Nicolas Guevara

Cytopathologic detection of circulating tumor cells using the isolation by size of epithelial tumor cell method: promises and pitfalls.

Detection of circulating tumor cells (CTCs) morphologically may be a promising new approach in clinical oncology. We tested the reliability of a cytomorphologic approach to identify CTCs: 808 blood samples from patients with benign and malignant diseases and healthy volunteers were examined using the isolation by size of epithelial tumor cell (ISET) method. Cells having nonhematologic features (so-called circulating nonhematologic cells [CNHCs]) were classified into 3 categories: CNHCs with malignant features, CNHCs with uncertain malignant features, and CNHCs with benign features. CNHCs were found in 11.1% and 48.9% of patients with nonmalignant and malignant pathologies, respectively (P < .001). CNHCs with malignant features were observed in 5.3% and in 43.1% of patients with nonmalignant and malignant pathologies, respectively. Cytopathologic identification of CTCs using the ISET method represents a promising field for cytopathologists. The possibility of false-positive diagnosis stresses the need for using ancillary methods to improve this approach.

Diagnostic value of immunohistochemistry for the detection of the BRAF V600E mutation in papillary thyroid carcinoma: Comparative analysis with three DNA-based assays

BACKGROUND The aim of this study was to compare the detection of BRAF(V600E) by immunohistochemistry (IHC) using a mutation-specific antibody with molecular biology methods for evaluation of papillary thyroid carcinoma (PTC) patients. PATIENTS AND METHODS This study concerned 198 consecutive conventional PTC patients, of which the majority were women (133/198; 67%), with a mean age of 56 years (range 19-79 years). BRAF mutation analysis was performed using DNA-based (direct sequencing, pyrosequencing, and SNaPshot) and IHC (VE1 antibody) methods. The sensitivity and specificity of IHC for BRAF(V600E) was compared with the molecular biology data. RESULTS A BRAF mutational result was obtained in 194 cases. A BRAF(V600E) mutation was detected in 153/194 (79%) cases of PTC when using at least one molecular method, and in 151/194 (78%) cases with IHC. No false positive results were noted using IHC to detect the BRAF(V600E) mutation. Besides this mutation, other rare BRAF mutations (BRAF(V600K) and BRAF(K601E)), used as negative controls, were consistently negative with IHC. The sensitivity and specificity of IHC for the detection of this mutation were 98.7% and 100% respectively. The IHC test demonstrated excellent performance at a level equivalent to two DNA-based counterparts (pyrosequencing and SNaPshot). Failure to achieve a result was more frequent with the direct sequencing method than with the three other methods. CONCLUSION IHC using the VE1 antibody is a specific and sensitive method for the detection of the BRAF(V600E) mutation in PTC. IHC may be an alternative to molecular biology approaches for the routine detection of this mutation in PTC patients.

Thyroid tumours of uncertain malignant potential: frequency and diagnostic reproducibility

The term thyroid tumours of uncertain malignant potential (TT-UMP) has been proposed for a subgroup of follicular-patterned thyroid tumours for which benignancy or malignancy cannot be assessed with certainty. The frequency, diagnostic reproducibility, immunohistochemistry and molecular genetic profiling of such tumours have been poorly explored. We, therefore, investigated (1) the frequency of TT-UMP diagnosed in a single institution (Nice, France: 2004–2008), (2) the observer variation among four pathologists, (3) whether immunohistochemical and molecular genetic profiling of TT-UMP provide additional information concerning such lesions. A series of 31 diagnosed TT-UMP (2.9%) out of 1,078 consecutive thyroidectomies were analysed. It comprised 15 follicular thyroid tumours of UMP (FT-UMP) and 16 well-differentiated tumours of UMP (WDT-UMP). Observer concordance was 70% for all TT-UMP. More than 50% of FT-UMP expressed galectin-3 and CK19, whereas more than 50% of WDT-UMP expressed HBME-1. Five cases of TT-UMP showed N-RAS mutations, while one showed H-RAS mutation and another PAX8/PPARγ rearrangement. In conclusion, the frequency of TT-UMP is low in our institution. Diagnostic reproducibility is within the same range as other published data on follicular-patterned thyroid tumours. The ancillary methods have a low impact on aiding diagnosis of such lesions.

