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BACKGROUND/AIM The clinical significance of frailty status on treatment outcome in patients with esophageal cancer (EC) has been seldom explored. This study aimed to evaluate the impact of pretreatment frailty on treatment-related toxicity and survival outcome in patients with EC undergoing concurrent chemoradiotherapy (CCRT). PATIENTS AND METHODS Patients aged ≥20 years and with newly diagnosed locally advanced EC receiving neoadjuvant radiotherapy and concurrent chemotherapy with weekly administration of carboplatin and paclitaxel for 5 weeks were prospectively enrolled. A pretreatment frailty assessment was performed within 7 days before CCRT initiation. The primary endpoint was treatment-related toxicity and complications of CCRT while the secondary endpoint was overall survival. RESULTS A total of 87 patients were enrolled, 41 (47%) and 46 (53%) of whom were allocated in the frail and fit group, respectively. Frail patients had a significantly higher incidence of having at least one severe hematological adverse event (63.4% vs. 19.6%, p

Background We sought to compare the prognostic significance of different preoperative complete blood count cell ratios in patients with oral cavity squamous cell carcinoma (OSCC) treated with surgery and postoperative radiotherapy (PORT). Methods We retrospectively reviewed the clinical records of 890 patients with OSCC who were treated with surgery and PORT. The following preoperative complete blood count cell ratios were collected: neutrophil‐to‐lymphocyte ratio (NLR), platelet‐to‐lymphocyte ratio (PLR), and lymphocyte‐to‐monocyte ratio (LMR). Overall survival (OS), local control, regional control, and distant control (DC) served as the main outcomes of interest. Results The results of multivariate analysis in the entire study cohort revealed that a low NLR was the only independently favorable marker of both OS (adjusted hazard ratio [HR]: 0.794, 95% confidence interval (CI): 0.656–0.961, bootstrap p = 0.028) and DC (adjusted HR: 0.659, 95% CI: 0.478–0.909, bootstrap p = 0.015). Both LMR and PLR were not retained in the model as independent predictors. Subgroup analyses in high‐risk patients (i.e., those bearing T4 disease, N3 disease, or poor differentiation) revealed that a high NLR was a significant adverse risk factor for both OS and DC (all p, This relatively large cohort reports a comparative result: pretreatment high neutrophil‐to‐lymphocyte ratio (NLR) was an independent unfavorable risk factor for both overall survival and distant metastasis in patients with oral cavity squamous cell carcinoma (OSCC) who underwent surgery and postoperative radiotherapy. Lymphocyte‐to‐monocyte ratio (LMR) and platelet‐to‐lymphocyte ratio (PLR) were not significant.

Purpose This study aimed to identify vulnerable patients with head and neck cancer undergoing concurrent chemoradiation therapy (CCRT) who are susceptible to higher treatment-related adverse effects and have poorer treatment tolerance. This study also aimed to determine whether comprehensive geriatric assessment, developed in the geriatric population, can predict vulnerability to treatment-related adverse events and survival even in nongeriatric patients with head and neck cancer, as well as the prevalence of vulnerability and its effect on toxicities and survival among these patients. Methods and Materials This prospective cohort study examined 461 patients with primary head and neck cancer who underwent definitive CCRT during 2016 to 2017 at 3 medical centers across Taiwan. Vulnerability is defined as susceptibility to cancer- and treatment-related adverse events that result in poor treatment tolerance and unexpected emergent medical needs, such as hospitalization and emergency room visits. Vulnerability was assessed as impairment with ≥2 dimensions on comprehensive geriatric assessment, 7 days before CCRT. The association of vulnerability with treatment-related adverse events and survival was analyzed. Results The prevalence of vulnerability was 22.2%, 27.3%, 30.2%, and 27.9% among patients aged 20 to 34, 35 to 49, 50 to 64, and >65 years, respectively. Survival was poorer in vulnerable patients than in nonvulnerable patients (hazard ratio, 1.97; 95% confidence interval, 1.26-3.07; P = .003). Vulnerable patients showed a higher tendency toward CCRT incompletion (19.5% vs 6.1%, P Conclusions Vulnerability, which is an urgent concern when it presents among patients with head and neck cancer, was independently associated with poorer survival and severe treatment-related complications. Vulnerability assessment should be routinely evaluated in all patients with primary head and neck cancer who are undergoing definitive CCRT, not only in such patients who are geriatric.

Nutritional counseling is frequently overlooked in cancer patients with normal nutritional status. This study aimed to evaluate the impact of nutritional counseling in head and neck cancer (HNC) patients with normal nutritional status prior to concurrent chemoradiotherapy (CCRT). A total of 243 patients with pretreatment normal nutritional status and locally advanced HNC receiving concurrent chemoradiotherapy (CCRT) at three medical centers were enrolled. All patients were retrospectively allocated into the early (≤ 2 weeks, n = 105, 43.2%), late (> 2 weeks, n = 102, 42.0%), and no nutritional counseling groups (n = 36, 14.8%) according to the time interval between the date of CCRT initiation and the first date of nutritional counseling for comparison. The 1-year overall survival rates were 95.0%, 87.5%, and 81.3% in the early, late, and no nutritional counseling groups (p = 0.035), respectively. The median body weight changes at end of CCRT were − 4.8% (range, − 13.3 to 8.7%), − 5.6% (range, − 21.9 to 5.6%), and − 8.6% (range, − 20.3 to 2.4%) in patients in the early, late, and no nutritional counseling groups, respectively. The early termination of chemotherapy rates and the incompletion rates of planned radiotherapy were 1.9% and 1.9%, 2.9%, and 2.0%, 13.9%, and 19.4% in patients in the early, late, and no nutritional counseling groups, respectively. Our findings strongly suggest that while some HNC patients may have pretreatment normal nutritional status, early nutritional counseling is nevertheless essential for the improvement of treatment tolerance and survival outcome.

The aim of this study is to develop a computer-aided diagnosis method to help classify medical images of neck lymph nodes in head and neck cancer patients. According to the current practice guidelines, the classification of lymph node status is critical for patient stratification before treatment. Take extra-nodal extension (ENE) of metastatic neck lymph nodes, the status of ENE has been considered a single factor affecting the decision of whether systemic treatment with toxicity should be given to patients with otherwise non-advanced cancer status. Medical imaging prior to surgery serves as tools for clinical staging and determining the extent of neck lymph node dissection during the tumor resection surgery. The information contained in these images may also help determine the status of ENE and thus stratify patients for more precise treatment. In the current practice, there has been not a reliable computer-aided tool for this task. In this study, we used open-source software to investigate radiomic features that help distinguish malignant from benign and ENE from non-ENE lymph nodes. We have identified 89 features that can differentiate malignant from benign and 4 features that can differentiate ENE from non-ENE lymph nodes. Furthermore, we fed the significant features to a multilayer perceptron neural network to predict malignancy and ENE of lymph nodes and achieved 84% and 77% of accuracy in each task, respectively.

Background/aim We compared the adequacy of five nutrition assessment tools with respect to their predictive value in patients with locally advanced gastric cancer (GC) receiving radical surgery. Patients and methods Five nutrition assessment tools-Glasgow prognostic score (GPS), malnutritional universal screening tool (MUST), nutritional risk screening, patient generated subjective global assessment (PG-SGA), and prognostic nutritional index (PNI)-were assessed preoperatively for stage III GC patients. The correlation between postoperative events and nutritional status was further analyzed. Results Most of the nutritional tools accurately predicted length of hospital stay and grade 3 or higher surgical complications, while only the GPS correlated with 30-day readmission and surgical complications. The PG-SGA performed the poorest among the five tools and failed to predict any postoperative event. Conclusion The application of GPS is recommended as a prognostic index for patients with locally advanced GC prior to radical surgery.

