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Background The aim of the study was to explore the treatment outcomes and prognostic factors for patients with previously irradiated but unresectable recurrent head and neck squamous cell carcinoma (rHNSCC) treated by stereotactic body radiotherapy (SBRT) plus cetuximab at a single institute in Taiwan. Methods From February 2016 to March 2019, 74 patients with previously irradiated but unresectable rHNSCC were treated with SBRT plus cetuximab. All patients received irradiation to the gross tumor and/or nodal area with 40-50 Gy in five fractions, with each fraction interval ≥ 2 days over a 2-week period by using the CyberKnife M6 machine. An18F-fluorodeoxyglucose positron emission tomography-computed tomography (PET-CT) scan was performed before treatment for treatment target delineation (n = 74) and 2 months later for response evaluation (n = 60). The median follow-up time was 9 months (range 1-36 months). Results The treatment response rate was complete response: 25.0%, partial response: 41.7%, stable disease: 11.7%, and progressive disease: 21.7% based on the criteria of the Response Evaluation Criteria in Solid Tumors (n = 72) and complete metabolic response: 21.7%, partial metabolic response: 51.7%, stable metabolic disease: 13.3%, and progressive metabolic disease: 13.3% based on PET-CT (n = 60), respectively. The 1-/2-year overall survival (OS) and progression-free survival (PFS) rates were 42.8%/22.0% and 40.5%/19.0%, respectively. In the logistic regression model, a re-irradiation interval > 12 months was observed to be the only significant prognostic factor for a favorable treatment response. In the Cox proportional hazards model, a re-irradiation interval > 12 months and gross tumor volume (GTV) ≦ 50 ml were favorable prognostic factors of OS and PFS. Conclusion SBRT plus cetuximab provides a promising salvage strategy for those patients with previously irradiated but unresectable rHNSCC, especially those with a re-irradiation interval > 12 months or GTV ≦ 50 ml.

Concurrent chemoradiation therapy (CCRT) is the mainstay treatment for patients with nasopharyngeal carcinoma (NPC). Baroreflex impairment can be a late sequela in patients after neck radiotherapy. We hypothesized that cardiovascular autonomic dysfunction is a progressive process that can begin after CCRT and persists for a longer period.Cardiovascular autonomic function was assessed in 29 newly diagnosed patients with NPC using standardized measures including heart rate response to deep breathing (HRDB), Valsalva ratio (VR), baroreflex sensitivity (BRS), and analyses of heart rate variability (HRV), biomarkers of oxidative stress, and inflammation at three different time points (baseline, immediately after CCRT, and 9 years after enrollment). A healthy control group was recruited for the comparison.Although there was an aging effect on autonomic parameters in both groups during the 9 years of follow-up, the between-group comparison showed that there was a significant decrease in HRDB, VR, and HRV at the 9th year of follow-up in the NPC group. Repeated measures ANOVA after controlling for age and sex showed that both HRDB and triangle index of HRV had statistically significant differences between the two groups.Based on our results, cardiovascular autonomic dysfunction after CCRT is a progressive and dynamic process. Cardiovagal impairment occurs in the early phase and persists in decline, while adrenergic dysfunction is significant only after a 9-year follow-up. In contrast to the current opinion, our study showed that both afferent and efferent baroreflex pathways can be involved after CCRT.

Patients with head and neck cancer (HNC) are vulnerable to psychiatric comorbidities, particularly anxiety and depression, and also suffer from cancer stigma. This study aimed to comprehensively compare HNC patients’ stigma, depression, and anxiety, and elucidate the underlying relationships among them. This cross-sectional study recruited inpatients with HNC from a medical center. Measurements included a psychiatric diagnostic interview, the Shame and Stigma Scale (SSS), the Hamilton Anxiety Rating Scale (HAM-A), the Hamilton Depression Rating Scale (HAM-D), the Explanatory Model Interview Catalogue (EMIC), and stressors of HNC patients. Structural equation modeling was used to establish models of potential mechanisms. Those patients having stressors of worry about health (t = 5.21, p

Oral squamous cell carcinoma (OSCC) remains one of the most challenging clinical problems in the field due to its high rate of locoregional and distant metastases. However, studies that assess the association between aspirin use and survival in patients with OSCC are limited. Moreover, patients that recruited from those studies might have tumors that arose from different anatomic regions of the head and neck, including the oral cavity, oropharynx, etc. Since tumors within these distinct anatomic regions are unique in the context of epidemiology and tumor progression, we sought to evaluate the association of aspirin use with squamous cell carcinomas located within the oral cavity only. In this 10-year cohort study, we evaluated aspirin use and survival rates in relation to clinical characteristics as well as duration of aspirin use in patients with OSCC. Our findings suggest that OSCC patients with aspirin use for more than 180 days showed improved overall and disease-specific survival rates. Aspirin also improves survival in patients across various stages of OSCC. Cox regression models indicated that aspirin use was associated with a good prognosis. In conclusion, this evidence indicates that aspirin may be potentially used as an adjuvant therapy for OSCC.

Objective: For patients with esophageal squamous cell carcinoma, preoperative chemoradiotherapy followed by planned esophagectomy is used as a curative treatment modality. However, the impact of radiotherapy dose remains undefined. Method: A total of 141 patients with stage III esophageal squamous cell carcinoma (ESCC, as defined by the 7th American Joint Committee on Cancer), receiving preoperative chemoradiotherapy followed by esophagectomy between 2000 and 2015 at Kaohsiung Chang Gung Memorial Hospital, Taiwan, were retrospectively reviewed. The radiotherapy dose of preoperative chemoradiotherapy (36 Gy before 2009 and 50–50.4 Gy after 2009) and other clinicopathological parameters were collected and correlated with the response to chemoradiotherapy and treatment outcome. Result: Of these 141 patients, the radiotherapy dose was 36 Gy in 59 (42%) patients and 50 Gy in 82 (58%) patients. A complete pathological response was noted in 12 (20%) of 59 patients receiving 36 Gy radiotherapy, and 37 (45%) of 82 patients receiving 50 Gy radiotherapy (p = 0.002). The three-year overall survival and disease-free survival rates were 31% and 25% in patients receiving 36 Gy radiotherapy, and 54% and 46% in patients receiving 50–50.4 Gy radiotherapy, respectively (p = 0.023 for overall survival, p = 0.047 for disease-free survival). Multivariate analysis showed that a higher radiotherapy dose was associated with increased pathological complete response (p = 0.003, hazard ratio: 3.215), better overall survival (p = 0.024, hazard ratio: 1.585), and superior disease-free survival (p = 0.049, hazard ratio: 1.493). However, higher radiotherapy doses revealed more surgical complications, including acute respiratory distress syndrome (p = 0.048) and anastomosis leaks (p = 0.004). Conclusion: For patients with locally advanced ESCC, preoperative chemoradiotherapy with higher radiotherapy doses led to increased pathologic complete response rates and improved survival.

Background To evaluate the longitudinal changes of quality of life (QoL) and survival in patients with nasopharyngeal carcinoma (NPC) treated by volumetric-modulated arc therapy (VMAT) versus intensity-modulated radiotherapy (IMRT). Methods One hundred and forty non-distant metastatic NPC patients treated by VMAT (n = 66) or IMRT (n = 74) with simultaneously integrated boost between March 2013 and December 2015 at a single institute were analyzed. QoL was prospectively assessed by the EORTC QLQ-C30 and HN35 questionnaires at the four time points: before RT, RT 42.4 Gy (20 fractions), and 3, 12 months after RT. Results The 3-year locoregional relapse-free survival, distant metastasis-free survival, failure-free survival, and overall survival rates were 96.6, 89.4, 86.1%, and 87.4 for the VMAT group, respectively, compared with 91.4, 90.0, 79.8, and 91.3% for the IMRT group (p value > 0.05). The pattern of QoL changes was similar between the VMAT and IMRT group. No statistically or clinically significant difference in all the QoL scales was observed between VMAT and IMRT group at each time point. Compared to before RT, we observed statistically (p Conclusion The study provides the evidence that the tumor control, survival and changes of QoL is compatible for NPC patients treated by VMAT versus IMRT.

Background Oral cancer with pT1-3N1 without extracapsular extension of the lymph node is classified as stage III according to the eighth edition of the AJCC staging system. Outcomes of a subgroup of patients classified as having stage III oral cancer with single nodal metastasis are observed to be various clinically. Therefore, such clinical outcomes for subgroup analyses in this cohort are necessary. Methods Patients with pT1-3N1 (based on the eighth edition of the AJCC staging system) oral cancer who underwent surgery between 2007 and 2016 were enrolled retrospectively for survival analyses. Results A total of 105 patients—including 28 patients with pT1N1 disease and 77 patients with pT2-3N1 disease—participated in the study. Pathological T classification was the only statistically significant prognosticator according to univariate analysis. The patients with pT1N1 disease showed better 5-year overall survival (OS), disease specific survival (DSS), and disease free survival (DFS) than those with pT2-3N1 disease (pT1N1 vs pT2-3N1, OS: 96.4% vs 72.2%, p = 0.004; DSS: 96.4% vs 77.3%, p = 0.021; DFS: 84.6% vs 62.3%, p = 0.023). Besides, there was no potential clinicopathological confounder which is significant associated with different pathological T classifications in this unique cohort. Conclusions Patients in the pT1N1 subgroup have significantly favorable prognosis than those with pT2-3N1 disease. Down-staging and reclassifying pT1N1 subgroup patients with oral cancer may be considered in tumor staging. Graphical Abstract

Background To investigate the toxicity, changes of quality of life (QOL), and survival for patients with nasopharyngeal cancer (NPC) treated by concurrent chemoradiotherapy (CCRT) with simultaneously integrated boost volumetric-modulated arc therapy (SIB-VMAT). Methods A total of 68 NPC patients treated by CCRT with SIB-VMAT technique were collected. QOL was longitudinally assessed by the EORTC QLQ-C30 and HN35 questionnaires at the 4 time points: baseline, 42.4 Gy (20 fractions), and 3, 12 months after CCRT. Results The 4-year locoregional relapse free, distant metastasis free, failure free, and overall survival rates were 97.0%, 86.4%, 82.0%, and 88.1%, respectively. The 4-year cumulative incidence rate of late toxicities with grade 3 or more was 3.0%. One year after CCRT, most QOL scales, except some oral related symptoms, recovered to baseline level. Conclusion CCRT with SIB-VMAT produces excellent locoregional control, few severe late toxicity, and good general health status for NPC patients.

