[Reirradiation of head and neck cancers]. / Réirradiation des cancers des voies aérodigestives supérieures.

Locoregional relapse in previously irradiated region for head and neck tumours is associated with a bad locoregional and distant prognosis. Reirradiation might be exclusive, or feasible in addition with surgery and/or chemotherapy, according to histopronostic factors. Data show that reirradiation is feasible with some severe toxicity due to the bad prognosis of this situation. Hyperfractionnated regimen with split course or normofractionnated regimen without split course are possible with similar efficacy. If tumour size is small, stereotactic ablative radiotherapy may be considered, and if the treatment centre has proton therapy, it could be proposed because of better organs at risk sparing. There is no standard regarding reirradiation schedules and several trials have to be done in order to determine the best technique. Nevertheless, it is agreed that a total dose of 60Gy (2Gy per fraction) is needed. Other trials testing the association with new systemic agents have to be performed, among them agents targeting the PD1/PD-L1 axis.

Transoral-transcervical oropharyngectomy without mandibulotomy, associated to fasciocutaneous radial forearm free-flap reconstruction, for oropharyngeal cancer: Postoperative course, oncologic and functional results, and prognostic factors.

OBJECTIVE: To analyze postoperative course, oncologic and functional results and prognostic factors of transoral-transcervical oropharyngeal cancer surgery without mandibulotomy, associated to radial forearm free-flap reconstruction. MATERIAL AND METHODS: Retrospective analysis of computerized medical records of all patients who underwent this type of surgery in our institution between 2004 and 2014. Predictive factors of oncologic and functional results were investigated on univariate and multivariate analyses. RESULTS: Forty-four patients (37 male, 7 female; mean age, 62.3±9.3years) were included. Three-year overall, disease-specific and recurrence-free survival was 90%, 92% and 79%, respectively. Functional scores were satisfactory (normal or slight impairment) for feeding, speech and oral opening functions in 86%, 93% and 100% of cases, respectively. ASA score≥III had significantly negative impact on overall survival (P=0.005) and on feeding (P=0.01) and speech (P=0.01). CONCLUSION: Transoral-transcervical oropharyngeal cancer surgery without mandibulotomy provided excellent oncologic and functional outcomes; it is an advantageous alternative to the conventional conservative transmandibular oropharyngectomy.

Molecular patterns in deficient mismatch repair colorectal tumours: results from a French prospective multicentric biological and genetic study.

BACKGROUND: To test the prognostic value of tumour protein and genetic markers in colorectal cancer (CRC) and examine whether deficient mismatch repair (dMMR) tumours had a distinct profile relative to proficient mismatch repair (pMMR) tumours. METHODS: This prospective multicentric study involved 251 stage I-III CRC patients. Analysed biomarkers were EGFR (binding assay), VEGFA, thymidylate synthase (TS), thymidine phosphorylase (TP) and dihydropyrimidine dehydrogenase (DPD) expressions, MMR status, mutations of KRAS (codons 12-13), BRAF (V600E), PIK3CA (exons 9 and 20), APC (exon 15) and P53 (exons 4-9), CpG island methylation phenotype status, ploidy, S-phase, LOH. RESULTS: The only significant predictor of relapse-free survival (RFS) was tumour staging. Analyses restricted to stage III showed a trend towards a shorter RFS in KRAS-mutated (P=0.005), BRAF wt (P=0.009) and pMMR tumours (P=0.036). Deficient mismatch repair tumours significantly demonstrated higher TS (median 3.1 vs 1.4) and TP (median 5.8 vs 3.5) expression relative to pMMR (P<0.001) and show higher DPD expression (median 14.9 vs 7.9, P=0.027) and EGFR content (median 69 vs 38, P=0.037) relative to pMMR. CONCLUSIONS: Present data suggesting that both TS and DPD are overexpressed in dMMR tumours as compared with pMMR tumours provide a strong rationale that may explain the resistance of dMMR tumours to 5FU-based therapy.

Clinical and histological prognostic factors in locally advanced oral cavity cancers treated with primary surgery.

