Dengue fever presenting with acute pancreatitis: A case report.

Acute pancreatitis is an acute inflammation of the pancreas, with subsequent involvement of surrounding tissues and organ systems. Viral etiology of acute pancreatitis is uncommon; however, multiple viruses have been implicated. Dengue virus has also been found responsible for acute pancreatitis, with possible etiologies linked to direct viral invasion, autoimmune mechanism, or as a complication of dengue shock syndrome. We present a case of a 24-year-old female who presented with epigastric pain and vomiting in the background of a febrile illness and was later diagnosed with mild acute pancreatitis complicating dengue fever.

CDK4/6 Inhibition Sensitizes Intracranial Tumors to PD-1 Blockade in Preclinical Models of Brain Metastasis.

PURPOSE: Brain metastases are associated with high morbidity and are often resistant to immune checkpoint inhibitors. We evaluated whether CDK4/6 inhibitor (CDKi) abemaciclib can sensitize intracranial tumors to programmed cell death protein 1 (PD-1) inhibition in mouse models of melanoma and breast cancer brain metastasis. EXPERIMENTAL DESIGN: Treatment response was evaluated in vivo using immunocompetent mouse models of brain metastasis bearing concurrent intracranial and extracranial tumors. Treatment effect on intracranial and extracranial tumor-immune microenvironments (TIME) was evaluated using immunofluorescence, multiplex immunoassays, high-parameter flow cytometry, and T-cell receptor profiling. Mice with humanized immune systems were evaluated using flow cytometry to study the effect of CDKi on human T-cell development. RESULTS: We found that combining abemaciclib with PD-1 inhibition reduced tumor burden and improved overall survival in mice. The TIME, which differed on the basis of anatomic location of tumors, was altered with CDKi and PD-1 inhibition in an organ-specific manner. Combination abemaciclib and anti-PD-1 treatment increased recruitment and expansion of CD8+ effector T-cell subsets, depleted CD4+ regulatory T (Treg) cells, and reduced levels of immunosuppressive cytokines in intracranial tumors. In immunodeficient mice engrafted with human immune systems, abemaciclib treatment supported development and maintenance of CD8+ T cells and depleted Treg cells. CONCLUSIONS: Our results highlight the distinct properties of intracranial and extracranial tumors and support clinical investigation of combination CDK4/6 and PD-1 inhibition in patients with brain metastases. See related commentary by Margolin, p. 257.

Novel Systemic Approaches for the Management of Meningiomas: Immunotherapy and Targeted Therapies.

Meningiomas, the most prevalent primary intracranial tumor, arise from the arachnoid cap cells in the meninges, the membranes that surround the brain and the spinal cord. The field has long sought effective predictors of meningioma recurrence and malignant transformation, as well as therapeutic targets to guide intensified treatment such as early radiation or systemic therapy. Novel and more targeted approaches are currently being tested in numerous clinical trials for patients who have progressed after surgery and/or radiation. In this review, the authors discuss relevant molecular drivers that have therapeutic implications and examine recent clinical trial data evaluating targeted therapies and immunotherapies.

Microenvironmental Landscape of Human Melanoma Brain Metastases in Response to Immune Checkpoint Inhibition.

Melanoma-derived brain metastases (MBM) represent an unmet clinical need because central nervous system progression is frequently an end stage of the disease. Immune checkpoint inhibitors (ICI) provide a clinical opportunity against MBM; however, the MBM tumor microenvironment (TME) has not been fully elucidated in the context of ICI. To dissect unique elements of the MBM TME and correlates of MBM response to ICI, we collected 32 fresh MBM and performed single-cell RNA sequencing of the MBM TME and T-cell receptor clonotyping on T cells from MBM and matched blood and extracranial lesions. We observed myeloid phenotypic heterogeneity in the MBM TME, most notably multiple distinct neutrophil states, including an IL8-expressing population that correlated with malignant cell epithelial-to-mesenchymal transition. In addition, we observed significant relationships between intracranial T-cell phenotypes and the distribution of T-cell clonotypes intracranially and peripherally. We found that the phenotype, clonotype, and overall number of MBM-infiltrating T cells were associated with response to ICI, suggesting that ICI-responsive MBMs interact with peripheral blood in a manner similar to extracranial lesions. These data identify unique features of the MBM TME that may represent potential targets to improve clinical outcomes for patients with MBM.

Preclinical Solid Tumor Models to Study Novel Therapeutics in Brain Metastases.

Metastases are the most common malignancy of the adult central nervous system and are becoming an increasingly troubling problem in oncology largely due to the lack of successful therapeutic options. The limited selection of treatments is a result of the currently poor understanding of the biological mechanisms of metastatic development, which in turn is difficult to achieve because of limited preclinical models that can accurately represent the clinical progression of metastasis. Described in this article are in vitro and in vivo model systems that are used to enhance the understanding of metastasis and to identify new therapies for the treatment of brain metastasis. © 2021 Wiley Periodicals LLC.