Clostridium butyricum Bacteremia Associated with Probiotic Use, Japan.

Clostridium butyricum, a probiotic commonly prescribed in Asia, most notably as MIYA-BM (Miyarisan Pharmaceutical Co., Ltd.; https://www.miyarisan.com), occasionally leads to bacteremia. The prevalence and characteristics of C. butyricum bacteremia and its bacteriologic and genetic underpinnings remain unknown. We retrospectively investigated patients admitted to Osaka University Hospital during September 2011-February 2023. Whole-genome sequencing revealed 5 (0.08%) cases of C. butyricum bacteremia among 6,576 case-patients who had blood cultures positive for any bacteria. Four patients consumed MIYA-BM, and 1 patient consumed a different C. butyricum-containing probiotic. Most patients had compromised immune systems, and common symptoms included fever and abdominal distress. One patient died of nonocclusive mesenteric ischemia. Sequencing results confirmed that all identified C. butyricum bacteremia strains were probiotic derivatives. Our findings underscore the risk for bacteremia resulting from probiotic use, especially in hospitalized patients, necessitating judicious prescription practices.

Fatal outcome of BK virus encephalitis in an allogeneic stem cell transplantation recipient.

BK virus (BKV) encephalitis is a rare complication after hematopoietic stem cell transplantation (HSCT). A 43-year-old woman with recurrent follicular lymphoma after autologous HSCT received allogeneic bone marrow transplantation from a human leukocyte antigen-matched related donor. Neutrophil engraftment was achieved on post-transplant day 13. Memory loss and noncooperative attitude toward the medical staff were observed on day 16, and her mental status worsened progressively. Magnetic resonance imaging (MRI) showed nonspecific findings on day 19; however, cerebrospinal fluid (CSF) analysis including real-time polymerase chain reaction on day 20 revealed elevated levels of BKV 4.67 × 104 copy/mL. BKV encephalitis was diagnosed based on CSF findings, intravenous administration of immunoglobulin and cidofovir was started, and the immunosuppressive agent dose was reduced. Diffusion-weighted MRI on day 28 showed signal abnormalities in the bilateral periventricular white matter. Although the follow-up CSF analysis on day 35 was negative for BKV, her mental status and MRI findings did not improve, and she died on day 55 because of respiratory failure. This case emphasizes the importance of considering BKV encephalitis as a differential diagnosis of post-transplant encephalitis, considering the central nervous system-associated immune reconstitution inflammatory syndrome in patients with worsening central nervous system findings after eradication of BKV in the CSF.

[Fulminant Clostridioides difficile infection during treatment with FLT3 inhibitor for acute myeloid leukemia].

An 80-year-old man with FLT3-TKD mutation-positive acute myeloid leukemia (AML) relapsed during consolidation therapy with venetoclax/azacitidine and was started on gilteritinib as salvage therapy. On the day after treatment initiation, febrile neutropenia was observed, but the fever resolved promptly after initiation of antimicrobial therapy. On the fifth day after completion of antimicrobial therapy, the patient experienced fever and watery diarrhea over 10 times a day, and a diagnosis of Clostridioides difficile infection (CDI) was made based on stool examination. The patient was treated with intravenous metronidazole, but renal dysfunction, hypotension, and hypoxemia developed, and a CT scan showed pleural and intraperitoneal effusion, significant intestinal wall thickening, and intestinal dilatation. Fidaxomicin was started under general monitoring in the intensive care unit and response was achieved. The patient was discharged from the intensive care unit on the 18th day after the onset of CDI. We report this case not only due to the rarity of fulminant CDI during AML treatment, but also because it is a valuable example of effective treatment of fulminant CDI with fidaxomicin.

Aneurysm Infection Caused by Desulfovibrio desulfuricans.

An 84-year-old man in Japan who had undergone endovascular aortic repair 9 years earlier had an infected aneurysm develop. We detected Desulfovibrio desulfuricans MB at the site. The patient recovered after surgical debridement, artificial vessel replacement, and appropriate antimicrobial therapy. Clinicians should suspect Desulfovibrio spp. infection in similar cases.

Comprehensive analysis of indels in whole-genome microsatellite regions and microsatellite instability across 21 cancer types.

