Long-term outcome of high risk patients with myelodysplastic syndromes or secondary acute myeloid leukemia receiving intensive chemotherapy

Abstract

Intensive chemotherapy (IC) used to be a common treatment approach for patients with higher-risk myelodysplastic syndromes (MDS) or acute myeloid leukemia after MDS (sAML). We conducted a retrospective analysis of 299 patients, including a matched pair analysis comparing 96 patients receiving IC with 96 patients not undergoing IC, in order to evaluate the impact of IC on overall survival (OS) and to identify factors that influence remission rates and OS. Complete remission (CR) after first induction chemotherapy was reached in 50% of patients. Parameters influencing the probability of achieving CR were blast count in the bone marrow (< 30%), age < 65 years, presence of Auer rods, duration of antecedent MDS shorter than 6 months, and timing of IC in relation to first diagnosis. The difference in survival time was not significantly better for patients receiving IC (median OS 12.7 months vs. 7 months). Parameters favorably influencing survival were the presence of Auer rods, age below 60 years, blast count below 30%, IC given shortly after first diagnosis, and achievement of CR. On multivariate analysis, achieving CR, presence of Auer rods, and percentage of blasts below or above 30% significantly influenced median survival. Relapse occurred in 63% of patients after a median of 9.9 months with a median survival of 7.6 months. Considering the high relapse rate and short survival, we conclude that intensive chemotherapy is not promising for high-risk MDS or sAML.

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Neuromuscular Complications of Programmed Cell Death-1 (PD-1) Inhibitors

Abstract

Purpose of Review

In recent years, immune checkpoint inhibitors have been increasingly used in patients with metastatic cancers with favorable oncological outcomes; however, there have also been increasing number of cancer survivors who have developed immune-related adverse events. Little is known about PD-1 inhibitor-associated neuromuscular complications.

Recent Findings

Neuromuscular disorders are the most common neurological complication reported in PD-1 inhibitor-treated patients. Myasthenia gravis, immune-mediated myopathies, and Guillain-Barre syndrome are among commonly reported immune-related neuromuscular complications. HyperCKemia occurs frequently in patients with PD-1 inhibitor-associated myasthenia gravis, indicating coexisting myopathies or myocarditis. Oculobulbar weakness is a unique and common presentation of PD-1 inhibitor-associated immune-mediated myopathies with or without concomitant myasthenia gravis. High-dose steroid monotherapy may be associated with clinical deterioration in some patients with PD-1 inhibitor-associated myasthenia gravis, immune-mediated myopathies, or Guillain-Barre syndrome.

Summary

PD-1 inhibitor-associated neuromuscular complications have some characteristic features compared to their idiopathic counterparts. Although steroid monotherapy is commonly used in non-neuromuscular autoimmune disorders triggered by anti-PD-1 therapy, this may lead to unfavorable outcomes in some patients with PD-1 inhibitor-associated neuromuscular complications.

https://ift.tt/2vgw2OT

Transanal Total Mesorectal Excision for Treatment of Carcinoma in the Middle or Lower Third Rectum: the Technical Feasibility of the Procedure, Pathological Results, and Clinical Outcome

Abstract

We are trying to illustrate operative, short-term, and pathological outcomes of transanal total mesorectal excision (TaTME) as a surgical procedure for patients who are suffering cancer in the lower or middle rectum. This study included 25 consecutive patients who underwent TaTME for the mid and low cancer rectum. The primary outcome measures included frequency of postoperative (PO) bleeding, leakage, ileus, days to regain bowel function, days for Foley's removal, and erectile function. The secondary outcome measures included operation time, status of resection margins, number, the quality of TME, and duration PO hospital stay. No recorded intraoperative complications. The mean hospital stay was 6.9 ± 2.6 days. The mean duration need for urinary catheter removal and flatus passage were 2.4 ± 2.1 and 1.5 + 0.9 days, respectively. The mean IPSS was returned to normal 12 months after surgery. The mean distal margin distance was 1.9 ± 1.1. Circumferential margin distance was > 1 mm in 23 (92%) patients. The mesorectum was complete in 22 (88%) patients. The survival rate was 88% over 3 years. TaTME could be considered as a safe, feasible, and effective surgical modality for patients who had mid and lower rectal tumors with an excellent pathological outcome.

https://ift.tt/2OauH33

Novel Therapies in Acute Lymphoblastic Leukemia

Abstract

Purpose of Review

Treatment options for patients with acute lymphoblastic leukemia (ALL) beyond standard chemotherapy have grown significantly in recent years. In this review, we highlight new targeted therapies in ALL, with an emphasis on immunotherapy.

Recent Findings

Major advances include antibody-based therapies, such as naked monoclonal antibodies, antibody-drug conjugates and bispecific T cell engaging (BiTE) antibodies, as well as adoptive cellular therapies such as chimeric antigen receptor (CAR) T cells. Apart from the above immunotherapeutic approaches, other targeted therapies are being employed in Philadelphia chromosome-positive (Ph+) ALL, Philadelphia-like (Ph-like) ALL, and T cell ALL.

Summary

These new treatment strategies are changing the treatment landscape of ALL and challenging the current standard of care. Clinical trials will hopefully help determine how to best incorporate these novel therapies into existing treatment algorithms.

