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Introduction: Minimal important change estimates (MIC) are useful for interpreting results of clinical research with quality of life (QoL) as an endpoint. For the European Organisation for Research and Treatment of Cancer head and neck cancer module, the EORTC QLQ-HN43, no such thresholds are established., Methods: Head and neck cancer patients under active treatment (n = 503) from 15 countries completed the EORTC QLQ-HN43 three times (t1: before treatment, t2: three months after t1, t3: six months after t1). A subgroup completed a Subjective Significance Questionnaire (SSQ), indicating experienced change from the previous time point in four QoL domains. QoL was assumed to deteriorate after t1 and improve again until t3. The MIC was established using the average of mean differences in SSQ groups (MIC mean ) and estimates based on logistic regressions (MIC predict ). Additionally, minimal detectable changes (MDC) were computed using 0.5 standard deviation and standard error of the mean., Results: For swallowing, speech, dry mouth, and global QoL, the MIC for deterioration were 13, 14, 26, and 10 respectively. The MIC for improvement were 8 (swallowing), 6 (dry mouth), and 5 (global QoL); no MIC for speech improvement can be presented because of insufficient correlation between change score and anchor. The MDC estimates for deterioration were 15, 14, 15, and 11. For improvement, the MDC estimates were 13, 14, 14, and 11., Conclusions: Our results underline that no single MIC or MDC can be applied to all EORTC QLQ-HN43 scales, and that the MIC for deterioration seems larger than those for improvement., Competing Interests: Declaration of Competing Interest Authors declare they have no conflicts of interest., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Importance: Clinicians should understand how patients who were treated with laryngeal cancer surgery think about this later on and what factors may be related with regretting surgery., Objective: To assess variables associated with a positive attitude toward laryngeal cancer surgery., Design, Setting, and Participants: This combination of 2 cohorts, based on patient interviews and questionnaires, was studied in 16 hospitals in Germany. Participants scheduled for laryngeal cancer surgery were enrolled before surgery and followed up until 1 year after surgery. Data collection began on November 28, 2001, and ended on March 15, 2015. Statistical analysis was performed from August 21, 2023, to January 19, 2024., Main Outcomes and Measures: The attitude toward surgery was measured with the Psychosocial Adjustment After Laryngectomy Questionnaire (scores range from 0 to 100, with high scores representing a positive attitude toward the surgery) at 1 year after surgery. In multivariate regression analysis, the following variables were investigated: type of surgery, number of surgeries to the larynx, receipt of radiotherapy and chemotherapy, quality of life, speech intelligibility (objectively measured), age, sex, educational level, employment status, having a partner or not, counseling by patient association, and shared decision-making., Results: Patients (n = 780; mean [SD] age, 60.6 [10.4] years; 701 [90%] male) who had received counseling from the patient association reported a more positive attitude toward surgery (adjusted B = 8.8; 95% CI, 1.0-16.6). Among patients after total laryngectomy, those with a university degree had a less positive attitude toward their surgery (adjusted B = -50.8; 95% CI, -84.0 to -17.6); this result was not observed in patients after partial laryngectomy (adjusted B = -4.8; 95% CI, -15.1 to 5.4). Among patients after partial laryngectomy, the attitude toward surgery was most positive in those who had experienced shared decision-making (mean [SD] questionnaire score, 84 [20] in those without a wish and 83 [20] in those with a wish for shared decision-making). Those who had wished they could decide together with the physician but where this eventually was not experienced expressed the most regret toward surgery (mean [SD] score, 71 [22]). There was no association between attitudes toward surgery and type of surgery (total vs partial laryngectomy) and all other variables tested., Conclusion and Relevance: In this cohort study, most patients with head and neck cancer reported a positive attitude toward surgery, suggesting low levels of decision regret. Counseling by members of patient associations as well as individualized shared decision-making prior to surgery may have a positive impact on decision regret and is advisable in daily practice.

Head and neck cancer (HNC) patients suffer from a range of health-related quality of life (HRQoL) issues, but little is known about their long-term HRQoL. This study explored associations between treatment group and HRQoL at least 5 years' post-diagnosis in HNC survivors. In an international cross-sectional study, HNC survivors completed the European Organization for Research and Treatment of Cancer (EORTC) quality of life core questionnaire (EORTC-QLQ-C30) and its HNC module (EORTC-QLQ-H&N35). Meaningful HRQoL differences were examined between five treatment groups: (a) surgery, (b) radiotherapy, (c) chemo-radiotherapy, (d) radiotherapy ± chemotherapy and neck dissection and (e) any other surgery (meaning any tumour surgery that is not a neck dissection) and radiotherapy ± chemotherapy. Twenty-six sites in 11 countries enrolled 1105 survivors. They had a median time since diagnosis of 8 years, a mean age of 66 years and 71% were male. After adjusting for age, sex, tumour site and UICC stage, there was evidence for meaningful differences (10 points or more) in HRQoL between treatment groups in seven domains (Fatigue, Mouth Pain, Swallowing, Senses, Opening Mouth, Dry Mouth and Sticky Saliva). Survivors who had single-modality treatment had better or equal HRQoL in every domain compared to survivors with multimodal treatment, with the largest differences for Dry Mouth and Sticky Saliva. For Global Quality of Life, Physical and Social Functioning, Constipation, Dyspnoea and Financial Difficulties, at least some treatment groups had better outcomes compared to a general population. Our data suggest that multimodal treatment is associated with worse HRQoL in the long-term compared to single modality., (© 2024 The Authors. International Journal of Cancer published by John Wiley & Sons Ltd on behalf of UICC.)

BACKGROUND: Systemic glucocorticoids are commonly used for primary therapy of idiopathic sudden sensorineural hearing loss (ISSNHL). However, the comparative effectiveness and risk profiles of high-dose over lower-dose regimens remain unknown. METHODS: We randomly assigned patients with sudden hearing loss of greater than or equal to 50 dB within 7 days from onset to receive either 5 days of high-dose intravenous prednisolone at 250 mg/d (HD-Pred), 5 days of high-dose oral dexamethasone at 40 mg/d (HD-Dex), or, as a control, 5 days of oral prednisolone (Pred-Control) at 60 mg/d followed by 5 days of tapering doses. The primary outcome was the change in hearing threshold (pure tone average) in the three most affected contiguous frequencies from baseline to day 30. Secondary outcomes included speech understanding, tinnitus, communication competence, quality of life, hypertension, and insulin resistance. RESULTS: A total of 325 patients were randomly assigned. Mean change in 3PTAmost affected hearing threshold from baseline to 30 days was 34.2 dB (95% CI, 28.4 to 40.0) in the HD-Pred group, 41.4 dB (95% CI, 35.6 to 47.2) in the HD-Dex group, and 41.0 dB (95% CI, 35.2 to 46.8) in the Pred-Control group (P=0.09 for analysis of variance). There were more adverse events related to trial medication in the HD-Pred (n=73) and HD-Dex (n=76) groups than in the Pred-Control group (n=46). CONCLUSIONS: Systemic high-dose glucocorticoid therapy was not superior to a lower-dose regimen in patients with ISSNHL, and it was associated with a higher risk of side effects. (Funded by the Federal Ministry of Education and Research [BMBF]; EudraCT number, 2015‐002602‐36.)

