Intra-arterial chemotherapy for retinoblastoma.

Intra-arterial chemotherapy (IAC) for retinoblastoma is a minimally invasive and chemotherapeutic approach resulting in eye salvage and vision restoration or preservation. Moreover, IAC has proven to effectively treat advanced retinoblastoma while not compromising patient survival. Our institutional experience with IAC for retinoblastoma has included over 500 patients and over 2400 intra-arterial infusions. Each infusion is completed with the use of a micropuncture for arterial access and microcatheter for infusion, eliminating the need for guide catheters and related complications (video 1). This treatment modality has resulted in >95% ocular survival and reduces enucleation to <5% for this population. In addition to local therapy, including cryotherapy, intravitreal chemotherapy, or laser treatments, by the ophthalmologist, IAC has become an important component of comprehensive multidisciplinary and multimodal therapy for this disease. For what used to require a possibly vision-sacrificing procedure, retinoblastoma treated with IAC minimizes the need for enucleation while maximizing both patient and ocular survival.DC1SP110.1136/neurintsurg-2022-018957.supp1Supplementary data neurintsurg;15/3/303/V1F1V1Video 1 .

The Benedict Arnold of the Central Nervous System Tumor Microenvironment? The Role of Microglia/Macrophages in Glioma.

The glioma microenvironment is heavily infiltrated by non-neoplastic myeloid cells, including bone marrow-derived macrophages and central nervous system-resident microglia. As opposed to executing the antitumor functions of immune surveillance, antigen presentation, and phagocytosis, these tumor-associated myeloid cells are co-opted to promote an immunosuppressive milieu and support tumor invasion and angiogenesis. This review explores evolving evidence and the research paradigms used to determine the interplay of tumor genetics, immune cell composition, and immune function in gliomas. Understanding these cells and how they are reprogrammed will be instrumental in finding new and effective treatments for these lethal tumors.

Perspectives on Microglia-Based Immune Therapies Against Glioblastoma.

Glioblastoma (GBM) is the most aggressive primary tumor of the central nervous system. Despite aggressive multimodal therapy, it has a dismal prognosis. Over the last 20 years, the approach to GBM research and therapy has involved viewing the pathologic condition as a complex organ system with multiple nonneoplastic cells supporting tumor growth directly or through enhancement of the tumor microenvironment. Understanding the immune system effects on glioma growth, invasion, tumor survival, immune suppression, and angiogenesis is critical in immunotherapy target development. In this review, we discuss how the immune system generates a favorable microenvironment, and clinical trials currently underway targeting immune system pathways. Tumor-associated macrophages, particularly the M2 phenotype, are important residents of the tumor microenvironment, promoting tumor growth through paracrine and direct signaling. Clinical trials targeting PD-L-1, CTLA-4, and colony stimulating factor-1 receptor in GBM are currently under investigation. Additionally, several phase I/II clinical trials are underway using vaccines, oncolytic viruses, antibodies, and chimeric antigen receptor T cells targeting glioma cells. Co-opting the immune system as a therapeutic partner against GBM is in early stages of investigation, and the potential use of such approaches as treatment adjuncts is indispensable for combating this highly heterogeneous disease.

Neurosurgery in COVID-19 Ground Zero: The Weill Cornell Medicine Experience.

The mobilization of subspecialty departments in reaction to the unique demands of the onset of the coronavirus disease 2019 (COVID-19) pandemic in New York City was swift and left little time for reflection and commemoration. The early days of the pandemic brought unprecedented stressors on the medical system that necessitated a restructuring of hospitals, reallocation of health care workers, and a shift in care and education paradigms to meet patient care demands and public health needs. As the number of cases, intensive care unit patients, and deaths skyrocketed in New York City, many struggled with a somewhat paradoxical difficulty in perceiving the human value of what these numbers mean. Easily lost in the statistics are the stories and experiences of the physicians and trainees who were counted on to halt their own clinical practices and adapt their skillsets to tackle the pandemic. In this article, we present 10 brief narratives from the student members of the Neurosurgery Publication Group at Weill Cornell Medical College and members of the Weill Cornell Medicine Neurological Surgery Residency Program and Department of Neurological Surgery faculty. Reflecting on these individual experiences gives us an opportunity to simultaneously contribute to a history of New York City's reaction to COVID-19 and commemorate the individuals who were impacted by or succumbed to this disease.

Updates on Surgical Management and Advances for Brain Tumors.

PURPOSE OF REVIEW: This review summarizes the modern approach to surgical management of malignant brain tumors, highlighting new technology and multimodal treatment paradigms. RECENT FINDINGS: Outcomes in patients with glioblastoma are strongly correlated with extent of initial surgical resection. Intraoperative MRI, 5-ALA, and neuronavigation are surgical tools that can help achieve a maximal safe resection. Stereotactic radiosurgery and brachytherapy can be used to enhance local control for brain metastases in conjunction with surgery, while combinatorial approaches are increasingly employed in patients with multiple metastases. Advances in surgical techniques allow for minimally invasive approaches, including the use of tubular retractors, endoscopes, and laser interstitial thermal therapy. Primary and metastatic brain tumors require a multimodal, multidisciplinary approach to treatment. Surgical resection can be paired with radiation for metastases to maximize tumor control, expanding systemic options. Technological innovations have improved the safety of surgical resection, while expanding the surgical options and indications for treatment.

Building Bridges to Address Health Disparities in Puerto Rico: the "Salud para Piñones" Project.

