APOBEC3 SNPs Predict APOBEC Mutagenesis and Cancer Risk [Mutations]

SNPs in APOBEC3 alter expression of APOBEC3A/APOBEC3B to affect somatic APOBEC-signature mutations.

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EZH2 and Tyrosine Kinase Inhibition in CML Stem Cells [Research Briefs]

A major obstacle to curing chronic myeloid leukemia (CML) is residual disease maintained by tyrosine kinase inhibitor (TKI)–persistent leukemic stem cells (LSC). These are BCR–ABL1 kinase independent, refractory to apoptosis, and serve as a reservoir to drive relapse or TKI resistance. We demonstrate that Polycomb Repressive Complex 2 is misregulated in chronic phase CML LSCs. This is associated with extensive reprogramming of H3K27me3 targets in LSCs, thus sensitizing them to apoptosis upon treatment with an EZH2-specific inhibitor (EZH2i). EZH2i does not impair normal hematopoietic stem cell survival. Strikingly, treatment of primary CML cells with either EZH2i or TKI alone caused significant upregulation of H3K27me3 targets, and combined treatment further potentiated these effects and resulted in significant loss of LSCs compared to TKI alone, in vitro, and in long-term bone marrow murine xenografts. Our findings point to a promising epigenetic-based therapeutic strategy to more effectively target LSCs in patients with CML receiving TKIs.

Significance: In CML, TKI-persistent LSCs remain an obstacle to cure, and approaches to eradicate them remain a significant unmet clinical need. We demonstrate that EZH2 and H3K27me3 reprogramming is important for LSC survival, but renders LSCs sensitive to the combined effects of EZH2i and TKI. This represents a novel approach to more effectively target LSCs in patients receiving TKI treatment. Cancer Discov; 6(11); 1248–57. ©2016 AACR.

See related article by Xie et al., p. 1237.

This article is highlighted in the In This Issue feature, p. 1197

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Dual Inhibition of MDM2 and XIAP Induces Cancer Cell Apoptosis [Drug Discovery]

Blocking the MDM2 protein–XIAP mRNA interaction reduces MDM2 and XIAP levels and activates p53.

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When Drug Trials Are Halted [News in Depth]

When significant safety questions arise during a trial, the FDA has the option to place a full or partial clinical hold on treatment and new enrollment. Clinical holds are designed to protect patients from serious harm but they can also cause expensive delays for drug developers and frustrations for patients. While some problems can be resolved quickly, others can permanently derail a drug's development.

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Stereotactic Radiosurgery Keeps Brain Metastases at Bay [News in Brief]

According to two clinical trials presented at the American Society for Radiation Oncology's 2016 annual meeting, stereotactic radiosurgery following surgical removal of brain metastases decreases the risk of local recurrence and, compared with whole-brain radiotherapy, offers patients a better quality of life. As such, postoperative stereotactic radiosurgery should be considered a new standard of care for patients whose cancer has spread to the brain.

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Radiation Therapy Advances for Prostate Cancer [News in Brief]

Three studies on prostate cancer indicate, respectively, that a hypofractionated schedule of intensity-modulated radiation therapy reduces treatment time without negatively affecting quality of life; treatment with stereotactic body radiotherapy is a powerful, potentially more cost-effective option; and prostate brachytherapy, without external radiation, may be sufficient to control disease progression. The data were presented at the American Society for Radiation Oncology's 2016 annual meeting.

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PGC1{alpha} Represses Melanoma Cell Invasion and Metastasis [Melanoma]

PGC1α inhibits melanoma metastasis independent of its role in mitochondrial energetic metabolism.

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Immunogenomics of a Hypermutated Glioblastoma [Research Briefs]

We present the case of a patient with a left frontal glioblastoma with primitive neuroectodermal tumor features and hypermutated genotype in the setting of a POLE germline alteration. During standard-of-care chemoradiation, the patient developed a cervical spine metastasis and was subsequently treated with pembrolizumab. Shortly thereafter, the patient developed an additional metastatic spinal lesion. Using whole-exome DNA sequencing and clonal analysis, we report changes in the subclonal architecture throughout treatment. Furthermore, a persistently high neoantigen load was observed within all tumors. Interestingly, following initiation of pembrolizumab, brisk lymphocyte infiltration was observed in the subsequently resected metastatic spinal lesion and an objective radiographic response was noted in a progressive intracranial lesion, suggestive of active central nervous system (CNS) immunosurveillance following checkpoint blockade therapy.

Significance: It is unclear whether hypermutated glioblastomas are susceptible to checkpoint blockade in adults. Herein, we provide proof of principle that glioblastomas with DNA-repair defects treated with checkpoint blockade may result in CNS immune activation, leading to clinically and immunologically significant responses. These patients may represent a genomically stratified group for whom immunotherapy could be considered. Cancer Discov; 6(11); 1230–6. ©2016 AACR.

See related commentary by Snyder and Wolchok, p. 1210.

This article is highlighted in the In This Issue feature, p. 1197

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Cyclin A2 Has a CDK-Independent Role as an RNA Binding Protein [Tumorigenesis]

Cyclin A2 binds to Mre11 mRNA to promote Mre11 translation and repair of replication errors.

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ERCC3 R109X Mutation and Breast Cancer [Research Briefs]

Known gene mutations account for approximately 50% of the hereditary risk for breast cancer. Moderate and low penetrance variants, discovered by genomic approaches, account for an as-yet-unknown proportion of the remaining heritability. A truncating mutation c.325C>T:p.Arg109* (R109X) in the ATP-dependent helicase ERCC3 was observed recurrently among exomes sequenced in BRCA wild-type, breast cancer–affected individuals of Ashkenazi Jewish ancestry. Modeling of the mutation in ERCC3-deficient or CRISPR/Cas9-edited cell lines showed a consistent pattern of reduced expression of the protein and concomitant hypomorphic functionality when challenged with UVC exposure or treatment with the DNA alkylating agent IlludinS. Overexpressing the mutant protein in ERCC3-deficient cells only partially rescued their DNA repair–deficient phenotype. Comparison of frequency of this recurrent mutation in over 6,500 chromosomes of breast cancer cases and 6,800 Ashkenazi controls showed significant association with breast cancer risk (OR_BC = 1.53, OR_ER+ = 1.73), particularly for the estrogen receptor–positive subset (P < 0.007).

Significance: A functionally significant recurrent ERCC3 mutation increased the risk for breast cancer in a genetic isolate. Mutated cell lines showed lower survival after in vitro exposure to DNA-damaging agents. Thus, similar to tumors arising in the background of homologous repair defects, mutations in nucleotide excision repair genes such as ERCC3 could constitute potential therapeutic targets in a subset of hereditary breast cancers. Cancer Discov; 6(11); 1267–75. ©2016 AACR.

