Recommendations on Surveillance for Differentiated Thyroid Carcinoma in Children with PTEN Hamartoma Tumor Syndrome.

BACKGROUND: PTEN hamartoma tumor syndrome (PHTS) represents a group of syndromes caused by a mutation in the PTEN gene. Children with a germline PTEN mutation have an increased risk of developing differentiated thyroid carcinoma (DTC). Several guidelines have focused on thyroid surveillance in these children, but studies substantiating these recommendations are lacking. OBJECTIVE: The present study intends to provide the available evidence for a thyroid carcinoma surveillance program in children with PHTS. METHODS: An extensive literature search was performed to identify all studies on DTC in pediatric PHTS patients. Two pediatric cases are presented to illustrate the pros and cons of thyroid carcinoma surveillance. Recommendations for other patient groups at risk for DTC were evaluated. Consensus within the study team on recommendations for children with PHTS was reached by balancing the incidence and behavior of DTC with the pros and cons of thyroid surveillance, and the different surveillance methods. RESULTS: In 5 cohort studies the incidence of DTC in childhood ranged from 4 to 12%. In total 57 cases of DTC and/or benign nodular disease in pediatric PHTS patients were identified, of which 27 had proven DTC, with a median age of 12 years (range 4-17). Follicular thyroid carcinoma (FTC) was diagnosed in 52% of the pediatric DTC patients. No evidence was found for a different clinical behavior of DTC in PHTS patients compared to sporadic DTC. CONCLUSIONS: Children with PHTS are at increased risk for developing DTC, with 4 years being the youngest age reported at presentation and FTC being overrepresented. DTC in pediatric PHTS patients does not seem to be more aggressive than sporadic DTC. RECOMMENDATIONS: Surveillance for DTC in pediatric PHTS patients seems justified, as early diagnosis may decrease morbidity. Consensus within the study team was reached to recommend surveillance from the age of 10 years onwards, since at that age the incidence of DTC seems to reach 5%. Surveillance for DTC should consist of yearly neck palpation and triennial thyroid ultrasound. Surveillance in children with PHTS should be performed in a center of excellence for pediatric thyroid disease or PHTS.

New national recommendations for the treatment of pediatric differentiated thyroid carcinoma in the Netherlands.

BACKGROUND: Currently, there are no European recommendations for the management of pediatric thyroid cancer. Other current international guidelines are not completely concordant. In addition, medical regulations differ between, for instance, the US and Europe. We aimed to develop new, easily accessible national recommendations for differentiated thyroid carcinoma (DTC) patients <18 years of age in the Netherlands as a first step toward a harmonized European Recommendation. METHODS: A multidisciplinary working group was formed including pediatric and adult endocrinologists, a pediatric radiologist, a pathologist, endocrine surgeons, pediatric surgeons, pediatric oncologists, nuclear medicine physicians, a clinical geneticist and a patient representative. A systematic literature search was conducted for all existing guidelines and review articles for pediatric DTC from 2000 until February 2019. The Appraisal of Guidelines, Research and Evaluation (AGREE) instrument was used for assessing quality of the articles. All were compared to determine dis- and concordances. The American Thyroid Association (ATA) pediatric guideline 2015 was used as framework to develop specific Dutch recommendations. Discussion points based upon expert opinion and current treatment management of DTC in children in the Netherlands were identified and elaborated. RESULTS: Based on the most recent evidence combined with expert opinion, a 2020 Dutch recommendation for pediatric DTC was written and published as an online interactive decision tree (www.oncoguide.nl). CONCLUSION: Pediatric DTC requires a multidisciplinary approach. The 2020 Dutch Pediatric DTC Recommendation can be used as a starting point for the development of a collaborative European recommendation for treatment of pediatric DTC.

Altered Energetics of Exercise Explain Risk of Rhabdomyolysis in Very Long-Chain Acyl-CoA Dehydrogenase Deficiency.