Over the past several decades, Puerto Ricans have faced increased health threats from chronic diseases, particularly diabetes and hypertension. The patient-provider relationship is the main platform for individual disease management, whereas the community, as an agent of change for the community's health status, has been limited in its support of individual health. Likewise, traditional research approaches within communities have placed academic researchers at the center of the process, considering their knowledge was of greater value than that of the community. In this paradigm, the academic researcher frequently owns and controls the research process. The primary aim is contributing to the scientific knowledge, but not necessarily to improve the community's health status or empower communities for social change. In contrast, the community-based participatory research (CBPR) model brings community members and leaders together with researchers in a process that supports mutual learning and empowers the community to take a leadership role in its own health and well-being. This article describes the development of the community-campus partnership between the University of Puerto Rico School of Medicine and Piñones, a semi-rural community, and the resulting CBPR project: "Salud para Piñones". This project represents a collaborative effort to understand and address the community's health needs and health disparities based on the community's participation as keystone of the process. This participatory approach represents a valuable ally in the development of long-term community-academy partnerships, thus providing opportunities to establish relevant and effective ways to translate evidence-based interventions into concrete actions that impact the individual and community's wellbeing.

A Three-Dimensional Organoid Culture System Derived from Human Glioblastomas Recapitulates the Hypoxic Gradients and Cancer Stem Cell Heterogeneity of Tumors Found In Vivo.

Many cancers feature cellular hierarchies that are driven by tumor-initiating cancer stem cells (CSC) and rely on complex interactions with the tumor microenvironment. Standard cell culture conditions fail to recapitulate the original tumor architecture or microenvironmental gradients and are not designed to retain the cellular heterogeneity of parental tumors. Here, we describe a three-dimensional culture system that supports the long-term growth and expansion of tumor organoids derived directly from glioblastoma specimens, including patient-derived primary cultures, xenografts, genetically engineered glioma models, or patient samples. Organoids derived from multiple regions of patient tumors retain selective tumorigenic potential. Furthermore, organoids could be established directly from brain metastases not typically amenable to in vitro culture. Once formed, tumor organoids grew for months and displayed regional heterogeneity with a rapidly dividing outer region of SOX2(+), OLIG2(+), and TLX(+) cells surrounding a hypoxic core of primarily non-stem senescent cells and diffuse, quiescent CSCs. Notably, non-stem cells within organoids were sensitive to radiotherapy, whereas adjacent CSCs were radioresistant. Orthotopic transplantation of patient-derived organoids resulted in tumors displaying histologic features, including single-cell invasiveness, that were more representative of the parental tumor compared with those formed from patient-derived sphere cultures. In conclusion, we present a new ex vivo model in which phenotypically diverse stem and non-stem glioblastoma cell populations can be simultaneously cultured to explore new facets of microenvironmental influences and CSC biology. Cancer Res; 76(8); 2465-77. ©2016 AACR.

The Lgr5 transgene is expressed specifically in glycinergic amacrine cells in the mouse retina.

Retinal amacrine cells are a diverse set of interneurons within the inner nuclear layer. The canonical Wnt pathway is highly active within mature amacrine cells, but its role remains unclear. Leucine-rich repeat containing G-protein receptor 5 (Lgr5) is a newly identified component of the Wnt receptor complex that potentiates beta-catenin signaling. In multiple epithelial organs Lgr5 marks adult tissue stem cells. We investigated the expression of this gene using Lgr5-eGFP-IRES-CreER transgenic reporter mice. In the eye, Lgr5 was exclusively expressed in glycinergic amacrine cells in adult mice. Amacrine cells are post-mitotic and represent the first neuronal and non-stem cell lineage to express Lgr5. We further interrogated the spatiotemporal labeling of individual amacrine cells with controlled fluorophore expression. This "fluorofilling" technique provides a tool to study amacrine morphology and dissect neural networks.

Ionizing radiation in glioblastoma initiating cells.

Glioblastoma (GBM) is the most common primary malignant brain tumor in adults with a median survival of 12-15 months with treatment consisting of surgical resection followed by ionizing radiation (IR) and chemotherapy. Even aggressive treatment is often palliative due to near universal recurrence. Therapeutic resistance has been linked to a subpopulation of GBM cells with stem cell-like properties termed GBM initiating cells (GICs). Recent efforts have focused on elucidating resistance mechanisms activated in GICs in response to IR. Among these, GICs preferentially activate the DNA damage response (DDR) to result in a faster rate of double-strand break (DSB) repair induced by IR as compared to the bulk tumor cells. IR also activates NOTCH and the hepatic growth factor (HGF) receptor, c-MET, signaling cascades that play critical roles in promoting proliferation, invasion, and resistance to apoptosis. These pathways are preferentially activated in GICs and represent targets for pharmacologic intervention. While IR provides the benefit of improved survival, it paradoxically promotes selection of more malignant cellular phenotypes of GBM. As reviewed here, finding effective combinations of radiation and molecular inhibitors to target GICs and non-GICs is essential for the development of more effective therapies.

Multiplex flow cytometry barcoding and antibody arrays identify surface antigen profiles of primary and metastatic colon cancer cell lines.

Colon cancer is a deadly disease affecting millions of people worldwide. Current treatment challenges include management of disease burden as well as improvements in detection and targeting of tumor cells. To identify disease state-specific surface antigen signatures, we combined fluorescent cell barcoding with high-throughput flow cytometric profiling of primary and metastatic colon cancer lines (SW480, SW620, and HCT116). Our multiplexed technique offers improvements over conventional methods by permitting the simultaneous and rapid screening of cancer cells with reduced effort and cost. The method uses a protein-level analysis with commercially available antibodies on live cells with intact epitopes to detect potential tumor-specific targets that can be further investigated for their clinical utility. Multiplexed antibody arrays can easily be applied to other tumor types or pathologies for discovery-based approaches to target identification.