Iron homeostasis in inflammation: a single centre prospective observational study in medical inpatients.

AIMS OF THE STUDY: We aimed to assess a potential association of iron status with mortality and morbidity of inpatients with systemic inflammation. METHODS: This was a single centre prospective observational study. From April 2014 to October 2014, all consecutive medical inpatients aged >=18 years with a C-reactive protein value >5 mg/l on hospital admission were eligible for the study. We excluded pregnant women and patients with terminal renal insufficiency or past allogeneic stem cell transplantation. For all patients, a complete set of serum iron parameters was obtained on hospital admission. In the final analysis, the in-hospital all-cause mortality and several morbidity measures (length of stay, number of secondary diagnoses and Charlson Comorbidity Index) were compared between four distinct iron status groups: patients having iron deficiency anaemia, iron deficiency without anaemia, anaemia without iron deficiency, and normal iron status. Iron deficiency was quantifies as the serum transferrin receptor / ferritin index, with a cut-off level of 1.5. RESULTS: A total of 438 patients were included in the final analysis. Patients with iron deficiency had a higher in-hospital mortality than patients with iron deficiency anaemia, anaemia without iron deficiency, or normal iron status (6% vs 1%, 5%, and 1%, respectively; p = 0.042). Patients with iron deficiency anaemia had a higher number of secondary diagnoses (mean 8.4; standard deviation 4.2) and a higher Charlson Comorbidity Index (mean 1.8; standard deviation 1.9) than patients with iron deficiency, anaemia without iron deficiency, or normal iron status (p <0.001 and p <0.001, respectively). The median length of stay did not differ significantly between the iron status groups (p = 0.080). CONCLUSIONS: In our study population, iron status was significantly associated with mortality and morbidity. Further studies are required to assess the pathophysiological and clinical effects of an altered iron metabolism and iron substitution therapies in inflammation.

Adverse events and retention of donors of double red cell units by apheresis.

BACKGROUND: Safety of double-erythrocyte (2RBC) collection and reasons for ceasing 2RBC donation were retrospectively analysed in the blood donor population of Basel, Switzerland. METHODS: Donors with at least 1 2RBC apheresis were included in the study. Minimal requirements were Hb ≥140 g/L and body weight ≥70 kg; serum ferritin (SF) values were measured routinely, but were not part of the selection criteria. 2RBC collections were performed with ALYX devices at 6-month intervals. Adverse events (AEs) were systematically recorded and classified according to the ISBT EHN 2008 criteria. Data of procedures were retrieved from the ALYX software. Demographics, apheresis data and AEs were analysed with descriptive statistics. RESULTS: Data of 4,377 2RBC aphereses performed in 793 donors (779 males) between 1(st) January 2003 and 31(st) May 2015 were evaluated. Mean donor age at first 2RBC donation was 44 years (standard deviation [SD] 21), median number of donations was 4 (interquartile range [IQR] 8); 32% of the donors underwent a single procedure. There were 161 AEs, mostly local haematomas (55%) and vasovagal reactions (20%); fatigue was reported in 6% of the cases and was more frequent than citrate toxicity. Two severe AEs were observed. The most frequent reasons for abandoning 2RBC donation were low SF levels and donor choice (both 11%), but most donors simply did not reply to invitations (16%). Overall, procedure-related causes (AEs, low SF levels, no time for apheresis, inadequate venous access) were observed in 14% of the cases. At the end of the observation period, 40% of the donors were still active blood donors, but only 20% were donating 2RBC. DISCUSSION: 2RBC donation is overall safe. Donor retention was low over a period of 11 years. An important reason for abandoning 2RBC was the detection of low SF levels. The impact of fatigue on donor retention and the course of iron stores after repeated 6-monthly 2RBC apheresis require further investigation.

GLCCI1 and Glucocorticoid Receptor Genetic Diversity and Response to Glucocorticoid-Based Treatment of Graft-versus-Host Disease.

