A phase II study of gemcitabine, carboplatin, dexamethasone, and rituximab in patients with relapsed or refractory non-Hodgkin lymphoma.

This study evaluated the efficacy and safety of salvage chemotherapy with gemcitabine, carboplatin, dexamethasone, and rituximab (GCD ± R) for Japanese patients with relapsed or refractory non-Hodgkin lymphoma (NHL). A multicenter, phase II trial of GCD ± R administered every 3 weeks for up to 6 cycles was conducted. Rituximab was administered as a therapeutic strategy for CD20-positive lymphoma. The primary endpoint was the complete response (CR) rate. Secondary endpoints included the overall response (OR) rate, overall survival (OS), progression-free survival (PFS), toxicity, and success rate of peripheral blood stem cell collection for eligible transplant patients. A total of 25 patients (median age 66 years) were evaluated, with a median follow-up period of 66.7 months. CR and OR rates were 28% and 52%, respectively. Median PFS and OS were 8.7 and 32.2 months, respectively. The major toxicity was myelosuppression, but the regimen was generally well-tolerated, with a low incidence of febrile neutropenia (20%) and no treatment-related deaths. Of the 6 patients who were eligible for autologous stem cell transplantation and underwent peripheral blood stem cell mobilization, the required number of CD34-positive cells was collected in 5 (83%). All 6 proceeded to transplantation and achieved successful engraftment without recurrence. The present results suggest that GCD ± R may be effective and well-tolerated in Japanese patients with relapsed or refractory NHL. However, further investigation is needed to confirm these results.

A New Concept for Interpretation of the Viscoelastic Behavior of Aqueous Sodium Carboxymethyl Cellulose Systems.

Viscoelastic behaviors of aqueous systems of commercially available sodium carboxymethyl cellulose (NaCMC) samples with the degrees of substitution (DS) of approximately 0.68 and 1.3, and the weight-average molar masses (Mw) higher than 200 kg mol-1 dissolved in pure water and aqueous sodium chloride solutions were investigated over a wide concentration (c) range of NaCMC samples. The dependencies of the specific viscosity (ηsp), the average relaxation time (τw), and the reciprocal of the steady-state compliance (Je-1) on c were discussed. The relationships ηsp ∝ c3, τw ∝ c2, and Je-1 ∝ c, characteristic of the rod particle suspensions, were clearly observed in a range lower than the c where the critical gel behavior was observed. Thus, a new concept based on the rheology of rod particle suspensions was employed to interpret the viscoelastic behaviors obtained in the c range. In this context, NaCMC polymer molecules are assumed to behave as extended rod particles with length (L) and diameter (d), including effective electrostatic repulsive distances, due to the dissociation of Na+ in aqueous systems. Thus, the number density of polymer molecules is given to be ν = c/Mw, and viscoelastic parameters such as ηsp, τw, and Je-1 are calculated using the theoretical model for rod particle suspensions proposed by Doi and Edwards. This concept reasonably described not only the viscoelastic data obtained in this study but also those from other groups using NaCMC samples with different DS and Mw values.

[Multiple myeloma with IgH::MYC and multiple extramedullary lesions].

A 41-year-old woman with right shoulder pain was found to have multiple tumors with osteolysis and M-proteinemia. Abnormal plasma cells (CD38+, CD138+, Igλ≫κ) were detected in 1.4% of bone marrow nucleated cells, and G-banding analysis revealed a 46,XX,t (8;14), (q24;q32) karyotype in 4 of 20 cells analyzed. A biopsy specimen from an extramedullary lesion had a packed proliferation of aberrant plasmacytoid cells with positive IgH::MYC fusion signals on fluorescence in situ hybridization. The patient was diagnosed with symptomatic multiple myeloma and treated with the BLd regimen, which significantly reduced M protein levels. Extramedullary lesions were initially reduced, but increased again after four cycles. The lesions disappeared with subsequent EPOCH chemotherapy and radiation, and complete remission was confirmed. The patient was then treated with high-dose chemotherapy with autologous peripheral blood stem cell transplantation. Complete remission was maintained for over one year with lenalidomide maintenance therapy. A solitary IgH::MYC chromosomal translocation is extremely rare in multiple myeloma and may be associated with high tumor proliferative capacity, multiple extramedullary lesions, and poor prognosis. Combined therapeutic modalities with novel and conventional chemotherapy and radiation might be a promising treatment strategy for patients with this type of multiple myeloma.

