Novel cellular systems unveil mucosal melanoma initiating cells and a role for PI3K/Akt/mTOR pathway in mucosal melanoma fitness.

BACKGROUND: Mucosal Melanomas (MM) are highly aggressive neoplasms arising from mucosal melanocytes. Current treatments offer a limited survival benefit for patients with advanced MM; moreover, the lack of pre-clinical cellular systems has significantly limited the understanding of their immunobiology. METHODS: Five novel cell lines were obtained from patient-derived biopsies of MM arising in the sino-nasal mucosa and designated as SN-MM1-5. The morphology, ultrastructure and melanocytic identity of SN-MM cell lines were validated by transmission electron microscopy and immunohistochemistry. Moreover, in vivo tumorigenicity of SN-MM1-5 was tested by subcutaneous injection in NOD/SCID mice. Molecular characterization of SN-MM cell lines was performed by a mass-spectrometry proteomic approach, and their sensitivity to PI3K chemical inhibitor LY294002 was validated by Akt activation, measured by pAkt(Ser473) and pAkt(Thr308) in immunoblots, and MTS assay. RESULTS: This study reports the validation and functional characterization of five newly generated SN-MM cell lines. Compared to the normal counterpart, the proteomic profile of SN-MM is consistent with transformed melanocytes showing a heterogeneous degree of melanocytic differentiation and activation of cancer-related pathways. All SN-MM cell lines resulted tumorigenic in vivo and display recurrent structural variants according to aCGH analysis. Of relevance, the microscopic analysis of the corresponding xenotransplants allowed the identification of clusters of MITF-/CDH1-/CDH2 + /ZEB1 + /CD271 + cells, supporting the existence of melanoma-initiating cells also in MM, as confirmed in clinical samples. In vitro, SN-MM cell lines were sensitive to cisplatin, but not to temozolomide. Moreover, the proteomic analysis of SN-MM cell lines revealed that RICTOR, a subunit of mTORC2 complex, is the most significantly activated upstream regulator, suggesting a relevant role for the PI3K-Akt-mTOR pathway in these neoplasms. Consistently, phosphorylation of NDRG1 and Akt activation was observed in SN-MM, the latter being constitutive and sustained by PTEN loss in SN-MM2 and SN-MM3. The cell viability impairment induced by LY294002 confirmed a functional role for the PI3K-Akt-mTOR pathway in SN-MM cell lines. CONCLUSIONS: Overall, these novel and unique cellular systems represent relevant experimental tools for a better understanding of the biology of these neoplasms and, as an extension, to MM from other sites.

Metabolic Clues to Bile Acid Patterns and Prolonged Survival in Patients with Metastatic Soft-Tissue Sarcoma Treated with Trabectedin.

Metastatic soft-tissue sarcomas (mSTS) encompass a highly heterogeneous group of rare tumours characterized by different clinical behaviours and outcomes. Currently, prognostic factors for mSTS are very limited, posing significant challenges in predicting patient survival. Within a cohort of 39 mSTS patients undergoing trabectedin treatment, it was remarkable to find one patient who underwent 73 cycles of trabectedin achieving an unforeseen clinical outcome. To identify contributing factors to her exceptional long-term survival, we have explored circulation metabolomics and biohumoral biomarkers to uncover a potential distinct host biochemical phenotype. The long-term survival patient compared with the other mSTS patients exhibited a distinctive metabolic profile characterized by remarkably higher levels of ursodeoxycholic acid (UDCA) derivatives and vitamin D and lower levels of lithocholic acid (LCA) derivatives, as well as reduced levels of inflammatory C-Reactive Protein 4 (C-RP4) biomarker. Despite its exploratory nature, this study reveals a potential association between specific bile acid metabolic profiles and mSTS patients' prognosis. Enhanced clinical understanding of the interplay between bile acid metabolism and disease progression could pave the way for new targeted therapeutic interventions which may improve the overall survival of mSTS patients.

