Paediatric Orbital Juvenile Xanthogranuloma: A Case Series and Review of the Literature.

PURPOSE: Juvenile xanthogranuloma (JXG) is a subtype of histiocytosis characterised histologically by foamy non-Langerhan cells with Touton giant cells. It typically manifests as a single self-limiting cutaneous nodule in the paediatric population. Orbital JXG is extremely rare, and its clinical course and management are not well understood or defined. Herein we present 3 cases of orbital JXG and provide a detailed literature review. METHODS: Review of 3 cases with orbital JXG and literature review of all published cases. RESULTS: Three presented cases demonstrate the heterogeneous clinical course of orbital JXG. Although centred around the use of steroids, there is neither robust evidence nor consensus on its management. The wider JXG literature is currently concentrated around the classification of JXG with respect to histiocytosis, especially the exclusion of extracutaneous JXG as separate diseases. This separation is based on clinical, histopathological, and molecular findings. It is unclear where orbital JXG best fits in this emerging classification of JXG. CONCLUSION: Our review of the cases and literature on orbital JXG show that it may manifest with variable clinical course and its molecular pathogenic mechanism may be different to that of the cutaneous JXG.

A Detailed Histologic and Molecular Assessment of the Diffuse Sclerosing Variant of Papillary Thyroid Carcinoma.

Diffuse sclerosing variant papillary thyroid carcinoma (DS-PTC) is characterized clinically by a predilection for children and young adults, bulky neck nodes, and pulmonary metastases. Previous studies have suggested infrequent BRAFV600E mutation but common RET gene rearrangements. Using strict criteria, we studied 43 DS-PTCs (1.9% of unselected PTCs in our unit). Seventy-nine percent harbored pathogenic gene rearrangements involving RET, NTRK3, NTRK1, ALK, or BRAF; with the remainder driven by BRAFV600E mutations. All 10 pediatric cases were all gene rearranged (P = .02). Compared with BRAFV600E-mutated tumors, gene rearrangement was characterized by psammoma bodies involving the entire lobe (P = .038), follicular predominant or mixed follicular architecture (P = .003), pulmonary metastases (24% vs none, P = .04), and absent classical, so-called "BRAF-like" atypia (P = .014). There was no correlation between the presence of gene rearrangement and recurrence-free survival. Features associated with persistent/recurrent disease included pediatric population (P = .030), gene-rearranged tumors (P = .020), microscopic extrathyroidal extension (P = .009), metastases at presentation (P = .007), and stage II disease (P = .015). We conclude that DS-PTC represents 1.9% of papillary thyroid carcinomas and that actionable gene rearrangements are extremely common in DS-PTC. DS-PTC can be divided into 2 distinct molecular subtypes and all BRAFV600E-negative tumors (1.5% of papillary thyroid carcinomas) are driven by potentially actionable oncogenic fusions.

Aneurysmal Bone Cyst of the Orbit With USP6 Gene Rearrangement.

PURPOSE: Aneurysmal bone cyst (ABC) of the orbit is a very rare tumor, occurring mostly in the pediatric population, and can result in sight threatening complications and disfigurement. This review discusses previously reported cases with a focus on evolving treatment options and molecular genetics. METHODS: We report the youngest case of an orbital ABC with a confirmed gene fusion: a 17-month-old girl, with confirmed FGFR-UPS6 (Fibroblast Growth Factor Receptor 1-ubiquitin specific peptidase 6/tre-2). A literature search for relevant publications on the topic was performed via Medline and PubMed, with the appropriate data extracted. RESULTS: Thirty-two cases of orbital aneurysmal bone cyst were identified in the literature. Presentations are varied and can include pain, proptosis, decreased vision, and extraocular motility disturbance. Typical imaging and histopathology findings are discussed, in particular the usefulness of identifying USP6 gene arrangements. Treatment modalities are reviewed including surgery, embolization, and receptor activator of nuclear factor kappa-B ligand (RANKL) inhibitors. Recurrences can occur, usually within 2 years. CONCLUSIONS: Orbital ABC is a neoplasm that presents unique diagnostic and treatment challenges. Gene rearrangements can confirm primary ABC and rule out other underlying pathology. Disfigurement and sight threatening complications can occur due to both the disease process and with treatment. Outcomes may be improved with the use of systemic therapy.

