Solid amorphous formulations for enhancing solubility and inhibiting Erlotinib crystallization during gastric-to-intestinal transfer.

The objective of this study was to improve the solubility and inhibit the crystallisation during the gastric-to-intestinal transfer of Erlotinib (ERL), a small molecule kinase inhibitor (smKI) compound class, which is classified as class II drug in the Biopharmaceutical Classification System (BCS). A screening approach combining different parameters (solubility in aqueous media, inhibitory effect of drug crystallisation from supersaturated drug solutions) was applied to selected polymers for the development of solid amorphous dispersions of ERL. ERL solid amorphous dispersions formulations were then prepared with 3 different polymers (Soluplus®, HPMC-AS-L, HPMC-AS-H) at a fixed drug: polymer ratio (1:4) by two different production methods (spray drying and hot melt extrusion). The spray-dried particles and cryo-milled extrudates were characterized by thermal properties, shape and particle size, solubility and dissolution behavior in aqueous media. The influence of the manufacturing process on these solid characteristics was also identified during this study. Based on the obtained results, it is concluded that the cryo-milled extrudates of HPMC-AS-L displayed better performance (enhanced solubility, reduced ERL crystallization during the simulated gastric-to-intestinal transfer) and represents a promising amorphous solid dispersion formulation for oral administration of ERL.

Peripheral neck nerve tumor: A 73-case study and literature review.

OBJECTIVES: Peripheral neck nerve tumors are rare and mostly benign neoplasms. The exceptional malignant forms are very aggressive, and diagnosis is difficult. The objective of this study was to evaluate diagnostic and therapeutic management and identify possible predictive factors. MATERIAL AND METHODS: A retrospective study was conducted of 73 patients treated for peripheral neck nerve tumor between 1995 and 2015. RESULTS: Mean age was 44years. The main presenting symptom was a cervical mass, isolated or associated with signs related to the affected nerve structure. Diagnosis was suspected by slow progression of a firm mass, featuring T1 hyposignal and T2 hypersignal on magnetic resonance imaging. Surgery was performed in 99% of cases, completed by adjuvant chemotherapy in case of malignant neuroblastic tumor. Type 1 neurofibromatosis and sudden increase in mass with or without associated pain suggested malignant transformation. Age below 10years suggested neuroblastic tumor. CONCLUSION: Neck nerve tumors are very often benign with low degenerative potential. Surgery is the treatment of choice after risk/benefit analysis. However, there is no clearly defined consensus regarding the timing of surgery for these lesions.

Intraoperative bacterial analysis in nasal polyposis: Clinical and functional impact.

BACKGROUND: The impact of Staphylococcus aureus on onset of nasal polyposis has been the focus of numerous studies, but there have been few studies of other germs found in the ethmoid of operated patients or of their impact on post-operative results. MATERIAL AND METHODS: All patients undergoing endoscopic radical ethmoidectomy for nasal polyposis in the teaching hospital of Nantes (France) between 2006 and 2016 had intraoperative ethmoid cavity bacterial sampling. Phenotypic characteristics, pre- and post-operative symptoms and endoscopic findings were analyzed. Mann-Whitney tests and Kruskal-Wallis correlation analysis were used to assess clinical/bacteriological correlations. OBJECTIVES: The main objective was to describe bacterial colonization of patients undergoing surgery for nasal polyposis, and to assess correlations with phenotypic features, functional results and postoperative clinical course. RESULTS: One hundred and seven patients were included. A total of 26% were not infected, 55% mono-infected and 19% multi-infected. In 27.3%, staphylococci were isolated; in 30.5%, isolates were gram-negative bacilli. There were no significant correlations between presence or type of pathogen and symptom profile. CONCLUSION: This study confirmed the high rate of pathogenic bacteria in nasal cavities in case of polyposis, with high frequencies of S. aureus but also of gram-negative bacilli, raising the question of their involvement in the inflammatory reactions underlying the nasal polyposis.

Comparing "intra operative" tissue engineering strategies for the repair of craniofacial bone defects.

