Blue Nevus Hidden within the Nevus of Ota.

A 3-year-old boy presented with bluish patch and scattered blue spots on the left side of his face. After several sessions of laser treatment, the azury patch in the periorbital area became even darker. Histopathology showed many bipolar, pigment-laden dendritic cells scattered in the papillary and upper reticular dermis. Immunohistochemically, these cells were positive for S100, SOX-10, melan-A, P16, and HMB-45. The positive rate of Ki-67 was less than 5%. Finally, the lesion was diagnosed with nevus of Ota concurrent with common blue nevus. Therefore, for cases of the nevus of Ota with poor response to laser treatment, the possible coexisting diseases should be suspected.

Acute radiation dermatitis among patients with nasopharyngeal carcinoma treated with proton beam therapy: Prognostic factors and treatment outcomes.

A high incidence of severe acute radiation dermatitis (ARD) has been reported for cancer patients treated by proton beam therapy (PBT). This observational study investigated the prognostic factors and treatment outcomes of ARD among patients with nasopharyngeal carcinoma (NPC) treated with PBT. Fifty-seven patients with newly diagnosed NPC and treated with PBT were enrolled. ARD was recorded weekly based on the criteria of Common Terminology Criteria for Adverse Events version 4.0 at treatment visits (1st to 7th weeks) and 1 week (8th week) and 1 month (11th week) after the completion of PBT. The maximum ARD grade was 1, 2, and 3 in 26 (45.6%), 24 (42.1%), and 7 (12.3%) of the patients, respectively. The peak incidence of grade 2 and 3 ARD was observed during the period of the 6th to 8th weeks. Treatment of ARD included topical corticosteroid alone in 24 (42.1%) patients, topical corticosteroid plus silver sulfadiazine in 33 (57.9%) patients, and non-adhering silicone dressing to cover severe skin wound area in 25 (43.8%) patients. In the 11th week, most grade 2 and 3 ARD had disappeared and 93.0% of the patients had ARD of grade 1 or lower. In the binary logistic regression model, we identified habitual smoking (odds ratio [OR]: 5.2, 95% confidence interval [CI]: 1.3-18.8, P = .012) and N2 to N3 nodal status (OR: 4.9, 95% CI: 1.6-15.4, P = .006) as independent predictors of grade 2 and 3 ARD. The results show ARD is a major concern for patients with NPC treated with PBT, especially those with habitual smoking or advanced nodal status. Topical corticosteroid, silver sulfadiazine, and non-adhering silicone dressing are effective for treating ARD induced by PBT.

Stigma, depression, and anxiety among patients with head and neck cancer.

PURPOSE: 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. METHODS: 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. RESULTS: Those patients having stressors of worry about health (t = 5.21, p < 0.001), worry about job (t = 2.73, p = 0.007), worry about family (t = 2.25, p = 0.026), or worry about economic problems (t = 2.09, p = 0.038) showed significantly higher SSS score than those having no such stressor. The SSS total score was significantly correlated with HAM-A (r = 0.509, p < 0.001), HAM-D (r = 0.521, p < 0.001), and EMIC (r = 0.532, p < 0.001) scores. Structural equation modeling was used to propose the possible effect of stigma on anxiety (ß = 0.51, p < 0.001), and then the possible effect of anxiety on depression (ß = 0.90, p < 0.001). CONCLUSION: Stigma is significantly correlated with anxiety and depression and might in HNC patients. Proper identification of comorbidities and a reduction of stigma should be advised in mental health efforts among patients with HNC.

RSF1 requires CEBP/ß and hSNF2H to promote IL-1ß-mediated angiogenesis: the clinical and therapeutic relevance of RSF1 overexpression and amplification in myxofibrosarcomas.

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-1ß-neutralizing antibodies (RD24, P2D7KK), highlighting the regulatory basis and targetability of downstream IL-1ß-mediated angiogenesis. Tumor samples were assessed for RSF1, IL-1ß, 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-1ß-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/ß to cotransactivate the IL1B promoter, which increased the IL1B mRNA level, IL-1ß secretion and angiogenic capacity. Angiogenesis induced by RSF1-upregulated IL-1ß was counteracted by IL1B knockdown and both IL-1ß-neutralizing antibodies. Clinically, RSF1 overexpression was highly associated with RSF1 amplification, IL-1ß 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-1ß 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/ß to cotransactivate IL1B, highlighting its prognostic, pathogenetic, and therapeutic relevance in myxofibrosarcomas.

