6064 Background: Clonal hematopoiesis (CH) is an age-related accumulation of somatic genetic alterations in hematopoietic stem cells. It is implicated in the evolution of myeloid neoplasms and has been associated with poor prognosis in patients with solid tumors. Immunotherapy (ITx) has become the standard of care in the treatment of recurrent/metastatic head and neck cancer (R/M HNSCC), however, response rate corresponds to 20% of total population and relies in a robust innate host immunity. This study aims to identify the presence of CH among ITx-treated R/M HNSCC patients and its potential association with treatment outcomes. Methods: Matched pre-treatment peripheral blood (PB) and tumor tissue samples of 32 ITx-treated R/M HNSCC patients were used for DNA extraction. The ten most commonly mutated CH genes were sequenced using a custom NGS Qiagen panel with unique molecular identifiers. Low confidence and synonymous variants were excluded. Pathogenic, likely pathogenic and conflicting with moderate or high annotation impact variants based on the ClinVar database were investigated for associations with progression-free (PFS) and overall survival (OS) as well as for differences in expression between blood and tissue. The same gene alterations and their correlation with survival in HNSCC were also explored in three public datasets (TCGA, GENIE, MSKCC) as an external validation of our findings. Results: A total of 2,088 variants were detected with 1,222 silent variants. After filtering,105 pathogenic, likely pathogenic and conflicting interpretation variants were retained. Mutations in CH related genes were identified in 18 out of 32 PB samples (56%). In tissue samples, (excluding TP53 ) mutations were identified in 12 out of 32 samples (37%). TP53 mutations were significantly higher in tissue samples versus PB ( P =0.028). PPM1D mutations in PB were correlated with shorter PFS ( P =0.003) and OS ( P =0.0116), while TP53 mutations in tissue showed a trend for decreased OS ( P =0.097). TCGA and MSKCC analysis confirmed a negative association of TP53 mutations in tissue with OS ( P =0.0020, P =0.0001, respectively). Conclusions: CH was frequently detected in PB and tumor tissue of R/M HNSCC patients. CH-related PPM1D mutations in PB and TP53 in tumor tissue, were associated with shorter PFS and OS to ITx, suggesting a potential association between both peripheral and intratumoral immune contexture and clinical outcomes.

Immune checkpoint inhibitors (ICIs), including anti-PD-1 and anti-CTLA-4 agents, exhibit notable efficacy across various types of cancer. Nevertheless, they can trigger immune-related adverse events, among which immune-mediated liver injury (ILICI) occurs in 5-10% of patients. Corticosteroids are currently recommended for management of ILICI; however, the timing, presentation and response to treatment may vary widely. The present study retrospectively reviewed five male patients (median age, 69 years) with various malignancies receiving ICIs who developed ILICI. All patients were treated with anti-PD-1 therapy, and two additionally received anti-CTLA-4 therapy. No patients had a history of liver disease, autoimmune disorders or notable alcohol use, and no relevant drug allergies or toxic exposures were reported. Four patients developed grade 3-4 hepatotoxicity. The median time to onset was 15.5 months (range: 1-30 months), illustrating the delayed and unpredictable nature of ILICI. All patients underwent comprehensive evaluation to exclude other causes of liver injury. In selected cases, liver biopsy revealed features consistent with autoimmune-like hepatitis, aiding in diagnosis and assessment of severity. All patients received systemic glucocorticoids, with resolution of liver injury in most cases. One patient required additional immunosuppressive therapy due to steroid-refractory disease. Notably, liver function tests normalized in three patients following treatment, whereas two patients died from ILICI. The present case series highlights the variable onset and presentation of ILICI, which may occur shortly or long after initiation of ICIs. Timely recognition and prompt treatment are integral components of clinical care. In addition, liver biopsy, while not routinely recommended, can provide valuable diagnostic information in complex cases. The current study provides detailed clinical documentation and biopsy information; however, its interpretation is influenced by the small sample size and retrospective nature of the study. The findings support existing guidelines,and underscore the need for enhanced clinical awareness and standardized management protocols.

