Association between serious psychological distress and nonparticipation in cancer screening and the modifying effect of socioeconomic status: Analysis of anonymized data from a national cross-sectional survey in Japan

BACKGROUND

It is unclear whether individuals who have serious psychological distress (SPD) are less likely to participate in screening tests for gastric cancer, lung cancer, and other types of cancer. Of the few studies that have examined the association between SPD and participation in cancer screening, none have reported modifying effects of educational, marital, or employment status.

METHODS

The authors analyzed a national representative data set from the 2010 Comprehensive Survey of Living Conditions of Japan., including individuals aged <69 years who met the national program criteria for each type of cancer screening (colorectal, gastric, and lung cancers, n = 29,926; breast cancer, n = 15,423; and cervical cancer, n = 24,735). SPD was defined as a score of 13 or greater on the Kessler 6 scale. Logistic regression analyses were conducted to examine the association between SPD and participation in cancer screening, and multivariate analyses stratified by socioeconomic status also were conducted.

RESULTS

SPD was significantly associated with a lower odds ratio (OR) for participation in screening for colorectal cancer (OR, 0.743; 95% confidence interval [CI], 0.638-0.866), gastric cancer (OR, 0.823; 95% CI, 0.717-0.946), and lung cancer (OR, 0.691; 95% CI, 0.592-0.807). Only educational status significantly modified the effect of SPD on participation in these 3 types of cancer screening (P < .05).

CONCLUSIONS

Individuals with SPD, especially those with lower education levels, were less likely to participate in screening for colorectal, gastric, and lung cancers. Individuals with SPD should be encouraged and supported to participate in cancer screening tests. Cancer 2017. © 2017 American Cancer Society.

from Cancer via ola Kala on Inoreader http://ift.tt/2yQKkWY
via IFTTT

Association between serious psychological distress and nonparticipation in cancer screening and the modifying effect of socioeconomic status: Analysis of anonymized data from a national cross-sectional survey in Japan

BACKGROUND

It is unclear whether individuals who have serious psychological distress (SPD) are less likely to participate in screening tests for gastric cancer, lung cancer, and other types of cancer. Of the few studies that have examined the association between SPD and participation in cancer screening, none have reported modifying effects of educational, marital, or employment status.

METHODS

The authors analyzed a national representative data set from the 2010 Comprehensive Survey of Living Conditions of Japan., including individuals aged <69 years who met the national program criteria for each type of cancer screening (colorectal, gastric, and lung cancers, n = 29,926; breast cancer, n = 15,423; and cervical cancer, n = 24,735). SPD was defined as a score of 13 or greater on the Kessler 6 scale. Logistic regression analyses were conducted to examine the association between SPD and participation in cancer screening, and multivariate analyses stratified by socioeconomic status also were conducted.

RESULTS

SPD was significantly associated with a lower odds ratio (OR) for participation in screening for colorectal cancer (OR, 0.743; 95% confidence interval [CI], 0.638-0.866), gastric cancer (OR, 0.823; 95% CI, 0.717-0.946), and lung cancer (OR, 0.691; 95% CI, 0.592-0.807). Only educational status significantly modified the effect of SPD on participation in these 3 types of cancer screening (P < .05).

CONCLUSIONS

Individuals with SPD, especially those with lower education levels, were less likely to participate in screening for colorectal, gastric, and lung cancers. Individuals with SPD should be encouraged and supported to participate in cancer screening tests. Cancer 2017. © 2017 American Cancer Society.

http://ift.tt/2yQKkWY

Prognostic significance of postoperative pneumonia after curative resection for patients with gastric cancer

Abstract

Few studies have been designed to investigate the incidence of postoperative pneumonia after radical gastrectomy and its effect on prognosis of these patients. Incidences of postoperative pneumonia after radical gastrectomy in our department between January 1996 and December 2014 were summarized. Their effects on prognosis were retrospectively analyzed using survival curves and Cox regression. A total of 5237 patients were included in this study, 767 (14.4%) of them had complications, including 383 cases of postoperative pneumonia (7.2%). The 5-year overall and disease-specific survival of patients with postoperative pneumonia were both lower than those without this complication (P < 0.001). Stratified analysis demonstrated that this difference existed in all Stage I, II, and III patients (log-rank, P < 0.05). Multivariate analysis revealed that age, neoadjuvant chemotherapy, tumor size, tumor stage, and postoperative pneumonia were independent risk factors for disease-specific survival. Postoperative pneumonia after radical gastrectomy is an independent risk factor for prognosis of gastric cancer patients, especially in stage III.

The study found that postoperative pneumonia after radical gastrectomy is an independent risk factor for prognosis of gastric cancer patients, especially in stage III. The prognoses of these pneumonic patients improve in the last decade.

from Cancer via ola Kala on Inoreader http://ift.tt/2zHe47U
via IFTTT

Progression-free survival at 2 years post-autologous transplant: a surrogate end point for overall survival in follicular lymphoma

Abstract

Overall survival (OS) is the gold-standard end point for studies evaluating autologous stem cell transplantation (ASCT) in follicular lymphoma (FL), but assessment may be elusive due to the lengthy disease course. We analyzed the validity of two earlier end points, proposed in the setting of first-line chemo-/immunotherapy, as surrogates for OS—progression-free survival (PFS) status at 24 months (PFS24) and complete response at 30 months (CR30) post-ASCT. We also have investigated the clinical features of patients with early progression after ASCT. Data were available for 626 chemosensitive FL patients who received ASCT between 1989 and 2007. Median follow-up was 12.2 years from ASCT. In the PFS24 analysis, 153 (24%) patients progressed within 24 months and 447 were alive and progression-free at 24 months post-ASCT (26 who died without disease progressions within 24 months were excluded). Early progression was associated with shorter OS (hazard ratio [HR], 6.8; P = 0.00001). In the subgroup of patients who received an ASCT in the setting or relapse after being exposed to rituximab, the HR was 11.3 (95% CI, 3.9–30.2; P < 0.00001). In the CR30 analysis, 183 of 596 (31%) response-evaluable patients progressed/died with 30 months post-ASCT. The absence of CR30 was associated with shorter OS (HR, 7.8; P < 0.00001), including in patients with prior rituximab (HR, 8.2). PFS24 and CR30 post-ASCT are associated with poor outcomes and should be primary end points. Further research is needed to identify this population to be offered alternative treatments.

Disease progression within 2 years and absence of CR at 30 months post-ASCT define new high-risk groups who should be ideally identified soon in order to be offered different therapeutic strategies, such as allogenic stem cell transplantation or novel drugs.

from Cancer via ola Kala on Inoreader http://ift.tt/2gMNQgx
via IFTTT

Prognostic significance of postoperative pneumonia after curative resection for patients with gastric cancer

Abstract

Few studies have been designed to investigate the incidence of postoperative pneumonia after radical gastrectomy and its effect on prognosis of these patients. Incidences of postoperative pneumonia after radical gastrectomy in our department between January 1996 and December 2014 were summarized. Their effects on prognosis were retrospectively analyzed using survival curves and Cox regression. A total of 5237 patients were included in this study, 767 (14.4%) of them had complications, including 383 cases of postoperative pneumonia (7.2%). The 5-year overall and disease-specific survival of patients with postoperative pneumonia were both lower than those without this complication (P < 0.001). Stratified analysis demonstrated that this difference existed in all Stage I, II, and III patients (log-rank, P < 0.05). Multivariate analysis revealed that age, neoadjuvant chemotherapy, tumor size, tumor stage, and postoperative pneumonia were independent risk factors for disease-specific survival. Postoperative pneumonia after radical gastrectomy is an independent risk factor for prognosis of gastric cancer patients, especially in stage III.

The study found that postoperative pneumonia after radical gastrectomy is an independent risk factor for prognosis of gastric cancer patients, especially in stage III. The prognoses of these pneumonic patients improve in the last decade.

http://ift.tt/2zHe47U

Progression-free survival at 2 years post-autologous transplant: a surrogate end point for overall survival in follicular lymphoma

Abstract

Overall survival (OS) is the gold-standard end point for studies evaluating autologous stem cell transplantation (ASCT) in follicular lymphoma (FL), but assessment may be elusive due to the lengthy disease course. We analyzed the validity of two earlier end points, proposed in the setting of first-line chemo-/immunotherapy, as surrogates for OS—progression-free survival (PFS) status at 24 months (PFS24) and complete response at 30 months (CR30) post-ASCT. We also have investigated the clinical features of patients with early progression after ASCT. Data were available for 626 chemosensitive FL patients who received ASCT between 1989 and 2007. Median follow-up was 12.2 years from ASCT. In the PFS24 analysis, 153 (24%) patients progressed within 24 months and 447 were alive and progression-free at 24 months post-ASCT (26 who died without disease progressions within 24 months were excluded). Early progression was associated with shorter OS (hazard ratio [HR], 6.8; P = 0.00001). In the subgroup of patients who received an ASCT in the setting or relapse after being exposed to rituximab, the HR was 11.3 (95% CI, 3.9–30.2; P < 0.00001). In the CR30 analysis, 183 of 596 (31%) response-evaluable patients progressed/died with 30 months post-ASCT. The absence of CR30 was associated with shorter OS (HR, 7.8; P < 0.00001), including in patients with prior rituximab (HR, 8.2). PFS24 and CR30 post-ASCT are associated with poor outcomes and should be primary end points. Further research is needed to identify this population to be offered alternative treatments.

Disease progression within 2 years and absence of CR at 30 months post-ASCT define new high-risk groups who should be ideally identified soon in order to be offered different therapeutic strategies, such as allogenic stem cell transplantation or novel drugs.

http://ift.tt/2gMNQgx

The utility of 68Ga-DOTATATE positron-emission tomography/computed tomography in the diagnosis, management, follow-up and prognosis of neuroendocrine tumors

Future Oncology, Ahead of Print.


from Cancer via ola Kala on Inoreader http://ift.tt/2y8T4dG
via IFTTT

The utility of 68Ga-DOTATATE positron-emission tomography/computed tomography in the diagnosis, management, follow-up and prognosis of neuroendocrine tumors

Future Oncology, Ahead of Print.


http://ift.tt/2y8T4dG

The utility of 68Ga-DOTATATE positron-emission tomography/computed tomography in the diagnosis, management, follow-up and prognosis of neuroendocrine tumors

Future Oncology, Ahead of Print.


from Cancer via ola Kala on Inoreader http://ift.tt/2y8T4dG
via IFTTT

Radiomics to predict immunotherapy-induced pneumonitis: proof of concept

Summary

We present the first reported work that explores the potential of radiomics to predict patients who are at risk for developing immunotherapy-induced pneumonitis. Despite promising results with immunotherapies, immune-related adverse events (irAEs) are challenging. Although less common, pneumonitis is a potentially fatal irAE. Thus, early detection is critical for improving treatment outcomes; an urgent need to identify biomarkers that predict patients at risk for pneumonitis exists. Radiomics, an emerging field, is the automated extraction of high fidelity, high-dimensional imaging features from standard medical images and allows for comprehensive visualization and characterization of the tissue of interest and corresponding microenvironment. In this pilot study, we sought to determine whether radiomics has the potential to predict development of pneumonitis. We performed radiomic analyses using baseline chest computed tomography images of patients who did (N = 2) and did not (N = 30) develop immunotherapy-induced pneumonitis. We extracted 1860 radiomic features in each patient. Maximum relevance and minimum redundancy feature selection method, anomaly detection algorithm, and leave-one-out cross-validation identified radiomic features that were significantly different and predicted subsequent immunotherapy-induced pneumonitis (accuracy, 100% [p = 0.0033]). This study suggests that radiomic features can classify and predict those patients at baseline who will subsequently develop immunotherapy-induced pneumonitis, further enabling risk-stratification that will ultimately lead to better treatment outcomes.

