Analyzing Blood Cells of High-Risk Myelodysplastic Syndrome Patients Using Interferometric Phase Microscopy and Fluorescent Flow Cytometry.

Myelodysplastic syndromes (MDSs) are a group of potentially deadly diseases that affect the morphology and function of neutrophils. Rapid diagnosis of MDS is crucial for the initiation of treatment that can vastly improve disease outcome. In this work, we present a new approach for detecting morphological differences between neutrophils isolated from blood samples of high-risk MDS patients and blood bank donors (BBDs). Using fluorescent flow cytometry, neutrophils were stained with 2',7'-dichlorofluorescin diacetate (DCF), which reacts with reactive oxygen species (ROS), and Hoechst, which binds to DNA. We observed that BBDs possessed two cell clusters (designated H and L), whereas MDS patients possessed a single cluster (L). Later, we used FACS to sort the H and the L cells and used interferometric phase microscopy (IPM) to image the cells without utilizing cell staining. IPM images showed that H cells are characterized by low optical path delay (OPD) in the nucleus relative to the cytoplasm, especially in cell vesicles containing ROS, whereas L cells are characterized by low OPD in the cytoplasm relative to the nucleus and no ROS-containing vesicles. Moreover, L cells present a higher average OPD and dry mass compared to H cells. When examining neutrophils from MDS patients and BBDs by IPM during flow, we identified ~20% of cells as H cells in BBDs in contrast to ~4% in MDS patients. These results indicate that IPM can be utilized for the diagnosis of complex hematological pathologies such as MDS.

The Effect of The Oral Iron Chelator Deferiprone on Iron Overload and Oxidative Stress in Patients with Myelodysplastic Syndromes A Study by the Israeli MDS Working Group.

BACKGROUND: Most patients with lower risk myelodysplastic neoplasms (MDS) become RBC transfusion-dependent, resulting in iron overload, which is associated with an increased oxidative stress state. Iron-chelation therapy is applied to attenuate the toxic effects of this state. Deferiprone (DFP) is an oral iron chelator, which is not commonly used in this patient population, due to safety concerns, mainly agranulocytosis. The purpose of this study was to assess the effect of DFP, on oxidative stress parameters in iron overloaded RBC transfusion-dependent patients with lower risk MDS. METHODS: Adult lower-risk MDS patients with a cumulative transfusion burden of >20 red blood cells units and evidence of iron overload (serum ferritin >1,000 ng/mL) were included in this study. DFP was administered (100 mg/kg/day) for 4 months. Blood samples for oxidative stress parameters and iron overload parameters were done at baseline and monthly: reactive oxygen species (ROS), phosphatidylserine, reduced glutathione, membrane lipid peroxidation, serum ferritin and cellular labile iron pool. The primary efficacy variable was ROS. Tolerability and side-effects were recorded as well. A paired t-test was applied for statistical analyses. RESULTS: Eighteen patients were treated with DFP. ROS significantly decreased in all cell lineages: median decrease of 58.6% in RBC, 33.3% in PMN, and 39.8% in platelets (p<0.01 for all). Other oxidative stress markers improved: phosphatidylserine decreased by 57.95%, lipid peroxidase decreased by 141.3%, and reduced gluthathione increased by 72.8% (p<0.01 for all). The iron-overload marker, cellular labile iron pool, decreased by 35% in RBCs, 44.3% in PMN, and 46.3% in platelets (p<0.01 for all). No significant changes were observed in SF levels. There were no events of agranulocytosis. All AEs were grade 1-2. CONCLUSIONS: Herein we showed preliminary evidence that DFP decreases iron-induced oxidative stress in MDS patients with a good tolerability profile (albeit a short follow-up period). No cases of severe neutropenia or agranulocytosis were reported. The future challenge is to prove that reduction in iron toxicity will eventually be translated into a clinically meaningful improvement.

MDS-Related Anemia Is Associated with Impaired Quality of Life but Improvement Is Not Always Achieved by Increased Hemoglobin Level.

