Clear Cell Stromal Tumor of the Lung: Clinicopathologic, Immunohistochemical, and Molecular Characterization of Eight Cases.

Clear cell stromal tumor is a recently described mesenchymal neoplasm of the lung, characterized by spindle cells with variably clear-to-pale eosinophilic cytoplasm and prominent vascularity, as well as a recurrent YAP1::TFE3 gene fusion in most cases. Diagnosis can be challenging given its rarity and the lack of supportive immunohistochemical (IHC) markers aside from TFE3. To date, less than 20 cases have been reported, and data on clinical behavior are also limited.

Preclinical evaluation of targeted therapies for central nervous system metastases.

The central nervous system (CNS) represents a site of sanctuary for many metastatic tumors when systemic therapies that control the primary tumor cannot effectively penetrate intracranial lesions. Non-small cell lung cancers (NSCLCs) are the most likely of all neoplasms to metastasize to the brain, with up to 60% of patients developing CNS metastases during the disease process. Targeted therapies such as tyrosine kinase inhibitors (TKIs) have helped reduce lung cancer mortality but vary considerably in their capacity to control CNS metastases.

Epithelioid Fibrous Histiocytoma Is on a Continuum With Superficial ALK-rearranged Myxoid Spindle Cell Neoplasm: A Clinicopathologic Series of 35 Cases Including Alternate RET and NTRK3 Fusions.

Anaplastic lymphoma kinase (ALK) rearrangements drive most examples of epithelioid fibrous histiocytoma (EFH) and have been reported in an emerging family of receptor tyrosine kinase (RTK) fusion-positive mesenchymal neoplasms, including superficial ones described under the rubric of "superficial ALK-rearranged myxoid spindle cell neoplasm" (SAMS). Here, we describe 35 superficial tumors with SAMS morphology, which occurred in 18 females (51%) and 17 males at a median age at presentation of 39 years (range: 6 to 82 y). Most tumors occurred on the lower extremity (25 tumors; 71%), followed by upper extremity (5; 14%), trunk (3; 9%), and face (2; 6%).

Combination of MDM2 and Targeted Kinase Inhibitors Results in Prolonged Tumor Control in Lung Adenocarcinomas With Oncogenic Tyrosine Kinase Drivers and Amplification.

Purpose: MDM2, a negative regulator of the TP53 tumor suppressor, is oncogenic when amplified. amplification (MDM2amp) is mutually exclusive with mutation and is seen in 6% of patients with lung adenocarcinoma (LUAD), with significant enrichment in subsets with receptor tyrosine kinase (RTK) driver alterations. Recent studies have shown synergistic activity of MDM2 and MEK inhibition in patient-derived LUAD models with MDM2amp and RTK driver alterations.

HER2 Antibody-Drug Conjugates Are Active against Desmoplastic Small Round Cell Tumor.

Purpose: Desmoplastic small round cell tumor (DSRCT) is a rare but highly aggressive soft tissue sarcoma that arises in the abdominopelvic cavity of young males. Since the discovery of EWSR1::WT1 fusion as the driver of DSRCT, no actionable genomic alterations have been identified, limiting disease management to a combination of surgery, chemotherapy, and radiation, with very poor outcomes. Herein, we evaluated ERBB2/HER2 expression in DSRCT as a therapeutic target.

A visual-language foundation model for computational pathology.

The accelerated adoption of digital pathology and advances in deep learning have enabled the development of robust models for various pathology tasks across a diverse array of diseases and patient cohorts. However, model training is often difficult due to label scarcity in the medical domain, and a model's usage is limited by the specific task and disease for which it is trained. Additionally, most models in histopathology leverage only image data, a stark contrast to how humans teach each other and reason about histopathologic entities.

Prognostic and predictive biomarkers in non-small cell lung carcinoma.

Lung cancer is the most common cause of cancer-related deaths globally, with the highest mortality rates among both men and women. Most lung cancers are diagnosed at late stages, necessitating systemic therapy. Modern clinical management of lung cancer relies heavily upon application of biomarkers, which guide the selection of systemic treatment.

Prevalence and Therapeutic Targeting of High-Level ERBB2 Amplification in NSCLC.

Introduction: ERBB2 amplification in lung cancer remains poorly characterized. HER2 (encoded by ERBB2) is a transmembrane tyrosine kinase capable of ligand-independent dimerization and signaling when overexpressed, and a common cause of HER2 overexpression is ERBB2 amplification. Here, we evaluated the clinicopathologic and genomic characteristics of ERBB2-amplified NSCLC and explored a HER2 antibody-drug conjugate (ADC) therapeutic strategy.

Vepafestinib is a pharmacologically advanced RET-selective inhibitor with high CNS penetration and inhibitory activity against RET solvent front mutations.

RET receptor tyrosine kinase is activated in various cancers (lung, thyroid, colon and pancreatic, among others) through oncogenic fusions or gain-of-function single-nucleotide variants. Small-molecule RET kinase inhibitors became standard-of-care therapy for advanced malignancies driven by RET. The therapeutic benefit of RET inhibitors is limited, however, by acquired mutations in the drug target as well as brain metastasis, presumably due to inadequate brain penetration.

Infantile Sinonasal Myxoma Is Clinically and Genetically Distinct From Other Myxomas of the Craniofacial Bones and From Desmoid Fibromatosis.

