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We previously reported that a novel haemoglobin-platelet index (HPI) based on anaemia and thrombocytopenia was useful to predict the prognosis of patients with diffuse large B-cell lymphoma not otherwise specified (DLBCL NOS). Here, we analyse the utility of HPI in a new validation cohort with DLBCL NOS (n = 94). As a result, we confirm that HPI was effective for differentiating progression-free survival (PFS) and overall survival in this validation cohort. So, we further compare the utility of HPI with previously reported prognostic markers such as the National Comprehensive Center Network-International Prognostic Index (NCCN-IPI), Glasgow prognostic score (GPS), and platelet-albumin (PA) score, using a larger number of 160 patients consisting of the derivation cohort (n = 66) and a validation cohort (n = 94). As a result, the patients with a higher HPI score had significantly worse outcomes, and HPI predicted the prognosis of DLBCL NOS independently of NCCN-IPI. HPI was more sensitive than GPS and almost the same as PA score in predicting PFS. Moreover, the patients whose lymphoma cells were positive for interleukin-6 (IL-6) (75/111 cases) judged by immunohistochemical staining had significantly lower haemoglobin levels and platelet counts than IL-6-negative cases (36/111 cases), suggesting the involvement of IL-6 produced by lymphoma cells in anaemia and thrombocytopenia in DLBCL NOS patients.

We previously examined the utility of rituximab-bendamustine (RB) in patients with follicular lymphoma (FL) exhibiting less than optimal responses to two-cycles of R-CHOP. The aim of this study was to identify molecular biomarkers that can predict prognosis in the RB-treated patients in the context of the prospective cohort. We first analyzed mutational status of 410 genes in diagnostic tumor specimens by target capture and sanger sequencing. CREBBP, KMT2D, MEF2B, BCL2, EZH2, and CARD11 were recurrently mutated as reported before, however, none of which was predictive for progression-free survival (PFS) in the RB-treated patients (n=34). A gene expression analysis by nCounter including 800 genes associated with carcinogenesis and/or immune response showed that expressions of CD8+ T-cell markers and half of the genes regulating Th1 and Th2 responses were significantly lower in progression of disease within 24 months (POD24)-group (n=8) than in noPOD24-group (n=31). Collectively, we selected 10 genes (TBX21, CXCR3, CCR4, CD8A, CD8B, GZMM, FLT3LG, CD3E, EOMES, GZMK), and generated an immune infiltration score (IIS) for predicting PFS by using principal component analysis, which dichotomized the RB-treated patients into immune IIShigh (n=19) and IISlow (n=20) groups. The 3-year PFS rate was significantly lower in the IISlow group than in the IIShigh group (50.0% [95% CI: 27.1-69.2%] vs. 84.2% [95% CI: 58.7-94.6%], p=0.0237). Furthermore, the IIS was correlates with absolute lymphocyte counts at diagnosis (r=0.460, p=0.00355). These results suggest that the T-cell-associated immune markers could be useful to predict prognosis in RB-treated FL patients. (UMIN:000013795, jRCT:051180181).

Side population (SP) is known to include therapy-resistant cells in various cancers. Here, we analyzed SP using multiple myeloma (MM) samples. The SP accounted for 2.96% in MM cells from newly diagnosed MM (NDMM). CD34 was expressed in 47.8% of SP cells, but only in 2.11% of bulk MM cells. CD34

Background: Several clinical risk stratification models have been proposed to predict the clinical outcomes of follicular lymphoma (FL) cases, however, few reports are available to predict prognosis of FL cases receiving bendamustine-based regimens. We previously examined the utility of rituximab-bendamustine (RB) treatment for newly diagnosed advanced FL, who showed non-optimal responses to two cycles of R-CHOP therapy. Methods: In this study, we explored the biomarkers that could influence outcomes for the RB-treated FL cases in the context of the prospective cohort by target capture and sanger sequencing, and gene-expression profiling analyses using 50 diagnostic biopsies.Results: We first examined the mutational status of 410 genes in tumor specimens derived from RB-treated cases. As reported before, CREBBP, KMT2D, MEF2B, BCL2, EZH2, CARD11, TNFRSF14, EP300, and APC were recurrently mutated, however, none of which was predictive for progression-free survival (PFS) in RB-treated cases. Similarly, the m7-FLIPI did not correlate with PFS or progression of disease within 24 months (POD24). A gene expression analysis using a panel of 770 genes associated with carcinogenesis and/or immune response showed that the expression of CD8+ T-cell markers (GZMM, FLT3LG, CD8A, CD8B, GZMK) and half of the genes regulating Th1 and Th2 responses were significantly lower in the POD24 group than in the noPOD24 group. Finally, we selected 10 genes (TBX21, CXCR3, CCR4, CD8A, CD8B, GZMM, FLT3LG, CD3E, EOMES, GZMK), and dichotomized RB-treated cases into immune infiltrationhigh (infilhigh) and infiltrationlow (infillow) clusters. The 3-years PFS rate was lower in the infillow cluster than in the infilhigh cluster (50.0% [95% CI: 27.1–69.2%] vs. 84.2% [95% CI: 58.7–94.6%], p=0.0237). Of note, the proportion of cases with peripheral lymphopenia (low cluster than in the infilhigh cluster (38.5% vs. 9.09%, OR: 6.25 [95%CI, 1.20-32.7], p=0.0235). Conclusion: These results suggest that the T-cell-associated immune markers could be useful to predict prognosis in RB-treated FL cases.Trial registration: This trial was retrospectively registered in UMIN on April. 24, 2014 (UMIN000013795; http://www.umin.ac.jp/icdr/index-j.html).

