Head Tumors Research Articles

The impact of radiation therapy on thyroid function in patient with head and neck tumors

Background. Head and neck cancers (HNC) accounted for 1,518,133 new cases and 510,771 new deaths worldwide. The first reports of hypothyroidism following radiotherapy (RT) for HNC were published in the 1960s. The objective of this study was to ascertain the frequency of thyroiditis in patients with HNC and to establish the threshold of radiation dose volume for radiation-induced hypothyroidism in HNC. Methods. This was a prospective study of 35 patients with HNC treated with IMRT-VMAT. The following characteristics were examined: age, gender, comorbidity, initial tumor site, histology, surgical margin resection, radiation therapy dosage, V40, V50, V60 (percentage of thyroid tissue volume), 95% dose received, mean dose, minimum dose, and maximum dose. Thyroid assessment was performed using ultrasonography of the neck. Thyroid function was determined by TFT tests (TSH, free T3, and free T4), which were done at baseline before treatment and after RT for each case. Results. In this study, the mean age was 57.71 ± 11.43 years, with males comprising 68.6% (24 patients) and females comprising 31.4% (11 patients). Regarding TSH, the results showed that post-RT, the mean level of TSH was significantly higher than pretreatment, with a significant difference (P = 0.009). Regarding fT3, the results showed that post-RT, the mean level of fT3 was significantly lower than pretreatment, with a significant difference (P = 0.007). Regarding fT4, the results showed that post-RT, the mean level of fT4 was significantly lower than pretreatment, with a significant difference (P = 0.015). In addition, the mean 95% dose was 6.8 Gy (median = 4 Gy). The percentages of thyroid tissue volumes at V40, V50, and V60 were 79.47%, 39.28%, and 38.02%, respectively. The incidence of hypothyroidism was 14.3%, and the euthyroid incidence rate was 85.7%. Conclusions. There is a strong correlation between radiation therapy doses exceeding 66 Gy and the occurrence of hypothyroidism. The levels of fT3 and fT4 decreased after RT, while TSH levels increased. In dosimetry, the mean 95% dose was 6.8 Gy. The percentages of thyroid tissue volumes at V40, V50, and V60 were 79.47%, 39.28%, and 38.02%, respectively. The incidence of hypothyroidism was 14.3%, and the euthyroid incidence rate was 85.7%.

Exploring the Uncommon, Tongue Schwannoma—A Rare Case Report

Schwannoma (neurilemmoma or neurinoma), is a benign tumor arising from Schwann cells that comprise the myelin sheaths surrounding peripheral nerve. They are encapsulated, usually solitary and slow-growing. Approximately 25%-45% of schwannoma occurs in the head and neck region. Intraoral incidence of schwannoma is 1%-12%. The most common intraoral site is tongue (1%) followed by palate, floor of the mouth, buccal mucosa, gingiva, lips and vestibular mucosa, retromolar region is the least common site. We describe a rare case of lingual schwannoma involving the left lateral part of tongue in a young male presented with a slow-growing, asymptomatic, painless mass on the left lateral part of tongue for several years. Magnetic resonance images demonstrated a well-defined almost oval-shaped isolated mass with uniform intensity on T2 weighted images relative to surrounding muscles. Patient was managed with complete surgical excision of the tumor and has not shown any recurrence in the follow-up period of 1 year. Schwannoma of tongue is a rare tumor of head and neck region. The diagnosis should be based on histopathological examination and in some cases after immunohistochemistry findings. Complete transoral resection allows removal of tumor to avoid recurrence and also avoids causing morbidity of tongue function.

