Outcomes of mini-invasive transoral surgery without neck dissection in supraglottic laryngeal cancer: Real world data from a tertiary cancer center.

PURPOSE: The neck management in early-stage cN0 supraglottic cancer represents an argument of debate. The aim of our study is to evaluate the oncological and functional outcomes in patients with early-stage cN0 supraglottic carcinoma treated with a wait-and-see policy for the neck. MATERIALS AND METHODS: Retrospective monocentric cohort study in a referral cancer care center. We collected a consecutive sample of patients from 2000 to 2020 with Squamous Cell Carcinoma of the supraglottis without clinical evidence of nodal metastases (cN0), surgically treated with Transoral Surgery (Laser or Robotic) without neck dissection. From 316 supraglottic cancer we finally selected 66 eligible participants that met all inclusion criteria. RESULTS: Sixty-six patients (M 75.8 % vs F 24.2 %), median age 65.8 years (IQR 60.9, 70.5). The most common subsite was the epiglottis (62.1 %). Tumor stage distribution was as follows: 35 % cT1, 53 % cT2, 15.2 % cT3. Neither deaths nor major treatment-related complications were reported after surgery. The median follow-up was 62 months. For oncological outcomes, we evaluated 56 patients (10 excluded for adjuvant radiotherapy): 5-year overall survival rate 87 % (CI 95 %: 73.1-94), disease- specific survival rate 95.3 % (CI 95 %: 82-98.8) and neck recurrence-free survival rate 87 % (CI 95 %: 73.1-94). Six patients developed neck recurrence, with a median time of 13 months. CONCLUSIONS: Supraglottic carcinoma has been historically associated to a considerable risk of occult metastasis. However, in early-stage cases data are still inconclusive. Our results suggest that in such patients a wait-and-see policy does not impact negatively on survival outcomes, while granting the reduced morbidity associated to a minimally invasive surgical approach.

Salvage transoral robotic surgery in recurrent oropharyngeal carcinoma: a single-center retrospective study.

PURPOSE: Salvage surgery is still the best therapeutic option for resectable recurrent oropharyngeal squamous cell carcinoma (rOPSCC). Transoral robotic surgery may potentially reduce the morbidity of standard open approaches. The aim of the study is to present oncological and functional outcomes of a monocentric experience in salvage transoral robotic surgery. METHODS: We performed a single-center retrospective analysis of patients submitted to transoral robotic salvage surgery with or without neck dissection for cT1-3 rOPSCC. We investigated complication rate, survival outcomes (Overall Survival, Disease Specific Survival, Loco-Regional Recurrence Free Survival) and functional outcomes (tracheal tube and/or gastrostomy dependence). RESULTS: Sixty-one patients were included in the analysis. No major complications or perioperative deaths were recorded. The estimated 2-year OS was 76.7%, DSS 81.8% and LRRFS 50.5%. In multivariable analysis rpT, PNI (perineural infiltration) and HPV-positivity were significantly associated with LRRFS (Hazard Ratios: T3 vs T1 6.43, PNI yes vs no 4.19, HPV+ yes vs no 2.63). At last follow up, 97% of patients were tracheal tube-free, while 93% were gastrostomy-free. CONCLUSION: Transoral robotic salvage surgery is a successful treatment in selected patients affected by rOPSCC because it grants good oncologic and functional outcomes.

Unlocking tracheoesophageal speech from pharyngoesophageal spasm: preliminary results of a videofluoroscopic-guided botulinum toxin A injection technique.

