransfusion HLA alloimmunization. This study evaluated the effect of increasing doses of UV-B radiation on stored PCs. Pooled PCs were irradiated at UV-B doses of 600, 2400 or 10,000 mJ per cm2 and stored up to 96 hours under standard blood bank conditions. Compared to nonirradiated room-temperature and 37 degrees C controls, the irradiated units showed no significant changes in platelet count, white cell count, discharge of lactate dehydrogenase, release of beta-thromboglobulin, metabolism of ATP, ADP, ammonia, glutamine, glutamate, hypoxanthine, pCO2, or pO2 at any time of storage following any of the three UV-B doses. However, after a dose of 10,000 mJ per cm2, there were significant decreases in in vitro assays of platelet function-specifically, osmotic recovery and morphology score. Some metabolic systems were also affected by the 10,000 mJ per cm2 radiation dose, as shown by a decline in pH and bicarbonate and an increase in glucose consumption and lactate production (p < 0.05). The changes in these latter assays appeared only after 96 hours of postirradiation storage. Such changes were not seen in either the room-temperature or 37 degrees C control groups. Thus, heat generated during irradiation, per se, did not appear responsible for the observed in vitro changes in platelet function and metabolism. On the basis of the assays analyzed, it is concluded that UV-B irradiation of PCs at doses up to 10,000 mJ per cm2 does not induce significant metabolic or functional derangements following short-term storage (24-48 hours).(ABSTRACT TRUNCATED AT 250 WORDS)

Based on comparing results of tests followed in the present work between the endotoxin model of the disseminated intravascular coagulation (DIC) and irradiated groups of rats we consider that after the whole-body irradiation by a high dose of 250 Gy, the DIC occurs, in spite of the fact that the first stage--hypercoagulation condition, can be hardly observed. In the experimental endotoxin model, an increase of activated partial thromboplastin test (APTT) values and prolongation of the thrombin time was observed up to 24 hours in both endotoxin doses. After both endotoxin doses, the fibrinogen level was transiently decreased with its subsequent increase. The fibrin monomers correspond to decreasing the fibrinogen level. After the first dose, they were positive between the 3rd and 12th hours and after the second dose, the positivity was observed 6 hours after the application. The antithrombin III level was decreased after 12 hours in both endotoxin doses. The thrombocyte count was considerably reduced already from the 6th hour after administering endotoxin to the end of the experiment. Considerable changes of the thrombocyte aggregation were observed only 3 hours after administering the second dose. When comparing the resulting values of these tests with values observed in irradiated animals, then we can see a certain agreement in the nature of the changes after the exposure to 250 Gy. The fibrinogen level was transiently decreased 3 hours after irradiation, when considerable changes in the thrombocyte aggregation also occurred.

Mice were placed in a cold environment (4 degrees C) directly after whole-body irradiation. Those irradiated with a lethal dose showed higher lethality than mice irradiated with the same dose but placed in room temperature. The response was also altered after irradiation with a sublethal dose. At various periods after irradiation mice were injected with 125IUdR, the tissue uptake of which is an index of DNA synthesis. The result showed that cold treatment after irradiation caused slower cell renewal in the spleen and bone marrow, but that the thymus was only marginally affected. Furthermore, the concentrations of erythrocytes in the peripheral blood reached a lower level in the cold-treated group. Finally, the levels of the thyroid hormones T3 and T4 in the blood were measured and it was found that the T3/T4 ratio was higher in the cold-treated mice. It is suggested that during prolonged exposure to cold after irradiation the cell recovery in the haemopoietic system is exposed to hormonal action that induces significant alterations in the postirradiation cell kinetics.