Consolidation immunotherapy following concurrent chemoradiotherapy in a patient with sinonasal NUT carcinoma: a case report

BackgroundNuclear protein in testis (NUT) cancers, also known as midline cancers, tends to occur in organs near the midline, such as the nasal sinuses and mediastinum. NUT carcinoma is very rare and has a poor prognosis.Case descriptionWe report the case of a 44-year-old female patient with sinonasal NUT carcinoma who presented with a soft tissue mass in the left frontal sinus, ethmoid sinus, and left nasal cavity on computed tomography; the tumor was poorly demarcated from the left rectus medialis. After discussion with a multidisciplinary team with expertise on head and neck tumors, the patient was considered inoperable, and definitive concurrent chemoradiotherapy (CCRT) was recommended. The patient underwent CCRT followed by three cycles of consolidation chemotherapy with albumin-bound paclitaxel and nedaplatin. Subsequently, the patient underwent 16 cycles of consolidation therapy with the programmed death–1 (PD-1) inhibitor tislelizumab. The immune-related adverse events included grade 2 hypothyroidism. After CCRT, consolidation chemotherapy, and consolidation immunotherapy, the patient achieved a favorable outcome. The patient survived for 31 months, and there were no signs of recurrence or metastasis during follow-up.ConclusionAt present, there is no clear consensus on the consolidation treatment plan after CCRT for sinonasal NUT cancer. We used consolidation immunotherapy for the first time and achieved good efficacy, providing an innovative and promising treatment plan for refractory sinonasal NUT cancer.

Unproven added benefit due to late changes to the appropriate comparator therapy

As part of the early benefit assessment, the added benefit of new medicinal products protected by documentation is assessed in comparison to the appropriate comparator therapy (ACT). At the request of the pharmaceutical company (MAH), the Federal Joint Committee (G-BA) discusses the documents to be submitted and the ACT. The G-BA can adjust the zVT determined in the course of a consultation over time. This can also be done after the start of a benefit assessment. In this paper, examples are presented that show how the change of the zVT in the ongoing benefit assessment procedure can lead to a usable randomised controlled trial (RCT) not being considered by the G-BA, which in turn leads to an unproven added benefit. Results: In this analysis, four practical cases were presented in which the manufacturer was confronted with the situation of an unsuitable study comparator due to a zVT amendment in the ongoing benefit assessment procedure. For example, drugs for the treatment of head and neck tumours, multiple sclerosis or chronic rhinosinusitis were denied the additional benefit initially determined by the Institute for Efficiency and Quality in Health Care (IQWiG) in the procedure in the final G-BA decision due to short-term changes to the zVT.

Single-nucleus CUT&RUN elucidates the function of intrinsic and genomics-driven epigenetic heterogeneity in head and neck cancer progression

Interrogating regulatory epigenetic alterations during tumor progression at the resolution of single cells has remained an understudied area of research. Here we developed a highly sensitive single-nucleus CUT&RUN (snCUT&RUN) assay to profile histone modifications in isogenic primary, metastatic, and cisplatin-resistant head and neck squamous cell carcinoma (HNSCC) patient-derived tumor cell lines. We find that the epigenome can be involved in diverse modes to contribute towards HNSCC progression. First, we demonstrate that gene expression changes during HNSCC progression can be comodulated by alterations in both copy number and chromatin activity, driving epigenetic rewiring of cell states. Furthermore, intratumour epigenetic heterogeneity (ITeH) may predispose subclonal populations within the primary tumour to adapt to selective pressures and foster the acquisition of malignant characteristics. In conclusion, snCUT&RUN serves as a valuable addition to the existing toolkit of single-cell epigenomic assays and can be used to dissect the functionality of the epigenome during cancer progression.

TRAIP enhances progression of tongue squamous cell carcinoma through EMT and Wnt/β-catenin signaling by interacting with DDX39A

BackgroundTongue squamous cell carcinoma (TSCC) is one of the most common malignant tumors with high mortality and poor prognosis. Its incidence rate is increasing gradually. Tumor necrosis factor receptor-associated factor interacting protein (TRAIP), as a factor related to several tumors, reveals that its gene expression is different between normal tissue and primary tumor of head and neck squamous cell carcinoma using bioinformatics analysis.MethodIn our study, TCGA database, immunohistochemistry, proliferation assay, colony formation, wound healing assay, Transwell, cell cycle analysis and tumor xenografts model were used to determine the expression and functions of TRAIP in TSCC.ResultWe found that TRAIP may promote the proliferation, migration and invasion of TSCC. Furthermore, the results of bioinformatics analysis, mass spectrometry and co-immunoprecipitation suggested that DDX39A may be a TRAIP interacting protein. DDX39A has been proven to be an oncogene in several tumors, which may have an important effect on cell proliferation and metastasis in multiple tumors. In addition, the high expression of DDX39A implies the poor prognosis of patients. Our study demonstrated that TRAIP probably interact with DDX39A to regulate cell progression through epithelial-mesenchymal transition and Wnt/β-catenin pathway. In addition, we show that the necessary domain of DDX39A for the interaction between DDX39A and TRAIP region.ConclusionThese results indicate that TRAIP is important in occurrence and development of TSCC and is expected to become the new promising therapeutic target.

