Chronic Sleep Deprivation Impairs Visual Functions via Oxidative Damage in Mice.

Sleep deprivation (SD) is a global public health burden, and has a detrimental role in the nervous system. Retina is an important part of the central nervous system; however, whether SD affects retinal structures and functions remains largely unknown. Herein, chronic SD mouse model indicated that loss of sleep for 4 months could result in reductions in the visual functions, but without obvious morphologic changes of the retina. Ultrastructural analysis by transmission electron microscope revealed the deterioration of mitochondria, which was accompanied with the decrease of multiple mitochondrial proteins in the retina. Mechanistically, oxidative stress was provoked by chronic SD, which could be ameliorated after rest, and thus restore retinal homeostasis. Moreover, the supplementation of two antioxidants, α-lipoic acid and N-acetyl-l-cysteine, could reduce retinal reactive oxygen species, repair damaged mitochondria, and, as a result, improve the retinal functions. Overall, this work demonstrated the essential roles of sleep in maintaining the integrity and health of the retina. More importantly, it points towards supplementation of antioxidants as an effective intervention strategy for people experiencing sleep shortages.

Comparative Clinicopathologic and Genomic Analysis of Hepatocellular Neoplasm, Not Otherwise Specified, and Hepatoblastoma.

Accurate diagnosis and treatment of hepatocellular neoplasm, not otherwise specified (HCN-NOS), poses significant challenges. Our study aimed to investigate the clinicopathologic and genomic similarities and differences between HCN-NOS and hepatoblastoma (HB) to guide diagnostic and treatment strategies. The clinicopathologic characteristics of 16 patients with HCN-NOS and 23 patients with HB were compared. Molecular studies, including the OncoKids DNA- and RNA-based next-generation sequencing panel, chromosomal microarray, and targeted Sanger sequencing analyses of CTNNB1 and TERT promoters, were employed. We found that patients with HCN-NOS were older (P < .001) and more frequently classified as high risk (P < .01), yet they showed no significant differences in alpha fetoprotein levels or survival outcomes compared with those with HB. HCN-NOS and HB had a comparable frequency of sequence variants, with CTNNB1 mutations being predominant in both groups. Notably, TERT promoter mutations (37.5%) and rare clinically significant variants (BRAF, NRAS, and KMT2D) were exclusive to HCN-NOS. HCN-NOS demonstrated a higher prevalence of gains in 1q, encompassing the MDM4 locus (17/17 vs 11/24; P < .001), as well as loss/loss of heterozygosity (LOH) of 1p (11/17 vs 6/24; P < .05) and chromosome 11 (7/17 vs 1/24; P < .01) when compared with HB. Furthermore, the recurrent loss/LOH of chromosomes 3, 4p, 9, 15q, and Y was only observed in HCN-NOS. However, no significant differences were noted in gains of chromosomes 2, 8, and 20, or loss/LOH of 4q and 11p between the 2 groups. Notably, no clinically significant gene fusions were detected in either group. In conclusion, our study reveals that HCN-NOS exhibits high-risk clinicopathologic features and greater structural complexity compared with HB. However, patients with HCN-NOS exhibit comparable alpha fetoprotein levels at diagnosis, CTNNB1 mutation rates, and survival outcomes when subjected to aggressive treatment, as compared with those with HB. These findings have the potential to enhance diagnostic accuracy and inform more effective treatments for HCN-NOS.

Epidural Analgesia Is Associated With Reduced Inpatient Opioid Consumption and Length of Stay After Wilms Tumor Resection.

