Trem2-expressing multinucleated giant macrophages are a biomarker of good prognosis in head and neck squamous cell carcinoma.

Patients with head and neck squamous cell carcinomas (HNSCC) often have poor outcomes due to suboptimal risk-management and treatment strategies; yet integrating novel prognostic biomarkers into clinical practice is challenging. Here, we report the presence of multinucleated giant cells (MGC) - a type of macrophages - in tumors from patients with HNSCC, which are associated with a favorable prognosis in treatment-naive and preoperative-chemotherapy-treated patients. Importantly, MGC density increased in tumors following preoperative therapy, suggesting a role of these cells in the anti-tumoral response. To enable clinical translation of MGC density as a prognostic marker, we developed a deep-learning model to automate its quantification on routinely stained pathological whole slide images. Finally, we used spatial transcriptomic and proteomic approaches to describe the MGC-related tumor microenvironment and observed an increase in central memory CD4 T cells. We defined an MGC-specific signature resembling to TREM2-expressing mononuclear tumor associated macrophages, which co-localized in keratin tumor niches.

Ultra-fast confocal fluorescence microscopy for neck lymph node imaging in head and neck cancer.

OBJECTIVES: We evaluated ultra-fast confocal fluorescence microscopy (UFCM) as a new modality for pathology practice in head and neck cancer (HNC). This was assessed through an ex vivo study to estimate the accuracy, specificity, and sensitivity of interpretation of UFCM images by pathologists for the detection of metastatic lymph nodes in HNC patients undergoing sentinel lymph node biopsy or selective or complete neck dissection. MATERIALS AND METHODS: 44 patients with 32 cN0 and 12 cN+ HNC were included. The macroscopically non-invaded fresh bisected lymph nodes were stained with acridine orange and imaged with Histolog® Scanner (UFCM). Two pathologists interpreted independently the UFCM images postoperatively and gave a consensus diagnosis in case of disagreement. The gold standard was the diagnosis based on hematoxylin-eosin-saffron (HES) sections. RESULTS: 201 lymph nodes were imaged by UFCM. Thirty nodes (15 %) were invaded on final histology: 3 with micrometastases and 27 with macrometastases. The concordance rate between the pathologists on the UFCM images was 192/201 = 95.5 % and the Cohen kappa coefficient was 0.80. The accuracy of UFCM was 95.5 % (95 %CI: 91.7 %-97.9 %) with a high specificity at 98.8 % (95 %CI: 95.8 %-99.9 %) but an insufficient sensitivity at 76.7 % (95 %CI: 57.7 %-90.1 %). The three micrometastases and four of the 27 macrometastases were missed on UFCM images. CONCLUSION: The UFCM is providing promising detection values with a very good specificity and moderate sensitivity carrying room for improvement.

Impact of lymphovascular invasion on otherwise low-risk papillary thyroid carcinomas: a retrospective and observational study.

PURPOSE: Presence of venous vascular invasion is a criterion of intermediate risk of recurrence in papillary thyroid carcinoma (PTC). However, the presence and type of vascular invasion (lymphatic or venous) is often underreported and its impact on PTCs without other risk features remains unknown. The aim of this study was to evaluate the impact of both lymphatic and venous invasion on the risk of recurrence/persistence on otherwise low-risk PTCs. METHODS: Retrospective study including patients with otherwise low-risk PTCs but with vascular invasion, diagnosed between 2013 and 2019. The persistence/recurrence during the follow-up was evaluated. Pathology was reviewed to confirm the presence of lymphovascular invasion and determine the type of invasion. RESULTS: A total of 141 patients were included. Lymphovascular invasion was confirmed in 20.6%. After surgery, 48.9% (N = 69) of the patients received radioactive iodine (RAI). The median follow-up time was 4 [3-6] years. Overall, 6 (4.2%) patients experienced persistent/recurrent disease in the neck, including 3 with lymphovascular invasion, confirmed as "only lymphatic". Overall, patients with tumors harboring lymphovascular invasion had sensibly more persistent/recurrence disease compared with those without lymphovascular invasion (10.3% vs 2.7%, p = 0.1), especially in the subgroup of patients not treated with RAI (20% vs 1.6%, p = 0.049) [OR 15.25, 95% CI 1.24-187.85, p = 0.033]. CONCLUSION: Lymphovascular invasion, including lymphatic invasion only, is associated with a sensibly higher risk of persistent/recurrent disease in otherwise low-risk PTCs, namely in patients not treated with RAI. Lymphatic invasion could have a role in risk-stratification systems for decision making.

