Accuracy and clinical utility of standard postmortem radiological imaging after early second trimester termination of pregnancy.

OBJECTIVE: This study aims to assess accuracy and clinical utility of postmortem radiological exams [Magnetic Resonance Imaging (MRI), Computed Tomography (CT) and Radiography (XR)] after termination of pregnancy at <23 weeks' gestation for congenital fetal malformations in comparison to autopsy. STUDY DESIGN: This a prospective single-center study on fetuses underwent termination of pregnancy for fetal defects. Overall concordance between any radiological exam and autopsy was evaluated. For postmortem MRI only, the following subgroups were analyzed: 1) total agreement; 2) agreement for main findings; 3) agreement for main findings but major relevant additional findings at autopsy; 4) total disagreement. RESULTS: 174 cases were collected. The overall concordance with autopsy for main findings was 71% (115/163) for postmortem MRI and 99% (173/174) for prenatal ultrasound (US). Postmortem MRI detection rate was high for central nervous system (CNS) defects (98%), gastrointestinal, genitourinary and respiratory defects (100%), while it was poor for cardiovascular and musculoskeletal defects (25% and 42%, respectively). For musculoskeletal abnormalities, the performance of postmortem XR and postmortem CT exams improved the detection rate from 42% for postmortem MRI alone to 92%. CONCLUSIONS: Postmortem MRI has a good overall concordance for fetal defects after termination of pregnancy performed at <23 weeks. Along with autopsy, postmortem MRI may be offered for all cases of CNS defects in order to prevent inconclusive exams due to autolysis of the brain tissue, while postmortem CT and postmortem XR are indicated for musculoskeletal defects. In the presence of multiple abnormalities or cardiac defects the couple should be counseled on the poor performance of radiological investigations.

Correlation of cochlear aperture stenosis with cochlear nerve deficiency in congenital unilateral hearing loss and prognostic relevance for cochlear implantation.

The use of neonatal hearing screening has enabled the identification of congenital unilateral sensorineural hearing loss (USNHL) immediately after birth, and today there are several intervention options available to minimize potential adverse effects of this disease, including cochlear implantation. This study aims to analyze the characteristics of the inner ear of a homogeneous group of congenital non-syndromic USNHL to highlight the features of the inner ear, which can help in clinical, surgical, and rehabilitative decision-making. A retrospective chart review was carried out at a tertiary referral center. Systematic diagnostic work-up and rigorous inclusion-exclusion criteria were applied to 126 children with unilateral hearing impairment, leading to a selection of 39 strictly congenital and non-syndromic USNHL cases, undergoing computed tomography (CT) and magnetic resonance (MR) imaging studies. The frequency and type of malformations of the inner ear in USNHL and unaffected contralateral ears were assessed, with an in-depth analysis of the deficiency of the cochlear nerve (CND), the internal auditory canal (IAC) and the cochlear aperture (CA). Inner ear anomalies were found in 18 out of 39 (46%) of the USNHL patients. In 1 subject, the anomalies were bilateral, and the CND resulted in the predominant identified defect (78% of our abnormal case series), frequently associated with CA stenosis. Only 3 out of 14 children with CND presented stenosis of the IAC. CND and CA stenosis (and to a much lesser extent IAC stenosis) are a frequent association within congenital and non-syndromic USNHL that could represent a distinct pathological entity affecting otherwise healthy infants. In the context of a diagnostic work-up, the evaluation with CT and MRI measurements should take place in a shared decision-making setting with thorough counseling. Both imaging techniques have proven useful in differentiating the cases that will most likely benefit from the cochlear implant, from those with potentially poor implant performance.

Six-year-old boy with a slow-onset persistent back pain.

A 6-year-old boy was evaluated for a 6-week history of low back pain. Initially, the pain was exacerbated by movements, eventually showing a milder and fluctuating trend. History was unremarkable for previous traumatic events, fever or nocturnal pain. Physical examination revealed localised pain at palpation of the spinous processes at the lumbosacral level. Blood tests showed a normal blood count, negative C reactive protein (CRP) and erythrocyte sedimentation rate, normal lactic acid dehydrogenase (LDH) and creatine phosphokinase. A posterior-anterior radiograph of the lumbar spine resulted normal. An MRI scan revealed a lumbosacral transitional vertebra with bone oedema of the posterior arch until the spinous process. For better bone definition, a CT scan was performed ( figure 1 ).

Intrauterine versus post-mortem magnetic resonance in second trimester termination of pregnancy for central nervous system abnormalities.