Targeting mTOR-CCL20 Signaling May Improve Response to Docetaxel in Head and Neck Squamous Cell Carcinoma.

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.

Differences in the outcomes and complications between elderly and younger uterine cervical cancer patients treated by definitive radiotherapy - A propensity score-matched study.

PURPOSE: To evaluate the differences in the treatment outcomes and complications between elderly patients and younger patients with uterine cervical cancer (CxCa). METHODS AND MATERIALS: From April 1993 to December 2007, 138 CxCa patients aged ≥75years (Elderly group) and 334 CxCa patients aged <60years (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. RESULTS: 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; p<0.001) 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). CONCLUSIONS: 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.

The Therapeutic Benefit of Radical Resection for T4b Oral Cavity Squamous Cell Carcinoma with Partial or Complete Response After Radical Chemo-Intensity-Modulated Radiotherapy (IMRT).

BACKGROUND: 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). METHODS: 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. RESULTS: 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 (p < 0.05). 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 %). CONCLUSIONS: 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.

Circulating CD105 shows significant impact in patients of oral cancer and promotes malignancy of cancer cells via CCL20.

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.

Betel nut chewing history is an independent prognosticator for smoking patients with locally advanced stage IV head and neck squamous cell carcinoma receiving induction chemotherapy with docetaxel, cisplatin, and fluorouracil.

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.

NAB2-STAT6 fusion types account for clinicopathological variations in solitary fibrous tumors.

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<0.001), older age (P=0.005), decreased mitoses (P=0.0028), and multifocal or diffuse STAT6 staining (P=0.013), but not found to correlate with disease-free survival. Conclusively, STAT6 nuclear expression was distinctive in the vast majority of SFTs, including all fusion-positive tumors, and exploitable as a robust diagnostics of CD34-negative cases. Despite the associations of NAB2-STAT6 fusion variants with several clincopathological factors, their prognostic relevance should be further validated in large-scale prospective studies of SFTs.

Prevalence and risk factors of depressive disorder in caregivers of patients with head and neck cancer.

OBJECTIVE: The purpose of this study is to examine the prevalence and risk factors of depressive disorder in caregivers of patients with head and neck cancer. METHODS: Study subjects were recruited from a multidisciplinary outpatient clinic for head and neck cancer in a medical center from February to July 2012. Caregivers of patients with head and neck cancer were enrolled and assessed using the Structured Clinical Interview for the DSM-IV, Clinician Version, the Short Form 36 Health Survey, and the Family APGAR index. The main aim of the study was to examine the difference in demographic data and clinical characteristics between the caregivers with and without depressive disorders. In addition, a stepwise forward model of logistic regression was used to test the possible risk factors. RESULTS: One hundred and forty-three caregivers were included in the study. The most prevalent psychiatric disorder was depressive disorder (14.7%), followed by adjustment disorder (13.3%). Nearly one-third of the caregivers had a psychiatric diagnosis. By using logistic regression analysis, it was found that unemployment (odds ratio (OR) = 3.16; 95% CI, 1.04-9.68), lower social functioning (OR = 1.43; 95% CI, 1.18-1.72), and lower educational level (OR = 1.16; 95% CI, 1.01-1.34) were significant risk factors for the depressive disorder. CONCLUSIONS: The clinical implication of our results is the value of using the standardized structured interview for early diagnosis of depressive disorder in caregivers of head and neck cancer patients. Early screening and management of depression in these caregivers will raise their quality of life and capability to care patients.

Overexpression of Rap-1A indicates a poor prognosis for oral cavity squamous cell carcinoma and promotes tumor cell invasion via Aurora-A modulation.

The functions of Rap-1A in oral carcinogenesis are largely unexplored. In this study, we examined the expression of Rap-1A at different malignant stages of oral cavity squamous cell carcinoma (OCSCC). Semiquantitative RT-PCR, quantitative RT-PCR, and Western blotting were used to evaluate Rap-1A mRNA and protein expressions, respectively, in paired OCSCC patient specimens. To determine the possible correlation between Rap-1A expression and various clinical characteristics, 256 samples from patients with OCSCC were evaluated by immunohistochemical staining. Strong Rap-1A expression was a significant prognostic marker and predictor of aggressive OCSCC. The overall and disease-specific 5-year survival rates were significantly correlated with strong expression of Rap-1A (P < 0.001). Functionally, overexpressed Rap-1A could promote oral cancer cell migration and invasion by Transwell chambers and wound healing assay. Conversely, the suppression of Rap-1A expression using Rap-1A-mediated siRNA was sufficient to decrease cell motility. Furthermore, our data also illustrated that Aurora-A could not only induce mRNA and protein expressions of Rap-1A for enhancing cancer cell motility but also co-localize and form a complex with Rap-1A in the oral cancer cell line. Finally, immunohistochemical staining, indirect immunofluorescence, and Western blotting analysis of human aggressive OCSCC specimens revealed a significantly positive correlation between Rap-1A and Aurora-A expression. Taken together, our results suggest that the Aurora-A/Rap-1A pathway is associated with survival, tumor progression, and metastasis of OCSCC patients.