Immune checkpoints are predominantly co-expressed by clonally expanded CD4+FoxP3+ intratumoral T-cells in primary human cancers.

BACKGROUND: In addition to anti-PD(L)1, anti-CTLA-4 and anti-LAG-3, novel immune checkpoint proteins (ICP)-targeted antibodies have recently failed to demonstrate significant efficacy in clinical trials. In these trials, patients were enrolled without screening for drug target expression. Although these novel ICP-targeted antibodies were expected to stimulate anti-tumor CD8 + T-cells, the rationale for their target expression in human tumors relied on pre-clinical IHC stainings and transcriptomic data, which are poorly sensitive and specific techniques for assessing membrane protein expression on immune cell subsets. Our aim was to describe ICP expression on intratumoral T-cells from primary solid tumors to better design upcoming neoadjuvant cancer immunotherapy trials. METHODS: We prospectively performed multiparameter flow cytometry and single-cell RNA sequencing (scRNA-Seq) paired with TCR sequencing on freshly resected human primary tumors of various histological types to precisely determine ICP expression levels within T-cell subsets. RESULTS: Within a given tumor type, we found high inter-individual variability for tumor infiltrating CD45 + cells and for T-cells subsets. The proportions of CD8+ T-cells (~ 40%), CD4+ FoxP3- T-cells (~ 40%) and CD4+ FoxP3+ T-cells (~ 10%) were consistent across patients and indications. Intriguingly, both stimulatory (CD25, CD28, 4-1BB, ICOS, OX40) and inhibitory (PD-1, CTLA-4, PD-L1, CD39 and TIGIT) checkpoint proteins were predominantly co-expressed by intratumoral CD4+FoxP3+ T-cells. ScRNA-Seq paired with TCR sequencing revealed that T-cells with high clonality and high ICP expressions comprised over 80% of FoxP3+ cells among CD4+ T-cells. Unsupervised clustering of flow cytometry and scRNAseq data identified subsets of CD8+ T-cells and of CD4+ FoxP3- T-cells expressing certain checkpoints, though these expressions were generally lower than in CD4+ FoxP3+ T-cell subsets, both in terms of proportions among total T-cells and ICP expression levels. CONCLUSIONS: Tumor histology alone does not reveal the complete picture of the tumor immune contexture. In clinical trials, assumptions regarding target expression should rely on more sensitive and specific techniques than conventional IHC or transcriptomics. Flow cytometry and scRNAseq accurately characterize ICP expression within immune cell subsets. Much like in hematology, flow cytometry can better describe the immune contexture of solid tumors, offering the opportunity to guide patient treatment according to drug target expression rather than tumor histological type.

Epithelial-Myoepithelial Carcinoma of the Maxilla Arising From Minor Salivary Glands of Hard Palate: A Rare Case Report.

