Evidence for T-cell clonal expansion in a patient with squamous cell carcinoma of the head and neck.

Squamous cell carcinomas of the head and neck (SCCHN) often contain a large mononuclear cell infiltrate, composed mainly of T-lymphocytes which could reflect an in situ immune reaction against the malignant SCCHN cells. We analyzed the molecular structure of the T-cell receptor (TCR) alpha and beta chains expressed by lymphocytes in the tumor, peripheral blood (PBMC), and in the peritumoral tissue in six cases of localized SCCHN. We first determined V alpha and V beta gene segment subfamily usage by polymerase chain reaction using a panel of V subfamily-specific oligonucleotide primers (V alpha 1-w29 and V beta 1-w24). An apparently unrestricted usage of V alpha or V beta gene segment subfamilies was observed for all three samples from the six cases examined. No major difference was observed in T-cell receptor repertoire expression of PBMC between SCCHN and healthy donors, making unlikely the expression of putative tumor-related superantigen(s) in these patients. Intersample comparisons for a given V alpha or V beta T-cell receptor specificity revealed some differences in V gene segment usage in tumor-infiltrating lymphocytes versus PBMC. A detailed analysis of these V segment subfamily specificities (cloning followed by sequencing and CDR3 size distribution analysis) in one patient revealed the presence of recurrent T-cell receptor transcripts (i.e., identical V-N-J sequences) in the tumor (e.g., 40%) and in PBMC (e.g., 75%). These results show that unique T-cell subpopulations are clonally amplified in SCCHN patients, possibly as a consequence of antigen-driven selection.

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.

Phase II study of cisplatin and continuous-infusion 5-fluorouracil and bleomycin for recurrent and metastatic head and neck squamous-cell carcinoma.

5-Fluorouracil (5-FU) and bleomycin (BLM) are active agents in head and neck squamous-cell cancer (H-N-scc). Less toxicity and an enhanced activity have been reported when these agents are administered by continuous infusion (CI), with or without a bolus of cisplatin (CDDP), another active agent. Thirty-three patients with recurrent and/or metastatic head and neck squamous cell carcinoma were treated with a combination regimen including CDDP (100 mg/m2) on day 1 plus BLM (15-mg bolus followed by 16 mg/m2/day by CI) and 5-FU (650 mg/m2/day by CI) on days 1-5 every 3 weeks. Thirty-one patients were evaluable for toxicity and response. The response rate (RR) was 15% (5 of 31), with one complete response (CR) and four partial responses (PRs), at a confidence interval of 95% (0-34%). Four of the five responders had not received previous radiotherapeutic treatment. Toxicity was deemed acceptable; nausea and vomiting and stomatitis were moderate. Only one patient had irreversible renal toxicity, after two cycles of chemotherapy. No symptomatic lung toxicity was observed. Good antitumour activity was noted for previously untreated disease (3 of 4; 75% RR). This combination of drugs proved to be inactive, however, in previously irradiated recurrent and/or metastatic H-N-scc (1 of 25; 4% RR). These results underscore the need to be extremely attentive to different patient populations when selecting therapeutic schedules and when analyzing reported results.

[Measurement of the kinetics of cell proliferation of cancer of the oropharynx in vivo by the incorporation of bromodeoxyuridine and flow cytometry]. / Mesure de la cinétique de prolifération in vivo des cancers de l'oropharynx par incorporation de bromodesoxyuridine et cytométrie de flux.

Forty-six tumors from patients with oropharyngeal carcinoma were analysed by flow cytometry after injection of bromodeoxyuridine (Budr) for the labelling index, the duration of S phase and the potential doubling time (Tpot). The results show large variations in Tpot (from 2.6 to 16.7 days) among these tumors from the same site and with the same histology. The variations in Tpot were not significantly related to TNM status and differentiation grade. However, aneuploid tumors had statistically significant shorter Tpot. The predictive value of Tpot regarding the response to radiotherapy is currently under investigation.

Combined transfacial and neurosurgical approach to malignant tumours of the ethmoid sinus.

In order to understand the risks and benefits of a combined transfacial and neurosurgical procedure for neoplasms of the ethmoid sinus, we reviewed all patients who underwent this surgical approach in our department between 1986 and 1994. The study included 41 patients. Pathological diagnoses included adenocarcinoma (31 patients), squamous cell carcinoma (three patients), aesthesioneuroblastoma (three patients), other (four patients). The overall morbidity rate was 39 per cent, and the post-operative mortality rate was 2.5 per cent. Complications were statistically more likely in patients with bone skull base reconstruction. The main carcinologic failures were local recurrences (24 per cent) and metastases (22 per cent). The one-year, three-year and five-year Kaplan Meir survival rates were respectively 84 per cent, 53 per cent and 36 per cent. In conclusion, the mortality and morbidity were acceptable, especially when no bone skull base reconstruction was performed. Better local control justifies a combined procedure with post-operative radiotherapy when tumours involve or reach the skull base.

