Cancer Science, EarlyView.
https://ift.tt/2KJoNoF
Cancer Medicine by Alexandros G.Sfakianakis,Anapafseos 5 Agios Nikolaos,Crete 72100,Greece,tel :00302841026182 & 00306932607174
Δευτέρα 7 Μαΐου 2018
Sonodynamic therapy‐assisted immunotherapy: A novel modality for cancer treatment
Sonodynamic therapy‐assisted immunotherapy: A novel modality for cancer treatment
Cancer Science, EarlyView.
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Report of a bi-allelic truncating germline mutation in TP53
Abstract
The TP53 gene is fundamental to genomic integrity, cell cycle regulation, and apoptosis; it is the most commonly mutated gene in human cancer. Heterozygous germline mutations cause the autosomal dominant cancer predisposition syndrome, Li-Fraumeni Syndrome. Homozygous germline TP53 mutations in humans are rare. We report an infant from a consanguineous family who presented with synchronous malignancies. Remarkably, he carries a homozygous germline TP53 mutation (NM_000546.4:c.52delA), predicted to cause protein truncation. The family history is consistent with Li-Fraumeni syndrome.
https://ift.tt/2K3kCTg
VISTA expression on tumor-infiltrating inflammatory cells in primary cutaneous melanoma correlates with poor disease-specific survival
Abstract
Adaptive immune responses contribute to the pathogenesis of melanoma by facilitating immune evasion. V-domain Ig suppressor of T-cell activation (VISTA) is a potent negative regulator of T-cell function and is expressed at high levels on monocytes, granulocytes, and macrophages, and at lower densities on T-cell populations within the tumor microenvironment. In this study, 85 primary melanoma specimens were selected from pathology tissue archives and immunohistochemically stained for CD3, PD-1, PD-L1, and VISTA. Pearson's correlation coefficients identified associations in expression between VISTA and myeloid infiltrate (r = 0.28, p = 0.009) and the density of PD-1+ inflammatory cells (r = 0.31, p = 0.005). The presence of VISTA was associated with a significantly worse disease-specific survival in univariate analysis (hazard ratio = 3.57, p = 0.005) and multivariate analysis (hazard ratio = 3.02, p = 0.02). Our findings show that VISTA expression is an independent negative prognostic factor in primary cutaneous melanoma and suggests its potential as an adjuvant immunotherapeutic intervention in the future.
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VISTA expression on tumor-infiltrating inflammatory cells in primary cutaneous melanoma correlates with poor disease-specific survival
Abstract
Adaptive immune responses contribute to the pathogenesis of melanoma by facilitating immune evasion. V-domain Ig suppressor of T-cell activation (VISTA) is a potent negative regulator of T-cell function and is expressed at high levels on monocytes, granulocytes, and macrophages, and at lower densities on T-cell populations within the tumor microenvironment. In this study, 85 primary melanoma specimens were selected from pathology tissue archives and immunohistochemically stained for CD3, PD-1, PD-L1, and VISTA. Pearson's correlation coefficients identified associations in expression between VISTA and myeloid infiltrate (r = 0.28, p = 0.009) and the density of PD-1+ inflammatory cells (r = 0.31, p = 0.005). The presence of VISTA was associated with a significantly worse disease-specific survival in univariate analysis (hazard ratio = 3.57, p = 0.005) and multivariate analysis (hazard ratio = 3.02, p = 0.02). Our findings show that VISTA expression is an independent negative prognostic factor in primary cutaneous melanoma and suggests its potential as an adjuvant immunotherapeutic intervention in the future.
https://ift.tt/2FU0xwn
VISTA expression on tumor-infiltrating inflammatory cells in primary cutaneous melanoma correlates with poor disease-specific survival
Abstract
Adaptive immune responses contribute to the pathogenesis of melanoma by facilitating immune evasion. V-domain Ig suppressor of T-cell activation (VISTA) is a potent negative regulator of T-cell function and is expressed at high levels on monocytes, granulocytes, and macrophages, and at lower densities on T-cell populations within the tumor microenvironment. In this study, 85 primary melanoma specimens were selected from pathology tissue archives and immunohistochemically stained for CD3, PD-1, PD-L1, and VISTA. Pearson's correlation coefficients identified associations in expression between VISTA and myeloid infiltrate (r = 0.28, p = 0.009) and the density of PD-1+ inflammatory cells (r = 0.31, p = 0.005). The presence of VISTA was associated with a significantly worse disease-specific survival in univariate analysis (hazard ratio = 3.57, p = 0.005) and multivariate analysis (hazard ratio = 3.02, p = 0.02). Our findings show that VISTA expression is an independent negative prognostic factor in primary cutaneous melanoma and suggests its potential as an adjuvant immunotherapeutic intervention in the future.
https://ift.tt/2FU0xwn
A Clinical Decision Support System to Assist Pediatric Oncofertility: A Short Report
Journal of Adolescent and Young Adult Oncology, Ahead of Print.
https://ift.tt/2FTUcB3
VISTA expression on tumor-infiltrating inflammatory cells in primary cutaneous melanoma correlates with poor disease-specific survival
Abstract
Adaptive immune responses contribute to the pathogenesis of melanoma by facilitating immune evasion. V-domain Ig suppressor of T-cell activation (VISTA) is a potent negative regulator of T-cell function and is expressed at high levels on monocytes, granulocytes, and macrophages, and at lower densities on T-cell populations within the tumor microenvironment. In this study, 85 primary melanoma specimens were selected from pathology tissue archives and immunohistochemically stained for CD3, PD-1, PD-L1, and VISTA. Pearson's correlation coefficients identified associations in expression between VISTA and myeloid infiltrate (r = 0.28, p = 0.009) and the density of PD-1+ inflammatory cells (r = 0.31, p = 0.005). The presence of VISTA was associated with a significantly worse disease-specific survival in univariate analysis (hazard ratio = 3.57, p = 0.005) and multivariate analysis (hazard ratio = 3.02, p = 0.02). Our findings show that VISTA expression is an independent negative prognostic factor in primary cutaneous melanoma and suggests its potential as an adjuvant immunotherapeutic intervention in the future.
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A Clinical Decision Support System to Assist Pediatric Oncofertility: A Short Report
Journal of Adolescent and Young Adult Oncology, Ahead of Print.
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Biomarkers defining probability of receiving second-line targeted therapy in metastatic renal cell carcinoma
Abstract
In order to facilitate long-term treatment decisions, we aimed to define biomarkers defining the probability of receiving second-line (SL) targeted therapy (TT) in patients with metastatic renal cell carcinoma (mRCC) based on their characteristics present at first-line TT initiation. We analysed 152 consecutive mRCC patients treated and used multivariable binominal logistic regression to identify factors contributing to the probability of receiving SL TT. Final model was assessed with bias-corrected indices (Nagelkerke's R2 and area under receiver operating characteristic curve [AUC]) and two bootstrap procedures were used for internal validation. Factors associated with the probability of SL TT eligibility were the presence of brain metastases (odds ratio [OR] 0.084, 95% confidence interval [CI] 0.010–0.707), number of metastatic sites (OR 0.740, 95% CI 0.575–0.953 per each site), platelet count (OR 0.971, 95% CI 0.947–0.997, per 104/ml), lactate dehydrogenase level (OR 0.952, 95% CI 0.910–0.997 per 10 units/l), and albumin concentration (OR 1.924, 95% CI 1.057–3.503 per 1 g/dl). We developed on-line calculator that enables practicing clinicians to estimate SL treatment probability (http://www.r-calc.com).
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Biomarkers defining probability of receiving second-line targeted therapy in metastatic renal cell carcinoma
Abstract
In order to facilitate long-term treatment decisions, we aimed to define biomarkers defining the probability of receiving second-line (SL) targeted therapy (TT) in patients with metastatic renal cell carcinoma (mRCC) based on their characteristics present at first-line TT initiation. We analysed 152 consecutive mRCC patients treated and used multivariable binominal logistic regression to identify factors contributing to the probability of receiving SL TT. Final model was assessed with bias-corrected indices (Nagelkerke's R2 and area under receiver operating characteristic curve [AUC]) and two bootstrap procedures were used for internal validation. Factors associated with the probability of SL TT eligibility were the presence of brain metastases (odds ratio [OR] 0.084, 95% confidence interval [CI] 0.010–0.707), number of metastatic sites (OR 0.740, 95% CI 0.575–0.953 per each site), platelet count (OR 0.971, 95% CI 0.947–0.997, per 104/ml), lactate dehydrogenase level (OR 0.952, 95% CI 0.910–0.997 per 10 units/l), and albumin concentration (OR 1.924, 95% CI 1.057–3.503 per 1 g/dl). We developed on-line calculator that enables practicing clinicians to estimate SL treatment probability (http://www.r-calc.com).
https://ift.tt/2FW5BQK
VISTA expression on tumor-infiltrating inflammatory cells in primary cutaneous melanoma correlates with poor disease-specific survival
Abstract
Adaptive immune responses contribute to the pathogenesis of melanoma by facilitating immune evasion. V-domain Ig suppressor of T-cell activation (VISTA) is a potent negative regulator of T-cell function and is expressed at high levels on monocytes, granulocytes, and macrophages, and at lower densities on T-cell populations within the tumor microenvironment. In this study, 85 primary melanoma specimens were selected from pathology tissue archives and immunohistochemically stained for CD3, PD-1, PD-L1, and VISTA. Pearson's correlation coefficients identified associations in expression between VISTA and myeloid infiltrate (r = 0.28, p = 0.009) and the density of PD-1+ inflammatory cells (r = 0.31, p = 0.005). The presence of VISTA was associated with a significantly worse disease-specific survival in univariate analysis (hazard ratio = 3.57, p = 0.005) and multivariate analysis (hazard ratio = 3.02, p = 0.02). Our findings show that VISTA expression is an independent negative prognostic factor in primary cutaneous melanoma and suggests its potential as an adjuvant immunotherapeutic intervention in the future.
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Regional therapies for locoregionally advanced and unresectable melanoma
Abstract
Locoregionally advanced and unresectable disease can be seen in up to 10% of melanoma patients. Treatment options for these patients have been evolving most notably over the past few decades and have demonstrated efficacy through multiple intra-arterial as well as intralesional therapies. Isolated limb perfusions and isolated limb infusions have been utilized to treat locoregionally advanced melanoma of the extremity with overall response rates up to 90% in some reports. Intralesional therapies, for in transit metastatic melanoma, such as Bacille Calmette–Guerin, talimogene laherparepvec, and PV-10 (Rose Bengal) have all demonstrated efficacy in the treatment of unresectable cutaneous melanoma. The treatment effect due to intralesional injection has been identified in directly injected lesions as well as in distant uninjected "bystander lesions" with some injectables. This bystander effect is likely an immunologic reaction due to tumor antigen release, antigen-presenting cell uptake, T cell activation and subsequent bystander tumor destruction in uninjected lesions. Treatment options for unresectable melanoma metastases limited to the liver include isolated hepatic perfusion, which can now be performed through a minimally invasive approach known as percutaneous hepatic perfusion. These intra-arterial and intralesional regional therapies offer a variety of effective treatment modalities for unresectable disease and may potentially be combined with systemic treatments, such as immunotherapy, in the future treatment of locoregionally advanced melanoma.