Objective To investigate the clinical outcomes and failure patterns of patients with unresectable cholangiocarcinoma (CC) who had been treated with proton beam therapy (PBT). Methods The authors retrospectively examined 30 patients with unresectable CC who had undergone PBT between November 2015 and December 2017. Survival curves were plotted with the Kaplan-Meier method. Independent predictors of survival were identified by multivariate Cox proportional hazard regression analyses. Complications were assessed using the Common Terminology Criteria for Adverse Events v4.0. Results The median tumor size was 7 cm. Seventeen patients (56.7%) had regional lymph node metastases. The median radiation dose was 72.6 cobalt gray equivalents, and 23 patients (76.7%) received concurrent chemotherapy. The 1-year local control, regional control, and distant metastases-free rates were 88%, 86%, and 68%, respectively. The median overall survival and progression-free survival were 19.3 and 10.4 months, respectively. The median jaundice-free survival was 13 months, with a 1-year biliary tract infection (BTI)-free rate of 58%. Patients who received concurrent chemotherapy had a better median progression-free survival (12.1 vs. 4.7 mo). The most common form of acute toxicity from PBT was acute skin reactions which were rarely severe (grade III: 7% of patients). Three and 2 patients had grade III-IV toxicities and radiation-induced liver disease. There were no deaths caused by PBT or concurrent chemotherapy. Conclusions PBT is clinically useful in patients with unresectable CC, even in the presence of large tumors or regional nodal metastases. Its use may induce durable symptom relief, without increasing acute or late toxicity.

Approximately, 25% of nasopharyngeal carcinoma (NPC) patients develop recurrent disease. NPC may involve relatively few genomic alterations compared to other cancers due to its association with Epstein‐Barr virus (EBV). We envisioned that in‐depth sequencing of tumor tissues might provide new insights into the genetic alterations of this cancer. Thirty‐three NPC paired tumor/adjacent normal or peripheral blood mononuclear cell samples were deep‐sequenced (>1000×) with respect to a panel of 409 cancer‐related genes. Newly identified mutations and its correlation with clinical outcomes were evaluated. Profiling of somatic mutations and copy number variations (CNV) in NPC tumors identified alterations in RTK/RAS/PI3K, NOTCH, DNA repair, chromatin remodeling, cell cycle, NF‐κB, and TGF‐β pathways. In addition, patients harbored CNV among 409 cancer‐related genes and missense mutations in TGF‐β/SMAD signaling were associated with poor overall survival and poor recurrence‐free survival, respectively. The CNV events were correlated with plasma EBV copies, while mutations in TGFBR2 and SMAD4 abrogate SMAD‐dependent TGF‐β signaling. Functional analysis revealed that the new TGFBR2 kinase domain mutants were incapable of transducing the signal, leading to failure of phosphorylation of SMAD2/3 and activation of downstream TGF‐β‐mediated cell growth arrest. This study provides evidence supporting CNV and dysregulated TGF‐β signaling contributes to exacerbating the NPC pathogenesis.

Background The prognostic relevance of extranodal extension (ENE) for salivary gland carcinoma (SGC) remains unclear. The present study is undertaken to investigate the predictive significance of pathological nodal parameters in surgically treated patients with nodal metastatic SGC. Methods This multicenter cohort included 114 patients with pathologically proven node-positive SGC between 2000 and 2014. Possible correlations of clinicopathological parameters and outcomes were examined. Results The median follow-up was 69 months (range, 11-173 months). The multivariate analysis identified metastatic node number (1-2 vs 3-6; 1-2 vs ≥7) as an independent predictor for regional control (P = 0.005; P = 0.02), locoregional control (P = 0.008; P = 0.04), distant metastasis-free survival (P = 0.17; P = 0.006), disease-free survival (P = 0.05; P = 0.002), and overall survival (P = 0.18; P = 0.009), whereas ENE was not associated with survival outcomes. Conclusions Metastatic node number, not ENE, is an independent node-related prognosticator for SGC. Integration of ENE into the American Joint Committee on Cancer 8th edition staging criteria may not improve prognostic performance.

Background/aim This study was designed to clarify the value of routine alpha-fetoprotein (AFP) testing for patients with gastric cancer (GC). Patients and methods A total of 905 patients with newly diagnosed GC and available pretreatment carcinoembryonic antigen (CEA), cancer-related antigen 19-9 (CA19-9), and AFP data from 2010 to 2016 were collected for comparison of tumor stage and survival. Results In total, 139 patients (15.4%), 155 patients (17.1%), and 27 patients (3.0%) had elevated CEA, CA19-9, and AFP levels, respectively. The c-index values of elevated AFP levels in predicting stage IV disease and the 1-year mortality rate were 0.564 (95%CI=0.520-0.608) and 0.594 (95%CI=0.553-0.635), respectively, which were significantly lower than those of CEA (0.673 and 0.665) and CA19-9 (0.619 and 0.618). Conclusion Elevated AFP is rare in patients with newly diagnosed GC. Routine AFP sampling would not provide a higher survival prediction in GC patients than CEA or CA19-9.

Concurrent chemoradiotherapy (CCRT) treatment incompletion is a known negative prognosticator for patients with head and neck cancer (HNC). Malnutrition is a common phenomenon which leads to treatment interruption in patients with HNC. We aimed to compare the performance of three nutritional tools in predicting treatment incompletion in patients with HNC undergoing definitive CCRT. Three nutritional assessment tools, Mini Nutritional Assessment-Short Form (MNA-SF), Malnutritional Universal Screening Tool (MUST), and Nutritional Risk Screening 2002 (NRS-2002), were prospectively assessed prior to CCRT for HNC patients. Patients were stratified into either normal nutrition or malnourished groups using different nutrition tools. Treatment incompletion and treatment-related toxicities associated with CCRT were recorded. A total of 461 patients were included in the study; malnourished rates ranged from 31.0 to 51.0%. The CCRT incompletion rates were 4.9–6.3% and 14.5–18.2% for normal nutrition patients and malnourished patients, respectively. The tools had significant correlations with each other (Pearson correlation 0.801–0.837, p

The most frequent location of metastatic EBV+ nasopharyngeal carcinoma (NPC) is the bone marrow, an adipocyte-dominant region. Several EBV-associated lymphoepithelioma-like carcinoma (LELC) types also grow in the anatomical vicinity of fat tissues. Here we show that in an adipose tissue-rich tumor setting, EBV targets adipocytes and remodels the tumor microenvironment. Positive immunoreactivity for EBV-encoded early antigen D was detected in adipose tissue near tumor beds of bone marrow metastatic NPC. EBV was capable of infecting primary human adipocytes in vitro, triggering expression of multiple EBV-encoded mRNA and proteins. In infected adipocytes, lipolysis was stimulated through enhanced expression of lipases and the AMPK metabolic pathway. The EBV-mediated imbalance in energy homeostasis was further confirmed by increased release of free fatty acids, glycerol, and expression of proinflammatory adipokines. Clinically, enhanced serum levels of free fatty acids in patients with NPC correlated with poorer recurrence-free survival. EBV-induced delipidation stimulated dedifferentiation of adipocytes into fibroblast-like cells expressing higher levels of S100A4, a marker protein of cancer-associated fibroblasts (CAF). IHC analyses of bone marrow metastatic NPC and salivary LELC revealed similar structural changes of dedifferentiated adipocytes located at the boundaries of EBV+ tumors. S100A4 expression in adipose tissues near tumor beds correlated with fibrotic response, implying that CAFs in the tumor microenvironment are partially derived from EBV-induced dedifferentiated adipocytes. Our data suggest that adipose tissue serves as an EBV reservoir, where EBV orchestrates the interactions between adipose tissues and tumor cells by rearranging metabolic pathways to benefit virus persistence and to promote a protumorigenic microenvironment. Significance: This study suggests that Epstein–Barr virus hijacks adipocyte lipid metabolism to create a tumor-promoting microenvironment from which reactivation and relapse of infection could potentially occur.

