Phase I dose-escalation study of NBTXR3 activated by intensity-modulated radiation therapy in elderly patients with locally advanced squamous cell carcinoma of the oral cavity or oropharynx.

PURPOSE: This phase I study assessed the safety of first-in-class radioenhancer nanoparticles, NBTXR3, in elderly or frail patients with locally advanced head and neck squamous cell carcinoma (HNSCC), ineligible for chemoradiation. METHODS: Patients with stage III or IVA (American Joint Committee on Cancer (AJCC) guidelines, 7th edition, 2010) HNSCC of the oral cavity or oropharynx, aged ≥70 or ≥65 years and ineligible to receive cisplatin, amenable to radiotherapy (RT) with curative intent, received NBTXR3 as a single intratumoural (IT) injection followed by activation by intensity-modulated radiation therapy (IMRT; 70 Gy). The NBTXR3 dose corresponded to a percentage of the baseline tumour volume, measured by magnetic resonance imaging. The primary objectives were to determine the recommended phase II dose (RP2D), dose-limiting toxicities (DLTs) and maximum tolerated dose (MTD). Safety and tolerability were assessed using National Cancer Institute CTCAE version 4.0. Antitumour activity was assessed by Response Evaluation Criteria in Solid Tumours 1.1. RESULTS: Nineteen patients were enrolled: 3 at the dose level of 5%, 3 at the dose level of 10%, 5 at the dose level of 15% and 8 at the dose level of 22% of the tumour volume. The MTD was not reached, and no DLTs or serious adverse event (SAEs) related to NBTXR3 were observed. Four adverse events related to NBTXR3 and/or the IT injection were reported (grade I-II). NBTXR3 remained in the injected tumour throughout RT, with no leakage in the surrounding healthy tissues. Specific RT-related toxicity was as expected with IMRT. The RP2D was determined as 22% baseline tumour volume. Preliminary signs of antitumour activity were observed. CONCLUSION: Intratumoural injection of NBTXR3 followed by IMRT is feasible and demonstrated a good safety profile, supporting further evaluation at the RP2D in this patient population. TRIAL REGISTRATION: ClinicalTrials.govNCT01946867.

Risk factors of cancer occurrence after surgery of oral intraepithelial neoplasia: A long-term retrospective study.

OBJECTIVE: Oral intraepithelial neoplasia (OIN) is a premalignant lesion of oral mucosa graded I through III according to the importance of atypic cells and the thickness of the dysplastic layers. The aim of this study was to evaluate the long-term clinical course of OIN lesions and identify predictive factors of outcomes. METHODS: The clinical, surgical, and follow-up data of the patients consecutively treated for OIN by primary surgical removal in a referral anti-cancer center from November 1998 to March 2009 were retrospectively analyzed. The main outcome parameters were the 10-year disease-free survival (DFS), cancer-free survival (CFS), overall survival (OS), and disease-specific survival (DSS) rates (Kaplan-Meier). RESULTS: Thirty-one patients were included. Patients with positive or close margins (n = 15) had a significantly lower 10-year CFS rate (46.7% vs. 92.38%; P = .004) than patients with negative margins. This predictive factor remained significant in multivariate analysis (hazard ratio, 9.157; 95% confidence interval, 1.4-60.6). There was no significant difference in the 10-year DFS (33.3% vs. 48.7%; P = .2), DSS (92.8% vs. 100%; P = .1), and OS (92.8% vs. 69.6%; P = .2) rates between these two groups. Neither the initial OIN grade nor other clinical or surgical parameters were found to be significant predictors of outcomes. CONCLUSION: In this long-term follow-up study on histologically proven OIN treated by primary surgery, positive or close margins status was the only independent predictive factor of progression to cancer. Therefore, we warmly recommand performing re-resection rather than surveillance in cases with positive margins. Oral intraepithelial neoplasia grading or lesion size were not significant predictors of outcomes. LEVEL OF EVIDENCE: 4. Laryngoscope, 2546-2551, 2018.

Prognostic factors of successful on-purpose tumor biopsies in metastatic cancer patients included in the SHIVA prospective clinical trial.