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Regional therapies for locoregionally advanced and unresectable melanoma
Abstract
Locoregionally advanced and unresectable disease can be seen in up to 10% of melanoma patients. Treatment options for these patients have been evolving most notably over the past few decades and have demonstrated efficacy through multiple intra-arterial as well as intralesional therapies. Isolated limb perfusions and isolated limb infusions have been utilized to treat locoregionally advanced melanoma of the extremity with overall response rates up to 90% in some reports. Intralesional therapies, for in transit metastatic melanoma, such as Bacille Calmette–Guerin, talimogene laherparepvec, and PV-10 (Rose Bengal) have all demonstrated efficacy in the treatment of unresectable cutaneous melanoma. The treatment effect due to intralesional injection has been identified in directly injected lesions as well as in distant uninjected "bystander lesions" with some injectables. This bystander effect is likely an immunologic reaction due to tumor antigen release, antigen-presenting cell uptake, T cell activation and subsequent bystander tumor destruction in uninjected lesions. Treatment options for unresectable melanoma metastases limited to the liver include isolated hepatic perfusion, which can now be performed through a minimally invasive approach known as percutaneous hepatic perfusion. These intra-arterial and intralesional regional therapies offer a variety of effective treatment modalities for unresectable disease and may potentially be combined with systemic treatments, such as immunotherapy, in the future treatment of locoregionally advanced melanoma.
https://ift.tt/2I53Pig
Matrix Metalloproteinase Inhibitors in Cancer Therapy: Turning Past Failures Into Future Successes
The matrix metalloproteinases (MMP) are a family of proteolytic enzymes that degrade multiple components of the extracellular matrix. A large body of experimental and clinical evidence has implicated MMPs in tumor invasion, neoangiogenesis, and metastasis, and therefore they represent ideal pharmacologic targets for cancer therapy. From the 1990s to early 2000s, synthetic inhibitors of MMPs (MMPI) were studied in various cancer types. Unexpectedly, despite strongly promising preclinical data, all trials were unsuccessful in reducing tumor burden or improving overall survival; in addition, MMPIs had unforeseen, severe side effects. Two main reasons can explain the failure of MMPIs in clinical trials. It has now become apparent that some MMPs have antitumor effects; therefore, the broad-spectrum MMPIs used in the initial trials might block these MMPs and result in tumor progression. In addition, although MMPs are involved in the early stages of tumor progression, MMPIs were tested in patients with advanced disease, beyond the stage when these compounds could be effective. As more specific MMPIs are now available, MMP targeting could be reconsidered for cancer therapy; however, new trials should be designed to test their antimetastatic properties in early-stage tumors, and endpoints should focus on parameters other than decreasing metastatic tumor burden. Mol Cancer Ther; 1–9. ©2018 AACR.
https://ift.tt/2I2t4BH
Matrix Metalloproteinase Inhibitors in Cancer Therapy: Turning Past Failures Into Future Successes
The matrix metalloproteinases (MMP) are a family of proteolytic enzymes that degrade multiple components of the extracellular matrix. A large body of experimental and clinical evidence has implicated MMPs in tumor invasion, neoangiogenesis, and metastasis, and therefore they represent ideal pharmacologic targets for cancer therapy. From the 1990s to early 2000s, synthetic inhibitors of MMPs (MMPI) were studied in various cancer types. Unexpectedly, despite strongly promising preclinical data, all trials were unsuccessful in reducing tumor burden or improving overall survival; in addition, MMPIs had unforeseen, severe side effects. Two main reasons can explain the failure of MMPIs in clinical trials. It has now become apparent that some MMPs have antitumor effects; therefore, the broad-spectrum MMPIs used in the initial trials might block these MMPs and result in tumor progression. In addition, although MMPs are involved in the early stages of tumor progression, MMPIs were tested in patients with advanced disease, beyond the stage when these compounds could be effective. As more specific MMPIs are now available, MMP targeting could be reconsidered for cancer therapy; however, new trials should be designed to test their antimetastatic properties in early-stage tumors, and endpoints should focus on parameters other than decreasing metastatic tumor burden. Mol Cancer Ther; 1–9. ©2018 AACR.
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Effects of high-intensity interval training on fatigue and quality of life in testicular cancer survivors
Effects of high-intensity interval training on fatigue and quality of life in testicular cancer survivors
Effects of high-intensity interval training on fatigue and quality of life in testicular cancer survivors, Published online: 08 May 2018; doi:10.1038/s41416-018-0044-7
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Addition of ultrasound to mammography in the case of dense breast tissue: systematic review and meta-analysis
Addition of ultrasound to mammography in the case of dense breast tissue: systematic review and meta-analysis
Addition of ultrasound to mammography in the case of dense breast tissue: systematic review and meta-analysis, Published online: 08 May 2018; doi:10.1038/s41416-018-0080-3
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Psychological impact of providing women with personalised 10-year breast cancer risk estimates
Psychological impact of providing women with personalised 10-year breast cancer risk estimates
Psychological impact of providing women with personalised 10-year breast cancer risk estimates, Published online: 08 May 2018; doi:10.1038/s41416-018-0069-y
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Mps1 inhibitors synergise with low doses of taxanes in promoting tumour cell death by enhancement of errors in cell division
Mps1 inhibitors synergise with low doses of taxanes in promoting tumour cell death by enhancement of errors in cell division
Mps1 inhibitors synergise with low doses of taxanes in promoting tumour cell death by enhancement of errors in cell division, Published online: 08 May 2018; doi:10.1038/s41416-018-0081-2
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Effects of high-intensity interval training on fatigue and quality of life in testicular cancer survivors
Effects of high-intensity interval training on fatigue and quality of life in testicular cancer survivors
Effects of high-intensity interval training on fatigue and quality of life in testicular cancer survivors, Published online: 08 May 2018; doi:10.1038/s41416-018-0044-7
Effects of high-intensity interval training on fatigue and quality of life in testicular cancer survivorshttps://ift.tt/2FWb7TO
Addition of ultrasound to mammography in the case of dense breast tissue: systematic review and meta-analysis
Addition of ultrasound to mammography in the case of dense breast tissue: systematic review and meta-analysis
Addition of ultrasound to mammography in the case of dense breast tissue: systematic review and meta-analysis, Published online: 08 May 2018; doi:10.1038/s41416-018-0080-3
Addition of ultrasound to mammography in the case of dense breast tissue: systematic review and meta-analysishttps://ift.tt/2KJSfuT
Psychological impact of providing women with personalised 10-year breast cancer risk estimates
Psychological impact of providing women with personalised 10-year breast cancer risk estimates
Psychological impact of providing women with personalised 10-year breast cancer risk estimates, Published online: 08 May 2018; doi:10.1038/s41416-018-0069-y
Psychological impact of providing women with personalised 10-year breast cancer risk estimateshttps://ift.tt/2FU4pNS
Mps1 inhibitors synergise with low doses of taxanes in promoting tumour cell death by enhancement of errors in cell division
Mps1 inhibitors synergise with low doses of taxanes in promoting tumour cell death by enhancement of errors in cell division
Mps1 inhibitors synergise with low doses of taxanes in promoting tumour cell death by enhancement of errors in cell division, Published online: 08 May 2018; doi:10.1038/s41416-018-0081-2
Mps1 inhibitors synergise with low doses of taxanes in promoting tumour cell death by enhancement of errors in cell divisionhttps://ift.tt/2I4pAPg
miRNA profiling of magnetic nanopore-isolated extracellular vesicles for the diagnosis of pancreatic cancer
Improved diagnostics for pancreatic ductal adenocarcinoma (PDAC) to detect the disease at earlier, curative stages and to guide treatments is crucial to progress against this disease. The development of a liquid biopsy for PDAC has proven challenging due to the sparsity and variable phenotypic expression of circulating biomarkers. Here we report methods we developed for isolating specific subsets of extracellular vesicles (EV) from plasma using a novel magnetic nanopore capture technique. In addition, we present a workflow for identifying EV miRNA biomarkers using RNA sequencing and machine-learning algorithms, which we used in combination to classify distinct cancer states. Applying this approach to a mouse model of PDAC, we identified a biomarker panel of 11 EV miRNAs that could distinguish mice with PDAC from either healthy mice or those with pre-cancerous lesions in a training set of N = 27 mice and a user-blinded validation set of N = 57 mice (88% accuracy in a three-way classification). These results provide strong proof-of-concept support for the feasibility of using EV miRNA profiling and machine learning for liquid biopsy.
https://ift.tt/2jGFl4o
Optimized dosing schedule based on circadian dynamics of mouse breast cancer stem cells improves the anti-tumor effects of aldehyde dehydrogenase
Although malignant phenotypes of triple-negative breast cancer (TNBC) are subject to circadian alterations, the role of cancer stem cells (CSC) in defining this circadian change remains unclear. CSC are often characterized by high aldehyde dehydrogenase (ALDH) activity, which is associated with the malignancy of cancer cells and used for identification and isolation of CSC. Here we show that the popultation of ALDH-positive cells in a mouse 4T1 breast tumor model exhibits pronounced circadian alterations. Alterations in the number of ALDH-positive cells was generated by time-dependent increases and decreases in the expression of Aldh3a1. Importantly, circadian clock genes were rhythmically expressed in ALDH-negative cells, but not in ALDH-positive cells. Circadian expression of Aldh3a1 in ALDH-positive cells was dependent on the time-dependent release of Wingless-type mmtv integration site family 10a (WNT10a) from ALDH-negative cells. Furthermore, anti-tumor and anti-metastatic effects of ALDH inhibitor N,N-diethylaminobenzaldehyde were enhanced by administration at the time of day when ALDH activity was increased in 4T1 tumor cells. Our findings reveal a new role for the circadian clock within the tumor microenvironment in regulating the circadian dynamics of CSC. These results should enable the development of novel therapeutic strategies for treatment of TNBC with ALDH inhibitors.
https://ift.tt/2wlQ3qh
HLA class I and II diversity contributes to the etiologic heterogeneity of non-Hodgkin lymphoma subtypes
A growing number of loci within the human leukocyte antigen (HLA) region have been implicated in non-Hodgkin lymphoma (NHL) etiology. Here, we test a complementary hypothesis of "heterozygote advantage" regarding the role of HLA and NHL, whereby HLA diversity is beneficial and homozygous HLA loci are associated with increased disease risk. HLA alleles at class I and II loci were imputed from genome-wide association studies (GWAS) using SNP2HLA for: 3,617 diffuse large B-cell lymphomas (DLBCL), 2,686 follicular lymphomas (FL), 2,878 chronic lymphocytic leukemia/small lymphocytic lymphomas (CLL/SLL), 741 marginal zone lymphomas (MZL), and 8,753 controls of European descent. Both DLBCL and MZL risk were elevated with homozygosity at class I HLA-B and -C loci (OR DLBCL=1.31, 95% CI=1.06-1.60; OR MZL=1.45, 95% CI=1.12-1.89) and class II HLA-DRB1 locus (OR DLBCL=2.10, 95% CI=1.24-3.55; OR MZL= 2.10, 95% CI=0.99-4.45). Increased FL risk was observed with the overall increase in number of homozygous HLA class II loci (p-trend<0.0001, FDR=0.0005). These results support a role for HLA zygosity in NHL etiology and suggests that distinct immune pathways may underly the etiology of the different NHL subtypes.
