TP53 undergoes multiple RNA-splicing events, resulting in at least nine mRNA transcripts encoding at least 12 functionally different protein isoforms. Antibodies specific to p53 protein isoforms have proven difficult to develop, thus researchers must rely on the transcript information to infer isoform abundance. In this study, we used deep RNA-seq, droplet digital PCR (ddPCR), and real-time quantitative reverse transcriptase PCR (RT-qPCR) from nine human cell lines and RNA-seq data available for tumors in The Cancer Genome Atlas to analyze TP53 splice variant expression. All three methods detected expression of the FL/40TP53α_T1 variant in most human tumors and cell lines. However, other less abundant variants were only detected with PCR-based methods. Using RNA-seq simulation analysis, we determined why RNA-seq is unable to detect less abundant TP53 transcripts and discuss the implications of these findings for the general interpretation of RNA-seq data. Cancer Res; 76(24); 7151–9. ©2016 AACR.
from Cancer via ola Kala on Inoreader http://ift.tt/2hRQcWe
via IFTTT
Cancer Medicine by Alexandros G.Sfakianakis,Anapafseos 5 Agios Nikolaos,Crete 72100,Greece,tel :00302841026182 & 00306932607174
Πέμπτη 15 Δεκεμβρίου 2016
A Study of TP53 RNA Splicing Illustrates Pitfalls of RNA-seq Methodology
Transglutaminase Interaction with {alpha}6/{beta}4-Integrin Stimulates YAP1-Dependent {Delta}Np63{alpha} Stabilization and Leads to Enhanced Cancer Stem Cell Survival and Tumor Formation
Transglutaminase 2 (TG2) expression is required for epidermal squamous cell carcinoma cancer stem cell survival. However, the molecular signaling mechanisms triggered by TG2 that mediate this survival action are not well understood. Here we show that TG2 is constitutively expressed in ECS cells, where it interacts with α6/β4 integrin to stimulate FAK and Src signaling, leading to PI3K activation of phosphoinositide-dependent kinase 1 (PDK1). PDK1 inhibits Hippo signaling, leading to enhanced nuclear accumulation of YAP1, which interacted with and stabilized ΔNp63α to enhance epidermal squamous cell carcinoma spheroid formation, invasion, and migration. Overall, these findings suggest that constitutive TG2 expression results in stabilization of ΔNp63α, leading to maintenance of cancer stem cell properties and enhanced tumor formation. Cancer Res; 76(24); 7265–76. ©2016 AACR.
from Cancer via ola Kala on Inoreader http://ift.tt/2gOVp3i
via IFTTT
A Hyaluronidase-Responsive Nanoparticle-Based Drug Delivery System for Targeting Colon Cancer Cells
The ability of nanoparticles to target tumors and to enable site-specific drug release provides a unique system for the delivery of effective therapy with reduced toxic side effects. In this study, we used mesoporous silica nanoparticles (MSN) to fabricate a targeted drug delivery system that is responsive to hyaluronidase (HAase). Following engraftment of desthiobiotin onto the surface of MSN, a streptavidin complex was generated, which was functionalized with biotin-modified hyaluronic acid (HA) to enable controlled drug release at cancer cells expressing HAase. Various technologies were used to confirm the successful fabrication of this MSN-based nanocarrier system for targeted drug delivery. In vitro analyses showed that the release of doxorubicin hydrochloride (Dox) was accelerated significantly in the presence of biotin or HAase and accelerated further in the presence of biotin and HAase. Uptake by cancer cells was mediated efficiently by CD44 receptor–mediated endocytosis and the MSN exhibited good biocompatibility in vitro and in vivo. MSN-HA/Dox nanoparticles induced apoptosis in cancer cells more efficiently than free doxorubicin and inhibited tumor growth with minimal systemic toxicity in vivo. Collectively, our findings offered a preclinical proof of concept for a novel targeted drug delivery carrier system for cancer therapy. Cancer Res; 76(24); 7208–18. ©2016 AACR.
http://ift.tt/2gOW9p3
Glucose Metabolism Reprogrammed by Overexpression of IKKϵ Promotes Pancreatic Tumor Growth
Aberrant expression of the kinase IKKε in pancreatic ductal adenocarcinoma (PDAC) has been associated with poor prognosis. In this study, we define a pathobiologic function for IKKε in reprogramming glucose metabolism and driving progression in PDAC. Silencing IKKε in PDAC cells, which overexpressed it endogenously, was sufficient to reduce malignant cell growth, clonogenic potential, glucose consumption, lactate secretion, and expression of genes involved in glucose metabolism, without impacting the basal oxygen consumption rate. IKKε silencing also attenuated c-Myc in a manner associated with diminished signaling through an AKT/GSK3β/c-MYC phosphorylation cascade that promoted MYC nuclear accumulation. In an orthotopic mouse model, IKKε-silenced PDAC exhibited a relative reduction in glucose uptake, tumorigenicity, and metastasis. Overall, our findings offer a preclinical mechanistic rationale to target IKKε to improve the therapeutic management of PDAC in patients. Cancer Res; 76(24); 7254–64. ©2016 AACR.
http://ift.tt/2hRSvss
Quantifying the Dynamics of Field Cancerization in Tobacco-Related Head and Neck Cancer: A Multiscale Modeling Approach
High rates of local recurrence in tobacco-related head and neck squamous cell carcinoma (HNSCC) are commonly attributed to unresected fields of precancerous tissue. Because they are not easily detectable at the time of surgery without additional biopsies, there is a need for noninvasive methods to predict the extent and dynamics of these fields. Here, we developed a spatial stochastic model of tobacco-related HNSCC at the tissue level and calibrated the model using a Bayesian framework and population-level incidence data from the Surveillance, Epidemiology, and End Results (SEER) registry. Probabilistic model analyses were performed to predict the field geometry at time of diagnosis, and model predictions of age-specific recurrence risks were tested against outcome data from SEER. The calibrated models predicted a strong dependence of the local field size on age at diagnosis, with a doubling of the expected field diameter between ages at diagnosis of 50 and 90 years, respectively. Similarly, the probability of harboring multiple, clonally unrelated fields at the time of diagnosis was found to increase substantially with patient age. On the basis of these findings, we hypothesized a higher recurrence risk in older than in younger patients when treated by surgery alone; we successfully tested this hypothesis using age-stratified outcome data. Further clinical studies are needed to validate the model predictions in a patient-specific setting. This work highlights the importance of spatial structure in models of epithelial carcinogenesis and suggests that patient age at diagnosis may be a critical predictor of the size and multiplicity of precancerous lesions. Cancer Res; 76(24); 7078–88. ©2016 AACR.
http://ift.tt/2gOVsfK
Preclinical Evidence That 3'-Deoxy-3'-[18F]Fluorothymidine PET Can Visualize Recovery of Hematopoiesis after Gemcitabine Chemotherapy
Molecular imaging with the PET tracer 3′-deoxy-3′-[18F]fluorothymidine ([18F]FLT) allows assessment of the proliferative state of organs in vivo. Although used primarily in the oncology clinic, it can also shed light on the proliferation of other tissues, as demonstrated here for monitoring hematopoietic organs that recover after myelosuppressive chemotherapy. In the NMRI nude mouse model, we observed up to a 4.5-fold increase in [18F]FLT uptake in bone marrow and spleen on days 2, 3, and 5 after treatment with gemcitabine, a chemotherapeutic agent that is powerfully myelosuppressive in the model. Specifically, we observed (i) a reduced spleen weight; (ii) reduced bone marrow cell counts and proliferation (BrdUrd flow cytometry, spleen IHC; 6 hours/day 1); and (iii) reduced leukocytes in peripheral blood (day 5). In conclusion, our results show how [18F]FLT PET can provide a powerful tool to noninvasively visualize the proliferative status of hematopoietic organs after myelosuppressive therapy. Cancer Res; 76(24); 7089–95. ©2016 AACR.
http://ift.tt/2hRSe8M
Alternative Polyadenylation in Triple-Negative Breast Tumors Allows NRAS and c-JUN to Bypass PUMILIO Posttranscriptional Regulation
Alternative polyadenylation (APA) is a process that changes the posttranscriptional regulation and translation potential of mRNAs via addition or deletion of 3′ untranslated region (3′ UTR) sequences. To identify posttranscriptional-regulatory events affected by APA in breast tumors, tumor datasets were analyzed for recurrent APA events. Motif mapping of the changed 3′ UTR regions found that APA-mediated removal of Pumilio regulatory elements (PRE) was unusually common. Breast tumor subtype–specific APA profiling identified triple-negative breast tumors as having the highest levels of APA. To determine the frequency of these events, an independent cohort of triple-negative breast tumors and normal breast tissue was analyzed for APA. APA-mediated shortening of NRAS and c-JUN was seen frequently, and this correlated with changes in the expression of downstream targets. mRNA stability and luciferase assays demonstrated APA-dependent alterations in RNA and protein levels of affected candidate genes. Examination of clinical parameters of these tumors found those with APA of NRAS and c-JUN to be smaller and less proliferative, but more invasive than non-APA tumors. RT-PCR profiling identified elevated levels of polyadenylation factor CSTF3 in tumors with APA. Overexpression of CSTF3 was common in triple-negative breast cancer cell lines, and elevated CSTF3 levels were sufficient to induce APA of NRAS and c-JUN. Our results support the hypothesis that PRE-containing mRNAs are disproportionately affected by APA, primarily due to high sequence similarity in the motifs utilized by polyadenylation machinery and the PUM complex. Cancer Res; 76(24); 7231–41. ©2016 AACR.
