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.

CHOP or THP-COP regimens in the treatment of newly diagnosed peripheral T-cell lymphoma, not otherwise specified: a comparison of doxorubicin and pirarubicin.

The CHOP regimen consisting of cyclophosphamide, doxorubicin (DOX), vincristine and prednisolone has been the most used regimen for peripheral T-cell lymphoma, not otherwise specified (PTCL-NOS). Pirarubicin [tetrahydropyranyladriamycin (THP)], a derivative of DOX, is an anthracycline with reportedly less cardiotoxicity than DOX. Here, we confirmed the efficacy of THP-COP using THP instead of DOX in the treatment of PTCL-NOS. The study protocol employed a retrospective, consecutive entry design. We retrospectively analysed 56 patients with PTCL-NOS who had received THP-COP or CHOP. These regimens were performed every 21 days. Twenty-nine patients received THP-COP, and 27 received CHOP. There were no significant differences in known prognostic factors, including in the International Prognostic Index (IPI) and the prognostic index for T-cell lymphoma (PIT), between the two groups. Complete remission rates in patients with THP-COP and CHOP were 52% in both groups; the 3-year overall survival (OS) rates were 67% and 52% (p = 0.074), and the 3-year progression-free survival (PFS) rates were 51% and 29% (p = 0.070), respectively. In patients with low IPI (low or low-intermediate), THP-COP had significantly better 3-year OS (100% vs. 64%; p < 0.001) and 3-year PFS (75% vs. 33%; p < 0.05) than CHOP. Similar differences between THP-COP and CHOP were observed in patients with a low PIT (groups 1 or 2). Our study showed that THP-COP produced results equivalent to CHOP regarding efficacy and safety in patients with PTCL-NOS. In patients with low IPI or PIT, THP-COP resulted in significantly better prognosis. Copyright © 2015 John Wiley & Sons, Ltd.

A salvage chemotherapy of R-P-IMVP16/CBDCA consisting of rituximab, methylprednisolone, ifosfamide, methotrexate, etoposide, and carboplatin for patients with diffuse large B cell lymphoma who had previously received R-CHOP therapy as first-line chemotherapy.

We have reported the efficacy of the salvage chemotherapy P-IMVP16/CBDCA for patients with diffuse large B cell lymphoma (DLBCL) who had previously received CHOP before the availability of rituximab (R). Here, we confirmed the efficacy of R combined with P-IMVP16/CBDCA as a salvage chemotherapy for patients with DLBCL, who had previously received R-CHOP. We retrospectively analysed 59 patients with relapse or refractory DLBCL (38 male patients and 21 female patients) presenting between June 2004 and June 2013. The patients received R 375 mg/m2 on day 1, methylprednisolone 1000 mg/body for 3 days (from day 3 to day 5), ifosfamide 1000 mg/m2 for 5 days (from day 3 to day 7), methotrexate 30 mg/m2 on day 5 and day 12, etoposide 80 mg/m2 for 3 days (from day 3 to day 5), and carboplatin 300 mg/m2 on day 3 every 21 days. Patients aged 70 years or older were given 75% of the standard dose. The overall response rate (complete response + partial response) was 64.4%. The 2-year overall survival rate was 55.3%. The 2-year progression free survival rate was 34.7%. The 2-year overall survival rate was 61.5% for the relapse patients, and 15.6% for the refractory patients (p < 0.0001). One patient died because of sepsis related to the treatment regimen. Non-hematological adverse effects were mild and tolerable. The R-P-IMVP-16/CBDCA regimen displayed a significant activity in relapsed DLBCL, with acceptable toxicity, and should be considered a candidate for salvage chemotherapy. Copyright © 2016 John Wiley & Sons, Ltd.

Serum concentrations of l-kynurenine predict clinical outcomes of patients with peripheral T-cell lymphoma, not otherwise specified.

