In Response to "Acute Oral Mucositis During Hypo-Fractionated Radiation in Squamous Cell Carcinoma of Oral Cavity".

Null.

A retrospective study of chemotherapeutic effect without wide-margin surgery or radiation therapy in dogs with oral malignant melanoma.

Background: Effective treatment for canine oral malignant melanoma (e.g., curative-intent surgery) may not be feasible or radiation therapy may be unavailable. However, chemotherapy is usually an option, and more information is needed regarding its use without adequate local treatments. Objective: Our objective was to investigate the efficacy of chemotherapy in canine oral malignant melanoma without adequate local control, using carboplatin with dose reduction in small-breed dogs and metronomic chemotherapy. Animals and procedure: Client-owned dogs with histopathologically diagnosed oral malignant melanoma were retrospectively enrolled from 2016 to 2022. The chemotherapy protocol in each case was determined by the attending clinician. Results: Thirteen dogs were included. The median progression-free interval of all 13 dogs was 42 d (14 to 953 d). The median overall survival time of dogs with chemotherapy as their only systemic treatment was 181 d (50 to 960 d; n = 11). The median dosage of carboplatin was 250 mg/m2. Response to treatment and clinical stage were significant prognostic factors. Conclusion and clinical relevance: As chemotherapy provided a median survival of 6 mo, it could be considered when adequate local control is infeasible. Earlier clinical stages or achievement of at least stable disease during chemotherapy may indicate better survival in dogs.

Une étude rétrospective de l'effet chimiothérapeutique sur le mélanome malin buccal canin dépourvu de chirurgie et de radiothérapie á large marge : le stade clinique et la réponse au traitement prédisent les résultats du patient. Mise en contexte: Des traitements efficaces pour le mélanome malin oral canin, tels que la chirurgie á visée curative, ne sont parfois pas réalisables ou la radiothérapie n'est pas disponible dans certaines régions. La chimiothérapie reste une option de traitement et davantage d'informations devraient être fournies pour les cas qui n'ont pas eu accés á un traitement local adéquat. Objectif: Cette étude visait á étudier l'efficacité de la chimiothérapie dans le mélanome malin oral canin sans contrôle local adéquat, en utilisant le carboplatine avec réduction de dose chez les chiens de petite race et la chimiothérapie métronomique. Animaux et procédure: Treize chiens appartenant á des clients atteints d'un mélanome malin oral diagnostiqué par histopathologie ont été rétrospectivement inscrits de 2016 á 2022. Le protocole de chimiothérapie a été déterminé par le clinicien traitant. Résultats: L'intervalle médian sans progression des treize chiens était de 42 jours (14­953 jours). La durée médiane de survie globale des chiens ayant reçu une chimiothérapie comme seul traitement systémique était de 181 jours (50­960 jours; n = 11). La dose médiane de carboplatine était de 250 mg/m2. La réponse au traitement et le stade clinique étaient des facteurs pronostiques importants. Conclusion et pertinence clinique: La chimiothérapie pouvait encore être envisagée lorsqu'un contrôle local adéquat était impossible. Des stades cliniques plus précoces ou des patients atteignant au moins une maladie stable pendant la chimiothérapie peuvent indiquer une meilleure survie.(Traduit par les auteurs).

Effect of radiotherapy on head and neck cancer tissues in patients receiving radiotherapy: a bioinformatics analysis-based study.

