Jiayi Yu

An Effective Treatment Option for Kümmell Disease With Neurological Deficits: Modified Transpedicular Subtraction and Disc Osteotomy Combined With Long-Segment Fixation.

Study Design. Retrospective cohort study. Objective. To illustrate the technique of modified transpedicular subtraction and disc osteotomy combined with long-segment fixation for the treatment of Kümmell disease with neurologic deficits and to evaluate clinical and radiographic results of patients treated with the technique. Summary of Background Data. Kümmell disease is a clinical condition in which patients develop a kyphosis in the lower thoracolumbar spinal region months to years after sustaining an otherwise asymptomatic minor spinal. Currently, for patients with neurological deficits, anterior decompression with bone grafting fusion, posterior decompression with pedicle subtraction osteotomy, or a combined anterior and posterior approach operation were used; however, there is no standard treatment and no single effective treatment for Kümmell disease. Methods. Between May 2009 and May 2012, we reviewed 12 patients experiencing Kümmell disease with neurological deficits who underwent modified transpedicular subtraction and disc osteotomy combined with long-segment fixation. Preoperative and postoperative Cobb angle, visual analog scale, Asia Spinal Injury Association, and sagittal balance were documented. The patients were followed up for 33 months on average. Results. The Cobb angles decreased from 43.33 ± 7.44° to 1.92 ± 2.74° (P < 0.01), the mean visual analog scale reduced from 7.17 ± 1.27° to 1.17 ± 1.03° (P < 0.01), and the sagittal vertical angle improved from 14.82 ± 3.56 cm to 5.15 ± 2.10 cm (P < 0.01). Kyphotic deformity was successfully corrected and solid fusion was achieved in all cases. Neurologic function of nine cases was improved to various degrees. Conclusion. Modified transpedicular subtraction and disc osteotomy combined with long-segment fixation is an effective treatment option for Kümmell disease with neurological deficits. Level of Evidence: 4

Frequent Genetic Aberrations in the CDK4 Pathway in Acral Melanoma Indicate the Potential for CDK4/6 Inhibitors in Targeted Therapy

Purpose: Effective therapies for the majority of metastatic acral melanoma patients have not been established. Thus, we investigated genetic aberrations of CDK4 pathway in acral melanoma and evaluated the efficacy of CDK4/6 inhibitors in targeted therapy of acral melanoma. Experimental Design: A total of 514 primary acral melanoma samples were examined for the copy number variations (CNV) of CDK4 pathway-related genes, including Cdk4, Ccnd1, and P16INK4a, by QuantiGenePlex DNA Assay. The sensitivity of established acral melanoma cell lines and patient-derived xenograft (PDX) containing typical CDK4 aberrations to CDK4/6 inhibitors was evaluated. Results: Among the 514 samples, 203 cases, 137 cases, and 310 cases, respectively, showed Cdk4 gain (39.5%), Ccnd1 gain (26.7%), and P16INK4a loss (60.3%). The overall frequency of acral melanomas that contain at least one aberration in Cdk4, Ccnd1, and P16INK4a was 82.7%. The median overall survival time for acral melanoma patients with concurrent Cdk4 gain with P16INK4a loss was significantly shorter than that for patients without such aberrations (P = 0.005). The pan-CDK inhibitor AT7519 and selective CDK4/6 inhibitor PD0332991 could inhibit the cell viability of acral melanoma cells and the tumor growth of PDX with Cdk4 gain plus Ccnd1 gain, Cdk4 gain plus P16INK4a loss, and Ccnd1 gain plus P16INK4a loss. Conclusions: Genetic aberration of CDK4 pathway is a frequent event in acral melanoma. Acral melanoma cell lines and PDX containing CDK4 pathway aberrations are sensitive to CDK4/6 inhibitors. Our study provides evidence for the testing of CDK4/6 inhibitors in acral melanoma patients. Clin Cancer Res; 23(22); 6946–57. ©2017 AACR.

