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Humans have six members of the ferlin protein family: dysferlin, myoferlin, otoferlin, fer1L4, fer1L5, and fer1L6. These proteins share common features such as multiple Ca2+-binding C2 domains, FerA domains, and membrane anchoring through their single C-terminal transmembrane domain, and are believed to play a key role in calcium-triggered membrane fusion and vesicle trafficking. Otoferlin plays a crucial role in hearing and vestibular function. In this review, we will discuss how we see otoferlin working as a Ca2+-dependent mechanical sensor regulating synaptic vesicle fusion at the hair cell ribbon synapses. Although otoferlin is also present in the central nervous system, particularly in the cortex and amygdala, its role in brain tissues remains unknown. Mutations in the OTOF gene cause one of the most frequent genetic forms of congenital deafness, DFNB9. These mutations produce severe to profound hearing loss due to a defect in synaptic excitatory glutamatergic transmission between the inner hair cells and the nerve fibers of the auditory nerve. Gene therapy protocols that allow normal rescue expression of otoferlin in hair cells have just started and are currently in pre-clinical phase. In parallel, studies have linked ferlins to cancer through their effect on cell signaling and development, allowing tumors to form and cancer cells to adapt to a hostile environment. Modulation by mechanical forces and Ca2+ signaling are key determinants of the metastatic process. Although ferlins importance in cancer has not been extensively studied, data show that otoferlin expression is significantly associated with survival in specific cancer types, including clear cell and papillary cell renal carcinoma, and urothelial bladder cancer. These findings indicate a role for otoferlin in the carcinogenesis of these tumors, which requires further investigation to confirm and understand its exact role, particularly as it varies by tumor site. Targeting this protein may lead to new cancer therapies.

BackgroundThe use of 18FDG-PET/CT for delineating a gross tumor volume (GTV, also called MTV metabolic tumor volume) in radiotherapy (RT) planning of head neck squamous cell carcinomas (HNSCC) is not included in current recommendations, although its interest for the radiotherapist is of evidence. Because pre-RT PET scans are rarely done simultaneously with dosimetry CT, the validation of a robust image registration tool and of a reproducible MTV delineation method is still required.ObjectiveOur objective was to study a CT-based elastic registration method on dual-time pre-RT 18FDG-PET/CT images to assess the feasibility of PET-based RT planning in patients with HNSCC.MethodsDual-time 18FDG-PET/CT [whole-body examination (wbPET) + 1 dedicated step (headPET)] were selected to simulate a 2-times scenario of pre-RT PET images deformation on dosimetry CT. ER-headPET and RR-headPET images were, respectively, reconstructed after CT-to-CT rigid (RR) and elastic (ER) registrations of the headPET on the wbPET. The MTVs delineation was performed using two methods (40%SUVmax, PET-Edge). The percentage variations of several PET parameters (SUVmax, SUVmean, SUVpeak, MTV, TLG) were calculated between wbPET, ER-headPET, and RR-headPET. Correlation between MTV values was calculated (Deming linear regression). MTVs intersections were assessed by two indices (OF, DICE) and compared together (Wilcoxon test). Additional per-volume analysis was evaluated (Mann-Whitney test). Inter- and intra-observer reproducibilities were evaluated (ICC = intra-class coefficient).Results36 patients (30M/6F; median age = 65 y) were retrospectively included. The changes in SUVmax, SUVmean and SUVpeak values between ER-headPET and RR-headPET images were 0.99). The ER-headPET MTVs had significant higher mean OF and DICE with the wbPET MTVs, for both delineation methods (p ≤ 0.002); and also when lesions had a volume > 5cc (excellent OF = 0.80 with 40%SUVmax). The inter- and intra-observer reproducibilities for MTV delineation were excellent (ICC ≥ 0.8, close to 1 with PET-Edge).ConclusionOur study demonstrated no significant changes in MTV after an elastic deformation of pre-RT 18FDG-PET/CT images acquired in dual-time mode. This opens possibilities for HNSCC radiotherapy planning improvement by transferring GTV-PET on dosimetry CT.

