Malignant glioma is the most common primary brain tumor in adults and has a poor prognosis. However, there are no effective targeted therapies for glioma patients. Thus, the development of novel targeted thera...
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Cancer Medicine by Alexandros G.Sfakianakis,Anapafseos 5 Agios Nikolaos,Crete 72100,Greece,tel :00302841026182 & 00306932607174
Δευτέρα 25 Σεπτεμβρίου 2017
High expression of Bruton’s tyrosine kinase (BTK) is required for EGFR-induced NF-κB activation and predicts poor prognosis in human glioma
An unusual foreign object mimicking an odontoma in a patient with cleft alveolus: a case report
The habit of inserting foreign objects into body cavities is seen in children and in adults with intellectual disability. Usually, the foreign objects cause chronic inflammation and local tissue destruction, w...
http://ift.tt/2fMU38k
Delayed response to maintenance therapy after first-line chemotherapy in metastatic intrahepatic cholangiocarcinoma: a case report
Intrahepatic cholangiocarcinoma is an aggressive tumor originating in the epithelium of the bile duct, often associated with distant dissemination. The prognosis is poor and treatment is challenging due to low...
http://ift.tt/2xt1b3I
Clinical impact of tumor location on the colon cancer survival and recurrence: analyses of pooled data from three large phase III randomized clinical trials
Abstract
The aim of the present study was to determine whether or not the overall survival (OS) and disease-free survival (DFS) were affected by the tumor location in patients who underwent curative resection for colon cancer in a pooled analysis of three large phase III studies performed in Japan. In total, 4029 patients were included in the present study. Patients were classified as having right-side colon cancer (RC) if the primary tumor was located in the cecum, ascending colon, hepatic flexure or transverse colon, and left-side colon cancer (LCC) if the tumor site was within the splenic flexure, descending colon, sigmoid colon or recto sigmoid junction. The risk factors for the OS and DFS were analyzed. In the present study, 1449 patients were RC, and 2580 were LCC. The OS rates at 3 and 5 years after surgery were 87.6% and 81.6% in the RC group and 91.5% and 84.5% in the LCC group, respectively. Uni- and multivariate analyses showed that RRC increased the risk of death by 19.7% (adjusted hazard ratio = 1.197; 95% confidence interval, 1.020–1.408; P = 0.0272). In contrast, the DFS was similar between the two locations. The present study confirmed that the tumor location was a risk factor for the OS in patients who underwent curative treatment for colon cancer. Tumor location may, therefore, need to be considered a stratification factor in future phase III trials of colon cancer.
The present study confirmed that the tumor location was a risk factor for the OS in patients who underwent curative treatment for colon cancer. Tumor location may, therefore, need to be considered a stratification factor in future phase III trials of colon cancer.
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Clinical impact of tumor location on the colon cancer survival and recurrence: analyses of pooled data from three large phase III randomized clinical trials
Abstract
The aim of the present study was to determine whether or not the overall survival (OS) and disease-free survival (DFS) were affected by the tumor location in patients who underwent curative resection for colon cancer in a pooled analysis of three large phase III studies performed in Japan. In total, 4029 patients were included in the present study. Patients were classified as having right-side colon cancer (RC) if the primary tumor was located in the cecum, ascending colon, hepatic flexure or transverse colon, and left-side colon cancer (LCC) if the tumor site was within the splenic flexure, descending colon, sigmoid colon or recto sigmoid junction. The risk factors for the OS and DFS were analyzed. In the present study, 1449 patients were RC, and 2580 were LCC. The OS rates at 3 and 5 years after surgery were 87.6% and 81.6% in the RC group and 91.5% and 84.5% in the LCC group, respectively. Uni- and multivariate analyses showed that RRC increased the risk of death by 19.7% (adjusted hazard ratio = 1.197; 95% confidence interval, 1.020–1.408; P = 0.0272). In contrast, the DFS was similar between the two locations. The present study confirmed that the tumor location was a risk factor for the OS in patients who underwent curative treatment for colon cancer. Tumor location may, therefore, need to be considered a stratification factor in future phase III trials of colon cancer.
The present study confirmed that the tumor location was a risk factor for the OS in patients who underwent curative treatment for colon cancer. Tumor location may, therefore, need to be considered a stratification factor in future phase III trials of colon cancer.
http://ift.tt/2y59Km5
CT imaging features associated with recurrence in non-small cell lung cancer patients after stereotactic body radiotherapy
Predicting recurrence after stereotactic body radiotherapy (SBRT) in non-small cell lung cancer (NSCLC) patients is problematic, but critical for the decision of following treatment. This study aims to investi...
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Comparative study of the effects of different radiation qualities on normal human breast cells
As there is a growing number of long-term cancer survivors, the incidence of carcinogenesis as a late effect of radiotherapy is getting more and more into the focus. The risk for the development of secondary m...
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CT imaging features associated with recurrence in non-small cell lung cancer patients after stereotactic body radiotherapy
Predicting recurrence after stereotactic body radiotherapy (SBRT) in non-small cell lung cancer (NSCLC) patients is problematic, but critical for the decision of following treatment. This study aims to investi...
http://ift.tt/2hvIUcj
Comparative study of the effects of different radiation qualities on normal human breast cells
As there is a growing number of long-term cancer survivors, the incidence of carcinogenesis as a late effect of radiotherapy is getting more and more into the focus. The risk for the development of secondary m...
http://ift.tt/2hulEyN
NY-ESO-1 Vaccination in Combination with Decitabine Induces Antigen-Specific T-Lymphocyte Responses in Patients with Myelodysplastic Syndrome
Purpose: Treatment options are limited for patients with high-risk myelodysplastic syndrome (MDS). The azanucleosides, azacitidine and decitabine, are front-line therapy for MDS that induce promoter demethylation and gene expression of the highly immunogenic tumor antigen NY-ESO-1. We demonstrated that AML patients receiving decitabine exhibit induction of NY-ESO-1 expression in circulating blasts. We hypothesized that vaccinating against NY-ESO-1 in MDS patients receiving decitabine would capitalize upon induced NY-ESO-1 expression in malignant myeloid cells to provoke an NY-ESO-1-specific-MDS directed cytotoxic T-cell immune response. Experimental Design: In a phase I study, 9 MDS patients received an HLA unrestricted NY-ESO-1 vaccine (CDX-1401 + poly-ICLC) in a non-overlapping schedule every four weeks with standard dose decitabine. Results: Analysis of samples serially obtained from the 7 patients who reached the end-of-study demonstrated induction of NY-ESO-1 expression in 7/7 patients and NY-ESO-1 specific CD4+ and CD8+ T-lymphocyte responses in 6/7 and 4/7 of the vaccinated patients respectively. Myeloid cells expressing NY-ESO-1, isolated from a patient at different time-points during decitabine therapy, were capable of activating a cytotoxic response from autologous NY-ESO-1-specific T-lymphocytes. Vaccine responses were associated with a detectable population of CD141Hi conventional dendritic cells, which are critical for the uptake of NY-ESO-1 vaccine and have a recognized role in anti-tumor immune responses. Conclusion: These data indicate that vaccination against induced NY-ESO-1 expression can produce an antigen-specific immune response in a relatively non-immunogenic myeloid cancer and highlight the potential for induced-antigen directed immunotherapy in a group of patients with limited options.
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Discrimination of germline EGFR T790M mutations in plasma cell-free DNA allows study of prevalence across 31,414 cancer patients
Purpose: Plasma cell-free DNA (cfDNA) analysis is increasingly used clinically for cancer genotyping, but may lead to incidental identification of germline risk alleles. We studied EGFR T790M mutations in non-small cell lung cancer (NSCLC) toward the aim of discriminating germline and cancer-derived variants within cfDNA. Experimental Design: Patients with EGFR-mutant NSCLC, some with known germline EGFR T790M, underwent plasma genotyping. Separately, deidentified genomic data and buffy coat specimens from a clinical plasma next-generation sequencing (NGS) laboratory were reviewed and tested. Results: In patients with germline T790M mutations, the T790M allelic fraction (AF) in cfDNA approximates 50%, higher than that of EGFR driver mutations. Review of plasma NGS results reveals three groups of variants: a low AF tumor group, a heterozygous group (~50% AF), and a homozygous group (~100% AF). As the EGFR driver mutation AF increases, the distribution of the heterozygous group changes, suggesting increased copy number variation from increased tumor content. Excluding cases with high copy number variation, mutations can be differentiated into somatic variants and incidentally identified germline variants. We then developed a bioinformatic algorithm to distinguish germline and somatic mutations; blinded validation in 21 cases confirmed a 100% positive predictive value for predicting germline T790M. Querying a database of 31,414 patients with plasma NGS, we identified 48 with germline T790M, 43 with non-squamous NSCLC (p<0.0001). Conclusion: With appropriate bioinformatics, plasma genotyping can accurately predict the presence of incidentally detected germline risk alleles. This finding in patients indicates a need for genetic counseling and confirmatory germline testing.
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Cytoplasmic Cyclin E Mediates Resistance to Aromatase Inhibitors in Breast Cancer
Purpose: Preoperative aromatase inhibitor (AI) therapy has demonstrated efficacy in hormone receptor (HR)-positive postmenopausal breast cancer. However, many patients have disease that is either intrinsically resistant to AIs or that responds initially but develops resistance after prolonged exposure. We have shown that patients with breast tumors expressing the deregulated forms of cyclin E (low molecular weight forms [LMW-E]) have poor overall survival. Herein, we hypothesize that LMW-E expression can identify HR-positive tumors that are unresponsive to neoadjuvant AI therapy due to the inability of AIs to induce a cytostatic effect. Experimental Design: LMW-E was examined in breast cancer specimen from 58 patients enrolled in the American College of Surgeons Oncology Group Z1031, a neoadjuvant AI clinical trial. The mechanisms of LMW-E mediated resistance to AI were evaluated in vitro and in vivo using an inducible model system of cyclin E (full-length and LMW-E) in aromatase-overexpressing MCF7 cells. Results: Breast cancer recurrence-free interval was significantly worst in LMW-E positive patients who received AI neoadjuvant therapy. Upon LMW-E induction, MCF7 xenografts were unresponsive to letrozole in vivo, resulting in increased tumor volume after treatment with AIs. LMW-E expression overcame cell cycle inhibition by AIs in a CDK2/Rb-dependent manner and inhibition of CDK2 by dinaciclib reversed LMW-E-mediated resistance, while treatment with palbociclib, a CDK4/6 inhibitor, did not. Conclusion: Collectively, these findings suggest that cell cycle deregulation by LMW-E mediates resistance to AIs and a combination of CDK2 inhibitors and AIs may be an effective treatment in patients with HR-positive tumors that express LMW-E.
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4-1BB agonist focuses CD8+ tumor-infiltrating T-cell growth into a distinct repertoire capable of tumor recognition in pancreatic cancer
Purpose: Survival for pancreatic ductal adenocarcinoma (PDAC) patients is extremely poor and improved therapies are urgently needed. Tumor-infiltrating lymphocyte (TIL) adoptive cell therapy (ACT) has shown great promise in other tumor types, such as metastatic melanoma where overall response rates of 50% have been seen. Given this success and the evidence showing that T-cell presence positively correlates with overall survival in PDAC, we sought to enrich for CD8+ TIL capable of autologous tumor recognition. Additionally, we explored the phenotype and TCR repertoire of the CD8+ TIL in the tumor microenvironment. Experimental Design: We used an agonistic 4-1BB mAb during the initial tumor fragment culture to provide 4-1BB co-stimulation and assessed changes in TIL growth, phenotype, repertoire, and anti-tumor function. Results: Increased CD8+ TIL growth from PDAC tumors was achieved with the aid of an agonistic 4-1BB mAb. Expanded TIL were characterized by an activated but not terminally differentiated phenotype. Moreover, 4-1BB stimulation expanded a more clonal and distinct CD8+ TIL repertoire than IL-2 alone. TIL from both culture conditions displayed MHC class I-restricted recognition of autologous tumor targets. Conclusions: Co-stimulation with an anti-4-1BB mAb increases the feasibility of TIL therapy by producing greater numbers of these tumor-reactive T cells. These results suggest that TIL ACT for PDAC is a potential treatment avenue worth further investigation for a patient population in dire need of improved therapy.
