Gilteritinib combined with venetoclax and azacitidine for relapsed acute myeloid leukemia cocurrent with pure red cell aplasia after allogeneic hematopoietic stem cell transplantation: a case report.

Pure red cell aplasia (PRCA) is a rare bone marrow (BM) disorder characterized by ineffective erythropoiesis, reduced reticulocyte count, normocytic anemia, and the absence of erythroid precursors. Here, we present a rare instance of PRCA occurring after ABO-matched allo-HSCT in a refractory/relapsed acute myeloid leukemia (R/R AML) patient. In this case, the patient received a combination treatment of Gilteritinib, Venetoclax, and Azacitidine. Remarkably, this treatment not only reduced myeloblasts but also facilitated the restoration of erythroid hematopoiesis.

Myelodysplastic neoplasms evolving from inherited bone marrow failure syndromes / germline predisposition syndromes: Back under the microscope.

Inherited bone marrow failure syndromes and germline predisposition syndromes (IBMFS/GPS) are associated with increased risk for hematologic malignancies, particularly myeloid neoplasms, such as myelodysplastic neoplasms (MDS) and acute myeloid leukemia (AML). The diagnosis of MDS in these syndromes poses difficulty due to frequent bone marrow hypocellularity and the presence of some degree of dysplastic features related to the underlying germline defect causing abnormal maturation of one or more cell lines. Yet, the diagnosis of MDS is usually associated with a worse outcome in several IBMFS/GPS. Criteria for the diagnosis of MDS in IBMFS/GPS have not been standardized with some authors suggesting a mixture of morphologic, cytogenetic, and genetic criteria. This review highlights these challenges and suggests a more standardized approach to nomenclature and diagnostic criteria.

Association of anatomical variants of the sacroiliac joint with bone marrow edema in patients with axial spondyloarthritis.

OBJECTIVE: To determine the prevalence of sacroiliac joint variants in patients with axial spondyloarthritis (axSpA) using MRI-based synthetic CT images and to evaluate their relationships with the presence of bone marrow edema, as this may potentially complicate diagnosing active sacroiliitis on MRI in patients with suspected axSpA. METHODS: 172 patients were retrospectively included. All patients underwent MRI because of clinical suspicion of sacroiliitis. The diagnosis of axSpA was made by a tertiary hospital rheumatologist. Two readers independently determined the presence of bone marrow edema and the presence of one or more of the nine known sacroiliac joint (SIJ) variants. RESULTS: SIJ variants were common in axSpA patients (82.9%) and the non-SpA group (85.4%); there were no significant differences in prevalence. Bone marrow edema was frequently found in axSpA (86.8%) and non-SpA patients (34%). AxSpA patients with SIJ variants (except for accessory joint) demonstrated 4 to 10 times higher odds for bone marrow edema, however not statistically significant. The more variants were present in this group, the higher the chance of bone marrow edema. However, some multicollinearity cannot be excluded, since bone marrow edema is very frequent in the axSpA group by definition. CONCLUSION: SIJ variants are common in axSpA and non-SpA patients. SIJ variants were associated with higher prevalence of bone marrow edema in axSpA patients, potentially due to altered biomechanics, except for accessory joint which may act as a stabilizer.

Spectrum of diabetes mellitus in patients with Shwachman-Diamond syndrome: case report and review of the literature.

BACKGROUND: Shwachman-Diamond syndrome (SDS) is a rare congenital disorder caused by mutations in the SBDS gene and characterized by exocrine pancreatic deficiency, hematologic dysfunction, and skeletal growth failure. Although the hematologic features and characteristics of the somatic disorders commonly associated with SDS are well known, emerging data from case reports and patient registries suggest that SDS may also be associated with an increased risk of diabetes mellitus. However, currently available data on SDS-associated diabetes are limited and do not allow conclusions regarding prevalence and incidence rates, clinical course, and outcomes. CASE PRESENTATION: Here we report the case of a 5-year-old girl with SDS who underwent bone marrow transplantation at the age of 3 months and developed autoantibody-positive type 1 diabetes mellitus at the age of 1.8 years. The manifestation and course of diabetes development were mild, complicated by concurrent spontaneous episodes of hypoglycemia even before the onset of antidiabetic treatment. Currently, adequate metabolic control can be achieved by dietary intervention. CONCLUSIONS: Considering that the SBDS protein regulates mitosis and ribosomal biosynthesis and that its suppression may cause immunologic instability and chronic inflammation, this case provides insight into the phenotype of rare Shwachman-Diamond syndrome-associated diabetes mellitus, which may be characterized by significant age-dependent differences in clinical course.

