Clinicopathologic conference: a large pulmonary cavitary lesion in a 2-year-old boy

Recent studies suggest that children are completing toilet training much later than the preceding generation. Our objective was to identify factors associated with later toilet training. Children between 17 and 19 months of age (n=406) were enrolled in the study. At enrollment, parents completed the Parenting Stress Index and the Receptive-Expressive Emergent Language Scale. Follow-up parent interviews were conducted every 2 to 3 months until children completed daytime toilet training. Information obtained at follow-up interviews included steps parents were taking to toilet train their child, child toilet training behaviors, presence and frequency of constipation, birth of a sibling, and child care arrangements. In a stepwise linear regression model predicting age at completion of toilet training, 3 factors were consistently associated with later training: initiation of toilet training at an older age, presence of stool toileting refusal, and presence of frequent constipation. Models including these variables explained 25% to 39% of the variance in age at completion of toilet training. In conclusion, a later age at initiation of toilet training, stool toileting refusal, and constipation may explain some of the trend toward completion of toilet training at later ages.     

Synergistic antitumor effect of melatonin with several chemotherapeutic drugs on human Ewing sarcoma cancer cells: potentiation of the extrinsic apoptotic pathway

Abstract:  Ewing sarcoma, the second most frequent bone cancer type, affects mainly adolescents, who have a survival of 50% 5 yr after diagnosis. Current treatments include a combination of surgery, radiotherapy and chemotherapy, which present potential serious side effects. Melatonin, a natural molecule without relevant side effects, has been previously shown to induce cytotoxicity in SK-N-MC cells, a Ewing sarcoma cell line. Here, we found that there is a synergy in the antitumor effect when melatonin (50 μ m –1 m m ) is combined with vincristine at the concentration of 5–10 n m or with ifosfamide at the range of 100 μ m –1 m m . This synergism is due to the potentiation of cell death, particularly to the potentiation of apoptosis, i.e., mainly the extrinsic apoptotic pathway. There is a significant increase in the activation of caspase-3, -8, -9 and Bid when melatonin is combined with vincristine or ifosfamide compared to the individual treatments. Finally, there is also a potentiation of the early free radical production, likely dependent on the extrinsic apoptosis pathway activation, when the drugs are combined with melatonin. Other proteins which are related to this pathway including mitogen-activated protein kinase or protein kinase B/Akt are not involved in apoptosis induced by these agents separately or when combined. The results shown here together with the facts that: (i) no relevant side effects have been reported for melatonin and (ii) melatonin has a cytoprotective effect on noncancer cells, opens the door for a new approach in the treatment of the Ewing sarcoma family of tumors.     