The long-term problems of head and neck cancer survivors (HNCS) are not well known. In a cross-sectional international study aimed at exploring the long-term quality of life in this population, 1114 HNCS were asked to state their two most serious long-term effects. A clinician recorded the responses during face-to-face appointments. A list of 15 example problems was provided, but a free text field was also available. A total of 1033 survivors responded to the question. The most frequent problems were 'dry mouth' (DM) ( n = 476; 46%), 'difficulty swallowing/eating' (DSE) ( n = 408; 40%), 'hoarseness/difficulty speaking' (HDS) ( n = 169; 16%), and 'pain in the head and neck' (PHN) ( n = 142; 14%). A total of 5% reported no problems. Logistic regression adjusted for age, gender, treatment, and tumor stage and site showed increased odds of reporting DM and DSE for chemo-radiotherapy (CRT) alone compared to surgery alone (odds ratio (OR): 4.7, 95% confidence interval (CI): 2.5-9.0; OR: 2.1, CI: 1.1-3.9), but decreased odds for HDS and PHN (OR: 0.3, CI: 0.1-0.6; OR: 0.2, CI: 0.1-0.5). Survivors with UICC stage IV at diagnosis compared to stage I had increased odds of reporting HDS (OR: 1.9, CI: 1.2-3.0). Laryngeal cancer survivors had reduced odds compared to oropharynx cancer survivors of reporting DM (OR: 0.4, CI: 0.3-0.6) but increased odds of HDS (OR: 7.2, CI: 4.3-12.3). This study provides evidence of the serious long-term problems among HNCS.

Purpose: The aim of this study was to explore what methods should be used to determine the minimal important difference (MID) and minimal important change (MIC) in scores for the European Organisation for Research and Treatment of Cancer Head and Neck Cancer Module, the EORTC QLQ-HN43., Methods: In an international multi-centre study, patients with head and neck cancer completed the EORTC QLQ-HN43 before the onset of treatment (t1), three months after baseline (t2), and six months after baseline (t3). The methods explored for determining the MID were: (1) group comparisons based on performance status; (2) 0.5 and 0.3 standard deviation and standard error of the mean. The methods examined for the MIC were patients' subjective change ratings and receiver-operating characteristics (ROC) curves, predictive modelling, standard deviation, and standard error of the mean. The EORTC QLQ-HN43 Swallowing scale was used to investigate these methods., Results: From 28 hospitals in 18 countries, 503 patients participated. Correlations with the performance status were |r|< 0.4 in 17 out of 19 scales; hence, performance status was regarded as an unsuitable anchor. The ROC approach yielded an implausible MIC and was also discarded. The remaining approaches worked well and delivered MID values ranging from 10 to 14; the MIC for deterioration ranged from 8 to 16 and the MIC for improvement from - 3 to - 14., Conclusions: For determining MIDs of the remaining scales of the EORTC QLQ-HN43, we will omit comparisons of groups based on the Karnofsky Performance Score. Other external anchors are needed instead. Distribution-based methods worked well and will be applied as a starting strategy for analyses. For the calculation of MICs, subjective change ratings, predictive modelling, and standard-deviation based approaches are suitable methods whereas ROC analyses seem to be inappropriate., (© 2021. The Author(s).)

Objective: The aim of our study was to examine how different causal attributions in patients with laryngeal cancer are associated with smoking behaviours (smoking cessation rates and amount of cigarettes per day) after partial resection of the larynx., Methods: Multicentre prospective cohort study including 4 interviews: between diagnosis and partial resection of larynx (t1), one week (t2), 3 months (t3) and 12 months (t4) after surgery. Presented in this study are t1 and t4. A total of 134 patients (mean age 62 years, 93% male) were interviewed at t1 and t4 between 2007 and 2013. Key items were causal attribution as well as previous and current smoking behaviour. Patients were grouped according to the subjectively stated causal attribution. Results were analysed descriptively and group as well as mean value comparisons were conducted., Results: Smoking was the most commonly stated causal attribution (43.3%). The quantity of cigarettes decreased significantly by about 6 cigarettes from 17 (range 3-40) to 11 (range 2-30) cigarettes per day in this group (p=0.001). 25% of patients did not recognize a reason for their illness. In longitudinal analyses of all groups of different causal attributions, there was a non-significant decrease in the percentage of smokers., Conclusion: We show that causal attribution does not affect smoking cessation rate significantly in a positive way. But active smokers after PRL reduce their quantity of cigarettes per day significantly. This impact is more noticeable in patients who were able to define a causal attribution. Psycho-oncological care, information services and smoking cessation programs could contribute to this effect by making the causal attribution a subject of discussion., Competing Interests: Die Autorinnen/Autoren geben an, dass kein Interessenkonflikt besteht., (Thieme. All rights reserved.)

The disease and treatment of patients with head and neck cancer can lead to multiple late and long-term sequelae. Especially pain, psychosocial problems, and voice issues can have a high impact on patients' health-related quality of life. The aim was to show the feasibility of implementing an electronic Patient-Reported Outcome Measure (PROM) in patients with head and neck cancer (HNC). Driven by our department's intention to assess Patient-Reported Outcomes (PRO) based on the International Classification of Functioning during tumor aftercare, the program "OncoFunction" has been implemented and continuously refined in everyday practice. The new version of "OncoFunction" was evaluated by 20 head and neck surgeons and radiation oncologists in an interview. From 7/2013 until 7/2017, 846 patients completed the PROM during 2,833 of 3,610 total visits (78.5%). The latest software version implemented newly developed add-ins and increased the already high approval ratings in the evaluation as the number of errors and the time required decreased (6 vs. 0 errors, 1.35 vs. 0.95 min; p <0.01). Notably, patients had different requests using PRO in homecare use. An additional examination shows that only 59% of HNC patients use the world wide web. Using OncoFunction for online-recording and interpretation of PROM improved data acquisition in daily HNC patients' follow-up. An accessory timeline grants access to former consultations and their visualization supported and simplified structured examinations. This provides an easy-to-use representation of the patient's functional outcome supporting comprehensive aftercare, considering all aspects of the patient's life., Competing Interests: TN is a shareholder of the software company IMPULS Technologiemanagement UG that provided the PROM software “OncoFunction”. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2020 Zebralla, Müller, Wald, Boehm, Wichmann, Berger, Birnbaum, Heuermann, Oeltze-Jafra, Neumuth, Singer, Büttner, Dietz and Wiegand.)