http://ift.tt/2gOSkQQ
Gemcitabine Mechanism of Action Confounds Early Assessment of Treatment Response by 3'-Deoxy-3'-[18F]Fluorothymidine in Preclinical Models of Lung Cancer
3′-Deoxy-3′-[18F]fluorothymidine positron emission tomography ([18F]FLT-PET) and diffusion-weighted MRI (DW-MRI) are promising approaches to monitor tumor therapy response. Here, we employed these two imaging modalities to evaluate the response of lung carcinoma xenografts in mice after gemcitabine therapy. Caliper measurements revealed that H1975 xenografts responded to gemcitabine treatment, whereas A549 growth was not affected. In both tumor models, uptake of [18F]FLT was significantly reduced 6 hours after drug administration. On the basis of the gemcitabine concentration and [18F]FLT excretion measured, this was presumably related to a direct competition of gemcitabine with the radiotracer for cellular uptake. On day 1 after therapy, [18F]FLT uptake was increased in both models, which was correlated with thymidine kinase 1 (TK1) expression. Two and 3 days after drug administration, [18F]FLT uptake as well as TK1 and Ki67 expression were unchanged. A reduction in [18F]FLT in the responsive H1975 xenografts could only be noted on day 5 of therapy. Changes in ADCmean in A549 xenografts 1 or 2 days after gemcitabine did not seem to be of therapy-related biological relevance as they were not related to cell death (assessed by caspase-3 IHC and cellular density) or tumor therapy response. Taken together, in these models, early changes of [18F]FLT uptake in tumors reflected mechanisms, such as competing gemcitabine uptake or gemcitabine-induced thymidylate synthase inhibition, and only reflected growth-inhibitory effects at a later time point. Hence, the time point for [18F]FLT-PET imaging of tumor response to gemcitabine is of crucial importance. Cancer Res; 76(24); 7096–105. ©2016 AACR.
http://ift.tt/2gOXMmX
CBX4 Suppresses Metastasis via Recruitment of HDAC3 to the Runx2 Promoter in Colorectal Carcinoma
Polycomb chromobox (CBX) proteins participate in the polycomb repressive complex (PRC1) that mediates epigenetic gene silencing and endows PRC1 with distinct oncogenic or tumor suppressor functions in a cell-type–dependent manner. In this study, we report that inhibition of cell migration, invasion, and metastasis in colorectal carcinoma requires CBX4-mediated repression of Runx2, a key transcription factor that promotes colorectal carcinoma metastasis. CBX4 inversely correlated with Runx2 expression in colorectal carcinoma tissues, and the combination of high CBX4 expression and low Runx2 expression significantly correlated with overall survival, more so than either CBX4 or Runx2 expression alone. Mechanistically, CBX4 maintained recruited histone deacetylase 3 (HDAC3) to the Runx2 promoter, which maintained a deacetylated histone H3K27 state to suppress Runx2 expression. This function of CBX4 was dependent on its interaction with HDAC3, but not on its SUMO E3 ligase, its chromodomain, or the PRC1 complex. Disrupting the CBX4–HDAC3 interaction abolished Runx2 inhibition as well as the inhibition of cell migration and invasion. Collectively, our data show that CBX4 may act as a tumor suppressor in colorectal carcinoma, and strategies that stabilize the interaction of CBX4 with HDAC3 may benefit the colorectal carcinoma patients with metastases. Cancer Res; 76(24); 7277–89. ©2016 AACR.
http://ift.tt/2hRMFHv
Surface Expression of TGF{beta} Docking Receptor GARP Promotes Oncogenesis and Immune Tolerance in Breast Cancer
GARP encoded by the Lrrc32 gene is the cell surface docking receptor for latent TGFβ, which is expressed naturally by platelets and regulatory T cells (Treg). Although Lrrc32 is amplified frequently in breast cancer, the expression and relevant functions of GARP in cancer have not been explored. Here, we report that GARP exerts oncogenic effects, promoting immune tolerance by enriching and activating latent TGFβ in the tumor microenvironment. We found that human breast, lung, and colon cancers expressed GARP aberrantly. In genetic studies in normal mammary gland epithelial and carcinoma cells, GARP expression increased TGFβ bioactivity and promoted malignant transformation in immunodeficient mice. In breast carcinoma–bearing mice that were immunocompetent, GARP overexpression promoted Foxp3+ Treg activity, which in turn contributed to enhancing cancer progression and metastasis. Notably, administration of a GARP-specific mAb limited metastasis in an orthotopic model of human breast cancer. Overall, these results define the oncogenic effects of the GARP–TGFβ axis in the tumor microenvironment and suggest mechanisms that might be exploited for diagnostic and therapeutic purposes. Cancer Res; 76(24); 7106–17. ©2016 AACR.
http://ift.tt/2hRQdcK
IDH2 Mutations Define a Unique Subtype of Breast Cancer with Altered Nuclear Polarity
Solid papillary carcinoma with reverse polarity (SPCRP) is a rare breast cancer subtype with an obscure etiology. In this study, we sought to describe its unique histopathologic features and to identify the genetic alterations that underpin SPCRP using massively parallel whole-exome and targeted sequencing. The morphologic and immunohistochemical features of SPCRP support the invasive nature of this subtype. Ten of 13 (77%) SPCRPs harbored hotspot mutations at R172 of the isocitrate dehydrogenase IDH2, of which 8 of 10 displayed concurrent pathogenic mutations affecting PIK3CA or PIK3R1. One of the IDH2 wild-type SPCRPs harbored a TET2 Q548* truncating mutation coupled with a PIK3CA H1047R hotspot mutation. Functional studies demonstrated that IDH2 and PIK3CA hotspot mutations are likely drivers of SPCRP, resulting in its reversed nuclear polarization phenotype. Our results offer a molecular definition of SPCRP as a distinct breast cancer subtype. Concurrent IDH2 and PIK3CA mutations may help diagnose SPCRP and possibly direct effective treatment. Cancer Res; 76(24); 7118–29. ©2016 AACR.
http://ift.tt/2gOWOXT
Ubiquitous Release of Exosomal Tumor Suppressor miR-6126 from Ovarian Cancer Cells
Cancer cells actively promote their tumorigenic behavior by reprogramming gene expression. Loading intraluminal vesicles with specific miRNAs and releasing them into the tumor microenvironment as exosomes is one mechanism of reprogramming whose regulation remains to be elucidated. Here, we report that miR-6126 is ubiquitously released in high abundance from both chemosensitive and chemoresistant ovarian cancer cells via exosomes. Overexpression of miR-6126 was confirmed in healthy ovarian tissue compared with ovarian cancer patient samples and correlated with better overall survival in patients with high-grade serous ovarian cancer. miR-6126 acted as a tumor suppressor by directly targeting integrin-β1, a key regulator of cancer cell metastasis. miR-6126 mimic treatment of cancer cells resulted in increased miR-6126 and decreased integrin-β1 mRNA levels in the exosome. Functional analysis showed that treatment of endothelial cells with miR-6126 mimic significantly reduced tube formation as well as invasion and migration capacities of ovarian cancer cells in vitro. Administration of miR-6126 mimic in an orthotopic mouse model of ovarian cancer elicited a relative reduction in tumor growth, proliferating cells, and microvessel density. miR-6126 inhibition promoted oncogenic behavior by leading ovarian cancer cells to release more exosomes. Our findings provide new insights into the role of exosomal miRNA-mediated tumor progression and suggest a new therapeutic approach to disrupt oncogenic phenotypes in tumors. Cancer Res; 76(24); 7194–207. ©2016 AACR.
http://ift.tt/2hRQaxr
TSC2 Deficiency Unmasks a Novel Necrosis Pathway That Is Suppressed by the RIP1/RIP3/MLKL Signaling Cascade
Tuberous sclerosis complex (TSC) is a genetic multiorgan disorder characterized by the development of neoplastic lesions in kidney, lung, brain, heart, and skin. It is caused by an inactivating mutation in tumor suppressor genes coding the TSC1/TSC2 complex, resulting in the hyperactivation of mTOR- and Raf/MEK/MAPK–dependent signaling that stimulates tumor cell proliferation and metastasis. Despite its oncogenic effect, cells with TSC deficiency were more sensitive to oxidative stress and dependent on mitochondrial metabolism, providing a rationale for a new therapeutic approach. The current study shows that simultaneous inhibition of two major pathways regulating redox homeostasis using l-buthionine-sulfoximine (BSO, glutathione synthesis inhibitor) and auranofin (thioredoxin reductase inhibitor) induces oxidative burst, mitochondrial damage, and necrotic cell death in TSC-deficient cells in a highly synergistic and cell context–specific manner. Furthermore, blocking RIP1/RIP3/MLKL–dependent signaling using chemical inhibitors necrostatin-1 (Nec-1) and necrosulfonamide (NSA) synergizes with BSO and auranofin in killing TSC-deficient cells. Expression analysis demonstrated that RIP1, RIP3, and MLKL protein levels are elevated in cells with TSC2 deficiency, and their inactivation enhances mitochondrial dysfunction in a glutaminolysis-dependent and autophagy-independent manner. Finally, supplementation with the mitochondrial metabolite α-ketoglutarate, whose synthesis is regulated by RIP1/RIP3/MLKL, rescues cells from the sensitizing effect of Nec-1 and NSA. Together, this study identifies a previously unrecognized novel regulated necrotic death pathway that involves mitochondrial homeostasis, is suppressed by the RIP1/RIP3/MLKL signaling in TSC-deficient cells, and could be a promising therapeutic target for TSC-associated tumors. Cancer Res; 76(24); 7130–9. ©2016 AACR.
