PD-1 expression on tumour-infiltrating cells is a prognostic factor for relapsed or refractory diffuse large B-cell lymphoma.

BACKGROUND: The tumour microenvironment (TME), which is modulated after immune-chemotherapy, is involved in tumour growth and metastasis. Programmed cell death 1 (PD-1) expressed on tumour-infiltrating non-malignant cells plays an important role in the TME through the PD-1/programmed cell death ligand 1 (PD-L1) signalling pathway. However, its impact in patients with relapsed or refractory (R/R) diffuse large B-cell lymphoma (DLBCL) remains unclear. METHODS: We conducted a retrospective study using tissue samples at relapse for patients with R/R DLBCL (n = 45) and evaluated the clinical impact of PD-1 expression on tumour-infiltrating non-malignant cells (microenvironmental PD-1, mPD-1). In addition, corresponding 27 samples at diagnosis were analysed to evaluate the changes in PD-1/PD-L1 expression in the TME after chemotherapy. RESULTS: Patients with mPD-1+ DLBCL showed significantly better overall survival compared with patients with mPD-1- DLBCL (hazard ratio, 0.30, p = 0.03). Among patients with mPD-1- DLBCL, those positive for neoplastic or microenvironmental PD-L1 (nPD-L1+ or mPD-L1+ ) showed significantly worse outcomes. Microenvironmental PD-1 and PD-L1 expression has high correlation at relapse, although none was found at diagnosis. CONCLUSION: We determined the clinical impact of microenvironmental PD-1 expression and its relationship with neoplastic or microenvironmental expression of PD-L1 in patients with R/R DLBCL. The expression of PD-1 and PD-L1 in the TME dramatically changes during the chemotherapy. Therefore, evaluating TME at relapse, not at diagnosis is useful to predict the outcomes of R/R DLBCL patients.

Sequential cellular and humoral responses after repetitive COVID-19 vaccination in patients treated with anti-CD20 antibodies.

Patients treated with anti-CD20 antibodies for haematological disorders have insufficient immune responses to mRNA COVID-19 vaccines; however, relevant sequential data are lacking. We sequentially evaluated the humoral and cellular immune responses in 22 patients who had received anti-CD20 antibodies within 12 months before the first vaccination, before and after the third and fourth vaccinations. Humoral responses improved gradually, along with the resolution of B-cell depletion. A steady increase was noted in cellular responses, regardless of the B-cell status. Our findings suggest the potential benefit of repeated vaccinations in these patients until B-cell recovery is confirmed while enhancing cellular responses.

The prognosis and risk factors for patients with complex karyotype myelodysplastic syndrome undergoing allogeneic haematopoietic stem cell transplantation.

Allogeneic haematopoietic stem cell transplantation (HCT) is the curative treatment for myelodysplastic syndrome with a complex karyotype (CK-MDS). However, only a few studies have been limited to patients with CK-MDS undergoing allogeneic HCT. This study aimed to identify the risk factors for patients with CK-MDS undergoing allogeneic HCT. We included 691 patients with CK-MDS who received their first allogeneic HCT. The overall survival (OS) was the primary end-point, estimated using the Kaplan-Meier method. Prognostic factors were identified using a Cox proportional hazards model. The 3-year OS was 29.8% (95% confidence interval [CI]: 26.3-33.3). In the multivariable analysis, older age (hazard ratio [HR]: 1.44, 95% CI: 1.11-1.88), male sex (HR: 1.38, 95% CI: 1.11-1.71), poor haematopoietic cell transplant comorbidity index (HR: 1.47, 95% CI: 1.20-1.81), red blood cell transfusion requirement (HR: 1.58, 95% CI: 1.13-2.20), platelet transfusion requirement (HR: 1.85, 95% CI: 1.46-2.35), not-complete remission (HR: 1.55, 95% CI: 1.16-2.06), a high number of karyotype abnormality (HR: 1.63, 95% CI: 1.18-2.25) and monosomal karyotype (HR: 1.49, 95% CI: 1.05-2.12) were significantly associated with OS. Thus, the 3-year OS of allogeneic HCT was 29.8% in patients with CK-MDS, and we identified risk factors associated with poor OS.

