Conserved stromal-immune cell circuits secure B cell homeostasis and function.

B cell zone reticular cells (BRCs) form stable microenvironments that direct efficient humoral immunity with B cell priming and memory maintenance being orchestrated across lymphoid organs. However, a comprehensive understanding of systemic humoral immunity is hampered by the lack of knowledge of global BRC sustenance, function and major pathways controlling BRC-immune cell interactions. Here we dissected the BRC landscape and immune cell interactome in human and murine lymphoid organs. In addition to the major BRC subsets underpinning the follicle, including follicular dendritic cells, PI16+ RCs were present across organs and species. As well as BRC-produced niche factors, immune cell-driven BRC differentiation and activation programs governed the convergence of shared BRC subsets, overwriting tissue-specific gene signatures. Our data reveal that a canonical set of immune cell-provided cues enforce bidirectional signaling programs that sustain functional BRC niches across lymphoid organs and species, thereby securing efficient humoral immunity.

PI16+ reticular cells in human palatine tonsils govern T cell activity in distinct subepithelial niches.

Fibroblastic reticular cells (FRCs) direct the interaction and activation of immune cells in discrete microenvironments of lymphoid organs. Despite their important role in steering innate and adaptive immunity, the age- and inflammation-associated changes in the molecular identity and functional properties of human FRCs have remained largely unknown. Here, we show that human tonsillar FRCs undergo dynamic reprogramming during life and respond vigorously to inflammatory perturbation in comparison to other stromal cell types. The peptidase inhibitor 16 (PI16)-expressing reticular cell (PI16+ RC) subset of adult tonsils exhibited the strongest inflammation-associated structural remodeling. Interactome analysis combined with ex vivo and in vitro validation revealed that T cell activity within subepithelial niches is controlled by distinct molecular pathways during PI16+ RC-lymphocyte interaction. In sum, the topological and molecular definition of the human tonsillar stromal cell landscape reveals PI16+ RCs as a specialized FRC niche at the core of mucosal immune responses in the oropharynx.

Prediction of extranodal extension in oropharyngeal cancer patients and carcinoma of unknown primary: value of metabolic tumor imaging with hybrid PET compared with MRI and CT.

OBJECTIVES: The aim of this study was to investigate the value of metabolic tumor imaging using hybrid PET for the preoperative detection of extranodal extension (ENE) in lymph node metastases of oropharyngeal squamous cell carcinoma (OPSCC). METHODS: We performed a retrospective analysis of a consecutive cohort of patients with OPSCC treated with primary surgery with or without adjuvant (chemo-) radiotherapy at the Kantonsspital Sankt-Gallen and the University Hospital Zurich, Switzerland, from 2010 until 2019. Hybrid PET was compared to conventional cross-sectional imaging with MRI and CT. Histopathological presence of ENE of neck dissection specimen served as gold standard. RESULTS: A total number of 234 patients were included in the study, 95 (40.6%) of which had pathological ENE (pENE). CT has a good specificity with 93.7%; meanwhile, MRI was the most sensitive diagnostic method (72.0%). The nodal metabolic tumor parameters (SUVmax, TLG, MTV) were significantly higher in patients with positive ENE (p < 0.001 for all three parameters) than in patients with negative ENE (p < 0.001, for all three parameters). CONCLUSIONS: CT achieved the best specificity, while MRI had the best sensitivity to detect ENE. Nodal metabolic tumor parameters differed significantly between ENE-positive/negative and p16-positive/negative patients. Hence, quantitative data obtained by metabolic imaging might predict presence of ENE and, therefore, could be helpful in customizing therapy management.

Prevalence of Transcriptionally Active HPV Infection in Tumor-Free Oropharyngeal Tissue of OPSCC-Patients.

