Cancer Medicine by Alexandros G.Sfakianakis,Anapafseos 5 Agios Nikolaos,Crete 72100,Greece,tel :00302841026182 & 00306932607174
Δευτέρα 6 Ιουνίου 2016
A parent-directed intervention for addressing academic risk in latino survivors of childhood leukemia: results of a pilot study
Key Points
Survivors of childhood acute lymphoblastic leukemia (ALL) are at risk for treatment-related neurocognitive dysfunction, which may be exacerbated by factors related to low socio-economic status and linguistic disparities.
- Approximately half of childhood ALL survivors at our institution are Latino and exhibit multiple socio-demographic risk factors that threaten academic functioning.
- To better serve these survivors, we developed a culturally competent, parent-directed intervention to improve academic success that is feasible to deliver, shows preliminary evidence of efficacy, and is valued by families.
- The approach outlined here enables pediatric cancer treatment centers to provide culturally competent assessment and academic support that exceed published guidelines for survivors at neurocognitive risk.
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Comparison of KRAS mutation status between primary tumor and metastasis in Chinese colorectal cancer patients
Abstract
Detection of KRAS mutation status is a routine clinical procedure for predicting response to anti-EGFR therapy in colorectal cancer (CRC) patients. Previous studies showed high concordance of KRAS mutation status in primary lesion and corresponding metastatic sites in CRC. However, the data were mostly from Caucasians. The aim of this study is to compare KRAS mutation and other molecules mutation status between primary tumor and corresponding metastatic lesion in Chinese patients with CRC. In this retrospective study, Chinese CRC patients with paired samples of primary tumor and metastatic site were detected for KRAS codon 12 and 13 with quantitative real-time PCR, or detected for OncoCarta™ panel of 19 genes with MassARRAY® technique, including KRAS, BRAF, NRAS and PIK3CA et al. Forty-eight paired CRC samples were analyzed for KRAS codon 12 and 13 using quantitative real-time PCR. Ten paired samples were analyzed by 19 genes OncoCarta™ Panel with MassARRAY® technique. KRAS mutation was found in 15 (25.9 %) primary tumors and 18 (31.0 %) metastases. The discordance of KRAS was observed in 11 (19.0 %) patients. Alteration of mutation points in primary site with mutant KRAS was not observed. In the 10 patients with multiple gene detection, PIK3CA mutation showed concordant mutation status in primary tumor and metastatic site, whereas discordance in BRAF, NRAS and AKT1 was detected. A concordance rate of 81.0 % was detected in KRAS mutation between primary tumor and metastatic lesion in Chinese patients with CRC. Discordance of BRAF, NRAS and AKT1 mutation status in primary tumor and metastases was observed.
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The Genomic Data Commons Launches
Making genomic and clinical data about cancer accessible to the cancer research community is imperative for our success in applying precision medicine to clinical oncology. The NCI Genomic Data Commons (GDC), released today, brings us a step closer to realizing this goal.
By analyzing large sets of shared data with the cutting-edge bioinformatics tools, we can improve our ability discover the genomic changes that drive rare cancers, puzzle out the complexity of tumor growth and drug resistance, and identify robust targets for therapy. The GDC is a data sharing platform to facilitate these types of discoveries. The GDC initially contains NCI-generated datasets including some of the most comprehensive cancer genomic datasets in the world, The Cancer Genome Atlas (TCGA), and the pediatric equivalent, TARGET.
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Tumor Microenvironment Influences Metabolism of Cancer Cells
When we think about tumor heterogeneity, we often imagine variation that originates from genetic and/or epigenetic mechanisms. However, there is increasing evidence that variation exists at the level of cellular metabolism and that this intratumoral heterogeneity could be important to tumor progression. The vast majority of RAS-driven tumors are notoriously aggressive and do not respond to chemotherapies, and it is conceivable that the metabolic heterogeneity found within these tumors could be contributing to their aggressiveness or to chemoresistance. Variations in metabolic wiring could allow some cancers cells within the tumor to be better positioned to survive specific stresses within the harsh tumor microenvironment. Moreover, metabolic adaptation to these stresses might also impact signaling pathways that regulate macropinocytosis and autophagy, both critical routes of nutrient supply in RAS-driven tumors1, 2.
In rapidly proliferating RAS-mutated pancreatic cancer cells, cellular metabolism comes in at least two broad flavors – cells that are glycolytic and those that are lipogenic3. Interestingly, the glycolytic cells, which have elevated levels of various components of glycolysis, are associated with more mesenchymal properties, while lipogenic cells that are enriched for various lipid metabolites are associated with a classical, more epithelial cell type3, 4. This is a great example of how metabolic heterogeneity within RAS-driven tumors might be contributing to tumor aggressiveness and/or invasion. In my lab we have observed that in addition to the differential usage of various metabolic pathways, RAS-mutated pancreatic cancers also exhibit intratumoral variation in how they obtain nutrients, with some cells depending on nutrient transporters and other cells relying on protein scavenging pathways, such as macropinocytosis. Altogether, it looks like it will be imperative to take into account this heterogeneity when designing novel therapeutic strategies for this disease.
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Patient-Derived Antibody Appears to Selectively Target Tumor Cells, Spur Immune Attack
Researchers have developed an antibody, derived from patients with early-stage lung cancer, that enlists the immune system to destroy cancer cells.
The antibody killed tumor cells in cell lines of several different cancer types and slowed tumor growth in mouse models of brain and lung cancer without obvious evidence of side effects, the researchers reported May 5 in Cell Reports.
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Roles of acid-extruding ion transporters in regulation of breast cancer cell growth in a 3-dimensional microenvironment
Abstract
Background
The 3-dimensional (3D) microenvironment of breast carcinomas is characterized by profoundly altered pH homeostasis, reflecting increased metabolic acid production and a confined extracellular space characterized by poor diffusion, yet the relative contributions of specific pH-regulatory transporters to 3D growth are poorly understood. The aim of this work was to determine how 3D spheroid growth of breast cancer cells impacts the expression and spatial organization of major acid extruding proteins, and how these proteins in turn are required for spheroid growth.
