Oropharyngeal squamous cell carcinomas differentially express granzyme inhibitors.

OBJECTIVES: Patients with human papillomavirus (HPV)-positive oropharyngeal squamous cell carcinomas (OPSCCs) have an improved prognosis compared to HPV-negative OPSCCs. Several theories have been proposed to explain this relatively good prognosis. One hypothesis is a difference in immune response. In this study, we compared tumor-infiltrating CD3+, CD4+, CD8+ T-cells, and granzyme inhibitors (SERPINB1, SERPINB4, and SERPINB9) between HPV-positive and HPV-negative tumors and the relation with survival. METHODS: Protein expression of tumor-infiltrating lymphocytes (TILs) (CD3, CD4, and CD8) and granzyme inhibitors was analyzed in 262 OPSCCs by immunohistochemistry (IHC). Most patients (67%) received primary radiotherapy with or without chemotherapy. Cox regression analysis was carried out to compare overall survival (OS) of patients with low and high TIL infiltration and expression of granzyme inhibitors. RESULTS: HPV-positive OPSCCs were significantly more heavily infiltrated by TILs (p < 0.001) compared to HPV-negative OPSCCs. A high level of CD3+ TILs was correlated with a favorable outcome in the total cohort and in HPV-positive OPSCCs, while it reached no significance in HPV-negative OPSCCs. There was expression of all three granzyme inhibitors in OPSCCs. No differences in expression were found between HPV-positive and HPV-negative OPSCCs. Within the group of HPV-positive tumors, a high expression of SERPINB1 was associated with a significantly worse overall survival. CONCLUSION: HPV-positive OPSCCs with a low count of CD3+ TILs or high expression of SERPINB1 have a worse OS, comparable with HPV-negative OPSCCs. This suggests that the immune system plays an important role in the carcinogenesis of the virally induced oropharynx tumors.

Effectiveness and cost-utility of a guided self-help exercise program for patients treated with total laryngectomy: protocol of a multi-center randomized controlled trial.

BACKGROUND: Total laryngectomy with or without adjuvant (chemo)radiation often induces speech, swallowing and neck and shoulder problems. Speech, swallowing and shoulder exercises may prevent or diminish these problems. The aim of the present paper is to describe the study, which is designed to investigate the effectiveness and cost-utility of a guided self-help exercise program built into the application "In Tune without Cords" among patients treated with total laryngectomy. METHODS/DESIGN: Patients, up to 5 years earlier treated with total laryngectomy with or without (chemo)radiation will be recruited for participation in this study. Patients willing to participate will be randomized to the intervention or control group (1:1). Patients in the intervention group will be provided access to a guided self-help exercise program and a self-care education program built into the application "In Tune without Cords". Patients in the control group will only be provided access to the self-care education program. The primary outcome is the difference in swallowing quality (SWAL-QOL) between the intervention and control group. Secondary outcome measures address speech problems (SHI), shoulder disability (SDQ), quality of life (EORTC QLQ-C30, QLQ-H&N35 and EQ-5D), direct and indirect costs (adjusted iMCQ and iPCQ measures) and self-management (PAM). Patients will be asked to complete these outcome measures at baseline, immediately after the intervention or control period (i.e. at 3 months follow-up) and at 6 months follow-up. DISCUSSION: This randomized controlled trial will provide knowledge on the effectiveness of a guided self-help exercise program for patients treated with total laryngectomy. In addition, information on the value for money of such an exercise program will be provided. If this guided self-help program is (cost)effective for patients treated with total laryngectomy, the next step will be to implement this exercise program in current clinical practice. TRIAL REGISTRATION: NTR5255 Protocol version 4 date September 2015.

Can Epstein-Barr virus DNA load in nasopharyngeal brushings or whole blood predict recurrent nasopharyngeal carcinoma in a non-endemic region? A prospective nationwide study of the Dutch Head and Neck Oncology Cooperative Group.

