Investigation of osteosarcoma genomics and its impact on targeted therapy: an international collaboration to conquer human osteosarcoma / 癌症

Osteosarcoma is a genetically unstable malignancy that most frequently occurs in children and young adults. The lack of progress in managing this devastating disease in the clinic has prompted international researchers to collaborate to profile key genomic alterations that define osteosarcoma. A team of researchers and clinicians from China, Finland, and the United States investigated human osteosarcoma by integrating transcriptome sequencing (RNA-seq), high-density genome-wide array comparative genomic hybridization (aCGH), fluorescence in situ hybridization (FISH), reverse transcription-polymerase chain reaction (RT-PCR), Sanger sequencing, cell culture, and molecular biological approaches. Systematic analysis of genetic/genomic alterations and further functional studies have led to several important findings, including novel rearrangement hotspots, osteosarcoma-specific LRP1-SNRNP25 and KCNMB4-CCND3 fusion genes, VEGF and Wnt signaling pathway alterations, deletion of the WWOX gene, and amplification of the APEX1 and RUNX2 genes. Importantly, these genetic events associate significantly with pathogenesis, prognosis, progression, and therapeutic activity in osteosarcoma, suggesting their potential impact on improved managements of human osteosarcoma. This international initiative provides opportunities for developing new treatment modalities to conquer osteosarcoma.

Novel anti-melanoma treatment: focus on immunotherapy / 癌症

Melanoma is an intractable cancer that is aggressive, lethal, and metastatic. The prognosis of advanced melanoma is very poor because it is insensitive to chemotherapy and radiotherapy. The incidence of melanoma has been ascending stably for years worldwide, accompanied by increasing mortality. New approaches to managing this deadly disease are much anticipated to enhance the cure rate and to extend clinical benefits to patients with metastatic melanoma. Due to its high degree of immunogenicity, melanoma could be a good target for immunotherapy, which has been developed for decades and has achieved certain progress. This article provides an overview of immunotherapy for melanoma.

High resolution melting analysis for detecting of JAK2V617F mutation in patients with myeloproliferative neoplasms / 中国实验血液学杂志

This study was purposed to investigate the feasibility of high resolution melting (HRM) in the detection of JAK2V617F mutation in patients with myeloproliferative neoplasm (MPN). The 29 marrow samples randomly selected from patients with clinically diagnosed MPN from January 2008 to January 2011 were detected by HRM method. The results of HRM analysis were compared with that detected by allele specific polymerase chain reaction (AS-PCR) and DNA direct sequencing. The results showed that the JAK2V617F mutations were detected in 11 (37.9%, 11/29) cases by HRM, and its comparability with the direct sequencing result was 100%. While the consistency of AS-PCR with the direct sequencing was moderate (Kappa = 0.179, P = 0.316). It is concluded that the HRM analysis may be an optimal method for clinical screening of JAK2V617F mutation due to its simplicity and promptness with a high specificity.

The prognostic role of PRUNE2 in leiomyosarcoma / 癌症

PRUNE2 plays an important role in regulating tumor cell differentiation, proliferation, and invasiveness in neuroblastoma. Our previous study revealed that PRUNE2/OBSCN two-gene relative expression classifer accurately differentiated leiomyosarcoma from gastrointestinal stromal tumor. However, the association between PRUNE2 expression and prognosis in leiomyosarcoma is poorly understood. In this study, we evaluated the prognostic role of PRUNE2 in leiomyosarcoma. PRUNE2 expression was detected using immunohistochemistry in 30 formalin-fixed, paraffin-embedded leiomyosarcoma tissues from MD Anderson Cancer Center, and high expression was detected in 36.7% (11/30) of the samples. To validate these results, immunohistochemistry was performed on another cohort of 45 formalin-fixed, paraffin-embedded leiomyosarcoma tissues from Tianjin Medical University Cancer Institute & Hospital, and high PRUNE2 protein expression was detected in 37.8% (17/45) of the samples. Moreover, elevated PRUNE2 expression was significantly associated with tumor size (P = 0.03) and hemorrhage/cyst (P = 0.014), and was an independent favorable prognostic factor for overall survival in leiomyosarcoma patients from Tianjin Medical University Cancer Institute & Hospital (P < 0.05). These data suggest that increased PRUNE2 protein expression may serve as a favorable prognostic marker in human leiomyosarcoma.