Background: We validated the new European Organisation for Research and Treatment of Cancer Quality of Life Head and Neck Module (EORTC QLQ-HN43)., Methods: We enrolled 812 patients with head and neck cancer from 18 countries. Group 1 completed the questionnaire before therapy, and 3 and 6 months later. In group 2 (survivors), we determined test-retest reliability using intraclass correlation coefficients (ICC). Internal consistency was assessed using Cronbach's Alpha, the scale structure with confirmatory factor analysis, and discriminant validity with known-group comparisons., Results: Cronbach's alpha was >0.70 in 10 of the 12 multi-item scales. All standardized factor loadings exceeded 0.40. The ICC was >0.70 in all but two scales. Differences in scale scores between known-groups were >10 points in 17 of the 19 scales. Sensitivity to change was found to be sufficient in 18 scales., Conclusions: Evidence supports the reliability and validity of the EORTC QLQ-HN43 as a measure of quality of life., (© 2019 Wiley Periodicals, Inc.)

Introduction: Despite high distress the majority of head and neck cancer patients does not use any psycho-oncological counselling or psychotherapeutic support. Additionally, patients with head and neck cancer have an increased risk of not returning to work compared to other cancer patients. Therefore, we have developed a group intervention program which aims at improving work ability in patients with head and neck cancer as well as their quality of life, self-efficacy and psychological well-being., Material and Methods: In a randomized controlled trial head and neck cancer patients either receive a group intervention or socio-legal counselling. Male head and neck cancer patients with elevated levels of psychological and work-related distress are included. The group intervention consists of eight sessions. Groups are led by both a psychotherapist and a former head and neck cancer patient (peer). Feasibility and acceptability of the group intervention were tested by means of a pilot group. Each session was evaluated by pilot group participants. Semi-structured interviews were used to assess relevance of content and practicability., Results: 113 patients were personally addressed, of which four patients participated in the pilot group. Patients reported that the intervention fit very well with their daily life and expressed satisfaction with it. Three patients emphasized the importance of the peer., Discussion: The presence of the peer as identification figure seems to be of crucial importance. To increase recruitment numbers inclusion criteria will be modified and participation costs will be reduced., Competing Interests: Die Autoren geben an, dass kein Interessenkonflikt besteht., (© Georg Thieme Verlag KG Stuttgart · New York.)

Background: Modified nucleosides (mNS) in urine are shown to be encouraging markers in cancer, mostly in patients presenting with high tumor mass such is breast and lung cancer. To our knowledge, mNS have not been investigated in head and neck squamous cell carcinoma (HNSCC). HNSCC is characterized by early metastasis into locoregional lymph nodes and slow infiltrating growth, but even in the advanced stage exhibits only a relatively low cancer volume. Therefore, reliable distinction between HNSCC and healthy controls by urinary mNS might pose substantial analytical problems and even more as patients with HNSCC mostly have an increased exposure to tobacco smoke and excessive alcohol consumption which affect the renal mNS pattern., Materials and Methods: Urinary mNS in samples of 93 therapy-naive patients with HNSCC and 242 healthy controls were quantified by reversed-phase high-performance liquid chromatography. Considering that the circadian rhythm causes diuresis-induced variations in concentration, the mNS-to-creatinine ratio was chosen to compare patients and controls. For sensitivity and specificity in discriminating between patients and controls, the corresponding curve was plotted. Additionally, logistic regression was carried out and a multilayer perceptron neuronal network (NN) was created., Results: Fifteen mNS were detectable in cases and controls; concentrations of 11 were found to be significantly different. The sensitivity and specificity depend on the total volume of the lesion; HNSCC with volume <20 ml was reliably detected, but those with a volume of 20 ml or greater produced amounts of mNS which led to the most accurate detection of HNSCC based on HNSCC-specific mNS patterns., Conclusion: Analysis of urinary mNS allows for detection of small-volume HNSCC, with acceptable specificity and sensitivity if the tumor volume exceeds 20 ml., (Copyright© 2018, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

To determine the sensitivity and specificity of HPV16 serology as diagnostic marker for HPV16-driven oropharyngeal squamous cell carcinoma (OPSCC), 214 HNSCC patients from Germany and Italy with fresh-frozen tumor tissues and sera collected before treatment were included in this study. Hundred and twenty cancer cases were from the oropharynx and 94 were from head and neck cancer regions outside the oropharynx (45 oral cavity, 12 hypopharynx and 35 larynx). Serum antibodies to early (E1, E2, E6 and E7) and late (L1) HPV16 proteins were analyzed by multiplex serology and were compared to tumor HPV RNA status as the gold standard. A tumor was defined as HPV-driven in the presence of HPV16 DNA and HPV16 transformation-specific RNA transcript patterns (E6*I, E1 ∧ E4 and E1C). Of 120 OPSCC, 66 (55%) were HPV16-driven. HPV16 E6 seropositivity was the best predictor of HPV16-driven OPSCC (diagnostic accuracy 97% [95%CI 92-99%], Cohen's kappa 0.93 [95%CI 0.8-1.0]). Of the 66 HPV-driven OPSCC, 63 were HPV16 E6 seropositive, compared to only one (1.8%) among the 54 non-HPV-driven OPSCC, resulting in a sensitivity of 96% (95%CI 88-98) and a specificity of 98% (95%CI 90-100). Of 94 HNSCC outside the oropharynx, six (6%) were HPV16-driven. In these patients, HPV16 E6 seropositivity had lower sensitivity (50%, 95%CI 19-81), but was highly specific (100%, 95%CI 96-100). In conclusion, HPV16 E6 seropositivity appears to be a highly reliable diagnostic marker for HPV16-driven OPSCC with very high sensitivity and specificity, but might be less sensitive for HPV16-driven HNSCC outside the oropharynx., (© 2017 UICC.)

