Resection of primary tumor in stage 4S neuroblastoma: a second study by the Italian Neuroblastoma Group.

PURPOSE: To clarify the role of primary tumor resection in stage 4S neuroblastoma. METHODS: We investigated a cohort of 172 infants diagnosed with stage 4S neuroblastoma between 1994 and 2013. Of 160 evaluable patients, 62 underwent upfront resection of the primary tumor and 98 did not. RESULTS: Five-year progression-free and overall survival were significantly better in those who had undergone upfront surgery (83.6% vs 64.2% and 96.8% vs 85.7%, respectively). One post-operative death and four non-fatal complications occurred in the resection group. Three patients who had not undergone resection died of chemotherapy-related toxicity. Thirteen patients underwent late surgery to remove a residual tumor, without complications: all but one alive. Outcomes were better in patients diagnosed from 2000 onwards. CONCLUSION: Infants diagnosed with stage 4S neuroblastoma who underwent upfront tumor resection had a better outcome. However, this result cannot be definitely attributed to surgery, since these patients were selected on the basis of their favorable presenting features. Although the question of whether to operate or not at disease onset is still unsolved, this study confirms the importance of obtaining enough adequate tumor tissue to enable histological and biological studies to properly address treatment, to achieve the best possible outcome.

Complete Posterior Sagittal Anorectal Mobilization (PSAM): A new surgical approach for pediatric pelvic-perineal tumor resections.

INTRODUCTION: Diffuse or massive tumors involving the perineal and pelvic compartments may require aggressive surgical treatment in children. The authors, propose and present their results using a Posterior Sagittal Anorectal Mobilization (PSAM) METHODS: The oncologic patient is placed in a prone position with the pelvis elevated, without a previous colostomy. A 10 Ch bladder catheter is positioned. A midline sagittal incision is performed from the coccyx to the posterior margin of the anus. Fine electrocautery is used to obtain an accurate dissection all around the anal margin itself. The incisional so involves the midline dissection into the perineal body. Reconstruction is achieved by the classical pelvic-perineal anatomical structure approximation. RESULTS: The authors describe for the first time a novel posterior anorectal mobilization technique for four children with pelvic-perineal tumors. No intraoperative or post-operative complications occurred. The oldest boy presented at follow-up a complete normal faecal and urinary continence (Krickenbeck criteria). CONCLUSION: The presented technical approach, defined as PSAM, is completely suitable for surgical resection of perineal-pelvic tumors, without the need of more invasive operations including transpubic dissection and/or anorectal split. Moreover, nervous and muscular sphincter structures are easily identified and preserved.

Diagnostic Criteria of Pediatric Intestinal Myopathies.

The authors aim to identify criteria for the diagnosis of intestinal visceral myopathy (IVM); results were compared with ultrastructural studies. Six IVM patients and 7 pediatric control cases (without gastrointestinal diseases) were studied. One case was a typical megacystis-microcolon-intestinal hypoperistalsis syndrome. The diagnostic path included: rectal suction biopsy, one-trocar transumbilical laparoscopic intestinal full-thickness biopsy technique. Pathological analysis included anti-alpha smooth muscle actin staining, and US study of intestinal biopsies. IVM histological examination demonstrated thinning of longitudinal muscle layer. The ratio of circular/longitudinal thickness was evaluated in all samples; in cases, this ratio presented as a mean value of 2.91, and in controls, a mean value of 1.472 (P = 0.0002). Ultrastructural diagnosis revealed variable myofibrils density in smooth muscle cells, irregularity of sarcolemma membranes, interstitial fibrosis, and myofiber disarray. The authors concluded that in IVM, circular/longitudinal thickness ratio and alpha smooth muscle actin staining can be used as significant tools to address the diagnosis.

Common PHOX2B poly-alanine contractions impair RET gene transcription, predisposing to Hirschsprung disease.

