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Complex female genitourinary system anomalies include a wide spectrum of uncommon pathologies, caused from the abnormal separation of the urorectal septum and the urogenital sinus in early embryonic life. The resulting fusion of the distal urinary, genital and intestinal tracts increases the risk of death in utero and alters the normal organ functionality and the quality of life in survivors. An accurate prenatal identification of these pathologies depends mainly on prior suspicion at ultrasound screening, but also requires a solid knowledge of embryology and familiarity with the different patterns of malformation. Prenatal MRI provides an excellent anatomic evaluation of the fetal anatomy that may improve the diagnosis in complex cases with inconclusive echographic findings. The additional information can help both families and medical teams to better evaluate the severity of the pathology and the postnatal prognosis and therefore to better orientate the management during pregnancy, at delivery and after birth. This review article describes the embryological basis and the clinical findings of the most relevant pathologies included in the spectrum. It also describes the imaging signs on prenatal MRI studies in a series of confirmed cases and proposes a diagnostic algorithm based on imaging findings for guiding prenatal diagnosis.

Wilson’s disease is a rare hereditary disorder of copper metabolism leading to progressive accumulation of copper in several organs including the brain and the liver. Acute liver failure is a relatively rare hepatic manifestation of WD which may require urgent liver transplantation if medical treatment fails. We report here the case of a young woman who presented with classic acute Wilsonian hepatitis complicated by liver and renal failure and a severe hemolysis related to massive nonceruloplasmin bound copper accumulation requiring repeated blood transfusions. The early initiation of a combined treatment including conventional chelation therapy and repeated MARS dialysis sessions allowed a rapid control of hemolysis, a progressive decrease of free copper overload, and clinical recompensation without liver transplantation.

Background The cellular infiltrate in protocol liver biopsies (PB) following pediatric liver transplantation remains mostly uncharacterized, yet there is increasing concern about the role of inflammation and fibrosis in long-term liver allografts. We aimed to define cell types in PB and to analyze their relationship with donor-specific antibodies (DSA) and histological phenotype. Methods PB were performed at least 1 year after transplantation. We identified 4 phenotypes: normal, fibrosis, inflammation, inflammation with fibrosis. Cell types were counted after immunostaining for CD3, CD4, CD8, CD68, CD20, MUM1, and FoxP3. Results Forty-four patients underwent 1 PB between 2000 and 2015. Eleven percent (5/44) of PB displayed normal histology, 13.6% (6/44) fibrosis, 34.1% (15/44) inflammation, and 40.9% (18/44) inflammation and fibrosis. The main cell types in the portal tracts and lobules were CD3+ and CD68+ cells. Frequency of de novo DSA was 63% (27/44). The presence of CD8+ cells in the lobules was associated with fibrosis. Inflammation and fibrosis in PB were associated with the presence of circulating de novo DSA, number of de novo DSA, and C1q binding activity when compared to other phenotypes. Conclusions T cells (CD3+) and macrophages (CD68+) were the most prevalent cell-types in PB. In the presence of inflammation, portal tracts were enriched in CD3+, CD20+ but displayed fewer CD68+. This coincided with the presence and number of de novo DSA. How these cellular and humoral actors interact is unclear, but peripheral DSA may be a marker of immune cellular activity in the seemingly quiescent allograft.

Outflow tract abnormalities are the most frequent congenital heart defects. These are due to the absence or dysfunction of the two main cell types, i.e., neural crest cells and secondary heart field cells that migrate in opposite directions at the same stage of development. These cells directly govern aortic arch patterning and development, ascending aorta dilatation, semi-valvular and coronary artery development, aortopulmonary septation abnormalities, persistence of the ductus arteriosus, trunk and proximal pulmonary arteries, sub-valvular conal ventricular septal/rotational defects, and non-compaction of the left ventricle. In some cases, depending on the functional defects of these cells, additional malformations are found in the expected spatial migratory area of the cells, namely in the pharyngeal arch derivatives and cervico-facial structures. Associated non-cardiovascular anomalies are often underestimated, since the multipotency and functional alteration of these cells can result in the modification of multiple neural, epidermal, and cervical structures at different levels. In most cases, patients do not display the full phenotype of abnormalities, but congenital cardiac defects involving the ventricular outflow tract, ascending aorta, aortic arch and supra-aortic trunks should be considered as markers for possible impaired function of these cells. Neural crest cells should not be considered as a unique cell population but on the basis of their cervical rhombomere origins R3-R5 or R6-R7-R8 and specific migration patterns: R3-R4 towards arch II, R5-R6 arch III and R7-R8 arch IV and VI. A better understanding of their development may lead to the discovery of unknown associated abnormalities, thereby enabling potential improvements to be made to the therapeutic approach.