Background: Personalized medicine and treatment stratification of patients with head and neck squamous cell carcinoma (HNSCC) today mostly ignore genetic heterogeneity in HNSCC but especially the patient's genetic background. We hypothesized that particular human leukocyte antigen (HLA) class I (HLA-A, B, Cw) and II proteins (DR, DQ) confer susceptibility for and influence development of HNSCC and may be prognostic factors for progression-free survival (PFS)., Methods: 90 consecutive HNSCC patients of the prospective observational cohort study LIFE treated between 08/2010 and 05/2011 at the University Leipzig underwent low resolution typing of HLA-A, B, Cw, DR, and DQ. Antigen and haplotype frequencies were compared to those in German blood donors. Effects on PFS were analyzed using Kaplan-Meier curves and Cox models., Results: HNSCC patients had overall altered HLA-B frequencies (P<0.05); frequencies of B∗44 were lower, those of B∗13, B∗52, and B∗57 increased (P<0.05). Almost all other antigen frequencies showed no deviation. Homozygous HLA-Cw and DRB4 were frequent and associated with reduced PFS (P<0.05). Altered haplotype frequencies were common and particular haplotypes accompanied by differing PFS. B∗13/Cw∗06 carriers had poorest outcome (P=0.011). However, multivariate Cox proportional hazard models revealed 3 clinical covariates (localization oropharynx, loco-regional metastasis, and T4 category), HPV16-DNA positivity, and 10 HLA traits as independent predictors for PFS., Conclusions: The relevance of the genetic background of HNSCC patients calls for future research to clarify the role of HLA traits in HNSCC and if PFS depends on HLA., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Background/aim: To analyze ex vivo effects of combined targeting of the epidermal growth factor-receptor (EGFR) by cetuximab (E) plus αVβ3 and αVβ5 integrins by cilengitide (Cil) on colony formation of epithelial cells (CF ec ) and release of pro-angiogenetic and pro-inflammatory cytokines in head and neck squamous cell carcinoma (HNSCC) cells., Materials and Methods: Collagenase-IV digests of 43 histopathological confirmed HNSCC cases were seeded into laminin-coated 96-well plates containing E, Cil, or Cil+E in final concentrations of 66.7 μg/ml, 10 μM, and 10 μM+66.7 μg/ml, respectively. Following the FLAVINO-assay protocol, supernatants were harvested after 3 days and adherent cells fixed in ethanol. Counting of CF ec was facilitated by FITC-labeled pan-cytokeratin antibodies. Out of 43 HNSCC cases, 39 had adherent growth (mean CF ec ≥4/well in triplicate controls). Cytokines in supernatants were measured using ELISA were interleukin 6 (IL-6), monocyte chemoattractant protein 1 (MCP-1) and vascular endothelial growth factor A (VEGFA)., Results: CF ec on laminin was significantly reduced by Cil, E, and Cil+E. Cytokine measurements also revealed significant suppression of MCP-1, IL-6 and VEGFA. The strongest suppression of CF ec , MCP-1 and VEGFA release was exerted by Cil and E combined. Efficacy of Cil+E exceeded those of the solely applied pharmaceutics but failed regarding significant synergism of both treatments as E was unable to significantly boost the effects of Cil. In contrast, IL-6 release was significantly suppressed by E but not by Cil, while their combination strongly reduced it., Conclusion: Combined targeting of EGFR and integrins with E and Cil heightens their suppressive effects regarding CF ec as well as release of pro-angiogenetic and pro-inflammatory cytokines., (Copyright© 2017, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Background: Dynamic contrast-enhanced magnetic resonance imaging (DCE MRI) can characterize perfusion and vascularization of tissues. DCE MRI parameters can differentiate between malignant and benign lesions and predict tumor grading. The purpose of this study was to correlate DCE MRI findings and various histopathological parameters in head and neck squamous cell carcinoma (HNSCC)., Patients and Methods: Sixteen patients with histologically proven HNSCC (11 cases primary tumors and in 5 patients with local tumor recurrence) were included in the study. DCE imaging was performed in all cases and the following parameters were estimated: K trans , V e , K ep , and iAUC. The tumor proliferation index was estimated on Ki 67 antigen stained specimens. Microvessel density parameters (stained vessel area, total vessel area, number of vessels, and mean vessel diameter) were estimated on CD31 antigen stained specimens. Spearman's non-parametric rank sum correlation coefficients were calculated between DCE and different histopathological parameters., Results: The mean values of DCE perfusion parameters were as follows: K trans 0.189 ± 0.056 min -1 , K ep 0.390 ± 0.160 min -1 , V e 0.548 ± 0.119%, and iAUC 22.40 ± 12.57. Significant correlations were observed between K ep and stained vessel areas (r = 0.51, P = .041) and total vessel areas (r = 0.5118, P = .043); between V e and mean vessel diameter (r = -0.59, P = .017). Cell count had a tendency to correlate with V e (r = -0.48, P = .058). In an analysis of the primary HNSCC only, a significant inverse correlation between K trans and KI 67 was identified (r = -0.62, P = .041). Our analysis showed significant correlations between DCE parameters and histopathological findings in HNSCC., (Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Long-term laryngectomy-free (LFS), tumour-specific (TSS) and overall survival (OS) is achieved by non-surgical larynx preservation (LP) only in a proportion of patients with locally advanced laryngeal or hypopharyngeal cancer. A score facilitating decision-making after 1 cycle induction chemotherapy (IC-1) may improve LFS and TSS., Methods: Early response to IC-1 with TPF ± cetuximab was assessed in 52 patients using endoscopic tumour staging for selecting total laryngectomy for non-responders with endoscopic tumour surface shrinkage <30% versus induction chemotherapy plus radiotherapy (IC + RT) for responders. Computed tomography (CT)-based volumetry was used to assess volumes of primary tumour, neck nodes and their sum; maximum and mean standardised uptake value (SUV max , SUV mean ) were measured by 18 F-FDG-PET/CT. Baseline and residual values after IC-1 were calculated and correlated with LFS, TSS and OS., Results: After IC-1, 39/52 patients (75%) were early responders. Early response predicted complete response to IC + RT (p = 8.48 × 10 -9 ). Early laryngectomised non-responders and responders with endoscopic tumour surface shrinkage > 70% had best OS. Significant independent predictors for LFS in responders are number of CT-staged suspect positive neck nodes (N+), residual primary tumour volume, residual total tumour volume and the ratio of residual SUV max and SUV mean (resSUV max /resSUV mean ). Our LFS-score combines >2N+, residual primary tumour volume > 20%, residual total tumour volume > 5.6 mL and resSUV max /resSUV mean  > 1.51 weighted by their hazard ratio (12, 6, 5 and 4); LFS-score ≤ 16 predicts increased LFS, OS and TSS (p < 0.05)., Conclusion: LFS-score ≤ 16 identifies in responders to IC-1 the patients with maximum benefit of non-surgical LP achieving long-term LFS. Even more importantly, a LFS-score > 16 defines patients unsuitable for LP applying the TPF/TP IC + RT protocol., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

