7 research outputs found
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Complete intracranial response to talimogene laherparepvec (T-Vec), pembrolizumab and whole brain radiotherapy in a patient with melanoma brain metastases refractory to dual checkpoint-inhibition
Background
Immunotherapy, in particular checkpoint blockade, has changed the clinical landscape of metastatic melanoma. Nonetheless, the majority of patients will either be primary refractory or progress over follow up. Management of patients progressing on first-line immunotherapy remains challenging. Expanded treatment options with combination immunotherapy has demonstrated efficacy in patients previously unresponsive to single agent or alternative combination therapy.
Case presentation
We describe the case of a patient with diffusely metastatic melanoma, including brain metastases, who, despite being treated with stereotactic radiosurgery and dual CTLA-4/PD-1 blockade (ipilimumab/nivolumab), developed systemic disease progression and innumerable brain metastases. This patient achieved a complete CNS response and partial systemic response with standard whole brain radiation therapy (WBRT) combined with Talimogene laherparepvec (T-Vec) and pembrolizumab.
Conclusion
Patients who do not respond to one immunotherapy combination may respond during treatment with an alternate combination, even in the presence of multiple brain metastases. Biomarkers are needed to assist clinicians in evidence based clinical decision making after progression on first line immunotherapy to determine whether response can be achieved with second line immunotherapy
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Racial/ethnic and educational inequities in restrictive abortion policy variation and adverse birth outcomes in the United States
Background
To examine racial/ethnic and educational inequities in the relationship between state-level restrictive abortion policies and adverse birth outcomes from 2005 to 2015 in the United States.
Methods
Using a state-level abortion restrictiveness index comprised of 18 restrictive abortion policies, we conducted a retrospective longitudinal analysis examining whether race/ethnicity and education level moderated the relationship between the restrictiveness index and individual-level probabilities of preterm birth (PTB) and low birthweight (LBW). Data were obtained from the 2005–2015 National Center for Health Statistics Period Linked Live Birth-Infant Death Files and analyzed with linear probability models adjusted for individual- and state-level characteristics and state and year fixed-effects.
Results
Among 2,250,000 live births, 269,253 (12.0%) were PTBs and 182,960 (8.1%) were LBW. On average, states had approximately seven restrictive abortion policies enacted from 2005 to 2015. Black individuals experienced increased probability of PTB with additional exposure to restrictive abortion policies compared to non-Black individuals. Similarly, those with less than a college degree experienced increased probability of LBW with additional exposure to restrictive abortion policies compared to college graduates. For all analyses, inequities worsened as state environments grew increasingly restrictive.
Conclusion
Findings demonstrate that Black individuals at all educational levels and those with fewer years of education disproportionately experienced adverse birth outcomes associated with restrictive abortion policies. Restrictive abortion policies may compound existing racial/ethnic, socioeconomic, and intersecting racial/ethnic and socioeconomic perinatal and infant health inequities
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Quantitative Analysis of Immune Infiltrates in Primary Melanoma.
Novel methods to analyze the tumor microenvironment (TME) are urgently needed to stratify melanoma patients for adjuvant immunotherapy. Tumor-infiltrating lymphocyte (TIL) analysis, by conventional pathologic methods, is predictive but is insufficiently precise for clinical application. Quantitative multiplex immunofluorescence (qmIF) allows for evaluation of the TME using multiparameter phenotyping, tissue segmentation, and quantitative spatial analysis (qSA). Given that CD3+CD8+ cytotoxic lymphocytes (CTLs) promote antitumor immunity, whereas CD68+ macrophages impair immunity, we hypothesized that quantification and spatial analysis of macrophages and CTLs would correlate with clinical outcome. We applied qmIF to 104 primary stage II to III melanoma tumors and found that CTLs were closer in proximity to activated (CD68+HLA-DR+) macrophages than nonactivated (CD68+HLA-DR-) macrophages (P < 0.0001). CTLs were further in proximity from proliferating SOX10+ melanoma cells than nonproliferating ones (P < 0.0001). In 64 patients with known cause of death, we found that high CTL and low macrophage density in the stroma (P = 0.0038 and P = 0.0006, respectively) correlated with disease-specific survival (DSS), but the correlation was less significant for CTL and macrophage density in the tumor (P = 0.0147 and P = 0.0426, respectively). DSS correlation was strongest for stromal HLA-DR+ CTLs (P = 0.0005). CTL distance to HLA-DR- macrophages associated with poor DSS (P = 0.0016), whereas distance to Ki67- tumor cells associated inversely with DSS (P = 0.0006). A low CTL/macrophage ratio in the stroma conferred a hazard ratio (HR) of 3.719 for death from melanoma and correlated with shortened overall survival (OS) in the complete 104 patient cohort by Cox analysis (P = 0.009) and merits further development as a biomarker for clinical application
Comparative in situ analysis reveals the dynamic nature of sclerenchyma cell walls of the fern Asplenium rutifolium
Background and Aims: A key structural adaptation of vascular plants was the evolution of specialized vascular and mechanical tissues, innovations likely to have generated novel cell wall architectures. While collenchyma is a strengthening tissue typically found in growing organs of angiosperms, a similar tissue occurs in the petiole of the fern Asplenium rutifolium. Methods: The in situ cell wall (ultra)structure and composition of this tissue was investigated and characterized mechanically as well as structurally through nano-indentation and wide-angle X-ray diffraction, respectively. Key Results: Structurally the mechanical tissue resembles sclerenchyma, while its biomechanical properties and molecular composition both share more characteristics with angiosperm collenchyma. Cell wall thickening only occurs late during cell expansion or after cell expansion has ceased. Conclusions: If the term collenchyma is reserved for walls that thicken during expansive growth, the mechanical tissue in A. rutifolium represents sclerenchyma that mimics the properties of collenchyma and has the ability to modify its mechanical properties through sclerification. These results support the view that collenchyma does not occur in ferns and most probably evolved in angiosperms