Idiotype‐pulsed antigen presenting cells following autologous transplantation for multiple myeloma may be associated with prolonged survival

Vaccines are attractive as consolidation therapy after autologous stem cell transplantation (ASCT) for multiple myeloma (MM). We report the results of a phase II trial of the immunotherapeutic, APC8020 (Mylovenge?), given after ASCT for MM. We compared the results with that of other patients with MM who underwent ASCT at Mayo Clinic during the same time period. Twenty‐seven patients were enrolled on the trial between July, 1998 and June, 2001, and the outcomes were compared to that of 124 consecutive patients transplanted during the same period, but not enrolled on the trial. The median (range) follow‐up for patients still alive from the vaccine trial is 6.5 (2.9–8 years), and 7.1 (6–8 years) in the control group. The median age was 57.4 range (36.1–71.3) in the DB group and 56.4 (range, 30–69) in the trial group. Known prognostic factors including PCLI, B2M, and CRP were comparable between the groups. The median overall survival for the trial patients was 5.3 years (95% CI: 4.0 years—N/A) compared to 3.4 years (95% CI: 2.7–4.6 years) for the DB group (P = 0.02). The median time to progression and progression‐free survival for the trial group was similar to the DB group. Although not a controlled trial, the vaccines given after ASCT appear to be associated with improved overall survival compared to historical controls. This approach warrants further investigation to confirm this and define the role of vaccine therapy in myeloma. Am. J. Hematol. 2009. © 2009 Wiley‐Liss, Inc.     

Impact of lenalidomide therapy on stem cell mobilization and engraftment post-peripheral blood stem cell transplantation in patients with newly diagnosed myeloma.

While initial therapies have become highly effective with introduction of lenalidomide and bortezomib and patients may opt for delayed stem cell transplantation, it is important to collect stem cells for future transplant. Given its increasing use as initial therapy, we examined if lenalidomide had any impact on the ability to collect peripheral blood stem cells (PBSC). We studied the entire cohort of patients with myeloma undergoing PBSC mobilization at our institution during a 5-year period, comparing the results between patients receiving different initial therapies. Among those mobilized with granulocyte-colony stimulating factor (G-CSF) alone, there was a significant decrease in total CD34(+) cells collected (P<0.001), average daily collection (P<0.001), day 1 collection (P<0.001) and increased number of aphereses (P=0.004) in patients treated with lenalidomide compared to those receiving dexamethasone, thalidomide-dexamethasone or VAD. A similar trend was seen in those mobilized with chemotherapy and G-CSF. A trend was seen towards decreased PBSC yield with increasing duration of lenalidomide therapy as well as increasing age (P=0.002). There was no effect on quality of PBSC collected based on similar engraftment across all groups. We recommend collection of PBSC within 6 months of initiation of therapy with lenalidomide containing regimens to minimize the risk of mobilization failures.     

Identifying the presence of antibodies against endometrial antigens. A preliminary study.

Serum and peritoneal fluid from women with and without evidence of endometriosis were tested for the presence of antibodies against endometrial tissue antigens with Western blot analysis. Serum antibodies against endometrial cytosolic antigens of molecular weight 45, 52, 58, 62 and 66 kd were present in samples obtained from women both with and without endometriosis. The patients with endometriosis had serum antibodies against 34-kd endometrial cytosolic antigen, which was not present in serum from fertile women without endometriosis. The peritoneal fluid from patients with endometriosis also reacted with 34-kd endometrial antigen but not the peritoneal fluid from control fertile women. There was no difference in the antigens detected with serum antibody when endometrium from fertile women without evidence of endometriosis and from women with endometriosis was used as a source of antigen. The presence of serum antibody against 34-kd endometrial antigen is specific to endometriosis. However, this antigen is expressed by endometrium of women both with or without endometriosis. Isolation and identification of this antigen may lead to development of a noninvasive aid for the diagnosis of endometriosis.     

Mildly abnormal retinal function in transgenic mice without Müller cell aquaporin-4 water channels

PURPOSE: Immunocytochemistry showed strong aquaporin (AQP)-4 water channel expression in Müller cells in mouse retina and fibrous astrocytes in optic nerve. This study was designed to test the hypothesis that AQP4 is required for vision by comparing electroretinograms and retinal morphology in wild-type mice and transgenic knockout mice with no AQP4. METHODS: Electroretinograms were recorded over a 10(5)-fold range of flash intensities in dark-adapted mice and analyzed for a- and b-wave amplitude and latency, a-wave normalized slope, and oscillatory potential amplitude and latency. AQP4 protein was localized in mouse retina by immunocytochemistry, and retinal morphology was studied by light and electron microscopy. RESULTS: Significantly reduced electroretinogram b-wave potentials were recorded in 10-month-old null mice with smaller changes in 1-month-old mice. Immunocytochemistry showed strong AQP4 protein expression in retina of wild-type mice. Morphologic analysis of retina by light and electron microscopy showed no differences in retinal ultrastructure. CONCLUSIONS: Retinal function is mildly impaired in AQP4-null mice, suggesting a role for AQP4 in Müller cell fluid balance. These results support the paradigm that AQP4 expression in supportive cells in the nervous system facilitates neural signal transduction in nearby electrically excitable cells.     

