High-dose melphalan (HDM) plus stem cell transplantation is an effective treatment for light-chain amyloidosis (AL), but is associated with high treatment-related mortality in patients with cardiac involvement. We studied 187 patients with cardiac involvement with AL who underwent HDM between 1996 and 2008. The median age was 57 years and the median time from diagnosis to HDM was 3.6 months. Half of the patients received reduceddose melphalan (100-160 mg/m 2 ). The median overall survival (OS) was 66 months, 54 months from diagnosis and HDM, respectively, and 91 patients (49%) were alive at the last follow-up 52 months (median) from HDM. Thirty patients (16%) died within 100 days of transplantation; only low serum albumin predicted early deaths. Overall, hematologic response (HR) and cardiac responses were seen in 66% and 41% of patients, respectively. The median OS for patients with and without HR was not reached and 22 months, respectively (P < .01); and for those with any decrease and no decrease in N-terminal-pro-brain natriuretic peptide was not reached and 26 months, respectively (P < .01). In multivariate analysis of baseline factors, only reduceddose melphalan predicted shorter OS. HDM is feasible in patients with cardiac amyloidosis, and achievement of HR and organ response is associated with improved survival. (Blood. 2012;119(5): 1117-1122) IntroductionAmyloidosis is a group of rare diseases characterized by multiorgan deposition of amyloid fibrils. In light-chain (AL) amyloidosis or primary systemic amyloidosis, the fibrils are derived from the immunoglobulin light chains secreted by clonal plasma cells. 1 AL amyloidosis represents the most common type of systemic amyloidosis and cardiac involvement is seen in more than half of patients at diagnosis. It affects approximately 10 patients per million per year, including 10%-15% of patients with multiple myeloma (MM). 2,3 The treatment approaches used for AL amyloidosis are directed toward the eradication of the abnormal plasma cell clone with the aim of eliminating the supply of the amyloidogenic light chains. 4 Compared with myeloma, AL is typically associated with a lower burden of clonal plasma cells. 5 High-dose melphalan (HDM) and peripheral blood stem cell transplantation (SCT) have been used since the mid-1990s and remain an effective treatment for AL amyloidosis. 6-8 However, the transplantation-related mortality (TRM) in AL amyloidosis (approximately 10%-15%) is significantly higher than that seen in patients with MM and lymphoma (1%-2%) and is often attributed to the presence of underlying cardiac and/or multiorgan involvement. 9 The outcome with HDM among patients with cardiac amyloidosis has not been examined systematically. Therefore, we undertook the present study to examine the outcome of patients with AL amyloidosis receiving HDM, with particular focus on transplantation-related complications, hematologic response (HR) and organ response rates, impact on cardiac function, and factors predicting post-HDM survival. MethodsWe selected the ...

No abstract

Dengue is a serious public health concern worldwide, with ∼3 billion people at risk of contracting dengue virus (DENV) infections, with some suffering severe consequences of disease and leading to death. Currently, there is no broad use vaccine or drug available for the prevention or treatment of dengue, which leaves only anti-mosquito strategies to combat the dengue menace. The present study is an extension of our earlier study aimed at determining the in vitro and in vivo protective effects of a plant-derived phytopharmaceutical drug for the treatment of dengue. In our previous report, we had identified a methanolic extract of aerial parts of Cissampelos pareira to exhibit in vitro and in vivo anti-dengue activity against all the four DENV serotypes. The dried aerial parts of C. pareira supplied by local vendors were often found to be mixed with aerial parts of another plant of the same Menispermaceae family, Cocculus hirsutus, which shares common homology with C. pareira. In the current study, we have found C. hirsutus to have more potent anti-dengue activity as compared with C. pareira. The stem part of C. hirsutus was found to be more potent (∼25 times) than the aerial part (stem and leaf) irrespective of the extraction solvent used, viz., denatured spirit, hydro-alcohol (50:50), and aqueous. Moreover, the anti-dengue activity of stem extract in all the solvents was comparable. Hence, an aqueous extract of the stem of C. hirsutus (AQCH) was selected due to greater regulatory compliance. Five chemical markers, viz., Sinococuline, 20-Hydroxyecdysone, Makisterone-A, Magnoflorine, and Coniferyl alcohol, were identified in fingerprinting analysis. In a test of primary dengue infection in the AG129 mice model, AQCH extract at 25 mg/kg body weight exhibited protection when administered four and three times a day. The AQCH was also protective in the secondary DENV-infected AG129 mice model at 25 mg/kg/dose when administered four and three times a day. Additionally, the AQCH extract reduced serum viremia and small intestinal pathologies, viz., viral load, pro-inflammatory cytokines, and vascular leakage. Based on these findings, we have undertaken the potential preclinical development of C. hirsutus-based phytopharmaceutical, which could be studied further for its clinical development for treating dengue.

No abstract

are employed by Millennium Pharmaceuticals Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited. S. Wang has ownership interests in Takeda Pharmaceutical Company Limited. K. Stumpo has equity ownership in Astra Zeneca and Teva, and has family members with stock ownership in Bristol-Myers Squibb, AstraZeneca, GSK. I. Proscurshim is a former employee of Agenus. F. Bosch declares consultancy for, and has received honoraria and paid expert testimony from Roche, Novartis, Janssen, AbbVie, Gilead, and Mundipharma, and has