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Aneuploidy occurs within a significant proportion of childhood B-cell acute lymphoblastic leukemia (B-ALL). Some copy number variations (CNV), associated with novel subtypes of childhood B-ALL, have prognostic significance. A total of 233 childhood B-ALL patients were enrolled into this study. Focal copy number alterations of ERG, IKZF1, PAX5, ETV6, RB1, BTG1, EBF1, CDKN2A/2B, and the Xp22.33/Yp11.31 region were assessed by Multiplex Ligation-dependent Probe Amplification (MLPA). The MLPA telomere kit was used to identify aneuploidy through detection of whole chromosome loss or gain. We carried out these procedures alongside measurement of DNA index in order to identify, aneuploidy status in our cohort. MLPA telomere data and DNA index correlated well with aneuploidy status at higher sensitivity than cytogenetic analysis. Three masked hypodiploid patients, undetected by cytogenetics, and their associated copy number neutral loss of heterozygosity (CN-LOH) were identified by STR and SNP arrays. Rearrangements of TCF3, located to 19p, were frequently associated with 19p deletions. Other genetic alterations including iAMP21, IKZF1 deletions, ERG deletions, PAX5 AMP , which have clinical significance or are associated with novel subtypes of ALL, were identified. In conclusion, appropriate application of MLPA aids the identifications of CNV and aneuploidy in childhood B-ALL.

The genomic landscape of breast cancer (BC) is complex. The purpose of this study was to decipher the mutational profiles of Taiwanese patients with BC using next-generation sequencing. We performed whole-exome sequencing on DNA from 24 tumor tissue specimens from BC patients. Sanger sequencing was used to validate the identified variants. Sanger sequencing was also performed on paired adjacent nontumor tissues. After genotype calling and algorithmic annotations, we identified 49 deleterious variants in canonical cancer-related genes in our BC cohort. The most frequently mutated genes were PIK3CA (16.67%), FKBP9 (12.5%), TP53 (12.5%), ATM (8.33%), CHEK2 (8.33%), FOXO3 (8.33%), NTRK1 (8.33%), and NUTM2B (8.33%). Seven mutated variants ( ATR p.V1581fs, CSF1R p.R579Q, GATA3 p.T356delinsTMKS, LRP5 p.W389*, MAP3K1 p.T918fs, MET p.K1161fs, and MTR p.P1178S) were novel variants that are not present in any gene mutation database. After grouping the samples according to molecular subtype, we found that the cell cycle, MAPK, and chemokine signaling pathways in the luminal A subtype of BC; the focal adhesion, axon guidance, and endocytosis pathways in the luminal B subtype; and amyotrophic lateral sclerosis in the basal-like subtype were exclusively altered. Survival curve analysis showed that the presence of the MAPK signaling pathway and endocytosis mutations were correlated with a poor prognosis. These survival data were consistent with cBioPortal analyses of 2,051 BC cases. We discovered novel mutations in patients with BC. These results have implications for developing strategic, adjuvant, and gene-targeted therapies.

KRAS mutation in tumor tissue is a well-known predictor of resistance to the treatment of anti-EGFR antibodies in metastatic colorectal cancers (mCRC). However, the prognostic value of low-frequency plasma circulating tumor DNA (ctDNA) KRAS mutation in predicting treatment resistance in pretreated mCRC patients remains controversial. This study retrospectively reviewed the clinical course, including response to anti-EGFR and anti-VEGF therapies, and changes in serum tumor marker levels along with image studies in mCRC patients with <1.5% KRAS mutations detected in plasma ctDNA by next-generation sequencing (NGS) at a single center in Taiwan. We identified six pretreated mCRC patients with low-frequency KRAS G12V/G12D/G12S/G13D mutations (variant allele frequency 0.26~1.23%) in plasma ctDNA. Co-occurring low-frequency ctDNA mutations in APC, TP53, MAP2K1, KEAP1, or CTNNB1 were also detected. Although all six patients had treatment adjustments within one month after the ctDNA genetic test, image-evident tumor progression was noted in all patients within a median of 4 months afterwards. Re-challenge therapy with a combination of anti-EGFR, anti-VEGF, and FOLFIRI chemotherapy was found to be ineffective in a patient with 0.38% KRAS G12D mutation in baseline ctDNA. Our study suggests that the detection of low-frequency KRAS mutations in ctDNA could be used as a predictor of treatment response in mCRC patients. [ABSTRACT FROM AUTHOR]

The role of Programmed Cell Death Ligand 1 (PD-L1) expression in predicting epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKIs) efficacy remains controversial. Recent studies have highlighted that tumor-intrinsic PD-L1 signaling can be modulated by STAT3, AKT, MET oncogenic pathway, epithelial–mesenchymal transition, or BIM expression. This study aimed to investigate whether these underlying mechanisms affect the prognostic role of PD-L1. We retrospectively enrolled patients with EGFR mutant advanced stage NSCLC who received first-line EGFR-TKI between January 2017 and June 2019, the treatment efficacy of EGFR-TKI was assessed. Kaplan–Meier analysis of progression-free survival (PFS) revealed that patients with high BIM expression had shorter PFS, regardless of PD-L1 expression. This result was also supported by the COX proportional hazard regression analysis. In vitro, we further proved that the knockdown of BIM, instead of PDL1, induced more cell apoptosis following gefitinib treatment. Our data suggest that among the pathways affecting tumor-intrinsic PD-L1 signaling, BIM is potentially the underlying mechanism that affects the role of PD-L1 expression in predicting response to EGFR TKI and mediates cell apoptosis under treatment with gefitinib in EGFR-mutant NSCLC. Further prospective studies are required to validate these results. [ABSTRACT FROM AUTHOR]