HSCR is a congenital disorder of the enteric nervous system, characterized by the absence of neurons along a variable length of the gut resulting from loss-of-function RET mutations. Congenital Central Hypoventilation Syndrome (CCHS) is a rare neurocristopathy characterized by impaired response to hypercapnia and hypoxemia caused by heterozygous mutations of the PHOX2B gene, mostly polyalanine (polyA) expansions but also missense, nonsense, and frameshift mutations, while polyA contractions are common in the population and believed neutral. HSCR associated CCHS can present in patients carrying PHOX2B mutations. Indeed, RET expression is orchestrated by different transcriptional factors among which PHOX2B, thus suggesting its possible role in HSCR pathogenesis. Following the observation of HSCR patients carrying in frame trinucleotide deletions within the polyalanine stretch in exon 3 (polyA contractions), we have verified the hypothesis that these PHOX2B variants do reduce its transcriptional activity, likely resulting in a down-regulation of RET expression and, consequently, favouring the development of the HSCR phenotype. Using proper reporter constructs, we show here that the in vitro transactivation of the RET promoter by different HSCR-associated PHOX2B polyA variants has resulted significantly lower compared to the effect of PHOX2B wild type protein. In particular, polyA contractions do induce a reduced transactivation of the RET promoter, milder compared to the severe polyA expansions associated with CCHS+HSCR, and correlated with the length of the deleted trait, with a more pronounced effect when contractions are larger.

Image-defined risk factors in unresectable neuroblastoma: SIOPEN study on incidence, chemotherapy-induced variation, and impact on surgical outcomes.

PURPOSE: To evaluate the impact of image-defined risk factor (IDRF) modification after chemotherapy on surgical outcomes, event-free survival (EFS), and overall survival (OS) among patients enrolled in the European Unresectable Neuroblastoma (EUNB) study. METHODS: IDRFs were assigned according to the corresponding surgical risk factors list reported in the database. Surgical outcomes, EFS, and OS were related to IDRF modification with chemotherapy. The predictive value of preoperative IDRF for surgical outcomes was analyzed. Cox proportional hazards models for EFS and OS, including preoperative IDRF, surgical outcomes, and other known clinical risk factors, were created. RESULTS: Of the 160 patients enrolled in the EUNB study, 143 patients met the inclusion criteria. A total of 228 IDRF were thus collected. Following chemotherapy, 76 (33%) IDRF disappeared in 32.2% of patients, 33 (14%) new IDRF appeared in 18.8% of patients, and 49% of patients did not show any IDRF change. Complete resection/minimal residual disease (71.2%) was more frequent among children who had disappearance/numerical reduction of IDRF (P = 0.005). Infiltration of the branches of the mesenteric artery was predictive of an unfavorable surgical outcome. Prolonged preoperative chemotherapy over five courses and encasement of the celiac axis and/or mesenteric artery origin impacted EFS and OS. CONCLUSIONS: The unchanged IDRF pattern in 50% of patients and the appearance of new IDRF during chemotherapy in approximately 20% of patients strengthens the idea that prolonged chemotherapy is useless for improving surgical resection in this population of patients. In addition, midline perivascular abdominal preoperative IDRF appeared to be predictive not only of surgical outcomes but also of EFS and OS.

Surgical Advances in Paediatric Neuroblastoma.

As an introduction to this "Special Issue" launched by Children (ISSN 2227-9067), I would firstly like to highlight those neoplasms should be labeled with the more appropriate term "Neuroblastomas" (NBs) [...].

TITF1 Screening in Human Congenital Diaphragmatic Hernia (CDH).

