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Syndactyly is the most common upper-extremity congenital condition, and cases can be associated with genetic syndromes or arise sporadically (nonsyndromic). The purpose of this investigation was to determine rates of both malignant and benign neoplasms among pediatric patients diagnosed with nonsyndromic syndactyly compared to matched controls. The TriNetX US Collaborative database was queried using International Classification of Disease, 10th Revision codes to identify patients aged 10 years or younger diagnosed with syndactyly. Patient history of syndactyly was utilized to categorize patients into 2 cohorts. These cohorts were propensity-matched by age, sex, race, ethnicity, and congenital malformation syndromes. Subsequent rate of neoplasms was compared between patients with and without syndactyly. A total of 7478 patients aged 10 years or younger diagnosed with syndactyly were identified. After 1:1 propensity matching, both cohorts included 5461 patients. The rate of digestive malignancies was significantly higher int he syndactyly cohort than that in the control cohort. The rate of benign neoplasms was significant at >5 years follow-up duration (P = .016, 95% CI 0.001-0.005) but was not significant at 1 year or 1 to 5 years. Similarly, rate of any neoplasm was significant at >5 years follow-up duration (P = .013, 95% CI 0.001-0.005) but not at 1 year or 1 to 5 years. Nonsyndromic syndactyly is associated with an increased rate of benign neoplasms and digestive malignancies. Further investigation is needed to better understand the relationship between the syndactyly phenotype and risk of malignancy.

Cisplatin remains the cornerstone radiosensitizer for definitive and adjuvant chemoradiation in patients with locally advanced squamous cell carcinoma of the head and neck. However, despite decades of clinical use, many practical aspects of cisplatin administration remain unstandardized in clinical practice and trials. Drawing on the collective experience of the NRG Oncology Head and Neck Working Group, this consensus article provides practical guidance on the administration of cisplatin during radiation therapy. We review and propose recommendations regarding the timing of chemotherapy and radiation initiation, premedication and hydration regimens by dose, monitoring and grading of cisplatin-induced ototoxicity, and management strategies during cisplatin shortages. Our guidance is informed by clinical trial protocols, retrospective and prospective data, and multidisciplinary expert consensus. We emphasize the importance of protocol flexibility to support equitable trial accrual, minimize treatment delays, and improve patient-centered outcomes. This article offers a unified framework to optimize the use of cisplatin in chemoradiation protocols, improve adherence, reduce toxicity, and preserve oncologic efficacy. Our recommendations are particularly timely in the context of evolving clinical practices and recent cisplatin shortages. Insights from the NRG Oncology collaborative group aim to inform future trial designs and clinical practice guidelines, ensuring consistent and equitable care for patients with head and neck cancer.

The dominant expression of lineage-related transcription factors (TFs)-ASCL1, NEUROD1, POU2F3, and, controversially, YAP1-has enabled the classification of small cell lung cancer (SCLC) into distinct subtypes (SCLC-A/N/P/Y, respectively). Emerging evidence suggests that a T cell-inflamed phenotype characterizes an SCLC subset. A large-scale multiomic analysis of samples from real-world patients with SCLC was conducted to examine the expression of clinically relevant biomarkers across SCLC subtypes. Comprehensive molecular profiling of patient samples (N = 944) was performed via next-generation DNA sequencing (592-gene panel or whole exome), RNA sequencing (whole transcriptome), and immunohistochemistry. Tumors were stratified on the basis of the dominant expression of an individual TF (SCLC-A/N/Y/P subtypes), coexpression of multiple TFs (mixed), or low expression of all four TFs (TF-) for characterization of immune-related gene signatures (T-cell inflamed, natural killer cell, and Stimulator of Interferon Genes pathway) and clinically relevant target genes. The cohort was composed of 25.6% SCLC-A, 10.2% SCLC-N, 12.5% SCLC-Y, 4.3% SCLC-P, 19.5% SCLC TF-, and 27.9% mixed subtypes. The SCLC-Y subtype exhibited the highest expression of immune-related gene signatures, with comparable expression observed in mixed samples expressing YAP1. Additionally, expression of clinically relevant target genes found in SCLC-A (DLL3, SEZ6, and BCL2) and SCLC-N (SSTR2) was increased in mixed samples expressing ASCL1 and NEUROD1. The TF- subtype was not associated with increased immune-related signatures or other target genes. This large-scale multiomic analysis revealed significant associations between SCLC subtypes and specific immune signatures and comutations. These findings provide insights into the molecular heterogeneity of SCLC, and highlight potential biomarkers for targeted therapies.

