Amy A. Mrazek

Surviving Cutaneous Melanoma:A Clinical Review of Follow-up Practices, Surveillance, and Management of Recurrence

The number of melanoma survivors in the United States continues to steadily increase 2.6% per year, while death rates have remained stable over time. Although controversy exists regarding optimal surveillance strategies, recommendations for clinical monitoring are based on tumor stage, tumor phenotype, likelihood of recurrence, prognosis, risk factors, psychosocial impact of disease, and patient well-being. Management guidelines for recurrent disease depend on the type of recurrence: local, satellite/in-transit, regional, or distant metastasis. This article is a current review of the literature concerning melanoma survivorship.

Apigenin inhibits pancreatic stellate cell activity in pancreatitis

BACKGROUND Chronic pancreatitis (CP) is characterized by recurrent pancreatic injury, resulting in inflammation, necrosis, and fibrosis. There are currently no drugs limiting pancreatic fibrosis associated with CP, and there is a definite need to fill this void in patient care. MATERIALS AND METHODS Pancreatitis was induced in C57/BL6 mice using supraphysiologic doses of cerulein, and apigenin treatment (once daily, 50 μg per mouse by oral gavage) was initiated 1 wk into the recurrent acute pancreatitis (RAP) protocol. Pancreata were harvested after 4 wk of RAP. Immunostaining with fibronectin antibody was used to quantify the extent of pancreatic fibrosis. To assess how apigenin may decrease organ fibrosis, we evaluated the effect of apigenin on the proliferation and apoptosis of human pancreatic stellate cells (PSCs) in vitro. Finally, we assessed apigenins effect on the gene expression in PSCs stimulated with parathyroid hormone-related protein, a profibrotic and proinflammatory mediator of pancreatitis, using reverse transcription-polymerase chain reaction. RESULTS After 4 wk of RAP, apigenin significantly reduced the fibrotic response to injury while preserving acinar units. Apigenin inhibited viability and induced apoptosis of PSCs in a time- and dose-dependent manner. Finally, apigenin reduced parathyroid hormone-related protein-stimulated increases in the PSC messenger RNA expression levels of extracellular matrix proteins collagen 1A1 and fibronectin, proliferating cell nuclear antigen, transforming growth factor-beta, and interleukin-6. CONCLUSIONS These in vivo and in vitro studies provide novel insights regarding apigenins mechanism(s) of action in reducing the severity of RAP. Additional preclinical testing of apigenin analogs is warranted to develop a therapeutic agent for patients at risk for CP.

Heart rate variability analysis is more sensitive at identifying neonatal sepsis than conventional vital signs

BACKGROUND Sepsis remains the largest preventable source of neonatal mortality in the world. Heart rate variability (HRV) analysis and noninvasive cardiac output have been shown to be useful adjuncts to sepsis detection in many patient groups. METHODS With Institutional Review Board approval, 4 septic and 6 nonseptic extremely low birth weight patients were enrolled. Data from septic and healthy patients were collected for 5 hours. Electrocardiogram waveform and traditional vital signs were collected and the RR intervals were calculated; then HRV analysis was performed in both the time and frequency domain. RESULTS HRV measurements in time domain, heart rate, and pulse oximetry (SpO2) were significantly different in septic patients vs nonseptic controls. CONCLUSIONS These results indicate that nonconventional vital signs such as HRV are more sensitive than traditionally used vital signs, such as cardiac output and mean arterial pressure, in the confirmation of sepsis in extremely low birth weight neonates. HRV may allow for earlier identification of septic physiology.

Increased coagulation and suppressed generation of activated protein C in aged mice during intra-abdominal sepsis.

Sepsis is a life-threatening clinical condition that is particularly serious among the elderly who experience considerably higher mortality rates compared with younger patients. Using a sterile endotoxemia model, we previously reported age-dependent mortality in conjunction with enhanced coagulation and insufficient levels of anti-coagulant factor activated protein C (aPC). The purpose of the present study was to further investigate the mechanisms for age-dependent coagulation and aPC insufficiency during experimental sepsis. Intra-abdominal sepsis was induced by cecal ligation and puncture (CLP) using 21 or 16 gauge (G) needles (double-puncture) on young (4 to 6 mo old) and aged (20 to 25 mo old) male C57BL/6 mice. When compared with young mice, aged mice showed significantly increased mortality (92% vs. 28%), systemic inflammation, and coagulation in the lung and kidney after 21G CLP. Young mice with more severe CLP (16G) showed a mortality rate and inflammation equivalent to aged mice with 21G CLP; however, enhanced coagulation and kidney dysfunction were significant only in the aged. In young mice, increased levels of aPC after CLP were coupled with reduced levels of protein C (PC), suggesting the conversion of PC to aPC; however, PC and aPC levels remained unchanged in aged mice, indicating a lack of PC to aPC conversion. Activation of fibrinolysis, determined by plasma d-dimer levels, was similar regardless of age or CLP severity, and plasminogen activator inhibitor-1, an inhibitor of fibrinolysis, showed severity-dependent induction independent of age. These results suggest that enhanced coagulation in aged mice during sepsis is due to dysfunction of the PC activation mechanism.