Epithelial-myoepithelial carcinoma is a rare malignant neoplasm of salivary glands. It is specifically found in the major salivary glands. The cases that emerge from minor salivary glands are rarely described. Histologically, it commonly exhibits a characteristic biphasic pattern consisting of epithelial and myoepithelial components. The histopathological resemblance to other benign and malignant neoplasms that also display myoepithelial characteristics makes the differential diagnosis challenging. Each differential diagnosis requires a very different management approach. Considering the difficulties of anatomopathological diagnosis and the rarity of epithelial-myoepithelial carcinomas emerging from minor salivary glands, we report a rare epithelial-myoepithelial carcinoma case of minor salivary glands in a 58-year-old woman. She was referred for a palatal swelling, evolving for more than 35 years, and reported recent pain and nasal obstruction. The mucosal swelling was located in the left maxilla within the hard palate, of a 45-mm-long axis crossing the medial line and extending to the premaxilla, without cervical lymph node involvement. A computed tomography scan revealed a palatal lesion involving the left and the right maxilla. Furthermore, the superior alveolar process, both left and right maxillary sinuses, the nasal cavities, and the nasal septum were included in the lesion. The final diagnosis was difficult to confirm despite multiple biopsies and was determined only from the excised specimen. The diagnosis of this tumor was challenging due to the clinical and histological similarities with other salivary tumors. The aim of this case report is to shed light on the distinctive features of these tumors and explore optimal screening and related management strategies.

Sox9 Inhibits Cochlear Hair Cell Fate by Upregulating Hey1 and HeyL Antagonists of Atoh1.

It is widely accepted that cell fate determination in the cochlea is tightly controlled by different transcription factors (TFs) that remain to be fully defined. Here, we show that Sox9, initially expressed in the entire sensory epithelium of the cochlea, progressively disappears from differentiating hair cells (HCs) and is finally restricted to supporting cells (SCs). By performing ex vivo electroporation of E13.5-E14.5 cochleae, we demonstrate that maintenance of Sox9 expression in the progenitors committed to HC fate blocks their differentiation, even if co-expressed with Atoh1, a transcription factor necessary and sufficient to form HC. Sox9 inhibits Atoh1 transcriptional activity by upregulating Hey1 and HeyL antagonists, and genetic ablation of these genes induces extra HCs along the cochlea. Although Sox9 suppression from sensory progenitors ex vivo leads to a modest increase in the number of HCs, it is not sufficient in vivo to induce supernumerary HC production in an inducible Sox9 knockout model. Taken together, these data show that Sox9 is downregulated from nascent HCs to allow the unfolding of their differentiation program. This may be critical for future strategies to promote fully mature HC formation in regeneration approaches.

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.

Risk staging with prophylactic unilateral central neck dissection in low-risk papillary thyroid carcinoma.

OBJECTIVE: Current guidelines favor thyroid lobectomy for intrathyroidal cT1bT2cN0 papillary thyroid carcinoma. Prophylactic neck dissection (PND) is not recommended for these low-risk tumors due to the lack of high-level evidence on improvement in outcomes, but the information from PND may be used for staging. The aim of this study was to evaluate the rate of upstaging with ipsilateral PND. MATERIALS AND METHODS: Retrospective study of patients with intrathyroidal unifocal cT1bT2cN0 papillary thyroid carcinoma from 2008 to 2021. All patients underwent total thyroidectomy and PND. Tumors were classified as low or intermediate risk based on the information from pathological analysis of the primary tumor and then from adding the analysis of the lymph nodes. The difference between the tumor-only and the PND-added risk staging was evaluated. RESULTS: Three hundred three patients (241 women, median age 45, median tumor size 17 mm) were included. Microscopic extrathyroidal extension was found in 23.4%, aggressive histology in 6.6%, vascular invasion in 29.3%, and lymph node metastases in 37.3%. One hundred ten patients (36.3%) were intermediate-risk based on the primary tumor. An additional 26 (8.6%) were upstaged to intermediate-risk based on the ipsilateral PND and 2% based on the contralateral PND. Kaplan-Meier 10-year event-free survival in tumors upstaged with ipsilateral PND was not statistically different from intermediate-risk tumors based on the primary tumor characteristics (92% versus 90.9%, Log Rank p = 0.943). CONCLUSIONS: Ipsilateral PND upstaged low-risk cT1bT2cN0 patients to intermediate risk in only 8.6% of cases, and contralateral PND in an additional 2%. Routinely performing PND may not be warranted.

Plasma galectins and metabolites in advanced head and neck carcinomas: evidence of distinct immune characteristics linked to hypopharyngeal tumors.

