RIMD2210633 secretes both chitinase and chitin oligosaccharide deacetylase and produces β-
-acetyl-d-glucosaminyl-(1,4)-d-glucosamine (GlcNAc-GlcN) from chitin. Previously, we reported that ...GlcNAc-GlcN induces chitinase production by several strains of
harboring chitin oligosaccharide deacetylase genes (T. Hirano, K. Kadokura, T. Ikegami, Y. Shigeta, et al., Glycobiology 19:1046-1053, 2009). The metabolism of chitin by
was speculated on the basis of the findings of previous studies, and the role of chitin oligosaccharide produced from chitin has been well studied. However, the role of GlcNAc-GlcN in the
chitin degradation system, with the exception of the above-mentioned function as an inducer of chitinase production, remains unclear.
,
'-Diacetylchitobiose, a homodisaccharide produced from chitin, is known to induce the expression of genes encoding several proteins involved in chitin metabolism in
strains (K. L. Meibom, X. B. Li, A. Nielsen, C. Wu, et al., Proc Natl Acad Sci U S A 101:2524-2529, 2004). We therefore hypothesized that GlcNAc-GlcN also affects the expression of enzymes involved in chitin metabolism in the same manner. In this study, we examined the induction of protein expression by several sugars released from chitin using peptide mass fingerprinting and confirmed the expression of genes encoding enzymes involved in chitin metabolism using real-time quantitative PCR analysis. We then confirmed that GlcNAc-GlcN induces the expression of genes encoding many soluble enzymes involved in chitin degradation in
Here, we demonstrate that GlcNAc-GlcN enhances the chitin-metabolizing ability of
We demonstrate that β-
-acetyl-d-glucosaminyl-(1,4)-d-glucosamine (GlcNAc-GlcN) enhances the chitin-metabolizing ability of
Members of the genus
are chitin-degrading bacteria, and some species of this genus are associated with diseases affecting fish and animals, including humans (F. L. Thompson, T. Iida, and J. Swings, Microbiol Mol Biol Rev 68:403-431, 2004; M. Y. Ina-Salwany, N. Al-Saari, A. Mohamad, F.-A. Mursidi, et al., J Aquat Anim Health 31:3-22, 2019). Studies on
are considered important, as they may facilitate the development of solutions related to health, food, and aquaculture problems attributed to this genus. This report enhances the current understanding of chitin degradation by
bacteria.
Somatic gene mutations related to acceleration disease and clonal evolution in multiple myeloma strongly influence severe clinical outcomes. In this study, we traced the transition of somatic ...mutations during the clinical course of myeloma patients over a long-term follow-up period (8.5 year average). Seven myeloma cases treated with immuno-chemotherapy at our institution were analyzed with clinical courses and the results of FISH and G-band analyses. Furthermore, the target sequences in regard to 121 genes, related to driver mutations or acceleration of disease in myeloma, were performed using bone marrow myeloma samples by next-generation sequencing, Ion Proton™ System. We detected a relationship between an increase in the dominant mutated gene (e.g.,
TP53, DIS3, FAM46C, KDM6B
, and
EGR1
) and poor prognosis. In particular, clonal escalation of the
TP53
mutation could not be overcome by any treatment. The selection of a combination treatment conducted in conjunction with the monitoring of gene mutations is appropriate for long-term survival. Our data demonstrate that long-term follow-up of somatic gene mutations during the clinical course of myeloma is helpful in the development of an effective treatment strategy.
