The Potential of MET Immunoreactivity for Prediction of Lymph Node Metastasis in Early Oral Tongue Squamous Cell Carcinoma.

OBJECTIVE: MET positivity is independently associated with survival in oral squamous cell carcinoma (OSCC). Since MET is a known orchestrator of invasive tumor growth, we investigated its association with LNM in early oral tongue squamous cell carcinoma (OTSCC). As it is recommended by the NCCN to use tumor depth of invasion (DOI) in making decisions on elective neck dissection (END), the results obtained for MET positivity were aligned with those for DOI > 4 mm. The cutoff value used in our institution. METHODS: Tumor samples from patients who underwent primary tumor resection and neck dissection between 1995 and 2013, were collected from the archives of the Leiden and Erasmus University Medical Center. Immunohistochemistry with D1C2 was performed to identify MET negative (< 10% uniform positivity) and MET positive (≥ 10% uniform positivity) cancers. ROC curve analysis and the Chi-squared test were used to investigate the association of MET positivity with LNM (pN+ and occult). Binary logistic regression was used to investigate the association of MET positivity with LNM. RESULTS: Forty-five (44.1%) of the 102 cancers were MET positive. Ninety were cN0 of which 20 were pN+ (occult metastasis). The remaining 12 cancers were cN+, of which 10 were proven pN+ and 2 were pN0. MET positivity was associated with LNM with a positive predictive value (PPV) of 44.4% and a negative predictive value (NPV) of 82.5% for pN+. For the occult group, the PPV was 36.8% and the NPV was 88.5%. Regression analysis showed that MET positivity is associated with pN+ and occult LNM (p-value < 0.05). CONCLUSION: MET positivity is significantly associated with LNM in early OTSCC, outperforming DOI. The added value of MET positivity could be in the preoperative setting when END is being considered during the initial surgery. For cases with DOI ≤ 4 mm, MET positivity could aid in the clinical decision whether regular follow-up, watchful waiting, or END is more appropriate. Realizing that these preliminary results need to be independently validated in a larger patient cohort, we believe that MET positivity could be of added value in the decision making on END in early OTSCC.

Physicians' clinical prediction of survival in head and neck cancer patients in the palliative phase.

BACKGROUND: The prognosis of patients with incurable head and neck cancer (HNC) is a relevant topic. The mean survival of these patients is 5 months but may vary from weeks to more than 3 years. Discussing the prognosis early in the disease trajectory enables patients to make well-considered end-of-life choices, and contributes to a better quality of life and death. However, physicians often are reluctant to discuss prognosis, partly because of the concern to be inaccurate. This study investigated the accuracy of physicians' clinical prediction of survival of palliative HNC patients. METHODS: This study was part of a prospective cohort study in a tertiary cancer center. Patients with incurable HNC diagnosed between 2008 and 2011 (n = 191), and their treating physician were included. Analyses were conducted between July 2018 and February 2019. Patients' survival was clinically predicted by their physician ≤3 weeks after disclosure of the palliative diagnosis. The clinical prediction of survival in weeks (CPS) was based on physicians' clinical assessment of the patient during the outpatient visits. More than 25% difference between the actual survival (AS) and the CPS was regarded as a prediction error. In addition, when the difference between the AS and CPS was 2 weeks or less, this was always considered as correct. RESULTS: In 59% (n = 112) of cases survival was overestimated. These patients lived shorter than predicted by their physician (median AS 6 weeks, median CPS 20 weeks). In 18% (n = 35) of the cases survival was correctly predicted. The remaining 23% was underestimated (median AS 35 weeks, median CPS 20 weeks). Besides the differences in AS and CPS, no other significant differences were found between the three groups. There was worse accuracy when predicting survival closer to death: out of the 66 patients who survived 6 weeks or shorter, survival was correctly predicted in only eight (12%). CONCLUSION: Physicians tend to overestimate the survival of palliative HNC patients. This optimism can result in suboptimal use of palliative and end-of-life care. The future development of a prognostic model that provides more accurate estimates, could help physicians with personalized prognostic counseling.

A novel immunohistochemical scoring system reveals associations of C-terminal MET, ectodomain shedding, and loss of E-cadherin with poor prognosis in oral squamous cell carcinoma.

