Vitamin D supplementation for children with cancer: A systematic review and consensus recommendations.

BACKGROUND: Prevalent vitamin D deficiency (VDD) and low bone mineral density (BMD) have led to vitamin D supplementation for children with cancer, regardless vitamin D status. However, it remains unsettled whether this enhances bone strength. We sought to address this issue by carrying out a systematic review of the literature. METHODS: We conducted a literature search using PubMed, Embase, and Cochrane databases. Studies including children up to 5 years after cancer therapy were assessed for the association between 25-hydroxyvitamin D (25OHD) levels and BMD Z-scores or fractures, and the effect of vitamin D supplementation on BMD or fractures. Evidence quality was assessed using the GRADE methodology. RESULTS: Nineteen studies (16 observational and 3 interventional, mainly involving children with hematologic malignancies) were included. One study which analyzed 25OHD as a threshold variable (≤10 ng/ml) found a significant association between 25OHD levels and BMD Z-scores, while 25OHD as a continuous variable was not significantly associated with BMD Z-scores in 14 observational studies. We found neither a significant association between lower 25OHD levels and fractures (2 studies), nor between vitamin D (and calcium) supplementation and BMD or fracture frequency (3 studies) (very low quality evidence). CONCLUSION: There is a lack of evidence for an effect of vitamin D (and calcium) supplementation on BMD or fractures in children with cancer. Further research is needed; until then, we recommend dietary vitamin D/calcium intake in keeping with standard national guidelines, and periodic 25OHD monitoring to detect levels <20 ng/ml. Vitamin D/calcium supplementation is recommended in children with low levels, to maintain levels ≥20 ng/ml year-long.

Targeting extracellular nutrient dependencies of cancer cells.

BACKGROUND: Cancer cells rewire their metabolism to meet the energetic and biosynthetic demands of their high proliferation rates and environment. Metabolic reprogramming of cancer cells may result in strong dependencies on nutrients that could be exploited for therapy. While these dependencies may be in part due to the nutrient environment of tumors, mutations or expression changes in metabolic genes also reprogram metabolic pathways and create addictions to extracellular nutrients. SCOPE OF REVIEW: This review summarizes the major nutrient dependencies of cancer cells focusing on their discovery and potential mechanisms by which metabolites become limiting for tumor growth. We further detail available therapeutic interventions based on these metabolic features and highlight opportunities for restricting nutrient availability as an anti-cancer strategy. MAJOR CONCLUSIONS: Strategies to limit nutrients required for tumor growth using dietary interventions or nutrient degrading enzymes have previously been suggested for cancer therapy. The best clinical example of exploiting cancer nutrient dependencies is the treatment of leukemia with l-asparaginase, a first-line chemotherapeutic that depletes serum asparagine. Despite the success of nutrient starvation in blood cancers, it remains unclear whether this approach could be extended to other solid tumors. Systematic studies to identify nutrient dependencies unique to individual tumor types have the potential to discover targets for therapy.

Results of the First Clinical Study in Humans That Combines Hyperbaric Oxygen Pretreatment with Autologous Peripheral Blood Stem Cell Transplantation.