We evaluated the safety, efficacy, pharmacokinetics, pharmacodynamics and predictive biomarkers of tirabrutinib, a second‐generation, enhanced‐selectivity Bruton's tyrosine kinase inhibitor in ...Japanese patients with relapsed/refractory B‐cell non−Hodgkin lymphoma (B‐cell NHL) and chronic lymphocytic leukemia (CLL). This was an open‐label, multicenter, phase I study. Seventeen patients (male N = 8) with a median age of 70 years were enrolled in 4 dose cohorts (160 mg once daily N = 3, 320 mg once daily N = 3, 480 mg once daily N = 4 and 300 mg twice daily N = 7); 4 patients had continued tirabrutinib administration as of 4 January 2018. The maximum tolerated dose was not reached. Pneumonitis (N = 1) was the dose‐limiting toxicity for 300 mg twice daily. Common adverse events (AEs) were rash (35.3%) and vomiting (29.4%). Eight patients (47.1%) developed grade ≥3 AEs: neutropenia (23.5%), anemia (11.8%) and leukopenia (11.8%) were frequent. The overall response rate (≥PR) was 76.5% (13/17 patients), including 4 DLBCL patients with no CD79A/B or MYD88 mutations, and 1 CLL patient with a TP53 mutation, providing promising data for future developments. Of 16 patients with measurable lesions during the screening period, 12 showed ≥50% reductions in tumor diameter. In many patients, the tumor size decreased soon after beginning treatment. The maximum serum concentration for tirabrutinib was 611, 1220, 1280 and 886 ng/mL on Day 1 and 484, 971 1940, and 961 ng/mL on Day 28 for Cohorts 1‐4, respectively. Tirabrutinib pharmacokinetics were linear, with little accumulation following multiple doses. Tirabrutinib was well tolerated and showed promising efficacy for B‐cell NHL/CLL.
This was an open‐label, multicenter, phase I study of tirabrutinib in 17 Japanese patients with relapsed or refractory B‐cell non−Hodgkin lymphoma and chronic lymphocytic leukemia. Patients were enrolled in 4 dose cohorts (160 mg QD N = 3, 320 mg QD N = 3, 480 mg QD N = 4 and 300 mg BID N = 7), and tirabrutinib was observed to have linear pharmacokinetics with little accumulation following multiple doses. The most common AE were rash (35.3%) and vomiting (29.4%). The overall response rate was 76.5% (13/17 patients) and the tumor diameter in 12 of 16 patients revealed ≥50% reductions, with 8 patients showing early response within 1 month after beginning treatment among 13 responders who achieved partial response or better; therefore, tirabrutinib was well tolerated and showed promising efficacy.
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.
Tucidinostat (formerly known as chidamide) is an orally available, novel benzamide class of histone deacetylase (HDAC) inhibitor that selectively blocks class I and class IIb HDAC. This multicenter ...phase IIb study aimed to investigate the efficacy and safety of tucidinostat, 40 mg twice per week (BIW), in patients with relapsed/refractory (R/R) peripheral T-cell lymphoma (PTCL). The primary endpoint was overall response rate (ORR) assessed by an independent overall efficacy review committee. Between March 2017 and March 2019, 55 patients were treated, and 46 and 55 were evaluated for efficacy and safety, respectively. Twenty-one of 46 patients achieved objective responses with an ORR of 46% (95% confidence interval : 30.9-61.0), including five patients with complete response (CR). Responses were observed across various PTCL subtypes. In angioimmunoblastic T-cell lymphoma, there were two CR and five partial responses (PR) among eight patients, achieving an ORR of 88%. The disease control rate (CR + PR + stable disease) was 72% (33/46). The median progression-free survival, duration of response, and overall survival were 5.6 months, 11.5 months, 22.8 months, respectively. The most common adverse events (AE) (all grades) were thrombocytopenia, neutropenia, leukopenia, anemia, and diarrhea. The grade ≥3 AE emerging in ≥20% of patients included thrombocytopenia (51%), neutropenia (36%), lymphopenia (22%), and leukopenia (20%). Importantly, most of the AE were manageable by supportive care and dose modification. In conclusion, the favorable efficacy and safety profiles indicate that tucidinostat could be a new therapeutic option in patients with R/R PTCL (clinicaltrials gov. Identifier: NCT02953652).
A classification tree was used to analyze background factors for granulocyte colony-stimulating factor (G-CSF) preparation selection for febrile neutropenia (FN) prophylaxis in Japanese patients with ...non-Hodgkin B-cell lymphoma receiving the first R-CHOP cycle.
This was a subanalysis of the retrospective observational study STOP FN in NHL 2 (UMIN000029534). Patient characteristics, changes in neutrophil count, incidence and severity of neutropenia, and risk factors for dose reduction/delay of R-CHOP were assessed by G-CSF formulation.
