美山 貴彦

ABSTRACT Objectives The understanding of usefulness of immunoglobulin replacement therapy (IgRT) for hypogammaglobulinemia (HGG) in patients with hematologic malignancies (HM) has changed over time. This is mainly caused by the introduction of new treatment, such as B‐cell targeted agents. We investigated the real world effectiveness of IgRT on the severe bacterial infection (SBI) incidence in patients with HGG secondary to HMs using a Japanese claims database provided by MDV Inc. Methods Patients who were diagnosed with both HM and HGG from May 2010 to March 2021 in this database and prescribed IgRT with the dosage of > 5 g/month were eligible. We compared the SBI incidence, which was defined as a prescription of intravenous antibacterial agents during hospitalization, between during 12‐month before IgRT initiation (baseline period) and 12‐month after IgRT initiation (follow‐up period). Results In total 1621 eligible patients, 37.9% and 17.7% of patients were for non‐Hodgkin's lymphoma (NHL) and multiple myeloma (MM), respectively. A total of 24.4% of patients were hematopoietic stem cell transplantation (HSCT) recipients. In the follow‐up period, SBI incidence significantly decreased than that in the baseline period (2.3 events per person‐year vs. 0.9; p < 0.001). Similar results were observed in various subgroups such as patients who were diagnosed with NHL or MM, treated with anti‐CD20 monoclonal antibody or anti‐CD38 monoclonal antibody, or HSCT recipients. In the small number of patients whose baseline serum IgG levels were available (n = 28), decrease of the SBI incidence in the follow‐up period was observed regardless of IgG levels. A reduction of the SBI incidence was seen in patients with < 400 mg/dL (2.6 vs. 0.6). Conclusion IgRT may decrease the SBI incidence in patients with HGG secondary to HM. Trial Registration: Registered at UMIN Clinical Trials Registry, UMIN000047418

BACKGROUND: Distinguishing between central nervous system lymphoma (CNSL) and CNS infectious and/or demyelinating diseases, although clinically important, is sometimes difficult even using imaging strategies and conventional cerebrospinal fluid (CSF) analyses. To determine whether detection of genetic mutations enables differentiation between these diseases and the early detection of CNSL, we performed mutational analysis using CSF liquid biopsy technique. METHODS: In this study, we extracted cell-free DNA from the CSF (CSF-cfDNA) of CNSL (N = 10), CNS infectious disease (N = 10), and demyelinating disease (N = 10) patients, and performed quantitative mutational analysis by droplet-digital PCR. Conventional analyses were also performed using peripheral blood and CSF to confirm the characteristics of each disease. RESULTS: Blood hemoglobin and albumin levels were significantly lower in CNSL than CNS infectious and demyelinating diseases, CSF cell counts were significantly higher in infectious diseases than CNSL and demyelinating diseases, and CSF-cfDNA concentrations were significantly higher in infectious diseases than CNSL and demyelinating diseases. Mutation analysis using CSF-cfDNA detected MYD88L265P and CD79Y196 mutations in 60% of CNSLs each, with either mutation detected in 80% of cases. Mutual existence of both mutations was identified in 40% of cases. These mutations were not detected in either infectious or demyelinating diseases, and the sensitivity and specificity of detecting either MYD88/CD79B mutations in CNSL were 80% and 100%, respectively. In the four cases biopsied, the median time from collecting CSF with the detected mutations to definitive diagnosis by conventional methods was 22.5 days (range, 18-93 days). CONCLUSIONS: These results suggest that mutation analysis using CSF-cfDNA might be useful for differentiating CNSL from CNS infectious/demyelinating diseases and for early detection of CNSL, even in cases where brain biopsy is difficult to perform.

Not all patients with cancer and severe neutropenia develop fever, and the fecal microbiome may play a role. In a single-center study of patients undergoing hematopoietic cell transplant (n = 119), the fecal microbiome was characterized at onset of severe neutropenia. A total of 63 patients (53%) developed a subsequent fever, and their fecal microbiome displayed increased relative abundances of Akkermansia muciniphila, a species of mucin-degrading bacteria (P = 0.006, corrected for multiple comparisons). Two therapies that induce neutropenia, irradiation and melphalan, similarly expanded A. muciniphila and additionally thinned the colonic mucus layer in mice. Caloric restriction of unirradiated mice also expanded A. muciniphila and thinned the colonic mucus layer. Antibiotic treatment to eradicate A. muciniphila before caloric restriction preserved colonic mucus, whereas A. muciniphila reintroduction restored mucus thinning. Caloric restriction of unirradiated mice raised colonic luminal pH and reduced acetate, propionate, and butyrate. Culturing A. muciniphila in vitro with propionate reduced utilization of mucin as well as of fucose. Treating irradiated mice with an antibiotic targeting A. muciniphila or propionate preserved the mucus layer, suppressed translocation of flagellin, reduced inflammatory cytokines in the colon, and improved thermoregulation. These results suggest that diet, metabolites, and colonic mucus link the microbiome to neutropenic fever and may guide future microbiome-based preventive strategies.