Quantification of circulating clonal plasma cells via multiparametric flow cytometry identifies patients with smoldering multiple myeloma at high risk of progression.

The presence of high numbers of circulating clonal plasma cells (cPCs) in patients with smoldering multiple myeloma (SMM), detected by a slide-based immunofluorescence assay, has been associated with a shorter time to progression (TTP) to MM. The significance of quantifying cPCs via multiparameter flow cytometry, a much more readily available diagnostic modality, in patients with SMM has not been evaluated. This study evaluated 100 patients with a known or new diagnosis of SMM who were seen at the Mayo Clinic, Rochester from January 2008 until December 2013. Patients with ⩾150 cPCs (N=9) were considered to have high number of cPCs based on the 97% specificity and 78% PPV of progression to MM within 2 years of cPC assessment. The median TTP of patients with ⩾150 cPCs was 9 months compared with not reached for patients with <150 cPCs (P<0.001). Thus, quantification of cPCs via multiparametric flow cytometry identifies patients with SMM at very high risk of progression to MM within 2 years and warrants confirmation in larger studies. In the future, this may allow reclassification of such patients as having MM requiring therapy prior to them enduring end-organ damage.

Early relapse following initial therapy for multiple myeloma predicts poor outcomes in the era of novel agents.

Outcomes for patients with multiple myeloma (MM) have improved in recent years owing to use of novel agents and high-dose therapy followed by autologous stem cell transplant (ASCT). We analyzed the outcomes of 511 consecutive patients treated with novel therapies at our institution between 2006 and 2014 to determine the impact of relapse within 12 months of initiating treatment. A total of 82 patients (16.0%) experienced early relapse, with median time to relapse of 8.0 months (95% confidence interval (CI); 6.3, 8.9). Median overall survival (OS) was significantly worse for this group at 21.0 months (95% CI; 16.3, 27.2) vs not reached (NR) (95% CI; 96.3, NR) for those with late relapse (P<0.001). Survival outcomes remained poor among early relapse patients irrespective of depth of response to initial therapy. In multivariate analysis, low albumin and high-risk cytogenetics predicted early relapse. Outcomes of early relapse from early ASCT were also considered; median OS from ASCT for those relapsing within 12 months was 23.1 months (95% CI; 15.7, 32.4) vs 122.2 months (95% CI; 111.5, 122.2) for the remaining patients (P<0.001). Early relapse remains a marker of poor prognosis in the current era, and such patients should be targeted for clinical trials.

Phase 2 trial of ixazomib in patients with relapsed multiple myeloma not refractory to bortezomib.

This phase 2 trial was designed to evaluate ixazomib, an orally bioavailable proteasome inhibitor, in patients with myeloma who have limited prior exposure to bortezomib. Thirty-three patients with relapsed multiple myeloma were enrolled. Ixazomib was given at 5.5 mg weekly for 3 of 4 weeks. Dexamethasone was added for lack of a minor response (MR) by end of cycle 2 or lack of a partial response (PR) by end of cycle 4 or for disease progression at any time. Median age was 69 years; patients had a median of two prior therapies (range 1-7). A grade 3 or 4 adverse event considered at least possibly related to drug was seen in 19 (59%) and 6 (19%) patients, respectively. The most common adverse events were thrombocytopenia, fatigue, nausea and diarrhea. Dexamethasone was initiated in 22 (67%) patients, 17 for not reaching the desired response and 5 for progression. Response (⩾PR) to single agent was seen in five patients within four cycles of therapy including three patients with PR, one patient with complete response (CR) and one patient with stringent CR. Six additional patients with either an MR (2) or SD (4) achieved a PR after addition of dexamethasone, translating to an overall response rate of 34%.

Abnormal FISH in patients with immunoglobulin light chain amyloidosis is a risk factor for cardiac involvement and for death.

