Discovery and Characterization of Novel Nonsubstrate and Substrate NAMPT Inhibitors

Cancer cells are highly reliant on NAD⁺-dependent processes, including glucose metabolism, calcium signaling, DNA repair, and regulation of gene expression. Nicotinamide phosphoribosyltransferase (NAMPT), the rate-limiting enzyme for NAD⁺ salvage from nicotinamide, has been investigated as a target for anticancer therapy. Known NAMPT inhibitors with potent cell activity are composed of a nitrogen-containing aromatic group, which is phosphoribosylated by the enzyme. Here, we identified two novel types of NAM-competitive NAMPT inhibitors, only one of which contains a modifiable, aromatic nitrogen that could be a phosphoribosyl acceptor. Both types of compound effectively deplete cellular NAD⁺, and subsequently ATP, and produce cell death when NAMPT is inhibited in cultured cells for more than 48 hours. Careful characterization of the kinetics of NAMPT inhibition in vivo allowed us to optimize dosing to produce sufficient NAD⁺ depletion over time that resulted in efficacy in an HCT116 xenograft model. Our data demonstrate that direct phosphoribosylation of competitive inhibitors by the NAMPT enzyme is not required for potent in vitro cellular activity or in vivo antitumor efficacy. Mol Cancer Ther; 16(7); 1236–45. ©2017 AACR.

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A Novel Galectin-1 Inhibitor Discovered through One-Bead Two-Compound Library Potentiates the Antitumor Effects of Paclitaxel in vivo

Through the one-bead two-compound (OB2C) ultra–high-throughput screening method, we discovered a new small-molecule compound LLS2 that can kill a variety of cancer cells. Pull-down assay and LC/MS-MS indicated that galectin-1 is the target protein of LLS2. Galectin-1 is known to be involved in the regulation of proliferation, apoptosis, cell cycle, and angiogenesis. Binding of LLS2 to galectin-1 decreased membrane-associated H-Ras and K-Ras and contributed to the suppression of pErk pathway. Importantly, combination of LLS2 with paclitaxel (a very important clinical chemotherapeutic agent) was found to exhibit synergistic activity against several human cancer cell lines (ovarian cancer, pancreatic cancer, and breast cancer cells) in vitro. Furthermore, in vivo therapeutic study indicated that combination treatment with paclitaxel and LLS2 significantly inhibits the growth of ovarian cancer xenografts in athymic mice. Our results presented here indicate that the OB2C combinatorial technology is a highly efficient drug screening platform, and LLS2 discovered through this method can be further optimized for anticancer drug development. Mol Cancer Ther; 16(7); 1212–23. ©2017 AACR.

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New Hybrid Type Squaramide Fused Amino Alcohol Organocatalysts for Enantioselective Diels-Alder Reaction of 3- Hydroxy-2-Pyridones with Maleimides

The hybrid type squaramide fused amino alcohol (SFAA) containing both Brønsted basic site and hydrogen bonding site in the molecule showed highly catalytic activity as an organocatalyst in the enantioselective Diels-Alder reaction (DA) of 3-hydroxy-2-pyridones with maleimides to afford the chiral endo-4-hydroxy-2-azabicyclo[2.2.2]octanes (4-hydroxy-isoquinuclidines) with excellent chemical yields and enantioselectivities (up to 95%, up to 98% ee). Particularly, the use of 4-brominated 2-pyridones afforded the corresponding chiral 4-hydroxyisoquinuclidines in both excellent chemical yield and enantioselectivity (95%, 98% ee) having an opposite absolute stereochemistry in comparison with the chiral endo-DA adduct from the reactions using common 3-hydroxy-2-pyridones. The obtained DA adducts could be used as synthetic precursors for the several natural products that have a broad spectrum of fascinating biologically activities.

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Delayed symptomatic haemorrhage from the remnants of a thalamic arteriovenous malformation after previous angiographic cure with radiotherapy

Abstract

In 1995 a 16-year old girl was diagnosed with a large left thalamic AVM that was considered unsuitable for microsurgical resection and was treated with radiotherapy twice, which led to angiographic cure. She re-presented 19 years after initial treatment with a symptomatic acute thalamic haemorrhage. Her digital subtraction angiography was negative for arterio-venous shunting. MRI/MRA showed cystic change with adjacent contrast enhancement in the region of the previously irradiated arteriovenous malformation. The patient underwent an interhemispheric transcallosal resection of the left thalamic haemorrhagic lesion via a contralateral craniotomy. Intra-operatively there was a cystic cavity filled with blood products in association with thrombosed, calcified vessels as well as actively filling vessels. Histologically there were aggregated abnormal blood vessels with a dilated lumen and surrounded by brain parenchyma. Some of the vessel walls were thickened with fibrosis and some were arterialised with presence of elastin fibres. Potential mechanisms for the delayed haemorrhage are discussed.

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Rhazes ( ad 865–925) and his early contributions to the field of pediatrics

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Lectin, Galactoside-Binding Soluble 3 Binding Protein Promotes 17-N-Allylamino-17-demethoxygeldanamycin Resistance through PI3K/Akt Pathway in Lung Cancer Cell Line

Heat shock protein 90 (HSP90) stabilizing oncoproteins has been an attractive target in cancer therapy. 17-N-Allylamino-17-demethoxygeldanamycin (17-AAG), an HSP90 inhibitor, was tested in phase II/III clinical trials, but due to lack of efficacy, clinical evaluation of 17-AAG has achieved limited success, which led to resistance to 17-AAG. However, the mechanism of 17-AAG resistance has not clearly been identified. Here, we identified LGALS3BP (Lectin, galactoside-binding soluble 3 binding protein), a secretory glycoprotein, as a 17-AAG resistance factor. In the clinical reports, it was suggested that LGALS3BP was associated with low survival rate, development of cancer progression, and enhancement of metastasis in human cancers. As we confirmed that the LGALS3BP level was increased in 17-AAG–resistant cells (H1299_17R) compared with that of the parental cell line (H1299_17P), knockdown of LGALS3BP expression increased sensitivity to 17-AAG in H1299_17R cells. Overexpression of LGALS3BP also augmented PI3K/Akt and ERK signaling pathways. Furthermore, we determined that the PI3K/Akt signaling pathway was involved in LGALS3BP-mediated 17-AAG resistance in vitro and in vivo, demonstrating that LGALS3BP mediates the resistance against 17-AAG through PI3K/Akt activation rather than ERK activation. These findings suggest that LGALS3BP would be a target to overcome resistance to 17-AAG in lung cancer. For example, the combination of 17-AAG and PI3K/Akt inhibitor would effectively suppress acquired resistance to 17-AAG. In conclusion, targeting of LGALS3BP-mediated–specific survival signaling pathway in resistant cells may provide a novel therapeutic model for the cancer therapy. Mol Cancer Ther; 16(7); 1355–65. ©2017 AACR.

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Cotargeting mTORC and EGFR Signaling as a Therapeutic Strategy in HNSCC

Head and neck squamous cell carcinomas (HNSCC) are frequently altered along the PI3K/AKT/mTORC signaling axis. Despite excellent preclinical data, the use of compounds targeting this pathway as monotherapy has been underwhelming in initial clinical trials, and identification of predictive biomarkers remains challenging. To investigate mTORC-specific inhibition, we tested catalytic mTORC (AZD8055) and PI3K/mTORC (NVP-BEZ-235) inhibitors ± cetuximab in a panel of HNSCC cell lines and patient-derived xenografts (PDX). Cell lines were assayed for response to all agents and siRNA knockdown of targets by multiple approaches. All cell lines showed similar response to both drug and siRNA inhibition of both PI3K and mTORC pathways, with anti-EGFR combination producing modest additive effect. Five PDX models that presented PIK3CA mutation or intrinsic cetuximab resistance were treated with a combination of cetuximab and AZD8055. In vivo single-agent mTORC inhibition inhibited growth of one PIK3CA-mutant cancer, but had little effect on any PIK3CA^WT or a second PIK3CA-mutant model. In all models, the combination therapy showed greater growth delay than monotherapy. The uniform ability of PI3K and mTORC inhibition to suppress the growth of HNSCC cells highlights the pathway's role in driving proliferation. Although single-agent therapy was largely ineffective in vivo, improved response of combination treatment in an array of PDXs suggests the potential for adding a catalytic mTORC inhibitor to cetuximab therapy. Overall, these results add to a growing body of evidence, suggesting that approaches that attempt to match biomarkers to the optimal therapy in HNSCC remain complex and challenging. Mol Cancer Ther; 16(7); 1257–68. ©2017 AACR.

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Ref-1/APE1 as a Transcriptional Regulator and Novel Therapeutic Target in Pediatric T-cell Leukemia

The increasing characterization of childhood acute lymphoblastic leukemia (ALL) has led to the identification of multiple molecular targets but has yet to translate into more effective targeted therapies, particularly for high-risk, relapsed T-cell ALL. Searching for master regulators controlling multiple signaling pathways in T-ALL, we investigated the multifunctional protein redox factor-1 (Ref-1/APE1), which acts as a signaling "node" by exerting redox regulatory control of transcription factors important in leukemia. Leukemia patients' transcriptome databases showed increased expression in T-ALL of Ref-1 and other genes of the Ref-1/SET interactome. Validation studies demonstrated that Ref-1 is expressed in high-risk leukemia T cells, including in patient biopsies. Ref-1 redox function is active in leukemia T cells, regulating the Ref-1 target NF-B, and inhibited by the redox-selective Ref-1 inhibitor E3330. Ref-1 expression is not regulated by Notch signaling, but is upregulated by glucocorticoid treatment. E3330 disrupted Ref-1 redox activity in functional studies and resulted in marked inhibition of leukemia cell viability, including T-ALL lines representing different genotypes and risk groups. Potent leukemia cell inhibition was seen in primary cells from ALL patients, relapsed and glucocorticoid-resistant T-ALL cells, and cells from a murine model of Notch-induced leukemia. Ref-1 redox inhibition triggered leukemia cell apoptosis and downregulation of survival genes regulated by Ref-1 targets. For the first time, this work identifies Ref-1 as a novel molecular effector in T-ALL and demonstrates that Ref-1 redox inhibition results in potent inhibition of leukemia T cells, including relapsed T-ALL. These data also support E3330 as a specific Ref-1 small-molecule inhibitor for leukemia. Mol Cancer Ther; 16(7); 1401–11. ©2017 AACR.

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MET Tyrosine Kinase Inhibition Enhances the Antitumor Efficacy of an HGF Antibody

Receptor tyrosine kinase therapies have proven to be efficacious in specific cancer patient populations; however, a significant limitation of tyrosine kinase inhibitor (TKI) treatment is the emergence of resistance mechanisms leading to a transient, partial, or complete lack of response. Combination therapies using agents with synergistic activity have potential to improve response and reduce acquired resistance. Chemoreagent or TKI treatment can lead to increased expression of hepatocyte growth factor (HGF) and/or MET, and this effect correlates with increased metastasis and poor prognosis. Despite MET's role in resistance and cancer biology, MET TKI monotherapy has yielded disappointing clinical responses. In this study, we describe the biological activity of a selective, oral MET TKI with slow off-rate and its synergistic antitumor effects when combined with an anti-HGF antibody. We evaluated the combined action of simultaneously neutralizing HGF ligand and inhibiting MET kinase activity in two cancer xenograft models that exhibit autocrine HGF/MET activation. The combination therapy results in additive antitumor activity in KP4 pancreatic tumors and synergistic activity in U-87MG glioblastoma tumors. Pharmacodynamic characterization of biomarkers that correlate with combination synergy reveal that monotherapies induce an increase in the total MET protein, whereas combination therapy significantly reduces total MET protein levels and phosphorylation of 4E-BP1. These results hold promise that dual targeting of HGF and MET by combining extracellular ligand inhibitors with intracellular MET TKIs could be an effective intervention strategy for cancer patients who have acquired resistance that is dependent on total MET protein. Mol Cancer Ther; 16(7); 1269–78. ©2017 AACR.

