Diagnostic and Treatment-Related Challenges in Sinonasal Teratocarcinosarcoma: A Report of Three Cases.

Background: Sinonasal teratocarcinosarcoma is a rare, aggressive malignancy located almost exclusively in the nasal cavity, paranasal sinuses, or anterior skull base. Histopathological diagnosis can be challenging due to the heterogeneous composition. Methods: Retrospective analysis of 3 patients with sinonasal teratocarcinosarcoma diagnosed and treated at the University Medical Center Utrecht was conducted. Results: Patients presented with nasal obstruction, epistaxis, headaches, or behavioral changes. All three patients had locally advanced disease, and one had lymph node metastases. Two patients underwent surgery followed by radiotherapy, and one underwent neoadjuvant chemotherapy followed by surgery. The follow-up duration ranged from 3 to 32 months. All three patients died due to progression of their disease. Conclusion: Sinonasal teratocarcinosarcoma is characterized by rapid, aggressive local expansion. The prognosis is poor due to a high risk of metastases and locally recurrent disease. Multimodality treatment consisting of surgery, followed by (chemo)-radiotherapy, is essential for optimizing outcomes. Neoadjuvant therapy offers a promising treatment option.

Low dose cisplatin weekly versus high dose cisplatin every three weeks in primary chemoradiotherapy in head and neck cancer patients with low skeletal muscle mass: The CISLOW-study protocol.

Chemoradiotherapy with cisplatin in a triweekly regimen of 100 mg/m2 body surface area, is used to treat locally advanced head and neck squamous cell carcinoma (HNSCC) with curative intent. Cisplatin dose limiting toxicity (CDLT) occurs often and impedes obtaining the planned cumulative cisplatin dose. A cumulative cisplatin dose of 200 mg/m2 or more is warranted for better survival and locoregional control. Patients with a low skeletal muscle mass (SMM) have a three-fold higher risk of developing CDLT than patients with a normal SMM. SMM can be assessed through measurements on routinely performed diagnostic head and neck CT- or MRI-scans. A weekly regimen of 40 mg/m2 body surface area cisplatin is proposed as a less toxic schedule, which possibly decreases the risk of developing CDLT and enables reaching a higher cumulative cisplatin dose. The aim of this multicenter randomized clinical trial (NL76533.041.21, registered in the Netherlands Trial Register) is to identify whether a regimen of weekly cisplatin increases compliance to the planned chemotherapy scheme in HNSCC patients with low SMM. The primary outcome is the difference in compliance rate, defined as absence of CDLT, between low SMM patients receiving either the weekly or triweekly regimen. Secondary outcomes consist of toxicities, the cumulative cisplatin dose, time to recurrence, incidence of recurrence at two years of follow-up, location of recurrence, 2-year overall, disease free and disease specific survival, quality of life, patient's experiences, and cost-effectiveness.

Oncological outcome of vocal cord-only radiotherapy for cT1-T2 glottic laryngeal squamous cell carcinoma.

PURPOSE: Early-stage glottic cancer can be treated with radiotherapy only. Modern radiotherapy solutions allow for individualized dose distributions, hypofractionation and sparing of organs at risk. The target volume used to be the entire voice box. This series describe the oncological outcome and toxicity of individualized vocal cord-only hypofractionated radiotherapy for early stage (cT1a-T2 N0). METHODS: Retrospective cohort study with patients treated in a single center between 2014 and 2020. RESULTS: A total of 93 patients were included. Local control rate was 100% for cT1a, 97% for cT1b and 77% for cT2. Risk factor for local recurrence was smoking during radiotherapy. Laryngectomy-free survival was 90% at 5 years. Grade III or higher late toxicity was 3.7%. CONCLUSION: Vocal cord-only hypofractionated radiotherapy appears to be oncologically safe in early-stage glottic cancer. Modern, image-guided radiotherapy led to comparable results as historical series with very limited late toxicity.

Long-term oncological follow-up after mold-based pulsed dose rate brachytherapy for early stage squamous cell carcinoma of the nasal vestibule: A single center experience of 68 patients over a 17-year period.