Patients undergoing high-dose chemotherapy and autologous hematopoietic cell transplantation (auto-HCT) are at risk for multiple morbidities, including mucosal inflammation and neutropenic fever, both related to neutropenia. Evidence from our preclinical work in an umbilical cord blood (UCB) transplantation murine model suggests that treatment with hyperbaric oxygen (HBO) before UCB infusion improves UCB CD34+ cell engraftment by reducing erythropoietin levels. A pilot clinical trial using HBO in patients undergoing UCB transplantation showed improvement in kinetics of blood count recovery. In this study, we evaluated HBO in combination with auto-HCT. Our primary aim was to determine the safety of HBO in this setting and secondarily to determine its efficacy in reducing time to neutrophil and platelet engraftment compared with matched historic controls. Patients with multiple myeloma, non-Hodgkin lymphoma, and Hodgkin disease eligible for auto-HCT were included. On day 0, patients received HBO treatment consisting of exposure to 2.5 atmosphere absolutes for a total of 90 minutes, in a monoplace hyperbaric chamber, breathing 100% oxygen. Six hours after the start of HBO, peripherally mobilized stem/progenitor cells were infused and patients were followed daily for toxicity and blood count recovery. All patients received daily granulocyte colony-stimulating factor starting on day +5 and until absolute neutrophil count (ANC) of ≥1500 or ANC of 500 for 3 consecutive days. A matched historic cohort of 225 patients who received auto-HCT between January 2008 and December 2012 was chosen for comparison and matched on sex, age, conditioning regimen, and disease type. We screened 26 patients for this study; 20 were treated and included in the primary analysis, and 19 completed the HBO therapy and were included in the secondary analysis. Although the median time to neutrophil count recovery was 11 days in both the HBO and control cohorts, the Kaplan-Meier estimates of the full distributions indicate that the time to neutrophil recovery was generally about 1 day sooner for HBO versus historical controls (log-rank P = .005; range, 9 to 13 for HBO patients and 7 to 18 for controls). The median time to platelet count recovery was 16 days (range, 14 to 21) for HBO versus 18 days (range, 11 to 86) for controls (log-rank P < .0001). In the secondary analysis comparing the HBO cohort who completed HBO therapy (n = 19) with our historical cohort, we evaluated neutropenic fever, growth factor use, mucositis, day +100 disease responses, and blood product use. HBO was associated with less growth factor use (median 6 days in HBO cohort versus median 8 days in controls, P < .0001). Packed RBC and platelet transfusion requirements were not statistically different between the 2 cohorts. Mucositis incidence was significantly lower in the HBO cohort (26.3% in HBO cohort versus 64.2% in controls, P = .002). HBO therapy appears to be well tolerated in the setting of high-dose therapy and auto-HCT. Prospective studies are needed to confirm potential benefits of HBO with respect to earlier blood count recovery, reduced mucositis, and growth factor use, and a cost-benefit analysis is warranted. © 2019 American Society for Blood and Marrow Transplantation.

Improving the safety of high-dose methotrexate for children with hematologic cancers in settings without access to MTX levels using extended hydration and additional leucovorin.

BACKGROUND: A lack of access to methotrexate levels is common in low- and middle-income countries (LMIC), relevant for 80% of children with cancer worldwide. We evaluated whether high-dose methotrexate (HD-MTX) can be administered safely with extended hydration and leucovorin rescue, with monitoring of serum creatinine and urine pH. METHODS: The prospective study was conducted at a single centre in Chandigarh, India in 2015. Patients with B-cell acute lymphoblastic leukemia (ALL) or with T-cell ALL or non-Hodgkin lymphoma (T-NHL) were administered 3 and 5 gm/m2 of MTX (24 hr infusion), respectively. Six doses of leucovorin (15 mg/m2 /dose), instead of recommended three (for optimally reduced levels) at standard timing (42 hr from start of HD-MTX) were administered. Hydration (125 ml/m2 /hr) was continued for 72 hr, instead of the recommended 30 hr. Hydration fluid consisted of 0.45% sodium chloride, 5% dextrose, 7.5% sodium bicarbonate (50 mmol/l) and potassium chloride (20 mmol/l). Serum creatinine and urine pH were measured at baseline, 24 and 48 hr. The volume of hydration was increased (200 ml/m2 /hr) for a serum creatinine > 1.25 times the baseline. RESULTS: The study included 100 cycles of HD-MTX in 53 patients: B-ALL 25 patients (51 cycles), T-ALL 16 patients (28 cycles), T-NHL 10 patients (18 cycles), and relapsed ALL 2 patients (3 cycles). The mean age was 6.8 ± 3.2 years. Patients were underweight in 15 (15%) cycles. Patients in 23% of cycles had a rise in creatinine to >1.25 times the baseline. Toxicities (NCI CTCAE v4.0) included mucositis (32%), diarrhoea (10%), and febrile neutropenia (9%). One patient died from dengue shock syndrome. CONCLUSIONS: It is safe to administer 3 or 5 gm/m2 of MTX (24 hr infusion) without measuring MTX levels, with extended hydration, additional doses of leucovorin, and monitoring of serum creatinine and urine pH.

Oral fish oil positively influences nutritional-inflammatory risk in patients with haematological malignancies during chemotherapy with an impact on long-term survival: a randomised clinical trial.