Indoleamine 2,3-dioxygenase exerts intense immunomodulatory effects due to enzymatic activities that catalyze the breakdown of the essential amino acid l-tryptophan. The activity of indoleamine 2,3-dioxygenase can be estimated by measuring serum l-kynurenine concentrations. Here, we aimed to determine the role of l-kynurenine as a prognostic factor for peripheral T-cell lymphoma, not otherwise specified (PTCL-NOS) in a retrospective analysis of data derived from 31 consecutive patients between June 2000 and March 2013 who were histologically diagnosed with PTCL-NOS according to the World Health Organization classification and treated with 6-8 cycles of cyclophosphamide, doxorubicin or pirarubicin, vincristine, and prednisolone. l-kynurenine concentrations in serum samples collected at admission were measured using high-performance liquid chromatography. The median serum concentration of l-kynurenine was 3.28 (range 0.92-8.16) µM. The l-kynurenine cutoff was set at 3.07 µM using receiver operating characteristics curves. The complete remission rates of patients with l-kynurenine <3.07 and ≥3.07 µM were 69% and 51%, respectively. The 5-year overall survival (OS) rates for patients with l-kynurenine <3.07 and ≥3.07 µM were 80.2% and 23.4%, respectively (p < 0.001). More advanced age, poor performance status, elevated lactate dehydrogenase, an unfavorable International Prognostic Index, and a poor prognostic index for T-cell lymphoma were significantly worse factors for OS. Multivariate analyses revealed only l-kynurenine as an independent prognostic factor for OS. In conclusion, serum concentrations of l-kynurenine might comprise a novel prognostic factor with which to determine the outcomes of treatment for PTCL-NOS. Copyright © 2016 John Wiley & Sons, Ltd.

Pathogenesis of Morquio A syndrome: an autopsied case reveals systemic storage disorder.

Mucopolysaccharidosis IVA (MPS IVA; Morquio A syndrome) is a lysosomal storage disorder caused by deficiency of N-acetylgalactosamine-6-sulfate sulfatase, which results in systemic accumulation of glycosaminoglycans (GAGs), keratan sulfate and chondroitin-6-sulfate. Accumulation of these GAGs causes characteristic features as disproportionate dwarfism associated with skeletal deformities, genu valgum, pigeon chest, joint laxity, and kyphoscoliosis. However, the pathological mechanism of systemic skeletal dysplasia and involvement of other tissues remain unanswered in the paucity of availability of an autopsied case and successive systemic analyses of multiple tissues. We report here a 20-year-old male autopsied case with MPS IVA, who developed characteristic skeletal features by the age of 1.5 years and died of acute respiratory distress syndrome five days later after occipito-C1-C2 cervical fusion. We pathohistologically analyzed postmortem tissues including trachea, lung, thyroid, humerus, aorta, heart, liver, spleen, kidney, testes, bone marrow, and lumbar vertebrae. The postmortem tissues relevant with clinical findings demonstrated 1) systemic storage materials in multiple tissues beyond cartilage, 2) severely vacuolated and ballooned chondrocytes in trachea, humerus, vertebrae, and thyroid cartilage with disorganized extracellular matrix and poor ossification, 3) appearance of foam cells and macrophages in lung, aorta, heart valves, heart muscle, trachea, visceral organs, and bone marrow, and 4) storage of chondrotin-6-sulfate in aorta. This is the first autopsied case with MPS IVA whose multiple tissues have been analyzed pathohistologically and these pathological findings should provide a new insight into pathogenesis of MPS IVA.

Serum level of soluble tumor necrosis factor receptor 2 is associated with the outcome of patients with diffuse large B-cell lymphoma treated with the R-CHOP regimen.

