MAdCAM-1 does not play a central role in the early pathophysiology of autoimmune hepatitis.

INTRODUCTION: CD4+ T cells are thought to have a central role in the pathogenesis of autoimmune hepatitis (AIH). Mucosal addressin cell adhesion molecule-1 (MAdCAM-1) directs homing of CD4+ T cells in the alimentary tract and is a therapeutic target in inflammatory bowel diseases. Here we assessed MAdCAM-1 expression in AIH and viral hepatitis and related its expression with immune infiltrate analysis and histopathological key features. METHODS: Hepatic portal areas of pretreatment biopsies (n=10) and follow-up biopsies (n=9) of patients with a confirmed diagnosis of AIH were assessed for MAdCAM-1 expression and infiltrate composition using immunohistochemistry and multispectral imaging (Vectra® Polaris™). Controls consisted of biopsies of patients with untreated chronic viral hepatitis B or C (n=22). RESULTS: MAdCAM-1 expression on endothelium was sparsely present in portal fields of two treatment-naïve AIH patients. Three patients showed MAdCAM-1 expression within lymphoid aggregates. No expression of significance (including single-cell expression) was observed in the remaining 6 patients. In contrast, viral hepatitis C biopsies showed endothelial MAdCAM-1 expression in 8 of 13 untreated patients. Densities of both B-cells (CD20+) and CD4+ T-cells (CD3+ CD8-) were increased in AIH and viral hepatitis patients with MAdCAM-1 expression. CONCLUSION: MAdCAM-1 was detected in liver biopsies in a minority of patients with AIH at the time of diagnosis suggesting no central role in its pathophysiology. Lymphoid or reticular MAdCAM-1 pattern expression was associated with more dense infiltrates of both B-cells and CD4+ T-cells, and may be related to the formation of secondary lymphoid follicles.

[Pathologist reporting to the patient]. / Rapportage van de uitslag door de patholoog aan de patiënt.

For many patients the pathology report plays a key role in diagnosis and treatment planning. The report is traditionally addressed to the clinician and not to the patient. Although nowadays the patient can read the report, the complex content most often is incomprehensible to him/her. In an era of shared decision-making in which the patient must be fully informed, direct communication between patient and pathologist could be of added value for successful therapeutic management. Some successful initiatives have been reported. However, in the Netherlands direct interaction between the pathologist and the patient is still rare. This article is a plea to view the pathology report from a patient's perspective and to investigate how the communication of the content can be optimized. This article discusses possibilities for practical implementation, potential benefits and bottlenecks, as a basis for starting a discussion with practitioners, pathologists and patients in the Netherlands.

Management and outcome of middle ear adenomatous neuroendocrine tumours: A systematic review.

Middle ear adenomatous neuroendocrine tumours (MEANTs) are rare, unpredictable tumours. Although most MEANTs are characterized by a benign biological behaviour and indolent growth pattern, some studies have reported locally invasive and metastastic disease. Currently, the optimal management strategy for MEANTs remains subject of debate. The aim of this study is to review the literature on MEANTs with focus on its clinical characteristics, treatment strategies and outcome. A systematic review was conducted using PubMed, Embase and Cochrane databases. A total of 111 studies comprising 198 patients with MEANT were included. Treatment modalities comprised surgery (90%), surgery with adjuvant radiotherapy (9%) and palliative (chemo)radiotherapy in (1%). Local recurrence was observed in 25% of the patients and 7% of the patients developed metastasis, over a median period of 5.7 years (range 7 months - 32 years). Twelve of 13 patients (92%) who developed metastases had a local recurrence. Four patients (2%) died of MEANT: three due to distant metastases and one due to extensive local recurrence. Reliable histopathologic predictors of outcome could not be identified. These findings indicate that the clinical presentations of MEANT vary substantially, the overall recurrence rate is considerable and initial local tumour control is paramount. Because of the unpredictable clinical course, prolonged follow-up is warranted.