Early-generation TRK tyrosine kinase inhibitors (TKIs) approved for treating NTRK fusion-positive (NTRK+) solid tumors provide clinical benefit; however, resistance emerges. Repotrectinib is a next-generation ROS1/TRK TKI with a compact macrocyclic structure designed to improve durability of response. TRIDENT-1 is a registrational phase 1/2 trial assessing repotrectinib, a next-generation ROS1/TRK TKI, in adults with advanced solid tumors, including NTRK+ disease. The primary endpoint was confirmed objective response; secondary endpoints included duration of response (DOR), progression-free survival (PFS), overall survival and safety. Median follow-up ranged between 21.3 months and 25.7 months. In the TKI-naive cohort (n = 51; 95% confidence interval (CI)), the response rate was 59% (44-72); the median DOR was not estimable (NE); and the median PFS was 30.3 months (9.0-NE). In the TKI-pretreated cohort (n = 69; 95% CI), the response rate was 48% (36-60); the median DOR was 9.8 months (7.4-13.0); and the median PFS was 7.4 months (3.9-9.7). Of 30 TKI-pretreated patients with NTRK solvent front mutations, 16 had a response (53%; 95% CI: 34-72). Intracranial responses were observed in two of three TKI-naive patients and in four of six TKI-pretreated patients with measurable intracranial disease at baseline. Among all treated patients (n = 565), the most common any-grade treatment-related adverse event (TRAE) was dizziness (57%); most TRAEs were low grade; and 4% discontinued repotrectinib due to a TRAE. Here repotrectinib demonstrated durable systemic and intracranial responses with generally low-grade adverse events in patients with NTRK+ solid tumors, including those with previous TRK TKI treatment and solvent front mutations. These results support the use of repotrectinib to treat patients with NTRK+ solid tumors. ClinicalTrials.gov identifier: NCT03093116 .

The management of head and neck squamous cell cancer in older adults requires an individualized approach that integrates oncologic efficacy with geriatric considerations. Chronological age alone should not preclude curative-intent therapy; rather, treatment selection should be guided by comorbidity burden, functional status, and frailty assessment. Comprehensive geriatric assessment provides prognostic insight beyond traditional staging, informing both tolerance and outcomes. Surgery and radiotherapy remain feasible options for appropriately selected patients, whereas systemic therapy is limited by increased toxicity, necessitating dose modifications or alternative regimens. Multidisciplinary evaluation is critical to balance disease control with quality-of-life priorities, including swallowing, speech, and independence. Shared decision-making, incorporating patient goals and life expectancy, is essential to optimize care. Critically, prospective clinical trials focused on older adults are urgently needed to refine prognostic tools, mitigate toxicity, and optimize patient selection and outcomes.

Retinoblastoma is diagnosed and treated without biopsy based solely on appearance (with the indirect ophthalmoscope and imaging). More than 20 benign ophthalmic disorders resemble retinoblastoma and errors in diagnosis continue to be made worldwide. A better noninvasive method for distinguishing retinoblastoma from pseudo retinoblastoma is needed. RetCam imaging of retinoblastoma and pseudo retinoblastoma from the largest retinoblastoma center in the U.S. (Memorial Sloan Kettering Cancer Center, New York, NY) were used for this study. We used several neural networks (ResNet-18, ResNet-34, ResNet-50, ResNet-101, ResNet-152, and a Vision Image Transformer, or VIT), using 80% of images for training, 10% for validation, and 10% for testing. Two thousand eight hundred eighty-two RetCam images from patients with retinoblastoma at diagnosis, 1,970 images from pseudo retinoblastoma at diagnosis, and 804 normal pediatric fundus images were included. The highest sensitivity (98.6%) was obtained with a ResNet-101 model, as were the highest accuracy and F1 scores of 97.3% and 97.7%. The highest specificity (97.0%) and precision (97.0%) was attained with a ResNet-152 model. Our machine learning algorithm successfully distinguished retinoblastoma from retinoblastoma with high specificity and sensitivity and if implemented worldwide will prevent hundreds of eyes from incorrectly being surgically removed yearly.

