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To determine the effects of nodal yield on survival in early stage oral cavity squamous cell carcinoma (OCSCC) in the context of primary tumor depth of invasion (DOI).Patients with early-stage clinically node-negative OCSCC who underwent upfront surgery at the primary site were identified using the National Cancer Database between 2004 and 2015.There were 3384 patients with4 mm DOI and 1387 patients with ≥4 mm DOI identified. Management of the neck included observation (40%), END with18 nodes harvested ± postoperative radiation (ND 18, 16%), and END with ≥18 nodes harvest ± postoperative radiation (ND ≥ 18, 44%). When adjusted for relevant covariates, ND ≥ 18 demonstrated statistically significant improvements in overall survival for both DOI 4 mm and ≥4 mm (DOI 4 mm: HR 0.67, 95%CI 0.54-0.85; DOI ≥ 4 mm: HR 0.47, 95%CI 0.34-0.64). However, ND 18 showed no significant difference from observation of the neck regardless of DOI (DOI 4 mm: HR 0.82, 95%CI 0.63-1.07; DOI ≥ 4 mm: HR 0.72, 95%CI 0.51-1.03). Of patients undergoing END, the most significant factors associated with obtaining a nodal yield of 18 or more were age less than 40 years (HR 2.58, 95%CI 1.84-3.63) and treatment at an academic facility (HR 2.47, 95%CI 2.06-2.96).END with 18 or more nodes is associated with improved survival outcomes in patients with early stage OCSCC regardless of DOI. END with less than 18 nodes, however, does not appear significantly different than observation of the neck alone. Achieving a lymph node yield of 18 or more is multifactorial and includes both patient and provider factors.

Objectives: The aim of this study was to investigate whether quantitative CT image-biomarkers (IBMs) can improve the prediction models with only classical prognostic factors for local-control (LC), regional-control (RC), distant metastasis-free survival (DMFS) and disease-free survival (DFS) for head and neck cancer (HNC) patients.Materials and Methods: The cohort included 240 and 204 HNC patients in the training and validation analysis, respectively. Clinical variables were scored prospectively and IBMs of the primary tumor and lymph nodes were extracted from planning CT-images. Clinical, IBM and combined models were created from multivariable Cox proportional-hazard analyses based on clinical features, IBMs, and both for LC, RC, DMFS and DFS.Results: Clinical variables identified in the multivariable analysis included tumor-site, WHO performance-score, tumor-stage and age. Bounding-box-volume describing the tumor volume and irregular shape, IBM correlation representing radiological heterogeneity, and LN_major-axis-length showing the distance between lymph nodes were included in the IBM models. The performance of IBM LC, RC, DMFS and DFS models (c-index(validated): 0.62, 0.80, 0.68 and 0.65) were comparable to that of the clinical models (0.62, 0.76, 0.70 and 0.66). The combined DFS model (0.70) including clinical features and IBMs performed significantly better than the clinical model. Patients stratified with the combined models revealed larger differences between risk groups in the validation cohort than with clinical models for LC, RC and DFS. For DMFS, the differences were similar to the clinical model.Conclusion: For prediction of HNC treatment outcomes, image-biomarkers performed as good as or slightly better than clinical variables.

Purpose: To compare multidisciplinary team conference (MDTC) decisions regarding treatment intent based on either chest X-ray + MRI of the head and neck (CXR/MRI) or 18 F-FDG-PET/CT (PET/CT) in patients with recurrent head and neck squamous cell carcinoma (HNSCC). Methods: Prospective blinded cohort study based on paired data. Consecutive patients with suspected recurrent HNSCC were invited to participate. All included patients underwent CXR/MRI and PET/CT before diagnostic biopsy. An ordinary MDTC using all available imaging data was conducted as per standard practice. After at least three months (to eliminate recall bias in the team), the first project MDTC, based on either CXR/MRI or PET/CT, was conducted, and the tumor board made conclusions regarding treatment. After an additional three months, a second project MDTC was conducted using the complementary imaging strategy. The separate treatment strategies were compared using McNemar's test. Results: A total of 110 patients (90 males and 20 females, median age 66 years, range 40–87) were included. The initial primary tumor originated from the pharynx in 56 (51%) patients, oral cavity in 17 (15%) patients, and larynx in 37 (34%) patients. Based on CXR/MRI, 87 patients (79%) were recommended curative treatment and 23 (21%) palliative treatment. Based on PET/CT, the MDTC decided that 52 (47%) patients were suitable for curative treatment and 58 (53%) for palliative treatment. The absolute difference of 32% was statistically significant (95% CI: 22–42%, p < 0.001). Conclusions: PET/CT affected MDTC decisions in patients with recurrent HNSCC towards less curative and more palliative treatment.

The prognostic value of metabolic tumor volume (MTV) in locally advanced laryngeal or hypopharyngeal cancer is established in the setting of chemoradiotherapy, while it remains unknown in the setting of upfront total laryngectomy.We retrospectively analyzed 88 patients receiving total laryngectomy and neck dissection, using Cox regression models.Variables related to metastatic lymph node were associated with overall survival, whereas those related to primary tumor were not. In multivariable models, MTV of metastatic lymph nodes (N-MTV) as a continuous variable (Akaike's information criterion (AIC), 277.5) was equivalent to pathological nodal status (AIC, 278.2; P = 0.40), and superior to pathological nodal classification as an ordinal variable (AIC, 281.4; P 0.05) in ability of predicting death. The risk of death was increased by 1.2-fold (95% confidence interval (CI), 1.0-1.4; P = 0.03) every 10-ml increment of N-MTV, while patients with pN+ disease were at a higher risk of death by 2.9-fold (95% CI, 1.0-12.2; P 0.05) compared with patients with pN0 disease. Using recursive partitioning analysis (RPA), we classified the patients as having a low, intermediate, or high risk of death on the basis of N-MTV and extranodal extension (ENE). This RPA classification system exhibited greater concordance with overall survival than the classification considering pathological nodal status and ENE (AIC, 275.8 versus 281.4; P = 0.02). In the setting of upfront total laryngectomy, N-MTV is a critical predictor of mortality. A staging system in which N-MTV is incorporated may better inform adjuvant treatment decisions.

Objectives microRNA (miRNA) expression patterns have provided new insight as biomarkers of prognosis as well as novel therapeutic targets for several neoplasms. However, the role of exosomal miRNA in the prognosis of oral squamous cell carcinoma (OSCC) has not yet been completely clarified. Paired primary tumor and normal oral epithelial cells from OSCC patients were obtained, and the exosomal miRNA profiles between them were compared by miRNA microarray analysis. The miRNA levels in the serum exosomes of OSCC patients were verified by real-time quantitative reverse transcription PCR (qRT-PCR) analysis. Finally, the biological functions and the potential as a prognostic marker of the selected miRNA candidates were analyzed in the OSCC cells and patients, respectively. Results Exosomal miR-155 and miR-21 were significantly upregulated, and exosomal miR-126 was dramatically downregulated in the primary OSCC cells and the serum of OSCC patients. In the analysis of oncogenic behaviors, coculture with either miR-155-rich or miR-21-rich exosomes could promote cell proliferation and invasion accompanied with downregulation of PTEN and Bcl-6 tumor suppressors. Moreover, treatment with miR-126-rich exosomes inhibited oncogenic behaviors and oncogene EGFL7 expression in OSCC cells. Finally, exosomal miR-126 was reduced in the serum of the late-staged OSCC patients, and downregulation of blood exosomal miR-126 was associated with poor survival in OSCC patients. Conclusion Exosomal miR-155 and miR-21 are oncogenic miRNAs which suppress PTEN and Bcl-6 expression, and exosomal miR-126 acts as a tumor suppressor which downregulates EGFL7 in OSCC. Furthermore, blood exosomal miRNAs may serve as biomarkers for the diagnosis and prognosis of OSCC.