http://ift.tt/2hRPF6L
FOXD1-ALDH1A3 Signaling Is a Determinant for the Self-Renewal and Tumorigenicity of Mesenchymal Glioma Stem Cells
Glioma stem–like cells (GSC) with tumor-initiating activity orchestrate the cellular hierarchy in glioblastoma and engender therapeutic resistance. Recent work has divided GSC into two subtypes with a mesenchymal (MES) GSC population as the more malignant subtype. In this study, we identify the FOXD1–ALDH1A3 signaling axis as a determinant of the MES GSC phenotype. The transcription factor FOXD1 is expressed predominantly in patient-derived cultures enriched with MES, but not with the proneural GSC subtype. shRNA-mediated attenuation of FOXD1 in MES GSC ablates their clonogenicity in vitro and in vivo. Mechanistically, FOXD1 regulates the transcriptional activity of ALDH1A3, an established functional marker for MES GSC. Indeed, the functional roles of FOXD1 and ALDH1A3 are likely evolutionally conserved, insofar as RNAi-mediated attenuation of their orthologous genes in Drosophila blocks formation of brain tumors engineered in that species. In clinical specimens of high-grade glioma, the levels of expression of both FOXD1 and ALDH1A3 are inversely correlated with patient prognosis. Finally, a novel small-molecule inhibitor of ALDH we developed, termed GA11, displays potent in vivo efficacy when administered systemically in a murine GSC-derived xenograft model of glioblastoma. Collectively, our findings define a FOXD1–ALDH1A3 pathway in controling the clonogenic and tumorigenic potential of MES GSC in glioblastoma tumors. Cancer Res; 76(24); 7219–30. ©2016 AACR.
http://ift.tt/2hRMyM6
Dysregulation of RUNX2/Activin-A Axis upon miR-376c Downregulation Promotes Lymph Node Metastasis in Head and Neck Squamous Cell Carcinoma
Epigenetic correlates of the head and neck cancer may illuminate its pathogenic roots. Through a gene set enrichment analysis, we found that the oncogenic transcription factor RUNX2 is widely upregulated in the head and neck squamous cell carcinoma (HNSCC) with lymph node metastasis, where it also predicts poor prognosis in patients with HNSCC. Enforced expression of ectopic RUNX2 promoted the metastatic capabilities of HNSCC, whereas RUNX2 silencing inhibited these features. Mechanistic investigations showed that manipulating levels of activin A (INHBA) could rescue or compromise the RUNX2-mediated metastatic capabilities of HNSCC cells. Furthermore, we found that miR-376c-3p encoded within the 3′-untranslated region of RUNX2 played a pivotal role in regulating RUNX2 expression in highly metastatic HNSCC cells, where it was downregulated commonly. Restoring miR-376c expression in this setting suppressed expression of RUNX2/INHBA axis along with metastatic capability. Clinically, we observed an inverse relationship between miR-376c-3p expression and the RUNX2/INHBA axis in HNSCC specimens. In summary, our results defined a novel pathway in which dysregulation of the RUNX2/INHBA axis due to miR-376c downregulation fosters lymph node metastasis in HNSCC. Cancer Res; 76(24); 7140–50. ©2016 AACR.
http://ift.tt/2gOVEvf
Mechanisms through Which Hypoxia-Induced Caveolin-1 Drives Tumorigenesis and Metastasis in Hepatocellular Carcinoma
In solid tumors, hypoxia triggers an aberrant vasculogenesis, enhances malignant character, and elevates metastatic risk. The plasma membrane organizing protein caveolin-1 (Cav1) is increased in a variety of cancers, including hepatocellular carcinoma (HCC), where it contributes to metastatic capability. However, the reason for elevation of Cav1 in tumor cells and the mechanistic basis for its contributions to metastatic risk are not fully understood. Here, we show that in HCC cells, hypoxia elevates expression of Cav1, which then acts through the calcium-binding protein S100P to promote metastasis. Hypoxic regions of HCC xenografts displayed elevated expression of Cav1. Hypoxia promoted HCC cell migration and invasion and distant pulmonary metastases, whereas Cav1 silencing abolished these effects. Gene expression profiling revealed that hypoxia-induced Cav1 functioned as a positive regulator of S100P via activation of the NF-κB pathway. S100P elevation under hypoxic conditions was abrogated by silencing of Cav1 or NF-κB function. Conversely, restoring S100P in Cav1-silenced cells rescued the migratory potential of HCC cells along with tumor formation and lung metastasis. In clinical specimens of HCC, we observed S100P overexpression to correlate with venous invasion, microsatellites, direct liver invasion, and absence of tumor encapsulation. Collectively, our findings demonstrated how hypoxia-induced expression of Cav1 in HCC cells enhances their invasive and metastatic potential. Cancer Res; 76(24); 7242–53. ©2016 AACR.
http://ift.tt/2gOSc3E
A Study of TP53 RNA Splicing Illustrates Pitfalls of RNA-seq Methodology
TP53 undergoes multiple RNA-splicing events, resulting in at least nine mRNA transcripts encoding at least 12 functionally different protein isoforms. Antibodies specific to p53 protein isoforms have proven difficult to develop, thus researchers must rely on the transcript information to infer isoform abundance. In this study, we used deep RNA-seq, droplet digital PCR (ddPCR), and real-time quantitative reverse transcriptase PCR (RT-qPCR) from nine human cell lines and RNA-seq data available for tumors in The Cancer Genome Atlas to analyze TP53 splice variant expression. All three methods detected expression of the FL/40TP53α_T1 variant in most human tumors and cell lines. However, other less abundant variants were only detected with PCR-based methods. Using RNA-seq simulation analysis, we determined why RNA-seq is unable to detect less abundant TP53 transcripts and discuss the implications of these findings for the general interpretation of RNA-seq data. Cancer Res; 76(24); 7151–9. ©2016 AACR.
http://ift.tt/2hRQcWe
Transglutaminase Interaction with {alpha}6/{beta}4-Integrin Stimulates YAP1-Dependent {Delta}Np63{alpha} Stabilization and Leads to Enhanced Cancer Stem Cell Survival and Tumor Formation
Transglutaminase 2 (TG2) expression is required for epidermal squamous cell carcinoma cancer stem cell survival. However, the molecular signaling mechanisms triggered by TG2 that mediate this survival action are not well understood. Here we show that TG2 is constitutively expressed in ECS cells, where it interacts with α6/β4 integrin to stimulate FAK and Src signaling, leading to PI3K activation of phosphoinositide-dependent kinase 1 (PDK1). PDK1 inhibits Hippo signaling, leading to enhanced nuclear accumulation of YAP1, which interacted with and stabilized ΔNp63α to enhance epidermal squamous cell carcinoma spheroid formation, invasion, and migration. Overall, these findings suggest that constitutive TG2 expression results in stabilization of ΔNp63α, leading to maintenance of cancer stem cell properties and enhanced tumor formation. Cancer Res; 76(24); 7265–76. ©2016 AACR.
http://ift.tt/2gOVp3i
HER2/HER3 pathway in biliary tract malignancies; systematic review and meta-analysis: a potential therapeutic target?
Abstract
Human epidermal growth factor receptor 2 (HER2) overexpression and amplification have been reported as predictive markers for HER2-targeted therapy in breast and gastric cancer, whereas human epidermal growth factor receptor 3 (HER3) is emerging as a potential resistance factor. The aim of this study was to perform a systematic review and meta-analysis of the HER2 and HER3 overexpression and amplification in biliary tract cancers (BTCs). An electronic search of MEDLINE, American Society of Clinical Oncology (ASCO), European Society of Medical Oncology Congress (ESMO), and American Association for Cancer Research (AACR) was performed to identify studies reporting HER2 and/or HER3 membrane protein expression by immunohistochemistry (IHC) and/or gene amplification by in situ hybridization (ISH) in BTCs. Studies were classified as "high quality" (HQ) if IHC overexpression was defined as presence of moderate/strong staining or "low quality" (LQ) where "any" expression was considered positive. Of 440 studies screened, 40 met the inclusion criteria. Globally, HER2 expression rate was 26.5 % (95 % CI 18.9–34.1 %). When HQ studies were analyzed (n = 27 studies), extrahepatic BTCs showed a higher HER2 overexpression rate compared to intrahepatic cholangiocarcinoma: 19.9 % (95 % CI 12.8–27.1 %) vs. 4.8 % (95 % CI 0–14.5 %), respectively, p value 0.0049. HER2 amplification rate was higher in patients selected by HER2 overexpression compared to "unselected" patients: 57.6 % (95 % CI 16.2–99 %) vs. 17.9 % (95 % CI 0.1–35.4 %), respectively, p value 0.0072. HER3 overexpression (4/4 HQ studies) and amplification rates were 27.9 % (95 % CI 9.7–46.1 %) and 26.5 % (one study), respectively. Up to 20 % of extrahepatic BTCs appear to be HER2 overexpressed; of these, close to 60 % appear to be HER2 amplified, while HER3 is overexpressed or amplified in about 25 % of patients. Clinical relevance for targeted therapy should be tested in prospective clinical trials.
from Cancer via ola Kala on Inoreader http://ift.tt/2hzF9lD
via IFTTT
HER2/HER3 pathway in biliary tract malignancies; systematic review and meta-analysis: a potential therapeutic target?