INTRODUCTION: Wilms' tumor (WT) is the most common renal malignancy in children and requires an extensive laparotomy for resection. Epidural analgesia (EA) is commonly used in postoperative pain management, but previous literature suggests it may prolong length of stay (LOS). We hypothesized that EA is associated with prolonged LOS but decreased postoperative opioid use in children undergoing WT resection. MATERIALS AND METHODS: A retrospective chart review was performed for all WT patients who underwent nephrectomy between January 1, 1998, and December 31, 2018, at a tertiary children's hospital. Patients with incomplete records, bilateral WT, caval or cardiac tumor extension, or intubation postoperatively were excluded. Outcomes included postoperative opioid consumption measured in oral morphine equivalents per kilogram, receipt of opioid prescription at discharge, and postoperative LOS. Mann-Whitney and multivariable regression analyses were performed. RESULTS: Overall, 46/77 children undergoing WT resection received EA. Children with EA used significantly less inpatient opioids than children without EA (median 1.0 vs. 3.3 oral morphine equivalents per kilogram; P < 0.001). Comparing patients with EA to patients without, there was no significant difference in opioid discharge prescriptions (57% vs. 39%; P = 0.13) or postoperative LOS (median 5 d vs. 6 d; P = 0.10). Controlling for age and disease stage, EA was associated with shorter LOS by multivariable regression (coefficient -0.73, 95% confidence interval: -1.4, -0.05; P = 0.04). CONCLUSIONS: EA is associated with decreased opioid use in children without an associated increase in postoperative LOS following WT resection. EA should be considered as part of multimodal pain management for children undergoing WT resection.

Clinical Value of Surveillance Biopsies in Pediatric Liver Transplantation.

Although pediatric liver transplantation (LT) results in excellent long-term outcomes, a high incidence of early acute cellular rejection and late graft fibrosis persists. Routine measurement of allograft enzymes may not reliably detect rejection episodes, identify candidates for immunosuppression minimization, or indicate allograft fibrosis. Surveillance biopsies (SBs) can provide valuable information in this regard, but their role in pediatric LT is not fully established. A retrospective cohort of 236 pediatric LT recipients from a high-volume center was studied to characterize the risks and benefits of SB versus for-cause biopsies (FCBs). The study population was 47.1% male and 54.7% Hispanic, and 31% received living donor grafts. Our data suggest that patients in the SB group had better transplant outcomes (rejection-free, graft, and patient survival) compared with patients who had FCBs or who never underwent biopsy. Among 817 biopsies obtained from 236 patients, 150 (18.4%) were SBs. Only 6 patients had a biopsy-related complication, and none were observed in the SB subset. Graft biochemical blood tests did not accurately predict rejection severity on biopsy, with aspartate aminotransferase area under the receiver operating characteristic curve (AUROC) 0.66, alanine aminotransferase AUROC 0.65 (very poor predictions), and gamma-glutamyltransferase AUROC 0.58 (no prediction). SBs identified subclinical rejection in 18.6% of biopsies, whereas 63.3% of SBs had evidence of fibrosis. SBs prompted changes in immunosuppression including dose reduction. Our experience suggests that SB in pediatric LT is safe, offers valuable information about subclinical rejection episodes, and can guide management of immunosuppression, including minimization. Improved outcomes with SB were likely multifactorial, potentially relating to a more favorable early posttransplant course and possible effect of management optimization through SB. Further multicenter studies are needed to examine the role of SBs on long-term outcomes in pediatric LT.

Diffuse Anaplastic Wilms Tumor in a Child With LAMA2 -related Muscular Dystrophy.

Laminin alpha-2-related muscular dystrophy ( LAMA2 -MD), caused by mutations in the LAMA2 gene, is inherited in an autosomal recessive manner. There is no known association of LAMA2 -MD with cancer predisposition. We present a 4-year-old female with LAMA2 -MD and Children's Oncology Group stage III diffuse anaplastic Wilms tumor (DAWT). Given our patient's comorbidities, it was essential to tailor her adjuvant chemotherapy by omitting vincristine and doxorubicin to avoid the potential worsening of her neuromuscular dysfunction and cardiomyopathy. This report illustrates the sporadic occurrence of 2 rare events in our patient and highlights the successful risk-adapted management of DAWT based on the pathophysiology of LAMA2 -MD.

Outcomes of Central Hepatectomy for Pediatric Liver Tumors.

