Predisposition to myeloid malignancies in Shwachman-Diamond syndrome: biological insights and clinical advances.

Shwachman-Diamond syndrome (SDS) is an inherited multisystem ribosomopathy characterized by exocrine pancreatic deficiency, bone marrow failure, and predisposition to myeloid malignancies. The pathobiology of SDS results from impaired ribosomal maturation due to the deficiency of SBDS and the inability to evict the antiassociation factor eIF6 from the 60S ribosomal subunit. Clinical outcomes for patients with SDS who develop myeloid malignancies are extremely poor because of high treatment-related toxicities and a high rate of refractory disease/relapse even after allogeneic hematopoietic stem cell transplant (HSCT). Registry data indicate that outcomes are improved for patients with SDS who undergo routine bone marrow surveillance and receive an HSCT before developing an overt malignancy. However, the optimal approach to hematologic surveillance and the timing of HSCT for patients with SDS is not clearly established. Recent studies have elucidated distinct patterns of somatic blood mutations in patients with SDS that either alleviate the ribosome defect via somatic rescue (heterozygous EIF6 inactivation) or disrupt cellular checkpoints, resulting in increased leukemogenic potential (heterozygous TP53 inactivation). Genomic analysis revealed that most myeloid malignancies in patients with SDS have biallelic loss-of-function TP53 mutations. Single-cell DNA sequencing of SDS bone marrow samples can detect premalignant biallelic TP53-mutated clones before clinical diagnosis, suggesting that molecular surveillance may enhance the detection of incipient myeloid malignancies when HSCT may be most effective. Here, we review the clinical, genetic, and biologic features of SDS. In addition, we present evidence supporting the hematologic surveillance for patients with SDS that incorporates clinical, pathologic, and molecular data to risk stratify patients and prioritize transplant evaluation for patients with SDS with high-risk features.

Differential diagnosis of bone marrow failure syndromes guided by machine learning.

The choice to postpone treatment while awaiting genetic testing can result in significant delay in definitive therapies in patients with severe pancytopenia. Conversely, the misdiagnosis of inherited bone marrow failure (BMF) can expose patients to ineffectual and expensive therapies, toxic transplant conditioning regimens, and inappropriate use of an affected family member as a stem cell donor. To predict the likelihood of patients having acquired or inherited BMF, we developed a 2-step data-driven machine-learning model using 25 clinical and laboratory variables typically recorded at the initial clinical encounter. For model development, patients were labeled as having acquired or inherited BMF depending on their genomic data. Data sets were unbiasedly clustered, and an ensemble model was trained with cases from the largest cluster of a training cohort (n = 359) and validated with an independent cohort (n = 127). Cluster A, the largest group, was mostly immune or inherited aplastic anemia, whereas cluster B comprised underrepresented BMF phenotypes and was not included in the next step of data modeling because of a small sample size. The ensemble cluster A-specific model was accurate (89%) to predict BMF etiology, correctly predicting inherited and likely immune BMF in 79% and 92% of cases, respectively. Our model represents a practical guide for BMF diagnosis and highlights the importance of clinical and laboratory variables in the initial evaluation, particularly telomere length. Our tool can be potentially used by general hematologists and health care providers not specialized in BMF, and in under-resourced centers, to prioritize patients for genetic testing or for expeditious treatment.

Clinical utility of relative telomere length analysis in pediatric bone marrow failure.