Abstract
Human epidermal growth factor receptor 2 (HER2) overexpression and amplification have been reported as predictive markers for HER2-targeted therapy in breast and gastric cancer, whereas human epidermal growth factor receptor 3 (HER3) is emerging as a potential resistance factor. The aim of this study was to perform a systematic review and meta-analysis of the HER2 and HER3 overexpression and amplification in biliary tract cancers (BTCs). An electronic search of MEDLINE, American Society of Clinical Oncology (ASCO), European Society of Medical Oncology Congress (ESMO), and American Association for Cancer Research (AACR) was performed to identify studies reporting HER2 and/or HER3 membrane protein expression by immunohistochemistry (IHC) and/or gene amplification by in situ hybridization (ISH) in BTCs. Studies were classified as "high quality" (HQ) if IHC overexpression was defined as presence of moderate/strong staining or "low quality" (LQ) where "any" expression was considered positive. Of 440 studies screened, 40 met the inclusion criteria. Globally, HER2 expression rate was 26.5 % (95 % CI 18.9–34.1 %). When HQ studies were analyzed (n = 27 studies), extrahepatic BTCs showed a higher HER2 overexpression rate compared to intrahepatic cholangiocarcinoma: 19.9 % (95 % CI 12.8–27.1 %) vs. 4.8 % (95 % CI 0–14.5 %), respectively, p value 0.0049. HER2 amplification rate was higher in patients selected by HER2 overexpression compared to "unselected" patients: 57.6 % (95 % CI 16.2–99 %) vs. 17.9 % (95 % CI 0.1–35.4 %), respectively, p value 0.0072. HER3 overexpression (4/4 HQ studies) and amplification rates were 27.9 % (95 % CI 9.7–46.1 %) and 26.5 % (one study), respectively. Up to 20 % of extrahepatic BTCs appear to be HER2 overexpressed; of these, close to 60 % appear to be HER2 amplified, while HER3 is overexpressed or amplified in about 25 % of patients. Clinical relevance for targeted therapy should be tested in prospective clinical trials.
http://ift.tt/2hzF9lD
Emphysematous pancreatitis: classic findings
Description
A 55-year-old man with diabetes presented to our hospital with recent onset acute abdominal pain and recurrent vomiting. He was immediately admitted to the intensive care unit for ionotropic and invasive respiratory support. He had an acutely tender abdomen with distension. Haematological examination showed leucopenia (880/mm3), thrombocytopenia (64 000/mm3), elevated C reactive protein (68 mg/mL), metabolic acidosis (pH: 6.88) with a severely elevated blood lactate (14 mmol/L), estimated creatinine clearance <14 mL/min, hyperlipidaemia (1280 U/L) and serum amylase levels of 5134 U/L. Plain CT revealed extensive gas in the pancreatic bed extending into the lesser sac and adjacent retroperitoneal space (figure 1A, B). A diagnosis of acute severe emphysematous pancreatitis was made; although the patient was aggressively treated, unfortunately he died. Retrospective blood cultures were positive for Enterobacter aerogenes.
Figure 1
(A) CT image showing the presence of air lucencies in the epigastric region at the level of L1–L2 vertebral...
http://ift.tt/2hxtciy
Unexplained lymphadenopathies: autoimmune lymphoproliferative syndrome in an adult patient
Autoimmune lymphoproliferative syndrome (ALPS) is characterised by massive enlargement of the lymphoid organs, autoimmune cytopenias and a predisposition to develop lymphoid malignancies. The basic defect is a disturbance of the lymphocyte apoptosis, and a high number of circulating TCRab CD3+CD4–CD8– T-cells (double-negative T cells (DNT cells)). We describe a case of a 41-year-old man with fever, hepatosplenomegaly, multiple lymphadenopathy, autoimmune haemolytic anaemia and severe thrombocytopenia. Peripheral blood immunophenotyping revealed elevation of the characteristic DNT cells in 8% and high levels of interleukin 10. Histopathological analysis of lymph nodes showed lymphadenitis with paracortical hyperplasia. It was assumed as a probable diagnosis of ALPS, and the procedure was to medicate the patient with steroids. As a result, a significant clinical improvement was achieved, and he has been in remission for 2 years. To our knowledge, this is the first case reported in a Portuguese adult patient.
http://ift.tt/2hAoON9
Concomitant multiple myeloma, gastric adenocarcinoma and Evan's syndrome in a patient presenting with anaemia
An association between multiple myeloma (MM) and solid tumours has been previously described.1 Furthermore, autoimmune disorders can precede plasma cell dyscrasias, and the pathogenesis of MM maybe linked to chronic immune stimulation. 2 We describe a case of concomitant MM and gastric adenocarcinoma preceded by Evan's syndrome. A previously healthy woman presented to the emergency room with symptomatic anaemia. Her initial workup was compatible with autoimmune haemolytic anaemia and monoclonal gammopathy of undetermined significance. On progression of the anaemia and development of thrombocytopenia, she was diagnosed with Evan's syndrome. Two months later, she presented with severe back pain and her MRI revealed L4–5 vertebral collapse. The clinical picture was compatible with MM. Occult blood was repeatedly positive in stools, and she underwent oesophagogastroduodenoscopy and was found to have gastric adenocarcinoma. The patient refused surgical resection of the adenocarcinoma and refused active treatment for MM.
http://ift.tt/2hxztuV
Rare cause of neck pain: tumours of the posterior elements of the cervical spine
Here we present two cases of primary bone tumours of the cervical spine in patients who had persistent neck pain—in one case, lasting 8 years. In each case, there was a delay in diagnosis and referral to a spine specialist was prolonged. Primary bone tumours of the spine are rare, which is in contrast to the wide prevalence of cervical neck pain. Many primary care providers may go an entire career without encountering a symptomatic primary cervical spine tumour. In this paper, we discuss the clinical course and treatment of each patient and review the current literature on primary bone tumours of the spine. Owing to the subtle roentgenographic findings of primary cervical tumours, we highlight the importance of advanced imaging in the clinical work-up of simple axial neck pain lasting >6 weeks to avoid misdiagnosis of serious pathology.
http://ift.tt/2hApNgr
Boari flap reconstruction in a male infant with solitary kidney and associated megaureter
A 1-year-old male infant presented with fever and abdominal lump for 3 months with increased leucocyte count (15 300/mm3) and serum creatinine (0.83 mg%). Abdominal ultrasound and renal scan demonstrated solitary left kidney with dilated tortuous left ureter. Voiding cystourethrogram was unequivocal. Left percutaneous nephrostomy was placed after poor response to perurethral catheterisation. His serum creatinine dropped to 0.58 mg/dL. Subsequent percutaneous nephrostogram and CT nephrostogram showed dilated left pelvicalyceal system, dilated, tortuous left ureter. A diagnosis of obstructed megaureter was made and ureteric plication and reimplantation planned. Intraoperatively, there were primitive ureteral valves until proximal one-third of the ureter. The distance between the upper ureter and bladder was ~6 cm. This defect was bridged by Boari flap. The postoperative period was uneventful and now after 6 months of follow-up, he is doing fine.
http://ift.tt/2hxwHFS
Unusual case of bilateral maxillary fungus ball
An otherwise healthy 34-year-old man was referred to our ear, nose and throat (ENT) clinic for a bilateral maxillary radiologic opacity. This condition was accidentally discovered with a panoramic radiography performed during a follow-up visit after a bilateral endodontic treatment. The patient did not report any specific sinonasal symptom such as purulent nasal discharge, loss of smell and cough, apart from an unspecific sinus pressure. The CT scans showed a bilateral inflammatory process into the maxillary-ethmoidal sinuses and an iron-like density within the maxillary sinuses, while nasal endoscopy showed purulent discharge in the ostiomeatal complex. The patient underwent functional endoscopic sinus surgery under general anaesthesia and the inflammatory material collected was histologically diagnosed as a rare case of bilateral fungus ball. The patient was dismissed the following day with no complications; there were not any sign of recurrence or symptoms during a 4 month follow-up.
http://ift.tt/2hAmrdk
Large intraocular foreign body following a firecracker injury
Description
An 8-year-old girl child presented with the history of firecracker injury to the right eye. There was a sudden loss of vision associated with pain, redness and watering. Primarily, she was diagnosed as panophthalmitis and started of intravenous antibiotics, but as the condition worsened she was referred to a tertiary eye hospital. Initial examination was painful tense upper and lower eyelid oedema (figure 1A) along with severely chemosed conjunctiva and with severely restricted extraocular motility in all the gazes; the child denied any perception of light in the right eye, whereas left eye was normal. Ultrasonography showed a large high-amplitude opacity filling almost two-third of the vitreous cavity with shadowing posterior. (figure 1B). Subsequent CT of the orbit showed large hyperdense foreign body almost filling the entire vitreous cavity. (figure 1C). The patient was started on intravenous antibiotics injection vancomycin 40 mg/kg...