BACKGROUND: Studies suggest that the ingestion of fish oil (FO), a source of the omega-3 polyunsaturated fatty acids docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA), can reduce the deleterious side-effects of chemotherapy. The aim of this randomised clinical trial was to evaluate the effect of supplementation with oral FO for 9 weeks on nutritional parameters and inflammatory nutritional risk in patients with haematological malignancies during the beginning of chemotherapy. METHODS: Twenty-two patients with leukaemia or lymphoma were randomised to the unsupplemented group (UG) (n = 13) or supplemented group (SG) (n = 9). SG received 2 g/day of fish oil for 9 weeks. Nutritional status, serum acute-phase proteins and plasma fatty acids were evaluated before (T0) and after (T1) the intervention period. Data were analysed using two models; model 1, comprising data from all patients included in the study, and model 2, comprising data from UG patients with no increase in the proportions of EPA and DHA in plasma and data from SG patients showing an at least 100% increase in plasma EPA and DHA. RESULTS: SG showed an increased plasma proportion of EPA and DHA in both models. In model 2, C-reactive protein (CRP) and CRP/albumin ratio showed larger reductions in the SG. Overall long-term survival in both models (465 days after the start of the chemotherapy) was higher in the group ingesting fish oil (P < 0.05). CONCLUSIONS: These findings indicate an improved nutritional-inflammatory risk and potential effects on long-term survival in patients with haematological malignancies supplemented with FO during the beginning of chemotherapy.

Variability in Trough Total and Unbound Teicoplanin Concentrations and Achievement of Therapeutic Drug Monitoring Targets in Adult Patients with Hematological Malignancy.

The objective of this study was to explore the following aspects of teicoplanin use in patients with hematological malignancy: early attainment of target trough concentrations with current high-dose teicoplanin regimens, variability in unbound teicoplanin fractions, factors associated with observed total and unbound trough concentrations, efficacy and toxicity, and renal function estimation. This was a single-center, prospective study. Samples for determination of trough concentrations were taken on days 3, 4, 7, and 10. Total and unbound teicoplanin concentrations were determined using validated high-performance liquid chromatography methods. Regression analyses were used to identify the factors associated with the trough concentration. Thirty teicoplanin-treated adults with hematological malignancy were recruited. Despite the use of dosages higher than the conventional dosages, the proportions of patients with a trough concentration of ≥20 mg/liter at 48 h and at 72 h were 16.7% and 37.9%, respectively. Renal function was significantly negatively associated with total trough concentrations at 48 h and 72 h (P < 0.05). For an average hematological malignancy patient (creatinine clearance = 70 ml/min), sequential loading doses of at least 12 mg/kg of body weight may be needed to achieve early adequate exposure. In the absence of measured creatinine clearance, estimates obtained using the Cockcroft-Gault (total body weight) equation could prove to be an acceptable surrogate. The unbound fractions of teicoplanin were highly variable (3.4 to 18.8%). Higher unbound fractions were observed in patients with low serum albumin concentrations. Teicoplanin was well tolerated. Teicoplanin loading doses higher than those in current use appear to be necessary. Increased dosing is needed in patients with increased renal function. The high variability in protein binding supports the contention for therapeutic drug monitoring of unbound teicoplanin concentrations. (This study has been registered with EudraCT under registration no. 2013-004535-72.).

Comparable efficacy with varying dosages of glucarpidase in pediatric oncology patients.

BACKGROUND: Glucarpidase rapidly reduces methotrexate plasma concentrations in patients experiencing methotrexate-induced renal dysfunction. Debate exists regarding the role of glucarpidase in therapy given its high cost. The use of reduced-dose glucarpidase has been reported, and may allow more institutions to supply this drug to their patients. This report explores the relationship between glucarpidase dosage and patient outcomes in pediatric oncology patients. METHODS: The authors evaluated data from 26 patients who received glucarpidase after high-dose methotrexate. Decrease in plasma methotrexate concentrations and time to renal recovery were evaluated for an association with glucarpidase dosage, which ranged from 13 to 90 units/kg. RESULTS: No significant relationship was found between glucarpidase dosage (units/kg) and percent decrease in methotrexate plasma concentrations measured by TDx (P > 0.1) or HPLC (P > 0.5). Patients who received glucarpidase dosages <50 units/kg had a median percent reduction in methotrexate plasma concentration of 99.4% (range, 98-100) measured by HPLC compared to a median percent reduction of 99.4% (range, 77.2-100) in patients who received ≥50 units/kg. Time to SCr recovery was not related to glucarpidase dosage (P > 0.8). CONCLUSIONS: The efficacy of glucarpidase in the treatment of HDMTX-induced kidney injury was not dosage-dependent in this retrospective analysis of pediatric oncology patients.