Current management and future challenges in salivary glands cancer.

Salivary gland cancers (SGCs) are rare, accounting for less than 5% of all malignancies of the head and neck region, and are morphologically heterogeneous. The diagnosis is mainly based on histology, with the complementary aid of molecular profiling, which is helpful in recognizing some poorly differentiated, borderline, or atypical lesions. Instrumental imaging defines the diagnosis, representing a remarkable tool in the treatment plan. Ultrasound and magnetic resonance are the most common procedures used to describe the primary tumour. The treatment of SGCs is multimodal and consists of surgery, radiotherapy, and systemic therapy; each treatment plan is, however, featured on the patient and disease's characteristics. On 24 June 2022, in the meeting "Current management and future challenges in salivary gland cancers" many experts in this field discussed the state of the art of SGCs research, the future challenges and developments. After the meeting, the same pool of experts maintained close contact to keep these data further updated in the conference proceedings presented here. This review collects the insights and suggestions that emerged from the discussion during and after the meeting per se.

Prospective, Multicenter Phase II Trial of Non-Pegylated Liposomal Doxorubicin Combined with Ifosfamide in First-Line Treatment of Advanced/Metastatic Soft Tissue Sarcomas.

Doxorubicin is a widely used anticancer agent as a first-line treatment for various tumor types, including sarcomas. Its use is hampered by adverse events, among which is the risk of dose dependence. The potential cardiotoxicity, which increases with higher doses, poses a significant challenge to its safe and effective application. To try to overcome these undesired effects, encapsulation of doxorubicin in liposomes has been proposed. Caelyx and Myocet are different formulations of pegylated (PLD) and non-pegylated liposomal doxorubicin (NPLD), respectively. Both PLD and NPLD have shown similar activity compared with free drugs but with reduced cardiotoxicity. While the hand-foot syndrome exhibits a high occurrence among patients treated with PLD, its frequency is notably reduced in those receiving NPLD. In this prospective, multicenter, one-stage, single-arm phase II trial, we assessed the combination of NPLD and ifosfamide as first-line treatment for advanced/metastatic soft tissue sarcoma (STS). Patients received six cycles of NPLD (50 mg/m2) on day 1 along with ifosfamide (3000 mg/m2 on days 1, 2, and 3 with equidose MESNA) administered every 3 weeks. The overall response rate, yielding 40% (95% CI: 0.29-0.51), resulted in statistical significance; the disease control rate stood at 81% (95% CI: 0.73-0.90), while only 16% (95% CI: 0.08-0.24) of patients experienced a progressive disease. These findings indicate that the combination of NPLD and ifosfamide yields a statistically significant response rate in advanced/metastatic STS with limited toxicity.

Novel metabolomics-biohumoral biomarkers model for predicting survival of metastatic soft-tissue sarcomas.

Soft tissue sarcomas (STSs) are rare malignant tumors that are difficult to prognosticate using currently available instruments. Omics sciences could provide more accurate and individualized survival predictions for patients with metastatic STS. In this pilot, hypothesis-generating study, we integrated clinicopathological variables with proton nuclear magnetic resonance (1H NMR) plasma metabolomic and lipoproteomic profiles, capturing both tumor and host characteristics, to identify novel prognostic biomarkers of 2-year survival. Forty-five metastatic STS (mSTS) patients with prevalent leiomyosarcoma and liposarcoma histotypes receiving trabectedin treatment were enrolled. A score combining acetate, triglycerides low-density lipoprotein (LDL)-2, and red blood cell count was developed, and it predicts 2-year survival with optimal results in the present cohort (84.4% sensitivity, 84.6% specificity). This score is statistically significant and independent of other prognostic factors such as age, sex, tumor grading, tumor histotype, frailty status, and therapy administered. A nomogram based on these 3 biomarkers has been developed to inform the clinical use of the present findings.

Pharmacometabolomics of trabectedin in metastatic soft tissue sarcoma patients.

