Publications by authors named "Elisabeth Bloemena"

108 Publications

The unveiled reality of human papillomavirus as risk factor for oral cavity squamous cell carcinoma.

Int J Cancer 2021 Feb 26. Epub 2021 Feb 26.

Amsterdam UMC, Vrije Universiteit Amsterdam, Otolaryngology/Head and Neck Surgery, Cancer Center Amsterdam, Amsterdam, Netherlands.

The prognostic impact of human papillomavirus (HPV) in oropharyngeal cancer is generally acknowledged, and HPV-status is assessed routinely in clinical practice. Paradoxically, while the oral cavity seems the predilection site for productive HPV-infections, figures on HPV-attribution in oral cavity squamous cell carcinoma (OCSCC) differ widely, and prognostic impact is uncertain. Major obstacles are the lack of reproducible assays for non-oropharyngeal cancers, the relatively small cohorts studied, and consequently the shortfall of convincing data. In this study, we used a validated, nucleic acid-based workflow to assess HPV-prevalence in a consecutive cohort of 1,016 OCSCCs, and investigated its prognostic impact. In parallel, we analyzed p16-immunohistochemistry (p16-IHC) as surrogate marker for transforming HPV-infection and independent prognosticator. All OCSCC-patients diagnosed between 2008-2014 at two Dutch university medical centers were included (N=1,069). Formalin-fixed, paraffin-embedded (FFPE)-samples of 1,016 OCSCCs could be retrieved. Punch biopsies were taken from the tumor area in the FFPE-blocks and tested for HPV. P16-IHC was performed on 580 OCSCCs, including all HPV-positive tumors. From 940 samples (92.5%) nucleic acids were of sufficient quality for HPV-testing. In total 21 (2.2%) OCSCCs were HPV DNA-positive. All HPV DNA-positive tumors were E6 mRNA-positive and considered as true HPV-positive. There was no difference in survival between HPV-positive and HPV-negative OCSCCs. In total 46 of 580 (7.9%) OCSCCs were p16-immunopositive, including all HPV-positive tumors. Survival was similar in p16-positive and p16-negative OCSCCs. To conclude, HPV-prevalence is very low in OCSCC and neither HPV-status nor p16-status affects outcome. Based on these data, determining HPV-status in OCSCC seems irrelevant.
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http://dx.doi.org/10.1002/ijc.33514DOI Listing
February 2021

Neuroendocrine neoplasms of the middle ear: Unpredictable tumor behavior and tendency for recurrence.

Head Neck 2021 Feb 19. Epub 2021 Feb 19.

Department of Otolaryngology - Head and Neck Surgery, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands.

Background: Middle ear adenomatous neuroendocrine tumors (MEANTs) are rare temporal bone tumors. This study evaluates its clinical behavior and therapy outcome.

Method: Retrospective case review in a tertiary referral center evaluating histopathology, immunohistochemistry, treatment, and outcome.

Results: Nine patients were diagnosed with MEANT. One patient presented with locally invasive tumor and underwent extensive en-bloc tumor resection with adjuvant radiotherapy. Seven of eight patients with locally non-aggressive tumor confined to the tympanomastoid space underwent tumor resection. Two patients were disease-free, five presented recurrence, even after apparent successful surgery. All tumors showed neuroendocrine features. Histopathology and immunohistochemistry did not yield prognostic tumor characteristics.

Conclusion: MEANTs are rare tumors with uncertain biological behavior and subsequent unpredictable clinical course. The preferred treatment is complete surgical tumor resection. They have a high tendency for recurrence, irrespective of negative intermediary surgery. As of yet, there are no prognostic biomarkers, including histopathology and immunohistochemistry.
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http://dx.doi.org/10.1002/hed.26658DOI Listing
February 2021

Annual malignant transformation rate of oral leukoplakia remains consistent: A long-term follow-up study.

Oral Oncol 2020 11 7;110:105014. Epub 2020 Oct 7.

Amsterdam UMC, location VUmc, Department of Oral and Maxillofacial Surgery / Oral Pathology, Cancer Center Amsterdam, Academic Centre for Dentistry Amsterdam (ACTA), P.O. Box 7057, 1007 MB Amsterdam, the Netherlands. Electronic address:

Objectives: Numerous clinical and histopathological characteristics have been associated with malignant transformation (MT) of oral leukoplakia (OL), including classic and differentiated epithelial dysplasia, but MT predictions remain suboptimal. The objective of this study was to determine the annual MT rate of OL and to identify clinicopathological risk factors associated with MT.

Patients And Methods: 170 patients with OL were included in this retrospective cohort study, 117 females and 53 males. Follow-up ranged from 12 to 219 months (median 54). The analyzed variables included age, gender, smoking habits, clinical presentation, subsite, size and treatment. In a subgroup of 140 patients, histopathological diagnoses were reviewed with regard to the presence of dysplasia, discerning both classic dysplasia and differentiated dysplasia.

Results: MT occurred in 23% of the patients, resulting in an annual MT rate of 4.9% (95% CI: 3.5 - 6.6) which remained consistent. High-risk subsite (tongue and floor of mouth) was the only clinical predictor for MT (Hazard Ratio = 2.7, 95% CI: 1.3 - 5.5, p = 0.007). In 140 patients, classic dysplasia (Hazard Ratio = 7.2, 95% CI: 1.6 - 33.1, p = 0.012) and differentiated dysplasia (Hazard Ratio = 6.6, 95% CI: 1.2 - 25.4, p = 0.026) were predictors for MT. Binary grading between dysplasia and no dysplasia was significant for predicting MT (Hazard Ratio = 6.4, 95% CI: 1.5 - 27.5, p = 0.013).

Conclusion: Since annual MT rate of OL remains stable during follow-up, regular long-term or even life-long follow-up is advocated. Specific oral subsites and epithelial dysplasia are predictors for MT of OL.
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http://dx.doi.org/10.1016/j.oraloncology.2020.105014DOI Listing
November 2020

Comparison of three PD-L1 immunohistochemical assays in head and neck squamous cell carcinoma (HNSCC).

Mod Pathol 2020 Aug 5. Epub 2020 Aug 5.

Department of Pathology, University Medical Center Utrecht, Heidelberglaan 100, 3584 CX, Utrecht, The Netherlands.