BACKGROUND: In craniofacial reconstruction, the gold standard procedure for bone regeneration is the autologous bone graft (BG). However, this procedure requiring bone harvesting is a source of morbidity. Bone substitutes, such as biphasic calcium phosphate (BCP), represent an interesting alternative but are not sufficient for bone healing in hypoplastic conditions. In such conditions, osteoprogenitors are essential to provide osteoinduction. Previous studies have shown that BCP associated with total bone marrow (TBM) provides same bone reconstruction as bone graft in a rat model of calvaria defect. Furthermore, adipose tissue stromal vascular fraction (SVF) seems to be another promising source of osteoprogenitor cells that can be used intra-operatively. This study aimed to combine, intra-operative BCP-based bone tissue engineering strategies with TBM or SVF from human sources. METHODS: 5 mm critical-size calvaria defects were performed in 18 nude rat. The defects were filled with intra-operative bone tissue engineering procedures: human BG, human TBM + BCP, human SVF + BCP and, rat TBM + BCP. Animals were sacrificed 8 weeks after implantation and calvaria were processed for histological and radiological examinations. Implanted cells were labelled with a fluorochrome. RESULTS: Micro-CT analysis revealed partial repair of bone defect. Only hBG significantly succeeded in healing the defect (43.1%). However, low rate of newly formed bone tissue was observed in all tissue engineering conditions (hTBM, hSVF, ratTBM). DISCUSSION: The lack of bone formation observed in this study could possibly be attributed to the model. CONCLUSION: This study combined with a literature analysis show the stringency of the nude rat calvaria model in term of bone regeneration.

Assessment of swallowing function after circumferential pharyngolaryngectomy. A multicenter study by the GETTEC group.

OBJECTIVE: Circumferential pharyngolaryngectomy is performed for advanced pharyngeal tumor or in a context of postradiation recurrence. Several free or pedicle flaps have been described for pharyngeal defect reconstruction, with choice at the surgeon's discretion. The aim of this study was to evaluate long-term swallowing function according to the type of flap used for reconstruction. MATERIAL AND METHOD: A multicenter retrospective study was conducted from January to September 2016 within the French GETTEC head and neck tumor study group. All patients in remission after circumferential pharyngolaryngectomy were included and filled out the Deglutition Handicap Index (DHI) questionnaire and underwent swallowing function fiberoptic endoscopy assessment. 46 patients (39 men, 7 women) were included. Reconstruction used a tubularized forearm free flap (FFF group) in 19 cases, pectoralis major myocutaneous flap (PMMF group) in 15 cases and free jejunum flap (FJF group) in 12 cases. RESULTS: Mean DHI was 24: 20 in the FFF group, 23 in the FJF group and 25 in the PMMF group, without significant differences. 27 patients had normal swallowing, 9 mixed diet, 8 liquid diet and 3 were fed by gastrostomy. On endoscopy, free flaps (FJF and FFF) were associated with significantly greater rates of normal swallowing of saliva and yogurt than in the PMMF group (P=0.04). CONCLUSION: Type of flap reconstruction after circumferential pharyngolaryngectomy had no significant impact on postoperative swallowing function assessed on the self-administered DHI questionnaire.

Outpatient management in plastic and reconstructive head and neck surgery in France.

The present review lays out the main principles governing outpatient management in the French health system in 2018, and more specifically in plastic and reconstructive head and neck surgery. The historical regulatory aspects and the changes of the last few years are explained, along with the trends and health authorities' expectations for the years to come. The main limitations to implementing outpatient procedures are the common to all surgical specialities, plastic and reconstructive head and neck surgery being no exception. Apart from purely technical aspects concerning surgical procedure and anesthesia, there are issues concerning institutional approval, the organization and continuity of health care, and the patient's environment. The French General Inspectorate of Social Affairs (IGAS), in its 2012 report on the assessment and pricing of hospital care and medical acts, stated that outpatient surgery was becoming standard practice and conventional admission a fall-back, with the aim of meeting the requirement to provide more care without more expenditure. Outpatient plastic and reconstructive head and neck surgery may be available for most patients, but still presupposes certain conditions.

International consensus (ICON) on assessment of oropharyngeal dysphagia.