BACKGROUND: Central hepatectomy (CH) is an uncommon surgical technique that is an option for resection of centrally located tumors, with the advantage of sparing normal hepatic parenchyma. Few studies have described outcomes in children undergoing CH. MATERIALS AND METHODS: An IRB-approved, retrospective chart review of patients who underwent CH at Children's Hospital Los Angeles between 2005 and 2016 was performed. Data included patient demographics, peri-operative factors, and post-operative outcomes. The IRB approved waiver of consent. RESULTS: Eight patients (4F:4M) with median age of 1.9 Y underwent CH: 7 patients for HB and 1 patient for focal nodular hyperplasia. Two of the seven HB patients had metastatic disease at diagnosis. Six of the seven HB patients received a median of 4 rounds (3-7 rounds) of pre-operative chemotherapy. The median operative time was 197.5 Min (143-394 Min) with median blood loss of 175 mL (100-1200 mL). Complications included a bile fluid collection requiring aspiration. Seven patients had negative margins on pathology. One patient with a positive margin successfully completed therapy, without recurrent disease. All patients survived to follow-up, with a median follow-up duration of 1.1 Y (0.1-12.1 Y). Two patients developed recurrent disease requiring formal hepatic lobectomy and orthotopic liver transplantation. These patients had negative pathologic margins, with tumor within 1 mm of resection margins. CONCLUSION: CH is an effective alternative to extended hepatectomy for patients with centrally located liver tumors and is associated with good clinical and pathologic outcomes.

Phox2b Immunohistochemical Staining in Detecting Enteric Neural Crest Cells in Hirschsprung Disease.

BACKGROUND: It can be challenging to recognize undifferentiated/immature ganglion cells, especially single forms. Ganglion cells and glia are derived from enteric neural crest cells (ENCCs), a group of autonomic nervous system (ANS)-lineage neural crest progenitors that PHOX2B regulates. Phox2b is an excellent marker for neoplastic and non-neoplastic ANS cells (eg, peripheral neuroblastic tumors [pNTs]). We hypothesized that Phox2b immunohistochemical staining (IHC) would also be useful for detecting ENCCs. METHODS: Hematoxylin and eosin, calretinin IHC, and Phox2b IHC were reviewed on 21 pull-through specimens and on a cohort of 12 rectal biopsies. RESULTS: Phox2b IHC demonstrated nuclear positivity in all of the ganglion cells across the different phases of differentiation without background staining. The Phox2b result correlated with the morphological findings, calretinin IHC results, and diagnoses based on the routine diagnostic method. The intensity was uniformly strong in the undifferentiated/immature forms and became variable in the mature forms; this pattern was similar to that seen in pNTs. CONCLUSION: Phox2b IHC was highly sensitive and specific for detecting ganglion cells. It worked especially well for immature ganglion cells, seen in premature neonates, and scattered single forms in transition zones. In basic research settings, Phox2b can be a useful marker for early differentiation of ENCCs.

Primary Knee Intra-articular Synovial Sarcoma in Pediatric and Adolescent Patients.

Synovial sarcoma (SS) arising within a knee joint is extremely rare, with 10 reported cases in pediatric and adolescent patients in English literature. Its rarity and nonspecific clinical and radiological features pose a diagnostic challenge. We present two cases of primary intra-articular SS of left knee to enhance awareness of this entity. One patient is a 17-year-old male complained of left knee pain and gait abnormality for 9 years. The other one is a 13-year-old female presented with left knee pain for one year. Both cases were clinically diagnosed as benign joint lesion and underwent biopsies. Histological examination, immunohistochemical staining and molecular study confirmed that both patients had primary intra-articular SS, monophasic spindle cell type. Intraarticular SS should be considered as a potential diagnosis with unexplained long-standing knee pain.

The Effect of Gross Total Resection on Patients with Pleuropulmonary Blastoma.