BACKGROUND: Serum soluble tumor necrosis factor receptor 2 (sTNFR2) concentration predicted the clinical outcome of patients with aggressive non-Hodgkin's lymphoma including diffuse large B-cell lymphoma (DLBCL) treated with CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisolone) in our previous study. However, after rituximab (R) was introduced in clinical practice, R-CHOP replaced CHOP as the standard therapy for DLBCL. PATIENTS AND METHODS: In this study, we re-evaluated the prognostic significance of serum sTNFR2 in 154 patients with DLBCL treated with R-CHOP. RESULTS: Five-yr overall survival (5-yr OS) rates with sTNFR2 ≥20 ng/mL and <20 ng/mL were 29.2% and 83.3% (P < 0.0001), respectively, and the corresponding 5-yr progression-free survival (5-yr PFS) rates were 26.9% and 76.4% (P < 0.0001), respectively. A multivariate analysis revealed that serum sTNFR2 and complete remission (CR) were independent prognostic factors for both OS (CR: P < 0.0001, sTNFR2: P = 0.0001) and PFS (CR: P < 0.0001, sTNFR2: P = 0.0001). The prognosis of patients with poor risk groups according to the revised International Prognostic Index who also had high serum sTNFR2 was especially poor. CONCLUSION: Serum sTNFR2 might be a powerful prognostic factor for patients with DLBCL in the rituximab era.

Challenges for fluoride superionic conductors: fundamentals, design, and applications.

Electronics, which harnesses the properties of electrons, has made remarkable progress since its inception and is a cornerstone of modern society. Ionics, which exploits the properties of ions, has also had a profound impact, as demonstrated by the award of the Nobel Prize in Chemistry in 2019 for achievements related to lithium-ion batteries (LIBs). Ionic conduction in solids is the flow of carrier ions through a solid owing to an electrical or chemical bias. Some ionic materials have been studied intensively because their ionic conductivities are higher than those of liquids, even though they are solids. Among various conductive species, fluoride ions are the most promising charge carriers for fluoride-ion batteries (FIBs) as post LIBs. Increasing fluoride-ion conductivity toward the superionic conductive region at room temperature would be a breakthrough for the room-temperature operation of all-solid-state FIBs. This review focuses on fluoride-ion conductors, from the general concept of ions to the characteristics of fluoride ions. Fluoride-ion conductors are classified according to material type and form, and our current understanding, identification of problems, and future directions are discussed from experimental and theoretical physics perspectives.

Unique Li deposition behavior in Li3PS4 solid electrolyte observed via operando X-ray computed tomography.

The problem of lithium dendrites must be addressed for practical lithium metal all-solid-state batteries. Herein, three-dimensional morphological changes within Li3PS4 electrolyte away from the anode were observed using operando X-ray computed tomography. We revealed that the electronic conduction of decomposition and the electrolyte/void interface cause the lithium deposition within the Li3PS4.

Improving the Cyclic Reversibility of Layered Li-Rich Cathodes by Combining Oxygen Vacancies and Surface Fluorination.

Layered-type Li-rich cathode materials have attracted significant attention for next-generation Li-ion batteries, but the advantage of their high capacity is eclipsed by their poor reversibility upon cycling. Irreversible oxygen redox activity and surface degradation have been deemed as the root cause and direct cause for their poor performance, respectively. We attempted to suppress surface degradation by inserting fluoride ions up to some depth on the surface. By fluorination with NH4HF2 after introducing a significant amount of oxygen vacancies in layered Li1.2Ni0.2Co0.2Mn0.4O2 by using CaH2 as a reducing agent, the reversible capacity reached 268 mAh/g, and the capacity retention after 100 cycles was about 99%. The scanning transmission electron microscopy-electron energy loss spectroscopy (STEM-EELS) technique revealed that, in contrast to directly fluorinated samples, our materials exhibit deeper fluorine signals besides surface signals, and hard X-ray photoelectron spectroscopy (HAXPES) patterns show ionic and covalent fluorine coordination. These results indicate that the combination of oxygen deficiency introduction and surface fluorination allows some F- ions to occupy near-surface oxygen vacancy sites rather than forming only a LiF layer on the surface, suggesting a new strategy to modify cathode materials for lithium-ion batteries.

Endoscopic ultrasound-guided fine needle aspiration biopsy for diagnosis of lymphoproliferative disorders: feasibility of immunohistological, flow cytometric, and cytogenetic assessments.

