Assessing bone mineralisation in children with chronic kidney disease: what clinical and research tools are available?

Mineral and bone disorder in chronic kidney disease (CKD-MBD) is a triad of biochemical imbalances of calcium, phosphate, parathyroid hormone and vitamin D, bone abnormalities and soft tissue calcification. Maintaining optimal bone health in children with CKD is important to prevent long-term complications, such as fractures, to optimise growth and possibly also to prevent extra-osseous calcification, especially vascular calcification. In this review, we discuss normal bone mineralisation, the pathophysiology of dysregulated homeostasis leading to mineralisation defects in CKD and its clinical consequences. Bone mineralisation is best assessed on bone histology and histomorphometry, but given the rarity with which this is performed, we present an overview of the tools available to clinicians to assess bone mineral density, including serum biomarkers and imaging such as dual-energy X-ray absorptiometry and peripheral quantitative computed tomography. We discuss key studies that have used these techniques, their advantages and disadvantages in childhood CKD and their relationship to biomarkers and bone histomorphometry. Finally, we present recommendations from relevant guidelines-Kidney Disease Improving Global Outcomes and the International Society of Clinical Densitometry-on the use of imaging, biomarkers and bone biopsy in assessing bone mineral density. Given low-level evidence from most paediatric studies, bone imaging and histology remain largely research tools, and current clinical management is guided by serum calcium, phosphate, PTH, vitamin D and alkaline phosphatase levels only.

Two decades of SPECT/CT - the coming of age of a technology: An updated review of literature evidence.

PURPOSE: Single-photon emission computed tomography (SPECT) combined with computed tomography (CT) was introduced as a hybrid SPECT/CT imaging modality two decades ago. The main advantage of SPECT/CT is the increased specificity achieved through a more precise localization and characterization of functional findings. The improved diagnostic accuracy is also associated with greater diagnostic confidence and better inter-specialty communication. METHODS: This review presents a critical assessment of the relevant literature published so far on the role of SPECT/CT in a variety of clinical conditions. It also includes an update on the established evidence demonstrating both the advantages and limitations of this modality. CONCLUSIONS: For the majority of applications, SPECT/CT should be a routine imaging technique, fully integrated into the clinical decision-making process, including oncology, endocrinology, orthopaedics, paediatrics, and cardiology. Large-scale prospective studies are lacking, however, on the use of SPECT/CT in certain clinical domains such as neurology and lung disorders. The review also presents data on the complementary role of SPECT/CT with other imaging modalities and a comparative analysis, where available.

Meckel's scan in children: a review of 183 cases referred to two paediatric surgery specialist centres over 18 years.

AIM: To review our practice of Meckel's Tc-99m pertechnetate scans over 18 years with regard to indications for the test, sensitivity and specificity in our particular referral patients' population. MATERIALS AND METHODS: This is a retrospective review of Meckel's scans performed in two paediatric tertiary care teaching hospitals from April 1993 to March 2011 and followed up till October 2011. The scan was performed according to published international guidelines. 183 patients were included in this study. We classified the patients into two groups: group 1, which included 77 patients (42 %) presenting with painless per rectum bleeding, and group 2, which included 106 patients (58 %) presenting with other non-specific symptoms (e.g. abdominal pain, possibly associated with nausea and/or vomiting, failure to thrive). Data were analysed using Chi square test, considering P value less than 0.05 as significant. The age of the patients ranged from 4 days to 16.5 years (median 3 years). RESULTS: 161 of the total 183 children on the study (88 %) had a negative Meckel's scan, and 22 children (12 %) had a positive scan. In the group with a positive Meckel's scan (22 children), all patients underwent surgical exploration and ectopic gastric mucosa was found in 17 cases (77 %, true positives). In the remaining 5 cases (23 %), there was no evidence of ectopic gastric mucosa (false positives). Within the group with a negative scan, 8 children (5 %) underwent surgery; only 1 child had a ectopic gastric mucosa detected following surgery (false negative). In other 52 children (32 %) of the group with a negative Meckel's scan, an endoscopy was done, which showed a normal result in 21 children and was abnormal in 31 children. Of the remaining 101 (63 %) children with a negative Meckel's scan, 74 children (46 %) improved without any further intervention. In 13 cases (8 %), other pathologies were identified. The sensitivity and specificity of the Meckel's scan for ectopic gastric mucosa were 94 and 97 %, respectively. The Meckel's scan was positive in 26 % of the patients of group 1 and in only 2 % patients of group 2. The difference between the two groups was highly significant [P < 0.0001 (Yates-corrected Chi square); odds ratio 18 (Woolf-logit method 95 % CI)]. CONCLUSION: The Meckel's scan retains a high diagnostic accuracy in children for detecting a Meckel's diverticulum with ectopic gastric mucosa within it, when performed according to the recommended guidelines. The test yields its highest positive result in children presenting with significant per rectum bleeding.