(1) Background: In patients with biliary atresia (BA) liver nodules can be identified either by pre-transplant imaging or on the explant. This study aimed to (i) analyze the histopathology of liver nodules, and (ii) to correlate histopathology with pretransplant radiological features. (2) Methods: Retrospective analysis of liver nodules in explants of BA patients transplanted in our center (2000–2021). Correlations with pretransplant radiological characteristics, patient age at liver transplantation (LT), time from Kasai hepatoportoenterostomy (KPE) to LT, age at KPE and draining KPE. (3) Results: Of the 63 BA-patients included in the analysis, 27/63 (43%) had nodules on explants. A majority were benign macroregenerative nodules. Premalignant (low-grade and high-grade dysplastic) and malignant (hepatocellular carcinoma) nodules were identified in 6/63 and 2/63 patients, respectively. On pretransplant imaging, only 13/63 (21%) patients had liver nodules, none meeting radiological criteria for malignancy. The occurrence of liver nodules correlated with patient age at LT (p < 0.001), time KPE-LT (p < 0.001) and draining KPE (p = 0.006). (4) Conclusion: In BA patients, pretransplant imaging did not correlate with the presence of liver nodules in explants. Liver nodules were frequent in explanted livers, whereby 25% of explants harboured malignant/pre-malignant nodules, emphasizing the need for careful surveillance in BA children whose clinical course may require LT.

Background: Children with biliary atresia rapidly develop liver fibrosis secondary to inflammatory destruction of the biliary tract. Noninvasive detection of liver fibrosis in neonatal/infantile cholestasis is an additional criterion for the diagnosis of biliary atresia, leading to prompt surgical exploration. Objective: To assess the value of US with acoustic radiation force impulse (ARFI) elastography to detect biliary atresia in the workup of neonatal/infantile cholestasis. Materials and methods: In this retrospective study, 20 children with cholestasis suspected of having biliary atresia were investigated by US and ARFI. We evaluated the association between US findings and the diagnosis of biliary atresia and with two scores of liver fibrosis obtained from liver biopsy. Results: In univariate analyses, gallbladder size, triangular cord sign, spleen size and ARFI values were found to be associated with biliary atresia, though only the triangular cord sign remained significant when elevated gamma glutamyltransferase (GGT) was included as a predictor. In contrast, spleen size and ARFI correlated with the degree of liver fibrosis on biopsy (r > 0.70, P

BackgroundCongenital Pulmonary Airway Malformation (CPAM) has an estimated prevalence between 0.87 and 1.02/10,000 live births and little is know about their pathogenesis. To improve our knowledge on these rare malformations, we analyzed the cellular origin of the two most frequent CPAM, CPAM types 1 and 2, and compared these malformations with adjacent healthy lung and human fetal lungs.MethodsWe prospectively enrolled 21 infants undergoing surgical resection for CPAM. Human fetal lung samples were collected after termination of pregnancy. Immunohistochemistry and proteomic analysis were performed on laser microdissected samples.ResultsCPAM 1 and 2 express mostly bronchial markers, such as cytokeratin 17 (Krt17) or α-smooth muscle actin (ACTA 2). CPAM 1 also expresses alveolar type II epithelial cell markers (SPC). Proteomic analysis on microlaser dissected epithelium confirmed these results and showed distinct protein profiles, CPAM 1 being more heterogeneous and displaying some similarities with fetal bronchi.ConclusionThis study provides new insights in CPAM etiology, showing clear distinction between CPAM types 1 and 2, by immunohistochemistry and proteomics. This suggests that CPAM 1 and CPAM 2 might occur at different stages of lung branching. Finally, the comparison between fetal lung structures and CPAMs shows clearly different protein profiles, thereby arguing against a developmental arrest in a localized part of the lung.

We report an unusual case of intermittent episodes of cholestasis in a young patient. The cholestatic attacks were preceded in each case by an infection and subsequent antibiotic therapies. After ruling out many possible causes of cholestatic hepatitis, the differential diagnoses were a benign recurrent intrahepatic cholestasis or a drug-induced liver injury. We discuss here the diagnostic approach and interpretation of the genetic analysis.