Pilot study of a comprehensive resource estimation method from environmental DNA using universal D-loop amplification primers.

Many studies have investigated the ability of environmental DNA (eDNA) to identify the species. However, when individual species are to be identified, accurate estimation of their abundance using traditional eDNA analyses is still difficult. We previously developed a novel analytical method called HaCeD-Seq (haplotype count from eDNA by sequencing), which focuses on the mitochondrial D-loop sequence for eels and tuna. In this study, universal D-loop primers were designed to enable the comprehensive detection of multiple fish species by a single sequence. To sequence the full-length D-loop with high accuracy, we performed nanopore sequencing with unique molecular identifiers (UMI). In addition, to determine the D-loop reference sequence, whole genome sequencing was performed with thin coverage, and complete mitochondrial genomes were determined. We developed a UMI-based Nanopore D-loop sequencing analysis pipeline and released it as open-source software. We detected 5 out of 15 species (33%) and 10 haplotypes out of 35 individuals (29%) among the detected species. This study demonstrates the possibility of comprehensively obtaining information related to population size from eDNA. In the future, this method can be used to improve the accuracy of fish resource estimation, which is currently highly dependent on fishing catches.

Umbilical Cord Blood Transplantation for Myelodysplastic Syndromes with Donor-Specific Anti-HLA Antibodies against HLA-DP.

The presence of donor-specific anti-human leukocyte antigen (HLA) antibodies (DSAs) against anti-HLA-A, -B, -C, and -DRB1 in HLA-mismatched hematopoietic stem cell transplantation (HSCT) is associated with graft failure. DSAs against HLA-A, -B, -C, and -DRB1 with a mean fluorescence intensity (MFI) of greater than > 1,000 was shown to increase the risk of graft failure in single-unit umbilical cord blood transplantation (UCBT). Nevertheless, the impact of DSAs against HLA-DP or -DQ on transplantation outcomes is not fully understood. In this report, we present a case of UCBT in a patient with myelodysplastic syndrome who was positive for DSAs against HLA-DP with MFI of 1,263 before UCBT but successfully achieved neutrophil engraftment. If HLA-DP or -DQ is mismatched in UCBT, evaluating DSAs against HLA-DP or -DQ is crucial to avoid graft failure. However, the criteria for DSAs against HLA-A, -B, -C, and -DRB1 may not be directly applicable to those against HLA-DP or -DQ.

Evaluation of the host specificity of Eimeria uekii and Eimeria raichoi for Japanese rock ptarmigans by oocyst transfer to taxonomically related birds.

Eimeria spp. are protozoan parasites that are commonly found in a broad range of vertebrate hosts. These parasites generally exhibit strict host specificity, but some Eimeria spp. can infect groups of closely related species such as species within a genus or family. Compared with Eimeria spp. that infect livestock, limited information is available about such infections in wild animals including data on host specificity, virulence, and prevalence. The Japanese rock ptarmigan, Lagopus muta japonica, is an endangered bird belonging to the family Phasianidae, order Galliformes, and inhabits only alpine areas of Japan. In conservation efforts for these birds, two Eimeria spp., E. uekii and E. raichoi, were frequently detected. Here, we examined cross-transmission of the parasites to other bird species to characterize their infectivity as well as the development of experimental bird models to contribute to conservation programs by the oocyst transfer. Consequently, among the examined eight bird species (chickens, Japanese pheasants, turkeys, chukar partridges, quails, helmeted guineafowls and ducks), only turkeys (family Phasianidae, order Galliformes) could be infected with E. raichoi. However, the number of oocysts per feces was relatively low, and few parasites in the intestinal mucosa could be found by histopathological analyses. These results might indicate that E. uekii and E. raichoi are highly adapted to Japanese rock ptarmigans that inhabit the alpine zone although further studies are anticipated.

Safety and effectiveness of oral blonanserin for schizophrenia: A review of Japanese post-marketing surveillances.