Usefulness of frozen section in rhinocerebral mucormycosis diagnosis and management

Aims: Rhinocerebral mucormycosis (RCM) is a well‐described fulminant fungal infection that presents acutely in patients with ketoacidosis and immunosuppression. Very early diagnosis, established with the demonstration of characterised hyphae in tissues, greatly improves the prognosis of RCM. In this regard, the specificity and the sensitivity of frozen section for the diagnosis and the surgical debridement of RCM were evaluated in this study. Methods and results: Frozen section was performed for the diagnosis (six of seven cases) and surgical treatment (three of seven cases) of RCM. In all cases, diagnosis was made by frozen section and confirmed by histological examination. Frozen section allowed radical surgical excision of infected tissue. In all cases, invasive, broad‐based non‐septated hyphae with branching at right angles were well demonstrated on toluidine blue staining. Cultures were positive for Rhizopus oryzae in three of seven cases. Outcome was favourable for five of seven patients and two patients died after the diagnosis. Conclusions: Frozen section is a specific and sensitive method to make both a quick initial diagnosis of RCM and to successfully eradicate the tissue infected by organisms belonging to the order Mucorales.

Multicenter Evaluation of the Digisonic SP Cochlear Implant Fixation System With Titanium Screws in 156 Patients

Objectives: We describe and evaluate the process of fixation of the Digisonic SP cochlear implant with two titanium screws. Methods: The characteristics of this implant allow cochlear implantation using a minimal incision, a subperiosteal pocket, and fixation with two titanium screws, without drilling a custom-fitted seat or creating suture-retaining holes in the skull. The fixation system relies on two tailfins for use of osseo-integratable screws, incorporated into the cochlear implant housing. The first version of this fixation system was modified after a case of device migration: The size of the titanium insert inside the silicone tailfin was increased. Data on 156 patients (8 months to 86 years of age) from a 4-year period in 6 cochlear implantation centers were retrospectively evaluated. Ten patients have undergone bilateral implantation. Results: Of 166 implantations, 4 postoperative infections and 1 device failure after head trauma were reported. No cerebrospinal fluid leaks or epidural hematomas were reported. One device migration was observed in the first series; no device migrations occurred in the second series. Conclusions: The fixation system with screws embedded in the Digisonic SP involves a fast and simple surgical technique that seems to efficiently prevent implant migration.

DENTALMAPS: Automatic Dental Delineation for Radiotherapy Planning in Head and Neck Cancer

PURPOSE To propose an automatic atlas-based segmentation framework of the dental structures, called Dentalmaps, and to assess its accuracy and relevance to guide dental care in the context of intensity-modulated radiotherapy. METHODS AND MATERIALS A multi-atlas-based segmentation, less sensitive to artifacts than previously published head-and-neck segmentation methods, was used. The manual segmentations of a 21-patient database were first deformed onto the query using nonlinear registrations with the training images and then fused to estimate the consensus segmentation of the query. RESULTS The framework was evaluated with a leave-one-out protocol. The maximum doses estimated using manual contours were considered as ground truth and compared with the maximum doses estimated using automatic contours. The dose estimation error was within 2-Gy accuracy in 75% of cases (with a median of 0.9 Gy), whereas it was within 2-Gy accuracy in 30% of cases only with the visual estimation method without any contour, which is the routine practice procedure. CONCLUSIONS Dose estimates using this framework were more accurate than visual estimates without dental contour. Dentalmaps represents a useful documentation and communication tool between radiation oncologists and dentists in routine practice. Prospective multicenter assessment is underway on patients extrinsic to the database.

MicroRNA-375/SEC23A as biomarkers of the in vitro efficacy of vandetanib.

In this study, we performed microRNA (miRNA) expression profiling on a large series of sporadic and hereditary forms of medullary thyroid carcinomas (MTC). More than 60 miRNAs were significantly deregulated in tumor vs adjacent non-tumor tissues, partially overlapping with results of previous studies. We focused our attention on the strongest up-regulated miRNA in MTC samples, miR-375, the deregulation of which has been previously observed in a variety of human malignancies including MTC. We identified miR-375 targets by combining gene expression signatures from human MTC (TT) and normal follicular (Nthy-ori 3-1) cell lines transfected with an antagomiR-375 inhibitor or a miR-375 mimic, respectively, and from an in silico analysis of thyroid cell lines of Cancer Cell Line Encyclopedia datasets. This approach identified SEC23A as a bona fide miR-375 target, which we validated by immunoblotting and immunohistochemistry of non-tumor and pathological thyroid tissue. Furthermore, we observed that miR-375 overexpression was associated with decreased cell proliferation and synergistically increased sensitivity to vandetanib, the clinically relevant treatment of metastatic MTC. We found that miR-375 increased PARP cleavage and decreased AKT phosphorylation, affecting both cell proliferation and viability. We confirmed these results through SEC23A direct silencing in combination with vandetanib, highlighting the importance of SEC23A in the miR-375-associated increased sensitivity to vandetanib. Since the combination of increased expression of miR-375 and decreased expression of SEC23A point to sensitivity to vandetanib, we question if the expression levels of miR-375 and SEC23A should be evaluated as an indicator of eligibility for treatment of MTC patients with vandetanib.