PURPOSE: The tracheoesophageal puncture for the voice prosthesis (VP) placement is the recognized gold standard in post-laryngectomy voice rehabilitation. Despite the development of specific intraoperative techniques, a subset of patients will suffer from poor functional outcomes due to pharyngoesophageal spasms (PES). This paper evaluates the functional outcomes after transcutaneous botulinum toxin type A (BTX-A) infiltration for PES with a videofluoroscopy-guided technique. METHODS: Since 2022, eight consecutive patients with VP and affected by PES were treated with BTX-A injection by a standard videofluoroscopic guided technique at the European Institute of Oncology, IRCCS (IEO) in Milan. A lidocaine test was performed pre-operatively to evaluate the potential effect of chemical neurectomy. All patients with positive lidocaine tests were injected with 50 IU of BTX-A (Allergan, Irvine, CA) according to the sites marked during the videofluoroscopy. Reported symptoms (VHI, SECEL), perceptual (INFVo), aerodynamic (MPT) and manometric parameters were collected before and after treatment. RESULTS: In all cases, BTX-A was performed as an outpatient procedure without complications. For seven patients, only one BTX-A injection was needed, while one patient required a re-injection. Subjective and perceptive improvement after BTX-A was significant for VHI, SECEL and INFVo. MPT showed significant improvement after a chemical neurectomy. After a mean follow-up of 6 months, all patients maintained a good TES quality. CONCLUSION: The videofluoroscopic guided BTX-A injection of the pharyngoesophageal tract showed to be a feasible and reproducible technique in all cases. The pharyngoesophageal videofluoroscopy allows defining of patients' anatomical landmarks that help the surgeon to perform a homogeneous injection, empowered by post-injection massage.

The T-N tract involvement as a new prognostic factor for PORT in locally advanced oral cavity tumors.

OBJECTIVE: The space comprised between tumor and neck lymph nodes (T-N tract) is one of the main routes of tumor spread in oral cavity tumors. Aim of the study was to investigate the impact of T-N tract involvement on the postoperative radiotherapy (PORT) outcomes. MATERIALS AND METHODS: Patients (pts) treated between 2000 and 2016 with indication to PORT were retrospectively retrieved. Inclusion criteria were: (a) locally advanced tumors of the oral cavity, (b) who received with indication to PORT (c) with a minimum follow-up of six months. RESULTS: One hundred and fifty-seven pts met the inclusion criteria (136 pts treated with PORT and 21 pts not treated with PORT). In the PORT cohort, the T-N tract involvement had no impact on both OS (p = .09) and LRFS (p = .2). Among the non-PORT cohort, both OS (p = .007) and LRFS (p = .017) were worse for pts with positive T-N tract compared to those with negative T-N tract. PORT improved both OS (p = .008) and LRFS (p = .003) in pts with positive T-N tract but not in those with negative T-N tract (p = .36 and p = .37, respectively). CONCLUSIONS: Our results suggest that involvement of T-N tract should be considered as prognostic factors informing the indication to PORT.

Post-diagnosis smoking cessation and survival of patients with head and neck cancer: a systematic review and meta-analysis.

Cigarette smoking is the main risk factor for head and neck cancer (HNC) and many HNC patients are active smokers at diagnosis. We conducted a systematic literature review and meta-analysis to quantify the survival impact of smoking cessation at or around the time of HNC diagnosis. We searched studies published until December 31, 2021, and used random-effects meta-analysis to pool study-specific estimates into summary hazard ratio (SHR) and corresponding 95% confidence intervals (CI). Sixteen studies were published between 1983 and 2021, and over 2300 HNC patients were included. Studies were diverse in terms of design, patients, tumours and treatment characteristics, and criteria used to discriminate quitters from continued smokers. HNC patients who quit smoking at or around diagnosis had significantly better overall survival than continued smokers (SHR 0.80, 95% CI 0.70-0.91, n studies = 10). A beneficial effect of post-diagnosis smoking cessation was suggested for other survival endpoints as well, but the results were based on fewer studies (n = 5) and affected by publication bias. Cessation counselling should be offered to all smokers who start a diagnostic workup for HNC and should be considered standard multidisciplinary oncological care for HNC patients. PROSPERO registration number CRD42021245560.

Upfront surgical organ-preservation strategy in advanced-stage laryngeal cancer.

PURPOSE: Advanced-stage laryngeal cancer is a challenging disease that needs multimodal treatment. Medical and surgical organ-preservation strategies have been developing in the last decades to spare these functions while granting cancer cure. The current work presents the experience of a tertiary-care center in conservative surgery for advanced-stage laryngeal cancer. MATERIALS AND METHODS: We collected clinical data of patients submitted to open partial horizontal laryngectomies (OPHLs) and any possible adjuvant treatment from 2005 to 2018. Outcomes were also compared to the most recent studies reporting on both medical and surgical organ-preservation strategies. RESULTS: One hundred ten patients were included in the analysis. Adjuvant therapy was employed in 51% of cases. The local control rate was 96.4%, while overall survival (OS) was 67%, and laryngo-esophageal dysfunction free survival (LEDFS) was 66%. Stage IV and vascular invasion were associated with a statistically-significant worse survival. CONCLUSIONS: OPHLs are valid as upfront treatment in fit patients affected by advanced-stage laryngeal cancer. Disease control and function preservation are granted in a significant percentage of cases, even when followed by adjuvant therapy.

