Compliance compromises an interventional study on iron supplementation in female combatants.

INTRODUCTION: Low iron levels are related to overuse injuries, poor physical performance and cognitive impairments in female recruits. The aim of this study was to evaluate iron supplement compliance in female combatants during basic training, and its effect on haemoglobin (Hgb), ferritin and injuries. METHODS: 329 female recruits to light infantry units filled induction questionnaires regarding smoking status, previous overuse injuries and iron deficiency. Blood was drawn for Hgb and ferritin. Subjects with ferritin levels below 20 ng/mL were considered iron depleted and were prescribed a ferrous fumarate supplement. After 4 months of basic training, the subjects completed a follow-up questionnaire regarding overuse injuries, reasons for failure to complete basic training and compliance with iron supplementation. Blood tests were repeated. RESULTS: Mean ferritin levels declined during training (from 18.1±18.2 to 15.3±9.6, p=0.01). Compliance with iron supplementation was observed in 26 (26.3%) of the subjects. In compliant subjects, Hgb levels remained constant and ferritin levels increased by 2.9±5.4 (p=0.07). The main reasons for reported non-compliance were forgetfulness, 26 (35.6%), and gastrointestinal side effects, 17 (23.3%). Injuries during training were not found to be associated with iron status. Smokers had a significantly higher rate of reported injuries prior to training (p<0.01). CONCLUSIONS: Ferritin levels decline during training. Compliance with iron supplementation is low. Iron supplementation has a significant effect on ferritin levels, even in the non-compliance group. Injuries were not related to iron status in this group. Further research is needed in order to clarify the most appropriate iron supplementation method.

Optimal timing of fetal reduction from twins to singleton: earlier the better or later the better?

OBJECTIVES: To determine the rate of pregnancy complications and adverse obstetric and neonatal outcomes of twin pregnancies that were reduced to singleton at an early compared with a later gestational age. METHODS: This was a historical cohort study of dichorionic diamniotic twin pregnancies that underwent fetal reduction to singletons in a single tertiary referral center between January 2005 and February 2017. The study population was divided into two groups according to gestational age at fetal reduction: those performed at 11-14 weeks' gestation, mainly at the patient's request or as a result of a complicated medical or obstetric history; and selective reductions performed at 15-23 weeks for structural or genetic anomalies. The main outcome measures compared between pregnancies that underwent early reduction and those that underwent late reduction included rates of pregnancy complications, pregnancy loss, preterm delivery and adverse neonatal outcome. RESULTS: In total, 248 dichorionic diamniotic twin pregnancies were included, of which 172 underwent early reduction and 76 underwent late reduction. Although gestational age at delivery was not significantly different between the late- and early-reduction groups (38 weeks, (interquartile range (IQR), 36-40 weeks) vs 39 weeks (IQR, 38-40 weeks); P = 0.2), the rates of preterm delivery < 37 weeks (28.0% vs 14.0%; P = 0.01), < 34 weeks (12.0% vs 1.8%; P = 0.002) and < 32 weeks (8.0% vs 1.8%; P = 0.026) were significantly higher in pregnancies that underwent late reduction. Regression analysis revealed that late reduction of twins was an independent risk factor for preterm delivery, after adjustment for maternal age, parity, body mass index and the location of the reduced sac. Rates of early complications linked to the reduction procedure itself, such as infection, vaginal bleeding and leakage of fluids, were comparable between the groups (7.0% for early reduction vs 9.2% for late reduction; P = 0.53). There was no significant difference in the rate of pregnancy loss before 24 weeks (0.6% for early reduction vs 1.3% for late reduction; P = 0.52), and no cases of intrauterine fetal death at or after 24 weeks were documented. There was no significant difference in the prevalence of gestational diabetes mellitus, hypertensive disorders of pregnancy, preterm prelabor rupture of membranes or small-for-gestational age. The rates of respiratory distress syndrome (6.7% vs 0%; P = 0.002), need for mechanical ventilation (6.7% vs 0.6%; P = 0.01) and composite neonatal morbidity (defined as one or more of respiratory distress syndrome, sepsis, necrotizing enterocolitis, intraventricular hemorrhage, need for respiratory support or neonatal death) (10.7% vs 2.9%; P = 0.025) were higher in the late- than in the early-reduction group. Other neonatal outcomes were comparable between the groups. CONCLUSIONS: Compared with late first-trimester reduction of twins, second-trimester reduction is associated with an increased rate of prematurity and adverse neonatal outcome, without increasing the rate of procedure-related complications. Technological advances in sonographic diagnosis and more frequent use of chorionic villus sampling have enabled earlier detection of fetal anatomic and chromosomal abnormalities. Therefore, efforts should be made to complete early fetal assessment to allow reduction during the first trimester. Copyright © 2020 ISUOG. Published by John Wiley & Sons Ltd.