Aim: Several series have already demonstrated that intratumoral subvolumes with high tracer avidity (hotspots) in 18F-flurodesoxyglucose positron-emission tomography (FDG-PET/CT) are preferential sites of local recurrence (LR) in various solid cancers after radiotherapy (RT), becoming potential targets for dose escalation. However, studies conducted on head and neck squamous cell carcinoma (HNSCC) found only a moderate overlap between pre- and post-treatment subvolumes. A limitation of these studies was that scans were not performed in RT treatment position (TP) and were coregistred using a rigid registration (RR) method. We sought to study (i) the influence of FDG-PET/CT acquisition in TP and (ii) the impact of using an elastic registration (ER) method to improve the localization of hotpots in HNSCC.Methods: Consecutive patients with HNSCC treated by RT between March 2015 and September 2017 who underwent FDG-PET/CT in TP at initial staging (PETA) and during follow-up (PETR) were prospectively included. We utilized a control group scanned in non treatment position (NTP) from our previous retrospective study. Scans were registered with both RR and ER methods. Various sub-volumes (AX; x = 30, 40, 50, 60, 70, 80, and 90%SUVmax) within the initial tumor and in the subsequent LR (RX; x = 40 and 70%SUVmax) were overlaid on the initial PET/CT for comparison [Dice, Jaccard, overlap fraction = OF, common volume/baseline volume = AXnRX/AX, common volume/recurrent volume = AXnRX/RX].Results: Of 199 patients included, 43 (21.6%) had LR (TP = 15; NTP = 28). The overlap between A30, A40, and A50 sub-volumes on PETA and the whole metabolic volume of recurrence R40 and R70 on PETR showed moderate to good agreements (0.41–0.64) with OF and AXnRX/RX index, regardless of registration method or patient position. Comparison of registration method demonstrated OF and AXnRX/RX indices (x = 30% to 50%SUVmax) were significantly higher with ER vs. RR in NTP (p < 0.03), but not in TP. For patient position, the OF and AXnRX/RX indices were higher in TP than in NTP when RR was used with a trend toward significance, particularly for x=40%SUVmax (0.50±0.22 vs. 0.31 ± 0.13, p = 0.094).Conclusion: Our study suggested that PET/CT acquired in TP improves results in the localization of FDG hotspots in HNSCC. If TP is not possible, using an ER method is significantly more accurate than RR for overlap estimation.

Abstract Objective We aimed at evaluating the impact of ultrasound‐guided (US) hookwire localization of nonpalpable cervical lymphadenopathy on operating time. Design and Methods Retrospective case control study (January 2017 and May 2021) of 26 patients with lateral nonpalpable cervical lymphadenopathy undergoing surgery with (H+) and without (H−) per operative US‐guided hook‐wire localization. Operative time (general anesthesiology onset, hookwire placement, end of surgery) and surgery‐related adverse events data were collected. Results Mean operative time was significantly shorter in H+ group versus H− group (26 ± 16 min vs. 43 ± 22 min) (p = 0.02). Histopathological diagnosis accuracy was 100% versus 94% (H+ vs. H−, p = 0.1). No significant between group difference in surgery‐related adverse events was reported (wound healing, p = 0.162; hematomas, p = 0.498; neoplasms removal failure, p = 1). Conclusion US‐guided hookwire localization of lateral nonpalpable cervical lymphadenopathy allowed a significant reduction in operative time, comparable histopathological diagnosis accuracy and adverse events compared with H−.

Abstract The main aim of this study was to evaluate the prognostic value of radiomic approach in pre-therapeutic 18F-fluorodeoxyglucose positron-emission tomography (FDG-PET/CT) in a large cohort of patients with gastro-esophageal junction cancer (GEJC). This was a retrospective monocenter study including 97 consecutive patients with GEJC who underwent a pre-therapeutic FDG-PET and were followed up for 3 years. Standard first-order radiomic PET indices including SUVmax, SUVmean, SUVpeak, MTV and TLG and 32 textural features (TFs) were calculated using LIFEx software on PET imaging. Prognostic significance of these parameters was assessed in univariate and multivariate analysis. Relapse-free survival (RFS) and overall survival (OS) were respectively chosen as primary and secondary endpoints. An internal validation cohort was used by randomly drawing one-third of included patients. The main characteristics of this cohort were: median age of 65 years [41–88], sex ratio H/F = 83/14, 81.5% of patients with a histopathology of adenocarcinoma and 43.3% with a stage IV disease. The median follow-up was 28.5 months [4.2–108.5]. Seventy-seven (79.4%) patients had locoregional or distant progression or recurrence and 71 (73.2%) died. In univariate analysis, SUVmean, Histogram-Entropy and 2 TFs (GLCM-Homogeneity and GLCM-Energy) were significantly correlated with RFS and OS, as well as 2 others TFs (GLRLM-LRE and GLRLM-GLNU) with OS only. In multivariate analysis, Histogram-Entropy remained an independent prognostic factor of both RFS and OS whereas SUVmean was an independent prognostic factor of OS only. These results were partially confirmed in our internal validation cohort of 33 patients. Our results suggest that radiomic approach reveals independent prognostic factors for survival in patients with GEJC.