OBJECTIVES: In addition to morphology, immunophenotype and genetic abnormalities should be assessed during diagnosis and subclassification of lymphoproliferative disorders. The objective of this study was to evaluate the yield of endoscopic ultrasound-guided fine needle aspiration biopsy (EUS-FNAB) using a standard 19-gauge needle for diagnosis and subclassification of lymphoma, assessing the feasibility of immunohistological, flow cytometric, and cytogenetic assessments. METHODS: Two hundred forty patients with suspected lymphoma were referred for EUS-FNAB to our quaternary EUS center between June 2005 and December 2010. EUS-FNAB using a conventional 19-gauge needle was attempted for all patients, followed by histological assessments including immunohistological staining, flow cytometry, and cytogenetic analysis (G-band karyotyping). Among the patients, 152 were ultimately diagnosed with lymphoma. The primary outcome measure of this study was the sensitivity of histological assessment, including immunohistological staining, flow cytometry, and G-band karyotyping, for diagnosis and subclassification of lymphoma. RESULTS: Among the 152 patients ultimately diagnosed with lymphoma, 147 patients (96.7%) were diagnosed by EUS-FNAB, and classification in accordance with the WHO (World Health Organization) system was also possible for 135 patients (88.8%) on the basis of histological findings, including immunohistological staining. Flow cytometry showed abnormal or unusual cell populations in 121 (79.6%) of the 152 patients diagnosed with lymphoma, and in 114 (90.5%) of the 126 patients diagnosed with B-cell lymphoma. Specific cytogenetic abnormalities were detected in 21 (13.8%) of the lymphoma patients. CONCLUSIONS: EUS-FNAB using a standard 19-gauge needle has high diagnostic value for lymphoma. Immunophenotyping is usually possible, while cytogenetic abnormalities can be identified in a relatively limited number of patients.

Arachidonate 5-lipoxygenase establishes adaptive humoral immunity by controlling primary B cells and their cognate T-cell help.

In this study, we report the unique role of arachidonate 5-lipoxygenase (Alox5) in the regulation of specific humoral immune responses. We previously reported an L22 monoclonal antibody with which human primary resting B cells in the mantle zones of lymphoid follicles are well-defined. Proteomics analyses enabled identification of an L22 antigen as Alox5, which was highly expressed by naive and memory B cells surrounding germinal centers. Cellular growth of mantle cell lymphoma cells also seemed to depend on Alox5. Alox5(-/-) mice exhibited weak antibody responses specific to foreign antigens at the initial and recall phases. This was probably attributable to the low number of follicular and memory B cells and the functional loss of interleukin-21-mediated responses of follicular B cells. Moreover, Alox5(-/-) mice could not fully foster the development of follicular B helper T (Tfh) cells even after immunization with foreign antigens. Further experiments indicated that Alox5 affected mortality in experimentally induced enterocolitis in germ-prone circumstances, indicating that Alox5 would endow immunologic milieu. Our results illustrate the novel role of Alox5 in adaptive humoral immunity by managing primary B cells and Tfh cells in vivo.

Serum soluble interleukin-2 receptor (sIL-2R) level is associated with the outcome of patients with diffuse large B cell lymphoma treated with R-CHOP regimens.

Serum concentration of soluble interleukin-2 receptor (sIL-2R) predicts the clinical outcome of patients with aggressive non-Hodgkin's lymphoma treated with the cyclophosphamide, doxorubicin, vincristine, and prednisolone (CHOP) regimen without rituximab. In the present study, we aim to re-assess the prognostic significance of serum sIL-2R for diffuse large B cell lymphoma (DLBCL) patients treated with CHOP plus rituximab and to assess sIL-2R with subtype of DLBCL, such as GCB type and non-GCB type. Two hundred and thirty-three patients with DLBCL were enrolled between December 2002 and March 2008. To evaluate serum levels of sIL-2R, venous blood samples were drawn from patients immediately before initiation of treatment. Serum sIL-2R was determined by sandwich enzyme-linked immunosorbent assay. The 5-year overall survival (OS) rates for patients with sIL-2R levels of ≥2,000 (110 cases) and <2,000 U/mL (123 cases) were 54.2% and 89.0% (P < 0.0001), respectively. Multivariate analysis using the proportional-hazards model revealed that serum sIL-2R (P = 0.0099) and extranodal involvement sites (P = 0.0392) were independent prognostic factors for OS and that clinical stage (P = 0.0168), performance status (P = 0.0181), sIL-2R (P = 0.0232), and LDH (P = 0.0316) were independent prognostic factors for progression-free survival in sIL-2R and every factor of the International Prognostic Index. Serum sIL-2R might be a useful prognostic factor for DLBCL patients in the rituximab era.

