Citations

Primary central nervous system choriocarcinoma is a non-germinomatous germ cell tumor with a highly malignant character, comprising up to 5% of all central nervous system germ cell tumors. Locations affected can include suprasellar or pineal locations most commonly, with others including the basal ganglia and lateral ventricles. Guidelines do not specify an optimal radiation regimen but recommend proceeding with maximally safe resection if feasible and then chemotherapy before radiotherapy. Radiation is often comprised of craniospinal irradiation with subsequent tumor bed boost. We present a case of an adult male with a primary central nervous system choriocarcinoma who underwent reversed sequence radiation therapy with photon tumor bed boost before proton craniospinal irradiation due to recurrent intracranial hemorrhages with long-term control of cancer and no subsequent hemorrhages. This case highlights the excellent outcome and feasibility of reversed sequence radiotherapy on choriocarcinoma in hemorrhage and tumor control.

Abstract The lung, one the largest branching organs in our body and vital for survival at first breath, is commonly known as the gas-exchange organ. Recent novel findings on lung sensing cells, molecules, and lung-brain crosstalk in the emerging discipline of interoception have highlighted the consideration of the lung as a sensory organ. Acknowledging the central importance of lung sensing to human health and disease, NHLBI convened a workshop to synthesize the past, current, and future of lung sensing research, with in-person presentations by ∼20 interdisciplinary experts and a large virtual audience. Here, we highlight the key topics discussed and summarize a blueprint for the future in this important field.

Abstract High-risk breast lesions (HRLs) encompass a heterogeneous group of pathologies that coexist with an adjacent or synchronous malignancy, confer an increased risk of future breast cancer, or warrant surgical consideration because of upgrade potential or local behavior. Despite their clinical importance, management of HRLs remains variable. The American Society of Breast Surgeons (ASBrS) and the Society of Breast Imaging are collaborating to establish unified, evidence-based guidelines for managing these lesions. While these recommendations are currently in development, this review summarizes the existing literature and current guidance, including ASBrS recommendations, to provide context for multidisciplinary management. The article reviews the histopathologic features, imaging appearance, and management strategies for HRLs, including atypical ductal hyperplasia (ADH), atypical lobular hyperplasia (ALH), lobular carcinoma in situ (LCIS), flat epithelial atypia (FEA), papillomas with and without atypia, radial scar/complex sclerosing lesion (RS/CSL), mucocele-like lesion (MLL), desmoid tumor, and pseudoangiomatous stromal hyperplasia (PASH). Recent literature supports nonoperative management for specific radiologic-pathologic concordant lesions, particularly limited ADH, pure FEA, and pure RS, highlighting the important role of multidisciplinary discussion for personalized care. Lesions such as LCIS subtypes, papilloma with atypia, and MLL with atypia continue to warrant excision due to higher reported upgrade rates to malignancy. Beyond short-term management, HRLs such as ADH, ALH, and LCIS serve as biomarkers of long-term breast cancer risk, informing recommendations for surveillance, risk assessment, and chemoprevention counseling. Achieving a consensus among radiology, pathology, and surgical disciplines is essential to ensure oncologic safety while minimizing overtreatment in the era of precision breast care.

Abstract Exposure to asbestos is the primary cause of mesothelioma, however the processes underpinning its initiation and evolutionary trajectory remain elusive. To address this knowledge gap, we conducted whole exome sequencing and phylogenetic analysis of 277 mesotheliomas. Using multidimensional Dirichlet process clustering we inferred phylogenies, uncovering mutation order dominated by early 13q,1p, 8p, 6q and 22q somatic copy number alterations. Mesotheliomas exhibit a spectrum of genomic intra-tumor heterogeneity spanning linear (L) to highly branched (B) tree topologies, quantifiable by the Weighted Shannon Entropy (WSE). Somatic copy number alterations emerge earlier than single nucleotide variants (SNVs), and at a much faster relative rate in L-mesotheliomas. BAP1 is the only positively selected driver in L-mesotheliomas, whereas, B-mesotheliomas harbor multiple positively selected drivers and an aggressive phenotype, including a bias of loss of RPL5, and MTAP deletion linked to breakpoint enriched with long interspersed nuclear elements. L-trees had lower WSE, but greater T-cell inflammation and tertiary lymphoid structures, despite having a lower neoantigen burden. WSE is higher in larger volume, immunologically cold mesotheliomas, and is associated with shorter survival. In summary, progressive genomic heterogeneity is a defining feature of more aggressive mesothelioma yet illuminates opportunities for precision therapeutic intervention.

Acute lymphoblastic leukemia (ALL) is the most common pediatric cancer, arising from both B and T cell lineages (B-ALL and T-ALL). Current therapy exploits ALL cells’ low expression of asparagine synthetase (ASNS) by using L-asparaginase, a bacterial enzyme that depletes circulating asparagine. However, resistance can emerge through induction of ASNS, mediated in part by the amino acid stress sensor GCN2. In this study, we addressed the efficacy of L-asparaginase in combination with genetic or pharmacological inhibition of GCN2 and the ASNS inhibitor ASX-173. Using a Kras G12D -driven mouse model of T-ALL, we found that GCN2 is dispensable for leukemogenesis. However, genetic inactivation or pharmacologic inhibition of GCN2 sensitized ALL cells to asparagine depletion, correlating with impaired ASNS induction. While GCN2 targeting enhanced sensitivity to asparagine depletion, a subset of Gcn2 –/– T-ALL cells retained high ASNS expression and remained resistant to L-asparaginase. Likewise, some human T-ALL cells with elevated ASNS levels were refractory to GCN2 inhibition even under asparagine-depleted conditions. When combined with L-asparaginase, ASX-173 effectively eliminated ASNS hi leukemic cells in vitro and in vivo. These findings suggest that direct targeting of ASNS provides therapeutic benefit in leukemias that express high levels of ASNS and are resistant to GCN2 inhibition under asparagine-depleted conditions.