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Poor graft function (PGF), including early and late PGF, is a serious complication following allotransplant. We recently reported that bone marrow microenvironment abnormalities may occur in cases of late PGF. Whether these abnormalities occur in early PGF remains unknown. To answer this question, we performed a nested case-control study comparing cellular elements of the bone marrow microenvironment in 10 subjects with early PGF, 30 subjects with late PGF and 40 subjects without PGF. Bone marrow endosteal cells, perivascular cells and endothelial cells were analyzed by flow cytometry and by hematoxylin-eosin and immunohistochemical staining in situ. Subjects with early and late PGF had similar abnormalities in these cell types compared with transplant recipients without PGF. However, none of the aforementioned elements of the bone marrow microenvironment were significantly different between early and late PGF patients. Our data suggest that similar abnormalities in the bone marrow microenvironment may occur in early and late PGF post allotransplant. Cellular approaches, such as the administration of mesenchymal stem cells, promise to be beneficial therapeutic strategies in patients with early or late PGF.

Chronic impairment of cardiac function can be an important health risk and impair the quality of life, and may even be life-threatening for long-term survivors of allogeneic hematopoietic cell transplantation (HCT). However, risk factors for and/or the underlying mechanism of cardiac dysfunction in the chronic phase of HCT are still not fully understood. We retrospectively investigated factors affecting cardiac function and left-ventricular hypertrophy (LVH) in the chronic phase of HCT. Sixty-three recipients who survived for >1 year after receiving HCT were evaluated using echocardiography. Based on simple linear regression models, high-dose TBI-based conditioning was significantly associated with a decrease in left-ventricular ejection fraction and the early peak flow velocity/atrial peak flow velocity ratio, following HCT (coefficient=-5.550, P=0.02 and coefficient=-0.268, P=0.02, respectively). These associations remained significant with the use of multiple linear regression models. Additionally, the serum ferritin (s-ferritin) level before HCT was found to be a significant risk factor for LVH on multivariable logistic analysis (P=0.03). In conclusion, our study demonstrated that a myeloablative regimen, especially one that involved high-dose TBI, impaired cardiac function, and that a high s-ferritin level might be associated with the development of LVH in the chronic phase of HCT.

To investigate the risk factors for acute GVHD (aGVHD), based on NIH consensus criteria (NCC), we evaluated 775 patients who underwent allogeneic transplantation. Of them, 346 patients developed aGVHD by NCC, in whom we also analyzed factors affecting aGVHD-specific survival. The cumulative incidence of aGVHD was 44.7%, consisting of classic aGVHD (n=320) and late-onset (n=26). Multivariate analyses revealed that younger age (P=0.015), unrelated donors (P=0.004) and acute leukemia compared with other hematologic malignancies (P=0.005) were significant risk factors for aGVHD, whereas PBSCs showed no association (P=0.720). Multivariate analyses, with only aGVHD patients, revealed that late-onset aGVHD had superior aGVHD-specific survival to classic aGVHD (P=0.044), and identified the association of visceral organ involvement (P=0.002), severity of aGVHD at onset (P=0.035) and advanced disease status (P<0.001) with inferior aGVHD-specific survival. In conclusion, this study demonstrates the risk and prognostic factors for aGVHD by NCC with some differences with the previous reports that were based on old criteria. The difference in the risk factors according to different criteria will give insights about the pathophysiology of GVHD. The better prognosis of late-onset aGVHD than of classic aGVHD raises the necessity for prospective trials with a large cohort focusing on the onset time.

