Oral cyclosporine A treatment is feasible after myeloablative conditioning in allogeneic hematopoietic stem cell transplantation.

WHAT IS KNOWN AND OBJECTIVE: The target level and route of administration of cyclosporine A (CsA) differ between transplantation centres. It is unclear whether oral CsA is sufficient to maintain target level of CsA. CASE SUMMARY: We retrospectively analysed data from 48 adult patients, who underwent myeloablative hematopoietic stem cell transplantation. Twenty-one patients (44%) tolerated CsA orally throughout the transplantation period without increased incidence of acute graft versus host disease(aGVHD). Low concentration of CsA in week 2 was associated with increased incidence of aGVHD. WHAT IS NEW AND CONCLUSION: Oral administration of CsA is safe, less time-consuming and economically advantageous. Close monitoring of CsA concentration is important.

Pilot study of a multimodal intervention: mixed-type exercise and psychoeducation in patients undergoing allogeneic stem cell transplantation.

Substantial physical and functional deconditioning and diminished psychological wellbeing are all potential adverse effects of allogeneic stem cell transplantation (allo-HSCT). The aim of this study was to evaluate the feasibility, safety and benefits (physical and functional capacity) of a 4-6 week supervised and structured mixed-type exercise, progressive relaxation and psychoeducation programme in patients undergoing allo-HSCT. Nineteen patients were randomized to an intervention or a conventional care group (CC) and were tested for physical and functional capacity before admission and upon hospital discharge. In all, 14 patients completed all study requirements (74%) and no adverse reactions that could be attributed to the intervention were observed. At the time of discharge, the intervention group showed significant improvements in several muscle strength scores as compared to the CC group; chest press (P=0.023), leg extension (P=0.007) and isometric right knee flexor (P=0.033). The intervention proved feasible, safe and well tolerated in this small sample of patients undergoing allo-HSCT. An intervention of this type may be a useful strategy for maintaining or improving muscle strength, and minimizing loss of physical and functional capacity in patients undergoing allo-HSCT.

Effect of recombinant human granulocyte-macrophage colony-stimulating factor in patients with Hodgkin's disease: a phase I/II study.

PURPOSE: As bone marrow toxicity is the major limitation of the optimal administration of chemotherapy, we investigated whether recombinant human granulocyte-macrophage colony-stimulating factor (rhGM-CSF) could prevent myelotoxicity or accelerate hematopoietic recovery after mechlorethamine, vincristine, procarbazine, and prednisone (MOPP) chemotherapy. PATIENTS AND METHODS: Twenty-four previously untreated patients with Hodgkin's disease were included in a phase I/II study in which standard MOPP chemotherapy was followed by 5 days of GM-CSF at every other cycle. Patients were entered sequentially to receive one of four dosc levels (2, 4, 8, and 16 micrograms/kg of glycoprotein; 1.4, 2.8, 5.5, and 11.0 micrograms/kg of protein) and were randomly allocated to either 24-hour continuous intravenous (IV) infusion or twice daily subcutaneous (SC) injection of rhGM-CSF. RESULTS: WBC counts (mainly neutrophils, eosinophils, and monocytes) were significantly higher in cycles with rhGM-CSF than in cycles with MOPP alone. The total number of days of leukopenia (WBC count less than or equal to 2.0 x 10(9)/L) and neutropenia (absolute neutrophil count [ANC] less than or equal to 1.0 x 10(9)/L) was reduced in cycles with rhGM-CSF from 6.3 to 0.8 days and from 5.4 to 1.0 days, respectively. All dose levels of rhGM-CSF were effective in increasing the ANC, but only at the dose levels of 8 and 16 micrograms/kg did this significantly affect the scheduling of chemotherapy. Mild and reversible adverse reactions included low-grade fever, chest/bone pain, myalgias, erythemia, headache, fatigue, and periorbital edema. CONCLUSIONS: rhGM-CSF can be administered safely to patients with Hodgkin's disease and results in improved hematologic recovery after MOPP. Full-dose chemotherapy can be administered on time, resulting in an increase in the overall tolerated dose of myelosuppressive drugs when compared with historical controls. SC administration proved to be at least as effective as continuous IV infusion and should be preferred.