Using tissue microarrays, it was shown that membranous C-terminal MET immunoreactivity and ectodomain (ECD) shedding are associated with poor prognosis in oral cancer. Seen the potential diagnostic value, extrapolation of these results to whole-tissue sections was investigated. Because MET orchestrates epithelial-to-mesenchymal transition (EMT), the results were benchmarked to loss of E-cadherin, a readout for EMT known to be associated with poor prognosis. C-terminal MET, N-terminal MET, and E-cadherin immunoreactivities were examined on formalin-fixed paraffin-embedded parallel sections of 203 oral cancers using antibody clones D1C2, A2H2-3, and NCH-38. Interantibody and intra-antibody relations were examined using a novel scoring system, nonparametric distribution, and median tests. Survival analyses were used to examine the prognostic value of the observed immunoreactivities. Assessment of the three clones revealed MET protein status (no, decoy, transmembranous C-terminal positive), ECD shedding, and EMT. For C-terminal MET-positive cancers, D1C2 immunoreactivity is independently associated with poor overall survival (hazard ratio [HR] = 2.40; 95% confidence interval [CI] = 1.25 to 4.61; and P = 0.008) and disease-free survival (HR = 1.83; 95% CI = 1.07-3.14; P = 0.027). For both survival measures, this is also the case for ECD shedding (43.4%, with HR = 2.30; 95% CI = 1.38 to 3.83; and P = 0.001 versus HR = 1.87; 95% CI = 1.19-2.92; P = 0.006) and loss of E-cadherin (55.3%, with HR = 2.21; 95% CI = 1.30 to 3.77; and P = 0.004 versus HR = 1.90; 95% CI = 1.20-3.01; P = 0.007). The developed scoring system accounts for MET protein status, ECD shedding, and EMT and is prognostically informative. These findings may contribute to development of companion diagnostics for MET-based targeted therapy.

Survival of patients with head and neck cancer with metachronous multiple primary tumors is surprisingly favorable.

BACKGROUND: The objectives of this study are to determine the incidence and survival rate of patients with head and neck squamous cell carcinoma (HNSCC) with multiple primary tumors (MPT) in the HN-region, lung, or esophagus. METHODS: Patient and tumor specific data of 1372 patients with HNSCC were collected from both the national cancer registry and patient records to ensure high-quality double-checked data. RESULTS: The total incidence of MPTs in the HN-region, lung, and esophagus in patients with HNSCC was 11% (149/1372). Patients with lung MPTs and esophageal MPTs had a significant worse 5-year survival than patients with HN-MPTs (29%, 14%, and 67%, respectively, P < 0.001). The 5-year survival rate for synchronous HN MPTs was only 25%, whereas it was surprisingly high for patients with metachronous HN MPT (85%, P < 0.001). CONCLUSIONS: One of 10 patients with HNSCC develop MPTs in the HN-region, lung, or esophagus. The 5-year survival of patients with metachronous HN MPTs was surprisingly favorable.

Elective neck treatment during salvage (pharyngo) laryngectomy.

PURPOSE: This study aimed at determining the importance of an elective neck dissection (END) in case of a cN0 laryngeal or hypopharyngeal carcinoma after (chemo) radiation. METHODS: Retrospective review was made of patients treated in a single tertiary center between 2002 and 2014. Influence of an END in case of a cN0 salvage laryngectomy on complications, recurrence-free survival and disease-specific survival was assessed. INCLUSION CRITERIA: squamous cell carcinoma and cN0 neck. EXCLUSION CRITERIA: second primary tumor in the head and neck, a total laryngectomy because of a dysfunctional larynx, or a previously performed neck dissection. RESULTS: Of the 86 included patients, 27 (31%) underwent an END, of which 1 had occult metastasis (4%). Of the remaining 59 patients (69%) without an END, 3 developed a regional recurrence (5%). The overall survival was significantly higher for patients who had an END (p = 0.037). The incidence of complications was not significantly different between the two groups. CONCLUSIONS: In light of the limited complications of an END and the poor prognosis of regional recurrence after previous (chemo)radiotherapy and a (pharyngo)laryngectomy, we advise consideration of an END at the time of a salvage laryngectomy.

