Faculty Bibliography

Lung adenocarcinoma (LUAD) remains a leading cause of cancer-related mortality. While for Stage IA LUAD surgery is often curative, recurrence rates remain significant. Liquid biopsy enables monitoring residual disease and predicts recurrence, however utility in Stage IA LUAD is not well-established. Tumor-informed whole genome sequencing (WGS) represents a highly sensitive liquid biopsy method for the analysis of circulating-tumor cell-free DNA (ctDNA) without designing and maintaining patient-specific probes. We aimed to determine the prognostic value of genome-wide tumor-informed minimal residual disease (MRD) monitoring in Stage IA NSCLC using WGS of ctDNA. WGS was performed on 42 patients with Stage IA NSCLC. Tumor was sequenced at 40x and germline DNA and plasma derived ctDNA at 20x and patient specific mutational signatures were developed from the tumor-normal comparison and applied to ctDNA WGS at each time point using AI-supported pattern recognition algorithm. ctDNA results were compared with clinical recurrence. WGS ctDNA was able to predict recurrence with 0.75 sensitivity and 0.83 specificity, with median 16.7 months lead time compared to clinical or imaging recurrence. ctDNA WGS was able to distinguish between a second primary and recurrence in histologically or clinically challenging cases. Whole genome sequencing of ctDNA can predict recurrence in the earliest clinical stage of NSCLC, identifying patients who will recur, and providing information to help guide radiological follow-up and adjuvant therapy.

IMPORTANCE/UNASSIGNED:Chordoma is a rare malignant bone tumor with high local recurrence, metastatic spread in 40% to 60% of patients over the disease course, and significant morbidity. Because of its rarity, anatomical complexity, and prolonged natural history, high-quality evidence to guide management is limited. International consensus guidelines for localized chordoma were first published in 2015; however, advances in pathology, imaging, surgery, radiotherapy, and supportive care since then necessitate updated multidisciplinary recommendations. OBJECTIVE/UNASSIGNED:To update and expand the 2015 consensus recommendations on the diagnosis, treatment, and follow-up of pediatric and adult patients with primary, localized chordoma. EVIDENCE REVIEW/UNASSIGNED:In June 2025, a meeting of the Global Chordoma Consensus Group was held in Milan, Italy, that included experts from all relevant specialties as well as patient representatives. A comprehensive literature review guided structured discussions on the management of primary localized disease. Levels of evidence and grades of recommendation were assigned. FINDINGS/UNASSIGNED:A total of 305 articles were included in the literature review. Management strategies were stratified by anatomical site (skull base, mobile spine, and sacrum). The central principal of care was treatment at experienced, multidisciplinary centers, with maximally safe surgery followed by high-dose, highly conformal radiotherapy. Guidance was provided on diagnosis, surgical approaches, and radiotherapy planning for each anatomical site. Systemic therapy options; long-term, risk-adapted follow-up; and supportive, palliative, and rehabilitative care were also addressed. CONCLUSIONS AND RELEVANCE/UNASSIGNED:This global consensus statement provided updated multidisciplinary guidance for the management of primary, localized chordoma. It aimed to harmonize clinical practice, support shared decision-making, and identify priorities for future collaborative research in this rare and challenging disease.

Papillary renal neoplasm with reverse polarity (PRNRP) has been proposed as a distinct subtype of renal cell neoplasm with recurrent KRAS mutations and indolent behavior. However, its epigenetic landscape is poorly understood. In this study, 12 PRNRPs and a PRNRP initially diagnosed as "papillary adenoma" were analyzed. All 13 cases underwent targeted next-generation sequencing for driver mutations. Eleven PRNRPs were profiled using the Illumina MethylationEPIC array and compared with a reference cohort of 71 common renal cell tumors. KRAS mutations were identified in 12 of 13 (92%) cases of PRNRP. Copy-number analysis from methylation profiling showed that 9 of 11 (82%) PRNRPs lacked copy-number changes. Two cases showed a focal loss of chromosome 8 and a gain of chromosome 16, respectively. Unsupervised clustering based on methylation data showed that PRNRPs form a distinct epigenetic group, separate from papillary renal cell carcinomas (pRCCs) and other major renal tumors, but with the closest affinity to clear cell papillary renal cell tumors. In addition, DNA methylation analysis suggested PRNRP may arise from the distal nephron, in contrast to pRCC, which appears to recapitulate proximal tubules. These findings support PRNRP as a subtype of renal cell neoplasm with a distinct epigenetic signature.

BACKGROUND:The widespread use of next-generation sequencing has allowed refinement of the classification and diagnosis of salivary gland neoplasms, leading to identification of recurrent gene fusions in a majority of salivary gland carcinoma types, and characterization of several novel entities. A small proportion of salivary gland carcinomas do not meet the diagnostic criteria for any known tumor type and are therefore classified as "salivary gland carcinoma, not otherwise specified". Given the ever-growing arsenal of tools to classify these lesions, the number of cases diagnosed as such is expected to continue decreasing. CASE PRESENTATION/METHODS:In this article we describe a novel DLG1::BRAF fusion in a high grade salivary gland carcinoma arising in the tongue of a 78 year-old woman. This tumor had solid and cribriform architectural features and was composed of a dual population of abluminal and mucinous cells. Immunohistochemically, it had variable SOX10 expression, variable and strong MUC4 reactivity and expression of p63 and p40 (delta Np63) in the abluminal cell population. The gene fusion retained the kinase domain of BRAF, without the self-inhibitory CR1 domain, which is expected to lead to upregulation of BRAF protein. The patient had a complete resection of her tumor, without evidence of local recurrence or metastasis 10 months after diagnosis. CONCLUSION/CONCLUSIONS:These findings may represent a previously undescribed type of salivary gland tumor. However, additional reports of similar lesions are necessary for definitive characterization.

