Photosensitivity reaction from operating room lights after oral administration of 5-aminolevulinic acid for fluorescence-guided resection of a malignant glioma

Orally administered 5-aminolevulinic acid (5-ALA), which was approved in the United States in 2017, is preferentially metabolized by malignant glioma cells into protoporphyrin IX and enhances tumor visualization when using a blue light filter on an operating microscope. Photosensitivity after 5-ALA administration is a known side effect, but a photosensitivity reaction from operating room lights has not yet been documented. We report the case of a 56-year-old man with a history of previous resection of a grade II astrocytoma who presented with imaging concerning for tumor recurrence and possible malignant transformation. Repeat surgical resection utilized 5-ALA. Soon after the surgery, he developed reddening of his skin, particularly over the right side of his head and neck, with blistering and peeling in a distribution that was particularly exposed to operating room lights during surgery. No other areas of his skin experienced the same redness, blistering, or peeling. Topical lotions were applied and the skin changes resolved spontaneously over weeks. Significant photosensitivity after administration of oral 5-ALA is a rare complication, but neurosurgeons who perform fluorescence-guided tumor resection should remain cognizant of its potential association with exposure to intense light, including in the operating room. Phototoxicity typically is self-limited, but awareness is important to minimize its occurrence

TERT, a promoter of CNS malignancies

As cells replicate their DNA during mitosis, telomeres are shortened due to the inherent limitations of the DNA replication process. Maintenance of telomere length is critical for cancer cells to overcome cellular senescence induced by telomere shortening. Telomerase reverse transcriptase (TERT) is the rate-limiting catalytic subunit of telomerase, an RNA-dependent DNA polymerase that lengthens telomeric DNA to maintain telomere homeostasis

Focused ultrasound-enabled brain tumor liquid biopsy

Abstract Although blood-based liquid biopsies have emerged as a promising non-invasive method to detect biomarkers in various cancers, limited progress has been made for brain tumors. One major obstacle is the blood-brain barrier (BBB), which hinders efficient passage of tumor biomarkers into the peripheral circulation. The objective of this study was to determine whether FUS in combination with microbubbles can enhance the release of biomarkers from the brain tumor to the blood circulation. Two glioblastoma tumor models (U87 and GL261), developed by intracranial injection of respective enhanced green fluorescent protein (eGFP)-transduced glioblastoma cells, were treated by FUS in the presence of systemically injected microbubbles. Effect of FUS on plasma eGFP mRNA levels was determined using quantitative polymerase chain reaction. eGFP mRNA were only detectable in the FUS-treated U87 mice and undetectable in the untreated U87 mice (maximum cycle number set to 40). This finding was replicated in GL261 mice across three different acoustic pressures. The circulating levels of eGFP mRNA were 1,500–4,800 fold higher in the FUS-treated GL261 mice than that of the untreated mice for the three acoustic pressures. This study demonstrated the feasibility of FUS-enabled brain tumor liquid biopsies in two different murine glioma models across different acoustic pressures

Increased expression of programmed death ligand 1 (PD-L1) in human pituitary tumors

PURPOSE: Subsets of pituitary tumors exhibit an aggressive clinical courses and recur despite surgery, radiation, and chemotherapy. Because modulation of the immune response through inhibition of T-cell checkpoints has led to durable clinical responses in multiple malignancies, we explored whether pituitary adenomas express immune-related biomarkers that could suggest suitability for immunotherapy. Specifically, programmed death ligand 1 (PD-L1) has emerged as a potential biomarker whose expression may portend more favorable responses to immune checkpoint blockade therapies. We thus investigated the expression of PD-L1 in pituitary adenomas. METHODS: PD-L1 RNA and protein expression were evaluated in 48 pituitary tumors, including functioning and non-functioning adenomas as well as atypical and recurrent tumors. Tumor infiltrating lymphocyte populations were also assessed by immunohistochemistry. RESULTS: Pituitary tumors express variable levels of PD-L1 transcript and protein. PD-L1 RNA and protein expression were significantly increased in functioning (growth hormone and prolactin-expressing) pituitary adenomas compared to non-functioning (null cell and silent gonadotroph) adenomas. Moreover, primary pituitary adenomas harbored higher levels of PD-L1 mRNA compared to recurrent tumors. Tumor infiltrating lymphocytes were observed in all pituitary tumors and were positively correlated with increased PD-L1 expression, particularly in the functional subtypes. CONCLUSIONS: Human pituitary adenomas harbor PD-L1 across subtypes, with significantly higher expression in functioning adenomas compared to non-functioning adenomas. This expression is accompanied by the presence of tumor infiltrating lymphocytes. These findings suggest the existence of an immune response to pituitary tumors and raise the possibility of considering checkpoint blockade immunotherapy in cases refractory to conventional management

Impact of CD4 T cells on intratumoral CD8 T-cell exhaustion and responsiveness to PD-1 blockade therapy in mouse brain tumors

BACKGROUND: Glioblastoma is a fatal disease despite aggressive multimodal therapy. PD-1 blockade, a therapy that reinvigorates hypofunctional exhausted CD8 T cells (T METHODS: Single-cell RNA sequencing was performed on flow sorted tumor-infiltrating lymphocytes from female C57/BL6 mice implanted with each model, with and without PD-1 blockade therapy. CD8 RESULTS: The CD8 T-cell compartment of the models is composed of heterogenous CD8 T CONCLUSIONS: Here, we describe that dysfunctional CD4 T cells are associated with terminal CD8 T-cell exhaustion, suggesting CD4 T cells impact PD-1 blockade efficacy by controlling the severity of exhaustion. Given that CD4 lymphopenia is frequently observed in patients with glioblastoma, this may represent a basis for resistance to PD-1 blockade. We demonstrate that CD40 agonism may circumvent a dysfunctional CD4 compartment to improve PD-1 blockade responsiveness, supporting a novel synergistic immunotherapeutic approach

Prognostic impact of CDKN2A/B deletion, TERT mutation, and EGFR amplification on histological and molecular IDH-wildtype glioblastoma

BACKGROUND: We aimed to evaluate the clinical outcomes of molecular glioblastoma (mGBM) as compared to histological GBM (hGBM) and to determine the prognostic impact of METHODS: IDH-wildtype GBM patients treated with radiation therapy (RT) between 2012 and 2019 were retrospectively analyzed. mGBM was defined as grade II-III IDH-wildtype astrocytoma without histological features of GBM but with one of the following molecular alterations: RESULTS: Of the 367 eligible patients, the median follow-up was 11.7 months. mGBM and hGBM did not have significantly different OS (median: 16.6 vs 13.5 months, respectively, CONCLUSION: Criteria for mGBM may require further refinement and validation