[Identification of differentiated dysplasia improves prediction of oral leukoplakia at increased risk of malignant progression]. / Onderkenning van gedifferentieerde dysplasie voor het voorspellen van de kans op maligne ontaarding van orale leukoplakie.

Oral leukoplakia is the most common potentially malignant disorder of the oral mucosa with a rate of malignant transformation into oral squamous cell carcinoma of 1-2% annually. The presence or absence of dysplasia as defined by the WHO is an important histological marker for malignant transformation risk assessment, but is not sufficiently accurate for patient stratification. We investigated whether identifying differentiated dysplasia contributes to oral leukoplakia malignant transformation risk assessment. We investigated whether classic or differentiated dysplasia were present in 84 oral leukoplakias. In 25 of these patients a squamous cell carcinoma developed during follow-up. Risk of malignant progression of oral leukoplakia increased from 3.3 (HR, p = 0.002) when only classic dysplasia was considered to 7.4 (HR, p = 0.001) when both classic and differentiated dysplasia were combined. This study demonstrates that identifying differentiated dysplasia as a separate type of dysplasia is important for the prognosis and stratification of patients with oral leukoplakia.

Bone microarchitecture and turnover in the irradiated human mandible.

OBJECTIVES: The aim of this study was to assess the microarchitecture and turnover in irradiated cancellous mandibular bone and the relation with radiation dose, to elucidate the effects of radiotherapy on the mandible. PATIENTS AND METHODS: Mandibular cancellous bone biopsies were taken from irradiated patients and controls. Micro-CT scanning was performed to analyze microstructural bone parameters. Bone turnover was assessed by histomorphometry. Local radiation dose at the biopsy site (Dmax) was estimated from radiotherapy plans. RESULTS: Twenty-seven irradiated patients and 35 controls were included. Osteoid volume (Osteoid Volume/Bone Volume, OV/BV) [0.066/0.168 (median/interquartile range (IQR), OV/BV; %), P < 0.001], osteoid surface (Osteoid Surface/Bone Surface, OS/BS) [0.772/2.17 (median/IQR, OS/BS; %), P < 0.001] and osteoclasts number (Osteoclasts per millimetre bone surface, Ocl/mmBS; mm2) [0.026/0.123 (median/IQR, Ocl/mmBS; mm2), P < 0.001] were decreased; trabecular number (Tb.N) was lower [1.63/0.63 (median/IQR, Tb.N; 1/mm-1), P = 0.012] and trabecular separation (Tb.Sp) [0.626/0.24 (median/IQR, Tb.Sp; µm), P = 0.038] was higher in irradiated mandibular bone. With higher Dmax, trabecular number increases (Spearman's correlation R = 0.470, P = 0.018) and trabecular separation decreases (Spearman's correlation R = -0.526, P = 0.007). Bone mineral density (BMD, milligrams hydroxyappetite per cubic centimetre, mgHA/cm3) [1016/99 (median/IQR, BMD; mgHA/cm3), P = 0.03] and trabecular separation [0.739/0.21 (median/IQR, Tb.Sp; µm), P = 0.005] are higher whereas connectivity density (Conn Dens) [3.94/6.71 (median/IQR, Conn Dens), P = 0.047] and trabecular number [1.48/0.44 (median/IQR, Tb.N; 1/mm-1), P = 0.002] are lower in Dmax ≤50 Gy compared to controls. CONCLUSIONS: Radiotherapy dramatically impairs bone turnover in the mandible. Deterioration in microarchitecture only affects bone irradiated with a Dmax of <50 Gy. The 50 Gy value seems to be a critical threshold to where the effects of the radiation is more detrimental.

[Dentogenic ghost cell tumour in the mandible]. / Dentinogene ghost cell-tumor in de onderkaak.

A 67-year-old man presented with a swelling on the right side of the mandible. Histopathological investigation of a biopsy revealed a peripheral dentogenic ghost cell tumour. Treatment consisted of thorough excochleation of the abnormality and 2 years after treatment, the patient was free of recurrence. In the literature, a distinction is made between peripheral and central dentogenic ghost cell tumours, which, like calcifying odontogenic cysts, are considered to be ghost cell odontogenic lesions. These are rarely occurring abnormalities, where the chances of recurrence after proper treatment are limited. The central dentogenic ghost cell tumour has a greater chance of recurring locally.

