Development of a Novel CD26-Targeted Chimeric Antigen Receptor T-Cell Therapy for CD26-Expressing T-Cell Malignancies.

Chimeric-antigen-receptor (CAR) T-cell therapy for CD19-expressing B-cell malignancies is already widely adopted in clinical practice. On the other hand, the development of CAR-T-cell therapy for T-cell malignancies is in its nascent stage. One of the potential targets is CD26, to which we have developed and evaluated the efficacy and safety of the humanized monoclonal antibody YS110. We generated second (CD28) and third (CD28/4-1BB) generation CD26-targeted CAR-T-cells (CD26-2G/3G) using YS110 as the single-chain variable fragment. When co-cultured with CD26-overexpressing target cells, CD26-2G/3G strongly expressed the activation marker CD69 and secreted IFNgamma. In vitro studies targeting the T-cell leukemia cell line HSB2 showed that CD26-2G/3G exhibited significant anti-leukemia effects with the secretion of granzymeB, TNFα, and IL-8, with 3G being superior to 2G. CD26-2G/3G was also highly effective against T-cell lymphoma cells derived from patients. In an in vivo mouse model in which a T-cell lymphoma cell line, KARPAS299, was transplanted subcutaneously, CD26-3G inhibited tumor growth, whereas 2G had no effect. Furthermore, in a systemic dissemination model in which HSB2 was administered intravenously, CD26-3G inhibited tumor growth more potently than 2G, resulting in greater survival benefit. The third-generation CD26-targeted CAR-T-cell therapy may be a promising treatment modality for T-cell malignancies.

A Novel Mechanism for Bone Loss: Platelet Count Negatively Correlates with Bone Mineral Density via Megakaryocyte-Derived RANKL.

A potential association between hematopoietic stem cell status in bone marrow and surrounding bone tissue has been hypothesized, and some studies have investigated the link between blood count and bone mineral density (BMD), although their exact relationship remains controversial. Moreover, biological factors linking the two are largely unknown. In our present study, we found no clear association between platelet count and BMD in the female group, with aging having a very strong effect on BMD. On the other hand, a significant negative correlation was found between platelet count and BMD in the male group. As a potential mechanism, we examined whether megakaryocytes, the source of platelet production, secrete cytokines that regulate BMD, namely OPG, M-CSF, and RANKL. We detected the production of these cytokines by megakaryocytes derived from bone marrow mononuclear cells, and found that RANKL was negatively correlated with BMD. This finding suggests that RANKL production by megakaryocytes may mediate the negative correlation between platelet count and BMD. To our knowledge, this is the first report to analyze bone marrow cells as a mechanism for the association between blood count and BMD. Our study may provide new insights into the development and potential treatment of osteoporosis.

DPP8 Selective Inhibitor Tominostat as a Novel and Broad-Spectrum Anticancer Agent against Hematological Malignancies.

DPP8/9 inhibition induces either pyroptotic or apoptotic cell death in hematological malignancies. We previously reported that treatment with the DPP8/9 inhibitor 1G244 resulted in apoptotic cell death in myeloma, and our current study further evaluates the mechanism of action of 1G244 in different blood cancer cell lines. Specifically, 1G244 inhibited DPP9 to induce GSDMD-mediated-pyroptosis at low concentrations and inhibited DPP8 to cause caspase-3-mediated-apoptosis at high concentrations. HCK expression is necessary to induce susceptibility to pyroptosis but does not participate in the induction of apoptosis. To further characterize this DPP8-dependent broad-spectrum apoptosis induction effect, we evaluated the potential antineoplastic role for an analog of 1G244 with higher DPP8 selectivity, tominostat (also known as 12 m). In vitro studies demonstrated that the cytotoxic effect of 1G244 at high concentrations was enhanced in tominostat. Meanwhile, in vivo work showed tominostat exhibited antitumor activity that was more effective on a cell line sensitive to 1G244, and at higher doses, it was also effective on a cell line resistant to 1G244. Importantly, the weight loss morbidity associated with increasing doses of 1G244 was not observed with tominostat. These results suggest the possible development of novel drugs with antineoplastic activity against selected hematological malignancies by refining and increasing the DPP8 selectivity of tominostat.