http://ift.tt/2i7sRS1

Radiomics to predict immunotherapy-induced pneumonitis: proof of concept

Summary

We present the first reported work that explores the potential of radiomics to predict patients who are at risk for developing immunotherapy-induced pneumonitis. Despite promising results with immunotherapies, immune-related adverse events (irAEs) are challenging. Although less common, pneumonitis is a potentially fatal irAE. Thus, early detection is critical for improving treatment outcomes; an urgent need to identify biomarkers that predict patients at risk for pneumonitis exists. Radiomics, an emerging field, is the automated extraction of high fidelity, high-dimensional imaging features from standard medical images and allows for comprehensive visualization and characterization of the tissue of interest and corresponding microenvironment. In this pilot study, we sought to determine whether radiomics has the potential to predict development of pneumonitis. We performed radiomic analyses using baseline chest computed tomography images of patients who did (N = 2) and did not (N = 30) develop immunotherapy-induced pneumonitis. We extracted 1860 radiomic features in each patient. Maximum relevance and minimum redundancy feature selection method, anomaly detection algorithm, and leave-one-out cross-validation identified radiomic features that were significantly different and predicted subsequent immunotherapy-induced pneumonitis (accuracy, 100% [p = 0.0033]). This study suggests that radiomic features can classify and predict those patients at baseline who will subsequently develop immunotherapy-induced pneumonitis, further enabling risk-stratification that will ultimately lead to better treatment outcomes.

from Cancer via ola Kala on Inoreader http://ift.tt/2i7sRS1
via IFTTT

Allogeneic human double negative T cells as a novel immunotherapy for acute myeloid leukemia and its underlying mechanisms.

Purpose: To explore the potential of ex vivo expanded healthy donor derived allogeneic CD4 and CD8 double negative cells (DNTs) as a novel cellular immunotherapy for leukemia patients. Experimental Design: Clinical grade DNTs from peripheral blood of healthy donors were expanded and their anti-leukemic activity and safety were examined using flow-cytometry based in vitro killing assays and xenograft models against AML patient blasts and healthy donor-derived hematopoietic cells. Mechanism of action was investigated using antibody-mediated blocking assays and recombinant protein treatment assays. Results:  Expanded DNTs from healthy donors target a majority(36/46) of primary AML cells including 9 chemotherapy-resistant patient samples in vitro and significantly reduce the leukemia load in patient-derived xenograft models in a DNT-donor unrestricted manner. Importantly, allogeneic DNTs do not attack normal hematopoietic cells or affect hematopoietic stem/progenitor cell engraftment and differentiation, nor cause xenogeneic graft-versus-host disease in recipients. Mechanistically, DNTs express high levels of NKG2D and DNAM-1 that bind to cognate ligands preferentially expressed on AML cells. Upon recognition of AML cells, DNTs rapidly release IFN which further increases NKG2D and DNAM-1 ligands expression on AML cells. IFN pretreatment enhances the susceptibility of AML cells to DNT-mediated cytotoxicity, including primary AML samples that are otherwise resistant to DNTs, and the effect of IFN treatment is abrogated by NKG2D and DNAM-1 blocking antibodies. Conclusion: This study supports healthy donor-derived allogeneic DNTs as a therapy to treat patients with chemotherapy-resistant AML and also reveals interrelated roles of NKG2D, DNAM-1, and IFN in selective targeting of AML by DNTs.

http://ift.tt/2i7p9Ig

Low PD-1 expression in Cytotoxic CD8+ Tumor infiltrating Lymphocytes Confers an Immune Privileged Tissue Microenvironment in NSCLC with a Prognostic and Predictive Value

The success of immune checkpoint inhibitors strengthens the notion that tumor growth and regression are immune regulated. To determine whether distinct tissue immune microenvironments differentially impact on clinical outcome in Non Small Cell Lung Cancer (NSCLC), an extended analysis of PD-L1 and Tumor Infiltrating Lymphocytes (TILs) was performed. Experimental Design Samples from resected adenocarcinoma (ADC 42) and squamous cell carcinoma (SCC 58) and from 26 advanced diseases (13 ADC, 13 SCC) treated with nivolumab were analyzed. PD-L1 expression and the incidence of CD3, CD8, CD4, PD-1, CD57, FOXP3, CD25 and Granzyme B TILs was immunohistochemically assessed. Results PD-L1 levels inversely correlated with N involvement although did not show a statistical significant prognostic value in resected patients. The incidence and phenotype of TILs differed in SCC vs ADC in which EGFR and KRAS mutations conditioned a different frequency and tissue localization of lymphocytes. NSCLC resected patients with high CD8 pos lymphocytes lacking PD-1 inhibitory receptor had a longer Overall Survival (OS:HR=2.268, 95%CI 1.056-4.871,p=0.03). PD-1-to-CD8 ratio resulted a prognostic factor both on univariate (HR=1.952, 95%CI 1.34-3.12,p=0.001) and multivariate (HR=1.943, 95%CI 1.38-2.86,p=0.009) analysis. Moreover, low PD-1 incidence among CD8^pos cells was a distinctive feature of nivolumab treated patients showing clinical benefit with a prolonged Progression-Free Survival (PFS:HR=4.51, 95%CI 1.45-13.94,p=0.004). Conclusions In the presence of intrinsic variability in PD-L1 expression, the reservoir of PD-1 negative effector T-lymphocytes provides an immune-privileged microenvironment with a positive impact on survival of patients with resected disease and response to immunotherapy in advanced NSCLC.

http://ift.tt/2gIjgRB

Concurrent inhibition of Pim and FLT3 kinases enhances apoptosis of FLT3-ITD acute myeloid leukemia cells through increased Mcl-1 proteasomal degradation

Purpose:fms-like tyrosine kinase 3 internal tandem duplication (FLT3-ITD) is present in 30% of acute myeloid leukemia (AML), and these patients have short disease-free survival. FLT3 inhibitors have limited and transient clinical activity, and concurrent treatment with inhibitors of parallel or downstream signaling may improve responses. The oncogenic serine/threonine kinase Pim-1 is upregulated downstream of FLT3-ITD and also promotes its signaling in a positive feedback loop, suggesting benefit of combined Pim and FLT3 inhibition. Experimental Design: Combinations of clinically active Pim and FLT3 inhibitors were studied in vitro and in vivo. Results: Concurrent treatment with the pan-Pim inhibitor AZD1208 and FLT3 inhibitors at clinically applicable concentrations abrogated in vitro growth of FLT3-ITD, but not wild-type FLT3 (FLT3-WT), cell lines. AZD1208 co-treatment increased FLT3 inhibitor-induced apoptosis of FLT3-ITD, but not FLT3-WT, cells measured by sub-G1 fraction, annexin V labeling, mitochondrial membrane potential and PARP and caspase-3 cleavage. Concurrent treatment with AZD1208 and the FLT3 inhibitor quizartinib decreased growth of MV4-11 cells, with FLT3-ITD, in mouse xenografts and prolonged survival, enhanced apoptosis of FLT3-ITD primary AML blasts, but not FLT3-WT blasts or remission marrow cells, and decreased FLT3-ITD AML blast colony formation. Mechanistically, AZD1208 and quizartinib co-treatment decreased expression of the anti-apoptotic protein Mcl-1. Decrease in Mcl-1 protein expression was abrogated by treatment with the proteasome inhibitor MG132, and was preceded by downregulation of the Mcl-1 deubiquitinase USP9X, a novel mechanism of Mcl-1 regulation in AML. Conclusion: The data support clinical testing of Pim and FLT3 inhibitor combination therapy for FLT3-ITD AML.

http://ift.tt/2i7S132

Prospective feasibility trial for genomics-informed treatment in recurrent and progressive glioblastoma

Purpose: Glioblastoma is an aggressive and molecularly heterogeneous cancer with few effective treatment options. We hypothesized that next-generation sequencing can be used to guide treatment recommendations within a clinically acceptable time frame following surgery for patients with recurrent glioblastoma. Methods: We conducted a prospective genomics-informed feasibility trial in adults with recurrent and progressive glioblastoma. Following surgical resection, genome-wide tumor/normal exome-sequencing and tumor RNA-sequencing was performed to identify molecular targets for potential matched therapy. A multi-disciplinary molecular tumor board issued treatment recommendations based on the genomic results, blood brain barrier penetration of the indicated therapies, drug-drug interactions, and drug safety profiles. Feasibility of generating genomics-informed treatment recommendations within 35 days of surgery was assessed. Results: Of the 20 patients enrolled in the study, 16 patients had sufficient tumor tissue for analysis. Exome-sequencing was completed for all patients and RNA-sequencing was completed for 14 patients. Treatment recommendations were provided within the study's feasibility time frame for 15 of 16 (94%) patients. Seven patients received treatment based on the tumor board recommendations. Two patients reached 12-month progression-free survival, both adhering to treatments based on the molecular profiling results. One patient remained on treatment and progression-free 21 months after surgery, three-times longer than the patient's previous time to progression. Analysis of matched non-enhancing tissue from 12 patients revealed overlapping as well as novel putatively actionable genomic alterations. Conclusion: Use of genome-wide molecular profiling is feasible and can be informative for guiding real-time, central nervous system (CNS)-penetrant, genomics-informed treatment recommendations for patients with recurrent glioblastoma.

http://ift.tt/2gFnVn4

Allogeneic human double negative T cells as a novel immunotherapy for acute myeloid leukemia and its underlying mechanisms.

Purpose: To explore the potential of ex vivo expanded healthy donor derived allogeneic CD4 and CD8 double negative cells (DNTs) as a novel cellular immunotherapy for leukemia patients. Experimental Design: Clinical grade DNTs from peripheral blood of healthy donors were expanded and their anti-leukemic activity and safety were examined using flow-cytometry based in vitro killing assays and xenograft models against AML patient blasts and healthy donor-derived hematopoietic cells. Mechanism of action was investigated using antibody-mediated blocking assays and recombinant protein treatment assays. Results:  Expanded DNTs from healthy donors target a majority(36/46) of primary AML cells including 9 chemotherapy-resistant patient samples in vitro and significantly reduce the leukemia load in patient-derived xenograft models in a DNT-donor unrestricted manner. Importantly, allogeneic DNTs do not attack normal hematopoietic cells or affect hematopoietic stem/progenitor cell engraftment and differentiation, nor cause xenogeneic graft-versus-host disease in recipients. Mechanistically, DNTs express high levels of NKG2D and DNAM-1 that bind to cognate ligands preferentially expressed on AML cells. Upon recognition of AML cells, DNTs rapidly release IFN which further increases NKG2D and DNAM-1 ligands expression on AML cells. IFN pretreatment enhances the susceptibility of AML cells to DNT-mediated cytotoxicity, including primary AML samples that are otherwise resistant to DNTs, and the effect of IFN treatment is abrogated by NKG2D and DNAM-1 blocking antibodies. Conclusion: This study supports healthy donor-derived allogeneic DNTs as a therapy to treat patients with chemotherapy-resistant AML and also reveals interrelated roles of NKG2D, DNAM-1, and IFN in selective targeting of AML by DNTs.

from Cancer via ola Kala on Inoreader http://ift.tt/2i7p9Ig
via IFTTT

Low PD-1 expression in Cytotoxic CD8+ Tumor infiltrating Lymphocytes Confers an Immune Privileged Tissue Microenvironment in NSCLC with a Prognostic and Predictive Value

