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Background Nivolumab, an anti-programmed cell death-1 (PD-1) monoclonal antibody used as an immune checkpoint inhibitor, is commonly employed for its anti-tumor effects against various types of malignant tumors. However, its administration is complicated by immune-related adverse events (irAEs), including pneumonitis. Case presentation We present a case series of four patients with malignant melanoma, non-small cell lung cancer, and hypopharyngeal carcinoma who demonstrated pneumonitis induced by nivolumab, and further review clinicopathological characteristics of these patients in comparison with those of previously reported patients with nivolumab-induced pneumonitis. In our series, 20% of patients who were treated with nivolumab developed pneumonitis, all of which occurred approximately 2 weeks after the initiation of nivolumab treatment. Prompt recognition of the nivolumab-induced pneumonitis allowed for successful resolution. Computed tomography scan images of the patients demonstrated predominantly cryptogenic organizing pneumonia patterns. All patients were males, who had been heavily treated with antitumor drugs prior to nivolumab. Conclusions Our case series showed that nivolumab had a high incidence of drug-induced pneumonitis with early onset, supporting the need for renewed attention to nivolumab-induced pneumonitis, particularly in patients with a history of heavy antitumor treatments.

Dasatinib is a BCR-ABL kinase inhibitor with improved potency compared with imatinib, for which efficacy and safety in imatinib-resistant and imatinib-intolerant patients with chronic myelogenous leukemia (CML) have been established. Here, an open-label phase II study evaluated the efficacy and safety of dasatinib in 50 Japanese patients with imatinib-resistant or imatinib-intolerant CML during the chronic phase (CML-CP). Dasatinib was effective in imatinib-resistant and imatinib-intolerant patients. After 12 months of dasatinib therapy, 35 patients (70%) had achieved a major molecular response (MMR) and 16 patients (32%) had achieved a complete molecular response (CMR). Among the imatinib-resistant CML-CP cohort, 21 and 8 patients had achieved an MMR and a CMR after 12 months of dasatinib therapy, respectively. Among the imatinib-intolerant CML-CP cohort, 14 and 8 patients had achieved an MMR and a CMR after 12 months of dasatinib therapy, respectively. After 18 months of dasatinib therapy, 38 out of 50 patients (76.0%) had achieved an MMR and 19 patients (38.0%) had achieved a CMR. A lower level of BCR-ABL transcript at 1 or 3 months after the initiation of dasatinib treatment was more strongly correlated with the BCR-ABL transcript level at 12 and 18 months (p ＜ 0.001) than a higher level of BCR-ABL. The T315I mutation was identified in two patients receiving dasatinib therapy. Dasatinib was generally well tolerated, with only 3 patients (5%) having treatment discontinuation as a result of adverse hematologic events (thrombocytopenia, anemia, neutropenia) and/or non-hematologic events at a 12-month follow-up evaluation. Dasatinib was a safe and effective treatment for Japanese patients with imatinib-resistant or imatinib-intolerant CML. In addition, the molecular response at 1 or 3 months predicted a response to dasatinib at 12 or 18 months.

5-HT3 receptor antagonists are widely used for prevention of chemotherapy-induced nausea and vomiting, though their antiemetic effects vary among patients. We investigated a method for evaluation of antiemetic effects in individual patients. We used the 5-HT3 receptor occupancy of serotonin for our evaluation, which was estimated based on the plasma concentration of granisetron and concentration of serotonin near the 5-HT3 receptor in the small intestine, obtained by measuring the urinary concentrations of granisetron and 5-hydroxyindoleacetic acid (5-HIAA)/creatinine (Cre). The mean cumulative percent for urinary excretion of granisetron at 24 h after administration and coefficient of variation were 16.19 ± 6.30% and 38.91%, respectively. The time course of urinary concentration of 5-HIAA/Cre also varied among the patients. The value for 5-HT3 receptor occupancy of serotonin without granisetron was higher than that prior to administration (blank), thus most treated patients had the possibility of induced emesis. In contrast, that with granisetron was lower than the blank value, indicating that those treated patients would not develop emesis. Furthermore, the estimated 5-HT3 receptor occupancy of serotonin in the small intestine and actual individual patient condition corresponded well, showing the validity of our method. Our results suggest that it is possible to evaluate individual antiemetic effects by estimating the 5-HT3 receptor occupancy of serotonin in the small intestine based on plasma concentrations of granisetron and serotonin near the 5-HT3 receptor in the small intestine using noninvasive urine samples. This method of individual evaluation is considered to be useful and effective.