Inherited bone marrow failure syndromes and germline predisposition to myeloid neoplasia: A practical approach for the pathologist.

The diagnostic work up and surveillance of germline disorders of bone marrow failure and predisposition to myeloid malignancy is complex and involves correlation between clinical findings, laboratory and genetic studies, and bone marrow histopathology. The rarity of these disorders and the overlap of clinical and pathologic features between primary and secondary causes of bone marrow failure, acquired aplastic anemia, and myelodysplastic syndrome may result in diagnostic uncertainty. With an emphasis on the pathologist's perspective, we review diagnostically useful features of germline disorders including Fanconi anemia, Shwachman-Diamond syndrome, telomere biology disorders, severe congenital neutropenia, GATA2 deficiency, SAMD9/SAMD9L diseases, Diamond-Blackfan anemia, and acquired aplastic anemia. We discuss the distinction between baseline morphologic and genetic findings of these disorders and features that raise concern for the development of myelodysplastic syndrome.

Bone marrow edema of the hip: a narrative review.

Bone marrow edema (BME) of the hip is a radiological-clinical condition with symptoms ranging from asymptomatic to severe, and it is characterized by increased interstitial fluid within the bone marrow, usually at the femur. Depending on the etiology it can be classified as primary or secondary. The primary cause of BME is unknown, while the secondary forms include traumatic, degenerative, inflammatory, vascular, infectious, metabolic, iatrogenic, and neoplastic etiologies. BME could be classified as reversible or progressive. Reversible forms include transient BME syndrome and regional migratory BME syndrome. Progressive forms include avascular necrosis of the femoral head (AVNH), subchondral insufficiency fracture, and hip degenerative arthritis. The diagnosis can be difficult, because at the beginning, the outbreak of hip pain, typically acute and disabling without any prior trauma or exceptional physical activity, is poorly supported by radiographic findings. MRI is the gold standard, and it shows an area of intermediate signal on T1-weighted MRI scans and a high signal on T2-weighted scans, usually lacking sharps margins. In the reversible form, BME is typically self-limiting, and it can be managed conservatively by means of pharmacological and physical therapy. Surgery is generally required for progressive forms in patients who failed non-operative treatment, and it ranges from femoral head and neck core decompression to total hip arthroplasty.

HTLV-1-associated myelopathy/tropical spastic paraplegia with sporadic late-onset nemaline myopathy: a case report.

BACKGROUND: Sporadic late onset nemaline myopathy (SLONM) is a muscle disorder characterized by the presence of nemaline rods in muscle fibers. SLONM has no known genetic cause but has been associated with monoclonal gammopathy of undetermined significance and with human immunodeficiency virus (HIV) infection. Human T-cell leukemia virus-1 (HTLV-1) is a known causative agent of adult T-cell leukemia/lymphoma and HTLV-1 associated myelopathy/tropical spastic paraplegia (HAM/TSP), a chronic inflammatory neurological disease. HTLV-1 has been reported to be implicated in inflammatory myopathies, as well as in HIV infection.; however, there have been no reports of an association between HTLV-1 infection and SLONM to date. CASE PRESENTATION: A 70-year-old Japanese woman presented with gait disturbance, lumbar kyphosis, and respiratory dysfunction. The diagnosis of HAM/TSP with SLONM was made based on characteristic clinical symptoms of HAM/TSP, such as spasticity in the lower extremities, and cerebrospinal fluid test results; and of SLONM, such as generalized head drooping, respiratory failure, and muscle biopsy results. Steroid treatment was initiated and improvement in her stooped posture was observed after 3 days of treatment. CONCLUSION: This is the first case report of SLONM combined with HTLV-1 infection. Further studies are needed to elucidate the relationship between retroviruses and muscle diseases.