This article is highlighted in the In This Issue feature, p. 1197

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PARP inhibitor combination therapy

Publication date: Available online 31 October 2016
Source:Critical Reviews in Oncology/Hematology
Author(s): Amy Drean, Christopher J. Lord, Alan Ashworth
In 2014, olaparib (Lynparza) became the first PARP (Poly(ADP-ribose) polymerase) inhibitor to be approved for the treatment of cancer. When used as single agents, PARP inhibitors can selectively target tumour cells with BRCA1 or BRCA2 tumour suppressor gene mutations through synthetic lethality. However, PARP inhibition also shows considerable promise when used together with other therapeutic agents. Here, we summarise both the pre-clinical and clinical evidence for the utility of such combinations and discuss the future prospects and challenges for PARP inhibitor combinatorial therapies.



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SLC44A4, an ADC Target for Pancreatic and Prostate Cancer

Here, we report the development of an antibody–drug conjugate, ASG-5ME, which targets the solute carrier receptor SLC44A4. SLC44A4 is a member of a family of putative choline transporters that we show to be markedly upregulated in a variety of epithelial tumors, most notably prostate and pancreatic cancer. SLC44A4 is normally expressed on the apical surface of secretory epithelial cells, but in cancer we show expression is not restricted to the luminal surface in advanced and undifferentiated tumors. ASG-5ME consists of a human IgG2 anti-SLC44A4 antibody conjugated through a cleavable linker to the microtubule-disrupting agent monomethylauristatin E. It has potent antitumor activity in both cell line – and patient-derived xenograft models of pancreatic and prostate cancers. Combination studies with ASG-5ME and nab-paclitaxel demonstrated combination effect in both pancreatic and prostate tumor models. Altogether, the data presented here suggest that ASG-5ME may have the potential to offer a new therapeutic option for the treatment of pancreatic and prostate cancers. Mol Cancer Ther; 15(11); 2679–87. ©2016 AACR.

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Bispecific Antibody-Drug Con{#x0237}ugate Targeting HER2 and CD63

Antibody–drug conjugates (ADC) are designed to be stable in circulation and to release potent cytotoxic drugs intracellularly following antigen-specific binding, uptake, and degradation in tumor cells. Efficient internalization and routing to lysosomes where proteolysis can take place is therefore essential. For many cell surface proteins and carbohydrate structures on tumor cells, however, the magnitude of these processes is insufficient to allow for an effective ADC approach. We hypothesized that we could overcome this limitation by enhancing lysosomal ADC delivery via a bispecific antibody (bsAb) approach, in which one binding domain would provide tumor specificity, whereas the other binding domain would facilitate targeting to the lysosomal compartment. We therefore designed a bsAb in which one binding arm specifically targeted CD63, a protein that is described to shuttle between the plasma membrane and intracellular compartments, and combined it in a bsAb with a HER2 binding arm, which was selected as model antigen for tumor-specific binding. The resulting bsHER2xCD63_his demonstrated strong binding, internalization and lysosomal accumulation in HER2-positive tumor cells, and minimal internalization into HER2-negative cells. By conjugating bsHER2xCD63_his to the microtubule-disrupting agent duostatin-3, we were able to demonstrate potent cytotoxicity of bsHER2xCD63_his-ADC against HER2-positive tumors, which was not observed with monovalent HER2- and CD63-specific ADCs. Our data demonstrate, for the first time, that intracellular trafficking of ADCs can be improved using a bsAb approach that targets the lysosomal membrane protein CD63 and provide a rationale for the development of novel bsADCs that combine tumor-specific targeting with targeting of rapidly internalizing antigens. Mol Cancer Ther; 15(11); 2688–97. ©2016 AACR.

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Pharmacodynamic Transcript Biomarkers of FGFR Inhibition

The challenge of developing effective pharmacodynamic biomarkers for preclinical and clinical testing of FGFR signaling inhibition is significant. Assays that rely on the measurement of phospho-protein epitopes can be limited by the availability of effective antibody detection reagents. Transcript profiling enables accurate quantification of many biomarkers and provides a broader representation of pathway modulation. To identify dynamic transcript biomarkers of FGFR signaling inhibition by AZD4547, a potent inhibitor of FGF receptors 1, 2, and 3, a gene expression profiling study was performed in FGFR2-amplified, drug-sensitive tumor cell lines. Consistent with known signaling pathways activated by FGFR, we identified transcript biomarkers downstream of the RAS-MAPK and PI3K/AKT pathways. Using different tumor cell lines in vitro and xenografts in vivo, we confirmed that some of these transcript biomarkers (DUSP6, ETV5, YPEL2) were modulated downstream of oncogenic FGFR1, 2, 3, whereas others showed selective modulation only by FGFR2 signaling (EGR1). These transcripts showed consistent time-dependent modulation, corresponding to the plasma exposure of AZD4547 and inhibition of phosphorylation of the downstream signaling molecules FRS2 or ERK. Combination of FGFR and AKT inhibition in an FGFR2-mutated endometrial cancer xenograft model enhanced modulation of transcript biomarkers from the PI3K/AKT pathway and tumor growth inhibition. These biomarkers were detected on the clinically validated nanoString platform. Taken together, these data identified novel dynamic transcript biomarkers of FGFR inhibition that were validated in a number of in vivo models, and which are more robustly modulated by FGFR inhibition than some conventional downstream signaling protein biomarkers. Mol Cancer Ther; 15(11); 2802–13. ©2016 AACR.

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Wedelolactone Interrupts c-Myc Oncogenic Signaling

The c-Myc gene encodes an oncoprotein transcription factor that is frequently upregulated in almost all cancer types and is the subject of intense investigation for management of cancer because of its pleiotropic effects controlling a spectrum of cellular functions. However, due of its nonenzymatic nature, development of suitable strategies to block its protein–protein or protein–DNA interaction is challenging. Thus, c-Myc has been recognized as an elusive molecular target for cancer control, and various approaches are in development to inhibit c-Myc transcriptional activity. We observed that wedelolactone (WDL), an anti-inflammatory botanical compound, severely downregulates the expression of c-Myc mRNA in prostate cancer cells. Moreover, WDL dramatically decreases the protein level, nuclear accumulation, DNA-binding, and transcriptional activities of c-Myc. c-Myc is a transforming oncogene widely expressed in prostate cancer cells and is critical for maintaining their transformed phenotype. Interestingly, WDL was found to strongly affect the viability of Myc-activated prostate cancer cells and completely block their invasion as well as soft agar colony formation in vitro. WDL was also found to downregulate c-Myc in vivo in nude mice xenografts. Moreover, WDL synergizes with enzalutamide to decrease the viability of androgen-sensitive prostate cancer cells via induction of apoptosis. These findings reveal a novel anticancer mechanism of the natural compound WDL, and suggest that the oncogenic function of c-Myc in prostate cancer cells can be effectively downregulated by WDL for the development of a new therapeutic strategy against Myc-driven prostate cancer. Mol Cancer Ther; 15(11); 2791–801. ©2016 AACR.