Microsatellites are repeats of 1- to 6-bp units, and approximately 10 million microsatellites have been identified across the human genome. Microsatellites are vulnerable to DNA mismatch errors and have thus been used to detect cancers with mismatch repair deficiency. To reveal the mutational landscape of microsatellite repeat regions at the genome level, we analyzed approximately 20.1 billion microsatellites in 2717 whole genomes of pan-cancer samples across 21 tissue types. First, we developed a new insertion and deletion caller (MIMcall) that takes into consideration the error patterns of different types of microsatellites. Among the 2717 pan-cancer samples, our analysis identified 31 samples, including colorectal, uterus, and stomach cancers, with a higher proportion of mutated microsatellite (≥0.03), which we defined as microsatellite instability (MSI) cancers of genome-wide level. Next, we found 20 highly mutated microsatellites that can be used to detect MSI cancers with high sensitivity. Third, we found that replication timing and DNA shape were significantly associated with mutation rates of microsatellites. Last, analysis of mutations in mismatch repair genes showed that somatic SNVs and short indels had larger functional impacts than germline mutations and structural variations. Our analysis provides a comprehensive picture of mutations in the microsatellite regions and reveals possible causes of mutations, as well as provides a useful marker set for MSI detection.

Predictive scoring system for distinguishing Stenotrophomonas maltophilia bacteremia from Pseudomonas aeruginosa bacteremia in patients with hematological malignancies.

Difficulties in immediately distinguishing Stenotrophomonas maltophilia (SM) bacteremia from Pseudomonas aeruginosa (PA) bacteremia in the clinical setting can lead to treatment delay. We aimed to develop a scoring system to immediately distinguish SM bacteremia from PA bacteremia using clinical indicators. We enrolled cases of SM and PA bacteremia in adult patients with hematological malignancies between January 2011 and June 2018. The patients were randomized into derivation and validation cohorts (2:1), and a clinical prediction tool for SM bacteremia was developed and verified. In total, 88 SM and 85 PA bacteremia cases were identified. In the derivation cohort, the following independent predictors of SM bacteremia were identified: no evidence of PA colonization, antipseudomonal ß-lactam breakthrough bacteremia, and central venous catheter insertion. We scored each of the three predictors according to their regression coefficient (2, 2, and 1, respectively). Receiver operating characteristic curve analysis confirmed the score's predictive performance, with an area under the curve of 0.805. The combined sensitivity and specificity (0.655 and 0.821) was highest with a cut-off value of 4 points. Positive and negative predictive values were 79.2% (19/24) and 69.7% (23/33), respectively. This novel predictive scoring system is potentially useful for distinguishing SM bacteremia from PA bacteremia, which would facilitate immediate administration of appropriate antimicrobial therapy.

Clinical and Microbiological Characteristics of Proven Invasive Aspergillosis Due to Rare/Cryptic Species in Allogeneic Hematopoietic Stem Cell Transplant Recipients.

There are few reports on the clinical course of proven invasive aspergillosis (IA) due to rare/cryptic species in allogeneic hematopoietic stem cell transplant (allo-HSCT) recipients. We retrospectively reviewed the electronic medical records of patients who underwent allo-HSCT between January 2012 and December 2018. Of 934 allo-HSCT recipients, 10 were diagnosed with proven IA and 61 were diagnosed with probable IA. DNA sequencing was performed in cases of proven IA, and Aspergillus could be identified to the species level in 8 of the 10 cases. Three were due to A. fumigatus, and 5 were due to rare/cryptic Aspergillus species, namely, A. turcosus, A. felis, A. viridinutans, A. nidulans, and A. calidoustus. In these 8 patients, no patients with IA due to A. fumigatus died, whereas 3 of the 5 with IA due to rare/cryptic species died within 12 weeks. The 2 surviving cases of IA due to rare/cryptic species were treated with surgical resection and antifungal treatment. Susceptibility testing for cryptic species in 4 cases showed an amphotericin B MIC > 1 mg/L in 3 cases, itraconazole MIC > 1 mg/L in 2 cases, and voriconazole MIC > 1 mg/L in 2 cases. In conclusion, more than half of the causative pathogens of proven IA were rare/cryptic species, so it is important to accurately identify the Aspergillus species. In addition, surgical treatment might be an important option in cases of proven IA, given the possibility that the causative organisms are azole-resistant A. fumigatus or rare/cryptic species.