Extensor carpi ulnaris tendon pathology and ulnar styloid bone marrow edema as diagnostic markers of peripheral triangular fibrocartilage complex tears on wrist MRI: a case-control study.

OBJECTIVES: To evaluate extensor carpi ulnaris (ECU) tendon pathology and ulnar styloid process bone marrow edema (BME) as diagnostic MRI markers for peripheral triangular fibrocartilage complex (TFCC) tears. METHODS: One hundred thirty-three patients (age range 21-75, 68 females) with wrist 1.5-T MRI and arthroscopy were included in this retrospective case-control study. The presence of TFCC tears (no tear, central perforation, or peripheral tear), ECU pathology (tenosynovitis, tendinosis, tear or subluxation), and BME at the ulnar styloid process were determined on MRI and correlated with arthroscopy. Cross-tabulation with chi-square tests, binary logistic regression with odds ratios (OR), and sensitivity, specificity, positive predictive value, negative predictive value, and accuracy were used to describe diagnostic efficacy. RESULTS: On arthroscopy, 46 cases with no TFCC tear, 34 cases with central perforations, and 53 cases with peripheral TFCC tears were identified. ECU pathology was seen in 19.6% (9/46) of patients with no TFCC tears, in 11.8% (4/34) with central perforations and in 84.9% (45/53) with peripheral TFCC tears (p < 0.001); the respective numbers for BME were 21.7% (10/46), 23.5% (8/34), and 88.7% (47/53) (p < 0.001). Binary regression analysis showed additional value from ECU pathology and BME in predicting peripheral TFCC tears. The combined approach with direct MRI evaluation and both ECU pathology and BME yielded a 100% positive predictive value for peripheral TFCC tear as compared to 89% with direct evaluation alone. CONCLUSIONS: ECU pathology and ulnar styloid BME are highly associated with peripheral TFCC tears and can be used as secondary signs to diagnose tears. KEY POINTS: • ECU pathology and ulnar styloid BME are highly associated with peripheral TFCC tears and can be used as secondary signs to confirm the presence of TFCC tears. • If there is a peripheral TFCC tear on direct MRI evaluation and in addition both ECU pathology and BME on MRI, the positive predictive value is 100% that there will be a tear on arthroscopy compared to 89% with direct evaluation alone. • If there is no peripheral TFCC tear on direct evaluation and neither ECU pathology nor BME on MRI, the negative predictive value is 98% that there will be no tear on arthroscopy compared to 94% with direct evaluation alone.

Intermediate-weighted MRI with fat suppression (IW-FS): diagnostic performance for bone marrow edema and erosion detection in axial spondyloarthritis.

BACKGROUND: Bone marrow edema (BME) and erosion of the sacroiliac joint are both key lesions for diagnosing axial spondyloarthritis (axSpA) on magnetic resonance imaging (MRI). PURPOSE: To qualitatively and quantitatively compare intermediate-weighted MRI with fat suppression (IW-FS) with T2-weighted short tau inversion recovery (T2-STIR) in assessment of sacroiliac BME and erosion in axSpA. MATERIAL AND METHODS: Patients aged 18-60 years with axSpA were prospectively enrolled. All patients underwent a 3.0-T MRI examination of the sacroiliac joints. Para-coronal IW-FS, T2-STIR, and T1-weighted (T1W) images were acquired. BME and erosion were scored by two readers in consensus on IW-FS and STIR using a modified Spondyloarthritis Research Consortium of Canada (SPARCC) scoring system. Consensus scores on T1WI were used as the reference for erosion. Signal-to-noise ratio (SNR) and contrast-to-noise ratio (CNR) were measured for BME. RESULTS: In total, 49 patients (mean age=33.4 ± 7.6 years) were included. More patients were scored as having BME on T2-STIR (36 vs. 29, P = 0.016). SPARCC-BME score on IW-FS was lower than that acquired on T2-STIR (mean, 11.5 vs. 14.7, P = 0.002). SNR and CNR of BME were both lower on IW-FS than on T2-STIR (mean SNR, 118 vs. 218, P < 0.001; mean CNR, 44 vs. 137, P < 0.001). The sensitivity of erosion detection was higher on IW-FS (83%) than on T2-STIR (54%, P = 0.006). CONCLUSION: IW-FS is not sufficient for BME detection using T2-STIR as the reference standard in patients with axSpA. IW-FS has a much higher sensitivity than T2-STIR for erosion detection in the sacroiliac joint.