Mitochondrial respiratory chain dysfunction in a patient with a heterozygous de novo CTBP1 variant.

The C-terminal binding protein 1 (CTBP1) functions as a transcriptional corepressor in vertebrates and has been identified to have critical roles in nervous system growth and development. Pathogenic variants in the CTBP1 gene has been shown to cause hypotonia, ataxia, developmental delay and tooth enamel defect syndrome (HADDTS). There have only been 16 cases reported to date with heterozygous, pathogenic variants in CTBP1 manifesting with a neurodevelopmental phenotype. We report a further case of a pathogenic, heterozygous, de novo variant in CTBP1 identified by whole exome sequencing in a female with the typical phenotype of global developmental delay, hypotonia, cerebellar dysfunction and failure to thrive. Additionally, muscle biopsy demonstrates evidence of a respiratory chain defect, only previously reported once in the literature. This supports the role of CTBP1 in maintenance of normal mitochondrial activity and highlights the importance of considering secondary mitochondrial dysfunction in genes not directly involved in the mitochondrial respiratory chain.

Yolk sac tumours of the orbit and sinonasal tract.

PURPOSE: The aim of this study is to report two cases of paediatric Yolk sac tumours (YST) of the orbit and sinonasal tract, with a major review on the subject. METHODS: Two case reports along with a comprehensive retrospective literature review of all English language publications between 1974 and 2021 is presented. Literature review examined the demographics, clinical presentation and diagnostic and prognostic factors of extragonadal YSTs of the orbit and sinonasal tract. RESULTS: Orbit and sinuses are rare sites for YST, with only 25 paediatric cases reported in the literature. Extragonadal yolk sac tumours carry a significantly worse outcome than those localised to the gonads, with the 5-year survival of 66% and 81-89%, respectively. Our review found the median age of presentation to be 18 months (18 months for males and 24 months for females), and females are more commonly affected. The most common presentations were proptosis, facial swelling and ophthalmoplegia. Treatments and therefore outcomes varied in the cases due to the large time period. Of the cases reported in the last 10 years, all patients with data provided were alive and disease-free at follow-up. CONCLUSION: Sino-orbital yolk sac tumours are rare and have variable presentations, dependent on the extent of local invasion. Early diagnosis and treatment with multimodal therapy are paramount in having improved overall survival.

Comparison of temporal evolution of computed tomography imaging features in COVID-19 and influenza infections in a multicenter cohort study.

Purpose: To compare temporal evolution of imaging features of coronavirus disease 2019 (COVID-19) and influenza in computed tomography and evaluate their predictive value for distinction. Methods: In this retrospective, multicenter study 179 CT examinations of 52 COVID-19 and 44 influenza critically ill patients were included. Lung involvement, main pattern (ground glass opacity, crazy paving, consolidation) and additional lung and chest findings were evaluated by two independent observers. Additional findings and clinical data were compared patient-wise. A decision tree analysis was performed to identify imaging features with predictive value in distinguishing both entities. Results: In contrast to influenza patients, lung involvement remains high in COVID-19 patients > 14 days after the diagnosis. The predominant pattern in COVID-19 evolves from ground glass at the beginning to consolidation in later disease. In influenza there is more consolidation at the beginning and overall less ground glass opacity (p = 0.002). Decision tree analysis yielded the following: Earlier in disease course, pleural effusion is a typical feature of influenza (p = 0.007) whereas ground glass opacities indicate COVID-19 (p = 0.04). In later disease, particularly more lung involvement (p < 0.001), but also less pleural (p = 0.005) and pericardial (p = 0.003) effusion favor COVID-19 over influenza. Regardless of time point, less lung involvement (p < 0.001), tree-in-bud (p = 0.002) and pericardial effusion (p = 0.01) make influenza more likely than COVID-19. Conclusions: This study identified differences in temporal evolution of imaging features between COVID-19 and influenza. These findings may help to distinguish both diseases in critically ill patients when laboratory findings are delayed or inconclusive.

Outcome of older myeloma patients in relationship to comorbidities and availability of second-generation novel agents in a real-life setting.

