Revisiting the most often used item in the haematological tool box-The extent of haemodilution in bone marrow aspirates.

In this issue, a nationwide retrospective Japanese study finds that, in a second opinion setting, one-third of bone marrow aspirates from patients suspected of myelodysplastic syndromes are heavily haemodiluted. Moreover, in four-fifths of such cases, the failure to obtain the correct material for diagnosis went undetected by the referring institution. These data are intriguing, but given their special set-up, caution should be exerted in transposing them to other countries. Commentary on: Ogata et al. Prevalence of massively diluted bone marrow cell samples aspirated from patients with myelodysplastic syndromes (MDS) or suspected MDS: A retrospective analysis of nationwide samples in Japan. Br J Haematol 2024;204:1856-1861.

Prevalence of massively diluted bone marrow cell samples aspirated from patients with myelodysplastic syndromes (MDS) or suspected of MDS: A retrospective analysis of nationwide samples in Japan.

Bone marrow (BM) examination is a key element in the diagnosis and prognostic grading of myelodysplastic syndromes (MDSs), and obtaining adequate BM cell samples is critical for accurate test results. Massive haemodilution of aspirated BM samples is a well-known problem; however, its incidence in patients with MDS has not been well studied. We report the first study to examine the incidence of massive haemodilution in nationwide BM samples aspirated from patients diagnosed with or suspected of MDS in Japan. Among 283 cases available for analysis, BM smears from 92 cases (32.5%) were hypospicular (massively haemodiluted) and, particularly, no BM particles were observed in 52 cases (18.4%). Regarding hypospicular cases, we examined how the doctors in charge interpreted the BM smears of their patients. In only 19 of 92 cases (20.7%), doctors realised that the BM smears were haemodiluted. Furthermore, the BM biopsy, which can help diagnose hypospicular cases, was oftentimes not performed when the haemodilution was overlooked by doctors (not performed in 50 of 73 such cases). These real-world data highlight that not only researchers who are working to improve diagnostic tests but also clinicians who perform and use diagnostic tests must realise this common and potentially critical problem.

Performance Evaluation of a Novel Artificial Intelligence-Assisted Digital Microscopy System for the Routine Analysis of Bone Marrow Aspirates.

Bone marrow aspiration (BMA) smear analysis is essential for diagnosis, treatment, and monitoring of a variety of benign and neoplastic hematological conditions. Currently, this analysis is performed by manual microscopy. We conducted a multicenter study to validate a computational microscopy approach with an artificial intelligence-driven decision support system. A total of 795 BMA specimens (615 Romanowsky-stained and 180 Prussian blue-stained) from patients with neoplastic and other clinical conditions were analyzed, comparing the performance of the Scopio Labs X100 Full Field BMA system (test method) with manual microscopy (reference method). The system provided an average of 1,385 ± 536 (range, 0-3,131) cells per specimen for analysis. An average of 39.98 ± 19.64 fields of view (range, 0-140) per specimen were selected by the system for analysis, of them 87% ± 21% (range, 0%-100%) were accepted by the qualified operators. These regions were included in an average of 17.62 ± 7.24 regions of interest (range, 1-50) per specimen. The efficiency, sensitivity, and specificity for primary and secondary marrow aspirate characteristics (maturation, morphology, and count assessment), as well as overall interuser agreement, were evaluated. The test method showed a high correlation with the reference method for comprehensive BMA evaluation, both on Romanowsky- (90.85% efficiency, 81.61% sensitivity, and 92.88% specificity) and Prussian blue-stained samples (90.0% efficiency, 81.94% sensitivity, and 93.38% specificity). The overall agreement between the test and reference methods for BMA assessment was 91.1%. For repeatability and reproducibility, all standard deviations and coefficients of variation values were below the predefined acceptance criteria both for discrete measurements (coefficient of variation below 20%) and differential measurements (SD below 5%). The high degree of correlation between the digital decision support system and manual microscopy demonstrates the potential of this system to provide a high-quality, accurate digital BMA analysis, expediting expert review and diagnosis of BMA specimens, with practical applications including remote BMA evaluation and possibly new opportunities for the research of normal and neoplastic hematopoiesis.

