History Of Glioblastoma Multiforme Research Articles

ORGANIZING PNEUMONITIS AS A FATAL ADVERSE EFFECT OF TEMOZOLOMIDE: A CASE REPORT AND REVIEW OF THE LITERATURE

TOPIC: Lung Pathology TYPE: Medical Student/Resident Case Reports INTRODUCTION: Glioblastoma Multiforme is the most aggressive Central Nervous system tumor and has a very poor prognosis in adults.[1] The current treatment regimen includes surgical resection, followed by radiation and Temozolomide.[2] Temozolomide is an oral Alkylating agent approved for the treatment of Glioblastoma Multiforme.[2] It has a very favorable side effect profile and is very well tolerated by most patients.[3] However, in few cases, there are fatal side effects, including organizing pneumonitis, which is characterized by subacute onset of fever, dyspnea, cough, and myalgia, as well as a CT scan finding pulmonary patchy consolidation and ground glass appearance. CASE PRESENTATION: 45- year-old man with a history of Glioblastoma multiforme, treated with tumor resection, radiation, and was started on Temozolomide for the last eight months, who was admitted to ICU for worsening respiratory distress. The Chest X-ray and the CT scan of the chest revealed multifocal interstitial ground-glass consolidations. Infectious causes were ruled out with blood and sputum cultures that were negative and bronchial alveolar lavage (BAL), which was negative for any organisms. The transbronchial biopsy also showed inflammation but no organisms on gram stain or PCR. He was preemptively started on PCP prophylaxis. High-dose steroids were started, for a diagnosis of organizing pneumonitis, with some improvement in radiological findings, but the overall condition deteriorated, with anoxic brain injury, mother changed the code status to control measures, and the patient expired. DISCUSSION: Temozolomide is an oral alkylating agent that has been used in combination with radiation therapy in improving disease progression-free survival in patients with glioblastoma multiforme (1). Multiple adverse effects have been reported in association with the use of temozolomide. Hematologic adverse reactions include thrombocytopenia, lymphopenia, CD4-selective lymphocytopenia with increased risk of opportunistic infections especially pneumocystis jirovecii for PCP prophylaxis treatment should be considered in a patient developing lymphopenia with temozolomide therapy (2). One of the rare but life-threatening idiosyncratic reactions which have been reported in association with temozolomide use is organizing pneumonitis. To our best knowledge, there have been a total of seven cases reported of organizing pneumonia secondary to Temozolomide use, we are summarizing them in table 1. CONCLUSIONS: Organizing pneumonitis is one of the fatal complications that has been reported with the use of temozolomide. Physicians should consider this as one of the differential diagnoses while treating acute respiratory distress in the setting of temozolomide use. Infection should be ruled out and high dose steroid therapy should be started as early as possible and is the key element to achieve medical response and decrease mortality in these patients. REFERENCE #1: 1.Ostrom QT, Gittleman H, Fulop J, et al. CBTRUS Statistical Report: Primary Brain and Central Nervous System Tumors Diagnosed in the United States in 2008-2012. Neuro-Oncology. 2015;17(suppl 4):iv1-iv62. doi:10.1093/neuonc/nov189 REFERENCE #2: 2.Ostrom QT, Bauchet L, Davis FG, et al. The epidemiology of glioma in adults: a "state of the science" review. Neuro-Oncology. 2014;16(7):896-913. doi:10.1093/neuonc/nou087 REFERENCE #3: 3.Alexander BM, Cloughesy TF. Adult Glioblastoma. Journal of Clinical Oncology. 2017;35(21):2402-2409. doi:10.1200/jco.2017.73.01194.Davis M. Glioblastoma: Overview of Disease and Treatment. Clinical Journal of Oncology Nursing. 2016;20(5):S2-S8. doi:10.1188/16.cjon.s1.2-8 DISCLOSURES: No relevant relationships by Lina Altameemi, source=Web Response No relevant relationships by Jaafar Alward, source=Web Response No relevant relationships by Arul Chandran, source=Web Response No relevant relationships by Harini Lakshman, source=Web Response