BACKGROUND: Pleuropulmonary blastoma (PPB) is the most common primary lung cancer in children. While rare, these tumors are highly aggressive. Tumor recurrence and overall survival are dependent on histologic grade and extent of surgical resection. We sought to examine our institutional experience with PPB to determine the effect of gross total resection (GTR) on recurrence and patient outcomes. MATERIALS AND METHODS: After IRB approval, a retrospective chart review from 1998 to 2018 was performed. Cases were confirmed by histology and Dehner Grade (I to III). Data collection included demographics, treatment, extent of surgical resection, and patient outcomes. RESULTS: Eight patients with nine procedures were identified. Histologically, three cases were type 1, 2 type 2, and four poor prognosis type 3. Three patients received neoadjuvant chemotherapy to facilitate surgical resection. The operative goal was to achieve GTR (>95%), and to this end, three partial lobectomies, five lobectomies, and one pneumonectomy were performed. All nine cases achieved GTR, of which eight had negative microscopic margins. Two patients with type III disease recurred (one locally, one distant) and died. One type 3 patient had a positive microscopic hilar margin not amenable to further resection. The patient recurred (distant) but is in remission. With respect to patient outcomes, the event-free survival was 2.3 y with an overall survival of 3.3 y. CONCLUSIONS: From our experience, GTR of PPB is associated with minimal surgical morbidity and good overall survival. Multi-institutional studies are needed to determine if positive surgical margins affect outcomes given the morbidity of mediastinal dissection.

Routine Surveillance Catheterization is Useful in Guiding Management of Stable Fontan Patients.

We developed a Fontan surveillance catheterization protocol as part of routine assessment of stable patients 10 years after Fontan completion. The surveillance catherization includes hemodynamic assessment with inhaled nitric oxide, angiography, liver biopsy, and transcatheter intervention if indicated. We aimed to describe hemodynamic and liver biopsy findings, response to pulmonary vasoreactivity testing, rates of transcatheter intervention, and changes in medical therapy following surveillance catheterization in stable Fontan patients. A single-center retrospective review of Fontan patients undergoing surveillance catheterization between November 2014 and May 2019 was performed. Liver biopsies were independently scored by two pathologists. Sixty-three patients underwent surveillance catheterization (mean age 14.6 ± 3.0 years). The mean Fontan pressure was 11.8 ± 2.1 mmHg. The mean cardiac index was 2.9 ± 0.6 L/min/m2. In the 51 patients who underwent pulmonary vasoreactivity testing, there was a significant decrease in median pulmonary vascular resistance (1.8 [range 0.8-4.1] vs 1.4 [range 0.7-3.0] Wood units × m2; p < 0.001). The mean cardiac index increased (3.0 ± 0.6 vs 3.2 ± 0.7 L/min/m2, p = 0.009). The Fontan pressure did not change significantly. Fifty-seven patients underwent liver biopsy, and all but one showed fibrosis. Nineteen patients (33.3%) demonstrated bridging fibrosis or cirrhosis. Twenty-five patients underwent 34 transcatheter interventions. Pulmonary artery or Fontan stent placement was performed in 19 patients. Phosphodiesterase type 5 inhibitors were initiated in nine patients following surveillance catheterization. Routine surveillance catheterization with liver biopsy in adolescent Fontan patients reveals information that can guide interventional and medical management. Further long-term follow-up and assessment are indicated to assess the benefit of these interventions.

A Multicenter Retrospective Review of Pediatric Leydig Cell Tumor of the Testis.

Leydig cell tumors (LCTs) are rare tumors arising from testosterone-producing Leydig cells. Although LCTs are usually benign, malignancy has been reported in 10% of cases in adults, and local recurrence or metachronous tumors of the contralateral testis have been described. Radical orchiectomy is the current standard of care. We report on 12 children with LCT at 3 institutions between 2000 and 2016. Presenting symptoms included precocious puberty, palpable testicular mass, and scrotal swelling. Radical orchiectomy was performed in 9 patients. Three patients were treated with enucleation. All patients were alive at last follow-up without evidence of local recurrence or metastasis.

Primary Epithelioid Sarcoma of the Zygomatic Bone.