Expression of programmed cell death-ligand 1 (PD-L1) is being used as predictive biomarker for immunotherapy in head and neck squamous cell carcinoma (HNSCC). Several antibodies are available for PD-L1 testing and multiple staining and scoring methods are used. This study aimed to compare the performance of two PD-L1 standardized assays (SP263 and 22C3 pharmDx) and one laboratory-developed test (LDT) (22C3) in HNSCC using the tumor proportion score (TPS) and the combined positive score (CPS). Pretreatment biopsies from 147 HNSCC patients were collected in a tissue-microarray (TMA). Serial sections of the TMA were immunohistochemically stained for PD-L1 expression using 22C3 pharmDx on the Dako Link 48 platform, SP263 on the Ventana Benchmark Ultra platform, and 22C3 as an LDT on the Ventana Benchmark Ultra. Stained slides were assessed for TPS and CPS. Cutoffs of ≥1% and ≥50% for TPS and ≥1 and ≥20 for CPS were used. Concordance between the different staining assays was moderate to poor for TPS (intraclass correlation coefficient (ICC) 0.46) as well as for CPS (ICC 0.34). When stratifying patients by clinically relevant cutoffs, considerable differences between the assays were observed: concordance was poor for both TPS and CPS. Generally, SP263 stained a higher percentage of cells than the other assays, especially when using the CPS. Moderate concordance was shown between three different PD-L1 immunohistochemical assays and considerable differences in PD-L1 positivity were observed when using clinically relevant cutoffs. This should be taken into account when using PD-L1 expression to guide clinical practice.
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http://dx.doi.org/10.1038/s41379-020-0644-7DOI Listing
August 2020

Elective Neck Dissection or Sentinel Lymph Node Biopsy in Early Stage Oral Cavity Cancer Patients: The Dutch Experience.

Cancers (Basel) 2020 Jul 3;12(7). Epub 2020 Jul 3.

Department of Head and Neck Surgical Oncology, University Medical Center Utrecht, 3584 CX Utrecht, The Netherlands.

Background: Sentinel lymph node biopsy (SLNB) has been introduced as a diagnostic staging modality for detection of occult metastases in patients with early stage oral cancer. Comparisons regarding accuracy to the routinely used elective neck dissection (END) are lacking in literature.

Methods: A retrospective, multicenter cohort study included 390 patients staged by END and 488 by SLNB.

Results: The overall sensitivity (84% vs. 81%, = 0.612) and negative predictive value (NPV) (93%, = 1.000) were comparable between END and SLNB patients. The END cohort contained more pT2 tumours (51%) compared to the SLNB cohort (23%) ( < 0.001). No differences were found for sensitivity and NPV between SLNB and END divided by pT stage. In floor-of-mouth (FOM) tumours, SLNB had a lower sensitivity (63% vs. 92%, = 0.006) and NPV (90% vs. 97%, = 0.057) compared to END. Higher disease-specific survival (DSS) rates were found for pT1 SLNB patients compared to pT1 END patients (96% vs. 90%, = 0.048).

Conclusion: In the absence of randomized clinical trials, this study provides the highest available evidence that, in oral cancer, SLNB is as accurate as END in detecting occult lymph node metastases, except for floor-of-mouth tumours.
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http://dx.doi.org/10.3390/cancers12071783DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7407164PMC
July 2020

Expression of let-7i and miR-192 is associated with resistance to cisplatin-based chemoradiotherapy in patients with larynx and hypopharynx cancer.

Oral Oncol 2020 Jun 22;109:104851. Epub 2020 Jun 22.

Amsterdam UMC, Vrije Universiteit Amsterdam, Department of Medical Oncology, Cancer Center Amsterdam, the Netherlands. Electronic address:

Objectives: The majority of patients with locally advanced larynx or hypopharynx squamous cell carcinoma are treated with organ-preserving chemoradiotherapy (CRT). Clinical outcome following CRT varies greatly. We hypothesized that tumor microRNA (miRNA) expression is predictive for outcome following CRT.

Methods: Next-generation sequencing (NGS) miRNA profiling was performed on 37 formalin-fixed paraffin-embedded (FFPE) tumor samples. Patients with a recurrence-free survival (RFS) of less than 2 years and patients with late/no recurrence within 2 years were compared by differential expression analysis. Tumor-specific miRNAs were selected based on normal mucosa miRNA expression data from The Cancer Genome Atlas database. A model was constructed to predict outcome using group-regularized penalized logistic ridge regression. Candidate miRNAs were validated by RT-qPCR in the initial sample set as well as in 46 additional samples.

Results: Thirteen miRNAs were differentially expressed (p < 0.05, FDR < 0.1) according to outcome group. Initial class prediction in the NGS cohort (n = 37) resulted in a model combining five miRNAs and disease stage, able to predict CRT outcome with an area under the curve (AUC) of 0.82. In the RT-qPCR cohort (n = 83), 25 patients (30%) experienced early recurrence (median RFS 8 months; median follow-up 42 months). Class prediction resulted in a model combining let-7i-5p, miR-192-5p and disease stage, able to discriminate patients with good versus poor clinical outcome (AUC:0.80).

Conclusion: The combined miRNA expression and disease stage prediction model for CRT outcome is superior to using either factor alone. This study indicates NGS miRNA profiling using FFPE specimens is feasible, resulting in clinically relevant biomarkers.
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http://dx.doi.org/10.1016/j.oraloncology.2020.104851DOI Listing
June 2020

A systematic review on Transoral robotic surgery (TORS) for carcinoma of unknown primary origin: Has tongue base mucosectomy become indispensable?

Clin Otolaryngol 2020 09 25;45(5):732-738. Epub 2020 May 25.

Department of Otolaryngology/Head and Neck Surgery, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands.

Background: Transoral robotic surgery (TORS) is increasingly used in head and neck surgery and in carcinoma of unknown primary (CUP) origin specifically. Due to the rising incidence of human papillomavirus (HPV)-related oropharyngeal squamous cell carcinoma (OPSCC), there is a rationale for finding ways to de-escalate treatment strategies. This review aims to test the hypothesis that TORS is a meaningful adjunct in the diagnostic (and therapeutic) pathway in CUP in head and neck.

Methods: A structured search of the literature was performed with the search terms 'TORS' and 'Carcinoma of Unknown Primary'.

Results: Two hundred and seventy four cases of CUP in which TORS was used were identified for further analysis. Workup for CUP was comparable in all series with regard to physical examination, fine and/or gross needle examination of cervical nodes, fibre optic endoscopy, imaging and robot assisted mucosectomy of the base of tongue (BOT). Identification rate of the primary tumour was 72% on average (range 17%- 90%), and 55%- 96% were HPV positive. Clear margins were achieved in 60% (range 0%-85%) of resected occult tumours. Complication rate of TORS BOT mucosectomy was low with mainly grade I-III sequelae according to Clavien-Dindo.

Conclusions: Transoral robotic surgery seems to be a useful and safe adjunct in the diagnostic and therapeutic pathway in case of CUP in an era of increasing incidence of HPV-positive OPSCC.
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http://dx.doi.org/10.1111/coa.13565DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7496155PMC
September 2020

Incorporation of differentiated dysplasia improves prediction of oral leukoplakia at increased risk of malignant progression.

Mod Pathol 2020 06 2;33(6):1033-1040. Epub 2020 Jan 2.

Amsterdam UMC and Academic Centre for Dentistry Amsterdam (ACTA), Vrije Universiteit Amsterdam, Department of Oral and Maxillofacial Surgery/Oral Pathology, Cancer Center Amsterdam, de Boelelaan, 1117, Amsterdam, The Netherlands.