OBJECTIVE To investigate the clinical utility of short-course induction chemotherapy followed by low-dose radiotherapy without a tumor bed boost in patients with primary central nervous system (CNS) germinomas. METHODS We retrospectively reviewed the clinical records of patients with primary CNS germinomas who received short-course induction chemotherapy (2 cycles of cisplatin 20 mg/m2 plus etoposide 40 or 100 mg/m2 for 5 days) followed by low-dose radiotherapy (dose: 2340 cGy) without a tumor bed boost. Disease-free survival and overall survival served as the main outcome measures. RESULTS Between February 2002 and June 2018, 24 patients (20 males and 4 females; median age: 14.1 y; age range: 7.9 to 21.2 y) with pathology-proven CNS germinomas were included. The median follow-up time was 106 months (range: 17 to 169 mo). Isolated and multifocal lesions were identified in 13 and 11 patients, respectively. Tumor location was as follows: pineal gland (n=17), suprasellar region (n=13), periventricular region (n=7), and basal ganglia (n=2). Five patients had increased levels (>5 mIU/mL) of beta-human chorionic gonadotropin (β-hCG), whereas alpha-fetoprotein concentrations were within the reference range in all participants. A total of 16 patients achieved remission after induction chemotherapy. The complete response rates of patients with increased and normal β-hCG levels were 40.0% and 72.2%, respectively (P=0.208). Low-dose radiotherapy without a tumor bed boost was subsequently delivered to either the whole ventricle (n=16) or the whole brain (n=8), resulting in complete remission in all participants. Compared with patients without increased β-hCG levels, those with β-hCG-secreting germinomas had less favorable 5-year disease-free survival rates (100% vs. 60%, respectively, P=0.000115). CONCLUSIONS Some children with primary CNS germinoma may benefit from short-course induction chemotherapy followed by low-dose radiotherapy to the whole ventricle without a tumor bed boost. The validity of our findings needs to be confirmed in a randomized phase II study for children with β-hCG levels

The significance of granuloma and amyloid deposition in primary nasopharyngeal carcinoma (NPC) has yet to be investigated. This study aimed to evaluate their clinicopathologic associations. The histopathologic findings of 747 consecutive patients with primary NPC were retrospectively reviewed between January 2001 and December 2015. The presence of granulomas and amyloid deposits was observed in 68 (9.1%) and 62 (8.3%) patients, respectively. Granulomas were significantly associated with lower T classification, N classification, and overall TNM stage (p = 0.014, p = 0.006, and p = 0.001, respectively). Their presence was an independent predictor of overall survival (p = 0.033), disease-free survival (p = 0.034), and recurrence-free survival (p = 0.040). Conversely, amyloid deposition was not a predictor in any survival analyses. The present study demonstrated the prevalence of granuloma and amyloid deposition in the largest single institution cohort of primary NPC patients so far. Our results provide evidence that granulomas are significantly associated with better prognosis and treatment outcome. Further studies are needed to elucidate the mechanism of action of granuloma formation on the anti-tumor immunity of NPC.

No gold standard of nutritional assessment is established among patients with head and neck cancer (HNC) receiving concurrent chemoradiotherapy (CCRT). This study aimed to evaluate the clinical significance of pre-treatment nutritional status using the Mini Nutritional Assessment-short form (MNA-SF) among HNC patients receiving CCRT. A total of 461 consecutive patients with newly diagnosed HNC treated with definitive CCRT at three medical institutes were prospectively enrolled. Nutritional status was assessed using MNA-SF within 7 days before CCRT initiation. Patients were classified as having normal nutrition, at risk of malnutrition, and malnourished groups according to MNA-SF for comparison. The 1-year overall survival rates were 89.8%, 76.8%, and 67.7% in the normal nutrition, at risk of malnutrition, and malnourished groups, respectively. Patients with normal nutrition had significantly lower rates of uncompleted radiotherapy and chemotherapy (4.5% and 4.1%, respectively) compared with patients at risk for malnutrition (14.1% and 11.5%, respectively) and those malnourished (11.1% and 11.1%, respectively). Patients with normal nutrition had significantly lower treatment-related complication rates regarding emergency room visits, hospital admission, and need for tubal feeding than those with at risk of malnutrition and malnourished. Patients with normal nutrition had significantly fewer severe hematologic toxicities (p = 0.044) and severe non-hematologic toxicities (p = 0.012) of CCRT than those malnourished. Pre-CCRT nutritional status identifies HNC patients vulnerable to treatment interruption and treatment complications. We suggest that nutritional assessment with MNA-SF should be incorporated in pre-CCRT evaluation for all HNC patients.

Background Comprehensive Geriatric Assessment (CGA) is the gold standard for detecting frailty in elderly patients with cancer. Since CGA is time- and resource-consuming, many alternative frailty screening tools have been developed; however, it remains unknown whether these tools are suitable for older and adult patients with cancer. Therefore, we used the data collected for a large longitudinal study to compare the diagnostic performances of two frailty screening tools (Geriatric 8 [G8] and Flemish version of the Triage Risk Screening Tool [fTRST]) to identify frailty risk profile among patients with cancer. Material and methods Patients aged ≥20 years with newly diagnosed cancer were enrolled. Frailty screening with G8, fTRST, and CGA were performed before anti-cancer treatment. Diagnostic characteristics obtained using G8 and fTRST were analyzed by C-index, and the validity of G8 and fTRST was also determined. Results 40.9% of the 755 patients with cancer displayed frailty on CGA. Both G8 and fTRST showed high sensitivity (80.6–88.4%) and negative predictive value (81.0–81.2%). The C-index of G8 was higher than that of fTRST (0.77 vs 0.71, p = .01). Moreover, the best G8 and fTRST cut-off points were ≤13 and ≥ 2, respectively. The validities of G8 and fTRST were also confirmed; however, frailty age differences were not observed in our study. Conclusion Frailty is a common problem for patients with cancer, and routine frailty screening is essential for both older and adult patients. G8 and fTRST are simple and useful frailty screening tools, while G8 is more suitable than fTRST for Taiwanese patients with cancer.

Metastasis remains a clinically unsolved issue in nasopharyngeal carcinoma. Here, we report that higher levels of cytoplasmic leukemia inhibitory factor (LIF) and LIF receptor are correlated with poorer metastasis/recurrence-free survival. Further, single nucleotide variations and signal peptide mutation of LIF are identified in NPC. Cytoplasmic LIF reprograms the invasive mode from collective to mesenchymal migration via acquisition of EMT and invadopodia-associated characteristics. Higher cytoplasmic LIF enhances cancer vascular dissemination and local invasion mechanistically through modulation of YAP1-FAK/PXN signaling. Immunohistochemical analyses of NPC biopsies reveal a positive correlation of cytoplasmic LIF expression with focal adhesion kinases. Pharmaceutical intervention with AZD0530 markedly reverses LIF-mediated cancer dissemination and local invasion through promotion of cytoplasmic accumulation of YAP1 and suppression of focal adhesion kinases. Given the significant role of LIF/YAP1-focal adhesion signaling in cancer dissemination, targeting of this pathway presents a promising opportunity to block metastasis., Molecular pathways regulating nasopharyngeal carcinoma (NPC) metastasis are unclear. Here they report higher levels of cytoplasmic leukemia inhibitory factor (cLIF) and LIF receptor (LIFR) to correlate with higher metastasis in NPC patients, and show cLIF to promote NPC metastasis and vascular dissemination via the YAP1-FAK/PXN axis.

Background Patient-derived xenograft (PDX) tumor model has become a new approach in identifying druggable tumor mutations, screening and evaluating personalized cancer drugs based on the mutated targets. Methods We established five nasopharyngeal carcinoma (NPC) PDXs in mouse model. Subsequently, whole-exome sequencing (WES) and genomic mutation analyses were performed to search for genetic alterations for new drug targets. Potential drugs were applied in two NPC PDX mice model to assess their anti-cancer activities. RNA sequencing and transcriptomic analysis were performed in one NPC PDX mice to correlate with the efficacy of the anti-cancer drugs. Results A relative high incident rate of copy number variations (CNVs) of cell cycle-associated genes. Among the five NPC-PDXs, three had cyclin D1 (CCND1) amplification while four had cyclin-dependent kinase inhibitor CDKN2A deletion. Furthermore, CCND1 overexpression was observed in > 90% FFPE clinical metastatic NPC tumors (87/91) and was associated with poor outcomes. CNV analysis disclosed that plasma CCND1/CDKN2A ratio is correlated with EBV DNA load in NPC patients’ plasma and could serve as a screening test to select potential CDK4/6 inhibitor treatment candidates. Based on our NPC PDX model and RNA sequencing, Palbociclib, a cyclin-dependent kinase inhibitor, proved to have anti-tumor effects by inducing G1 arrest. One NPC patient with liver metastatic was treated with Palbociclib, had stable disease response and a drop in Epstein Barr virus (EBV) EBV titer. Conclusions Our integrated information of sequencing-based genomic studies and tumor transcriptomes with drug treatment in NPC-PDX models provided guidelines for personalized precision treatments and revealed a cyclin-dependent kinase inhibitor Palbociclib as a novel candidate drug for NPC.