This study estimated the value of quantitative measurements of EBV markers in the clinical management of nasopharyngeal carcinoma in a non-endemic area. The aim was to predict prognosis and detect recurrent and residual disease. In 72 patients, EBV DNA load in blood and nasopharyngeal brushes, and IgA VCA-p18 and EBNA1 in plasma were measured at different time points. At diagnosis and post-treatment, a cut-off value was used for detecting disease [positive (PPV) and negative (NPV) predictive value]. The markers were correlated as a continuous variable with tumor stage, disease-free survival (DFS) and overall survival (OS). The Cox hazard ratio model assessed hazard ratios. At diagnosis, the markers were above the COV in 45, 92, 85 and 83 % of the patients, respectively. Post-treatment, DNA load test in blood and brush had the best discriminating power (blood DNA load test: PPV 39 % and NPV 97 %, brush for local disease: PPV 75 % and NPV 99 %). Post-treatment, DNA load in blood was the best predictor for OS and DFS [hazard ratio 3.2 (95 % CI 1.51-3.5) and 2.3 (95 % CI 1.72-5.8)]. Assessing the EBV DNA load in blood has significant prognostic value, although the clinical value is for discussion. The EBV DNA load in the brush might improve early detection of local failures post-treatment.

TP53 Y220C Is a Hotspot Mutation in Oropharyngeal Squamous Cell Carcinoma.

OBJECTIVES: Although TP53 mutations in head and neck squamous cell carcinoma (HNSCC) have been extensively studied, their association with the different subsites in the head and neck region has never been described. METHODS: Sanger sequence analysis evaluating exons 4-9 in the TP53 gene was performed on 116 HNSCC patients. The exon location, exact codon and corresponding substitution in relation to the anatomical site (subsite) of the HNSCC were evaluated. RESULTS: We found nonsynonymous TP53 mutations in 70% (81/116) of the patients. In oral cavity carcinomas, most mutations occurred in exon 7 (37%). In oropharyngeal and laryngeal tumors, mutations were mainly found in exons 6 and 7. The most common mutation was located in codon 220, and all of these were an Y220C mutation. Five out of nine (56%) Y220C mutations occurred in oropharyngeal tumors. Additionally, 22% of all mutations observed in oropharyngeal squamous cell carcinoma (OPSCC) consisted of Y220C mutations. CONCLUSION: In this study, the subsite-related distribution of TP53 mutations underlines the biological diversity between tumors arising from different anatomical regions in the head and neck region. Moreover, the Y220C mutation was by far the most prevalent TP53 mutation in HNSCC and a relative hotspot mutation in the oropharynx. © 2015 S. Karger AG, Basel.

Diagnostic and Treatment-Related Challenges in Sinonasal Teratocarcinosarcoma: A Report of Three Cases.

Background: Sinonasal teratocarcinosarcoma is a rare, aggressive malignancy located almost exclusively in the nasal cavity, paranasal sinuses, or anterior skull base. Histopathological diagnosis can be challenging due to the heterogeneous composition. Methods: Retrospective analysis of 3 patients with sinonasal teratocarcinosarcoma diagnosed and treated at the University Medical Center Utrecht was conducted. Results: Patients presented with nasal obstruction, epistaxis, headaches, or behavioral changes. All three patients had locally advanced disease, and one had lymph node metastases. Two patients underwent surgery followed by radiotherapy, and one underwent neoadjuvant chemotherapy followed by surgery. The follow-up duration ranged from 3 to 32 months. All three patients died due to progression of their disease. Conclusion: Sinonasal teratocarcinosarcoma is characterized by rapid, aggressive local expansion. The prognosis is poor due to a high risk of metastases and locally recurrent disease. Multimodality treatment consisting of surgery, followed by (chemo)-radiotherapy, is essential for optimizing outcomes. Neoadjuvant therapy offers a promising treatment option.

Arterial calcification on preoperative computed tomography imaging as a risk factor for pharyngocutaneous fistula formation after total laryngectomy.