Factors Associated with Breakthrough Fungemia Caused by Candida, Trichosporon, or Fusarium Species in Patients with Hematological Disorders.

Limited data are available on breakthrough fungemia, defined as fungemia that develops on administration of antifungal agents, in patients with hematological disorders. We reviewed the medical and microbiological records of adult patients with hematological diseases who had breakthrough fungemia between January 2008 and July 2019 at Toranomon Hospital and Toranomon Hospital Kajigaya in Japan. A total of 121 cases of breakthrough fungemia were identified. Of the 121 involved patients, 83, 11, 5, and 22 were receiving micafungin, voriconazole, itraconazole, and liposomal amphotericin B, respectively, when the breakthrough occurred. Of the 121 causative breakthrough fungal strains, 96 were Candida species, and the rest were 13 cases of Trichosporon species, 7 of Fusarium species, 2 of Rhodotorula mucilaginosa, and 1 each of Cryptococcus neoformans, Exophiala dermatitidis, and Magnusiomyces capitatus. The crude 14-day mortality rate of breakthrough fungemia was 36%. Significant independent factors associated with the crude 14-day mortality rate were age of ≥60 years (P = 0.011), chronic renal failure (P = 0.0087), septic shock (P < 0.0001), steroid administration (P = 0.0085), and liposomal amphotericin B breakthrough fungemia (P = 0.0011). An absolute neutrophil count of >500/µL was significantly more common in candidemia in the multivariate analysis (P = 0.0065), neutropenia and nonallogeneic hematopoietic stem cell transplants were significantly more common in Trichosporon fungemia (P = 0.036 and P = 0.033, respectively), and voriconazole breakthrough fungemia and neutropenia were significantly more common in Fusarium fungemia (P = 0.016 and P = 0.016, respectively). The epidemiological and clinical characteristics of breakthrough fungemia of patients with hematological disorders were demonstrated. Some useful factors to predict candidemia, Trichosporon fungemia, and Fusarium fungemia were identified.

Prophylactic antiviral therapy for hepatitis B virus surface antigen-positive patients with diffuse large B-cell lymphoma treated with rituximab-containing chemotherapy.

We conducted a nationwide retrospective analysis of 116 hepatitis B virus (HBV) surface antigen (HBsAg)-positive patients with diffuse large B-cell lymphoma (DLBCL) and 278 HBsAg-negative patients with DLBCL, as a control cohort, who received rituximab-containing regimens as an induction chemotherapy at 30 Japanese medical centers between January 2004 and December 2014. Hepatitis was defined as an absolute serum alanine aminotransferase (ALT) level of ≥100 U/L. HBV reactivation-related hepatitis was defined as hepatitis with an absolute serum HBV DNA level of ≥3.3 log IU/mL or an absolute increase of ≥2 log compared with the baseline value. HBsAg-positive patients were divided into three groups based on anti-HBV prophylactic therapy: no nucleos(t)ide analogue (non-NA, n = 9), lamivudine (LAM, n = 20), and entecavir (ETV, n = 87). The 4-year cumulative incidence (CI) of hepatitis in HBsAg-positive and HBsAg-negative patients was 21.1% and 14.6% (P = .081), respectively. The 4-year CI of HBV reactivation-related hepatitis was higher in HBsAg-positive patients than in HBsAg-negative patients (8.0% vs 0.4%; P < .001). Among HBsAg-positive patients, the 4-year CI of HBV reactivation-related hepatitis was the highest in the non-NA group (33.3%), followed by the LAM (15.0%) and ETV (3.8%) groups (P < .001). Of note, 3 non-NA patients (33%) and 1 LAM patient (5%) (but no ETV patients) died due to HBV hepatitis. Based on Cox multivariate analysis, HBsAg positivity was not associated with poor overall survival. Prophylactic use of ETV would reduce the occurrence of HBV reactivation-related hepatitis and mortality in HBsAg-positive DLBCL patients receiving rituximab-containing chemotherapy.

Retrospective analyses of other iatrogenic immunodeficiency-associated lymphoproliferative disorders in patients with rheumatic diseases.