Impact of late toxicities on quality of life for survivors of nasopharyngeal carcinoma.

BACKGROUND: To investigate the impact of physician-assessed late toxicities on patient-reported quality of life (QoL) for nasopharyngeal carcinoma (NPC) patients with long-term survival. METHODS: A cross-sectional survey of QoL and late toxicities was conducted in 242 NPC patients with disease-free survival of more than 5 years after treatment. The QoL was assessed by the European Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30). Late toxicities including neuropathy, hearing loss, dysphagia, xerostomia, and neck fibrosis were recorded based on the criteria of Common Terminology Criteria for Adverse Events version 4.0 (CTCAE v.4.0). The general linear model multiple analysis of variance (GLM-MANOVA) was performed to predict factors associated with the QoL. RESULTS: In the multifactor model of GLM-MANOVA, of the five late toxicities of CTCAE scales, neuropathy, hearing loss, and xerostomia were observed to be significantly associated with the overall outcome of the fifteen QLQ-C30 scales. A statistically significant trend (p <0.05) was observed, indicating that NPC survivors with more severe neuropathy, hearing loss or xerostomia had a worse outcome on global QoL, all five functional scales, and a variety of symptomatic scales. CONCLUSIONS: To improve QoL outcome for NPC survivors, the development of a modern radiotherapeutic technique should not only focus on reduction of the dose to the salivary glands, but also on anatomical structures that are involved in neuropathy and hearing loss.

Longitudinal Assessment of Quality of Life in Nasopharyngeal Cancer Patients Treated with Intensity-Modulated Proton Therapy and Volumetric Modulated Arc Therapy at Different Time Points.

PURPOSE: This retrospective cohort study aims to compare the quality of life (QoL) in patients with nasopharyngeal cancer (NPC) treated with intensity-modulated proton therapy (IMPT) versus volumetric modulated arc therapy (VMAT) at different time points. MATERIALS AND METHODS: We conducted a longitudinal assessment of QoL on 287 newly diagnosed NPC patients (IMPT: 41 and VMAT: 246). We collected outcomes of global QoL, functional QoL, C30 symptoms, and HN35 symptoms from EORTC QLQ-C30 and QLQ-HN35 questionnaires at pre-radiotherapy, during radiotherapy (around 40 Gy), 3 months post radiotherapy, and 12-months post radiotherapy (RT). The generalized estimating equation was utilized to interpret the group effect, originating from inherent group differences; time effect, attributed to RT effects over time; and interaction of the group and time effect. RESULTS: IMPT demonstrated superior mean dose reductions in 12 of the 16 organs at risk compared to VMAT, including a significant (>50%) reduction in the oral cavity and larynx. Both groups exhibited improved scores of global QoL, functional QoL, and C30 symptoms at 12 months post RT compared to the pre-RT status. Regarding global QoL and C30 symptoms, there was no interaction effect of group over time. In contrast, significant interaction effects were observed on functional QoL (p = 0.040) and HN35 symptoms (p = 0.004) during RT, where IMPT created an average of 7.5 points higher functional QoL and 10.7 points lower HN35 symptoms than VMAT. CONCLUSIONS: Compared to VMAT, dose reduction attributed to IMPT could translate into better functional QoL and HN35 symptoms, but the effect is time dependent and exclusively observed during the RT phase.

Development of a risk prediction model for radiation dermatitis following proton radiotherapy in head and neck cancer using ensemble machine learning.

