AGAP3: A novel BRAF fusion partner in pediatric pancreatic-type acinar cell carcinoma.

Most available molecular data on pancreatic acinar cell carcinoma (PACC) are provided by studies of adult cases. BRAF, RAF1, or RET rearrangements have been described in approximately 30% of cases. To the best of our knowledge, only seven cases with molecular data have been reported in pediatric PACC. We report here the comprehensive study of a pancreatic-type ACC from a 6-year-old patient. We detected an AGAP3::BRAF fusion. This result showing a BRAF rearrangement demonstrates a molecular link between adult and pediatric PACC. Moreover, it identifies AGAP3, a gene located at 7q36.1 that encodes a major component of the N-methyl-d-aspartate (NMDA) receptor signaling complex, as a partner gene of BRAF. The variability of BRAF partners is consistent with a driver role of BRAF alterations in PACC. The identification of such alterations is noteworthy for considering the use of MEK inhibitors in metastatic cases. We did not detect associated genomic instability. The better outcome of pediatric cases might be related to their stable genomic background.

High-dose chemotherapy followed by autologous stem cell rescue in Wilms tumors: French report on toxicity and efficacy.

BACKGROUND: Heterogeneous data have been reported on high-dose chemotherapy (HDCT) with autologous stem cell rescue (ASCR) in Wilms tumors (WTs). We aimed to define its safety and efficacy in the French cohort, and to compare this management to current international recommendations. METHODS: Data prospectively collected from children, adolescents, and young adults with WT treated with HDCT/ASCR between 2000 and 2016 in French centers were retrospectively analyzed. Toxicity was reported according to CTCAE v4.03. RESULTS: Fifty-four patients received HDCT/ASCR (first line, n = 13; recurrence, n = 41). Their median age at the time of ASCR was 5.3 years (range 2.2-21.6). Main nonhematological acute grades 3-4 toxicities were digestive and renal. No significant difference of toxicity rate was observed among HDCT regimens and schedules. Two patients died shortly after ASCR (renal and multiorgan failure), and one heavily pretreated patient died of late respiratory failure. The selection criteria applied to define those patients eligible for HDCT/ASCR retrospectively matched to those currently used in the International Society of Pediatric Oncology (SIOP) UMBRELLA protocol for 38 patients, with encouraging survival rates compared to published data. The objective response rate to HDCT was 21%, with a disease control rate after HDCT of 85%. After a median follow-up of 7 years, the 5-year event-free survival (EFS) and overall survival (OS) were 54% (95% CI: 32%-76%) and 62% (95% CI: 31%-82%) for frontline patients, and 57% (95% CI: 39%-71%) and 69% (95% CI: 52%-81%) at recurrence. CONCLUSION: HDCT was feasible and showed encouraging results in well-defined settings. Data from the current prospective protocol will help to better evaluate HDCT impact on survival.

Genotype-Phenotype Relationships in Inheritable Idiopathic Pulmonary Fibrosis: A Greek National Cohort Study.

BACKGROUND: Monogenic and polygenic inheritances are evidenced for idiopathic pulmonary fibrosis (IPF). Pathogenic variations in surfactant protein-related genes, telomere-related genes (TRGs), and a single-nucleotide polymorphism in the promoter of MUC5B gene encoding mucin 5B (rs35705950 T risk allele) are reported. This French-Greek collaborative study, Gen-Phen-Re-GreekS in inheritable IPF (iIPF), aimed to investigate genetic components and patients' characteristics in the Greek national IPF cohort with suspected heritability. PATIENTS AND METHODS: 150 patients with familial PF, personal-family extrapulmonary disease suggesting short telomere syndrome, and/or young age IPF were analyzed. RESULTS: MUC5B rs35705950 T risk allele was detected in 103 patients (90 heterozygous, 13 homozygous, allelic frequency of 39%), monoallelic TRG pathogenic variations in 19 patients (8 TERT, 5 TERC, 2 RTEL1, 2 PARN, 1 NOP10, and 1 NHP2), and biallelic ABCA3 pathogenic variations in 3. Overlapping MUC5B rs35705950 T risk allele and TRG pathogenic variations were shown in 11 patients (5 TERT, 3 TERC, 1 PARN, 1 NOP10, and 1 NHP2), MUC5B rs35705950 T risk allele, and biallelic ABCA3 pathogenic variations in 2. In 38 patients, neither MUC5B rs35705950 T risk allele nor TRG pathogenic variations were detectable. Kaplan-Meier curves showed differences in time-to-death (p = 0.025) where patients with MUC5B rs35705950 T risk allele alone or in combination with TRG pathogenic variations presented better prognosis. CONCLUSION: The Gen-Phen-Re-GreekS in iIPF identified multiple and overlapping genetic components including the rarest, underlying disease's genetic "richesse," complexity and heterogeneity. Time-to-death differences may relate to diverse IPF pathogenetic mechanisms implicating "personalized" medical care driven by genotypes in the near future.