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Targeting Insulin Receptor in Breast Cancer Using Small Engineered Protein Scaffolds

Insulin receptor (InsR) and the type I insulin-like growth factor (IGF1R) are homologous receptors necessary for signal transduction by their cognate ligands insulin, IGF-I and IGF-II. IGF1R mAbs, intended to inhibit malignant phenotypic signaling, failed to show benefit in patients with endocrine-resistant tumors in phase III clinical trials. Our previous work showed that in tamoxifen-resistant cells, IGF1R expression was lacking, but InsR inhibition effectively blocked growth. In endocrine-sensitive breast cancer cells, insulin was not growth stimulatory, likely due to the presence of hybrid InsR/IGF1R, which has high affinity for IGF-I, but not insulin. Combination inhibition of InsR and IGF1R showed complete suppression of the system in endocrine-sensitive breast cancer cells. To develop InsR-binding agents, we employed a small protein scaffold, T7 phage gene 2 protein (Gp2) with the long-term goal of creating effective InsR inhibitors and diagnostics. Using yeast display and directed evolution, we identified three Gp2 variants (Gp2 #1, #5, and #10) with low nanomolar affinity and specific binding to cell surface InsR. These Gp2 variants inhibited insulin-mediated monolayer proliferation in both endocrine-sensitive and resistant breast cancer, but did not downregulate InsR expression. Gp2 #5 and Gp2 #10 disrupted InsR function by inhibiting ligand-induced receptor activation. In contrast, Gp2 #1 did not block InsR phosphorylation. Notably, Gp2 #1 binding was enhanced by pretreatment of cells with insulin, suggesting a unique receptor-ligand–binding mode. These Gp2 variants are the first nonimmunoglobulin protein scaffolds to target insulin receptor and present compelling opportunity for modulation of InsR signaling. Mol Cancer Ther; 16(7); 1324–34. ©2017 AACR.

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Nanoformulation of Olaparib Amplifies PARP Inhibition and Sensitizes PTEN/TP53-Deficient Prostate Cancer to Radiation

The use of PARP inhibitors in combination with radiotherapy is a promising strategy to locally enhance DNA damage in tumors. Here we show that radiation-resistant cells and tumors derived from a Pten/Trp53-deficient mouse model of advanced prostate cancer are rendered radiation sensitive following treatment with NanoOlaparib, a lipid-based injectable nanoformulation of olaparib. This enhancement in radiosensitivity is accompanied by radiation dose-dependent changes in -H2AX expression and is specific to NanoOlaparib alone. In animals, twice-weekly intravenous administration of NanoOlaparib results in significant tumor growth inhibition, whereas previous studies of oral olaparib as monotherapy have shown no therapeutic efficacy. When NanoOlaparib is administered prior to radiation, a single dose of radiation is sufficient to triple the median mouse survival time compared to radiation only controls. Half of mice treated with NanoOlaparib + radiation achieved a complete response over the 13-week study duration. Using ferumoxytol as a surrogate nanoparticle, MRI studies revealed that NanoOlaparib enhances the intratumoral accumulation of systemically administered nanoparticles. NanoOlaparib-treated tumors showed up to 19-fold higher nanoparticle accumulation compared to untreated and radiation-only controls, suggesting that the in vivo efficacy of NanoOlaparib may be potentiated by its ability to enhance its own accumulation. Together, these data suggest that NanoOlaparib may be a promising new strategy for enhancing the radiosensitivity of radiation-resistant tumors lacking BRCA mutations, such as those with PTEN and TP53 deletions. Mol Cancer Ther; 16(7); 1279–89. ©2017 AACR.

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Cotargeting mTORC and EGFR Signaling as a Therapeutic Strategy in HNSCC

Head and neck squamous cell carcinomas (HNSCC) are frequently altered along the PI3K/AKT/mTORC signaling axis. Despite excellent preclinical data, the use of compounds targeting this pathway as monotherapy has been underwhelming in initial clinical trials, and identification of predictive biomarkers remains challenging. To investigate mTORC-specific inhibition, we tested catalytic mTORC (AZD8055) and PI3K/mTORC (NVP-BEZ-235) inhibitors ± cetuximab in a panel of HNSCC cell lines and patient-derived xenografts (PDX). Cell lines were assayed for response to all agents and siRNA knockdown of targets by multiple approaches. All cell lines showed similar response to both drug and siRNA inhibition of both PI3K and mTORC pathways, with anti-EGFR combination producing modest additive effect. Five PDX models that presented PIK3CA mutation or intrinsic cetuximab resistance were treated with a combination of cetuximab and AZD8055. In vivo single-agent mTORC inhibition inhibited growth of one PIK3CA-mutant cancer, but had little effect on any PIK3CA^WT or a second PIK3CA-mutant model. In all models, the combination therapy showed greater growth delay than monotherapy. The uniform ability of PI3K and mTORC inhibition to suppress the growth of HNSCC cells highlights the pathway's role in driving proliferation. Although single-agent therapy was largely ineffective in vivo, improved response of combination treatment in an array of PDXs suggests the potential for adding a catalytic mTORC inhibitor to cetuximab therapy. Overall, these results add to a growing body of evidence, suggesting that approaches that attempt to match biomarkers to the optimal therapy in HNSCC remain complex and challenging. Mol Cancer Ther; 16(7); 1257–68. ©2017 AACR.

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Ref-1/APE1 as a Transcriptional Regulator and Novel Therapeutic Target in Pediatric T-cell Leukemia

The increasing characterization of childhood acute lymphoblastic leukemia (ALL) has led to the identification of multiple molecular targets but has yet to translate into more effective targeted therapies, particularly for high-risk, relapsed T-cell ALL. Searching for master regulators controlling multiple signaling pathways in T-ALL, we investigated the multifunctional protein redox factor-1 (Ref-1/APE1), which acts as a signaling "node" by exerting redox regulatory control of transcription factors important in leukemia. Leukemia patients' transcriptome databases showed increased expression in T-ALL of Ref-1 and other genes of the Ref-1/SET interactome. Validation studies demonstrated that Ref-1 is expressed in high-risk leukemia T cells, including in patient biopsies. Ref-1 redox function is active in leukemia T cells, regulating the Ref-1 target NF-B, and inhibited by the redox-selective Ref-1 inhibitor E3330. Ref-1 expression is not regulated by Notch signaling, but is upregulated by glucocorticoid treatment. E3330 disrupted Ref-1 redox activity in functional studies and resulted in marked inhibition of leukemia cell viability, including T-ALL lines representing different genotypes and risk groups. Potent leukemia cell inhibition was seen in primary cells from ALL patients, relapsed and glucocorticoid-resistant T-ALL cells, and cells from a murine model of Notch-induced leukemia. Ref-1 redox inhibition triggered leukemia cell apoptosis and downregulation of survival genes regulated by Ref-1 targets. For the first time, this work identifies Ref-1 as a novel molecular effector in T-ALL and demonstrates that Ref-1 redox inhibition results in potent inhibition of leukemia T cells, including relapsed T-ALL. These data also support E3330 as a specific Ref-1 small-molecule inhibitor for leukemia. Mol Cancer Ther; 16(7); 1401–11. ©2017 AACR.

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MET Tyrosine Kinase Inhibition Enhances the Antitumor Efficacy of an HGF Antibody

Receptor tyrosine kinase therapies have proven to be efficacious in specific cancer patient populations; however, a significant limitation of tyrosine kinase inhibitor (TKI) treatment is the emergence of resistance mechanisms leading to a transient, partial, or complete lack of response. Combination therapies using agents with synergistic activity have potential to improve response and reduce acquired resistance. Chemoreagent or TKI treatment can lead to increased expression of hepatocyte growth factor (HGF) and/or MET, and this effect correlates with increased metastasis and poor prognosis. Despite MET's role in resistance and cancer biology, MET TKI monotherapy has yielded disappointing clinical responses. In this study, we describe the biological activity of a selective, oral MET TKI with slow off-rate and its synergistic antitumor effects when combined with an anti-HGF antibody. We evaluated the combined action of simultaneously neutralizing HGF ligand and inhibiting MET kinase activity in two cancer xenograft models that exhibit autocrine HGF/MET activation. The combination therapy results in additive antitumor activity in KP4 pancreatic tumors and synergistic activity in U-87MG glioblastoma tumors. Pharmacodynamic characterization of biomarkers that correlate with combination synergy reveal that monotherapies induce an increase in the total MET protein, whereas combination therapy significantly reduces total MET protein levels and phosphorylation of 4E-BP1. These results hold promise that dual targeting of HGF and MET by combining extracellular ligand inhibitors with intracellular MET TKIs could be an effective intervention strategy for cancer patients who have acquired resistance that is dependent on total MET protein. Mol Cancer Ther; 16(7); 1269–78. ©2017 AACR.

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ONC201 Demonstrates Antitumor Effects in Both Triple-Negative and Non-Triple-Negative Breast Cancers through TRAIL-Dependent and TRAIL-Independent Mechanisms

Breast cancer is a major cause of cancer-related death. TNF-related apoptosis-inducing ligand (TRAIL) has been of interest as a cancer therapeutic, but only a subset of triple-negative breast cancers (TNBC) is sensitive to TRAIL. The small-molecule ONC201 induces expression of TRAIL and its receptor DR5. ONC201 has entered clinical trials in advanced cancers. Here, we show that ONC201 is efficacious against both TNBC and non-TNBC cells (n = 13). A subset of TNBC and non-TNBC cells succumbs to ONC201-induced cell death. In 2 of 8 TNBC cell lines, ONC201 treatment induces caspase-8 cleavage and cell death that is blocked by TRAIL-neutralizing antibody RIK2. The proapoptotic effect of ONC201 translates to in vivo efficacy in the MDA-MB-468 xenograft model. In most TNBC lines tested (6/8), ONC201 has an antiproliferative effect but does not induce apoptosis. ONC201 decreases cyclin D1 expression and causes an accumulation of cells in the G₁ phase of the cell cycle. pRb expression is associated with sensitivity to the antiproliferative effects of ONC201, and the compound synergizes with taxanes in less sensitive cells. All non-TNBC cells (n = 5) are growth inhibited following ONC201 treatment, and unlike what has been observed with TRAIL, a subset (n = 2) shows PARP cleavage. In these cells, cell death induced by ONC201 is TRAIL independent. Our data demonstrate that ONC201 has potent antiproliferative and proapoptotic effects in a broad range of breast cancer subtypes, through TRAIL-dependent and TRAIL-independent mechanisms. These findings develop a preclinical rationale for developing ONC201 as a single agent and/or in combination with approved therapies in breast cancer. Mol Cancer Ther; 16(7); 1290–8. ©2017 AACR.