Diagnostic yield of bone marrow aspiration in paediatric primary immune thrombocytopenia: impact of evolution and adherence to medical guidelines over the last 25 years.

The aim of this study is to analyse the diagnostic value of bone marrow aspiration (BMA) in a retrospective cohort of patients with suspected immune thrombocytopaenia (ITP). We further measure changes in the percentage of patients who underwent this study and whether testing or not was in accordance with current guidelines at the time of diagnosis. We conducted a chart review of 243 patients with ITP who underwent follow-up in our institution between 1995 and 2022. The patients were divided into historical cohorts based on the practice guidelines of the Spanish Society of Pediatric Hematology and Oncology (SEHOP) and the American Society of Hematology (ASH) in place at the time of follow-up. For each case, time of disease presentation or initial diagnosis was defined as that which occurred in the first 72 h following disease onset. Based on data from the historical cohorts studied, we observed a lower total number of BMAs at diagnosis over time (p < 0.005). A gradual reduction was seen in the number of BMAs with the introduction of guidelines, including a progressively lower number of BMAs performed without indication (p < 0.05). Subsequent to the initial diagnosis, the procedure played a decisive role in only 2 patients (0.58%), allowing for a diagnosis of acquired aplastic anaemia in both cases. In both of them on diagnosis, BMA did not appear to be indicated, although subsequent analysis after 72 h raised suspicion of bone marrow failure. CONCLUSION: BMA at presentation did not significantly alter the diagnosis in our cohort of patients with an initial suspicion of ITP, although the procedure was decisive in diagnosing 2 cases of acquired aplastic anaemia during the subsequent course of the disease. Regarding the number of aspirations performed, our findings show that increased physician compliance with current guidelines reduced the rate of unnecessary BMAs. WHAT IS KNOWN: • BMA is a supplementary test for the diagnosis of ITP. • The usefulness of this invasive diagnostic procedure is not clearly stated in current guidelines. WHAT IS NEW: • Adjustments to scientific guidelines have led to a reduction in the number of BMAs performed on our patients with suspected ITP in the last 27 years. • While the risks and benefits of BMA at the time of diagnosis are unclear in patients with suspected ITP, the procedure does not contribute significant information to support the diagnosis.

Deep learning identifies Acute Promyelocytic Leukemia in bone marrow smears.

BACKGROUND: Acute promyelocytic leukemia (APL) is considered a hematologic emergency due to high risk of bleeding and fatal hemorrhages being a major cause of death. Despite lower death rates reported from clinical trials, patient registry data suggest an early death rate of 20%, especially for elderly and frail patients. Therefore, reliable diagnosis is required as treatment with differentiation-inducing agents leads to cure in the majority of patients. However, diagnosis commonly relies on cytomorphology and genetic confirmation of the pathognomonic t(15;17). Yet, the latter is more time consuming and in some regions unavailable. METHODS: In recent years, deep learning (DL) has been evaluated for medical image recognition showing outstanding capabilities in analyzing large amounts of image data and provides reliable classification results. We developed a multi-stage DL platform that automatically reads images of bone marrow smears, accurately segments cells, and subsequently predicts APL using image data only. We retrospectively identified 51 APL patients from previous multicenter trials and compared them to 1048 non-APL acute myeloid leukemia (AML) patients and 236 healthy bone marrow donor samples, respectively. RESULTS: Our DL platform segments bone marrow cells with a mean average precision and a mean average recall of both 0.97. Further, it achieves high accuracy in detecting APL by distinguishing between APL and non-APL AML as well as APL and healthy donors with an area under the receiver operating characteristic of 0.8575 and 0.9585, respectively, using visual image data only. CONCLUSIONS: Our study underlines not only the feasibility of DL to detect distinct morphologies that accompany a cytogenetic aberration like t(15;17) in APL, but also shows the capability of DL to abstract information from a small medical data set, i. e. 51 APL patients, and infer correct predictions. This demonstrates the suitability of DL to assist in the diagnosis of rare cancer entities. As our DL platform predicts APL from bone marrow smear images alone, this may be used to diagnose APL in regions were molecular or cytogenetic subtyping is not routinely available and raise attention to suspected cases of APL for expert evaluation.