Objectives: Perineural invasion (PNI) was quantitatively analyzed in oral squamous cell carcinoma (OSCC) specimens obtained by radical surgery to correlate with survival outcomes. Methods: This is a retrospective study that reviewed the Cancer registry data between 2009 and 2015. Inclusion criteria were oral cavity cancer, treatment by radical surgery, presence of PNI, and available pathologic samples for S100 staining. Patients with M1 disease and those with synchronous or metachronous cancer during staging work-up were excluded. All pathologic samples were reviewed to confirm PNI status and processed by immunohistochemical staining for S100 to quantify PNI. Pathologic information and staging results were also reviewed, and clinical outcomes were analyzed. Results: The retrospective study included 92 patients; 63 had intratumoral PNI (IPNI) and 29 had extratumoral PNI (EPNI). The average number of PNI foci (APNI) was higher in the EPNI group than in the IPNI group (6.7 vs 3.8, t -test 2-tail significance = 0.021). The 3-year overall survival (OS) and time-to-recurrence (TTR) rates of all patients were 82.5% and 81.2%, respectively. Univariate analysis showed that pathological T4 or N2-3 stage correlated with poor OS, whereas APNI ≥4 correlated with poor TTR. In multivariate analysis, only the pathological N2-3 stage was significantly correlated with poor OS, whereas only APNI ≥ 4 was an independent factor of poor TTR. The 3-year TTR rates were 92.4% and 65.6% for diseases with APNI < 4 and ≥ 4, respectively (P =.008). Conclusions: In patients with OSCC with PNI, a greater amount of PNI identified by S100 staining indicated a poorer TTR regardless of stage and other prognostic factors. Quantification of PNI by S100 immunohistochemistry is a potential method for prognosis prediction. [ABSTRACT FROM AUTHOR]

Simple Summary: Intravoxel incoherent motion (IVIM) diffusion-weighted imaging (DWI) is an advanced MRI technique from which both diffusion and perfusion parameters of tumor tissues can be extracted. The question as to whether 18F-FDG PET/MRI using the IVIM-DWI technique may provide prognostic information in patients with head-and-neck cancers remains unanswered. This prospective study was therefore designed to evaluate the prognostic significance of IVIM, dynamic contrast-enhanced MRI (DCE-MRI), and PET parameters derived from integrated PET/MRI in patients with oropharyngeal or hypopharyngeal squamous cell carcinomas (OHSCC). Our results indicated that metabolic tumor volume on 18F-FDG PET and D* derived from IVIM-DWI were independent risk factors for overall survival, whereas Ktrans and iAUC derived from DCE-MRI were significant predictors of recurrence-free survival. Combining PET/MRI biomarkers with clinical risk factors aided in formulating prognostic models, which demonstrated higher accuracy in predicting overall or recurrence-free survival over the traditional TNM staging system. To prospectively investigate the prognostic value of 18F-FDG PET/MRI in patients with oropharyngeal or hypopharyngeal squamous cell carcinomas (OHSCC) treated by chemoradiotherapy. The study cohort consisted of patients with OHSCC who had undergone integrated PET/MRI prior to chemoradiotherapy or radiotherapy. Imaging parameters derived from intravoxel incoherent motion (IVIM), dynamic contrast-enhanced MRI (DCE-MRI), and 18F-FDG PET were analyzed in relation to overall survival (OS) and recurrence-free survival (RFS). In multivariable analysis, T classification (p < 0.001), metabolic tumor volume (p = 0.013), and pseudo-diffusion coefficient (p = 0.008) were identified as independent risk factors for OS. The volume transfer rate constant (p = 0.015), initial area under the curve (p = 0.043), T classification (p = 0.018), and N classification (p = 0.018) were significant predictors for RFS. The Harrell's c-indices of OS and RFS obtained from prognostic models incorporating clinical and PET/MRI predictors were significantly higher than those derived from the traditional TNM staging system (p = 0.001). The combination of clinical risk factors with functional parameters derived from IVIM and DCE-MRI plus metabolic PET parameters derived from 18F-FDG PET in integrated PET/MRI outperformed the information provided by traditional TNM staging in predicting the survival of patients with OHSCC. [ABSTRACT FROM AUTHOR]

Background: We compared the clinical outcomes of patients with oral cavity squamous cell carcinoma (OCSCC) with cN+pN0 versus cN0pN0 disease. Methods: A total of 1309 OCSCC patients with pN0 disease were included. Of them, 1019 and 290 cases had cN0pN0 and cN+pN0 disease, respectively. For comparison purposes, we also examined 799 patients with pN+disease (cN0pN+/cN+pN+, n = 239/560). Subgroup analysis was performed in a propensity score‐matched cohort with cN0pN0 and cN+pN0 disease (n = 284 each). Results: Compared with cN0pN0, patients with cN+pN0 had a higher prevalence of the following variables: betel chewing, pT3−4, depth ≥10 mm, perineural invasion, and treatment with surgery and adjuvant therapy. The prognosis of patients with cN+pN0 (mean: 52 nodes) and cN0pN0 (mean: 39 nodes) disease was similar both in the original cohort and after propensity score matching. However, the 5‐year outcomes were more favorable for cN+pN0/cN0pN0 compared with cN0pN+/cN+pN+ (local control, 88%/88%/83%/81%; neck control, 94%/93%/82%/76%; distant metastases, 4%/3%/13%/31%; disease‐free survival, 84%/83%/68%/52%; disease‐specific survival, 92%/92%/77%/57%; overall survival, 81%/82%/59%/42%; all p values <0.001; cN+pN0 versus cN0pN0, all p values >0.05). cN+pN0 disease (vs. cN0pN0) was not significantly associated with local control, neck control, distant metastases, and survivals either in univariable or multivariable analyses. Conclusions: Despite a higher risk factor burden, the prognosis of patients with cN+pN0 disease did not differ from that of cases with cN0pN0. The higher nodal yield and the more frequent use of adjuvant therapy in cN+pN0 disease may explain the lack of significant differences in terms of neck control compared with cN0pN0 disease. [ABSTRACT FROM AUTHOR]

