Primary clear cell sarcoma of the tongue and surgical reconstruction: About a rare case report.

Clear cell sarcomas (SCC), also called "soft-tissue melanoma", are rare and aggressive tumors that preferentially affect the lower limbs (tendons and fasciae) and which have also been described in head and neck localizations. Their clinical and immunohistochemical mimicry with melanoma makes it difficult to diagnose sarcomas. SCC treatment is mainly focused on large-scale resection surgery with adjuvant radiotherapy because of their low chemo-sensitivity and extreme lymphophilia. In case of head and neck localization, these treatments may lead to function and aesthetic sequelae thus requiring the use of modern techniques of reconstructive surgery. The authors describe the diagnosis, treatment and follow-up of large lingual SCC case using a DIEP free flap reconstruction according to an original technique developed in the department. Given the characteristics of patients with SCC (a high proportion of women between 20 and 40 years old) and its inherent qualities (low morbidity of the donor site, volume delivered and excellent plasticity), the fascio-cutaneous free flap type "DIEP" "taken according to the design of the" Cathedral triptych seems to be a viable choice among the range of reconstruction solutions.

The anterolateral thigh perforator flap in pharyngo-esophageal reconstruction.

Today's customary techniques for pharyngo-esophageal reconstruction are jejunum and radial forearm free flaps. In this type of reconstruction, the jejunum flap is considered as the reference, but when its harvesting is not possible, the radial forearm flap is used. Since perforator flaps have begun to be developed, the anterolateral thigh flap (ATF) has become increasingly prominent in pharyngo-esophageal reconstruction. The aim of our study was to describe the use of the anterolateral perforator flap in pharyngo-esophageal reconstruction (indications, harvesting method, flap design) and to discuss its advantages and drawbacks as regards oral feeding and esophageal speech.

Squamous cell carcinoma of the larynx with subglottic extension: is larynx preservation possible?

PURPOSE: Squamous cell carcinoma of larynx with subglottic extension (sSCC) is a rare location described to carry a poor prognosis. The aim of this study was to analyze outcomes and feasibility of larynx preservation in sSCC patients. PATIENTS AND METHODS: Between 1996 and 2012, 197 patients with sSCC were treated at our institution and included in the analysis. Stage III-IV tumors accounted for 76%. Patients received surgery (62%), radiotherapy (RT) (18%), or induction chemotherapy (CT) (20%) as front-line therapy. RESULTS: The 5-year actuarial overall survival (OS), locoregional control (LRC), and distant control rate were 59% (95% CI 51-68), 83% (95% CI 77-89), and 88% (95% CI 83-93), respectively, with a median follow-up of 54.4 months. There was no difference in OS and LRC according to front-line treatments or between primary subglottic cancer and glottosupraglottic cancers with subglottic extension. In the multivariate analysis, age > 60 years and positive N stage were the only predictors for OS (HR 2, 95% CI 1.2-3.6; HR1.9, 95% CI 1-3.5, respectively). A lower LRC was observed for T3 patients receiving a larynx preservation protocol as compared with those receiving a front-line surgery (HR 14.1, 95% CI 2.5-136.7; p = 0.02); however, no difference of ultimate LRC was observed according to the first therapy when including T3 patients who underwent salvage laryngectomy (p = 0.6). In patients receiving a larynx preservation protocol, the 5-year larynx-preservation rate was 55% (95% CI 43-68), with 36% in T3 patients. The 5-year larynx preservation rate was 81% (95% CI 65-96) and 35% (95% CI 20-51) for patients who received RT or induction CT as a front-line treatment, respectively. CONCLUSION: Outcomes of sSCC are comparable with other laryngeal cancers when managed with modern therapeutic options. Larynx-preservation protocols could be a suitable option in T1-T2 (RT or chemo-RT) and selected T3 sSCC patients (induction CT).

Occult nodal metastases in T1-T2cN0 oral squamous cell carcinoma: Correlation between sentinel node positivity and completion neck dissection analysis.