Mosaic somatic mutations in the isocitrate dehydrogenase 1/2 (IDH1/2) genes have been identified in most enchondromas by targeted mutation analysis. Next-generation sequencing (NGS), that may detect even low-level mosaic mutation rates, has not previously been applied to enchondromas. Immunohistochemistry using the H09 clone is routinely used as a surrogate for the common R132H IDH1 mutation in gliomas. We compared immunohistochemistry and NGS results in a series of 13 enchondromas from 8 pediatric patients. NGS identified a heterozygous IDH mutation in all enchondromas, showing identical mutation status in patients with multiple tumors assessed, thereby confirming somatic mosaicism. A majority of the tumors harbored an IDH1 mutation (p.R132H in 3 tumors; p.R132C in 4 tumors from 2 patients; p.R132L and p.R132G in one tumor each). A p.R172S IDH2 mutation was identified in 4 enchondromas, but not in the ependymoma from one patient with Ollier disease, who further displayed a heterozygous STK11 missense mutation. IDH mutation rates varied between 14% (indicative of mutations in 28% of the cells and of intratumoral mosaicism) and 45% (tumor content was close to 100%). Cytoplasmic H09 reactivity was observed as expected in tumors with an IDH1 p.R132H mutation; cross-reactivity was seen with the p.R132L variant. This first NGS study of pediatric enchondromas confirms that IDH mutations may occur in a mosaic fashion. STK11 gene mutations may provide insights in the development of multiple cartilaginous tumors in enchondromatosis, this tumor suppressor gene having been shown in animal models to regulate both chondrocyte maturation and growth plate organization during development.

Although the nail is a small anatomical structure, it can be affected by various tumors and tumor-like conditions. Because of the distinctive nail anatomy, the clinical presentation of tumors is modified, thus rendering the diagnosis challenging. As nail biopsy and surgery are painful procedures associated with an increased risk of permanent onychodystrophy, pre-operative diagnosis is desirable. Although conventional radiographs are still the first-line radiologic examination for the assessment of bony structures beneath the nail matrix, they do not allow detailed evaluation of the phalangeal soft tissues. High resolution MRI allows accurate detection and mapping of nail lesions and can suggest a specific diagnosis. This review focuses on high resolution MRI of nail tumors and tumor-like lesions. We review the nail anatomy and the optimal MRI protocol. We then discuss a variety of tumors and tumor-like lesions in relation to the clinical presentation, anatomic location, histological features and imaging characteristics. We herewith describe common benign tumors (glomus tumor, onychomatricoma, keratoakanthoma, fibroma, subungual exostosis, hemangioma, chondroma, pyogenic granuloma), malignant tumors (subungual melanoma, subungual squamous cell carcinoma), as well as tumor mimics (mucoid cyst, epidermoid cyst). Although not entirely specific, MRI is a valuable tool in treatment planning of these tumors.

Background Heterozygous ABCB4 variants are not routinely tested in adults with cholestasis because of their supposed rarity and high costs. Methods Nineteen adult patients presenting with unexplained cholestasis, and/or recurrent gallstones were included; genotyping was not done in five due to lack of health insurance approval. Results heterozygous ABCB4 variants were identified in seven patients, followed by cascade testing of 12 family members: one patient underwent liver transplantation at age 40 for end-stage liver disease; one had compensated cirrhosis; all symptomatic adults had gallstones, including four with low phospholipid-associated cholelithiasis; four had intrahepatic cholestasis of pregnancy; all children and one 54-year old female were asymptomatic. Genotype: Families A and C: c.2211G>A (p.Ala737=) combined with c.959C>T (p.Ser320Phe) in one subject; Family B: c.1130T>C (p.Ile377Thr); Family D: large deletion removing ABCB4 exons 1-4 plus ABCB1, RUNDC3B, SLC25A40, DBF4, ADAM22 exons 1-3; Family E: c.1565T>C (p.Phe522Ser) ; Family F: c.1356+2T>C combined with c.217C>G (p.Leu73Val). All patients responded to ursodeoxycholic acid. Conclusions We found ABCB4 variants in half of the adults with unexplained cholestasis and/or recurrent gallstones presenting at our center, suggesting that this condition is underdiagnosed and undertreated, with serious consequences not only for the patients and their families, but also in terms of healthcare costs.

