Search

Abstract VAV2 is an activator of RHO GTPases that promotes and maintains regenerative proliferation-like states in normal keratinocytes and oral squamous cell carcinoma (OSCC) cells. Here, we demonstrate that VAV2 also regulates ribosome biogenesis in those cells, a program associated with poor prognosis of human papilloma virus-negative (HPV−) OSCC patients. Mechanistically, VAV2 regulates this process in a catalysis-dependent manner using a conserved pathway comprising the RAC1 and RHOA GTPases, the PAK and ROCK family kinases, and the c-MYC and YAP/TAZ transcription factors. This pathway directly promotes RNA polymerase I activity and synthesis of 47S pre-rRNA precursors. This process is further consolidated by the upregulation of ribosome biogenesis factors and the acquisition of the YAP/TAZ-dependent undifferentiated cell state. Finally, we show that RNA polymerase I is a therapeutic Achilles’ heel for both keratinocytes and OSCC patient-derived cells endowed with high VAV2 catalytic activity. Collectively, these findings highlight the therapeutic potential of modulating VAV2 and the ribosome biogenesis pathways in both preneoplastic and late progression stages of OSCC.

Abstract Background Tumor mutational burden (TMB) has been demonstrated to predict the response to immune checkpoint inhibitors (ICIs) in various cancers. However, the role of TMB in head and neck squamous cell carcinoma (HNSCC) has not yet been specifically addressed. Since HNSCC patients exhibit a rather limited response to ICIs, there is an unmet need to develop predictive biomarkers to improve patient selection criteria and the clinical benefit of ICI treatment. Methods We conducted a systematic review and meta-analysis according to Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) reporting guidelines. HNSCC cohort studies were selected when TMB prior to ICI treatment was evaluated, TMB cutoff value was available, and the prognostic value of TMB was evaluated by time-to-event survival analysis. A total of 11 out of 1960 articles were analyzed, including 1200 HNSCC patients. Results The results showed that those patients harboring high TMB exhibited a significantly superior overall response rate (OR = 2.62; 95% CI 1.74–3.94; p

Abstract Recent introduction of monoclonal antibodies targeting immune checkpoints to harness antitumor immunity has revolutionized the cancer treatment landscape. The therapeutic success of immune checkpoint blockade (ICB)-based therapies mainly relies on PD-1/PD-L1 and CTLA-4 blockade. However, the limited overall responses and lack of reliable predictive biomarkers of patient´s response are major pitfalls limiting immunotherapy success. Hence, this reflects the compelling need of unveiling novel targets for immunotherapy that allow to expand the spectrum of ICB-based strategies to achieve optimal therapeutic efficacy and benefit for cancer patients. This review thoroughly dissects current molecular and functional knowledge of BTLA/HVEM axis and the future perspectives to become a target for cancer immunotherapy. BTLA/HVEM dysregulation is commonly found and linked to poor prognosis in solid and hematological malignancies. Moreover, circulating BTLA has been revealed as a blood-based predictive biomarker of immunotherapy response in various cancers. On this basis, BTLA/HVEM axis emerges as a novel promising target for cancer immunotherapy. This prompted rapid development and clinical testing of the anti-BTLA blocking antibody Tifcemalimab/icatolimab as the first BTLA-targeted therapy in various ongoing phase I clinical trials with encouraging results on preliminary efficacy and safety profile as monotherapy and combined with other anti-PD-1/PD-L1 therapies. Nevertheless, it is anticipated that the intricate signaling network constituted by BTLA/HVEM/CD160/LIGHT involved in immune response regulation, tumor development and tumor microenvironment could limit therapeutic success. Therefore, in-depth functional characterization in different cancer settings is highly recommended for adequate design and implementation of BTLA-targeted therapies to guarantee the best clinical outcomes to benefit cancer patients.

TINCR encodes a p53-regulated ubiquitin-like microprotein expressed in stratified epithelia. Tincr loss promotes UVB-induced skin carcinogenesis in mice and deletions and mutations in human squamous cell carcinoma support a tumor suppressor role.

