Koos Koole

FGFR1 is a potential prognostic biomarker and therapeutic target in head and neck squamous cell carcinoma

Purpose: FGFR1 is a promising therapeutic target in multiple types of solid tumors, including head and neck squamous cell carcinoma (HNSCC). FGFR inhibitors have shown great therapeutic value in preclinical models. However, resistance remains a major setback. In this study, we have investigated the prognostic value of FGFR1 expression in HNSCC, the therapeutic relevance of targeting FGFR with AZD4547, and potential resistant mechanisms. Experimental Design: IHC and FISH were applied on tissue microarrays to investigate FGFR1 protein expression and FGFR1 gene copy numbers in 452 HNSCCs. The sensitivity of HNSCC cell lines to AZD4547, either as single or combination treatment with the EGFR inhibitor gefitinib, was assessed using long-term colony formation assays, short-term viability assays, and biochemical analysis. Results: FGFR1 protein overexpression occurred in 82% (36/44) of human papillomavirus (HPV)–positive HNSCC and 75% (294/392) of HPV-negative HNSCC and relates with poor overall survival and disease-free survival in HPV-negative HNSCC [HR, 3.07; 95% confidence interval (CI), 1.74–6.90; P = 0.001 and HR, 1.53; 95% CI, 1.04–2.39; P = 0.033]. Moreover, the FGFR1 gene was amplified in 3% (3/110) of HPV-negative HNSCC. Treatment of the high FGFR1-expressing cell line CCL30 with AZD4547 reduced cell proliferation and FGFR signaling. Two FGFR-amplified cell lines, SCC147 and BICR16, were resistant to AZD4547 treatment due to EGFR signaling. Combined AZD4547 and gefitinib treatment synergistically inhibited the proliferation of resistant cell lines. Conclusions: Here, we identify high FGFR1 expression as a candidate prognostic biomarker in HPV-negative HNSCC. Furthermore, we provide a rationale for treating FGFR1-expressing HNSCC with the FGFR inhibitor AZD4547 and for combining AZD4547 and gefitinib in FGFR inhibitor–resistant HNSCC patients. Clin Cancer Res; 22(15); 3884–93. ©2016 AACR.

FGFR1, 2 and 3 protein overexpression and molecular aberrations of FGFR3 in early stage non‐small cell lung cancer

This study aimed to determine protein expression levels of fibroblast growth factor receptors (FGFR) 1, 2 and 3 in early stage non‐small cell lung cancer (NSCLC). Additionally, a screen to define the frequency of FGFR3‐TACC3 translocation and FGFR3 amplification was performed. Archived tissues from 653 NSCLC samples (adenocarcinoma (AC), squamous cell carcinoma (SCC) and large cell carcinoma (LCC)) were analysed with immunohistochemistry (IHC) for expression of FGFR1, 2 and 3. Expression levels of FGFR1, 2 and 3 were correlated with clinicopathological features. The presence of FGFR3‐TACC3 translocation was detected by RT‐PCR and FGFR3 amplification was detected by fluorescence in situ hybridization. FGFR1, 2 and 3 proteins were highly expressed in 64 (10.6%), 76 (12.9%) and 20 (3.3%) NSCLC tumour samples, respectively. Protein expression of FGFR1 was significantly related to worse overall survival in NSCLC. Furthermore, FGFR1 protein expression was associated with light smoking and histological subtype (AC), FGFR2 protein expression with female gender, younger age, histological subtype (AC) and lower tumour stage, and FGFR3 protein was significantly overexpressed in tumours of older patients and SCC histology. The FGFR3‐TACC3 fusion was detected in 3.0% (6/200) of NSCLC samples and the FGFR3 gene was amplified in 4.7% of IHC positive NSCLC samples (2/43). FGFR1, 2 and 3 proteins are expressed in a high number of early stage NSCLC and FGFR1 protein expression may serve as a prognostic biomarker. Recurrent translocations and amplifications in FGFR3 can be found in NSCLC. This study shows that FGFR family members are frequently aberrant in NSCLC and could be interesting therapeutic targets for the treatment of NSCLC.

Fibroblast growth factor receptor 3 protein is overexpressed in oral and oropharyngeal squamous cell carcinoma