Importance of interphase fluorescent in situ hybridization (FISH) with cytoplasmic staining of immunoglobulin FISH (cIg-FISH) on bone marrow is not well understood in light chain amyloidosis (AL). This is in contrast with multiple myeloma where prognostic and treatment related decisions are dependent on cytogenetic testing. This retrospective study reviewed 401 AL patients with cIg-FISH testing performed at our institution between 2004 and 2012. Eighty-one percent of patients had an abnormal cIg-FISH. Common abnormalities involved translocations of chromosome 14q32 (52%), specifically: t(11;14) (43%), t(14;16) (3%) and t(4;14) (2%). Other common abnormalities include monosomy 13/deletion 13q (30%), trisomies 9 (20%), 15 (14%), 11 (10%) and 3 (10%). Median overall survival for this cohort of patients is 3.5 years. When plasma cell burden was greater than 10% trisomies predicted for worse survival (44 vs 19 months), and when it was ⩽10% t(11;14) predicted for worse survival (53 months vs not reached). Abnormal cIg-FISH was significantly associated with advanced cardiac involvement, and remained a prognostic factor on multivariate analysis. This large AL cohort demonstrates that abnormal FISH at diagnosis is prognostic for survival and advanced cardiac disease. Particularly, trisomies and t(11;14) affect survival when degree of plasma cell burden is considered.

Metal concentrations in sediments from tourist beaches of Miri City, Sarawak, Malaysia (Borneo Island).

Forty-three sediment samples were collected from the beaches of Miri City, Sarawak, Malaysia to identify the enrichment of partially leached trace metals (PLTMs) from six different tourist beaches. The samples were analyzed for PLTMs Fe, Mn, Cr, Co, Cu, Ni, Pb, Sr and Zn. The concentration pattern suggest that the southern side of the study area is enriched with Fe (1821-6097 µg g(-1)), Mn (11.57-90.22 µg g(-1)), Cr (51.50-311 µg g(-1)), Ni (18-51 µg g(-1)), Pb (8.81-84.05 µg g(-1)), Sr (25.95-140.49 µg g(-1)) and Zn (12.46-35.04 µg g(-1)). Compared to the eco-toxicological values, Cr>Effects range low (ERL), Lowest effect level (LEL), Severe effect level (SEL); Cu>Unpolluted sediments, ERL, LEL; Pb>Unpolluted sediments and Ni>ERL and LEL. Comparative results with other regions indicate that Co, Cr, Cu, Ni and Zn are higher, indicating an external input rather than natural process.

Diabetic Ulcers Treated with Bi-layered Collagen Membrane / 대한피부과학회지

Diabetic foot ulcer is a serious clinical problem with significant medical and economic effects on health systems worldwide. Some patients undergo amputation and others experience disability for an extended period of time. Treatment of diabetic foot ulcer is complex and difficult. Even with proper management, the wounds may not heal as well as expected. To promote wound healing, many advanced topical dressing materials have been developed. Among them, bi-layered collagen membrane, which is composed of collagen and hyaluronic acid, is believed to enhance wound healing. Herein we report two cases of diabetic foot ulcer which were successfully treated using bi-layered collagen membranes.

Diabetic Ulcers Treated with Bi-layered Collagen Membrane / 대한피부과학회지

Diabetic foot ulcer is a serious clinical problem with significant medical and economic effects on health systems worldwide. Some patients undergo amputation and others experience disability for an extended period of time. Treatment of diabetic foot ulcer is complex and difficult. Even with proper management, the wounds may not heal as well as expected. To promote wound healing, many advanced topical dressing materials have been developed. Among them, bi-layered collagen membrane, which is composed of collagen and hyaluronic acid, is believed to enhance wound healing. Herein we report two cases of diabetic foot ulcer which were successfully treated using bi-layered collagen membranes.

An analysis of turbulent shear stresses in leakage flow through a bileaflet mechanical prostheses.

In this work, estimates of turbulence were made from pulsatile flow laser Doppler velocimetry measurements using traditional phase averaging and averaging after the removal of cyclic variation. These estimates were compared with estimates obtained from steady leakage flow LDV measurements and an analytical method. The results of these studies indicate that leakage jets which are free and planar in shape may be more unstable than other leakage jets, and that cyclic variation does not cause a gross overestimation of the Reynolds stresses at large distances from the leakage jet orifice.

Amino acid sequence of piratoxin-II, a myotoxic lys49 phospholipase A(2) homologue from Bothrops pirajai venom.

