Uncertainty about the prognostic significance of neurotrophic tropomyosin receptor kinase (NTRK) fusions complicates clinical decisions and interpretation of survival outcomes in oncology care. Drawing on the largest cohort of NTRK fusion-positive (NTRK+) patients, we establish the prognostic effect of NTRK fusions in adults with advanced cancers.

We used a large real-world clinicogenomic research database from the United States to emulate a pragmatic randomized trial that determines the causal effect of harboring an NTRK gene fusion (NTRK+) on survival prognosis for adult patients with advanced solid tumors. We 1:1 matched NTRK+ patients to patients with no identified NTRK genomic alterations (NTRK-) using a machine learning matching approach. Excluding patients who received TRK inhibitors, we conducted stratified matching within common tumor groups. We used Kaplan-Meier and Weibull regression survival analyses and estimated the difference in restricted mean survival time (RMST) over 1-, 2-, 3-, and 5-year study periods.

We included 68,145 NTRK- patients for matching to 73 NTRK+ patients within seven tumor groups, including colorectal (n = 22), non-small cell lung (n = 13), sarcoma (n = 13), breast (n = 10), head and neck (n = 7), neuroendocrine (n = 4), and prostate (n = 4), and 14 NTRK+ patients representing eight other cancers. The difference in overall survival over 1 year was statistically significant using the Kaplan-Meier estimate (P = .008), Weibull regression (hazard ratio, 2.105 [95% CI, 1.207 to 3.673]), and RMST (-50 days [95% CI, -96 to -5]; P = .029). Differences were also statistically different at 2 years and 3 years. At 5 years, no survival differences were statistically significant.

In this large real-world target trial emulation, NTRK gene fusions were associated with clinically meaningful reductions in overall survival among adults with advanced cancers not treated with TRK inhibitors. These findings clarify the prognostic role of NTRK fusions and inform clinical interpretation of outcomes in routine oncology.

NCT03222609 [REFINE]; NCT04468984 [TRANSFORM-2]).

Phyllodes tumors (PTs) are rare fibroepithelial neoplasms of the breast. PTs may pose significant diagnostic challenges, especially when they lack the classic leaf-like architecture and resemble cellular fibroadenomas. Accurate distinction between these entities is clinically important because of differences in management and recurrence risk. We report a 21-year-old woman who developed an early local recurrence of a fibroepithelial lesion initially diagnosed as a cellular complex fibroadenoma. The recurrence demonstrated stromal hypercellularity, multifocal infiltrative growth, and non-atypical smooth muscle differentiation without characteristic leaflike architecture, rendering morphological classification inconclusive. Next-generation sequencing demonstrated a pathogenic frameshift mutation in the BCOR gene. When integrated with the patient's clinical history and the lesion's morphology, these molecular findings supported a diagnosis of borderline PT. This report emphasizes the importance of integrating histopathological, clinical, and molecular data in the evaluation of fibroepithelial lesions with ambiguous morphology. Molecular alterations, such as BCOR mutations, may provide valuable diagnostic support, in particular in fibroadenoma-like PTs.

Pituitary neuroendocrine tumor (PitNET) is one of the most common intracranial neuroendocrine tumors. Surgical resection is the first choice for most subtypes of PitNETs. However, radical removal of invasive tumors remains challenging. A novel pharmacological therapy is objectively needed. Sirtuin 6 (Sirt6) is a member of the NAD⁺-dependent class III deacetylase sirtuin family, which plays a key role in tumorigenesis in many tumors. However, the role of Sirt6 and its activator in PitNETs is still unclear.

In the study, we investigated the expression of Sirt6 and the antitumor effect of the Sirt6 activator MDL-800 in PitNETs.

The expression of Sirt6 was detected in PitNET and cell lines by RNA-seq, immunohistochemistry, and western blotting. To test Sirt6 and its activator MDL-800, the cell viability, clone formation, and xenograft experiment were conducted. Autophagy was evaluated by microscopy and western blotting analysis. The efficacy of MDL-800 in the human primary PitNET cells was also investigated by the cell viability assay.

Low expression of Sirt6 was found in PitNET tissues and two pituitary cell lines. Sirt6 inhibited cell proliferation and clone formation. Treatment with MDL-800 suppressed cell growth in vitro and in vivo. Further mechanistic studies showed that MDL-800 could lead to lethal autophagy and exert an antitumor effect in human primary PitNET cells.

Our results suggest that activation of Sirt6 by its selective activator MDL-800 is a promising therapy for PitNETs.

Breast cancer-related lymphedema (BCRL) is a chronic condition caused by impaired lymphatic drainage following cancer treatment, manifesting as fluid accumulation, adipogenesis, and lymph reflux to the skin (dermal backflow). The affected regions are diverse and therefore, improved understanding of the spatial distribution of lymphatic dysfunction may facilitate earlier detection and disease monitoring. This study aimed to develop a spatial atlas of dermal backflow in BCRL and apply machine learning (ML) models to predict disease severity.

