DPD-based adaptive dosing of 5-FU in patients with head and neck cancer: impact on treatment efficacy and toxicity.

BACKGROUND: Fluoropyrimidine drugs are widely used in head and neck cancer (HNC). DPD deficiency is a pharmacogenetics syndrome associated with severe/lethal toxicities upon 5-FU or capecitabine intake. We have developed a simple, rapid, and inexpensive functional testing for DPD activity, as a means to identify deficient patients and to anticipate subsequent 5-FU-related toxicities. We present here the impact of fluoropyrimidine dose tailoring based on DPD functional screening in a prospective, open, non-controlled study, both in term of reduction in severe toxicities and of treatment efficacy. METHODS: About 65 patients with HNC (59 ± 9 years, 52M/13F, Prospective Group) were entered into the study. Screening for DPD deficiency was performed prior to the beginning of the chemotherapy or radiochemotherapy. DPD status was evaluated by monitoring U/UH2 ratio levels in plasma as a surrogate marker for enzymatic functionality. 5-FU doses were reduced according to the extent of the detected DPD impairment, and adjusted on the basis of age, general condition, and other clinical/paraclinical covariates, if required. Treatment-related toxicities and subsequent impact on treatment delay were carefully monitored next for comparison with a retrospective, Reference subset of 74 other patients with HNC (mean age: 59 ± 10, 58M/16F, Reference Group), previously treated in the same institute with similar schedule but using standard 5-FU dosage. RESULTS: Thirty-one out of 65 patients (48%) were identified as mildly (28%) to markedly (20%) DPD deficient. Subsequently, dose reductions ranging from 10 to 100% with 5-FU were applied in those patients. In this group, six patients (9%) experienced severe toxicities, none of them being life threatening, and no toxic death was encountered. In comparison, 16 out of 74 patients (22%) of the Reference Group displayed severe side effects after standard 5-FU administration, 13% being life-threatening toxicities (e.g., G4 neutropenia + sepsis). Moreover, one toxic death was observed in this Reference Group. No postponement or cancelation of forthcoming chemoradiotherapy courses occurred in the Prospective Group, whereas treatment had to be disrupted in six patients (8%) from the Reference Group. No difference in first-line therapy efficacy was evidenced between the two subsets (78 vs. 79% response, P = 0.790). CONCLUSIONS: Although non-randomized, this study strongly suggests that prospective determination of DPD status has an immediate clinical benefit by reducing the drug-induced toxicities incidence in patients treated with 5-FU, allowing an optimal administration of several courses in a row, while maintaining efficacy. Our preliminary results thus advocate for systematic DPD screening in patients eligible for treatment with fluoropyrimidine drugs in HNC.

[Kinetic values of lymphoscintigraphy of sentinel ganglion in cutaneous cervicofacial melanomas]. / Valeurs cinetiques de la lymphoscintigraphie du ganglion sentinelle dans les melanomes malins cutanes cervico-faciaux.

OBJECTIVE: The aim of this study was to evaluate the lymphoscintigraphy appearance time (LAT) of the sentinel lymph node (SLN) in head and neck cutaneous melanoma and to determine whether a correlation exists between LAT and SLN status (negativity or positivity). DESIGN/SETTING: In vivo study. MATERIALS AND METHODS: A retrospective cohort of 33 patients with Breslow index >or= 1.5 mm, Clark index >or= 4 mm, and ulceration > 1 mm underwent a lymphoscintigraphy and SLN biopsy for a cutaneous head and neck melanoma. MAIN OUTCOME MEASURES: LAT was noted and correlated to SLN status, Breslow and Clark indices, ulceration, and recurrence. RESULTS: Sixty SLNs were identified; 58 were removed, and 17 were positive. In 31% (n = 18), the LAT was < 10 minutes; in 59% (n = 34), the LAT was > 10 minutes and < 30 minutes; and in 10% (n = 6), the LAT was > 30 minutes. SLN was significantly positive (p = .02) when the LAT was less than 10 minutes and the negative predictive value was 100% for LAT > 30 minutes. A recurrence was significantly observed (p = .02) for LAT < 10 minutes. CONCLUSION: LAT > 30 minutes is associated with negative SLN in head and neck melanoma; however, a prospective study on a more important cohort is needed for a better evaluation of this new variable.

Impact of the prophylactic gastrostomy for unresectable squamous cell head and neck carcinomas treated with radio-chemotherapy on quality of life: Prospective randomized trial.