After the introduction of ICI treatment, data about feasibility and activity of a cetuximab-containing first-line therapy in patients with recurrent and/or metastatic head and neck cancer (R/M HNSCC) are still not available. We sought to analyze the clinical outcomes in the real-world setting.This retrospective study was conducted at two tertiary medical centers in Taiwan. Patients with R/M HNSCC receiving cetuximab-containing first-line therapy were included between January 2017 and July 2019. The study endpoints were the response, Progression-Free Survival (PFS), and Overall Survival (OS). Subgroup analyses were conducted to evaluate survival outcomes by platinum resistance and the use of immunotherapy.We identified 290 patients treated with cetuximab-containing first-line therapy. The most primary tumor site was oral cavity cancer (59.3%). 44% of patients were resistant to platinum. The median PFS and OS were 5.0 months and 9.1 months, respectively, for the total population. In patients with platinum resistance, the median OS was 10.4 months with ICIs versus 6.3 months without ICIs; p = 0.01. In patients with platinum sensitivity, the median OS was 20.6 months with ICIs versus 9.1 months without ICs; p 0.01. OS benefit with ICIs was similar between patients who received ICIs after progression on Cetuximab and receiving Cetuximab in combination with ICIs. Independent favorable prognostic factors for OS were platinum-sensitive, better response to cetuximab, and ICIs use.ICIs are indicated to improve OS in R/M HNSCC receiving cetuximab-containing first-line therapy, even in platinum-resistant populations. The reduction in risk of death with ICIs was similar regarding the combination or sequencing of cetuximab.

Background Oropharyngeal squamous cell carcinoma (OPSCC) has now surpassed cervical cancer as the most common site of HPV-related cancer in the United States. HPV-positive OPSCCs behave differently from HPV-negative tumors and often present with early lymph node involvement. The bacterial microbiome of HPV-associated OPSCC may contribute to carcinogenesis, and certain bacteria may influence the spread of cancer from the primary site to regional lymphatics. Objective To determine the bacterial microbiome in patients with HPV-associated, early tonsil SCC and compare them to benign tonsil specimens. Method The microbiome of primary tumor specimens and lymph nodes was compared to benign tonsillectomy specimens with pan-pathogen microarray (PathoChip). Results A total of 114 patients were enrolled in the study. Patients with OPSCC had a microbiome that shifted towards more gram-negative. Numerous signatures of bacterial family and species were associated with the primary tumors and lymph nodes of cancer patients, including the urogenital pathogens Proteus mirabilis and Chlamydia trachomatis, Neisseria gonorrhoeae, Shigella dysenteriae, and Orientia tsutsugamushi. Conclusion Our results suggest that detection of urogenital pathogens is associated with lymph node metastasis for patients with HPV-positive OPSCCs. Additional studies are necessary to determine the effects of the OPSCC microbiome on disease progression and clinical outcomes.

Objective Over the last few decades, there have been changes in the diagnostic capabilities and treatment of head and neck squamous cell carcinoma (HNSCC) patients. However, the impact of these changes on the ultimate survival of patients remains unclear. The objective of this study was to analyze the changes in disease-specific survival of patients with HNSCC treated consecutively over a period of 30 years in a tertiary center. Material and methods We carried out a retrospective analysis of 5,206 carcinomas located in the oral cavity, nasopharynx, oropharynx, hypopharynx, larynx or with metastatic squamous cell carcinoma without a known primary tumor treated in our center during the period 1985–2016. The overall and disease-specific survival was analyzed according to the year of diagnosis of the tumor. Results There was a significant trend towards an increase in disease-specific survival over the study period, with an average survival gain of 0.28% per year, which means an increase in 5-year disease-specific survival values from about 63.5% during the initial years of the study to 72% during the final years. Patients who had a greater increase in survival were those with primary tumors located in the rhino-oro-hypopharynx, with advanced tumors (stages III-IV) and treated with radiotherapy or chemoradiotherapy. This increase in disease-specific survival did not translate into overall survival. Conclusion Over the last 30 years we have observed a significant increase in the disease-specific survival of the patients with HNSCC, with an average increase of 0.28% per year in the 5-year specific-disease survival.

Objectives The impact of regulatory T (Treg) cells as a prognostic factor of survival in head and neck squamous cell carcinoma (HNSCC) remains controversial. We aimed to evaluate the prognostic value of Treg cells in patients with HNSCC through a meta-analysis. Materials and Methods Through a literature search in PubMed, Embase, and Cochrane, we included 11 articles in this meta-analysis and investigated the effect of Treg cell level on the survival of patients with HNSCC. Also, we performed a subgroup analysis according to the study sample (blood vs. tumor tissue), primary tumor site, HPV infectivity, or Treg cell marker. Results High levels of circulating Treg cells in the peripheral blood of patients with HNSCC can significantly increase the disease specific survival rate of patients. Moreover, subgroup analysis showed that high levels of Treg in peripheral blood were significantly associated with better disease specific survival in patients with oral cancer, a subsite of HNSCC, but not in those with other head and neck subsite. Positivity of HPV infection did not influence the prognosis of patients with HNSCC. Conclusion Increase in the levels of circulating Treg cells in peripheral blood can be a prognostic factor of survival in patients with oral cancer.

High-risk human papillomavirus (HPV) is an etiologic factor in a spectrum of squamous cell carcinomas including anal, cervical, and oropharyngeal. HPV cell free DNA (cfDNA) is shed from the primary tumor into systemic circulation and can be detected using several platforms including quantitative PCR, digital droplet PCR, or next generation sequencing. Levels of HPV cfDNA at time of initial presentation is associated with known poor prognostic clinicopathologic variables, such as advanced stage and, locoregional and distant metastases. Moreover, longitudinal sampling revealed that persistent or increasing HPV cfDNA levels are indicative of treatment relapse and, in some studies, HPV cfDNA detection predicted treatment failures prior to routine post- treatment clinical imaging. A liquid biopsy platform using HPV cfDNA offers unique advantages over traditional approaches and may have clinical utility for detection of minimum residual disease, treatment response, and disease progression in patients with HPV+ cancers.

Introduction Tumor-specific genetic aberrations in cell-free DNA (cfDNA) from plasma are promising biomarkers for diagnosis of recurrent head and neck squamous cell carcinoma (HNSCC). However, the sensitivity when using somatic mutations only in cfDNA is suboptimal. Here, we combined detection of copy number aberrations (CNAs), human papillomavirus (HPV) DNA and somatic mutations in a single sequencing workflow. Methods Pretreatment plasmas of 40 patients and 20 non-cancer controls were used for analysis. Plasma DNA underwent low-coverage whole genome sequencing (lcWGS) to detect both CNAs and HPV-DNA, and deep sequencing to detect mutations in 12 frequently altered cancer driver genes in HNSCC using the same sequencing library. A specific analysis pipeline line was developed for data mining. The corresponding tumors were analyzed using slightly adapted protocols. Results Using the developed method, somatic mutations and CNAs were detected in plasma DNA of HNSCC patients in 67% and 52%, respectively. HPV-DNA in plasma was detected in 100% of patients with HPV-positive tumors, and not in plasma of patients with HPV-negative tumors or non-cancer controls. Combined analysis increased the detection rate of tumor DNA in plasma to 78%. The detection rate was significantly associated with the stage of disease of the tumor. Neither HPV status nor location of the primary tumor influenced detection of CNAs or somatic mutations in plasma. Conclusions This study demonstrates that the combined analysis of CNAs, HPV and somatic mutations in plasma of HNSCC patients is feasible and contributes to a higher sensitivity of the assay compared to single modality analyses.