Humanized anti-IL-26 monoclonal antibody as a novel targeted therapy for chronic graft-versus-host disease.

IL-26 is a Th17 cytokine, with its gene being absent in rodents. To characterize the in vivo immunological effects of IL-26 in chronic systemic inflammation, we used human IL26 transgenic (hIL-26Tg) mice and human umbilical cord blood mononuclear cells (hCBMC) in mouse allogeneic-graft-versus-host disease (GVHD) and chronic xenogeneic-GVHD model, respectively. Transfer of bone marrow and spleen T cells from hIL-26Tg mice into B10.BR mice resulted in GVHD progression, with clinical signs of tissue damage in multiple organs. IL-26 markedly increased neutrophil levels both in the GVHD-target tissues and peripheral blood. Expression levels of Th17 cytokines in hIL-26Tg mice-derived donor CD4 T cells were significantly increased, whereas IL-26 did not affect cytotoxic function of donor CD8 T cells. In addition, granulocyte-colony stimulating factor, IL-1ß, and IL-6 levels were particularly enhanced in hIL-26Tg mice. We also developed a humanized neutralizing anti-IL-26 monoclonal antibody (mAb) for therapeutic use, and its administration after onset of chronic xenogeneic-GVHD mitigated weight loss and prolonged survival, with preservation of graft-versus-leukemia effect. Taken together, our data elucidate the in vivo immunological effects of IL-26 in chronic GVHD models and suggest that a humanized anti-IL-26 mAb may be a potential therapeutic agent for the treatment of chronic GVHD.

Involvement of activation induced cytidine deaminase in malignant B-cells expressing two distinct M-components as an etiology of biclonal gammopathy.

Biclonal gammopathy (BG) is a rare phenomenon in which 2 M proteins are detected in the same patient, with 2 major hypotheses regarding its etiology. One potential explanation is that completely different malignant B-cell clones produce different M proteins, while the other is that there is a malignant clone that produces both M proteins simultaneously. In this study, we examined 2 cases of B-cell malignancy with BG and found that some cells were double positive for both M proteins by immunofluorescence and flow cytometry. However, most of the remaining cells were single positive cells that produced only one of the M proteins. We hypothesized that double positive cells were in the process of transitioning from 1 single positive cell to another single positive cell, and that class switch recombination (CSR) would be involved as a mechanism. We then examined the expression of activation induced cytidine deaminase (AICDA), which is responsible for CSR, and found that lymphoma/myeloma cells in 2 BG patients were positive for AICDA by immunostaining. Our study is the first report suggesting that AICDA may be involved in the pathogenesis of BG.

Secondary Gamma-Delta T-Cell Lymphoma Not Otherwise Specified (NOS) From Chronic Immunosuppression.

Herein, we present the case of a 63-year-old female with a history of Behçet's disease managed with long-term prednisone and azathioprine who initially presented for symptomatic anemia, which progressed to pancytopenia with neutropenic fever. Initial workup ruled out infectious etiologies but was indeterminate for immune-mediated or neoplastic causes. Bone marrow biopsy demonstrated a CD8+ gamma-delta T-cell neoplasm; however, imaging and skin biopsy pathology did not support hepatosplenic or cutaneous lymphoma involvement. By the 2017 World Health Organization (WHO) classifications, these findings were defined as gamma-delta peripheral T-cell lymphoma, not otherwise specified (NOS). This is suspected to be secondary to chronic immunosuppression from long-term steroid and azathioprine use. The patient was treated with one cycle of the EPOCH chemotherapy regimen ((etoposide, vincristine, cyclophosphamide, doxorubicin, and prednisone), but the treatment course was complicated by an angioinvasive fungal infection and the patient subsequently transitioned to symptom-focused therapy in a hospice facility.