http://ift.tt/2hxyHOA
Pulmonary sarcoidosis: calcification within the galaxy sign
Description
A 34-year-old woman had breathlessness, dry cough and low-grade fever for 6 months. Chest X-ray showed bilateral hilar lymphadenopathy and patchy alveolar right mid-zone shadows along with bilateral lower zone nodular opacities (figure 1A). Contrast-enhanced high-resolution CT(HRCT) of thorax demonstrated enlarged, non-necrotic right paratracheal, subcarinal and bilateral hilar lymph nodes. The lung window in right upper lobe revealed a large nodule with irregular margins encircled by multiple small nodules suggestive of 'galaxy' sign (figure 1B). In addition, mediastinal window divulged dense calcification within the nodule and mediastinal lymphnodes (figure 1C). Fibreoptic bronchoscopy visualised multiple endobronchial granulomatous lesions throughout the tracheobronchial tree (figure 2A) and was confirmed on biopsy (figure 2B). The diagnosis of pulmonary sarcoidosis was based on (1) chest imaging, (2) elevated serum ACE levels (126 IU/mL [8–65 IU/mL]), (3) negative tuberculin test and (4) visible endobronchial lesions and...
http://ift.tt/2hAkJIR
Melphalan-induced cardiotoxicity: ventricular arrhythmias
Description
A 61-year-old man, with multiple myeloma (IgA lambda), was planned for autologous stem cell transplantation (ASCT). He also suffered a left thalamic haemorrhagic stroke in 1998 secondary to aneurysmal bleed. Following melphalan infusion of 200 mg at 45 mL/min, he developed acute onset rhythm abnormalities (intermittent ventricular ectopic and ventricular tachycardia). The patient's premelphalan evaluation was unremarkable with normal ECG (1A), ejection fraction (55%) and renal/hepatic function. He was evaluated by sequential 2D echocardiography and troponin I (immediately, 2, 4, 12 and 24 hours) which were normal excluding acute STEMI. These rhythm abnormalities were dynamic probably secondary to the plasma melphalan concentrations and normalised by 18 h postinfusion (figure 1B–F). There has been no recurrence of these rhythm abnormalities thereafter. He was transplanted with abbreviated melphalan conditioning.
Figure 1
(A) Normal ECG before starting melphalan infusion. (B) ECG after 200 mg of melphalan infusion, showing acute onset ventricular rhythm...
http://ift.tt/2hxz6R3
Rare case of glioblastoma multiforme located in posterior corpus callosum presenting with depressive symptoms and visual memory deficits
Most of the primary brain tumours are located in the supratentorial region, and it is uncommon to see tumour growth on deep brain structures such as posterior corpus callosum (PCC). In addition, lesions in PCC are also difficult to recognise, because construction apraxia, visuospatial perception and attentional capacity impairment may be the only presenting symptoms. Here, we represent a rare case of gliobastoma multiforme located in PCC, which solely presents with depressive symptoms and visual memory deficits. Initial manifestations of primary brain tumours with psychiatric symptoms and memory disturbances, in addition to headaches and seizures, should be kept in mind.
http://ift.tt/2hxtQgf
Cancers, Vol. 8, Pages 114: Erratum: Roche, J. et al. Global Decrease of Histone H3K27 Acetylation in ZEB1-Induced Epithelial to Mesenchymal Transition in Lung Cancer Cells. Cancers, 2013, 5, 334–356
n/a
from Cancer via ola Kala on Inoreader http://ift.tt/2hA0GKD
via IFTTT
Case 38-2016: A 52-Year-Old Woman with Recurrent Oligodendroglioma
Presentation of Case. Dr. Andrew S. Chi: A 52-year-old woman with a history of oligodendroglioma was seen in the outpatient neuro-oncology clinic of this hospital for routine follow-up. Twelve years earlier, the patient presented with a generalized tonic–clonic seizure 4 days after she had…
http://ift.tt/2gO4YzJ
Τετάρτη 14 Δεκεμβρίου 2016
Malignant Phyllodes Tumor Presenting in Bone, Brain, Lungs, and Lymph Nodes
Case Rep Oncol 2016;9:861–868
http://ift.tt/2hvxdBy
A Patient with Supraclavicular Lymphadenopathy and Anterior Mediastinal Mass Presenting as a Rare Case of Composite Lymphoma: A Case Report and Literature Review
Composite lymphoma (CL) is a rare disease with 2 distinct lymphomas concurrently arising in a single patient with an estimated incidence of 1–4.7% of newly diagnosed lymphomas per year. CL most commonly involves 2 B-cell non-Hodgkin lymphomas (NHL) or a B-cell NHL with a Hodgkin lymphoma. Our case is unique in that it was a bilineage CL with both a T-cell and B-cell NHL, which has only been reported in a few case reports. A 49-year-old woman presented with several months of progressive cough, weight loss, dyspnea, and supraclavicular lymphadenopathy. Computed tomographic imaging done upon admission to the hospital found that she had extensive anterior and middle mediastinal lymphadenopathy as well as bilateral supraclavicular lymphadenopathy. The patient underwent an excisional biopsy on the supraclavicular lymph node and was found to have a composite lymphoma involving both a T-cell and B-cell NHL. Her final pathological diagnosis was peripheral T-cell lymphoma and lymphoplasmacytic lymphoma. The patient was found to have stage IIIB disease. Her HIV, hepatitis panel, and tuberculosis tests were all negative. She then underwent chemotherapy with dose-adjusted EPOCH-R (etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin, and rituximab). The patient showed a complete response and was then referred to a bone marrow transplant center for an autologous hematopoietic stem cell transplant. CL is a rare disease composed of at least 2 distinct lymphomas concurrently arising in a single patient. Due to the complexity in having to treat multiple types of lymphoma simultaneously CL presents challenges with treatment and assessing prognosis.
Case Rep Oncol 2016;9:854–860
http://ift.tt/2htgG3R
A Case of Poorly Differentiated Large-Cell Neuroendocrine Carcinoma of the Cecum: A Rare Malignancy, with Review of the Literature
Poorly differentiated neuroendocrine carcinomas (NECs) are rare tumors that can arise anywhere along the gastrointestinal tract. They often present in advanced stage and portend a poor prognosis when compared to adenocarcinomas of the same stage. Characterization of these tumors is best accomplished with tissue biopsy, as peripheral tumor markers commonly used in NECs are of little utility. Therapeutic strategies often involve chemotherapeutic regimens that have been used to treat small-cell lung cancer. Recent studies have shown that programmed death-ligand 1 (PD-L1) expression within poorly differentiated NECs is a poor prognostic indicator. However, PD-L1 expression may represent a possible target for immunotherapy drugs, often called checkpoint inhibitors, such as anti-PD-1 inhibitors.
Case Rep Oncol 2016;9:847–853
http://ift.tt/2hvuHer
Use of thromboelastography in the management of liver cirrhosis and accelerated intravascular coagulation and fibrinolysis (AICF)
In the presented case, the authors describe an obese middle-aged man that presented to the emergency department for persistent oedema, scleral icterus and fatigue. He was admitted to the hospital and diagnosed with liver cirrhosis via transjugular liver biopsy. He continued to bleed from the biopsy site for 5 days from accelerated intravascular coagulation and fibrinolysis (AICF) requiring multiple transfusions of packed red blood cells, fresh-frozen plasma and cryoprecipitate. The authors then used thromboelastography (TEG) to further characterise the patient's coagulopathy, which revealed platelet inhibition. The results of the TEG significantly changed future transfusion management. Finally, the authors conducted a literature review to summarise the current literature available for the use of TEG in the management of liver cirrhosis with AICF.
http://ift.tt/2hELpLR
Combined central retinal vein and branch retinal artery occlusion in hyperhomocysteinaemia
Description
A woman aged 30 years reported of blurred vision in the right eye (RE) for 2 days. Visual acuity was 6/24 in the RE and 6/6 in the left eye (LE). Funduscopy of RE showed combined non-ischaemic central retinal vein occlusion (CRVO) and supero-temporal branch retinal artery occlusion (BRAO) (figure 1A). LE examination was normal. Optical coherence tomography (OCT) of the RE showed thickening of inner retinal layers corresponding to the area of BRAO (figure 1A: white arrow). Thorough systemic investigations and cardiac workup revealed raised serum homocysteine levels (37.21 μmol/L). She was started on oral folic acid and pyridoxine. Over the next 6 months, her visual acuity improved to 6/12 with clearing of retinal whitening and resolution of retinal haemorrhages (figure 1B–D).