Methods: We sought to compare the prognostic impact of tumor differentiation with respect to adverse risk factors (RFs) identified by the National Comprehensive Cancer Network (NCCN) guidelines––including extranodal extension (ENE), positive/close margins, perineural invasion, lymphatic invasion, and vascular invasion––in patients with locally advanced oral cavity squamous cell carcinoma (OCSCC). Results: Between 1996 and 2018, 1179 consecutive patients with first primary pT3–4 OCSCC were included. A three‐level grading system was adopted––in which the final classification was assigned according to the most prevalent tumor grade. We identified 382/669/128 patients with well/moderately/poorly differentiated tumors, respectively. Compared with well/moderately differentiated tumors, poorly differentiated OCSCC had a higher prevalence of the following variables: female sex (4%/6%/11%), ENE, (14%/36%/61%), positive margins (0.5%/2%/4%), close margins (10%/14%/22%), perineural invasion (22%/50%/63%), lymphatic invasion (2%/9%/17%), vascular invasion (1%/4%/10%), and adjuvant therapy (64%/80%/87%). The 5‐year rates of patients with well/moderately/poorly differentiated OCSCC were as follows: local control (LC, 85%/82%/84%, p = 0.439), neck control (NC, 91%/83%/70%, p < 0.001), distant metastases (DM, 6%/18%/40%, p < 0.001), disease‐free survival (DFS, 78%/63%/46%, p < 0.001), disease‐specific survival (DSS, 85%/71%/49%, p < 0.001), and overall survival (OS, 68%/55%/39%, p < 0.001). Multivariable analysis identified the following variables as independent prognosticators for 5‐year outcomes: ENE (LC/NC/DM/DFS/DSS/OS), poorly differentiated tumors (NC/DM/DFS/DSS/OS), positive margins (LC/DFS), lymphatic invasion (DFS/DSS/OS), perineural invasion (DM), and age ≥65 years (OS). Conclusions: In addition to ENE, poor tumor differentiation was identified as the second most relevant adverse RF for patients with pT3–4 OCSCC. We suggest that the NCCN guidelines should include poor tumor differentiation as an adverse RF to refine and tailor clinical management. [ABSTRACT FROM AUTHOR]

Abstract Background Oral cavity cancers (ORC) are the most common cancers, and standard treatment is radical surgery with postoperative radiotherapy. However, locoregional failure remains a major problem, indicating radioresistance an important issue. Our previous work has shown that GP96 contributed to radioresistance in nasopharyngeal and oral cancer cell lines. In this study, we determined clinical significance of GP96 in ORC by evaluation of GP96 expression and its association with disease prognosis in patients receiving radiotherapy Methods Total of 79 ORC patients (77 males, median age: 48 years old) receiving radical surgery and postoperative radiotherapy between Oct 1999 and Dec 2004 were enrolled. Patients in pathological stages II, III and IV were 16.5%, 16.5% and 67%, respectively. For each patient, a pair of carcinoma tissue and grossly adjacent normal mucosa was obtained. GP96-expression was examined by western blot analysis, and the association with clinicopathological status was determined. Results Three-year locoregional control (LRC), distant metastasis-free survival (DMFS), disease-specific survival (DSS) and overall survival (OS) rates were 69%, 79%, 63% and 57%, respectively. We found that 55 patients (70%) displayed GP96-overexpression in the tumor tissue, which correlated with a higher pN stage (p = 0.020) and tumor depth (> 10 mm) (p = 0.045). Nodal extracapsular spreading (ECS) and GP96-overexpression predicted adverse LRC (p = 0.049 and p = 0.008). When stratified by nodal ECS, the adverse impact of GP96 remained significant in three-year LRC (p = 0.004). In multivariate analysis, GP96-overexpression was also an independent predictor of LRC, DSS and OS (p = 0.018, p = 0.011 and p = 0.012). Conclusion GP96 may play roles in radioresistance which attributes to tumor invasiveness in oral cancer patients receiving radiotherapy. GP96 may serve as a novel prognostic marker of radiotherapy. However, further independent studies are required to validate our findings in a larger series.

Objectives: To investigate the prognostic value of the preoperative systemic immune‐inflammation index (SII) in patients with oral cavity squamous cell carcinoma (OC‐SCC) treated with curative surgery followed by adjuvant radiotherapy (RT) or chemoradiotherapy (CCRT). Materials and Methods: We retrospectively reviewed the clinical records of patients with OC‐SCC who received surgery and postoperative adjuvant RT/CCRT between January 2005 and December 2012. Blood samples were drawn in the 2 weeks preceding surgery. SII was calculated by multiplying the absolute neutrophil and platelet counts, and then, divided by the absolute lymphocyte count, and its optimal cutoff value was identified using the Youden's index. The study endpoints included overall survival (OS), local control (LC), regional control (RC), and distant control (DC). Results: The study sample consisted of 993 patients (58.8% of them treated with CCRT). The optimal cutoff value for SII was 810.6. A total of 347 (34.9%) study participants had high preoperative SII values. After allowance for potential confounders in multivariable analysis, high SII values were independently associated with less favorable DC (adjusted hazard ratio [HR] = 1.683, p = 0.001) and OS (adjusted HR = 1.466, p < 0.001). No independent association between SII and LC/RC was observed. Conclusion: Increased SII values predict poor DC and OS in patients with OC‐SCC treated with curative resection and adjuvant RT/CCRT. Owing to the higher risk of systemic failure in this patient group, a thorough follow‐up surveillance schedule may be advisable pending independent confirmation of our data. [ABSTRACT FROM AUTHOR]

