Nodal Extracapsular Spread Research Articles

Integrating pretreatment MRI-detected nodal features and Epstein-Barr virus DNA to identify optimal candidates for intensity-modulated radiotherapy alone in patients with stage II nasopharyngeal carcinoma

ObjectivesTo develop and validate a prognostic nomogram based on MRI-detected features of retropharyngeal and cervical lymph nodes and Epstein–Barr virus (EBV) DNA in patients with stage II nasopharyngeal carcinoma (NPC) to distinguish low-risk patients for whom intensity-modulated radiotherapy (IMRT) alone is sufficient. MethodsThis retrospective study enrolled 894 patients with stage II NPC (596 and 298 in the training and validation cohorts, respectively) with pretreatment MRI between August 2010 and May 2019. All patients received IMRT with or without additional chemotherapy. We identified independent risk factors using univariate and multivariate Cox regression analyses. Survival was compared using Kaplan–Meier curves with the log-rank test. ResultsIndependent factors derived from the multivariate analysis include cervical nodal necrosis (CNN), the extracapsular spread (ECS) of cervical and retropharyngeal lymph nodes, and gamma-glutamyl transferase (γ-GGT). Nomograms A, B, and C were established based on the clinical [tumor-node-metastasis (TNM) stage + Epstein–Barr virus (EBV) DNA], the clinical-radiological [all independent predictors] and the combined models [the clinical-radiological model + EBV DNA], respectively. Nomogram C (C-index 0.769 [0.718–0.820]) demonstrated better risk discrimination than nomogram B (0.762 [0.715–0.809]), nomogram A (0.619 [0.564–0.674]), and the TNM stage (0.560 [0.509–0.611]). In the low-risk group divided by nomogram C, no significant survival differences were observed between patients treated with radiotherapy (RT) alone and other regimens including additional chemotherapy. ConclusionsThe nomogram combining MRI-detected retropharyngeal and cervical lymph node features with pretreatment EBV-DNA improved the prognostic risk stratification for stage II NPC.

Matted Lymph Nodes on MRI in Nasopharyngeal Carcinoma: Prognostic Factor and Potential Indication for Induction Chemotherapy Benefits.

Lymph node characteristics markedly affect nasopharyngeal carcinoma (NPC) prognosis. Matted node (MN), an important characteristic for lymph node, lacks explored MRI-based prognostic implications. Investigate MRI-determined MNs' prognostic value in NPC, including 5-year overall survival (OS), distant metastasis-free survival (DMFS), local recurrence-free survival (LRFS), progression-free survival (PFS), and its role in induction chemotherapy (IC). Retrospective cohort survival study. Seven hundred ninety-two patients with non-metastatic NPC (female: 27.3%, >45-year old: 50.1%) confirmed by biopsy. 5-T/3.0-T, T1-, T2- and post-contrast T1-weighted fast spin echo sequences acquired. MNs were defined as ≥3 nodes abutting with intervening fat plane replaced by extracapsular nodal spread (ENS). Patients were observed every 3 months for 2 years and every 6 months for 5 years using MRI. Follow-up extended from treatment initiation to death or final follow-up. MNs were evaluated by three radiologists with inter-reader reliability calculated. A 1:1 matched-pair method compared survival differences between MN-positive patients with or without IC. Primary endpoints (OS, DMFS, LRFS, PFS) were calculated from therapy initiation to respective event. Kappa values assessed inter-reader reliability. Correlation between MN, ENS, and LNN was studied through Spearman's correlation coefficient. Clinical characteristics were calculated via Fisher's exact, Chi-squared, and Student's t-test. Kaplan-Meier curves and log-rank tests analyzed all time-to-event data. Confounding factors were included in Multivariable Cox proportional hazard models to identify independent prognostic factors. P-values <0.05 were considered statistically significant. MNs incidence was 24.6%. MNs independently associated with decreased 5-year OS, DMFS, and PFS; not LRFS (P = 0.252). MN-positive patients gained significant survival benefit from IC in 5-year OS (88.4% vs. 66.0%) and PFS (76.4% vs. 53.5%), but not DMFS (83.1% vs. 69.9%, P = 0.145) or LRFS (89.9% vs. 77.8%, P = 0.140). MNs may independently stratify NPC risk and offer survival benefit from IC. 3 TECHNICAL EFFICACY: Stage 2.