Primary epithelioid sarcoma (ES) of bone is extremely rare with only 2 reported cases in the English literature. A previously healthy 18-year-old man presented with a 6-month history of right facial numbness and tingling and right eye diplopia. A computerized tomography scan revealed an ill-defined mass with dense osseous matrix centered in the right zygomatic bone. An outside biopsy was read as osteosarcoma. The resection specimen revealed large epithelioid and spindle cells embedded in a prominent hyalinized matrix with focal metaplastic bone formation. The tumor cells were strongly and diffusely positive for AE1/AE3 and epithelial membrane antigen, but a definitive diagnosis of ES was not immediately reached due to the presence of dense hyalinized matrix and weak expression of SAT2B by tumor cells. Deficient INI1 protein expression by immunohistochemistry and homozygous loss of the SMARCB1 gene by chromosomal microarray analysis ultimately justified this tumor's designation as ES.

A 10-Month-Old Infant Presenting With Signs of Precocious Puberty Secondary to a Sclerosing Stromal Tumor of the Ovary in the Absence of Hormonal Elevation.

Precocious puberty in an infant is an alarming and infrequent finding, making the differential diagnosis difficult for practitioners. Precocious puberty secondary to a sclerosing stromal tumor (SST) of the ovary is rare. We present a case of a child that began precocious puberty at 3 months of age including development of breast buds, pubic hair, growth spurt, and menarche 5 days prior to presenting to pediatric endocrinology at 10 months. She underwent right salpingo-oophorectomy which demonstrated a soft tissue mass occupying almost the entire ovary with a tan-pink fleshy cut surface. Histological examination confirmed a variant of SST. This case represents an extremely young onset of precocious puberty secondary to a variant of SST without hormonal elevation.

Hepatocellular malignant neoplasm, NOS: a clinicopathological study of 11 cases from a single institution.

AIMS: The primary aim of this study is to characterize hepatocellular malignant neoplasm, NOS (HEMNOS), a new provisional entity describing a subset of paediatric hepatocellular tumours, which have histological features of neither typical hepatoblastoma (HB) nor hepatocellular carcinoma (HCC). METHODS AND RESULTS: The clinicopathological features of 11 patients with HEMNOS were analysed retrospectively. The median age and serum alpha-fetoprotein level at diagnosis was 7 years and 182 000 ng/ml, respectively. Ten patients presented with pretreatment extent of disease (PRETEXT) stages III/IV multifocal tumours, eight with major vascular involvement, three with lung metastases and three with extrahepatic extension. The original pathology diagnoses were: HB in seven patients, HCC in two and HEMNOS in two. Our pathology review of pre-chemotherapy specimens showed that six tumours had equivocal/overlapping histological features of HB and HCC, four had predominant HB histology along with focal HCC-like histology and one had HB histology. Seven of nine post-chemotherapy resection specimens showed predominant HCC-like histology. Beta-catenin, glypican 3 and spalt-like transcription factor 4 immunostaining showed that all the tumours had a mixed HB/HCC immunophenotype. Telomerase reverse transcriptase immunostaining showed nuclear staining in nine of the 11 tumours. All patients received chemotherapy and achieved gross total primary tumour resection. Nine of the 11 patients were treated with established HB chemotherapy regimens. After a median follow-up of 6.1 years (range: 1.2-11.8 years), all patients were in remission. CONCLUSIONS: HEMNOS is a subtype of HB with focal HCC-like histology, a high-risk clinical profile but favourable outcome following chemotherapy and complete tumour resection.

The diagnostic and prognostic value of SALL4 in hepatoblastoma.

AIMS: To investigate the expression of spalt-like transcription factor 4 (SALL4), a regulator of embryonal development, in three epithelial components of hepatoblastoma (HB) and the relationship between SALL4 expression levels and patients' clinicopathological features. METHODS AND RESULTS: A total of 115 specimens from 79 patients with HB were selected for immunostaining of SALL4. Nuclear staining was semi-quantified using the immunoreactive score (IS; range: 0-12). SALL4 expression was seen in all embryonal components (mean IS = 8.58) and in 41% of fetal components (mean IS = 0.78). No SALL4 expression was seen in either small cell undifferentiated or mesenchymal components of HB. Neither chemotherapy nor metastasis altered SALL4 expression significantly. High SALL4 expression levels were associated significantly with decreased overall survival (OS) (P = 0.004), event-free survival (EFS) (P = 0.003) and the presence of metastasis (P = 0.049) on univariate analysis. Multivariate analysis identified SALL4 as an independent prognostic predictor for OS (P = 0.029). CONCLUSIONS: SALL4 is useful for subtyping HB, and high SALL4 expression is associated with decreased survival in HB.

