Cancer Medicine by Alexandros G.Sfakianakis,Anapafseos 5 Agios Nikolaos,Crete 72100,Greece,tel :00302841026182 & 00306932607174
Τρίτη 24 Απριλίου 2018
Phenformin-Induced Mitochondrial Dysfunction Sensitizes Hepatocellular Carcinoma for Dual Inhibition of mTOR
Purpose: Hepatocellular carcinoma (HCC) ranks second in cancer mortality and has limited therapeutic options. We recently described the synergistic effect of allosteric and ATP-site competitive inhibitors against the mammalian target of rapamycin (mTOR) for the treatment of HCC. However, such inhibitors induce glycemia and increase mitochondrial efficiency. Here we determined whether the mitochondrial complex I inhibitor Phenformin could reverse both side effects, impose an energetic-stress on cancer cells and suppress the growth of HCC. Experimental Design: Human HCC cell lines were used in vitro to access the signaling and energetic impact of mTOR inhibitors and Phenformin, either alone or in combination. Next, the therapeutic utility of these drugs alone or in combination was investigated pre-clinically in human orthotopic tumors implanted in mice, by analyzing their impact on the tumor burden and overall survival. Results: We found Phenformin caused mitochondrial dysfunction and fragmentation, inducing a compensatory shift to glycolysis. In contrast, dual inhibition of mTOR impaired cell growth and glycolysis, while increasing mitochondrial fusion and efficiency. In a mouse model of human HCC, dual inhibition of mTOR, together with Phenformin, was highly efficacious in controlling tumor burden. However, more striking, pretreatment with Phenformin sensitized tumors to dual inhibition of mTOR, leading to a dramatic improvement in survival. Conclusion: Treatment of HCC cells in vitro with the biguanide Phenformin causes a metabolic shift to glycolysis, mitochondrial dysfunction and fragmentation, and dramatically sensitizes orthotopic liver tumors to dual inhibition of mTOR. We therefore propose this therapeutic approach should be tested clinically in HCC.
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Immunotherapy for glioblastoma: playing chess, not checkers
Patients with glioblastoma (GBM) exhibit a complex state of immune dysfunction involving multiple mechanisms of local, regional, and systemic immune suppression and tolerance. These pathways are now being identified and their relative contributions explored. Delineating how these pathways are interrelated is paramount to effectively implementing immunotherapy for GBM.
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Validation of a plasma-based comprehensive cancer genotyping assay utilizing orthogonal tissue- and plasma-based methodologies
Purpose: Liquid biopsies are powerful tools that enable non-invasive genotyping of advanced solid tumors; however, comprehensive, structured validation studies employing validated orthogonal comparator methods are lacking. Experimental Design: Analytical validation was conducted according to established principles and guidelines. Blood-to-blood clinical validation comprised blinded external comparison to clinical digital droplet PCR across 222 consecutive biomarker-positive clinical samples. Blood-to-tissue clinical validation comprised comparison of Digital Sequencing calls to those documented in the medical record of 543 consecutive lung cancer patients. Clinical experience was reported from 10,593 consecutive clinical samples. Results: Digital Sequencing technology enabled variant detection down to 0.02%-0.04% allelic fraction/2.12 copies with ≤0.3%/2.24-2.76 copies 95% limits of detection while maintaining high specificity (prevalence-adjusted PPVs >98%). Clinical validation using orthogonal plasma- and tissue-based clinical genotyping across >750 patients demonstrated high accuracy and specificity (PPAs and NPAs >99% and PPVs 92-100%). Clinical use in 10,593 advanced adult solid tumor patients demonstrated high feasibility (>99.6% technical success rate) and clinical sensitivity (85.9%), with high potential actionability (16.7% with FDA-approved on-label treatment options; 72.0% with treatment or trial recommendations), particularly in non-small cell lung cancer where 34.5% of patient samples comprised a directly targetable standard-of-care biomarker. Conclusions: High concordance with orthogonal clinical plasma- and tissue-based genotyping methods supports the clinical accuracy of Digital Sequencing across all four types of targetable genomic alterations. Digital Sequencing's clinical applicability is further supported by high rates of technical success and biomarker target discovery.
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Reciprocal Network between Cancer Stem-Like Cells and Macrophages Facilitates the Progression and Androgen Deprivation Therapy Resistance of Prostate Cancer
Purpose: Cancer stem-like cells (CSCs) contribute to the progression and androgen deprivation therapy (ADT) resistance of prostate cancer. Since CSCs depend on their specific niche, including tumor-associated macrophages (TAMs), elucidating the network between CSCs and TAMs may help to effectively inhibit the progression and ADT resistance of prostate cancer. Experimental Design: The underlying intracellular mechanism that sustains the stem-like characteristics of CSCs in prostate cancer was assessed via RNA-seq, co-IP, ChIP and other assays. A co-culture system and cytokine antibody arrays were employed to examine the interaction network between CSCs and TAMs. In addition, an orthotopic prostate cancer model was established to evaluate the in vivo effects of the combined targeting of CSCs and their interaction with TAMs on ADT resistance. Results: Autophagy-related gene 7 (ATG7) facilitated the transcription of OCT4 via β-catenin which binds to the OCT4 promoter, promoting CSC characteristics in prostate cancer, including self-renewal, tumor initiation and drug resistance. In addition, CSCs remodeled their specific niche by educating monocytes/macrophages towards TAMs, and the CSC-educated TAMs reciprocally promoted the stem-like properties of CSCs, progression and ADT resistance of prostate cancer via interleukin 6 (IL6)/STAT3. Furthermore, the combined targeting of CSCs and their interaction with TAMs by inhibiting ATG7/OCT4 and IL6 receptor effectively ameliorated ADT resistance in an orthotopic prostate cancer model. Conclusions: Targeting CSCs and their niche may prove to be a more powerful strategy than targeting CSCs alone, providing a rational approach to ameliorating ADT resistance in prostate cancer.
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Tryptophan metabolism contributes to radiation-induced immune checkpoint reactivation in glioblastoma
Purpose: Immune checkpoint inhibitors designed to revert tumor-induced immune suppression have emerged as potent anti-cancer therapies. Tryptophan metabolism represents an immune checkpoint and targeting this pathway's rate limiting enzyme IDO1 is actively being investigated clinically. Here, we studied the intermediary metabolism of tryptophan metabolism in glioblastoma and evaluated the activity of the IDO1 inhibitor GDC-0919, both alone and in combination with radiation (RT). Experimental Design: LC/GC-MS and expression profiling was performed for metabolomic and genomic analyses of patient-derived glioma. Immune competent mice were injected orthotopically with genetically engineered murine glioma cells and treated with GDC-0919 alone or combined with RT. Flow-cytometry was performed on isolated tumors to determine immune consequences of individual treatments. Results: Integrated cross-platform analyses coupling global metabolomic and gene-expression profiling identified aberrant tryptophan metabolism as a metabolic node specific to the mesenchymal and classical subtypes of glioblastoma. GDC-0919 demonstrated potent inhibition of this node and effectively crossed the blood brain barrier. Although GDC-0919 as a single agent did not demonstrate anti-tumor activity, it had a strong potential for enhancing RT response in glioblastoma, which was further augmented with a hypofractionated regimen. RT response in glioblastoma involves immune stimulation, reflected by increases in activated and cytotoxic T-cells, which was balanced by immune checkpoint reactivation, reflected by an increase in IDO1 expression and Tregs. GDC-0919 mitigated RT-induced Tregs and enhanced T-cell activation. Conclusion: Tryptophan metabolism represents a metabolic node in glioblastoma and combining RT with IDO1 inhibition enhances therapeutic response by mitigating RT-induced immune suppression.
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Enhanced Therapeutic Activity of Non-Internalizing Small Molecule-Drug Conjugates Targeting Carbonic Anhydrase IX in Combination With Targeted Interleukin-2
Purpose: Antibody-drug conjugates and small molecule-drug conjugates have been proposed as alternatives to conventional anti-cancer cytotoxic agents, with the potential to deliver bioactive payloads to the site of disease, helping spare normal tissues. Experimental Design: Here we describe a novel small molecule-drug conjugate, based on a high-affinity ligand specific to carbonic anhydrase IX. The product featured a peptidic linker, suitable for cleavage in the tumor extracellular environment, and monomethyl auristatin E as cytotoxic payload. Results: A potent anti-cancer activity was observed in nude mice bearing SKRC-52 renal cell carcinoma xenografts, but no durable complete responses could be observed in this model. However, when the product was administered together with L19-IL2 (a clinical-stage fusion protein capable of delivering interleukin-2 to the tumor neo-vasculature), all treated mice in the combination group could be rendered tumor-free, in a process which favored the influx of natural killer cells into the tumor mass. The combination of L19-IL2 and the new small molecule-drug conjugate also eradicated cancer in 100% of immunocompetent mice, bearing subcutaneously-grafted CT26 colorectal cancer cells, which stably expressed carbonic anhydrase IX. Conclusions: These findings may be of clinical significance, since carbonic anhydrase IX is over-expressed in the majority of clear-cell renal cell carcinomas and in approximately 30% of colorectal cancers. The targeted delivery of interleukin-2 helps potentiate the action of targeted cytotoxics leading to cancer eradication in models that cannot be cured by conventional chemotherapy.
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Andecaliximab/GS-5745 alone and combined with mFOLFOX6 in advanced gastric and gastroesophageal junction adenocarcinoma: Results from a phase 1 study
Purpose: Matrix metalloproteinase-9 (MMP9) is implicated in pro-tumorigenic processes. Andecaliximab (GS-5745, a monoclonal antibody targeting MMP9) was evaluated as monotherapy and in combination with mFOLFOX6. Experimental Design: Three dosages of andecaliximab monotherapy (200, 600, and 1800 mg IV every 2 weeks [q2w]) were investigated in patients with advanced solid tumors (n=13 in a 3+3 design). After determining a recommended dose, patients with advanced HER2-negative gastric/gastroesophageal junction (GEJ) adenocarcinoma (n=40) received 800 mg andecaliximab + mFOLFOX6 q2w. Pharmacokinetics, pharmacodynamics, safety, and efficacy were assessed. Results: Andecaliximab monotherapy demonstrated no dose-limiting toxicity (DLT) in any cohort, displaying target-mediated drug disposition at the lowest dose (200 mg) and linear pharmacokinetics at higher doses. Based on target engagement, recommended doses for further study are 800 mg q2w or 1200 mg q3w. Maximal andecaliximab target binding, defined as undetectable andecaliximab-free MMP9 in plasma, was observed in the gastric/GEJ adenocarcinoma cohort. We observed no unusual toxicity, although there were 4 deaths on study not attributed to andecaliximab treatment. In first-line patients (n=36), median progression free survival (PFS) was 9.9 months (95% CI 5-13.9 months) and the overall response rate (ORR) was 50%. Among all patients (n=40), median PFS was 7.8 (90% CI, 5.5-13.9) months and ORR was 48%, with a median duration of response of 8.4 months. Conclusions: Andecaliximab monotherapy achieved target engagement without DLT. Andecaliximab + mFOLFOX6 showed encouraging clinical activity without additional toxicity in patients with HER2-negative gastric/GEJ adenocarcinoma. A phase 3 study evaluating mFOLFOX6 +/- andecaliximab in this setting is ongoing.