Radiotherapy is pivotal in treating head and neck cancers including nasopharyngeal, tongue, hypopharyngeal, larynx, maxillary sinus, parotid gland, and oral cancers. It holds the potential for curative effects and finds application in conjunction with chemotherapy, either as a radical method to preserve organ function or as an adjuvant postoperative treatment. We used bioinformatics analysis to investigate the effects of radiotherapy on head and neck cancer tissues in patients who had received radiotherapy. In this study, the expression and mutation profiles of The Cancer Genome Atlas-Head-Neck Squamous Cell Carcinoma were downloaded from the UCSC-Xena database, categorizing patients into two groups-those receiving radiotherapy and those not receiving radiotherapy. Subsequently, differential expression analysis and gene set enrichment analysis (GSEA) were performed. Following this, single-sample GSEA (ssGSEA) scores related to glucose and lipid metabolism were compared between the two groups. Additionally, immune cell infiltration analysis and single-cell verification were performed. Finally, the mutation profiles of the two groups were compared. The analyses revealed that patients receiving radiotherapy exhibited prolonged survival, enhanced apoptosis in head and neck cancer tissue, and diminished keratinocyte proliferation and migration. A comparison of ssGSEA scores related to glucose and lipid metabolism between the two groups indicated a reduction in glycolysis, tricarboxylic acid cycle activity, and fat synthesis in tissues treated with radiotherapy, suggesting that radiotherapy can effectively inhibit tumour cell energy metabolism. Analyses of immune cell infiltration and single-cell verification suggested decreased infiltration of immune cells post-radiotherapy in head and neck cancer tissues. A comparison of mutation profiles revealed a higher frequency of TP53, TTN, and CDKN2A mutations in patients receiving radiotherapy for head and neck cancer. In conclusion, the bioinformatics analyses delved into the effect of radiotherapy on patients with head and neck carcinoma. This study provides a theoretical framework elucidating the molecular mechanisms underlying radiotherapy's efficacy in treating head and neck cancer and presents scientific recommendations for drug therapy following radiotherapy.

Are oral cancers effectively palliated with radiotherapy? Outcomes of treatment with a modified QUAD SHOT regimen.

BACKGROUND: This study assessed a palliative radiotherapy regimen using daily radiation over 4 days for three courses in inoperable head and neck cancers, emphasizing oral primary cancers. METHODS: Retrospective data of 116 patients treated with a daily dose of 3.6-3.7 Gy in four fractions over 4 days to a total of three courses, with a 2-week gap after every course, were analyzed for survival outcomes. A subgroup analysis was done for oral cancer. RESULTS: Ninety-nine (85%) completed three courses. Overall subjective response rate was 77%. Median overall survival and progression-free survival were 12 months (95% confidence interval [CI]: 8-20) and 8 months (95% CI: 6-10), with numerically higher overall survival in oral cancer. The treatment was well tolerated, with no on-treatment hospitalization or grade 3-4 toxicities. CONCLUSION: The modified QUAD SHOT regimen is practical for palliation in head and neck cancers.

Postoperative Radiotherapy and Survival in Oral Cavity Squamous Cell Carcinoma With Mandibulectomy.

Importance: Oral cavity squamous cell carcinoma (SCC) tumors with mandibular invasion are upstaged to pT4a regardless of their size. Even small tumors with boney invasion, which would otherwise be classified as pT1-2, are recommended for the locally advanced treatment pathway to receive administration of postoperative radiotherapy (PORT). Objective: To evaluate the association of PORT with overall survival according to tumor size among patients who received mandibulectomy for pT4aN0 oral cavity SCC. Design, Setting, and Participants: This was a retrospective analysis using data from the US National Cancer Database from January 1, 2004, through December 31, 2019. All patients who received mandibulectomy for treatment-naive pT4aN0 oral cavity SCC with negative surgical margins were included. Data analyses were performed in January 2023 and finalized in July 2023. Exposure: PORT vs no PORT. Main Outcomes and Measures: Entropy balancing was used to balance covariate moments between treatment groups. Weighted multivariable Cox proportional hazards regression was used to measure the association of PORT with overall survival associated with tumor size. Results: Among 3268 patients with pT4aN0 oral cavity SCC (mean [SD] age, 65.9 [12.1] years; 2024 [61.9%] male and 1244 [38.1%] female), 1851 (56.6%) received PORT and 1417 (43.4%) did not receive PORT. On multivariable analysis was adjusted for age, insurance status, Charlson Comorbidity Index score, tumor site, tumor grade, tumor size, and PORT. Findings indicated that PORT was associated with improved overall survival and that this relative survival advantage trended upwards with increasing tumor size. That is, the larger the tumor, the greater the survival advantage associated with the use of PORT. For the 1068 patients with tumors greater than 4 cm, the adjusted hazard ratio (aHR) in favor of PORT was 0.63 (95% CI, 0.48-0.82); for the 1774 patients with tumors greater than 2 cm but less than or equal to 4 cm, the aHR was 0.76 (95% CI, 0.62-0.93); and for 426 patients with tumors less than 2 cm, the aHR was 0.81 (95% CI, 0.57-1.15). Conclusions and Relevance: In this retrospective analysis of patients who received mandibulectomy for pT4aN0 oral cavity SCC, PORT was associated with improved overall survival, the benefit of which improved relatively with increasing tumor size. These findings suggest that tumor size should be considered in guidelines for PORT administration in this patient population.