Orthotopic liver transplant for multifocal lymphangioendotheliomatosis with thrombocytopenia.

An eight-yr-old female with a history of multifocal lymphangioendotheliomatosis and thrombocytopenia presented for MVT. The patient had multiple vascular lesions in the skin and stomach in infancy. Although her cutaneous lesions resolved with vincristine and methylprednisolone, her gastric lesions persisted. Eight yr later, she was diagnosed with portal hypertension and decompensating liver function despite therapy with bevacizumab, propranolol, furosemide, and spironolactone. Upon presentation, she was found to have a Kasabach-Merritt-like coagulopathy in association with multiple lesions in her GI tract and persistent gastric lesions. Although treatment with methylprednisolone and sirolimus normalized her coagulation factors and d-dimer levels, she never developed sustained improvement in her thrombocytopenia. Her liver function continued to deteriorate and she developed hepatorenal syndrome. Given better outcomes after OLT in comparison with MVT, she underwent OLT, with the plan to manage her GI lesions with APC post-transplant. Post-transplant, her liver function and coagulopathy normalized, and GI tract lesions disappeared upon screening with capsule endoscopy. The patient is doing well, without recurrence of either GI lesions or thrombocytopenia, at 18 months after transplantation.

Expansion of prominin-1-expressing cells in association with fibrosis of biliary atresia.

UNLABELLED: Biliary atresia (BA), the most common cause of end-stage liver disease and the leading indication for pediatric liver transplantation, is associated with intrahepatic ductular reactions within regions of rapidly expanding periportal biliary fibrosis. Whereas the extent of such biliary fibrosis is a negative predictor of long-term transplant-free survival, the cellular phenotypes involved in the fibrosis are not well established. Using a rhesus rotavirus-induced mouse model of BA, we demonstrate significant expansion of a cell population expressing the putative stem/progenitor cell marker, PROMININ-1 (PROM1), adjacent to ductular reactions within regions of periportal fibrosis. PROM1positive (pos) cells express Collagen-1α1. Subsets of PROM1pos cells coexpress progenitor cell marker CD49f, epithelial marker E-CADHERIN, biliary marker CYTOKERATIN-19, and mesenchymal markers VIMENTIN and alpha-SMOOTH MUSCLE ACTIN (αSMA). Expansion of the PROM1pos cell population is associated with activation of Fibroblast Growth Factor (FGF) and Transforming Growth Factor-beta (TGFß) signaling. In vitro cotreatment of PROM1-expressing Mat1a-/- hepatic progenitor cells with recombinant human FGF10 and TGFß1 promotes morphologic transformation toward a myofibroblastic cell phenotype with increased expression of myofibroblastic genes Collagen-1α1, Fibronectin, and α-Sma. Infants with BA demonstrate similar expansion of periportal PROM1pos cells with activated Mothers Against Decapentaplegic Homolog 3 (SMAD3) signaling in association with increased hepatic expression of FGF10, FGFR1, and FGFR2 as well as mesenchymal genes SLUG and SNAIL. Infants with perinatal subtype of BA have higher tissue levels of PROM1 expression than those with embryonic subtype. CONCLUSION: Expansion of collagen-producing PROM1pos cells within regions of periportal fibrosis is associated with activated FGF and TGFß pathways in both experimental and human BA. PROM1pos cells may therefore play an important role in the biliary fibrosis of BA.

Quantification of glypican 3, ß-catenin and claudin-1 protein expression in hepatoblastoma and paediatric hepatocellular carcinoma by colour deconvolution.