Perioperative PET/CT lymphoscintigraphy and fluorescent real-time imaging for sentinel lymph node mapping in early staged colon cancer.

PURPOSE: Using current optical imaging techniques and gamma imaging modalities, perioperative sentinel lymph node (SLN) identification in colon cancer can be difficult when the SLN is located near the primary tumour or beneath a thick layer of (fat) tissue. Sentinel lymph node mapping using PET/CT lymphoscintigraphy combined with real-time visualization of the SLN using near-infrared imaging has shown promising results in several types of cancer and may facilitate the successful identification of the number and location of the SLN in early colon cancer. METHODS: Clinical feasibility of PET/CT lymphoscintigraphy using preoperative endoscopically injected [89Zr]Zr-Nanocoll and intraoperative injection of the near-infrared (NIR) tracer Indocyanine Green (ICG) was evaluated in ten early colon cancer patients. Three preoperative PET/CT scans and an additional ex vivo scan of the specimen were performed after submucosal injection of [89Zr]Zr-Nanocoll. All SLNs and other lymph nodes underwent extensive pathological examination for metastases. A histopathological proven lymph node visible at preoperative PET/CT and identified at PET/CT of the specimen was defined as SLN. RESULTS: A total of 27 SLNs were harvested in seven out of eight patients with successful injection of both tracers. In one patient no SLNs were assigned preoperatively. In two patients injection of [89Zr]Zr-Nanocoll failed due to incorrect needle positioning. Twenty-one (78%) SLNs were found intraoperatively using NIR-imaging. Eleven of the 27 (41%) SLNs were located near the primary tumour (< 2 cm). Those six SLNs not found intraoperatively with NIR-imaging were all located close to the tumour. In all seven patients at least one SLN could be assigned at preoperative imaging 24 h after tracer administration. One SLN contained metastases detected by immunohistochemistry. No metastases were found in the non-SLNs. CONCLUSIONS: This study shows the potential of preoperative PET/CT lymphoscintigraphy to inform the surgeon about the number and location of SLNs in patients with early colon cancer. The additional use of NIR-imaging allows for intraoperative identification of these SLNs which are invisible with conventional white light imaging. Further research is necessary to improve and simplify the technique. We recommend perioperative SLN identification using a preoperative lymphoscintigraphy scan just before surgery approximately 24 h after injection. Additionally a postoperative scan of the specimen combined with intraoperative real-time NIR-imaging should be performed.

The irradiated human mandible: A quantitative study on bone vascularity.

OBJECTIVES: Hypovascularisation is thought to play an important role in the pathogenesis of osteoradionecrosis. The objective of this study was to assess the microvascular system in the irradiated mandibular bone marrow. MATERIALS AND METHODS: Mandibular bone biopsies were taken from 20 irradiated patients and 24 controls. Blood vessels were visualized using CD34 antibody stain to detect endothelial cells. The vascular density (VD) and vascular area fraction (VAF) were measured. Mean vessel lumen area, perimeter and diameter of the vessels were calculated for each vessel. A distinction was made between large and small vessels (cut-off point <400 µm2). RESULTS: Vascular density and vascular area fraction were lower in the irradiated group. The mean vascular perimeter and mean vascular diameter were higher in samples with a local radiation dose of ≥50 Gy, whereas the percentage of small vessels was lower. Larger vessel perimeter is associated with higher radiation dose. A longer interval between biopsy and radiotherapy is associated with a larger mean vessel perimeter and a lower percentage of small vessels. CONCLUSIONS: Radiation dosages higher than 50 Gy mainly affect the smaller vessels. With increased time after irradiation, the share of smaller vessels in the mandibular bone marrow seems to decrease. In search of the exact mechanisms of irradiation damage and osteoradionecrosis of the mandible, the role of the microvascular system in the mandibular bone marrow should be further explored.

