Background: Although survival outcomes of multiple myeloma (MM) have improved with the development of new and effective agents, infection remains the major cause of morbidity and mortality. Here, we evaluated the efficacy of levofloxacin prophylaxis (in a real-world setting) during bortezomib, melphalan, and prednisone (VMP) therapy in elderly patients with newly diagnosed MM. Methods: This study retrospectively analyzed the records of patients with newly diagnosed MM treated with the VMP regimen between February 2011 and September 2020 at three institutes of the Republic of Korea. Results: Of a total of 258 patients, 204 (79.1%) received levofloxacin prophylaxis during VMP therapy. The median number of levofloxacin prophylaxis cycles was 4 (range, 1‒9), but 10 patients did not complete the planned prophylaxis because of side effects. Sixty-six patients (25.5%) experienced severe infections during VMP therapy, most of which (74.7%) occurred within the first four cycles of VMP therapy regardless of levofloxacin prophylaxis status. Early severe infection was significantly associated with poor survival.In multivariate analysis, levofloxacin prophylaxis was significantly associated with a lower risk in early severe infection. Conclusion Our findings suggest that levofloxacin prophylaxis should be considered at least during the first four cycles of VMP therapy in elderly patients with newly diagnosed MM.

Since the introduction of an alkylator to the treatment of multiple myeloma (MM), new effective agents have been developed, such as immunomodulatory drugs including thalidomide, lenalidomide, and pomalidomide; proteasome inhibitors including bortezomib, carfilzomib, and ixazomib; monoclonal antibodies including daratumumab and elotuzumab; and deacetylase inhibitors including panobinostat. Numerous regimens with these new agents have been developed and they have contributed in improving survival outcomes in MM patients. In addition, the recommended therapies for newly diagnosed MM change every year based on the results of clinical trials. This review will discusses the appropriate induction therapies based on recent clinical trials for patients with newly diagnosed MM.

The migration of dendritic cells (DCs) to secondary lymphoid organs depends on chemoattraction through the interaction of the chemokine receptors with chemokines. However, the mechanism of how lymphoid chemokines attract DCs to lymphoid organs remains unclear. Here, we demonstrate the mechanism of DC migration in response to the lymphoid chemokine CCL21. CCL21-mediated DC migration is controlled by the regulation of sarcoplasmic reticulum Ca²⁺ ATPase 2 (SERCA2) expression rather than through the activation of mitogen-activated protein kinases CCL21-exposed mature DCs (mDCs) exhibited decreased SERCA2 expression but not decreased phospholamban (PLB) or Hax-1 expression, which are known to be SERCA2-interacting proteins. In addition, CCL21 did not affect the mRNA levels of SERCA2 or its interacting protein Hax-1. Interestingly, SERCA2 expression was inversely related to DC migration in response to chemokine stimulation. The migratory capacity of CCL21-treated mDCs was decreased by the phospholipase C inhibitor U73122 and by the protein kinase C inhibitor BAPTA-AM. The migratory capacities of mDCs were increased in response to SERCA2 siRNA expression but were decreased by SERCA2 overexpression. In addition, DCs treated with a SERCA2-specific inhibitor (cyclopiazonic acid) had significantly increased migratory capacities as mDCs regardless of SERCA2 expression. Moreover, SERCA2 expression was dependent on DC maturation induced by cytokines or Toll-like receptor agonists. Therefore, the migratory capacities differed in differentially matured DCs. Taken together, these results suggest that SERCA2 contributes to the migration of CCL21-activated DCs as an important feature of the adaptive immune response and provide novel insights regarding the role of SERCA2 in DC functions.
Adaptive Immunity ; Adenosine Triphosphatases* ; Chemokine CCL21 ; Chemokines ; Cytokines ; Dendritic Cells* ; Mitogen-Activated Protein Kinases ; Protein Kinase C ; Receptors, Chemokine ; RNA, Messenger ; RNA, Small Interfering ; Sarcoplasmic Reticulum* ; Toll-Like Receptors ; Type C Phospholipases

