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Oral cavity squamous cell carcinoma (OCSCC) predominantly affects the tongue and the floor of the mouth, primarily in patients over 50 years of age. Incidence and mortality rates vary significantly worldwide, influenced by geographic areas and demographic characteristics. Epidemiological studies revealed an increase in incidence of OCSCC among young adults (YA) <44 years old. This narrative review, provides updated information on the incidence, risk factors, and prognosis of YA-OCSCC using data published from 2018 to 2023 from different geographic locations. The studies indicate that the incidence of YA-OCSCC in Asia is approximately twice that in the US and that the incidence is strongly linked to risk factors such as betel quid chewing, tobacco use, and high alcohol consumption. The prognosis for YA-OCSCC, compared to that in older patients, shows similar or better overall survival, even in cases with relapses, but worse 5-year disease-free survival, despite receiving similar treatments. Consequently, a concerted effort is crucial to raise awareness about the cessation of tobacco and areca nut use, alcohol control, and the promotion of healthy lifestyle behaviors. Recent molecular data on YA-OCSCC suggests a potential profile characterized by epidermal growth factor receptor overexpression, low tumor mutation burden and an attenuated immune response. Upon confirmation in larger cohorts of YA-OCSCC patients from different geographical areas, the validated markers could aid in selecting tailored treatments., Competing Interests: LL declares the following conflicts of interest: research funds donated directly to the institute for clinical trials from AstraZeneca, BMS, Boehringer Ingelheim, Celgene International, Eisai, Exelixis, Debiopharm International SA, Hoffmann-La Roche Ltd, IRX Therapeutics, Medpace, Merck-Serono, MSD, Novartis, Pfizer, Roche, and Buran; occasional fees for participation as a speaker at conferences/congresses or as a scientific consultant for advisory boards from AstraZeneca, Bayer, MSD, Merck-Serono, AccMed, Neutron Therapeutics, Inc., and Alentis. SC declares occasional fees for participation as a speaker at conferences/congresses from AccMed; support for attending meetings and/or travel from AccMed, MultiMed Engineers srl, Care Insight sas. The remaining authors declare that the research was conducted without any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Lenoci, Moresco, Cavalieri, Bergamini, Torchia, Botta, Canevari, Trama, Licitra and De Cecco.)