OBJECTIVES: Sentinel node procedure (SN) is a standard procedure that has shown its safety and effectiveness for T1/T2 cN0 oral squamous cell carcinoma (OSCC), with completion neck dissection (CND) for patients with positive SN. The aim of this study was to characterize the nodal involvement in a cohort of SN + OSCC. MATERIALS AND METHODS: Patients with T1/T2 cN0 OSCC with positive SN with CND were included in this single-center, prospective cohort study between 2000 and 2013. RESULTS: 54/301 patients had at least one positive SN. In 43/54 (80 %) cases, only the SN(s) were invaded; with only one SN involved (SN+=1) in 36/54 (67 %) cases. No predictive factors of nodal involvement in the CND were found considering the followings: SN micro/macrometastases, primary tumor's depth of invasion (DOI), perineural spread, lymphovascular involvement, primary tumor location, T stage and extranodal extension. The SN micrometastatic involvement (n = 22) was significantly associated with only one SN + CND- (p = 0.017). In the group of patients with unique micrometastatic involvement in the SN (n = 20/54), there was a higher isolated nodal recurrence free time (p = 0.017). CONCLUSION: 80% of T1/T2 cN0 OSCC with positive SN had no other lymph node metastases in the CND, questioning the potential benefits of this procedure. Predictive factors such as the size of the SN metastasis need to be tested to stratify the risk of positive non-SN lymph nodes leading to a personalized treatment, lowering the therapeutic morbidity while maintaining the oncologic safety.

Replacement of lip-split mandibulotomy by pull-through approach for T3-4 oral carcinomas.

At the study hospital, the lip-split mandibulotomy (LSM) has progressively been replaced by a pull-through (PT) approach. This study compared the outcomes of the LSM and PT approaches in a series of 192 patients with T3-T4a oral tongue and floor of the mouth squamous cell carcinoma treated over the two last decades. No difference in margin status (P = 0.254), rate of early complications (local infections) (P = 0.867), haematoma/haemorrhage (P = 0.221), delayed wound healing (P = 0.438), re-operation (P = 0.083), or Clavien-Dindo classification (P= 0.5281) was found. The LSM approach was associated with a higher rate of late complications such as pseudarthrosis (14.5% vs 0.9%; OR 17.89, P = 0.0005) and trismus (35% vs 13.8%; OR 3.32, P = 0.025), and a trend towards a higher rate of fistulas (24.6% vs 13.1%; OR 2.16, P = 0.088). The quality of life of long-term survivors (median 132 months) was similar in the two groups, with a mean QLQC30 score of 59.7 (P = 0.099) and mean MDADI score of 57.4 (P = 0.213). The 5-year local control rate was 86.4% in the PT group and 86.2% in the LSM group (P = 0.878), while the 5-year overall survival rates were 50.0% and 48.3%, respectively (P = 0.68). In our experience, replacement of LSM by a PT approach in oral carcinoma was associated with decreased rates of late complications such as pseudarthrosis, fistula, and trismus, without any difference in oncological outcomes.

Long-term recurrences of jaw osteoradionecrosis after apparent healing with the PENTOCLO protocol.

Osteoradionecrosis of the jaws (ORNJ) is a late complication of head and neck irradiation estimated at around 3% of irradiated patients. The PENTO protocol (Pentoxyfilline and Tocopherol), with the eventual adjunction of Clodronate (PENTOCLO), showed interesting results even in advanced ORNJ. The current literature does not describe the long-term outcomes and particularly after the completion of the protocol. The PENTO or PENTOCLO protocol should be prescribed as a life-long treatment or the outcome should be monitored at least as long as the duration of the protocol after its end.

Oncologic outcomes, prognostic factor analysis and therapeutic algorithm evaluation of head and neck mucosal melanomas in France.