Extra-cellular galectins 1, 3 and 9 (gal-1, -3 and -9) are known to act as soluble immunosuppressive agents in various malignancies. Previous publications have suggested that their expression is dependent on the metabolic status of producing cells and reciprocally that they can influence metabolic pathways in their target cells. Very little is known about the status of gal-1, -3 and -9 in patients bearing head and neck squamous cell carcinomas (HNSCC) and about their relationships with the systemic metabolic condition. This study was conducted in plasma samples from a prospective cohort of 83 HNSCC patients with advanced disease. These samples were used to explore the distribution of gal-1, -3 and -9 and simultaneously to profile a series of 87 metabolites assessed by mass spectrometry. We identified galectin and metabolic patterns within five disease categories defined according to the primary site and human papillomavirus (HPV) status (HPV-positive and -negative oropharyngeal carcinomas, carcinomas of the oral cavity, hypopharynx and larynx carcinomas). Remarkably, samples related to hypopharyngeal carcinomas displayed the highest average concentration of gal-9 (p = .017) and a trend toward higher concentrations of kynurenine, a potential factor of tumor growth and immune suppression. In contrast, there was a tendency toward higher concentrations of fatty acids in samples related to oral cavity. These observations emphasize the diversity of HPV-negative HNSCCs. Depending on their primary site, they evolve into distinct types of immune and metabolic landscapes that seem to be congruent with specific oncogenic mechanisms.

Intraoperative Parathyroid Gland Identification Using Autofluorescence Imaging in Thyroid Cancer Surgery with Central Neck Dissection: Impact on Post-Operative Hypocalcemia.

Hypoparathyroidism is the most frequent complication in thyroid surgery. The aim of this study was to evaluate the impact of intraoperative parathyroid gland identification, using autofluorescence imaging, on the rate of post-operative (PO) hypoparathyroidism in thyroid cancer surgery. Patients undergoing total thyroidectomy with central neck dissection from 2018 to 2022 were included. A prospective cohort of 77 patients operated on using near-infrared autofluorescence (NIRAF+) with the Fluobeam® (Fluoptics, Grenoble, France) system was compared to a retrospective cohort of 94 patients (NIR-). The main outcomes were the rate of PO hypocalcemia, with three cutoffs: corrected calcium (Cac) < 2.10 mmol/L, <2.00 mmol/L and <1.875 mmol/L, and the rate of permanent hypoparathyroidism, at 12 months. The rate of PO Cac < 2.10 mmol/L was statistically lower in the NIRAF+ group, compared to the control group (36% and 60%, p = 0.003, respectively). No statistically significant difference was observed for the other two thresholds. There was a lower rate of permanent hypoparathyroidism in the NIRAF+ group (5% vs. 14% in the control group), although not statistically significant (p = 0.07). NIRAF is a surgically non-invasive adjunct, and can improve patients' outcomes for thyroid cancer surgery by reducing post-operative temporary hypoparathyroidism. Larger prospective studies are warranted to validate our findings.

2011-2021 rising prevalence of HPV infection among oropharyngeal carcinoma in France.

BACKGROUND: The objective of our study was to investigate changes over the past decade in patient age and the prevalence of HPV in the population of patients with oropharyngeal carcinoma (OPC) treated at our center. METHODS: We performed a retrospective cohort study of patients treated at our cancer center for OPC between 2011 and 2021. Tissue biopsies were assessed for HPV status based on p16 staining for all patients. RESULTS: There were 1,365 treated patients. The proportion of p16-positive patients increased from 43% in 2011 to 57.3% in 2021 (p = 0.01). The sex ratio was 3.6 M/1F for p16-positive and 3.7 M/1F for p16-negative patients (p = 0.94). The mean age increased from 60.2 y in 2011 to 63.6 y in 2021. The mean ages were 61.9 y for p16-positive and 61.7 y for p16-negative patients (p = 0.71), but there was a broader age distribution for the p16-positive patients (p = 0.03). The proportion of patients older than 70 y increased from 11% in 2011 to 28.2% in 2021, and this aging was similar between p16-positive (30.7% in 2021) and p16-negative (26.3% in 2021) patients. The 2-year and 5-year OS rates were 73.7% and 56.5% for the entire cohort. p16-positive patients had 2-year and 5-year OS rates of 86.8% and 77.4%, respectively, whereas p16-negative patients had 2-year and 5-year OS rates of 63.9% and 40.5%. CONCLUSIONS: Assessment of the change over the past decade in the population of patients with OPC at our center showed that HPV-positive OPC now appear to have overtaken HPV-negative cases in France, with 57.3% in 2021, and showed significant aging, with almost thirty percent of patients now older than 70 years. Those combined changes emphasize some of the challenges to be addressed in future OPC management.