(PSEUDO)HYPONATREMIA SECONDARY TO LIPOPROTEIN X

SESSION TITLE: Medical Student/Resident Critical Care Posters SESSION TYPE: Med Student/Res Case Rep Postr PRESENTED ON: October 18-21, 2020 INTRODUCTION: Hyponatremia can be associated with clinically significant disease and often portends worse outcomes, significant hospital morbidity, increased length of stay and hospital cost.[1] Pseudohyponatremia, may be a culprit in overusing hospital resources and unnecessary workup. Here we present a case of altered mental status (AMS) thought initially to be due to hyponatremia. CASE PRESENTATION: A 58 year-old Caucasian male with a history of glioblastoma multiforme (GBM) treated with resection, radiation and temozolomide, on chronic tube feeds (TF) through gastrostomy tube presented with two weeks of AMS. The spouse reported maintenance of TF but was unsure of how much free water she was actually giving. The patient’s exam was significant for blood pressure of 89/60 mmHg, tachycardia at 101 beats per minute, he had lethargy with response to painful stimuli, significant scleral icterus, dry mucous membranes with no gross motor deficits and unremarkable lung and cardiac exams. His workup was significant for sodium of 120 mmol/L, blood urea nitrogen of 48 mg/dL, creatinine of 1.5 mg/dL, direct hyperbilirubinemia of 47 mg/dL (thought to be due to hepatic injury from temozolomide), aspartate aminotransferase of 1,025 U/L, alanine aminotransferase of 595 U/L, alkaline phosphatase of >1,200 U/L, undetectable ammonia level and a negative drug screen. He was started on intravenous fluids and lactulose without any clinical improvement and minimal change in sodium levels. Further workup showed a serum osmolality of 315 mOs/kg (which pointed towards a pseudohyponatremia picture), triglycerides of 343 mg/dL, cholesterol of 1,652 mg/dL, LDL of 24 mg/dL. Full lipoprotein profile and lipid electrophoresis identified lipoprotein X (LpX) which accounted for the observed pseudohyponatremia. MRI head showed possible recurrent GBM without intracranial shift, thought to be the culprit behind his AMS. DISCUSSION: LpX appears in the serum secondary to cholestasis. It is a result of reflux of bile acid into the serum that combines with albumin to form LpX. It is also composed of small amounts of triglycerides, free cholesterol and apolipoprotein C.[2] Interestingly, LpX was not found to be associated with ischemic heart disease. This is thought to be due to a particle size of 18-25 nm, which prevents it from incorporating into the endothelium. It may even be protective against LDL induced atherosclerosis as it decreases LDL oxidation.[3] Thus, lipid lowering medication may not be needed. It is important to note that LpX may cause a hyperviscosity syndrome and could require lipopheresis. CONCLUSIONS: Our case highlights LpX as a rare cause of pseudohyponatremia and the importance of differentiating between true hyponatremia and pseudohyponatremia to avoid unnecessary workup and therapy that may increase morbidity and length of hospital stay. Physicians should be aware of this entity and include it in future practice. Reference #1: Corona G, Giuliani C, Parenti G, et al. The Economic Burden of Hyponatremia: Systematic Review and Meta-Analysis. Am J Med. 2016;129(8):823-835.e4. doi:10.1016/j.amjmed.2016.03.007 Reference #2: Fellin R, Manzato E. Lipoprotein-X fifty years after its original discovery. Nutr Metab Cardiovasc Dis. 2019;29(1):4-8. doi:10.1016/j.numecd.2018.09.006 Reference #3: Chang PY, Lu SC, Su TC, et al. Lipoprotein-X reduces LDL atherogenicity in primary biliary cirrhosis by preventing LDL oxidation. J Lipid Res. 2004;45(11):2116-2122. doi:10.1194/jlr.M400229-JLR200 DISCLOSURES: No relevant relationships by Youssef Abouleish, source=Web Response Speaker/Speaker's Bureau relationship with Genentech Please note: $5001 - $20000 Added 04/01/2020 by Joshua Sill, source=Web Response, value=Honoraria

