Citations

Denosumab is a monoclonal antibody used for prevention of skeletal-related events (SREs) in patients with bone metastases from solid tumors. Hypocalcemia is a rare and dangerous side effect of the drug Denosumab. We present a case of a patient with metastatic prostate cancer who developed severe hypocalcemia after the administration of the drug. The patient’s vitamin D levels were low when checked after administration of the drug, which likely predisposed him to the development of hypocalcemia. He was placed on high doses of oral and intravenous (IV) calcium and vitamin D without any appreciable response in the serum calcium level. His ionized calcium remained below 0.71 mmol/L despite very high doses of oral and IV calcium supplements. During the hospital course, he developed hydronephrosis from the spread of a tumor and did not want to undergo percutaneous nephrostomy tube placement; therefore, it was decided to dialyse him for acute renal failure and to correct his hypocalcemia. Checking calcium and vitamin D levels prior to the administration of Denosumab is vital in preventing hypocalcemia. If hypocalcemia is severe and not responsive to high doses of vitamin D, oral and IV calcium, then hemodialysis with a high calcium bath can correct this electrolyte abnormality.

Abstract Studies in cancer patients have suggested that breast tumors recruit regulatory T cells (Tregs) into the tumor microenvironment. The extent to which local Tregs suppress antitumor immunity in breast cancer is unknown. We questioned whether inhibiting systemic Tregs with an IL-2 immunotoxin in a model of neu-mediated breast cancer, the neu-transgenic mouse, could impact disease progression and survival. As in human breast cancer, cancers that develop in these mice attract Tregs into the tumor microenvironment to levels of ∼10–25% of the total CD4+ T cells. To examine the role of Tregs in blocking immune-mediated rejection of tumor, we depleted CD4+CD25+ T cells with an IL-2 immunotoxin. The treatment depleted Tregs without concomitant lymphopenia and markedly inhibited tumor growth. Depletion of Tregs resulted in a persistent antitumor response that was maintained over a month after the last treatment. The clinical response was immune-mediated because adoptive transfer of Tregs led to a complete abrogation of the therapeutic effects of immunotoxin treatment. Further, Treg down-modulation was accompanied by increased Ag-specific immunity against the neu protein, a self Ag. These results suggest that Tregs play a major role in preventing an effective endogenous immune response against breast cancer and that depletion of Tregs, without any additional immunotherapy, may mediate a significant antitumor response.

Background and Purpose— Meta-analyses of extant genome-wide data illustrate the need to focus on subtypes of ischemic stroke for gene discovery. The National Institute of Neurological Disorders and Stroke SiGN (Stroke Genetics Network) contributes substantially to meta-analyses that focus on specific subtypes of stroke. Methods— The National Institute of Neurological Disorders and Stroke SiGN includes ischemic stroke cases from 24 genetic research centers: 13 from the United States and 11 from Europe. Investigators harmonize ischemic stroke phenotyping using the Web-based causative classification of stroke system, with data entered by trained and certified adjudicators at participating genetic research centers. Through the Center for Inherited Diseases Research, the Network plans to genotype 10 296 carefully phenotyped stroke cases using genome-wide single nucleotide polymorphism arrays and adds to these another 4253 previously genotyped cases, for a total of 14 549 cases. To maximize power for subtype analyses, the study allocates genotyping resources almost exclusively to cases. Publicly available studies provide most of the control genotypes. Center for Inherited Diseases Research–generated genotypes and corresponding phenotypes will be shared with the scientific community through the US National Center for Biotechnology Information database of Genotypes and Phenotypes, and brain MRI studies will be centrally archived. Conclusions— The Stroke Genetics Network, with its emphasis on careful and standardized phenotyping of ischemic stroke and stroke subtypes, provides an unprecedented opportunity to uncover genetic determinants of ischemic stroke.