We explored the relationship between socio-economic characteristics and cancer stage at presentation. Patients admitted to a university hospital for diagnosis and treatment of cancer provided data on their education, vocational training, income, employment, job, health insurance and postcode. Tumor stage was classified according to the Union International Contre le Cancer (UICC). To analyze disparities in the likelihood of late-stage (UICC III/IV vs. I/II) diagnoses, logistic regression models adjusting for age and gender were used. Out of 1,012 patients, 572 (59%) had late-stage cancer. Separately tested, increased odds of advanced disease were associated with post-compulsory education compared to college degrees, with apprenticeship and no vocational training, with unemployment, disability pension, jobs with a low hierarchy level, blue collar jobs and with low income. Health insurance and community size were not related with late-stage cancer. Jointly modelled, there was evidence for an independent effect of unemployment (odds ratio (OR) 1.7, CI 1.0-2.8), disability pension (OR 1.8, CI 1.0-3.2) and very low income (OR 2.6, CI 1.1-6.1) on the likelihood of advanced disease stage. It is of great concern that these socio-economic gradients occur even in systems with equal access to health care., (© 2016 UICC.)

Stratification of head and neck squamous cell carcinomas (HNSCC) based on HPV16 DNA and RNA status, gene expression patterns, and mutated candidate genes may facilitate patient treatment decision. We characterize head and neck squamous cell carcinomas (HNSCC) with different HPV16 DNA and RNA (E6*I) status from 290 consecutively recruited patients by gene expression profiling and targeted sequencing of 50 genes. We show that tumors with transcriptionally inactive HPV16 (DNA+ RNA-) are similar to HPV-negative (DNA-) tumors regarding gene expression and frequency of TP53 mutations (47%, 8/17 and 43%, 72/167, respectively). We also find that an immune response-related gene expression cluster is associated with lymph node metastasis, independent of HPV16 status and that disruptive TP53 mutations are associated with lymph node metastasis in HPV16 DNA- tumors. We validate each of these associations in another large data set. Four gene expression clusters which we identify differ moderately but significantly in overall survival. Our findings underscore the importance of measuring the HPV16 RNA (E6*I) and TP53-mutation status for patient stratification and identify associations of an immune response-related gene expression cluster and TP53 mutations with lymph node metastasis in HNSCC., (© 2015 UICC.)

Purpose: Many treatment approaches are available for head and neck cancer (HNC), leading to challenges for a multidisciplinary medical team in matching each patient with an appropriate regimen. In this effort, primary diagnostics and its reliable documentation are indispensable. A three-dimensional (3D) documentation system was developed and tested to determine its influence on interpretation of these data, especially for TNM classification., Methods: A total of 42 HNC patient data sets were available, including primary diagnostics such as panendoscopy, performed and evaluated by an experienced head and neck surgeon. In addition to the conventional panendoscopy form and report, a 3D representation was generated with the "Tumor Therapy Manager" (TTM) software. These cases were randomly re-evaluated by 11 experienced otolaryngologists from five hospitals, half with and half without the TTM data. The accuracy of tumor staging was assessed by pre-post comparison of the TNM classification., Results: TNM staging showed no significant differences in tumor classification (T) with and without 3D from TTM. However, there was a significant decrease in standard deviation from 0.86 to 0.63 via TTM ([Formula: see text]). In nodal staging without TTM, the lymph nodes (N) were significantly underestimated with [Formula: see text] classes compared with [Formula: see text] with TTM ([Formula: see text]). Likewise, the standard deviation was reduced from 0.79 to 0.69 ([Formula: see text]). There was no influence of TTM results on the evaluation of distant metastases (M)., Conclusion: TNM staging was more reproducible and nodal staging more accurate when 3D documentation of HNC primary data was available to experienced otolaryngologists. The more precise assessment of the tumor classification with TTM should provide improved decision-making concerning therapy, especially within the interdisciplinary tumor board.

Background: The objective of this study was to pilot test an updated version of the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Head and Neck Module (EORTC QLQ-H&N60)., Methods: Patients with head and neck cancer were asked to complete a list of 60 head and neck cancer-specific items comprising the updated EORTC head and neck module and the core questionnaire EORTC QLQ-C30. Debriefing interviews were conducted to identify any irrelevant items and confusing or upsetting wording., Results: Interviews were performed with 330 patients from 17 countries, representing different head and neck cancer sites and treatments. Forty-one of the 60 items were retained according to the predefined EORTC criteria for module development, for another 2 items the wording was refined, and 17 items were removed., Conclusion: The preliminary EORTC QLQ-H&N43 can now be used in academic research. Psychometrics will be tested in a larger field study., (© 2014 Wiley Periodicals, Inc.)

Background: The outcome of patients with head and neck squamous cell carcinoma (HNSCC) is still poor. To improve therapy of HNSCC, biomarkers indicating progression of the disease or modifiers with potential as therapeutic targets and therapy need to be investigated. Since monocyte chemoattractant protein (MCP1) is potentially involved in tumorigenesis of HNSCC, we aimed to clarify its role in HNSCC and investigated the influence of stimulation by MCP1 and its depletion using antibodies against MCP1 (anti-MCP1) on colony formation by HNSCC cells., Materials and Methods: Biopsies of HNSCC were treated according to the protocol of the FLAVINO assay with cisplatin, docetaxel, temsirolimus or cilengitide alone, or combined with MCP1 or anti-MCP1. After a 72-h incubation, ethanol-fixed and fluoresceine-isothiocyanate (FITC)-labeled epithelial colonies were counted., Results: Colony formation was significantly suppressed by MCP1 and 3.3 μM cisplatin, while docetaxel, cilengitide and temsirolimus at concentrations of 0.275, 10 and 0.50 μM caused insignificant effects. Addition of MCP1 to cisplatin, docetaxel and cilengitide increased efficacy of cytostatics in inhibition of colony formation, whereas those with temsirolimus were increased by anti-MCP1 that when applied alone failed to modulate colony formation. Overall regarding facilitated chemosensitivity, there was a statistical trend in favor of MCP1 stimulation over depletion., Conclusion: Our ex vivo results show context-dependent effects of MCP1 in HNSCC cells. An increase of MCP1 level or its addition to cisplatin, docetaxel and cilengitide reduce colony formation but the efficacy of temsirolimus is augmented by MCP1 depletion. These context-dependently opposite outcomes call for further translational investigations in HNSCC., (Copyright© 2015 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.)