PURPOSE: Cancer of the nasal vestibule is a rare type of malignancy constituting less than one percent of all head and neck cancers. These tumors are typically diagnosed at an early stage. Both surgery and radiotherapy provide excellent oncological results, but esthetic results are better after radiotherapy. The aim of this study was to evaluate the long-term oncological follow-up after brachytherapy for early stage squamous cell carcinoma of the nasal vestibule. METHODS AND MATERIALS: Retrospective analysis of patients with carcinoma of the nasal vestibule who were treated with primary brachytherapy in the Utrecht University Medical Center. RESULTS: In this single center experience over a 17-year period 68 patients with early stage squamous cell carcinoma of the nasal vestibule were treated with brachytherapy. Two patients had lymph node metastases at first clinical presentation. Median follow-up duration was 46.5 months. Five-year locoregional recurrence-free survival, disease-specific survival, and overall survival were 91.1%, 96.1%, and 66.2%, respectively. All recurrences occurred within the first 3 years of follow-up. CONCLUSIONS: Brachytherapy offers excellent oncological outcomes and is a safe and effective treatment for early stage carcinoma of the nasal vestibule. Recurrences typically occur within 3 years after treatment.

Cut-off values for low skeletal muscle mass at the level of the third cervical vertebra (C3) in patients with head and neck cancer.

Background: Low skeletal muscle mass is associated with adverse outcomes in patients with cancer. For patients with head and neck cancer (HNC), skeletal muscle mass is often assessed at the third cervical vertebra on head and neck imaging. Due to the unavailability of standardized cut-off values for low skeletal muscle mass in patients with head and cancer, there is heterogeneousness of cut-off values for low skeletal muscle mass described in literature. Therefore, we aim to provide standardized cut-off values for low skeletal muscle mass in HNC patients. Methods: A retrospective cohort study was performed. Between 2008 and 2018, HNC patients with head and neck imaging were included. Skeletal muscle area (SMA) was manually delineated at the level of the third cervical vertebra and corrected for patients squared height to obtain the cervical skeletal muscle mass index. Gender and body-mass index specific cut-off values for low skeletal muscle mass were calculated based on mean cervical skeletal muscle mass index minus 2 standard deviations as suggested in literature. Results: Of the 1,415 included patients, the majority was male (69.8%) and had a body mass index below 25 kg/m2 (59.2%). A primary tumor localization in the oropharynx (35.3%) and a tumor, node, metastasis stage IV tumor (60.5%) were most frequently observed. Cervical skeletal muscle mass index was significantly correlated with gender (r2=0.4, P<0.01) and body mass index (r2=0.4, P<0.01). For male patients with a body mass index <25 and ≥25 kg/m2, a cervical skeletal muscle mass index of respectively ≤6.8 and ≤8.5 cm2/m2 was defined for low skeletal muscle mass. For female patients with a body mass index <25 and ≥25 kg/m2, a cervical skeletal muscle mass index of respectively ≤5.3 and ≤6.4 cm2/m2 was defined for low skeletal muscle mass. Conclusions: This study is the first to provide standardized cut-off values for low skeletal muscle mass at the level of the third cervical vertebra in patients with HNC. This information may aid in the uniformity of low skeletal muscle mass definition in research.

Image-based analysis of skeletal muscle mass predicts cisplatin dose-limiting toxicity in patients with locally advanced head and neck cancer.

PURPOSE: Evidence suggests that patients' skeletal muscle mass (SMM) can predict the patients at risk for cisplatin dose-limiting toxicities (DLT). Cisplatin is currently dosed on body surface area (BSA). The predictive value of SMM for cisplatin DLT in patients with locally advanced head and neck cancer (LA-HNC) is investigated. METHODS: Patients with LA-HNC treated with cisplatin-based chemoradiotherapy (CRT) were included. SMM was measured using pre-treatment scans. Logistic regression analysis was performed to identify the predictive impact of low SMM for DLT. RESULTS: In total, 343 patients were included of which 199 patients (58.0%) had low SMM and 154 patients (44.9%) experienced cisplatin DLT. In multivariate analysis, low SMM at diagnosis was the only predictive factor for DLT (HR 1.8, 95% CI 1.1-2.9). CONCLUSIONS: Low SMM was associated with an increased risk of DLT. Trials are needed to investigate cisplatin dosing with consideration of SMM rather than solely BSA.

Masseter muscle parameters can function as an alternative for skeletal muscle mass assessments on cross-sectional imaging at lumbar or cervical vertebral levels.