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NY-ESO-1 Vaccination in Combination with Decitabine Induces Antigen-Specific T-Lymphocyte Responses in Patients with Myelodysplastic Syndrome
Purpose: Treatment options are limited for patients with high-risk myelodysplastic syndrome (MDS). The azanucleosides, azacitidine and decitabine, are front-line therapy for MDS that induce promoter demethylation and gene expression of the highly immunogenic tumor antigen NY-ESO-1. We demonstrated that AML patients receiving decitabine exhibit induction of NY-ESO-1 expression in circulating blasts. We hypothesized that vaccinating against NY-ESO-1 in MDS patients receiving decitabine would capitalize upon induced NY-ESO-1 expression in malignant myeloid cells to provoke an NY-ESO-1-specific-MDS directed cytotoxic T-cell immune response. Experimental Design: In a phase I study, 9 MDS patients received an HLA unrestricted NY-ESO-1 vaccine (CDX-1401 + poly-ICLC) in a non-overlapping schedule every four weeks with standard dose decitabine. Results: Analysis of samples serially obtained from the 7 patients who reached the end-of-study demonstrated induction of NY-ESO-1 expression in 7/7 patients and NY-ESO-1 specific CD4+ and CD8+ T-lymphocyte responses in 6/7 and 4/7 of the vaccinated patients respectively. Myeloid cells expressing NY-ESO-1, isolated from a patient at different time-points during decitabine therapy, were capable of activating a cytotoxic response from autologous NY-ESO-1-specific T-lymphocytes. Vaccine responses were associated with a detectable population of CD141Hi conventional dendritic cells, which are critical for the uptake of NY-ESO-1 vaccine and have a recognized role in anti-tumor immune responses. Conclusion: These data indicate that vaccination against induced NY-ESO-1 expression can produce an antigen-specific immune response in a relatively non-immunogenic myeloid cancer and highlight the potential for induced-antigen directed immunotherapy in a group of patients with limited options.
http://ift.tt/2wgOLYU
Discrimination of germline EGFR T790M mutations in plasma cell-free DNA allows study of prevalence across 31,414 cancer patients
Purpose: Plasma cell-free DNA (cfDNA) analysis is increasingly used clinically for cancer genotyping, but may lead to incidental identification of germline risk alleles. We studied EGFR T790M mutations in non-small cell lung cancer (NSCLC) toward the aim of discriminating germline and cancer-derived variants within cfDNA. Experimental Design: Patients with EGFR-mutant NSCLC, some with known germline EGFR T790M, underwent plasma genotyping. Separately, deidentified genomic data and buffy coat specimens from a clinical plasma next-generation sequencing (NGS) laboratory were reviewed and tested. Results: In patients with germline T790M mutations, the T790M allelic fraction (AF) in cfDNA approximates 50%, higher than that of EGFR driver mutations. Review of plasma NGS results reveals three groups of variants: a low AF tumor group, a heterozygous group (~50% AF), and a homozygous group (~100% AF). As the EGFR driver mutation AF increases, the distribution of the heterozygous group changes, suggesting increased copy number variation from increased tumor content. Excluding cases with high copy number variation, mutations can be differentiated into somatic variants and incidentally identified germline variants. We then developed a bioinformatic algorithm to distinguish germline and somatic mutations; blinded validation in 21 cases confirmed a 100% positive predictive value for predicting germline T790M. Querying a database of 31,414 patients with plasma NGS, we identified 48 with germline T790M, 43 with non-squamous NSCLC (p<0.0001). Conclusion: With appropriate bioinformatics, plasma genotyping can accurately predict the presence of incidentally detected germline risk alleles. This finding in patients indicates a need for genetic counseling and confirmatory germline testing.
http://ift.tt/2fnX6TH
Cytoplasmic Cyclin E Mediates Resistance to Aromatase Inhibitors in Breast Cancer
Purpose: Preoperative aromatase inhibitor (AI) therapy has demonstrated efficacy in hormone receptor (HR)-positive postmenopausal breast cancer. However, many patients have disease that is either intrinsically resistant to AIs or that responds initially but develops resistance after prolonged exposure. We have shown that patients with breast tumors expressing the deregulated forms of cyclin E (low molecular weight forms [LMW-E]) have poor overall survival. Herein, we hypothesize that LMW-E expression can identify HR-positive tumors that are unresponsive to neoadjuvant AI therapy due to the inability of AIs to induce a cytostatic effect. Experimental Design: LMW-E was examined in breast cancer specimen from 58 patients enrolled in the American College of Surgeons Oncology Group Z1031, a neoadjuvant AI clinical trial. The mechanisms of LMW-E mediated resistance to AI were evaluated in vitro and in vivo using an inducible model system of cyclin E (full-length and LMW-E) in aromatase-overexpressing MCF7 cells. Results: Breast cancer recurrence-free interval was significantly worst in LMW-E positive patients who received AI neoadjuvant therapy. Upon LMW-E induction, MCF7 xenografts were unresponsive to letrozole in vivo, resulting in increased tumor volume after treatment with AIs. LMW-E expression overcame cell cycle inhibition by AIs in a CDK2/Rb-dependent manner and inhibition of CDK2 by dinaciclib reversed LMW-E-mediated resistance, while treatment with palbociclib, a CDK4/6 inhibitor, did not. Conclusion: Collectively, these findings suggest that cell cycle deregulation by LMW-E mediates resistance to AIs and a combination of CDK2 inhibitors and AIs may be an effective treatment in patients with HR-positive tumors that express LMW-E.
http://ift.tt/2whSOEy
4-1BB agonist focuses CD8+ tumor-infiltrating T-cell growth into a distinct repertoire capable of tumor recognition in pancreatic cancer
Purpose: Survival for pancreatic ductal adenocarcinoma (PDAC) patients is extremely poor and improved therapies are urgently needed. Tumor-infiltrating lymphocyte (TIL) adoptive cell therapy (ACT) has shown great promise in other tumor types, such as metastatic melanoma where overall response rates of 50% have been seen. Given this success and the evidence showing that T-cell presence positively correlates with overall survival in PDAC, we sought to enrich for CD8+ TIL capable of autologous tumor recognition. Additionally, we explored the phenotype and TCR repertoire of the CD8+ TIL in the tumor microenvironment. Experimental Design: We used an agonistic 4-1BB mAb during the initial tumor fragment culture to provide 4-1BB co-stimulation and assessed changes in TIL growth, phenotype, repertoire, and anti-tumor function. Results: Increased CD8+ TIL growth from PDAC tumors was achieved with the aid of an agonistic 4-1BB mAb. Expanded TIL were characterized by an activated but not terminally differentiated phenotype. Moreover, 4-1BB stimulation expanded a more clonal and distinct CD8+ TIL repertoire than IL-2 alone. TIL from both culture conditions displayed MHC class I-restricted recognition of autologous tumor targets. Conclusions: Co-stimulation with an anti-4-1BB mAb increases the feasibility of TIL therapy by producing greater numbers of these tumor-reactive T cells. These results suggest that TIL ACT for PDAC is a potential treatment avenue worth further investigation for a patient population in dire need of improved therapy.
http://ift.tt/2fnhB31
Approved Drugs Might Work in More Cancers [News in Brief]
Multiarm trial successfully matches patients with available therapies based on mutation, tissue type.
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Checkpoint Inhibitor Combo Effective for RCC [News in Brief]
Nivolumab plus ipilimumab increases progression-free survival in high- and intermediate-risk patients.
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The DNA repair inhibitor Dbait is specific for malignant hematologic cells in blood
Hematologic malignancies are rare cancers that develop refractory disease upon patient relapse, resulting in decreased life expectancy and quality of life. DNA repair inhibitors are promising strategy to treat cancer but are limited by their hematologic toxicity in combination with conventional chemotherapies. Dbait are large molecules targeting the signaling of DNA damage and inhibiting all the double-strand DNA break pathways. Dbait have been shown to sensitize resistant solid tumors to radiotherapy and Platinium salts. Here, we analyze the efficacy and lack of toxicity of AsiDNA, a cholesterol form of Dbait, in hematologic malignancies. We show that AsiDNA, enters cells via LDL receptors and activates its molecular target, the DNA dependent protein kinase (DNA-PKcs) in 10 lymphoma and leukemia cell lines (Jurkat-E6.1, MT-4, MOLT-4, 174xCEM.T2, Sup-T1, HuT-78, Raji, IM-9, THP-1 and U-937) and in normal primary human PBMCs, resting or activated T-cells, and CD34+ progenitors. The treatment with AsiDNA induced necrotic and mitotic cell death in most cancer cell lines and had no effect on blood or bone marrow cells, including immune activation, proliferation or differentiation. Sensitivity to AsiDNA was independent of p53 status. Survival to combined treatment with conventional therapies (etoposide, cyclophosphamides, vincristine, or radiotherapy) was analyzed by isobolograms and combination index. AsiDNA synergized with all treatments, except vincristine, without increasing their toxicity to normal blood cells. AsiDNA is a novel, potent, and wide range drug with the potential to specifically increase DNA damaging treatment toxicity in tumor without adding toxicity in normal hematologic cells or inducing immune dysregulation.
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Restricted delivery of talazoparib across the blood-brain barrier limits the sensitizing effects of poly (ADP-ribose) polymerase inhibition on temozolomide therapy in glioblastoma
Poly (ADP-ribose) polymerase PARP inhibitors, including talazoparib (TAL), potentiate temozolomide (TMZ) efficacy in multiple tumor types, however TAL-mediated sensitization has not been evaluated in orthotopic glioblastoma (GBM) models. This study evaluates TAL ± TMZ in clinically relevant GBM models. TAL at 1-3 nmol/L sensitized T98G, U251 and GBM12 cells to TMZ, and enhanced DNA damage signaling and G2/M arrest in vitro. In vivo cyclical therapy with TAL (0.15 mg/kg twice daily) combined with low dose TMZ (5 mg/kg daily) was well tolerated. This TAL/TMZ regimen prolonged tumor stasis more than TMZ alone in heterotopic GBM12 xenografts [median time to endpoint: 76 days vs. 50 days TMZ (p=0.005), 11 days placebo (p <0.001)]. However, TAL/TMZ did not accentuate survival beyond that of TMZ alone in corresponding orthotopic xenografts (median survival 37 vs. 30 days with TMZ (p=0.93), 14 days with placebo, p<0.001). Average brain and plasma TAL concentrations at 2 hours after a single dose (0.15 mg/kg) were 0.49±0.07 ng/g and 25.5±4.1 ng/ml, respectively. The brain/plasma distribution of TAL in Bcrp-/- versus WT mice did not differ, while the brain/plasma ratio in Mdr1a/b-/- mice was higher than WT mice (0.23 vs. 0.02, p<0.001). Consistent with the in vivo brain distribution, overexpression of MDR1 decreased TAL accumulation in MDCKII cells. These results indicate that TAL has significant MDR1 efflux liability that may restrict delivery across the blood-brain barrier, and this may explain the loss of TAL-mediated TMZ sensitization in orthotopic versus heterotopic GBM xenografts.