OBJECTIVE: To present international recommendations regarding the proper evaluation of oropharyngeal dysphagia (OD), both objectively and subjectively (self-evaluation). METHODS: Following a thorough review of the literature, 5 experts in the field from 4 different continents answered separately a questionnaire regarding the work-up of OD. Individual answers were presented and discussed during the world ENT conference that was held in Paris in June 2017. This article will present the recommendations issued from that meeting. RESULTS: For the initial objective assessment of OD, it is recommended to perform either a functional endoscopic evaluation of swallowing (FEES) or a videofluoroscopic swallowing study (VFSS). FEES is the more popular investigation given its increased ease of use and accessibility. When evaluating for the presence of aspiration during the objective evaluation of OD, it is recommended to perform either a FEES or a VFSS. In this case, FEES is the favored investigation given its likely increased sensitivity. In order to highlight the presence of oropharyngeal food residue following the deglutition process, it is recommended to perform either a FEES or a VFSS; FEES likely being the more sensitive investigation while VFSS allows a better quantification of the amount of pharyngeal residue. Is it also recommended to objectify the quality of the deglutition process by means of a score during the objective evaluation of OD. Finally, it is recommended to utilize a self-evaluation questionnaire during research studies exploring the deglutition process.

Prognostic factors for parotid metastasis of cutaneous squamous cell carcinoma of the head and neck.

BACKGROUND: Cutaneous squamous cell carcinoma (CSCC) develops on the head in 80% of cases. Parotid metastasis (PM) is rare, but treatment, which associates surgery and radiation therapy, is heavy and prognosis poor. MATERIAL AND METHODS: All cases of parotidectomy for PM of CSCC of the head and neck between 2005 and 2015 were studied retrospectively. Epidemiologic, oncologic and therapeutic data were analyzed. Overall and specific survival were calculated following Kaplan-Meier. Log-rank and Cox models were used to identify prognostic factors for PM. OBJECTIVES: The principal study objective was to identify factors for survival in PM from CSCC of the head and neck. RESULTS: Thirty-five patients were included. Mean time to onset of PM was 13months. Overall 1-, 2- and 5-year survival was respectively 70, 66 and 59%. Independent prognostic factors comprised immunodepression, age at treatment, positive CSCC margins, macroscopic facial nerve involvement, and metastatic cervical adenopathies. CONCLUSION: The study confirmed an association of several independent prognostic factors at the stage of parotid lymph-node metastasis, related to patient, primary CSCC and PM. Complete primary resection is essential to reduce the risk of PM. Intensified radiologic and clinical surveillance should enable early diagnosis.

Sinonasal mucosal melanoma: A 44-case study and literature analysis.

OBJECTIVES: Sinonasal mucosal melanoma is a rare disease, representing 4% of nasal cavity and paranasal sinus malignancies. The aim of this study was to assess the clinical characteristics, progression and treatment of this disease and to identify prognostic factors. MATERIAL AND METHODS: This retrospective review presents a cohort of 44 patients treated for a melanoma arising from the nasal cavity and paranasal sinuses, in the ENT Head and Neck Surgery Department of the University Hospital of Nantes (France) between 1988 and 2015. RESULTS: Mean age at diagnosis was 71.2 years. The main signs at diagnosis were epistaxis and unilateral nasal obstruction. 25% of patients were initially classified as T4. Surgical treatment was performed in 42 patients. Postoperative radiotherapy was performed in 19 cases and adjuvant immunotherapy in 14 cases. Mean follow-up was 50 months. Cumulative overall survival was 71.5% at 1 year and 33% at 5 years. Clinically, headache, facial pain and trigeminal V2 nerve anesthesia were significant factors for poor prognosis. Exclusively nasal involvement was a factor for better overall survival than sinus involvement. Adjuvant radiation therapy showed a non-significant trend toward improved local control. CONCLUSIONS: Mucosal melanoma of the sinonasal cavities has poor prognosis due to high metastatic potential. Surgical resection followed by radiation therapy is the main treatment. There is no consensus regarding new systemic adjuvant treatments in this indication, unlike for primary cutaneous melanoma.

Diagnostic and prognostic contribution of laryngeal electromyography in unilateral vocal-fold immobility in adults.

OBJECTIVES: To study the diagnostic and prognostic contribution of laryngeal electromyography in unilateral vocal-fold immobility in adults. MATERIAL AND METHODS: A retrospective study included patients with unilateral vocal-fold immobility undergoing laryngeal electromyography between 2007 and 2015. Neurogenic, normal or myogenic findings were compared to the clinical aspect. Prognosis for recovery was assessed from motor unit potentials on laryngeal electromyography, and compared to subsequent progress on laryngoscopy. RESULTS: Sixty-three patients (mean age, 59 years) were initially included; 2 were subsequently excluded from analysis. Mean time from onset of immobility to laryngeal electromyography was 7 months. 85% of the 61 patients showed neurogenic findings, indicating neural lesion; 13% showed normal electromyography, indicating cricoarytenoid joint ankylosis; and 1 patient showed a myogenic pattern. Neurogenic cases were usually secondary to cervical surgery. Thirty-eight patients were followed up. In total, 75% of patients showing reinnervation potentials recovered. The positive predictive value of laryngeal electromyography was 69.2%. CONCLUSION: Laryngeal electromyography is effective in specifying the origin of unilateral vocal-fold immobility in adults. It also has a prognostic role, lack of reinnervation potentials being a possible indication for early medialization surgery.

