Dysregulation of ß-catenin, WISP1 and TCF21 predicts disease-specific survival and primary response against radio(chemo)therapy in patients with locally advanced squamous cell carcinomas of the head and neck.

OBJECTIVE: The objective of this study was to determine the prognostic and predictive impact of ß-catenin, TCF21 and WISP1 expression in patients with squamous cell carcinomas of the head and neck who underwent primary radiotherapy or concomitant chemoradiotherapy. STUDY DESIGN: Prospective cohort study. SETTING: University hospital. PARTICIPANTS: Protein expression profiles of ß-catenin, TCF21, WISP1 and p16 were determined by immunohistochemical analyses in tissue samples of 59 untreated patients. Expression was correlated with different outcome parameters. MAIN OUTCOME MEASURES: Impact of TNM classification, grading, sex, age, gender, type of therapy, response to therapy and p16 status on disease-specific (DSS) and disease-free survival (DFS). RESULTS: Patients with high expression of TCF21 were associated with significantly worse disease-specific survival (P = 0.005). In a multivariable analysis, TCF21 was a significant determinant of disease-specific survival. (HR 3.01; P = 0.036). Conversely, low expression of ß-catenin (P = 0.025) and WISP1 (P = 0.037) revealed a better response to radiotherapy. CONCLUSION: Since data show that TCF21 is a prognostic factor for disease-specific survival and WISP1 and ß-catenin are predictive factors for clinical outcome after definitive radiotherapy, further studies are warranted to prove these preliminary but very promising findings.

Impact of anatomic origin of primary squamous cell carcinomas of the nasal cavity and ethmoidal sinus on clinical outcome.

PURPOSE: Since squamous cell carcinomas (SCCs) of the nasoethmoidal complex are rare and aggressive malignancies, the purpose of this study was to evaluate whether anatomic subsites of SCCs of the nasal cavity and ethmoid sinuses affect clinical outcome. METHODS: We retrospectively analyzed data from 47 patients with primary SCCs of the nasal cavity and ethmoid sinuses who were treated at the Department of Otorhinolaryngology, Head and Neck Surgery, Medical University of Vienna, between 1993 and 2018. The impact of anatomic subsites of nasoethmoidal SCCs was evaluated with respect to tumor and nodal classification, disease-free survival (DFS) and disease-specific survival (DSS). RESULTS: Of the 47 cases, 17 SCCs (36.2%) originated from lateral nasal wall followed by 13 (27.7%) tumors of the edge of naris to mucocutaneous junction, 11 (23.4%) SCCs of the nasal septum, 3 tumors of the nasal floor (6.4%) and 3 SCCs of the ethmoid sinuses (6.4%), respectively. SCCs of the nasal septum were associated with significantly higher rates of neck node metastasis (p = 0.007), which represented a significantly worse prognostic factor for DSS (HR 7.87; p < 0.001). Moreover, advanced tumor stage (HR 5.38; p = 0.014) and tumor origin of nasal septum (HR 4.05; p = 0.025) were also significantly worse prognostic factors for DSS. Fourteen patients (29.8%) developed recurrent disease, including eight local (17.0%), five regional (10.6%) and one distant (2.1%) recurrence. Elective neck dissection (ND) was associated with lower (0 vs. 20.0%) but not significantly different regional and distant DFS (p = 0.075). CONCLUSION: Anatomic origin of nasal SCC has significant impact on clinical outcome. SCCs of the nasal septum were associated with higher rates of positive neck nodes and worse outcome.

Minor salivary gland carcinoma: a review of 35 cases.