https://ift.tt/2jGUUZZ
Novel Richter's syndrome xenograft models to study genetic architecture, biology and therapy responses
Richter's syndrome (RS) represents the evolution of chronic lymphocytic leukemia into an aggressive tumor, most commonly diffuse large B cell lymphoma. The lack of in vitro and in vivo models has severely hampered drug testing in a disease that is poorly responsive to common chemo-immunotherapeutic combinations as well as to novel kinase inhibitors. Here we report for the first time the establishment and genomic characterization of two patient-derived tumor xenograft models of RS, RS9737 and RS1316. RS xenografts were genetically, morphologically and phenotypically stable and similar to the corresponding primary tumor. RS9737 was characterized by biallelic inactivation of CDKN2A and TP53, monoallelic deletion of 11q23 (ATM), and mutations of BTK, KRAS, EGR2, and NOTCH1. RS1316 carried trisomy 12 and showed mutations in BTK, KRAS, MED12, and NOTCH2. RNA sequencing confirmed that in both cases >80% of the transcriptome was shared between primary tumor and PDX. In line with the mutational profile, pathway analyses revealed over-activation of the B cell receptor, NF-kB, and NOTCH pathways in both tumors, potentially providing novel tumor targets. In conclusion, these two novel models of RS represent useful tools to study biology and response to therapies of this highly aggressive and still incurable tumor.
https://ift.tt/2wlPX1T
MicroRNA 339 promotes development of Stem Cell Leukemia/Lymphoma syndrome via downregulation of the BCL2L11 and BAX pro-apoptotic genes
Development of myeloid and lymphoid neoplasms related to overexpression of FGFR1 kinases as a result of chromosome translocations depends on promotion of a stem cell phenotype, suppression of terminal differentiation, and resistance to apoptosis. These phenotypes are related to the stem cell leukemia/lymphoma syndrome (SCLL), which arises through the effects of activated FGFR1 kinase on gene transcription, including dysregulation of microRNAs. In a screen for miRNAs that are directly regulated by FGFR1 and that stimulate cell proliferation and survival, we identified miR-339-5p, which is highly upregulated in cells carrying various different chimeric kinases. Overexpression of miR-339-5p in SCLL cell types enhanced cell survival, wherease inhibition of its function reduced cell viability. miR-339-5p overexpression also protected cells from the effects of FGFR1 inactivation, promoting cell cycle progression and reducing apoptosis. BCR-FGFR1 fusion directly regulated miR-339-5p expression in cells lines; this correlation between miR-339-5p and FGFR1 expression was also observed in primary human B cell precursor acute lymphoblastic leukemia. In a screen to identify targets of miR-339-5p, we identified and verified the pro-apoptotic genes BCL2L11 and BAX. In vivo, SCLL cells forced to overexpress miR-339-5p exhibited a more rapid onset of disease and poorer survival compared with cells expressing endogenous levels of miR-339-5p. Analysis of human primary B-cell precursor ALL showed significantly higher expression of miR339-5p compared with two cohorts of CLL patient samples, suggesting direct roles for miR339-5p in disease progression and supporting the evidence generated in mouse models of SCLL.
https://ift.tt/2rrOwtP
Mechanistic distinctions between CHK1 and WEE1 inhibition guide the scheduling of triple therapy with gemcitabine
Combination of cytotoxic therapy with emerging DNA damage response inhibitors (DDRi) has been limited by tolerability issues. However, the goal of most combination trials has been to administer DDRi with standard-of-care doses of chemotherapy. We hypothesised that mechanism-guided treatment scheduling could reduce the incidence of dose-limiting toxicities and enable tolerable multitherapeutic regimens. Integrative analyses of mathematical modelling and single-cell assays distinguished the synergy kinetics of WEE1i from CHK1i by potency, spatiotemporal perturbation, and mitotic effects when combined with gemcitabine. These divergent properties collectively supported a triple-agent strategy, whereby a pulse of gemcitabine and CHK1i followed by WEE1i durably suppressed tumour cell growth. In xenografts, CHK1i exaggerated replication stress without mitotic CDK hyperactivation, enriching a geminin-positive subpopulation and intratumoral gemcitabine metabolite. Without overt toxicity, addition of WEE1i to low-dose gemcitabine and CHK1i was most effective in tumour control compared to single and double agents. Overall, our work provides quantitative insights into the mechanisms of DDRi chemosensitisation, leading to the rational development of a tolerable multitherapeutic regimen.
https://ift.tt/2wlQvot
TNFRSF19 inhibits TGF{beta} signaling through interaction with TGF{beta} receptor type I to promote tumorigenesis
Genetic susceptibility underlies the pathogenesis of cancer. We and others have previously identified a novel susceptibility gene TNFRSF19, which encodes an orphan member of the TNF receptor superfamily known to be associated with nasopharyngeal carcinoma (NPC) and lung cancer risk. Here we show that TNFRSF19 is highly expressed in NPC and is required for cell proliferation and NPC development. However, unlike most of TNF receptors, TNFRSF19 was not involved in NF-κB activation or associated with TRAF proteins. We identified TGFβ receptor type-I (TβRI) as a specific binding partner for TNFRSF19. TNFRSF19 bound the kinase domain of TβRI in the cytoplasm, thereby blocking Smad2/3 association with TβRI and subsequent signal transduction. Ectopic expression of TNFRSF19 in normal epithelial cells conferred resistance to the cell cycle block induced by TGFβ, whereas knockout of TNFRSF19 in NPC cells unleashed a potent TGFβ response characterized by upregulation of Smad2/3 phosphorylation and TGFβ target gene transcription. Furthermore, elevated TNFRSF19 expression correlated with reduced TGFβ activity and poor prognosis in NPC patients. Our data reveal that gain-of-function of TNFRSF19 in NPC represents a mechanism by which tumor cells evade the growth-inhibitory action of TGFβ.
https://ift.tt/2rsy64h
Epigenetic regulation of CXCL12 plays a critical role in mediating tumor progression and the immune response in osteosarcoma
The mechanism by which osteosarcomas metastasize is elusive, and challenges remain regarding its treatment with modalities including immunotherapy. CXCL12 is deeply involved in the process of tumor metastasis and T-cell homing, which is driven by a chemokine gradient, but healthy bones are supposed to preferentially express CXCL12. Here we show for the first time that osteosarcomas epigenetically downregulate CXCL12 expression via DNA methyltransferase 1 (DNMT1) and consequently acquire the ability to metastasize and impair cytotoxic T-cell homing to the tumor site. Analysis of human osteosarcoma cases further revealed that CXCL12 expression strongly correlated with overall survival. Evaluations on fresh human chemotherapy-free osteosarcoma samples also showed a positive correlation between CXCL12 concentration and the number of intratumoral lymphocytes. Critically, treatment targeting DNMT1 in immunocompetent mouse models significantly elevated expression of CXCL12 in tumors, resulting in a robust immune response and consequently eradicating early lung metastases in addition to suppressing subcutaneous tumor growth. These antitumor effects were abrogated by CXCL12-CXCR4 blockade or CD8+ T-cell depletion. Collectively, our data show that CXCL12 regulation plays a significant role in both tumor progression and immune response, and targeting CXCL12 is promising for therapeutics against osteosarcoma.
https://ift.tt/2wkHGel
Long noncoding RNA AB074169 inhibits cell proliferation via modulation of KHSRP-mediated p21 expression in papillary thyroid carcinoma
Long noncoding RNAs (lncRNAs) are emerging as a novel class of regulators in gene expression associated with tumorigenesis. However, the role of lncRNAs in papillary thyroid carcinoma (PTC) is poorly understood. Here we conducted global lncRNA profiling and identified lncRNA AB074169 (lncAB) as significantly downregulated in PTC. Decreased expression of lncAB in PTC was caused by CpG hypermethylation within its gene promoter. Functional studies showed that lncAB overexpression led to cell cycle arrest and tumor growth inhibition in vitro and in vivo, whereas lncAB knockdown promoted cell proliferation. Mechanistic analyses revealed that lncAB bound KH-type splicing regulatory protein (KHSRP) and also decreased expression of KHSRP, thus increasing CDKN1a (p21) expression and decreasing CDK2 expression to repress cell proliferation. Taken together, these findings demonstrate that lncAB functions as a tumor suppressor during PTC tumorigenesis.
https://ift.tt/2jDUenW
Nuclear IGF-1R interacts with regulatory regions of chromatin to promote RNA polymerase II recruitment and gene expression associated with advanced tumor stage
Internalization of ligand-activated type 1 IGF receptor (IGF-1R) is followed by recycling to the plasma membrane, degradation or nuclear translocation. Nuclear IGF-1R reportedly associates with clinical response to IGF-1R inhibitory drugs, yet its role in the nucleus is poorly characterized. Here we investigated the significance of nuclear IGF-1R in clinical cancers and cell line models. In prostate cancers, IGF-1R was predominantly membrane-localized in benign glands, while malignant epithelium contained prominent internalized (nuclear/cytoplasmic) IGF-1R, and nuclear IGF-1R associated significantly with advanced tumor stage. Using ChIP-seq to assess global chromatin occupancy, we identified IGF-1R binding sites at or near transcription start sites of genes including JUN and FAM21, most sites coinciding with occupancy by RNA polymerase II (RNAPol2) and histone marks of active enhancers/promoters. IGF-1R was inducibly recruited to chromatin, directly binding DNA and interacting with RNAPol2 to upregulate expression of JUN and FAM21, shown to mediate tumor cell survival and IGF-induced migration. IGF-1 also enriched RNAPol2 on promoters containing IGF-1R binding sites. These functions were inhibited by IGF-1/2 neutralizing antibody xentuzumab (BI 836845), or by blocking receptor internalization. We detected nuclear IGF-1R on JUN and FAM21 promoters in fresh prostate cancers that contained abundant nuclear IGF-1R, with evidence of correlation between nuclear IGF-1R content and JUN expression in malignant prostatic epithelium. Taken together, these data reveal previously unrecognized molecular mechanisms through which IGFs promote tumorigenesis, with implications for therapeutic evaluation of anti-IGF drugs.
https://ift.tt/2wlKp7l
Loss of MED12 induces tumor dormancy in human epithelial ovarian cancer via downregulation of EGFR
A high rate of disease relapse makes epithelial ovarian cancer (EOC) the leading cause of death among all gynecological malignancies. These relapses are often due to tumor dormancy. Here we identify the RNA polymerase II transcriptional Mediator subunit 12 (MED12) as an important molecular regulator of tumor dormancy. MED12 knockout (KO) induced dormancy of EOC cells in vitro and in vivo, and microarray analysis showed that MED12 KO decreased expression of EGFR. Restoration of EGFR expression in MED12 KO cells restored proliferation. Additionally, MED12 bound to the promoter of EGFR, and correlation studies showed that MED12 expression positively correlated with EGFR expression in EOC patient samples. Clinical data demonstrated that chemotherapy-resistant patients expressed lower levels of MED12 compared to responsive patients. Overall, our data show that MED12 plays an important role in regulating dormancy of EOC through regulation of EGFR.