BACKGROUND: Head and neck mucosal melanoma (HNMM) is aggressive and rare, with a poor prognosis because of its high metastatic potential. The two main subtypes are sinonasal (sinonasal mucosal melanoma [SNMM]) and oral cavity (oral cavity mucosal melanoma [OCMM]). Consensual therapeutic guidelines considering the primary tumour site and tumour-node-metastasis (TNM) stage are not well established. MATERIAL & METHODS: Patients with HNMM from the prospective national French Rare Head and Neck Cancer Expert Network database between 2000 and 2017 were included. Clinical characteristics, treatment modalities, outcomes and prognostic factors were analysed. RESULTS: In total, 314 patients were included. The 5-year overall survival (OS) and progression-free survival (PFS) rates were 49.4% and 24.7%, respectively, in the surgery group; no long-term survivors were observed when surgery was not feasible. Moreover, even after surgery, a high recurrence rate was reported with a median PFS of 22 months. In multivariate analysis, Union for International Cancer Control (UICC) stage and tumour site correlated with PFS and OS. Postoperative radiotherapy (PORT) improved the PFS but not OS in patients with small (T3) SNMM and OCMM tumours. Nodal involvement was more frequent in patients with OCMM (p < 10-4), although, as in SNMM, it was not a significant prognostic predictor. CONCLUSION: Even early HNMM was associated with poor oncologic outcomes due to distant metastases despite surgical resection with clear margins. Lymph node metastases had no impact on the prognosis, suggesting treatment de-escalation in cervical node management. PORT might be useful for local control.

Reconstruction of maxillectomy and midfacial defects using latissimus dorsi-scapular free flaps in a comprehensive cancer center.

BACKGROUND: The standard of care for sinonasal malignancies is a large surgical resection followed by radiotherapy. Midfacial defects resulting from maxillectomy require a complex reconstruction procedure. Given their adaptability, chimeric flaps such as latissimus dorsi-scapular (LDS) free flaps appear to be a good option. MATERIAL & METHODS: We performed a single-center retrospective study of consecutive patients with sinonasal cancers where a LDS free flap was used for reconstruction. We assessed the postoperative complications and the functional, aesthetic and oncologic outcomes. RESULTS: Eighty-four patients were included. Primary tumors were staged as T4a in 68% of cases; 38.3% of the patients received induction chemotherapy and 82.7% received adjuvant radiotherapy. Based on our classification of midfacial and palatal defects, the majority of the patients (69%) had a type IIa with interruption of the three facial pillars. The orbital floor was removed in 55.9% of cases. The median follow-up was 45 months. Total flap necrosis with no possible revascularization occurred in 5.9% of cases. For the orbital reconstruction, a revision procedure was needed for necrosis and/or infection of the costal cartilage graft in eight cases (17%). More than 90% of the patients had no functional disorders regarding speaking, swallowing and chewing. Soft palate involvement was a prognostic factor of speech (p < 10-4) and swallowing (p = .005) disorders. Dental rehabilitation was realized in 70.2% of the patients. No severe complications were observed in the donor site, except for one seroma. CONCLUSION: A LDS free flap is a reliable technique for the reconstruction of complex midfacial defects.

Quantitative methylation analyses of resection margins predict local recurrences and disease-specific deaths in patients with head and neck squamous cell carcinomas.

This study sought to determine whether the presence of hypermethylated genes in the surgical margins can predict local recurrences in head and neck squamous cell carcinomas (HNSCCs). We prospectively collected tumour and surgical margin specimens from patients with HNSCCs who had undergone surgical resections. Quantitative methylation-specific PCR (QMSP) of CDKN2A, CCNA1 and DCC were performed in these specimens and correlated with clinical data. Of the 42 patients eligible for the study, 27 were hypermethylation informative for the above three genes. This latter group was associated with longer disease-free survivals (P=0.007) and longer time to disease-specific deaths (P=0.004). Multivariate analyses confirmed hypermethylation non-informative tumours as an independent prognosticating factor for disease-specific deaths (risk ratio 3.8, P=0.026). Quantitative MSP of the margins of 24 hypermethylation informative tumours revealed that 11 patients had molecularly positive margins, of which, five developed disease-specific events (DSEs, three local recurrences and two metastases), compared to none in patients with molecularly negative margins, after a median follow-up of 48 months. Log-rank analyses showed that molecularly positive margins were associated with shorter time to local recurrences and disease-specific deaths (P=0.03 and 0.01, respectively). This study demonstrated that QMSP of hypermethylated promoters in surgical margins predicted all the local recurrences in our series of HNSCC patients. We have also identified hypermethylation non-informative tumours as an independent predictor for the development of DSEs.