We have studied the in vivo effects of recombinant human interleukin-6 (rhIL-6) on hematopoiesis in eight healthy and nine irradiated cynomolgus monkeys. Of the healthy animals, three received rhIL-6 alone (10 micrograms/kg/d, subcutaneously [SC]), one received rhIL-6 in combination with rhIL-3 (10 micrograms/kg/d, SC), one received rhIL-6 in combination with recombinant cynomolgus granulocyte-macrophage colony-stimulating factor (rcGM-CSF; 10 micrograms/kg/d, SC), two received rhIL-6 in combination with recombinant human granulocyte-CSF (rhG-CSF; 10 micrograms/kg/d, SC), and one received rhIL-6 in combination with recombinant human leukemia inhibitory factor (rhLIF; 10 micrograms/kg/d, SC). All animals were treated for at least 2 weeks with rhIL-6 or the above mentioned combinations. rhIL-6 alone significantly increased the peripheral blood platelet counts (2- to 3.5-fold). The platelets reached a plateau between days 10 and 15 of treatment. No synergistic effects on platelet numbers were observed when rhIL-6 was combined with rhIL-3, rcGM-CSF, rhG-CSF, or rhLIF. In addition to rhIL-6, only rhLIF increased the platelet numbers when administered alone. To test whether rhIL-6 might also protect the animal from thrombocytopenia or shorten the time of thrombocytopenia after irradiation, we treated nine animals with total body irradiation (3.8 Gy). Six of the animals were additional treated with rhIL-6 (4 with 10 micrograms/kg/d; and 2 with 100 micrograms/kg/d) from day -1 or +1 to day 28 post irradiation. In these animals, rhIL-6 at the same dose effective in healthy animals (10 micrograms/kg/d) was not capable of protecting the animals from platelet nadir. However, when pegylated rhIL-6 was used at a dosage of 100 micrograms/kg/d post irradiation, the mean of the nadirs was 71,000/microL as compared with 39,000/microL in control animals and the time of thrombocytopenia was shorter (3 v 5 days). In all animals (healthy and irradiated), rhIL-6 did not increase the number of bone marrow megakaryocytes but induced a right shift of DNA ploidy in megakaryocytes. These data suggest that IL-6 acts as "thrombopoietin"-like activity, but not as "megakaryocyte-CSF"-like activity.

The oedema which forms around an intracerebral haemorrhage has a complex aetiology. The immune response may have a role in its formation. There is clinical and experimental evidence that circulating leucocytes and platelets may mediate oedema formation. Global depletion of circulating leucocytes and platelets by whole body irradiation in a rodent model of intracerebral haemorrhage was found to confer protection against both ischaemia and oedema formation. This was not a direct effect of irradiation of the brain. The possible mechanisms for this protection are discussed.

The effect of global immunosuppression by sublethal whole body X-irradiation on the development of cerebral oedema was assessed 24 h after right middle cerebral artery occlusion in the rat. Irradiation produced a significant leukopenia and thrombocytopaenia, and significantly reduced cortical oedema when compared to non-irradiated control animals.

Unlabelled: Total lymphoid irradiation (TLI) has been shown experimentally to induce a state of partial tolerance when administered before organ transplantation. Anecdotal reports in clinical transplantation have suggested efficacy of TLI in the treatment of recurrent rejection after heart transplantation. To further assess the safety and efficacy of TLI, 19 patients were entered into a protocol of TLI for the treatment of recurrent or early severe rejection despite conventional therapy. Rejection rate decreased from 1.3 episodes/month before TLI to 0.53 during TLI and 0.07 after TLI (p < 0.0001). Infections increased during TLI (possibly related to recent augmented immunosuppression before TLI), but all infections were successfully treated. One death occurred after TLI from acute allograft rejection. White blood cell (WBC) and platelet counts were depressed during and after (3 months) TLI. Frequent adjustments of dosing interval and, occasionally of the dosage were required to control WBC and platelet counts. Five patients experienced transient WBC of less than 1000/ml. More rejection episodes (and thus greater overall immunosuppression) before TLI and a lower tolerated dose of azathioprine before TLI predicted (by multivariate analysis) a lower WBC during TLI., Conclusions: (1) TLI is an effective adjunct for the intermediate control of early or recurring acute allograft rejection. (2) Close surveillance of WBC and platelets with appropriate adjustment of TLI dose and interval is necessary during TLI therapy. (3) The long-term benefits, possible late deleterious effects, and potential role of TLI as induction therapy remain to be elucidated.