Oral leukoplakia is the most common oral potentially malignant disorder with a malignant transformation rate into oral squamous cell carcinoma of 1-3% annually. The presence and grade of World Health Organization defined dysplasia is an important histological marker to assess the risk for malignant transformation, but is not sufficiently accurate to personalize treatment and surveillance. Differentiated dysplasia, known from differentiated vulvar intraepithelial neoplasia, is hitherto not used in oral dysplasia grading. We hypothesized that assessing differentiated dysplasia besides World Health Organization defined (classic) dysplasia will improve risk assessment of malignant transformation of oral leukoplakia. We investigated a retrospective cohort consisting of 84 oral leukoplakia patients. Biopsies were assessed for dysplasia presence and grade, and the expression of keratins 13 (CK13) and 17, known to be dysregulated in dysplastic vulvar mucosa. In dysplastic oral lesions, differentiated dysplasia is as common as classic dysplasia. In 25 out of 84 (30%) patients, squamous cell carcinoma of the upper aerodigestive tract developed during follow-up. Considering only classic dysplasia, 11 out of 56 (20%) patients with nondysplastic lesions progressed. With the incorporation of differentiated dysplasia, only 2 out of 30 (7%) patients with nondysplastic lesions progressed. The risk of progression increased from 3.26 (Hazard ratio, p = 0.002) when only classic dysplasia is considered to 7.43 (Hazard ratio, p = 0.001) when classic and differentiated dysplasia are combined. Loss of CK13, combined with presence of dysplasia, is associated with greater risk of malignant progression (p = 0.006). This study demonstrates that differentiated dysplasia should be recognized as a separate type of dysplasia in the oral mucosa and that its distinction from classic dysplasia is of pathological and clinical significance since it is a strong (co)prognostic histopathological marker for oral malignant transformation. In oral lesions without dysplasia and retained CK13 staining the risk for progression is very low.
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http://dx.doi.org/10.1038/s41379-019-0444-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7280084PMC
June 2020

Development and Validation of a Novel and Rapid Molecular Detection Method for High-Risk Human Papillomavirus in Formalin-Fixed, Paraffin-Embedded Tumor Tissue.

J Mol Diagn 2020 02 16;22(2):262-271. Epub 2019 Dec 16.

Department of Otolaryngology-Head and Neck Surgery, Amsterdam University Medical Center, Vrije Universiteit Amsterdam, Cancer Center Amsterdam, Amsterdam, the Netherlands.

The most widely applied algorithm for human papillomavirus (HPV) detection in formalin-fixed, paraffin-embedded (FFPE) specimens of oropharyngeal head and neck squamous cell carcinoma (HNSCC) consists of p16INK4A immunostaining followed by PCR-based detection of high-risk HPV DNA on p16INK4A-immunopositive samples. However, in nonoropharyngeal HNSCC this algorithm fails, hampering correct interpretation of the prevalence and prognosis of HPV in these cases. In this study, we developed and validated a molecular HPV detection method for FFPE specimens of oropharyngeal and nonoropharyngeal HNSCC. Sectioning of FFPE blocks was circumvented by using punch biopsies from tumor-enriched regions of FFPE tissue blocks, and combined extraction was applied to obtain high-quality DNA and RNA from the punch biopsy. Next, PCR-based detection of HPV DNA was performed for 15 high-risk HPV types with subsequent detection of E6 mRNA for validation. The combined DNA/RNA FFPE test of tissue cores was assessed in well-characterized cohorts with known HPV status based on earlier work, that is, a cohort of oropharyngeal HNSCC (n = 80) and oral cavity HNSCC (n = 25), and reached an accuracy of 97% and 100%, respectively. In conclusion, our method is rapid, simple, and shows an excellent diagnostic performance for detection of HPV type 16. Ultimately, it can be applied for large cohort studies to determine the etiologic fraction and prognostic implication of HPV in nonoropharyngeal HNSCC.
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http://dx.doi.org/10.1016/j.jmoldx.2019.10.009DOI Listing
February 2020

Molecular Characterization of Locally Relapsed Head and Neck Cancer after Concomitant Chemoradiotherapy.

Clin Cancer Res 2019 12 22;25(23):7256-7265. Epub 2019 Aug 22.

Amsterdam UMC, Vrije Universiteit Amsterdam, Otolaryngology/Head & Neck Surgery, Cancer Center Amsterdam, Amsterdam, the Netherlands.

Purpose: To investigate the pathobiological origin of local relapse after chemoradiotherapy, we studied genetic relationships of primary tumors (PT) and local relapses (LR) of patients treated with chemoradiotherapy.

Experimental Design: First, low-coverage whole genome sequencing was performed on DNA from 44 biopsies of resected head and neck squamous cell carcinoma (HNSCC) specimens (median 3 biopsies/tumor) to assess suitability of copy number alterations (CNAs) as biomarker for genetic relationships. CNAs were compared within and between tumors and an algorithm was developed to assess genetic relationships with consideration of intratumor heterogeneity. Next, this CNA-based algorithm was combined with target enrichment sequencing of genes frequently mutated in HNSCC to assess the genetic relationships of paired tumors and LRs of patients treated with chemoradiotherapy.

Results: Genetic relationship analysis using CNAs could accurately (96%) predict tumor biopsy pairs as patient-matched or independent. However, subsequent CNA analysis of PTs and LRs after chemoradiotherapy suggested genetic relationships in only 20% of cases, and absence in 80%. Target enrichment sequencing for mutations confirmed absence of any genetic relationship in half of the paired PTs and LRs.

Conclusions: There are minor variations in CNA profiles within different areas of HNSCC tumors and many between independent tumors, suggesting that CNA profiles could be exploited as a marker of genetic relationship. Using CNA profiling and mutational analysis of cancer driver genes, relapses after chemoradiotherapy appear to be partially genetically related to the corresponding PTs, but seem often genetically unrelated. This remarkable observation warrants further studies and will impact therapeutic innovations and prognostic modeling when using index tumor characteristics.
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http://dx.doi.org/10.1158/1078-0432.CCR-19-0628DOI Listing
December 2019

Odontogenic keratocysts located in the buccal mucosa: A description of two cases and review of the literature.

SAGE Open Med Case Rep 2019 19;7:2050313X19849828. Epub 2019 May 19.

Department of Pathology, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands.