Perturbation of a radially oscillating single-bubble by a micron-sized object.

A single bubble oscillating in a levitation cell is acoustically monitored by a piezo-ceramics microphone glued on the cell external wall. The correlation of the filtered signal recorded over distant cycles on one hand, and its harmonic content on the other hand, are shown to carry rich information on the bubble stability and existence. For example, the harmonic content of the signal is shown to increase drastically once air is fully dissociated in the bubble, and the resulting pure argon bubble enters into the upper branch of the sonoluminescence regime. As a consequence, the bubble disappearance can be unambiguously detected by a net drop in the harmonic content. On the other hand, we perturb a stable sonoluminescing bubble by approaching a micron-sized fiber. The bubble remains unperturbed until the fiber tip is approached within a critical distance, below which the bubble becomes unstable and disappears. This distance can be easily measured by image treatment, and is shown to scale roughly with 3-4 times the bubble maximal radius. The bubble disappearance is well detected by the drop of the microphone harmonic content, but several thousands of periods after the bubble actually disappeared. The delay is attributed to the slow extinction of higher modes of the levitation cell, excited by the bubble oscillation. The acoustic detection method should however allow the early detection and imaging of non-predictable perturbations of the bubble by foreign micron-sized objects, such as crystals or droplets.

Vascular imaging with contrast agent in hard and soft tissues using microcomputed-tomography.

Vascularization is essential for many tissues and is a main requisite for various tissue-engineering strategies. Different techniques are used for highlighting vasculature, in vivo and ex vivo, in 2-D or 3-D including histological staining, immunohistochemistry, radiography, angiography, microscopy, computed tomography (CT) or micro-CT, both stand-alone and synchrotron system. Vascularization can be studied with or without a contrast agent. This paper presents the results obtained with the latest Skyscan micro-CT (Skyscan 1272, Bruker, Belgium) following barium sulphate injection replacing the bloodstream in comparison with results obtained with a Skyscan In Vivo 1076. Different hard and soft tissues were perfused with contrast agent and were harvested. Samples were analysed using both forms of micro-CT, and improved results were shown using this new micro-CT. This study highlights the vasculature using micro-CT methods. The results obtained with the Skyscan 1272 are clearly defined compared to results obtained with Skyscan 1076. In particular, this instrument highlights the high number of small vessels, which were not seen before at lower resolution. This new micro-CT opens broader possibilities in detection and characterization of the 3-D vascular tree to assess vascular tissue engineering strategies.

Cervicofacial non-tuberculous mycobacteria: A report of 30 cases.

BACKGROUND: Mycobacterial infection is the most common cause of cervical granuloma, implicating either a tuberculous or a non-tuberculous mycobacterium (NTM). NTM is a ubiquitous organism, found in soil, water, food, etc. The most frequently implicated is Mycobacterium avium-intracellular. Most authors agree that NTM is increasingly isolated, due to a decrease in vaccination rates. Initial diagnosis is difficult and management is not clearly codified. METHODS: A retrospective study conducted in the University Hospital of Nantes, France, between 2005 and 2014, included all patients treated for head and neck NTM lymphadenitis. The research was conducted on the database of the institution's bacteriology department. Population, history, symptoms and diagnostic features were noted. Treatment, surgical complications, adverse reactions to antibiotics, patient adherence, antibiotic therapy duration, time to remission and prognosis were analyzed. RESULTS: Between 2005 and 2014, 30 patients were diagnosed with head and neck NTM lymphadenitis: 17 female, 13 male; mean age at diagnosis, 4.5 years. Locations were submandibular (n=16), parotid, (n=7), cervical (n=5), parapharyngeal (n=4) and, for 1 patient, in the auricle concha. Eight patients received first-line surgical treatment, which was effective in 75% of cases, 2 patients requiring additional antibiotic therapy. Twenty-two patients were treated with first-line antibiotherapy, which was effective in 90% of cases. There were no relapses at a mean 32 weeks' follow-up. CONCLUSIONS: Total resection of all affected nodes and infiltrated subcutaneous fatty tissue is the treatment of choice. Drug therapy (including at least a macrolide) seems indicated only in case of incomplete resection or if surgery would entail functional and/or esthetic risk. Increased incidence, since BCG vaccination was stopped, will continue to confront the practitioner with an infantile disease in which management must be multidisciplinary.