This report was aimed at confirming the potential clinical use for a genetically engineered glycosylated human interleukin-6 (rhIL-6) in hematopoiesis. Its tolerance and efficacy were assessed on hematopoietic restoration after neutron radiation-induced bone marrow injury on baboons, which represent an adequate model of parallelism for studying hematology in the human. The particular neutron radiation absorption pattern in the body allows the preservation of underexposed bone marrow areas that mimics an autotransplantation-like situation. An initial dose finding study (1 microgram up to 20 micrograms/kg/d for 8 consecutive days) in normal baboons established a dose-dependent response regarding the peripheral platelet count (range of increase, 1.5- to 4-fold). A significant elevation in white blood cell (WBC) count, as well as a substantial reversible normochromic normocytic anemia, were observed for the highest doses only (10 and 20 micrograms/kg/d). All rhIL-6 administered doses were clinically well tolerated. In myelosuppressed baboons, a selected dose of 10 micrograms/kg/d of rhIL-6 for 13 consecutive days significantly lessened the degree of induced thrombocytopenia as compared with the control group (P = .01) and shortened the time to occurrence of the nadir, showing that the onset of recovery occurs much earlier, ie, an average of 5 days (P = .003), in the treated group. Moreover, this accelerated platelet recovery is evidenced by an 8-day shorter mean time back to baseline values (P = .03) in the rhIL-6--treated animals. At this dose no effect was observed on the WBC recovery pattern. Importantly rhIL-6 did not accentuate the radiation-induced anemia and was clinically well tolerated. All tested monkeys recovered from their induced pancytopenia and no animal loss was recorded. IL-6, tumor necrosis factor, and IL-1 blood measurements are reported. In conclusion, rhIL-6 is a potent thrombopoietic factor for the treatment of induced thrombocytopenia in nonhuman primates at a clinically well-tolerated dose.

The response of megakaryocytes and platelets to the administration of recombinant human interleukin-6 (IL-6) was investigated in normal and sublethally irradiated dogs. IL-6 was administered for 2 weeks at doses of 10 to 160 micrograms/kg/d to normal animals to assess dose-response and toxicity. Subsequently, 40, 80, or 160 micrograms/kg/d for 2 weeks was administered to animals treated with 200 cG total body irradiation. Analysis of normal dogs showed a significant increment in the platelet count detectable approximately 11 days after initiation of IL-6 at all administered doses. Large platelets greater than 6.3 microns in diameter were observed 1 day after beginning IL-6, progressively increasing to as many as 19.1% of the total circulating platelets by day 10. The ploidy distribution of the marrow megakaryocytes did not differ from the normal at doses of less than or equal to 80 micrograms/kg/d, but at 160 micrograms/kg/d, a shift toward higher ploidy cells was noted. No change in total white count was noted; however, a decrease in hematocrit was seen at all doses. In the irradiated animals, the platelet count recovered earlier in the IL-6-treated dogs than in the controls, but no consistent change in the ploidy distribution was observed irrespective of dose. Large platelets were also noted in the treated animals, comprising up to 6.9% of the total platelet count. Fibrinogen levels were elevated to greater than 4 times normal. A significant decrease in hematocrit was seen in all animals, while no consistent change was noted in the white count. Elevations in serum cholesterol, triglycerides, and alkaline phosphatase, together with a decline in serum albumin were observed in all the treated animals (both normal and irradiated), but clinical symptoms were observed only in the dogs receiving greater than or equal to 80 micrograms/kg/d. The data show that IL-6 alone is capable of enhancing platelet recovery in dogs with bone marrow suppression.

