Slipped capital femoral epiphyses: A major on-target adverse event associated with FGFR tyrosine kinase inhibitors in pediatric patients

Fibroblast growth factor receptor (FGFR) tyrosine kinase inhibitors (TKIs) are increasingly being used off label in pediatrics. Long-term safety data are limited, and serious toxicities unique to pediatrics may emerge. In a retrospective analysis of patients less than 18 years of age with recurrent/refractory FGFR altered gliomas treated with FGFR TKIs at MSKCC (n = 7), we observed slipped capital femoral epiphyses in three of seven patients along with increased linear growth velocity. Clinicians should closely monitor bone health and have a low index of suspicion for serious orthopedic complications including slipped capital femoral epiphyses and inform patients of related risks as part of consent when treating with FGFR TKIs.     

An unusual cause of infantile gynecomastia: sertoli cell tumor

Prepubertal testicular masses are relatively rare. Sertoli cell tumors account for 2% of prepubertal testicular tumors and very few have occurred in the first decade of life. Gynecomastia can be seen in approximately 5% of patients with testicular mass. We present an 8-month-old boy admitted with bilateral gynecomastia and unilateral testicular mass.     

尿道下裂患儿包皮组织中FGFR2表达检测及意义

目的 检测成纤维细胞生长因子受体2(fibroblast growth factor receptor 2,FGFR2)蛋白和mRNA在包皮环切组和尿道下裂组包皮组织中的表达情况,初步探究FGFR2蛋白表达、基因功能和尿道下裂的关系.方法 采用Western blotting(免疫印迹)方法和RT-PCR方法;检测两组中FGFR2表达情况;结果包皮环切组和尿道下裂组FGFR2蛋白相对定量值分别为0.39±0.12和0.19±0.09(P＜0.05),尿道下裂组较包皮环切组降低.尿道下裂轻、中、重度三组间FGFR2蛋白相对定量值分别为0.27±0.08、0.16±0.04、0.09±0.03;中度和重度之间比较无统计学差异(P＞0.05).包皮环切组和尿道下裂组FGFR2 mRNA表达量分别为1.30±0.069和1.22±0.052,包皮环切组高于尿道下裂组(P＜0.05).尿道下裂轻、中、重度三组间FGFR2 mRNA定量值分别为1.23±0).054、1.24±0.034、1.16±0.020;轻度和中度之间之间无统计学差异(P＞0.05),重度尿道下裂FGFR2mRNA表达量低于其他两组.结论 尿道下裂患儿包皮组织中FGFR2蛋白和mRNA较包皮环切组表达下调.提示FGFR2和尿道下裂关系密切,进一步研究FGFR2蛋白和基因功能有助于明确FGFR2在尿道下裂发病机制中的重要地位,有可能揭示尿道下裂的发病机制.     

A novel mutation leading to a deletion in the SH3 domain of Bruton's tyrosine kinase

X-linked agammaglobulinemia (XLA) is a primary B cell immunodeficiency disorder, caused by a defect in the Bruton tyrosine kinase (BTK) gene. Here, we describe a novel four base pair mutation (838delGAGT) in intron 9 of the BTK gene leading to the skipping of exon 9 in a 2.5-year-old boy with this disorder.     

Genotype-phenotype correlation in Bruton's tyrosine kinase deficiency

Bruton's tyrosine kinase (Btk) belongs to the Tec family of nonreceptor protein tyrosine kinases. Mutations in the BTK gene cause X-linked agammaglobulinemia (XLA); a primary immunodeficiency disorder in human. No clear genotype-phenotype correlation has been established in XLA so far. To determine how differently mutations in BTK affect the severity of the disease and if BTK promoter polymorphic variant or intron 1 polymorphic variant in Tec, a cytoplasmic tyrosine kinase that might substitute for Btk, could contribute to the clinical phenotype, we analyzed the clinical and molecular findings in a cohort of XLA patients. Polymorphisms in BTK promoter and TEC intron 1 regions include substitutions of C>T (rs2071219) and T>C (rs2664019), respectively. Btk expression was evaluated by means of western immunoblotting and fluorescence-activated cell sorter analysis. Mutations were categorized as mild or severe and patients were evaluated for the clinical severity of disease. On the basis of the results, severe genotypes do not necessarily lead to severe phenotypes. More over, in a considerable number of patients with mild phenotype we showed a severe mutation with a tendency toward C substitution in the polymorphic site on TEC intron 1.     