[Functional surgery in cancer of the laryngeal vestibule. Apropos of 149 cases treated at the Institut Gustave-Roussy]. / La chirurgie fonctionnelle dans les cancers du vestibule laryngé. A propos de 149 cas traités à l'Institut Gustave-Roussy.

Functional surgery for treatment of 149 cases of cancer of vestibule of larynx admitted to the Institut Gustave-Roussy, Paris, included 92 supraglottic horizontal laryngectomies and 57 reconstructive subtotal laryngectomies with crico-hyoidopexy. General selection criteria for performing subtotal laryngectomy were very strict: local criteria included tumor of vestibule with possible extension to ventricle, to an arytenoid cartilage or to the HTE space, and regional criteria, more particularly, required absence of any palpable gland or mobile gland of less than 2.5 cm. This rigorous selection explains excellent carcinologic results: 90.8% survival after 5 years following subtotal laryngectomy as against 37.9% after supraglottic horizontal laryngectomy, equivalent to a survival rate for all cases of cancer of vestibule of larynx treated by functional surgery of 65% at 3 years and 58% at 5 years.

[Myocutaneous flaps in cervicofacial oncology. Results apropos of 87 patients]. / Les lambeaux myo-cutanés en carcinologie cervico-faciale. Résultats à propos de 87 malades.

Results are reported of the use of 93 musculocutaneous flaps, distinction being drawn between those used for secondary reconstruction and those employed during surgical excision. Secondary flaps were used to close 19 pharyngostomies, 10 orostomies, and 2 necrotic skin lesions, and for reconstruction of a circular pharyngectomy. Large radiation doses had been given in 29 of these 32 patients. Treatment was a total failure in 3 cases, and was partially ineffective in 5 patients, with the need for alternative surgery. Flaps obtained during initial surgery (57 cases) included 33 patients treated by radiation. Partial healing was obtained in 5 cases but the treatment was unsuccessful in 4 cases: all on previously radiated tissue. Unfavourable factors are mainly previous radiation and the hypopharyngeal site of loss of substance. Indications for the different types of flap are discussed.

[Primary synovial sarcoma of head and neck. Materials of The Gustave Roussy Institute. Report of 13 cases]. / Synovialosarcomes cervico-faciaux. Expérience de 1'Institut Gustave Roussy. A propos de 13 cas.

This report presents the result of our experience with 13 primary synovial sarcoma of the head and neck. The 9 males and 4 females had a median age of 32 years. The predominant location of the tumor was the pharynx, treatment consist of surgical excision alone or associated with post-operative radiotherapy or chemotherapy. Mean follow-up was 48 month. Local recurrence occurred in 2 patient, 4 patient died of pulmonary metastasis. The five year survival rate was 55%. Favorable prognostic findings included age < 20 years and complete initial resection.

[Olfactory esthesioneuroma. Clinical description and therapeutic results apropos of 45 cases observed at the Gustave Roussy Institute from 1956 to 1986]. / Esthésioneurome olfactif. Présentation clinique et résultats thérapeutiques à propos de 45 cas observés à l'Institut Gustave-Roussy de 1956 à 1986.

Olfactory esthesioneuroma is a rare malignant nerve tumour of the nasal fossa, generally developing from the olfactory epithelium, 45 cases seen at the Gustave-Roussy Institute between 1956 and 1986 are studied. From a clinical standpoint, this tumour usually progresses slowly and essentially locally, but it is important to be aware of the possibility of a rapid progression with diffuse bone metastases. The diagnosis, borne in mind of the presence of any tumor of the upper part of the nasal fossa, is based upon histo-pathological examination. It has benefitted from the use of new indicators. The role of CAT scan in the evaluation of spread is confirmed in the present series. Treatment is based above all on surgical excision followed by radiotherapy (the neurosurgical approach being of a certain value). The prognosis of these malignant tumors is similar to that of adenocarcinomas of the ethmoid and better than that of squamous carcinomas of the facial bone structure. The role of chemotherapy is discussed.

Botulinum toxin A for quality of life improvement in post-parotidectomy gustatory sweating (Frey's syndrome).