Case Report: Chloroquine Induced Keratopathy – Toxicity from Systemic Use

The application of chloroquine has been expanded over time from the treatment of malaria to a variety of connective tissue, inflammatory, and dermatologic disorders. More recently, chloroquine and its derivative, hydroxychloroquine, have been investigated for its possible application against SARS-CoV-2 due to their antiviral properties. We present a case of a patient receiving chloroquine as adjuvant therapy for glioblastoma multiforme who developed significant keratopathy and review this overlooked entity in view of the resurgence of this enduring medication. A 48-year-old woman with a history of Marfan syndrome presented with a five-day history of pain and discomfort in her right eye. She had a history of glioblastoma multiforme that had been treated with surgical resection, radiation, and chemotherapy and was currently undergoing adjuvant treatment with chloroquine and cimetidine. Her exam was notable for decreased visual acuity, bilateral epithelial erosions, multiple subepithelial white dots in a whorl-like distribution, and decreased corneal sensation. These corneal changes reversed following cessation of chloroquine. While chloroquine related retinopathy is reported frequently in the literature, the corneal changes related to chloroquine have been less frequently discussed. With the resurgence of interest in using chloroquine and hydroxychloroquine as therapy for SARS-CoV-2 due to their promising in-vitro activity against the virus [1, 2], corneal toxicity is an important side effect to identify and monitor.

On the Concepts and History of Glioblastoma Multiforme - Morphology, Genetics and Epigenetics.

Glioblastoma multiforme (GBM) is a grade IV WHO malignant tumor with astrocytic differentiation. As one of the most common clinically diagnosed central nervous system (CNS) oncological entries, there have been a wide variety of historical reports of the description and evolution of ideas regarding these tumors. The first recorded reports of gliomas were given in British scientific reports, by Berns in 1800 and in 1804 by Abernety, with the first comprehensive histomorphological description being given in 1865 by Rudolf Virchow. In 1926 Percival Bailey and Harvey Cushing gave the base for the modern classification of gliomas. Between 1934 and 1941 the most prolific researcher in glioma research was Hans-Joachim Scherer, who postulated some of the clinico-morphological aspects of GBM. With the introduction of molecular and genetic tests the true multifomity of GBM has been established, with different genotypes bearing the same histomorphological and IHC picture, as well as some of the aspects of gliomagenesis. For a GBM to develop, a specific trigger mutation needs to occur in a GBM stem cell - primary GBM, or a slow aggregation of individual mutations, without a distinct trigger mutation - secondary GBM. Knowledge of GBM has been closely related to general medical knowledge of the CNS since these malignancies were first described more than 200 years ago. Several great leaps have been made in that time, in the footsteps of both CNS and advancements in general medical knowledge.

A whole greater than the sum of the parts: Close collaboration between palliative care and clinical ethics.

53 Background: The disciplines of palliative care (PC) and clinical ethics (CE) share common content but also important distinctions in method, skill set, and clinical role in a given patient encounter. Particularly in cases of advance care planning, complex decision-making, and clarifying goals oncology teams may be challenged to know which consultation service to involve. Methods: Case report and commentary. Results: A 60 year-old man with a 3-year history of glioblastoma multiforme presented with sudden onset right-sided weakness and altered mental status. In the emergency department, a computed tomography (CT) scan demonstrated a left-sided intracranial bleed with concomitant cerebral edema and left-to-right midline shift. The patient was admitted to a surgical intensive care unit (SICU) where neurosurgery declined to operate. Within hours of admission, while the patient’s son (also his durable healthcare power-of-attorney) was considering a do-not-resuscitate order, local police arrived at the hospital, having received a 911 call from the patient’s daughter who claimed her brother and medical providers were attempting to murder her father by shifting to comfort care. The SICU team urgently consulted PC and CE. Within an hour, PC and CE clinicians met with the patient’s family to review the patient’s advance directive, counsel regarding clinical management strategies and prognosis, broach comfort care, introduce hospice, and liaise with a hospice case manager. Additionally, PC collaborated with the SICU to provide best symptom management; CE worked with hospital risk management and security to ethically mitigate escalation of more reactive family members. Within 4 hours of the consults, the patient was being transferred to a local inpatient hospice facility, where he died several days later. Conclusions: As this case demonstrates, models of close collaboration between PC and CE consultative services may swiftly facilitate appropriate transitions in care for patients with advanced cancer and simultaneous de-escalation of hospital risk. Evolving models for quality supportive care should further examine such strategies.

