Joji Shimono

PD-L1 expression on neoplastic or stromal cells is respectively a poor or good prognostic factor for adult T-cell leukemia/lymphoma.

Programmed cell death ligand 1 (PD-L1) is expressed on both tumor and tumor-infiltrating nonmalignant cells in lymphoid malignancies. The programmed cell death 1 (PD-1)/PD-L1 pathway suppresses host antitumor responses, although little is known about the significance of PD-1/PD-L1 expression in the tumor microenvironment. To investigate the clinicopathological impact of PD-L1 expression in adult T-cell leukemia/lymphoma (ATLL), we performed PD-L1 immunostaining in 135 ATLL biopsy samples. We observed 2 main groups: 1 had clear PD-L1 expression in lymphoma cells (nPD-L1(+), 7.4% of patients), and the other showed minimal expression in lymphoma cells (nPD-L1(-), 92.6%). Within the nPD-L1(-) group, 2 subsets emerged: the first displayed abundant PD-L1 expression in nonmalignant stromal cells of the tumor microenvironment (miPD-L1(+), 58.5%) and the second group did not express PD-L1 in any cell (PD-L1(-), 34.1%). nPD-L1(+) ATLL (median survival time [MST] 7.5 months, 95% CI [0.4-22.3]) had inferior overall survival (OS) compared with nPD-L1(-) ATLL (MST 14.5 months, 95% CI [10.1-20.0]) (P = .0085). Among nPD-L1(-) ATLL, miPD-L1(+) ATLL (MST 18.6 months, 95% CI [11.0-38.5]) showed superior OS compared with PD-L1(-) ATLL (MST 10.2 months, 95% CI [8.0-14.7]) (P = .0029). The expression of nPD-L1 and miPD-L1 maintained prognostic value for OS in multivariate analysis (P = .0322 and P = .0014, respectively). This is the first report describing the clinicopathological features and outcomes of PD-L1 expression in ATLL. More detailed studies will disclose clinical and biological significance of PD-L1 expression in ATLL.

Prognostic Value of Programmed Death Ligand 1 and Programmed Death 1 Expression in Thymic Carcinoma

Purpose: The immune checkpoint of the programmed death 1/programmed death ligand 1 (PD-1/PD-L1) pathway is believed to play an important role in evasion of host antitumor immune surveillance in various malignancies; however, little is known about its role in thymic carcinoma. This study investigated PD-1/PD-L1 expression and its association with clinicopathologic features, the expression of immune-related proteins in tumor-infiltrating lymphocytes (TIL), and patient prognosis. Experimental Design: PD-L1 and PD-1 expression was evaluated by IHC in 25 thymic carcinoma tissue specimens. Copy number alterations of the PD-L1 gene in 11 cases were assessed in formalin-fixed, paraffin-embedded material using qRT-PCR. Results: Compared with normal subjects, 3 thymic carcinoma patients showed an increase in PD-L1 copy number, whereas 8 did not. PD-L1 was significantly overexpressed in cases with copy number gain as compared with normal cases. High PD-L1 expression was associated with higher disease-free and overall survival rates as compared to cases with low expression. Prognostic analysis revealed low PD-L1 expression and high number of PD-1+ TILs as significant predictors of poor survival, together with Masaoka–Koga stage IVa/IVb disease and incomplete resection. In the quantitative analysis of TILs, PD-L1 expression correlated proportionally with the number of infiltrating CTLs. Conclusions: Here, for the first time, we report that PD-L1 and PD-1 expression might be useful prognostic predictors in thymic carcinoma. Further studies are expected to substantiate the prognostic value of PD-L1 and PD-1 expression, and the potential efficacy of targeting the PD-1/PD-L1 pathway in thymic carcinoma via immunotherapy. Clin Cancer Res; 22(18); 4727–34. ©2016 AACR.

CCR4 frameshift mutation identifies a distinct group of adult T cell leukaemia/lymphoma with poor prognosis.

Adult T cell leukaemia/lymphoma (ATLL) is an intractable T cell neoplasm caused by human T cell leukaemia virus type 1. Next‐generation sequencing‐based comprehensive mutation studies have revealed recurrent somatic CCR4 mutations in ATLL, although clinicopathological findings associated with CCR4 mutations remain to be delineated. In the current study, 184 cases of peripheral T cell lymphoma, including 113 cases of ATLL, were subjected to CCR4 mutation analysis. This sequence analysis identified mutations in 27% (30/113) of cases of ATLL and 9% (4/44) of cases of peripheral T cell lymphoma not otherwise specified. Identified mutations included nonsense (NS) and frameshift (FS) mutations. No significant differences in clinicopathological findings were observed between ATLL cases stratified by presence of CCR4 mutation. All ATLL cases with CCR4 mutations exhibited cell‐surface CCR4 positivity. Semi‐quantitative CCR4 protein analysis of immunohistochemical sections revealed higher CCR4 expression in cases with NS mutations of CCR4 than in cases with wild‐type (WT) CCR4. Furthermore, among ATLL cases, FS mutation was significantly associated with a poor prognosis, compared with NS mutation and WT CCR4. These results suggest that CCR4 mutation is an important determinant of the clinical course in ATLL cases, and that NS and FS mutations of CCR4 behave differently with respect to ATLL pathophysiology. Copyright

Analysis of the influence of dabigatran on coagulation factors and inhibitors

Dabigatran is an oral intake thrombin inhibitor for preventive administration against stroke accompanied by atrial fibrillation. Although dabigatran causes prolonged activated partial thromboplastin time (APTT), the effect of dabigatran on each coagulation factor and coagulation factor inhibitor remains to be investigated. Our aim was to analyze the influence of dabigatran on coagulation factors and coagulation factor inhibitors.