Laryngeal dysplasia: Oncological outcomes in a large cohort of patients treated in a tertiary comprehensive cancer centre.

PURPOSE: Laryngeal dysplasia represents a series of precancerous lesions, observed as laryngeal leukoplakia. General agreement has been lacking for their management and treatment ranging from simple biopsy to complete excision with cold blade/laser. In this work, we aim at providing the oncological outcomes of patients affected by laryngeal dysplasia, treated with a single modality, and at identifying clinical parameters predictive of malignant transformation. MATERIALS AND METHODS: We performed a retrospective analysis of patients treated with transoral laser microsurgery between January 2005 and December 2015 in a tertiary comprehensive cancer centre. Data were collected about smoke and alcohol habits, site of the laryngeal lesion, surgical outcomes and progression to invasive squamous cell carcinoma. RESULTS: The grade of dysplasia, margins' status and smoke habit were not associated with a significantly worse DFS and a higher risk of invasive SCC. We identified three parameters (supraglottic involvement, multifocality and history of more than one recurrence of dysplasia) that have a significant prognostic value. CONCLUSIONS: On the base of these clinical parameters, a more intensive follow-up might be warranted for high-risk patients.

Mixed-beam approach in locally advanced nasopharyngeal carcinoma: IMRT followed by proton therapy boost versus IMRT-only. Evaluation of toxicity and efficacy.

Objective: To compare radiation-induced toxicity and dosimetry parameters in patients with locally advanced nasopharyngeal cancer (LANPC) treated with a mixed-beam (MB) approach (IMRT followed by proton therapy boost) with an historic cohort of patients treated with a full course of IMRT-only.Material and methods: Twenty-seven patients with LANPC treated with the MB approach were compared to a similar cohort of 17 patients treated with IMRT-only. The MB approach consisted in a first phase of IMRT up to 54-60 Gy followed by a second phase delivered with a proton therapy boost up to 70-74 Gy (RBE). The total dose for patients treated with IMRT-only was 69.96 Gy. Induction chemotherapy was administrated to 59 and 88% and concurrent chemoradiotherapy to 88 and 100% of the MB and IMRT-only patients, respectively. The worst toxicity occurring during the entire course of treatment (acute toxicity) and early-late toxicity were registered according to the Common Terminology Criteria Adverse Events V4.03.Results: The two cohorts were comparable. Patients treated with MB received a significantly higher median total dose to target volumes (p = .02). Acute grade 3 mucositis was found in 11 and 76% (p = .0002) of patients treated with MB and IMRT-only approach, respectively, while grade 2 xerostomia was found in 7 and 35% (p = .02) of patients treated with MB and IMRT-only, respectively. There was no statistical difference in late toxicity. Local progression-free survival (PFS) and progression-free survival curves were similar between the two cohorts of patients (p = .17 and p = .40, respectively). Local control rate was 96% and 81% for patients treated with MB approach and IMRT-only, respectively.Conclusions: Sequential MB approach for LANPC patients provides a significantly lower acute toxicity profile compared to full course of IMRT. There were no differences in early-late morbidities and disease-related outcomes (censored at two-years) but a longer follow-up is required to achieve conclusive results.

Prognostic significance of neutrophil-to-lymphocyte ratio in HPV status era for oropharyngeal cancer.