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Restricted delivery of talazoparib across the blood-brain barrier limits the sensitizing effects of poly (ADP-ribose) polymerase inhibition on temozolomide therapy in glioblastoma
Poly (ADP-ribose) polymerase PARP inhibitors, including talazoparib (TAL), potentiate temozolomide (TMZ) efficacy in multiple tumor types, however TAL-mediated sensitization has not been evaluated in orthotopic glioblastoma (GBM) models. This study evaluates TAL ± TMZ in clinically relevant GBM models. TAL at 1-3 nmol/L sensitized T98G, U251 and GBM12 cells to TMZ, and enhanced DNA damage signaling and G2/M arrest in vitro. In vivo cyclical therapy with TAL (0.15 mg/kg twice daily) combined with low dose TMZ (5 mg/kg daily) was well tolerated. This TAL/TMZ regimen prolonged tumor stasis more than TMZ alone in heterotopic GBM12 xenografts [median time to endpoint: 76 days vs. 50 days TMZ (p=0.005), 11 days placebo (p <0.001)]. However, TAL/TMZ did not accentuate survival beyond that of TMZ alone in corresponding orthotopic xenografts (median survival 37 vs. 30 days with TMZ (p=0.93), 14 days with placebo, p<0.001). Average brain and plasma TAL concentrations at 2 hours after a single dose (0.15 mg/kg) were 0.49±0.07 ng/g and 25.5±4.1 ng/ml, respectively. The brain/plasma distribution of TAL in Bcrp-/- versus WT mice did not differ, while the brain/plasma ratio in Mdr1a/b-/- mice was higher than WT mice (0.23 vs. 0.02, p<0.001). Consistent with the in vivo brain distribution, overexpression of MDR1 decreased TAL accumulation in MDCKII cells. These results indicate that TAL has significant MDR1 efflux liability that may restrict delivery across the blood-brain barrier, and this may explain the loss of TAL-mediated TMZ sensitization in orthotopic versus heterotopic GBM xenografts.
http://ift.tt/2jZjzvP
The DNA repair inhibitor Dbait is specific for malignant hematologic cells in blood
Hematologic malignancies are rare cancers that develop refractory disease upon patient relapse, resulting in decreased life expectancy and quality of life. DNA repair inhibitors are promising strategy to treat cancer but are limited by their hematologic toxicity in combination with conventional chemotherapies. Dbait are large molecules targeting the signaling of DNA damage and inhibiting all the double-strand DNA break pathways. Dbait have been shown to sensitize resistant solid tumors to radiotherapy and Platinium salts. Here, we analyze the efficacy and lack of toxicity of AsiDNA, a cholesterol form of Dbait, in hematologic malignancies. We show that AsiDNA, enters cells via LDL receptors and activates its molecular target, the DNA dependent protein kinase (DNA-PKcs) in 10 lymphoma and leukemia cell lines (Jurkat-E6.1, MT-4, MOLT-4, 174xCEM.T2, Sup-T1, HuT-78, Raji, IM-9, THP-1 and U-937) and in normal primary human PBMCs, resting or activated T-cells, and CD34+ progenitors. The treatment with AsiDNA induced necrotic and mitotic cell death in most cancer cell lines and had no effect on blood or bone marrow cells, including immune activation, proliferation or differentiation. Sensitivity to AsiDNA was independent of p53 status. Survival to combined treatment with conventional therapies (etoposide, cyclophosphamides, vincristine, or radiotherapy) was analyzed by isobolograms and combination index. AsiDNA synergized with all treatments, except vincristine, without increasing their toxicity to normal blood cells. AsiDNA is a novel, potent, and wide range drug with the potential to specifically increase DNA damaging treatment toxicity in tumor without adding toxicity in normal hematologic cells or inducing immune dysregulation.
http://ift.tt/2y4KWe1
PD-1 expression in head and neck squamous cell carcinomas derives primarily from functionally anergic CD4+ TILs in the presence of PD-L1+ TAMs
Oral tongue squamous cell carcinoma (OTSCC) is the most common oral cavity tumor. In this study, we examined the basis for the activity of PD-1-based immune checkpoint therapy that is being explored widely in head and neck cancers. Using multispectral imaging, we systematically investigated the OTSCC tumor microenvironment (TME) by evaluating the frequency of PD-1 expression in CD8+, CD4+ and FoxP3+ tumor-infiltrating lymphocytes (TIL). We also defined the cellular sources of PD-L1 to evaluate the utility of PD-1:PD-L1 blocking antibody therapy in this patient population. PD-L1 was expressed in 79% of the OTSCC specimens examined within the TME. Expression of PD-L1 was associated with moderate to high levels of CD4+ and CD8+ TIL. We found that CD4+ TIL were present in equal or greater frequencies than CD8+ TIL in 94% of OTSCC, and that CD4+ FOXP3neg TIL were co-localized with PD-1/PD-L1/CD68 more frequently than CD8+ TIL. However, both CD4+PD1+ and CD8+PD1+ TIL were anergic in the setting of PD-L1 expression. Overall, our results highlight the importance of CD4+ TIL as pivotal regulators of PD-L1 levels and in determining the responsiveness of OTSCC to PD1-based immune checkpoint therapy.
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Mesenchymal stem cells promote hepatocarcinogenesis via lncRNA-MUF interaction with ANXA2 and miR-34a
Accumulating evidence suggests that cancer-associated mesenchymal stem cells (MSC) contribute to the development and metastasis of hepatocellular carcinoma (HCC). Aberrant expression of long noncoding RNAs (lncRNA) has been associated with these processes but cellular mechanisms are obscure. In this study, we report that HCC-associated mesenchymal stem cells (HCC-MSC) promote epithelial-mesenchymal transition (EMT) and liver tumorigenesis. We identified a novel lncRNA that we termed lncRNA-MUF (MSC upregulated factor) that is highly expressed in HCC tissues and correlated with poor prognosis. Depleting lncRNA-MUF in HCC cells repressed EMT and inhibited their tumorigenic potential. Conversely, lncRNA-MUF overexpression accelerated EMT and malignant capacity. Mechanistic investigations showed that lncRNA-MUF bound annexin A2 (ANXA2) and activated Wnt/β-catenin signaling and EMT. Furthermore, lncRNA-MUF acted as a competing endogenous RNA (ceRNA) for miR-34a, leading to Snail1 upregulation and EMT activation. Collectively, our findings establish a lncRNA mediated process in MSC that facilitates hepatocarcinogenesis, with potential implications for therapeutic targeting.
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Skp2-mediated stabilization of MTH1 promotes survival of melanoma cells upon oxidative stress
MTH1 helps prevent misincorporation of ROS-damaged dNTPs into genomic DNA, however, there is little understanding of how MTH1 itself is regulated. Here we report that MTH1 is regulated by polyubiquitination mediated by the E3 ligase Skp2. In melanoma cells, MTH1 was upregulated commonly mainly due to its improved stability caused by K63-linked polyubiquitination. While Skp2 along with other components of the Skp1-cullin-F-box (SCF) ubiquitin ligase complex were physically associated with MTH1, blocking the SCF function ablated MTH1 ubiquitination and expression. Conversely, overexpressing Skp2 elevated levels of MTH1 associated with an increase in its K63-linked ubiquitination. In melanoma cell lines and patient specimens, we observed a positive correlation of Skp2 and MTH1 expression. Mechanistic investigations showed that Skp2 limited DNA damage and apoptosis triggered by oxidative stress and that MAPK upregulated Skp2 and MTH1 to render cells more resistant to such stress. Collectively, our findings identify Skp2-mediated K63-linked polyubiquitination as a critical regulatory mechanism responsible for MTH1 upregulation in melanoma, with potential implications to target the MAPK/Skp2/MTH1 pathway to improve its treatment.
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Integrated analysis of whole-genome ChIP-Seq and RNA-Seq data of primary head and neck tumor samples associates HPV integration sites with open chromatin marks
Chromatin alterations mediate mutations and gene expression changes in cancer. Chromatin immunoprecipitation followed by sequencing (ChIP-Seq) has been utilized to study genome-wide chromatin structure in human cancer cell lines, yet numerous technical challenges limit comparable analyses in primary tumors. Here we have developed a new whole-genome analytical pipeline to optimize ChIP-Seq protocols on patient-derived xenografts from human papillomavirus-related (HPV+) head and neck squamous cell carcinoma (HNSCC) samples. We further associated chromatin aberrations with gene expression changes from a larger cohort of the tumor and normal samples with RNA-Seq data. We detect differential histone enrichment associated with tumor-specific gene expression variation, sites of HPV integration in the human genome, and HPV-associated histone enrichment sites upstream of cancer driver genes, which play central roles in cancer associated pathways. These comprehensive analyses enable unprecedented characterization of the complex network of molecular changes resulting from chromatin alterations that drive HPV-related tumorigenesis.
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KIT suppresses BRAFV600E-mutant melanoma by attenuating oncogenic RAS/MAPK signaling
The receptor tyrosine kinase KIT promotes survival and migration of melanocytes during development, and excessive KIT activity hyperactivates the RAS/MAPK pathway and can drive formation of melanomas, most notably of rare melanomas that occur on volar and mucosal surfaces of the skin. The much larger fraction of melanomas that occur on sun-exposed skin is driven primarily by BRAF or NRAS activating mutations, but these melanomas exhibit a surprising loss of KIT expression, which raises the question of whether loss of KIT in these tumors facilitates tumorigenesis. To address this question, we introduced a kit(lf) mutation into a strain of Tg(mitfa:BRAFV600E); p53(lf) melanoma-prone zebrafish. Melanoma onset was accelerated in kit(lf); Tg(mitfa:BRAFV600E); p53(lf) fish. Tumors from kit(lf) animals were more invasive and had higher RAS/MAPK pathway activation. KIT knockdown also increased RAS/MAPK pathway activation in a BRAFV600E-mutant human melanoma cell line. We found that pathway stimulation upstream of BRAFV600E could paradoxically reduce signaling downstream of BRAFV600E, and wild-type BRAF was necessary for this effect, suggesting that its activation can dampen oncogenic BRAFV600E signaling. In vivo, expression of wild-type BRAF delayed melanoma onset, but only in a kit-dependent manner. Together, these results suggest that KIT can activate signaling through wild-type RAF proteins, thus interfering with oncogenic BRAFV600E-driven melanoma formation.
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Combined CDK4/6 and PI3K{alpha} inhibition is synergistic and immunogenic in triple negative breast cancer
New treatments for triple-negative breast cancer (TNBC) are urgently needed. Despite there being little evidence of clinical activity as single-agent therapies, we show that dual blockade of PI3Kα and CDK4/6 is synergistically effective against multiple RB1-wildtype TNBC models. Combined PI3Kα and CDK4/6 inhibition significantly increased apoptosis, cell cycle arrest, and tumor immunogenicity and generated immunogenic cell death in human TNBC cell lines. Combination treatment also significantly improved disease control in human xenograft models compared with either monotherapy. Combined PI3Kα and CDK4/6 inhibition significantly increased tumor-infiltrating T cell activation and cytotoxicity and decreased the frequency of immunosuppressive myeloid-derived suppressor cells in a syngeneic TNBC mouse model. Notably, combined PI3Kα and CDK4/6 inhibition, along with inhibition of immune checkpoints PD-1 and CTLA-4, induced complete and durable regressions (>1 year) of established TNBC tumors in vivo. Overall, our results illustrate convergent mechanisms of PI3Kα and CDK4/6 blockade on cell cycle progression, DNA damage response, and immune-modulation and may provide a novel therapeutic approach for TNBC.
