Search for Prognostic Biomarkers in Inoperable and / or Metastatic Mucosal Melanoma; : Translational Regulation of SOX10 by Hexokinase 2 and Modulation of Tumor Aggressiveness in Cutaneous Melanoma

Les mélanomes muqueux sont rares avec un potentiel métastatique important. L’immunothérapie est un traitement prometteur dans ce sous-type agressif de mélanome. L’analyse de biomarqueurs de réponse à une immunothérapie anti-PD1 chez 23 patients présentant un mélanome muqueux non opérable et/ou métastatique a montré que l’activation du complexe d’initiation de la traduction, eIF4F, était fortement prédictive de cette réponse. Cette activation a été mesurée par un test de proximité entre les sous-unités eIF4E et eIF4G. Les autres marqueurs admis, tels que l’expression tumorale de PD-L1 ou les caractéristiques de l’infiltrat lymphocytaire intra-tumoral, n’ont pas de valeur pronostique significative dans cette cohorte.La glycolyse anaérobie est la voie métabolique que la plupart des cellules tumorales privilégient lors de lacancérogenèse. Ce phénomène est appelé « effet Warburg ». Au cours de la mélanomagénèse, il existe un continuum entre l’expression croissante de l’hexokinase 2 (ou HK2, première enzyme de la glycolyse) et l’agressivité tumorale. Dans cette étude, nous avons montré que l’inhibition d’expression d’HK2 (par siARN) induisait, in vitro, une diminution majeure de la migration et de l’invasion tumorales indépendamment du métabolisme glucidique ou de l’expression initiale d’HK2. Par une technique de profilage des polysomes, nous avons observé que HK2 régulait la traduction de l’ARNm de SOX10, un facteur de transcription impliqué dans l’initiation et la progression du mélanome. Nous avons alors réalisé une immunoprécipitation de l’ARN après induction de liaisons protéine-ARN par du formaldéhyde, nous permettant ainsi de démontrer que la protéine HK2 se liait à l’ARNm de SOX10.Mucosal melanoma is a rare tumor with a high metastatic potential. Immunotherapy has promising results in this aggressive subtype of melanoma. In a cohort of 23 patients with non-resectable and/or metastatic mucosal melanoma who received anti-PD1 immunotherapy, we showed that the activation of the eukaryotic translation initiation complex, eIF4F, was a strong prognostic biomarker of response. This activation was assessed with a proximity ligation assay between eIF4E and eIF4G. The other biomarkers, such as the PD-L1 tumoral expression or the characteristics of tumor-infiltrating lymphocytes, had no prognostic value in this cohort.Aerobic glycolysis is usually the main metabolic pathway in tumor cells during cancerogenesis. This specificprocess is called “Warburg effect”. During melanomagenesis, we observed a positive correlation between the expression level of hexokinase 2 (HK2, first enzyme of glycolysis) and the tumor invasiveness. In this study, we showed that inhibition of HK2 expression (by siRNA) induced, in vitro, a major decrease of migration and invasion potential independently of the basal glycolytic metabolism or HK2 expression level in the cell lines. Moreover, performing a polysome profiling analysis, we demonstrated that HK2 was regulating the translation of SOX10 mRNA, a transcription factor involved in initiation and progression of melanoma. We, then, realized an RNA immunoprecipitation in formaldehyde and showed that HK2 was an RNA-binding protein, able to interact with the SOX10 mRNA

Total ossiculoplasty in children: predictive factors and long-term follow-up.

International audienceOBJECTIVE: To evaluate the long-term results and predictive factors of a good outcome with the use of a total ossicular replacement prosthesis in children. DESIGN: Retrospective case review. SETTING: Tertiary referral center. PATIENTS: The study included 114 children (116 ears). INTERVENTIONS: A total of 116 ears underwent total ossicular chain reconstruction with a titanium prosthesis. Cartilage was always used for tympanic membrane reconstruction. MAIN OUTCOME MEASURES: Audiological results were evaluated according to the guidelines of the American Academy of Otolaryngology-Head and Neck Surgery. Predictive factors of audiological results were determined. Logistic regression and χ(2) tests were used for statistical analysis. RESULTS: The mean age at surgery was 9.8 years. Ossiculoplasty was performed during second-look surgery in 91 ears (78.4%) and during another stage in 25 ears (21.6%). The first-stage procedure was always performed for cholesteatoma. Audiometric results were available for 116 ears at 1 year, for 89 ears (76.7%) at 2 years, and for 42 ears (36.2%) at 5 years. Closure of the average air-bone gap (ABG) to within 20 dB was achieved in 65 ears (56%) at 1 year. The mean (SD) preoperative and postoperative (at 1 year) ABGs were 41.0 (9.5) dB and 22.4 (12.6) dB, respectively. There were no cases of extrusion, but 17 luxations of the prosthesis were confirmed by computed tomography. Luxation occurred on average at 31.4 months. Only three 4000-Hz degradations of bone conduction were reported, with no dead ears. We examined 3 predictive factors of auditory results: preoperative ABG, footplate status, and postoperative otoscopic findings. CONCLUSIONS: Total ossiculoplasty is a reliable technique in children. Long-term hearing outcomes are stable and satisfactory, but luxation can occur at any time. Preoperative ABG and footplate status are negative predictive factors of auditory results

