Novel human lymph node-derived matrix supports the adhesion of metastatic oral carcinoma cells.

BACKGROUND: 3D culture is increasingly used in cancer research, as it allows the growth of cells in an environment that mimics in vivo conditions. Metastases are the primary cause of morbidity and mortality in cancer patients, and solid tumour metastases are mostly located in lymph nodes. Currently, there are no techniques that model the pre-metastatic lymph node microenvironment in vitro. In this study, we prepared a novel extracellular matrix, Lymphogel, which is derived from lymph nodes, mimicking the tumour microenvironment (TME) of metastatic carcinoma cells. We tested the suitability of the new matrix in various functional experiments and compared the results with those obtained using existing matrices. METHODS: We used both commercial and patient-derived primary and metastatic oral tongue squamous cell carcinoma (OTSCC) cell lines. We characterized the functional differences of these cells using three different matrices (human uterine leiomyoma-derived Myogel, human pre-metastatic neck lymph node-derived Lymphogel (h-LG), porcine normal neck lymph node-derived Lymphogel (p-LG) in proliferation, adhesion, migration and invasion assays. We also performed proteomic analyses to compare the different matrices in relation to their functional properties. RESULTS: OTSCC cells exhibited different adhesion and invasion patterns depending on the matrix. Metastatic cell lines showed improved ability to adhere to h-LG, but the effects of the matrices on cell invasion fluctuated non-significantly between the cell lines. Proteomic analyses showed that the protein composition between matrices was highly variable; Myogel contained 618, p-LG 1823 and h-LG 1520 different proteins. The comparison of all three matrices revealed only 120 common proteins. Analysis of cellular pathways and processes associated with proteomes of each matrix revealed similarities of Myogel with h-LG but less with p-LG. Similarly, p-LG contained the least adhesion-related proteins compared with Myogel and h-LG. The highest number of unique adhesion-related proteins was present in h-LG. CONCLUSIONS: We demonstrated that human pre-metastatic neck lymph node-derived matrix is suitable for studying metastatic OTSCC cells. As a whole-protein extract, h-LG provides new opportunities for in vitro carcinoma cell culture experiments.

Timing and frequency of oropharyngeal squamous cell carcinoma recurrences after treatment with curative intent.

BACKGROUND: The increasing number of patients under surveillance after treatment of human papillomavirus-related oropharyngeal squamous cell carcinoma (OPSCC) places a great burden on healthcare providers. AIMS/OBJECTIVES: The aim of this study was to explore OPSCC recurrences in a long follow-up period: their site, frequency and timepoint after primary treatment, treatment and outcome. The secondary aim was to investigate if the recurrences are diagnosed on routine follow-up visits, and if the p16 status will have an effect on the pattern of recurrences. MATERIAL AND METHODS: We analyzed recurrences within a 10-year follow-up period after completed curatively intended treatment among OPSCC patients in Finland treated between 2000 and 2009. Patient-, tumor-, treatment- and follow-up -related parameters were investigated. RESULTS: Out of 495 patients with no residual tumor during the first six months, 71 (14%) were diagnosed with a recurrence, of which 47 were locoregional and 28 were treated with curative intent. Of the recurrences, 86% were diagnosed during the first 36 months after primary treatment. Only ten recurrences appeared after 36 months. The median OS after recurrence was 10.9 months. CONCLUSIONS AND SIGNIFICANCE: Routine follow-up longer than three years after treatment seems not to be effective in terms of detecting OPSCC recurrences.

Diagnostic prediction models for CT-confirmed and bacterial rhinosinusitis in primary care: individual participant data meta-analysis.