OBJECTIVE: The primary objective of this study was to determine the clinical and pathological prognostic factors in locally advanced oral cavity cancers treated by primary surgery. METHODS: All patients treated by primary surgery with free-flap reconstruction for locally advanced oral cavity squamous cell carcinoma in our institution between 2000 and 2010 were included in this retrospective study. Overall, cause-specific and locoregional disease-free survivals were determined by Kaplan-Meier analyses. Clinical and histological prognostic factors were assessed by univariate (Log Rank tests) and multivariate (Cox models) analyses. RESULTS: A total of 149 patients (102 men and 47 women; mean age=61.3±12.1 years) were included in the study. Five-year overall, cause-specific and locoregional disease-free survivals were 55%, 68% and 71%, respectively. Age, comorbidity and tumour size (histological evaluation) were significantly correlated with overall survival (P<0.05). Age, tumour size, bone invasion and surgical margins were significantly correlated with locoregional disease-free survival (P<0.05). CONCLUSION: The main prognostic factors identified in this study were clinical (age and comorbidity) and histological (pathological tumour size, bone invasion and surgical margins).

Prognostic impact of tumour multifocality in thyroid papillary microcarcinoma based on a series of 160 cases.

OBJECTIVE: The objective of this study was to evaluate the prognostic impact of tumour multifocality in papillary thyroid microcarcinoma (PTMC). METHODS: All patients who underwent total thyroidectomy and central neck dissection for PTMC in our institution between 1990 and 2007 were included in this retrospective study. Statistical correlations between tumour multifocality and various clinical or pathological prognostic parameters were assessed by univariate and multivariate analyses. RESULTS: A total of 160 patients (133 women and 27 men; mean age: 47.8±13.7 years) were included in this study. Tumour multifocality was demonstrated in 59 (37%) patients. Central neck metastatic lymph node involvement was identified in 46 (28%) patients. No statistical correlation was demonstrated between tumour multifocality and the following factors: age, gender, tumour size, extension beyond the thyroid, metastatic central neck lymph node involvement and risk of recurrence. A tumour diameter greater than 5mm was associated with a higher risk of recurrence (P=0.008). CONCLUSION: Tumour multifocality does not appear to have a prognostic impact in PTMC.

Acceleration of clear cell renal cell carcinoma growth in mice following bevacizumab/Avastin treatment: the role of CXCL cytokines.

The anti-VEGF targeted antibody bevacizumab (BVZ) has been approved for treating renal cell carcinomas (RCCs). Although BVZ increases the progression-free survival of patients with metastatic RCC, the effect on overall survival is poor. To gain insight into the limited efficacy of BVZ on overall survival, we analyzed patient samples of RCC for angiogenic factors that may participate in escape from anti-VEGF therapy. Our study shows that the level of vascular endothelial growth factor (VEGF) in tumors was increased compared with normal tissue. The level of interleukin-8/CXCL8, a pro-angiogenic member of the CXCL family of cytokines, was also increased in tumors. These observations gave us a good reason to analyze the combined effects of BVZ and anti-CXCL8 antibodies on tumor growth. Surprisingly, we report that BVZ accelerates the growth of RCC in nude mice with in vivo selection of tumor cells with an increased growth capacity. Downregulation of receptor tyrosine phosphatase-κ, a phosphatase implicated in EGF receptor regulation, may partly explain this phenomenon. Modification of the vascular network and development of lymphatic vessels through VEGF-C production and compensatory production of pro-angiogenic CXCL cytokines were also observed. The apparent normalization of the vascular network prompted us to associate BVZ with the chemotherapeutic agent paclitaxel. While efficient in vitro, paclitaxel did not reverse the anti-VEGF effects in vivo. Anti-CXCL8-targeting antibodies were promising as they decreased intra-tumor VEGF production; decreased the pro-angiogenic CXCL/anti-angiogenic CXCL ratio and did not induce lymphangiogenesis. These observations hold clinical implication as they highlight putative markers implicated in escape from BVZ treatment. They also recommend proceeding with caution in the use of anti-VEGF therapy alone for treatment of RCC.

Cervical sympathetic chain schwannoma.

INTRODUCTION: Cervical schwannoma is a benign peripheral nerve tumor specifically developing from Schwann cells. Cervical sympathetic chain schwannoma is rare. Following a case report, the authors describe its specific radiological and histological characteristics. Treatment is surgical. CLINICAL CASE: A 56-year-old woman consulted for an isolated left lateral cervical mass of several years' standing, but with recently associated pharyngeal discomfort. Cervical CT revealed a vascularized retrostyloid mass with venous-time enhancement, inducing anterior displacement of the jugulo-carotid axis. The tumor could not be identified on fine-needle aspiration cytology, and surgical resection was performed by cervicotomy. Surgical exploration found a tumor developing from the cervical sympathetic nerve, posterior to the jugular vein and carotid sheath. Histopathologic examination diagnosed schwannoma. Postoperative outcome featured Horner's syndrome. CONCLUSION: Cervical sympathetic chain schwannoma is a rare benign tumor, to be suspected in the presence of an isolated lateral cervical mass. Preoperative CT is mandatory to guide diagnosis; treatment is surgical, to confirm histologic diagnosis. Postoperative Horner's syndrome often confirms cervical sympathetic chain involvement.