AIMS: To identify an immunohistochemical panel for paediatric malignant epithelial liver tumours. METHODS AND RESULTS: Forty-five hepatoblastomas (HBs), 13 paediatric hepatocellular carcinomas (HCCs) and two hepatocellular malignant neoplasms not otherwise specified (NOS) were chosen for immunohistochemical staining of glypican 3 (GPC3), ß-catenin, claudin-1, delta-like protein (DLK), and forkhead box protein G1 (FOXG1). Immunostaining was quantitatively analysed with NIH imagej software coupled with colour deconvolution. Different subtypes of HB and HCC showed distinct staining patterns of GPC3, ß-catenin, and claudin-1. Moreover, GPC3, ß-catenin and claudin-1 all showed higher expression in classic HCC and embryonal HB than in fetal HB; GPC3 showed complete negativity in small-cell undifferentiated (SCU) HB and fibrolamellar HCC (FLC); ß-catenin showed the strongest expression in SCU HB but the weakest expression in FLC. A panel of these three immunomarkers was useful for the diagnosis of hepatocellular malignant neoplasms NOS. The expression of DLK and FOXG1 was inconstant among fetal and embryonal HB and classic HCC. CONCLUSIONS: A panel of GPC3, ß-catenin and claudin-1 is helpful for differentiating HB subtypes and distinguishing HB from HCC.

Toxicity induced by Basic Violet 14, Direct Red 28 and Acid Red 26 in zebrafish larvae.

Basic Violet 14, Direct Red 28 and Acid Red 26 are classified as carcinogenic dyes in the European textile ecology standard, despite insufficient toxicity data. In this study, the toxicity of these dyes was assessed in a zebrafish model, and the underlying toxic mechanisms were investigated. Basic Violet 14 and Direct Red 28 showed acute toxicity with a LC50 value at 60.63 and 476.84 µg ml(-1) , respectively, whereas the LC50 of Acid Red 26 was between 2500 and 2800 µg ml(-1) . Treatment with Basic Violet 14, Direct Red 28 and Acid Red 26 resulted in common developmental abnormalities including delayed yolk sac absorption and swimming bladder deflation. Hepatotoxicity was observed in zebrafish treated with Basic Violet 14, and cardiovascular toxicity was found in zebrafish treated with Acid Red 26 at concentrations higher than 2500 µg ml(-1) . Basic Violet 14 also caused significant up-regulation of GCLC gene expression in a dose-dependent manner whereas Acid Red 26 induced significant up-regulation of NKX2.5 and down-regulation of GATA4 at a high concentration in a dose-dependent manner. These results suggest that Basic Violet 14, Direct Red 28 and Acid Red 26 induce developmental and organ-specific toxicity, and oxidative stress may play a role in the hepatotoxicity of Basic Violet 14, the suppressed GATA4 expression may have a relation to the cardiovascular toxicity of Acid Red 26.

High dose alkylator therapy for extracranial malignant rhabdoid tumors in children.

BACKGROUND: Extracranial malignant rhabdoid tumor (MRT) is a rare pediatric cancer with a poor prognosis. The kidney is the most common site. Isolated reports have shown improvements in patient survival, but no specific treatment regimen has shown efficacy over others. PROCEDURE: Retrospective review of patients diagnosed with extracranial MRT at Children's Hospital Los Angeles between 1983 and 2012. RESULTS: The median age at presentation for the 21 patients was 13 months (range, 0-108 months). Ten patients had renal primary tumors. The median time to progression was 4 months (range, 0.4-7 months). The 5-year event free survival (EFS) and overall survival (OS) of the entire cohort was 38 ± 10.6%. After 2002, patients diagnosed with extracranial MRT were administered a chemotherapy regimen of vincristine, doxorubicin and high dose cyclophosphamide (VDC). The OS for the patients diagnosed before and after 2002 were 20 ± 12% and 54 ± 15%, respectively. Of the 13 patients who received VDC containing regimen, eight patients achieved a complete radiological remission; five of these patients are long-term survivors. Four patients who received autologous bone marrow transplantation were alive at last follow-up. All patients with unresectable primary tumors died. Patients who had disease progression or relapse did not survive. CONCLUSIONS: Patients with extracranial MRT have a poor prognosis. Treatment with high dose alkylator therapy followed by consolidation with high dose chemotherapy and autologous bone marrow transplant for those patients in radiographic complete remission appears to have a beneficial effect on survival.