Immune checkpoint blockade (ICB) has revolutionized cancer treatment; however, many patients develop therapeutic resistance. We previously identified and validated a pretreatment peripheral blood biomarker, characterized by a high frequency of LAG-3+ lymphocytes, that predicts resistance in patients receiving anti-PD-1 (aPD-1) ICB. To better understand the mechanism of aPD-1 resistance, we identified murine tumor models with a high LAG-3+ lymphocyte frequency (LAG-3hi), which were resistant to aPD-1 therapy, and LAG-3lo murine tumor models that were aPD-1 sensitive, recapitulating the predictive biomarker we previously described in patients. LAG-3hi tumor-bearing mice were sensitive to aPD-1 + anti-LAG-3 (aLAG-3) therapy, and this benefit was CD8+ T cell dependent. The efficacy of combination therapy was enhanced in LAG-3hi (but not LAG-3lo) mice with depletion of CD4+ T cells. Furthermore, responses to aPD-1 + aLAG-3 correlated with regulatory T cell (Treg) phenotypic plasticity in LAG-3hi mice, suggesting a specific role for Tregs in response to aPD-1 + aLAG-3 treatment. Using Treg fate-tracking Foxp3GFP-Cre-ERT2 × ROSAYFP reporter mice, we demonstrated that expanded populations of unstable Tregs correlated with improved response to combination therapy in LAG-3hi mice. Complementing these preclinical data, an increased proportion of unstable Tregs also correlated with higher response rate and improved survival after aPD-1 + aLAG-3 therapy in a cohort of patients with metastatic melanoma (n = 117). These data indicate that Treg phenotypic plasticity affects aPD-1 + aLAG-3 responsiveness, which may represent a biomarker to aid patient selection and a rational therapeutic target for a subset of PD-1-refractory patients.

Charting the spatiotemporal dynamics of cell fate determination in development and disease is a long-standing objective in biology. Here, we present the design, development, and extensive validation of PEtracer, a prime editing (PE)-based, evolving lineage tracing technology compatible with both single-cell sequencing and multimodal imaging methodologies, created to jointly profile cell state and lineage in dissociated cells or while preserving cellular context in tissues with high spatial resolution. Using PEtracer coupled with MERFISH spatial transcriptomic profiling in a syngeneic mouse model of tumor metastasis, we reconstructed the growth of individually seeded tumors in vivo and uncovered distinct modules of cell-intrinsic and -extrinsic factors that coordinate tumor growth. More generally, PEtracer enables systematic characterization of cell state and lineage relationships in intact tissues over biologically relevant temporal and spatial scales.

Inhibitors of murine double minute homolog 2 (MDM2) represent a promising therapeutic approach for the treatment of TP53 wild-type glioblastomas (GBMs), reactivating p53 signaling to induce cancer cell death. We conducted a surgical window-of-opportunity trial (NCT03107780) of the MDM2 inhibitor navtemadlin (KRT-232) in 21 patients with TP53 wild-type recurrent GBM to determine achievable drug concentrations within tumor tissues and biological mechanisms of response and resistance. Participants received navtemadlin at 120 mg (n = 10) or 240 mg (n = 11) for 2 days before surgical resection and after surgery until progression or unacceptable toxicity. Both 120 and 240 mg daily dosing achieved a pharmacodynamic impact, but median progression-free survival was 3.1 months. DNA sequencing of three recurrent tumors revealed an absence of TP53-inactivating mutations, indicating alternative mechanisms of resistance. To understand the mechanisms of response and resistance associated with navtemadlin, we conducted functional and spatial analyses of human tissue and patient-derived GBM neurosphere models. Navtemadlin induced partial tumor cell death as monotherapy, and combination with temozolomide enhanced apoptosis in GBM neurospheres while sparing normal bone marrow cells in vitro. We also observed up-regulation of oligodendrocyte differentiation genes with navtemadlin treatment and enrichment of oligodendrocyte transcription factor 2 (OLIG2)-positive cells at relapse, suggesting an unexplored mechanism of navtemadlin tolerance in GBM. Overall, these results indicated that clinically achievable doses of navtemadlin exert pharmacodynamic effects on GBM and suggest that combined treatment with temozolomide may be a route to more durable survival benefits.