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Survival outcomes in cancer patients predicted by a partial EMT gene expression scoring metric
Metastasis is a significant contributor to morbidity and mortality for many cancer patients and remains a major obstacle for effective treatment. In many tissue types, metastasis is fueled by the epithelial-to-mesenchymal transition (EMT), a dynamic process characterized by phenotypic and morphologic changes concomitant with increased migratory and invasive potential. Recent experimental and theoretical evidence suggests that cells can be stably halted en route to EMT in a hybrid E/M phenotype. Cells in this phenotype tend to move collectively, forming clusters of circulating-tumor-cells that are key tumor-initiating agents. Here we developed an inferential model built on the gene expression of multiple cancer subtypes to devise an EMT metric that characterizes the degree to which a given cell line exhibits hybrid E/M features. Our model identified drivers and fine-tuners of epithelial-mesenchymal plasticity and recapitulates the behavior observed in multiple in vitro experiments across cancer types. We also predicted and experimentally validated the hybrid E/M status of certain cancer cell lines, including DU145 and A549. Lastly, we demonstrated the relevance of predicted EMT scores to patient survival and observed that the role of the hybrid E/M phenotype in characterizing tumor aggressiveness is tissue- and subtype-specific. Our algorithm is a promising tool to quantify the EMT spectrum, to investigate the correlation of EMT score with cancer treatment response and survival, and to provide an important metric for systematic clinical risk stratification and treatment.
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PD-1 expression in head and neck squamous cell carcinomas derives primarily from functionally anergic CD4+ TILs in the presence of PD-L1+ TAMs
Oral tongue squamous cell carcinoma (OTSCC) is the most common oral cavity tumor. In this study, we examined the basis for the activity of PD-1-based immune checkpoint therapy that is being explored widely in head and neck cancers. Using multispectral imaging, we systematically investigated the OTSCC tumor microenvironment (TME) by evaluating the frequency of PD-1 expression in CD8+, CD4+ and FoxP3+ tumor-infiltrating lymphocytes (TIL). We also defined the cellular sources of PD-L1 to evaluate the utility of PD-1:PD-L1 blocking antibody therapy in this patient population. PD-L1 was expressed in 79% of the OTSCC specimens examined within the TME. Expression of PD-L1 was associated with moderate to high levels of CD4+ and CD8+ TIL. We found that CD4+ TIL were present in equal or greater frequencies than CD8+ TIL in 94% of OTSCC, and that CD4+ FOXP3neg TIL were co-localized with PD-1/PD-L1/CD68 more frequently than CD8+ TIL. However, both CD4+PD1+ and CD8+PD1+ TIL were anergic in the setting of PD-L1 expression. Overall, our results highlight the importance of CD4+ TIL as pivotal regulators of PD-L1 levels and in determining the responsiveness of OTSCC to PD1-based immune checkpoint therapy.
http://ift.tt/2hveqqB
Mesenchymal stem cells promote hepatocarcinogenesis via lncRNA-MUF interaction with ANXA2 and miR-34a
Accumulating evidence suggests that cancer-associated mesenchymal stem cells (MSC) contribute to the development and metastasis of hepatocellular carcinoma (HCC). Aberrant expression of long noncoding RNAs (lncRNA) has been associated with these processes but cellular mechanisms are obscure. In this study, we report that HCC-associated mesenchymal stem cells (HCC-MSC) promote epithelial-mesenchymal transition (EMT) and liver tumorigenesis. We identified a novel lncRNA that we termed lncRNA-MUF (MSC upregulated factor) that is highly expressed in HCC tissues and correlated with poor prognosis. Depleting lncRNA-MUF in HCC cells repressed EMT and inhibited their tumorigenic potential. Conversely, lncRNA-MUF overexpression accelerated EMT and malignant capacity. Mechanistic investigations showed that lncRNA-MUF bound annexin A2 (ANXA2) and activated Wnt/β-catenin signaling and EMT. Furthermore, lncRNA-MUF acted as a competing endogenous RNA (ceRNA) for miR-34a, leading to Snail1 upregulation and EMT activation. Collectively, our findings establish a lncRNA mediated process in MSC that facilitates hepatocarcinogenesis, with potential implications for therapeutic targeting.
http://ift.tt/2hsSgcg
Skp2-mediated stabilization of MTH1 promotes survival of melanoma cells upon oxidative stress
MTH1 helps prevent misincorporation of ROS-damaged dNTPs into genomic DNA, however, there is little understanding of how MTH1 itself is regulated. Here we report that MTH1 is regulated by polyubiquitination mediated by the E3 ligase Skp2. In melanoma cells, MTH1 was upregulated commonly mainly due to its improved stability caused by K63-linked polyubiquitination. While Skp2 along with other components of the Skp1-cullin-F-box (SCF) ubiquitin ligase complex were physically associated with MTH1, blocking the SCF function ablated MTH1 ubiquitination and expression. Conversely, overexpressing Skp2 elevated levels of MTH1 associated with an increase in its K63-linked ubiquitination. In melanoma cell lines and patient specimens, we observed a positive correlation of Skp2 and MTH1 expression. Mechanistic investigations showed that Skp2 limited DNA damage and apoptosis triggered by oxidative stress and that MAPK upregulated Skp2 and MTH1 to render cells more resistant to such stress. Collectively, our findings identify Skp2-mediated K63-linked polyubiquitination as a critical regulatory mechanism responsible for MTH1 upregulation in melanoma, with potential implications to target the MAPK/Skp2/MTH1 pathway to improve its treatment.
http://ift.tt/2hw9txK
Integrated analysis of whole-genome ChIP-Seq and RNA-Seq data of primary head and neck tumor samples associates HPV integration sites with open chromatin marks
Chromatin alterations mediate mutations and gene expression changes in cancer. Chromatin immunoprecipitation followed by sequencing (ChIP-Seq) has been utilized to study genome-wide chromatin structure in human cancer cell lines, yet numerous technical challenges limit comparable analyses in primary tumors. Here we have developed a new whole-genome analytical pipeline to optimize ChIP-Seq protocols on patient-derived xenografts from human papillomavirus-related (HPV+) head and neck squamous cell carcinoma (HNSCC) samples. We further associated chromatin aberrations with gene expression changes from a larger cohort of the tumor and normal samples with RNA-Seq data. We detect differential histone enrichment associated with tumor-specific gene expression variation, sites of HPV integration in the human genome, and HPV-associated histone enrichment sites upstream of cancer driver genes, which play central roles in cancer associated pathways. These comprehensive analyses enable unprecedented characterization of the complex network of molecular changes resulting from chromatin alterations that drive HPV-related tumorigenesis.
http://ift.tt/2htqXOY
KIT suppresses BRAFV600E-mutant melanoma by attenuating oncogenic RAS/MAPK signaling
The receptor tyrosine kinase KIT promotes survival and migration of melanocytes during development, and excessive KIT activity hyperactivates the RAS/MAPK pathway and can drive formation of melanomas, most notably of rare melanomas that occur on volar and mucosal surfaces of the skin. The much larger fraction of melanomas that occur on sun-exposed skin is driven primarily by BRAF or NRAS activating mutations, but these melanomas exhibit a surprising loss of KIT expression, which raises the question of whether loss of KIT in these tumors facilitates tumorigenesis. To address this question, we introduced a kit(lf) mutation into a strain of Tg(mitfa:BRAFV600E); p53(lf) melanoma-prone zebrafish. Melanoma onset was accelerated in kit(lf); Tg(mitfa:BRAFV600E); p53(lf) fish. Tumors from kit(lf) animals were more invasive and had higher RAS/MAPK pathway activation. KIT knockdown also increased RAS/MAPK pathway activation in a BRAFV600E-mutant human melanoma cell line. We found that pathway stimulation upstream of BRAFV600E could paradoxically reduce signaling downstream of BRAFV600E, and wild-type BRAF was necessary for this effect, suggesting that its activation can dampen oncogenic BRAFV600E signaling. In vivo, expression of wild-type BRAF delayed melanoma onset, but only in a kit-dependent manner. Together, these results suggest that KIT can activate signaling through wild-type RAF proteins, thus interfering with oncogenic BRAFV600E-driven melanoma formation.
http://ift.tt/2hvGeen
Combined CDK4/6 and PI3K{alpha} inhibition is synergistic and immunogenic in triple negative breast cancer
New treatments for triple-negative breast cancer (TNBC) are urgently needed. Despite there being little evidence of clinical activity as single-agent therapies, we show that dual blockade of PI3Kα and CDK4/6 is synergistically effective against multiple RB1-wildtype TNBC models. Combined PI3Kα and CDK4/6 inhibition significantly increased apoptosis, cell cycle arrest, and tumor immunogenicity and generated immunogenic cell death in human TNBC cell lines. Combination treatment also significantly improved disease control in human xenograft models compared with either monotherapy. Combined PI3Kα and CDK4/6 inhibition significantly increased tumor-infiltrating T cell activation and cytotoxicity and decreased the frequency of immunosuppressive myeloid-derived suppressor cells in a syngeneic TNBC mouse model. Notably, combined PI3Kα and CDK4/6 inhibition, along with inhibition of immune checkpoints PD-1 and CTLA-4, induced complete and durable regressions (>1 year) of established TNBC tumors in vivo. Overall, our results illustrate convergent mechanisms of PI3Kα and CDK4/6 blockade on cell cycle progression, DNA damage response, and immune-modulation and may provide a novel therapeutic approach for TNBC.
http://ift.tt/2htqSLa
Survival outcomes in cancer patients predicted by a partial EMT gene expression scoring metric
Metastasis is a significant contributor to morbidity and mortality for many cancer patients and remains a major obstacle for effective treatment. In many tissue types, metastasis is fueled by the epithelial-to-mesenchymal transition (EMT), a dynamic process characterized by phenotypic and morphologic changes concomitant with increased migratory and invasive potential. Recent experimental and theoretical evidence suggests that cells can be stably halted en route to EMT in a hybrid E/M phenotype. Cells in this phenotype tend to move collectively, forming clusters of circulating-tumor-cells that are key tumor-initiating agents. Here we developed an inferential model built on the gene expression of multiple cancer subtypes to devise an EMT metric that characterizes the degree to which a given cell line exhibits hybrid E/M features. Our model identified drivers and fine-tuners of epithelial-mesenchymal plasticity and recapitulates the behavior observed in multiple in vitro experiments across cancer types. We also predicted and experimentally validated the hybrid E/M status of certain cancer cell lines, including DU145 and A549. Lastly, we demonstrated the relevance of predicted EMT scores to patient survival and observed that the role of the hybrid E/M phenotype in characterizing tumor aggressiveness is tissue- and subtype-specific. Our algorithm is a promising tool to quantify the EMT spectrum, to investigate the correlation of EMT score with cancer treatment response and survival, and to provide an important metric for systematic clinical risk stratification and treatment.
http://ift.tt/2hw9v8Q
IKZF1 gene in childhood B cell precursor acute lymphoblastic leukemia: interplay between genetic susceptibility and somatic abnormalities
Single nucleotide polymorphisms (SNPs) in IKZF1 are associated with inherited susceptibility to B-cell precursor acute lymphoblastic leukemia (BCP-ALL). Besides, somatic copy number abnormalities (CNAs) in genes related to lymphopoiesis (e.g. IKZF1, CDKN2A/B, BTG1) impact patient's outcome. Therefore, this study aimed to investigate an association between germline susceptibility and CNAs in BCP-ALL. The IKZF1 SNPs (rs11978267 and rs4132601) were genotyped in 276 cases and 467 controls. Bone marrow samples were used to determine the presence of somatic abnormalities. The IKZF1 transcript levels were quantified and associated with the SNPs and CNAs. Categorical variables were compared by Chi-square test. Odds ratios (ORs) were estimated with unconditional logistic regression with 95% confidence interval (CI). The variant allele of IKZF1 rs4132601 conferred increased risk of BCP-ALL (OR 2.09, 95% CI: 1.16-3.74). Individuals with either rs11978267 or rs4132601 had an increased risk for harboring IKZF1 deletion (OR 2.80, 95% CI: 1.25-6.23 and OR 2.88, 95% CI: 1.24-6.69, respectively). Increased risks were observed for individuals harboring both IKZF1 and BTG1 deletions (OR 4.90, 95% CI: 1.65-14.55, rs11978267 and OR 5.80, 95% CI: 1.94-17.41, rs4132601). Germline genetic variation increases the risk for childhood ALL in general, but also acts as a susceptibility factor bound for risk of specific somatic alterations. These findings provide new insight into the development of childhood ALL regarding causal variants and the biological basis of the risk association, offering the opportunity for future tailored research.