Single-unit unrelated cord blood transplantation versus HLA-matched sibling transplantation in adults with advanced myelodysplastic syndrome: A registry-based study from the adult MDS working group of the Japanese society for transplantation and cellular therapy.

Allogeneic hematopoietic stem cell transplantation (HCT) remains the only potential curative therapeutic modality for advanced myelodysplastic syndrome (MDS). Within HCT, the advancement of cord blood transplantation (CBT) procedures has resulted in a drastic expansion of CBT as a donor source for MDS. However, data comparing matched sibling donors (MSDs) HCT with CBT for advanced MDS, which was defined as refractory anemia with an excess of blasts (RAEB)-1 and RAEB-2 according to the World Health Organization classification at the time of HCT, have not been explored. We retrospectively compared survival and other posttransplant outcomes in 999 adult patients with advanced MDS after receiving allogeneic HCT in Japan between 2011 and 2020, using either MSD (n = 331) or single-unit unrelated cord blood (UCB) (n = 668). In the multivariate analysis, there were no significant differences in overall survival (hazard ratio [HR], 1.10; 95% confidence interval [CI], 0.90-1.34; P = 0.347), disease-free survival (HR, 1.01; 95% CI, 0.84-1.23; P = 0.845), relapse (HR, 0.88; 95% CI, 0.68-1.15; P = 0.370), or non-relapse mortality (HR, 1.15; 95% CI, 0.87-1.50; P = 0.310) between MSD recipients and UCB recipients. UCB was significantly associated with lower neutrophil (HR, 0.28; 95% CI, 0.24-0.33; P < 0.001) and lower platelet (HR, 0.29; 95% CI, 0.23-0.36; P < 0.001) recovery compared to MSD. UCB was significantly associated with a lower incidence of chronic graft-versus-host disease (GVHD) (HR, 0.57; 95% CI, 0.44-0.75; P < 0.001) and extensive chronic GVHD (HR, 0.46; 95% CI, 0.32-0.67; P < 0.001) compared to MSD. Similar results were observed after adjusting for differences between MSD and UCB recipients by propensity score matching analysis. Our study demonstrated that single CBT and MSD HCT had similar survival outcomes for adult patients with advanced MDS despite the lower hematopoietic recovery in CBT recipients and higher chronic GVHD in MSD recipients.

Intestinal Bacteria Fluctuating in Early-Stage Colorectal Cancer Carcinogenesis are Associated with Diet in Healthy Adults.

This hospital-based, cross-sectional study aimed to explore the association between diet and fluctuating intestinal bacteria in early-stage colorectal cancer (CRC) (Atopobium parvulum, Actinomyces odontolyticus, Solobacterium moorei, and Bifidobacterium longum). Healthy participants (n = 212) who underwent total colonoscopy at National Cancer Center Hospital (Tokyo, Japan) were divided into two groups according to the relative abundance of bacteria in their feces: those in the top 25% of relative bacterial abundance as cases and the bottom 25% as controls. The participants were divided into three groups (low, medium, and high) according to their intake of food groups associated with CRC. Multivariable logistic regression analysis was conducted to estimate the association between dietary intake and higher relative abundance of bacteria. Dairy products were inversely associated with a higher relative abundance of A. parvulum, A. odontolyticus, and S. moorei, with odds ratios (high vs. low) and 95% confidence interval as follows: 0.16 (0.06-0.44), 0.25 (0.08-0.82), and 0.29 (0.11-0.78), respectively. Additionally, dietary fiber was inversely associated with a higher relative abundance of S.moorei (0.29 [0.11-0.78]). No association was observed between diet and B.longum. In conclusion, healthy adults with a higher intake of dairy products and fiber had lower odds of having a higher relative abundance of CRC-associated microbiota.

Mediation effect of intestinal microbiota on the relationship between fiber intake and colorectal cancer.