Regional migratory osteoporosis of the knee: a literature overview.

The purpose of this article is to review the clinical syndrome of regional migratory osteoporosis (RMO) of the knee and to highlight all the important aspects of diagnosis and management that can be helpful to the physician. RMO is a rare, self-limiting disease characterized by migrating arthralgia, bone marrow edema and osteoporosis. The pathogenesis of RMO remains controversial and is not yet fully elucidated. A thorough presentation of the disease is conducted with presentation of the clinical features (progressive pain and local tenderness), differential diagnosis and appropriate diagnostic criteria. The role of MRI is underlined and strategies for the treatment of RMO are presented.

Prediction of radiographic progression during a treat-to-target strategy by the sequential application of MRI-proven bone marrow oedema and power-Doppler grade ≥2 articular synovitis in rheumatoid arthritis: Retrospective observational study.

OBJECTIVES: To investigate the appropriate timing, useful findings and combination of magnetic resonance imaging (MRI) and ultrasound (US) for predicting the radiographic progression in early rheumatoid arthritis (RA). METHODS: Forty-four active RA patients, who examined by both of MRI and US in the symptomatic wrist and finger joints, were recruited in Nagasaki University Hospital from 2010 to 2017 and treated by the treat-to-target therapeutic strategy for 1 year. MRI was evaluated by RA MRI scoring and US by Outcomes Measures in Rheumatology Clinical Trial, respectively. Plain radiographs were assessed by the Genant-modified Sharp score for the symptomatic side in the same manner as MRI and US. Radiographic progression was defined as an annual increase ≥0.75 at 1 year. Factors associated with radiographic progression were analysed. Also, the optimal combination of MRI and US at each timepoint was considered. RESULTS: Logistic regression model revealed that MRI-proven bone marrow oedema at baseline and 6 months and joint counts of power-Doppler grade ≥2 articular synovitis at 3 or 6 months were significantly associated with radiographic progression at 1 year. CONCLUSION: This study may suggest the favourable timing and combination of MRI and US at each point to predict radiographic progression in patients with early-stage RA.

Bone Marrow Edema: pathogenetic features.

Abstract: The term "bone marrow edema" was used for the first time in 1988 by Wilson. He noticed a high signal on fluid-sensitive sequences at MRI located in the subchondral bone. We can find bone marrow edema in many musculoskeletal diseases such as Inflammatory and Rheumatic diseases (Rheumatoid Arthritis, Spondylarthritis, etc.), Osteoarthritis (BMLs) and Bone Marrow Edema Syndromes (BMES). This classification is based on pathophysiological, histological and clinical differences despite the same imaging evidence. The distinction is useful also in terms of treatment. Bisphosphonates in association with NSAIDs or corticosteroids are the main therapy while TNF-a Inhibitors are used for the specific inflammatory origin. Bone marrow edema has become an important aspect to consider in the diagnostic path of the main musculoskeletal diseases. This paper starts from a systematic review of literature. We chose the most decisive contributions in order to develop a better description of the pathogenetic features about this "new" evidence.

Spine abnormalities associated with bone edema on sacroiliac joints MRI in patients with non-inflammatory chronic back pain.