Patients with advanced head and neck squamous cell carcinoma (HNSCC) usually show a dismal prognosis. It is this worthwhile to develop new, effective therapeutic regimens for these patients, such as molecular targeted therapy, which is promising as an alternative or combination treatment for HNSCC. The mammalian target of rapamycin (mTOR) pathway, which plays an important role in the carcinogenesis of HNSCC, is the most frequently activated, and is thus worthy of further investigation. In this study, two human HNSCC cell lines, FaDu and SAS, were evaluated for cell growth with trypan blue staining and tumor growth using an orthotopic xenograft model. The immunohistochemical expression of mTOR in the subcutaneous xenograft model and the inhibitory effects of docetaxel on the growth and state of activation of the PI3K/mTOR pathway were also evaluated and examined by colony formation and Western blot, respectively. Cell proliferation and migration were measured by water-soluble tetrazolium salt (WST-1) and OrisTM cell migration assay, respectively. Furthermore, the effects of rapamycin and BEZ235, a phosphatidylinositol 3-kinases (PI3K) and mTOR inhibitor in combination with docetaxel or CCL20 were evaluated in the FaDu and SAS cells. The results showed that the expression of mTOR was significantly higher in the SAS and FaDu xenograft models than in the control. Docetaxel treatment significantly suppressed HNSCC cell proliferation and migration in vitro via the PI3K/mTOR/CCL-20 signaling pathway. Additionally, when administered in a dose-dependent fashion, mTOR inhibitors inhibited the growth and migration of the HNSCC cells. This combination was synergistic with docetaxel, resulting in almost complete cell growth and migration arrest. In conclusion, docetaxel significantly inhibited HNSCC cell proliferation and migration in vitro via the PI3K/mTOR/CCL-20 signaling pathway. The synergistic and additive activity of mTOR inhibitors combined with docetaxel shows potential as a new treatment strategy for HNSCC.

Background: To assess the presence of adverse pathological features at the time of salvage total laryngectomy (TL) associated with oncologic outcome. Methods: Ninety patients with persistent/locally recurrent disease and who subsequently underwent salvage TL after definitive treatment by radiation alone (RTO) or concurrent chemo-radiation (CCRT) from 2009 to 2018 were retrospectively enrolled. Kaplan&ndash, Meier methods were used to estimate overall survival (OS), disease-specific survival (DSS), and disease-free survival (DFS). Results: Lymphovascular invasion (LVI), perineural invasion, positive margin, and stage IV disease were associated with worse survival in the univariate analysis. In the multivariate analysis, the presence of LVI and positive margin were both independent negative predictors in OS (LVI: adjusted hazard ratio (aHR) = 2.537, 95% CI: 1.163&ndash, 5.532, p = 0.019, positive margin: aHR = 5.68, 95% CI: 1.996&ndash, 16.166, p = 0.001), DSS (LVI: aHR = 2.975, 95% CI: 1.228&ndash, 7.206, p = 0.016), positive margin: aHR = 11.338, 95% CI: 2.438&ndash, 52.733, p = 0.002), and DFS (LVI: aHR 2.705, 95% CI: 1.257&ndash, 5.821, p = 0.011, positive margin (aHR = 6.632, 95% CI: 2.047&ndash, 21.487, p = 0.002). Conclusions: The presence of LVI and positive margin were both associated with poor OS, DSS, and DFS among patients who underwent salvage TL after failure of RTO/CCRT. The role of adjuvant therapy for high-risk patients after salvage TL to improve the chance of survival requires more investigation in the future.

Myxofibrosarcoma is genetically complex and lacks effective nonsurgical treatment strategies; thus, elucidation of novel molecular drivers is urgently needed. Reanalyzing public myxofibrosarcoma datasets, we identified mRNA upregulation and recurrent gain of RSF1 and characterized this chromatin remodeling gene. Myxofibrosarcoma cell lines were employed to elucidate the oncogenic mechanisms of RSF1 by genetic manipulation and two IL-1β-neutralizing antibodies (RD24, P2D7KK), highlighting the regulatory basis and targetability of downstream IL-1β-mediated angiogenesis. Tumor samples were assessed for RSF1, IL-1β, and microvascular density (MVD) by immunohistochemistry and for RSF1 gene status by FISH. In vivo, RSF1-silenced and P2D7KK-treated xenografts were analyzed for tumor-promoting effects and the IL-1β-linked therapeutic relevance of RSF1, respectively. In vitro, RSF1 overexpression promoted invasive and angiogenic phenotypes with a stronger proangiogenic effect. RT-PCR profiling identified IL1B as a top-ranking candidate upregulated by RSF1. RSF1 required hSNF2H and CEBP/β to cotransactivate the IL1B promoter, which increased the IL1B mRNA level, IL-1β secretion and angiogenic capacity. Angiogenesis induced by RSF1-upregulated IL-1β was counteracted by IL1B knockdown and both IL-1β-neutralizing antibodies. Clinically, RSF1 overexpression was highly associated with RSF1 amplification, IL-1β overexpression, increased MVD and higher grades (all P ≤ 0.01) and independently predicted shorter disease-specific survival (P = 0.019, hazard ratio: 4.556). In vivo, both RSF1 knockdown and anti-IL-1β P2D7KK (200 μg twice weekly) enabled significant growth inhibition and devascularization in xenografts. In conclusion, RSF1 overexpression, partly attributable to RSF1 amplification, contributes a novel proangiogenic function by partnering with CEBP/β to cotransactivate IL1B, highlighting its prognostic, pathogenetic, and therapeutic relevance in myxofibrosarcomas.

The management of cT4b thoracic esophageal cancer (EC) is challenging. The optimal treatment remains unclear, and prospective or large-scale retrospective reports on treatment outcomes are lacking. The present study was conducted to investigate the treatment outcomes, failure patterns, treatment responses, and prognostic factors focusing on cT4b thoracic EC treated by definitive concurrent chemoradiotherapy (dCRT).A retrospective review of cT4b thoracic EC patients treated with curative intent dCRT at our institution between 2009 and 2017 was conducted. Survival analysis was calculated using the Kaplan-Meier method, and prognostic factors were examined by the Cox proportional hazards model.A total of 95 cT4b EC patients were included, and the median survival was 11.4 months. The 1-year, 3-year, and 5-year survival rates were 49.4%, 22.2%, and 19.0%, respectively. Forty-six patients (48.4%) experienced locoregional failure, 3 patients (3.2%) developed distant metastasis, and 11 patients had synchronous locoregional and distant failure. The corresponding 1-year, 3-year, and 5-year locoregional failure rates were 62.6%, 74.5%, and 79.2%, respectively. The treatment response rate was 76.9%, and clinical complete response was achieved in 25.3% of patients. Multivariable analysis revealed that age ≤ 65 (p = 0.003), pre-dCRT body mass index (BMI) 21 (p 0.001), clinical N stage 0-1 (p = 0.014), and tumor length ≤ 6 cm (p = 0.026) were independent prognosticators for better survival.Our study revealed that long-term survival is achievable for cT4b EC patients treated by dCRT, with a 3-year survival rate of more than 20%. Locoregional recurrence was the most common failure pattern. Age, BMI, N stage, and tumor length were significant prognosticators for survival in this group of patients.

ObjectiveTo determine the predictive factors of postoperative hospital stay and total hospital medical cost among patients who underwent total laryngectomy.MethodsA total of 213 patients who underwent total laryngectomy in a tertiary referral center for tumor ablation were enrolled retrospectively between January 2009 and May 2018. Statistical analyses including Pearson's chi-squared test were used to determine whether there was a significant difference between each selected clinical factors and outcomes. The outcomes of interest including postoperative length of hospital stay and inpatient total medical cost. Logistic regression analyses were performed to reveal the relationship between clinical factors and postoperative length of hospital stay or total inpatient medical cost.ResultsPreoperative radiotherapy (p = 0.007), method of wound closure (p < 0.001), postoperative serum albumin level (p = 0.025), and postoperative serum hemoglobin level (p = 0.04) were significantly associated with postoperative hospital stay in univariate analysis. Postoperative hypoalbuminemia (odds ratio [OR]: 2.477; 95% confidence interval [CI]: 1.189-5.163; p = 0.015) and previous radiotherapy history (OR 2.194; 95% CI: 1.228-3.917; p = 0.008) are independent predictors of a longer postoperative hospital stay in multiple regression analysis. With respect to total inpatient medical cost, method of wound closure (p < 0.001), preoperative serum albumin level (p = 0.04), postoperative serum albumin level (p < 0.001), and history of liver cirrhosis (p = 0.037) were significantly associated with total inpatient medical cost in univariate analysis. Postoperative hypoalbuminemia (OR: 6.671; 95% CI: 1.927-23.093; p = 0.003) and microvascular free flap reconstruction (OR: 5.011; 95% CI: 1.657-15.156; p = 0.004) were independent predictors of a higher total inpatient medical cost in multiple regression analysis.ConclusionsPostoperative albumin status is a significant factor in predicting prolonged postoperative hospital stay and higher inpatient medical cost among patients who undergo total laryngectomy. In this cohort, the inpatient medical cost was 48% higher and length of stay after surgery was 35% longer among hypoalbuminemia patients.

