Future Oncology Ahead of Print.
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Cancer Medicine by Alexandros G.Sfakianakis,Anapafseos 5 Agios Nikolaos,Crete 72100,Greece,tel :00302841026182 & 00306932607174
Τρίτη 17 Μαΐου 2016
Management of chemotherapy-induced nausea and vomiting in patients receiving multiple-day highly or moderately emetogenic chemotherapy: role of transdermal granisetron
Freezing oocytes or embryos after controlled ovarian hyperstimulation in cancer patients: the state of the art
Future Oncology Ahead of Print.
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Evidence-based analysis of self-expanding metallic stent as a bridge to surgery versus emergency surgery for colon cancer
Future Oncology Ahead of Print.
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Management of chemotherapy-induced nausea and vomiting in patients receiving multiple-day highly or moderately emetogenic chemotherapy: role of transdermal granisetron
Future Oncology Ahead of Print.
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Freezing oocytes or embryos after controlled ovarian hyperstimulation in cancer patients: the state of the art
Future Oncology Ahead of Print.
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Evidence-based analysis of self-expanding metallic stent as a bridge to surgery versus emergency surgery for colon cancer
Future Oncology Ahead of Print.
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F8-SIP mediated targeted photodynamic therapy leads to microvascular dysfunction and reduced glioma growth
Abstract
The extra domain A (ED A) of fibronectin has been identified as a tumor vessel specific neovascular marker in glioma. Antibody based vascular targeting against ED A of fibronectin allows precise accumulation of photosensitizer in glioma microvasculature and thereby promises to overcome drawbacks of current photodynamic therapy (PDT) for glioma treatment. Our aim was to characterize microcirculatory consequences of F8-small immunoprotein (SIP) mediated PDT by intravital microscopy (IVM) and to analyze the effects on glioma growth. For IVM SF126 glioma cells were implanted into dorsal skinfold-chamber of nude mice. PDT was performed after intravenous injection of photosensitizer (PS)-coupled F8-SIP or PBS (n = 4). IVM was performed before and after PDT for 4 days. Analysis included total and functional (TVD, FVD) vessel densities, perfusion index (PI), microvascular permeability and blood flow rate (Q). To assess tumor growth SF126 glioma cells were implanted subcutaneously. PDT was performed as a single and repetitive treatment after PS-F8-SIP injection (n = 5). Subcutaneous tumors were treated after uncoupled F8-SIP injection as control group (n = 5). PDT induced microvascular stasis and thrombosis with reduced FVD (24 h: 115.98 ± 0.7 vs. 200.8 ± 61.9 cm/cm2) and PI (39 ± 11 vs. 70 ± 10 %), whereas TVD was not altered (298 ± 39.2 vs. 278.2 ± 51 cm/cm2). Microvascular dysfunction recovered 4 days after treatment. Microvascular dysfunction led to a temporary reduction of glioma growth in the first 48 h after treatment with complete recovery 5 days after treatment. Repetitive PDT resulted in sustained reduction of tumor growth. F8-SIP mediated PDT leads to microvascular dysfunction and reduced glioma growth in a preclinical glioma model with recovery of microcirculation 4 days after treatment. Repetitive application of PDT overcomes microvascular recovery and leads to prolonged antiglioma effects.
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MicroRNA-21 promotes cell proliferation, migration, and resistance to apoptosis through PTEN/PI3K/AKT signaling pathway in esophageal cancer
Abstract
Our study aimed to explore associations between microRNA-21 (miR-21) and PTEN/PI3K/AKT signaling pathway and, further, to elucidate the regulation of miR-21 on biological behaviors in human esophageal cancer cells. The expressions of miR-21, PTEN, PI3K, and AKT were detected in 89 esophageal cancer samples and 58 adjacent normal tissues respectively. The human esophageal cancer cells (TE11) were grouped as following: blank (TE11 cells without transfection), negative (TE11 cells with miR-21 negative inhibitor), and Inhibition-miR21 (TE11 cells with miR-21 inhibitor). Western blot was used for detection of PTEN, P13K, and AKT protein expressions, MTT method for cell proliferation, Transwell assay for cell migration and invasion, and flow cytometry for cell cycle and apoptosis. MiR-21, PI3K, and AKT have higher expressions, but PTEN has lower expression in esophageal cancer tissues compared with adjacent normal tissues. The esophageal cancer tissues with lymph node metastasis and poor differentiation showed significantly low positive rate of PTEN protein, but high positive rates of PI3K and AKT proteins. Compared with blank and negative groups, PTEN expression of TE11 cells in Inhibition-miR21 group was significantly up-regulated, but PI3K and AKT were down-regulated. Further, PTEN was a target gene of miR-21. Besides, compared with blank and negative groups, the proliferation, migration, and invasion of TE11 cells were less active in Inhibition-miR21 group. TE11 cells were significantly increased in the G0/G1 phase of cell cycles, but decreased in the S and G2/M phase in Inhibition-miR21 group. The TE11 cells exhibited significantly increased apoptosis rates. MiR-21 targets key proteins in PTEN/PI3K/AKT signal pathway, promoting proliferation, migration, invasion, and cell cycle, and inhibiting apoptosis of human esophageal cancer cells. It may serve as a novel therapeutic target in esophageal cancer.
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Bone marrow-derived cells are recruited by the melanoma tumor with endothelial cells contributing to tumor vasculature
Abstract
Purpose
Tumor expansion is dependent on neovascularization, a process that requires sustained new vessel formation. Although the critical role of angiogenesis by endothelial sprouting in this process, controversy still prevails on whether angiogenesis involving bone marrow-derived endothelial cells, does contribute to this process. This study aims to evaluate the recruitment of bone marrow-derived cells by the melanoma tumor, including endothelial cells, and if they contribute to angiogenesis.
Methods
A chimeric mouse model of GFP bone marrow was used to induce melanoma tumors derived from murine B16-F10 cell line. These tumors were evaluated for the presence of myeloid cells (CD11b), T lymphocytes (CD3, CD4 and CD8) and endothelial cells (VEGFR2 and CD31) derived from bone marrow.
Results
Mice transplanted with GFP+ cells showed significant bone marrow chimerism (90.9 ± 0.87 %) when compared to the GFP transgenic mice (90.66 ± 2.1 %, p = 0.83) demonstrating successful engraftment of donor bone marrow stem/progenitor cells. Analysis of the murine melanoma tumor showed the presence of donor cells in the tumors (3.5 ± 1.7 %) and interestingly, these cells represent endothelial cells (CD31+ cells; 11.5 ± 6.85 %) and myeloid cells (CD11b+ cells; 80 ± 21 %), but also tumor-infiltrating lymphocytes (CD8+ T cells, 13.31 ± 0.2 %; CD4+ T-cells, 2.1 ± 1.2 %). Examination of the tumor endothelium by confocal microscopy suggests the presence of donor CD31+/GFP+ cells in the wall of some blood vessels.
Conclusion
This study demonstrates that bone marrow-derived cells are recruited by the murine melanoma tumor, with myeloid cells and CD4 and CD8 T lymphocytes migrating as antitumor immune response, and endothelial cells participating of the tumor blood vessels formation.
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Epigenetically maintained SW13+ and SW13- subtypes have different oncogenic potential and convert with HDAC1 inhibition
Abstract
Background
The BRM and BRG1 tumor suppressor genes are mutually exclusive ATPase subunits of the SWI/SNF chromatin remodeling complex. The human adrenal carcinoma SW13 cell line can switch between a subtype which expresses these subunits, SW13+, and one that expresses neither subunit, SW13-. Loss of BRM expression occurs post-transcriptionally and can be restored via histone deacetylase (HDAC) inhibition. However, most previously used HDAC inhibitors are toxic and broad-spectrum, providing little insight into the mechanism of the switch between subtypes. In this work, we explore the mechanisms of HDAC inhibition in promoting subtype switching and further characterize the oncogenic potential of the two epigenetically distinct SW13 subtypes.