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Expression of Vascular Morphogenesis Genes and CLM

Angiogenesis-related gene expression is associated with the efficacy of anti-VEGF therapy. We tested whether intratumoral mRNA expression levels of genes involved in vascular morphogenesis and early vessel maturation predict response, recurrence-free survival (RFS), and overall survival (OS) in a unique cohort of patients with colorectal liver metastases (CLM) treated with bevacizumab-based chemotherapy followed by curative liver resection. Intratumoral mRNA was isolated from resected bevacizumab-pretreated CLM from 125 patients. In 42 patients, a matching primary tumor sample collected before bevacizumab treatment was available. Relative mRNA levels of 9 genes (ACVRL1, EGFL7, EPHB4, HIF1A, VEGFA, VEGFB, VEGFC, FLT1, and KDR) were analyzed by RT-PCR and evaluated for associations with response, RFS, and OS. P values for the associations between the individual dichotomized expression level and RFS were adjusted for choosing the optimal cut-off value. In CLM, high expression of VEGFB, VEGFC, HIF1A, and KDR and low expression of EGFL7 were associated with favorable RFS in multivariable analysis (P < 0.05). High ACVRL1 levels predicted favorable 3-year OS (P = 0.041) and radiologic response (PR = 1.093, SD = 0.539, P = 0.002). In primary tumors, low VEGFA and high EGFL7 were associated with radiologic and histologic response (P < 0.05). High VEGFA expression predicted shorter RFS (10.1 vs. 22.6 months; HR = 2.83, P = 0.038). High VEGFB (46% vs. 85%; HR = 5.75, P = 0.009) and low FLT1 (55% vs. 100%; P = 0.031) predicted lower 3-year OS rates. Our data suggest that intratumoral mRNA expression of genes involved in vascular morphogenesis and early vessel maturation may be promising predictive and/or prognostic biomarkers. Mol Cancer Ther; 15(11); 2814–21. ©2016 AACR.

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TLR4-Dependent Tight Junction Regulation

We have previously shown increased intestinal permeability, to 4-kDa FITC-dextran, in BALB/c mice treated with irinotecan. Importantly, genetic deletion of Toll-like receptor 4 (TLR4; Tlr4^–/–) protected against loss of barrier function, indicating that TLR4 is critical in tight junction regulation. The current study aimed (i) to determine the molecular characteristics of intestinal tight junctions in wild-type and Tlr4^–/– BALB/c mice and (ii) to characterize the secretory profile of the distal colon. Forty-two female wild-type and 42 Tlr4^–/– BALB/c mice weighing between 18 and 25 g received a single 270 mg/kg [intraperitoneal (i.p.)] dose of irinotecan hydrochloride or vehicle control and were killed at 6, 24, 48, 72, and 96 hours. The secretory profile of the distal colon, following carbachol and forksolin, was assessed using Ussing chambers at all time points. Tight junction integrity was assessed at 24 hours, when peak intestinal permeability and diarrhea were reported, using immunofluorescence, Western blotting, and RT-PCR. Irinotecan caused internalization of claudin-1 with focal lesions of ZO-1 and occludin proteolysis in the ileum and colon of wild-type mice. Tlr4^–/– mice maintained phenotypically normal tight junctions. Baseline conductance, a measure of paracellular permeability, was increased in irinotecan-treated wild-type mice at 24 hours (53.19 ± 6.46 S/cm²; P = 0.0008). No change was seen in Tlr4^–/– mice. Increased carbachol-induced chloride secretion was seen in irinotecan-treated wild-type and Tlr4^–/– mice at 24 hours (wild-type: 100.35 ± 18.37 μA/cm²; P = 0.022; Tlr4^–/–: 102.72 ± 18.80 μA/cm²; P = 0.023). Results suggest that TLR4-dependent claudin-1 internalization and secondary anion secretion contribute to irinotecan-induced diarrhea. Mol Cancer Ther; 15(11); 2767–79. ©2016 AACR.

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Dinaciclib Inhibits CDK1/2-Inducing Anaphase Catastrophe

Despite advances in targeted therapy, lung cancer remains the most common cause of cancer-related mortality in the United States. Chromosomal instability is a prominent feature in lung cancer and, because it rarely occurs in normal cells, it represents a potential therapeutic target. Our prior work discovered that lung cancer cells undergo anaphase catastrophe in response to inhibition of cyclin-dependent kinase 2 (CDK2), followed by apoptosis and reduced growth. In this study, the effects and mechanisms of the multi-CDK inhibitor dinaciclib on lung cancer cells were investigated. We sought to determine the specificity of CDK-dependent induction of anaphase catastrophe. Live cell imaging provided direct evidence that dinaciclib caused multipolar cell divisions resulting in extensive chromosome missegregation. Genetic knockdown of dinaciclib CDK targets revealed that repression of CDK2 and CDK1, but not CDK5 or CDK9, triggered anaphase catastrophe in lung cancer cells. Overexpression of CP110, which is a mediator of CDK2 inhibitor–induced anaphase catastrophe (and a CDK1 and 2 phosphorylation substrate), antagonized anaphase catastrophe and apoptosis following dinaciclib treatment. Consistent with our previous findings, acquisition of activated KRAS sensitized lung cancer cells to dinaciclib-mediated anaphase catastrophe and cell death. Combining dinaciclib with the mitotic inhibitor taxol augmented anaphase catastrophe induction and reduced cell viability of lung cancer cells. Thus, the multi-CDK inhibitor dinaciclib causes anaphase catastrophe in lung cancer cells and should be investigated as a potential therapeutic for wild-type and KRAS-mutant lung cancer, individually or in combination with taxanes. Mol Cancer Ther; 15(11); 2758–66. ©2016 AACR.

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JNK/MKP-1 Interplay Determines Resistance in Breast Cancer

MAPK phosphatase-1 (MKP-1) is overexpressed during malignant transformation of the breast in many patients, and it is usually associated with chemoresistance through interference with JNK-driven apoptotic pathways. Although the molecular settings of the mechanism have been documented, details about the contribution of MKP-1 to the failure of chemotherapeutic interventions are unclear. Transient overexpression of MKP-1 and treatment with JNK-modulating agents in breast carcinoma cells confirmed the mediation of MKP-1 in the resistance to taxanes and anthracyclines in breast cancer, through the inactivation of JNK1/2. We next assessed MKP-1 expression and JNK1/2 phosphorylation status in a large cohort of samples from 350 early breast cancer patients treated with adjuvant anthracycline–based chemotherapy. We detected that MKP-1 overexpression is a recurrent event predominantly linked to dephosphorylation of JNK1/2 with an adverse impact on relapse of the tumor and overall and disease-free survival. Moreover, MKP-1 and p-JNK1/2 determinations in 64 locally advanced breast cancer patients treated with neoadjuvant taxane–based chemotherapy showed an inverse correlation between MKP-1 overexpression (together with JNK1/2 inhibition) and the pathologic response of the tumors. Our results emphasize the importance of MKP-1 as a potential predictive biomarker for a subset of breast cancer patients with worse outcome and less susceptibility to treatment. Mol Cancer Ther; 15(11); 2780–90. ©2016 AACR.

