Functional or radical surgical treatment of laryngeal chondrosarcoma, analysis of survival and prognostic factors: A REFCOR and NetSarc-ResOs multicenter study of 74 cases.

INTRODUCTION: Laryngeal chondrosarcoma (LCS) is a rare tumor of slow evolution whose treatment is poorly codified. For a long time, a radical treatment by total laryngectomy (TL) was proposed. More recent studies tend to propose a conservative surgical approach of the larynx. The objective of this study was to compare the overall survival (OS) of total laryngectomized patients (TL+) versus non-laryngectomized patients (TL-). The secondary objectives were to analyse the reoperation free survival (RFS), the total laryngectomy free survival (TLFS) and to identify the preoperative factors leading surgeons to propose TL. MATERIALS AND METHODS: A retrospective analysis of prospectively collected incident cases from the REFCOR and NetSarc-ResOs multicenter databases between March 1997 and June 2021 was conducted. A propensity score matching analysis was performed to compare the OS of TL+ and TL-patients. RESULTS: 74 patients were included. After propensity score, the 5-year OS of TL+ and TL-patients was comparable (100 %, p = 1). The 5-year RFS rate was 69.2 % (95 % CI [57.5-83.4]) and the 5-year TLFS was 61.7 % (95 % CI [50.4-75.5]). Cricoid involvement greater than 50 % (HR 3.58; IC 95 % [1.61-7.92] p < 0.001), an ASA score of 3 or 4 (HR 5.07; IC 95 % [1.64-15.67] p = 0.009) and involvement of several cartilages (HR 5.26; IC 95 % [1.17-23.6] p = 0.04) are prognostic factors for TL. Dyspnea caused by the tumour is a prognostic factor for reoperation (HR 2.59; IC 95 % [1.04-6.45] p = 0.03). CONCLUSION: These results demonstrate that conservative treatment should be considered as first-line treatment for laryngeal chondrosarcoma.

Effect of nasal airway nonlinearities on oscillometric resistance measurements in infants.

Oscillometric measurements of respiratory system resistance (Rrs) in infants are usually made via the nasal pathways, which not only significantly contribute to overall Rrs but also introduce marked flow (V')-dependent changes. We employed intrabreath oscillometry in casts of the upper airways constructed from head CT images of 46 infants. We examined oscillometric nasal resistance (Rn) in upper airway casts with no respiratory flow (R0) and the effect of varying V' on Rn by simulating tidal breathing. A characteristic nonlinear relationship was found between Rn and V', exhibiting segmental linearity and a prominent breakpoint (V'bp) after log-log transformation. V'bp was linearly related to the preceding value of end-expiratory volume acceleration (V″eE; on average r2 = 0.96, P < 0.001). Rn depended on V', and R at end-expiration (ReE) showed a strong dependence on V″eE in every cast (r2 = 0.994, P < 001) with considerable interindividual variability. The intercept of the linear regression of ReE versus V″eE was found to be a close estimate of R0. These findings were utilized in reanalyzed Rrs data acquired in vivo in a small group of infants (n = 15). Using a graphical method to estimate R0 from ReE, we found a relative contribution of V'-dependent nonlinearity to total resistance of up to 33%. In conclusion, we propose a method for correcting the acceleration-dependent nonlinearity error in ReE. This correction can be adapted to estimate R0 from a single intrabreath oscillometric measurement, which would reduce the masking effects of the upper airways on the changes in the intrathoracic resistance.NEW & NOTEWORTHY Oscillometric measurements of respiratory system resistance (Rrs) in infants are usually made via the nasal pathways, which not only significantly contribute to overall Rrs but also introduce marked flow acceleration-dependent distortions. Here, we propose a method for correcting flow acceleration-dependent nonlinearity error based on in vitro measurements in 3D-printed upper airway casts of infants as well as in vivo measurements. This correction can be adapted to estimate Rrs from a single intrabreath oscillometric measurement.

Genomics and precision surgery for head and neck squamous cell carcinoma.

The identification of the biological determinants that shape the response of tumors to medical therapies offers perspectives for better patient stratification and therapeutic targeting. Here, we discuss how genomics could help to improve the surgical treatment of head and neck squamous cell carcinoma (HNSCC). We examine the potential use of genomic analyses for: i) refining and standardizing the indications for surgery, ii) the choice of surgical procedure, and iii) the follow-up of patients with resected tumors. We highlight the studies that used genomics to explore the contribution of tumor biology to the outcome of surgery. We discuss the important developments that are challenging current surgical practice in HNSCC, such as neoadjuvant immunotherapy and the analysis of circulating DNA. Genomic analyses provide practical tools that could help improve the pathological diagnosis and staging of HNSCC, and increase the appreciation of the importance of tumor biology in the outcome of surgery. Identification of biomarkers will likely contribute to a move toward precision surgery of HNSCC, i.e. the personalization of surgical practice based on tumor biology.