Methods
SW13 subtype morphology, chemotaxis, growth rates, and gene expression were assessed by standard immunofluorescence, transwell, growth, and qPCR assays. Metastatic potential was measured by anchorage-independent growth and MMP activity. The efficacy of HDAC inhibitors in inducing subtype switching was determined by immunofluorescence and qPCR. Histone modifications were assessed by western blot.
Results
Treatment of SW13- cells with HDAC1 inhibitors most effectively promotes re-expression of BRM and VIM, characteristic of the SW13+ phenotype. During treatment, hyperacetylation of histone residues and hypertrimethylation of H3K4 is pronounced. Furthermore, histone modification enzymes, including HDACs and KDM5C, are differentially expressed during treatment but several features of this differential expression pattern differs from that seen in the SW13- and SW13+ subtypes. As the SW13- subtype is more proliferative while the SW13+ subtype is more metastatic, treatment with HDACi increases the metastatic potential of SW13 cells while restoring expression of the BRM tumor suppressor.
Conclusions
When compared to the SW13- subtype, SW13+ cells have restored BRM expression, increased metastatic capacity, and significantly different expression of a variety of chromatin remodeling factors including those involved with histone acetylation and methylation. These data are consistent with a multistep mechanism of SW13- to SW13+ conversion and subtype stabilization: histone hypermodification results in the altered expression of chromatin remodeling factors and chromatin epigenetic enzymes and the re-expression of BRM which results in restoration of SWI/SNF complex function and leads to changes in chromatin structure and gene expression that stabilize the SW13+ phenotype.
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Impact of incident diabetes on atherosclerotic cardiovascular disease according to statin use history among postmenopausal women
Abstract
To compare impact of incident diabetes on atherosclerotic cardiovascular disease (ASCVD) risk among postmenopausal women according to statin use. Prospective data from 120,499 postmenopausal women without prevalent diabetes or cardiovascular disease at baseline from the Women's Health Initiative were used. Incident diabetes was self-reported annually and defined as treatment with pills or injectable medication for diabetes. Current statin use was determined at enrollment and years 1, 3, 6, 9 and 13.5 in the three clinical trial arms, and at baseline, year 3, and 13.5 for the observational study. The primary outcome was incident ASCVD events, self-reported annually and adjudicated by blinded local and central physicians. Incident diabetes and statin use status were fitted as time-varying covariates in Cox regression models to assess ASCVD risk during an average follow-up of 13.6 years. For those not on statins at the time of diabetes diagnosis, there was a 42 % increased risk of ASCVD [hazard ratio (HR) 1.42, 95 % CI 1.28–1.58] among women with incident diabetes versus those without diabetes. Among women on statins, there was a 39 % increased risk of ASCVD (HR 1.39, 95 % CI 1.12–1.74) in women with incident diabetes versus those without diabetes. The increased ASCVD risk due to diabetes was similar between women before or after initiating statins (P = 0.89). Whether diabetes was diagnosed before or after statin use did not alter the increased risk of ASCVD associated with diabetes. Mitigating the increased incidence of diabetes in statin users could increase the ASCVD benefit-to-risk ratio of statins.
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MicroRNA-21 promotes cell proliferation, migration, and resistance to apoptosis through PTEN/PI3K/AKT signaling pathway in esophageal cancer
Abstract
Our study aimed to explore associations between microRNA-21 (miR-21) and PTEN/PI3K/AKT signaling pathway and, further, to elucidate the regulation of miR-21 on biological behaviors in human esophageal cancer cells. The expressions of miR-21, PTEN, PI3K, and AKT were detected in 89 esophageal cancer samples and 58 adjacent normal tissues respectively. The human esophageal cancer cells (TE11) were grouped as following: blank (TE11 cells without transfection), negative (TE11 cells with miR-21 negative inhibitor), and Inhibition-miR21 (TE11 cells with miR-21 inhibitor). Western blot was used for detection of PTEN, P13K, and AKT protein expressions, MTT method for cell proliferation, Transwell assay for cell migration and invasion, and flow cytometry for cell cycle and apoptosis. MiR-21, PI3K, and AKT have higher expressions, but PTEN has lower expression in esophageal cancer tissues compared with adjacent normal tissues. The esophageal cancer tissues with lymph node metastasis and poor differentiation showed significantly low positive rate of PTEN protein, but high positive rates of PI3K and AKT proteins. Compared with blank and negative groups, PTEN expression of TE11 cells in Inhibition-miR21 group was significantly up-regulated, but PI3K and AKT were down-regulated. Further, PTEN was a target gene of miR-21. Besides, compared with blank and negative groups, the proliferation, migration, and invasion of TE11 cells were less active in Inhibition-miR21 group. TE11 cells were significantly increased in the G0/G1 phase of cell cycles, but decreased in the S and G2/M phase in Inhibition-miR21 group. The TE11 cells exhibited significantly increased apoptosis rates. MiR-21 targets key proteins in PTEN/PI3K/AKT signal pathway, promoting proliferation, migration, invasion, and cell cycle, and inhibiting apoptosis of human esophageal cancer cells. It may serve as a novel therapeutic target in esophageal cancer.
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Variable RBE in proton therapy: comparison of different model predictions and their influence on clinical-like scenarios
Abstract
Background
In proton radiation therapy a constant relative biological effectiveness (RBE) of 1.1 is usually assumed. However, biological experiments have evidenced RBE dependencies on dose level, proton linear energy transfer (LET) and tissue type. This work compares the predictions of three of the main radio-biological models proposed in the literature by Carabe-Fernandez, Wedenberg, Scholz and coworkers.
Methods
Using the chosen models, a spread-out Bragg peak (SOBP) as well as two exemplary clinical cases (single field and two fields) for cranial proton irradiation, all delivered with state-of-the-art pencil-beam scanning, have been analyzed in terms of absorbed dose, dose-averaged LET (LETD ), RBE-weighted dose (D RBE) and biological range shift distributions.
Results
In the systematic comparison of RBE predictions by the three models we could show different levels of agreement depending on (α/β)x and LET values. The SOBP study emphasizes the variation of LETD and RBE not only as a function of depth but also of lateral distance from the central beam axis. Application to clinical-like scenario shows consistent discrepancies from the values obtained for a constant RBE of 1.1, when using a variable RBE scheme for proton irradiation in tissues with low (α/β)x , regardless of the model. Biological range shifts of 0.6– 2.4 mm (for high (α/β)x ) and 3.0 – 5.4 mm (for low (α/β)x ) were found from the fall-off analysis of individual profiles of RBE-weighted fraction dose along the beam penetration depth.
Conclusions
Although more experimental evidence is needed to validate the accuracy of the investigated models and their input parameters, their consistent trend suggests that their main RBE dependencies (dose, LET and (α/β)x ) should be included in treatment planning systems. In particular, our results suggest that simpler models based on the linear-quadratic formalism and LETD might already be sufficient to reproduce important RBE dependencies for re-evaluation of plans optimized with the current RBE = 1.1 approximation. This approach would be a first step forward to consider RBE variations in proton therapy, thus enabling a more robust choice of biological dose delivery. The latter could in turn impact clinical outcome, especially in terms of reduced toxicities for tumors adjacent to organs at risk.