Sentinel node biopsy in early oral squamous cell carcinomas: Long-term follow-up and nodal failure analysis.

OBJECTIVES: Evaluate the reliability of sentinel node biopsy (SNB) in T1/T2 cN0 oral squamous cell carcinoma (OSCC), and compare recurrence-free time (RFT) and overall survival (OS) between patients undergoing SNB and neck dissection (ND). PATIENTS AND METHODS: Patients with T1/T2 cN0 OSCC underwent SNB followed by systematic ND in the first cohort and SNB followed by selective ND in case of positive sentinel nodes (SN) in the second cohort. RESULTS: A total of 229 patients were followed (first cohort 50, second cohort 179). SNs were successfully detected in 93.9% (215/229) of cases. Median follow-up was 5.6 years. Recurrence occurred in 38/215 patients, with isolated nodal recurrence in 18/215 patients. At 5 years, the rate of recurrence-free patients was 80.0% and the rate of patients without isolated nodal recurrence was 90.4%. Negative predictive value of SNB was 92.7%. No statistically significant difference was observed between the two groups regarding RFT and OS. In 83% (10/12) of ipsilateral isolated nodal recurrences, primary tumor was located in anterior part of oral cavity. Only 43% (3/7) of SN+ patients with nodal recurrence were eligible for salvage surgery, compared to 91% (10/11) of SN- patients. SNB resulted in fewer complications than ND (8% vs 28%, p < 0.0001). CONCLUSION: SNB is a reliable staging tool for T1/T2 cN0 OSCC, without adverse effect on patient survival and fewer complications. No late recurrences occurred in long-term follow-up. Close follow-up is mandatory for SN+ patients, who are at higher risk of nodal recurrence and have worse prognosis.

Long-term response in patient with recurrent oropharyngeal carcinoma treated with cetuximab, docetaxel and cisplatin (TPEx) as first-line treatment followed by cetuximab maintenance.

BACKGROUND: Cetuximab, an anti-EGFR monoclonal antibody in combination with platinum and 5FU is the standard of care in first-line treatment of patients with recurrent head and neck squamous cell carcinoma (HNSCC), with an expected median outcome of 10months. For this population, development of efficacious and safer therapies is still needed. CASE REPORT: A 62-year-old male with a first recurrence of human papillomavirus positive stage IVA (T3N2bM0) adenocarcinoma of the glossotonsillar sulcus not amenable to locoregional curative treatment was offered chemotherapy as part of the TPEx clinical trial. He was treated by cetuximab (loading dose 400mg/m2 on day 1 cycle 1, then 250mg/m2 weekly), and chemotherapy (cisplatin 75mg/m2 and docetaxel 75mg/m2, on day 1). Cycles were repeated every 21days for 4 cycles (TPEx regimen) with systematic granulocyte colony-stimulating factor support at each cycle. Bi-monthly maintenance cetuximab 500mg/m2 was then administered. The patient showed a clinical complete response according to RECIST 1.1 criteria after 5months maintenance, with progression-free survival of 25months. Relapses that followed were treated with stereotactic irradiation, radiofrequency ablation, cetuximab and paclitaxel. The patient is alive eleven years after cancer diagnosis and remains controlled for his disease, with a cumulative period of 59months of cetuximab administration (equivalence of 121 injections). CONCLUSION: This case report demonstrated that TPEx regimen, by synergistic interaction between taxanes and cetuximab, followed by bimonthly cetuximab maintenance may lead to patient complete remission within the first year of treatment. Furthermore, prolonged intermittent treatment with cetuximab seems to participate in the improved survival associated with preserved quality of life. Key favorable prognostic factors may be moderate tumor differentiation, oropharyngeal location, HPV p16 positive tumor status.