BACKGROUND: Antibiotics are overused in patients with acute rhinosinusitis (ARS) as it is difficult to identify those who benefit from antibiotic treatment. AIM: To develop prediction models for computed tomography (CT)-confirmed ARS and culture-confirmed acute bacterial rhinosinusitis (ABRS) in adults presenting to primary care with symptoms suggestive of ARS. DESIGN AND SETTING: This was a systematic review and individual participant data meta-analysis. METHOD: CT-confirmed ARS was defined as the presence of fluid level or total opacification in any maxillary sinuses, whereas culture-confirmed ABRS was defined by culture of fluid from antral puncture. Prediction models were derived using logistic regression modelling. RESULTS: Among 426 patients from three studies, 140 patients (32.9%) had CT-confirmed ARS. A model consisting of seven variables: previous diagnosis of ARS, preceding upper respiratory tract infection, anosmia, double sickening, purulent nasal discharge on examination, need for antibiotics as judged by a physician, and C-reactive protein (CRP) showed an optimism-corrected c-statistic of 0.73 (95% confidence interval [CI] = 0.69 to 0.78) and a calibration slope of 0.99 (95% CI = 0.72 to 1.19). Among 225 patients from two studies, 68 patients (30.2%) had culture-confirmed ABRS. A model consisting of three variables: pain in teeth, purulent nasal discharge, and CRP showed an optimism-corrected c-statistic of 0.70 (95% CI = 0.63 to 0.77) and a calibration slope of 1.00 (95% CI = 0.66 to 1.52). Clinical utility analysis showed that both models could be useful to rule out the target condition. CONCLUSION: Simple prediction models for CT-confirmed ARS and culture-confirmed ABRS can be useful to safely reduce antibiotic use in adults with ARS in high-prescribing countries.

Finnish Version of the Eating Assessment Tool (F-EAT-10): A Valid and Reliable Patient-reported Outcome Measure for Dysphagia Evaluation.

Our aim was to validate a Finnish version of the Eating Assessment Tool (F-EAT-10) for clinical use and to test its reliability and validity in a multicenter nationwide study. Normative data were acquired from 180 non-dysphagic participants (median age 57.0 years, 62.2% female). Dysphagia patients (n = 117, median age 69.7 years, 53.0% female) referred to fiberoptic endoscopic evaluation of swallowing (FEES) completed F-EAT-10 before the examination and after 2 weeks. Patients underwent the 100-ml water swallow test (WST) and FEES was evaluated using the following three scales: the Yale Pharyngeal Residue Severity Rating Scale, Penetration-Aspiration Scale, and the Dysphagia Outcome Severity Scale. An operative cohort of 19 patients (median age 75.8 years, 57.9% female) underwent an endoscopic operation on Zenker's diverticulum, tight cricopharyngeal muscle diagnosed in videofluorography, or both. Patients completed the F-EAT-10 preoperatively and 3 months postoperatively. The cut-off score for controls was < 3 (sensitivity 94.0%, specificity 96.1%) suggesting that ≥ 3 is abnormal. Re-questionnaires for test-retest reliability analysis were available from 92 FEES patients and 123 controls. The intraclass correlation coefficient was excellent for the total F-EAT-10 score (0.93, 95% confidence interval 0.91-0.95). Pearson correlation coefficients were strong (p < 0.001) for each of the questions and the total score. Internal consistency as assessed by Cronbach's alpha was excellent (0.95). Some correlations between findings in FEES and 100-ml WST with F-EAT-10 were observed. The change in subjective symptoms of operative patients paralleled the change in F-EAT-10. F-EAT-10 is a reliable, valid, and symptom-specific patient-reported outcome measure for assessing dysphagia among Finnish speakers.

Total or partial tonsillar resection (tonsillectomy or tonsillotomy) to change the quality of life for adults with recurrent or chronic tonsillitis: study protocol for a randomised controlled trial.