SALL4 promotes cancer stem-like cell phenotype and radioresistance in oral squamous cell carcinomas via methyltransferase-like 3-mediated m6A modification.

Radioresistance imposes a great challenge in reducing tumor recurrence and improving the clinical prognosis of individuals having oral squamous cell carcinoma (OSCC). OSCC harbors a subpopulation of CD44(+) cells that exhibit cancer stem-like cell (CSC) characteristics are involved in malignant tumor phenotype and radioresistance. Nevertheless, the underlying molecular mechanisms in CD44( + )-OSCC remain unclear. The current investigation demonstrated that methyltransferase-like 3 (METTL3) is highly expressed in CD44(+) cells and promotes CSCs phenotype. Using RNA-sequencing analysis, we further showed that Spalt-like transcription factor 4 (SALL4) is involved in the maintenance of CSCs properties. Furthermore, the overexpression of SALL4 in CD44( + )-OSCC cells caused radioresistance in vitro and in vivo. In contrast, silencing SALL4 sensitized OSCC cells to radiation therapy (RT). Mechanistically, we illustrated that SALL4 is a direct downstream transcriptional regulation target of METTL3, the transcription activation of SALL4 promotes the nuclear transport of ß-catenin and the expression of downstream target genes after radiation therapy, there by activates the Wnt/ß-catenin pathway, effectively enhancing the CSCs phenotype and causing radioresistance. Herein, this study indicates that the METTL3/SALL4 axis promotes the CSCs phenotype and resistance to radiation in OSCC via the Wnt/ß-catenin signaling pathway, and provides a potential therapeutic target to eliminate radioresistant OSCC.

Impact of Adjuvant Radiotherapy in Squamous Cell Carcinoma of the Oral Cavity with Perineural Invasion.

OBJECTIVE: Current guidelines indicate postoperative radiotherapy (PORT) in oral squamous cell carcinoma (OSCC) with perineural invasion (PNI), however, its real benefit has never been proven. The aim of our study is to investigate the benefit of PORT in OSCC patients with PNI in terms of survival and disease control. DATA SOURCES: The Pubmed/MEDLINE, Cochrane Library, and Scopus databases. REVIEW METHODS: Patients with PNI + OSCC treated with primary surgery were extracted from the included studies. The pooled logHR was calculated by comparing patients who underwent PORT to those who underwent only observation for overall survival (OS), disease-specific survival (DSS), disease-free survival (DFS), and locoregional control (LRC). RESULTS: About 690 patients with primary OSCC and PNI were included from nine studies. 374 (54.2%) patients underwent PORT, while 316 (45.8%) underwent observation. Analyses showed non-significant difference between the two groups for OS (HR: 1.01; 95% CI: 0.38-2.69), DSS (HR: 2.03; 95% CI: 0.54-7.56), and LRC (HR: 0.89; 95% CI: 0.53-1.50). They showed a significant difference in terms of DFS (HR: 0.86; 95% CI: 0.77-0.97). CONCLUSION: The real benefit of PORT in OSCC patients with PNI is still unclear, although it may have a positive impact on DFS. Clinicians should consider individual patient's characteristics, tumor factors, and treatment goals when deciding whether to recommend PORT. Further studies are needed to clarify which entity of PNI really benefits from PORT. LEVEL OF EVIDENCE: NA Laryngoscope, 134:2019-2027, 2024.

Dental rehabilitation in irradiated oral cancer patients using patient-specific dental implants - Clinical outcome and oral health-related quality of life.