The success of immune checkpoint inhibitors strengthens the notion that tumor growth and regression are immune regulated. To determine whether distinct tissue immune microenvironments differentially impact on clinical outcome in Non Small Cell Lung Cancer (NSCLC), an extended analysis of PD-L1 and Tumor Infiltrating Lymphocytes (TILs) was performed. Experimental Design Samples from resected adenocarcinoma (ADC 42) and squamous cell carcinoma (SCC 58) and from 26 advanced diseases (13 ADC, 13 SCC) treated with nivolumab were analyzed. PD-L1 expression and the incidence of CD3, CD8, CD4, PD-1, CD57, FOXP3, CD25 and Granzyme B TILs was immunohistochemically assessed. Results PD-L1 levels inversely correlated with N involvement although did not show a statistical significant prognostic value in resected patients. The incidence and phenotype of TILs differed in SCC vs ADC in which EGFR and KRAS mutations conditioned a different frequency and tissue localization of lymphocytes. NSCLC resected patients with high CD8 pos lymphocytes lacking PD-1 inhibitory receptor had a longer Overall Survival (OS:HR=2.268, 95%CI 1.056-4.871,p=0.03). PD-1-to-CD8 ratio resulted a prognostic factor both on univariate (HR=1.952, 95%CI 1.34-3.12,p=0.001) and multivariate (HR=1.943, 95%CI 1.38-2.86,p=0.009) analysis. Moreover, low PD-1 incidence among CD8^pos cells was a distinctive feature of nivolumab treated patients showing clinical benefit with a prolonged Progression-Free Survival (PFS:HR=4.51, 95%CI 1.45-13.94,p=0.004). Conclusions In the presence of intrinsic variability in PD-L1 expression, the reservoir of PD-1 negative effector T-lymphocytes provides an immune-privileged microenvironment with a positive impact on survival of patients with resected disease and response to immunotherapy in advanced NSCLC.

from Cancer via ola Kala on Inoreader http://ift.tt/2gIjgRB
via IFTTT

Concurrent inhibition of Pim and FLT3 kinases enhances apoptosis of FLT3-ITD acute myeloid leukemia cells through increased Mcl-1 proteasomal degradation

Purpose:fms-like tyrosine kinase 3 internal tandem duplication (FLT3-ITD) is present in 30% of acute myeloid leukemia (AML), and these patients have short disease-free survival. FLT3 inhibitors have limited and transient clinical activity, and concurrent treatment with inhibitors of parallel or downstream signaling may improve responses. The oncogenic serine/threonine kinase Pim-1 is upregulated downstream of FLT3-ITD and also promotes its signaling in a positive feedback loop, suggesting benefit of combined Pim and FLT3 inhibition. Experimental Design: Combinations of clinically active Pim and FLT3 inhibitors were studied in vitro and in vivo. Results: Concurrent treatment with the pan-Pim inhibitor AZD1208 and FLT3 inhibitors at clinically applicable concentrations abrogated in vitro growth of FLT3-ITD, but not wild-type FLT3 (FLT3-WT), cell lines. AZD1208 co-treatment increased FLT3 inhibitor-induced apoptosis of FLT3-ITD, but not FLT3-WT, cells measured by sub-G1 fraction, annexin V labeling, mitochondrial membrane potential and PARP and caspase-3 cleavage. Concurrent treatment with AZD1208 and the FLT3 inhibitor quizartinib decreased growth of MV4-11 cells, with FLT3-ITD, in mouse xenografts and prolonged survival, enhanced apoptosis of FLT3-ITD primary AML blasts, but not FLT3-WT blasts or remission marrow cells, and decreased FLT3-ITD AML blast colony formation. Mechanistically, AZD1208 and quizartinib co-treatment decreased expression of the anti-apoptotic protein Mcl-1. Decrease in Mcl-1 protein expression was abrogated by treatment with the proteasome inhibitor MG132, and was preceded by downregulation of the Mcl-1 deubiquitinase USP9X, a novel mechanism of Mcl-1 regulation in AML. Conclusion: The data support clinical testing of Pim and FLT3 inhibitor combination therapy for FLT3-ITD AML.

from Cancer via ola Kala on Inoreader http://ift.tt/2i7S132
via IFTTT

Prospective feasibility trial for genomics-informed treatment in recurrent and progressive glioblastoma

Purpose: Glioblastoma is an aggressive and molecularly heterogeneous cancer with few effective treatment options. We hypothesized that next-generation sequencing can be used to guide treatment recommendations within a clinically acceptable time frame following surgery for patients with recurrent glioblastoma. Methods: We conducted a prospective genomics-informed feasibility trial in adults with recurrent and progressive glioblastoma. Following surgical resection, genome-wide tumor/normal exome-sequencing and tumor RNA-sequencing was performed to identify molecular targets for potential matched therapy. A multi-disciplinary molecular tumor board issued treatment recommendations based on the genomic results, blood brain barrier penetration of the indicated therapies, drug-drug interactions, and drug safety profiles. Feasibility of generating genomics-informed treatment recommendations within 35 days of surgery was assessed. Results: Of the 20 patients enrolled in the study, 16 patients had sufficient tumor tissue for analysis. Exome-sequencing was completed for all patients and RNA-sequencing was completed for 14 patients. Treatment recommendations were provided within the study's feasibility time frame for 15 of 16 (94%) patients. Seven patients received treatment based on the tumor board recommendations. Two patients reached 12-month progression-free survival, both adhering to treatments based on the molecular profiling results. One patient remained on treatment and progression-free 21 months after surgery, three-times longer than the patient's previous time to progression. Analysis of matched non-enhancing tissue from 12 patients revealed overlapping as well as novel putatively actionable genomic alterations. Conclusion: Use of genome-wide molecular profiling is feasible and can be informative for guiding real-time, central nervous system (CNS)-penetrant, genomics-informed treatment recommendations for patients with recurrent glioblastoma.

from Cancer via ola Kala on Inoreader http://ift.tt/2gFnVn4
via IFTTT

Hepatitis C virus-induced prion protein expression facilitates hepatitis C virus replication

Abstract

Hepatitis C virus (HCV) infects approximately 180 million people worldwide. Significant progress has been made since the establishment of in vitro HCV infection models in cells. However, the replication of HCV is complex and not completely understood. Here, we found that the expression of host prion protein (PrP) was induced in an HCV replication cell model. We then showed that increased PrP expression facilitated HCV genomic replication. Finally, we demonstrated that the KKRPK motif on the N-terminus of PrP bound nucleic acids and facilitated HCV genomic replication. Our results provided important insights into how viruses may harness cellular protein to achieve propagation.

from Cancer via ola Kala on Inoreader http://ift.tt/2zHwBky
via IFTTT

Hepatitis C virus-induced prion protein expression facilitates hepatitis C virus replication

Abstract

Hepatitis C virus (HCV) infects approximately 180 million people worldwide. Significant progress has been made since the establishment of in vitro HCV infection models in cells. However, the replication of HCV is complex and not completely understood. Here, we found that the expression of host prion protein (PrP) was induced in an HCV replication cell model. We then showed that increased PrP expression facilitated HCV genomic replication. Finally, we demonstrated that the KKRPK motif on the N-terminus of PrP bound nucleic acids and facilitated HCV genomic replication. Our results provided important insights into how viruses may harness cellular protein to achieve propagation.

http://ift.tt/2zHwBky

Pseudomyxoma pleuri as a Surgical Emergency: a Rare Case Report

Abstract

Pseudomyxoma pleuri is a rare condition and it mostly results from secondary involvement of an abdominal pathology. Massive pleural disease impedes cardiopulmonary functions and threatens life. We are reporting our experience about managing a middle-age lady with a known case of Pseudomyxoma peritonei, who presented to causality with progressive breathing difficulty in acute exacerbation and cardiopulmonary compromise.

from Cancer via ola Kala on Inoreader http://ift.tt/2yTR9ZM
via IFTTT

Pseudomyxoma pleuri as a Surgical Emergency: a Rare Case Report

Abstract

Pseudomyxoma pleuri is a rare condition and it mostly results from secondary involvement of an abdominal pathology. Massive pleural disease impedes cardiopulmonary functions and threatens life. We are reporting our experience about managing a middle-age lady with a known case of Pseudomyxoma peritonei, who presented to causality with progressive breathing difficulty in acute exacerbation and cardiopulmonary compromise.

http://ift.tt/2yTR9ZM

Conversion of PRPS hexamer to monomer by AMPK-mediated phosphorylation inhibits nucleotide synthesis in response to energy stress [Research Articles]

Tumors override energy stress to grow. However, how nucleotide synthesis is regulated under energy stress is unclear. We demonstrate here that glucose deprivation or hypoxia results in the AMPK-mediated phosphorylation of phosphoribosyl pyrophosphate synthetase (PRPS) 1 S180 and PRPS2 S183, leading to conversion of PRPS hexamers to monomers and thereby inhibiting PRPS1/2 activity, nucleotide synthesis, and nicotinamide adenine dinucleotide (NAD) production. Knock-in of non-phosphorylatable PRPS1/2 mutants, which have uninhibited activity, in brain tumor cells under energy stress exhausts cellular ATP and NADPH and increases ROS levels, thereby promoting cell apoptosis. The expression of those mutants inhibits brain tumor formation and enhances the inhibitory effect of the glycolysis inhibitor 2-deoxy-D-glucose on tumor growth. Our findings highlight the significance of recalibrating tumor cell metabolism by fine tuning nucleotide and NAD synthesis in tumor growth.

from Cancer via ola Kala on Inoreader http://ift.tt/2zICZYv
via IFTTT

FDA Disperses $22 Million for Rare Diseases [News in Brief]

Several grants will support clinical trials investigating novel treatments for rare cancers.

from Cancer via ola Kala on Inoreader http://ift.tt/2heiT1R
via IFTTT

Flaxseed Consumption Inhibits Chemically-induced Lung Tumorigenesis andModulates Expression of Phase II Enzymes and Inflammatory Cytokines in A/JMice

Flaxseed consumption is associated with reduced oxidative stress and inflammation in lung injury models, and has shown anti-cancer effects for breast and prostate tissues. However, the chemopreventive potential of flaxseed remains unexplored for lung cancer. In this study, we investigated the effect of flaxseed on tobacco smoke carcinogen (NNK)-induced lung tumorigenesis in an A/J mouse model. Mice exposed to NNK were fed a control diet or a 10% flaxseed-supplemented diet for 26 weeks. Flaxseed-fed mice showed reduced lung tumor incidence (78%) and multiplicity, with an average of 2.7 ± 2.3 surface lung tumor nodules and 1.0 ± 0.9 H&E cross-section nodules per lung compared to the control group which had 100% tumor incidence and an average of 10.2 ± 5.7 surface lung tumor nodules and 3.9 ± 2.6 H&E cross-section nodules per lung. Further, flaxseed-fed mice had a lower incidence of adenocarcinomas compared to control-fed mice. Western blotting performed on normal lung tissues showed flaxseed suppressed phosphorylation (activation) of p-AKT, p-ERK, and p-JNK kinases. RNA-Seq data obtained from normal lung and lung tumors of control and flaxeed-fed mice suggested that flaxseed intake resulted in differential expression of genes involved inflammation-mediated cytokine signaling (IL-1,-6,-8,-9, and -12α), xenobiotic metabolism (several CYPs, GSTs, and UGTs), and signaling pathways (AKT and MAPK) involved in tumor cell proliferation. Together, our results indicate that dietary flaxseed supplementation may be an effective chemoprevention strategy for chemically-induced lung carcinogenesis by altering signaling pathways, inflammation, and oxidative stress.