GOYA was a randomized phase 3 study comparing obinutuzumab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) vs standard-of-care rituximab plus CHOP in patients with previously untreated diffuse large B-cell lymphoma (DLBCL). This retrospective analysis of GOYA aimed to assess the association between progression-free survival (PFS) and overall survival (OS) with positron emission tomography (PET)–based complete response (CR) status. Overall, 1418 patients were randomly assigned to receive 8 21-day cycles of obinutuzumab (n = 706) or rituximab (n = 712) plus 6 or 8 cycles of CHOP. Patients received a mandatory fluoro-2-deoxy-d-glucose–PET/computed tomography scan at baseline and end of treatment. After a median follow-up of 29 months, the numbers of independent review committee–assessed PFS and OS events in the entire cohort were 416 (29.3%) and 252 (17.8%), respectively. End-of-treatment PET CR was highly prognostic for PFS and OS according to Lugano 2014 criteria (PFS: hazard ratio [HR], 0.26; 95% confidence interval [CI], 0.19-0.38; P < .0001; OS: HR, 0.12; 95% CI, 0.08-0.17; P < .0001), irrespective of international prognostic index score and cell of origin. In conclusion, the results from this prospectively acquired large cohort corroborated previously published data from smaller sample sizes showing that end-of-treatment PET CR is an independent predictor of PFS and OS and a promising prognostic marker in DLBCL. Long-term survival analysis confirmed the robustness of these data over time. Additional meta-analyses including other prospective studies are necessary to support the substitution of PET CR for PFS as an effective and practical surrogate end point. This trial was registered at www.clinicaltrials.gov as #NCT01287741.

Patients with mycosis fungoides (MF), the most common subtype of primary cutaneous T-cell lymphoma, have an increased risk of developing secondary malignancies. We herein report two rare cases of MF concurring with diffuse large B cell lymphoma (B lymphoid lineage) and acute myeloid leukemia (myeloid lineage) in two otherwise healthy elderly patients. Potential etiologic factors, including the impact of the therapy-associated inflammatory response on the development of secondary tumors in patients with MF, are discussed. Further clinical, experimental and genetic studies are needed to elucidate possible physiopathogenic associations among the three concurrent malignancies occurring in the cases presented here.

This phase I/II multicenter study evaluated romidepsin treatment in Japanese patients with relapsed/refractory peripheral T-cell lymphoma (PTCL) or cutaneous T-cell lymphoma (CTCL). Patients aged ≥20 years received romidepsin via a 4-h intravenous infusion on days 1, 8, and 15 of each 28-day cycle. Phase I used a 3 + 3 design to identify any dose-limiting toxicity (DLT) for regimens of romidepsin 9 and 14 mg/m2. The primary endpoints for phase I and II were DLT and overall response rate (ORR), respectively. Intent-to-treat patients were those who received ≥1 romidepsin dose (PTCL, n = 48; CTCL, n = 2). In phase I, none of the patients (n = 3, 9 mg/m2; n = 6, 14 mg/m2) exhibited DLT. In phase II, 40 patients with PTCL were treated with 14 mg/m2 romidepsin. The most common treatment-emergent grade ≥3 adverse events were lymphopenia (74%), neutropenia (54%), leukopenia (46%), and thrombocytopenia (38%). Patients in phase II showed a 43% ORR, including 25% complete responses. Median progression-free survival was 5.6 months and median duration of response was 11.1 months. This phase I/II study identified a well-tolerated dose of romidepsin, with an acceptable toxicity profile and clinically meaningful efficacy in Japanese patients with relapsed/refractory PTCL. ClinicalTrials.gov Identifier NCT01456039.

Despite duodenal-type follicular lymphoma (DTFL) being morphologically, immunophenotypically and genetically indistinguishable from nodal FL (nFL), this entity typically shows a significantly better prognosis. Here, we analysed the tumour immune microenvironments of diagnostic specimens from patients with DTFL (n = 30), limited-stage FL (LSFL; n = 19) and advanced-stage FL (ASFL; n = 31). The mean number of CD8+ tumour-infiltrating lymphocytes (TILs) in the neoplastic follicles was higher in DTFL (1,827/mm2 ) than in LSFL (1,150/mm2 ) and ASFL (1,188/mm2 ) (P = 0·002, P = 0·002, respectively). In addition, CD8+ PD1- T cells with non-exhausting phenotype were more abundant in the peripheral blood (PB) of DTFL than in LSFL and ASFL, indicating that DTFL may exhibit a better and longer-lasting T cell-mediated immune response. Moreover, whereas FOXP3+ CTLA-4+ effector regulatory T cells (eTregs) were rarely observed in the neoplastic follicles of DTFL (mean: 12/mm2 ), they were more abundant in LSFL (78/mm2 ) and ASFL (109/mm2 ) (P = 2·80 × 10-5 , P = 4·74 × 10-8 , respectively), and the numbers of eTregs correlated inversely with those of CD8+ TILs (r = -0267; P = 0·018). Furthermore, DTFL showed significantly fewer circulating FOXP3hi CD45RA- CD25hi eTregs (0·146%) than ASFL (0·497%) and healthy controls (0·639%) (P = 0·0003, P = 6·79 × 10-7 , respectively). These results suggest that the augmented anti-tumour immune reactions may contribute to a better prognosis on DTFL.

A 62-year-old male was diagnosed with chronic lymphocytic leukemia (CLL) and treated with a fludarabine-containing regimen which maintained the disease in a partial response. Nine years after diagnosis, a rapidly growing systemic lymphadenopathy was observed, and a biopsy specimen revealed the presence of typical Hodgkin/Reed-Sternberg (HRS) cells, surrounded by T-lymphocytes and CLL cells. Sequencing analysis of the germline complementary determining region 3 (CDR3) region of the immunoglobulin heavy chain (IGH) gene showed that the Hodgkin/Reed-Sternberg cells were clonally unrelated to the preexisting CLL cells and the HRS cells were composed of five different clones, leading to the molecular diagnosis of de novo lymphocyte-rich classic Hodgkin lymphoproliferative diseases (LPDs) with small lymphocytic lymphoma (SLL). As the initial treatment was neither effective for classic Hodgkin LPDs nor for SLL, Bendamustine, Rituximab (BR) was started and complete remission was achieved, which has continued for more than one year so far. BR may be a good therapeutic option for both entities without causing hematological toxicity.

