Haifeng Wei

Surgery in the cervicothoracic junction with an anterior low suprasternal approach alone or combined with manubriotomy and sternotomy: an approach selection method based on the cervicothoracic angle: Clinical article

OBJECT The authors propose an easy MR imaging method to measure and categorize individual anatomical variations within the cervicothoracic junction (CTJ). Furthermore, they propose guidelines for selection of the appropriate approach based on this new categorization system. METHODS In the midsagittal section of the cervicothoracic MR imaging studies obtained in 95 Chinese patients, a triangle was drawn among 3 points: the suprasternal notch (SSN), the midpoint of the anterior border of the C7/T1 intervertebral disc, and the corresponding anterior border in the CTJ at the level of the SSN. The angle above the SSN was specified as the cervicothoracic angle (CTA). The spatial position between the brachiocephalic vein (BCV), the aortic arch, and the CTA was also measured. Based on these measurements involving the CTA, 3 different patient-specific categorizations are proposed to assist surgeons with selection of the appropriate anterior approach to the CTJ. Three categories of operative approach based on whether the most caudal part of the lesion site was above, within, or below the area of the CTA were classified. The patients were divided into long- or short-necked groups based on whether their own CTA was greater than (long necked) or less than (short necked) the average CTA. Finally, a left BCV was called superiorly located when it coursed above the manubrium. The method was evaluated in 21 patients with spinal bone tumors in the CTJ to illustrate the measurement of both the CTA and the great vessels, and corresponding approach selections. RESULTS In this series of 95 patients, the most common vertebra above the SSN was T-3, especially the upper one-third of T-3. The mean CTA was 47.64 degrees . The left BCV was superior to the manubrium in 21.1% of the 95 cases, and 93.6% of the left BCVs were at the T-2 and T-3 levels. Type A and most Type B lesions could be addressed via a low suprasternal approach, or this approach combined with manubriotomy, if necessary. Type C lesions falling below the CTA will need alternative exposure techniques, including manubriotomy, sternotomy, lateral extracavitary, or thoracotomy. The spinal levels that could be exposed in the long-necked CTJ group were always 1 or 2 vertebral levels lower than those in the short-necked CTJ group during the anterior low suprasternal approach without the manubriotomy. CONCLUSIONS Imaging of the thoracic manubrium should be routinely included on MR imaging studies obtained in the CTJ. It is important for the surgeon to understand the pertinent anatomy of the individual patients and to determine the feasible surgical approaches after evaluating the CTA and vascular factors preoperatively. An anterior low suprasternal approach, or this approach combined with manubriotomy, is applicable in most of the cases in the CTJ. It should be cautioned that preoperatively unrecognized variations of the left BCV above the SSN might result in potential intraoperative trauma during an anterior approach.

P50-associated COX-2 extragenic RNA (PACER) overexpression promotes proliferation and metastasis of osteosarcoma cells by activating COX-2 gene

P50-associated cyclooxygenase-2 (COX-2) extragenic RNA (PACER) is a novel long noncoding RNA that has been found to activate the COX-2 gene, which may function as an oncogene in osteosarcoma. However, the role of PACER and the relationship between PACER and COX-2 in osteosarcoma progression have been unknown until now. Here, we examined the expression levels of PACER in clinical tumor samples and human osteosarcoma cell lines, assessed the functions of PACER in osteosarcoma cell proliferation and invasion, and then explored the mechanism of PACER dysregulation in osteosarcoma. The results showed that PACER was overexpressed in osteosarcoma tissues and cell lines compared with normal tissues and osteoblasts, respectively. PACER knockdown inhibited the proliferation and invasion of human osteosarcoma cells. Downregulation of PACER significantly suppressed the expression of COX-2, and the effects of PACER on cell proliferation and invasion were rescued by COX-2 overexpression. Furthermore, COX-2 activation by PACER was NF-κB-dependent. The regulation of PACER by CCCTC-binding factor (CTCF) was associated with DNA methylation status. Taken together, these findings suggest that PACER promotes proliferation and metastasis of osteosarcoma cells by activating the COX-2 gene and its own expression was influenced by DNA methylation.