Objective: Trabectedin is an anti-cancer drug commonly used for the treatment of patients with metastatic soft tissue sarcoma (mSTS). Despite its recognized efficacy, significant variability in pharmacological response has been observed among mSTS patients. To address this issue, this pharmacometabolomics study aimed to identify pre-dose plasma metabolomics signatures that can explain individual variations in trabectedin pharmacokinetics and overall clinical response to treatment. Methods: In this study, 40 mSTS patients treated with trabectedin administered by 24 h-intravenous infusion at a dose of 1.5 mg/m2 were enrolled. The patients' baseline plasma metabolomics profiles, which included derivatives of amino acids and bile acids, were analyzed using multiple reaction monitoring LC-MS/MS together with their pharmacokinetics profile of trabectedin. Multivariate Partial least squares regression and univariate statistical analyses were utilized to identify correlations between baseline metabolite concentrations and trabectedin pharmacokinetics, while Partial Least Squares-Discriminant Analysis was employed to evaluate associations with clinical response. Results: The multiple regression model, derived from the correlation between the AUC of trabectedin and pre-dose metabolomics, exhibited the best performance by incorporating cystathionine, hemoglobin, taurocholic acid, citrulline, and the phenylalanine/tyrosine ratio. This model demonstrated a bias of 4.6% and a precision of 17.4% in predicting drug AUC, effectively accounting for up to 70% of the inter-individual pharmacokinetic variability. Through the use of Partial least squares-Discriminant Analysis, cystathionine and hemoglobin were identified as specific metabolic signatures that effectively distinguish patients with stable disease from those with progressive disease. Conclusions: The findings from this study provide compelling evidence to support the utilization of pre-dose metabolomics in uncovering the underlying causes of pharmacokinetic variability of trabectedin, as well as facilitating the identification of patients who are most likely to benefit from this treatment.

International Multicenter Study of Clinical Outcomes of Sinonasal Melanoma Shows Survival Benefit for Patients Treated with Immune Checkpoint Inhibitors and Potential Improvements to the Current TNM Staging System.

Objectives Sinonasal mucosal melanoma (SNMM) is an extremely rare and challenging sinonasal malignancy with a poor prognosis. Standard treatment involves complete surgical resection, but the role of adjuvant therapy remains unclear. Crucially, our understanding of its clinical presentation, course, and optimal treatment remains limited, and few advancements in improving its management have been made in the recent past. Methods We conducted an international multicenter retrospective analysis of 505 SNMM cases from 11 institutions across the United States, United Kingdom, Ireland, and continental Europe. Data on clinical presentation, diagnosis, treatment, and clinical outcomes were assessed. Results One-, three-, and five-year recurrence-free and overall survival were 61.4, 30.6, and 22.0%, and 77.6, 49.2, and 38.3%, respectively. Compared with disease confined to the nasal cavity, sinus involvement confers significantly worse survival; based on this, further stratifying the T3 stage was highly prognostic ( p < 0.001) with implications for a potential modification to the current TNM staging system. There was a statistically significant survival benefit for patients who received adjuvant radiotherapy, compared with those who underwent surgery alone (hazard ratio [HR] = 0.74, 95% confidence interval [CI]: 0.57-0.96, p = 0.021). Immune checkpoint blockade for the management of recurrent or persistent disease, with or without distant metastasis, conferred longer survival (HR = 0.50, 95% CI: 0.25-1.00, p = 0.036). Conclusions We present findings from the largest cohort of SNMM reported to date. We demonstrate the potential utility of further stratifying the T3 stage by sinus involvement and present promising data on the benefit of immune checkpoint inhibitors for recurrent, persistent, or metastatic disease with implications for future clinical trials in this field.

Carboplatin and paclitaxel plus avelumab compared with carboplatin and paclitaxel in advanced or recurrent endometrial cancer (MITO END-3): a multicentre, open-label, randomised, controlled, phase 2 trial.

