"Real-life" data of the efficacy and safety of belantamab mafodotin in relapsed multiple myeloma-the Mayo Clinic experience.

Belantamab mafodotin is a highly selective targeted therapy for multiple myeloma. It targets the B cell maturation antigen (BCMA) on plasma cells and showed promising results in several randomized clinical trials. We report the outcomes of 36 patients treated at Mayo Clinic. Our cohort received a median of eight prior lines of therapy. Six patients received belantamab in combination with other medications (pomalidomide, cyclophosphamide, thalidomide), 13 patients (36%) were 70 years or older, two patients had a creatinine of >2.5 mg/dL, and one patient was on dialysis. All three patients with renal failure received full dose belantamab. Chimeric antigen receptor (CAR-T) therapy was used prior to belantamab in seven patients and none of them responded to belantamab therapy. The overall response rate (ORR) was 33% (CR 6%, VGPR 8%, PR 19%), like the ORR reported in the DREAMM-2 trial. Keratopathy developed in 16 patients (43%), grade 1 in six patients, grade 2 in seven patients, and grade 3 in three patients. Eight percent discontinued therapy due to keratopathy. The median PFS and OS was 2 months and 6.5 months, respectively.

Pomalidomide-dexamethasone in refractory multiple myeloma: long-term follow-up of a multi-cohort phase II clinical trial.

Despite therapeutic advances, multiple myeloma remains incurable, with limited options for patients with refractory disease. We conducted a large, multi-cohort clinical trial testing various doses and treatment schedules of pomalidomide and dexamethasone (Pom/dex) in patients with refractory multiple myeloma. Overall, 345 patients were enrolled to six cohorts based on number and type of prior lines of therapy, pomalidomide dose and schedule. Median prior lines of therapy were three with near universal prior exposure to proteasome inhibitors and/or immunomodulatory drugs. A confirmed response rate of 35% was noted for all cohorts (range 23-65%) with higher responses in cohorts with fewer prior lines of therapy. Median time to confirmed response was ⩽2 months and the longest progression-free survival and overall survival seen in any cohort were 13.1 and 47.9 months, respectively. Observed adverse reactions were as expected, with myelosuppression and fatigue being the most common hematologic and non-hematologic adverse events (AEs), respectively. Longer durations of treatment and response, higher response rates and fewer AEs were noted with the 2 mg pomalidomide dose. This is the longest follow-up data for Pom/dex in refractory multiple myeloma and will help shape the real-world utilization of this regimen.

Delayed Anaphylaxis to the flu vaccine unrelated to known non-viral components.

On February 4, 2010 the CDC's Advisory Committee on Immunization Practices voted for universal flu vaccination to expand protection against the flu throughout the United States. In addition to this administration expansion, six new influenza vaccines have been introduced into the market possibly introducing new allergenic potentials. We report two cases of delayed anaphylaxis to the flu vaccine.

Partners for Life: a theoretical approach to developing an intervention for cardiac risk reduction.

Long-term maintenance of behavioral change to reduce health risk factors is essential to producing a positive effect on medical outcomes. This study examines whether an ongoing, long-term relationship can be used to help patients diagnosed with coronary artery disease adhere to a risk-reducing behavioral intervention and maintain healthy behavioral changes. One hundred and sixty patients with diagnosed coronary artery disease will be randomized to a standard behavioral treatment group or to a standard behavioral treatment group including a couples intervention and followed for 18 months. The treatment in both groups follows tenets of cognitive behavioral and Self-Determination Theories as well as the Transtheoretical Model of Behavior Change. In addition, the couples intervention is designed to (1) change the patient's environment to facilitate cardiac risk-reducing behavioral changes, (2) optimize social reinforcement and motivation for behavior change, and (3) decrease relationship stress. Behavioral outcomes assessed include adherence to an exercise regimen, adherence to dietary recommendations and adherence to lipid-lowering medication. Lipid values, psychological variables and relationship variables are assessed throughout the study and at follow-up. While we expect both groups of cardiac patients to successfully adapt new health behaviors, we expect the couples intervention to be superior in helping maintain long-term health behaviors.