Development and application of a sensitive radioimmunoassay for human granulocyte-macrophage colony-stimulating factor able to measure normal concentrations in blood.

A radioimmunoassay (RIA) for human granulocyte-macrophage colony-stimulating factor (GM-CSf) was developed based on antibodies from rabbits immunized with glycosylated recombinant human (rh) GM-CSF. The antibodies are specific for human GM-CSF and do not crossreact with other human hematopoietic growth factors or mouse GM-CSF. The antibodies also react with nonglycosylated rhGM-CSF, so E. coli-derived rhGM-CSF can be assayed as well. The RIA has a measuring range of about 10 to 200 pg/mL. Normal blood was found to contain 13 to 24 pg/mL (95% limits) with a mean of 18.5 pg/mL (n = 34). Monoclonal antibodies against GM-CSF could remove GM-CSF from normal human serum, thus ensuring that the GM-CSF measured in serum is real and does not represent nonspecific reactivity with our polyclonal rabbit antibodies. While previously published methods have been unable to measure GM-CSF in human serum under normal conditions, our more sensitive RIA does confirm the presence of small amounts of GM-CSF in serum or plasma and can therefore be used to detect fluctuations of GM-CSF in health and in disease.

S-phase induction by interleukin-6 followed by chemotherapy in patients with refractory multiple myeloma.

The plasma cell labeling index (PCLI) in patients with multiple myeloma (MM) is relatively low and this has been associated with the low rate of remission following chemotherapy. Interleukin-6 (IL-6) has been demonstrated to be a major growth factor of myeloma cells. In order to increase the S-phase proportion of myeloma cells, which might increase the sensitivity to chemotherapy, we gave rhIL-6 followed by chemotherapy to 15 myeloma patients with refractory disease. A total of 25 treatment cycles were administered since ten patients had two cycles. The rhIL-6 dose was 2.5 (n = 3), 5.0 (n = 6) and 10.0 microg/kg (n = 6) by subcutaneous injection once daily for 5 days and chemotherapy was administered on the last day of rhIL-6 injection. The effect of rhIL-6 treatment on labeling index (LI) was heterogeneous, but no statistically significant change was noted for this particular group as a whole. In two patients an increase (mean 7.7%) in LI of mononuclear bone marrow cells during the rhIL-6 treatment was demonstrated and in one patient a decrease of 2.8% was seen. Assessment of PCLI demonstrated an increase of 2.9% in one out of six patients and a decrease of 1.9% in one out of six patients. None of the 15 patients achieved remission according to standard criteria. During the rhIL-6 treatment, 14 of the 15 patients developed mild constitutional adverse events (AE) well known in patients treated with IL-6, and none of the AE in the subsequent chemotherapy phase were related to IL-6. In conclusion, our study demonstrated that rhIL-6 can be administered safely to patients with refractory MM, but the cell cycle recruitment approach was not sufficiently effective to be of clinical value.

A phase I/II study of dose and administration of non-glycosylated bacterially synthesized G-M CSF in chemotherapy-induced neutropenia in patients with non-Hodgkin's lymphomas.