Fibroblast growth factor receptor 3 (FGFR3) is a member of the fibroblast growth factor receptor tyrosine kinase family. It has been identified as a promising therapeutic target in multiple types of cancer. We have investigated FGFR3 protein expression and FGFR3 gene copy‐numbers in a single well‐documented cohort of oral and oropharyngeal squamous cell carcinoma. Tissue microarray sets containing 452 formalin‐fixed paraffin‐embedded tissues were immunohistochemically stained with an anti‐FGFR3 antibody and hybridized with a FGFR3 fluorescence in situ hybridization probe. FGFR3 protein expression was correlated with clinicopathological and survival data, which were retrieved from electronic medical records. FGFR3 mRNA data of 522 head and neck squamous cell carcinoma (HNSCC) were retrieved from The Cancer Genome Atlas (TCGA). Fibroblast growth factor receptor 3 (FGFR3) protein was overexpressed in 48% (89/185) of oral and 59% (124/211) of oropharyngeal squamous cell carcinoma. Overexpression of FGFR3 protein was not related to overall survival or disease‐free survival in oral (HR[hazard ratio]: 0.94; 95% CI: 0.64–1.39; P = 0.77, HR: 0.94; 95% CI: 0.65–1.36; P = 0.75) and oropharyngeal squamous cell carcinoma (HR: 1.21; 95% CI: 0.81–1.80; P = 0.36, HR: 0.42; 95% CI: 0.79–1.77; P = 0.42). FGFR3 mRNA was upregulated in 3% (18/522) of HNSCC from the TCGA. The FGFR3 gene was gained in 0.6% (1/179) of oral squamous cell carcinoma but no amplification was found in oral and oropharyngeal squamous cell carcinoma. In conclusion, FGFR3 protein is frequently overexpressed in oral and oropharyngeal squamous cell carcinoma. Therefore, it may serve as a potential therapeutic target for FGFR3‐directed therapies in oral and oropharyngeal squamous cell carcinoma.

FGFR4 Is a Potential Predictive Biomarker in Oral and Oropharyngeal Squamous Cell Carcinoma

Objective: The aim of this study was to investigate whether fibroblast growth factor receptor 4 (FGFR4) could serve as a potential therapeutic target, prognostic biomarker or biomarker predicting radiotherapy sensitivity in oral squamous cell carcinoma (OSCC) and oropharyngeal squamous cell carcinoma (OPSCC). Methods: FGFR4 immunohistochemistry and FGFR4/CEN5q FISH were performed on tissue microarrays from 212 OSCC and 238 OPSCC patients. FGFR4 genotypes were determined by PCR and DNA sequencing in 76 random OPSCC samples. The response to radiotherapy was evaluated 3 months after the last radiotherapy treatment session by a head and neck radiation oncologist and/or surgeon during clinic visits. The results were correlated to overall survival and response to radiotherapy. Results: The FGFR4 protein was overexpressed in 64% (153/238) of OPSCCs and 41% (87/212) of OSCCs. The FGFR4 gene was amplified in 0.47% (1/212) of OSCCs and 0.42% (1/238) of OPSCCs, and the FGFR4 Gly388Arg polymorphism was detected in 62% (47/76) of OPSCCs. FGFR4 protein expression, FGFR4 gene copy numbers and FGFR4 genotypes were not related to overall survival or response to radiotherapy in OSCC or OPSCC. Conclusion: FGFR4 is frequently overexpressed in OSCC and OPSCC in the absence of gene amplification, and may serve as a potential predictive marker for FGFR4-directed targeted therapy in OSCC and OPSCC.

Association of varicosities and concomitant deep venous thrombosis in patients with superficial venous thrombosis, a systematic review

Abstract Background: In patients with superficial venous thrombosis (SVT) co-existence of deep venous thrombosis (DVT) can be present. Varicosities are considered as a risk factor for both SVT and DVT separately. However, current evidence is contradictory whether varicosities are associated with an increased or reduced prevalence of concomitant DVT in patients with SVT. Objectives: To determine the diagnostic value of both presence and absence of varicosities in the detection of concomitant DVT in non-hospitalized patients with SVT. Methods: In MEDLINE and EMBASE, a systematic search was performed to collect all published studies on this topic. The selected papers were critically appraised. By diagnostic 2 × 2 tables prior probabilities and predictive values were computed. Results: Six relevant articles were identified. The prior probability of concomitant DVT in patients referred from primary care to the outpatient clinic varied between 13 and 34%. In five studies, absence of varicosities was related to a higher probability of concomitant DVT (33–44%) compared to a presence of varicosities (3–23%). The sixth study showed an inversed, non-significant association: DVT was present in 21% of patients with SVT on non-varicose veins versus in 35% of patients with SVT on varicose veins. Conclusion: In five out of six studies on patients with SVT in outpatient settings, absence of varicosities was related to a higher probability of concomitant DVT. Further research is needed to determine whether an assessment of varicosities in general practice could result in an improved selection of patients who require additional imaging to detect or exclude DVT.

Contents Vol. 82, 2015

Founded 1938 as ‘Schweizerische Zeitschrift für allgemeine Pathologie und Bakteriologie’ by A. v. Albertini, A. Grumbach and H. Mooser, continued as ‘Pathologia et Microbiologia’ (1960–1975) and ‘Experimental Cell Biology’ (1976–1989); incorporating ‘Pathology and Immunopathology Research’, founded 1982 as ‘Survey and Synthesis of Pathology Research’ by J.M. Cruse and R.E. Lewis, continued as ‘Pathobiology’, edited by J.M. Cruse and R.E. Lewis (1990–1998) Continued by Ch. Wittekind (1999–2004)