Serial profile of vitamins and trace elements during the acute phase of allogeneic stem cell transplantation.

Currently, we utilize vitamins and trace elements formulations that are not prepared specifically for patients receiving hematopoietic stem cell transplantation (HSCT), and adequacy of this strategy has not been evaluated. We prospectively measured blood level of vitamins and trace elements in 15 patients once per week at 6 time points around the acute phase of allogeneic HSCT. We provided standard nutrition support, including administration of parenteral nutrition with vitamin and trace elements formulation in case of impairment of oral intake. Most patients had vitamin B1 deficiency from the start of preparative regimens. Vitamin C deficiency was prominent throughout the acute phase of HSCT and this was significantly associated with high inflammatory markers, C-reactive protein and ferritin. Remarkable vitamin K overload associated with administration of parenteral supplementation and ferritin overload caused by repeated transfusions was observed. Moderate deficiency of zinc was at least partially linked to gastrointestinal loss by diarrhea. We revealed several features of vitamin and trace element status in the acute phase of HSCT and provided a basis for attempts to improve the nutritional condition in HSCT recipients.

Anemia treatment of lymphoproliferative malignancies with erypoiesis: an overview of state of the art.

Anemia is a common comorbidity of lymphoproliferative malignancies, especially in multiple myeloma. Blood transfusions and ESAs (erythropoiesis stimulating agents) are both possible treatment options, but the latter is often preferred because of the potential risks of unwanted side effects related to blood transfusions. Evidence is accumulating that the use of ESAs in above clinical conditions is safe and effective and not associated with an increase in mortality or serious adverse events. 69.1% of patients achieved a hemoglobin response defined as an increase in hemoglobin of>2g/dl while receiving ESAs and concomitant chemotherapy. If supplemented with iron the hemoglobin response rate can be increased and hence the total dosage and financial cost reduced. A hemoglobin response is often accompanied by an increase in quality of life. HYPO% (hypochromic erythrocytes<5%) is believed to be both a significant positive predictor for the Hb response and also an indicator for iron supplementation if⩾5%. Conventional biochemical markers like serum ferritin concentration and transferrin saturation are not reliable for this use. The effect of EPO stimulating agents as the predictor of the Hb response, quality of life, mortality and the potential adverse events are discussed.

Personalised treatment of haematological malignancies through systems medicine based on single molecules in single cells.

Molecular diagnostics in haematological malignancies continues to advance towards more personalized treatment and accordingly demand is increasing for procedures providing quantitative analyses of heterogeneous tissue in malignancies. Circulating leukaemic cells are diverse and comprise discrete clonal populations arising from a common progenitor cell. Some of the current diagnostic techniques possess an attenuated dynamic quantitative range that prevents a clear comprehension of intercellular interactions. Quantitative measurements will facilitate an accurate appreciation of holistic cellular processes, assist with predictions pertaining to perturbations and reveal functional moieties that are truly a facet of the disease, and thus add to current biomarker discovery which often lack assessment of functional involvement in disease mechanisms and processes. This review focuses on quantitative studies related to peripheral blood and haematological malignancies. Data retrieval for either of these diseases is hampered by the high and unchartered degree of heterogeneity typically existing within clinical samples. The likelihood of analysis across single cell populations is highly probable in the near future. This will allow a patient to be readily screened for malignancies and assigned to a risk group based on a quantitative profile of a complex of molecules related to disease. The future analysis of molecular pathology based on detailed molecular dissection looks promising, requiring the integration of various disciplines encompassing morphology, genetics, expression profiling and new and evolving predictive modeling via systems medicine. From this detailed view into patient health, an increasingly personalized treatment plan can be administered, commencing with stratified medicine.

Antibacterial effects on acinetobacter species of commonly employed antineoplastic agents used in the treatment of haematological malignancies: an in vitro laboratory evaluation.