Next-generation sequencing in the diagnosis of non-cirrhotic splanchnic vein thrombosis.

BACKGROUND & AIMS: Myeloproliferative neoplasms (MPNs) are the most frequent cause of non-tumoural non-cirrhotic splanchnic vein thrombosis (NC-SVT). Diagnosis of MPN is based on blood cell count alterations, bone marrow histology, and detection of specific gene mutations. Next-generation sequencing (NGS) allows the simultaneous evaluation of multiple genes implicated in myeloid clonal pathology. The aim of this study was to evaluate the potential role of NGS in elucidating the aetiology of NC-SVT. METHODS: DNA samples from 80 patients (75 with idiopathic or exclusively local factor [Idiop/loc-NC-SVT] and 5 with MPN and NC-SVT [SVT-MPN] negative for Janus kinase 2 gene [JAK2] [V617F and exon 12], calreticulin gene [CALR], and thrombopoietin gene [MPL] mutations by classic techniques) were analysed by NGS. Mutations involved in myeloid disorders different from JAK2, CALR, and MPL genes were categorised as high-molecular-risk (HMR) variants or variants of unknown significance. RESULTS: In 2/5 triple-negative SVT-MPN cases (40%), a mutation in exon 12 of JAK2 was identified. JAK2-exon 12 mutation was also identified in 1/75 patients with Idiop/loc-NC-SVT. Moreover, 28/74 (37.8%) of the remaining Idiop/loc-NC-SVT had at least 1 HMR variant. Sixty-two patients with Idiop/loc-NC-SVT were not receiving long-term anticoagulation and 5 of them (8.1%) had recurrent NC-SVT. This cumulative incidence was significantly higher in patients with HMR variants than in those without. CONCLUSIONS: NGS identified JAK2-exon12 mutations not previously detected by conventional techniques. In addition, NGS detected HMR variants in approximately one-third of patients with Idiop/loc-NC-SVT. These patients seem to have a higher risk of splanchnic rethrombosis. NGS might be a useful diagnostic tool in NC-SVT. LAY SUMMARY: Next-generation sequencing (NGS) performs massive sequencing of DNA allowing the simultaneous evaluation of multiple genes even at very low mutational levels. Application of this technique in a cohort of patients with non-cirrhotic non-tumoral portal vein thrombosis (NC-SVT) and a negative study for thrombophilic disorders was able to identify patients with a mutation in exon 12 not previously detected by conventional techniques. Moreover, NGS detected High Molecular Risk (HMR)-variants (Mutations involved in myeloid disorders different from JAK2, CALR and MPL genes) in approximately one third of patients. These patients appear to be at increased risk of rethrombosis. All these findings supports NGS as a potential useful tool in the management of NC-SVT.

The reliability of bone marrow cytology as response criterion in metastatic neuroblastoma.

BACKGROUND: The quantitative assessment of neuroblastoma cell content in bone marrow aspirates for response evaluation has been introduced recently. Data on the concordance of interobserver reports are lacking so far. METHODS: Investigators of seven European countries representing national reference or large oncological centers convened in 2016. They agreed to quantitatively assess routine bone marrow smears of the participating institutions and to discuss the discrepant results in joint meetings. RESULTS: From 2017 through 2019, three cytology rounds with 24, 28, and 28 bone marrow samples were run evaluating the representativity of the smears (yes/[restricted]/no) and the presence of tumor cells (yes/no and %). The comparison of the reports using κ (Fleiss) and α (Krippendorff) statistics demonstrated no robust reliabilities. The agreement on the representativity was moderate to poor, on the presence of tumor cells moderate to good, and on the percentage of tumor cells slight to moderate. Though the value of cytology is unquestioned to detect even tiny metastatic cells in bone marrow, the investigators unanimously agreed that a reliable quantification of the tumor cell content in bone marrow smears is unrealistic. For the key issue of representativity, a new practical definition was developed. CONCLUSION: For any work with bone marrow aspirates, the representativity of the material is of paramount importance. A practical definition is proposed. A reliable quantitative cytological assessment of tumor cell content in bone marrow aspirates is not feasible in metastatic neuroblastoma. Therefore, its use as response criterion should be reconsidered.