Sustained CD4 and CD8 lymphopenia after rituximab maintenance therapy following bendamustine and rituximab combination therapy for lymphoma.

Bendamustine (B), which was initially synthesized around 50 years ago in the former East Germany, has become an important drug in combination with rituximab (R) (BR therapy) in the treatment of B-cell lymphoma [1]. One major side effect of B is CD4 lymphopenia. R is another key drug for the treatment of B-cell lymphoma. Since a recent study suggested that B-cell depletion by R also impairs the survival of memory T cells [2], R therapy might further enhance CD4 lymphopenia mediated by B. In this study, we investigated the effects of R maintenance therapy on CD4 and CD8 lymphopenia following BR therapy in patients with relapsed or refractory indolent B-cell lymphoma or mantle cell lymphoma. This study is a retrospective analysis of data from patients with relapsed/refractory indolent lymphoma or mantle cell lymphoma who were treated with BR from January 2011 to March 2013. It was approved by the Hakodate Municipal Hospital Institutional Review Board. All patients gave written informed consent according to the Declaration of Helsinki. Patients were treated with R (375 mg/m2 on day 1) and B (90 mg/m2 on days 2 and 3) every 28 days for 4–6 courses. The treatment response was determined 1 month after the last BR course. R maintenance therapy (375 mg/m2) was administered every 2–3 months. The CD4 and CD8 counts were analyzed after each cycle of chemotherapy and once every 1–3 months thereafter. The therapeutic effect was evaluated based on the Revised International Workshop Criteria [3]. Progression-free survival (PFS) was calculated from the date of initiation of treatment to the date of disease progression or last follow-up. The overall survival (OS) rate was calculated from the date of initiation of treatment to the date of death for any reason or the last date of evaluation. These were estimated using the Kaplan–Meier method, and the survival curves were compared by log-rank test. We analyzed the corrected independent data by means of the Mann–Whitney U-test with StatMate V (ATMS Co., Ltd., Tokyo, Japan). Thirty patients were enrolled for this analysis. Diseases were follicular lymphoma in 19 patients, mantle cell lymphoma in four patients, mucosa associated lymphoid tissue (MALT) lymphoma in three patients, small lymphocytic lymphoma/chronic lymphocytic leukemia (SLL/CLL) in two patients, plasmablastic lymphoma in one patient and macrogloblinemia in one patient. All patients had a history of prior treatments mostly with R-CHOP (R, cyclophosphamide, doxorubicin, vincristine, prednisone) or R-CHOP like chemotherapies. All 30 patients were treated with BR therapy, followed by R maintenance therapy. Twenty-two patients remained on R maintenance therapy for a median of 24 months, while the remaining eight were off R after a median 7 months of maintenance. Varicella zoster virus infection developed in seven patients, hepatitis B virus (HBV) reactivation developed in two patients and infection complications developed in 12. One patient developed fatal sepsis, and another developed fatal Fournier gangrene during R maintenance; three patients died due to disease progression. The OS rate was 77.7% at 45 months, and PFS was 59% at 45 months in this analysis. Figure 1(a) shows the course of the CD4 counts. Day 0 was 1 month after the completion of BR therapy in patients on R maintenance and 1 month after the completion of R maintenance in those off R maintenance. There were no significant differences in CD4 counts at the onset of treatment (p  0.45). CD4 lymphopenia was sustained, and the CD4 levels were lower in patients on R maintenance therapy than in those off maintenance treatment, although the difference was not statistically significant. CD8 cell counts also tended to be lower in the on-maintenance group than in off-maintenance treatment, although again the difference was not statistically significant [Figure 1(b)]. The reduction of CD4 cell counts is one adverse effect of B [4,5]. Our study also demonstrated CD4 lymphopenia after BR therapy, which reached its lowest level 6 months after

Clinical features of diffuse large B‐cell lymphoma with polyploidy

Polyploidy, defined as more than two sets of homologous chromosomes, is found in a variety of malignant tumors and is thought to be related to disease pathogenesis. However, there have been no studies that have investigated polyploidy in diffuse large B‐cell lymphoma (DLBCL). Here we reviewed clinicopathological features of 16 cases of DLBCL with polypoidy, which was defined as DLBCL with either near‐tetraploid or greater number of chromosomes as detected by the G‐band method. The frequency of polyploid DLBCL was 2.9 % (16/544), including 15 near‐tetraploid and one near‐pentaploid case.