A three-gene expression signature associated with positive surgical margins in tongue squamous cell carcinomas: Predicting surgical resectability from tumour biology?

OBJECTIVES: Achieving complete tumour resection is one of the main goals of surgery for head and neck squamous cell carcinoma (HNSCC) tumours. Whether biological characteristics of tumours contribute to the surgical resectability and the presence of positive surgical margins (SM) after resection of HNSCC is unclear. We aimed to address this issue. MATERIALS AND METHODS: We used data from The Cancer Genome Atlas (TCGA) to relate the SM status of 356 HNSCC tumours covering five major primary locations (tongue, larynx, tonsils, floor of mouth and buccal mucosa) with data from multiple omics approaches (transcriptomic, genomic and proteomic analyses). RESULTS: We identified three differentially expressed genes whose expression was significantly associated with the presence of positive SM in tongue tumours (n = 144). The three genes (CCDC66, ZRANB2 and VCPKMT) displayed significantly higher mRNA levels in tongue tumours with positive SM compared to tumours with negative SM. The corresponding gene expression signature identified tongue tumours with a positive SM with high sensitivity and specificity (85% and 76%, respectively, Area Under the Curve (AUC) = 0.84). Tongue tumours with this signature were characterised by a high grade, elevated proliferation levels and a tumour stroma with fewer fibroblasts and endothelial cells. CONCLUSION: Positive SM were found to be strikingly associated with tumour biology in tongue tumours. These findings offer interesting perspectives for biomarker identification and precision surgery in these tumours.

Otitis media with effusion in children: Pathophysiology, diagnosis, and treatment. A review.

Otitis media with effusion (OME) is a frequent paediatric disorder. The condition is often asymptomatic, and so can easily be missed. However, OME can lead to hearing loss that impairs the child's language and behavioural development. The diagnosis is essentially clinical, and is based on otoscopy and (in some cases) tympanometry. Nasal endoscopy is only indicated in cases of unilateral OME or when obstructive adenoid hypertrophy is suspected. Otitis media with effusion is defined as the observation of middle-ear effusion at consultations three months apart. Hearing must be evaluated (using an age-appropriate audiometry technique) before and after treatment, so as not to miss another underlying cause of deafness (e.g. perception deafness). Craniofacial dysmorphism, respiratory allergy and gastro-oesophageal reflux all favour the development of OME. Although a certain number of medications (antibiotics, corticoids, antihistamines, mucokinetic agents, and nasal decongestants) can be used to treat OME, they are not reliably effective and rarely provide long-term relief. The benchmark treatment for OME is placement of tympanostomy tubes (TTs) and (in some cases) adjunct adenoidectomy. The TTs rapidly normalize hearing and effectively prevent the development of cholesteatoma in the middle ear. In contrast, TTs do not prevent progression towards tympanic atrophy or a retraction pocket. Adenoidectomy enhances the effectiveness of TTs. In children with adenoid hypertrophy, adenoidectomy is indicated before the age of 4 but can be performed later when OME is identified by nasal endoscopy. Children must be followed up until OME has disappeared completely, so that any complications are not missed.

Usefulness of ENT clinical examinations in hospitalised patients chronically addicted to alcohol and tobacco to detect head and neck squamous cell carcinomas. A retrospective study of 159 patients.

OBJECTIVE: To determine whether an ENT clinical screening examination done on all patients chronically addicted to alcohol or tobacco would allow the early diagnosis of cancer of the upper aerodigestive tract. STUDY DESIGN: Case series with chart review. SETTING: Non-university general hospital. SUBJECTS AND METHODS: A total of 159 patients presenting chronic addiction to alcohol or tobacco hospitalized in an addiction center or a comprehensive medical clinic were included in this study covering the period 2011-2016. All patients systematically benefitted from an ENT clinical examination to detect mucous membrane lesions. The lesions were categorized as: cancerous, pre-cancerous, or benign. The patients were divided into two groups for comparison: 1) patients with symptoms (dysphagia, dysphonia, dyspnea upon inhalation, cervico-facial pain, secondary otalgia, pharyngeal discomfort unrelated to deglutition, presence of a cervical swelling, or weight loss), and 2) asymptomatic patients. RESULTS: The ENT exam was normal in 121 patients (76.1%). Fifty-two patients (32.7%) had at least one symptom. The ENT exam allowed us to detect a benign lesion in 11 patients, a pre-cancerous lesion in 11 patients, and a cancer in 16 (13.22%) patients. All patients with cancer had at least one symptom. CONCLUSION: An ENT clinical screening examination done on patients chronically addicted to alcohol or tobacco can allow early diagnosis of cancer, particularly in patients with at least one symptom.