The genetic diversity of loci implicated in glucocorticoid (GC) response has been associated with interindividual variations in responsiveness to GC in various diseases, such as asthma and inflammatory bowel disorders. In acute graft-versus-host disease (aGVHD), similar differences of first-line therapy responsiveness are also observed, with approximately 40% of patients failing to respond to GC. Here, the distribution of functionally relevant single nucleotide polymorphisms (SNP) belonging to the GC-induced transcript 1 GLCCI1 (rs37972) and the glucocorticoid receptor (rs41423247, rs6195 and rs6198) gene loci were analyzed alongside clinical factors for their association with the response to corticosteroids in aGVHD. The frequencies of variant alleles did not differ significantly between corticoresistant patients, their donors, and their corticosensitive peers (P = .10 to 1.00). Severe and early onset of aGVHD, bone marrow as the stem cell source, and an HLA mismatch were associated with the failure to respond to GC in logistic regression. After including the single SNPs to the model, carriers of the rs41423247 polymorphism had a higher probability of responding to GC, whereas all other polymorphisms did not affect the likelihood of response.

Use of Eculizumab in Patients With Allogeneic Stem Cell Transplant-Associated Thrombotic Microangiopathy: A Study From the SFGM-TC.

BACKGROUND: Thrombotic microangiopathy (TMA) occurring after allogeneic hematopoietic stem cell transplantation (HSCT) has a devastating prognosis. Response rates to current therapies (mainly plasma exchange) are unsatisfactory. Thrombotic microangiopathy after allogeneic HSCT shares similarities with atypical hemolytic uremic syndrome (aHUS) in the underlying pathomechanisms. Eculizumab has been associated with impressive results in aHUS. MATERIALS AND METHODS: We retrospectively analyzed 12 patients who received Eculizumab in France between 2010 and 2013 for severe post-HSCT TMA. RESULTS: All 12 patients had severe TMA with neurological and/or renal involvement. Fifty-eight percent were refractory to first-line plasma exchange. At the time of TMA diagnosis, infections were present in 50% of the patients and acute graft-versus-host disease in 33%. Patients were treated with Eculizumab according to the aHUS therapeutic scheme. With a median follow-up of 14 months, hematological response and overall survival were 50% and 33%, respectively. Active acute graft-versus-host disease at TMA diagnosis was the only factor associated with worse overall survival (P = 0.009). DISCUSSION: Response rate and overall survival after Eculizumab in our cohort compare favorably with previously published data in TMA after allogeneic HSCT. Prospective trials are warranted to confirm these results. Early initiation of Eculizumab may have a favorable effect on long-term renal function and further contribute to the prolongation of survival.

CD24(hi)CD27⁺ and plasmablast-like regulatory B cells in human chronic graft-versus-host disease.

Interleukin 10 (IL-10)-producing B cells (regulatory B cells [Bregs]) regulate autoimmunity in mice and humans, and a regulatory role of IL-10-producing plasma cells has been described in mice. Dysfunction of B cells that maintain homeostasis may play a role in the pathogenesis of chronic graft-versus-host disease (cGVHD) after allogeneic stem cell transplantation. Here, we found a relation between decreased Breg frequencies and cGVHD severity. An impaired ability of B cells to produce IL-10, possibly linked to poor signal transducer and activator of transcription 3 and extracellular signal-regulated kinase phosphorylation, was found in patients with active cGVHD. IL-10 production was not confined to a single B-cell subset, but enriched in both the CD24(hi)CD27(+) and CD27(hi)CD38(hi) plasmablast B-cell compartments. In vitro plasmablast differentiation increased the frequency of IL-10-producing B cells. We confirmed that allogeneic transplant recipients had an impaired reconstitution of the memory B-cell pool. cGVHD patients had less CD24(hi)CD27(+) B cells and IL-10-producing CD24(hi)CD27(+) B cells. Patients with cGVHD had increased plasmablast frequencies but decreased IL-10-producing plasmablasts. These results suggest a role of CD24(hi)CD27(+) B-cell and plasmablast-derived IL-10 in the regulation of human cGVHD.

Impact of recipient ABH secretor status on outcome in minor ABO-incompatible hematopoietic stem cell transplantation.