INTRODUCTION: Dental rehabilitation in oral cancer patients is essential for good oral health-related quality of life (OHRQoL). Patient-specific dental implants are suitable for treating tumor-related bony defects, resulting in satisfactory OHRQoL. However, knowledge concerning the clinical outcome and OHRQoL following tumor irradiation is lacking. MATERIAL AND METHODS: A retrospective analysis was carried out to evaluate clinical outcomes and OHRQoL in eight patients who received patient-specific dental implants and implant-supported dentures after surgical treatment for oral cancer with additional irradiation. OHRQoL assessment was performed using the German long version of the oral health impact profile (OHIP) questionnaire (OHIP-G53). RESULTS: Clinical examination revealed successful dental rehabilitation in all the patients with only minor impairments. Restricted stability and function of implants were not observed. OHIP sum-scores of all the patients indicated acceptable OHRQoL, but this varied between patients treated in the upper or lower jaw. Single-item sum-scores concerning the adverse events "difficulty in chewing," "food catching," "sore jaw," "sore spots," and "unclear speech" were detected to be the worst, and pain-related OHIP dimensions demonstrated the highest scores (followed by functional limitation, physical disability, and psychosocial impact) with a worse OHRQoL following lower jaw treatment. Other dimension sum-scores were overall lower and nearly equally distributed in patients. CONCLUSIONS: Dental rehabilitation of irradiated oral cancer patients using patient-specific dental implants may be suitable, leading to acceptable OHRQoL. However, implant insertion in the upper jaw seems to be more favorable. Further studies on patient-specific dental implants are warranted to validate the current results.

Bromodomain-containing protein 4 inhibition improves the efficacy of cisplatin and radiotherapy in oral squamous cell carcinoma by suppressing programmed cell death-ligand 1 expression.

The bromodomain-containing protein 4 (BRD4) is highly expressed in oral squamous cell carcinoma (OSCC) and plays a crucial role in tumour progression. However, the impact of BRD4 on the efficacy of chemotherapy and radiotherapy by regulating the expression of programmed cell death-ligand 1 (PD-L1) in OSCC remains unclear. In this study, we found that the BRD4 inhibitor JQ1 effectively enhanced the inhibitory effects of cisplatin and radiotherapy on cell proliferation and promoted the apoptosis of OSCC cells by cisplatin and radiotherapy. Furthermore, treatment with JQ1 reversed the increase of the expression of PD-L1 by cisplatin and radiotherapy, whereas the overexpression of PD-L1 partially countered the beneficial effects of JQ1 on the anticancer efficacy of cisplatin and radiotherapy. These results demonstrate that the inhibition of BRD4 improves the anticancer effect of chemotherapy and radiotherapy by suppressing the expression of PD-L1 in OSCC, suggesting that targeting BRD4 could be a promising therapeutic approach for chemo/radioresistant OSCC.

Adjuvant Radiotherapy in Moderately Advanced (T3) Oral Cavity Cancers.

OBJECTIVE: To investigate the impact of adjuvant radiotherapy in isolated locally advanced oral cavity cancers (pT3N0M0) without adverse features. METHODS: We selected all patients from the National Cancer Database (2004-2019) who underwent surgical treatment where the final pathology was T3N0M0 with negative margins. Demographics, details of treatment, and outcomes were abstracted. The impact of radiotherapy on survival was assessed with univariable, multivariable, and propensity score-matched analyses. RESULTS: We identified 571 patients in our survival cohort. Most were male (348, 60.9%), and median age was 65. Less than one-third (176, 30.8%) received adjuvant radiotherapy. The median length of follow-up was 29 months. Overall, adjuvant radiotherapy was associated with improved survival (87.2% vs. 77.7%, at 2 years, p < 0.01). On multivariable analysis controlling for age and comorbidities, this survival difference persisted (HR: 0.62, 95% CI: 0.43-0.90, p = 0.01). In a propensity score-matched population of 278 patients matched on age and comorbidities, adjuvant radiotherapy was still associated with longer survival (87.4% vs. 78.5%, p = 0.014). CONCLUSION: In our study, adjuvant radiotherapy was associated with improved survival in completely excised locally advanced oral cavity tumors (T3N0M0). However, a significant proportion of patients do not receive adjuvant radiotherapy. These findings highlight the need for continued efforts to promote guideline-recommended care. LEVEL OF EVIDENCE: 3 Laryngoscope, 134:2236-2242, 2024.