TITF1 (Thyroid Transcription Factor-1) is a homeodomain-containing transcription factor. Previous studies showed that Titf1 null mice are characterized by failure of tracheo-oesophageal separation and impaired lung morphogenesis resulting in Pulmonary Hypoplasia (PH). In this study, we aim to evaluate the role of TITF1 in the pathogenesis of congenital diaphragmatic hernia (CDH) in humans. We investigated TITF1 expression in human trachea and lungs and performed direct mutation analysis in a CDH population. We studied 13 human fetuses at 14 to 24 weeks of gestation. Five µm sections were fixed in paraformaldehyde and incubated with anti-TITF1 primary antibody. Positive staining was visualized by biotinylated secondary antibody. We also performed TITF1 screening on genomic DNA extracted from peripheral blood of 16 patients affected by CDH and different degrees of PH, searching for mutations, insertions, and/or deletions, by sequencing the exonic regions of the gene. Histochemical studies showed positive brown staining of fetal follicular thyroid epithelium, normal fetal trachea, and normal fetal lung bronchial epithelium. Fetal esophageal wall was immunohistochemically negative. Molecular genetic analysis showed complete identity between the sequences obtained and the Wild Type (WT) form of the gene in all cases. No mutation, insertion and/or deletion was detected. Although TITF1 is expressed in the human fetal lung and has been considered to have a role in the pathogenesis of PH in CDH, the results of our study do not support the hypothesis that TITF1 mutations play a key role in the etiopathogenesis of CDH.

An example of parenchymal renal sparing in the context of complex malformations due to a novel mutation in the PBX1 gene.

INTRODUCTION: PBX1 encodes the pre-B cell leukemia factor 1, a Three Amino acid Loop Extension (TALE) transcription factor crucial to regulate basic developmental processes. PBX1 loss-of-function variants have been initially described in association with renal malformations in both isolated and syndromic forms. CASE REPORT: Herein, we report a male infant presenting multiple organ malformations (cleidosternal dysostosis, micrognathia, left lung hypoplasia, wide interatrial defect, pulmonary hypertension, total anomalous pulmonary venous return, intestinal malrotation) and carrying the heterozygous de novo c.868C > T (p.Arg290Trp) variant in PBX1. This novel variant affects the highly conserved homeodomain of the protein, leading to a non-conservative substitution and consequently altering its tridimensional structure and DNA-binding capacity. CONCLUSION: So far, PBX1 has been reported in association with a broad spectrum of renal anomalies. However, given the role of this gene in many different developing processes, whole-exome sequencing can detect mutations in PBX1 even in patients with different phenotypes, not necessarily involving the renal primordium. This report presents a novel PBX1 variant with a predicted strong deleterious effect. The mutation leads to a non-conservative substitution in a very highly conserved domain of the protein, thus altering its tertiary structure and DNA-binding capacity.

Surgical Approaches to Neuroblastoma: Review of the Operative Techniques.

Neuroblastoma (NB) is the most commonly occurring soft-tissue malignancy of childhood. Surgery plays an important role in multidisciplinary treatment and its principal aim is a local control of the disease, respecting the integrity of the surrounding structures. There is no unanimous consensus on the best surgical technique, and the operative approach largely depends on the anatomical location and the extension of the mass. To have a complete overview of the different type of treatment, we made a review of the literature from the last twenty years of all the surgical approaches applied for NBs resection, accordingly to the anatomical site.

The Cervico-Parasternal Thoracotomy (CPT): A New Surgical Approach for the Resection of Cervicothoracic Neuroblastomas.

Cervicothoracic neuroblastomas (NBs) pose unique surgical challenges due to the complexity of the neurovascular structures located in the thoracic inlet. To date, two main techniques have been reported to completely remove these tumours in children: the trans-manubrial and the trap-door approaches. Herein, the authors propose a third new surgical approach that allows a complete exposure of the posterior costovertebral space starting from the retro-clavicular space: Cervico-Parasternal Thoracotomy (CPT). The incision is made along the anterior margin of the sternocleidomastoid muscle until its sternal insertion, and then the incision proceeds vertically following the ipsilateral parasternal line. The major pectoralis muscle is detached, and the clavicle and the ribs are disarticulated from their sternal insertions. Following an accurate isolation of the major subclavian blood vessels and the brachial plexus roots, the tumour is then completely exposed and resected by switching from a frontal to a lateral view of the costo-vertebral space. By adopting this technique, five cervicothoracic NBs were completely resected in a median operative time of 370 min (range: 230-480 min). By proceeding in safety with the heart apart, neither vascular injuries nor nerve damages occurred, and all patients were safely discharged in a median postoperative time of 11 days (range: 7-14 days). At the last follow-up visit (median: 16 months, range: 13-21 months), all patients were alive and disease-free.