The ideal cancer therapeutic strategy is to inhibit the tumor with minimal influence on the normal tissue. Recently, applying an alternating electric field for inhibiting tumor was developed; but, it has not been adopted to be one of the regular therapeutic options. More basic scientific evidence is needed to clarify the efficacy and safety. In the current study, co-culturing cancer cells and normal cells under the electrical stimulation was conducted to provide evidence of this novel cancer therapy. A microfluidic cell culture biochip has been developed and consisted of nine culture chambers incorporating with stimulating electrodes. Cells cultured in the chamber received uniform electric field and cell viability was studied during the culture course. The electric field perturbs cell division and the correlation between cell proliferation rate and inhibition effect was studied among five cell lines, i.e., Huh7, HeLa, TW06, BM1, and HEL299. The results confirmed that cells with higher proliferation rate responded to a higher inhibition. In addition, co-culturing cancer cells and normal cells was conducted to mimic in vivo microenvironment that consists of both cancer and stromal cells. The cancer cells and normal cells were respectively transduced with green fluorescent protein and red fluorescent protein in order to differentiate the cells in a same culture chamber. During the culture course, the electric field was applied to the culture chamber and both cells simultaneously received the field. The results indicated that the growth of the cancer cells were inhibited while the normal cells were maintained. These results provided the evidence of the therapeutic efficacy and safety. Moreover, the microfluidic cell culture biochip could be used for the systematic and precise investigations of the cellular responses under the electrical stimulation.

We aimed to investigate the prognostic significance of combined pretreatment lymphocyte counts (LCs) and body mass index (BMI) in patients with head and neck cancer (HNC) treated with radiation therapy (RT). Nine hundred and twelve patients with HNC who were treated with RT were retrospectively reviewed. Survival was analyzed by stratifying the patients according to pretreatment LCs and BMI. Patients with low pretreatment LCs and BMI were characterized by a more advanced T stage, fewer nasopharyngeal subsites, less smoking and drinking, and fewer comorbidities. Patients with low pretreatment LCs and BMI had a significantly poorer overall and distant metastasis‐free survival than those with high pretreatment LCs and BMI. No significant differences were observed in terms of local or regional recurrence‐free survival. Combined pretreatment LCs and BMI may be more effective at predicting overall and distant metastasis‐free survival in patients with HNC treated with RT.

We aimed to determine whether body composition assessment before treatment can predict outcomes in patients with head and neck cancer (HNC). All 881 patients with locoregional head and neck cancer treated with curative intent radiotherapy (RT) between 2005 and 2012 were retrospectively investigated. Body composition was analyzed via pre‐RT planning computed tomography (CT) images. Subcutaneous adipose tissue (SAT) and skeletal muscle (SM) indices were measured cross‐sectionally at the level of the third thoracic vertebra. Overall survival (OS), locoregional control (LRC), and distant metastasis‐free survival (MFS) were analyzed by body composition index and body mass index (BMI). Survivors were followed up for a median of 4.68 years. The SAT indices in female patients were significantly higher than those in males (P

We aimed to compare the overall survival (OS) of patients with bone metastases (BM) from solid tumors after standard‐dose radiotherapy ([RT]; 30 Gy administered in 10 fractions; EQD2Gy = 32.5 Gy) and dose‐escalated RT (EQD2Gy > 32.5 Gy). We retrospectively reviewed the clinical charts of 1795 patients (median age, 62.3 years; age range, 18–96 years) with BM from solid tumors who were referred for RT to our institute between 2000 and 2013. These patients were assigned to the standard‐dose (n = 1125; 63%) and dose‐escalated (n = 670; 37%) RT groups. OS, estimated as the duration between the first RT session and death, served as the main outcome measure. The dose‐escalated RT group had a significantly better OS than the standard‐dose RT group (P = 0.000). After allowing potential confounders in multivariate analysis, the RT dose retained its independent association with OS (hazard ratio [HR], 0.837; 95% confidence interval [CI], 0.753–0.929, P = 0.001). After propensity score matching of the baseline characteristics of both groups, RT dose retained its independent association with OS (HR, 0.887; 95% CI, 0.737–0.951; P = 0.011) on multivariate analysis. Dose‐escalated RT exerted more favorable effects on OS in patients with non‐lung cancer, those without multiple metastases, those without symptoms, and those with favorable prognosis. Dose‐escalated RT was significantly associated with better OS in patients with BM from solid malignancies, particularly among those with non‐lung cancer, those without multiple metastases, those without symptoms, and those with favorable prognosis.

We previously reported that tumor inflammasomes play a key role in tumor control and act as favorable prognostic markers in nasopharyngeal carcinoma (NPC). Activated inflammasomes frequently form distinguishable specks and govern the cellular secretion of IL-1β. However, we know little about the biological and biochemical differences between cells with and without apoptosis-associated speck-like protein containing a caspase-recruitment domain (ASC) speck formation. In this study, we used proteomic iTRAQ analysis to analyze the proteomes of NPC cells that differ in their ASC speck formation upon cisplatin treatment. We identified proteins that were differentially over-expressed in cells with specks, and found that they fell into two Gene ontology (GO) pathways: mitochondrial oxidative phosphorylation (OxPhos) and ubiquinone metabolism. We observed up-regulation of various components of the OxPhos machinery (including NDUFB3, NDUFB8 and ATP5B), and subsequently found that these changes lead to mitochondrial ROS (mtROS) production, which promotes the formation and activation of NLRP3 inflammasomes and subsequent pyroptosis. In NPC patients, better local recurrence-free survival was significantly associated with high-level expression of NDUFB8 (p = 0.037) and ATP5B (p = 0.029), as examined using immunohistochemistry. However, there were no significant associations between the expression of NDUFB8 and ATP5B with overall survival of NPC patients. Together, our results demonstrate that up-regulated mitochondrial OxPhos components are strongly associated with NLRP3 inflammasome activation in NPC. Our findings further suggest that high-level expression of OxPhos components could be markers for local recurrence and/or promising therapeutic targets in patients with NPC.

Introduction Palliative chemotherapy is the standard treatment for patients with unresectable pancreatic cancer. Whether the early initiation of palliative chemotherapy is associated with a favorable survival outcome for these patients is not known. This study aimed to analyze the association of the time interval between cancer diagnosis and initiation of palliative chemotherapy with survival outcome in patients with pancreatic cancer. Method A total of 838 patients with unresectable pancreatic cancer who underwent palliative chemotherapy from 2010 to 2016 at 4 institutions in Taiwan were retrospectively enrolled. All patients were categorized according to time interval between cancer diagnosis and initiation of palliative chemotherapy for comparison of the survival outcome. Result The median time interval was 14 days (range, 0 to 163 days) in our patient cohort. Accordingly, 22%, 29%, and 49% of the patients underwent palliative chemotherapy within 1, 1 to 2, and >2 weeks after cancer diagnosis, respectively. The survival outcome had no statistical difference among these 3 patient groups. Subgroup analyses revealed that patients with the time interval ≤2 weeks exhibited poorer survival outcome than those with the time interval >2 weeks if they initially presented with jaundice (6.1 months vs 8.4 months, P = 0.029). In contrast, patients with the time interval ≤2 weeks revealed a better survival outcome than those with the time interval >2 weeks if they initially presented with pain (8.0 vs 6.3 months, P = 0.014). Conclusion In our study, time interval between cancer diagnosis and the initiation of palliative chemotherapy >2 weeks was not associated with a poorer survival outcome for patients with unresectable pancreatic cancer. Our result might help clinicians to clarify that early initiation of palliative chemotherapy might provide survival benefit for patients who present with tumor pain, but not for those who present with jaundice.