PURPOSE: This study aims to develop an ensemble machine learning-based (EML-based) risk prediction model for radiation dermatitis (RD) in patients with head and neck cancer undergoing proton radiotherapy, with the goal of achieving superior predictive performance compared to traditional models. MATERIALS AND METHODS: Data from 57 head and neck cancer patients treated with intensity-modulated proton therapy at Kaohsiung Chang Gung Memorial Hospital were analyzed. The study incorporated 11 clinical and 9 dosimetric parameters. Pearson's correlation was used to eliminate highly correlated variables, followed by feature selection via LASSO to focus on potential RD predictors. Model training involved traditional logistic regression (LR) and advanced ensemble methods such as Random Forest and XGBoost, which were optimized through hyperparameter tuning. RESULTS: Feature selection identified six key predictors, including smoking history and specific dosimetric parameters. Ensemble machine learning models, particularly XGBoost, demonstrated superior performance, achieving the highest AUC of 0.890. Feature importance was assessed using SHAP (SHapley Additive exPlanations) values, which underscored the relevance of various clinical and dosimetric factors in predicting RD. CONCLUSION: The study confirms that EML methods, especially XGBoost with its boosting algorithm, provide superior predictive accuracy, enhanced feature selection, and improved data handling compared to traditional LR. While LR offers greater interpretability, the precision and broader applicability of EML make it more suitable for complex medical prediction tasks, such as predicting radiation dermatitis. Given these advantages, EML is highly recommended for further research and application in clinical settings.

HuR cytoplasmic expression is associated with increased cyclin A expression and inferior disease-free survival in patients with gastrointestinal stromal tumours (GISTs).

AIMS: HuR is an RNA-binding protein that post-transcriptionally modulates the expression of various target genes involved in carcinogenesis, such as CCNA2, which encodes cyclin A. The aim of this study was to evaluate the significance of HuR expression and subcellular localization in a large cohort of gastrointestinal stromal tumours (GISTs). METHODS AND RESULTS: HuR immunostaining was assessable for nuclear and cytoplasmic expression in 341 cases on tissue microarrays of primary GISTs, of which 318, 296 and 193 cases were also characterized for Ki67 labelling, cyclin A immunoexpression, and KIT and PDGFRA receptor tyrosine kinase (RTK) genotypes, respectively. The results of HuR nuclear and cytoplasmic expression were correlated with disease-free survival (DFS) and clinicopathological, immunohistochemical and RTK genotypic variables. HuR cytoplasmic expression was present in 42% of primary GISTs, and was significantly related to epithelioid histology, larger tumour size, NIH risk category, and nuclear expression of Ki67 and cyclin A. Importantly, HuR cytoplasmic expression (P < 0.001) and cyclin A overexpression (P < 0.001) were strongly associated with worse DFS. Both variables remained independently predictive of adverse outcome [P = 0.020 and risk ratio (RR) 2.605 for cytoplasmic HuR; P = 0.026 and RR 2.763 for cyclin A]. CONCLUSIONS: HuR cytoplasmic expression not only correlates with adverse prognosticators and cyclin A overexpression, but also independently predicts worse DFS, indicating a causative role in conferring tumour aggressiveness.

Long-term effects of neck irradiation on cardiovascular autonomic function: a study in nasopharyngeal carcinoma patients after radiotherapy.

INTRODUCTION: Baroreflex failure has been reported as a late sequalum of neck radiotherapy. In this study we investigated cardiovascular autonomic function in patients after neck radiotherapy to determine predictive factors associated with outcome. METHODS: Eighty-nine patients with nasopharyngeal carcinoma were evaluated ≥6 months after radiotherapy for cardiovascular autonomic function and compared with 48 control subjects. Inflammatory markers and carotid intima-media thickness were also assessed. RESULTS: Autonomic parameters of heart rate response to deep breathing and Valsalva ratio were significantly lower in the patient group. Cardiovascular autonomic impairment was generally mild with relative sparing of the efferent cardiovagal pathway. By univariate and multivariate analyses, the time after radiotherapy and C-reactive protein level were significantly associated with the degree of cardiovascular autonomic dysfunction. CONCLUSIONS: Radiation-induced cardiovascular autonomic impairment is a dynamic and progressive process that occurs long after radiotherapy. Chronic inflammation plays a major role in this process.

Prognostic value of quality of life measured after treatment on subsequent survival in patients with nasopharyngeal carcinoma.

