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Introduction: Bendamustine has been reported to be effective against low-grade B-cell lymphoma. We examined the effect of bendamustine on the lymphocyte-monocyte ratio (LMR) in low-grade B-cell lymphoma patients., Methods: We retrospectively reviewed 127 cases of first line or relapse/refractory low-grade B-cell lymphoma in three individual institutions (Asahikawa Municipal Hospital, Aiiku Hospital, and Hakodate Municipal Hospital). Only patients who had received at least three courses of bendamustine therapy were selected; the LMR was evaluated at starting the initial course of bendamustine therapy. Time to next treatment (TTNT) was used to ascertain the efficacy of bendamustine therapy., Results: Follicular lymphoma (FL), at 68.5% (87/127), is the most common histological subtype of low-grade B-cell lymphoma. The receiver operating characteristic (ROC) curve for the LMR showed a cutoff value of 2.0, and 33 cases (26.0%) had an LMR ≤2.0. Cases with LMR ≤2.0 had a significantly earlier progression than those with LMR > 2.0, based on the TTNT (P = .0007). Additionally, LMR ≤2.0 indicates earlier progression in TTNT when comparing only FL and low-grade B-cell lymphoma cases without FL (P = .007, 0.002). For multivariate analysis, the factors associated with an LMR ≤2.0 (HR, 2.741; 95% CI, 1.4330-5.245; P = .002) were considered as early progression factors with regard to the TTNT., Conclusion: Lymphocyte-monocyte ratio effectively predicts the efficacy of bendamustine therapy for low-grade B-cell lymphoma, particularly FL; its application may improve treatment strategies for this disease., (© 2020 John Wiley & Sons Ltd.)

Introduction: Diffuse large B-cell lymphoma (DLBCL) is the most frequent lymphoma. Three prognostic factors are widely used in DLBCL: International Prognostic Index (IPI), Revised-IPI (R-IPI), and National Comprehensive Cancer Network-IPI (NCCN-IPI)., Method: We established a prognostic model using peripheral blood absolute lymphocyte/absolute monocyte counts ratio (LMR), hemoglobin, and platelet counts obtained from complete blood cell counts (CBC) data at diagnosis based on 214 cases of DLBCL who received more than one course of R-CHOP therapy at a single institution., Results: The cutoff values for using the receiver operating characteristics (ROC) curve for LMR, hemoglobin, and platelet counts were 1.6, 100 g/L, and 150 × 10 9 /L, respectively. Stratification was performed using the three factors (LMR < 1.6, hemoglobin < 100 g/L, and platelet counts < 150 × 10 9 /L). CBC Group 1 (none of the 3 factors) included 92 cases, CBC Group 2 (1 or 2 of these factors) included 108 cases, and CBC Group 3 (all 3 factors) included 11 cases. The 5-year OS rates were 78.2%, 60.9%, and 10.1%, respectively. In multivariate analysis, CBC Group 3 (hazard ratio, 2.9760; 95% confidence interval, 1.2670-6.991; P = .01) were prognostic factors for OS. CBC Group 3 had factors based on which the further stratification of the poor prognosis group into IPI high-risk and R-IPI poor-risk groups (P = .01, <.0001, respectively) was possible., Conclusions: In DLBCL, combination of three CBC parameters has the potential to be a useful prognostic tool., (© 2019 John Wiley & Sons Ltd.)

High costs of molecule-targeted drugs, such as rituximab, ibritumomab, and tositumomab have given rise to an economical issue for treating patients with non-Hodgkin's lymphoma (NHL). Granulocyte colony-stimulating factors (G-CSFs), which are also expensive, are widely used for treating neutropenia after chemotherapy. In Japan, lenograstim at 2 microg/kg (about 100 microg/body) or filgrastim at 50 microg/m(2) (about 75 microg/body) is commonly administered for patients with NHL after chemotherapy. Therefore, cost-effectiveness is an important issue in treatment for NHL. Patients with advanced-stage NHL who needed chemotherapy with cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) or a CHOP-like regimen with or without rituximab were enrolled in this randomized cross-over trial to investigate the efficacy and safety of low-dose G-CSF. Half of the patients were administered 75 microg filgrastim in the first course after neutropenia and 50 microg lenograstim in the second course, and the other half were crossed over. Forty-seven patients were enrolled in this cross-over trial, and 24 patients completed the trial. Frequencies and durations of grade 4 leukocytopenia and neutropenia were similar in the two groups. Severe infection was rare and was observed at similar frequency. Frequencies of antibiotics use were also similar. The total cost of G-CSF (cost/drug x duration of administration) was significantly lower in patients who received 50 microg lenograstim. Hence, a low dose of lenograstim might be safe, effective and pharmaco-economically beneficial in patients with advanced-stage NHL.