Quality of life is impaired in MDS, but the role of hemoglobin level is unclear. To study the Hb-QoL correlation at diagnosis and 1 year later, patients filled out the EQ-5D questionnaire, assessing their mobility, self care, daily activities, pain/discomfort, and anxiety/depression, using scores of 0 (normal), 1 (mild/moderate), or 2 (poor). They also evaluated their health using a visual analogue scale, scoring from 0 (poor) to 100 (excellent). The anemia subgroups were: none/normal (Hb ≥ 12.5 g/dL), mild (10 ≤ Hb < 12.5), moderate (9 ≤ Hb < 10), severe (8 ≤ Hb < 9), or very severe (Hb < 8). LR-MDS patients (n = 127) and inpatient controls (n = 141) participated. The anemic patients had a poor QoL and the MDS patients had a lower QoL with a lower Hb. The controls had no QoL difference among the various anemia subgroups. In addition, the MDS QoL sharply decreased with an Hb of < 9. The MDS patients showed a wide QoL variability, i.e., different QoL scores in the same Hb subgroup, suggesting that other factors affect QoL (e.g., age and comorbidities). After 1 year (n = 61), the QoL was still poor for most MDS patients (including 27 patients with an increased Hb). In summary: (1) a poor QoL in MDS-anemia is non-linear, suggesting other influencing factors on QoL. (2) The sharp QoL drop with Hb < 9 g/dL challenges the transfusion Hb threshold. (3) The QoL in anemic MDS patients might differ from that in non-MDS patients. (4) Raising Hb, while recommended, does not guarantee an improved QoL.

Janus Kinase-2 V617F Mutation and Antiphospholipid Syndrome in Cerebral Sinus Venous Thrombosis: Natural History and Retrospective Bicenter Analysis.

Background: Cerebral sinus venous thrombosis (CSVT) is a rare neurovascular entity, usually associated with acquired or genetic hypercoagulable states. In up to 30% of the cases it remains idiopathic. Bone marrow proliferation disorders that are associated with Janus Kinase 2 V617F mutation (JAK-2) are known causes of the systemic and cerebral thrombosis-at times despite normal blood counts-for which hematologic treatment exists. However, JAK-2 prevalence in the CSVT cases is not clear. Methods: In this retrospective analysis, data of 236 patients with CSVT admitted to two tertiary centers between 2010 and 2020 were analyzed, with emphasis on laboratory and imaging data and clinical and interventional outcomes. Results: A total of 236 patients were included in the analysis. The patients' median age was 42 years and the average age was 44 years (±19 years), with 59% female patients. JAK-2 positivity rate was 18% (among 77 patients tested for the mutation). Patients with normal blood counts on presentation comprised 36% of the JAK-2 positive cases. Other hypercoagulability states were also investigated, with the antiphospholipid syndrome (APLA) showing the highest prevalence (11%) followed by other etiologies including oral contraceptive use, Factor V Leiden, prothrombin mutation, and malignancy. Selected JAK-2, APLA, and prothrombin mutation cases showed a more severe clinical course. Conclusion: JAK-2 mutation is underdiagnosed and its screening may be warranted in the cases of idiopathic CSVT, even despite normal blood counts, to allow disease-modifying treatment and blood cell count monitoring. JAK-2, APLA, and prothrombin mutation may be associated with a more complicated clinical course.

Acute Myeloid Leukemia Patients Requiring Two Cycles of Intensive Induction for Attainment of Remission Experience Inferior Survival Compared with Patients Requiring a Single Course of Induction Chemotherapy.