Methods
MCF-7 (Luminal-A) and MDA-MB-231 (Triple-negative) human breast cancer cells were grown as ~700-950 μm diameter spheroids, which were subjected to Western blotting for relevant transporters (2- and 3D growth), quantitative immunohistochemical analysis, and spheroid growth assays. Individual transporter contributions were assessed (i) pharmacologically, (ii) by stable shRNA- and transient siRNA-mediated knockdown, and (iii) by CRISPR/Cas9 knockout.
Results
In MCF-7 spheroids, expression of the lactate-H+ cotransporter MCT1 (SLC16A1) increased from the spheroid periphery to its core, the Na+,HCO3− cotransporter NBCn1 (SLC4A7) was most highly expressed at the periphery, and the Na+/H+ exchanger NHE1 (SLC9A1) and MCT4 (SLC16A3) were evenly distributed. A similar pattern was seen in MDA-MB-231 spheroids, except that these cells do not express MCT1. The relative total expression of NBCn1 and NHE1 was decreased in 3D compared to 2D, while that of MCT1 and MCT4 was unaltered. Inhibition of MCT1 (AR-C155858) attenuated MCF-7 spheroid growth and this was exacerbated by addition of S0859, an inhibitor of Na+,HCO3− cotransporters and MCTs. The pharmacological data was recapitulated by stable knockdown of MCT1 or NBCn1, whereas knockdown of MCT4 had no effect. CRISPR/Cas9 knockout of NHE1, but neither partial NHE1 knockdown nor the NHE1 inhibitor cariporide, inhibited MCF-7 spheroid growth. In contrast, growth of MDA-MB-231 spheroids was inhibited by stable or transient NHE1 knockdown and by NHE1 knockout, but not by knockdown of NBCn1 or MCT4.
Conclusions
This work demonstrates the distinct expression and localization patterns of four major acid-extruding transporters in 3D spheroids of human breast cancer cells and reveals that 3D growth is dependent on these transporters in a cell type-dependent manner, with potentially important implications for breast cancer therapy.
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Expression of the Insulin-like Growth Factor-1 Receptor in Odontogenic Myxoma
Odontogenic myxoma (OM) is a rare mesenchymal tumour arising in the jaws. The origin and pathogenesis of OM is poorly understood. The aim of this study was to characterize OM by immunolocalization of certain antigens in the tumour that are relevant for cellular differentiation, migration and maintenance. Materials and Methods: Five OMs were immunohistochemically investigated for expression of nestin, CD133, podoplanin, and insulin-like growth factor 1 receptor (IGF-1R). Results: OM failed to react with antibodies applied in this study, with the exception of IGF-1R in tumour cells. Discussion: OM is a poorly characterized benign, invasive tumour of the jaws. The absence of stem cell marker in OM does not exclude possible temporary expression of these antigens during certain phases of tumour development. The identification of IGF-1R in OM is shared with numerous tumours and indicates the ability of these tumour cells to respond to growth factors.
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Imaging of Gastrointestinal Stromal Tumors: From Diagnosis to Evaluation of Therapeutic Response
Once considered an obscure tumor entity with poor prognosis, gastrointestinal stromal tumors (GISTs) are nowadays recognized as the most common mesenchymal tumors of the alimentary tract. GISTs differ from other mesenchymal neoplasms at pathology since 90% of them exhibit strong immunohistochemical staining for KIT, a tyrosinase kinase growth factor receptor. In the early 2000s, the ability of imatinib mesylate, a tyrosine kinase inhibitor, to inhibit KIT established a new paradigm for cancer treatment. A reduction in lesion size may not be observed or may appear many months after therapy; thus, tumor response criteria alternative to the Response Evaluation Criteria in Solid Tumors were developed. This review highlights the role of imaging in the detection, characterization, preoperative staging, postoperative assessment, therapy-response evaluation and treatment-related toxicities. All this information is crucial in optimizing patient management. Contrast-enhanced computed tomography is the most commonly used modality for staging the disease and assessing treatment response, whereas positron-emission tomography adds valuable functional information. Magnetic resonance imaging (MRI) may also be useful, especially in ano-rectal GISTs. Diffusion-weighted MRI may provide promising indicators of tumor response to targeted molecular therapy. Radiologists and oncologists should be aware of all these issues related to GISTs, since multidisciplinary teams gathering different expertise are usually needed to properly treat patients with GISTs.
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Birinapant (TL32711) Improves Responses to GEM/AZD7762 Combination Therapy in Triple-negative Breast Cancer Cell Lines
Background: Triple-negative breast cancer (TNBC) is an aggressive form of breast cancer currently lacking targeted therapies. Our previous work demonstrated a therapeutic synergism with gemcitabine (GEM) and the CHK1 inhibitor (AZD7762) combination treatment in a TNBC cell line. We hypothesized that the response to this combination therapy would differ among heterogeneous TNBC patients and that addition of a SMAC mimetic (TL32711) could improve efficacy. Materials and Methods: Therapeutic responses to GEM, GEM/AZD7762, and GEM/AZD7762/TL32711 combinations were investigated by XTT assays and western blotting of cell cycle and apoptosis-related proteins in ten TNBC cell lines. Results: TNBC cell lines harboring low levels of endogenous CHK1, cIAP1 and cIAP2 were responsive to GEM alone, whereas cell lines demonstrating a minimal increase in phospho-S345 CHK1 after treatment were responsive to GEM/AZD7762 or GEM/AZD7762/TL32711 combination. Conclusion: The response of TNBC cells to particular therapies varies and will require development of predictive biomarkers.
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Endometrial Adenocarcinoma: Analysis of Circulating Tumour Cells by RT-qPCR
Background: Endometrial adenocarcinoma is a frequently occurring cancer in women, accounting for 42,000 deaths every year. Despite treatment with standard therapy, occurrence of remote metastases and local recurrences is high. Through help of RT-qPCR minimal residual disease could be detected and characterized, facilitating therapeutic decision making. Materials and Methods: A number of marker genes were first tested in model systems and genes that performed best, were consequently used for the examination of 13 blood samples from endometrial carcinoma patients. Results: Cytokeratin 19 and MIG7 were chosen for the analysis in patient samples. Both genes were found up-regulated in small tumours and in one large tumour, but no statistical correlations could be revealed between expression levels of these two genes and tumour characteristics. Conclusion: There seems to be a coherence between gene expression and the stage of tumorigenesis, but the number of samples is still too small, to be able to obtain statistical significant differences.