Regional intra-arterial steroid treatment in 120 patients with steroid-resistant or -dependent GvHD.

GvHD results in death in the majority of steroid-resistant patients. This report assesses the safety and efficacy of two regional intra-arterial steroid (IAS) treatment protocols in the largest published cohort of patients with resistant/dependent hepatic and/or gastrointestinal GvHD, as well as identification of predictors of response to IAS and survival. One hundred and twenty patients with hepatic, gastrointestinal GvHD or both were given IAS. Gastrointestinal initial response (IR) and complete response (CR) were documented in 67.9% and 47.6%, respectively, whereas hepatic IR/CR in 54.9% and 33.3%, respectively. The predictors of gastrointestinal CR were lower peak GvHD and steroid-dependent (SD) GvHD. The predictors for hepatic CR were male patient, reduced intensity conditioning and SD GvHD. Twenty-six of the 120 patients (21.6%) are currently alive (median follow-up for the survivors 91.5 months). The 12 months' overall survival is 30% with no treatment-associated deaths. Predictors of 12 months' survival were as follows: first transplant, age<20 years, non-TBI regimen and GvHD CR. Shorter time to gastrointestinal IR but not time to hepatic IR was associated with improved 12 months' survival. IAS appears to be safe and effective. Gastrointestinal treatment is more effective than hepatic treatment. In our study, we conclude our current recommendations for IAS treatment.

IVF for fertility preservation in breast cancer patients--efficacy and safety issues.

BACKGROUND: Potential risks on future fertility have become a dominant issue in consultation and management of newly diagnosed young cancer patients. Several fertility preservation strategies are currently available. Of those, ovarian stimulation followed by IVF and embryo cryopreservation is the most established one and is especially applicable in reproductive aged breast cancer patients. AIM: The aim of this study is to provide a comprehensive review on ovarian stimulation and IVF for fertility preservation in newly diagnosed breast cancer patients. METHODS: Review of relevant literature is available through PubMed and Google scholar. RESULTS: The use of IVF for fertility preservation in breast cancer patients raises dilemmas regarding efficacy and safety of controlled ovarian stimulation. Among these are the suggested role of malignancy and BRCA mutation in reducing ovarian response to stimulation, strategies designated to protect against hyper-estrogenic state associated with stimulation (co-treatment with tamoxifen or letrozole), and possible adjustments to accommodate oncologic-related time constraints. CONCLUSION: Ovarian stimulation followed by IVF forms an important fertility preservation strategy for newly diagnosed young breast cancer patients, though live born rates following thawed embryo transfer in these patients are still lacking. Recent advances in controlled ovarian stimulation protocols provide practical options for some of the challenges that breast cancer patients present.

Incidence and risk factors for moderate-to-severe veno-occlusive disease of the liver after allogeneic stem cell transplantation using a reduced intensity conditioning regimen.

The incidence and outcome of moderate-to-severe veno-occlusive (VOD) disease was analyzed in 271 consecutive patients with hematological malignancies who underwent allogeneic SCT (allo-SCT) using the same reduced intensity regimen (RIC). RIC consisted of fludarabine, BU and antithymocyte globulin (ATG). Twenty-four out of 271 patients (8.8%) developed VOD, which was severe in only 4 (1.4%) out of 24 cases. All four patients with severe VOD finally succumbed to their disease. In multivariate analysis, i.v. administration of BU was associated with significant reduced incidence of VOD as compared with per os administration. In conclusion, VOD remains a serious complication of allo-SCT using RIC regimens containing BU. Although the incidence of severe VOD is very low, the overall mortality rate in the group of patients with severe VOD remains extremely high and therefore novel treatment approaches are needed.

Colistin is relatively safe in hematological malignancies and hematopoietic stem cell transplantation patients.