BACKGROUND: Achievement of initial remission remains the most important clinical factor predicting long term survival in acute myeloid leukemia (AML) patients treated with intensive chemotherapy. Yet, whether the patient subset in need of a second cycle of intensive induction chemotherapy to reach remission experiences inferior outcomes compared to patients reaching remission after a single cycle of therapy, remains uncertain. PATIENTS AND METHODS: Retrospective analysis of 302 consecutive AML patients treated with intensive induction chemotherapy in our institution in 2007-2020. RESULTS: Median patient age was 55 years with a median follow-up duration of 23 months. In terms of European LeukemiaNet (ELN) 2017 classification, 122 patients (40%) were designated as favorable risk disease, 108 patients (36%) were intermediate risk, and 71 patients (24%) were adverse risk. A hundred and seventy-seven patients (60%) attained remission following initial chemotherapy while 58 patients (20%) required an additional cycle of intensive chemotherapy for remission. Patients requiring 2 cycles to reach remission were less likely to be NPM1 mutated (33% versus 51%; P=.025) or be in the ELN 2017 favorable risk category (25% versus 57%; P<.001). In multivariate analysis achievement of remission following 2 cycles of intensive compared with a single cycle resulted in significantly inferior survival [hazard ratio (HR)=1.67, 95% CI, 1.07-2.59; P=.025] whereas leukemia-free survival was not significantly impacted (HR=1.26, 95% CI, 0.85-1.85) (P=.23). Relapse rates also did not differ to a significant degree between groups (45% versus 47%, P=.8). CONCLUSION: Attainment of an early remission significantly impacts long term survival in AML patients.

Reassessing the role of high dose cytarabine and mitoxantrone in relapsed/refractory acute myeloid leukemia.

A substantial segment of patients with acute myeloid leukemia (AML) will relapse following an initial response to induction therapy or will prove to be primary refractory. High-dose cytarabine and mitoxantrone (HiDAC/MITO) is an established salvage therapy for these patients. We studied all adult patients with relapsed/refractory (R/R) AML who were treated with HiDAC/MITO in our center between the years 2008-2017. To determine whether responding patients harbored a unique molecular signature, we performed targeted next-generation sequencing (NGS) on a subset of patients. The study cohort consisted of 172 patients with a median age of 54 years (range 18-77). The composite complete remission rate was 58%; 11 patients (6%) died during salvage therapy. Median survival was 11.4 months with a 1-year survival rate of 48%. In multivariate analysis favorable risk cytogenetics [Odds ratio (OR)=0.34, confidence interval (CI) 95%, 0.17-0.68; P = 0.002], and de-novo AML (OR = 0.4, CI 95%, 0.16-0.98; P = 0.047) were independently associated with a favorable response. Patients who attained a complete remission had a median survival of 43.7 months compared with 5.2 months for refractory patients (p < 0.0001). Neither the FLT3-ITD and NPM1 mutational status nor the indication for salvage therapy significantly impacted on the response to HiDAC/MITO salvage. NGS analysis identified 20 different mutations across the myeloid gene spectrum with a distinct TP53 signature detected in non-responding patients. HiDAC/MITO is an effective salvage regimen in R/R AML, however patients with adverse cytogenetics or secondary disease may not benefit as much from this approach.

Is fluorescence in-situ hybridization sufficient in patients with myelodysplastic syndromes and insufficient cytogenetic testing?

Chromosome banding analysis (CBA) in myelodysplastic syndromes (MDS) remains the 'gold standard' for identification of chromosomal abnormalities, while interphase fluorescence in-situ hybridization (I-FISH) is mainly used to complement CBA. This study, retrospectively, evaluated CBA and I-FISH results in 600 patients with suspected MDS and determined the effect of CBA/FISH reallocation on IPSS-R. Our result demonstrated that in 7/586 (1.2%) patients with satisfactory karyotype, I-FISH provided additional information. In 25/453 (5.5%) of the patients with normal I-FISH, CBA detected chromosomal abnormalities, and in 68/147 (46%) of the patients with abnormal I-FISH, CBA detected additional chromosomal aberrations. When 5q- aberration was alone or accompanied by additional abnormalities by I-FISH, CBA revealed a complex karyotype (16/25;64%, 35/43;81%, respectively). Our results suggest that in cases of karyotype failure, if I-FISH is used alone, patients are at risk of being misclassified into the wrong cytogenetic risk groups and a repeat sample for CBA should be attempted.

Gender disparities in the functional significance of anemia among apparently healthy adults.