Here we report a case of secondary graft failure that was effectively treated with donor lymphocyte infusion (DLI). A 64-year-old female patient with acute myeloid leukemia obtained partial remission with azacitidine therapy and subsequently underwent unrelated allogeneic bone marrow transplantation (BMT). After confirming successful engraftment and achieving complete remission with incomplete blood count recovery, she was subsequently followed up at an outpatient clinic. A routine test performed by day 110 after BMT revealed the presence of pancytopenia. A bone marrow aspirate did not reveal any evidence of disease relapse or hemophagocytic syndrome but demonstrated hematopoietic insufficiency. Donor chimerism also declined over time; thus, the patient was diagnosed with secondary graft failure. Supportive treatment, including granulocyte-colony stimulating factor and blood transfusion, failed to improve the blood parameters. Because the patient refused a second BMT, we performed DLI on day 147 after BMT (CD3

Radioimmunotherapy (RIT) is an effective therapeutic option for patients with indolent B-cell non-Hodgkin lymphomas (NHL), for the first-line and the second-line therapies. The target molecule of RIT is CD20, and the clinical outcomes have been demonstrated even in the lack of phase III studies to clearly define the efficacy of RIT. However, the best practice to employ RIT is still controversial. CD20 is an activated-glycosylated phosphoprotein expressed on the surface of all B cells beginning at the pro-B phase (CD45R+, CD117+) and progressively increasing in concentration until maturity. As most of the B-cell lymphomas are derived from the germinal center B-cell stage, they must be potential targets for RIT. For the determination of an appropriate treatment policy of RIT, the background information on the biology and pathology are indispensable. In this chapter, we review the biology and pathology of B-cell lymphoma.

It generally requires a complicated reaction protocol for the synthesis of silylated fluorescent lanthanide complexes. In this study, a silylated terbium complex was prepared by a very simple procedure through formation of a Schiff base between a terbium complex bearing a formyl group and 3-aminopropyltriethoxysilane. Using the silylated terbium complex, highly fluorescent silica nanoparticles modified chemically with terbium complexes (Tb-SNPs) were efficiently synthesized by a reverse micelle method with Triton X-100 as a surfactant in cyclohexane. The fluorescence properties of Tb-SNPs were remarkably improved by photostability, pH dependence and fluorescence lifetime, compared to free terbium complexes. Also, Tb-SNPs hardly aggregated under aqueous conditions with different salt concentrations and pHs. From these results, it was found that Tb-SNPs are applicable under physiological aqueous conditions. Furthermore, as an application model, Tb-SNPs were used as the fluorescent label for the imaging of African green monkey kidney cells.

Immunosuppressive therapy after solid organ transplantation is known to be a risk factor for the development of myelodysplastic syndromes (MDS). Herein, we report 2 patients, both of whom developed low-risk MDS after solid organ transplantation and were successfully treated with azacitidine (AZA). The 1st case was a 74-year-old man who had received liver transplantation. The initial immunosuppressive therapy consisted of cyclosporine and prednisolone. Nine years after transplantation, he was diagnosed as having MDS (RCMD). The 2nd case was a 47-year-old woman who had received cadaveric renal transplantation. The initial immunosuppressive therapy was comprised of cyclosporine, azathioprine, and prednisolone. Twenty-seven years after transplantation, she developed MDS (RA). Both patients received 75 mg/m

Purpose Rituximab (R) plus CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone) chemotherapy is the standard of care in previously untreated diffuse large B-cell lymphoma (DLBCL). Obinutuzumab (G) is a glycoengineered, type II, anti-CD20 monoclonal antibody. GOYA was a randomized phase III study that compared G-CHOP with R-CHOP in patients with previously untreated advanced-stage DLBCL. Methods Patients (N = 1,418) were randomly assigned to receive eight 21-day cycles of G (n = 706) or R (n = 712), plus six or eight cycles of CHOP. Primary end point was investigator-assessed progression-free survival (PFS). Results After median observation of 29 months, the number of investigator-assessed PFS events was similar between G (201; 28.5%) and R (215; 30.2%), stratified hazard ratio was 0.92 (95% CI, 0.76 to 1.11; P = .39), and 3-year PFS rates were 70% and 67%, respectively. Secondary end points of independently reviewed PFS, other time-to-event end points, and tumor response rates were similar between arms. In exploratory subgroup analyses, patients with germinal-center B cell–like subtype had a better PFS than did patients with activated B cell–like subtype, irrespective of treatment. Frequencies of grade 3 to 5 adverse events (AEs; 73.7% v 64.7%, respectively) and serious AEs (42.6% v 37.6%, respectively) were higher with G-CHOP compared with R-CHOP. Fatal AE frequencies were 5.8% for G-CHOP and 4.3% for R-CHOP. The most common AEs were neutropenia (G-CHOP, 48.3%; R-CHOP, 40.7%), infusion-related reactions (G-CHOP, 36.1%; R-CHOP, 23.5%), nausea (G-CHOP, 29.4%; R-CHOP, 28.3%), and constipation (G-CHOP, 23.4%; R-CHOP, 24.5%). Conclusion G-CHOP did not improve PFS compared with R-CHOP in patients with previously untreated DLBCL. AEs reported with G were consistent with the known safety profile. Biomarker analyses may help define a future role for G in DLBCL.

Primary effusion lymphoma (PEL) is a rare type of non-Hodgkin lymphoma that usually develops in immunosuppressed patients infected with human herpes virus-8 (HHV-8) in conjunction with human immunodeficiency virus (HIV) infection. However, there are several reports of HHV-8-related HIV-negative cases and HHV-8-unrelated HIV-negative cases, mainly in immunodeficient and elderly patients. Here, we report one case of HHV-8-related HIV-negative PEL with gastric cancer (case 1) and one case of HHV-8-unrelated HIV-negative effusion-based lymphoma (case 2), both in elderly men. A 73-year-old man and a 79-year-old man were admitted because of lymphomatous effusions, and no mass was detectable in both cases. They were diagnosed as having malignant effusion lymphoma on the basis of cytological findings indicating atypical lymphoid cells and the expression of CD20 and CD79a. To detect evidence of HHV-8 infection in neoplastic cells, immunocytochemical staining for ORF73/ latent nuclear antigen-1 (LNA-1) was performed. The results revealed that case 1 was ORF73-positive, and case 2 was ORF73-negative. Rituximab-based chemotherapy (R-THPCOP: rituximab, pirarubicin, cyclophosphamide, vincristine, prednisolone) was administered to both patients and complete remission was achieved in both. Compared to most HIV-positive PEL cases, these two cases showed a good response to chemotherapy. In cases of PEL, we should focus on HHV-8 infection and HIV status for determining prognosis.