Background: This retrospective cohort study was to assess the prognostic value of preoperative albumin-to-alkaline phosphatase ratio (AAPR) on survival outcome for patients with locally advanced oral squamous cell carcinoma (LAOSCC). Methods: A total of 250 patients with LAOSCC receiving upfront radical surgery at a single institute from January 2008 to December 2017 were enrolled. The primary endpoint was the survival predictability of preoperative AAPR on the 5-year overall survival (OS), cancer-specific survival (CSS), and disease-free survival (DFS). Cox proportional hazards model was used for survival analysis. The X-tile software was used to estimate the optimal cut-off value of preoperative AAPR on survival prediction. A predictive nomogram incorporating the clinicopathological factors on OS was further generated. Results: The 5-year OS, CSS, and DFS rates were 68.6%, 79.7%, and 61.7%, respectively. The optimal cut-off of preoperative AAPR to predict the 5-year OS was observed to be 0.51. For those with preoperative AAPR≧0.51, the 5-year OS, CSS, and DFS were statistically significantly superior to those with preoperative AAPR

Objectives Angiotensin II receptor blockers (ARBs) improve the survival rates of patients with various cancers. However, it remains unclear whether ARBs confer a survival benefit on patients with oral squamous cell carcinoma (OSCC). Here, we assessed the associations between ARB use and survival in patients with OSCC of different stages. Materials and methods This was a 10-year retrospective cohort study of OSCC patients. We enrolled 7,558 patients diagnosed with oral cancer between January 2007 and December 2017 whose details had been entered into the Chang Gung Research Database. Seven hundred and fourteen patients were recruited from the Chang Gung Research Database after performing 1:1 propensity score-matching between ARB users and non-users. Cox’s regression models with adjusted covariates were employed to detect factors influencing the survival rates of patients with OSCC. Results Kaplan-Meier analysis revealed that the overall survival (OS) rate of 180-day ARB users increased (p = 0.038). Cox’s regression models indicated that ARB use, younger patients, early-stage OSCC, and patients without diabetes mellitus were independently prognostic of improved OS. Increased OS was more prominent in 180-day ARB users in stage III, Iva, and IVb categories. Conclusions ARB use for more than 180 days is associated with an increased survival rate and is a positive, independent prognostic factor in patients with OSCC. A further two-arm study should be conducted to confirm the clinical usefulness of ARBs in OSCC patients.

To evaluate the differences in the treatment outcomes and complications between elderly patients and younger patients with uterine cervical cancer (CxCa).From April 1993 to December 2007, 138 CxCa patients aged ≥75years (Elderly group) and 334 CxCa patients aged60years (Young group) who underwent definitive radiotherapy/chemoradiotherapy at our institution were reviewed. Two propensity score-matched cohorts of patients were selected from both age groups to evaluate the differences in the outcomes and complications. The overall survival (OS), cancer-specific survival (CSS), local failure (LF), distant failure (DF), late proctitis, and cystitis were compared between the age groups.The median follow-up time for survivors was 60.6months. A cohort of 99 pairs of patients was selected for the outcome comparison; there was a significant difference in the 5-year OS between the Elderly and Young groups (49.2% and 71.5%, respectively; p0.001) but no differences in CSS, LF, and DF. Another cohort of 79 pairs of patients was selected for complication analysis. Significant differences between the Elderly and Young groups were observed in the 5-year cumulative grade 2 proctitis (39.7% and 17.2%, respectively; p=0.015) and grade 3 proctitis (18.1% and 6.2%, respectively; p=0.040).Although OS was worse in the elderly patients, no differences were observed in CSS, LF, and DF. Meanwhile, elderly patients tended to have higher radiation-related proctitis than younger patients. A more conservative treatment strategy for elderly CxCa patients is reasonable in our future practice.

// Chien-Feng Li 1, 2, 3, 8 , Ting-Ting Liu 4 , I-Chieh Chuang 4, 8 , Yen-Yang Chen 5 , Fu-Min Fang 6 , Ti-Chun Chan 1 , Wan-Shan Li 7, 8 , Hsuan-Ying Huang 4, 8 1 Department of Pathology, Chi-Mei Medical Center, Tainan, Taiwan 2 National Institute of Cancer Research, National Health Research Institutes, Tainan, Taiwan 3 Department of Biotechnology, Southern Taiwan University of Science and Technology, Tainan, Taiwan 4 Department of Pathology, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan 5 Division of Oncology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan 6 Department of Radiation Oncology, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan 7 Department of Pathology, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan 8 Bone and Soft Tissue Study Group, Taiwan Society of Pathology, Taiwan Correspondence to: Hsuan-Ying Huang, email: cfli.hyhuang@gmail.com Keywords: metabolism, lipid catabolism, PLCB4, transcriptome, GIST Abbreviations: GIST, gastrointestinal stromal tumor; NIH, National Institute of Health; NCCN, National Comprehensive Cancer Network; PLCB4, phospholipase C-s4. Received: October 09, 2016 Accepted: December 08, 2016 Published: February 13, 2017 ABSTRACT To explore the implications of lipid catabolism-associated genes in gastrointestinal stromal tumors, we reappraised transcriptomic and genomic datasets and identified copy-gained and differentially upregulated PLCB4 gene associated with tumor progression. On full sections, PLCB4 mRNA abundance and PLCs4 immunoexpression were validated in 70 cases. On tissue microarrays, PLCB4 gene copies and PLCs4 immunoexpression were both informative in 350 cases with KIT/PDGFRA/BRAF genotypes noted in 213. In GIST48 cell line, we stably silenced PLCB4 and YAP1 to characterize their functional effects and regulatory link. Compared with normal tissue, PLCB4 mRNA abundance significantly increased across tumors of various risk levels (p

This study investigated the therapeutic benefit of radical resection (SRR) for clinical T4b oral cavity squamous cell carcinoma (OSCC) with partial or complete response after radical chemoradiotherapy (CRT).At the authors' institution, 79 patients with newly diagnosed non-metastatic T4b OSCC were treated with CRT from January 2009 to December 2014. All of them were irradiated using intensity-modulated radiotherapy (IMRT), with a radical dose (median 70 Gy; range 66-76 Gy) in the gross tumor area. Of the 65 cases achieving partial or complete response after CRT, 33 were treated further with SRR and 32 with adjuvant chemotherapy or observation. The locoregional control (LRC), overall survival (OS), and cancer-free survival (CFS) rates were compared between the two groups.The 3-year LRC, OS, and CFS rates were respectively 72.3, 75.1, and 72.6 % in the SRR group compared with 32.8, 47.7, and 44.3 % in the non-SRR group (p0.05). Multivariate analysis showed that SRR was the only statistically significant prognostic factor related to LRC, OS, and CFS. For those with SRR, pathologic downstaging was observed in 27 cases (81.8 %). Perioperative flap failure was observed in three cases (9.2 %) and neck wound necrosis in four cases (12.1 %).For T4b OSCC, incorporating SRR in the therapy is technically safe and has survival benefit, with a significant response after CRT applied by IMRT, with a radical dose in the gross tumor area.

The role of deregulated cellular metabolism, particularly lipid metabolism, in gastrointestinal stromal tumors (GISTs) remains unclear. Through data mining of published transcriptomes, we examined lipid metabolism-regulating drivers differentially upregulated in high-risk cases and identified monoglyceride lipase (MGLL) as the top-ranking candidate involved in GIST progression. MGLL expression status was examined in three GIST cell lines and two independent sets of primary localized GISTs. MGLL mRNA abundance and immunoexpression was determined in 70 cases through the QuantiGene assay and H-scoring on whole sections, respectively. H-scoring was extended to another cohort for evaluating MGLL immunoexpression on tissue microarrays, yielding 350 informative cases, with KIT/PDGFRA mutation genotypes noted in 213 of them. Both imatinib-sensitive (GIST882) and -resistant (GIST48 and GIST430) cell lines exhibited increased MGLL expression. MGLL mRNA levels significantly increased from adjacent normal tissue to the non-high-risk group (p = 0.030) and from the non-high-risk group to high-risk GISTs (p = 0.012), and were associated with immunoexpression levels (p < 0.001, r = 0.536). MGLL overexpression was associated with the nongastric location (p = 0.022) and increased size (p = 0.017), and was strongly related to mitosis and risk levels defined by NIH and NCCN criteria (all p ≤ 0.001). Univariately, MGLL overexpression was strongly predictive of poorer disease-free and overall survival (both p < 0.001), which remained prognostically independent for both endpoints, along with higher risk levels. Conclusively, MGLL is a lipid metabolic enzyme causatively implicated in GIST progression given its association with unfavorable clincopathological factors and independent negative prognostic effects.

Background To scrutinize the pretreatment prognosticators on survival and late toxicities in a homogenous cohort of nasopharyngeal carcinoma (NPC) patients treated by simultaneous integrated boost intensity-modulated radiation therapy (SIB-IMRT). Methods A total of 219 non-distant metastatic NPC patients consecutively treated by SIB-IMRT at a single institute were collected. The pretreatment factors including the socio-demographic variables, TNM stages, gross tumor volume (GTV), Epstein-Barr virus (EBV)-DNA, and hematologic inflammatory markers were analyzed. Cox model was used to screen the prognostic factors of late toxicities and four survival outcomes including locoregional relapse-free survival (LRRFS), distant metastasis-free survival (DMFS), failure-free survival (FFS), and overall survival (OS). Results Statistically significant inter-correlations were observed between the values of EBV-DNA, some hematologic inflammatory markers, GTV, and N classification. The 5-year LRRFS, DMFS, FFS, and OS rates were 87.9%, 89.4%, 79.4%, and 81.3%, respectively. Multivariate analysis revealed that advanced N classification (N2–3 vs. N0–1) remained the only significant negative prognosticator for all the four survival outcomes. An increased monocyte percentage and a decreased lymphocyte-to-monocyte ratio were significantly associated with poorer FFS and OS, respectively. Larger GTV was observed to be predictive of poorer LRRFS. Patients with T3–4 (HR: 3.5, 95% CI: 1.0–12.1, p = 0.048) or higher GTV (HR: 1.006, 95% CI: 1.001–1.011, p = 0.027) were associated with higher incidence of radiation neuropathy. Conclusion N classification remains the most significant survival predictor for NPC patients treated by SIB-IMRT after adjusting these biomarkers. GTV impacts not only on locoregional control but also radiation neuropathy.