PURPOSE: Colistin is increasingly used as the last-resort treatment option against infections caused by multidrug-resistant (MDR) Gram-negative pathogens, but its nephrotoxicity is of concern, especially in severely ill patients. The aim of this study was to analyze the toxicity of colistin therapy in adults and children with hematological malignancies (HM) and hematopoietic stem cell transplantation (HSCT) recipients. METHODS: Data on HSCT recipients and HM patients, treated with intravenous colistin (2.5-5 mg/kg/day in children and 3-6 million international units (IU) in adults, adjusted to renal function) during the period 2008-2011 in our center, were retrospectively collected and analyzed. Nephrotoxicity was defined according to the RIFLE criteria (Risk, Injury, Failure, Loss, and End-stage kidney disease). RESULTS: Twenty-nine children and adults received 38 courses of intravenous colistin (2.5-5 mg/kg/day in children and 3-6 × 10(6) IU in adults, adjusted to renal function) [allogeneic HSCT (22 courses) and HM (16 courses)] for 3-28 days (median 10 days) for empirical therapy for nosocomial clinical sepsis (28) or local infection (6), and bacteremia with MDR Gram-negative rods (4). Nephrotoxicity was observed at the end of 4 (10.5%) courses. In 32 (84%) courses, nephrotoxic medications were concomitantly administered. Two patients had convulsions, probably unrelated to colistin. Seven patients (18%) died while on colistin therapy. No death was attributed to an adverse effect of colistin. CONCLUSIONS: Treatment with intravenous colistin, with dosage adjusted to renal function, was relatively safe for HM/HSCT patients, even with concomitantly administered nephrotoxic medications. Concern about nephrotoxicity should not justify a delay in initiating empirical colistin treatment in situations where infection with MDR Gram-negative rods is likely.

The number of infused CD34+ cells does not influence the incidence of GVHD or the outcome of allogeneic PBSC transplantation, using reduced-intensity conditioning and antithymocyte globulin.

The influence of graft composition on the outcome of reduced-intensity (RIC) allogeneic PBSC transplantation (allo-PBSC) remains controversial. In this study, we analyzed the impact of CD34+ cell dose on the incidence of GVHD, and on the outcome after allo-PBSC, in 103 patients with hematological malignancies, using a uniform RIC regimen. The following variables were included in statistical analysis: (1) number of C34+ cells, (2) high-risk vs low-risk disease status, (3) matched related vs matched unrelated donor, (4) female donor to male recipient vs any other combination, (5) age of recipient (above vs below the median). Univariate and multivariate analysis did not reveal any association between CD34+ cell dose and acute grade-2 to grade-4, cGVHD, non-relapse mortality (NRM), relapse rate (RR) and OS. High-risk disease status was the only variable independently associated with increased NRM (P=0.001), increased RR (P=0.012) and decreased OS (P<0.001). The same results were obtained when analysis was restricted to a subgroup of 55 patients with myeloid neoplasms. The influence of graft composition on the outcome of RIC allo-PBSC should be further investigated via well-controlled randomized prospective studies.

Assessment of CD4 T-lymphocyte reactivity by the Cylex ImmuKnow assay in patients following allogeneic hematopoietic SCT.

After allogeneic hematopoietic SCT (alloHSCT), immunosuppressed patients are susceptible to opportunistic infections, and uncontrolled function of the graft can result in GVHD. Accurate immune monitoring may help early detection and treatment of these severe complications. Between October 2005 and November 2007, a total of 170 blood samples were collected from 40 patients after alloHSCT in the Hadassah Hebrew University Medical Center and from 13 healthy controls. We utilized the Cylex ImmuKnow assay for CD4 ATP levels to compare known clinically immunocompromised vs immunocompetent patients after alloHSCT. We also compared the reconstitution of WBC count to the ImmuKnow results and clinical status. The patients' clinical course correlated with the stratification of immune response established by the ImmuKnow assay for solid organ transplantation (immunocompetent vs immunocompromised), and this often differed from their WBC count. On the basis of our observations, we conclude that the ImmuKnow assay is a simple and fast immune-monitoring technique for patients undergoing alloHSCT, with potential to predict clinical course and facilitate prompt management of post-HSCT complications. The assay should be evaluated prospectively in clinical trials.

Quantitative monitoring of multi-donor chimerism: a systematic, validated framework for routine analysis.