BACKGROUND: Tonsillar surgery has been used for decades to treat recurrent and chronic tonsillitis in adults. Recurrent and chronic tonsillitis result in disturbing symptoms, treatment costs, sick leave, and impaired quality of life (QoL). Theoretically, removing all or part of the altered pathological palatal lymphoid tissue alleviates the symptoms and enhances the QoL. Whether this is true with total or partial tonsillar resection (tonsillectomy (TE) and tonsillotomy (TT), respectively) has not been reported in a randomised trial yet. METHODS: We conduct a multicentre, partly blinded, randomised, 6-month, parallel-group clinical study including 285 adult participants referred to surgical treatment for chronic or recurrent tonsillitis. The participants will either have TE, TT or watchful waiting (WW). The primary outcome will be the difference between the mean disease-specific Tonsillectomy Outcome Inventory-14 (QoL questionnaire) scores at 6 months. Comparison is made firstly between the combined TE+TT and WW groups (superiority analysis), and secondly between the TE and TT groups (non-inferiority analysis). DISCUSSION: This study will add significant new information to the effects and harms of TE and TT procedures in the treatment of adults with chronic or recurrent tonsillitis. TRIAL REGISTRATION: ClinicalTrials.gov: NCT04657549.

Long-term Quality of Life After Treatment of Oropharyngeal Squamous Cell Carcinoma.

OBJECTIVES: To analyze the long-term quality of life (QOL) among oropharyngeal squamous cell carcinoma (OPSCC) survivors. STUDY DESIGN: Retrospective chart analysis and patient response to European Organization for Research and Treatment of Cancer Quality of Life Questionnaire, Core Module (EORTC QLQ-C30), Head and Neck Module (EORTC QLQ-H&N35), and M.D. Anderson Dysphagia Inventory (MDADI) survey questionnaires. METHODS: All survivors of OPSCC diagnosed and treated between 2000 and 2009 in Finland were included. There were 263 survivors (44.2% of all curatively treated patients), of which a total of 164 participated in this study (62.4%). Median follow-up was 11.79 years (range = 8.59-18.53 years, interquartile range [IQR] = 4.64 years). The mean age of the participants was 67.9 years (standard deviation = 8.0 years) at QOL follow-up. RESULTS: Most survivors reported a good QOL. The EORTC QLQ-C30 global health status median was 75.00 (IQR = 31.25). The single modality treatment group had significantly better QOL outcomes than the combined treatment group. Nonsmokers and previous smokers had significantly better QOL outcomes than patients who smoked at the time of diagnosis. A history of heavy alcohol use resulted in significantly worse QOL outcomes. The p16-positive cancer patients had significantly better QOL outcomes than p16-negative patients. Percutaneous endoscopic gastrostomy (PEG) tube-dependent patients reported a significantly worse QOL than patients without a PEG tube. CONCLUSIONS: Long-term QOL in OPSCC survivors is generally good. In line with previous literature, single modality treatment was superior to combined treatment in long-term QOL outcomes, and it should be pursued whenever possible. LEVEL OF EVIDENCE: 4 Laryngoscope, 131:E1172-E1178, 2021.

Interpretation of Tonsillectomy Outcome Inventory-14 scores: a prospective matched cohort study.

PURPOSE: Knowledge of disease-specific instruments enables the evaluation of health- related quality-of-life (QoL) change associated with chronic and recurrent tonsillitis in adults. The main objective was to explore the interpretation of scores according to the throat-related QoL instrument, Tonsillectomy Outcome Inventory-14 (TOI-14), by determining the typical scores in healthy subjects and patients and define the minimum important change (MIC). METHODS: We performed a prospective matched cohort study in a secondary care area of Oulu University Hospital. The surgical cohort consisted of 42 patients referred to tonsillectomy due to recurrent or chronic tonsillitis. The control cohort consisted of 42 age- and sex-matched healthy controls obtained from the escorts of patients in the same hospital. We translated and validated the Finnish TOI-14 instrument and collected TOI-14 scores at entry and at 6 months and compared results to the anchor question. RESULTS: At entry, the mean TOI-14 scores were significantly higher in the surgical cohort than in the control cohort [mean (95% confidence interval)] 33.0 (27.0-39.1) vs. 5.0 (3.6-6.4), respectively. At 6 months follow-up, the mean TOI-14 scores had improved markedly after tonsillectomy to the level of the control cohort. In the healthy population, the score was in most cases under 15.0 points. In patients, a score of about 20.0 indicated mild symptoms, 30.0 moderate symptoms and 40.0 or higher intense symptoms. The MIC value was 10.0 points. CONCLUSIONS: These results enable the more accurate interpretation of the scores of the only disease-specific QoL instrument for adult throat-related diseases.