BACKGROUND: Data on the functional impact of anemia on cardiorespiratory fitness (CRF) and survival in healthy individuals are limited. Our aim was to evaluate the association between anemia thresholds, low CRF, and survival in otherwise healthy adults. METHODS: Study population included 16 334 apparently healthy subjects attending annual periodic health screening examinations (71 200 annual visits), including exercise stress testing (EST). Anemia was defined by the World Health Organization (WHO) or Beutler and Waalens' (BW) criteria. Low CRF was defined as the lowest fitness quintile according to the Bruce protocol. RESULTS: The mean age was 46±10 years, and 70% were men. Mean Hb levels were 13±1 and 15±1 among women and men, respectively, with higher proportion of anemia among women. The majority of anemic subjects had mild anemia. When analyzing repeated annual visits, anemia was associated with a significant 39% and 64% increased risk of low CRF according the WHO and BW criteria only in women (n=18 672). Baseline anemia at first visit was associated with 2.6- and 1.9-fold increased risk of all-cause mortality using the WHO and BW criteria, exclusively in men (n=11 511). CONCLUSIONS: Overall, the functional and prognostic impact of anemia is gender dependent, based on the WHO and BW arbitrary criteria, suggesting differing mechanism and responses.

Second line azacitidine for elderly or infirmed patients with acute myeloid leukemia (AML) not eligible for allogeneic hematopoietic cell transplantation-a retrospective national multicenter study.

Elderly and infirm patients with acute myeloid leukemia (AML) with either induction refractory or relapse disease may benefit from treatment with azacitidine. We retrospectively reviewed the data from five tertiary centers in Israel, treated between 2009 and 2015. Thirty-four patients (median age 74 years) were identified. Sixty-two percent of the patients had relapsed disease and 38% had refractory disease. Median time of follow-up was 12.1 months. Out of a total of 327 courses, incidence of infectious episodes was 6%. Eighteen percent experienced major bleeding. Thirty-two percent of the patients achieved morphologic complete remission, and 26% had stabilization of disease during at least three courses. At 12 and 18 months after the first course of azacitidine, 33 and 10% of the patients were progression-free, respectively. Incidences of overall survival at 12 and 24 months were 54.5 and 16%, respectively. Age <75 years was associated with better overall survival. Normal leukocyte count at the first dose of azacitidine and standard doses of azacitidine were both associated with a better progression-free and overall survival. We conclude that azacitidine is feasible in patients who have failed induction chemotherapy and may be associated with prolongation of survival. A prospective trial to validate these results is warranted.

Clinical Experience With Deferiprone Treatment for Friedreich Ataxia.

Friedreich ataxia is an inherited disorder characterized by degeneration of the peripheral and central nervous system and hypertrophic cardiomyopathy. Homozygous mutations in the frataxine (FXN) gene reduce expression of frataxin and cause accumulation of iron in the mitochondria. Deferiprone, an oral iron chelator, has been shown effective in cell and animal models of Friedreich ataxia. The results of a 6-month randomized, double blind placebo-controlled study suggested that deferiprone 20 mg/kg/day may reduce disease progression. The authors present their experience of 5 Friedreich ataxia patients treated with deferiprone (20 mg/kg/day), in addition to idebenone treatment, followed over a period of 10-24 months, under off-label authorization. The patients were monitored for laboratory parameters, cardiac assessment, neurological evaluations, and quality of life. The authors conclude that combined therapy of a low dose of deferiprone with idebenone is relatively safe, might improve neurological function, and seems to improve heart hypertrophy, warranting further studies.

Higher infection rate after 7- compared with 5-day cycle of azacitidine in patients with higher-risk myelodysplastic syndrome.

