Circulating tumor DNA (ctDNA) is a powerful tool for the molecular characterization of cancer. The most frequent pediatric kidney tumors (KT) are Wilms’ tumors (WT), but other diagnoses may occur. ...According to the SIOP strategy, in most countries pediatric KT have a presumptive diagnosis of WT if they are clinically and radiologically compatible. The histologic confirmation is established after post‐chemotherapy nephrectomy. Thus, there is a risk for a small fraction of patients to receive neoadjuvant chemotherapy that is not adapted to the disease. The aim of this work is to perform molecular diagnosis of pediatric KT by tumor genetic characterization based on the analysis of ctDNA. We analyzed ctDNA extracted from plasma samples of 18 pediatric patients with KT by whole‐exome sequencing and compared the results to their matched tumor and germline DNA. Copy number alterations (CNAs) and single nucleotide variations (SNVs) were analyzed. We were able to detect tumor cell specific genetic alterations—CNAs, SNVs or both—in ctDNA in all patients except in one (for whom the plasma sample was obtained long after nephrectomy). These results open the door to new applications for the study of ctDNA with regards to the molecular diagnosis of KT, with a possibility of its usefulness for adapting the treatment early after diagnosis, but also for disease monitoring and follow up.
What's new?
The analysis of cell‐free DNA (cfDNA) in pediatric patients with kidney tumors is of interest for the molecular diagnosis and early identification of aggressive disease subtypes. In this study, significant amounts of circulating tumor DNA (ctDNA) were successfully isolated from pediatric patients with malignant kidney tumors. Accurate copy number profile and mutation calling to identify specific tumor cell genetic alterations was performed with whole‐exome sequencing using only low volumes of blood (≥100 μL) and low amounts of cfDNA (≥4 ng). The findings suggest that ctDNA analysis can facilitate the molecular diagnosis of specific subtypes of pediatric kidney tumors, potentially enabling earlier treatment.
We report the case of a 5‐year‐old girl with congenital right‐sided facial hemihypertrophy and right hemi‐macroglossia with lingual mucosal neuromas. The segmental presentation of findings suggested ...the diagnosis of congenital infiltrating lipomatosis of the face (CILF), which belongs within the PIK3CA‐related overgrowth spectrum (PROS). This was confirmed by genetic analysis showing a mosaic mutation in PIK3CA H1047R. CILF/PROS should be considered in the differential diagnosis of mucosal neuromas.
In Hirschsprung's disease (HSCR), postoperative course remains unpredictable. Our aim was to define predictive factors of the main postoperative complications: obstructive symptoms (OS) and ...Hirschsprung-associated enterocolitis (HAEC). In this prospective multicentre cohort study, samples of resected bowel were collected at time of surgery in 18 neonates with short-segment HSCR in tertiary care hospitals. OS and HAEC were noted during postoperative follow-up. We assessed the enteric nervous system and the intestinal epithelial barrier (IEB) in ganglionic segments by combining immunohistochemical, proteomic and transcriptomic approaches, with functional ex vivo analysis of motility and para/transcellular permeability. Ten HSCR patients presented postoperative complications (median follow-up 23.5 months): 6 OS, 4 HAEC (2 with OS), 2 diarrhoea (without OS/HAEC). Immunohistochemical analysis showed a significant 41% and 60% decrease in median number of nNOS-IR myenteric neurons per ganglion in HSCR with OS as compared to HSCR with HAEC/diarrhoea (without OS) and HSCR without complications (p = 0.0095; p = 0.002, respectively). Paracellular and transcellular permeability was significantly increased in HSCR with HAEC as compared to HSCR with OS/diarrhoea without HAEC (p = 0.016; p = 0.009) and HSCR without complications (p = 0.029; p = 0.017). This pilot study supports the hypothesis that modulating neuronal phenotype and enhancing IEB permeability may treat or prevent postoperative complications in HSCR.