Sentinel lymph node biopsy versus selective neck dissection in patients with early oral squamous cell carcinoma: A cost analysis

International audienceObjective: Sentinel lymph node biopsy (SLNB) has been proved to be as efficient as selective neck dissection (SND) for the treatment of occult metastases in T1-T2cN0 oral squamous cell carcinoma (OSCC). The aim of our study was to assess and compare the cost of these two surgical procedures. Patients and methods: This retrospective cost analysis includes consecutive patients treated between 2012 and 2017 in two French hospitals either by SLNB or SND. Hospital cost (hospital stay for initial surgery and re-hospitalizations over a period of 60 days after the initial surgery), the length of hospital stay for the initial surgery and the perioperative management were described and compared between the two techniques. The propensity score regression adjustment method was used to address selection bias. Results: Ninety-four patients underwent SLNB procedure and seventy-seven patients underwent SND. The length of hospital stay for initial surgery was lower in SLNB group: 5.8 days (SD: 3.8) versus 9.2 days (SD: 5) in the SND group. Hospital costs were lower in SLNB group: €7 489 (standard deviation: €3 691) versus €8 886 (standard deviation: €4 381) but this difference was not significant after propensity score regression adjustment. The rate of complication, the delay of full oral feeding and postoperative drainage were lower in SLNB group. Conclusion: SLNB in T1-T2cN0 OSCC is less invasive than SND with fewer complications, a shorter length of hospital stay and favorable perioperative management. This study shows that this technique could be also less expensive than SND

Mucosal melanomas of the head and neck: State of the art and current controversies

Mucosal melanomas of the head and neck (sinonasal and oral cavity) account for 1% of neoplasms, 4% of all melanomas and over 50% of all mucosal melanomas. They have a high metastatic potential. Five-year overall survival does not exceed 30%. Diagnosis may be difficult and includes adequate immunohistochemical staining. Risk factors, presentation and molecular biology are different from those of cutaneous melanomas. The mainstay of treatment is surgery and postoperative radiotherapy. Endoscopic surgery should be evaluated prospectively. Neck dissection is recommended for N0 oral cavity melanomas, while it can generally be omitted for sinonasal melanomas. Inoperable tumors can be treated with exclusive radiotherapy. Molecular guidance for metastatic cases is a relevant option despite low level of evidence, based on the rarity of disease and low response rates to chemotherapy. c-KIT inhibitors and immunotherapy appear promising

Indications and Clinical Outcomes of Transoral Robotic Surgery and Free Flap Reconstruction

We reviewed the indications, peroperative feasibility, and postoperative clinical outcomes of our first 50 consecutive patients who underwent free flap reconstruction after TORS for complex pharyngeal defects at our institution. We analyzed indications according to previous radiotherapy, the size of the resection, and the transoral exposure of critical structures. We reviewed surgical data, postoperative complications, and functional outcomes comprising tracheostomy and alimentation management. Indications were upfront surgery (34%), a second primary surgery after radiotherapy (28%), or salvage surgery after chemoradiotherapy failure (38%). Localizations were the tongue base (44%), tonsillar fossa (28%), pharyngeal wall (22%), and soft palate (6%). T-classifications were T1 (6%), T2 (52%), T3 (20%), and T4 (22%). The mean length of the surgery was 574 min. Two patients were intraoperatively converted to a conventional approach at the beginning of the learning curve. In conclusion, TORS and free flap reconstruction in complex situations were associated with low rates of postoperative complications and satisfactory functional outcomes. They were, however, associated with a renewed learning curve

Imaging of Skull Base and Orbital Invasion in Sinonasal Cancer: Correlation with Histopathology