Epstein-Barr virus (EBV) related- nasopharyngeal carcinoma (NPC) is a squamous carcinoma of the nasopharyngeal mucosal lining. Endemic areas (EA) are east and Southeast Asia, were NPC was recorded with higher incidence and longer estimated survival than in non-endemic area (NEA) such as Europe, We analyzed the gene expression and microenvironment properties of NPC in both areas to identify molecular subtypes and assess biological and clinical correlates that might explain the differences in incidence and outcome between EA- and NEA-NPCs. Six EA-NPC transcriptomic datasets, including tumor and normal samples, were integrated in a meta-analysis to identify molecular subtypes using a ConsensusClusterPlus bioinformatic approach. Based on the biological/functional characterization of four identified clusters were identified: Cl1, Immune-active; Cl2, defense-response; Cl3, proliferation; Cl4, perineural-interaction/EBV-exhaustion. Kaplan-Meier survival analysis, applied to the single dataset with available disease-free survival indicated Cl3 as the cluster with the worst prognosis (P = 0.0476), confirmed when applying four previously published prognostic signatures. A Cl3 classifier signature was generated and its prognostic performance was confirmed (P = 0.0368) on a validation dataset. Prediction of treatment response suggested better responses to: radiotherapy and immune checkpoint inhibitors immune-active and defense-response clusters; chemotherapy proliferation cluster; cisplatin perineural-interaction/EBV-exhaustion cluster. RNA sequencing for gene expression profiling was performed on 50 NEA-NPC Italian samples. In the NEA cohort, Cl1, Cl2 and Cl3 were represented, while perineural-interaction/EBV-exhaustion was almost absent. The immune/biological characterization and treatment-response prediction analyses of NEA-NPC partially replicated the EA-NPC results. Well characterized EA- and NEA-NPC retrospective and prospective cohorts are needed to validate the obtained results and can help designing future clinical studies., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: Immune checkpoint inhibitors have been approved and currently used in the clinical management of recurrent and metastatic head and neck squamous cell carcinoma (R/M HNSCC) patients. The reported benefit in clinical trials is variable and heterogeneous. Our study aims at exploring and comparing the predictive role of gene-expression signatures with classical biomarkers for immunotherapy-treated R/M HNSCC patients in a multicentric phase IIIb trial., Methods: Clinical data were prospectively collected in Nivactor tiral (single-arm, open-label, multicenter, phase IIIb clinical trial in platinum-refractory HNSCC treated with nivolumab). Findings were validated in an external independent cohort of immune-treated HNSCC patients, divided in long-term and short-term survivors (overall survival >18 and <6 months since the start of immunotherapy, respectively). Pretreatment tumor tissue specimen from immunotherapy-treated R/M HNSCC patients was used for PD-L1 (Tumor Proportion Score; Combined Positive Score (CPS)) and Tumor Mutational Burden (Oncopanel TSO500) evaluation and gene expression profiling; classical biomarkers and immune signatures (retrieved from literature) were challenged in the NIVACTOR dataset., Results: Cluster-6 (Cl6) stratification of NIVACTOR cases in high score (n=16, 20%) and low score (n=64, 80%) demonstrated a statistically significant and clinically meaningful improvement in overall survival in the high-score cases (p=0.00028; HR=4.34, 95% CI 1.84 to 10.22) and discriminative ability reached area under the curve (AUC)=0.785 (95% CI 0.603 to 0.967). The association of high-score Cl6 with better outcome was also confirmed in: (1) NIVACTOR progression-free survival (p=4.93E-05; HR=3.71, 95% CI 1.92 to 7.18) and objective-response-rate (AUC=0.785; 95% CI 0.603 to 0.967); (2) long survivors versus short survivors (p=0.00544). In multivariate Cox regression analysis, Cl6 was independent from Eastern Cooperative Oncology Group performance status, PDL1-CPS, and primary tumor site., Conclusions: These data highlight the presence of underlying biological differences able to predict survival and response following treatment with immunotherapy in platinum-refractory R/M HNSCC that could have translational implications improving treatment selection., Trial Registration Number: EudraCT Number: 2017-000562-30., Competing Interests: Competing interests: No, there are no competing interests., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: There is a strong need for preventive approaches to reduce the incidence of recurrence, second cancers, and late toxicities in head and neck squamous cell carcinoma (HNSCC) survivors. We conducted a randomized controlled trial (RCT) to assess a dietary intervention as a non-expensive and non-toxic method of tertiary prevention in HNSCC survivors., Methods: Eligible participants were disease-free patients with HNSCC in follow-up after curative treatments. Subjects were randomized 1:1 to receive a highly monitored dietary intervention plus the Word Cancer Research Fund/American Institute for Cancer Research recommendations for cancer prevention (intervention arm) or standard-of-care recommendations (control arm). The planned sample size for the event-free survival evaluation (primary endpoint) was not reached, and the protocol was amended in order to investigate the clinical (nutritional and quality-of-life questionnaires) and translational study [plasma-circulating food-related microRNAs (miRNAs)] as main endpoints, the results of which are reported herein., Results: One hundred patients were screened, 94 were randomized, and 89 were eligible for intention-to-treat analysis. Median event-free survival was not reached in both arms. After 18 months, nutritional questionnaires showed a significant increase in Recommended Food Score (p = 0.04) in the intervention arm vs. control arm. The frequency of patients with and without a clinically meaningful deterioration or improvement of the C30 global health status in the two study arms was similar. Food-derived circulating miRNAs were identified in plasma samples at baseline, with a significant difference among countries., Conclusion: This RCT represented the first proof-of-principle study, indicating the feasibility of a clinical study based on nutritional and lifestyle interventions in HNSCC survivors. Subjects receiving specific counseling increased the consumption of the recommended foods, but no relevant changes in quality of life were recorded between the two study arms. Food-derived plasma miRNA might be considered promising circulating dietary biomarkers., Competing Interests: LL declares the following conflicts of interest: research funds donated directly to the institute for clinical trials from AstraZeneca, BMS, Boehringer Ingelheim, Celgene International, Eisai, Exelixis, Debiopharm International SA, Hoffmann-La Roche ltd, IRX Therapeutics, Medpace, Merck-Serono, MSD, Novartis, Pfizer, Roche, Buran; occasional fees for participation as a speaker at conferences/congresses or as a scientific consultant for advisory boards from Astrazeneca, Bayer, MSD, Merck-Serono, AccMed, Neutron Therapeutics, Inc, Alentis. TF declares the following conflicts of interest: honoraria or advisor by MSD, Merck, BMS, Böhringer Ingelheim, Roche, Sanofi, Amgen, Janssen, Takeda, Invios, GlaxoSmithKline; Research Grants by MSD, Merck. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision, (Copyright © 2024 Cavalieri, Bruno, Serafini, Lenoci, Canevari, Lopez-Perez, Hernandez, Mariani, Miceli, Gavazzi, Pasanisi, Rosso, Cordero, Bossi, Golusinski, Dietz, Strojan, Fuereder, De Cecco and Licitra.)