from Cancer via ola Kala on Inoreader http://ift.tt/2gN3EQb
via IFTTT

A Novel Application of Structural Equation Modeling Estimates the Association between Oxidative Stress and Colorectal Adenoma

In vitro evidence implicates oxidative stress in many adverse health conditions, including colorectal neoplasia. In human studies, however, oxidative stress is measured by imperfect biomarkers, which are inconsistently associated with health outcomes. Structural equation modeling (SEM) offers one possible solution by modeling a latent (unobserved) construct from multiple biomarkers. Our goal was to investigate the association of a latent oxidative stress variable with colorectal adenoma. Using SEM, we analyzed pooled data from two cross-sectional studies of colorectal adenoma (n=526) that measured five plasma biomarkers of oxidative stress and inflammation that comprised the latent oxidative stress variable: F2-isoprostanes (FIP), fluorescent oxidation products (FOP), mitochondrial DNA (MtDNA) copy number, -tocopherol (Gtoc), and C-reactive protein (CRP). Higher levels of oxidative stress were associated with colorectal adenoma (odds ratio=3.23 per standard deviation increase in oxidative stress, 95% confidence interval: 1.28, 8.18). The latent variable estimate was considerably stronger than the associations of adenoma with the individual biomarkers, which were modest and mostly non-significant. Risk factors were associated with adenoma via the oxidative stress pathway, particularly overweight and obesity with an OR=1.50, 95% CI: 1.10, 2.81; and OR=2.95, 95% CI: 1.28, 12.45, respectively. Oxidative stress may be positively associated with colorectal adenoma and important risk factors may act through this mechanism, but the cross-sectional design of the current study precludes observing the directionality of associations. The presence of an adenoma could affect levels of the circulating biomarkers thus we should be cautious of strong conclusions until the findings are replicated in a follow-up study.

from Cancer via ola Kala on Inoreader http://ift.tt/2yP7yiE
via IFTTT

Genetic variants in metabolic signaling pathways and their interaction with lifestyle factors on breast cancer risk: A random survival forest analysis

Genetic variants in the insulin-like growth factor-I (IGF-I)/insulin resistance axis may interact with lifestyle factors, influencing postmenopausal breast cancer risk, but these interrelated pathways are not fully understood. In this study, we examined 54 single-nucleotide polymorphisms (SNPs) in genes related to IGF-I/insulin phenotypes and signaling pathways and lifestyle factors in relation to post-menopausal breast cancer, using data from 6,567 postmenopausal women in the Women's Health Initiative Harmonized and Imputed Genome-Wide Association Studies. We employed a machine learning method, two-stage random survival forest analysis. We identified 3 genetic variants (AKT1 rs2494740, AKT1 rs2494744, and AKT1 rs2498789) and 2 lifestyle factors (body mass index [BMI] and dietary alcohol intake) as the top 5 most influential predictors for breast cancer risk. The combination of the 3 SNPs, BMI, and alcohol consumption (≥ 1 gm/day) significantly increased the risk of breast cancer in a gene and lifestyle dose-dependent manner. Our findings provide insight into gene-lifestyle interactions and will enable researchers to focus on individuals with risk genotypes to promote intervention strategies. These data also suggest potential genetic targets in future intervention/clinical trials for cancer prevention in order to reduce the risk for breast cancer in postmenopausal women.

from Cancer via ola Kala on Inoreader http://ift.tt/2gLYx2R
via IFTTT

TGF-{beta} promotes genomic instability after loss of RUNX3

Studies of genomic instability have historically focused on intrinsic mechanisms rather than extrinsic mechanisms based on the tumor microenvironment (TME). TGF-β is the most abundantly secreted cytokine in the TME where it imparts various aggressive characteristics including invasive migration, drug resistance and epithelial-to-mesenchymal transition (EMT). Here we show that TGF-β also promotes genomic instability in the form of DNA double strand breaks (DSB) in cancer cells which lack the tumor suppressor gene RUNX3. Loss of RUNX3 resulted in transcriptional downregulation of the redox regulator heme oxygenase-1 (HO-1 or HMOX1). Consequently, elevated oxidative DNA damage disrupted genomic integrity and triggered cellular senescence, which was accompanied by tumor-promoting inflammatory cytokine expression and acquisition of the senescence-associated secretory phenotype (SASP). Recapitulating the above findings, tumors harbouring a TGF-β gene expression signature and RUNX3 loss exhibited higher levels of genomic instability. In summary, RUNX3 creates an effective barrier against further TGF-β-dependent tumor progression by preventing genomic instability. These data suggest a novel cooperation between cancer cell-extrinsic TGF-β signaling and cancer cell-intrinsic RUNX3 inactivation as aggravating factors for genomic instability.

http://ift.tt/2lm4tBg

NF-kB promotes ovarian tumorigenesis via classical pathways supporting proliferative cancer cells and alternative pathways supporting ALDH+ cancer stem-like cells

Understanding the mechanisms supporting tumor-initiating cells (TIC) is vital to combat advanced stage recurrent cancers. Here we show that in advanced ovarian cancers NF-kB signaling via the RelB transcription factor supports TIC populations by directly regulating the cancer stem-like associated enzyme aldehyde dehydrogenase (ALDH). Loss of RelB significantly inhibited spheroid formation, ALDH expression and activity, chemoresistance, and tumorigenesis in subcutaneous and intrabursal mouse xenograft models of human ovarian cancer. RelB also affected expression of the ALDH gene ALDH1A2. Interestingly, classical NF-kB signaling through the RelA transcription factor was equally important for tumorigenesis in the intrabursal model, but had no effect on ALDH. In this case, classical signaling via RelA was essential for proliferating cells, whereas the alternative signaling pathway was not. Our results show how NF-kB sustains diverse cancer phenotypes via distinct classical and alternative signaling pathways, with implications for improved understanding of disease recurrence and therapeutic response.

http://ift.tt/2y7YqpI

TGF-{beta} promotes genomic instability after loss of RUNX3

Studies of genomic instability have historically focused on intrinsic mechanisms rather than extrinsic mechanisms based on the tumor microenvironment (TME). TGF-β is the most abundantly secreted cytokine in the TME where it imparts various aggressive characteristics including invasive migration, drug resistance and epithelial-to-mesenchymal transition (EMT). Here we show that TGF-β also promotes genomic instability in the form of DNA double strand breaks (DSB) in cancer cells which lack the tumor suppressor gene RUNX3. Loss of RUNX3 resulted in transcriptional downregulation of the redox regulator heme oxygenase-1 (HO-1 or HMOX1). Consequently, elevated oxidative DNA damage disrupted genomic integrity and triggered cellular senescence, which was accompanied by tumor-promoting inflammatory cytokine expression and acquisition of the senescence-associated secretory phenotype (SASP). Recapitulating the above findings, tumors harbouring a TGF-β gene expression signature and RUNX3 loss exhibited higher levels of genomic instability. In summary, RUNX3 creates an effective barrier against further TGF-β-dependent tumor progression by preventing genomic instability. These data suggest a novel cooperation between cancer cell-extrinsic TGF-β signaling and cancer cell-intrinsic RUNX3 inactivation as aggravating factors for genomic instability.

from Cancer via ola Kala on Inoreader http://ift.tt/2lm4tBg
via IFTTT

NF-kB promotes ovarian tumorigenesis via classical pathways supporting proliferative cancer cells and alternative pathways supporting ALDH+ cancer stem-like cells

Understanding the mechanisms supporting tumor-initiating cells (TIC) is vital to combat advanced stage recurrent cancers. Here we show that in advanced ovarian cancers NF-kB signaling via the RelB transcription factor supports TIC populations by directly regulating the cancer stem-like associated enzyme aldehyde dehydrogenase (ALDH). Loss of RelB significantly inhibited spheroid formation, ALDH expression and activity, chemoresistance, and tumorigenesis in subcutaneous and intrabursal mouse xenograft models of human ovarian cancer. RelB also affected expression of the ALDH gene ALDH1A2. Interestingly, classical NF-kB signaling through the RelA transcription factor was equally important for tumorigenesis in the intrabursal model, but had no effect on ALDH. In this case, classical signaling via RelA was essential for proliferating cells, whereas the alternative signaling pathway was not. Our results show how NF-kB sustains diverse cancer phenotypes via distinct classical and alternative signaling pathways, with implications for improved understanding of disease recurrence and therapeutic response.

from Cancer via ola Kala on Inoreader http://ift.tt/2y7YqpI
via IFTTT

Global metabolomic profiling of uterine leiomyomas

Global metabolomic profiling of uterine leiomyomas

British Journal of Cancer, Published online: 26 October 2017; doi:10.1038/bjc.2017.361

http://ift.tt/2zSPC4r

Intratumoural PD-L1 expression is associated with worse survival of patients with Epstein–Barr virus-associated gastric cancer

Intratumoural PD-L1 expression is associated with worse survival of patients with Epstein–Barr virus-associated gastric cancer

British Journal of Cancer, Published online: 26 October 2017; doi:10.1038/bjc.2017.369

http://ift.tt/2xq8k1q

Tetracycline use and risk of incident skin cancer: a prospective study

Tetracycline use and risk of incident skin cancer: a prospective study

British Journal of Cancer, Published online: 26 October 2017; doi:10.1038/bjc.2017.378

http://ift.tt/2zSWr60

Global metabolomic profiling of uterine leiomyomas

Global metabolomic profiling of uterine leiomyomas

British Journal of Cancer, Published online: 26 October 2017; doi:10.1038/bjc.2017.361

from Cancer via ola Kala on Inoreader http://ift.tt/2zSPC4r
via IFTTT

Intratumoural PD-L1 expression is associated with worse survival of patients with Epstein–Barr virus-associated gastric cancer

Intratumoural PD-L1 expression is associated with worse survival of patients with Epstein–Barr virus-associated gastric cancer

British Journal of Cancer, Published online: 26 October 2017; doi:10.1038/bjc.2017.369

from Cancer via ola Kala on Inoreader http://ift.tt/2xq8k1q
via IFTTT

Tetracycline use and risk of incident skin cancer: a prospective study

Tetracycline use and risk of incident skin cancer: a prospective study

British Journal of Cancer, Published online: 26 October 2017; doi:10.1038/bjc.2017.378

from Cancer via ola Kala on Inoreader http://ift.tt/2zSWr60
via IFTTT

Antitumor activity of Lepidium latifolium and identification of the epithionitrile 1-cyano-2,3-epithiopropane as its major active component