Prevalence of age-related hearing loss, including sex differences, in older adults in a large cohort study.

OBJECTIVES/HYPOTHESIS: To obtain actual status of age-related hearing loss in a general unscreened population of older Dutch adults and to investigate whether the prevalence or degree has changed over time. STUDY DESIGN: To investigate the prevalence and degree of hearing loss, we conducted a large prospective cohort study of older adults between February 2011 and July 2015. METHODS: Pure-tone air- and bone-conduction thresholds were measured for 4,743 participants. Results were compared to previous cohort studies. RESULTS: As expected, hearing loss increased with age. We found a correlation of R2 = 0.317 for men and R2 = 0.354 for women (right ears). A prevalence of hearing loss greater than 35 dB hearing level the average of 0.5/1/2/4 kHz in the better ear, was found in 33% of the male and almost 29% of the female participants aged 65 years and older. Compared with previous studies, men had less hearing loss at the frequencies of 2 kHz and above. Hearing thresholds in women were significantly higher at 4 and 8 kHz. The difference in hearing loss between men and women is significantly less than in earlier studies. CONCLUSIONS: Our study confirms that hearing loss is highly prevalent in the general unscreened population of older adults. However, the difference in hearing between sexes was considerably less than previously reported. This is probably due to changing lifestyle and environmental circumstances, LEVEL OF EVIDENCE: 2b Laryngoscope, 127:725-730, 2017.

Contributing Determinants to Hearing Loss in Elderly Men and Women: Results from the Population-Based Rotterdam Study.

To contribute to a better understanding of the etiology in age-related hearing loss, we carried out a cross-sectional study of 3,315 participants (aged 52-99 years) in the Rotterdam Study, to analyze both low- and high-frequency hearing loss in men and women. Hearing thresholds with pure-tone audiometry were obtained, and other detailed information on a large number of possible determinants was collected. Hearing loss was associated with age, education, systolic blood pressure, diabetes mellitus, body mass index, smoking and alcohol consumption (inverse correlation). Remarkably, different associations were found for low- and high-frequency loss, as well as between men and women, suggesting that different mechanisms are involved in the etiology of age-related hearing loss.

Hearing Loss Progresses Faster in Patients With Growing Intracanalicular Vestibular Schwannomas.

OBJECTIVE: To determine whether certain patient and tumor characteristics influence the progression of hearing loss in vestibular schwannoma (VS) patients. STUDY DESIGN: Retrospective study. SETTING: Tertiary referral center, Erasmus Medical Centre in Rotterdam, The Netherlands. PATIENTS: One hundred fifty-five patients referred from 2000 through 2010 with intracanalicular, small or medium sized, unilateral VS, managed without active treatment. INTERVENTION: Wait and scan protocol with sequential magnetic resonance imaging and audiometry. MAIN OUTCOME MEASURES: Hearing loss as pure-tone average (PTA) in dB and progression of hearing loss expressed as the annual change in PTA or annual hearing decreasing rate (AHDR) in dB/yr. RESULTS: At presentation the mean hearing loss was 47 dB and the mean asymmetry between the tumor ear and the contralateral ear was 28 dB. The mean AHDR in wait and scan patients was 3.5 dB/yr (sd 4.6). Tumor growth was associated with the AHDR in patients with intracanalicular tumors. In patients with tumors extending into the cerebellopontine angle, we found a negative association between the AHDR and the PTA of the contralateral side. The explained variance, however, was low. No association was found between the AHDR and patient age, PTA in the tumor ear, tumor size, speech discrimination score at diagnosis or hypo-intensity of the cochlear fluids on magnetic resonance imaging. CONCLUSION: There is no association between hearing deterioration and clinical characteristics in our 155 VS patients. Hearing loss is associated with tumor growth in intracanalicular tumors only.

Noncompliance to guidelines in head and neck cancer treatment; associated factors for both patient and physician.