Characteristics and outcome of pediatric renal cell carcinoma patients registered in the International Society of Pediatric Oncology (SIOP) 93-01, 2001 and UK-IMPORT database: A report of the SIOP-Renal Tumor Study Group.

In children, renal cell carcinoma (RCC) is rare. This study is the first report of pediatric patients with RCC registered by the International Society of Pediatric Oncology-Renal Tumor Study Group (SIOP-RTSG). Pediatric patients with histologically confirmed RCC, registered in SIOP 93-01, 2001 and UK-IMPORT databases, were included. Event-free survival (EFS) and overall survival (OS) were analyzed using the Kaplan-Meier method. Between 1993 and 2019, 122 pediatric patients with RCC were registered. Available detailed data (n = 111) revealed 56 localized, 30 regionally advanced, 25 metastatic and no bilateral cases. Histological classification according to World Health Organization 2004, including immunohistochemical and molecular testing for transcription factor E3 (TFE3) and/or EB (TFEB) translocation, was available for 65/122 patients. In this group, the most common histological subtypes were translocation type RCC (MiT-RCC) (36/64, 56.3%), papillary type (19/64, 29.7%) and clear cell type (4/64, 6.3%). One histological subtype was not reported. In the remaining 57 patients, translocation testing could not be performed, or TFE-cytogenetics and/or immunohistochemistry results were missing. In this group, the most common RCC histological subtypes were papillary type (21/47, 44.7%) and clear cell type (11/47, 23.4%). Ten histological subtypes were not reported. Estimated 5-year (5y) EFS and 5y OS of the total group was 70.5% (95% CI = 61.7%-80.6%) and 84.5% (95% CI = 77.5%-92.2%), respectively. Estimated 5y OS for localized, regionally advanced, and metastatic disease was 96.8%, 92.3%, and 45.6%, respectively. In conclusion, the registered pediatric patients with RCC showed a reasonable outcome. Survival was substantially lower for patients with metastatic disease. This descriptive study stresses the importance of full, prospective registration including TFE-testing.

A Spontaneously Necrotic Wilms' Tumor Mimicking Renal Abscess: A Tricky Diagnosis not to Miss.

Wilms' tumor (WT) is the most common renal malignancy in children. Its clinical and radiologic presentation may mimic other pediatric renal diseases, including pyonephrosis or renal abscess. The authors report a case of a 3-year-old girl presenting with pyelonephritis and right renal mass suggestive of a renal abscess, not responding to antibiotics. Further investigations were conducted, including a percutaneous renal needle core biopsy. A stage I fully necrotic WT was finally diagnosed. This amazing case of a fully necrotic WT at diagnosis demonstrates the importance of anatomopathologic analyses in pediatric renal masses, even when the infection is suspected.

Functional assessment and phenotypic heterogeneity of SFTPA1 and SFTPA2 mutations in interstitial lung diseases and lung cancer.

