Cancer-testis gene PIWIL1 promotes cell proliferation, migration, and invasion in lung adenocarcinoma

Abstract

Piwi-like RNA-mediated gene silencing 1 (PIWIL1) has been identified as a novel extremely highly expressed cancer-testis (CT) gene in lung adenocarcinoma. However, the exact function and mechanism of PIWIL1 in lung adenocarcinoma remains unclear. Herein, we sought to investigate the role of PIWIL1 in the occurrence and development of lung adenocarcinoma. We examined the expression pattern of PIWIL1 in The Cancer Genome Atlas (TCGA) lung adenocarcinoma samples, and validated it by Real-Time PCR (RT-PCR) in additional 21 paired lung adenocarcinoma tissues and 16 normal tissues. Subsequently, we explored the biological function of PIWIL1 in A549 and H1299 cell lines by gain and loss-of-function analyses. Using TCGA lung adenocarcinoma data, we further performed coexpression and Gene Ontology (GO) analyses, and analyzed the association of DNA methylation levels in PIWIL1 promoter region with its expression. Finally, we evaluated its expression in different mutation status of significantly mutated genes (SMGs) in TCGA lung adenocarcinoma data. We observed that PIWIL1 was expressed in testis and lung adenocarcinoma but not in other normal tissues, and its high expression was associated with shortened survival of lung cancer patients. Overexpression of PIWIL1 could facilitate the proliferation, invasion and migration of lung adenocarcinoma cells and vice versa. GO analysis revealed that PIWIL1 upregulated genes were enriched in embryonic development, cell proliferation and regulation of transcription. Moreover, promoter DNA hypomethylation of PIWIL1 could contribute to its aberrant expression in tumors. Interestingly, PIWIL1 expression was significantly higher in patients without hepatocyte growth factor (HGF) or serine/threonine kinase 11 (STK11) mutation (P = 0.006 and 0.005, respectively). PIWIL1 is an epidriver gene in lung adenocarcinoma, indicating a potential target for further therapy.

PIWIL1 is a novel extremely highly expressed cancer-testis gene in lung adenocarcinoma. PIWIL1 could promote the ability of proliferation, invasion, and migration in lung adenocarcinoma. The expression status of PIWIL1 is regulated by methylation in promoter region.

http://ift.tt/2hYzpXg

Prognostic value of PD-L1 expression in combination with CD8+ TILs density in patients with surgically resected non-small cell lung cancer

Abstract

To investigate the prognostic value of PD-L1 expression combined with CD8⁺ TILs density in patients with resected NSCLC and correlations with clinicopathological features. We retrospectively enrolled 178 patients with resected NSCLC from 2011 to 2015. All surgical primary and 58 matched metastatic lymph node specimens were tested for PD-L1, CD8⁺ TILs, and oncogenic alterations. PD-L1⁺ was detected in 71 (39.9%) and CD8^high TILs in 74 (41.6%) cases. Smoking, SqCC, and EGFR⁻ were associated with both PD-L1⁺ and CD8^high TILs. Patients with CD8^high TILs had longer OS (P = 0.012). PD-L1⁻ was significantly associated with longer OS in patients with oncogenic alterations (P = 0.047). By multivariate analysis, CD8^high TILs (HR = 0.411; 95% CI, 0.177–0.954; P = 0.038), rather than PD-L1, was the independent predictive factor for OS. The longest and shortest OS were achieved in patients with PD-L1⁺/CD8^high and PD-L1⁺/CD8^low, respectively (P = 0.025). Inconsistent PD-L1 expression levels were observed in 23 of 58 (39.7%) patients with primary and matched metastatic lymph node specimens. Of them, CD8^high TILs was significantly associated with longer OS in patients with metastatic lymph nodes and/or consistent PD-L1 expression (P = 0.017 and 0.049, respectively). The combination of PD-L1 and CD8⁺ TILs density, instead of PD-L1 alone, suggested impressive prognostic values in NSCLC patients. Less than half of patients with resected NSCLC experienced inconsistent PD-L1 expression between primary and metastatic lesions. The level of PD-L1 expression in advanced NSCLC needs to be evaluated more comprehensively.

