This phase I/II trial evaluated the maximum tolerated dose (MTD) and pharmacokinetics of afatinib plus temozolomide as well as the efficacy and safety of afatinib as monotherapy (A) or with temozolomide (AT) vs temozolomide monotherapy (T) in patients with recurrent glioblastoma (GBM).
Phase I followed a traditional 3 + 3 dose-escalation design to determine MTD. Treatment cohorts were: afatinib 20, 40, and 50 mg/day (plus temozolomide 75 mg/m(2)/day for 21 days per 28-day cycle). In phase II, participants were randomized (stratified by age and KPS) to receive A, T or AT; A was dosed at 40 mg/day and T at 75 mg/m(2) for 21 of 28 days. Primary endpoint was progression-free survival rate at 6 months (PFS-6). Participants were treated until intolerable adverse events (AEs) or disease progression.
Recommended phase II dose was 40 mg/day (A) + T based on safety data from phase I (n = 32). Most frequent AEs in phase II (n = 119) were diarrhea (71% [A], 82% [AT]) and rash (71% [A] and 69% [AT]). Afatinib and temozolomide pharmacokinetics were unaffected by coadministration. Independently assessed PFS-6 rate was 3% (A), 10% (AT), and 23% (T). Median PFS was longer in afatinib-treated participants with epidermal growth factor receptor (EFGR) vIII-positive tumors versus EGFRvIII-negative tumors. Best overall response included partial response in 1 (A), 2 (AT), and 4 (T) participants and stable disease in 14 (A), 14 (AT), and 21 (T) participants.
Afatinib has a manageable safety profile but limited single-agent activity in unselected recurrent GBM patients.
© The Author(s) 2014. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: [email protected].

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Cryopreserved hematopoietic stem cell products are widely used for certain hematologic malignancies. Dimethyl sulfoxide (DMSO) is the most widely used cryoprotective agent (CPA) today, but due to indications of cellular toxicity, changes of the cellular epigenetic state, and patient-related side effects, there is an increasing demand for DMSO-free alternatives. We therefore investigated whether Pentaisomaltose (PIM), a low-molecular-weight carbohydrate (1 kDa), can be used for cryopreservation of peripheral blood stem cells, more specifically hematopoietic progenitor cell apheresis (HPC(A)) product.
We cryopreserved patient or donor HPC(A) products using 10% DMSO or 16% PIM and quantified the recovery of CD34+ cells and CD34+ subpopulations by multicolor flow cytometry. In addition, we compared the frequency of HPCs after DMSO and PIM cryopreservation using the colony-forming cells (CFCs) assay.
The mean CD34+ cell recovery was 56.3 ± 23.7% (11.4%-97.3%) and 58.2 ± 10.0% (45.7%-76.9%) for 10% DMSO and 16% PIM, respectively. The distribution of CD34+ cell subpopulations was similar when comparing DMSO or PIM as CPA. CFC assay showed mean colony numbers of 70.7 ± 25.4 (range, 37.8-115.5) and 67.7 ± 15.7 (range, 48-86) for 10% DMSO and 16% PIM, respectively.
Our findings demonstrate that PIM cryopreservation of HPC(A) products provides recovery of CD34+ cells, CD34+ subpopulations, and CFCs similar to that of DMSO cryopreservation and therefore may have the potential to be used for cryopreservation of peripheral blood stem cells.
© 2016 The Authors Transfusion published by Wiley Periodicals, Inc. on behalf of AABB.

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The induction of apoptosis in tumor cells represents a promising approach to the treatment of cancer. Accordingly, compounds that interact with the Bcl-2 family of proteins, which are critical regulators of the apoptotic process, have been widely pursued as potential anticancer agents. While encouraging antitumor activity in clinical trials has been observed with some of these compounds, their therapeutic utility is often limited by accompanying toxicities associated with the interaction with this family of proteins. As a result, there has been recent interest in identifying agents that can selectively target a single Bcl-2 family member (such as Bcl-2 or Bcl-xL), with the expectation that improved therapeutic margins can be achieved. In this review, we outline the biological rationale behind this approach, and highlight key examples of selective compounds from the recent literature alongside the structural basis for the reported selectivity.
Copyright © 2016 Elsevier Ltd. All rights reserved.

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We aimed to investigate the feasibility of droplet digital PCR (ddPCR) for the quantitative and dynamic detection of EGFR mutations and next generation sequencing (NGS) for screening EGFR-tyrosine kinase inhibitors (EGFR-TKIs) resistance-relevant mutations in circulating tumor DNA (ctDNA) from advanced lung adenocarcinoma (ADC) patients.
Detection limit of EGFR mutation in ctDNA by ddPCR was 0.04%. Taking the EGFR mutation in tumor tissue as the golden standard, the concordance of EGFR mutations detected in ctDNA was 74% (54/73). Patients with EGFR mutation in ctDNA (n = 54) superior progression-free survival (PFS, median, 12.6 vs. 6.7 months, P < 0.001) and overall survival (OS, median, 35.6 vs. 23.8 months, P = 0.028) compared to those with EGFR wild type in ctDNA (n = 19). Patients with high EGFR-mutated abundance in ctDNA (> 5.15%) showed better PFS compared to those with low EGFR mutated abundance (≤ 5.15%) (PFS, median, 15.4 vs. 11.1 months, P = 0.021). NGS results showed that 66.6% (8/12) total mutational copy number were elevated and 76.5% (26/34) mutual mutation frequency increased after disease progression.
Seventy-three advanced ADC patients with tumor tissues carrying EGFR mutations and their matched pre- and post-EGFR-TKIs plasma samples were enrolled in this study. Absolute quantities of plasma EGFR mutant and wild-type alleles were measured by ddPCR. Multi-genes testing was performed using NGS in 12 patients.
Dynamic and quantitative analysis of EGFR mutation in ctDNA could guide personalized therapy for advanced ADC. NGS shows good performance in multiple genes testing especially novel and uncommon genes.

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Selective phosphoinositide 3-kinase (PI3K)/AKT/mTOR inhibitors are currently under evaluation in clinical studies. To identify tumor types that are sensitive to PI3K pathway inhibitors we screened compounds targeting PI3Kα/δ (AZD8835), PI3Kβ/δ (AZD8186), AKT (AZD5363) and mTORC1/2 (AZD2014) against a cancer cell line panel (971 cell lines). There was an enrichment of hematological malignancies that were sensitive to AKT and mTOR inhibition, with the greatest degree of sensitivity observed in T-cell acute lymphoblastic leukemia (T-ALL). We found that all NOTCH mutant T-ALL cell lines were sensitive to AKT and mTORC1/2 inhibitors, with only partial sensitivity to agents that target the PI3K α, β or δ isoforms. Induction of apoptosis only occurred following AKTi treatment in cell lines with PTEN protein loss and high levels of active AKT. In summary, we have demonstrated that T-ALL cell lines show differential sensitivity to inhibition at different nodes in the PI3K/AKT/mTOR pathway and inhibiting AKT or mTOR may have a therapeutic benefit in this disease setting.

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