Frequency of Cervical Lymph Node Extracapsular Spread in Oral Squamous Cell Carcinoma Patients

Aim: To estimate the frequency of cervical lymph node extracapsular spread in oral squamous cell carcinoma patients. Methodology: This prospective study was conducted in the Department of Oral and Maxillofacial Surgery, The University of Lahore from 1st December 2021 to 30th November 2022 and 50 diagnosed cases of oral squamous cell carcinoma were enrolled. Computed tomography scan was conducted for the diagnosis in addition to the histopathology of the samples. The CT scan images were used for identification of lymph node size, shape, and central necrosis. The frequency of the extracapsular extension of lymph nodes with the central necrosis was correlated with histopathology. Results: The mean age of the patients was 60.5± 11.1 years with 60% of the cases were males and 40% of the cases were females. 36% of those patients were having a history of smoking, 22% were having a history of taking pan, 14% supari &amp; chalia, 8% alcoholics and 6% consuming gutka. The primary tumor site identified through clinical and diagnostic imaging was anterior 2/3rd of tongue in 38% followed by posterior 1/3rd of tongue in 20%, buccal mucosa 14%, mandible and lip each as 10%, maxilla 4%, floor of mouth and retromolar trigone region each as 2%. It was observed that T3 and T4 cases had more ECS than T1 and T2 with a percentage of 20% and 30% respectively. Practical implication: Knowledge of frequency and burden of this disease in Pakistan will assist in generating more efficient management and treatment protocols with early detection strategies of oral squamous cell carcinoma through association analysis and biomarker role of cervical lymph node extracapsular spread. Conclusion: Extracapsular spread is observed more in patients having advanced stage tumor or having advanced grade of oral squamous cell carcinoma. Key words: Extracapsular spread, Oral squamous cell carcinoma, Recurrence, Histopathological examination

Prognostic value of CD247 in patients with head and neck squamous cell carcinoma: bioinformatic analysis of TCGA database.

BackgroundHead and neck squamous cell carcinoma (HNSC) is the 7th most common type of cancer in the world. Through the advantages of The Cancer Genome Atlas (TCGA) large-scale sequencing-based genome analysis technology, we can explore the potential molecular mechanisms that can improve the prognosis of HNSC patients.MethodsThe HNSC transcriptome and clinical data were downloaded from TCGA database. A univariate survival analysis and differential expression analysis were conducted to obtain the intersection gene set. A protein-protein interaction (PPI) analysis, modular analysis, and Gene Ontology (GO)/Kyoto Encyclopedia of Genes and Genomes (KEGG) functional enrichment analysis were then conducted to identify the hub genes. Clinical correlation analysis, univariate and multivariate Cox regression analyses were performed on the identified hub genes to determine the prognostic impact of hub genes on HNSC patients.ResultsIn total, 601 intersecting gene sets were obtained. A modular analysis was conducted, and the highest scoring module was 19.304. Based on the GO/KEGG enrichment analysis results, CD247 molecule (CD247) was ultimately selected as the gene for this study. The CD247 were divided into a high-expression group and a low-expression group. The Kaplan-Meier survival curve analysis showed that there was a significant difference between the 2 groups (P<0.0001). The median survival time of the low-expression CD247 group was 30.9 months, and the 5-year survival rate was 36.4%. While the median survival time of the high-expression CD247 group was 68.8 months, and the 5-year survival rate was 52.3%. The clinical correlation analysis showed that CD247 was significantly negatively correlated with pathological tumor stage (pT) and pathological nodal extracapsular spread. Gene Set Enrichment Analysis (GSEA) showed that CD247 activating KEGG pathway hsa04650 and hsa04660.ConclusionsCD247 is an independent protective factor in the prognosis of HNSC patients. By activating the hsa04650 and hsa04660 pathways, the expression of interferon gamma, interleukin (IL)-2, and IL-10 is promoted, which in turn improves the tumor immune monitoring ability of the body, induces tumor cell apoptosis, and inhibits tumor cell growth. CD247 is a potential target for improving the clinical treatment effect of HNSC and the prognosis of patients.