INTRODUCTION: Azacitidine (AZA) dose reduction is a common practice in cytopenic patients. However, a correlation between AZA dose and infection complications has never been studied. PATIENTS AND METHODS: Higher-risk patients with myelodysplastic syndrome or acute myeloid leukemia treated with AZA in 18 Israeli hospitals between the years 2008 and 2011 were included in a former national survey. To reveal the effect of AZA dosage on infection risk we limited our analysis to the infection rate after the first AZA dose alone. We excluded subsequent cycles of AZA from the analysis, because infectious events during these cycles might be related to other cofactors such as disease response to AZA therapy. RESULTS: After the first AZA cycle, infectious events were more frequent after doses of 75 mg/m(2) for 7 days than 75 mg/m(2) for 5 days (36/106 [34%] and 10/67 [14.9%], respectively; P = .008), regardless of the patient's age. Of the 46 recorded infectious events, the causative pathogen was identified as bacterial in 25 (54.3%) and as viral or fungal in 2 (4.3%) and 2 (4.3%) cases, respectively. No pathogen was identified in 17 (37%) cases. Infections were significantly more prevalent among patients who presented with platelet counts < 20,000 (43.6% vs. 23.6%; P = .012) and poor risk cytogenetics (40.7% vs. 19.8%; P = .008). CONCLUSION: Reduction of AZA dose might decrease infection rate and therefore should be considered in patients with high infection risk.

The impact of R-VACOP-B and interim FDG-PET/CT on outcome in primary mediastinal large B cell lymphoma.

The choice of a rituximab-based regimen and the prognostic significance of interim 2-[fluorine-18]fluoro-2-deoxy-D-glucose-positron emission tomography/computed tomography (FDG-PET/CT) in primary mediastinal large B cell lymphoma (PMBCL) are debatable. We evaluated the clinical features and outcomes of 95 consecutive patients with PMBCL who were treated between 1985 and 2009. Forty-three patients received rituximab-based chemotherapy, R-VACOP-B (N = 30) or R-CHOP21 (N = 13), whereas 52 patients were treated with VACOP-B (N = 47) or CHOP21 (N = 5). Radiotherapy was not given. Patients who received rituximab had a 5-year progression-free survival (PFS) of 79 % and overall survival (OS) of 97 % compared with 58 % (p = 0.06) and 88 % (p = 0.2), respectively, without rituximab. Five-year PFS in patients treated with R-VACOP-B, R-CHOP21, VACOP-B, and CHOP21 were 83, 69, 62, and 20 %, respectively (p = 0.039). However, direct comparison showed that the difference between PFS rates in patients receiving R-VACOP-B compared to R-CHOP21 was not statistically significant (p = 0.3). None of the standard clinical risk factors predicted for PFS and OS in patients receiving rituximab (R)-chemotherapy. Mid-interim FDG-PET/CT scans were performed in 30/43 patients who received R-chemotherapy. The negative predictive values of mid-PET activity were high (100 % for R-VACOP-B and 86 % for R-CHOP21) while the positive predictive values (PPV) were relatively low (30 and 75 %, respectively). Despite the low PPV, the 5-year PFS for mid-PET-negative patients (N = 16) was significantly higher (94 %) than that for mid-PET-positive (N = 14) patients (57 %, p = 0.015). This retrospective analysis demonstrates that the superiority of VACOP-B over CHOP21 for treatment of PMBCL disappeared once rituximab was added. The potential benefit of using interim PET activity as a guide for continuing therapy in patients with PMBCL remains unclear due to the relatively low PPV.

Toward resolving the unsettled role of iron chelation therapy in myelodysplastic syndromes.

Transfusion dependent low risk myelodysplastic syndromes (MDS) patients, eventually develop iron overload. Iron toxicity, via oxidative stress, can damage cellular components and impact organ function. In thalassemia major patients, iron chelation therapy lowered iron levels with recovery of cardiac and liver functions and significant improvement in survival. Several noncontrolled studies show inferior survival in MDS patients with iron overload, including an increase in transplant-related mortality and infection risk while iron chelation appears to improve survival in both lower risk MDS patients and in stem cell transplant settings. Collated data are presented on the pathophysiological impact of iron overload; measuring techniques and chelating agents' therapy positive impact on hematological status and overall survival are discussed. Although suggested by retrospective analyses, the lack of clear prospective data of the beneficial effects of iron chelation on morbidity and survival, the role of iron chelation therapy in MDS patients remains controversial.

