Causes of Death and End-of-Life Care in Patients With Intracranial High-Grade Gliomas: A Retrospective Observational Study.

BACKGROUND AND OBJECTIVES: To understand patterns of care and circumstances surrounding end of life in patients with intracranial gliomas. METHODS: We retrospectively analyzed end-of-life circumstances in patients with intracranial high-grade gliomas at Columbia University Irving Medical Center who died from January 2014 to February 2019, including cause of death, location of death, and implementation of comfort measures and resuscitative efforts. RESULTS: There were 152 patients (95 men, 57 women; median age at death 61.5 years, range 24-87 years) who died from January 2014 to February 2019 with adequate data surrounding end-of-life circumstances. Clinical tumor progression (n = 117, 77.0%) was the most common cause of death, with all patients transitioned to comfort measures. Other causes included, but were not limited to, infection (19, 12.5%); intratumoral hemorrhage (5, 3.3%); seizures (8, 5.3%); cerebral edema (4, 2.6%); pulmonary embolism (4, 2.6%); autonomic failure (2, 1.3%); and hemorrhagic shock (2, 1.3%). Multiple mortal events were identified in 10 (8.5%). Seventy-three patients (48.0%) died at home with hospice. Other locations were inpatient hospice (40, 26.3%); acute care hospital (34, 22.4%), including 27 (17.8%) with and 7 (4.6%) without comfort measures; skilled nursing facility (4, 3.3%), including 3 (2.0%) with and 1 (0.7%) without comfort measures; or religious facility (1, 0.7%) with comfort measures. Acute cardiac or pulmonary resuscitation was performed in 20 patients (13.2%). DISCUSSION: Clinical tumor progression was the most common (77.0%) cause of death, followed by infection (12.5%). Hospice or comfort measures were ultimately implemented in 94.7% of patients, although resuscitation was performed in 13.2%. Improved understanding of circumstances surrounding death, frequency of use of hospice services, and frequency of resuscitative efforts in patients with gliomas may allow physicians to more accurately discuss end-of-life expectations with patients and caregivers, facilitating informed care planning.

Chemotherapy Treatment and Trials in Low-Grade Gliomas.

There is currently no universally accepted standard of care treatment for low-grade gliomas, a molecularly heterogeneous group of tumors with similarly heterogeneous clinical outcomes. Risk stratification by clinical and molecular features is useful to help determine which patients benefit the most from adjuvant treatment. The addition of combination chemotherapy with procarbazine, lomustine, and vincristine confers survival advantage, as likely does temozolomide, but radiochemotherapy may not be appropriate for all patients owing to its toxicity profile. We review the approach to treatment in patients with low-grade gliomas with an emphasis on the clinical trials focusing on adjuvant chemotherapy in this population.

Headaches in Patients with Pituitary Tumors: a Clinical Conundrum.

PURPOSE OF REVIEW: Pituitary tumors account for approximately 17% of all intracranial neoplasms, with the majority being pituitary adenomas. Often, these are found incidentally during a workup for headache; however, the relationship between symptom and pathology remains unclear. The purpose of this article is to review the most recent literature on the epidemiology, pathophysiology, and management of headaches in patients with pituitary tumors. RECENT FINDINGS: The current literature is limited, with few prospective trials focusing on this question. With the exception of pituitary apoplexy, the relationship between headaches and pituitary masses remains unclear. Intervention does not always improve headache and can lead to development of new headache syndromes. Further research is needed to better elucidate the relationship between pituitary tumors and headaches. Headache alone is rarely an indication for surgical management of a pituitary adenoma.

Widely metastatic atypical pituitary adenoma with mTOR pathway STK11(F298L) mutation treated with everolimus therapy.

Pituitary adenomas are the commonest intracranial tumor, but metastases are rare (0.2% yearly incidence) and portend poor prognosis. CAPecitabine and TEMozolomide improved outcomes for neuroendocrine tumors. However, no chemotherapy is approved for refractory pituitary carcinomas. Next-generation sequencing revealed an actionable mTOR pathway STK11 mutation in a woman with adrenocorticotropic hormone-secreting pituitary carcinoma refractory to six resections, radiation and CAPecitabine and TEMozolomide. Given efficacy in preclinical pancreatic cancer models with STK11 mutations, she received radiation and everolimus leading to clinical improvement and stability on MRI and PET for >6 months. She ultimately expired from widely metastatic disease. Next-generation sequencing can identify actionable mutations in rare or treatment refractory tumors. Earlier targeted therapy may improve outcomes.

Quantitative analysis of the detergent-insoluble brain proteome in frontotemporal lobar degeneration using SILAC internal standards.

A hallmark of neurodegeneration is the aggregation of disease related proteins that are resistant to detergent extraction. In the major pathological subtype of frontotemporal lobar degeneration (FTLD), modified TAR-DNA binding protein 43 (TDP-43), including phosphorylated, ubiquitinated, and proteolytically cleaved forms, is enriched in detergent-insoluble fractions from post-mortem brain tissue. Additional proteins that accumulate in the detergent-insoluble FTLD brain proteome remain largely unknown. In this study, we used proteins from stable isotope-labeled (SILAC) human embryonic kidney 293 cells (HEK293) as internal standards for peptide quantitation across control and FTLD insoluble brain proteomes. Proteins were identified and quantified by liquid-chromatography coupled with tandem mass spectrometry (LC-MS/MS) and 21 proteins were determined to be enriched in FTLD using SILAC internal standards. In parallel, label-free quantification of only the unlabeled brain derived peptides by spectral counts (SC) and G-test analysis identified additional brain-specific proteins significantly enriched in disease. Several proteins determined to be enriched in FTLD using SILAC internal standards were not considered significant by G-test due to their low total number of SC. However, immunoblotting of FTLD and control samples confirmed enrichment of these proteins, highlighting the utility of SILAC internal standard to quantify low-abundance proteins in brain. Of these, the RNA binding protein PTB-associated splicing factor (PSF) was further characterized because of structural and functional similarities to TDP-43. Full-length PSF and shorter molecular weight fragments, likely resulting from proteolytic cleavage, were enriched in FTLD cases. Immunohistochemical analysis of PSF revealed predominately nuclear localization in control and FTLD brain tissue and was not associated with phosphorylated pathologic TDP-43 neuronal inclusions. However, in a subset of FTLD cases, PSF was aberrantly localized to the cytoplasm of oligodendrocytes. These data raise the possibility that PSF directed RNA processes in oligodendrocytes are altered in neurodegenerative disease.