Novel algorithm for assigning risk/disease-directed treatment (DDT) choice in locally advanced primary squamous cell carcinoma head and neck (SCCHN): Using pretreatment data only.

e18070 Background: Locally advanced primary SCCHN, DDT options (radiotherapy (RTx) or concurrent Chemoradiotherapy (CRTx)) is performed only following surgery (National Comprehensive Cancer Network [NCCN] Guidelines). A novel 2-step exclusion algorithm was developed, based only on N classification and imaging (CT; MRI +/- PET) to detect clinical features only from screening/entry findings. The algorithm was developed using the IT-MATTERS SCCHN pivotal study (Clinical trials.gov NCT01265849) data to identify treatment naïve lower risk (LR) for recurrence subjects receiving neoadjuvant immunotherapy prior to surgery to optimize long-term overall survival (OS). Methods: SCCHN patients are routinely examined and imaged at entry/screening to establish TNM classification and disease stage. Imaging is performed using CT, MRI, and/or PET-CT/PET-MRI per NCCN Guidelines. These imaging techniques can reliably detect extracapsular cervical lymph node spread before surgery, allowing the algorithm to be constructed and validated. Algorithm rules target CRTx bound (“High-Risk”) patients leaving RTx bound (“Low-Risk”) locally advanced primary disease patients at entry. The 2-step exclusions are: (1) exclude all N2 leaving only those with N0-N1, (2) further exclude those exhibiting extra capsular spread (PET-CT or PET-MRI). We retained those determined by study physicians to receive CRTx for the algorithm validation exercise only. The n = 923 pivotal study intent to treat (ITT) population was used to validate the algorithm. Results: Overall algorithm coverage was 99.9% (922/923 ITT except one missing N case) with 24.6% having N2 and 75.3% N0/N1. Among algorithm exclusions, 81.3% (282/347) were High-Risk; among algorithm inclusions, 60.6% (349/576) were Low-Risk. Algorithm validation: Among all Low-Risk cases in the study (n = 380), 91.8% (349/380) met the algorithm criteria; among all High-Risk cases, 60.4% (282/467) were correctly excluded by the algorithm. Remaining were physician choice. Overall, algorithm alone predicted 74.5% (631/847) risk group (combined low and high) accurately. Significant OS advantage (2-sided log rank p = 0.0376) to Immunotherapy regimen + standard of care (SOC) surgery + RTx vs SOC alone was seen for Low-Risk cases selected only by the 2-step algorithm. Conclusions: The algorithm provided near perfect (99.9%) ITT population coverage, achieved near 75% overall accuracy, with 91.8% accurate predictive value for the low-risk group demonstrating significant OS. Thus, risk group can be inferred at screening consistent with clinical practice and NCCN Guidelines. The algorithm can be used to help identify low risk SCCHN patients at entry to receive neoadjuvant immunotherapy before surgery.

Predictors of Recurrence of Peritoneal Carcinomatosis among Patients with Colorectal Cancer Following Cytoreductive Surgery alone versus Cytoreductive Surgery Plus HIPEC

Abstract Background Peritoneal carcinomatosis (PC) is a lethal regional progression in patients with colorectal cancer (CRC). Treatment with complete cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) achieves better local control than systemic palliative chemotherapy. Objectives To assess the efficacy on the prognosis of CRS and HIPEC compared with CRS only and to identify possible clinicopathological factors associated with the recurrence of PC. Methods The present retrospective study included all colorectal carcinoma cases with PC subjected to CRS with or without HIPC from January 2009 to June 2018 at the National Cancer Institute (NCI), Cairo University, Cairo, Egypt. The outcome is evaluated in terms of recurrence-free survival (RFS) and its predictors. Results Out of the 61 patients, 45 patients (73.8%) underwent CRS plus HIPEC, and 16 (26.2%) underwent CRS alone. The 1-year RFS was 55.7%, with a median of 12 months. The risk factors for recurrence identified in the univariate analysis were T4 primary tumor, high-grade, positive lymphovascular invasion (LVI), positive extracapsular nodal spread, and patients treated with CRS only, without HIPEC. In the multivariate analysis, the independent risk factors for recurrence were high grade and patients treated with CRS only. Conclusion T4 primary tumor, high grade, positive LVI, and positive extracapsular nodal spread seemed to be important predictors of recurrence following the treatment of PC. Our study also demonstrated that the addition of HIPEC to CRS improved the RFS.

Machine learning and magnetic resonance imaging radiomics for predicting human papilloma virus status and prognostic factors in oropharyngeal squamous cell carcinoma.