Cooperative tumor inhibition by CpG-oligodeoxynucleotide and cyclic dinucleotide in head and neck cancer involves T helper cytokine and macrophage phenotype reprogramming

Head and neck cancer ranks as the sixth most common cancer worldwide, highlighting the critical need for the development of new therapies to enhance treatment efficacy. The activation of innate immune receptors given their potent immune stimulatory properties aid in the eradication of cancer cells. In this study, we investigated the immune mechanism and anti-tumor function of a Toll-like receptor 9 (TLR9) agonist, CpG-oligodeoxynucleotide-2722 (CpG-2722), in combination with cyclic dinucleotides, which are agonists of stimulator of interferon genes (STING). Our results revealed that CpG-2722 stimulation increased the expression of Th1 pro-inflammatory cytokines. Stimulation by STING agonists exhibited lower expression of Th1 cytokines but higher expression of Th2 cytokines compared to CpG-2722. However, the combination of these two agonists significantly enhanced Th1 cytokines while reducing Th2 cytokines. Moreover, in vivo experiment showed that both CpG-2722 and 2'3'-c-di-AMP suppressed head and neck tumor growth, with their combination proving more effective than the use of these agonists alone. The combined treatment cooperatively promoted the production of Th1 cytokines and type I interferons, while suppressing Th2 cytokines in the tumors as observed in vitro. Additionally, it led to the accumulation of M1 macrophages, dendritic cells, and T cells, shaping a favorable tumor microenvironment for T cell-mediated tumor killing. The anti-tumor activity of the CpG-2722 and 2'3'-c-di-AMP combination depends on the macrophage presence but does not directly activate M1 macrophage polarization, instead working through a reprogrammed cytokine profile. Furthermore, this combination shows a cooperative anti-tumor activity with anti-PD-1 in treating head and neck tumors. Overall, these findings highlight a Th response and macrophage phenotype reprograming involved functional mechanism underlying the cooperative activity of the combination of TLR9 and STING agonists in the immunotherapy of head and neck cancer.

Cutting-edge insights: near-infrared imaging for surgical margin assessment in head and neck tumor resection: a systematic review and meta-analysis.

In head and neck cancer (HNC), real-time evaluation of tumor margin status following surgical excision of the tumor is of critical importance. This systematic review aimed to assess the effectiveness of near-infrared fluorescence (NIRF) imaging for the real-time delineation of tumor margins in HNC resections. Two investigators independently conducted a comprehensive search following the Preferred Reporting Items for a Systematic Review and Meta-analysis of Diagnostic Test Accuracy Studies (PRISMA-DTA) guidelines across the PubMed, Scopus, Embase, and China National Knowledge Infrastructure (CNKI) databases until August 1st, 2023. Observational studies were included, while other studies with inappropriate study design were excluded. The primary outcomes included the specificity, sensitivity, and area under the summary receiver operating characteristic (SROC) curve when using NIRF imaging to assess surgical margins. We compared fluorescence in the resection specimen margins and residual fluorescence in the surgical cavity margins as methods of utilizing NIRF to evaluate surgical margins. Diagnostic trial quality was assessed, and statistical heterogeneity was determined. The initial search yielded 1,607 articles. After reviewing the full texts, seven articles with 103 patients were included, among which five were incorporated for quantitative analysis. The selected studies had an average score of 10.1 of quality. Heterogeneity analysis revealed I2 values of 26% [95% confidence interval (CI): 0-100%] and 78% (95% CI: 52-100%) for NIRF specimen imaging with close margin considered positive or negative. Comparing NIRF imaging to the gold standard of pathology for surgical margin diagnosis, with close margin considered positive, sensitivity and specificity in excised specimens were 0.84 (95% CI: 0.39-0.98) and 0.96 (95% CI: 0.80-0.99), respectively. When a close margin was considered negative, sensitivity and specificity were 0.98 (95% CI: 0.10-1.00) and 0.96 (95% CI: 0.45-1.00), respectively. The areas under the SROC curves were 0.97 (95% CI: 0.95-0.98) and 0.99 (95% CI: 0.98-1.00), respectively. A quantitative analysis of residual fluorescence at surgical cavity margins was not performed due to an insufficient number of studies. NIRF imaging is a promising method for real-time surgical margin assessment of HNC. With its robust diagnostic capabilities in excised tumor specimens, it is also an effective technique for detecting residual tumor fluorescence in the surgical cavity for supplementary assessment. But the results should be interpreted with caution.