Clinicopathological characteristics and outcome of 31 patients with ETV6-NTRK3 fusion gene confirmed (mammary analogue) secretory carcinoma of salivary glands.

OBJECTIVES: In 2010, a new subtype of salivary gland cancer (SGC), (mammary analogue) secretory carcinoma (SC), was defined, characterized by the ETV6-NTRK3 fusion gene. As clinical behavior and outcome data of this histological subtype tumor are still sparse, we aimed to describe the clinicopathological course and outcome of a series of translocation positive SC patients. PATIENT AND METHODS: We re-evaluated the pathological diagnosis of a subset of SGCs, diagnosed in 4 of 8 Dutch head and neck centers. Subsequently, tumors with a morphological resemblance to SC were tested for the ETV6-NTRK3 fusion gene using RT-PCR. Furthermore, patients prospectively diagnosed with SC were included. The clinical characteristics and outcomes were retrieved from the patient files. RESULTS: Thirty-one patients with ETV6-NTRK3 fusion gene positive SC were included. The median age was 49 years, 17 patients (55%) were male. Eighteen tumors (58%) arose in the parotid gland. One patient presented with lymph node metastasis. All patients underwent tumor resection and 4 patients had a neck dissection. Four patients had re-resection and 15 patients (48%) received postoperative radiotherapy. One patient developed a local recurrence, no regional recurrences or distant metastases were observed. After a median follow-up of 49 months the 5- and 10-year overall survival were 95%, the 5- and 10-year disease free survival were 89%. CONCLUSION: The clinical course of SC is favorable with a low rate of locoregional recurrence and excellent survival. Given the low incidence of nodal metastases, elective neck treatment, i.e. surgery and/or radiotherapy, does not seem to be indicated.

Evaluation of the eighth TNM classification on p16-positive oropharyngeal squamous cell carcinomas in the Netherlands and the importance of additional HPV DNA testing.

Background: Oropharyngeal squamous cell carcinomas (OPSCCs) are traditionally caused by smoking and excessive alcohol consumption. However, in the last decades high-risk human papillomavirus (HPV) infections play an increasingly important role in tumorigenesis. HPV-driven OPSCCs are known to have a more favorable prognosis, which has led to important and marked changes in the recently released TNM-8. In this 8th edition, OPSCCs are divided based on p16 immunostaining, with p16 overexpression as surrogate marker for the presence of HPV. The aims of this study are to evaluate TNM-8 on a Dutch consecutive cohort of patients with p16-positive OPSCC and to determine the relevance of additional HPV DNA testing. Patients and methods: All OPSCC patients without distant metastases at diagnosis and treated with curative intent at VU University Medical Center (2000-2015) and Erasmus Medical Center (2000-2006) were included (N = 1204). HPV status was determined by p16 immunostaining followed by HPV DNA PCR on the p16-immunopositive cases. We compared TNM-7 and TNM-8 using the Harrell's C index. Results: In total, 388 of 1204 (32.2%) patients were p16-immunopositive. In these patients, TNM-8 had a markedly better predictive prognostic power than TNM-7 (Harrell's C index 0.63 versus 0.53). Of the 388 p16-positive OPSCCs, 48 tumors (12.4%) were HPV DNA-negative. This subgroup had distinct demographic, clinical and morphologic characteristics and showed a significantly worse five-year overall survival compared with the HPV DNA-positive tumors (P < 0.001). Conclusions: TNM-8 has a better predictive prognostic power than TNM-7 in patients with p16-positive OPSCC. However, within p16-positive OPSCCs, there is an HPV DNA-negative subgroup with distinct features and a worse overall survival, indicating the importance to perform additional HPV DNA testing when predicting prognosis and particularly for selecting patients for de-intensified treatment regimens.

Epidemiologic associations of HPV-positive oropharyngeal cancer and (pre)cancerous cervical lesions.