Purpose: Perineural invasion (PNI) is an adverse prognostic factor in patients with oral cavity squamous cell carcinoma (OCSCC). The American Joint Committee on Cancer Staging Manual, eighth edition, introduced a subdivision of PNI into two distinct forms, that is, extratumoral and intratumoral PNI (EPNI and IPNI, respectively). We designed the current study to assess whether EPNI and IPNI have different prognostic implications in terms of disease control and survival outcomes in patients with OCSCC. Materials and methods: We retrospectively examined 229 consecutive patients with OCSCC and PNI who underwent radical surgery between July 2003 and November 2016. EPNI and IPNI were identified in 76 and 153 patients, respectively. The 5‐year locoregional control (LRC), distant metastasis, disease‐free survival (DFS), and overall survival (OS) rates served as the main outcome measures. Results: Compared with patients showing IPNI, those with EPNI had a higher prevalence of worst pattern of invasion type‐5 (P < 0.001), alcohol consumption (P = 0.03), and close margins (P = 0.002). Univariate analysis revealed that EPNI was a significant predictor of 5‐year LRC (P = 0.024), DFS (P = 0.007), and OS (P = 0.034) rates. After allowance for potential confounders in multivariable analysis, ENPI was retained in the model as an independent predictor of 5‐year LRC (P = 0.028), DFS (P = 0.011), and OS (P = 0.034) rates. Conclusion: Compared with IPNI, the presence of EPNI in OCSCC portends less favorable outcomes. Patients with EPNI are potential candidates for definite aggressive treatment modalities aimed at improving prognosis. [ABSTRACT FROM AUTHOR]

Abstract: 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. [ABSTRACT FROM AUTHOR]

Objectives: We prospectively investigated the roles of pretreatment dynamic contrast-enhanced MR imaging (DCE-MRI), diffusion-weighted MR imaging (DWI) and 18F-fluorodeoxyglucose-positron emission tomography (18F-FDG PET)/CT for predicting survival of oropharyngeal or hypopharyngeal squamous cell carcinoma (OHSCC) patients treated with chemoradiation.Methods: Patients with histologically proven OHSCC and neck nodal metastases scheduled for chemoradiation were eligible. Clinical variables as well as DCE-MRI-, DWI- and 18F-FDG PET/CT-derived parameters of the primary tumours and metastatic neck nodes were analysed in relation to 3-year progression-free survival (PFS) and overall survival (OS) rates.Results: Eighty-six patients were available for analysis. Multivariate analysis identified the efflux rate constant (K ep)-tumour < 3.79 min-1 (P = 0.001), relative volume of extracellular extravascular space (V e)-node < 0.23 (P = 0.004) and SUVmax-tumour > 19.44 (P = 0.025) as independent risk factors for both PFS and OS. A scoring system based upon the sum of each of the three imaging parameters allowed stratification of our patients into three groups (patients with 0/1 factor, patients with 2 factors and patients with 3 factors, respectively) with distinct PFS (3-year rates = 72 %, 38 % and 0 %, P < 0.0001) and OS (3-year rates = 81 %, 46 % and 20 %, P < 0.0001).Conclusions: K ep-tumour, V e-node and SUVmax-tumour were independent prognosticators for OHSCC treated with chemoradiation. Their combination helped survival stratification.Key Points: • K ep -tumour, V e -node and SUV max -tumour are independent predictors of survival rates. • The combination of these three prognosticators may help stratification of survival. • MRI and FDG-PET/CT play complementary roles in prognostication of head and neck cancer. [ABSTRACT FROM AUTHOR]

Objectives: Simultaneous second primary tumors (SSPT) are not uncommon in patients with oral cavity squamous cell carcinoma (OSCC) living in areas where the habit of betel quid chewing is widespread. We sought to identify the main prognostic factors in OSCC patients with SSPT and incorporate them into a risk stratification scheme. Methods: A total of 1822 consecutive patients with primary OSCC treated between January 1996 and February 2014 were analyzed for the presence of SSPT. The 18-month and 5-year overall survival (OS) rates served as the main outcome measures. Results: Of the 1822 patients, 77 (4%) were found to have SSPT (i.e, two malignancies identified within one month of each other). The 18-month and 5-year OS rates in patients without SSPT and with SSPT were 82% and 69%, and 72% and 53%, respectively (p = 0.0063). Patients with SSPT were further divided into patients with either esophageal cancer or hepatocellular carcinoma (eso-HCC subgroup, n = 8) and other tumors (NO eso-HCC subgroup, n = 69). After multivariate analysis, neck nodal extracapsular spread (ECS, n = 18) and the presence of eso-HCC were identified as independent adverse prognostic factors. The 18-month OS rates of SSPT patients with both eso-HCC and ECS (n = 5) vs. the remaining patients (n = 72) were 0% and 78%, respectively (p < 0.0001). Conclusion: OSCC patients with neck nodal ECS and esophageal cancer or hepatocellular carcinoma as SSPT have a dismal short-term prognosis. [ABSTRACT FROM AUTHOR]