Hyperselective intra-arterial preoperative chemotherapy in patients with squamous cell carcinoma of the oral cavity: preliminary results.

OBJECTIVES: To investigate radiological response and findings after Intra Arterial Chemotherapy (IAC) for patients with Squamous Cell Carcinoma (SCC) of the oral cavity. MATERIALS AND METHODS: Patients received 1-2 cycles of IAC. Radiological assessment was performed on day 7 and day 21 after each cycle using CT scan and MRI. RESULTS: Six patients (median age: 52, ranging 46-60; male/female: 5/1) received 10 cycles (4 patients received 2 cycles). Primary tumors were floor of the mouth (4 patients) and oral tongue (2 patients). TNM classification was T2N0-2b in 3 patients and T4N0-1 in 3 patients. All patients had good locoregional/systemic tolerance and 3 showed clinical objective response (OR). Four patients were evaluable on both CT and MRI, 1 patient on MRI only and 1 patient did not tolerate imaging. Three patients showed OR both on CT and MRI, 1 patient showed stable disease (SD) on CT and OR on MRI and 1 patient showed SD on MRI. Contrast-enhancement of hemiperfused tongue was reported in all evaluable patients. Two patients presented intratumoral necrosis and 5 patients displayed local edema (MRI). One patient had modification of the sternocleidomastoid muscle after IAC. CONCLUSION: Radiological modifications were observed in the infused area and correlated well with clinical response. This study is ongoing.

Comparison of mouse and human colon tumors with regard to phase I and phase II drug-metabolizing enzyme systems.

Since human colorectal tumors are insensitive to most chemotherapeutic agents, there is a need for the discovery of new drugs that would show activity against this disease. In an attempt to better appreciate the relevance of a widely used mouse colon tumor (colon adenocarcinoma Co38) as a screening model for human colorectal tumors, we compared the main phase I and phase II drug-metabolizing enzyme systems in both tumoral and nontumoral colon tissues. The following enzymes were assayed by Western blot: cytochromes P-450 (1A1/A2, 2B1/B2, 2C, 2E1, and 3A), epoxide hydrolase, and glutathione-S-transferases (GST-alpha, -mu, and -pi). The activities of the following enzymes or cofactors were determined by spectrophotometric or fluorometric assays: total cytochrome P-450, 1-chloro-2,4-dinitrobenzene-GST, selenium-independent glutathione peroxidase, 3,4-dichloronitrobenzene-GST, ethacrynic acid-GST, total glutathione, epoxide hydrolase, UDP-glucuronosyltransferase, beta-glucuronidase, sulfotransferase, and sulfatase. Results obtained by Western blot showed that mouse colon adenocarcinoma Co38 did not express any of the probed cytochromes P-450, whereas human colorectal tumors expressed only low levels of cytochrome P-450 3A. GST-alpha and GST-pi were detected in all tumoral and nontumoral tissues of both species. The neutral GST-mu was expressed in all murine tissues investigated and was found to be polymorphic in human tissues. For human peritumoral and tumoral colorectal tissues there was no significant difference between GST isoenzyme levels, whereas mouse colon adenocarcinoma Co38 had a lower expression of GST-mu and GST-pi, compared to normal mouse colon. Enzymatic activities for glutathione peroxidase, 3,4-dichloronitrobenzene-GST, and ethacrynic acid-GST confirmed the Western blot results for GST-alpha, GST-mu, and GST-pi, respectively. Total GSH levels were similar between murine and human tumors but were 3-fold higher in human tumors than in peritumoral tissues, whereas they were 7-fold lower in mouse colon tumor Co38, compared to normal mouse colon. Epoxide hydrolase was not expressed in either mouse colon adenocarcinoma Co38 or normal mouse colon tissues, whereas it was expressed in human colon peritumoral and tumoral tissues at similar levels. No significant difference was observed between human tumors and peritumoral tissues for UDP-glucuronosyltransferase, beta-glucuronidase, sulfotransferase, and sulfatase. For murine colon tissues, the conjugation pathways (UDP-glucuronosyltransferase and sulfotransferase) were lower in colon adenocarcinoma Co38, whereas the converse was observed for the corresponding hydrolytic enzymes (beta-glucuronidase and sulfatase).(ABSTRACT TRUNCATED AT 400 WORDS)