Higher fiber intake has been associated with a lower risk of colorectal cancer (CRC) and has been shown to protect against CRC based on probable evidence. Recent studies revealed a possible mechanism whereby the interaction between intestinal microbiota and fiber intake mediates CRC risk. However, the specific intestinal bacteria and the amount of these bacteria involved in this mechanism are not fully known. Therefore, this single-center study aimed to determine whether specific intestinal bacteria mediated the relationship between fiber intake and CRC risk. We enrolled patients who received colonoscopy at National Cancer Center Hospital. This cross-sectional study included 180 patients with clinically diagnosed CRC and 242 controls. We conducted a causal mediation analysis to assess the natural indirect effect and natural direct effect of specific intestinal bacteria on association between fiber intake and CRC risk. The median age was 64 (interquartile range, 54-70) years, and 58% of the participants were males. We used metagenomics for profiling gut microbiomes. The relative abundance of each species in each sample was calculated. Among the candidate, Fusobacterium nucleatum and Gemella morbillorum had a significant natural indirect effect based on their highest fiber intake compared to the lowest fiber intake, with a risk difference (95% confidence interval, proportion of mediation effect) of -0.06 [-0.09 to -0.03, 23%] and -0.03 [-0.06 to -0.01, 10.5%], respectively. Other bacteria did not display natural indirect effects. In conclusion, Fusobacterium nucleatum and Gemella morbillorum were found to mediate the relationship between fiber intake and CRC risk.

Fludarabine plus reduced-intensity busulfan versus fludarabine plus myeloablative busulfan in patients with non-Hodgkin lymphoma undergoing allogeneic hematopoietic cell transplantation.

Allogeneic hematopoietic cell transplantation (HCT) offers a possible cure for patients with relapsed and refractory non-Hodgkin lymphoma (NHL) through potentially beneficial graft versus lymphoma effects. However, allogeneic HCT is associated with high nonrelapse mortality (NRM). Fludarabine with reduced-intensity busulfan (Flu/Bu2) and myeloablative busulfan (Flu/Bu4) are commonly used in conditioning regimens for allogeneic HCT; however, data on their use in patients with NHL is limited. We investigated the effect of busulfan dose on outcomes by comparing Flu/Bu2 and Flu/Bu4 in patients with NHL who underwent allogeneic HCT. Our study included 415 adult patients with NHL who received Flu/Bu2 (315 patients) or Flu/Bu4 (100 patients) between January 2008 and December 2019. All patients were enrolled in the Transplant Registry Unified Management Program 2 of the Japanese Data Center for Hematopoietic Cell Transplantation. The primary endpoint was the 5-year overall survival (OS). To minimize potential confounding factors that may influence outcomes, we performed propensity score matching. The 5-year OS was 50.6% (95% confidence interval (CI), 39.4%-60.8%) and 32.2% (95% CI, 22.4-42.4%) in the Flu/Bu2 and Flu/Bu4 groups, respectively (p = 0.006). The hazard ratio comparing the two groups was 2.13 (95% CI, 1.30-3.50; p = 0.003). Both groups had a similar 5-year cumulative incidence of relapse (38.2% vs 41.3%; p = 0.581), and the Flu/Bu4 group had a higher cumulative incidence of 5-year NRM (15.7% vs 31.9%; p = 0.043). In this study, Flu/Bu4 was associated with worse OS compared with Flu/Bu2 because of high NRM in patients with NHL.

Trajectories of the SARS-CoV-2 RNA load in patients with hematological malignancy.

OBJECTIVES: The higher risk of prolonged viral shedding in coronavirus disease (COVID-19) patients with hematological malignancies (HM) necessitates test-based de-isolation strategies. However, evidence to establish their appropriate isolation period is insufficient. This study investigated the factors affecting prolonged viral shedding and the requisite isolation period in these patients. METHODS: We retrospectively reviewed 14 COVID-19 patients with HM between January and April 2022, who were subjected to our test-based de-isolation strategy, followed by analysis of the viral load trajectory. The viral loads of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) were evaluated using the cycle threshold (Ct ) of the reverse-transcription quantitative polymerase chain reaction. The trajectories were classified according to the time-interval from COVID-19 onset to the attainment of Ct values >30. RESULTS: The median interval between onset and attainment of a Ct value >30 was 22 days. Five patients with mild or moderate COVID-19 without intense treatment histories achieved Ct values >30 within 20 days. The other nine patients needed more than 20 days, including three patients who did not meet this criterion during the observation period. CONCLUSIONS: The SARS-CoV-2 viral load trajectories in patients with HM can be stratified by treatment history for the underlying HM and severity of COVID-19.