Motivation: The primary economy-driven documentation of patient-specific information in clinical information systems leads to drawbacks in the use of these systems in daily clinical routine. Missing meta-data regarding underlying clinical workflows within the stored information is crucial for intelligent support systems. Unfortunately, there is still a lack of primary clinical needs-driven electronic patient documentation. Hence, physicians and surgeons must search hundreds of documents to find necessary patient data rather than accessing relevant information directly from the current process step. In this work, a completely new approach has been developed to enrich the existing information in clinical information systems with additional meta-data, such as the actual treatment phase from which the information entity originates., Methods: Stochastic models based on Hidden Markov Models (HMMs) are used to create a mathematical representation of the underlying clinical workflow. These models are created from real-world anonymized patient data and are tailored to therapy processes for patients with head and neck cancer. Additionally, two methodologies to extend the models to improve the workflow recognition rates are presented in this work., Results: A leave-one-out cross validation study was performed and achieved promising recognition rates of up to 90% with a standard deviation of 6.4%., Conclusions: The method presented in this paper demonstrates the feasibility of predicting clinical workflow steps from patient-specific information as the basis for clinical workflow support, as well as for the analysis and improvement of clinical pathways., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Objectives: The management of patient-specific information is a challenging task for surgeons and physicians because existing clinical information systems are insufficiently integrated into daily clinical routine and contained information entities are distributed across different proprietary databases. Thus, existing information is hardly usable for further electronic processing, workflow support or clinical studies., Methods: A Web-based clinical information system has been developed that automatically imports patient-specific information from different information systems. The system is tailored to the existing workflow for the treatment of patients with head and neck cancer. In this paper, the clinical assistance functions and a quantitative as well as a qualitative system evaluation are presented., Results: The information system has been deployed at a clinical site and is in use in daily clinical routine. Two evaluation studies show that the information integration, the structured information presentation in the Web browser and the assistance functions improve the physician's workflow. The studies also show that the usage of the new information system does not impair the time physicians need for a process step compared with the usage of the existing information system., Conclusions: Information integration is crucial for efficient workflow support in the clinic. The central access to information within a modern and structured user interface saves valuable time for the physician. The comprehensive database allows an instant usage of the existing information clinical workflow support or the conduction of trial studies.

Background: The objective of this study was to identify relevant quality of life (QOL) issues in patients with head and neck cancer receiving multimodal and/or targeted therapies., Methods: The literature was searched for QOL issues reported after multimodal and/or targeted therapies resulting in a list of potentially relevant issues. These were discussed within a multiprofessional expert group, revised, and subsequently rated for relevance by patients and health care providers., Results: Twenty-seven issues were extracted that are not covered by the current version of the European Organization for Research and Treatment of Cancer (EORTC) questionnaires. Interviews (96 health care providers from 13 countries, 137 patients from 8 countries) revealed that 26 of these issues were relevant for patients with head and neck cancer., Conclusions: Studies investigating targeted and/or multimodal therapy should consider that some QOL issues specific to these treatments are not covered by the current version of the EORTC instruments. Consequently, the EORTC head and neck cancer module is currently in revision., (Copyright © 2012 Wiley Periodicals, Inc.)

Background: Lapatinib targets human epidermal growth factor-receptor (EGFR) and Her2/neu receptor tyrosine-kinases and hence is under investigation in multimodal therapy concepts of advanced head and neck squamous cell carcinoma (HNSCC). We studied combined effects of lapatinib and cisplatin on colony formation (CF) of epithelial cells of individual HNSCC in short term ex vivo assays., Materials and Methods: Biopsies of HNSCC were minced, collagenase-digested and exposed to serial lapatinib dilutions or solvent control (DMSO). The same lapatinib concentrations were tested in mixture with 1.67 μM, 3.33 or 6.67 μM cisplatin. After α 72-h incubation, adherent cells were ethanol-fixed and epithelial cells were stained using a Cy2™-labeled pan-cytokeratin antibody; then fluorescent colonies were counted., Results: 33 of 51 ex vivo growing HNSCC (64.7%) exhibited epithelial CF allowing for cut-off detection. Lowest cut-off (complete chemotherapeutical suppressed CF) was noted at 6.25 μM lapatinib in three HNSCC (9.1%). The percentage of HNSCC achieving cut-off by 6.67 μM cisplatin (21.2%) was raised by addition of lapatinib at 6.25, 12.5, and 25 μM up to 33%, 45.5%, and 60.6%, respectively. However, we observed significant inter-individual different dose-response curves of HNSCC in response to lapatinib, e.g. variation in concentrations inhibiting CF to 50% (IC(50)) was 60-fold. At the individual level, antagonism, additivity, and synergism were detected as appropriate models describing the mode of action of cisplatin and lapatinib mixtures., Conclusion: Lapatinib suppresses CF of epithelial HNSCC cells, and in combination with cisplatin its efficacy is increased. However, caution is advisable due to significant heterogeneity in the response of HNSCC to lapatinib alone and when combined with cisplatin.

Purpose: Distance measures are required for diagnoses, therapy decision and documentation. With today's high-resolution CT and MR imaging techniques, high- quality images have become possible. Yet, manual measurement can be tedious. We present a method for automatically determining different distance-based measures on segmented anatomic structures, like shortest distances, diameters, and wall thicknesses., Methods: Our method is inspired from computational geometry and based on a surface mesh representation. The computation takes all primitives (points, edges, faces) into account and organizes them efficiently in a spatial tree structure. We followed the generic design paradigm in order to achieve maximum flexibility., Results: The generic approach allows for a variety of intervention-relevant distance measures to be computed, using only a single type of data structure. For shortest distance, our approach in empirical tests turned out to be more efficient than previous methods from medical application literature. Besides the numerical value, also its defining geometric primitives are determined., Conclusions: The presented technique is both, fast and flexible. It can be used to interactively derive automatic distance measures for arbitrary mesh-based segmentations. Due to the geometrically exact measurements, it is possible to reliably estimate safety margins, assess possible infiltrations and other clinically relevant measures. To exploit this benefit, the method requires precise segmentations as input data.

