Safety and efficacy of sargramostim (GM-CSF) in the treatment of Alzheimer's disease.

INTRODUCTION: Inflammatory markers have long been observed in the brain, cerebrospinal fluid (CSF), and plasma of Alzheimer's disease (AD) patients, suggesting that inflammation contributes to AD and might be a therapeutic target. However, non-steroidal anti-inflammatory drug trials in AD and mild cognitive impairment (MCI) failed to show benefit. Our previous work seeking to understand why people with the inflammatory disease rheumatoid arthritis are protected from AD found that short-term treatment of transgenic AD mice with the pro-inflammatory cytokine granulocyte-macrophage colony-stimulating factor (GM-CSF) led to an increase in activated microglia, a 50% reduction in amyloid load, an increase in synaptic area, and improvement in spatial memory to normal. These results called into question the consensus view that inflammation is solely detrimental in AD. Here, we tested our hypothesis that modulation of the innate immune system might similarly be used to treat AD in humans by investigating the ability of GM-CSF/sargramostim to safely ameliorate AD symptoms/pathology. METHODS: A randomized, double-blind, placebo-controlled trial was conducted in mild-to-moderate AD participants (NCT01409915). Treatments (20 participants/group) occurred 5 days/week for 3 weeks plus two follow-up (FU) visits (FU1 at 45 days and FU2 at 90 days) with neurological, neuropsychological, blood biomarker, and imaging assessments. RESULTS: Sargramostim treatment expectedly changed innate immune system markers, with no drug-related serious adverse events or amyloid-related imaging abnormalities. At end of treatment (EOT), the Mini-Mental State Examination score of the sargramostim group increased compared to baseline (P = .0074) and compared to placebo (P = .0370); the treatment effect persisted at FU1 (P = .0272). Plasma markers of amyloid beta (Aß40 [decreased in AD]) increased 10% (P = .0105); plasma markers of neurodegeneration (total tau and UCH-L1) decreased 24% (P = .0174) and 42% (P = .0019), respectively, after sargramostim treatment compared to placebo. DISCUSSION: The innate immune system is a viable target for therapeutic intervention in AD. An extended treatment trial testing the long-term safety and efficacy of GM-CSF/sargramostim in AD is warranted.

Pancreatic Cancer in Pregnancy Presenting with Thromboembolic Events: Case Report and Review of the Literature.

Stroke and hepatic vein thrombosis are highly associated with neoplasia but are extremely rare events in young, pregnant women. Rare and recurrent thrombotic events in pregnancy increase the suspicion for occult malignancy. We describe the case of a healthy 31-year-old G2P1 who presented with visual changes and dysarthria during pregnancy. Imaging showed cerebral infarcts. Her thrombophilia evaluation was negative. During delivery, she was diagnosed with fulminant Budd-Chiari Syndrome. Hepatic ultrasound suggested malignancy or metastasis, and postpartum CT scan and biopsy confirmed the diagnosis of Stage IV pancreatic cancer. Although rare in pregnancy, a new diagnosis of malignancy should be considered in patients with recurrent unexplained hypercoagulable complications. We propose an evidence-based algorithm for evaluation of occult malignancy in pregnancy based upon this case and review of the literature.

Growth hormone tumor histological subtypes predict response to surgical and medical therapy.

Growth hormone (GH) pituitary tumors are associated with significant morbidity and mortality. Current treatments, including surgery and medical therapy with somatostatin analogs (SSA), dopamine agonists and/or a GH receptor antagonist, result in disease remission in approximately half of patients. Predictors of GH tumor response to different therapies have been incompletely defined based on histologic subtype, particularly densely (DG) versus sparsely (SG) granulated adenomas. The aim of this study was to examine our own institutional experience with GH adenomas and correlate how subtype related to clinical parameters as well as response to surgery and medical therapies. A retrospective chart review of 101 acromegalic patients operated by a single neurosurgeon was performed. Clinical data were correlated with histologic subtype and disease control, as defined by IGF-1 levels, and random growth hormone levels in response to surgery and/or medical therapies. SG tumors, compared to DG, occurred in younger patients (p = 0.0010), were 3-fold larger (p = 0.0030) but showed no differences in tumor-invasion characteristics (p = 0.12). DG tumors had a higher rate of remission in response to surgery compared to SG, 65.7 vs. 14.3 % (p < 0.0001), as well as to medical therapy with SSAs (68.8 % for DG vs. 28.6 % for SG tumors; p = 0.028). SG tumors not controlled with SSAs consistently responded to a switch to, or addition of, a GH receptor antagonist. Histological GH tumor subtyping implicates a different clinical phenotype and biologic behavior, and provides prognostic significance for surgical success and response to medical therapies.