Narrow-band imaging features of oral lichenoid conditions: A multicentre retrospective study.

OBJECTIVE: Narrow-band imaging (NBI), which highlights epithelial intrapapillary capillary loops (IPCLs) classified into five patterns (0 toIV) with increasing correlation to malignancy, has demonstrated effectiveness for detection of oral squamous cell carcinoma (OSCC). Lack of standardised procedures limits its use for routine inspection of oral lichenoid lesions including oral lichen planus (OLP), oral lichenoid lesion (OLL) and oral lichenoid reaction (OLR). The aim of this study was to analyse IPCL patterns of such lesions, assessing correlations with histopathological outcomes. MATERIALS AND METHODS: A multicentre, retrospective study was performed on 84 patients who underwent NBI and subsequent biopsy for suspected OLP/OLL/OLR. Patients were examined with Evis Exera III NBI system. Recorded NBI video endoscopies were evaluated to assess IPCL patterns and correlated with histopathological outcomes. RESULTS: No significant differences were detected among OLP/OLL/OLR on NBI inspection. All lichenoid lesions were significantly related to low-grade (0-II) IPCL patterns, clearly distinguishable from OSCC, showing pattern IV (p < 0.05). CONCLUSIONS: NBI cannot discern among OLP/OLL/OLR lesions. Interpretation should be modulated when assessing lichenoid lesions. NBI has potential to discern malignant transformation occurring in lichenoid lesions undergoing long-term follow-up, as IPCL pattern IV may be used as a clinical marker of malignancy arising in chronic inflammatory lesions.

Clinical and microbiological efficacy of indocyanine green-based antimicrobial photodynamic therapy as an adjunct to non-surgical treatment of periodontitis: a randomized controlled clinical trial.

OBJECTIVES: The aim of the present randomized clinical trial (RCT) with a parallel arm design was to evaluate the clinical and microbiological efficacy of repeated ICG-aPDT as an adjunct to full-mouth subgingival debridement in the treatment of periodontitis. MATERIALS AND METHODS: Twenty-four periodontitis patients were treated with full-mouth ultrasonic subgingival debridement (FMUD). Initial sites with probing depth (PD) > 4 mm were randomly assigned to receive the test (ICG-aPDT with an 810 nm diode laser) or the control treatment (off-mode aPDT) one and four weeks after FMUD. Clinical parameters were registered after 3 and 6 months. The presence of the main periodontal pathogens in subgingival samples was assessed with real-time PCR. RESULTS: Both treatment modalities resulted in significant clinical improvements at 3 and 6 months. The only significant differences in favour of the test group were found at 6 months for a higher PD reduction in initial deep pockets (PD ≥ 6 mm) and a higher percentage of closed pockets (PD ≤ 4 mm/no bleeding on probing). Limited microbiological changes were observed in both groups after treatment with no inter-group difference, except for a more significant reduction in Aggregatibacter actinomycetemcomitans and Parvimonas micra levels in the test group at 3 months. CONCLUSION: The combination of repeated ICG-aPDT and FMUD provided no benefits except for selective clinical and microbiological improvements compared to FMUD alone. CLINICAL RELEVANCE: Based on the obtained results, only limited adjunctive effects could be found for the combined use of ICG-aPDT and FMUD. Further, well-designed RCT with larger sample sizes are required to confirm these findings. TRIAL REGISTRATION: ClinicalTrials.gov NCT04671394.

Surgical oncology of the head and neck district during COVID-19 pandemic.

PURPOSE: A new member of the Coronaviridae family caused a worldwide pandemic emergency called Coronavirus disease 2019 (COVID-19). Health care workers who come into contact with the upper aero-digestive tract during diagnostic and therapeutic procedures, such as otolaryngologists, oral and maxillofacial surgeons, and head and neck surgeons, may undergo profound changes in their activities and are particularly at risk. We analysed the impact of COVID-19 on our oncological surgical activity. METHODS: To address the emergency and guarantee safety of patients referred to our Unit, reproducible guidelines were followed. Surgical activity data during COVID-19 were compared to previous years (2018 and 2019). RESULTS: From 21st February to 25th of May 113 surgical procedures were performed. The average of the two selected years (2018-2019) is 84.5, showing an increase of 34.5% of our activities (statistically significant, p = 0.0011). No patient showed perioperative or postoperative contagion. CONCLUSION: Due to the conversion of regular Hospitals into COVID Centers, Cancer Centers may encounter an increased demand for procedures. Following strict guidelines, it seems possible to face surgical activity on cancer patients and respect standard procedures aimed at containing the spread of COVID-19 infection.