BACKGROUND: Adding immunotherapy to first-line chemotherapy might improve outcomes for patients with advanced or recurrent endometrial cancer. We aimed to compare carboplatin and paclitaxel versus avelumab plus carboplatin and paclitaxel as first-line treatment with avelumab given concurrent to chemotherapy and as maintenance after the end of chemotherapy. METHODS: MITO END-3 is an open-label, randomised, controlled, phase 2 trial conducted at 31 cancer institutes, hospitals, and universities in Italy. Eligible patients were aged 18 years or older with histologically confirmed advanced (FIGO stage III-IV) or recurrent endometrial cancer, an Eastern Cooperative Oncology Group (ECOG) performance status of 0-1, and no previous systemic anticancer therapy as primary treatment for advanced or metastatic disease. Participants were randomly assigned (1:1) using a computerised minimisation procedure stratified by centre, histology, and stage at study entry, to either receive carboplatin (area under the curve [AUC] 5 mg/mL × min) and paclitaxel (175 mg/m2; standard group) intravenously every 3 weeks for six to eight cycles or avelumab (10 mg/kg intravenously) added to carboplatin and paclitaxel (experimental group) every 3 weeks and then every 2 weeks as a single maintenance treatment after the end of chemotherapy until disease progression or unacceptable toxicity. Patients, treating clinicians, and those assessing radiological examinations were not masked to study treatment. The primary endpoint was investigator-assessed progression-free survival, measured in the intention-to-treat (ITT) population. Patients who received at least one dose of study drug were included in the safety analysis. Experimental group superiority was tested with 80% power and one-tailed α 0·20. This trial is registered with ClinicalTrials.gov (NCT03503786) and EudraCT (2016-004403-31). FINDINGS: From April 9, 2018, to May 13, 2021, 166 women were assessed for eligibility and 39 were excluded. 125 eligible patients were randomly assigned to receive carboplatin and paclitaxel (n=62) or avelumab plus carboplatin and paclitaxel (n=63) and included in the ITT population. The median follow-up was 23·3 months (IQR 13·2-29·6) and was similar between the two groups. 91 progression-free survival events were reported, with 49 events in 62 patients in the standard group and 42 events in 63 patients in the experimental group. The median progression-free survival was 9·9 months (95% CI 6·7-12·1) in the standard group and 9·6 months (7·2-17·7) in the experimental group (HR of progression or death 0·78 [60% CI 0·65-0·93]; one-tailed p=0·085). Serious adverse events were reported more frequently in the experimental group (24 vs seven events in the standard group); neutrophil count decrease was the most frequent grade 3-4 adverse event (19 [31%] of 61 patients in the experimental group vs 26 [43%] of 61 patients in the standard group). Two deaths occurred in the experimental group during treatment (one respiratory failure following severe myositis [possibly related to treatment] and one cardiac arrest [not related to treatment]). INTERPRETATION: Adding avelumab to first-line chemotherapy deserves further testing in patients with advanced or recurrent endometrial cancer, although consideration of mismatch repair status is warranted. FUNDING: Pfizer.

Temporal Evolution and Prognostic Role of Indeterminate Response Sub-Groups in Patients with Differentiated Thyroid Cancer after Initial Therapy with Radioiodine.