Lactobacillus acidophilus strain L-92 induces CD4(+)CD25(+)Foxp3(+) regulatory T cells and suppresses allergic contact dermatitis.

The anti-allergic mechanism of heat-killed Lactobacillus acidophilus strain L-92 has not been fully investigated. Recent studies have reported that CD4(+)CD25(+)Foxp3(+) (forkhead box P3) T regulatory (Treg) cells play important roles in controlling allergic diseases. Hence, we examined the effect of orally administered L-92 on CD4(+)CD25(+)Foxp3(+) cell populations. BALB/c mice were supplemented daily with L-92 by gavage for 5 weeks. 2,4-Dinitrofluorobenzene (DNFB) was used to induce allergic contact dermatitis (ACD) in mice. Fluorescent-activated cell sorter (FACS) analysis was used to determine CD4(+)CD25(+)Foxp3(+) T cell populations in spleen and cervical lymph nodes (CLN). Interleukin-10 (IL-10), transforming growth factor-ß (TGF-ß), and Foxp3 mRNA expressions in mouse ear skin were investigated by real-time reverse transcription-polymerase chain reaction (RT-PCR). The percentage of CD4(+)CD25(+)Foxp3(+) T cell populations were significantly increased in both spleen and CLN of L-92-fed group than vehicle and control. In addition, L-92 produced higher levels of Foxp3, IL-10 and TGF-ß compared to control mice. These results suggest that L-92 can up-regulate the number of Treg cells to suppress the progression of DNFB-induced contact dermatitis in mice.

Clinical significance of oxidative stress for untreated patients with diffuse large B-cell lymphoma.

Oxidative stress serves an important role in carcinogenesis. The present study investigated the clinical significance of oxidative stress as a prognostic factor for diffuse large B-cell lymphoma (DLBCL). The participants comprised 55 consecutive patients with DLBCL. A commercially available derivatives of reactive oxygen metabolites (d-ROMs) test kit was used to assess oxidant levels. Similarly, a commercially available biological antioxidant potential (BAP) test was used to assess antioxidant levels. The antioxidative/oxidative stress ratio was calculated as d-ROMs/BAP. The median serum concentration of d-ROMs was 425 µM. The levels of d-ROMs were significantly higher in patients with DLBCL than in healthy volunteers (P<0.01). The complete remission (CR) rates in patients with d-ROMs <425 and ≥425 µM were 81.5 and 85.7%, respectively [not significant (NS)]. The 3-year overall survival (OS) rates for patients with d-ROMs <425 and ≥425 µM were 67.2 and 72.0%, respectively (NS). The median BAP was 2,002 µM. The CR rates of patients with BAP <2,002 and ≥2,002 µM were 77.8 and 88.9%, respectively (NS). The 3-year OS rates of patients with BAP <2,002 and ≥2,002 µM were 60.9 and 75.9%, respectively (NS). No significant difference in the d-ROMs/BAP ratio was observed between groups. Multivariate analysis revealed that d-ROMs were an independent prognostic factor for progression-free survival.

Indoleamine 2,3-dioxygenase in tumor tissue indicates prognosis in patients with diffuse large B-cell lymphoma treated with R-CHOP.