A 32-year-old woman was referred to our hospital due to systemic lymphadenopathy. The patient's peripheral blood showed expansion of CD5+CD20+ CD38+ CD23- mature lymphocytes. However, the axillary lymph nodes were infiltrated by both CD23+ large lymphocytes and CD23- small lymphocytes. Because the pattern of the rearranged immunoglobulin heavy chain gene was different between the peripheral blood and lymph node samples in a Southern blot analysis, the patient was diagnosed with Richter syndrome, in which diffuse large B-cell lymphoma develops from a clone distinct from B-cell chronic lymphocytic leukemia. After undergoing rituximab, cyclophosphamide, doxorubicin, vincristine and prednisolone (R-CHOP) therapy, the patient was successfully treated with allogeneic hematopoietic transplantation, and no relapse was observed for three years.

A 70-year-old man with diffuse large B cell lymphoma, who had been in complete remission without treatment, presented with a visual disorder in the right eye. Vitreous biopsy was performed, although the results were not typically suggestive of lymphoma. The concentration of interleukin-10 (IL-10) in the vitreous humor was markedly elevated, suggesting intraocular lymphoma (IOL). Weekly intravitreal injections of methotrexate (MTX) resulted in remission of the visual disorder. During this remission, 10 months after the last intravitreal MTX treatment, a cerebral tumor was observed in the corpus callosum and atypical lymphocytes were detected in the cerebrospinal fluid. The concentration of IL-10 in the CSF was markedly elevated and the IL-6 level was slightly elevated, suggesting central nervous system (CNS) involvement. The patient was treated with intrathecal MTX, systemic rituximab, high-dose cytarabine, and high-dose methotrexate. After this therapy, the cerebral tumor disappeared, atypical lymphocytes were undetectable in the CSF, and the CSF IL-10 level was significantly reduced. IL-10 and IL-6 concentrations in the vitreous humor and CSF are important for diagnosis of IOL with CNS involvement and for monitoring the efficacy of therapy.

Wada N, Zaki M A A, Hori Y, Hashimoto K, Tsukaguchi M, Tatsumi Y, Ishikawa J, Tominaga N, Sakoda H, Take H, Tsudo M, Kuwayama M, Morii E & Aozasa K (2012) Histopathology 60, 313–319 Tumour-associated macrophages in diffuse large B-cell lymphoma: a study of the Osaka Lymphoma Study Group Aims: To evaluate the role of tumour-associated macrophages (TAMs) of the M1 and M2 types in the behaviour of diffuse large B-cell lymphoma (DLBCL). Methods and results: Double immunohistochemical staining of HLA-DR/CD68 (M1) or CD163/CD68 (M2) was performed in 101 cases of DLBCL. CD68+ cells represent the total number of TAMs. The average number of double-positive cells was counted, and the cut-off value was set at the mean number of counts, i.e. 30.7 and 27.0 for M1 TAMs and M2 TAMs, respectively. That for total TAMs was set at the 90th percentile number of total counts, i.e. 132.3. Cases were categorized into three pairs: high (34 cases) and low (67 cases) M1 TAM groups, high (39 cases) and low (62 cases) M2 TAM groups, and high (10 cases) and low (91 cases) total TAM groups. The difference in overall survival rates was statistically significant between the high and low M2 TAM groups (P

To evaluate roles of tumor-associated macrophages (TAMs) for prognosis of classical Hodgkin lymphoma (CHL). Expression of markers for TAMs, CD68, HLA-DR, CD163, HLA-DR/CD68 (M1), and CD163/CD68 (M2) was immunohistochemically examined in 82 cases with CHL. Positively stained cells were counted and correlation of number of TAMs and patients’ survival time was analyzed. Number of CD163+ cells and M2 cells was significantly correlated with shorter overall survival (P < 0.05), while it was marginally significant for CD68+ cells (P = 0.0827). HLA-DR + cells and M1 cells showed no significant correlation with overall survival. When confined to mixed cellularity subtype, number of M1 cells was correlated with favorable prognosis (P < 0.05), while M2 did not (P = 0.7). Older age and male sex were unfavorable factors for prognosis. At multivariate analysis, number of CD163+ cells, M2+ cells, and age were independent factors for poor overall survival (P = 0.03, 0.02, and 0.01, respectively). CD163+ cells and M2 cells might work to be tumor promotive in CHL. M1 cells might be tumor suppressive in mixed cellularity type.

To clarify the change in the fluorodeoxyglucose (FDG) uptake by the bone marrow over time after administration of granulocyte colony-stimulating factor (G-CSF), we evaluated the correlation between the interval from the last day of administration of G-CSF to positron emission tomography/computed tomography (PET/CT) study and spinal bone marrow accumulation in patients with non-Hodgkin's lymphoma.A total of 127 patients with confirmed non-Hodgkin's lymphoma who underwent FDG PET within 60 days from the last administration of G-CSF were retrospectively reviewed. Thirty age-matched and sex-matched healthy controls were also included to evaluate physiological FDG uptake. PET/CT examinations were retrospectively reviewed, and maximum standardized uptake value (SUVmax) was measured by placing volumetric regions of interest over each thoracic and lumbar vertebra on PET images referring to CT images. Bone marrow SUV was defined as the mean SUVmax of the vertebra. The correlation between the interval after G-CSF and the bone marrow SUV was plotted and analyzed with polynomial approximation.In controls, physiological bone marrow SUV of the spine was determined. In patients with lymphoma, bone marrow SUV decreased over time and reached a plateau at about 14 days after G-CSF administration, and this was higher by 5% than the plateau at 10 days. SUV declined to the 'physiological range', that is, mean+1 standard deviation of patients, at about 7 days.For a PET/CT study, an interval of 10 days after G-CSF administration is recommended to minimize the influence of G-CSF on the bone marrow when evaluating treatment response in patients with non-Hodgkin's lymphoma.

