Retinoblastoma (Rb) is the most common primary intraocular tumor in children. Local treatment of the intraocular disease is usually effective if diagnosed early; however advanced Rb can metastasize through routes that involve invasion of the choroid, sclera and optic nerve or more broadly via the ocular vasculature. Metastatic Rb patients have very high mortality rates. While current therapy for Rb is directed toward blocking tumor cell division and tumor growth, there are no specific treatments targeted to block Rb metastasis. Two such targets are matrix metalloproteinases-2 and -9 (MMP-2, −9), which degrade extracellular matrix as a prerequisite for cellular invasion and have been shown to be involved in other types of cancer metastasis. Cancer Clinical Trials with an anti-MMP-9 therapeutic antibody were recently initiated, prompting us to investigate the role of MMP-2, −9 in Rb metastasis. We compare MMP-2, −9 activity in two well-studied Rb cell lines: Y79, which exhibits high metastatic potential and Weri-1, which has low metastatic potential. The effects of inhibitors of MMP-2 (ARP100) and MMP-9 (AG-L-66085) on migration, angiogenesis, and production of immunomodulatory cytokines were determined in both cell lines using qPCR, and ELISA. Cellular migration and potential for invasion were evaluated by the classic wound-healing assay and a Boyden Chamber assay. Our results showed that both inhibitors had differential effects on the two cell lines, significantly reducing migration in the metastatic Y79 cell line and greatly affecting the viability of Weri-1 cells. The MMP-9 inhibitor (MMP9I) AG-L-66085, diminished the Y79 angiogenic response. In Weri-1 cells, VEGF was significantly reduced and cell viability was decreased by both MMP-2 and MMP-9 inhibitors. Furthermore, inhibition of MMP-2 significantly reduced secretion of TGF-β1 in both Rb models. Collectively, our data indicates MMP-2 and MMP-9 drive metastatic pathways, including migration, viability and secretion of angiogenic factors in Rb cells. These two subtypes of matrix metalloproteinases represent new potential candidates for targeted anti-metastatic therapy for Rb.

CDK4/6 inhibition becomes effective in preclinical models of melanoma when combined with MDM2 antagonism.

Objectives: Inhibition of the PI3K/mTOR pathway suppresses breast cancer (BC) growth, enhances anti-tumor immune responses, and works synergistically with immune checkpoint inhibitors (ICI). The objective here was to identify a subclass of PI3K inhibitors that, when combined with paclitaxel, is effective in enhancing response to ICI. Methods: C57BL/6 mice were orthotopically implanted with syngeneic luminal/triple-negative-like PyMT cells exhibiting high endogenous PI3K activity. Tumor growth in response to treatment with anti-PD-1 + anti-CTLA-4 (ICI), paclitaxel (PTX), and either the PI3Kα-specific inhibitor alpelisib, the pan-PI3K inhibitor copanlisib, or the broad spectrum PI3K/mTOR inhibitor gedatolisib was evaluated in reference to monotherapy or combinations of these therapies. Effects of these therapeutics on intratumoral immune populations were determined by multicolor FACS. Results: Treatment with alpelisib + PTX inhibited PyMT tumor growth and increased tumor-infiltrating granulocytes but did not significantly affect the number of tumor-infiltrating CD8⁺ T cells and did not synergize with ICI. Copanlisib + PTX + ICI significantly inhibited PyMT growth and increased activation of intratumoral CD8⁺ T cells as compared to ICI alone, yet did not inhibit tumor growth more than ICI alone. In contrast, gedatolisib + ICI resulted in significantly greater inhibition of tumor growth compared to ICI alone and induced durable dendritic-cell, CD8⁺ T-cell, and NK-cell responses. Adding PTX to this regimen yielded complete regression in 60% of tumors. Conclusion: PI3K/mTOR inhibition plus PTX heightens response to ICI and may provide a viable therapeutic approach for treatment of metastatic BC.

OBJECT: Various bibliometric indices based on the citations accumulated by scholarly articles, including the h-index, g-index, e-index, and Google’s i10-index, may be used to evaluate academic productivity in neurological surgery. The present article provides a comprehensive assessment of recent academic publishing output from 103 US neurosurgical residency programs and investigates intradepartmental publishing equality among faculty members. METHODS: Each institution was considered a single entity, with the 5-year academic yield of every neurosurgical faculty member compiled to compute the following indices: ih(5), cumulative h, ig(5), ie(5), and i10(5) (based on publications and citations from 2009 through 2013). Intradepartmental comparison of productivity among faculty members yielded Gini coefficients for publications and citations. National and regional comparisons, institutional rankings, and intradepartmental publishing equality measures are presented. RESULTS: The median numbers of departmental faculty, total publications and citations, ih(5), summed h, ig(5), ie(5), i10(5), and Gini coefficients for publications and citations were 13, 82, 716, 12, 144, 23, 16, 17, 0.57, and 0.71, respectively. The top 5 most academically productive neurosurgical programs based on ih(5)-index were University of California, San Francisco, University of California, Los Angeles, University of Pittsburgh, Brigham & Women’s Hospital, and Johns Hopkins University. The Western US region was most academically productive and displayed greater intradepartmental publishing equality (median ih[5]-index = 18, median Gini_pub = 0.56). In all regions, large departments with relative intradepartmental publishing equality tend to be the most academically productive. Multivariable logistic regression analysis identified the ih(5)-index as the only independent predictor of intradepartmental publishing equality (Gini_pub ≤ 0.5 [OR 1.20, 95% CI 1.20–1.40, p = 0.03]). CONCLUSIONS: The ih(5)-index is a novel, simple, and intuitive metric capable of accurately comparing the recent scholarly efforts of neurosurgical programs and accurately predicting intradepartmental publication equality. The ih(5)-index is relatively insensitive to factors such as isolated highly productive and/or no longer academically active senior faculty, which tend to distort other bibliometric indices and mask the accurate identification of currently productive academic environments. Institutional ranking by ih(5)-index may provide information of use to faculty and trainee applicants, research funding institutions, program leaders, and other stakeholders.

Current methodologies for developing PDX in humanized mice in preclinical trials with immune-based therapies are limited by GVHD. Here, we compared two approaches for establishing PDX tumors in humanized mice: (1) PDX are first established in immune-deficient mice; or (2) PDX are initially established in humanized mice; then established PDX are transplanted to a larger cohort of humanized mice for preclinical trials. With the first approach, there was rapid wasting of PDX-bearing humanized mice with high levels of activated T cells in the circulation and organs, indicating immune-mediated toxicity. In contrast, with the second approach, toxicity was less of an issue and long-term human melanoma tumor growth and maintenance of human chimerism was achieved. Preclinical trials from the second approach revealed that rigosertib, but not anti-PD-1, increased CD8/CD4 T cell ratios in spleen and blood and inhibited PDX tumor growth. Resistance to anti-PD-1 was associated with PDX tumors established from tumors with limited CD8+ T cell content. Our findings suggest that it is essential to carefully manage immune editing by first establishing PDX tumors in humanized mice before expanding PDX tumors into a larger cohort of humanized mice to evaluate therapy response.