BACKGROUND: Research in esophageal surgery showed that computed tomography (CT) assessed arterial calcification (AC) is associated with postoperative complications. We investigated the association between AC and pharyngocutaneous fistula (PCF) formation after laryngectomy. METHODS: This was a retrospective cohort study of patients undergoing laryngectomy. AC was scored at 10 different anatomical locations on CT imaging, blinded for PCF occurrence. Association with PCF was investigated using logistic regression. RESULTS: The 224 patients were included; 62 (27.7%) developed a PCF. Moderate to severe AC was widespread in patients undergoing TL; 7.1% of patients had at most mild AC, of whom 1 experienced a PCF (p = 0.05). A higher cumulative calcification score was associated with PCF in univariable (OR 1.11, p = 0.04) and multivariable analysis (OR 1.14, p = 0.05). CONCLUSION: AC is widespread in patients undergoing laryngectomy and its burden is associated with PCF. Extensive AC on preoperative imaging may be considered a risk factor for PCF.

Application and accuracy of ultrasound-guided resections of tongue cancer.

OBJECTIVES: Surgical removal of squamous cell carcinoma of the tongue (SCCT) with tumour-free margin status (≥5 mm) is essential for loco-regional control. Inadequate margins (<5 mm) often indicate adjuvant treatment, which results in increased morbidity. Ultrasound (US)-guided SCCT resection may be a useful technique to achieve more adequate resection margins compared to conventional surgery. This study evaluates the application and accuracy of this technique. METHODS: Forty patients with SCCT were included in a consecutive US cohort. During surgery, the surgeon aimed for a 10-mm echographic resection margin, while the tumour border and resection plane were captured in one image. Ex-vivo US measurements of the resection specimen determined whether there was a need for an immediate re-resection. The margin status and the administration of adjuvant treatment were compared those of with a consecutive cohort of 96 tongue cancer patients who had undergone conventional surgery. A receiver operating characteristic analysis was done to assess the optimal margin of ex-vivo US measurements to detect histopathologically inadequate margins. RESULTS: In the US cohort, the frequency of free margin status was higher than in the conventional cohort (55% vs. 16%, p < 0.001), and the frequency of positive margins status (<1 mm) was lower (5% vs. 15%, respectively, p < 0.001). Adjuvant radiotherapy was halved (10% vs. 21%), and the need for re-resection was comparable (10% vs. 9%). A cut-off value of 8 mm for ex-vivo measurements prevented histopathologically inadequate margins in 76%. CONCLUSION: US-guided SCCT resections improve margin status and reduce the frequency of adjuvant radiotherapy.

Evaluation of subclasses for T4-classified squamous cell carcinoma of the external auditory canal.

BACKGROUND: T4-classified squamous cell carcinoma (SCC) of external auditory canal (EAC) can potentially involve different anatomical structures, which could translate into different treatment strategies and survival outcomes within one classification. Our aim is to evaluate the clinical added value of T4-subclasses proposed by Lavieille and by Zanoletti. METHODS: Retrospective data, including patients with primary operated cT4-classified EAC SCC, was obtained from 12 international hospitals. We subclassified according to the T4-subclasses. The treatment strategies, disease-free survival (DFS) and overall survival per subclass were calculated. RESULTS: A total of 130 T4-classified EAC SCC were included. We found commonly used treatment strategies per subclass according to Lavieille and the DFS seems also to differ per subclass. Subclass according to Zanoletti showed comparable treatment strategies and survival outcomes per subclass. CONCLUSION: Our study suggests that the subclass according Lavieille might have added value in clinical practice to improve care of T4-classified EAC SCC.

Evaluation of the modified Pittsburgh classification for predicting the disease-free survival outcome of squamous cell carcinoma of the external auditory canal.

BACKGROUND: Squamous cell carcinoma (SCC) of the external auditory canal (EAC) is a rare disease, which is commonly classified with the modified Pittsburgh classification. Our aim was to evaluate the predictive performance of this classification in relation to disease-free survival (DFS). METHODS: We examined retrospective data from a nationwide Dutch cohort study including patients with primary EAC SCC. These data were combined with individual patient data from the literature. Using the combined data, the predictive performances were calculated using the c-index. RESULTS: A total of 381 patients were included, 294 for clinical and 281 for the pathological classification analyses. The c-indices of the clinical and the pathological modified Pittsburgh classification predicting DFS were 0.725 (0.668-0.782) and 0.729 (0.672-0.786), respectively. CONCLUSION: The predictive performance of the modified Pittsburgh classification system as such appears to be acceptable to predict the DFS of EAC SCC. Other factors need to be added to a future model to improve the predicted performance.