Effects of feeding patterns after hospital discharge on increase rates of growth indices in preterm and low-birth-weight infants within 3 months after birth / 中国当代儿科杂志

<p><b>OBJECTIVE</b>To study the effects of post-discharge formula (PDF) for preterm infants, breast milk (BM) and term infant formula (TF) on increase rates of body weight, length and head circumference in preterm and low-birth-weight infants (PLBWIs) from discharge to 3 months after birth, and to provide a reference for the choice of feeding pattern for PLBWIs.</p><p><b>METHODS</b>A total of 407 PLBWIs discharged from the newborn departments of ten hospitals in Guangzhou City and Foshan City in Guangdong Province, China were chosen for this study. According to feeding pattern, they were assigned to three groups: PDF-fed (n=258), BM-fed (n=58) and TF-fed (n=91). Their body weight, length and head circumference were measured at 3 months after birth, and the increase rates of growth indices relative to baseline values (at birth) were calculated and compared.</p><p><b>RESULTS</b>At 3 months after birth, the PDF-fed group had significantly greater body weight, length and head circumference than the BM-fed and TF-fed groups (P<0.05). The increase rates of body weight and length were significantly higher in the PDF-fed group than in the BM-fed and TF-fed groups (P<0.05).</p><p><b>CONCLUSIONS</b>Compared with those fed with BM and TF after discharge, the PDF-fed PLBWIs have higher increase rates of body weight and length and show greater body weight and length at 3 months after birth. However, further study is needed to investigate the long-term effects.</p>

Expression of PRUNE2 mRNA and its positive correlation with non-coding RNA PCA3 in leiomyosarcoma / 中华肿瘤杂志

<p><b>OBJECTIVE</b>Our previous study shows that PURNE2 mRNA plays an important role in the differential diagnosis of leiomyosarcoma and gastrointestinal stromal tumor (GIST). Non-coding RNA PCA3 locates in the intron of PRUNE2 and may play a role in PRUNE2 expression. The aim of this study was to explore the expression of PCA3 mRNA and PRUNE2 in leiomyosarcoma and their correlation.</p><p><b>METHODS</b>The expression of PRUNE2 mRNA was analyzed by agilent gene expression microarray CHIP in 31 leiomyosarcomas and 37 GISTs, and the correlation of the PRUNE2 expression and prognosis of leiomyosarcoma was predicted. Real-Time PCR assay was used to detect the mRNA levels of PCA3 and PRUNE2 in 13 leiomyosarcomas and to investigate their correlation. Seven prostate cancer tissues were used as control of PCA3.</p><p><b>RESULTS</b>The level of PRUNE2 mRNA expression was significantly higher in the 31 leiomyosarcomas than that in the 37 GISTs, and the level of PRUNE2 mRNA expression was correlated with survival of the leiomyosarcoma patients. Compared with prostate cancer, the non-coding RNA PCA3 expression level was significantly lower in leiomyosarcoma, and it had no correlation with the prognosis of leiomyosarcoma. Most importantly, the PRUNE2 and PCA3 mRNA expressions were both upregulated in leiomyosarcoma and showed a significant positive correlation.</p><p><b>CONCLUSIONS</b>Our findings demonstrate for the first time that PRUNE2 expression is correlated with the survival of leiomyosarcoma patients. Furthermore, non-coding RNA PCA3, which locates in the intron of PRUNE2, has a significant positive correlation with PRUNE2 and may play an important role in the pathogenesis of leiomyosarcoma.</p>

Abnormalities of chromosome 8, APC and beta-catenin genes in aggressive fibromatosis / 中华肿瘤杂志

<p><b>OBJECTIVE</b>To explore the role of abnormalities of chromosome 8, APC and beta-catenin genes in tumorigenesis of aggressive fibromatosis.</p><p><b>METHODS</b>Trisomy 8 was detected by interphase fluorescence in situ hybridization (FISH). The APC gene and beta-catenin gene mutations were detected by denaturing high performance liquid chromatography (DHPLC) and direct sequence analysis after the PCR transition.</p><p><b>RESULTS</b>The rate of trisomy 8 in recurrent tumors (62.5%, 5/8) was significantly higher than that in the primary tumors (8.3%, 1/12). Somatic substitution of APC gene was found in 18 of 69 (26.1%) aggressive fibrometases. Somatic transition of beta-catenin gene was detected in 13 of 69 (18.8%) and mutation at codon 41 in exon 3 involving threonine residues implicated in the degradation of beta-catenin. The abnormal expression of beta-catenin had no significant correlation with the mutation of APC or beta-catenin gene. The group with positively expressed beta-catenin protein showed a significant higher c-myc protein expression than those without (P = 0.001). The Ki-67 index was extremely low in all the lesions. The apoptosis index (AI) of the groups with positively expressed c-myc and cyclin D1 showed significantly lower AI than those without.</p><p><b>CONCLUSION</b>Trisomy 8 may serve as a useful predictor of recurrence in aggressive fibromatosis. There are somatic mutations of the APC and beta-catenin genes in the aggressive fibromatosis, and there are abnormalities in the Wnt signaling pathway. These abnormalities may result in the aberrances of cell proliferation and apoptosis, which are likely to be import factors in the tumorigenesis.</p>