Wernicke’s encephalopathy is an acute neurologic disorder caused by thiamine (vitamin B1) deficiency, which is most commonly associated with alcoholism. Rare cases of Wernicke’s encephalopathy have been described in cancer patients, mostly with gastrointestinal and hematologic malignancies. Head and neck cancer patients frequently have reduced oral intake as a direct result of their tumor or from chemoradiation treatments. We report a case of Wernicke’s encephalopathy in a 44-year-old woman with adenoid cystic carcinoma following chemoradiotherapy. Through a literature review we identified additional cases of Wernicke’s encephalopathy in head and neck cancer patients, highlighting the importance of recognizing nutritional deficiencies and associated complications. The findings emphasize the need for heightened awareness regarding the risk of thiamine deficiency in cancer patients, particularly those experiencing poor nutritional intake due to treatment-related side effects. Prompt diagnosis and intervention are critical to prevent serious morbidity and mortality associated with this condition.

The lungs represent the most common sites of distant metastases in soft tissue sarcoma (STS) patients. The relative radioresistance of STS renders them ideal targets for stereotactic radiotherapy (SRT). In this study, the treatment of a complex STS lung metastases case involving complete main bronchus occlusion and lung collapse using an image-guided, personalized ultrafractionated stereotactic adaptive radiotherapy (PULSAR) approach is reported. A biologically effective dose (BED) of 102 Gy10 was delivered in two stages separated by 21 days using the CyberKnifeTM platform (Accuray Inc., Sunnyvale, CA, USA) and the Synchrony Lung Optimized (Synchrony-LOTTM) motion management system (Accuray Inc.). Each treatment stage was based on real-time imaging data, allowing for the adaption of the treatment plan to the tumor's size and shape. Prior to the second stage, significant tumor regression was observed, leading to lung re-expansion and restoration of pulmonary function. This expansion enabled the visualization and treatment of a second peripheral lesion, which received a BED of 106 Gy10 in a single session. The applied treatment protocol resulted in excellent local control and minimal toxicity. The combination of the PULSAR approach and real-time imaging techniques hold significant promise for treating complex cases and marks a shift toward more adaptive and personalized radiation oncology.

Harlequin syndrome is a rare autonomic disorder with at least 83 reported cases in literature, 6% of which are congenital. When the fibers responsible for sudomotor and vasomotor supply to the face at the T2-T3 level are unilaterally blocked, it leads to hemifacial discoloration. This results in one-half of the face appearing flushed and hyperemic, sharply contrasting with the pale appearance of the other half. The cause of this syndrome is unknown; however, it appears to involve an autonomic nervous system dysfunction. It can be caused by an injury, compression, or blockade of sympathetic fibers along the pathway. The present study was a case of a metastatic osteosarcoma patient with a history of video-assisted thoracic surgery pleurectomy that presented in Attikon University Hospital (Athens, Greece) with worsening dyspnea and right-sided facial flushing.

Brain gliomas are highly infiltrative and heterogenous tumors, whose early and accurate detection as well as therapeutic management are challenging. Artificial intelligence (AI) has the potential to redefine the landscape in neuro-oncology and can enhance glioma detection, imaging segmentation, and non-invasive molecular characterization better than conventional diagnostic modalities through deep learning-driven radiomics and radiogenomics. AI algorithms have been shown to predict genotypic and phenotypic glioma traits with remarkable accuracy and facilitate patient-tailored therapeutic decision-making. Such algorithms can be incorporated into surgical planning to optimize resection extent while preserving eloquent cortical structures through preoperative imaging fusion and intraoperative augmented reality-assisted navigation. Beyond resection, AI may assist in radiotherapy dose distribution optimization, thus ensuring maximal tumor control while minimizing surrounding tissue collateral damage. AI-guided molecular profiling and treatment response prediction models can facilitate individualized chemotherapy regimen tailoring, especially for glioblastomas with MGMT promoter methylation. Applications in immunotherapy are emerging, and research is focusing on AI to identify tumor microenvironment signatures predictive of immune checkpoint inhibition responsiveness. AI-integrated prognostic models incorporating radiomic, histopathologic, and clinical variables can additionally improve survival stratification and recurrence risk prediction remarkably, to refine follow-up strategies in high-risk patients. However, data heterogeneity, algorithmic transparency concerns, and regulatory challenges hamstring AI implementation in neuro-oncology despite its transformative potential. It is therefore imperative for clinical translation to develop interpretable AI frameworks, integrate multimodal datasets, and robustly validate externally. Future research should prioritize the creation of generalizable AI models, combine larger and more diverse datasets, and integrate multimodal imaging and molecular data to overcome these obstacles and revolutionize AI-assisted patient-specific glioma management.