The clinical outcome of patients affected by Differentiated Thyroid Carcinoma (DTC) and an indeterminate response (IR) after initial therapy is not yet clear. IR includes three different sub-groups of patients: (1) IRTg+ group: Detectable thyroglobulin (Tg), regardless of antithyroglobulin antibodies (TgAb) presence or imaging studies; (2) IRTgAb+ group: Positive TgAb, regardless of Tg levels and nonspecific imaging findings; (3) IRImaging+ group: Nonspecific findings on neck ultrasonography or faint uptake in the thyroid bed on the whole-body scan, negative TgAb, and undetectable Tg. The main aim of this retrospective study was to investigate the dynamic evolution and prognostic role of these patients. From January 2010 to December 2017, 2176 patients who received radioiodine for DTC after total thyroidectomy were included. Two-hundred-eighty-eight patients had IR one year after therapy (187 TgAb+, 76 Tg+, 25 imaging+). After two years, 110 patients (38%) were reclassified as an excellent response and 5 (2%) as an incomplete response; after five years, 221 (77%) achieved an excellent response and 11 (4%) showed an incomplete response. One-year stimulated Tg and nodal disease at diagnosis may predict the final status of the disease. Progression-free survival was significantly shorter in IRTg+ than in IRTgAb+ and IRimaging+ groups. Considering Tg+ patients, a threshold of 3.3 ng/mL is best to predict prognosis.

Functional profiles of curatively treated adenoid cystic carcinoma unveil prognostic features and potentially targetable pathways.

Adenoid cystic carcinoma (ACC) of salivary gland is a slowly growing tumor showing a propensity for delayed recurrence, with decreased survival rates. The identification of poor prognosis patients may help in defining molecular-based targeted strategies in this rare disease orphan of new treatments. Through a gene expression microarray-based approach followed by GSE functional analysis the expression profile of 46 primary untreated ACC samples and of ACC (h-TERT) tumor cells was analyzed. Patients who experienced early relapse showed enrichment in proliferation-related gene sets, including the G2-M checkpoint, E2F and myc targets, and in gene sets related to IFN signaling and aberrant proteostasis (FDR < 0.1), indicating increased mitotic and transcriptional activity in aggressive ACC. Similar functions were enriched in ACC samples classified by immunohistochemical staining as p63-negative, which exhibited increased protein burden and activation of pro-survival stress response pathways compared to p63-positive tumors. Compared to ACC tissues, ACC (h-TERT) cells share transcriptional features of aggressive p63-negative tumors. These data suggest association of specific pathway alterations with histopathological features of ACC, as recapitulated by p63 testing in patient prognostic stratification, anticipating new avenues for therapeutic intervention.

Cytotoxic effects of targeted agent alone or with chemotherapy in the treatment of adenoid cystic carcinoma: a preclinical study.

Adenoid cystic carcinoma (ACC) is a rare malignancy characterized by high incidence of relapse. When relapsing, ACC has an indolent but relentless behaviour, thus leading to a poor long-term prognosis. The treatment of choice of relapsing ACC remains surgery followed by radiotherapy, whenever feasible. Therapeutic weapons are limited to systemic drugs. The most widely used chemotherapy regimen is the combination of cisplatin and doxorubicin, however with low response rate and not long lasting; there is also a lack of alternatives for second line therapies in case of disease progression. Therefore, a more comprehensive strategy aimed at identifying at preclinical level the most promising drugs or combination is clearly needed. In this study, the cytotoxic effects of two standard chemotherapy drugs, cisplatin and doxorubicin, and of five targeted therapy-drugs was tested in vitro, on an h-TERT immortalized ACC cell line, and in vivo, on zebrafish embryos with ACC tumoral cell xenograft. Then, combinations of one standard chemotherapy drug plus one targeted therapy drug were also evaluated, in order to find the best treatment strategy for ACC. Data obtained demonstrated that both vorinostat and olaparib significantly increased the standard chemotherapy cytotoxic effects, suggesting new interesting therapeutic options for ACC.

Clinical and Histological Prognostic Factors of Recurrence and Malignant Transformation in a Large Series of Oral Potentially Malignant Disorders.