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Bone marrow-derived cells are recruited by the melanoma tumor with endothelial cells contributing to tumor vasculature
Abstract
Purpose
Tumor expansion is dependent on neovascularization, a process that requires sustained new vessel formation. Although the critical role of angiogenesis by endothelial sprouting in this process, controversy still prevails on whether angiogenesis involving bone marrow-derived endothelial cells, does contribute to this process. This study aims to evaluate the recruitment of bone marrow-derived cells by the melanoma tumor, including endothelial cells, and if they contribute to angiogenesis.
Methods
A chimeric mouse model of GFP bone marrow was used to induce melanoma tumors derived from murine B16-F10 cell line. These tumors were evaluated for the presence of myeloid cells (CD11b), T lymphocytes (CD3, CD4 and CD8) and endothelial cells (VEGFR2 and CD31) derived from bone marrow.
Results
Mice transplanted with GFP+ cells showed significant bone marrow chimerism (90.9 ± 0.87 %) when compared to the GFP transgenic mice (90.66 ± 2.1 %, p = 0.83) demonstrating successful engraftment of donor bone marrow stem/progenitor cells. Analysis of the murine melanoma tumor showed the presence of donor cells in the tumors (3.5 ± 1.7 %) and interestingly, these cells represent endothelial cells (CD31+ cells; 11.5 ± 6.85 %) and myeloid cells (CD11b+ cells; 80 ± 21 %), but also tumor-infiltrating lymphocytes (CD8+ T cells, 13.31 ± 0.2 %; CD4+ T-cells, 2.1 ± 1.2 %). Examination of the tumor endothelium by confocal microscopy suggests the presence of donor CD31+/GFP+ cells in the wall of some blood vessels.
Conclusion
This study demonstrates that bone marrow-derived cells are recruited by the murine melanoma tumor, with myeloid cells and CD4 and CD8 T lymphocytes migrating as antitumor immune response, and endothelial cells participating of the tumor blood vessels formation.
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Concurrent SPECT/PET-CT imaging as a method for tracking adoptively transferred T-cells in vivo
Abstract
Background
The ability of T-cells to traffic to and penetrate tumors impacts the clinical efficacy of T-cell therapy therefore methods to track transferred T-cells in vivo are needed. In this preliminary report, we evaluated the use of concurrent SPECT/PET-CT imaging to monitor the egress of HER-2/neu specific T-cells in a breast cancer patient with extensive bone-only metastatic disease.
Findings
Indium (In-111) labeled T-cells demonstrated similar or greater viability than unlabeled T-cells at either a low or high dose of In-111 over a 24-h incubation period in vitro. The function of labeled or unlabeled T-cells was not significantly different (p > 0.05) at either dose. T-cells trafficked to all sites of metastatic disease and infiltrated the tumor as assessed by SPECT imaging. In-111 uptake at 24 h after infusion varied from 3.8 (right proximal humerus) to 6.3 (right sacrum) background corrected counts per pixel and remained elevated at 48 h. Concurrent PET-CT imaging demonstrated a fluorodeoxyglucose flare, measured by increase in tumor site uptake as high as 32 % and at most sites of disease at 48 h. This flare was associated with focal pain after T-cell infusion at metastatic sites. The patient had stable disease for 18 months after completion of T-cell therapy.
Conclusion
Concurrent SPECT/PET-CT imaging, over a 48-h period after T-cell infusion, provided evidence of T-cell homing to all disease sites as well as a tumor metabolism flare response. This technique may be useful for monitoring T-cell trafficking after autologous as well as chimeric antigen receptor T-cell infusion.
Trial Registraion
Trial registered at ClinicalTrials.gov registration number NCT00791037, registered 13 November 2008.
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Can abscopal effects of local radiotherapy be predicted by modeling T cell trafficking?
Abstract
The abscopal effect of radiation describes tumor regression in metastases outside of the field upon treatment of one site, and is mediated by radiation-induced anti-tumor T cells. The ability of radiation to generate an in situ tumor vaccine and improve responses to immunotherapy is under intense investigation in the clinic. Preclinical and clinical evidence shows that multiple factors regulate radiation interaction with the immune system within and outside of the irradiated tumor. Poleszczuk and colleagues developed a mathematical model of T cell trafficking between metastases, and in a recent publication propose that the specific metastatic site irradiated determines the ability of T cells to traffic to other metastases and mediate abscopal responses and should dictate clinical decision making [Poleszczuk et al. Cancer Res 76:1009-18, 2016]. Here we critically discuss this model in light of the currently available information about abscopal responses in mice and patients. Caution in relying upon overly simplified models, before validation in real patients, is recommended.
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Agonist anti-GITR monoclonal antibody and stereotactic radiation induce immune-mediated survival advantage in murine intracranial glioma
Abstract
Background
Glioblastoma (GBM) is a poorly immunogenic neoplasm treated with focused radiation. Immunotherapy has demonstrated synergistic survival effects with stereotactic radiosurgery (SRS) in murine GBM. GITR is a co-stimulatory molecule expressed constitutively on regulatory T-cells and by effector T-cells upon activation. We tested the hypothesis that anti-GITR monoclonal antibody (mAb) and SRS together would confer an immune-mediated survival benefit in glioma using the orthotopic GL261 glioma model.
Methods
Mice received SRS and anti-GITR 10 days after implantation. The anti-GITR mAbs tested were formatted as mouse IgG1 D265A (anti-GITR (1)) and IgG2a (anti-GITR (2a)) isotypes. Mice were randomized to four treatment groups: (1) control; (2) SRS; (3) anti-GITR; (4) anti-GITR/SRS. SRS was delivered to the tumor in one fraction, and mice were treated with mAb thrice. Mice were euthanized on day 21 to analyze the immunologic profile of tumor, spleen, and tumor draining lymph nodes.
Results
Anti-GITR (1)/SRS significantly improved survival over either treatment alone (p < .0001) with a cure rate of 24 % versus 0 % in a T-lymphocyte-dependent manner. There was elevated intratumoral CD4+ effector cell infiltration relative to Treg infiltration in mice treated with anti-GITR (1)/SRS, as well as significantly elevated IFNγ and IL-2 production by CD4+ T-cells and elevated IFNγ and TNFα production by CD8+ T-cells. There was increased mRNA expression of M1 markers and decreased expression of M2 markers in tumor infiltrating mononuclear cells. The anti-GITR (2a)/SRS combination did not improve survival, induce tumor regression, or result in Treg depletion.
Conclusions
These findings provide preclinical evidence for the use of anti-GITR (1) non-depleting antibodies in combination with SRS in GBM.
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Glimpse into the future: harnessing autophagy to promote anti-tumor immunity with the DRibbles vaccine
Abstract
Because the benefits of immune checkpoint blockade may be restricted to tumors with pre-existing immune recognition, novel therapies that facilitate de novo immune activation are needed. DRibbles is a novel multi-valent vaccine that is created by disrupting degradation of intracellular proteins by the ubiquitin proteasome system. The DRibbles vaccine is comprised of autophagosome vesicles that are enriched with defective ribosomal products and short-lived proteins, known tumor-associated antigens, mediators of innate immunity, and surface markers that encourage phagocytosis and cross-presentation by antigen presenting cells. Here we summarize the rationale and preclinical development of DRibbles, translational evidence in support of DRibbles as a therapeutic strategy in humans, as well as recent developments and expected future directions of the DRibbles vaccine in the clinic.
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Circulating long non-coding RNAs in cancer: current status and future perspectives
Abstract
Long non-coding RNAs (lncRNAs) comprise a diverse class of RNA transcripts >200 nucleotides in length with limited protein-coding potential. In addition to their possible role in cancer biology, circulating lncRNAs have emerged as a new class of promising cancer biomarkers, with independent studies demonstrating the feasibility of their use as tools in the diagnosis and prognosis of different types of malignancies and for predicting and possibly monitoring treatment response. However, critical issues are represented by nonuniform sample choice, handling and processing, blood cell contamination during sample preparation and the lack of consensus regarding data normalization. In this review, we discuss the value of circulating lncRNAs in the clinical setting, particularly with respect to their possible implementation as diagnostic and prognostic markers in cancer. Although the great potential of circulating lncRNAs as cancer biomarkers would be an important development in disease management, both intrinsic and extrinsic factors that may affect their measurement have not been fully characterized. Moreover, the clinical significance of circulating lncRNA may not be proven without a global consensus regarding procedures and standardized protocols for their detection.
