The fact that the identity of the cells that initiate metastasis in most human cancers is unknown hampers the development of antimetastatic therapies. Here we describe a subpopulation of CD44
cells ...in human oral carcinomas that do not overexpress mesenchymal genes, are slow-cycling, express high levels of the fatty acid receptor CD36 and lipid metabolism genes, and are unique in their ability to initiate metastasis. Palmitic acid or a high-fat diet specifically boosts the metastatic potential of CD36
metastasis-initiating cells in a CD36-dependent manner. The use of neutralizing antibodies to block CD36 causes almost complete inhibition of metastasis in immunodeficient or immunocompetent orthotopic mouse models of human oral cancer, with no side effects. Clinically, the presence of CD36
metastasis-initiating cells correlates with a poor prognosis for numerous types of carcinomas, and inhibition of CD36 also impairs metastasis, at least in human melanoma- and breast cancer-derived tumours. Together, our results indicate that metastasis-initiating cells particularly rely on dietary lipids to promote metastasis.
Fatty acid uptake and altered metabolism constitute hallmarks of metastasis
, yet evidence of the underlying biology, as well as whether all dietary fatty acids are prometastatic, is lacking. Here we ...show that dietary palmitic acid (PA), but not oleic acid or linoleic acid, promotes metastasis in oral carcinomas and melanoma in mice. Tumours from mice that were fed a short-term palm-oil-rich diet (PA), or tumour cells that were briefly exposed to PA in vitro, remained highly metastatic even after being serially transplanted (without further exposure to high levels of PA). This PA-induced prometastatic memory requires the fatty acid transporter CD36 and is associated with the stable deposition of histone H3 lysine 4 trimethylation by the methyltransferase Set1A (as part of the COMPASS complex (Set1A/COMPASS)). Bulk, single-cell and positional RNA-sequencing analyses indicate that genes with this prometastatic memory predominantly relate to a neural signature that stimulates intratumoural Schwann cells and innervation, two parameters that are strongly correlated with metastasis but are aetiologically poorly understood
. Mechanistically, tumour-associated Schwann cells secrete a specialized proregenerative extracellular matrix, the ablation of which inhibits metastasis initiation. Both the PA-induced memory of this proneural signature and its long-term boost in metastasis require the transcription factor EGR2 and the glial-cell-stimulating peptide galanin. In summary, we provide evidence that a dietary metabolite induces stable transcriptional and chromatin changes that lead to a long-term stimulation of metastasis, and that this is related to a proregenerative state of tumour-activated Schwann cells.
Oral squamous cell carcinoma (OSCC) is a very aggressive cancer, representing one of the most common malignancies worldwide. Oral potentially malignant disorders (OPMDs) regroup a variegate set of ...different histological lesions, characterized by the potential capacity to transform in OSCC. Most of the risk factors associated with OSCC are present also in OPMDs’ development; however, the molecular mechanisms and steps of malignant transformation are still unknown. Treatment of OSCC, including surgery, systemic therapy and radiotherapy (alone or in combination), has suffered a dramatic change in last years, especially with the introduction of immunotherapy. However, most cases are diagnosed during the advanced stage of the disease, decreasing drastically the survival rate of the patients. Hence, early diagnosis of premalignant conditions (OPMDs) is a priority in oral cancer, as well as a massive education about risk factors, the understanding of mechanisms involved in malignant progression and the development of specific and more efficient therapies. The aim of this article is to review epidemiological, clinical, morphological and molecular features of OPMDs, with the purpose to lay the foundation for an exhaustive comprehension of these lesions and their ability of malignant transformation and for the development of more effective and personalized treatments.
•Patients with R/M HNSCC treated with immunotherapy (IO) were reviewed.•PNI was the only parameter associated with both PFS and OS.•The incidence of irAEs was not associated with IO PFS or OS.•The ...nutritional status should be considered in HNSCC patients treated with IO.
Beyond programmed death-ligand 1 (PD-L1) assessed by the combined positive score (CPS) and tumor mutational burden (TMB), no other biomarkers are approved for immunotherapy interventions. Here, we investigated whether additional clinical and pathological variables may impact on immunotherapy outcomes in recurrent or metastatic (R/M) head and neck squamous cell carcinoma (HNSCC) patients.
R/M HNSCC patients treated with immunotherapy were reviewed. Analyzed variables at baseline included: clinicopathological, laboratory, and variables reflecting the host nutritional status such as the prognostic nutritional index (PNI) and albumin. The primary endpoint was progression free survival (PFS). The secondary endpoints were overall survival (OS) and objective response rate (ORR). Univariable and multivariable Cox models were fitted and random forest algorithm was used to estimate the importance of each prognostic variable.
A total of 100 patients were treated with immunotherapy; 50% with single agent and 50% with experimental immunotherapy combinations. In the multivariable analysis, both ECOG performance status (HR: 1.73; 95%CI 1.07–2.82; p = 0.03) and PNI levels (10-point increments, HR: 0.66; 0.46–0.95; p = 0.03) were significantly associated with PFS. However, the derived neutrophil to lymphocyte ratio (dNLR) and lactate dehydrogenase (LDH) were not significantly associated with PFS (p-values > 0.15). In the OS analysis, albumin and PNI were the only statistically significant factors in the multivariable model (p < 0.001).
In our cohort, PNI and ECOG performance status were most strongly associated with PFS in R/M HNSCC patients treated with immunotherapy. These results suggest that parameters informative of nutritional status should be considered before immunotherapy.
