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ABSTRACTImmunocompromised individuals, particularly autologous hematopoietic stem cell transplant (auHSCT) recipients, are at high risk for herpes zoster (HZ). We provide an in-depth description of humoral and cell-mediated immune (CMI) responses by age (protocol-defined) or underlying disease (post-hoc) as well as efficacy by underlying disease (post-hoc) of the adjuvanted recombinant zoster vaccine (RZV) in a randomized observer-blind phase III trial (ZOE-HSCT, NCT01610414). 1846 adult auHSCT recipients were randomized to receive a first dose of either RZV or placebo 50–70 days post-auHSCT, followed by the second dose at 1–2 months (M) later. In cohorts of 114–1721 participants, at 1 M post-second vaccine dose: Anti-gE antibody geometric mean concentrations (GMCs) and median gE-specific CD4[2+] T-cell frequencies (CD4 T cells expressing ≥2 of four assessed activation markers) were similar between 18–49 and ≥50-year-olds. Despite lower anti-gE antibody GMCs in non-Hodgkin B-cell lymphoma (NHBCL) patients, CD4[2+] T-cell frequencies were similar between NHBCL and other underlying diseases. The proportion of polyfunctional CD4 T cells increased over time, accounting for 79.6% of gE-specific CD4 T cells at 24 M post-dose two. Vaccine efficacy against HZ ranged between 42.5% and 82.5% across underlying diseases and was statistically significant in NHBCL and multiple myeloma patients. In conclusion, two RZV doses administered early post-auHSCT induced robust, persistent, and polyfunctional gE-specific immune responses. Efficacy against HZ was also high in NHBCL patients despite the lower humoral response.

I ntroduction

We report the unique role of CX3CL1 (or fractalkine) on CD11b+myelomonocytic cells expressing CX3CR1, the only known receptor for CX3CL1, in promoting blood perfusion recovery. In a mouse ischemic hind‐limb model, CD11b+CX3CR1+cells migrated to ischemic femoral muscles through CX3CL1‐mediated chemotaxis. CD11b+CX3CR1+macrophages isolated from ischemic tissues [tissue (T)‐CD11b+CX3CR1+] of muscle exert a proangiogenic effect through platelet factor‐4 (CXCL4; PF‐4) production. PF‐4 does not promote angiogenesis by itself but, instead, increases VEGF‐mediated angiogenesis. Despite proangiogenic effects of muscle‐derived T‐CD11b+CX3CR1+macrophages, their clinical implementation is limited because muscle excision is required for cell harvesting. Therefore, we focused on the more accessible bone marrow (BM)‐CD11b+CX3CR1+monocytes, which migrate from BM into ischemic muscles via CX3CL1‐mediated chemotaxis. PF‐4 expression was not detected in BM‐CD11b+CX3CR1+monocytes under normal conditions, but CX3CL1 (50 ng/ml) induced high PF‐4 expression and enabled BM‐CD11b+CX3CR1+monocytes to achieve a similar angiogenic potential to that of T‐CD11b+CX3CR1+macrophages ex vivo. Furthermore, we were able to identify a subset of monocytes that express CD11b and CX3CR1 in human peripheral blood and confirmed the proangiogenic effect of CX3CL1 treatment. Thus, CX3CL1‐treated CD11b+CX3CR1+monocytes may be of potential therapeutic use to significantly accelerate recovery of blood perfusion in ischemic diseases.