OBJECTIVE: To investigate whether bone marrow edema (BME) fulfilling the ASAS definition of magnetic resonance imaging (MRI) sacroiliitis is associated with non-inflammatory spine abnormalities in patients with definite mechanical chronic back pain (CBP). METHODS: Patients with definite mechanical CBP, according to the physician, started before the age of 45 and be lasting for more than 3months but less than 3years underwent a protocolized MRI and radiographs of sacroiliac joint (SIJ) and spine. BME and structural changes were scored, by three readers, for SIJ as well as non-inflammatory abnormalities for spine, including degenerative lesions and static disorders. Univariate analysis by Chi2 test was performed to search a statistical association between BME fulfilling the ASAS definition of MRI sacroiliitis and the presence of at least one non-inflammatory spine abnormality. RESULTS: A total of 94 patients were analyzed, 27 (29%) patients had BME and 16 (17%) patients had BME fulfilling the ASAS definition of MRI sacroiliitis; 86 (91.5%) patients had at least one non-inflammatory spine abnormality which are associated into 3 distinct clusters. BME was slightly more frequent at the lower and posterior part of the SIJ. MRI sacroiliitis was associated with interspinous bursitis, facet joint effusion and lateral spinal deviation and was more likely in patients with at least one non-inflammatory spine abnormality (OR: 4.96, 95% CI [1.47; 16.72]). CONCLUSIONS: BME fulfilling the ASAS definition of MRI sacroiliitis is significantly associated with non-inflammatory spine abnormalities in patients with mechanical CBP.

Recent advances in hematopoietic cell transplantation for inherited bone marrow failure syndromes.

Inherited bone marrow failure syndromes (IBMFSs) are a group of rare genetic disorders characterized by bone marrow failure with unique phenotypes and predisposition to cancer. Classical IBMFSs primarily include Fanconi anemia with impaired DNA damage repair, dyskeratosis congenita with telomere maintenance dysfunction, and Diamond-Blackfan anemia with aberrant ribosomal protein biosynthesis. Recently, comprehensive genetic analyses have been implemented for the definitive diagnosis of classic IBMFSs, and advances in molecular genetics have led to the identification of novel disorders such as AMeD and MIRAGE syndromes. Allogeneic hematopoietic cell transplantation (HCT), a promising option to overcome impaired hematopoiesis in patients with IBMFSs, does not correct nonhematological defects and may enhance the risk of secondary malignancies. Disease-specific management is necessary because IBMFSs differ in underlying defects and are associated with varying degrees of risk for clonal evolution and early or late complications after HCT. In addition, long-term follow-up is essential to detect complications related to the IBMFS or HCT. This review provides a summary of current clinical practices along with the latest data on HCT in IBMFSs.

Inherited bone marrow failure in the pediatric patient.

Inherited bone marrow (BM) failure syndromes are a diverse group of disorders characterized by BM failure, usually in association with ≥1 extrahematopoietic abnormalities. BM failure, which can involve ≥1 cell lineages, often presents in the pediatric age group. Furthermore, some children initially labeled as having idiopathic aplastic anemia or myelodysplasia represent cryptic cases of inherited BM failure. Significant advances in the genetics of these syndromes have been made, identifying more than 100 disease genes, giving insights into normal hematopoiesis and how it is disrupted in patients with BM failure. They have also provided important information on fundamental biological pathways, including DNA repair: Fanconi anemia (FA) genes; telomere maintenance: dyskeratosis congenita (DC) genes; and ribosome biogenesis: Shwachman-Diamond syndrome and Diamond-Blackfan anemia genes. In addition, because these disorders are usually associated with extrahematopoietic abnormalities and increased risk of cancer, they have provided insights into human development and cancer. In the clinic, genetic tests stemming from the recent advances facilitate diagnosis, especially when clinical features are insufficient to accurately classify a disorder. Hematopoietic stem cell transplantation using fludarabine-based protocols has significantly improved outcomes, particularly in patients with FA or DC. Management of some other complications, such as cancer, remains a challenge. Recent studies have suggested the possibility of new and potentially more efficacious therapies, including a renewed focus on hematopoietic gene therapy and drugs [transforming growth factor-ß inhibitors for FA and PAPD5, a human poly(A) polymerase, inhibitors for DC] that target disease-specific defects.