BACKGROUND: Decisions on head and neck squamous cell carcinoma (HNSCC) treatment are widely recognized as being difficult, due to high morbidity, often involving vital functions. Some patients may therefore decline standard, curative treatment. In addition doctors may propose alternative, nonstandard treatments. Little attention is devoted, both in literature and in daily practice, to understanding why and when HNSCC patients or their physicians decline standard, curative treatment modalities. Our objective is to determine factors associated with noncompliance in head and neck cancer treatment for both patients and physicians and to assess the influence of patient compliance on prognosis. METHODS: We did a retrospective study based on the medical records of 829 patients with primary HNSCC, who were eligible for curative treatment and referred to our hospital between 2010 and 2012. We analyzed treatment choice and reasons for nonstandard treatment decisions, survival, age, gender, social network, tumor site, cTNM classification, and comorbidity (ACE27). Multivariate analysis using logistic regression methods was performed to determine predictive factors associated with non-standard treatment following physician or patient decision. To gain insight in survival of the different groups of patients, we applied a Cox regression analysis. After checking the proportional hazards assumption for each variable, we adjusted the survival analysis for gender, age, tumor site, tumor stage, comorbidity and a history of having a prior tumor. RESULTS: 17 % of all patients with a primary HNSCC did not receive standard curative treatment, either due to nonstandard treatment advice (10 %) or due to the patient choosing an alternative (7 %). A further 3 % of all patients refused any type of therapy, even though they were considered eligible for curative treatment. Elderliness, single marital status, female gender, high tumor stage and severe comorbidity are predictive factors. Patients declining standard treatment have a lower overall 3-year survival (34 % vs. 70 %). CONCLUSIONS: Predictive factors for nonstandard treatment decisions in head and neck cancer treatment differed between the treating physician and the patient. Patients who received nonstandard treatment had a lower overall 3-year survival. These findings should be taken into account when counselling patients in whom nonstandard treatment is considered.

Prognosis: a variable parameter: dynamic prognostic modeling in head and neck squamous cell carcinoma.

BACKGROUND: In general, the estimated prognosis of patients with cancer is based on patient characteristics known at the time of diagnosis and presented as if a lifetime verdict. However, the prognosis of patients with cancer who survive the first critical years changes, along with the prognosis for those with local or regional recurrences or distant metastases. METHODS: This study concerns 2927 patients with a primary head and neck squamous cell carcinoma (HNSCC). We developed prognostic models after initial treatment and at different time points during follow-up. RESULTS: The developed models show the effects of survival time, recurrences, and distant metastasis during follow-up. The C-statistics ranged from 0.76 to 0.69. CONCLUSION: Prognosis is dynamic: the passage of time and the occurrence of life events change the predicted probabilities of survival. The models enhance our insight in the effect of recurrences and metastasis during follow-up and could be used for better patient counseling.

High complication risk of salvage surgery after chemoradiation failures.

CONCLUSIONS: Although organ preservation can be achieved with chemoradiation protocols for laryngeal or pharyngeal cancers, salvage surgery is accompanied by high complication rates. OBJECTIVES: To determine the rate of complications associated with salvage surgery after chemoradiation for laryngeal and pharyngeal cancers. METHODS: A multicenter retrospective study was performed of 24 patients treated with total laryngectomy combined with total or partial pharyngectomy between 1995 and 2004 who had previously been treated with chemoradiation. The main outcome measures were early and late complication rates. Quality of life analysis was determined by two questionnaires. RESULTS: The complication rate after salvage surgery was 92% in the direct postoperative period. The most frequent complication was pharyngocutaneous fistula formation. Narrowing of the esophagus and tracheostoma were the most common late sequelae. The quality of life, measured at least 2 years after salvage surgery, showed a social dysfunctioning.

Cytology and histology have limited added value in prognostic models for salivary gland carcinomas.

Univariate analyses on malignant salivary gland tumors report a strong relation of histological subtypes and prognosis. However, multivariate analyses with sufficient patients and reflecting the broad spectrum of putative prognostic factors are rare. In order to study the prognostic value of cytology and histology in salivary carcinoma we performed multivariate analyses on 666 newly diagnosed patients. In multivariate analyses sex, tumor size, N- and M-staging, localization, comorbidity, skin involvement and pain were independent predictors of survival. Histology was an independent prognostic factor, mainly because acinic cell carcinoma acted differently from the other histological subtypes. However, a simple prognostic model without cytology and/or histology has similar predictive power compared to more elaborate models. The added prognostic value of cytology and/or histology factors in salivary carcinoma is limited, largely due to the combined prognostic value of other prognostic factors such as tumor size, N- and M-classification and comorbidity.