Preoperative low skeletal muscle mass as a risk factor for pharyngocutaneous fistula and decreased overall survival in patients undergoing total laryngectomy.

BACKGROUND: Low skeletal muscle mass (SMM) is associated with postoperative complications, prolonged hospital stay, and short overall survival (OS) in surgical oncology. We aimed to investigate this association in patients undergoing total laryngectomy (TL). METHODS: A retrospective study was performed of patients undergoing TL. SMM was measured using CT or MRI scans at the level of the third cervical vertebra (C3). RESULTS: In all, 235 patients were included. Low SMM was observed in 109 patients (46.4%). Patients with low SMM had more pharyngocutaneous fistulas (PCFs) than patients with normal SMM (34.9% vs 20.6%; P = .02) and prolonged hospital stay (median, 17 vs 14 days; P < .001). In multivariate analysis, low SMM (hazards ratio, 1.849; 95% confidence interval, 1.202-2.843) and high N stage were significant prognosticators of decreased OS. CONCLUSION: Low SMM is associated with PCF and prolonged hospital stay in patients undergoing TL. Low SMM is an independent prognostic factor for shorter OS.

Prognostic role of tumor infiltrating lymphocytes in EBV positive and EBV negative nasopharyngeal carcinoma.

OBJECTIVES: Tumor infiltrating lymphocytes (TILs) correlate with both better and worse prognosis in solid tumors. As therapeutic modalities for nasopharyngeal carcinoma (NPC) are limited, immunotherapy could be a potential alternative. Up till now there is limited prognostic data on the role of TILs in NPC, so we assessed the prognostic role of TILs in Epstein-Barr-virus (EBV) positive and negative NPC. METHODS: Tissue of 92 NPCs was assessed for CD3, CD4, CD8, PD1 and PDL1 expression in the tumor's micro-environment. Correlations between clinicopathological characteristics was assessed using the Pearson X2 test, Fisher's exact test and ANOVA. Survival was analyzed with the Kaplan-Meier method and Cox regression. Differences in CD3, CD4, CD8, PD1, PDL1 counts/(co)expression between EBV positive and negative NPCs were evaluated using the Mann-Whitney U test. Two-tailed P values below 0.05 were considered statistically significant. RESULTS: EBV positive NPC contains significantly more CD3, CD4 and CD8 TILs than EBV negative NPC. In the whole NPC group, increased CD8 count is associated with better overall survival (OS) (HR 0.219 (95%CI 0.075-0.640)), but also in cases with PDL1 co-expression (HR 0.073 (95%CI 0.010-0.556)). In EBV positive NPC co-expression of CD8 and PDL1 showed better disease free survival (HR 0.407 (95%CI 0.195-0.850)) and OS (HR 0.170 (95%CI 0.037-0.787)). CONCLUSIONS: Although TILs are significantly different between EBV positive and negative NPCs, it is especially composition of the infiltrate which determines prognosis. Effects of PD1 and CD8 need more study, because these findings show much potential in using immunotherapeutic modalities in NPC treatment.

The involvement of physician assistants in inpatient care in hospitals in the Netherlands: a cost-effectiveness analysis.

OBJECTIVE: To investigate the cost-effectiveness of substitution of inpatient care from medical doctors (MDs) to physician assistants (PAs). DESIGN: Cost-effectiveness analysis embedded within a multicentre, matched-controlled study. The traditional model in which only MDs are employed for inpatient care (MD model) was compared with a mixed model in which, besides MDs, PAs are also employed (PA/MD model). SETTING: 34 hospital wards across the Netherlands. PARTICIPANTS: 2292 patients were followed from admission until 1 month after discharge. Patients receiving daycare, terminally ill patients and children were excluded. PRIMARY AND SECONDARY OUTCOME MEASURES: All direct healthcare costs from day of admission until 1 month after discharge. Health outcome concerned quality-adjusted life years (QALYs), which was measured with the EuroQol five dimensions questionnaire (EQ-5D). RESULTS: We found no significant difference for QALY gain (+0.02, 95% CI -0.01 to 0.05) when comparing the PA/MD model with the MD model. Total costs per patient did not significantly differ between the groups (+€568, 95% CI -€254 to €1391, p=0.175). Regarding the costs per item, a difference of €309 per patient (95% CI €29 to €588, p=0.030) was found in favour of the MD model regarding length of stay. Personnel costs per patient for the provider who is primarily responsible for medical care on the ward were lower on the wards in the PA/MD model (-€11, 95% CI -€16 to -€6, p<0.01). CONCLUSIONS: This study suggests that the cost-effectiveness on wards managed by PAs, in collaboration with MDs, is similar to the care on wards with traditional house staffing. The involvement of PAs may reduce personnel costs, but not overall healthcare costs. TRIAL REGISTRATION NUMBER: NCT01835444.

