Background Myelosuppressive chemotherapy-induced febrile neutropenia (FN) is a life-threatening condition. Patients receiving granulocyte colony-stimulating factors (G-CSF) have shorter duration of neutropenia, faster recovery from fever, and shorter duration of antibiotics use. Most strategies for FN prevention using daily G-CSF and pegfilgrastim are based on overseas studies. Data on Japanese patients were lacking; thus, we previously determined the incidence of FN in non-Hodgkin B cell lymphoma (B-NHL) patients at our center. Here, we aimed to gain additional insights into pegfilgrastim use in this population. Methods This single-center, retrospective, observational study (STOP FN in NHL 2) enrolled patients with B-NHL who underwent a regimen comprising rituximab and CHOP therapy over a 2-year period (January 2015-June 2017). The incidence of FN in cycle 1 of chemotherapy, risk factors for FN development, and use of daily G-CSF and pegfilgrastim were evaluated. Results We evaluated 239 patients: 61 patients did not receive G-CSF and 178 received G-CSF. The incidence of FN was 10.5% (95% confidence interval [CI] 6.9-15.1%) in cycle 1 and 13.0% (95% CI 9.0-17.9%) in all cycles. The FN incidence was significantly lower (P = 0.0008) in patients receiving daily G-CSF and pegfilgrastim than patients not receiving G-CSF. Significant risk factors for FN were age ≥ 65 years, albumin < 3.5 g/dL, hemoglobin < 12 g/dL, and no prophylaxis with daily G-CSF/pegfilgrastim during cycle 1. Conclusions The incidence of FN in cycle 1 and in all cycles and the identified risk factors were similar with those we previously reported; thus, our results validate previous findings. Trial registration UMIN000029534.Keywords Febrile neutropenia . Incidence . Japan . Non-Hodgkin B cell lymphoma . R-CHOP . Risk factor Background Myelosuppressive chemotherapy-induced febrile neutropenia (FN) is a life-threatening condition associated with increased morbidity and mortality [1, 2] that often results in extended hospitalization and death [3]. FN may lead to unwanted chemotherapy dose reductions or may halt treatment altogether, which can compromise treatment outcomes [2].According to the current Japanese guidelines [4], all patients who present an FN incidence ≥ 20% should receive prophylaxis granulocyte colony-stimulating factor (G-CSF), regardless of the presence or absence of risk factors, in order to prevent and treat FN induced by chemotherapy [5]. Further, all patients with risk factors for FN and FN incidence of 10 to < 20% should receive prophylaxis with G-CSF [4].Findings from this study were presented as a poster presentation at the

Proteasome inhibitor MG132 was shown to enhance the secretion of interleukin 8 (IL-8) by various cells. The enhancement is regulated by the transcription factor activator protein-1 (AP-1) at the transcriptional level. AP-1 is a dimer formed by AP-1 family proteins. The purpose of the present study was to explore the combinations of the AP-1 family proteins that contribute to MG132-driven IL-8 secretion. Oral squamous cell carcinoma-derived cell lines, Ca9-22 and HSC3, were used to demonstrate their response to MG132. IL-8 secretion was augmented by MG132 in both cell lines. c-Jun expression was detected in both the cell lines, whereas c-Fos expression was detected only in the HSC3. The influence of MG132 stimulation on c-Jun and c-Fos expression was further examined by western blot analysis. c-Jun expression was increased by MG132 stimulation, whereas c-Fos expression was not detected even after MG132 stimulation. As JunB is reported to inhibit the transcriptional activity of the AP-1 complex, we speculated that the c-Jun homodimer should contribute to IL-8 enhancement. Expression vectors encoding wild type and c-Jun mutants, M17 and M22-23, respectively, were constructed and transfected into the Ca9-22 cells. In contrast to our expectations, MG132-induced IL-8 secretion was significantly reduced in all the transfectants suggesting that other c-Jun members might form homodimers with c-Jun and contribute to IL-8 enhancement. Transfection of the cells with c-Jun or JunB small hairpin RNA (shRNA) reduced IL-8 secretion up to 50% and 65% of the control shRNA transfectant. Furthermore, cotransfection of both shRNA almost completely inhibited the IL-8 secretion. These results indicate that JunB not only inhibits but also enhances the transcription of c-Jun targets in combination with c-Jun.