Prior studies established that ultraviolet-B light (UVB) irradiation of platelet concentrates (PCs) at appropriate doses can eliminate the mixed lymphocyte culture-stimulating and -responding capacity of lymphocytes in the PCs without adversely affecting in vitro platelet function. The in vivo recovery and survival and in vitro characteristics of UVB-irradiated platelets were investigated in paired studies. PCs were stored for 1 day and then exposed to UVB. Platelet recovery, survival, and function were comparable to those of nonirradiated platelets. Recovery and survival of platelets stored for 5 days before UVB exposure were decreased relative to controls, although they were considered clinically acceptable. Paired transfusion studies were also performed in seven thrombocytopenic patients by using platelets obtained by apheresis. Comparable posttransfusion platelet increments and bleeding time corrections were obtained with both irradiated and control (nonirradiated) platelets. It can be concluded that platelets survive and function relatively normally in vivo after UVB irradiation sufficient to abolish lymphocyte reactivity in mixed lymphocyte culture. Long-term studies of UVB-irradiated PCs are needed to assess their potential in reducing recipient alloimmunization.

In experiments with gamma-irradiated (LD50/30) F1(CBA x C57Bl) hybrid mice, thrombocytopoietic effect of low-intensity laser radiation has been detected. The data obtained may be used in developing modes of haemopoiesis stimulation in a gamma-irradiated organism.

Repeated injections of recombinant human granulocyte colony-stimulating factor (rhG-CSF) to lethally irradiated mice increased the rate of animal survival. Dose modification factor was 1.20 when 4.5 micrograms/mouse of rhG-CSF was given daily for 14 days after whole body irradiation. Haematological examinations revealed that rhG-CSF increased the number of blood-circulating leukocytes, neutrophils, monocytes and erythrocytes, but not that of lymphocytes and thrombocytes. Spleen weight and number of endogenous spleen colonies were also increased by rhG-CSF treatment compared with the values for mice irradiated only.

In a multi-centre study strontium-89 was shown to be effective in relieving bone pain from prostatic carcinoma in patients who had failed conventional therapies. Of 83 patients assessed at 3 months, following the administration of a dose of at least 1.5 MBq/kg, 75% derived benefit and 22% became pain free. Symptomatic improvement usually occurred within 6 weeks and continued for between 4 and 15 months (mean 6 months). Based on the dose estimation part of this study the recommended dose of strontium-89 is 150 MBq. Toxicity was low, provided platelet levels were above 100 x 10(9) l-1 at the time of treatment. Repeat treatments with strontium-89 may be given at intervals of not less than 3 months. Strontium-89 is administered intravenously on an out-patient basis with no special radiological protection precautions.

A randomized trial was performed to compare two regimens of total body irradiation in patients with chronic myeloid leukemia treated by allogeneic marrow transplantation while in the chronic phase. All patients received cyclophosphamide 120 mg/kg followed by total body irradiation and marrow from HLA-identical siblings. Cyclosporine and methotrexate were used for prophylaxis against acute graft-versus-host disease. Fifty-seven patients were randomized to receive 2.0 Gy fractions of irradiation daily for 6 days and 59 were randomized to receive 2.25 Gy fractions daily for 7 days. The probabilities of relapse at 4 years were 0.25 for the 12.0 Gy group and 0.00 for the 15.75 Gy group (P = .008). The actuarial probabilities of survival and relapse-free survival at 4 years were 0.60 and 0.58 among the patients who received 12.0 Gy compared with 0.66 and 0.66 for those who received 15.75 Gy. The 4-year probabilities of transplant-related mortality were 0.24 and 0.34 respectively (P = .13) while the probability of moderate to severe acute graft-versus-host disease was 0.33 for the 12.0 Gy group and 0.44 for the 15.75 Gy group (P = .15). The lower relapse probability in the patients receiving the higher dose of total body irradiation did not result in improved survival because mortality from causes other than relapse was increased.