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Reciprocal activation between STAT3 and miR-181b regulates the proliferation of esophageal cancer stem-like cells via the CYLD pathway
Abstract
Background
Recent studies have suggested that cancer cells contain subpopulations that can initiate tumor growth, self-renew, and maintain tumor cell growth. However, for esophageal cancer cells, the relationship between STAT3, microRNAs and cancer stem cells remains unclear.
Methods
Serum-free culture was used to enrich esophageal cancer stem-like cells (ECSLC). Flow cytometry determined the proportion of ECSLC. qPCR were performed to examine expression level of stemness factors, mesenchymal markers, ATP-binding cassette (ABC) transporters, STAT3, miR-181b, CYLD. Western blot were performed to analyze the expression of STAT3, p-STAT3 and CYLD (cylindromatosis). BALB/c mice xenograft studies were conducted to evaluate the tumorigenicity of enriched ECSLC. Sphere formation assay and colony formation assays were employed to analyze the relationship between STAT3 and miR-181b. Luciferase assays were used to evaluate activity which CYLD is a target of miR-181b.
Results
Sphere formation cells (SFCs) with properties of ECSLC were enriched. Enriched SFCs in serum-free suspension culture exhibited cancer stem-like cell properties and increased single-positive CD44 + CD24-, stemness factor, mesenchymal marker expression ABC transporters and tumorigenicity in vivo compared with the parental cells. Additionally, we found that reciprocal activation between STAT3 and miR-181b regulated SFCs proliferation. Moreover, STAT3 directly activated miR-181b transcription in SFCs and miR-181b then potentiated p-STAT3 activity. Luciferase assays indicated that CYLD was a direct and functional target of miR-181b.
Conclusion
The mutual regulation between STAT3 and miR-181b in SFCs was required for proliferation and apoptosis resistance. STAT3 and miR-181b control each other's expression in a positive feedback loop that regulates SFCs via CYLD pathway. These findings maybe is helpful for targeting ECSLC and providing approach for esophageal cancer treatments.
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Impact of incident diabetes on atherosclerotic cardiovascular disease according to statin use history among postmenopausal women
Abstract
To compare impact of incident diabetes on atherosclerotic cardiovascular disease (ASCVD) risk among postmenopausal women according to statin use. Prospective data from 120,499 postmenopausal women without prevalent diabetes or cardiovascular disease at baseline from the Women's Health Initiative were used. Incident diabetes was self-reported annually and defined as treatment with pills or injectable medication for diabetes. Current statin use was determined at enrollment and years 1, 3, 6, 9 and 13.5 in the three clinical trial arms, and at baseline, year 3, and 13.5 for the observational study. The primary outcome was incident ASCVD events, self-reported annually and adjudicated by blinded local and central physicians. Incident diabetes and statin use status were fitted as time-varying covariates in Cox regression models to assess ASCVD risk during an average follow-up of 13.6 years. For those not on statins at the time of diabetes diagnosis, there was a 42 % increased risk of ASCVD [hazard ratio (HR) 1.42, 95 % CI 1.28–1.58] among women with incident diabetes versus those without diabetes. Among women on statins, there was a 39 % increased risk of ASCVD (HR 1.39, 95 % CI 1.12–1.74) in women with incident diabetes versus those without diabetes. The increased ASCVD risk due to diabetes was similar between women before or after initiating statins (P = 0.89). Whether diabetes was diagnosed before or after statin use did not alter the increased risk of ASCVD associated with diabetes. Mitigating the increased incidence of diabetes in statin users could increase the ASCVD benefit-to-risk ratio of statins.
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TFE3-Expressing Perivascular Epithelioid Cell Neoplasm (PEComa) of the Sella Turcica
Abstract
We report a primary central nervous system (CNS) perivascular epithelioid cell tumor (PEComa) in a middle-aged female patient. The tumor occurred in suprasellar location with secondary extension into the sella turcica. The patient presented with intracranial hemorrhage and an altered level of consciousness. The tumor had morphologic features matching those of other previously described TFE3-translocated PEComas, including epithelioid morphology, diffuse and strong nuclear immunoreactivity for TFE3, and minimal staining with myoid markers. The TFE3 break-apart FISH testing showed a slight splitting of one of the TFE3 signals in 49.5 % of nuclei. This case illustrates that PEComas should be added to the growing list of mesenchymal tumors that can be encountered in the CNS and specifically in the vicinity of the pituitary gland. The recognition of this entity is of significance given their underlying pathogenesis and possible management implications.
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Employment in French young adult survivors of childhood leukemia: an LEA study (for Leucemies de l’Enfant et de l’Adolescent—childhood and adolescent leukemia)
Abstract
Purpose
Our principal aim was to assess the occupational outcomes of French survivors of childhood leukemia, compared to national population. The secondary objective was to identify determinants linked with employment stability after childhood leukemia.
Methods
All survivors aged 15 and over enrolled in the French LEA Cohort (Childhood and Adolescent Leukemia) were included. Occupational data were self-reported. The occupational distributions expected in the cohort for each age range were established based on the distribution in France as reference, and comparisons between observed and expected distributions were performed. Logistic regression model was used to explore determinants of stability of survivors' employment.
Results
The questionnaire was completed by 845 eligible survivors (response rate 87.8 %), with a mean age of 22.3 ± 5.4 years and a mean follow-up duration of 14.3 ± 6.3 years. Among the 361 survivors currently in the labor market, 36 (10.0 %) were seeking a job, which is significantly lower than expected (19.3 %) compared to French population. Conversely, among those currently employed, the number of survivors in unstable employment (43.9 %) was significantly higher than expected (33.5 %). Younger age and higher number of late effects were risk factors for unstable employment.
Conclusions
While the employment rate of the young French adult population of childhood leukemia survivors seems rather positive, access to a steady job appears to be compromised for some survivors.
Implications for Cancer Survivors
A strategy to better identify particular subgroups of survivors at greatest risk for difficulties in their professional achievement will help ensure the development of specific intervention strategies and support procedures.
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Fluoride exposure in public drinking water and childhood and adolescent osteosarcoma in Texas
Abstract
Purpose
The purpose of this study was to examine the association between fluoride levels in public drinking water and childhood and adolescent osteosarcoma in Texas; to date, studies examining this relationship have been equivocal. Using areas with high and low naturally occurring fluoride, as well as areas with optimal fluoridation, we examined a wide range of fluoride levels in public drinking water.
Methods
This was a population-based case–control study, with both cases and controls obtained from the Texas Cancer Registry. Eligible cases were Texas children and adolescents <20 years old diagnosed with osteosarcoma between 1996 and 2006. Controls were sampled from children and adolescents diagnosed with either central nervous system (CNS) tumors or leukemia during the same time frame. Using geocoded patient addresses at the time of diagnosis, we estimated patients' drinking water fluoride exposure levels based on the fluoride levels of their residence's public water system (PWS). Unconditional logistic regression models were used to assess the association between osteosarcoma and public drinking water fluoride level, adjusting for several demographic risk factors.
Results
Three hundred and eight osteosarcoma cases, 598 leukemia controls, and 604 CNS tumor controls met selection criteria and were assigned a corresponding PWS fluoride level. PWS fluoride level was not associated with osteosarcoma, either in a univariable analysis or after adjusting for age, sex, race, and poverty index. Stratified analyses by sex were conducted; no association between PWS fluoride level and osteosarcoma was observed among either males or females.