Tympanostomy tubes for serous otitis media and risk of recurrences.

OBJECTIVES: To determine the value of tympanostomy tubes (TTs) in the management of serous otitis media (SOM) and the risk factors for SOM recurrence. METHOD: This single-centre cohort study was performed in the University hospital of Amiens, France; and concerned 215 under-12 children having undergone at least one bilateral TT (Shepard grommet-type) placements for SOM. RESULTS: The mean TT retention time was 10 months. SOM recurred in 79 children (62.79%) and thus required a second TT placement (bilaterally in 90% of these cases). Overall, 29.3% of the patients underwent a total of two TT placements, 5.58% underwent three placements and 0.93% underwent four placements. After their first-ever TT placement, 17 children had complications: 10 cases of otorrhoea (4.6%), 4 cases of retraction pocket (1.9%) and 3 perforations of the tympanic membrane (1.4%). At last follow-up, the most common complications were tympanosclerosis (6.9%) and perforation of the tympanic membrane (6.5%). In a multivariate analysis, the only significant risk factors for SOM recurrence were age below 48 months at the time of TT placement, and a TT retention time below 9 months. In contrast, a history of allergy, gastro-oesophageal reflux, prematurity or passive smoking were not significantly associated with recurrence. CONCLUSION: Age at the time of TT placement and the TT retention time were significantly associated with SOM recurrence. The TT retention time and the number of TT placements were not associated with the risk of long-term complications.

PCR-based detection of Aspergillus fumigatus and absence of azole resistance due to TR34 /L98H in a french multicenter cohort of 137 patients with fungal rhinosinusitis.

Fungal rhinosinusitis (FRS) has a worldwide distribution, comprises distinct clinical entities but is mostly due to Aspergillus among which Aspergillus fumigatus plays a major role in European countries. Although, there is accumulating evidence for the emergence of environmentally acquired-azole resistance in A. fumigatus (such as TR34 /L98H) in various clinical settings, there is few data for patients with FRS. In this study, we aimed to investigate the prevalence of A. fumigatus azole resistance due to TR34 /L98H in a multicentre cohort of patients with FRS. One hundred and thirty-seven patients with FRS admitted between 2002 and 2016 at four French medical centres were retrospectively enrolled. Clinical and mycological findings were collected. Aspergillus fumigatus and the TR34 /L98H alteration conferring azole resistance were investigated directly from clinical samples using the commercial CE-IVD marked MycoGENIE® A. fumigatus real-time PCR assay. Fungal ball was the more frequent clinical form (n = 118). Despite the presence of fungal hyphae at direct microscopic examination, mycological cultures remained negative for 83 out of the 137 patients (60.6%). The PCR assay proved to be useful allowing the identification of A. fumigatus and etiological diagnosis in 106 patients (77.4%) compared with 44 patients (32.1%) when using culture as the reference method. Importantly, neither TR34 nor L98H alterations were evidenced.

A case of acute clival osteomyelitis in a 7-year-old boy secondary to infection of a Thornwaldt cyst.

Clival osteomyelitis is a potentially life-threatening infection that can occur in healthy children. It can be related to congenital anomalies. We report the case of a 7-year-old boy with Streptococcus intermedius and Fusobacterium clival osteomyelitis arising from a Thornwaldt cyst situated in a fossa navicularis magna of the occipital bone. Multidisciplinary management is necessary to ensure rapid improvement and complete healing.

Therapeutic Management of Pyriform Sinus Cancer.

Objective To analyze the survival rate of a nonselected pyriform sinus cancer population. Study Design Case series with chart review. Setting University hospital. Subjects and Methods A total of 122 patients were included in this study covering the 2002-2008 period. All patients had squamous cell carcinoma originating from the pyriform sinus. Survival and prognostic factors were analyzed. Results The 3- and 5-year overall survival rates were 39.7% and 2.4%, respectively. The 3- and 5-year survival rates without recurrence were 34% and 27%, respectively. The median survival rates by UICC stage were as follows: stage 1 and 2 patients, 60 months; stage 3, 40 months; stage 4, 19 months. Stage 4 patients had a lower median survival rate than other stages ( P = .039). The 5-year survival rate was 46% for patients having T3-T4 operable cancers treated by surgery vs 45% for patients treated by laryngeal conservation protocol (not significant). The 5-year survival rate for patients having nonoperable T4 cancers was 17.2%. The 3- and 5-year overall survival rates of N0 patients was significantly higher than N1 patients ( P = .042). N2 and N3 patients had 100% 5-year mortality. Conclusion This study showed that overall survival and therapeutic management depend on the initial stage of pyriform sinus cancer, notably on the N status. In particular, nonoperable T4 pyriform sinus cancer and N2 and N3 patients had a very poor prognosis. A laryngeal conservation protocol seemed as effective as surgical management in terms of survival.