Radiation doses of medical radiation workers performing low-dose-rate brachytherapy with 198Au grains and 192Ir pins for patients with oral cancers.

OBJECTIVES: Low-dose-rate brachytherapy (LDR-BT) with 198Au grains and 192Ir pins is an essential treatment option for oral cancer due to its high rate of local control and low invasiveness. However, the radiation exposure of medical radiation workers is concerning. Thus, we aimed to determine the radiation dose delivered to medical radiation workers during LDR-BT using 198Au grains and 192Ir pins for oral cancer. METHODS: Thirty-two patients with oral cancer underwent 198Au grain interstitial LDR-BT between June 2016 and May 2023, and 23 patients with tongue cancer underwent 192Ir pin interstitial LDR-BT between March 2015 and November 2017 at our hospital. Dosimetry was performed by attaching a dosimeter to the chest pocket of the operator and assistant during 198Au grain or 192Ir pin LDR-BT. Since the operator also loads 198Au grains into the implantation device, the operator's radiation dose includes the dose received during this preparation. RESULTS: Mean radiation doses of the operators with 198Au grain and 192Ir pin LDR-BT were 165.8 and 211.2 µSv, respectively. Statistically significant differences between the radioactive sources of 198Au grain and 192Ir pin LDR-BT were observed (p = 0.0459). The mean radiation doses of the assistants with 198Au grain and 192Ir pin LDR-BT were 92.0 and 162.0 µSv, respectively. Statistically significant differences were observed between the radioactive sources of 198Au grains and 192Ir pin LDR-BT (p = 0.0003). CONCLUSIONS: Regarding radioactive source differences, 192Ir pin LDR-BT resulted in higher doses delivered to medical radiation workers than 198Au grain LDR-BT.

Astaxanthin Synergizes with Ionizing Radiation (IR) in Oral Squamous Cell Carcinoma (OSCC).

Astaxanthin (ATX) is known for its antioxidant and anti-inflammation functions yet its role in cancers requires more research. This study is aimed to reveal the potential synergetic effect of ATX with ionizing radiation (IR) in OSCC. Cell survival was measured after human OSCC cells including CAL27 and SCC9, and normal human oral keratinocytes (NHOKs) were treated with different concentrations of ATX for 24 h. Colony formation assays were performed after OSCC cells were treated with IR, ATX (20 µ M), or combined and survival fraction was analyzed. Malondialdehyde (MDA), glutathione (GSH), and intercellular iron levels were measured. Western blot method was used to measure the ferroptosis-related proteins, GPX4, SLC7A11, and ACSL4. In xenograft mice model, we evaluated the tumor volumes, tumor growth, and examined the GPX4/ACSL4 proteins in tumor tissues using Immunohistochemistry (IHC). ATX inhibited viability of OSCC cells but not NHOK. In OSCC cells, ATX further enhanced the cell death induced by IR. In addition, ATX promoted the MDA content, Iron levels but inhibited the GSH regulated by IR in cells. ATX could synergize with IR, further inhibiting GPX4, SLC7A11 and promoting ACSL4 in OSCC cells. In vivo, ATX and IR treatment inhibited OSCC tumor growth and the group with combined treatment showed the most inhibitory effect. GPX4 was inhibited by IR and further inhibited in the combined group while ACSL4 was promoted by IR and enhanced more significantly in the combined group. ATX might synergize with IR treatment in OSCC partly via ferroptosis.

Can interventional radiotherapy (brachytherapy) be an alternative to surgery in early-stage oral cavity cancer? A systematic review.