Tumor-to-tumor metastasis of diffuse large B cell lymphoma to gastric adenocarcinoma via CXCL12 (SDF-1)/CXCR4 axis: a case report.

BACKGROUND: Tumor-to-tumor metastasis is the rare phenomenon in which one tumor exhibits metastatic deposits from another. To the best of our knowledge, there has been no prior reported case of tumor-to-tumor metastasis of a diffuse large B cell lymphoma (DLBCL) to a primary gastric adenocarcinoma. CASE PRESENTATION: A 70-year-old man presented with chest discomfort. An echocardiogram showed the presence of a right ventricular tumor. A positron emission tomogram showed multiple foci of abnormal activity in right cervical lymph nodes, cardiac wall, and stomach. A right cervical lymph node biopsy specimen revealed histological features of DLBCL. An esophagogastroduodenoscopy showed a large circumferential ulceration on the gastric body. Subsequent biopsy revealed adenocarcinoma cells surrounded by infiltrating lymphoma cells. On immunohistochemical staining, lymphoma cells were positive for CXCR4 and adenocarcinoma cells were positive for CXCL12/SDF-1. The patient was treated with six cycles of R-CHOP chemotherapy regimen, resulting in a complete remission. CONCLUSIONS: This patient's case implies that the interaction between a chemokine and its receptor may be the underlying mechanism for the observed tumor-to-tumor metastasis. Specifically, our case would suggest an involvement of the CXCL12 (SDF-1)/CXCR4 axis in the observed metastasis of DLBCL to primary gastric adenocarcinoma.

A Multi-Center Retrospective Analysis Examining the Effect of Dipeptidyl Peptidase-4 Inhibitors on Progression-Free Survival in Patients With Prostate Cancer.

Background Cluster of differentiation 26/dipeptidyl peptidase-4 (DPP4) is a cell surface glycoprotein with multifaceted roles, including immune regulation, glucose metabolism, and tumorigenesis. Recent literature has identified DPP4 inhibitors to improve survival in diabetic patients with prostate cancer. DPP4 inhibitors have been proposed to play a role in prostate cancer, as DPP4 is found at higher levels in malignant prostate tissue compared to benign and correlates with PSA levels and cancer stage. In this multi-center retrospective study, we aim to define the effects of DPP4 inhibitors on progression-free survival (PFS) in diabetic patients with advanced-stage prostate cancer. Methodology We performed a retrospective analysis of 161 patients with diabetes and advanced-stage (III or IV) prostate cancer at the University of Florida Health Cancer Center and Moffitt Cancer Center. Our cohort included 120 patients on metformin (control group) and 41 on a DPP4 inhibitor (study group). Results No significant difference in progression of prostate cancer was identified between those on DPP4 inhibitors versus metformin (hazard ratio [HR]: 1.01; 95% confidence interval [CI]: 0.64-1.61; p = 0.955). Median time to progression was 3.5 years (range: 2.4-4.6 years). Conclusions Despite prior literature indicating survival benefit of DPP4 inhibitors in prostate cancer, our study did not identify a statistically significant improvement of PFS in diabetic patients with advanced prostate cancer. Additional analysis with larger sample sizes and prospective investigation with study of tumor microenvironment are needed to evaluate clinical impact and potential survival benefit of DPP4 inhibitors in prostate cancer.

Diffuse Large B-Cell Lymphoma Presenting as an Unusual Paraneoplastic Neurologic Syndrome Affecting the Central and Peripheral Nervous Systems.

