Survival outcomes, prognostic factors, and effect of adjuvant radiotherapy and prophylactic neck dissection in salivary acinic cell carcinoma: A prospective multicenter REFCOR study of 187 patients.

BACKGROUND: Acinic cell carcinomas (AciCCs) are malignant tumours of the salivary glands. The aim of this work was to analyse data from the national REFCOR multicenter cohort (i) to investigate the prognostic factors influencing survival outcomes in AciCC, (ii) to assess the impact on survival of postoperative radiotherapy (RT) in patients treated for AciCC without high-grade transformation and (iii) to explore the prognostic impact of prophylactic neck dissection (ND) in patients treated for AciCC of the major salivary glands. PATIENTS AND METHODS: Data from all the patients treated for salivary AciCC between 2009 and 2020 were extracted from the REFCOR database. Survival outcomes and prognostic factors influencing Disease-Free Survival (DFS) and Overall Survival (OS) were investigated using univariate and multivariate analyses. Propensity score matching was used to assess the impact of postoperative RT and prophylactic ND on DFS. RESULTS: A total of 187 patients were included. After a median follow-up of 53 months, their 5-year OS and DFS rates were 92.8% and 76.2%, respectively. In multivariate analysis, male sex, older age, higher T and N status, and high grade were independently associated with a worse DFS. In the subpopulation analysed after propensity score matching, patients with cN0 AciCC without high-grade transformation who were treated by surgery and RT did not have an improved DFS compared to patients who were treated by surgery alone (hazard ratio (HR) = 0.87, p = 0.8). Factors associated with nodal invasion were T3-T4 status and intermediate/high histological grade. After propensity score matching, prophylactic ND was associated with a trend toward a better DFS (HR = 0.46, p = 0.16). CONCLUSIONS: These results suggest that (i) long-term follow-up (>5 years) should be considered in patients with AciCC, (ii) treatment by surgery alone could be an option in selected cN0 patients with AciCC without high-grade transformation and (iii) prophylactic ND may be considered preferentially in patients with T3-T4 status and/or intermediate/high histological grade.

Bone Regeneration in Small and Large Segmental Bone Defect Models after Radiotherapy Using Injectable Polymer-Based Biodegradable Materials Containing Strontium-Doped Hydroxyapatite Particles.

The reconstruction of bones following tumor excision and radiotherapy remains a challenge. Our previous study, performed using polysaccharide-based microbeads that contain hydroxyapatite, found that these have osteoconductivity and osteoinductive properties. New formulations of composite microbeads containing HA particles doped with strontium (Sr) at 8 or 50% were developed to improve their biological performance and were evaluated in ectopic sites. In the current research, we characterized the materials by phase-contrast microscopy, laser dynamic scattering particle size-measurements and phosphorus content, before their implantation into two different preclinical bone defect models in rats: the femoral condyle and the segmental bone. Eight weeks after the implantation in the femoral condyle, the histology and immunohistochemistry analyses showed that Sr-doped matrices at both 8% and 50% stimulate bone formation and vascularization. A more complex preclinical model of the irradiation procedure was then developed in rats within a critical-size bone segmental defect. In the non-irradiated sites, no significant differences between the non-doped and Sr-doped microbeads were observed in the bone regeneration. Interestingly, the Sr-doped microbeads at the 8% level of substitution outperformed the vascularization process by increasing new vessel formation in the irradiated sites. These results showed that the inclusion of strontium in the matrix-stimulated vascularization in a critical-size model of bone tissue regeneration after irradiation.

Tele-rehabilitation in voice disorders during the pandemic: a consensus paper from the French Society of Phoniatrics and Laryngology.