Objectives: Reliable prognostic factors that serve as a guide to follow-up of patients with locoregionally advanced nasopharyngeal carcinoma (NPC) have not yet been identified. We sought to investigate the prognostic implications of post-therapy PET in patients with NPC treated with chemoradiotherapy. Methods: Patients with locoregionally advanced NPC (stages III and IVa-b) who had completed primary curative treatment for 3 months were eligible. All of the patients underwent F-FDG PET and conventional work-up (CWU) for the assessment of treatment response. Results: A total of 165 patients were enrolled. Over a median follow-up of 58 months, 30 patients died and 41 had disease recurrence. The results of the 3-month post-therapy PET and total lesion glycolysis (TLG) of the primary tumor were independent predictors of overall survival. TNM tumor stage, TLG, and post-therapy PET findings were independently associated with disease-free survival (DFS). The results of post-therapy PET were more predictive of DFS than TNM tumor stage ( P < 0.001 vs. P = 0.005). Among patients with stage IVa-b disease, there was a trend toward better 5-DFS rates in patients with a complete metabolic response (CMR) on PET than in those who showed a complete response in the CWU (5-year DFS = 70.7 vs. 63.1 %). Notably, the 1- and 2-year DFS rates were significantly better in the former group compared with the latter. In contrast, the results of post-therapy CWU were not a reliable predictor for DFS. Conclusion: The results of post-therapy PET are an important independent prognostic factor in locoregionally advanced NPC. CMR on PET is associated with better DFS rates and could serve as a guidance to individualize the surveillance protocols for patients with stage IVa-b disease. [ABSTRACT FROM AUTHOR]

Purpose: Human papillomavirus type 16 (HPV-16) positivity is associated with favourable survival in oropharyngeal squamous cell carcinoma (OPSCC). We report here a study of the prognostic significance of F-FDG PET/CT functional parameters and HPV-16 infection in OPSCC patients. Methods: We retrospectively analysed 60 patients with stage III or IV OPSCC who had had a pretherapy F-FDG PET/CT scan and had completed concurrent chemoradiotherapy ( n = 58) or curative radiotherapy ( n = 2). All patients were followed up for ≥24 months or until death. We determined total lesion glycolysis (TLG) and the maximal standardized uptake values (SUV) of the primary tumour and neck lymph nodes from the pretherapy F-FDG PET/CT scan. Optimal cut-offs of the F-FDG PET/CT parameters were obtained by receiver operating characteristic (ROC) curve analyses. Pretherapy tumour biopsies were studied by polymerase chain reaction to determine HPV infection status. Results: The pretherapy tumour biopsies were positive for HPV-16 in 12 patients (20.0 %). Cox regression analyses revealed HPV-16 positivity and tumour TLG >135.3 g to be independently associated with overall survival ( p = 0.027 and 0.011, respectively). However, only tumour TLG >135.3 g was independently associated with progression-free survival, disease-free survival and locoregional control ( p = 0.011, 0.001 and 0.034, respectively). A scoring system was formulated to define distinct overall survival groups using tumour TLG and HPV-16 status. Patients positive for HPV-16 and with tumour TLG ≤135.3 g experienced better survival than those with tumour TLG >135.3 g and no HPV infection ( p = 0.001). Conclusion: Tumour TLG was an independent predictor of survival in patients with locally advanced OPSCC. A scoring system was developed and may serve as a risk stratification strategy for guiding therapy. [ABSTRACT FROM AUTHOR]

Background To investigate the pretreatment copy number and the clearance rate of plasma Epstein-Barr virus (EBV) DNA as novel prognostic outcome markers for metastatic nasopharyngeal carcinoma (NPC). Methods Seventy-three patients with metastatic NPC were treated at outpatient department. Plasma EBV DNA concentrations and half-life values of plasma viral clearance rates, were determined by real-time quantitative polymerase chain reaction. Results Treatment response evaluated after 3 to 6 months of treatment showed that the overall response rate was 53.5%. The pretreatment plasma EBV DNA concentrations and the half-life of plasma EBV DNA clearance rates had significant effects on treatment response and overall survival prediction. In the chemotherapy regimen, gemcitabine plus cisplatin had a better treatment outcome than the cisplatin plus oral UFT and calcium folinate-based regimens. Conclusions The pretreatment plasma EBV DNA copy number and their clearance rates are significant predictors for NPC treatment outcome. © 2011 Wiley Periodicals, Inc. Head Neck, 2012 [ABSTRACT FROM AUTHOR]

Summary: Objectives: To investigate the prognostic value of prepontine cistern invasion (PPCI) in nasopharyngeal carcinoma (NPC) patients treated with intensity-modulated radiotherapy (IMRT). Materials and methods: Five hundred and four non-disseminated NPC patients who underwent magnetic resonance imaging examination before radical IMRT between November 2000 and December 2008 were retrospectively reviewed. The diagnostic criteria for PPCI were tumor invasion through the posterior cortex of clivus and extension into the prepontine cistern. Results: The median follow-up of the patients in this study was 63.5months. PPCI was found in 44 patients (25% of T4 patients). The 5-year progression-free survival (PFS), local control (LC), distant metastasis-free survival (DMFS), and overall survival (OS) of all patients, with and without PPCI, were 44.3% and 70.5% (p <0.001), 84.4% and 89.1% (p =0.376), 66.6% and 87.3% (p <0.001), and 59.6% and 80.2% (p <0.001), respectively. In T4 patients with PPCI and without PPCI, the 5-year PFS, LC, DMFS, and OS were 44.3% and 62.5% (p =0.023), 84.4% and 84.9% (p =0.946), 66.6% and 83.1% (p =0.022), and 59.6% and 71.0% (p =0.045), respectively. Using multivariate analysis, PPCI was found to be an independent poor prognostic factor for PFS (HR=1.816; p =0.007), DMFS (HR=1.928; p =0.045), and OS (HR=1.798; p =0.016). Conclusion: Prepontine cistern invasion was an independent prognostic factor for poor DMFS and OS but not LC in NPC patients treated with IMRT, even within T4 patients. [Copyright &y& Elsevier]