A descriptive study highlighting the differences in the treatment protocol for oral tongue cancer in Sweden and Finland.

Background and aims: Stage II cancer of the tongue is mostly managed surgically both locally and regionally. However, indications for postoperative radiotherapy and reconstructive options vary between centers. This paper aims to describe differences in treatment in a geographically homogenous cohort.Methods: A retrospective comparison was made between two cohorts of clinical T2N0 tongue cancer from Finland and Sweden. The Finnish cohort included 75 patients and the Swedish 54. All patients had curative intent of treatment and no previous head and neck cancer. Data analyzed consisted of pathological stage, size and thickness of tumor, frequency of reconstruction, radiotherapy delivered, and survival.Results: The Finnish cohort included a higher proportion of patients managed with reconstructive surgery (67%) than the Swedish cohort (0%), p < .00001. More patients were treated with postoperative radiotherapy (84%) in the Swedish cohort than in the Finnish (54%), p < .0002. The Finnish cohort had a higher level of survival and included more frequent downstaging (cTNM to pTNM).Conclusions and significance: Our data indicate a major difference in the management of T2N0 oral tongue cancer. The optimal cut-off size and growth pattern of the tumor warranting reconstruction should be further evaluated in a prospective manner considering both survival and quality of life.

Inflammatory Biomarkers During Bacterial Acute Rhinosinusitis.

PURPOSE OF REVIEW: Diagnosis of bacterial acute rhinosinusitis is difficult. Several attempts have been made to clarify the diagnostic criteria. Inflammatory biomarkers are easily obtainable variables that could shed light on both the pathophysiology and diagnosis of bacterial acute rhinosinusitis. The purpose of this review article is to assess literature concerning the course of inflammatory biomarkers during acute rhinosinusitis and the use of inflammatory biomarkers in diagnosing bacterial acute rhinosinusitis. RECENT FINDINGS: We included C-reactive protein, erythrocyte sedimentation rate, white blood cell counts, procalcitonin, and nasal nitric oxide in this review and found that especially elevated C-reactive protein and erythrocyte sedimentation rate are related to a higher probability of a bacterial cause of acute rhinosinusitis. Still, normal levels of these two biomarkers are quite common as well, or the levels can be heightened even during viral respiratory infection without suspicion of bacterial involvement. Elevated levels of C-reactive protein or erythrocyte sedimentation rate support diagnosis of bacterial acute rhinosinusitis, but due to a lack of sensitivity, they should not be used to screen patients for bacterial acute rhinosinusitis.

Longitudinal analysis of inflammatory biomarkers during acute rhinosinusitis.

OBJECTIVE: To illuminate the pathophysiology of acute rhinosinusitis (ARS) with sequential monitoring of inflammatory biomarkers during an ARS episode and to clarify their diagnostic usability in bacterial ARS. STUDY DESIGN: Inception cohort study with 50 conscripts with ARS. METHODS: We collected peripheral blood high-sensitive C-reactive protein (hs-CRP), white blood cell (WBC), procalcitonin, and nasal nitric oxide (nNO) counts at 2 to 3 and 9 to 10 days of symptoms during an ARS episode. We simultaneously gathered various clinical parameters and microbiological samples. Bacterial ARS was confirmed with a positive culture of sinus aspirate. RESULTS: Reciprocal correlations and a significant change in biomarker levels between the two visits suggest that ARS involves a local and systemic inflammatory response that was strongest at 2 to 3 days. High-sensitive CRP and nNO reflected responses best (52% had increased CRP levels at 2-3 days; 66% had decreased nNO levels). White blood cell and procalcitonin counts rarely exceeded the reference range. Increased local and systemic inflammatory response were linked to multiple, adenoviral, or influenza A viral etiology or the detection of bacterial ARS. Local response correlated with imaging findings of wide paranasal sinus involvement and ostiomeatal complex occlusion. At 9 to 10 days, elevated (≥ 11 mg/L) and moderately elevated (≥ 49 mg/L) hs-CRP predicted bacterial ARS well (likelihood ratio [LR]+ 3.3 and LR+ 15.8, respectively), but the sensitivity for both findings remained low. CONCLUSION: Acute rhinosinusitis (particularly bacterial ARS) involves a local and systemic inflammatory response that is strongest at the beginning of symptoms. Elevated hs-CRP supports the diagnosis of bacterial ARS. LEVEL OF EVIDENCE: 4. Laryngoscope, 2016 127:E55-E61, 2017.