Children undergoing hematopoietic SCT (HSCT) typically receive parenteral nutrition (PN) due to gastrointestinal toxicities. Accurate determination of resting energy expenditure (REE) may facilitate optimal energy provision and help avoid unintended overfeeding or underfeeding. A multicenter, prospective cohort study of children undergoing allogeneic HSCT was performed, in which REE was measured by indirect calorimetry at baseline and twice weekly until 30 days after transplantation. Change in percent predicted REE over time from admission was analyzed using repeated measures regression analysis. In all, 26 children (14 females) with a mean (s.d.) age of 14.9 (4.2) years who underwent an HLA-matched sibling or unrelated donor transplantation were enrolled. Mean (s.d.) percent predicted REE at baseline was 92.4 (15.2). Baseline REE was highly correlated with lean body mass measured by dual energy X-ray absorptiometry (r=0.78, P<0.0001). REE decreased significantly over time, following a quadratic curve to a nadir of 79% predicted at 14 days post transplantation (P<0.001) and returned to near baseline by day 30. Children undergoing HSCT exhibit a significant reduction in REE in the early weeks after transplantation, a phenomenon that places them at risk for overfeeding. Serial measurements of REE or reductions in energy intake should be considered when PN is the primary mode of nutrition.

In this 3-year prospective inpatient study, 220 patients received stem-cell transplantation (SCT) for hematologic cancer at a single institution. The objective of the study is to provide data on patient-rated emotional (depression and anxiety) and physical (overall physical status, energy level, and systemic symptomatology) functioning during hospitalization for SCT and to compare whether these differ between autologous and allogeneic SCT. Patients were assessed at hospital admission (T1), day of SCT (T2), and 7 days (T3) and 14 days (T4) after SCT, yielding a total of 852 evaluations. For the overall sample, anxiety was highest at T1 and decreased afterwards; a marked worsening in physical health status variables corresponded with a sharp increase in depression from T1 to T3, and was followed by an improvement in physical health and a reduction of depression. Compared to allogeneic SCT, a better physical outcome for autologous SCT was demonstrated by the significant group effect for systemic symptomatology and by the significant group x time interaction for overall physical status and energy level; there were no significant differences in depression or anxiety between SCT groups. These findings have implications for treatment decision making, coping with the transplantation process, and improving prevention and treatment strategies.

Prior studies suggest that patients undergoing hematopoietic stem cell transplantation (HSCT) for malignancy have nutritional needs that are greater than their estimated needs. To determine whether energy estimation equations accurately predict energy expenditure of pediatric patients undergoing HSCT, we prospectively compared the estimated energy expenditure (EEE) and measured energy expenditure (MEE) of 40 patients at four time-points. We also investigated whether energy requirements changed during the transplant period. MEE was determined by indirect calorimetry. Data from 34 patients (autologous HSCT = 10, allogeneic HSCT = 24) were sufficient for analysis. The World Health Organization equation adequately approximated MEE only on day 14 after HSCT. At all other time-points, measured energy expenditure was significantly less than estimated energy expenditure obtained by using the WHO equation (applicable to all patients), the Seashore equation (for patients <15 years of age; n = 19), or the Harris-Benedict equation (for patients > or =15 years of age; n = 15). The median measured energy expenditure varied significantly over the study period and was greatest on day 14 after HSCT. Until accurate equations have been identified for estimating these patients' needs, the use of indirect calorimetry may be medically warranted.

Recent research has shown that cancer patients undergoing bone marrow transplantation (BMT) experience moderate to severe mouth pain due to treatment-related mucositis in spite of morphine therapy. Treatment-related emotional distress in BMT patients is also described widely. This study examined several biomedical, psychological and social variables as possible predictors for the intensity of treatment-related mouth pain and anxious mood in 63 cancer patients undergoing BMT or stem cell transplantation (SCT) within a prospective longitudinal design. Biomedical predictors included biomedical risk, mucositis, the mode of transplantation, total body irradiation, age and gender. Psychological predictors were depression (BDI), BMT-related distress, chronic stress and resources in everyday life (KISS), pain-related coping behaviour (KPI-17) and social support (ISSS). Among the social variables we evaluated education, being married and the living situation. Criteria variables were the intensity of mouth pain and anxious mood which were assessed daily by numeric self-rating scales for 24 days after transplantation. Results of stepwise multiple regressions indicated that psychological and social variables were important predictors of mouth pain, besides biomedical variables. Whereas the biomedical variables revealed the most predictive power during the second week after BMT, psychological predictors were more important during the early and late phases of the treatment. Daily anxious mood was best predicted by psychological and social variables. Among the biomedical variables mucositis was most strongly related to mouth pain besides mode of transplantation, risk, TBI and age. Among the psychological variables BMT-related distress was the most important predictor, with resources in private life or at work and pain-related coping modes as further significant predictors. These results imply that relevant predictors should be assessed as high risk factors for an increased vulnerability for treatment-related side-effects before treatment starts indicating an additional offer of psychological treatment in high risk patients.