OBJECTIVES: To establish a consensus protocol for telerehabilitation in speech therapy for voice disorders. METHODS: The study was conducted according to a modified Delphi method. Twenty speech therapist or laryngologist experts of the French Society of Phoniatrics and Laryngology assessed 24 statements of voice telerehabilitation with a 10-point visual analog scale ranging from 1 (totally disagree) to 10 (totally agree). The statements were accepted if more than 80% of the experts rated the item with a score of ≥ 8/10. The statements with ≥ 8/10 score by 60-80% of experts were improved and resubmitted to voting until they were validated or rejected. RESULTS: The French Society of Phoniatrics and Laryngology experts validated 10, 6, and 2 statements after the first, second and third voting round, respectively. Seven statements did not reach agreement threshold and were rejected. The validated statements included recommendations for setting (N = 4), medical/speech history (N = 2), subjective voice evaluations (N = 3), objective voice quality measurements (N = 3), and voice rehabilitation (N = 5). The experts agreed for a follow-up consisting of combined telerehabilitation and in-office rehabilitation. The final protocol may be applied in context of pandemic but could be assessed out of pandemic period for patients located in rural regions. CONCLUSIONS: This Delphi study established the first telerehabilitation protocol of the French Society of Phoniatrics and Laryngology for patients with voice disorders. Future controlled studies are needed to assess its feasibility, reliability, and the patient perception about telerehabilitation versus in-office rehabilitation.

Voice Quality Outcomes After Transoral CO2 Laser Cordectomy: A Longitudinal Prospective Study.

OBJECTIVE: To evaluate the evolution of voice quality in patients after type I-VI transoral CO2 laser cordectomy (TLC) by using validated voice outcome measures over a 12-month period. STUDY DESIGN: Prospective uncontrolled study. SETTING: Monocenter study. METHODS: Patients with laryngeal carcinoma who were eligible for type I-IV TLC were prospectively recruited from a tertiary medical center. The following outcomes were assessed throughout the 12-month posttreatment period: Voice Handicap Index (VHI), GRBAS (grade of dysphonia, roughness, breathiness, asthenia, strain), maximal phonation time, fundamental frequency (F0), F0 standard deviation, percentage jitter, percentage shimmer, noise-to-harmonic ratio, and speech fluency. Analyses were performed considering 2 groups of cordectomies: type I-III vs IV-VI. RESULTS: A total of 131 patients completed the evaluations, totaling 76 type I-III and 55 type IV-VI cordectomies. In type IV-VI, breathiness and maximal phonation time significantly worsened from pretreatment to 1 month posttreatment (P < .05). In the type I-III cordectomy group, VHI, shimmer, roughness, breathiness, and strain significantly improved from pretreatment to 3 months posttreatment, while VHI, F0 standard deviation, shimmer, jitter, grade of dysphonia, roughness, breathiness, and strain improved from baseline to 6 months. Assessments at 12 months posttreatment revealed significant improvements for VHI, shimmer, jitter, noise-to-harmonic ratio, grade of dysphonia, roughness, breathiness, and strain. In the type IV-VI group, VHI significantly improved from baseline to 3, 6, and 12 months posttreatment. Strain improved at 6 and 12 months while roughness improved from baseline to 12 months. Maximal phonation time significantly worsened over the 12-month evaluation period. CONCLUSION: The effect of TLC on voice quality depends on its type. VHI was identified as the most indicative tool of voice changes irrespective of TLC type.

Impact of HPV status in T1-2 oropharyngeal squamous cell carcinoma with bulky N3 nodes: a multicenter GETTEC study.

PURPOSE: The purpose of our study was to investigate the impact of HPV status in oncologic outcomes in patients with T1-2 oropharyngeal SCC associated with bulky N3 nodes, and to determine progression prognosis factors aiming to define the best therapeutic strategies for these patients. METHODS: This multicenter retrospective study included patients with T1-2 oropharyngeal SCC with N3 nodes treated between 2010 and 2015 in 8 French comprehensive cancer centers. HPV status was determined with P16 hyperexpression in immunohistochemistry. HPV-positive patients were separated into 2 groups according to the associated smoking history (HPV + T +) or not (HPV + T-). We compared the oncological outcomes of patients according to HPV-status and smoking history. RESULTS: Of 67 patients with T1-2 N3 oropharyngeal SCC, 36 patients (53.7%) were HPV negative and 31 patients (46.3%) HPV positive. 2-year PFS was significantly better in HPV + T- group (p = 0.036). The risk of death or progression was significantly reduced in HPV + T- comparatively to HPV- (HR 0.25 95%CI [0.07; 0.89]). 2-year OS was significantly better in HPV + T- group than in the other two groups (p = 0.017). CONCLUSION: In patients with T1-2 oropharyngeal SCC associated with bulky N3 nodes, HPV positive patients without smoking history had better OS and PFS than HPV positive patients with smoking history and HPV negative patients. Thus, HPV status is a significant prognostic factor for survival but this benefit is altered when smoking history is associated. N3 HPV positive patients with smoking history have to be classified as high-risk.