Comparison of MALDI-TOF mass spectrometry analysis of peripheral blood and bone marrow-based flow cytometry for tracking measurable residual disease in patients with multiple myeloma.

Matrix-assisted laser desorption ionisation time-of-flight mass spectrometry (MALDI-TOF MS) may soon replace routine electrophoretic methods for monitoring monoclonal proteins in patients with multiple myeloma. To further evaluate the clinical utility of this assay, we compared the performance of MALDI-TOF-MS head-to-head with an established bone marrow-based measurable residual disease assay by flow cytometry (Flow-BM-MRD), using Memorial Sloan Kettering Cancer Center's 10-color, single-tube method. Our results suggest that MALDI-TOF-MS adds value to bone marrow-based MRD testing and may be most useful for early detection of relapse in peripheral blood compared to current electrophoretic methods.

Lower Serum miR-145 Predicts Poor Prognosis in Patients with Acute Myeloid Leukemia.

BACKGROUND: The current study mainly aims to evaluate the role and clinical significance of miR-145 in the progression of AML. METHODS: Serum and bone marrow nucleated cells (BMNc) were collected and the level of miR-145 was detected by RT-PCR. Pearson's correlation assay was carried out to analyze the correlation between serum miR-145 and clinical index. The receiver operating characteristic (ROC) curve was constructed to determine the diagnosis value of serum miR-145. RESULTS: MiR-145 was significantly decreased in serum and BMNc of patients with AML compared with the control group. Pearson's correlation assay showed that serum miR-145 was positively correlated with miR-145 levels in BMNc. Further study showed that the level of serum miR-145 was much lower in AML patients with initial WBC count ≥ 50 x 109/L than that of WBC count < 50 x 109/L. Moreover, the level of serum miR-145 in prednisone poor responders was significantly lower than that in prednisone good responders. Compared with minimal residual disease (MRD) < 0.01% group, serum miR-145 was much lower in AML patients with MRD ≥ 0.01% group. Pearson's correlation analysis showed that serum miR-145 was positively correlated with MRD. In addition, miR-145 diagnosed AML with an AUC of 0.915 (95% confidence interval: 0.828 to 1.000; p < 0.001). CONCLUSIONS: The level of miR-145 in serum and BMNc of AML patients was significantly lower than those of the control group. Serum miR-145 was related to poor prognosis and disease recurrence of AML.

The Expression and Clinical Significance of MicroRNA-409-3p in Acute Myeloid Leukemia.

BACKGROUND: MicroRNA-409-3p, is down-regulated in a variety of malignant diseases. However, the expression level and clinical value of microRNA-409-3p in acute myeloid leukemia has not yet been systematically studied. METHODS: We collected 88 bone marrow samples derived from 73 patients with acute myeloid leukemia and 15 healthy controls. Then we evaluated the expression of microRNA-409-3p by quantitative real-time PCR. RESULTS: The results revealed that compared with the healthy controls, microRNA-409-3p expression in a newly diagnosed group was significantly lower (p < 0.001). In addition, the microRNA-409-3p expression in the complete remission group was strikingly higher compared to that of the newly diagnosed group (p < 0.001). There was a correlation between microRNA-409-3p expression and white blood cells (p = 0.021). Most importantly, the micro-RNA-409-3p low expression group indicated a shorter event-free survival compared with microRNA-409-3p high expression group by using Kaplan-Meier analysis (p < 0.0438). CONCLUSIONS: The microRNA-409-3p expression level could be a novel potential biomarker for acute myeloid leukemia diagnosis and prognosis, providing a new therapeutic strategy for acute myeloid leukemia treatment.