PURPOSE: Brachytherapy (BT), also known as interventional radiotherapy (IRT), has proven its utility in the treatment of localized tumors. The aim of this review was to examine the efficacy of modern BT in early-stage oral cavity cancer (OCC) in terms of local control (LC), overall survival (OS), disease-free survival (DFS), cancer-specific survival (CSS), and safety. METHODS: The SPIDER framework was used, with sample (S), phenomena of interest (PI), design (D), evaluation (E), and research type (R) corresponding to early-stage oral cavity cancer (S); BT (PI); named types of qualitative data collection and analysis (D); LC, OS, DFS, CSS, and toxicity (E); qualitative method (R). Systematic research using PubMed and Scopus was performed to identify full articles evaluating the efficacy of BT in patients with early-stage OCC. The studies were identified using medical subject headings (MeSH). We also performed a PubMed search with the keywords "brachytherapy oral cavity cancer, surgery." The search was restricted to the English language. The timeframe 2002-2022 as year of publication was considered. We analyzed clinical studies of patients with OCC treated with BT alone only as full text; conference papers, surveys, letters, editorials, book chapters, and reviews were excluded. RESULTS: The literature search resulted in 517 articles. After the selection process, 7 studies fulfilled the inclusion criteria and were included in this review, totaling 456 patients with early-stage node-negative OCC who were treated with BT alone (304 patients). Five-year LC, DFS, and OS for the BT group were 60-100%, 82-91%, and 50-84%, respectively. CONCLUSION: In conclusion, our review suggests that BT is effective in the treatment of early-stage OCC, particularly for T1N0 of the lip, mobile tongue, and buccal mucosa cancers, with good functional and toxicity profiles.

Long-term outcomes of patients with oral cavity cancer receiving postoperative radiotherapy after salvage neck dissection for cervical lymph node recurrence.

BACKGROUNDS: We aimed to clarify the outcomes of postoperative radiotherapy (PORT) after salvage neck dissection for cervical lymph node (LN) recurrence in oral cavity cancer. METHODS: We retrospectively evaluated overall survival (OS), recurrence-free survival (RFS), recurrence patterns, and adverse events of 51 patients with high-risk features receiving PORT after salvage neck dissection between 2009 and 2019. RESULTS: After a median follow-up of 7.4 years from PORT initiation, the 7-year OS and RFS rates were 66.3% (95% CI: 54.0-81.3) and 54.6% (95% CI: 42.1-70.9), respectively. Age <70 years and isolated LN recurrence were significantly associated with longer OS and RFS. Among the 22 patients who experienced recurrence, 14 experienced recurrence within the radiation field. PORT-related grade 3 acute mucositis (35%) and late adverse events (osteoradionecrosis [4%] and laryngeal stenosis [2%]) were observed. CONCLUSIONS: PORT after salvage neck dissection for cervical LN recurrence achieved good survival with acceptable toxicity.

Cold Atmospheric Plasma Jet Irradiation Decreases the Survival and the Expression of Oncogenic miRNAs of Oral Carcinoma Cells.

Despite recent advancements, therapies against advanced oral squamous cell carcinoma (OSCC) remain ineffective, resulting in unsatisfactory therapeutic outcomes. Cold atmospheric plasma (CAP) offers a promising approach in the treatment of malignant neoplasms. Although the effects of CAP in abrogating OSCC have been explored, the exact mechanisms driving CAP-induced cancer cell death and the changes in microRNA (miRNA) expression are not fully understood. We fabricated and calibrated an argon-CAP device to explore the effects of CAP irradiation on the growth and expression of oncogenic miRNAs in OSCC. The analysis revealed that, in OSCC cell lines following CAP irradiation, there was a significant reduction in viability; a downregulation of miR-21, miR-31, miR-134, miR-146a, and miR-211 expression; and an inactivation of the v-akt murine thymoma viral oncogene homolog (AKT) and extracellular signal-regulated kinase (ERK) signals. Pretreatment with blockers of apoptosis, autophagy, and ferroptosis synergistically reduced CAP-induced cell death, indicating a combined induction of variable death pathways via CAP. Combined treatments using death inhibitors and miRNA mimics, alongside the activation of AKT and ERK following the exogenous expression, counteracted the cell mortality associated with CAP. The CAP-induced downregulation of miR-21, miR-31, miR-187, and miR-211 expression was rescued through survival signaling. Additionally, CAP irradiation notably inhibited the growth of SAS OSCC cell xenografts on nude mice. The reduced expression of oncogenic miRNAs in vivo aligned with in vitro findings. In conclusion, our study provides new lines of evidence demonstrating that CAP irradiation diminishes OSCC cell viability by abrogating survival signals and oncogenic miRNA expression.