The anti-mouse antibody response was examined in patients receiving repeated i.v. therapy with radiolabelled mouse monoclonal antibody (MAb) to carcinoembryonic antigen (CEA): 131I anti-CEA was given approximately every 2 weeks with cyclosporin A, to suppress the anti-mouse antibody response. Two schedules of cyclosporin A--intermittent therapy for 6 days with each course of anti-CEA and continuous therapy--were compared. Suppression of the immune response in the intermittent high-dose (3 patients) and continuous low-dose groups (4 patients) was equivalent, but the latter regimen was less toxic. Repeated therapy led to the formation of small amounts of anti-mouse antibody, but provided that cyclosporin A was continued it did not prevent further therapy or lead to an increase in the rate of clearance of anti-CEA from blood. Without cyclosporin A no more than 2 courses of antibody therapy could be given. Patients received up to 4 doses of 131I anti-CEA. The nadir platelet count was related to the half-life of 131I anti-CEA in blood. Thrombocytopenia limited the amount of 131I anti-CEA that could be given and determined the interval between treatments. Effective suppression of the anti-antibody response is possible and this study has determined that myelosuppression is the principal obstacle to repeated therapy with radiolabelled antibody.

One of the major obstacles facing radioimmunotherapy (RIT) is the lack of a device to measure directly tumor and normal tissue radiation absorbed dose. Calculations based on the clearance and imaging scans have several limitations; hence we design and fabricate a sheathed clinical thermoluminescent dosimeter (TLD) for the measurement of absorbed dose by implantation in humans. Preclinical studies are performed in nine normal rabbits. Complete blood count, body temperature monitoring, clinical observation and necropsy show no untoward effects from the TLD. Consistent bone marrow radiation doses are noted in the four rabbits receiving 131I-labeled monoclonal antibody A6H. By using up to 20 clinical TLDs in one sheath, it will be possible to determine macroscopic heterogeneities in organs undergoing RIT.

The palliative efficacy of strontium-89 chloride has been evaluated in a prospective double-blind crossover study comparing it with stable strontium as placebo in 32 patients with prostate cancer metastatic to bone. Response was assessed 5 weeks after each treatment. 26 patients were evaluable. Complete pain relief was only reported following strontium-89 injection. Statistical comparison between placebo and strontium-89 showed clear evidence of a therapeutic response to strontium-89 compared with only a limited placebo effect (P less than 0.01).

Platelet counts were evaluated in 714 patients with advanced non-small cell lung cancer (N-SCLC), small cell carcinoma of the lung (SCCL), and colon cancer entered to a clinical trial. Patients had not received prior chemotherapy. Platelet counts were not different in patients who had received radiation therapy prior to entry to the study. In comparison to the other tumor types, patients with N-SCLC demonstrated an increased prevalence of thrombocytosis (counts greater than 400,000/mm3), higher platelet counts at the time of entry to the study, higher over all mean platelet counts, relative preservation of high platelet levels during disease progression, and no relationship between platelet numbers and the amount of chemotherapy given. By contrast, platelet counts in patients with SCCL were negatively correlated with the absolute amount of cyclophosphamide and adriamycin given, and declined most dramatically with disease progression and death. Platelet numbers did not correlate with fibrinopeptide A or fibrin split product levels suggesting that disseminated intravascular coagulation or fibrinolysis may have had less influence on platelet numbers than certain other factors. By contrast, significant correlations were found for all three tumor types between platelet numbers and other indicators of bone marrow function including anemia, total leukocyte count, and absolute neutrophil count; and the fibrinogen level. Based upon these findings, we postulate that the host response to malignancy, possibly in the form of production of bone marrow-stimulating cytokines, may play a prominent role in regulation of platelet counts in these (and perhaps other) neoplasms, and that a particularly prominent and persistent degree of marrow stimulation exists in patients with N-SCLC.