PURPOSE: To identify patient/tumor characteristics associated with success of biopsy in patients who received multiple lines of chemotherapy. METHODS: Patients with refractory cancer from our center, who were included in a prospective randomized phase II trial comparing targeted therapies based on molecular profile of tumors versus conventional chemotherapy, were retrospectively included in this IRB-approved study. All patients had a biopsy of a tumor lesion performed during surgery, or using CT/palpation/endoscopic guidance. A biopsy was considered successful if the neoplastic cellularity was greater than 30%. Primary lesion, size and location of biopsied lesion, on-going chemotherapy and the differential attenuation between non-enhanced and venous phase (HU) for CT-guided biopsied lesions were recorded. RESULTS: 228 patients (age=59±15yo; M/F=1.9) were included. One hundred and sixty biopsies (72%) of the 221 biopsies performed were successful. Prognostic factors of biopsy success were: no ongoing chemotherapy, surgical or palpation-guided biopsy, lymph nodes/soft tissue location(P <0.01). Among the 221 performed biopsies, 122 (55%) were performed using CT guidance and 82 (67%) were successful. In this subgroup, biopsied lesions located in lymph nodes/soft tissue were associated with a higher success rate while lung location was associated with failure (P <0.01). The mean differential attenuation was significantly higher in lesions with a successful biopsy (P <0.001). CONCLUSION: Success of biopsy was less frequent with CT guidance than with surgical or palpation-guided biopsy and was higher in soft tissues and lymph nodes than that in visceral metastasis. Ongoing chemotherapy decreased tumor cell content and consequently the success of the biopsy samples for molecular profiling.

Ligand-receptor dissociated expression explains high TSLP without prognostic impact in human primary head and neck squamous cell carcinoma.

Thymic stromal lymphopoietin (TSLP) is an interleukin (IL)-7-like cytokine expressed by epithelial cells during allergic inflammation, and activating dendritic cells (DC). Its expression and functional role in cancer remain controversial. We conducted retrospective (n = 89), and prospective studies including patients with untreated primary head and neck squamous cell carcinoma (HNSCC). We found that TSLP was overexpressed by HNSCC tumor cells, and associated with a highly differentiated status. However, no significant difference in overall and recurrence-free survival was found between patients bearing a tumor with high and low TSLP levels, respectively. Surprisingly, there was no significant association between the levels of TSLP expression, and the number of tumor-infiltrating mature DCLAMP(+) DC. In order to explain the apparent lack of TSLP-induced DC activation, we performed phenotypic and functional experiments on freshly resected tumors. Tumor-infiltrating immune cells, including DC, did not express the TSLP receptor heterodimer (TSLPR chain, IL-7Ralpha chain). Furthermore, freshly sorted blood CD11c(+) DC from healthy donors cultured with tumor-conditioned supernatant exhibited an activated profile, but this was not affected by an anti-TSLP blocking antibody, suggesting a DC activation pathway independent of tumor-derived TSLP. Overall, our results demonstrate that TSLP is overexpressed in HNSCC but its function is hampered by the lack of TSLPR-expressing cells in the tumor microenvironment. Such a dissociated ligand-receptor expression may impact intercellular communication in other immune activation pathways, and tumor types.

Identification of new candidate therapeutic target genes in head and neck squamous cell carcinomas.

BACKGROUND: We aimed at identifying druggable molecular alterations at the RNA level from untreated HNSCC patients, and assessing their prognostic significance. METHODS: We retrieved 96 HNSCC patients who underwent primary surgery. Real-time quantitative RT-PCR was used to analyze a panel of 42 genes coding for major druggable proteins. Univariate and multivariate analyses were performed to assess the prognostic significance of overexpressed genes. RESULTS: Median age was 56 years [35-78]. Most of patients were men (80%) with a history of alcohol (70.4%) and/or tobacco consumption (72.5%). Twelve patients (12%) were HPV-positive. Most significantly overexpressed genes involved cell cycle regulation (CCND1 [27%], CDK6 [21%]), tyrosine kinase receptors (MET [18%], EGFR [14%]), angiogenesis (PGF [301%], VEGFA [14%]), and immune system (PDL1/CD274 [28%]). PIK3CA expression was an independent prognostic marker, associated with shorter disease-free survival. CONCLUSIONS: We identified druggable overexpressed genes associated with a poor outcome that might be of interest for personalizing treatment of HNSCC patients.

