Aging- and Tumor-Mediated Increase in CD8+CD28- T Cells Might Impose a Strong Barrier to Success of Immunotherapy in Glioblastoma.

Clinical use of various forms of immunotherapeutic drugs in glioblastoma (GBM), has highlighted severe T cell dysfunction such as exhaustion in GBM patients. However, reversing T cell exhaustion using immune checkpoint inhibitors in GBM clinical trials has not shown significant overall survival benefit. Phenotypically, CD8+ T cells with downregulated CD28 coreceptors, low CD27 expression, increased CD57 expression, and telomere shortening are classified as senescent T cells. These senescent T cells are normally seen as part of aging and also in many forms of solid cancers. Absence of CD28 on T cells leads to several functional irregularities including reduced TCR diversity, incomplete activation of T cells, and defects in Ag-induced proliferation. In the context of GBM, presence and/or function of these CD8+CD28- T cells is unknown. In this clinical correlative study, we investigated the effect of aging as well as tumor microenvironment on CD8+ T cell phenotype as an indicator of its function in GBM patients. We systematically analyzed and describe a large population of CD8+CD28- T cells in both the blood and tumor-infiltrating lymphocytes of GBM patients. We found that phenotypically these CD8+CD28- T cells represent a distinct population compared with exhausted T cells. Comparative transcriptomic and pathway analysis of CD8+CD28- T cell populations in GBM patients revealed that tumor microenvironment might be influencing several immune related pathways and thus further exaggerating the age associated immune dysfunction in this patient population.

Resection of a pineal region papillary tumor using robotic exoscope: improved visualization and ergonomics for deep seeded tumor.

Surgery for pineal region tumors is technically challenging due to their deep location and close proximity to critical deep venous structures, midbrain, and thalamus. A high-definition video exoscope was recently proposed as an alternative to the operating microscope. The authors illustrate a case of the midline supracerebellar infratentorial approach to resect a pineal region tumor using the Modus V exoscope and demonstrate the improved visualization of critical structures in this deep location. Additionally, the marked improvement in surgeon comfort suggests that this system may have significant advantages over traditional microscope-based surgery for tumors of the pineal region. The video can be found here: https://stream.cadmore.media/r10.3171/2021.4.FOCVID2127.

The Evolving Role of CD8+CD28- Immunosenescent T Cells in Cancer Immunology.

Functional, tumor-specific CD8+ cytotoxic T lymphocytes drive the adaptive immune response to cancer. Thus, induction of their activity is the ultimate aim of all immunotherapies. Success of anti-tumor immunotherapy is precluded by marked immunosuppression in the tumor microenvironment (TME) leading to CD8+ effector T cell dysfunction. Among the many facets of CD8+ T cell dysfunction that have been recognized-tolerance, anergy, exhaustion, and senescence-CD8+ T cell senescence is incompletely understood. Naïve CD8+ T cells require three essential signals for activation, differentiation, and survival through T-cell receptor, costimulatory receptors, and cytokine receptors. Downregulation of costimulatory molecule CD28 is a hallmark of senescent T cells and increased CD8+CD28- senescent populations with heterogeneous roles have been observed in multiple solid and hematogenous tumors. T cell senescence can be induced by several factors including aging, telomere damage, tumor-associated stress, and regulatory T (Treg) cells. Tumor-induced T cell senescence is yet another mechanism that enables tumor cell resistance to immunotherapy. In this paper, we provide a comprehensive overview of CD8+CD28- senescent T cell population, their origin, their function in immunology and pathologic conditions, including TME and their implication for immunotherapy. Further characterization and investigation into this subset of CD8+ T cells could improve the efficacy of future anti-tumor immunotherapy.

Efficacy of pre-operative stereotactic radiosurgery followed by surgical resection and correlative radiobiological analysis for patients with 1-4 brain metastases: study protocol for a phase II trial.