Schizophrenia significantly limits social functioning with positive and negative symptoms and cognitive dysfunction. Blonanserin (LONASEN®), a novel second-generation antipsychotic approved for treating schizophrenia in Japan in 2008, reportedly shows beneficial effects on cognitive function as well as positive and negative symptoms, with potential for improving social functioning. To understand the safety and effectiveness of blonanserin in the real clinical practice, five Japanese post-marketing surveillances have been conducted and published to date. In this article, we reviewed all the Japanese post-marketing surveillances and discussed the clinical usefulness of blonanserin in patients with schizophrenia having diverse clinical characteristics. Adverse drug reactions, such as akathisia and extrapyramidal symptoms, were common in all surveillances. However, those specific to second-generation antipsychotics, such as weight gain and abnormalities in glycometabolism or lipid metabolism, were rarely observed. In addition, no adverse drug reactions apart from clinical trial results were found. Brief Psychiatric Rating Scale total scores in all surveillances significantly lowered at the last evaluation than at baseline. These results were consistent through 1-year of treatment, suggesting that effectiveness is maintained even after long-term use. In conclusion, blonanserin is considered a beneficial drug in real clinical practice for patients with schizophrenia having diverse characteristics.

Long-term oral blonanserin treatment for schizophrenia: a review of Japanese long-term studies.

In general, the course of schizophrenia is chronic accompanied not only by positive and negative symptoms but also by cognitive dysfunction associated with psychosocial disability, and thus treatment combining antipsychotics and psychological therapy is considered promising. This review focused on two prospective, open-label, multicenter, phase 3 long-term studies for approval of oral blonanserin for the treatment of schizophrenia. These two studies included both inpatients and outpatients with variable disease duration or symptom prominence according to the Positive and Negative Syndrome Scale (PANSS). The selected two studies consisted of almost the same study schedule and eligibility criteria but different protocols regarding prior medications and concomitant antipsychotics. The proportion of patients who had a baseline PANSS negative score higher than the positive score was 82.2 and 67.2% in the two studies. In both studies, patients with an illness duration of ≥ 10 years were the most common. Based on the clinical symptoms at baseline, the physician determined the treatment: blonanserin monotherapy, blonanserin in combination with the existing antipsychotic medication, or therapy simplified to haloperidol together with blonanserin. The 28-week completion rate for long-term blonanserin treatment was high in both studies (82.2 and 78.7%). The types of adverse events in both studies were similar to those in the preceding 8-week randomized, active-controlled studies in Japan, which were included in the application package for the approval of oral blonanserin for patients with schizophrenia. Long-term blonanserin use did not increase the risk of extrapyramidal symptoms but reduced the dose of antiparkinsonian drugs, minimally affecting functioning. In both studies, the PANSS total score, positive score, and negative score were improved at the last observation carried forward compared with those at baseline. In conclusion, blonanserin is useful for long-term treatment of chronic schizophrenic patients when the appropriate management of clinical symptoms and adverse drug reactions are applied. Blonanserin might represent a promising treatment option that partially or completely relieves patients with chronic schizophrenia of polypharmacy. Blonanserin may possibly fit both the current real-world clinical setting and the currently recommended approach to antipsychotic medication.

The (PATAN)-CheY-Like Response Regulator PixE Interacts with the Motor ATPase PilB1 to Control Negative Phototaxis in the Cyanobacterium Synechocystis sp. PCC 6803.

The cyanobacterium Synechocystis sp. PCC 6803 can move directionally on a moist surface toward or away from a light source to reach optimal light conditions for its photosynthetic lifestyle. This behavior, called phototaxis, is mediated by type IV pili (T4P), which can pull a single cell into a certain direction. Several photoreceptors and their downstream signal transduction elements are involved in the control of phototaxis. However, the critical steps of local pilus assembly in positive and negative phototaxis remain elusive. One of the photoreceptors controlling negative phototaxis in Synechocystis is the blue-light sensor PixD. PixD forms a complex with the CheY-like response regulator PixE that dissociates upon illumination with blue light. In this study, we investigate the phototactic behavior of pixE deletion and overexpression mutants in response to unidirectional red light with or without additional blue-light irradiation. Furthermore, we show that PixD and PixE partly localize in spots close to the cytoplasmic membrane. Interaction studies of PixE with the motor ATPase PilB1, demonstrated by in vivo colocalization, yeast two-hybrid and coimmunoprecipitation analysis, suggest that the PixD-PixE signal transduction system targets the T4P directly, thereby controlling blue-light-dependent negative phototaxis. An intriguing feature of PixE is its distinctive structure with a PATAN (PatA N-terminus) domain. This domain is found in several other regulators, which are known to control directional phototaxis. As our PilB1 coimmunoprecipitation analysis revealed an enrichment of PATAN domain response regulators in the eluate, we suggest that multiple environmental signals can be integrated via these regulators to control pilus function.