Background The American Joint Committee on Cancer (AJCC) has changed the staging system of oral squamous cell carcinoma (OSCC) in the 8th edition of its staging manual to include depth of invasion (DOI) of the primary tumor as a modifier to the T category and extranodal extension (ENE) to upstage node positive OSCC. This study aims to evaluate the performance of the AJCC 8 pathologic staging system in OSCC and compare it to its predecessor (AJCC 7). Methods Analysis of 663 patients with OSCC from a prospective database was performed using the Cox proportional hazards competing risk model. The prognostic performance of the pathologic staging system was assessed using the Akaike Information Criterion (AIC) and Harrell’s concordance index (C-index). Results AJCC 8 led to upstaging of 35.6% (N = 235) of patients in this cohort. Both AJCC 7 and 8 show limited monotonicity and poor stratification between stage groups I to III. The estimates for model performance reveal that AJCC 8 has modest predictive capacity for overall survival (OS) and disease specific survival (DSS) (Harrell’s C of 0.70 and 0.74, respectively) but is superior to AJCC 7 (Harrell’s C of 0.65 and 0.69, respectively). Conclusions The AJCC 8 staging system is more complex than its former version due to the inclusion of DOI and ENE. Compared with AJCC 7, it performs better in stratifying survival of OSCC patients by stage.

This is a retrospective dose-volume-outcome analysis of radiation-induced nasopharyngeal ulcers after intensity modulated radiotherapy in primary nasopharyngeal carcinoma (NPC) patients, with the aim to determine how the radiation doses to nasopharynx influence the occurence of radiation-induced nasopharyngeal ulcer (RINU) and predict the most serious complication of radiotherapy for NPC.Data from 6023 consecutive and nonselected histologically proven primary NPC patients treated with definitive IMRT were collected and 25 patients were diagnosed with nasopharyngeal ulcer and met the diagnosis criteria of RINU. Predictive dosimetric factors were identified by using univariate and multivariate analysis.Paired samples t-tests showed all dosimetric factors were significantly correlated with the development of RINU, and these factors were associated with each other closely. (P 0.001) Multivariate analysis revealed D3cc (dose to 3 mL of the nasopharynx) was an independent predictor for RINU (P = 0.01); the area under the ROC curve for D3cc was 0.87 (P 0.001), and the cutoff point 73.67 Gy may be the dose tolerance of the nasopharynx. The primary tumor location, distribution of high dose regions and the location of RINU were consistent.The study indicates that radiation-induced nasopharyngeal ulcer is consistent with primary tumor location and 'hottest spots' regions and we suggest a D3cc limit of 73.67 Gy for the nasopharynx. Physicians should be cautious of such 'hot spots' in the nasopharynxduring IMRT treatment plan optimization, review and approval to avoid the most serious complication of radiotherapy for NPC.

Objectives To screen subgroup potentially benefiting from cumulative cisplatin dose (CCD) ≥ 200 mg/m2 during concurrent chemoradiotherapy (CCRT) of patients with locoregionally-advanced nasopharyngeal carcinoma (LA-NPC) receiving induction chemotherapy (IC) and CCRT. Materials and Methods In total, 2 063 patients with non-disseminated LA-NPC diagnosed from 2009 to 2015 receiving IC plus CCRT were enrolled. Patients were restaged based on proposed stage groupings and risk groupings was established. After propensity score matching, survival outcomes were compared within different risk groupings with 200 mg/m2 CCD. Post-IC gross primary tumor (GTVp) and lymph node (GTVnd) volumes were calculated from planning computed tomography. The role of risk groupings and post-IC tumor volume to CCD was explored. Results Compared with the low-risk group, the high-risk group showed poor survival outcomes in terms of 5-year progression-free survival (PFS), overall survival (OS), distant metastasis-free survival (DMFS), and locoregional relapse-free survival (LRRFS). CCD ≥ 200 mg/m2 improved survival in terms of 5-year PFS, OS and DMFS in the high-risk group but not in the low-risk group. High-risk patients with unfavorable response to IC benefited from CCD ≥ 200 mg/m2 with respect to PFS and DMFS; while those in low-risk group or with favorable response to IC didn’t. Conclusions Risk groupings was effective for risk stratification. Combining risk groupings and post-IC tumor volume is a simple and useful method to guide individualized CCD treatment of CCRT for patients with LA-NPC receiving IC and CCRT. CCD ≥ 200 mg/m2 may be indicated for high-risk patients with unfavorable response to IC.

Objective Presence of extracapsular spread (ECS) significantly decreases survival in oral cancer patients. Considering its prognostic impact, we have studied the incidence and factors predicting ECS in clinically node negative early oral cancers. Materials and Methods We performed a retrospective chart review of 354 treatment naive clinically node negative early oral cancer patients operated between 2012 and 2014. Chi-square test and logistic regression were used for identifying predictors of ECS, while cox-regression test was used for survival analysis. Results The incidence of occult nodal metastasis was 28.5% (101/354). Among them, ECS was seen in 15.3%(54/354) patients. The incidence of ECS in T1 and T2 lesion was 13.4% (21/157) and 16.8% (33/197), respectively. The overall incidence of ECS was 48% and 29% in lymph nodes smaller than 10 mm and 5 mm respectively. We found that tumor depth of invasion (>5 mm; p-0.027) and node (metastatic) size >15 mm (p-0.018) were significant predictors of ECS. p N2b disease was seen in 41/354 (11.6%) of which 31/354 (8.7%) had ECS, i.e. 75.6% of pN2b patients been ECS positive (p-0.000). The 3-year OS of patients without nodal metastasis, nodal metastasis without ECS and nodal metastasis with ECS was 88.4%, 66.9% and 59.2% (p-0.000) respectively. Conclusion A significant number of patients with metastatic nodal size less than 1 cm have ECS which suggests aggressive behavior of the primary tumor. Thus, elective neck dissection is the only way of detecting ECS in these patients which may warrant treatment intensification.

Objectives Human papillomavirus-negative oropharyngeal squamous cell carcinoma (OPSCC) has unfavorable survival outcomes. Two outcomes have been identified based on smoking history and tumor stage. We investigate the prognostic role of pre-treatment positron emission tomography (PET) in high-risk OPSCC. Materials and Methods We enrolled 147 M0 OPSCC patients with p16-negative staining and a history of heavy smoking (>10 pack-years) or T4 disease. All patients completed primary chemoradiotherapy, and 42% maximum standard uptake values (SUVmax) were used as the threshold for primary tumor. Patients were classified into training and validation cohorts with a ratio of 1:1.5 according to the PET date. Heterogeneity and irregularity indices were obtained. PET parameters with significant impact on progression-free survival (PFS) in receiver operating characteristic curves and univariate Cox models were identified and included in recursive partitioning analysis (RPA) for constructing a prognostic model. The RPA-based prognostic model was further tested in the validation cohort using multivariate Cox models. Results Fifty-eight and 89 patients were in the training and validation groups, respectively. Heterogeneity parameter, SUV-entropy (derived from histogram analysis), and irregularity index, and asphericity were significantly associated with PFS. The RPA model revealed that patients with both high SUV-entropy and high asphericity experienced the worst PFS. Results were confirmed in the validation group. The overall concordance index for PFS of the model was 0.75, which was higher than the clinical stages, performance status, SUVmax, and metabolic tumor volume of PET. Conclusions PET prognostic model provided useful prediction of PFS for patients with high-risk OPSCC.