Other iatrogenic immunodeficiency-associated lymphoproliferative disorders (OIIA-LPDs) occur in patients receiving immunosuppressive drugs for autoimmune diseases; however, their clinicopathological and genetic features remain unknown. In the present study, we analysed 67 patients with OIIA-LPDs, including 36 with diffuse large B-cell lymphoma (DLBCL)-type and 19 with Hodgkin lymphoma (HL)-type. After discontinuation of immunosuppressive drugs, regression without relapse was achieved in 22 of 58 patients. Spontaneous regression was associated with Epstein-Barr virus positivity in DLBCL-type (P = 0·013). The 2-year overall survival and progression-free survival (PFS) at a median follow-up of 32·4 months were 92·7% and 72·1% respectively. Furthermore, a significant difference in the 2-year PFS was seen between patients with DLBCL-type and HL-type OIIA-LPDs (81·0% vs. 40·9% respectively, P = 0·021). In targeted sequencing of 47 genes in tumour-derived DNA from 20 DLBCL-type OIIA-LPD samples, histone-lysine N-methyltransferase 2D (KMT2D; eight, 40%) and tumour necrosis factor receptor superfamily member 14 (TNFRSF14; six, 30%) were the most frequently mutated genes. TNF alpha-induced protein 3 (TNFAIP3) mutations were present in four patients (20%) with DLBCL-type OIIA-LPD. Cases with DLBCL-type OIIA-LPD harbouring TNFAIP3 mutations had shorter PFS and required early initiation of first chemotherapy. There were no significant factors for spontaneous regression or response rates according to the presence of mutations. Overall, OIIA-LPDs, especially DLBCL-types, showed favourable prognoses.

Hematopoietic stem cell transplantation for diffuse large B-cell lymphoma having 8q24/MYC rearrangement in Japan.

The prognosis of diffuse large B-cell lymphoma (DLBCL) having MYC rearrangement (MYC-R), including double hit lymphoma (DHL), is poor by standard immunochemotherapy. To evaluate the significance of hematopoietic stem cell transplantation (SCT) for DLBCL with MYC-R, we retrospectively analyzed Japanese SCT registry data. In total, 54 patients with DLBCL with MYC-R were identified from 4336 registered adult DLBCL patients. Detailed clinical and cytogenetic information was obtained for 48 patients. The median age at diagnosis of the 48 patients was 54.5 (range 21-67) years. Twenty-six (54%) patients had MYC-R only (single hit), and 22 (46%) had MYC-R and BCL2, and/or BCL6 rearrangement (double/triple hit). In 12 patients who received auto-SCT during the first complete response (CR), both the 2-year overall survival (OS) and progression-free survival (PFS) rates were 75.0% (95% confidence interval [CI], 40.8%-91.2%). In 20 patients who received auto-SCT after relapsed or refractory state, the 2-year OS and PFS rates were 68.2% (95% CI, 41.9%-84.5%) and 59.6% (95% CI, 35.1%-77.4%), respectively. In 17 patients who received allo-SCT, only 4 patients underwent SCT in CR. The 2-year OS and PFS rates were 29.4% (95% CI, 10.7%-51.1%) and 17.6% (95% CI, 4.3%-38.3%), respectively. The rate of non-relapse mortality at 1 year was 41.2% (95% CI, 17.1%-64.0%) in this group. The outcomes of single hit and double or triple hit were not different. These findings suggest that auto-SCT may be effective for MYC-R DLBCL, including DHL patients of chemosensitive relapsed or refractory state. Since most patients received allo-SCT not in CR, the outcome of allo-SCT was unsatisfactory due to high non-relapse mortality and early relapse. To clarify the role of allo-SCT for MYC-R DLBCL, further accumulation of patients is necessary.

Characteristics of gram-negative bacteremia during febrile neutropenia among allogeneic hematopoietic stem cell transplant recipients on levofloxacin prophylaxis.