Treatment options for older patients with malignancies remain suboptimal. An accurate prognostic stratification could inform treatment decisions, which can potentially improve patient outcomes. Here, we sought to investigate whether the neutrophil-to-lymphocyte ratio (NLR) may have prognostic significance in patients with metastatic malignant tumors, with a special focus on older individuals.We retrospectively reviewed the clinical records of 3981 patients with histology-proven metastatic cancer who underwent radiotherapy between 2000 and 2013. The pretreatment NLR was determined within 7 days before treatment initiation. Patients aged ≥65 years were considered as older. We analyzed the prognostic significance of NLR for overall survival (OS) across all age groups.Compared with their younger counterparts, older patients showed a higher NLR (P 0.001) and a lower OS (P 0.001). Multivariate analysis revealed that a pretreatment NLR below the median was an independent favorable predictor of OS in both older (hazard ratio [HR]: 0.669, 95.0% CI: 0.605-0.740; P 0.001) and younger patients (HR: 0.704; 95.0% CI: 0.648-0.765; P 0.001). Regardless of age, patients who underwent systemic therapy showed more favorable OS, especially when NLR was low. In the older subgroup, the OS of patients with a low pretreatment NLR who did not undergo systemic therapy and of those with high pretreatment NLR who underwent systemic therapy was similar.A low pretreatment NLR predicts a more favorable OS in older patients with metastatic cancer. The most favorable OS was observed in patients with a low pretreatment NLR who received systemic therapy.

Key Points Question What are the optimal factors to use for constructing a nomogram to assess the probability of survival in patients with bone metastases arising from lung cancer? Findings This prognostic study of 477 patients with metastatic lung cancer found that age, histological type, smoking status, epidermal growth factor receptor mutation status, body mass index, and neutrophil to lymphocyte ratio were ideal parameters to construct a nomogram for potentially indicating 3-, 6-, and 12-month survival. This nomogram was successfully validated in a separate cohort of 235 patients at another institution. Meaning The study’s nomogram can guide radiation oncologists in making treatment decisions and determining the proper timing for end-of-life discussions and/or hospice referrals., Importance A survival prediction model for patients with bone metastases arising from lung cancer would be highly valuable. Objective To develop and validate a nomogram for assessing the survival probability of patients with metastatic lung cancer receiving radiotherapy for osseous metastases. Design, Setting, Participants In this prognostic study, the putative prognostic indicators for constructing the nomogram were identified using multivariable Cox regression analysis with backward elimination and model selection based on the Akaike information criterion. The nomogram was subjected to internal (bootstrap) and external validation; its calibration and discriminative ability were evaluated with calibration plots and the Uno C statistic, respectively. The training and validation set cohorts were from a tertiary medical center in northern Taiwan and a tertiary institution in southern Taiwan, respectively. The training set comprised 477 patients with metastatic lung cancer who received radiotherapy for osseous metastases between January 2000 and December 2013. The validation set comprised 235 similar patients treated between January 2011 and December 2017. Data analysis was conducted May 2018 to July 2018. Main Outcomes and Measures The nomogram end points were death within 3, 6, and 12 months. Results Of 477 patients in the training set, 292 patients (61.2%) were male, and the mean (SD) age was 62.86 (11.66) years. Of 235 patients in the validating set, 113 patients (48.1%) were male, and the mean (SD) age was 62.65 (11.49) years. In the training set, 186 (39%), 291 (61%), and 359 (75%) patients died within 3, 6, and 12 months, respectively, and the median overall survival was 4.21 (95% CI, 3.68-4.90) months. In the validating set, 84 (36%), 120 (51%), and 144 (61%) patients died within 3, 6, and 12 months, respectively, and the median overall survival was 5.20 (95% CI, 4.07-7.17) months. Body mass index (18.5 to, This prognostic study develops and validates a nomogram to assess the probability of survival at 3, 6, and 12 months in patients from Taiwan with metastatic lung cancer who were referred for radiotherapy to treat osseous metastases.

// Hung-Ming Wang 1, * , Tung-Liang Lin 1, * , Yung-Chia Kuo 1 , Hsin-Pai Li 2 , Kai-Ping Chang 3 , Chien-Yu Lin 4 , Hsien-Chi Fan 1 , An-Chi Lin 1 , Chia-Hsun Hsieh 1 , Ngan-Ming Tsang 4 , Li-Yu Lee 5 , Sheng-Chieh Chan 6 , Kar-Wai Lui 7 , Yu-Sun Chang 2 , Cheng-Lung Hsu 1 1 Division of Hematology-Oncology, Department of Internal Medicine, Chang Gung Memorial Hospital, Chang Gung University, Taoyuan, Taiwan, ROC 2 Department of Cell and Molecular Biology, Chang Gung University, Taoyuan, Taiwan, ROC 3 Department of Otolaryngology-Head and Neck Surgery, Chang Gung Memorial Hospital, Chang Gung University, Taoyuan, Taiwan, ROC 4 Department of Radiation Oncology, Chang Gung Memorial Hospital, Chang Gung University, Taoyuan, Taiwan, ROC 5 Department of Pathology, Chang Gung Memorial Hospital, Chang Gung University, Taoyuan, Taiwan, ROC 6 Department of Nuclear Medicine, Chang Gung Memorial Hospital, Chang Gung University, Taoyuan, Taiwan, ROC 7 Department of Diagnostic Radiology, Chang Gung Memorial Hospital, Chang Gung University, Taoyuan, Taiwan, ROC * These authors contributed equally to this work Correspondence to: Cheng-Lung Hsu, email: hsu2221@adm.cgmh.org.tw Keywords: nasopharyngeal carcinoma, metastasis, EB virus, EBV DNA, IP-10 Received: March 10, 2016 Accepted: June 09, 2016 Published: July 18, 2016 ABSTRACT Differential overall survival of nasopharyngeal carcinoma (NPC) with different organ site metastases has been documented. Here, we attempted to determine the underlying mechanisms by assessing plasma and tumor tissue markers in relation to patient survival. Pretreatment plasma Epstein-Barr virus (EBV) DNA concentrations, cytokines and tissue macrophages, proliferation and apoptosis markers were determined in 178 patients with metastatic NPC. The median overall survival (OS) was 19 months. Patients with single organ metastases had better outcomes than those with multiple organ metastases (median OS: 26 months vs. 16 months), with statistical significance. Among the single organ involvement cases, patients with lung metastasis only showed longer survival than those with bone or liver involvement (median OS: 50 months vs. 21 months vs. 18 months; P < 0.001). Pretreatment plasma EBV DNA concentrations were lower in patients with lung metastasis than bone or liver metastasis among single organ site groups. Plasma interferon-γ-inducible protein-10 (IP-10) and monocyte chemotactic protein-1 (MCP-1) expression levels were correlated with differential single organ site metastasis OS and EBV DNA load. Liver metastatic tissue had higher density of infiltrating macrophages and proliferative index than the lung metastatic group. Low pretreatment plasma EBV DNA load, expression of cytokines, such as IP-10 and MCP-1, tissue macrophage infiltration, and proliferative index may contribute to the differences in overall survival.

Recent studies conducted in patients with chronic diseases have reported an inverse association between body mass index (BMI) and mortality. However, the question as to whether BMI may predict prognosis in patients with metastatic cancer remains open. We therefore designed the current retrospective study to investigate the potential association between BMI and overall survival (OS) in patients with distant metastases (DM) and a favorable performance status. Between 2000 and 2012, a total of 4010 cancer patients with DM who required radiotherapy (RT) and had their BMI measured at the initiation of RT were identified. The relation between BMI and OS was examined by univariate and multivariable analysis. The median OS time was 3.23 months (range: 0.1–122.17) for underweight patients, 6.08 months (range: 0.03–149.46) for normal‐weight patients, 7.99 months (range: 0.07–158.01) for overweight patients, and 12.49 months (range, 0.2–164.1) for obese patients (log‐rank: P

Background Growing evidence indicates that measures of body composition may be related to clinical outcomes in patients with malignancies. The aim of this study was to investigate whether measures of regional adiposity–including subcutaneous adipose tissue index (SATI) and visceral adipose tissue index (VATI)–can be associated with overall survival (OS) in Taiwanese patients with bone metastases. Methods This is a retrospective analysis of prospectively collected data. We examined 1280 patients with bone metastases who had undergone radiotherapy (RT) between March 2005 and August 2013. Body composition (SATI, VATI, and muscle index) was assessed by computed tomography at the third lumbar vertebra and normalized for patient height. Patients were divided into low- and high-adiposity groups (for both SATI and VATI) according to sex-specific median values. Results Both SATI (hazard ratio [HR]: 0.696; P