Studying bone mineral density in young people: The complexity of choosing a pQCT reference database.

BACKGROUND: Many chronic illnesses affect bone health, and commonly lead to mineralization abnormalities in young people. As cortical and trabecular bone may be differentially affected in certain diseases, an imaging technique that allows for detailed study of the bone structure is required. Peripheral quantitative computed tomography (pQCT) overcomes the limitations of dual energy X-ray absorptiometry (DXA) and is perhaps more widely available for use in research than bone biopsy. However, in contrast to DXA, where there are large reference datasets, this is not the case for pQCT. METHODS: Fifty-five children and young adults aged 7 to 30 years had the non-dominant tibia scanned at the 3% & 4% sites for trabecular bone mineral density and the 38% site for cortical bone mineral density and bone mineral content. Image acquisition and analysis was undertaken according to the protocols of two of the largest reference datasets for tibial pQCT. The Z-scores generated were compared to examine the differences between protocols and the differences from the expected median of zero in a healthy population. RESULTS: The trabecular bone mineral density Z-scores generated by the two protocols were similar. The same was true for cortical mineral content Z-scores at the 38% site. Cortical bone mineral density was significantly different between protocols and likely affected by differences in the ethnicity of our cohort compared to the reference datasets. Only one reference dataset extended from childhood to young adulthood. Only trabecular bone mineral density, periosteal and endosteal circumference Z-scores from one methodology were not significantly biased when tested for deviation of the median from zero. CONCLUSIONS: pQCT is a useful tool for studying trabecular and cortical compartments separately but, there are variations in pQCT scanning protocols, analysis methodology, and a paucity of reference data. Reference datasets may not be generalizable to local study populations, even when analysed using identical analysis protocols.

Bone mineral density in Anorexia Nervosa versus Avoidant Restrictive Food Intake Disorder.

BACKGROUND: Avoidant Restrictive Food Intake Disorder (ARFID) and Anorexia Nervosa (AN) cause significant underweight in children and young people (CYP). The association of low bone mineral density (BMD) and underweight CYP in AN is well established, but less is known about BMD in ARFID. METHODS: Retrospective case-note review and analysis of BMD measures by DXA on underweight patients referred to a paediatric clinic for eating disorders between 2014 and 2019. Indications for BMD measurement were age > 5 years and underweight for at least 6 months. RESULTS: Of 134 cases where BMD was measured, 118 (88%) had AN and 16 (12%) ARFID. Age range was 6-19 years. 19% were males. ARFID cases were more likely to be male, have lower Body Mass Index (BMI), BMI z-score (BMIz), and longer underweight duration. For all cases, BMI and BMIz were positively associated with BMD z-score (BMI: coefficient 0.13,95%CI 0.04 to 0.22, p = 0.01; BMIz: coefficient 0.34, 95%CI 0.17 to 0.51, p < 0.001) and bone mineral areal density z-score (BMI: coefficient 0.12, 95% CI 0.01 to 0.23, p = 0.04 and BMIz: coefficient 0.27, 95% CI 0.05 to 0.49, p = 0.02). However, there were no associations of BMD with diagnosis (ARFID vs AN). Paired t-testing of 13 age, sex and pubertally matched pairs from AN and ARFID cases also showed no difference in standardized BMD scores. CONCLUSION: Low BMD in our sample of underweight AN and ARFID cases was associated with BMI but not diagnosis. BMD may be as important in ARFID as AN. Further research should examine mechanisms and potential interventions.

