Stable mixed chimerism and tolerance using a nonmyeloablative preparative regimen in a large-animal model.

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.

Chronic radiation-induced alteration in hematopoietic repair during preclinical phases of aplastic anemia and myeloproliferative disease: assessing unscheduled DNA synthesis responses.

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.

Effects of rhIL-11 on normal dogs and after sublethal radiation.

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)

A prospective, randomised double-blind crossover study to examine the efficacy of strontium-89 in pain palliation in patients with advanced prostate cancer metastatic to bone.

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).

A dose-controlled study of 153Sm-ethylenediaminetetramethylenephosphonate (EDTMP) in the treatment of patients with painful bone metastases.

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.

Influence of whole-body gamma irradiation upon arachidonic acid metabolism in rat platelets.

The effects of whole-body gamma irradiation (8.4 Gy) were studied on arachidonic acid (AA) metabolism in rats' blood platelets, from day D + 1 to day D + 10 after irradiation. AA conversion into thromboxane B2 (TxB2) increased at D + 1 and then gradually decreased to very low values from D + 7 to D + 10. This decrease in the conversion of exogenous AA into TxB2 was due to a lower AA incorporation into platelets and not to a decrease of cyclooxygenase and thromboxane-synthetase activities. AA incorporation into membrane phospholipids of blood platelets was much more decreased than AA incorporation into whole platelets; moreover, the lipid composition of the platelet membranes was markedly modified after irradiation, which must have resulted in structural and functional changes in these membranes; from these effects of whole-body gamma irradiation on platelets, the latter's membranes appeared as a major site of in vivo radiation damage in these cells.

Outcome of radiation therapy for patients with Kasabach-Merritt syndrome.

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.

The utility of serial complete blood count monitoring in patients receiving radiation therapy for localized prostate cancer.

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.

Hyperfractionated split-course whole abdominal radiotherapy for ovarian carcinoma: tolerance and toxicity.

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.

Analysis of weekly complete blood counts in patients receiving standard fractionated partial body radiation therapy.

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.

Evaluation of thrombocytopenia in patients treated with rhenium-186-HEDP: guidelines for individual dosage recommendations.

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.

Clinical and clinicopathologic response of canine bone tumor patients to treatment with samarium-153-EDTMP.

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.

Bone marrow absorbed dose of rhenium-186-HEDP and the relationship with decreased platelet counts.

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.

The platelet count in carcinoma of the lung and colon.

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.

Predictors for optimal mobilization and subsequent engraftment of peripheral blood progenitor cells following intermediate dose cyclophosphamide and G-CSF.

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.

Total lymphoid irradiation in the treatment of early or recurrent heart rejection.

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.

Mediastinal irradiation for graft-versus-host disease in a heart-lung transplant recipient.

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.

High-dose chemotherapy with autologous marrow rescue for malignant brain tumors: analysis of the impact of prior chemotherapy and cranio-spinal irradiation on hematopoietic recovery.

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.

Ultraviolet-A light in the treatment of rheumatoid arthritis.

Ultraviolet-A (UV-A) light penetrates the epidermis, reaches the macrophages and circulating mononuclear cells within the dermis, and has immunoregulatory effects in humans. We examined the effect of UV-A irradiation on disease activity in 26 patients with rheumatoid arthritis (RA) and on immunologic function in these patients and in 11 normal subjects. Ten joules/cm2/day of total body UV-A irradiation, given 5 days each week for 3 weeks, resulted in significant improvement in the duration of morning stiffness, fatigue, joint tenderness, joint swelling, grip strength, patient assessment of disease activity, and physician assessment of disease activity. Platelet counts decreased significantly in the RA patients. Phytohemagglutinin (PHA)-stimulated lymphocyte production of interleukin-2 (IL-2) increased significantly in the combined RA and normal groups. These results suggest that UV-A light may be effective in the treatment of patients with RA, but elucidation of its precise role will require further study including double-blind trials.

Haematopoietic radioprotection by Cremophor EL: a polyethoxylated castor oil.

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.