To evaluate the antiemetic effects of 5-HT(3) receptor antagonists, we investigated the relationship between condition of food intake and occurrence of nausea and vomiting. We collected data such as sex, age, disease, combination of steroids and central antiemetic agents, eating condition, and vomiting condition from medical records in 33 hematologic cancer patients receiving chemotherapy; combination with 5-HT(3) receptor antagonists. The conditions of food intake and nausea/vomiting were checked at 4 mealtime points (lunch, supper, breakfast, and next lunch) after chemotherapy, and were recorded as 1, 3, or 5 as each condition score. To calculate eating scores and nausea/vomiting scores, the sum of scores from 4 mealtime points was used. We found a significant negative correlation between eating scores and nausea/ vomiting scores (n=62, p

We measured plasma nm23-H1 level (nm23-H1), a differentiation inhibitory factor, by an enzyme-linked immunosorbent assay (ELISA) in patients with aplastic anemia (AA) and myelodysplastic syndrome (MDS). The nm23-H1 in AA was not significantly elevated when compared to normal subjects (6.66 +/- 1.20 ng/ml vs 5.13 +/- 0.81 ng/ml; P = 0.274). In contrast, MDS patients had significantly high levels of nm23-H1 compared not only to normal subjects (11.16 +/- 1.42 vs 5.13 +/- 0.81 ng/ml; P = 0.0004) but also to those of the AA group (11.16 +/- 1.42 ng/ml vs 6.66 +/- 1.20 ng/ml; P = 0.018). In the MDS group of patients, no significant difference was observed in the nm23-H1 levels between patients with refractory anemia (RA) and RA with excess blasts (RAEB)/RAEB in transformation (10.71 +/- 1.61 ng/ml vs 9.24 +/- 2.66 ng/ml; P = 0.672). Of the patients with RA, patients with low risk according to the International Prognostic Scoring System (IPSS) had significantly low levels of nm23-H1 compared to those of IPSS INT-1 level cases (6.40 +/- 1.36 ng/ml vs 13.05 +/- 2.50 ng/ml; P = 0.0028), suggesting that nm23-H1 may be useful as a prognostic marker for MDS, especially in low risk patients.

We have investigated the possible role of anti-tumor antibody detected in a case of follicular lymphoma which demonstrated the spontaneous reduction of leukemic tumor cells. The tumor cells genotypically had monoclonal rearrangements of the immunoglobulin J H and C kappa genes, but phenotypically exhibited surface IgG, A, kappa and lambda (kappa lambda dual positivity). The culture study revealed that IgGlambda, at least, was derived from the serum, and IgAkappa was expressed intrinsically. Furthermore, the positive correlation between the densities of both surface light chains on two-color flow cytometry, the rosette formation study and its inhibition test by the Fcgamma fragment suggested that the serum IgGlambda combined with some antigens on the tumor-cell surface via its Fab portion and with the Fcgamma receptor of macrophages via its Fc portion. From these findings, we regarded the present case as an anti-tumor antibody-coated lymphoma. In addition, the phagocytic study disclosed that the serum-derived IgGlambda, at least, might have induced the phagocytosis of circulating lymphoma cells by macrophages. In conclusion, the existence of the anti-tumor antibody-coated lymphoma may be helpful in clarifying the immunological mechanism of the spontaneous regression occasionally seen in lymphomas.

Using a factor-dependent cell line MO7ER, which contains a stably transduced human erythropoietin (EPO) receptor gene in human megakaryoblastic cell line MO7e and which resulted in concomitant expression of EPO receptor, c-Mpl and c-Kit, we investigated the biological effects of these cytokines in terms of cell growth and differentiation. Thrombopoietin (TPO), EPO and Steel factor (SLF) all stimulated MO7ER cell proliferation in a dose-dependent manner. Combined stimulation of cells with SLF plus either TPO or EPO resulted in striking synergistic enhancement of MO7ER cell growth as compared with each cytokine alone, whereas combination of TPO plus EPO showed only an additive effect on cell proliferation. With regards to cell differentiation, either TPO or EPO treatment induced enhancement of platelet glycoprotein (GP) IIb/IIIa and GPIb expression. SLF induced GPIIb/IIIa and GPIb expression, but the effect was much weaker than that of EPO or TPO. However, addition of SLF to either TPO- or EPO- containing cultures (which induced potent mitogenesis in MO7ER cells) resulted in suppression of these megakaryocyte specific antigens. Addition of low-dose cytosine arabinoside (Ara-C)(1 to 10 ng/ml) enhanced TPO- or EPO- induced megakaryocytic differentiation in MO7ER cells while mildly suppressing cell growth. Treatment the cells with low-dose Ara-C plus TPO plus SLF overrode the proliferative enhancing effects of SLF and induced GPIIb/IIIa and GPIb expression as efficient as TPO alone. Retardation of TPO-induced megakaryocytic maturation was also observed in normal murine bone marrow cells by combined stimulation with TPO and SLF as assessed by the numbers of acetylcholinesterase staining-positive cells and megakaryocyte nuclear polyploidy. These results suggest that megakaryocytic maturation is, at least in part, regulated by countering cytokine-induced cell proliferation.