Solitary fibrous tumor (SFT) is characterized by the inv12(q13q13)-derived NAB2-STAT6 fusion, which exhibits variable breakpoints and drives STAT6 nuclear expression. The implications of NAB2-STAT6 fusion variants in pathological features and clinical behavior remain to be characterized in a large cohort of SFTs. We investigated the clinicopathological correlates of this genetic hallmark and analyzed STAT6 immunoexpression in 28 intrathoracic, 37 extrathoracic, and 23 meningeal SFTs. These 88 tumors were designated as histologically nonmalignant in 75 cases and malignant in 13, including 1 dedifferentiated SFT. Eighty cases had formalin-fixed and/or fresh samples to extract assessable RNAs for RT-PCR assay, which revealed NAB2-STAT6 fusion variants comprising 12 types of junction breakpoints in 73 fusion-positive cases, with 65 (89%) falling into 3 major types. The predominant NAB2ex4-STAT6ex2 (n=33) showed constant breakpoints at the ends of involved exons, whereas the NAB2ex6-STAT6ex16 (n=16) and NAB2ex6-STAT6ex17 (n=16) might exhibit variable breakpoints and incorporate NAB2 or STAT6 intronic sequence. Including 73 fusion-positive and 7 CD34-negative SFTs, STAT6 distinctively labeled 87 (99%) SFTs in nuclei, exhibited diffuse reactivity in 73, but did not decorate 98 mimics tested. In seven fusion-negative cases, 6 were STAT6-positive, suggesting rare fusion variants not covered by RT-PCR assay. Regardless of histological subtypes, intrathoracic SFTs affected older patients (P=0.035) and tended to be larger in size (P=0.073). Compared with other variants, NAB2ex4-STAT6ex2/4 fusions were significantly predominant in the SFTs characterised by intrathoracic location (P

CD105 is rich in endothelium cells and is involved in angiogenesis. Higher microvascular density of tumor is also related to the prognosis in a variety of cancers. In this present study, patients with positive N classification, advanced T classification, advanced TNM stage, extracapsular spread of lymph nodes (ECS), and perineural invasion had significantly higher levels of peripheral vein (pCD105) and venous return from tumor (tCD105) in 71 patients with OSCC compared to 13 healthy volunteers. Those with higher pCD105 or tCD105 levels had significantly poorer 5-year disease-specific survival rate (DDS) and overall survival rate (OS). The tCD105 and pCD105 levels and ECS were the independent prognostic factors by the multivariate analysis according to the Cox regression model in 5-year DDS and OS rate. SAS and SCC4 cells treated with CD105 showed the increase in migration, invasion, and proliferation in vitro and in vivo. Furthermore, CCL20 expression participated in CD105-elicited cell motility in oral cancer cells. In conclusion, higher level of circulating CD105 is related to adverse pathological features among patients with OSCC. It is also a useful marker for evaluating the prognosis and targeting therapeutics of OSCC.

Background Until recently, post-radiotherapy brain abscess was considered rare, but it has become an increasingly important aetiology. Discussions of the relationship between bacterial brain abscess and radiotherapy (RT) are rare in the literature. Our clinical study was conducted to analyse the role of RT in the pathogenesis of bacterial brain abscess. Methods For our retrospective study, 146 patients with bacterial brain abscess were recruited. Ten patients with a history of RT before brain abscess formation were reviewed. Results Eight of these patients underwent RT treatment for nasopharyngeal carcinoma, one for olfactory neuroblastoma, and another for nasal plasmacytoma. Three showed presence of temporal lobe radiation necrosis neighbouring abscess. Eight patients were shown to have the evidence of tumour invasion. Seven had evidence of nasal infection or otitis media. Statistically significant differences between the RT and non-RT patients were observed for radionecrosis, bone defects between the middle fossa/sphenoid sinus, and the presence of nasal infection/otitis media. The mortality rate was 30%. Conclusion This study shows possible pathogenesis of bacterial brain abscess formation in post-irradiated patients, which is complicated by both radiation effects and tumour effects. Skull base deficits (either from tumour erosion or osteonecrosis) and nasal/ear infection were significantly different in patients who received radiation vs. those who did not. Radiation-related temporal lobe necrosis was also a predisposing factor. Further study based on a proper patient cohort is warranted.

Conventional therapeutic processes in patient with OSCC are associated with several unfavorable effects leading to patients with poor survival rate. Metformin has been shown to protect against a variety of specific diseases, including cancer. However, the precise roles and mechanisms underlying the therapeutic effects of metformin on OSCC remain elusive. In the current study, in vitro and xenograft model experiments revealed that metformin inhibited growth and metastasis of oral cancer cells. Importantly, metformin-restrained tumorigenesis of oral cancer was accompanied with strong decrease of both Aurora-A and Late SV40 Factor (LSF) expressions. Furthermore, LSF contributed to Aurora-A-elicited malignancy behaviors of oral cancer via binding to the promoter region of Aurora-A. A significant correlation was observed between LSF and Aurora-A levels in a cohort of specimens of oral cancer. These findings showed that a novel LSF/Aurora-A-signaling inhibition supports the rationale of using metformin as potential OSCC therapeutics.

Purpose: Myxofibrosarcomas frequently display arm-level gains on 5p. We characterized the pathogenetic and therapeutic relevance of the α-methylacyl coenzyme A racemase (AMACR) at 5p13.3. Experimental Design: AMACR mRNA expression in myxofibrosarcomas was analyzed using the public transcriptome and laser-microdissected sarcoma cells. We performed florescence in situ hybridization (FISH) and immunohistochemistry in independent samples for clinical correlates. In AMACR-overexpressing myxofibrosarcoma cells and xenografts, we elucidated the biologic function of AMACR using RNA interference and explored the therapeutic effect and mechanism of an AMACR inhibitor, ebselen oxide. Results: AMACR protein overexpression and gene amplification were significantly associated with each other (P < 0.001), with higher tumor grades (both P ≤ 0.002), and univariately with worse metastasis-free survival (MFS; both P < 0.0001) and disease-specific survival (DSS; P = 0.0002 for overexpression; P = 0.0062 for amplification). AMACR protein overexpression also independently portended adverse outcome (DSS, P = 0.007; MFS, P = 0.001). However, 39% of AMACR-overexpression cases did not show gene amplification, implying alternative regulatory mechanisms. In myxofibrosarcoma cell lines, stable AMACR knockdown suppressed cell proliferation, anchorage-independent growth, and expression of cyclin D1 and cyclin T2. These growth-promoting attributes of AMACR were corroborated in the AMACR-silenced xenograft model and AMACR-underexpressed myxofibrosarcomas, showing decreased labeling for cyclin D1, cyclin T2, and Ki-67. Compared with fibroblasts, AMACR-expressing myxofibrosarcoma cells were more susceptible to ebselen oxide, which not only decreased viable cells, promoted proteasome-mediated degradation of AMACR protein, and induced cellular apoptosis in vitro, but also dose-dependently suppressed xenografted tumor growth in vivo. Conclusions: Overexpressed AMACR in myxofibrosarcomas can be amplification-driven, associated with tumor aggressiveness, and may be relevant as a druggable target. Clin Cancer Res; 20(23); 6141–52. ©2014 AACR.

Myxofibrosarcomas are genetically complex and involve recurrently deleted chromosome 9p, for which we characterized the pathogenically relevant target(s) using genomic profiling. In 12 of the 15 samples, we detected complete or partial losses of 9p. The only aggressiveness-associated, differentially lost region was 9p21.3, spanning the potential inactivated methylthioadenosine phosphorylase (MTAP) that exhibited homozygous (4/15) or hemizygous (3/15) deletions. In independent samples, MTAP gene status was assessed using quantitative- and methylation-specific PCR assays, and immunoexpression was evaluated. We applied MTAP reexpression or knockdown to elucidate the functional roles of MTAP and the therapeutic potential of L-alanosine in MTAP-preserved and MTAP-deficient myxofibrosarcoma cell lines and xenografts. MTAP protein deficiency (37%) was associated with MTAP gene inactivation (P < 0.001) by homozygous deletion or promoter methylation, and independently portended unfavorable metastasis-free survival (P = 0.0318) and disease-specific survival (P = 0.014). Among the MTAP-deficient cases, the homozygous deletion of MTAP predicted adverse outcome. In MTAP-deficient cells, MTAP reexpression inhibited cell migration and invasion, proliferation, and anchorage-independent colony formation and downregulated cyclin D1. This approach also attenuated the tube-forming abilities of human umbilical venous endothelial cells, attributable to the transcriptional repression of MMP-9, and abrogated the susceptibility to L-alanosine. The inhibiting effects of MTAP expression on tumor growth, angiogenesis, and the induction of apoptosis by L-alanosine were validated using MTAP-reexpressing xenografts and reverted using RNA interference in MTAP-preserved cells. In conclusion, homozygous deletion primarily accounts for the adverse prognostic impact of MTAP deficiency and confers the biological aggressiveness and susceptibility to L-alanosine in myxofibrosarcomas.

Summary Purpose This study was designed to estimate the life expectancy (LE) and quality-adjusted life expectancy (QALE) in non-metastatic nasopharyngeal cancer (NPC) patients. Methods and materials Patients were eligible for the present study if they were diagnosed with NPC and had been treated with intensity-modulated radiotherapy (IMRT) between January 1, 2003 and December 31, 2010. The quality of life (QOL) data were collected using the questionnaires of the European Organization for Research and Treatment of Cancer (EORTC) QLQ-C30 and QLQ-H&N35. The LE of NPC patients was obtained using linear extrapolation of a logit-transformed curve and was adjusted by the corresponding QOL function to calculate the QALE. Results During the study period, 110 patients met the inclusion criteria, and 53 of these completed questionnaires. The median follow-up was 65.2 months (range 4.0–117.3 months). The average LE and QALE were estimated to be 20.6 years and 11.6 quality-adjusted life years (QALYs) for NPC patients and 24.4 years and 24.4 QALYs for the reference population, respectively. Compared to the reference population, the loss of LE and QALE for NPC patients were 3.8 years and 12.8 QALYs, respectively. Conclusions This study offers a quick overview of the LE and the QALE of NPC patients treated with IMRT. Moreover, the results appear more understandable than the 5 year survival outcomes when communicating with patients or the general population regarding cancer risk. In the future, evaluating the robustness of comparative assessments for the outcome of NPC patients undergoing different treatment protocols will be possible.