We attempted to predict pathological factors and treatment outcomes using machine learning and radiomic features extracted from preoperative magnetic resonance imaging (MRI) of oropharyngeal squamous cell carcinoma (OPSCC) patients. The medical records and imaging data of 155 patients who were diagnosed with OPSCC were analyzed retrospectively. The logistic regression model showed that the area under the receiver operating characteristic curve (AUC) of the model was 0.792 in predicting human papilloma virus (HPV) status. The LightGBM model showed an AUC of 0.8333 in predicting HPV status. The performance of the logistic model in predicting lymphovascular invasion, extracapsular nodal spread, and metastatic lymph nodes showed AUC values of 0.7871, 0.6713, and 0.6638, respectively. In predicting disease recurrence, the LightGBM model showed an AUC of 0.8571. In predicting patient death, the logistic model showed an AUC of 0.8175. A machine learning model using MRI radiomics showed satisfactory performance in predicting pathologic factors and treatment outcomes of OPSCC patients.

Nutritional and immunological parameters as prognostic factors in patients with advanced oral cancer

ObjectiveThe aim of the present study was to analyze the prognostic relationship of weight loss and preoperative hematological indexes in patients surgically treated for pT4a squamous cell carcinoma of the oral cavity. MethodsA retrospective cohort study. ResultsPercent weight loss greater than 10% was identified in 49 patients (28.2%), and any weight loss in relation to the usual weight occurred in 140 patients (78.7%). Percent weight loss greater than 10% (HR = 1.679), Red cell distribution width (RDW) values greater than 14.3% (HR = 2.210) and extracapsular spread (HR = 1.677) were independent variables associated with risk of death. ConclusionPatients with advanced squamous cell carcinoma of the oral cavity present significant weight loss and as significantly immunocompromised. Increased values of RDW and higher percentages of weight loss in relation to the individual's usual weight, together with extracapsular spread of metastatic lymph nodes, were risk factors for lower survival, regardless of other clinical and anatomopathological characteristics. Level of evidence3.

The Emerging Theoretical Framework of Two-Person Neuroscience

Whether the submandibular gland (SMG) can be preserved during neck dissection in the surgical treatment of oral squamous cell carcinoma (OSCC) is controversial. This study investigated the SMG involvement rate and provides a basis for preserving the SMG during neck dissection in appropriate cases of OSCC.A comprehensive systematic review was conducted on the PubMed and MEDLINE, Embase, and Cochrane Library databases for studies on SMG involvement in OSCC published before December 2017 with a data analysis technique. Predictor variables were numbers of patients and resected SMGs, primary site, and tumor, node, and metastasis stage. Outcome variables were the number of involved SMGs and mode of involvement. Other variables, namely first author, publication year, mean age, and condition of neck lymph nodes at level Ib, also were extracted. A random-effects model was used to analyze the rate of SMG involvement in OSCC.Twelve studies involving 2,126 patients with OSCC who underwent neck dissection were included in the study. Fifty-two SMGs were involved, and the pooled involvement rate was 2% (I2 = 73%; 95% confidence interval [CI], 1-3). Forty-eight SMGs were involved through direct spread from the primary site or extracapsular spread of positive lymph nodes, and the pooled involvement rate was 1.9% (I2 = 72%; 95% CI, 0.9-3.1). Except for direct spread, 4 SMGs were involved through the intraglandular lymph node or carcinoma growing along Wharton ducts, and the pooled involvement rate was only 0.1% (I2 = 0%; 95% CI, 0-0.2).The rate of SMG involvement in OSCC is very low, and the most common mode of involvement is by direct spread. The SMG might be preserved during neck dissection in OSCC when it is unlikely to be involved through direct spread.

Evaluation of Histopathological Risk Model in a Cohort of Oral Squamous Cell Carcinoma Patients Treated with Accompanying Neck Dissection

To investigate the applicability of the validated histological risk model in a cohort of oral cavity squamous cell carcinoma patients treated concurrently with neck dissections. Primary tumours from 85 patients with primary excision of T1 and T2 Oral Squamous Cell Carcinomas (TNM 7th edition) including neck dissection were scored by three pathologists in consensus according to the validated risk model. The risk score data, along with traditional dataset values, were analysed to determine possible association with nodal metastasis and extracapsular spread. Seventy-two patients (54%) were classified with low or intermediate risk and 62 (46%) patients were ‘high risk’. A chi squared test showed that cases with nodal metastasis were highly statistically significant with the overall risk model score (X2 = 22.62 p = 0.0001). None of the neck dissections from tumours with low risk score showed evidence of metastasis (NPV = 100%) suggesting the risk score may also be a useful tool for predicting an absence of metastasis. Risk assessment of low-stage oral squamous cell carcinoma primary tumours may be predictive of the presence or absence of metastasis at presentation. Knowledge of the risk score and its constituent parts may inform treatment decisions at multidisciplinary meetings. Low risk squamous cell carcinoma may be a rare variant with low metastatic potential and excellent long-term survival.