Objectives: The natural history of HPV-related oropharyngeal squamous cell carcinoma (OPSCC) is still largely unknown. Since reports of second primary tumors (SPTs) in patients with HPV-related OPSCCs are increasing, a multifocal HPV infection, hinting a «virus-induced field effect¼, has been hypothesized. This study aimed to investigate the HPV-prevalence in normal appearing oropharyngeal tissue in patients with OPSCCs. Materials and Methods: 49 OPSCC patients undergoing panendoscopy were prospectively enrolled. Tumor specimens and biopsies of normal appearing oropharyngeal tissue adjacent to and distant from the index OPSCC underwent histopathological examination, p16INK4A immunohistochemical staining, HPV DNA and mRNA-detection. Patient characteristics and follow-up data on SPTs were obtained. Results: 26 of 49 (53%) OPSCC were positive for HPV DNA and p16INK4A. HPV mRNA was detected in 23 of 26 (88%) of these tumor samples. HPV DNA was detected in 36% adjacent mucosa and in 17% distant mucosa samples and only in patients with an HPV-related index OPSCC. HPV mRNA could not be detected in tumor-free distant and adjacent mucosa samples. No evidence of association between HPV detection in normal appearing mucosa and development of second primary tumors was found. Conclusions: HPV was detectable but not transcriptionally active in adjacent/distant tumor-free oropharyngeal tissue. This suggests that a multifocal HPV infection, hinting a «virus-induced fielcd cancerization¼, may not be pertaining to HPV-related OPSCC.

Distinct microbial communities colonize tonsillar squamous cell carcinoma.

Squamous cell carcinoma of the tonsil is one of the most frequent cancers of the oropharynx. The escalating rate of tonsil cancer during the last decades is associated with the increase of high risk-human papilloma virus (HR-HPV) infections. While the microbiome in oropharyngeal malignant diseases has been characterized to some extent, the microbial colonization of HR-HPV-associated tonsil cancer remains largely unknown. Using 16S rRNA gene amplicon sequencing, we have characterized the microbiome of human palatine tonsil crypts in patients suffering from HR-HPV-associated tonsil cancer in comparison to a control cohort of adult sleep apnea patients. We found an increased abundance of the phyla Firmicutes and Actinobacteria in tumor patients, whereas the abundance of Spirochetes and Synergistetes was significantly higher in the control cohort. Furthermore, the accumulation of several genera such as Veillonella, Streptococcus and Prevotella_7 in tonsillar crypts was associated with tonsil cancer. In contrast, Fusobacterium, Prevotella and Treponema_2 were enriched in sleep apnea patients. Machine learning-based bacterial species analysis indicated that a particular bacterial composition in tonsillar crypts is tumor-predictive. Species-specific PCR-based validation in extended patient cohorts confirmed that differential abundance of Filifactor alocis and Prevotella melaninogenica is a distinct trait of tonsil cancer. This study shows that tonsil cancer patients harbor a characteristic microbiome in the crypt environment that differs from the microbiome of sleep apnea patients on all phylogenetic levels. Moreover, our analysis indicates that profiling of microbial communities in distinct tonsillar niches provides microbiome-based avenues for the diagnosis of tonsil cancer.

Impact of the new TNM Staging System (8th edition) on oral tongue cancers.

AIM OF THE STUDY: For tumours of the oral tongue, the most recent 8th edition of the AJCC/UICC staging system has introduced depth of infiltration (DOI) as a novel parameter. With this study we wanted to investigate its impact regarding this risk stratification compared with the preceding 7th edition. METHODS: Between 2008 and 2017, 161 patients of two tertiary referral centres in Switzerland (Kantonsspital St. Gallen and University Hospital Zurich) with T1 N0 or T2 N0 tongue cancers were enrolled in this study. The primary tumours were restaged according to the 8th edition of the TNM classification. Kaplan-Meier curves for overall and disease-specific survival were calculated. RESULTS: According to the 7th edition, of the 161 patients, 102 were staged after surgery as pT1 (stage I) and 59 as pT2 (stage II). According to the 8th edition, 36 patients (22.4%) were re-staged to a higher stage. Of these 36 patients, 8 (22.2%) experienced a recurrence, and 9 (25%) died. In the remaining, not re-staged group, 20 patients (16.0%) experienced a recurrence (p = 0.55) and 14 (11.2%) died (p = 0.025*). The 7th edition showed a statistically significant difference between pT1 and pT2 tumours for overall survival (p = 0.025), but not for disease-specific survival (p = 0.091), whereas the 8th edition was able to well discriminate between pT1, pT2 and pT3 for both overall (pT1 vs pT2, p = 0.016*; pT2 vs pT3, p = 0.031*) and disease-specific survival (pT1 vs pT2, p = 0.037*; pT2 vs pT3, p = 0.023*). CONCLUSION: The recent TNM 8th edition provides a more accurate prediction of overall and disease-specific survival for this subgroup of patients. Hence, a more aggressive treatment should be considered for patients re-staged to pT3 due to depth of infiltration.