Development of minimally invasive surgery for sinonasal malignancy.

Sinonasal malignancies are rare and histologically heterogeneous. Treatment is complicated by tumor aggressiveness and location near critical anatomic structures (orbita, skull base, etc.). This low incidence and histologic diversity make prospective studies unfeasible, and thus therapeutic guidelines difficult to establish. The gold standard for surgery is a transfacial approach, with craniofacial resection in case of skull-base involvement. However, these techniques are associated with non-negligible perioperative morbidity. In the past two decades, endoscopic surgery has made major progress, extending its indications: initially developed for functional sinus surgery, it is now applied in benign skull-base pathologies (CSF leakage, meningocele, etc.) and, more recently, in sinonasal malignancy. Literature analysis shows a significant decrease in morbidity and improved quality of life associated with endoscopic endonasal surgery, with oncologic safety and efficacy in well-selected cases, although dependent on operator experience. Additional studies with longer follow-up and comparison between histologic subtypes will be needed.

Head and neck adenoid cystic carcinoma: A prospective multicenter REFCOR study of 95 cases.

OBJECTIVES: To describe the clinical, histological and therapeutic characteristics of a prospective multicenter series of 95 head and neck adenoid cystic carcinoma patients, and to determine any prognostic factors for disease-free survival. PATIENTS AND METHODS: Ninety-five patients with adenoid cystic carcinoma were included in the Réseau d'Expertise Français Des Cancers ORL Rares (REFCOR, French Rare Head and Neck Cancer Expert Network) database between 2009 and 2012. The primary site was the salivary glands in 39 cases, sinus cavities (including hard palate) in 36 cases, pharynx-larynx-trachea in 14 cases, and lips and oral cavity in 4 cases. The tumor was stage I in 15% of cases, stage II in 23%, stage III in 26% and stage IV in 36%. Nine patients had cervical lymph node involvement and 5 had metastases at diagnosis. Fifty-six percent of patients were managed by surgery with postoperative radiation therapy. During follow-up, 3 patients died, 9 developed metastases and 12 showed recurrence or local progression. RESULTS: Mean follow-up was 18 months. On univariate analysis, disease-free survival correlated with T stage (P=0.05), N stage (P=0.003), resection margins (P=0.04), lymph node involvement on histology (P=0.01), and absence of chemotherapy (P=0.03). On multivariate analysis, disease-free survival correlated with T stage (P=0.01), N stage (P=0.09) and surgery (P=0.005). CONCLUSION: The essential issue in adenoid cystic carcinoma is long-term control. The present results confirm that the reference attitude is radical surgical resection for optimal local control. Adjuvant radiation therapy did not emerge as a prognostic factor. This study also provides a starting-point for translational studies in pathology and genetics.

[Oral cavity cancers among young people: Clinical results and prognostic analysis]. / Cancers de la cavité buccale chez les sujets jeunes: résultats thérapeutiques et analyse de facteurs pronostiques.