INTRODUCTION: Telomere length related studies are limited in pediatric marrow failure cases due to difficulty in establishing population specific age related normograms. Moreover, there is paucity of data related to clinical relevance of telomere length in idiopathic aplastic anemia (IAA) and non telomere biology inherited bone marrow failure syndrome (IBMFS) cases. METHODOLOGY: Hence, in current study we investigated Relative telomere length (RTL) by RQ-PCR in 83 samples as: healthy controls (n = 44), IAA (n = 15) and IBMFS (n = 24). In addition, we performed chromosomal breakage studies and targeted NGS to screen for pathogenic variants. RESULTS & CONCLUSION: Median RTL was significantly different between control vs. IBMFS (p-0.002), IAA vs. IBMFS (p-0.0075) and DC vs. non-DC IBMFS (p-0.011) but not between control vs. IAA (p-0.46). RTL analysis had clinical utility in differentiating BMF cases as 75 % (9/12) of DC had short/very short telomeres compared to only 17 % (2/12) of non-DC IBMFS, 7 % (1/15) of IAA and 7 % (3/44) of controls (p < 0.001).

The terminologies of transient, migratory, or localized osteoporosis, and bone marrow edema syndrome: a scoping review.

There is no formally defined terminology for the related entities transient osteoporosis of the hip (TOH), localized or regional migratory osteoporosis (RMO) and bone marrow edema syndrome (BMES). This study aimed to map the diversity and frequency of diagnostic terms and vocabulary utilized in the literature. A comprehensive search of electronic databases and reference lists was conducted. Publications that reported on patients with TOH, RMO, BMES, or related variants were eligible for inclusion. The terminologies were categorized based on the wording of the titles, abstracts, or texts. We included 561 publications, of which 423 were case reports, involving 2921 patients. Overall, TOH was the most commonly used term, occurring in 257 (45.8%). RMO was used in 34 (6.1%) and BMES in 57 (10.2%). The remaining used various combinations of transient, migratory, and regional in conjunction with either osteoporosis or bone marrow edema. Localized osteoporosis was not used. We identified three different terms related to pregnancy. In 76.3% of the publications, the terminology was related to osteoporosis and in 18.2% to bone marrow edema, although terminology did not correspond to actual findings. Bone marrow edema occurred as often as osteoporosis, and osteoporosis was generally ascertained by visual inspection of radiographs, seldom by bone densitometry. Many publications used osteoporosis-related terms without evidence that osteoporosis had been detected. The terminology of these closely related entities is confusing and unstandardized. The lack of formal definitions impedes accurate diagnosis, research on disease mechanisms, and effective treatment.

A Rare Inherited Bone Marrow Failure Syndrome Disclosed by Reanalysis of the Exome Data of a Patient Evaluated for Cytopenia and Dysmorphic Features.

BACKGROUND: Multisystemic findings of inherited bone marrow failure syndromes may cause difficulty in diagnosis. Exome sequencing (ES) helps to define the etiology of rare diseases and reanalysis offers a valuable new diagnostic approach. Herein, we present the clinical and molecular characteristics of a girl who was referred for cytopenia and frequent infections. CASE REPORT: A 5-year-old girl with cytopenia, dysmorphism, short stature, developmental delay, and myopia was referred for genetic counseling. Reanalysis of the ES data revealed a homozygous splice-site variant in the DNAJC21 (NM_001012339.3:c.983+1G>A), causing Shwachman-Diamond Syndrome (SDS). It was shown by the RNA sequencing that exon 7 was skipped, causing an 88-nucleotide deletion. CONCLUSIONS: Precise genetic diagnosis enables genetic counseling and improves patient management by avoiding inappropriate treatment and unnecessary testing. This report would contribute to the clinical and molecular understanding of this rare type of SDS caused by DNAJC21 variants and expand the phenotypic features of this condition.

Management of transient bone osteoporosis: a systematic review.

INTRODUCTION: Transient bone osteoporosis (TBO) is characterized by persistent pain, loss of function, no history of trauma and magnetic resonance image (MRI) findings of bone marrow edema. SOURCE OF DATA: PubMed, Google scholar, EMABSE and Web of Science were accessed in February 2023. No time constrains were used for the search. AREAS OF AGREEMENT: TBO is rare and misunderstood, typically affecting women during the third trimester of pregnancy or middle-aged men, leading to functional disability for 4-8 weeks followed by self-resolution of the symptoms. AREAS OF CONTROVERSY: Given the limited evidence in the current literature, consensus on optimal management is lacking. GROWING POINTS: This systematic review investigates current management of TBO. AREAS TIMELY FOR DEVELOPING RESEARCH: A conservative approach leads to the resolution of symptoms and MRI findings at midterm follow-up. Administration of bisphosphonates might alleviate pain and accelerate both clinical and imaging recovery.