Development and Validation of a Prognostic Model of Swallowing Recovery and Enteral Tube Feeding After Ischemic Stroke.

Importance: Predicting the duration of poststroke dysphagia is important to guide therapeutic decisions. Guidelines recommend nasogastric tube (NGT) feeding if swallowing impairment persists for 7 days or longer and percutaneous endoscopic gastrostomy (PEG) placement if dysphagia does not recover within 30 days, but, to our knowledge, a systematic prediction method does not exist. Objective: To develop and validate a prognostic model predicting swallowing recovery and the need for enteral tube feeding. Design, Setting, and Participants: We enrolled participants with consecutive admissions for acute ischemic stroke and initially severe dysphagia in a prospective single-center derivation (2011-2014) and a multicenter validation (July 2015-March 2018) cohort study in 5 tertiary stroke referral centers in Switzerland. Exposures: Severely impaired oral intake at admission (Functional Oral Intake Scale score <5). Main Outcomes and Measures: Recovery of oral intake (primary end point, Functional Oral Intake Scale ≥5) or return to prestroke diet (secondary end point) measured 7 (indication for NGT feeding) and 30 (indication for PEG feeding) days after stroke. Results: In total, 279 participants (131 women [47.0%]; median age, 77 years [interquartile range, 67-84 years]) were enrolled (153 [54.8%] in the derivation study; 126 [45.2%] in the validation cohort). Overall, 64% (95% CI, 59-71) participants failed to recover functional oral intake within 7 days and 30% (95% CI, 24-37) within 30 days. Prolonged swallowing recovery was independently associated with poor outcomes after stroke. The final prognostic model, the Predictive Swallowing Score, included 5 variables: age, stroke severity on admission, lesion location, initial risk of aspiration, and initial impairment of oral intake. Predictive Swallowing Score prediction estimates ranged from 5% (score, 0) to 96% (score, 10) for a persistent impairment of oral intake on day 7 and from 2% to 62% on day 30. Model performance in the validation cohort showed a discrimination (C statistic) of 0.84 (95% CI, 0.76-0.91; P < .001) for predicting the recovery of oral intake on day 7 and 0.77 (95% CI, 0.67-0.87; P < .001) on day 30, and a discrimination for a return to prestroke diet of 0.94 (day 7; 95% CI, 0.87-1.00; P < .001) and 0.71 (day 30; 95% CI, 0.61-0.82; P < .001). Calibration plots showed high agreement between the predicted and observed outcomes. Conclusions and Relevance: The Predictive Swallowing Score, available as a smartphone application, is an easily applied prognostic instrument that reliably predicts swallowing recovery. It will support decision making for NGT or PEG insertion after ischemic stroke and is a step toward personalized medicine.

Preoperative assessment of CD44-mediated depth of invasion as predictor of occult metastases in early oral squamous cell carcinoma.

BACKGROUND: Epithelial-mesenchymal transition and cancer stem-like cells (CSC) have been linked to increased metastatic potential. We evaluated the prognostic impact of CD44, a CSC biomarker, on depth of invasion (DOI) and outcome in oral squamous cell carcinoma (OSCC). METHODS: Using a multivariable logistic regression model, we evaluated in early OSCCs the relationship between CD44 expression at the invasive tumor front, DOI, sentinel lymph node biopsy, extension of nodal involvement, and survival. We also assessed whether CT and/or MRI could predict DOI preoperatively. RESULTS: CD44 expression was associated with increased DOI (P = .018), worse disease-specific survival (P = .041) but not with positive sentinel lymph node biopsy (P > .05). Each millimeter increase in DOI was associated with a 31.1% higher risk for positive sentinel lymph node biopsy (95% CI: 5.8%-62.4%, P = .013) and with higher metastatic ratio (P = .015). Preoperative estimation of DOI by CT and/or MRI and histopathological DOI showed a strong correlation (P < .0001). CONCLUSIONS: CD44 expression correlates with DOI, which predicts occult lymph node metastasis. Preoperative CT and/or MRI provides an accurate estimation of histopathological DOI. Both pieces of information gained preoperatively can help surgeons tailor their operation in regard to the surgical management of the neck.