Proton Compared to X-Irradiation Induces Different Protein Profiles in Oral Cancer Cells and Their Derived Extracellular Vesicles.

Extracellular vesicles (EVs) are membrane-bound particles released from cells, and their cargo can alter the function of recipient cells. EVs from X-irradiated cells have been shown to play a likely role in non-targeted effects. However, EVs derived from proton irradiated cells have not yet been studied. We aimed to investigate the proteome of EVs and their cell of origin after proton or X-irradiation. The EVs were derived from a human oral squamous cell carcinoma (OSCC) cell line exposed to 0, 4, or 8 Gy from either protons or X-rays. The EVs and irradiated OSCC cells underwent liquid chromatography-mass spectrometry for protein identification. Interestingly, we found different protein profiles both in the EVs and in the OSCC cells after proton irradiation compared to X-irradiation. In the EVs, we found that protons cause a downregulation of proteins involved in cell growth and DNA damage response compared to X-rays. In the OSCC cells, proton and X-irradiation induced dissimilar cell death pathways and distinct DNA damage repair systems. These results are of potential importance for understanding how non-targeted effects in normal tissue can be limited and for future implementation of proton therapy in the clinic.

Dosimetric comparison of postoperative interstitial high-dose-rate brachytherapy and modern external beam radiotherapy modalities in tongue and floor of the mouth tumours in terms of doses to critical organs.

BACKGROUND: The aim of the study was to dosimetrically compare interstitial high-dose-rate (HDR) brachytherapy (BT) and modern external beam radiotherapy modalities, as volumetric modulated arc therapy (VMAT) and stereotactic radiotherapy with Cyberknife (CK) of tumours of the tongue and floor of the mouth in terms of dose to the critical organs. PATIENTS AND METHODS: In National Institute of Oncology, Budapest, between March 2013 and August 2022 twenty patients (11 male/9 female) with stage T1-3N0M0 tongue (n = 14) and floor of mouth (n = 6) tumours received postoperative radiotherapy because of close/positive surgical margin and/or lymphovascular and/or perineural invasion. High-dose-rate interstitial brachytherapy applying flexible plastic catheters with a total dose of 15 × 3 Gy was used for treatment. In addition to BT plans VMAT and stereotactic CK plans were also made in all cases, using the same fractionation scheme and dose prescription. As for the organs at risk, the doses to the mandible, the ipsilateral and the contralateral salivary glands were compared. RESULTS: The mean volume of the planning target volume (PTV) was 12.5 cm3, 26.5 cm3 and 17.5 cm3 in BT, VMAT and CK techniques, respectively, due to different safety margin protocols. The dose to the mandible was the most favourable with BT, as for the salivary glands (parotid and submandibular) the CK technique resulted in the lowest dose. The highest dose to the critical organs was observed with the VMAT technique. The mean values of D2cm3 and D0.1cm3 for the critical organs were as follows for BT, VMAT and CK plans: 47.4% and 73.9%, 92.2% and 101.8%, 68.4% and 92.3% for the mandible, 4.8% and 6.7%, 7.3% and 13.8%, 2.3% and 5.1% for the ipsilateral parotid gland, 3.5% and 4.9%, 6.8% and 10.9%, 1.5% and 3.3% for the contralateral parotid gland, 7.3% and 9.4%, 9.0% and 14.3%, 3.6% and 5.6% for the contralateral submandibular gland. CONCLUSIONS: The present results confirm that BT, despite being an invasive technique, is dosimetrically clearly beneficial in the treatment of oral cavity tumours and is a modality worth considering when applying radiotherapy, not only as definitive treatment, but also postoperatively. The use of the CK in the head and neck region requires further investigation.

Analyzing the impact of close margins and extra-resection margins on failure rates in postoperative oral cavity cancers.