Minor salivary gland carcinomas represent a heterogeneous group of tumors with broad variation in clinical appearance and histopathology. Clinical data of patients with small salivary gland malignancies were collected from the medical records. Tissue microarray was constructed to determine the expression pattern of 24 proteins in 35 patients with minor salivary gland carcinomas. The choice of markers was based on involvement in neoangiogenesis, cell-to-cell contact, cell-cycle regulation and carcinogenesis. Protein expression data were correlated to patients' clinical data. Overexpression of patched (p = 0.046) and Smo (p = 0.032) was linked to a better overall survival and Glutathione S-transferase π overexpression was linked to prolonged disease-free survival (p = 0.005). Cox-1 (p = 0.035) and VEGFR2 (p = 0.009) were significantly linked to decreased survival for recurrent disease. Bcl-x (84 %), ß-catenin (87 %) and Cox-2 (87 %) were significantly overexpressed in minor salivary gland carcinomas. We have shown that Smo resulted in a better overall survival, whereas Gstπ in improved disease-free survival. VEGFR2 was a prognostic factor for survival after recurrence in patients with minor salivary gland carcinomas. Cyclooxygenase inhibitors and anti-Wnt-1 antibodies might be a potential therapeutic option in an adjuvant setting or for patients with unresectable tumors of the minor salivary glands.

Prognostic significance of lymph node ratio in patients with Merkel cell carcinoma.

Merkel cell carcinoma is a rare and aggressive metastasizing tumor of the skin. Lymph node metastasis is a significant clinical prognostic factor for overall and disease-free survival in patients with Merkel cell carcinoma. A retrospective medical chart review of 12 Merkel cell carcinoma patients was performed. All patients received treatment at the Medical University of Vienna and underwent lymph node dissection between 1994 and 2013. The lymph node ratio was determined by dividing the total number of positive lymph nodes by the entire number of dissected lymph nodes. A positive lymph node ratio was defined as a number >0 and the negative lymph node ratio was defined by zero. The median follow-up was 44 months (range 4-92). A positive lymph node ratio (range 1.00-0.04) was found in 7 (58%) out of 12 patients of whom 5 (71%) died of disease. A negative lymph node ratio was found in 5 (42%) out of 12 patients of whom 2 (40%) patients died of disease. The disease-specific death rate was higher in patients diagnosed with a positive lymph node ratio compared to patients diagnosed with a negative lymph node ratio. Based on these preliminary findings, there might be a prognostic impact of lymph node ratio in patients suffering from Merkel cell carcinoma.

New diagnostic markers in salivary gland tumors.

Parotid gland tumors are a rare and heterogeneous entity. Molecular markers are sparse. The aim of the study was to identify new diagnostic markers in benign and malignant salivary tumors. A tissue microarray was constructed with 158 tumor samples. Expression of 21 tumor antigens involved in tumor cell survival and known for prognostic potential was assessed immunohistochemically in all parotid gland samples. CEA, Cox-1, Cox-2, Sigma, beta-Catenin, WISP-1 and PDGF-beta were differently regulated in benign and malignant parotid tumors. Subsequently, these seven proteins entered the step-wise logistic regression analysis. As a second step, we defined a score for differentiating benign versus malignant parotid lesions: 4*CEA+15*Cox-1+4*Cox-2+4*Sigma+3*PDGF-beta+10*beta-Catenin+14*Wisp1. Sensitivity and specificity of 94 and 83% were reached. Besides routine hematoxylin and eosin staining, definition of new diagnostic markers and subsequently a new diagnostic score are an attempt to create an additional tool for the diagnosis of parotid gland tumors.

A successful intervention to improve conceptual knowledge of medical students who rely on memorization of disclosed items.

Background: The mere memorization of isolated facts without the claim of integrating them is detrimental to the desired learning outcomes in medical education. The current study was conducted within an environment where items from summative assessments are regularly disclosed by the university and consequently collected into an item bank that is shared between students. Within this environment, we aimed to quantify 1) to which extent students use disclosed items for their preparation for the summative exam, 2) a putative mismatch between (isolated factual) knowledge regarding distinct questions from the item bank and conceptual knowledge, and 3) to which extent this mismatch can be ameliorated by a project aiming to steer student learning away from the memorization of isolated facts toward the acquisition of conceptual knowledge. Methods: This steering project in the midst of the first semester consisted of the implementation of an oral exam based on selected learning objectives, preceded by two seminars. After their summative exam at the end of semester, 135 students performed a voluntary exam for study purposes. Here, authentic (i.e., presumably preknown) physiology questions taken from the item bank were used to assess students' ability to 1) recognize the correct answer in a multiple choice (MC) question, 2) recall the answer (short answer), or 3) display conceptual knowledge closely corresponding to the question presented in the other formats. Additionally, students received a questionnaire addressing their learning habits and attitudes. Results: The median reported percentage of learning time for the summative exam exclusively spent with this item bank was 80%. The results of the voluntary exam indicate that students frequently recognize and recall correct answers of included items without displaying knowledge of the underlying concept. Compared to recall of the correct answer, the probability of giving a correct answer regarding the corresponding basal physiologic concept was lower by 47 percentage points (p <0.001) for topics not included in the steering project. Regarding topics included in the steering project, this discrepancy was reduced to 25.5% (p <0.001). Conclusion: The results of this study demonstrate the influence of disclosed items on student learning and learning outcomes and suggest that a carefully implemented assessment is able to improve conceptual knowledge in physiology.