Time definition of reintubation most relevant to patient outcomes in critically ill patients: a multicenter cohort study.

BACKGROUND: Reintubation is a common complication in critically ill patients requiring mechanical ventilation. Although reintubation has been demonstrated to be associated with patient outcomes, its time definition varies widely among guidelines and in the literature. This study aimed to determine the association between reintubation and patient outcomes as well as the consequences of the time elapsed between extubation and reintubation on patient outcomes. METHODS: This was a multicenter retrospective cohort study of critically ill patients conducted between April 2015 and March 2021. Adult patients who underwent mechanical ventilation and extubation in intensive care units (ICUs) were investigated utilizing the Japanese Intensive Care PAtient Database. The primary and secondary outcomes were in-hospital and ICU mortality. The association between reintubation and clinical outcomes was studied using Cox proportional hazards analysis. Among the patients who underwent reintubation, a Cox proportional hazard analysis was conducted to evaluate patient outcomes according to the number of days from extubation to reintubation. RESULTS: Overall, 184,705 patients in 75 ICUs were screened, and 1849 patients underwent reintubation among 48,082 extubated patients. After adjustment for potential confounders, multivariable analysis revealed a significant association between reintubation and increased in-hospital and ICU mortality (adjusted hazard ratio [HR] 1.520, 95% confidence interval [CI] 1.359-1.700, and adjusted HR 1.325, 95% CI 1.076-1.633, respectively). Among the reintubated patients, 1037 (56.1%) were reintubated within 24 h after extubation, 418 (22.6%) at 24-48 h, 198 (10.7%) at 48-72 h, 111 (6.0%) at 72-96 h, and 85 (4.6%) at 96-120 h. Multivariable Cox proportional hazard analysis showed that in-hospital and ICU mortality was highest in patients reintubated at 72-96 h (adjusted HR 1.528, 95% CI 1.062-2.197, and adjusted HR 1.334, 95% CI 0.756-2.352, respectively; referenced to reintubation within 24 h). CONCLUSIONS: Reintubation was associated with a significant increase in in-hospital and ICU mortality. The highest mortality rates were observed in patients who were reintubated between 72 and 96 h after extubation. Further studies are warranted for the optimal observation of extubated patients in clinical practice and to strengthen the evidence for mechanical ventilation.

Humoral response and safety of the BNT162b2 and mRNA-1273 COVID-19 vaccines in allogeneic hematopoietic stem cell transplant recipients: An observational study.

BACKGROUND: The effectiveness of mRNA COVID-19 vaccines and the optimal timing of vaccine administration in allogeneic hematopoietic stem cell transplantation (Allo-HSCT) recipients remains inadequately investigated. We examine the effectiveness and safety of mRNA COVID-19 vaccines in allo-HSCT recipients. METHOD: This prospective observational study included 44 allo-HSCT recipients and 38 healthy volunteers. The proportion of subjects acquiring anti-S1 IgG antibodies were considered as the primary endpoint. The occurrence of adverse events after vaccination and objective deterioration of chronic graft-versus-host disease (GVHD) were defined as secondary endpoints. In addition, we compared the geometric mean titers (GMT) of anti-S1 antibody titers in subgroups based on time interval between transplantation and vaccination. RESULTS: A humoral response to the vaccine was evident in 40 (91%) patients and all 38 healthy controls. The GMT of anti-S1 titers in patients and healthy controls were 277 (95% confidence interval [CI]: 120-643) BAU/mL and 532 (95% CI 400-708) BAU/mL, respectively. (p = 0.603). A short time interval between transplantation and vaccination (≤6 months) was associated with low anti-S1 IgG antibody titers. No serious adverse events and deterioration of chronic GVHD were observed. Only one case of new development of mild chronic GVHD was recorded. CONCLUSION: Messenger RNA COVID-19 vaccines induce humoral responses in allo-HSCT recipients and can be administered safely.