Conclusions
No relationship was found between fluoride levels in public drinking water and childhood/adolescent osteosarcoma in Texas.
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Recurrence of Solid Pseudopapillary Neoplasms of the Pancreas: Results of a Nationwide Study of Risk Factors and Treatment Modalities
Background
Solid pseudopapillary neoplasms of the pancreas (SPPN) can relapse very late, but little is known about risk factors for recurrence and optimal treatment. We aimed to identify risk factors for recurrence and to analyze treatment modalities in all French pediatric cases of SPPN over the past 20 years.
Material and methods
Data were collected from pediatric oncologists and surgeons, and also from adult pancreatic surgeons in order to identify late recurrences.
Results
Fifty-one patients (41 girls) were identified. Median age at diagnosis was 13.1 years [8.7–17.9]. Abdominal pain was the commonest presenting symptom (32/49, 65%). The tumor was located in the pancreatic head in 24 patients (47%). Preoperative biopsy or cytology was performed in 14 cases (28%). All patients were operated with a median of 23 days [0–163] after diagnosis. The rate of postoperative morbidity was 29%. With a median follow-up of 65 months [0.3–221], the overall and event-free survival was 100% and 71%, respectively. Seven patients (13.7%) relapsed with a median of 43 months [33–94] after initial surgery. Six were treated surgically, either alone (n = 3) or with perioperative chemotherapy (n = 2) or hyperthermic intraperitoneal chemotherapy (n = 1). One patient in whom further treatment was not feasible was still alive at last news. Risk factors for recurrence were positive surgical margins (P = 0.03) and age less than 13.5 years at diagnosis (P = 0.03).
Conclusions
SPPN recurrence in this pediatric series was a rare and late event that did not undermine overall survival. Complete surgical removal of recurrent tumors appears to be the best option.
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The Feasibility of Physical Activity Interventions During the Intense Treatment Phase for Children and Adolescents with Cancer: A Systematic Review
Background
Physical activity may have benefits for children undergoing intense treatment for cancer, but such programmes are challenging to implement. This systematic review aimed to investigate the feasibly of physical activity interventions during intense cancer treatment for children and adolescents.
Procedure
A systematic search of seven electronic databases (Cumulative Index to Nursing and Allied Health Literature, Medical Literature Analysis and Retrieval System Online, Public/Publisher MEDLINE, Psychological Information Database, Sportsdiscuss, Excerpta Medica Database, Allied and Complementary Medicine Database) from 2005 to August 2015 was completed. The risk of bias was assessed using the Downs and Black Checklist and The Critical Review Form–Qualitative Studies. Results were summarised descriptively across eight domains of feasibility: acceptability, demand, implementation, adaptation, practicality, integration, expansion and limited efficiency testing (including effectiveness).
Results
Eleven quantitative studies and one qualitative study were identified for inclusion. Physical activity interventions were typically supervised, individualised programmes that prescribed a variety of activity types for hospital inpatients. There was evidence that physical activity interventions during the intense phase of cancer treatment were acceptable to parents and children, safe and successfully implemented. A trend of positive effects across all aspects of functioning was noted. Data were unavailable documenting feasibility for the domains of integration, adaptation and expansion.
Conclusion
There is preliminary evidence that physical activity interventions are feasible, in that they are acceptable, safe and potentially beneficial for children with cancer but more work needs to be done to understand the most effective ways to implement these types of programmes.
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Parental Grief Following the Death of a Child from Cancer: The Ongoing Odyssey
Background
The death of a child is a devastating event that results in profound grief and significant psychosocial and physical morbidities in parents. The parental grief journey is a complex phenomenon necessitating the utilization of newer models of bereavement with a focus on relationships and exploration of parents' perceived meanings of the experience.
Objectives
To further characterize the grief journey of parents whose child died from cancer in order to better identify parents who can benefit from additional bereavement support and design strategies to improve bereavement services for these parents.
Design
We conducted focus group sessions with 11 bereaved parents. The parents were given two prompts to describe their grief journey before and after their child's death, and their responses in a narrative form were audio-recorded. The responses were coded and studied independently by semantic content analysis.
Results
Collation and analysis of the coded responses to both prompts results in the emergence of four concepts from the parental narratives: (1) description of the grief trajectory and evolution of grief over time, (2) mechanisms of parental coping throughout the grief journey, (3) factors that exacerbate parental grief, and (4) sources of parental support throughout the grief journey.
Conclusions
The narratives highlighted that parents whose child died of cancer experience a unique and evolving form of grief and they wish to continue their bond with the deceased child. We recommend that healthcare providers and institutions incorporate support systems into a comprehensive bereavement program for families of children who die from cancer.
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Severe Radiation Necrosis Successfully Treated With Bevacizumab in an Infant with Low-Grade Glioma and Tumor-Associated Intractable Trigeminal Neuralgia
We present a unique case of radiation necrosis in a child with brain stem low-grade glioma (LGG) presenting with trigeminal neuralgia. Despite extensive therapies, severe pain persisted. She received proton beam radiation with significant improvement. However, she developed radiation necrosis and hydrocephalus. Despite surgical correction of hydrocephalus, the patient remained critically ill. She was treated with dexamethasone and bevacizumab with rapid clinical improvement. Subsequent MRIs revealed almost complete resolution of the necrosis. This case illustrates the successful treatment of trigeminal neuralgia with radiation and a rare case of radiation necrosis in an LGG successfully treated with bevacizumab and dexamethasone.
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The Role of Leukapheresis in the Current Management of Hyperleukocytosis in Newly Diagnosed Childhood Acute Lymphoblastic Leukemia
Background
Hyperleukocytosis in children with acute lymphoblastic leukemia (ALL) has been associated with early morbidity and mortality. The use of leukapheresis in these children treated with contemporary therapy remains controversial.
Procedure
We analyzed clinical data from patients enrolled onto frontline protocols for ALL (Total Therapy XV and XVI) between 2003 and 2014. We documented adverse events within the first 14 days in patients with a white blood cell (WBC) count ≥200 × 109/l and reviewed their management.
Results
Fifty-three (7.8%) of 678 consecutive pediatric patients with newly diagnosed ALL presented with hyperleukocytosis (median WBC count 393 × 109/l; range 200–1,014). Two deaths in patients without initial hyperleukocytosis occurred within the first 2 weeks from diagnosis secondary to bacterial sepsis. A total of 21 (40%) patients with ALL and hyperleukocytosis developed grade 3 or 4 adverse events regardless of the use of leukapheresis (P > 0.99 and P = 0.19). Sixteen of 53 (30%) patients with ALL received low-dose chemotherapy for leukocytoreduction initially. One-third of patients received urate oxidase, and none of the patients with hyperleukocytosis required hemodialysis.
Conclusions
The early morbidity and mortality commonly associated with hyperleukocytosis in children with newly diagnosed ALL can be avoided with contemporary supportive care and conservative management possibly obviating the need for costly and potentially dangerous leukapheresis.
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Primary Effusion Lymphoma (PEL)-Like Lymphoma in a Child With Congenital Immunodeficiency
Primary effusion lymphoma (PEL) is a rare lymphoma that occurs more frequently in immunocompromised adults and has a poor survival. We report a 9-year-old female with combined immunodeficiency with an Epstein–Barr virus positive/human herpes virus 8 negative PEL-like lymphoma. The treatment with systemic chemotherapy for non-Hodgkin lymphoma, zidovudine, and interferon-α failed to control disease progression. This is the first reported pediatric case of PEL-like lymphoma. Increased diagnostic awareness and more effective treatment strategies are needed for this rare lymphoma.