AIM: To evaluate the role of baseline neutrophil-to-lymphocyte ratio (NLR) as prognostic marker in squamous cell carcinoma of the oropharynx (OPC) treated with definitive chemoradiotherapy (CRT) in the era of HPV status. PATIENTS AND METHODS: A retrospective analysis of 125 patients (pts) affected with locally advanced OPC was performed. Inclusion criteria were age >18 years, stage III or IV (TNM 7th ed.) and definitive CRT. Haematological marker for their independent role as prognostic biomarkers for progression-free survival (PFS) and overall survival (OS). Logistic models were used to assess the association with downstage in TNM 8th ed. RESULTS: Seventy-seven (61.6%) pts had HPV/p16 + related OPC. Therapeutic choice consisted in sequential and concurrent CRT. Median follow-up was 50 months. A value of NLR ≥3 was associated with poorer OS. Two-year OS was 91% and 81% in pts with NLR <3 and ≥3, respectively. CONCLUSION: A baseline NLR ≥ 3 at treatment initiation represented a negative prognostic marker for OPC treated with definitive CRT. These results are in line with literature data, and prognostic value of NLR has been confirmed restaging our cohort with new TNM staging (8th ed.). Therefore, NLR could be considered a valuable biomarker for risk stratification in pts with OPC.

Ultrasound dye-assisted parathyroidectomy (USDAP): Experience of a tertiary center.

BACKGROUND: Primary hyperparathyroidism is primarily caused by parathyroid adenoma, followed by hyperplasia and parathyroid carcinoma. In the era of minimally invasive, targeted parathyroidectomy, the main challenge remains that of distinguishing intraoperatively pathological parathyroid from normal glands and peri-thyroid fat tissue. The aim of this study is to evaluate the surgical outcomes of a novel minimally invasive technique called ultrasound-guided dye-assisted parathyroidectomy (USDAP). METHODS: We perform a retrospective analysis of patients affected by parathyroid adenoma, treated with USDAP at our institution between 2014 and 2019. Data were collected on patient age and sex, tumor location and size, preoperative investigations, histopathology, perioperative complications and surgical outcomes. RESULTS: Between January 2014 and June 2019, 43 patients underwent parathyroidectomy in our Institute. Each case was discussed by the Institutional Multidisciplinary Board. All patients undergoing thyroidectomy together with USDAP or patients undergoing USDAP under endoscopic control were excluded from the present study. The final cohort, the largest to our knowledge, consisted of 29 patients. All patients were successfully treated with USDAP and remained disease-free during follow up. In all cases, pathological parathyroid was correctly identified and removed. There was no postoperative allergic reaction, nor were there neurotoxicity complications. USDAP permitted a shortening of operative and hospitalization time. CONCLUSIONS: USDAP is an effective and safe procedure both as first line treatment and as a re-operative procedure after previous surgical failures in selected cases.

The Role of Transoral Robotic Surgery for Parapharyngeal Space: Experience of a Tertiary Center.

The parapharyngeal space (PPS) is an anatomically and functionally complex region of the craniofacial district. Tumors that originate from this region are rare, and surgery is currently the best practice in the vast majority of cases with different surgical approaches being reported in the literature. Recently, mini-invasive robotic/endoscopic techniques have begun to emerge as effective alternatives in selected cases. In this work, we retrospectively analyzed 17 patients affected by PPS tumors, and managed by transoral robotic surgery (TORS) as a therapeutic or diagnostic procedure. TORS was used alone or combined with a transcervical approach for huge lesions of the PPS, at risk of fragmentation (curative intent). TORS also permitted biopsies of unknown lesions of the PPS to be conducted (diagnostic intent) otherwise unreachable without performing a mandibulotomy. All patients treated with curative intent benefited from radical surgery. No major complications were observed, and tumor fragmentation occurred only in 2 of 17 patients (11.8%). All patients receiving TORS with diagnostic intent were successfully referred to nonsurgical treatments based on the final histhopathological findings. This work also demonstrated TORS to be effective and safe on a larger group of patients compared to our preliminary study in 2016. TORS provides good oncological and functional outcomes when used with curative intent and is an effective diagnostic tool in cases of suspicious lesions of the PPS.

Autophagy regulates UBC9 levels during viral-mediated tumorigenesis.