Anterior gradient-2 (AGR2) promotes tumor growth, cell migration, and cellular transformation, and is one of the specific mRNA markers for circulating tumor cells in patients with gastrointestinal cancer. We investigated the feasibility of AGR2 as a potent antigen for tumor immunotherapy against colorectal cancer (CRC) cells using dendritic cells (DCs) transduced with a recombinant adenovirus harboring the AGR2 gene (AdAGR2). DCs transduced with a recombinant adenovirus encoding the AGR2 gene (AdAGR2/DCs) were characterized. These genetically-modified DCs expressed AGR2 mRNA as well as AGR2 protein at a multiplicity of infection of 1,000 without any significant alterations in DC viability and cytokine secretion (IL-10 and IL-12p70) compared with unmodified DCs as a control. In addition, AdAGR2 transduction did not impair DC maturation, but enhanced expression of HLA-DR, CD80, and CD86. AdAGR2/DCs augmented the number of IFN-gamma-secreting T-cells and elicited potent AGR2-specific cytotoxic T lymphocytes capable of lysing AGR2-expressing CRC cell lines. These results suggest that AGR2 act as a potentially important antigen for immunotherapy against CRC in clinical applications.
Adenoviridae ; Antigen Presentation/genetics ; Antigens, Neoplasm/immunology ; Carcinoma/*therapy ; Cell Line, Tumor ; Colorectal Neoplasms/*therapy ; Cytotoxicity, Immunologic/genetics ; Dendritic Cells/immunology ; Humans ; *Immunotherapy, Adoptive ; Interferon-gamma/secretion ; Lymphocyte Activation/genetics ; Proteins/genetics/*metabolism ; T-Lymphocytes, Cytotoxic/*immunology ; Transduction, Genetic ; Transgenes/genetics ; Tumor Markers, Biological/immunology

PURPOSE: Many urologists have performed prostate biopsy in men with a high level of prostate-specific antigen (PSA) alone. However, high levels of PSA may be induced by infection. We studied the effects of antibiotics on serum total PSA and PSA density (PSAD) in men with total PSA between 4 and 10 ng/ml and normal digital rectal examination (DRE) and transrectal sonographic findings. MATERIALS AND METHODS: From January 2005 to October 2009, a total of 107 patients with complaints of lower urinary tract symptoms (LUTS) or benign prostatic hyperplasia (BPH) were evaluated. To be included in this study, patients had to be at least 50 years old, have a palpably normal DRE, have infection in the prostate, have a total serum PSA of 4 to 10 ng/ml, and have transrectal ultrasound findings that did not show a hypoechoic lesion in the prostate. Only patients in whom the PSA level was rechecked after short-term antibiotics administration (8 weeks) were included. Serum PSA and PSAD were measured before transrectal ultrasound or EPS and after 8 weeks of treatment with antibiotics (quinolone). Age, prostate volume, serum PSA, PSAD, and PSA rate of change were compared. RESULTS: The mean age of the patients was 66.3 years. The mean prostate size was 48.8+/-24.9 g. Forty patients had a high level of PSAD. Total PSA and PSAD significantly decreased after treatment (p<0.05). In 45 of the 107 men, total PSA after antibiotics treatment was normalized (less than 4 ng/ml). PSAD after treatment was normalized (less than 0.15 ng/ml/cm3) in 23 of the 40 patients with a high level of PSAD. Conclusion: Antibiotics treatment for at least 8 weeks in BPH patients with an increased PSA level (4-10 ng/ml), infection, and normal DRE and transrectal sonographic findings may decrease serum PSA significantly. However, because the PSA level was not decreased to the normal range (less than 4 ng/ml) in all patients, it seems that antibiotics therapy before prostatic biopsy is not necessary.
Anti-Bacterial Agents ; Biopsy ; Digital Rectal Examination ; Humans ; Lower Urinary Tract Symptoms ; Male ; Prostate ; Prostate-Specific Antigen ; Prostatic Hyperplasia ; Prostatitis ; Reference Values ; Urinary Tract