BACKGROUND: Postoperative oral cancers with close margins belong to medium- to high-risk category for local failure. During re-surgery for close margins, there is sufficient doubt as to whether the re-excised tissue is from the same region as the close margin. Therefore, we planned a retrospective review of these cases of close margins that were re-excised with extra-resection margins (ERMs). MATERIAL AND METHODS: Details of 2011 oral cavity patients resected at our hospital were retrieved. Cases with close margins were segregated and the status of ERMs was noted. The postoperative histopathological details, radiotherapy details, and failure patterns in all these cases were documented. The primary objective of the study was to assess the overall survival (OS) and disease-free survival (DFS) in cases with ERMs. The secondary objective was to assess the local and regional control rates and variation with the number and status of close and ERMs. OS, DFS, and local failure rates were defined from the date of registration. Statistical analysis was performed with the SPSS statistical software package. All survival analyses were performed using the Kaplan-Meier method. Log-rank test was used to test the statistical significance. A P-value of 0.05 was considered statistically significant. RESULTS: Sixty-four cases with a median age of 47 years (range: 29-76) were considered for the final analysis. The median follow-up was 40 months (range: 9.5-56.5). The 2-year OS and DFS rates were 91.5% and 88.5%, respectively. The crude local and regional failure rates were 10.9% and 3.1%, respectively. The 3-year locoregional control rate was 90.2%. The 2-year locoregional control rate for one close margin was significantly better as compared to more than one close margin (P = 0.049). No difference in survival and failure rates was found between the number of ERMs resected (one vs. two) and ≤ vs. > 3 mm close margin status. Two patients developed bone metastases. CONCLUSION: The survival rates and locoregional control rates did not differ much between the groups that had one or more ERMs. However, the locoregional control rates were better in cases with one close margin as compared to those with more than one close margin. A larger study with longer follow-up is needed to detect statistically significant differences in outcomes and identify the factors that portend poor prognosis in these cases with close margins and ERMs.

PAICS/DYRK3 Multienzyme Interactions as Coregulators of Purinosome Formation and Metabolism on Radioresistance in Oral Squamous Cell Carcinoma.

Oral squamous cell carcinoma (OSCC) is a prevalent type of oral cancer. While therapeutic innovations have made strides, radioresistance persists as a significant hindrance in OSCC treatment. Despite identifying numerous targets that could potentially suppress the oncogenic attributes of OSCC, the exploration of oncogenic protein kinases for cancer therapy remains limited. Consequently, the functions of many kinase proteins in OSCC continue to be largely undetermined. In this research, we aim to disclose protein kinases that target OSCC and elaborate their roles and molecular mechanisms. Through the examination of the kinome library of radiotherapy-resistant/sensitive OSCC cell lines (HN12 and SAS), we identified a key gene, the tyrosine phosphorylation-regulated kinase 3 (DYRK3), a member of the DYRK family. We developed an in vitro cell model, composed of radiation-resistant OSCC, to scrutinize the clinical implications and contributions of DYRK3 and phosphoribosylaminoimidazole carboxylase and phosphoribosylaminoimidazolesuccinocarboxamide synthase (PAICS) signaling in OSCC. This investigation involves bioinformatics and human tissue arrays. We seek to comprehend the role of DYRK3 and PAICS signaling in the development of OSCC and its resistance to radiotherapy. Various in vitro assays are utilized to reveal the essential molecular mechanism behind radiotherapy resistance in connection with the DYRK3 and PAICS interaction. In our study, we quantified the concentrations of DYRK3 and PAICS proteins and tracked the expression levels of key pluripotency markers, particularly PPAT. Furthermore, we extended our investigation to include an analysis of Glut-1, a gene recognized for its linkage to radioresistance in oral squamous cell carcinoma (OSCC). Furthermore, we conducted an in vivo study to affirm the impact of DYRK3 and PAICS on tumor growth and radiotherapy resistance, focusing particularly on the role of DYRK3 in the radiotherapy resistance pathway. This focus leads us to identify new therapeutic agents that can combat radiotherapy resistance by inhibiting DYRK3 (GSK-626616). Our in vitro models showed that inhibiting PAICS disrupts purinosome formation and influences the survival rate of radiation-resistant OSCC cell lines. These outcomes underscore the pivotal role of the DYRK3/PAICS axis in directing OSCC radiotherapy resistance pathways and, as a result, influencing OSCC progression or therapy resistance. Our findings also reveal a significant correlation between DYRK3 expression and the PAICS enzyme in OSCC radiotherapy resistance.