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BAL101553 Activity on Glioblastoma Stem-like Cells

Glioblastoma patients have limited treatment options. Cancer stem-like cells (CSLC) contribute to glioblastoma invasiveness and repopulation; hence, they represent promising targets for novel therapies. BAL101553 is a prodrug of BAL27862, a novel microtubule-destabilizing agent inhibiting tumor cell proliferation through activation of the spindle assembly checkpoint, which is currently in phase I/II clinical development. Broad anticancer activity has been demonstrated against human cancer models, including tumors refractory to conventional treatments. We have shown that overexpression of microtubule + end-binding 1-protein (EB1) correlates with glioblastoma progression and poor survival. Here, we show that BAL27862 inhibits the growth of two glioblastoma CSLCs. As EB1 is overexpressed in the CSLC line GBM6, which displays a high tumorigenicity and infiltrative pattern of migration in vivo, we investigated drug activity on GBM6 according to EB1 expression. BAL27862 inhibited migration and colony formation at subcytotoxic concentrations in EB1-expressing control cells (GBM6-sh0) but only at cytotoxic concentrations in EB1-downregulated (GBM-shE1) cells. Three administrations of BAL101553 were sufficient to provoke an EB1-dependent survival benefit in tumor-bearing mice. Patterns of invasion and quantification of tumor cells in brain demonstrated that GBM6-sh0 cells were more invasive than GBM6-shEB1 cells, and that the antiproliferative and anti-invasive effects of BAL101553 were more potent in mice bearing control tumors than in EB1-downregulated tumors. This was associated with inhibition of stem cell properties in the GBM6-sh0 model. Finally, BAL27862 triggered astrocytic differentiation of GBM6 in an EB1-dependent manner. These results support the potential of BAL101553 for glioblastoma treatment, with EB1 expression as a predictive biomarker of response. Mol Cancer Ther; 15(11); 2740–9. ©2016 AACR.

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Targeting Homologous Recombination in Glioma Chemotherapy

Malignant gliomas exhibit a high level of intrinsic and acquired drug resistance and have a dismal prognosis. First- and second-line therapeutics for glioblastomas are alkylating agents, including the chloroethylating nitrosoureas (CNU) lomustine, nimustine, fotemustine, and carmustine. These agents target the tumor DNA, forming O⁶-chloroethylguanine adducts and secondary DNA interstrand cross-links (ICL). These cross-links are supposed to be converted into DNA double-strand breaks, which trigger cell death pathways. Here, we show that lomustine (CCNU) with moderately toxic doses induces ICLs in glioblastoma cells, inhibits DNA replication fork movement, and provokes the formation of DSBs and chromosomal aberrations. Since homologous recombination (HR) is involved in the repair of DSBs formed in response to CNUs, we elucidated whether pharmacologic inhibitors of HR might have impact on these endpoints and enhance the killing effect. We show that the Rad51 inhibitors RI-1 and B02 greatly ameliorate DSBs, chromosomal changes, and the level of apoptosis and necrosis. We also show that an inhibitor of MRE11, mirin, which blocks the formation of the MRN complex and thus the recognition of DSBs, has a sensitizing effect on these endpoints as well. In a glioma xenograft model, the Rad51 inhibitor RI-1 clearly enhanced the effect of CCNU on tumor growth. The data suggest that pharmacologic inhibition of HR, for example by RI-1, is a reasonable strategy for enhancing the anticancer effect of CNUs. Mol Cancer Ther; 15(11); 2665–78. ©2016 AACR.

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Fenretinide + ABT-751 in Neuroblastoma Xenografts

ABT-751 is a colchicine-binding site microtubule inhibitor. Fenretinide (4-HPR) is a synthetic retinoid. Both agents have shown activity against neuroblastoma in laboratory models and clinical trials. We investigated the antitumor activity of 4-HPR + the microtubule-targeting agents ABT-751, vincristine, paclitaxel, vinorelbine, or colchicine in laboratory models of recurrent neuroblastoma. Drug cytotoxicity was assessed in vitro by a fluorescence-based assay (DIMSCAN) and in subcutaneous xenografts in nu/nu mice. Reactive oxygen species levels (ROS), apoptosis, and mitochondrial depolarization were measured by flow cytometry; cytochrome c release and proapoptotic proteins were measured by immunoblotting. 4-HPR + ABT-751 showed modest additive or synergistic cytotoxicity, mitochondrial membrane depolarization, cytochrome c release, and caspase activation compared with single agents in vitro; synergism was inhibited by antioxidants (ascorbic acid, α-tocopherol). 4-HPR + ABT-751 was highly active against four xenograft models, achieving multiple maintained complete responses. The median event-free survival (days) for xenografts from 4 patients combined was control = 28, 4-HPR = 49, ABT-751 = 77, and 4-HPR + ABT-751 > 150 (P < 0.001). Apoptosis (terminal deoxynucleotidyl transferase–mediated dUTP nick end labeling, TUNEL) was significantly higher in 4-HPR + ABT-751–treated tumors than with single agents (P < 0.01) and was inhibited by ascorbic acid and α-tocopherol (P < 0.01), indicating that ROS from 4-HPR enhanced the activity of ABT-751. 4-HPR also enhanced the activity against neuroblastoma xenografts of vincristine or paclitaxel, but the latter combinations were less active than 4-HPR + ABT-751. Our data support clinical evaluation of 4-HPR combined with ABT-751 in recurrent and refractory neuroblastoma. Mol Cancer Ther; 15(11); 2653–64. ©2016 AACR.

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Inhibiting Scaffold-MAPK in Multiple Myeloma

Despite improved outcomes in newly diagnosed multiple myeloma, virtually all patients relapse and ultimately develop drug-resistant disease. Aberrant RAS/MAPK signaling is activated in the majority of relapsed/refractory multiple myeloma patients, but its biological consequences are not fully understood. Self-renewal, as defined by the long-term maintenance of clonogenic growth, is essential for disease relapse, and we examined the role of RAS/MAPK activation on multiple myeloma self-renewal by targeting IQ motif–containing GTPase-activating protein 1 (IQGAP1), an intracellular scaffold protein required for mutant RAS signaling. We found that loss of IQGAP1 expression decreased MAPK signaling, cell-cycle progression, and tumor colony formation. Similarly, a peptide mimicking the WW domain of IQGAP1 that interacts with ERK inhibited the clonogenic growth and self-renewal of multiple myeloma cell lines and primary clinical specimens in vitro as well as tumor-initiating cell frequency in immunodeficient mice. During multiple myeloma progression, self-renewal may be enhanced by aberrant RAS/MAPK signaling and inhibited by targeting IQGAP1. Mol Cancer Ther; 15(11); 2733–9. ©2016 AACR.