Phonological development in very-low-birthweight children: an exploratory study.

AIM: Very-low-birthweight (VLBW; birthweight<1500 g and/or gestational age <32 wks) children are at risk for speech problems. However, there are few studies on speech development in VLBW children at an early age. The aim of this study was to investigate phonological development in 2-year-old VLBW children. METHOD: Twenty VLBW children without major neurosensory impairment (7 males, 13 females; mean birthweight 971 g, SD 315; mean gestational age 28 wks, SD 1.81) and 20 term children (7 males, 13 females; mean birthweight 3503 g, SD 416; mean gestational age 40 wks, SD 1.26) were compared on measures of phonological development derived from 20-minute spontaneous speech samples of standardized mother-child play interaction as well as on standardized tests of cognitive and psychomotor development, language, and behaviour. RESULTS: VLBW children had significantly fewer acquired consonants (median 9, p=0.02) and a significantly lower phonological mean length of utterance (pMLU; median 4.1, p<0.01) than term children (median acquired consonants 10, median pMLU 5.0). INTERPRETATION: This study provides evidence for poor phonological development in even healthy VLBW children, compared with term-matched children, independent of their cognitive, psychomotor, and language development, and their behavioural functioning.

The applicability of the dysphonia severity index and the voice handicap index in evaluating effects of voice therapy and phonosurgery.

The objective was to investigate the applicability of the Dysphonia Severity Index (DSI) and the Voice Handicap Index (VHI) in evaluating effects of intervention between groups of patients and for intrasubject differences and whether DSI and VHI are complementing measurements. Analyses of measurement data before and after intervention of 171 patients with voice disorders. The voice quality was measured objectively with the DSI. The perceived voice handicap was measured with the VHI. Three groups of patients were used: patients who had voice therapy, phonosurgery, or no intervention. DSI and VHI improved significantly after intervention in the voice therapy and the surgery group (median difference DSI 1.19 and 3.03, VHI -8 and -26, respectively). The intrasubject results were analyzed based on the test-retest variability of DSI and VHI. Significant better DSI and VHI scores after intervention were found in, respectively, 22% and 38% of the patients with voice therapy, and 56% and 78% of the patients with surgery. In the no intervention group, this was 11% and 12%. In 37% of the patients, the differences before and after intervention in DSI and VHI were in discordance. The DSI and VHI are able to show significant differences after intervention for voice disorders between groups of patients. The DSI and VHI can be used to determine a significant intrasubject result of intervention. The DSI and VHI measure each different aspects of the voice and are complementing measurements. The DSI is therefore applicable in clinical practice for objective evaluation of voice quality and the VHI for subjective evaluation of the perceived handicap by the patient self.

The impact of ambient NO on online measurements of exhaled and nasal NO: the PIAMA study.

The guidelines of the American Thoracic Society (ATS) and the European Respiratory Society (ERS) for standardized measurements of exhaled nitric oxide (NO) state that for online measurements the inhaled air should be free of NO. As it is not always possible to create an NO-free environment, inhalation through an NO-scrubber is used. To describe the relationship between ambient NO and measurements of fractional exhaled NO (FENO) and nasal NO (nNO) investigated according to the ATS-ERS guidelines in a large population of children. The present work makes use of data collected during the 8-yr follow-up of the Dutch PIAMA birth cohort study. FENO and nNO were measured in three hospitals in a total of 1005 children with a NIOX chemiluminescence analyser. In two hospitals, almost half of the measured ambient NO levels exceeded 5 p.p.b. Maximum levels were >100 p.p.b. in all hospitals. Despite its large variation, ambient NO did not have an effect on FENO, but it did have a significant impact on nNO in two of the three centres. The currently recommended technique including inhalation through an NO scrubber effectively deals with variable levels of ambient NO on FENO. In contrast, ambient NO has an effect on measurements of nNO.

Adenotonsillectomy and the development of overweight.