The primary aim of this study was to investigate whether the allergen-induced synthesis of cytokines by peripheral blood mononuclear cells (PBMCs) obtained immediately before the pollen season could predict the clinical efficacy of immunotherapy during the following pollen season. PBMCs (1.0 x 106 cells/ml) were obtained from 17 nonatopic subjects and from 60 patients receiving immunotherapy for seasonal allergic rhinitis (caused by Japanese cedar pollens) immediately before the pollen season of 1998, and were cultured for 24 h in the presence of 10 mg/ml of Cry j 1, a major allergen of Japanese cedar pollens, at 37 degrees C in a fully humidified 5% CO2 atmosphere. Total cellular RNA was extracted from the PBMCs, and the allergen-induced interleukin (IL)-4, IL-5 and interferon-gamma (IFN-gamma) mRNA expression was determined using a reverse transcription-polymerase chain reaction. According to the nasal symptoms during the pollen season of 1998, the 60 patients on immunotherapy were divided into 36 good responders (who had no nasal symptoms and no requirement for rescue medications) and 24 poor responders who needed rescue medications to control nasal symptoms. Neither IL-4 mRNA nor IL-5 mRNA was expressed in any of the 17 nonatopic individuals. By contrast, IL-4 mRNA was expressed in 26 good responders and in 22 poor responders, and IL-5 mRNA was expressed in eight good responders (22.2%) and in 23 poor responders (95.8%). IFN-gamma mRNA was expressed in four nonatopic subjects, in nine good responders and in seven poor responders. The expression of IFN-gamma did not differ significantly among the nonatopic subjects, the good responders and the poor responders. The mRNA expression of IL-5 (P < 0.0001), but not of IL-4 (P = 0.0999) and IFN-gamma (P = 0. 7713), differed significantly between the good and poor responders. Therefore, our study has highlighted that positive expression of IL-5 mRNA in PBMCs sampled immediately before the pollen season could be predictive of a poor clinical outcome of immunotherapy during the following pollen season and that the down-regulation of IL-5 mRNA expression in PBMCs could be an important mechanism of pollen immunotherapy related to the clinical efficacy.

Increased attention has recently been directed at the possibility that the clinical efficacy of immunotherapy might be elaborated by alteration of T-cell reactivity. However, there is no general agreement among different investigators regarding the effect of immunotherapy on Th-cell reactivity. Peripheral blood mononuclear cells (PBMCs) from 15 nonatopic subjects and 76 patients with perennial allergic rhinitis (18 untreated patients and 58 patients on immunotherapy) were cultured in the absence and in the presence of a major Dermatophagoides farinae allergen, Der f 1, and the levels of IgE, interleukin-5 (IL-5), interferon-gamma (IFN-gamma) and tumor necrosis factor-alpha (TNF-alpha) in the culture supernatants were determined. The difference between the absence and presence of Der f 1 was calculated to consider the Der f 1-dependent synthesis of IgE, IL-5, IFN-gamma and TNF-alpha. The levels of Der f 1-dependent synthesis of IgE, IL-5 and TNF-alpha were significantly higher in the untreated group than in the nonatopic group, whereas Der f 1-dependent synthesis of IFN-gamma was significantly lower in the untreated group than in the nonatopic group. Immunotherapy decreased the enhanced Der f 1-dependent synthesis of IgE, IL-5 and TNF-alpha, and further decreased the suppressed Der f 1-dependent synthesis of IFN-gamma as the therapy proceeded. The levels of Der f 1-dependent synthesis of IgE and IL-5 did not differ between nonatopic individuals and patients whose duration of immunotherapy was 10 or more years. The levels of Der f 1-dependent synthesis of IgE and IL-5, but not of IFN-gamma and TNF-alpha, were correlated significantly with the levels of symptom scores. In addition, the levels of Der f 1-dependent synthesis of IgE and IL-5, but not of IFN-gamma and TNF-alpha, differed significantly between good and poor responders. In conclusion, immunotherapy for perennial allergic rhinitis may possibly work via induction of tolerance or anergy of both Th1- and Th2 cells. However, our study is likely to support a view that the mechanisms responsible for the clinically beneficial effects of immunotherapy principally involve the tolerance of Th2- rather than Th1 cells. In addition, suppression of IgE synthesis is also likely to be linked to the clinical efficacy of immunotherapy for perennial allergic rhinitis.