The prognostic value of programmed death-ligand 1 (PD-L1) expression in nasopharyngeal carcinoma (NPC) is controversial, with previous studies showing conflicting results. Most NPCs in endemic areas are Epstein-Barr virus (EBV)-positive. Our aim was to evaluate the clinical significance of PD-L1 expression in EBV-positive NPC. We retrospectively analyzed PD-L1 expression on tumor cells (TCs) and immune cells (ICs) by immunohistochemistry in 208 EBV-positive NPC patients who underwent radiotherapy (203 with concurrent chemotherapy). The percentages of TCs and ICs expressing PD-L1 were evaluated respectively. There was a strong correlation between local recurrence and low PD-L1 expression on ICs (p = 0.0012), TCs (p = 0.013) or both (p = 0.000044), whereas all clinical parameters had no influence on local recurrence. Using multivariate analysis, low PD-L1 expression on ICs was an independent adverse prognostic factor (p = 0.0080, HR = 1.88, 95% CI = 1.18&ndash, 3.00) for disease-free survival. High PD-L1 expression on both ICs and TCs was an independent favorable prognostic factor (p = 0.022, HR = 0.46, 95% CI = 0.24&ndash, 0.89) for overall survival. We show for the first time that low PD-L1 expression on ICs and TCs strongly correlates with local recurrence in EBV-positive NPC patients after radiation-based therapy. A simple immunohistochemical study for PD-L1 can identify patients prone to local recurrence, and such patients might benefit from more aggressive treatment in future clinical trials.

PURPOSE To identify predictors of radiation-induced liver disease (RILD) in patients with hepatocellular carcinoma (HCC) treated with proton beam therapy (PBT). METHODS This multicenter study included 136 patients with HCC (eastern, n = 102; western, n = 34) without evidence of intrahepatic tumor progression after PBT. The RILD was defined as ascites with alkaline-phosphatase abnormality, grade ≥3 hepatic toxicity, or Child-Pugh score worsening by ≥2 within 4 months after PBT completion. The proton doses were converted to equivalent doses in 2-GyE fractions. The unirradiated liver volume (ULV) was defined as the absolute liver volume (LV) receiving

Most of the current cancer therapies may induce serious side effects and affect patient quality of life. Recently, a novel treatment using an alternating low-intensity and intermediate-frequency electric field was proposed and found to be a noninvasive and minimally toxic approach. However, additional fundamental studies and scientific evidence are required to further support the development of this treatment into a standard cancer therapy. In the current work, an in-house fabricated culture plate was developed to study the responses of hepatocellular carcinoma spheroids to treatment with an alternating electric field. From the results of the viability study, the electric field was confirmed to influence the dividing cells in the spheroids. Fluorescent staining of live and dead cells revealed that a fraction of the cells were damaged in the field-treated spheroids. Moreover, flow cytometry analyses were conducted and showed that a fraction of the cells in the spheroids underwent apoptosis and cell cycle arrest. Additionally, the apoptosis pathway (Bax/caspase) and cell cycle arrest pathway (p53/p21) were found to be activated after exposure to the electric field. In summary, the results further elucidated the cellular and molecular mechanism inducing apoptosis and cell cycle arrest in the field-treated hepatocellular carcinoma spheroids. This study provides more evidence to support the efficacy of electric-field-based cancer therapy.

Background: In clinical trials, adjuvant therapy (AT) has been shown to improve the prognosis in patients with gastric adenocarcinoma who undergo curative gastrectomy and adequate lymph node dissection. However, the optimal timing for initiating AT is still unclear. Method: We collected data from 538 patients with stage II-III gastric cancer who underwent curative gastrectomy and AT in two tertiary hospitals from 2006 to 2013. Patients were divided into the early group (≤8 weeks, n=393) and the late group (>8 weeks, n=145), based on the interval between gastrectomy and initiation of AT. Propensity score matching was applied according to baseline characteristics. Results: After 1:1 propensity score matching, an even distribution of characteristics in both groups (143:143) was achieved. The 5-year overall survival (OS) rates were 56.6% and 40.2% in the matched early and late groups, respectively (p=0.062), while the corresponding 5-year recurrence-free survival (RFS) rates were 57.6% and 46.4%, respectively (p=0.028). The time to AT initiation was correlated with RFS and had a positive association with OS. The 5-year distant metastasis-free survival was also significantly better (HR 0.682, 95% CI 0.472-0.985, p=0.040), suggesting an early AT results in a better outcome in patients. Conclusion: We observed that initiation of AT within 8 weeks of curative gastrectomy produces better disease control and may contribute to better overall survival.

The management of recurrent hypopharyngeal cancer after primary curative-intent radiation or chemoradiation therapy is inconclusive. The benefit of salvage surgery may be reduced by its high complication rate. The improvement of medical care modalities may change the survival after management for loco-reginal recurrences. The present study aims to determine the role of salvage surgery. From December 2007 to November 2013, 46 patients with recurrent hypopharyngeal squamous cell carcinoma (HPSCC) after radiation or chemoradiation therapy and without double cancers were recruited. Two year loco-regional failure and overall survival were analyzed and compared between failure patterns. Five-year survival was 24% in patients after loco-regional recurrences. Those who received salvage surgery for loco-regional recurrences had significantly better survival (P

Background Sinonasal adenoid cystic carcinoma is a rare malignancy of the head and neck. Cavernous sinus invasion from sinonasal adenoid cystic carcinoma and its related management have rarely been investigated. This study evaluated the relationship between treatment outcome and cavernous sinus involvement in addition to other parameters. Methods A retrospective case series study was conducted at a tertiary referral center. The medical records of 47 patients diagnosed with primary sinonasal adenoid cystic carcinoma between 1984 and 2015 were retrospectively reviewed. The survival impact of the primary treatment modalities and the anatomic sites of tumor involvement were analyzed. Results Cavernous sinus invasion was observed in 8 patients (17%), of whom 7 had ACC tumors originating from the maxillary sinus. The results of univariate analysis revealed that tumor stage, primary surgery, and the absence of skull-base and infratemporal fossa invasion were associated with better overall survival (P = 0.033, P = 0.012, P = 0.011, and P = 0.040, respectively) and better disease-free survival (P = 0.019, P = 0.001, P = 0.017, and P = 0.029, respectively). Multivariate analysis identified primary surgery as the only independent prognostic factor for disease-free survival (P = 0.026). Cavernous sinus invasion by sinonasal adenoid cystic carcinoma was not associated with worse overall survival or disease-free survival (P = 0.200 and P = 0.198, respectively). Conclusions Because maxillary adenoid cystic carcinoma is associated with a higher rate of cavernous sinus invasion, such cases warrant caution during preoperative planning. Primary surgery as the initial therapy provides better locoregional control and survival for patients with sinonasal adenoid cystic carcinoma. Cavernous sinus invasion did not significantly impact survival; thus, it should not be regarded as a contraindication for curative treatment.

PURPOSE:This study evaluated the outcomes of hepatocellular carcinoma (HCC) patients with small normal liver volume (NLV) treated with proton beam therapy (PBT) and introduced estimated standard liver volume (eSLV) as a new constraint. MATERIALS AND METHODS:HCC patients with NLV < 800 cm3 and no distant metastasis who received treatment in our proton center were included. The doses of PBT were mainly 72.6 Gray equivalents (GyE) in 22 fractions and 66 GyE in 10 fractions according to tumor locations. The Urata equation was used to calculate eSLV. RESULTS:Twenty-two patients were treated between November 2015 and December 2016. The 1-year progression-free and overall survival rates were 40.4% and 81.8%, respectively. The 1-year in-field failure-free rate was 95.5%. NLV ranged from 483.9 to 795.8 cm3 (median = 673.8 cm3), eSLV ranged from 889.3 to 1290.0 cm3 (median = 1104.5 cm3), and the resulting NLV/eSLV ratio ranged from 44.3 to 81.2% (median = 57.7%). Non-irradiated liver volume (NILV) ranged from 232.9 to 531.6 cm3 (median = 391.2 cm3). The NILV/eSLV ratio ranged from 21.2 to 48.0% (median = 33.3%). NLV in the patients who received 20% and an rV30/eSLV ratio of >30% are acceptable.