To report the prevalenceof osteoradionecrosis (ORN) in oral cavity (OC) cancer patients following intensity-modulation radiation therapy (IMRT) or proton therapy (PRT). A retrospective study was conducted on consecutive cohort of OC cancer patients treated with IMRT or PRT for squamous cell carcinoma (SCC). Patient information and treatment related variables were collected from medical records. Patients who developed ORN were uniformly graded using CTCAE v5. Cox proportional hazards model was used to compare risk factors between IMRT and PRT.Kaplan-Meier method was used to estimate the cumulative incidence (CI) of ORN. A total of 479 OC SCC patients (426 treated with IMRT and 53 treated with PRT) were included in this study. The median follow-up time was 35&#xa0;months (IQR, 17-68&#xa0;months). The prevalence of ORN was similar between groups: 11% (47/426) in the IMRT group (21 Grade 1, 13 Grade 2, 13 Grade 3) and 11.3% (6/53) in the PRT group (2 Grade 1, 3 Grade 2, 1 Grade 3). The median time to ORN development was shorter following IMRT [13 months (IQR, 9-39)] compared to PRT [28 months (IQR, 4-42)].The 3-year CI of any grade ORN was 9.6&#xa0;% and 11.4&#xa0;% for IMRT and PRT (log-rank P-value&#xa0;=&#xa0;0.550), respectively. On univariable analysis, smoking history (P&#xa0;=&#xa0;0.072), tumor stage (P&#xa0;=&#xa0;0.011), tumor with mandibular invasion (P&#xa0;=&#xa0;0.007), and extent of mandibular intervention (P&#xa0;<&#xa0;0.001) was associated with ORN development. On multivariable analysis, the extent of mandibular intervention remained a significant risk factor (P&#xa0;<&#xa0;0.001). In this single-institution study, we found a similar prevalence of ORN following IMRT (11%) and PRT (11.3&#xa0;%) in OC cancer patients.

Cutaneous adnexal carcinomas (CACs) are rare skin cancers with no established treatment guidelines. Given the limited data, this study aims to explore the characteristics and outcomes of patients with CAC treated with radiation therapy (RT). Patients diagnosed with CAC between 2000 and 2020 who received RT were included. Kaplan-Meier methods measured time to local recurrence (LR), regional recurrence (RR), locoregional recurrence (LRR), distant metastasis (DM), and progression-free survival (PFS). Fisher exact test compared frequency distributions. Forty-nine patients with an average age of 65 years were studied. Most were White males with head and neck tumors. Common subtypes were adnexal adenocarcinoma, sebaceous carcinoma, and microcystic adnexal carcinoma. Patients received RT diagnosis or recurrence. The median overall survival was 44 months, with a median follow-up of 41 months for surviving patients. For patients with de novo cancer treated with surgery and adjuvant RT (n=22), 2-year PFS, LR, RR, LRR, DM, and OS were 77%, 5%, 0%, 5%, 10%, and 95%, respectively, with all LRR occurring outside the irradiated area. Patients with de novo cancer who received definitive RT (n=9) experienced 2-year PFS, LR, RR, LRR, DM, and OS of 30%, 46%, 13%, 55%, 40%, and 67%, respectively, with all LRR events occurring within the irradiated area. LR within the irradiated volume was associated with immunosuppression (95% CI: 19-99). Patients treated at recurrence had inferior outcomes. Surgical resection and adjuvant RT effectively control CAC, while definitive RT shows lower disease control. Novel strategies are needed to improve outcomes in patients receiving definitive RT.

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Although relatively rare, acute myeloid leukemia (AML) is the most common type of acute leukemia in adults. AML is associated with poor 5-year overall survival and prompt treatment is critical. Classifying AML based on World Health Organization criteria is important for determining prognosis and applying a risk-adapted treatment approach. Throughout therapy, patients require comprehensive supportive care measures with blood product transfusions, antimicrobial treatment, and frequent monitoring for chemotherapy-related complications. This article provides an overview of AML and its treatments. Clinicians in all specialties must be able to recognize the early signs of AML and ensure their patients seek appropriate expert medical care with a hematologist/oncologist.