Survival Outcome in True Carcinoma of Unknown Primary (tCUP) with p16 + Cervical Metastasis.

Introduction Age and lymph node ratio have been attributed as independent predictors for survival and recurrence in carcinoma of unknown primary (CUP). Objective The purpose of this study was to analyze the prognostic value of p16 overexpression for CUP in the absence of true primary (TP). Methods The study involved 43 patients who underwent therapeutic lymph node dissection (LND) from 2000 to 2015 after all the diagnostic work up for CUP. Immunohistochemistry for p16 overexpression was performed. Cox proportional hazard regression analysis was used to analyze the prognostic impact on 5-year overall survival (OS) and recurrence-free survival (RFS). Results The male-to-female ratio was 5.1:1, with a median age of 62 years. The clinicopathological data, except for p16 overexpression, did not differ significantly in terms of 5-year OS and RFS. The Cox regression analysis proposed p16 positivity to be an independent prognosticator of regional recurrence-free survival (RRFS) (hazard ratio [HR] 6.180, p = 0.21). The median time to recurrence and death were 10 and 25 months, respectively. Conclusion Cervical metastasis with p16 overexpression is a significant prognostic factor of improved RFS after surgery in CUP. The prognostic significance of lymph node p16 positivity should be further studied.

Prognostic factors in mammary analogue secretory carcinomas of the parotid gland: Systematic review and meta-analysis.

Mammary analogue secretory carcinomas (MASCs) of the parotid gland are considered as low-grade malignancies with good clinical outcome but lacking data regarding prognostic factors. We performed meta-analysis assessing prognostic factors for disease-free survival (DFS) and overall survival (OS) in 256 patients with MASCs of the parotid gland. A total of 73 studies have met the inclusion criteria and 76.3% of patients were seen with T1 and T2 tumors and negative neck nodes. Lymph node metastasis (57.4%) and distant recurrences (46.2%) were particularly found in T4 tumors (p < 0.001). DFS at 5 and 10 years was 77.9% and 47.2% compared to 88.1% and 77.2% for OS at the same time points. Male sex, T3-T4 tumors, and recurrent disease represented independent worse prognosticators for survival outcome. Altogether, parotid gland MASCs show good long-term outcome, but T4 tumors behave significantly more aggressive and require extended treatment strategies along with close follow-ups.

Do Salivary Bypass Tubes Reduce the Risk of Pharyngocutaneous Fistula after Laryngopharyngectomy-A Systematic Review and Meta-Analysis.

To evaluate the effect of salivary bypass tube (SBT) usage on the occurrence of pharyngocutaneous fistula (PCF) in patients after a laryngopharyngectomy, a total of 20 studies, published between 1988 and 2021, were identified including 2946 patients. We performed a meta-analysis assessing the risk of PCF occurrence in patients after SBT application compared to those without. PCF occurred in 26.8% of cases (669/2496) and SBT was applied in 33.0% of patients (820/2483). There was an overall trend towards lower PCF rates when using SBTs (22.2% vs. 35.3%; p = 0.057). We further selected five studies, comprising 580 patients who underwent laryngopharyngectomies, for meta-analysis showing that application of SBT reduced the risk of PCF formation (OR 0.46; 95% CI 0.18-1.18; p = 0.11). The meta-analysis demonstrates a beneficial effect of SBT insertion on PCF formation in patients after laryngopharyngectomy.