Strategies for Radioiodine Treatment: What's New.

Radioiodine treatment (RAI) represents the most widespread and effective therapy for differentiated thyroid cancer (DTC). RAI goals encompass ablative (destruction of thyroid remnants, to enhance thyroglobulin predictive value), adjuvant (destruction of microscopic disease to reduce recurrences), and therapeutic (in case of macroscopic iodine avid lesions) purposes, but its use has evolved over time. Randomized trial results have enabled the refinement of RAI indications, moving from a standardized practice to a tailored approach. In most cases, low-risk patients may safely avoid RAI, but where necessary, a simplified protocol, based on lower iodine activities and human recombinant TSH preparation, proved to be just as effective, reducing overtreatment or useless impairment of quality of life. In pediatric DTC, RAI treatments may allow tumor healing even at the advanced stages. Finally, new challenges have arisen with the advancement in redifferentiation protocols, through which RAI still represents a leading therapy, even in former iodine refractory cases. RAI therapy is usually well-tolerated at low activities rates, but some concerns exist concerning higher cumulative doses and long-term outcomes. Despite these achievements, several issues still need to be addressed in terms of RAI indications and protocols, heading toward the RAI strategy of the future.

Pathological Analysis of Encased Resected Recurrent Nerves in Locally Invasive Thyroid Cancer.

OBJECTIVE: Thyroid cancer encasing the recurrent nerve is rare, and the decision to resect or preserve the nerve is multifactorial. The objective of this study was to histopathologically analyze resected encased nerves to assess the rate of nerve invasion and risk factors. MATERIALS AND METHODS: A retrospective study was carried out on consecutive patients with resection of the recurrent nerve for primary or recurrent follicular cell-derived or medullary thyroid carcinoma from 2005 to 2020. Demographics, pathology, locoregional invasion, metastases, recurrences and survival were analyzed. Slides were reviewed blindly by two specialized pathologists (AAG, RC) for diagnosis of invasion deep to the epineurium. RESULTS: Fifty-two patients were included: 25 females; average age, 55 (range 8-87). In total, 87% percent (45/52) were follicular cell-derived with 17/45 (37.8%) aggressive variants; 13% (7/52) were medullary carcinoma. Preoperative vocal fold (VF) paralysis was present in 16/52 (30.7%). Pathologically, the nerve was invaded in 44/52 cases (85%): 82% of follicular cell-derived tumors (37/45), 88% of pediatric cases, and 100% of medullary carcinomas (7/7). Nerve invasion was observed in 11/16 (69%) with preoperative VF paralysis and 33/36 (92%) with normal VF function. Only aggressive histology was correlated with nerve invasion in follicular cell-derived tumors (p = 0.019). CONCLUSIONS: The encased nerves were pathologically invaded in 82% of follicular cell-derived tumors and in 100% of medullary carcinomas. Nerve invasion was statistically correlated with aggressive histopathological subtypes and was observed in the absence of VF paralysis in 92% of cases.

Unmet Needs and Perspectives in Oral Cancer Prevention.