Although about 75-80% of neutropenic fevers are thought to be caused by infections, a causal organism can be confirmed microbiologically or suspected clinically in only 30-50%, and even fewer of these cases (16%) have a documented bacteraemia. The cause of neutropenic fever in the remaining cases remains elusive. The reasons for this failure may be due to the difficulty in recovering low numbers of organisms, fastidious organisms which fail to grow using conventional culture media, the presence of non-culturable organisms, or the presence of inhibitory substances in specimens. Previously, the authors showed the presence of Acinetobacter in peripheral blood of febrile neutropenic patients with a haematological malignancy, using 16S rDNA polymerase chain reaction (PCR) and sequencing techniques. However, conventional culture was unable to detect these organisms. Hence, it was felt necessary to examine the antibacterial properties of four antineoplastic agents used in the treatment of haematological malignancy, namely bleomycin, cisplatin, doxorubicin and vincristine. A total of 56 wild-type Acinetobacter including seven species (A. calcoaceticus [n=17], A. septicus [n=11], A. baumannii [n=10], A. johnsonii [n=7], A. lwoffii [n=8] A. haemolyticus [n=2] and A. radioresistens [n=1]) were examined for their susceptibility to the four antineoplastic agents at therapeutic concentration. No inhibition was observed, but inhibition was seen at higher concentrations of both bleomycin and doxorubicin. Time to detection of blood culture bottles containing separate antineoplastic agents (i.e., bleomycin and doxorubicin) was compared to that containing saline using a paired t-test. Samples containing doxorubicin at 1 pg/mL were shown to have a mean time to detection of 21.8 h (range: 15.6-31.4 h). Bottles containing saline had a mean time to detection of 22.9 h (range: 18.2-31.3 h). Statistical analysis showed no significant difference (P=0.3361) between time to detection for blood culture bottles containing doxorubicin at achievable plasma concentration and corresponding negative controls. With regard to bleomycin (300 miu/mL), the mean time to detection was 27.29 h (range: 20.2-38.4 h) in the test bottles, with mean time to detection in the saline negative controls of 22.56 h (range: 17.0-30.1 h). Paired t-test gave P=0.000451, hence a significant difference in time to detection for blood cultures containing therapeutic levels of bleomycin. Overall, the antineoplastic agents vincristine, cisplatin or doxorubicin did not have any inhibitory effects on the Acinetobacter organisms examined. At worst, therapeutic concentrations of bleomycin may delay automated detection of an Acinetobacter bacteraemia by a mean time of 5.9 h.

Risk factors for infection and treatment outcome of extended-spectrum ß-lactamase-producing Escherichia coli and Klebsiella pneumoniae bacteremia in patients with hematologic malignancy.

This study was performed to evaluate the impact of extended-spectrum ß-lactamase (ESBL)-producing bacteremia on outcome in patients with hematologic malignancy. We collected and analyzed data on 156 hematologic malignancy patients with Escherichia coli or Klebsiella pneumoniae bacteremia from the database of nationwide surveillance studies for bacteremia. Thirty-seven of the 156 patients (23.7%) harbored ESBL-producing bacteremia. No significant differences in underlying diseases were found in either group. The multivariate analysis showed that significant factors associated with ESBL-producing bacteremia were ICU care (OR = 7.03, 95% CI = 1.79-27.6) and nosocomial acquisition (OR = 5.66, 95% CI = 1.60-20.23). There was an association between prior receipt of cephalosporins and ESBL-producing bacteremia, although this association was not statistically significant (OR = 2.27, 95% CI = 0.99-5.23). The overall 30-day mortality rate of the study population was 20.4% (29/142), and the 30-day mortality rate for the ESBL group was significantly higher than that for the non-ESBL group (44.8% vs. 14.2%, P < 0.001). Multivariate analysis showed that ESBL-producing bacteremia was the most important risk factor associated with 30-day mortality (OR, 5.64; 95% CI, 1.91-16.67), along with ICU care (OR = 4.35, 95% CI = 1.16-16.26) and higher Pitt bacteremia score (per 1-point increment) (OR = 1.50, 95% CI = 1.18-1.92). In conclusion, ESBL-producing bacteremia was the most important risk factor associated with 30-day mortality in patients with hematologic malignancy, along with ICU care and higher Pitt bacteremia score. Our data suggest that determining the optimal empiric antimicrobial therapy in patients with hematologic malignancy is now becoming a challenge for clinicians in the era of multidrug-resistant Gram-negative bacilli.