OBJECTIVE: To evaluate if limiting factors of intrauterine magnetic resonance imaging (iuMRI) performed in the early second trimester of pregnancy (19-23 weeks) affect its accuracy in comparison to post-mortem MRI (pmMRI) in fetuses that underwent termination of pregnancy (TOP) for central nervous system (CNS) defects. STUDY DESIGN: This is a secondary analysis of a 10 years prospective observational study. Cases of TOP < 23 weeks for CNS malformation that had undergone neurosonography (NSG), iuMRI, pmMRI and autopsy were included. The agreement between iuMRI and pmMRI was calculated. The autopsy represented the gold-standard. RESULTS: Overall, 143 TOPs for fetal congenital anomaly underwent the post-mortem diagnostic protocol. Of these, 31 cases underwent iuMRI and pmMRI for CNS abnormality. Three cases were excluded due to brain autolysis at autopsy. Corpus callosum defects were the most represented (16/28; 57 %). In only one case of posterior fossa defect, pmMRI identified the presence of vermian hypoplasia not diagnosed at iuMRI. In 2 cases (7%), iuMRI added clinically relevant additional findings to NSG, that were posteriorly confirmed by pmMRI. CONCLUSIONS: The study shows that, at 19-23 weeks and for CNS defects, limiting factors that might influence the performance of iuMRI have little influence on iuMRI accuracy. This finding is particularly important for professionals who work in countries with legal bound for TOP in the early second trimester.

Hematopoietic stem cell transplantation-induced bone remodeling in autosomal recessive osteopetrosis: Interaction between skeleton and hematopoietic and sensory nervous systems.

OBJECTIVE: Autosomal recessive osteopetrosis (ARO) is a rare congenital disorder of defective bone resorption. The inability of osteoclasts to resorb bone compromises the development of bone marrow cavity, and ultimately, leads to defective hematopoiesis and death within the first decade. The only curative treatment currently available for certain forms of ARO is hematopoietic stem cell transplantation (HSCT). Infants over ten months of age suffering from ARO are defined as patients with advanced disease; HSCT to these patients is associated with high risk of transplant-related mortality (TRM). Because of the extreme variability of ARO clinical phenotypes, the most reliable predictive factor of TRM and graft failure risk is the residual bone marrow space volume. CASE REPORT: We report clinical and radiological outcomes of one patient affected by ARO and treated with HSCT at advance stage of the disease. We describe the anomalies in various tissues, including bone marrow and bones at the moment of the diagnosis and document their gradual disappearance after HSCT until their complete resolution based on magnetic resonance imaging (MRI) observations. We provided radiological images of the cranial vault bone structure modifications, correlating the radiological appearance of the optical canals and nerves and of the cerebellum with the neurological manifestations of the disease. CONCLUSIONS: Our results demonstrate that MRI is a highly sensitive technique that provides excellent images of bone marrow space before and after HSCT without exposing children to ionizing radiation. MRI also permits us to evaluate post-transplant skeletal remodeling and the deriving changes in the hematopoietic and sensory system.

What is known about deferasirox chelation therapy in pediatric HSCT recipients: two case reports of metabolic acidosis.

To date, in pediatric field, various hematological malignancies are increasingly treated with allogeneic hematopoietic stem cell transplantation (allo-HSCT). Iron overload and systemic siderosis often occur in this particular cohort of patients and are associated with poor prognosis. We describe herein the case of two allo-HSCT patients, on treatment with deferasirox; they showed histopathological elements compatible with venoocclusive disease or vanishing bile duct syndrome in ductopenic evolution before deferasirox started. The first patient developed drug-induced liver damage with metabolic acidosis and the second one a liver impairment with Fanconi syndrome. After withdrawing deferasirox treatment, both patients showed improvement. Measurements of drug plasma concentrations were performed by HPLC assay. The reduction and consequent disappearance of symptoms after the suspension of deferasirox substantiate its role in inducing hepatic damage, probably enabling the diagnosis of drug-induced liver damage. But the difficulties in diagnosing drug-related toxicity must be underlined, especially in compromised subjects. For these reasons, in patients requiring iron-chelating therapy, close and careful drug therapeutic monitoring is strongly recommended.

Total body irradiation and iron chelation treatment are associated with pancreatic injury following pediatric hematopoietic stem cell transplantation.