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Rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) therapy is the standard of care for patients with diffuse large B-cell lymphoma (DLBCL). Typically, the dose of rituximab is 375 mg/m2; data obtained from recent clinical trials about the pharmacokinetics of rituximab showed that elderly women have a better outcome than elderly men and a more favorable pharmacokinetics of rituximab than all other patients with DLBCL. Therefore, optimization of the dose and schedule of rituximab is required for the subpopulation of patients with DLBCL that show a fast clearance of rituximab. The metabolism of rituximab, which is mostly excreted through the kidneys, is not completely understood thus far. Renal function, which is determined using creatinine clearance (CCr), at the time of administration may affect the clearance of rituximab, and thus, the therapeutic outcomes. We examined the association between the rate of CCr and survival outcome in patients with DLBCL treated with R-CHOP. We evaluated 653 patients with newly diagnosed de novo DLBCL, excluding those with transformed DLBCL, at the Cancer Institute Hospital of the Japanese Foundation for Cancer Research from January 2005 to December 2015. All patients were treated with R-CHOP or modified regimens. CCr was calculated using the Cockcroft-Gault formula. Tumour staging and response assessment were performed using the revised response criteria for malignant lymphoma and the International Conference on Malignant Lymphomas Imaging Working Group by using positron emission tomography-computed tomography and bone marrow biopsy. Progression-free survival (PFS) and overall survival (OS) were defined as the time from the date of initiation of R-CHOP to the date of disease progression, relapse, last follow-up, or death from lymphoma. Deaths due to reasons other than lymphoma were censored. PFS and OS were estimated using the Kaplan-Meier method, and the differences were compared using the log-rank test. The Cox proportional hazards regression models were used to identify the prognostic factors to predict the PFS and OS. A total of 653 patients with DLBCL were met the inclusion criteria, and the median follow-up for survival was 64 months. Our results showed that 133 (20.3%) patients had a CCr rate less than 60 mL/min. Patients with a low rate of CCr were older, had an advanced stage of DLBCL, extranodal disease, high levels of lactate dehydrogenase (LDH), and high proportion of non-germinal cell (GC) subtype, which are indicators of a poor prognosis. Therefore, patients with a lower rate of CCr showed poorer PFS (5-year PFS 74.2% vs. 80.8%, p = 0.13) and OS (5-year OS 77.1% vs. 86.9%, p=0.013). Further, we performed subgroup analysis according to CCr using the revised International Prognostic Index (R-IPI), which includes of age >60 years, stage III/IV disease, elevated LDH levels, performance status ≥ 2, more than one extranodal site of disease. Although all prognostic groups did not show a significant difference depending on the CCr, the groups with very good and good prognosis showed superior PFS in a low rate of CCr group than high rate of CCr group (Figure 1). The results of subgroup analysis for OS were similar to those observed for PFS. Thus, patients with very good and good prognosis determined using R-IPI may be affected by the subtle difference in the clearance of rituximab, whereas those with poor prognosis may not be affected by this difference. Results of multivariate analysis for PFS and OS showed that a low rate of CCr was not a significant prognostic factor. Thus, our results showed that although CCr may be a factor for clearance of rituximab, no significant association exists between the rate of CCr and survival. Our findings suggest that modification of the dose of rituximab depending on CCr is not recommended for improving survival. Further studies are required to establish an optimal dose and schedule of rituximab in all subgroups of patients with DLBCL. Disclosures Nishimura: Chugai Pharmaceutical Co., Ltd.: Other: commissioned work. Mishima:Chugai pharmaceutical inc, Roche: Other: commissioned work. Yokoyama:Chugai pharmaceutical inc, Roche: Other: commissioned work. Terui:Bristol myers Squib: Honoraria; Celgene: Honoraria; Janssen Pharmaceutical KK: Honoraria; Takeda pharmaceutical: Honoraria; Novartis pharma: Honoraria.