Some individuals with detectable levels of Japanese cedar (Criptomeria japonica) pollen-specific immunoglobulin (Ig)E in serum have no apparent nasal symptoms during the pollen season. The response of CD4+ T-helper (Th) cells to the pollen allergen might differ fundamentally between asymptomatic and symptomatic individuals who are already sensitized to the pollen. The aim of this study was to discern the possible differences in responses of peripheral blood mononuclear cells (PBMCs) to the pollen allergen between asymptomatic and symptomatic subjects who have been sensitized to the pollen. This study included 20 non-atopic healthy volunteers (non-atopic group) and 48 patients who had detectable levels of the pollen-specific IgE before the pollen season in 1997. In the review of nasal symptoms during the pollen season 1997, 24 patients had typical symptoms of seasonal allergic rhinitis (symptomatic group), and the remainder had no seasonal aggravation of nasal symptoms (asymptomatic group). Peripheral blood mononuclear cells (1.0 x 10(7) cells/well) were obtained from each individual during the pollen season and cultured in the absence or presence of 12.5 microg of Cry j 1 for 4 days. The concentrations of IgE, interleukin-5 (IL-5), and interferon-gamma (IFN-gamma) in the culture supernatants were measured. The levels of IgE produced by Cry j 1-stimulated PBMCs of the asymptomatic and symptomatic groups were significantly higher than those of the non-atopic group, but did not differ between the asymptomatic and symptomatic groups. The levels of IL-5 produced by Cry j 1-stimulated PBMCs did not differ significantly between the non-atopic group and the asymptomatic group, but the levels of IL-5 were significantly higher in the symptomatic group than in the asymptomatic group as well as the non-atopic group. The levels of IFN-gamma produced by Cry j 1-stimulated PBMCs did not differ significantly among the three groups. In conclusion, our study has suggested that Japanese cedar pollen-induced synthesis of IL-5, but not of IgE or IFN-gamma, is likely to be a key mechanism linked to the symptomatic episode of seasonal allergic rhinitis in individuals sensitized to the pollen.

Soluble forms of intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) have been identified in the peripheral blood and other body fluids. These soluble adhesion molecules have been reported to reflect the upregulation of cell surface ICAM-1 and VCAM-1 expression in inflammatory diseases. The levels of soluble ICAM-1 and soluble VCAM-1 in 37 middle ear effusions from 37 patients with chronic otitis media with effusion (OME) were quantitatively determined with enzyme-linked immunosorbent assays. The levels of soluble ICAM-1 in mucoid effusions were significantly higher than those in serous effusions, but the levels of soluble VCAM-1 did not differ significantly between the two types of effusion. The levels of soluble VCAM-1 in effusions from atopic patients were significantly higher than those from non-atopic patients, whereas the levels of soluble ICAM-1 in samples from atopic patients were significantly lower than those from non-atopic patients. Therefore, our data suggest that an increase in soluble VCAM-1 plays a more important role in the pathogenesis of OME in atopic patients than in non-atopic patients. In addition, soluble ICAM-1 is likely to play a more important role in the pathogenesis of OME in nonatopic patients than soluble VCAM-1.