TGF-β1-induced miR-202 mediates drug resistance by inhibiting apoptosis in human osteosarcoma

PurposeA number of studies have demonstrated that microRNAs play a critical role in osteosarcoma progression, therapy and drug resistance. MicroRNA-202 has proven to be dysregulated in many human cancer studies. This study aimed to explore miR-202 contributions to drug resistance in osteosarcoma.MethodsmiR-202 expression was measured by real-time PCR in patient tissues, cell lines or cells treated with TGF-β1, using siRNA to knock down the expression of Smad2, Smad3 and Smad4. miR-202 mimics, inhibitor and scramble siRNA were transfected into osteosarcoma cells to observe effects on cell apoptosis and drug resistance. Moreover, relationships of miR-202 level with PDCD4 were investigated by luciferase reporter assay, real-time PCR and Western blotting.ResultsWe found that miR-202 is overexpressed in osteosarcoma tissues when compared with normal human osteoblasts and TGF-β1 can induce the expression of miR-202. Transfection of miR-202 mimics into osteosarcoma cell lines significantly promotes chemotherapy resistance by targeting PDCD4, a tumor suppressor which is involved in apoptosis. In contrast, transfection of miR-202 inhibitor enhances the drug sensitivity and apoptosis.ConclusionsThis study provides new insights into miRNA-202 in osteosarcoma as a potential molecular target for chemotherapy.

Malignant fibrous histiocytoma of the spine: a series of 13 clinical case reports and review of 17 published cases.

Study Design. Retrospective case study of 13 primary malignant fibrous histiocytomas (MFH) ofthe spine. Objective. To analyze the clinic, radiologic, histologic, and prognostic features of 13 cases with the MFH of the spine. Summary of Background Data. MFH, a soft tissue sarcoma, rarely occurs at the spine. Only sporadical cases have been reported in the English literature concerning the clinical and prognostic features of the primary MFH at the spine. Methods. Between January 1999 and December 2006, 13 cases with primary MFH of the spine were treated in the authors’ spine center. Clinical history, radiographic, surgery resection, and pathologic features were recorded. The patients were followed up regarding their local recurrence and survivals. The 17 cases with primary MFH at the spine in the literature were reviewed. Results. Paraspinal or epidural mass at multiple spinal levels developed in 11 cases, with osteolytic destruction in all 13 cases. The tumor size averaged on 10.4 cm in greatest dimension. Metastases occurred in 10 of 13 cases. Compared with the 14 ± 0.60-months median survival of the debulking surgeries in seven cases, the median survival of the en bloc resection in six cases was 25 ± 6.12 months (P ∇ 0.009). The median survival was 8.7 months in 10 cases of the literature group, with 30% 1-year survival and 6.7% 2-year survival, respectively; while the median survival was 18.0 months in the authors’ series, with 92.3% 1-year survival and 38.5% 2-year survival, respectively. The 5-year survival was between 25% and 69% in the extremities of MFH, but it was 28% in the head and neck and 26.7% in the abdominal cavity, compared with 7.7% in the spine in the authors’ series. Conclusion. The MFH of the spine tends to extensively invade paraspinal structures at multiple spinal levels, with aggressive osteolytic destruction in the vertebrae, resulting to local huge mass, radiculopathy, and myelopathy. Regardless of recent advancements in the diagnosis, treatment methods, and adjuvant therapies, for its biologically aggressive nature, it frequently recurs at the primary site and metastasizes. It has a worse prognosis than that of MFH in other sites.

En Bloc Resection of Primary Malignant Bone Tumor in the Cervical Spine Based on 3-Dimensional Printing Technology.

To investigate the feasibility and safety of en bloc resection of cervical primary malignant bone tumors by a combined anterior and posterior approach based on a three‐dimensional (3‐D) printing model.

An Up-regulation of IRF-1 After a Spinal Cord Injury: Implications for Neuronal Apoptosis

IRF-1, a kind of transcription factor, is expressed in many cell types, except in early embryonal cells. IRF-1 has played an essential role in various physiological and pathological processes, including tumor immune surveillance, viral infection, development of immunity system and pro-inflammatory injury. However, the expression and function of IRF-1 in spinal cord injury (SCI) are still unknown. In this study, we have performed an acute SCI model in adult rats and investigated the dynamic changes of IRF-1 expression in the spinal cord. Western blot have shown that IRF-1 protein levels gradually increased, reaching a peak at day 3 and then gradually declined to a normal level at day 14 after SCI. Double immunofluorescence staining showed that IRF-1 immunoreactivity was found in neurons, but not in astrocytes and microglia. Additionally, colocalization of IRF-1/active caspase-3 was detected in neurons. In vitro, IRF-1 depletion, by short interfering RNA, obviously decreases neuronal apoptosis. In conclusion, this is the first description of IRF-1 expression in spinal cord injury. Our results suggested that IRF-1 might play crucial roles in CNS pathophysiology after SCI.