Systemic Immune-Inflammation Index and Circulating T-Cell Immune Index Predict Outcomes in High-Risk Acral Melanoma Patients Treated with High-Dose Interferon

High-dose interferon alfa-2b (IFN-α-2b) improves the survival of patients with high-risk melanoma. We aimed to identify baseline peripheral blood biomarkers to predict the outcome of acral melanoma patients treated with IFN-α-2b. Pretreatment baseline parameters and clinical data were assessed in 226 patients with acral melanoma. Relapse-free survival (RFS) and overall survival (OS) were assessed using the Kaplan-Meier method, and multivariate Cox regression analyses were applied after adjusting for stage, lactate dehydrogenase (LDH), and ulceration. Univariate analysis showed that neutrophil-to-lymphocyte ratio ≥2.35, platelet-to-lymphocyte ratio ≥129, systemic immune-inflammation index (SII) ≥615 × 109/l, and elevated LDH were significantly associated with poor RFS and OS. The SII is calculated as follows: platelet count × neutrophil count/lymphocyte count. On multivariate analysis, the SII was associated with RFS [hazard ratio (HR)=1.661, 95% confidence interval (CI): 1.066-2.586, P=.025] and OS (HR=2.071, 95% CI: 1.204-3.564, P=.009). Additionally, we developed a novel circulating T-cell immune index (CTII) calculated as follows: cytotoxic T lymphocytes/(CD4+ regulatory T cells × CD8+ regulatory T cells). On univariate analysis, the CTII was associated with OS (HR=1.73, 95% CI: 1.01-2.94, P=.044). The SII and CTII might serve as prognostic indicators in acral melanoma patients treated with IFN-α-2b. The indexes are easily obtainable via routine tests in clinical practice.

Mutations in BRAF codons 594 and 596 predict good prognosis in melanoma

B-Raf proto-oncogene serine/threonine kinase (BRAF) V600E is the most common kinase-activating mutation and is associated with poor prognosis in melanoma. However, the clinical significance of kinase-impairing mutations remains unclear. The present study aimed to analyze kinase-impairing mutations in BRAF codons 594 and 596 in non-Caucasian patients with melanoma and to investigate their possible clinical significance. To detect hotspot mutations, exon 15 of the BRAF gene was amplified using polymerase chain reaction in samples from 1,554 patients with melanoma. Among these patients, a total of 912 valid follow-up data were obtained. These patients were divided into three groups according to their BRAF activation status: BRAF wild-type (n=752), BRAF V600E (n=147); and BRAF D594/G596 (n=13). Then the correlation between BRAF activation status, and the clinicopathological features and overall survival (OS) of the patients were analyzed. The prevalence of BRAF mutations in non-Caucasian patients with melanoma was 24.3% (377/1554). Three patients carried two mutations simultaneously. The overall mutation frequencies of kinase-activating mutations, kinase-impairing mutations, and mutations with unknown effects were 93.4 (355/380), 3.4 (13/380), and 3.2% (12/380), respectively. BRAF V600E was identified to be associated with a poor prognosis. Patients with BRAF mutations in codons 594 and 596 had a longer OS time compared with those with a BRAF V600E mutation [median OS, 45 vs. 25 months; HR, 0.45 (95% confidence interval, 0.31–0.97); P=0.043]. To the best of our knowledge, this is the first study to examine a large number of samples from non-Caucasian patients with melanoma and report the characteristics of BRAF mutations according to mutant kinase activity. Melanoma arising from a mutation in BRAF codon 594 or 596 can be differentiated from BRAF V600E-induced melanoma, and mutations in these codons may be good prognostic factors for melanoma. The results of the present study are thus of significance for the development of accurate personalized medicine to treat melanoma.