Odontogenic keratocysts make up 4%-12% of all odontogenic cysts. Most cysts are sporadic but sometimes they arise in the context of basal cell nevus syndrome (Gorlin syndrome). Most odontogenic keratocysts arise in the posterior region of the mandible, but they can occur anywhere in the jaw. In rare instances, they are located peripherally in the gingiva. Even more rare, they are found in the soft tissues of the mouth. There have been a few case reports and small case series of such peripheral odontogenic keratocysts. Some controversy exists as to whether these truly represent a peripheral counterpart of the intraosseous odontogenic keratocysts and if their origin is at all odontogenic. We hereby present two cases of peripheral odontogenic keratocysts, both being located in the soft tissue of the buccal mucosa, and review the literature on peripheral odontogenic keratocysts.
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http://dx.doi.org/10.1177/2050313X19849828DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6537049PMC
May 2019

Limited relevance and progression of histological alterations in the liver during thioguanine therapy in inflammatory bowel disease patients.

Scand J Gastroenterol 2019 Jun 16;54(6):753-760. Epub 2019 Jun 16.

Department of Gastroenterology and Hepatology, Amsterdam UMC, Vrije Universiteit Amsterdam , Amsterdam , the Netherlands.

Thioguanine is associated with liver toxicity, especially nodular regenerative hyperplasia (NRH). We assessed if liver histology alters during long-term maintenance treatment with thioguanine in patients with inflammatory bowel disease (IBD). Liver specimens of thioguanine treated IBD patients with at least two liver biopsies were revised by two independent liver pathologists, blinded to clinical characteristics. Alterations in histopathological findings between first and sequential liver specimen were evaluated and associated clinical data, including laboratory parameters and abdominal imaging reports, were collected. Twenty-five IBD patients underwent sequential liver biopsies prior to, at time of, or after cessation of thioguanine treatment. The median time between the first and second biopsy was 25 months (range: 14-54). Except for one normal liver specimen, any degree of irregularities including inflammation, steatosis, fibrosis and some vascular disturbances were observed in the biopsies. The rates of perisinusoidal fibrosis (91%), sinusoidal dilatation (68%) and nodularity (18%) were the same in the first and second liver biopsies. A trend towards statistical significance was observed for phlebosclerosis (36% of the first vs. 68% of the second biopsies,  = .092). Presence of histopathological liver abnormalities was not associated with clinical outcomes. Furthermore, two patients in this cohort had portal hypertension in presence of phlebosclerosis. In another two patients, nodularity of the liver resolved upon thioguanine withdrawal. Vascular abnormalities of the liver were commonly observed in thioguanine treated IBD patients, although these were not progressive and remained of limited clinical relevance over time.
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http://dx.doi.org/10.1080/00365521.2019.1629006DOI Listing
June 2019

High rate of unexpected lymphatic drainage patterns and a high accuracy of the sentinel lymph node biopsy in oral cancer after previous neck treatment.

Oral Oncol 2019 07 21;94:68-72. Epub 2019 May 21.

Department of Head and Neck Surgical Oncology, UMC Utrecht Cancer Center, University Medical Center Utrecht, the Netherlands. Electronic address:

Rationale: This study evaluates the lymphatic drainage patterns and determines the accuracy of the sentinel lymph node biopsy (SLNB) in patients diagnosed with a cT1-2N0 OSCC and a history of neck surgery or radiotherapy in three Dutch head and neck centers.

Materials And Methods: Retrospective analysis of 53 cT1-2N0 OSCC patients, who underwent SLNB between 2007 and 2016, after a history of neck surgery or radiotherapy. Ten patients had previous treatment of the neck only contralateral from the current tumour. These ten patients were not used for the analysis of lymphatic drainage patterns. The 43 patients with previous ipsilateral or bilateral treatment of the neck had a history of ipsilateral SLN extirpation (n = 9; 21%), neck dissection (n = 16; 37%), radiotherapy (n = 10; 23%), or combined neck dissection and radiotherapy (n = 8; 19%).

Results: SLNs were detected in 45 patients, resulting in an identification rate of 85% (45/53). Three patients (7%) had at least one positive SLN. One patient (1/45; 2%) was diagnosed with regional recurrence during the follow-up after a negative SLNB (sensitivity 75%, negative predictive value 98%). The first SLN was detected in level I-III in 58% of the patients, unexpected drainage patterns were observed in 30% (first SLN level IV 9% and level V 5% and contralateral neck in well-lateralized tumours 16%). In 12% no lymphatic drainage pattern was visible.

Conclusions: SLNB seems to be a reliable procedure for neck staging of cT1-2N0 OSCC patients with a previously treated neck. SLNB determines the individual lymphatic drainage patterns, enabling visualization of unexpected drainage pattern variability in 30% of these patients.
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http://dx.doi.org/10.1016/j.oraloncology.2019.05.007DOI Listing
July 2019

Depth of invasion in patients with early stage oral cancer staged by sentinel node biopsy.

Head Neck 2019 07 28;41(7):2100-2106. Epub 2019 Jan 28.

Department of Head and Neck Surgical Oncology, UMC Utrecht Cancer Center, University Medical Center Utrecht, Utrecht, The Netherlands.

Background: To investigate if depth of invasion (DOI) can predict occult nodal disease in patients with cT1-2N0 (7th TNM) oral squamous cell carcinoma (OSCC) staged by sentinel lymph node biopsy (SLNB).

Methods: In 199 OSCC patients, DOI measurements and SLNB were performed.

Results: Metastases were found in 64 of 199 patients (32%). Of these 64 patients, the mean DOI was 6.6 mm compared to 4.7 mm in patients without metastases (P = .003). The ROC-curve showed an area under the curve of 0.65 with a most optimal cutoff point of 3.4 mm DOI (sensitivity 83% and specificity 47%). Regional metastases were found in 15% of patients with DOI ≤ 3.4 mm.

Conclusion: DOI seems to be a poor predictor for regional metastasis in patients with cT1-2N0 OSCC. Therefore, staging of the neck using SLNB in patients with early stage oral cancer should also be performed in tumors with limited DOI and probably in T3 (8th TNM) OSCC ≤4 cm diameter.
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http://dx.doi.org/10.1002/hed.25665DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6618049PMC
July 2019

Biochemical Changes in Irradiated Oral Mucosa: A FTIR Spectroscopic Study.

Biosensors (Basel) 2019 Jan 13;9(1). Epub 2019 Jan 13.

SIB Labs, University of Eastern Finland, P.O. Box 1627, 70211 Kuopio, Finland.

Radiation exposure during the course of treatment in head and neck cancer (HNC) patients can induce both structural and biochemical anomalies. The present study is focused on utilizing infrared imaging for the identification of the minor biochemical alterations in the oral mucosa. Chemical maps generated using glycoprotein band indicates its differential distribution along the superficial layer. Spectra extracted from this layer suggests changes in overall nucleic acid and protein content in response to the therapeutic irradiation. Discrimination among control and irradiated groups have been achieved using principal component analysis. Findings of this preliminary study further support prospective utilization of Fourier Transform InfraRed (FTIR) imaging as a non-destructive, label-free tool for objective assessment of the oral mucosa in patient groups with or without radiation therapy.
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http://dx.doi.org/10.3390/bios9010012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6468735PMC
January 2019

Increased Mortality Among Patients With vs Without Cirrhosis and Autoimmune Hepatitis.