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Undifferentiated sarcomas in children harbor clinically-relevant oncogenic fusions and gene copy-number alterations: A report from the Children's Oncology Group
Purpose: A comprehensive analysis of the genomics of undifferentiated sarcomas (UDS) is lacking. We analyzed copy number alterations and fusion status in patients with UDS prospectively treated on Children's Oncology Group protocol ARST0332. Experimental Design: Copy number alterations were assessed by Oncoscan FFPE Express on 32 UDS. Whole-exome and transcriptome libraries from 8 tumors with sufficient archived material were sequenced on HiSeq (2x100 bp). Targeted RNA-sequencing using Archer chemistry was performed on two additional cases. Results: Five-year overall survival for patients with UDS was 83% (95% CI: 69% to 97%) with risk adapted therapy (surgery, chemotherapy, radiotherapy). Both focal and arm-level copy number alterations were common including gain of 1q (8/32, 25%) and loss of 1p (7/32, 22%), both of which occurred more often in clinically defined high risk tumors. Tumors with both loss of 1p and gain of 1q carried an especially poor prognosis with a five-year event free survival of 20%. GISTIC analysis identified recurrent amplification of FGF1 on 5q31.3 (q=0.03) and loss of CDKN2A and CDKN2B on 9p21.3 (q=0.07). Known oncogenic fusions were identified in 8 of 10 cases analyzed by next generation sequencing. Conclusions: Pediatric UDS generally has a good outcome with risk-adapted therapy. A high-risk subset of patients whose tumors have copy number loss of 1p and gain of 1q was identified with only 20% survival. Oncogenic fusions are common in UDS and next generation sequencing should be considered for children with UDS to refine the diagnosis and identify potentially targetable drivers.
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Metformin targets Mitochondrial Glycerophosphate Dehydrogenase (mGPDH) to control Rate of Oxidative Phosphorylation and growth of thyroid cancer in vitro and in vivo
Purpose: Mitochondrial glycerophosphate dehydrogenase (mGPDH) is the key enzyme connecting oxidative phosphorylation (OXPHOS) and glycolysis as well as a target of the antidiabetic drug metformin (MF) in the liver. There are no data on the expression and role of mGPDH as a metformin target in cancer. In this study, we evaluated mGPDH as a potential target of metformin in thyroid cancer and investigated its contribution in thyroid cancer metabolism. Experimental design: We analyzed mGPDH expression in 253 thyroid cancer and normal tissues by immunostaining and examined its expression and localization in thyroid cancer-derived cell lines (FTC133, BCPAP) by confocal microscopy. The effects of metformin on mGPDH expression were determined by qRT-PCR and western blot. Seahorse analyzer was utilized to assess the effects of metformin on OXPHOS and glycolysis in thyroid cancer cells. We analyzed the effects of metformin on tumor growth and mGPDH expression in metastatic thyroid cancer mouse models. Results: We show for the first time that mGPDH is overexpressed in thyroid cancer compared with normal thyroid. We demonstrate that mGPDH regulates human thyroid cancer cell growth and OXPHOS rate in vitro. Metformin treatment is associated with downregulation of mGPDH expression and inhibition of OXPHOS in thyroid cancer in vitro. Cells characterized by high mGPDH expression are more sensitive to OXPHOS-inhibitory effects of metformin in vitro and growth inhibitory effects of metformin in vitro and in vivo. Conclusion: Our study established mGPDH as a novel regulator of thyroid cancer growth and metabolism that can be effectively targeted by metformin.
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Phenformin-Induced Mitochondrial Dysfunction Sensitizes Hepatocellular Carcinoma for Dual Inhibition of mTOR
Purpose: Hepatocellular carcinoma (HCC) ranks second in cancer mortality and has limited therapeutic options. We recently described the synergistic effect of allosteric and ATP-site competitive inhibitors against the mammalian target of rapamycin (mTOR) for the treatment of HCC. However, such inhibitors induce glycemia and increase mitochondrial efficiency. Here we determined whether the mitochondrial complex I inhibitor Phenformin could reverse both side effects, impose an energetic-stress on cancer cells and suppress the growth of HCC. Experimental Design: Human HCC cell lines were used in vitro to access the signaling and energetic impact of mTOR inhibitors and Phenformin, either alone or in combination. Next, the therapeutic utility of these drugs alone or in combination was investigated pre-clinically in human orthotopic tumors implanted in mice, by analyzing their impact on the tumor burden and overall survival. Results: We found Phenformin caused mitochondrial dysfunction and fragmentation, inducing a compensatory shift to glycolysis. In contrast, dual inhibition of mTOR impaired cell growth and glycolysis, while increasing mitochondrial fusion and efficiency. In a mouse model of human HCC, dual inhibition of mTOR, together with Phenformin, was highly efficacious in controlling tumor burden. However, more striking, pretreatment with Phenformin sensitized tumors to dual inhibition of mTOR, leading to a dramatic improvement in survival. Conclusion: Treatment of HCC cells in vitro with the biguanide Phenformin causes a metabolic shift to glycolysis, mitochondrial dysfunction and fragmentation, and dramatically sensitizes orthotopic liver tumors to dual inhibition of mTOR. We therefore propose this therapeutic approach should be tested clinically in HCC.
https://ift.tt/2Kb94OY
Immunotherapy for glioblastoma: playing chess, not checkers
Patients with glioblastoma (GBM) exhibit a complex state of immune dysfunction involving multiple mechanisms of local, regional, and systemic immune suppression and tolerance. These pathways are now being identified and their relative contributions explored. Delineating how these pathways are interrelated is paramount to effectively implementing immunotherapy for GBM.
https://ift.tt/2Jp97FA
Validation of a plasma-based comprehensive cancer genotyping assay utilizing orthogonal tissue- and plasma-based methodologies
Purpose: Liquid biopsies are powerful tools that enable non-invasive genotyping of advanced solid tumors; however, comprehensive, structured validation studies employing validated orthogonal comparator methods are lacking. Experimental Design: Analytical validation was conducted according to established principles and guidelines. Blood-to-blood clinical validation comprised blinded external comparison to clinical digital droplet PCR across 222 consecutive biomarker-positive clinical samples. Blood-to-tissue clinical validation comprised comparison of Digital Sequencing calls to those documented in the medical record of 543 consecutive lung cancer patients. Clinical experience was reported from 10,593 consecutive clinical samples. Results: Digital Sequencing technology enabled variant detection down to 0.02%-0.04% allelic fraction/2.12 copies with ≤0.3%/2.24-2.76 copies 95% limits of detection while maintaining high specificity (prevalence-adjusted PPVs >98%). Clinical validation using orthogonal plasma- and tissue-based clinical genotyping across >750 patients demonstrated high accuracy and specificity (PPAs and NPAs >99% and PPVs 92-100%). Clinical use in 10,593 advanced adult solid tumor patients demonstrated high feasibility (>99.6% technical success rate) and clinical sensitivity (85.9%), with high potential actionability (16.7% with FDA-approved on-label treatment options; 72.0% with treatment or trial recommendations), particularly in non-small cell lung cancer where 34.5% of patient samples comprised a directly targetable standard-of-care biomarker. Conclusions: High concordance with orthogonal clinical plasma- and tissue-based genotyping methods supports the clinical accuracy of Digital Sequencing across all four types of targetable genomic alterations. Digital Sequencing's clinical applicability is further supported by high rates of technical success and biomarker target discovery.
https://ift.tt/2KetIxx
Reciprocal Network between Cancer Stem-Like Cells and Macrophages Facilitates the Progression and Androgen Deprivation Therapy Resistance of Prostate Cancer
Purpose: Cancer stem-like cells (CSCs) contribute to the progression and androgen deprivation therapy (ADT) resistance of prostate cancer. Since CSCs depend on their specific niche, including tumor-associated macrophages (TAMs), elucidating the network between CSCs and TAMs may help to effectively inhibit the progression and ADT resistance of prostate cancer. Experimental Design: The underlying intracellular mechanism that sustains the stem-like characteristics of CSCs in prostate cancer was assessed via RNA-seq, co-IP, ChIP and other assays. A co-culture system and cytokine antibody arrays were employed to examine the interaction network between CSCs and TAMs. In addition, an orthotopic prostate cancer model was established to evaluate the in vivo effects of the combined targeting of CSCs and their interaction with TAMs on ADT resistance. Results: Autophagy-related gene 7 (ATG7) facilitated the transcription of OCT4 via β-catenin which binds to the OCT4 promoter, promoting CSC characteristics in prostate cancer, including self-renewal, tumor initiation and drug resistance. In addition, CSCs remodeled their specific niche by educating monocytes/macrophages towards TAMs, and the CSC-educated TAMs reciprocally promoted the stem-like properties of CSCs, progression and ADT resistance of prostate cancer via interleukin 6 (IL6)/STAT3. Furthermore, the combined targeting of CSCs and their interaction with TAMs by inhibiting ATG7/OCT4 and IL6 receptor effectively ameliorated ADT resistance in an orthotopic prostate cancer model. Conclusions: Targeting CSCs and their niche may prove to be a more powerful strategy than targeting CSCs alone, providing a rational approach to ameliorating ADT resistance in prostate cancer.
https://ift.tt/2FeZWVz
Tryptophan metabolism contributes to radiation-induced immune checkpoint reactivation in glioblastoma
Purpose: Immune checkpoint inhibitors designed to revert tumor-induced immune suppression have emerged as potent anti-cancer therapies. Tryptophan metabolism represents an immune checkpoint and targeting this pathway's rate limiting enzyme IDO1 is actively being investigated clinically. Here, we studied the intermediary metabolism of tryptophan metabolism in glioblastoma and evaluated the activity of the IDO1 inhibitor GDC-0919, both alone and in combination with radiation (RT). Experimental Design: LC/GC-MS and expression profiling was performed for metabolomic and genomic analyses of patient-derived glioma. Immune competent mice were injected orthotopically with genetically engineered murine glioma cells and treated with GDC-0919 alone or combined with RT. Flow-cytometry was performed on isolated tumors to determine immune consequences of individual treatments. Results: Integrated cross-platform analyses coupling global metabolomic and gene-expression profiling identified aberrant tryptophan metabolism as a metabolic node specific to the mesenchymal and classical subtypes of glioblastoma. GDC-0919 demonstrated potent inhibition of this node and effectively crossed the blood brain barrier. Although GDC-0919 as a single agent did not demonstrate anti-tumor activity, it had a strong potential for enhancing RT response in glioblastoma, which was further augmented with a hypofractionated regimen. RT response in glioblastoma involves immune stimulation, reflected by increases in activated and cytotoxic T-cells, which was balanced by immune checkpoint reactivation, reflected by an increase in IDO1 expression and Tregs. GDC-0919 mitigated RT-induced Tregs and enhanced T-cell activation. Conclusion: Tryptophan metabolism represents a metabolic node in glioblastoma and combining RT with IDO1 inhibition enhances therapeutic response by mitigating RT-induced immune suppression.
https://ift.tt/2Kbr3ol
Enhanced Therapeutic Activity of Non-Internalizing Small Molecule-Drug Conjugates Targeting Carbonic Anhydrase IX in Combination With Targeted Interleukin-2
Purpose: Antibody-drug conjugates and small molecule-drug conjugates have been proposed as alternatives to conventional anti-cancer cytotoxic agents, with the potential to deliver bioactive payloads to the site of disease, helping spare normal tissues. Experimental Design: Here we describe a novel small molecule-drug conjugate, based on a high-affinity ligand specific to carbonic anhydrase IX. The product featured a peptidic linker, suitable for cleavage in the tumor extracellular environment, and monomethyl auristatin E as cytotoxic payload. Results: A potent anti-cancer activity was observed in nude mice bearing SKRC-52 renal cell carcinoma xenografts, but no durable complete responses could be observed in this model. However, when the product was administered together with L19-IL2 (a clinical-stage fusion protein capable of delivering interleukin-2 to the tumor neo-vasculature), all treated mice in the combination group could be rendered tumor-free, in a process which favored the influx of natural killer cells into the tumor mass. The combination of L19-IL2 and the new small molecule-drug conjugate also eradicated cancer in 100% of immunocompetent mice, bearing subcutaneously-grafted CT26 colorectal cancer cells, which stably expressed carbonic anhydrase IX. Conclusions: These findings may be of clinical significance, since carbonic anhydrase IX is over-expressed in the majority of clear-cell renal cell carcinomas and in approximately 30% of colorectal cancers. The targeted delivery of interleukin-2 helps potentiate the action of targeted cytotoxics leading to cancer eradication in models that cannot be cured by conventional chemotherapy.