A 68-year-old man presented with a two-week history of ascending, symmetric, sensory neuropathy concerning an acute inflammatory demyelinating polyneuropathy that briefly responded to intravenous immunoglobulin (IVIg) therapy. The initial workup was negative for acquired causes. After three months of poor response to standard therapies, he was hospitalized for severe disability, unintentional weight loss, and additional, unexplained neurologic symptoms including cerebellar ataxia, dysarthria, and muscle twitching. Positron emission tomography revealed hypermetabolism isolated to the bone marrow. Bone marrow biopsy confirmed the diagnosis of diffuse large B-cell lymphoma (DLBCL). Due to rapidly worsening performance status, plasmapheresis was initiated prior to treatment with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) chemotherapy. His symptoms initially improved following plasmapheresis and resolved with chemotherapy. One year following treatment, he remains in complete remission. This case describes a unique paraneoplastic neurologic syndrome involving the central and peripheral nervous system that responded well to plasmapheresis and systemic chemotherapy.

IL-26 mediates epidermal growth factor receptor-tyrosine kinase inhibitor resistance through endoplasmic reticulum stress signaling pathway in triple-negative breast cancer cells.

Triple-negative breast cancer (TNBC) has a poor prognosis compared to other breast cancer subtypes. Although epidermal growth factor receptor (EGFR) is overexpressed in TNBC, clinical trials with EGFR inhibitors including tyrosine kinase inhibitors (EGFR-TKI) in TNBC have heretofore been unsuccessful. To develop effective EGFR-targeted therapy for TNBC, the precise mechanisms of EGFR-TKI resistance in TNBC need to be elucidated. In this study, to understand the molecular mechanisms involved in the differences in EGFR-TKI efficacy on TNBC between human and mouse, we focused on the effect of IL-26, which is absent in mice. In vitro analysis showed that IL-26 activated AKT and JNK signaling of bypass pathway of EGFR-TKI in both murine and human TNBC cells. We next investigated the mechanisms involved in IL-26-mediated EGFR-TKI resistance in TNBC. We identified EphA3 as a novel functional receptor for IL-26 in TNBC. IL-26 induced dephosphorylation and downmodulation of EphA3 in TNBC, which resulted in increased phosphorylation of AKT and JNK against EGFR-TKI-induced endoplasmic reticulum (ER) stress, leading to tumor growth. Meanwhile, the blockade of IL-26 overcame EGFR-TKI resistance in TNBC. Since the gene encoding IL-26 is absent in mice, we utilized human IL-26 transgenic (hIL-26Tg) mice as a tumor-bearing murine model to characterize the role of IL-26 in the differential effect of EGFR-TKI in human and mice and to confirm our in vitro findings. Our findings indicate that IL-26 activates the bypass pathway of EGFR-TKI, while blockade of IL-26 overcomes EGFR-TKI resistance in TNBC via enhancement of ER stress signaling. Our work provides novel insights into the mechanisms of EGFR-TKI resistance in TNBC via interaction of IL-26 with its newly identified receptor EphA3, while also suggesting IL-26 as a possible therapeutic target in TNBC.

CD26/Dipeptidyl Peptidase IV and Its Multiple Biological Functions.

CD26/Dipeptidyl peptidase IV (DPPIV) is a cell surface glycoprotein with numerous roles including glucose metabolism, immunomodulation, and tumorigenesis. CD26/DPPIV is well recognized in diabetes, with DPPIV inhibitors being a class of oral hypoglycemic drugs called gliptins that are commonly used to treat type two diabetes mellitus. Recent work also indicated a potential role for CD26 in infectious diseases, including COVID-19, and immune-mediated disorders such as rheumatoid arthritis, inflammatory bowel disease, and graft-versus-host disease. In cancer, CD26/DPPIV expression has been characterized in numerous tumors such as hematologic malignancies, malignant pleural mesothelioma (MPM), renal cell carcinoma (RCC), hepatocellular carcinoma (HCC), gastrointestinal stromal tumor (GIST), and prostate, lung, colorectal, and ovarian (PLCO) cancer. Hence, CD26 has been frequently studied as a tumor biomarker and therapeutic target. CD26/DPPIV-targeted therapies have been evaluated in various cancers, including the use of anti-CD26 monoclonal antibodies as anticancer treatment in selected neoplasms. This review highlights our current understanding of the role of CD26 in cancer, diabetes, immune-mediated diseases, and infectious diseases. Enhanced understanding of CD26 biology and function may lead to novel therapeutic approaches in multiple human diseases.