We report a rare case of chronic myelomonocytic leukemia (CMML) with pericardial effusion. After receving the diagnosis of CMML, she had been successfully treated with hydroxycarbamide (HU). However, she was admitted to our hospital due to pericardial effusion. The majority of the cells in the pericardial fluid were monocytes. We made the diagnosis of pericardial involvement with CMML cells and intravenously administered etoposide (100 mg/body daily for 5 days). Although CMML cells disappeared from the peripheral blood, the pericardial effusion still persisted. This case indicates that pericardial effusion is a possible and life-threatening complication in CMML patients despite stably controlled leukocytes.

We previously reported mRNA expression of glutathione S-transferases theta (GSTT)-1, wild type (623 bp) and mutant (500 bp), in patients with myelodysplastic syndrome (MDS). The deletion of 123 bp creates a sequence that is homologous to the mammalian target of rapamycin (mTOR). To analyze the function of mutant GSTT-1 gene, stable transformants for the mutant and wild-type GSTT-1 gene, respectively, were established. In this study, the expression of the wild and mutant type of the GSTT-1 gene of those stable transformants in cell lines and in bone marrow cells from MDS patients by reverse-transcription polymerase chain reaction (RT-PCR) was observed in the presence or absence of rapamycin. Significant growth inhibition by rapamycin was observed among stable transformants for the mutant GSTT-1 gene, but not wild type GSTT-1 gene, and was indicative of typical apoptosis.

Change of CD20 expression was examined in cases of diffuse large B-cell lymphoma (DLBCL). CD20 expression after treatment with anti-CD20 antibody (rituximab, Rx) for DLBCL was examined in 23 cases who received serial biopsy by immunohistochemistry (IHC) and flow cytometry (FCM). CD20– by IHC and/or FCM was defined as CD20–. Four cases were CD20– at initial biopsy but became CD20+ after chemotherapy with Rx (CH-R) (group A). Recurrent tumors in three group A cases became resistant to CH-R. Initial and recurrent tumors were CD20+ before and after CH-R in 17 cases (group B). Tumors before CH-R were CD20– in two cases (group C) and continued to be CD20– in one and turned CD20+ in the other with survival time after the relapse of 8 and 23 months, respectively. Evaluation of CD20 expression with immunohistochemical and flow cytometric methods is used for the prediction of responsiveness of relapsed DLBCL for CH-R.

We previously reported that all-trans retinoic acid (ATRA) inhibited growth in HTLV-1-positive T-cell lines and fresh cells from patients with adult T-cell leukemia. Interestingly, ATRA significantly inhibited reverse transcriptase (RT) activity similar to azidothimidine (AZT) in HTLV-1-positive T-cell lines. To clarify whether ATRA has an inhibitory effect on the replication of HIV, we examined HIV proviral DNA in a HIV-1-positive cell line (8E5) using real time PCR. ATRA as well as AZT reduced the proviral DNA load of 8E5 in a dose-dependent manner. These results suggest that there is a common element of ATRA signaling in both HTLV-1 and HIV. Furthermore, we examined the effects of ATRA on viral replication in primary lymphocytes of three individuals infected with HIV. ATRA reduced viral replication significantly similar to AZT. These findings suggested that ATRA acts as a RT inhibitor, reducing the HIV-1 proviral DNA load. Finally, we conclude that ATRA may be a potential therapeutic agent for HIV infection.

A 68-year-old man was referred to our hospital due to a high fever and pancytopenia. Neither tumors nor infectious lesions were detected. Hemophagocytosis was observed on the bone marrow (BM) smear, although without abnormal cells. Prednisolone therapy was ineffective for the patient's high fever. Later on, we obtained the results of a BM biopsy indicating the presence of infiltration of atypical Reed-Sternberg cells, leading to a diagnosis of HIV-negative primary bone marrow Hodgkin lymphoma (PBMHL). However, the patient died of multiple organ failure before receiving chemotherapy. As the clinical course of PBMHL is rapid, physicians must keep in mind its possibility in similar cases.

The entity of serrated adenoma of the colorectum was first proposed in 1990, and it was characterized as epithelial neoplasia combining the architectural features of a hyperplastic polyp with the cytological features of an adenoma. Over the past few years, various clinicopathological studies on serrated adenoma have been reported, but its histogenesis remains unclear. Recently the existence of a "serrated neoplasia pathway" leading to malignancy, which is different from the so-called adenoma-carcinoma sequence, has been discussed. Yao et al. reported that hyperplastic polyps and serrated adenomas share a common cell lineage with gastric differentiation. To clarify the existence of the serrated neoplasia pathway, we performed immunohistochemical staining of cytokeratin 7 (CK7) and cytokeratin 20 (CK20), which are commonly used to determine the primary site of a metastatic lesion, and we examined the pattern of CK7/CK20 expression in various colorectal lesions including 44 serrated adenomas, 25 hyperplastic polyps, 20 traditional adenomas, and 48 carcinomas. An obvious difference existed in the pattern of CK7/CK20 expression between the serrated lesions (hyperplastic polyps and serrated adenomas) and others. The majority of serrated adenomas and hyperplastic polyps presented a CK7+/CK20+ pattern, whereas most conventional adenomas and adenocarcinomas expressed CK7-/CK20+. Adenocarcinoma developing in serrated adenoma also presented a CK7+/CK20+ pattern. There are several reports that CK7 is a possible marker of transient dedifferentiation in the gastric carcinogenesis process. Taken together with the present results, a distinct pathway of colorectal carcinogenesis must exist, which is different from the adenoma-carcinoma sequence. CK7 is a possible marker for the serrated neoplasia pathway of colorectal carcinogenesis.