OBJECTIVE: Studies among patients have shown accelerated weight gain after (adeno)tonsillectomy. Whether (adeno)tonsillectomy is also a risk factor for the development of overweight is unknown. We investigated the association between (adeno)tonsillectomy and the subsequent development of overweight in the general population. METHODS: The study population consisted of 3963 children participating in the Dutch Prevention and Incidence of Asthma and Mite Allergy birth cohort. Data on weight and height, adenoidectomy and tonsillectomy, and covariates (gender, birth weight, maternal education, maternal overweight, maternal smoking during pregnancy, breastfeeding, and smoking in the home) were obtained from annual questionnaires completed by the parents. In addition to the questionnaire data, weight and height were measured by the investigators when the children were 8 years old. RESULTS: (Adeno)tonsillectomy between 0 and 7 years of age was significantly associated with overweight and obesity at age 8. Overweight at the age of 2 years was not associated with increased risk of (adeno)tonsillectomy in later years, indicating that the association between (adeno)tonsillectomy and overweight was not explained by preexisting overweight. Longitudinal data on weight and height in the years before and after surgery suggest that (adeno)tonsillectomy forms a turning point between a period of growth faltering and a period of catch-up growth, which might explain the increased risk to develop overweight after the operation. CONCLUSION: Children who undergo (adeno)tonsillectomy are at increased risk to develop overweight in the years after surgery.

The influence of parental educational level on the development of atopic sensitization, wheezing and eczema during the first year of life.

Several studies have investigated the association between socioeconomic status and the occurrence of allergies. Nevertheless, the results remain contradictory. The aim of this study was to evaluate the associations between parental education and the occurrence of atopic sensitization, recurrent wheezing and eczema during the first year of life, differentiating between atopic and non-atopic disorders based on specific serum IgE. We conducted an aetiological study in 690 children, based on a prospective birth cohort project in which environmental and health information was gathered using questionnaires. At the age of 1 yr a blood sample was taken for quantification of specific IgE. Adjusted odds ratios and 95% confidence intervals were computed as measures of association between the outcomes and parental education. Parental educational level was positively associated with the occurrence of atopic sensitization (OR: 2.1; 95% CI: 1.0-4.4) and eczema (OR: 1.9; 95% CI: 1.1-3.4), but negatively with the occurrence of recurrent wheezing (OR: 0.4; 95% CI: 0.2-0.8) in the first year of life. Atopic recurrent wheezing was positively associated with the education of the parents, whereas non-atopic recurrent wheezing was negatively associated. When maternal and paternal education were considered separately, only maternal education had a significant influence. Our results suggest that aspects associated with a high maternal educational level may play an important role in the development of atopic disorders.

Bile acids identified in middle ear effusions of children with otitis media with effusion.

OBJECTIVES/HYPOTHESIS: Several studies have shown the presence of pepsin in the middle ear effusions of children with otitis media with effusion (OME). When gastric reflux is the cause, other noxious reflux products might be present. We therefore investigated the presence of bile acids in the middle ear effusions of children with OME. STUDY DESIGN: We evaluated 38 children (63 samples of middle ear secretions (ME samples)) in a prospective study at a tertiary care children's hospital. METHODS: ME samples were collected from children with OME during ventilation tube insertion. Most ME samples were diluted with albumin. The presence of bile acids was measured with the 3alpha-hydroxy steroid dehydrogenase enzymatic method. A ME sample was considered positive when it contained at least 5 mumol/l bile acids, independent of dilution. Blood samples were taken simultaneously as a reference to determine bile acids serum levels. RESULTS: We found bile acids in 32 % (20/63) of all ME samples and in 42% (16/38) of all children. Bile acids concentrations of 12 well-soluble ME samples ranged from 5.9-40.9 mumol/L and were 3.1-19.7 times higher than the serum concentrations. In 4 of the corresponding serums, no bile acids were measurable at all. CONCLUSIONS: Bile acids are present in a number of the ME samples of children with OME. Because of dilution, it is possible that more ears contain bile acids. Bile acids are known to be noxious to mucosal cells at a higher (pH) than pepsin and, therefore, might play a role in the pathology of OME.