The aim of this retrospective cohort study was to analyze the impact of surgery on the outcomes and qualities of life (QOL) in patients with intestinal diffuse large B-cell lymphoma (DLBCL). We assessed 345 patients with either localized or disseminated intestinal DLBCL and compared them according to treatment: surgical resection followed by chemotherapy versus chemotherapy alone. In patients with localized disease (Lugano stage I/II), surgery plus chemotherapy yielded a lower relapse rate (15.3%) than did chemotherapy alone (36.8%, P < .001). The 3-year overall survival rate was 91% in the surgery plus chemotherapy group and 62% in the chemotherapy-alone group (P < .001). The predominant pattern in the chemotherapy group was local relapse (27.6%). When rituximab was used with cyclophosphamide, doxorubicin, vincristine, and prednisolone (CHOP), there was no improvement of the outcomes in patients treated with primary surgical resection. The QOL of patients who underwent surgery and chemotherapy was lower than chemotherapy alone, but its difference was acceptable. Multivariate analysis showed that surgical resection plus chemotherapy was an independent prognostic factor for overall survival. Surgical resection followed by chemotherapy might be an effective treatment strategy with acceptable QOL deterioration for localized intestinal DLBCL. This study was registered at www.clinicaltrials.gov as #NCT01043302.

Multiple primary malignancies are defined as two or more malignancies in an individual without any relationship between the tumors. Because of advances in the early detection, treatment, and supportive care for cancer, the number of cancer survivors has been gradually increasing, and this has led to an increase in the possible occurrence of subsequent malignancies. Recently, there have been reports that smoking is associated with a specific genetic mutation (the tumor suppressor gene TP53), and this genetic predisposition may be related to the development of multiple primary malignancies. Here we present a rare case of quadruple primary malignancies of the liver, bladder, lung and stomach, some of which possibly linked to smoking-related TP53 mutation. Because of its extreme rarity and the clear relationship between multiple primary malignancies and smoking-related TP53 mutation, we report this case along with a review of the relevant literature. Free full text available at www.tumorionline.it

Kim: Takeda: Research Funding; Novartis: Consultancy, Honoraria, Research Funding, Speakers Bureau; ILYANG: Consultancy, Honoraria, Research Funding; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Sun Pharma.: Research Funding.

Background: Peripheral T-Cell Lymphoma (PTCL) is an aggressive malignancy which lacks effective treatment. Emerging data suggests that the JAK-STAT pathway may play an important role in mediating pathogenesis of PTCL. DZD4205 (AZD4205) is an orally available, potent and highly selective JAK1 inhibitor. In T-cell lymphoma cell lines, DZD4205 modulates pSTAT3 pathway and suppresses cell proliferation, and in tumor xenograft models, DZD4205 exhibits dose-dependent anti-tumor activities, with good correlation with drug exposure and modulations of pSTAT3 in tumor tissues. A phase I/II study (JACKPOT8) was initiated to assess the safety, tolerability, pharmacokinetics and anti-tumor efficacy of DZD4205 in patients with refractory/relapsed (r/r) PTCL.

IL-2-activated killer lymphocytes (LAK cells) secrete inflammatory cytokines such as interferon-γ (IFN-γ) and tumor necrosis factor α (TNFα) that can induce nitric oxide (NO) synthesis. We evaluated whether LAK cells could activate NO synthesis in human cancer cells. LAK cells and their culture supernatants induced NO synthesis in DLD-1 colon cancer cells in a dose-dependent manner. NO synthesis was inhibited completely by blocking antibodies to IFN-γ, demonstrating a key role for this LAK cell cytokine in regulating NO synthesis. The addition of TNFα antibodies resulted in partial inhibition. Induction of iNOS mRNA and protein expression in DLD-1 cells was detected. Endogenous NO production inhibited DLD-1 cell proliferation and induced apoptosis, processes that were inhibitable by the NO synthase inhibitor N^G-monomethyl-

T lymphocytes are critical players in graft-versus-host disease (GVHD); however, their specific roles and mechanisms in GVHD have not been clearly defined. Co-inhibitory receptors including PD1, TIM3, TIGIT, and LAG3 play a key role in regulating T cell responses and maintaining immune homeostasis. TIM3 expression on lymphocytes was identified to induce immune tolerance in a mouse GVHD model; in addition, PD1 +TIM3 +double-positive T cells displayed more potent immunosuppression compared to PD1 +T cells. However, despite the strong immunosuppression exerted by PD1 +TIM3 +double-positive T cells, their clinical potential is greatly limited by their low cell number in peripheral blood. In this study, we introduce a novel method to isolate CD3 +cells from G-CSF mobilized peripheral blood stem cells (G-PBSCs), and culture CD3 +PD1 +TIM3 +lymphocytes to treat GVHD.