A New Classification System to Predict Functional Outcome after Laryngectomy and Laryngopharyngectomy.

(1) Objective: To evaluate long-term functional outcome in patients who underwent primary or salvage total laryngectomy (TL), TL with partial (TLPP), or total pharyngectomy (TLTP), and to establish a new scoring system to predict complication rate and long-term functional outcome; (2) Material and Methods: Between 1993 and 2019, 258 patients underwent TL (n = 85), TLPP (n = 101), or TLTP (n = 72). Based on the extent of tumor resection, all patients were stratified to (i) localization I: TL; II: TLPP; III: TLTP and (ii) surgical treatment (A: primary resection; B: salvage surgery). Type and rate of complication and functional outcome, including oral nutrition, G-tube dependence, pharyngeal stenosis, and voice rehabilitation were evaluated in 163 patients with a follow-up ≥ 12 months and absence of recurrent disease; (3) Results: We found 61 IA, 24 IB, 63 IIA, 38 IIB, 37 IIIA, and 35 IIIA patients. Complications and subsequently revision surgeries occurred most frequently in IIIB cases but rarely in IA patients (57.1% vs. 18%; p = 0.001 and 51.4% vs. 14.8%; p = 0.002), respectively. Pharyngocutaneous fistula (PCF) was the most common complication (33%), although it did not significantly differ among cohorts (p = 0.345). Pharyngeal stenosis was found in 27% of cases, with the highest incidence in IIIA (45.5%) and IIIB (72.7%) patients (p < 0.001). Most (91.1%) IA patients achieved complete oral nutrition compared to only 41.7% in class IIIB patients (p < 0.001). Absence of PCF (odds ratio (OR) 3.29; p = 0.003), presence of complications (OR 3.47; p = 0.004), and no need for pharyngeal reconstruction (OR 4.44; p = 0.042) represented independent favorable factors for oral nutrition. Verbal communication was achieved in 69.3% of patients and was accomplished by the insertion of voice prosthesis in 37.4%. Acquisition of esophageal speech was reached in 31.9% of cases. Based on these data, we stratified patients regarding the extent of surgery and previous treatment into subgroups reflecting risk profiles and expectable functional outcome; (4) Conclusions: The extent of resection accompanied by the need for reconstruction and salvage surgery both carry a higher risk of complications and subsequently worse functional outcome. Both factors are reflected in our classification system that can be helpful to better predict patients' functional outcome.

A Nomogram to Predict the Outcome of Fine Needle Aspiration Cytology in Head and Neck Masses.

Fine needle aspiration cytology (FNAC) is an important diagnostic tool for tumors of the head and neck. However, non-diagnostic or inconclusive results may occur and lead to delay in treatment. The aim of this study was to evaluate the factors that predict a successful FNAC. A retrospective search was performed to identify all patients who received an FNAC at the Department of Otorhinolaryngology, Head and Neck Surgery, Medical University of Vienna. The variables were patients' age and sex, localization and size of the punctured structure, previous radiotherapy, experience of the head and neck surgeon, experience of the pathologist and the FNAC result. Based on these parameters, a nomogram was subsequently created to predict the probability of accurate diagnosis. After performing 1221 FNACs, the size of the punctured lesion (p = 0.0010), the experience of the surgeon and the pathologist (p = 0.00003) were important factors for a successfully procedure and reliable result. FNACs performed in nodes smaller than 20 mm had a significantly worse diagnostic outcome compared to larger nodes (p = 0.0004). In conclusion, the key factors for a successful FNAC are nodal size and the experience of the head and neck surgeon and the pathologist.

ELMO3 - a Negative Prognostic Marker in Minor Salivary Gland Carcinoma.