• Radiologic extranodal extension (rENE) correlated with poor treatment outcomes. • rENE correlated with clinical N stage in patients with hypopharyngeal cancer. • Metastatic lymph nodes >6 cm coexisted with rENE and correlated with poor survival. • It may be more appropriate to classify as N3b disease in future staging systems. • rENE of lymph nodes <6 cm should be staged as N3a disease. We aimed to evaluate the prognostic value of radiologic extranodal extension (rENE) in patients with hypopharyngeal cancer (HPC) treated with primary chemoradiation. Cancer registry data were reviewed from 2005 to 2014. Inclusion criteria included HPC, clinical N1–3 disease (AJCC staging system, 7th edition), and receiving radiotherapy. Patients with M1 diseaseor with synchronous/metachronous cancer were excluded. Staging images were reviewed by two radiologists. rENE was defined as infiltration of adjacent fat/muscles, irregular nodal surface, or irregular capsular enhancement. Clinical stage, rENE status, and clinical outcome were analyzed. Overall, 355 patients were included. Patients with rENE had lower 3-year overall survival (OS) and recurrence-free survival (RFS) rates. Univariate analysis showed that clinical T4 or N3 stage, overall stage IV, and rENE correlated with OS and RFS. In multivariate analysis, clinical T4 or N3 stage correlated with poor OS, while clinical T4 or N3 stage and rENE were independent predictors of poor RFS. N1/2 without rENE was designated as Group 1, N1/2 with rENE as Group 2, and N3 with/without rENE as Group 3. The 3-year RFS rates in Groups 1, 2, and 3 were 55.8%, 41.0%, and 29.3%, respectively. The 3-year RFS rate in Group 1 was significantly higher than that in the other two groups. rENE is an adverse prognostic factor for survival in patients with HPC treated with primary chemoradiation. It correlated with inferior RFS regardless of N stage. rENE may be used as a criterion for clinical ENE in future staging systems. [ABSTRACT FROM AUTHOR]

• CT-simulation based radiomic models during radiotherapy carry significant prognostic value for both progression-free survival and overall survival in patients with laryngeal and hypopharyngeal cancer. • Mid-radiotherapy peritumoral and intratumoral radiomic models were superior to AJCC staging and tumor volume. • Mid-radiotherapy peritumoral and intratumoral radiomic models were superior to pre-radiotherapy intratumoral radiomic models. We aimed to investigate the prognostic value of peritumoral and intratumoral computed tomography (CT)-based radiomics during the course of radiotherapy (RT) in patients with laryngeal and hypopharyngeal cancer (LHC). A total of 92 eligible patients were 1:1 randomly assigned into training and validation cohorts. Pre-RT and mid-RT radiomic features were extracted from pre-treatment and interim CT. LASSO–Cox regression was used for feature selection and model construction. Time-dependent area under the receiver operating curve (AUC) analysis was applied to evaluate the models' prognostic performances. Risk stratification ability on overall survival (OS) and progression-free survival (PFS) were assessed using the Kaplan–Meier method and Cox regression. The associations between radiomics and clinical parameters as well as circulating lymphocyte counts were also evaluated. The mid-RT peritumoral (AUC: 0.77) and intratumoral (AUC: 0.79) radiomic models yielded better performance for predicting OS than the pre-RT intratumoral model (AUC: 0.62) in validation cohort. This was confirmed by Kaplan-Meier analysis, in which risk stratification depended on the mid-RT peritumoral (p = 0.009) and intratumoral (p = 0.003) radiomics could be improved for OS, in comparison to the pre-RT intratumoral radiomics (p = 0.199). Multivariate analysis identified mid-RT peritumoral and intratumoral radiomic models as independent prognostic factors for both OS and PFS. Mid-RT peritumoral and intratumoral radiomics were correlated with treatment-related lymphopenia. Mid-RT peritumoral and intratumoral radiomic models are promising image biomarkers that could have clinical utility for predicting OS and PFS in patients with LHC treated with RT. [ABSTRACT FROM AUTHOR]

• LMR significantly changed during RT in patients with head and neck cancer. • The dynamic changes in LMR during RT carried prognostic value. • Longitudinal assessment of LMR during RT may serve as a promising biomarker. We sought to investigate whether dynamic changes in lymphocyte-to-monocyte ratio (LMR) occurring during the course of radiotherapy (RT) may have prognostic value in patients with head and neck cancer (HNC). We retrospectively reviewed the clinical records of patients with HNC who underwent RT at our center between 2005 and 2013. Generalized estimating equations were used to longitudinally assess changes in LMR through the course of RT. Delta-LMR was calculated as the difference between LMR measured during treatment and baseline LMR values. Freedom from metastasis (FFM) and overall survival (OS) served as the main outcome measures. A total of 1431 patients with HNC were enrolled. After a median follow-up of 9 years, 636 (44.4%) patients died and 240 (16.8%) had distant metastases. Compared with patients with low delta-LMR at two weeks, those with high delta-LMR experienced less favorable outcomes (five-year OS: 73% versus 59%, respectively, p < 0.001; five-year FFM: 87% versus 80%, respectively, p = 0.015). Similar findings were observed for delta-LMR measured at four weeks (five-year OS: 72% versus 60%, p < 0.001; five-year FFM: 86% versus 79%, respectively, p = 0.002) and six weeks (five-year OS: 72% versus 57%, p < 0.001; five-year FFM: 87% versus 79%, respectively, p = 0.002). Multivariate analysis identified delta-LMR as an independent prognostic factor for both FFM and OS. Delta-LMR is a simple and inexpensive biomarker that may be clinically useful for predicting FFM and OS in patients with HNC treated with RT. [ABSTRACT FROM AUTHOR]