Background: Hypo-fractionation can be an effective strategy to lower costs and save time, increasing patient access to advanced radiation therapy. To demonstrate this potential in practice within the context of temporal evolution, a twenty-year analysis of a representative radiation therapy facility from 2003 to 2022 was conducted. This analysis utilized comprehensive data to quantitatively evaluate the connections between advanced clinical protocols and technological improvements. The findings provide valuable insights to the management team, helping them ensure the delivery of high-quality treatments in a sustainable manner., Methods: Several parameters related to treatment technique, patient positioning, dose prescription, fractionation, equipment technology content, machine workload and throughput, therapy times and patients access counts were extracted from departmental database and analyzed on a yearly basis by means of linear regression., Results: Patients increased by 121 ± 6 new per year (NPY). Since 2010, the incidence of hypo-fractionation protocols grew thanks to increasing Linac technology. In seven years, both the average number of fractions and daily machine workload decreased by -0.84 ± 0.12 fractions/year and -1.61 ± 0.35 patients/year, respectively. The implementation of advanced dose delivery techniques, image guidance and high dose rate beams for high fraction doses, currently systematically used, has increased the complexity and reduced daily treatment throughput since 2010 from 40 to 32 patients per 8 h work shift (WS8). Thanks to hypo-fractionation, such an efficiency drop did not affect NPY, estimating 693 ± 28 NPY/WS8, regardless of the evaluation time. Each newly installed machine was shown to add 540 NPY, while absorbing 0.78 ± 0.04 WS8. The COVID-19 pandemic brought an overall reduction of 3.7% of patients and a reduction of 0.8 fractions/patient, to mitigate patient crowding in the department., Conclusions: The evolution of therapy protocols towards hypo-fractionation was supported by the use of proper technology. The characteristics of this process were quantified considering time progression and organizational aspects. This strategy optimized resources while enabling broader access to advanced radiation therapy. To truly value the benefit of hypo-fractionation, a reimbursement policy should focus on the patient rather than individual treatment fractionation.

Background: . At present, the prognostic prediction in advanced oral cavity squamous cell carcinoma (OCSCC) is based on the tumor-node-metastasis (TNM) staging system, and the most used imaging modality in these patients is magnetic resonance image (MRI). With the aim to improve the prediction, we developed an MRI-based radiomic signature as a prognostic marker for overall survival (OS) in OCSCC patients and compared it with published gene expression signatures for prognosis of OS in head and neck cancer patients, replicated herein on our OCSCC dataset., Methods: For each patient, 1072 radiomic features were extracted from T1 and T2-weighted MRI (T1w and T2w). Features selection was performed, and an optimal set of five of them was used to fit a Cox proportional hazard regression model for OS. The radiomic signature was developed on a multi-centric locally advanced OCSCC retrospective dataset (n = 123) and validated on a prospective cohort (n = 108)., Results: The performance of the signature was evaluated in terms of C-index (0.68 (IQR 0.66-0.70)), hazard ratio (HR 2.64 (95% CI 1.62-4.31)), and high/low risk group stratification (log-rank p < 0.001, Kaplan-Meier curves). When tested on a multi-centric prospective cohort (n = 108), the signature had a C-index of 0.62 (IQR 0.58-0.64) and outperformed the clinical and pathologic TNM stage and six out of seven gene expression prognostic signatures. In addition, the significant difference of the radiomic signature between stages III and IVa/b in patients receiving surgery suggests a potential association of MRI features with the pathologic stage., Conclusions: Overall, the present study suggests that MRI signatures, containing non-invasive and cost-effective remarkable information, could be exploited as prognostic tools., (© 2023. The Author(s).)

Epidermal growth factor receptor (EGFR) pathway has been shown to play a crucial role in several inflammatory conditions and host immune-inflammation status is related to tumor prognosis. This study aims to evaluate the prognostic significance of a four-gene inflammatory signature in recurrent/metastatic (R/M) head and neck squamous cell carcinoma (HNSCC) patients treated with the EGFR inhibitor cetuximab plus chemotherapy. The inflammatory signature was assessed on 123 R/M HNSCC patients, enrolled in the multicenter trial B490 receiving first-line cetuximab plus platinum-based chemotherapy. The primary endpoint of the study was progression free survival (PFS), while secondary endpoints were overall survival (OS) and objective response rate (ORR). The patient population was subdivided into 3 groups according to the signature score groups. The four-genes-signature proved a significant prognostic value, resulting in a median PFS of 9.2 months in patients with high vs. 6.2 months for intermediate vs. 3.9 months for low values ( p = 0.0016). The same findings were confirmed for OS, with median time of 18.4, 13.4, and 7.5 months for high, intermediate, and low values of the score, respectively ( p = 0.0001). When ORR was considered, the signature was significantly higher in responders than in non-responders ( p = 0.0092), reaching an area under the curve (AUC) of 0.65 (95% CI: 0.55-0.75). Our findings highlight the role of inflammation in the response to cetuximab and chemotherapy in R/M-HNSCC and may have translational implications for improving treatment selection.