Major improvements in outcome of older patients with multiple myeloma (MM) have been achieved with the introduction of novel agents. Their impact in real-life treatment of older patients is unclear. In this single center retrospective study, we analyzed the outcome of patients >65 years treated with first-generation (FGNA) and second-generation novel agents (SGNA) within two time periods 2012-2014 and 2015-2017. Patients were analyzed based on age, Charlson Comorbidity Index (CCI), International Staging System stage, year of diagnosis and withdrawal of agents due to toxicities. Overall 96 patients were included for analysis. Median age was 73 years (range 65-90), 55 (57%) patients were 65-75 years and 41 (43%) were >75 years old. 84 patients received a first-line therapy, whereas 45 patients had ≥2 lines of systemic therapy. 20 patients were consolidated with autologous stem cell transplantation. 12 patients had no systemic therapy at all. In 17 of 21 cases a FGNA and in 4 of 21 a SGNA was withdrawn due to toxicity. Median overall survival (OS) for all patients with systemic therapy was 4.75 years (95% CI, 3.05-NA). Borderline significant improvement of OS was observed in patients diagnosed 2015-2017 compared to 2012-2014 with HR 0.57 (95% CI, 0.31-1.02) p = 0.06. OS significantly differed for comorbid patients with low and intermediate risk CCI, HR 1.94 (95% CI, 1.07-3.54), p = 0.03 in the overall population. OS in patients treated with SGNA was not significantly different in patients with intermediate versus low risk CCI (HR 1.48 (95% CI 0.43-5.14, p = 0.54)). In conclusion, we found a trend toward improved survival for older MM patients after the introduction of novel agents during the observed time period. In patients treated with SGNA a smaller effect that comorbidity negatively affects survival was observed.

Kidney biopsy adequacy and complications in children - does technique matter?

Kidney biopsy is part of the diagnostic workup of many children with renal disease. Traditionally, a perpendicular approach to the biopsy has been used, but more recently, some proceduralists have favoured a tangential approach. It is not clear if one technique is superior with regards to tissue adequacy or complication rates. In our centre, interventional radiologists (IR) use general anaesthetic and a tangential approach, whereas paediatric nephrologists (PN) use sedation and a perpendicular approach. We examined consecutive native kidney biopsies performed between January 2008 and December 2017 for adequacy (sufficient tissue for light and electron microscopy and immunofluorescence) and examined the electronic medical records for data regarding technique and complications. IR performed 72 (29%) of the 245 native kidney biopsies, obtaining more total glomeruli (median 39 vs 16, p < 0.001) and more glomeruli per tissue core (median 13 vs 8, p < 0.001) than PN. No differences in specimen adequacy were observed between the two groups (79% IR vs 81% PN, p = 0.75) and a diagnosis could be made in 99% and 94% respectively (p = 0.1). A statistically lower rate of peri-nephric haematoma (28% vs 42%, p = 0.04) was detected in the IR group, but there were no significant differences in other complications. One patient required a blood transfusion (PN) and another required surgical intervention for a perinephric haematoma (IR). CONCLUSION: IR obtained larger samples and number of glomeruli, but the overall adequacy for native kidney biopsies was good using both perpendicular and tangential techniques, with low rates of significant complications. WHAT IS KNOWN: • Kidney biopsy is integral to the diagnostic work-up of many children with kidney disease. • Kidney biopsy is a safe procedure with well-established complications in a minority of children. WHAT IS NEW: • Interventional radiologists had higher biopsy yield than paediatric nephrologists, possibly due to the tangential approach. • Biopsy adequacy rates are high using both techniques and provided a diagnosis in over 95% of cases.

Perioperative blood transfusions in hip and knee arthroplasty: a retrospective assessment of combined risk factors.