INTRODUCTION: Interstitial lung diseases (ILDs) can be caused by mutations in the SFTPA1 and SFTPA2 genes, which encode the surfactant protein (SP) complex SP-A. Only 11 SFTPA1 or SFTPA2 mutations have so far been reported worldwide, of which five have been functionally assessed. In the framework of ILD molecular diagnosis, we identified 14 independent patients with pathogenic SFTPA1 or SFTPA2 mutations. The present study aimed to functionally assess the 11 different mutations identified and to accurately describe the disease phenotype of the patients and their affected relatives. METHODS: The consequences of the 11 SFTPA1 or SFTPA2 mutations were analysed both in vitro, by studying the production and secretion of the corresponding mutated proteins and ex vivo, by analysing SP-A expression in lung tissue samples. The associated disease phenotypes were documented. RESULTS: For the 11 identified mutations, protein production was preserved but secretion was abolished. The expression pattern of lung SP-A available in six patients was altered and the family history reported ILD and/or lung adenocarcinoma in 13 out of 14 families (93%). Among the 28 SFTPA1 or SFTPA2 mutation carriers, the mean age at ILD onset was 45 years (range 0.6-65 years) and 48% underwent lung transplantation (mean age 51 years). Seven carriers were asymptomatic. DISCUSSION: This study, which expands the molecular and clinical spectrum of SP-A disorders, shows that pathogenic SFTPA1 or SFTPA2 mutations share similar consequences for SP-A secretion in cell models and in lung tissue immunostaining, whereas they are associated with a highly variable phenotypic expression of disease, ranging from severe forms requiring lung transplantation to incomplete penetrance.

Pulmonary giant chondromatous hamartoma with multifocal evolution in an infant.

Hamartoma is the most common benign pulmonary tumor in adults, but is rarely described in the pediatric population. Giant chondromatous and progressive forms are even rarer. We report the novel case of a 13-month-old infant hospitalized for giant pulmonary chondromatous hamartoma discovered during a septic episode, rapidly progressive, with severe multifocal lesions, without clear response to several cytotoxic therapies. No predisposition syndrome was identified.

Liver metastasis at diagnosis in children with nephroblastoma enrolled in SIOP2001 protocol: A French multicentric study.

BACKGROUND: Liver metastases are rare in children with Wilms tumor (WT), and their impact on the outcome is unclear. PATIENTS AND METHODS: The French cohort of patients with WT presenting liver metastases at diagnosis and enrolled in the International Society of Pediatric Oncology (SIOP) 2001 study was reviewed. RESULTS: From 2002 to 2012, 906 French patients were enrolled in the SIOP2001 trial. Among them, 131 (14%) presented with stage IV WT and 18 (1.9%) had liver metastases at diagnosis. Isolated liver metastases were displayed in four of them. After preoperative chemotherapy, persistent liver disease was reported in 14/18 patients, and 13 of them underwent metastasectomy after nephrectomy. In resected liver lesions, the same histology of the primary tumor was reported for three patients, blastemal cells without anaplasia were identified in one patient with DA-WT, and post-chemotherapy necrosis/fibrosis was identified for the other 10 patients. For the four patients who had liver and lung surgery, both sites had nonviable cells with post-chemotherapy necrosis/fibrosis. Six patients had hepatic radiotherapy. Sixteen patients achieved primary complete remission and were alive at the last follow-up (median follow-up: 6.4 years). The only two deceased patients presented diffuse anaplasia histology. The five-year EFS and OS were 83% (60%-94%) and 88% (66%-97%), respectively. CONCLUSION: Liver involvement does not appear to be an adverse prognostic factor in metastatic WT. The role of hepatic surgery and radiotherapy remains unclear, and should be carefully considered in case of persistent liver metastases, according to histology and radiological response to other metastatic sites.

Is radiotherapy required in first-line treatment of stage I diffuse anaplastic Wilms tumor? A report of SIOP-RTSG, AIEOP, JWiTS, and UKCCSG.