Clin Gastroenterol Hepatol 2019 04 3;17(5):940-947.e2. Epub 2018 Oct 3.

Amsterdam Gastroenterology and Metabolism, Department of Gastroenterology and Hepatology, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam, the Netherlands. Electronic address:

Background & Aims: There have been few reproducible studies of mortality in patients with autoimmune hepatitis (AIH) and its variants. We calculated mortality in a large national cohort of patients with AIH, with vs without cirrhosis, in the Netherlands.

Methods: We collected data from 449 patients with established AIH (77% female), from 6 academic and 10 non-academic hospitals in the Netherlands. We identified 29 patients with AIH and primary biliary cholangitis and 35 patients with AIH and primary sclerosing cholangitis (AIH-PSC). Mortality and liver transplantation data were assessed from August 1, 2006 through July 31, 2016. Standardized mortality ratios (SMR) were calculated using age-, sex-, and calendar year-matched mortality for the general Dutch population.

Results: During the 10-year follow-up period, 60 patients (13%) died (mean age, 71 years; range, 33-94 years). Twenty-six causes of death were liver related (43%), whereas the others could not be attributed to liver disease. Patients with AIH and cirrhosis had significantly higher mortality than the general population (SMR, 1.9; 95% CI, 1.2-3.4), whereas patients without cirrhosis did not (SMR, 1.2; 95% CI, 0.8-1.8). Patients with AIH-PSC had the largest increase in mortality, compared to the general population (SMR, 4.7; 95% CI, 1.5-14.6), of all groups analyzed. Mortality in patients with AIH and primary biliary cholangitis was not greater than the general population. Four or more relapses per decade or not achieving remission was associated with an increase in liver-related death or liver transplantation. Nine patients underwent liver transplantation; 2 died from non-liver related causes. Four of 9 patients on the waitlist for transplantation died before receiving a donated liver.

Conclusion: In an analysis of data from a large national cohort of patients with AIH, we found increased mortality of patients with cirrhosis, but not of patients without cirrhosis, compared to the general Dutch population. Survival was significantly reduced in patients with AIH and features of concurrent PSC.
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http://dx.doi.org/10.1016/j.cgh.2018.09.046DOI Listing
April 2019

Establishment and Genetic Landscape of Precancer Cell Model Systems from the Head and Neck Mucosal Lining.

Mol Cancer Res 2019 01 17;17(1):120-130. Epub 2018 Sep 17.

Amsterdam UMC, Vrije Universiteit Amsterdam, Otolaryngology-Head and Neck Surgery, Cancer Center Amsterdam, Amsterdam, the Netherlands.

Head and neck squamous cell carcinomas (HNSCC) develop in fields of genetically altered cells. These fields are often dysplastic and a subset can be recognized as (erythro)leukoplakia, but most are macroscopically invisible. There is a lack of adequate treatment options to eradicate these fields, whereas they underlie the development of primary tumors as well as part of the local relapses. Unfortunately, there are almost no representative cellular models available to identify suitable treatment options. To this end, clinical biopsy specimens ( = 98) were cultured from normal appearing mucosa of the surgical margins of patients with primary HNSCCs ( = 32) to generate precancer cell culture models. This collection was extended with six previously established precancer cell cultures. Genetic analysis was performed on cultures with an extended life span (≥20 population doublings), the previously established cultures, and some randomly selected cultures. In total, cancer-associated changes were detected in 18 out of 34 (53%) cultures analyzed, which appeared to be independent of life span. A variety of genetic changes were identified, including somatic mutations as well as chromosomal copy-number aberrations (CNA). Loss of /p16 and mutations in /p53 were most prominent. Remarkably, in some of these precancer cell cultures only chromosomal CNAs were detected, and none of the frequently occurring driver mutations. IMPLICATIONS: The precancer cell cultures, characterized herein, form a representative collection of field models that can be exploited to identify and validate new therapeutic strategies to prevent primary HNSCCs and local relapses.
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http://dx.doi.org/10.1158/1541-7786.MCR-18-0445DOI Listing
January 2019

A review of the most promising biomarkers for early diagnosis and prognosis prediction of tongue squamous cell carcinoma.

Br J Cancer 2018 09 21;119(6):724-736. Epub 2018 Aug 21.

Department of Oral and Maxillofacial Surgery and Oral Pathology, Academic Centre for Dentistry, VU University Medical Center, Amsterdam, The Netherlands.

Background: There is a great interest in developing biomarkers to enhance early detection and clinical management of tongue squamous cell carcinoma (TSCC). However, the developmental path towards a clinically valid biomarker remains extremely challenging. Ideally, the initial key step in moving a newly discovered biomarker towards clinical implementation is independent replication. Therefore, the focus of this review is on biomarkers that consistently showed clinical relevance in two or more publications.

Methods: We searched PubMed database for relevant papers across different TSCC sample sources, i.e., body fluids (saliva, serum/plasma) and tissues. No restriction regarding the date of publication was applied except for immunohistochemistry (IHC); only studies published between 2010 and June 2017 were included.

Results: The search strategy identified 1429 abstracts, of which 96 papers, examining 150 biomarkers, were eventually included. Of these papers, 66% were exploratory studies evaluating single or a panel of biomarkers in one publication. Ultimately, based on studies that had undergone validation for their clinical relevance in at least two independent studies, we identified 10 promising candidates, consisting of different types of molecules (IL-6, IL-8, and Prolactin in liquid samples; HIF-1α, SOX2, E-cadherin, vimentin, MALAT1, TP53, and NOTCH1 in tissue biopsies) CONCLUSIONS: Although more exploratory research is needed with newer methods to identify biomarkers for TSCC, rigorous validation of biomarkers that have already shown unbiased assessment in at least two publications should be considered a high priority. Further research on these promising biomarkers or their combination in multi-institutional studies, could provide new possibilities to develop a specific panel for early diagnosis, prognosis, and individualized treatments.
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http://dx.doi.org/10.1038/s41416-018-0233-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6173763PMC
September 2018

Biochemical efficacy of tioguanine in autoimmune hepatitis: a retrospective review of practice in the Netherlands.

Aliment Pharmacol Ther 2018 10 15;48(7):761-767. Epub 2018 Aug 15.

Department of Gastroenterology and Hepatology, Amsterdam Gastroenterology and Metabolism, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands.

Background: Azathioprine (AZA) and mercaptopurine (MP) are the cornerstone of steroid-sparing strategies in autoimmune hepatitis (AIH). Up to 20% of patients do not tolerate or respond to these regimens.

Aim: To evaluate retrospectively the tolerability and efficacy of tioguanine (thioguanine) (TG) therapy in selected patients with AIH and AIH variant syndromes.

Methods: Records of 52 patients who received TG therapy were retrieved from nine hospitals in the Netherlands. Indications for TG treatment were intolerable side effects on AZA or MP (n = 38), insufficient response (n = 11) or first-line treatment (n = 3). Treatment efficacy was defined as normalisation of serum aminotransferases and serum immunoglobulin G.