UBC9, the sole E2-conjugating enzyme required for SUMOylation, is a key regulator of essential cellular functions and, as such, is frequently altered in cancers. Along these lines, we recently reported that its expression gradually increases during early stages of human papillomavirus (HPV)-mediated cervical lesions transformation. However, a better understanding of how UBC9 is exploited by transforming viral oncoproteins is still needed. In the present study, we show that in human samples HPV drives UBC9 up-regulation also in very early steps of head and neck tumorigenesis, pointing to the important role for UBC9 in the HPV-mediated carcinogenic program. Moreover, using HPV-infected pre-cancerous tissues and primary human keratinocytes as the natural host of the virus, we investigate the pathological meaning and the cellular mechanisms responsible for UBC9 de-regulation in an oncoviral context. Our results show that UBC9 overexpression is promoted by transforming viral proteins to increase host cells' resistance to apoptosis. In addition, ultrastuctural, pharmacological and genetic approaches crucially unveil that UBC9 is physiologically targeted by autophagy in human cells. However, the presence of HPV E6/E7 oncoproteins negatively impacts the autophagic process through selective inhibition of autophagosome-lysosome fusion, finally leading to p53 dependent UBC9 accumulation during viral-induced cellular transformation. Therefore, our study elucidates how UBC9 is manipulated by HPV oncoproteins, details the physiological mechanism by which UBC9 is degraded in cells, and identifies how HPV E6/E7 impact on autophagy. These findings point to UBC9 and autophagy as novel hallmarks of HPV oncogenesis, and open innovative avenues towards the treatment of HPV-related malignancies.

From transmandibular to transoral robotic approach for parapharyngeal space tumors.

PURPOSE: Parapharyngeal space (PPS) tumors are rare, accounting for 0.5% of all head-and-neck masses. Surgery remains the standard treatment for most cases, including different approaches (cervical approach, parotidectomy, mandibulotomy, transoral/robotic). We report our experience in the management of PPS tumors, aiming to create a surgical algorithm on the base of tumor's radiological and clinical characteristics. MATERIALS AND METHODS: Critical retrospective analysis of patients with PPS neoplasms who underwent surgery at our Institute. Data were collected on patient age and sex, tumor location and size, preoperative investigations, surgical approaches, histopathology, complications and outcomes. RESULTS: Between January 2000 and July 2015, 53 patients were treated at our Institute. Salivary gland tumors were the most common neoplasms followed by neurogenic tumors. CT scan/MRI were the most used preoperative imaging studies. The cervical approach with or without parotidectomy is the most used, providing the best compromise between the need for radicality and low risk of damage to the neurovascular structures. Mandibulotomy is used whenever the mass extends to the cranial base, assuming a higher morbidity, a slower functional recovery and the need for tracheotomy. Recently, TORS has been used for tumors of the PPS with promising outcomes. CONCLUSIONS: PPS surgery includes a wide spectrum of approaches but it is still a matter of debate which one guarantees better functional and oncological outcomes. We report a surgical algorithm based on surgical invasiveness and tumor characteristics to standardize PPS tumors management. We also highlight the upcoming role of TORS in this field.

Small tongue squamous cell carcinoma with neck metastasis at diagnosis: operative insights and surgical technique.

BACKGROUND: The treatment of tongue tumors includes different surgical procedures ranging from a simple mucosal resection to complex combined resection depending on the tumor stage and size. In 2019 we reported an international glossectomy classification with the purpose of standardizing all the different types of surgical procedures adopted for tongue cancer. METHODS: The present communication aims at providing further insight into the glossectomy classification. More specifically, it is intended to better specify the indications to glossectomy type IIIA and B in selected tongue cancers, with positive cervical lymph nodes at the diagnosis. RESULTS AND CONCLUSIONS: Type IIIA glossectomy permits a high function sparing surgery in selected cases, with better postoperative functional outcomes. From an oncological perspective, it permits a radical surgery, avoiding postoperative radiation in the absence of extracapsular spread, multiple nodal metastases or T-N tract involvement.

c-MYC-dependent transcriptional inhibition of autophagy is implicated in cisplatin sensitivity in HPV-positive head and neck cancer.