Engulfment and cell motility 3 protein (ELMO3) is a protein that is involved in cell migration and promotes the remodeling of the cytoskeleton. Moreover, it is described as a prognostic marker in several cancers. The aim of this study was to evaluate ELMO3 expression in patients with minor salivary gland carcinoma. The expression of ELMO3 was examined by immunohistochemistry. The intensity of staining was evaluated and data was correlated to clinical outcome. Forty-six patients with complete clinical data were included into statistical analysis. ELMO3 expression was observed in 85% of the cases. High staining intensity of ELMO3 correlated with a significantly worse disease free survival (p = .0495) and a higher recurrence rate (p = .0071). In conclusion, it is still difficult to predict the clinical outcome of patients with minor salivary gland carcinoma. Evaluation of ELMO3 might serve as a clinical prognostic marker in future.

Elevated levels of circulating endothelial progenitor cells in head and neck cancer patients.

BACKGROUND AND OBJECTIVES: Measurement of circulating endothelial cells (CECs) and progenitor cells (EPCs) has potential as a surrogate marker for monitoring anticancer treatment. This study evaluated the significance of CECs and EPCs in the blood of patients with head and neck squamous cell carcinoma. METHODS: In a prospective trial fresh blood samples from 22 tumor patients and 18 controls were tested using multiparametric flow-cytometry. CECs were defined as CD31(+)/CD146(+) and CD45(-)/7AAD(-). EPCs were defined as CD133(+)/KDR(+) and CD3(-)/CD19(-)/CD33(-)/7AAD(-). RESULTS: Median levels (min/max) of CECs in the tumor group were 2 (0/5) at the time of diagnosis, 1 (0/5) 1 year after therapy and 2 (0/6) in the control cohort. Median levels of EPCs were 5 (1/41) before and 10 (0/21) after treatment in the tumor group compared to 2 (0/7) in the control cohort (P < 0.001 and P = 0.03). CEC and EPC levels showed no apparent correlation with tumor size and response to radiotherapy after 18 months of observation. CONCLUSIONS: In this pilot study CD133(+)/KDR(+) EPCs were significantly elevated in head and neck tumor patients before and after therapy. Our results warrant further studies on the use of EPCs as a surrogate marker for anticancer therapies in these patients.

Survival Outcome in True Carcinoma of Unknown Primary (tCUP) with p16 + Cervical Metastasis

Abstract Introduction Age and lymph node ratio have been attributed as independent predictors for survival and recurrence in carcinoma of unknown primary (CUP). Objective The purpose of this study was to analyze the prognostic value of p16 overexpression for CUP in the absence of true primary (TP). Methods The study involved 43 patients who underwent therapeutic lymph node dissection (LND) from 2000 to 2015 after all the diagnostic work up for CUP. Immunohistochemistry for p16 overexpression was performed. Cox proportional hazard regression analysis was used to analyze the prognostic impact on 5-year overall survival (OS) and recurrence-free survival (RFS). Results The male-to-female ratio was 5.1:1, with a median age of 62 years. The clinicopathological data, except for p16 overexpression, did not differ significantly in terms of 5-year OS and RFS. The Cox regression analysis proposed p16 positivity to be an independent prognosticator of regional recurrence-free survival (RRFS) (hazard ratio [HR] 6.180, p = 0.21). The median time to recurrence and death were 10 and 25 months, respectively. Conclusion Cervical metastasis with p16 overexpression is a significant prognostic factor of improved RFS after surgery in CUP. The prognostic significance of lymph node p16 positivity should be further studied.

Prognostic survival value of retropharyngeal lymph node involvement in sinonasal tumors: A retrospective, descriptive, and exploratory study.

BACKGROUND: Sinonasal carcinomas are rare. The purpose of this study was for us to present our assessment of the effects of retropharyngeal lymph node involvement at diagnosis on patient outcomes. METHODS: Retropharyngeal lymph node involvement in 36 patients with sinonasal carcinoma was determined by radiology at initial presentation. Clinical outcome, in particular, overall survival (OS) and locoregional control, was assessed by Kaplan-Meier analysis and log-rank testing. RESULTS: Retropharyngeal lymph node involvement was associated with statistically significant decreased OS (P = .0066) in the patient collective. In the squamous cell carcinoma (SCC) subgroup (n = 23), decreased OS (P = .0046) and worse locoregional control (P = .0065) were observed. In these patients, decreased OS (P = .0423) and worse locoregional control (P = .0315) were also seen in the advanced tumor subgroup. CONCLUSION: Retropharyngeal lymph node involvement at diagnosis is a significant prognostic factor for decreased OS and locoregional control in sinonasal carcinoma.