Rhabdomyolysis is common in very long-chain acyl-CoA dehydrogenase deficiency (VLCADD) and other metabolic myopathies, but its pathogenic basis is poorly understood. Here, we show that prolonged bicycling exercise against a standardized moderate workload in VLCADD patients is associated with threefold bigger changes in phosphocreatine (PCr) and inorganic phosphate (Pi) concentrations in quadriceps muscle and twofold lower changes in plasma acetyl-carnitine levels than in healthy subjects. This result is consistent with the hypothesis that muscle ATP homeostasis during exercise is compromised in VLCADD. However, the measured rates of PCr and Pi recovery post-exercise showed that the mitochondrial capacity for ATP synthesis in VLCADD muscle was normal. Mathematical modeling of oxidative ATP metabolism in muscle composed of three different fiber types indicated that the observed altered energy balance during submaximal exercise in VLCADD patients may be explained by a slow-to-fast shift in quadriceps fiber-type composition corresponding to 30% of the slow-twitch fiber-type pool in healthy quadriceps muscle. This study demonstrates for the first time that quadriceps energy balance during exercise in VLCADD patients is altered but not because of failing mitochondrial function. Our findings provide new clues to understanding the risk of rhabdomyolysis following exercise in human VLCADD.

Systematic review and meta-analysis on the diagnostic performance of FDG-PET/CT in detecting bone marrow involvement in newly diagnosed Hodgkin lymphoma: is bone marrow biopsy still necessary?

BACKGROUND: This study aimed to systematically review and meta-analyze published data on the diagnostic performance of (18)F-fluoro-2-deoxy-d-glucose positron emission tomography/computed tomography (FDG-PET/CT) in detecting bone marrow involvement in newly diagnosed Hodgkin lymphoma, and to determine whether FDG-PET/CT can replace blind bone marrow biopsy (BMB) in these patients. PATIENTS AND METHODS: The PubMed/Medline and Embase databases were systematically searched for relevant studies. Methodological quality of each study was assessed. Sensitivities and specificities of FDG-PET/CT in individual studies were calculated and underwent meta-analysis with a random effects model. A summary receiver operating characteristic curve (sROC) was constructed with the Moses-Shapiro-Littenberg method. The weighted summary proportion of FDG-PET/CT-negative patients with a positive BMB among all cases was calculated under the fixed effects model. RESULTS: Nine eligible studies, comprising a total of 955 patients with newly diagnosed Hodgkin lymphoma, were included. Overall, the studies were of moderate methodological quality. The sensitivity and specificity of FDG-PET/CT for the detection of bone marrow involvement ranged from 87.5% to 100% and from 86.7% to 100%, respectively, with pooled estimates of 96.9% [95% confidence interval (CI) 93.0% to 99.0%] and 99.7% (95% CI 98.9% to 100%), respectively. The area under the sROC curve was 0.9860. The weighted summary proportion of FDG-PET/CT-negative patients with a positive BMB among all cases was 1.1% (95% CI 0.6% to 2.0%). CONCLUSION: Although the methodological quality of studies that were included in this systematic review and meta-analysis was moderate, the current evidence suggests that FDG-PET/CT may be an appropriate method to replace BMB in newly diagnosed Hodgkin lymphoma.

Apparent diffusion coefficient measurements in the differentiation between benign and malignant lesions: a systematic review.

OBJECTIVES: To systematically review the value of apparent diffusion coefficient (ADC) measurement in the differentiation between benign and malignant lesions. METHODS: A systematic search of the Medline/Pubmed and Embase databases revealed 109 relevant studies. Quality of these articles was assessed using the Quality Assessment of the Studies of Diagnostic Accuracy Included in Systematic Reviews (QUADAS) criteria. Reported ADC values of benign and malignant lesions were compared per organ. RESULTS: The mean quality score of the reviewed articles was 50%. Comparison of ADC values showed marked variation among studies and between benign and malignant lesions in various organs. In several organs, such as breast, liver, and uterus, ADC values discriminated well between benign and malignant lesions. In other organs, such as the salivary glands, thyroid, and pancreas, ADCs were not significantly different between benign and malignant lesions. CONCLUSION: The potential utility of ADC measurement for the characterisation of tumours differs per organ. Future well-designed studies are required before ADC measurements can be recommended for the differentiation of benign and malignant lesions. These future studies should use standardised acquisition protocols and provide complete reporting of study methods, to facilitate comparison of results and clinical implementation of ADC measurement for tumour characterisation.

Radiation exposure and mortality risk from CT and PET imaging of patients with malignant lymphoma.