No relevant conflicts of interest to declare.

We evaluated the effect of antithrombin III (ATIII), a serine protease inhibitor (SERPIN), on induction of nitric oxide (NO) synthesis in murine peritoneal macrophages. Incubation of macrophages with ATIII plus interferon-γ (IFN-γ) but not ATIII alone induced nitrite accumulation (a metabolite of NO) in a dose-dependent manner. Expression of the inducible nitric oxide synthase isoform was confirmed by Western blot. NO synthesis was inhibited byNG-monomethyl-l-arginine, by complexing ATIII with thrombin or by rabbit anti-human ATIII antiserum. Addition of polymyxin B to macrophage cultures failed to inhibit ATIII/IFN-γ-induced NO synthesis, excluding lipopolysaccharide contamination.125I-ATIII bound to macrophages in a dose-dependent, specific, and saturable manner, with aKmof ∼7.1 nM. Our results demonstrate that ATIII, but not ATIII/thrombin complex, acts to costimulate macrophage activation and NO synthesis via a novel receptor mediated mechanism, which may indicate a role for SERPINs in macrophage activation.

Peripheral T-cell lymphomas (PTCLs) are uncommon and their frequency is regionally heterogeneous. Several studies have been conducted to evaluate the clinical features and treatment outcomes of this disease entity, but the majority of these were conducted in limited areas, making it difficult to comprehensively analyze their relative frequency and clinical features. Furthermore, no consensus treatment for PTCLs has been established. Therefore, we conducted an Asia-specific study to understand the relative frequency of PTCLs and assess treatments and their outcomes in Asian patients.

Background: Primary breast diffuse large B-cell lymphoma (DLBCL) has poor outcomes with frequent extranodal failures, particularly in the central nervous system (CNS). To prevent CNS recurrence, we designed this phase II trial that addressed feasibility and activity of conventional immunochemotherapy and CNS prophylaxis.

Introduction

Yoon: F. Hoffmann-La Roche Ltd: Research Funding. Kim:Celltrion: Research Funding; Novartis: Research Funding; Donga: Research Funding; Kyowa-Kirin: Research Funding; Novartis: Research Funding; J + J: Research Funding; F. Hoffmann-La Roche Ltd: Research Funding.

Kim: F. Hoffmann-La Roche Ltd: Research Funding; Celltrion: Research Funding; Novartis: Research Funding; Donga: Research Funding; Kyowa-Kirin: Research Funding; Novartis: Research Funding; J + J: Research Funding.

Kim: Il-Yang co.: Research Funding; Pfizer: Research Funding; Takeda: Research Funding; BMS: Research Funding; Novartis: Research Funding.

BackgroundThe recent discontinuation clinical trials have demonstrated that IM discontinuation can be employed based on clinical study in patients who had enough IM therapy and undetectable molecular residual disease (UMRD) durations prior to IM discontinuation. Moreover, treatment rechallenge in patients with molecular recurrence lead a second deep molecular response, suggesting that IM discontinuation is safe. However, the issues on the definition of molecular relapse requiring treatment resumption and the occurrence of late relapse with a long-term follow-up after IM discontinuation are important. Therefore, here we analyzed the long-term follow-up results of the patients who lost UMRD after IM discontinuation

No relevant conflicts of interest to declare.

No relevant conflicts of interest to declare.

No relevant conflicts of interest to declare.

Bunworasate: IL-YANG: Research Funding. Comia:IL-YANG: Research Funding. Mun:IL-YANG: Research Funding. Caguioa:IL-YANG: Research Funding. Kim:Pfizer: Research Funding; Novartis: Research Funding; BMS: Research Funding; Ilyang: Research Funding.

No relevant conflicts of interest to declare.