Among 234 patients in cycle 1, 25.6% received no G-CSF preparation, 52.1% received daily G-CSF, and 22.2% received pegfilgrastim. Pegfilgrastim use was most frequent among patients aged ≥ 80 years, while that of daily G-CSF was most frequent in patients with lymphocyte count (LC) < 1000 cells/μL. Changes in neutrophil count were more marked with pegfilgrastim compared with daily G-CSF and no G-CSF. Relevant factors for G-CSF preparation selection in the first R-CHOP cycle were age ≥ 80 years and LC < 1000 cells/μL; for chemotherapy dose reduction were FN onset in cycle 1 and female sex; and for dose delay was hemoglobin (< 12 g/dL). After cycle 2 and onward, pegfilgrastim use increased markedly (72.6%) compared with cycle 1 (22.2%), with significantly greater proportions continuing pegfilgrastim use and switching from daily G-CSF.
Relevant factors for G-CSF preparation selection were age ≥ 80 years and LC < 1000 cells/μL. The use of pegfilgrastim increased markedly after cycle 2. These results may be useful for selecting appropriate G-CSF preparations in the first R-CHOP cycle.
UMIN000029534; registered on 13 October 2017, https://upload.umin.ac.jp/cgi-open-bin/ctr_e/ctr_view.cgi?recptno=R000033733 .
The aim of this study was to evaluate the value of scheduled imaging for patients who achieved first complete remission after CHOP-like chemotherapy plus rituximab. In this retrospective cohort ...study, we included 759 patients newly diagnosed with de novo diffuse large B-cell lymphoma (DLBCL) at the Cancer Institute, Japanese Foundation for Cancer Research. Relapsed patients were divided into two groups based on method of diagnosis: clinical symptoms (symptom group,
n
= 57) or scheduled imaging (imaging group,
n
= 27). Our primary goal was to compare overall survival and relapse-free survival between the two groups. No significant difference in outcomes was found between the symptom and imaging groups. Median overall survival 7.5 years; 95% confidence interval (CI) 4.0–9.7 vs. 9.1 years; 95% CI 2.7 to not reached;
P
= 0.747), and median relapse-free survival (1.8 years; 95% CI 1.4–2.5 vs. 2.4 years; 95% CI 1.2–4.4;
P
= 0.108). Surveillance imaging in patients with DLBCL who achieved first complete remission did not demonstrate an advantage in terms of overall survival or relapse-free survival.
A phase 1 dose-escalation study of polatuzumab vedotin (pola) was conducted to assess safety, pharmacokinetics and preliminary antitumor activity of pola in Japanese patients with relapsed/refractory ...B-cell non-Hodgkin lymphoma.
Patients received pola (1.0 or 1.8 mg/kg) intravenously every 21 days until disease progression or intolerance. Intra-patient dose escalation was prohibited. Tolerability was determined by the standard 3 + 3 rule. Blood sampling was performed to characterize pharmacokinetics. Antitumor activity was evaluated through computed tomography and bone marrow sampling.
Four patients received pola 1.0 mg/kg; three received 1.8 mg/kg. Patients had follicular lymphoma (n = 4) or diffuse large B-cell lymphoma (n = 3), median age of 62 years, received a median of 3 prior therapies; six were female. Pola was well tolerated in both cohorts, with no dose-limiting toxicities observed. The most common adverse event was peripheral sensory neuropathy (n = 4). Grade 3 adverse events were cholecystitis and neutrophil count decreased (one each; both 1.0 mg/kg), and syncope and cataract (one each; both 1.8 mg/kg). The plasma half-life of antibody-conjugate monomethyl auristatin E was 4.43-7.98 days, and systemic exposure of unconjugated monomethyl auristatin E was limited in both cohorts. Four patients achieved objective responses (three complete, one partial) without disease progression during the study.
This phase 1 dose-escalation study demonstrated that pola has an acceptable safety profile and offers encouraging antitumor activity to Japanese patients with relapsed/refractory B-cell non-Hodgkin lymphoma. Pola 1.8 mg/kg, the recommended phase 2 dose, was tolerable in Japanese patients.
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