https://ift.tt/2Jo5rE8
Andecaliximab/GS-5745 alone and combined with mFOLFOX6 in advanced gastric and gastroesophageal junction adenocarcinoma: Results from a phase 1 study
Purpose: Matrix metalloproteinase-9 (MMP9) is implicated in pro-tumorigenic processes. Andecaliximab (GS-5745, a monoclonal antibody targeting MMP9) was evaluated as monotherapy and in combination with mFOLFOX6. Experimental Design: Three dosages of andecaliximab monotherapy (200, 600, and 1800 mg IV every 2 weeks [q2w]) were investigated in patients with advanced solid tumors (n=13 in a 3+3 design). After determining a recommended dose, patients with advanced HER2-negative gastric/gastroesophageal junction (GEJ) adenocarcinoma (n=40) received 800 mg andecaliximab + mFOLFOX6 q2w. Pharmacokinetics, pharmacodynamics, safety, and efficacy were assessed. Results: Andecaliximab monotherapy demonstrated no dose-limiting toxicity (DLT) in any cohort, displaying target-mediated drug disposition at the lowest dose (200 mg) and linear pharmacokinetics at higher doses. Based on target engagement, recommended doses for further study are 800 mg q2w or 1200 mg q3w. Maximal andecaliximab target binding, defined as undetectable andecaliximab-free MMP9 in plasma, was observed in the gastric/GEJ adenocarcinoma cohort. We observed no unusual toxicity, although there were 4 deaths on study not attributed to andecaliximab treatment. In first-line patients (n=36), median progression free survival (PFS) was 9.9 months (95% CI 5-13.9 months) and the overall response rate (ORR) was 50%. Among all patients (n=40), median PFS was 7.8 (90% CI, 5.5-13.9) months and ORR was 48%, with a median duration of response of 8.4 months. Conclusions: Andecaliximab monotherapy achieved target engagement without DLT. Andecaliximab + mFOLFOX6 showed encouraging clinical activity without additional toxicity in patients with HER2-negative gastric/GEJ adenocarcinoma. A phase 3 study evaluating mFOLFOX6 +/- andecaliximab in this setting is ongoing.
https://ift.tt/2Keqquo
Undifferentiated sarcomas in children harbor clinically-relevant oncogenic fusions and gene copy-number alterations: A report from the Children's Oncology Group
Purpose: A comprehensive analysis of the genomics of undifferentiated sarcomas (UDS) is lacking. We analyzed copy number alterations and fusion status in patients with UDS prospectively treated on Children's Oncology Group protocol ARST0332. Experimental Design: Copy number alterations were assessed by Oncoscan FFPE Express on 32 UDS. Whole-exome and transcriptome libraries from 8 tumors with sufficient archived material were sequenced on HiSeq (2x100 bp). Targeted RNA-sequencing using Archer chemistry was performed on two additional cases. Results: Five-year overall survival for patients with UDS was 83% (95% CI: 69% to 97%) with risk adapted therapy (surgery, chemotherapy, radiotherapy). Both focal and arm-level copy number alterations were common including gain of 1q (8/32, 25%) and loss of 1p (7/32, 22%), both of which occurred more often in clinically defined high risk tumors. Tumors with both loss of 1p and gain of 1q carried an especially poor prognosis with a five-year event free survival of 20%. GISTIC analysis identified recurrent amplification of FGF1 on 5q31.3 (q=0.03) and loss of CDKN2A and CDKN2B on 9p21.3 (q=0.07). Known oncogenic fusions were identified in 8 of 10 cases analyzed by next generation sequencing. Conclusions: Pediatric UDS generally has a good outcome with risk-adapted therapy. A high-risk subset of patients whose tumors have copy number loss of 1p and gain of 1q was identified with only 20% survival. Oncogenic fusions are common in UDS and next generation sequencing should be considered for children with UDS to refine the diagnosis and identify potentially targetable drivers.
https://ift.tt/2FdJTHR
Metformin targets Mitochondrial Glycerophosphate Dehydrogenase (mGPDH) to control Rate of Oxidative Phosphorylation and growth of thyroid cancer in vitro and in vivo
Purpose: Mitochondrial glycerophosphate dehydrogenase (mGPDH) is the key enzyme connecting oxidative phosphorylation (OXPHOS) and glycolysis as well as a target of the antidiabetic drug metformin (MF) in the liver. There are no data on the expression and role of mGPDH as a metformin target in cancer. In this study, we evaluated mGPDH as a potential target of metformin in thyroid cancer and investigated its contribution in thyroid cancer metabolism. Experimental design: We analyzed mGPDH expression in 253 thyroid cancer and normal tissues by immunostaining and examined its expression and localization in thyroid cancer-derived cell lines (FTC133, BCPAP) by confocal microscopy. The effects of metformin on mGPDH expression were determined by qRT-PCR and western blot. Seahorse analyzer was utilized to assess the effects of metformin on OXPHOS and glycolysis in thyroid cancer cells. We analyzed the effects of metformin on tumor growth and mGPDH expression in metastatic thyroid cancer mouse models. Results: We show for the first time that mGPDH is overexpressed in thyroid cancer compared with normal thyroid. We demonstrate that mGPDH regulates human thyroid cancer cell growth and OXPHOS rate in vitro. Metformin treatment is associated with downregulation of mGPDH expression and inhibition of OXPHOS in thyroid cancer in vitro. Cells characterized by high mGPDH expression are more sensitive to OXPHOS-inhibitory effects of metformin in vitro and growth inhibitory effects of metformin in vitro and in vivo. Conclusion: Our study established mGPDH as a novel regulator of thyroid cancer growth and metabolism that can be effectively targeted by metformin.
https://ift.tt/2Kd4IXI
NFATc1 promotes anti-tumoral effector functions and memory CD8+ T cell differentiation during non-small cell lung cancer development
Nuclear factor of activated T cells 1 (NFATc1) is a transcription factor activated by T cell receptor (TCR) and Ca2+-signaling that affects T cell activation and effector function. Upon tumor antigen challenge, TCR and calcium-release-activated channels are induced, promoting NFAT dephosphorylation and translocation into the nucleus. In this study, we report a progressive decrease of NFATc1 in lung tumor tissue and in tumor-infiltrating lymphocytes (TIL) of patients suffering from advanced stage non-small cell lung cancer (NSCLC). Mice harboring conditionally inactivated NFATc1 in T cells (NFATc1ΔCD4) showed increased lung tumor growth associated with impaired T cell activation and function. Furthermore, in the absence of NFATc1, reduced IL 2 influenced the development of memory CD8+ T cells. We found a reduction of effector memory and CD103+ tissue-resident memory (TRM) T cells in the lung of tumor-bearing NFATc1ΔCD4 mice, underlining an impaired cytotoxic T cell response and a reduced TRM tissue-homing capacity. In CD4+ICOS+ T cells, programmed cell death 1 (PD-1) was induced in the draining lymph nodes of these mice and associated with lung tumor cell growth. Targeting PD-1 resulted in NFATc1 induction in CD4+ and CD8+ T cells in tumor-bearing mice and was associated with increased anti-tumor cytotoxic functions. This study reveals a role of NFATc1 in the activation and cytotoxic functions of T cells, in the development of memory CD8+ T cell subsets, and in the regulation of T cell exhaustion. These data underline the indispensability of NFATc1 for successful anti-tumor immune responses in NSCLC patients.
https://ift.tt/2HpICzi
The inhibitory NKR-P1B:Clr-b recognition axis facilitates detection of oncogenic transformation and cancer immunosurveillance
Natural killer (NK) cells express receptors specific for MHC class I (MHC-I) molecules involved in "missing-self" recognition of cancer and virus-infected cells. Here we elucidate the role of MHC-I-independent NKR-P1B:Clr-b interactions in the detection of oncogenic transformation by NK cells. Ras oncogene overexpression was found to promote a real-time loss of Clr-b on mouse fibroblasts and leukemia cells, mediated in part via the Raf/MEK/ERK and PI3K pathways. Ras-driven Clr-b downregulation occurred at the level of the Clrb (Clec2d) promoter, nascent Clr-b transcripts, and cell surface Clr-b protein, in turn promoting missing-self recognition via the NKR-P1B inhibitory receptor. Both Ras- and c-Myc-mediated Clr-b loss selectively augmented cytotoxicity of oncogene-transformed leukemia cells by NKR-P1B+ NK cells in vitro and enhanced rejection by WT mice in vivo. Interestingly, genetic ablation of either one (Clr-b+/-) or two Clr-b alleles (Clr-b-/-) enhanced survival of Eμ-cMyc transgenic mice in a primary lymphoma model despite preferential rejection of Clr-b-/- hematopoietic cells previously observed following adoptive transfer into naïve wild-type mice in vivo. Collectively, these findings suggest that the inhibitory NKR-P1B:Clr-b axis plays a beneficial role in innate detection of oncogenic transformation via NK cell-mediated cancer immune surveillance, in addition to a pathological role in the immune escape of primary lymphoma cells in Eμ-cMyc mice in vivo. These results provide a model for the human NKR-P1A:LLT1 system in cancer immunosurveillance in lymphoma patients and suggest it may represent a target for immune checkpoint therapy.
https://ift.tt/2HWN6hY
High USP6NL levels in breast cancer sustain chronic AKT phosphorylation and GLUT1 stability fueling aerobic glycolysis
USP6NL, also named RN-tre, is a GTPase activating protein (GAP) involved in control of endocytosis and signal transduction. Here we report that USP6NL is overexpressed in breast cancer (BC), mainly of the basal-like/integrative cluster 10 subtype. Increased USP6NL levels were accompanied by gene amplification and were associated with worse prognosis in the METABRIC dataset, retaining prognostic value in multivariable analysis. High levels of USP6NL in BC cells delayed endocytosis and degradation of the epidermal growth factor receptor (EGFR), causing chronic AKT activation. In turn, AKT stabilized the glucose transporter GLUT1 at the plasma membrane, increasing aerobic glycolysis. In agreement, elevated USP6NL sensitized BC cells to glucose deprivation, indicating that their glycolytic capacity relies on this protein. Depletion of USP6NL accelerated EGFR/AKT downregulation and GLUT1 degradation, impairing cell proliferation exclusively in BC cells that harbored increased levels of USP6NL. Overall, these findings argue that USP6NL overexpression generates a metabolic rewiring that is essential to foster the glycolytic demand of BC cells and promote their proliferation.
https://ift.tt/2FeQVfn
Eradicating H. Pylori Reduces Gastric Cancer Risk [News in Brief]
Patients with early disease treated for the bacterial infection were half as likely to develop a subsequent gastric cancer.