Recombinant human granulocyte-macrophage colony-stimulating factor (rhGM-CSF) derived from E. coli was administered to 24 previously untreated patients with non-Hodgkin's lymphoma following the first cycle of CHOP chemotherapy. Four dose levels were examined, 1.5, 3.0, 5.5 and 11 micrograms/kg and patients were randomized to receive the drug either once or twice daily subcutaneously (s.c.). During rhGM-CSF treatment, the leucocyte counts increased up to 3-4 fold in 20/24 patients, reaching a peak 24-48 (mean 35) hours after initiation of rhGM-CSF. The leukopenic period in cycle one of the CHOP chemotherapy with rhGM-CSF, was shorter than after the course of chemotherapy without rhGM-CSF and also shorter when compared to cycle one of CHOP in the 127 historical controls (p < 0.05 and p < 0.001 respectively). Similar results were observed for neutrophil counts. No effect was seen on platelet counts at nadir but a significant, although moderate increase occurred in the recovery period on days 15 and 22 when compared to control cycles and historical controls. When dose levels were compared, there was only a trend to higher WBC counts at the higher dose groups (5.5 and 11 micrograms/kg) when compared to the two lower dose groups (1.5 and 3.0 micrograms/kg). In the overall evaluation there was no statistical significant difference in results between patients treated s.c. once daily versus twice daily. However when only the two highest dose levels (5.5 + 11 micrograms/kg) were compared, s.c. administration of rhGM-CSF twice daily led to higher leucocyte counts than once daily in the recovery period on day 15 (p < 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

Effect of Granulocyte-Macrophage Colony-Stimulating Factor on Chemotherapy-Related Neutropenia in Patients with Non-Hodgkin's Lymphomas-A Phase I/II Study of Dose and Mode of Administration.

The effect of mammalian glycosylated recombinant granulocyte-macrophage colony-stimulating factor was investigated in 24 patients with newly diagnosed non-Hodgkin's lymphoma in a phase I/II study. All patients received standard chemotherapy with CHOP. RhGM-CSF was administered after the first cycle for 5 days, and at one of four dose levels (2, 4, 8 and 16 µg/kg). Patients were randomized to receive the drug either by continuous intravenous infusion or twice daily as subcutaneous injection. No significant difference in results was observed between subcutaneous administration of rhGM-CSF and continuous i.v. infusion and these patient groups could therefore be combined in the analysis. Administration of rhGM-CSF resulted in a significant dose-dependent increase of total WBC, mainly neutrophils, eosinophils and monocytes. The increase was observed in 18/24 patients, reaching a peak 24-72 (median 24) hours after the start of rhGM-CSF. The CHOP chemotherapy-induced leucocyte nadir occurred on day 12 (mean) compared to day 14 for the 127 historical controls. The WBC nadir values were higher (2.4 ± 1.4) than for historical controls (1.8 ± 1.1) and the leucopenic/neutropenic period was of shorter duration. Following the chemotherapy nadir a more rapid recovery of WBC was seen than in controls. GM-CSF was well tolerated, the side effects were mild and transient, and included myalgias, low grade fever, headache, chest/bone discomfort, nausea, erythema at injection site and superficial phlebitis. The encouraging results of this phase I/II study indicate the need for a prospective controlled study of GM-CSF in chemotherapy of malignant lymphoma.

Granulocyte colony stimulating factor in neutropenic patients with infective endocarditis.

A well known complication in the treatment of infectious endocarditis is development of neutropenia caused by treatment with antibiotics in high concentrations over long periods. Neutropenia often necessitates discontinuation of antibiotic treatment. Three patients with infectious endocarditis who developed neutropenia are reported. The patients were treated with granulocyte colony stimulating factor (G-CSF), a haematopoietic growth factor that stimulates neutrophils. G-CSF induced an immediate increase in white blood cell count, primarily neutrophils. G-CSF may be effective in ameliorating neutropenia in patients who receive antibiotics for treatment of infectious endocarditis.

Chronic Achilles tendinopathy in athletic individuals: results of nonsurgical treatment.

We report the results of nonsurgical treatment of chronic Achilles tendinopathy in 22 patients with a follow-up of 33 to 72 months. Immediately after the treatment period, 70% of the patients were either improved or cured. At follow-up, 65% were improved or cured, and 35% failed treatment or had a poor long-term result. In these patients, early surgery might have been considered, but only one patient received a peritendinitis operation in the follow-up period. In athletic individuals with chronic Achilles tendinopathy, nonsurgical treatment with emphasis on active training is recommended. Surgery should be considered if the athlete has been treated for 3 to 6 months without progress.