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Genomic and Molecular Screenings Identify Different Mechanisms for Acquired Resistance to MET Inhibitors in Lung Cancer Cells

The development of resistance to tyrosine kinase inhibitors (TKI) limits the long-term efficacy of cancer treatments involving them. We aimed to understand the mechanisms that underlie acquired resistance (AR) to MET inhibitors in lung cancer. EBC1 cells, which have MET amplification and are sensitive to TKIs against MET, were used to generate multiple clones with AR to a MET-TKI. Whole-exome sequencing, RNA sequencing, and global DNA methylation analysis were used to scrutinize the genetic and molecular characteristics of the resistant cells. AR to the MET-TKI involved changes common to all resistant cells, that is, phenotypic modifications, specific changes in gene expression, and reactivation of AKT, ERK, and mTOR. The gene expression, global DNA methylation, and mutational profiles distinguished at least two groups of resistant cells. In one of these, the cells have acquired sensitivity to erlotinib, concomitantly with mutations of the KIRREL, HDAC11, HIATL1, and MAPK1IP1L genes, among others. In the other group, some cells have acquired inactivation of neurofibromatosis type 2 (NF2) concomitantly with strong overexpression of NRG1 and a mutational profile that includes changes in LMLN and TOMM34. Multiple independent and simultaneous strategies lead to AR to the MET-TKIs in lung cancer cells. The acquired sensitivity to erlotinib supports the known crosstalk between MET and the HER family of receptors. For the first time, we show inactivation of NF2 during acquisition of resistance to MET-TKI that may explain the refractoriness to erlotinib in these cells. Mol Cancer Ther; 16(7); 1366–76. ©2017 AACR.

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Nanoformulation of Olaparib Amplifies PARP Inhibition and Sensitizes PTEN/TP53-Deficient Prostate Cancer to Radiation

The use of PARP inhibitors in combination with radiotherapy is a promising strategy to locally enhance DNA damage in tumors. Here we show that radiation-resistant cells and tumors derived from a Pten/Trp53-deficient mouse model of advanced prostate cancer are rendered radiation sensitive following treatment with NanoOlaparib, a lipid-based injectable nanoformulation of olaparib. This enhancement in radiosensitivity is accompanied by radiation dose-dependent changes in -H2AX expression and is specific to NanoOlaparib alone. In animals, twice-weekly intravenous administration of NanoOlaparib results in significant tumor growth inhibition, whereas previous studies of oral olaparib as monotherapy have shown no therapeutic efficacy. When NanoOlaparib is administered prior to radiation, a single dose of radiation is sufficient to triple the median mouse survival time compared to radiation only controls. Half of mice treated with NanoOlaparib + radiation achieved a complete response over the 13-week study duration. Using ferumoxytol as a surrogate nanoparticle, MRI studies revealed that NanoOlaparib enhances the intratumoral accumulation of systemically administered nanoparticles. NanoOlaparib-treated tumors showed up to 19-fold higher nanoparticle accumulation compared to untreated and radiation-only controls, suggesting that the in vivo efficacy of NanoOlaparib may be potentiated by its ability to enhance its own accumulation. Together, these data suggest that NanoOlaparib may be a promising new strategy for enhancing the radiosensitivity of radiation-resistant tumors lacking BRCA mutations, such as those with PTEN and TP53 deletions. Mol Cancer Ther; 16(7); 1279–89. ©2017 AACR.

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Tumor-Associated Macrophages Can Contribute to Antitumor Activity through Fc{gamma}R-Mediated Processing of Antibody-Drug Conjugates

The primary mechanism of antibody–drug conjugates (ADC) is targeted delivery of a cytotoxic payload to tumor cells via cancer-associated membrane receptors. However, the tumor microenvironment likely plays a role in ADC penetration, distribution, and processing and thus impacts the overall antitumor activity. Here, we report on the potential contribution of Fc–FcR interactions between ADCs and tumor-associated macrophages (TAM) to the preclinical antitumor activities of ADCs. In the CD30⁺ L-428 Hodgkin lymphoma model, anti-CD30-vcMMAE and a non-binding control (hIgG-vcMMAE) demonstrated similar antitumor activity as well as similar payload release in the tumors. IHC analysis revealed L-428 tumors contained highly abundant TAMs, which were confirmed to bind ADCs by IHC and flow cytometry. The infiltration of TAMs was further found to correlate with the antitumor activity of the non-binding hIgG-vcMMAE in five additional xenograft models. hIgG1V1-vcMMAE, bearing a mutation in the Fc region which ablates Fc gamma receptor (FcR) binding, lost antitumor activity in three TAM-high xenograft models, suggesting Fc–FcR interactions modulate the TAM-ADC interaction. Our results suggest that TAMs can contribute to ADC processing through FcR interaction in preclinical tumor models and may represent an important additional mechanism for drug release from ADCs. Correlative studies in clinical trials will further shed light on whether TAMs play a role in patients' response to ADC therapies. Mol Cancer Ther; 16(7); 1347–54. ©2017 AACR.

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Synergy between Androgen Receptor Antagonism and Inhibition of mTOR and HER2 in Breast Cancer

The androgen receptor (AR) is widely expressed in breast cancer, and evidence suggests dependence on AR signaling for growth and survival. AR antagonists such as enzalutamide and seviteronel have shown success in preclinical models and clinical trials of prostate cancer and are currently being evaluated in breast cancer. Reciprocal regulation between AR and the HER2/PI3K/mTOR pathway may contribute to resistance to HER2- and mTOR-targeted therapies; thus, dual inhibition of these pathways may synergistically inhibit breast cancer growth. HER2⁺ and triple-negative breast cancer cell lines were treated with AR antagonist plus anti-HER2 mAb trastuzumab or mTOR inhibitor everolimus. Apoptosis, cell proliferation, and drug synergy were measured in vitro. Pathway component genes and proteins were measured by qRT-PCR, Western blot, and reverse phase protein array. In vivo, HER2⁺ breast cancer xenografts were treated with enzalutamide, everolimus, trastuzumab, and combinations of these drugs. AR antagonists inhibited proliferation of both HER2⁺ and TNBC cell lines. Combining AR antagonist and either everolimus or trastuzumab resulted in synergistic inhibition of proliferation. Dihydrotestosterone caused increased phosphorylation of HER2 and/or HER3 that was attenuated by AR inhibition. Everolimus caused an increase in total AR, phosphorylation of HER2 and/or HER3, and these effects were abrogated by enzalutamide. Growth of trastuzumab-resistant HER2⁺ xenograft tumors was inhibited by enzalutamide, and combining enzalutamide with everolimus decreased tumor viability more than either single agent. AR antagonists synergize with FDA-approved breast cancer therapies such as everolimus and trastuzumab through distinct mechanisms. Treatment combinations are effective in trastuzumab-resistant HER2⁺ breast cancer cells in vivo. Mol Cancer Ther; 16(7); 1389–400. ©2017 AACR.

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Genomic and Molecular Screenings Identify Different Mechanisms for Acquired Resistance to MET Inhibitors in Lung Cancer Cells

The development of resistance to tyrosine kinase inhibitors (TKI) limits the long-term efficacy of cancer treatments involving them. We aimed to understand the mechanisms that underlie acquired resistance (AR) to MET inhibitors in lung cancer. EBC1 cells, which have MET amplification and are sensitive to TKIs against MET, were used to generate multiple clones with AR to a MET-TKI. Whole-exome sequencing, RNA sequencing, and global DNA methylation analysis were used to scrutinize the genetic and molecular characteristics of the resistant cells. AR to the MET-TKI involved changes common to all resistant cells, that is, phenotypic modifications, specific changes in gene expression, and reactivation of AKT, ERK, and mTOR. The gene expression, global DNA methylation, and mutational profiles distinguished at least two groups of resistant cells. In one of these, the cells have acquired sensitivity to erlotinib, concomitantly with mutations of the KIRREL, HDAC11, HIATL1, and MAPK1IP1L genes, among others. In the other group, some cells have acquired inactivation of neurofibromatosis type 2 (NF2) concomitantly with strong overexpression of NRG1 and a mutational profile that includes changes in LMLN and TOMM34. Multiple independent and simultaneous strategies lead to AR to the MET-TKIs in lung cancer cells. The acquired sensitivity to erlotinib supports the known crosstalk between MET and the HER family of receptors. For the first time, we show inactivation of NF2 during acquisition of resistance to MET-TKI that may explain the refractoriness to erlotinib in these cells. Mol Cancer Ther; 16(7); 1366–76. ©2017 AACR.

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Editorial: the risk of cancer in patients with gastric intestinal metaplasia—Authors’ reply

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Validation of PDE5 as a Chemoprevention Target

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Do Aspirin and Other NSAIDs Confer a Survival Benefit in Men Diagnosed with Prostate Cancer? A Pooled Analysis of NIH-AARP and PLCO Cohorts

Prostate cancer is one of the leading causes of cancer-related death in U.S. men. There is an unmet need to identify modifiable risk factors for prostate cancer survival. Experimental studies have suggested that nonsteroidal anti-inflammatory drugs (NSAIDs) may improve prostate cancer survival through antithrombotic and anti-inflammation mechanisms. Results from previous observational studies have been equivocal, and few have assessed whether an etiologically relevant time window of exposure exists. We sampled incident prostate cancer cases from two large U.S. prospective cohorts, NIH-AARP Diet and Health Study and PLCO Cancer Screening Trial, to investigate whether pre- and postdiagnostic aspirin and non-aspirin NSAID use were associated with prostate cancer-specific and all-cause mortality. Cox proportional hazards regression models estimated hazard ratios (HRs) and 95% confidence intervals (CIs). Study-specific results were meta-analyzed using fixed-effects models. Pre- and postdiagnostic aspirin or non-aspirin NSAID use were not statistically significantly associated with prostate cancer–specific mortality. However, occasional (less than daily) and daily aspirin users five years or more before prostate cancer diagnosis had 18% (HR = 0.82; 95% CI = 0.75–0.90) and 15% (HR = 0.85; 95% CI = 0.77–0.94) reduced all-cause mortality versus nonusers. Similarly, postdiagnostic occasional and daily aspirin use were associated with 17% (HR = 0.83; 95% CI=0.72–0.95) and 25% (HR = 0.75; 95% CI = 0.66–0.86) reduced all-cause mortality, independent of prediagnostic aspirin use. This study suggests that aspirin or non-aspirin NSAIDs are not associated with prostate cancer survival. However, aspirin use both before and after prostate cancer diagnosis was associated with longer overall survival, highlighting the importance of comorbidity prevention among prostate cancer survivors. Cancer Prev Res; 10(7); 410–20. ©2017 AACR.