GATA2 mutation underlies hemophagocytic lymphohistiocytosis in an adult with primary cytomegalovirus infection.

We report a case of a 27-year old woman with persistent fever and pancytopenia who had multiple episodes of a hemophagocytic lymphohistiocytosis (HLH) like condition. The criterion for HLH was satisfied; primary cytomegalovirus (CMV) infection was identified as the cause. Further examination revealed a GATA binding protein 2 mutation. Reports of GATAs deficiency presenting with HLH after primary CMV infection is very limited. As early recognition and diagnosis will improve patients' outcomes, internists and infectious disease specialists should be aware of this disease.

Bone marrow particle enrichment analysis for the laboratory diagnosis of multiple myeloma: A case study.

BACKGROUND: Bone marrow smear and biopsy are the main methods for the diagnosis of multiple myeloma (MM), bone marrow infiltration, and metastasis in lymphoma and cancer. However, several factors, including the focal growth of tumor cells, inappropriate puncture sites, and hemodilution of bone marrow aspirates, lower the rate of target cell detection. To solve this problem, we developed a novel method-bone marrow particle enrichment analysis-and here, we describe this procedure and its use in the diagnosis of a rare case of MM. METHODS: An 88-year-old man with primary gastric gamma delta T-cell lymphoma (γδTCL) was found to have anemia. As the cause of anemia could not be determined, hemodilution was suspected, warranting the re-examination of the bone marrow aspirate. Re-puncture could not be performed because of the patient's age and unwillingness to undergo this procedure. Hence, we used a novel approach to enrich bone marrow particles and isolate marrow cells, and subsequently performed morphological and flow cytometric analysis. RESULTS: Examinations performed after bone marrow particle enrichment revealed the presence of myeloma cells, and the patient was diagnosed with primary gastric γδTCL accompanied by MM. CONCLUSIONS: Bone marrow particle enrichment analysis may be applied to overcome the problems caused by hemodilution of bone marrow aspirates and to improve the rate of tumor cell detection. The application of this method for the diagnosis of hematological disorders should be explored further.

Induction-remission response in peadiatric acute lymphoblastic leukaemia, Lahore protocol versus UKALL 2011 interim guidelines.

OBJECTIVE: To compare the outcome of induction-remission in acute lymphoblastic leukaemia patients treated according to two different guidelines. METHODS: The descriptive retrospective cohort study was conducted at The Children's Hospital Lahore, Pakistan, and comprised clinical information sheets of acute lymphoblastic leukaemia patients from September 2014 to August 2015. Data regarding demographics, risk categorisation, rapid early response and induction-remission assessment was collected separately for Group 1 patients treated with Lahore protocol and Group 2 patients using United Kingdom acute lymphoblastic leukaemia-2011 interim guidelines. Data was analysed using SPSS version 20.0. RESULTS: Of the 98 patients who had a median age of 6.4 years (interquartile range: 1.5-16 years), 48(49%) were in Group 1 and 50(51%) in Group 2. There were 14(29%) patients with standard risk in Group 1 while 34(71%) were high-risk. The corresponding numbers in Group 2 were 30(60%) and 20(40%) in Group 2. Rapid early response was noted in 18(37.5%) patients in Group 1 and 11(28%) in Group 2. Remission was achieved in 38(79%) patients in Group 1 and 36(72%) in Group 2. There was significant association of rapid early response with induction-remission in Group 2 (p<0.05) but not in Group 1 (p>0.05). CONCLUSIONS: Induction-remission rate was comparable in the two treatment groups, but significant association of rapid early response with induction-remission was observed only in patients treated using United Kingdom acute lymphoblastic leukaemia-2011 interim guidelines.

Discarded portions of bone marrow aspirates are a new resource for patient-derived mesenchymal stem and stromal cells.