AIMS OF THE STUDY The European Society of Medical Oncology (ESMO) recommends that countries should have reference centres to provide adequate diagnosis and treatment of gestational trophoblastic disease. A trophoblastic disease centre in the French-speaking part of Switzerland was inaugurated in 2009. The objectives of this study were to report the activity of the centre during the last 10 years and analyse gestational trophoblastic disease outcomes. METHODS This was a retrospective study with data collected from all cases of gestational trophoblastic disease referred to the centre from 2009 to 2018. All histological specimens as well as data for treatment and follow-up of gestational trophoblastic disease and neoplasia were reviewed. Clinical features, including age, prognostic score and International Federation of Gynecology and Obstetrics (FIGO) stages (in the case of gestational trophoblastic neoplasia), human chorionic gonadotropin (hCG) follow-up, treatment and outcome were reported. RESULTS The centre registered 354 patients, and these patients presented 156 cases of partial hydatidiform moles, 163 cases of complete hydatidiform moles and 14 cases of gestational trophoblastic neoplasia. During follow-up, 35 gestational trophoblastic neoplasms were diagnosed after hCG persistence. After pathology review, the overall agreement rates between our centre and a participating provider hospital was 82%. Methotrexate was the first line of single-agent chemotherapy for most patients, with resistance rates of 23%. Multi-agent chemotherapy was used as first-line treatment for five patients. None of the patients followed up by the centre died from gestational trophoblastic disease. CONCLUSIONS This study reflects the activity of the Swiss trophoblastic disease centre from the French-speaking part of Switzerland created in 2009, and its role as local and national reference centre, in terms of global health, for women with gestational trophoblastic disease.

We report the case of a 5-year-old boy who developed chronic plastic bronchitis after Fontan surgery for a complex congenital heart disease. During a new admission for acute exacerbation of plastic bronchitis, he started on a mucolytic treatment with inhaled rhDNAse instead of inhaled fibrinolytics because of the potential bleeding risk in a patient on combined coumarin and aspirin treatment. Respiratory symptoms resolved promptly, and the patient was discharged home on rhDNAse treatment. He remained clinically stable on rhDNAse treatment without further hospitalization until definitive treatment with dynamic lymphangiography and percutaneous embolization.

Despite growing interest about the impact of donor-specific HLA antibodies (DSA) in LT limited data are available for pediatric recipients. Our aim was to perform a retrospective single-center chart review of children (0-16 years) having undergone LT between January 1, 2005 and December 31, 2017, to characterize DSA, to identify factors associated with the development of de novo DSA, and to analyze potential associations with the diagnosis of TCMR. Information on patient- and donor-characteristics and LB reports were analyzed retrospectively. Serum obtained before LT and at LB was analyzed for presence of recipient HLA antibody using Luminex® technology. MFI > 1000 was considered positive. In 63 pediatric LT recipients with a median follow-up of 72 months, the overall prevalence of de novo DSA was 60.3%. Most were directed against class II antigens (33/38, 86.8%). Preformed DSA were present in 30% of patients. Twenty-eight (28/63) patients (44.4%) presented at least one episode of TCMR, mostly (12/28, 43%) moderate (Banff 6-7). De novo DSA were significantly more frequent in patients with TCMR than in patients without (75% vs 48.6%, P = .03), and patients with preformed and de novo DSA had a significantly higher rate of TCMR than patients without any DSA (66.7% vs 20%, P = .02). Neither preformed DSA nor de novo DSA were associated with frequency or severity of TCMR. Recipients with lower weight at LT developed de novo DSA more frequently (P = .04). De novo DSA were highly prevalent in pediatric LT recipients. Although associated with the development of TCMR, they did not appear to impact the frequency or severity of TCMR or graft survival. Instead, de novo DSA may suggest a state of insufficient IS.