Oncologic outcomes of patients with positive margins after laser cordectomy for T1 and T2 glottic squamous cell carcinoma.

BACKGROUND: The oncologic impact of surgical margins after transoral laser microsurgery (TLM) for T1 and T2 glottic carcinoma is controversial. The purpose of this study was to assess the prognostic value of margin status in terms of local control. METHODS: Records of 266 patients treated from 1990 to 2013 were evaluated. Patients with previous cordectomy or without preoperative CT scan were excluded from the study. RESULTS: A total 110 patients (85 T1a, 8 T1b, and 17 T2) were enrolled. A local recurrence was observed in 23 patients. Five-year disease-free survival was significantly impaired in patients with positive margins (p = .009) and in patients with deep involvement of the vocal muscle (p = .004). CONCLUSION: The present study shows that invaded margin is a factor of poor local control even though laser vaporization was systematically applied after resection. In case of deep vocal fold involvement, TLM should be extended beyond the vocal muscle to improve local control. © 2016 Wiley Periodicals, Inc. Head Neck 38: 1804-1809, 2016.

Short-term culture of tumour slices reveals the heterogeneous sensitivity of human head and neck squamous cell carcinoma to targeted therapies.

BACKGROUND: Despite recent progress, investigating the impact of targeted therapies on Head and Neck Squamous Cell Carcinoma (HNSCC) remains a challenge. We investigated whether short-term culture of tumour fragments would permit the evaluation of tumour sensitivity to targeted therapies at the individual level. METHODS: We cultivated tumour slices prepared from 18 HNSCC tumour samples obtained during surgical resection. The samples were treated for 48 h with a panel of 8 targeted therapies directed against selected oncogenic transduction pathways. We analysed the cell proliferation index (CPI) of tumour cells using Ki67 labelling and the activation status of the RAF-MEK-ERK cascade through ERK phosphorylation analysis. RESULTS: Fourteen tumours were successfully analysed after short-term culture of tumour samples, revealing a striking individual heterogeneity of HNSCC in terms of tumour cell sensitivity to targeted therapies. Using 50% inhibition of CPI as threshold, sorafenib was shown to be active in 5/14 tumours. Cetuximab, the only approved targeted drug against HNSCC, was active in only 2/14 tumours. A more than 50% inhibition was observed with at least one drug out of the eight tested in 10/14 tumours. Cluster analysis was carried out in order to examine the effect of the drugs on cell proliferation and the RAF-MEK-ERK cascade. CONCLUSIONS: In vitro culture of tumour fragments allows for the evaluation of the effects of targeted therapies on freshly resected human tumours, and might be of value as a possible guide for the design of clinical trials and for the personalization of the medical treatment of HNSCC.

Personalization of the medical treatment of solid tumours using patient-derived tumour explants (Review).

Improving the pre-clinical characterization of therapeutic approaches and developing new biological assays that will enable treatment personalization for individual patients are promising developments in oncology. Here we describe a new approach consisting of culturing human tumour explants. This approach involves the preparation of slices from freshly-obtained, surgically-resected material that can be maintained ex vivo for several days. Recent studies have provided proof of principle that this approach can be easily implemented in order to explore the mode of action of various anticancer drugs and the responses of 'real' tumours at the individual patient level. We present the practical aspects and highlight the versatility of this approach, which allows for the analysis of the susceptibility of any individual tumour to multiple anticancer drugs in parallel. We discuss its potential as a companion assay in the design of optimal clinical trials and as a guide for the prescription of medical treatment. We discuss which future clinical and biological studies are needed to validate the information gathered from cultured tumour explants, and to integrate this information with that gathered from other assays in order to optimize the medical treatment of cancer.

Evaluation of individual sensitivity of head and neck squamous cell carcinoma to cetuximab by short-term culture of tumor slices.

