Kuiran Dong

Sirolimus, a promising treatment for refractory Kaposiform hemangioendothelioma

AbstractBackgroundnKaposiform hemangioendothelioma (KHE) is a locally aggressive vascular tumor that usually occurs in infants. It is commonly associated with Kasabach–Merritt phenomenon which is directly responsible for the significant morbidity and mortality, including hemodynamic instability, local invasion, and compression of vital structures. Treatment is particularly difficult for those who had no response to conventional therapies. This paper wants to share experience of mTOR inhibitors sirolimus in the treatment of refractory KHE.Materials and methodsSix cases of refractory KHE were diagnosed and treated in Children’s Hospital of Fudan University from Jan 2010–June 2013; all of them were treated with sirolimus in June 2012 after failing multiple other therapies.ResultsIn six patients, gender was equally distributed between male and female patients. The mean age at the time of initial diagnosed as KHE was 3.1xa0±xa01.8xa0months. All of them had been pretreated with at least 2 medical therapies. All of them showed significant improvement in clinical status with tolerable side effects. The average time to response was 5.3xa0±xa01.0xa0days; the average stabilization time of platelet was 15.1xa0±xa08.0xa0days; and the average time for sirolimus treated as single agent was 1.7xa0±xa00.4xa0months. No recurrence of their symptoms happened.ConclusionsSirolimus appears to be effective and safe in patients with life-threatening KHE and represents a promising tool in treating refractory KHE.

Exome sequencing of hepatoblastoma reveals novel mutations and cancer genes in the Wnt pathway and ubiquitin ligase complex

Hepatoblastoma (HB) is the most common primary liver tumor in children. Mutations in the β‐catenin gene that lead to constitutive activation of the Wnt pathway have been detected in a large proportion of HB tumors. To identify novel mutations in HB, we performed whole‐exome sequencing of six paired HB tumors and their corresponding lymphocytes. This identified 24 somatic nonsynonymous mutations in 21 genes, many of which were novel, including three novel mutations targeting the CTNNB1 (G512V) and CAPRIN2 (R968H/S969C) genes in the Wnt pathway, and genes previously shown to be involved in the ubiquitin ligase complex (SPOP, KLHL22, TRPC4AP, and RNF169). Functionally, both the CTNNB1 (G512V) and CAPRIN2 (R968H/S969C) were observed to be gain‐of‐functional mutations, and the CAPRIN2 (R968H/S969C) was also shown to activate the Wnt pathway in HB cells. These findings suggested the activation of the Wnt pathway in HB, which was confirmed by immunohistochemical staining of the β‐catenin in 42 HB tumors. We further used short hairpin RNA (shRNA)‐mediated interference to assess the effect of 21 mutated genes on HB cell survival. The results suggested that one novel oncogene (CAPRIN2) and three tumor suppressors (SPOP, OR5I1, and CDC20B) influence HB cell growth. Moreover, we found that SPOP S119N is a loss‐of‐function mutation in HB cells. We finally demonstrated that one of the mechanisms by which SPOP inhibits HB cell proliferation is through regulating CDKN2B expression. Conclusion: These results extend the landscape of genetic alterations in HB and highlight the dysregulation of Wnt and ubiquitin pathways in HB tumorigenesis. (Hepatology 2014;;60:1686–1696)

Genome-Wide Analysis of Long Noncoding RNA (lncRNA) Expression in Hepatoblastoma Tissues