Results: No serious adverse events occurred in patients treated with TG during a median follow-up of 18 months (range 1-194). Treatment was well tolerated in 41 patients (79%), whereas four had tolerable (8%) and seven (13%) intolerable side effects. Thirty-eight patients were treated with TG after intolerable side effects on AZA or MP; 29 patients continued TG therapy of whom 24 (83%) achieved complete biochemical remission, four (14%) had incomplete and one (3%) had no response; nine discontinued treatment. Seven of 11 patients with insufficient response to AZA or MP were responsive to TG, three with complete and four with incomplete biochemical remission; four discontinued due to intolerance (n = 2) and non-response (n = 2). TG was effective in all AIH patients as first-line maintenance treatment.

Conclusion: In our retrospective review of TG therapy in selected patients with AIH or AIH variants who previously failed on AZA or MP, TG appeared tolerable with biochemical efficacy.
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http://dx.doi.org/10.1111/apt.14939DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6175236PMC
October 2018

Clear Cell Odontogenic Carcinoma: Occurrence of EWSR1-CREB1 as Alternative Fusion Gene to EWSR1-ATF1.

Head Neck Pathol 2019 Jun 25;13(2):225-230. Epub 2018 Jul 25.

Department of Pathology, Radboud University Medical Center, P.O. Box 9101, 6500 HB, Nijmegen, The Netherlands.

Clear cell odontogenic carcinoma (CCOC) is a rare, low-grade malignant epithelial neoplasm, occurring in the jawbones, mainly affecting the mandible of elderly patients. In addition to hyalinizing clear cell carcinoma of the salivary gland, it is one of the epithelial neoplasms known to harbor an EWSR1-ATF1 fusion. Therefore, a link between these tumors seems plausible. We describe six cases of CCOC showing EWSR1 rearrangements, with two cases being positive for the ATF1 partner gene using FISH analysis. In one case, an EWSR1-CREB1 fusion was identified using RT-PCR, which we report for the first time in this tumor type. The other three cases investigated by FISH were negative for ATF1, CREB1 and CREB3L2. In conclusion, our data show that EWSR1-CREB1 is an alternative fusion gene to EWSR1-ATF1 in CCOC.
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http://dx.doi.org/10.1007/s12105-018-0953-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6514205PMC
June 2019

Resorption of the mandibular residual ridge: A micro-CT and histomorphometrical analysis.

Gerodontology 2018 May 21. Epub 2018 May 21.

Department of Clinical Chemistry, VU University Medical Centre, Amsterdam, The Netherlands.

Objectives: The aim of this study was to investigate whether the extent of mandibular resorption and gender is related to the bone turnover and microarchitecture of the edentulous mandible.

Participants And Methods: A mandibular bone sample was obtained at canine position from 36 edentulous participants (50% women; mean age: 65 years) during dental implant surgery. All female participants were postmenopausal. Mandibular height, duration of edentulous state and resorption pattern (Cawood classification) were recorded. Microcomputed tomography was used to determine bone mineral density, bone volume fraction, trabecular connectivity density, trabecular number, trabecular thickness and trabecular separation. Histomorphometric analysis was used to assess bone turnover: osteoid area and surface were measured as a parameter for bone formation and osteoclast numbers were determined as a parameter for bone resorption. Correlations between micro-CT, histomorphometrical parameters and clinical data were analysed with correlation coefficients and parametric and non-parametric tests.

Results: Lower mandibular height was strongly associated with higher bone mineral density in trabecular bone. Women showed higher osteoclast numbers in trabecular bone than men. In trabecular bone of women, bone volume was significantly related to osteoclast numbers, osteoid surface and osteoid area.

Conclusions: The higher trabecular bone mineral density found in the edentulous mandible could either indicate a restructuring process of the resorbed mandible or suggests that the inferior region of the mandible is more highly mineralised. In women, higher bone turnover is associated with lower bone volume, suggesting an effect of postmenopausal oestrogen deficiency on bone turnover in the edentulous mandible.
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http://dx.doi.org/10.1111/ger.12343DOI Listing
May 2018

Genetic profiling of poorly differentiated sinonasal tumours.

Sci Rep 2018 03 5;8(1):3998. Epub 2018 Mar 5.

Department Otolaryngology, IUOPA, CIBERONC, Hospital Universitario Central de Asturias, Oviedo, Asturias, Spain.

The sinonasal cavities harbour a variety of rare tumour types. Many carry a poor prognosis while therapeutic options are limited. Histopathological classification can be difficult, especially for poorly differentiated tumours such as olfactory neuroblastoma (ONB), sinonasal neuroendocrine carcinoma (SNEC) and sinonasal undifferentiated carcinoma (SNUC). We analysed Affymetrix OncoScan genome-wide copy number profiles of these three tumour types, both as originally diagnosed and as regrouped by their cytokeratin (Ck) and neuroendocrine (Ne) expression pattern, aiming to find a relation between phenotype and genotype. According to the original histopathological classification our series consisted of 24 ONB, 11 SNEC and 19 SNUC, while immunohistochemistry indicated 11 Ck-Ne+/ONB, 18 Ck+Ne+/SNEC, 24 Ck+Ne-/SNUC, and 1 Ck-Ne-/unclassified. As originally diagnosed, the three tumour types showed similar copy number profiles. However, when regrouped by Ck/Ne immunostaining we found a distinct set of gains and losses; Ck-Ne+/ONB harboured few and predominantly whole chromosomes abnormalities, Ck+Ne+/SNEC carried both gains and losses in high frequency, and Ck+Ne-/SNUC showed mostly gains. In addition, each tumour carried a number of unique chromosomal deletions. Genome-wide copy number profiling supports the value of immunohistochemical CkNe staining of ONB, SNEC and SNUC for tumour classification, which is important for prognosis and therapeutic decision-making.
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http://dx.doi.org/10.1038/s41598-018-21690-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5838253PMC
March 2018

A clinicopathological study and prognostic factor analysis of 177 salivary duct carcinoma patients from The Netherlands.

Int J Cancer 2018 08 23;143(4):758-766. Epub 2018 Mar 23.

Department of Medical Oncology, Radboud University Medical Center, Nijmegen, The Netherlands.