Grading facial nerve function: why a new grading system, the MoReSS, should be proposed.

OBJECTIVE: To compare the interobserver variability of a new grading system to the currently recommended House-Brackmann Grading Scale. STUDY DESIGN: Prospective case-control study. SETTING: Tertiary referral center. PATIENTS: All patients with a facial nerve paresis/paralysis (whatever the cause). INTERVENTION: All patients were evaluated for their facial nerve function by three observers, independently, using both the new system and the House-Brackmann Grading Scale. MAIN OUTCOME MEASURE: The level of agreement between the three observers using both scales. RESULTS: With the movement, rest, secondary defects, and subjective scoring grading scale, a higher percentage of agreement between the observers was noticed than with the House-Brackmann Grading Scale. CONCLUSION: The movement, rest, secondary defects, and subjective scoring grading system is more useful for grading facial nerve dysfunction in clinical practice than the House-Brackmann Grading Scale.

Prognostic significance of the EGFR pathway in nasopharyngeal carcinoma: a systematic review and meta-analysis.

OBJECTIVE: To evaluate the prognostic impact of the EGF receptor (EGFR) pathway molecules and assess their clinical usefulness. METHODS: We conducted a systematic review. Pubmed and EMBASE were searched January 2014. The prognostic relevance of EGFR, JAK, PI3K, PIK3CA, STAT3, STAT5, PTEN, AKT, mTOR, GRB2, SOS, RAF, RAS, MAPK, ERK, MEK and CCND1 in nasopharyngeal carcinoma was assessed. The outcomes considered were overall survival, disease-free survival and tumor-node-metastasis stage. Twenty-two studies were included. Risk of bias was evaluated. Meta-analysis for which pooled hazard ratios and 95% CIs were calculated. CONCLUSION: EGFR overexpression predicts a worse overall survival and disease-free survival in nasopharyngeal carcinoma, but no specific causal pathway molecule could be identified.

Clinical relevance of copy number profiling in oral and oropharyngeal squamous cell carcinoma.

Current conventional treatment modalities in head and neck squamous cell carcinoma (HNSCC) are nonselective and have shown to cause serious side effects. Unraveling the molecular profiles of head and neck cancer may enable promising clinical applications that pave the road for personalized cancer treatment. We examined copy number status in 36 common oncogenes and tumor suppressor genes in a cohort of 191 oropharyngeal squamous cell carcinomas (OPSCC) and 164 oral cavity squamous cell carcinomas (OSCC) using multiplex ligation probe amplification. Copy number status was correlated with human papillomavirus (HPV) status in OPSCC, with occult lymph node status in OSCC and with patient survival. The 11q13 region showed gain or amplifications in 59% of HPV-negative OPSCC, whereas this amplification was almost absent in HPV-positive OPSCC. Additionally, in clinically lymph node-negative OSCC (Stage I-II), gain of the 11q13 region was significantly correlated with occult lymph node metastases with a negative predictive value of 81%. Multivariate survival analysis revealed a significantly decreased disease-free survival in both HPV-negative and HPV-positive OPSCC with a gain of Wnt-induced secreted protein-1. Gain of CCND1 showed to be an independent predictor for worse survival in OSCC. These results show that copy number aberrations, mainly of the 11q13 region, may be important predictors and prognosticators which allow for stratifying patients for personalized treatment of HNSCC.

Differences in methylation profiles between HPV-positive and HPV-negative oropharynx squamous cell carcinoma: a systematic review.