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Decreased Expression of Retinoid X Receptors During Human and Azoxymethane-induced Colorectal Carcinogenesis in the Rat
Background/Aim: The family of retinoid X receptors (RXRs) including RXRα, β and , is involved in regulating cell proliferation, differentiation, apoptosis and development. Materials and Methods: In order to characterize the role of RXRs during colorectal carcinogenesis, the expression of RXRs in human and azoxymethane (AOM)-induced rat colorectal tumors was profiled by immunohistochemistry. Results: Both human and rat normal colorectal epithelia and hyperplasia exhibited strong nuclear, but weak cytoplasmic staining for all three proteins. Expression of RXRα, β and was significantly reduced in rat carcinomas compared to high-grade dysplasia whether in aberrant crypt foci or in adenomas. All three proteins displayed dramatically reduced nuclear expression in both human adenomas and carcinomas. Reduced expression of RXRα and RXR seems more significant than RXRβ in both human and rat carcinomas. Conclusion: Reduced expression of RXRs is associated with colorectal carcinogenesis in both humans and AOM-treated rats.
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The Contribution of Dental Implants to Functional Artificial Restoration After Treatment of Oral Cancer
Background/Aim: The aim of this study was to evaluate dental implants with regard to artificial restoration of oral function and quality of life in patients with oral cancer. Patients and Methods: We examined 134 implants in 41 patients who had undergone jawbone resection as treatment for oral cancer. The patients were aged 44-89 (mean=61.5) years, and the male to female ratio was 27:14. Results: The 5-year implant success rate was 91.0%. Of the 12 unsuccessful implants, four were embedded on bone grafts with skin flaps, four were embedded on skin flaps using muscle, and four were embedded after peripheral resection. Of the 41 patients, 11 received radiation, but exposure to radiation was not associated with implant loss. The level of satisfaction on the visual analog scale before development of oral cancer was set at 100 mm. Satisfaction fell to 47.0 mm after primary treatment, but recovered to 82.6 mm after implant therapy. Conclusion: Patient satisfaction after implant therapy was high, and the implants resulted in improved quality of life. A high proportion of cases involving use of skin flaps resulted in implant loss. Constructing an immobile mucous membrane by replacement of a skin flap with a skin graft may facilitate self-maintenance of implants.
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Induction of Apoptosis by Functionalized Fullerene-based Sonodynamic Therapy in HL-60 cells
Ultrasound has been widely utilized for medical diagnosis and therapy due to its ability to penetrate deep-seated tissue with less attenuation of energy and minimal undesirable side-effects. Functionalized fullerenes, such as polyhydroxy fullerene (PHF), have attracted particular attention due to their water solubility and potential application in tumor imaging and therapy as carbon nanomaterials. The present study investigated sonodynamically-induced apoptosis using PHF. Cell suspensions were treated with 2-MHz continuous ultrasound in the presence of PHF for 3 min and apoptosis was assessed by cell morphology using confocal microscopy, fragmentation of DNA (ladder pattern after agarose-gel electrophoresis) and caspase-3 activation. Cells were ultrasound-irradiated from the bottom of the culture dishes under the following condition: frequency, 2 MHz; output power, 3 W/cm2. Electron spin resonance was used to measure reactive oxygen species. The number of apoptotic cells after sonodynamic exposure (ultrasound and PHF) was significantly higher than produced from other treatments, such as ultrasound alone and PHF alone. Furthermore, DNA fragmentation, caspase-3 activation and enhanced 2,2,6,6-tetramethyl-4-piperidinyloxy (4oxoTEMPO) formation were observed in the sonodynamically-treated cells. Histidine, a well-known reactive oxygen scavenger, significantly inhibited sonodynamically-induced apoptosis, caspase-3 activation and 4oxoTEMPO formation. Sonodynamic therapy with PHF induced apoptosis that was characterized by a series of typical morphological features, such as shrinkage of the cell and fragmentation into membrane-bound apoptotic bodies, in HL-60 cells. The significant inhibition of sonodynamically-induced apoptosis, caspase-3 activation, and 4oxoTEMPO formation due to histidine and tryptophan suggests that reactive oxygen species, such as singlet oxygen, are involved in the sonodynamic induction of apoptosis. These findings indicate that PHF-mediated sonodynamic therapy can trigger caspase-dependent apoptosis and oxidative injury, thus possibly playing a vital role in apoptotic signaling cascades.
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Expansive Extracranial Growth of Intracranial Meningioma in Neurofibromatosis Type 2
The purpose of this report is to detail three rare cases of neurofibromatosis type 2 (NF2) with symptomatic extracranial extension of intracranial meningioma. We present ocular findings, imaging techniques applied, pathological findings of the space-occupying lesions, and therapy. One of these patients, the daughter of one of the other individuals, presented with a large neck mass, but no surgically treatable findings associated with the external growth of the meningioma. The patients complained of symptoms associated with the extracranial portion of the intracranial meningioma, rather than of the intracranial primaries. However, facial and neck surgical care is very limited in patients with such advanced-stage tumours. The prolongation of life was unquestionably predominantly determined by the behaviour of the intracranial tumour. Head and neck surgeons should be aware of the rare possibility that solid tumours of this region could be extracranial-extending meningioma in an inherited disease.