Bone marrow-derived mesenchymal stem and stromal cells (BM-MSCs) protect malignant cells from chemotherapy and are important potential therapeutic targets. Isolating primary BM-MSCs for research traditionally requires the sacrifice of valuable cell populations from within the same sample. To avoid this, we report here a resource for isolating patient-derived BM-MSCs from the red blood cell layer of ficoll gradients of bone marrow aspirates, a resource that has until now been universally discarded. This resource yields BM-MSCs nearly identical to those obtained conventionally and includes cells with a more stem-cell like nature. Obtaining primary BM-MSCs in this way will likely expand opportunities to study this important cell population.

Revisiting Bone Marrow Core Biopsy Adequacy Criteria in the Era of Extensive Ancillary Testing.

BACKGROUND: Bone marrow core biopsy is a routine component of comprehensive marrow evaluation, and adequacy criteria have been recommended. However, the effectiveness of these adequacy criteria for diagnostic bone marrow evaluation needs to be reassessed in the current era of extensive ancillary testing. We aimed to determine the impact of core biopsy length and intertrabecular area of evaluable bone marrow on overall adequacy for diagnostic marrow evaluation at our tertiary care institution. METHODS: Five hundred sequential cases of iliac crest bone marrow sampling were identified by retrospective re-view at our tertiary care institution. In this cohort, 470 core biopsies were obtained for histologic evaluation. Data including gross core biopsy length, number of intertrabecular 40x high power fields of evaluable marrow, and other pathologic/clinical parameters were compiled. RESULTS: The mean core biopsy length was 1.2 cm, and only 23% measured the recommended ≥ 1.5 cm. However, 96% of the core biopsies were interpretable and contributed to the comprehensive bone marrow evaluation. Notably, 100% of biopsies with ≥ 5.5 intertrabecular areas were contributory. Ancillary testing including immunophenotypic, cytogenetic, and/or molecular studies were performed in > 99% of cases. CONCLUSIONS: When histology was integrated with ancillary testing, the overall diagnosis was substantially limited in only 0.4% of cases and material deemed entirely insufficient in 0.4%. The number of intertrabecular 40x areas of evaluable marrow is a better predictor of adequacy than core biopsy length, and adequacy criteria should be revised in this era of extensive ancillary testing.

Bone marrow aspirations in oncological patients: experience from an in-house standard in paediatrics.

BACKGROUND: Nearly all paediatric patients require deep sedation when undergoing bone marrow aspiration (BMA). We analyzed the data from our protocols documented in a standardised procedure for bone marrow puncture over a period of 2 years. METHODS: Our standard included the documentation of personal data as well as vital parameters. In addition, we documented all medications administered, potential complications and required intervention measures, as necessary. RESULTS: A total of 107 protocols were available for the evaluation. Our standard covered the usage of midazolam and S­ketamine and resulted in complications in just 9 patients, which could be remedied using simple measures. For both active substances, the dosage necessary to reach sufficient deep analgosedation was significantly higher for patients under 24 months of age. CONCLUSIONS: Our standard for BMA provides a practical and feasible procedure. In addition to good examination conditions, our standard also helps ensure the safety of our patients.

Bone marrow core biopsy in 508 consecutive patients with chronic myeloid leukemia: Assessment of potential value.

BACKGROUND: The diagnosis of chronic myeloid leukemia (CML) is based on characteristic clinical and laboratory findings and the presence of BCR/ABL1 in the blood and/or bone marrow (BM). The utility of BM core biopsy in the workup of patients with CML has been questioned. METHODS: The potential added value of BM biopsy versus aspiration in the workup of a single-institution series of 508 patients with CML at their initial presentation was systematically assessed. BM biopsy was considered essential when it was needed to establish the disease phase, often because blast counts derived from aspirate smears were misleading because the biopsy specimen was more representative of the disease. BM biopsy was considered helpful if it was needed for other nonessential reasons. RESULTS: In 127 patients (25%), BM biopsy was either essential (109 patients) or helpful (18 patients). Patients with accelerated-phase (AP) or blast-phase (BP) disease often required a biopsy related to essential reasons. High-grade myelofibrosis (MF) was more frequent in patients with AP/BP disease than patients with chronic-phase disease (P = .0005), and the identification of BP disease required a BM biopsy assessment in 75% of the patients (P = .001). A follow-up BM evaluation more often yielded inadequate aspirates in patients with inadequate BM aspirates at the time of their initial diagnosis. CONCLUSIONS: BM core biopsy remains valuable in the workup of 25% of patients with CML because it facilitates identification of the disease phase or MF. The initial grade of MF is associated with the disease stage and outcome after therapy. BM biopsy is, therefore, indicated for patients with CML who have AP/BP disease or other findings suggestive of progressive disease.