Necrotizing otitis externa: a systematic review.

Objective To carry out a systematic review of scientific evidence available about necrotizing otitis externa, emphasizing epidemiologic data, diagnosis criteria, treatment protocols, follow-up criteria, prognosis factors, and chronologic evolution. Data Sources PubMed/MEDLINE and the Cochrane Database of Systematic Reviews were searched for publications in English and French languages, between 1968 and October 1, 2011. Study Selection We included publications of all types including at least 6 cases. We excluded publications focused on cranial base osteomyelitis not originating from the external ear and publications limited to a specific population. Data Extraction We assessed publication quality according to international guidelines. Data Synthesis For each publication, data were entered in a spreadsheet software for analysis. We excluded individual data already published in other studies or reviews. Conclusion Our review revealed the absence of strong scientific evidence regarding diagnosis criteria, treatment protocols and follow-up criteria. This implies the use of highly empirical indexes of suspicion in clinical practice. Our review confirmed the existence of a typical but not exclusive population at risk (aged, male, and diabetic patient) and also revealed major issues: lack of primary prevention in population at risk, delays before referral and management, bacteriologic issues caused by antibiotic misuse (agent identification problems, rise of resistant strains), persistence of recurrent cases. A better diffusion of medical information should help improve the management of this severe disease.

Cochlear implantation surgery without posterior tympanotomy: Can we still improve it?

Conclusion: The amendments made to pre-existing transcanal approaches limit the possibility of extrusion of the electrode and reduce the time of ‘blind’ surgery. Objective: Alternative techniques to classic mastoidectomy and posterior tympanotomy for cochlear implantation have already been described but their main drawbacks result in either: (i) the risk of an electrode extrusion through the skin as the groove is drilled into the auditory canal or (ii) the risk of a facial nerve injury as the tunnel is drilled blindly into the posterior canal wall. The aim of this study was to describe and evaluate a new transcanal approach for cochlear implantation ruling out these difficulties. Patients and methods: Through a minimal retroauricular skin incision, a cochleostomy is performed directly via the auditory canal. The passage for the electrode is performed after drilling both a suprameatal hollow and a 1.5 mm hole into the superior-posterior canal wall, which opens the facial recess by an anterior approach. Thanks to this hole a transwall tunnel can afterwards be dug safely. Results: Twenty-three patients (8 adults, 15 children) were implanted without any difficulty. The mean follow-up was 22 months. No postoperative complication was observed.

Management of the Neck in the Setting of Definitive Chemoradiation: Is There a Consensus? A GETTEC Study

BackgroundThe management of the neck remains controversial in the definitive chemoradiation setting of advanced N2–3 head and neck squamous cell carcinoma. Most published data favor omission of neck dissection (ND) after complete response for N2–3 or selective ND for residual diseaseMethodsWe studied the patterns of care in the French-Belgian Groupe d’Etude des Tumeurs de la Tête Et du Cou (GETTEC) through a questionnaire-based survey.ResultsEighteen percent of institutions never performed up-front ND, 20% rarely, 40% sometimes, 14% often, and 8% systematically. Induction chemotherapy was indicated in 30% of the cases, and most ND were performed either between induction and radiation or after chemoradiation for residual disease. Response to chemoradiation was assessed by computed tomographic scan and positron emission tomography in 72% of cases. Selective ND was more common than radical ND.ConclusionsOmission of ND based on computed tomographic scan and positron emission tomography–based complete response to chemoradiation is the most common strategy for advanced nodal disease among centers. However, neck management strategies vary among institutions, and some institutions continue advocating systematic ND before irradiation. The new treatment options and the changing epidemiology, namely docetaxel-based induction chemotherapy and human papilloma virus–related head and neck squamous cell carcinoma having better response profiles and prognosis, are adding to the nonconsensual approach. The best therapeutic index in terms of neck management remains to be defined in this evolving context.