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siRNA Targeting of MDR1 Reverses Multidrug Resistance in a Nude Mouse Model of Doxorubicin-resistant Human Hepatocellular Carcinoma
Aim: To investigate the effects of vector-based small interfering RNA (siRNA) targeting MDR1 on the reversal of multidrug resistance in a mouse model of doxorubicin (DOX)-resistant human hepatocellular carcinoma. Materials and Methods: Three siRNAs plasmid vectors (MDR1 siRNA1, MDR1 siRNA2 and MDR1 siRNA3) targeting MDR1 were constructed and transfected into DOX-resistant human hepatocellular carcinoma Bel-7402/ADM cells. The expression of MDR1 mRNA and P-glycoprotein (P-gp) was detected with RT-PCR and western blotting, respectively. A nude mouse model of DOX-resistance was established with untransfected Bel-7402/ADM or Bel-7402/ADM transfected with MDR1 siRNA (Bel-7402/ADMsi). The nude mice with tumors from untransfected Bel-7402/ADM cells were treated with either saline (Group 1); intravenous DOX (Group 2); or the combination of intra-tumoral MDR1 siRNA and intravenous DOX (Group 3). The nude mice with tumors from Bel-7402/ADMsi cells were treated with intravenous DOX (Group 4). DOX and MDR1 siRNA were administered twice a week at 20 mg/kg/dose and 9.8 mg/kg/dose, respectively. Tumor growth was measured to assess reversal of multidrug resistance by MDR1 siRNA. Results: MDRl mRNA and P-gp expression of Bel-7402/ADM cells was reduced by transfection of three siRNAs with different silencing efficiency (p<0.05). DOX treatment (Group 4) resulted in significant reduction in tumor size in the Bel-7402/ADMsi tumor model (p<0.05), indicating reversal of multidrug resistance in tumor by MDR1 siRNA. However, the combination treatment of intratumoral MDR1 siRNA and DOX (Group 3) showed no significant anti-tumor efficacy in the untransfected Bel-7402/ADM (p>0.05) tumor model, suggesting poor in vivo transfection efficiency of MDR1 siRNA. Analysis of the tumor samples showed the reduced expression level of MDR1 mRNA and P-gp was due to efficacy of MDR1 siRNA. Conclusion: In vitro transfection of siRNAs' vectors targeting the MDR1 gene can effectively silence MDR1 mRNA and P-gp expression in DOX-resistant human hepatocellular carcinoma Bel-7402/ADM cells that resulted in reversal of multidrug resistance to DOX in the xenograft tumor model.
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Heterogeneity of Vascular Endothelial Growth Factor Receptors 1, 2, 3 in Primary Human Colorectal Carcinoma
Background: The vascular endothelial growth factor (VEGF) pathway plays an important role in growth and progression of human cancer, including colorectal carcinomas (CRC). The key mediators of VEGF signaling are VEGFR1, VEGFR2, and VEGFR3, part of a family of related receptor tyrosine kinases. The relative expression, activity, or interplay among these receptors may determine the response of CRC patients to anti-angiogenic therapies. Materials and Methods: We developed technically sound immunohistochemical (IHC) assays to quantify VEGFR1, 2 and 3, and using a well-annotated CRC tissue microarray (TMA), we carried out comprehensive comparative evaluation of the three VEGFRs in archival primary CRC tissues (n=84). For each TMA core, tumor cell VEGFR1 expression was reported as H-score (range=0-300); vascular VEGFR2/VEGFR3 expression was manually scored as the number of receptor-positive tumor stromal vessels. Each case was defined as VEGFR1/ VEGFR2/VEGFR3-negative, low, medium or high. Results: Based on the differential expression of the three VEGFRs, eight VEGFR staining profiles were observed: Triple VEGFR positive (n=12, 14%), VEGFR1 predominant (n=17, 20%), VEGFR2 predominant (n=7, 8%), VEGFR3 predominant (n=1, 1%), VEGFR1/2 predominant (n=39, 46%), VEGFR1/3 predominant (n=2, 2%), VEGFR2/3 predominant (n=3, 4%), and triple-VEGFR-negative (n=3, 4%). Conclusion: Herein we demonstrated heterogeneity of expression of VEGFRs in human CRC stromal vessels and tumor cells. The observed VEGFR expression-based subsets of human CRCs may reflect differences in biology of pathologic angiogenesis in primary CRC tissues. Furthermore, the heterogeneity of expression of VEGFRs unraveled in this analysis merits independent validation in larger cohorts of primary and metastatic human CRC tissues and in pertinent experimental models treated with various anti-angiogenic therapies.
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Activation of the PERK-eIF2{alpha} Pathway Is Associated with Tumor-infiltrating Lymphocytes in HER2-Positive Breast Cancer
Background: We evaluated endoplasmic reticulum stress and unfolded protein response (UPR) activation, as possible mechanisms for influx of tumor infiltrating lymphocytes (TILs), and the correlation between UPR activation and mammalian target of rapamycin (mTOR) pathway activation. Materials and Methods: TILs and the immunohistochemical expression of protein kinase RNA-like endoplasmic reticulum kinase (PERK), phospho-eukaryotic translation initiation factor 2α (p-eIF2α) and phosphorylated S6 (pS6) were evaluated in 447 human epidermal growth factor receptor 2 (HER2)-positive breast cancer tissues. Results: High expression of PERK, p-eIF2α and pS6 was observed in 270 (60.4%), 259 (57.9%), and 187 (41.8%) cases, respectively, and was significantly associated with a high histological grade, high numbers of TILs, peritumoral lymphocytic infiltration, and tertiary lymphoid structures in HER2-positive breast cancer tissues. Conclusion: The results suggest endoplasmic reticulum stress and UPR activation as possible mechanisms for the influx of TILs in HER2-positive breast cancer. Evaluation of PERK and p-eIF2α expression might be important in identifying targets for cancer therapies in modulating endoplasmic reticulum stress.
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Chronomodulated oxaliplatin plus Capecitabine (XELOX) as a first line chemotherapy in metastatic colorectal cancer: A Phase II Brunch regimen study
Abstract
Purpose
The aim of this study was to evaluate safety and toxicity of chronomodulated capecitabine administered in the morning and at noon according to a specific time schedule (Brunch Regimen: Breakfast and Lunch) as a part of first-line XELOX chemotherapy in patients with metastatic colorectal cancer.
Methods
A total of 30 treatment-naïve colorectal cancer patients with metastatic disease were included. Oxaliplatin 130 mg/m2 on day 1 plus chronomodulated oral capecitabine 2000 mg/m2 per day were administered (50 % dose at 8:00 a.m. and 50 % dose at 12:00 noon on days 1–14, every 21 days). All adverse events, treatment responses and survival were evaluated. In addition, pharmacokinetic profile of capecitabine was examined in a subset of 5 patients.
Results
Median age was 57.1 years (range 32–77 years). Median follow-up was 19 months (range 3–36 months). Three patients (10 %) had complete response, 13 patients (43.3 %) had partial response and 4 patients (13.3 %) had stabile disease. Ten patients had progressive disease at their first evaluation (33.3 %). The median progression-free survival (PFS) was 10 months (range 2–36 months). There were no grade 4 toxicities. One patient (3.3 %) had grade 3 neutropenia. Hand-foot syndrome developed in three patients (10 %): 6.6 %, grade 1 and 3.3 %, grade 2.
