Emergency department disposition of non-neutropenic febrile patients with cancer.

OBJECTIVES: National data reveal that 60% of the 4.5 million annual emergency department (ED) visits by patients with cancer result in admission. Many of these visits are due to a febrile illness. Current literature provides limited guidance on how to treat non-neutropenic febrile ED patients. This study characterizes clinical outcomes of non-neutropenic febrile patients with cancer presenting to an academic, Comprehensive Cancer Center affiliated ED. METHODS: Retrospective chart review of 101 randomly selected adult patients with active cancer presenting with a chief complaint of fever or a documented fever in the ED and an absolute neutrophil count above 1000 between October 2015 and September 2016. Descriptive statistics were calculated. RESULTS: The primary malignancies represented were hematologic (24%), gastrointestinal (13%), head and neck (13%), and genitourinary (8%). Sixty-two percent were on chemotherapy, 15% on radiation therapy, and 12% were on targeted therapy. Severe illness outcomes occurred in 39% and 83% were admitted with a median length of stay of 4 days. Among admitted patients, 24% experienced a length of stay ≤2 days. A return visit to the ED or an in-system hospitalization within 7 days of the index visit occurred in 10% and death occurred within 7 days of the index visit in 4%. CONCLUSION: A majority of patients presenting to the ED with non-neutropenic fever are admitted (83%), of whom nearly a quarter experience a length of stay of ≤2 days with infrequent serious illness outcomes. Future efforts should focus on the development of risk stratification tools in this population to avoid potentially unnecessary hospitalizations.

Intraparenchymal hemorrhage after heroin use.

Heroin-associated stroke is a rare complication of use. Various proposed mechanisms of heroin-associated ischemic stroke have been proposed, including the following: cardioembolism in the setting of infective endocarditis, hypoxic ischemic brain injury in the setting of hypoxemia and hypotension, and infective arteritis or vasculitis from drug adulterants. A previously healthy 28-year-old woman presented to the emergency department with altered mental status and normal vitals after she was found wandering outside her apartment. During ambulance transport, she endorsed heroin use. The patient was alert but could not recall her name, place, or time. She intermittently responded "I don't know" to questioning and could not perform simple commands. No motor or sensory deficits were apparent other than sluggish pinpoint pupils. There were no signs of trauma other than antecubital track marks. Her laboratory results were unremarkable. Reevaluation at 2 hours after presentation showed persistent confusion and disorientation. A computed tomographic scan of the head was obtained, which showed a large 5.1 × 5-cm intraparenchymal hemorrhage in the left frontal lobe, vasogenic edema, and a 5-mm midline shift. A workup for cardioembolic, vasculitis, and other etiologies for stroke did not reveal an underlying cause. The patient remained confused with significant memory loss throughout her hospital stay and was eventually discharged to a long-term care facility. Drug abuse should be considered a risk factor for stoke in young adults. In patients with persistent neurologic deficits, physicians must be vigilant and order appropriate workup while managing drug overdose.

Antitumor activity of IFIX, a novel interferon-inducible HIN-200 gene, in breast cancer.

We identified IFIX as a new member of the hematopoietic interferon (IFN)-inducible nuclear protein with the 200-amino-acid repeat (HIN-200) family. Six different alternatively spliced forms of mRNA are transcribed from the IFIX gene, which are predicted to encode six different isoforms of IFIX proteins (IFIXalpha1, alpha2, beta1, beta2, gamma1, and gamma2). The IFIX proteins are primarily localized in the nucleus. They share a common N-terminal region that contains a predicted pyrin domain and a putative nuclear localization signal. Unlike IFIXalpha and IFIXbeta, IFIXgamma isoforms do not have the 200-amino-acid signature motif. Interestingly, the expression of IFIX was reduced in most human breast tumors and breast cancer cell lines. Expression of IFIXalpha1, the longest isoform of IFIX, in human breast cancer cell lines reduced their anchorage-dependent and -independent growth in vitro and tumorigenicity in nude mice. Moreover, a liposome-mediated IFIXalpha1 gene transfer suppressed the growth of already-formed tumors in a breast cancer xenograft model. IFIXalpha1 appears to suppress the growth of breast cancer cells in a pRB- and p53-independent manner by increasing the expression of the cyclin-dependent kinase inhibitor p21(CIP1), which leads to the reduction of the kinase activity of both Cdk2 and p34(Cdc2). Together, our results show that IFIXalpha1 possesses a tumor-suppressor activity and suggest IFIXalpha1 may be used as a therapeutic agent in cancer treatment.

A delayed chemically induced tumorigenesis in Brca2 mutant mice.

BRCA2 is a breast cancer susceptibility gene. Germline mutations of BRCA2 account for about 10-30% of familial breast cancer cases. Consistent with its tumor-suppressor activity, BRCA2 plays an important role in DNA repair. To assess the susceptibility of carriers of mutant BRCA2 to tumorigenesis induced by DNA-damaging carcinogens, we generated a Brca2 knockout mouse strain and studied its susceptibility to chemically induced tumorigenesis. Similar to previously reported Brca2 knockout mice, our Brca2-/- embryos die at E8.5-9.5, while the Brca2+/- mice are tumor-free and fertile. Unexpectedly, Brca2+/- mice developed tumors slower than did their wild-type littermates when treated with a potent carcinogen 7,12-dimethylbenz[a]anthracene (DMBA). In vitro experiments showed that Brca2+/- mouse cells and Capan-1 cells, a human pancreatic cancer cell line deficient of BRCA2, were more sensitive to DMBA-induced apoptosis, than were Brca2+/+ mouse cells and a derivative of Capan-1 cells that expressed exogenous wild-type BRCA2, respectively. Our results suggest that enhanced sensitivity of Brca2 mutant cells to DMBA-induced apoptosis at the dose of DMBA we used contributes to the delayed tumorigenesis of Brca2+/- animals. This suggestion may also provide a rational explanation for a previous unexpected finding that cigarette smoking appears to reduce the breast cancer risk of BRCA2 mutation carriers.

Stat3 activation regulates the expression of vascular endothelial growth factor and human pancreatic cancer angiogenesis and metastasis.

Expression of vascular endothelial growth factor (VEGF), a key angiogenic protein, has been linked with pancreatic cancer progression. However, the molecular basis for VEGF overexpression remains unclear. Immunohistochemical studies have indicated that VEGF overexpression coincides with elevated Stat3 activation in human pancreatic cancer specimens. In our study, more than 80% of the human pancreatic cancer cell lines used exhibited constitutively activated Stat3, with Stat3 activation correlated with the VEGF expression level. Blockade of activated Stat3 via ectopic expression of dominant-negative Stat3 significantly suppressed VEGF expression, angiogenesis, tumor growth, and metastasis in vivo. Furthermore, constitutively activated Stat3 directly activated the VEGF promoter, whereas dominant-negative Stat3 inhibited the VEGF promoter. A putative Stat3-responsive element on the VEGF promoter was identified using a protein-DNA binding assay and confirmed using a promoter mutagenesis assay. These results indicate that Stat3 directly regulates VEGF expression and hence angiogenesis, growth, and metastasis of human pancreatic cancer, suggesting that Stat3 signaling may be targeted for treatment of pancreatic cancer.