Oral potentially malignant disorders (OPMD) may precede oral squamous cell carcinoma (OSCC). Reported rates of malignant transformation of OPMD range from 3 to 50%. While some clinical, histological, and molecular factors have been associated with a high-risk OPMD, they are, to date, insufficiently accurate for treatment decision-making. Moreover, this range highlights differences in the clinical definition of OPMD, variation in follow-up periods, and molecular and biological heterogeneity of OPMD. Finally, while treatment of OPMD may improve outcome, standard therapy has been shown to be ineffective to prevent OSCC development in patients with OPMD. In this perspective paper, several experts discuss the main challenges in oral cancer prevention, in particular the need to (i) to define an OPMD classification system by integrating new pathological and molecular characteristics, aiming (ii) to better identify OPMD at high risk of malignant transformation, and (iii) to develop treatment strategies to eradicate OPMD or prevent malignant transformation.

Confocal laser endomicroscopy and confocal microscopy for head and neck cancer imaging: Recent updates and future perspectives.

Confocal laser endomicroscopy (CLE) is a promising technology that provides real-time histological visualization of living tissue, described as "optical biopsy". It has been used successfully in dermatology, gastroenterology and ophthalmology for clinical diagnosis and tumor margin assessment. In addition to in vivo tissue assessment, confocal microscopy can also be used ex vivo on freshly excised or fixed tissue for intraoperative tumor margin assessment. While CLE and ex vivo confocal microscopy (EVCM) have shown promising results for the identification of head and neck cancers at cell level, several methodological issues need to be addressed before they can be widely used in routine clinical use. The present review will focus on recent advances in CLE and EVCM in the diagnosis and management of head and neck cancer and discuss remaining challenges for their clinical application.

Preoperative ultrasound mapping of the vagus nerve in thyroid surgery.

BACKGROUND: Intraoperative neuromonitoring (IONM) in thyroid surgery requires electric stimulation of the vagus nerve to verify correct electrode placement. Classically the nerve is found deep to or in-between the common carotid artery and internal jugular vein, but previous studies have shown that the nerve can sometimes be found superficial to the vessels. Our aim was to determine the incidence of a superficial vagus nerve using ultrasound (US) and study possible clinical factors associated with an anteriorly-located vagus nerve. METHODS: Retrospective study of patients undergoing thyroid surgery (lobectomy or total thyroidectomy) with intermittent IONM. Substernal goiters, locally invasive tumors or bulky lymph nodes were excluded. The vagus nerve was identified at the level of the mid-thyroid lobe on each side on preoperative US performed by two specialized radiologists, and its location according to 6 possible positions in relationship to the common carotid artery was recorded. The anatomic variability of the vagus nerve was analyzed in relationship to patient demographics and thyroid pathology. RESULTS: Five-hundred twenty-seven patients were included. The right vagus nerve (n=522) was in-between, superficial or deep to the vessels in 92.3%, 6.1% and 1.5% and of cases, respectively, and the left vagus (n=517) in 80.2%, 18.6% and 1.2% of cases, respectively, with a statistically significant difference between right and left vagus nerves (P<0.001). The type of pathology, size of the dominant nodule or the volume of the thyroid lobe were not correlated to finding a superficial vagus nerve. CONCLUSIONS: The vagus nerve was identified in all cases on US and found to be anterior to common carotid artery at the level of the thyroid lobe in 18.6% of cases on the left and 6.1% of cases on the right. Identifying this anatomic variant preoperatively may facilitate IONM and avoid inadvertent trauma to the vagus nerve during thyroid surgery.

Patterns of disease events and causes of death in patients with HPV-positive versus HPV-negative oropharyngeal carcinoma.