Conclusions
Chronomodulated XELOX seems to represent a promising therapeutic option in the first-line treatment of metastatic colorectal carcinoma due to good tumor control and favorable toxicity profile. Phase III randomized trials are required to assess the actual clinical efficacy and side effect profile of this regimen.
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Uncoupling protein 2 regulates metabolic reprogramming and fate of antigen-stimulated CD8+ T cells
Abstract
Adoptive cell therapy (ACT) employing ex vivo-generated tumor antigen-specific CD8+ T cells shows tumor efficacy when the transferred cells possess both effector and memory functions. New strategies based on understanding of mechanisms that balance CD8+ T cell differentiation toward effector and memory responses are highly desirable. Emerging information confirms a central role for antigen-induced metabolic reprogramming in CD8+ T cell differentiation and clonal expansion. The mitochondrial protein uncoupling protein 2 (UCP2) is induced by antigen stimulation of CD8+ T cells; however, its role in metabolic reprogramming underlying differentiation and clonal expansion has not been reported. Employing genetic (siRNA) and pharmacologic (Genipin) approaches, we note that antigen-induced UCP2 expression reduces glycolysis, fatty acid synthesis and production of reactive oxygen species to balance differentiation with survival of effector CD8+ T cells. Inhibition of UCP2 promotes CD8+ T cell terminal differentiation into short-lived effector cells (CD62LloKLRG1HiIFNγHi) that undergo clonal contraction. These findings are the first to reveal a role for antigen-induced UCP2 expression in balancing CD8+ T cell differentiation and survival. Targeting UCP2 to regulate metabolic reprogramming of CD8+ T cells is an attractive new approach to augment efficacy of tumor therapy by ACT.
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Immunotherapy after hematopoietic stem cell transplantation using umbilical cord blood-derived products
Abstract
Umbilical cord blood (UCB) is being increasingly used as a source of hematopoietic stem cells (HSC) for transplantation. UCB transplantation (UCBT) has some advantages such as less stringent HLA-matching requirements, fast availability of the graft and reduced incidence and severity of graft-versus-host disease. However, UCBT is also associated with a higher incidence of infection, graft failure, slow engraftment and slow immune reconstitution. UCB is mainly used as a source of HSC; however, it is also rich in immune cells that could be used to treat some of the main complications post-UCBT as well as other diseases, thus implicating the use of UCB for immunotherapy. Here, we aim to describe some of the therapies currently developed that use UCB as a cell source, focusing in particular on regulatory T cells and natural killer cells.
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Immunoglobulin G4 (IgG4)-positive plasma cell infiltration is associated with the clinicopathologic traits and prognosis of pancreatic cancer after curative resection
Abstract
Interactions between pancreatic cancer cells and inflammatory cells play crucial roles in the biological behavior of pancreatic cancer. Abundant infiltration of immunoglobulin G4 (IgG4)-positive plasma cells in the pancreas is the most significant feature of autoimmune pancreatitis; however, the clinical significance of IgG4-positive plasma cell infiltration in pancreatic cancer has not previously been reported. Herein, we analyzed intratumoral and peritumoral infiltrations of IgG4-positive plasma cells in 95 pancreatic cancer cases after curative resection. The correlations between IgG4-positive plasma cell infiltration and the clinicopathologic traits and overall survival of pancreatic cancer were investigated. IgG4-positive plasma cells were found in 86 % of tumor tissue samples compared with 69 % of peritumoral tissue samples (P = 0.0063). The high-level infiltration of intratumoral IgG4-positive plasma cells was positively correlated with poor histological grade (P = 0.017). The high-level infiltration of intratumoral IgG4-positive plasma cells was significantly correlated with worse prognosis (P = 0.01) in multivariate analysis. We further found that intratumoral M2-polarized tumor-associated macrophages (TAMs) were positively, linearly correlated with IgG4-positive plasma cells. In conclusion, IgG4-positive plasma cell infiltration is correlated with the clinicopathologic traits and overall survival of pancreatic cancer. High-level intratumoral infiltration of IgG4-positive plasma cells is an independent predictor for poor overall survival in pancreatic cancer patients after curative resection. Intratumoral M2-polarized TAMs probably induce IgG4-positive plasma cells.
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Chronomodulated oxaliplatin plus Capecitabine (XELOX) as a first line chemotherapy in metastatic colorectal cancer: A Phase II Brunch regimen study
Abstract
Purpose
The aim of this study was to evaluate safety and toxicity of chronomodulated capecitabine administered in the morning and at noon according to a specific time schedule (Brunch Regimen: Breakfast and Lunch) as a part of first-line XELOX chemotherapy in patients with metastatic colorectal cancer.
Methods
A total of 30 treatment-naïve colorectal cancer patients with metastatic disease were included. Oxaliplatin 130 mg/m2 on day 1 plus chronomodulated oral capecitabine 2000 mg/m2 per day were administered (50 % dose at 8:00 a.m. and 50 % dose at 12:00 noon on days 1–14, every 21 days). All adverse events, treatment responses and survival were evaluated. In addition, pharmacokinetic profile of capecitabine was examined in a subset of 5 patients.
Results
Median age was 57.1 years (range 32–77 years). Median follow-up was 19 months (range 3–36 months). Three patients (10 %) had complete response, 13 patients (43.3 %) had partial response and 4 patients (13.3 %) had stabile disease. Ten patients had progressive disease at their first evaluation (33.3 %). The median progression-free survival (PFS) was 10 months (range 2–36 months). There were no grade 4 toxicities. One patient (3.3 %) had grade 3 neutropenia. Hand-foot syndrome developed in three patients (10 %): 6.6 %, grade 1 and 3.3 %, grade 2.
Conclusions
Chronomodulated XELOX seems to represent a promising therapeutic option in the first-line treatment of metastatic colorectal carcinoma due to good tumor control and favorable toxicity profile. Phase III randomized trials are required to assess the actual clinical efficacy and side effect profile of this regimen.
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Long non-coding RNA ATB promotes glioma malignancy by negatively regulating miR-200a
Glioma is one of the most common and aggressive primary malignant tumor in the brain. Accumulating evidences indicated that aberrantly expressed non-coding RNAs (ncRNAs), including long non-coding RNAs (lncRNA...