INTRODUCTION: Accurate identification of patients at risk of blood transfusion can reduce complications and improve institutional resource allocation. Probabilistic models are used to detect risk factors and formulate patient blood management strategies. Whether these predictors vary among institutions is unclear. We aimed to identify risk factors among our patients who underwent total hip (THA) or knee (TKA) arthroplasty, and combine these predictors to improve our model. MATERIALS AND METHODS: We retrospectively assessed risk factors among 531 adults who underwent elective THA or TKA from January 2016 to November 2018. Using relevant surgical and patient characteristics gathered from electronic medical records, we conducted univariable and multivariable analyses. For our logistic regression model, we measured the impact of independent variables (age, gender, operation type (THA or TKA) and preoperative hemoglobin concentration) on the need for a transfusion. RESULTS: Of the 531 patients, 321 had THA (uncemented) and 210 had TKA. For the selected period, our transfusion rate of 8.1% (10.6% THA and 4.3% TKA) was low. Univariable analyses showed that lower BMI (p < 0.001) was associated with receiving a transfusion. Important factors identified through logistic regression analyses were age (estimated effect of an interquartile range increase in age: OR 3.89 [CI 95% 1.96-7.69]), TKA (OR - 0.77 [CI 95% - 1.57-0.02]), and preoperative hemoglobin levels (estimated effect of interquartile range increase in hemoglobin: OR 0.47 [CI 95% 0.31-0.71]). Contrary to findings from previous reports, gender was not associated with transfusion. CONCLUSIONS: Previously published predictors such as advanced age, low preoperative hemoglobin, and procedure type (THA) were also identified in our analysis. However, gender was not a predictor, and BMI showed the potential to influence risk. We conclude that, when feasible, the determination of site-specific transfusion rates and combined risk factors can assist practitioners to customize care according to the needs of their patient population. LEVEL OF EVIDENCE: Level 3, retrospective cohort study.

Rare germline variants in childhood cancer patients suspected of genetic predisposition to cancer.

Identification of cancer-predisposing germline variants in childhood cancer patients is important for therapeutic decisions, disease surveillance and risk assessment for patients, and potentially, also for family members. We investigated the spectrum and prevalence of pathogenic germline variants in selected childhood cancer patients with features suggestive of genetic predisposition to cancer. Germline DNA was subjected to exome sequencing to filter variants in 1048 genes of interest including 176 known cancer predisposition genes (CPGs). An enrichment burden analysis compared rare deleterious germline CPG variants in the patient cohort with those in a healthy aged control population. A subset of predicted deleterious variants in novel candidate CPGs was investigated further by examining matched tumor samples, and the functional impact of AXIN1 variants was analyzed in cultured cells. Twenty-two pathogenic/likely pathogenic (P/LP) germline variants detected in 13 CPGs were identified in 19 of 76 patients (25.0%). Unclear association with the diagnosed cancer types was observed in 11 of 19 patients carrying P/LP CPG variants. The burden of rare deleterious germline variants in autosomal dominant CPGs was significantly higher in study patients versus healthy aged controls. A novel AXIN1 frameshift variant (Ser321fs) may impact the regulation of ß-catenin levels. Selection of childhood cancer patients for germline testing based on features suggestive of an underlying genetic predisposition could help to identify carriers of clinically relevant germline CPG variants, and streamline the integration of germline genomic testing in the pediatric oncology clinic.

Randomised, quadruple blinded, placebo controlled, multicentre trial investigating prophylactic tamsulosin in prevention of postoperative urinary retention in men after endoscopic total extraperitoneal inguinal hernia repair (STOP-POUR trial): a study protocol.

INTRODUCTION: Postoperative urinary retention (POUR) is a common complication after inguinal hernia repair with a reported incidence up to 34%. It can be described as the inability to initiate urination or insufficient bladder emptying following surgery. It usually requires the use of catheterisation to empty the bladder in order to prevent further injury to the bladder or kidneys and to relief from pain. Tamsulosin is a medication that is commonly used in men with urinary symptoms related to an enlarged prostate. There is some evidence to suggest that it may also potentially be beneficial for preventing POUR. METHODS AND ANALYSIS: This is a multicentre, blinded, prospective, phase IV randomised controlled trial with parallel allocation. Six hundred and thirty-four patients scheduled for elective endoscopic inguinal hernia repair surgery will be recruited. There will be effective (concealed) randomisation of the subjects to the intervention/control groups. Group assignment will be performed using a covariate-adaptive allocation procedure to provide a balance for selected covariates. The interventional group receives 0.4 mg tamsulosin hydrochloride and the control-group receives one placebo capsule matching the active study drug, both daily, starting from 5 days prior to the day of surgery, at the day of surgery and for 1 day following surgery. The primary outcome is any need for urinary catheterisation postoperatively as a binary outcome. Secondary outcome measures include postoperative pain, change in International Prostate Symptom Score from baseline prior to surgery to after surgery and hospital stay. ETHICS AND DISSEMINATION: The study has been approved by the Northwestern and Central Switzerland Ethics Committee (2020-00569) and it is being conducted in accordance with the Declaration of Helsinki and Good Clinical Practice. Study results will be disseminated through peer-reviewed journals and national and international scientific conferences. TRIAL REGISTRATION NUMBERS: SNCTP000003904. NCT04491526.