Salivary duct carcinoma (SDC) is a subtype of salivary gland cancer with a dismal prognosis and a need for better prognostication and novel treatments. The aim of this national cohort study was to investigate clinical outcome, prognostic factors, androgen receptor (AR) and human epidermal growth factor receptor 2 (HER2) expression. SDC patients diagnosed between 1990 and 2014 were identified by the Nationwide Network and Registry of Histo- and Cytopathology in the Netherlands (PALGA). Subsequently, medical records were evaluated and pathological diagnoses reviewed. Data were analyzed for overall survival (OS), disease-free survival (DFS), distant metastasis-free survival (DMFS) and prognostic factors. AR was evaluated by immunohistochemistry (IHC), HER2 by IHC and fluorescent in-situ hybridization. A total of 177 patients were included. The median age was 65 years, 75% were male. At diagnosis, 68% presented with lymph node metastases and 6% with distant metastases. Median OS, DFS and DMFS were 51, 23 and 26 months, respectively. In patients presenting without distant metastases, the absolute number of positive lymph nodes was associated with poor OS and DMFS in a multivariable analysis. AR and HER2 were positive in 161/168 (96%) and 44/153 (29%) tumors, respectively, and were not prognostic factors. SDC has a dismal prognosis with primary lymph node involvement in the majority of patients. The absolute number of lymph node metastases was found to be the only prognostic factor for DMFS and OS. AR expression and-to a lesser extent-HER2 expression hold promise for systemic treatment in the metastatic and eventually adjuvant setting.
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http://dx.doi.org/10.1002/ijc.31353DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6055864PMC
August 2018

Targeting PLK1 as a novel chemopreventive approach to eradicate preneoplastic mucosal changes in the head and neck.

Oncotarget 2017 Nov 16;8(58):97928-97940. Epub 2017 May 16.

Department of Otolaryngology-Head and Neck Surgery, VU University Medical Center, Cancer Center Amsterdam, Amsterdam, The Netherlands.

Head and neck squamous cell carcinomas (HNSCC) and local relapses thereof develop in preneoplastic fields in the mucosal linings of the upper aerodigestive tract. These fields are characterized by tumor-associated genetic changes, are frequently dysplastic and occasionally macroscopically visible. Currently, no adequate treatment options exist to prevent tumor development. Array-based screening with a panel of tumor-lethal small interfering RNAs (siRNAs) identified () as essential for survival of preneoplastic cells. Inhibition of PLK1 caused cell death of preneoplastic and HNSCC cells, while primary cells were hardly affected. Both siRNAs and small molecule inhibitors caused a strong G2/M cell cycle arrest accompanied by formation of monopolar spindles. In a xenografted mouse model PLK1 caused a significant tumor growth delay and cures, while chemoradiation had no effect. Thus, PLK1 seems to be a promising target for chemopreventive treatment of preneoplastic cells, and could be applied to prevent HNSCC and local relapses.
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http://dx.doi.org/10.18632/oncotarget.17880DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5716703PMC
November 2017

Evaluation of vascular features of vocal cords proposed by the European Laryngological Society.

Eur Arch Otorhinolaryngol 2018 Jan 30;275(1):147-151. Epub 2017 Oct 30.

Department of Otolaryngology-Head and Neck surgery, VU University Medical Center, De Boelelaan 1117, 1081 HV, Amsterdam, The Netherlands.

A newly proposed classification by the European Laryngological Society (ELS) of glottic lesions by narrow-band imaging (NBI) divides their vascular patterns into longitudinal and perpendicular ones. The latter are further subdivided into the wide and narrow patterns. The longitudinal, wide, and narrow patterns are characteristic of benign disease, papilloma, and malignancy, respectively. The aim of the study was to investigate the diagnostic effectiveness of the classification. Forty patients with glottic lesions underwent microlaryngoscopy. The vascular patterns of all vocal cords were defined with NBI. The affected vocal cords were histologically analysed and comprised the arm (A). Unaffected vocal cords were not histologically analysed but followed-up and comprised the arm (B) and were regarded as true negatives if no suspicious changes appeared during the follow-up. The vocal cords from the arm A were categorised into the benign and malignant group according to the histologic result. The ratio of vascular patterns was determined and the groups were statistically compared using the Chi-square test and Fisher's exact test. Perpendicular changes were observed in 36.6% (9/26) of benign diseases and in 100% (23/23) of cancer conditions (p < 0.001). Wide perpendicular changes appeared only in papillomas (6/6) while narrow ones mostly in malignancies (23/26) and also in benign conditions (3/26) (p < 0.001). The sensitivity, specificity, positive and negative predictive values, and accuracy were 100, 95, 88, 100 and 96%, respectively. The new ELS classification can be used effectively and safely to differentiate malignant from benign disease.
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http://dx.doi.org/10.1007/s00405-017-4791-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5754403PMC
January 2018

High number of chromosomal copy number aberrations inversely relates to t(11;19)(q21;p13) translocation status in mucoepidermoid carcinoma of the salivary glands.

Oncotarget 2017 Sep 20;8(41):69456-69464. Epub 2017 Apr 20.

Department of Oral and Maxillofacial Surgery and Oral Pathology VU University Medical Center, Academic Centre for Dentistry Amsterdam (ACTA) Amsterdam, The Netherlands.

Although rare, mucoepidermoid carcinoma (MEC) is one of the most common malignant salivary gland tumors. The presence of the t(11;19)(q21;p13) translocation in a subset of MECs has raised interest in genomic aberrations in MEC. In the present study we conducted genome-wide copy-number-aberration analysis by micro-array comparative-genomic-hybridization on 27 MEC samples. Low/intermediate-grade MECs had significantly fewer copy-number-aberrations compared to high-grade MECs (low vs high: 3.48 vs 30; = 0.0025; intermediate vs high: 5.7 vs 34.5; = 0.036). The translocation-negative MECs contained more copy-number-aberrations than translocation-positive MECs (average amount of aberrations 15.9 vs 2.41; =0.04). Within all 27 MEC samples, 16p11.2 and several regions on 8q were the most frequently gained regions , while 1q23.3 was the most frequently detected loss. Low/intermediate-grade MEC samples had copy-number-aberrations in chromosomes 1, 12 and 16, while high-grade MECs had a copy-number-aberration in 8p. The most commonly observed copy-number-aberration was the deletion of 3p14.1, which was observed in 4 of the translocation-negative MEC samples. No recurrent copy-number-aberrations were found in translocation-positive MEC samples. Based on these results, we conclude that MECs may be classified as follows: (i) t(11;19)(q21;p13) translocation-positive tumors with no or few chromosomal aberrations and (ii) translocation-negative tumors with multiple chromosomal aberrations.
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http://dx.doi.org/10.18632/oncotarget.17282DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5642491PMC
September 2017

Prognostic modeling of oral cancer by gene profiles and clinicopathological co-variables.

Oncotarget 2017 Aug 26;8(35):59312-59323. Epub 2017 Jul 26.

Department of Otolaryngology - Head and Neck Surgery, VU University Medical Center, Amsterdam, The Netherlands.

