Novel therapeutic approaches for multiple myeloma

Summary: Multiple myeloma (MM) affects 15 000 new patients annually in the US, with 50 000 total patients, and remains incurable. Our preliminary in vitro and animal studies suggest a role for MM–host interactions in regulating MM cell growth, drug resistance, and migration in the bone marrow. Importantly, treatment strategies which target mechanisms whereby MM cells grow and survive in the bone marrow, including thalidomide and its potent immunomodulatory derivatives and proteasome inhibitor PS‐341, can overcome classical drug resistance in preclinical and early clinical studies.     

Proteasome inhibition

Proteasome inhibition is a new approach under investigation for cancer therapy. Protein degradation by the proteasome is a fundamental metabolic process. Inhibition of the proteasome has been shown to result in cell-cycle arrest and programmed cell death. Bortezomib (Velcade®; formerly PS-341, Millennium Pharmaceuticals, Inc, Cambridge, Massachusetts) is the first proteasome inhibitor to enter clinical trials and is approved for the treatment of multiple myeloma in patients who have received at least two prior therapies and progressed on their last therapy. It is also being investigated for the treatment of a range of other cancers, both solid and hematologic. In preclinical studies, bortezomib causes apoptosis in cancer cells and seems to enhance the cytotoxicity of other conventional tumoricidal agents in human tumor cell lines, murine tumor models, and human xenograft models. In addition to targeting cancer cells directly, there is growing evidence that proteasome inhibition interferes with protective interactions between cancer cells and the bone marrow and may also act to prevent tumor-associated angiogenesis. Preliminary data suggest that bortezomib inhibits proteasome activity in a dose-dependent and reversible manner, and has manageable toxicities. A phase II trial in relapsed and refractory multiple myeloma patients indicated that patients experienced substantial anticancer activity when treated with bortezomib monotherapy.     

Potentially Life-threatening Arrhythmia Triggered by an Excessive Consumption of Dried Sweet Potato “Hoshi-Imo”

We herein report two cases of potentially life-threatening arrhythmia due to hyperkalemia triggered by the excessive consumption of “Hoshi-Imo” (dried sweet potato). Both patients with chronic renal disease on renin-angiotensin-aldosterone system inhibitors presented at the emergency room with non-specific symptoms. Electrocardiograms revealed potentially life-threatening arrhythmia due to hyperkalemia in both cases: sinus arrest with a ventricular escape rhythm, tall and peaked T waves; and a widened QRS complex in a nearly sine-wave configuration without discernible P wave. Both patients fully recovered after intensive care for hyperkalemia. Physicians should recognize the excessive consumption of “Hoshi-Imo” may lead to the development of life-threatening arrhythmia, especially in patients with risk factors for hyperkalemia.     

Proteasome inhibition in hematologic malignancies

Hematologic malignancies, including multiple myeloma (MM), will account for more than 100,000 new cases of cancer and over 57,000 deaths in the United States in 2003. Treatment of MM is a serious challenge, because despite a variety of available therapies, median survival is short. A new therapeutic area focuses on inhibiting the activity of the proteasome, a 26S protease complex involved in cell cycle regulation, cell adhesion, inflammation, and protein turnover. The novel proteasome inhibitor, bortezomib (Velcade®), was recently approved for use in patients with refractory and relapsed MM and to date is the only proteasome inhibitor to have entered clinical trials. Bortezomib has demonstrated activity with manageable toxicity in a variety of hematologic malignancies in addition to MM, including leukemia and non‐Hodgkin's lymphoma. This article reviews clinical information on bortezomib in hematologic malignancies both as monotherapy and in combination with dexamethasone. Preliminary reports of bortezomib in combination with Doxil (pegylated liposomal doxorubicin), melphalan, and thalidomide are discussed, and current trials are described. Available data suggest that bortezomib will be useful in the treatment of a variety of hematologic malignancies.     