BACKGROUND: Stereotactic radiosurgery (SRS) has emerged as a common adjuvant modality used with surgery for resectable brain metastases (BMs). However, the optimal sequence of the multi-modality therapy has not been established. The goal of the study is to evaluate 6-month local control utilizing pre-operative SRS followed by surgical resection for patients with 1-4 brain metastases. METHODS: This prospective, single arm, phase II trial will recruit patients with up to 4 brain metastases and at least one resectable lesion. All lesions will be treated with SRS and symptomatic lesions will be resected within 1-4 days after SRS. Patients will be monitored for 6-month local control, in-brain progression free survival, distant in-brain failure, rate of leptomeningeal spread, radiation necrosis and overall survival. Additionally, we will also perform correlative radiobiological molecular studies to assess the effect of radiation dosing on the tumor tissue and clinical outcomes. We expect that pre-operative SRS to the gross tumor prior to surgical resection will improve local control and decrease leptomeningeal failure. DISCUSSION: Our study is the second prospective trial to investigate the efficacy of pre-operative SRS in the treatment of multiple BMs. In addition, the correlative molecular studies will be the first to investigate early response of BMs at a cellular and genetic level in response to radiation doses and potentially provide molecular prognostic markers for local control and overall survival. TRIAL REGISTRATION: Clinicaltrials.gov identifier: NCT03398694 (registration date: January 12, 2018).

Multicenter retrospective evaluation of the validity of the Thoracolumbar Injury Classification and Severity Score system in children.

OBJECTIVE The Thoracolumbar Injury Classification and Severity Score (TLICS) system was developed to streamline injury assessment and guide surgical decision making. To the best of the authors' knowledge, external validation in the pediatric age group has not been undertaken prior to this report. METHODS This study evaluated the use of the TLICS in a large retrospective series of children and adolescents treated at 4 pediatric medical centers (Texas Children's Hospital, Children's Healthcare of Atlanta, Riley Children's Hospital, and Doernbecher Children's Hospital). A total of 147 patients treated for traumatic thoracic or lumbar spine trauma between February 1, 2002, and September 1, 2015, were included in this study. Clinical and radiographic data were evaluated. Injuries were classified using American Spinal Injury Association (ASIA) status, Denis classification, and TLICS. RESULTS A total of 102 patients (69%) were treated conservatively, and 45 patients (31%) were treated surgically. All patients but one in the conservative group were classified as ASIA E. In this group, 86/102 patients (84%) had Denis type compression injuries. The TLICS in the conservative group ranged from 1 to 10 (mean 1.6). Overall, 93% of patients matched TLICS conservative treatment recommendations (score ≤ 3). No patients crossed over to the surgical group in delayed fashion. In the surgical group, 26/45 (58%) were ASIA E, whereas 19/45 (42%) had neurological deficits (ASIA A, B, C, or D). One of 45 (2%) patients was classified with Denis type compression injuries; 25/45 (56%) were classified with Denis type burst injuries; 14/45 (31%) were classified with Denis type seat belt injuries; and 5/45 (11%) were classified with Denis type fracture-dislocation injuries. The TLICS ranged from 2 to 10 (mean 6.4). Eighty-two percent of patients matched TLICS surgical treatment recommendations (score ≥ 5). No patients crossed over to the conservative management group. Eight patients (8/147, 5%) had a calculated TLICS of 4, which meant they were candidates for surgery or conservative therapy by TLICS criteria. Excluding these patients, the degree of agreement between TLICS and surgeon decision was deemed to be very good (κ = 0.878). CONCLUSIONS The TLICS results and recommendations matched treatment in 96% of conservative group cases. In the surgical group, TLICS recommendations matched treatment in 93% of cases. The TLICS recommendations and surgeon decision making displayed very good concordance. The TLICS appears to be effective in the classification of thoracic and lumbar spine injuries and in guiding treatment in the pediatric age group.

Rathke's cleft cysts in twins with type 2C von Hippel-Lindau disease.

Von Hippel-Lindau disease (VHLD) is characterized by a spectrum of benign and malignant tumors in the CNS and visceral organs. Rathke's cleft cysts are benign, nonneoplastic sellar lesions that are often asymptomatic. The authors report the case of twin sisters with VHLD Type 2C with radiographically similar sellar lesions. One twin required surgery for progressive visual loss. Pathological examination of resected tissue demonstrated Rathke's cleft cyst.