Recurrent oropharyngeal cancer: Analysis of surgical treatment outcomes

BACKGROUND The main goal of our research is to introduce transoral robotic surgery and laser resection (TLR) as a considerable way of treating patients with recurrent oropharyngeal malignancies. AIM To develop a foundation of minimally invasive transoral surgical technique for patients with oropharyngeal recurrence. METHODS This study prospectively and retrospectively included patients with recurrent tumors from 2003 to 2018. Subjects were allocated into two groups: (1) Group I; underwent TLR; and (2) Group II (control); underwent open surgeries of varying volume. Evaluation was done with intraoperative blood loss, postoperative infection incidence, and quality of life using the scale for patients with head and neck tumors known as the Functional Assessment of Cancer Therapy-Head & Neck Scale. RESULTS One-hundred and forty one patients were included (103 males and 38 females), in 82 cases (85.4%), a recurrent tumor developed earlier than a year after primary tumor therapy; forty-six were in group I and 69 in group II, age ranging from 18 years to 86 years (average: 57.6 years). The first group showed a statistically significant less amount of blood loss and a decreased incidence of infectious complications (P < 0.05). Additionally, there was a significant difference in functional outcomes (quality of life scores) but no significant difference in survival curves. CONCLUSION In properly elected patients, TLR is not just reasonable but tends to be a favorable alternative for recurrent oropharyngeal cancers compared to the outcomes of the open surgery group.

Therapeutic Outcomes in 691 Angiosarcomas of the Head and Neck-A Retrospective SEER Study.

Angiosarcomas (AS) are an aggressive subtype of head and neck tumors. Current outcome research is limited to single-surgeon and/or single-institution data. This study analyzes the Surveillance, Epidemiology, and End Results program (SEER) database data to improve outcomes of head and neck AS. In this study, the authors accessed the SEER database from 2000 to 2020 to identify patients who underwent surgical and/or nonsurgical treatment of head and neck AS. Data included demographics, diagnostic workup, tumor characteristics, treatment pathways, and therapy outcomes. The study included 691 patients (210 females, 481 males) with AS of the head and neck. The median tumor size was 40mm. Most patients (63%) underwent surgery, with surgery followed by radiation being the most common treatment combination (50%). Median survival was 16 months. Patients treated with surgery showed significantly longer survival (18mo) compared with nonsurgery cases (12mo, P<0.001). Neoadjuvant treatment significantly improved survival (28mo) compared with non-neoadjuvant cases (15mo, P=0.023). Adjuvant treatment also improved overall survival (19mo) versus nonadjuvant treatment (14mo, P<0.001). There was no significant difference between neoadjuvant and adjuvant treatment outcomes (P=0.270). Bottom of Form This study compares the outcomes of multimodal treatments, especially surgery and radiotherapy, for head and neck AS, emphasizing tailored approaches to optimize patient outcomes and extend survival. Future research should refine these strategies.

TFE3-rearranged Head and Neck Neoplasms: Twenty-two Cases Spanning the Morphologic Continuum Between Alveolar Soft Part Sarcoma and PEComa and Highlighting Genotypic Diversity.