This article gives an overview on different current strategies of assay-based response evaluation in head and neck squamous cell carcinomas (HNSCC) and critically summarizes their role and needs for future clinical evaluation. Due to a growing amount of data of phase III clinical trials of multimodality treatment options for HNSCC, treatment planning in regard to optimal outcome is becoming an interdisciplinary challenge. New concepts such as induction chemotherapy with bi- or ternary combinations of chemotherapeutics, integration of targeted therapies, concurrent and sequential chemoradiation concepts, and multimodality-based organ preservation strategies strongly compete with traditional definitive surgical procedures. Moreover, the outcome is difficult to predict due to heterogeneity of a tumor's response, impaired late functional outcome, and increased late toxicity if simultaneously applied to radiation. Retrospectively looking at non-responders with tumors classified as resectable, primary surgery is very likely to have achieved better results, since chemoradiation causes a high degree of early and late toxicities leading to extremely complicated terms and conditions in surgery following current multimodal therapeutic strategies. Unfortunately, predictive information on response characteristics of a given tumor before starting the therapy is not available in daily routine, although heterogeneity in response of a given tumor entity to treatments has been known for decades. Therefore, current therapy strategies for HNSCC still have to ignore this fact, creating an urgent need for the development of proper predictive assays. There are interesting clinical observations showing that response on induction chemotherapy may predict the outcome after radiotherapy. Some trials use this empiric phenomenon to pre-select non-responders for primary surgical treatment avoiding severe salvage complications after failure of complete chemoradiation treatment. Moving one step further, recent literature and our own investigations implicate that response evaluation of the individual patient's HNSCC in a suitable ex vivo assay just before starting the treatment is mature for clinical research. To this end, essential needs and hints are addressed and discussed.

Background: In multimodal therapy concepts for advanced head and neck squamous cell carcinoma (HNSCC), a valid predictive assay for the quick detection of efficient chemotherapeutic agents is desirable. Questionable so far was whether tissue samples of about 100 mg correctly reflect the chemoresponse of a whole HNSCC. This was proven using an ex-vivo colony-forming assay., Materials and Methods: Of 14 HNSCC, 3 biopsies each were taken from separate sites, minced, and collagenase digested. HNSCC digests were added to microtiter plates containing serial dilutions of chemotherapeutic agents or medium as control. After 72-h incubation, wells were washed and cultures methanol-fixed before Giemsa-staining. Epithelial colonies were counted., Results: 11/14 HNSCC (78.6%) showed sufficient colony formation allowing reliable cut-off detection. Cut-off concentrations (complete chemotherapeutically suppressed colony formation) between 3.3 microM and >50 microM cisplatin, and 0.55 microM and 17.6 microM docetaxel were detected. Inhibition of colony formation to 50% of colonies detected in controls (IC50) was found between 0.2 microM and 17.9 microM cisplatin or 1.5 microM and 13.7 microM docetaxel. Cut-off concentrations and IC50 of the HNSCC fragments showed a strong correlation (docetaxel: r > 0.80, p < 0.005; cisplatin: r > 0.67, p < 0.044), while being only insignificantly different in the t-test for paired samples (docetaxel: p > 0.163; cisplatin: p > 0.167)., Conclusion: In most cases, tissue samples of about 100 mg allow a representative assessment of chemoresponse of HNSCC., (Copyright (c) 2009 S. Karger AG, Basel.)

This review focuses on the current and upcoming options of targeted therapy (biologicals) in head and neck squamous cell carcinoma (HNSCC) with special regard to conceptual integration in future strategies. Epidermal growth factor receptor (EGFR) is the most prominent candidate for therapeutic targeting because of its more than 90% expression rate in HNSCC and influence on the regulation of proliferation, apoptosis, metastasis, angiogenesis and cell differentiation. The point of view of head and neck surgeons is mainly adjusted to reach a balance between targeted, minimal ablative surgery and the evidence-based demand of oncologic accurate surgery with clear margins and, if needed, adjuvant or primary systemic chemoradiation. Therefore, the long-term effects of chemoradiation regimens, such as dysphagia, aspiration and laryngeal immobility caused by fibrosis, are just beginning to be studied and are becoming one of the major problems in the ongoing treatment of HNSCC. In this context, molecular targeting biologicals with a different toxicity profile and hopefully less late damage to functionally important tissues may open new strategies in primary and adjuvant treatment of HNSCC. Besides cetuximab and other EGFR targeting mAbs, this review focuses on receptor and non-receptor tyrosine kinase inhibitors, which further might play a role in the future treatment of HNSCC. To complete the current picture, the problem of multi drug resistance in cancer progenitor cells, targeting members of several relevant pathways and novel agents like pemetrexed and enzastaurin, are discussed in a broader sense of targeted therapy.

Objective: To evaluate the effect of central corneal thickness (CCT), corneal curvature, and axial length on applanation tonometry in an in vivo study., Methods: In a masked, prospective clinical trial, we examined 125 eyes of 125 patients scheduled for cataract surgery. Corneal curvature was measured by means of keratometry and axial length by A-scan ultrasonography. By cannulating the anterior chamber before surgery, intraocular pressure (IOP) was set to 20, 35, and 50 mm Hg in a closed system by means of a water column. After measuring thickness, the IOP was measured with an applanation tonometer. Pearson product moment correlations and multiple linear regression analyses were performed, and significance levels were evaluated by the paired, 2-tailed t test., Results: The difference between measured and real IOP was significantly dependent (P < .001) on CCT. The associations between IOP and corneal curvature or IOP and axial length were not statistically significant (P = .31). The association between IOP reading and CCT is shown in the "Dresdner correction table," which illustrates an approximately 1-mm Hg correction for every 25-microm deviation from a CCT of 550 microm. The correction values were positive as thickness decreased and negative as thickness increased., Conclusions: Central corneal thickness significantly affects IOP readings obtained by applanation tonometry according to the Goldmann principle. A correction of IOP readings by considering CCT according to the Dresdner correction table might be helpful for determining an accurate IOP value.

Purpose: To create a correction formula to determine the real intraocular pressure (IOP) after LASIK considering the altered corneal thickness, corneal curvature, and corneal stability., Methods: This prospective clinical trial comprised 101 eyes of 59 patients (34 women and 25 men) that underwent LASIK with a mean preoperative spherical equivalent refraction of -6.3 +/- 2.17 diopters (D) (-3.0 to -11.5 D). Mean patient age was 32 +/- 9 years. Preoperatively and 6 months postoperatively, IOP (by Goldmann applanation tonometry), keratometry (by topography), and central corneal thickness (CCT) (by ultrasound pachymetry) were evaluated. These parameters were measured in all patients between 8 and 11 o'clock in the morning., Results: Due to the LASIK procedure, IOP was reduced from 16.5 +/- 2.1 mmHg (range: 12 to 22 mmHg) to 12.9 +/- 1.9 mmHg (range: 8 to 16 mmHg). Multiple linear regression analysis of the IOP values before and after LASIK showed a significant correlation between the measured IOP and CCT and keratometry values (R2=0.631; P<.001). After LASIK, the biomechanical bending strength of the cornea is reduced by the cut so that the measured IOP must be additionally corrected by 0.75 mmHg. An equation containing all three changes is given: IOP (real) = IOP (measured) + (540-CCT)/71 + (43-K-value)/2.7 + 0.75 mmHg., Conclusions: Intraocular pressure measurements after LASIK for the correction of myopia are inaccurate as a consequence of changes in CCT, corneal curvature, and corneal flap stability. After LASIK, the measured IOP should be corrected to avoid false low IOP applanation readings.