BACKGROUND AND PURPOSE: Concomitant radio-chemotherapy is the gold standard treatment for unresectable head and neck carcinomas. Placement of prophylactic gastrostomy has been proposed to provide adequate nutrition during the therapeutic sequence. The objectives of this study were to assess the impact of prophylactic gastrostomy on the 6-month quality of life, and to determine the factors related to this quality of life. MATERIALS AND METHODS: Design. randomized, controlled, open study ("systematic percutaneous gastrostomy" versus "no systematic gastrostomy"). Patients. squamous cell head and neck carcinoma (stages III and IV, UICC 1997). Setting. oncological departments of French university teaching hospitals. Treatment. optimal concomitant radio-chemotherapy. Evaluations. T0 baseline evaluation, T1 during the treatment, T2 end of the treatment, and T3 6-month post-inclusion. Primary endpoint. 6-month quality of life (Qol) assessed using SF36, EORTC QLQ-C30, EORTC QLQ H&N35 questionnaires. RESULTS: The Qol changes from baseline included a decline (T1 and T2) followed by an improvement (T3). Qol at 6 months was significantly higher in the group receiving systematic prophylactic gastrostomy (p=10(-3)). Higher initial BMI and lower initial Karnofsky index were significant factors related to a higher 6-month Qol. CONCLUSIONS: The study results suggest that prophylactic gastrostomy improves post-treatment quality of life for unresectable head and neck cancer patients, after adjusting for other potential predictive quality of life factors.

Nutritional factors as predictors of response to radio-chemotherapy and survival in unresectable squamous head and neck carcinoma.

BACKGROUND AND PURPOSE: This study sought to evaluate nutritional prognostic factors before treatment in patients with unresectable head and neck cancer treated by concomitant radio-chemotherapy. METHODS AND MATERIALS: Seventy-two consecutive patients were treated. We studied the potential effects of CRP, Alb, preAlb, orosomucoid, weight, weight history, BMI, PINI, OPR and NRI on response to treatment, Event-Free Survival (EFS) and Overall Survival (OS). Effects of potential risk factors on OS and on EFS were analyzed by computing Kaplan-Meier estimates, and curves were compared using the log-rank test. RESULTS: All biological nutritional factors were statistically correlated with the response to radio-chemotherapy. In multivariate analysis, only CRP (p=0.004) remained statistically significant. A statistical correlation was found between Alb and EFS in multivariate analysis (p=0.04). The factors influencing OS in univariate analysis were Alb (p=0.008), CRP (p=0.004), orosomucoid (p=0.01) and NRI (p=0.01), response to radio-chemotherapy (p<0.001) and staging (p=0.04). In multivariate analysis, only the response to radio-chemotherapy (p<0.001) remained significant. CONCLUSIONS: This study illustrates the prognostic value of nutritional status. CRP and Alb may be useful in the assessment of advanced head and neck cancer patients at diagnosis and for stratifying patients taking part in randomized trials.

Cervical paragangliomas: is SDH genetic analysis systematically required?

To evaluate the prevalence of succinate dehydrogenase (SDH) B, C, and D germline mutations in a surgical series of cervical paragangliomas and to precise the characteristics of patients presenting with familial form. Among 29 patients operated on cervical paragangliomas (carotid or vagal body) at our institution between 1994 and 2007, 23 could be asked for a genetic analysis and a familial study. Clinical characteristics of patients harboring a germline SDH mutation were studied and compared with those presenting without mutation. Mutations were found in 8/23 (35%) patients, mostly in SDHD gene (6 cases), and in SDHB and SDHC gene, respectively, in one case each. Mean age at onset was significantly lower for patients with mutation (34 vs. 51.5 years, P = 0.01). In patients presenting with a mutation, 50% had a family history of paraganglioma compared with 0% for others (P = 0.008) and 87.5% had a multifocal form of paragangliomas versus 0% for others (P = 0.001). No difference was found concerning malignant forms between the two groups (12.5 vs. 13.3%). In the 16 patients who had an apparently sporadic paraganglioma, 6% had mutations in the SDH gene. A positive family history of paraganglioma and/or the presence of bilateral or multiple paragangliomas and/or an early age of onset are the main parameters associated with SDH mutations. Genetic testing should be considered for all patients with a cervical paraganglioma, even for those presenting with an apparently sporadic tumor as familial form may be such identified in 6% of cases.

Management of invasive juvenile nasopharyngeal angiofibromas: the role of a multimodality approach.