Laryngeal chondrosarcoma: report of two cases.

OBJECTIVE: The present study describes the clinical, radiological and histological features of laryngeal chondrosarcoma, on the basis of two clinical cases, and discusses management. CASE STUDIES: Two male patients, aged 63 and 51 years, presented with low-grade chondrosarcoma revealed respectively by a mass in the lateral neck and by laryngeal dyspnea. CT showed a tumoral process with calcification, developed from the thyroid and cricoid cartilage, respectively. The first patient underwent partial and the second total laryngectomy. DISCUSSION: Chondrosarcoma is diagnosed on the basis of combined clinical, radiological and histological signs. Differential diagnosis with chondroma may be difficult, especially in grade-1 chondrosarcoma. CONCLUSION: Laryngeal chondrosarcoma is a rare tumor. Management is basically surgical. Prognosis is generally good, depending essentially on histologic grade.

Head and neck free-flap reconstruction in the elderly.

OBJECTIVE: To evaluate the reliability of free-flap head and neck reconstruction in the elderly. MATERIAL AND METHODS: All patients who underwent free-flap head and neck reconstruction in our institution between 2000 and 2010 were included in this retrospective study. In all, 418 patients (301 men and 117 women) were enrolled, including 95 patients aged 70 years or older (mean age=60.2±11.6 years). The impact of age on free-flap failure and local and general complication rates was assessed on univariate and multivariate analysis. RESULTS: Advanced age had no impact on free-flap failure and local complications rate but was correlated with a higher risk of general complications (multivariate analysis: P=0.007). A high level of comorbidity also had a significant impact on the general complications rate (multivariate analysis: P=0.001). Patients who underwent circular total pharyngolaryngectomy showed elevated risk of free-flap failure (P=0.005) and local complications (P=0.001) on multivariate analysis. CONCLUSION: Free-flap reconstruction of the head and neck is safe and reliable in the elderly. Nevertheless, meticulous patient selection, mainly based on the level of comorbidity, is necessary.

[Total pharyngolaryngectomy in the 21st century: indications, oncologic and functional outcomes]. / Les pharyngo-laryngectomies totales au 21ème siècle : indications, résultats carcinologiques et fonctionnels.

INTRODUCTION: The development of laryngeal preservation protocols has considerably modified the indications for total (pharyngo-)laryngectomy (TPL). The objectives of our study are to analyze the current indications for TPL and to evaluate the oncologic and functional outcomes after TPL and their predictive factors. METHODS: All patients who underwent TPL for squamous cell carcinoma of the larynx or hypopharynx, at our institution, between 2000 and 2009, were included in this retrospective study. Predictive factors of oncologic and functional outcomes were assessed in univariate and multivariate analyzes. RESULTS: A total of 130 patients were enrolled in our study including 119 men and 11 women, with a mean age of 65.9 years. TPL was realized for salvage in 65 patients. Extra-laryngeal tumor extension (n = 42) was the main indication for TPL in the 65 remaining patients. Overall survival was 49 and 41% at 3 and 5 years respectively. In multivariate analysis, primary tumor site (hypopharynx in comparison to larynx; p = 0.04) has a significant pejorative impact on overall survival. Oral alimentation (no enteral nutrition) was recovered successfully by 94% of the patients. In multivariate analysis, primary tumor site (hypopharynx) has a significant pejorative impact on functional results (deglutition: p < 0.0001; phonation: p = 0.03). CONCLUSION: Primary tumor site is one of the main predictive factor of oncologic and functional outcomes after TPL.

[Transoral and cervical approach without mandibulotomy for oropharynx cancer with fasciocutaneous radial forearm free flap reconstruction]. / Voie d'abord transorale et cervicale sans mandibulotomie dans les cancers de l'oropharynx avec réparation par lambeau libre fasciocutané antébrachial.

OBJECTIVE: To evaluate the role of a combined transoral and cervical approach without mandibulotomy for surgery of oropharyngeal cancer with fasciocutaneous radial forearm free flap reconstruction. MATERIAL AND METHODS: All patients who underwent this type of surgery between 2003 and 2007 were included in this retrospective study. We analyzed postoperative outcomes, surgical margins (histological study) and the oncological and functional results. RESULTS: A total of 24 patients were included in this study. There was no free flap failure. Surgical margins were negative for 23 of the 24 patients. At 3 years, overall, cause-specific, and disease-free survival rates were 73, 76 and 68%, respectively. A good functional result (normal or slightly impaired function) was obtained for oral diet, speech, mouth opening and esthetic outcome in 78, 82, 92 and 86% of the patients, respectively. CONCLUSION: This double surgical approach without mandibulotomy in selective cases can replace the transmandibular approach in locally advanced oropharyngeal cancer surgery.