Long noncoding RNAs (lncRNAs) have crucial roles in cancer biology. We performed a genome-wide analysis of lncRNA expression in hepatoblastoma tissues to identify novel targets for further study of hepatoblastoma. Hepatoblastoma and normal liver tissue samples were obtained from hepatoblastoma patients. The genome-wide analysis of lncRNA expression in these tissues was performed using a 4×180 K lncRNA microarray and Sureprint G3 Human lncRNA Chips. Quantitative RT-PCR (qRT-PCR) was performed to confirm these results. The differential expressions of lncRNAs and mRNAs were identified through fold-change filtering. Gene Ontology (GO) and pathway analyses were performed using the standard enrichment computation method. Associations between lncRNAs and adjacent protein-coding genes were determined through complex transcriptional loci analysis. We found that 2736 lncRNAs were differentially expressed in hepatoblastoma tissues. Among these, 1757 lncRNAs were upregulated more than two-fold relative to normal tissues and 979 lncRNAs were downregulated. Moreover, in hepatoblastoma there were 420 matched lncRNA-mRNA pairs for 120 differentially expressed lncRNAs, and 167 differentially expressed mRNAs. The co-expression network analysis predicted 252 network nodes and 420 connections between 120 lncRNAs and 132 coding genes. Within this co-expression network, 369 pairs were positive, and 51 pairs were negative. Lastly, qRT-PCR data verified six upregulated and downregulated lncRNAs in hepatoblastoma, plus endothelial cell-specific molecule 1 (ESM1) mRNA. Our results demonstrated that expression of these aberrant lncRNAs could respond to hepatoblastoma development. Further study of these lncRNAs could provide useful insight into hepatoblastoma biology.

Comment on: Steroid-resistant Kaposiform Hemangioendothelioma: A retrospective study of 37 patients treated with vincristine and long-term follow-up

To the Editor: We read with great interest the report by Wang et al. (Pediatr Blood Cancer 2015; 62:577–580)[1] providing a retrospective review of 37 cases of Kaposiform Hemangioendothelioma (KHE) treated with vincristine, and the accompanying highlight by Francine Blei, pages 551–552).[2] Evidence-based management of vascular anomalies has been impeded by a dearth of prospective clinical trials. Reasons include a lack of a phenotype/genotype classification system, limited numbers of specialists with clinical trial acumen, a historical slant toward surgical and interventional treatments, a paucity of funding options, and rarity of the individual diagnoses. These deficits have pushed patients and families to rally together to demand improved clinical and basic science research and expertise. Presently, the field of vascular anomalies is flourishing with a recently expanded classification system[3] as well as new prospective clinical trials. We believe that collaborative clinical trials among multidisciplinary disease specialists are mandatory for vascular anomalies to emulate the advances made in pediatric oncology by the Children’s oncology group. KHE is a vascular tumor treated by Pediatric Hematologists/ Oncologists. Vincristine treatment is the current consensus-derived treatment for this tumor.[4] After compassionate use of sirolimus for one patient, Cincinnati Children’s Hospital Medical Center (CCHMC) prospectively studied sirolimus as treatment in a total of 60 patients with complicated vascular anomalies.[5] This phase 2 study (NCT# 00975819) was completed in 2014, presented at ISSVA and ASPHO, and recently submitted for publication. The clinical trial proved sirolimus to be safe and efficacious for a majority of vascular anomalies, with 13 of 13 participants with KHE with KMP having partial responses. Preliminary results with sirolimus appear favorable but many questions remain unanswered, including effectiveness compared to standard vincristine-based therapy, time to response, durability of response, and long-term effects. The present retrospective study[1] and the expert opinion consensus paper[4] recommend vincristine and steroids as the first line treatment for KHEwith KMP. Dr. Blei’s thoughtful highlight article[2] provides historical perspective on KHE therapy, but concludes with the suggestion of sirolimus as a first line agent. We suggest caution before considering sirolimus as first line therapy based on small numbers of patients. We strongly recommend that these questions be answered in a randomized controlled trial. This study actually recently opened at CCHMC (NCT # 02110069—“A Randomized Phase 2 Study of Vincristine vs. Sirolimus to treat High Risk Kaposiform Hemangioendothelioma [KHE]”). This FDA-funded and Pfizer-supported trial will open at seven additional sites throughout the United States in coming months, establishing an efficient referral network. This study will establish the most efficacious treatment for KHE with KMP, incorporatingmulti-faceted outcomemonitoring, long-term followup, and the use of adaptive trial design with early stopping rules. Collaborative studies are needed for many of the disease entities within the field of vascular anomalies. Pediatric hematologist/ oncologists are taking leadership roles in the treatment of these diseases. ThroughASPHO, theVascular Anomalies Special Interest Group has drawn tremendous interest and is one example of a collaborative group forming within our specialty to utilize our clinical research expertise to improve outcomes for patients with vascular anomalies.