Despite therapeutic advantages, double-donor (DD) HSCTs present technical problems for molecular chimerism (CHM) monitoring. These DD chimeras contain three matched DNAs, so that the genomes of donor(s) and recipient often share the same alleles. In the STR assay, shared recipient/donor alleles are common and have identical physico-chemical properties. As a consequence of the latter, they co-migrate in the same band ('shared peak'), which prevents measuring each allele separately. Without individual allelic measurements, the direct calculation of the chimeric recipient/donor DNA ratio is precluded. This is the first study to document and systematically examine these problems. Its goal was to provide a validated framework for accurate, routine monitoring based on a stepwise analytic paradigm for approximating percent CHM (%CHM) from shared STR-alleles. Analysis of STR-DNA from DD loci showed that at least four of six alleles were typically shared. Despite such extensive allelic sharing, we show how simple arithmetic procedures can be applied for standardized calculation of %CHM based on peak measurements. Criteria for selecting loci suitable for such analysis are provided. Validation of the computational results required analyzing 18 'informative' loci with pre-established reference values for %CHM. In all cases, the results for %CHM, calculated from peak measurements, were +/-5% of the reference value. The conclusions of the study are as follows: (1) Multi-donor chimeras, with shared alleles, can be accurately and simply analyzed within the usual limits of STR measurement error; (2) by examining these various facets of DD CHM analysis, this novel study has provided a basis for standardized, routine quantitative monitoring using the STR/VNTR assay.

Alefacept treatment for refractory chronic extensive GVHD.

Alefacept (Amevive) is an immunosuppressive dimeric fusion protein that is used for psoriasis control. We recently showed its effect in acute steroid-resistant/dependent GVHD. In this study, we describe the effect of alefacept treatment on chronic extensive GVHD (cGVHD). Twelve patients were included in this study; of these 8 (9 of 13 episodes) showed response. The median time to initial response was 2.25 weeks and the response was marked (n=3), moderate (n=2) or minimal (n=4). In two responding patients, the response was only temporary. Complications that appeared during treatment included infection, pericarditis and squamous cell carcinoma of the lip. All these events may be related to other drugs given simultaneously. With a 30-month median follow-up, 6 of 12 patients are alive, with all but one with stable or improved cGVHD. Six patients died because of GVHD progression, whereas none of the patients experienced relapse of the disease for which the transplantation was done. As reported earlier in psoriatic patients treated with alefacept, we found a consistent increase in the percentage of naive T cells as a consequence of treatment. In conclusion, alefacept is effective for the treatment of cGVHD, and dose and time intervals of treatment should be explored further.

Time to engraftment following allogeneic stem cell transplantation is significantly longer in patients with myelodysplastic syndrome than with acute myeloid leukemia.

Patients with myelodysplastic syndrome (MDS) commonly present with pancytopenia, suggesting that the marrow stroma fails to support the growth of both malignant and normal stem cells. We therefore retrospectively analyzed the duration to engraftment of neutrophils (> or =0.5 x 10(9)/l and > or =1.0 x 10(9)/l) and platelets (> or =20 and > or =50 x 10(9)/l) in 37 MDS patients and 42 patients suffering from primary AML, following allogeneic SCT. A significantly shorter time to engraftment was documented in AML as compared to MDS patients in all four parameters. These results held true even when we subgrouped the patients according to gender, age (50 years being the cutoff age between young and elderly patients), patient-donor relationship, donor match and intensity of conditioning. To the best of our knowledge, this is the first time that such a comparison has been made. We suggest that the longer duration of post transplant pancytopenia that is frequently observed in MDS patients may also influence post transplant outcome.

Peliosis hepatis following treatment with androgen-steroids in patients with bone marrow failure syndromes.

Androgens widely used in the treatment of bone marrow failure syndromes can in rare cases cause hepatic peliosis, a pathological entity characterized by multiple blood-filled cavities in the liver parenchyma. Bone marrow failure syndromes per se are associated with a low coagulation status, which is further magnified by bone marrow transplantation for aplastic anaemia due to deep thrombocytopenia. Both these conditions can cause bleeding; their combination is especially dangerous. We describe two cases of aplastic anaemia due to paroxysmal nocturnal hemoglobinuria and Fanconi syndrome, in which patients developed peliosis hepatis after prolonged treatment with androgens. One patient developed severe subcapsular bleeding, successfully treated with catheterization of the right hepatic artery and embolization of the bleeding site. The second patient bridged over deep post-transplant aplasia with high frequency platelet transfusions, and demonstrated an uncomplicated post-BMT course. We suggest avoiding or interrupting treatment with androgens in patients preparing for BMT.

Allogeneic stem cell transplantation from matched related and unrelated donors in thalassemia major patients using a reduced toxicity fludarabine-based regimen.