Mycoplasma in the spotlight of AIDS: partial biochemical characterization of mycoplasma-derived components inducing TNF alpha secretion and blast transformation.

We have previously demonstrated that the AIDS-associated Mycoplasma fermentans as well as Mycoplasma capricolum membranes activated bone marrow macrophages to secrete tumor necrosis factor alpha (TNF alpha) and induce blast transformation of splenic lymphocytes. Herein, we show that the membrane component of Mycoplasma capricolum capable of inducing TNF alpha secretion is a hydrophobic protein. This is supported by our findings that the TNF alpha inducing activity was eluted by a phenyl-Sepharose column in a peak distinct from bulk membrane lipids. The hydrophobic nature of the protein is indicated by the activity of the "hydrophobic protein" fraction of the membranes, and the pattern of elution obtained by the phenyl-Sepharose column. Fractionation of the M. capricolum membranes, solubilized by CHAPS (3-[(3-cholamidopropyl)-dimethylammoniol]1-propane sulfate) on a gel filtration column revealed a major peak of TNF alpha inducing activity of about 75,000 daltons, and a minor peak of about 55,000 daltons. The mitogenic activity, though spread throughout the column, peaked in the same fractions as the TNF alpha inducing activity. Both activities co-eluted by the phenyl-Sepharose column as well. However, the mitogenic activity of the membranes was much more resistant to elevated temperatures and extreme pH treatment.

Activation of a human peroxisome proliferator-activated receptor by the antitumor agent phenylacetate and its analogs.

The aromatic fatty acid phenylacetate and its analogs induce tumor cytostasis and differentiation in experimental models. Although the underlying mechanisms of action are not clear, effects on lipid metabolism are evident. We have now examined whether these compounds, structurally similar to the peroxisome proliferator clofibrate, affect the human peroxisome proliferator-activated receptor (hPPAR), a homolog of the rodent PPAR alpha, a transcriptional factor regulating lipid metabolism and cell growth. Gene transfer experiments showed activation of hPPAR, evident by the increased expression of the reporter gene chloramphenicol acetyltransferase linked to PPAR-response element from either the rat acyl-CoA oxidase or rabbit CYP4A6 genes. The relative potency of tested drugs in the co-transfection assay was: 4-iodophenylbutyrate > 4-chlorophenylbutyrate > clofibrate > phenylbutyrate > naphthylacetate > 2,4-D > 4-chlorophenylacetate > phenylacetate >> indoleacetate. Phenylacetylglutamine, in which the carboxylic acid is blocked, was inactive. The ability of the aromatic fatty acids to activate PPAR was confirmed in vivo, as CYP4A mRNA levels increased in hepatocytes of treated rats. Further studies using human prostate carcinoma, melanoma, and glioblastoma cell lines showed a tight correlation between drug-induced cytostasis, increased expression of the endogenous hPPAR, and receptor activation documented in the gene-transfer model. These results identify phenylacetate and its analogs as a new class of aromatic fatty acids capable of activating hPPAR, and suggest that this nuclear receptor may mediate tumor cytostasis induced by these drugs.

cDNA cloning, chromosomal mapping, and functional characterization of the human peroxisome proliferator activated receptor.

The human peroxisome proliferator activated receptor (hPPAR) was cloned from a human liver cDNA library. The cDNA exhibited 85% and 91% DNA and deduced amino acid sequence identity with mouse PPAR (mPPAR), respectively. The hPPAR gene was mapped on human chromosome 22 slightly telomeric to a linkage group of six genes and genetic markers that are located in the general region 22q12-q13.1. Cotransfection assays of mouse Hepa 1 cells were used to roughly compare the ability of hPPAR- and mPPAR-expressed cDNAs to trans-activate the acyl CoA oxidase (ACO) PPAR response element located 5' upstream to the minimal thymidine kinase promoter driving the expression of the chloramphenicol acetyl transferase (CAT) reporter gene. Both receptors elicited a response with the prototypical peroxisome proliferators nafenopin, clofibrate, and WY-14,643. Moreover, using cotransfection assays in which the CAT reporter plasmid contained the CYP4 A6 gene response element rather than the ACO element, it was shown that hPPAR is capable of very efficiently trans-activating a second PPAR response element. These results indicate that the PPAR is present in humans in a form that is functional and can trans-activate response elements derived from two different genes, the rat ACO and the rabbit CYP4A6.