Figure 1
Funduscopy of the right eye (RE) showing dilated torturous retinal veins with multiple retinal haemorrhages in all four quadrants...
http://ift.tt/2gAqODf
Iliopsoas abscess caused by chronic urolithiasis and pyelonephritis
Description
A man aged 45 years, with a history of recurrent urolithiasis and pyelonephritis, presented with a 3-month history of fever. Physical examination revealed a nodule in his right inguinal area. CT with contrast showed a right iliopsoas abscess that extended to the inguinal area and a right urethral stone (figure 1). Drainage under fluoroscopic guidance was performed, and the contrast was injected into the cavity from the drainage tube to assess the abscess cavity. The contrast study demonstrated a connection between the urethra and abscess cavity (figure 2). The patient was administered 1 g cefotiam every 8 hours. Blood, urine and fluid cultures from the abscess were positive for Escherichia coli. Surgical drainage and right nephrectomy was performed. The patient was discharged 3 months after the surgery without any complication. The penetration of an iliopsoas abscess into the urinary tract is extremely rare, while the symptoms...
http://ift.tt/2hEU5Sc
Vertical muscle transposition with silicone band belting in VI nerve palsy
A woman aged 60 years developed a Millard-Gubler syndrome after a diagnosis of a cavernous angioma in the median and paramedian areas of the pons. In this context, she presented a right VI nerve palsy, right conjugate gaze palsy, facial palsy and left hemiparesis. To improve the complete VI nerve palsy, we planned a modified transposition approach, in which procedure we made a partial transposition of vertical rectus with a silicone band that was fixated posteriorly. After the procedure, the patient gained the ability to slightly abduct the right eye. We found no compensatory torticollis in the primary position of gaze. There was also an improvement of elevation and depression movements of the right eye. We obtained satisfactory results with a theoretically reversible technique, which is adjustable intraoperatively with no need of muscle detachment, preventing anterior segment ischaemia and allowing simultaneous recession of the medial rectus muscles, if necessary.
http://ift.tt/2gAxbXn
Short overview on the current treatment of chronic myeloid leukemia in chronic phase
Summary
This short review on current treatment options in chronic myeloid leukemia (CML) in the chronic phase summarizes the latest version of the ELN treatment recommendations dating from 2013 and indicates treatment situations not yet reflected in these recommendations. Daily practice in CML management is complicated by the recently observed treatment-emergent vascular and pulmonary adverse events in second- or later-generation tyrosine kinase inhibitors (TKIs), the lack of guidance with respect to the best TKI for initial treatment, as well as the optimal TKI sequence because no prospective randomized comparative data for second- and third-generation TKIs are available. Physicians have to balance the efficacy issues and safety aspects of the respective TKI and consider patient-specific factors such as comorbidities. Patients with any cardiovascular or pulmonary disease or treatment-requiring cardiovascular risk factor should receive nilotinib or ponatinib only if risk factors and comorbidities are treated accordingly and are further monitored. If these comorbidities are insufficiently controlled, other TKIs might be preferred. Dasatinib treatment should be critically evaluated in patients with pulmonary disease and other TKIs might be preferred in this setting. For as long as CML treatment is considered to be maintained lifelong, and no survival benefit for later-generation TKIs has been demonstrated, safety issues dominate the choice of treatment options. The concept of discontinuing TKI treatment after achieving a deep molecular response might in future change these considerations.
from Cancer via ola Kala on Inoreader http://ift.tt/2hwmCqt
via IFTTT
Short overview on the current treatment of chronic myeloid leukemia in chronic phase
Summary
This short review on current treatment options in chronic myeloid leukemia (CML) in the chronic phase summarizes the latest version of the ELN treatment recommendations dating from 2013 and indicates treatment situations not yet reflected in these recommendations. Daily practice in CML management is complicated by the recently observed treatment-emergent vascular and pulmonary adverse events in second- or later-generation tyrosine kinase inhibitors (TKIs), the lack of guidance with respect to the best TKI for initial treatment, as well as the optimal TKI sequence because no prospective randomized comparative data for second- and third-generation TKIs are available. Physicians have to balance the efficacy issues and safety aspects of the respective TKI and consider patient-specific factors such as comorbidities. Patients with any cardiovascular or pulmonary disease or treatment-requiring cardiovascular risk factor should receive nilotinib or ponatinib only if risk factors and comorbidities are treated accordingly and are further monitored. If these comorbidities are insufficiently controlled, other TKIs might be preferred. Dasatinib treatment should be critically evaluated in patients with pulmonary disease and other TKIs might be preferred in this setting. For as long as CML treatment is considered to be maintained lifelong, and no survival benefit for later-generation TKIs has been demonstrated, safety issues dominate the choice of treatment options. The concept of discontinuing TKI treatment after achieving a deep molecular response might in future change these considerations.
http://ift.tt/2hwmCqt
Successful treatment of mature B-cell lymphoma with rituximab-based chemotherapy in a patient with Bloom syndrome
Abstract
This report presents a case of Bloom syndrome (BS) in a consanguineous Saudi family. The patient, an 11-year-old male with mature B-cell lymphoma, had minimal therapeutic response and significant dose-limiting toxicity with standard chemotherapy treatment. He later responded successfully to a rituximab-based chemotherapy protocol. This case highlights that the rituximab-based chemotherapy protocol is an effective and safe treatment alternative for mature B-cell lymphoma in patients with BS. Further trials are warranted to investigate this modality of treatment.
http://ift.tt/2gA4V6Y
Overexpression of TEAD4 in atypical teratoid/rhabdoid tumor: New insight to the pathophysiology of an aggressive brain tumor
Abstract
Background
Atypical teratoid/rhabdoid tumor (AT/RT) is a highly malignant embryonal brain tumor that occurs mainly in early childhood. Although most of the tumors are characterized by inactivating mutations of the tumor suppressor gene, SMARCB1, the biological basis of its tumorigenesis and aggressiveness is still unknown.
Procedure
We performed high-throughput copy number variation analysis of primary cell lines generated from primary and relapsed tumors from one of our patients to identify new genes involved in AT/RT biology. The expression of the identified gene was validated in 29 AT/RT samples by gene expression profiling, quantitative real-time polymerase chain reaction, and immunohistochemistry (IHC). Furthermore, we investigated the function of this gene by mutating it in rhabdoid tumor cells.
Results
TEAD4 amplification was detected in the primary cell lines and its overexpression was confirmed at mRNA and protein levels in an independent cohort of AT/RT samples. TEAD4's co-activator, YAP1, and the downstream targets, MYC and CCND1, were also found to be upregulated in AT/RT when compared to medulloblastoma. IHC showed TEAD4 and YAP1 overexpression in all samples. Cell proliferation and migration were significantly reduced in TEAD4-mutated cells.
Conclusions
We report the overexpression of TEAD4 in AT/RT, which is a key component of Hippo pathway. Recent reports revealed that dysregulation of the Hippo pathway is implicated in tumorigenesis and poor prognosis of several human cancers. Our results suggest that TEAD4 plays a role in the pathophysiology of AT/RT, which represents a new insight into the biology of this aggressive tumor.
http://ift.tt/2hEnbkz
Yield of screening echocardiograms during pediatric follow-up in survivors treated with anthracyclines and cardiotoxic radiation
Abstract
Background
Guidelines published by the Children's Oncology Group recommend screening echocardiograms for childhood cancer survivors exposed to anthracyclines and/or cardiotoxic radiation. This study aims to assess risk factors for cardiac late effects while evaluating the overall yield of screening echocardiograms.
Procedure
Demographics, exposures, and echocardiogram results were abstracted from the medical records of survivors diagnosed at ≤ 21 years old and ≥ 2 years off therapy who were exposed to anthracyclines and/or potentially cardiotoxic radiotherapy. Descriptive statistics and logistic regressions were performed and the yield of screening echocardiograms was calculated.
Results
Of 853 patients, 1,728 screening echocardiograms were performed, and 37 patients had an abnormal echocardiogram (overall yield 2.1%). Yields were only somewhat higher in more frequently screened patients. Risk factors for an abnormal result included anthracycline dose of ≥300 mg/m2 (adjusted odds ratio [aOR] 3.1; 95% confidence interval [CI]: 1.3−7.2; P < 0.01) with a synergist relationship in patients who also received radiation doses ≥30 Gy (aOR 7.0; 95% CI: 1.6–31.9; P = 0.01), as well as autologous bone marrow transplant (OR 3.3; 95% CI: 1.3–8.5; P = 0.01). Sex, race, age at diagnosis, and cyclophosphamide exposure were not statistically significant risk factors, and no patient receiving <100 mg/m2 anthracycline dose without concomitant radiation had an abnormal echocardiogram.
Conclusions
Dose-dependent and synergist anthracycline and cardiotoxic radiotherapy risks for developing cardiomyopathy were confirmed. However, previously identified risk factors including female sex, black race, and early age at diagnosis were not replicated in this cohort. The yields showed weak correlation across frequency categories. Echocardiographic screening recommendations for low-risk pediatric patients may warrant re-evaluation.
http://ift.tt/2gzYJvR
Delayed elimination of high-dose methotrexate and use of carboxypeptidase G2 in pediatric patients during treatment for acute lymphoblastic leukemia
Abstract
Background
Carboxypeptidase G2 (CPDG2) can be used as rescue treatment in cases of delayed methotrexate elimination (DME) and Mtx-induced nephrotoxicity.
Procedure
Between July 2008 and December 2014, all children (1.0–17.9 years) in the Nordic countries diagnosed with Philadelphia chromosome negative acute lymphoblastic leukemia (ALL) were treated according to the Nordic Organization for Pediatric Hematology and Oncology (NOPHO) ALL 2008 protocol, including administration of six to eight high-dose (5 g/m2/24 hr) Mtx (HDMtx) courses. The protocol includes recommendations for CPDG2 administration in cases of DME (clinicaltrials.gov NCT01305655).