Aim
Angiomatosis of soft tissue (AST) is a rare, high‐flow, intramuscular vascular anomaly. In the context of PTEN hamartoma tumour syndrome (PHTS), this AST is referred to as PTEN hamartoma of soft ...tissue. Given that AST is observed in patients with no history of PHTS, we hypothesised that non‐syndromic AST arises as a consequence of a somatic mutation.
Methods and results
Thirteen patients with histologically confirmed AST were retrospectively studied. Details of the patients’ personal and family medical histories and symptoms were retrieved from their medical records. The histological analyses were reviewed and a tissue sample was used for genetic testing. Somatic mutations in the PIK3CA gene (p.Glu542Lys; p.Glu545Lys; p.His1047Arg) were identified in the tissue samples from seven patients, all of whom had unremarkable medical histories and had presented with a single lesion located in the lower limb. Five pathogenic variations in the PTEN gene (mutations: p.Lys263Arg; c.1026+2T>A; p.Ala126Thr; p.Leu108Arg; deletion, log ratio −0.55) were identified in the lesions of four patients; two of the latter had multifocal lesions. All four patients displayed macrocephaly, three boys presented with penile freckles, but none had a family history of PHTS. There were no histological differences between the PIK3CA and PTEN groups.
Conclusions
AST can be related to either PTEN or PIK3CA mutations and may be multifocal in PHTS. AST appears to be a manifestation of PHTS that occurs in early childhood. The patient's medical history and clinical presentation should prompt the physician to perform specific genetic testing.
Introduction
Prognosis of dumbbell neuroblastoma (NBL) is mainly determined by the sequelae induced by the tumor itself and the neurosurgical approach. However, after primary chemotherapy, surgical ...management of the residual tumor, especially the spinal canal component, remains controversial.
Methods
We conducted a single‐center retrospective cohort study over the last 15 years (2002–2017) including patients treated for NBL with spinal canal extension focusing on timing and type of surgery, complications, and functional and oncological follow‐up.
Results
Thirty‐two children (14 M, 18 F) were managed for NBL, with the majority (26) presenting with NBL stroma poor while four had ganglioneuroblastoma intermixed, one nodular, and one ganglioneuroma. All but two patients received neoadjuvant chemotherapy. Upfront laminotomy for spinal cord decompression was performed in two patients; nine patients had extraspinal surgery with a follow‐up neurosurgical procedure in seven cases; eight patients had initial neurosurgery followed by an extraspinal procedure, while six patients underwent a combined multidisciplinary approach. With a median follow up of 3.6 years (0.1–14.9), 29 patients (90.6) are alive and two out of three (19, 65.5%) have functional sequelae.
Conclusion
Patients with NBL with persistent spinal canal extension of the tumor after neoadjuvant chemotherapy treated at our center had outcomes that compare favorably with the literature. This is likely due to the multidisciplinary approach to optimal surgical strategy and continuous evaluation of the respective risks of tumor progression. Neurological disability results from initial spinal cord compression or the radicular sacrifice required for tumor resection.
Pulmonary hypertension is a rare but important cause of mortality after haematopoietic stem cell transplantation (HSCT) in children. This complication is poorly characterised in the literature. We ...report here a series of children who developed pulmonary hypertension after HSCT.
Between January 2008 and December 2015, we retrospectively analysed 366 children who underwent HSCT (age range 0.5-252 months; median 20.3 months). During the post-HSCT course, echocardiography scans motivated by respiratory symptoms identified 31 patients with elevated tricuspid regurgitation velocity (>2.8 m·s
), confirmed when possible by right heart catheterisation (RHC).
22 patients had confirmed pulmonary hypertension with mean±sd pulmonary arterial pressure 40.1±10 mmHg (range 28-62 mmHg) and pulmonary vascular resistance 17.3±9.2 Wood Units (range 8-42 Wood Units). Among the 13 responders at reactivity test, only one patient responded to calcium channel blockers. Seven patients (32%) died. 15 pulmonary hypertension patients were alive after a mean±sd follow-up of 6.5±2.3 years (range 2-10 years). All survivors could be weaned off pulmonary hypertension treatment after a median follow-up of 5 months (range 3-16). The delay between clinical symptoms and initiation of pulmonary hypertension therapy was significantly longer in patients who subsequently died (mean±sd 33.5±23 days; median 30 days) than in survivors (mean±sd 7±3 days) (p<0.001).