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Metabolomics and metabolic pathway networks from human colorectal cancers, adjacent mucosa, and stool
Abstract
Background
Colorectal cancers (CRC) are associated with perturbations in cellular amino acids, nucleotides, pentose-phosphate pathway carbohydrates, and glycolytic, gluconeogenic, and tricarboxylic acid intermediates. A non-targeted global metabolome approach was utilized for exploring human CRC, adjacent mucosa, and stool. In this pilot study, we identified metabolite profile differences between CRC and adjacent mucosa from patients undergoing colonic resection. Metabolic pathway analyses further revealed relationships between complex networks of metabolites.
Methods
Seventeen CRC patients participated in this pilot study and provided CRC, adjacent mucosa ~10 cm proximal to the tumor, and stool. Metabolomes were analyzed by gas chromatography-mass spectrometry (GC/MS) and ultra-performance liquid chromatography-mass spectrometry (UPLC-MS/MS). All of the library standard identifications were confirmed and further analyzed via MetaboLyncTM for metabolic network interactions.
Results
There were a total of 728 distinct metabolites identified from colonic tissue and stool matrices. Nineteen metabolites significantly distinguished CRC from adjacent mucosa in our patient-matched cohort. Glucose-6-phosphate and fructose-6-phosphate demonstrated 0.64-fold and 0.75-fold lower expression in CRC compared to mucosa, respectively, whereas isobar: betaine aldehyde, N-methyldiethanolamine, and adenylosuccinate had 2.68-fold and 1.88-fold higher relative abundance in CRC. Eleven of the 19 metabolites had not previously been reported for CRC relevance. Metabolic pathway analysis revealed significant perturbations of short-chain fatty acid metabolism, fructose, mannose, and galactose metabolism, and glycolytic, gluconeogenic, and pyruvate metabolism. In comparison to the 500 stool metabolites identified from human CRC patients, only 215 of those stool metabolites were also detected in tissue. This CRC and stool metabolome investigation identified novel metabolites that may serve as key small molecules in CRC pathogenesis, confirmed the results from previously reported CRC metabolome studies, and showed networks for metabolic pathway aberrations. In addition, we found differences between the CRC and stool metabolomes.
Conclusions
Stool metabolite profiles were limited for direct associations with CRC and adjacent mucosa, yet metabolic pathways were conserved across both matrices. Larger patient-matched CRC, adjacent non-cancerous colonic mucosa, and stool cohort studies for metabolite profiling are needed to validate these small molecule differences and metabolic pathway aberrations for clinical application to CRC control, treatment, and prevention.
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Reducing Anesthesia and Health Care Cost through Utilization of Child Life Specialists in Pediatric Radiation Oncology
Publication date: Available online 5 June 2016
Source:International Journal of Radiation Oncology*Biology*Physics
Author(s): Michael T. Scott, Kimberly E. Todd, Heather Oakley, Julie Bradley, Ronny Rotondo, Christopher G. Morris, Stuart Klein, Nancy P. Mendenhall, Daniel J. Indelicato
PurposeDuring a typical 6-week course of radiotherapy, daily anesthesia for immobilization of young children increases the cost of treatment. Through education and therapeutic play interventions, a certified child life specialist (CCLS) may reduce the need for daily anesthesia. This report quantifies the healthcare payer cost savings of CCLS utilization in the U.S.Materials/MethodsFrom 2006-2014, 738 children (age ≤21 years) were treated with radiotherapy at our institution. We retrospectively analyzed the frequency of daily anesthesia before and after hiring a CCLS in 2011 after excluding patients age 0-2 and >12 years. In the analyzed cohort of 425 patients, the median age was 7.6 years (range, 3–12.9 years). For the pre-CCLS period, the overall median age was 7.5 years; for the post-CCLS period, the median age was 7.7 years. An average 6-week course of pediatric anesthesia for radiotherapy costs $50,000 in charges to the payer. The average annual cost to employ one CCLS is approximately $50,000.ResultsBefore employing a CCLS, 69 of 121 (57%) children ages 3-12 required daily anesthesia, including 33 of 53 (62.3%) children ages 5-8 years. After employing a CCLS, 124 of 304 (40.8%) children ages 3-12 required daily anesthesia, including only 34 of 118 (28.8%) children ages 5-8 years (p<0.0001).With a >16% absolute reduction in anesthesia use after employment of a CCLS, the healthcare payer cost savings was approaching $50,000 per 6 children ages 3-12 treated annually with radiotherapy in our institution. This reduction resulted in a total of only 6 children ages 3-12 who required to be treated per year at our center to achieve nearly break-even cost savings to the healthcare payer if the payer were to subsidize the employment expense of a CCLS. Overall, the CCLS intervention can provide an average annualized healthcare payer cost savings of "$[(Anesthesia cost to payer during radiotherapy course/6) – (CCLS expense to payer/N)]" per child (N) treated with radiotherapy where N equals the number of children ages 3-12 treated in one year. This formula assumes that the payer subsidize the cost for the employment of a CCLS, although our institution absorbed this expense for this data cohort. The predicted annualized healthcare system cost savings from reducing the frequency of anesthesia with radiotherapy when treating 100 children ages 3-12 per year could exceed $775,000.ConclusionsThis data suggest that a CCLS significantly reduces the frequency of daily anesthesia for children treated with radiotherapy. Healthcare system payers may achieve significant cost savings by financially supporting the employment of a CCLS in high-volume pediatric radiotherapy centers.