Background: Pretreatment assessment of local extension in sinonasal cancer is essential for prognostic evaluation and surgical planning. The aim of this study was to assess the diagnostic performance of two common imaging techniques (CT and MRI) for the diagnosis of skull base and orbital invasion by comparing imaging findings to histopathological data. Methods: This was a retrospective two-center study including patients with sinonasal cancer involving the skull base and/or the orbit operated on between 2000 and 2019. Patients were included only if pre-operative CT and/or MRI, operative and histopathologic reports were available. A double prospective blinded imaging review was conducted according to predefined radiological parameters. Radiologic tumor extension was compared to histopathological reports, which were considered the gold standard. The predictive positive value (PPV) for the diagnosis of skull base/orbital invasion was calculated for each parameter. Results: A total of 176 patients were included. Ethmoidal intestinal-type adenocarcinoma was the most common type of cancer (41%). The PPV for major modification of the bony skull base was 78% on the CT scan, and 89% on MRI. MRI signs of dural invasion with the highest PPVs were: contact angle over 45° between tumor and dura (86%), irregular deformation of dura adjacent to tumor (87%) and nodular dural enhancement over 2 mm in thickness (87%). Signs of orbital invasion had low PPVs (<50%). Conclusions: This retrospective study provides objective data about the diagnostic value of pretreatment imaging in patients with sinonasal cancer

Clin Otolaryngol

During multidisciplinary tumor board meetings, practitioners did not assess local extension in the same way. 76% of pre-operative T stages of adenocarcinoma were overestimated. 73% of patients underwent skull base removal for pT1 and T2 previously classified as cT3 and T4. The concordance of extension assessment between radiologist and pathologist was poor whereas it was good between surgeon and pathologist. These findings point to the opportunity to improve patient care and avoid therapeutic escalation

Intraoperative Autofluorescence Imaging for Parathyroid Gland Identification during Total Laryngectomy with Thyroidectomy

Objective: Hypoparathyroidism is a known complication of total laryngectomy, although parathyroid preservation and/or reimplantation are not routine. Autofluorescence is a new technique for identifying parathyroid glands intraoperatively. The aim of this study was to evaluate the feasibility of autofluorescence in this context. Materials and Methods: A retrospective study of patients undergoing total laryngectomy/pharyngectomy with concomitant thyroidectomy using the Fluobeam® (Fluoptics, Grenoble, France) and frozen section of a parathyroid fragment in case of reimplantation. The rates of identification using autofluorescence, reimplantation, and hypoparathyroidism were evaluated. Results: Eighteen patients (16 males, median age 67) underwent total laryngectomy/pharyngectomy with total thyroidectomy (n = 12) or hemithyroidectomy (n = 6). A median of 2 parathyroid glands were identified per patient. Ninety-two percent were identified by autofluorescence before visualisation. All parathyroids were reimplanted due to devascularization. Temporary hypoparathyroidism occurred in nine patients, and was permanent in one patient. After 34 months of median follow-up (range 1–49), no tumor recurrence was observed in the reimplantation sites. Conclusions: To our knowledge, this is the largest study to evaluate autofluorescence during total laryngectomy with thyroidectomy. No tumor recurrence occurred in the sites of parathyroid reimplantation

Multicenter study to assess surgical treatments of 452 sinonasal intestinal-type adenocarcinomas: A REFCOR study

PURPOSE: The objective was to assess the local oncological outcomes of endoscopic versus external surgical treatment of sinonasal intestinal-type adenocarcinomas (ITAC) and the factors of recurrence. METHODS: a retrospective non-randomized case-control multicenter study was carried out, including 452 untreated sinonasal ITACs recruited from 10 tertiary referral centers. The tumors were re-classified according to the UICC 2017 (pT). Survival curves were obtained using the Kaplan-Meier method. Univariate analysis was done with the log-rank test. Multivariate analysis was performed with a Cox model adjusted for age, T stage, and radiotherapy. A binary logistic regression compared surgical complications and performed two supplementary analyses on positive margins. RESULTS: We compared 195 and 257 patients operated by the external and endoscopic approach, respectively. The mean follow-up was 59.2 ± 48.7 months. Post-operative margins were invaded in 30.6 versus 18.9% of patients, respectively (p = 0.007). The overall recurrence rate was 33.8 versus 24.6%, respectively (p = 0.034). There was a significant difference in favor of the endoscopic approach regarding local recurrence-free survival thanks to better surgical margins in univariate and multivariate analysis (Odd Ratio = 2.01 (1.2-3.36) p = 0.0087). The complication rate (Odds Ratio = 3.4 (1.79-6.32) p < 0.001) was significantly lower in the endoscopic group. The histological positivity of signet-ring cells shows a statistically significant difference in recurrence-free survival (p = 0.0028). CONCLUSION: the oncological control of ITAC is better through the endoscopic approach, with negative margins and the absence of signet-ring-cells, two independent factors of recurrence