BACKGROUND: As a significant proportion of relapses occurred in the tumor bed or abdomen on patients with the fifth National Wilms Tumor Study stage I anaplastic Wilms tumor (WT), flank radiotherapy was added for stage I anaplastic WT in the subsequent study of the Children's Oncology Group (AREN0321). Preliminary results revealed reduction of relapse rate and improved survival. In cases treated with preoperative chemotherapy, such as in International Society of Pediatric Oncology (SIOP), the value of radiotherapy has never been studied. The aim of this observational study is to describe the pattern of recurrence and survival of patients with stage I diffuse anaplastic WT (DAWT) after induction chemotherapy. METHODS: Retrospective data analysis of the pattern of relapse and survival of all patients with stage I DAWT were included in recent SIOP, L'Associazone Italiana Ematologica Oncologia Pediatrica (AIEOP), Japan Wilms Tumor Study Group (JWiTS), United Kingdom Children's Cancer Study Group (UKCCSG) renal tumor registries. Postoperative treatment consisted of actinomycin D, vincristine, and doxorubicin for 28 weeks without local irradiation. RESULTS: One hundred nine cases with stage I DAWT were identified, of which 95 cases received preoperative chemotherapy. Of these, seven patients underwent preoperative true-cut biopsy. Sixteen of the 95 patients relapsed (17%), six locally, four at distant site, and six combined, and all treated according to SIOP 2001 relapse protocol, which resulted in a 5-year overall survival of 93%. CONCLUSION: Despite 13% locoregional relapse rate, an excellent rescue rate was achieved after salvage treatment, in patients with stage I DAWT whose first-line treatment comprised three-drug chemotherapy (including doxorubicin), without flank irradiation. Therefore, we continue not to advocate the use of radiotherapy in first-line treatment after preoperative chemotherapy in stage I DAWT in the next SIOP protocol.

Germline SFTPA1 mutation in familial idiopathic interstitial pneumonia and lung cancer.

Idiopathic interstitial pneumonias (IIPs) comprise a heterogeneous group of rare lung parenchyma disorders with high morbidity and mortality, which can occur at all ages. In adults, the most common form of IIPs, idiopathic pulmonary fibrosis (IPF), has been associated with an increased frequency of lung cancer. The molecular basis of IIPs remains unknown in most cases. This study investigates IIP pathophysiology in 12 families affected by IPF and lung cancer. We identified, in a multigenerational family, nine members carrying a heterozygous missense mutation with evidence of pathogenicity in SFTPA1 that encodes the surfactant protein (SP)-A1. The mutation (p.Trp211Arg), which segregates with a disease phenotype characterized by either isolated IIP/IPF, or IPF associated with lung adenocarcinoma, is located in the carbohydrate recognition domain (CRD) of SP-A1 and involves a residue invariant throughout evolution, not only in SP-A1, but also in its close paralog SP-A2 and other CRD-containing proteins. As shown through functional studies, the p.Trp211Arg mutation impairs SP-A1 secretion. Immunohistochemistry studies on patient alveolar epithelium showed an altered SP-A expression pattern. Overall, this first report of a germline molecular defect in SFTPA1 unveils the key role of SP-A1 in the occurrence of several chronic respiratory diseases, ranging from severe respiratory insufficiency occurring early in life to the association of lung fibrosis and cancer in adult patients. These data also clearly show that, in spite of their structural and functional similarities, SP-A1 and SP-A2 are not redundant.

The clinical phenotype of YWHAE-NUTM2B/E positive pediatric clear cell sarcoma of the kidney.

Clear cell sarcoma of the kidney (CCSK) although uncommon, is the second most frequent renal malignancy of childhood. Until now, the sole recurrent genetic aberration identified in CCSKs is t(10;17)(q22;p13), which gives rise to a fusion transcript of YWHAE and NUTM2B/E. So far, the clinical relevance of this fusion transcript is unknown. The aim of this descriptive study was to determine the clinical phenotype of t(10;17)(q22;p13) positive CCSKs. Snap-frozen tissues, formalin-fixed paraffin-embedded tissues or RNA previously extracted from CCSK samples throughout European, North-American and Japanese study groups were screened by RT-PCR for the YWHAE-NUTM2B/E transcript. Clinical characteristics, tumor characteristics, and outcome of patients with and without the fusion transcript were studied. The cohort comprised 51 previously published cases to which were added 139 internationally collected CCSK samples. RNA from 57 of these additionally collected cases was of sufficient quality to be successfully screened for the YWHAE-NUTM2B/E transcript. In total, seven of the 108 cases harbored the fusion transcript. Patients with tumors containing the fusion transcript were relatively young (median age 10 months), had associated low median tumor volumes and stage I disease was not observed in these patients. Two of seven patients relapsed and one of seven patients died of disease. Ranges of values were not overtly different between patients with and without the fusion transcript; however, the number of fusion transcript positive cases turned out to be too small to permit reliable statistical analysis. The current study did not identify an explicit clinical phenotype of CCSK cases harboring the YWHAE-NUTM2B/E fusion transcript.