BACKGROUND AND PURPOSE: There have been no studies to date of patterns of events after oropharyngeal squamous cell carcinoma (OPC) treatment comprising disease progression immediately after treatment or after a disease-free interval (DFI), and causes of death, according to HPV status. MATERIALS AND METHODS: Patients with a T1-4, N0-3, M0 OPC who completed treatment in a curative intent at our center between 2011 and 2020 were analyzed. A DFI was defined as the absence of the disease confirmed by both physical and radiological evaluation. RESULTS: We analyzed 888 patients, of who 451 were p16-positive and 437 were p16-negative. The 5-year survival rates were 82.4% vs. 44%, respectively (p < 0.0001, HR 0.24). The rates of disease progression at the end of the treatment without a DFI were 7.8% vs. 21.1% in the p16-positive vs. the p16-negative patients (p < 0.0001, OR 0.38). The 5-year competing risks of disease recurrence after a DFI were 5.6% vs. 20.5%, respectively (p < 0.0001, HR 0.26). Patients who were p16-positive had a lower risk of death from OPC disease (p < 0.0001, HR 0.23). The 5-year competing risks of a second primary cancer during follow-up were 16.1% vs. 49.9% (p = 0.0002) in the p16-positive vs. the p16- negative patients. Patients who were p16-positive had a lower risk of death from intercurrent causes (p < 0.0001, HR 0.17). CONCLUSION: Clinical trials and medical interventions dedicated to each category of events and causes of death are needed to improve survival in HPV-positive and HPV-negative OPC patients.

Disease-free time stratification in locally recurrent head and neck carcinoma after definitive radiotherapy or chemoradiotherapy.

PURPOSE: There is no standard definition of disease-free interval before local recurrence after treatment in head and neck carcinoma (HNSCC). We evaluated an easy-to-use stratification and its association with survival in a large cohort of patients. METHODS: We performed a retrospective cohort analysis of prognostic variables in 325 HNSCC patients with a local recurrence after definitive radiotherapy or concurrent chemoradiotherapy. Endpoints were overall survival (OS) and post-recurrence survival (PRS). RESULTS: Variables associated with the survival were the patient age (OS p < 0.0001, PRS p < 0.0001), the initial disease stage (OS p = 0.24, PRS p = 0.0358), localization (OS p = 0.012, PRS p = 0.0002), a complete initial response to treatment (OS p < 0.0001, PRS p = 0.019), synchronous regional or distant metastatic disease (OS p = 0.0094, PRS p < 0.0001), a salvage surgery (OS p < 0.0001, PRS p < 0.0001) and time to recurrence (OS p = 0.0002, PRS p = 0.0029). Time to recurrence could be stratified between specific prognostic time categories that comprised disease persistence, early recurrence (< 12 months), standard recurrence (12 months-5 years) and late recurrence (> 5 years). CONCLUSION: In HNSCC patients, time to local recurrence is a prognostic variable that can be defined using an easy-to-use stratification.

Diagnostic accuracy of in vivo early tumor imaging from probe-based confocal laser endomicroscopy versus histologic examination in head and neck squamous cell carcinoma.

OBJECTIVES: Probe-based confocal laser endomicroscopy (pCLE) is a noninvasive and real-time imaging technique allowing acquisition of in situ images of the tissue microarchitecture during oral surgery. We aimed to assess the diagnostic performance of pCLE combined with patent blue V (PB) in improving the management of early oral cavity, oro/hypopharyngeal, and laryngeal cancer by imaging squamous cell carcinoma in vivo. MATERIALS AND METHODS: The prospective study enrolled 44 patients with early head and neck lesions. All patients underwent white-light inspection or panendoscopy depending on the lesion's location, followed by pCLE imaging of the tumor core and its margins after topical application of PB. Each zone imaged by pCLE was interpreted at distance of the exam by three pathologists blinded to final histology. RESULTS: Most imaged zones could be presented to pathologists; the final sensitivity and specificity of pCLE imaging in head and neck cancers was 73.2-75% and 30-57.4%, respectively. During imaging, head and neck surgeons encountered some challenges that required resolving, such as accessing lesions with the flexible optical probe, achieving sufficiently precise imaging on the targeted tissues, and heterogeneous tissue staining by fluorescent dye. CONCLUSION: Final sensitivity scores were reasonable but final specificity scores were low. pCLE zones used to calculate specificity were acquired in areas of tumor margins, and the poor quality of the images acquired in these areas explains the final low specificity scores. CLINICAL RELEVANCE: Practical adjustments and technical training are needed to analyze head and neck lesions in various anatomical sites in real-time by pCLE.