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ERBB2 Overexpression Creates Withaferin A Hypersensitivity

The catalytically deficient ERBB3 strongly synergizes with the receptor tyrosine kinase ERBB2, and elevated levels represent an overall risk factor for unfavorable disease outcomes in breast cancer. Although itself not a target of pan-ERBB kinase inhibitors, it contributes to resistance in ERBB2-targeted treatment regiments. The steroidal lactone Withaferin A (WA) has established broad anticancer properties through several modes of action and was shown to be effective against triple-negative breast cancers at elevated concentrations. We found that ERBB2 overexpression does render cells hypersensitive to WA. Although ERBB2 downregulation is one aspect of WA treatment at high concentrations, it is not causal for the elevated sensitivity at lower dosages. Instead, WA targets the ability of ERBB3 to amplify ERBB2 signaling. ERBB3 receptor levels, constitutive phosphorylation of both ERBB3 and ERBB2, as well as signaling through AKT are eliminated by WA treatment. By targeting ERBB2/ERBB3 as a functional unit, it is also effective in cases in which ERBB2-directed inhibitors, such as lapatinib, alone show reduced potency. Hence, WA or derivatives thereof may present a low toxicity addition to ERBB2-targeting therapeutics, especially in cases in which ERBB3 involvement is driving resistance or reduced overall sensitivity. Mol Cancer Ther; 15(11); 2750–7. ©2016 AACR.

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Site-Specific Trop-2 ADC with Enhanced Stability

Trop-2, also known as TACSTD2, EGP-1, GA733-1, and M1S1, is frequently expressed on a variety of human carcinomas, and its expression is often associated with poor prognosis of the diseases. However, it is also present on the epithelium of several normal tissues. A comprehensively designed Trop-2–targeting antibody–drug conjugate (ADC), balancing both efficacy and toxicity, is therefore necessary to achieve clinical utility. To this end, we developed a cleavable Trop-2 ADC (RN927C) using a site-specific transglutaminase-mediated conjugation method and a proprietary microtubule inhibitor (MTI) linker-payload, PF-06380101. Robust in vitro cytotoxicity of RN927C was observed on a panel of Trop-2–expressing tumor cell lines, with IC₅₀ generally in the subnanomolar range. As expected for an MTI-containing ADC, RN927C readily induced mitotic arrest of treated cells in vitro and in vivo, followed by subsequent cell death. The in vivo efficacy of RN927C was tested in multiple cell line and patient-derived xenograft tumor models, including pancreatic, lung, ovarian, and triple-negative breast tumor types. Single-dose administration of RN927C at 0.75 to 3 mg/kg was generally sufficient to induce sustained regression of Trop-2–expressing tumors and showed superior efficacy over standard treatment with paclitaxel or gemcitabine. Administration of RN927C in nonhuman primate toxicity studies resulted in target-mediated effects in skin and oral mucosa, consistent with Trop-2 expression in these epithelial tissues with minimal, non–dose limiting off-target toxicities. On the basis of the combined efficacy and safety results, RN927C is postulated to have a favorable therapeutic index for treatment of solid tumors. Mol Cancer Ther; 15(11); 2698–708. ©2016 AACR.

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ADCT-301 Targets CD25-Expressing Hematological Malignancies

Despite the many advances in the treatment of hematologic malignancies over the past decade, outcomes in refractory lymphomas remain poor. One potential strategy in this patient population is the specific targeting of IL2R-α (CD25), which is overexpressed on many lymphoma and leukemic cells, using antibody–drug conjugates (ADC). ADCT-301 is an ADC composed of human IgG1 HuMax-TAC against CD25, stochastically conjugated through a dipeptide cleavable linker to a pyrrolobenzodiazepine (PBD) dimer warhead with a drug–antibody ratio (DAR) of 2.3. ADCT-301 binds human CD25 with picomolar affinity. ADCT-301 has highly potent and selective cytotoxicity against a panel of CD25-expressing human lymphoma cell lines. Once internalized, the released warhead binds in the DNA minor groove and exerts its potent cytotoxic action via the formation of DNA interstrand cross-links. A strong correlation between loss of viability and DNA cross-link formation is demonstrated. DNA damage persists, resulting in phosphorylation of histone H2AX, cell-cycle arrest in G₂–M, and apoptosis. Bystander killing of CD25-negative cells by ADCT-301 is also observed. In vivo, a single dose of ADCT-301 results in dose-dependent and targeted antitumor activity against both subcutaneous and disseminated CD25-positive lymphoma models. In xenografts of Karpas 299, which expressed both CD25 and CD30, marked superiority over brentuximab vedotin (Adcetris) is observed. Dose-dependent increases in DNA cross-linking, -H2AX, and PBD payload staining were observed in tumors in vivo indicating a role as relevant pharmacodynamic assays. Together, these data support the clinical testing of this novel ADC in patients with CD25-expressing tumors. Mol Cancer Ther; 15(11); 2709–21. ©2016 AACR.

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Dual-Targeting APE1/Ref-1 and CA9 in Hypoxic PDAC Cells

Pancreatic ductal adenocarcinoma (PDAC) is the fourth leading cause of cancer-related mortality in the United States. Aggressive treatment regimens have not changed the disease course, and the median survival has just recently reached a year. Several mechanisms are proposed to play a role in PDAC therapeutic resistance, including hypoxia, which creates a more aggressive phenotype with increased metastatic potential and impaired therapeutic efficacy. AP Endonuclease-1/Redox Effector Factor 1 (APE1/Ref-1) is a multifunctional protein possessing a DNA repair function in base excision repair and the ability to reduce oxidized transcription factors, enabling them to bind to their DNA target sequences. APE1/Ref-1 regulates several transcription factors involved in survival mechanisms, tumor growth, and hypoxia signaling. Here, we explore the mechanisms underlying PDAC cell responses to hypoxia and modulation of APE1/Ref-1 redox signaling activity, which regulates the transcriptional activation of hypoxia-inducible factor 1 alpha (HIF1α). Carbonic anhydrase IX (CA9) is regulated by HIF1α and functions as a part of the cellular response to hypoxia to regulate intracellular pH, thereby promoting cell survival. We hypothesized that modulating APE1/Ref-1 function will block activation of downstream transcription factors, STAT3 and HIF1α, interfering with the hypoxia-induced gene expression. We demonstrate APE1/Ref-1 inhibition in patient-derived and established PDAC cells results in decreased HIF1α–mediated induction of CA9. Furthermore, an ex vivo three-dimensional tumor coculture model demonstrates dramatic enhancement of APE1/Ref-1–induced cell killing upon dual targeting of APE1/Ref-1 and CA9. Both APE1/Ref-1 and CA9 are under clinical development; therefore, these studies have the potential to direct novel PDAC therapeutic treatment. Mol Cancer Ther; 15(11); 2722–32. ©2016 AACR.