Human papillomavirus (HPV)-induced oropharyngeal squamous cell carcinoma (OPSCC) remains increasing worldwide. We aimed to investigate if the HPV-prevalence of OPSCC in the Netherlands is rising as well, also in female patients. In addition, we evaluated the association between HPV-positive OPSCC and suspicious Pap results of the cervix in these female patients. Patients with OPSCC treated in the period 2000-2015 at the VU University Medical Center Amsterdam, were included (n = 926). The presence of an oncogenic HPV infection was determined by p16-immunostaining, followed by a high-risk HPV general primer 5+/6+ DNA PCR on the p16-immunopositive cases. A review of pathology reports in all female patients (n = 305) was undertaken to identify cytological signs of HPV-related (pre)cancer of the cervix. In total 281 of 926 (30.3%) OPSCCs were HPV-positive. Moreover, a significant increase in the prevalence of HPV-positive OPSCCs was observed from 14.0% in 2000 to 48.1% in 2015 (p < 0.001). Among the female patients with an HPV-positive OPSSC (n = 70), the results of cervical smears were available in 56 of 70 patients (80.0%). Of the female patients with HPV-positive OPSCC, 9 of 56 (16.1%) patients had a vaginal cuff Papanicolaou (Pap) test ≥3b in their medical history compared to 7 of 168 (4.2%) in the HPV-negative group (p = 0.003). In conclusion, a continuous increase in the HPV-attributable fraction of OPSCC was demonstrated in the period 2000-2015 in the Amsterdam region. HPV-positive OPSCC has a significant association with a history of suspicious Pap results of the cervix in female patients.

Non-classic EGFR mutations in a cohort of Dutch EGFR-mutated NSCLC patients and outcomes following EGFR-TKI treatment.

BACKGROUND: Data on non-small-cell lung cancer (NSCLC) patients with non-classic epidermal growth factor receptor (EGFR) mutations are scarce, especially in non-Asian populations. The purpose of this study was to evaluate prevalence, clinical characteristics and outcome on EGFR-TKI treatment according to type of EGFR mutation in a Dutch cohort of NSCLC patients. METHODS: We retrospectively evaluated a cohort of 240 EGFR-mutated NSCLC patients. Data on demographics, clinical and tumour-related features, EGFR-TKI treatment and clinical outcome were collected and compared between patients with classic EGFR mutations, EGFR exon 20 insertions and other uncommon EGFR mutations. RESULTS: Classic EGFR mutations were detected in 186 patients (77.5%) and non-classic EGFR mutations in 54 patients (22.5%); 23 patients with an exon 20 insertion (9.6%) and 31 patients with an uncommon EGFR mutation (12.9%). Median progression-free survival (PFS) and overall survival (OS) on EGFR-TKI treatment were 2.9 and 9.7 months, respectively, for patients with an EGFR exon 20 insertion, and 6.4 and 20.2 months, respectively, for patients with an uncommon EGFR mutation. Patients with a double uncommon EGFR mutation that included G719X/L861Q/S768I had longer PFS and OS on EGFR-TKI treatment compared with patients with a single G719X/L861Q/S768I EGFR mutation (both P=0.02). CONCLUSIONS: In our Dutch cohort, prevalence and genotype distribution of non-classic EGFR mutations were in accordance with previously reported data. The PFS and OS on EGFR-TKI treatment in patients with an uncommon EGFR mutation were shorter compared with patients with classic EGFR mutations, but varied among different uncommon EGFR mutations.

Different prognostic models for different patient populations: validation of a new prognostic model for patients with oropharyngeal cancer in Western Europe.