Background: Soft tissue sarcomas represent a heterogeneous group of tumors with considerable diagnostic challenges. Gene amplification of the MDM2 oncogene occurs in certain types of liposarcomas and is mainly detected through genetic methods. Aim: The present study investigates the potential clinical utility of MDM2 gene amplification in the diagnostic work-up of soft tissue tumors. Methodology: An analysis of 55 mesenchymal tumor samples was performed using fluorescence in situ hybridization (FISH) with appropriate probes targeting the MDM2 gene. Subsequently, the results of the genetic analysis were compared with immunohistochemistry (IHC) findings, where available in the initial histological diagnosis. Results: MDM2 gene amplification was detected in 22 out of 55 samples (40% of cases), with 14 demonstrating high-level amplification and the remaining 8 showing intermediate-level amplification. In most of the cases, concordance was ascertained between the two methods (IHC and FISH). Conclusion: According to the findings, detection of MDM2 amplification by FISH appears to be a reliable diagnostic marker for specific types of mesenchymal tumors of adipocytic origin. To this end, MDM2 amplification by FISH is suggested to be applied as a complementary tool to morphological examination and classical immunohistochemistry, especially in cases with ambiguous results.

Background: Following the success of immune checkpoint inhibitors (ICI) in other cancer types, their role is being evaluated in sarcomas. They have been assessed as monotherapy, or in combination with other ICI, chemotherapeutic drugs and tyrosine kinase inhibitors (TKI) in several clinical trials. So far the results have been limited to non-selected sarcoma populations. Further work is required to select patients who will benefit from immunotherapy. Patients and methods: We conducted a pooled retrospective analysis of the use of ICI in patients with advanced sarcomas in multiple European institutions. ICI-based treatments included ICI monotherapy (n = 43, 59.7%), double ICI (n = 5, 6.9%), ICI plus TKI (n = 21, 29.2%) and ICI plus chemotherapy (n = 3, 4.2%). Results: Seventy-two patients from 10 European institutions, with metastatic (87.5%) or locally advanced (12.5%) disease were included. The most common subtype was undifferentiated pleomorphic sarcoma (16.7%), followed by leiomyosarcoma (12%), liposarcoma (10%) and angiosarcoma (9.7%). The median number of prior lines of systemic therapy was 2 (0–8). The objective response rate was 34.4% and was higher in combination regimens versus ICI monotherapy. With a median follow-up of 20.7 months, median progression-free survival (PFS) was 4.6 and median overall survival (OS) 18.8 months. Line of therapy (1st/2nd vs. ≥ 3rd line) and best response to ICI was significantly associated with PFS and OS. Histological subtype was significantly associated with OS. Toxicity was in general manageable; only six (8.3%) patients discontinued therapy for AE. Interpretation: Our study provided additional real-world data on the outcome of ICI in patients with advanced sarcomas.

Importance:Sarcomas comprise a heterogeneous group of malignant neoplasms that include genomically simple (driven by recurrent genetic alterations) and genomically complex (characterized by extensive genomic rearrangements) subtypes. Regardless, sarcomas exhibit a remarkably low mutational burden. In this context, there is a growing demand for the use of next-generation sequencing (NGS)-based technologies to aid in the clinical management of patients with sarcoma. However, a broad, clinically impactful implementation faces inherent challenges associated with their rarity, heterogeneity, and limited molecular understanding. Observations:From a diagnostic standpoint, there is a lack of prospective studies comparing up-front, indiscriminate use of NGS fusion panels in all new cases suggestive of sarcoma diagnosis in comparison with a use only indicated by a sarcoma-expert pathologist during the assessment. Therefore, although a significant proportion of sarcomas harbor specific molecular alterations, not all cases require NGS for a definitive diagnosis given that most sarcoma subtypes display classic histologic features. From a therapeutic perspective, current evidence does not support routine clinical use of NGS in all patients with sarcoma due to the small number of actionable alterations and the limited evidence for clinical benefit achieved with NGS-matched treatments. Although certain entities and molecular backgrounds demonstrate potential advantages, the consensus group emphasizes that indication of targeted agents for treatment is largely based on the specific subtype, and therefore, an accurate diagnosis is indispensable. Conclusions and Relevance:Evidence supporting the routine, nonselective use of NGS in patients with sarcoma is currently limited. Given the complexity, the decision to perform an NGS panel, as well as the interpretation and use of its results for diagnostic or therapeutic purposes, should take place only in sarcoma-expert institutions, including a multidisciplinary review. The results of multigene panels performed in nonexpert sarcoma centers cannot replace the pathology review or the recommendation of NGS-guided therapies without prior evaluation by sarcoma experts.