Association between meat, fish, and fatty acid intake and incidence of acute myeloid leukemia and myelodysplastic syndrome: the Japan Public Health Center-based Prospective Study.

BACKGROUND: The association between meat, fish, or fatty acid intake and acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) has been investigated in a few studies, and the results were inconsistent. In addition, most studies are mainly based on the United States and European countries, in which the dietary patterns differ from that in Asia. Therefore, the risk of AML/MDS from meat, fish, or fatty acid intake in Asia requires further exploration. The aim of this study was to investigate the association between AML/MDS incidence and meat, fish, or fatty acid intake using the Japan Public Health Center-based prospective study. METHODS: The present study included 93,366 participants who were eligible for analysis and followed up from the 5-year survey date until December 2012. We estimated the impact of their intake on AML/MDS incidence using a Cox proportional hazards model. RESULTS: The study participants were followed up for 1,345,002 person-years. During the follow-up period, we identified 67 AML and 49 MDS cases. An increased intake of processed red meat was significantly associated with the incidence of AML/MDS, with a hazard ratio of 1.63 (95% confidence interval, 1.03-2.57) for the highest versus lowest tertile and a Ptrend of 0.04. Meanwhile, the intake of other foods and fatty acids was not associated with AML/MDS. CONCLUSION: In this Japanese population, processed red meat was associated with an increased incidence of AML/MDS.

Association between Meat, Fish, and Fatty Acid Intake and Non-Hodgkin Lymphoma Incidence: The Japan Public Health Center-Based Prospective Study.

BACKGROUND: Meat, fish, and fatty acid intakes have been reported to be associated with non-Hodgkin lymphoma (NHL), although results have been inconclusive. We hypothesized that red meat and SFA intakes increase NHL risk, and fish and PUFA intakes decrease NHL risk. OBJECTIVES: We investigated the association between NHL incidence and meat, fish, and various fatty acid type intakes using the Japan Public Health Center-based Prospective Study. METHODS: The current cohort study included 93,366 participants aged 45-74 y who were eligible for analysis; they were followed up until December 2012. Participants answered an FFQ between 1995 and 1999. We analyzed the effects of meat, fish, total fatty acid, SFA, and PUFA intakes on NHL incidence using the Cox proportional hazard model. RESULTS: The median age was 57 y (IQR: 51-63 y), and 46.5% of the participants were men. Participants were followed up for 1,345,001 person-years, and 230 patients with NHL were identified. Total fatty acid and SFA intakes were associated with an increased incidence of NHL, with an adjusted HR of 1.56 (95% CI: 1.04, 2.34 highest compared with lowest quartile; P-trend = 0.062), and 1.63 (95% CI: 1.11, 2.41; P-trend = 0.074), respectively. In subtype analysis, total fatty acid and SFA intakes were also associated with increased incidence of follicular lymphoma but were not significantly associated with diffuse large B-cell lymphoma. Conversely, total meat, processed meat, unprocessed meat, red meat, poultry, fish, MUFA, PUFA, n-3 (ω-3) PUFA, and n-6 (ω-6) PUFA intakes were not significantly associated with the incidence of NHL or its subtypes. CONCLUSIONS: Total fatty acid and SFA intakes were associated with increased incidence of NHL in the Japanese adult population. Further large-scale studies are warranted to test whether fatty acid intakes affect the development of NHL.

Extramedullary relapse of acute myeloid leukemia in brachial plexus after allogeneic stem cell transplantation: a case report.

BACKGROUND: Allogeneic hematopoietic stem cell transplantation is a potentially curative treatment for acute myeloid leukemia. However, extramedullary relapse of acute myeloid leukemia can occur after hematopoietic stem cell transplantation, causing treatment failure. Extramedullary relapse rarely involves the peripheral nerves, and it is not influenced by the effect of the graft on leukemia. CASE PRESENTATION: We report a case of extramedullary relapse of acute myeloid leukemia in the brachial plexus of a 41-year-old woman treated with allogeneic hematopoietic stem cell transplantation (HSCT). Complete hematological remission was confirmed by bone marrow examination 1 month after HSCT, and she developed no major complications immediately after HSCT. The immunosuppressant was discontinued 5 months later. However, 2 weeks after immunosuppressant withdrawal, the patient developed left arm pain and paresthesia, with subsequent development of a mass in the left brachial plexus. She was initially diagnosed with brachial plexus neuropathy because of concomitant graft-versus-host disease. Despite the administration of immunosuppressive agents, the mass continued to enlarge. The biopsy of the lesion revealed leukemic relapse. Thus, the patient was diagnosed with extramedullary relapse and underwent radiotherapy, resulting in tumor shrinkage. CONCLUSION: Extramedullary relapse should be considered a differential diagnosis in post-transplant patients with leukemia presenting with paresthesia.

