Brea Lipe

Lipoprotein lipase links dietary fat to solid tumor cell proliferation.

Many types of cancer cells require a supply of fatty acids (FA) for growth and survival, and interrupting de novo FA synthesis in model systems causes potent anticancer effects. We hypothesized that, in addition to synthesis, cancer cells may obtain preformed, diet-derived FA by uptake from the bloodstream. This would require hydrolytic release of FA from triglyceride in circulating lipoprotein particles by the secreted enzyme lipoprotein lipase (LPL), and the expression of CD36, the channel for cellular FA uptake. We find that selected breast cancer and sarcoma cells express and secrete active LPL, and all express CD36. We further show that LPL, in the presence of triglyceride-rich lipoproteins, accelerates the growth of these cells. Providing LPL to prostate cancer cells, which express low levels of the enzyme, did not augment growth, but did prevent the cytotoxic effect of FA synthesis inhibition. Moreover, LPL knockdown inhibited HeLa cell growth. In contrast to the cell lines, immunohistochemical analysis confirmed the presence of LPL and CD36 in the majority of breast, liposarcoma, and prostate tumor tissues examined (n = 181). These findings suggest that, in addition to de novo lipogenesis, cancer cells can use LPL and CD36 to acquire FA from the circulation by lipolysis, and this can fuel their growth. Interfering with dietary fat intake, lipolysis, and/or FA uptake will be necessary to target the requirement of cancer cells for FA. Mol Cancer Ther; 10(3); 427–36. ©2011 AACR.

Deficiencies of Natural Anticoagulants, Protein C, Protein S, and Antithrombin

You or a family member may have developed a blood clot in one of the deep veins in the body (ie, a deep vein thrombosis, or DVT) or had a blood clot that traveled to the lungs (ie, a pulmonary embolism, or PE). As part of your medical care, your doctor may have evaluated you for conditions that may have contributed to developing a blood clot. Thrombophilia is a condition in which there is an increased tendency to form blood clots. It may be hereditary and conferred by genes inherited from one or more parents, or it may be acquired through situations such as surgery, cancer, pregnancy, or certain medications (eg, some contraceptive and menopausal hormone replacement products). The two most common hereditary thrombophilia conditions are the factor V Leiden and prothrombin 20210 gene mutations, both of which have been the subject of previous Cardiology Patient Pages.1,2 This Cardiology Patient Page will describe deficiencies in the natural anticoagulants, protein C, protein S, and antithrombin that may result in either hereditary or acquired thrombophilia. Blood flows through blood vessels to deliver oxygen and nutrients to all the bodys tissues. When a blood vessel is injured, a process called coagulation causes blood to form clots that stop the bleeding from the damaged blood vessel. Once coagulation begins, other substances in the blood, the natural anticoagulants, act as brakes to limit coagulation to the specific area of damage, thus avoiding formation of clots large enough to obstruct normal blood flow. There is a delicate balance at work to ensure that there is enough—but not too much—clotting ability in the blood. Too little clotting ability leads to bleeding problems, whereas too much clotting ability (thrombophilia) can lead to blood clot formation. The state of this balance between bleeding and clotting differs …

A pharmacokinetics and safety phase 1/1b study of oral ixazomib in patients with multiple myeloma and severe renal impairment or end-stage renal disease requiring haemodialysis

Renal impairment (RI) is a major complication of multiple myeloma (MM). This study aimed to characterize the single‐dose pharmacokinetics (PK) of the oral proteasome inhibitor, ixazomib, in cancer patients with normal renal function [creatinine clearance (CrCl) ≥90 ml/min; n = 20), severe RI (CrCl <30 ml/min; n = 14), or end‐stage renal disease requiring haemodialysis (ESRD; n = 7). PK and adverse events (AEs) were assessed after a single 3 mg dose of ixazomib. Ixazomib was highly bound to plasma proteins (~99%) in all renal function groups. Unbound and total systemic exposures of ixazomib were 38% and 39% higher, respectively, in severe RI/ESRD patients versus patients with normal renal function. Total ixazomib concentrations were similar in pre‐ and post‐dialyser samples collected from ESRD patients; therefore, ixazomib can be administered without regard to haemodialysis timing. Except for anaemia, the incidence of the most common AEs was generally similar across groups, but grade 3 and 4 AEs were more frequent in the severe RI/ESRD groups versus the normal group (79%/57% vs. 45%), as were serious AEs (43%/43% vs. 15%). The PK and safety results support a reduced ixazomib dose of 3 mg in patients with severe RI/ESRD.