Whereas many studies have addressed the risk of organ dysfunction following hematopoietic stem cell transplantation (HSCT), little is known about pancreatic susceptibility in this setting. We aimed to investigate the effect of iron overload (IO) and total body irradiation (TBI) on pancreatic function of children undergoing HSCT. We retrospectively evaluated children admitted between 2012-2016 fulfilling the following criteria: normal pancreatic iron concentration (PIC), regular pancreatic function before HSCT, availability of abdominal magnetic resonance imaging with gradient-recalled-echo sequences and a full set of biochemical markers of IO and pancreatic function performed before HSCT and at discharge. We divided the patients according to the use of TBI or myeloablative chemotherapy (MCHT) in the conditioning regimen. All patients with severe IO or moderate IO with a high risk of engraftment delay or transplantation-related complications underwent chelation therapy with deferoxamine (DFO) from the first day of conditioning to discharge. 63 patients had a HSCT in the study period, 13 did not fulfill the inclusion criteria; 50 (25 in each group) are included in the analysis, and did not show differences at baseline evaluation. At follow up testing the TBI group showed a significantly higher PIC (107,8±100,3 µmol/g vs 28,4±37,9 in MCHT group, p<0,0001). In the TBI group the patients who had DFO treatment had higher PIC (223,2±48,8 µmol/g vs 55,7±10,5 without DFO treatment, p<0,0001), and all patients having PIC >100 µmol/g at follow up had DFO-based chelation therapy, versus 26% of those with lower PIC (p<0,0001). The number of patients presenting exocrine pancreatic dysfunctions one month after transplantation was significantly higher in the TBI group (48% vs 4%; p<0.0001). The mean pancreatic volume reduction was significantly greater in the TBI group (39,1% vs 0,9% in the MCHT group; p<0,05), and was significantly worse on those who received DFO therapy. Based on our data, we suggest that TBI is detrimental for pancreatic functions, and speculate that DFO may contribute to the rapid pancreatic IO observed in these patients.

Dealing with Chronic Non-Bacterial Osteomyelitis: a practical approach.

BACKGROUND: Chronic Non-Bacterial Osteomyelitis (CNO) is an inflammatory disorder that primarily affects children. Although underestimated, its incidence is rare. For these reasons, no diagnostic and no therapeutic guidelines exist. The manuscript wants to give some suggestions on how to deal with these patients in the every-day clinical practice. MAIN BODY: CNO is characterized by insidious onset of bone pain with local swelling. Systemic symptoms such as fever, skin involvement and arthritis may be sometimes present. Radiological findings are suggestive for osteomyelitis, in particular if multiple sites are involved. CNO predominantly affects metaphyses of long bones, but clavicle and mandible, even if rare localizations of the disease, are very consistent with CNO diagnosis. CNO pathogenesis is still unknown, but recent findings highlighted the crucial role of cytokines such as IL-1ß and IL-10 in disease pathogenesis. Moreover, the presence of non-bacterial osteomyelitis among autoinflammatory syndromes suggests that CNO could be considered an autoinflammatory disease itself. Differential diagnosis includes infections, malignancies, benign bone tumors, metabolic disorders and other autoinflammatory disorders. Radiologic findings, either with Magnetic Resonance or with Computer Scan, may be very suggestive. For this reason in patients in good clinical conditions, with multifocal localization and very consistent radiological findings bone biopsy could be avoided. Non-Steroidal Anti-Inflammatory Drugs are the first-choice treatment. Corticosteroids, methotrexate, bisphosphonates, TNFα-inhibitors and IL-1 blockers have also been used with some benefit; but the choice of the second line treatment depends on bone lesions localizations, presence of systemic features and patients' clinical conditions. CONCLUSION: CNO may be difficult to identify and no consensus exist on diagnosis and treatment. Multifocal bone lesions with characteristic radiological findings are very suggestive of CNO. No data exist on best treatment option after Non-Steroidal Anti-Inflammatory Drugs failure.

MRI-based evaluation of multiorgan iron overload is a predictor of adverse outcomes in pediatric patients undergoing allogeneic hematopoietic stem cell transplantation.

The medical records of 44 pediatric patients who underwent allogeneic transplantation from 2011 to 2015 were retrospectively reviewed. Magnetic resonance imaging was used to measure iron concentrations in the liver, spleen, pancreas and bone. These patients were divided into two groups, 18 with non-elevated (< 100 µmol/g; Group 1) liver iron concentration before transplantation and 26 with elevated (> 100 µmol/g; Group 2) concentration . We compared transplant-related outcomes in the two groups. Iron overload was a negative prognostic risk factor for sinusoidal obstruction syndrome (OR = 17), osteoporosis (OR = 6.8), pancreatic insufficiency (OR = 17) and metabolic syndrome (OR = 15.1). No statistically significant differences in overall survival, disease-free survival, relapse incidence and incidence of acute or chronic graft-versus host disease were observed between the two groups. Mean times to engraftment of platelets (43.0 ± 35.3 days vs. 22.1 ± 9.5 days, p < 0.05) and neutrophils (23.1 ± 10.4 days vs. 17.8 ± 4.6 days, p < 0.05) appear significantly longer in Group 2 than in Group 1. Time to platelet engraftment showed statistically significant correlation with pre-transplant liver (r = 0.5775; p < 0.001) and bone iron concentration (r = 0.7305; p < 0.001). Post-transplant evaluation pointed out that iron concentration analyzed at the first follow-up peaked in all tissues. The iron accumulation was highest in bone, followed by the spleen, liver and pancreas. One year post transplant 9 of 18 (50%) patients in Group 1 and 6 of 22 (27%) in Group 2 presented with bone and/or spleen iron overload, but not with liver overload. Liver iron concentration is not always a reliable indicator of systemic siderosis or of the efficacy of chelation therapy.