Background: Argon plasma coagulation (APC) has been proven to be safe in vitro, and has been widely introduced to therapeutic endoscopy. We evaluated the thermal effects on esophageal or gastric wall in vivo, and its effectiveness as an adjunct to incomplete resection of early esophageal and gastric cancer after endoscopic mucosal resection (EMR). Methods: Thermal injuries were made using endoscopic APC irradiation in porcine esophagus and stomach under various conditions during general anesthesia, and depth of tissue damage was determined histopathologically. Patients with early gastric cancer (n = 24) and early esophageal cancer (n = 5) were treated with additional APC following microscopically incomplete EMR. APC was applied to coagulate the entire edge of EMR-induced ulcer 1 week after resection at power/gas settings of 50 W and 1.5 L/min in the stomach, and 40 W and 1.5 L/min in the esophagus for less than 5 s at each point. Results: Depth of tissue damage was related to pulse duration and power output. At power/gas settings of 60 W and 2.0 L/min, thermal damage extended across the submucosal layer with 5-s pulse duration in the stomach. Thermal damage with 5-s pulse duration at power/gas settings of 40 W and 2.0 L/min extended to the muscularis propria in the esophagus. In the clinical study of additional APC therapy, the recurrence rate was 6.9% (two of 29 cases). Conclusion: To avoid perforation, we recommend an APC power setting of 40–60 W for less than 5 s in the stomach and a lower power setting with shorter duration in the esophagus. APC seems to reduce recurrence of esophageal or gastric cancer after incomplete EMR.

Recent studies have suggested that nonsteroidal anti-inflammatory drugs (NSAIDs) reduce the risk of gastrointestinal cancer, and that cyclooxygenase-2 (COX-2) may be a target enzyme for the prevention or regression of cancer by the use of NSAIDs. Mucin histochemistry has made possible a clear distinction between the differentiated characteristics of gastrointestinal epithelial cells, and the possibility that phenotypic shifts from gastric- to intestinal-type in gastric carcinoma progression has been suggested. To evaluate the role of COX-2 in gastric cancer progression, we immunohistochemically investigated COX-2 expression, and examined its relationship to proliferative activity, mucin phenotype, and clinicopathological parameters in human advanced gastric carcinomas.Forty-five surgical specimens of advanced gastric carcinomas (invaded the muscularis propria or subserosa) were examined. Immunohistochemical staining was performed with monoclonal antibodies against COX-2, Ki-67, CD10 (brush border), MUC-2 (goblet-cell mucin), MUC-5AC (gastric foveolar mucin), and MUC-6 (pyloric mucin). COX-2 expression was scored by the percentage of COX-2-positive neoplastic cells, and proliferative activity was assessed by the Ki-67 labeling index at the deepest area of invasion. The mucin phenotype of the carcinomas was classified into three categories; gastric, intestinal, and unclassified.COX-2 staining was restricted to the cytoplasm, not only in cancer cells but also in intestinal metaplasia and some inflammatory cells and COX-2 expression in cancer cells varied greatly, but the staining in some samples was preferentially found at the invasive front. COX-2 positivity was found to correlate with Ki-67 labeling. The mean COX-2 scores were 2.29%, 2.71%, and 2.75%; and the Ki-67 labeling indices were 23.6%, 40.6%, and 56.5%, in gastric-, intestinal-, and unclassified- type carcinomas, respectively.A close relationship between COX-2 expression and proliferative activity was confirmed in the deepest areas of advanced gastric carcinoma, and the proliferative activity increased from gastric- to intestinal- and to unclassified- type gastric carcinoma, suggesting a role for COX-2 expression and differences in biological behavior according to mucin phenotype expression during gastric cancer progression.

Fractalkine (CX3CL1) and its receptor CX3CR1 play an important role in natural killer (NK) cell- and cytotoxic T cell-mediated endothelium damage. Here we describe the cytotoxicity of myelodysplastic syndrome (MDS)-derived T cell line, K2-MDS, through the fractalkine–CX3CR1 system. K2-MDS cells induced apoptosis against CD34 + cells from normal bone marrow (BM) in a direct cell contact manner. K2-MDS cells expressed perforin and granzyme B, but they lacked Fas ligand expression. A specific inhibitor for perforin, concanamycin A, blocked K2-MDS-dependent cytotoxicity. Furthermore, a CX3C-chemokine, fractalkine, was expressed in CD34 + cells, and its receptor, CX3CR1, was expressed on K2-MDS cells. The neutralizing monoclonal antibody (MoAb) for fractalkine and soluble fractalkine significantly inhibited K2-MDS-dependent cytotoxicity. K2-MDS cells also induced the cytotoxicity against human umbilical cord endothelial cells (HUVECs) expressing fractalkine. These data indicate that K2-MDS may be a perforin–granzyme-positive T cell line that exerts a cytotoxic effect on CD34 + cells mediated through the fractalkine–CX3CR1 system.

Esophageal intramural pseudodiverticulosis (EIPD) is an uncommon benign abnormality, characterized by a typical radiological appearance of multiple flask-shaped outpouchings in the esophageal wall, measuring a few millimeters in length. EIPD is mainly a disease of the elderly and is more frequent in males. It presents with progressive dysphagia related to esophageal stenosis or strictures in the great majority of patients. The etiology of this rare disease is unknown. Hiatal hernias, gastroesophageal reflux, esophageal strictures, candidiasis, herpes esophagitis, diabetes mellitus, and chronic alcoholism have been found to be associated with EIPD. According to the available literature, EIPD can be missed easily because of its subtle endoscopic and radiological abnormalities, but once it is diagnosed, conservative management leads to satisfactory control of the symptoms. We encountered a young female patient with EIPD. She had a severe stricture in the upper esophagus, although she had no other complications such as candidiasis or reflux esophagitis. Here we report this rare case of a young patient with EIPD, who was treated successfully with endoscopic esophageal balloon dilation therapy, and discuss this disease on review of the relevant literature.