e23018 Background: Patients with advanced or metastatic sarcoma face several challenges regarding their quality of life.SARC-Digital prospective randomized study aims to evaluate the effectiveness of digital health interventions on the quality of life of patients with advanced/metastatic sarcoma receiving any treatment. The statistical design requires 108 patients. This is an interim analysis. Methods: Patients use an online platform to self-report their quality of life through a questionnaire of 10 preselected side effects (SEs). In a 1:1 randomization, those on the control arm are reminded to inform their medical team of their SEs; those on the intervention arm receive personalized self-care material in addition to these reminders.The SEs in scope are related to daily and not urgent experiences. The material is based on evidence and best practices and does not constitute nor replace medical advice.For patients with 2 or more questionnaire submissions, the evaluation of each SE improvement is based on the most recent submission compared to all previous ones. Results: The study sites’geographic allocation and diversity (public, university and private hospitals) ensure representative population regarding patients’ socioeconomic status and digital skills. As of January 2025, 63 patients have enrolled in the study across 9 sites; 50 have submitted SE questionnaires at least once. Currently, 30% report no SE among the possible options; 26% report 1; 40% report 2-4. The most frequent SEs are fatigue, constipation, nausea (reported by 78%, 52% &50% of patients, respectively); the least frequent is lymphedema (10%). Fatigue has been the most frequent on a site level too (reported by 33%-100% of site-specific patients). 48 patients have submitted questionnaires at least twice, enabling improvement evaluation: Patients in the intervention arm experience higher rates of improvement of their SEs vs the control arm (71.52% vs 59.82%). Among the 10 SEs, patients in the intervention arm exhibit higher improvement in 8, equal in 1, and lower in 1 SE. Conclusions: Real-world data collected in this study showcase the substantial value of patient reported outcomes that capture the experience of metastatic sarcoma patients.Digital health interventions appear to have positive results for most of the side effects. The table illustrates SE frequency, and comparative improvement between the two arms. Side Effect Frequency (reported at least once) Improvement (Intervention Arm) Improvement (Control Arm) Percentage point difference: Intervention vs Control Fatigue 78% 47% 37% +10% Constipation 52% 77% 75% +2% Nausea 50% 92% 86% +6% Dry skin 48% 58% 75% -17% Mucositis 38% 64% 50% +14% Rash 30% 57% 57% +0% Vomiting 26% 90% 50% +40% Sexual dysfunction 18% 75% 60% +15% Neuropathy 16% 75% 50% +25% Lymphedema 10% 50% 33% +17%

Background/Aim:Advanced osteosarcomas tend to have poor prognosis with limited therapeutic options beyond first-line therapy. This retrospective, multi-institutional study aimed to evaluate the association between histological response to chemotherapy and survival outcomes, as well as the influence of sex, tumor size, location, and other factors in a Greek cohort. Patients and Methods:We retrospectively studied the predictive value of distant metastasis, percentage of necrosis, and grade of tumor in 77 cases of sarcoma treated in 8 medical centers in Greece between 2004 and 2022. Median follow up time from the time of diagnosis was 27 months. Statistical analysis was performed using a two-sided significance level of p=0.05. Results:Our analysis revealed that short bones were affected significantly more frequently in older [median age=43 years, interquartile range (IQR)=30-50] than younger patients (median age=26 years, IQR=18-40). Distant metastasis was significantly associated with shorter overall survival [OS; HR=3.7, 95% confidence interval (CI)=1.5-9.16, p=0.01]. In addition, we found that 90% or greater tumor necrosis was significantly associated with longer disease-free survival (DFS; HR=0.09, 95% CI=0.01-0.09, p=0.003) but not with OS (HR=0.62, 95% CI=0.24-1.58, p=0.3). Male sex was associated with shorter DFS (HR=5.61, 95% CI=2.12-14.9), p<0.001). Grade or bone affected (long vs. short) were not significantly associated with survival. Conclusion:Osteosarcoma patients with 90% or more tumor necrosis were found to have survival advantage. Differences in DFS between sexes highlight the need for tailored treatment approaches and further exploration of biological underpinnings.

HPV-related head and neck cancers are increasing globally and although they constitute a major public health problem, there are currently no validated screening or early detection methods in widespread clinical use. This review discusses advances in clinical and molecular aspects of prevention, screening, and early detection of HPV-related head and neck cancers (HNCs), such as potential use of HPV blood or saliva seropositivity, RNA biomarkers, liquid biopsy, circulating tumor DNA, and proteomics. In addition to HPV vaccination, public education about vaccination, smoking, and safe sexual practices is warranted. Continued research is warranted to define optimal use and integration of approaches for prevention, screening, and early detection methods of HNCs.