OBJECTIVE: The presence of human papillomavirus (HPV) infection in oropharyngeal squamous cell carcinoma (OPSCC) is a major determinant in prognostic risk modelling. Recently, a prognostic model was proposed in which HPV status, comorbidity and nodal stage were the most important prognostic factors to determine high-, intermediate- and low-risk survival groups. Here, we report on the validation of this model using an independent single-institutional cohort. METHODS: A total number of 235 patients curatively treated for OPSCC in the period 2000-2011 at the MUMC (Maastricht University Medical Center, The Netherlands) were included. The presence of an oncogenic HPV infection was determined by p16 immunostaining, followed by a high-risk HPV DNA PCR on the p16-positive cases. The model variables included were HPV status, comorbidity and nodal stage. As a measure of model performance, the Harrell's Concordance index (Harrell's C-index) was used. RESULTS: The 5-year overall survival (OS) estimates were 84.6%, 54.5% and 28.7% in the low-, intermediate- and high-risk group, respectively. The difference between the survival curves was highly significant (P<0.001). The Harrell's C-index was 0.69 (95% confidence interval (CI): 0.63-0.75). CONCLUSION: In this study a previously developed prognostic risk model was validated. This model will help to personalise treatment in OPSCC patients. This model is publicly available at www.predictcancer.org.

Response evaluation after chemoradiotherapy for advanced nodal disease in head and neck cancer using diffusion-weighted MRI and 18F-FDG-PET-CT.

OBJECTIVES: Evaluation of accuracy and interobserver variation of diffusion-weighted magnetic resonance imaging (DW-MRI) and 18F-fluorodeoxyglucose positron emission tomography-computed tomography (18F-FDGPET-CT) to detect residual lymph node metastases after chemoradiotherapy (CRT) in advanced staged head and neck squamous cell carcinoma (HNSCC). MATERIALS AND METHODS: Retrospectively, routinely performed DW-MRI (n=73) and 18F-FDG-PET-CT (n=58) 3months after CRT in HNSCC-patients with advanced nodal disease (N2-N3) were assessed by two radiologists and two nuclear medicine physicians (individually and in consensus). Imaging was scored dichotomously and on a five-point Likert scale. We also explored different scenarios for the potential added value of DW-MRI to PET-CT using the consensus Likert scale. Histopathology and a follow-up of 9months after CRT served as reference standard. RESULTS: Five patients (7%) had residual regional disease. DW-MRI showed a sensitivity of 60% and a specificity of 93%, vs. 100% and 84% for PET-CT, respectively. DW-MRI and PET-CT observers had 'moderate' and 'substantial' interobserver agreement (κ=0.58 and κ=0.64, respectively) with the dichotomous system. The combination of PET-CT and DW-MRI showed a sensitivity of 100% and a specificity of 95%. CONCLUSION: The high sensitivity of PET-CT authorizes a neck dissection in all patients with a positive test result and the high specificity of DW-MRI justifies avoidance of invasive neck dissections if the test is negative. Interobserver agreement varied as a function of test positivity criteria. Adding DW-MRI to PET-CT seemed to increase the specificity of PET-CT alone, thereby ensuring that less patients are exposed to unnecessary neck dissections.

Quantitative diffusion-weighted MRI parameters and human papillomavirus status in oropharyngeal squamous cell carcinoma.

BACKGROUND AND PURPOSE: Patients with human papillomavirus-positive oropharyngeal squamous cell carcinomas have a better survival rate than those with human papillomavirus-negative oropharyngeal squamous cell carcinomas. DWI characterizes biologically relevant tumor features, and the generated ADC may also provide prognostic information. We explored whether human papillomavirus status and ADC values are independent tumor characteristics. MATERIALS AND METHODS: Forty-four patients with oropharyngeal squamous cell carcinomas underwent pretreatment DWI. ADC values for the primary tumors were determined by using 3 b-values in an ROI containing the largest area of solid tumor on a single section of an axial DWI image. Human papillomavirus status was determined with p16 immunostaining, followed by high-risk human papillomavirus DNA detection on the p16-positive cases. RESULTS: Twenty-two patients were human papillomavirus-positive (50.0%). ADC values were not significantly different between human papillomavirus-negative (ADC(mean) = 1.56 [1.18-2.18] × 10(3) mm(2)/s) and human papillomavirus-positive tumors (ADC(mean) = 1.46 [1.07-2.16] × 10(3) mm(2)/s). CONCLUSIONS: No significant association between ADC and human papillomavirus status was found in oropharyngeal squamous cell carcinomas. In our study population, differences in genetic and histologic features between human papillomavirus-positive and human papillomavirus-negative oropharyngeal squamous cell carcinomas did not translate into different ADC values. Long-term follow-up studies are needed to establish whether ADC has prognostic value and whether this is independent of the human papillomavirus status.