Expanded phenotypic and hematologic abnormalities beyond bone marrow failure in MECOM-associated syndromes.

The MECOM gene encodes multiple protein isoforms that are essential for hematopoietic stem cell self-renewal and maintenance. Germline MECOM variants have been associated with congenital thrombocytopenia, radioulnar synostosis and bone marrow failure; however, the phenotypic spectrum of MECOM-associated syndromes continues to expand and novel pathogenic variants continue to be identified. We describe eight unrelated patients who add to the previously known phenotypes and genetic defects of MECOM-associated syndromes. As each subject presented with unique MECOM variants, the series failed to demonstrate clear genotype-to-phenotype correlation but may suggest a role for additional modifiers that affect gene expression and subsequent phenotype. Recognition of the expanded hematologic and non-hematologic clinical features allows for rapid molecular diagnosis, early identification of life-threatening complications, and improved genetic counseling for families. A centralized international publicly accessible database to share annotated MECOM variants would advance their clinical interpretation and provide a foundation to perform functional MECOM studies.

Preliminary evaluation of dual-energy CT to quantitatively assess bone marrow edema in patients with diabetic foot ulcers and suspected osteomyelitis.

OBJECTIVES: The purpose of this study is to evaluate the value of dual-energy CT (DECT) with virtual non-calcium (VNCa) in quantitatively assessing the presence of bone marrow edema (BME) in patients with diabetic foot ulcers and suspected osteomyelitis. METHODS: Patients with a diabetic foot ulcer and suspected osteomyelitis that underwent DECT (80 kVp/Sn150 kVp) with VNCa were retrospectively included. Two observers independently measured CT values of the bone adjacent to the ulcer and a reference bone not related to the ulcer. The patients were divided into two clinical groups, osteomyelitis or no-osteomyelitis, based on the final diagnosis by the treating physicians. RESULTS: A total of 56 foot ulcers were identified of which 23 were included in the osteomyelitis group. The mean CT value at the ulcer location was significantly higher in the osteomyelitis group (- 17.23 ± 34.96 HU) compared to the no-osteomyelitis group (- 69.34 ± 49.40 HU; p < 0.001). Within the osteomyelitis group, the difference between affected bone and reference bone was statistically significant (p < 0.001), which was not the case in the group without osteomyelitis (p = 0.052). The observer agreement was good for affected bone measurements (ICC = 0.858) and moderate for reference bone measurements (ICC = 0.675). With a cut-off value of - 40.1 HU, sensitivity was 87.0%, specificity was 72.7%, PPV was 69.0%, and NPV was 88.9%. CONCLUSION: DECT with VNCa has a potential value for quantitatively assessing the presence of BME in patients with diabetic foot ulcers and suspected osteomyelitis. KEY POINTS: • Dual-energy CT (DECT) with virtual non-calcium (VNCa) is promising for detecting bone marrow edema in the case of diabetic foot ulcers with suspected osteomyelitis. • DECT with VNCa has the potential to become a more practical alternative to MRI in assessing the presence of bone marrow edema in suspected osteomyelitis when radiographs are not sufficient to form a diagnosis.

Inherited bone marrow failure syndromes: a review of current practices and potential future research directions.