Combination of sunitinib, cetuximab and irradiation in an orthotopic head and neck cancer model.

BACKGROUND: Recent preclinical and clinical studies indicate beneficial effects from combining radiotherapy with either anti-angiogenic drugs or anti-epidermal growth factor receptor (EGFR)-targeting agent. To investigate the effect of combining these approaches, we evaluated in vivo the antitumor efficacy of the anti-angiogenic compound sunitinib, an oral, multi-targeted tyrosine kinase inhibitor that inhibits among others vascular endothelial growth factor (VEGF) receptors-1, -2 and -3, cetuximab, a mAb targeting the EGFR, and irradiation (RT) given alone and in combination. MATERIALS AND METHODS: Investigations were carried out using a VEGF-secreting human head and neck tumor cell line, CAL33, with a high EGFR content, growing as orthotopic xenografts in nude mice. Three days after tumor cell injection, sunitinib (20 mg/kg, p.o.), cetuximab (1 mg/kg, i.p.), both 5 days/week seven doses, and RT (6 Gy, 3 days/week, four doses) were administered alone and in combination during 9 days. RESULTS: Concomitant administration of drugs produced a marked and significant supra-additive decrease, and the addition of RT completely abolished tumor growth. The drug association markedly reduced tumor cell proliferation (Ki67) and the number of the vessels, but enhanced cell differentiation. CONCLUSION: The efficacy of this combination of sunitinib, cetuximab and RT may be of clinical importance in the management of head and neck cancer patients.

[Papillary thyroid microcarcinomas: review of 230 cases]. / Les microcarcinomes papillaires de la glande tyroïde: à propos de 230 cas.

OBJECTIVES: Papillary microcarcinoma (PMC) is one of the most frequent pathological forms of thyroid cancer Here, we describe the circumstances of diagnosis and the clinical and pathological characteristics of this tumour We also analyze the therapeutic management and compare it with the recent published guidelines. METHODS: Between 2000 and 2006, a total of 230 patients with a PMC of the thyroid gland were included in this retrospective study. We have investigated the correlations between some pathological parameters (plurifocality, lymph node invasion...) and several factors (age, gender, tumour size...). RESULTS: The diagnosis of PMC was suspected in the preoperative period in 15% of the patients, and was confirmed intraoperatively by the pathologist in 42% of the cases. Plurifocal or bilateral PMC were discovered in respectively 30 and 17% of the patients. The rate of lymph node invasion in the central neck (level VI) was 26%. An elevated tumor size was correlated with a higher rate of plurifocal or bilateral PMC and of lymph node metastasis (p < 0.05). The indications for postoperative radioiodine therapy were reduced by approxiately 50% in the second part of our study. There were no case of thyroid PMC-related death. CONCLUSIONS: Even for these small tumours, tumour size remains correlated with the tumour aggressiveness. The place of radioiodine therapy in the management of thyroid PMC was progressively reduced because of the good prognosis of this tumour.

Combined effects of bevacizumab with erlotinib and irradiation: a preclinical study on a head and neck cancer orthotopic model.

Clinical benefit has been demonstrated in patients with head and neck tumours receiving an anti-epidermal growth factor receptor (EGFR) agent in combination with radiotherapy (RT). Recent preclinical and clinical studies suggest beneficial effects from combining anti-angiogenic drugs with RT. To investigate the effect of combining these approaches, we evaluated in vivo the anti-tumour efficacy of the anti-angiogenic compound bevacizumab, a highly specific monoclonal antibody directed against the vascular endothelial growth factor (VEGF), erlotinib, an EGFR tyrosine kinase inhibitor, and irradiation given alone and in combination. Investigations were performed using a VEGF-secreting human head and neck tumour cell line, CAL33, with a high EGFR content, injected as orthotopic xenografts into the mouth floor of nude mice. Three days after tumour cell injection, bevacizumab (5 mg kg(-1), 5 days a week, i.p.), erlotinib (100 mg kg(-1), 5 days a week, orally) and irradiation (6 Gy, 3 days a week) were administered alone and in combination for 10 days. As compared with the control, concomitant administration of drugs produced a marked and significant supra-additive decrease in tumour mass; the addition of irradiation almost completely abolished tumour growth. The drug association markedly reduced the number of metastatic nodes and the triple combination significantly reduced the total number of pathologically positive lymph nodes as compared with controls. The RT-induced proliferation, reflected by Ki67 labelling, was reduced to control level with the triple combination. Radiotherapy induced a strong and very significant increase in tumour angiogenesis, which was no longer observed when combined with erlotinib and bevacizumab. The efficacy of the combination of bevacizumab+erlotinib and RT may be of clinical importance in the management of head and neck cancer patients.