CD38 expression is an important prognostic marker in diffuse large B-cell lymphoma.

Diffuse large B-cell lymphoma (DLBCL) is a heterogeneous group of diseases with variable outcomes. Although several prognostic markers have been developed, specific biomarkers for stratifying treatment strategies have not been fully investigated. This study aimed to analyze the clinical impact of the expression of cluster of differentiation (CD) 38, which is associated with cellular proliferation and disease progression, in patients with de-novo DLBCL. Using flow cytometry analysis, 137 cases with DLBCL were investigated for surface expression of CD38. Based on the cut-off value by the survival classification and regression tree analysis, the patients were categorized into a CD38HIGH group (n = 37) and CD38LOW group (n = 100). The 4-years progression-free survival (PFS) was 31.6% in the CD38HIGH group and 60.7% in the CD38LOW group (p < 0.001). Multivariate analysis showed the CD38HIGH group to be associated with significantly worse PFS (adjusted hazard ratio [aHR], 2.15, 95% CI: 1.26-3.68, p = 0.005) and poor overall survival (OS) (aHR, 2.54, 95% CI: 1.25-5.19, p = 0.010) than the CD38LOW group. In conclusion, we demonstrated that high CD38 expression is an independent adverse prognostic factor associated with poor clinical outcomes compared to low CD38 expression. CD38 expression in DLBCL cells might be useful for predicting outcomes and designing risk-adapted therapies for patients with de-novo DLBCL.

Safety and efficacy evaluation of low-dose trimethoprim-sulfamethoxazole for prophylaxis of Pneumocystis pneumonia in HIV uninfected patients undergoing hemodialysis: a retrospective observational study.

BACKGROUND: Pneumocystis pneumonia (PCP) is a potentially life-threatening infection. Trimethoprim-sulfamethoxazole (TMP-SMX) is considered as the first regimen for PCP prophylaxis according to several guidelines. The recommended prophylactic dose of TMP-SMX has been determined based on patients with normal renal function, but the appropriate dosage for patients undergoing hemodialysis is unknown. The aim of this study was to investigate the efficacy and safety of low-dose TMP-SMX in patients undergoing hemodialysis. METHODS: HIV-uninfected adult patients who were undergoing hemodialysis and administered TMP-SMX for PCP prophylaxis, were included, and divided into standard-dose (≥6 single strength (SS, TMP-SMX 80 mg/400 mg tablets/week) and low-dose groups (< 6 SS tablets/week). The endpoints were cumulative incidence of PCP and cumulative discontinuation rate of TMP-SMX due to adverse events. For comparison of the groups, we employed the chi-squared test for categorical variables and the Mann-Whitney U test for continuous variables. Risk factors for the endpoints were evaluated using the Cox Fine and Gray method. RESULTS: The median age of the 81 patients included in the study was 67 years (IQR: 60-76 years), and 52 patients (64.2%) were men. No patients in either group developed PCP during the observation period. The yearly cumulative incidence of discontinuation was 12.1% (95% confidence interval [CI]: 0.027-0.29) in the low-dose group and 35.6% (95% CI: 0.20-0.52) in the standard-dose group (P = 0.019). The adjusted hazard ratio of the low-dose group compared to standard-dose group was 0.18 (95% CI: 0.04-0.86, P = 0.032). CONCLUSIONS: None of the study patients developed PCP, and the cumulative discontinuation rate of TMP-SMX due to adverse events was significantly lower in the low-dose group compared to that in the standard-dose group (P = 0.032). These results indicate that low-dose TMP-SMX is an appropriate regimen to maintain a balance between PCP prophylaxis and prevention of adverse events due to TMP-SMX administration. These findings can guide health care professionals to determine TMP-SMX dosage when considering PCP prophylaxis for patients undergoing hemodialysis.