We have previously reported that vitamin K2 (VK2) but not VK1 has a potent apoptosis-inducing effect on freshly isolated leukemia cells from patients with various types of leukemia. By multi-color flow cytometric analysis using monoclonal antibody (mAb), APO2.7, which detects mitochondrial 7A6 antigen specifically expressed by cells undergoing apoptosis, we further investigated the apoptosis-inducing effect of VK2 on minor populations of leukemic blast cells in bone marrow from patients with myelodysplastic syndrome (MDS) and overt myeloid leukemia (post-MDS AML). Limiting dilution of CD95 (anti-Fas) mAb-treated apoptotic Jurkat cells with nonapoptotic CTB-1 cells revealed that APO2.7-positive Jurkat cells were consistently detectable by flow cytometry when present at levels of at least 5% in the CTB-1 suspension. In patient samples the gating area for leukemic clone was determined using cell surface antigen-specific mAbs conjugated with either fluorescein isothionate (FITC) or phycoerythrin (PE) and subsequently the cells stained with phycoerythrin cyanine (PE-Cy5)-conjugated APO2.7 mAb were assessed within the gating area of the leukemic clone for monitoring apoptosis. Treatment of the bone marrow mononuclear cells with 3-10 microM of VK2 (menaquinone-3, -4 and -5) in vitro potently induced apoptosis of the leukemic blast cells as compared with the untreated control cells in all 15 MDS patients tested. This effect was more prominent on blastic cells than that on mature myeloid cells such as CD34-/CD33+ gated cells. In addition, VK2 performed much less effectively on CD3-positive lymphoid cells. In contrast to VK2, VK1 did not show apoptosis-inducing activity. These data suggest that VK2 may be used for treatment of patients with MDS in blastic transformation.

In the treatment of severe infections complicated to blood dyscrasia, the efficacy and usefulness of fosfomycin (FOM) in combination with sulbactam (SBT)/cefoperazone (CPZ) were compared between patients receiving FOM in the first followed by SBT/CPZ (Group A) and those receiving both drugs simultaneously (Group B). The following results were obtained. 1. The efficacy rate was 56.3% for Group A and 47.9% for Group B, with no significant difference. 2. The efficacy for patients suspected of the presence of septicemia, the efficacy rate was 57.9% for Group A and 54.3% for Group B, with no significant difference. 3. As for underlying disease, patients with acute myelogenous leukemia were most prevailing. In these patients, the efficacy rate was 57.1% for Group A and 27.3% for Group B, with no statistically significant difference. However, the efficacy rate tended to be higher in Group A. 4. The administration of antibiotics was effective to restore the neutrophil count to 501/microliters or higher in 77.8% and 45.5% of the cases for Groups A and B, respectively, with significantly higher efficacy for Group A. 5. In the safety evaluation a total of 115 cases were included. Side effects and laboratory abnormalities were seen in 3 cases each, but none of them were serious in degree. From these results, it was confirmed that the combination therapy consisting of administration of FOM followed by SBT/CPZ with some interval is effective for severe infections complicated to blood dyscrasia.

5-HT3 receptor antagonists are widely used for prevention of chemotherapy-induced nausea and vomiting, though their antiemetic effects vary among patients. We investigated a method for evaluation of antiemetic effects in individual patients. We used the 5-HT3 receptor occupancy of serotonin for our evaluation, which was estimated based on the plasma concentration of granisetron and concentration of serotonin near the 5-HT3 receptor in the small intestine, obtained by measuring the urinary concentrations of granisetron and 5-hydroxyindoleacetic acid (5-HIAA)/creatinine (Cre). The mean cumulative percent for urinary excretion of granisetron at 24 h after administration and coefficient of variation were 16.19 ± 6.30% and 38.91%, respectively. The time course of urinary concentration of 5-HIAA/Cre also varied among the patients. The value for 5-HT3 receptor occupancy of serotonin without granisetron was higher than that prior to administration (blank), thus most treated patients had the possibility of induced emesis. In contrast, that with granisetron was lower than the blank value, indicating that those treated patients would not develop emesis. Furthermore, the estimated 5-HT3 receptor occupancy of serotonin in the small intestine and actual individual patient condition corresponded well, showing the validity of our method. Our results suggest that it is possible to evaluate individual antiemetic effects by estimating the 5-HT3 receptor occupancy of serotonin in the small intestine based on plasma concentrations of granisetron and serotonin near the 5-HT3 receptor in the small intestine using noninvasive urine samples. This method of individual evaluation is considered to be useful and effective.