Serum selenium concentration at diagnosis and outcome in patients with haematological malignancies.

We have previously reported presentation serum selenium level to be predictive of outcome in diffuse large B-cell lymphoma. This has now been studied in a further 430 patients, 163 with acute myeloid leukaemia (AML), 156 with Hodgkin Lymphoma (HL), and 111 with Follicular Lymphoma (FL). Serum selenium was below the UK normal reference range in 45% of patients, and correlated with serum albumin (r=0·24-0·46, P<0·001-0·003) in all tumour types. Independent predictors of presentation selenium were; French-American-British subtype and albumin (P<0·001 for both) in AML, haemoglobin (P=0·002) and B-symptoms (P=0·01) in HL, and albumin (P<0·001) in FL. In AML and HL, response to first line therapy was lower in patients with low serum selenium, but selenium was no longer predictive of response when other variables were entered into a multivariate model. Low selenium was also associated with a worse overall survival in FL [Hazard Ratio (HR) 2·3, 95% confidence interval (CI) 1·4, 4·0] and a trend to a worse overall survival in AML (HR 1·43, 95% CI 0·96, 2·13) by univariate Cox regression analysis, but not by multivariate analysis. In conclusion, low serum selenium is associated with a worse outcome in patients with haematological malignancies, but is not independently predictive, suggesting that it reflects other factors.

Transfusion-associated iron overload as a predictive factor for poor stem cell mobilization in patients with haematological malignancies.

Transfusion-associated iron overload is often observed in patients with haematological malignancies. We analysed the effect of iron overload, indicated by high serum ferritin level, on the mobilization of CD34(+) peripheral blood stem cells (PBSCs). We evaluated the association between the serum ferritin level prior to PBSC collection and the number of CD34(+) cells collected through leukapheresis in 51 patients with various haematological malignancies. Patients with serum ferritin level over 1000 ng mL(-1) were defined as high-ferritin group. Comparing the good (> or =1 x 10(6) per kg CD34(+) cells) and poor (<1 x 10(6) per kg CD34(+) cells) mobilizing groups, there was no difference in disease status, previous chemotherapies and white blood cell count at the first day of apheresis. However, there was a significant difference in the median units of red blood cell transfused between the good and poor mobilizer (2 vs. 8 units; P = 0.012). Serum ferritin level was notably higher in the poor mobilizer (1670 +/- 1320 ng mL(-1)) compared with the good mobilizer (965 +/- 705 ng mL(-1), P = 0.035). The cumulative number of CD34(+) cells per kg collected during the whole procedure was significantly lower in the high-ferritin group (5.5 +/- 4.7 x 10(6) per kg vs. 13.1 +/- 9.1 x 10(6) per kg, P = 0.01). Multivariate analysis revealed that serum ferritin level remained as an independent predictive factor for poor PBSC mobilization. Our study indicated that transfusion-associated iron overload is a predictive factor for poor PBSC mobilization. Iron chelation therapy prior to apheresis may be required to collect sufficient numbers of PBSCs in the iron overload patients.

Transfusion-associated iron overload as an adverse risk factor for transplantation outcome in patients undergoing reduced-intensity stem cell transplantation for myeloid malignancies.

Transfusion-associated iron overload could be an important risk factor in myeloablative hematopoietic stem cell transplantation. However, few studies have evaluated the effect of iron overload in reduced-intensity stem cell transplantation (RIST). We evaluated 38 patients with myeloid malignancies, 16 with and 22 without iron overload, who received RIST. We used pretransplant serum ferritin as a marker of iron overload. There was a positive correlation between the number of transfused packed red blood cells and pretransplant serum ferritin levels (21.5 units and 1,578.7 microg/l in the iron overload group vs. 12 units and 739.3 microg/l in the iron non-overload group; p <0.01). Engraftment day and chimerism analysis were not affected by iron overload (p = 0.71 and 0.47, respectively). There were no differences in treatment-related mortality (p = 0.94), veno-occlusive disease (p = 0.99), acute and chronic graft versus host disease (p = 0.58 and 0.99, respectively) according to iron overload. There was a significant difference in disease-free and overall survival (35.8 and 27% in the iron overload group vs. 80.6 and 54.6% in the iron non-overload group; p = 0.01 and 0.03, respectively). We conclude that transfusion-associated iron overload is an adverse risk factor in RIST for myeloid malignancies. The clinical outcomes according to iron overload in RIST were different in myeloablative hematopoietic stem cell transplantation. A serial follow-up of serum ferritin level and judicious iron chelation therapy will be needed to manage the side effect of iron overload in RIST and improve transplantation outcomes.