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NFATc1 promotes anti-tumoral effector functions and memory CD8+ T cell differentiation during non-small cell lung cancer development
Nuclear factor of activated T cells 1 (NFATc1) is a transcription factor activated by T cell receptor (TCR) and Ca2+-signaling that affects T cell activation and effector function. Upon tumor antigen challenge, TCR and calcium-release-activated channels are induced, promoting NFAT dephosphorylation and translocation into the nucleus. In this study, we report a progressive decrease of NFATc1 in lung tumor tissue and in tumor-infiltrating lymphocytes (TIL) of patients suffering from advanced stage non-small cell lung cancer (NSCLC). Mice harboring conditionally inactivated NFATc1 in T cells (NFATc1ΔCD4) showed increased lung tumor growth associated with impaired T cell activation and function. Furthermore, in the absence of NFATc1, reduced IL 2 influenced the development of memory CD8+ T cells. We found a reduction of effector memory and CD103+ tissue-resident memory (TRM) T cells in the lung of tumor-bearing NFATc1ΔCD4 mice, underlining an impaired cytotoxic T cell response and a reduced TRM tissue-homing capacity. In CD4+ICOS+ T cells, programmed cell death 1 (PD-1) was induced in the draining lymph nodes of these mice and associated with lung tumor cell growth. Targeting PD-1 resulted in NFATc1 induction in CD4+ and CD8+ T cells in tumor-bearing mice and was associated with increased anti-tumor cytotoxic functions. This study reveals a role of NFATc1 in the activation and cytotoxic functions of T cells, in the development of memory CD8+ T cell subsets, and in the regulation of T cell exhaustion. These data underline the indispensability of NFATc1 for successful anti-tumor immune responses in NSCLC patients.
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The inhibitory NKR-P1B:Clr-b recognition axis facilitates detection of oncogenic transformation and cancer immunosurveillance
Natural killer (NK) cells express receptors specific for MHC class I (MHC-I) molecules involved in "missing-self" recognition of cancer and virus-infected cells. Here we elucidate the role of MHC-I-independent NKR-P1B:Clr-b interactions in the detection of oncogenic transformation by NK cells. Ras oncogene overexpression was found to promote a real-time loss of Clr-b on mouse fibroblasts and leukemia cells, mediated in part via the Raf/MEK/ERK and PI3K pathways. Ras-driven Clr-b downregulation occurred at the level of the Clrb (Clec2d) promoter, nascent Clr-b transcripts, and cell surface Clr-b protein, in turn promoting missing-self recognition via the NKR-P1B inhibitory receptor. Both Ras- and c-Myc-mediated Clr-b loss selectively augmented cytotoxicity of oncogene-transformed leukemia cells by NKR-P1B+ NK cells in vitro and enhanced rejection by WT mice in vivo. Interestingly, genetic ablation of either one (Clr-b+/-) or two Clr-b alleles (Clr-b-/-) enhanced survival of Eμ-cMyc transgenic mice in a primary lymphoma model despite preferential rejection of Clr-b-/- hematopoietic cells previously observed following adoptive transfer into naïve wild-type mice in vivo. Collectively, these findings suggest that the inhibitory NKR-P1B:Clr-b axis plays a beneficial role in innate detection of oncogenic transformation via NK cell-mediated cancer immune surveillance, in addition to a pathological role in the immune escape of primary lymphoma cells in Eμ-cMyc mice in vivo. These results provide a model for the human NKR-P1A:LLT1 system in cancer immunosurveillance in lymphoma patients and suggest it may represent a target for immune checkpoint therapy.
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High USP6NL levels in breast cancer sustain chronic AKT phosphorylation and GLUT1 stability fueling aerobic glycolysis
USP6NL, also named RN-tre, is a GTPase activating protein (GAP) involved in control of endocytosis and signal transduction. Here we report that USP6NL is overexpressed in breast cancer (BC), mainly of the basal-like/integrative cluster 10 subtype. Increased USP6NL levels were accompanied by gene amplification and were associated with worse prognosis in the METABRIC dataset, retaining prognostic value in multivariable analysis. High levels of USP6NL in BC cells delayed endocytosis and degradation of the epidermal growth factor receptor (EGFR), causing chronic AKT activation. In turn, AKT stabilized the glucose transporter GLUT1 at the plasma membrane, increasing aerobic glycolysis. In agreement, elevated USP6NL sensitized BC cells to glucose deprivation, indicating that their glycolytic capacity relies on this protein. Depletion of USP6NL accelerated EGFR/AKT downregulation and GLUT1 degradation, impairing cell proliferation exclusively in BC cells that harbored increased levels of USP6NL. Overall, these findings argue that USP6NL overexpression generates a metabolic rewiring that is essential to foster the glycolytic demand of BC cells and promote their proliferation.
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Evaluation of biodistribution of sulforaphane after administration of oral broccoli sprout extract in melanoma patients with multiple atypical nevi
Broccoli sprout extract containing sulforaphane (BSE-SFN) has been shown to inhibit ultraviolet radiation-induced damage and tumor progression in skin. This study evaluated the toxicity and potential effects of oral BSE-SFN at three dosages. Seventeen patients who each had at least 2 atypical nevi and a prior history of melanoma were randomly allocated to 50, 100, or 200 µmol oral BSE-SFN daily for 28 days. Atypical nevi were photographed on days 1 and 28, and plasma and nevus samples were taken on days 1, 2, and 28. Endpoints assessed were safety, plasma and skin sulforaphane levels, gross and histologic changes, immunohistochemistry for phospho-STAT3(Y705), Ki-67, Bcl-2, HMOX1, and TUNEL, plasma cytokine levels, and tissue proteomics. All 17 patients completed 28 days with no dose-limiting toxicities. Plasma sulforaphane levels pooled for days 1, 2, and 28 showed median post-administration increases of 120 ng/mL for 50 µmol, 206 ng/mL for 100 µmol, and 655 ng/mL for 200 µmol. Median skin sulforaphane levels on day 28 were 0.0 ng/g, 3.1 ng/g, and 34.1 ng/g for 50, 100, and 200 µmol, respectively. Plasma levels of pro-inflammatory cytokines decreased from day 1 to 28. The tumor suppressor decorin was increased from day 1 to 28. Oral BSE-SFN is well-tolerated at daily doses up to 200 µmol and achieves dose-dependent levels in plasma and skin. A larger efficacy evaluation of 200 µmol daily for longer intervals is now reasonable to better characterize clinical and biological effects of BSE-SFN as chemoprevention for melanoma.
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Challenges in recruiting African-American women for a breast cancer genetics study
Abstract
Background
African-American women, especially in the southern United States, are underrepresented in cancer genetics research. A study was designed to address this issue by investigating the germline mutation rate in African-American women in Arkansas with a personal and/or family history of breast cancer. Women were tested for these mutations using a large panel of breast cancer susceptibility genes. In this analysis, we discuss the challenges encountered in recruiting African-American women from an existing biorepository to participate in this study.
Methods
We attempted to contact 965 African-American women with a personal and/or family history of breast cancer who participated in Spit for the Cure (SFTC) between 2007 and 2013 and provided consent to be recontacted. The SFTC participants were invited by telephone and email to participate in the genetic study. Enrollment required completion of a phone interview to obtain a family and medical history and return of a signed consent form.
Results
Among eligible SFTC participants, 39.6% (382/965) were able to be contacted with the phone numbers and email addresses they provided. Of these, 174 (45.5%) completed a phone interview and returned a signed consent form. Others were not able to be contacted (n = 583), declined to participate (n = 57), did not keep phone interview appointments (n = 82), completed the phone interview but never returned a signed consent (n = 54), were deceased (n = 13), or were too confused to consent to participate (n = 2).
Conclusions
Recruiting African-American women into our breast cancer genetics study proved challenging primarily due to difficulty establishing contact with potential participants. Given their prior participation in breast cancer research, we anticipated that this would be a highly motivated population. Indeed, when we were able to contact SFTC participants, only 14.9% declined to participate in our study. Innovative communication, retention, and recruitment strategies are needed in future studies to address the recruitment challenges we faced.
https://ift.tt/2qUutUi
Challenges in recruiting African-American women for a breast cancer genetics study
Abstract
Background
African-American women, especially in the southern United States, are underrepresented in cancer genetics research. A study was designed to address this issue by investigating the germline mutation rate in African-American women in Arkansas with a personal and/or family history of breast cancer. Women were tested for these mutations using a large panel of breast cancer susceptibility genes. In this analysis, we discuss the challenges encountered in recruiting African-American women from an existing biorepository to participate in this study.
Methods
We attempted to contact 965 African-American women with a personal and/or family history of breast cancer who participated in Spit for the Cure (SFTC) between 2007 and 2013 and provided consent to be recontacted. The SFTC participants were invited by telephone and email to participate in the genetic study. Enrollment required completion of a phone interview to obtain a family and medical history and return of a signed consent form.
Results
Among eligible SFTC participants, 39.6% (382/965) were able to be contacted with the phone numbers and email addresses they provided. Of these, 174 (45.5%) completed a phone interview and returned a signed consent form. Others were not able to be contacted (n = 583), declined to participate (n = 57), did not keep phone interview appointments (n = 82), completed the phone interview but never returned a signed consent (n = 54), were deceased (n = 13), or were too confused to consent to participate (n = 2).
Conclusions
Recruiting African-American women into our breast cancer genetics study proved challenging primarily due to difficulty establishing contact with potential participants. Given their prior participation in breast cancer research, we anticipated that this would be a highly motivated population. Indeed, when we were able to contact SFTC participants, only 14.9% declined to participate in our study. Innovative communication, retention, and recruitment strategies are needed in future studies to address the recruitment challenges we faced.