Background: Stage I epithelial ovarian cancer (EOC) encompasses five histologically different subtypes of tumors confined to the ovaries with a generally favorable prognosis. Despite the intrinsic heterogeneity, all stage I EOCs are treated with complete resection and adjuvant therapy in most of the cases. Owing to the lack of robust prognostic markers, this often leads to overtreatment. Therefore, a better molecular characterization of stage I EOCs could improve the assessment of the risk of relapse and the refinement of optimal treatment options., Materials and Methods: 205 stage I EOCs tumor biopsies with a median follow-up of eight years were gathered from two independent Italian tumor tissue collections, and the genome distribution of somatic copy number alterations (SCNAs) was investigated by shallow whole genome sequencing (sWGS) approach., Results: Despite the variability in SCNAs distribution both across and within the histotypes, we were able to define three common genomic instability patterns, namely stable, unstable, and highly unstable. These patterns were based on the percentage of the genome affected by SCNAs and on their length. The genomic instability pattern was strongly predictive of patients' prognosis also with multivariate models including currently used clinico-pathological variables., Conclusions: The results obtained in this study support the idea that novel molecular markers, in this case genomic instability patterns, can anticipate the behavior of stage I EOC regardless of tumor subtype and provide valuable prognostic information. Thus, it might be propitious to extend the study of these genomic instability patterns to improve rational management of this disease., Competing Interests: Conflict of interest statement The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Summary: Hundreds of gene expression signatures have been developed during the last two decades. However, due to the multitude of development procedures and sometimes a lack of explanation for their implementation, it can become challenging to apply the original method on custom data. Moreover, at present, there is no unified and tidy interface to compute signature scores with different single sample enrichment methods. For these reasons, we developed hacksig, an R package intended as a unified framework to obtain single sample scores with a tidy output as well as a collection of manually curated gene signatures and methods from cancer transcriptomics literature., Availability and Implementation: The hacksig R package is freely available on CRAN (https://CRAN.R-project.org/package=hacksig) under the MIT license. The source code can be found on GitHub at https://github.com/Acare/hacksig., Supplementary Information: Supplementary data are available at Bioinformatics online., (© The Author(s) 2022. Published by Oxford University Press.)

The most common arrhythmia associated with COronaVIrus-related Disease (COVID) infection is sinus tachycardia. It is not known if high Heart Rate (HR) in COVID is simply a marker of higher systemic response to sepsis or if its persistence could be related to a long-term autonomic dysfunction. The aim of our work is to assess the prevalence of elevated HR at discharge in patients hospitalized for COVID-19 and to evaluate the variables associated with it. We enrolled 697 cases of SARS-CoV2 infection admitted in our hospital after February 21 and discharged within 23 July 2020. We collected data on clinical history, vital signs, laboratory tests and pharmacological treatment. Severe disease was defined as the need for Intensive Care Unit (ICU) admission and/or mechanical ventilation. Median age was 59 years (first-third quartile 49, 74), and male was the prevalent gender (60.1%). 84.6% of the subjects showed a SARS-CoV-2 related pneumonia, and 13.2% resulted in a severe disease. Mean HR at admission was 90 ± 18 bpm with a mean decrease of 10 bpm to discharge. Only 5.5% of subjects presented HR > 100 bpm at discharge. Significant predictors of discharge HR at multiple linear model were admission HR (mean increase = β = 0.17 per bpm, 95% CI 0.11; 0.22, p < 0.001), haemoglobin (β = -0.64 per g/dL, 95% CI -1.19; -0.09, p = 0.023) and severe disease (β = 8.42, 95% CI 5.39; 11.45, p < 0.001). High HR at discharge in COVID-19 patients is not such a frequent consequence, but when it occurs it seems strongly related to a severe course of the disease.