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Sildenafil Suppresses Inflammation-Driven Colorectal Cancer in Mice

Intestinal cyclic guanosine monophosphate (cGMP) signaling regulates epithelial homeostasis and has been implicated in the suppression of colitis and colon cancer. In this study, we investigated the cGMP-elevating ability of the phosphodiesterase-5 (PDE5) inhibitor sildenafil to prevent disease in the azoxymethane/dextran sulfate sodium (AOM/DSS) inflammation-driven colorectal cancer model. Treatment of mice with sildenafil activated cGMP signaling in the colon mucosa and protected against dextran-sulfate sodium (DSS)-induced barrier dysfunction. In mice treated with AOM/DSS, oral administration of sildenafil throughout the disease course reduced polyp multiplicity by 50% compared with untreated controls. Polyps that did form in sildenafil treated mice were less proliferative and more differentiated compared with polyps from untreated mice, but apoptosis was unaffected. Polyps in sildenafil treated mice were also less inflamed; they exhibited reduced myeloid-cell infiltration and reduced expression of iNOS, IFN, and IL6 compared with untreated controls. Most of the protection conferred by sildenafil was during the initiation stage of carcinogenesis (38% reduction in multiplicity). Administration of sildenafil during the later promotion stages did not affect multiplicity but had a similar effect on the polyp phenotype, including increased mucus production, and reduced proliferation and inflammation. In summary, the results demonstrate that oral administration of sildenafil suppresses polyp formation and inflammation in mice treated with AOM/DSS. This validation of PDE5 as a target highlights the potential therapeutic value of PDE5 inhibitors for the prevention of colitis-driven colon cancer in humans. Cancer Prev Res; 10(7); 377–88. ©2017 AACR.

See related editorial by Piazza, p. 373.

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Fusobacterium Nucleatum Subspecies Animalis Influences Proinflammatory Cytokine Expression and Monocyte Activation in Human Colorectal Tumors

Chronic infection and associated inflammation have long been suspected to promote human carcinogenesis. Recently, certain gut bacteria, including some in the Fusobacterium genus, have been implicated in playing a role in human colorectal cancer development. However, the Fusobacterium species and subspecies involved and their oncogenic mechanisms remain to be determined. We sought to identify the specific Fusobacterium spp. and ssp. in clinical colorectal cancer specimens by targeted sequencing of Fusobacterium 16S ribosomal RNA gene. Five Fusobacterium spp. were identified in clinical colorectal cancer specimens. Additional analyses confirmed that Fusobacterium nucleatum ssp. animalis was the most prevalent F. nucleatum subspecies in human colorectal cancers. We also assessed inflammatory cytokines in colorectal cancer specimens using immunoassays and found that expression of the cytokines IL17A and TNFα was markedly increased but IL21 decreased in the colorectal tumors. Furthermore, the chemokine (C-C motif) ligand 20 was differentially expressed in colorectal tumors at all stages. In in vitro co-culture assays, F. nucleatum ssp. animalis induced CCL20 protein expression in colorectal cancer cells and monocytes. It also stimulated the monocyte/macrophage activation and migration. Our observations suggested that infection with F. nucleatum ssp. animalis in colorectal tissue could induce inflammatory response and promote colorectal cancer development. Further studies are warranted to determine if F. nucleatum ssp. animalis could be a novel target for colorectal cancer prevention and treatment. Cancer Prev Res; 10(7); 398–409. ©2017 AACR.

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Tamoxifen Acceptance and Adherence among Patients with Ductal Carcinoma In Situ (DCIS) Treated in a Multidisciplinary Setting

Tamoxifen and other endocrine agents have proven benefits for women with ductal carcinoma in situ (DCIS), but low patient acceptance is widely reported. We examined factors associated with tamoxifen acceptance and adherence among DCIS patients who received a recommendation for therapy in a multidisciplinary setting. Using our institutional database, we identified women diagnosed with DCIS, 1998 to 2009, who were offered tamoxifen. We recorded data on demographics, tumor and therapy variables, tamoxifen acceptance, and adherence to therapy for ≥4 years. Univariable and multivariable analyses were conducted using logistic regression to identify factors specific to each group that were related to acceptance and adherence. A total of 555 eligible women identified, of whom 369 were offered tamoxifen; 298 (81%) accepted, among whom 214 (72%) were adherent, 59 of 298 (20%) were nonadherent, and for 25 (8%), adherence was undetermined. After stepwise elimination in adjusted logistic regression models, acceptance of breast radiotherapy was associated with acceptance of tamoxifen [OR, 2.22; 95% confidence interval (CI), 1.26–3.90; P < 0.01], as was a medical oncology consultation (OR, 1.76; 95% CI, 0.99–3.15; P = 0.05). Insured patients were more likely to adhere to tamoxifen (OR, 6.03; 95% CI, 2.60–13.98; P < 0.01). The majority of nonadherent women (n = 38/56, 68%) discontinued the drug during the first year of treatment with 48 (86%) citing adverse effect(s) as the reason. In a multidisciplinary, tertiary care setting, we observed relatively high rates of acceptance and adherence of tamoxifen. Acceptance of tamoxifen and radiotherapy were associated, and adherence was influenced by insurance status.

Key Message: Tamoxifen acceptance and adherence following resection of DCIS of the breast is related to acceptance of radiotherapy and may be improved by confirmation of the recommendation by a medical oncologist. Despite the low cost of tamoxifen, adherence to therapy is significantly impacted by lack of insurance; those who discontinue therapy report adverse effects as a major reason. Cancer Prev Res; 10(7); 389–97. ©2017 AACR.

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Development of a Cancer Risk Prediction Tool for Use in the UK Primary Care and Community Settings

Several multivariable risk prediction models have been developed to asses an individual's risk of developing specific cancers. Such models can be used in a variety of settings for prevention, screening, and guiding investigations and treatments. Models aimed at predicting future disease risk that contains lifestyle factors may be of particular use for targeting health promotion activities at an individual level. This type of cancer risk prediction is not yet available in the UK. We have adopted the approach used by the well-established U.S.-derived "YourCancerRisk" model for use in the UK population, which allow users to quantify their individual risk of developing individual cancers relative to the population average risk. The UK version of "YourCancerRisk" computes 10-year cancer risk estimates for 11 cancers utilizing UK figures for prevalence of risk factors and cancer incidence. Because the prevalence of risk factors and the incidence rates for cancer are different between the U.S. and the UK population, this UK model provides more accurate estimates of risks for a UK population. Using an example of breast cancer and data from UK Biobank cohort, we demonstrate that the individual risk factor estimates are similar for the U.S. and UK populations. Assessment of the performance and validation of the multivariate model predictions based on a binary score confirm the model's applicability. The model can be used to estimate absolute and relative cancer risk for use in Primary Care and community settings and is being used in the community to guide lifestyle change. Cancer Prev Res; 10(7); 421–30. ©2017 AACR.

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Sleepiness in subjects with possible attention-deficit hyperactivity disorder

Publication date: Available online 4 July 2017
Source:Sleep Medicine
Author(s): Tomoyuki Kawada




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Efficacy and safety of almorexant in adult chronic insomnia: a randomized placebo-controlled trial with an active reference

Publication date: August 2017
Source:Sleep Medicine, Volume 36
Author(s): Jed Black, Giora Pillar, Jan Hedner, Olli Polo, Ouali Berkani, Sara Mangialaio, Abdel Hmissi, Gary Zammit, Goran Hajak
Background and objectivesThe orally active dual OX1R and OX2R antagonist, almorexant, targets the orexin system for the treatment of primary insomnia. This clinical trial assessed the effect of almorexant on sleep maintenance and other sleep endpoints, and its safety and tolerability in adults.Patients and methodsProspective, randomized, double-blind, placebo-controlled, active referenced trial in male and female adults aged 18–64 years with chronic, primary insomnia. Patients were randomized 1:1:1:1 to receive placebo, almorexant 100 mg, almorexant 200 mg, or zolpidem 10 mg (active reference) for 16 days. Primary efficacy assessments were objective (polysomnography-measured) and subjective (patient-recorded) wake time after sleep onset (WASO). Further sleep variables were also evaluated.ResultsFrom 709 randomized patients, 707 (mean age 45.4 years; 61.7% female) received treatment and 663 (93.8%) completed the study. A significant decrease versus placebo in median objective WASO was observed with almorexant 200 mg at the start and end of randomized treatment (−26.8 min and −19.5 min, respectively; both p < 0.0001); subjective WASO also decreased over the two-week treatment period (p = 0.0006). Objective and subjective total sleep time (TST) were increased with almorexant 200 mg (p < 0.0001). Almorexant 200 mg significantly reduced objective and subjective latency to persistent sleep and latency to sleep onset at initiation of therapy, and provided longer duration of sleep stages with no suppression of slow-wave sleep. No impaired next-day performance, rebound insomnia, or withdrawal effects were observed. Adverse events were similar with almorexant and placebo.ConclusionAlmorexant reduced time to sleep onset and maintained sleep without residual effects on next-day performance or safety concerns. This study provides further support for the role of the endogenous orexin system in insomnia disorder.ClinicalTrials.gov registrationNCT00608985.



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The Short and Long of Adolescent Sleep: The Unique Impact of Day Length

Publication date: Available online 5 July 2017
Source:Sleep Medicine
Author(s): Kate Bartel, Annette van Maanen, Jamie Cassoff, Oddgeir Friborg, Anne Marie Meijer, Frans Oort, Paul Williamson, Reut Gruber, Bärbel Knäuper, Michael Gradisar
Study ObjectivesVariation in day length is proposed to impact sleep, yet it is unknown whether this is above the influence of behavioural factors. Day length, sleep hygiene and parent-set bedtime were simultaneously explored, to investigate the relative importance of each on adolescents’ sleep.MethodsAn online survey was distributed in 4 countries at varying latitudes/longitudes (Australia, The Netherlands, Canada, Norway).ResultsOverall, 711 (242 male; age M=15.7+1.6, range=12-19yrs) adolescents contributed data. Hierarchical regression analyses showed good sleep hygiene was associated with earlier bedtime, shorter sleep latency and longer sleep (ß=-.34;-.30;.32, p<.05, respectively). Shorter day length predicted later bedtime (ß=.11, p=.009), decreased sleep latency (ß=-.21, p<.001), and total sleep (ß=-.14, p=.001). Longer day length predicted earlier bedtimes (ß=-.11, p=.004) and longer sleep (ß=.10, p=.011).ConclusionsSleep hygiene had the most clinical relevance for improving sleep, thus should be considered when implementing adolescent sleep interventions, particularly as small negative effects of shorter day length may be minimised through sleep hygiene techniques.



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Summertime Blues? A Re-Examination of the Seasonality of Web Searches for Restless Legs and Leg Cramps

Publication date: Available online 4 July 2017
Source:Sleep Medicine
Author(s): Shaun T. O'Keeffe
ObjectiveStudies examining internet searches for restless legs and leg cramps have found a strong seasonal effect with peaks in summer and troughs in winter months. This study used an econometric approach to examine the seasonality of such searches in greater detail.MethodsMonthly relative search volumes for “restless legs” and “leg cramps” from 2004 to March 2017 in the United Kingdom (UK) and Australia were obtained from Google Trends. Average percentage change from winter to summer months was examined. The TRAMO-SEATS procedure from DEMETRA statistical software was used to decompose the data into trend, seasonal and noise components and to determine if a combined seasonality test was positive.ResultsThere were substantial percentage increases in Google Trends searches between winter and summer months regarding restless legs in the UK (median increase 46%) and in Australia (33%) and regarding leg cramps in the UK (95%) and in Australia (50%). However, the combined seasonality test was positive only for leg cramps and not for restless legs in both countries: although there was significant stable seasonality in restless legs searches, this was outweighed by substantial moving seasonality and noise components.ConclusionsExamination of average percentage increase in search volume from winter to summer exaggerates the degree of seasonality. Seasonal effects for restless legs searches are non-significant when the trend and noise components of the data are taken into account, although this does not exclude a clinical significance for the identified stable seasonality. Significant seasonality, with a summer peak, is present for leg cramp searches and suggests an increase in the incidence or severity of leg cramps in summer.