Oral lichen planus and other confounding factors in narrow band imaging (NBI) during routine inspection of oral cavity for early detection of oral squamous cell carcinoma: a retrospective pilot study.

BACKGROUND: Narrow Band Imaging is a noninvasive optical diagnostic tool. It allows the visualization of sub-mucosal vasculature; four patterns of shapes of submucosal capillaries can be recognized, increasingly associated with neoplastic transformation. With such characteristics, it has showed high effectiveness for detection of Oral Squamous Cell Carcinoma. Still, scientific literature highlights several bias/confounding factors, such as Oral Lichen Planus. We performed a retrospective observational study on patients routinely examined with Narrow Band Imaging, investigating for bias, confounding factors and conditions that may limit its applicability. METHODS: Age, sex, smoking, use of dentures, history of head & neck radiotherapy, history of Oral Squamous Cell Carcinoma, site of the lesion and thickness of the epithelium of origin were statistically evaluated as possible bias/confounding factors. Pearson's Chi-squared test, multivariate logistic regression, Positive Predictive Value, Negative Predictive Value, Sensitivity, Specificity, Positive Likelihood Ratio, Negative Likelihood Ratio and accuracy were calculated, normalizing the cohort with/without patients affected by Oral Lichen Planus, to acknowledge its role as bias/confounding factor. RESULTS: Five hundred fifty-six inspections were performed on 106 oral cavity lesions from 98 patients. Age, sex, smoking, use of dentures and anamnesis of Oral Squamous Cell Carcinoma were not found to influence Narrow Band Imaging. History of head & neck radiotherapy was not assessed due to insufficient sample. Epithelium thickness does not seem to interfere with feasibility. Presence of Oral Lichen Planus patients in the cohort led to false positives but not to false negatives. Among capillary patterns, number IV was the most significantly associated to Oral Squamous Cell Carcinoma (p < 0.001), not impaired by the presence of Oral Lichen Planus patients in the cohort (accuracy: 94.3, 95% confidence interval: 88.1-97.9%; odds ratio: 261.7, 95% confidence interval: 37.7-1815.5). CONCLUSION: Narrow Band Imaging showed high reliability in detection of Oral Squamous Cell Carcinoma in a cohort of patients with oral cavity lesions not normalized for bias/confounding factors. Still, Oral Lichen Planus may lead to false positives. Narrow Band Imaging could help in the follow-up of patients with multiple lesions through detection of capillary pattern IV, which seems to be the most significantly associated to neoplastic epithelium.

Stage-specific therapeutic strategies of medication-related osteonecrosis of the jaws: a systematic review and meta-analysis of the drug suspension protocol.

OBJECTIVE: The most debated topic about medication-related osteonecrosis of the jaws (MRONJ) is its therapy, as there are no definitive guidelines. The aims of this systematic review were (a) to outline the best therapeutic approach according to the stage at diagnosis and (b) to perform a meta-analysis to assess whether the drug-holiday protocol may be or not an effective method in the management of MRONJ patients. MATERIALS AND METHODS: The systematic review was performed following the PRISMA principles. Results were screened according to inclusion and exclusion criteria regarding staging before/after treatment, follow-up, and information provided by the authors. For statistical analysis, linear variables are reported as means and standard deviations, medians, and inter-quartile range (IQR); normality of data, according to the distribution of complete healing (primary outcome variable), was assessed with the Kolmogorov-Smirnov test. A p value < 0.05 was considered statistically significant for all tests. RESULTS: Thirteen studies were selected out of 1480. None of them was case-controlled or randomized. Conservative approach showed good results at early stages, but heterogeneous result at advanced stages (100% stage 0, stage I range 81-97%, stage II range 63.6-100%, stage III 73%). Surgical approach showed heterogeneous results at all stages (stage I range 0-100%, stage II range 52-100%, stage III range 50-100%). Statistical analysis showed a significantly higher prevalence of completely healed sites in patients who followed the drug-holiday protocol. CONCLUSIONS: The results suggest that the current stage-specific approach for MRONJ therapy is based on a sound clinical rationale. Conservative treatment appears to yield better outcomes at early stages, while further investigations are needed to elucidate the best protocols for the management of advanced stages. The drug-holiday protocol statistically promotes complete healing after oral surgery procedures but the application should be dictated by the condition of each patient. CLINICAL RELEVANCE: At present, early MRONJ stages should be primarily treated by means of a conservative approach while more advanced stages must be carefully evaluated. Individual decisions should be made for every single case even with respect to the drug-holiday protocol.