Reversible renal-limited thrombotic microangiopathy due to gemcitabine-dexamethasone-cisplatin therapy: a case report.

BACKGROUND: Gemcitabine and cisplatin are chemotherapeutic agents used for treating multiple cancers, and these agents are sometimes used in combination. Drug-induced thrombotic microangiopathy (TMA) is a rare but potentially fatal complication. It typically presents as a systemic disease with the classical triad of hemolytic anemia, thrombocytopenia, and organ damage. In contrast to systemic TMA, cases of renal-limited TMA, defined as biopsy-proven renal TMA without the classical triad, have been reported with relatively good prognosis. Most cases of renal-limited TMA are associated with calcineurin inhibitors, and cases of drug-induced renal-limited TMA due to gemcitabine-dexamethasone-cisplatin therapy have been rarely reported. CASE PRESENTATION: A 43-year-old woman with lymphoma developed acute kidney injury with marked proteinuria, microhematuria, and abnormal urinary casts after receiving one cycle of gemcitabine-dexamethasone-cisplatin therapy. Although she did not show hemolytic anemia and thrombocytopenia, renal biopsy showed diffuse injury to the glomerular endothelial cells, supporting the diagnosis of renal-limited TMA. Her condition improved only with the cessation of gemcitabine and cisplatin treatment. She received another chemotherapy without gemcitabine and platinum agents, and no recurrence of renal-limited TMA was observed. CONCLUSIONS: Drug-induced TMA occurs early after gemcitabine and cisplatin use in renal-limited form and is reversible when detected and managed in a timely manner. Urinalysis, which is simple and inexpensive and can be easily performed, is a beneficial screening tool for early-onset drug-induced TMA among patients who receive gemcitabine-dexamethasone-cisplatin therapy.

Population pharmacokinetics of tacrolimus in umbilical cord blood transplant patients focusing on the variation in red blood cell counts.

WHAT IS KNOWN AND OBJECTIVE: The distribution of tacrolimus (TAC), an immunosuppressant used during cord blood transplantation (CBT)-one of the haematopoietic stem cell transplantations, to red blood cell (RBC) is approximately 90% in whole blood. In CBT patients, the total RBC count shows dramatic fluctuation due to conditioning before transplantation, including anticancer agents and total body irradiation, as well as RBC transfusions during the treatment period. Therefore, the amount of TAC in whole blood may show wide variation. However, therapeutic drug monitoring (TDM) of TAC has been performed based on the whole blood concentration. In this study, to contribute to TDM of TAC in CBT, we performed the population pharmacokinetic (PPK) analysis of TAC in 56 CBT patients and investigated the factors that affected the concentration of TAC, focusing the variation of RBC count. METHOD: A one-compartment model was applied to the observed whole blood TAC concentrations, and a PPK analysis was conducted with a non-linear mixed effect model. RESULTS AND DISCUSSION: Our final PPK model indicated good robustness and accuracy. In addition, haemoglobin (Hb) level was an influential covariate on Vd, which was expressed as Vd(L) = 91.4 × (Hb/8.2)(-1.07) . WHAT IS NEW AND CONCLUSION: In this study, our results showed the necessity for the Hb level monitoring during TDM of TAC in CBT patients and provided useful information for improving TDM strategy of TAC.

Outcome of Allogeneic Hematopoietic Stem Cell Transplantation in Patients with Myelodysplastic/Myeloproliferative Neoplasms-Unclassifiable: A Retrospective Nationwide Study of the Japan Society for Hematopoietic Cell Transplantation.