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The molecular genetics of chemotherapy–induced peripheral neuropathy: A systematic review and meta-analysis
Source:Critical Reviews in Oncology/Hematology
Author(s): J. Cliff, A.L. Jorgensen, R. Lord, F. Azam, L. Cossar, D.F. Carr, M. Pirmohamed
Chemotherapy-induced peripheral neuropathy (CIPN) can adversely affect completion of systemic anti-cancer treatment and cause long-term morbidity. Increasingly pharmacogenetic studies have been performed to explore susceptibility to this important adverse effect.A systematic review was conducted to identify pharmacogenetic studies, assess their quality and findings and undertake meta-analysis where possible.93 studies were included. Notable methodological issues included lack of standardisation and detail in phenotype definition and acknowledgement of potential confounding factors. Insufficient data was presented in many studies meaning only a minority could be included in meta-analysis showing mainly non-significant effects. Nonetheless, SNPs in CYP2C8, CYP3A4, ARHGEF10, EPHA and TUBB2A genes (taxanes), FARS2, ACYP2 and TAC1 (oxaliplatin), and CEP75 and CYP3A5 (vincristine) are of potential interest. These require exploration in large cohort studies with robust methodology and well-defined phenotypes.Seeking standardisation of phenotype, collaboration and subsequently, individual-patient-data meta-analysis may facilitate identifying contributory SNPs which could be combined in a polygenic risk score to predict those most at risk of CIPN.
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The molecular genetics of chemotherapy–induced peripheral neuropathy: A systematic review and meta-analysis
Source:Critical Reviews in Oncology/Hematology
Author(s): J. Cliff, A.L. Jorgensen, R. Lord, F. Azam, L. Cossar, D.F. Carr, M. Pirmohamed
Chemotherapy-induced peripheral neuropathy (CIPN) can adversely affect completion of systemic anti-cancer treatment and cause long-term morbidity. Increasingly pharmacogenetic studies have been performed to explore susceptibility to this important adverse effect.A systematic review was conducted to identify pharmacogenetic studies, assess their quality and findings and undertake meta-analysis where possible.93 studies were included. Notable methodological issues included lack of standardisation and detail in phenotype definition and acknowledgement of potential confounding factors. Insufficient data was presented in many studies meaning only a minority could be included in meta-analysis showing mainly non-significant effects. Nonetheless, SNPs in CYP2C8, CYP3A4, ARHGEF10, EPHA and TUBB2A genes (taxanes), FARS2, ACYP2 and TAC1 (oxaliplatin), and CEP75 and CYP3A5 (vincristine) are of potential interest. These require exploration in large cohort studies with robust methodology and well-defined phenotypes.Seeking standardisation of phenotype, collaboration and subsequently, individual-patient-data meta-analysis may facilitate identifying contributory SNPs which could be combined in a polygenic risk score to predict those most at risk of CIPN.
http://ift.tt/2fMEFJ6
32 Consecutive Cases of Whipple’s Operation with Single-Layer End to Side Dunking Pancreatojejunostomy Without Any Pancreatic Fistula: Our Institutional Experience
Abstract
The aim of this paper is to study the outcome of single-layer end to side dunking pancreatojejunostomy technique in 32 patients of malignant pancreatic disease undergoing Whipple's surgery in a tertiary care oncology centre in India. From January 2013 to January 2016, 32 consecutive patients who underwent pancreatoduodenectomy for malignant diseases were analysed retrospectively. All the patients underwent standard Whipple's operation. Pancreatojejunostomy was established in a single-layer end to side dunking manner with PDS 4-0. Various patient data, i.e. preoperative symptoms and demography, intra-operative time, blood loss and need of blood transfusion, postoperative hospital stay and complications, were noted. Mean operative time was 3.5 h approximately. Mean blood loss was 328 ml approx (range 150–600 ml). Postoperative delayed gastric emptying was observed in 8 (25%) patients. Three (9.4%) patients developed superficial surgical site infection. Mean hospital stay was 16.5 days (range 13–20 days). There were no pancreatic leak or fistula and no perioperative mortality. It is a feasible technique. It achieved zero leak rates, zero mortality and minimal morbidity without compromising any oncologic principles.
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32 Consecutive Cases of Whipple’s Operation with Single-Layer End to Side Dunking Pancreatojejunostomy Without Any Pancreatic Fistula: Our Institutional Experience
Abstract
The aim of this paper is to study the outcome of single-layer end to side dunking pancreatojejunostomy technique in 32 patients of malignant pancreatic disease undergoing Whipple's surgery in a tertiary care oncology centre in India. From January 2013 to January 2016, 32 consecutive patients who underwent pancreatoduodenectomy for malignant diseases were analysed retrospectively. All the patients underwent standard Whipple's operation. Pancreatojejunostomy was established in a single-layer end to side dunking manner with PDS 4-0. Various patient data, i.e. preoperative symptoms and demography, intra-operative time, blood loss and need of blood transfusion, postoperative hospital stay and complications, were noted. Mean operative time was 3.5 h approximately. Mean blood loss was 328 ml approx (range 150–600 ml). Postoperative delayed gastric emptying was observed in 8 (25%) patients. Three (9.4%) patients developed superficial surgical site infection. Mean hospital stay was 16.5 days (range 13–20 days). There were no pancreatic leak or fistula and no perioperative mortality. It is a feasible technique. It achieved zero leak rates, zero mortality and minimal morbidity without compromising any oncologic principles.
http://ift.tt/2htO9N8
TNFα-YAP/p65-HK2 axis mediates breast cancer cell migration
TNFα-YAP/p65-HK2 axis mediates breast cancer cell migration
Oncogenesis 6, e383 (September 2017). doi:10.1038/oncsis.2017.83
Authors: Y Gao, Y Yang, F Yuan, J Huang, W Xu, B Mao, Z Yuan & W Bi
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Xanthine dehydrogenase downregulation promotes TGFβ signaling and cancer stem cell-related gene expression in hepatocellular carcinoma
Xanthine dehydrogenase downregulation promotes TGFβ signaling and cancer stem cell-related gene expression in hepatocellular carcinoma
Oncogenesis 6, e382 (September 2017). doi:10.1038/oncsis.2017.81
Authors: G-L Chen, T Ye, H-L Chen, Z-Y Zhao, W-Q Tang, L-S Wang & J-L Xia
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PRAS40 promotes NF-κB transcriptional activity through association with p65
PRAS40 promotes NF-κB transcriptional activity through association with p65
Oncogenesis 6, e381 (September 2017). doi:10.1038/oncsis.2017.80
Authors: G Zhu, Q Qi, J J Havel, Z Li, Y Du, X Zhang & H Fu
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Spatial distribution of disease-associated variants in three-dimensional structures of protein complexes
Spatial distribution of disease-associated variants in three-dimensional structures of protein complexes
Oncogenesis 6, e380 (September 2017). doi:10.1038/oncsis.2017.79
Authors: A Gress, V Ramensky & O V Kalinina
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TNFα-YAP/p65-HK2 axis mediates breast cancer cell migration
TNFα-YAP/p65-HK2 axis mediates breast cancer cell migration
Oncogenesis 6, e383 (September 2017). doi:10.1038/oncsis.2017.83
Authors: Y Gao, Y Yang, F Yuan, J Huang, W Xu, B Mao, Z Yuan & W Bi
http://ift.tt/2yoxVb6
Xanthine dehydrogenase downregulation promotes TGFβ signaling and cancer stem cell-related gene expression in hepatocellular carcinoma
Xanthine dehydrogenase downregulation promotes TGFβ signaling and cancer stem cell-related gene expression in hepatocellular carcinoma
Oncogenesis 6, e382 (September 2017). doi:10.1038/oncsis.2017.81
Authors: G-L Chen, T Ye, H-L Chen, Z-Y Zhao, W-Q Tang, L-S Wang & J-L Xia
http://ift.tt/2yoxKwt
PRAS40 promotes NF-κB transcriptional activity through association with p65
PRAS40 promotes NF-κB transcriptional activity through association with p65
Oncogenesis 6, e381 (September 2017). doi:10.1038/oncsis.2017.80
Authors: G Zhu, Q Qi, J J Havel, Z Li, Y Du, X Zhang & H Fu
http://ift.tt/2yoxJIV
Spatial distribution of disease-associated variants in three-dimensional structures of protein complexes
Spatial distribution of disease-associated variants in three-dimensional structures of protein complexes
Oncogenesis 6, e380 (September 2017). doi:10.1038/oncsis.2017.79
Authors: A Gress, V Ramensky & O V Kalinina
http://ift.tt/2yoxRYU
Evaluation of 18 F-FDG PET/CT Parameters for Detection of Lymph Node Metastasis in Cutaneous Melanoma
Abstract
Purpose
The purpose of this study was to investigate the value of 18F-fluorodeoxyglucose positron emission tomography/computed tomography (FDG PET/CT) parameters in the detection of regional lymph node (LN) metastasis in patients with cutaneous melanoma.
Methods
We evaluated patients with cutaneous melanoma who underwent FDG PET/CT for initial staging or recurrence evaluation. A total of 103 patients were enrolled, and 165 LNs were evaluated. LNs that were confirmed pathologically or by follow-up imaging were included in this study. PET parameters, including maximum standardized uptake value (SUVmax), total lesion glycolysis and tumour-to-liver ratio, were used to determine the presence of metastases, and the results were compared with CT-determined LN metastasis. Receiver operating characteristic (ROC) curve analysis was used to determine the optimal cut-off values of the FDG PET parameters.
Results
A total of 93 LNs were malignant, and 84 LNs were smaller than 10 mm. In all 165 LNs, an SUVmax of >2.51 showed a sensitivity of 73.1%, a specificity of 88.9%, and an accuracy of 80.0% in detecting metastatic LNs. CT showed a higher specificity (87.3%) and lower accuracy (65.5%). For non-enlarged regional LNs (<10 mm), an SUVmax cut-off value of 1.4 showed the highest negative predictive value (81.3%). For enlarged LNs (≥10 mm), an SUVmax cut-off value of 2.4 showed the highest sensitivity (90.7%) and accuracy (88.9%) in detecting metastatic LNs.
Conclusions
In patients with cutaneous melanoma, an SUVmax of >2.4 showed a high sensitivity (91%) and accuracy (89%) in detecting metastasis in LNs ≥1 cm, and LNs <1 cm with an SUVmax <1.4 were likely to be benign.
http://ift.tt/2fL7w0f
Evaluation of 18 F-FDG PET/CT Parameters for Detection of Lymph Node Metastasis in Cutaneous Melanoma
Abstract
Purpose
The purpose of this study was to investigate the value of 18F-fluorodeoxyglucose positron emission tomography/computed tomography (FDG PET/CT) parameters in the detection of regional lymph node (LN) metastasis in patients with cutaneous melanoma.