Surgical management of the acute paediatric scrotum: a three-year single centre experience.

BACKGROUND: Acute scrotal pain is a common emergency presentation in paediatric surgery. Torsion of the testicular appendage (TTA) is the most common cause for pain, with testicular torsion (TT) being the sinister pathology to exclude. Outcomes are time dependent, and a delayed scrotal exploration could result in testicular loss. METHODS: We performed a review on a large retrospective cohort of 449 surgical scrotal explorations at a large referral paediatric surgical centre over three years. RESULTS: Only about a quarter of children with testicular pain presented within 4 h. TT is commonly associated with nausea and an abnormal lie. Two children with a classical 'blue dot' sign were later found to have a testicular torsion. 19% of all children with a TTA were also seen to have Bell clapper anomaly (BCA). Recurrent testicular pain was associated with 84.7% (p < 0.001) of BCA. Intra-operative diagnosis of TTA correlated with histopathology in 84.6% (p=0.021). The sensitivity of intraoperative diagnosis was 90.9% with a specificity of 75.3%. CONCLUSION: Routine histopathology for a classic TTA may not be required especially in resource poor situations. All children presenting with recurrent episodes of testicular pain must be considered for surgical scrotal exploration. And in view of the incidence of BCA in this cohort, all scrotal explorations for acute scrotal pain should include an assessment for BCA.

Mucomuscular Elastic Flap for Lower Lip Vermilion Reconstruction: Experience in a Series of Cases in Pediatric Patients.

ABSTRACT: The mucocutaneous line and the lip vermilion are important structures from an esthetic standpoint but also in relation to the functionality of the mouth. In the literature, several types of flaps have been described for reparation of labial defects in adults. In this study, the authors analyze results of surgical reconstruction of the lower lip in the pediatric population using unilateral or bilateral mucomuscular elastic flaps for labial reconstruction. A retrospective analysis of 10 patients operated between 2003 and 2018 at our institution was made. The following demographic and clinical data were collected: age, sex, diagnosis, type of flap, follow-up, results, and complications. The Strasser scale was chosen for assessment of postoperative photographic results. Average age was 8.1 years (range 3-18). The most frequent etiology was arteriovenous malformation seen in 60% of cases. All cases corresponded to a defect of the lower lip. The average percentage of lip compromised was 44% and the largest length of compromise observed was 60% of the lip. Follow-up was on average 2.4 years. Esthetic results according to the Strasser method were as follows: 1 patient presented an excellent esthetic result, 5 good, 4 regular, and 0 poor.Considering the esthetic outcomes and low incidence of complications of the mucomuscular elastic flap, it is an acceptable and recommended technique of choice for lip vermilion reconstruction.

Fractional CO2 laser to improve noticeable scars after skin cancer surgery: An appraisal by the patients, laypersons, and experts.

Ablative fractionated carbon dioxide (fCO2 ) laser may be a useful tool to improve noticeable scars after skin cancer surgery. Therefore we evaluated 40 patients who have been treated with fCO2 laser for facial scars after skin cancer surgery. This retrospective study is based on blinded evaluation of pre- and postoperative photographs. Patients (n = 40), laypersons (n = 5) and experts (n = 5) evaluated the esthetics and the Vancouver scar scale as primary endpoints. Secondary endpoints included patient satisfaction and treatment safety. Patients, laypersons and experts consistently assessed a significant improvement of scar quality and appearance after fCO2 laser treatment, which was paralleled by high patient satisfaction. In conclusion, ablative fCO2 laser is effective in improving noticeable postsurgical scars. Patients are highly satisfied with post-laser results.