https://ift.tt/2rrATKW
RASSF1A Deficiency Enhances RAS-Driven Lung Tumorigenesis
Mutant K-RAS has been shown to have both tumor-promoting and -suppressing functions, and growing evidence suggests that the RASSF family of tumor suppressors can act as RAS apoptosis and senescence effectors. It has been hypothesized that inactivation of the RASSF1A tumor suppressor facilitates K-RAS–mediated transformation by uncoupling it from apoptotic pathways such as the Hippo pathway. In human lung tumors, combined activation of K-RAS and inactivation of RASSF1A is closely associated with the development of the most aggressive and worst prognosis tumors. Here, we describe the first transgenic mouse model for activation of K-RAS in the lung in a RASSF1A-defective background. RASSF1A deficiency profoundly enhanced the development of K-RAS–driven lung tumors in vivo. Analysis of these tumors showed loss of RASSF1A-uncoupled RAS from the proapoptotic Hippo pathway as expected. We also observed an upregulation of AKT and RALGEF signaling in the RASSF1A− tumors. Heterozygosity of RASSF1A alone mimicked many of the effects of RAS activation on mitogenic signaling in lung tissue, yet no tumors developed, indicating that nonstandard Ras signaling pathways may be playing a key role in tumor formation in vivo. In addition, we observed a marked increase in inflammation and IL6 production in RASSF1A-deficient tumors. Thus, RASSF1A loss profoundly affects RAS-driven lung tumorigenesis and mitogenic signaling in vivo. Deregulation of inflammatory pathways due to loss of RASSF1A may be essential for RAS-mediated tumorigenesis. These results may have considerable ramifications for future targeted therapy against RAS+/RASSF1A− tumors.Significance: A transgenic mouse model shows that suppression of RASSF1A dramatically enhances Ras-driven tumorigenesis and alters Ras signaling pathway activity. Cancer Res; 78(10); 1–10. ©2018 AACR. F1
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PML Recruits TET2 to Regulate DNA Modification and Cell Proliferation in Response to Chemotherapeutic Agent
Aberrant DNA methylation plays a critical role in the development and progression of cancer. Failure to demethylate and to consequently reactivate methylation-silenced genes in cancer contributes to chemotherapeutic resistance, yet the regulatory mechanisms of DNA demethylation in response to chemotherapeutic agents remain unclear. Here, we show that promyelocytic leukemia (PML) recruits ten–eleven translocation dioxygenase 2 (TET2) to regulate DNA modification and cell proliferation in response to chemotherapeutic agents. TET2 was required by multiple chemotherapeutic agents (such as doxorubicin) to promote 5-hydroxymethylcytosine (5hmC) formation. Stable isotope labeling with amino acids in cell culture, followed by immunoprecipitation–mass spectrometry, identified potential binding partners of TET2, of which PML mostly enhanced 5hmC formation. PML physically bound to TET2 via the PML C-terminal domain and recruited TET2 to PML-positive nuclear bodies. This interaction was disrupted by the PML-RARA t(15;17) mutation, which stems from chromosomal translocation between DNA encoding the C-terminal domain of PML and the retinoic acid receptor alpha (RARA) gene. In response to chemotherapeutic drugs, PML recruited TET2, regulated DNA modification, reactivated methylation-silenced genes, and impaired cell proliferation. Knockout of PML abolished doxorubicin-promoted DNA modification. In addition, PML and TET2 levels positively correlated with improved overall survival in patients with head and neck cancer. These findings shed insight into the regulatory mechanisms of DNA modification in response to chemotherapeutic agents.Significance: Promyeloctic leukemia protein recruits TET2, regulating DNA modification and cell proliferation in response to chemotherapeutic agents. Cancer Res; 78(10); 1–15. ©2018 AACR.
https://ift.tt/2jEyrfW
Loss of MED12 induces tumor dormancy in human epithelial ovarian cancer via downregulation of EGFR
A high rate of disease relapse makes epithelial ovarian cancer (EOC) the leading cause of death among all gynecological malignancies. These relapses are often due to tumor dormancy. Here we identify the RNA polymerase II transcriptional Mediator subunit 12 (MED12) as an important molecular regulator of tumor dormancy. MED12 knockout (KO) induced dormancy of EOC cells in vitro and in vivo, and microarray analysis showed that MED12 KO decreased expression of EGFR. Restoration of EGFR expression in MED12 KO cells restored proliferation. Additionally, MED12 bound to the promoter of EGFR, and correlation studies showed that MED12 expression positively correlated with EGFR expression in EOC patient samples. Clinical data demonstrated that chemotherapy-resistant patients expressed lower levels of MED12 compared to responsive patients. Overall, our data show that MED12 plays an important role in regulating dormancy of EOC through regulation of EGFR.
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Mechanistic distinctions between CHK1 and WEE1 inhibition guide the scheduling of triple therapy with gemcitabine
Combination of cytotoxic therapy with emerging DNA damage response inhibitors (DDRi) has been limited by tolerability issues. However, the goal of most combination trials has been to administer DDRi with standard-of-care doses of chemotherapy. We hypothesised that mechanism-guided treatment scheduling could reduce the incidence of dose-limiting toxicities and enable tolerable multitherapeutic regimens. Integrative analyses of mathematical modelling and single-cell assays distinguished the synergy kinetics of WEE1i from CHK1i by potency, spatiotemporal perturbation, and mitotic effects when combined with gemcitabine. These divergent properties collectively supported a triple-agent strategy, whereby a pulse of gemcitabine and CHK1i followed by WEE1i durably suppressed tumour cell growth. In xenografts, CHK1i exaggerated replication stress without mitotic CDK hyperactivation, enriching a geminin-positive subpopulation and intratumoral gemcitabine metabolite. Without overt toxicity, addition of WEE1i to low-dose gemcitabine and CHK1i was most effective in tumour control compared to single and double agents. Overall, our work provides quantitative insights into the mechanisms of DDRi chemosensitisation, leading to the rational development of a tolerable multitherapeutic regimen.
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miRNA profiling of magnetic nanopore-isolated extracellular vesicles for the diagnosis of pancreatic cancer
Improved diagnostics for pancreatic ductal adenocarcinoma (PDAC) to detect the disease at earlier, curative stages and to guide treatments is crucial to progress against this disease. The development of a liquid biopsy for PDAC has proven challenging due to the sparsity and variable phenotypic expression of circulating biomarkers. Here we report methods we developed for isolating specific subsets of extracellular vesicles (EV) from plasma using a novel magnetic nanopore capture technique. In addition, we present a workflow for identifying EV miRNA biomarkers using RNA sequencing and machine-learning algorithms, which we used in combination to classify distinct cancer states. Applying this approach to a mouse model of PDAC, we identified a biomarker panel of 11 EV miRNAs that could distinguish mice with PDAC from either healthy mice or those with pre-cancerous lesions in a training set of N = 27 mice and a user-blinded validation set of N = 57 mice (88% accuracy in a three-way classification). These results provide strong proof-of-concept support for the feasibility of using EV miRNA profiling and machine learning for liquid biopsy.
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Optimized dosing schedule based on circadian dynamics of mouse breast cancer stem cells improves the anti-tumor effects of aldehyde dehydrogenase
Although malignant phenotypes of triple-negative breast cancer (TNBC) are subject to circadian alterations, the role of cancer stem cells (CSC) in defining this circadian change remains unclear. CSC are often characterized by high aldehyde dehydrogenase (ALDH) activity, which is associated with the malignancy of cancer cells and used for identification and isolation of CSC. Here we show that the popultation of ALDH-positive cells in a mouse 4T1 breast tumor model exhibits pronounced circadian alterations. Alterations in the number of ALDH-positive cells was generated by time-dependent increases and decreases in the expression of Aldh3a1. Importantly, circadian clock genes were rhythmically expressed in ALDH-negative cells, but not in ALDH-positive cells. Circadian expression of Aldh3a1 in ALDH-positive cells was dependent on the time-dependent release of Wingless-type mmtv integration site family 10a (WNT10a) from ALDH-negative cells. Furthermore, anti-tumor and anti-metastatic effects of ALDH inhibitor N,N-diethylaminobenzaldehyde were enhanced by administration at the time of day when ALDH activity was increased in 4T1 tumor cells. Our findings reveal a new role for the circadian clock within the tumor microenvironment in regulating the circadian dynamics of CSC. These results should enable the development of novel therapeutic strategies for treatment of TNBC with ALDH inhibitors.
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HLA class I and II diversity contributes to the etiologic heterogeneity of non-Hodgkin lymphoma subtypes
A growing number of loci within the human leukocyte antigen (HLA) region have been implicated in non-Hodgkin lymphoma (NHL) etiology. Here, we test a complementary hypothesis of "heterozygote advantage" regarding the role of HLA and NHL, whereby HLA diversity is beneficial and homozygous HLA loci are associated with increased disease risk. HLA alleles at class I and II loci were imputed from genome-wide association studies (GWAS) using SNP2HLA for: 3,617 diffuse large B-cell lymphomas (DLBCL), 2,686 follicular lymphomas (FL), 2,878 chronic lymphocytic leukemia/small lymphocytic lymphomas (CLL/SLL), 741 marginal zone lymphomas (MZL), and 8,753 controls of European descent. Both DLBCL and MZL risk were elevated with homozygosity at class I HLA-B and -C loci (OR DLBCL=1.31, 95% CI=1.06-1.60; OR MZL=1.45, 95% CI=1.12-1.89) and class II HLA-DRB1 locus (OR DLBCL=2.10, 95% CI=1.24-3.55; OR MZL= 2.10, 95% CI=0.99-4.45). Increased FL risk was observed with the overall increase in number of homozygous HLA class II loci (p-trend<0.0001, FDR=0.0005). These results support a role for HLA zygosity in NHL etiology and suggests that distinct immune pathways may underly the etiology of the different NHL subtypes.
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Novel Richter's syndrome xenograft models to study genetic architecture, biology and therapy responses
Richter's syndrome (RS) represents the evolution of chronic lymphocytic leukemia into an aggressive tumor, most commonly diffuse large B cell lymphoma. The lack of in vitro and in vivo models has severely hampered drug testing in a disease that is poorly responsive to common chemo-immunotherapeutic combinations as well as to novel kinase inhibitors. Here we report for the first time the establishment and genomic characterization of two patient-derived tumor xenograft models of RS, RS9737 and RS1316. RS xenografts were genetically, morphologically and phenotypically stable and similar to the corresponding primary tumor. RS9737 was characterized by biallelic inactivation of CDKN2A and TP53, monoallelic deletion of 11q23 (ATM), and mutations of BTK, KRAS, EGR2, and NOTCH1. RS1316 carried trisomy 12 and showed mutations in BTK, KRAS, MED12, and NOTCH2. RNA sequencing confirmed that in both cases >80% of the transcriptome was shared between primary tumor and PDX. In line with the mutational profile, pathway analyses revealed over-activation of the B cell receptor, NF-kB, and NOTCH pathways in both tumors, potentially providing novel tumor targets. In conclusion, these two novel models of RS represent useful tools to study biology and response to therapies of this highly aggressive and still incurable tumor.