Human herpes virus 8 (Kaposi's sarcoma herpes virus) and malignant lymphoproliferations in France: a molecular study of 250 cases including two AIDS-associated body cavity based lymphomas.

The new human herpes virus 8 (HHV8) was recently detected in cases of body cavity based lymphoma (BCBL), a rare B cell lymphoma, mostly AIDS-associated. We investigated for HHV8 DNA sequences a series of 250 B or T cell lymphoproliferative malignancies, as seen in France, including 126 leukemias and 124 lymphomas (232 non-AIDS-associated and 18 AIDS-associated tumors). HHV8 sequences were detected in only three patients. The first two were homosexual males, HIV-infected since 1985 who suffered from a BCBL initially characterized in one case by a pleural lymphomatous effusion and a peritoneal one in the other case. A high level of HHV8 copies was detected in the tumoral cells of these two BCBL. In contrast, in the third positive patient who had an AIDS-associated immunoblastic lymphoma, the HHV8 sequences level was quite low. In the two BCBL patients, the HHV8-infected clonal B cells had a large immunoblastic feature with an indeterminate phenotype and were also infected by Epstein-Barr virus. In one BCBL case, a semiquantitative PCR analysis revealed that the HHV8 sequences were much more abundant in the effusion tumor cells than in the cutaneous Kaposi's biopsy while no HHV8 sequence was detectable in the peripheral blood lymphocytes. This study reports HHV8-associated BCBL in European AIDS patients and confirms that HHV8 is present at a high copy number in the tumoral B cells of this malignancy. Furthermore, HHV8 does not seem to play a pathogenic role in any of the other T or B malignant lymphoid neoplasias studied so far. This study also stresses the necessity for quantification studies in interpretation of a positive PCR analysis for HHV8 sequences, especially in patients at risk for HIV infection or Kaposi's sarcoma.

Simultaneous progressive multifocal leukoencephalopathy, Epstein-Barr virus (EBV) latent infection and cerebral parenchymal infiltration during chronic lymphocytic leukemia.

We report a non-HIV patient who had B chronic lymphocytic leukemia (CLL) with progressive multifocal leukoencephalopathy (PML) and diffuse cerebral leukemic parenchymal infiltration in the presence of JC virus and Epstein-Barr virus (EBV) cerebral co-infection. Multiple subcortical hypodensities lining the cortico-subcortical junction were present within the white matter on computerized tomography (CT) scan, with large areas of high signal intensity on T2-weighted sequences on magnetic resonance imaging (MRI). JCV DNA was identified in peripheral blood nuclear cells and cerebrospinal fluid polymerase chain reaction (PCR) DNA/DNA hybridization plus Southern blot analysis. Frontal stereotactic biopsy confirmed the diagnosis of PML by immunocytochemistry, in situ hybridization (ISH) with JC Enzo probe and electron microscopy. Leukemic B cells with the same phenotype as leukemic blood cells were disseminated in the demyelinated areas. They were labeled by anti-latent membrane protein and by BamHl W EBV probe after ISH. Adhesion and activation molecules were positive for CD23. Autopsy showed diffuse visceral leukemic infiltration without acutization. EBV-transformed B lymphocytes would favour JCV penetration and/or intracerebral reactivation of previously latent JCV infection with further development of simultaneous PML and cerebral CLL infiltration in an immunosuppressed patient.

[Tuberculosis. Role of fine needle puncture in the current diagnostic approach]. / La tuberculose. Place de la ponction à l'aiguille fine dans les approches diagnostiques actuelles.

Twenty-one fine needle aspiration biopsies were performed with a diagnosis of tuberculosis or granulomatous inflammation. The ages of the patients ranged from 26 to 66 years (mean, 36 years); 16 were men and 5 women. Two of them were positive for the human immunodeficiency virus. In twenty cases, the cytological diagnosis was confirmed by culture and/or by recovery under a specific anti-tuberculous treatment. In one case, the necrosis observed cytologically was a tumoral necrosis after histological control. According to these results with a global accuracy of 95.2%, fine needle aspiration biopsy which offers the possibility of a thorough diagnosis in a short time (24 hours or less) is a useful method for the diagnosis of tuberculosis.