Pathology of soft tissue sarcomas: 238 cases of the childhood tumor registry

Until April 1981 malignant soft tissue sarcomas were registered from 238 patients. Rhabdomyosarcoma was the most common tumor (115/238 = 48.3%). The embryonal subtype was predominantly seen among the rhabdomyosarcomas (83/115 = 72.2%). Rhabdomyosarcomas were localized most frequently in the head and neck area (40/115 = 34.8%), followed by genitourinary system (15/115), pelvis soft tissue (12), abdomen (10) and extremities (10). Non-rhabdomyosarcomatous soft tissue sarcomas (123/238 = 51.7%) were synovial sarcomas (20 = 8.4%), fibrosarcomas including spindle cell sarcoma (17 = 7.4%), leiomyosarcomas (12 = 5.0%), malignant tumors of the vascular system (11 = 4.6%) and neurofibrosarcomas (9 = 3.8%). Other types of sarcoma were extremely rare. 42 (17.6%) of all soft tissue sarcomas could not be classified histogenetically. Rhabdomyosarcomas could be diagnosed much more accurately (105/115 = 91.3%), compared to all other soft tissue sarcomas (99/121 = 81.8%). At present, the most difficult diagnostic problems remain with the tumors of connective tissue, in particular with fibrosarcomas and with the differential diagnosis of juvenile fibrosarcomas versus juvenile fibromatoses.     

FMS样酪氨酸激酶3靶向RNA干扰对急性单核细胞白血病细胞株THP-1增殖和凋亡的影响

目的探讨短发夹状干扰RNA（shRNA）诱导FMS样酪氨酸激酶3（FLT3）的靶向抑制对急性单核细胞白血病（AMOL）细胞株THP-1增殖、凋亡的影响。方法设计并体外转录合成FLT3靶向shRNA（FLT3-shRNA）,转染THP-1细胞。以半定量逆转录PCR（RT-PCR）、流式细胞法（FCM）检测细胞FLT3在mRNA、蛋白水平表达,细胞计数试剂8（CCK-8）检测细胞增殖活力,FCM法检测细胞周期,DNA梯度条带（DNA Ladder）和Annexin V—FITC染色法分析细胞凋亡。结果合成的FLT3-shRNA 15nmol／L转染48h对FLT3 mRNA和蛋白的抑制率分别达（72．95±2．07）％、（65．39±5．57）％。shRNA干扰后细胞增殖活力受到抑制,48h抑制率达（36．66±3．67）％,72h达（35．56±0．73）％。转染48h细胞周期出现G0／G1期到S期的阻滞,FLT3-shRNA组G0／G1期的细胞百分比（65．71±4．47）％明显高于对照组,S期（25．11±2．70）％低于对照组。FLT3-shRNA作用48h有明显的凋亡条带出现,Annexin V-FITC检测细胞的早期凋亡率（18．59±2．07）％明显高于对照组。结论由shRNA诱导的FLT3靶向干扰可有效的抑制THP-1细胞增殖、诱导凋亡,显示其在儿童AMOL治疗中具有潜在的价值。     

Hepatic spindle cell tumors in HIV positive children

Spindle cell tumors (leiomyoma, leiomyosarcoma) have been described in HIV infected children involving the gastrointestinal tract, respiratory tract and liver. The same tumor has been reported in immuno-compromised children following liver and renal transplantation. A case of hepatic spindle cell tumor in an HIV infected child is discussed.     

Ossification in a soft tissue embryonal rhabdomyosarcoma

We describe the previously unreported finding of ossification within a rhabdomyosarcoma of the extremity in the absence of bone destruction. Rhabdomyosarcoma is a highly malignant tumor but could not be radiographically differentiated from benign or other malignant causes of soft-tissue masses containing calcium. Definitive diagnosis and thus appropriate therapy requires prompt pathologic examination.Picker Research Scholar, James Picker Foundation     