PURPOSE: Pretreatment quality of life (QoL) has been used to predict survival in cancer patients. In this study, we examined the prognostic value of QoL measured after treatment on subsequent survival in patients with nasopharyngeal carcinoma (NPC). METHODS: We enrolled 273 patients with NPC who had been curatively treated for more than 1 year. The EORTC QLQ-C30 and H&N35 questionnaires were completed 1 year after radiotherapy. The predictability of QoL variables on disease-specific survival (DSS) and overall survival (OS) was analyzed using Cox's proportional hazards models. RESULTS: Twenty-nine (10.6%) patients developed locoregional relapse and 27 (9.9%) had distant metastasis after the QoL survey with subsequent 5-year DSS and OS rates of 87.9% and 84.0 %, respectively. Based on the QLQ-C30, scales of physical functioning, fatigue, and appetite loss significantly predicted DSS and OS (p < 0.05). In the H&N35, only sexuality was significantly correlated with DSS and OS (p < 0.05). An increment of 10 points in physical functioning (HR: 0.69; 95% CI: 0.48-0.90; p = 0.004) or a decline of 10 points in fatigue problems (HR: 1.40; 95% CI: 1.19-1.61; p = 0.0002), appetite loss (HR: 1.21; 95% CI: 1.03-1.40; p = 0.02), and sexuality (HR: 1.14; 95% CI: 1.02-1.25; p = 0.019) was associated with better OS. CONCLUSION: Some QoL variables measured after the treatment provide prognostic value on subsequent survival in patients with NPC.

PAK1 overexpression promotes myxofibrosarcoma angiogenesis through STAT5B-mediated CSF2 transactivation: clinical and therapeutic relevance of amplification and nuclear entry.

Myxofibrosarcoma is genetically complex without established nonsurgical therapies. In public datasets, PAK1 was recurrently gained with mRNA upregulation. Using myxofibrosarcoma cells, we explored the oncogenic underpinning of PAK1 with genetic manipulation and a pan-PAK inhibitor (PF3758309). Myxofibrosarcoma specimens were analyzed for the levels of PAK1, phospho-PAKT423, CSF2 and microvascular density (MVD) and those of PAK1 gene and mRNA. PAK1-expressing xenografts were assessed for the effects of PF3758309 and CSF2 silencing. Besides pro-proliferative and pro-migrator/pro-invasive attributes, PAK1 strongly enhanced angiogenesis in vitro, which, not phenocopied by PAK2-4, was identified as CSF2-mediated using antibody arrays. PAK1 underwent phosphorylation at tyrosines153,201,285 and threonine423 to facilitate nuclear entry, whereby nuclear PAK1 bound STAT5B to co-transactivate the CSF2 promoter, increasing CSF2 secretion needed for angiogenesis. Angiogenesis driven by PAK1-upregulated CSF2 was negated by CSF2 silencing, anti-CSF2, and PF3758309. Clinically, overexpressed whole-cell phospho-PAKT423, related to PAK1 amplification, was associated with increased grades, stages, and PAK1 mRNA, higher MVD, and CSF2 overexpression. Overexpressed whole-cell phospho-PAKT423 and CSF2 independently portended shorter metastasis-free survival and disease-specific survival, respectively. In vivo, both CSF2 silencing and PF3758309 suppressed PAK1-driven tumor proliferation and angiogenesis. Conclusively, the nuclear entry of overexpressed/activated PAK1 endows myxofibrosarcomas with pro-angiogenic function, highlighting the vulnerable PAK1/STAT5B/CSF2 regulatory axis.

Low p16 Cytoplasmic Staining Predicts Poor Treatment Outcome in Patients with p16-Negative Locally Advanced Head and Neck Squamous Cell Carcinoma Receiving TPF Induction Chemotherapy.

Human papillomavirus (HPV) has been proven to be associated with head and neck squamous cell carcinoma (HNSCC), and diffuse p16 unclear staining is usually considered as HPV-positive. The aim of the current study was to investigate the role of p16 cytoplasmic staining in HNSCC prognosis. A total of 195 HNSCC patients who received docetaxel, cisplatin, and 5-fluouracil (TPF) induction chemotherapy followed by chemoradiotherapy were enrolled. The status of p16 cytoplasmic staining was determined using immunohistochemistry. The median follow-up was 26.0 months for the whole study population and 90.3 months for 51 living survivors. p16 cytoplasmic staining was low in 108 patients and high in 87 patients. Low expression of p16 cytoplasmic staining and primary tumor location in the oral cavity were both independent factors indicating a worse response rate to TPF induction chemotherapy in the univariate and multivariate analyses. The logistic regression model also showed that low expression of p16 cytoplasmic staining and clinical N2-3 status were independent prognostic factors for worse progression-free survival and overall survival. Our study showed that p16 cytoplasmic staining could predict the treatment response to TPF induction chemotherapy and is an independent prognostic factor of survival in HNSCC.