Phase I safety data of lenalidomide, bortezomib, dexamethasone, and elotuzumab as induction therapy for newly diagnosed symptomatic multiple myeloma: SWOG S1211.

Phase I safety data of lenalidomide, bortezomib, dexamethasone, and elotuzumab as induction therapy for newly diagnosed symptomatic multiple myeloma: SWOG S1211

The role of maintenance therapy in multiple myeloma

Multiple myeloma is the second most common type of blood cancer and remains incurable despite advances in therapy. Current therapy for multiple myeloma includes a phased-approach, often consisting of initial induction therapy, consolidation and maintenance therapy. With an ever-growing landscape of treatment options, the approach to optimal therapy has become increasingly complex. Specifically, controversy surrounds the optimal use and duration of maintenance therapy. We conducted a comprehensive literature search to analyze the most current literature and to provide recommendations for maintenance therapy in multiple myeloma.

Erythropoietin modulation is associated with improved homing and engraftment after umbilical cord blood transplantation

Umbilical cord blood (UCB) engraftment is in part limited by graft cell dose, generally one log less than that of bone marrow (BM)/peripheral blood (PB) cell grafts. Strategies toward increasing hematopoietic stem/progenitor cell (HSPC) homing to BM have been assessed to improve UCB engraftment. Despite recent progress, a complete understanding of how HSPC homing and engraftment are regulated is still elusive. We provide evidence that blocking erythropoietin (EPO)-EPO receptor (R) signaling promotes homing to BM and early engraftment of UCB CD34+ cells. A significant population of UCB CD34+ HSPC expresses cell surface EPOR. Exposure of UCB CD34+ HSPC to EPO inhibits their migration and enhances erythroid differentiation. This migratory inhibitory effect was reversed by depleting EPOR expression on HSPC. Moreover, systemic reduction in EPO levels by hyperbaric oxygen (HBO) used in a preclinical mouse model and in a pilot clinical trial promoted homing of transplanted UCB CD34+ HSPC to BM. Such a systemic reduction of EPO in the host enhanced myeloid differentiation and improved BM homing of UCB CD34+ cells, an effect that was overcome with exogenous EPO administration. Of clinical relevance, HBO therapy before human UCB transplantation was well-tolerated and resulted in transient reduction in EPO with encouraging engraftment rates and kinetics. Our studies indicate that systemic reduction of EPO levels in the host or blocking EPO-EPOR signaling may be an effective strategy to improve BM homing and engraftment after allogeneic UCB transplantation. This clinical trial was registered at www.ClinicalTrials.gov (#NCT02099266).

IgG kappa monoclonal gammopathy of undetermined significance presenting as acquired type III Von Willebrand syndrome.

Acquired von Willebrand syndrome (AVWS) is a rare bleeding disorder associated with hematoproliferative disorders, autoimmune conditions, neoplasia and cardiovascular disorders that often present a diagnostic challenge. Monoclonal gammopathy of undetermined significance (MGUS) is one of the most common causes of AVWS that typically presents later in life with mucocutaneous or postsurgical bleeding and multimers consistent with type I or II von Willebrand disease (VWD). Here, we present the case of a patient with a 32-year history of type III VWD that was ultimately found to be AVWS related to an IgG MGUS. In this case report, we highlight the diagnostic challenges of AVWS to ensure proper identification and potentially lifesaving treatment of this rare disorder.