// Chih-Yen Chien 1,2,* , Hsin-Ting Tsai 1,2,7,* , Li-Jen Su 3 , Hui-Ching Chuang 1,2 , Li-Yen Shiu 4 , Chao-Cheng Huang 2,5 , Fu-Min Fang 2,6 , Chun-Chieh Yu 7 , Huei-Ting Su 7 , and Chang-Han Chen 1,2,7 1 Department of Otolaryngology, Kaohsiung Chang Gung Memorial Hospital, and Chang Gung University College of Medicine, Kaohsiung, Taiwan 2 Kaohsiung Chang Gung Head and Neck Oncology Group, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung Taiwan 3 Graduate Institute of Systems Biology and Bioinformatics, National Central University, Jhongli, Taiwan 4 Department of Medical Research, Cell Therapy and Research Center, E-Da Hospital, I-shou University, Kaohsiung, Taiwan 5 Department of Pathology, Kaohsiung Chang Gung Memorial Hospital, and Chang Gung University College of Medicine, Kaohsiung Taiwan 6 Department of Radiation Oncology, Kaohsiung Chang Gung Memorial Hospital, and Chang Gung University College of Medicine, Kaohsiung Taiwan 7 Center for Translational Research in Biomedical Sciences, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung Taiwan * The authors contributed this study equally Correspondence: Chang-Han Chen, email: // Keywords : HNSCC, Aurora-A, osteopontin, CD44, ERK Received : February 5, 2014 Accepted : April 11, 2014 Published : April 11, 2014 Abstract The clinical significances, cellular effects, and molecular mechanisms by which Aurora-A mediate its invasive effects in HNSCC are still unclear. Here, we found that Aurora-A expression is significantly higher in tumor tissues on 14-microarray of HNSCC in Oncomine-databases. The activity of Aurora-A was not only found in HNSCC specimens, but also significantly correlated with advanced-T-classification, positive-N-classification, TNM-stage and the poor 5-year survival rate. HNSCC-microarray profile showed that osteopontin and Aurora-A exhibited positive correlation. Stimulation of HNC cells with osteopontin results in an increase in Aurora-A expression where localized at the centrosome. Functionally, Aurora-A had the abilities to stimulate cell motility in HNC cells through increase ERK1/2 activity under osteopontin stimulation. Conversely, depletion of Aurora-A expression by siRNAs suppressed ERK1/2 activity as well as inhibition of cell invasiveness. Treatment with anti-CD44 antibodies in HNC cells not only caused a decrease of mRNA/protein of Aurora-A and ERK1/2 activity upon osteopontin stimulation, but also affected the abilities of Aurora-A-elicited cell motility. Finally, immunohistochemical/Western-blotting analysis of human aggressive HNSCC specimens showed a significant positively correlation between osteopontin-Aurora-A and ERK1/2. These findings suggest that Aurora-A is not only an important prognostic factor but also a new therapeutic target in the osteopontin/CD44/ERK pathway for HNSCC treatment.

OBJECTIVES: Metachronous oesophageal squamous cell carcinoma (OSCC) has been increasing in long-term survivors of upper aerodigestive tract (UADT) cancers in recent years, but the treatment of such cases is not well established. The aim of this study was to compare the prognosis between patients with metachronous OSCC who had antecedent UADT cancers and patients with isolated OSCC. METHODS: From January 1995 to December 2009, we retrospectively compared the data from 84 patients with metachronous OSCC who had antecedent UADT cancers (metachronous group) with the data from 527 patients with isolated OSCC (isolated group) according to their treatment modalities at Kaohsiung Chang Gung Memorial Hospital. RESULTS: Overall, the metachronous group had significantly (P= 0.03) worse overall survival than the isolated group. For patients receiving surgery or preoperative chemoradiotherapy followed by surgery, the overall survival rates and incidence of postoperative complications were not significantly different. For patients receiving definite chemoradiotherapy or radiotherapy alone, the metachronous group had significantly (P= 0.02) inferior overall survival compared with the isolated group. CONCLUSIONS: Offering a radical approach for the treatment of patients with metachronous OSCC who had antecedent UADT cancers is justifiable, with survival rates similar to those of patients with isolated OSCC.

We investigated the expression and clinical significance of activin receptor-like kinase 1 (ACVRL1) in patients with head and neck squamous cell carcinoma (HNSCC).Case series with chart review.Academic Institute of Otolaryngology, Kaohsiung, Taiwan.Patients diagnosed with HNSCC (n = 169) underwent surgical resection followed by radiotherapy and/or chemotherapy for aggressive tumors between November 2000 and March 2004. ACVRL1 expression was assessed using quantitative reverse transcription polymerase chain reaction (qRT-PCR) and immunohistochemistry approaches.High levels of ACVRL1 expression were significantly correlated with advanced T classification (P.001), positive N classification (P = .002), advanced TNM stage (P.001), lymphovascular invasion (P.001), and extracapsular spread of lymph node metastasis (P = .021). A poor 5-year overall survival rate was correlated with high ACVRL1 expression (P = .0048), advanced T classification (P = .0075), positive N classification (P = .0024), advanced TNM stage (P = .0077), and extracapsular spread of lymph node (P = .0002), but a multivariate analysis using the Cox regression model revealed that the only independent prognostic factors for survival were ACVRL1 expression (P = .043; odds ratio [OR], 1.635; 95% confidence interval [CI], 1.017-2.629) and extracapsular spread of lymph node metastasis (P = .003; OR, 2.052; 95% CI, 1.270-3.315).A high level of ACVRL1 expression in tumor tissue is significantly correlated with advanced T classification, positive N classification, advanced TNM stage, and poorer prognosis.

Purpose: In gastrointestinal stromal tumors (GIST), lipid-metabolizing enzymes remain underexplored, including fatty acid synthase (FASN). Experimental Design: Forty GISTs were quantitated for FASN mRNA abundance. FASN immunoexpression was informative in 350 GISTs, including 213 with known KIT/PDGFRA/BRAF genotypes. In imatinib-resistant FASN-overexpressing GIST cells, the roles of overexpressed FASN and FASN-targeting C75 in tumor phenotypes, apoptosis and autophagy, KIT transcription, PI3K/AKT/mTOR activation, and imatinib resistance were analyzed by RNAi or myristoylated-AKT transfection. The therapeutic relevance of dual blockade of FASN and KIT was evaluated in vivo. Results: FASN mRNA abundance significantly increased from very low/low-risk to high-risk levels of NCCN guidelines (P < 0.0001). FASN overexpression was associated with a nongastric location (P = 0.05), unfavorable genotype (P = 0.005), and increased risk level (P < 0.001) and independently predicted shorter disease-free survival (P < 0.001). In vitro, FASN knockdown inhibited cell growth and migration, inactivated the PI3K/AKT/mTOR pathway, and resensitized resistant GIST cells to imatinib. C75 transcriptionally repressed the KIT promoter, downregulated KIT expression and phosphorylation, induced LC3-II and myristoylated AKT-suppressible activity of caspases 3 and 7, attenuated the PI3K/AKT/mTOR/RPS6/4E-BP1 pathway activation, and exhibited dose-dependent therapeutic additivism with imatinib. Compared with both monotherapies, the C75/imatinib combination more effectively suppressed the growth of xenografts, exhibiting decreased KIT phosphorylation, Ki-67, and phosphorylated PI3K/AKT/mTOR levels and increased TUNEL labeling. Conclusions: We have characterized the prognostic, biological, and therapeutic implications of overexpressed FASN in GISTs. C75 represses KIT transactivation, abrogates PI3K/AKT/mTOR activation, and provides a rationale for dual blockade of KIT and FASN in treating imatinib-resistant GISTs. Clin Cancer Res; 23(16); 4908–18. ©2017 AACR.

Background Smoking and betel nut chewing are well-known risk factors for head and neck squamous cell carcinoma (HNSCC). Smoking is also a strong prognosticator for patients with locally advanced HNSCC receiving induction chemotherapy. Smoking with or without betel nut chewing is a common practice in Asia. However, little is known regarding whether betel nut chewing can serve as a prognostic factor for smoking patients with locally advanced HNSCC receiving induction chemotherapy. The aim of this study was to evaluate the prognostic impact of betel nut chewing in such patients receiving induction chemotherapy with docetaxel, cisplatin, and fluorouracil (TPF). Methods From January 2010 to December 2012, we retrospectively analyzed 162 smoking patients with locally advanced HNSCC who received induction chemotherapy with TPF at our institution. Background characteristics, including a history of betel nut chewing, were analyzed as potential prognostic factors. Results Among the 162 smoking patients, 131 patients (81 %) were betel nut chewers, while 31 (19 %) were non-betel nut chewers. One hundred fifty-six (96 %) were men, and 6 (4 %) were women. The median age was 53 years. The overall response rates to induction chemotherapy were 57 and 77 % in patients with and without betel nut chewing history, respectively (P = 0.038). The 2-year progression survival rates were 37 and 67 % in patients with and without betel nut chewing history, respectively (P = 0.004). The 2-year overall survival rates were 47 and 71 % in patients with and without betel nut chewing history, respectively (P = 0.017). Betel nut chewing history was independently associated with a poor response to induction chemotherapy, an inferior progression-free survival rate, and a poor overall survival rate. Conclusions Our results indicate that betel nut chewing history is independently associated with poor prognosis in smoking patients with locally advanced HNSCC receiving induction chemotherapy with TPF. Further investigation is warranted to explain this effect of betel nut chewing history on these patients’ prognosis.