Skeletal muscle and jejunal protein synthesis in normal and ethanol-treated rats: the effect of the nitric oxide synthase inhibitors,L-omega-nitro-L-arginine methyl ester and N(G)-nitro-L-arginine in vivo

The nitric oxide synthase (NOS) inhibitors, L-omega-nitro-L-arginine methyl ester (L-NAME; 25 mg/kg and 100 mg/kg) and N(G)-nitro-L-arginine (L-NNA; 100 mg/kg) were used to investigate the role of NO on in vivo skeletal muscle and jejunal (mucosa and seromuscular layer) protein synthesis rates in normal (ie, untreated) and ethanol-dosed (75 mmol/kg body weight) rats. Fractional rates of protein synthesis, ie, percentage of protein pool renewed each day, k(s), %/d) were measured with a flooding dose of L-[(3)H-4]phenylalanine. In response to both doses of L-NAME and L-NNA, k(s) in skeletal muscle of normal rats decreased by 9% to 31% (P between <.05 and <.001). In the mucosa, k(s) was significantly reduced only by the higher dose of L-NAME (-49%, P <.001). In the seromuscular layer, k(s) was reduced by 15% to 57% (P between <.05 and <.001) in response to both doses of L-NAME and L-NNA. Ethanol dosage reduced k(s) in skeletal muscle (-35%, P <.001), and small reductions also occurred in the jejunal mucosal and seromuscular layers (-14% P <.05 and -12% P <.05, respectively). However, in the presence of L-NAME, ethanol reduced k(s) in jejunal mucosal and seromuscular layers by -35% (P <.01) and -30% (P <.01), respectively, compared with controls. This exacerbating effect of L-NAME predosage in ethanol-treated rats was not demonstrable in skeletal muscle. The data thus suggest that (1) endogenous NO facilitates constitutive skeletal muscle and jejunal protein synthesis in control animals in vivo; (2) the sensitivity of jejunal (but not skeletal muscle) protein synthesis to acute ethanol is increased when inhibitors of NOS are used. This tentatively implies that, in response to ethanol, overproduction of NO is not involved in the ethanol-induced reduction of protein synthesis in skeletal muscle or the jejunum.     

Primary systemic amyloidosis

Opinion statement Primary amyloidosis is a plasma cell dyscrasia in which insoluble immunoglobulin light chain fragments are produced and polymerize into fibrils that deposit extracellularly, causing visceral organ dysfunction and death. The disorder is rare. Its recognition requires understanding the association between nephrotic syndrome, cardiomyopathy, peripheral neuropathy, and hepatomegaly with amyloidosis. The most important screening test for amyloidosis is immunofixation of the serum and urine to detect a monoclonal immunoglobulin light chain. All patients need the diagnosis confirmed histologically. The least invasive source of tissue for amyloid detection is the subcutaneous fat. The most important prognostic factor is whether there is cardiac involvement, which is best assessed by echocardiography with Doppler studies. Therapies used include oral melphalan/prednisone and high-dose corticosteroids. High-dose chemotherapy followed by stem cell reconstitution seems to provide the highest reported response rates. Transplant is associated with unique morbidities not seen in the transplantation of patients with other hematologic malignancies.     

Biological and prognostic significance of interphase fluorescence in situ hybridization detection of chromosome 13 abnormalities (delta13) in multiple myeloma: an eastern cooperative oncology group study

Chromosome 13 abnormalities (Delta13) have been associated with an unfavorable prognosis in patients with multiple myeloma (MM). The significance of this has been unresolved because of diverse methods of detection and heterogeneous groups of patients. We conducted a study of Delta13 in patients entered into the Eastern Cooperative Oncology Group trial E9486/E9487. Patients with newly diagnosed MM (median follow-up of survivors >100 months) were studied for Delta13, using bone marrow samples obtained at study enrollment. We used interphase fluorescence in situ hybridization with the probes LSI13 (Rb)/D13S319 with simultaneous immunofluorescence detection of bone marrow plasma cells (PCs). We detected Delta13 in 176 of 325 (54%) evaluable patients. Patients with Delta13 were more likely to have a serum monoclonal protein at a concentration < or =1 g/dl (22 versus 13%; P = 0.04), light-chain-only MM (19.3 versus 10.8%; P = 0.04), gamma light chain (42 versus 28%; P = 0.027), stage III (56 versus 42%; P = 0.014), and be female (60 versus 50%; P = 0.087). The PC labeling index and Delta13 correlated (P = 0.03). Patients with Delta13 were less likely to respond to treatment (74 versus 63%; P = 0.041) and had a significantly shorter median overall survival (34.9 versus 51 months; P = 0.021). The association of Delta13 and survival remained an independent prognostic variable in a regression model. Among patients with Delta13, those receiving IFN had a worse overall survival that those not receiving the medication (P = 0.03). The presence of Delta13 is an important and independent adverse prognostic factor in newly diagnosed MM and is associated with specific biological features.