Results
Forty-seven of the 1,286 children (3.6%) received CPDG2 during 50 HDMtx courses at a median dose of 50 IU/kg. In 49% of the cases, CPDG2 was used during the first HDMtx course. Within a median of 6 hr from CPDG2 administration, the Mtx concentration decreased by 75% when measured with immune-based methods, and by 100% when measured with high-performance liquid chromatography. The median time from the start of Mtx infusion to plasma levels ≤ 0.2 μM was 228 hr (range: 48–438). The maximum increase in plasma creatinine was 375% (range: 100–1,310). Creatinine peaked after a median of 48 hr (range: 36–86). Mtx elimination time was shorter in patients with body surface area < 1 m2 (median 198.5 vs. 257 hr; P = 0.004) and was inversely correlated to the maximum creatinine increase (209 vs. 258 hr; P = 0.034). All patients normalized their renal function as measured with s-creatinine.
Conclusions
CPDG2 administration is highly effective as rescue in case of delayed Mtx clearance. Subsequent HDMtx courses could be administered without events in most of the patients.
http://ift.tt/2hEeHtU
Gene Therapy for Epidermolysis Bullosa: Sticky Business
Gene Therapy for Epidermolysis Bullosa: Sticky Business
Molecular Therapy 24, 2035 (December 2016). doi:10.1038/mt.2016.199
Authors: Alexander Nyström & Leena Bruckner-Tuderman
http://ift.tt/2hv7KYO
Robust Oncolytic Virotherapy Induces Tumor Lysis Syndrome and Associated Toxicities in the MPC-11 Plasmacytoma Model
Robust Oncolytic Virotherapy Induces Tumor Lysis Syndrome and Associated Toxicities in the MPC-11 Plasmacytoma Model
Molecular Therapy 24, 2109 (December 2016). doi:10.1038/mt.2016.167
Authors: Lianwen Zhang, Michael B Steele, Nathan Jenks, Jacquelyn Grell, Marshall Behrens, Rebecca Nace, Shruthi Naik, Mark J Federspiel, Stephen J Russell & Kah-Whye Peng
http://ift.tt/2cKT2cp
In This Issue
In This Issue
Molecular Therapy 24, 2037 (December 2016). doi:10.1038/mt.2016.200
http://ift.tt/2hved5V
Remodeling of the Extracellular Matrix by Endothelial Cell-Targeting siRNA Improves the EPR-Based Delivery of 100 nm Particles
Remodeling of the Extracellular Matrix by Endothelial Cell-Targeting siRNA Improves the EPR-Based Delivery of 100 nm Particles
Molecular Therapy 24, 2090 (December 2016). doi:10.1038/mt.2016.178
Authors: Yu Sakurai, Tomoya Hada, Shoshiro Yamamoto, Akari Kato, Wataru Mizumura & Hideyoshi Harashima
http://ift.tt/2hv32KD
Research Highlights
Research Highlights
Molecular Therapy 24, 2038 (December 2016). doi:10.1038/mt.2016.201
http://ift.tt/2hv32dB
Corrigendum to “Targeted Delivery of C/EBPα -saRNA by Pancreatic Ductal Adenocarcinoma-specific RNA Aptamers Inhibits Tumor Growth In Vivo”
Corrigendum to "Targeted Delivery of C/EBPα -saRNA by Pancreatic Ductal Adenocarcinoma-specific RNA Aptamers Inhibits Tumor Growth In Vivo"
Molecular Therapy 24, 2131 (December 2016). doi:10.1038/mt.2016.197
http://ift.tt/2huZDvj
One Size Fits All?: Ethical Considerations for Examining Efficacy in First-in-Human Pluripotent Stem Cell Studies
One Size Fits All?: Ethical Considerations for Examining Efficacy in First-in-Human Pluripotent Stem Cell Studies
Molecular Therapy 24, 2039 (December 2016). doi:10.1038/mt.2016.202
Authors: Michelle GJL Habets, Johannes JM van Delden, Sophie L Niemansburg, Harold L Atkins & Annelien L Bredenoord
http://ift.tt/2hv5osQ
Targeted Delivery of an Anti-inflammatory PDE4 Inhibitor to Immune Cells via an Antibody–drug Conjugate
Targeted Delivery of an Anti-inflammatory PDE4 Inhibitor to Immune Cells via an Antibody–drug Conjugate
Molecular Therapy 24, 2078 (December 2016). doi:10.1038/mt.2016.175
Authors: Shan Yu, Aaron D Pearson, Reyna KV Lim, David T Rodgers, Sijia Li, Holly B Parker, Meredith Weglarz, Eric N Hampton, Michael J Bollong, Jiayin Shen, Claudio Zambaldo, Danling Wang, Ashley K Woods, Timothy M Wright, Peter G Schultz, Stephanie A Kazane, Travis S Young & Matthew S Tremblay
http://ift.tt/2hv3yrQ
The Mucus Barrier to Inhaled Gene Therapy
The Mucus Barrier to Inhaled Gene Therapy
Molecular Therapy 24, 2043 (December 2016). doi:10.1038/mt.2016.182
Authors: Gregg A Duncan, James Jung, Justin Hanes & Jung Soo Suk
http://ift.tt/2hv31q3
The Niemann-Pick C1 Inhibitor NP3.47 Enhances Gene Silencing Potency of Lipid Nanoparticles Containing siRNA
The Niemann-Pick C1 Inhibitor NP3.47 Enhances Gene Silencing Potency of Lipid Nanoparticles Containing siRNA
Molecular Therapy 24, 2100 (December 2016). doi:10.1038/mt.2016.179
Authors: Haitang Wang, Yuen Yi C Tam, Sam Chen, Josh Zaifman, Roy van der Meel, Marco A Ciufolini & Pieter R Cullis
http://ift.tt/2hv6rck
Low-dose Gene Therapy Reduces the Frequency of Enzyme Replacement Therapy in a Mouse Model of Lysosomal Storage Disease
Low-dose Gene Therapy Reduces the Frequency of Enzyme Replacement Therapy in a Mouse Model of Lysosomal Storage Disease
Molecular Therapy 24, 2054 (December 2016). doi:10.1038/mt.2016.181
Authors: Marialuisa Alliegro, Rita Ferla, Edoardo Nusco, Chiara De Leonibus, Carmine Settembre & Alberto Auricchio
http://ift.tt/2hv3xEi
Intracellular Delivery of Anti-pPKCθ (Thr538) via Protein Transduction Domain Mimics for Immunomodulation
Intracellular Delivery of Anti-pPKCθ (Thr538) via Protein Transduction Domain Mimics for Immunomodulation
Molecular Therapy 24, 2118 (December 2016). doi:10.1038/mt.2016.177
Authors: E Ilker Ozay, Gabriela Gonzalez-Perez, Joe A Torres, Jyothi Vijayaraghavan, Rebecca Lawlor, Heather L Sherman, Daniel T Garrigan, Amy S Burnside, Barbara A Osborne, Gregory N Tew & Lisa M Minter
http://ift.tt/2hv1mAJ
Linc00152 Functions as a Competing Endogenous RNA to Confer Oxaliplatin Resistance and Holds Prognostic Values in Colon Cancer
Linc00152 Functions as a Competing Endogenous RNA to Confer Oxaliplatin Resistance and Holds Prognostic Values in Colon Cancer
Molecular Therapy 24, 2064 (December 2016). doi:10.1038/mt.2016.180
Authors: Ben Yue, Donglan Cai, Chenchen Liu, Changyi Fang & Dongwang Yan
http://ift.tt/2esRCoz
Corrigendum to “A Self-restricted CRISPR System to Reduce Off-target Effects”
Corrigendum to "A Self-restricted CRISPR System to Reduce Off-target Effects"
Molecular Therapy 24, 2132 (December 2016). doi:10.1038/mt.2016.198
http://ift.tt/2hv125b
Indian Journal of Medical and Paediatric Oncology (Indian J Med Paediatr Oncol)
Savio George Barreto
[ABSTRACT] [HTML FULL TEXT] [PDF] [Mobile HTML Full text ] [EPub]
Ulrich Nitsche, Bo Kong, Alexander Balmert, Helmut Friess, Jörg Kleeff
[ABSTRACT] [HTML FULL TEXT] [PDF] [Mobile HTML Full text ] [EPub]
Rita V Vora, RahulKrishna S Kota, Nilofar G Diwan, Nidhi B Jivani, Shailee S Gandhi
[ABSTRACT] [HTML FULL TEXT] [PDF] [Mobile HTML Full text ] [EPub]
Abhishek Mahajan, Subash Desai, Nilesh Pandurang Sable, Meenakshi Haresh Thakur
[ABSTRACT] [HTML FULL TEXT] [PDF] [Mobile HTML Full text ] [EPub]
Khadijeh Abbasi, Maryam Hazrati, Abolfazl Mohammadbeigi, Jasem Ansari, Mahboubeh Sajadi, Azam Hosseinnazzhad, Esmail Moshiri
[ABSTRACT] [HTML FULL TEXT] [PDF] [Mobile HTML Full text ] [EPub]
K Govind Babu, MC Suresh Babu, D Lokanatha, Gita R Bhat
[ABSTRACT] [HTML FULL TEXT] [PDF] [Mobile HTML Full text ] [EPub]
Azizfatema Munawer Khan, Megha S Sheth, Romsha R Purohit
[ABSTRACT] [HTML FULL TEXT] [PDF] [Mobile HTML Full text ] [EPub]
Stalin Bala, Sadashivudu Gundeti, Vijay Gandhi Linga, Lakshmi Srinivas Maddali, Raghunadha Rao Digumarti, Shantveer G Uppin
[ABSTRACT] [HTML FULL TEXT] [PDF] [Mobile HTML Full text ] [EPub]
Mehnaaz Sultan Khuroo, Summyia Farooq Khwaja, Ajaz Rather, Zhahid Hassan, Ruby Reshi, Naira Sultan Khuroo
[ABSTRACT] [HTML FULL TEXT] [PDF] [Mobile HTML Full text ] [EPub]