BACKGROUND:Replication-repair-deficiency is associated with increased risk of developing malignant gliomas. The aim of this study was to investigate primary mismatch repair deficient gliomas (PMMRDGs), a group of IDH-wildtype and H3-wildtype gliomas that is enriched among patients with CMMRD and Lynch syndrome. METHODS:We investigated how PMMRDGs differ from other gliomas with respect to DNA methylation profile, genomic alterations, histopathology, and clinical outcomes. RESULTS:PMMRDGs occur in pediatric, adolescents and the elderly, falling in two related methylation clusters and are characterized by a high frequency of replication repair deficiency. Histology showed multinucleated giant cells, and immunohistochemistry demonstrated loss of MMR protein expression. Survival analysis revealed long-term survival in patients with high mutational burden (>50 mut/Mb) and an intact chromosome 9p region, which was validated in an independent reference cohort. CONCLUSIONS:Overall, our findings indicate that PMMRDGs represent a distinct type of IDH-wildtype gliomas with potential for long-term survival likely driven by immune activation.

BACKGROUND:Accurate molecular classification of medulloblastoma is critical for prognosis and treatment planning, but current methods rely on surgical tissue sampling and molecular profiling. This study evaluated whether in vivo proton MR spectroscopy (¹H-MRS) can provide noninvasive metabolic markers to support pre-surgical molecular group stratification. METHODS:In this single-center retrospective study, pre-treatment ¹H-MRS data were analyzed from 95 pediatric patients with medulloblastoma (median age 7.4 years; 56 male). Single-voxel PRESS spectra (TE = 35 ms, TR = 1.5-2.0 s) were acquired during routine clinical MRI, adding approximately 5 minutes of scan time. Absolute metabolite concentrations and selected ratios were quantified using automated spectral fitting. Metabolic profiles were compared across molecular groups (Group 3, n = 22; Group 4, n = 35; SHH, n = 26; WNT, n = 12) and assessed for qualitative concordance with prior ex vivo high-resolution HR-MAS NMR findings. Group differences were tested using Kruskal-Wallis with Dunn post hoc correction. RESULTS:Significant metabolic differences were observed across molecular groups, with strong group effects for taurine, creatine, choline, glutamate, and GABA (all P < .0015). Taurine was elevated in Group 3 and Group 4 relative to SHH (log₂FC = 1.77 and 1.40, adjusted P < 4 × 10⁻⁵). SHH tumors exhibited lower creatine compared with Group 3, Group 4, and WNT (adjusted P < .05). Glutamate was higher in SHH than WNT, while WNT tumors showed increased choline and GABA relative to other groups (adjusted P < .05). In vivo patterns were qualitatively concordant with ex vivo NMR findings. CONCLUSIONS:In vivo ¹H-MRS is a widely available, clinically feasible imaging biomarker that complements existing diagnostics and supports pre-surgical stratification of medulloblastoma.

BACKGROUND AND PURPOSE/OBJECTIVE:-wt GBMs to help radiologists in differentiating them from nonmalignant mimic diagnoses (eg, encephalitis). Additionally, the histologic, genomic, and survival profiles of nonenhancing GBMs were compared with those of enhancing GBMs. MATERIALS AND METHODS/METHODS:-wt GBMs with nonmalignant mimics. Histopathologic and genomic analyses were performed on institutional cases. Overall survival between nonenhancing and enhancing GBMs was compared using Kaplan-Meier analysis. RESULTS:= .078). CONCLUSIONS:Nonenhancing GBMs demonstrate distinct MRI features that must be recognized for early diagnosis and differentiation from nonmalignant mimics. Nonenhancing GBMs demonstrated longer overall survival compared with enhancing GBMs, though they were not statistically significant.

BACKGROUND:Astroblastomas are rare brain tumors predominantly affecting children and young adults, for which molecular subtypes and clinical management remain undefined. METHODS:We analyzed tumor samples, molecular profiles, and clinical data from 200 patients, classified as "Astroblastoma, MN1-altered" under WHO criteria, using DNA methylation profiling, DNA/RNA profiling/sequencing, and survival analyses. RESULTS:DNA methylation analyses identified 3 groups: Group A (n = 143, characterized by MN1::BEND2 fusions, predominantly supratentorial location, with striking female predominance and favorable survival); Group B (n = 37, epigenetically and transcriptionally closely related to Group A, but characterized by EWSR1::BEND2 fusions, with spinal and infratentorial locations and poor prognosis); and Group C (n = 20, epigenetically and transcriptionally distinct, characterized by MN1::CXXC5 fusions, exclusively supratentorially located, with favorable survival). Progression-free and overall survival were significantly shorter in Group B (5-year PFS 14%; 10-year OS 54%) compared to A (5-year PFS 47%; 10-year OS 89%) and C (5-year PFS 75%; 10-year OS 89%). Radiotherapy improved PFS in Group B (hazard ratio 0.25), while no clear benefit was identified for Groups A and C. CONCLUSIONS:Astroblastoma, MN1-altered, comprises 3 molecularly and clinically distinct groups, characterized by different fusion genes, including those without MN1. These new insights, including the identification of potential predictive biomarkers like 14q/16q loss, provide a framework for the development of risk-stratified therapeutic approaches. Importantly, we identified a molecularly defined high-risk group that benefits from radiation therapy. Our findings redefine Astroblastoma as a molecularly diverse tumor type, propose a refined classification, support the development of risk-adapted therapeutic strategies and provide a rational standard of care.