Imaging follow-up study of acute rhinosinusitis.

OBJECTIVES/HYPOTHESIS: To evaluate with imaging the course of acute rhinosinusitis (ARS) and the associations between paranasal imaging results, symptoms, bony anatomic variations, and culture-proven bacterial ARS. STUDY DESIGN: Inception cohort study with 50 conscripts with ARS. METHODS: During a single ARS episode, we collected symptoms daily and took sequential cone-beam computed tomography (CBCT) scans of the paranasal sinuses of the same patients 2 to 3, 5 to 6 and 9 to 10 days after the onset of symptoms. Culture-proven bacterial ARS was verified with maxillary sinus aspiration and bacterial culture at 9 to 10 days. RESULTS: At 2 to 3 days, 38% of the patients had major abnormalities, 42% had minor abnormalities in their paranasal sinuses, and 68% had an occluded ostiomeatal complex (OMC). At 5 to 6 days and 9 to 10 days, these proportions remained essentially the same. At 2 to 3 days, patients with bacterial ARS had slightly higher CBCT scores than those without bacterial ARS. Later, the CBCT and symptom scores gradually increased in patients with bacterial ARS and decreased in those without bacterial ARS. The CBCT and symptom scores had only a weak correlation (rs = 0.36), and anatomic variations were not related to development of bacterial ARS. CONCLUSIONS: Paranasal mucosal abnormalities and occlusion of the OMC do not develop gradually during ARS, but are present when symptoms begin and remain fairly constant in most patients both with and without bacterial ARS. This indicates that the spread of the disease process to the paranasal sinuses and obstruction of the OMC may not be etiological factors in the development of bacterial ARS. LEVEL OF EVIDENCE: 4 Laryngoscope, 126:1965-1970, 2016.

Middle ear findings and need for ventilation tubes among pediatric cleft lip and palate patients in northern Finland.

PURPOSE: Middle ear problems are common in cleft patients. This study aimed to determine the need for ventilation tubes (VTs) and complications such as tympanic perforation and cholesteatoma. MATERIAL AND METHODS: Data of 156 children with clefts managed in northern Finland spanning 15 years from 1997 to 2011 were collected from 6 hospitals. The following were recorded: birth date, gender, cleft type, surgery timing, surgery type, number of tube insertions, tube material, middle ear findings, and tube placement timing. Clefts were divided into 4 groups: cleft palate (CP), cleft lip and palate (CLP), cleft lip (CL), and submucous cleft palate. The prevalence of middle ear findings was reported. RESULTS: Mucous secretion was noted in 96.8% of CLP patients, 69.2% of CP patients, and 13.0% of CL patients. In all, 82.7% of study group had 1 or more VTs placed during follow-up. All CLP patients required more than 1 VT placement. A total of 94.5% of CP patients required VTs compared to 13.0% of CL patients. In the presence of residual oral nasal fistula, the mean number of tube insertions was 5.3. The prevalence of tympanic perforations in clefts was 35.9% and cholesteatoma in 2.6% of patients. CONCLUSIONS: CLP and isolated CP patients have frequent middle ear infections requiring multiple VT placements.

The association of cleft severity and cleft palate repair technique on hearing outcomes in children in northern Finland.