OBJECTIVE: Juvenile nasopharyngeal angiofibromas involving the cranial base and intracranial compartment are challenging tumors. We reviewed our experience of these tumors and analyzed the efficacy of a multimodality management. METHODS: Between 1981 and 2000, 15 extensive juvenile nasopharyngeal angiofibromas (Fisch Grade III or IV) were treated at our institution. The mean age of the patients was 14.5 years, and the mean interval between the first symptom and diagnosis was 12.9 months. Initial management included preoperative embolization of the external carotid artery feeders, followed by tumor removal. A maxillofacial procedure was performed in eight cases, a combination of maxillofacial and neurosurgical approach was performed in four cases, and a neurosurgical cranial base approach was performed in three cases. RESULTS: Total removal after the initial procedure was obtained in eight patients. Subtotal removal justified additional surgery in one case, gamma knife radiosurgery in two cases, and fractionated irradiation in four cases. True recurrences were observed in four cases at a mean interval of 37 months (range, 24-46 mo) and required tailored multimodality management. No cases of perioperative death were observed. One patient underwent hemiparesis after embolization in the early period of our experience. Permanent facial numbness was reported in four cases, moderate cosmetic problems were reported in three cases, and hyposmia was reported in three cases. Except for one patient who was lost to follow-up at 18 months, 12 patients were free of disease and two patients were free of tumor progression. All patients had normal or near-normal daily life at the last check-up, with a median follow-up period of 108 months (mean, 117 mo; range, 91-252 mo). CONCLUSION: Extensive juvenile nasopharyngeal angiofibromas are efficiently managed with a multimodal protocol in which preoperative embolization is followed by optimal surgical removal using various transcranial or transfacial approaches. Adjunctive gamma knife radiosurgery is a valuable option for intracavernous residual tumor. Our protocol offers long-term cure with acceptable morbidity.

Comparison between PET and PET/CT in recurrent head and neck cancer and clinical implications.

The aim of this retrospective study was to compare the diagnostic accuracy between positron emission tomography (PET) and combined PET/computed tomography (PET/CT) in the detection of recurrent head and neck squamous cell carcinoma (HNSCC) and to evaluate the degree of interobserver agreement. Thirty-two patients who had undergone curative treatment for HNSCC and who presented with a suspicion of recurrent local disease were studied with fluoro-2-deoxy-D-glucose (FDG)-PET imaging. All patients had undergone an inconclusive conventional workup (nasofibroscopy, CT scan and/or MRI). PET and PET/CT were reviewed by two nuclear medicine physicians independently. Performances of PET and PET/CT were compared using biopsy and/or clinical follow-up of at least 8 months as gold-standard. ROC curves were employed for statistical analysis. Out of 32 patients, 18 (56%) had a local recurrence. Intraclass correlation coefficients were strong (>90) and statistically significant (P < 0.0001) for the two reviewers in all cases. The sensitivity, specificity and accuracy of PET were found to be 94%, between 36 and 50% and between 69 and 75%, respectively, depending on the consideration of equivocal cases. Results for PET/CT were found to be 94, 57 and 78%. The utility scores of PET and PET/CT were 0.72 and 0.78, respectively. PET/CT could have a direct impact on patient care with the avoidance of 8/14 (57%) unnecessary invasive procedures (panendoscopy under general anaesthesia). Combined PET/CT is more accurate than PET alone for detection of recurrent HNSCC. The findings of this study are reinforced by the strong interobserver agreement in the interpretation of the results.

[Role of [18F]-FDG PET-CT in the management of the head and neck cancers]. / Intérêt de la TEP-TDM au [(18)F]-FDG dans la prise en charge des cancers des voies aérodigestives supérieures.

OBJECTIVES: To evaluate the impact of [(18)F]-FDG PET/CT image fusion in the management of carcinomas of the upper aero-digestive tract. METHODS: This retrospective study included 169 patients with squamous cell cacinoma of the upper aerodigestive tract who underwent a PET/CT for : initial staging (n = 47), cervical lymphadenopathy from an unknown primary (n = 22), post treatment surveillance (n = 68) and detection of recurrent cancer (n = 32). Results of PET/CT were compared with those of standard workup (CT scan of head, neck and chest and abdominal ultrasound). Histology and clinical follow-up were used as gold-standard. RESULTS: PET/CT was more accurate than standard workup for 6.4 % of patients for the initial staging, 18,2 % of patients for cervical lymphadenopathy from an unknown primary, 20,6 % of patients for post-treatment surveillance and 25 % of patients for detection of cancer recurrence. In all patients, 17,9 % of FDG uptake foci found by PET/CT were false-positives. CONCLUSION: PET/CT is a reliable tool for the management of carcinomas of the upper aerodigestive tract. The high rate of false-positive findings represents the main limitation of this exam.

Lymph node biopsy specimens and diagnosis of cat-scratch disease.