Introduction Reference ranges in fetal postmortem anthropometric data derive from heterogeneous studies and rely on data obtained after intrauterine fetal death and abortion, which may introduce bias in the reported fetal growth parameters. We report anthropometric findings in fetuses with the least variation due to cause of death or developmental anomalies. Methods We analyzed fetuses after the termination of pregnancy for psychosocial reasons. The external measurements, X-ray dimensions, and body and organ weights were recorded as well as the placenta weight. A thorough and standardized postmortem analysis allowed the design of 2 different groups. Group 1 was composed of fetuses (1) born to mothers with no relevant obstetrical history, (2) no X-ray anomaly, (3) no abnormal autopsy findings, and (4) unremarkable placenta histology. An anomaly in any of these 4 entities moved the fetuses to Group 2. For reference ranges and graph construction, a well-designed statistical methodology was applied. Results A total of 335 fetuses were analyzed during an 11-year period. Group 1 comprised 232 fetuses aged 12 to 20 gestational weeks, whereas 103 fetuses were considered in Group 2. Comparison between the 2 groups showed almost no differences. Only the Group 1 results were submitted to statistical analysis, and reference ranges and graphs were constructed. Conclusions To the best of our knowledge, we provide in this study the first anthropometric references established from almost normal fetuses, albeit for a limited fetal timeframe.

Introduction Pediatric neuroendocrine tumors (NETs) of the appendix are mostly detected incidentally after appendectomy for acute appendicitis. NET management is a matter of controversy. In this national, multicenter study, we aimed to establish guidelines based on our results and the literature. Materials and Methods Medical records of children (0–16 years) with NET of the appendix, treated in Switzerland (1991–2012), were reviewed. Results Forty cases (28 girls) were analyzed. Median age at diagnosis was 12.7 years (interquartile range [IQR]: 4.0). Tumor size was 0.1–24 mm (median: 0.6, IQR: 0.6). Four patients (10%) underwent additional surgery because of either tumor size > 15 mm (1/4), extension to the mesoappendix (1/4), or incomplete resection (2/4). Three patients with a tumor of ≥ 20 mm had no additional surgery. No patient had lymph node metastases. All patients were in complete remission at the last follow-up (median: 3.0 years, IQR: 10.9). Conclusion We conclude from this study and from an extensive review of the literature that two criteria may point to the need for additional surgery, i.e., the possibility of regional lymph node involvement: tumor size > 20 mm and incomplete surgical resection margins. Childhood NET of the appendix has an excellent prognosis.

Hepatoblastoma is the most common malignant pediatric liver cancer. Histological evaluation of tumor biopsies is used to distinguish among the different subtypes of hepatoblastoma, with fetal and embryonal representing the two main epithelial components. With frequent CTNNB1 mutations, hepatoblastoma is a Wnt/β-catenin-driven malignancy. Considering that Wnt activation has been associated with tumor metabolic reprogramming, we characterized the metabolic profile of cells from hepatoblastoma and compared it to cells from hepatocellular carcinoma. First, we demonstrated that glucose transporter GLUT3 is a direct TCF4/β-catenin target gene. RNA sequencing enabled to identify molecular and metabolic features specific to hepatoblastoma and revealed that several glycolytic enzymes are overexpressed in embryonal-like compared to fetal-like tumor cells. This led us to implement successfully three biomarkers to distinguish embryonal from fetal components by immunohistochemistry from a large panel of human hepatoblastoma samples. Functional analyses demonstrated that embryonal-like hepatoblastoma cells are highly glycolytic and sensitive to hexokinase-1 silencing. Altogether, our findings reveal a new, metabolic classification of human hepatoblastoma, with potential future implications for patients' diagnosis and treatment.

We report a rare case of late complication of a complex intestinal malformation. At day 1 of life, a baby girl underwent resection of an atretic jejunal segment, associated with an enteric duplication harboring foci of gastric and duodenal heterotopia. After an asymptomatic period of 19 years, the patient presented with acute bowel obstruction. Recurrence of the jejunal occlusion at the previous anastomotic site was caused by mucosa hyperplasia in association with heterotopic gastric and duodenal tissue. A Wnt/β-catenin pathway deregulation was hypothesized but not confirmed by CTNNB1 exon 3 mutation analysis. This case illustrates a rare association of 3 pathologies—namely, intestinal atresia, enteric duplication, and heterotopia, with a late-occurring acute complication.

Pleomorphic hyalinizing angiectatic tumor (PHAT) is a rare mesenchymal tumor of intermediate malignancy. PHAT, and the related hemosiderotic fibrolipomatous tumor, show a recurrent t(1;10)(p22;q24). Fluorescence in situ hybridization (FISH) and BAC (bacterial artificial chromosome) clones have previously identified TGFBR3 and MGEA5 as fusion partners. However, targeted RNA-sequencing allowed for the correct identification of FBXW4 and not MGEA5 as the fusion partner of TGFBR3 in a subcutaneous PHAT, a finding further confirmed by RT-PCR. FBXW4 and MGEA5 share a common cytogenetic location at 10q24.32, thereby suggesting that the use of less precise technology may have led to inaccurate gene identification. The study of additional cases is however required.

