Health-related qualify of life, angina type and coronary artery disease in patients with stable chest pain

Background: Health-related quality of life (HRQoL) is impaired in patients with stable angina but patients often present with other forms of chest pain. The aim of this study was to compare the pre-diagnostic HRQoL in patients with suspected coronary artery disease (CAD) according to angina type, gender, and presence of obstructive CAD. Methods: From the pilot study for the European DISCHARGE trial, we analysed data from 24 sites including 1263 patients (45.9% women, 61.1 ± 11.3 years) who were clinically referred for invasive coronary angiography (ICA; 617 patients) or coronary computed tomography angiography (CTA; 646 patients). Prior to the procedures, patients completed HRQoL questionnaires: the Short Form (SF)-12v2, the EuroQoL (EQ-5D-3 L) and the Hospital Anxiety and Depression Scale. Results: Fifty-five percent of ICA and 35% of CTA patients had typical angina, 23 and 33% had atypical angina, 18 and 28% had non-anginal chest discomfort and 5 and 5% had other chest discomfort, respectively. Patients with typical angina had the poorest physical functioning compared to the other angina groups (SF-12 physical component score; 41.2 ± 8.8, 43.3 ± 9.1, 46.2 ± 9.0, 46.4 ± 11.4, respectively, all age and gender-adjusted p < 0.01), and highest anxiety levels (8.3 ± 4.1, 7.5 ± 4.1, 6.5 ± 4.0, 4.7 ± 4.5, respectively, all adjusted p < 0.01). On all other measures, patients with typical or atypical angina had lower HRQoL compared to the two other groups (all adjusted p < 0.05). HRQoL did not differ between patients with and without obstructive CAD while women had worse HRQoL compared with men, irrespective of age and angina type. Conclusions: Prior to a diagnostic procedure for stable chest pain, HRQoL is associated with chest pain characteristics, but not with obstructive CAD, and is significantly lower in women. Trial registration: Clinicaltrials.gov, NCT02400229

Cytokine influence on killing of fresh chronic lymphocytic leukemia cells by human leukocytes

Abstract The feasibility of combining the Lym-1 monoclonal antibody (MoAb) with interferon-gamma (IFN-gamma) in the treatment of chronic lymphocytic leukemia (CLL) was evaluated. We used an in vitro tumor lysis model that incorporated fresh CLL cells from 21 different patients as targets for two distinct normal human leukocyte effector subsets, neutrophils, and peripheral blood mononuclear cells (PBMCs). Lym-1 antigen (Lym-1- Ag) expression varied greatly and did not correlate with the expression of other CLL-associated antigens such as CD5, CD19, or HLA-DR. CLL cells were not lysed by neutrophils alone or with IFN-gamma in the absence of Lym-1. Neutrophil Lym-1-dependent cytotoxicity (ADCC) in the absence of IFN-gamma was weak and inconsistent. IFN-gamma exposure induced MoAb-dependent lysis of 80% of 21 CLL targets and resulted in an eightfold augmentation of neutrophil ADCC against the remainder. Cytotoxicity correlated directly and positively with Lym-1-Ag expression. Confirmation of the need for interaction between neutrophil IgG Fc receptors (Fc gamma Rs) and the Fc portion of the Lym-1 MoAb was obtained by demonstrating that purified Staphylococcus aureus Protein A (SpA) inhibited ADCC. IFN-gamma exposure caused no consistent alternations in Lym-1-Ag expression on CLL cells so that target antigen upregulation was unlikely to account for augmentation of neutrophil ADCC. PBMCs alone, exposed to interkeukin-2 (IL-2) or IFN-gamma, or with Lym-1 in the presence or absence of IL-2 or IFN-gamma were unable to lyse CLL targets. PBMCs were able to kill Raji Burkitt lymphoma cells in conjunction with Lym-1, so their ability to interact with Lym- 1-coated targets and their lytic functions appeared intact. These results emphasize the importance of examining fresh tumor cells with different leukocyte effector subsets before designing a clinical trial that combines a therapeutic MoAb with a cytokine.</jats:p

Interferon gamma augments Lym-1-dependent, granulocyte-mediated tumor cell lysis

Abstract Lym-1 is a therapeutically promising IgG2a monoclonal antibody (MoAb) that reacts with variant class II molecules expressed on B-lineage malignancies. To optimize antitumor immunotherapy with Lym-1, we determined whether granulocytes could participate in tumor lysis mediated by Lym-1 and whether recombinant interferon gamma (IFN-gamma) could influence this reaction. Granulocytes had minimal activity in mediating Lym-1 antibody-dependent cellular cytotoxicity (ADCC) compared with peripheral blood mononuclear cells (PBMC). However, IFN- gamma markedly augmented and occasionally induced granulocyte Lym-1 ADCC in a dose-dependent fashion (optimal 100 U/mL). Granulocytes primed with IFN-gamma for 24 hours displayed greatly increased ADCC in the absence of further IFN-gamma exposure. In most individuals, IFN- gamma also enhanced PBMC Lym-1 ADCC. Interferon alfa (IFN-alpha), although able to enhance PBMC-mediated Lym-1 ADCC and non-ADCC lysis, had no effect on granulocyte activity. Lym-1 ADCC involved an interaction between Fc receptor-bearing granulocytes and Lym-1 antigen positive targets based on the following: (1) The reaction was Lym-1 dose-dependent with cytotoxicity detectable at concentrations as low as 0.5 microgram/mL. (2) An irrelevant, isotype-matched MoAb (UPC-10) was unable to mediate ADCC. (3) In the absence of Lym-1, granulocytes--with or without IFN-gamma--displayed no intrinsic tumor lytic ability. Conversely, without granulocytes, Lym-1 or Lym-1 plus IFN-gamma had no effect. (4) Protein A, which binds avidly to Lym-1, inhibited the reaction 95%. (5) IFN-gamma induced granulocyte expression of CD64, the IgG Fc receptor that binds murine IgG2a MoAbs. (6) Of nine malignant human cell lines, only the three that moderately or strongly expressed the Lym-1 antigen were consistently lysed. Preclinical studies such as these may provide a rational basis for designing clinical trials with Lym-1 in combination with IFN-gamma.</jats:p