The aim of this study was to investigate the prognostic relevance of β-catenin expression in oral squamous cell carcinoma (OSCC) and to explore relationships with the tumor immune microenvironment. Expression of β-catenin and PD-L1, as well as lymphocyte and macrophage densities, were evaluated by immunohistochemistry in 125 OSCC patient specimens. Membranous β-catenin expression was detected in 102 (81.6%) and nuclear β-catenin in 2 (1.6%) tumors. There was an association between β-catenin expression, tumoral, and stromal CD8+ T-cell infiltration (TIL) and also the type of tumor immune microenvironment (TIME). Tumors harboring nuclear β-catenin were associated with a type II TIME (i.e., immune ignorance defined by a negative PD-L1 expression and low CD8+ TIL density), whereas tumors with membranous β-catenin expression were predominantly type IV (i.e., immune tolerance defined by negative PD-L1 and high CD8+ TIL density). Combined, but not individual, high stromal CD8+ TILs and membranous β-catenin expression was independently associated with better disease-specific survival (HR = 0.48, p = 0.019). Taken together, a combination of high stromal CD8+ T-cell infiltration and membranous β-catenin in the tumor emerges as an independent predictor of better survival in OSCC patients.

Background: The management of cT3 laryngeal cancers remains controversial, with studies recommending surgical or non-surgical approaches. Despite the many papers that have been published on the subject, there is a lack of studies showing which treatment has better results in terms of survival. Objective: To determine the difference in survival outcomes following total laryngectomy (TL), concurrent chemoradiation (CRT) or radiation therapy (RT) alone in T3 laryngeal cancers. Methods: Search of PubMed, Scopus, and Google Scholar databases from 1995 to 2023 employing specific keywords and Boolean operators to retrieve relevant articles. Statistical analysis was conducted using a random-effects model, and heterogeneity was evaluated using the Q-test and I2 statistic. Funnel plot asymmetry was assessed using rank correlation and regression tests. Results: The qualitative data synthesis comprised 10,940 patients from 16 included studies. TL was performed in 2149 (19.4%), CRT in 6723 (61.5%), RT in 295 (2.7%), while non-surgical treatment was not specified in 1773 (16.2%) patients. The pooled 2-year overall survival (OS) rates were TL = 73%, CRT = 74.7%, RT = 57.9%, 3-year OS rates were TL = 64.3%, CRT = 62.9%, RT = 52.4%, and 5-year OS rates were TL = 54.2%, CRT = 52.7%, RT = 40.8%. There was a significant heterogeneity in the included studies. There was no statistically significant difference in 2-year OS (logOR= −0.88 (95% confidence interval (CI): −1.99 to 0.23), p = 0.12), 3-year OS (logOR = −0.6 (95% CI: −1.34 to 0.15), p = 0.11), and 5-year OS (logOR = −0.54 (95% CI: −1.29 to 0.21), p = 0.16) between TL and CRT. Instead, there was significant difference in 2-year OS (logOR= −1.2383 (95% CI: −2.1679 to −0.3087), p = 0.009), 3-year OS (−1.1262 (95% CI: −1.6166 to −0.6358), p < 0.001), and 5-year OS (−0.99 (95% CI: −1.44 to −0.53)), p < 0.001) between TL and RT alone. Conclusions and Significance: TL followed with adjuvant (chemo)radiation on indication and CRT with salvage surgery in reserve appear to have similar OS outcomes. Both resulted in better OS outcomes compared to RT alone in the treatment of T3 laryngeal cancers. If patients are unfit for chemotherapy, making CRT impossible, surgery may become the choice of treatment.

The Rho signalling pathway is frequently activated in squamous carcinomas. Here, the authors find that the Rho GEF VAV2 is over expressed in both cutaneous and head and neck squamous cell carcinomas and that at the molecular level VAV2 promotes a pro-tumorigenic stem cell-like signalling programme.

In head and neck cancer (HNC) there is a need for more personalized treatment based on risk assessment for treatment related adverse events (i.e. toxicities and complications), expected survival and quality of life. Sarcopenia, defined as a condition characterized by loss of skeletal muscle mass and function, can predict adverse outcomes in HNC patients. A review of the literature on the measurement of sarcopenia in head and neck cancer patients and its association with frailty was performed. Skeletal muscle mass (SMM) measurement only is often used to determine if sarcopenia is present or not. SMM is most often assessed by measuring skeletal muscle cross-sectional area on CT or MRI at the level of the third lumbar vertebra. As abdominal scans are not always available in HNC patients, measurement of SMM at the third cervical vertebra has been developed and is frequently used. Frailty is often defined as an age-related cumulative decline across multiple physiologic systems, with impaired homeostatic reserve and a reduced capacity of the organism to withstand stress, leading to increased risk of adverse health outcomes. There is no international standard measure of frailty and there are multiple measures of frailty. Both sarcopenia and frailty can predict adverse outcomes and can be used to identify vulnerable patients, select treatment options, adjust treatments, improve patient counselling, improve preoperative nutritional status and anticipate early on complications, length of hospital stay and discharge. Depending on the definitions used for sarcopenia and frailty, there is more or less overlap between both conditions. However, it has yet to be determined if sarcopenia and frailty can be used interchangeably or that they have additional value and should be used in combination to optimize individualized treatment in HNC patients.