To compare the grade 3 genitourinary toxicity and oncological outcome for localized prostate cancer between high-dose-rate (HDR) brachytherapy and external beam radiation therapy (EBRT) alone in patients with previously undergone Transurethral resection of the prostate (TURP).From November 1998 to November 2008, 78 patients with a history of TURP underwent radiation therapy for localized prostate cancer. Of these, 59 were enrolled in this study. In this study, 34 patients underwent HDR brachytherapy and 25 patients underwent EBRT alone.Grade 3 genitourinary complication was observed in 8.8 % of HDR brachytherapy group and 44 % in EBRT alone group. Five-year urinary incontinence rate was 2.9 % in HDR brachytherapy and 24 % in EBRT alone group. The results showed that significant higher incidence of grade 3 genitourinary complication (p = 0.003) and urinary incontinence was the most significant (p = 0.023) in the EBRT alone group. Five-year biochemical survival rate was 82.4 % in HDR brachytherapy group and 72.0 % in EBRT alone group (p = 0.396).In patients with prostate cancer who have previously undergone TURP, we observed that HDR brachytherapy was able to control prostate cancer with fewer GU morbidities and oncological outcomes that were similar to those associated with traditional EBRT alone. Moreover, HDR brachytherapy led to a decrease in major GU toxicity and also preserved the sphincter function more than that in TURP patients who underwent EBRT alone.

Aims To compare the performance of volumetric-modulated arc radiotherapy (VMAT) by dual arc with fixed beam intensity-modulated radiotherapies (IMRTs) and single arc VMAT on nasopharyngeal carcinomas (NPC). Materials and methods Twenty NPC cases were re-planned using the planning system of the Pinnacle 3® SmartArc (SA) module to compare the performance of the following four techniques: seven-field (7F) and 18-field (18F) fixed beam IMRT, and single (SA 1 ) and dual arc VMAT (SA 2 ). The plan was delivered on an Elekta Synergy™ Linac equipped with an 80-leaf 1cm multileaf collimator. Three dose levels of planning target volumes (PTVs) with 70/59.4/54.0Gy in 33 fractions were prescribed and delivered as a simultaneous integrated boost. The conformity index and homogeneity index of the PTVs, the comprehensive quality index (CQI), the normal tissue complication probability for the organs at risk (OARs), and the planning time, delivery efficiency and accuracy were analysed. Results A significantly inferior conformity index at the three dose levels of PTV and homogeneity index of PTV 70 were observed in SA 1 compared with the other techniques. Comparable conformity index and homogeneity index of the PTV were observed among 7F/18F IMRT and SA 2 . Based on the CQI of the 11 OARs, the most efficient dose reduction was observed in 18F IMRT followed in order by SA 2 , 7F IMRT and SA 1 . The planning time was on average 13.2/24.9/40.1/42.8min for 7F/18F IMRT/SA 1 /SA 2 , respectively. With regards to the delivery efficiency compared with 7F IMRT, a 51 and 41% reduction in delivery time was achieved by SA 1 and SA 2 , respectively. All techniques presented a high quality assurance pass rate (>98%) of the Γ 3mm,3% criterion. Conclusion In NPC cases, SA 2 gave superior results in terms of PTV coverage and OAR sparing compared with SA 1 and approached the performance achieved by 18F IMRT, but without sacrificing the delivery efficiency.

Purpose: Myxofibrosarcoma remains obscure in molecular determinants of clinical aggressiveness, for which we elucidated implications of SKP2 amplification. Experimental Design: Array comparative genomic hybridization was applied on samples and cell lines (NMFH-1 to OH931) to search causal genes of tumor progression. SKP2 gene dosage was determined in 82 independent tumors for clinical correlates. Stable SKP2 knockdown was achieved in myxofibrosarcoma cells to assess its oncogenic attributes and candidate mediators in prometastatic function. Pharmacologic assays were evaluated in vitro and in vivo for the therapeutic relevance of bortezomib. Results: DNA gains frequently involved 5p in which three amplicons were differentially overrepresented in samples behaving unfavorably, encompassing mRNA-upregulated TRIO, SKP2, and AMACR genes. Detected in NMFH-1 cells and 38% of tumors, SKP2 amplification was associated with SKP2 immunoexpression and adverse prognosticators and independently predictive of worse outcomes. Nevertheless, SKP2-expressing OH931 cells and 14% of such tumors lacked gene amplification. Knockdown of SKP2 suppressed proliferation, anchorage-independent growth, migration, and invasion of sarcoma cells and downregulated motility-promoting genes, including ITGB2, ACTN1, IGF1, and ENAH. In vitro, bortezomib downregulated SKP2 expression at the mRNA level with p27kip1 accumulation, induced caspase activation, and decreased cell viability in myxofibrosarcoma cells but not in fibroblasts. In vivo, bortezomib inhibited growth of NMFH-1 xenografts, the cells of which displayed decreased SKP2 expression but increased p27kip1 and terminal deoxynucleotidyl transferase–mediated dUTP nick end labeling (TUNEL). Conclusions: As a predominant mechanism driving protein overexpression, SKP2 amplification confers tumor aggressiveness in myxofibrosarcoma. The sensitivity of myxofibrosarcoma cells to bortezomib with SKP2-repressing effect indicates the potentiality of ubiquitin-proteasome pathway as a therapeutic target. Clin Cancer Res; 18(6); 1598–610. ©2012 AACR.

Little is known about any consequences of swallowing tobacco-free betel-quid (TF-BQ) juice/remnants following chewing and its carcinogenic impact on the upper aerodigestive tract (UADT) to gastrointestinal tract (GIT). We investigated the neoplastic impact of TF-BQ on different anatomical locations along UADT and GIT, and differences according to their histological categories. We conducted a multicenter case–control study examining patients with 2,163 pathology-proven UADT and GIT cancers, comparing them with 2,250 control subjects. Generalized additive models, piecewise regression and polytomous logistic models were applied to identify possible dose-dependent structures and cancer risks. Contrary to nonsignificant GIT-adenocarcinoma risk (aOR = 0.9), TF-BQ users experienced a 1.7- to 16.2-fold higher risk of UADT-squamous cell carcinomas than nonusers, with the peak risk discovered in oral neoplasms. We separately observed a curvilinear and linear TF-BQ dose-risk relationship in oral/pharyngeal/esophageal and laryngeal cancers. Chewers of betel inflorescence were generally at a greater UADT cancer risk. A higher first-piecewise increased risk of esophageal cancer was recognized among areca-fluid swallowers than among nonswallowers (continuous aOR = 1.12 vs. 1.03). TF-BQ use accounted for 66.1–78.7% and 17.8–33.2% of the cases of oral/pharyngeal and esophageal/laryngeal cancers, respectively. However, a reduction from heavy TF-BQ consumption to low-to-moderate consumption only reduced 11.3–34.6% of etiologic fraction of oral/pharyngeal cancers. Alcohol supra-additively modified the risk of TF-BQ in determining the development of oral, pharyngeal and esophageal cancers. In conclusion, the interplay of TF-BQ and alcohol/tobacco use, combined with how chewing habit is practiced, influences carcinogenic consequences on anatomically diverse sites of UADT and GIT cancers, and histologically different types.

As a key component of polycomb-repressive complex 2, enhancer of zeste homolog 2 (EZH2) represses target genes through histone methylation and is frequently overexpressed and associated with poor prognosis in common carcinomas. For the first time, we reported EZH2 expression and its biological and clinical significance in nasopharyngeal carcinoma (NPC).In NPC cell lines and specimens, endogenous expression of EZH2 mRNA and protein was determined by semiquantitative reverse transcription-polymerase chain reaction and immunoblotting, respectively. To analyze the effect on cell growth, stable silencing of EZH2 was established in EZH2-expressing TW02 NPC cells with RNA interference. EZH2 immunolabeling was assessable for 89 primary NPC biopsy samples and correlated with clinicopathological variables, disease-specific survival (DSS), and overall survival (OS).Growth activity of TW02 cells was significantly suppressed (p0.001) with stable EZH2 silencing. Compared with normal nasopharyngeal tissue, expression levels of EZH2 transcript and protein were apparently upregulated in NPC specimens. As a continuous variable, higher EZH2 expression preferentially occurred in NPCs of T3 to T4 stages (p = 0.03) and significantly predicted inferior DSS (p = 0.0010) and OS (p = 0.004). The prognostic implications for DSS (p = 0.010) and OS (p = 0.006) still remained valid when using the median (≥ 60%) of EZH2 immunolabeling index to dichotomize the cohort. In the multivariate model, higher EZH2 expression was an independent adverse factor of both DSS (p = 0.012) and OS (p = 0.011), along with American Joint Committee on Cancer Stages III to IV (p = 0.024 for DSS, p = 0.017 for OS).At least partly through promoting cell growth, EZH2 implicates disease progression, confers tumor aggressiveness, and represents an independent adverse prognosticator in patients with NPC.

To evaluate whether pretreatment carcinoembryonic antigen (CEA) levels have a prognostic role in patients after definitive radiotherapy for squamous cell carcinoma (SCC) of the uterine cervix.A retrospective study of 550 patients was performed. The SCC antigen (SCC-Ag) and CEA levels were regarded as elevated when they were ≥2 and ≥5 ng/mL, respectively. A total of 208 patients underwent concurrent chemoradiotherapy (CCRT). The Kaplan-Meier method was used to calculate the distant metastasis (DM), local failure (LF), disease-free survival (DFS), and overall survival (OS) rates. Multivariate analysis was performed using the Cox proportional hazards model. The hazard ratio (HR) with 95% confidence interval (CI) was evaluated for the risk of a poor prognosis.Compared with the patients with normal CEA/SCC-Ag levels, CEA levels ≥10 ng/mL but without elevated SCC-Ag levels was an independent factor for LF (HR, 51.81; 95% CI, 11.51-233.23; p.001), DM (HR, 6.04; 95% CI, 1.58-23.01; p = .008), DFS (HR, 10.17; 95% CI, 3.18-32.56; p.001), and OS (HR, 5.75; 95% CI, 1.82-18.18; p = .003) after RT alone. However, no significant role for CEA was noted in patients with SCC-Ag levels ≥2 ng/mL. In patients undergoing CCRT, a CEA level ≥10 ng/mL was an independent factor for LF (HR, 2.50; 95% CI, 1.01-6.21; p = .047), DM (HR, 3.41; 95% CI, 1.56-7.46; p = .002), DFS (HR, 2.73; 95% CI, 1.39-5.36; p = .003), and OS (HR, 3.93; 95% CI 1.99-7.75; p.001). A SCC-Ag level of ≥40 ng/mL was another prognostic factor for DM, DFS, and OS in patients undergoing not only CCRT, but also RT alone. The 5-year OS rate for CCRT patients with CEA10 ng/mL and ≥10 ng/mL was 75.3% and 35.8%, respectively (p.001). CCRT was an independent factor for better OS (HR, 0.69; 95% CI, 0.50-0.97; p = .034).Pretreatment CEA levels in patients with SCC of the uterine cervix provide complementary information for predicting LF, DM, DFS, and OS, except for in patients with abnormal SCC-Ag levels before RT alone. More aggressive therapy might be advisable for patients with CEA levels of ≥10 ng/mL.