Entanglement occurs when a marine turtle becomes trapped within anthropogenic materials such as debris or fishery gear, inducing strangulation of anatomical parts such as flippers or the neck, causing deep lacerations, maiming, amputation, or choking. Often, severely entangled flippers in captured or stranded turtles are removed surgically. Turtles with flipper impairment have difficulty in swimming, diving, and feeding. Our aim was to use color Doppler ultrasound and multi-detector computer tomography to evaluate residual vascularization or neovascularization in severely entangled flippers of loggerhead sea turtles ( Caretta caretta ) to assess viability of flippers, even in the absence of limb sensation. We studied 12 turtles with either unilateral ( n =8) or bilateral ( n =4) involvement. A total of 14 flippers were severely entangled and two flippers were spontaneously amputated. Only two of the 14 entangled flippers had to be removed surgically. For 12 entangled flippers, after surgical curettage, the treatment protocol was based on the use of a plant-derived commercial dressing. The animals were monitored and treated for 1-3 mo, until the soft tissue defects were completely healed by secondary intention. Interestingly, in the treated animals the healing flippers steadily recovered motility and sensation, restoring the complete functionality of the flipper. Vascularization of the limb was found to be critical to prevent amputation of entangled flippers, preserving the flipper and its functionality with conservative therapy and avoiding amputation as much as possible. Our study showed that in cases of entanglement, amputation does not need to be performed immediately but can wait for nonviability to declare itself following conservative therapy and should be reserved as a last-resort treatment.

Loggerhead sea turtles ( Caretta caretta) are among the most frequent victims of bycatch in drifting longlines, and the ingestion of fish hooks and fishing lines is one of the most frequent causes of death of sea turtles. The aim of this study was to evaluate whether coelomic ultrasound (US) can be decisive, not only for diagnosis but also to optimize surgical planning based on preoperative evaluation of the bowel conditions and, in addition, to see if there are characteristic sonographic findings in sea turtles associated with the ingestion of fishing lines. Physical examination, hematology, blood chemistry, radiographs, and US examination were performed in 37 loggerhead sea turtles with suspected or known ingestion of fish hooks or monofilament fishing lines. During the ultrasonographic examinations, the loggerhead sea turtles were placed in dorsal recumbency and the prefemoral left and right acoustic windows were used. Nine wild loggerheads had sonographic findings of intestinal and coelomic abnormalities, and the sonographic images were compared with the surgical findings. Ultrasonography positively identified the foreign body in 89% (8/9) animals. The presence of intestinal plication (in all loggerhead turtles) and ultrasonographic visualization of the linear foreign body was always consistent with the ingestion of a fishing line. In sea turtles, fishing lines cause a corrugated appearance in the small intestine due to increased/unproductive peristalsis. The affected small bowel loops are usually dilated with fluid. In the present study, coelomic US allowed us to make a thorough evaluation of the characteristics, number, and severity of the bowel wall lesions in the animals, thus ensuring the planning of a correct surgical procedure. We suggest that US examination of the coelomic cavity should be complementary to radiographic survey in cases of suspected ingestion of fish hooks and fishing lines by sea turtles.

Onchocerca lupi, a zoonotic nematode infecting the eyes of carnivores, has been increasingly reported in dogs from Europe and the USA. In order to improve the current status of knowledge on this neglected filarioid, diagnostic imaging tools (i.e., ultrasound scan, computed tomography and magnetic resonance imaging) are herein used to diagnose canine onchocercosis in two dogs, which scored positive for O. lupi microfilariae at the skin snip test and to assess the anatomical location of the nematode within the ocular apparatus. Results indicate that ultrasound tools are useful to address the diagnosis of O. lupi in dogs and to evaluate the localization of nodules or cysts containing the adult nematode., (Copyright © 2014 Elsevier B.V. All rights reserved.)

The molecular characterization of a strain of Canine minute virus (CnMV) associated with neonatal death is reported. Three newborn puppies of a litter of Jack Russell terrier dogs died after displaying systemic disease, whereas 2 surviving puppies showed no clinical signs with the exception of transient cardiac abnormalities that were evident by electrocardiography. Necropsy of 1 dead puppy revealed severe lesions in the internal organs. A strain of Canine minute virus was detected in tissue samples collected from the puppy, and virus circulation was demonstrated by molecular or serological testing in the dam, puppies of the same litter, and other puppies in the same kennel. By sequence and phylogenetic analysis of the gene encoding for the VP2 capsid protein, the strain circulating in the kennel was found to be related to recent Asian CnMV isolates. Continuous molecular surveillance for CnMV in kennels, shelters, and rescue centers would expand the knowledge base on the epidemiological and pathogenetic features of CnMV, which has been known for several decades but still poorly understood.