OBJECTIVE: To quantify radiation exposure and mortality risk from computed tomography (CT) and positron emission tomography (PET) imaging with (18)F-fluorodeoxyglucose ((18)F-FDG) in patients with malignant lymphoma (Hodgkin's disease [HD] or non-Hodgkin's lymphoma [NHL]). METHODS: First, organ doses were assessed for a typical diagnostic work-up in children with HD and adults with NHL. Subsequently, life tables were constructed for assessment of radiation risks, also taking into account the disease-related mortality. RESULTS: In children with HD, cumulative effective dose from medical imaging ranged from 66 mSv (newborn) to 113 mSv (15 years old). In adults with NHL the cumulative effective dose from medical imaging was 97 mSv. Average fractions of radiation-induced deaths for children with HD [without correction for disease-related mortality in brackets] were 0.4% [0.6%] for boys and 0.7% [1.1%] for girls, and for adults with NHL 0.07% [0.28%] for men and 0.09% [0.37%] for women. CONCLUSION: Taking into account the disease-related reduction in life expectancy of patients with malignant lymphoma results in a higher overall mortality but substantial lower incidence of radiation induced deaths. The modest radiation risk that results from imaging with CT and (18)F-FDG PET can be considered as justified, but imaging should be performed with care, especially in children.

Diagnostic performance of radiographers as compared to radiologists in magnetic resonance colonography.

PURPOSE: To evaluate the diagnostic performance of radiographers compared to radiologists in the detection of colorectal lesions in MR colonography. MATERIAL AND METHODS: 159 patients at increased risk of colorectal cancer were included. Four different experienced observers, one MR radiologist, one radiologist in training and two radiographers evaluated all MR colonography examinations. The protocol included T1-weighted and T2-weighted sequences in prone and supine position. Colonoscopy was used as reference standard. Mean sensitivity rates with 95% confidence intervals (CIs) were determined on a per-patient and per-polyp basis, segmented by size (>or= 6mm and >or= 10mm). Specificity was calculated on a per-patient basis. The McNemar and chi-square (chi(2)) test was used to determine significant differences. RESULTS: At colonoscopy 74 patients (47%) had normal findings; 23 patients had 40 polyps with a size > or = 6mm. In 10 patients at least 1 polyp >or= 10mm was found (20 polyps in total). Similar sensitivities for patients with lesions >or= 10mm were found for radiologists and radiographers (65% (95%CI: 44-86%) vs. 50% (95%CI: 28-72%)) (p=n.s.). For lesions >or=10mm combined per-patient specificity for radiologists and radiographers was 96% (95%CI: 94-98%) and 73% (95%CI: 68-79%) (p<0.0001). Combined per-patient sensitivity for lesions >or=6mm differed significantly between both groups of observers (57% (95%CI: 42-71%) vs. 33% (95%CI: 19-46%)) (p=0.03). CONCLUSION: Radiographers have comparable sensitivity but lower specificity relative to radiologists in the detection of colorectal lesions >or= 10mm at MR colonography. Adequate training in evaluating MR colonography is necessary, especially for readers with no prior experience with colonography.

Magnetic resonance imaging in children with anorectal malformations: embryologic implications.

PURPOSE: The aim of this study was to evaluate the spectrum of developmental anomalies in the caudal region of patients with anorectal malformations (ARM) and relate them to the new insights in the embryogenesis of this region. METHODS: Forty-nine patients with ARM were investigated with magnetic resonance imaging (MRI); 24 preoperatively (preop) and 25 postoperatively (postop). Of this group, 17 patients had a high (or intermediate) ARM, 28 a low ARM, and 4 a cloacal malformation (CM). The evaluation of the imaging studies included the level and type of ARM (preop); the developmental state of the sphincter muscle complex (SMC); and the associated anomalies of spinal cord, spine, and urogenital system. The anomalies detected were ordered and related to recent embryologic observations in the caudal region. RESULTS: With MRI, the level of ARM was depicted effectively in 23 of 24 patients (96%) investigated preop, including 5 of 9 clinically proven fistulae in those with high ARM and CM (56%). Maldevelopment of the SMC was observed in 14 of 49 patients (29%). Associated anomalies of spinal cord and spine were found in 51% of patients, more frequently in those with high ARM, low ARM with fistulae, and cloacal malformations. Associated anomalies of the urogenital system were found in 37% of patients. CONCLUSIONS: As illustrated by the current study, MRI has become indispensable for the visualization of the nature of congenital ARM and associated anomalies. Moreover, MRI aids in understanding the morphology and pathogenesis of these complex congenital malformations. Based on the MRI and recent embryologic observations, a new and simplified classification of ARM is introduced, including a more appropriate nomenclature.