Dual inhibition of PI3K and mTOR signaling pathways decreases human pancreatic neuroendocrine tumor metastatic progression.

Objectives Patients with advanced pancreatic neuroendocrine tumors have limited therapeutic options. Everolimus (RAD001), an inhibitor of the mammalian target of rapamycin (mTOR) pathway, has been shown to increase progression-free survival, but not overall survival, indicating a need to identify additional therapeutic targets. Inhibition of mTOR complex 1 by RAD001 may induce upstream AKT upregulation. We hypothesized that dual inhibition of AKT along with mTOR will overcome the limited activity of RAD001 alone. Methods The BON cell line has been used as a model to study pancreatic neuroendocrine tumor cell biology. Western blots and cell growth assays were performed with mTOR inhibitor RAD001 (50 nM), mitogen-activated protein kinase inhibitor PD0325901 (50 nM), PI3K (phosphatidylinositol 3-kinase) inhibitor LY294002 (25 &mgr;M), or vehicle control. Nude mice were treated daily for 6 weeks with RAD001 (oral gavage) and with LY29400 (subcutaneous) 1 week after intrasplenic injection of BON cells. Results Cellular proliferation was most attenuated with the combination therapy of LY29400 and RAD001. Similarly, the volume of liver metastasis was lowest in the group treated with both LY29400 (100 mg/kg per week, subcutaneous) and RAD001 (2.5 mg/kg per day) compared with that in the vehicle group (P = 0.04). Conclusion The combination therapy of LY29400 and RAD001 decreased the cell growth in vitro and progression of liver metastasis in vivo compared with vehicle or with single-drug therapy.

Tu1975 H2S Inhibition of Cystathionine-β-Synthase (CBS) Using Novel Prodrug Decreases Colorectal Cancer Xenograft Growth With Less Toxicity Than Aminooxyacetic Acid (AOAA)

G A A b st ra ct s enhanced MEK/ERK activation coincided with those that inhibited mTORC2-mediated Akt phosphorylation on Ser473, suggesting a role of mTORC2. Knockdown of Rictor markedly increased baseline levels of ERK phosphorylation and treatment with NVP-BEZ235 did not produce further enhancement of ERK activation. These results imply that Rictor or mTORC2 exerts feedback inhibition of the MEK/ERK pathway in pancreatic cancer cells. Conclusion: We propose that dual PI3K/mTOR inhibitors suppress a novel negative feedback loop mediated by mTORC2 thereby leading to enhanced MEK/ERK pathway activity in pancreatic cancer cells.

Triple Negative Breast Cancer: A Review of Clinicopathologic Characteristics And Treatment Options

Breast cancer is the second leading cause of cancer death in women. Approximately 15-20% are triple negative breast cancer (TNBC: no protein expression of estrogen receptor, progesterone receptor, nor human epidermal growth factor receptor 2), representing one of the most challenging molecular subtypes of breast cancer. TNBC encompasses a heterogenous group of breast cancers that are not generally responsive to targeted therapies for hormone and growth factor receptors. Compared to their hormone receptor-positive counterparts, TNBC cases are associated with poor prognosis, worse overall survival and earlier recurrence. The purpose of this review is to describe the clinicopathologic features, molecular variants, associations with the BRCA genes, and therapeutic approaches for TNBC. New TNBC-targeted drug therapies are currently under investigation and include poly-ADP-ribose polymerase (PARP) inhibitors, platinum-based drugs, anti-epidermal growth factor receptor (EGFR) inhibitors, and anti-vascular endothelial growth factor receptor (VEGF) inhibitors. Both clinical trials and basic research are needed to further our understanding of the best treatment options for patients with TNBC. Keyword: Triple negative breast cancer.