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Targeting Mitochondria in Drug-Resistant Osteosarcoma

Doxorubicin is one of the leading drugs for osteosarcoma standard chemotherapy. A total of 40% to 45% of high-grade osteosarcoma patients are unresponsive, or only partially responsive, to doxorubicin (Dox), due to the overexpression of the drug efflux transporter ABCB1/P-glycoprotein (Pgp). The aim of this work is to improve Dox-based regimens in resistant osteosarcomas. We used a chemically modified mitochondria-targeted Dox (mtDox) against Pgp-overexpressing osteosarcomas with increased resistance to Dox. Unlike Dox, mtDox accumulated at significant levels intracellularly, exerted cytotoxic activity, and induced necrotic and immunogenic cell death in Dox-resistant/Pgp-overexpressing cells, fully reproducing the activities exerted by anthracyclines in drug-sensitive tumors. mtDox reduced tumor growth and cell proliferation, increased apoptosis, primed tumor cells for recognition by the host immune system, and was less cardiotoxic than Dox in preclinical models of drug-resistant osteosarcoma. The increase in Dox resistance was paralleled by a progressive upregulation of mitochondrial metabolism. By widely modulating the expression of mitochondria-related genes, mtDox decreased mitochondrial biogenesis, the import of proteins and metabolites within mitochondria, mitochondrial metabolism, and the synthesis of ATP. These events were paralleled by increased reactive oxygen species production, mitochondrial depolarization, and mitochondria-dependent apoptosis in resistant osteosarcoma cells, where Dox was completely ineffective. We propose mtDox as a new effective agent with a safer toxicity profile compared with Dox that may be effective for the treatment of Dox-resistant/Pgp-positive osteosarcoma patients, who strongly need alternative and innovative treatment strategies. Mol Cancer Ther; 15(11); 2640–52. ©2016 AACR.

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Bazedoxifene as a Novel GP130 Signaling Inhibitor

The IL6/GP130/STAT3 pathway is crucial for tumorigenesis in multiple cancer types, including pancreatic cancer, and presents as a viable target for cancer therapy. We reported Bazedoxifene, which is approved as a selective estrogen modulator by FDA, as a novel inhibitor of IL6/GP130 protein–protein interactions using multiple ligand simultaneous docking and drug repositioning approaches. STAT3 is one of the major downstream effectors of IL6/GP130. Here, we observed Bazedoxifene inhibited STAT3 phosphorylation and STAT3 DNA binding, induced apoptosis, and suppressed tumor growth in pancreatic cancer cells with persistent IL6/GP130/STAT3 signaling in vitro and in vivo. In addition, IL6, but not INF, rescued Bazedoxifene-mediated reduction of cell viability. Bazedoxifene also inhibited STAT3 phosphorylation induced by IL6 and IL11, but not by OSM or STAT1 phosphorylation induced by INF in pancreatic cancer cells, suggesting that Bazedoxifene inhibits the GP130/STAT3 pathway mediated by IL6 and IL11. Furthermore, Bazedoxifene combined with paclitaxel or gemcitabine synergistically inhibited cell viability and cell migration in pancreatic cancer cells. These results indicate that Bazedoxifene is a potential agent and can generate synergism when combined with conventional chemotherapy in human pancreatic cancer cells and tumor xenograft in mice. Therefore, our results support that Bazedoxifene as a novel inhibitor of GP130 signaling and may be a potential and safe therapeutic agent for human pancreatic cancer therapy. Mol Cancer Ther; 15(11); 2609–19. ©2016 AACR.

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E7090, a Novel Selective Inhibitor of FGFR

The FGFR signaling pathway has a crucial role in proliferation, survival, and migration of cancer cells, tumor angiogenesis, and drug resistance. FGFR genetic abnormalities, such as gene fusion, mutation, and amplification, have been implicated in several types of cancer. Therefore, FGFRs are considered potential targets for cancer therapy. E7090 is an orally available and selective inhibitor of the tyrosine kinase activities of FGFR1, -2, and -3. In kinetic analyses of the interaction between E7090 and FGFR1 tyrosine kinase, E7090 associated more rapidly with FGFR1 than did the type II FGFR1 inhibitor ponatinib, and E7090 dissociated more slowly from FGFR1, with a relatively longer residence time, than did the type I FGFR1 inhibitor AZD4547, suggesting that its kinetics are more similar to the type V inhibitors, such as lenvatinib. E7090 showed selective antiproliferative activity against cancer cell lines harboring FGFR genetic abnormalities and decreased tumor size in a mouse xenograft model using cell lines with dysregulated FGFR. Furthermore, E7090 administration significantly prolonged the survival of mice with metastasized tumors in the lung. Our results suggest that E7090 is a promising candidate as a therapeutic agent for the treatment of tumors harboring FGFR genetic abnormalities. It is currently being investigated in a phase I clinical trial. Mol Cancer Ther; 15(11); 2630–9. ©2016 AACR.

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DPP-23 Treatment of Cisplatin-Resistant HNC

Many cancer cells show acquired resistance to chemotherapeutic agents, such as cisplatin. This is a major cause of cancer treatment failure, and novel agents to overcome resistance are thus urgently required. A novel synthetic polyphenol conjugate, (E)-3-(3,5-dimethoxyphenyl)-1-(2-methoxyphenyl)prop-2-en-1-one (DPP-23), selectively kills tumor cells via the reactive oxygen species (ROS)–mediated unfolded protein response. We investigated the ability of DPP-23 to overcome cisplatin resistance in head and neck cancer (HNC) cells and further clarified its molecular mechanisms of action. Cisplatin-resistant HNC cell lines and their parental and other HNC cell lines were used. The effects of cisplatin and DPP-23 were assessed alone and in combination in HNC and normal cells using cell viability, cell cycle, and cell death assays, by measuring glutathione (GSH), ROS, and protein levels, and via preclinical mouse studies. DPP-23 induced selective cell death in HNC cells, including cisplatin-resistant HNC cells, but spared normal cells, via cellular GSH depletion and ROS accumulation. The effect was blocked by the antioxidant N-acetyl-L-cysteine. DPP-23 activated p53 and its related cell death pathways via a robust accumulation of cellular ROS that involved inhibition of nuclear factor erythroid 2–related factor 2 antioxidant defense mechanisms. Thus, DPP-23 significantly overcame cisplatin resistance in HNC cells in vitro and in vivo. As a promising anticancer strategy, ROS generation and subsequent selective cancer cell killing by DPP-23 might help to overcome cisplatin resistance in HNC. Mol Cancer Ther; 15(11); 2620–9. ©2016 AACR.