PURPOSE OF REVIEW: Recent advances in diagnosis and treatment of inherited bone marrow failure syndromes (IBMFS) have significantly improved disease understanding and patient outcomes. Still, IBMFS present clinical challenges that require further progress. This review aims to provide an overview of the current state of diagnosis and treatment modalities of the major IBMFS seen in paediatrics and present areas of prioritization for future research. RECENT FINDINGS: Haematopoietic cell transplantation (HCT) for IBMFS has greatly improved in recent years, shifting the research and clinical focus towards cancer predispositions and adverse effects of treatment. Each year, additional novel genes and pathogenic variants are described, and genotype-phenotype mapping becomes more sophisticated. Moreover, novel therapeutics exploring disease-specific mechanisms show promise to complement HCT and treat patients who cannot undergo current treatment options. SUMMARY: Research on IBMFS should have short-term and long-term goals. Immediate challenges include solidifying diagnostic and treatment guidelines, cancer detection and treatment, and continued optimization of HCT. Long-term goals should emphasize genotype-phenotype mapping, genetic screening tools and gene-targeted therapy.

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.

Clinical features, epidemiology, and treatment of Shwachman-Diamond syndrome: a systematic review.

BACKGROUND: Shwachman-Diamond syndrome (SDS) is an autosomal recessive disease which results in inherited bone marrow failure (IBMF) and is characterized by exocrine pancreatic dysfunction and diverse clinical phenotypes. In the present study, we reviewed the internationally published reports on SDS patients, in order to summarize the clinical features, epidemiology, and treatment of SDS. METHODS: We searched the WangFang and China National Knowledge Infrastructure databases with the keywords "Shwachman-Diamond syndrome," "SDS," "SBDS gene" and "inherited bone marrow failure" for relevant articles published from January 2002 to October 2022. In addition, studies published from January 2002 to October 2022 were searched from the Web of Science, PubMed, and MEDLINE databases, using "Shwachman-diamond syndrome" as the keyword. Finally, one child with SDS treated in Tongji Hospital was also included. RESULTS: The clinical features of 156 patients with SDS were summarized. The three major clinical features of SDS were found to be peripheral blood cytopenia (96.8%), exocrine pancreatic dysfunction (83.3%), and failure to thrive (83.3%). The detection rate of SDS mutations was 94.6% (125/132). Mutations in SBDS, DNAJC21, SRP54, ELF6, and ELF1 have been reported. The male-to-female ratio was approximately 1.3/1. The median age of onset was 0.16 years, but the diagnostic age lagged by a median age of 1.3 years. CONCLUSIONS: Pancreatic exocrine insufficiency and growth failure were common initial symptoms. SDS onset occurred early in childhood, and individual differences were obvious. Comprehensive collection and analysis of case-related data can help clinicians understand the clinical characteristics of SDS, which may improve early diagnosis and promote effective clinical intervention.

[Diagnosis and treatment of Shwachman-Diamond syndrome in Chinese children: An evidence-based study].

OBJECTIVE: To explore the characteristics of Shwachman-Diamond syndrome (SDS) in Chinese children in order to provide a reference for early diagnosis. METHODS: With Shwachman-Diamond syndrome, SDS, SBDS gene and inherited bone marrow failure as the keywords, the search period was set from January 2002 to October 2022. Relevant literature was retrieved from the Wanfang Database and China National Knowledge Infrastructure (CNKI) database. In addition, by using Shwachman-diamond syndrome as a keyword, the search period was also retrieved from the Web of Science, PubMed, and MEDLINE databases from January 2002 to October 2022. A child with SDS treated at the Tongji Hospital was also included. A total of 44 cases with complete clinical data were analyzed with reference to the International Standard for SDS Diagnosis. Chi-square test and t test were used for statistical analysis. Evidence-based research was carried out in the form of systematic review. The epidemiology, clinical characteristics and key points of early diagnosis of the Chinese SDS children were summarized and compared with the international data. RESULTS: The main characteristics of SDS in Chinese children were summarized as follows: The ratio of males to females was about 1.3 : 1, the median age of onset was 3 months, and the median age of diagnosis was 14 months. The first symptoms were often exocrine pancreatic insufficiency (31.8%) and granulocytopenia with infection (31.8%). According to the international consensus, the incidence rates of the three major diseases of SDS were hemocytopenia (95.4%), pancreatic disease (72.7%), and bone abnormality (40.9%). The common factors underlying SDS disease were variants of the SBDS gene (c.258+2T>C and c.183_184TA>CT), albeit there was no significant correlation between genotype and phenotype (P > 0.05). Compared with international reports, the clinical manifestations and genotypes of Chinese SDS children are different (P < 0.05). CONCLUSION: The SDS children have an early age of onset and significant individual difference. It is necessary to analyze the case-related data to facilitate early recognition, diagnosis and clinical intervention.