Patients with acquired haemophilia A usually show widespread subcutaneous bleeding. We describe an 86-year-old man with acquired haemophilia A associated with prostate carcinoma, showing initial localised giant haematoma and subsequent widespread subcutaneous bleeding. A localised giant haematoma may present as a first and important sign of acquired haemophilia A.

Diethyl sebacate is used in topical medicaments in United States and Japan. We described a case of allergic contact dermatitis from diethyl sebacate in a topical antimycotic medicament. Allergic reaction to diethyl sebacate is likely more common because our group has found three of eight sensitized cases. We believe that an investigation regarding the sensitized frequency to diethyl sebacate would conduct to improve the safety of products in United States and Japan.

Background The purpose of this study was to quantitatively evaluate the tumor accumulation and heterogeneity of 111In-ibritumomab tiuxetan (Zevalin®) and tumor accumulation of 18F-fluoro-deoxyglucose (FDG) and compare them to the tumor response in B-cell non-Hodgkin’s lymphoma patients receiving 90Y-ibritumomab tiuxetan (Zevalin®) therapy. Methods Sixteen patients with histologically confirmed non-Hodgkin’s B-cell lymphoma who underwent 90Y-ibritumomab tiuxetan therapy along with 111In-ibritumomab tiuxetan single-photon emission computerized tomography (SPECT)/CT and FDG positron emission tomography (PET)/CT were enrolled in this retrospective study. On pretherapeutic FDG PET/CT images, the maximum standardized uptake value (SUVmax) was measured. On SPECT/CT images, a percentage of the injected dose per gram (%ID/g) and SUVmax of 111In-ibritumomab tiuxetan were measured at 48 h after its administration. The skewness and kurtosis of the voxel distribution were calculated to evaluate the intratumoral heterogeneity of tumor accumulation. As another intratumoral heterogeneity index, cumulative SUV-volume histograms describing the percentage of the total tumor volume above the percentage thresholds of pretherapeutic FDG and 111In-ibritumomab tiuxetan SUVmax (area under the curve of the cumulative SUV histograms (AUC-CSH)) were calculated. All lesions (n = 42) were classified into responders and non-responders lesion-by-lesion on pre- and post-therapeutic CT images. Results A positive correlation was observed between the FDG SUVmax and accumulation of 111In-ibritumomab tiuxetan in lesions. A significant difference in pretherapeutic FDG SUVmax was observed between responders and non-responders, while no significant difference in 111In-ibritumomab tiuxetan SUVmax was observed between the two groups. In contrast, voxel distribution of FDG demonstrated no significant differences in the three heterogeneity indices between responders and non-responders, while 111In-ibritumomab tiuxetan demonstrated skewness of 0.58 ± 0.16 and 0.73 ± 0.24 (p p p Conclusions Pretherapeutic FDG accumulation was predictive of the tumor response in 90Y-ibritumomab tiuxetan therapy. The heterogeneity of the intratumoral distribution rather than the absolute level of 111In-ibritumomab tiuxetan was correlated with the tumor response.

Follicular lymphoma (FL) is defined as a neoplastic proliferation of follicle center cells with varying follicular areas. To learn the time trend of FL in the Osaka area, an adult T-cell leukemia/lymphoma (ATL) nonendemic area of Japan, we examined the frequency of FL among all non-Hodgkin ’s lymphomas (NHLs) during the period 1964 to 1987 (n = 1000) and 1999 to 2001 (n = 659). The frequency of FL with varying follicular areas increased from 1964-1987 to 1999-2001. There was a significant difference in frequency of total cases of FL (14.2% versus 18.8%) (P 15 CB, grade 3. Immunohistochemical staining with monoclonal antibodies for bcl-2 and CD10 was performed. There was an inverse correlation between follicular area and cytological grade (P < .0001) and bcl-2 expression and cytological grade (P < .01). That is, the larger the follicular area in cases with a lower cytological grade, the stronger was bcl-2 expression in a lower cytological grade. There was a significant correlation between follicular area and stage of disease (P < .05). That is, the follicular area was larger in cases in an advanced stage. This study showed the increase in frequency of FL in Osaka, Japan. Change of lifestyle in Japan may be one of the causative factors for the increase.Int J Hematol. 2002;76:333-337.

Recent studies have shown that cyclooxygenase-2 (COX-2) inhibitors may participate in the proliferation of cancer cells. Because the cadherin-catenin complex is not only a key component of the adherens junction but also has been suggested to regulate cell proliferation, modulation of these molecules may be a mechanism by which COX-2 activity affects cell proliferation. In this study, we evaluated the effect of a COX-2 inhibitor on the proliferation and expression of E-cadherin-complexes in gastrointestinal cancer cell lines. Methods: The gastrointestinal cancer cell lines Caco2, HT29, and MKN45 were grown for 24 h in the presence and absence of a selective COX-2 inhibitor, etodolac (10−5, 10−4, and 10−3 M). Cell proliferation was assessed by 3H-thymidine incorporation, and the expression of E-cadherin and catenins was assessed by Western blotting, Northern blotting, and immunofluorescence. Results: Etodolac induced a significant reduction in cell proliferation in Caco2 and MKN45 cells. E-cadherin expression was upregulated after stimulation with etodolac in Caco2 cells, whereas the expression of α-, β-, γ- and p120-catenins was not modified. The expression of E-cadherin mRNA was also upregulated in Caco2 cells, and was upregulated also in MKN45 cells, which did not express normal E-cadherin protein by the use of a mouse monoclonal antibody against human E-cadherin, HECD-1 antibody. Immunofluorescence revealed that the increased E-cadherin was localized at the cytoplasmic membrane. Conclusions: The inhibition of cell growth by etodolac in Caco-2 cells was associated with a dose-dependent upregulation and intense cytoplasmic localization of E-cadherin. No quantitative change in catenin expression was found in this phenomenon. These findings suggest that the COX-2 inhibitor affects the transcription of E-cadherin, or that there may be some homeostatic link between the cell cycle and E-cadherin transcription.