Compression Stocking With 100% Donning and Doffing Success: An Open Label Randomised Controlled Trial.

OBJECTIVE: The aim of this study was to test whether an investigational two layer stocking exerting 27-29 mmHg pressure at the medial supramalleolar level, but without compression in the foot and heel, is easier to put on and take off than a standard stocking of the same compression class (23-32 mmHg), and also to assess the prevention of diurnal oedema with both types of stocking. METHODS: This was an open label randomised controlled trial, which included 47 patients. All participants were at least 65 years of age and suffered from chronic venous disease class C3 - C6 in one leg. The primary end point was donning success; secondary endpoints were doffing success, prevention of diurnal oedema over one day, and the comfort of wearing the stocking. Patients were randomly allocated to one of two groups. Both types of compression stocking were compared in each group for ease of donning and doffing in the manner of a crossover study. Subsequently, patients wore the stocking type assigned to their group for a whole day to evaluate comfort and the effect on diurnal leg volume. RESULTS: All participants were able to don the investigational stocking unaided, compared with 75% for the standard stocking (p < .001). Unaided removal success was 100% with the investigational stocking vs. 66% for the standard stocking (p < .001). There was no significant difference in leg volume reduction between the study groups after a day of wear. The investigational stocking was also rated as being more comfortable than the standard stocking (p < .001). CONCLUSION: The investigational stocking, which has no compression in the foot or heel area, is significantly easier to don and doff, with no inferiority in oedema prevention, compared with a standard stocking of the same compression class.

Non-invasive continuous blood pressure monitoring (ClearSight™ system) during shoulder surgery in the beach chair position: a prospective self-controlled study.

BACKGROUND: The beach chair position that is commonly used in shoulder surgery is associated with relative hypovolemia, which leads to a reduction in arterial blood pressure. The effects of patient positioning on the accuracy of non-invasive continuous blood pressure monitoring with the ClearSight™ system (CS-BP; Edwards Lifesciences, Irvine CA, USA) have not been studied extensively. Our research aim was to assess agreement levels between CS-BP measurements with traditional blood pressure monitoring techniques. METHODS: For this prospective self-controlled study, we included 20 consecutively treated adult patients undergoing elective shoulder surgery in the beach chair position. We performed Bland-Altman analyses to determine agreement levels between blood pressure values from CS-BP and standard non-invasive (NIBP) methods. Perioperative measurements were done in both the supine (as reference) and beach chair surgical positions. Additionally, we compared invasive blood pressure (IBP) measurements with both the non-invasive methods (CS-BP and NIBP) in a sub-group of patients (n = 10) who required arterial blood pressure monitoring. RESULTS: We analyzed 229 data points (116 supine, 113 beach chair) from the entire cohort; per patient measurements were based on surgical length (range 3-9 supine, 2-10 beach chair). The mean difference (±SD; 95% limits of agreement) in the mean arterial pressure (MAP) between CS-BP and NIBP was - 0.9 (±11.0; - 24.0-22.2) in the beach chair position and - 4.9 mmHg (±11.8; - 28.0-18.2) when supine. In the sub-group, the difference between CS-BP and IBP in the beach chair position was - 1.6 mmHg (±16.0; - 32.9-29.7) and - 2.8 mmHg (±15.3; - 32.8-27.1) in the supine position. Between NIBP and IBP, we detected a difference of 3.0 mmHg (±9.1; - 20.8-14.7) in the beach chair position, and 4.6 mmHg (±13.3; - 21.4-30.6) in the supine position. CONCLUSIONS: We found clinically acceptable mean differences in MAP measurements between the ClearSight™ and non-invasive oscillometric blood pressure systems when patients were in either the supine or beach chair position. For all comparisons of the monitoring systems and surgical positions, the standard deviations and limits of agreement were wide. TRIAL REGISTRATION: This study was prospectively registered at the German Clinical Trial Register (www.DRKS.de; DRKS00013773 ). Registered 26/01/2018.

Exploration of CTNNB1 ctDNA as a putative biomarker for hepatoblastoma.