Background The purpose of this study was to evaluate the recovery kinetics of voice and quality of life (QOL) over time in patients with early glottic cancer who underwent transoral laser microsurgery (TLM). Methods A prospective cohort study was conducted in which acoustic and aerodynamic voice assessments and QOL analyses were done using health-related questionnaires (European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30-questions [EORTC-QLQ-C30] and European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Head and Neck 35-questions [EORTC-QLQ-H&N35]) were administered at designated times. Results Most voice laboratory parameters worsened during the first month, then recovered to baseline after 6 months. The QLQ-H&N35 speech subscale was significantly improved. Among the voice laboratory parameters, pretreatment harmonics-to-noise ratio was an independent predictor (P = .041) for improvement on the speech subscale at the endpoint. Conclusion Despite an initial deterioration of voice and QOL in the first month, patients who underwent TLM recovered to a plateau since the sixth month and then to better than preoperative status afterward. A greater improvement in QOL was seen in patients with poorer baseline voice quality.

Objectives/Hypothesis The role of tumor volume in T4a laryngeal cancer remains unclear among different treatment modalities. Using tumor volumetry, we investigated the impact of primary tumor volume on this subset of patients. Study Design Retrospective cohort study of 62 T4a laryngeal cancer patients. Methods From October 2002 to September 2010, 48 patients were treated with definitive chemoradiation therapy (CRT), and 14 patients had undergone total laryngectomy. Tumor volume was calculated and was correlated with the overall survival (OS), progression-free survival (PFS), and local control rate (LCR) data of each treatment group. Results The 5-year OS, PFS, and LCR were significantly lower in the CRT group with tumor volume ≥ 15 cm3 (22.5% vs. 48.7%, P = 0.009; 32.2% vs. 64.3%, P = 0.003; 45.2% vs. 67.3%, P = 0.039). Multivariate analysis showed that tumor volume was an independent poor prognosticator for OS, PFS, and LCR in the CRT group. For tumor volume ≥ 15 cm3, total laryngectomy provided a significantly higher 5-year OS and PFS (54.5% vs. 22.5%, P = 0.039; 80.0% vs. 32.2%, P = 0.017) than for those tumors treated with definitive CRT. Conclusions Patients with T4a laryngeal cancer with primary tumor volume ≥ 15 cm3 had poorer survival outcomes after definitive CRT compared with total laryngectomy. It was also an independent poor prognosticator on LCR, PFS, and OS for those receiving definitive CRT. For patients with tumor volume ≥ 15 cm3, total laryngectomy provided a better survival outcome than definitive CRT. Level of Evidence 4. Laryngoscope, 124:1134–1140, 2014

Hypofractionated radiotherapy (RT) has been employed to treat hepatocellular carcinoma (HCC). The present study aimed to report the treatment effects, the dose-response associations and the factors that are associated with radiation-induced liver disease (RILD) in a high-dose hypofractionated RT procedure. A total of 40 patients with non-metastatic HCC who underwent RT for local control of irradiated tumors were studied. The treatment technique was that of three-dimensional conformal or intensity-modulated radiation therapy, with a fraction size of 3 Gy and a total dose of 40–66 Gy in 14–23 fractions. The biologically-effective dose (BED) was 52.0–85.8 Gy10 (median, 74.1 Gy10). Tumor regression was observed in 28 patients (70.0%) with a complete response, partial response, stable disease and progressive disease status in 11 (27.5%), 17 (42.5%), five (12.5%) and seven patients (17.5%), respectively. The one-, two- and five-year overall survival (OS) and in-field control (IFC) rates were 60, 40 and 21% and 73, 62 and 56%, respectively. A positive correlation also emerged between the radiation dose and the IFC (P=0.035). Eight of the 40 patients (20%) developed non-classic RILD. A higher Cancer of the Liver Italian Program score was associated with a higher probability of non-classic RILD (P=0.02). The tumor response and IFC rate of HCC following irradiation were significantly dose-dependent. High-dose hypofractionated X-ray RT is a feasible and effective treatment for HCC in patients with good liver function and for those who meet the criteria for a curative attempt.

Nasopharyngeal carcinoma (NPC), which is closely associated with Epstein–Barr virus (EBV), is a metastasis-prone epithelial cancer. We previously showed that tumor necrosis factor α-induced protein 2 (TNFAIP2) is highly expressed in NPC tumor tissues and is correlated with metastasis and poor survival in NPC patients. However, the underlying mechanism remains unclear. In this study, we demonstrate that the EBV oncoprotein, latent membrane protein 1 (LMP1), can transcriptionally induce TNFAIP2 expression via NF-κB. Quantitative RT–PCR and western blotting revealed that LMP1 induces TNFAIP2 expression through its C-terminal-activating region (CTAR2) domain, which is required for transduction of NF-κB (nuclear factor kappa-light-chain-enhancer of activated B cells) signaling. Inhibition of NF-κB activation or depletion of p65 (a component of NF-κB) by RNA interference abolished the LMP1-induced expression of TNFAIP2, whereas ectopic expression of p65 was sufficient to induce TNFAIP2 expression. Luciferase reporter assays showed that LMP1 transcriptionally induces TNFAIP2 expression through a newly identified NF-κB-binding site within the TNFAIP2 promoter (−3 869 to −3 860 bp). Immunohistochemical analysis of NPC biopsy specimens further revealed a significant correlation between the protein levels of TNFAIP2 and activated p65 (R=0.689, P

Summary Objective In this study, we investigated the usefulness and limitations of EBV-DNA follow-up in patients who had treated localized nasopharyngeal carcinoma. Methods Study subjects comprised 389 patients who had received treatment for localized nasopharyngeal carcinoma in our department. Copy numbers of EBV-DNA in plasma were assessed by real-time quantitative PCR. Patients in whom disease recurrence was suspected underwent image evaluation, esp. PET scan, and tissue proof if it is feasible. Lesions of undermined nature were confirmed by sequential follow-up. Results Plasma EBV-DNA was detectable in 60 of 63 (95%) patients with metastatic disease and all had positive PET findings. In addition, of the 45 patients with localized recurrent disease, plasma EBV-DNA was detectable in 23 (51%) patients and positive PET scan results were obtained in 40 (89%) of the patients. Of the 284 patients who were disease free, plasma EBV-DNA was detected in 90 (32%) patients. Of the 19 patients in disease free group who were suspected disease recurrence receiving PET scanning, 7 positive PET images were found including 3 second primary malignancy and 4 non-cancer lesions. Two lymphoma cases with positive EBV-DNA value sequentially attacked before or after their NPC were diagnosed. With the cutoff value of 400 copies/ml of EBV-DNA, the positive predict value was 73.5% and the negative predict value was 82.1%. The sensitivity was 0.46 and the specificity was 0.94. Conclusions EBV-DNA was a good marker for detecting metastatic failure in treated localized NPC. However, careful interpretation with complements from image examination was needed for locoregional failure and other false positive or false negative situations.