BACKGROUND: Patients with head and neck cancer are at increased risk of developing low skeletal muscle mass (SMM), which is associated with adverse treatment outcomes and prognosis. Low SMM is most commonly assessed by the skeletal muscle cross sectional area (CSA) at the third lumbar vertebra (L3) or more recently the third cervical vertebra (C3). L3 is not routinely imaged and C3 may be impacted by disease or treatment. As an alternative we analyzed masseter muscle characteristics and their relationship with L3 and C3 skeletal muscle CSA and overall survival (OS). METHODS: In this single-center retrospective study, 99 patients with head and neck cancer who underwent whole body FDG-PET/CT-scans were reviewed. Of these patients, L3 CSA, C3 CSA, masseter CSA, masseter thickness, masseter volume, masseter Hounsfield Unit values, lumbar skeletal muscle index (LSMI), cervical skeletal muscle index (CSMI), and masseter skeletal muscle index (MSMI) were recorded and correlated with each other and with OS. RESULTS: We included 72 male and 27 female patients. The masseter muscle parameters differed significantly between sexes. The Spearman correlation coefficients for C3 CSA-Masseter volume and L3 CSA-Masseter volume were 0.639 and 0.531 (P<0.001) respectively. In multivariate analysis low MSMI was a predictor of OS (HR 2.227, P=0.009). CONCLUSIONS: There is a moderate to strong association between the masseter muscle volume (MV) and C3 CSA and L3 CSA. MSMI predicts OS. Further research should investigate the relationship between muscle function and masseter muscle parameters and impacting factors on masseter muscle dimensions.

Arterial calcification on preoperative computed tomography imaging as a risk factor for pharyngocutaneous fistula formation after total laryngectomy.

BACKGROUND: Research in esophageal surgery showed that computed tomography (CT) assessed arterial calcification (AC) is associated with postoperative complications. We investigated the association between AC and pharyngocutaneous fistula (PCF) formation after laryngectomy. METHODS: This was a retrospective cohort study of patients undergoing laryngectomy. AC was scored at 10 different anatomical locations on CT imaging, blinded for PCF occurrence. Association with PCF was investigated using logistic regression. RESULTS: The 224 patients were included; 62 (27.7%) developed a PCF. Moderate to severe AC was widespread in patients undergoing TL; 7.1% of patients had at most mild AC, of whom 1 experienced a PCF (p = 0.05). A higher cumulative calcification score was associated with PCF in univariable (OR 1.11, p = 0.04) and multivariable analysis (OR 1.14, p = 0.05). CONCLUSION: AC is widespread in patients undergoing laryngectomy and its burden is associated with PCF. Extensive AC on preoperative imaging may be considered a risk factor for PCF.

Hearing Outcome After Linear Accelerator-Based Radiotherapy for Vestibular Schwannomas: A Retrospective Analysis of a Single Center.

OBJECTIVE: To report our results on hearing preservation after linear accelerator (LINAC)-based stereotactic radiotherapy for vestibular schwannomas (VS) in a tertiary referral center. METHODS: All patients who presented with VS in our center between 2010 and 2018 and who were treated with LINAC-based radiotherapy were retrospectively analyzed. Pure tone average and speech discrimination score represented hearing outcome, pre- and postradiotherapy. A Gardner-Robertson grade I or II hearing represented functional hearing. RESULTS: In total, 35 patients were treated with LINAC-based radiotherapy. Median age was 55 years (range 18-86 years), 22 (63%) were female. Sixteen patients had a Koos grade III or IV tumor. Twenty-four patients were treated with radiosurgery (1 or 5 fractions; stereotactic radiosurgery), and eleven patients were treated with fractionated stereotactic radiotherapy. Mean follow-up was 4.8 years (range 1.8-8.4 years). In 34 patients, hearing was assessed pre- and post-radiotherapy. In seventeen patients, hearing remained stable. In eleven patients, a decrease in GR scale was observed, of which seven patients showed a decrease from a functional to a non-functional level (4 GR III, 2 GR IV, and 1 GR V). Tumor control was 95% (34/35), and except for hearing loss, all post-radiation complications and morbidity were transient. CONCLUSION: These data emphasize that although the rate of tumor control (the primary goal of radiotherapeutic treatment) is high, it is important to adequately manage patients' expectations regarding the outcomes of the secondary possibly positive outcome; hearing preservation.