Indoleamine 2,3-dioxygenase (IDO) exerts immunomodulatory effects due to enzymatic activities catalyzing the essential amino acid L-tryptophan. IDO activity might play an important role in regulating immune responses exerted by antigen-presenting cells as a potent tool to help escape from assault by the immune system. In this study, we performed immunohistochemical analysis for IDO expression using mouse anti-human IDO monoclonal antibody in 119 tissue samples of diffuse large B-cell lymphoma (DLBCL) obtained before treatment with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP). Not only the lymphoma cells themselves but also dendritic cells (DCs) expressed IDO. Positive IDO expression in lymphoma cells was found in 38 cases (32%). Complete remission rates in patients with IDO-positive DLBCL and IDO-negative DLBCL were 55.3% and 79.0% (p=0.008), while 3-year overall survival rates were 49.8% and 78.8%, respectively (p=0.0003). IDO activity might thus play an important role in DLBCL and cells that express IDO appear important for determining outcomes after R-CHOP treatment. IDO might represent a candidate therapeutic target for DLBCL patients who show resistance to chemotherapy.

Serum interleukin-18 level is associated with the outcome of patients with diffuse large B-cell lymphoma treated with CHOP or R-CHOP regimens.

BACKGROUND: We have previously reported that serum interleukin-18 (IL-18) concentration predicted the clinical outcome of patients with aggressive non-Hodgkin's lymphoma treated with cyclophosphamide, doxorubicin, vincristine, and prednisolone (CHOP). When rituximab (R) was added to this regimen, the prognosis of diffuse large B-cell lymphoma (DLBCL) was markedly improved. PATIENTS AND METHODS: In this study, we re-evaluated the prognostic significance of serum IL-18 in 227 DLBCL patients. Seventy-three patients received CHOP before R-era, and 154 patients received rituximab-cyclophosphamide, doxorubicin, vincristine, and prednisolone (R-CHOP) recently. RESULT: Four-year overall survival (4-yr OS) rates for patients in CHOP group with IL-18 ≥720 pg/mL and <720 pg/mL were 8.2% and 67.3% (P<0.0001), respectively, and 4-yr OS rates with IL-18 ≥590 and <590 pg/mL in R-CHOP group were 53.4% and 77.8% (P=0.0008), respectively. Multivariate analysis revealed that serum IL-18 correlated most significantly with OS and progression-free survival (PFS) in both groups (OS: P<0.0001, PFS: P<0.0001, in CHOP group; OS: P=0.0147, PFS: P=0.0084 in R-CHOP group). The high serum IL-18 patients with poor prognostic group in revised IPI or with non-germinal center B-cell phenotype had a very poor prognosis. CONCLUSION: Serum IL-18 might be a powerful prognostic factor for DLBCL in R-era.

Follicular variant of peripheral T-cell lymphoma mimicking follicular lymphoma: a case report with a review of the Literature.

Peripheral T-cell lymphoma (PTCL) with a follicular growth pattern is very rare. Herein, a case of follicular variant of PTCL in a 50-year-old man who complained of tonsillar and generalized lymph node swelling is reported. The resected tonsil revealed a vague nodular growth pattern of atypical cells, medium to large in size, with abundant pale cytoplasm. The lymphoma cells were CD3(+) CD4(+) CD5(+) CD8(-) CD10(+) CD56(-) CD57(-) BCL6(+) PD-1(+) CXCL13(+) and were associated with a meshwork of CD21(+) follicular dendritic cells. Molecular studies revealed clonal rearrangement of the T-cell receptor gamma chain gene but not of the immunoglobulin gene. Cytogenetic analysis disclosed a complex abnormality in 18 of 20 cells with the exclusion of t(5; 9). These findings suggest that the present case is a follicular variant of PTCL derived from follicular T-helper cells.

Serum concentration of L-kynurenine predicts the clinical outcome of patients with diffuse large B-cell lymphoma treated with R-CHOP.