A distinct subtype of Epstein-Barr virus-positive T/NK-cell lymphoproliferative disorder: adult patients with chronic active Epstein-Barr virus infection-like features

The characteristics of adult patients with chronic active Epstein-Barr virus infection are poorly recognized, hindering early diagnosis and an improved prognosis. We studied 54 patients with adult-onset chronic active Epstein-Barr virus infection diagnosed between 2005 and 2015. Adult onset was defined as an estimated age of onset of 15 years or older. To characterize the clinical features of these adults, we compared them to those of 75 pediatric cases (estimated age of onset <15 years). We compared the prognosis of adult-onset chronic active Epstein-Barr virus infection with that of patients with nasal-type (n=37) and non-nasal-type (n=45) extranodal NK/T-cell lymphoma. The median estimated age of onset of these lymphomas was 39 years (range, 16–86 years). Compared to patients with pediatric-onset disease, those in whom the chronic active Epstein-Barr virus infection developed in adulthood had a significantly decreased incidence of fever (P=0.005), but greater frequency of skin lesions (P<0.001). Moreover, hypersensitivity to mosquito bites and the occurrence of hydroa vacciniforme were less frequent in patients with adult-onset disease (P<0.001 and P=0.0238, respectively). Thrombocytopenia, high Epstein-Barr virus nuclear antigen antibody titer, and the presence of hemophagocytic syndrome were associated with a poor prognosis (P=0.0087, P=0.0236, and P=0.0149, respectively). Allogeneic hematopoietic stem cell transplantation may improve survival (P=0.0289). Compared to pediatric-onset chronic active Epstein-Barr virus infection and extranodal NK/T-cell lymphoma, adult-onset chronic active Epstein-Barr virus infection had a poorer prognosis (P<0.001 and P=0.0484, respectively). Chronic active Epstein-Barr virus infection can develop in a wide age range, with clinical differences between adult-onset and pediatric-onset disease. Adult-onset chronic active Epstein-Barr virus infection is a disease with a poor prognosis. Further research will be needed.

Expression pattern of immunosurveillance‐related antigen in adult T cell leukaemia/lymphoma

Adult T cell leukaemia/lymphoma (ATLL) is an aggressive malignancy with a poor prognosis. Human leucocyte antigen (HLA) and β2 microglobulin (β2M) serve as key molecules in tumour immunity, and their expression is reduced frequently in tumour cells. Programmed cell death (PD)‐1/PD‐ligand1 (PD‐L1) interactions play a role in escape of tumour cells from T cell immunity. Therefore, this study aimed to determine the clinicopathological relevance of HLA and β2M expressions in ATLL cells and PD‐L1 expression in lymphoma or stromal cells and predict the overall survival of patients with ATLL.

Prognostic factors for histiocytic and dendritic cell neoplasms

Histiocytic and dendritic cell neoplasms are rare and poorly studied. We report the clinical characteristics and prognostic factors in such cases in Japan. We investigated the clinical characteristics and survival in 87 adult patients with histiocytic and dendritic cell neoplasms. Fifty patients had histiocytic sarcoma, 12 had Langerhans cell histiocytosis, 11 had follicular dendritic cell sarcoma, 8 had Langerhans cell sarcoma, 6 had interdigitating cell sarcoma and 1 had indeterminate dendritic cell sarcoma. The median follow-up period was 18.0 (range: 9.6-71.8) months, and median overall survival (OS) was 23.5 months. The 2-year OS rate was 49.2%. In the multivariate analysis, elevated lactate dehydrogenase (LDH) (p =.004), ECOG performance status (PS) 2-4 (p =.006), and Ann Arbor stage III-IV (p =.008) affected OS. Stratification by elevated LDH, ECOG PS 2-4, and Ann Arbor stage III-IV allowed classification of patients into low risk, intermediate risk, and high risk groups. The same classification was applicable for HS and non-HS categories. In the rare neoplasms of histiocytic and dendritic cell sarcoma, ECOG PS, Ann Arbor stage, and LDH are important prognostic factors for predicting survival.

Synchronous case of follicular lymphoma and Langerhans cell sarcoma in the same lymph node: Follicular lymphoma and Langerhans tumor

Langerhans cell sarcoma (LCS) is a very rare histiocytic and dendritic cell neoplasm originating from Langerhans cells. There are case reports of histiocytic and dendritic cell neoplasms synchronously or sequentially observed in patients with malignant lymphoma. We present a case in which LCS and follicular lymphoma (FL) grade 3a were observed within the same lymph node. A 66‐year‐old male visited our hospital with a general malaise. Pleural effusion and systemic lymph adenopathy were detected. Biopsy of an inguinal lymph node was performed. The lymph node had regions with follicular structure and regions with acidophilic cytoplasm and large proliferating atypical cells. The tumor cells in the regions with follicular structure showed positivity for CD20 and BCL2 consistent with an FL grade 3a diagnosis. The tumor cells in the regions without follicular structure showed positivity for CD1a and S‐100 and were consistent with an LCS diagnosis. Both tumor cells showed the positivity of BCL6 split by FISH. PCR detected IgH clonality in DNA collected from each region, and direct sequence analysis of cells from both tumors detected almost identical amino acid sequences. This finding is important for future research on the development of very rare histiocytic and dendritic cell neoplasms.