The effect of intra-articular glucocorticosteroids and exercise on symptoms and bone marrow lesions in knee osteoarthritis: a secondary analysis of results from a randomized controlled trial.

OBJECTIVE: To evaluate if the relative volume of bone marrow lesions (BMLs) changed in patients with knee osteoarthritis (OA) during a therapeutic study. DESIGN: This study is a sub-study to a larger clinical trial which compared the clinical effects of intra-articular corticosteroid injection in knee OA to placebo injection, both given prior to exercise therapy. Clinical assessment using the Knee injury and Osteoarthritis Outcome Score (KOOS) and magnetic resonance imaging (MRI) examinations with BML assessments were performed at baseline and follow-up after 14 weeks and 26 weeks, respectively. The BML volume was determined using a computer assisted method focusing on participants with valid baseline and follow-up MRI examinations. Any changes in BML and KOOS were analyzed and investigated for associations. RESULTS: Fifty participants received steroid and placebo injection, respectively, of which 41 and 45 had complete MRI examinations at week 14, and 36 and 33 at week 26, respectively. All participants received 12 weeks of exercise. A significant change in relative BML volume was observed between the corticosteroid group and the placebo group after 14 weeks [-1.1% vs 2.7%; between-group difference, 3.8% (95% CI 0.5-7.0)] but not after 26 weeks [0.8% vs 1.6%; between-group difference, 0.8% (95% CI -2.8 to 4.4)]. No significant association was found between changes in relative BML volume and KOOS. CONCLUSIONS: Despite the statistically significant difference in BML volume at 14 weeks after corticosteroid injection and 12 weeks exercise therapy compared to placebo injection and exercise, there is very little evidence on a relationship between corticosteroids and BML volume. EU CLINICAL TRIALS REGISTER: EudraCT number: 2012-002607-18.

Comparison of nebulised dexmedetomidine, ketamine, or midazolam for premedication in preschool children undergoing bone marrow biopsy.

BACKGROUND: The aim of our study was to compare the efficacy of dexmedetomidine, ketamine, and midazolam for sedative premedication administered by nebuliser 30 min before general anaesthesia in preschool children undergoing bone marrow biopsy and aspiration. METHODS: Ninety children aged 3-7 yr were randomly allocated into three equal groups to be premedicated with either nebulised ketamine 2 mg kg-1 (Group K), dexmedetomidine 2 µg kg-1 (Group D), or midazolam 0.2 mg kg-1 (Group M). The primary endpoint was a five-point sedation score on arrival in the operating room 30 min after end of study drug administration. Secondary outcomes included: parental separation anxiety scale; medication and mask acceptance scales; haemodynamic variables; recovery time; postoperative face, legs, activity, cry, and consolability scale; emergence agitation scale; and adverse effects. RESULTS: The median (range) sedation score on arrival in the operating room was 3.5 (1-4), 2.0 (2-3) and 2.0 (1-3) in Groups M, D, and K, respectively (P=0.000). Subjects in Group D showed higher medication (P<0.03) and mask acceptance scores (P<0.015) and more satisfactory parental separation anxiety scale (P<0.044). The median (range) recovery time was significantly shorter in Group D [5.5 (4-8) min] compared with Group K [10.0 (5-15) min, P=0.000] and M [8.0 (6-15) min, P=0.000]. The incidence of emergence agitation was lower in Group D (P<0.008). CONCLUSIONS: Preschool children premedicated with nebulised dexmedetomidine had more satisfactory sedation, shorter recovery time, and less postoperative agitation than those who received nebulised ketamine or midazolam. CLINICAL TRIAL REGISTRATION: NCT02935959.