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An unusual site of metastasis: splenic metastastasis from a colon cancer

Splenic metastasis from colorectal cancers is a very rare occurrence. Few cases have been reported in the literature. We report herein an additionnal case of metachronous splenic metastasis from adenocarcinoma of the sigmoid colon, 3 years after the diagnosis of the primary tumor. A 62-year old woman presented for regular follow-up after colectomy for sigmoid colon adenocarcinoma. A computed tomography-scan found two splenic metastatic nodules for which splenectomy had been performed. The histological analysis of the resected spleen showed a well-differentiated metastatic adenocarcinoma from colon. The patient recovered well after surgery, and 10 months after, she had no signs of the disease.

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Pancreatic pseudocyst: combined single incision laparoscopic cystogastrostomy and cholecystectomy in a resource poor setting

Laparoscopic cystogastrostomy is a well-accepted minimally invasive modality to treat pancreatic pseudocysts. There has been one prior report of cystogastrostomy via single incision laparoscopic surgery (SILS) in which specialized instrumentation and access platforms were used.

We report the challenges encountered in a low resource setting with the SILS approach to drainage using only standard laparoscopic instruments. To the best of our knowledge this is the second report of SILS cystogastrostomy and the first to be performed in a resource poor setting without specialized instruments or platforms.

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Inflammatory myofibroblastic tumour of the urinary bladder managed with partial cystectomy: a case report & literature review

Inflammatory myofibroblastic tumour (IMT) is a rare neoplasm which can affect many different organs throughout the body. We report the case of a 62-year old female presenting with visible haematuria found to have IMT of the urinary bladder exhibiting anaplastic lymphoma kinase-1 gene rearrangement, initially managed with local resection and then definitively with partial cystectomy.

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Effects of acotiamide on esophageal motility in healthy subjects: a randomized, double-blind, placebo-controlled crossover study

Abstract

Background

Acotiamide is a new drug that exhibits prokinetic activity by enhancing the release of acetylcholine. However, its effects on esophageal motility currently remain unknown. Therefore, we herein investigated the effects of acotiamide on esophageal motility in healthy, asymptomatic subjects.

Methods

Thirty healthy subjects received 100 mg of acotiamide or placebo three times a day for 7 days separated by a 28-day washout period in a randomized, double-blind, placebo-controlled crossover study. On the seventh day of treatment, esophagogastric junction pressure, integrated relaxation pressure, and primary peristalsis were assessed using high-resolution manometry.

Results

Esophagogastric junction pressure was significantly higher in the acotiamide group (median 28.2 mmHg) than in the placebo group (24.0 mmHg), whereas no significant differences were observed in integrated relaxation pressure, the distal contractile integral, or contraction patterns between the two groups. Among 13 healthy subjects with peristaltic abnormalities, no significant differences were noted in integrated relaxation pressure or the distal contractile integral between the acotiamide and placebo groups; however, the esophagogastric junction pressure (acotiamide 23.4 mmHg; placebo 21.7 mmHg) significantly increased, the contraction pattern significantly improved, and the frequency of esophageal peristaltic abnormalities significantly decreased in the acotiamide group.

Conclusion

Acotiamide improves the peristaltic pattern in patients with peristaltic abnormalities by decreasing weak peristalsis with a small break.

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Evaluation of bilateral central retinal artery occlusions with optical coherence tomography-based microangiography: a case report

We report a case of bilateral central retinal artery occlusion and the evaluation of retinal vasculature and capillaries by using optical coherence tomography angiography.

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A randomized adaptive phase II/III study of buparlisib, a pan-Class I PI3K inhibitor, combined with paclitaxel for the treatment of HER2- advanced breast cancer (BELLE-4)

In the randomized, adaptive phase II/III BELLE-4 study, addition of buparlisib to paclitaxel did not improve progression free survival compared with paclitaxel alone in women with human epidermal growth factor receptor 2-negative locally advanced or metastatic breast cancer at adaptive interim analysis. The trial was stopped for futility at the end of phase II, and phase III was not initiated.

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Management of Chronic Lymphocytic Leukemia (CLL) in the Elderly: A Position Paper from an International Society of Geriatric Oncology (SIOG) Task Force

CLL mostly affects the elderly. Optimum management requires evaluation of disease characteristics, comorbidities, and geriatric impairments. Based on these assessments, elderly patients can be divided into those fit for standard intensive therapies, those in whom such therapies need to be adapted, and those best suited to supportive care. Novel agents greatly increase available options.

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The role of staging and adjuvant chemotherapy in stage I Malignant ovarian germ cell tumors (MOGTs): the MITO-9 study

Patients affected by stage I dysgerminoma and immature teratoma can be spare the risk of acute and late morbility and mortality associated with adjuvant chemotherapy. Chemotherapy should be reserved to relapse with high cure rate. Incomplete peritoneal surgical staging is associated with recurrence and surgical staging should be performed. Yolk sac histology worsens the prognosis.

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Mismatch-repair deficient metastatic pancreatic ductal adenocarcinoma with a germline PALB2 mutation: unusual genetics, unusual clinical course

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Vandetanib in Pretreated Patients with Advanced Non-Small Cell Lung Cancer Harboring RET Rearrangement: A Phase II Clinical Trial

We performed a single-arm, phase II trial of vandetanib in 18 adult patients with advanced NSCLC with RET rearrangement. The efficacy outcomes show an objective response rate of 18%, a disease control rate of 65%, a progression-free survival of 4.5 months, and an overall survival of 11.6 months during 14 months of follow-up indicating that vandetanib is moderately active in this population.

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Hepatitis B virus reactivation in patients with solid tumors receiving systemic anticancer treatment

Most drugs used for the treatment of solid tumors can induce hepatitis B reactivation in HBs antigen-positive patients. The risk is well documented for conventional chemotherapy agents, everolimus and imatinib. HBV screening can be recommended before systemic treatment initiation. In patients with positive HBs antigen, preemptive treatment should be given, using lamivudine.

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Molecular signature of intermediate risk prostate cancer

A new 30-gene signature has been described that separates prostate cancers of Gleason score {less than or equal to} 6 from those of Gleason score {greater than or equal to} 8. It provides independent prognostic information for prostate cancers of intermediate risk (Gleason score of 7) which has the potential to stratify these patients into different risk groups.

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Chimeric antigen receptors targeting CD70

Purpose:CD70 expression in normal tissues is restricted to activated lymphoid tissues. Targeting CD70 on CD70-expressing tumors could mediate "on-target, off-tumor" toxicity. This study was to evaluate the feasibility and safety of using anti-human CD70 CARs to treat cancer patients whose tumors express CD70. Experimental Design:Seven anti-human CD70 CARs with binding moieties from human CD27 combined with CD3-zeta and different co-stimulatory domains from CD28 and/or 41BB were constructed. In vitro functionality of these receptors was compared and in vivo treatment efficacy was evaluated in a xenograft mouse model. A homologous, all murine anti-CD70 CAR model was also used to assess treatment-related toxicities. Results:The CAR consisting of the extracellular binding portion of CD27 fused with 41BB and CD3-zeta (trCD27-41BB-zeta) conferred the highest IFN-gamma production against CD70-expressing tumors in vitro, and NSG mice bearing established CD70-expressing human tumors could be cured by human lymphocytes transduced with this CAR. In the murine CD27-CD3-zeta CAR model, significant reduction of established tumors and prolonged survival were achieved using CAR-transduced splenocytes in a dose-dependent manner. Host pre-irradiation enhanced treatment efficacy but increased treatment-related toxicities such as transient weight loss and hematopoetic suppression. The treatment did not appear to block adaptive host immune responses. Conclusions:Pre-clinical testing supports the safety and efficacy of a CD27-containing CAR targeting CD70-expressing tumors.