[Epidemiology, diagnosis and treatment of head and neck cancers]. / Épidémiologie, diagnostic et traitement des cancers ORL.

Cancers of the upper aerodigestive tracts are the fourth most common cancer in France. The main risk factors are smoking and alcohol. They do not necessarily present specific signs, making their early diagnosis difficult. A change in the patient's general condition is a late sign leading to a poor prognosis of the disease.

Measure of herpesvirus-specific ocular antibody production in patients with uveitis.

BACKGROUND: The amount of specific antiviral IgG in aqueous humour (AH) provides a major contribution to the diagnosis of herpesvirus uveitis. Ocular antibody production is often evaluated by comparing levels of specific and total IgG in serum and AH. The small volume of AH is a major limit for diagnosis. OBJECTIVES: To simplify the measure of ocular antibody production, we tested the quotient of serum/AH ratios of specific and control antiviral IgG, using automated quantitative serology methods on minimal volumes of AH, in confirmed and suspected herpesvirus uveitis. STUDY DESIGN: Serum and AH samples from herpesvirus PCR-positive uveitis patients, and from PCR-negative cases who were highly suspected to have viral uveitis were retrospectively analysed for ocular production of specific antiviral IgG using 40 µl of AH, and quantitative Enzygnost ELISA-based methods. Cataract and Fuchs cyclitis cases were used as controls. RESULTS: Ocular production of specific antiviral IgG was demonstrated in 32 (51.6%) of 62 herpesvirus PCR-positive uveitis cases, in none of 42 controls, and in 21 (55.2%) of 38 PCR-negative cases clinically suspected to have herpesvirus uveitis. The test had absolute specificity, and its sensitivity depended on the virus, pathology and timing of sampling. CONCLUSION: Ocular antibody production can be measured by simple quantitative ELISA-based methods on serum and minimal volumes of AH. This specific and sensitive test, implemented in the routine virology laboratory should help the diagnosis and specific antiviral therapy management of herpesvirus uveitis.

Transoral robotic-assisted free flap reconstruction after radiation therapy in hypopharyngeal carcinoma: report of two cases.

The objective was to assess the feasibility and safety of transoral robotic surgery (TORS)-assisted free flap reconstruction for hypopharyngeal carcinoma after radiation therapy. The study evaluated the feasibility, surgical margins, the need for a tracheotomy, a nasogastric tube as well as surgery-related complications. Two patients underwent TORS-assisted free flap reconstruction after radiation therapy. The resection margins were free of tumor in both patients. A tracheotomy was performed in one patient who had been decannulated on the sixth postoperative day. One patient resumed satisfactory oral feeding in the fourth postoperative month and the second patient on postoperative day 7. No intraoperative complication and one postoperative complication (neck hematoma) were reported. After a follow-up period of 24 and 30 months, no local recurrence was observed. TORS is feasible for hypopharyngeal resection and assisted free flap reconstruction after radiation therapy. It represents a further step in the development of minimally invasive surgery for the treatment of head and neck cancers with laryngeal preservation.

Latissimus dorsi free flap reconstruction of anterior skull base defects.

INTRODUCTION: Surgery of extensive skull base tumour results of a defect of soft and hard tissue and dura. Free flap reconstruction provides tissue to restore the defect and separate the intracranial content from the bacterial flora of the nasal fossae. Vertical and transverse rectus abdominis myocutaneous free flap are usually used. This study was designed to compare our experience of latissimus dorsi free flap reconstruction of extensive skull base defects after tumour resection with the literature concerning the use of other types of free flaps. MATERIAL AND METHOD: All extensive skull base tumour resections with latissimus free flap reconstruction made in the head and neck oncology unit of the Institut Curie, Cancer Centre, between January 2004 and December 2009 were reviewed. RESULTS: Two infectious complications were observed (11.7%), two cases of CSF leak (11.7%), one case of wound dehiscence following tumour resection comprising the nasal skin (5.9%) and one case of partial distal necrosis of the flap in a zone of skin resection (5.9%) were observed. No flaps were lost. Two latissimus dorsi donor site haematomas were observed (11.7%). CONCLUSION: When reconstruction of extensive skull base defect need free flap, the latissimus dorsi free flap is a reliable solution.

Skull base surgery for pediatric parameningeal sarcomas.