Hepatitis C Virus RNA Transcript Associates with Prognosis in Non-human Papillomavirus Associated Head and Neck Squamous Cell Carcinoma.

Hepatitis C virus (HCV) was reported to associate with head and neck squamous cell carcinoma (HNSCC) in many studies. However, its correlation with prognosis of non-human papillomavirus (HPV) associated HNSCC remains unknown. Here, we sought to investigate clinical significance of HCV RNA transcript in non-HPV associated HNSCC by analyzing corresponding RNA-seq data. A retrospective cohort study. Four hundred and forty-eight non-HPV associated HNSCC patients with aligned RNA-seq and clinical follow-up data were included and divided into two groups: low-HCV and high-HCV. Means of continuous variables and proportions of categorical variables were compared using independent sample t-test and chi-square test, respectively. Survival data were compared using Cox regression analysis, Kaplan-Meier curves, and log-rank test. Expression of genome-wide mRNAs and abundance of immune cells were compared using volcano plot and cell signature estimated score analysis. HCV RNA transcript negatively correlates with pathologic (P=.028) and clinical-stage (P=.023), clinical N stage (P=.025), and nodal extracapsular spread (P=.042) and is an independent prognosis factor in non-HPV associated HNSCC (HR=1.488; 95% CI: 1.004-2.206; P=.048). Elevated expression of HCV improved 5-year overall survival (43.6% vs. 53.2%; P=.035) in all non-HPV associated HNSCC patients, the same as in male (46.6% vs. 58.7%; P=.049), clinical M0 stage (42.8% vs. 52.9%; P=.036), white (42.9% vs. 55.9%; P=.010), and histologic grade 1 to 2 subgroups (42.1% vs. 57.2%; P=.043). The expression of several immune-related genes and abundance of some immune cells significantly changed with the increase of HCV RNA transcript, while HCV-related oncogenes and tumor suppressor gene did not. HCV RNA transcript is an independent favorable factor for prognosis of non-HPV associated HNSCC. 4 Laryngoscope, 131:1774-1781, 2021.

MRI-detected residual retropharyngeal lymph node after intensity-modulated radiotherapy in nasopharyngeal carcinoma: Prognostic value and a nomogram for the pretherapy prediction of it

Background and purposeTo evaluate the prognostic value of MRI-detected residual retropharyngeal lymph node (RRLN) at three months after intensity-modulated radiotherapy (IMRT) in patients with nasopharyngeal carcinoma (NPC) and second, to establish a nomogram for the pretherapy prediction of RRLN. Materials and methodsWe included 1103 patients with NPC from two hospitals (Sun Yat-Sen University Cancer Center [SYSUCC, n = 901] and Dongguan People's Hospital [DGPH, n = 202]). We evaluated the prognostic value of RRLN using Cox regression model in SYSUCC cohort. We developed a nomogram for the pretherapy prediction of RRLN using logistic regression model in SYSUCC training cohort (n = 645). We assessed the performance of this nomogram in an internal validation cohort (SYSUCC validation cohort, n = 256) and an external independent cohort (DGPH validation cohort, n = 202). ResultsRRLN was an independent prognostic factor for OS (HR 2.08, 95% CI 1.32–3.29), DFS (HR 2.45, 95% CI 1.75–3.42), DMFS (HR 3.31, 95% CI 2.15–5.09), and LRRFS (HR 3.04, 95% CI 1.70–5.42). We developed a nomogram based on baseline Epstein–Barr virus DNA level and three RLN status-related features (including minimum axial diameter, extracapsular nodal spread, and laterality) that predicted an individual's risk of RRLN. Our nomogram showed good discrimination in the training cohort (C-index = 0.763). The favorable performance of this nomogram was confirmed in the internal and external validation cohorts. ConclusionMRI-detected RRLN at three months after IMRT was an unfavorable prognostic factor for patients with NPC. We developed and validated an easy-to-use nomogram for the pretherapy prediction of RRLN.