'Canalization' of the frontal sinus: a functional approach for the management of post-traumatic sinusitis with lateral bony septa. Report of two cases and long-term follow-up.

The patency of the naso-frontal duct is a key issue in the surgical management of chronic frontal sinusitis. Most of the current operative techniques only provide access to the paramedian portions of the frontal sinus. A canalization approach that allows a functional frontal sinus to be maintained while providing good access to the most lateral areas of the sinus is described herein. Two cases of severe post-traumatic frontal sinusitis, operated on successfully by canalization method based on the conservation of the frontal sinus and the maintenance of the patency of the naso-frontal duct, using both open and endonasal approaches, are reported. One patient was followed-up for 8 years and the other for 7 months. Canalization requires validation in a larger series. This approach provides an alternative to both cranialization and strictly endoscopic methods in lateralized frontal sinus retentions and allows mucocele to be avoided.

Isolated lateral semicircular canal aplasia: Functional consequences.

INTRODUCTION: Lateral semicircular canal aplasia is a malformation of the inner ear, usually associated with vestibular and cochlear malformations in the context of congenital malformation syndromes. We report a rare case of a young patient with isolated lateral semicircular canal aplasia and no associated vestibular symptoms. CLINICAL CASE SUMMARY: A 20-year-old man with no personal or family history presented with persistent unilateral tinnitus for three years with no associated vestibular symptoms. Moderate unilateral right sensorineural hearing loss was detected. Magnetic resonance imaging demonstrated isolated aplasia of the right lateral semicircular canal. Videonystagmography revealed right hyporeflexia. Vestibular evoked myogenic potentials were absent after stimulation on the right side and normal on the left side. DISCUSSION: Although the morphological abnormalities appeared to be isolated on imaging, the patient presented functional signs of global cochlear, semicircular canal and otolithic lesions, probably related to a developmental disorder of the membranous labyrinth. Functional investigations must be performed in the presence of isolated semicircular canal aplasia, even when it is an incidental finding, to exclude more extensive labyrinthine lesions.

Theoretical model of ice nucleation induced by inertial acoustic cavitation. Part 2: Number of ice nuclei generated by a single bubble.

In the preceding paper (part 1), the pressure and temperature fields close to a bubble undergoing inertial acoustic cavitation were presented. It was shown that extremely high liquid water pressures but quite moderate temperatures were attained near the bubble wall just after the collapse providing the necessary conditions for ice nucleation. In this paper (part 2), the nucleation rate and the nuclei number generated by a single collapsing bubble were determined. The calculations were performed for different driving acoustic pressures, liquid ambient temperatures and bubble initial radius. An optimal acoustic pressure range and a nucleation temperature threshold as function of bubble radius were determined. The capability of moderate power ultrasound to trigger ice nucleation at low undercooling level and for a wide distribution of bubble sizes has thus been assessed on the theoretical ground.

Theoretical model of ice nucleation induced by acoustic cavitation. Part 1: Pressure and temperature profiles around a single bubble.

This paper deals with the inertial cavitation of a single gas bubble in a liquid submitted to an ultrasonic wave. The aim was to calculate accurately the pressure and temperature at the bubble wall and in the liquid adjacent to the wall just before and just after the collapse. Two different approaches were proposed for modeling the heat transfer between the ambient liquid and the gas: the simplified approach (A) with liquid acting as perfect heat sink, the rigorous approach (B) with liquid acting as a normal heat conducting medium. The time profiles of the bubble radius, gas temperature, interface temperature and pressure corresponding to the above models were compared and important differences were observed excepted for the bubble size. The exact pressure and temperature distributions in the liquid corresponding to the second model (B) were also presented. These profiles are necessary for the prediction of any physical phenomena occurring around the cavitation bubble, with possible applications to sono-crystallization.