Integrative Histologic and Bioinformatics Analysis of BIRC5/Survivin Expression in Oral Squamous Cell Carcinoma.

Survivin is a well-known protein involved in the inhibition of apoptosis in many different cancer types. The aim of this study was to perform an integrated bioinformatic and histologic analysis in order to study the expression and prognostic role of Survivin and its related gene BIRC5 in oral cancer. Publicly available databases were accessed via Gene Expression Omnibus and Oncomine, in addition raw data from The Cancer Genome Atlas (TCGA) were also obtained in order to analyze the rate of gene mutation, expression and methylation in patients with oral squamous cells carcinoma (OSCC). Immunohistochemistry (IHC) was also performed in order to evaluate the nuclear and cytoplasmic expression of Survivin and their correlation with cell proliferation in samples from OSCC patients. Results of this study revealed that Survivin is rarely mutated in OSCC samples and upregulated when compared to non-cancerous tissue. A negative correlation between the methylation of the island cg25986496 and BIRC5 mRNA expression was detected from TCGA data. IHC staining revealed that cytoplasmic (and not nuclear) expression of Survivin is associated with poor overall survival in OSCC patients, while the nuclear expression correlates with higher proliferation rate. In addition, data from TCGA database revealed that BIRC5 gene expression is an independent prognostic factor for OSCC patients.

Monkeypox: A New Challenge for Global Health System?

The COVID-19 pandemic, starting in 2020, has presented a major challenge in terms of early diagnosis and the subsequent containment and management of severe cases. The spread of viruses such as monkeypox in non-endemic countries is now creating new difficulties for healthcare professionals. Proper case definition and clinical examination are crucial for the early identification of suspected cases. For this reason, we performed a review of the literature in order to report the first signs, which are useful for healthcare providers for early case identification. Since 2022 to date, 86,930 laboratory-confirmed cases and 1051 probable cases have been reported worldwide, and of these, 116 were fatal cases and, for the first time, most of the cases were registered in countries that have not historically reported monkeypox and that lack direct or immediate epidemiological links to areas of West or Central Africa where the disease is endemic. Patients with Monkeypox experience prodromal symptoms, such as fever, fatigue, headache, muscle aches, and a rash after an incubation period of 5-21 days. The disease is usually self-limiting within 2-4 weeks but can lead to complications, such as pneumonia, encephalitis, kidney injury, and myocarditis in children, pregnant individuals, and those with weakened immune systems. The case-fatality ratio is between 1 and 10%. Today, prevention campaigns and the control of human monkeypox are the best weapons to prevent infection and stop transmission. Prevention strategies, such as avoiding contact with sick or dead animals, and the proper preparation of all foods containing animal meat or parts, should be adopted. Furthermore, close contact with infected people or contaminated materials should be avoided to prevent human-to-human transmission.

Bone marrow mesenchymal stem cell response to nano-structured oxidized and turned titanium surfaces.

OBJECTIVES: The aim of this study was to analyse the topographic features of a novel nano-structured oxidized titanium implant surface and to evaluate its effect on the response of human bone marrow mesenchymal stem cells (BM-MSC) compared with a traditional turned surface. METHODS: The 10 × 10 × 1 mm turned (control) and oxidized (test) titanium samples (P.H.I. s.r.l.) were examined by scanning electron microscopy (SEM) and atomic force microscopy (AFM) and characterized by height, spatial and hybrid roughness parameters at different dimensional ranges of analysis. Primary cultures of BM-MSC were seeded on titanium samples and cell morphology, adhesion, proliferation and osteogenic differentiation, in terms of alkaline phosphatase activity, osteocalcin synthesis and extracellular matrix mineralization, were evaluated. RESULTS: At SEM and AFM analyses turned samples were grooved, whereas oxidized surfaces showed a more complex micro- and nano-scaled texture, with higher values of roughness parameters. Cell adhesion and osteogenic parameters were greater on oxidized (P<0.05 at least) vs. turned surfaces, whereas the cell proliferation rate was similar on both samples. CONCLUSIONS: Although both control and test samples were in the range of average roughness proper of smooth surfaces, they exhibited significantly different topographic properties in terms of height, spatial and, mostly, of hybrid parameters. This different micro- and nano-structure resulted in an enhanced adhesion and differentiation of cells plated onto the oxidized surfaces.