PURPOSE: Squamous cell carcinomas of the oral cavity occurring in young people represent a specific entity. Its management and prognosis are controversial. We performed a retrospective chart review of all patients aged less than 40 years old and treated at Gustave-Roussy Cancer Centre for a squamous cell carcinomas of the oral cavity between 1999 and 2011. METHODS: Patients and tumour characteristics, type of treatment and follow-up data were collected. Survival data were analysed according to the methods of Kaplan-Meier and both univariate and multivariate analyses were performed to look for prognostic factors regarding overall survival and progression-free survival. RESULTS: Sixty-three patients were identified. Median follow-up was 64 months. Most of the tumours were initially located in the mobile tongue (n=54, 85.7%). Overall 17 patients had died, including 15 from the treated cancer. Overall and progression-free survival rates at 5 years were respectively 79.6% and 68.6%. The corresponding 5 years local, regional and metastatic relapse free survival rates were 80%, 91% and 89% respectively. In the multivariate analysis only the absence of initial surgery (hazard ratio [HR]: 13.5 [2.0; 90.5]; P=0.007) was prognostic for overall survival, while alcohol abuse (HR: 0.37 [0.15; 0.9]; P=0.03) and the absence of surgery (HR: 13.6 [2.5; 74.2]; P=0.002) were associated with a decreased progression-free survival. A younger age (less than 30 year old) was not associated with the risk of recurrence or death. CONCLUSION: Survival rates and tumour control probabilities are relatively high among young patients suffering from squamous cell carcinomas of the oral cavity treated at a tertiary centre. The early identification of patients at risk of relapse is currently difficult. The balance between recurrence and treatment toxicity warrants further studies, both on the clinical level and for the development of prognostic biomarkers.

P73 expression in basal layers of head and neck squamous epithelium: a role in differentiation and carcinogenesis in concert with p53 and p63?

P73, a p53-homologue gene, has been studied for its possible role in head and neck squamous epithelium (HNSE) differentiation and carcinogenesis. P73 RNA and protein were analysed in 50 biopsies, including well- and moderately-differentiated carcinomas, and 21 matched normal adjacent tissues. P73 immunohistochemical analyses revealed intense p73 nuclear staining in basal and parabasal cells of normal squamous epithelium, in contrast with complete absence of staining in the more superficial cell layers. Moderately-differentiated carcinomas demonstrated homogeneous and diffuse staining in all tumour cells, while only basal cells were stained in well-differentiated carcinomas as in normal tissue. No correlation was observed between p73 and p53 protein expression. Immunostaining for p63, another p53-related protein previously described as being involved in HNSE morphogenesis and overexpressed in head and neck squamous cell carcinomas (HNSCC), was found to be similar to p73 labelling in carcinomas, but spread to the more differentiated layers in normal epithelium. Biallelic expression of p73 was found in tumours as well as in matched normal tissues. Comparison of p73 transcript levels between tumours and normal tissues showed decreased mRNA expression in 5/17 (30%) tumours independently of the differentiation status. Mutation and loss of heterozygosity analyses of the p73 gene revealed wild type status and no deletion. Our results strongly suggest that: (i) p73 is associated with homeostasis and control of differentiation of head and neck squamous epithelium probably in concert with p53 and p63; (ii) down-regulation of p73 expression could participate in HNSE carcinogenesis.

Intensive concomitant chemoradiotherapy in locally advanced unresectable squamous cell carcinoma of the head and neck: a phase II study of radiotherapy with cisplatin and 7-week continuous infusional fluorouracil.