The complete amino acid sequence of the 121 amino acid residues of piratoxin II, a phospholipase A(2) like myotoxin from Bothrops pirajai venom, is reported. PrTX-II is a basic protein with a molecular mass of 13740 Da, a calculated pI of 9.03, but an experimental pI of 8.4 +/- 0.2, showing sequence similarity with other bothropic (90-99%) or non-bothropic ( approximately 80%) Lys49 PLA(2)-like myotoxins. This similarity falls to approximately 70% when this sequence is aligned with that of Asp49 PLA(2). Due to the substitution of Asp49 by Lys49 and alterations in the calcium binding loop structure, as the replacement of Gly32 by Leu32, piratoxin-II shows no PLA(2) activity when assayed on egg yolk. Piratoxin-II showed the same primary structure as piratoxin-I, except that it has Lys116 for Leu116. Despite this slightly higher basicity at the C-terminal region, piratoxin-II was shown to be less myotoxic than piratoxin-I. The change Leu --> Lys induced an alteration of the molecule surface shape and probably of the environment charge high enough to slightly decrease the myotoxic activity. When aligned with B. jararacussu bothropstoxin-I and with B. asper Basp-II, piratoxin-II revealed a single (position 132) and a quintuple (positions 17, 90, 111, 120 and 132) amino acid substitution, respectively, suggesting a common evolutionary origin for these three myotoxins.

Expression and activity of human Na+/I- symporter in human glioma cells by adenovirus-mediated gene delivery.

Radioiodide concentrating activity in the thyroid, mediated by human Na+/I- symporter (hNIS), provides a mechanism for effective radioiodide treatment for patients who have invasive, recurrent, and metastatic thyroid cancers after total thyroidectomy. In an attempt to develop hNIS gene transfer for radioiodide therapy for patients with brain tumors, we have constructed recombinant adenoviruses, rAd-CMV-hNIS9 and rAd-CMV-FLhNIS, to express exogenous hNIS in U1240 and U1240Tag human glioma cells. U1240Tag differs from U1240 glioma cells in that it expresses the SV40 large T antigen oncoprotein. In both U1240 and U1240Tag cells, radioiodide uptake (RAIU) activity in the cells infected with rAd-CMV-hNIS9 or rAd-CMV-FLhNIS increases as the adenoviral MOI increases. The protein expression profile of hNIS in infected cells is generally in agreement with their RAIU activity profile. Although the expressed hNIS9 protein appeared to have a shorter half-life than FLhNIS, hNIS9 expression could be maintained by multiple infections in these cells. In addition, we show that hNIS can be expressed and function in a xenografted human glioma by intratumoral injection of rAd-CMV-hNIS9.

Corticosterone regulation of insulin-like growth factor I, IGF-binding proteins, and growth in streptozotocin-induced diabetic rats.

The experiments reported herein were conducted to determine how corticosterone regulates growth and plasma insulin-like growth factor (IGF) I and IGF-binding protein (IGFBP) concentrations in normal and streptozotocin (STZ)-induced diabetic rats. Males were bilaterally adrenalectomized (Ax) or sham Ax and given intravenous injections of 0, 30, or 65 mg STZ per kg body wt (0, 30, or 65 STZ) to induce varying degrees of insulin deficiency and implanted with 100-mg pellets containing 0, 40, or 80% corticosterone in cholesterol. Changes in plasma IGFBP concentrations were determined by Western ligand blotting or immunoblots. Neither IGFBP-5 nor IG-FBP-6 was detected in any of the treatment groups. Plasma IGFBP-2 was elevated and IGF-I was reduced in the nondiabetic Ax rats compared with sham Ax controls, but plasma IGFBP-3 and -4 were not significantly changed. Adrenalectomy had no affect on tibial growth or plasma IGFBP-1 in these animals. Plasma IGF-I, IGFBP-1 and -3, and tibial growth were equal among 0, 30, and 65 STZ Ax rats that did not receive corticosterone. Plasma IGFBP-4 was inversely related to the amount of STZ injected in these animals, and IGFBP-2 was elevated in those given the high dose of STZ. In the 0 STZ Ax rats, plasma IGF-I and IGFBP-3 increased in proportion to the corticosterone implant dose, but IGFBP-1 was unaffected. By contrast, IGF-I and IGFBP-3 were unaltered by corticosterone in the 30 STZ Ax rats, and IGFBP-1 increased in proportion with the dose of corticosterone.(ABSTRACT TRUNCATED AT 250 WORDS)