Teaser
For young children treated with radiotherapy, daily anesthesia required for immobilization increases the cost of treatment and adds potential long-term morbidity. Through education and therapeutic play interventions, a certified child life specialist (CCLS) reduces the need for daily anesthesia, particularly in children ages 3-8 years. The CCLS intervention results in significant healthcare cost savings to the payer and eliminates unnecessary potential risks from weeks of daily anesthesia.from Cancer via ola Kala on Inoreader http://ift.tt/1PBxT79
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Association between gait characteristics and endothelial oxidative stress and inflammation in patients with symptomatic peripheral artery disease
Abstract
The aim of the study was to determine whether gait characteristics were associated with endothelial cell inflammation, oxidative stress, and apoptosis and with circulating biomarkers of inflammation and antioxidant capacity in older patients with symptomatic peripheral artery disease (PAD). Gait measurements of 231 symptomatic men and women with PAD were assessed during a 4-m walk test. Patients were further characterized on endothelial effects of circulating factors present in the sera using a cell culture-based bioassay on primary human arterial endothelial cells and on circulating inflammatory and vascular biomarkers. In a multivariate regression model for gait speed, the significant independent variables were age (p < 0.001), intercellular cell adhesion molecule-1 (ICAM-1) (p < 0.001), diabetes (p = 0.003), sex (p = 0.003), and history of cerebrovascular accidents (p = 0.021). In multivariate analyses for gait cadence, the significant independent predictors included high-sensitivity C-reactive protein (HsCRP) (p < 0.001), diabetes (p = 0.001), and hypertension (p = 0.001). In a multivariate regression model for gait stride length, the significant independent variables were HsCRP (p < 0.001), age (p < 0.001), ICAM-1 (p < 0.001), hypertension (p = 0.002), cellular reactive oxygen species production (p = 0.007), and sex (p = 0.008). Higher levels of circulating biomarkers of inflammation and endothelial cell oxidative stress were associated with slower gait speed, slower cadence, and shorter stride length in older symptomatic patients with PAD. Additionally, this profile of impaired gait was more evident in older patients, in women, and in those with diabetes, hypertension, and history of cerebrovascular accidents.
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Military Metaphors and the Consequences of the Language of Cancer
Publication date: Available online 6 June 2016
Source:Practical Radiation Oncology
Author(s): Edward C. Halperin
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Clinicopathological differences between variants of the NAB2 – STAT6 fusion gene in solitary fibrous tumors of the meninges and extra-central nervous system
Abstract
Investigations on the NAB2–STAT6 fusion gene in solitary fibrous tumors (SFTs) and hemangiopericytomas (HPCs) have increased since its discovery in 2013. Although several SFTs reported without NAB2–STAT6 fusion gene analysis, we reviewed 546 SFTs/HPCs with NAB2–STAT6 fusion gene analysis in this study and investigated differences between the gene variants. In total, 452 cases tested positive for the NAB2–STAT6 fusion gene, with more than 40 variants being detected. The most frequent of these were NAB2 exon 6-STAT6 exon 16/17/18 and NAB2 exon 4-STAT6 exon 2/3, with the former occurring most frequently in SFTs in meninges, soft tissues, and head and neck; the latter predominated in SFTs in the pleura and lung. There was no difference between the histology of SFTs and fusion gene variants. A follow-up analysis of SFTs showed that 51 of 202 cases had a recurrence, with 18 of 53 meningeal SFTs having a local recurrence and/or metastasis within 0–19 years. In meninges and soft tissue, SFTs with the NAB2 exon 6-STAT6 exon 16/17/18 tended to recur more frequently than SFTs with the NAB2 exon 4-STAT6 exon 2/3. Clinicopathological data, including yearly follow-ups, are required for meningeal SFTs/HPCs to define the correlation of variants of NAB2–STAT6 fusion gene.
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Serum microRNA panels as potential biomarkers for early detection of hepatocellular carcinoma on top of HCV infection
Abstract
The identification of new high-sensitivity and high-specificity markers for hepatocellular carcinoma (HCC) is essential. We aimed at identifying serum microRNAs (miRNAs) as potential biomarkers for early detection of HCC on top hepatitis C virus (HCV) infection. We investigated serum expression of 13 miRNAs in 384 patients with HCV-related chronic liver disease (192 with HCC, 96 with liver cirrhosis (LC), and 96 with chronic hepatitis C (CHC)) in addition to 96 healthy participants enrolled as a control group. The miRNA expression was performed using real-time quantitative PCR-based SYBR Green custom miRNA arrays. The area under the receiver operating characteristic curve (AUC) was used to evaluate the diagnostic performance of miRNA panels for early detection of HCC. Using miRNA panel of miR-122, miR-885-5p, and miR-29b with alpha fetoprotein (AFP) provided high diagnostic accuracy (AUC = 1) for early detection of HCC in normal population while using miRNA panel of miR-122, miR-885-5p, miR-221, and miR-22 with AFP provided high diagnostic accuracy (AUC = 0.982) for early detection of HCC in LC patients. However, using miRNA panel of miR-22 and miR-199a-3p with AFP provided high diagnostic accuracy (AUC = 0.988) for early detection of HCC in CHC patients. We identified serum miRNA panels that could have a considerable clinical use in early detection of HCC in both normal population and high-risk patients.
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PPAR-delta promotes survival of breast cancer cells in harsh metabolic conditions
PPAR-delta promotes survival of breast cancer cells in harsh metabolic conditions
Oncogenesis 5, e232 (June 2016). doi:10.1038/oncsis.2016.41
Authors: X Wang, G Wang, Y Shi, L Sun, R Gorczynski, Y-J Li, Z Xu & D E Spaner
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NIK regulates MT1-MMP activity and promotes glioma cell invasion independently of the canonical NF-κB pathway
NIK regulates MT1-MMP activity and promotes glioma cell invasion independently of the canonical NF-κB pathway
Oncogenesis 5, e231 (June 2016). doi:10.1038/oncsis.2016.39
Authors: C L Duran, D W Lee, J-U Jung, S Ravi, C B Pogue, L G Toussaint, K J Bayless & R Sitcheran
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Pharmacokinetic profiles of significant adverse events with crizotinib in Japanese patients with ABCB1 polymorphism
Summary
Crizotinib is a standard treatment for advanced ALK-positive non-small-cell lung cancer (NSCLC). We conducted this study to investigate the pharmacokinetics of crizotinib and clinical and pharmacogenomic factors that may increase the risk of adverse events (AEs). We defined clinically significant AEs as grade 4 hematological toxicity, grade ≥ 3 non-hematological toxicity, and any grade of interstitial lung disease. Eight subjects with ALK-positive NSCLC scheduled to receive crizotinib 250 mg twice daily were studied. Six patients were female and two were male, and most of the patients had low body weight with a median body weight of 46.8 kg (range 42.4–61.0). All patients developed AEs, five developing six clinically significant AEs. Six patients required dose reduction. In pharmacokinetics analysis, blood samples were obtained on days 1 and 15. The mean area under the plasma concentration–time curve from 0–12 hours (AUC0–12) on day 15 was significantly increased in patients with clinically significant AEs (n = 5) compared with those without (n = 3) (P = 0.04). Genetic polymorphisms of ABCB1 were analyzed. One patient with the ABCB1 1236TT-2677TT-3435TT genotype was an outlier, with an AUC0–12 and peak concentrations on day 15 of 2.84 × and 2.61 × the mean, respectively, compared with those with other genotypes. Our results suggest that some Japanese patients treated with crizotinib developed clinically significant toxicities, which were related with altered pharmacokinetics parameters due to genotype and body weight factors.