Interferon gamma augments Lym-1-dependent, granulocyte-mediated tumor cell lysis

Lym-1 is a therapeutically promising IgG2a monoclonal antibody (MoAb) that reacts with variant class II molecules expressed on B-lineage malignancies. To optimize antitumor immunotherapy with Lym-1, we determined whether granulocytes could participate in tumor lysis mediated by Lym-1 and whether recombinant interferon gamma (IFN-gamma) could influence this reaction. Granulocytes had minimal activity in mediating Lym-1 antibody-dependent cellular cytotoxicity (ADCC) compared with peripheral blood mononuclear cells (PBMC). However, IFN- gamma markedly augmented and occasionally induced granulocyte Lym-1 ADCC in a dose-dependent fashion (optimal 100 U/mL). Granulocytes primed with IFN-gamma for 24 hours displayed greatly increased ADCC in the absence of further IFN-gamma exposure. In most individuals, IFN- gamma also enhanced PBMC Lym-1 ADCC. Interferon alfa (IFN-alpha), although able to enhance PBMC-mediated Lym-1 ADCC and non-ADCC lysis, had no effect on granulocyte activity. Lym-1 ADCC involved an interaction between Fc receptor-bearing granulocytes and Lym-1 antigen positive targets based on the following: (1) The reaction was Lym-1 dose-dependent with cytotoxicity detectable at concentrations as low as 0.5 microgram/mL. (2) An irrelevant, isotype-matched MoAb (UPC-10) was unable to mediate ADCC. (3) In the absence of Lym-1, granulocytes--with or without IFN-gamma--displayed no intrinsic tumor lytic ability. Conversely, without granulocytes, Lym-1 or Lym-1 plus IFN-gamma had no effect. (4) Protein A, which binds avidly to Lym-1, inhibited the reaction 95%. (5) IFN-gamma induced granulocyte expression of CD64, the IgG Fc receptor that binds murine IgG2a MoAbs. (6) Of nine malignant human cell lines, only the three that moderately or strongly expressed the Lym-1 antigen were consistently lysed. Preclinical studies such as these may provide a rational basis for designing clinical trials with Lym-1 in combination with IFN-gamma.</jats:p

Cytokine influence on killing of fresh chronic lymphocytic leukemia cells by human leukocytes

The feasibility of combining the Lym-1 monoclonal antibody (MoAb) with interferon-gamma (IFN-gamma) in the treatment of chronic lymphocytic leukemia (CLL) was evaluated. We used an in vitro tumor lysis model that incorporated fresh CLL cells from 21 different patients as targets for two distinct normal human leukocyte effector subsets, neutrophils, and peripheral blood mononuclear cells (PBMCs). Lym-1 antigen (Lym-1- Ag) expression varied greatly and did not correlate with the expression of other CLL-associated antigens such as CD5, CD19, or HLA-DR. CLL cells were not lysed by neutrophils alone or with IFN-gamma in the absence of Lym-1. Neutrophil Lym-1-dependent cytotoxicity (ADCC) in the absence of IFN-gamma was weak and inconsistent. IFN-gamma exposure induced MoAb-dependent lysis of 80% of 21 CLL targets and resulted in an eightfold augmentation of neutrophil ADCC against the remainder. Cytotoxicity correlated directly and positively with Lym-1-Ag expression. Confirmation of the need for interaction between neutrophil IgG Fc receptors (Fc gamma Rs) and the Fc portion of the Lym-1 MoAb was obtained by demonstrating that purified Staphylococcus aureus Protein A (SpA) inhibited ADCC. IFN-gamma exposure caused no consistent alternations in Lym-1-Ag expression on CLL cells so that target antigen upregulation was unlikely to account for augmentation of neutrophil ADCC. PBMCs alone, exposed to interkeukin-2 (IL-2) or IFN-gamma, or with Lym-1 in the presence or absence of IL-2 or IFN-gamma were unable to lyse CLL targets. PBMCs were able to kill Raji Burkitt lymphoma cells in conjunction with Lym-1, so their ability to interact with Lym- 1-coated targets and their lytic functions appeared intact. These results emphasize the importance of examining fresh tumor cells with different leukocyte effector subsets before designing a clinical trial that combines a therapeutic MoAb with a cytokine.</jats:p