Impact of combined treatment with nimesulide and cisplatin on oral carcinoma cells.

BACKGROUND: Despite significant advances in diagnosis and therapy, the rate of survival of patients with oral cancers still remains poor as an appropriate treatment has not been found yet, due to side effects of chemo/radiotherapy. AIM: This study aimed to identify molecular mechanisms of cell death of oral cancer cells caused by treatment with a nonselective Cox-2 inhibitor in combination with a low-dose chemotherapeutic drug. METHODS: Squamous cell carcinoma (SCC) cells SCC9 and SCC25 were subjected to mono- and combination therapy with nimesulide and cisplatin. Fluorescence-activated cell sorting (FACS), immunohistochemistry, high-pressure liquid chromatography (HPLC), microarray gene chips, and isobaric tags for a relative and absolute quantitation (iTRAQ) system were used. RESULTS: Increased numbers of apoptotic and necrotic SCC9/SCC25 cells were detected after combined exposure. ATP levels and the energy charge of SCC9 cells were significantly decreased after both individual and combined treatment. We detected and quantified a responsible gene, keratin 6a, and 540 relevant proteins. In SCC25 cells, ATP levels significantly decreased only after combination therapy. After combined treatment of SCC9 cells, significant upregulation of Histon-H2A/H2B/H4 was found, with a local discovery false rate of 0.003 for Histon-H2A and 0.0027 for Histon-H2B, respectively. CONCLUSION: Compared to the single-drug treatment, combined treatment of the oral cancer cells with nimesulide and cisplatin increases and induces necrosis and apoptosis through different pathways. A significant effect of the cytoplasmic increase was also observed in histones of cell lines SCC9 and SCC25 that were previously treated with combined nimesulide and cisplatin therapy.

Expression of Merkelcell polyomavirus (MCPyV) large T-antigen in Merkel cell carcinoma lymph node metastases predicts poor outcome.

BACKGROUND: The aim of this study was to determine the prevalence of MCPyV in Merkel cell carcinoma (MCC) primaries versus lymph node metastasis and to evaluate possible prognostic factors. METHODS: Samples of MCC primaries and lymph node metastases were stained immunohistochemically for the MCPyV large T-antigen and expression was compared to patients´ clinical outcome. RESULTS: 41 MCC patients were included. 33 (61%) out of 54 specimens were MCPyV-positive in the immunohistochemistry. 15 (47%) out of 32 primary tumors were positive compared to 18 (82%) out of 22 lymph node metastases. Eleven patients with positive polyomavirus expression died from the carcinoma compared to 4 patients without virus expression. Cox regression analysis showed worse disease-free survival in patients with MCPyV compared to virus-negative lymph nodes (p = 0.002). CONCLUSIONS: To our knowledge this is the first study to describe a negative prognostic effect of the MCPyV expression in lymph node metastasis in MCC patients.

Carotid resection and reconstruction for locally advanced head and neck tumors.

Head and neck surgeons hesitate to resect the carotid artery because of the postoperative risk of neurologic sequelae. However, there is no curative therapeutic option for head and neck neoplasms involving the carotid artery, with the exception of complete tumor removal. To evaluate the benefits and risks of carotid revascularization techniques in locally advanced head and neck tumors we performed a retrospective analysis in an institutional, tertiary care medical center. Seven patients (5 males, 2 females) with a median age of 58 years underwent en bloc removal of locally advanced head and neck tumors, including carotid resection and revascularization, in the University of Vienna General Hospital, over a 15-year period. In six patients carotid reconstruction was accomplished by bypass grafting (five autologous grafts, one synthetic graft) and in one patient angiopatchplasty was used. There were no perioperative neurologic complications or deaths. Survival was > 12 months in 5/7 patients; the other 2 patients died within 6 months due to untractable progression of cancer. We conclude that carotid revascularization techniques offer the possibility of better local control for advanced head and neck tumors without additional risks of neuromorbidity or mortality.