A randomized trial on the effect of a multimodal intervention on physical capacity, functional performance and quality of life in adult patients undergoing allogeneic SCT.

The aim of this randomized controlled trial was to investigate the effect of a 4- to 6-week multimodal program of exercise, relaxation and psychoeducation on physical capacity, functional performance and quality of life (QOL) in allogeneic hematopoietic cell transplantation (allo-HSCT) adult recipients. In all, 42 patients were randomized to a supervised multimodal intervention or to a control group receiving usual care. The primary end point was on aerobic capacity measured in VO(2) max. Secondary end points were muscle strength, functional performance, physical activity level, QOL, fatigue, psychological well-being and clinical outcomes. The multimodal intervention had a significant effect on physical capacity: VO(2) max (P<0.0001) and muscle strength: chest press (P<0.0001), leg extension (P=0.0003), right elbow flexor (P=0.0009), right knee extensor (P<0.0001) and functional performance (stair test) (0.0008). Moreover, the intervention group showed significantly better results for the severity of diarrhea (P=0.014) and fewer days of total parenteral nutrition (P=0.019). Longitudinal changes in QOL, fatigue and psychological well-being favored the intervention group, but did not reach statistical significance. Assignment of a multimodal intervention during allo-HSCT did not cause untoward events, sustained aerobic capacity and muscle strength and reduced loss of functional performance during hospitalization.

The social and economic consequences of finger amputations.

120 patients with amputation of at least 1 of the 4 ulnar fingers were admitted to hospital. In none was replantation considered to be possible because of serious damage to the soft tissues and bone. 12 (3-18) years after the accident 80 percent of the patients assessed their condition as good or fair, even those with proximal amputation or loss of 2 or 3 fingers. Our observations do not support replantation when only one of the second-to-fifth fingers have been amputated.

Effects of interleukin-3 following chemotherapy of non-Hodgkin's lymphoma. A prospective, controlled phase I/II study.

The effect of rhIL-3 was investigated in 32 patients with newly diagnosed non-Hodgkin lymphoma in a phase I/II trial. All patients received 6 cycles of standard CHOP chemotherapy, and each patient was his own control where rhIL-3 was given as a daily s.c. injection for 14 days (day 2-15) in cycle 2 and 4, while cycle 1 and 3 were control cycles. Five dose levels were examined (0.5 - 1 - 5 - 7.5 - 10 micrograms/kg). Compared to the other more lineage-specific hemopoietic growth factors G- and GM-CSF, the effect of rhIL-3 on the hemopoiesis was less dramatic and more delayed, i.e. the most apparent effect was observed in the 2 weeks of treatment. Thus, the neutrophil counts from days 15 to 22 following CHOP were significantly raised and the duration of neutropenia was shorter (significantly only at 10 micrograms/kg), while the nadir values were unaffected. Platelet recovery from days 12-22 was significantly increased and nadir values occurred earlier compared to control cycles, but were only increased in some subsets. Other cell populations affected moderately in the recovery period were eosinophils and monocytes. Reticulocytes increased, but no effect on hemoglobin or RBC transfusion requirement was noted. Only moderate adverse reactions occurred such as fever, chills, flushing of the face and flu-like symptoms. There was no evidence of stimulation of tumor growth. Most significant, the rhIL-3 treatment at all but the lowest dose levels led to an improved tolerance to chemotherapy, as indicated by a decline in number of delayed cycles. A conclusion concerning the role of rhIL-3 as post-chemotherapy adjuvant should await studies using rhIL-3 in combination with more lineage-restricted hemopoietic growth factors.

The in vivo effects of interleukin-3 on histamine levels in non-Hodgkin's lymphoma patients.