Comparison of contemporary staging systems for oropharynx cancer in a surgically treated multi-institutional cohort.

BACKGROUND: Between the publication of the Union of International Cancer Control staging system (UICC) 7th and 8th editions, other staging algorithms for oropharyngeal squamous cell carcinoma (OPSCC) were proposed from Radiation Therapy Oncology Group (RTOG), MD Anderson Cancer Center (MDACC), and Yale University. METHODS: With C-statistics, the above-mentioned five staging algorithms were compared for overall and relapse-free survival endpoints in a multi-institutional cohort of OPSCC cases (n = 338) treated with primary surgery. RESULTS: Pathological UICC 8th ed yielded the highest C-indexes in the entire cohort and in the HPV- subset, whereas MDACC was superior for HPV+ OPSCC. RTOG was the simplest and holistic algorithm with a noninferior discriminatory power. CONCLUSION: UICC 8th ed, MDACC, and RTOG offer moderate and comparable efficacy for staging in this OPSCC patient cohort undergoing surgical treatment. Notable discrepancy between clinical and pathological UICC 8th ed algorithms poses potential concerns in diagnosis, treatment, research, and data management.

Prognostic significance of cell cycle-associated proteins p16, pRB, cyclin D1 and p53 in resected oropharyngeal carcinoma.

BACKGROUND: Human papillomavirus (HPV)-related oropharyngeal squamous cell carcinoma (OPSCC) has an improved outcome and may allow for treatment de-escalation. High-risk HPV (HR-HPV) infection is associated with deregulated expression of the cell cycle-associated proteins p16INK4, pRB, cyclin D1 and p53. The objective of this study was to assess cell cycle proteins as potential surrogate markers for HR-HPV DNA testing to identify OPSCC with favorable prognosis after resection. METHODS: Tissue microarray cores of 313 surgically treated OPSCC were stained for p16INK4a, pRB, cyclin D1 and p53 using immunohistochemistry. Protein expression was scored as high or low based on the proportion of positive carcinoma cells. Tumor samples were analysed for HR-HPV DNA with polymerase chain reaction-based testing. Associations between cell cycle protein expression and HR-HPV DNA status were evaluated by calculating sensitivity, specificity, predictive values, and diagnostic odds ratios (DOR). Kaplan-Meier and Cox regression analysis were applied to evaluate associations between cell cycle protein expression and patient outcome. RESULTS: High expression of p16INK4a, cyclin D1, pRB and p53 in tumor cells were observed in 51.8%, 51.4%, 41.9% and 33.5% of OPSCC, respectively. HR-HPV DNA positive were 158/313 (50.5%) tumor samples (HPV16: 147, HPV18: 1, HPV33: 5, HPV35: 2, HPV56: 2, and HPV59: 1). P16INK4a showed a higher DOR to predict HR-HPV DNA positivity than pRB, cyclin D1 and p53. Both the p16INK4a/pRB and the p16INK4a/pRB/cyclin D1/p53 signatures had lower DOR than p16INK4a alone. Improved 5-year overall and disease-specific survival were associated with HR-HPV DNA positivity, high p16INK4a, low pRB, low cyclin D1, and low p53 expression. Associations with improved outcome were also observed for the marker combinations high p16INK4a/positive HR-HPV DNA, high p16INK4a/low pRB and high p16INK4a/low pRB/low cyclin D1/low p53. In a multivariate analysis adjusted for age, smoking history, pT and pN category, high p16INK4a expression showed the lowest hazard ratio for death. CONCLUSIONS: High p16INK4a expression is a reliable marker for survival prognostication in surgically treated OPSCC patients. Protein signatures including the pRB, cyclin D1 and p53 proteins do not further increase the prognostic performance of p16INK4a as a single marker.