PURPOSE: To evaluate an intensive concomitant chemoradiotherapy protocol of conventional radiotherapy with intermittent cisplatin (CDDP) and continuous-infusion fluorouracil (5-FU) in unresectable, locally advanced squamous cell carcinoma of the head and neck (SCCHN). PATIENTS AND METHODS: Fifty-seven patients with unresectable stage IV MO disease (International Union Against Cancer [UICC]/American Joint Committee on Cancer [AJCC], 1987) received radiotherapy 70 Gy followed by CDDP 80 mg/m2 and 5-FU 300 mg/m2/d. Response was assessed 2 months after treatment completion. RESULTS: Thirty patients (52%) received the full treatment schedule; 53 (93%) received full-dose radiotherapy, while 48 (84%) were given at least 75% of the planned chemotherapy doses. Severe mucositis (World Health Organization [WHO]) grade 3 to 4 was the limiting toxicity and was seen in 79% of patients. The median time for mucositis resolution was 8 weeks. Other toxicities were generally manageable, but there were four treatment related deaths (7%). Fifty patients were assessable for activity, with an overall response rate of 70% (95% confidence interval [CI], 58% to 82%). Complete response (CR) and partial response (PR) rates were 42% and 28%, respectively. CONCLUSION: This simultaneous combined-modality regimen was feasible at the cost of severe mucosal toxicity, which required hospitalization with nutritional, parenteral, and hydroelectrolytic support. The high response rate achieved (70%) did not translate into improved survival, probably due to patient eligibility. The likelihood of cure of this high-tumoral-volume patient population remains low (approximately 10%), despite the association of two therapeutic modalities at full standard therapeutic intensity.

Full-dose reirradiation for unresectable head and neck carcinoma: experience at the Gustave-Roussy Institute in a series of 169 patients.

PURPOSE: To review our experience using full-dose external reirradiation given with a curative intent for patients with unresectable head and neck carcinoma (HNC). PATIENTS AND METHODS: Between January 1980 and December 1996, 169 patients who presented with unresectable nonmetastatic HNC in a previously irradiated area were included in this series. The median time between the first and the second irradiation was 33 months. Reirradiation protocols were as follows: radiotherapy alone (65 Gy over 6.5 weeks at 2 Gy/d), 27 patients; Vokes protocol, ie, five to six cycles of radiotherapy (median total dose, 60 Gy; 2 Gy/d) with simultaneous fluorouracil (5-FU) and hydroxyurea, 106 patients; and bifractionated radiotherapy (median total dose, 60 Gy; 2 x 1.5 Gy/d) with concomitant mitomycin, 5-FU, and cisplatin, 36 patients. The median cumulative dose of the two irradiations was 120 Gy. Eighty-five percent of the tumors were squamous cell carcinoma, 14% undifferentiated carcinoma of nasopharyngeal type, and 1% adenocarcinoma. Forty-four percent were local recurrences, 23% nodal recurrences, 14% both local and nodal, and 19% second primary tumors. RESULTS: Mucositis grade 3 (World Health Organization [WHO]) was found in 32% and grade 4 in 14% of cases. Four patients presented with neutropenia or thrombocytopenia (grade 3 or 4 WHO). Late toxicities (> 6 months) were as follows: cervical fibrosis (grade 2 to 3 Radiation Therapy Oncology Group [RTOG]), 41%; mucosal necrosis, 21%; osteoradionecrosis, 8%; and trismus, 30%. Five patients died of carotid hemorrhage, apparently in complete remission. Six months after the onset of reirradiation, 37% of patients were in complete response. Patterns of failure were local only (53%), nodal only (20%), metastatic only (7%), and multiple (20%). Median follow-up time was 70 months. Overall survival rate (Kaplan-Meier) was 21% (95% confidence interval [CI], 15% to 29%) at 2 years and 9% (95% CI, 5% to 16%) at 5 years. Median survival time was 10 months for the entire population. Thirteen patients, of whom 12 were treated with the Vokes protocol, were long-term disease-free survivors. In a multivariate analysis, the volume of the second irradiation was the only factor significantly associated with the risk of death: relative risk=1.8 (95% CI, 1.13 to 5.7) (P=.01). CONCLUSION: Full-dose reirradiation combined with chemotherapy was feasible in patients with inoperable HNC. The incidence and severity of late toxicity was markedly increased in comparison to that observed after the first irradiation. Median survival was better than that generally obtained using palliative chemotherapy alone. A small proportion of patients were long-term disease-free survivors.