Dendritic cells (DCs) play a role in natural killer (NK) cell activation, while NK cells are also able to activate and mature DCs. Toll-like receptors (TLRs) on the surface of DCs and NK cells induce the maturation and activation of these cells when engaged with their cognate ligand. We investigated to generate potent DCs by maturation with NK cells in the presence of TLR agonist in vitro and tested the efficacy of these DC vaccinations in mouse colon cancer model. The optimal ratios of DCs versus NK cells were 1:1 to 1:2. Immature DCs were mature with NK cells in the presence of lipopolysaccharide, which is TLR4 agonist, and further addition of IL-2 induced phenotypically and functionally mature bone marrow-derived DCs. These potent DCs exhibited not only high expression of several costimulatory molecules and high production of IL-12p40 and IL-12p70, but also high allogeneic T cells stimulatory capacity, and the induction of the high activities to generate tumor-specific CTLs. Consistently, vaccination with these DCs efficiently inhibited CT-26 tumor growth in mouse colon cancer model when compared to other vaccination strategies. Interestingly, combination therapy of these DC-based vaccines and with low-dose cyclophosphamide showed dramatic inhibition effects of tumor growth. These results suggest that the DCs maturated with NK cells in the presence of TLR agonist are potent inducer of antitumor immune responses in mouse model and may provide a new source of DC-based vaccines for the development of immunotherapy against colon cancer.
Animals ; Cancer Vaccines/immunology/metabolism ; Carcinoma/immunology/pathology/*therapy ; Cell Line, Tumor ; Cells, Cultured ; Colonic Neoplasms/immunology/pathology/*therapy ; Dendritic Cells/*drug effects/*immunology/transplantation ; Female ; Immunotherapy, Adoptive/*methods ; Killer Cells, Natural/*immunology/physiology ; Lipopolysaccharides/pharmacology ; Mice ; Mice, Inbred BALB C ; Toll-Like Receptor 4/agonists ; Toll-Like Receptors/*agonists

We measured serum lipoprotein (a) [Lp (a)] concentrations in 304 uremic patients treated on predialysis, hemodialysis (HD) and continuous ambulatory peritoneal dialysis (CAPD), and compared them with those in 43 normal controls. The mean values were 46.1mg/dl in predialysis, 35.7mg/dl in HD, 54.7mg/dl in CAPD patients and 17.0mg/dl in controls, respectively. Serum Lp (a) levels were elevated both in the predialysis patients (P<0.001) and in the CAPD patients (P<0.001) compared with those in controls, and were also elevated in the CAPD patients (P<0.01) compared with HD patients. Serum Lp (a) levels tended to be higher in HD patients compared with controls, although these differences did not reach statistical significance. We observed statistically significant positive correlations of Lp (a) to serum levels of total cholesterol (TC) (r=0.279, P<0.01), LDL-cholesterol (r=0.335, P<0.01), and Apo (B) (r=0.352, P<0.01), and significant negative correlation of Lp (a) to serum level of albumin (r=-0.278, P<0.01) in 304 CRF patients. CAPD patients had a more atherogenic lipoprotein profile than did HD patients; besides significantly higher Lp (a) levels (P<0.01), total (P<0.001) and LDL (P<0.001) cholesterol, triglycerides (P<0.05), and apo (B) (P<0.001) were significantly elevated in comparison to HD patients. The marked elevation of serum Lp (a) in patients on CAPD may be due to increased hepatic synthesis as a consequence of the substantial amounts of plasma proteins lost in the dialysate. The increased serum concentrations of Lp (a) may contribute to the high risk for atherosclerosis in end stage renal disease, especially in patients treated by CAPD.
Atherosclerosis ; Blood Proteins ; Cholesterol ; Humans ; Kidney Failure, Chronic* ; Lipoprotein(a) ; Lipoproteins* ; Peritoneal Dialysis, Continuous Ambulatory ; Renal Dialysis ; Triglycerides