Maximum Standardized Uptake Value (SUVmax) of Primary Tumor Predicts Occult Neck Metastasis in Oral Cancer.

The aim of this study was to investigate the predictability of occult lymph node metastasis using maximum standardized uptake value (SUVmax) in the primary tumor on pre-treatment 18-fluorodeoxyglucose positron emission tomography FDG-PET in oral squamous cell carcinoma (OSCC) patients who were clinically node negative (cN0) before surgery. A retrospective analysis of all patients treated at the University Hospital Zurich from 2007 to 2016 for OSCC with available pre-therapeutic FDG-PET was performed. We assessed the correlation of SUVmax of the primary tumors with the presence of occult nodal disease in the neck dissection specimen (pN+). The study included a total of 71 patients. In the nodal negative group (cN0/pN0), the median SUVmax of primary tumors was 9.0 (interquartile range (IQR) 7.4-13.9), while it was 11.4 (IQR 9.9-15.7) in the occult metastatic group (cN0/pN+). The difference was statistically significant (independent samples median test, P = 0.037). In a multivariable model, the only independent predictor of occult metastatic disease for cN0 patients was a SUVmax ≥ 9.5 (P = 0.028). Further, primary tumors with SUVmax ≥ 9.5 had a significantly higher risk of local recurrence (Log rank test, P = 0.020). In conclusion, we showed that higher SUVmax (≥9.5) of the primary tumor is associated with higher occurrence of occult metastatic nodal disease and worse local survival. High SUVmax of the primary tumor may encourage clinicians towards more aggressive treatment.

Impact of human papillomavirus on outcome in patients with oropharyngeal cancer treated with primary surgery.

BACKGROUND: Knowledge about prognostic factors in surgically treated patients with oropharyngeal squamous cell carcinoma (SCC) is limited. The purpose of this study was to identify influential factors on survival in a large cohort of patients with surgically treated oropharyngeal SCC. METHODS: Retrospective analysis of survival estimates in patients with surgically treated oropharyngeal SCC using tumoral positivity for human papillomavirus (HPV) and risk-of-death categories according to a study from 2010 as stratification factors. RESULTS: The 5-year overall survival (OS) and disease-specific survival (DSS) rates after surgery alone were higher in HPV-associated oropharyngeal SCC (OS 80% vs 62%; P = .01; DSS 92% vs 76%; P = .03). Patients in the low-risk category had higher survival rates (OS 91%; DSS 99%) than patients in the intermediate-risk group (OS 63%; DSS 83%), and high-risk group (OS 61%; DSS 75%). CONCLUSION: Nonsmokers with HPV-positive oropharyngeal SCC have a better prognosis than smokers with HPV-positive oropharyngeal SCC and also than patients with HPV-negative tumors when treated by surgery alone.

Evaluation of type-specific antibodies to high risk-human papillomavirus (HPV) proteins in patients with oropharyngeal cancer.

OBJECTIVES: High risk human papillomavirus (HR-HPV) infection leads to a subgroup of oropharyngeal cancer (OPSCC) characterized by improved treatment response. However an universally accepted definition of an HR-HPV-attributable cancer is lacking. METHODS: Detailed, type-specific HPV antibody responses were analyzed by multiplex serology in HR-HPV-attributable OPSCC patients, defined by p16INK4A overexpression and HR-HPV DNA detection by PCR amplification and sequencing. RESULTS: Fifty patients were prospectively enrolled. 26/50 (52%) tumor samples were positive for both p16INK4A expression and HR-HPV DNA (22 HPV16, 4 HPV33). Seropositivity was present in 26/26 HPV-attributable OPSCC and one p16INK4A-positive/HPV DNA-negative case. The sensitivity and specificity to diagnose an HR-HPV-attributable tumor was 100% and 96%, respectively for anti-E6 reactivity, 82% and 100%, respectively for anti-E2 reactivity, and clearly lower for anti-E7, anti-E1, anti-E4 and anti-L1-reactivity. 3yr-overall (OS) and disease specific survival (DSS) was higher in patients with HR-HPV-attributable tumors (OS 88% vs 64%, p=0.02; DSS 90% vs 80%, p=0.07) and seropositive patients (OS 88% vs 62%, p=0.01; DSS 92% vs 78%, p=0.05) than HR-HPV-negative or seronegative patients. CONCLUSIONS: Detection of HR-HPV type-specific antibodies highly correlated with HPV-attributable OPSCC and was associated with better survival. HR-HPV antibodies are promising diagnostic, prognostic and potentially screening markers in HR-HPV-attributable OPSCC.