OBJECTIVE: To measure patient-reported quality of life before and after botulinum toxin A treatment of post-parotidectomy Frey's syndrome (gustatory sweating). PATIENTS AND METHODS: A questionnaire concerning functional, social and emotional aspects of Frey's syndrome (14 questions, with responses on a zero to three point scale) was administered to 17 patients (13 women and four men) before and one month after intradermal injection of botulinum toxin A. Parotidectomy had been performed one to 19 years previously, for benign (n = 10) or malignant (n = 7) tumours, with gustatory sweating occurring a median of 15 months after surgery (range: one month to 14 years). Pre- and post-treatment quality of life scores were compared using Wilcoxon's test (p < 0.05). RESULTS: Patients' reported functional quality of life improved significantly (p = 0.0004). Their social and emotional scores were not significantly modified (p = 0.155 and 0.142, respectively). Seven patients (41 per cent) found the injections painful, but all patients said that the effects were beneficial, that they would undergo new injections if necessary and that they would recommend this treatment to other patients. The benefit lasted over 1.5 years for 60 per cent of patients. No correlation was found between duration of the effect and the extent of parotidectomy (p = 0.067). CONCLUSIONS: Botulinum toxin A significantly improved patients' functional quality of life, without significant improvement in their social or emotional quality of life, according to our questionnaire results. The duration of the effect was longer than the reported physiological effect of botulinum toxin A on acetylcholine receptors.

[Perioperative chemotherapy of squamous cell carcinoma of the hypopharynx]. / Chimiothérapie périopératoire des carcinomes épidermoïdes de I'hypopharynx.

The aim of this prospective study was to decrease the rate of locoregional recurrence (LRR) and distant metastasis (DM) with a multi-modality approach in hypopharyngeal squamous cell carcinoma (HSCC). Patients presenting with squamous cell carcinoma of the pyriform sinus, epilarynx or postcricoid area with indication of pharyngolaryngectomy, without previous treatment, distant metastasis, multiple primaries or general contraindications for surgery and chemotherapy were included in the study. Patients received three consecutive cycles of chemotherapy (CDDP cisplatinium 100 mg/m2 D1, 5-FU 1 g/m2 D1 to D5) before surgery, then two postoperative courses of the same chemotherapy at day 10 and 31 after surgery. Postoperative radiotherapy was initiated at day 50. Between 1986 and 1989, of 198 patients with HSCC, 60 were included in this study. Tumour response of the induction chemotherapy was: no response (NR): 22; partial response (PR): 25; complete response (CR): 11; non evaluable: 2. Forty-seven patients underwent surgery. Only two patients had no viable tumour in the surgical specimen and two others only keratin debris. Of 39 patients in which protocol treatment was respected, 4 LRR, 4 LRR + DM, 8 DM, three second head and neck primaries, and one acute myeloblastic leukemia were observed. Results were compared with those of historical series, with the same mean delay of follow up. The rate of survival at 2 and 5 years was 78% and 42% in the present series, while it was 77% and 33% in the control group, respectively (NS).

[Ligation of the common carotid. Studies of the circumstances and follow up of 42 ligations]. / Contribution à l'étude des ligatures de l'axe carotidien principal. Etudes des circonstance et des suites de 42 ligatures.

The authors report the results of a series, between 1969 and 1978, of 42 patients who had received ligation to the carotid arterial trunk. In 36 patients, the ligation was performed as an emergency measure, often under extemporary circumstances, because of massive hemorrhage in individuals who had received surgery after previous radiotherapy. The complications after applying these ligatures have been catastrophic for many reasons. Fifteen rapid recurrent hemorrhages occurred, leading to the deaths of 13 patients. Twenty-two patients developed major neurological problems and 12 of these subsequently died. The third complication observed was the onset of extensive necrosis. This necrosis was the direct result of applying a ligature, as a last resort, to the carotid trunk supplying a vascular territory already compromised by previous radiotherapy and surgery. The authors propose different techniques for these subsequent ameliorating operations. They insist, particularly, on performing an arterectomy instead of simply applying a ligature to the carotid trunk.

[Isolated mandibular metastases. Therapeutic strategy. Apropos of 7 cases]. / Les métastases mandibulaires isolées. Stratégie thérapeutique. A propos de 7 cas.

Among the mandibular tumours, the secondary malignant tumours are uncommon. We relate 7 cases observed between 1977 and 1995. Two cases have revealed the original cancer (rectum, prostate). The five other cases were discovered during the evolution of the original cancer (colon, lung, kidney, thyroid, breast). These 7 mandibular metastases were isolated. The treatment included a mandibular resection in 6 cases. In one of these cases, the reconstruction was performed with a free vascularized fibular transplant with success. Among the seven cases, two patients are alive, at the present time, with a mean follow-up of 3 years. This justifies a curative treatment.

[Isolated mandibular metastasis of cancer of the thyroid. Mandibulectomy and reconstruction using a free vascularized peroneal graft]. / Métastase mandibulaire isolée d'un cancer de la thyroïde. Mandibulectomie et reconstruction par un transplant libre de péroné vascularisé.