Molecular Genetics in Neuroblastoma Prognosis.

In recent years, much research has been carried out to identify the biological and genetic characteristics of the neuroblastoma (NB) tumor in order to precisely define the prognostic subgroups for improving treatment stratification. This review will describe the major genetic features and the recent scientific advances, focusing on their impact on diagnosis, prognosis, and therapeutic solutions in NB clinical management.

The Role of Biopsy in the Workup of Patients with Neuroblastoma: Comparison of the Incidence of Surgical Complications and the Diagnostic Reliability of Diverse Techniques.

Neuroblastoma (NB) is the most common extracranial solid tumor in childhood, accounting for approximately 15% of all cancer-related deaths in the pediatric population. The overall survival of children with high-risk disease is around 40-50% despite the aggressive treatment protocols. In accordance with the most recent guidelines, a complete classification of the primary tumor, including its histopathological and molecular analysis, is necessary. In this regard, the biopsy of the primary tumor is an important diagnostic procedure adopted not only to confirm the diagnosis but also for staging and risk stratification of the disease. In this study, the authors describe their unicentric experience with four different approaches adopted for sampling NB tumors: (i) the open incisional biopsy; (ii) the minimally invasive thoracoscopic/laparoscopic incisional biopsy; (iii) the ultrasound-guided core needle biopsy; (iv) the laparoscopic-assisted core needle biopsy. The benefits of each technique are analyzed along with their contraindications.

Cardiovascular MRI assessment of pectus excavatum in pediatric patients and postoperative simulation using vacuum bell.

BACKGROUND: The sternal lift by Vacuum Bell (VB) is effective, as largely demonstrated by its intraoperative use during surgical procedure to elevate the sternum during the Nuss procedure routinely. Indeed, the thoracic remodelling during VB application is comparable to post-surgical scenario, and suitable to compare cardiovascular parameters of the two different thoracic configurations immediately. OBJECTIVE: We would quantify and correlate preoperative parameters which determine the severity of the pectus excavatum (PE), and the cardiovascular effects at the baseline. Than we would assess the cardiovascular changes during VB positioning, mimicking the immediate, temporary effect of Pectus-correction. MATERIALS AND METHODS: We included 26 consecutive patients (mean age is 13,3 +/- 2,2 years) symptomatic and non, with a previous clinical diagnosis of PE. CMR was performed before and during application of VB, using the same imaging protocol. In both conditions, we measured thoracic indexes, and cardiac function as well as flow through main vessels. RESULTS: Mean expiratory Haller Index (HI) was 5,4 (+/-1,4 SD; normal <3). During VB application, all patients showed improvement in the main morphologic parameters of the thorax (mean expiratory HI = 4,7 (+/-1,6 SD, delta -13%, P = 0,01). During VB application, a minimal but not significant increase of Right Ventricle End Diastolic Volume (RVEDVi) (delta +4,6%, P = 0,12), and Right Ventricle Ejection Fraction (RVEF) (delta +1,2%, P = 0,2) was observed. CONCLUSION: In adolescents affected by PE, cardiacMRI (CMR) demonstrates normal values of biventricular volume and systolic function. During VB application, beside significative improvements in chest wall anatomy, CMR shows a minimal positive variation in right ventricle volume and function. A minority of patients showed some degree of diastolic dysfunction at baseline, unchanged after VB application, with possible correlation between valve inflow and sternal impingement.