In order to examine the effect of hematopoietic stem cell transplantation (HSCT) on cardiac systolic function, we measured left ventricular ejection fraction (LVEF) by radioventriculography (RVG) before and after the transplantation procedure. One hundred and forty-eight patients were examined, 96 undergoing allogeneic grafting and 52 autologous. Fifty patients had CML, 48 AML, 21 ALL, 18 multiple myeloma and 11 breast cancer. The second RVG examination was performed 22 to 227 days (median 60 days) after HSCT. The mean LVEF value in the whole patient group was 60.2% (range 39-81%) before and 61.1% (35-86%) after transplantation. Patients with CML had significantly higher LVEF before transplantation than patients with acute leukemia (P = 0.007) and multiple myeloma (P = 0.005). No significant changes in mean LVEF between the pre- and post-transplant measurements were seen in any of the diagnostic subgroups or in allogeneic or autologous recipients. None of the 148 patients in the study has shown any signs of clinical heart failure at 2, 5 to 10 years follow-up. Patients who had received anthracyclines in the previous treatment had significantly lower LVEF before transplantation but showed no increased risk of decline in cardiac function. In conclusion, the HSCT procedure does not seem to affect myocardial function 1-7 months after transplantation.

Several studies have reported a reduced pulmonary diffusion capacity for carbon monoxide after total body irradiation (TBI) and/or high-dose chemotherapy (HDCT) and autologous peripheral blood progenitor transplantation (APBPC). The present study describes the oxygenation of arterial plasma (paO2), the maximum exercise capacity (Wmax) and maximum oxygen transport (VO2max) before and after such treatment. Pulmonary gas exchange and paO2 were measured in 15 patients at maximum dynamic bicycle exercise, performed before and at 8+/-0.9 (s.e.m.) months after TBI/HDCT (n = 12) and HDCT (n = 3) followed by APBPC. Wmax was 169+/-14 and 157+/-15 watts (P>0.05) before and after therapy, respectively. VO2max, 1.8+/-0.1 l/min before treatment, fell to 1.6+/-0.1 l/min (P<0.05) after therapy. The maximum exercise paO2 was 13.2+/-0.4 kPa before and 13.6+/-0.4 kPa (P>0.05) after the treatment period. The findings indicate no significant reduction of Wmax or pulmonary diffusion capacity for O2 after TBI/HDCT and APBPC while VO2max fell modestly by approximately 11%. The study was restricted to patients who remained in remission.

An interim report evaluating the feasibility of myeloablative therapy followed by peripheral blood stem cell (PBSC) autotransplant in patients aged >60 years is presented. In the last 2 years 19 patients >60 years old with several oncological conditions, mostly hematological, underwent PBSC autotransplant either as salvage therapy following relapse or resistance to conventional treatment, or as consolidating therapy as a part of a well defined protocol. There were 13 males and six females; the mean age was 66.9 years (range 61-76 years); nine patients had resistant or relapsed lymphoma, six myeloma, two acute leukemia, one Waldenstrom's disease and one lung cancer. Myeloablative schemes included BEAM exclusively for lymphomas, busulfan and melphalan (Bu-MPH) mainly for myeloma, busulfan and cyclophosphamide (Bu-CTX) for lymphomas and leukemia and VP-16 and CTX for lung cancer. Mobilization of CD34+ cells was achieved in all patients with the combination of high-dose CTX and G-CSF with collections between 2.83 to 19.04 x 10(6)/kg (mean 7.1). All patients engrafted with a median time for recovery of PMN (>0.5 x 10(3)/microl) of 10 days (range 8-12 days) and for PLT (>20 x 10(3)/microl) of 12 days (range 10-17 days). Major responses were obtained in 15 of 16 patients evaluable for response and eight patients entered CR; overall eight patients are in CR, five are alive with disease, five are dead from disease progression and one is dead because of congestive heart failure 7 months following PBSC autotransplant. No early deaths following the procedure occurred; major side-effects were grade I-II mucositis (58%), fever with documented sepsis (10%), pneumonia (5%), cardiac, renal and liver toxicity (5%). Cardiac function was evaluated before and after myeloablative therapy by VEF in all patients; no significant modifications were necessary. In conclusion, our experience demonstrates that myeloablative therapies in older selected patients can be feasible; the feasibility of introducing PBSC autotransplantation following myeloablative therapy as a front-line treatment in patients aged >60 years, needs accurate guide lines for selection of appropriate patients.