Discovery of a novel unsymmetrical structural class of HCV NS5A inhibitors with low picomolar antiviral activity.

A novel unsymmetrical structural class of HCV NS5A inhibitors showing picomolar range antiviral activity has been identified. An unsymmetrical lead compound 2, generated from a substructure of a known symmetrical inhibitor 1, was optimized by extension of its substituents to interact with the hitherto unexplored site of the target protein. This approach afforded novel highly potent unsymmetrical inhibitor 20, which not only equally inhibited HCV genotypes1a, 1b, and 2a with EC50 values in the picomolar range, but also inhibited the 1a Q30K mutant induced by a launched symmetrical inhibitor daclatasvir with an EC50 in the low nanomolar range.

Orally bioavailable HCV NS5A inhibitors of unsymmetrical structural class.

A novel unsymmetrical structural class of orally bioavailable hepatitis C virus (HCV) nonstructural 5A protein (NS5A) inhibitors has been generated by improving both the solubility and membrane permeability of the lead compound found in our previous work. The representative compound 14, with a 5-hydroxymethylpyrazine group and a 3-t-butylpropargyl group on each side of the molecule, exhibited the best oral bioavailability in this study, inhibiting not only the HCV genotype 1a, 1b, 2a, and 3a replicons with EC50 values in the picomolar range, but also inhibited 1a Q30 mutants induced by launched symmetrical inhibitors with EC50 values in the low nanomolar range.

Safety of endoscopic procedures with monopolar versus bipolar instruments in an ex vivo porcine model.

BACKGROUND: Monopolar instruments are generally used in colorectal endoscopic mucosal resection (EMR). Bipolar instruments have previously been reported to be as safe as monopolar instruments. We sought to compare the safety of the monopolar and bipolar snare and hemostatic forceps in an animal model. METHODS: We created 5-mm, 10-mm, and 15-mm target lesions on an ex vivo porcine rectum. Two lesions of each size were resected via monopolar polypectomy (M-P), monopolar EMR (M-E), bipolar polypectomy (B-P), and bipolar EMR (B-E). We performed a pathological evaluation of the conditions of perforation and the effects of burning on the tissues. In addition, we burned the muscularis propria covered with submucosal layer using monopolar and bipolar hemostatic forceps and performed pathological evaluations. RESULTS: Polypectomy and EMR were performed in a total of 24 target lesions. A perforation was found on histology in one case of M-P and one case of M-E after removing target lesions of 15 mm in diameter. There were no perforations during endoscopic resection using the bipolar snare. The thermal denaturation in B-P did not reach the muscularis propria layer regardless of the size of the target lesion. Although thermal damage after using monopolar hemostatic forceps was extensive, thermal denaturation was only seen on the surface of the submucosal layer when bipolar hemostatic forceps were used. CONCLUSIONS: Bipolar instruments cause less damage to the tissue than monopolar instruments. Our results also suggest that bipolar instruments may be safer than monopolar instruments in endoscopic procedures for colorectal lesions.

Comparison of breakthrough Gram-positive cocci infection during vancomycin vs teicoplanin therapy in patients receiving haematopoietic stem cell transplantation.