Introduction: Quantitative 18fluorodeoxyglucose positron emission tomography (PET)/computed tomography assessment using total metabolic tumor volume (TMTV) and tumor lesion glycolysis (TLG) measurements has been found promising as an objective method to predict survival in diffuse large B-cell lymphoma (DLBCL) patients (pts). However, the methodology for PET-derived metrics is still evolving, and their predictive value is yet to be proven in large-scale, prospective, multicenter studies. We investigated the prognostic value of baseline maximum standardized uptake value (SUVmax), TMTV and TLG for progression-free survival (PFS) in a large pt cohort treated with obinutuzumab (GA101; G) or rituximab (R) combined with cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) in the Phase 3 GOYA study (NCT01287741; Vitolo et al. J Clin Oncol 2017). Methods: Pts aged ≥18 years, with previously untreated, CD20-positive DLBCL and an International Prognostic Index (IPI) score ≥2 and low-risk pts with IPI scores of 1 (not due to age alone) or 0 (with bulky disease) were randomized 1:1 to receive 8 x 21-day cycles of G (1000mg intravenous [IV] on Days [D] 1, 8, and 15 of Cycle [C] 1 and D1, C2-8) or R (375mg/m2 IV on D1, C1-8) plus 6 or 8 cycles of CHOP. All pts had a baseline and end of treatment (EOT) PET. PET images were segmented using an automated workflow program in MIM software, applying thresholds of 1.5 x liver background and a minimum volume of 1mL to the whole body PET images. The data were analyzed for the overall population and according to germinal center B-cell-like (GCB), unclassified, and activated B-cell-like (ABC) subtypes of DLBCL. TMTV, TLG, and SUVmax were split into 4 categories/levels according to the following quartiles: Q1, Results: Of 1418 enrolled pts, 1346 had a baseline PET scan and 1334 had detectable lesions. There was no statistical difference in PFS between the treatment arms (G vs R), thus the entire cohort was analyzed as a whole. Results of the predictive value of baseline TMTV for PFS are presented in quartiles in Figure 1, and results of the predictive value of TLG for PFS are presented in quartiles in Figure 2, for the overall PET intent-to-treat population. After a median follow-up of 29 months TMTV and TLG were highly predictive of PFS when comparing Q4 vs Q1: HR=2.21, 95% CI 1.48-3.29, p Three-year PFS for pts in TMTV Q1, 2, 3 and 4 was 86% (95% CI 81-89%), 84% (95% CI 78-88%), 78% (95% CI 72-83%) and 66% (95% CI 59-71%), respectively. TMTV also showed a trend for a better prediction of PFS (Figure 3) and OS in pts with the unclassified and ABC DLBCL subtypes when compared with those with the GCB subtype. Conclusions: This large prospective study confirms baseline TMTV and TLG as predictors of PFS and OS in DLBCL after first-line immunochemotherapy, while SUVmax may not be a predictor. Furthermore, TMTV and TLG appear to be better predictors of survival for pts with the unclassified and ABC subtypes of DLBCL than for those pts with the GCB subtype. Further analyses are underway comparing these results with the predictive value of percentage change from baseline to EOT PET, Deauville score-based analysis of EOT PET, and the various molecular DLBCL subtypes. Figure 1 Figure 1. Disclosures Kostakoglu: Roche: Consultancy, Other: GOYA is sponsored by F. Hoffmann-La Roche Ltd. Third-party editorial support, under the direction of Lale Kostakoglu and Denis Sahin, was provided by Helen Cathro of Gardiner-Caldwell Communications, and was funded by F. Hoffmann-La Roche Ltd. Sehn: Celgene: Consultancy, Honoraria; Seattle Genetics: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Roche/Genentech: Consultancy, Honoraria. Chua: Lundbeck: Honoraria; Roche: Honoraria; Seattle Genetics: Honoraria; Gilead Sciences: Honoraria; Merck: Honoraria. Gonzalez-Barca: Gilead: Consultancy; Sandot: Consultancy; Janssen: Speakers Bureau; Roche: Speakers Bureau. Pinto: Millenium Takeda: Research Funding; Gilead: Honoraria; Roche: Honoraria; Bristol Myers Squibb: Honoraria; Merck Sharp Dome: Honoraria; Celgene: Honoraria; Helssin: Honoraria; Mundipharma EDO: Speakers Bureau. Fingerle-Rowson: F. Hoffmann-La Roche Ltd: Employment, Equity Ownership. Knapp: Roche: Employment. Mattiello: Roche: Employment. Nielsen: F. Hoffmann-La Roche Ltd: Employment, Equity Ownership. Sellam: Roche: Employment. Sahin: Roche: Employment, Equity Ownership. Vitolo: Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Gilead: Honoraria; Mundipharma: Honoraria; Takeda: Honoraria; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Trněný: Janssen: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria; Gilead: Consultancy, Honoraria; BMS: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Roche: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding.

ejd.2011.1410 Auteur(s) : Naoki Oiso1 naoiso@med.kindai.ac.jp, Yoichi Tatsumi2, Shinya Rai2, Itaru Matsumura2, Akira Kawada1 1 Department of Dermatology, Kinki University Faculty of Medicine, 377-2 Ohno-Higashi, Osaka-Sayama 589-8511, Japan 2 Department of Hematology, Kinki University Faculty of Medicine, 377-2 Ohno-Higashi, Osaka-Sayama 589-8511, Japan Superimposed linear graft-versus-host disease (GVHD) is rarely present in recipients of allogeneic bone-marrow transplantation as an early lichenoid [...]

A 53-year-old male with myelodysplastic syndrome developed Sweet's syndrome extensively over his left iliac and inguinal regions that was refractory to standard treatment with corticosteroids and chemotherapy, received a stem cell transplant from an HLA-matched unrelated donor, conditioned by reduced-intensity regimen. The patient achieved complete hematological remission, and the cutaneous lesions improved gradually and then disappeared completely despite the patient receiving granulocyte colony-stimulating factor after transplantation and developing acute graft-versus-host disease.