Accurate staging and outcome prediction is a major problem in clinical management of oral cancer patients, hampering high precision treatment and adjuvant therapy planning. Here, we have built and validated multivariable models that integrate gene signatures with clinical and pathological variables to improve staging and survival prediction of patients with oral squamous cell carcinoma (OSCC). Gene expression profiles from 249 human papillomavirus (HPV)-negative OSCCs were explored to identify a 22-gene lymph node metastasis signature (LNMsig) and a 40-gene overall survival signature (OSsig). To facilitate future clinical implementation and increase performance, these signatures were transferred to quantitative polymerase chain reaction (qPCR) assays and validated in an independent cohort of 125 HPV-negative tumors. When applied in the clinically relevant subgroup of early-stage (cT1-2N0) OSCC, the LNMsig could prevent overtreatment in two-third of the patients. Additionally, the integration of RT-qPCR gene signatures with clinical and pathological variables provided accurate prognostic models for oral cancer, strongly outperforming TNM. Finally, the OSsig gene signature identified a subpopulation of patients, currently considered at low-risk for disease-related survival, who showed an unexpected poor prognosis. These well-validated models will assist in personalizing primary treatment with respect to neck dissection and adjuvant therapies.
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http://dx.doi.org/10.18632/oncotarget.19576DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5601734PMC
August 2017

Radiation-induced changes in the microstructure of epithelial cells of the oral mucosa: A comparative light and electron microscopic study.

J Oral Pathol Med 2017 Nov 15;46(10):1004-1010. Epub 2017 Sep 15.

Faculty of Health Sciences, Institute of Dentistry, School of Medicine, University of Eastern, Kuopio, Finland.

Objectives: The microplicae is a typical structure of the epithelial cell surface of the oral mucosa. The cell surface is potentially of great significance, as it provides the underlying basis for the protective function of the salivary pellicle. The aim of this study was to investigate whether radiation therapy affects the surface morphology of the superficial cells of the human oral mucosa in patients who have received radiotherapy for oral cancer.

Material And Methods: Oral mucosal tissue samples from 91 patients were collected during dental implant surgery or ablative surgery. Study group 1 consisted of 28 patients who underwent dental implant surgery after radiotherapy. Group 2 consisted of five patients who developed osteoradionecrosis. Group 3 consisted of eight oral cancer patients without radiotherapy. Group 4 consisted of 50 clinically healthy subjects as controls. The samples were studied with scanning electron microscopy and compared with both light and transmission electron micrographs.

Results: Radiation therapy (RT) induces breakage and destruction in the microplicae morphology and declines the density of the microplicae surface structures. In some of the irradiated cells, the microplicae were completely vanished, especially in patients who developed osteoradionecrosis. In non-irradiated tissue, the microplicae of the superficial epithelial cells were intact in all cases.

Conclusion: Scanning electron microscopy, in contrast to light microscopy, appears to be a useful tool to reveal the condition of superficial oral mucosal cells. In respect of the possible pathogenesis of osteoradionecrosis, the radiation-induced damage of the microplicae and its influence on the mucosal salivary pellicle is discussed.
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http://dx.doi.org/10.1111/jop.12639DOI Listing
November 2017

Mucoepidermoid carcinoma-associated expression of MUC5AC, MUC5B and mucin-type carbohydrate antigen sialyl-Tn in the parotid gland.

Arch Oral Biol 2017 Oct 13;82:121-126. Epub 2017 Jun 13.

Department of Oral Biochemistry, Academic Centre for Dentistry Amsterdam, University of Amsterdam and VU University Amsterdam, Amsterdam, The Netherlands. Electronic address:

Objectives: The aberrant expression of mucins and mucin-type carbohydrates has been described in many types of cancer, including mucoepidermoid carcinoma (MEC), a malignant salivary gland tumor. In this study, we examined the aberrant expression patterns of mucins (MUC1, MUC4, MUC5AC and MUC5B), simple mucin-type carbohydrate antigens (Tn, sialyl-Tn and T) and mature carbohydrate antigens (Lewis and sulfo-Lewis antigens) in MEC originating from the parotid gland, which normally does not secrete mucins.

Design: We conducted an immunohistochemical study to investigate the presence of mucins and carbohydrates in 24 MEC samples originating from the parotid gland and in surrounding normal tissue of the same gland in comparison 6 samples of normal salivary glands. The expression levels were compared with respect to the histological grading. Furthermore, 24 MEC samples from non-parotid salivary glands were included.

Results: We observed loss of topology of membrane-bound MUC1 and MUC4, and de novo expression of MUC5AC, MUC5B and sialyl-Tn in MEC that originated in the parotid gland. Furthermore, mucins MUC1, MUC4 and carbohydrate antigens Tn, sialyl-Tn, T, Lewis and sulfo-Lewis were overexpressed in MEC samples compared to surrounding normal salivary gland tissues. MUC1 was expressed in both low- and high grade MECs, whereas MUC4 was not expressed in high grade MECs of the parotid gland.

Conclusion: During the development of MEC in the parotid gland, the genes for gel-forming secretory mucins are switched on. Besides these MEC tissues overexpress short oligosaccharides, suggesting that the glycosylation machinery is altered.
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http://dx.doi.org/10.1016/j.archoralbio.2017.06.010DOI Listing
October 2017

Smoking is associated with severity of liver fibrosis but not with histological severity in nonalcoholic fatty liver disease. Results from a cross-sectional study.

Scand J Gastroenterol 2017 Aug 27;52(8):881-885. Epub 2017 Apr 27.

a Department of Gastroenterology and Hepatology , Radboud university medical center , Nijmegen , the Netherlands.

Objectives: To assess the influence of smoking on histological disease severity and fibrosis in real-world NAFLD patients.

Material And Methods: Consecutive NAFLD patients were identified with liver biopsies performed between 2008 and 2015. Characteristics such as smoking status and total number of pack years were collected. Biopsies were revised and BRUNT fibrosis and NAFLD activity score (NAS) determined. Patients with a high NAS (≥5) were compared to patients with a low NAS (<5) and with advanced fibrosis (stage 3-4) to patients with no-early fibrosis (stage 0-2). Patients with a history of smoking (current or past smoker) were defined ever smokers.

Results: Fifty-six patients were included (mean age 49 ± 14.3, 68.9% males and 39.3% history of smoking). Ever smokers had a higher fibrosis score than never smokers; two (IQR 0-3) versus one (IQR 1-1.5) (p = .040). Patients with advanced fibrosis smoked significantly more pack years than patients with no-early fibrosis; 10.6 (IQR 0-25.8) versus 0 (IQR 0-7) (p = .011). There is a weak to moderate correlation between fibrosis stage and number of pack years (Spearman's Rho = 0.341, p = .012). There was no difference in NAS between never and ever smokers; 2.8 ± 1.5 versus 3.3 ± 1.4 (p = .205). Patients with NAS <5 had a median number of pack years of 0 (IQR 0-9) versus a median of 10.3 pack years (IQR 0-24) in patients with NAS ≥5 (p = .127).

Conclusion: Smoking is associated with severity of NAFLD-related liver fibrosis but not with histological disease severity. This supports the recommendation to cease smoking for NAFLD patients.
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http://dx.doi.org/10.1080/00365521.2017.1315169DOI Listing
August 2017