小儿肝脏血管内皮细胞瘤组织中VEGF表达的研究

目的：研究血管内皮生长因子（VEGF）、CD34在小儿肝脏血管内皮细胞瘤（IHHE）组织中的表达,探讨VEGF在血管内皮细胞瘤诊断和治疗中的作用。方法14例肝脏血管内皮细胞瘤石蜡标本来自2002年7月至2009年7月北京儿童医院手术切除并经病理诊断的临床病例,术前未行其他治疗,并选取小儿肝脏恶性肿瘤组织（肝母细胞瘤20例）,其他肝脏良性肿瘤组织（结节样增生10例,错构瘤10例）及IHHE瘤旁组织作为对照组;空白对照选取良性肿瘤术中切取部分肝脏组织。组织切片SP法进行免疫组织化学染色,兔抗VEGF和CD34相关抗原标记;计算出VEGF表达阳性率,CD34相关抗原抗体检测出肿瘤间质血管,分析其表达的不同及相互关系。应用统计软件进行数据分析。结果①VEGF在肝母细胞瘤组织中表达率为90.0％（18/20）,在良性肿瘤组中表达阳性率为10.0％（2/20）;VEGF在正常肝组织、瘤旁组织中呈低水平、稳定表达,染色浅,而在IHHE肿瘤组织中则呈阴性表达。在肝母细胞瘤组阳性表达率明显高于其他组,差异有显著性（P＜0.05）,其余两两比较,差异均无显著性（P＞0.05）。②CD34在已知正常肝组织肝窦处未见阳性表达;在IHHE组织中的阳性表达率为100.0％（14/14）,肝母细胞瘤为90.0％（18/20）,肝脏良性肿瘤为15.0％（3/20）,瘤旁组织未见表达。MVD在IHE,肝母细胞瘤组,良性肿瘤组及瘤旁组织分别为31.55±4.86,29.75±5.56,11.23±3.97。结论 IHHE中,高表达CD34,低表达VEGF,表明其不是单纯的血管、内皮细胞病变,很有可能是血管瘤与血管畸形的混合体。IHE增殖期抗血管生成治疗可能促进肿瘤退化。     

Successful liver transplantation for non‐resectable desmoplastic nested spindle cell tumor complicated by Cushing's syndrome

Desmoplastic spindle cell tumors of liver are rare tumors of low malignant potential characterized by well‐demarcated nests of spindle and epithelioid cells in a dense desmoplastic stroma. While surgery remains the definitive treatment, there have been reports of tumor recurrence locally and metastasis which respond poorly to chemotherapy. Hepatic transplant has been attempted in cases of recurrence or large size of primary tumor. Long‐term follow‐up and imaging surveillance are required as these tumors have shown a tendency for recurrence many years after initial therapy.     

Continuing response to subsequent treatment lines with tyrosine kinase inhibitors in an adolescent with metastatic renal cell carcinoma

A 14-year-old girl with metastatic renal cell carcinoma was treated with nephrectomy, interferon, and several lines of the targeted agents sorafenib, bevacizumab, sunitinib, and everolimus, either alone or in combination. Treatment was well tolerated, but the patient developed hypothyroidism and significant hypertension with bevacizumab and sunitinib. She responded to all agents and was given radiation treatment twice at the time of symptomatic disease progression; she died 33 months from diagnosis.     

脾酪氨酸激酶在血小板源性生长因子诱导的肺血管平滑肌细胞表型转换中的作用

目的 观察在血小板源性生长因子(PDGF-BB)诱导增殖的肺血管平滑肌细胞(VSMC)中,脾酪氨酸激酶(syk)的特异性抑制剂piceatannol对VSMC表型转换的影响.方法 以SD大鼠VSMC为基础,设空白对照组(不作任何处理)、对照组(PDGF-BB培养)和药物干预组(PDGF-BB和piceatannol培养).[3H]-TdR掺入量测定DNA合成;透射电镜观察细胞超微结构变化;用RT-PCR和Western blot对syk、平滑肌α肌动蛋白(α-SM-actin)及平滑肌22α蛋白(SM22α)表达活性进行检测;激光共聚焦显微镜观察F-actin的改变,并对荧光的改变程度进行定量分析.通过以上方法 观察syk在VSMC增殖和表型转换过程中所起的作用.结果 和空白对照组比较,对照组[3H]-TdR掺入量明显升高(2429.25±253.36 vs.242.75±14.33,P<0.01);细胞超微结构呈现增殖状态;syk mRNA(1.70±0.25 vs.1.01±0.12,P<0.05)和蛋白表达水平明显上升;α-SM-actin(0.10±0.00 vs.1.00±0.00,P<0.01)和SM22α(0.18±0.00 vs.1.00±0.01,P<0.01)的mRNA和蛋白表达水平明显下降;细胞骨架蛋白F-actin的荧光强度降低(263.75±19.21 vs.1146.23±62.61,P<0.01).piceatannol可明显抑制这些生物学效应(药物干预组).结论 piceatannol可以抑制血小板源性生长因子介导的VSMC内SM22α和α-SM-aetin的表达,从而抑制VSMC表型的转换,进而抑制VSMC的增殖.说明在VSMC中,PDGF-BB是通过syk信号通路对其表型转换进行调控,进而影响VSMC的迁移和增殖.