Data from 282 female BCRL patients (289 affected limbs) were obtained from the Australian Lymphedema Education, Research and Treatment (ALERT) Centre Databank, including indocyanine green (ICG) lymphography studies and clinical information. A spatial atlas of dermal backflow prevalence in the upper extremities was constructed by co-registering and segmenting clinician-annotated ICG diagrams. Five ML models were developed to classify MD Anderson Cancer Center (MDACC) lymphedema stage, incorporating dermal backflow percentage and clinical features.

The atlas revealed consistent spatial patterns of dermal backflow, with the highest prevalence in the wrist, forearm, and the olecranon region. Subgroup-specific heat maps stratified by MDACC stage, L-Dex ratio, limb volume difference, drainage regions, and hand dermal backflow further demonstrated distinct spatial variations with disease severity. The inclusion of dermal backflow percentage improved ML prediction of MDACC stage, with the best performance achieved by multinomial logistic regression and random forest models.

Dermal backflow prevalence revealed non-uniform, region-specific patterns in BCRL patients, which can be visualized using spatial atlases. Integrating quantitative imaging features into ML models improves BCRL staging and supports objective, data-driven disease assessment.

Brain-only metastatic breast cancer (BO-MBC), defined as breast cancer with brain metastases (BrM) in the absence of extracranial metastatic disease (ECM), may represent a distinct metastatic phenotype. We characterized clinicopathologic features, treatment patterns, and outcomes of BO-MBC and evaluated associations between metastatic pattern, treatment, and survival.

Patients with isolated BrM at our institution were evaluated for intracranial progression-free survival (iPFS), extracranial progression-free survival (ePFS), leptomeningeal disease-free survival (LMD-PFS), and overall survival (OS). Patients with MBC diagnosed between 2010 and 2020 were identified from the NCDB and classified as BO-MBC or BrM with concurrent ECM (BrM + ECM). Overlap propensity score-weighted Cox models evaluated associations between metastatic pattern, treatment, and OS.

In the institutional cohort (n = 30), intracranial progression was the predominant pattern of failure, with median iPFS of 14.6 months versus ePFS of 30.4 months. In the NCDB cohort (n = 8,909), 1,540 patients (17.3%) had BO-MBC. Compared with BrM + ECM, BO-MBC was associated with node-negative, triple-negative, and fewer HR+/HER2- disease (p < 0.001). BO-MBC patients were more likely to receive brain radiotherapy (54.8% vs. 41.0%, p < 0.001) but less likely to receive systemic therapy (67.2% vs. 74.5%, p < 0.001). In unadjusted Kaplan-Meier analyses, BO-MBC was associated with longer median OS than BrM + ECM (12.5 months [95% CI, 3.6-43.6] vs. 10.6 months [95% CI, 2.6-33.8]). Systemic therapy was associated with improved OS, with the greatest benefit in BO-MBC (adjusted HR 0.22, 95%CI 0.18-0.27). Brain radiotherapy was associated with improved OS in BO-MBC but not BrM + ECM.

BO-MBC may represent a distinct clinical subgroup with unique clinicopathologic characteristics, treatment patterns, and improved survival. Intracranial progression predominated despite durable extracranial control, supporting optimized brain-directed management and prospective investigation of BO-MBC as a unique metastatic phenotype.

Not applicable.

Lynch syndrome (LS) is underdiagnosed in India, particularly outside colorectal cancer (CRC), because pan-cancer data on microsatellite instability (MSI), mismatch repair deficiency (MMRd), and germline predisposition remain limited. We consecutively recruited 519 patients with CRC and extracolonic cancers from 17 centres in India between 2019 and 2025, and applied a tumour-first approach using MSI testing by PCR-fragment length analysis (PCR-FLA) across all tumours, MMR immunohistochemistry (MMR-IHC) in extracolonic tumours, BRAF V600E testing in MSI-high (MSI-H) CRCs, and germline whole exome sequencing in MSI-H/BRAF wildtype CRCs and MSI-H/MMRd extracolonic tumours. MSI-H/MMRd status was identified in 24.9% (129/519) of tumours, and 51.2% (66/129) patients harboured pathogenic or likely pathogenic germline variants consistent with LS. CRC showed the highest LS yield, followed by endometrial and ovarian cancers, whereas several extracolonic tumour groups showed lower yields, in part reflecting cohort composition and tumour-specific MSI/MMRd prevalence. MLH1 accounted for most LS diagnoses (69.7%, 46/66) followed by MSH2 (18.2%, 12/66). Two recurrent MLH1 variants, c.306G>T and c.156delA, together accounted for 36.4% of all LS cases. Haplotype analysis supported c.156delA as a novel founder variant originating in Gujarat. Concordance between PCR-FLA and MMR-IHC in extracolonic tumours was 93.8%, supporting combined tumour-based screening in pan-cancer workflows. These findings establish the clinical utility of pan-cancer tumour-first LS detection in India and support broader implementation of reflex MSI/MMRd testing, germline confirmation, and cascade testing to improve surveillance, chemoprevention, and risk-reducing management in India.

National Comprehensive Cancer Network (NCCN) guidelines emphasize detailed reporting of tumor-vessel relationships for pancreatic ductal adenocarcinoma (PDAC), but the completeness and prognostic significance of vascular findings documented in routine clinical CT reports remain uncertain in the contemporary era of neoadjuvant therapy (NAT).