Dual X-ray absorptiometry (DXA) of the lumbar spine in a clinical paediatric setting: does the method of size-adjustment matter?

UNLABELLED: Dual X-ray absorptiometry (DXA) is increasingly used in a clinical setting to evaluate bone mass in children. Areal Bone Mineral Density (aBMD) measurements are known to be influenced by body size, but there is no consensus on the optimal way to deal with this for individual patients. AIM: To compare parameters of bone mass with varying degrees of size correction and to determine the effect on the categorisation of patients as normal or abnormal. SUBJECTS AND METHODS: Healthy children (n = 78) and 4 groups of patients (n = 194) underwent DXA scans of the lumbar spine (L2-4, GE Lunar Prodigy). Five measures of bone mass were derived, all adjusted for age and sex: aBMD, BMAD (BMC/BA (1.5)), BMCh (BMC/height3), BMCa (BMC adjusted for BA), BMCt (BMC adjusted for BA and height). SD scores were calculated for each parameter for patients using data from healthy controls. RESULTS: Compared to healthy children, all patient groups had significantly reduced BMD SD scores (P < 0.001). Mean BMAD, BMCa and BMCt SD scores were significantly lower in only 2/4 patient groups, whilst BMCh SD scores were low only in one group. BMCt showed no advantage over BMCa. The proportion of patients with SD scores <-2 was 27% for aBMD but between 10-13% for BMAD, BMCh and BMCa. CONCLUSIONS: All size-corrected parameters of bone mass performed similarly and classified significantly fewer patients as abnormal than did aBMD. The use of one of these parameters should reduce the number of patients diagnosed inappropriately with 'low bone mass'. However, without validation against an outcome measure or 'gold standard' of bone density or structure, it is not possible to determine which parameter is most correct.

Epidoxorubicin plus ifosfamide in advanced and/or metastatic soft-tissue sarcomas.

We undertook this phase II study to evaluate the efficacy and toxicity of epidoxorubicin and ifosfamide in the treatment of locally advanced and/or metastatic soft-tissue sarcomas. We used escalating doses of epidoxorubicin (from 60 to 75 mg/m2) on day 1 and 1.2 g/m2 ifosfamide on days 1-5. Chemotherapy courses were repeated every 3-4 weeks. A total of 16 patients--13 who had not previously been treated and 3 who had undergone prior therapy with anthracyclines--entered the study. In all, 15 patients were evaluable for response and 16, for toxicity. At least two courses of chemotherapy were given. A complete remission (CR) was seen in 1 patient, a partial remission (PR) in 5, and a minor response (MR) in 1, for an objective response rate (CR + PR) of 40% (6/15); this value reached 50% in non-pretreated patients (6/12). Stable disease (SD) was observed in 40% (6/15) of patients. The relative dose intensity of epidoxorubicin ranged from 10 to 23.3 mg/m2 (median, 16.6 mg/m2). The time to objective response ranged from 4 to 12 weeks (median, 8.5 weeks). The duration of response was 4 months for the single CR, and that for the five PRs was 6+ months (range, 4-18 months). Toxicity was evaluated according to WHO criteria in 16 patients; it was mild and consisted mainly of alopecia, nausea and vomiting, and leucopenia. In only three patients did we observe grade 3 leucopenia. In one case an ifosfamide-associated encephalopathy occurred, but it regressed after 24 h. Neither chronic nor acute cardiac toxicity was reported. In this preliminary analysis, the response rate obtained with the combination of epidoxorubicin and ifosfamide was encouraging and the toxicity was acceptable.

Efficacy of immunoscintigraphy for detection of lymph node metastases.