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MicroRNA 339 promotes development of Stem Cell Leukemia/Lymphoma syndrome via downregulation of the BCL2L11 and BAX pro-apoptotic genes
Development of myeloid and lymphoid neoplasms related to overexpression of FGFR1 kinases as a result of chromosome translocations depends on promotion of a stem cell phenotype, suppression of terminal differentiation, and resistance to apoptosis. These phenotypes are related to the stem cell leukemia/lymphoma syndrome (SCLL), which arises through the effects of activated FGFR1 kinase on gene transcription, including dysregulation of microRNAs. In a screen for miRNAs that are directly regulated by FGFR1 and that stimulate cell proliferation and survival, we identified miR-339-5p, which is highly upregulated in cells carrying various different chimeric kinases. Overexpression of miR-339-5p in SCLL cell types enhanced cell survival, wherease inhibition of its function reduced cell viability. miR-339-5p overexpression also protected cells from the effects of FGFR1 inactivation, promoting cell cycle progression and reducing apoptosis. BCR-FGFR1 fusion directly regulated miR-339-5p expression in cells lines; this correlation between miR-339-5p and FGFR1 expression was also observed in primary human B cell precursor acute lymphoblastic leukemia. In a screen to identify targets of miR-339-5p, we identified and verified the pro-apoptotic genes BCL2L11 and BAX. In vivo, SCLL cells forced to overexpress miR-339-5p exhibited a more rapid onset of disease and poorer survival compared with cells expressing endogenous levels of miR-339-5p. Analysis of human primary B-cell precursor ALL showed significantly higher expression of miR339-5p compared with two cohorts of CLL patient samples, suggesting direct roles for miR339-5p in disease progression and supporting the evidence generated in mouse models of SCLL.
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TNFRSF19 inhibits TGF{beta} signaling through interaction with TGF{beta} receptor type I to promote tumorigenesis
Genetic susceptibility underlies the pathogenesis of cancer. We and others have previously identified a novel susceptibility gene TNFRSF19, which encodes an orphan member of the TNF receptor superfamily known to be associated with nasopharyngeal carcinoma (NPC) and lung cancer risk. Here we show that TNFRSF19 is highly expressed in NPC and is required for cell proliferation and NPC development. However, unlike most of TNF receptors, TNFRSF19 was not involved in NF-κB activation or associated with TRAF proteins. We identified TGFβ receptor type-I (TβRI) as a specific binding partner for TNFRSF19. TNFRSF19 bound the kinase domain of TβRI in the cytoplasm, thereby blocking Smad2/3 association with TβRI and subsequent signal transduction. Ectopic expression of TNFRSF19 in normal epithelial cells conferred resistance to the cell cycle block induced by TGFβ, whereas knockout of TNFRSF19 in NPC cells unleashed a potent TGFβ response characterized by upregulation of Smad2/3 phosphorylation and TGFβ target gene transcription. Furthermore, elevated TNFRSF19 expression correlated with reduced TGFβ activity and poor prognosis in NPC patients. Our data reveal that gain-of-function of TNFRSF19 in NPC represents a mechanism by which tumor cells evade the growth-inhibitory action of TGFβ.
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Epigenetic regulation of CXCL12 plays a critical role in mediating tumor progression and the immune response in osteosarcoma
The mechanism by which osteosarcomas metastasize is elusive, and challenges remain regarding its treatment with modalities including immunotherapy. CXCL12 is deeply involved in the process of tumor metastasis and T-cell homing, which is driven by a chemokine gradient, but healthy bones are supposed to preferentially express CXCL12. Here we show for the first time that osteosarcomas epigenetically downregulate CXCL12 expression via DNA methyltransferase 1 (DNMT1) and consequently acquire the ability to metastasize and impair cytotoxic T-cell homing to the tumor site. Analysis of human osteosarcoma cases further revealed that CXCL12 expression strongly correlated with overall survival. Evaluations on fresh human chemotherapy-free osteosarcoma samples also showed a positive correlation between CXCL12 concentration and the number of intratumoral lymphocytes. Critically, treatment targeting DNMT1 in immunocompetent mouse models significantly elevated expression of CXCL12 in tumors, resulting in a robust immune response and consequently eradicating early lung metastases in addition to suppressing subcutaneous tumor growth. These antitumor effects were abrogated by CXCL12-CXCR4 blockade or CD8+ T-cell depletion. Collectively, our data show that CXCL12 regulation plays a significant role in both tumor progression and immune response, and targeting CXCL12 is promising for therapeutics against osteosarcoma.
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Long noncoding RNA AB074169 inhibits cell proliferation via modulation of KHSRP-mediated p21 expression in papillary thyroid carcinoma
Long noncoding RNAs (lncRNAs) are emerging as a novel class of regulators in gene expression associated with tumorigenesis. However, the role of lncRNAs in papillary thyroid carcinoma (PTC) is poorly understood. Here we conducted global lncRNA profiling and identified lncRNA AB074169 (lncAB) as significantly downregulated in PTC. Decreased expression of lncAB in PTC was caused by CpG hypermethylation within its gene promoter. Functional studies showed that lncAB overexpression led to cell cycle arrest and tumor growth inhibition in vitro and in vivo, whereas lncAB knockdown promoted cell proliferation. Mechanistic analyses revealed that lncAB bound KH-type splicing regulatory protein (KHSRP) and also decreased expression of KHSRP, thus increasing CDKN1a (p21) expression and decreasing CDK2 expression to repress cell proliferation. Taken together, these findings demonstrate that lncAB functions as a tumor suppressor during PTC tumorigenesis.
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Nuclear IGF-1R interacts with regulatory regions of chromatin to promote RNA polymerase II recruitment and gene expression associated with advanced tumor stage
Internalization of ligand-activated type 1 IGF receptor (IGF-1R) is followed by recycling to the plasma membrane, degradation or nuclear translocation. Nuclear IGF-1R reportedly associates with clinical response to IGF-1R inhibitory drugs, yet its role in the nucleus is poorly characterized. Here we investigated the significance of nuclear IGF-1R in clinical cancers and cell line models. In prostate cancers, IGF-1R was predominantly membrane-localized in benign glands, while malignant epithelium contained prominent internalized (nuclear/cytoplasmic) IGF-1R, and nuclear IGF-1R associated significantly with advanced tumor stage. Using ChIP-seq to assess global chromatin occupancy, we identified IGF-1R binding sites at or near transcription start sites of genes including JUN and FAM21, most sites coinciding with occupancy by RNA polymerase II (RNAPol2) and histone marks of active enhancers/promoters. IGF-1R was inducibly recruited to chromatin, directly binding DNA and interacting with RNAPol2 to upregulate expression of JUN and FAM21, shown to mediate tumor cell survival and IGF-induced migration. IGF-1 also enriched RNAPol2 on promoters containing IGF-1R binding sites. These functions were inhibited by IGF-1/2 neutralizing antibody xentuzumab (BI 836845), or by blocking receptor internalization. We detected nuclear IGF-1R on JUN and FAM21 promoters in fresh prostate cancers that contained abundant nuclear IGF-1R, with evidence of correlation between nuclear IGF-1R content and JUN expression in malignant prostatic epithelium. Taken together, these data reveal previously unrecognized molecular mechanisms through which IGFs promote tumorigenesis, with implications for therapeutic evaluation of anti-IGF drugs.
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RASSF1A Deficiency Enhances RAS-Driven Lung Tumorigenesis
Mutant K-RAS has been shown to have both tumor-promoting and -suppressing functions, and growing evidence suggests that the RASSF family of tumor suppressors can act as RAS apoptosis and senescence effectors. It has been hypothesized that inactivation of the RASSF1A tumor suppressor facilitates K-RAS–mediated transformation by uncoupling it from apoptotic pathways such as the Hippo pathway. In human lung tumors, combined activation of K-RAS and inactivation of RASSF1A is closely associated with the development of the most aggressive and worst prognosis tumors. Here, we describe the first transgenic mouse model for activation of K-RAS in the lung in a RASSF1A-defective background. RASSF1A deficiency profoundly enhanced the development of K-RAS–driven lung tumors in vivo. Analysis of these tumors showed loss of RASSF1A-uncoupled RAS from the proapoptotic Hippo pathway as expected. We also observed an upregulation of AKT and RALGEF signaling in the RASSF1A− tumors. Heterozygosity of RASSF1A alone mimicked many of the effects of RAS activation on mitogenic signaling in lung tissue, yet no tumors developed, indicating that nonstandard Ras signaling pathways may be playing a key role in tumor formation in vivo. In addition, we observed a marked increase in inflammation and IL6 production in RASSF1A-deficient tumors. Thus, RASSF1A loss profoundly affects RAS-driven lung tumorigenesis and mitogenic signaling in vivo. Deregulation of inflammatory pathways due to loss of RASSF1A may be essential for RAS-mediated tumorigenesis. These results may have considerable ramifications for future targeted therapy against RAS+/RASSF1A− tumors.Significance: A transgenic mouse model shows that suppression of RASSF1A dramatically enhances Ras-driven tumorigenesis and alters Ras signaling pathway activity. Cancer Res; 78(10); 1–10. ©2018 AACR. F1
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PML Recruits TET2 to Regulate DNA Modification and Cell Proliferation in Response to Chemotherapeutic Agent
Aberrant DNA methylation plays a critical role in the development and progression of cancer. Failure to demethylate and to consequently reactivate methylation-silenced genes in cancer contributes to chemotherapeutic resistance, yet the regulatory mechanisms of DNA demethylation in response to chemotherapeutic agents remain unclear. Here, we show that promyelocytic leukemia (PML) recruits ten–eleven translocation dioxygenase 2 (TET2) to regulate DNA modification and cell proliferation in response to chemotherapeutic agents. TET2 was required by multiple chemotherapeutic agents (such as doxorubicin) to promote 5-hydroxymethylcytosine (5hmC) formation. Stable isotope labeling with amino acids in cell culture, followed by immunoprecipitation–mass spectrometry, identified potential binding partners of TET2, of which PML mostly enhanced 5hmC formation. PML physically bound to TET2 via the PML C-terminal domain and recruited TET2 to PML-positive nuclear bodies. This interaction was disrupted by the PML-RARA t(15;17) mutation, which stems from chromosomal translocation between DNA encoding the C-terminal domain of PML and the retinoic acid receptor alpha (RARA) gene. In response to chemotherapeutic drugs, PML recruited TET2, regulated DNA modification, reactivated methylation-silenced genes, and impaired cell proliferation. Knockout of PML abolished doxorubicin-promoted DNA modification. In addition, PML and TET2 levels positively correlated with improved overall survival in patients with head and neck cancer. These findings shed insight into the regulatory mechanisms of DNA modification in response to chemotherapeutic agents.Significance: Promyeloctic leukemia protein recruits TET2, regulating DNA modification and cell proliferation in response to chemotherapeutic agents. Cancer Res; 78(10); 1–15. ©2018 AACR.