Introduction:We successfully identified a subset of CD11b+monocytes expressing CX3CR1, the only receptor of fractalkine (Fkn; CX3CL1), in G-CSF mobilized peripheral blood stem cell collection (PBSC). We found that Fkn-treated CD11b+CX3CR1+monocytes express pigment epithelium-derived factor (PEDF) once Fkn activates Fkn/CX3CR1 signaling. PEDF is a glycoprotein, which belongs to the serpin family and involves various physiologic processes such as angiogenesis, cell proliferation, and survival. In this study, we investigate the role of PEDF and its mechanism of action in promoting angiogenesis. Materials andmethods: To mobilize mononuclear cells (MNCs) including CD11b+CX3CR1+monocytes into peripheral blood (PB), heathy donors were subcutaneously injected with G-CSF (10μg/kg) for 5 days. Apheresis MNCs were collected from donor PB using a COBE spectra cell separator (COBE, Lakewood, CO) 5 days after daily G-CSF injection. Then, CD11b+CX3CR1+cells were isolated with a MoFlo™ XDP Cell Sorter (Beckman Coulter, Brea, CA). Human umbilical vein endothelial cells (HUVECs) were isolated from human cords and cultured at 37 °C in 5% CO2 on top of collagen in four different settings: (1) untreated (HUVECs alone) (2) VEGF (1ng/mL) treated HUVECs; (3) PEDF (3,30 and 300 ng/mL) treated HUVECs; (4) VEGF (1ng/mL)+PEDF (3,30 and 300 ng/mL) treated HUVECs. To assess dose-dependency, PEDF was administered at different dosages (0, 3, 30 and 300 ng/mL) for 7 days in either the presence or absence of VEGF (1ng/mL). HUVEC growth areas were measured by image J. Results: CD11b+CX3CR1+monocytes were found at 19.6±3.58% of total MNCs in human G-CSF mobilized PBSC. Fractalkine treatment (50ng/mL for 30 minutes) of these monocytes promoted endothelial cell proliferation of HUVECs and increased PEDF expression according to the angiogenic protein array results. Administration of PEDF inhibitor significantly decreased HUVEC proliferation and vascular structure formation compared to the control group (p <0.001). We further investigated pro-angiogenic effects of PEDF on HUVEC proliferation. In PEDF (3,30 and 300 ng/mL) treated HUVECs, PEDF itself has minimal effect on HUVEC proliferation. However, EC sprouting at the edge of vessel-like structures was greater in the 3 and 30 ng/mL. Interestingly, there was no EC sprouting with 300 ng/mL PEDF. PEDF (3 and 30 ng/mL) itself showed little effect on HUVEC proliferation. However, co-culturing with VEGF (1ng/mL) and low PEDF concentrations (3 and 30 ng/mL) significantly increased EC proliferation (EC proliferation area (mm2), 1.7±0.4 (VEGF only) vs 3.0±0.6 (VEGF+3 ng/mL PEDF) and 2.5±1.1 (VEGF+30 ng/mL PEDF); p=0.002 and 0.048, respectively). Higher concentration of PEDF did not induced EC proliferation even in the presence VEGF (1.7±0.4 (VEGF only) vs 1.5±0.9 (VEGF+300 ng/mL PEDF); p=0.192). The results suggest that low concentrations of PEDF (3 and 30 ng/mL) has no effect on HUVEC proliferation, but has a potent effect on HUVEC migration regardless of VEGF activity. PEDF is not pro-angiogenic by itself, but can markedly enhance HUVEC proliferation in PEDF (3 and 30 ng/mL) treated HUVECs with VEGF. Conclusion: Fractalkine-treated CD11b+CX3CR1+monocytes promote angiogenesis by increasing PEDF expression, which acts as a pro-angiogenic factor only under conditions where VEGF is present.