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Periorbital Integrated Potentials: Useful phasic REM sleep markers

Publication date: Available online 4 July 2017
Source:Sleep Medicine
Author(s): Sudhansu Chokroverty, Sushanth Bhat, Mitch Rubinstein




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Flange Gastroenterostomy Results in Reduction in Delayed Gastric Emptying after Standard Pancreatoduodenectomy: A Prospective Cohort Study

Publication date: Available online 4 July 2017
Source:Journal of the American College of Surgeons
Author(s): Adeel S. Khan, Greg Williams, Cheryl Woolsey, Jingxia Liu, Ryan C. Fields, Majella MB. Doyle, William G. Hawkins, Steven M. Strasberg
IntroductionDelayed gastric emptying (DGE) is a common serious problem after pancreatoduodenectomy (PD). Flange gastrojejunostomy (FL-GE) is a previously described technique that creates an internal flange in a hand sewn gastroenterostomy. Results of FL-GE on incidence and severity of DGE after PD are presented.MethodsData were extracted from a prospective database of PD. Standard PD with antrectomy were performed –with Flange Gastroenterostomy (FL-GE) or other techniques (NonFL-GE) at a single institution. International Study Group (ISGPS) definition of DGE was used and DGE severity was graded based on ISGPS grading system and the Modified Accordion Grading System (MAGS).Results215 standard PDs were performed. 68 (32%) were FL-GE and 147 (68%) were NonFL-GE. DGE rates in FL-GE and NonFL-GE were 9% and 23% respectively (p=0.012). The differences in severity of DGE were even more prominent. 29% of DGEs in NonFL-GE group were ISGPS grade C versus 0% in FL-GE. Also, 35% of DGEs in NonFL-GE group were MAGS3 versus 0% in FL-GE. Because of some differences in sex and inflammatory complications between groups, a propensity score analysis was performed creating 57 matched patients in FL-GE and NonFL-GE groups. DGE incidence remained significantly different in the groups: 5% in FL-GE vs. 18% in NonFL-GE; p=0.039).ConclusionIn this cohort study, the Flange technique was associated with a marked reduction in the incidence of DGE after PD.

Teaser

Flange gastroenterostomy is associated with reduced incidence of delayed gastric emptying after standard pancreatoduodenectomy.


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Erratum to “Changing prevalence and treatment outcomes of patients with p16 human papillomavirus related oropharyngeal squamous cell carcinoma in New Zealand” [Br. J. Oral Maxillofac. Surg. 54 (8) (2016) 898–903]

Publication date: Available online 4 July 2017
Source:British Journal of Oral and Maxillofacial Surgery
Author(s): H.J. Kwon, H.D. Brasch, S. Benison, R.W. Marsh, T. Itinteang, G.W. Titchener, J. Evans, S.T. Tan




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Incidence, clinical characteristics, and outcomes of nosocomial Enterococcus spp. bloodstream infections in a tertiary-care hospital in Beijing, China: a four-year retrospective study

Enterococcus spp. are the common cause of nosocomial bloodstream infections (BSIs) with high morbidity and mortality. The purpose of this study was to characterize the incidence, clini...

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A Rare Case of Primary Bilateral Adrenal Lymphoma

Lymphoma may involve the adrenal glands, but primary lymphoma is rare. Only a few cases have been reported in medical literature. Primary adrenal lymphoma is extremely rare, accounting for

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Succesful Management of Laparoscopic Sleeve Gastrectomy Leak with Negative Pressure Therapy

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Erratum to: A phase I dose-escalation study of Selumetinib in combination with Erlotinib or Temsirolimus in patients with advanced solid tumors

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Summertime Blues? A Re-Examination of the Seasonality of Web Searches for Restless Legs and Leg Cramps

Studies examining internet searches for restless legs and leg cramps have found a strong seasonal effect with peaks in summer and troughs in winter months. This study used an econometric approach to examine the seasonality of such searches in greater detail.

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The Short and Long of Adolescent Sleep: The Unique Impact of Day Length

Variation in day length is proposed to impact sleep, yet it is unknown whether this is above the influence of behavioural factors. Day length, sleep hygiene and parent-set bedtime were simultaneously explored, to investigate the relative importance of each on adolescents’ sleep.

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Advances towards fully automated in vivo assessment of oral epithelial dysplasia by nuclear endomicroscopy – A pilot study

Abstract

Background

uncertainties in detection of oral epithelial dysplasia (OED) frequently result from sampling error especially in inflammatory oral lesions. Endomicroscopy allows non-invasive, “en face” imaging of upper oral epithelium but parameters of OED are unknown.

Methods

mucosal nuclei were imaged in 34 toluidine blue stained oral lesions with a commercial endomicroscope. Histopathological diagnosis showed 4 biopsies in “dys-/ neoplastic”, 23 in “inflammatory”, 7 in “others” disease groups. Strength of different assessment strategies of nuclear scoring, nuclear count and automated nuclear analysis were measured by area under ROC–curve (AUC) to identify histopathological “dys-/neoplastic” group. Nuclear objects from automated image analysis were visually corrected.

Results

best performing parameters of nuclear-to-image ratios were the count of large nuclei (AUC=.986) and 6-nearest-neighborhood relation (AUC=.896) and for parameters of nuclear polymorphism the count of atypical nuclei (AUC=.996) and compactness of nuclei (AUC=.922). Excluding low grade OED nuclear scoring and count reached 100% sensitivity and 98% specificity for detection of dys-/neoplastic lesions. In automated analysis, combination of parameters enhanced diagnostic strength. Sensitivity of 100% and specificity of 87% was seen for distances of 6-nearest-neighbors and aspect ratios even in uncorrected objects. Correction improved measures of nuclear polymorphism only. The hue of background color was stronger than nuclear density (AUC=.779 vs. .687) to detect dys-/neoplastic group indicating that macroscopic aspect is biased.

Conclusions

nuclear-to-image ratios are applicable for automated optical in vivo diagnostics for oral potentially malignant disorders. Nuclear endomicroscopy may promote non-invasive, early detection of dys-/neoplastic lesions by reducing sampling error.

This article is protected by copyright. All rights reserved.

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Methodology, outcome, safety and in vivo accuracy in traditional frame-based stereoelectroencephalography

Abstract

Background

Stereoelectroencephalography (SEEG) is an established diagnostic technique for the localization of the epileptogenic zone in drug-resistant epilepsy. In vivo accuracy of SEEG electrode positioning is of paramount importance since higher accuracy may lead to more precise resective surgery, better seizure outcome and reduction of complications.

Objective

To describe experiences with the SEEG technique in our comprehensive epilepsy center, to illustrate surgical methodology, to evaluate in vivo application accuracy and to consider the diagnostic yield of SEEG implantations.

Methods

All patients who underwent SEEG implantations between September 2008 and April 2016 were analyzed. Planned electrode trajectories were compared with post-implantation trajectories after fusion of pre- and postoperative imaging. Quantitative analysis of deviation using Euclidean distance and directional errors was performed. Explanatory variables for electrode accuracy were analyzed using linear regression modeling. The surgical methodology, procedure-related complications and diagnostic yield were reported.

Results

Seventy-six implantations were performed in 71 patients, and a total of 902 electrodes were implanted. Median entry and target point deviations were 1.54 mm and 2.93 mm. Several factors that predicted entry and target point accuracy were identified. The rate of major complications was 2.6%. SEEG led to surgical therapy of various modalities in 53 patients (69.7%).

Conclusions

This study demonstrated that entry and target point localization errors can be predicted by linear regression models, which can aid in identification of high-risk electrode trajectories and further enhancement of accuracy. SEEG is a reliable technique, as demonstrated by the high accuracy of conventional frame-based implantation methodology and the good diagnostic yield.

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Sleepiness in subjects with possible attention-deficit hyperactivity disorder

Ito et al. investigated the relationship between excessive daytime sleepiness (EDS) and attention deficit/hyperactivity disorder (ADHD) symptoms in adults with possible ADHD [1]. Compared with non-ADHD participants, participants with possible ADHD showed an evening chronotype, depressive symptoms, sleepiness and sleep disturbances. Hierarchical logistic regression analyses revealed that adjusted odds ratio (95% CI) of possible ADHD symptoms for EDS was 1.91 (1.59-2.29). Furthermore, the inattention score in relation to ADHD was significantly higher in the severe EDS group compared with the moderate and non-EDS groups.

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Periorbital Integrated Potentials: Useful phasic REM sleep markers

Although mentioned as one of the rapid eye movement (REM) sleep phasic events in the 1970s [1-3], periorbital integrated potentials (PIPs) have generally escaped the attention of contemporary sleep clinicians. There are certain situations where it is difficult to identify the classical REM sleep physiologic criteria (REM atonia, rapid eye movements [REMs] and desynchronized EEG with or without saw tooth waves). Such situations include inadequate impedance reduction in chin EMG making it difficult to identify muscle atonia or hypotonia, REM sleep behavior disorder (RBD), REM without atonia (RWA), status dissociatus, parasomnia overlap disorder, agrypnia excitata and in patients on antidepressants (eg., selective serotonin and norepinephrine reuptake inhibitors [ SSRIs and SNRIs]).

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Summertime Blues? A Re-Examination of the Seasonality of Web Searches for Restless Legs and Leg Cramps

Studies examining internet searches for restless legs and leg cramps have found a strong seasonal effect with peaks in summer and troughs in winter months. This study used an econometric approach to examine the seasonality of such searches in greater detail.

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The Short and Long of Adolescent Sleep: The Unique Impact of Day Length

Variation in day length is proposed to impact sleep, yet it is unknown whether this is above the influence of behavioural factors. Day length, sleep hygiene and parent-set bedtime were simultaneously explored, to investigate the relative importance of each on adolescents’ sleep.

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Nasal administration of the neuroprotective candidate NeuroEPO to healthy volunteers: a randomized, parallel, open-label safety study

Delivery of therapeutic agents as erythropoietin (EPO) into Central Nervous System through intranasal route could benefit patients with neurological disorders. A new nasal formulation containing a non-hematopo...