Abstract

Consumption of Brassica (Cruciferae) vegetables is associated with a reduced risk of cancer, but identification of the active components and insights into the underlying molecular events are scarce. Here we found that an extract of Lepidium latifolium, a cruciferous plant native to southern Europe, Mediterranean countries and Asia, showed in vitro cytotoxic activity, inducing caspase-dependent apoptosis, in a variety of human tumor cells, and the plant juice showed in vivo antitumor activity in a HT-29 human colon cancer xenograft mouse model. The epithionitrile 1-cyano-2,3-epithiopropane (CETP) was identified as the major active cancer cell-killing principle of L. latifolium. Synthetic and plant-derived CETP displayed similar proapoptotic activities as assessed by biochemical and morphological analyses. Analysis of the antiproliferative capacity of CETP on a wide number of cancer cell lines from the NCI-60 cell line panel followed by COMPARE analysis, revealed an activity profile different from known anticancer agents. Flow cytometry and biochemical analyses revealed that CETP-induced apoptosis involved mitochondria, as assessed by loss of mitochondrial transmembrane potential and generation of reactive oxygen species, while overexpression of Bcl-X_L and Bcl-2 prevented CETP-induced apoptosis. Inhibition of reactive oxygen species by glutathione and N-acetyl cysteine reduced the apoptotic response induced by CETP. FADD dominant negative form, blocking Fas/CD95 signaling, and a specific caspase-8 inhibitor also inhibited CETP-induced killing. Taken together, our data suggest that the cancer cell-killing action of CETP, involving both intrinsic and extrinsic apoptotic signaling pathways, underlies the antitumor activity of L. latifolium plant, which could be of potential interest in cancer treatment. This article is protected by copyright. All rights reserved

from Cancer via ola Kala on Inoreader http://ift.tt/2zInHmM
via IFTTT

Inhibition of Autophagy Initiation Potentiates Chemosensitivity in Mesothelioma

Abstract

The benefits of inhibiting autophagy in cancer are still controversial, with differences in outcome based on the type of tumor, the context and the particular stage of inhibition. Here, we investigated the impact of inhibiting autophagy at different stages on chemosensitivity using 3-dimensional (3D) models of mesothelioma, including ex vivo human tumor fragment spheroids. As shown by LC3B accumulation, we successfully inhibited autophagy using either an early stage ULK1/2 inhibitor (MRT 68921) or a late stage inhibitor (hydroxychloroquine). We found that inhibition of autophagy at the early stage, but not at late stage, potentiated chemosensitivity. This effect was seen only in those spheroids with high autophagy and active initiation at steady state. Inhibition of autophagy alone, at either early or late stage, did not cause cell death, showing that the inhibitors were non-toxic and that mesothelioma did not depend on autophagy at baseline, at least over 24 h. Using ATG13 puncta analysis, we found that autophagy initiation identified tumors that are more chemosensitive at baseline and after autophagy inhibition. Our results highlight a potential role of autophagy initiation in supporting mesothelioma cells during chemotherapy. Our work also highlights the importance of testing the inhibition of different stages in order to uncover the role of autophagy and the potential of its modulation in the treatment of cancer. This article is protected by copyright. All rights reserved

from Cancer via ola Kala on Inoreader http://ift.tt/2hddGaj
via IFTTT

Eugenol potentiates cisplatin anti-cancer activity through inhibition of ALDH-positive breast cancer stem cells and the NF-κB signaling pathway

Abstract

Triple-negative breast tumors are very aggressive and contain relatively high proportion of cancer stem cells, and resistant to chemotherapeutic drugs including cisplatin. To overcome these limitations, we combined eugenol, a natural polyphenolic molecule with cisplatin to normalize cisplatin mediated toxicity and potential drug resistance. Interestingly, the combination treatment provided significantly greater cytotoxic and pro-apoptotic effects as compared to treatment with eugenol or cisplatin alone on several triple-negative breast cancer cells both in vitro and in vivo. Furthermore, adding eugenol to cisplatin potentiated the inhibition of breast cancer stem cells by inhibiting ALDH enzyme activity and ALDH-positive tumor initiating cells. We provide also clear evidence that eugenol potentiates cisplatin inhibition of the NF-κB signaling pathway. Indeed, the binding of NF-κB to its cognate binding sites present in the promoters of IL-6 and IL-8 was dramatically reduced, which led to potent down-regulation of the IL-6 and IL-8 cytokines upon combination treatment relative to the single agents. Similar effects were observed on proliferation, inhibition of epithelial-to-mesenchymal transition and stemness markers in tumor xenografts. These results provide strong preclinical justification for combining cisplatin with eugenol as therapeutic approach for triple-negative breast cancers through targeting the resistant ALDH-positive cells and inhibiting the NF-κB pathway. This article is protected by copyright. All rights reserved

from Cancer via ola Kala on Inoreader http://ift.tt/2zInCzu
via IFTTT

Mouse double minute 4 variants modify susceptibility to risk of recurrence in patients with squamous cell carcinoma of the oropharynx

Abstract

Given the crucial role of Mouse double minute 4 (MDM4) oncoprotein in p53 pathway, single nucleotide polymorphisms (SNPs) could serve as such biomarkers for prediction of SCCOP recurrence. Thus, we investigated associations between three tagging putatively functional variants of MDM4, two in the 3' untranslated region of 3' UTR [rs11801299 (NC_000001.10:g.204529084G>A) and rs10900598(NC_000001.10:g.204525568G>T)] and one in intron 1 [rs1380576(NC_000001.10:g.204488278G>C)], and recurrence risk of SCCOP in 1,008 incident patients. A log-rank test and multivariable Cox models were used to assess associations. Patients with MDM4-rs10900598 GT/TT had a worse disease-free survival (DFS) compared with corresponding GG genotype, while those with rs11801299 AG/AA genotypes had a lower recurrence risk than the cases with rs11801299 GG genotype (both log-rank, P<0.001). Multivariable analysis showed that significantly different recurrence risk were found among patients with MDM4-rs10900598 GT/TT and rs11801299 AG/AA variant genotypes (HR, 2.0, 95% CI, 1.4–2.9 and HR, 0.4, 95% CI, 0.3–0.6, respectively) compared with their corresponding common homozygous genotypes. Furthermore, after combining the risk genotypes of the three SNPs, patients among low-risk group had a significantly lower risk of SCCOP recurrence than those in high-risk group (HR, 0.2, 95% CI, 0.1–0.3). The risk for both individual SNPs or combined risk genotypes was restricted to HPV-positive SCCOP patients. Our findings suggest that the MDM4 polymorphisms may, individually or in combination, confer an independent risk of SCCOP recurrence, particularly in HPV-positive SCCOP patients. However, larger studies are needed to validate our findings. This article is protected by copyright. All rights reserved

from Cancer via ola Kala on Inoreader http://ift.tt/2hca7Bg
via IFTTT

Antitumor activity of Lepidium latifolium and identification of the epithionitrile 1-cyano-2,3-epithiopropane as its major active component

Abstract

Consumption of Brassica (Cruciferae) vegetables is associated with a reduced risk of cancer, but identification of the active components and insights into the underlying molecular events are scarce. Here we found that an extract of Lepidium latifolium, a cruciferous plant native to southern Europe, Mediterranean countries and Asia, showed in vitro cytotoxic activity, inducing caspase-dependent apoptosis, in a variety of human tumor cells, and the plant juice showed in vivo antitumor activity in a HT-29 human colon cancer xenograft mouse model. The epithionitrile 1-cyano-2,3-epithiopropane (CETP) was identified as the major active cancer cell-killing principle of L. latifolium. Synthetic and plant-derived CETP displayed similar proapoptotic activities as assessed by biochemical and morphological analyses. Analysis of the antiproliferative capacity of CETP on a wide number of cancer cell lines from the NCI-60 cell line panel followed by COMPARE analysis, revealed an activity profile different from known anticancer agents. Flow cytometry and biochemical analyses revealed that CETP-induced apoptosis involved mitochondria, as assessed by loss of mitochondrial transmembrane potential and generation of reactive oxygen species, while overexpression of Bcl-X_L and Bcl-2 prevented CETP-induced apoptosis. Inhibition of reactive oxygen species by glutathione and N-acetyl cysteine reduced the apoptotic response induced by CETP. FADD dominant negative form, blocking Fas/CD95 signaling, and a specific caspase-8 inhibitor also inhibited CETP-induced killing. Taken together, our data suggest that the cancer cell-killing action of CETP, involving both intrinsic and extrinsic apoptotic signaling pathways, underlies the antitumor activity of L. latifolium plant, which could be of potential interest in cancer treatment. This article is protected by copyright. All rights reserved

http://ift.tt/2zInHmM

Inhibition of Autophagy Initiation Potentiates Chemosensitivity in Mesothelioma

Abstract

The benefits of inhibiting autophagy in cancer are still controversial, with differences in outcome based on the type of tumor, the context and the particular stage of inhibition. Here, we investigated the impact of inhibiting autophagy at different stages on chemosensitivity using 3-dimensional (3D) models of mesothelioma, including ex vivo human tumor fragment spheroids. As shown by LC3B accumulation, we successfully inhibited autophagy using either an early stage ULK1/2 inhibitor (MRT 68921) or a late stage inhibitor (hydroxychloroquine). We found that inhibition of autophagy at the early stage, but not at late stage, potentiated chemosensitivity. This effect was seen only in those spheroids with high autophagy and active initiation at steady state. Inhibition of autophagy alone, at either early or late stage, did not cause cell death, showing that the inhibitors were non-toxic and that mesothelioma did not depend on autophagy at baseline, at least over 24 h. Using ATG13 puncta analysis, we found that autophagy initiation identified tumors that are more chemosensitive at baseline and after autophagy inhibition. Our results highlight a potential role of autophagy initiation in supporting mesothelioma cells during chemotherapy. Our work also highlights the importance of testing the inhibition of different stages in order to uncover the role of autophagy and the potential of its modulation in the treatment of cancer. This article is protected by copyright. All rights reserved

http://ift.tt/2hddGaj

Eugenol potentiates cisplatin anti-cancer activity through inhibition of ALDH-positive breast cancer stem cells and the NF-κB signaling pathway

Abstract

Triple-negative breast tumors are very aggressive and contain relatively high proportion of cancer stem cells, and resistant to chemotherapeutic drugs including cisplatin. To overcome these limitations, we combined eugenol, a natural polyphenolic molecule with cisplatin to normalize cisplatin mediated toxicity and potential drug resistance. Interestingly, the combination treatment provided significantly greater cytotoxic and pro-apoptotic effects as compared to treatment with eugenol or cisplatin alone on several triple-negative breast cancer cells both in vitro and in vivo. Furthermore, adding eugenol to cisplatin potentiated the inhibition of breast cancer stem cells by inhibiting ALDH enzyme activity and ALDH-positive tumor initiating cells. We provide also clear evidence that eugenol potentiates cisplatin inhibition of the NF-κB signaling pathway. Indeed, the binding of NF-κB to its cognate binding sites present in the promoters of IL-6 and IL-8 was dramatically reduced, which led to potent down-regulation of the IL-6 and IL-8 cytokines upon combination treatment relative to the single agents. Similar effects were observed on proliferation, inhibition of epithelial-to-mesenchymal transition and stemness markers in tumor xenografts. These results provide strong preclinical justification for combining cisplatin with eugenol as therapeutic approach for triple-negative breast cancers through targeting the resistant ALDH-positive cells and inhibiting the NF-κB pathway. This article is protected by copyright. All rights reserved

http://ift.tt/2zInCzu

Mouse double minute 4 variants modify susceptibility to risk of recurrence in patients with squamous cell carcinoma of the oropharynx

Abstract

Given the crucial role of Mouse double minute 4 (MDM4) oncoprotein in p53 pathway, single nucleotide polymorphisms (SNPs) could serve as such biomarkers for prediction of SCCOP recurrence. Thus, we investigated associations between three tagging putatively functional variants of MDM4, two in the 3' untranslated region of 3' UTR [rs11801299 (NC_000001.10:g.204529084G>A) and rs10900598(NC_000001.10:g.204525568G>T)] and one in intron 1 [rs1380576(NC_000001.10:g.204488278G>C)], and recurrence risk of SCCOP in 1,008 incident patients. A log-rank test and multivariable Cox models were used to assess associations. Patients with MDM4-rs10900598 GT/TT had a worse disease-free survival (DFS) compared with corresponding GG genotype, while those with rs11801299 AG/AA genotypes had a lower recurrence risk than the cases with rs11801299 GG genotype (both log-rank, P<0.001). Multivariable analysis showed that significantly different recurrence risk were found among patients with MDM4-rs10900598 GT/TT and rs11801299 AG/AA variant genotypes (HR, 2.0, 95% CI, 1.4–2.9 and HR, 0.4, 95% CI, 0.3–0.6, respectively) compared with their corresponding common homozygous genotypes. Furthermore, after combining the risk genotypes of the three SNPs, patients among low-risk group had a significantly lower risk of SCCOP recurrence than those in high-risk group (HR, 0.2, 95% CI, 0.1–0.3). The risk for both individual SNPs or combined risk genotypes was restricted to HPV-positive SCCOP patients. Our findings suggest that the MDM4 polymorphisms may, individually or in combination, confer an independent risk of SCCOP recurrence, particularly in HPV-positive SCCOP patients. However, larger studies are needed to validate our findings. This article is protected by copyright. All rights reserved

http://ift.tt/2hca7Bg

Reconstruction of extensive thoracic wall defect using the external oblique myocutaneous flap: An analysis on 20 Chinese patients with locally advanced soft tissue sarcoma

Background

Soft tissue sarcomas are rare neoplasms that can occur in the thoracic wall, abdominal wall, extremities, and inguinal region. Wide local resection, with precise histological margin control, results in large skin defects that are challenging to close. Various repair procedures, such as vertical rectus abdominis flaps (VRAM), latissimus dorsi flaps, and tensor fascia lata (TFL) flaps are used to cover broad thoracic wall defects. Although the cosmetic reconstruction results of using these flaps are often excellent, each has significant drawbacks. The external oblique musculocutaneous flap is a simple and safe surgical procedure for covering thoracic wall defects.