Shwachman-Diamond Syndrome With Congenital Myogenic Ptosis: Case Report of a Rare Association?

BACKGROUND: Shwachman-Diamond syndrome (SDS) is a multisystem disorder characterized by exocrine pancreatic insufficiency and bone marrow failure. There is considerable variation in the phenotypes of SDS. We present a case of an infant presenting with SDS and left-sided ptosis. OBSERVATION: We report a case of an infant who presented with 2 episodes of severe sepsis and cytopenia, without overt symptoms of exocrine pancreatic deficiency or skeletal abnormalities. Persistent left-sided ptosis was noted in both presentations. Genetic testing confirmed the diagnosis of SDS. The left-sided ptosis was diagnosed as congenital myogenic ptosis. CONCLUSION: The association of ptosis and other congenital bone marrow failure syndromes is well established, but this is the first description of SDS with ptosis. This association may expand our understanding of SDS phenotypes if similar cases are reported in the future.

Hematologic complications with age in Shwachman-Diamond syndrome.

Shwachman-Diamond syndrome (SDS) is an inherited bone marrow failure syndrome with leukemia predisposition. An understanding of the hematologic complications of SDS with age could guide clinical management, but data are limited for this rare disease. We conducted a cohort study of 153 subjects from 143 families with confirmed biallelic SBDS mutations enrolled on the North American Shwachman Diamond Registry or Bone Marrow Failure Registry. The SBDS c.258 + 2T>C variant was present in all but 1 patient. To evaluate the association between blood counts and age, 2146 blood counts were analyzed for 119 subjects. Absolute neutrophil counts were positively associated with age (P < .0001). Hemoglobin was also positively associated with age up to 18 years (P < .0001), but the association was negative thereafter (P = .0079). Platelet counts and marrow cellularity were negatively associated with age (P < .0001). Marrow cellularity did not correlate with blood counts. Severe marrow failure necessitating transplant developed in 8 subjects at a median age of 1.7 years (range, 0.4-39.5), with 7 of 8 requiring transplant prior to age 8 years. Twenty-six subjects (17%) developed a myeloid malignancy (16 myelodysplasia and 10 acute myeloid leukemia) at a median age of 12.3 years (range, 0.5-45.0) and 28.4 years (range, 14.4-47.3), respectively. A lymphoid malignancy developed in 1 patient at the age of 16.9 years. Hematologic complications were the major cause of mortality (17/20 deaths; 85%). These data inform surveillance of hematologic complications in SDS.

Pregnancy-related sacroiliac joint findings in females with low back pain: a four-year magnetic resonance imaging follow-up study.

BACKGROUND: Pregnancy-related pain may be associated with sacroiliac joint (SIJ) changes, detectable by magnetic resonance imaging (MRI). PURPOSE: To analyze the prevalence and course of SIJ MRI and clinical findings in women referred with low back pain and relate these to pregnancy. MATERIAL AND METHODS: A retrospective follow-up study from a longitudinally collected cohort comprising 328 women. RESULTS: Women reporting debut of pain in relation to a pregnancy (PP group) tended to have a higher baseline prevalence of all investigated MRI findings, cumulated positive SIJ tests, and a potential fulfilment of the spondyloarthritis diagnosis compared to remainders. The prevalence of subchondral bone marrow edema (BME), any SIJ MRI finding, and potential fulfilment of the spondyloarthritis diagnosis were significantly higher in the PP group compared to women who had not been pregnant. In the total study group, the prevalence of ≥1 MRI finding increased over the four-year study period from 34% to 47% (P<0.001), driven by increasing prevalence of BME (25% to 32%; P=0.008) and fatty marrow deposition (FMD) (20% to 25%; P=0.020). In addition, the BME volume score increased. Over time, the PP group had persisting high prevalence of buttock pain and total MRI findings and their FMD volume score increased, but there were no between-group differences in MRI variables at follow-up. CONCLUSION: Overall, the prevalence of MRI findings increased over time. Although the PP group had different clinical and SIJ MRI characteristics cross-sectional at baseline compared to remainders, longitudinal analyses revealed that these diminished over time.