BACKGROUND: The impact of ABO incompatibility on hematopoietic stem cell transplantation (HSCT) outcome is controversial. As ABH substances are expressed on tissues and secreted in body fluids, they could drive an immune response in minor ABO-incompatible HSCT. The aim of the study was to investigate the prognostic role of the recipients' ABH secretor status. STUDY DESIGN AND METHODS: Patients who underwent minor ABO-incompatible HSCT were included. Secretor status was determined either serologically or by molecular genetics. RESULTS: Between March 1996 and June 2012, a total of 176 patients received minor ABO-incompatible HSCT and 150 (85%) were secretors. Incidence and severity of acute graft-versus-host disease (GVHD) and chronic GVHD did not differ between secretors and nonsecretors (cumulative incidences ± standard errors: acute GVHD on Day 100, 41 ± 11 and 46 ± 5%, p = 0.59; chronic GVHD at 2 years, 52 ± 13 and 56 ± 5%, p = 0.62, for secretors and nonsecretors, respectively). Additionally, nonrelapse mortality (NRM) and overall survival (OS) were similar in the two groups (2-year NRM, 27 ± 9 and 23 ± 3%, p = 0.45; 4-year OS, 64 ± 10 and 55 ± 4%, p = 0.28, for secretors and nonsecretors, respectively). CONCLUSION: The recipients' ABH secretor status in minor ABO-incompatible HSCT has no prognostic impact on major transplant outcomes.

Forty years of haematopoietic stem cell transplantation: a review of the Basel experience.

The purpose of this study was to examine changes in haematopoietic stem cell transplant (HSCT) characteristics and outcome in our combined paediatric and adult programme over the past four decades, since its implementation in 1973. The total number of transplant procedures rose from 109 in the first decade (1973-82) to 939 in the last decade (2003-12). Transplant characteristics changed significantly over time: patient age increased, peripheral blood largely replaced bone marrow as stem cell source, unrelated donors became an alternative to matched siblings, and patients are increasingly transplanted in more advanced disease stages. Advances such as improved supportive care and histocompatibility typing resulted in a steady decrease of transplant-related mortality after allogeneic HSCT (43% in the first decade, 22% in the last decade). Despite this, unadjusted survival rates were stable in the last three decades for allogeneic HSCT (approximately 50% 5-year survival) and in the last two decades for autologous HSCT (approximately 60% 5-year survival). After adjustment for covariates such as donor type, age and stage, the relative risk of treatment failure continuously dropped (for allogeneic HSCT: first decade 1.0, second decade 0.58, third decade 0.51, last decade 0.41). Collectively, these data suggest that improvements in peri- and post-transplant care have allowed considerable extension of transplant indications without having a negative impact on outcome.

Role of donor and recipient sex in platelet transfusion.

BACKGROUND: H-Y proteins are ubiquitously expressed Y chromosome-encoded minor histocompatibility antigens, which are relevant in the transplantation of hematopoietic stem cells (HSCT) and solid organs. No studies have so far analyzed whether H-Y incompatibility influences the outcome of platelet (PLT) transfusion. STUDY DESIGN AND METHODS: We studied the effect of donor and recipient sex on outcome of 9038 single-donor PLT transfusions. RESULTS: Using standard corrected count increment or percent PLT recovery (PPR) calculations, male patients showed inferior recovery rates, irrespective of donor sex. Using an adjusted PPR, which takes into account differences in blood volume between males and females, neither donor nor recipient sex played any role in PLT recovery after transfusion. Similarly, the time to next PLT transfusion was unaffected by both donor and recipient sex. In a subgroup analysis of patients with graft-versus-host disease after allogeneic HSCT, male recipients of a female allograft-which may carry anti-H-Y T cells and antibodies-had significantly lower time to next PLT transfusion. However, this occurred after both male donor and female donor PLT transfusions, arguing against an involvement of alloreactivity against H-Y antigens on PLTs. CONCLUSION: This large analysis found no evidence that donor-recipient sex matching influences the outcome of PLT transfusion.

Allogeneic stem cell transplantation for relapsed or refractory lymphoma after conditioning with BEAM/fludarabine/TBI.