Denosumab has shown promising results in the management of giant cell tumor of bone, a primary bone tumor with locally aggressive behaviour. We report a case of premature denosumab interruption due to radiological and clinical tumor expansion of a giant cell tumor of the distal ulna. Although denosumab is known to induce tumor regression, with progressive ossification and loss of the characteristic morphology of giant cell tumor of bone, the ulnar tumor specimen showed a moderately to highly cellular proliferation of short spindle-shaped cells, and no osteoclast-like giant cells. There were no abnormal mitotic figures. We considered the surgical specimen as a giant cell tumor of bone with partial regression after prematurely interrupted denosumab treatment. This case illustrates the diagnostic issues of an initially unfavourable evolution raising concern for malignancy, and the difficulties in histological assessment of a partially treated giant cell tumor of bone, that may mimic osteosarcoma.

Background: Acoustic radiation force impulse (ARFI) imaging) is correlated with histopathological findings using METAVIR and semiquantitative scoring system (SSS) criteria for liver fibrosis. Objective: To compare acoustic radiation force impulse imaging with biopsy results in the evaluation of liver fibrosis in children. Materials and methods: Children with chronic liver disease and healthy children underwent acoustic radiation force impulse imaging liver measurements. ARFI gives a shear-wave velocity corresponding to tissue elasticity. In 39 children with liver disease, the values obtained were correlated with biopsy results. Receiver-operating characteristic (ROC) curves were used to determine the reliability of ARFI in estimating liver fibrosis in children. Results: ARFI mean value was 1.12 in the healthy group and 1.99 in children with chronic liver disease. ROC curves show that an ARFI cutoff of 1.34m/s is predictive of both METAVIR and SSS scores with a sensitivity of SSS > 2:0.85; METAVIR > F0:0.82. A cutoff of 2m/s yielded a sensitivity of 100% to detect SSS > 4 or METAVIR > F2. Conclusion: Acoustic radiation force impulse imaging is a reliable, noninvasive and rapid method to estimate moderate to severe liver fibrosis in children. It might prove useful to clinicians for fibrosis monitoring in children with liver disease and postpone the time of liver biopsy

Transdifferentiation is a complete and stable change in cell identity that serves as an alternative to stem-cell-mediated organ regeneration. In adult mammals, findings of transdifferentiation have been limited to the replenishment of cells lost from preexisting structures, in the presence of a fully developed scaffold and niche 1 . Here we show that transdifferentiation of hepatocytes in the mouse liver can build a structure that failed to form in development-the biliary system in a mouse model that mimics the hepatic phenotype of human Alagille syndrome (ALGS) 2 . In these mice, hepatocytes convert into mature cholangiocytes and form bile ducts that are effective in draining bile and persist after the cholestatic liver injury is reversed, consistent with transdifferentiation. These findings redefine hepatocyte plasticity, which appeared to be limited to metaplasia, that is, incomplete and transient biliary differentiation as an adaptation to cell injury, based on previous studies in mice with a fully developed biliary system3-6. In contrast to bile duct development7-9, we show that de novo bile duct formation by hepatocyte transdifferentiation is independent of NOTCH signalling. We identify TGFβ signalling as the driver of this compensatory mechanism and show that it is active in some patients with ALGS. Furthermore, we show that TGFβ signalling can be targeted to enhance the formation of the biliary system from hepatocytes, and that the transdifferentiation-inducing signals and remodelling capacity of the bile-duct-deficient liver can be harnessed with transplanted hepatocytes. Our results define the regenerative potential of mammalian transdifferentiation and reveal opportunities for the treatment of ALGS and other cholestatic liver diseases.