Varying proliferative and clonogenic potential in NRAS-mutated congenital melanocytic nevi according to size.

Congenital melanocytic nevi (CMN) are benign proliferations that may be associated with various consequences depending on their size. They are characterized by a specific molecular signature, namely a postzygotic somatic NRAS or BRAF mutation. We have recently reported that large CMN (lCMN), which are classically associated with an increased melanoma risk, harbour cell subpopulations with specific clonogenic and tumorigenic potential. We wished to ascertain whether cells displaying similar properties persisted postnatally in medium CMN (mCMN). Eighteen medium M1, nine large and one giant NRAS-mutated CMN were prospectively included in the study. Subpopulations of mCMN cells expressed stem cell/progenitor lineage markers such as Sox10, nestin and Oct4, as was the case in lCMN. Nevertheless, conversely to lCMN, mCMN cells with clonogenic properties were rarer. In vitro, approximatively one in 1500 cells isolated from fresh mCMN formed colonies that could be passaged. In vivo, mCMN seemed to harbour cells with less proliferative potential than the larger lesions as lCMN biopsies displayed a threefold expansion compared to mCMN when xenografted in Rag2(-/-) mice. Thus, our data revealed variations in clonogenicity and tumorigenic properties in NRAS-mutated CMN according to size.

Is Nephron Sparing Surgery Justified in Wilms Tumor With Beckwith-Wiedemann Syndrome or Isolated Hemihypertrophy?

BACKGROUND: Patients with Beckwith-Wiedemann syndrome (BWS) or isolated hemihypertrophy (HH) treated for a Wilms tumor (WT) carry an increased risk of developing metachronous lesion. There are no guidelines on precise indications for nephron sparing surgery (NSS) in unilateral WT (UWT). The objective of this retrospective study was to delineate the indications of NSS in patients with BWS/HH treated for WT and to evaluate their outcome. PROCEDURE: All cases of BWS/HH treated for a WT according to SIOP protocols from 1980 to 2013 were reviewed. Patients were divided into two groups (G): isolated UWT (G1) and bilateral lesions (G2) with two subgroups: bilateral tumors suspected of malignancy (G2a), and unilateral tumor suspected of malignancy with contralateral nephroblastomatosis (G2b). RESULTS: Forty-six patients were included (34 G1, three G2a, and nine G2b). Nine NSS and 25 total nephrectomies (TN) were performed in G1, two bilateral NSS and one NSS with contralateral TN in G2a, and eight NSS and one TN in G2b. The 3-year event-free survival was 92.3% (95% CI [77.9-97.5%]). One death occurred after a local relapse following a TN for a stage III stromal WT (G1) and another after a combined local and distant relapse following a NSS for a stage I diffuse anaplastic WT (G2b). There were two metachronous WT (4%), 3 years after a TN (G1) and 12 years after a NSS (G2b). CONCLUSIONS: NSS is recommended in bilateral WT and may be an option in selected UWT patients with BWS/HH because it was not associated with an increased risk of local relapse.

Acinar Dysplasia in a Full-Term Newborn with a NKX2.1 Variant.

Acinar dysplasia (AcDys) is one of the three main diffuse developmental disorders of the lung. The transcription factor NK2 homeobox 1 (NKX2.1) partly controls the synthesis of surfactant proteins by type 2 alveolar epithelial cells (AEC2), and germline mutations are known to be associated with brain-lung thyroid syndrome. We report the case of a full-term neonate who developed refractory respiratory failure with pulmonary hypertension requiring venoarterial extracorporeal membrane oxygenation. Histological examination of the lung biopsy specimen was consistent with the diagnosis of AcDys. Molecular analyses led to the identification of the missense heterozygous variant in NKX2.1 (NM_001079668) c.731A>G p.(Tyr244Cys), which is predicted to be pathogenic. After 5 weeks, because AcDys is a fatal disorder and the patient's status worsened, life-sustaining therapies were withdrawn, and she died after a few hours. This study is the first to extend the phenotype of NKX2.1 pathogenic variant, to a fatal form of AcDys.

Lung biopsies in infants and children in critical care situation.