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Apatinib reverses alectinib resistance by targeting vascular endothelial growth factor receptor 2 and attenuating the oncogenic signaling pathway in echinoderm microtubule-associated protein-like 4-anaplastic lymphoma kinase fusion gene-positive lung cancer cell lines

Overexpression of insulin growth factor 1 receptor (IGF-1R) and its ligand, insulin growth factor 1 (IGF-1), is related to treatment resistance and worse prognosis in many types of tumors. We reported recently that IGF-1R activation by IGF induces resistance to alectinib and stimulates the production of vascular endothelial growth factor, which indicates that IGF induces alectinib resistance and angiogenesis. This study aimed to determine the effect of bigeminal inhibition of anaplastic lymphoma kinase (ALK) and angiogenesis on human insulin growth factor 1 receptor (hIGF-1)-triggered drug resistance in echinoderm microtubule-associated protein-like 4-anaplastic lymphoma kinase (EML4-ALK)-positive lung cancer. Human lung adenocarcinoma H3122 and H2228 cells were exposed to a combination of insulin growth factor 1 receptor (IGF-1), alectinib, or apatinib. The effects of the combination therapy were examined using cell the Cell Counting Kit-8 assay, the colony-forming assay, the scratch test, and flow cytometry analysis, and the molecular mechanism was assessed by western blot. At nontoxic concentrations, apatinib restored alectinib sensitivity by increasing drug-induced apoptosis and inhibiting viability, migration, and invasion in IGF-triggered drug resistant cells. Moreover, we found that apatinib restored sensitivity to alectinib mainly through suppression of the ALK downstream signaling pathway and antiangiogenesis signaling. Taken together, our results indicate that simultaneous inhibition of ALK and vascular endothelial growth factor R2 by the combination of alectinib with apatinib may be useful for controlling progression of EML4-ALK fusion gene lung cancer by reversing ALK-TKI resistance and inhibiting angiogenesis. This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal. https://ift.tt/1hexVwJ Correspondence to Shaozhang Zhou, Second Department of Chemotherapy, Affiliated Cancer Hospital, Guangxi Medical University, 71 Heti road, Nanning, Guangxi, 530021, Peoples's Republic of China Tel: +86 077 1533 4955; fax: +86 077 1530 0613; e-mail: zhoushaozhang@qq.com Received January 17, 2018 Accepted June 20, 2018 Copyright © 2018 Wolters Kluwer Health, Inc. All rights reserved.

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Increased antitumor activities of glypican-3-specific chimeric antigen receptor-modified T cells by coexpression of a soluble PD1–CH3 fusion protein

Abstract

Our recent clinical study demonstrated that glypican-3 (GPC3)-specific chimeric antigen receptor-modified T (CAR-T) cells are a promising treatment for hepatocellular carcinoma (HCC). However, the interaction of programmed cell death 1 (PD-1) and PD-L1-mediated T-cell inhibition is involved in immune evasion in a wide range of solid tumors, including HCC. To overcome this problem, we introduced a fusion protein composed of a PD-1 extracellular domain and CH3 from IgG4 into GPC3-specific CAR-T cells (GPC3-28Z) to block the PD-1/PD-L1 pathway. GPC3-specific CAR-T cells carrying the PD-1–CH3 fusion protein (sPD1) specifically recognized and lysed GPC3-positive HCC cells. The proliferation capacity of GPC3-28Z-sPD1 T cells after weekly stimulation with target cells was much higher than that of control GPC3-28Z T cells. Additionally, the coexpression of sPD1 could protect CAR-T cells from exhaustion when incubated with target cells, as phosphorylated AKT and Bcl-xL expression levels were higher in GPC3-28Z-sPD1 T cells than in GPC3-28Z cells. Importantly, in two HCC tumor xenograft models, GPC3-28Z-sPD1 T cells displayed a significantly higher tumor suppression capacity than GPC3-28Z T cells. In addition, an increased number of CD3⁺ T cells in the circulation and tumors and increased granzyme B levels and decreased Ki67 expression levels in the tumors were observed in the mice treated with GPC3-28Z-sPD1 T cells. Together, these data indicated that GPC3-specific CAR-T cells carrying sPD1 show promise as a treatment for patients with HCC.

https://ift.tt/2OIFH92

Increased antitumor activities of glypican-3-specific chimeric antigen receptor-modified T cells by coexpression of a soluble PD1–CH3 fusion protein

Abstract

Our recent clinical study demonstrated that glypican-3 (GPC3)-specific chimeric antigen receptor-modified T (CAR-T) cells are a promising treatment for hepatocellular carcinoma (HCC). However, the interaction of programmed cell death 1 (PD-1) and PD-L1-mediated T-cell inhibition is involved in immune evasion in a wide range of solid tumors, including HCC. To overcome this problem, we introduced a fusion protein composed of a PD-1 extracellular domain and CH3 from IgG4 into GPC3-specific CAR-T cells (GPC3-28Z) to block the PD-1/PD-L1 pathway. GPC3-specific CAR-T cells carrying the PD-1–CH3 fusion protein (sPD1) specifically recognized and lysed GPC3-positive HCC cells. The proliferation capacity of GPC3-28Z-sPD1 T cells after weekly stimulation with target cells was much higher than that of control GPC3-28Z T cells. Additionally, the coexpression of sPD1 could protect CAR-T cells from exhaustion when incubated with target cells, as phosphorylated AKT and Bcl-xL expression levels were higher in GPC3-28Z-sPD1 T cells than in GPC3-28Z cells. Importantly, in two HCC tumor xenograft models, GPC3-28Z-sPD1 T cells displayed a significantly higher tumor suppression capacity than GPC3-28Z T cells. In addition, an increased number of CD3⁺ T cells in the circulation and tumors and increased granzyme B levels and decreased Ki67 expression levels in the tumors were observed in the mice treated with GPC3-28Z-sPD1 T cells. Together, these data indicated that GPC3-specific CAR-T cells carrying sPD1 show promise as a treatment for patients with HCC.

https://ift.tt/2OIFH92