The cell surface phenotype of immunoregulatory lymphocytes in bone marrow (BM) and peripheral blood (PB) in myelodysplastic syndrome (MDS), a stem cell disorder, was analyzed. Mononuclear cells from 25 patients with refractory anemia (RA) and nine with RA with an excess of blasts (RAEB) were characterized by two-color flow cytometry using various monoclonal antibodies. No significant change of CD3+, CD4+, and CD8+ cells in PB, but a decrease of the percent of positive cells for CD8+ among the total lymphocyte (%CD8+ +) was noticed in RA patients. On the other hand, in BM of RA patients, a decrease in the number of CD4+cells, but not CD8+ +cells, was noted. In RAEB patients, the absolute numbers of CD3+, CD4+, CD8+, and CD8+ +cells in BM were decreased; however, the ratio of these lymphocytes was not changed. No change was observed among the CD4 + subsets in PB of RA or RAEB patients. In BM, a decrease in percentage of CD4+ CD45RA+ (% CD4+ CD45RA+; naive cell) and increases in CD4+ CD45RO+ (% CD4+ CD45RO+; memory cell) and CD4+ CD29+ (%CD4+ CD29+; helper/inducer) among CD4+ cells were found in both RA and RAEB patients. Analysis of the CD8+ + subset showed an increased number of CD8+ + CD11a+ cells (activated CTL) in both BM and PB of RA patients, but not of RAEB patients. Furthermore, increments in CD56+ and CD16+ cells among CD3- cells (natural killer; NK cells) were seen in RA patients but not in RAEB patients. It remains unclear whether lymphocytes in MDS patients were involved in the abnormal (MDS) clones, but our results regarding the increments of CD8+ + CD11a+ and NK cells in RA patients suggest that the mechanism of immune surveillance against the abnormal MDS clones was activated in these RA patients, but not in RAEB patients. Further investigation is required to clarify the functions of these immunoregulatory lymphocytes in MDS patients.

Background: Previous studies of the safety of outpatient chemotherapy of severe adverse events (SAEs) and chemotherapy errors do not clearly consider the prevention. Objective: We treat approximately 2,500 outpatient-years with chemotherapy without explicit criteria in our ambulatory chemotherapy center (ACC). Our purpose is to develop safety, efficiency and risk management in our ACC by clarifying safety standards. Method, We investigated 3,067 case-years that reserved chemotherapy at ACC between Jun, 2012 and May, 2013. We have studied the effectiveness using criteria received chemotherapy in our ACC. In addition, to prevent HBV reactivation, we have tested newly-outpatients (n = 332) for serologic markers of HBV infection before chemotherapy. Results: The median age was 65 years. Treatment-related grade 3 or 4 adverse events were discontinued or deferred. HBsAg-positive, HBsAb-positive and HBcAb-positive patients were 0.9%(3 of 332), 13.8% (46 of 332) and 15% (3 of 332). Nobody developed HBV reactivation in our ACC. Conclusion: In this study, the chemotherapy received rate is relatively high, SAEs are low. The results suggest strategies for prevention in the outpatient chemotherapy.

20歳女性の急性リンパ性白血病.第二寛解期にHLA一致の姉をdonorとして同種骨髄移植を施行,急性移植片対宿主病は認められなかった.移植後day49の骨髄検査にて再発を疑い, day50, 57にdonor leukocyte transfusion (DLT)を施行した. Day77の骨髄検査にてリンパ芽球は認められず, DLTが有効と思われた.