18F-FDG-PET/CT-based treatment planning for definitive (chemo)radiotherapy in patients with head and neck squamous cell carcinoma improves regional control and survival.

BACKGROUND AND PURPOSE: Multimodality imaging including 18F-FDG-PET has improved the detection threshold of nodal metastases in head and neck squamous cell carcinoma (HNSCC). The aim of this retrospective analysis is to investigate the impact of FDG-PET/CT-based nodal target volume definition (FDG-PET/CT-based NTV) on radiotherapy outcomes, compared to conventional CT-based nodal target volume definition (CT-based NTV). MATERIALS AND METHODS: Six-hundred-thirty-three patients treated for HNSCC with definitive (chemo)radiotherapy using IMRT/VMAT techniques between 2008 and 2017 were analyzed. FDG-PET/CT-based NTV was performed in 46% of the patients. The median follow-up was 31 months. Diagnostic imaging depicting the regional recurrence was co-registered with the initial CT-scan to reconstruct the exact site of the recurrence. Multivariate Cox regression analysis was performed to identify variables associated with radiotherapy outcome. RESULTS: FDG-PET/CT-based NTV improved control of disease in the CTVelective-nodal (HR: 0.33, p = 0.026), overall regional control (HR: 0.62, p = 0.027) and overall survival (HR: 0.71, p = 0.033) compared to CT-based NTV. The risk for recurrence in the CTVelective-nodal was increased in case of synchronous local recurrence of the primary tumor (HR: 12.4, p < 0.001). CONCLUSION: FDG-PET/CT-based NTV significantly improved control of disease in the CTVelective-nodal, overall regional control and overall survival compared to CT-based NTV. A significant proportion of CTVelective-nodal recurrences are potentially new nodal manifestations from a synchronous local recurrent primary tumor. These results support the concept of target volume transformation and give an indication of the potential of FDG-PET to guide gradual radiotherapy dose de-escalation in elective neck treatment in HNSCC.

Patterns of re-irradiation for recurrent gliomas and validation of a prognostic score.

PURPOSE OR OBJECTIVE: Re-irradiation is a generally accepted method for salvage treatment in patients with recurrent glioma. However, no standard radiation regimen has been defined. This study aims to compare the efficacy and safety of different treatment regimens and to independently externally validate a recently published reirradiation risk score. MATERIAL AND METHODS: We retrospectively analyzed a cohort of patients with recurrent malignant glioma treated with salvage conventionally fractionated (CFRT), hypofractionated (HFRT) or stereotactic radiotherapy (SRT) between 2007 and 2017 at the University Medical Centers in Utrecht and Groningen. RESULTS: Of the 121 patients included, 60 patients (50%) underwent CFRT, 22 (18%) HFRT and 39 (32%) SRT. The primary tumor was grade II-III in 52 patients and grade IV in 69 patients with median Overall Survival (mOS) since first surgery of 113 [Interquartile range: 53.2-137] and 39.7 [24.6-64.9] months respectively (p < 0.01). Overall, mOS from the first day of re-irradiation was 9.7 months [6.5-14.6]. No significant difference in mOS was found between the treatment groups. In multivariate analysis, the Karnofsky performance scale ≥70% (p < 0.01), re-irradiation for first recurrence (p = 0.02), longer time interval between RT start dates (p < 0.01) and smaller planning target volume (p < 0.05) were significant favorable prognostic factors. The reirradiation risk score was validated. CONCLUSION: In our series, mOS after reirradiation was sufficient to justify use of this modality. Until a reliable treatment decision tool is developed based on larger retrospective research, the decision for re-irradiation schedule should remain personalized and based on a multidisciplinary evaluation of each patient.

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.

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.

Combined therapy for thyroid squamous cell carcinoma.

BACKGROUND.: Squamous carcinoma of the thyroid is a rare aggressive disease, resulting in poor prognosis. METHODS AND RESULTS.: We combined cisplatin with paclitaxel on a weekly basis as induction therapy, achieving a high cumulative dose, in a patient with squamous cell tumor of the thyroid with arterial encasement. After surgery, pathologic examination confirmed a complete resection of the primary tumor with clear margins, revealing a successful induction treatment with chemotherapy. CONCLUSIONS.: Our patient now has a recurrence-free survival of >20 months, longer than the mean survival described in the literature.