Steroid-resistant kaposiform hemangioendothelioma: A retrospective study of 37 patients treated with vincristine and long-term follow-up: Vincristine for Steroid-Resistant KHE

Kaposiform hemangioendothelioma (KHE) with Kasabach–Merritt phenomenon (KMP) still remains a particular and life‐threatening disease. The purpose of this study was to evaluate the efficacy of vincristine (VCR) and the possibility of replacement with steroids in the treatment of steroid‐resistant KHE with KMP.

Successful treatment of kaposiform lymphangiomatosis with sirolimus.

Generalized lymphatic anomaly (GLA) is a rare and often fatal congenital lymphatic disorder that also commonly affects bone. Kaposiform lymphangiomatosis (KLA) is a novel subtype of GLA with poor prognosis and no proper treatment guidelines. A 9‐year‐old male with recurrent pleural effusion was clinically diagnosed as KLA. Following sirolimus therapy at a dose of 0.8u2009mg/m2 twice daily, pleural effusion was significantly decreased and the general status of the patient markedly improved. The clinical course indicates that sirolimus may present an effective therapeutic option in KLA. Moreover, KLA should be considered in differential diagnosis for cases of GLA with coagulopathy. Pediatr Blood Cancer 2015;62:1291–1293.

Conservative management of neonatal hepatic hemangioma: a report from one institute

PurposeTo summarize the conservative treatment of neonatal hepatic hemangioma at one institute.Patients and materialsFifteen cases of neonatal hepatic hemangioma were managed in our hospital during the previous 5xa0years. Initial symptoms, combination symptoms, diagnosis, and treatment were analyzed.ResultsInitial symptoms were abdominal mass, hepatomegaly, jaundice, and pneumonia. Combination symptoms were multiple skin hemangiomas, pneumonia, and cardiac insufficiency. Ultrasound and CT showed the typical characteristics of the liver hemangioma. There were three types of hepatic hemangioma: nine cases had a single focus, four cases were multiple foci, and two had diffuse changes in the liver. The diameter of a single focus in this group was about 53–99xa0mm. Four cases of single focus received resection and two received biopsy. Six cases received corticosteroid treatment. The other five cases were kept under observation only. Those with cardiac insufficiency and pneumonia received diuretics and antibiotic treatment. One neonate with cardiac insufficiency and pneumonia had postoperative MODS and died. One patient having multi-focus in the liver gave up the treatment after biopsy. Other patients were followed-up at 5–17xa0months. Two cases that received total tumor resection did not have recurrence. In those who received conservative therapy, all hemangiomas disappeared within 1xa0year.ConclusionThe diagnosis of hepatic hemangioma can be made from symptomology, ultrasound, and CT; pathologic samples are not necessary. Corticosteroid therapy is the widely used therapy. Proactive therapy for congestive heart failure is helpful for those endangering liver hemangioma. Surgery can increase the risk of complications and is not advised for treatment of neonatal hepatic hemangioma.

Refractory Kasabach–Merritt phenomenon successfully treated with sirolimus, and a mini-review of the published work

Kasabach–Merritt phenomenon (KMP) is a rare and life‐threatening disease involving a vascular tumor combined with severe consumptive coagulopathy. We present for the first time a case of KMP with the vascular tumor involving two anatomical sites; the patient failed to respond to steroids and vincristine. Following sirolimus therapy at a dose of 0.8 mg/m2 twice daily, the lesions shrank and the platelet count improved and remained normal 4 months after initial therapy. Current treatments for KMP are not particularly effective. Sirolimus at 0.8 mg/m2 per dose, administrated twice daily, appears to be a safe and effective management option. It appears to be an interesting therapeutic option in refractory KMP, but the time to response is variable.

Diagnosis and outcome of neutropenic enterocolitis: experience in a single tertiary pediatric surgical center in China.