Abstract 691 Background: Tyrosine kinase inhibitor (TKI) therapy has become the standard treatment for patients with chronic phase chronic myelogenous leukemia (CML-CP). Compared with imatinib, dasatinib is known to induce a faster and better response as a first- and second-line treatment. A unique effect of dasatinib treatment is the induction of clonal lymphocytosis with large granular lymphocyte (LGL) morphology, presumed to be the effect of off-target kinase inhibition. These LGLs are known to possess either cytotoxic T-cell (CTL) or natural-killer (NK) cell phenotype. Several reports have shown that this clonal LGL expansion is associated with a better response to dasatinib treatment. Purpose: To prospectively analyze the immunoprofile of Japanese patients treated with dasatinib, and to correlate the increase of lymphocytes and their subsets (LGL, CTL and NK cells) with the clinical efficacy of dasatinib. Method and Patients: Japanese patients with CML-CP who were resistant or intolerant to first-line imatinib therapy participated in the prospective phase II study assessing the efficacy and safety of dasatinib. Peripheral blood LGL, CTL and NK cell counts before and 2 weeks, 1 month (M), 3M, and 6M after the initiation of treatment were analyzed at the central laboratory (BML Inc.) by flow cytometry. LGL, CTL and NK cells were defined as CD57+/CD14-, CD8+/CD4- and CD56+/CD3- cells, respectively. Lymphocytosis was defined as a lymphocyte count of >3.0×109/L. The clinical efficacy of dasatinib was evaluated at 12M as complete molecular response (CMR) or less than CMR by peripheral blood quantitative RT-PCR (BML Inc.). The full data set was available for 50 out of 65 patients and was included in this analysis. Results: The median age of the patients enrolled was 57 years (range: 16 – 87 years). There were 37 male and 13 female patients. Twenty patients were switched to dasatinib due to intolerance to imatinib and 30 due to resistance. Lymphocytosis was observed in 19 patients (38%) at 3M. Of those 19 patients, 14 (73.7%) had lymphocytosis persisting at 6M. In total, 21 patients (42%) achieved CMR at 12M. The absolute count of lymphocytes, LGL, CTL or NK cells, did not differ significantly between patients who achieved CMR at 12M and those who did not (p>0.05). However, there were significant differences between these two groups in the relative increase of these cell counts. Relative increase of lymphocytes compared to baseline as early as 2 weeks after initiation of treatment was identified by univariate analysis as a significant factor associated with CMR at 12M (p=0.0348). This increase persisted at each time point observed until 6M. As for the different subsets of lymphocytes, the relative increase of CTL at 3 and 6M and LGL at 1, 3 and 6M were also significantly associated with a higher rate of CMR at 12M. When adjusted for possible confounding factors (age, sex, performance status, whether 1st or 2nd CP, resistance or intolerance to imatinib), the relative increase of lymphocytes at 1, 3 and 6M, CTL and LGL at 3 and 6M remained significant (Fig a-c). Patients who showed an increase of lymphocytes of over 1.5-fold at 1M showed a significantly higher rate of CMR at 12M (66.7% vs 25.8%, p=0.0007). Similar differences were seen in patients with increases of over 2-fold in CTL, LGL and NK cells (70.6% vs 22.6%, p=0.0011; 74% vs 21%, p=0.0003; and 57.9% vs 28.6%, p=0.0444). Detailed analysis at 3M showed a further significant difference in the treatment effect. An increase of over 2-fold in lymphocytes (81.3% vs 21.2%, p Conclusion: Lymphocytosis after the initiation of dasatinib was seen in a substantial proportion of Japanese patients treated with dasatinib. A relative increase of lymphocytes together with LGL, CTL and NK cells, uniformly defined by flow cytometry, at 1 and 3M after the initiation of treatment were associated with a higher rate of CMR at 12M. To our knowledge, this is the first large prospective study analyzing the clinical significance of lymphocytosis associated with dasatinib therapy in Japanese patients with CML-CP using flow cytometry. Our results suggest that a relative increase of lymphocytes as early as 1M after the initiation of dasatinib is a reliable predictive marker for achieving CMR at 12M. Disclosures: No relevant conflicts of interest to declare.

The shape-selective disproportionation of xylene to form 1,2,4-trimethylbenzene over the partially exchanged H-mordenite catalysts by various cations has been studied. The catalysts were prepared by a conventional or rapid cation-exchange method. The shape selectivity depends on the ionic radius of exchanged cation. The most suitable ionic radius is nearly 0.096 nm. The most suitable catalyst is the H-mordenite exchanged by Cu cation. This catalyst has a high selectivity, not only because there is not enough space to form the transition state leading to 1,3,5-trimethylbenzene, but also because the diffusion of 1,3,5-trimethylbenzene is inhibited. The rapid cation exchange is more effective than the conventional one, because a smaller amount of cation controls the pore dimension and provides a high selectivity without a drop in activity.