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Lymphoid aggregates in desmoplastic melanoma have features of tertiary lymphoid structures
Desmoplastic melanomas (DM) have unique and challenging clinical presentations and histomorphology. A characteristic feature is the presence of scattered lymphoid aggregates. However, the nature of these aggregates is not defined. We hypothesized that they may be tertiary lymphoid structures (TLS), and may be associated with programmed death ligand 1 (PD-L1) expression. We searched our tissue database for 'pure' DMs and for scars as control tissues, collected clinical information, and reviewed H&E histology. We performed multispectral imaging after staining for CD8, CD20, PNAd, FoxP3, CD83, and Ki67, and assessed PD-L1 expression by immunohistochemistry. Pure DM samples were evaluable in 11 patients. All had desmoplastic stroma and lymphoid aggregates on H&E. The lymphoid aggregates of eight of the 11 (72%) DM samples and only three of the 11 scars contained features of TLS, defined as distinct clusters of B cells and CD8+ T cells, CD83+ dendritic cells in T-cell zones, and PNAd+ vasculature resembling high endothelial venules. PD-L1 was expressed by at least 1% of melanoma cells in six and by at least 5% of immune cells in 10 of the 11 DM samples. We found that most lymphoid aggregates in DM are organized, classical TLS. PD-L1 expression was detected in most cases and was highest in two cases of DM with TLS. However, low PD-L1 expression in some cases suggests that some DM cells may be unresponsive to interferon-γ. TLS support antigen presentation and T-cell responses in chronic inflammation and cancer. Their presence in DM likely reflects an adaptive immune response, which may be enhanced with immune therapies.https://ift.tt/2HV0naF
TRAF3-interacting protein 3, a new oncotarget, promotes tumor growth in melanoma
TRAF3-interacting protein 3 (TRAF3IP3) is expressed in the immune system and participates in cell maturation, tissue development, and immune response. In a previous study, we reported that TRAF3IP3 levels were substantially increased in the vasculature of breast cancer tissues, suggesting a proangiogenic role. In this study, we investigated TRAF3IP3 tumorigenic function. TRAF3IP3 protein was present in several cancer cell lines, with highest levels in melanoma. In addition, tumor microarray analysis on 23 primary melanoma and nine positive lymph nodes revealed that 70% of human primary melanoma and 66% of lymph node metastases were positive for TRAF3IP3. Importantly, TRAF3IP3 downregulation correlated with an 83% reduction of tumor growth in a subcutaneous xenograft mouse model (n=10, P=0.005). Immunohistochemistry analysis of the tumors revealed that TRAF3IP3-shRNA tumors had increased apoptosis (n=4, Phttps://ift.tt/2HrTdtB
Combination immunotherapies implementing adoptive T-cell transfer for advanced-stage melanoma
Immunotherapy is a promising method of treatment for a number of cancers. Many of the curative results have been seen specifically in advanced-stage melanoma. Despite this, single-agent therapies are only successful in a small percentage of patients, and relapse is very common. As chemotherapy is becoming a thing of the past for treatment of melanoma, the combination of cellular therapies with immunotherapies appears to be on the rise in in-vivo models and in clinical trials. These forms of therapies include tumor-infiltrating lymphocytes, T-cell receptor, or chimeric antigen receptor-modified T cells, cytokines [interleukin (IL-2), IL-15, IL-12, granulocyte-macrophage colony stimulating factor, tumor necrosis factor-α, interferon-α, interferon-γ], antibodies (αPD-1, αPD-L1, αTIM-3, αOX40, αCTLA-4, αLAG-3), dendritic cell-based vaccines, and chemokines (CXCR2). There are a substantial number of ongoing clinical trials using two or more of these combination therapies. Preliminary results indicate that these combination therapies are a promising area to focus on for cancer treatments, especially melanoma. The main challenges with the combination of cellular and immunotherapies are adverse events due to toxicities and autoimmunity. Identifying mechanisms for reducing or eliminating these adverse events remains a critical area of research. Many important questions still need to be elucidated in regard to combination cellular therapies and immunotherapies, but with the number of ongoing clinical trials, the future of curative melanoma therapies is promising.https://ift.tt/2HVPXYf
Early evolution of BRAFV600 status in the blood of melanoma patients correlates with clinical outcome and identifies patients refractory to therapy
Serial analysis of BRAF mutations in circulating-free DNA (cfDNA) could be of prognostic value in melanoma patients. We collected blood samples from 63 advanced BRAFV600E/K melanoma patients and determined BRAFV600E/K status in cfDNA using a quantitative 5′-nuclease PCR-based assay. Levels of BRAF mutation in pre-cfDNAs were associated significantly with tumour burden, progression-free survival and overall survival. Changes in BRAF status in cfDNA after initiation of treatment (early-cfDNA) had a significant correlation with outcome. In patients with persistent BRAF mutations (n=12), progression-free survival and overall survival were 3.5 months [95% confidence interval (CI): 1.6–4.6] and 5.3 months (95% CI: 3.4–8.1) compared with 16.6 months (95% CI: 8.2–22.3) and 21.9 months (95% CI: 10.2–NR) in patients with BRAF negativization (n=16), and 15.1 months (95% CI: 2.3–NR) and NR (95% CI: 5.1–NR) in patients who maintained their initial negative status (n=12) (Phttps://ift.tt/2Fdl7aQ
Potential clinical and immunotherapeutic utility of talimogene laherparepvec for patients with melanoma after disease progression on immune checkpoint inhibitors and BRAF inhibitors
Talimogene laherparepvec is a genetically modified herpes simplex virus type 1–based oncolytic immunotherapy for the local treatment of unresectable subcutaneous and nodal tumors in patients with melanoma recurrent after initial surgery. We report on two patients with melanoma who, after progression on numerous systemic therapies, derived clinical benefit from talimogene laherparepvec in an expanded-access protocol (ClinicalTrials.gov, NCT02147951). Intralesional talimogene laherparepvec (day 1, ≤4 ml 106 PFU/ml; after 3 weeks, ≤4 ml 108 PFU/ml every 2 weeks) was administered until complete response, no injectable tumors, progressive disease, or intolerance occurred. Patient 1 was 71 years old, had stage IIIB disease, and had previously received granulocyte–macrophage colony-stimulating factor, vemurafenib, metformin, ipilimumab, dabrafenib, trametinib, and pembrolizumab. Patient 2 was 45 years old, had stage IIIC disease, and had previously received nivolumab/ipilimumab combination therapy. There were marked reductions in the number and size of melanoma lesions during treatment with talimogene laherparepvec. Both patients experienced mild-to-moderate nausea and vomiting, which were managed using ondansetron, metoclopramide, and pantoprazole. Both patients completed treatment with talimogene laherparepvec in the expanded-access protocol on 24 November 2015, but received talimogene laherparepvec in clinical practice. Patient 1 continues to receive therapy (>60 weeks); patient 2 experienced a complete response at 23 weeks. Immunohistochemistry of a biopsied dermal metastasis from patient 1 showed a marked infiltration of CD4+ and CD8+ T cells after 1 year of treatment. Talimogene laherparepvec was active in patients with advanced melanoma with disease progression following multiple previous systemic therapies; no new safety signals were identified.https://ift.tt/2HVPOUH
STAT5 expression correlates with recurrence and survival in melanoma patients treated with interferon-α
Interferons (IFN) have a direct growth-inhibiting effect on tumor cells through Janus kinase-dependent activation of the transcription factor signal transducer and activator of transcription (STAT1). In vitro, signaling through STAT5 has been demonstrated to counteract this effect and lead to IFN resistance of melanoma cell lines. In 32 patients treated with IFN-α in an adjuvant setting, we investigated paraffin-embedded tumor tissue from primary melanomas and melanoma metastases for expression of STAT3 and STAT5, by immunohistochemistry, and for expression of phosphorylated signaling transduction activating transcription factor (pSTAT)3 and pSTAT5, by immunofluorescence. Tumor cell expression levels of these proteins were correlated with patient characteristics and clinical outcomes. The patient cohort consisted of 12 (37.5%) patients at AJCC stage I/II (primary melanoma) and 20 (62.5%) at stage III/IV (metastatic melanoma). Recurrence was observed for 25 (78.1%) either during or after IFN-α therapy. χ2 Correlation of staining intensities with clinical data revealed association of pSTAT3 and STAT5 expression with sex (P=0.003 and 0.016, respectively) and of STAT3 with tumor stage (P=0.019). Recurrence of melanoma was found to be associated with high STAT5 expression (P=0.017). Multivariable regression analysis revealed STAT5 expression as an independent factor for predicting progression-free survival (Phttps://ift.tt/2HsyfuH
Sarcoid-like reactions in patients receiving modern melanoma treatment
The development of cancer immunotherapy and targeted therapy has reached an important inflection point in the history of melanoma. Immune checkpoint inhibitors and kinase inhibitors are today's standard of care treatments in advanced melanoma patients. Treatment-related toxicities can be very intriguing and quite challenging. Sarcoidosis is a multisystemic granulomatous disease characterized by an aberrant immune response to unknown antigens, whereas sarcoid-like reactions (SLRs) refer to localized clinical features. We carried out a single-center observational study in patients with stage IIB–IV melanoma treated with BRAF/MEK inhibitors and immune checkpoint inhibitors. A description of the sarcoidosis-related manifestations was provided from patients' records. We observated eight cases of SLRs in a cohort of 200 patients. The clinical courses were characterized by a variety of symptoms, accompanied by cutaneous signs and extracutaneous manifestations such as bilateral, hilar lymphadenopathy. We identified a histologically granulomatous inflammation involving the skin, the lungs, and the lymph nodes. Two patients presented with cutaneous lesions only, and three patients had lung involvement only. Three patients achieved complete and partial response of the melanoma disease, and three patients had stable disease. Disease progression was documented in two patients. The reported immune-related adverse events were mild to severe and in most of the cases were continued without any treatment cessation. SLRs appear during treatment with both kinase and immune checkpoint inhibitors. Awareness of these can avoid misdiagnosis of disease progression and unnecessary treatment changes.https://ift.tt/2HVPF3B
Three antigen-loading methods in dendritic cell vaccines for metastatic melanoma
In the current era of checkpoint inhibitors, some patients with metastatic melanoma have shown a significant improvement in survival. However, optimization of immunotherapy is an ongoing effort. Monocyte-derived dendritic cell (MODC) vaccines have been shown in clinical trials to be safe and capable of inducing tumor-specific immunity as well as occasional objective clinical responses. Here, we conducted a three-arm pilot clinical study in 15 patients with metastatic melanoma to evaluate three types of MODC vaccines, differing only by strategies of tumor antigen delivery. MODCs were isolated from each patient and loaded with patients' own melanoma cells as sources of antigens. Antigen loading was achieved ex vivo by fusing melanoma cells with MODCs, co-culturing melanoma cells with MODCs, or by pulsing MODCs with melanoma cell lysates. The vaccines were then injected into superficial lymph nodes using high-resolution ultrasound guidance. Primary end points included delayed-type hypersensitivity responses and positive ELISpot result, which measures interferon-γ production. Five of 15 patients achieved delayed-type hypersensitivity responses and six of 15 patients had positive ELISpot results. We demonstrated that the vaccines were safe and well-tolerated by all patients and produced immunological responses in all arms. Although MODC vaccine monotherapy has limited efficacy, combining this vaccine with other immunotherapies, such as checkpoint inhibitors, to engage multiple components of the immune system may be an effective and viable future approach.https://ift.tt/2Huetit
CDKN2A germline alterations in melanoma patients with personal or familial history of pancreatic cancer
CDKN2A germline mutations increase the risk of melanoma development and are present in 20 and 10% of familial and multiple melanoma cases, respectively. Pancreatic cancer has been associated with CDKN2A in some populations and, accordingly, its presence in first-degree or second-degree relatives of a melanoma patient is considered as a criterion for genetic testing. In this study, we show that in an area with low melanoma incidence, CDKN2A germline mutations in patients with melanoma and personal or family history of pancreatic cancer are mainly present in the setting of familial or multiple melanoma cases. In addition, a relatively young age (≤52 years) at pancreatic diagnosis is an additional single criterion that might also be considered.https://ift.tt/2HYRMUr
Lymph node ratio as a prognostic factor in melanoma: results from European Organization for Research and Treatment of Cancer 18871, 18952, and 18991 studies
The aim of this study was to assess the prognostic importance of lymph node ratio (LNR) in stage III melanoma after complete lymph nodal dissections. From European Organization for Research and Treatment of Cancer randomized trials 18871, 18952, and 18991, 2358 patients had full information on positive and examined lymph nodes (LNs) and were included. Cox proportional hazards models stratified by trial were used to assess the prognostic impact of LNR adjusted for confounders on melanoma-specific survival. Optimal cutoff values for LNR were calculated for each LN dissection site (axillary, inguinal, and neck). LNR (≥ vs.https://ift.tt/2FdQ8eH
Histiocytoid Sweet’s syndrome during combined therapy with BRAF and MEK inhibitors for metastatic melanoma
No abstract availablehttps://ift.tt/2I0HraI
Automatic quantification of calcifications in the coronary arteries and thoracic aorta on radiotherapy planning CT scans of Western and Asian breast cancer patients
This study automatically quantified calcifications in coronary arteries (CAC) and thoracic aorta (TAC) on breast planning computed tomography (CT) scans and assessed its reproducibility compared to manual scoring.
https://ift.tt/2FdaB3e
Heart volume reduction during radiotherapy involving the thoracic region in children: An unexplained phenomenon
Radiotherapy involving the thoracic region is associated with cardiotoxicity in long-term childhood cancer survivors. We quantified heart volume changes during radiotherapy in children (<18 years) and investigated correlations with patient and treatment related characteristics.
https://ift.tt/2KcTNwU
Improving the modelling of irradiation-induced brain activation for in vivo PET verification of proton therapy
A reliable Monte Carlo prediction of proton-induced brain tissue activation used for comparison to particle therapy positron-emission-tomography (PT-PET) measurements is crucial for in vivo treatment verification. Major limitations of current approaches to overcome include the CT-based patient model and the description of activity washout due to tissue perfusion.