TFE3 rearrangements characterize histogenetically, topographically, and biologically diverse neoplasms. Besides being a universal defining feature in alveolar soft part sarcoma (ASPS) and clear cell stromal tumor of the lung, TFE3 fusions have been reported in subsets of renal cell carcinoma, perivascular epithelioid cell tumor (PEComa), epithelioid hemangioendothelioma and ossifying fibromyxoid tumors. TFE3-related neoplasms are rare in the head and neck and may pose diagnostic challenges. We herein describe 22 TFE3 fusion neoplasms affecting 11 males and 11 females aged 4 to 79 years (median, 25) and involving different head and neck sites: sinonasal cavities (n = 8), tongue (n = 4), oral cavity/oropharynx (n = 3), salivary glands (n = 2), orbit (n = 2), and soft tissue or unspecified sites (n = 3). Based on morphology and myomelanocytic immunophenotype, 10 tumors qualified as ASPS, 7 as PEComas (3 melanotic; all sinonasal), and 5 showed intermediate (indeterminate) histology overlapping with ASPS and PEComa. Immunohistochemistry for TFE3 was homogeneously strongly positive in all cases. Targeted RNA sequencing/FISH testing confirmed TFE3 fusions in 14 of 16 successfully tested cases (88%). ASPSCR1 was the most frequent fusion partner in ASPS (4 of 5 cases); one ASPS had a rare VCP::TFE3 fusion. The 6 successfully tested PEComas had known fusion partners as reported in renal cell carcinoma and PEComas (NONO, PRCC, SFPQ, and PSPC1). The indeterminate tumors harbored ASPSCR1::TFE3 (n = 2) and U2AF2::TFE3 (n = 1) fusions, respectively. This large series devoted to TFE3-positive head and neck tumors illustrates the recently proposed morphologic overlap in the spectrum of TFE3-associated mesenchymal neoplasms. While all PEComas were sinonasal, ASPS was never sinonasal and occurred in diverse head and neck sites with a predilection for the tongue. The indeterminate (PEComa-like) category is molecularly more akin to ASPS but shows different age, sex, and anatomic distribution compared with classic ASPS. We report VCP as a novel fusion partner in ASPS and PSPC1 as a novel TFE3 fusion partner in PEComa (detected in one PEComa). Future studies should shed light on the most appropriate terminological subtyping of these highly overlapping tumors.

Head Tumor Segmentation and Detection Based on Resunet

Deep learning algorithms are designed to mimic the functions of the human brain. These algorithms can simulate the human brain for feature extraction, i.e. neural networks with many hidden layers. This algorithm is being trained and tested using the MRI brain tumor segmentation dataset provided by Kaggle. ResNet50 is used for tumor classification tasks due to its powerful feature extraction capability. Through its deep residual structure, ResNet50 can effectively extract different lesion features and improve classification accuracy. At the same time, ResUNet combines the feature extraction capabilities of ResNet with the segmentation advantages of U-Net, accurately capturing tumor boundaries and achieving high-quality tumor segmentation. For the MRI dataset, the accurate segmentation rate of the model is 91.68%, which provides a certain reference for the medical field. In summary, this study demonstrates the usability of combining ResUNet50 and ResNet in brain tumor detection. In the field of medical image analysis, accurate brain tumor segmentation and classification are crucial for clinical diagnosis and treatment planning, and provide new ideas and methods for future medical image analysis and clinical applications.

Comparison of preoperative biliary metallic and plastic stents in terms of intraoperative effects in malignant pancreatic head tumors.

Comparison of preoperative biliary metallic and plastic stents in terms of intraoperative effects in malignant pancreatic head tumors.

Research and application of chromatic effect in laser-driven proton therapy

Based on the rapid development of ultra high-power laser technology and due to the urgent need for miniaturized particle radiotherapy accelerator construction, compact laser accelerators have been studied as a research focus. The collection of the beam with large divergence angle and the selection of beam energy spread from initial generated beam are core issues in the design of laser accelerator. Chromatic effect is an effective method of energy selection while collecting beam. However, it is found that the nonlinear effect introduced by the actual edge field of a strong magnetic field and the special beam distribution produced by laser acceleration directly affect the energy selection. Based on the design of CLAPA-II, we analyze chromatic effect of energy selection by combining the 3-D strong magnetic field of particle collecting solenoid and the initial particle library of laser acceleration generated by PIC. We further propose a more compact laser-driven proton therapy design using the chromatic effect and energy reducer. And we research a broad-spectrum treatment planning system corresponding to it. It can effectively reduce proportion of low energy particles and complete energy selection after considering nonlinear effect of high 3-D magnetic field and special initial distribution. This can be applied in the design of gantry, which can be lighter than the traditional gantry. And for head, neck, and lung tumor models, dose delivery can be completed in 10 min and 20 min.