Proposal for an algorithm to avoid neck dissection during salvage total laryngectomy. A GETTEC multicentric study.

OBJECTIVES: To identify the factors related to the presence of occult metastases before salvage total laryngectomy (STL) in rcN0 patients and to propose an algorithm to identify patients who do not require neck dissection (ND). PATIENTS AND METHODS: This multicentric retrospective study included five centers with recruitment from 2008 to 2018. Inclusion criteria were: i) having been treated for laryngeal squamous cell carcinoma in first intention by radiotherapy (either alone or potentiated or preceded by induction chemotherapy), ii) having received STL with or without ND, iii) having an rcN0 neck at the time of STL. RESULTS: 120 patients met the inclusion criteria. The overall rate of occult metastases was 9.1 %. The rate was significantly higher in patients with an initial positive cN+ lymph node status (p < 0.005) and in advanced stages with rcT3-T4 lesions at recurrence (p < 0.005). Patients with occult metastases recurred earlier than those without (p = 0.002). The overall survival of patients was the same with or without ND (p = 0.16). There were significantly more healing complications requiring revision surgery in the group with ND than in the group without (p = 0.048). CONCLUSION: ND does not confer a net survival benefit and is associated with significant complications. Patients without initial lymph node metastases who are rcT1-T2 at recurrence or rcT3-T4 with a recurrence period of more than 12 months could benefit from STL without ND. This decisional algorithm, which needs to be validated, would help avoid 58 % of ND procedures and their proven morbidity. DISCIPLINE: Head and neck surgery.

Oral tongue squamous cell carcinomas in young patients according to their smoking status: a GETTEC study.

BACKGROUND: Incidence of oral tongue squamous cell carcinoma (OTSCC) is increasing, especially in young adults, despite decreasing tobacco and alcohol consumption. METHODS: This multicentric retrospective study of 185 young adults with OTSCC (median follow-up 43 months), investigated risk factors, tumour characteristics and oncological outcomes according to the smoking status. RESULTS: Overall, 38% of patients were smokers (S). Non-smokers (NS) were significantly younger than S. Sex ratios were 1.1 for N and 1.8 for S. NS patients were less frequently cannabis or alcohol users than S, but were more likely to have a history of leukoplakia. Second primaries were observed in NS (4.4%) and in S (12.7%). Despite more frequent local relapse in NS (p = 0.018), there was no difference in diagnostic stage and overall survival between groups. CONCLUSION: OTSCC affects differently young S and NS patients suggesting the existence of a specific clinical entity of OTSCC in non-smoking young adults.

Oncological and Surgical Outcomes of Patients Treated by Transoral CO2 Laser Cordectomy for Early-Stage Glottic Squamous Cell Carcinoma: A Retrospective Chart Review.

OBJECTIVE: To investigate the feasibility and the outcomes of transoral laser CO2 microsurgery (TLM) for resection of early-stage squamous cell carcinoma (SCC) of the vocal folds through several additional surgical procedures and tips improving the glottic exposure. METHODS: Retrospective chart review of patients treated by TLM cordectomy in a single European University Hospital for early-stage vocal fold SCCs (Tis, T1a, T1b, and T2). The following TLM outcomes were studied regarding the tumor size (Tis and T1a vs T1b and T2) and the margin status (negative vs positive/suspicious): patient position; type of laryngoscope; requirement to external counter pressure; resection of supraglottic structures (eg, ventricular band, epiglottic petiole, and suprahyoid epiglottis); pre- and postoperative complications; overall survival; disease-specific survival (DSS); and disease-free survival (DFS). RESULTS: A total of 148 patients were included. The TLM was realized in 95.3% of cases. External counter pressure, partial, or total vestibulectomy were necessary in 65.9%, 57.4%, and 4.2% of cases, respectively. A resection of the epiglottic petiole was required in 24.8% of cases. The realization of both epiglottis petiole resection and vestibulectomies were significantly higher in patients with T2 and T1b SCCs compared to those with T1a and Tis SCCs (P = .01). Different procedure tips were described for improving the laryngeal exposition. The 5-year laryngeal preservation rate, DSS, and DFS were significantly better in patients without SCC involvement of the anterior commissure, and did not vary according to the margin status. The laryngeal exposure difficulties did not impact the margin status. CONCLUSION: The exposure of glottis is possible in 95% of cases of early-stage vocal cord SCC but requires the use of several additional surgical procedures, especially for anterior commissure SCCs. The SCC involvement of the vocal fold anterior commissure is associated with lower DSS, DFS, and laryngeal preservation rate.