Allogeneic stem cell transplant (SCT) after high-dose conditioning with BEAM/fludarabine/total body irradiation (TBI) in patients with relapsed or refractory lymphoma has shown promising results in a pilot study. In this trial, we treated 50 consecutive patients with refractory or relapsed lymphoma or chronic lymphocytic leukemia (CLL). The patients included were considered to have poor-prognosis disease (eg, one-third was chemo-refractory at transplantation and more than one-half had failed previous autologous or allogeneic SCT). All patients engrafted and achieved full donor chimerism. Grade II-IV acute graft-versus-host disease (aGVHD) occurred in 64% of patients (95% confidence interval [CI], 52% to 79%), and chronic GVHD (cGVHD) in 51% (95% CI, 36% to 66%). At 3 years, overall survival was 61% (95% CI, 46% to 75%). Progression-free survival was 55% (95% CI, 40% to 70%), with 30% (95% CI, 19% to 47%) transplantation-related mortality and a relapse incidence of 15% (95% CI, 7% to 32%). Disease classification and stage as well as remission status at transplantation and type of previous treatment (including previous SCT) had no significant impact on transplantation outcome. In conclusion, allogeneic SCT after BEAM/fludarabine/TBI provides excellent tumor control with complete and durable remissions in patients with poor-prognosis lymphoma and CLL. High rates of GVHD and GVHD-related mortality associated with this regimen are a major concern and warrant modification of the regimen in the future.

Prognostic impact of posttransplantation iron overload after allogeneic stem cell transplantation.

In patients referred for allogeneic hematopoietic stem cell transplantation (HSCT), iron overload is frequent and associated with increased morbidity and mortality. Both the evolution of iron overload after transplantation and its correlation with late posttransplantation events are unknown. We studied 290 patients undergoing myeloablative allogeneic HSCT between 2000 and 2009. Serum ferritin, transferrin saturation, transferrin, iron, and soluble transferrin receptor were determined regularly between 1 and 60 months after HSCT, and values were correlated with transplantation outcome. Ferritin levels peaked in the first 3 months posttransplantation and then decreased to normal values at 5 years. Transferrin saturation and iron behaved analogously, whereas transferrin and soluble transferrin receptor increased after an early nadir. Landmark survival analysis showed that hyperferritinemia had a detrimental effect on survival in all periods analyzed (0 to 6 months P < .001; 6 to 12 months P < .001; 1 to 2 years P = .02; 2 to 5 years P = .002). This effect was independent of red blood cell transfusion dependency and graft-versus-host disease. Similar trends were seen for other iron parameters. These data show the natural dynamics of iron parameters in the setting of allogeneic HSCT and provide evidence for a prognostic role of iron overload extending beyond the immediate posttransplantation period. Interventions to reduce excessive body iron might therefore be beneficial both before and after HSCT.

Switching iron-deficient whole blood donors to plateletpheresis.

BACKGROUND: Iron deficiency is a frequent side effect of whole blood (WB) donation. In contrast, less red blood cell loss and therefore less iron loss results from plateletpheresis. STUDY DESIGN AND METHODS: WB donors presenting a decrease in either hemoglobin (Hb) or ferritin levels were offered to switch to plateletpheresis with or without iron supplementation. We analyzed the effect of this intervention on deferral rates for an insufficient Hb level in 168 donors. Further, we assessed how this intervention affected Hb and ferritin levels, anemia occurrence, and platelet (PLT) concentrate yields in the donors who presented at least four successive times for thrombapheresis. RESULTS: Switching WB donors to repetitive plateletpheresis procedures resulted in an increase of median Hb (+12 g/L, p < 0.001) and ferritin (+15.5 ng/mL, p = 0.002) values. Anemia and deferral rates were reduced by 23% (p = 0.004) and 13% (p < 0.001). Between high- and low-frequency apheresis donors, no significant differences in Hb and ferritin levels were found. Similarly, discrepancies in Hb and ferritin values between donors that adopted iron supplementation and those who did not were insignificant. The median PLT concentrate yield was 5.43 × 10(11) PLTs. CONCLUSION: Switching iron-deficient WB donors to plateletpheresis was an effective intervention that permitted us to correct low Hb and ferritin levels while retaining donors in our pool.

Prognostic value of red blood cell parameters and ferritin in predicting deferral due to low hemoglobin in whole blood donors.