lnterleukin-2 (IL-2) is known to cause xerostomia and skin manifestations similar to graft-versus-host disease (GVHD). We therefore evaluated major salivary gland function in patients with hematological malignancies treated with IL-2 and interferon-alpha (IFN-alpha) after ABSCT. Eleven patients (seven male, four female) of median age 40 (24-47) were evaluated, seven with non-Hodgkin lymphoma (NHL); one with Hodgkin's disease (HD) and three with acute myelogenous leukemia (AML). Parotid and submandibular salivary gland function was assessed before, during and after IL-2/IFN-alpha administration by evaluation of the salivary flow rate and the composition of secreted saliva. Significant reductions in both the resting and stimulated parotid and submandibular salivary flow rates were observed during IL-2/IFN-alpha immunotherapy compared with the pre- and post-therapy values (P < 0.01), while no hyposalivation was observed in the control patients who underwent ABSCT and did not received IL-2. Sialochemical evaluation revealed a significant increase in potassium concentration (24.4+/-0.6 mEq/l to 28.9+/-1.4 mEq/l) and a significant decrease in sodium concentration (6.7+/-2.1 mEq/l to 3.3+/-1.0 mEq/l) (P < 0.05) in the stimulated parotid gland saliva secreted during IL-2/IFN-alpha administration. Salivary protein concentrations were not altered by the IL-2/IFN-alpha immunotherapy. Similar changes were previously observed in mice and humans with chronic GVHD. We conclude that IL-2 immunotherapy induces major salivary gland dysfunction in humans, similar to our previous observations in patients with chronic GVHD, which may indicate similar pathophysiologic mechanisms.

Pubertal development and androgen production were evaluated 1-10 years after bone marrow transplantation (BMT) in 15 females aged 14-23 (mean 17) years. Before BMT, these patients had received combination chemotherapy for hematologic malignancy, and all had had a transplant program including total body irradiation (TBI). Of the nine patients who were pre-menarcheal at BMT, two had subsequently experienced spontaneous menarche at 11.5 and 13.3 years of age. Six were post-menarcheal, but became amenorrheic after BMT. Menstruation subsequently started spontaneously in one of them 6 years after BMT. At the time of the study, three patients were early to mid-pubertal and 12 late pubertal or post-pubertal. Twelve patients were receiving sex steroid substitution therapy. Serum concentrations of testosterone, androstenedione, dehydroepiandrosterone (DHEA) and DHEA sulfate (DHEAS) were determined. Androgen levels of late pubertal and post-pubertal transplanted patients were compared with 19 post-menarcheal patients aged 14-21 (mean 17) years who had been treated for hematologic malignancy with conventional chemotherapy. Testosterone levels of 52 healthy post-menarcheal females aged 14-29 (mean 19) years were measured as controls. Androgen levels of the BMT patients were lower than those of the conventionally treated patients. Differences in testosterone, androstenedione and DHEA levels were significant. Three spontaneously menstruating BMT patients had normal androgen levels. Testosterone levels of the conventionally treated patients and healthy controls were similar. Subnormal androgen production might be one factor behind the problems in pubertal development and sex life experienced by females after BMT. The use of these hormone levels for follow-up purposes and the potential value of androgen replacement therapy in females after TBI merit further study.