Sentinel Node in Oral Cancer: The Nuclear Medicine Aspects. A Survey from the Sentinel European Node Trial.

PURPOSE: Nuclear imaging plays a crucial role in lymphatic mapping of oral cancer. This evaluation represents a subanalysis of the original multicenter SENT trial data set, involving 434 patients with T1-T2, N0, and M0 oral squamous cell carcinoma. The impact of acquisition techniques, tracer injection timing relative to surgery, and causes of false-negative rate were assessed. METHODS: Three to 24 hours before surgery, all patients received a dose of Tc-nanocolloid (10-175 MBq), followed by lymphoscintigraphy. According to institutional protocols, all patients underwent preoperative dynamic/static scan and/or SPECT/CT. RESULTS: Lymphoscintigraphy identified 723 lymphatic basins. 1398 sentinel lymph nodes (SNs) were biopsied (3.2 SN per patient; range, 1-10). Dynamic scan allowed the differentiation of sentinel nodes from second tier lymph nodes. SPECT/CT allowed more accurate anatomical localization and estimated SN depth more efficiently. After pathological examination, 9.9% of the SN excised (138 of 1398 SNs) showed metastases. The first neck level (NL) containing SN+ was NL I in 28.6%, NL IIa in 44.8%, NL IIb in 2.8%, NL III in 17.1%, and NL IV in 6.7% of positive patients. Approximately 96% of positive SNs were localized in the first and second lymphatic basin visualized using lymphoscintigraphy. After neck dissection, the SN+ was the only lymph node containing metastasis in approximately 80% of patients. CONCLUSIONS: Best results were observed using a dynamic scan in combination with SPECT/CT. A shorter interval between tracer injection, imaging, and surgery resulted in a lower false-negative rate. At least 2 NLs have to be harvested, as this may increase the detection of lymphatic metastases.

Technique for reliable sentinel node biopsy in squamous cell carcinomas of the floor of mouth.

BACKGROUND: Applicability of sentinel node biopsy (SNB) for tumors of the floor of mouth (FOM) is controversial. METHODS: Prospective evaluation of the accuracy of gamma-probe-guided superselective neck dissection of the preglandular triangle of level I for SNB in FOM squamous cell carcinoma (SCC) after preoperative lymphoscintigraphy and single photon emission CT (SPECT)/CT. RESULTS: In total, 22 sentinel lymph nodes were harvested in level I. Eight of 22 (36%) were seen on lymphoscintigraphy and 11 (50%) on SPECT/CT. Eleven sentinel lymph nodes (50%) were only detected intraoperatively. In unilateral tumors, 20% were contralateral, and, in midline tumors, 93% showed bilateral level I sentinel lymph nodes. The false-negative rate was 8.3%, the negative predictive value was 96.4%, and the false-omission rate was 3.6%. The ultimate neck control rate, including salvage treatment, was 100%. CONCLUSION: SNB in FOM can be reliably performed using the presented surgical technique. Level I exploration, bilaterally in midline tumors, is mandatory irrespective of the visualization of sentinel lymph nodes in other levels. © 2016 Wiley Periodicals, Inc. Head Neck 38: 1367-1372, 2016.

Endoscopic dilation of complete oesophageal obstructions with a combined antegrade-retrograde rendezvous technique.