A single-center retrospective study was designed to assess the outcomes of autologous fat grafting for improving surgery- and radiotherapy-related sequelae in 40 patients with head and neck cancer. ...All patients underwent surgical resection of primary tumors and radiotherapy (50-70 Gy) and were followed over 12 months after fat grafting. Eligibility for fat grafting procedures included complete remission after at least 3 years of oncological treatment. The cervical and paramandibular regions were the most frequently treated areas. Injected fat volumes ranged between 7.5 and 120 mL (mean: 23 mL). Esthetic improvement was obtained in 77.5% of patients, being significant in 17.5%, and functional improvement in 89.2%, being significant in 29.7% of patients. Minor complications occurred in three patients. There was a high degree of satisfaction regarding esthetic improvement, global satisfaction, and 92.5% of patients would recommend the procedure. This study confirms the benefits of fat grafting as a volumetric correction reconstructive strategy with successful cosmetic and functional outcomes in patients suffering from sequelae after head and neck cancer treatment.
Squamous cell carcinoma (SCC) is the most common malignant neoplasm of the oral cavity. The performance of END (elective neck dissection) in cases of maxillary SCC is controversial because the ...literature traditionally classified maxillary tumors as having low metastatic potential. The aim of this systematic review and meta‐analysis was to determine the percentage of occult cervical metastases in maxillary SCC to identify in which cases there is the need to perform an END. We searched the PubMed database to select articles dated from 2000 to 2020 that fulfilled our inclusion criteria; finally, we reviewed 27 manuscripts. We show that the overall cervical and occult metastases rate was 35% and 19%, respectively. For T1, the percentage of occult metastasis rate was 11%; for T2, it was 16%; for T3, it was 20%; and for T4, it was 32%. We suggest END (levels I–II–III) as treatment to T3/T4 cN0 patients.
Immunoglobulin G4–related disease is a recently identified entity. The cervicofacial location is not frequent. We report the case of a patient with an inflammatory pseudotumor in the mandible, who ...had to undergo surgery for diagnosis. We review the clinical manifestations, diagnostic criteria, differential diagnosis, and treatment proposed by recent publications in the literature. This case report represents the first case located in the mandible and the second one with bone destruction.
A single-center retrospective study was conducted to assess health-related quality of life (HRQoL) in 23 consecutive patients undergoing mandibular reconstruction using the computer-aided design ...(CAD) and computer-aided manufacturing (CAM) technology, free fibula flap, and titanium patient-specific implants (PSIs). HRQoL was evaluated after at least 12 months of surgery using the University of Washington Quality of Life (UW-QOL) questionnaire for head and neck cancer patients. In the 12 single question domains, the highest mean scores were found for "taste" (92.9), "shoulder" (90.9), "anxiety" (87.5), and "pain" (86.4), whereas the lowest scores were observed for "chewing" (57.1), "appearance" (67.9), and "saliva" (78.1). In the three global questions of the UW-QOL questionnaire, 80% of patients considered that their HRQoL was as good as or even better than it was compared to their HRQoL before cancer, and only 20% reported that their HRQoL had worsened after the presence of the disease. Overall QoL during the past 7 days was rated as good, very good or outstanding by 81% of patients, respectively. No patient reported poor or very poor QoL. In the present study, restoring mandibular continuity with free fibula flap and patient-specific titanium implants designed with the CAD-CAM technology improved HRQoL.
Abstract We conducted a systematic review of the literature to evaluate treatment of oral leukoplakia with the carbon dioxide (CO2 ) laser. A comprehensive search of studies published between 1981 ...and 2015 and listed in the PubMed (National Library of Medicine, NCBI) database yielded 378 articles which were screened in detail. Relevant studies were selected according to predetermined inclusion and exclusion criteria. A total of 33 articles met the final inclusion criteria and were analysed in detail in accordance with the PRISMA-P statement. These full-text papers were classified as synopses (n=7), recurrence and malignant transformation studies (n=17), comparative studies between CO2 laser and cold knife surgery (n=3) and studies evaluating the efficacy of CO2 , Nd:YAG and KTP lasers. According to the literature the CO2 laser is the workhorse of oral leukoplakia treatment due to its effectiveness and low associated morbidity. However, randomized clinical trials are needed to compare CO2 laser with other lasers. The results of our systematic review showed that there is no consensus regarding the factors involved in higher recurrence and malignization rates, so further studies are needed.
Abstract The use of CO2 laser has become a routine procedure for the treatment of oral leukoplakia. In this retrospective study, we evaluated 65 patients with oral leukoplakia treated with CO2 laser ...vaporization. The main location was the tongue (n = 21/65, 32.3%). The initial biopsy showed mild/moderate dysplasia in almost half the patients (n = 29, 44.6%) and hyperplasia without dysplasia in around a third of the patients (n = 21, 32.3%). The recurrence and malignant transformation rates were 33.8% (n = 22) and 15.4% (n = 10), respectively. The follow-up mean (standard deviation) was 15.0 (10.6) months. The procedure-related complications rate was 7.7% (n = 5). The Kaplan–Meier curves for time to recurrence showed differences only for gingiva lesions compared to tongue lesions (log rank, p = 0.032). Malignant leukoplakia transformation is independent of treatment, although it seems advisable to treat leukoplakia with or without dysplasia.
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