Objectives Describe the influence of pretreatment tracheotomy and treatment modality (surgical versus non-surgical) on oncologic and functional outcomes. Materials and methods Retrospective study of previously untreated advanced-stage laryngeal squamous cell carcinoma patients at two academic tertiary care institutions from 1995 to 2014. Results Primary outcomes evaluated were disease-free survival, disease-specific survival, and overall survival of pretreatment tracheotomy versus no pretreatment tracheotomy cohorts. Functional status, measured by tracheotomy decannulation and gastrostomy tube placement/removal, was assessed. Of the 226 patients, 31.4% underwent pretreatment tracheotomy. Five-year disease-specific survival was 72.9%, and overall survival was 48.8% for entire cohort. There was a statistically significant decrease in overall survival (p = .03) and disease-free survival (p = .02) for the pretreatment tracheotomy group compared to no pretreatment tracheotomy, which was largely explained by primary tumor stage. Pretreatment tracheotomy was associated with gastrostomy tube placement and was an independent predictor of worse odds of gastrostomy tube removal. Disease stage, distant metastasis, and age independently conferred worse odds of gastrostomy tube removal. Conclusion Patients undergoing pretreatment tracheotomy for primary T4 laryngeal cancer had decreased overall survival compared to patients without pretreatment tracheotomy. There was no difference in local recurrence rates based on tracheotomy status. Organ preservation with chemotherapy and radiation did not result in better functional outcomes than surgery in the pretreatment tracheotomy group as nearly half of patients treated with organ preservation remained tracheotomy dependent. Based on this data, pretreatment tracheotomy may impact oncologic and functional outcomes in advanced disease, and it should be a consideration in an informed decision-making process.

To investigate the prognostic significance and identify optimal candidates of primary tumor resection (PTR) for patients with metastatic major salivary gland carcinoma (MaSGC) at diagnosis.Patients with metastatic MaSGC were identified from the Surveillance, Epidemiology and End Results (SEER) database. Kaplan-Meier analyses, log-rank tests and multivariate Cox regression models were employed to evaluate the therapeutic roles of PTR in the overall cohort and different subgroups.Overall, 255 patients were included in our study, among whom 80 (31.4%) received PTR. PTR was associated with decreased overall mortality (OM) and cancer-specific mortality (CSM) in the overall cohort (PTR vs No-PTR, HR: 0.363, 95%CI: 0.204-0.646, p = .001 for OM; HR: 0.439, 95%CI: 0.243-0.794, p = .006 for CSM). When we focused on site-specific metastases, receipt of PTR significantly reduced the risk of OM for patients with lung, bone or distant lymph node involvement (all p .05), whereas this surgical procedure not only failed to bring survival benefit, but even seemed to insignificantly increase the mortality risk once liver metastases were presented (PTR vs No-PTR, HR: 1.109, 95%CI: 0.279-4.412 for OM; HR: 1.596, 95%CI: 0.364-7.004 for CSM). In addition, subgroup analyses showed that patients with stage T1-3 disease, younger age (65), single-site metastases and high-risk pathologies might benefit from PTR.Our study for the first time verifies the favorable prognostic impact of PTR for highly-selected patients with metastatic MaSGC at diagnosis and has the potential to be adopted in future clinical practice, although long-term prospective studies are warranted.

Objectives The use of primary tumor tissue in experimental and pre-clinical cancer research is becoming increasingly important. Especially the use of tissue slice cultures of tumor specimen, so called ex vivo cultures or tumor explants, promises functional analysis under approximate physiological conditions. This includes screening and testing of targeted therapeutics directed against deregulated protein kinases. However, it is unclear if ex vivo cultures indeed represent the in situ situation especially with respect to very sensitive and transient molecular processes such as kinase dependent signaling. We now asked here, if and to what extent ex vivo culturing affects kinase activity. Materials and Methods We analyzed the activity of protein tyrosine kinases (PTK) using functional kinome profiling of either snap frozen or ex vivo-cultured tumor tissue samples of head and neck cancer patients. Results Although we observed a quantitative decline in overall kinase activity after 24 h or 48 h of ex vivo cultivation, we most importantly noticed that the signaling characteristics were conserved in most samples; approximately two thirds of all ex vivo-cultured samples displayed a signaling pattern which was qualitatively comparable to the parental tumor. We could also demonstrate kinase inhibition by treatment of ex vivo slice cultures with the multi-kinase inhibitor staurosporine, although higher concentrations were needed compared to cell cultures. Conclusion We here demonstrate that the tyrosine kinase dependent signaling is conserved under ex vivo culturing conditions in the majority of samples, which highlights the power of this method in experimental and pre-clinical cancer research.

Purpose/Objectives Extranodal extension (ENE) and more than 4 pathologically involved lymph nodes (pN2) are critical prognostic factors in HPV-associated oropharyngeal cancer (HPV(+) OPSCC). We analyze a patient cohort with HPV(+) OPSCC to determine the sensitivity and specificity of CT and PET/CT in identifying involvement of more than 4 lymph nodes (rN2) compared to pN2 and radiographic ENE (rENE) compared to pathologic ENE (pENE). Materials/Methods The dataset consisted of 261 patients enrolled in two prospective clinical trials. All imaging studies were independently reviewed by a blinded neuroradiologist, classifying the presence or absence of rENE and rN2. Secondary analyses included correlations of imaging accuracy and pathologic size of the primary tumor. Results CT demonstrated sensitivity of 59%, specificity of 92%, positive predictive value (PPV) of 53%, negative predictive value (NPV) of 94%, and accuracy of 88% for pN2. PET/CT showed similar results. Patients with up to 4 involved lymph nodes (rN0-1) had a 93–94% chance of remaining pN0-1. CT and PET/CT identified an equal number of involved nodes in 81% of patients. CT demonstrated sensitivity of 54%, specificity of 71%, PPV of 72%, NPV of 53%, and accuracy of 62% for pENE. PET/CT showed similar outcomes. Notably, when multiple radiographic criteria were used to identify rENE, PPV increased for both CT (84%) and PET/CT (79%). Conclusion Patients with rN0-1 had a 93–94% chance of remaining pN0-1, suggesting rN0-1 could effectively stratify patients for clinical trials and treatment de-escalation. While CT and PET/CT were highly correlated, both showed low sensitivity for identifying pENE.

Objectives Metastasis in a single lymph node without adverse tumour factors and perineural invasion has been assigned to a lower risk category by the ASCO recommendations of 2019. We analyzed patients with a single positive node with a view to identifying high risk features and their impact on prognosis within this subgroup. Materials and Methods The study retrospectively analyzed 707 patients with OSCC. Descriptive statistics were used to compare distribution of clinicopathologic risk features between 323 N0 and 121 single node positive (Ns) patients. The Ns group was further analyzed for the impact of clinicopathologic factors on disease free (DFS) and overall survival (OS) using univariate and multivariate models. Results The Ns group exhibited greater depth of invasion compared to the N0 group and significantly higher proportion of lymphovascular invasion (LVI), perineural invasion (PNI) and poorly differentiated tumors. Within the Ns group, primary tumor localised to the gingivobuccal subsite (HR 2.55, 1.18–5.52 95%CI, p = 0.02) and PNI (HR 2.55, 1.14–5.62, 95%CI p = 0.02) exhibited poor DFS. PNI also contributed to poor OS (HR 2.86, 1.27–6.47 95%CI, p = 0.01). Uninvolved margins (HR 0.46, 0.22–0.96 95%CI, p = 0.04) and chemoradiation (HR 0.18,0.05–0.68 95% CI, p = 0.01) improved OS. Conclusion Significant differences are noted in the prevalence of pathologic risk factors between the single node positive and node negative groups. Within the single node positive group, tumour factors like the gingivobuccal subsite, PNI and margin positivity impacted survival. Among nodal factors, deposit size of 12 mm or more and presence of ENE are pointers to poor prognosis. These patients would benefit from adjuvant treatment.