The role of hypomethylating agents in myelodysplastic syndrome: changing the management paradigm.

Modern treatment of myelodysplastic syndromes (MDS) with hypomethylating agents (HMAs) such as azacitidine (Vidaza) and decitabine (Dacogen) has changed the clinical landscape of these disorders. Novel drug combinations of HMAs with histone deacetylase inhibitor therapy may synergistically target different dysregulated molecular mechanisms within MDS clones. This article reviews current trial data concerning the use of the main HMAs in MDS patients where intensive chemotherapy and allogeneic stem cell transplantation is generally not an option. Collated data are presented of the clinical response outcomes, toxicity profiles and prognostic response criteria. Vidaza use in low-risk MDS cases, the selected place of allogeneic stem cell transplantation in older patients with significant comorbidity and the novel drug combination strategies for the future are discussed.

Predicting infections in high-risk patients with myelodysplastic syndrome/acute myeloid leukemia treated with azacitidine: a retrospective multicenter study.

Hypomethylating agents have become the standard therapy for patients with high-risk myelodysplastic syndrome (MDS). In Israel, azacitidine (AZA) is routinely used. Yet, infectious complications are common during AZA therapy. The current study was aimed to evaluate the incidence and predisposing risk factors for infections in AZA-treated patients. This retrospective study included patients treated with AZA in 18 Israeli medical institutions between 2008 and 2011. Data on 184 patients [157 high-risk MDS and 27 acute myeloid leukemia (AML)], with a median age of 71.6 (range 29-92) were recorded. Overall, 153 infectious events were reported during 928 treatment cycles (16.5%) administered to 100 patients. One hundred fourteen, 114/153 (75%) events required hospitalization and 30 (19.6%) were fatal. In a univariate analysis, unfavorable cytogenetics, low neutrophil, hemoglobin (Hb) and platelet (PLT) counts were found to be associated with infections (24.4% vs. 12.9%, P < 0.0001; 27% vs. 13.5%, P < 0.0001; 20.4% vs. 11%, P < 0.0001 and 29.2% vs. 14.2%, P < 0.0001, respectively). In multivariate analysis, only low Hb level, low PLT count, and unfavorable cytogenetics remained significant. Prior to therapy, poor cytogenetics, PLT count below 20 × 109/L and neutrophil count below 0.5 × 109/L were predictive of the risk of infection during the first two cycles of therapy. In conclusion, patients with unfavorable cytogenetics, presenting with low neutrophil and PLT counts, are susceptible to infections. Evaluation of infection risk should be repeated prior to each cycle. Patients with poor cytogenetics in whom AZA is prescribed despite low PLT count are particularly at high risk for infections and infection prophylaxis may be considered.

Anemia, iron deficiency, and stress fractures in female combatants during 16 months.

Yanovich, R, Merkel, D, Israeli, E, Evans, RK, Erlich, T, and Moran, DS. Anemia, iron deficiency, and stress fractures in female combatants during 16 months. J Strength Cond Res 25(12): 3412-3421, 2011-The purpose of this study is to evaluate the hematological profile of military recruits in different settings and training programs and to investigate the link between anemia and iron deficiency with stress fracture (SF) occurrence. We surveyed 3 groups of recruits for 16 months: 221 women (F) and 78 men (M) from 3 different platoons of a gender-integrated combat battalion and a control group (CF) of 121 female soldiers from a noncombat unit. Data were fully collected upon induction and at 4 and 16 months from 48F, 21M, and 31CF. Blood tests, anthropometry, physical aerobic fitness, and SF occurrence were evaluated. On induction day, 18.0 and 19.0% of F and CF were found to be anemic, and 61.4 and 50.9%, respectively, were found to have iron deficiency, whereas 7.7% of M were found to be anemic and 10.2% iron deficient. During the 4 months of army basic training (ABT), anemia and iron deficiency prevalence did not change significantly in any group. After 16-months, anemia prevalence decreased by 8% among F and CF and abated in M. Iron deficiency was prevalent in 50.0, 59.4, and 18.8% of F, CF, and M, respectively. Stress fractures were diagnosed in 14 F during ABT, and they had a significantly higher prevalence (p < 0.05) of anemia and iron deficiency anemia compared to F without SFs. The observed link between anemia and iron deficiency on recruitment day and SFs suggests the importance of screening female combat recruits for these deficiencies. To minimize the health impact of army service on female soldiers, preventative measures related to anemia and iron deficiency should be administered. Further research is needed for evaluating the influence of low iron in kosher meat as a possible explanation for the high prevalence of iron deficiency among young Israeli recruits.