https://ift.tt/2FdN5Ty
A long-awaited guideline for the delineation of primary tumor in head and neck cancer, and a few concerns about it
We read the article entitled 'Delineation of the primary tumour Clinical Target Volumes (CTV-P) in laryngeal, hypopharyngeal, oropharyngeal and oral cavity squamous cell carcinoma: AIRO, CACA, DAHANCA, EORTC, GEORCC, GORTEC, HKNPCSG, HNCIG, IAG-KHT, LPRHHT, NCIC CTG, NCRI, NRG Oncology, PHNS, SBRT, SOMERA, SRO, SSHNO, TROG consensus guidelines' with great interest [1]. There was a lack of a guideline for the delineation of the primary tumor in head and neck cancer. This paper might shed light on the accurate delineation the clinical target volume (CTV).
https://ift.tt/2KcTL8g
Efficacy of thoracic radiotherapy in patients with stage IIIB–IV epidermal growth factor receptor-mutant lung adenocarcinomas who received and responded to tyrosine kinase inhibitor treatment
Large-scale, prospective, randomized studies of the efficacy of thoracic radiotherapy (RT) in patients with unresectable stage IIIB–IV epidermal growth factor receptor (EGFR)-mutant lung adenocarcinomas who received and responded to EGFR tyrosine kinase inhibitor (TKI) treatment are not currently available. Therefore, we designed a propensity score-matched, nationwide, population-based, cohort study for estimating the effects of thoracic RT on patients with EGFR-mutant lung adenocarcinomas.
https://ift.tt/2JmoHSi
Overview of research and therapy facilities for radiobiological experimental work in particle therapy. Report from the European Particle Therapy Network radiobiology group
Particle therapy (PT) as cancer treatment, using protons or heavier ions, can provide a more favorable dose distribution compared to X-rays. While the physical characteristics of particle radiation have been the aim of intense research, less focus has been placed on the actual biological responses arising from particle irradiation.One of the biggest challenges for proton radiobiology is the RBE, with an increasing concern that the clinically-applied generic RBE-value of 1.1 is an approximation, as RBE is a complex quantity, depending on both biological and physical parameters, such as dose, LET, cellular and tissue radiobiological characteristics, as well as the endpoints being studied.
https://ift.tt/2Kddbdt
Applying new Magee equations for predicting the Oncotype Dx recurrence score
Abstract
Background
Breast cancer is one of the most prevalent cancers in women. Oncotype Dx is a multi-gene assay frequently used to predict the recurrence risk for estrogen receptor-positive early breast cancer, with values < 18 considered low risk; ≥ 18 and ≤ 30, intermediate risk; and > 30, high risk. Patients at a high risk for recurrence are more likely to benefit from chemotherapy treatment.
Methods
In this study, clinicopathological parameters for 37 cases of early breast cancer with available Oncotype Dx results were used to estimate the recurrence score using the three new Magee equations. Correlation studies with Oncotype Dx results were performed. Applying the same cutoff points as Oncotype Dx, patients were categorized into low-, intermediate- and high-risk groups according to their estimated recurrence scores.
Results
Pearson correlation coefficient (R) values between estimated and actual recurrence score were 0.73, 0.66, and 0.70 for Magee equations 1, 2 and 3, respectively. The concordance values between actual and estimated recurrence scores were 57.6%, 52.9%, and 57.6% for Magee equations 1, 2 and 3, respectively. Using standard pathologic measures and immunohistochemistry scores in these three linear Magee equations, most low and high recurrence risk cases can be predicted with a strong positive correlation coefficient, high concordance and negligible two-step discordance.
Conclusions
Magee equations are user-friendly and can be used to predict the recurrence score in early breast cancer cases.
https://ift.tt/2vIZwY7
Low concentrations of 25-hydroxyvitamin D and long-term prognosis of COPD: a prospective cohort study
Abstract
Role and importance of vitamin D deficiency in long-term prognosis of chronic obstructive pulmonary disease (COPD) still remains undetermined. We tested the hypothesis that among individuals with COPD, those with low concentrations of 25-hydroxyvitamin D have a poorer prognosis compared to those with normal concentrations. We studied 35,153 individuals from the general population aged 20–100 years with 25-hydroxyvitamin D measurements and spirometry, the Copenhagen City Heart Study [median follow-up 21 years (range 13 days–36 years)] and the Copenhagen General Population Study [7.1 years (3 days–13 years)]. Spirometric COPD (n = 5178; 15% of all) was defined as forced expiratory volume in 1 s (FEV1)/forced vital capacity (FVC) < 0.70 in individuals without asthma and clinical COPD (n = 2033; 6%) as FEV1/FVC < 0.70 and FEV1 < 80% of predicted in ever-smokers aged > 40 years without asthma and with cumulative tobacco consumption ≥ 10 pack-years. In spirometric COPD, median age at death in years was 70.2 (95% confidence interval [CI] 64.4–71.2) for individuals with 25-hydroxyvitamin D < 12.5 nmol/L and 80.3 (74.4–83.4) for those with ≥ 50 nmol/L. In clinical COPD, corresponding values were 69.0 (63.3–70.9) and 76.2 (73.8–78.0). In spirometric COPD, multivariable adjusted hazard ratios for individuals with 25-hydroxyvitamin D < 12.5 nmol/L versus those with ≥ 50 nmol/L were 1.35 (95% CI 1.09–1.67) for all-cause mortality, 1.63 (1.00–2.64) for respiratory mortality, 1.14 (0.76–1.70) for cardiovascular mortality, 1.37 (0.90–2.06) for cancer mortality, and 1.61 (1.04–2.49) for other mortality. In clinical COPD, corresponding values were 1.39 (1.07–1.82), 1.57 (0.91–2.72), 0.88 (0.51–1.53), 1.63 (0.99–2.67), and 2.00 (1.12–3.56). Low concentrations of 25-hydroxyvitamin D were associated with an increased risk of death in individuals with COPD. No clear pattern of association could be observed for cause of death; however, there may be an increased risk of respiratory, cancer, and other mortality. It is likely that low concentrations of 25-hydroxyvitamin D is a marker of poor health in COPD.
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Acceleration of carboxylesterase-mediated activation of irinotecan to SN-38 by serum from patients with end-stage kidney disease
Abstract
Purpose
Pharmacokinetics and pharmacodynamics of irinotecan have been reported to be altered in cancer patients with end-stage kidney disease (ESKD). Carboxylesterase (CES) has an important role in metabolism of irinotecan to its active metabolite, SN-38, in human liver. The purpose of the present study was to investigate whether CES activity was altered in ESKD patients.
Methods
The present study investigated the effects of uremic serum, uremic toxins, and fatty acids on the hydrolysis of irinotecan and a typical CES substrate, p-nitrophenyl acetate (PNPA), in human liver microsomes. Normal and uremic serum samples were deproteinized by treatment with methanol were used in the present study.
Results
The present study showed that both normal and uremic serum significantly inhibited CES-mediated metabolism of both irinotecan and PNPA. The inhibition by uremic serum was weaker than that by normal serum, suggesting that CES activity may be higher in ESKD patients. Although four uremic toxins did not affect PNPA metabolism, arachidonic acid inhibited it. There was no difference in inhibitory effect of PNPA metabolism between both mixtures of seven fatty acids used at concentrations equivalent to those present in 10% normal or uremic serum. Interestingly, those mixtures had a more pronounced effect than either 10% normal or uremic serum.
Conclusions
The present study showed that the inhibition of CES activity by uremic serum was weaker than that by normal serum, suggesting that an increase in maximum plasma concentration of SN-38 in cancer patients with ESKD can be attributed to an accelerated CES-mediated irinotecan hydrolysis.
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IL-8 regulates the doxorubicin resistance of colorectal cancer cells via modulation of multidrug resistance 1 (MDR1)
Abstract
Cytokines play important roles in tumorigenesis and progression of cancer cells, while their functions in drug resistance remain to be illustrated. We successfully generated doxorubicin (Dox)-resistant CRC HCT-116 and SW480 cells (namely HCT-116/Dox and SW480/Dox, respectively). Cytokine expression analysis revealed that IL-8, while not FGF-2, EGF, TGF-β, IL-6, or IL-10, was significantly increased in Dox-resistant CRC cells as compared with their corresponding parental cells. Targeted inhibition of IL-8 via siRNAs or its inhibitor reparixin can increase the Dox sensitivity of HCT-116/Dox and SW480/Dox cells. The si-IL-8 can decrease the mRNA and protein expression of multidrug resistance 1 (MDR1, encoded by ABCB1), while has no effect on the expression of multidrug resistance-associated protein 1 (ABCC1), in CRC Dox-resistant cells. IL-8 can increase the phosphorylation of p65 and then upregulate the binding between p65 and promoter of ABCB1. BAY 11-7082, the inhibitor of NF-κB, suppressed the recombination IL-8 (rIL-8) induced upregulation of ABCB1. It confirmed that NF-κB is involved in IL-8-induced upregulation of ABCB1. rIL-8 also increased the phosphorylation of IKK-β, which can further activate NF-κB, while specific inhibitor of IKK-β (ACHP) can reverse rIL-8-induced phosphorylation of p65 and upregulation of MDR1. These results suggested that IL-8 regulates the Dox resistance of CRC cells via modulation of MDR1 through IKK-β/p65 signals. The targeted inhibition of IL-8 might be an important potential approach to overcome the clinical Dox resistance in CRC patients.
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Acceleration of carboxylesterase-mediated activation of irinotecan to SN-38 by serum from patients with end-stage kidney disease
Abstract
Purpose
Pharmacokinetics and pharmacodynamics of irinotecan have been reported to be altered in cancer patients with end-stage kidney disease (ESKD). Carboxylesterase (CES) has an important role in metabolism of irinotecan to its active metabolite, SN-38, in human liver. The purpose of the present study was to investigate whether CES activity was altered in ESKD patients.
Methods
The present study investigated the effects of uremic serum, uremic toxins, and fatty acids on the hydrolysis of irinotecan and a typical CES substrate, p-nitrophenyl acetate (PNPA), in human liver microsomes. Normal and uremic serum samples were deproteinized by treatment with methanol were used in the present study.
Results
The present study showed that both normal and uremic serum significantly inhibited CES-mediated metabolism of both irinotecan and PNPA. The inhibition by uremic serum was weaker than that by normal serum, suggesting that CES activity may be higher in ESKD patients. Although four uremic toxins did not affect PNPA metabolism, arachidonic acid inhibited it. There was no difference in inhibitory effect of PNPA metabolism between both mixtures of seven fatty acids used at concentrations equivalent to those present in 10% normal or uremic serum. Interestingly, those mixtures had a more pronounced effect than either 10% normal or uremic serum.