Methods
We evaluated patients with cutaneous melanoma who underwent FDG PET/CT for initial staging or recurrence evaluation. A total of 103 patients were enrolled, and 165 LNs were evaluated. LNs that were confirmed pathologically or by follow-up imaging were included in this study. PET parameters, including maximum standardized uptake value (SUVmax), total lesion glycolysis and tumour-to-liver ratio, were used to determine the presence of metastases, and the results were compared with CT-determined LN metastasis. Receiver operating characteristic (ROC) curve analysis was used to determine the optimal cut-off values of the FDG PET parameters.
Results
A total of 93 LNs were malignant, and 84 LNs were smaller than 10 mm. In all 165 LNs, an SUVmax of >2.51 showed a sensitivity of 73.1%, a specificity of 88.9%, and an accuracy of 80.0% in detecting metastatic LNs. CT showed a higher specificity (87.3%) and lower accuracy (65.5%). For non-enlarged regional LNs (<10 mm), an SUVmax cut-off value of 1.4 showed the highest negative predictive value (81.3%). For enlarged LNs (≥10 mm), an SUVmax cut-off value of 2.4 showed the highest sensitivity (90.7%) and accuracy (88.9%) in detecting metastatic LNs.
Conclusions
In patients with cutaneous melanoma, an SUVmax of >2.4 showed a high sensitivity (91%) and accuracy (89%) in detecting metastasis in LNs ≥1 cm, and LNs <1 cm with an SUVmax <1.4 were likely to be benign.
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Inactivated Sendai Virus Particles upregulate cancer cell ICAM-1 expression with enhancing NK cell sensitivity on cancer cell
Summary
We have already reported that the inactivated Sendai virus (hemagglutinating virus of Japan; HVJ) envelope (HVJ-E) has multiple anti-cancer effects, including induction of cancer-selective cell death and activation of anti-cancer immunity. HVJ-E stimulates dendritic cells (DCs) to produce cytokines and chemokines such as IFN-β, IL-6, CCL5 and CXCL10, which activate both CD8+ T cells and NK cells and recruit them to the tumor microenvironment. However, the effect of HVJ-E on modulating the sensitivity of cancer cells to immune cell attack has yet to be investigated. In this study, we found that HVJ-E induced the production of intercellular adhesion molecule-1 (ICAM-1, CD54), a ligand of LFA-1, in several cancer cell lines through the activation of NF-κB downstream of retinoic acid-inducible gene I (RIG-I) and the mitochondrial antiviral signaling (MAVS) pathway. The upregulation of ICAM-1 on the surface of cancer cells increased the sensitivity of cancer cells to NK cells. Knocking out expression of ICAM-1 in MDA-MB-231 cells using the CRISPR/Cas9 method significantly reduced the killing effect of NK cells on ICAM-1-depleted MDA-MB-231 cells. HVJ-E suppressed tumor growth in MDA-MB-231 tumor-bearing SCID mice, and the HVJ-E anti-tumor effect was impaired when NK cells were depleted by treatment with the anti-asialo-GM1 antibody. Our findings suggest that HVJ-E enhances NK cell sensitivity against cancer cells by increasing ICAM-1 expression on the cancer cell surface.
This article is protected by copyright. All rights reserved.
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Characterization of ascites-derived tumor cells from an endometrial cancer patient
Summary
Improved treatment outcomes for the endometrial cancer patient required precision methods to investigate the biology of this disease and clinically relevant models to test treatment drugs. Hence, we applied a personalized platform to investigate whether in vitro and in vivo models could accurately predict effective treatment regimens. We successfully expanded ascites-derived tumor cells from an endometrial cancer patient with malignant ascites using ascites collected prior to chemotherapy treatment. H&E and IHC staining of ascites-derived tumor cells confirmed the source of endometrial cancer cells. Ascites-derived tumor cells were sensitive to cisplatin and doxorubicin single-agent treatments in CCK8 assay and 3D culture, a condition that more closely mimics in vivo environment. We further demonstrated that ascites-derived tumor cells from this patient could form tumors in NOD/SCID mice with preserved morphological characteristics. A remarkable concordance between the clinical response of cisplatin and the results of in vitro and in vivo drug test reflected the reliability of our personalized approach in this case. Together, our results indicated that an effective platform for ex vivo and in vivo culture of ascites-derived tumor cells from our endometrial cancer patient could be applied to identify treatment options, and may be commonly used in treating cancer patients with malignant ascites in the future.
This article is protected by copyright. All rights reserved.
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Differences in the Impact of Prognostic Factors for Hepatocellular Carcinoma Over Time
Summary
To evaluate the prognostic significance of serum markers that reflect tumor progression, liver function, or liver fibrosis in patients with hepatocellular carcinoma (HCC), focusing on how their impact changes over time after diagnosis. Alpha-fetoprotein (AFP), des-gamma-carboxy prothrombin (DCP), albumin-bilirubin (ALBI) score, aspartate aminotransferase to platelet ratio index (APRI), and FIB-4 index were measured at the time of initial non-recurrent HCC diagnosis in 1669 patients between 1997 and 2016. Survival rates after diagnosis were compared after stratifying patients by these markers. Time-dependent receiver-operating characteristics (ROC) analysis was performed to assess how these markers predict patient survival or death. Serum AFP and DCP levels, ALBI score, APRI, and FIB-4 index were strongly correlated with HCC progression, liver function, and degree of liver fibrosis, respectively. Survival rates after diagnosis were significantly different when patients were stratified by these markers. In the time-dependent ROC analysis, AFP and DCP had a high prognostic impact within 3 years of diagnosis but the impact decreased thereafter. In contrast, APRI and FIB-4 index had higher prognostic impact 10 years after diagnosis. ALBI score had a high prognostic impact throughout the study period. Time-dependent ROC analysis clearly showed changes in the prognostic importance of serum markers based on the duration after diagnosis. Whereas the prognostic impact of tumor progression markers was strong in the short term, liver fibrosis markers had higher prognostic impact long after diagnosis. Liver function had constant prognostic impact on patient survival after diagnosis.
This article is protected by copyright. All rights reserved.
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Inactivated Sendai Virus Particles upregulate cancer cell ICAM-1 expression with enhancing NK cell sensitivity on cancer cell
Summary
We have already reported that the inactivated Sendai virus (hemagglutinating virus of Japan; HVJ) envelope (HVJ-E) has multiple anti-cancer effects, including induction of cancer-selective cell death and activation of anti-cancer immunity. HVJ-E stimulates dendritic cells (DCs) to produce cytokines and chemokines such as IFN-β, IL-6, CCL5 and CXCL10, which activate both CD8+ T cells and NK cells and recruit them to the tumor microenvironment. However, the effect of HVJ-E on modulating the sensitivity of cancer cells to immune cell attack has yet to be investigated. In this study, we found that HVJ-E induced the production of intercellular adhesion molecule-1 (ICAM-1, CD54), a ligand of LFA-1, in several cancer cell lines through the activation of NF-κB downstream of retinoic acid-inducible gene I (RIG-I) and the mitochondrial antiviral signaling (MAVS) pathway. The upregulation of ICAM-1 on the surface of cancer cells increased the sensitivity of cancer cells to NK cells. Knocking out expression of ICAM-1 in MDA-MB-231 cells using the CRISPR/Cas9 method significantly reduced the killing effect of NK cells on ICAM-1-depleted MDA-MB-231 cells. HVJ-E suppressed tumor growth in MDA-MB-231 tumor-bearing SCID mice, and the HVJ-E anti-tumor effect was impaired when NK cells were depleted by treatment with the anti-asialo-GM1 antibody. Our findings suggest that HVJ-E enhances NK cell sensitivity against cancer cells by increasing ICAM-1 expression on the cancer cell surface.
This article is protected by copyright. All rights reserved.
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Differences in the Impact of Prognostic Factors for Hepatocellular Carcinoma Over Time
Summary
To evaluate the prognostic significance of serum markers that reflect tumor progression, liver function, or liver fibrosis in patients with hepatocellular carcinoma (HCC), focusing on how their impact changes over time after diagnosis. Alpha-fetoprotein (AFP), des-gamma-carboxy prothrombin (DCP), albumin-bilirubin (ALBI) score, aspartate aminotransferase to platelet ratio index (APRI), and FIB-4 index were measured at the time of initial non-recurrent HCC diagnosis in 1669 patients between 1997 and 2016. Survival rates after diagnosis were compared after stratifying patients by these markers. Time-dependent receiver-operating characteristics (ROC) analysis was performed to assess how these markers predict patient survival or death. Serum AFP and DCP levels, ALBI score, APRI, and FIB-4 index were strongly correlated with HCC progression, liver function, and degree of liver fibrosis, respectively. Survival rates after diagnosis were significantly different when patients were stratified by these markers. In the time-dependent ROC analysis, AFP and DCP had a high prognostic impact within 3 years of diagnosis but the impact decreased thereafter. In contrast, APRI and FIB-4 index had higher prognostic impact 10 years after diagnosis. ALBI score had a high prognostic impact throughout the study period. Time-dependent ROC analysis clearly showed changes in the prognostic importance of serum markers based on the duration after diagnosis. Whereas the prognostic impact of tumor progression markers was strong in the short term, liver fibrosis markers had higher prognostic impact long after diagnosis. Liver function had constant prognostic impact on patient survival after diagnosis.
This article is protected by copyright. All rights reserved.
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Characterization of ascites-derived tumor cells from an endometrial cancer patient
Summary
Improved treatment outcomes for the endometrial cancer patient required precision methods to investigate the biology of this disease and clinically relevant models to test treatment drugs. Hence, we applied a personalized platform to investigate whether in vitro and in vivo models could accurately predict effective treatment regimens. We successfully expanded ascites-derived tumor cells from an endometrial cancer patient with malignant ascites using ascites collected prior to chemotherapy treatment. H&E and IHC staining of ascites-derived tumor cells confirmed the source of endometrial cancer cells. Ascites-derived tumor cells were sensitive to cisplatin and doxorubicin single-agent treatments in CCK8 assay and 3D culture, a condition that more closely mimics in vivo environment. We further demonstrated that ascites-derived tumor cells from this patient could form tumors in NOD/SCID mice with preserved morphological characteristics. A remarkable concordance between the clinical response of cisplatin and the results of in vitro and in vivo drug test reflected the reliability of our personalized approach in this case. Together, our results indicated that an effective platform for ex vivo and in vivo culture of ascites-derived tumor cells from our endometrial cancer patient could be applied to identify treatment options, and may be commonly used in treating cancer patients with malignant ascites in the future.
This article is protected by copyright. All rights reserved.
http://ift.tt/2wRrHzn
Clinical evaluation of macrophages in cancer: role in treatment, modulation and challenges
Abstract
The focus of immunotherapeutics has been placed firmly on anti-tumour T cell responses. Significant progress has been made in the treatment of both local and systemic malignancies, but low response rates and rising toxicities are limiting this approach. Advancements in the understanding of tumour immunology are opening up a new range of therapeutic targets, including immunosuppressive factors in the tumour microenvironment. Macrophages are a heterogeneous group of cells that have roles in innate and adaptive immunity and tissue repair, but become co-opted by tumours to support tumour growth, survival, metastasis and immunosuppression. Macrophages also support tumour resistance to conventional therapy. In preclinical models, interference with macrophage migration, macrophage depletion and macrophage re-education have all been shown to reduce tumour growth and support anti-tumour immune responses. Here we discuss the role of macrophages in prognosis and sensitivity to therapy, while examining the significant progress which has been made in modulating the behaviour of these cells in cancer patients.