This study was designed to investigate the clinical role of specific IgG4 and IgE responses in patients during immunotherapy for seasonal allergy. The study included 109 patients with seasonal allergic rhinitis due to Japanese cedar pollens. They were divided into the control group and the immunotherapy group. Serum samples were obtained at the start of immunotherapy, before the pollen season and during the season, to determine serum specific IgE and IgG4. In the control group specific IgE was significantly increased, but specific IgG4 was not changed during the pollen season. In the immunotherapy group specific IgE was not significantly increased, but specific IgG4 was significantly increased during the season. In the patients having immunotherapy for 2 years or less, the seasonal increase in specific IgG4 related to the magnitude of the clinical effect. In the patients having immunotherapy for 3 years or more, the seasonal increase in specific IgE related to the magnitude of the clinical effect. In conclusion, the specific IgG4 response and specific IgE response during the pollen season make a significant contribution to the clinical effect of immunotherapy. However, modulation of specific IgE and IgG4 responses out of the pollen season was unlikely to be an important phenomenon related to the clinical effect of immunotherapy.

Recent double-blind placebo-controlled trials for perennial allergic rhinitis have all clearly shown the efficacy of immunotherapy. Although several mechanisms for the clinical efficacy of immunotherapy have been proposed, the exact mechanisms related to the clinical effect still remain unclear. Since immunotherapy is a form of systemic treatment and its clinical benefit is likely to be, at least in part, a consequence of its systemic effects on different phases of immunological events, our study focused exclusively on several immunological parameters in serum. A total of 47 patients with perennial allergic rhinitis due to Dermatophagoides farinae enrolled in this prospective study. Venous blood was collected for determination of specific immunoglobulin (Ig)E, specific IgG4, soluble interleukin-2 receptor (IL-2R), interleukin-4 (IL-4), soluble intercellular adhesion molecule-1 (ICAM-1) and soluble vascular cell adhesion molecule-1 (VCAM-1), six times from 20 untreated patients and 27 patients on immunotherapy, at enrolment, and 1, 2, 3, 5, and 10 years after enrollment. No specific IgE, IgG4, soluble IL-2R, IL-4 and soluble ICAM-1 levels changed significantly for a span of 10 years in the untreated patients. By contrast, immunotherapy affected serum levels of specific IgE, specific IgG4, soluble IL-2R, IL-4 and soluble ICAM-1, but not of soluble VCAM-1. The rates of increase in specific IgG4 and the rates of decrease in soluble IL-2R were correlated with the rates of decrease in symptom scores during the first 3 years, but not 5 and 10 years after the course of immunotherapy. On the other hand, the rates of decrease in specific IgE, IL-4 and soluble ICAM-1 were significantly correlated with the rates of decrease in symptom scores at 5 and 10 years, but not during the first 3 years. Each immunological modulation by immunotherapy was likely to be involved in the working mechanism related to clinical efficacy at different phases of immunotherapy.

This study was designed to determine seasonal changes in cytokines, soluble CD23 and specific IgE in the serum of patients with seasonal allergic rhinitis, and the effect of immunotherapy on these seasonal changes. Fifty-four patients with seasonal allergic rhinitis caused by Japanese ceder pollens were divided into a medication group and an immunotherapy group. The patients of the medication group were treated with non-sedating antihistamines alone during the pollen season. The patients of the immunotherapy group had been treated for variable periods (mean, 5.0 +/- 3.2 years) with immunotherapy using japanese cedar pollen antigens. Serum samples were collected before and during the pollen season from each patient, to determine specific IgE, interleukin-4 (IL-4), interferon-gamma (IFN-gamma) and soluble CD23 levels in serum. A significant increase in specific IgE and IL-4 and a significant decrease in IFN-gamma were observed during the pollen season in the medication group. In contrast, in the immunotherapy group, none of specific IgE, IL-4 and IFN-gamma was significantly changed following natural exposure to pollens. However, these effects were not significant in patients undergoing immunotherapy for 3 or fewer years. Seasonal rates of increase in specific IgE and IL-4 differed significantly between good responders and poor responders to immunotherapy, but seasonal rates of decrease in IFN-gamma did not. A seasonal rate of increase in soluble CD23 was significantly correlated with a seasonal rate of increase in specific IgE, in both the medication and the immunotherapy groups. The seasonal rate of increase in soluble CD23 was significantly smaller in the good responders than in the poor responders to immunotherapy. In conclusion, pollen immunotherapy reduces the seasonal increase in specific IgE, IL-4 and soluble CD23 in serum, and in addition switches the seasonal preferential activation of Th-2 cells to reciprocal activation of Th-1 cells with treatment over several years. It is likely that the mechanisms responsible for the clinically beneficial effects of immunotherapy principally involve the modulation of Th-2 rather than Th-1 cytokines.