Safety and tolerability of deferasirox in pediatric hematopoietic stem cell transplant recipients: one facility's five years' experience of chelation treatment.

42 pediatric patients with iron overload, who underwent liver biopsy and DFX treatment after hematopoietic stem cell transplantation were included in the study group. The patients were divided into two groups diversified according to deferasirox trough plasma concentrations (DFX Ctrough) with cut-off equal to10 mcg/mL. The average dose of DFX was 25.9 mg/kg in the DFX Ctrough < 10 mcg/mL group versus 19.2 mg/kg in the DFX Ctrough > 10 mcg/mL group (p=0,0003). The mean duration of DFX treatment was 135.7 days in the DFX Ctrough < 10 mcg/mL group versus 41.8 days in the DFX Ctrough > 10 mcg/mL group (p<0.0001). The mean tissue iron concentration in the DFX Ctrough < 10 mcg/mL group was 261.9 µmol/g versus 133.4 µmol/g in the DFX Ctrough > 10 mcg/mL group (p < 0.0001). 21 patients (100%) in the DFX Ctrough > 10 mcg/mL group had ductopenia which was complete in 47.6% of them and severe in 52.4%. All patients with particularly high Ctrough (> 25 mcg/mL) were found to have total ductopenia. 90.5% of all deferasirox-related adverse events and 100% of major adverse events occurred in the DFX Ctrough > 10 mcg/mL group. In the DFX Ctrough < 10 mcg/mL group only one patient interrupted chelation therapy versus 16 (84.2%) patients in the DFX Ctrough > 10 mcg/mL group. We would recommend a close monitoring in pediatric hematopoietic transplant recipients subjected to deferasirox-based therapy because we have observed a high incidence of adverse events and discontinuation of chelation treatment.

"Safety and utility of percutaneous liver biopsy in hematopoietic stem cell transplant pediatric recipients: a retrospective study".

BACKGROUND: Liver biopsies in pediatric hematopoietic stem cell transplantation (HSCT) patients are as and effective when performed at bedside in the Bone Marrow Transplant Unit (BMTU) than in the Day Surgery Unit (DSU), with better patient compliance and lower emotional distress for these children. METHODS: The study group consisted of 45 children who underwent allogeneic HSCT. We reviewed 68 liver biopsies performed between April 2006 and September 2015. 12 (17.6 %) biopsies were performed in the DSU and 56 (82.3 %) in the BMTU; nine (13.2 %) prior to HSCT and 59 (86.7 %) after HSCT. Pre-procedural behavioral status (subjective score) was evaluated by pediatric transplant physicians by filling in a questionnaire employing a three-point scale: "calm and cooperative", "agitated and non-cooperative" or "frightened and suffering". Objective score was obtained measuring patient's heart rate before the procedure and comparing it with mean heart rate. RESULTS: Patients who underwent the procedure at the BMTU experienced less emotional distress than those who underwent it in the DSU: 58.3 % of patients treated at the DSU were agitated as compared with 16.1 % of those treated at the BMTU (p < 0.01). Among the 59 biopsies performed after HSCT, 41 (69.5 %) were taken from symptomatic patients for a diagnostic purpose and 18 (30.5 %) in asymptomatic ones in order to rule out hepatic GVHD. Among these 18 procedures, GVHD was diagnosed in 16 (88.9 %) cases. Minor complications occurred in about 17 % of procedures (12 biopsies), at a rate of 25 % for the DSU location compared with 16 % for the BMTU location. Only two major complications were reported, one in the DSU and one in the BMTU. CONCLUSION: Liver biopsy performed at bedside in HSCT patients does not carry a higher risk of adverse events than the same procedure performed in the DSU and has lower emotional distress associated with better patient compliance, thus contributing significantly to a higher standard of care.