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Long-term Cardiovascular Outcomes Among Endometrial Cancer Survivors in a Large, Population-Based Cohort Study
Abstract
Background
Endometrial cancer is the second most common cancer among female cancer survivors in the United States. Cardiovascular disease is the leading cause of death among endometrial cancer survivors. Studies that examine long-term cardiovascular outcomes among endometrial cancer survivors are critical. Methods
Cohorts of 2648 endometrial cancer survivors diagnosed between 1997 and 2012 and 10 503 age-matched women from the general population were identified. Cardiovascular disease diagnoses were identified from electronic medical records and statewide ambulatory surgery and statewide inpatient data. Cox regression models were used to estimate hazard ratios (HRs) at one to five years, more than five to 10 years, and more than 10 years after cancer diagnosis. Results
Between one and five years after diagnosis, increased cardiovascular risks among endometrial cancer survivors were observed for phlebitis, thrombophlebitis, and thromboembolism (HR = 2.07, 99% confidence interval [CI] = 1.57 to 2.72), pulmonary heart disease (HR = 1.74, 99% CI = 1.26 to 2.40), and atrial fibrillation (HR = 1.50, 99% CI = 1.07 to 2.11). At more than five to 10 years, some elevated risk persisted for cardiovascular diseases. Compared with patients who had surgery, patients who additionally had radiation therapy and/or chemotherapy were at increased risk for heart and circulatory system disorders between one and five years after cancer diagnosis. Older age and obesity were also risk factors for hypertension and heart disease among endometrial cancer survivors. Conclusions
Endometrial cancer survivors are at higher risk for various adverse long-term cardiovascular outcomes compared with women from the general population. This study suggests that increased monitoring for cardiovascular diseases may be necessary for endometrial cancer patients for 10 years after cancer diagnosis.https://ift.tt/2KGC8hs
The management of adolescents and young adults with cancer
Source:Cancer Treatment Reviews
Author(s): Nicola Hughes, Dan Stark
Adolescents and Young Adults (AYA) with cancer are young people developing serious illness when at the interface between the responsibilities of paediatric and adult cancer services. Personally, they are in a period of transition both biologically and in major social roles[1]. For these and other reasons they present a unique set of clinical challenges in their management. Over the last 20 years the requirement for specific services to address their needs has been identified and this has become a growing field of research. Despite this survival rates still lag behind those of children and older adults with cancer[2].Why do AYA patients have worse outcomes? The observation is that the reason is multifactorial with path to diagnosis, unique cancer biology, uncertainty of treatment protocol, compliance issues and poor recruitment to clinical trials all playing a part. In this review we will discuss the unique challenges faced by healthcare professionals when managing AYA patients who are commonly and accurately described as being in an 'interface' position.
https://ift.tt/2rwmvR8
Clinical implications of the non-luminal intrinsic subtypes in hormone receptor-positive breast cancer
Publication date: Available online 7 May 2018
Source:Cancer Treatment Reviews
Author(s): Juan Miguel Cejalvo, Tomás Pascual, Aranzazu Fernández-Martínez, Fara Brasó-Maristany, Roger R. Gomis, Charles M. Perou, Montserrat Muñoz, Aleix Prat
Gene expression profiling has had a considerable impact on our understanding ofbreastcancer biology. Duringthelast decade, 4 intrinsic molecular subtypes of breast cancer (Luminal A, Luminal B, HER2-enriched [HER2-E] and Basal-like) have been identified and intensively studied. In this article, we review and discuss the clinical implications of the 2 non-luminal subtypes (i.e. HER2-E and Basal-like) identified within hormone receptor (HR)-positive disease. After reviewing 32 studies for a total of 13,091 samples, ∼8% and ∼15% of early and metastatic HR+/HER2-negative breast cancer, respectively, were found to be non-luminal. Clinically, HR+/HER2-negative/non-luminal subtypes have been associated with estrogen independence, chemo-sensitivity, resistance to CDK4/6 inhibition and poor outcome. Interestingly, EGFR/HER2 tyrosine kinase inhibition might be of value in the HR+/HER2-negative/HER2-E subtype. Finally, the HER2-E subtype within HR+/HER2+ disease represents ∼30% and has been associated with anti-HER2 sensitivity, chemo-sensitivity and resistance to CDK4/6 inhibition. In the upcoming years, retrospective and prospective clinical trials evaluating both biomarkers should lead to improvements in patient outcomes.
https://ift.tt/2KLhxsq
CTLA-4 gene variant -1661A>G may predict the onset of endocrine adverse events in metastatic melanoma patients treated with ipilimumab
Source:European Journal of Cancer
Author(s): Paola Queirolo, Beatrice Dozin, Anna Morabito, Barbara Banelli, Roberta Carosio, Vincenzo Fontana, Pier Francesco Ferrucci, Chiara Martinoli, Emilia Cocorocchio, Paolo A. Ascierto, Gabriele Madonna, Ester Simeone, Federica De Galitiis, Gian Carlo Antonini Cappellini, Paolo Marchetti, Michele Guida, Stefania Tommasi, Laura Ghilardi, Barbara Merelli, Paolo Fava, Simona Osella-Abate, Massimo Guidoboni, Massimo Romani, Diego Ferone, Francesco Spagnolo, Maria Pia Pistillo
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The Flavonoid Apigenin Is a Progesterone Receptor Modulator with In Vivo Activity in the Uterus
Abstract
Apigenin is a flavonoid with well-documented anti-cancer properties; however, its mechanisms of action are still unclear. We previously identified apigenin as a potential phytoprogestin, a natural product with a chemical scaffold that interacts with the progesterone receptor (PR). Our objective was to characterize the ability of apigenin to interact with PR through molecular docking studies, in vitro activity assays, and the ability of apigenin to elicit progestin-like effects in vivo. Molecular docking confirmed that apigenin could interact with PR, though with lower affinity than progesterone due to fewer van der Waals interactions. In Ishikawa cells stably expressing PR-B, apigenin significantly increased progesterone response element/luciferase (PRE/Luc) activity at 5 and 10 μM, but not in the parental Ishikawa cells that lack PR expression. In the presence of 100 nM of progesterone, 10 μM apigenin reduced PRE/Luc activity, indicative of mixed agonist activity. Apigenin also triggered degradation of PR in Ishikawa PR-B cells as measured by western blot. Apigenin reduced proliferation of Ishikawa cells, but through a PR-independent mechanism. In contrast, apigenin and progesterone both stimulated proliferation of T47D cells, an effect blocked by RU486. Apigenin activated other nuclear receptors evidenced by increased luciferase activity in MDA-MB-231 cells, which are PR negative. In vivo, apigenin blocked the genistein-stimulated increase in uterine epithelial cell height; stimulated endometrial expression of Hand2, a transcription factor stimulated by PR, and significantly reduced genistein-induced proliferation. In summary, apigenin is a phytoprogestin, with mixed agonist activity that demonstrates activity in vivo by hindering estrogen receptor-mediated uterine proliferation.
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The Impact of ESR1 Mutations on the Treatment of Metastatic Breast Cancer
Abstract
After nearly 20 years of research, it is now established that mutations within the estrogen receptor (ER) gene, ESR1, frequently occur in metastatic breast cancer and influence response to hormone therapy. Though early studies presented differing results, sensitive sequencing techniques now show that ESR1 mutations occur at a frequency between 20 and 40% depending on the assay method. Recent studies have focused on several "hot spot mutations," a cluster of mutations found in the hormone-binding domain of the ESR1 gene. Throughout the course of treatment, tumor evolution can occur, and ESR1 mutations emerge and become enriched in the metastatic setting. Sensitive techniques to continually monitor mutant burden in vivo are needed to effectively treat patients with mutant ESR1. The full impact of these mutations on tumor response to different therapies remains to be determined. However, recent studies indicate that mutant-bearing tumors may be less responsive to specific hormonal therapies, and suggest that aromatase inhibitor (AI) therapy may select for the emergence of ESR1 mutations. Additionally, different mutations may respond discretely to targeted therapies. The need for more preclinical mechanistic studies on ESR1 mutations and the development of better agents to target these mutations are urgently needed. In the future, sequential monitoring of ESR1 mutational status will likely direct personalized therapeutic regimens appropriate to each tumor's unique mutational landscape.
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The Flavonoid Apigenin Is a Progesterone Receptor Modulator with In Vivo Activity in the Uterus
Abstract
Apigenin is a flavonoid with well-documented anti-cancer properties; however, its mechanisms of action are still unclear. We previously identified apigenin as a potential phytoprogestin, a natural product with a chemical scaffold that interacts with the progesterone receptor (PR). Our objective was to characterize the ability of apigenin to interact with PR through molecular docking studies, in vitro activity assays, and the ability of apigenin to elicit progestin-like effects in vivo. Molecular docking confirmed that apigenin could interact with PR, though with lower affinity than progesterone due to fewer van der Waals interactions. In Ishikawa cells stably expressing PR-B, apigenin significantly increased progesterone response element/luciferase (PRE/Luc) activity at 5 and 10 μM, but not in the parental Ishikawa cells that lack PR expression. In the presence of 100 nM of progesterone, 10 μM apigenin reduced PRE/Luc activity, indicative of mixed agonist activity. Apigenin also triggered degradation of PR in Ishikawa PR-B cells as measured by western blot. Apigenin reduced proliferation of Ishikawa cells, but through a PR-independent mechanism. In contrast, apigenin and progesterone both stimulated proliferation of T47D cells, an effect blocked by RU486. Apigenin activated other nuclear receptors evidenced by increased luciferase activity in MDA-MB-231 cells, which are PR negative. In vivo, apigenin blocked the genistein-stimulated increase in uterine epithelial cell height; stimulated endometrial expression of Hand2, a transcription factor stimulated by PR, and significantly reduced genistein-induced proliferation. In summary, apigenin is a phytoprogestin, with mixed agonist activity that demonstrates activity in vivo by hindering estrogen receptor-mediated uterine proliferation.
https://ift.tt/2FQkkNj
The Impact of ESR1 Mutations on the Treatment of Metastatic Breast Cancer
Abstract
After nearly 20 years of research, it is now established that mutations within the estrogen receptor (ER) gene, ESR1, frequently occur in metastatic breast cancer and influence response to hormone therapy. Though early studies presented differing results, sensitive sequencing techniques now show that ESR1 mutations occur at a frequency between 20 and 40% depending on the assay method. Recent studies have focused on several "hot spot mutations," a cluster of mutations found in the hormone-binding domain of the ESR1 gene. Throughout the course of treatment, tumor evolution can occur, and ESR1 mutations emerge and become enriched in the metastatic setting. Sensitive techniques to continually monitor mutant burden in vivo are needed to effectively treat patients with mutant ESR1. The full impact of these mutations on tumor response to different therapies remains to be determined. However, recent studies indicate that mutant-bearing tumors may be less responsive to specific hormonal therapies, and suggest that aromatase inhibitor (AI) therapy may select for the emergence of ESR1 mutations. Additionally, different mutations may respond discretely to targeted therapies. The need for more preclinical mechanistic studies on ESR1 mutations and the development of better agents to target these mutations are urgently needed. In the future, sequential monitoring of ESR1 mutational status will likely direct personalized therapeutic regimens appropriate to each tumor's unique mutational landscape.
https://ift.tt/2jEcTQA
Is prophylactic cranial irradiation indicated for patients with extensive-stage small cell lung cancer with a complete response to first-line treatment?