BACKGROUND: Localized pediatric parameningeal sarcomas are usually treated exclusively by chemotherapy and radiotherapy. In this location, surgery is complicated but sometimes attempted to improve local control. METHODS: A retrospective bicentric study was conducted to examine its place with particular reference to acute and long-term morbidity. Fifteen patients under the age of 20 years with parameningeal sarcoma underwent surgery between 2000 and 2007. RESULTS: Surgery was performed for 8 primary sarcomas and 7 radiation-induced sarcomas, mainly in infratemporal fossa. Three children had intracranial extension, 3 had metastases, and 1 had both. Median follow-up was 46 months (16-154 months). Five children experienced local relapse. Eight presented sequelae. Eleven children are alive with no evidence of disease, and 4 died. CONCLUSION: Skull base surgery should be considered as a possible treatment in pediatric parameningeal sarcomas. Surgery is the only option in radiation-induced sarcoma. Larger studies are necessary to more clearly define surgical indications.

Metallothionein expression in mobile tongue squamous cell carcinoma: associations with clinicopathological parameters and patient survival.

AIMS: Metallothionein (MT) has been implicated in several aspects of cancer pathobiology, such as differentiation, proliferation, apoptosis and invasion. The aim of the present study was to evaluate the clinical significance of MT expression in mobile tongue squamous cell carcinoma (SCC). METHODS AND RESULTS: MT protein expression was assessed immunohistochemically on 49 mobile tongue SCC specimens, and was analysed in relation to clinicopathological characteristics, and overall and disease-free patient survival. All of the examined mobile tongue SCC cases showed MT positivity in tumour cells; however, neither MT overexpression nor staining intensity was significantly associated with clinicopathological parameters. MT cellular distribution was significantly associated with histopathological grade of differentiation and depth of invasion (P = 0.0188 and P = 0.0484, respectively). MT staining intensity was identified as a significant predictor of overall patient survival at both univariate (P = 0.0377) and multivariate (P = 0.0472) levels. Twenty-seven (55.10%) of the examined SCC cases showed MT positivity in squamous tongue epithelium adjacent to the tumour, the MT positivity being correlated with depth of invasion (P = 0.0281), vascular invasion (P = 0.0194), and the existence of lymph node metastases (P = 0.0194). CONCLUSIONS: MT may be implicated in the development and progression of mobile tongue SCC and could be considered as a useful clinical marker for patient management and prognosis.

RCAS1 expression in mobile tongue squamous cell carcinoma: an immunohistochemical study.

BACKGROUND: The receptor-binding cancer antigen expressed on SiSo cells (RCAS1) is a human tumor-associated antigen that has been considered to play a crucial role in tumor progression by enabling cancer cells to evade immune surveillance. The present study aimed to evaluate the clinical significance of RCAS1 expression in mobile tongue squamous cell carcinoma (SCC). MATERIAL/METHODS: RCAS1 protein expression was assessed immunohistochemically on 49 mobile tongue SCC tissue samples obtained from an equal number of patients and was statistically analyzed with clinicopathological characteristics and overall and disease-free patients' survival. RESULTS: Enhanced RCAS1 expression was significantly associated with reduced depth of invasion (p=0.0069), low mitotic index (p=0.0251) and no evidence of muscular invasion (p=0.0098). A borderline association between RCAS1 expression and stromal inflammatory reaction was also noted (p=0.0660). RCAS1 expression was not associated with overall and disease-free survival. CONCLUSIONS: Our data support evidence for possible implication of RCAS1 at the early stage of tumor progression in mobile tongue SCC, whereas the survival prediction using RCAS1 expression as a clinical marker seems uncertain for this type of malignancy.

Histone deacetylase-1 and -2 expression in mobile tongue squamous cell carcinoma: associations with clinicopathological parameters and patients survival.