Background: Oral potentially malignant disorders (OPMDs) represent a heterogeneous set of different histological lesions, characterized by the capacity to transform in oral squamous cell carcinoma (OSCC). Despite optimal surgical treatment, approximately 20%-30% of OPMDs may evolve into OSCC. No clear clinical/histological factors are able to identify OPMDs at higher risk of malignant transformation. Materials and Methods: We considered surgically treated patients with a diagnosis of OPMDs, enrolled from 1996 to 2019 at ASST Spedali Civili of Brescia without a diagnosis of OSCC within the previous 2 years. Clinical and histological characteristics were recorded. Outcomes of interest were recurrence-free survival (RFS), defined as the time from surgery for primary OPMD to any relapse of OPMD or malignant transformation, whichever occurred first, and carcinoma-free survival (CFS), defined as the time from surgery for OPMD to malignant transformation. Results: We retrospectively reviewed 106 OPMDs cases. Median age at first diagnosis was 64 years old (IQR = 18.75); female patients comprise 51.9% of the cases. During a median follow-up of 30.5 months (IQR = 44), in 23.5% of patients, malignant transformation occurred. RFS at 1, 5, and 10 years was 92.4%, 60.9%, and 43.2%, respectively. Female sex and history of previous OSCC were independent risk factors for RFS. CFS at 1, 5, and 10 years of follow-up was 97.1%, 75.9%, and 64.4%, respectively. Previous OSCC was an independent risk factor for CFS. Conclusions: In this large series of OPMDs, only previous diagnosis of OSCC was a prognostic factor for further OSCC occurrence. Given the lack of additional clinical/pathological prognostic factors, we advocate further studies into molecular characterization of OPMDs to better stratify the risk of malignant transformation.

Baseline prognostic factors affecting survival in recurrent and/or metastatic salivary gland adenoid cystic carcinoma.

OBJECTIVES: Adenoid cystic carcinoma (AdCC) is a rare disease, with indolent behavior and poor long-term survival. Many studies have evaluated the role of clinical and pathological factors at presentation on the risk of recurrence. In this study we investigated whether baseline demographic, clinical, and pathological characteristics at the time of primary curative treatment could influence the prognosis of patients once local and/or distant recurrence occurred. METHODS: All patients affected by primary salivary gland AdCC and treated with curative surgery from January 1997 to June 2016 were reviewed, evaluating those who later developed loco-regional recurrence and/or distant metastasis. Time from the first relapse to death (recurrent/metastatic overall survival, RMOS) was considered the outcome of interest. RESULTS: Out of 87 surgically treated AdCC patients, 36 relapsing lesions were included. Median ages at first presentation and recurrence were 55 and 60-year-old, respectively; 58% were females. Median disease-free-interval (DFI) was 22.0 months. Five-year RMOS was 47%. At univariate analysis, age ≥ 60-year-old (HR:2.67, p = 0.030), primary tumor lympho-vascular invasion (LVI) (HR:5.38, p = 0.003), adjuvant radiotherapy (RT) in the primary setting (HR:0.37, p = 0.043), and DFI < 30 months (HR:3.94, p = 0.008) significantly affected RMOS. Multivariable analysis confirmed the presence of LVI and shorter DFI as independent risk factors. CONCLUSIONS: Knowledge of baseline clinicopathological features is helpful in the prognostic stratification of patients with recurrent AdCC, with LVI as the most relevant baseline factor. Adjuvant RT demonstrated its protective role on survival even once recurrence occurred, further supporting its adoption in the primary setting.

Long-Term Outcomes Using Electron IOERT APBI for Early Stage Breast Cancer: The Verona University Hospital Experience.

METHODS AND MATERIALS: From July 2006 to December 2015, 295 patients suitable for breast-conserving therapy entered a single-arm phase II study and were treated with IOERT as radical treatment. Inclusion criteria were age >50, postmenopausal status, cT1N0M0 stage, grade G1-G2, positive estrogen receptor status; unicentric and unifocal disease, histologically proven invasive ductal carcinoma no previous breast irradiation, good performance status. RESULTS: With a median follow-up of 7.1 years (95% CI, 6.5;7.4) 6 women (2.0%) experienced a true local recurrence (reappearance of the tumour in the same quadrant). Five-year overall survival and local recurrence-free survival were 96% (95% CI, 92.9;97.8) and 94.9% (95% CI, 91.6;97.0) respectively. CONCLUSION: Our trial suggests that, in highly selected early stage breast cancers, a single-dose IOERT can be safely delivered with excellent results and very low long-term recurrence rates.