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.

[Exclusive diagnosis of aplastic anemia].

As an independent disease, aplastic anemia (AA) has been recognized for more than a century. When AA is diagnosed, other non-AA bone marrow failures should be excluded. It is termed as exclusive diagnosis of AA. The exclusive diagnosis of AA is helplessly based on that there is no parameter by which AA can be sensitively and specifically diagnosed now. So further searching for the meaningful diagnostic parameters of AA should be carried on to establish a direct diagnostic protocol of this disease and make it possible to differentiate it clearly from other bone marrow failure disease such as congenenital bone marrow failure, hypoplastic myelodysplastic syndromes, AA-paroxysmal nocturnal hemoglobinuria syndromes, large granules lymphocyte leukemia, clonal cytopenia of undetermined significance, immunorelated pancytopenia, acute hemopoietic arresting and idiopathic cytopenia of undetermined significance. The new markers and technologies being helpful for distinguishing AA from other bone marrow failures should be used in diagnosing AA. Correct understanding and application of exclusive diagnosis is not only related to the correctness of diagnosis and treatment of excluded diseases, but also to the quality of AA diagnosis, treatment and research.

The interactions between MRI-detected osteophytes and bone marrow lesions or effusion-synovitis on knee symptom progression: an exploratory study.

OBJECTIVES: To investigate the longitudinal association between MRI-detected osteophyte scores and progression of knee symptoms, and whether the association was modified in the presence of bone marrow lesions (BMLs) or effusion-synovitis. METHODS: Data from Vitamin D Effects on Osteoarthritis (VIDEO) study, a randomized, double-blinded and placebo-controlled clinical trial in symptomatic knee osteoarthritis (OA) patients, were analyzed as an exploratory study. Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) was used to assess knee symptoms. Osteophytes, BMLs and effusion-synovitis were measured using MRI. RESULTS: 334 participants with MRI information and WOMAC score (baseline and follow-up) were included in the analyses, with 24.3% of them having knee pain increased 2 years later. Statistically significant interactions were found between MRI-detected osteophytes and BMLs or effusion-synovitis on increased knee symptoms. In participants with BMLs, higher baseline scores of MRI-detected osteophytes in most compartments were significantly associated with increased total knee pain, weight-bearing pain, stiffness, and physical dysfunction, after adjustment for age, sex, body mass index, intervention and effusion-synovitis. In participants with effusion-synovitis, higher baseline scores of MRI-detected osteophytes in almost all the compartments were significantly associated with increased total knee pain, weight-bearing pain, stiffness, and physical dysfunction, after adjustment for age, sex, body mass index, intervention and BMLs. In contrast, MRI-detected osteophyte scores were generally not associated with knee symptom progression in participants without baseline BMLs or effusion-synovitis. CONCLUSIONS: MRI-detected OPs are associated with increased total knee pain, weight-bearing knee pain, stiffness and physical dysfunction in participants presenting BMLs or effusion-synovitis, but not in participants lacking BMLs or effusion-synovitis. This suggests they could interact with bone or synovial abnormalities to induce symptoms in knee OA.

Data-driven definitions for active and structural MRI lesions in the sacroiliac joint in spondyloarthritis and their predictive utility.