Prophylactic cranial irradiation (PCI) has been considered standard of care for patients with limited-stage small-cell lung cancer who achieve complete response to definitive treatment after a meta-analysis revealed its favorable effects on survival. In a European trial, PCI was also shown to confer a survival advantage for patients with extensive-stage (ES) SCLC who experienced any positive response after initial chemotherapy, leading to PCI also being considered a standard treatment for these patients as well.
https://ift.tt/2I0r652
Assessment of image quality of a radiotherapy-specific hardware solution for PET/MRI in head and neck cancer patients
Functional PET/MRI has great potential to improve radiotherapy planning (RTP). However, data integration requires imaging with radiotherapy-specific patient positioning. Here, we investigated the feasibility and image quality of radiotherapy-customized PET/MRI in head-and-neck cancer (HNC) patients using a dedicated hardware setup.
https://ift.tt/2jJ9tMF
Is prophylactic cranial irradiation (PCI) needed in patients with extensive-stage small cell lung cancer showing complete response to first-line chemotherapy?
Throughout the entire world, prophylactic cranial irradiation (PCI) is the standard care for patients with small cell lung cancer (SCLC) in whom a favorable therapeutic effect is achieved after front-line treatment, regardless of whether the disease is in the limited stage or extensive stage. In the EORTC study, PCI was shown to confer a survival benefit for patients with extensive-stage small cell lung cancer (ES-SCLC) who experienced any positive response after initial chemotherapy. However, the Japan study failed to confirm a survival benefit.
https://ift.tt/2I2iNpa
Urothelial carcinoma in children: A case series.
| Related Articles |
Urothelial carcinoma in children: A case series.
Bull Cancer. 2018 Apr 30;:
Authors: Marinoni F, Destro F, Selvaggio GGO, Riccipetitoni G
Abstract
OBJECTIVE: To report a series of 5 patients with urothelial bladder cancer (UBC) three of them with a history of exposure to amines and only two with gross hematuria.
MATERIALS AND METHODS: After obtaining ethical and legal authorization, we performed a restrospective monocentric study. We collected information of patients with UBC over a period of 10 years. We recorded: age, sex, reason for presentation, familial history and risk factors, preoperative assessment, surgical details, histological type and grade, follow-up.
RESULTS: 2 children came to our attention for hematuria and 3 for incidental bladder mass finding, at a median age of 11.8 years. We performed microscopically complete transurethral resection of the tumor (TURB). Median tumor size was 1.8cm. No further therapy was required. All cancers belonged to NMIBC (Non-muscle-invasive Bladder Cancer) considering the 2004 WHO classification: 2 urothelial papillomas, 2 papillary tumors with low grade malignancy (PUN-LPM) and 1 papillary urothelial carcinoma of low histological grade (LG-PUC Ta, N0, M0). There was not any complications and no relapse occurred during follow-up (median 30 months).
CONCLUSIONS: In this study, UBCs presenting at a young age were low-grade and have not recurred in follow-up. This confirms the results of other series reported in Literature. Therefore there might be the space to perform a follow-up dedicated to children.
PMID: 29724585 [PubMed - as supplied by publisher]
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Exercise attenuates age-associated changes in motoneuron number, nucleocytoplasmic transport proteins and neuromuscular health
Abstract
Life expectancy continues to extend, although frailty caused by loss of skeletal muscle mass continues unimpeded. Muscle atrophy caused by withdrawal of motor nerves is a feature of old age, as it is in amyotrophic lateral sclerosis (ALS) in which skeletal muscle denervation results from motoneuron death. In ALS, direct links have been established between motoneuron death and altered nucleocytoplasmic transport, so we ask whether similar defects accompany motoneuron death in normal ageing. We used immunohistochemistry on mouse tissues to explore potential links between neuromuscular junction (NMJ) degeneration, motoneuron death and nucleocytoplasmic transport regulatory proteins. Old age brought neuromuscular degeneration, motoneuron loss and reductions in immunodetectable levels of key nucleocytoplasmic transport proteins in lumbar motoneurons. We then asked whether exercise inhibited these changes and found that active elderly mice experienced less motoneuron death, improved neuromuscular junction morphology and retention of key nucleocytoplasmic transport proteins in lumbar motoneurons. Our results suggest that emergent defects in nucleocytoplasmic transport may contribute to motoneuron death and age-related loss of skeletal muscle mass, and that these defects may be reduced by exercise.
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Quality, Readability, and Understandability of German Booklets Addressing Melanoma Patients
Abstract
Booklets are the preferably used form among patient education materials and are often handed out during medical consultations in dermatological oncology settings. However, little is known about how beneficial they are and whether they correspond to essential quality characteristics. To assess the quality, readability, and understandability of currently freely available booklets written in German addressing melanoma patients (MP). Melanoma booklets in accordance with predefined criteria were searched and analyzed. Three reviewers independently assessed their quality and understandability by applying the DISCERN tool and PEMAT-P. The Flesch Reading Ease Score (FRES) was calculated to determine readability. Nine booklets addressing MP were analyzed. The overall median DISCERN score was 3.6 (interquartile range (IQR) 2.9–4.1), median PEMAT-P score was 91% (IQR 83–94.5), and median FRES was 43 (IQR 33.5–47.5), indicating a medium quality, a high application of understandability elements, but low readability in at least half of the booklets. Incomplete reporting on treatments and insufficient meta-information caused the main quality deficits. There is a need of content and didactic revision of German booklets for MP to raise their quality and to make them beneficial and understandable for more patients. An adaption in accordance with evidence-based criteria and an even stronger involvement of MP in assessment and development of patient education material are considered to be the best approaches.
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Quality, Readability, and Understandability of German Booklets Addressing Melanoma Patients
Abstract
Booklets are the preferably used form among patient education materials and are often handed out during medical consultations in dermatological oncology settings. However, little is known about how beneficial they are and whether they correspond to essential quality characteristics. To assess the quality, readability, and understandability of currently freely available booklets written in German addressing melanoma patients (MP). Melanoma booklets in accordance with predefined criteria were searched and analyzed. Three reviewers independently assessed their quality and understandability by applying the DISCERN tool and PEMAT-P. The Flesch Reading Ease Score (FRES) was calculated to determine readability. Nine booklets addressing MP were analyzed. The overall median DISCERN score was 3.6 (interquartile range (IQR) 2.9–4.1), median PEMAT-P score was 91% (IQR 83–94.5), and median FRES was 43 (IQR 33.5–47.5), indicating a medium quality, a high application of understandability elements, but low readability in at least half of the booklets. Incomplete reporting on treatments and insufficient meta-information caused the main quality deficits. There is a need of content and didactic revision of German booklets for MP to raise their quality and to make them beneficial and understandable for more patients. An adaption in accordance with evidence-based criteria and an even stronger involvement of MP in assessment and development of patient education material are considered to be the best approaches.
https://ift.tt/2I5flKB
Long-term survival in trastuzumab-treated patients with HER2-positive metastatic breast cancer: real-world outcomes and treatment patterns in a whole-of-population Australian cohort (2001–2016)
Abstract
Purpose
Patients treated with trastuzumab for HER2-positive metastatic breast cancer (HER2+MBC) are living longer, but there is little information on their outcomes and treatment experience beyond the median survival from clinical trials and real-world observational studies. We aim to describe the real-world treatment patterns and overall survival (OS) for women surviving five or more years from initiation of trastuzumab for HER2+MBC.
Methods
This is a retrospective, whole-of-population cohort study of women initiating trastuzumab for HER2+MBC between 2001 and 2011, followed to 2016. We defined long-term survivors (LTS) as those patients surviving ≥ 5 years from trastuzumab initiation. We used dispensing claims to describe timing of cancer treatments used by LTS and to estimate time on and off HER2-targeted therapies, and OS from trastuzumab initiation for HER2+MBC.
Results
Of 4177 women initiating trastuzumab for HER2+MBC, 1082 (26%) survived ≥ 5 years. Median age for LTS was 54 years (IQR 46–63). At a median follow-up of 9.4 years, 36% of LTS died; their conditional probability of surviving an additional 5 years was 55%. Median time on trastuzumab and all HER2-targeted therapy was 58.9 months (27.6–88.1) and 69.1 months (35.6–124.5), respectively. 85% of LTS had a period off HER2 therapy, lasting a median of 30.4 months (8.2–NR).
Conclusions
LTS generally receive HER2-targeted therapies for periods of time longer than in clinical trials, but most LTS also had breaks in treatment. More research is needed to understand the effects of long-term treatment and to identify patients who may be able to safely discontinue HER2-targeted therapy.
https://ift.tt/2I0PUK5
Socioeconomic status and quality of life in patients with locally advanced head and neck cancer
Abstract
Purpose
Socioeconomic aspects play an important role in health care. Patients with locally advanced head and neck cancer (LAHNC) experience detrimental effects on their quality of life (QoL). This prospective study examines QoL differences between patients with different socioeconomic status (SES) after intensity-modulated radiation therapy (IMRT).
Patients and methods
In all, 161 patients were questioned at the end of IMRT and at 12 and 24 months follow-up using the questionnaires of the European Organization for Research and Treatment of Cancer (EORTC) QLQ-30 and QLQ-HN35. Patients' QoL 2 years after IMRT was compared to a population reference sample and QoL of patients from lower, middle, and higher social class 2 years after IMRT was analyzed by ANCOVA using baseline QoL (end of radiation treatment) as a covariate.
Results
Patients with high SES report worse QoL at the end of IMRT in the domains global health status (−15.2; p = 0.005), role function (−23.8; p = 0.002), and social function (−19.4; p = 0.023) compared to patients with middle and low SES. QoL improved during the first 12 and 24 months. However, 2 years after IMRT, middle and low SES patients report lower QoL in the domains global health status, physical function, and role function, and report a higher general (fatigue, pain, dyspnea) and head and neck cancer-specific symptom burden (pain, swallowing, senses, speech, social eating, opening mouth, and felt ill) than patients with high SES.