Oropharyngeal squamous cell carcinoma (OPSCC) is associated with human papillomavirus (HPV). HPV-positive OPSCC is considered a distinct molecular entity with a better prognosis than HPV-negative cases of OPSCC. However, the exact pathogenic mechanisms underlying the differences in clinical and molecular behavior between HPV-positive and HPV-negative OPSCC remain poorly understood. Epigenetic events play an important role in the development of cancer. Hypermethylation of DNA in promoter regions and global hypomethylation are 2 epigenetic changes that have been frequently observed in human cancers. It is suggested that heterogeneous epigenetic changes play a role in the clinical and biological differences between HPV-positive and HPV-negative tumors. Unraveling the differences in methylation profiles of HPV-associated OPSCC may provide for promising clinical applications and may pave the road for personalized cancer treatment. This systematic review aims to assess the current state of knowledge regarding differences in promoter hypermethylation and global methylation between HPV-positive and HPV-negative OPSCC.

HPV-positive oropharyngeal squamous cell carcinoma is associated with TIMP3 and CADM1 promoter hypermethylation.

Oropharyngeal squamous cell carcinoma (OPSCC) is associated with human papillomavirus (HPV) in a proportion of tumors. HPV-positive OPSCC is considered a distinct molecular entity with a prognostic advantage compared to HPV-negative cases. Silencing of cancer-related genes by DNA promoter hypermethylation may play an important role in the development of OPSCC. Hence, we examined promoter methylation status in 24 common tumor suppressor genes in a group of 200 OPSCCs to determine differentially methylated genes in HPV-positive versus HPV-negative primary OPSCC. Methylation status was correlated with HPV status, clinical features, and patient survival using multivariate methods. Additionally, methylation status of 16 cervical squamous cell carcinomas (SCC) was compared with HPV-positive OPSCC. Using methylation-specific probe amplification, HPV-positive OPSCC showed a significantly higher cumulative methylation index (CMI) compared to HPV-negative OPSCC (P=0.008). For the genes CDH13, DAPK1, and RARB, both HPV-positive and HPV-negative OPSCC showed promoter hypermethylation in at least 20% of the tumors. HPV status was found to be an independent predictor of promoter hypermethylation of CADM1 (P < 0.001), CHFR (P = 0.027), and TIMP3 (P < 0.001). CADM1 and CHFR showed similar methylation patterns in OPSCC and cervical SCC, but TIMP3 showed no methylation in cervical SCC in contrast to OPSCC. Methylation status of neither individual gene nor CMI was associated with survival. These results suggest that HPV-positive tumors are to a greater extent driven by promotor hypermethylation in these tumor suppressor genes. Especially CADM1 and TIMP3 are significantly more frequently hypermethylated in HPV-positive OPSCC and CHFR in HPV-negative tumors.

Surgical instrument tracking optimizes trans-sphenoidal endoscopic treatment of petrous apex cholesterol granuloma.

During endoscopic trans-sphenoidal treatment of petrous apex cholesterol granuloma, the challenge for the surgeon is to drill the posterior wall of the sphenoid sinus to reach the lesion while attempting to avoid the internal carotid artery (ICA). A refined neuronavigation technique is presented that diminishes bonework needed for exposure and marsupialization, and simultaneously minimizes risks of accidental harm to the ICA. The technique utilizes real-time intraoperative instrument tracking of a drill, enabling safe creation of a direct canal toward the cyst just medial to the paraclival ICA and of a curette for entirely image-guided marsupialization of the cyst's deep areas through the canal.

Gastric conduit resection and jejunal interposition for recurrent esophageal cancer.

We describe the case of a 58-year-old man with recurrent adenocarcinoma at the site of an esophagogastrostomy that we treated by radical surgical resection and jejunal interposition. Oral intake was started on the 6th postoperative day and the patient was discharged on the 11th postoperative day. Seven months after the surgical procedure no signs of tumor recurrence were detected. Resection of localized (recurrent) esophageal cancer may well be a valuable treatment option and is therefore an interesting therapeutic option in patients with recurrent disease. However this needs to be investigated in a randomized controlled trial.