Anti-CS1 humanized monoclonal antibody HuLuc63 inhibits myeloma cell adhesion and induces antibody-dependent cellular cytotoxicity in the bone marrow milieu

Currently, no approved monoclonal antibody (mAb) therapies exist for human multiple myeloma (MM). Here we characterized cell surface CS1 as a novel MM antigen and further investigated the potential therapeutic utility of HuLuc63, a humanized anti-CS1 mAb, for treating human MM. CS1 mRNA and protein was highly expressed in CD138-purified primary tumor cells from the majority of MM patients (more than 97%) with low levels of circulating CS1 detectable in MM patient sera, but not in healthy donors. CS1 was expressed at adhesion-promoting uropod membranes of polarized MM cells, and short interfering RNA (siRNA) targeted to CS1 inhibited MM cell adhesion to bone marrow stromal cells (BMSCs). HuLuc63 inhibited MM cell binding to BMSCs and induced antibody-dependent cellular cytotoxicity (ADCC) against MM cells in dose-dependent and CS1-specific manners. HuLuc63 triggered autologous ADCC against primary MM cells resistant to conventional or novel therapies, including bortezomib and HSP90 inhibitor; and pretreatment with conventional or novel anti-MM drugs markedly enhanced HuLuc63-induced MM cell lysis. Administration of HuLuc63 significantly induces tumor regression in multiple xenograft models of human MM. These results thus define the functional significance of CS1 in MM and provide the preclinical rationale for testing HuLuc63 in clinical trials, either alone or in combination.     

Clinical Characteristics of Portal Hemodynamics in Alcoholic Liver Cirrhosis

Background: Low incidence of reversal blood flow at the portal vein has been reported by measurement in larger and extrahepatic blood vessels but not in intrahepatic blood vessels in patients with liver cirrhosis. Moreover, there is little information regarding the incidence of reversal blood on the basis of the cause of liver cirrhosis. The aim of this study was to measure the reversal blood flow in the portal vein including intrahepatic branches in patients with alcoholic and viral cirrhosis.
Methods: The blood flow in the portal vein and existence of portosystemic shunt were studied in 52 and 27 patients with alcoholic and viral cirrhosis, respectively, by Doppler ultrasonography. The parameters of liver function test and the prevalence of ascites and esophageal varices were compared between patients with and without reversal blood flow.
Results: Reversal blood flow at the portal vein was found only in patients with only alcoholic cirrhosis (17 of 52 patients) but not in any patients with viral cirrhosis (0 of 27 patients; p < 0.05). The incidence of portosystemic ascites and red color of esophageal varices was also higher in patients with alcoholic cirrhosis with reversal blood flow in the portal vein compared with patients without reversal blood flow ( p < 0.05).
Conclusions: Reversal blood flow in the portal vein is a characteristic feature of alcoholic cirrhosis. The presence of reversal blood flow indicates severe liver diseases, and this feature may have prognostic importance for patients with alcoholic cirrhosis.     

2-Methoxyestradiol overcomes drug resistance in multiple myeloma cells

2-Methoxyestradiol (2ME2) an estrogen derivative, induces growth arrest and apoptosis in leukemic cells and is also antiangiogenic. In this study, we demonstrate that 2ME2 inhibits growth and induces apoptosis in multiple myeloma (MM) cell lines and patient cells. Significantly, 2ME2 also inhibits growth and induces apoptosis in MM cells resistant to conventional therapies including melphalan (LR-5), doxorubicin (Dox-40 and Dox-6), and dexamethasone (MM.1R). In contrast to its effects on MM cells, 2ME2 does not reduce the survival of normal peripheral blood lymphocytes. Moreover, 2ME2 enhances Dex-induced apoptosis, and its effect is not blocked by interleukin-6 (IL-6). We next examined the effect of 2ME2 on MM cells in the bone marrow (BM) milieu. 2ME2 decreases survival of BM stromal cells (BMSCs), as well as secretion of vascular endothelial growth factor (VEGF), and IL-6 triggered by the adhesion of MM cells to BMSCs. We show that apoptosis induced by 2ME2 is mediated by the release of mitochondrial cytochrome-c (cyto-c) and Smac, followed by the activation of caspases-8, -9, and -3. Finally, 2ME2 inhibits MM cell growth, prolongs survival, and decreases angiogenesis in a murine model. These studies, therefore, demonstrate that 2ME2 mediates anti-MM activity directly on MM cells and in the BM microenvironment. They provide a framework for the use of 2ME2, either alone or in combination with Dex, to overcome drug resistance and to improve outcome in MM.     