Therapeutic implications of narrow or positive surgical margins in head and neck tumors

IntroductionThe treatment of squamous cell carcinomas of the head and neck region involves a multidisciplinary approach that combines surgery, radiotherapy and chemotherapy.AimThe aim of this article is to discuss the therapeutic implications of narrow or positive surgical margins in head and neck cancers.Material and methodsThe article was written based on the analysis of the literature on the subject.Results and discussionSurgical resection is an important part of a approach to treatment and the adequacy of resection during surgery is determined by the margin status. A margin greater than 5 mm is considered free, less than 5 mm - narrow, and less than one mm is considered positive. For proper planning of radiotherapy, i.e. adequate selection of areas and doses, the following are necessary: imaging, endoscopy, pathology report. It should also be remembered that the lack of important information from the treatment and the fear of making a geographical error and/or not matching the dose to the actual stage of the disease and the status of the margins; affects the decision of the radiotherapist who will escalate the dose, which may lead to long-term tissue damage with loss of their function and significantly affect the quality of life of these patients.ConclusionsBefore initiating treatment, each patient should undergo analysis in multidisciplinary consultations to tailor the optimal therapeutic decision to the stage of the disease and any coexisting conditions.Patients with advanced disease and/or challenging localization and/or rare disease diagnoses should be treated in highly specialized centers where close collaboration between facilities is essential.

Small Cell Neuroendocrine Carcinoma of the Nasopharynx

Background: Nasopharyngeal malignant tumors were relatively rare head and neck tumors with a low global incidence. There were various pathologic types of nasopharyngeal malignant tumors, and small cell neuroendocrine carcinoma (SCNEC) was a highly malignant subtype with rapid growth and early metastasis. SCNEC was rare in the nasopharynx, and its clinical presentation and treatment strategy were different from other types of nasopharyngeal malignancies, posing a challenge to clinicians. Therefore, a comprehensive analysis of its diagnosis and treatment was essential. Case presentations: In February 2024, a 32-year-old male presented with nasal congestion, right ear stuffiness, right ear hearing loss, and right ear pain. Electron nasopharyngoscopy and nasopharyngeal magnetic resonance imaging (MRI) showed a large tumor in the nasopharynx. Pathologic examination confirmed the pathologic type as SCNEC. The patient was finally diagnosed with SCNEC. After chemotherapy, immunotherapy, and radiotherapy, the tumor size was significantly reduced, and the clinical symptoms were significantly improved. Conclusion: This case provided insights into the diagnosis and treatment of nasopharyngeal malignancies, particularly for a rare pathologic type (SCNEC), potentially enhancing the overall understanding of the disease.

Cervical CT Angiography: The Advantage of Ultra-High-Resolution CT Versus Conventional HRCT.

Pre-treatment depiction of the cervical arteries is important for better intra-arterial infusion therapy of malignant head and neck tumors. There have not been any studies on the image quality of ultra-high-resolution computed tomography (U-HRCT) for cervical CT angiography (CTA). The aim of this study is to evaluate the advantages of U-HRCT over conventional HRCT for cervical CTA; Methods: Forty-one patients underwent cervical CTA prior to selective intra-arterial infusion chemotherapy for malignant head and neck tumors. Twenty-two patients were scanned on conventional HRCT, while the remaining nineteen on U-HRCT. U-HRCT super-high-resolution (SHR) mode was used in 8 patients, while high-resolution (HR) mode was used in 11 patients. On CTA, the visibility of 18 branches from bilateral external carotid arteries was evaluated using a 5-point scale by three radiologists in consensus. Prior to the patient study, a head-neck CT phantom study regarding mock arterial density and its visibility was performed; Results: Regarding the patient study, the mean score of the SHR mode for visibility was significantly higher than that of conventional HRCT in 17 of 18 arteries (p < 0.05). The mean score of the HR mode for visibility was significantly higher than that of conventional HRCT in all arteries (p < 0.05). Regarding the phantom study, the maximum density of the SHR mode was significantly higher than that of conventional HRCT for mock proximal and peripheral arteries (p < 0.01). In addition, the visual score of the SHR mode for mock arteries was significantly higher than that of conventional HRCT (p < 0.05); Conclusions: U-HRCT provides higher image quality in terms of visualization of the arteries than conventional HRCT in cervical CTA.