The size of a lymph node is not in principle a limitation for the detection of cancer by Nuclear Medicine techniques. A radioactive pinhead is detectable if it has enough radioactivity on it. The approach of Nuclear Medicine to the demonstration of impalpable lymph nodes or to those lymph nodes detected by radiological techniques that are under 1 cm as to whether or not they contain cancer, is to increase the activity attached to cancer cells in such a lymph node as much as possible and to use sophisticated image analysis techniques to distinguish such uptake from its environment. This may be undertaken using a non specific technique such as F-18 Deoxyglucose and Positron Emission Tomography which is highly sensitive and which has been successful. The alternative approach is to use a highly specific and sensitive agent, such as a radio-labelled peptide or a radio-labelled monoclonal antibody together with image analysis. This paper describes these approaches and in particular the use of Tc-99m SM3 monoclonal antibody in the detection of impalpable axillary nodes in patients with breast cancer before surgery, using a change detection analysis providing a probability map of the significance of uptake of this radiopharmaceutical. It is a robust approach, providing the patient and the surgeon with information as to the likely need for extensive axillary surgery well prior to operation. A negative study should be followed by a sentinel node evaluation at surgery.

Radiolabelled monoclonal antibodies in clinical and surgical oncology: a review.

Over the past decade, the role of immunoscintigraphy using radiolabelled monoclonal antibodies has been steadily growing in clinical oncology, and in particular, in radioimmunotherapy and radioimmunoguided surgery for the treatment of primary, recurrent, and metastatic colorectal, ovarian, gastric, and prostate cancer. Herein, the authors review the requirements for successful tumour radioimmunodetection and related procedures.

The immunolocalization of PGP 9.5 in normal human kidney and renal cell carcinoma.

The Authors studied the localization of protein gene product (PGP) 9.5-like immunoreactivity in normal human kidney tissue and compared the results with the same immunostaining in renal cell carcinoma. PGP 9.5-like immunoreactivity was found in cells of distal convoluted tubules and in some glomerular capillaries. The cells of proximal convoluted tubules did not show any immunostaining. Sections from renal cell carcinoma showed a very low immunostaining or were negative for PGP 9.5. As PGP 9.5 is a marker of the diffuse endocrine system, the Authors believe that the stained cells of distal tubules should be considered as neuroendocrine cells. The negative reaction to PGP 9.5 antibodies in renal cell carcinoma is rather surprising since not only tumours of neuroectodermal origin, but also tumours of other origin and tissues from some chronic degenerative diseases show a positive reaction. The explication of a negative reaction in renal cell carcinoma remains open: one of the possible explanations could be the specific histogenesis of this tumour.

Dual energy x-ray absorptiometry and quantitative ultrasound are not interchangeable in diagnosing abnormal bones.

OBJECTIVE: To evaluate whether dual energy x-ray absorptiometry (DXA) and quantitative ultrasound (QUS) classify the same children as 'abnormal' (SD (z) score (SDS) ≤-2). METHODS: Speed of sound (SOS) was measured at the radius and tibia using QUS and lumbar spine bone mineral density (BMD) using DXA in 621 subjects aged 5-20 years; healthy 412, cystic fibrosis 117 and obese 92. RESULTS: BMD SDS positively (p<0.001) and tibia SOS SDS negatively correlated with size (p<0.05). Disagreement between DXA and QUS for 'abnormal' scans occurred in 6-31%. Those with abnormal BMD and normal SOS SDS had lower mean BMI SDS than those with normal BMD and abnormal SOS SDS. SOS measurements were unobtainable in some children, especially in the obese group. CONCLUSIONS: DXA and QUS identify different individuals as 'abnormal'. Agreement between BMD and tibia SOS is lower in obese subjects. Without a gold-standard, it is difficult to determine which technique is more 'correct'.

Pitfalls in paediatric oncology imaging.

Imaging a new mass lesion in a child requires careful consideration of a variety of issues. The age of the child is an important factor in determining the appropriate test to start with and the age also helps provide an appropriate differential diagnosis, which can then be used to guide further imaging. The long-term outcome for most children with cancer is very good, with over 70% achieving 5-year survival and presumed cure. Consequently their imaging requirements should be regarded as equal to all other children. Minimizing exposure to ionizing radiation, particularly where follow-up imaging is required is an important consideration. This article focuses specifically on general paediatric radiology and neuro-oncology imaging is not addressed. The pitfalls to be aware of in plain radiography, ultrasonography, computed tomography, magnetic resonance imaging and nuclear medicine (positron emission tomography-computed tomography and single photon emission computed tomography) in children with a proven or suspected malignancy are discussed.