Identification of the yolk sac tumor (YST) component in germ cell tumors (GCT) may prove challenging, and highly sensitive and specific immunohistochemical markers are still lacking. Preliminary data from the literature suggest that HNF1β may represent a sensitive marker of YST. The specificity of HNF1β has not been addressed in GCT. A cohort of 49 YST specimens from 45 patients was designed, occurring either as pure tumors, or as a component of a mixed GCT. Immunohistochemistry was conducted on whole tumor sections using HNF1β. SALL4, OCT4, CD30, CDX2, Cytokeratin 19, Glypican 3, and GATA3 were used for classification of the GCT components. Patients were mostly male (39/45), aged 14 months to 49 years, with primary testicular tumors (37/39), or primary mediastinal pure YSTs (2/39). All 6 primary tumors occurring in females (6/45) were pure ovarian YSTs; age range was 4 to 72 years. HNF1β nuclear reactivity was seen in the YST component in all 49 tumors, with a moderate to strong nuclear pattern of staining. Embryonal carcinoma (EC, 0/32) and seminoma (0/6) were negative. Choriocarcinoma (6/6) showed faint focal cytoplasmic reactivity to HNF1β but no nuclear staining. In teratomas, only enteric-type glands showed nuclear reactivity to HNF1β (11/16). Therefore, HNF1β sensitivity in YST component identification was 100% and specificity was 80%. Thus, in our experience, HNF1β is a sensitive and reliable marker of the YST component in GCT, and allows distinction of YST from intricately admixed EC, especially in the diffuse embryoma pattern.

Supplemental material, Appendix G for Fetal Anthropometric Features: A Postmortem Study of Fetuses After the Termination of Pregnancy for Psychosocial Reasons Between 12 and 20 Gestational Weeks by Anne-Claude Muller Brochut, Patrick Taffe, Romain Piaget-Rossel, Laurence de Leval and Anne-Laure Rougemont in Pediatric and Developmental Pathology

Supplemental material, Appendix D for Fetal Anthropometric Features: A Postmortem Study of Fetuses After the Termination of Pregnancy for Psychosocial Reasons Between 12 and 20 Gestational Weeks by Anne-Claude Muller Brochut, Patrick Taffe, Romain Piaget-Rossel, Laurence de Leval and Anne-Laure Rougemont in Pediatric and Developmental Pathology

OBJECTIVES Open arterial revascularization using venous segments is frequently associated with the development of intimal hyperplasia (IH), leading to severe restenosis and graft failure. The lack of treatment to prevent this pathology is a major problem. Therefore, we generated a new porcine model, which closely mimics the clinical development of human IH, to test the therapeutic potential of candidate drugs. METHODS A patch of jugular vein was sutured to the right common carotid artery of pigs, to expose the vein to haemodynamic conditions of the arterial bed. Four weeks after surgery, the operated vessels which received no further treatment (the control group) were compared with (i) contralateral, non-operated vessels (the healthy group); (ii) vessels of pigs that received a perivascular application of a drug-free microparticle gel (the placebo group) and (iii) vessels of pigs that perioperatively received the same gel loaded with 10-mg atorvastatin (the atorvastatin group). RESULTS When compared with non-operated vessels, all operated segments displayed a sizable IH which was thicker in the venous patch than in the host artery. These alterations were associated with a thickening of the intima layer of both vessels in the absence of inflammation. The intima/media ratio has been significantly increased by 2000-fold in the vein patches. Perivascular application of atorvastatin did not prevent IH formation. However, the drug increased the adventitial neovascularization in the operated vessels. CONCLUSIONS The novel porcine model allows for monitoring IH formation under haemodynamic conditions which mimic clinical situations. It should facilitate the screening of innovative treatments to prevent restenosis.

Malignant or nonmalignant lymphoproliferative disorders together with repeated ear, nose, and throat infections should strongly motivate immunologic investigations. Indeed, we report a 7-year-old patient with a history of persistent abdominal symptoms along with recurrent ear, nose, and throat infections, who presented with intra-abdominal masses highly suggestive of a diagnostic of lymphoma, and who was diagnosed with activated-PI3K-delta syndrome, a recently described primary immunodeficiency prone to lymphoproliferation.

Although rare, masses and mass-like lesions of developmental and genetic origin may affect the paediatric craniofacial skeleton. They represent a major challenge in clinical practice because they can lead to functional impairment, facial deformation and disfigurement. The most common lesions include fibrous dysplasia, dermoid cysts, vascular malformations and plexiform neurofibromas. Less common lesions include torus mandibularis and torus palatinus, cherubism, nevoid basal cell carcinoma syndrome, meningoencephalocele and nasal sinus tract. This article provides a comprehensive approach for the evaluation of children with masses or mass-like lesions of developmental and genetic origin affecting the craniofacial skeleton. Typical findings are illustrated and the respective roles of computed tomography (CT), cone beam CT (CBCT), magnetic resonance imaging (MRI) with diffusion-weighted imaging (DWI) sequences and ultrasonography (US) are discussed for the pre-therapeutic assessment, complex treatment planning and post-treatment surveillance. Key imaging findings and characteristic clinical manifestations are reviewed. Pitfalls of image interpretation are addressed and how to avoid them. • Masses of developmental and genetic origin may severely impair the craniofacial skeleton. • Although rare, these lesions have characteristic imaging features. • CT, MRI and ultrasonography play a key role in their work-up. • Recognition of pivotal imaging pearls and diagnostic pitfalls avoids interpretation errors.