Conclusions
The present study showed that the inhibition of CES activity by uremic serum was weaker than that by normal serum, suggesting that an increase in maximum plasma concentration of SN-38 in cancer patients with ESKD can be attributed to an accelerated CES-mediated irinotecan hydrolysis.
https://ift.tt/2HTYTxj
IL-8 regulates the doxorubicin resistance of colorectal cancer cells via modulation of multidrug resistance 1 (MDR1)
Abstract
Cytokines play important roles in tumorigenesis and progression of cancer cells, while their functions in drug resistance remain to be illustrated. We successfully generated doxorubicin (Dox)-resistant CRC HCT-116 and SW480 cells (namely HCT-116/Dox and SW480/Dox, respectively). Cytokine expression analysis revealed that IL-8, while not FGF-2, EGF, TGF-β, IL-6, or IL-10, was significantly increased in Dox-resistant CRC cells as compared with their corresponding parental cells. Targeted inhibition of IL-8 via siRNAs or its inhibitor reparixin can increase the Dox sensitivity of HCT-116/Dox and SW480/Dox cells. The si-IL-8 can decrease the mRNA and protein expression of multidrug resistance 1 (MDR1, encoded by ABCB1), while has no effect on the expression of multidrug resistance-associated protein 1 (ABCC1), in CRC Dox-resistant cells. IL-8 can increase the phosphorylation of p65 and then upregulate the binding between p65 and promoter of ABCB1. BAY 11-7082, the inhibitor of NF-κB, suppressed the recombination IL-8 (rIL-8) induced upregulation of ABCB1. It confirmed that NF-κB is involved in IL-8-induced upregulation of ABCB1. rIL-8 also increased the phosphorylation of IKK-β, which can further activate NF-κB, while specific inhibitor of IKK-β (ACHP) can reverse rIL-8-induced phosphorylation of p65 and upregulation of MDR1. These results suggested that IL-8 regulates the Dox resistance of CRC cells via modulation of MDR1 through IKK-β/p65 signals. The targeted inhibition of IL-8 might be an important potential approach to overcome the clinical Dox resistance in CRC patients.
https://ift.tt/2HobA2t
Low concentrations of 25-hydroxyvitamin D and long-term prognosis of COPD: a prospective cohort study
Abstract
Role and importance of vitamin D deficiency in long-term prognosis of chronic obstructive pulmonary disease (COPD) still remains undetermined. We tested the hypothesis that among individuals with COPD, those with low concentrations of 25-hydroxyvitamin D have a poorer prognosis compared to those with normal concentrations. We studied 35,153 individuals from the general population aged 20–100 years with 25-hydroxyvitamin D measurements and spirometry, the Copenhagen City Heart Study [median follow-up 21 years (range 13 days–36 years)] and the Copenhagen General Population Study [7.1 years (3 days–13 years)]. Spirometric COPD (n = 5178; 15% of all) was defined as forced expiratory volume in 1 s (FEV1)/forced vital capacity (FVC) < 0.70 in individuals without asthma and clinical COPD (n = 2033; 6%) as FEV1/FVC < 0.70 and FEV1 < 80% of predicted in ever-smokers aged > 40 years without asthma and with cumulative tobacco consumption ≥ 10 pack-years. In spirometric COPD, median age at death in years was 70.2 (95% confidence interval [CI] 64.4–71.2) for individuals with 25-hydroxyvitamin D < 12.5 nmol/L and 80.3 (74.4–83.4) for those with ≥ 50 nmol/L. In clinical COPD, corresponding values were 69.0 (63.3–70.9) and 76.2 (73.8–78.0). In spirometric COPD, multivariable adjusted hazard ratios for individuals with 25-hydroxyvitamin D < 12.5 nmol/L versus those with ≥ 50 nmol/L were 1.35 (95% CI 1.09–1.67) for all-cause mortality, 1.63 (1.00–2.64) for respiratory mortality, 1.14 (0.76–1.70) for cardiovascular mortality, 1.37 (0.90–2.06) for cancer mortality, and 1.61 (1.04–2.49) for other mortality. In clinical COPD, corresponding values were 1.39 (1.07–1.82), 1.57 (0.91–2.72), 0.88 (0.51–1.53), 1.63 (0.99–2.67), and 2.00 (1.12–3.56). Low concentrations of 25-hydroxyvitamin D were associated with an increased risk of death in individuals with COPD. No clear pattern of association could be observed for cause of death; however, there may be an increased risk of respiratory, cancer, and other mortality. It is likely that low concentrations of 25-hydroxyvitamin D is a marker of poor health in COPD.
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Low concentrations of 25-hydroxyvitamin D and long-term prognosis of COPD: a prospective cohort study
Abstract
Role and importance of vitamin D deficiency in long-term prognosis of chronic obstructive pulmonary disease (COPD) still remains undetermined. We tested the hypothesis that among individuals with COPD, those with low concentrations of 25-hydroxyvitamin D have a poorer prognosis compared to those with normal concentrations. We studied 35,153 individuals from the general population aged 20–100 years with 25-hydroxyvitamin D measurements and spirometry, the Copenhagen City Heart Study [median follow-up 21 years (range 13 days–36 years)] and the Copenhagen General Population Study [7.1 years (3 days–13 years)]. Spirometric COPD (n = 5178; 15% of all) was defined as forced expiratory volume in 1 s (FEV1)/forced vital capacity (FVC) < 0.70 in individuals without asthma and clinical COPD (n = 2033; 6%) as FEV1/FVC < 0.70 and FEV1 < 80% of predicted in ever-smokers aged > 40 years without asthma and with cumulative tobacco consumption ≥ 10 pack-years. In spirometric COPD, median age at death in years was 70.2 (95% confidence interval [CI] 64.4–71.2) for individuals with 25-hydroxyvitamin D < 12.5 nmol/L and 80.3 (74.4–83.4) for those with ≥ 50 nmol/L. In clinical COPD, corresponding values were 69.0 (63.3–70.9) and 76.2 (73.8–78.0). In spirometric COPD, multivariable adjusted hazard ratios for individuals with 25-hydroxyvitamin D < 12.5 nmol/L versus those with ≥ 50 nmol/L were 1.35 (95% CI 1.09–1.67) for all-cause mortality, 1.63 (1.00–2.64) for respiratory mortality, 1.14 (0.76–1.70) for cardiovascular mortality, 1.37 (0.90–2.06) for cancer mortality, and 1.61 (1.04–2.49) for other mortality. In clinical COPD, corresponding values were 1.39 (1.07–1.82), 1.57 (0.91–2.72), 0.88 (0.51–1.53), 1.63 (0.99–2.67), and 2.00 (1.12–3.56). Low concentrations of 25-hydroxyvitamin D were associated with an increased risk of death in individuals with COPD. No clear pattern of association could be observed for cause of death; however, there may be an increased risk of respiratory, cancer, and other mortality. It is likely that low concentrations of 25-hydroxyvitamin D is a marker of poor health in COPD.
https://ift.tt/2Jk8AVt
Tumor-originated exosomal lncUEGC1 as a circulating biomarker for early-stage gastric cancer
Abstract
Conventional tumor markers for non-invasive diagnosis of gastric cancer (GC) exhibit insufficient sensitivity and specificity to facilitate detection of early gastric cancer (EGC). We aimed to identify EGC-specific exosomal lncRNA biomarkers that are highly sensitive and stable for the non-invasive diagnosis of EGC. Hence, in the present study, exosomes from the plasma of five healthy individuals and ten stage I GC patients and from culture media of four human primary stomach epithelial cells and four gastric cancer cells (GCCs) were isolated. Exosomal RNA profiling was performed using RNA sequencing to identify EGC-specific exosomal lncRNAs. A total of 79 and 285 exosomal RNAs were expressed at significantly higher levels in stage I GC patients and GCCs, respectively, than that in normal controls. Through combinational analysis of the RNA sequencing results, we found two EGC-specific exosomal lncRNAs, lncUEGC1 and lncUEGC2, which were further confirmed to be remarkably up-regulated in exosomes derived from EGC patients and GCCs. Furthermore, stability testing demonstrates that almost all the plasma lncUEGC1 was encapsulated within exosomes and thus protected from RNase degradation. The diagnostic accuracy of exosomal lncUEGC1 was evaluated, and lncUEGC1 exhibited AUC values of 0.8760 and 0.8406 in discriminating EGC patients from healthy individuals and those with premalignant chronic atrophic gastritis, respectively, which was higher than the diagnostic accuracy of carcinoembryonic antigen. Consequently, exosomal lncUEGC1 may be promising in the development of highly sensitive, stable, and non-invasive biomarkers for EGC diagnosis.
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Tumor-originated exosomal lncUEGC1 as a circulating biomarker for early-stage gastric cancer
Abstract
Conventional tumor markers for non-invasive diagnosis of gastric cancer (GC) exhibit insufficient sensitivity and specificity to facilitate detection of early gastric cancer (EGC). We aimed to identify EGC-specific exosomal lncRNA biomarkers that are highly sensitive and stable for the non-invasive diagnosis of EGC. Hence, in the present study, exosomes from the plasma of five healthy individuals and ten stage I GC patients and from culture media of four human primary stomach epithelial cells and four gastric cancer cells (GCCs) were isolated. Exosomal RNA profiling was performed using RNA sequencing to identify EGC-specific exosomal lncRNAs. A total of 79 and 285 exosomal RNAs were expressed at significantly higher levels in stage I GC patients and GCCs, respectively, than that in normal controls. Through combinational analysis of the RNA sequencing results, we found two EGC-specific exosomal lncRNAs, lncUEGC1 and lncUEGC2, which were further confirmed to be remarkably up-regulated in exosomes derived from EGC patients and GCCs. Furthermore, stability testing demonstrates that almost all the plasma lncUEGC1 was encapsulated within exosomes and thus protected from RNase degradation. The diagnostic accuracy of exosomal lncUEGC1 was evaluated, and lncUEGC1 exhibited AUC values of 0.8760 and 0.8406 in discriminating EGC patients from healthy individuals and those with premalignant chronic atrophic gastritis, respectively, which was higher than the diagnostic accuracy of carcinoembryonic antigen. Consequently, exosomal lncUEGC1 may be promising in the development of highly sensitive, stable, and non-invasive biomarkers for EGC diagnosis.
https://ift.tt/2K6XzrP
CXCL9/10/11, a regulator of PD-L1 expression in gastric cancer
Abstract
Background
Programmed death-ligand 1 (PD-L1) is an immunosuppressor that plays an important role in cancer treatments. Although majority of the studies demonstrated that PD-L1 expression was regulated by cellular intrinsic and extrinsic controls, and IFN-γ was a key molecule of extrinsic control, other studies imply that other cytokines play important roles in PD-L1 expression. In this study, we investigated the regulation of PD-L1 by chemokine signaling pathway in gastric cancer (GC) cells.
Methods
Bioinformatics was used to explore the PD-L1-related genes in GC and propose a hypothesis. PD-L1 and CXCR3 expression were detected by western blot in SGC7901 and MKN74 cell lines. Meanwhile, PD-L1 and CXCR3 expressions were immunohistochemically assessed for their relevance. Moreover, PD-L1, pSTAT3 and pAkt were detected after treatment with CXCL9/10/11. Furthermore,PD-L1, pSTAT3 and pAkt were evaluated after blocking chemokine signaling in SGC7901 cells.
Results
Based on online database analysis, CXCL9/10/11-CXCR3 is proposed to upregulate PD-L1 expression by activating the STAT and PI3K-Akt pathways. This hypothesis was confirmed by in vitro and vivo experiments. CXCR3 and PD-L1 were expressed in GC cell lines and tissues, and the expression of CXCR3 and PD-L1 was positively related. PD-L1 was upregulated after treatment with CXCL9/10/11, accompanied by activation of STAT3 and Akt. After blocking chemokine signaling, upregulation of PD-L1 and activation of STAT3 and Akt were diminished.
Conclusions
CXCL9/10/11-CXCR3 upregulated the expression of PD-L1 by activating the STAT and PI3K-Akt signaling pathways in GC cells. There was a significant positive correlation between the expression of PD-L1 and CXCR3 in gastric cancer patient tissues.
from Cancer via ola Kala on Inoreader https://ift.tt/2HsyGVA
via IFTTT
CXCL9/10/11, a regulator of PD-L1 expression in gastric cancer
Abstract
Background
Programmed death-ligand 1 (PD-L1) is an immunosuppressor that plays an important role in cancer treatments. Although majority of the studies demonstrated that PD-L1 expression was regulated by cellular intrinsic and extrinsic controls, and IFN-γ was a key molecule of extrinsic control, other studies imply that other cytokines play important roles in PD-L1 expression. In this study, we investigated the regulation of PD-L1 by chemokine signaling pathway in gastric cancer (GC) cells.