Thoraco-abdominal neuroblastoma resection: the thoracophrenolaparotomic (TPL) approach.

OBJECTIVE: The aim of the present study is to describe, for the first time in paediatric age, the technique and the outcomes of the thoracophrenolaparotomic (TPL) approach for surgical resection of thoraco-abdominal neuroblastomas (NBs) in children. METHODS: A retrospective study was performed analysing clinical features and surgical outcomes of all children undergoing surgical resection of thoraco-abdominal NBs via the TPL approach in our third referral children's hospital, from January 2010 to November 2018. The details of the surgical technique were also reported. RESULTS: 5 children suffering from thoraco-abdominal NBs (n = 4 stage L2, n = 1 stage M-according to the International Neuroblastoma Risk Group Staging System, INRGSS-and n = 4 stage 3, n = 1 stage 4-according to International Neuroblastoma Staging System, INSS) underwent the TPL approach at a mean age of 72 months (range 27-180 months). The surgical procedure was performed in a mean operative time of 5 h 57 min (range 2 h 56 min-9 h) without any major intraoperative or postoperative complications. Following 24 h in intensive care unit, all patients were safely discharged in a mean time of 12 days (range 4-21 days). All patients were alive, without any tumour relapse, at the last follow-up visit (mean 3.2 years, range 1-7 years). CONCLUSION: This is the first study reporting the excellent surgical results we gained applying the TPL approach for surgical excision of multi-compartment tumours in children, allowing a gross total resection without intra- or post-operative complications.

Endocavitary electrocardiography during central vein catheter positioning in a newborn with persistent left superior vena cava.

We report an unusual presentation of the P wave and QRS complex during ECG-guided endocavitary assessment of the proper location of the central venous catheter in a pre-term infant operated on for esophageal atresia. The P wave and QRS complex had a normal morphology, but lay specularly to normal above the isoelectric line. The chest x-ray showed that the unusual ECG pattern was due to the left paracardiac position of the catheter, just lateral to the aortic arch within a persistent left superior vena cava.

Antibiotic prophylaxis in children undergoing abdominal surgery for neoplastic diseases.

Little is known about the effectiveness of antibiotic prophylaxis for prevention of surgical site infections (SSIs) in paediatric abdominopelvic surgical oncology. A retrospective analysis was performed upon the incidence of SSIs in children receiving a 24-hour antibiotic prophylaxis with cefazolin for abdominopelvic oncological surgery. In all, 145 patients (57% females) with a median age of 4 years underwent surgical procedures for abdominopelvic tumours. No SSIs were detected, despite the various risk factors known to be associated with their occurrence (such as pre- and post- surgical chemotherapy, long hospitalization, intensive care unit admission and drain placement). Cefazolin prophylaxis seems to be safe and effective in preventing SSIs in children undergoing abdominopelvic surgery for oncological diseases.

Adrenal masses in children: the role of minimally invasive surgery.

The development of laparoscopic surgery has extended its uses to include adrenalectomy in children and in adults. Because conventional adrenalectomy requires a large incision, minimally invasive surgery offers a less aggressive solution in some selected cases. Twenty-nine adrenal masses in 26 children were treated using adrenalectomy between 1994 and 2004 (12 were treated laparoscopically, the remaining 17 with open surgery). Minimally invasive procedures were limited to the removal of small localized adrenal tumors and to biopsies. Although this approach must be limited to operations on lesions presumed to be benign, preoperative criteria for nonmalignancy are often difficult to define. Indications can be expanded to include to stage I neuroblastoma. There seems to be no age and weight limit. The technique applied varies in accordance with anatomy and the surgeon's experience: minimally invasive adrenalectomy, in our experience, was preferentially performed through a lateral retroperitoneal approach. Laparoscopic adrenalectomy can be used if the selection of cases is rigorous and the operations are performed by well-trained laparoscopic surgeons.