Parotid pleomorphic and non-pleomorphic adenomas: a mono-institutional series of 512 patients.

PURPOSE: Pleomorphic adenoma (PA) is the most common benign parotid tumor, with a well-known propensity to recur. Many factors have been advocated as prognostic, but there is no consensus on how they affect local control. We studied how PA recurrence-free survival (RFS) may be affected by the most relevant risk factors in a time-to-event analysis, comparing them with those observed in a population of non-PA (NPA). METHODS: Patients undergoing parotidectomy for benign lesions between 2002 and 2018 in a single academic tertiary referral center were included. A description of patients, tumors, and treatment characteristics was performed, highlighting differences between PA and NPA. Analysis of PA RFS and relative risk factors was also conducted. RESULTS: Eight hundred fifty patients underwent parotidectomy for benign lesions, 455 (53.5%) for PA and 57 (6.7%) for NPA. Significant differences between PA and NPA were age at surgery, surgical procedure, and resection margins. Recurrence occurred in 3.1% of PA, with a median disease-free interval of 54 months. 2-, 5-, and 10-year RFS were 99.2, 98.5, and 93.9%, respectively. Age < 18 years (HR = 31.31, p < 0.001), intraoperative tumor spillage (HR = 6.57, p = 0.041), extensive pseudo-capsule interruption (HR = 5.85, p = 0.023), and resection margins < 1 mm (HR = 3.16, p = 0.085) were associated with RFS. CONCLUSION: Patients affected by NPA were significantly older and treated with more conservative surgical procedures compared to those with PA. In PA, younger age, major pseudo-capsule defects, and surgical margins were the most relevant factors affecting local control. These results confirm the importance of an appropriate surgical management and long-term follow-up in PA.

Regional disease in head and neck cutaneous squamous cell carcinoma: the role of primary tumor characteristics and number of nodal metastases.

PURPOSE: To identify potential risk factors impacting on overall survival (OS) of patients affected by lymph node metastasis from cutaneous squamous cell carcinoma (cSCC) of the head and neck (HN), with special emphasis on primary tumor characteristics and pattern of nodal recurrence (intraparotid and/or cervical). METHODS: A bi-institutional retrospective study on consecutive patients affected by cervical and/or intraparotid NM from HN cSCC and surgically treated with curative intent from May 2010 to January 2020 was conducted. OS was considered the outcome of interest. RESULTS: The study included 89 patients (M:F = 3.4:1; median age, 78 years; range, 22-99). Among the primary tumor characteristics, the most relevant prognostic factors were diameter ≥ 4 cm (hazard ratio [HR] = 2.56, p = 0.010) and depth of infiltration ≥ 6 mm (HR = 3.54, p = 0.027). Cervical NM was associated with worse OS (HR = 2.09, p = 0.016) compared to purely intraparotid NM (5-year OS: 60.9% vs. 28.1%, p = 0.014). At multivariable analysis, age, immunosuppression, pT3-T4 categories and a high burden of nodal disease (> 2 NM) confirmed to be independent risk factors, whereas adjuvant radiotherapy was independently associated with better outcome. CONCLUSION: This study confirms the association of several independent prognosticators related to the patient, primary tumor, and nodal burden status. Patients with cervical NM should be considered at risk for harboring a higher number of metastatic lymph nodes.

Novel Multidisciplinary Salivary Gland Society (MSGS) Questionnaire: An International Consensus.