Objectives Sinonasal and skull base tumors comprise a heterogeneous group of malignancies with a significant rate of distant recurrence (DR). The aim of this study was to analyze tumor and host factors, including pretreatment neutrophil-to-lymphocyte ratio (NLR), that predict DR in these patients. Materials and Methods We retrospectively reviewed sinonasal tumors and/or tumors involving the skull base treated with surgery between 1973 and 2015 (n = 473). We stratified NLR using the top 5 percentile as cutoff. Factors predictive of outcome were determined by Cox proportional hazards model. Results Most tumors were primary (81%) and 67% had skull base resection. The most common site was the nasal cavity (37%) and the most common histology was squamous cell carcinoma (34%). Most patients presented with advanced primary tumor stage (pT3/T4; 80%) and most had no regional neck disease (pNx/N0; 93%). A total of 104 patients developed DR. The 5-year overall and disease-specific survival for patients who developed DR were 36.4% and 35.8%, compared to 69.0% and 74.9% for patients who did not. Patients with DR had a higher percentage of NLR-high patients compared patients without DR (11% vs 3%, p = .006). In a multivariable analysis, melanoma histology (HR = 5.469, 95% CI 3.171–9.433), pT3/T4 (HR = 2.686, 95% CI 1.150–6.275), pN+ (HR = 6.864, 95% CI 3.450–13.653), and NLR-high (HR = 3.489, 95% CI 1.593–7.639) were independent predictors of DR. Conclusion Melanoma histology, pT, pN, and high NLR predict DR, suggesting that both tumor and host factors need to be considered. NLR may act as a surrogate marker of the hosts immune system.

Introduction Though the submandibular gland (SMG) is routinely sacrificed for several reasons during neck dissection in patients undergoing curative surgery for oral cavity cancers, it might be an innocent bystander and should be considered for preservation. This study aimed to identify the incidence, different patterns of invasion, and risk factors of SMG involvement in oral cavity squamous cell carcinoma (SCC). Methods This was a retrospective study of the patients who underwent upfront curative surgery for a biopsy-proven oral cavity SCC. A consistent protocol-based treatment strategy was followed during the study period. Data about clinical profile including demographics, clinical and histology details, and treatment profile were extracted and analysed. Results A total of 303 patients underwent unilateral and bilateral neck dissections contributing 79.2% (n = 240) and 20.8% (n = 63) of patients respectively. The common primary sites were buccal mucosa (n = 129, 42.5%), tongue (n = 100, 33.0%) and alveolar gingiva (n = 52, 17.2%). A total of four SMGs showed tumor involvement resulting in a prevalence of 1.09% per neck dissection (n = 366) and 1.32% per patient (n = 303). Of these four cases of SMG involvement, one patient with alveolar cancer had direct tumor invasion while the other three (alveolar cancer – two, tongue cancer – one) patients had neck node metastasis. Conclusion The present study confirms a very low incidence of SMG involvement in patients with oral cavity cancer who undergo neck dissection. It is often observed in patients with high neck node burden (≥N2 disease and the presence of extracapsular spread) or direct invasion by the primary tumor.

Objectives Our primary objective is to describe the post- operative management in patients with an unknown primary squamous cell carcinoma of the head and neck (HNSCC) treated with trans-oral robotic surgery (TORS). Materials & Methods We conducted a retrospective multi-institutional case series including all patients diagnosed with an unknown primary HNSCC who underwent TORS to identify the primary site from January 1, 2010 to June 30, 2016. We excluded those with recurrent disease, ≤6 months of follow up from TORS, previous history of radiation therapy (RT) to the head and neck, or evidence of primary tumor site based on previous biopsies. Our main outcome measure was receipt of post-operative therapy. Results The tumor was identified in 26/35 (74.3%) subjects. Post-TORS, 2 subjects did not receive adjuvant therapy due to favorable pathology. Volume reduction of RT mucosal site coverage was achieved in 12/26 (46.1%) subjects who had lateralizing tumors, ie. those confined to the palatine tonsil or glossotonsillar sulcus. In addition, for 8/26 (30.1%), the contralateral neck RT was also avoided. In 9 subjects, no primary was identified (pT0); four of these received RT to the involved ipsilateral neck nodal basin only without pharyngeal mucosal irradiation. Conclusion Surgical management of an unknown primary with TORS can lead to deintensification of adjuvant therapy including avoidance of chemotherapy and reduction in RT doses and volume. There was no increase in short term treatment failures. Treatment after TORS can vary significantly, thus we advocate adherence to NCCN guideline therapy post-TORS to avoid treatment-associated variability.

Objectives To characterize the recognized but poorly understood long-term toxicities of radiation therapy (RT) for head and neck cancer (HNC). Materials and methods We retrospectively evaluated patients treated with curative-intent RT for HNC between 1990 and 2005 at a single institution with systematic multidisciplinary follow-up ≥10 years. Long-term toxicities of the upper aerodigestive tract were recorded and assigned to two broad categories: pharyngeal-laryngeal and oral cavity toxicity. Kaplan-Meier estimates and Chi-square tests were used for univariable analysis (UVA). Cox model and logistic regression were used for multivariable analysis (MVA). Results We identified 112 patients with follow-up ≥10 years (median 12.2). The primary tumor sites were pharynx (42%), oral cavity (34%), larynx (13%), and other (11%). Forty-four percent received postoperative RT, 24% had post-RT neck dissection, and 47% received chemotherapy. Twenty-eight (25%) patients developed pharyngeal-laryngeal toxicity, including 23 (21%) requiring permanent G-tube placed at median of 5.6 years (0–20.3) post-RT. Fifty-three (47%) developed oral cavity toxicity, including osteoradionecrosis in 25 (22%) at a median of 7.2 years (0.5–15.3) post-RT. On MVA, pharyngeal-laryngeal toxicity was significantly associated with chemotherapy (HR 3.24, CI 1.10–9.49) and age (HR 1.04, CI 1.00–1.08); oral cavity toxicity was significantly associated with chemotherapy (OR 4.40, CI 1.51–12.9), oral cavity primary (OR 5.03, CI 1.57–16.1), and age (OR 0.96, CI 0.92–1.00). Conclusion Among irradiated HNC patients, pharyngeal-laryngeal and oral cavity toxicity commonly occur years after radiation, especially in those treated with chemotherapy. Follow-up for more than five years is essential because these significant problems afflict patients who have been cured.

Objectives: To explore prognostic and predictive value of radiomics in patients with locally advanced head and neck squamous cell carcinomas (LAHNSCC) treated with concurrent chemoradiotherapy (CRT) or bioradiotherapy (BRT).Materials and Methods: Data of 120 patients (CRT vs. BRT matched 2: 1) were retrospectively analyzed. A total of 544 radiomics features of the primary tumor were extracted from radiotherapy planning computed tomography scans. Cox proportional hazards models were used to examine the association between survival and radiomics features with false discovery rate correction. The discriminatory performance was evaluated using receiver operating characteristic curve analysis.Results: Multivariate analysis showed a 24-feature based signature significantly predicted for OS (HR = 0.3, P = 0.02) and progression-free survival (PFS) (HR = 0.3, P = 0.01). Combining the radiomics signature with p16 status showed a significant improvement of prognostic performance compared with p16 (AUC = 0.78 vs. AUC = 0.64 at 5 years, P = 0.01) or radiomics signature (AUC = 0.78 vs. AUC = 0.67, P = 0.01) alone. When patients were stratified according to this combination, OS and PFS were significantly different according to the 4 sub-types (p16+ with low/high signature score; p16-with low/high signature score) (P Conclusion: Our analysis suggests an added value of radiomics features as prognostic and predictive biomarker in HNSCC treated with CRT/BRT. Moreover, the radiomics signature provided additional information to HPV/p16 status to further stratify patients. External validation of such findings is mandatory given the risk of overfitting. (C) 2017 Elsevier Ltd. All rights reserved.

Objectives To develop and characterize in vitro salivary duct carcinoma as a surrogate for functional studies. Materials and methods Cells were dispersed from tumor tissue fragments under sterile conditions in RPMI media. Disassociated cells were cultivated, immortalized with hTERT and propagated for more than 100 passages. Morphologic, linage, cytogenetic and genomic analyses were performed on different passages of cell line and primary tumor. Soft agar growth was performed. Results Analysis of cytomorphologic features, growth characteristics and lineage specific markers expression confirmed the epithelial derivation and the neoplastic nature of the cell line. DNA STRs analysis showed identical match of both cell line and primary tumor. Cultivated cells expressed Androgen Receptor (AR), PTEN, and EFGR proteins and the AR-V7 isoform transcript. Comparative exome-sequencing identified common mutated genes in both cell line and primary tumor. In-vitro colony formation of late passages is established. Conclusion We report the development of the first human salivary duct carcinoma cell line (MDA-SDC-04) that retains critical biological and genomic features of the donor tumor.