We report microbiologic analysis of 786 lymph node biopsy specimens from patients with suspected cat-scratch disease (CSD). The specimens were examined by standard, cell culture, and molecular methods. Infectious agents were found in samples from 391 (49.7%) of 786 patients. The most commonly identified infectious agent was Bartonella henselae (245 patients, 31.2%), the agent of CSD. Mycobacteriosis was diagnosed in 54 patients (6.9%) by culture and retrospectively confirmed by using a specific real-time PCR assay. Neoplasm was diagnosed in 181 specimens suitable for histologic analysis (26.0%) from 47 patients. Moreover, 13 patients with confirmed Bartonella infections had concurrent mycobacteriosis (10 cases) or neoplasm (3 cases). A diagnosis of CSD does not eliminate a diagnosis of mycobacteriosis or neoplasm. Histologic analysis of lymph node biopsy specimens should be routinely performed because some patients might have a concurrent malignant disease or mycobacteriosis.

Yearly incidence of rhinitis, nasal bleeding, and other nasal symptoms in mature women.

OBJECTIVES/HYPOTHESIS: To evaluate, by a prospective questionnaire study, the incidence of spontaneous nasal pathology in mature women over a 12-month period, in particular nasal bleeding and the relationships of these symptoms with various factors. METHODS: Participants were drawn from a sample of 12,735 adult French volunteers participating in a study of antioxidant nutrients ("SU.VI.MAX"); 3500 women aged 50-64 years were randomly selected from good responders in the SU.Vl.MAX population. The responses of 2197 women were analysed. RESULTS: Nearly 70% of subjects reported at least one episode of rhinitis, with a mean (SD) of 1.88 (2.17) episodes per subject. Rhinitis was related to passive exposure to tobacco smoke (adjusted odds ratio [OR] 1.31, 95% CI 1.05-1.63), menopause (OR 1.47, 95% CI 1.16-1.88), and occupational exposure to vapours or dusts (OR 1.55, 95% CI 1.01-2.37). Nasal bleeding was reported as traces of blood by 16.5% of subjects, and as epistaxis (significant nasal bleeding) by 7.6%. Both symptoms were related to passive exposure to tobacco smoke (OR 1.63, 95% CI 1.22-2.19; OR 1.56, 95% CI 1.05-2.32, respectively) but not to use of systemic or topical medication. CONCLUSION: A substantial number of mature women experience nasal symptoms during the course of a year. Rhinitis and nasal bleeding were correlated with passive exposure to tobacco smoke.

Ability of lymphoscintigraphy to direct sentinel node biopsy in the clinically NO check for patients with head and neck squamous cell carcinoma; a prospective study (preliminary results).

Detection of metastasis involvement of lymph nodes is essential for management and prognostic evaluation in most cancer cases. The success of lymphatic mapping depends on identifying the sentinel lymph node(s) draining the primary tumour. In this preliminary study we prospectively evaluated the feasibility of sentinel node radio localisation in head and neck squamous cell carcinoma N0 stage to gain insight as to whether the sentinel lymph node (SLN) could be prognostic of regional metastasis disease or not. In 14 patients with squamous cell carcinoma of the head and neck region preoperative lymphoscintigraphy (LSG) mapping of the tumour was performed after subcutaneous injection of 22 to 30 MBq of Tc99m-labelled sulfur colloid. SLN was detected and localised by LSG in all patients with a gamma camera and a hand-held gamma probe. All the patients underwent surgery SLN and cervical nodes dissection. Six SLNs for five patients revealed occult metastasis disease. No skip metastasis were found in the 9 necks with negative SLN analysis. The results of this preliminary study are encouraging. They showed that SLN in squamous cell carcinoma of the head and neck N0 is accurately feasible and could predict the presence of occult metastasis. Nevertheless, more data are needed to validate these results.

[Pathology of myxoid bone tumors of the skull base]. / Tumeurs osseuses myxoïdes de la base du crâne: à propos de 9 cas.

Myxoid bone tumors of the skull encompass chordomas and chondrosarcomas. Their accurate diagnosis is usually a challenge and it is of utmost importance to identify chordomas because of the poorer prognosis. Even if the topography of the tumor is suggestive (median versus lateral), modern imaging is not specific enough and the diagnosis is based on histological features. We report nine cases of myxoid bone tumors of the skull including four chordomas, one chondroid chordoma and four chondrosarcomas. Smears are useful for rapid intraoperative diagnosis. Chondrosarcomas show cords of small round cells in a myxoid background while chordomas are made of multilayered sheets of larger, often vacuolated cells. Histology shows areas of cartilaginous matrix associated with myxoid areas in chondrosarcomas and in chondroid chordomas. Immunohistochemistry is determinant showing the expression of epithelial markers and Tau protein in chordomas only.