Background/purposeNeutropenic enterocolitis (NE) is clinically defined by the triad of neutropenia, abdominal pain and fever. This retrospective study is to review 24 cases of NE in a single Chinese tertiary center, to elucidate clinical feature, treatments and outcome for this dangerous gastrointestinal complication of neutropenia.Patients and methodsThe medical records of pediatric patients who were diagnosed with neutropenic enterocolitis from 2000 to 2009 were reviewed.ResultsOf 24 cases, the ratio of male to female was 2:1, the mean age was 7.2xa0years. There were eight cases of acute lymphocytic leukemia, eight cases of acute non-lymphocytic leukemia, four cases of non-Hodgkin’s lymphoma, one case of severe aplastic anemia, one case of neuroblastoma and two cases of simple neutropenia without underlying cause. The hematologic malignancy was significantly associated with the occurrence of NE (ORxa0=xa019.4). Seventeen cases developed NE during anticancer chemotherapy (chemo group), four cases presented with leukemia and one case presented with aplastic anemia before the initiation of chemotherapy and their presenting event leading to diagnosis. Two cases simply presented with NE without definitive reasons (no chemo group). All the patients had the typical clinical presentation, six cases had disseminated peritonitis, toxic shock, and assisted ventilations were necessary in three of these six cases. CT or ultrasound demonstrated bowel wall thickness, paucity of air in the cecum and/or right colon, pneumatosis or pneumoperitoneum. There was no difference in the nadir neutrophil count in patients, who received chemotherapy versus those who did not (Pxa0=xa00.001), but the recovering time from NE in chemo group (9.3xa0±xa01.9) was shorter than non-chemo group (10.7xa0±xa05.3, Pxa0=xa00.034). Sixteen (88.8%) cases have been successfully managed medically, using aggressive hemodynamic support, bowel rest, and broad-spectrum antibiotic therapy with surgical intervention reversed only for the more severe six cases (25%). Two cases died.ConclusionNE is a life-threatening gastrointestinal complication of neutropenia. Physicians might remain vigilant and consider NE in any neutropenic patient rather than only in oncologic patients. It has typical clinical presentation and CT can provide clear delineation for diagnosis. Early recognition and progressed management have reduced mortality. Most children with NE may be treated without surgery with favorable outcome.

Analysis of clinical features and outcomes for inflammatory myofibroblastic tumors in China: 11 years of experience at a single center

PurposeInflammatory myofibroblastic tumor (IMT) is a rare benign neoplasm. The purpose of this study was to review the clinical characteristics, imaging and pathological features, and outcomes of children with IMTs from a single center in China.MethodsA retrospective file review was conducted involving 23 cases of pathologically confirmed IMTs treated at the Children’s Hospital between April 2003 and April 2014.ResultsThe tumor locations included multiple anatomic sites, as follows: abdomen or pelvis (nxa0=xa017); lungs (nxa0=xa02); head and neck (nxa0=xa01); trunk (nxa0=xa01); and extremities (nxa0=xa02). The tumors were associated with various clinical presentations. The predominant symptoms included an anemic appearance, fevers, and an asymptomatic mass. Computed tomography scanning showed solid, heterogeneous, well-demarcated masses; the appearance of enhancement was variable. MRI appeared hypointense on T1-weighted images and hypointense or hyperintense on T2-weighted images. Immunohistochemical staining revealed anaplastic lymphoma kinase was negative in 11 of 13 cases tested. One patient quit treatmentxa0for the unresectable mass after biopsy and died 2xa0years later, and another patient with incompletely resection is alive at 30xa0months following chemotherapy. The remaining 21 cases had complete resections; one patient died due to a recurrence, and the other 20 patients survived and were tumor free. The follow-up ranged from 7 to 141xa0months, with a mean of 56xa0months. The 3-year OS was 88xa0% (95xa0% CI, 57–97xa0%).ConclusionsIMT is a benign neoplasm that rarely presents with malignant features. Complete resection is curative in most patients. ALK+ is variable for diagnosis. Close follow-up is necessary for patients who undergo surgical resection.