Glossodynia and coeliac disease.

Coeliac disease is an immune-mediated chronic inflammatory disorder of the small bowel caused by irritant gluten and, possibly, other environmental cofactors, in genetically prone people. Coeliac disease is characterized by no (or elusive or varied) symptoms. Oral clinical settings include aphthous stomatitis and dental enamel defects. Association with other signs in the oral mucosa (such as, for example, soreness, a burning sensation, erythema or atrophy) is much less common and, often, not considered by clinicians. We report on a 72-year-old woman with a four months history of oral burning sensation as a single clinical manifestation of coeliac disease. Clinical presentation and symptomatology are discussed in relation to the differential diagnosis of oral glossodynia. This case history highlights the importance of considering coeliac disease in managing cases of idiopathic glossodynia.

Stomatognathic Diseases: State of the Art and Future Perspectives.

The World Health Organization (WHO) considers oral heath to be a key indicator of overall health, as it is linked to physical well-being and quality of life [...].

Dental Emergencies and Coronavirus Disease-2019: Scoping Review of the Literature and Single Centre Experience.

Understanding the impact of the COVID-19 pandemic on dental emergencies. A systematic review of the literature (PubMed/Scopus) searching for articles on COVID-19 and dental abscess and a retrospective cohort study with quantitative/qualitative data analysis of our hospital E.R. patients admitted for cervico-facial abscess of dental origin were performed. Thirteen studies could be included in the review, concerning characteristics/management of patients with dental emergencies in hospitals/private practices, generally with poor evidence. For the retrospective analysis, 232 consecutive patients were included (100 study vs. 132 control). The prevalence of dental emergencies (abscess) and relative complications (mediastinitis, exitus) increased. Dental care availability was limited, with strong heterogeneity amongst regions/nations. At-risk (aerosol-generating) procedures were generally avoided, and hospitalization length reduced. Comorbidity patients and males seem less likely to restore regular dentist attendance during the post-lockdown pandemic. Despite the poor scientific evidence, COVID-19 seems to have impacted dental emergencies through limited routine dental care availability and influence on physicians' and patients' behaviour.

Cancer Cell Metabolism Reprogramming and Its Potential Implications on Therapy in Squamous Cell Carcinoma of the Head and Neck: A Review.

Carcinogenesis is a multistep process that consists of the transformation of healthy cells into cancer cells. Such an alteration goes through various stages and is closely linked to random mutations of genes that have a key role in the neoplastic phenotype. During carcinogenesis, cancer cells acquire and exhibit several characteristics including sustaining proliferative signaling, evading growth suppressors, resisting cell death, enabling replicative immortality, inducing angiogenesis, activating invasion and metastasis, and expressing an immune phenotype, which allow them to evade recognition and destruction through cognate immune cells. In addition, cancer cells may acquire the ability to reprogram their metabolism in order to further promote growth, survival, and energy production. This phenomenon, termed metabolic reprogramming, is typical of all solid tumors, including squamous carcinomas of the head and neck (SCCHN). In this review, we analyze the genetic and biological mechanisms underlying metabolic reprogramming of SCCHN, focusing on potential therapeutic strategies that are able to counteract it.

Early-Stage Oral Tongue Squamous Cell Carcinoma and a Positive Sentinel Lymph Node Biopsy: Description of a Prognostic Correlation between Pre-Treatment Inflammatory Biomarkers, the Depth of Invasion and the Worst Pattern of Invasion.