Background:In RERISE phase 3 study, radotinib demonstrated significantly higher and faster rates of major molecular response (MMR) than imatinib in patients with newly diagnosed CML-CP. By 36 months follow up, MMR (BCR-ABL1IS≤ 0.1%) and MR4.5(BCR-ABL1IS≤ 0.0032%) in radotinib 300 mg twice daily (bid) were higher than imatinib group. Also, early molecular response (EMR) at 3 months could predict better long term outcomes in both radotinib and imatinib groups. Here, authors updated 48 months long-term benefits and risks of 300mg bid and imatinib 400mg qd from RERISE phase 3 study (NCT01511289).

Background

Background

Purpose: The clinical role of 18F-fluorodeoxyglucose (FDG)-positron emission tomography-computed tomography (PET/CT) in performing upfront high-dose chemotherapy followed by autologous stem cell transplantation (ASCT) remains unclear in peripheral T cell lymphomas (PTCLs). This study investigated the prognostic relevance of interim and final FDG-PET/CT in predicting the outcome of upfront ASCT for the treatment of PTCLs.

Background: Recent studies have demonstrated that early molecular milestones were able to identify high-risk chronic myeloid leukemia patients treated with frontline imatinib (IM) and second-generation tyrosine kinase inhibitors (2G-TKIs). 2G-TKI treated patients achieved faster and deeper molecular responses compared with IM treated patients. Because CML patients currently have multiple treatment options, the impact of early molecular milestones on long-term outcomes needs to be determined in each agent treated patients. The aim of this study is to evaluate the impact of 3-month early molecular response (EMR) on long-term outcomes of CML patients treated with IM and different 2G-TKIs, as additional information to guide clinical decisions on switching to a different TKI.

Background: ABL kinase domain (KD) mutations cause resistance to tyrosine kinase inhibitors (TKIs) in chronic myeloid leukemia (CML) patients through impaired binding of TKI to the target site. To date, several mutations have been strongly associated with clinical resistance and have different susceptibility to TKIs depending on the type of mutation. One of the characteristics of patients with ABL KD mutation is the fact that some patients have multiple mutations and show poor prognosis for treatment than patients with single mutation. Although multiple mutations can be firstly detected by Sanger sequencing, it is not possible to determine whether mutations are in the same clone (compound mutations) or in different clones.

Background

Introduction:Myelo-monocytic cells expressing CD11b are involved in angiogenesis, but their specific roles and underlying mechanisms are unclear. We successfully identified a subset of CD11b+monocytes expressing CX3CR1, the only receptor of fractalkine (Fkn; CX3CL1), in G-CSF mobilized peripheral blood stem cell collection (PBSC). We first verified Fkn triggers proangiogenic activities in CD11b+CX3CR1+monocytes. Subsequently, we found that Fkn-treated CD11b+CX3CR1+monocytes express pigment epithelium-derived factor (PEDF) once Fkn activates Fkn/CX3CR1 signaling. PEDF is a glycoprotein, which belongs to the serpin family and stimulates various physiologic processes such as angiogenesis, cell proliferation, and survival. In this study, we investigated the role of Fkn-treated CD11b+CX3CR1+monocytes in angiogenesis and their mechanisms of action involving PEGF expression.

BackgroundThe early molecular response (EMR) by tyrosine kinase inhibitors (TKIs) is important to predict optimal response and survival in chronic phase chronic myeloid leukemia (CML-CP). However, EMR achievement can be affected by various clinical factors such as dose intensity, adverse events, blood level and risk scores. However, innate intrinsic sensitivity to TKIs of CML clones has not been considered.

Background

No relevant conflicts of interest to declare.

Noh: Il-Yang Pharmaceutical: Research Funding. Jung:Il-Yang Pharmaceutical: Research Funding. Park:Il-Yang Pharmaceutical: Employment. Jo:Il-Yang Pharmaceutical: Employment. Shin:Il-Yang Pharmaceutical: Employment. Kim:BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Novartis: Consultancy, Honoraria, Research Funding, Speakers Bureau; ILYANG: Consultancy, Honoraria, Research Funding. Lee:Il-Yang Pharmaceutical: Research Funding.

No relevant conflicts of interest to declare.

Kim: Celltrion, Inc.: Consultancy, Honoraria.

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