RSF-1, also known as hepatitis B X-antigen associated protein (HBXAP), is a subunit of an ISWI chromatin remodeling complex, remodeling and spacing factor (RSF). Recent studies have provided new evidence that chromatin remodeling participates in the pathogenesis of neoplastic diseases by altering cell cycle regulation and gene expression. In this report, we studied the biological roles of RSF-1 in oral squamous cell carcinoma (OSCC), a highly invasive neoplastic disease. Based on IHC and quantitative real-time PCR, we demonstrated that RSF-1 expression could be detected in the majority of OSCC cases, and the levels were significantly higher in OSCC cells than in their normal counterparts. Moreover, expression levels of RSF-1 significantly correlated with the presence of angiolymphatic invasion, abnormal mitoses, metastasis, tumor recurrence, and advanced stage disease at presentation. Univariate and multivariate analyses showed a significant association of RSF-1 overexpression and worse overall survival in OSCC patients. RSF-1 knockdown remarkably decreased cellular proliferation and induced apoptosis in OSCC cells with high RSF-1 expression levels, but not in those without. Taken together, our results suggest that RSF-1 up-regulation is associated with several clinicopathological features of disease aggressiveness in OSCC patients, and RSF-1 plays an important role in maintaining cellular growth and survival in OSCC.

The dosimetric results of stereotactic radiosurgery (SRS) for vestibular schwannoma (VS) performed using dynamic conformal arc therapy (DCAT) with the Novalis system and helical TomoTherapy (HT) were compared using plan quality indices. The HT plans were created for 10 consecutive patients with VS previously treated with SRS using the Novalis system. The dosimetric indices used to compare the techniques included the conformity index (CI) and homogeneity index (HI) for the planned target volume (PTV), the comprehensive quality index (CQI) for nine organs at risk (OARs), gradient score index (GSI) for the dose drop-off outside the PTV, and plan quality index (PQI), which was verified using the plan quality discerning power (PQDP) to incorporate 3 plan indices, to evaluate the rival plans. The PTV ranged from 0.27-19.99 cm(3) (median 3.39 cm(3)), with minimum required PTV prescribed doses of 10-16 Gy (median 12 Gy). Both systems satisfied the minimum required PTV prescription doses. HT conformed better to the PTV (CI: 1.51 ± 0.23 vs. 1.94 ± 0.34; p < 0.01), but had a worse drop-off outside the PTV (GSI: 40.3 ± 10.9 vs. 64.9 ± 13.6; p < 0.01) compared with DCAT. No significant difference in PTV homogeneity was observed (HI: 1.08 ± 0.03 vs. 1.09 ± 0.02; p = 0.20). HT had a significantly lower maximum dose in 4 OARs and significant lower mean dose in 1 OAR; by contrast, DCAT had a significantly lower maximum dose in 1 OAR and significant lower mean dose in 2 OARs, with the CQI of the 9 OARs = 0.92 ± 0.45. Plan analysis using PQI (HT 0.37 ± 0.12 vs. DCAT 0.65 ± 0.08; p < 0.01), and verified using the PQDP, confirmed the dosimetric advantage of HT. However, the HT system had a longer beam-on time (33.2 ± 7.4 vs. 4.6 ± 0.9 min; p < 0.01) and consumed more monitor units (16772 ± 3803 vs. 1776 ± 356.3; p < 0.01). HT had a better dose conformity and similar dose homogeneity but worse dose gradient than DCAT. Plan analysis confirmed the dosimetric advantage of HT, although not all indices revealed a better outcome for HT. Whether this dosimetric advantage translates into a clinical benefit deserves further investigation.

It remains obscure in myxofibrosarcoma about the basis of tumorigenesis, progression, and metastasis. Chromosome 7 gains are common in some sarcomas, including myxofibrosarcoma, whereas the specific oncogenes are yet to be characterized. We performed an integrative study of MET gene at 7q31.2 to elucidate its implication in myxofibrosarcoma. Focused on candidate oncogenes on chromosome 7, 385K array comparative genomic hybridization was used to profile DNA copy number alterations of 12 samples. MET transcript was successfully quantified by real-time RT-PCR for 16 laser-microdissected tumors and two myxofibrosarcoma cell lines (NMFH-1, OH931). MET immunoexpression was assessable in 86 primary localized tumors with follow-up. To analyze endogenous MET expression and activation, NMFH-1 and OH931 cells, both with wild-type MET gene, were subjected to Western blotting and hepatocyte growth factor-treated NMFH-1 cells were evaluated for the kinetics of MET tyrosine phosphorylation. Non-random large-scale gains on 7q were detected in five cases, delineating three recurrent amplicons, 7q21.11-7q21.3, 7q22.1-22.3, and 7q31.1-7q32.3, in which the locus of MET displayed increased copy number, among others. MET mRNA was upregulated in OH931, NMFH-1, and nine tumors (56%), whereas neither gene dosage nor mRNA expression of MET was associated with clinicopathological factors. In contrast, MET protein overexpression, present in 67% of cases, was highly related to deep location (P=0.004), higher grades (P=0.001), and more advanced stages (P

Purpose The purpose of this study was to examine the prognostic value of pretreatment quality of life (QoL) data on locoregional control (LRC), distant metastasis-free survival (DMFS), and overall survival (OS) in patients with nasopharyngeal carcinoma (NPC). Patients and Methods A total of 347 new patients with NPC, who were curatively treated by conformal radiotherapy from March 2003 to December 2007, were recruited. The Taiwan Chinese version of the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire C30 was completed before treatment. Multivariate Cox's proportional hazards models were used to analyze the impact of clinical and QoL variables on the treatment results. Results The 5-year LRC, DMFS, and OS rates were 72.9%, 79.1%, and 68.4%, respectively. After adjusting the clinical variables, 10 QoL variables were observed to be significantly (P < .05) related to OS, and four QoL variables were related to DMFS. No QoL variable was predictive of LRC. Among the QoL variables that significantly predicted OS and DMFS, physical functioning was the most powerful predictor. A 10-point increase in the physical functioning score was associated with a 23% (95% CI, 12% to 34%) reduction in the likelihood of death and a 22% (95% CI, 9% to 36%) reduction in the likelihood of distant metastasis. Conclusion Our findings indicate that pretreatment QoL variables, especially physical functioning, provide easily available prognostic value for distant metastasis and survival in patients with NPC.

Purpose: Chromosome 9 is frequently deleted in high-risk gastrointestinal stromal tumors (GISTs), whereas its specific tumor suppressor genes (TSGs) are less understood. We did an integrative study of MTAP gene at 9p21 to analyze its implication in GISTs. Experimental Design: To search TSGs on chromosome 9, we used ultrahigh-resolution array comparative genomic hybridization to profile DNA copy number alterations of 22 GISTs, with special attention to MTAP gene. MTAP immunoexpression was assessable for 306 independent GISTs on tissue microarrays, with 146 cases analyzed for MTAP homozygous deletion, 181 for mutations of KIT and PDGFRA receptor tyrosine kinase genes, and 7 for MTAP hypermethylation. Results: Array comparative genomic hybridization identified 11 candidate TSGs on 9p and six on 9q. MTAP and/or CDKN2A/CDKN2B at 9p21.3 were deleted in one intermediate-risk (11) and seven high-risk (70) GISTs with two cases homozygously codeleted at both loci. MTAP homozygous deletion, present in 25 of 146 cases, was highly associated with larger size and higher mitotic rate, Ki-67 index, and risk level (all P < 0.01) but not with receptor tyrosine kinase genotypes. Whereas MTAP homozygous deletion correlated with MTAP protein loss (P < 0.001), 7 of 30 GISTs without MTAP expression did not show homozygous deletion, including three MTAP-hypermethylated cases. MTAP homozygous deletion was univariately predictive of decreased disease-free survival (P < 0.0001) and remained multivariately independent (P = 0.0369, hazard ratio = 2.166), together with high-risk category (P < 0.0001), Ki-67 index >5 (P = 0.0106), and nongastric location (P = 0.0416). Conclusions: MTAP homozygous deletion, the predominant mechanism to deplete protein expression, is present in 17 of GISTs. It correlates with important prognosticators and independently predicts worse outcomes, highlighting the role in disease progression. (Clin Cancer Res 2009;15(22):696372)

Ezrin, a member of the ezrin–radixin–moesin family, acts as a link between the cell membrane and actin cytoskeleton to integrate cell adhesion-mediated signaling. It implicates tumor progression, metastatic dissemination, and adverse outcomes in several cancer types, including pediatric and adult sarcomas. Although ezrin upregulation was shown by cDNA expression profiling, no study has systematically evaluated the significance of ezrin expression in a large cohort of gastrointestinal stromal tumors (GISTs). Ezrin immunostaining was carried out on tissue microarrays of primary GISTs and assessable in 347 cases, 188 of which were successfully evaluated for mutation variants of KIT and PDGFRA receptor tyrosine kinase (RTK) genes by sequencing with or without screening by denatured high-performance liquid chromatography. These GISTs with known RTK genotypes were dichotomized into two prognostically different groups. The endogenous expression and phosphorylation of ezrin in GIST cell lines were analyzed by western blotting. By immunohistochemistry, ezrin overexpression was present in 66% of GISTs and significantly associated with the non-gastric location (P=0.002) and decreased disease-free survival (P=0.032, univariately). However, it was not related to the National Institute of Health (NIH) risk category, Ki-67 labeling index, RTK genotypes, and other variables. In multivariate analyses, ezrin overexpression remained independently predictive of adverse outcome (P=0.008, risk ratio=2.363), together with Ki-67 labeling index >5% (P