WHAT IS KNOWN AND OBJECTIVE: Our previous report indicated that teicoplanin (TEIC) caused fewer adverse effects than vancomycin (VCM) in patients with febrile neutropenia (FN) receiving haematopoietic stem cell transplantation (HSCT). However, we observed breakthrough methicillin-resistant-Staphylococcus haemolyticus (MR-S haemolyticus) infection during TEIC therapy in these patients. In this study, we sought to compare the incidence of breakthrough Gram-positive cocci (GPC) infection during VCM and TEIC therapy in this population. METHODS: A single-centre, retrospective cohort study was conducted. Patients who had received HSCT and were administered VCM (n = 19) or TEIC (n = 38) for FN from 1 September 2011 to 31 August 2019 were enrolled. We compared the incidence of breakthrough GPC infection between the VCM and TEIC groups. RESULTS: Breakthrough GPC infection during glycopeptide therapy in febrile neutropenic patients received HSCT was observed in three patients (7.9%) in the TEIC group but in none of patients (0%) in the VCM group. MR-S haemolyticus with low glycopeptide susceptibility (TEIC MIC = 2-8 µg/mL, VCM MIC = 2-4 µg/mL) was isolated from blood cultures in all patients with breakthrough GPC infections. All breakthrough infections were cured by changing from TEIC to daptomycin (DAP). WHAT IS NEW AND CONCLUSION: The incidence of breakthrough GPC infection during glycopeptide therapy in febrile neutropenic HSCT patients was higher in the TEIC group than in the VCM group. MR-S haemolyticus with low glycopeptide susceptibility was isolated from all patients with breakthrough GPC infection and successfully treated with DAP.

[Acquired hemophilia A complicated by dipeptidyl peptidase-4 inhibitor-associated bullous pemphigoid].

A 72-year-old man developed dipeptidyl peptidase-4 inhibitor-associated bullous pemphigoid (BP) during treatment for type 2 diabetes mellitus and was administered prednisolone (PSL, 0.5 mg/kg). Despite PSL treatment at a daily dose of 19 mg/day, purpura appeared on his bilateral forearms 3 months later. He was diagnosed with acquired hemophilia A (AHA) based on a prolonged activated partial thromboplastin time, decrease in factor VIII activity, and the presence of factor VIII inhibitor. Immunosuppressive therapy (IST) comprising PSL (1 mg/kg) and cyclophosphamide (300 mg/week) did not reduce the inhibitor level, and he subsequently developed the complication of pneumonia caused by a fungal infection. Weekly rituximab (RTX) therapy (375 mg/m2) for 4 weeks not only reduced the inhibitor level, but also enabled a rapid PSL dose reduction. Finally, a coagulative complete remission was achieved with improvements in pneumonia and BP. The prevention of adverse events of IST is particularly important in patients with AHA, who have a high median age. Therefore, RTX-based IST may be safer for AHA patients with complicating infections.

Prognostic impact of skeletal muscle assessed by computed tomography in patients with acute myeloid leukemia.

Skeletal muscle atrophy and loss of adipose tissue, referred to as sarcopenia and adipopenia, respectively, are often observed in cancer patients. We investigated the impact of sarcopenia and adipopenia on clinical outcomes in 90 adult patients with newly diagnosed acute myeloid leukemia (AML) who received induction chemotherapy. Computed tomography (CT) before treatment revealed sarcopenia in 39 patients (43%) and adipopenia in 35 patients (39%). We analyzed the treatment efficacy of induction chemotherapy and survival outcomes. Three-year overall survival (OS) was 35% in the sarcopenic group and 67% in the non-sarcopenic group (P < 0.001). Three-year OS was 33% in the adipopenic group and 67% in the non-adipopenic group (P < 0.005). Multivariate analysis showed an association between sarcopenia and lower OS (hazard ratio, 2.27; 95% confidence interval, 1.11-4.79; P < 0.05), with other prognostic factors of performance status > 2 (P < 0.05) and adverse cytogenetic risk (P < 0.05). In elderly patients over 60 years old, 3-year OS was 0% for the sarcopenic group and 49% for the non-sarcopenic group (P < 0.0005). These results indicate the prognostic values of sarcopenia in adult patients with AML.

[Thrombotic thrombocytopenic purpura during pregnancy refractory to plasma exchange and rituximab].