Thermal and chemical ablation are minimally invasive procedures that avoid removal of the thyroid gland and target symptomatic nodules directly. Internationally, Radiofrequency ablation (RFA) is among one of the most widely used thermal ablative techniques, and is gaining traction in North America. Surgery remains the standard of care for most thyroid cancer, and in the right clinical setting, Active Surveillance (AS) can be a reasonable option for low risk disease. Minimally invasive techniques have emerged as an alternative option for patients deemed high risk for surgery, or for those patients who wish to receive a more active treatment approach compared to AS. Herein, we review the literature on the safety and efficacy of RFA for treating benign non-functioning thyroid nodules, autonomously functioning thyroid nodules, primary small low risk thyroid cancer (namely papillary thyroid cancer) as well as recurrent thyroid cancer.

BackgroundPatients with metastases in the lymph nodes of the neck and no obvious primary tumor, neck cancer with unknown primary (NCUP), represent a management challenge. A majority of patients have metastatic squamous cell carcinoma (SCC), although other histologies do occur.MethodsWe comprehensively reviewed the literature, compared available guidelines, and conferred with an international team of experts.ResultsPositron emission tomography-computed tomography (PET-CT) and fine needle aspiration (FNA) under ultrasound guidance increase accuracy of diagnosis. Immunohistochemistry (IHC), determination of human papilloma virus (HPV) status, by p16 staining or by in situ hybridization (ISH), and next-generation gene sequencing can guide us regarding probable primary sites and tumor biology. Narrow Band Imaging (NBI) has been introduced for the early detection of subtle mucosal lesions. Direct laryngoscopy (DL) and tonsillectomy have long been procedures used in the search for a primary site. More recently, TransOral Robotic Surgery (TORS) or Transoral LASER Microsurgery (TLM) have been introduced for lingual tonsillectomy.ConclusionsNew technologies have been developed which can better detect, diagnose, and treat occult primary tumors. Decisions regarding therapy are based on the primary tumor site (if discovered) and N stage. Options include neck dissection with or without postoperative adjuvant therapy, primary irradiation, or combined chemotherapy with irradiation. The preferred treatment of patients whose primary remains unidentified is controversial.

Deregulated SRC/FAK signaling leads to enhanced migration and invasion in many types of tumors. In myxoid and round cell liposarcoma (MRCLS), an adipocytic tumor characterized by the expression of the fusion oncogene FUS-CHOP, SRC have been found as one of the most activated kinases. Here we used a cell-of-origin model of MRCLS and an MRCLS cell line to thoroughly characterize the mechanisms of cell invasion induced by FUS-CHOP using in vitro (3D spheroid invasion assays) and in vivo (chicken chorioallantoic membrane model) approaches. FUS-CHOP expression activated SRC-FAK signaling and increased the invasive ability of MRCLS cells. In addition, FAK expression was found to significantly correlate with tumor aggressiveness in sarcoma patient samples. The involvement of SRC/FAK activation in FUS-CHOP–mediated invasion was further confirmed using the SRC inhibitor dasatinib, the specific FAK inhibitor PF-573228, and FAK siRNA. Notably, dasatinib and PF573228 could also efficiently block the invasion of cancer stem cell subpopulations. Downstream of SRC/FAK signaling, we found that FUS-CHOP expression increases the levels of the RHO/ROCK downstream effector phospho-MLC2 (T18/S19) and that this activation was prevented by dasatinib or PF573228. Moreover, the ROCK inhibitor RKI-1447 was able to completely abolish invasion in FUS-CHOP–expressing cells. These data uncover the involvement of SRC/FAK/RHO/ROCK signaling axis in FUS-CHOP–mediated invasion, thus providing a rationale for testing inhibitors of this pathway as potential novel antimetastatic agents for MRCLS treatment.