Objectives Local recurrence and the development of second primary tumors (SPT) are important factors that can influence the survival rate of oral squamous cell carcinoma (OSCC) patients. We investigate the concept of field cancerization which proposes that normal tissue adjacent to the primary tumor harbor pre-neoplastic alterations that can lead to the development of local recurrence and SPTs. Materials and methods To examine the concept of field cancerization, we applied whole-exome and targeted ultra-deep sequencing on 5 freshly frozen samples from a stage III OSCC patient from three tumor sites, lymph node metastasis and blood. Lastly, we sequenced one formalin-fixed paraffin-embedded recurrence biopsy that was collected approximately a year and half later located in the same area as before. Results Sequencing identified 126 somatic mutations. We identified 24 mutations in the recurrence biopsy and 14 mutations are shared by the primary tumor. Conclusion The low number of shared mutations indicates that either these mutations represent a very early clone in the primary tumor’s evolution, or that these mutations represent a pre-neoplastic field, in which the primary tumor and recurrence are derived from. In both instances, the clinical recurrence is of a monoclonal origin which suggests either field cancerization by migration of mutated cells in the adjacent mucosa, or that the recurrence developed out of remaining tumor tissue.

Objectives To report the complications occurring following TORS and to identify the factors predictive of complications. Methods Following IRB approval a retrospective analysis of all TORS operations at our institution was performed. Postoperative complications within 45 days were collected and graded with the Clavien-Dindo system. Complications were categorized into groups: all complications, not related to TORS and TORS related. Unadjusted odds ratios were calculated to test association between patients with and without a complication. Results 122 TORS operations were carried out between June 2010 and August 2015. 77% were male, with a median age of 57. There were 92 primary tumor resections, 10 second head and neck primary resections, 13 salvage procedures and 7 other indications. Surgical resection involved 1, 2 or >3 sub-sites in 36%, 28% and 36% patients, respectively. Overall, there were 107 complications (66 TORS related, 41 non-TORS related) that occurred in 57 patients (47%). A major complication occurred in 23 patients (18%). 19 patients had a TORS related major complication and 6 patients experienced a non-TORS related major complication. There was a temporal trend in TORS related major complication rate decreasing from 33% in 2010 to 10% in 2015. Statistical analysis showed that the odds of having any complication were 3 times greater in patients over 60 years old (p = 0.017), and 2.5 times greater when there were more than 2 subsites resected (p = 0.022). Conclusions Age over 60 years and a larger extent of resection were the significant factors predictive of major complications.

Importance Management of cervical unknown primary squamous cell carcinoma (CUP) has evolved with the introduction of transoral robotic surgery (TORS). Objectives 1. To describe the efficacy of TORS lingual and palatine tonsillectomy in identifying the primary site of malignancy. 2. To explore how the extent of surgery affects diagnostic yield. 3. To report margin status of TORS resections. Design, setting and participants A retrospective, single-center cohort study utilizing a prospectively collected database of CUP patients in a high-volume tertiary referral center. Patient underwent operative laryngoscopy plus TORS as clinically indicated. Main outcomes and measures Primary end point was successful identification of the primary. The extent of surgery and margin status were also examined. Results From 2010–2016, 64 patients with CUP were treated. The primary tumor was found in 51 patients (80%). Fourteen patients (22%) were identified with operative laryngoscopy alone. Fifty patients underwent TORS lingual tonsillectomy ± palatine tonsillectomy with 37 primary tumors identified (74%). The primary was located in the lingual tonsil in 32 patients (86%) and palatine tonsil in 5 patients (10%, p Conclusion and relevance Operative laryngoscopy with TORS is efficacious, localizing the primary in 80% of patients. If a margin was positive, it was most commonly the deep margin. This study provides valuable information that can help standardize surgical technique, further increasing the diagnostic yield and decreasing the negative margin rate of TORS for CUP.

Introduction: Whereas salivary gland pleomorphic adenoma (SGPA) is the most common type of salivary gland tumor, little is known about its epidemiology because national cancer registries do not register this disease.Objectives: To establish SGPA incidence trends, rates of secondary malignant transformation and recurrence and associated factors in the Netherlands. Materials and methods: Data on incidence, epidemiology, secondary malignant transformation and recurrence were retrieved from the Dutch pathology registry (PALGA) for the years 1992, 1997, 2002, 2007, and 2012. Multivariate analysis was performed to discover the risk factors for recurrence.Results: 3506 cases of SGPA were recorded implying an overall European standardized rate of 4.2-4.9 per 100,000 person-years. Our figures showed a female preponderance (1: 1.43) with an annual 1% rise in female incidence (95% confidence interval [CI]: 0.2-1.8) and a bimodal age distribution in women (p Positive and uncertain resection margins and younger age at diagnosis were risk factors for recurrence, with odds ratios (ORs) of 4.62 (95% CI 2.84-7.51), 4.08 (95% CI 2.24-7.43), and 0.42 (95% CI 0.29-0.63) respectively. Tumor locations in the minor salivary glands had lower odds of recurrence than tumors in the parotid (OR 0.24; 95% CI: 0.07-0.77; p Conclusion: This first nationwide study clearly showed sex differences in SGPA epidemiology, possibly suggesting some underlying hormonal mechanism. Long-term recurrence risks were low, and secondary malignant transformation risks were very low. (C) 2017 The Authors. Published by Elsevier Ltd.

Background and purpose Adenoid cystic carcinoma (ACC) of salivary glands is characterized by long-term distant metastasis, most commonly in lungs. No agreement has been reached about the role of surgical treatment of pulmonary lesions. We evaluated the long-term results of lung metastasectomy for ACC in order to identify factors that should be taken into account in selecting patients eligible for surgery and treatment planning. Patients and methods A retrospective study was conducted on 109 patients selected from our institutional experience and from the International Registry of Lung Metastases. Survival was calculated by Kaplan-Meier estimate and prognostic factors endowed with a predictive power for most other metastatic cancers were investigated. Results The cumulative survival was 66.8% at 5 years and 40.5% at 10 years. In patients with a disease-free interval (DFI) greater than 36 months, the overall survival was 76.5% at 5 years. Survival in case of complete surgical resection was 69.5% at 5 years. Multivariate analysis confirmed DFI and completeness of resection resulted in the best prognostic variables. Discussion Lung metastasectomy should be considered as a therapeutic option to achieve local control of disease when 2 conditions are met: (1) complete surgical resection is feasible and (2) the time to pulmonary relapse after primary tumor treatment is greater than 36 months. Symptomatic benefits of an incomplete lung resection in slow-growing tumors such as ACC remain uncertain. The turning point in the management of disseminated cancers will be clarified with biological profiling of ACC and the development of targeted therapies.

Volumetric tumor growth velocity (TGV) reflects in vitro tumor aggressiveness, but its prognostic value has not been investigated in vivo. We examined the prognostic impact of TGV on oncologic outcomes in patients with oropharyngeal squamous cell cancer (OSCC).101 OSCC patients with two pretreatment CTs with time gap of 2 or more weeks treated at a single institution between 2004 and 2008 were identified. Primary tumor and nodal targets were segmented in scans. Linear growth rates were calculated. Recursive partitioning analysis (RPA) identified cut point associated with outcomes.Median follow-up was 59months (range 7-118). Median primary TGV was 0.65% increase per day (range 0-9.37%). RPA identified TGV cut point associated with local control (LC) of 1% per day. Patients with higher TGV had decreased 5-year LC (73% vs. 98%, p=0.0004), distant control (DC, 62% vs. 91%, p=0.0007), and overall survival (OS, 38% versus 93%, p0.0001). In multivariate analysis including demographics, tumor stage, subsite, and treatment factors, TGV⩾1% per day independently predicted worsened LC (p = 0.02), DC (p = 0.003), and OS (p0.0001). However, this TGV cutoff was not significantly predictive of LC, DC, or OS for a subset of presumed HPV-positive patients.OSCC TGV⩾1% per day is a substantive negative prognostic indicator for disease control and overall survival, particularly in HPV non-associated tumors. This novel CT-based volumetric assessment of TGV suggests a simple methodology for risk stratification of patients.