Subhash Gupta, Kunhi Parambath Haresh, Soumyajit Roy, Lakhan Kashyap, Narayan Adhikari, Rambha Pandey, Dayanand Sharma, Pramod Kumar Julka, Goura Kishor Rath
[ABSTRACT] [HTML FULL TEXT] [PDF] [Mobile HTML Full text ] [EPub]
Karnam Ashok Kumar, Gundeti Sadashivudu, KV Krishnamani, Vijay Gandhi Linga, Lakshmi Srinivas Maddali, Raghunadha Rao Digumarti
[ABSTRACT] [HTML FULL TEXT] [PDF] [Mobile HTML Full text ] [EPub]
Richa Bhartiya, Mahasweta Mallik, Nawanita Kumari, Brijendra Narayan Prasad
[ABSTRACT] [HTML FULL TEXT] [PDF] [Mobile HTML Full text ] [EPub]
Bhawna Sirohi, Vikas Ostwal, Shaheenah Dawood, Gilberto Lopes, Sanjay Talole, Chaitali Nashikkar, Shailesh Shrikhande
[ABSTRACT] [HTML FULL TEXT] [PDF] [Mobile HTML Full text ] [EPub]
Saurabh Bobdey, Jignasa Sathwara, Aanchal Jain, Ganesh Balasubramaniam
[ABSTRACT] [HTML FULL TEXT] [PDF] [Mobile HTML Full text ] [EPub]
ATM Emdadul Haque, Muhammad Afif Bin Mohd Hisham, Noor Azwa Laili Binti Ahmad Adzman, Nur Atiqah Binti Azudin, Nursakinah Binti Shafri, Mainul Haque
[ABSTRACT] [HTML FULL TEXT] [PDF] [Mobile HTML Full text ] [EPub]
Abhilasha Ashok Sampagar, Rahul R Jahagirdar, Vibha Sanjay Bafna, Sandip P Bartakke
[ABSTRACT] [HTML FULL TEXT] [PDF] [Mobile HTML Full text ] [EPub]
Javvid Muzamil, Aejaz Aziz Shiekh, Gull Mohammad Bhat, Abdul Rashid Lone, Shuaeb Bhat, Firdousa Nabi
[ABSTRACT] [HTML FULL TEXT] [PDF] [Mobile HTML Full text ] [EPub]
Nishitha Shetty, Ranvijay Singh, Maryam Naveed, Ashwini M Ronghe, Falguni Shashikant Barot
[ABSTRACT] [HTML FULL TEXT] [PDF] [Mobile HTML Full text ] [EPub]
Sandesh Madi, Vishnu Senthil, Monappa Naik, Sandeep Vijayan
[ABSTRACT] [HTML FULL TEXT] [PDF] [Mobile HTML Full text ] [EPub]
Gaurav Tripathi, Manas Kalra, Amita Mahajan
[ABSTRACT] [HTML FULL TEXT] [PDF] [Mobile HTML Full text ] [EPub]
Pratishtha Banga Chaudhari
[ABSTRACT] [HTML FULL TEXT] [PDF] [Mobile HTML Full text ] [EPub]
Beuy Joob, Viroj Wiwanitkit
[ABSTRACT] [HTML FULL TEXT] [PDF] [Mobile HTML Full text ] [EPub]
Manoj Lakhotia, Hans Raj Pahadiya, Akanksha Choudhary, Ronak Gandhi, Ramesh Chand Purohit
[ABSTRACT] [HTML FULL TEXT] [PDF] [Mobile HTML Full text ] [EPub]
Rita V Vora, RahulKrishna SureshKumar Kota, Nilofar G Diwan
[ABSTRACT] [HTML FULL TEXT] [PDF] [Mobile HTML Full text ] [EPub]
Mansoor C Abdulla, Jemshad Alungal, Ram Naryan, Neena Mampilly
[ABSTRACT] [HTML FULL TEXT] [PDF] [Mobile HTML Full text ] [EPub]
Ravi Kumar Paluri
[ABSTRACT] [HTML FULL TEXT] [PDF] [Mobile HTML Full text ] [EPub]
[ABSTRACT] [HTML FULL TEXT] [PDF] [Mobile HTML Full text ] [EPub]
[ABSTRACT] [HTML FULL TEXT] [PDF] [Mobile HTML Full text ] [EPub]
Anapafseos 5 . Agios Nikolaos
Crete.Greece.72100
2841026182
Successful treatment of mature B-cell lymphoma with rituximab-based chemotherapy in a patient with Bloom syndrome
Abstract
This report presents a case of Bloom syndrome (BS) in a consanguineous Saudi family. The patient, an 11-year-old male with mature B-cell lymphoma, had minimal therapeutic response and significant dose-limiting toxicity with standard chemotherapy treatment. He later responded successfully to a rituximab-based chemotherapy protocol. This case highlights that the rituximab-based chemotherapy protocol is an effective and safe treatment alternative for mature B-cell lymphoma in patients with BS. Further trials are warranted to investigate this modality of treatment.
from Cancer via ola Kala on Inoreader http://ift.tt/2gA4V6Y
via IFTTT
Research Highlights
Research Highlights
Molecular Therapy 24, 2038 (December 2016). doi:10.1038/mt.2016.201
from Cancer via ola Kala on Inoreader http://ift.tt/2hv32dB
via IFTTT
Overexpression of TEAD4 in atypical teratoid/rhabdoid tumor: New insight to the pathophysiology of an aggressive brain tumor
Abstract
Background
Atypical teratoid/rhabdoid tumor (AT/RT) is a highly malignant embryonal brain tumor that occurs mainly in early childhood. Although most of the tumors are characterized by inactivating mutations of the tumor suppressor gene, SMARCB1, the biological basis of its tumorigenesis and aggressiveness is still unknown.
Procedure
We performed high-throughput copy number variation analysis of primary cell lines generated from primary and relapsed tumors from one of our patients to identify new genes involved in AT/RT biology. The expression of the identified gene was validated in 29 AT/RT samples by gene expression profiling, quantitative real-time polymerase chain reaction, and immunohistochemistry (IHC). Furthermore, we investigated the function of this gene by mutating it in rhabdoid tumor cells.
Results
TEAD4 amplification was detected in the primary cell lines and its overexpression was confirmed at mRNA and protein levels in an independent cohort of AT/RT samples. TEAD4's co-activator, YAP1, and the downstream targets, MYC and CCND1, were also found to be upregulated in AT/RT when compared to medulloblastoma. IHC showed TEAD4 and YAP1 overexpression in all samples. Cell proliferation and migration were significantly reduced in TEAD4-mutated cells.
Conclusions
We report the overexpression of TEAD4 in AT/RT, which is a key component of Hippo pathway. Recent reports revealed that dysregulation of the Hippo pathway is implicated in tumorigenesis and poor prognosis of several human cancers. Our results suggest that TEAD4 plays a role in the pathophysiology of AT/RT, which represents a new insight into the biology of this aggressive tumor.
from Cancer via ola Kala on Inoreader http://ift.tt/2hEnbkz
via IFTTT
Yield of screening echocardiograms during pediatric follow-up in survivors treated with anthracyclines and cardiotoxic radiation
Abstract
Background
Guidelines published by the Children's Oncology Group recommend screening echocardiograms for childhood cancer survivors exposed to anthracyclines and/or cardiotoxic radiation. This study aims to assess risk factors for cardiac late effects while evaluating the overall yield of screening echocardiograms.
Procedure
Demographics, exposures, and echocardiogram results were abstracted from the medical records of survivors diagnosed at ≤ 21 years old and ≥ 2 years off therapy who were exposed to anthracyclines and/or potentially cardiotoxic radiotherapy. Descriptive statistics and logistic regressions were performed and the yield of screening echocardiograms was calculated.
Results
Of 853 patients, 1,728 screening echocardiograms were performed, and 37 patients had an abnormal echocardiogram (overall yield 2.1%). Yields were only somewhat higher in more frequently screened patients. Risk factors for an abnormal result included anthracycline dose of ≥300 mg/m2 (adjusted odds ratio [aOR] 3.1; 95% confidence interval [CI]: 1.3−7.2; P < 0.01) with a synergist relationship in patients who also received radiation doses ≥30 Gy (aOR 7.0; 95% CI: 1.6–31.9; P = 0.01), as well as autologous bone marrow transplant (OR 3.3; 95% CI: 1.3–8.5; P = 0.01). Sex, race, age at diagnosis, and cyclophosphamide exposure were not statistically significant risk factors, and no patient receiving <100 mg/m2 anthracycline dose without concomitant radiation had an abnormal echocardiogram.
Conclusions
Dose-dependent and synergist anthracycline and cardiotoxic radiotherapy risks for developing cardiomyopathy were confirmed. However, previously identified risk factors including female sex, black race, and early age at diagnosis were not replicated in this cohort. The yields showed weak correlation across frequency categories. Echocardiographic screening recommendations for low-risk pediatric patients may warrant re-evaluation.
from Cancer via ola Kala on Inoreader http://ift.tt/2gzYJvR
via IFTTT