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Osteosarcoma After Hematopoietic Stem Cell Transplantation in Children and Adolescents: Case Report and Review of the Literature
Osteosarcoma as a secondary malignancy after hematopoietic stem cell transplantation (HSCT) is very rare. We present a case and review of 18 other cases reported to date. Our patient underwent HSCT for myelodysplastic syndrome at the age of 4 years. She developed osteosarcoma 13 years later. She underwent surgery after three courses of neoadjuvant chemotherapy followed by chemotherapy and mifamurtide. She has no evidence of disease 28 months after termination of chemotherapy. In 18 other cases of secondary osteosarcoma in the literature, 15 had received total body irradiation, eight had received alkylating agents, and six had received etoposide. The median interval from HSCT to the onset of osteosarcoma was 6.5 years (range 2.5–15.3), which confirms that children undergoing HSCT should be followed up for many years. In conclusion, osteosarcoma must be included in the differential diagnosis among solid tumors that may develop following HSCT.
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KIT polymorphisms were associated with the risk for head and neck squamous carcinoma in Chinese population
KITLG/KIT pathway plays a vital role in multiple types of human cancer including head and neck squamous cell carcinoma (HNSCC). Genetic variations in KITLG and KIT may affect the expression or function of these genes, thereby modifying cancer risk. In this study, we evaluated the association of KITLG and KIT polymorphisms with HNSCC risk among Chinese population. Twenty-two tagging SNPs in KITLG and KIT genes were genotyped in a case-control study with 576 HNSCC patients and 1552 healthy controls. Logistic regression analyses revealed that an upstream SNP rs6554198 [additive model: adjusted odds ratio (OR) = 0.85, 95% confidence interval (CI) = 0.74–0.97, P = 0.019] and two intron SNPs rs2237025 (additive model: adjusted OR = 0.82, 95%CI = 0.70–0.95, P = 0.007), and rs17084687 (additive model: adjusted OR = 0.85, 95%CI = 0.73–0.99, P = 0.042) of KIT were significantly associated with the decreased risk of HNSCC. Combined analysis of the three SNPs showed that subjects carrying the protective alleles had decreased risk of HNSCC in a dose-response manner (Ptrend = 0.001). Furthermore, interaction analyses revealed a significant multiplicative interaction between rs17084687 and drinking on HNSCC risk (P = 0.012). Luciferase activity assay indicated that the allele A of potentially functional rs6554198 led to significantly lower transcription activity of KIT compared to the risk allele G. Summarily, our findings suggested that SNPs in KIT gene may play a role in genetic susceptibility to HNSCC, which may improve our understanding of the pathogenic mechanisms of this disease. © 2016 Wiley Periodicals, Inc.
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Variable RBE in proton therapy: comparison of different model predictions and their influence on clinical-like scenarios
In proton radiation therapy a constant relative biological effectiveness (RBE) of 1.1 is usually assumed. However, biological experiments have evidenced RBE dependencies on dose level, proton linear energy tra...
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Disparities in cancer treatment among patients infected with the human immunodeficiency virus
BACKGROUND
Patients with cancer who are infected with the human immunodeficiency virus (HIV) are less likely to receive cancer treatment compared with HIV-uninfected individuals. However, to the authors' knowledge, the impact of insurance status and comorbidities is unknown.
METHODS
Data from the National Cancer Data Base were used to study nonelderly adults diagnosed with several common cancers from 2003 to 2011. Cancer treatment was defined as chemotherapy, surgery, radiotherapy, or any combination during the first course of treatment. Multivariate logistic regression was used to examine associations between HIV status and lack of cancer treatment, and identify predictors for lack of treatment among HIV-infected patients.
RESULTS
A total of 10,265 HIV-infected and 2,219,232 HIV-uninfected cases were included. In multivariate analysis, HIV-infected patients with cancer were found to be more likely to lack cancer treatment for cancers of the head and neck (adjusted odds ratio [aOR], 1.48; 95% confidence interval [95% CI], 1.09-2.01), upper gastrointestinal tract (aOR, 2.62; 95% CI, 2.04-3.37), colorectum (aOR, 1.70; 95% CI, 1.17-2.48), lung (aOR, 2.46; 95% CI, 2.19-2.76), breast (aOR, 2.14; 95% CI, 1.16-3.98), cervix (aOR, 2.81; 95% CI, 1.77-4.45), prostate (aOR, 2.16; 95% CI, 1.69-2.76), Hodgkin lymphoma (aOR, 1.92; 95% CI, 1.66-2.22), and diffuse large B-cell lymphoma (aOR, 1.82; 95% CI, 1.65-2.00). Predictors of a lack of cancer treatment among HIV-infected individuals varied by tumor type (solid tumor vs lymphoma), but black race and a lack of private insurance were found to be predictors for both groups.
CONCLUSIONS
In the United States, HIV-infected patients with cancer appear to be less likely to receive cancer treatment regardless of insurance and comorbidities. To the authors' knowledge, the current study is the largest study of cancer treatment in HIV-infected patients with cancer in the United States and provides evidence of cancer treatment disparities even after controlling for differences with regard to insurance status and comorbidities. Further work should focus on addressing differential cancer treatment. Cancer 2016. © 2016 American Cancer Society.
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Thrombin—unique coagulation system protein with multifaceted impacts on cancer and metastasis
Abstract
The association between blood coagulation and cancer development is well recognized. Thrombin, the pleiotropic enzyme best known for its contribution to fibrin formation and platelet aggregation during vascular hemostasis, may also trigger cellular events through protease-activated receptors, PAR-1 and PAR-4, leading to cancer progression. Our pioneering findings provided evidence that thrombin contributes to cancer metastasis by increasing adhesive potential of malignant cells. However, there is evidence that thrombin regulates every step of cancer dissemination: (1) cancer cell invasion, detachment from primary tumor, migration; (2) entering the blood vessel; (3) surviving in vasculature; (4) extravasation; (5) implantation in host organs. Recent studies have provided new molecular data about thrombin generation in cancer patients and the mechanisms by which thrombin contributes to transendothelial migration, platelet/tumor cell interactions, angiogenesis, and other processes. Though a great deal is known regarding the role of thrombin in cancer dissemination, there are new data for multiple thrombin-mediated events that justify devoting focus to this topic with a comprehensive approach.
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Will Testicular Germ Cell Tumors Remain Untargetable?
Abstract
Testicular Germ cell tumors (TGCT) represent the most common solid tumors affecting young men. They constitute a distinct entity because of their embryonic origin and their unique biological behavior. Recently, new preclinical data on genetic and epigenetic susceptibility profiles, biological signaling machinery as well as on molecular patterns of tumors and pathways of pathogenesis helped to elucidate the pathogenesis and the differentiation of TGCTs and to understand the mechanisms behind the development of resistance to treatment. In the present work, we have reviewed new clues to the development, differentiation and progression of TGCTs. We focus on the most important epigenetic and molecular biomarkers, and discussed their diagnostic and prognostic accuracy compared to the currently used biomarkers. The mechanisms underlying the development of resistance to cisplatin and commonly used chemotherapeutic agents are also discussed in detail. Finally, we summarize failed and ongoing clinical trials using targeted therapies in resistant TGCTs, and analyze the potential of new targeted therapies.
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The Immune Revolution in Gastrointestinal Tumours: Leading the Way or Just Following?