Objective To evaluate the prognostic effect of allogenic red blood cell transfusion (RBT) and preoperative anemia in patients with oral squamous cell carcinoma (OSCC) undergoing primary tumor resection. Methods We retrospectively analyzed a cohort of 621 patients, diagnosed with OSCC receiving tumor resection in curative intention. Preoperative anemia and perioperative RBT were evaluated according to WHO definition. Overall survival (OAS) as well as recurrence-free survival (RFS) was evaluated in transfused and non-transfused as well as in anemic and non-anemic patients. In addition, outcome parameters were calculated for distinct amounts of perioperatively administered RBTs. Data analysis was performed by uni- and multivariate statistics. Mean follow-up time was 7.3 years. Results Preoperative anemia was diagnosed in 29% of OSCC patients. Anemic patients displayed a significantly decreased five-year OAS (44%) in comparison to non-anemic equivalents (69%). 70% of non-transfused OSCC patients were alive after five years, whereas in case of RBT five-year OAS was 41%. These findings were substantiated by subgroup analysis in patients without preoperative anemia. For anemic patients however, no deleterious effect on survival in case of perioperative RBT was seen. Increasing numbers of received RBTs were shown to worsen outcome of OSCC patients in a dose-dependent manner. Conclusion Preoperative anemia and RBT are significantly associated with impaired long-term outcome of patients suffering from OSCC. Future studies are needed to evaluate differentiated effects of RBTs in anemic and non-anemic OSCC patients and accordingly providing individual transfusion strategies to ameliorate outcome of patients suffering from OSCC.

This study aimed to explore the prognostic value of extensive invasion of primary tumor volume for local control in patients with T3-4 NPC receiving intensity-modulated radiotherapy (IMRT).Between January 2009 and December 2015, initial volume of GTV-P, the confined and extensive invasion part of GTV-P (GTV-C and GTV-E) were obtained from 159 prospectively enrolled non-metastatic T3-4 NPC patients. GTV-E included the tumor with infiltration of bony structures at skull base, cervical vertebra, paranasal sinuses or with intracranial extension. GTV-C was calculated by the subtraction of GTV-E from GTV-P. The effects of tumor volume levels on local control rate (LC) were evaluated by Kaplan-Meier method and multivariate analysis.GTV-P (P = 0.015) and GTV-E (P = 0.001) were significantly correlated with local failure, while GTV-C (P = 0.494) was not. Then optimal cut-off values of GTV-P (43 mL) and GTV-E (22 mL) were determined by receiver operating characteristic curve analysis. Patients with small (22 mL) GTV-E achieved better 5-year LC rate than those with large (≥22 mL) GTV-E (96.3% vs.76.1%, P 0.001), but no significant difference was found between patients with small (43 mL) and large (≥43 mL) GTV-P (95.9% vs. 85.5%, P = 0.094). Multivariate analysis also demonstrated large (≥22 mL) GTV-E to be an independent unfavorable prognostic factor for LC (hazard ratio [HR], 3.805; 95% CI, 1.100-13.166; P = 0.035).GTV-E is an independent prognostic factor for LC in T3-4 NPC and may further assist in the optimization of treatment strategies.

Background and Purpose Adenoid cystic carcinomas (ACC) are characterized by high rate of local recurrence and late distant metastasis. Chromosomal changes in the evolution from primary tumors to metastatic disease of ACC have not been appointed. Here we investigated the chromosomal alterations of 53 primary tumors from ACC patients with different progressive states by shallow whole genome sequencing to identify potential new markers for metastatic spread. Methods Illumina paired-end libraries were generated using DNA from the primary tumor of 53 ACC patients. Fragmented DNA was end-repaired, A-tailed and multiplex sequencing adapters were ligated. Sequence data were mapped to HG19 and a copy-number analysis was conducted using the QDNAseq R package (version 1.10.0). Outliers were removed and data was smoothed by applying the circular binary segmentation algorithm implemented in the R package copynumber version 1.22.0. A modified chromosomal instability (CNI) score was used to analyze deletions and amplifications. Results Cluster analysis of the whole genome sequencing revealed that the frequency of chromosomal aberrations were increased in ACC with local recurrence and distant metastases in comparison to ACC patients with no metastatic spread. Specifically, chromosome 6 and 12 and exclusively the entire chromosome 4 showed an increased frequency of chromosomal alterations with tumor progression. Conclusion Our data show a molecular evolution from primary tumors to local recurrences and distant metastases and pinpoint the critical chromosomal regions involved in this process. These regions should be in the focus of the search for therapeutic targets of progressive ACC.

To develop a multidimensional nomogram for predicting the progression-free survival (PFS) in patients with locoregionally advanced nasopharyngeal carcinoma (NPC) (stage III-IVa).A total of 224 patients with locoregionally advanced NPC (training cohort, n = 149; validation cohort, n = 75) were retrospectively included. We extracted 260 radiomic features from the primary tumor and lymph nodes on the axial contrast-enhanced T1 weighted and T2 weighted MRI. Radiomic signatures of the gross tumor volume (RSnx) and lymph node (RSnd), Dose Volume Histogram (DVH) signature reflecting planning score (PS), and clinical characteristics were included as potential predictors of PFS. The least absolute shrinkage and selection operator (LASSO) regression were applied for feature selection and data dimension reduction. A nomogram was developed by incorporating the selected predictors. The C-index and calibration curve were used to assess discrimination and calibration power of the nomogram, respectively.RSnd, PS, and tumor-node-metastasis (TNM) stage were the independent predictors for PFS (all p 0.05). The nomogram integrating the three factors achieved a C-index of 0.811 (95% CI: 0.74-0.882) in the validation cohort for predicting PFS, which outperformed than that of the TNM stage alone (C-index, 0.613, 95% CI: 0.532-0.694). Subgroup analysis showed Epstein-Barr virus (EBV) DNA status improved the predictive accuracy of the nomogram (C-index, 0.86, 95% CI: 0.787-0.933).The multidimensional nomogram incorporating RSnd, PS, and TNM stage showed high performance for predicting PFS in patients with locoregionally advanced NPC.

Objectives To develop and validate an algorithm to predict occult nodal metastasis in clinically node negative oral cavity squamous cell carcinoma (OCSCC) using machine learning. To compare algorithm performance to a model based on tumor depth of invasion (DOI). Materials and methods Patients who underwent primary tumor extirpation and elective neck dissection from 2007 to 2013 for clinical T1-2N0 OCSCC were identified from the National Cancer Database (NCDB). Multiple machine learning algorithms were developed to predict pathologic nodal metastasis using clinicopathologic data from 782 patients. The algorithm was internally validated using test data from 654 patients in NCDB and was then externally validated using data from 71 patients treated at a single academic institution. Performance was measured using area under the receiver operating characteristic (ROC) curve (AUC). Machine learning and DOI model performance were compared using Delong’s test for two correlated ROC curves. Results The best classification performance was achieved with a decision forest algorithm (AUC = 0.840). When applied to the single-institution data, the predictive performance of machine learning exceeded that of the DOI model (AUC = 0.657, p = 0.007). Compared to the DOI model, machine learning reduced the number of neck dissections recommended while simultaneously improving sensitivity and specificity. Conclusion Machine learning improves prediction of pathologic nodal metastasis in patients with clinical T1-2N0 OCSCC compared to methods based on DOI. Improved predictive algorithms are needed to ensure that patients with occult nodal disease are adequately treated while avoiding the cost and morbidity of neck dissection in patients without pathologic nodal disease.