Involvement of the submandibular gland in oral squamous cell carcinoma patients with positive lymph nodes

BackgroundNo consensus exists about submandibular glands (SMGs) involvement in oral squamous cell carcinoma (OSCC) patients with cervical lymph node metastasis. We aimed to investigate the prevalence of SMG involvement in OSCC patients with positive lymph nodes. MethodsRetrospective analysis of data of 302 study subjects with positive lymph nodes in OSCC operated between January 2002 and December 2012. ResultsOnly 1/302 (0.3%) study subject had SMG involvement. The mode of spread was by direct extension of the primary carcinoma. Extracapsular spread of level IB lymph nodes was seen in 12/302 (4%) patients. Only one of these patients had involvement of the fibrous tissue around the SMG. ConclusionSMG involvement is very rare in OSCC patients with cervical lymph node metastasis. Preservation of the ipsilateral SMG during neck dissection might be oncologically safe when involvement by direct spread is unlikely.

Accuracy of contrast-enhanced CT and predictive factors for extracapsular spread in unknown primary head and neck squamous cell cancer

To determine the accuracy of contrast-enhanced computed tomography (CECT) for nodal extracapsular spread (ECS) and identify predictive radiological signs and clinicopathological features for ECS in unknown-primary head and neck squamous cell cancer (UPHNSCC). The CECT imaging of patients who underwent primary neck dissection for UPHNSCC during 2011-2015 was analysed. The largest pathological-looking node at each radiologically involved level was evaluated in consensus by two head and neck radiologists. Parameters included longest diameter, margin sharpness, haziness in adjacent fat, necrosis, and loss of fat plane with adjacent structures. Independent assessment was also made regarding the presence/absence of ECS. Findings and clinicopathological parameters were correlated with histopathology. Thirty-one patients with 39 neck levels had metastatic nodal involvement determined on CECT. Confirmed ECS was found at 26 levels in 23 patients. Sensitivity of radiological assessment for ECS by nodal level was 81-85% (95% confidence interval [CI]=65-93%) and specificity 46-54% (95% CI=19-81%); kappa 0.87. On univariate analysis based on the largest involved node per patient, longest diameter being ≥30mm (p=0.007), haziness in adjacent fat (p=0.023), increasing age (p=0.006), and more advanced pathological nodal status (p=0.027) were statistically significantly associated with ECS. Haziness and increasing age were independent predictors on multivariate analysis (odds ratio [OR]=26.4 and 1.24). Expert assessment of ECS on CECT had good sensitivity with excellent interobserver agreement. A longest nodal diameter of ≥30mm, haziness in the surrounding fat on CECT, advanced pathological nodal status, and advancing patient age were significantly associated with ECS in UPHNSCC patients, findings not previously reported.

Extracapsular Lymph Node Involvement in Ovarian Carcinoma.

Ovarian cancer (OC) spread to retro-peritoneal lymph nodes is detected in about one out of two patients at primary diagnosis. Whether the histologic pattern of lymph node involvement i.e., intra-(ICG) or extracapsular (ECG) cancer growth may affect patients’ prognosis remains unknown. The aim of the current study was to analyze the prevalence of ECG and ICG in lymph node positive ovarian cancer. We further investigated whether ECG may be related to patients’ prognosis and whether biomarkers expressed in the primary tumor may predict the pattern of lymph node involvement. Lymph node samples stemming from 143 OC patients were examined for presence of ECG. Capsular extravasation was tested for statistical association with clinico-pathological variables. We further tested 27 biomarkers that had been determined in primary tumor tissue for their potential to predict ECG in metastatic lymph nodes. ECG was detected in 35 (24.5%) of 143 lymph node positive patients. High grade (p = 0.043), histologic subtype (p = 0.006) and high lymph node ratio (LNR) (p < 0.001) were positively correlated with presence of ECG. Both ECG (p = 0.024) and high LNR (p = 0.008) were predictive for shortened overall survival. A four-protein signature determined from the primary tumor tissue was associated with presence of concomitant extracapsular spread in lymph nodes of the respective patient. This work found extracapsular spread of lymph node metastasis to be a common feature of lymph node positive ovarian cancer. Since ECG was positively associated with grade, LNR and shortened overall survival, we hypothesize that the presence of ECG may be interpreted as an indicator of tumor aggressiveness.