Objective

This study aimed to retrospectively assess the safety and technique of using the external oblique musculocutaneous flap to cover large thoracic wall defects after radical excision of locally advanced sarcomas in 20 patients at a single institution.

Method

From January 2006 to December 2016, 20 Chinese patients with large advanced sarcomas on their trunks received wide local resection, with precise histological negative margins. The external oblique musculocutaneous flap, mobilized from the ipsilateral abdominal wall, was harvested to cover broad thoracic wall defects.

Results

Among the 20 sarcoma patients (12 females and 8 males, ranging in age from 25 to 73 years), there were five patients with primary tumors and 15 patients with recurrent tumors. The median tumor diameter was approximately 15.3 cm. After excising the lesion, the median time to cover the defect with the external oblique myocutaneous flap was 66 min. The average blood loss when harvesting the flap was approximately 48 mL. For the 20 patients in our cohort, the external oblique flap achieved closure of defects measuring an average area of 256 cm. No other flaps or reconstruction techniques were used to cover the large defects in this study. There were no deaths directly related to the flap reconstruction procedures.

Conclusion

The external oblique musculocutaneous flap was a safe and reliable method of covering broad thoracic wall defects after radical tumor excision.

http://ift.tt/2iDkVMt

Effective excision of cutaneous squamous cell carcinoma of the face using analysis of intra-operative frozen sections from the whole specimen

Background and Objectives

We excised cutaneous squamous cell carcinoma (cSCC) of the face while using intra-operative frozen section analysis of the margins in an optimized bread-loafing fashion (WIFSA).

Methods

Medical records were reviewed of 160 cSCCs of the face that were treated by surgical excision with WIFSA between April 2007 and January 2013. The accuracy of WIFSA was verified by comparing results with postoperative formalin-fixed paraffin-embedded (FFPE) sections. Also, recurrence and metastasis during follow-up were studied and duration of treatment and complications were analyzed.

Results

The 160 cSCCs affected 152 patients. In 131 cSCCs (mean follow-up: 41.0 months, SD: ±26.3, range: 3.0-110.7) occurred 6 (4.6%) recurrences and 2 (1.5%) metastases. Of the WIFSA results, 98.8% corresponded with postoperative FFPE sections. Mean duration of treatment was 77 min (SD: ±25, range: 34-159) and complication rate was 8.1%.

Conclusions

Surgical excision with WIFSA is an excellent treatment modality for cSCC of the face because of its accurate method for assessment of complete tumor removal, low recurrence and metastasis rate, short average duration of treatment, and low complication rate.

http://ift.tt/2iBZY4w

Tetracycline use and risk of incident skin cancer: a prospective study

http://ift.tt/2yTh04d

Global metabolomic profiling of uterine leiomyomas

http://ift.tt/2gGZW75

Tetracycline use and risk of incident skin cancer: a prospective study

from Cancer via ola Kala on Inoreader http://ift.tt/2yTh04d
via IFTTT

Intratumoural PD-L1 expression is associated with worse survival of patients with Epstein–Barr virus-associated gastric cancer

from Cancer via ola Kala on Inoreader http://ift.tt/2yTgT8N
via IFTTT

Reconstruction of extensive thoracic wall defect using the external oblique myocutaneous flap: An analysis on 20 Chinese patients with locally advanced soft tissue sarcoma

Background

Soft tissue sarcomas are rare neoplasms that can occur in the thoracic wall, abdominal wall, extremities, and inguinal region. Wide local resection, with precise histological margin control, results in large skin defects that are challenging to close. Various repair procedures, such as vertical rectus abdominis flaps (VRAM), latissimus dorsi flaps, and tensor fascia lata (TFL) flaps are used to cover broad thoracic wall defects. Although the cosmetic reconstruction results of using these flaps are often excellent, each has significant drawbacks. The external oblique musculocutaneous flap is a simple and safe surgical procedure for covering thoracic wall defects.

Objective

This study aimed to retrospectively assess the safety and technique of using the external oblique musculocutaneous flap to cover large thoracic wall defects after radical excision of locally advanced sarcomas in 20 patients at a single institution.

Method

From January 2006 to December 2016, 20 Chinese patients with large advanced sarcomas on their trunks received wide local resection, with precise histological negative margins. The external oblique musculocutaneous flap, mobilized from the ipsilateral abdominal wall, was harvested to cover broad thoracic wall defects.

Results

Among the 20 sarcoma patients (12 females and 8 males, ranging in age from 25 to 73 years), there were five patients with primary tumors and 15 patients with recurrent tumors. The median tumor diameter was approximately 15.3 cm. After excising the lesion, the median time to cover the defect with the external oblique myocutaneous flap was 66 min. The average blood loss when harvesting the flap was approximately 48 mL. For the 20 patients in our cohort, the external oblique flap achieved closure of defects measuring an average area of 256 cm. No other flaps or reconstruction techniques were used to cover the large defects in this study. There were no deaths directly related to the flap reconstruction procedures.

Conclusion

The external oblique musculocutaneous flap was a safe and reliable method of covering broad thoracic wall defects after radical tumor excision.

from Cancer via ola Kala on Inoreader http://ift.tt/2iDkVMt
via IFTTT

Effective excision of cutaneous squamous cell carcinoma of the face using analysis of intra-operative frozen sections from the whole specimen

Background and Objectives

We excised cutaneous squamous cell carcinoma (cSCC) of the face while using intra-operative frozen section analysis of the margins in an optimized bread-loafing fashion (WIFSA).

Methods

Medical records were reviewed of 160 cSCCs of the face that were treated by surgical excision with WIFSA between April 2007 and January 2013. The accuracy of WIFSA was verified by comparing results with postoperative formalin-fixed paraffin-embedded (FFPE) sections. Also, recurrence and metastasis during follow-up were studied and duration of treatment and complications were analyzed.

Results

The 160 cSCCs affected 152 patients. In 131 cSCCs (mean follow-up: 41.0 months, SD: ±26.3, range: 3.0-110.7) occurred 6 (4.6%) recurrences and 2 (1.5%) metastases. Of the WIFSA results, 98.8% corresponded with postoperative FFPE sections. Mean duration of treatment was 77 min (SD: ±25, range: 34-159) and complication rate was 8.1%.

Conclusions

Surgical excision with WIFSA is an excellent treatment modality for cSCC of the face because of its accurate method for assessment of complete tumor removal, low recurrence and metastasis rate, short average duration of treatment, and low complication rate.

from Cancer via ola Kala on Inoreader http://ift.tt/2iBZY4w
via IFTTT

Reconstruction of extensive thoracic wall defect using the external oblique myocutaneous flap: An analysis on 20 Chinese patients with locally advanced soft tissue sarcoma

Background

Soft tissue sarcomas are rare neoplasms that can occur in the thoracic wall, abdominal wall, extremities, and inguinal region. Wide local resection, with precise histological margin control, results in large skin defects that are challenging to close. Various repair procedures, such as vertical rectus abdominis flaps (VRAM), latissimus dorsi flaps, and tensor fascia lata (TFL) flaps are used to cover broad thoracic wall defects. Although the cosmetic reconstruction results of using these flaps are often excellent, each has significant drawbacks. The external oblique musculocutaneous flap is a simple and safe surgical procedure for covering thoracic wall defects.

Objective

This study aimed to retrospectively assess the safety and technique of using the external oblique musculocutaneous flap to cover large thoracic wall defects after radical excision of locally advanced sarcomas in 20 patients at a single institution.

Method

From January 2006 to December 2016, 20 Chinese patients with large advanced sarcomas on their trunks received wide local resection, with precise histological negative margins. The external oblique musculocutaneous flap, mobilized from the ipsilateral abdominal wall, was harvested to cover broad thoracic wall defects.

Results

Among the 20 sarcoma patients (12 females and 8 males, ranging in age from 25 to 73 years), there were five patients with primary tumors and 15 patients with recurrent tumors. The median tumor diameter was approximately 15.3 cm. After excising the lesion, the median time to cover the defect with the external oblique myocutaneous flap was 66 min. The average blood loss when harvesting the flap was approximately 48 mL. For the 20 patients in our cohort, the external oblique flap achieved closure of defects measuring an average area of 256 cm. No other flaps or reconstruction techniques were used to cover the large defects in this study. There were no deaths directly related to the flap reconstruction procedures.

Conclusion

The external oblique musculocutaneous flap was a safe and reliable method of covering broad thoracic wall defects after radical tumor excision.

http://ift.tt/2iDkVMt

Effective excision of cutaneous squamous cell carcinoma of the face using analysis of intra-operative frozen sections from the whole specimen

Background and Objectives

We excised cutaneous squamous cell carcinoma (cSCC) of the face while using intra-operative frozen section analysis of the margins in an optimized bread-loafing fashion (WIFSA).

Methods

Medical records were reviewed of 160 cSCCs of the face that were treated by surgical excision with WIFSA between April 2007 and January 2013. The accuracy of WIFSA was verified by comparing results with postoperative formalin-fixed paraffin-embedded (FFPE) sections. Also, recurrence and metastasis during follow-up were studied and duration of treatment and complications were analyzed.

Results

The 160 cSCCs affected 152 patients. In 131 cSCCs (mean follow-up: 41.0 months, SD: ±26.3, range: 3.0-110.7) occurred 6 (4.6%) recurrences and 2 (1.5%) metastases. Of the WIFSA results, 98.8% corresponded with postoperative FFPE sections. Mean duration of treatment was 77 min (SD: ±25, range: 34-159) and complication rate was 8.1%.