Postural change in ventilation and perfusion secondary to a thoracic scoliosis with complete resolution after surgery.

We present the case of a child with a thoracic scoliosis causing respiratory impairment in whom pre-surgical ventilation-perfusion lung scintigraphy in different postures was able to predict improvement in ventilation and perfusion after surgery.

The new EANM paediatric dosage card: additional notes with respect to F-18.

INTRODUCTION: The previously published European Association of Nuclear Medicine (EANM) paediatric dosage card recommends 70 MBq F-18 or F-18 Fluoro-2-Deoxyglucose (F-18-FDG) as the "minimum recommended activity". DISCUSSION: Two recent publications demonstrate that when utilising F-18-labelled radiopharmaceuticals the administration of lower activities for small children is possible without losing image quality. CONCLUSION: In the light of these findings the EANM dosimetry and paediatrics committee have decided to reduce the value for the "minimum recommended activity" for both F-18 and F-18-FDG to 26 MBq for 2D- and 14 MBq for 3D-acquisitions.

Guidelines for 18F-FDG PET and PET-CT imaging in paediatric oncology.

OBJECTIVE: The purpose of these guidelines is to offer to the nuclear medicine team a framework that could prove helpful in daily practice. These guidelines contain information related to the indications, acquisition, processing and interpretation of (18)F-fluorodeoxyglucose positron emission tomography ((18)F-FDG PET) in paediatric oncology. The Oncology Committee of the European Association of Nuclear Medicine (EANM) has published excellent procedure guidelines on tumour imaging with (18)F-FDG PET (Bombardieri et al., Eur J Nucl Med Mol Imaging 30:BP115-24, 2003). These guidelines, published by the EANM Paediatric Committee, do not intend to compete with the existing guidelines, but rather aim at providing additional information on issues particularly relevant to PET imaging of children with cancer. CONCLUSION: The guidelines summarize the views of the Paediatric Committee of the European Association of Nuclear Medicine. They should be taken in the context of "good practice" of nuclear medicine and of any national rules, which may apply to nuclear medicine examinations. The recommendations of these guidelines cannot be applied to all patients in all practice settings. The guidelines should not be deemed inclusive of all proper procedures or exclusive of other procedures reasonably directed to obtaining the same results.

The new EANM paediatric dosage card.

INTRODUCTION: In a recent publication, Jacobs et al. proposed the use of three tracer-dependent dosage cards for paediatric nuclear medicine. MATERIALS AND METHODS: Based upon this work, the EANM dosimetry and paediatrics committees introduce a condensed and revised version of this dosage card for major nuclear medicine paediatric diagnostic procedures, replacing the previous card by Piepsz et al. and including a set of minimum activities. RESULTS: The activities to be administered result in weight-independent effective doses to the children. In addition, the introduction of minimum activities guarantees a minimum standard of image quality throughout Europe and avoids a variety of administered activities in children of the same weight in different countries, which was the case when using the previous EANM dosage card.

Tc-99m DTPA renography in children following renal transplantation: its value in the evaluation of rejection.

A retrospective analysis of the value of Tc-99m DTPA DRS in children requiring renal biopsy following transplantation. Thirty-one children following renal transplantation with possible rejection underwent thirty-nine DRS and biopsy within a 72-h period and clinical followed up for 12 months. The biopsy was classified according to the Banff 97. The DRS assessed semi-quantitatively images of renal perfusion and filtration, and the balance between these two images. The clinical notes were reviewed. Based on the biopsy results 15 children had acute rejection, three children chronic rejection, nine children a mixed appearance of both acute and chronic rejection while 12 children had no rejection. Based on the long-term clinical outcome, the DRS had an overall sensitivity of 76% and specificity of 86%. While renal biopsy remains the gold standard for the diagnosis of rejection, if the perfusion and filtration phases of the DRS are analysed separately and the results integrated, there is a possibility of suggesting that acute rejection is not the cause of the increase in creatinine. The DRS provides useful information to the nephrologist when taken in conjunction with the biopsy result and other investigations.