Programmed cell death protein 1 (PD-1) inhibitors have modest efficacy as a monotherapy in hepatocellular carcinoma (HCC). A personalized therapeutic cancer vaccine (PTCV) may enhance responses to PD-1 inhibitors through the induction of tumor-specific immunity. We present results from a single-arm, open-label, phase 1/2 study of a DNA plasmid PTCV (GNOS-PV02) encoding up to 40 neoantigens coadministered with plasmid-encoded interleukin-12 plus pembrolizumab in patients with advanced HCC previously treated with a multityrosine kinase inhibitor. Safety and immunogenicity were assessed as primary endpoints, and treatment efficacy and feasibility were evaluated as secondary endpoints. The most common treatment-related adverse events were injection-site reactions, observed in 15 of 36 (41.6%) patients. No dose-limiting toxicities or treatment-related grade &#x2265;3 events were observed. The objective response rate (modified intention-to-treat) per Response Evaluation Criteria in Solid Tumors 1.1 was 30.6% (11 of 36 patients), with 8.3% (3 of 36) of patients achieving a complete response. Clinical responses were associated with the number of neoantigens encoded in the vaccine. Neoantigen-specific T cell responses were confirmed in 19 of 22 (86.4%) evaluable patients by enzyme-linked immunosorbent spot assays. Multiparametric cellular profiling revealed active, proliferative and cytolytic vaccine-specific CD4+ and CD8+ effector T cells. T cell receptor &#x3b2;-chain (TCR&#x3b2;) bulk sequencing results demonstrated vaccination-enriched T cell clone expansion and tumor infiltration. Single-cell analysis revealed posttreatment T cell clonal expansion of cytotoxic T cell phenotypes. TCR complementarity-determining region cloning of expanded T cell clones in the tumors following vaccination confirmed reactivity against vaccine-encoded neoantigens. Our results support the PTCV's mechanism of action based on the induction of antitumor T cells and show that a PTCV plus pembrolizumab has clinical activity in advanced HCC. ClinicalTrials.gov identifier: NCT04251117 .

The early-generation ROS1 tyrosine kinase inhibitors (TKIs) that are approved for the treatment of ROS1 fusion-positive non-small-cell lung cancer (NSCLC) have antitumor activity, but resistance develops in tumors, and intracranial activity is suboptimal. Repotrectinib is a next-generation ROS1 TKI with preclinical activity against ROS1 fusion-positive cancers, including those with resistance mutations such as ROS1 G2032R. In this registrational phase 1-2 trial, we assessed the efficacy and safety of repotrectinib in patients with advanced solid tumors, including ROS1 fusion-positive NSCLC. The primary efficacy end point in the phase 2 trial was confirmed objective response; efficacy analyses included patients from phase 1 and phase 2. Duration of response, progression-free survival, and safety were secondary end points in phase 2. On the basis of results from the phase 1 trial, the recommended phase 2 dose of repotrectinib was 160 mg daily for 14 days, followed by 160 mg twice daily. Response occurred in 56 of the 71 patients (79%; 95% confidence interval [CI], 68 to 88) with ROS1 fusion-positive NSCLC who had not previously received a ROS1 TKI; the median duration of response was 34.1 months (95% CI, 25.6 to could not be estimated), and median progression-free survival was 35.7 months (95% CI, 27.4 to could not be estimated). Response occurred in 21 of the 56 patients (38%; 95% CI, 25 to 52) with ROS1 fusion-positive NSCLC who had previously received one ROS1 TKI and had never received chemotherapy; the median duration of response was 14.8 months (95% CI, 7.6 to could not be estimated), and median progression-free survival was 9.0 months (95% CI, 6.8 to 19.6). Ten of the 17 patients (59%; 95% CI, 33 to 82) with the ROS1 G2032R mutation had a response. A total of 426 patients received the phase 2 dose; the most common treatment-related adverse events were dizziness (in 58% of the patients), dysgeusia (in 50%), and paresthesia (in 30%), and 3% discontinued repotrectinib owing to treatment-related adverse events. Repotrectinib had durable clinical activity in patients with ROS1 fusion-positive NSCLC, regardless of whether they had previously received a ROS1 TKI. Adverse events were mainly of low grade and compatible with long-term administration. (Funded by Turning Point Therapeutics, a wholly owned subsidiary of Bristol Myers Squibb; TRIDENT-1 ClinicalTrials.gov number, NCT03093116.).

Cholangiocarcinoma (CCA) is a neoplasm of the biliary tract that has become increasingly prevalent throughout the world. Common risk factors for developing CCA include cirrhosis, primary sclerosing cholangitis, and trematode fluke infestation, although there are no set screening guidelines in high-risk groups. Lesions are typically identified via cross-sectional imaging and/or elevated serum carbohydrate antigen 19-9 levels, often followed by cytology or brushings with fluorescence in situ hybridization for confirmation. Treatments can vary among CCA subtypes but frequently involve systemic therapies such as gemcitabine and cisplatin with durvalumab or pembrolizumab. Targeted therapies may also be effective (eg, ivosidenib, pemigatinib, infigratinib, futibatinib) depending on the molecular alterations present. Resection is the most common surgical treatment for CCA, although liver transplantation is also an option in highly selected patients with liver-limited unresectable disease. Radiotherapy may also be a treatment option, as well as transarterial radioembolization (eg, yttrium-90), which is often utilized in combination with systemic therapy. Although patients with CCA have traditionally had a poor prognosis, recent advances in treatment, including new systemic therapies and increased utilization of liver transplantation, have improved expected survival. This article reviews screening modalities, pros and cons of diagnostic techniques, and therapies that are currently available to treat patients with CCA.