Conclusions

Surgical excision with WIFSA is an excellent treatment modality for cSCC of the face because of its accurate method for assessment of complete tumor removal, low recurrence and metastasis rate, short average duration of treatment, and low complication rate.

http://ift.tt/2iBZY4w

Human immunodeficiency virus infection acquired through a traditional healer’s ritual: a case report

Globally, over 36 million people were infected with human immunodeficiency virus by the end of 2015. The Sub-Saharan African region home to less than one-fifth of the global population disproportionately harbo...

http://ift.tt/2i76Xyo

Benefit of salvage total pharyngolaryngoesophagectomy for recurrent locally advanced head and neck cancer after radiotherapy

The treatment modalities for recurrent locally advanced head and neck cancer failure after radiotherapy are limited with poor prognosis. Salvage supra-radical operation seems to be an option. It has not been e...

http://ift.tt/2y7jBbu

Benefit of salvage total pharyngolaryngoesophagectomy for recurrent locally advanced head and neck cancer after radiotherapy

The treatment modalities for recurrent locally advanced head and neck cancer failure after radiotherapy are limited with poor prognosis. Salvage supra-radical operation seems to be an option. It has not been e...

from Cancer via ola Kala on Inoreader http://ift.tt/2y7jBbu
via IFTTT

Social cytopathology: Building a stronger cytopathology community through social media

Social media use can enhance education, networking, and collaboration in cytopathology. It can increase the impact of cytopathologists and elevate the understanding of cytopathology specifically and pathology in general among patients, colleagues, and the general public.

from Cancer via ola Kala on Inoreader http://ift.tt/2z9t4iE
via IFTTT

High-grade urothelial carcinoma in urine cytology with jet black and smooth or glassy chromatin

BACKGROUND

Some high-grade urothelial carcinomas (UCs) in urine cytology can have jet black, smooth, or glassy chromatin, but to the authors' knowledge, the incidence and criteria for diagnosis are not well described. The current study was performed to define the incidence and appearance of high-grade UC in urine cytology in cytospin preparations with jet black and smooth or glassy chromatin.

METHODS

Cytospin preparations from 331 cases with biopsy follow-up (230 benign/low-grade UCs and 101 malignant UCs) were reviewed.

RESULTS

Cases with malignant cells with jet black and smooth or glassy chromatin were identified in a total of 60 cases (59.4% of all malignancies). These comprised 18 carcinoma in situ cases, 28 high-grade papillary UCs, 8 invasive UCs, 3 squamous cell carcinomas, 2 adenocarcinomas, and 1 melanoma. Of the 93 high-grade UCs, 51 (54.8%) had cells with either jet black and smooth or glassy chromatin. These cells were the only type of malignant cell in 6 of 101 cases (5.9%). All cases had at least 50 cells with jet black nuclei. Nuclei with jet black and smooth chromatin often were smaller than normal urothelial cells, often but not always elongate, had irregular nuclear outlines including pointed areas, and usually were accompanied by necrosis. Cells with glassy chromatin often were larger than normal urothelial cells, had rounder but still irregular nuclei, and also had frequent necrosis.

CONCLUSIONS

Malignant urothelial cells in urine cytology with jet black chromatin are common and can be diagnosed as "positive for malignancy" based on their irregular nuclear outline, increased cellularity (≥50 abnormal cells), and frequent necrosis. Cancer Cytopathol 2017. © 2017 American Cancer Society.

from Cancer via ola Kala on Inoreader http://ift.tt/2iAHfWO
via IFTTT

Social cytopathology: Building a stronger cytopathology community through social media

Social media use can enhance education, networking, and collaboration in cytopathology. It can increase the impact of cytopathologists and elevate the understanding of cytopathology specifically and pathology in general among patients, colleagues, and the general public.

http://ift.tt/2z9t4iE

High-grade urothelial carcinoma in urine cytology with jet black and smooth or glassy chromatin

BACKGROUND

Some high-grade urothelial carcinomas (UCs) in urine cytology can have jet black, smooth, or glassy chromatin, but to the authors' knowledge, the incidence and criteria for diagnosis are not well described. The current study was performed to define the incidence and appearance of high-grade UC in urine cytology in cytospin preparations with jet black and smooth or glassy chromatin.

METHODS

Cytospin preparations from 331 cases with biopsy follow-up (230 benign/low-grade UCs and 101 malignant UCs) were reviewed.

RESULTS

Cases with malignant cells with jet black and smooth or glassy chromatin were identified in a total of 60 cases (59.4% of all malignancies). These comprised 18 carcinoma in situ cases, 28 high-grade papillary UCs, 8 invasive UCs, 3 squamous cell carcinomas, 2 adenocarcinomas, and 1 melanoma. Of the 93 high-grade UCs, 51 (54.8%) had cells with either jet black and smooth or glassy chromatin. These cells were the only type of malignant cell in 6 of 101 cases (5.9%). All cases had at least 50 cells with jet black nuclei. Nuclei with jet black and smooth chromatin often were smaller than normal urothelial cells, often but not always elongate, had irregular nuclear outlines including pointed areas, and usually were accompanied by necrosis. Cells with glassy chromatin often were larger than normal urothelial cells, had rounder but still irregular nuclei, and also had frequent necrosis.

CONCLUSIONS

Malignant urothelial cells in urine cytology with jet black chromatin are common and can be diagnosed as "positive for malignancy" based on their irregular nuclear outline, increased cellularity (≥50 abnormal cells), and frequent necrosis. Cancer Cytopathol 2017. © 2017 American Cancer Society.

http://ift.tt/2iAHfWO

Influence of neutrophil–lymphocyte ratio in prognosis of glioblastoma multiforme

Abstract

Neutrophil–lymphocyte ratio (NLR) is a hematological marker of systemic inflammation and several studies demonstrate an association between a higher NLR and a worse prognosis in many malignancies. However, literature analyzing its prognostic value in glioblastoma multiforme (GBM) is still scarce. We intended to analyze the correlation of NLR with overall survival and progression-free survival in patients with GBM performing a retrospective review of the patients with diagnosis of GBM submitted to a resection surgery in the department of neurosurgery of a tertiary care hospital, between January/2005 and January/2013. 140 patients were included. Mean age at surgery was 62.9 ± 10.0 years and mean age at death was 64.4 ± 9.8 years. Mean overall survival was 19.4 ± 14.3 months and mean progression-free survival was 9.4 ± 8.7 months. There was no correlation of NLR, platelets-lymphocyte ratio (PLR) or absolute counts of neutrophils, lymphocytes and platelets with overall survival in multivariate analysis. However, a preoperative NLR ≤ 5 correlated with a shorter progression-free survival [HR 1.56 (SD 95% 1.04–2.34); p = 0.032]. We performed a subgroup analysis of patients who completed Stupp protocol. In this subgroup of 117 patients, a preoperative NLR > 7 correlated with a shorter overall survival [HR 1.65 (SD 95% 1.07–2.53); p = 0.023]. The results from our total cohort didn't confirm the correlation between a higher NRL and worse survival in GBM. However, in the subgroup analysis of patients who completed Stupp protocol, a higher NLR was an independent prognostic factor to a shorter overall survival, similar to existent literature data about GBM.

from Cancer via ola Kala on Inoreader http://ift.tt/2zIC8XM
via IFTTT

Influence of neutrophil–lymphocyte ratio in prognosis of glioblastoma multiforme

Abstract

Neutrophil–lymphocyte ratio (NLR) is a hematological marker of systemic inflammation and several studies demonstrate an association between a higher NLR and a worse prognosis in many malignancies. However, literature analyzing its prognostic value in glioblastoma multiforme (GBM) is still scarce. We intended to analyze the correlation of NLR with overall survival and progression-free survival in patients with GBM performing a retrospective review of the patients with diagnosis of GBM submitted to a resection surgery in the department of neurosurgery of a tertiary care hospital, between January/2005 and January/2013. 140 patients were included. Mean age at surgery was 62.9 ± 10.0 years and mean age at death was 64.4 ± 9.8 years. Mean overall survival was 19.4 ± 14.3 months and mean progression-free survival was 9.4 ± 8.7 months. There was no correlation of NLR, platelets-lymphocyte ratio (PLR) or absolute counts of neutrophils, lymphocytes and platelets with overall survival in multivariate analysis. However, a preoperative NLR ≤ 5 correlated with a shorter progression-free survival [HR 1.56 (SD 95% 1.04–2.34); p = 0.032]. We performed a subgroup analysis of patients who completed Stupp protocol. In this subgroup of 117 patients, a preoperative NLR > 7 correlated with a shorter overall survival [HR 1.65 (SD 95% 1.07–2.53); p = 0.023]. The results from our total cohort didn't confirm the correlation between a higher NRL and worse survival in GBM. However, in the subgroup analysis of patients who completed Stupp protocol, a higher NLR was an independent prognostic factor to a shorter overall survival, similar to existent literature data about GBM.

from Cancer via ola Kala on Inoreader http://ift.tt/2zIC8XM
via IFTTT

Influence of neutrophil–lymphocyte ratio in prognosis of glioblastoma multiforme

Abstract

Neutrophil–lymphocyte ratio (NLR) is a hematological marker of systemic inflammation and several studies demonstrate an association between a higher NLR and a worse prognosis in many malignancies. However, literature analyzing its prognostic value in glioblastoma multiforme (GBM) is still scarce. We intended to analyze the correlation of NLR with overall survival and progression-free survival in patients with GBM performing a retrospective review of the patients with diagnosis of GBM submitted to a resection surgery in the department of neurosurgery of a tertiary care hospital, between January/2005 and January/2013. 140 patients were included. Mean age at surgery was 62.9 ± 10.0 years and mean age at death was 64.4 ± 9.8 years. Mean overall survival was 19.4 ± 14.3 months and mean progression-free survival was 9.4 ± 8.7 months. There was no correlation of NLR, platelets-lymphocyte ratio (PLR) or absolute counts of neutrophils, lymphocytes and platelets with overall survival in multivariate analysis. However, a preoperative NLR ≤ 5 correlated with a shorter progression-free survival [HR 1.56 (SD 95% 1.04–2.34); p = 0.032]. We performed a subgroup analysis of patients who completed Stupp protocol. In this subgroup of 117 patients, a preoperative NLR > 7 correlated with a shorter overall survival [HR 1.65 (SD 95% 1.07–2.53); p = 0.023]. The results from our total cohort didn't confirm the correlation between a higher NRL and worse survival in GBM. However, in the subgroup analysis of patients who completed Stupp protocol, a higher NLR was an independent prognostic factor to a shorter overall survival, similar to existent literature data about GBM.

http://ift.tt/2zIC8XM

CD209 -336A/G Promotor Polymorphism and its Clinical Associations in Sickle cell disease Egyptian Pediatric Patients

Publication date: Available online 26 October 2017
Source:Hematology/Oncology and Stem Cell Therapy
Author(s): Rasha Abdel-Raouf Afifi, Dina Kamal, Riham El. Sayed, Sherif M.M. Ekladious, Gehan H. Shaheen, Sherif M. Yousry, Rania Elsayed Hussein
ObjectivesTo detect the frequency of CD209 A>G polymorphism in sickle cell disease (SCD) Egyptian patients and to evaluate the use of CD209 A>G polymorphism as a genetic predictor of SCD clinical heterogeneity.MethodsA total of 100 Egyptian children with SCD and 100 Egyptian controls were tested for CD209 A>G polymorphism and were followed up prospectively between June 2012 and December 2014.ResultsComparison of CD209 A>G polymorphism among cases and controls did not show statistically significant difference (p = .742). In addition, comparison of the allelic frequency did not show statistically significant difference (p = .738). Infections occurred more frequently among the heterozygous genotype (AG; 60.5%) and homozygous genotype (GG; 75%) patients than among the wild (AA) genotype (24.1%; p < .001). The use of hydroxyurea treatment was significantly higher among the wild (AA) genotype (47%) than the heterozygous (AG; 21%) and homozygous (GG; 5%) genotypes (p = .003).ConclusionWe found no significant difference between our population of Egyptian SCD cases and controls regarding CD209 A>G polymorphism. Infections occurred more frequently among the heterozygous genotype (AG) and homozygous genotype (GG) patients.