A 30-year-old woman who was 14 weeks pregnant was admitted to our hospital due to purpura, nasal bleeding, and abdominal pain. She was diagnosed with acquired thrombotic thrombocytopenic purpura (TTP) based on the presence of hemolytic anemia, thrombocytopenia, decreased ADAMTS 13 activity (<0.01 IU/ml), and high ADAMTS 13 inhibitor levels (4.8 BU/ml). Plasma exchange (PE) and steroid therapy were immediately administered. However, because she did not respond to these therapeutic approaches, rituximab was additionally administered on the sixth day of treatment. The level of ADAMTS 13 inhibitor increased to 12.5 BU/ml on the seventh day. Renal insufficiency, disturbed consciousness, and genital bleeding did not improve in spite of daily PE, steroid therapy, and second dose of rituximab. She finally died after sudden convulsions on the 14th day. Although the treatment outcomes of TTP have remarkably improved, some cases are refractory to therapy. Establishment of adequate treatment strategies for acquired TTP in pregnant women is required.

R-THP-COP versus R-CHOP in patients younger than 70 years with untreated diffuse large B cell lymphoma: A randomized, open-label, noninferiority phase 3 trial.

Pirarubicin (tetrahydropyranyl adriamycin [THP]) is an anthracyclin with less cardiotoxicity than doxorubicin (DOX). We previously reported the efficacy and safety of R-THP-COP consisting of rituximab (R), THP, cyclophosphamide (CPA), vincristine (VCR), and prednisolone (PSL) for diffuse large B cell lymphoma (DLBCL) in phase 2 studies. Here, we prospectively compared the efficacy and safety of the R-THP-COP and standard R-CHOP regimen (consisting of R, CPA, DOX, VCR, and PSL) in a noninferiority phase 3 trial. This prospective, randomized phase 3 study included patients younger than 70 years of age with previously untreated DLBCL. The regimen consisted of R (day 1), DOX, or THP (day 3), CPA (day 3), VCR (day 3), and PSL for 5 days every 3 weeks for 6 to 8 cycles. Between July 5, 2006 and June 11, 2013, 81 patients were randomly assigned to the treatment groups (R-CHOP group, 40 patients; R-THP-COP group, 41 patients). R-THP-COP was noninferior to R-CHOP, as assessed by the primary endpoint of complete response rate (85% vs 85% respectively). With a median follow-up of 75.2 months, the 5-year overall survival was 87% in the R-CHOP group and 82% in the R-THP-COP group (hazard ratio [HR]: 0.89, 95% confidence interval [CI]: 0.31-2.49; P = .82). The 5-year progression-free survival was 74% in the R-CHOP group and 79% in the R-THP-COP group (HR: 1.37, 95% CI: 0.56-3.55; P = .49). No grade 3 cardiac side effects were observed in either group. No serious late adverse reactions were observed in either group, with the exception of therapy-related acute myeloid leukemia in the R-THP-COP group. These data indicate that R-THP-COP is noninferior to R-CHOP with regard to clinical response, and has an acceptable safety profile. Thus, this regimen may be an alternative therapy to R-CHOP.

Bone morphological factors influencing cartilage degeneration in the knee.

OBJECTIVES: Morphological features of the distal femur and proximal tibia associated with cartilage degeneration are unknown. This study aimed to elucidate local anatomical parameters of the knee which correlate with articular cartilage degeneration using MRI T1ρ mapping. METHODS: This study involved 200 subjects with knee pain (mean age, 48.7 years; range, 14-80 years) with no severe osteoarthritic changes on plain X-ray. T1ρ values were measured in the regions of interest on the surface layer of the cartilage on mid-coronal images of the femorotibial joint. Assessment of medial and lateral posterior tibial slope (MTS, LTS) and medial and lateral femoral condylar offset ratio (MFCOR, LFCOR) was performed using sagittal proton density-weighted imaging. Morphological assessment of posterior root and horn of menisci was also performed according to a modified Whole Organ Magnetic Resonance Imaging Score (WORMS) of the knee. RESULTS: Multiple regression analysis revealed that a decrease in MTS was associated with increased T1ρ values in the medial tibia, independent of age, osteoarthritic changes on plain X-ray, femur-tibia angle (FTA), and posterior medial meniscal lesions. CONCLUSIONS: Shallow MTS correlates with cartilage degeneration in symptomatic patients. This parameter could help in understanding the etiology of osteoarthritis in the early stage. Future kinematic studies will be needed to confirm our findings.