AIM: To investigate the combined antegrade-retrograde endoscopic rendezvous technique for complete oesophageal obstruction and the swallowing outcome. METHODS: This single-centre case series includes consecutive patients who were unable to swallow due to complete oesophageal obstruction and underwent combined antegrade-retrograde endoscopic dilation (CARD) within the last 10 years. The patients' demographic characteristics, clinical parameters, endoscopic therapy, adverse events, and outcomes were obtained retrospectively. Technical success was defined as effective restoration of oesophageal patency. Swallowing success was defined as either percutaneous endoscopic gastrostomy (PEG)-tube independency and/or relevant improvement of oral food intake, as assessed by the functional oral intake scale (FOIS) (≥ level 3). RESULTS: The cohort consisted of six patients [five males; mean age 71 years (range, 54-74)]. All but one patient had undergone radiotherapy for head and neck or oesophageal cancer. Technical success was achieved in five out of six patients. After discharge, repeated dilations were performed in all five patients. During follow-up (median 27 mo, range, 2-115), three patients remained PEG-tube dependent. Three of four patients achieved relevant improvement of swallowing (two patients: FOIS 6, one patient: FOIS 7). One patient developed mediastinal emphysema following CARD, without a need for surgery. CONCLUSION: The CARD technique is safe and a viable alternative to high-risk blind antegrade dilation in patients with complete proximal oesophageal obstruction. Although only half of the patients remained PEG-tube independent, the majority improved their ability to swallow.

Sentinel European Node Trial (SENT): 3-year results of sentinel node biopsy in oral cancer.

PURPOSE: Optimum management of the N0 neck is unresolved in oral cancer. Sentinel node biopsy (SNB) can reliably detect microscopic lymph node metastasis. The object of this study was to establish whether the technique was both reliable in staging the N0 neck and a safe oncological procedure in patients with early-stage oral squamous cell carcinoma. METHODS: An European Organisation for Research and Treatment of Cancer-approved prospective, observational study commenced in 2005. Fourteen European centres recruited 415 patients with radiologically staged T1-T2N0 squamous cell carcinoma. SNB was undertaken with an average of 3.2 nodes removed per patient. Patients were excluded if the sentinel node (SN) could not be identified. A positive SN led to a neck dissection within 3 weeks. Analysis was performed at 3-year follow-up. RESULTS: An SN was found in 99.5% of cases. Positive SNs were found in 23% (94 in 415). A false-negative result occurred in 14% (15 in 109) of patients, of whom eight were subsequently rescued by salvage therapy. Recurrence after a positive SNB and subsequent neck dissection occurred in 22 patients, of which 16 (73%) were in the neck and just six patients were rescued. Only minor complications (3%) were reported following SNB. Disease-specific survival was 94%. The sensitivity of SNB was 86% and the negative predictive value 95%. CONCLUSION: These data show that SNB is a reliable and safe oncological technique for staging the clinically N0 neck in patients with T1 and T2 oral cancer. EORTC Protocol 24021: Sentinel Node Biopsy in the Management of Oral and Oropharyngeal Squamous Cell Carcinoma.

Brush cytology for the detection of high-risk HPV infection in oropharyngeal squamous cell carcinoma.

BACKGROUND: High-risk human papillomavirus (HR-HPV) infection is associated with improved prognosis and a better response to treatment in patients with oropharyngeal squamous cell carcinoma (OPSCC). Brush cytology is a noninvasive method with which to collect cells from the surface of mucosal lesions. The objective of the current study was to assess the performance of OPSCC brush cytology for the detection of HR-HPV. METHODS: Liquid-based brush cytology specimens were prospectively collected during panendoscopy from 51 patients with OPSCC. Cell suspensions were analyzed with Papanicolaou staining, polymerase chain reaction-based HPV DNA testing, and p16 immunostaining. HPV testing and p16 staining were also performed on paired OPSCC biopsy or surgical resection specimens. The detection of HR-HPV DNA alone and the combined positivity for HR-HPV DNA and p16 protein in dysplastic squamous cells were used to calculate accuracy, sensitivity, specificity, and positive and negative predictive values for HR-HPV detection using brush cytology samples. RESULTS: Approximately 96% of OPSCC brush cytology samples (49 of 51 samples) were classified as satisfactory for evaluation. Dysplastic squamous cells were found in 88% of samples (43 of 49 samples). HPV DNA testing was conclusive in 95% of samples (41 of 43 samples) and revealed HR-HPV DNA in approximately 54% of patients (22 of 41 patients) (HPV type 16 in 19 patients and HPV type 33 in 3 patients). Approximately 49% of brush cytology samples (20 of 41 samples) were positive for HR-HPV DNA and p16 expression. The accuracy, sensitivity, specificity, positive predictive value, and negative predictive value of brush cytology to identify HR-HPV DNA-positive and p16-positive OPSCC samples were 88%, 83%, 94%, 95%, and 81%, respectively. CONCLUSIONS: Brush cytology appears to be a valid approach with which to determine the HR-HPV status of patients with OPSCC.