http://ift.tt/2yTjPC5

Taxane Followed by Anthracycline or Vice Versa—Reply

In Reply Dr Altundag suggests that giving a taxane first followed by an anthracycline, as was done in the FinXX trial, might be beneficial to patients who also receive capecitabine in the adjuvant setting. In the FinXX trial, the patients were randomly allocated to either 3 cycles of docetaxel followed by 3 cycles of cyclophosphamide, epirubicin, and fluorouracil or to 3 cycles of docetaxel plus capecitabine followed by 3 cycles of cyclophosphamide, epirubicin, and capecitabine. Therefore, the patients who participated in this trial received a taxane (docetaxel) first, followed by an anthracycline (epirubicin).

from Cancer via ola Kala on Inoreader http://ift.tt/2lkoeJe
via IFTTT

VHL and Pancreatic Neuroendocrine Tumor in von Hippel–Lindau Disease

This study evaluates the natural history of von Hippel–Lindau disease–associated pancreatic lesions to determine the factors associated with pancreatic neuroendocrine tumor phenotype and prognosis.

from Cancer via ola Kala on Inoreader http://ift.tt/2y7iPLK
via IFTTT

Hypermetabolic Vocal Cord Focus With Recurrent Oral Cancer History

A woman in her 80s with a history of recurrent oral cancer was diagnosed with squamous cell carcinoma located at the margin of a palatal graft; surveillance imaging reveals metabolic activity in her left vocal cord. What is your diagnosis?

from Cancer via ola Kala on Inoreader http://ift.tt/2ljdKK1
via IFTTT

HER3 and Panitumumab Efficacy in Advanced Colorectal Cancer

This biomarker study examines the efficacy of irinotecan plus panitumumab in patients with advanced colorectal cancer whose tumors had high HER3 messenger RNA expression.

from Cancer via ola Kala on Inoreader http://ift.tt/2y8nyN1
via IFTTT

Error in Kaplan-Meier Curves

In the Original Investigation titled "Proton Beam Radiotherapy and Concurrent Chemotherapy for Unresectable Stage III Non–Small Cell Lung Cancer: Final Results of a Phase 2 Study," published online July 20, 2017, there were errors in Figure 2a in the Kaplan-Meier curves. This article was previously corrected in September 2017 to fix the numbers at risk in Figure 2a. This article was corrected online.

from Cancer via ola Kala on Inoreader http://ift.tt/2ljdI4R
via IFTTT

Taxane Followed by Anthracycline or Vice Versa

To the Editor I want to congratulate Joensuu and colleagues for their article in which they investigated the effect of adjuvant capecitabine in combination with docetaxel, epirubicin, and cyclophosphamide for early breast cancer. They reported that capecitabine with docetaxel, epirubicin, and cyclophosphamide did not prolong recurrence-free survival or overall survival compared with a regimen that contained only standard agents. Patients with triple-negative breast cancer had favorable survival outcomes when treated with the capecitabine-containing regimen in an exploratory subgroup analysis. Herein, I want to touch on the sequential order of taxane and anthracycline therapy in breast cancer. Pachmann et al hypothesized that a neoadjuvant regimen of a taxane followed by an anthracycline may result in a greater decline in the amount of circulating breast cancer cells than the regimen of an anthracycline followed by a taxane. The study showed that neoadjuvant chemotherapy with paclitaxel in patients with breast cancer interestingly causes the release of breast cancer cells into circulation, while at the same time reducing tumor size. In this study, during the applied combination therapy, 3 different phases were observed: an initial decline in the number of circulating tumor cells during the epirubicin-containing part of the regimen, followed by a steep increase during paclitaxel treatment, and a subsequent redecrease if a third regimen with the cyclophosphamide-methotrexate-fluorouracil combination was administered. This, in turn, might lead to longer-term survival benefit if the taxane is administered first in the neoadjuvant setting. Taken all together, I assume that giving a taxane first followed by an anthracyline as in the current FinXX Trial might show additional benefit with adjuvant capecitabine in patients with high-risk breast cancer.

from Cancer via ola Kala on Inoreader http://ift.tt/2y6TilR
via IFTTT

Incorrect Hazard Ratio in Figure 2

In the article titled "Prognostic and Predictive Relevance of Primary Tumor Location in Patients With RAS Wild-Type Metastatic Colorectal Cancer: Retrospective Analyses of the CRYSTAL and FIRE-3 Trials," an incorrect hazard ratio on the right panel of Figure 2B has been corrected from 1.44 to 1.31. The article was corrected online.

from Cancer via ola Kala on Inoreader http://ift.tt/2ljdavP
via IFTTT

Association of 70-GS Findings With Treatment Guidance for Patients With Early Breast Cancer

This study determines whether 70-gene signature assay findings are associated with physicians' adjuvant treatment recommendations among patients with early breast cancer.

from Cancer via ola Kala on Inoreader http://ift.tt/2yOTRhb
via IFTTT

Where is the Road-Map for Glioblastoma?

Muscoe was an architect with an impeccable sense of direction and we were lost on the way to our son's soccer game, a route we had navigated many times before. That should have been my first clue. But the signs and symptoms of glioblastoma multiforme (GBM) emerge slowly and intermittently, and they are easy to explain away, at first. Why was he not paying attention to me—drifting off in the middle of a response when I asked him a question. Was he having an affair? Lyme disease was a much more acceptable diagnosis, so when the astute primary care physician we went to see for a Lyme titer test suggested a computed tomographic scan of the head, "just to be sure," I dropped my husband at the hospital for the scan and pushed on to work. He called me a couple of hours later reporting that they saw something. I raced to the hospital to meet him, but when I got there, he was gone.

from Cancer via ola Kala on Inoreader http://ift.tt/2yTCBt9
via IFTTT

Incorporation of Treatment Response, Tumor Grade and Receptor Status Improves Staging Quality in Breast Cancer Patients Treated with Neoadjuvant Chemotherapy

Abstract

Background

Improved staging systems that better predict survival for breast cancer patients who receive neoadjuvant chemotherapy (NAC) by accounting for clinical pathological stage plus estrogen receptor (ER) and grade (CPS+EG) and ERBB2 status (Neo-Bioscore) have been proposed. We sought to evaluate the generalizability and performance of these staging systems in a national cohort.

Methods

The National Cancer Database (2006–2012) was reviewed for patients with breast cancer who received NAC and survived ≥90 days after surgery. Four systems were evaluated: clinical/pathologic American Joint Committee on Cancer (AJCC) 7th edition, CPS+EG, and Neo-Bioscore. Unadjusted Kaplan–Meier analysis and adjusted Cox proportional hazards models quantified overall survival (OS). Systems were compared using area under the curve (AUC) and integrated discrimination improvement (IDI).

Results

Overall, 43,320 patients (5-year OS 76.0, 95% confidence interval [CI] 75.4–76.5%) were included, 12,002 of whom had evaluable Neo-Bioscore. AUC at 5 years for CPS+EG (0.720, 95% CI 0.714–0.726) and Neo-Bioscore (0.729, 95% CI 0.716–0.742) were improved relative to AJCC clinical (0.650, 95% CI 0.643–0.656) and pathologic (0.683, 95% CI 0.676–0.689) staging. Both CPS+EG (IDI 7.2, 95% CI 6.6–7.7%) and Neo-Bioscore (IDI 9.8, 95% CI 8.0–11.6%) demonstrated superior discrimination when compared with AJCC clinical staging at 5 years. Comparison of CPS+EG with Neo-Bioscore yielded an IDI of 2.6% (95% CI 0.9–4.5%), indicating that Neo-Bioscore is the best staging system.

Conclusions

In a heterogenous national cohort of breast cancer patients treated with NAC and surgery, the incorporation of chemotherapy response, tumor grade, ER status, and ERBB2 status into the staging system substantially improved on the AJCC TNM staging system in discrimination of OS. Neo-Bioscore provided the best staging discrimination.

from Cancer via ola Kala on Inoreader http://ift.tt/2yOAxTM
via IFTTT

Clinical Impact of Tumor-Infiltrating Lymphocytes in Esophageal Squamous Cell Carcinoma

Abstract

Background

Recently, several immune checkpoint inhibitors have been developed and are being used to treat malignant melanoma, lung cancer, and other cancers. Several reports have indicated that tumor-infiltrating lymphocytes (TILs) are associated with clinical and histopathologic risk factors in various cancers. However, the role of TILs in esophageal squamous cell carcinoma (ESCC) has not been well studied. This study aimed to investigate the perilesional status of TILs in ESCC and to show associations between TILs and clinical variables.

Methods

The study enrolled 277 ESCC patients. Evaluation of TILs was performed according to the criteria of the International TILs Working Group 2014, and associations between TIL and clinicopathologic variables were examined.

Results

Most of the clinicopathologic factors were not statistically associated with TIL status. The number of patients who received adjuvant therapy was significantly larger in the TIL-negative group. Cancer-specific survival (CSS) of patients in the TIL-positive group was significantly better than in the TIL-negative group. Among the patients who received adjuvant therapy, CSS was significantly better in the TIL-positive group than in the TIL-negative group. Uni- and multivariate analyses identified tumor depth and TIL status as independent prognostic factors for CSS. Among the other clinicopathologic variables, TIL status was the strongest CSS indicator.

Conclusion

Tumor-infiltrating lymphocyte status is a strong predictor of good prognosis for ESCC patients.

from Cancer via ola Kala on Inoreader http://ift.tt/2ksvnmN
via IFTTT

Risk Factors for Lateral Neck Recurrence of N0/N1a Papillary Thyroid Cancer

Abstract

Background

Current guidelines advocate no prophylactic dissection of the lateral neck compartment for papillary thyroid carcinoma (PTC) without clinical evidence of lateral neck metastasis (cN1b). However, lateral neck recurrence can affect patient treatment outcomes and quality of life. Therefore, this study examined the risk factors for lateral neck recurrence after the definitive treatment of PTC without cN1b.

Methods

The study enrolled 1928 consecutive patients who underwent total thyroidectomy between 2006 and 2012 for PTC without cN1b. Logistic regression analysis was used to identify the relationship of clinicopathologic factors with lateral neck recurrence. Uni- and multivariate Cox-proportional hazards regression analyses were used to identify factors predictive of lateral neck recurrence-free survival (LRFS).

Results

During a median follow-up period of 94 months (range, 24–133 months), lateral neck recurrence occurred in 47 patients (2.4%). Binary logistic regression showed that tumor size (>2 cm), multifocality, clinical central neck metastasis (cN1a), number of positive lymph nodes (LNs, >5), and LN ratio (>0.5) were significantly associated with lateral neck recurrence (P < 0.05). Multivariate analyses showed that multifocality (hazards ratio [HR], 2.338; 95% confidence interval [CI], 1.126–4.858; P = 0.023), cN1a (HR, 5.301; 95% CI, 2.416–11.630; P < 0.001), LN ratio (HR, 2.628; 95% CI, 1.228–5.626; P = 0.013), extranodal extension (HR, 2.570; 95% CI, 1.063–6.213; P = 0.036), and MACIS (distant metastasis, patient age, completeness of resection, local invasion and tumour size) score (HR, 2.513; 95% CI, 1.211–5.216; P = 0.013) were independent factors for LRFS.

Conclusions

Lateral neck recurrence after thyroidectomy is predicted by the clinicopathologic factors of multifocality, cN1a, LN ratio, extranodal extension, and MACIS score in N0/N1a PTC patients.

from Cancer via ola Kala on Inoreader http://ift.tt/2gJRbwK
via IFTTT