健脾补肾中药对恶性骨肿瘤化疗后骨髓抑制患者外周血象的影响

目的:观察健脾补肾中药对恶性骨肿瘤化疗后骨髓抑制患者外周血象的影响。方法:将符合要求的60例恶性骨肿瘤化疗后骨髓抑制患者随机分为2组,每组30例。联合治疗组采用健脾补肾中药口服联合重组人粒细胞集落刺激因子皮下注射治疗,单纯西药组采用重组人粒细胞集落刺激因子皮下注射治疗;均连续治疗7 d为1个疗程,共治疗1个疗程。比较2组患者治疗前后外周血液中白细胞计数、血红蛋白含量及血小板计数,并评估白细胞、血红蛋白及血小板抑制程度。治疗结束1周后,评价患者临床症状改善情况及生活质量。结果:①白细胞计数。治疗前2组患者的白细胞计数比较,差异无统计学意义[(3.28±0.64)×10⁹个·L^-1,(3.19±0.76)×10⁹个·L^-1,t=0.566,P=0.576];治疗结束1周后,2组患者的白细胞计数均高于治疗前(t=-6.606,P=0.000;t=-3.583,P=0.000),且联合治疗组患者的白细胞计数高于单纯西药组[(8.68±1.75)×10⁹个·L^-1,(4.63±1.20)×10⁹个·L^-1,t=10.954,P=0.000]。②血红蛋白含量。治疗前2组患者的血红蛋白含量比较,差异无统计学意义[(112.47±10.05)g·L^-1,(108.63±9.67)g·L^-1,t=-1.941,P=0.062];治疗结束1周后,2组患者的血红蛋白含量均高于治疗前(t=-11.750,P=0.000;t=-5.695,P=0.000),且联合治疗组患者的血红蛋白含量高于单纯西药组[(140.83±17.36)g·L^-1,(126.87±15.56)g·L^-1,t=4.331,P=0.000]。③血小板计数。治疗前2组患者的血小板计数比较,差异无统计学意义[(121.10±23.51)×10⁹个·L^-1,(126.90±30.52)×10⁹个·L^-1,t=-1.250,P=0.221];治疗结束1周后,2组患者的血小板计数均高于治疗前(t=-12.528,P=0.000;t=-5.846,P=0.000),且联合治疗组患者的血小板计数高于单纯西药组[(224.23±60.28)×10⁹个·L^-1,(187.70±55.89)×10⁹个·L^-1,t=2.741,P=0.010]。④白细胞抑制程度。治疗结束1周后,联合治疗组0度9例、Ⅰ度11例、Ⅱ度7例、Ⅲ度3例,单纯西药组0度4例、Ⅰ度7例、Ⅱ度8例、Ⅲ度6例、Ⅳ度5例;联合治疗组患者的白细胞抑制程度优于单纯西药组(Z=-2.717,P=0.007)。⑤血红蛋白抑制程度。治疗结束1周后,联合治疗组0度8例、Ⅰ度10例、Ⅱ度12例,单纯西药组0度3例、Ⅰ度10例、Ⅱ度6例、Ⅲ度6例、Ⅳ度5例;联合治疗组患者的血红蛋白抑制程度优于单纯西药组(Z=-2.547,P=0.011)。⑥血小板抑制程度。治疗结束1周后,联合治疗组0度11例、Ⅰ度13例、Ⅱ度4例、Ⅲ度2例,单纯西药组0度8例、Ⅰ度7例、Ⅱ度8例、Ⅲ度4例、Ⅳ度3例;联合治疗组患者的血小板抑制程度优于单纯西药组(Z=-2.009,P=0.045)。⑦临床症状改善情况。治疗结束1周后,联合治疗组显著改善13例、部分改善14例、无效3例,单纯西药组显著改善7例、部分改善12例、无效11例;联合治疗组患者的临床症状改善情况优于单纯西药组(Z=-2.363,P=0.018)。⑧生活质量。治疗结束1周后,联合治疗组改善16例、稳定10例、降低4例,单纯西药组改善9例、稳定8例、降低13例;联合治疗组患者的生活质量高于单纯西药组(Z=-2.430,P=0.015)。⑨其他。治疗过程中,单纯西药组6例应用促红细胞生成素、3例输注血小板,联合治疗组无1例采取上述措施。结论:对于恶性骨肿瘤化疗后骨髓抑制患者,在采用重组人粒细胞集落刺激因子皮下注射治疗的基础上,应用健脾补肾中药口服治疗,可以增加外周血液中白细胞计数、血红蛋白含量及血小板计数,减轻骨髓抑制程度,有利于改善临床症状、提高生活质量,其疗效优于单纯采用重组人粒细胞集落刺激因子皮下注射治疗。     