Autophagy is important for the removal, degradation and recycling of damaged organelles, proteins, and lipids through the degradative action of lysosomes. In addition to its catabolic function, autophagy is important in cancer and viral-mediated tumorigenesis, including Human Papillomavirus (HPV) positive cancers. HPV infection is a major risk factor in a subset of head and neck cancer (HNC), for which no targeted therapies are currently available. Herein, we assessed autophagy function in HPV-positive HNC. We showed that HPV-positive HNC cells presented a transcriptional and functional impairment of the autophagic process compared to HPV-negative cells, which were reactivated by knocking down HPV E6/E7 oncoproteins, the drivers of cellular transformation. We found that the oncoprotein c-MYC was stabilized and triggered in HPV-positive cell lines. This resulted in the reduced binding of the MiT/TFE transcription factors to their autophagy targets due to c-MYC competition. Thus, the knock-down of c-MYC induced the upregulation of autophagic and lysosomal genes in HPV-positive HNC cells, as well as the increase of autophagic markers at the protein level. Moreover, HPV oncoprotein E7 upregulated the expression of the phosphatase inhibitor CIP2A, accounting for c-MYC upregulation and stability in HPV+ HNC cells. CIP2A mRNA expression negatively correlated with autophagy gene expression in tumor tissues from HNC patients, showing, for the first time, its implication in a transcriptional autophagic context. Both CIP2A and c-MYC knock-down, as well as pharmacological downregulation of c-MYC, resulted in increased resistance to cisplatin treatment. Our results not only show a novel way by which HPV oncoproteins manipulate the host machinery but also provide more insights into the role of autophagy in chemoresistance, with possible implications for targeted HPV-positive HNC therapy.

The Genetic and Immunologic Landscape Underlying the Risk of Malignant Progression in Laryngeal Dysplasia.

(1) Background: The development of laryngeal cancer is a multistep process involving structural alterations of the epithelial mucosa, from dysplasia (LDy) to invasive carcinoma. In this study, we define new biomarkers, prognostic for malignant transformation, in patients affected by LDy. (2) Methods: We used targeted next-generation sequencing and immunohistochemical analysis to define the mutational and immunological landscape of 15 laryngeal dysplasia progressing to invasive cancer (progressing dysplasia), as well as 31 cases of laryngeal dysplasia that did not progress to carcinoma (non-progressing dysplasia). Two pathologists independently analyzed the presence of tumor-infiltrating lymphocytes in LDy pre-embedded paraffin-fixed specimens. The RNA-based next-generation sequencing panel OIRRA was used to evaluate the expression of 395 genes related to immune system activation. (3) Results: High TILs are significantly correlated with a higher risk of malignant transformation. The non-brisk pattern was significantly associated with an 86% reduced risk of malignant progression (OR = 0.16, 95% CI: 0.03-0.5, p = 0.008). TILs showed a highly positive correlation with CCR6, CD83, HLA-DPB1, MX1 and SNAI1, and they were inversely correlated with CD48, CIITA, CXCR4, FCER1G, IL1B, LST1 and TLR8. (4) Conclusions: TILs have a great potential to identify high-risk progression dysplasia and thus to define surveillance protocols and prevention programs.

Are sex and gender considered in head and neck cancer clinical studies?

We analyzed the inclusion of sex and/or gender (S/G) in Head and Neck Cancer (HNC) clinical studies, through inspecting ClinicalTrials.gov (AACT) and the mention of Human Papilloma Virus (HPV) on a specific subgroup, namely oral cavity, larynx and oropharynx. Only 5% of HNC studies mention S/G as a planned analytical variable. Proportionally more observational studies treated S/G as an analytical variable than interventional studies (10% vs 5%, P-value ≤ 0.001), 8% of studies that mentioned S/G involved more than 100 subjects while 4% less than 100 (P-value ≤ 0.001). In randomized protocols, S/G was mentioned more in studies with a planned sample of more than 100 patients and including HPV status (P-value < 0.05). Small controlled studies have lower mention of S/G as an analytical variable than uncontrolled studies (4% and 10%, respectively among studies with less than 100 subjects). Significantly greater mention of S/G as an analytical variable is observed in controlled and randomized studies with a sample size greater than 100 subjects. HPV was mentioned in only 18% of oral cavity-larynx-oropharynx studies. Interventional studies do not regularly account for S/G during HNC study design. Thus, although fundamental, in studies concerning HNC the S/G variable is often not considered. In trials published in scientific journals (P-value = 0.01) and in more recent clinical trials (P-value = 0.002), S/G is taken more into account suggesting an increasing awareness on its importance. However, the need to systematically include S/G in study design clearly emerges, to better highlight sex-related differences in disease incidence and prognosis and best imbue science and medicine with the proper biological and cultural differences.