Objectives To determine the feasibility of pre-treatment primary tumor FDG-PET and DWI-MR imaging parameters in predicting HPV status and the second aim was to assess the feasibility of those imaging parameters to predict response to therapy. Material and Methods We retrospectively analyzed primary tumors in 33 patients with proven OPSCC. PET/MRI was performed before and 6 months after chemo-radiotherapy for assessing treatment response. PET Standardized uptake value (SUVmax), total lesion glycolysis (TLG), metabolic tumor volume (MTV), and apparent diffusion coefficient (ADC) from pre-treatment measurements were assessed and compared to the clinicopathological characteristics (T stages, N stages, tumor grades, HPV and post-treatment follow up). HPV was correlated to the clinicopathological characteristics. Results ADCmean was significantly lower in patients with HPV+ve than HPV-ev, (P = 0.001), cut off value of (800 ± 0.44*10-3mm2/s) with 76.9% sensitivity, and 72.2% specificity is able to differentiate between the two groups. No significant differences were found between FDG parameters (SUVmax, TLG, and MTV), and HPV status, (P = 0.873, P = 0.958, and P = 0.817), respectively. Comparison between CR and NCR groups; ADCmean, TLG, and MTV were predictive parameters of treatment response, (P = 0.017, P = 0.013, and P = 0.014), respectively. HPV+ve group shows a higher probability of lymph nodes involvement, (P = 0.006) Conclusion Our study found that pretreatment ADC of the primary tumor can predict HPV status and treatment response. On the other hand, metabolic PET parameters (TLG, and MTV) were able to predict primary tumor response to therapy.

It is well known that head and neck squamous cell carcinomas are characterized by genetic alterations, genomic instability and different immune defects and Telomerase reverse transcriptase promoter mutations have been found with high rates in patients with tongue squamous cell carcinomas. We presented a non-smoker, no alcohol consuming woman who had a second primary tongue SCC after four and a half years later of her first tongue SCC with TERT promoter mutation. The primary tumor and its recurrences in woman with tongue SCC who have never smoked and had no alcohol consumption may need to be differing from other tongue carcinomas. TERT promoter mutations may have a relation in etiopathogenesis of tumor and mutations need to be on mind in future studies.

Summary Background Despite the promise of metabolic tumor volume (MTV) as a risk-stratifying marker, the retrospective design of the initial study limits its generalizability. Therefore, this study sought to validate MTV as a prognostic factor for oral cavity squamous cell carcinoma (OCSCC) treated with primary surgery within an independent data set. Methods The validation data set consisted of 42 patients diagnosed with OCSCC between 2008 and 2012. The original cohort consisted of 80 patients. MTV and SUVmax were calculated for the primary tumor and nodal metastasis separately, as well as combined. Before statistical analysis, MTV and SUVmax values were divided into intertertile thirds to allow for intergroup survival analysis. Validation analysis was conducted on the validation data set alone. Data from both cohorts were then combined ( n = 122) to increase statistical power. Results An increase in combined MTV of 17.5 cm 3 was associated with statistically significant increase in risk of disease recurrence (HR = 19.2, p p p > 0.05) and disease-free survival (HR = 1.0, p > 0.05). Increase in the MTV of the primary tumor was associated with an increase in the risk of disease recurrence (HR = 21.7, p = 0.0001) and risk of death (HR = 7.0, p = 0.0001), while increase in the MTV of the locoregional neck metastasis was not ( p > 0.05). An MTV cutoff value of greater than 10.2 cm 3 was found to significantly affect survival. Conclusion Due to the reproducibility of MTV findings, this study validates MTV as an independent prognostic factor for OCSCC treated with primary surgery.

PURPOSE: To identify whether radiomic features from pre-treatment computed tomography (CT) scans can predict molecular differences between head and neck squamous cell carcinoma (HNSCC) using The Cancer Imaging Archive (TCIA) and The Cancer Genome Atlas (TCGA). METHODS: 77 patients from the TCIA with HNSCC had imaging suitable for analysis. Radiomic features were extracted and unsupervised consensus clustering was performed to identify subtypes. Genomic data was extracted from the matched patients in the TCGA database. We explored relationships between radiomic features and molecular profiles of tumors, including the tumor immune microenvironment. A machine learning method was used to build a model predictive of CD8+ T-cells. An independent cohort of 83 HNSCC patients was used to validate the radiomic clusters. RESULTS: We initially extracted 104 two-dimensional radiomic features, and after feature stability tests and removal of volume dependent features, reduced this to 67 features for subsequent analysis. Consensus clustering based on these features resulted in two distinct clusters. The radiomic clusters differed by primary tumor subsite (p=0.0096), HPV status (p=0.0127), methylation-based clustering results (p=0.0025), and tumor immune microenvironment. A random forest model using radiomic features predicted CD8+ T-cells independent of HPV status with R(2)=0.30 (p

Target volume selection and delineation for both the primary tumor and the lymph nodes are critical steps in the treatment of head and neck tumors with Intensity Modulated Radiation therapy (IMRT). These steps should be based on a probabilistic approach, which is that selection and delineation will be considered as optimal when reaching the best compromise between a too tight volume that could be associated to an unacceptable rate of local recurrence, and a too large volume, which could be associated to an unacceptable rate of treatment morbidity. Failure to do so have been reported to be associated to a higher risk of loco-regional recurrences and/or morbidity after treatment. In this framework, groups of experts proposed sets of guidelines for the radiation oncology community, aiming at standardizing radiotherapy practices of head and neck cancer patients. Although in constant improvement, such guidelines have been shown to translate into more consistent treatment approaches. This review article summarizes the knowledge accumulated over the years on target volume selection and delineation and tries to reconcile the various schools of thoughts on the topic.

Metastases to the cervical lymph nodes from a occult primary (CUP) of head and neck squamous carcinomas has been increasing in presentation (HNSCC). Modern diagnostic workup, including clinical evaluation, conventional imaging, FDG-PET/CT and panendoscopy/tonsillectomy enables detection of the primary site in over half of all cases, and is associated with significantly improved survival rates. Recent studies have demonstrated the utility of novel molecular pathology and transoral surgical techniques in improving diagnosis and treatment. We present a new, evidence-based protocol incorporating these novel diagnostic modalities. It aims to identify the site of the primary tumor, and determine the stage of the disease, including extranodal extension. This information can personalise treatment recommendations, rationalise combinations of treatment modalities, and thereby potentially minimise toxicity and improving functional outcomes.

Background The 8th edition American Joint Committee on Cancer staging system for resected HPV-positive oropharynx carcinoma (HPV+ OPC) highlights high node number as a critical determinant of survival. We sought to characterize outcomes and patterns of failure in patients with high pathologically involved node number oropharynx cancer. Methods We retrospectively identified 116 HPV+ OPC patients sequentially treated with neck dissection and either resection or intraoperative brachytherapy of the primary tumor between 2010 and 2016. External beam radiation was given based on the pathologic findings. Cox proportional hazards regression was used for multivariate analysis. Results With a median follow-up of 27 months, the 3-year overall survival and progression free survival (PFS) were 89% and 81%, respectively. On multivariate analysis, ≥5 involved lymph nodes was significantly associated with worse PFS (hazard ratio 4.3, 95% confidence interval (CI) 1.5–12.0, P = 0.001). Rates of 3-year locoregional recurrence (LRR) in patients with ≤4 vs ≥5 were 6% and 22% (log-rank P = 0.12). Rates of 3-year distant metastases (DM) were 12% and 53% between ≤4 and ≥5 (log-rank P Conclusion Our findings confirm that patients with 5 or more involved lymph nodes appear to have substantially worsened rates of disease recurrence. While these patients appear to be at high risk of both LRR and DM, the predominant mechanism of failure is distant, and the rate of DM in this group was over 50%. Dedicated clinical trials in this patient population are warranted with a focus on mitigating the high DM rate.