Pulmonary hypertension is a severe complication of HSCT with an underestimated incidence and high mortality. Aggressive and timely up-front combination therapy allowed normalisation of pulmonary pressure and improved survival.
CIC-fused sarcomas represent an emerging family of tumors, for long connected to the Ewing family group of tumors, but underlined by distinct CIC fusions with different partners. 3′ Fusion partners ...include DUX4, FOXO4, and, as recently emphasized, NUTM1. In this study, we report the clinicopathologic and molecular features of a series of 6 CIC-NUTM1 sarcomas. Mean age at diagnosis was 6 years (2 to 27 y), and 4 patients were male individuals. Primary tumors were located in the central nervous system (n=3), paravertebral soft tissue and epidural spaces (n=1, each), and lung (n=1). Median overall survival was 17.5 months (7 to 37 mo), and all but one patient died of disease. All tumors displayed classic features of CIC-DUX4 sarcomas with round cell to epithelioid microscopic appearance. Most tumors expressed ETV4 and NUTM1 (n=5/6 and 6/6, respectively), whereas WT1cter was positive in only 2 cases. All tested tumors were positive for break-apart fluorescence in situ hybridization for CIC and NUTM1. Apart from CIC or NUTM1 genomic breakpoints, no other recurrent copy number alteration was seen on genomic profiles. Fusion transcripts were identified by RNA-sequencing on either formalin-fixed paraffin-embedded or frozen material. CIC and NUTM1 breakpoints were located between exons 16 and 20 and exons 2 and 5, respectively. Altogether, CIC-NUTM1 sarcomas represent a new molecular variant of CIC-fused sarcomas with a predilection for the central nervous system and younger pediatric population. Its phenotype may be confused with NUT carcinomas.
This study investigated relationships between neuroblastomas (NBs) imaging phenotypes, tumor genomic profile and patient outcome.
This IRB-approved retrospective observational study included 133 NB ...patients (73 M, 60 F; median age 15 months, range 0-151) treated in a single institution between 1998 and 2012. A consensus review of imaging (CT-scan, MRI) categorized tumors according to both the primarily involved compartment (i.e., neck, chest, abdomen or pelvis) and the sympathetic anatomical structure the tumors rose from (i.e., cervical, paravertebral or periarterial chains, or adrenal gland). Tumor shape, volume and image-defined surgical risk factors (IDRFs) at diagnosis were recorded. Genomic profiles were assessed using array-based comparative genomic hybridization and divided into three groups: "numerical-only chromosome alterations" (NCA), "segmental chromosome alterations" (SCA) and "MYCN amplification" (MNA). Statistical analyses included Kruskal-Wallis, Chi2 and Fisher's exact tests and the Kaplan-Meier method with log-rank tests and Cox model for univariate and multivariate survival analyses.
A significant association between the sympathetic structure origin of tumors and genomic profiles was demonstrated. NBs arising from cervical sympathetic chains were all NCA. Paravertebral NBs were NCA or SCA in 75% and 25%, respectively and none were MNA. Periarterial NBs were NCA, SCA or MNA in 33%, 56% and 11%, respectively. Adrenal NBs were NCA, SCA or MNA in 16%, 36% and 48%, respectively. Among MNA NBs, 92% originated from the adrenal gland. The sympathetic anatomical classification was significantly better correlated to overall survival than the compartmental classification (P < .0003). The tumor volume of MNA NBs was significantly higher than NCA or SCA NBs (P < .0001). Patients with initial volume less than 160 mL had significantly better overall survival (P < .009). A "single mass" pattern was significantly more frequent in NCA NBs (P = .0003). The number of IDRFs was significantly higher in MNA NBs (P < .0001).
Imaging phenotypes of neuroblastomas, including tumor origin along the sympathetic system, correlate with tumor genomic profile and patient outcome.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
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