[Clinical implications of high cobalamin blood levels for internal medicine]. / Implications cliniques de la découverte d'une hypervitaminémie B12 en médecine interne.

PURPOSE: The high incidence of cobalamin (vitamin B12) deficiency results in frequent dosages of this vitamin in a department of internal medicine may reveal paradoxically high blood levels of cobalamin. The objective of the study was to estimate underlying diseases and potential diagnostic relevance of high cobalamin blood levels in internal medicine. METHODS: A retrospective study was conducted, including in-patients from December 2005 to July 2006 presenting high cobalamin blood levels, as determined with our laboratory normal values (200-950 pg/mL). RESULTS: High cobalamin blood level is not unusual (18.5% of all dosages) and, most of time, it is associated with one or several diseases, among which acute and chronic liver diseases (often of alcoholic origin), various neoplasias, malignant hemopathies (myelodysplasia, myeloproliferative diseases, multiple myeloma), renal insufficiency and transient hematologic abnormalities (neutrophilic hyperleucocytosis, hypereosinophilia). Vitamin B12 supplementation and chronic myeloid leukemia represent less than 5% of all hypervitaminemia. There is no correlation between the level of cobalamin blood level and the number of underlying diseases for each patients. However, very high cobalamin blood levels (>1275 pg/mL) are significantly associated to malignant hemopathies (p<0.05). It is noteworthy that most of diagnosed neoplasia were unknown and at a non-metastatic stage. CONCLUSION: Very high cobalamin blood levels are significantly associated to malignant hemopathies among the population of a department of internal medicine. Referent laboratory should actively advertise the numerous diseases involved with high cobalamin blood levels.

Unique abnormalities of CD4(+) and CD8(+) central memory cells associated with chronic graft-versus-host disease improve after extracorporeal photopheresis.

Chronic graft-versus-host disease (cGVHD) remains a problematic complication of allogeneic hematopoietic stem cell transplantation. Laboratory parameters correlated with cGVHD have not been fully defined, although changes in CD4/CD8 ratios occur and a decrease in CD4(+) central memory T cells has been noted. Extracorporeal photopheresis (ECP) is an effective therapy for steroid-refractory cGVHD. We have noted changes in lymphocyte subsets after ECP. CD4(+) and CD8(+) T-cell central and effector memory populations were enumerated by flow cytometry in a cohort of 37 patients postallogeneic transplantation with symptomatic cGVHD. Of the patients with symptomatic cGVHD, 7 were treated with ECP over 6 months and prospectively assessed for changes in lymphocyte subsets. There was a highly significant correlation of an increase in CD8(+) central memory cells and a concomitant decrease in CD4(+) central memory cells in patients with symptomatic cGVHD. These changes were not detected in patients without cGVHD posttransplantation. In all, 7 patients with cGVHD followed up prospectively during ECP treatment showed a statistically significant normalization of the pattern of CD4(+) and a trend toward normalization of CD8(+) central memory T cells coincident with improvement of cGVHD. These data indicate a high correlation between disturbances in the balance of central and effector memory populations and cGVHD suggesting use in following up responses to therapy. The normalization of central and effector memory populations in response to ECP coincident with clinical improvement of cGVHD support a correlation between these laboratory parameters and cGVHD. Further studies are needed to demonstrate whether laboratory measurements of the magnitude of changes in central and effector memory populations are useful prognostically or can be used to guide response to therapy. The contrasting change in central memory cells (CD8(+) increased versus CD4(+) decreased) in cGVHD provide support for recent reports suggesting unique differences in the differentiation pathways for CD8(+) versus CD4(+) T cells.