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Phenotypic alterations in breast cancer associated with neoadjuvant chemotherapy: A comparison with baseline rates of change

Publication date: December 2017
Source:Annals of Diagnostic Pathology, Volume 31
Author(s): Nosaibah Hariri, Andres A. Roma, Farnaz Hasteh, Vighnesh Walavalkar, Oluwole Fadare
Several studies have documented phenotypic alterations in breast cancer associated with neoadjuvant chemotherapy [NACT], but many of these studies are limited by the fact that they did not account for the baseline rate of expected phenotypic change between biopsies and resections in the absence of NACT. Herein, we assess whether the NACT-associated rate of phenotypic change is significantly different than would be expected in a control population of patients that did not receive NACT. From a pathologic database, we documented the estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor-2 (HER2/neu) phenotypes of consecutive invasive breast carcinomas (n=826), as well as the subset in which at least one of these tests was assessed in both the biopsy and resection (n=340). We then compared the rates of phenotypic change in the patients that did (n=65) and did not (n=275) receive NACT. Respectively, 49.2% and 36% of the NACT and non-NACT groups showed a biopsy-to-resection change in status for at least one biomarker (p=0.0005). The NACT and non-NACT groups showed the following respective rates of a biopsy-to-resection change in phenotype: ER (9.2% vs 2.5%, p=0.02); PR (30.7% vs 8%, p=0.000006); Her2/neu-IHC (25% vs 22.3%, p=0.7), Her2/neu-FISH (7% vs 3%, p=0.6). The direction of change in the NACT group was positive in the biopsy to negative in the resection in >70% of cases for all markers. For ER and PR, there was no statistically significant difference between cases that showed a biopsy-to-excision change in phenotype and those that were more phenotypically stable regarding a wide array of clinicopathologic variables. The average percentage of ER/PR-immunoreactive tumor cells in the pre-NACT biopsies was significantly lower in the phenotypically altered cases as compared to the phenotypically stable cases. Our findings confirm that phenotypic alterations in breast cancer occur after NACT, and that these changes are more pronounced for hormone receptors (especially PR); Significant NACT-associated alterations were not apparent for HER2/neu. A distinct pathologic profile for cases displaying a phenotypic change within the NACT group was not demonstrable. The pre-NACT levels of ER and PR may affect the likelihood of a phenotypic change. These results highlight the need for repeat testing in residual tumors after NACT.



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Accuracy and interobserver agreement of retroareolar frozen sections in nipple-sparing mastectomies

Publication date: August 2017
Source:Annals of Diagnostic Pathology, Volume 29
Author(s): David A. Suarez-Zamora, Luis E. Barrera-Herrera, Mauricio A. Palau-Lazaro, Fabio Torres-Franco, Alejandro Orozco-Plazas, Lisette Barreto-Hauzeur, Paula A. Rodriguez-Urrego
In the last decades, surgical treatment of breast cancer has enormously changed. As a result, nipple-sparing mastectomy (NSM) has evolved as an oncologically safe and cosmetic approach. NSM includes a subareolar frozen section to evaluate malignancy. We determined the accuracy of subareolar frozen section diagnosis, analyzed the discrepancy factor, and estimated the interobserver agreement of frozen section in NSM. A retrospective review of all NSMs at our institution from 2009 to 2015 was performed. Frozen sections were compared to the final diagnoses to analyze the accuracy of subareolar frozen sections. Discordant results were rigorously evaluated to identify discrepancy factors. Some cases were randomly chosen to assess the interobserver agreement (kappa) among pathologists. The agreement results were evaluated with and without knowledge of the tumor morphology. Among 34 NSMs, the frozen section false-negative and false-positive rate was 5.9% and 8.8%, respectively. The sensitivity and specificity was 77.8% and 88.0%, respectively. Sampling errors and diathermy artifacts explained our false-negative diagnoses. Freezing artifacts and an intraductal papilloma explained our false-positive diagnoses. The interobserver agreement between breast and general pathologists was 0.87 (p<0.0001) and 0.31 (p=0.0001), respectively. The interobserver agreement increased to 0.35 (p<0.0001) in general pathologists with knowledge of the tumor morphology. Subareolar frozen section showed to be a specific test with moderate sensitivity. Papillary lesions can mimic atypical cells and influence the frozen section interpretation. Frozen section in NSM had a better performance in breast pathologists (almost perfect) versus general pathologists (fair). Interobserver agreement may improve with knowledge of tumor morphology.



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Usefulness of a direct immunofluorescence in the diagnosis of plaque type oral lichen planus

Publication date: December 2017
Source:Annals of Diagnostic Pathology, Volume 31
Author(s): Patricia Alejandra Masquijo-Bisio, Mariana Silvia Gandolfo, Alicia Keszler, Maria Elina Itoiz, María Luisa Paparella




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Lymphocytic thrombophilic arteritis: A distinct inflammatory type I interferon and C5b-9 mediated subcutaneous endovasculitis

Publication date: December 2017
Source:Annals of Diagnostic Pathology, Volume 31
Author(s): Cynthia M. Magro, Jad Saab
BackgroundLymphocytic thrombophilic arteritis is a recently recognized subcuticular larger vessel vasculitis characterized by striking vascular luminal thrombosis.MethodsThe clinical features, histopathology and phenotypic profile of ten patients with lymphocytic thrombophilic arteritis were explored in an attempt to better define the entity from a clinical and pathophysiologic perspective.ResultsThe patients were all female (mean age of 43) presenting with generally asymptomatic lower and upper extremity hyperpigmented macules. A consistent picture diagnostic of a connective tissue disease syndrome was not seen. The disease was not progressive although it was typically persistent.The morphology was characterized by a temporally heterogeneous subcutaneous arteritis targeting the endothelium and intima with changes ranging from incipient intimal expansion by hyaluronic acid to concentric intimal fibrin deposition to one of an end stage acellular intraluminal obliterative fibrous arteriopathy. The infiltrate was predominated by lymphocytes and histiocytes. The intimal elastic lamina was intact in most cases. All tested cases showed intimal and endothelial C5b-9 deposition, an upregulated type I interferon microenvironment and marked upregulation of the inducible interferon gamma 16 protein.ConclusionsLymphocytic thrombophilic arteritis is a unique form of C5b-9 mediated arteritic endotheliopathy where the brunt of the changes involves the endothelium and intima and that is morphologically distinct from the transmural arteritis of benign cutaneous polyarteritis nodosa.



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Low-grade fibromyxoid sarcoma: Clinical, morphologic and genetic features

Publication date: June 2017
Source:Annals of Diagnostic Pathology, Volume 28
Author(s): Mustafa Mohamed, Cyril Fisher, Khin Thway
Low-grade fibromyxoid sarcoma (LGFMS) is a bland spindle cell neoplasm that typically arises in the deep soft tissues of the proximal extremities or trunk of young adults. The majority of LGFMS are characterized by a recurrent (7;16)(q34;p11) translocation, resulting in the FUS-CREB3L2 fusion gene, which generates a chimeric protein with transcriptional regulatory activity. Small numbers harbor a FUS-CREB3L1 fusion resulting from t(11;16)(p11;p11), whilst rare cases harbor the EWSR1-CREB3L1 fusion. LGFMS is of low to moderate cellularity and consists of bland spindle cells with small, angulated nuclei and scant, wispy cytoplasm, arranged in a whorled growth pattern and typically showing abrupt transition from myxoid to fibrous areas. Immunohistochemical expression of MUC4 is a consistent finding. Hyalinized spindle cell tumor with giant rosettes (HSCTGR) is a morphological variant of LGFMS that shares the same balanced translocation, and is also immunoreactive for MUC4. A potential relationship between LGFMS and sclerosing epithelioid fibrosarcoma (SEF), a rare fibroblastic neoplasm that most commonly arises in the deep soft tissues of the lower extremities, limb girdles or trunk, has also been suggested. SEF is classically composed of nests and cords of epithelioid cells with clear or eosinophilic cytoplasm embedded within densely sclerotic stroma. In some cases, areas indistinguishable from LGFMS are present, and these have been shown to contain FUS-CREB3L2 fusion transcripts. The majority of pure SEF tumors harbor EWSR1 rearrangements, with EWSR1-CREB3L1 and more rarely EWSR1-CREB3L2 gene fusions more common than those involving FUS. MUC4 immunoreactivity is also seen in approximately 70% of SEF. Surgical resection of these tumors with clear margins is the treatment of choice. Correct diagnosis is important because of the significant potential for recurrence and late metastatic spread. We review LGFMS and SEF, discussing morphology and immunohistochemistry, genetics and molecular findings, and the differential diagnosis.



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IMP3 contributes to poor prognosis of patients with metaplastic breast carcinoma: A clinicopathological study

Publication date: December 2017
Source:Annals of Diagnostic Pathology, Volume 31
Author(s): Ryuji Ohashi, Maoka Sangen, Shigeki Namimatsu, Hiroyuki Takei, Zenya Naito
Metaplastic breast carcinoma (MBC) is a rare type of tumor with heterogenous histological patterns. We investigated the immunohistochemical expression of IMP3, an oncofetal protein, in 31 MBC patients in association with histological subtypes and clinical outcomes. The cohort consisted of spindle cell carcinoma (SPC) (n=11), squamous cell carcinoma (SCC) (n=14), matrix-producing carcinoma (MPC) (n=4), carcinoma with osteocartilaginous elements (COC) (n=1), and low grade adenosquamous cell carcinoma (ASC) (n=1). IMP3 expression was identified in 7 cases of SPC (64%) and 6 patients of all the other subtypes (p=0.051). In comparison between IMP3 high (n=13) and low (n=18) groups, a large-sized tumor (≥4.0cm) was identified in 9 IMP3 high patients, and 14 IMP3 low patients had a small-sized tumor (p=0.01). High Ki67 positivity was detected in all of the IMP3 high patients and in 7 of the IMP3 low patients (p=0.002). During the follow-up period, 9 IMP3 high patients died, whereas 15 of the 18 IMP3 low patients remained alive (p=0.004). A univariate analysis revealed that IMP3 expression and tumor size were significantly associated with poor clinical outcomes (p=0.03 and <0.001, respectively). The IMP3 high group was likely to be associated with reduced overall survival compared to the IMP3 low group (p=0.06). These findings indicate that IMP3 may contribute to the aggressive behavior of MBC, and that this expression could potentially be a prognostic marker of MBC.



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IMP3 contributes to poor prognosis of patients with metaplastic breast carcinoma: A clinicopathological study

Publication date: December 2017
Source:Annals of Diagnostic Pathology, Volume 31
Author(s): Ryuji Ohashi, Maoka Sangen, Shigeki Namimatsu, Hiroyuki Takei, Zenya Naito
Metaplastic breast carcinoma (MBC) is a rare type of tumor with heterogenous histological patterns. We investigated the immunohistochemical expression of IMP3, an oncofetal protein, in 31 MBC patients in association with histological subtypes and clinical outcomes. The cohort consisted of spindle cell carcinoma (SPC) (n=11), squamous cell carcinoma (SCC) (n=14), matrix-producing carcinoma (MPC) (n=4), carcinoma with osteocartilaginous elements (COC) (n=1), and low grade adenosquamous cell carcinoma (ASC) (n=1). IMP3 expression was identified in 7 cases of SPC (64%) and 6 patients of all the other subtypes (p=0.051). In comparison between IMP3 high (n=13) and low (n=18) groups, a large-sized tumor (≥4.0cm) was identified in 9 IMP3 high patients, and 14 IMP3 low patients had a small-sized tumor (p=0.01). High Ki67 positivity was detected in all of the IMP3 high patients and in 7 of the IMP3 low patients (p=0.002). During the follow-up period, 9 IMP3 high patients died, whereas 15 of the 18 IMP3 low patients remained alive (p=0.004). A univariate analysis revealed that IMP3 expression and tumor size were significantly associated with poor clinical outcomes (p=0.03 and <0.001, respectively). The IMP3 high group was likely to be associated with reduced overall survival compared to the IMP3 low group (p=0.06). These findings indicate that IMP3 may contribute to the aggressive behavior of MBC, and that this expression could potentially be a prognostic marker of MBC.