EphA2 receptor is a key player in the metastatic onset of Ewing sarcoma

Ewing sarcoma (ES) is the second most common bone malignancy affecting children and young adults with poor prognosis due to high metastasis incidence. Our group previously described that EphA2, a tyrosine kinase receptor, promotes angiogenesis in Ewing sarcoma (ES) cells via ligand‐dependent signaling. Now we wanted to explore EphA2 ligand‐independent activity, controlled upon phosphorylation at S897 (p‐EphA2^S897), as it has been linked to metastasis in several malignancies. By reverse genetic engineering we explored the phenotypic changes after EphA2 removal or reintroduction. Gene expression microarray was used to identify key players in EphA2 signaling. Mice were employed to reproduce metastatic processes from orthotopically implanted engineered cells. We established a correlation between ES cells aggressiveness and p‐EphA2^S897. Moreover, stable overexpression of EphA2 in low EphA2 expression ES cells enhanced proliferation and migration, but not a non‐phosphorylable mutant (S987A). Consistently, silencing of EphA2 reduced tumorigenicity, migration and invasion in vitro, and lung metastasis incidence in experimental and spontaneous metastasis assays in vivo. A gene expression microarray revealed the implication of EphA2 in cell signaling, cellular movement and survival. ADAM19 knockdown by siRNA technology strongly reproduced the negative effects on cell migration observed after EphA2 silencing. Altogether, our results suggest that p‐EphA2^S897 correlates with aggressiveness in ES, so blocking its function may be a promising treatment.     

Cerebral venous sinus thrombosis in an adolescent with Ewing sarcoma

BACKGROUND: Although thromboembolic complications are common in adult patients with malignant diseases, cerebral venous sinus thrombosis has been rarely described in cancer afflicted pediatric and adolescent population. CASE HISTORY: A 16-year-old adolescent girl referred for complaints of pain and swelling on her left leg. On physical examination, a solid tibial mass was discovered. After the diagnosis of Ewing sarcoma with a tru-cut biopsy, chemotherapy protocol consisting of cisplatin, ifosfamide, adriamycine, and vincristine was started. During the first course of the treatment, the patient expressed headache, diplopia, and ptosis. Contrast-enhanced magnetic resonance (MR) images and MR angiography showed superior sagittal and transverse sinus thromboses. After anticoagulant therapy, the thromboses disappeared within 1.5 months. She received her chemotherapy protocol with the anticoagulant prophylaxis. After a follow-up period of 12 months, she is still in a good neurological recovery without any sequel. CONCLUSION: Children and adolescents with cancer should be monitored closely for thrombotic complications. We discuss this uncommon case to draw attention to the importance of early diagnosis and adequate treatment of intracranial thrombosis in childhood cancer, and we review the relevant literature.     

Radiological findings of primary retroperitoneal Ewing sarcoma

Ewing sarcomas are most commonly located in bone, while extraskeletal involvement of the retroperitoneum is extremely rare. We describe the radiologic and pathological findings in an adult patient with retroperitoneal extraskeletal Ewing sarcoma.     

Chemotherapy response is an important predictor of local recurrence in Ewing sarcoma

BACKGROUND: Local recurrence in Ewing sarcoma is associated with a poor prognosis. The purpose of the study was to determine the factors that predict local recurrence after surgical treatment of the primary tumor. METHODS: Between 1990 and 2001, 64 patients underwent surgical resection of Ewing sarcoma. Surgical margins were assessed histologically and radiologically. Response to preoperative chemotherapy was determined by detailed specimen mapping. Local recurrence-free survival (LRFS) was calculated by Kaplan-Meier analysis. Multivariate analysis was performed with the Cox proportional hazards model. RESULTS: A number of factors were found to be associated with local recurrence on univariate analysis. Patients with a good response to chemotherapy (> or = 90% tumor necrosis), had superior LRFS at 5 years (86% vs 51%, P = .015). Central site of disease was associated with an increased rate of recurrence. The LRFS at 5 years was 50% for the chest wall, 74% for pelvic/scapular, and 86% for extremity tumors (P = .083). Positive surgical margin was not a strong predictor of recurrence (P = .72). A critical analysis of minimal surgical margin based on preoperative magnetic resonance imaging (MRI) and computed tomography (CT) scans also failed to reveal an association between margin and local recurrence. In multivariate analysis, the 2 independent predictors of local recurrence were histological response to chemotherapy and central site of disease. CONCLUSION: Local recurrence after surgical resection is a complex phenomenon. An important predictive factor is the response to chemotherapy. In the current study, this seems to have the largest impact. Central site of disease may be a second independent predictive factor.