PURPOSE: Introduction of rituximab has largely improved the prognosis of patients with diffuse large B-cell lymphoma(DLBCL). Such change in therapeutic outcome necessitates the identification of additional prognostic factors to conventional indexes that have been validated for CHOP without rituximab. Indoleamine 2,3-dioxygenase (IDO) exerts intense immunomodulatory effects because of enzymatic activities that catalyze the breakdown of the essential amino acid L-tryptophan. The activity of IDO can be estimated by measuring the serum concentration of L-kynurenine. Here, we investigated the role of L-kynurenine as a prognostic marker in R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisolone) therapy. EXPERIMENTAL DESIGN: Data from 73 consecutive patients treated with eight cycles of R-CHOP or R-THP (tetrahydropyranyl adriamycin)-COP between December 2002 and March 2007 were analyzed. L-kynurenine concentrations in serum samples obtained at admission were measured by high-performance liquid chromatography. RESULTS: The median serum L-kynurenine level was 1.575 microm (range 0.537-9.588). The complete response (CR) rates of patients with L-kynurenine <1.5 and > or =1.5 microm were 83% and 61%, respectively (P < 0.05). The three-yr overall survival (OS) rates for patients with L-kynurenine <1.5 and > or =1.5 microm were 89% and 58%, respectively (P < 0.005). In addition, higher age, poor performance status, elevated serum lactate dehydrogenase, and unfavorable as well as revised International Prognosis Index were significantly worse factors for CR rate and OS. Multivariate analyses revealed only L-kynurenine as an independent prognostic factor for OS. CONCLUSIONS: Serum L-kynurenine might be a novel prognostic factor to determine the treatment outcome of DLBCL with the R-CHOP regimen.

Tissue characterization of coronary plaques and assessment of thickness of fibrous cap using integrated backscatter intravascular ultrasound. Comparison with histology and optical coherence tomography.

BACKGROUND: The purpose of this study was to develop a new online integrated backscatter intravascular ultrasound (IB-IVUS) system and to validate its ability to measure fibrous cap thickness by comparing IB-IVUS images with those from optical coherence tomography (OCT). METHODS AND RESULTS: Images were acquired from 125 segments of 26 coronary arteries obtained at autopsy from 11 cadavers. In the training study (n=30), 242 regions-of-interest on color-coded maps were compared with histology. In the validation study, 95 cross-sections were diagnosed by IB-IVUS and histology. In 24 patients with stable angina, 28 arterial cross-sections were imaged by IB-IVUS and OCT in vivo. In the training study, cutoff values of 39 decibels (dB) and 17dB were the optimal predictors of lipid pool/fibrosis and fibrosis/calcification, respectively, with 38-MHz mode; 42dB and 20dB, respectively, with 43-MHz mode. In the validation study, IB classified the fibrous, lipid-rich and fibrocalcific components with an accuracy of 92%, 91% and 95%, respectively. Agreement between the histological and IB-IVUS diagnoses was excellent (Cohen's κ=0.83). There was a correlation between the fibrous cap thickness measured by IB-IVUS and OCT (r=0.74, P<0.001). CONCLUSIONS: The IB-IVUS system with improved resolution provides high diagnostic accuracy for the analysis of the tissue characteristics of coronary plaques, and enables estimation of the thickness of the fibrous cap in the clinical setting.

Tumor-associated macrophage/microglia infiltration in human gliomas is correlated with MCP-3, but not MCP-1.

The monocyte chemotactic protein 3 (MCP-3) belongs to the MCP subgroup of the CC chemokines and promotes chemotaxis of immune cells. MCP-1 is believed to play an important role in monocyte infiltration into tumor tissues; however, the relationship between tumor-infiltrating macrophage/microglia (TIM/M) and the expression of chemokines has not been investigated in detail in human glioma samples; therefore, we first examined the expression of several chemokines and chemokine receptors in human tumor cell lines, which included glioma lines, using real-time PCR. We found that several glioma lines expressed MCP-3 predominantly, and not MCP-1. In order to assess the significance of MCP-3 expression in human glioma tissues, we then examined the number of CD68+ TIM/M, the percentage of TIM/M in the total cell population, and the expression of MCP-1 and MCP-3 in glioma tissues. There was a correlation between the percentage of TIM/M and MCP-3 expression levels; however, there was no correlation between the percentage of TIM/M and MCP-1 expression. There was no correlation between the number of TIM/M and prognosis of patients. These data indicate that tumor cell-derived MCP-3, but not MCP-1, facilitates the infiltration of macrophage/microglia into tumor tissues. This is the first study that clearly compared the significance of MCP-3 with that of MCP-1 in the tumor infiltration rates of TIM/M.