The importance of immunohistochemical expression of EGFr in squamous cell carcinoma of the oral cavity treated with surgery and postoperative radiotherapy.

PURPOSE: The aim of this study was to investigate the prognostic significance of epidermal growth factor (EGFr) expression in oral cavity squamous cell carcinoma (OCSCC) treated with curative surgery and postoperative radiotherapy. METHODS AND MATERIALS: This retrospective study included 165 OCSCC patients. The expression of EGFr was assessed on paraffin-embedded tissue of the primary tumor by immunohistochemistry using a monoclonal antibody directed against EGFr. Intensity of the EGFr expression was scored by two authors blinded for the clinical outcome. RESULTS: In the univariate analysis, locoregional control at 3 years (LRC) in the EGFr-negative cases was 69% compared with 77% in the EGFr-positive cases (p = 0.22). In the multivariate analysis for local control, a significant interaction was found between EGFr and overall treatment time of radiation (OTT). After stratification for EGFr expression, the OTT was of no importance in the EGFr-negative cases, whereas a significant difference in LRC was found in the EGFr-positive cases, in which the LRC after 3 years was 69% and 94% in case of an OTT of 0-42 days and >42 days, respectively (p = 0.009; hazard ratio = 3.42; 95% confidence interval, 1.28-8.96). No significant association was found between EGFr expression and overall survival. CONCLUSIONS: In the present study, no association was found between EGFr expression and outcome regarding locoregional control and overall survival. However, the results of the present study suggest that patients with squamous cell carcinoma of the oral cavity with high EGFr expression benefit more from a reduction of the overall treatment time of postoperative radiation than those with low EGFr expression.

Combined modality therapy of gemcitabine and irradiation on human glioma spheroids derived from cell lines and biopsy tissue.

Multicellular tumor spheroids have been used to examine aspects of combined modality treatment since they often recreate the in vivo tumor environment much more closely than other models. The radioenhancement by gemcitabine (dFdC) on human glioma spheroids derived from cell lines (CLS) and biopsy tissue, grown as organotypic multicellular spheroids (OMS), was studied. CLS of GaMg and U87 and OMS of four glioblastoma patients were used. Radiochemosensitvity was determined using migration and proliferation assays on CLS. In OMS, histology and immunohistochemical studies of MIB-1, p53, and p21 expression were examined 24 and 48 h following treatment. Cell death (ethidium homodimer) was studied using a fluorescence cell viability assay. In CLS, combination treatment led to migration inhibition in GaMg and U87 of 85% and 62% (dFdC 46% and 52%, RT 21% and 43%) and proliferation inhibition of 83% and 85%, respectively. Following dFdC + RT in OMS (% of cases), apoptosis and p21 expression increased (50%), p53 expression increased (75%) and cell proliferation decreased (75%). Only minor morphological damage was observed. Confocal laser scanning microscopy identified an increased dead cell core after dFdC + RT (50%). In conclusion, dFdC can lead to an additively radioenhancement in CLS and individual OMS.

Effects of irradiation and cisplatin on human glioma spheroids: inhibition of cell proliferation and cell migration.

PURPOSE: Investigation of cell migration and proliferation of human glioma cell line spheroids (CLS) and evaluation of morphology, apoptosis, and immunohistochemical expression of MIB-1, p53, and p21 of organotypic muticellular spheroids (OMS) following cisplatin (CDDP) and irradiation (RT). MATERIAL AND METHODS: Spheroids of the GaMg glioma cell line and OMS prepared from biopsy tissue of six glioblastoma patients were used. Radiochemosensitvity (5 microg/ml CDDP followed by RT) was determined using migration and proliferation assays on CLS. In OMS, histology and immunohistochemical studies of MIB-1, p53, and p21 expression were examined 24 and 48 h following treatment. RESULTS: Combination treatment led to a migration inhibition of 38% (CDDP 13%; RT 27%) and specific growth delay of 2.6 (CDDP 1.3; RT 2.1) in CLS. Cell cycle analysis after combination treatment showed an accumulation of cells in the G2/M phase. In OMS, apoptosis increased, cell proliferation decreased, and p53/p21 expression increased more pronounced following CDDP+RT. No morphological damage was observed. CONCLUSION: CDDP can lead to enhancement of the RT effect in spheroids of both human glioma cell line spheroids and biopsy spheroids from glioblastoma specimens. The exerted effect is additive rather than synergistic.