To report safety and efficacy (on terms of long-term pain reduction results) after percutaneous splanchnic nerve cryoneurolysis for the treatment of refractory pancreatic cancer-related pain. This single-center, institutional review board-approved, retrospective observational study recruited consecutive patients with pancreatic cancer-related pain refractory to conservative treatment who underwent CT-guided cryoneurolysis of the splanchnic nerves. Outcomes included overall pain reduction rate (> 4 pain score units in the VAS pain scores), technical success (successful cryoprobe placement at the level of interest), and opioid usage reduction. Fifty patients were included (mean age 65 ± 7 years). Overall, clinically relevant pain reduction was achieved in 76

BACKGROUND:Rib involvement in Ewing sarcoma (ES) is very rare (3-5 %) and may often lead to unique presentations due to mass effect within the thorax. Molecular studies may sometimes offer insights into disease prognosis and possible targeted treatment approaches. CASE PRESENTATION:Here we present the case of a 39-year-old female who presented with shortness of breath from a massive primary tumor in the right rib and lung. She was diagnosed with ES, which was confirmed by the presence of EWSR1/FLI-1 rearrangement and received multimodal therapy with neoadjuvant VDC-IE (vincristine-doxorubicin-cyclophosphamide, and ifosfamide-etoposide) followed by surgical excision after partial response, and adjuvant chemoradiation. Unfortunately, the patient experienced histologically confirmed local and distant recurrence after several months. NGS of the recurrent tumor revealed a pathogenic PTEN c.640C>T(p.Q214*) nonsense variant with a very high variant allele frequency (VAF) of 82.6 % but negative germline assessment. She received several lines of chemotherapy but only demonstrated a short response to the oral multi-tyrosine kinase inhibitor cabozantinib before eventually passing away. CONCLUSIONS:PTEN mutations in ES, although rare, may result in a higher likelihood of chemotherapy resistance and poor prognosis. Clinical studies targeting specific molecular traits of these tumors, such as PTEN inactivation, could help improve outcomes in selected cases.

INTRODUCTION/OBJECTIVE:Significant advancements have been achieved with the use of targeted molecular therapies for the treatment of Soft Tissue Sarcomas (STS). However, data remain scarce about the potential benefits and toxicity of this therapeutic option. In this narrative review, we aim to better clarify the potential wound healing complications in STS patients undergoing neoadjuvant (NA) radiotherapy (RT) combined with targeted therapies. METHODS:We used the PubMed database to retrieve journal articles, and the inclusion criteria were all studies that illustrated the potential RT toxicity, combined with targeted therapies, in the NA setting of STS patients. RESULTS:Our search resulted in seven studies that fulfilled the inclusion criteria. Delayed wound complication rates were observed similarly to RT alone, while one study reported intolerable toxicity without referring specifically to wound complications. CONCLUSION:The combination of RT with targeted therapies in STS seems to be effective and well tolerated. Due to the lack of studies with a high level of evidence, further research is required to enhance the existing knowledge for its potential value in this field.

BACKGROUND:Accumulating evidence suggests that deregulation of DNA damage response (DDR) network affects multiple aspects of the immune system. Herein, we tested the hypothesis that DDR-related signals, measured in peripheral blood mononuclear cells (PBMCs) from Head and Neck Squamous Cell Carcinoma (HNSCC) patients, correlate with the response to immune checkpoint inhibitors. METHODS:Oxidative stress and DDR-related signals were evaluated in PBMCs from 26 healthy controls and 50 recurrent/metastatic HNSCC patients at baseline, who participated in a phase II nivolumab trial (NCT03652142). Spatial transcriptomics in three molecularly defined tissue compartments (tumour, leucocyte, macrophage) from biopsies of overlapping cases were also investigated. RESULTS:PBMCs from responders to nivolumab therapy showed significantly lower oxidative stress, endogenous DNA damage, DNA repair capacities and apoptosis rates compared with non-responders (all P < 0.04). The analysis of tissue RNA in situ data illustrated that DNA repair pathways showed enrichment in the macrophage compartment of baseline tissue biopsies of responders compared with non-responders (P = 0.049). CONCLUSIONS:Our findings demonstrate that oxidative stress and deregulated DDR-related signals measured in PBMCs from HNSCC patients at baseline correlate with response to nivolumab and, if further validated, may be exploited as novel non-invasive biomarkers and the design of clinical trials.