To date, there are no data focusing on outcomes of allogeneic hematopoietic stem cell transplantation (allo-HSCT) in patients with myelodysplastic/myeloproliferative neoplasms, unclassifiable (MDS/MPN-U). This study aimed to evaluate outcomes and prognostic factors in patients with MDS/MPN-U after allo-HSCT using Japanese nationwide registry data. The primary endpoint was 3-year overall survival (OS); secondary endpoints included the cumulative incidence of relapse and nonrelapse mortality (NRM). We evaluated the prognostic factors for 3-year OS by univariate analysis using the log-rank test. In our cohort of 86 patients with MDS/MPN-U, we found a 3-year OS of 48.5%, cumulative incidence of relapse of 23.7%, and NRM of 26.3%. The 3-year OS was significantly worse in patients age ≥50 years compared with those age <50 years (38.1% versus 65.0%; P = .049) and in patients with disease progression compared with those without disease progression (28.4% versus 57.2%; P = .042). Our results suggest that allo-HSCT may offer a curative option for patients with MDS/MPN-U, and that age and disease status could be important indicators in helping clinicians determine treatment options for these patients.

Anti-Ma-associated paraneoplastic cerebellar degeneration in a patient with nodular lymphocyte-predominant Hodgkin lymphoma: a case report.

BACKGROUND: Paraneoplastic cerebellar degeneration (PCD) is a devastating paraneoplastic syndrome that occasionally occurs in patients with Hodgkin lymphoma (HL). Anti-Ma2 is a well-characterized onconeuronal antibody and one of the causes of PCD. There has been only one previous report of anti-Ma2-associated paraneoplastic syndrome as a complication of HL. Here we present a rare case of anti-Ma2-associated PCD in a patient with nodular lymphocyte-predominant HL (NLPHL). CASE PRESENTATION: A 77-year-old man with a 3-month history of gait instability and a 2-month history of oscillopsia was referred to our hospital for further investigation. On examination, his cognition was normal. He had nystagmus in all directions of gaze; specifically, he had horizontal and rotatory nystagmus in the primary position, downbeat nystagmus after right, left, and up gaze, and upbeat nystagmus after down gaze. Although his limb ataxia was mild, his trunk ataxia was so pronounced that he was unable to walk without support. We strongly suspected paraneoplastic syndrome and tested for neuronal autoantibodies. The anti-Ma2 antibody was strongly positive in the blood and cerebrospinal fluid but other antineuronal autoantibodies were negative. Computed tomography showed an enlarged lymph node in the right axilla but no masses. Biopsy confirmed a diagnosis of NLPHL. The NLPHL cells stained with anti-Ma-2 antibody in the cytoplasm, suggesting these abnormal cells contained protein that was cross-reactive with Ma-2. CONCLUSIONS: To the best of our knowledge, this is the first case of anti-Ma2-associated PCD in a patient with NLPHL that was confirmed using immunostaining of the lymph node tissue with anti-Ma2 antibody. Our case confirms an association between anti-Ma2-associated PCD and NLPHL.

Risk Factors for Skin Toxicities Associated with Bendamustine-Based Chemotherapy in Patients with Non-Hodgkin Lymphoma.

Bendamustine plays an especially important role as a treatment for non-Hodgkin lymphoma (NHL). However, patients administered bendamustine alone or in combination with rituximab (BR) may experience drug-associated skin toxicities that can profoundly impact their health-related QOL through both physical discomfort and psychological distress. Moreover, worsening skin symptoms may lead to dose reduction or termination in the management of cancer chemotherapy. We retrospectively investigated patient backgrounds and pretreatment characteristics from medical records of NHL patients treated with bendamustine alone or BR therapy and identified predictive factors for skin toxicities at the start of chemotherapy. Patients were eligible for the study if they were 20 years older, diagnosed with NHL, and received bendamustine alone or BR therapy at the Department of Hematology, Kobe City Medical Center General Hospital, between April 1, 2011, and March 31, 2018. This study included 95 patients with newly diagnosed or refractory or relapsed NHL. Multivariate stepwise logistic regression analysis with backward selection revealed that baseline non-prior chemotherapy (odds ratio (OR), 15.72; 95% confidence interval (CI), 4.24-83.13, p < 0.001) was a significant factor influencing the occurrence of skin toxicity. Our results demonstrated that non-prior chemotherapy was a significant risk factor for skin toxicities in patients with NHL receiving bendamustine alone or BR therapy. No patient experience serious side effects of grade 3 or higher and that bendamustine is very useful as a first-line treatment.