Conclusion
After IMRT for LAHNC, patients with high SES report worse QoL compared to patients with middle or low SES. There is a marked improvement within the first 24 months in many domains. However, the magnitude of improvement in patients with middle or low SES is significantly smaller compared to patients with high SES.
https://ift.tt/2I5Ck87
Quality, Readability, and Understandability of German Booklets Addressing Melanoma Patients
Abstract
Booklets are the preferably used form among patient education materials and are often handed out during medical consultations in dermatological oncology settings. However, little is known about how beneficial they are and whether they correspond to essential quality characteristics. To assess the quality, readability, and understandability of currently freely available booklets written in German addressing melanoma patients (MP). Melanoma booklets in accordance with predefined criteria were searched and analyzed. Three reviewers independently assessed their quality and understandability by applying the DISCERN tool and PEMAT-P. The Flesch Reading Ease Score (FRES) was calculated to determine readability. Nine booklets addressing MP were analyzed. The overall median DISCERN score was 3.6 (interquartile range (IQR) 2.9–4.1), median PEMAT-P score was 91% (IQR 83–94.5), and median FRES was 43 (IQR 33.5–47.5), indicating a medium quality, a high application of understandability elements, but low readability in at least half of the booklets. Incomplete reporting on treatments and insufficient meta-information caused the main quality deficits. There is a need of content and didactic revision of German booklets for MP to raise their quality and to make them beneficial and understandable for more patients. An adaption in accordance with evidence-based criteria and an even stronger involvement of MP in assessment and development of patient education material are considered to be the best approaches.
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Quality, Readability, and Understandability of German Booklets Addressing Melanoma Patients
Abstract
Booklets are the preferably used form among patient education materials and are often handed out during medical consultations in dermatological oncology settings. However, little is known about how beneficial they are and whether they correspond to essential quality characteristics. To assess the quality, readability, and understandability of currently freely available booklets written in German addressing melanoma patients (MP). Melanoma booklets in accordance with predefined criteria were searched and analyzed. Three reviewers independently assessed their quality and understandability by applying the DISCERN tool and PEMAT-P. The Flesch Reading Ease Score (FRES) was calculated to determine readability. Nine booklets addressing MP were analyzed. The overall median DISCERN score was 3.6 (interquartile range (IQR) 2.9–4.1), median PEMAT-P score was 91% (IQR 83–94.5), and median FRES was 43 (IQR 33.5–47.5), indicating a medium quality, a high application of understandability elements, but low readability in at least half of the booklets. Incomplete reporting on treatments and insufficient meta-information caused the main quality deficits. There is a need of content and didactic revision of German booklets for MP to raise their quality and to make them beneficial and understandable for more patients. An adaption in accordance with evidence-based criteria and an even stronger involvement of MP in assessment and development of patient education material are considered to be the best approaches.
https://ift.tt/2I5flKB
Pelvic dystopia of right rudimentary multicystic dysplastic kidney as a rare cause of bedwetting in a patient with a single pelvic ectopic left kidney, and agenesis of the uterus and vagina (Mayer-Rokitansky-Küster-Hauser syndrome): a case report
Pelvic dystopia of rudimentary multicystic dysplastic kidney as a rare cause of bedwetting in children.
https://ift.tt/2KJwBqf
Pre-surgical trial of the AKT inhibitor MK-2206 in patients with operable invasive breast cancer: a New York Cancer Consortium trial
Abstract
Introduction
The PI3K/AKT/mTOR pathway is an oncogenic driver in breast cancer (BC). In this multi-center, pre-surgical study, we evaluated the tissue effects of the AKT inhibitor MK-2206 in women with stage I–III BC.
Materials and methods
Two doses of weekly oral MK2206 were administered at days − 9 and − 2 before surgery. The primary endpoint was reduction of pAktSer473 in breast tumor tissue from diagnostic biopsy to surgery. Secondary endpoints included changes in PI3K/AKT pathway tumor markers, tumor proliferation (ki-67), insulin growth factor pathway blood markers, pharmacokinetics (PK), genomics, and MK-2206 tolerability. Paired t tests were used to compare biomarker changes in pre- and post-MK-2206, and two-sample t tests to compare with prospectively accrued untreated controls.
Results
Despite dose reductions, the trial was discontinued after 12 patients due to grade III rash, mucositis, and pruritus. While there was a trend to reduction in pAKT after MK-2206 (p = 0.06), there was no significant change compared to controls (n = 5, p = 0.65). After MK-2206, no significant changes in ki-67, pS6, PTEN, or stathmin were observed. There was no significant association between dose level and PK (p = 0.11). Compared to controls, MK-2206 significantly increased serum glucose (p = 0.02), insulin (p < 0.01), C-peptide (p < 0.01), and a trend in IGFBP-3 (p = 0.06).
Conclusion
While a trend to pAKT reduction after MK-2206 was observed, there was no significant change compared to controls. However, the accrued population was limited, due to toxicity being greater than expected. Pre-surgical trials can identify in vivo activity in the early drug development, but side effects must be considered in this healthy population.
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Homologous recombination deficiency and host anti-tumor immunity in triple-negative breast cancer
Abstract
Purpose
Triple-negative breast cancer (TNBC) is associated with worse outcomes relative to other breast cancer subtypes. Chemotherapy remains the standard-of-care systemic therapy for patients with localized or metastatic disease, with few biomarkers to guide benefit.
Methods
We will discuss recent advances in our understanding of two key biological processes in TNBC, homologous recombination (HR) DNA repair deficiency and host anti-tumor immunity, and their intersection.
Results
Recent advances in our understanding of homologous recombination (HR) deficiency, including FDA approval of PARP inhibitor olaparib for BRCA1 or BRCA2 mutation carriers, and host anti-tumor immunity in TNBC offer potential for new and biomarker-driven approaches to treat TNBC. Assays interrogating HR DNA repair capacity may guide treatment with agents inducing or targeting DNA damage repair. Tumor infiltrating lymphocytes (TILs) are associated with improved prognosis in TNBC and recent efforts to characterize infiltrating immune cell subsets and activate host anti-tumor immunity offer promise, yet challenges remain particularly in tumors lacking pre-existing immune infiltrates. Advances in these fields provide potential biomarkers to stratify patients with TNBC and guide therapy: induction of DNA damage in HR-deficient tumors and activation of existing or recruitment of host anti-tumor immune cells. Importantly, these advances provide an opportunity to guide use of existing therapies and development of novel therapies for TNBC. Efforts to combine therapies that exploit HR deficiency to enhance the activity of immune-directed therapies offer promise.
Conclusions
HR deficiency remains an important biomarker target and potentially effective adjunct to enhance immunogenicity of 'immune cold' TNBCs.
https://ift.tt/2KHbLIc
A double-blind, randomised trial of a polyphenolic-rich nail bed balm for chemotherapy-induced onycholysis: the UK polybalm study
Abstract
Purpose
Nail damage is common amongst patients receiving chemotherapy causing disfigurement and pain. This investigation evaluated whether a topical balm containing steam-extracted, bioactive polyphenolic-rich herbal oils blended with organic waxes could protect the nails via their reported anti-inflammatory, analgesic, anti-oxidant and anti-microbial properties.
Methods
60 patients (23M, 37F) were randomised to apply (2–3/day) either the plant balm (PB) or a petroleum control (PC) to their nail beds. Demographics, type and number of chemotherapy cycles did not differ between the two groups, recruited between Sept 2015 and Sept 2016. An unpaired t test was used to test the differences in symptoms and physical nail damage between the two groups.
Results
Symptom scores recorded with the dermatology life quality questionnaire (DLQQ) were significantly better, between the start and end of chemotherapy, in the group applying the PB versus PC. Likewise, the mean fall in nail damage, scored with the Nail Psoriasis Index by the supervising physician, was also significantly different.
Conclusion
The polyphenolic-rich essential oils and plant-based waxes in this nail bed balm profoundly reduced chemotherapy-related nail damage and improved nail-related quality of life, compared to a control. A further analysis is planned combining this balm with nail bed cooling.
https://ift.tt/2FRkHHm
Pre-surgical trial of the AKT inhibitor MK-2206 in patients with operable invasive breast cancer: a New York Cancer Consortium trial
Abstract
Introduction
The PI3K/AKT/mTOR pathway is an oncogenic driver in breast cancer (BC). In this multi-center, pre-surgical study, we evaluated the tissue effects of the AKT inhibitor MK-2206 in women with stage I–III BC.
Materials and methods
Two doses of weekly oral MK2206 were administered at days − 9 and − 2 before surgery. The primary endpoint was reduction of pAktSer473 in breast tumor tissue from diagnostic biopsy to surgery. Secondary endpoints included changes in PI3K/AKT pathway tumor markers, tumor proliferation (ki-67), insulin growth factor pathway blood markers, pharmacokinetics (PK), genomics, and MK-2206 tolerability. Paired t tests were used to compare biomarker changes in pre- and post-MK-2206, and two-sample t tests to compare with prospectively accrued untreated controls.
Results
Despite dose reductions, the trial was discontinued after 12 patients due to grade III rash, mucositis, and pruritus. While there was a trend to reduction in pAKT after MK-2206 (p = 0.06), there was no significant change compared to controls (n = 5, p = 0.65). After MK-2206, no significant changes in ki-67, pS6, PTEN, or stathmin were observed. There was no significant association between dose level and PK (p = 0.11). Compared to controls, MK-2206 significantly increased serum glucose (p = 0.02), insulin (p < 0.01), C-peptide (p < 0.01), and a trend in IGFBP-3 (p = 0.06).
Conclusion
While a trend to pAKT reduction after MK-2206 was observed, there was no significant change compared to controls. However, the accrued population was limited, due to toxicity being greater than expected. Pre-surgical trials can identify in vivo activity in the early drug development, but side effects must be considered in this healthy population.
https://ift.tt/2FTI5Uy
Pre-surgical trial of the AKT inhibitor MK-2206 in patients with operable invasive breast cancer: a New York Cancer Consortium trial
Abstract
Introduction
The PI3K/AKT/mTOR pathway is an oncogenic driver in breast cancer (BC). In this multi-center, pre-surgical study, we evaluated the tissue effects of the AKT inhibitor MK-2206 in women with stage I–III BC.
Materials and methods
Two doses of weekly oral MK2206 were administered at days − 9 and − 2 before surgery. The primary endpoint was reduction of pAktSer473 in breast tumor tissue from diagnostic biopsy to surgery. Secondary endpoints included changes in PI3K/AKT pathway tumor markers, tumor proliferation (ki-67), insulin growth factor pathway blood markers, pharmacokinetics (PK), genomics, and MK-2206 tolerability. Paired t tests were used to compare biomarker changes in pre- and post-MK-2206, and two-sample t tests to compare with prospectively accrued untreated controls.
Results
Despite dose reductions, the trial was discontinued after 12 patients due to grade III rash, mucositis, and pruritus. While there was a trend to reduction in pAKT after MK-2206 (p = 0.06), there was no significant change compared to controls (n = 5, p = 0.65). After MK-2206, no significant changes in ki-67, pS6, PTEN, or stathmin were observed. There was no significant association between dose level and PK (p = 0.11). Compared to controls, MK-2206 significantly increased serum glucose (p = 0.02), insulin (p < 0.01), C-peptide (p < 0.01), and a trend in IGFBP-3 (p = 0.06).
Conclusion
While a trend to pAKT reduction after MK-2206 was observed, there was no significant change compared to controls. However, the accrued population was limited, due to toxicity being greater than expected. Pre-surgical trials can identify in vivo activity in the early drug development, but side effects must be considered in this healthy population.
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