HIF1/2α mediates hypoxia-induced LDHA expression in human pancreatic cancer cells

Glycolysis is a typical conduit for energy metabolism in pancreatic cancer (PC) due to the hypoxic microenviroment. Lactate dehydrogenase A (LDHA) catalyzes the conversion of pyruvate to lactate and is considered to be a key checkpoint of anaerobic glycolysis. The aim of the present study was to explore the mechanism of interactions between hypoxia, HIF-1/2α and LDHA, and the function of LDHA on PC cells by analyzing 244 PC and paratumor specimens. It was found that LDHA was over-expressed and related to tumor stages. The result of in vitro study demonstrated that hypoxia induced LDHA expression. To explore the relationship between HIF and LDHA, chromatin immunoprecipitation assay and luciferase assay were performed. The result showed that HIF-1/2α bound to LDHA at 89bp under the hypoxic condition. Furthermore, knockdown of endogenous HIF-1α and HIF-2α decreased the LDHA expression even in the hypoxic condition, which was accompanied with a significant decrease in lactate production and glucose utilization (p < 0.01). Immunofluorescence in the 244 specimens showed that HIF-1/2α was over-expressed and associated with LDHA over-expression (p < 0.0001). Forced expression of LDHA promoted the growth and migration of PC cells, while knocking down the expression of LDHA inhibited the cell growth and migration markedly. In summary, the present study proved that HIF1/2α could activate LDHA expression in human PC cells, and high expression of LDHA promoted the growth and migration of PC cells.

MDM2 knockdown mediated by a triazine-modified dendrimer in the treatment of non-small cell lung cancer

Non-small cell lung cancer (NSCLC) is the most common type of lung cancer and the five-year survival rate is lower in advanced NSCLC patients. Chemotherapy is a widely used strategy in NSCLC treatment, but is usually limited by poor therapeutic efficacy and adverse effects. Therefore, a new therapeutic regimen is needed for NSCLC treatment. Gene therapy is a new strategy in the treatment of NSCLC. However, the lack of efficient and low toxic vectors remains the major obstacle. Here, we developed a biocompatible dendrimer as a non-viral vector for the delivery of mouse double minute2 (MDM2) siRNA in vitro and in vivo to treat NSCLC. The triazine-modified dendrimer efficiently stimulates the down-regulation of MDM2 gene in NSCLC PC9 cells, which induces significant cell apoptosis through the activation of apoptosis markers such as caspase-8 and poly(ADP-ribose) polymerase (PARP) cleavage. Furthermore, the dendrimer/MDM2 siRNA polyplexes showed excellent activity in the inhibition of tumor growth in a PC9 xenograft tumor model. These results suggested that inhibition the expression of MDM2 might be a potential target in NSCLC treatment.

HIF-1α activates hypoxia-induced BCL-9 expression in human colorectal cancer cells

B-cell CLL/lymphoma 9 protein (BCL-9), a multi-functional co-factor in Wnt signaling, induced carcinogenesis as well as promoting tumor progression, metastasis and chemo-resistance in colorectal cancer (CRC). However, the mechanisms for increased BCL-9 expression in CRC were not well understood. Here, we report that hypoxia, a hallmark of solid tumors, induced BCL-9 mRNA expression in human CRC cells. Analysis of BCL-9 promoter revealed two functional hypoxia-responsive elements (HRE-B and HRE-C) that can be specifically bound with and be transactivated by hypoxia inducible factors (HIF) -1α but not HIF-2α. Consistently, ectopic expression of HIF-1α but not HIF-2α transcriptionally induced BCL-9 expression levels in cells. Knockdown of endogenous HIF-1α but not HIF-2α by siRNA largely abolished the induction of HIF by hypoxia. Furthermore, there was a strong association of HIF-1α expression with BCL-9 expression in human CRC specimens. In summary, results from this study demonstrated that hypoxia induced BCL-9 expression in human CRC cells mainly through HIF-1α, which could be an important underlying mechanism for increased BCL-9 expression in CRC.

XCR1 promotes cell growth and migration and is correlated with bone metastasis in non-small cell lung cancer.

Bone metastasis occurs in approximately 30-40% patients with advanced non-small cell lung cancer (NSCLC), but the mechanism underlying this bone metastasis remains poorly understood. The chemokine super family is believed to play an important role in tumor metastasis in lung cancer. The chemokine receptor XCR1 has been identified to promote cell proliferation and migration in oral cancer and ovarian carcinoma, but the role of XCR1 in lung cancer has not been reported. In this study, we demonstrated for the first time that XCR1 was overexpressed in lung cancer bone metastasis as compared with that in patients with primary lung cancer. In addition, the XCR1 ligand XCL1 promoted the proliferation and migration of lung cancer cells markedly, and knockdown of XCR1 by siRNA abolished the effect of XCL1 in cell proliferation and migration. Furthermore, we identified JAK2/STAT3 as a novel downstream pathway of XCR1, while XCL1/XCR1 increased the mRNA level of the downstream of JAK2/STAT3 including PIM1, JunB, TTP, MMP2 and MMP9. These results indicate that XCR1 is a new potential therapeutic target for the treatment of lung cancer bone metastasis.