Forty dogs with spontaneous skeletal neoplasia were treated with 153Sm-EDTMP (ethylenediaminetetramethylene phosphonic acid). Both primary and metastatic lesions were treated. Two treatment regimes, a single (37 MBq (1.0 mCi)/kg dose or two 37 MBq (1.0 mCi)/kg doses separated by 1 wk) were tested. Response to treatment was varied. Large lesions with minimal tumor bone formation responded poorly, while primary lesions with substantial ossification usually exhibited a transient response. Small lesions with minimal lysis, metastatic lesions, and axial skeleton lesions generally responded well. The major adverse side effects of treatment were platelet and white blood cell count depression below baseline values for up to 4 wk (p less than 0.05). Minor depression of packed cell volume and transient elevation of serum alkaline phosphatase were also noted (p less than 0.05). No significant differences (p greater than 0.05) between the two treatment groups, either in treatment effect or undesirable side effects, were detected.

In order to investigate the role of blood platelets in regenerative proliferation of hepatocytes in vivo, partial hepatectomy was carried out under conditions of severe thrombocytopenia achieved by X-irradiation and the time-dependent degree of hepatocyte regeneration was measured as labeling index (LI) after 3H-thymidine injection. LI values reached a maximum 36 h after hepatectomy performed 7 days subsequent to a whole-body irradiation of 7.5 Gy, although the maximum rate was found to be only about one-third of that found in unirradiated control rats. At this time point, the number of peripheral blood platelets was decreased to about 2% of that of unirradiated controls and bone marrow megakaryocytes were virtually undetectable. A decrease of LI, similar to that found for the whole-body irradiation in degree, was also observed after local irradiation of the liver with the same dose but without an apparent decrease in platelets. When whole-body irradiation was performed with the liver shielded, under which conditions the numbers of blood platelets decreased to about 8% of the control levels, almost no decrease in LI was found. The results thus suggest that the observed inhibition of hepatocyte regeneration was directly due to liver irradiation and that depletion of blood platelets itself does not interfere with the regeneration process, providing evidence against a dominant role of the platelets in the regeneration as proposed by other authors.

We studied 10 male and 2 female normal non-smoker volunteers (mean age 25) by labeling of autologous platelets with 111-In oxine. Daily samples for platelet survival were obtained in all, gamma-camera images in 10 and blood pool digital subtraction with 99m-Tc labeled erythrocytes in 6. Mean platelet count was 594 +/- 235 10(3)/mm3; collagen platelet aggregation pre and post labeling was 74 +/- 4.8 and 70 +/- 10%, respectively. Mean labeling efficacy was 65 +/- 15.4%, mean labeling dose was 201 +/- 79.5 microCi. A linearized initial survival of 7.9 +/- 1 day was obtained. Scintigraphic images showed circulating activity, greater in the spleen, persisting after digital subtraction. The method described can be used for clinical evaluation of platelet disorders and thrombosis.

The effect of supernatant of thymus-cell conditioned medium (TCCM) on blood element recovery in peripheral blood was followed in mice exposed to a single whole body dose of 5.8 Gy of gamma radiation. As follows from our results. TCCM administered 18 h before irradiation accelerated the recovery of the reticulocyte and, in part, thrombocyte and granulocyte counts. However, no effect on the rate of lymphocyte recovery was found.

Whole abdominal irradiation after chemotherapy and second look laparotomy for advanced ovarian carcinoma is poorly tolerated because of hematologic toxicity that frequently necessitates interruption or abandonment of treatment. A new treatment strategy using a hyperfractionated split course schedule to deliver a total of 30 Gy in 30 fractions over 6 weeks was designed in an attempt to overcome this problem, while not compromising the tolerance of late reacting normal tissues. Of 23 patients treated between August 1984 and June 1986, only one failed to complete therapy as scheduled. Six patients with gross residual disease also received a limited field boost of 15 Gy in 15 fractions after completion of treatment to the whole abdomen. None of these six patients achieved disease control, and five required surgery for intestinal obstruction with pathologic evidence of radiation bowel injury. Of the 17 patients who received no boost, five developed gut obstructions associated with tumor recurrence and not attributable to irradiation. We conclude that whole abdominal irradiation using the hyperfractionated split course schedule without a boost is safe and feasible but its therapeutic efficacy appears confined to subsets of patients with no visible residual disease at the time of second look laparotomy, or in whom all visible residual tumor can be resected.