Abstract Annexin A1 (ANXA1) down-regulation is an early and frequent event in the development of head and neck squamous cell carcinomas (HNSCC). In an attempt to identify the underlying mechanisms of reduced ANXA1 protein expression, this study investigated ANXA1 mRNA expression in HNSCC specimens by both in situ hybridization and RT-qPCR. Results showed a perfect concordance between the pattern of ANXA1 mRNA and protein detected by immunofluorescence in tumors, precancerous lesions and normal epithelia, reflecting that ANXA1 down-regulation occurs at transcriptional level. We also found that both miR-196a and miR-196b levels inversely correlated with ANXA1 mRNA levels in paired HNSCC tissue samples and patient-matched normal mucosa. In addition, endogenous levels of ANXA1 mRNA and protein were consistently and significantly down-regulated upon miR-196a and miR-196b over-expression in various HNSCC-derived cell lines. The direct interaction of both mature miR-196a and miR-196b was further confirmed by transfection with Anxa1 3′UTR constructs. Combined bioinformatics and functional analysis of ANXA1 promoter activity contributed to identify key regions and potential mediators of ANXA1 transcriptional control. This study unveils that, in addition to miR-196a, miR-196b also directly targets ANXA1 in HNSCC.

Purpose: To review the current options in the management of Warthin tumors (WTs) and to propose a working management protocol. Methods: A systematic literature search was conducted using PubMed and ScienceDirect database. A total of 141 publications were selected and have been included in this review. Publications were selected based on relevance, scientific evidence, and actuality. Results: The importance of parotid WTs is increasing due to its rising incidence in many countries, becoming the most frequently encountered benign parotid tumor in certain parts of the world. In the past, all WTs were treated with surgery, but because of their slow growth rate, often minimal clinical symptoms, and the advanced age of many patients, active observation has gradually become more widely used. In order to decide on active surveillance, the diagnosis of WT must be reliable, and clinical, imaging, and cytological data should be concordant. There are four clear indications for upfront surgery: uncertain diagnosis; cosmetic problems; clinical complaints, such as pain, ulceration, or recurrent infection; and the patient’s wish to have the tumor removed. In the remaining cases, surgery can be elective. Active surveillance is often suggested as the first approach, with surgery being considered if the tumor progresses and/or causes clinical complaints. The extent of surgery is another controversial topic, and the current trend is to minimize the resection using partial parotidectomies and extracapsular dissections when possible. Recently, non-surgical options such as microwave ablation, radiofrequency ablation, and ultrasound-guided ethanol sclerotherapy have been proposed for selected cases. Conclusions: The management of WT is gradually shifting from superficial or total parotidectomy to more conservative approaches, with more limited resections, and to active surveillance in an increasing number of patients. Additionally, non-surgical treatments are emerging, but their role needs to be defined in future studies.

The diagnosis is the art of determining the nature of a disease, and an accurate diagnosis is the true cornerstone on which rational treatment should be built. Within the workflow in the management of head and neck tumours, there are different types of diagnosis. The purpose of this work is to point out the differences and the aims of the different types of diagnoses and to highlight their importance in the management of patients with head and neck tumours. Qualitative diagnosis is performed by a pathologist and is essential in determining the management and can provide guidance on prognosis. The evolution of immunohistochemistry and molecular biology techniques has made it possible to obtain more precise diagnoses and to identify prognostic markers and precision factors. Quantitative diagnosis is made by the radiologist and consists of identifying a mass lesion and the estimation of the tumour volume and extent using imaging techniques, such as CT, MRI, and PET. The distinction between the two types of diagnosis is clear, as the methodology is different. The accurate establishment of both diagnoses plays an essential role in treatment planning. Getting the right diagnosis is a key aspect of health care, and it provides an explanation of a patient’s health problem and informs subsequent decision. Deep learning and radiomics approaches hold promise for improving diagnosis.