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Beta-catenin and p53 expression in topographic compartments of colorectal cancer and its prognostic value following surgery

Publication date: December 2017
Source:Annals of Diagnostic Pathology, Volume 31
Author(s): Juan Daniel Prieto, Martina Álvarez, María Isabel Hierro, Isabel García, Luis Vicioso
Colorectal cancer (CRC) is the third most prevalent neoplasm worldwide and the fourth cause of cancer-related death. From Vogelstein's initial model, new molecular knowledge has been incorporated which includes an elevated number of genetic mutations, many of them located in the Wnt pathway, which affect its principle effector: β-catenin. Additionally, it is necessary to keep the heterogeneity of CRCs in mind, both in terms of morphology and biology. The aim of this work is to study the interaction between the Wnt molecular pathway, by means of immunoexpression of β-catenin, in CRC and other molecular mechanisms, such as the p53 pathway, in order to determine the pattern - if one exists - of different immunohistochemical expression of β-catenin and p53 in the superficial and deep tumor components, and lastly, to determine the impact of these markers on prognosis.Our cases showed an increasing gradient of β-catenin immunoexpression that parallels depth in the tumor, with a greater degree of nuclear immunoexpression in the deep compartment. We observe that in those cases with positivity for nuclear p53 and an absence of immunostaining of β-catenin show higher rates of survival, whereas one of the lowest rates was observed in patients who co-expressed p53 and β-catenin. We conclude that a combined analysis of β-catenin and p53 could have prognostic importance as markers for predicting the disease's progression and contribute to the identification of patients with a high risk of mortality.



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Comparison of HER2 status determination methods in HER2 (2+) patients: Manual fluorescent in situ hybridization (FISH) vs. dual silver enhanced in situ hybridization (SISH)

Publication date: December 2017
Source:Annals of Diagnostic Pathology, Volume 31
Author(s): Burcin Pehlivanoglu, Gurdeniz Serin, Levent Yeniay, Osman Zekioglu, Erhan Gokmen, Necmettin Ozdemir
HER2 amplification has been demonstrated in 15–25% of invasive breast carcinomas and can be assessed using immunohistochemical and in situ hybridization methods. Here, we compared the accuracy of dual SISH to manual FISH in HER2 (2+) breast carcinoma and evaluated the feasibility of dual SISH method in routine practice. Sixty HER2 (2+) consecutive tumor samples diagnosed between January 2009 and February 2013 were selected. Demographic, histological and immunohistochemical features and FISH results were recruited from patient records and compared to dual SISH results. Nine (15%) of the 60 tumor samples were excluded from statistical analysis due to lack of interpretable SISH signals. HER2 staining percentages by immunohistochemistry differed between 20 and 80%. HER2 amplification was shown in 7 (13.7%) and 8 (15.7%) patients by FISH and SISH, respectively. Very good agreement was observed between FISH and SISH methods (kappa value: 0.92). Significant correlation was found between HER2 staining percentage and FISH positivity, in contrast to SISH positivity (p=0.012 vs. p=0.069). Our results are consistent with previously reported literature, indicating SISH can be used to determine HER2 status. However, preanalytical and analytical problems may cause inadequate or uncountable signals, making interpretation impossible for the pathologist and highlighting the importance of standardization and quality control programs.



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AMPK expression patterns are significantly associated with poor prognosis in breast cancer patients

Publication date: August 2017
Source:Annals of Diagnostic Pathology, Volume 29
Author(s): Jaudah Al-Maghrabi, Kaltoom Al-Sakkaf, Imtiaz Ahmad Qureshi, Nadeem Shafique Butt, Lila Damnhory, Mohamed Elshal, Basim Al-Maghrabi, Alia Aldahlawi, Sawsan Ashoor, Barry Brown, Pauline Dobson, Mohamad Nidal Khabaz
Many investigators have examined the functions of AMP-activated protein kinase (AMPK) in cancer biology and its anti-neoplastic features in cancer models. The goal of this research is to assess the association of the immunohistochemical expression of AMPK in human mammary tumours with the clinical data of breast cancer patients. 449 cases of previously diagnosed breast cancer, and 27 tissue samples of fibroadenomas and normal breast were utilized for detection of AMPK expression using tissue microarrays and immunohistochemistry. Brownish nuclear and cytoplasmic staining were present in epithelial cells and stromal cells in 333 (74.16%) and 348 (77.5%) cancer cases respectively indicating AMPK expression. Twenty two (81.48%) control cases showed AMPK immunoexpression in both epithelial and stromal cells. Significant statistical association has been found between advanced stages of breast cancer and increased intensity of AMPK immunostaining only in epithelial cells (p-value=0.0001). Histotypes have been correlated with AMPK immunostaining in epithelial cells only (p-value=0.029). Low AMPK immunostaining scores were more dominant in DCIS, ductal and mixed type's ductal and mucinous histotypes, while high intense staining was more common in the lobular type. Furthermore, breast tumour cases with lymph node metastases showed significant AMPK expression in both epithelial and stromal cells (p-value=0.0001 and p-value=0.026). Low scores of AMPK immunostaining were common in breast cancer cases with positive vascular invasion (p-value=0.007) and disease recurrence (p-value=0.008). No significant differences in survival behavior distributions were observed for the different categories of AMPK immunostaining in epithelial and stromal cells.In conclusion, our results showed decreased AMPK expression in breast cancer in comparison with the control group. AMPK expression was significantly correlated with some clinicopathological factors like advanced stage, lymph node involvement, vascular invasion and disease recurrence which give indications for poor clinical outcomes. Immunohistochemical staining of AMPK protein is a valuable method which could predict cases of breast cancer with poor prognosis.



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Expression of pRb, Ki67 and HER 2/neu in gastric carcinomas: Relation to different histopathological grades and stages

Publication date: October 2017
Source:Annals of Diagnostic Pathology, Volume 30
Author(s): Azza Abdel-Aziz, Rehab Allah Ahmed, Afaf Taha Ibrahiem




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Editorial Board

Publication date: June 2017
Source:Annals of Diagnostic Pathology, Volume 28





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Expression of dog1 in low-grade fibromyxoid sarcoma: A study of 19 cases and review of the literature

Publication date: October 2017
Source:Annals of Diagnostic Pathology, Volume 30
Author(s): Ana Vallejo-Benítez, Enrique Rodríguez-Zarco, Sara Pabón Carrasco, Sofia Pereira-Gallardo, Javier Brugal Molina, Antonio García-Escudero, Antonio Robles Frías, David Marcilla, Ricardo González-Cámpora
DOG1 is a highly-sensitive marker often included in the immunohistochemical panel for the diagnosis of gastrointestinal stromal tumors (GISTs). Recent research has shown that DOG1 may also be expressed by low-grade fibromyxoid sarcomas (LGFMSs); this may give rise to diagnostic error when the sarcoma is located in the abdominal cavity. This paper reports on immnohistochemical expression of DOG1 in 19 LGFMSs using two different monoclonal antibodies: K9 (Leica, Novocastra Laboratories, Newcastle upon Tyne, UK) and SP31 (Thermo Scientific, Freemont, USA). All LGFMSs displayed the standard histological pattern of alternating myxoid and fibrous areas, low cellularity and bland spindle-cell morphology. Positive staining for MUC4 was observed in 18/19 cases (94.7%), while there was rearrangement of the FUS gene in 14/19 (73.7%) cases and of the EWR1 gene in 2/19 (10.5%). The sarcoma staining negative for MUC4 displayed FUS gene rearrangement. Whole-section immunohistochemistry revealed positive staining for DOG1 in 8/19 cases (42.1%), though only with clone K9. Cytoplasmic as well as membrane staining was observed in all cases; staining was focal (10–30%) and of varying intensity (1+ to 2+).In conclusion, DOG1 clone K9 exhibited low sensitivity (42.1%) for the diagnosis of LGFMS, although higher than clone SP31. Since the two clones display similar sensitivity and specificity for GIST diagnosis, SP31 would appear to be more specific for this purpose, since no reaction was observed here with LGFMS, a GIST-mimicking lesion.



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Histological, immunohistochemical features and pathogenesis of pseudoangiosarcomatous urothelial carcinoma

Publication date: October 2017
Source:Annals of Diagnostic Pathology, Volume 30
Author(s): Pelin Yıldız, Kemal Behzatoğlu, Ezgi Hacıhasanoğlu, Oğuzhan Okcu, Haydar Durak, Uğur Yücetaş




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Chronic inflammation in refractory hippocampal sclerosis-related temporal lobe epilepsy

Publication date: October 2017
Source:Annals of Diagnostic Pathology, Volume 30
Author(s): Jordan M. Gales, Richard A. Prayson
Emerging evidence suggests chronic inflammation may play a role in hippocampal sclerosis-associated temporal lobe epilepsy. We sought to systematically evaluate for its presence in a group of 315 patients who underwent surgery for medically-refractory epilepsy and who had hippocampal sclerosis. Upon histologic review of hematoxylin and eosin stained tissue sections, 95 (41%) cases demonstrated the presence of lymphocytes within the perivascular region and diffusely within the brain parenchyma. Those cases with chronic inflammation evident on hematoxylin and eosin staining were significantly more likely to experience a post-operative seizure recurrence than those without it (p=0.03). In 9 cases of hippocampi with chronic inflammation observed on hematoxylin and eosin stained sections, there was a mixture of both T (CD3+) and B (CD20+) lymphocytes located around blood vessels and interspersed within the brain parenchyma and a predominance of CD4 positive T cells versus CD8 positive cells. Ten hippocampi, apparently devoid of chronic inflammation upon inspection with hematoxylin and eosin stained sections, were stained with the lymphocyte common antigen CD45. In all 10 cases, scattered lymphoid cells were observed in the brain parenchyma, suggesting some level of chronic inflammation may be present in more cases than casual inspection might suggest. This study was the first to evaluate the incidence of chronic inflammation within a large temporal lobe epilepsy population. The study findings suggest chronic inflammation may be a more common component of hippocampal sclerosis -associated temporal lobe epilepsy than previously believed.