Locoregional control, progression-free survival and morbidity rates in N3 head and neck cancer patients with low primary tumour burden: A 301-patient study.

OBJECTIVES: In patients with N3 head and neck squamous cell carcinoma (HNSCC), N3 disease is associated with high regional relapse and metastatic risks. Patients with resectable N3 disease have better prognosis although their metastatic risk may be similar as in patients with unresectable disease. Neoadjuvant chemotherapy has been associated with lower metastatic rates, but N3 patients may die of rapid locoregional progression. We assessed outcomes with the three modalities in patients with low primary burden to better assess the specific prognosis of N3 disease. METHODS: This retrospective multicentric study included T0-2 N3 HNSCC patients. Outcomes and morbidity in upfront neck dissection (uND) vs non-surgical groups were analysed and oncological outcomes and morbidity compared between patients undergoing chemoradiation or neoadjuvant chemotherapy in patients with initially unresectable N3 nodes. RESULTS: Of 301 patients, 142 (47%) underwent uND, 68 (23%) neoadjuvant chemotherapy and 91 (30%) chemoradiation. The 24- and 60-month incidence of locoregional relapse was 23.2% [18.3%; 28.4%] and 27.4% [21.8%; 33.3%]; it was lower in patients undergoing uND (P = .006). In patients with non-surgical treatments, success rates were 57.8% [49.4%; 66.3%] after chemoradiation and 38.1% [29.6%; 46.7%] after neoadjuvant chemotherapy (P = .001). Overall morbidity was more frequent in patients undergoing uND (68.8%) (P < .001). CONCLUSION: uND improved locoregional control but increased morbidity and showed no survival benefit. Success rates were better after chemoradiation versus neoadjuvant chemotherapy. Neoadjuvant chemotherapy did not reduce metastatic rates but non-responders to chemoradiation had poor PFS and survival rate, suggesting that predictive criteria are warranted.

Consensus on resectability in N3 head and neck squamous cell carcinomas: GETTEC recommendations.

BACKGROUND: Among patients with T0-2 N3 head and neck squamous cell carcinomas (HNSCC), those undergoing upfront neck dissection have better oncological outcomes. However, there is no consensual definition of disease resectability of N3 nodes, leading to major treatment attrition and interpretation biases between studies. We established a Delphi method-based consensus to define resectability and impact on decision-making for upfront neck dissection in N3 patients. METHODS: The Delphi method was designed as recommended by the French Haute Autorite de Sante among head and neck surgeons from university hospitals and cancer centers, using a 24-item questionnaire. Strong and relative agreements were subsequently established, and recommendations were written. The resulting recommendations were assessed by 30 independent surgeons. RESULTS: N3 nodes with intraparenchymal brain invasion, foramen invasion, skull base erosion, nodes requiring bilateral XIIth cranial nerve sacrifice, retropharyngeal N3 node or a node above the plan of soft palate are major contraindications to neck dissection. When neck dissection requires unilateral sacrifice of the IXth or Xth or XIIth cranial nerves or cervical nerve roots, upfront neck dissection may be performed, based on a case-by-case assessment of other patient and tumor estimates. CONCLUSION: Consensual contraindications to neck dissection in patients with T0-2 N3 HNSCC were defined among French head and neck surgeons as concerns skull base invasion, retropharyngeal nodes and bilateral XIIth cranial nerve sacrifice. This consensus should allow more reliable comparisons between surgical and non-surgical strategies in N3 patients.

Surgery or Radiotherapy of the Primary Tumor in T1-2 Head and Neck Squamous Cell Carcinoma with Resectable N3 Nodes: A Multicenter GETTEC Study.