Background: In a previous study it was shown that nimodipine 30 mg twice daily leads to an improvement in the visual field in a subgroup of normal-pressure glaucoma patients. To understand the mechanism of action of nimodipine on the visual system, the aim of this study was to examine the influence of nimodipine on different hemodynamic parameters and contrast sensitivity in healthy subjects., Methods: Thirty-two healthy subjects (21-49 years old, mean age 28 years, 10 male, 22 female) received either nimodipine 30 mg twice a day or a placebo according to the same dosage regimen in a double-blind cross-over study design. The ocular blood flow was measured by means of the ocular blood flow system, the optic nerve head blood flow with the continuous laser Doppler flowmeter (Riva), and contrast sensitivity using the MCT 8000 Multivision Contrast Tester. Measurements were taken at baseline (1T0), 120 min after initial dose (1T3) and after 3 days (3T3) of therapy with 150 mg nimodipine or placebo in total., Results: Contrast sensitivity improved significantly throughout almost all spatial frequencies in the nimodipine-treated subjects ( P=0.01), whereas there was no change in the placebo group. Ocular blood flow and optic nerve head blood flow increased slightly but not significantly in the nimodipine group (1T0: 706.6 microl/min, 9.33 AU; 3T3: 854.3 microl/min, 9.39 AU) and remained unchanged or were even lower in the placebo group ( P>0.05)., Conclusion: The results showed a significant increase in contrast sensitivity during treatment with nimodipine in healthy subjects. This increase in visual function, however, was not correlated with an increase in ocular or optic nerve head blood flow. Therefore, another mechanism, e.g., a direct effect on the visual system, might be responsible for the improvement in visual function in healthy volunteers under nimodipine therapy.

Background: Focal arteriolar narrowing has been reported to be more common in glaucoma eyes compared to normal eyes. The current study was performed to compare two methods for standardized assessment of focal arteriolar narrowing., Material and Methods: Stereoscopic optic disc photographs (from one randomly selected eye per subject) of 48 normal subjects, 20 ocular hypertensive patients (OHT), and 29 glaucoma patients, were reviewed independently in a masked fashion by two graders. Focal arteriolar narrowing within one disc diameter from the rim edge was evaluated based on two different grading methods: (1) narrowing present if the arteriole was wider distal to the narrowing, and (2) narrowing present if the arteriole was wider both distal and proximal to the narrowing., Results: Focal arteriolar narrowing was observed with grading method 1 in 37.5% (18/48), 35.0% (7/20), and 65.5% (19/29) of normals, OHT, and glaucoma patients, respectively. It was observed with grading method 2 in 18.8% (9/48), 0% (0/22), and 48.3% (14/29) of normals, OHT, and glaucoma patients, respectively. With both grading methods, focal arteriolar narrowing was significantly more frequent in glaucoma versus normal eyes (chi-square test: grading method 1 P=0.03, and grading method 2 P=0.0001). The number of eyes with focal arteriolar narrowing was significantly more frequent with method 1 than with method 2 across all photographs and all subgroups (chi-square test: P=0.0001). The overall agreement between the two graders was kappa 0.77+/-0.06 for grading method 1, and 0.43+/-0.11 for grading method 2., Conclusions: The prevalence of focal arteriolar narrowing is highly dependent upon the grading method. A uniform grading method of focal arterial narrowing is needed to achieve comparable and reproducible results among studies.

Purpose: To compare the ability of several machine learning classifiers to predict development of abnormal fields at follow-up in ocular hypertensive (OHT) eyes that had normal visual fields in baseline examination., Methods: The visual fields of 114 eyes of 114 patients with OHT with four or more visual field tests with standard automated perimetry over three or more years and for whom stereophotographs were available were assessed. The mean (+/-SD) number of visual field tests was 7.89 +/- 3.04. The mean number of years covered (+/-SD) was 5.92 +/- 2.34 (range, 2.81-11.77). Fields were classified as normal or abnormal based on Statpac-like methods (Humphrey Instruments, Dublin, CA) and by several machine learning classifiers. The machine learning classifiers were two types of support vector machine (SVM), a mixture of Gaussian (MoG) classifier, a constrained MoG, and a mixture of generalized Gaussian (MGG). Specificity was set to 96% for all classifiers, using data from 94 normal eyes evaluated longitudinally. Specificity cutoffs required confirmation of abnormality., Results: Thirty-two percent (36/114) of the eyes converted to abnormal fields during follow-up based on the Statpac-like methods. All 36 were identified by at least one machine classifier. In nearly all cases, the machine learning classifiers predicted the confirmed abnormality, on average, 3.92 +/- 0.55 years earlier than traditional Statpac-like methods., Conclusions: Machine learning classifiers can learn complex patterns and trends in data and adapt to create a decision surface without the constraints imposed by statistical classifiers. This adaptation allowed the machine learning classifiers to identify abnormality in visual field converts much earlier than the traditional methods.

Objective: To evaluate the relationship between visual field loss and glaucomatous optic discs in eyes in which field loss spreads across the horizontal meridian., Subjects and Methods: Ninety-six patients with glaucoma (9 advanced, 60 moderate, and 27 early) with 2 successive abnormal fields were included. Standard achromatic automated perimetry defects were identified with a nerve fiber bundle map to identify abnormal sectors. Crossover was present if the superior and inferior sectors at the horizontal meridian (nasal, central, or temporal) were both abnormal. Optic disc damage was assessed by masked grading of simultaneous stereophotographs., Results: Only 30% (29) of glaucomatous eyes showed crossover, and only 2 of those eyes had early loss. The most frequent pattern of visual field loss (41% of eyes) was single hemifield damage with defects in contiguous sectors. Regardless of the pattern or severity of visual loss, most eyes (66 [69%] of 96) had both superior and inferior optic disc damage., Conclusions: Early glaucomatous visual field loss rarely crosses the horizontal meridian, but defects in both hemifields at the horizontal meridian are more common in more advanced field loss. In 26 (90%) of 29 eyes with crossover, it could be explained by changes at the optic nerve head.