INTRODUCTION: Lung biopsy is considered as the last step investigation for diagnosing lung diseases; however, its indication must be carefully balanced with its invasiveness. The present study aims to evaluate the diagnostic yield of lung biopsy in critically ill patients hospitalized in the pediatric intensive care unit (ICU). MATERIAL AND METHODS: Children who underwent a lung biopsy in the ICU between 1995 and 2022 were included. Biopsies performed in the operating room and post-mortem biopsies were excluded. RESULTS: Thirty-one patients were included, with a median age of 18 days (2 days to 10.8 years); 21 (67.7%) were newborns. All patients required invasive mechanical ventilation, 26 (89.7%) had a pulmonary hypertension, and 22 (70.9%) were placed under extracorporeal membrane oxygenation (ECMO). The lung biopsy led to a diagnosis in 81% of the patients. The diagnostic reliability seemed to decrease with age (95% in newborns, 71% in 1 month to 2 years and 0/3 patients aged over 2 years old). Diffuse developmental disorders of the lung accounted for 15 (49%) patients, primarily alveolar capillary dysplasia, followed by surfactant disorders in 5 (16%) patients. Complications occurred in 9/31 (29%) patients including eight under ECMO, with massive hemorrhages in seven cases. DISCUSSION AND CONCLUSION: In critical situations, lung biopsy should be performed. Lung biopsy is a reliable diagnostic procedure for neonates in critical situation when a diffuse developmental disorder of the lung is suspected. The majority of lung biopsy complication was associated with the use of ECMO. The prospective evaluation of the complications of such procedure under ECMO, and particularly over 10 days of ECMO and in children over 2-year-old remains to be ascertained.

The significance of multidisciplinary team meetings in diagnosing and managing childhood interstitial lung disease within the RespiRare network.

INTRODUCTION: Childhood Interstitial Lung Disease (chILD) represents a rare and severe group of diseases for which the etiologic workup, classification, and management remain a challenge for most pediatric pulmonologists. In France in 2018, the RespiRare network established the first multidisciplinary team meetings (MDTm) dedicated to chILD. This study aims to investigate the impact of MDTm in chILD diagnosis and management as well as user satisfaction. METHODS: The MDTm took place on a monthly basis through video conferences. The participants consisted of a quorum and included pediatric pulmonologists, radiologists, geneticists, and pulmonologists, with an average of 10.5 participants per meeting. Patients provided consent to participate in MDTm and for data collection. Data were retrospectively extracted from MDTm reports. To evaluate the usefulness of the MDTm and the satisfaction of the participants, a survey was sent by email at least 3 months after the MDTm to the participants. RESULTS: A total of 216 chILD cases were discussed during 56 MDTm sessions. The median age of onset was 0.5 years (interquartile range 0-7). The MDTm sessions resulted in the correction of chILD etiology in 25% of cases (neuroendocrine cell hyperplasia of infancy 17%, surfactant metabolism disorder 8%, pulmonary alveolar proteinosis 4%, hemosiderosis 3%, sarcoidosis 3%, and others 34%), and chILD was ruled out in 7% of cases. A change in therapy was proposed for 46% of cases. User satisfaction was significant, particularly regarding their confidence in managing these rare diseases. DISCUSSION AND CONCLUSION: Dedicated MDTm sessions offer a unique opportunity to enhance chILD etiologic diagnosis and management, leading to increased physician knowledge and confidence in managing these patients.

Human CD4+ CD25+ Foxp3+ regulatory T cells do not constitutively express IL-35.