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Microsurgical resection of tumors of the lateral and third ventricles: operative corridors for difficult-to-reach lesions

Abstract

Tumors of the lateral and third ventricles are cradled on all sides by vital vascular and eloquent neural structures. Microsurgical resection, which always requires attentive planning, plays a critical role in the contemporary management of these lesions. This article provides an overview of the open microsurgical approaches to the region highlighting key clinical perspectives.

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Outcomes of surgery for lung cancer in patients with atrial fibrillation as a preoperative comorbidity: a decade of experience at a single institution in Japan

Abstract

Purpose

To investigate the surgical outcomes of surgery for non-small cell lung cancer (NSCLC) in patients with atrial fibrillation (AF) as a preoperative comorbidity.

Methods

Among 805 patients who underwent surgery for NSCLC, 27 (3.4%) had a history of AF. We analyzed the perioperative and long-term outcomes of these 27 patients.

Results

Fourteen patients (52%) had chronic AF and 13 (48%) had paroxysmal AF; being high rates of a comorbid illness. Nineteen patients (70%) underwent lobectomy, and 8 (30%) underwent sublobar resection. Ten patients (37%) received perioperative heparinization. There was no mortality. Other non-AF postoperative complications developed in 8 patients (30%), this incidence being higher than among the patients without AF (16%, 127 out of 778, p = 0.09). A thromboembolic event occurred in one patient (4%). With respect to the long-term outcomes, the 5-year overall survival and disease-free survival rates among the patients with AF were 70.3 and 60.8%, respectively, which were similar to those in the patients without AF (79.8 and 72.6%, p = 0.30 and 0.31).

Conclusions

Lung cancer surgery in patients with AF is safe and provides favorable long-term outcomes; however, thoracic surgeons should monitor these patients carefully for postoperative thromboembolic events.

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"Asian Pac J Cancer Prev"[jour]; +51 new citations

51 new pubmed citations were retrieved for your search. Click on the search hyperlink below to display the complete search results:

"Asian Pac J Cancer Prev"[jour]

These pubmed results were generated on 2016/11/01

PubMed comprises more than 24 million citations for biomedical literature from MEDLINE, life science journals, and online books. Citations may include links to full-text content from PubMed Central and publisher web sites.

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Prognostic Factors for Locoregional Recurrence in Patients with Thoracic Esophageal Squamous Cell Carcinoma Treated with Radical Two-Field Lymph Node Dissection: Results from Long-Term Follow-Up

Abstract

Objective

To aim of this study was to determine the clinical and biological prognostic factors for locoregional recurrence (LRR) in patients with thoracic esophageal squamous cell carcinoma (ESCC) undergoing radical two-field lymph node dissection (2FLD).

Methods

A total of 462 patients diagnosed with thoracic ESCC underwent radical esophagectomy between March 2001 and May 2010 at Sun Yat-Sen University Cancer Center. Clinical characteristics, CD44 expression, and tumor-infiltrating lymphocyte (TIL) levels were evaluated in 198 patients who underwent R0 dissection with long-term follow-up. Partial Cox regression analysis with leave-one-out cross-validation was performed to validate the selected risk factors.

Results

With a median follow-up of 54 months, the 5-year local failure-free survival (LFFS) rate of 198 patients was 62.5%. Multivariate analysis revealed that T stage (p = 0.043), pathological positive tumor above the carina (p = 0.000), CD44 expression level (p = 0.045) and TIL level (p = 0.007) were prognostic factors for LFFS, while the Cox model with risk scores had an area under the curve value of 83.6% for the prediction of 5-year LFFS. The best cut-off value (sum score = 11.19) was used to determine the high- and low-risk groups, with patients at high risk having a significantly shorter 5-year LFFS than patients at low risk (p = 0.000). The LRR pattern revealed significantly high incidences of recurrent disease at the supraclavicular and cervical sites, mediastinum (above the carina), and anastomosis.

Conclusions

Our predictive model was able to distinguish between patients at high risk for LRR and patients at low risk for LRR. LRR primarily involved the upper thorax and this area must be considered in future study designs for radical trimodality treatment.

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Hydrogen-rich water achieves cytoprotection from oxidative stress injury in human gingival fibroblasts in culture or 3D-tissue equivalents, and wound-healing promotion, together with ROS-scavenging and relief from glutathione diminishment

Abstract

The aim of the present study is to investigate protective effects of hydrogen-rich water (HW) against reactive oxygen species (ROS)-induced cellular harmful events and cell death in human gingival fibroblasts (HGF) and three-dimensional (3D-) gingival tissue equivalents. HW was prepared with a magnesium stick in 600-mL double distilled water (DDW) overnight. Dissolved hydrogen was about 1460 ± 50 μg/L versus approximately 1600 μg/L for the saturated hydrogen. Under cell-free conditions, HW, dose-dependently, significantly scavenged peroxyl radicals (ROO·) derived from 2,2′-azobis(2-amidinopropane) dihydrochloride (AAPH). Extract from HW-treated HGF cells scavenged ROO· more markedly than that from DDW-treated cells, suggesting that HW can increase the intracellular antioxidant capacity. Hydrogen peroxide dose-dependently increased the intracellular ROS generation, which was significantly repressed by HW, both in the cytoplasm and nuclei. LIVE/DEAD staining and our original cell viability dye-extraction assay showed that HW significantly protected HGF cells from hydrogen peroxide-induced cell death. Hydrogen peroxide also diminished the contents of intracellular glutathione, which were appreciably relieved by HW-pretreatment. Additionally, HW noticeably prevented cumene hydroperoxide-induced generation of cellular ROS in epidermis parts of 3D-gingival equivalents. The in vitro scratch assay showed that HW was able to diminish physical injury-induced ROS generation and promote wound healing in HGF cell monolayer sheets. In summary, HW was able to increase intracellular antioxidative capacity and to protect cells and tissue from oxidative damage. Thus, HW might be used for prevention/treatment of oxidative stress-related diseases.

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"Anticancer Res"[jour]; +75 new citations

75 new pubmed citations were retrieved for your search. Click on the search hyperlink below to display the complete search results:

"Anticancer Res"[jour]

These pubmed results were generated on 2016/11/01

PubMed comprises more than 24 million citations for biomedical literature from MEDLINE, life science journals, and online books. Citations may include links to full-text content from PubMed Central and publisher web sites.

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