Chromosome-containing micronuclei are a hallmark of aggressive cancers. Micronuclei frequently undergo irreversible collapse, exposing their enclosed chromatin to the cytosol. Micronuclear rupture catalyzes chromosomal rearrangements, epigenetic abnormalities, and inflammation, yet mechanisms safeguarding micronuclear integrity are poorly understood. In this study, we found that mitochondria-derived reactive oxygen species (ROS) disrupt micronuclei by promoting a noncanonical function of charged multivesicular body protein 7 (CHMP7), a scaffolding protein for the membrane repair complex known as endosomal sorting complex required for transport III (ESCRT-III). ROS retained CHMP7 in micronuclei while disrupting its interaction with other ESCRT-III components. ROS-induced cysteine oxidation stimulated CHMP7 oligomerization and binding to the nuclear membrane protein LEMD2, disrupting micronuclear envelopes. Furthermore, this ROS-CHMP7 pathological axis engendered chromosome shattering known to result from micronuclear rupture. It also mediated micronuclear disintegrity under hypoxic conditions, linking tumor hypoxia with downstream processes driving cancer progression.

Glutamatergic neuron-glioma synaptogenesis and peritumoral hyperexcitability promote glioma growth in a positive feedback loop. The objective of this study was to evaluate the feasibility and estimated effect sizes of the targeted AMPA receptor antagonist perampanel on peritumoral hyperexcitability. An open-label trial was performed comparing perampanel with standard of care (SOC) in patients undergoing resection of newly diagnosed radiologic high-grade glioma. Perampanel was administered as a preoperative loading dose followed by maintenance therapy until progressive disease or up to 12 months. SOC treatment involved levetiracetam for 7 days or as clinically indicated. The primary outcome of hyperexcitability was defined by intraoperative electrocorticography high-frequency oscillation (HFO) rates. Seizure freedom and overall survival were estimated by the Kaplan-Meier method. Tissue concentrations of perampanel, levetiracetam, and correlative biomarkers were measured by mass spectrometry. HFO rates were similar between patients treated with perampanel and levetiracetam. The trial was terminated early after a planned interim analysis, and outcomes assessed in 11 patients (seven perampanel treated; four treated with SOC). Over a median 281 days of postenrollment follow-up, 27% of patients had seizures, including 14% maintained on perampanel and 50% treated with SOC. Overall survival in perampanel-treated patients was similar to that in a glioblastoma reference cohort. Glutamate concentrations in surface biopsies were positively correlated with HFO rates in adjacent electrode contacts and were not significantly associated with treatment assignment or drug concentrations. Glioma peritumoral glutamate concentrations correlated with high-gamma oscillation rates. Targeting glutamatergic activity with perampanel achieved similar electrocorticographic hyperexcitability levels as in levetiracetam-treated patients.

T cell receptors (TCR) are pivotal in mediating tumour cell cytolysis via recognition of mutation-derived tumour neoantigens (neoAgs) presented by major histocompatibility class-I (MHC-I). Understanding the factors governing the emergence of neoAg from somatic mutations is a major focus of current research. However, the structural and cellular determinants controlling TCR recognition of neoAgs remain poorly understood. This study describes the multi-level analysis of a model neoAg from the B16F10 murine melanoma, H2-Db/Hsf2 p.K72N68-76, as well as its cognate TCR 47BE7. Through cellular, molecular and structural studies we demonstrate that the p.K72N mutation enhances H2-Db binding, thereby improving cell surface presentation and stabilizing the TCR 47BE7 epitope. Furthermore, TCR 47BE7 exhibited high functional avidity and selectivity, attributable to a broad, stringent, binding interface enabling recognition of native B16F10 despite low antigen density. Our findings provide insight into the generation of anchor-residue modified neoAg, and emphasize the value of molecular and structural investigations of neoAg in diverse MHC-I contexts for advancing the understanding of neoAg immunogenicity.