OBJECTIVES: To determine quantitative SI joint MRI lesion cut-offs that optimally define a positive MRI for inflammatory and structural lesions typical of axial SpA (axSpA) and that predict clinical diagnosis. METHODS: The Assessment of SpondyloArthritis international Society (ASAS) MRI group assessed MRIs from the ASAS Classification Cohort in two reading exercises where (A) 169 cases and 7 central readers; (B) 107 cases and 8 central readers. We calculated sensitivity/specificity for the number of SI joint quadrants or slices with bone marrow oedema (BME), erosion, fat lesion, where a majority of central readers had high confidence there was a definite active or structural lesion. Cut-offs with ≥95% specificity were analysed for their predictive utility for follow-up rheumatologist diagnosis of axSpA by calculating positive/negative predictive values (PPVs/NPVs) and selecting cut-offs with PPV ≥ 95%. RESULTS: Active or structural lesions typical of axSpA on MRI had PPVs ≥ 95% for clinical diagnosis of axSpA. Cut-offs that best reflected a definite active lesion typical of axSpA were either ≥4 SI joint quadrants with BME at any location or at the same location in ≥3 consecutive slices. For definite structural lesion, the optimal cut-offs were any one of ≥3 SI joint quadrants with erosion or ≥5 with fat lesions, erosion at the same location for ≥2 consecutive slices, fat lesions at the same location for ≥3 consecutive slices, or presence of a deep (i.e. >1 cm depth) fat lesion. CONCLUSION: We propose cut-offs for definite active and structural lesions typical of axSpA that have high PPVs for a long-term clinical diagnosis of axSpA for application in disease classification and clinical research.

Decrease in dysbaric osteonecrosis severity as a result of 45-minute oxygen pre-breathe.

Sudden decompression can result in bubble formation as the result of nitrogen gas (N2) dissolved in tissue during disabled submarine escape (DISSUB). This may cause dysbaric osteonecrosis (DON), a condition in long bones where bubbles in fatty marrow result in ischemia and necrosis. Previous research has shown that oxygen (O2) pre-breathe of two hours resulted in a reduction of DON; however, effects of shorter O2 pre-breathe remain uncertain. This study's aim was to understand the effect of shorter lengths of O2 pre-breathe. Eight adult Suffolk ewes (89.5± 11.5 kg) were exposed to 33 feet of seawater (fsw) for 24 hours. They were placed randomly into four groups and exposed to either 45, 30 or 15 minutes of O2 (91-88%) pre-breathe; the controls received none. They were then rapidly decompressed. Alizarin complexone was later injected intravenously to visualize the extent of DON in the right and left long bones (radii, tibiae, femur and humeri). The 30- and 15-minute pre-breathe groups saw the greatest deposition. There was significant decrease of variance in the 45-minute group when compared with all other treatments, suggesting that 45 minutes of O2 pre-breathe is required to effectively increase confidence in the reduction of DON. Similar confidence was not reflected in the 30-minute and 15-minute groups: 45 minutes of pre-breathe was the minimum amount needed to effectively prevent against DON in DISSUB escape at 33 fsw. However, future research is needed to determine how to calculate effective dosages of O2 pre-breathe to prevent DON in any given scenario.

Cost-effectiveness analysis of pretreatment screening for NUDT15 defective alleles.

