Justin E. Swartz

Clinical implications of hypoxia biomarker expression in head and neck squamous cell carcinoma: a systematic review.

Awareness increases that the tumor biology influences treatment outcome and prognosis in cancer. Tumor hypoxia is thought to decrease sensitivity to radiotherapy and some forms of chemotherapy. Presence of hypoxia may be assessed by investigating expression of endogenous markers of hypoxia (EMH) using immunohistochemistry (IHC). In this systematic review we investigated the effect of EMH expression on local control and survival according to treatment modality in head and neck cancer (head and neck squamous cell carcinoma [HNSCC]). A search was performed in MEDLINE and EMBASE. Studies were eligible for inclusion that described EMH expression in relation to outcome in HNSCC patients. Quality was assessed using the Quality in Prognosis Studies (QUIPS) tool. Hazard ratios for locoregional control and survival were extracted. Forty studies of adequate quality were included. HIF‐1a, HIF‐2a, CA‐IX, GLUT‐1, and OPN were identified as the best described EMHs. With exception of HIF‐2a, all EMHs were significantly related to adverse outcome in multiple studies, especially in studies where patients underwent single‐modality treatment. Positive expression was often correlated with adverse clinical characteristics, including disease stage and differentiation grade. In summary, EMH expression was common in HNSCC patients and negatively influenced their prognosis. Future studies should investigate the effect of hypoxia‐modified treatment schedules in patients with high In summary, EMH expression. These may include ARCON, treatment with nimorazole, or novel targeted therapies directed at hypoxic tissue. Also, the feasibility of surgical removal of the hypoxic tumor volume prior to radiotherapy should be investigated.

The value of postoperative anticoagulants to improve flap survival in the free radial forearm flap: a systematic review and retrospective multicentre analysis.

Free radial forearm flap (FRFF) reconstruction is a valuable technique in head and neck surgery, which allows closure of large defects while striving to maintain functionality. Anticoagulative drugs are often administered to improve flap survival, although evidence regarding effectiveness is lacking.

Feasibility of using head and neck CT imaging to assess skeletal muscle mass in head and neck cancer patients

OBJECTIVES Patients with head and neck cancer (HNC) have a higher risk of malnutrition and sarcopenia, which is associated with adverse clinical outcome. As abdominal CT-imaging is often used to detect sarcopenia, such scans are rarely available in HNC patients, possibly explaining why no studies investigate the effect of sarcopenia in this population. We correlated skeletal muscle mass assessed on head and neck CT-scans with abdominal CT-imaging. METHODS Head and neck, and abdominal CT-scans of trauma (n=51) and HNC-patients (n=52) were retrospectively analyzed. On the head and neck CT-scans, the paravertebral and sternocleidomastoid muscles were delineated. On the abdominal CT-scans, all muscles were delineated. Cross-sectional area (CSA) of the muscles at the level of the C3 vertebra was compared to CSA at the L3 level using linear regression. A multivariate linear regression model was established. RESULTS HNC-patients had significantly lower muscle CSA than trauma patients (37.9 vs. 45.1cm2, p<0.001, corrected for sex and age). C3 muscle CSA strongly predicted L3 muscle CSA (r=0.785, p<0.001). This correlation was stronger in a multivariate model including sex, age and weight (r=0.891, p<0.001). DISCUSSION Assessment of skeletal muscle mass on head and neck CT-scans is feasible and may be an alternative to abdominal CT-imaging. This method allows assessment of sarcopenia using routinely performed scans without additional imaging or additional patient burden. Identifying sarcopenic patients may help in treatment selection, or to select HNC patients for physiotherapeutic or nutritional interventions to improve their outcome.