BACKGROUND: The prognosis of advanced nodal (N3) squamous cell carcinoma of the head and neck (HNSCC) is poor. We investigated whether surgery or radiotherapy of early (T1-2) primary stage HSNCC is preferable to limit the overall morbidity after upfront neck dissection (uND) for N3 disease. METHODS: This retrospective multicentric Groupe d'Étude des Tumeurs de la Tête Et du Cou study included patients undergoing uND and surgery or radiotherapy of their primary. Prognostic factors were evaluated using propensity score matching to account for biases in performing surgery depending on primary site and stage. RESULTS: Of 189 T1-2, N3 HNSCC patients, 70 (37.0%) underwent uND: 42 with surgery of their primary and 28 with radiotherapy only. Radiotherapy alone was more frequent in patients with hypopharyngeal primaries. All local (N = 3) and regional (N = 10) relapses (included 2 locoregional relapses) occurred within the first 2 years. There were 16 distant metastatic failures. Five-year locoregional relapse and survival incidences were 15.7% and 66.5% and were similar regardless of the treatment of the primary. The overall morbidity rate was 65.2% and was similar after weighting by the inverse propensity score (p = 0.148). The only prognostic factor for morbidity was the radicality of the uND. Prolonged parenteral feeding was not more frequent in patients only irradiated to their primary (p = 0.118). Prolonged tracheostomy was more frequent after surgery of the primary. CONCLUSIONS: In patients with T1-2, N3 HNSCC undergoing uND, radiotherapy and surgery of the primary yield similar oncological outcomes. Morbidity was related to the extent of neck dissection.

Oncologic outcomes with transoral robotic surgery for supraglottic squamous cell carcinoma: Results of the French Robotic Surgery Group of GETTEC.

BACKGROUND: Transoral robotic surgery (TORS) is an option to treat supraglottic squamous cell carcinomas (SCCs). We studied the oncologic outcomes after TORS for supraglottic laryngectomy (SGL). METHODS: We conducted a multicenter observational study of SGL using TORS for patients with supraglottic SCC with at least 2 years of follow-up. RESULTS: One hundred twenty-two patients were included in our study. Mean follow-up was 42.8 months. Local control was 94.3% at 2 years and 90.2% at 5 years. Overall survival and disease-free survival were 86.9% and 95.1% at 2 years, and 78.7% and 94.3% at 5 years, respectively. Sixty-three patients (51.6%) received adjuvant radiotherapy. For 16 of them, this was due to close or positive margins. CONCLUSION: Local control rate after TORS SGL was at least equivalent to what has been described in the literature for open or transoral laser surgery, or with radiotherapy. Using TORS seems to be an effective therapeutic treatment of early-stage and intermediate-stage supraglottic SCCs.

Induction chemotherapy with the EXTREME regimen in frail patients with locally advanced head and neck squamous cell carcinoma.

BACKGROUND: Induction chemotherapy (IC) with TPF (docetaxel, cisplatin, 5FU) for locally advanced head and neck squamous cell carcinoma (LAHNSCC) is limited to fit patients. OBJECTIVE: We conducted a retrospective cohort study to assess the use of the EXTREME regimen (platinum-based therapy, 5FU, cetuximab) as IC in frail patients with LAHNSCC. PATIENTS AND METHODS: Retrospective analysis of all consecutive patients with unresectable LAHNSCC treated with the EXTREME regimen, with or without 5FU as IC, from two French centers from 2008 to 2015. We assessed the rate of completed sequence defined as at least two cycles of IC and definitive radiation therapy. RESULTS: We included 34 patients with a median age of 56 years [44-70]. The primary site of tumor development was the oropharynx (67%, n=23, all HPV negative), hypopharynx (21%, n=7) and the oral cavity (12%, n=4). At inclusion, patients presented: T4 76, 5% (n=26), N2c 41% (n=14), N3 26% (n=9), stage disease IVa 62% (n=21), IVb 38% (n=13), ECOG PS2 38% (n=13), decreased weight (10% in one month or 15% in 6 months) 74% (n=25). The sequence was achieved for 76% (n=26) of patients and 80% (n=27) presented a clinical response after the chemotherapy course with notably increased weight (40%, n=11) or general status (75%, n=26). Median PFS and OS were 5.7 and 15.5 months, respectively. Disease progression at 3 months was significantly associated with decreased median overall survival (13.6 versus 21.9 months, p=0.01). CONCLUSION: This is the first study to report the use of the EXTREME regimen as induction chemotherapy, and although this IC was used in a very frail population, the majority completed the sequence with significant clinical benefit.