Objectives: The postoperative outcomes of patients with oral cavity squamous cell carcinoma (OCSCC) vary greatly. To improve risk stratification, we sought to identify genetic biosignatures by whole-exome sequencing (WES).Materials and Methods: We retrieved patients with OCSCC patients with paired freshly frozen malignant and non-malignant tissue specimens and performed WES by Illumina HiSeq4000 platform. We further applied a tree-based method to analyze copy number variations and obtain signature classification and driver-gene identification. We further confirmed the prognostic impact of the WES biosignature in an external independent validation set.Results: We examined 168 paired samples from patients with surgically treated OCSCC. Similar to the literature, the most commonly mutated genes were TP53 (66%), FAT1 (32%), and NOTCH1 (24%). The signatures 13 (APOBEC Cytidine deaminase [C > G]), 1 (spontaneous deamination of 5-methylcytosine), and 7 (UV exposure) showed the highest concordance rates. Using the MutSigCV, MuSiC, 20/20+, OncodriveFML, e-Driver, OncodriveCLUST, and tree-based methods, we identified a nine-gene OCSCC panel (RYR1, HLA-B, TSHZ2, PCDH17, DNAH17, GRID1, SBNO2, KSR2, and GCN1L1) predicting survival outcomes in our sample. We used the TCGA database to validate the prognostic value of the panel independently. Furthermore, gene-gene covariance analysis confirmed the coexistence of several gene alterations.Conclusion: We identified and independently validated a WES biosignature that predicts outcomes in surgically treated OCSCC in Taiwan, a betel-quid-chewing-prevent area. We proposed that the panel might help clinical trial designation for adjuvant therapy based on the risk stratification from the novel gene panel and identify targets for liquid biopsy monitoring during surveillance. [ABSTRACT FROM AUTHOR]

Summary: Objectives: We have previously shown that the resection outcomes of cT4a and cT4b oral cavity squamous cell carcinoma (OSCC) are comparable, but whether similar conclusions can be applied for the pathological stage of this disease needs investigation. In this study, we sought to compare the outcomes and to identify the risk factors for both pT4a and pT4b tumors. Methods: We retrospectively examined 181 pT4 OSCC patients who had radical resections between 2003 and 2010. The 5-year control and survival rates were the main outcome measures. Results: Of the 181 resected pT4 OSCC patients, 133 (73%) had pT4a disease, and 48 (27%) had pT4b disease. All of the resected T4b tumors were below the mandibular notch (infra-notch pT4b). The 5-year outcomes of the patients with infra-notch pT4b and pT4a were comparable: local control, 80% vs. 78%, p =0.7275; neck control, 87% vs. 82%, p =0.4798; distant metastases, 22% vs. 23%, p =0.8871; disease-free survival, 63% vs. 55%, p =0.2813; disease-specific survival, 68% vs. 60%, p =0.3526; and overall survival, 62% vs. 44%, p =0.2643, respectively. Extracapsular spread was the only independent prognostic factor for 5-year survival rates in pT4a patients. Poor tumor differentiation and pN2 status were the independent 5-year survival prognostic factors for the infra-notch pT4b tumor patients. Conclusions: Infra-notch pT4b had outcomes comparable with those of pT4a tumors, although they displayed different risk factors. We therefore recommend that resectable infra-notch pT4b tumors should be classified as pT4a disease in the AJCC tumor staging. [ABSTRACT FROM AUTHOR]

Summary: Objectives: To evaluate the prognostic value of maximum standardized uptake value (SUVmax) measured in [18F]-fluorodeoxyglucose positron emission tomography (18F-FDG PET) for patients with non-disseminated nasopharyngeal carcinoma (NPC). Materials and methods: From January 2002 to July 2008, 371 NPC patients who underwent 18F-FDG-PET before radical intensity-modulated radiotherapy (IMRT) were recruited. The SUVmax was recorded for the primary tumor (SUVmax-T) and neck lymph nodes (SUVmax-N). Results: The median follow-up was 64months. The optimal cutoff value was 9.3 for SUVmax-T and 7.4 for SUVmax-N. Patients with a lower SUVmax-T or SUVmax-N had a significantly better 5-year distant metastasis-free survival (DMFS), but showed no significant difference in local control or regional control. Patients were divided into four groups by SUVmax, as follows: (a) both lower SUVmax-T and SUVmax-N, (b) higher SUVmax-T only, (c) higher SUVmax-N only, and d) both higher SUVmax-T and SUVmax-N. There were significant differences between these four groups in 5-year DMFS: (a) 95.5%, (b) 90.0%, (c) 83.3%, and (d) 79.9%, respectively (p =0.004). When looking at the stage of disease, the 5-year DMFSs in group a, b, c, d were 96.9%, 94.6%, 97.4%, and 84.3%, respectively in stage I–III patients (p =0.037) and were 91.6%, 82.9%, 68.5%, and 76.7% in stage IVA–B patients (p =0.145). Using multivariate analysis, the SUVmax grouping, gender, and stage were independent factors for DMFS. Conclusion: The SUVmax of the primary tumor and neck lymph nodes were independent prognostic factors for DMFS in NPC patients treated with IMRT. [Copyright &y& Elsevier]

Summary: Pathological lymph node metastases (pN+) are an established prognostic factor in oral cavity squamous cell carcinoma (OSCC). We retrospectively examined the prognostic significance of lymph node (LN) density in pN+ OSCC patients who underwent neck dissection (ND) and postoperative adjuvant therapy. We examined 309 pN+ patients who underwent levels I–III ND and 148 pN+ patients treated with levels I–V ND. The 5-year control and survival rates served as the main outcome measures. The 5-year rates for patients treated with levels I–III and I–V NDs were as follows: local control, 79%, 74% (p =0.0630); neck control, 81%, 68% (p =0.0014); distant metastasis, 21%, 36% (p =0.0003); disease-free survival (DFS), 59%, 43% (p =0.0001); disease-specific survival (DSS), 66%, 46% (p <0.0001); and overall survival (OS), 49%, 37% (p =0.0048), respectively. Multivariate analysis demonstrated that an LN density ⩾0.16 was an independent prognostic factor for 5-year neck control (all data presented as p, hazard ratio [95% confidence interval]) (0.003, 2.691 [1.412–5.128]), distant metastases (0.001, 2.831 [1.520–5.270]), DFS (<0.001, 2.464 [1.571–3.866]), and DSS (0.036, 1.781 [1.040–3.052]) in levels I–III ND patients. An LN density ⩾0.048 was an independent predictor of 5-year local control (0.004, 4.871 [1.654–14.344]), neck control (0.002, 24.738 [3.367–181.771]), DFS (<0.001, 4.151 [2.264–7.610]), DSS (<0.001, 3.791 [2.017–7.125]), and OS (<0.001, 2.806 [1.706–4.613]) in levels I–V ND patients. Our findings demonstrate the prognostic value of LN density for guiding treatment strategies in OSCC patients who are to receive adjuvant therapy. [Copyright &y& Elsevier]