Risk factors for deferral from red blood cell (RBC) donation due to low hemoglobin are not well defined. We analyzed in a large cohort of returning donors the prognostic value of RBC parameters and serum ferritin regarding low hemoglobin levels at the subsequent visit. Between 2004 and 2009, RBC indices and serum ferritin were recorded in 45,533 visits by 7,994 donors. In 689 instances, donation was deferred at the subsequent visit due to low hemoglobin levels (<123 g/l for female donors, <133 g/l for male donors). Pre-donation hemoglobin at the current visit correlated best with hemoglobin at the subsequent visit (R (2) = 0.63), whereas other RBC indices and serum ferritin correlated only poorly (R (2) ≤ 0.15). Similar results were obtained in ROC curve analysis and in multivariable binary logistic regression. A pre-donation hemoglobin within 5 g/l from the deferral threshold (<128 g/l for female, <138 g/l for male donors) predicted below-threshold hemoglobin levels at the subsequent visit with a sensitivity of 52% and a specificity of 94%. In conclusion, pre-donation hemoglobin is a useful marker identifying donors at risk of developing low hemoglobin levels. Diagnostic and therapeutic interventions should be aimed at donors presenting with hemoglobin levels near the threshold of donor deferral.

The value of routine ferritin measurement in blood donors.

BACKGROUND: Iron store deficiency is a common side effect of whole blood donation. Early recognition and reversal of excessive iron loss may avoid symptomatic iron store depletion in blood donors and reduce volunteer loss due to iron deficiency (ID) anemia. STUDY DESIGN AND METHODS: Between 1996 and 2009, a total of 160,612 visits with the intention to donate blood by 23,557 healthy volunteers were recorded at our center. As of 2004, routine serum ferritin testing and additional counseling of donors at risk for donation-induced anemia were implemented. We analyzed the impact of this measure on the hemoglobin (Hb) levels and anemia occurrence in our donor population and in particular in women of childbearing age. Donation rejections due to low Hb counts, the intervals to next donation, and return rates thereafter were also assessed. RESULTS: The introduction of routine serum ferritin analysis resulted in an increase of mean Hb levels in blood donors particularly in women of childbearing age. The incidence of predonation anemia and donation ineligibility due to a low Hb concentration decreased significantly. The return intervals of donors rejected on account of low Hb levels were shortened; however, the return rates thereafter were also curtailed. CONCLUSIONS: Systematic serum ferritin measurements allowed an optimized management of ID in our donors and efficacious prevention of ID anemia.

Frequent expression of the breast differentiation antigen NY-BR-1 in mammary and extramammary Paget's disease.

While mammary Paget's disease (MPD) is clearly linked to breast cancer, the histogenesis of extramammary Paget's disease (EMPD) is controversial. Recently NY-BR-1, a differentiation antigen expressed in the breast and in skin adnexal structures was identified. Its protein expression is restricted to normal and neoplastic breast epithelium and to adnexal tumors of the skin. In this study, we examine NY-BR-1 expression by immunohistochemistry in 24 MPD cases with synchronous ductal carcinoma in situ or invasive breast cancer. Results were compared with 26 cases of EMPD of men (n= 4) and women (n= 22) as well as in apoeccrine glands of the axilla and mammary-like glands of the anogenital region. We found NY-BR-1 positivity in 18 of 24 MPD (75%) and in 21 of 26 EMPD (80.8%). All apoeccrine glands of the axilla and mammary-like glands of the anogenital region were NY-BR-1-positive. NY-BR-1 expression is a common finding in MPD and in EMPD. When considering the diagnosis of Paget's disease, NY-BR-1 is a useful diagnostic marker. Furthermore NY-BR-1 positivity in apoeccrine glands of the axilla and anogenital region suggests a potential histogenetic link between these structures and Paget's disease.

Case report: Recurrence of a uterine tumor resembling ovarian sex-cord tumor.

BACKGROUND: Uterine tumors resembling ovarian sex-cord tumors are very rare uterine neoplasias that generally behave in a benign manner. We report the case of a uterine tumor resembling an ovarian sex-cord tumor that recurred after hysterectomy. CASE: A 35-year-old nulliparous woman presented with abdominal discomfort, galactorrhea and abnormal vaginal bleeding. Ultrasound examination showed a heterogeneous uterine tumor composed of cystic and solid parts. Because of the patient's desire to preserve fertility, tumor resection was scheduled. Frozen sections suggested malignancy and led to abdominal hysterectomy. The final histological diagnosis was uterine tumor resembling ovarian sex-cord tumor. Three years into follow-up, metastasis occurred. CONCLUSION: Although uterine tumors resembling ovarian sex-cord tumors generally behave in a benign manner, they may in rare cases metastasize.