Functional outcome after gamma knife surgery or microsurgery for vestibular schwannomas.

OBJECT: Microsurgical excision is an established treatment for vestibular schwannoma (VS). In 1992 the authors used a patient questionnaire to evaluate the functional outcome and quality of life in a series of 224 consecutive patients. In addition, starting with gamma knife surgery (GKS) in 1992, the authors decided to use the same methodology to evaluate prospectively the results of this modality to compare the two alternatives. METHODS: Among the 500 patients who were included prospectively, the authors only evaluated patients in whom GKS was the primary treatment for unilateral VS. Four years of follow up was available for the first 104 consecutive patients. Statistical analysis of the GKS and microsurgery populations has shown that only a comparison of Stage II and III (according to the Koos classification) was meaningful in terms of group size and preoperative risk factor distribution. Objective results and questionnaire answers from the first 97 consecutive patients were compared with the 110 patients in the microsurgery group who fulfilled the inclusion criteria. Questionnaire answers indicated that 100% of patients who underwent GKS compared with 63% of patients who underwent microsurgery had no new facial motor disturbance. Forty-nine percent of patients who underwent GKS (17% in the microsurgery study) had no ocular symptoms, and 91% of patients treated with GKS (61% in the microsurgery study) had no functional deterioration after treatment. The mean hospitalization stay was 3 days after GKS and 23 days after microsurgery. All the patients who underwent GKS who had been employed, except one, had kept the same professional activity (56% in the microsurgery study). The mean time away from work was 7 days for GKS (130 days in the microsurgery study). Among patients whose preoperative hearing level was Class 1 according to the Gardner and Robertson scale, 70% preserved functional hearing after GKS (Class 1 or 2) compared with only 37.5% in the microsurgery group. CONCLUSIONS: Functional side effects happen during the first 2 years after radiosurgery. Findings after 4 years of follow up indicated that GKS provided better functional outcomes than microsurgery in this patient series.

Correlation of instrumental voice evaluation with perceptual voice analysis using a modified visual analog scale.

Various rating scales have been used for perceptual voice analysis including ordinal (ORD) scales and visual analog (VA) scales. The purpose of this study was to determine the most suitable scale for studies using perceptual voice analysis as a gold standard for validation of objective analysis protocols. The study was carried out on 74 female voice samples from 68 dysphonic patients and 6 controls. A panel of 4 raters with experience in perceptual analysis was asked to score voices according to the G component (overall quality) of the GRBAS system. Two rating scales were used. The first was a conventional 4-point ORD scale. The second was a modified VA (mVA) scale obtained by transforming the VA scale into an ORD scale using a weighted conversion scheme. Objective voice evaluation was performed using the EVA workstation. Objective measurements included acoustic, aerodynamic, and physiologic parameters as well as parameters based on nonlinear mathematics (e.g., Lyapunov coefficient). Instrumental measurements were compared with results of perceptual analysis using either the conventional ORD scale or mVA scale. Results demonstrate that correlation between perceptual and objective voice judgments is better using a mVA scale than a conventional ORD scale (concordance, 88 vs. 64%). Data also indicate that the mVA scale described herein improves the correlation between objective and perceptual voice analysis.

Acoustic and aerodynamic measurements of voice production after near-total laryngectomy with epiglottoplasty.

Objective voice analysis based on simultaneous aerodynamic and acoustic measurements is not common and there have been no reports dealing specifically with aerodynamic features of laryngeal performance after partial laryngectomy. The present study describes objective voice analysis after near-total laryngectomy using the Tucker technique (NTLT). We performed and compared acoustic and aerodynamic measurements in patients who underwent NTLT (n = 21) and normal controls (n = 10). Acoustic indexes of instability of frequency and intensity (jitter and shimmer) were always higher in patients. Oral airflow and estimated subglottic pressure (ESPG) were significantly greater in patients than in controls (400 vs. 169 cm(3)/s and 23 vs. 6.2 hPa, respectively). Poor closure of the glottis after surgery leads to a significant increase in glottal leakage in comparison with controls. Higher ESGP values observed in patients are probably related to two factors. The first involves compensation for glottal leakage in order to achieve sufficient air pressure to initiate vibration of the mucosa. The second factor is the poor vibratory quality of the residual mucosa, which may require higher pressure levels than the more compliant normal cord to initiate vibration. Our findings confirm the adverse effects of NTLT on the aerodynamic efficiency of the larynx due to glottal leakage and poor compliance of postoperative mucosa. Aerodynamic measurements could provide the basis for standardized objective evaluation of postoperative voice quality.