HLA-DRB1*03:01 and HLA-DRB1*04:01 modify the presentation and outcome in autoimmune hepatitis type-1.

The classical human leukocyte antigen (HLA)-DRB1*03:01 and HLA-DRB1*04:01 alleles are established autoimmune hepatitis (AIH) risk alleles. To study the immune-modifying effect of these alleles, we imputed the genotypes from genome-wide association data in 649 Dutch AIH type-1 patients. We therefore compared the international AIH group (IAIHG) diagnostic scores as well as the underlying clinical characteristics between patients positive and negative for these HLA alleles. Seventy-five percent of the AIH patients were HLA-DRB1*03:01/HLA-DRB1*04:01 positive. HLA-DRB1*03:01/HLA-DRB1*04:01-positive patients had a higher median IAIHG score than HLA-DRB1*03:01/HLA-DRB1*04:01-negative patients (P<0.001). We did not observe associations between HLA alleles and alanine transaminase levels (HLA-DRB1*03:01: P=0.2; HLA-DRB1*04:01; P=0.5); however, HLA-DRB1*03:01 was independently associated with higher immunoglobulin G levels (P=0.04). The HLA-DRB1*04:01 allele was independently associated with presentation at older age (P=0.03) and a female predominance (P=0.04). HLA-DRB1*03:01-positive patients received immunosuppressive medication and liver transplantation. In conclusion, the HLA-DRB1*03:01 and HLA-DRB1*04:01 alleles are both independently associated with the aggregate diagnostic IAIHG score in type-1 AIH patients, but are not essential for AIH development. HLA-DRB1*03:01 is the strongest genetic modifier of disease severity in AIH.

Hepatocellular carcinoma: Dutch guideline for surveillance, diagnosis and therapy.

UNLABELLED: Hepatocellular carcinoma (HCC) is rare in the Netherlands, even though the incidence has increased quite sharply in recent years. Standard treatment options consist of surgery, orthotopic liver transplantation, radiofrequency ablation, transarterial chemoembolisation (TACE) and systemic therapy with sorafenib. The consensus-based Dutch HCC guideline, established in 2013, serves to guide surveillance, diagnosis and treatment options: Surveillance should be performed by ultrasound at six-month intervals in well-defined cirrhotic patients and in selected high-risk hepatitis B carriers; A nodule > 1 cm in cirrhotic patients with arterial hypervascularity and venous or delayed phase washout at four-phase CT or MRI scan establishes the diagnosis of HCC; In patients with HCC without underlying cirrhosis, resection should be considered regardless of tumour size; In cirrhotic HCC patients, tumour stage, severity of underlying cirrhosis, and performance status determine treatment options. The algorithm of the Barcelona Clinic Liver Cancer (BCLC) staging system should be followed; Patients with Child-Pugh A-B cirrhosis (CP < 8 points) and performance status 0-2 are candidates for any active treatment other than transplantation; In early stage HCC (BCLC stage 0 or A, compensated cirrhosis without portal hypertension) surgical resection, liver transplantation, or radiofrequency ablation should be considered; In intermediate stage HCC (BCLC stage B) TACE and÷ or radiofrequency ablation should be considered; In advanced stage HCC (BCLC stage C) sorafenib should be considered. CONCLUSION: The Dutch HCC guideline offers advice for surveillance, diagnosis and treatment of HCC.

Sentinel lymph node biopsy in clinically N0 T1-T2 staged oral cancer: the Dutch multicenter trial.