Abstract
The encouraging results in immunotherapy for melanoma also led the way for translational and clinical research about immune-related mechanisms possibly relevant for gastrointestinal tumours. It is in fact now evident that the immune checkpoint modulation and in particular cell-mediated immune-response through programmed cell death-1 (PD-1) and the cytotoxic T-lymphocyte antigen-4 (CTLA4) receptors along with the regulatory T cells activity all have a relevant role in gastrointestinal cancers as well. This review aims to explore the state of the art of immunotherapy for gastrointestinal tumours, deepening recent scientific evidence regarding anti PD-1/PDL-1 and anti CTLA4 monoclonal antibodies, peptide based vaccine, DNA based vaccine, and pulsed dendritic cells, either alone or in combination with other antineoplastic medical therapy and locoregional treatments. Considering the non-negligible toxicity profile deriving from such a treatment approach, predictive biomarkers of response to immunotherapy in gastrointestinal cancer are also urgently needed in order to better select the patients' group with the highest likelihood of benefit.
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Combinatorial Study of a Novel Poly (ADP-ribose) Polymerase Inhibitor and an HDAC Inhibitor, SAHA, in Leukemic Cell Lines
Abstract
Background
Cancer is a multifactorial disease, which makes it difficult to cure. Since more than one defective cellular component is often involved during oncogenesis, combination therapy is gaining prominence in the field of cancer therapeutics.
Objective
The purpose of this study was to investigate the combinatorial effects of a novel PARP inhibitor, P10, and HDAC inhibitor, SAHA, in leukemic cells.
Methods
Combinatorial effects of P10 and SAHA were tested using propidium iodide staining in different leukemic cells. Further, flowcytometry-based assays such as calcein-AM/ethidium homodimer staining, annexin-FITC/PI staining, and JC-1 staining were carried out to elucidate the mechanism of cell death. In addition, cell-cycle analysis, immunocytochemistry studies, and western blotting analysis were conducted to check the combinatorial effect in Nalm6 cells.
Results
Propidium iodide staining showed that P10 in combination with SAHA induced cell death in Nalm6 cells, in which PARP expression and activity is high with a combination index of <0.2. Annexin-FITC/PI staining, JC-1 staining, and other biochemical assays revealed that P10 in combination with SAHA induced apoptosis by causing a change in mitochondrial membrane potential in >65 % cells. Importantly, combinatorial treatment induced S phase arrest in 40-45 % cells due to DNA damage and plausible replicative stress. Finally, we demonstrated that treatment with P10 led to DNA strand breaks, which were further potentiated by SAHA (p < 0.01), leading to activation of apoptosis and increased cell death in PARP-positive leukemic cells.
Conclusions
Our study reveals that coadministration of PARP inhibitor with SAHA could be used as a combination therapy against leukemic cells that possess high levels of intrinsic PARP activity.
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Role of prophylactic central compartment lymph node dissection in clinically N0 differentiated thyroid cancer patients: analysis of risk factors and review of modern trends
Abstract
In the last years, especially thanks to a large diffusion of ultrasound-guided FNBs, a surprising increased incidence of differentiated thyroid cancer (DTC), "small" tumors and microcarcinomas have been reported in the international series. This led endocrinologists and surgeons to search for "tailored" and "less aggressive" therapeutic protocols avoiding risky morbidity and useless "overtreatment". Considering the most recent guidelines of referral endocrine societies, we analyzed the role of routine or so-called prophylactic central compartment lymph node dissection (RCLD), also considering its benefits and risks. Literature data showed that the debate is still open and the surgeons are divided between proponents and opponents of its use. Even if lymph node metastases are commonly observed, and in up to 90 % of DTC cases micrometastases are reported, the impact of lymphatic involvement on long-term survival is subject to intensive research and the best indications of lymph node dissection are still controversial. Identification of prognostic factors for central compartment metastases could assist surgeons in determining whether to perform RLCD. Considering available evidence, a general agreement to definitely reserve RCLD to "high-risk" cases was observed. More clinical researches, in order to identify risk factors of meaningful predictive power and prospective long-term randomized trials, should be useful to validate this selective approach.
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Cancers, Vol. 8, Pages 50: Frizzled7: A Promising Achilles’ Heel for Targeting the Wnt Receptor Complex to Treat Cancer
Frizzled7 is arguably the most studied member of the Frizzled family, which are the cognate Wnt receptors. Frizzled7 is highly conserved through evolution, from Hydra through to humans, and is expressed in diverse organisms, tissues and human disease contexts. Frizzled receptors can homo- or hetero-polymerise and associate with several co-receptors to transmit Wnt signalling. Notably, Frizzled7 can transmit signalling via multiple Wnt transduction pathways and bind to several different Wnt ligands, Frizzled receptors and co-receptors. These promiscuous binding and functional properties are thought to underlie the pivotal role Frizzled7 plays in embryonic developmental and stem cell function. Recent studies have identified that Frizzled7 is upregulated in diverse human cancers, and promotes proliferation, progression and invasion, and orchestrates cellular transitions that underscore cancer metastasis. Importantly, Frizzled7 is able to regulate Wnt signalling activity even in cancer cells which have mutations to down-stream signal transducers. In this review we discuss the various aspects of Frizzled7 signalling and function, and the implications these have for therapeutic targeting of Frizzled7 in cancer.
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Immunotherapy for genitourinary cancer: state of the art and new perspectives.
In the last few years, cancer immunotherapy has changed the natural history and treatment strategies of a number of solid tumors, including melanoma and lung cancer. The anti-PD-1 nivolumab showed a survival benefit compared with everolimus in the second-line treatment of renal cell carcinoma, resulting in a radical shift in perspective in the treatment of this neoplasia and suggesting a new scenario beyond tyrosine kinase inhibitors. Checkpoint inhibitors might also improve the treatment of urothelial cancer, considering the promising results achieved so far and the relatively low efficacy of currently available treatments. Sipuleucel-T was the first approved immunotherapy for prostate cancer, showing a clear benefit in overall survival, and paved the way for the clinical testing of other novel cancer vaccines. This review provides a comprehensive overview of the current knowledge and new perspectives of immunotherapy in the treatment of urogenital malignancies. Copyright (C) 2016 Wolters Kluwer Health, Inc. All rights reserved.
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Flavonoid and lignan intake and pancreatic cancer risk in the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort
Abstract
Despite the potential cancer preventive effects of flavonoids and lignans, their ability to reduce pancreatic cancer risk has not been demonstrated in epidemiological studies. Our aim was to examine the association between dietary intakes of flavonoids and lignans and pancreatic cancer risk in the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort.
A total of 865 exocrine pancreatic cancer cases occurred after 11.3 years of follow-up of 477,309 cohort members. Dietary flavonoid and lignan intake was estimated through validated dietary questionnaires and the U.S. Department of Agriculture (USDA) and Phenol Explorer databases. Hazard ratios (HR) and 95% confidence intervals (CIs) were calculated using age, sex and center-stratified Cox proportional hazards models, adjusted for energy intake, body mass index (BMI), smoking, alcohol and diabetes status.
Our results showed that neither overall dietary intake of flavonoids nor of lignans were associated with pancreatic cancer risk (multivariable-adjusted HR for a doubling of intake = 1.03, 95% CI: 0.95-1.11 and 1.02; 95% CI: 0.89-1.17, respectively). Statistically significant associations were also not observed by flavonoid subclasses. An inverse association between intake of flavanones and pancreatic cancer risk was apparent, without reaching statistical significance, in microscopically confirmed cases (HR for a doubling of intake = 0.96, 95% CI: 0.91-1.00).
In conclusion, we did not observe an association between intake of flavonoids, flavonoid subclasses or lignans and pancreatic cancer risk in the EPIC cohort. This article is protected by copyright. All rights reserved.