Supplementing behavioral marital therapy with cognitive restructuring and emotional expressiveness training: an outcome investigation.

The current study investigated whether the effectiveness of behavioral marital therapy (BMT) would be increased by the addition of cognitive restructuring (CR) and/or emotional expressiveness training (EET) for maritally distressed couples. Sixty such couples were randomly assigned to 1 of 3 therapists and 1 of 5 treatment conditions (BMT Alone, CR + BMT, BMT + EET, CR + BMT + EET, or waiting list) for 12 weeks of conjoint marital therapy. Within each treatment condition, couples typically improved on the variables focused on in treatment. However, comparisons among active treatment conditions showed few significant differences among treatments; the treatments were equally effective in increasing marital adjustment. Thus, the addition of CR and EET did not appear to increase the overall effectiveness of treatment. Possible reasons for the current findings are provided, and suggestions for future marital outcome investigations are outlined.

Partial biochemical characterization of spiroplasma membrane component inducing tumor necrosis factor alpha.

We have recently found that membranes of Spiroplasma spp. strain MQ-1 (hereafter referred to as MQ-1) induce both tumor necrosis factor alpha (TNF alpha) secretion by bone marrow macrophages and blast transformation of lymphocytes via a mechanism different from that operated by bacterial lipopolysaccharide (LPS). This report presents evidence indicating that the MQ-1-derived membrane component(s) which activates bone marrow macrophages to secrete TNF alpha is, at least in part, protein. This conclusion is supported by our findings that TNF alpha secretion was reduced following exposure of MQ-1 membranes to elevated temperatures, extreme acidic pH treatment and incubation with protease K or pronase. Furthermore, following lipid extraction of MQ-1 membranes, most of both induction of TNF alpha secretion and blast transformation activities appeared in the 'protein' fraction. When membranes were chromatographed on a phenyl-Sepharose column, two major peaks were obtained, one containing most of the TNF alpha induction activity and the other the mitogenic activity. Neither peak coeluted with the peak of bulk membrane lipids. The possibility that the spiroplasma membrane component inducing TNF alpha secretion is acylated protein is discussed.

In vitro induction of tumor necrosis factor alpha, tumor cytolysis, and blast transformation by Spiroplasma membranes.

Membranes of Spiroplasma sp. strain MQ-1 (hereafter referred to as MQ-1) were potent inducers of tumor necrosis factor alpha (TNF alpha) secretion and of blast transformation. Specific anti-recombinant murine TNF alpha antibodies markedly inhibited macrophage-mediated tumor cytolysis of A9 fibrosarcoma target cells following activation by MQ-1 membranes. Thus, TNF alpha plays a major role in mediation of tumor cytolysis induced by MQ-1 membranes, which is similar to its role in lipopolysaccharide (LPS)-induced tumor cytolysis. Two findings, however, suggested that the mechanism of macrophage activation by MQ-1 membranes differs from that by LPS: (a) macrophages, taken from C3H/HeJ mice showing a low responsiveness to LPS, were activated by MQ-1 membranes to enhanced TNF alpha secretion, resulting in a high-level tumor cytolysis compared with the negligible tumor cytolysis induced by LPS; and (b) MQ-1 membranes and LPS synergized to highly augment TNF alpha secretion by macrophages of C57BL/6 mice. MQ-1 membranes were capable of inducing blast transformation of murine lymphocytes as well. In addition, they activated human monocytes to secrete high levels of TNF alpha. Further studies need to be carried out using in vivo models to evaluate the therapeutic potential of MQ-1 membranes in the treatment of malignant diseases.

Mycoplasma capricolum membranes induce tumor necrosis factor alpha by a mechanism different from that of lipopolysaccharide.