Sinonasal myxomas are rare benign tumors of the maxillary bone and sinus. There is published evidence that sinonasal myxomas occurring in children up to 3 years of age ("infantile sinonasal myxomas") are clinically distinctive and harbor Wnt signaling pathway alterations. Here, we characterized 16 infantile sinonasal myxomas and compared them to 19 maxillary myxomas and 11 mandibular myxomas in older patients.

Combination Therapy With MDM2 and MEK Inhibitors Is Effective in Patient-Derived Models of Lung Adenocarcinoma With Concurrent Oncogenic Drivers and MDM2 Amplification.

Introduction: Although targeted therapies have revolutionized the therapeutic landscape of lung adenocarcinomas (LUADs), disease progression on single-agent targeted therapy against known oncogenic drivers is common, and therapeutic options after disease progression are limited. In patients with MDM2 amplification (MDM2amp) and a concurrent oncogenic driver alteration, we hypothesized that targeting of the tumor-suppressor pathway (by means of restoration of p53 using MDM2 inhibition) and simultaneous targeting of co-occurring MAPK oncogenic pathway might represent a more durably effective therapeutic strategy.

Methods: We evaluated genomic next-generation sequencing data using the Memorial Sloan Kettering Cancer Center-Integrated Mutation Profiling of Actionable Cancer Targets platform to nominate potential targets for combination therapy in LUAD.

Primary Clear Cell Sarcoma of Bone: Clinicopathologic Study of a Rare Presentation.

Clear cell sarcoma (CCS) is an uncommon malignant mesenchymal neoplasm of young adults with a predilection for tendons and aponeuroses of distal extremities, a distinctive nested growth pattern, melanocytic differentiation, and usually an EWSR1::ATF1 fusion. Distinction from melanoma can be challenging but is critical for clinical management. Rare cases of primary bone CCS have been reported.

Zenocutuzumab, a HER2xHER3 Bispecific Antibody, Is Effective Therapy for Tumors Driven by NRG1 Gene Rearrangements.

Unlabelled: NRG1 rearrangements are recurrent oncogenic drivers in solid tumors. NRG1 binds to HER3, leading to heterodimerization with other HER/ERBB kinases, increased downstream signaling, and tumorigenesis. Targeting ERBBs, therefore, represents a therapeutic strategy for these cancers.

CIC-Mediated Modulation of MAPK Signaling Opposes Receptor Tyrosine Kinase Inhibitor Response in Kinase-Addicted Sarcoma.

Unlabelled: Kinase fusions have been identified in a growing subset of sarcomas, but a lack of preclinical models has impeded their functional analysis as therapeutic targets in the sarcoma setting. In this study, we generated models of sarcomas bearing kinase fusions and assessed their response to molecularly targeted therapy. Immortalized, untransformed human mesenchymal stem cells (HMSC), a putative cell of origin of sarcomas, were modified using CRISPR-Cas9 to harbor a RET chromosomal translocation (HMSC-RET).

Functional impact and targetability of , , and mutations in a spindle cell rhabdomyosarcoma with MYOD1 L122R mutation.

Spindle cell/sclerosing rhabdomyosarcoma (ssRMS) is a rare subtype of rhabdomyosarcoma, commonly harboring a gain-of-function L122R mutation in the muscle-specific master transcription factor MYOD1. -mutated ssRMS is almost invariably fatal, and development of novel therapeutic approaches based on the biology of the disease is urgently needed. MYOD1 L122R affects the DNA-binding domain and is believed to confer MYC-like properties to MYOD1, driving oncogenesis.

Novel patient-derived models of desmoplastic small round cell tumor confirm a targetable dependency on ERBB signaling.

Desmoplastic small round cell tumor (DSRCT) is characterized by the t(11;22)(p13;q12) translocation, which fuses the transcriptional regulatory domain of EWSR1 with the DNA-binding domain of WT1, resulting in the oncogenic EWSR1-WT1 fusion protein. The paucity of DSRCT disease models has hampered preclinical therapeutic studies on this aggressive cancer. Here, we developed preclinical disease models and mined DSRCT expression profiles to identify genetic vulnerabilities that could be leveraged for new therapies.

Determination of biological behavior of solitary fibrous tumors: correlation of expression of Ki-67, TPX2 and TERT mRNA subunit level and NAB2-STAT6 fusion compared to morphological aspects of SFTs.

We present a retrospective study of 65 cases of solitary fibrous tumors (SFTs) of several localizations including the most common site of origin in the pleura and lungs. SFTs are mesenchymal fibroblastic tumors with an unpredictable biological potential ranging from benign to malignant. We investigated morphologic characteristics, proliferation activity evaluated by immunohistochemical expression of Ki-67 antigen, and the existence of NAB2-STAT6 fusion gene together with Ki-67, TPX2, and TERT mRNA expression levels.

Novel Preclinical Patient-Derived Lung Cancer Models Reveal Inhibition of HER3 and MTOR Signaling as Therapeutic Strategies for NRG1 Fusion-Positive Cancers.

Introduction: NRG1 rearrangements produce chimeric ligands that subvert the ERBB pathway to drive tumorigenesis. A better understanding of the signaling networks that mediate transformation by NRG1 fusions is needed to inform effective therapeutic strategies. Unfortunately, this has been hampered by a paucity of patient-derived disease models that faithfully recapitulate this molecularly defined cancer subset.