RNF8 is associated with radioresistance, nodal stage and extranodal spread in oral cavity squamous-cell carcinoma

Background: Oral cavity cancer has an early metastatic profile and poor adjuvant therapy response when compared with other head and neck cancers, which is reflected in more aggressive clinical management. Accurate prognostic prediction is dependent on histological disease staging and extranodal spread, however these parameters are not available in preoperative clinical decision making. E3-ubiquitin ligase RNF8 is involved in the DNA repair cascade and dysregulation has been shown to promote in vitro genomic instability. Methods: A single-site retrospective series of 53 patients with oral cavity cancer were selected from 2006 to 2012. Clinical data was obtained from chart review, and survival data obtained from the Queensland Cancer Registry. Immunohistochemical analysis for RNF8 was performed against a constructed tissue microarray. Results: Sixteen (30.3%) tumours stained positive for RNF8 expression. RNF8 negative disease showed a significant survival advantage in patients who did not receive radiotherapy, while a non-significant inverse association was suggested in patients who did receive radiotherapy. RNF8 positivity was associated with increased tumour thickness (P=0.021), nodal extracapsular spread (ECS) (P=0.037) and pathological N-stage (P=0.036). Conclusions: RNF8 shows significant correlation with established tumour prognostic features of tumour thickness, ECS and nodal stage.

A Five-MicroRNA Signature Predicts Survival and Disease Control of Patients with Head and Neck Cancer Negative for HPV Infection.

Human papillomavirus (HPV)-negative head and neck squamous cell carcinoma (HNSCC) is associated with unfavorable prognosis, while independent prognostic markers remain to be defined. We retrospectively performed miRNA expression profiling. Patients were operated for locally advanced HPV-negative HNSCC and had received radiochemotherapy in eight different hospitals (DKTK-ROG; n = 85). Selection fulfilled comparable demographic, treatment, and follow-up characteristics. Findings were validated in an independent single-center patient sample (LMU-KKG; n = 77). A prognostic miRNA signature was developed for freedom from recurrence and tested for other endpoints. Recursive-partitioning analysis was performed on the miRNA signature, tumor and nodal stage, and extracapsular nodal spread. Technical validation used qRT-PCR. An miRNA-mRNA target network was generated and analyzed. For DKTK-ROG and LMU-KKG patients, the median follow-up was 5.1 and 5.3 years, and the 5-year freedom from recurrence rate was 63.5% and 75.3%, respectively. A five-miRNA signature (hsa-let-7g-3p, hsa-miR-6508-5p, hsa-miR-210-5p, hsa-miR-4306, and hsa-miR-7161-3p) predicted freedom from recurrence in DKTK-ROG [hazard ratio (HR) 4.42; 95% confidence interval (CI), 1.98-9.88, P < 0.001], which was confirmed in LMU-KKG (HR 4.24; 95% CI, 1.40-12.81, P = 0.005). The signature also predicted overall survival (HR 3.03; 95% CI, 1.50-6.12, P = 0.001), recurrence-free survival (HR 3.16; 95% CI, 1.65-6.04, P < 0.001), and disease-specific survival (HR 5.12; 95% CI, 1.88-13.92, P < 0.001), all confirmed in LMU-KKG data. Adjustment for relevant covariates maintained the miRNA signature predicting all endpoints. Recursive-partitioning analysis of both samples combined classified patients into low (n = 17), low-intermediate (n = 80), high-intermediate (n = 48), or high risk (n = 17) for recurrence (P < 0.001). The five-miRNA signature is a strong and independent prognostic factor for disease recurrence and survival of patients with HPV-negative HNSCC.See related commentary by Clump et al., p. 1441.