Low skeletal muscle mass is a predictive factor for chemotherapy dose-limiting toxicity in patients with locally advanced head and neck cancer

OBJECTIVES Low skeletal muscle mass (SMM) or sarcopenia is emerging as an adverse prognostic factor for chemotherapy dose-limiting toxicity (CLDT) and survival in cancer patients. Our aim was to determine the impact of low SMM on CDLT in patients with locally advanced head and neck squamous cell carcinoma (LA-HNSCC) treated with primary radiochemotherapy (RCT). PATIENTS AND METHODS Consecutive patients diagnosed with LA-HNSCC and treated with primary RCT between 2007 and 2011 in our center were included. Clinical variables were retrospectively retrieved and SMM was measured at the level of the third cervical vertebra using pre-treatment head and neck CT-scans. After determining a cut-off value for low SMM, multivariate analysis was performed to identify prognostic factors for CDLT. RESULTS Of 112 patients included, 30.4% experienced CDLT. The optimal cut-off value for low SMM as a predictor of CDLT was ≤43.2cm2/m2. Using this cut-off, 54.5% patients had low SMM. Patients with low SMM experienced CDLT more frequently than patients with normal SMM (44.3% vs. 13.7%, p<0.001) and received a higher dose of chemotherapy/kg lean body mass (estimated from SMM, p=0.044). At multivariate analysis, low SMM was independently inversely associated with CDLT (OR 0.93, 95%CI: 0.88-0.98). Patients experiencing CDLT had a lower overall survival than patients who did not (mean 36.6vs. 54.2months, p=0.038). CONCLUSION Low SMM is an independent risk factor for CDLT in LA-HNSCC patients treated with primary RCT. Pre-therapeutic estimation of SMM using routine CT-scans of the head and neck region may identify patients at risk of CDLT.

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.

Poor prognosis in human papillomavirus-positive oropharyngeal squamous cell carcinomas that overexpress hypoxia inducible factor-1α.

Hypoxia induces stabilization of the transcription factor HIF‐1alpha (HIF‐1α), associated with (chemo‐)radiotherapy resistance in oropharyngeal squamous cell carcinoma (SCC). We investigated the effect of HIF‐1α expression on survival in relation to human papillomavirus (HPV) status in oropharyngeal SCC.

Influence of tumor and microenvironment characteristics on diffusion-weighted imaging in oropharyngeal carcinoma : A pilot study

OBJECTIVES Diffusion weighted imaging (DWI) is a frequently performed MRI sequence in cancer patients. While previous studies have shown the clinical value of the apparent diffusion coefficient (ADC) for response prediction and response monitoring, less is known about the biological background of ADC. In the tumor microenvironment, hypoxia and increased proliferation of tumor cells contribute to resistance to (radio-)therapy, while high T-cell influx is related to better prognosis. We investigated the correlation between these three tissue characteristics and ADC in 20 oropharyngeal squamous cell carcinoma patients. MATERIALS AND METHODS 20 patients with oropharyngeal squamous cell carcinoma (OPSCC) who underwent 1.5 T MRI, including DWI were included in this pilot study. Corresponding formalin-fixed paraffin-embedded tumor tissues were immunohistochemically analyzed for protein expression of hypoxia-inducible factor 1a (HIF-1a), Ki-67 and CD3. Expression of these markers was correlated with ADC. RESULTS ADC negatively correlated with Ki-67 expression (p = .024) in tumor cells. There was a significant negative correlation between ADC and CD3-positive cell count (p = .009). No correlation was observed between HIF-1a expression and ADC. CONCLUSION This study suggests that ADC reflects characteristics of tumor cells as well as the surrounding microenvironment. Interestingly, high tumor proliferation (a negative prognostic factor) and high T-cell influx (a beneficial prognostic factor) are both associated with a lower ADC. Further studies should be performed to correlate ADC to these histological characteristics in relation to previously known factors that affect ADC, to gain further knowledge on the role of DW-MRI in diagnostics and personalized medicine.

Use of the 2‐μm continuous wave thulium laser for the resection of oral squamous cell carcinomas does not impair pathological assessment

Current resection modalities for oral squamous cell carcinomas (OSCC) vary from cold steel over CO2 laser to monopolar electro‐surgery (MO). We compared thulium laser (TL) as a new modality with MO with regards to pathological assessment.

A systematic review of the effect of different crimping techniques in stapes surgery for otosclerosis

To evaluate the effect of crimping techniques in stapes surgery for otosclerosis patients measured by hearing outcomes on pure‐tone audiometry.