Incidence of anemia and iron deficiency in strenuously trained adolescents: results of a longitudinal follow-up study.

PURPOSE: Combat soldiers have a higher prevalence of anemia than age- and gender-matched civilians. This may be caused by hemodilution, which is typical among athletes, or by reduced body iron stores. The aim of this study was to investigate the incidence of iron-deficiency anemia in recruits to the Israel Defense Force after 6 months of training. METHODS: Blood was collected from recruits before training. After 6 months of follow-up, 153 paired blood samples were collected from the initial cohort. Total blood count and serum iron, transferrin, and ferritin were measured at both time points. Soluble transferrin receptor (sTfR) was measured in 119 of the paired samples and the sTfR/log ferritin ratio was calculated. RESULTS: At recruitment, mean hemoglobin concentration was 14.7 +/- .9 g/dl. Iron-transferrin saturation was 34.1% +/- 13.6%, and mean ferritin concentration was 53.6 +/- 33.2 ng/ml. Anemia prevalence (Hb <14 g/dl) was 17.6%, and 14.9% of participants were iron-deficient (ferritin <22 mg/dl). At 6 months, 50.3% of the cohort was anemic, and 27.3% demonstrated iron-store depletion. Paired analysis showed an average reduction of .83 g/dl in hemoglobin (p < .001), and of 9.8 mg/dl in ferritin (p < .001). sTfR increased from 1.9 to 2.1 mg/dl (p < .003) among recruits who became anemic. Half of the recruits experienced mild anemia after 6 months of training. Iron store depletion was observed among 24.5% of the cohort after training, as opposed to 15% at recruitment. Overall, these changes were not accompanied by a significant increase in sTfR, but among the subset of anemic subjects, there was a slight increase in index value. CONCLUSIONS: In half of the cases, new-onset anemia was attributable to iron deficiency, and in the remainder, to hemodilution.

The association between hematological and inflammatory factors and stress fractures among female military recruits.

BACKGROUND: With the growing number of females accepted for combat-related military duties in the Israeli Defense Forces, their special needs should be addressed. Previous studies on females in combat training have found a high prevalence of iron deficiency at recruitment as well as an increased rate of stress fractures (SF) and overuse injuries during training when compared with males. The aim of this study was to assess the correlation between hematological and inflammatory variables and SF occurrence among military recruits during basic training. METHODS: Three gender-integrated light infantry units were followed prospectively. Female recruits inducted for medic and dental assistants' courses were followed for comparison. Hemoglobin, iron, transferrin, ferritin, C-reactive protein, and interleukin-6 levels were measured for all participants at recruitment and at 2 and 4 months of training. SF were diagnosed radiographically or scintigraphically according to the Israeli Defense Forces protocol. RESULTS: A total of 438 subjects were recruited (female combatants = 227, male combatants = 83, noncombatant females = 128). At induction, 18% of female combatants had anemia compared with 8% of males and 19% of noncombatants. Iron deficiency was noted in 40%, 6%, and 38%, respectively. There were no clinically significant changes during training. Twelve percent of female combatants developed SF, whereas none occurred among male combatants or noncombatants. Subjects sustaining an SF had significantly lower levels of serum iron and iron saturation. CONCLUSIONS: A high incidence of anemia as well as iron deficiency was found in this young asymptomatic cohort, with no significant change during training. The lower level of iron in female combatants sustaining SF warrants further investigation.