Rate of Submandibular Gland Involvement in Oral Squamous Cell Carcinoma

Whether the submandibular gland (SMG) can be preserved during neck dissection in the surgical treatment of oral squamous cell carcinoma (OSCC) is controversial. This study investigated the SMG involvement rate and provides a basis for preserving the SMG during neck dissection in appropriate cases of OSCC. A comprehensive systematic review was conducted on the PubMed and MEDLINE, Embase, and Cochrane Library databases for studies on SMG involvement in OSCC published before December 2017 with a data analysis technique. Predictor variables were numbers of patients and resected SMGs, primary site, and tumor, node, and metastasis stage. Outcome variables were the number of involved SMGs and mode of involvement. Other variables, namely first author, publication year, mean age, and condition of neck lymph nodes at level Ib, also were extracted. A random-effects model was used to analyze the rate of SMG involvement in OSCC. Twelve studies involving 2,126 patients with OSCC who underwent neck dissection were included in the study. Fifty-two SMGs were involved, and the pooled involvement rate was 2% (I2=73%; 95% confidence interval [CI], 1-3). Forty-eight SMGs were involved through direct spread from the primary site or extracapsular spread of positive lymph nodes, and the pooled involvement rate was 1.9% (I2=72%; 95% CI, 0.9-3.1). Except for direct spread, 4 SMGs were involved through the intraglandular lymph node or carcinoma growing along Wharton ducts, and the pooled involvement rate was only 0.1% (I2=0%; 95% CI, 0-0.2). The rate of SMG involvement in OSCC is very low, and the most common mode of involvement is by direct spread. The SMG might be preserved during neck dissection in OSCC when it is unlikely to be involved through direct spread.

Does p16+ Predict a Favorable Prognosis for Oropharyngeal Cancer? Risk Factors for Treatment Failure for Patients Who Underwent Surgery-Based Therapy.

This study aimed to identify prognostic clinicopathologic factors that could predict treatment failure and to analyze clinical data from p16+ oropharyngeal squamous cell carcinoma (OPSCC) patients who underwent surgery. Data from p16+ OPSCC patients who underwent surgery at Severance Hospital of Yonsei University were retrospectively reviewed. The average smoking history was 14.6 pack-years (range 0-94 pack-years). Of the 188 patients, 73 (38.8%) underwent transoral robotic surgery (TORS) for surgical treatment of their primary lesions, and the remaining 115 patients (61.2%) underwent conventional surgery. Extracapsular nodal spread was detected in 87 patients (46.3%). At histologic examination, 67 patients (35.6%) showed positive surgical margins, and 121 patients (64.4%) had negative surgical margins. Postoperative adjuvant treatment was performed for 167 patients (88.8%). During the follow-up period, there were 18 recurrences including 2 local recurrences, 10 regional recurrences, and 6 distant metastases. During the study period, 17 deaths occurred. The univariate analysis showed that the American Joint Committee on Cancer (AJCC) 8th-edition staging system, lymphovascular invasion, more than four metastatic lymph nodes, and a smoking history of more than 10 pack-years were significantly associated with treatment failure. In the multivariate analysis, only the AJCC 8th-edition staging system was significantly associated with the patient's survival. Surgical treatment methods including TORS for p16+ OPSCC patients showed excellent oncologic results, and many previously known clinicopathologic factors did not show a significant relationship with patient prognosis. Only the newly revised AJCC 8th-edition staging system showed a significant relationship with patient survival, and this should be considered in the setting of p16+ OPSCC treatment guidelines in the future.

A gene expression profile associated with perineural invasion identifies a subset of HNSCC at risk of post-surgical recurrence

ObjectivesPerineural invasion (PNI) is a common histopathological finding in head and neck squamous cell carcinoma (HNSCC). We aimed to explore the molecular mechanisms involved in PNI and the role of PNI as an aggressive pathological feature. Materials and methodsWe used data from The Cancer Genome Atlas (TCGA) to relate the histological presentation of 528 HNSCC tumours to clinical, whole genome expression and proteomic data. ResultsWe identified a specific gene expression profile highly enriched in genes related to muscle differentiation/function and associated with PNI in HNSCC. We explored the clinical significance of this profile in three groups of HNSCC tumours stratified according to their low, intermediate or high risk of post-surgical recurrence. In the “low-risk” group, defined as tumours indicated for surgery without adjuvant radiotherapy (n = 51), the PNI gene expression profile identified a subset of HNSCC with a higher rate of tumour recurrence, decreased Disease Free Survival (DFS) and Overall Survival (OS) (p < 0.0001 and p = 0.0064, respectively). Comparable results were observed in “intermediate risk” tumours (n = 112), but not in “high risk” tumours (n = 147), whose prognosis was driven by the presence of lymph node extracapsular spread. Finally, we found that tumours with histological PNI had increased activation levels of the Akt/PKB and mTOR (mammalian Target Of Rapamycin) kinases. ConclusionPNI is characterised by a specific gene expression profile and distinct biological characteristics. Analysing the PNI gene expression profile holds potential for therapeutic stratification of HNSCC and identification of a subset of tumours with a higher risk of recurrence.