Serum soluble CD26/DPP4 titer variation is a potential prognostic biomarker in cancer therapy with a humanized anti-CD26 antibody.

BACKGROUND: The phase I trial of the humanized anti-CD26 monoclonal antibody YS110 for CD26-expressing tumors was conducted recently. The present study identifies a potential prognostic biomarker for CD26-targeted therapy based on the phase I data. METHODS: Box and Whisker plot analysis, Scatter plot analysis, Peason product moment correlation/Spearman's rank-difference correlation, Bar graph analysis, and Receiver Operating Characteristics (ROC) were used to examine the correlation between sCD26 titer variation with YS110 administration and tumor volume change, RECIST criteria evaluation and progression free survival (PFS). Mechanism for serum sCD26 titer variation was confirmed by in vitro experimentation. RESULTS: Serum sCD26/DPP4 titer was reduced following YS110 administration and gradually recovered until the next infusion. Serum sCD26/DPP4 titer before the next infusion was sustained at lower levels in Stable Disease (SD) cases compared to Progressive Disease cases. ROC analysis defined the cut-off level of serum sCD26/DPP4 titer variation at day 29 pre/post for the clinical outcome of SD as tumor response or PFS. In vitro experimentation confirmed that YS110 addition reduced sCD26 production from CD26-expressing tumor and non-tumor cells. CONCLUSIONS: Our study indicates that serum sCD26/DPP4 titer variation in the early phase of YS110 treatment is a predictive biomarker for evaluating therapeutic efficacy.

Reduction of immunosuppression for post-transplant lymphoproliferative disorder (PTLD): a single-center experience of allograft survival outcomes.

Post-transplant lymphoproliferative disorder (PTLD) is a well-known complication of hematopoietic stem cell transplant and solid organ transplant. While reduction in immunosuppression (RIS) is the first-line treatment for PTLD, outcomes of allograft function as a result of RIS remain understudied. In this retrospective study, we examine rates of allograft rejection and graft failure after RIS in 141 patients diagnosed with PTLD at the University of Florida. Compared to prior literature demonstrating around 32-40% rate of allograft rejection as result of RIS, our institutional analysis revealed a much lower treatment-related allograft rejection rate of 18.4%. Out of the patients who experienced acute allograft rejection, 23.1% ultimately progressed to allograft failure. Interestingly, acute allograft rejection episodes during PTLD treatment were not statistically found to impact overall survival. RIS remains an overall beneficial treatment modality of PTLD due to its low allograft rejection rate relative to treatment rate.

Intravascular Large B-Cell Lymphoma Presenting as Acute Axonal Polyneuropathy: A Case Report and Literature Review.

Intravascular large B-cell lymphoma (ILBL) is a rare and difficult to diagnose subtype of large B-cell lymphoma. The most common locations of presentation are in the central nervous system and the skin, but there are reports of other organ involvement. Due to the indolence, nonspecific symptoms, and rarity of the disease, this form of lymphoma is most often diagnosed postmortem. In this article, we describe a case of ILBL that presented as a rapidly progressive acute axonal polyneuropathy. Acute axonal polyneuropathy is a common disease process with a wide differential diagnosis, but there is limited literature on its prevalence as the presenting symptom of ILBL. This patient was treated with R-EPOCH and intrathecal methotrexate with significant improvement in his polyneuropathy after 1 cycle, and complete remission after 6 cycles. Data on chemotherapy regimens and their success rates for this disease are lacking.

Post Transplant Lymphoproliferative Disorder risk factors in children: Analysis of a 23-year single-institutional experience.