Impact of clinical risk scores and BRAF V600E mutation status on outcome in papillary thyroid cancer.

BACKGROUND: To evaluate the relationship between the BRAF V600E mutation and clinicopathologic parameters and to assess the impact of the BRAF V600E mutation and established risk scores on survival in patients with papillary thyroid carcinoma (PTC). METHODS: Retrospective analysis of a consecutive, single-institutional cohort of patients with PTC larger than 1 cm. Clinical risk scores according to the Metastases, Age, Completeness of Resection, Invasion, Size (MACIS), European Organisation for Research and Treatment of Cancer (EORTC), and tumor, node, metastases (TNM) scoring systems were determined. BRAF exon 15 mutation analysis was performed by polymerase chain reaction and Sanger sequencing. RESULTS: BRAF V600E mutations were found in 75/116 (65%) PTC. The rates for 5- and 10-year overall survival (OS), disease-specific survival (DSS), and recurrence-free survival (RFS) were 92% and 87%, 98% and 96%, and 96% and 94%, respectively. Low MACIS scores were associated with longer OS (10 y 95% vs 75%, P = .008), DSS (10 y 100% vs 89%, P = .02) and RFS (100% vs 85%, P = .006). Comparable survival advantages were observed for patients with early EORTC scores and low TNM stage. BRAF V600E mutation status was not associated with clinicopathologic characteristics of aggressive behavior such as extrathyroidal extension, lymph node metastases, higher T-categories, male sex, and greater age. Furthermore, BRAF V600E mutation status was not correlated with clinical risk scores and decreased survival. CONCLUSION: In concordance with other studies, we did not find a negative prognostic impact of a positive BRAF V600E mutation status on survival. In contrast, the risk algorithms MACIS, EORTC score, and TNM stage were associated with impaired prognosis. Therefore, clinical staging systems represent better tools for risk stratification than BRAF V600E mutation status.

Zenker's diverticulum: outcome of endoscopic surgery is dependent on the intraoperative exposure.

The purpose of the present study is to evaluate long-term outcome and patients' satisfaction after endoscopic therapy of Zenker's diverticulum (ZD) and to analyze the results of the stapler technique in comparison with the application of the carbon dioxide (CO2) laser. A retrospective cohort study with outcome analysis of patients undergoing endoscopic cricopharyngeal myotomy with either stapler or CO2 laser between October 2000 and December 2010 by a single surgeon was performed. Patient's medical charts were reviewed with respect to symptoms before intervention, intra and post operative complications, reasons for the choice of endoscopic technique, and postoperative relief of symptoms. Long-term follow-up was acquired by a standardized self-assessment questionnaire. Seventy-four patients (51 men, 23 women) with a median age at operation of 74 years (range 45-93 years) were enrolled in this study. Forty-five patients underwent endoscopic repair of a ZD with stapler, 29 patients with CO2 laser. The mean follow-up was 4.7 years. We did not observe significant differences for intra and post operative complications, hospital stay, time until normal oral food intake, need for revision, and long-term subjective symptom relief between the two groups. Overall complication (12 %) and recurrence rate (11 %) for the endoscopic techniques were low. Endoscopic surgery had also a high success rate in recurrence cases (87.5 %). According to our study, the most important factor for the success rate of endoscopic treatment was the intraoperative exposure of the ZD. The endoscopic minimally invasive approach is a safe and effective treatment modality and can be considered as the treatment of choice for primary and recurrent ZD. The intraoperative exposure is decisive for the technique applied and the long-term success.