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Clinical evaluation of macrophages in cancer: role in treatment, modulation and challenges
Abstract
The focus of immunotherapeutics has been placed firmly on anti-tumour T cell responses. Significant progress has been made in the treatment of both local and systemic malignancies, but low response rates and rising toxicities are limiting this approach. Advancements in the understanding of tumour immunology are opening up a new range of therapeutic targets, including immunosuppressive factors in the tumour microenvironment. Macrophages are a heterogeneous group of cells that have roles in innate and adaptive immunity and tissue repair, but become co-opted by tumours to support tumour growth, survival, metastasis and immunosuppression. Macrophages also support tumour resistance to conventional therapy. In preclinical models, interference with macrophage migration, macrophage depletion and macrophage re-education have all been shown to reduce tumour growth and support anti-tumour immune responses. Here we discuss the role of macrophages in prognosis and sensitivity to therapy, while examining the significant progress which has been made in modulating the behaviour of these cells in cancer patients.
http://ift.tt/2xvTuas
Clinical evaluation of macrophages in cancer: role in treatment, modulation and challenges
Abstract
The focus of immunotherapeutics has been placed firmly on anti-tumour T cell responses. Significant progress has been made in the treatment of both local and systemic malignancies, but low response rates and rising toxicities are limiting this approach. Advancements in the understanding of tumour immunology are opening up a new range of therapeutic targets, including immunosuppressive factors in the tumour microenvironment. Macrophages are a heterogeneous group of cells that have roles in innate and adaptive immunity and tissue repair, but become co-opted by tumours to support tumour growth, survival, metastasis and immunosuppression. Macrophages also support tumour resistance to conventional therapy. In preclinical models, interference with macrophage migration, macrophage depletion and macrophage re-education have all been shown to reduce tumour growth and support anti-tumour immune responses. Here we discuss the role of macrophages in prognosis and sensitivity to therapy, while examining the significant progress which has been made in modulating the behaviour of these cells in cancer patients.
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Clinical evaluation of macrophages in cancer: role in treatment, modulation and challenges
Abstract
The focus of immunotherapeutics has been placed firmly on anti-tumour T cell responses. Significant progress has been made in the treatment of both local and systemic malignancies, but low response rates and rising toxicities are limiting this approach. Advancements in the understanding of tumour immunology are opening up a new range of therapeutic targets, including immunosuppressive factors in the tumour microenvironment. Macrophages are a heterogeneous group of cells that have roles in innate and adaptive immunity and tissue repair, but become co-opted by tumours to support tumour growth, survival, metastasis and immunosuppression. Macrophages also support tumour resistance to conventional therapy. In preclinical models, interference with macrophage migration, macrophage depletion and macrophage re-education have all been shown to reduce tumour growth and support anti-tumour immune responses. Here we discuss the role of macrophages in prognosis and sensitivity to therapy, while examining the significant progress which has been made in modulating the behaviour of these cells in cancer patients.
http://ift.tt/2xvTuas
Nano-Pulse Stimulation Induces Potent Immune Responses, Eradicating Local Breast Cancer while Reducing Distant Metastases
Abstract
Nano-Pulse Stimulation (NPS) as a developing technology has been studied for minimally invasive, non-thermal local cancer elimination for more than a decade. Here we show that a single NPS treatment results in complete regression of the poorly immunogenic, metastatic 4T1-Luc mouse mammary carcinoma. Impressively, spontaneous distant organ metastases were largely prevented, even in those animals with incomplete tumor regression. All tumor-free mice were protected from secondary tumor cell challenge, demonstrating a vaccine-like effect. NPS treatment induced anti-tumor immunity, long-term memory T cells, destruction of tumor microenvironment and reversal of the massive increase of immune suppressor cells in the tumor microenvironment and blood. NPS-treated 4T1 cells exhibited release of damage-associated molecular patterns (DAMPs), including calreticulin, HMGB1 and ATP, and activated dendritic cells. Those findings suggest that NPS is a potent immunogenic cell death inducer that elicits anti-tumor immunity to prevent distant metastases in addition to local tumor eradication. This article is protected by copyright. All rights reserved.
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Expression of miRNA-26b-5p and its target TRPS1 is associated with radiation exposure in post-Chernobyl breast cancer
Abstract
Ionising radiation is a well-recognised risk factor for the development of breast cancer, however, it is unknown whether radiation-specific molecular oncogenic mechanisms exist. We investigated post-Chernobyl breast cancers from radiation-exposed female clean-up workers and non-exposed controls for molecular changes. Radiation-associated alterations identified in the discovery cohort (n=38) were subsequently validated in a second cohort (n=39). Increased expression of hsa-miR-26b-5p was associated with radiation exposure in both of the cohorts. Moreover, downregulation of the TRPS1 protein, which is a transcriptional target of hsa-miR-26b-5p was associated with radiation exposure. Since TRPS1 overexpression is common in sporadic breast cancer its observed downregulation in radiation-associated breast cancer warrants clarification of the specific functional role of TRPS1 in the radiation context. For this purpose, the impact of TRPS1 on the transcriptome was characterised in two radiation-transformed breast cell culture models after siRNA-knockdown. Deregulated genes upon TRPS1 knockdown were associated with DNA-repair, cell cycle, mitosis, cell migration, angiogenesis and EMT pathways. Furthermore, we identified the interaction partners of TRPS1 from the transcriptomic correlation networks derived from gene expression data on radiation-transformed breast cell culture models and sporadic breast cancer tissues provided by the TCGA database. The genes correlating with TRPS1 in the radiation-transformed breast cell lines were primarily linked to DNA damage response and chromosome segregation, whilst the transcriptional interaction partners in the sporadic breast cancers were mostly associated with apoptosis. Thus, upregulation of hsa-miR-26b-5p and downregulation of TRPS1 in radiation-associated breast cancer tissue samples suggests these molecules representing radiation markers in breast cancer. This article is protected by copyright. All rights reserved.
from Cancer via ola Kala on Inoreader http://ift.tt/2xAvdlw
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Nano-Pulse Stimulation Induces Potent Immune Responses, Eradicating Local Breast Cancer while Reducing Distant Metastases
Abstract
Nano-Pulse Stimulation (NPS) as a developing technology has been studied for minimally invasive, non-thermal local cancer elimination for more than a decade. Here we show that a single NPS treatment results in complete regression of the poorly immunogenic, metastatic 4T1-Luc mouse mammary carcinoma. Impressively, spontaneous distant organ metastases were largely prevented, even in those animals with incomplete tumor regression. All tumor-free mice were protected from secondary tumor cell challenge, demonstrating a vaccine-like effect. NPS treatment induced anti-tumor immunity, long-term memory T cells, destruction of tumor microenvironment and reversal of the massive increase of immune suppressor cells in the tumor microenvironment and blood. NPS-treated 4T1 cells exhibited release of damage-associated molecular patterns (DAMPs), including calreticulin, HMGB1 and ATP, and activated dendritic cells. Those findings suggest that NPS is a potent immunogenic cell death inducer that elicits anti-tumor immunity to prevent distant metastases in addition to local tumor eradication. This article is protected by copyright. All rights reserved.
http://ift.tt/2wRrMTP
Expression of miRNA-26b-5p and its target TRPS1 is associated with radiation exposure in post-Chernobyl breast cancer
Abstract
Ionising radiation is a well-recognised risk factor for the development of breast cancer, however, it is unknown whether radiation-specific molecular oncogenic mechanisms exist. We investigated post-Chernobyl breast cancers from radiation-exposed female clean-up workers and non-exposed controls for molecular changes. Radiation-associated alterations identified in the discovery cohort (n=38) were subsequently validated in a second cohort (n=39). Increased expression of hsa-miR-26b-5p was associated with radiation exposure in both of the cohorts. Moreover, downregulation of the TRPS1 protein, which is a transcriptional target of hsa-miR-26b-5p was associated with radiation exposure. Since TRPS1 overexpression is common in sporadic breast cancer its observed downregulation in radiation-associated breast cancer warrants clarification of the specific functional role of TRPS1 in the radiation context. For this purpose, the impact of TRPS1 on the transcriptome was characterised in two radiation-transformed breast cell culture models after siRNA-knockdown. Deregulated genes upon TRPS1 knockdown were associated with DNA-repair, cell cycle, mitosis, cell migration, angiogenesis and EMT pathways. Furthermore, we identified the interaction partners of TRPS1 from the transcriptomic correlation networks derived from gene expression data on radiation-transformed breast cell culture models and sporadic breast cancer tissues provided by the TCGA database. The genes correlating with TRPS1 in the radiation-transformed breast cell lines were primarily linked to DNA damage response and chromosome segregation, whilst the transcriptional interaction partners in the sporadic breast cancers were mostly associated with apoptosis. Thus, upregulation of hsa-miR-26b-5p and downregulation of TRPS1 in radiation-associated breast cancer tissue samples suggests these molecules representing radiation markers in breast cancer. This article is protected by copyright. All rights reserved.
http://ift.tt/2xAvdlw
Clinical evaluation of macrophages in cancer: role in treatment, modulation and challenges
Abstract
The focus of immunotherapeutics has been placed firmly on anti-tumour T cell responses. Significant progress has been made in the treatment of both local and systemic malignancies, but low response rates and rising toxicities are limiting this approach. Advancements in the understanding of tumour immunology are opening up a new range of therapeutic targets, including immunosuppressive factors in the tumour microenvironment. Macrophages are a heterogeneous group of cells that have roles in innate and adaptive immunity and tissue repair, but become co-opted by tumours to support tumour growth, survival, metastasis and immunosuppression. Macrophages also support tumour resistance to conventional therapy. In preclinical models, interference with macrophage migration, macrophage depletion and macrophage re-education have all been shown to reduce tumour growth and support anti-tumour immune responses. Here we discuss the role of macrophages in prognosis and sensitivity to therapy, while examining the significant progress which has been made in modulating the behaviour of these cells in cancer patients.
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Sporadic Retroperitoneal Fibrosis: a Gentle Giant
Abstract
Fibromatosis covers a broad spectrum of benign fibrous tissue proliferation and is characterized by slow growing, locally infiltrative growth pattern with a high propensity for local recurrence. We report on a case of multicentric fibromatosis originating from the retroperitoneal space and submandibular triangle, in an 18-year-old lady. Computed tomography revealed a retroperitoneal abdominopelvic tumor extending from the left sub-diaphragmatic space to the pelvic inlet which had enveloped the solid viscera in the left upper quadrant with a displaced celiac axis. She also had a recurrent resectable fibromatosis in left submandibular gland. Histopathological evaluation revealed fibromatosis. Preoperatively, Vinblastin-, Methotrexate-, Tamoxifen-based systemic chemotherapy was offered for 12 weeks in an attempt to downsize the mass. An en bloc complete resection of tumor with multi-visceral resection was performed to achieve negative margins and since then, the patient has remained asymptomatic without any signs of tumor recurrence during the 12th month follow-up visit. Complete resection with negative margins is the treatment of choice and majority of the lesions are amenable for surgical resections. Adjuvant therapy using non-steroidal anti-inflammatory agents, tamoxifen, interferon, anti-neoplastic agents, and radiotherapy, either alone or in combination finds application for un-resectable or recurrent cases.
http://ift.tt/2hrO0tw
Sporadic Retroperitoneal Fibrosis: a Gentle Giant
Abstract
Fibromatosis covers a broad spectrum of benign fibrous tissue proliferation and is characterized by slow growing, locally infiltrative growth pattern with a high propensity for local recurrence. We report on a case of multicentric fibromatosis originating from the retroperitoneal space and submandibular triangle, in an 18-year-old lady. Computed tomography revealed a retroperitoneal abdominopelvic tumor extending from the left sub-diaphragmatic space to the pelvic inlet which had enveloped the solid viscera in the left upper quadrant with a displaced celiac axis. She also had a recurrent resectable fibromatosis in left submandibular gland. Histopathological evaluation revealed fibromatosis. Preoperatively, Vinblastin-, Methotrexate-, Tamoxifen-based systemic chemotherapy was offered for 12 weeks in an attempt to downsize the mass. An en bloc complete resection of tumor with multi-visceral resection was performed to achieve negative margins and since then, the patient has remained asymptomatic without any signs of tumor recurrence during the 12th month follow-up visit. Complete resection with negative margins is the treatment of choice and majority of the lesions are amenable for surgical resections. Adjuvant therapy using non-steroidal anti-inflammatory agents, tamoxifen, interferon, anti-neoplastic agents, and radiotherapy, either alone or in combination finds application for un-resectable or recurrent cases.