OBJECTIVES: Results of the Dutch multi-institutional trial on sentinel lymph node (SLN) biopsy in oral cancer. PATIENTS AND METHODS: Patients were consecutively enrolled from 4 institutions, with T1/T2 oral cancer and cN0 neck based on palpation and ultrasound guided fine needle aspiration cytology. Lymphatic mapping consisted of preoperative lymphoscintigraphy. For intraoperative SLN detection a gamma-probe was used and in some patients additional blue dye. SLN negative patients were carefully observed, SLN positive patients were treated by neck dissection, radiotherapy or a combination of both. Endpoints of the study were risk of occult lymp node metastases, neck control, accuracy, 5-year disease-free survival (DFS), overall survival (OS) and disease-specific survival (DSS). RESULTS: Twenty of 62 patients (32%) had positive SLNs. Macrometastases were found in 9 patients, micrometastases in 8, and isolated tumour cells in 3 patients. Median follow-up was 52.5 months. Of the 42 SLN negative patients, 5 developed a regional recurrence of whom 4 patients could be successfully salvaged. DFS, OS and DSS of SLN negative patients were 72.0%, 92.7% and 97.4%, and for SLN positive patients these numbers were 73.7%, 79.7%, 85.0%, respectively (DFS: p=0.916, OS: p=0.134, DSS: p=0.059, respectively). Neck control rate was 97% in SLN negative and 95% in SLN positive patients. Sensitivity was 80% and negative predictive value 88%. CONCLUSION: SLN biopsy is able to reduce the risk of occult lymph node metastases in T1/T2 oral cancer patients from 40% to 8%, and enables excellent control of the neck.

TP53 mutation and human papilloma virus status of oral squamous cell carcinomas in young adult patients.

OBJECTIVE: Little is known about the molecular carcinogenesis of oral squamous cell carcinoma (OSCC) in young adult patients. The aim of this study was to investigate the detailed TP53 mutation and human papilloma virus (HPV) status of OSCC in patients, younger than 45 years. METHODS: TP53 mutations were determined with direct sequencing on paraffin-embedded carcinoma tissue from 31 young patients and compared with two older age OSCC reference groups: one from the same institute (N = 87) and an independent one (N = 675). Biologically active tumour HPV was detected by p16-immunohistochemistry followed by a HPV-DNA GP5 + /6 + -PCR. RESULTS: HPV16 was present in one OSCC (3%). TP53 mutations were found in 14 (45%) OSCC: five were missense and nine resulted in a truncated protein. Six of these latter were insertions or deletions of one or more nucleotides leading to frameshift, one was at a splice site and two resulted in a stop codon. The percentage of truncating mutations (64% of all mutations) was higher than that observed in the institute's reference group (44%, P = 0.23) and in the independent reference group (24%, P = 0.002). CONCLUSIONS: This study shows that TP53 mutations are common in OSCC of young adult patients; infection with biologically active HPV is rare.

Malignant transformation of oral leukoplakia in a well-defined cohort of 144 patients.

OBJECTIVES: Oral leukoplakia is a potentially malignant disorder of the oral mucosa. The aim of this retrospective study was to identify the factors that possibly predict malignant transformation in a well-defined cohort of patients with a long-term follow-up. All leukoplakias were staged according to a clinicopathological classification and staging system. Furthermore, a certainty factor has been used with which the diagnosis has been established. MATERIAL AND METHODS: The group consisted of 144 patients. The size, presence and degree of epithelial dysplasia were incorporated into a clinicopathological classification and staging system. Initial management consisted of surgical excision, CO2 laser vaporisation or observation only. The mean follow-up period was 51.2 months (s.d. = 39.33, range 12-179 months). RESULTS: In 16 of 144 patients (11%), malignant transformation occurred between 20 and 94 months (mean 57.0 months) after the first visit, the annual malignant transformation rate being approximately 2.6%. A large size of the lesion (≥ 4 cm) showed to be the only statistically significant predictor of malignant transformation (P = 0.034). CONCLUSION: A size of ≥ 4 cm showed to be the only significant predicting factor of malignant transformation in oral leukoplakia. No other epidemiological, aetiological, clinical or histopathological parameters were of statistical significance.