Recombinant human Interleukin-3 (RhIL-3) is a haemopoietic growth factor with effect both on early and differentiated cells, such as eosinophils and basophils, and it also acts as a histamine-releasing agent. The purpose of the present study was to examine whether in vivo rhIL-3 administration after chemotherapy affected basophil histamine levels and whether a concordance between rhIL-3 induced histamine release and side effects during the treatment could be demonstrated. Thirty patients with non-Hodgkin's lymphoma entered the study. All patients received 6 courses of chemotherapy, rhIL-3 was administered subcutaneously once daily after the second and the fourth course of chemotherapy from cycle day 2-15 at the dose levels 0.5, 1.0, 5.0, 7.5 and 10 micrograms/kg with 6 patients at each dose level. In cycle 6 recombinant human Granulocyte-Macrophage Colony-Stimulating Factor (rhGM-CSF) (3.0 micrograms/kg) was administered sequential/concurrent day 9-15 to rhIL-3 (day 2-15) at all dose levels except 7.5 micrograms/kg, where rhIL-3 was given day 2-8 and rhGM-CSF sequential day 9-15. Cycles 1, 3 and 5 served as control cycles with no cytokine therapy. During rhIL-3 treatment, and after CHOP chemotherapy, the basophil counts increased moderately especially during the recovery period day 15-22, and mainly at the two highest dose levels 7.5 and 10 micrograms/kg, but never exceeded the normal upper limit. Histamine levels in basophils were the same in patients before chemotherapy and healthy volunteers, and except from a trend to increased histamine level at 10 micrograms/kg on day 15, no difference was noted between rhIL-3 cycles and control cycles. Within 3-4 hr after rhIL-3 administration, a drop in histamine level in basophils was noted, which could be due to histamine-releasing properties of rhIL-3 as previously demonstrated by in vitro studies. No serious side effects were noted during the cytokine treatment, and despite that most patients had mild flushing of the face, neck and upper chest, no patients experienced sensitization throughout the study. Although a significant increase in rhIL-3-induced histamine release from basophils was noted in some of the patients, no correlation to the dose of rhL-3 was found, and no correlation was noted between side effects and histamine release or histamine levels in basophils.

Serum hyaluronan is increased in malignant lymphoma.

The serum concentration of hyaluronan (HYA) was measured in 41 patients with malignant lymphoma, including 21 patients with non-Hodgkin's malignant lymphoma and 20 patients with Hodgkin's disease. Thirty-four patients were studied at diagnosis. The remaining 7 patients had relapsing or resistant disease. The patients were categorized into four stages according to conventional staging procedures. The median serum HYA concentration in patients with malignant lymphoma was significantly higher (median 40.7 ng/ml; 95% confidence limits 26.1-57.6 ng/ml) than in an age-matched healthy reference group (median 14.5 ng/ml, 95% confidence limits 11-19.4 ng/ml) (P = 0.00032). The highest serum HYA levels were found in patients with relapsing/resistant disease, all being in stages III and IV (median 181.5; range 11.9-500 ng/ml), as compared to previously untreated patients (median 29.8; range 9.1-108) (P = 0.0002) and controls (median 14.2; range 6.7-51.2). Decreased uptake and degradation of HYA owing to malignant transformation of lymphatic tissue is the most plausible explanation to these findings.

Bacteremia and candidemia in hematological malignancies: microbiological findings and antibiotic susceptibilities.

The microorganisms isolated in 1981-1985 from 171 cases of septicemia in patients with hematological malignancies were on the whole the same as those found in 1970-1972. The distribution between species was also quite similar for the two periods except within staphylococci, where the isolation rate of coagulase-negative staphylococci was higher in the latter period while that of Staphylococcus aureus was lower. Of 67 strains of Enterobacteriaceae tested for an aminoglycoside, 6% were found to be resistant, whereas 8% of 48 Enterobacteriaceae strains were found to be cefotaxime resistant. Methicillin- or aminoglycoside resistant S. aureus did not occur.