The role of serum eosinophil cationic protein levels in allergic rhinitis is controversial. It is also unclear whether with immunotherapy it is possible to reduce these serum levels in allergic diseases. We studied serum eosinophil cationic protein levels in patients with cedar-induced allergic rhinitis and compared them with non-atopic controls. The second aim of this study was to elucidate whether immunotherapy is capable of decreasing the seasonal elevation in serum eosinophil cationic protein levels in seasonal allergic rhinitis. The serum eosinophil cationic protein levels of the untreated patient group were significantly higher than those of the non-atopic controls. The levels in patients who received immunotherapy for 2 yr were also significantly higher than those of the non-atopic controls. However, the levels were not different between the patients undergoing immunotherapy for over 3 yr and the non-atopic controls. The serum levels of the 31 patients treated with immunotherapy correlated with the duration of immunotherapy. In conclusion, the serum eosinophil cationic protein levels are higher in untreated patients with seasonal allergic rhinitis and this seasonal activation in circulating eosiohophils decreases gradually during immunotherapy, but this inhibitory effect becomes apparent only after a number of years of immunotherapy. This prevention of seasonal eosinophil activation is one of the mechanisms responsible for the clinical effect of immunotherapy.

The rate of release of the soluble form of interleukin-2 receptor (soluble IL-2R) reflects T cell activation in vivo. Since T lymphocytes play a central role in respiratory allergic disorders, the measurement of serum levels of soluble IL-2R may be useful in analysing the disease state of allergic disorders. The study has aimed at investigating the seasonal changes in serum soluble IL-2R in 81 patients with seasonal allergic rhinitis due to Japanese cedar pollens, with special reference to the effect of anti-allergic pharmacotherapy and immunotherapy. Serum samples were obtained twice from each patient, before and during the pollen season, and all the serum samples were simultaneously used for determination of soluble IL-2R and cedar pollen-specific immunoglobin E (IgE). Seasonal elevation in soluble IL-2R was not associated with the good clinical outcome but was associated with the poor clinical outcome, irrespective of pharmacotherapy or immunotherapy. Additionally, successful immunotherapy suppressed seasonal elevation of serum soluble IL-2R more strongly than successful pharmacotherapy, and seasonal increase rates in soluble IL-2R were inversely correlated with the duration of immunotherapy. Seasonal increase rates in soluble IL-2R were significantly correlated with seasonal increase rates in specific IgE in both the medication group and the immunotherapy patients. These results may suggest that seasonal changes in serum soluble IL-2R may serve as an indicator for clinical outcome of seasonal allergic rhinitis, that the magnitude of T cell activation could affect specific IgE production, and that T cell activation could be gradually modulated as immunotherapy proceeds. In conclusion, seasonal changes in serum soluble IL-2R may serve as an objective indicator for clinical outcome of seasonal allergic rhinitis.

Interleukin-4 (IL-4) may play a central role in the IgE synthesis system, the development of Th-2-like cells, and co-ordination as well as the persistence of airway inflammatory process in allergic disorders. Therefore, IL-4 plays a key role in airway allergic disorders. This study aimed at investigating the serum concentrations of IL-4 in patients with perennial allergic rhinitis, with special reference to the possible changes and the clinical relevance following long-term immunotherapy. The study has demonstrated that the serum level of IL-4 in allergic rhinitis patients before immunotherapy is significantly higher than that in non-atopic individuals. However, the serum IL-4 level in allergic rhinitis patients did not decrease following anti-allergic medications but significantly decreased following immunotherapy. The percentage decrease in IL-4 was correlated significantly with the percentage decrease in specific IgE antibodies following long-term immunotherapy. Immunotherapy also significantly decreased specific IgE anti-bodies, but this reduction in specific IgE antibodies was not significantly correlated with the clinical improvement. In contrast, the percentage decrease in serum IL-4 was significantly correlated with the percentage decrease in symptomatic scores. The authors interpret these data to mean that immunotherapy alters T-cell cytokine profiles in the long-term, and a decline of IL-4 following immunotherapy could modulate not only production of specific IgE antibodies but also inflammatory cellular events, leading to symptomatic relief in allergic rhinitis.