Adenoid cystic carcinoma is a slowly growing malignant tumor with high local recurrence, perineural and vascular invasion. This tumor might arise from the glands of upper respiratory tract and oral cavity (eg, salivary or serous or mucous). Here we report the case of a 65-year-old woman who was referred to our unit for left retro-auricular radiating pain with trigger points and frontal headache since 6 months. There was no involvement of cranial nerves. Imaging screening using MRI, Positron emission tomography with 2-[fluorine-18] fluoro-2-deoxy-D-glucose, Gallium-68 DOTA-Phe1-Tyr3-Octreotide (68Ga DOTATOC) Positron emission tomography-CT suggested a suspicion of schwannoma or paraganglioma of the jugular foramen. However, the CT-guided biopsy revealed presence of adenoid cystic carcinoma. These warrants performing mandatory histological analysis combined with imaging screening suspicion of schwannoma or paraganglioma.

Epithelial-myoepithelial carcinoma (EMC) is a rare malignant neoplasm arising most frequently in the salivary glands and exceptionally in the nasal cavity. EMC accounts for ~1–2% of salivary gland tumors. Even if the nodal and distant metastasis rates are low, tumor staging remains indicated. Here, the authors present the 2-deoxy-2-[18F]fluoro-D-glucose PET-CT (18F-FDG-PET/CT) study of a very rare case of biopsy-proven EMC of the left nasal cavity. This 18F-FDG-PET/CT was performed to stage this tumor and guide the therapeutic strategy due to an atypical high-grade presentation in immunohistochemistry. To our knowledge, this is the first case reporting such high 18F-FDG avidity of EMC of the nasal cavity in PET/CT.

Background: The objective of this study was to assess the therapeutic and prognostic impact of integrating18F-fluorodeoxyglucose (18-FDG) positron emission tomography (PET)/computed tomography (CT) into work-up (WU) at initial staging of patients with head and neck squamous cell carcinoma (HNSCC).Method: 477 consecutive patients (414M/63F, mean age 62.3 ± 9.7 years) with newly diagnosed HNSCC who underwent pre-treatment 18-FDG PET/CT were retrospectively included. The 18-FDG PET/CT stage (sPET) was compared to the conventional work-up stage (sCWU). A group of cancer specialists determined whether integrating PET/CT into WU at initial staging had an impact on the therapeutic decision, classifying the clinical impact as high (change in therapeutic modality), medium (change in the radiotherapy or surgical procedure), or low (modification of TNM staging and/or detection of synchronous cancer without high or medium impact). Three-year overall survival (OS) was considered as primary endpoint of the prognostic analysis.Results: 18-FDG PET/CT had a clinical impact in 221 patients (46.3%) with a medium or high impact on management in 94 (19.5%) patients. Medium and high impact of 18-FDG PET/CT was statistically equivalent between sCWU-stage I/II and III/IV subgroups (p = 0.02). 42 patients were PET/CT-upstaged from early stage I/II to advanced stage III/IV and had a significantly lower 3-year OS than those with concordant CWU and 18-FDG PET/CT early stage (54.8 vs. 82.6%, p = 0.001).Conclusion: This study demonstrated that implementing 18-FDG PET/CT in the initial WU of HNSCC provides valuable staging information with a better prognostic stratification. Patient management was modified for any disease stage, even for early stage I-II, with consequences on survival.