The presence of tumor-infiltrating lymphocytes (TIL) in the tumor microenvironment has been demonstrated to be of prognostic value in various cancers. In this systematic review and meta-analysis, we investigated the prognostic value of TIL in laryngeal squamous cell carcinoma (LSCC). We performed a systematic search in PubMed for publications that investigated the prognostic value of TIL in LSCC. A meta-analysis was performed including all studies assessing the association between TIL counts in hematoxylin-eosin (HE)-stained sections, for CD8+ and/or CD3+/CD4+ TIL and overall survival (OS) or disease-free survival (DFS). The pooled meta-analysis showed a favorable prognostic role for stromal TIL in HE sections for OS (HR 0.57, 95% CI 0.36–0.91, p = 0.02), and for DFS (HR 0.56, 95% CI 0.34–0.94, p = 0.03). High CD8+ TIL were associated with a prolonged OS (HR 0.62, 95% CI 0.4–0.97, p = 0.04) and DFS (HR 0.73, 95% CI 0.34–0.94, p = 0.002). High CD3+/CD4+ TIL demonstrated improved OS (HR 0.32, 95% CI 0.16–0.9, p = 0.03) and DFS (HR 0.23, 95% CI 0.10–0.53, p = 0.0005). This meta-analysis confirmed the favorable prognostic significance of TIL in LSCC. High stromal TIL evaluated in HE sections and intra-tumoral and stromal CD3+, CD4+ and/or CD8+ TIL might predict a better clinical outcome.

Lectin-like transcript 1 (LLT1) expression by tumor cells contributes to immune evasion, thereby emerging as a natural killer (NK) cell-mediated immunotherapeutic target. This study is the first to investigate LLT1 expression (encoded by CLEC2D gene) in head and neck cancers to ascertain its impact on patient prognosis. LLT1 expression was analyzed by immunohistochemistry in a homogeneous cohort of human papillomavirus (HPV)-negative oropharyngeal squamous cell carcinomas (OPSCC), and correlated with clinical data. Results were further validated using transcriptomic data from the TCGA database. Tumoral LLT1 expression was detected in 190/221 (86%) OPSCC specimens, whereas normal pharyngeal epithelium was negative. Patients harboring LLT1-positive tumors showed significantly lower disease-specific (DSS) and overall survival (OS) (p = 0.049 and p = 0.036, respectively, log-rank test). High density of LLT1-positive tumor-infiltrating lymphocytes (TIL) was also frequently detected in 160 (73%) OPSCC samples, and significantly associated with better DSS and OS (p < 0.001 and p = 0.007, respectively). Multivariate Cox analysis further revealed that tumoral LLT1 expression and infiltration of LLT1-positive TIL were independent prognostic factors for DSS and OS. CLEC2D mRNA levels are also significantly increased in primary tumors compared to normal tissue. Strikingly, the prognostic impact of CLEC2D mRNA levels varied depending on HPV status in OPSCC, and among distinct cancer types. CLEC2D expression was significantly correlated with NK cell infiltration using the MCP-counter model. These findings uncover LLT1/CLEC2D as an independent prognostic factor in HPV-negative OPSCC, and a potential novel target for immunotherapy.

The molecular pathways involving p21 and mTORC1 are frequently deregulated in head and neck squamous cell carcinomas (HNSCC). Here, Llanos et al. report a mechanism that regulates p21 stability through the mTORC1/4E-BP1 pathway independently of p53, and show that the mechanism is prevalent in HNSCC.

Osteosarcoma (OS) is the most common type of primary solid tumor that develops in bone. Although standard chemotherapy has significantly improved long-term survival over the past few decades, the outcome for those patients with metastatic or recurrent OS remains dismally poor and, therefore, novel agents and treatment regimens are urgently required. A hypothesis to explain the resistance of OS to chemotherapy is the existence of drug resistant CSCs with progenitor properties that are responsible of tumor relapses and metastasis. These subpopulations of CSCs commonly emerge during tumor evolution from the cell-of-origin, which are the normal cells that acquire the first cancer-promoting mutations to initiate tumor formation. In OS, several cell types along the osteogenic lineage have been proposed as cell-of-origin. Both the cell-of-origin and their derived CSC subpopulations are highly influenced by environmental and epigenetic factors and, therefore, targeting the OS-CSC environment and niche is the rationale for many recently postulated therapies. Likewise, some strategies for targeting CSC-associated signaling pathways have already been tested in both preclinical and clinical settings. This review recapitulates current OS cell-of-origin models, the properties of the OS-CSC and its niche, and potential new therapies able to target OS-CSCs.

Copyright of RED - Revista de Educación a Distancia is the property of Universidad de Murcia and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)