BACKGROUND: Cetuximab is a targeted therapy with demonstrated efficacy in the management of head and neck squamous cell carcinoma (HNSCC). However, no laboratory assay is available to predict its efficacy in an individual patient. METHODS: Short-term cultures of tumor slices were performed on 9 tumor samples obtained after surgical resection in patients. Cancer cell proliferation was evaluated by immunohistochemistry and the impact of cetuximab on cell proliferation was examined. RESULTS: Tumor architecture and the heterogeneous composition of HNSCC were preserved for at least 48 hours during short-term culture of tumor slices. HNSCC cells demonstrated a heterogeneous individual response to cetuximab. CONCLUSION: Short-term culture of tumor slices is a strategy to estimate the clinical activity of cetuximab in individual patients with HNSCC. Further studies are required to correlate the results obtained with the clinical response of individual patients to cetuximab. © 2015 Wiley Periodicals, Inc. Head Neck 38: E911-E915, 2016.

Human parvovirus B19 and autoimmune diseases. Review of the literature and pathophysiological hypotheses.

A number of arguments support the role played by PVB19 in autoimmunity, in the broad sense of the term essentially derived from numerous clinical case reports and/or small series over the past 20-30 years in the medical literature. PVB19 can induce a very broad spectrum of autoantibody production, especially including: anti-soluble nuclear antigen antibodies, antiphospholipid antibodies anti-native DNA antibodies, antilymphocyte antibody, anticardiolipin antibodies, antinuclear antibodies and rheumatoid factor. Notably acute PVB19 infection can mimic or stimulate autoimmune systemic diseases as rheumatoid arthritis or systemic lupus erythematosus. However, at the present time, there is no formal scientific evidence demonstrating a direct role of PVB19 in autoimmunity, bearing in mind that there are also no formal arguments against it. Further large studies are needed to understand the eventual role of PVB19 in autoimmune diseases.

Immunohistochemical- and PCR-based assay for the reproducible, routine detection of erythrovirus B19 in thyroid tissues.

It is generally accepted that thyroid follicle cells are at least semi-permissive for erythrovirus B19 (EVB19). Thus, various laboratory techniques have been successfully used to detect EVB19 in the thyroid gland, including polymerase chain reaction (PCR), immunohistochemistry, and in situ hybridization. However, the detection of EVB19 within the thyroid gland is problematic, and none of the detection protocols in the literature have been unequivocally validated. This multidisciplinary study in which 32 thyroidectomy subjects undergoing thyroidectomy in a French University hospital were prospectively recruited was performed over a period of 3 years. Prior to surgery, all the subjects were assayed for blood levels of anti-EVB19 antibodies and (using a quantitative PCR [qPCR] assay) EVB19 itself. A qPCR assay for EVB19 and an immunohistochemical assay (based on polyclonal anti-VP2 antibodies) were performed on the thyroidectomy samples. None of the subjects had an acute EVB19 infection. A viral load was detected in two serum samples and six thyroid biopsies. Three subjects had both a positive immunohistochemical assay and a positive qPCR assay for the thyroid tissue. It is noteworthy that the thyroid immunohistochemical and qPCR assays were negative in the two patients with detectable serum loads of EVB19. In conclusion, EVB19 can be detected in thyroid follicle cells by using immunohistochemical and qPCR assays. Ideally, patients should be tested with both PCR and immunohistochemical assays, in order to unequivocally confirm or rule out the presence of EVB19 in the thyroid gland. The present protocol must now be validated in larger series--notably with respect to its reliability and in order to determine qPCR positivity thresholds for application in future large-scale studies.

Erythrovirus B19 and autoimmune thyroid diseases. Review of the literature and pathophysiological hypotheses.

Erythrovirus B19 (EVB19) has been incriminated, over recent years, in the onset and/or pathogenesis of many diseases, especially autoimmune thyroid diseases. This review of the literature (published over the last 40 years using Pubmed and Science Direct search engines) was designed to define the role of EVB19, particularly in autoimmune thyroid diseases.Two cases of subacute thyroiditis, one case of Graves' disease (associated with type 1 diabetes and rheumatoid arthritis), and one case of Hashimoto's thyroiditis following acute EVB19 infection were reported. A retrospective case-control study in a pediatric population demonstrated the role of EVB19 in Hashimoto's thyroiditis. Four retrospective studies of pathology slides (including PCR, immunohistochemistry or in situ hybridization) and a prospective case-control study on pathology slides demonstrated the presence of EVB19 in thyroid tissue of patients with benign multinodular goiter, Graves' disease, autoimmune thyroiditis (including Hashimoto's thyroiditis), and thyroid cancer. EVB19 can be demonstrated in the thyroid gland in a wide range of diseases. Although acute EVB19 infection could theoretically trigger autoimmune thyroid disease, there is currently no evidence that EVB19 plays a specific role in the pathophysiology of autoimmune thyroid diseases.