Matrix metalloproteinase (MMP)-2 plays critical roles in tumor development and in the metastasis of multiple cancers, including human oral cavity squamous cell carcinoma (OCSCC). One of the upstream regulators of MMP-2 is FOXM1, which is overexpressed in a microarray dataset of OCSCC. It is interesting that FLJ10540 exhibits similar gene expression profiles with MMP-2 and FOXM1, raising the possibility that these molecules might participate in MMP-2-elicited cancer progression and metastasis of OCSCC. To examine this connection, we first showed that FLJ10540 was significantly overexpressed in OCSCC. A strong FLJ10540 expression was significantly correlated with an advanced tumor node metastasis stage and the cumulative 5-year survival rate. Thus, an elevated FLJ10540 expression is an indicator of poor survival. Functionally, FLJ10540 had the abilities to stimulate cell migration and invasion in oral cancer cells through increased FOXM1 and MMP-2 expressions. Conversely, the depletion of the FLJ10540 expression by small interefering RNAs suppressed the FOXM1 and MMP-2 protein expressions. The suppression of either FLJ10540 or FOXM1 could cause significant inhibition on cell migratory and invasive ability in oral cancer cells. Finally, the immunohistochemical and western blotting analyses of human aggressive OCSCC specimens showed a significant positive correlation among FLJ10540, FOXM1 and MMP-2 expressions. These findings suggest that FLJ10540 is not only an important prognostic factor but also a new therapeutic target in the FLJ10540/FOXM1/MMP-2 pathway for OCSCC treatment.

To review the response to radiation therapy for hepatocellular carcinoma (HCC) with portal vein thrombosis (PVT) and determine the factors favoring its efficacy.Patients with HCC and PVT referred for radiation therapy between 1997 and 2005 were retrospectively reviewed. Patients who had undergone treatment to primary HCC before radiation or had extrahepatic metastasis were excluded. A radiation dose of 60 Gy with 2 to 3Gy per fraction was prescribed. Clinical features before therapy were investigated, and the most significant imaging change after radiotherapy was regarded as the treatment response. Survival times were compared and the hazard ratios of independent variables were determined.The treatment response rate of the 326 patients included in the study was 25.2% (n = 82). The median survival times were 13.3, 11.6, 9.0, 4.5, and 2.1 months for complete response, partial response, vascular transformation, no response, and the lost follow-up patients, respectively. Statistically significant differences in survival were not found among responder groups (p = 0.224-0.916) but were found between responders and nonresponders (p = 0.002). The most significant independent variables associated with survival (p0.001) were performance status and radiation dose. Minor independent factors were ascites, alfa-fetoprotein, albumin, and HBsAg (p = 0.009-0.038). In patients with favorable performance status, those with no more than one minor risk factor had a superior prognosis after radiation therapy (p = 0.013). This result was verified by a review of similar patients in 2006.Radiation therapy is the treatment of choice for selected HCC patients with PVT.

Purpose The S-phase kinase-associated protein 2 (Skp2) oncoprotein is an E3 ubiquitin ligase targeting the p27 Kip1 tumor suppressor for degradation. We evaluated the prognostic utility of Skp2 in nasopharyngeal carcinoma (NPC), with an emphasis on distant metastasis-free (DMF) survival. Methods and Materials Immunohistochemical expression of Skp2 was assessed by H-score for 233 NPC patients without initial distant metastasis and correlated with the clinicopathologic features, therapeutic modalities, locoregional control rate, DMF survival, and overall survival (OS). No selection bias in essential parameters was shown between these and another 113 control patients. Results Skp2 was detectable in most patients (95%) but displayed a wide range of expression. Despite no correlation between Skp2 and any clinicopathologic factor, greater Skp2 expression (H-score >80) significantly portended inferior DMF survival ( p = 0.01) and OS ( p = 0.02) when categorically dichotomizing the study cohort. The associations with DMF survival ( p = 0.003) and OS ( p = 0.003) became even stronger when the H-score was expressed as a continuous variable. In the multivariate model, greater Skp2 expression remained significantly predictive of poorer DMF survival and OS ( p = 0.01 for both), along with T stage ( p = 0.04 for DMF survival; p = 0.005 for OS), N stage ( p = 0.008 for DMF survival; p = 0.02 for OS), and/or age ( p = 0.001 for OS). In contrast, T stage ( p = 0.01) was the single independent prognosticator of LCR. Conclusions The results of our study have shown that Skp2 expression is frequent in NPC and has a wide range of distribution in H-score. Skp2 overexpression is significantly predictive of DMF survival and OS, independent of the T stage and/or older age. Therefore, Skp2 might represent a useful prognostic adjunct to risk stratify NPC patients for appropriate allocation of adjuvant therapy.

Purpose: Most gastrointestinal stromal tumors harbor a mutated KIT or PDGFRA receptor tyrosine kinase (RTK). Heat shock protein 90 (Hsp90) is a chaperone mediating the folding and stabilization of many oncoproteins, including KIT. An Hsp90 inhibitor, 17-AAG, can attenuate KIT activation and proliferation of gastrointestinal stromal tumor cell lines. We further evaluated Hsp90 immunoexpression and the difference between α and β isoforms in gastrointestinal stromal tumor specimens. Experimental Design: Hsp90 immunostain was assessable in 306 cases on tissue microarrays of primary gastrointestinal stromal tumors and correlated with various variables and disease-free survival (DFS). RTK mutation variants, confirmed in 142 cases by sequencing with or without precedent denaturing high pressure liquid chromatography screening, were dichotomized into two prognostically different groups. Differential expression of transcript and protein isoforms was measured by real-time reverse transcription-PCR and Western blotting in 16 and 6 cases, respectively. Results: Hsp90 overexpression (55%) significantly correlated with larger size, nongastric location, higher mitotic count and NIH risk level, Ki-67 overexpression (all P ≤ 0.001), and unfavorable RTK genotypes (P = 0.020). It strongly portended inferior DFS univariately (P < 0.0001) and remained independent in multivariate analysis (P = 0.031; risk ratio, 2.44), along with high-risk category, Ki-67 overexpression, and old age. For both mRNA and protein, Hsp90β was more abundant than Hsp90α, whereas the latter was significantly higher in high-risk cases. Conclusions: Hsp90 overexpression represents a poor prognosticator that correlates with several adverse parameters, highlighting its role in disease progression and alternative therapy for high-risk, imatinib-resistant gastrointestinal stromal tumors. Hsp90α seems more relevant to the intrinsic aggressiveness of gastrointestinal stromal tumors, albeit less abundant than Hsp90β.

Purpose To evaluate the pretreatment risk factors of para-aortic lymph node (PALN) recurrence after primary radiotherapy for cervical cancer. Methods and Materials Between May 1992 and January 2006, the data from 758 patients with squamous cell carcinoma of the uterine cervix were retrospectively analyzed. No patient had undergone PALN radiotherapy as their initial treatment. PALN recurrence was diagnosed by computed tomography. PALN relapse-free status was determined clinically or radiographically. We analyzed the actuarial rates of PALN recurrence using Kaplan-Meier curves. Multivariate analyses were performed with Cox regression models. Results Of the 758 patients, 38 (5%) and 42 (6%) had isolated and nonisolated PALN recurrences after a median follow-up of 50 months (range, 2–159 months), respectively. The 3-year and 5-year overall survival rate after PALN recurrence was 35% and 28%, respectively. A squamous cell carcinoma antigen (SCC-Ag) level >40 ng/mL ( p p = 0.002), and the presence of pelvic lymphadenopathy ( p = 0.007) were independent factors associated with PALN relapse on multivariate analysis. The 5-year PALN recurrence rate in patients with a SCC-Ag level >40 ng/mL, SCC-Ag level of 20–40 ng/mL, parametrial score of 4–6, pelvic lymphadenopathy, and no risk factors was 57%, 22%, 34%, 37%, and 9%, respectively. Conclusions Patients with squamous cell carcinoma of the uterine cervix and a high SCC-Ag level, pelvic lymphadenopathy, or advanced PM involvement were predisposed to PALN recurrence after definitive radiotherapy. More intensive follow-up schedules are suggested for early detection and salvage in high-risk patients.

beta2-Microglobulin (beta2M), a component of MHC class I molecules, is believed to be associated with tumour status in various cancers. In this study, we examined the expression of beta2M at different malignant stages of oral cavity squamous cell carcinoma (OCSCC). To determine the possible correlation between beta2M expression and various clinical characteristics, 256 samples from patients with OCSCC were evaluated by immunohistochemical staining. Strong beta2M expression was significantly correlated with a relatively advanced tumour stage (P0.001), positive nodal status (P0.001), and TNM stage (P0.001). The cumulative 5-year survival rate was significantly correlated with a relatively advanced tumour stage (P0.001), positive nodal status (P0.001), TNM stage (P0.001), and strong expression of beta2M (P0.001). Thus, elevated beta2M expression is an indicator of poor survival (P0.001). In addition, we extended our analysis of beta2M expression to the FaDu and SCC25 oral cancer cell lines. beta2-Microglobulin expression was positively correlated with cell migration and invasion in beta2M-overexpressing transfectants in Transwell chambers. The suppression of beta2M expression using small interfering RNA (siRNA) was sufficient to decrease cell migration and invasion in vitro. Taken together, our results suggest that beta2M expression in the tissues is associated with survival and may be involved in tumour progression and metastasis in OCSCC.