Abstract B034: Engineering the tumor microenvironment: Patient-specific microphysiological systems of the head and neck cancer tumor microenvironment

Abstract Introduction: Survival rates in advanced head and neck cancer (HNC) remain poor with no clinically approved biomarkers to predict treatment efficacy. HNC is a highly heterogenous disease and the lack of available models that capture patient heterogeneity and the complexity of the tumor microenvironment (TME) contributes to these poor patient outcomes. Microphysiological systems (MPS) are complex multicellular in vitro models that can recapitulate three-dimensional organ structure and function. The low cell number requirements for MPS permits the creation of patient-specific TME models, where all the cell types can be isolated from a single piece of tumor tissue. These patient-specific MPS represent a promising strategy for elucidating the contribution of the TME to treatment resistance, predicting the best treatment for each patient and improving patient outcomes in HNC. Here, we report a patient-specific MPS that contains multiple TME compartments and recapitulates patient heterogeneity. Methods: Tumor tissue was collected from patients with oral cavity carcinoma undergoing standard of care surgery followed by radiation or chemoradiation. Tissue from each patient was digested and tumor infiltrating leukocytes (TIL) were isolated using CD45 magnetic beads, while epithelial cells and fibroblasts were expanded in culture using specific media formulations. Tissue was also snap frozen for single cell RNA sequencing analysis. To build the MPS, a custom designed microfluidic device was filled with a hydrogel matrix containing patient-matched TIL, fibroblasts and epithelial spheroids to mimic the solid tumor. Lumens molded from the hydrogel were seeded with blood or lymphatic endothelial cells to create vasculature. Multiple replicate MPS can be built from each patient, which are cultured in an optimized media formulation to support the multiple primary cell types. Patient-specific MPS were treated with radiation or cisplatin + radiation to mimic the treatment the patient received. Multiple orthogonal endpoints were measured including tumor cell migration and viability, cytokine secretion and angiogenesis. Single cell sequencing was also performed on the original tumor tissue and matched MPS. Results: We have successfully created patient-specific models of the HNC TME. Single cell RNA sequencing analysis of the MPS suggests that cellular heterogeneity is being retained. Patient characteristics varied between MPS with some patient TME MPS showing highly migratory tumor cells or angiogenic responses. Treatment responses were measured for each patient-specific MPS and ongoing work will characterize the contributions of the TME to treatment resistance. These data demonstrate the feasibility of using patient-specific MPS to investigate the contribution of the TME to treatment response and resistance and lays important groundwork for using MPS to identify patient treatment responses. Citation Format: Adeel Ahmed, Marcos Lares, Fauzan Ahmed, Adam R. Burr, Paul M. Harari, David J. Beebe, Sheena C. Kerr. Engineering the tumor microenvironment: Patient-specific microphysiological systems of the head and neck cancer tumor microenvironment [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Tumor-body Interactions: The Roles of Micro- and Macroenvironment in Cancer; 2024 Nov 17-20; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2024;84(22_Suppl):Abstract nr B034.

Trends and Outcomes of Neoadjuvant Chemotherapy for Clinical Stage T1 Pancreatic Cancer.