This article is protected by copyright. All rights reserved.
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HIF-targeting prodrug TOP3 combined with gemcitabine or TS-1 improves pancreatic cancer survival in an orthotopic model
Abstract
Pancreatic cancer is one of the most lethal digestive system cancers with a 5-year survival rate of 4%–7%. Despite extensive efforts, recent chemotherapeutic regimens have provided only limited benefits to pancreatic cancer patients. Gemcitabine and TS-1, the current standard-of-care chemotherapeutic drugs for treatment of this severe cancer, have a low response rate. Hypoxia is one of the factors contributing to treatment resistance. Specifically, overexpression of hypoxia inducible factor (HIF), a master transcriptional regulator of cell adaption to hypoxia, is strongly correlated with poor prognosis in many human cancers. TAT-ODD-Procaspase-3 (TOP3) is a protein prodrug that is specifically processed and activated in HIF-active cells in cancers, leading to cell death. Here, we report combination therapies in which TOP3 was combined with gemcitabine or TS-1. As monotherapy, gemcitabine and TS-1 showed a limited effect on hypoxic and starved pancreatic cancer cells, whereas co-treatment with TOP3 successfully overcame this limitation in vitro. Furthermore, combination therapies of TOP3 with these drugs resulted in a significant improvement in survival of orthotopic pancreatic cancer models involving the human pancreatic cancer cell line SUIT-2. Overall, our study demonstrates that the combination of TOP3 with current chemotherapeutic drugs can significantly improve treatment outcome, offering a promising new therapeutic option for patients with pancreatic cancer.
This article is protected by copyright. All rights reserved.
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Targeting key metabolic enzymes involved in lipid and protein biosyntheses for breast anticancer therapies.
Targeting key metabolic enzymes involved in lipid and protein biosyntheses for breast anticancer therapies.
Curr Cancer Drug Targets. 2016 Jun 3;
Authors: Guerram M, Hamdi AM, Zhang LY, Jiang Z
Abstract
The evolution of genomic research enabled the genetic and molecular profiling of breast cancer and revealed the profound complexity and heterogeneity of this disease. Subtypes of breast cancer characterized by mutations and/or amplifications of some proto-oncogenes are associated with an increased rate of recurrence and poor prognosis. They represent a challenge in the clinic with limited arsenal to attack them. Nowadays, metabolic reprogramming is firmly established as a hallmark of cancer. An increased rate of lipid and protein syntheses in cancerous tissues, a direct consequence of alterations in key metabolic enzymes involved in these pathways, is now recognized as an important aspect of the rewired metabolism of neoplastic cells. Over the past several years, accumulating evidence has revealed that mutations or amplifications of some proto-oncogenes are primarily involved in this metabolic dysregulation. It is thus critically important to dissect the molecular mechanisms tumors use to link metabolic reprogramming with upstream altered signaling. In this article, we review the recent findings that support the importance of lipid and protein biosyntheses in breast tumorigenesis, discuss the crosstalk between growth factor signal transduction and key metabolic enzymes involved in these processes, and point out the potentials of developing new strategies and therapeutics to target these key parameters in order to help breast cancer patients by providing new therapeutic opportunities.
PMID: 27262320 [PubMed - as supplied by publisher]
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Molecular Targeted Magnetic Resonance Imaging of Human Colorectal Carcinoma (LoVo) Cells Using Novel Superparamagnetic Iron Oxide- Loaded Nanovesicles: In Vitro and in vivo Studies.
Molecular Targeted Magnetic Resonance Imaging of Human Colorectal Carcinoma (LoVo) Cells Using Novel Superparamagnetic Iron Oxide- Loaded Nanovesicles: In Vitro and in vivo Studies.
Curr Cancer Drug Targets. 2016 Jun 3;
Authors: Feng ST, Li H, Luo Y, Cai H, Dong Z, Fang Z, Shuai X, Li ZP
Abstract
OBJECTIVE: To investigate the feasibility of superparamagnetic iron oxide (SPIO) nanoparticles (SPIO) as a magnetic resonance (MR) contrast agent to enhance tumor imaging in vivo.
METHODS: Hydrophobic SPIO (oil-soluble SPIO; OSPIO) and hydrophilic SPIO (water-soluble SPIO; WSPIO) were loaded in methoxy-poly(ethylene glycol)-block-poly(D,L-lactic acid) (PEG-PDLLA) nanovesicles. Three groups of nude mice (n=12/group) xenografted with human colorectal carcinoma (LoVo) cells were injected into the caudal vein with WSPIO, OSPIO-loaded nanovesicles, or WSPIO-loaded nanovesicles. MRI scans were performed on all of the mice, and the relative T2 values were measured in the tumor and the liver. The differences in these T2 values between the three groups were compared.
RESULTS: The peak relative T2 values in the tumors detected by the OSPIO- or WSPIO-loaded contrast agents were reduced by 10.12% and 11.40%, respectively. The relative T2 values in the WSPIO- and OSPIO-loaded polymeric nanovesicle groups were more pronounced than the relative T2 value in the WSPIO group (P<0.05), but there was no significant difference in the T2 value between the OSPIO- and WSPIO-loaded vesicle groups (P＞0.05). The greatest T2 value decreases in the liver in the WSPIO, OSPIO-loaded and WSPIO-loaded vesicle groups were 32.85%, 52.77% and 56.89%, respectively. The decrease in the T2 values was more pronounced in the WSPIO- and OSPIO-loaded nanovesicle groups than in the WSPIO group (P<0.05) and was more apparent in the WSPIO-loaded nanovesicle group than in the OSPIO-loaded nanovesicle group (P<0.05).
CONCLUSION: SPIO-loaded polymeric nanovesicles generate significant T2WI signal intensity decreases in vivo and are anticipated to be used as novel and effective contrast agents for tumor imaging.
PMID: 27262319 [PubMed - as supplied by publisher]
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