Influence of External Beam Radiotherapy on the Properties of Polymethyl Methacrylate-Versus Silicone-Induced Membranes in a Bilateral Segmental Bone Defect in Rats.

INTRODUCTION: Standard care for malignant tumors arising next to a bone structure is surgical removal with safety margins, followed by external beam radiotherapy (EBRT). Complete tumor removal can result in large bone defects. A two-step bone reconstruction technique using the induced membrane (IM) technique has proven its efficacy to bridge gap nonunion. During the first step, a spacer is placed in the bone gap. The spacer then is removed and the IM around it is filled with autologous cancellous bone graft. However, the feasibility of this technique with the addition of adjuvant EBRT between the two reconstruction steps has not yet been studied. Polymethyl methacrylate (PMMA) used to be the standard spacer material for the first step. Silicone spacers could replace them owing to their good behavior when submitted to EBRT and their easier removal from the surgical site during the second step. The aim of this study was to evaluate the influence of EBRT on the histological and biochemical properties of IM induced using PMMA or silicone as spacer. MATERIALS AND METHODS: The analyses were performed on PMMA- or silicone-IM with and without EBRT in a 6-mm bilateral femoral defect in 32 rats. Thickness and vessel content were measured in both groups. Bone morphogenetic protein 2 (BMP2) and vascular endothelial growth factor (VEGF) content in lysates of the crushed membranes were measured by enzyme immunoassay. Finally, alkaline phosphatase activity was analyzed in human bone marrow stromal cell cultures in contact with the same lysates. RESULTS: EBRT did not change the histological structure of the cellular internal layer or the fibrous outer layer. The nature of the spacer only influenced IM thickness, PMMA-IM with external radiotherapy being significantly thicker. EBRT decreased the vascular density of IM but was less effective on VEGF/BMP2 production. In vitro, IM could have an osteoinductive potential on human bone marrow stem cells. CONCLUSION: EBRT did not modify the histological properties of IMs but decreased their vascular density. VEGF and BMP2 production within IMs was not affected by EBRT. Silicone spacers are able to induce membranes with similar histological characteristics to PMMA-IM.

Transtympanic pseudoaneurysm of the internal carotid artery complicating a myringotomy in a four-year old child: Case report and literature review.

We report the first case of a transtympanic iatrogenic internal carotid artery (ICA) pseudoaneurysm diagnosed in a 4-year-old child following a myringotomy. An endovascular treatment with a covered-stent was decided; spontaneous thrombosis was found during the therapeutic arteriography, and the procedure was aborted. Otoscopy and computed tomography (CT) scan monitoring showed a prolonged thrombosis and the disappearance of the pseudoaneurysm 18months after the diagnostic arteriography. Based on literature review, endovascular techniques seem to be preferred to the surgical approach for treatment of intrapetrous ICA pseudoaneurysm, however clinical and CT scan monitoring may also be a valid option.

Immune checkpoint inhibitors and elderly people: A review.

Immune checkpoint inhibitors, including targeting programmed cell death 1, programmed cell death ligand 1, and cytotoxic T lymphocyte antigen 4 pathways, are a new type of cancer treatment. This approach of targeting the immune system has demonstrated dramatic efficacy for several cancers, and various drugs have been approved by health authorities and are used in clinical practice. Elderly patients (≥65 years) represent most of the cancers diagnosed and deaths by age group, with an increase expected over the next decade. However, this subgroup of patients is under-represented in clinical trials. Ageing is also associated with a decrease in the effectiveness of the immune system and in alterations to it. Few specific trials have been carried out for immunotherapy in elderly people, with most patients considered to be fit. In this review, we discuss the impact of ageing and immunosenescence on immune system functions, and we assess the safety and efficacy of immune checkpoint inhibitors in elderly patients, principally from the data of pivotal clinical trials with subgroup analysis. Tolerance in elderly patients seems similar to younger people, but efficacy seems different between younger and elderly patients according to the type of cancer, some showing no difference and others less efficacy in the elderly subgroup. However, the numbers in elderly groups are small and more investigation is needed, with specific clinical trials for elderly cancer patients.