Thomas Jouffroy

The value of pretreatment cell kinetic parameters as predictors for radiotherapy outcome in head and neck cancer: a multicenter analysis.

PURPOSE The aim of this study was to assess the potential of pre-treatment cell kinetic parameters to predict outcome in head and neck cancer patients treated by conventional radiotherapy. MATERIALS AND METHODS Data from 11 different centers were pooled. Inclusion criteria were such that the patients received radiotherapy alone, and that the radiotherapy was given in an overall time of at least 6 weeks with a dose of at least 60 Gy. All patients received a tracer dose of either iododeoxyuridine (IdUrd) or bromodeoxyuridine (BrdUrd) intravenously prior to treatment and a tumor biopsy was taken several hours later. The cell kinetic parameters labeling index (LI), DNA synthesis time (Ts) and potential doubling time (Tpot) were subsequently calculated from flow cytometry data, obtained on the biopsies using antibodies against I/BrdUrd incorporated into DNA. Each center carried out their own flow cytometry analysis. RESULTS From the 11 centers, a total of 476 patients conforming to the inclusion criteria were analyzed. Median values for overall time and total dose were 49 days and 69 Gy, respectively. Fifty one percent of patients had local recurrences and 53% patients had died, the majority from their disease. Median follow-up was 20 months; being 30 months for surviving patients. Multivariate analysis revealed that T-stage, maximum tumor diameter, differentiation grade, N-stage, tumor localization and overall time correlated with locoregional control, in decreasing order of significance. For the cell kinetic parameters, univariate analysis showed that only LI was significantly associated with local control (P=0.02), with higher values correlating with a worse outcome. Ts showed some evidence that patients with longer values did worse, but this was not significant (P=0.06). Tpot showed no trend (P=0.8). When assessing survival in a univariate analysis, neither LI nor Tpot associated with outcome (P=0.4, 0.4, respectively). Surprisingly, Ts did correlate with survival, with longer values being worse (P=0.02). In the multivariate analysis of local control, LI lost its significance (P=0.16). CONCLUSIONS The only pretreatment kinetic parameter for which some evidence was found for an association with local control (the best end-point for testing the present hypothesis) was LI, not Tpot, and this evidence disappeared in a multivariate analysis. It therefore appears that pretreatment cell kinetic measurements carried out using flow cytometry, only provide a relatively weak predictor of outcome after radiotherapy in head and neck cancer.

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

Theocharis S, Klijanienko J, Giaginis C, Rodriguez J, Jouffroy T, Girod A, Point D, Tsourouflis G & Sastre‐Garau X
(2011) Histopathology59, 514–525

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.

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.

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 Fishers 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.

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.

RCAS1 expression in mobile tongue squamous cell carcinoma: An immunohistochemical study

Summary 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.

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.

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.

ABSTRACT 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.