Objectives: This large-scale cohort study was designed to compare the clinical outcomes of Taiwanese patients with squamous cell carcinoma (SCC) of the upper versus lower gum.Methods: Between 2004 and 2017, we identified 4244 patients with first primary SCC of the gum (694 upper gum; 3550 lower gum) who were treated with surgery either with or without adjuvant therapy. Of them, 1990 patients (329 upper gum; 1661 lower gum) enrolled from 2011 to 2017 had a higher number of histopathological variables and entered subgroup analyses. Five-year disease-specific survival (DSS) and overall survival (OS) rates served as outcome measures.Results: The 5-year DSS and OS rates of patients with upper gum SCC were lower than those of cases with lower gum SCC (65%/74%, p < 0.0001; and 55%/65%, respectively, p < 0.0001). Compared with lower gum SCC, upper gum SCC had a higher prevalence of the following variables: female sex, age ≥ 65 years, pNx (without neck dissection), no-betel chewing (2011-2017), no-smoking (2011-2017), and margin status ≤ 4 mm (positive and close margins, 2011-2017). On multivariable analysis, gum subsite (upper versus lower), age (≥65 versus < 65 years), pT (T3 - 4 versus T1 - 2), pN (N1 - 3 versus N0/Nx), depth (≥10 mm versus < 10 mm, 2011-2017), ENE (present versus absent, 2011-2017), and margins (≤4 mm versus > 4 mm 2011-2017, only DSS) were identified as independent adverse prognostic factors for 5-year DSS and OS.Conclusions: Compared to lower gum SCC, upper gum SCC had less favorable 5-year outcomes. Wide resection margins are recommended to improve prognosis of upper gum SCC. [ABSTRACT FROM AUTHOR]

Objectives: To investigate the prognostic value of the relative maximum standardized uptake value (SUV) ratio between neck lymph node and primary tumor (NTR) measured by pretreatment 18F-FDG PET in patients with nasopharyngeal carcinoma (NPC).Materials and Methods: We retrospectively reviewed patients with non-disseminated NPC who underwent PET scans before radical intensity-modulated radiotherapy (IMRT). Receiver operating characteristic analysis was performed to identify the optimal cut-off value for NTR. The prognostic value of NTR for distant metastasis-free survival (DMFS) was evaluated using Kaplan-Meier method for survival analyses and Cox regression for multivariable analysis.Results: Among the 437 eligible patients, the median follow-up time was 62.9 (range, 2.1-113.0) months. Patients with high NTR (NTR > 0.9181) experienced significantly worse DMFS (5-year 80.5% vs. 91.6%, P < 0.001). In the subgroup analysis, we found that patients with high NTR had significantly lower DMFS in T1-2 category (5-year 86.1% vs. 98.1%, P = 0.002), T3-4 category (5-year 71.5% vs. 86.2%, P = 0.010), N2-3 category (5-year 75.3% vs. 86.2%, P = 0.048), and stage IVA-B (5-year 69.8% vs. 85.4%, P = 0.012). Multivariable analysis showed that NTR was an independent prognostic factor for DMFS (HR 2.20, 95% CI 1.20-4.03, P = 0.011).Conclusion: Pretreatment NTR is an easily accessible but potential prognosticator for DMFS in NPC patients treated by IMRT, which may help in providing more personalized treatment or designing future clinical trials. [ABSTRACT FROM AUTHOR]

Purpose: The aim of the present study was to evaluate whether texture features extracted from 18F-FDG PET/CT images may provide additional prognostic information in patients with metastatic nasopharyngeal carcinoma (NPC).Materials and Method: We retrospectively examined 52 patients with metastatic NPC who underwent assessment of EBV DNA titers and pretreatment 18F-FDG PET/CT imaging. All participants were followed up for at least two years. The following 18F-FDG PET parameters were analyzed: standardized uptake value (SUV), metabolic tumor volume (MTV), total lesion glycolysis (TLG), and texture parameters. Independent predictors of outcomes were identified using receiver operating characteristic curve analysis and multivariate Cox proportional hazards models.Results: On multivariate analysis, EBV DNA titers > 3500 copies/mL and TLG of metastatic lesions > 138 mL were identified as independent predictors of overall survival (OS) (P = 0.036 and P = 0.047, respectively). Patients were divided into two subgroups based on their EBV DNA titers (high versus low). In the high EBV DNA titer group, a lower homogeneity of distant metastatic lesions and higher TLG values of distant metastatic lesions were independent risk factors for OS (P = 0.033 and P < 0.001, respectively). In the low EBV DNA titer group, a reduced uniformity of distant metastatic lesions and a higher SUVmax of distant metastatic lesions were unfavorable risk factors for OS (P = 0.004 and P = 0.005, respectively). Based on these results, we devised two prognostic scoring systems for the prediction of 2-year OS in each EBV DNA titer group.Conclusion: Some of the PET-derived texture parameters are independent predictors of outcomes in patients with metastatic NPC and provide complementary information to EBV DNA titers. [ABSTRACT FROM AUTHOR]