Abstract B1-11: Application of the CN-AVG method to reconstruct the evolutionary history of glioblastoma multiforme

Abstract We have constructed evolutionary histories of cancer genomes using a new method, the Copy Number Ancestral Variation Graph (CN-AVG). Unlike previous cancer evolutionary studies which infer the clonal structure and evolutionary history of a tumor using single nucleotide variant frequencies, the CN-AVG method predicts the ordering of structural rearrangements, such as inversions, duplications, and deletions, using copy number changes and breakpoints derived from whole genome sequencing data. Because finding the most parsimonious ordering of genomic rearrangements is an NP hard problem, we build a consensus history by merging a large number of possible evolutionary histories generated from MCMC sampling. We tested the CN-AVG method on simulated rearranged genomes and achieved an average accuracy of 62%. We also found that accuracy decreased with increasing complexity of the simulated rearrangements, as expected. We then applied the method to TCGA Glioblastoma Multiforme genomes to search for evolutionary patterns in this disease. The CN-AVG method may distinguish driver mutations as the early rearrangement events and passenger or secondary mutations as the later events in the reconstructed evolutionary history of the tumor, and will be powerful for both the clinic and for research. Citation Format: Tracy J. Ballinger, Daniel Zerbino, Benedict Paten, David Haussler. Application of the CN-AVG method to reconstruct the evolutionary history of glioblastoma multiforme. [abstract]. In: Proceedings of the AACR Special Conference on Computational and Systems Biology of Cancer; Feb 8-11 2015; San Francisco, CA. Philadelphia (PA): AACR; Cancer Res 2015;75(22 Suppl 2):Abstract nr B1-11.

Glioblastoma Multiforme Metastastic to the Bone

Extracranial metastases from glioblastoma multiforme (GBM) are rare. We report a case of osseous metastases from GBM diagnosed by F-NaF PET/CT. A 30-year-old man with a history of GBM presented with bone pain and underwent F-NaF PET/CT for further evaluation. On PET/CT, intense uptake in 2 bone lesions was noted. Histopathologic evaluation revealed osseous metastases from GBM. Although rare, bone metastases have to be considered in patients with axial tumors and atraumatic bone pain. F-NaF PET/CT is a highly sensitive and valuable tool for detection of osseous metastases.

Cryptococcal meningitis in patients with glioma: a report of two cases

We describe two patients with high-grade glioma undergoing treatment with corticosteroids and chemotherapy who presented with cryptococcal meningitis and sepsis. This report of two cases highlights the importance of examining the efficacy of prophylactic antibiotic and/or antifungal regimens in this patient population due to their increased risk of opportunistic infections. A 73-year-old man with a history of glioblastoma multiforme (GBM), on dexamethasone and status post radiation therapy and two cycles of temozolamide, presented with decreased level of consciousness for 24 h and was found to have cerebrospinal fluid (CSF) and blood cultures positive for Cryptococcus neoformans. A 33-year-old man with a history of anaplastic astrocytoma, on dexamethasone and status post radiation therapy, four cycles of temozolomide and two cycles of Lomustine (CCNU), presented with headache, dizziness and photophobia and was found to have CSF and blood cultures positive for Cryptococcus neoformans. Both patients were treated with an initial regimen of amphotericin B and flucytosine for a minimum of two weeks and switched to fluconazole for 6 months to 1 year of treatment. Patients with high-grade glioma treated with long-term corticosteroid therapy and chemotherapy are at increased risk of developing opportunistic infections. The two patients reported here developed cryptococcal meningitis and sepsis. Prophylactic regimens with either fluconazole or itraconazole currently exist that effectively decrease the incidence of both cryptococcal infections. Further investigations into the risk:benefit ratio of primary prophylactic therapy in this patient population may prove beneficial.

Health-related quality of life and symptom research in glioblastoma multiforme patients

Health-related quality of life is increasingly becoming an important end point in cancer research. Until recently, relatively little was known about the health-related quality of life of glioblastoma multiforme patients. This is due to the relative scarcity of this disease compared with other cancers and its dismal prognosis. Now, there is progress in the treatment of this tumor: new (combination) treatments will be studied in randomized trials and health-related quality will be incorporated as a (secondary) end point next to progression-free survival. Glioblastoma multiforme patient health-related quality of life may also have prognostic significance and may, therefore, be used with the individual patient to tailor treatment. This review aims to chart the history of glioblastoma multiforme and treatment, reporting on the latest health-related quality of life tools and research findings.