The aim of this study was to investigate the correlation between pre-treatment inflammatory biomarkers and the post-operative depth of invasion (DOI) and worst pattern of invasion (WPOI) in early-stage oral tongue squamous cell carcinoma (OTSCC) by means of positive sentinel lymph node biopsy (SLNB). A retrospective analysis of patients affected by cN0 T1-T2 OTSCC who had undergone an SLNB at the National Cancer Institute of Naples was performed. The patients were studied using an evaluation of the pre-treatment neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), systemic immune-inflammatory index (SII), and a histopathological analysis of the DOI and WPOI. The statistical analysis showed that among the prognostic biomarkers, the NLR was a significant predictor of high WPOI values (p = 0.002). The cut-off NLR value was 2.52 with a probability of developing a positive sentinel lymph node biopsy (SLNB) of 30.3%. In contrast, the DOI value was 5.20 with a probability of developing a positive SLNB of 31.82%. Regarding the WPOI, increasing the WPOI class increased the likelihood of a positive SLNB occurrence, and a positive significant correlation was found between the WPOI and SLNB (Csp = 0.342; p < 0.001). Pre-treatment NLR, together with post-surgical DOI and WPOI, can be a reliable predictor of occult neck metastasis in patients affected by early-stage OTSCC with a clinically negative neck. Further prospective studies with a larger series will be needed to confirm the results obtained and to better define the NLR, WPOI and DOI cut-off values in order for elective neck dissection to be recommended in relation to a clinically negative neck.

Calcifying odontogenic cysts associated with odontomas: confocal laser scanning microscopy analysis of 13 cases.

The so-called calcifying odontogenic cyst (COC) represents a heterogeneous group of lesions that exhibit a variety of clinico-pathologic features. It is an uncommon lesion and represents less than 2% of all odontogenic cysts and tumors. Recently, these lesions have been reclassified as calcifying cystic odontogenic tumors (CCOT), according to the new World Health Organization (WHO) classification. CCOT are frequently found in association with, or containing areas histologically identical to, various types of odontogenic tumors, such as complex/compound odontomas. This work analyzed clinical and histological data deriving from 13 patients affected by CCOT associated with odontomas. Moreover, a confocal laser scanning microscope (CLSM) analysis was undertaken to further a better understanding of the nature of this peculiar lesion.

Orthodontic-aided extraction of impacted third molar to improve the periodontal status of the neighboring tooth.

OBJECTIVES: In the present clinical report, we describe the management and the long-term (3-year) outcome of a periodontally compromised lower second molar healed by orthodontic-aided extraction of the neighboring impacted third molar. METHODS: A healthy 21-year-old woman referred signs and symptoms of pericoronitis of impacted tooth 48 and periodontal injury on the distal aspect of tooth 47. The wisdom tooth was surgically exposed, and an orthodontic appliance was anchored to the neighboring teeth to stimulate eruption. After 5 months, third molar could be easily extracted. RESULTS: Three years after extraction, clinical and radiographic controls revealed a complete healing of the periodontal defect. CONCLUSIONS: Orthodontic-aided extraction of impacted third molars may improve the periodontal status of the neighboring tooth. This protocol is not free from drawbacks and limitations and should be applied only when third-molar extraction is associated with a concrete risk of postoperative complications.

Candida-associated denture stomatitis.

Candida albicans is a dimorphic yeast strongly gram positive able to live as normal commensal organism in the oral cavity of healthy people. It is the yeast more frequently isolated in the oral cavity. Under local and systemic factors related to the host conditions, it becomes virulent and responsible of oral diseases known as oral candidiasis. It has been shown that the presence of denture is a predisposing factor to the onset of pathologies related to C. albicans. Clinical studies have shown that C. albicans is not only able to adhere to the mucous surfaces, but also to stick to the acrylic resins of the dental prostheses. Both the plaque accumulated on the denture and the poor oral hygiene contribute to the virulence of Candida, offering the clinical picture of Candida-associated denture stomatitis. The therapeutic strategies currently adopted in the clinical practice to overcome these fungal infections provide for the use of topical and/or systemic antifungal and topical antiseptics and disinfectants, the irradiation with microwaves and the accurate mechanical removal of the bacterial plaque from the denture surfaces and from the underlying mucosa. A correct oral hygiene is important for the control of the bacterial biofilm present on the denture and on the oral mucosa and it is the fundamental base for the prophylaxis and the therapy of the Candida-associated denture stomatitis.

New-generation anticancer drugs and medication-related osteonecrosis of the jaw (MRONJ): Late onset 3 years after ipilimumab endovenous administration with a possible role of target therapy.

Association of immunotherapy and/or chemotherapy and/or targeted therapy, in sequence or as single therapies, may induce osteonecrosis of the jaw. Multidisciplinary team management of these patients should be provided.

Recurrent/Metastatic Squamous Cell Carcinoma of the Head and Neck: A Big and Intriguing Challenge Which May Be Resolved by Integrated Treatments Combining Locoregional and Systemic Therapies.