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Table of Contents

Publication date: June 2017
Source:Annals of Diagnostic Pathology, Volume 28





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Utility of different immunostains for diagnosis of metastatic breast carcinomas in both surgical and cytological specimens

Publication date: October 2017
Source:Annals of Diagnostic Pathology, Volume 30
Author(s): Yanjun Hou, Rulong Shen, Shweta Chaudhary, Dena Tonkovich, Zaibo Li
ObjectiveA panel of immunostains is usually performed to confirm a metastatic carcinoma origin. GATA3 is a transcription factor and has been proven to be a useful marker for breast carcinoma. Other immunostains including mammaglobin (MGB), gross cystic disease fluid protein 15 (GCDFP-15), estrogen receptor (ER) and progesterone receptor (PR) are also used in diagnosing metastatic breast cancer. In this study, we aimed to compare the performance of these immunostains in the work up of metastatic breast carcinoma in both surgical and cytological specimens.Study designThis study cohort was composed of 242 metastatic breast carcinomas (142 surgical and 100 cytological specimens) during a study period from October 2013 to December 2015. Immunostain results of GATA3, CK7, MGB, GCDFP-15, ER and PR and their correlations were examined.ResultsIn surgical specimens, GATA3 and CK7 were highly expressed (88% and 87%), but MGB and GCDFP-15 showed much lower positivity rates (43% and 29%). In cytological specimens, GATA3, CK7 and MGB showed similar positivity rates to those in surgical specimens; but GCDFP-15, ER and PR showed significantly lower positivity rates than those in surgical specimens. All ER-positive cases were positive for GATA3 in both surgical and cytological specimens; however, GATA3 positivity showed a significantly stronger correlation with ER positivity in surgical specimens than in cytological specimens.ConclusionsGATA3 and CK7 performed better than other immunostains to detect metastatic breast carcinoma in both surgical and cytological specimens. GATA3 expression was positively correlated with ER expression, and the correlation was stronger in surgical specimens than in cytological specimens.



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Wnt signaling pathway protein LEF1 in cancer, as a biomarker for prognosis and a target for treatment.

Wnt signaling pathway protein LEF1 in cancer, as a biomarker for prognosis and a target for treatment.

Am J Cancer Res. 2017;7(6):1389-1406

Authors: Santiago L, Daniels G, Wang D, Deng FM, Lee P

Abstract
Transcription factors are regulatory proteins that either activate or repress the transcription of genes via binding to DNA regulatory sequences and regulating recruitment of transcriptional complexes. Lymphoid enhancer-binding factor 1 (LEF1), a member of the T-cell Factor (TCF)/LEF1 family of high-mobility group transcription factors, is a downstream mediator of the Wnt/β-catenin signaling pathway, but can also modulate gene transcription independently. LEF1 is essential in stem cell maintenance and organ development, especially in its role in epithelial-mesenchymal transition (EMT) by activating the transcription of hallmark EMT effectors including N-Cadherin, Vimentin, and Snail. Aberrant expression of LEF1 is implicated in tumorigenesis and cancer cell proliferation, migration, and invasion. LEF1's activity in particular cancer cell types, such as chronic lymphocytic leukemia (CLL), Burkitt lymphoma (BL), acute lymphoblastic leukemia (ALL), oral squamous cell carcinoma (OSCC), and colorectal cancer (CRC), makes it a valuable biomarker in predicting patient prognosis. Additionally, due to aberrant LEF1 activity resulting in cancer progression, knockdown and inhibition treatments designed to target LEF1 have proven effective in alleviating cancer growth, migration, and invasion in CLL, CRC, glioblastoma multiforme (GBM), and renal cell carcinoma (RCC). In prostate cancer cells, LEF1 promotes androgen receptor expression and activity in an androgen-independent manner, ultimately increasing prostate cancer growth regardless of androgen ablation therapy. In this review, we review LEF1 regulation, its role in tumorigenesis in several cancer types, and its clinical value as a biomarker for predicting prognoses and as a target for treatment.

PMID: 28670499 [PubMed]

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Treatment of early-onset scoliosis with a hybrid of a concave magnetic driver (MCGR) and a contralateral passive sliding rod construct with apical control: preliminary report on 17 cases

Magnetic controlled growth rods (MCGRs) are increasingly popular for surgical treatment of severe early-onset scoliosis (EOS), because they allow non-invasive extensions with good growth maintenance. We combined a MCGR with a contralateral passive sliding rod construct with apical control on the convex side to improve efficiency in terms of costs and 3D correction.

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Heavy metals and minerals contents in pikeperch ( Sander lucioperca ), carp ( Cyprinus carpio ) and flathead grey mullet ( Mugil cephalus ) from Sidi Salem Reservoir (Tunisia): health risk assessment related to fish consumption

Abstract

The aim of this study was to investigate heavy metals and selected minerals contents in filets of pikeperch (Sander lucioperca), carp (Cyprinus carpio) and flathead grey mullet (Mugil cephalus), the major fish species produced in Sidi-Salem reservoir; the largest Tunisian freshwater ecosystem. Concentrations of Ca, Mg, Fe, Zn, Cd, Pb and Hg were determined by inductively coupled plasma-optical emission spectrometry, while concentrations of Na and P were determined by flame photometry and spectrophotometry, respectively. Results concerning heavy metals are considered quantitatively reliable for Hg and Cd but must be taken with precautions concerning Pb levels as the LOD (limit of detection) of the analytical process was higher than acceptable limit. They showed greater accumulations of both Hg and Cd in filets of pikeperch than in filets of carp and mullet, but none of the values exceeded the normative maximum levels (0.500 and 0.050 mg kg⁻¹ w.w., respectively). Considering provisional intakes, target hazard quotient and hazard index, estimated for a fish portion per week, consumption of any of the species did not appear to be potentially hazardous for the health as they were far below threshold values. A fish portion would provide substantial amounts (>15% of daily requirements) in essential mineral nutrients (P, Mg and Fe) and thus should be considered an interesting contribution to a healthy diet. It is strongly advocated to authorities including freshwater fish in the official national annual control survey of contaminants in fishery products, which in addition to guaranteeing security of consumers, would also allow diversifying valorisation opportunities and thus increase the economic value of this fish production.

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Bitterness in sugar: O-GlcNAcylation aggravates pre-B acute lymphocytic leukemia through glycolysis via the PI3K/Akt/c-Myc pathway.

Bitterness in sugar: O-GlcNAcylation aggravates pre-B acute lymphocytic leukemia through glycolysis via the PI3K/Akt/c-Myc pathway.

Am J Cancer Res. 2017;7(6):1337-1349

Authors: Zhang B, Zhou P, Li X, Shi Q, Li D, Ju X

Abstract
Abnormal cellular energetics has emerged as a hallmark of cancer cells. Deregulating aerobic glycolysis can alter multiple metabolic and signaling pathways in cancer cells, and trigger unlimited growth and proliferation. Accumulating evidence suggests that elevated levels of protein modification with β-N-acetylglucosamine (O-GlcNAcylation) along with dysregulation of O-GlcNAc transferase (OGT) and/or O-GlcNAcase (OGA) levels may act as a nutrient sensor in cancer cells. However, the underlying mechanism of O-GlcNAcylation and the relationship between O-GlcNAcylation and glycolysis are largely unknown in pre-B acute lymphocytic leukemia (pre-B-ALL). In this study, CD19(+) bone marrow mononuclear cells (BM-MNCs) from untreated pre-B-ALL patients displayed increased O-GlcNAcylation levels, upregulated OGT, and downregulated OGA. Patients with higher lactate dehydrogenase (LDH) levels exhibited higher O-GlcNAcylation levels with OGT upregulation and overactivation of the PI3K/Akt/c-Myc pathway. The extracellular acidification rate (ECAR) and the mRNA expression of key enzymes in glycolysis were determined to assess glycolysis activation. Our results revealed the existence of abnormal glycolysis in the CD19(+) BM-MNCs of pre-B-ALL patients. The knockdown of OGT decreased the ECAR and downregulated glycolysis-related enzymes in Nalm-6 cells via the PI3K/Akt/c-Myc pathway. The suppression of OGT slowed the rate of proliferation and induced apoptosis in Nalm-6 cells. The glycolysis inhibitor 2-deoxy-D-glucose induced cytotoxicity of Nalm-6 cells, which was potentiated by OGT-siRNA. These findings suggested that O-GlcNAcylation could be a hallmark of pre-B-ALL, which has considerable therapeutic potential in clinical practice.

PMID: 28670495 [PubMed]

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Lycopene reduces ovarian tumor growth and intraperitoneal metastatic load.

Lycopene reduces ovarian tumor growth and intraperitoneal metastatic load.

Am J Cancer Res. 2017;7(6):1322-1336

Authors: Holzapfel NP, Shokoohmand A, Wagner F, Landgraf M, Champ S, Holzapfel BM, Clements JA, Hutmacher DW, Loessner D

Abstract
Mutagens like oxidants cause lesions in the DNA of ovarian and fallopian tube epithelial cells, resulting in neoplastic transformation. Reduced exposure of surface epithelia to oxidative stress may prevent the onset or reduce the growth of ovarian cancer. Lycopene is well-known for its excellent antioxidant properties. In this study, the potential of lycopene in the prevention and treatment of ovarian cancer was investigated using an intraperitoneal animal model. Lycopene prevention significantly reduced the metastatic load of ovarian cancer-bearing mice, whereas treatment of already established ovarian tumors with lycopene significantly diminished the tumor burden. Lycopene treatment synergistically enhanced anti-tumorigenic effects of paclitaxel and carboplatin. Immunostaining of tumor and metastatic tissues for Ki67 revealed that lycopene reduced the number of proliferating cancer cells. Lycopene decreased the expression of the ovarian cancer biomarker, CA125. The anti-metastatic and anti-proliferative effects were accompanied by down-regulated expression of ITGA5, ITGB1, MMP9, FAK, ILK and EMT markers, decreased protein expression of integrin α5 and reduced activation of MAPK. These findings indicate that lycopene interferes with mechanisms involved in the development and progression of ovarian cancer and that its preventive and therapeutic use, combined with chemotherapeutics, reduces the tumor and metastatic burden of ovarian cancer in vivo.

PMID: 28670494 [PubMed]

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Application of AFP whole blood one-step rapid detection kit in screening for HCC in Qidong.

Application of AFP whole blood one-step rapid detection kit in screening for HCC in Qidong.

Am J Cancer Res. 2017;7(6):1384-1388

Authors: Jin J, Zhang XY, Shi JL, Xue XF, Lu LL, Lu JH, Jiang XP, Hu JF, Duan BS, Yang CQ, Lu DR, Lu DL, Chen JG, Gao HJ

Abstract
Hepatocellular carcinoma (HCC) is a big problem in China where the Hepatitis B (HBV) infection patients are near to 120 million. Early screening and diagnosis is the key to reduce the incidence and mortality of HCC. Serum AFP detection is the main methods for diagnosis, recurrent monitoring and therapeutic evaluation of primary HCC. Hepatitis patients should detect the AFP at least once every six months to help early diagnosis of HCC. Unfortunately, most hepatitis and other liver disease patients do not test their AFP regularly. Therefore, a rapid, convenient detect kit for AFP is necessary for the hepatitis patients to test AFP at home by themselves. It will be very helpful to the HCC early screening and early diagnosis. We screened 859 individuals who were HBsAg positive and had high risk of HCC in Qidong by using two different kits, AFP one-step rapid detection kit (Shanghai Outdo Biotech) and AFP Diagnostics ELISA kit (Zhengzhou Autobio Diagnostics), and compared the results. As a result, the positive accordance rate and the negative accordance rate of AFP one-step rapid detection kit and the Autobio ELISA kit were 95.65% (22/23) and 99.40% (831/836), respectively. The total diagnose accordance rate reached up to 99.30% (853/859). The screening results showed a high accordance rate of two methods. It is so meaningful to achieve home-test and improve HCC early screening and diagnosis by using AFP one-step rapid detection kit.

PMID: 28670498 [PubMed]

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