Y Shape Osteotomy in Ankylosing Spondylitis, a Prospective Case Series with Minimum 2 Year Follow-Up

The aim of the study is to evaluate the efficacy of a spinal osteotomy technique, Y shape osteotomy, for correcting kyphosis in AS patients planned preoperatively with computer software-assistance. 36 consecutive AS patients with thoracolumbar kyphosis were treated with one-stage posterior Y shape osteotomy and preoperative surgical planning was done with the aid of the Surgimap Spine. Radiological parameters of simulation and immediate postoperation were documented. Clinical and radiological results were evaluated in the preoperative, the early postoperative periods and during the last follow-up. The lumbar lordosis was found as 40.7 ± 4.1 degrees in the surgical planning and 49.7 ± 3.9 degrees postoperatively (p<0.01). PI-LL was 3.8± 0.9°in the simulation procedure and 6.6± 1.5°postoperatively (p<0.01). At the final follow-up, Global sagittal balance was restored and Both Oswestry Disability Index and Scoliosis Research Society scores improved largely. In conclusion, Y shape osteotomy is a safe and effective treatment option for AS patients with kyphosis deformity.

Lymphocyte-Related Inflammation and Immune-Based Scores Predict Prognosis of Chordoma Patients After Radical Resection

The inflammatory microenvironment plays a critical role in the development and progression of malignancies. In the present study, we aimed to evaluate the prognostic value of lymphocyte-related inflammation and immune-based prognostic scores in patients with chordoma after radical resection, including the neutrophil-lymphocyte ratio (NLR), platelet-lymphocyte ratio (PLR), monocyte-lymphocyte ratio (MLR), and systemic immune-inflammation index (SII). A total of 172 consecutive patients with chordoma who underwent radical resection were reviewed. R software was used to randomly select 86 chordoma patients as a training set and 86 chordoma patients as a validation set. Potential prognostic factors were also identified, including age, sex, tumor localization, KPS, Enneking stage, tumor size, and tumor metastasis. Overall survival (OS) was calculated using the Kaplan–Meier method and multivariate Cox regression analyses. NLR, PLR, SII, Enneking stage, tumor differentiation and tumor metastasis were identified as significant factors from the univariate analysis in both the training and validation sets and were subjected to multivariate Cox proportional hazards analysis. The univariate analysis showed that NLR ≥1.65, PLR ≥121, and SII ≥370×109/L were significantly associated with poor OS. In the multivariate Cox proportional hazard analysis, SII, Enneking stage and tumor metastasis were significantly associated with OS. As noninvasive, low-cost, reproducible prognostic biomarkers, NLR, PLR and SII could help predict poor prognosis in patients with chordoma after radical resection. This finding may contribute to the development of more effective tailored therapy according to the characteristics of individual tumors.

Increased AURKA Gene Copy Number Correlates with Poor Prognosis and Predicts the Efficacy of High-dose Interferon Therapy in Acral Melanoma

Background: AURKA kinase is an essential serine/threonine kinase for mitosis and chromosome stability. The aberrant amplification and overexpression of AURKA are commonly observed in various types of cancer, including cutaneous melanoma. However, the status and the clinical significance of AURKA copy number (CN) in acral melanoma (AM) have not been fully elucidated. Methods: Four hundred and seventy-two AM samples were included in the study. AURKA CN was examined using the QuantiGenePlex DNA Assay. We analysed the relationship of AURKA CN to clinicopathological characteristics and survival of patients with AM. Results: In this study, AURKA copy gain (set as more than 2.0 copies) was detected in 24.6% (116/472) of the samples. We did not observe any obvious correlation between clinicopathological characteristics and AURKA copy gain of the patients. However, patients with AURKA copy gain had a significantly shorter overall survival time (OS) and progression-free survival time (PFS) than those with normal AURKA CN (OS: P = 0.022; PFS: P < 0.001). Furthermore, multivariate Cox regression analysis showed that AURKA copy gain was an independent poor prognostic factor for patients with AM undergoing adjuvant interferon therapy. Conclusions: This study suggested that AURKA copy gain is an adverse prognostic factor for AM. Furthermore, AURKA copy gain may be a useful biomarker to predict the outcome of interferon therapy in patients with AM.