Objectives/Hypothesis Plasma Epstein-Barr virus (EBV) DNA concentrations predict prognosis in patients with nasopharyngeal carcinoma (NPC). Recent evidence also indicates that intratumor heterogeneity on F-18 fluorodeoxyglucose positron emission tomography (18F-FDG PET) scans is predictive of treatment outcomes in different solid malignancies. Here, we sought to investigate the prognostic value of heterogeneity parameters in patients with primary NPC. Study Design Retrospective cohort study. Methods We examined 101 patients with primary NPC who underwent pretreatment 18F-FDG PET/computed tomography. Circulating levels of EBV DNA were measured in all participants. The following PET heterogeneity parameters were collected: histogram-based heterogeneity parameters, second-order texture features (uniformity, contrast, entropy, homogeneity, dissimilarity, inverse difference moment), and higher-order (coarseness, contrast, busyness, complexity, strength) texture features. Results The median follow-up time was 5.14 years. Total lesion glycolysis (TLG), tumor heterogeneity measured by histogram-based parameter skewness, and the majority of second-order or higher-order texture features were significantly associated with overall survival (OS) and/or recurrence-free survival (RFS). In multivariate analysis, age (P =.005), EBV DNA load (P = .0002), and uniformity (P = .001) independently predicted OS. Only skewness retained the independent prognostic significance for RFS. Tumor stage, standardized uptake value, or TLG did not show an independent association with survival endpoints. The combination of uniformity, EBV DNA load, and age resulted in a more reliable prognostic stratification (P < .001). Conclusions Tumor heterogeneity is superior to traditional PET parameters for predicting outcomes in primary NPC. The combination of uniformity with EBV DNA load can improve prognostic stratification in this clinical entity. Level of Evidence 4 Laryngoscope, 127:E22–E28, 2017

Cell invasion is the first step of cancer metastasis that is the primary cause of death for cancer patients and defined as cell movement through extracellular matrix (ECM). Investigation of the correlation between cell invasive and extracellular stimulation is critical for the inhabitation of metastatic dissemination. Conventional cell invasion assay is based on Boyden chamber assay, which has a number of limitations. In this work, a microfluidic device incorporating with impedance measurement technique was developed for quantitative investigation of cell invasion process. The device consisted of 2 reservoirs connecting with a microchannel filled with hydrogel. Malignant cells invaded along the microchannel and impedance measurement was concurrently conducted by measuring across electrodes located at the bottom of the microchannel. Therefore, cell invasion process could be monitored in real-time and non-invasive manner. Also, cell invasion rate was then calculated to study the correlation between cell invasion and extracellular stimulation, i.e., IL-6 cytokine. Results showed that cell invasion rate was directly proportional to the IL-6 concentration. The microfluidic device provides a reliable and convenient platform for cell-based assays to facilitate more quantitative assessments in cancer research.

Xerostomia is one of the most common acute and late complications of radiotherapy for head and neck cancer, and it affects quality of life. We conducted a prospective study to evaluate the efficacy of traditional Chinese medicine (TCM) in toxicities and quality of life during radiotherapy. Head and neck cancer patients who were scheduled for radiotherapy were checked for inclusion/exclusion criteria before enrollment. Patients in the study group (inpatients) were hospitalized in a Chinese medicine ward and received concomitant TCM intervention during radiotherapy, while those in the control group (outpatients) received only conventional cancer treatments at the Western outpatient department. The primary end point was amelioration of postradiotherapy side effects. The secondary end points were quality of life during the cancer therapy and occurrence of adverse events following the TCM treatments. Thirty inpatients and 50 outpatients completed the study. Compared to the control group, those in the TCM group had decreased severity of xerostomia. There was no treatment-related impairment of renal or hepatic function among TCM group. Although better outcomes of social contact, dyspnea, physical and emotional function, and financial problems were found in the TCM group, we need further confirmation about the impact of hospitalization itself on these results.

OBJECTIVE To evaluate the outcomes and prognostic factors in patients with parotid gland cancers treated with adjuvant radiotherapy with or without chemotherapy. METHODS Eighty-five patients with parotid gland cancers were identified between October 2001 and September 2011. The median radiation dose was 66 Gy (range, 9-76 Gy). The outcomes assessment included overall survival, locoregional control, distant metastasis-free survival and disease-free survival. RESULTS The stage distribution was 20 patients (23.5%) in stage I, 28 (32.9%) stage II, 14 (16.5%) stage III and 23 (27.1%) stage IV. Fifty-five patients (64.7%) had positive margins and 23 patients (27.1%) had close margins (

The identification of early distant metastases (DM) in patients with newly diagnosed, previously untreated nasopharyngeal carcinoma (NPC) plays an important role in selecting the most appropriate treatment approach. Here, we sought to investigate the predictive value of distinct MRI parameters for the detection of early DM. Between November 2010 and June 2011, a total of 51 newly diagnosed NPC patients were included. All of the study participants were followed until December 2014 at a single institution after completion of therapy. DM was defined as early when they were detected on pretreatment FDG-PET scans or within 6 months after initial diagnosis. The following parameters were tested for their ability to predict early DM: pretreatment FDG-PET standardized uptake value (SUV), MRI-derived AJCC tumor staging, tumor volume, and dynamic contrast-enhanced (DCE) values. The DCE-derived ve was defined as the volume fraction of the extravascular, extracellular space. Compared with patients without early DM, patients with early DM had higher SUV, tumor volume, DCE mean (median) ve, ve skewness, ve kurtosis, and the largest mean ve selected among sequential slices (P

Background.The aims of this study were to analyze the clinical characteristics of SPM in patients with well-differentiated thyroid cancer and to determine the long-term prognosis in patients with double malignancies.Materials and Methods.We retrospectively analyzed 2,864 patients with well-differentiated thyroid cancer and a mean age of44.0±14.4years. Of these, 200 (7.0%) were diagnosed with SPM, 115 of which were diagnosed with metachronous SPM.Results.Of 2,864 patients, 163 (5.7%) patients died of thyroid cancer and 301 (10.5%) died of any cause by the end of the follow-up period. Multivariate analysis identified age, SPM, external radiotherapy, TNM stage, and postoperative serum Tg level to be factors independently associated with decreased survival. Of 200 patients with SPM, 74 (37.0%) died. In comparison to the anachronous and synchronous groups, the metachronous SPM group had a higher mean age; more advanced tumor, node, and metastasis stage; lower remission rate; higher postoperative radioactive iodide (131I) accumulated dose; a higher proportion of patients who underwent external radiotherapy; and higher thyroid cancer and total mortality rates.Conclusions.Patients with well-differentiated thyroid carcinoma and metachronous SPM had worse prognoses compared to patients without SPM.

Background. Portal vein tumor thrombosis (PVTT) is a common event in advanced hepatocellular carcinoma (HCC). The optimal treatment for these patients remains controversial. Methods. A retrospective review of 149 patients who had unresectable HCC associated with PVTT between January 2005 and December 2012 was performed. Outcomes related to external beam radiation-based treatment were measured, and clinicopathological features and parameters affecting prognosis were analyzed as well. Results. The radiotherapeutic response of PVTT was an important element that affected the overall treatment response of HCC. Serum α-fetoprotein < 400 ng/mL, the presence of a radiotherapeutic response on PVTT, and receiving additional locoregional therapy were significant prognostic factors affecting the survival of patients. Patients who had received additional locoregional therapy obtained a better outcome, and six of them were eventually able to undergo surgical management with curative intent. Conclusion. The outcome of HCC associated with PVTT remains pessimistic. In addition to the current recommended treatment using sorafenib, a combination of external beam radiotherapy targeting PVTT and locoregional therapy for intrahepatic HCC might be a promising strategy for patients who had unresectable HCC with PVTT. This approach could perhaps offer patients a favorable outcome as well as a possible cure with following surgical management.

The plasma concentration of Epstein-Barr virus (EBV) DNA is associated with tumor burden and prognosis in patients with nasopharyngeal carcinoma (NPC), but data on the relationship between viral load and (18)F-FDG PET functional parameters are lacking. We examined the association of (18)F-FDG PET functional parameters and EBV DNA load with the clinicopathologic characteristics and clinical outcomes of patients with NPC.One hundred eight patients with NPC who underwent (18)F-FDG PET before treatment were included in this study. We determined total lesion glycolysis (TLG) of the primary tumor, the cervical nodes, and their combination and the maximal standardized uptake value of the primary tumor and cervical lymph nodes. EBV DNA was measured by real-time polymerase chain reaction.EBV DNA was significantly associated with total TLG (R(2) = 0.589). Total TLG values had the highest correlation with EBV DNA load and were significantly associated with tumor, nodal, and overall stages. However, tumor TLG greater than the median (65 g) was the only parameter significantly associated with overall, local recurrence-free, disease-free, and distant metastasis-free survivals (P = 0.033, 0.014,0.001, and 0.023, respectively). After allowance for potential confounders, tumor TLG retained its independent significance for overall and disease-free survival rates (P = 0.045 and 0.006, respectively).Total TLG values are primarily associated with tumor burden and clinical stage, whereas tumor TLG is the best predictor of patient survival after treatment.