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Cancers, Vol. 9, Pages 130: Alcohol and Hepatocellular Carcinoma: Adding Fuel to the Flame
Cancers, Vol. 9, Pages 130: Alcohol and Hepatocellular Carcinoma: Adding Fuel to the Flame
Cancers doi: 10.3390/cancers9100130
Authors: Pierluigi Ramadori Francisco Cubero Christian Liedtke Christian Trautwein Yulia Nevzorova
Primary tumors of the liver represent the fifth most common type of cancer in the world and the third leading cause of cancer-related death. Case-control studies from different countries report that chronic ethanol consumption is associated with an approximately 2-fold increased odds ratio for hepatocellular carcinoma (HCC). Despite the substantial epidemiologic data in humans demonstrating that chronic alcohol consumption is a major risk factor for HCC development, the pathways causing alcohol-induced liver cancer are poorly understood. In this overview, we summarize the epidemiological evidence for the association between alcohol and liver cancer, review the genetic, oncogenic, and epigenetic factors that drive HCC development synergistically with ethanol intake and discuss the essential molecular and metabolic pathways involved in alcohol-induced liver tumorigenesis.
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Cancers, Vol. 9, Pages 130: Alcohol and Hepatocellular Carcinoma: Adding Fuel to the Flame
Cancers, Vol. 9, Pages 130: Alcohol and Hepatocellular Carcinoma: Adding Fuel to the Flame
Cancers doi: 10.3390/cancers9100130
Authors: Pierluigi Ramadori Francisco Cubero Christian Liedtke Christian Trautwein Yulia Nevzorova
Primary tumors of the liver represent the fifth most common type of cancer in the world and the third leading cause of cancer-related death. Case-control studies from different countries report that chronic ethanol consumption is associated with an approximately 2-fold increased odds ratio for hepatocellular carcinoma (HCC). Despite the substantial epidemiologic data in humans demonstrating that chronic alcohol consumption is a major risk factor for HCC development, the pathways causing alcohol-induced liver cancer are poorly understood. In this overview, we summarize the epidemiological evidence for the association between alcohol and liver cancer, review the genetic, oncogenic, and epigenetic factors that drive HCC development synergistically with ethanol intake and discuss the essential molecular and metabolic pathways involved in alcohol-induced liver tumorigenesis.
http://ift.tt/2wNdhW1
Evaluation and treatment of Langerhans cell histiocytosis patients with central nervous system abnormalities: Current views and new vistas
Abstract
Central nervous system (CNS) involvement in Langerhans cell histiocytosis (LCH) can include mass lesions of the hypothalamic pituitary axis, choroid plexus, cerebrum, and cerebellum or magnetic resonance imaging (MRI) signal abnormalities of the cerebellum, pons, and basal ganglia. The term neurodegenerative (ND) CNS-LCH has been given to the MRI signal abnormalities and neurologic dysfunction, although initially patients may have no clinical symptoms. Standardized evaluations to better understand the natural history and response to therapy are needed. We propose guidelines for clinical, radiologic, and physiologic tests as a framework for developing the best methods of evaluation, which can then be tested in prospective treatment protocols.
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Desire for parenthood and reproductive health knowledge in adolescents and young adults with sickle cell disease and their caregivers
Abstract
Background/objective
Sickle cell disease (SCD) and hydroxyurea have implications for fertility and reproductive health. The goal of this study was to examine desire for parenthood and reproductive health knowledge among a cohort of adolescent and young adult (AYA) with SCD receiving hydroxyurea and their caregivers at a large pediatric academic center.
Methods
Patients with SCD were approached from September 2016 to July 2017 if they were: (1) 12–20 years old, (2) prescribed hydroxyurea for at least 6 months, (3) proficient in English, and (4) accompanied by a caregiver who was proficient in English and willing to participate. Participants self-reported sociodemographic characteristics and completed surveys to assess their/their child's desire for parenthood and other life goals, and reproductive health knowledge.
Results
Eighteen patient–caregiver dyads completed the study (78.3% of those eligible); 61.1% indicated that they wanted to have future biological children. Few participants reported receiving information about fertility (16.7% of AYA and 27.8% of caregivers) or birth control (11.1% of AYA and 22.2% of caregivers) from their/their child's health care provider, and the majority had received no information on these topics. Less than half of participants reported that SCD (22.2% of AYA and 50.0% of caregivers) or hydroxyurea (11.1% of AYA and 27.8% of parents) could potentially impair fertility.
Conclusions
Biological parenthood was important to this cohort yet fertility and reproductive health knowledge was low, suggesting that clinicians should prioritize conversations about infertility risk and birth control options with AYA with SCD on hydroxyurea and their caregivers. More research is needed to identify optimal approaches to these discussions.
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Evaluation and treatment of Langerhans cell histiocytosis patients with central nervous system abnormalities: Current views and new vistas
Abstract
Central nervous system (CNS) involvement in Langerhans cell histiocytosis (LCH) can include mass lesions of the hypothalamic pituitary axis, choroid plexus, cerebrum, and cerebellum or magnetic resonance imaging (MRI) signal abnormalities of the cerebellum, pons, and basal ganglia. The term neurodegenerative (ND) CNS-LCH has been given to the MRI signal abnormalities and neurologic dysfunction, although initially patients may have no clinical symptoms. Standardized evaluations to better understand the natural history and response to therapy are needed. We propose guidelines for clinical, radiologic, and physiologic tests as a framework for developing the best methods of evaluation, which can then be tested in prospective treatment protocols.
http://ift.tt/2xEst7d
Desire for parenthood and reproductive health knowledge in adolescents and young adults with sickle cell disease and their caregivers
Abstract
Background/objective
Sickle cell disease (SCD) and hydroxyurea have implications for fertility and reproductive health. The goal of this study was to examine desire for parenthood and reproductive health knowledge among a cohort of adolescent and young adult (AYA) with SCD receiving hydroxyurea and their caregivers at a large pediatric academic center.
Methods
Patients with SCD were approached from September 2016 to July 2017 if they were: (1) 12–20 years old, (2) prescribed hydroxyurea for at least 6 months, (3) proficient in English, and (4) accompanied by a caregiver who was proficient in English and willing to participate. Participants self-reported sociodemographic characteristics and completed surveys to assess their/their child's desire for parenthood and other life goals, and reproductive health knowledge.
Results
Eighteen patient–caregiver dyads completed the study (78.3% of those eligible); 61.1% indicated that they wanted to have future biological children. Few participants reported receiving information about fertility (16.7% of AYA and 27.8% of caregivers) or birth control (11.1% of AYA and 22.2% of caregivers) from their/their child's health care provider, and the majority had received no information on these topics. Less than half of participants reported that SCD (22.2% of AYA and 50.0% of caregivers) or hydroxyurea (11.1% of AYA and 27.8% of parents) could potentially impair fertility.
Conclusions
Biological parenthood was important to this cohort yet fertility and reproductive health knowledge was low, suggesting that clinicians should prioritize conversations about infertility risk and birth control options with AYA with SCD on hydroxyurea and their caregivers. More research is needed to identify optimal approaches to these discussions.
http://ift.tt/2frb8rt
Treatment of immune thrombocytopenic purpura associated with cytomegalovirus infection in a child with pre-B cell acute lymphoblastic leukaemia after central nervous system relapse
A 13-year-old male patient with a history of pre-B cell acute lymphoblastic leukaemia (ALL) with isolated central nervous system relapse on maintenance chemotherapy presented with severe thrombocytopenia refractory to platelet transfusions. The patient showed only modest responses to two courses of intravenous immunoglobulin and steroids. He was found to be positive for cytomegalovirus (CMV) with modest viral load. His thrombocytopenia normalised with rituximab therapy and CMV treatment supporting the diagnosis of CMV-associated immune thrombocytopenic purpura (ITP). Following treatment, the patient continued to have a stable platelet count well above the threshold for transfusions. He continued to be intermittently treated for CMV when viral loads became detectable. This report discusses the unique management considerations of ITP in a patient undergoing therapy for ALL with a review of previously reported cases and discusses the possibility of CMV viraemia as a modulating factor.
http://ift.tt/2wR8r51
Unusual presentation of silently growing abdominal aortic aneurysm causing biliary obstruction
Biliary obstruction is a rare presentation of abdominal aortic aneurysm (AAA). The most common symptoms of AAA are abdominal or back pain and limb ischaemia from thromboembolism. We report a case of a 67-year-old male who was diagnosed with obstructive jaundice secondary to an AAA. CT angiogram revealed compression of the common bile duct by the large AAA, causing diffuse intrahepatic and extrahepatic ductal dilatation. Surgical repair of the aortic aneurysm was successful, and patient's symptoms improved.
http://ift.tt/2xAdlau
Phase I/II trial of dendritic cell-based active cellular immunotherapy with DCVAC/PCa in patients with rising PSA after primary prostatectomy or salvage radiotherapy for the treatment of prostate cancer
Abstract
Objective
Immunotherapy of cancer has the potential to be effective mostly in patients with a low tumour burden. Rising PSA (prostate-specific antigen) levels in patients with prostate cancer represents such a situation. We performed the present clinical study with dendritic cell (DC)-based immunotherapy in this patient population.
Materials and methods
The single-arm phase I/II trial registered as EudraCT 2009-017259-91 involved 27 patients with rising PSA levels. The study medication consisted of autologous DCs pulsed with the killed LNCaP cell line (DCVAC/PCa). Twelve patients with a favourable PSA response continued with the second cycle of immunotherapy. The primary and secondary objectives of the study were to assess the safety and determine the PSA doubling time (PSADT), respectively.
Results
No significant side effects were recorded. The median PSADT in all treated patients increased from 5.67 months prior to immunotherapy to 18.85 months after 12 doses (p < 0.0018). Twelve patients who continued immunotherapy with the second cycle had a median PSADT of 58 months that remained stable after the second cycle. In the peripheral blood, specific PSA-reacting T lymphocytes were increased significantly already after the fourth dose, and a stable frequency was detected throughout the remainder of DCVAC/PCa treatment.
Summary
Long-term immunotherapy of prostate cancer patients experiencing early signs of PSA recurrence using DCVAC/PCa was safe, induced an immune response and led to the significant prolongation of PSADT. Long-term follow-up may show whether the changes in PSADT might improve the clinical outcome in patients with biochemical recurrence of the prostate cancer.
http://ift.tt/2fsa4Uk
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