BACKGROUND: Histone deacetylases (HDACs) have been associated with tumor development and progression in several types of human malignancy and HDAC inhibitors are currently being explored as anti-cancer agents in clinical trials. The aim of the present study was to evaluate the clinical significance of HDAC-1 and -2 protein expression in mobile tongue squamous cell carcinoma (SCC). METHODS: HDAC-1 and -2 protein expression was assessed immunohistochemically on 49 mobile tongue SCC tissue samples and was analyzed in relation with clinicopathological characteristics, overall and disease-free patients' survival. RESULTS: HDAC-1 overexpression was significantly associated with younger patients' age (P = 0.0381) and male gender (P = 0.0345), poor histopathological grade of differentiation (P = 0.0236) and the presence of lymph node metastases (P = 0.0104). Intense HDAC-1 staining intensity was significantly associated with male gender (P = 0.0127), increased stromal infiltration reaction (P = 0.0125) and well-defined shape of tumor invasion (P = 0.0396). HDAC-2 overexpression did not show significant correlations with any clinicopathological parameters, whereas intense HDAC-2 staining intensity was significantly associated with the presence of muscular invasion (P = 0.0466) and advanced depth of invasion (P = 0.0251). Mobile tongue SCC patients with HDAC-1 overexpression presented shorter overall and disease-free survival compared to those with no evidence of HDAC-1 overexpression (log-rank test, P = 0.0651 and 0.0247, respectively). CONCLUSIONS: The present study supported evidence that HDACs may participate in the formation and progression of mobile tongue SCC, reinforcing their possible use as biomarkers as also the therapeutic utility of HDAC inhibitors in mobile tongue SCC chemoprevention and treatment.

Expression of DNA repair proteins, MSH2, MLH1 and MGMT in mobile tongue squamous cell carcinoma: associations with clinicopathological parameters and patients' survival.

BACKGROUND: DNA repair is a major defense mechanism, which contributes to the maintenance of genetic sequence, minimizing cell death, mutation rates, replication errors, DNA damage persistence and genomic instability. Alterations of proteins participating in DNA repair mechanisms have been associated with several aspects of cancer biology. The present study aimed to evaluate the clinical significance of DNA repair proteins, MSH2, MLH1 and MGMT in mobile tongue squamous cell carcinoma (SCC). METHODS: MSH2, MLH1 and MGMT protein expression was assessed immunohistochemically on 49 mobile tongue SCC tissue samples and was analyzed in relation with clinicopathological characteristics, overall and disease-free patients' survival. RESULTS: MSH2 expression was significantly associated with depth of invasion (P=0.0335), tumor shape (P=0.0396) and muscular invasion (P=0.0098). MLH1 expression was significantly associated with lymph node metastases (P=0.0484) and borderline with perineural invasion (P=0.0699). MGMT expression was significantly associated with depth of invasion (P=0.0472), tumor shape (P=0.0187), perineural invasion (P=0.0115) and lymph node metastases (P=0.0032) and borderline with vascular invasion (P=0.0755). MSH2 expression was significantly associated with disease-free patients' survival in univariate analysis (P=0.0441), being also identified as an independent prognostic factor in multivariate analysis (P=0.0451). CONCLUSIONS: The present study supported evidence for possible implication of MSH2, MLH1 and MGMT proteins in the formation and progression of mobile tongue SCC.

Peroxisome proliferator-activated receptor-γ in mobile tongue squamous cell carcinoma: associations with clinicopathological parameters and patients survival.

PURPOSE: Peroxisome proliferator-activated receptor-γ (PPAR-γ) is a ligand-activated transcription factor, implicated in various aspects of cancer biology, such as differentiation, proliferation, invasion and angiogenesis. The present study aimed to evaluate the clinical significance of PPAR-γ in mobile tongue squamous cell carcinoma (SCC). METHODS: PPAR-γ protein expression was assessed immunohistochemically on 49 mobile tongue SCC tissue samples obtained from an equal number of patients. PPAR-γ expression and intensity of immunostaining were statistically analyzed in relation with clinicopathological characteristics, mitotic index and patients' survival. RESULTS: Elevated PPAR-γ expression was more frequently observed in patients with reduced depth of invasion (P = 0.0111). Moderate/intense PPAR-γ staining intensity was more frequently observed in patients with no evidence of muscular infiltration (P = 0.0229) and reduced depth of invasion (P = 0.0176). Mobile tongue SCC patients presenting enhanced PPAR-γ expression had significantly longer overall and disease-free survival times compared to those with low PPAR-γ expression (log-rank test, P = 0.0162 and P = 0.0114, respectively). CONCLUSIONS: PPAR-γ immunoreactivity in mobile tongue SCC was correlated with clinicopathological characteristics crucial for patients' management and prognosis. PPAR-γ may be considered as a useful prognostic marker in mobile tongue SCC and a potential therapeutic target for tongue cancer chemoprevention and treatment.