Supplemental material, Appendix C for Fetal Anthropometric Features: A Postmortem Study of Fetuses After the Termination of Pregnancy for Psychosocial Reasons Between 12 and 20 Gestational Weeks by Anne-Claude Muller Brochut, Patrick Taffe, Romain Piaget-Rossel, Laurence de Leval and Anne-Laure Rougemont in Pediatric and Developmental Pathology

Background: Methadone maintenance treatments (MMTs) are the commonest substitution treatments offered to opiate addiction in Switzerland, in order to reduce criminal behaviour, infectious disease transmission and overdose death. Method: To investigate the relationship between the increase in the number of methadone maintenance treatments, criminal activity of addicts and overdose-related deaths, an ecological study was undertaken in the Canton of Geneva, from 1983 to 1999. Results: The regular and extensive increase in the number of MMTs is not significantly associated, during the 1983–1999 period, with a fall either in drug addict incarcerations or in overdose-related deaths. However, a slight decrease is observed in the number of imprisoned opiate addicts since 1994, and a marked decrease is seen in overdose deaths from 1997 on. An important and stable number of these deaths is due to methadone itself. Conclusion: Public health objectives to diminish delinquency and overdose deaths cannot solely be fulfilled by extensive use of MMTs. A positive result could appear when access to MMT is highly favoured. This hypothesis must be proved correct by observational studies conducted on a general population.

Tracheal agenesis is a rare and often lethal congenital defect that leads to airway emergency at birth. Computed tomography (CT) is the modality of choice to evaluate anomalous tracheal anatomy. The absence of spontaneous aeration of the tracheobronchial tree in children with tracheal agenesis makes CT interpretation difficult. We describe a procedure of airway management applied in two newborns with suspected tracheal agenesis. Correct airway management was performed immediately prior to CT examination by airway ventilation, with bag-valve mask alone in one case, and attached to an endotracheal tube placed into the esophagus in the other case. The images allowed for classification of tracheal agenesis. Computed tomography with appropriate airway ventilation is fundamental for the diagnosis of tracheal agenesis.

Alagille syndrome (ALGS) is a complex, multisystem disease associated with mutations in the JAG1 gene. In the liver, ALGS is characterized by paucity of intrahepatic bile ducts. Gene dosage analysis performed on a large, central regenerative nodule with preserved interlobular bile ducts of 2 unrelated ALGS patients, and on surrounding cirrhotic and ductopenic liver parenchyma, showed in both cases complete JAG1 heterozygous deletion in the regenerative nodule and the ductopenic liver, with no differences in gene dosage. Thus, JAG1 mosaicism and differential haploinsufficiency do not explain the presence of bile ducts in centrally located regenerative nodules.

INTRODUCTION: Acute fibrinous and organizing pneumonia (AFOP) is a recently described histologic pattern of diffuse pulmonary disease. In children, all cases reported to date have been fatal. In this study, we describe the first nonfatal AFOP in a child and review the literature. DESCRIPTION: A 10-year-old boy developed very severe aplastic anemia (VSAA) after being admitted to our hospital with a fulminant hepatic failure of unknown origin. A chest computed tomography scan revealed multiple lung nodules and a biopsy of a pulmonary lesion showed all the signs of AFOP. Infectious workup remained negative. We started immunosuppressive therapy with antithymocyte globulin and cyclosporine to treat VSAA. Subsequent chest computed tomography scans showed a considerable diminution of the lung lesions but the VSAA did not improve until we performed hematopoietic stem cell transplantation 5 months later. CONCLUSIONS: Aplastic anemia is associated with a variety of autoimmune syndromes. The sequence of events in our patient suggests that the hepatic failure, AFOP, and the VSAA may all have been part of an autoimmune syndrome. AFOP could be the result of immune dysregulation in this pediatric case with favorable outcome after immunosuppressive therapy and hematopoietic stem cell transplantation.