BACKGROUND: Nucleotide triphosphate diphosphatase (NUDT15) genetic testing in addition to thiopurine methyl transferase (TPMT) is recommended to reduce the incidence of adverse severe myelotoxicity episodes induced by thiopurines. OBJECTIVE: We assessed the cost-effectiveness ratio of combined screening for TMPT and NUDT15 defective alleles by genotyping or next-generation sequencing (NGS) using TPMT genotyping as the reference. Because of the genetic differences in thiopurine toxicity, we tested the screening strategies on individuals of Caucasian and Asian descent. METHODS: A decision tree compared conventional TPMT genotyping with combined TPMT/NUDT15 genotyping or NGS using a Monte-Carlo microsimulation model of patients with inflammatory bowel disease. The main outcome was the incremental cost-effectiveness ratios (ICER) with effectiveness being one averted severe myelotoxicity requiring hospitalization. RESULTS: The mean estimated cost of the TPMT genotyping for one year is twice in Asian compared with Caucasian patients (980 euro/patient versus 488 euro/patient), and the effectiveness of TPMT genotyping in Caucasian avoided 43 severe myelosuppressions per 10 000 patients over a year compared with 3.6 per 10 000 patients in Asian. Combined TPMT/NUDT15 genotyping compared with TPMT genotyping had an ICER of 7 491 281 euro per severe myelotoxicity averted in Caucasian, compared to 619 euro in Asian. The ICER of the NGS-based screening strategy is disproportionally high compared with genotyping, irrespective of ethnic descent. CONCLUSION: With a low cost-effectiveness threshold, combined screening for NUDT15 and TPMT defective alleles is cost-effective compared to TMPT screening alone in patients of Asian descent, but is unrealistic from a cost-effectiveness point of view in Caucasians.

Inflammatory manifestations in patients with Shwachman-Diamond syndrome: A novel phenotype.

Shwachman-Diamond syndrome (SDS) is an autosomal recessive multisystem disorder characterized by exocrine pancreatic dysfunction, bone marrow failure, and leukemia predisposition. Approximately 90% of cases are due to biallelic mutations in the Shwachman-Bodian-Diamond (SBDS) gene. Additional phenotypic features variably associated with SDS include skeletal, neurologic, hepatic, cardiac, endocrine, and dental abnormalities. We report five subjects with SDS who developed a range of inflammatory manifestations. Three patients developed inflammatory eye conditions. Single cases of juvenile idiopathic arthritis, chronic recurrent multifocal osteomyelitis, and scleroderma were also noted. Clinical presentation and treatment responses are described. Proteomic analysis revealed increased inflammatory signatures in SDS subjects as compared to controls. Treatment of inflammatory manifestations in patients with SDS may be complicated by potential myelosuppressive toxicities of anti-rheumatic medications. Further research is needed to better understand the potential link between inflammatory disorders and SDS to inform effective treatment strategies.

Detection of different degree traumatic vertebral bone marrow oedema by virtual non-calcium technique of dual-source dual-energy CT.

AIM: To evaluate the diagnostic performance of dual-energy computed tomography (DECT) using the virtual non-calcium (VNCa) technique for the detection of different degrees of vertebral bone marrow oedema. MATERIALS AND METHODS: The present prospective study was approved by the institutional ethics committee. Informed consent was obtained from all patients. Twenty patients underwent both DECT and MRI. Vertebral bodies on VNCa images were graded visually by two blinded, independent radiologists using a three-point classification system (0=normal bone marrow, 2=distinct abnormal bone marrow attenuation). DECT values obtained from VNCa images were calculated by a third radiologist. Vertebral bodies on MRI images were graded by a forth radiologist using the same classification as DECT; magnetic resonance imaging (MRI) served as the reference standard. RESULTS: The agreement between VNCa and MRI images for the grading of bone marrow oedema was substantial (κ=0.694). If MRI at grade 2 was regarded as positive for bone marrow oedema, VNCa images achieved an overall sensitivity of 85%, specificity of 97.5%, positive predictive value of 81%, negative predictive value of 98.1%. Receiver operating characteristic analysis based on CT values for the diagnosis of distinct bone marrow oedema revealed an area under the curve of 0.950. A cut-off value of -11.80 HU provided a sensitivity of 95% and specificity of 86.3% for the diagnosis of distinct bone marrow oedema at DECT. CONCLUSION: DECT images of VNCa showed excellent diagnostic performance for the detection of distinct vertebral bone marrow oedema.