EBV-induced gene 3 (EBI3) can associate with p28 to form the heterodimeric cytokine IL-27, or with the p35 subunit of IL-12 to form the EBI3/p35 heterodimer, recently named IL-35. In mice, IL-35 has been shown to be constitutively expressed by CD4(+)CD25(+)Foxp3(+) regulatory T cells (Treg cells) and suggested to contribute to their suppressive activity. In this study, we investigated whether human Treg cells express IL-35. Double-staining analysis of human thymuses showed that neither Foxp3(+) nor CD25(+) cells coexpressed EBI3. Similarly, Foxp3(+) cells present in human lymph nodes, tonsils, spleens, and intestines did not express EBI3. Consistent with these in situ observations, Treg cells purified from blood or tonsils were negative for EBI3 by immunoblotting. Other human T cell subsets, including effector T cells, naive and memory CD4(+) T cells, CD8(+) and gammadelta T cells also did not constitutively express EBI3, which contrasts with IL-35 expression observed in murine CD8(+) and gammadelta T cells. Furthermore, although CD3/CD28 stimulation consistently induced low levels of EBI3 in various CD4(+) T cell subsets, no EBI3 could be detected in CD3/CD28-stimulated Treg cells. RT-PCR analysis showed that, whereas p35 transcripts were detected in both Teff and Treg cells, EBI3 transcripts were detected only in activated Teff cells, but not in resting or activated Treg cells. Thus, in contrast to their murine counterpart, human Treg cells do not express detectable amounts of IL-35.

Environmental exposures related to parental habits in the perinatal period and the risk of Wilms' tumor in children.

INTRODUCTION: Wilms' tumor is the most frequently diagnosed renal tumor in children. Little is known about its etiology. The aim of this study was to investigate the potential role of specific exposures related to parental habits such as parental smoking, maternal alcohol consumption and the use of household pesticides during pregnancy. METHODS: The ESTELLE study was a nationwide case-control study that included 117 Wilms' tumor cases and 1100 control children from the general French population, frequency-matched by age and gender. Unconditional logistic regression was used to estimate odds ratios and 95 % confidence intervals. RESULTS: After controlling for matching variables and potential confounders, the maternal use of any type of pesticide during pregnancy was associated with the risk of Wilms' tumor in children (OR 1.6 [95 % CI 1.1-2.3]). Insecticides were the most commonly reported type of pesticide and there was a positive association with their use (OR 1.7 [95 % CI 1.1-2.6]. The association was stronger when they were used more often than once a month (OR 1.9 [95 % CI 1.2-3.0]. Neither maternal smoking during pregnancy nor paternal smoking during preconception/pregnancy was associated with a risk of Wilms' tumor (ORs 1.1[95 % CI 0.7-1.8] and 1.1 [95 % CI 0.7-1.7], respectively). No association was observed with maternal alcohol intake during pregnancy (OR 1.2 [95 % CI 0.8-2.0]). CONCLUSION: Our findings suggest an association between the maternal use of household pesticides during pregnancy and the risk of Wilms' tumor.

Outcome of patients with stage IV high-risk Wilms tumour treated according to the SIOP2001 protocol: A report of the SIOP Renal Tumour Study Group.

INTRODUCTION: High-risk (HR) metastatic (stage IV) Wilms tumours (WTs) have a particular poor outcome. METHODS: Here, we report the results of HR (diffuse anaplastic [DA] or blastemal type [BT]) stage IV WT treated patients according to the HR arm in the SIOP2001 prospective study. RESULTS: From January 2002 to August 2014, 3559 patients with WT were included in the SIOP2001 trial. Among the 525 patients (15%) with metastatic WT, 74 (14%) had stage IV HR-WT. The median age at diagnosis was 5.5 years (range: 1.4-18.3). Thirty-four patients (47%) had BT-WT and 40 (53%) had DA-WT. Five-year event-free survival rates were 44 ± 17% and 28 ± 15% for BT-WT and DA-WT, respectively (p = 0.09). Five-year overall survival rates were 53 ± 17% and 29 ± 16% for BT-WT and DA-WT, respectively (p = 0.03). Metastatic complete response after preoperative treatment was significantly associated with outcome in univariate and multivariate analyses (hazards ratio = 0.3; p = 0.01). Postoperative radiotherapy of metastatic sites might also be beneficial. Forty-three of 74 patients experienced a relapse or progression predominantly in the lungs (80%). The median time to relapse/progression after diagnosis was 7.3 months (range: 1.6-33.3) and 4.9 months (range: 0.7-28.4) for BT-WT and DA-WT, respectively (p = 0.67). This is the first prospective evidence of inferior survival of stage IV BT-WT as compared with historical intermediate-risk WT. Survival of patients with stage IV DA-WT has not improved compared to the previous SIOP93-01 study. CONCLUSION: These results call for new treatment approaches for patients with HR stage IV WT.