INTRODUCTION: PTLD is the most frequent malignancy following SOT in children and the second most common SOT complication in adults. However, factors determining outcomes in children are poorly understood due to its relative rarity. METHODS: This study was performed at the University of Florida. Univariate and multivariate analyses were used to identify prognostic factors in pediatric patients diagnosed with PTLD. RESULTS: We reviewed records of 54 pediatric (younger than 18 years old at diagnosis) patients diagnosed with PTLD from 1994 to 2017. The median follow-up was 28.8 months. The estimated 5-year survival rate was 87.6% (95% CI 74.3-94.2%). Univariate analysis showed that organ transplanted (specifically heart transplant), poor response to initial treatment, allograft rejection, and low Karnofsky score were statistically significant for negative prognostic factors in determining survival. Multivariate analysis determined progression in response to initial treatment and presence of allograft rejection as statistically significant prognostic factors affecting overall survival. We found no statistically significant impact of EBV serological status on PTLD prognosis. CONCLUSIONS: Disease progression and allograft rejection were strong negative prognostic indicators in our study cohort. Close attention to graft status and development of therapies that protect the graft from rejection while bolstering anti-EBV immunity will be essential to further improving PTLD outcomes in children.

Impact of DPP4 Inhibitors in Survival of Patients With Prostate, Pancreas, and Breast Cancer.

Background: Dipeptidyl peptidase-4 (DPP4), a cell surface protein, exhibits a crucial role in tumor biology and regulation of the immune system. We aim to study the impact of DPP4 inhibitors (DPP4i) in patients with prostate cancer (PRC), pancreatic cancer (PC) and breast cancer (BC). Methods: Using the SEER and Medicare linked database, we identified patients with PRC or PC or BC with coexisting type II diabetes mellitus between 2007 and 2015. Patients were classified into four groups: (1) not on either DPP4i or metformin (reference group), this group included patient that were on anti-diabetic agents other than metformin or DPP4i (2) metformin only, (3) DPP4i only, and (4) DPP4i along with metformin (combination group). Overall survival (OS) analyses were performed using SAS®, version 9.4. Results: We identified 15,330 patients with PRC, 5,359 patients with PC and 16,085 patients with BC. In PRC cohort, patients on DPP4i had significant survival advantage with HR 0.77 (95% CI: 0.64-0.93), P = 0.005 when compared to the reference group. Patients taking metformin also had significant OS benefit with HR 0.87 (95% CI: 0.81-0.93), P < 0.0001 when compared to the reference group. However, in BC cohort, OS did not favor the patients taking DPP4i with HR 1.07 (95% CI: 0.93-1.25, P = 0.33). Similarly, in PC cohort, OS was indifferent for the patients on DPP4i with HR 1.07 (95% CI: 0.93-1.24, P = 0.68). Upon subgroup analyses of PRC patients, the survival favored the group taking DPP4i, irrespective of stage, use of chemotherapy, androgen-deprivation therapy, and prostatectomy or radiation therapy. Conclusions: DPP4i seems to improve survival in PRC patients; however, not in PC or BC patients. While the exact mechanism involved remains to be elucidated, a prospective clinical trial would help to confirm these findings.

Successful Surgical Removal of the Largest Known Spleen.

BACKGROUND: Splenic marginal zone lymphoma (SMZL) is a rare subtype of non-Hodgkin lymphoma that typically presents with symptomatic splenomegaly. The optimal treatment of SMZL not well established. Case Presentation. A 44-year-old man with a history of low-grade B-cell lymphoproliferative disorder previously treated with chemotherapy presented with a three-month history of rapidly enlarging abdominal girth. He was found to have large symptomatic splenomegaly by computed tomography. After workup, he underwent preoperative angioembolization of the splenic artery followed by successful splenectomy. The spleen measured 45 cm in greatest dimension and weighed 12.14 kg, more than 12% of the patient's total body weight, making this both the largest spleen on record as well as the largest spleen ever surgically removed. Pathology was consistent with splenic marginal zone lymphoma. The patient did well and was discharged home on postoperative day 3. CONCLUSIONS: SMZL is an infrequent condition that leads to progressive symptomatic splenomegaly which can be managed surgically providing symptomatic improvement and an overall satisfactory oncologic outcome. A multidisciplinary approach to complex cases of SMZL splenomegaly is imperative to achieving optimal outcomes.