Methods
Bioinformatics was used to explore the PD-L1-related genes in GC and propose a hypothesis. PD-L1 and CXCR3 expression were detected by western blot in SGC7901 and MKN74 cell lines. Meanwhile, PD-L1 and CXCR3 expressions were immunohistochemically assessed for their relevance. Moreover, PD-L1, pSTAT3 and pAkt were detected after treatment with CXCL9/10/11. Furthermore,PD-L1, pSTAT3 and pAkt were evaluated after blocking chemokine signaling in SGC7901 cells.
Results
Based on online database analysis, CXCL9/10/11-CXCR3 is proposed to upregulate PD-L1 expression by activating the STAT and PI3K-Akt pathways. This hypothesis was confirmed by in vitro and vivo experiments. CXCR3 and PD-L1 were expressed in GC cell lines and tissues, and the expression of CXCR3 and PD-L1 was positively related. PD-L1 was upregulated after treatment with CXCL9/10/11, accompanied by activation of STAT3 and Akt. After blocking chemokine signaling, upregulation of PD-L1 and activation of STAT3 and Akt were diminished.
Conclusions
CXCL9/10/11-CXCR3 upregulated the expression of PD-L1 by activating the STAT and PI3K-Akt signaling pathways in GC cells. There was a significant positive correlation between the expression of PD-L1 and CXCR3 in gastric cancer patient tissues.
https://ift.tt/2HsyGVA
Favourable response of serum prostate-specific antigen to conjugated oestrogen in castrate-resistant prostate cancer in Jamaica
Andrew Condappa, Maxine Gossell-Williams and William Aiken
from Cancer via ola Kala on Inoreader https://ift.tt/2HXSPnN
via IFTTT
The current state of prostate cancer treatment in Trinidad and Tobago
Satyendra Persaud, Maliza Persaud, Lester Goetz and Dylan Narinesingh
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Oncological and reproductive outcomes of adenocarcinoma in situ of the cervix managed with the loop electrosurgical excision procedure
Abstract
Background
The standard treatment for cervical adenocarcinoma in situ (AIS) is hysterectomy, which is a more aggressive treatment than that used for squamous intraepithelial lesions. Several previous studies have primarily demonstrated that the loop electrosurgical excision procedure (LEEP) is as safe and effective as cold knife cone (CKC) biopsy when AIS is unexpectedly found in a loop excision. This study evaluated the safety of LEEP as the initial treatment for patients with AIS who were strictly selected and evaluated before and after loop resection.
Methods
The oncological and reproductive outcomes of a series of AIS patients who underwent LEEP as the initial treatment between February 2006 and December 2016 were retrospectively evaluated.
Results
A total of 44 women were eligible for analysis. The mean age at diagnosis was 36.1 years, and 14 patients were nulliparous. Multiple lesions were identified in 4 (9.1%) patients. Either hysterectomy (6 patients) or repeat cone biopsies (3 patients) were performed in 8 of the 10 patients who presented positive or not evaluable surgical resection margins (SMs) on the initial LEEP specimens. Residual disease was detected in two patients. All patients were closely followed for a mean of 36.9 months via human papillomavirus testing, PAP smears, colposcopy, and endocervical curettage when necessary. No recurrences were detected. Of the 16 patients who desired to become pregnant, 8 (50%) successfully conceived, and the full-term live birth rate was 83.3% among this subgroup.
Conclusions
LEEP with negative SMs was a safe and feasible fertility-sparing surgical procedure for patients with AIS, and the obstetric outcome was satisfactory. However, long-term follow-up is mandatory.
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Radiogenic angiosarcoma of the breast: case report and systematic review of the literature
Abstract
Background
Radiogenic angiosarcoma of the breast (RASB) is a rare late sequela of local irradiation of the breast or chest wall after breast cancer. The prognosis of women with RASB is poor and there is no standardized therapy for this type of malignancy.
Case presentation
We present the case of a 54 year old woman with RASB (poorly differentiated angiosarcoma of the left breast; pT1, pNX, M0, L0, V0) and a history of invasive-ductal cancer of the left breast (pT1b, G2, pN0, ER positive, PR positive, HER-2/neu negative) treated in July 2012 with breast-conserving surgery, adjuvant chemotherapy with 6 cycles of epirubicin and cyclophosphamide, adjuvant irradiation of the left breast with 50 Gray, and adjuvant endocrine therapy with an aromatase inhibitor. In August 2016, a bilateral salpingo-oophorectomy was performed to remove a tumor of the left ovary, which was diagnosed as breast cancer recurrence. At the same time, a small, purple skin lesion of 1.2 cm in diameter was noted in the inner upper quadrant of the right breast. RASB was diagnosed by punch biopsy and the tumor was excised with clear margins. Imaging studies showed no evidence of further metastases. A systemic chemotherapy with 6 cycles of liposomal doxorubicin was initiated. Five months later, a local recurrence of RASB was diagnosed and mastectomy was performed. Six months later, the patient is alive with no evidence of disease.
Three hundred seven cases of RASB were identified. The pooled incidence rate of RASB was 1/3754 women. The most common treatment of RASB was mastectomy in 83% of cases. Adjuvant radiotherapy or chemotherapy were rarely used with 6 and 4%, respectively, whereas in case of recurrence, chemotherapy was the mainstay of treatment, used in 58% of cases. Radiotherapy and repeated surgery were also common with 30 and 33% of cases, respectively. Overall, the prognosis of women with RASB was poor and the recurrence-free survival was short with a mean of 15.9 months. Mean overall survival was 27.4 months.
Conclusion
RASB is a rare late complication of breast irradiation. The prognosis of women with RASB is poor. Surgery is the mainstay of treatment for localized disease while systemic chemotherapy and re-irradiation are appropriate for women with disseminated or recurrent RASB.
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Low expression of c-Myc protein predicts poor outcomes in patients with hepatocellular carcinoma after resection
Abstract
Background
Embryonic Liver Fodrin (ELF) is an adaptor protein of transforming growth factor (TGF-β) signaling cascade. Disruption of ELF results in mislocalization of Smad3 and Smad4, leading to compromised TGF-β signaling. c-Myc is an important oncogenic transcription factor, and the disruption of TGF-β signaling promotes c-Myc-induced hepatocellular carcinoma (HCC) carcinogenesis. However, the prognostic significance of c-Myc in HCC is less understood
Methods
The expression of c-Myc protein and mRNA were measured by immunohistochemistry (IHC) and qRT- PCR, respectively. IHC was performed to detect TGF-β1 and ELF expression in HCC tissues. Their relationship with clinicopathological factors and overall survival (OS) and disease free survival (DFS) were examined.
Results
The expression of c-Myc protein and mRNA in HCC tissues were significantly higher in HCC area than those in normal liver tissues. However, the expression were low compared with those adjacent to HCC area. c-Myc protein was independently predictive of DFS and OS, and it was negatively correlated with tumor size (P = 0.031), tumor number (P = 0.038), and recurrence (P = 0.001). Low c-Myc expression was associated with short-term recurrence and poor prognosis. The predictive value of c-Myc combined with TGF-β1 or/and ELF was higher than that of any other single marker. Low c-Myc, high TGF-β1 or/and low ELF expression was associated with the worst DFS and OS.
Conclusions
Low expression of c-Myc protein predicts poor outcomes in patients with HCC with hepatectomy. The combination of the expression of c-Myc, TGF-β1, and ELF can be used to accurately predict outcomes of patients with HCC.
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Favourable response of serum prostate-specific antigen to conjugated oestrogen in castrate-resistant prostate cancer in Jamaica
Andrew Condappa, Maxine Gossell-Williams and William Aiken
https://ift.tt/2HXSPnN
The current state of prostate cancer treatment in Trinidad and Tobago
Satyendra Persaud, Maliza Persaud, Lester Goetz and Dylan Narinesingh
https://ift.tt/2FdguNY
Oncological and reproductive outcomes of adenocarcinoma in situ of the cervix managed with the loop electrosurgical excision procedure
Abstract
Background
The standard treatment for cervical adenocarcinoma in situ (AIS) is hysterectomy, which is a more aggressive treatment than that used for squamous intraepithelial lesions. Several previous studies have primarily demonstrated that the loop electrosurgical excision procedure (LEEP) is as safe and effective as cold knife cone (CKC) biopsy when AIS is unexpectedly found in a loop excision. This study evaluated the safety of LEEP as the initial treatment for patients with AIS who were strictly selected and evaluated before and after loop resection.
Methods
The oncological and reproductive outcomes of a series of AIS patients who underwent LEEP as the initial treatment between February 2006 and December 2016 were retrospectively evaluated.
Results
A total of 44 women were eligible for analysis. The mean age at diagnosis was 36.1 years, and 14 patients were nulliparous. Multiple lesions were identified in 4 (9.1%) patients. Either hysterectomy (6 patients) or repeat cone biopsies (3 patients) were performed in 8 of the 10 patients who presented positive or not evaluable surgical resection margins (SMs) on the initial LEEP specimens. Residual disease was detected in two patients. All patients were closely followed for a mean of 36.9 months via human papillomavirus testing, PAP smears, colposcopy, and endocervical curettage when necessary. No recurrences were detected. Of the 16 patients who desired to become pregnant, 8 (50%) successfully conceived, and the full-term live birth rate was 83.3% among this subgroup.
Conclusions
LEEP with negative SMs was a safe and feasible fertility-sparing surgical procedure for patients with AIS, and the obstetric outcome was satisfactory. However, long-term follow-up is mandatory.
https://ift.tt/2Hr6cM7
Radiogenic angiosarcoma of the breast: case report and systematic review of the literature
Abstract
Background
Radiogenic angiosarcoma of the breast (RASB) is a rare late sequela of local irradiation of the breast or chest wall after breast cancer. The prognosis of women with RASB is poor and there is no standardized therapy for this type of malignancy.
Case presentation
We present the case of a 54 year old woman with RASB (poorly differentiated angiosarcoma of the left breast; pT1, pNX, M0, L0, V0) and a history of invasive-ductal cancer of the left breast (pT1b, G2, pN0, ER positive, PR positive, HER-2/neu negative) treated in July 2012 with breast-conserving surgery, adjuvant chemotherapy with 6 cycles of epirubicin and cyclophosphamide, adjuvant irradiation of the left breast with 50 Gray, and adjuvant endocrine therapy with an aromatase inhibitor. In August 2016, a bilateral salpingo-oophorectomy was performed to remove a tumor of the left ovary, which was diagnosed as breast cancer recurrence. At the same time, a small, purple skin lesion of 1.2 cm in diameter was noted in the inner upper quadrant of the right breast. RASB was diagnosed by punch biopsy and the tumor was excised with clear margins. Imaging studies showed no evidence of further metastases. A systemic chemotherapy with 6 cycles of liposomal doxorubicin was initiated. Five months later, a local recurrence of RASB was diagnosed and mastectomy was performed. Six months later, the patient is alive with no evidence of disease.
Three hundred seven cases of RASB were identified. The pooled incidence rate of RASB was 1/3754 women. The most common treatment of RASB was mastectomy in 83% of cases. Adjuvant radiotherapy or chemotherapy were rarely used with 6 and 4%, respectively, whereas in case of recurrence, chemotherapy was the mainstay of treatment, used in 58% of cases. Radiotherapy and repeated surgery were also common with 30 and 33% of cases, respectively. Overall, the prognosis of women with RASB was poor and the recurrence-free survival was short with a mean of 15.9 months. Mean overall survival was 27.4 months.
Conclusion
RASB is a rare late complication of breast irradiation. The prognosis of women with RASB is poor. Surgery is the mainstay of treatment for localized disease while systemic chemotherapy and re-irradiation are appropriate for women with disseminated or recurrent RASB.
https://ift.tt/2HWtoCJ
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