Clinicopathologic and genetic studies of desmoid-type fibromatosis / 中华病理学杂志

<p><b>OBJECTIVE</b>To study the clinicopathological and genetic features of desmoid-type fibromatosis, and to investigate the feasibility of detecting trisomy 8 in formalin fixed, paraffin embedded (FFPE) tissue by fluorescence in-situ hybridization (FISH).</p><p><b>METHODS</b>A total of 96 cases were included in this study. All patients had clinical information. Histopathologic and immunohistochemical evaluations were available in 69 cases, and ultrastructural evaluation was done in 2 cases of desmoid-type fibromatosis. FFPE tissue sections were available in 20 tumors for the trisomy 8 detection by FISH.</p><p><b>RESULTS</b>There were 20 male and 76 female patients with ages ranging from 8 to 86 years (mean 35.3 years). Clinically, there were 44 extra-abdominal tumors, 28 abdominal wall tumors and 23 intra-abdominal lesions mostly involving the mesentery. Most cases presented with nodular or funicular masses with white firm cut surfaces, measuring 0.6 to 24.0 cm (mean 8.4 cm) in size. Histologically, desmoid-type fibromatoses showed longitudinal fascicles of spindle fibroblasts and myofibroblasts in a predominantly collagenous background. The tumor cells stained positive for vimentin, alpha-smooth muscle actin, desmin, and beta-catenin (47.8%, 33/69). Ultrastructurally, most tumor cells had features of fibroblasts, including rich endoplasmic reticulum and Golgi apparatus. Some tumor cells were myofibroblast-like cells exhibiting intercellular junctions, fibronexous junctions and stress fibers. Trisomy 8 was detected in 6 of 20 cases of desmoid-type fibromatosis including 5 of the 8 recurrent tumors but only one of the 12 primary tumors. The latter tumor also recurred three years later.</p><p><b>CONCLUSIONS</b>Desmoid-type fibromatosis is an intermediate (locally aggressive) tumor that occurs predominantly in young females. The lesion consists of fibroblasts and myofibroblasts with the latter showing characteristic features including stress fibers and fibronexous junctions. Trisomy 8 can be detected in FFPE tissue by FISH, and its presence serves as a useful predictor of tumor recurrence and may define a subtype of desmoid-type fibromatosis with high recurrence rate.</p>

Desmoplastic small round cell tumor: a clinicopathologic study of 15 cases / 中华病理学杂志

<p><b>OBJECTIVE</b>To study the clinicopathologic features and immunophenotype of desmoplastic small round cell tumor (DSRCT), and to assess the feasibility of reverse transcriptase-polymerase chain reaction (RT-PCR) as a diagnostic adjunct for DSRCT in routine practice.</p><p><b>METHODS</b>The clinical (number = 15), cytologic (number = 1) and histopathologic (number = 14) features of 15 cases of DSRCT were investigated. The immunophenotype was studied by LSAB method using a panel of antibodies. RT-PCR was performed in one case using formalin-fixed, paraffin-embedded tissue for EWS-WT1 fusion gene mRNA.</p><p><b>RESULTS</b>Among the 15 patients studied, 13 were males and 2 were females. Their age ranged from 12 to 38 years (mean age = 23.8 years). Most presented with vague abdominal discomfort, distension or pain, accompanied by nausea, constipation and weight loss. Physical examination showed a palpable abdominal mass with ill-defined borders and tenderness. Ultrasound and computerized tomographic examination revealed single or multiple nodular tumor mass(es) in the peritoneal cavity, measuring 3 cm to 25 cm in greatest diameter (mean tumor diameter = 8.6 cm). Cytologic examination in 1 case showed clusters of small round cells in a hemorrhagic background. The tumor nuclei were hyperchromatic and contained inconspicuous nucleoli. Mitotic figures were readily identified. The cytoplasm however was scant. Histologically, the tumor was composed of small, round, ovoid to spindled cells arranged in nests of various shapes and sizes, embedded in a desmoplastic and focally hyalinized stroma. Immuno- histochemically, all cases showed diffuse and strong staining for AE1/AE3, vimentin, desmin and neuron-specific enolase. Some of them also expressed CAM5.2, epithelial membrane antigen, CD57, chromogranin A, synaptophysin and WT1. They were all negative for myogenin, CK5/6, CD117, calretinin and CD99. RT-PCR successfully amplified the EWS-WT1 chimeric mRNA in 1 case using paraffin-embedded tissue. Subsequent DNA sequencing showed that the gene fusion involved exon 7 of EWS and exon 8 of WT1 genes. The fusion gene contained KTS sequence.</p><p><b>CONCLUSIONS</b>DSRCT is a highly malignant small round cell tumor occurring predominantly in the abdominal or pelvic cavity of young to middle-aged males. It is characterized by multiphenotypic differentiation. The peculiar perinuclear dot-like staining pattern for vimentin and desmin is characteristic for DSRCT. EWS-WT1 fusion transcript can be detected in formalin-fixed, paraffin-embedded tissue by RT-PCR, which may thus serve as a useful diagnostic adjunct for DSRCT.</p>