Squamous cell carcinoma of the head and neck (SCCHN) is a complex group of malignancies, posing several challenges to treating physicians. Most patients are diagnosed with a locally advanced disease and treated with strategies integrating surgery, chemotherapy, and radiotherapy. About 50% of these patients will experience a recurrence of disease. Recurrent/metastatic SCCHN have poor prognosis with a median survival of about 12 months despite treatments. In the last years, the strategy to manage recurrent/metastatic SCCHN has profoundly evolved. Salvage treatments (surgery or re-irradiation) are commonly employed in patients suffering from locoregional recurrences and their role has gained more and more importance in the last years. Re-irradiation, using some particularly fractionating schedules, has the dual task of reducing the tumor mass and eliciting an immune response against cancer (abscopal effect). In this review, we will analyze the main systemic and/or locoregional strategies aimed at facing the recurrent/metastatic disease, underlining the enormous importance of the multidisciplinary approach in these types of patients.

Patients affected by squamous cell carcinoma of the head and neck: A population particularly prone to developing severe forms of COVID-19.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is responsible for the recent Coronavirus Disease 2019 (COVID-19) pandemic, which has spread all over the world over the past year. Comorbidities appear to affect the prognosis of patients with such diseases, but the impact of cancer on the course of SARS-CoV2 has remained largely elusive. The aim of the present study is to analyze the outcome of patients affected by squamous cell carcinoma of the head and neck (SCCHN) and a number of their comorbidities, if infected with SARS-CoV2. The clinical data of 100 patients affected by SCCHN, who were undergoing treatment or who had finished their oncologic treatment in the past 6 months, were retrospectively collected and analysed. For each patient, the Charlson Comorbidity Index (CCI) was calculated to provide a score assessing the real weight of comorbidities on the patient's outcome at the time of diagnosis. It was discovered that these patients, besides the SCCHN, frequently presented at diagnosis with several other comorbidities, including hypertension, type 2 diabetes, cardiac arrhytmia, chronic obstructive pulmonary disease and various forms of vasculopathy (and thus a poor CCI). This feature suggest that, given the high frequency of various comorbidities in patients with SCCHN, additional SARS-CoV2 infection could have particularly devastating consequences.

Electrochemotherapy as a First Line Treatment in Recurrent Squamous Cell Carcinoma of the Oral Cavity and Oropharynx PDL-1 Negative and/or with Evident Contraindication to Immunotherapy: A Randomized Multicenter Controlled Trial.

BACKGROUND: A significant proportion of patients with head and neck squamous cell carcinoma (HNSCC) have advanced-stage disease (stages III to IVB) that do not respond to therapy despite aggressive, site-specific multimodality therapy. A great number of them will develop disease recurrence, with up to 60% risk of local failure and up to 30% risk of distant failure. Therapy can be very demanding for the patient especially when important anatomical structures are involved. For these reasons, therapies that preserve organ functionality in combination with effective local tumor control, like electrochemotherapy (ECT), are of great interest. Until few months ago, systemic cetuximab + platinum-based therapy + 5-fluorouracil represented the standard treatment for HNSCC relapses with a median overall survival of 10.1 months and an objective response rate of 36%. Recently the results of KEYNOTE-048 study were published and a new combination of monoclonal antibody named pembrolizumab and chemotherapy emerged as standard first line therapy of recurrent or metastatic tumor that overexpress tissue PDL-1 (Programmed Death 1 ligand). Nevertheless, a variable percentage from 10 to 15% of patients with recurrent/metastatic disease have a tumor that does not overexpress tissue PDL-1, and therefore, according to the results of the KEYNOTE-048 study, does not benefit from replacement of cetuximab with pembrolizumab. These patients will be treated with the "gold standard": cetuximab, cisplatin/carboplatin and 5-fluorouracil. AIM: To verify whether electrochemotherapy performed with bleomycin of HNSCC relapses of the oral cavity and oropharynx (single relapse on T) is able to lead to an increase in the objective response rate in comparison with the systemic treatment with cetuximab + platinum-based therapy + 5-fluorouracil in patients with PDL-1 negative tumors. METHODS: The phase IIb study involves the enrolment of 96 patients who meet the inclusion criteria (48 in the control arm and 48 in the treatment arm). The control arm involves the treatment of HNSCC with systemic treatment (cetuximab + platinum-based therapy + 5-fluorouracil). The treatment arm involves the ECT with bleomycin. The primary objective is to verify the objective response rate of patients in the control arm compared to the treatment arm.