BACKGROUND: The consequences of cleft lip and palate include scaring, dental malformations, tooth misalignment, speech problems, and hearing loss. Otitis media with effusion causing hearing loss is a problem for many cleft palate patients. METHODS: This study examines the association among cleft severity, palate repair technique, and hearing outcomes in children from northern Finland with clefts, aged 3-9 years. The study included 90 cleft patients who were treated at the Oulu University Hospital Cleft Lip and Palate Center between 1998 and 2011. The severity of the cleft, the surgical technique used to repair the palate, audiogram configuration data, and the need for ventilation tube placement were determined retrospectively from patient records. RESULTS: Only 3.3% of cleft patients had an abnormal pure tone average hearing threshold representing abnormal hearing. Neither the surgical technique used to repair the cleft palate nor the severity of the cleft was a significant factor related to hearing loss or to the number of ventilation tubes required. Hearing improved significantly with increasing age over a span of 6 years. CONCLUSIONS: Continuous follow-up with proactive placement of ventilation tubes before or at the time of palatoplasty results in hearing outcomes in cleft children that are similar to those reported in non-cleft children.

Diagnostic accuracy of history and physical examination in bacterial acute rhinosinusitis.

OBJECTIVES/HYPOTHESIS: To evaluate the diagnostic accuracy of symptoms, the symptom progression pattern, and clinical signs in identifying bacterial acute rhinosinusitis (ARS). STUDY DESIGN: We conducted an inception cohort study among 50 military recruits with ARS. METHODS: We collected symptoms daily from the onset of symptoms to approximately 10 days. At 9 to 10 days, standardized data on symptoms and physical findings were gathered. A positive culture of maxillary sinus aspirate was considered to be the reference standard for bacterial ARS. RESULTS: At 9 to 10 days, the presence or deterioration after 5 days of any of the symptoms could not be used to diagnose bacterial ARS. Toothache had an adequate positive likelihood ratio (positive likelihood ratio [LR+] 4.4) but was too rare to be used for screening. In contrast, several physical findings at 9 to 10 days were of more diagnostic use and frequent enough for screening. Moderate or profuse (vs. none/minimal) amount of secretion in nasal passage seen in anterior rhinoscopy satisfactorily either ruled in, if present (LR+ 3.2), or ruled out, if absent (negative likelihood ratio 0.2), bacterial ARS. If any secretion was seen in the posterior pharynx or middle meatus, the probability of bacterial ARS increased markedly (LR+ 5.3 and LR+ 11.0, respectively). CONCLUSION: We found symptoms or their change to be of little use in identifying bacterial ARS. In contrast, we observed several clinical findings after 9 to 10 days of symptoms to predict bacterial ARS quite accurately.

The role of microbes in the pathogenesis of acute rhinosinusitis in young adults.

OBJECTIVES/HYPOTHESIS: To provide information on the course of acute rhinosinusitis (ARS) with sequential nasal and paranasal microbiological data and their correlation with clinical outcomes. STUDY DESIGN: We conducted a prospective cohort study among 50 Finnish military recruits with clinically diagnosed ARS in spring 2012. METHODS: We collected symptom, nasal endoscopy, and cone-beam CT (CBCT) scores during the early (2-3 days from onset) and later phases (9-10 days). We took viral samples from the nasopharynx (multiplex respiratory virus polymerase chain reaction [PCR]), bacterial culture from the middle meatus during both phases, and both viral and bacterial samples from the maxillary sinus aspirate (respiratory virus PCR, bacterial culture, broad-range bacterial PCR) during the later phase. Cilia destruction and microbial biofilms were sought from a nasal mucosal biopsy sample. RESULTS: We found that 42 (84%) of the subjects had viral nucleic acid in the nasopharynx during ARS. During the early phase, 28 (56%) of the subjects had nontypeable H. influenzae (NTHi) in the middle meatus, which was associated with wider paranasal mucosal changes in CBCT scans and increased symptoms during the study period. After 9 to 10 days from the onset, NTHi was found in the maxillary sinus in eight subjects (40%, 8/20) and led to prolonged symptoms. Bacterial biofilm was ruled out in 39 (78%) cases, and cilia destruction did not correlate with microbiological or clinical outcomes. CONCLUSION: Nasal and paranasal H. influenzae coinfection during viral infection may modify the symptoms and the extent of sinonasal mucosal disease observed in CBCT scans already from the beginning of the ARS episode.