Neoadjuvant chemotherapy (NC) for early pancreatic ductal adenocarcinoma (PDAC) remains controversial. We investigate the adoption of NC and its impact on survival in clinical T1 (cT1) PDAC. National Cancer Database (2006-2017) was reviewed for cT1 PDAC. Patients receiving NC and surgery were compared with patients undergoing upfront surgery (US). A total of 5886 patients were included. NC use increased from 4.8% in 2006 to 18.8% in 2017. The NC group (n = 618) versus the US group (n = 5268) had: younger age (66 years vs. 68 years), smaller tumor size (2 cm vs. 2.2 cm), more pancreas head tumors (77% vs. 70.6%), lower lymph-vascular invasion (25.9% vs. 40.6%), and less lymph node positivity (43.6% vs. 54.5%), p < 0.001. Factors associated with receipt of NC were: younger age, recent year of diagnosis, and treatment at an academic program. In the NC group versus the US group, median OS was 35.2 months versus 28.3 months, p < 0.001. Factors associated with improved survival included: well differentiated pathology, R0 surgical margins, and receipt of chemotherapy. In cT1 PDAC, chemotherapy is associated with improved survival. In a surgery-first approach, only 59% of patients receive adjuvant chemotherapy. These data suggest consideration of neoadjuvant therapy for early pancreatic cancer.

Abstract PR004: Biological insights into tissue-agnostic plasma cfDNA methylation signature for surveillance of head and neck tumor recurrence

Abstract BACKGROUND: We recently described a clinical validation of a tissue-agnostic genome-wide methylome enrichment molecular residual disease (MRD) assay for head and neck cancers (HNC) (Liu, ESMO 2024). Herein, we investigate the cfDNA methylation signature utilized by this test to demonstrate the biological relevance with respect to the tissue of origin and epigenetic mechanisms of dysregulation that alter normal cellular activity. We evaluate the signature to gain insights and to characterize the biology of this biomarker and to investigate the application of cfMeDIP-seq assay as a diagnostic tool. METHODS: From unblinded training set of 163 HNC patients, including HPV+ (n = 76), HPV- (n = 43), and HPV-unknown (n = 44) individuals, a cfDNA methylation classifier signature was developed to detect recurrence (n MRD+ = 62, n MRD- = 101) in samples from blood draws approximately at 3, 12, and 24 months post curative intent treatment using cfMeDIP-seq assay. Clinical performance of the signature was then successfully validated in a blinded HNC validation cohort (n = 162), including HPV+ and HPV- patients (Liu, ESMO 2024). Here, the signature’s ability to detect ctDNA was assessed using HNC tumor tissue (n = 523), adjacent normal tissue (n = 45), and healthy peripheral blood leukocytes (n = 93) DNA methylation data from TCGA. The signature’s ability to provide biological insights was assessed by evaluating enrichment in CpG elements, epigenetic regulators, regulatory pathways, and other biological pathways. RESULTS: Identified differentially methylated regions (DMRs) were significantly hypermethylated in HNC tumor tissue samples when compared to adjacent normal and healthy peripheral blood leukocytes (P = 1.3e-131), and the mean signature signal within tumor tissue samples correlated with tumor purity (P = 2.47e-21). These DMRs were also significantly enriched in CpG islands, shores, and shelves and could classify HNC patients into identifiable molecular subtypes. Further analysis of the DMRs, based on their genomic coordinates, shows association with known cancer genes and significant enrichment in pathways known to be associated with HNC, for example, epithelial to mesenchymal transition (P = 1.76e-4), and multiple functional pathways involved in DNA and transcription factor binding, transcriptional regulation, and chromatin remodeling. CONCLUSIONS: These results, along with the previous clinical validation, provide strong evidence that the cfDNA methylation signature developed in HNC detects ctDNA shed from residual tumor and provide insights into relevant tumor biology and epigenetic mechanisms, including CpG island hypermethylation and epithelial to mesenchymal transition. Furthermore, these data support the generalization of biomarker detection utilizing cfMeDIP-seq to a broad spectrum of indications. Citation Format: Yulia Newton, Justin Burgener, Margaret Gruca, Collin Melton, Jun Min, Abel Licon, Scott Bratman, Alan Williams, Daniel D De Carvalho. Biological insights into tissue-agnostic plasma cfDNA methylation signature for surveillance of head and neck tumor recurrence [abstract]. In: Proceedings of the AACR Special Conference: Liquid Biopsy: From Discovery to Clinical Implementation; 2024 Nov 13-16; San Diego, CA. Philadelphia (PA): AACR; Clin Cancer Res 2024;30(21_Suppl):Abstract nr PR004.