Age-related changes in the electrophysiologic properties of the atrium in patients with no history of atrial fibrillation

Although atrial fibrillation is a common arrhythmia, especially in the elderly, little is known about age-related changes in the electrophysiologic properties of the atrium. The aim of this study was to analyze the effect of aging on atrial vulnerability to atrial fibrillation. An electrophysiologic study was performed in 45 patients with no history of atrial fibrillation, Wolff-Parkinson-White syndrome, structural heart disease, or conditions with potential effects on cardiac hemodynamic or electrophysiologic function (15 females; mean age, 52 +/- 18 years; range, 14 to 84 years). The following atrial excitability parameters were assessed: spontaneous or paced (A1) and extrastimulated (A2) atrial electrogram widths, percent maximum atrial fragmentation (A2/A1 x 100), effective refractory period, wavelength index (ERP/A2), and inducibility of atrial fibrillation. Atrial fibrillation was induced in 9 patients. Percent maximum atrial fragmentation was greater (176 +/- 36 vs 137 +/- 26%, P < 0.001) and wavelength index was shorter (2.4 +/- 0.4 vs 3.2 +/- 0.9, P < 0.01) in the patients with than without inducible atrial fibrillation. However, age was similar in patients with and without inducible atrial fibrillation (47 +/- 11 vs 53 +/- 19 years, P = 0.36). Percent maximum atrial fragmentation and effective refractory period directly correlated with age (r = 0.32, P < 0.05 and r = 0.45, P < 0.001, respectively). On the other hand, wavelength index (3.1 +/- 0.9) did not correlate with age (r = -0.05, P = 0.77). This study suggests that the mechanism triggering atrial fibrillation may be very well different between older and younger patients with atrial fibrillation, because younger patients have no marked substrate for atrial fibrillation.     

Quantification of Pancreatic Stiffness on Intraoperative Ultrasound Elastography and Evaluation of its Relationship With Postoperative Pancreatic Fistula

“Soft pancreas” has often been reported as a predictive factor for postoperative pancreatic fistula (POPF) after pancreatectomy. However, pancreatic stiffness is judged subjectively by surgeons, without objective criteria. In the present study, pancreatic stiffness was quantified using intraoperative ultrasound elastography, and its relevance to POPF and histopathology was investigated. Forty-one patients (pancreatoduodenectomy, 30; distal pancreatectomy, 11) who underwent intraoperative elastography during pancreatectomy were included. The elastic ratio was determined at the pancreatic resection site (just above the portal vein) and at the remnant pancreas (head or tail). Correlations between the incidence of POPF and patient characteristics, operative variables, and the elastic ratio were examined. In addition, the relationship between the elastic ratio and the percentage of the exocrine gland at the resection stump was investigated. For pancreatoduodenectomy patients, main pancreatic duct diameter < 3.2 mm and elastic ratio < 2.09 were significant risk factors for POPF. In addition, the elastic ratio, but not main pancreatic duct diameter, was significantly associated with the percentage of exocrine gland area at the pancreatic resection stump. Pancreatic stiffness can be quantified using intraoperative elastography. Elastography can be used to diagnose “soft pancreas” and may thus be useful in predicting the occurrence of POPF.Key words: Elastography, Exocrine gland, Pancreatectomy, Pancreatic stiffness, Postoperative pancreatic fistulaDespite current advances in surgical techniques, pancreatectomy is a very difficult procedure associated with the risk of multiple postoperative complications. The morbidity and mortality are reported to be 20–50% and 1–5%, respectively.¹ In particular, a postoperative pancreatic fistula (POPF) can sometimes lead to life-threatening complications, such as hemoperitoneum and sepsis. The worldwide incidence of POPF is reported to be 5–50%. Several predictive factors for POPF have been reported to date, and, of these, “soft pancreas” has often been mentioned.^2–4 However, in all of these reports, evaluation of pancreatic stiffness has depended on subjective judgment by the surgeon, without objective parameters as criteria.Elastography has recently been developed to enable real-time visualization of the relative stiffness of tissue elasticity, and its usefulness in various clinical disciplines for tumor diagnosis and differential diagnosis has been described.⁵ In gastroenterology, evaluation of liver fibrosis and diagnosis of pancreatic tumors and chronic pancreatitis using endoscopic ultrasound (EUS) have been reported,^6,7 but the use of elastography in surgery has not been reported. An objective assessment of pancreatic stiffness as a predictive risk factor for POPF can help in choosing the intraoperative surgical technique and in planning the postoperative management strategy. Therefore, in the present study, pancreatic stiffness was quantified using intraoperative ultrasound elastography, and its relevance to POPF and histopathology was investigated.