Heat-inactivated (60 degrees C, 45 min) Mycoplasma capricolum strain JR cells activate murine macrophages to secrete high levels of tumor necrosis factor alpha (TNF alpha) and to lyse tumor target cells efficiently. Fractionation of the intact M. capricolum cells, obtained from cells harvested at the exponential phase of growth, shows that their capacity to induce TNF alpha secretion by macrophage resides exclusively in the membrane fraction. The macrophage-mediated cytolysis following activation by M. capricolum membranes was significantly inhibited by specific anti-recombinant murine TNF alpha antibodies. M. capricolum membranes are a potent inducer of TNF alpha as the commonly used bacterial lipopolysaccharide, indicated by their dose-response curve for macrophage activation. Our study further showed that M. capricolum membranes and lipopolysaccharide synergize to augment TNF alpha secretion by C57BL/6-derived macrophages markedly. Moreover, lipopolysaccharide-unresponsive C3H/HeJ-derived macrophages, were pronouncedly activated by M. capricolum membranes, which do not contain lipopolysaccharide. These findings suggest that the mechanism by which M. capricolum membranes activate macrophages differs from that of lipopolysaccharide. Results of preliminary experiments show that human monocytes as well secrete TNF alpha following activation by M. capricolum membranes. Thus, in contrast with the prohibitive toxicity of lipopolysaccharide to animals and humans, M. capricolum membranes, which contain no lipopolysaccharide and are nontoxic in nature, may be of therapeutic value in the treatment of cancer.

Tumor necrosis factor as a mediator of Mycoplasma orale-induced tumor cell lysis by macrophages.

We and other investigators have previously demonstrated that mycoplasmas induce macrophage-mediated lysis of tumor cells, but the mechanism responsible for this process had, thus far, not been clarified. We now report that addition of either viable or heat-killed Mycoplasma orale to murine macrophages induces a cytolytic activity which, due to its neutralization by a specific antiserum against murine cloned recombinant tumor necrosis factor (rTNF), was identified as TNF-mediated. Both thioglycollate-elicited peritoneal macrophages and the normal macrophages cloned from our JBM phi 1.1 bone-marrow-derived cell line effectively produced TNF at levels similar to, or higher than, those obtained in the presence of high concentrations of lipopolysaccharide (LPS). Four other mycoplasma species demonstrated a varied capacity to induce TNF production by macrophages. Elevated TNF levels were also observed during macrophage-mediated cytolysis of murine A9 fibrosarcoma cells in the presence of either M. orale or LPS. Addition of the specific antiserum against rTNF at a concentration which neutralized all TNF activity in the co-cultures partially inhibited concomitant A9 cell killing. We can, therefore, conclude that M. orale induces TNF production which is, at least partially, responsible for subsequent tumor cell killing.

Metabisulfite sensitivity and local dental anesthesia.

A case of sulfite sensitivity first manifesting as urticaria and acute airway obstruction following local anesthesia is described. A positive parenteral provocation test to metabisulfite was observed weeks after recovery of the patient from the clinical event.

The role of cognitions in marital relationships: definitional, methodological, and conceptual issues.

Although there have recently been numerous investigations exploring the role of couples' cognitions in an attempt to understand marital distress, at present there is little cohesion and direction in the study of how couples think about their relationships. The current article asserts that this lack of direction results from at least three factors: (a) a lack of delineation of the important cognitive variables to be considered in marital functioning, (b) conceptual and methodological difficulties that arise in attempts to operationalize cognitive variables, and (c) a dearth of models of marital functioning that incorporate cognitions in a detailed manner. These three factors are discussed, along with a review of empirical investigations supporting the importance of cognitions in intimate relationships.

Allergic Aspergillus sinusitis with concurrent allergic bronchopulmonary Aspergillus: report of a case.

A 42-year-old female patient with previously diagnosed seasonal allergic rhinitis, anaphylactic food sensitivity, and exertional asthma is described who developed concomitant allergic bronchopulmonary aspergillosis and allergic aspergillus sinusitis. We believe that the present article is the first fully documented case in which these two syndromes coexist in the same patient.