Driver mutations in the CTNNB1 gene (encoding ß-catenin) are a hallmark of sporadic hepatoblastoma (HBL). Our results show that CTNNB1 circulating tumour DNA (ctDNA) is readily detected in patients diagnosed with localised HBL, with serial sampling along the course of therapy and follow up providing a sensitive mechanism to monitor tumour dynamics and response to treatment. This exciting potential for CTNNB1 ctDNA to serve as a biomarker for treatment response in HBL holds clinical value, and requires assessment in a larger cohort of mixed tumour stages and recurrent disease.

Undifferentiated round cell sarcoma with BCOR internal tandem duplications (ITD) or YWHAE fusions: a clinicopathologic and molecular study.

Until recently, undifferentiated round cell sarcomas (URCS) in infants have been considered a wastebasket diagnosis, composed of various pathologic entities and lacking consistent genetic alterations. The recent identification of recurrent BCOR internal tandem duplications (ITD) and less common alternative YWHAE-NUTM2B/E fusions in half of infantile URCS and the majority of so-called primitive myxoid mesenchymal tumors of infancy (PMMTI) suggests a common pathogenesis with clear cell sarcoma of the kidney which also harbors the same genetic alterations. These tumors also share a similar morphology and immunoprofile, including positivity for BCOR, cyclin D1, and SATB2. In this study, we investigate the largest cohort to date of genetically confirmed URCS and PMMTI with BCOR ITD or YWHAE fusions to better define their morphologic spectrum and clinical behavior. Twenty-eight cases harbored BCOR ITD and five YWHAE fusions, occurring in 29 infants and 4 children, 19 males and 14 females. Microscopically, 20 were classified as URCS and 13 as PMMTI. Follow-up was available in 25 patients, with 14 (56%) succumbing to their diseases at a mean duration of 18-months follow-up (range: 2-62). Six patients remained with no evidence of disease at a mean follow-up of 63 months (range: 4-192), four patients were still alive with disease (mean follow-up: 46 months, range: 4-120), and one died of other causes. Local recurrence and distant metastasis were each observed in 11/25 (44%) of the patients. The overall survival was 42% at 3 years and 34% at 5 years (median survival: 26 months). There was no statistically significant survival difference between cases diagnosed as URCS and PMMTI and between those with BCOR ITD and YWHAE fusions.

The association between human leukocyte antigen eplet mismatches, de novo donor-specific antibodies, and the risk of acute rejection in pediatric kidney transplant recipients.

BACKGROUND: The longitudinal relationship between HLA class I and II eplet mismatches, de novo donor-specific antibodies (dnDSA) development, and acute rejection after transplantation in childhood is unknown. METHODS: Eplet mismatches at HLA class I and II loci were calculated retrospectively for each donor/recipient pair transplanted between 2005 and 2015 at a single Australian center. Logistic regression analyses were conducted to determine the association between the number of eplet mismatches, dnDSA, and acute rejection. RESULTS: The cohort comprised 59 children (aged 0-18 years) who received their first kidney allograft and were followed for median (interquartile range) 4.5 (± 2.6) years. Overall, 32% (19/59) developed dnDSA (class I 3% (2/59), class II 14% (8/59), 15% class I and II (9/59)), and 24% (14/59) developed biopsy-proven acute rejection. Every unit increase in class I and II eplet mismatches corresponded to an increase in risk of class I (odds ratio (OR) 1.22, 95% CI 1.07-1.39, p < 0.01) and class II (OR 1.06, 95% CI 1.01-1.11, p = 0.02) dnDSA development. Compared with recipients without dnDSA, class I and II dnDSA were associated with direction of effect towards increased risk of acute cellular rejection (class I: OR 5.87, 95% CI 0.99-34.94, p = 0.05; class II: OR 12.00, 95% CI 1.25-115.36, p = 0.03) and acute antibody-mediated rejection (class I: OR 25.67, 95% CI 3.54-186.10, p < 0.01; class II: OR 9.71, 95% CI 1.64-57.72, p = 0.01). CONCLUSIONS: Increasing numbers of HLA class I or II eplet mismatches were associated with the development of dnDSA. Children who developed dnDSA were also more likely to develop acute rejection compared with children without dnDSA.