Prognostic significance of tumor shape and stromal chronic inflammatory infiltration in squamous cell carcinomas of the oral tongue.

BACKGROUND: Squamous cell carcinoma (SCC) of the oral tongue is well known to be an aggressive disease with early metastatic spread in early stage tumors. It is also established that locoregional recurrences are the main causes of treatment failure. Thus, the identification of histopathological factors possessing a predictive value remains important for the management of the disease. The aim of the present study was to define histopathological parameters of the tumor and to compare with the follow-up and status in primary SCCs of the mobile tongue. METHODS: Histopathological parameters such as mitotic index, the presence of vascular emboli or perineural invasion, the thickness of the tumor, the histological grade, the tumor shape as well as chronic stromal inflammatory infiltration were assessed in 52 patients with SCC of the mobile tongue and compared with the follow-up and status in patients treated initially by surgery. RESULTS: Tumor shape was significantly associated with the presence of perineural invasion. Well-defined shaped tumors displayed almost half the incidence of perineural invasion when compared with ill-defined shaped tumors. In addition, the high density of the chronic inflammatory infiltration of the stroma exhibited significant correlation with the survival of the patients. Finally, the intense chronic inflammatory infiltration of the stroma was associated with well-defined shaped tumors. CONCLUSION: Tumor shape and stromal chronic inflammatory infiltration should be considered in the planning of the management of patients with SCC of the mobile tongue.

Study of the length of hospital stay for free flap reconstruction of oral and pharyngeal cancer in the context of the new French casemix-based funding.

The French national health insurance reimbursement system has recently changed from a global hospital funding system to casemix-based funding. The authors studied the factors likely to influence the length of hospital stay for free flap reconstructions after surgery for cancers of the oral cavity or pharynx. Data concerning 207 oral cavity or pharynx free flap reconstructions were extracted from a prospective registration. Lengths of hospital stay were compared by an analysis of variance F test or a nonparametric Kruskal-Wallis test, and transfusion rates were compared by Chi-square test or Fisher's exact test, as appropriate. The median length of hospital stay was 24 days (range: 7-145 days). Length of hospital stay was significantly longer according to the type of flap (p<0.005), in N2-N3 patients (p<0.02), a PINI score more than 10, a 3-4 American Society of Anesthesiologists (ASA) score, the presence of a tracheotomy and in patients requiring transfusion (p<0.0001). As the nodal status, the American Society of Anesthesiologists (ASA) score of the patient, the need of tracheotomy and the type of flap cannot be corrected, the management of preoperative haemoglobin and nutritional status are the sole factors which can improve the length of hospital stay. In the context of the new casemix-based funding, this study raises the problem of harvesting of the fibula flap, management of preoperative haemoglobin and nutritional status.

Women and squamous cell carcinomas of the oral cavity and oropharynx: is there something new?

PURPOSE: Incidence of squamous cell carcinoma (SCC) of the oral cavity and oropharynx is increasing in French female patients. The objective of this study was to study the clinical and demographic characteristics and the prognosis of this female population. Secondary outcomes were to determine if a subgroup of patient had a different prognosis. MATERIALS AND METHODS: A prospective study from 1989 to 2002 of all female patients presenting SCC of the upper aerodogestive tract was conducted. Data for 171 women were extracted. Clinical and histological features were analyzed using chi(2) and log-rank tests along with the Kaplan Meier method and multivariate analysis using the Cox regression procedure. RESULTS: Mean patient age was 62 years. Of the study population, 48.5% used tobacco and 34.5% used alcohol. The relative risk of death for overall and cancer-specific survival increased for patients below the age of 45 or over the age of 70 (95% Cl; 0.3-1.05; P = .0085). Tobacco consumption decreased cancer-specific and overall survival (P = .0008 and .0001, respectively). The other prognostic factors we found were tumor and nodal status, previous or simultaneous cancer, oral cavity primary site. CONCLUSIONS: Prognosis of oropharyngeal and oral squamous cell carcinomas is less favorable in females who smoke as well as in younger and older women. With these patients, the oversight must be closer. Smoking, however, should be stopped.