Isolated mandibular metastasis from a thyroid cancer is exceptional. In our observation, it was revealed 13 years after the thyroid cancer (papillo-vesicular carcinoma which was treated with total thyroidectomy, nodes resection and I 131). Treatment included interruptive mandibulectomy and reconstruction with a free composed vascularized fibular transplant. Follow-up was uneventful. Functional and morphological results were excellent. Isolated cases are reported in the literature. Surgical resection must be achieved. The originality of our observation is the mandibular reconstruction with a free vascularized fibular transplant.

Malignant tumours of the parotid: a study of 76 patients.

This study presents a series of malignant parotid tumours treated at the Institut Gustave-Roussy between 1975 and 1984. The lesions represented a wide variety of histological types. Few preoperative investigations were required, management being based on histology. Effective local control requires a total parotidectomy preserving the facial nerve where possible. It should be followed by routine radiotherapy which appears to reduce the incidence of local recurrence. The rate of local recurrence also depends on the histological type. It is seen more frequently in an adenocarcinoma following a pleomorphic adenoma than in simple adenocarcinoma. Patients with inoperable disease are treated with radiotherapy alone as chemotherapy has not so far been effective. Percentage 5-year survival for the three most common tumour types is as follows: adenocarcinoma: 49; adenoid cystic carcinoma: 83, and mucoepidermoid carcinoma: 75.

[Free forearm flap used in the reconstruction of the cervico-cephalic region. 43 cases]. / Le transplant libre antébrachial appliqué à la reconstruction de l'extrémité cervico-céphalique. 43 cas.

The free neurovascular antebrachial transplant was described by Yang-Guofan in 1978. In 1981, we brought the description of this free transplant to Europe. Forty-three antebrachial grafts were made to reconstruct the cervicocephalic extremity. We had various indications: floor of the mouth and base of the tongue: 18 cases, facial structures: 7 cases, posterior wall of the pharynx: 9 cases, rescue surgery for esophagoplasty: 6 cases, mandible: 2 cases (using a bone rod taken from the radius), internal aspect of the cheek: 1 case. All grafts were revascularized. In 41 cases, the indications were carcinological, the last 2 cases being benign lesions. The early postoperative mortality included 1 case, not related to the nature of the operation (neoplasm). There was no failure of free transplants. Surveillance was ensured every half-hour during 12 hours, then every 3 hours. Discriminating sensation was recovered in 39 of 43 cases. Mandibular bone reconstructions were knit at the 3rd month. The main disadvantage of removing this graft is esthetic, as it leaves a considerable scar on the forearm. The free antebrachial transplant provides an effective solution to the reconstructions of the cervicocephalic extremity, when a narrow, thin, supple, reinnervated, compound transplant is needed.

Correlation between p53 gene expression and tumor-cell proliferation in oropharyngeal cancer.

The aim of our study was to analyze the correlation between tumor-cell kinetics measured in vivo and p53 gene expression in a series of 49 oropharyngeal cancers. The duration of the S phase (TS), the labelling index (LI) and the potential doubling time (Tpot) were obtained by flow-cytometry measurements of a tumor biopsy obtained after i.v. injection of 200 mg bromodeoxyuridine into patients. An adjacent section of the same samples was studied by immunohistochemistry for the detection of p53 protein. Over-expression of the p53 protein, as defined by strong p53 immunostaining of tumor nuclei, was found in 23/49 of the samples. Aneuploid tumors showed a higher LI, a shorter Tpot and a higher proportion of p53 gene over-expression. A significant correlation was seen between p53 over-expression and short Tpots. Indeed 87.5% of the tumors with a very short Tpot (< or = 3 days) had p53 over-expression, as compared with 27% of tumors with a longer Tpot (> 3 days). Our data strongly suggest that over-expression of the p53 gene is associated with rapid tumor-cell proliferation in this type of cancer.

Prognostic value of histological and biological markers in pharyngeal squamous cell carcinoma: a case-control study.

Between 1980 and 1985, 914 patients with head and neck squamous cell carcinoma underwent lymph node dissection in our institution. The prognostic value of clinical factors has already been reported (Mamelle et al, 1994, Am J Surg 168: 494-498). We present here a comparison of biological characteristics of pharyngeal tumours in patients who developed distant metastasis and in patients without metastasis, matched on tumour site, node site and size, and year of diagnosis. Tumour differentiation, keratinization, vascular emboli, immunohistochemical expression of p53, c-erb-B2, Rb and bcl2 were first assessed in 31 pairs of patients. Factors of potential interest were then determined in 32 additional pairs of patients. Statistical analysis showed that the risk of distant metastasis was halved in patients with tumours expressing c-erb-B2 compared with patients with c-erb-B2-negative tumours (P = 0.05). The significance of c-erb-B2 expression and its potential value as a prognostic factor is discussed.