Methylation of O6-methylguanine DNA methyltransferase promoter is a predictive biomarker in Chinese melanoma patients treated with alkylating agents

Background: The O6-methylguanine-DNA methyltransferase gene ( MGMT ) promoter methylation status can be used to predict the prognosis of patients with various cancers following treatment with alkylating agents. Moreover, MGMT promoter methylation often coexists with TP53 gene mutation. However, MGMT has not been identified as a biomarker of melanoma. Therefore, this study systematically analyzed the prognostic role of MGMT and the correlation between MGMT methylation and TP53 mutation in non-Caucasian patients with melanoma. Methods: This study involved tumor samples and clinical data collected from 205 melanoma patients treated with alkylating agents at Peking University Cancer Hospital & Institute. The MGMT promoter methylation and TP53 mutation status were analyzed respectively using methylation-specific polymerase chain reaction and polymerase chain reaction followed by Sanger sequencing. Additionally, MGMT protein expression in tumor samples was assessed via immunohistochemistry. Results: MGMT promoter methylation was detected in 97 (47%) of the 205 tumor samples, and was significantly associated with a loss of MGMT protein expression (P=0.021). MGMT promoter methylation was also significantly associated with the presence of TP53 mutation (P=0.004). Regarding prognosis, patients without MGMT promoter methylation exhibited worse overall survival outcomes, compared to those with methylation (hazard ratio: 1.443; 95% confidence interval: 0.731–2.342; P=0.015). Conclusions: MGMT promoter methylation appears to coexist frequently with TP53 mutation. Patients harboring MGMT promoter methylation within tumors may benefit from therapy with alkylating agents.

Gene expression screening identifies CDCA5 as a potential therapeutic target in acral melanoma

Acral melanoma (AM) is a rapidly progressing subtype of melanoma with poor prognosis. The complete array of molecular changes that occur during AM metastasis remains unclear. In this study, we compared the gene expression profiles of 6 primary and 12 lymph node metastatic AM samples by tissue microarray analysis. We found that the expression levels of 396 genes were increased and that of 766 genes were decreased in the metastatic tissues compared with that in the primary tumors. The top 19 genes upregulated in the metastatic tissue specimens were selected for high-content short interfering RNA screening. We found that inhibition of cell division cycle-associated 5 (CDCA5) significantly suppressed AM cell migration and invasion. Furthermore, we demonstrated that upregulation of CDCA5 was correlated with higher tumor-node-metastases stages (P=.025) and a shorter disease-free survival in patients with AM (P=.038). Cox regression analyses showed that high CDCA5 expression was also an independent factor of disease-free survival for patients with AM (hazard ratio =1.86, P=.041). Overall, our data define the gene expression signature of AM metastasis and indicate that CDCA5 is a potential therapeutic target in AM.

High G2 and S-phase expressed 1 expression promotes acral melanoma progression and correlates with poor clinical prognosis

G2 and S‐phase expressed 1 (GTSE1) regulates cell cycle progression in human cancers. However, its significance and mechanism of action in acral melanoma (AM) remain unknown. In the present study, we found that GTSE1 expression was upregulated in advanced stage/metastatic AM tissues and metastatic cell lines, and correlated with higher stage (P = .028) and poor disease‐free survival (DFS) in patients with AM (P = .003). Cox regression assays validated GTSE1 expression to be an independent prognostic factor of DFS for patients with AM (P = .004). Ectopic expression of GTSE1 enhanced primary AM cell proliferation, invasion, and migration. Loss‐of‐function in GTSE1 attenuated metastatic AM cell proliferation and metastatic ability in vitro and in vivo. We additionally observed that inhibition of migration and invasion occurred concomitantly with a GTSE1 knockdown‐mediated increase in E‐cadherin and decreases in N‐cadherin and Slug. We further showed that integrin subunit alpha 2 (ITGA2) interacts with GTSE1 and is a downstream effector of GTSE1. Further, ITGA2 levels were positively correlated with GTSE1 expression in human AM tissues. Ectopic ITGA2 expression rescued siGTSE1‐mediated inhibition of migration and invasion, thereby restoring epithelial‐to‐mesenchymal transition (EMT). In conclusion, GTSE1 expression promotes AM progression and correlates with clinical outcomes of patients with AM, and may represent a promising therapeutic target to suppress AM progression.