Von Willebrand Disease in Pregnancy

Because von Willebrand factor (VWF) levels increase during pregnancy, many women with VWD, though not requiring support with hemostatic agents, are at increased risk for delayed postpartum hemorrhage as coagulation factor levels fall to their prepregnancy levels in the puerperium. Women with moderate or severe disease or complicated pregnancies are best served by delivering at a center with an obstetrician, hematologist, and anesthesiologist experienced in managing coagulation disorders. In addition, on-site laboratory facilities with specialized coagulation testing capability, pharmacy, and blood bank support are critical for success. Ensuring optimal outcomes for pregnant women with VWD requires a multidisciplinary approach.

Combined deficiency of factor V and factor VIII: management during cardiothoracic surgery.

&NA; Combined factor V and factor VIII deficiency is an extremely rare bleeding disorder for which research is lacking. We present the case of a 33-year-old man requiring repeat mitral valve replacement. A multidisciplinary team approach was utilized to minimize his risk of bleeding which included the use of plasma exchange, intravenous factor replacement, and platelet transfusion. This approach created an operative experience that did not require blood transfusion or the use of other hemostatic medications.

Correlation between markers of bone metabolism and vitamin D levels in patients with monoclonal gammopathy of undetermined significance (MGUS)

Multiple myeloma (MM) lies along a spectrum of plasma cell disorders and represents the incurable malignant phase of disease. MM is felt to be uniformly preceded by an asymptomatic clonal disease called monoclonal gammopathy of undetermined significance (MGUS) that carries a lifelong risk of disease progression. While we are currently unable to predict which patients with MGUS will develop MM, the Mayo group has devised a risk stratification system to help in predicting patients with a higher risk of disease progression. Smoldering multiple myeloma (SMM) is distinguished from MGUS by a higher burden of plasma cells and an increased risk of progression to MM. There is currently no treatment for MGUS or SMM, and no treatment has been proven to reduce the risk of disease progression, though SMM remains an area of active research. Alterations in bone metabolism, mediated in part through upregulation of receptor activator of nuclear factor κβ (RANKL) and the decoy receptor osteoprotegrin (OPG), via effects on osteoblasts and osteoclastogenesis are common to both MM and MGUS and may play a role in disease progression. While patients with MGUS and SMM are generally felt to be asymptomatic, these patients do have an increased risk of bone fracture, linked to decreased bone strength and altered bone architecture. Vitamin D is a key regulator of bone metabolism associated with progressive disease in several malignancies, including MM. Dysregulation of RANKL and OPG correlates with disease activity and decreased survival, and has also been linked to altered bone metabolism in MGUS. Based on the abnormal bone metabolism observed in patients with MGUS and the central role for vitamin D in bone metabolism, we hypothesized that abnormal bone metabolism would correlate with disease risk in MGUS and that vitamin D supplementation would improve bone metabolism and markers of disease. We investigated this hypothesis by correlating the vitamin D level with the risk category of MGUS and markers of bone metabolism, RANKL and OPG. We further evaluated the impact of vitamin D supplementation on RANKL and OPG levels, as well as markers of disease activity, including serum protein electrophoresis (SPEP) and free light chains (FLCs). In this open-label trial, 50 patients with MGUS or SMM per the International Myeloma Working Group criteria who were older than 18 years of age were recruited to this study from a plasma cell dyscrasia clinic between June 2012 and November 2014. Patients with a history of osteoporosis, or other bone diseases, bisphosphonate usage within 1 year or glucocorticoid use within 3 months, pregnant patients, patients on bile acid sequestrants, anticonvulsive, or antiretroviral therapy, and patients with a history of malignancy other than in situ cancers within 5 years were excluded. Patients were stratified into two groups based on risk of disease progression, those with 0 or 1 risk factor for progression (low risk or intermediate-1 risk) vs. those with 2 or 3 risk factors (intermediate-2 or high risk), or SMM. Per the Mayo risk stratification system, possible risk factors include a non-IgG isotype, an IgG paraprotein level >1.5 g/dL, and an abnormal FLC ratio. Ethical approval for