The only radical cure for thalassemia major patients today is the replacement of the defective hematopoietic system by allogeneic stem cell transplantation (allo-SCT). The major obstacles for the application of allo-SCT even from matched family members have been the transplant-related morbidity and mortality and graft failure that is usually associated with the recurrence of the thalassemia hematopoiesis. The outcome of allo-SCT from HLA-identical family donors is largely dependent on the age of the recipient as well as on pretransplant parameters reflecting the degree of organ damage from iron overload. In this study we report our experience of allo-SCT from matched related and unrelated donors, using a reduced toxicity conditioning consisting of fludarabine, busulfan or more recently busulfex and antithymocyte globulin, in a cohort of 20 patients with thalassemia major. The regimen-related toxicity was minimal, while the incidence of acute grade II-IV and chronic GVHD was 25 and 25%, respectively. With a median follow-up period of 39 months (range: 5-112 months) the overall survival was 100%, while thalassemia-free survival was 80%. Although the results of our study look promising, larger cohorts of patients and prospective clinical trials are required to confirm the benefits of our approach as a possible better alternative to the existing protocols.

The effect of high-dose thiotepa, alone or in combination with other chemotherapeutic agents, on a murine B-cell leukemia model simulating autologous stem cell transplantation.

The use of thiotepa (TH) is increasing, especially in stem cell transplantation, mainly due to its safety and blood-brain barrier penetration. We evaluated the use of TH in a murine model simulating autologous stem cell transplantation, with or without additional agents. Between 1 and 11 days following inoculation of BALB/c mice with 10(5)-10(8) B-cell leukemia (BCL1) cells (simulating pre-transplant leukemia loads), each group received an 'induction-like' irradiation and/or cytotoxic regimen. Animals were either followed without treatment, or an adoptive transfer (AT) was performed to untreated BALB/c mice. Administered alone without AT, high-dose TH did not change the time to appearance of leukemia. Nevertheless, in the AT experiments, TH as a single agent showed better antileukemic activity than busulfan (BU). Cyclophosphamide (CY)-containing regimens were the most effective, and the TH-CY combination was as effective as the commonly used BU-CY combination, and more effective than the BU-TH combination. Moreover, a synergistic effect was seen in the TH-CY combination (none of the animals developed leukemia, whereas 4/10 animals in the CY-TBI group developed leukemia (P=0.029)). In conclusion, although TH produced only a moderate effect against BCL1 leukemia when used alone, its combination with CY is promising and should be tested further in allogeneic murine models and clinical studies.

Interleukin-7 induced facilitation of immunological reconstitution of sublethally irradiated mice following treatment with alloreactive spleen cells in a murine model of B-cell leukemia/lymphoma (BCL1).

Interleukin-7 (IL-7) plays a key role in maturation and function of both T and B cells. We investigate the potential use of recombinant human IL-7 for facilitation of graft-versus-leukemia (GVL) effects mediated by T cells following transplantation in a murine model. Administration of IL-7 in vivo to allogeneic-transplanted mice improved disease-free survival: 67% of mice treated with IL-7 remained alive and disease free for more than 60 days, in comparison to 17% of the controls (P<0.05). Similar results were obtained when C57BL/6 spleen cells sensitized against irradiated B-cell leukemia (BCL(1)) cells in the presence of IL-7 were transplanted to F(1) mice, followed by IL-7 treatment in vivo. Of the BALB/c mice that received spleen cells from F(1) mice treated with IL-7 following transplantation of C57BL/6 spleen cells sensitized with irradiated BCL(1) in the presence of IL-7, only 29% developed leukemia, as compared to 79% in the control group (P<0.05). Mice treated with IL-7 showed increased splenic and thymic cellularity and improved T cell-dependent proliferative responses compared to the controls (P<0.05). IL-7 may provide a novel tool to enhance immune reconstitution following transplantation of mismatched stem cells and for enhancement of GVL effects mediated by alloreactive lymphocytes.

A patient with progressive multiple myeloma treated successfully with arsenic trioxide after allogeneic bone marrow transplantation.

Multiple myeloma (MM) is an incurable progressive disease. Many therapeutic options are available to delay progression, including autologous and allogeneic bone marrow transplantation. At advanced stages, MM is often refractory to treatment. We report a heavily pretreated patient with graft-versus-host disease after bone marrow transplantations, treated at a terminal stage with a modified protocol for arsenic trioxide (ATO). This patient with poor clinical status tolerated the treatment very well. He had a remarkable clinical response and achieved complete remission. The mechanisms of ATO are presented and the potential role of ATO for MM is discussed.