Single-institution Retrospective Analysis of Prognostic Factors Influencing Very Late-onset Post-transplant Lymphoproliferative Disorder.

Background Post-transplant lymphoproliferative disorder (PTLD) is a rare complication following transplant (solid organ or allogeneic) due to the proliferation of lymphoid cells in the immunosuppressed state. The incidence of PTLD follows a bimodal distribution, with high incidence immediately after transplant (early-onset PTLD), followed by a decline and then a high-incidence again five years after transplantation (late-onset PTLD). This study exclusively aims to identify prognostic factors for the subgroup of PTLD, described as very late-onset PTLD, occurring after 10 years of transplant. Methods This study was conducted at the University of Florida, with the requisite study population identified through the cancer registry. Data were collected by individual chart review and analyzed. Survival estimates and univariate and multivariate analyses were performed to measure the effects of each variable on overall survival. Results A total of 33 patients were identified, with a median age at transplant of 42.3 years, while the median age at PTLD diagnosis was 54.7 years. Median time from transplant to PTLD diagnosis was 13.3 years. Kidney (30.3%), liver (27.3%), and heart (24.2%) transplants were the most common allografts associated with very late PTLD development. The most common pathology was diffuse large B-cell lymphoma (DLBCL) in 45.5% of patients. CHOP+/-R (cyclophosphamide, doxorubicin hydrochloride (hydroxydaunorubicin), vincristine sulfate (Oncovin), prednisone, rituximab) was the most common chemo regimen used as the initial choice in 36.4% of patients. Median survival was 5.4 years. Univariate analysis showed that age at diagnosis over 65, male gender, bone marrow involvement, past medical history (PMH) of malignancy, immunosuppression regimen at PTLD diagnosis, and initial and final best response to treatment were statistically significant (p <0.05) factors associated with survival. On multivariate analysis, bone marrow involvement was significantly associated with poor survival (p=0.008). Surprisingly, performance status, Epstein-Barr virus (EBV) status, pathology type, Ann-Arbor stage, and chemotherapy regimen were not significantly associated with survival. At the end of the study, 48.5% of patients achieved complete remission and the allograft survived in 84.8%. Conclusions In this retrospective study of very-late onset PTLD, we identified factors associated with survival different from early and late PTLD. These factors should be considered during the treatment of this subgroup of PTLD patients.

DPP8 is a novel therapeutic target for multiple myeloma.

Dipeptidyl peptidases (DPPs) are proteolytic enzymes that are ideal therapeutic targets in human diseases. Indeed, DPP4 inhibitors are widely used in clinical practice as anti-diabetic agents. In this paper, we show that DPP4 inhibitors also induced cell death in multiple human myeloma cells. Among five DPP4 inhibitors, only two of them, vildagliptin and saxagliptin, exhibited apparent cytotoxic effects on myeloma cell lines, without any difference in suppression of DPP4 activity. As these two DPP4 inhibitors are known to have off-target effects against DPP8/9, we employed the specific DPP8/9 inhibitor 1G244. 1G244 demonstrated anti-myeloma effects on several cell lines and CD138+ cells from patients as well as in murine xenograft model. Through siRNA silencing approach, we further confirmed that DPP8 but not DPP9 is a key molecule in inducing cell death induced by DPP8/9 inhibition. In fact, the expression of DPP8 in CD38+ cells from myeloma patients was higher than that of healthy volunteers. DPP8/9 inhibition induced apoptosis, as evidenced by activated form of PARP, caspases-3 and was suppressed by the pan-caspase inhibitor Z-VAD-FMK. Taken together, these results indicate that DPP8 is a novel therapeutic target for myeloma treatment.