The aim of this study is to clarify the characteristics of gram-negative bacteremia (GNB), including extended-spectrum ß-lactamase (ESBL)-producing pathogens, among allogeneic hematopoietic stem cell transplant (allo-HSCT) recipients on levofloxacin (LVFX) prophylaxis. A retrospective analysis on GNB at the first episode of febrile neutropenia (FN) was conducted among allo-HSCT recipients (age ≥ 20 years) on 500 mg/day of oral LVFX prophylaxis. Epidemiological and microbiological features of GNB were investigated and compared between the inappropriate and appropriate empiric therapy groups. In total, FN occurred in 414 allo-HSCT cases, and bacteremia at the first episode of FN occurred in 169 cases. Overall, 29 GNB cases were documented, and the causative organisms identified were Escherichia coli in 21 cases (including 10 ESBLs), Klebsiella pneumoniae in 2, Pseudomonas aeruginosa in 2, and other in 4. The crude 30-day mortality rate was not significantly different among cases of GNB (6.9%), gram-positive bacteremia (GPB) (7.1%), or non-bacteremia (5.4%; P = 0.78). Cefepime (CFPM) was administered in all cases in the inappropriate empiric therapy group, and all causative organisms were ESBL-producing E. coli (ESBL-EC). All patients in the inappropriate empiric therapy group had a low Pitt bacteremia score (≤ 2). Thirty-day mortality did not differ significantly between the inappropriate and appropriate empiric therapy groups (1/10 vs. 1/15, P = 0.61). In conclusion, GNB was not a significant cause of death. In LVFX breakthrough ESBL-EC bacteremia among allo-HSCT recipients, the administration of CFPM as empiric therapy did not lead to significantly poor prognosis. Empiric CFPM administration might be an acceptable strategy.

A phase II Japanese trial of fludarabine, cyclophosphamide and rituximab for previously untreated chronic lymphocytic leukemia.

OBJECTIVE: Fludarabine, cyclophosphamide and rituximab (FCR) is the standard regimen for fit patients with untreated CD20-positive chronic lymphocytic leukemia (CLL). However, this combination is unavailable in Japan because rituximab is not approved for CLL. We investigated the efficacy and safety of FCR in this single-arm, multicenter study designed as a bridging study to the CLL8 study by the German CLL Study Group. METHODS: The study enrolled previously untreated patients with CLL of Binet stage B or C with active disease. Patients with a Cumulative Illness Rating Scale score of ≤6 and creatinine clearance of ≥70 ml/min were eligible. Patients received 6 cycles of FCR every 28 days and were followed for up to 1 year. RESULTS: Seven patients were enrolled. The best overall response rate according to the 1996 NCI-WG Guidelines, the primary endpoint of the study, was 71.4% (95% confidence interval, 29.0-96.3%), with one patient achieving complete response. No deaths or progression occurred during follow-up. The main adverse event was hematotoxicity. CD4-positive T-cell count decreased in all patients; most patients showed no reduction in serum immunoglobulin G. CONCLUSION: Although the number of patients was limited, FCR appears to be effective with manageable toxicity for treatment-naïve fit Japanese patients with CD20-positive CLL. CLINICAL TRIAL NUMBER: JapicCTI-132285.

Incidence of germline variants in Lynch syndrome-related genes among Japanese endometrial cancer patients aged 40 years or younger.

[Objective] Lynch syndrome (LS) is an autosomal dominant inherited disorder caused by a germline pathogenic variant in DNA mismatch repair (MMR) genes. Endometrial cancer frequently precedes another LS-associated tumor. This study aimed to clarify the incidence and features of LS in young Japanese endometrial cancer patients.[Methods] Sixty-five patients aged 40 years or younger, who were diagnosed with endometrial cancer, were enrolled in this study. Targeted sequencing of a hereditary colorectal cancer-related gene panel including the MMR genes MLH1, MSH2, MSH6, and PMS2 was conducted on DNA samples extracted from blood cells.[Results] Overall, 6 missense variants (2 in MSH2, 2 in MSH6, and 2 in PMS2), 1 inframe deletion variant in MSH2, 1 splice variant in MSH2, and 1 two-base substitution in the 3' untranslated region in MLH1 were detected in 9 (13.8%) patients. Among these, the splice variant c.1276G > T (p.Ile411_Gly426del16) in MSH2 was annotated as pathogenic, while other variants were of uncertain significance. The patient with the pathogenic variant had a family history of endometrial and colorectal cancer and was diagnosed with endometrial cancer at age 35.[Conclusion] The incidence of LS among Japanese endometrial cancer patients of reproductive age (≤ 40 years) in this study was at least 1.5%; however, 12.3% of patients had variants of uncertain significance in MMR genes.