To assess the completeness of NCCN-relevant vascular reporting in routine preoperative CT examinations and determine whether CT-reported vascular findings and derived NCCN resectability categories are associated with margin-positive (R1) resection.

In this retrospective single-center study, 528 patients who underwent resection for pathologically confirmed PDAC between 2011 and 2026 were identified. For each patient, the most recent preoperative staging CT report and corresponding surgical pathology report were linked. Tumor-vessel relationships involving the superior mesenteric artery (SMA), celiac axis, common hepatic artery (CHA), superior mesenteric vein (SMV), and portal vein (PV) were extracted from routine clinical reports via a large language model, which underwent validation against 2 readers. Multivariable logistic regression was used to evaluate associations between vascular findings, NCCN resectability category, and R1 resection after adjustment for age, sex, tumor size, tumor location, and NAT status.

Among 528 patients (mean age, 69.2 years ±9.9; 277 men), 257 (48.7%) received NAT and 172 (32.6%) had R1 resection. Complete reporting of all five NCCN vessels was present in 224/528 (42.4%) reports. NCCN resectability category could be assigned in 322 patients, including 150 (46.6%) resectable, 123 (38.2%) borderline resectable, and 49 (15.2%) locally advanced tumors. R1 rates increased progressively across categories (26.7%, 45.5%, and 53.1%, respectively; p < 0.001). After adjustment, SMA abutment (OR, 2.85; p = 0.001), SMA encasement (OR, 2.49; p = 0.023), celiac encasement (OR, 2.81; p = 0.021), CHA encasement (OR, 2.31; p = 0.031), PV abutment (OR, 2.31; p = 0.007), and SMV encasement (OR, 2.50; p = 0.014) were independently associated with R1 resection. In sensitivity analysis assuming unreported vessels had no tumor contact, borderline resectable tumors (OR, 2.68; 95% CI, 1.60-4.50) and locally advanced tumors (OR, 4.77; 95% CI, 2.22-10.23) demonstrated progressively higher odds of R1 resection relative to resectable tumors.

Complete NCCN-compliant vascular reporting was uncommon in routine PDAC CT reports, limiting standardized resectability classification. Nevertheless, CT-reported vascular findings and NCCN resectability categories derived from routine reports retained significant associations with margin-positive resection, supporting the continued clinical relevance of vascular staging information communicated in everyday radiology practice.

Surgical resection is the primary treatment for solid pseudopapillary neoplasms (SPN). Systemic treatment options are limited; no prospective trials or consensus guidelines exist given the rarity of SPN.

We retrospectively reviewed patients treated for SPN at Memorial Sloan Kettering Cancer Center from 2009-2024, summarizing demographics, treatments, outcomes, and genetic testing results when available.

Of 45 patients, 42 (93%) underwent surgical resection and 8 (18%) received systemic or locoregional treatment (average 3.25 therapies per patient). Genetic testing was available for 10 patients (22%), 9 of whom had Wnt/β-catenin pathway alterations. One patient whose tumor harbored a CTNNB1 mutation was treated with an investigational therapy inhibiting β-catenin, achieving disease control for 7 months.

This is the largest single-institution series of treatment of advanced SPN, demonstrating that select therapies can provide disease control. Molecular characterization of SPN frequently identifies Wnt/β-catenin pathway alterations, demonstrating a potential clinical benefit for drugs targeting this pathway.

Lung squamous cell carcinoma (LUSC) has limited treatment options, motivating investigation of molecular pathways that support tumor-cell growth. Forkhead box D1 (FOXD1) expression was assessed using gene expression profiling interactive analysis (GEPIA), quantitative reverse-transcription polymerase chain reaction (qRT-PCR), western blotting, and immunohistochemistry in paired tissues and cell lines. FOXD1 or methyltransferase-like 3 (METTL3) was depleted in LUSC cells, and cell viability, apoptosis, migration, global N6-methyladenosine (m6A), transcript stability, and protein stability were evaluated. A FOXD1-knockdown xenograft model tested the in vivo role of FOXD1; METTL3 was not manipulated in animals. FOXD1 expression was higher in LUSC tissues and cells than in corresponding controls. FOXD1 knockdown reduced viability and migration, increased apoptosis, and suppressed xenograft growth. METTL3 expression correlated with FOXD1 in paired LUSC tissues. In cultured cells, METTL3 knockdown lowered global m6A and FOXD1 abundance, whereas FOXD1 re-expression partially rescued the associated phenotypes. Actinomycin D, cycloheximide, and MG132 assays were consistent with METTL3-associated changes in FOXD1 RNA and protein stability. These data support a functional association between METTL3 and FOXD1 in LUSC cells. In vivo, FOXD1 knockdown suppressed xenograft growth and reduced Ki-67 staining, establishing FOXD1 as a promoter of xenograft growth. Direct METTL3-FOXD1 binding, site-specific m6A modification, reader dependence, and in vivo validation of the complete METTL3-FOXD1 pathway remain to be established.