OBJECTIVES: First, establishment and validation of a novel questionnaire documenting the burden of xerostomia and sialadenitis symptoms, including quality of life. Second, to compare two versions regarding the answering scale (proposed developed answers Q3 vs. 0-10 visual analogue scale Q10) of our newly developed questionnaire, in order to evaluate their comprehension by patients and their reproducibility in time. STUDY DESIGN: The study is a systematic review regarding the evaluation of the existing questionnaire and a cohort study regarding the validation of our new MSGS questionnaire. MATERIALS AND METHODS: A Multidisciplinary Salivary Gland Society (MSGS) questionnaire consisting of 20 questions and two scoring systems was developed to quantify symptoms of dry mouth and sialadenitis. Validation of the questionnaire was carried out on 199 patients with salivary pathologies (digestive, nasal, or age-related xerostomia, post radiation therapy, post radioiodine therapy, Sjögren's syndrome, IgG4 disease, recurrent juvenile parotitis, stones, and strictures) and a control group of 66 healthy volunteers. The coherence of the questionnaire's items, its reliability to distinguish patients from healthy volunteers, its comparison with unstimulated sialometry, and the time to fill both versions were assessed. RESULTS: The novel MSGS questionnaire showed good internal coherence of the items, indicating its pertinence: the scale reliability coefficients amounted to a Cronbach's alpha of 0.92 for Q10 and 0.90 for Q3. The time to complete Q3 and Q10 amounted, respectively, to 5.23 min (±2.3 min) and 5.65 min (±2.64 min) for patients and to 3.94 min (±3.94 min) and 3.75 min (±2.11 min) for healthy volunteers. The difference between Q3 and Q10 was not significant. CONCLUSION: We present a novel self-administered questionnaire quantifying xerostomia and non-tumoral salivary gland pathologies. We recommend the use of the Q10 version, as its scale type is well known in the literature and it translation for international use will be more accurate. Laryngoscope, 132:322-331, 2022.

Prognostic indicators in clinically node-negative malignant primary salivary tumours of the parotid: A multicentre experience.

OBJECTIVES: Nodal metastasis is an important prognosticator in primary parotid cancers. The management of the clinically node-negative neck is an area lacking consensus. This study investigates the occult nodal metastasis rate, and prognostic indicators in primary parotid cancers. MATERIALS AND METHODS: We performed a multicentre retrospective case note review of patients diagnosed and treated surgically with curative intent between 1997 and 2020. Demographic, clinic-pathological and follow-up data was recorded. RESULTS: After exclusions, 334 patients were included for analysis, with a median follow-up of 48 months. The overall rate of occult lymph node metastasis amongst patients undergoing elective neck dissection was 22.4%, with older age, high-grade and more advanced primary tumours being associated with higher rates. On multivariable analysis, age ≥ 60 years (HR = 2.69, p = 0.004), high-grade tumours (HR = 2.70, p = 0.005) and advanced primary tumours (pT3-4, HR = 2.06, p = 0.038) were associated with worse overall survival. Occult nodal metastasis on final pathology was associated with a close-to-significant reduction in regional recurrence free survival (HR = 3.18, p = 0.076). CONCLUSION: This large series confirms the significant occult lymph node metastasis rate in primary parotid cancer, and demonstrates the importance of primary histology, tumour grade and stage in predicting survival outcome. This data supports the use of elective neck dissection in patients with high-risk tumours.

Anterior and Central Skull Base Tumors: Key Points for the Radiologist to Analyze Prior to Endoscopic Approaches.

Initially developed as a minimally invasive technique to approach inflammatory conditions, transnasal endoscopic surgery has progressively expanded its anatomic targets and clinical indications. Consequently, numerous surgical approaches to the anterior and central skull base were developed, referred to as extended endonasal approaches (EEA). The intrinsic advantage of EEA is the exploitation of a natural corridor provided by sinonasal airspaces, with no need for skin incision and osteotomy and limited soft tissue damage. In this context, imaging plays essential role, demonstrating the relevant anatomic relationships of the lesion, the proper surgical corridor, the anatomic variants that may increase the surgical risk.