Splenomegaly Negatively Impacts Neutrophil Engraftment in Cord Blood Transplantation.

Delayed neutrophil engraftment (NE) has been reported in cord blood transplantation (CBT) compared with other stem cell transplantation methods. The numbers of total nucleated cells (TNCs), CD34+ cells (generally ≥ 1 × 105/kg), and granulocyte/macrophage colony-forming units (CFU-GM) significantly impact NE. Splenomegaly exerts negative effects on NE, but the appropriate cell dose for the patients with splenomegaly has not yet been determined, especially in CBT. We retrospectively investigated the effect of splenomegaly and number of CD34+ cells infused on NE through the analysis of outcomes of 502 consecutive patients who underwent single CBT for the first time at Toranomon Hospital between 2011 and 2018. Spleen index, Lmax × Hvert (SI Lmax × Hvert), was defined as maximal length at any transverse section, (Lmax) × vertical height (Hvert), and splenomegaly was defined as SI Lmax × Hvert ≥ 115 cm2. Our results show that splenomegaly (hazard ratio [HR], .60; P < .01) and low dose of infused CD34+ cells (HR, .58; P < .01) had significant negative impact on NE, whereas neither CFU-GM dose nor TNC dose had any impact on NE in multivariate analysis. Other factors with a significant negative impact on NE in multivariate analysis were myeloid disease (HR, .62; P < .01), nonremission status at CBT (HR, .71; P < .01), low Eastern Cooperative Oncology Group Performance Status (HR, .68; P < .01), and graft-versus-host disease prophylaxis (other than tacrolimus alone) (HR, .76; P < .01). Without splenomegaly, even patients infused with < .8 × 105/kg CD34+ cells achieved up to 94.3% NE, with the median value observed at 21 days post-CBT. This study shows that splenomegaly has a significant negative impact on NE after CBT. Cord blood units with < .8 × 105/kg CD34+ cells may still be a suitable choice for patients without splenomegaly.

Prognostic Impact of Cytogenetic Evolution on the Outcome of Allogeneic Stem Cell Transplantation in Patients with Acute Myeloid Leukemia in Nonremission: A Single-Institute Analysis of 212 Recipients.

Recent progress in genetic analysis technology has helped researchers understand the pathogenesis of acute myeloid leukemia (AML). Considering this progress, AML karyotype is still one of the most significant prognostic factors that provides risk-adapted treatment approaches. Karyotype changes during treatment have been observed at times, but their prognostic impact is sparse, especially on allogeneic stem cell transplantation (allo-SCT). Here, we retrospectively investigated the effect of chromosomal changes between diagnosis and pretransplantation on the prognosis of allo-SCT by analyzing the outcomes of 212 consecutive patients who underwent allo-SCT for the first time at Toranomon Hospital, Tokyo, Japan, between 2008 and 2018. Cytogenetic abnormalities at diagnosis and pretransplantation were categorized based on the 2017 European Leukemia Net risk stratification. Genetic abnormalities such as FLT3-ITD and NPM1 were not considered in this study due to lack of genetic information in most patients. We defined cytogenetic evolution as chromosomal changes classified from lower category to higher category. Seventeen patients (8%) had cytogenetic evolution between diagnosis and pretransplantation, and they showed a significantly worse relapse rate than those who were categorized in the intermediate group based on the karyotype at diagnosis (3-year confidence interval [CI] of relapse, 57.4% versus 24.9%; P < .01). In multivariate analysis, cytogenetic evolution before allo-SCT had a significant impact on the CI of relapse (hazard ratio [HR], 3.89; CI, 1.75 to 8.67; P < .01), as well as the high score of the hematopoietic cell transplantation-specific comorbidity index (HR, 0.54; CI, 0.31 to 0.94; P = .03), but had no significant impact on overall survival or nonrelapse mortality. These results indicate that cytogenetic evolution has a significant impact after allo-SCT and should be considered during AML treatment.

DA-EPOCH-R combined with high-dose methotrexate in patients with newly diagnosed stage II-IV CD5-positive diffuse large B-cell lymphoma: a single-arm, open-label, phase II study.