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Reduction in squamous cell carcinomas in mouse skin by dietary zinc supplementation
Abstract
Inadequate dietary Zn consumption increases susceptibility to esophageal and other cancers in humans and model organisms. Since Zn supplementation can prevent cancers in rodent squamous cell carcinoma (SCC) models, we were interested in determining if it could have a preventive effect in a rodent skin cancer model, as a preclinical basis for considering a role for Zn in prevention of human nonmelanoma skin cancers, the most frequent cancers in humans. We used the 7,12-dimethyl benzanthracene carcinogen/phorbol myristate acetate tumor promoter treatment method to induce skin tumors in Zn-sufficient wild-type and Fhit (human or mouse protein) knockout mice. Fhit protein expression is lost in >50% of human cancers, including skin SCCs, and Fhit-deficient mice show increased sensitivity to carcinogen induction of tumors. We hypothesized that: (1) the skin cancer burdens would be reduced by Zn supplementation; (2) Fhit−/−(Fhit, murine fragile histidine triad gene) mice would show increased susceptibility to skin tumor induction versus wild-type mice. 30 weeks after initiating treatment, the tumor burden was increased ~2-fold in Fhit−/− versus wild-type mice (16.2 versus 7.6 tumors, P < 0.001); Zn supplementation significantly reduced tumor burdens in Fhit−/− mice (males and females combined, 16.2 unsupplemented versus 10.3 supplemented, P = 0.001). Most importantly, the SCC burden was reduced after Zn supplementation in both strains and genders of mice, most significantly in the wild-type males (P = 0.035). Although the mechanism(s) of action of Zn supplementation in skin tumor prevention is not known in detail, the Zn-supplemented tumors showed evidence of reduced DNA damage and some cohorts showed reduced inflammation scores. The results suggest that mild Zn supplementation should be tested for prevention of skin cancer in high-risk human cohorts.
Zn supplementation can suppress tumor formation in rodent models. To determine if it could suppress development of nonmelanoma skin cancers, the most common cancer in humans, occurring with high frequency and morbidity in patients, we induced skin papillomas and squamous cell carcinoma (SCCs) in mice by carcinogen treatment. Zn supplementation suppressed the frequency of SCCs in both sexes of two mouse strains, suggesting that Zn supplementation should be tested for prevention of SCCs in high-risk humans.
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An examination of racial differences in 5-year survival of cervical cancer among African American and white American women in the southeastern US from 1985 to 2010
Abstract
Disparities in Cervical Cancer (CC) mortality outcomes between African American (AA) and White women have been studied for decades. However, conclusions about the effect of race on CC survival differ across studies. This study assessed differences in CC survival between AA and White women diagnosed between 1985 and 2010 and treated at two major hospitals in the southeastern US. The study sample included 925 AA and 1192 White women diagnosed with cervical adenocarcinoma, adenosquamous cell carcinoma, or squamous cell carcinoma. Propensity score adjustment and matching were employed to compare 5-year survival between the two racial groups. Crude comparisons suggested relevant racial differences in survival. However, the racial differences became of small magnitude after propensity-score adjustment and in matched analyses. Nonlinear models identified age at diagnosis, cancer stage, mode of treatment, and histological subtype as the most salient characteristics predicting 5-year survival of CC, yet these characteristics were also associated with race. Crude racial differences in survival might be partly explained by underlying differences in the characteristics of racial groups, such as age at diagnosis, histological subtype, cancer stage, and the mode of treatment. The study results highlight the need to improve access to early screening and treatment opportunities for AA women to improve posttreatment survival from CC.
We did not observe strong evidence for racial differences in survival of cervical cancer. The study suggests that the age at diagnosis, cancer stage, mode of treatment, and histological subtype are the most salient characteristics predicting 5-year survival.
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Expressions of SH3BP5, LMO3, and SNAP25 in diffuse large B-cell lymphoma cells and their association with clinical features
Abstract
Diffuse large B-cell lymphoma (DLBCL) is clinicopathologically and genetically heterogeneous with variable clinical outcomes. We previously identified signature genes overexpressed in CD5-positive (CD5+) DLBCL, which is a poor prognostic subgroup of DLBCL. To elucidate the clinical significance of the protein expression of the signature genes overexpressed in CD5+ DLBCL with regard to all DLBCL, not otherwise specified (NOS), 10 genes (SH3BP5, LMO3, SNAP25, SYT5, SV2C, CABP1, FGF1, FGFR2, NEUROD1, and SYN2) were selected and examined immunohistochemically with samples from 28 patients with DLBCL, NOS. Only three protein expressions, SH3BP5, LMO3, and SNAP25, were detected in DLBCL cells and then analyzed further with samples from 187 patients with DLBCL, NOS. The SH3BP5, LMO3, and SNAP25 proteins were expressed in 60% (103/173), 34% (59/175), and 46% (77/168) of DLBCL patients, respectively. These protein expressions were associated with CD5 expression, and only SH3BP5 was frequently expressed in activated B-cell-like DLBCL (P = 0.046). Compared to the SH3BP5-negative group, the SH3BP5+ group was correlated with elderly onset (>60 years, P = 0.0096) and advanced-stage disease (stage III/IV, P = 0.037). The LMO3+ group showed a worse performance status (>1, P = 0.0004). The SH3BP5+ group and the LMO3+ group had significantly worse overall survival than the negative groups (P = 0.030, 0.034; respectively) for the entire group. In a subgroup analysis of patients treated with rituximab-containing chemotherapy, there was no significant difference between groups. To the best of our knowledge, this is the first report showing the protein expressions of SH3BP5, LMO3, and SNAP25 in DLBCL cells and their clinical significance in patients with DLBCL. The SH3BP5 and LMO3 protein expressions are associated with the baseline clinical characteristics of DLBCL.
DLBCL cells can express SH3BP5, LMO3, and SNAP25 proteins. The SH3BP5 and LMO3 protein expressions are associated with clinical features of DLBCL patients.
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High expression of integrin β6 in association with the Rho–Rac pathway identifies a poor prognostic subgroup within HER2 amplified breast cancers
Abstract
Integrin αvβ6 is involved in the transition from ductal carcinoma in situ (DCIS) to invasive ductal carcinoma (IDC) of the breast. In addition, integrin β6 (ITGB6) is of prognostic value in invasive breast cancers, particularly in HER2+ subtype. However, pathways mediating the activity of integrin αvβ6 in clinical progression of invasive breast cancers need further elucidation. We have examined human breast cancer specimens (N = 460) for the expression of integrin β6 (ITGB6) mRNA by qPCR. In addition, we have examined a subset (N = 147) for the expression of αvβ6 integrin by immunohistochemistry (IHC). The expression levels of members of Rho–Rac pathway including downstream genes (ACTR2, ACTR3) and effector proteinases (MMP9, MMP15) were estimated by qPCR in the HER2+ subset (N = 59). There is a significant increase in the mean expression of ITGB6 in HER2+ tumors compared to HR+HER2- and triple negative (TNBC) subtypes (P = 0.00). HER2+ tumors with the highest levels (top quartile) of ITGB6 have significantly elevated levels of all the genes of the Rho–Rac pathway (P-values from 0.01 to 0.0001). Patients in this group have a significantly shorter disease-free survival compared to the group with lower ITGB6 levels (HR = 2.9 (0.9–8.9), P = 0.05). The mean level of ITGB6 expression is increased further in lymph node-positive tumors. The increased regional and distant metastasis observed in HER2+ tumors with high levels of ITGB6 might be mediated by the canonical Rho–Rac pathway through increased expression of MMP9 and MMP15.
The evidence for the involvement of αvβ6 integrin in the progression of breast cancer rests on data from two large European cohorts of patients. However, the identity of the downstream pathways involved is unclear. We have used two independent case series (N = 460) and have confirmed the observations of Moore et al. More importantly, we have found supporting evidence for the activation of the Rho–Rac pathway in HER2+ patients with elevated levels of ITGB6 expression.
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