CD5-positive diffuse large B-cell lymphoma (CD5+ DLBCL) is characterized by poor prognosis and a high frequency of central nervous system relapse after standard immunochemotherapy. We conducted a phase II study to investigate the efficacy and safety of dose-adjusted (DA)- EPOCH-R (etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin, and rituximab) combined with high-dose methotrexate (HD-MTX) in newly diagnosed patients with CD5+ DLBCL. Previously untreated patients with stage II to IV CD5+ DLBCL according to the 2008 World Health Organization classification were eligible. Four cycles of DA-EPOCH-R followed by two cycles of HD-MTX and four additional cycles of DAEPOCH- R (DA-EPOCH-R/HD-MTX) were planned as the protocol treatment. The primary end point was 2-year progression-free survival (PFS). Between September 25, 2012, and November 11, 2015, we enrolled 47 evaluable patients. Forty-five (96%) patients completed the protocol treatment. There were no deviations or violations in the DA-EPOCH-R dose levels. The complete response rate was 91%, and the overall response rate was 94%. At a median follow up of 3.1 years (range, 2.0-4.9 years), the 2- year PFS was 79% [95% confidence interval (CI): 64-88]. The 2-year overall survival was 89% (95%CI: 76-95). Toxicity included grade 4 neutropenia in 46 (98%) patients, grade 4 thrombocytopenia 12 (26%) patients, and febrile neutropenia in 31 (66%) patients. No treatment-related death was noted during the study. DA-EPOCH-R/HD-MTX might be a first-line therapy option for stage II-IV CD5+ DLBCL and warrants further investigation. (Trial registered at: UMIN-CTR: UMIN000008507.).

Phase 1b study to investigate the safety and tolerability of idelalisib in Japanese patients with relapsed/refractory follicular lymphoma and chronic lymphocytic leukemia.

OBJECTIVE: Idelalisib is an orally administered, highly selective inhibitor of phosphatidylinositol 3-kinase-δ. In this phase 1b study, the safety, tolerability and pharmacokinetics of idelalisib, an oral inhibitor of phosphatidylinositol 3-kinase-δ, were evaluated in Japanese patients with relapsed or refractory indolent B-cell non-Hodgkin lymphoma. METHODS: In total, six patients (follicular lymphoma: n = 3, chronic lymphocytic leukemia: n = 3) were enrolled to receive idelalisib 150 mg twice daily. RESULTS: No dose-limiting toxicities were reported. The most common adverse events were diarrhea (n = 5), gastritis (n = 3), insomnia (n = 3) and pyrexia (n = 3). The most common ≥grade 3 adverse events were diarrhea (n = 2), increased transaminase levels (n = 2) and decreased appetite (n = 2). The maximum idelalisib plasma concentrations (Cmax) were achieved at 2.50 h (range: 1.50-4.00 h). The mean idelalisib plasma concentrations decreased over time but remained detectable in most patients at 12 h. All enrolled patients underwent efficacy evaluation by investigators, and five patients (follicular lymphoma: n = 2, chronic lymphocytic leukemia: n = 3) achieved partial response. The median duration of partial response was 14.5 months (range: 3.7-31.3 months). CONCLUSION: Idelalisib 150 mg twice daily was considered tolerable in Japanese patients with follicular lymphoma or chronic lymphocytic leukemia.(Clinical trial registration: NCT02242045).

Cryptococcal meningitis following umbilical cord blood transplantation, association between the occurrence of cryptococcal infection and tacrolimus discontinuation among allogeneic hematopoietic stem cell recipients.

Few cases of cryptococcal infection following umbilical cord blood transplantation (UCBT) have been reported. We report a case, where cryptococcal infection occurred soon after rapidly reducing the dose of tacrolimus in a UCBT recipient who received micafungin prophylaxis during the early phase of transplantation. The etiology of cryptococcal infection following allogeneic hematopoietic stem cell transplantation (allo-HSCT), including UCBT, might be associated with rapid dose-reduction of calcineurin inhibitors, such as tacrolimus during early phase of allo-HSCT. To our knowledge, this is the first English-language report to describe in detail a case of cryptococcal meningitis with fungemia during early phase of UCBT.