Combination of PD-L1 and CD8⁺ TILs density may suggest impressive prognostic value in NSCLC patients instead of PD-L1 alone. Less than half of patients with resected NSCLC experienced inconsistent PD-L1 expression between primary and metastatic lesions, and significance of PD-L1 expression in a single-biopsy specimen in advanced NSCLC may be overestimated in clinical practice.

http://ift.tt/2jRngUs

Patient satisfaction with information on oral anticancer agent use

Abstract

Adequate information on oral anticancer agent (OACA) use is an essential element of optimal cancer care. The present study aimed to get insight into the experiences of patients with information on OACA treatment and their characteristics regarding information dissatisfaction. Patients of four Dutch university hospitals using OACA participated in this observational study and completed the Satisfaction with Information about Medicines Scale (SIMS), EORTC Quality of Life Questionnaire-C30, Brief Illness Perception Questionnaire, and Beliefs about Medicines Questionnaire-Specific. Logistic regression analyses were used to determine factors associated with dissatisfaction with information. Patients (n = 208) using capecitabine (35%), lenalidomide (15%), imatinib (14%), temozolomide (12%), sunitinib (11%), thalidomide (5%), dasatinib (4%), erlotinib (2%), and nilotinib (2%) participated. Information on the following SIMS-items was inadequate: how OACA elicit their effect, how long it takes before treatment works, how to conclude that treatment is effective, the risk of side effects and its management, interference with sex life, drowsiness, interference with other medication and alcohol and what to do in case of a missed dose. Younger age, hematological malignancy, dyspnoea, positive perception of consequences of the cancer, low perception of treatment control, and indifferent attitude towards OACA were associated with dissatisfaction with information. In conclusion, a considerable number of patients would have appreciated receiving more information on specific issues relating to the consequences of OACA treatment such as the effects and side effects of OACA and the interference of treatment with various aspects of their daily life. Oncologists, hematologists, lung-oncologists and pharmacists may reconsider the provision of information on OACA treatment.

This observational study showed that a substantial number of cancer patients perceived a lack of information on oral anticancer agent (OACA) treatment. Particularly information on the following subjects should be improved: self-monitoring of treatment effectiveness, side effects and their management, interference of treatment with sex life, interference of treatment with other medicines and alcohol use, and what to do in case of missed doses. Healthcare providers may reconsider the provision of information on OACA treatment.

http://ift.tt/2hYzcDs

Cancer-testis gene PIWIL1 promotes cell proliferation, migration, and invasion in lung adenocarcinoma

Abstract

Piwi-like RNA-mediated gene silencing 1 (PIWIL1) has been identified as a novel extremely highly expressed cancer-testis (CT) gene in lung adenocarcinoma. However, the exact function and mechanism of PIWIL1 in lung adenocarcinoma remains unclear. Herein, we sought to investigate the role of PIWIL1 in the occurrence and development of lung adenocarcinoma. We examined the expression pattern of PIWIL1 in The Cancer Genome Atlas (TCGA) lung adenocarcinoma samples, and validated it by Real-Time PCR (RT-PCR) in additional 21 paired lung adenocarcinoma tissues and 16 normal tissues. Subsequently, we explored the biological function of PIWIL1 in A549 and H1299 cell lines by gain and loss-of-function analyses. Using TCGA lung adenocarcinoma data, we further performed coexpression and Gene Ontology (GO) analyses, and analyzed the association of DNA methylation levels in PIWIL1 promoter region with its expression. Finally, we evaluated its expression in different mutation status of significantly mutated genes (SMGs) in TCGA lung adenocarcinoma data. We observed that PIWIL1 was expressed in testis and lung adenocarcinoma but not in other normal tissues, and its high expression was associated with shortened survival of lung cancer patients. Overexpression of PIWIL1 could facilitate the proliferation, invasion and migration of lung adenocarcinoma cells and vice versa. GO analysis revealed that PIWIL1 upregulated genes were enriched in embryonic development, cell proliferation and regulation of transcription. Moreover, promoter DNA hypomethylation of PIWIL1 could contribute to its aberrant expression in tumors. Interestingly, PIWIL1 expression was significantly higher in patients without hepatocyte growth factor (HGF) or serine/threonine kinase 11 (STK11) mutation (P = 0.006 and 0.005, respectively). PIWIL1 is an epidriver gene in lung adenocarcinoma, indicating a potential target for further therapy.

PIWIL1 is a novel extremely highly expressed cancer-testis gene in lung adenocarcinoma. PIWIL1 could promote the ability of proliferation, invasion, and migration in lung adenocarcinoma. The expression status of PIWIL1 is regulated by methylation in promoter region.

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Prognostic value of PD-L1 expression in combination with CD8+ TILs density in patients with surgically resected non-small cell lung cancer

Abstract

To investigate the prognostic value of PD-L1 expression combined with CD8⁺ TILs density in patients with resected NSCLC and correlations with clinicopathological features. We retrospectively enrolled 178 patients with resected NSCLC from 2011 to 2015. All surgical primary and 58 matched metastatic lymph node specimens were tested for PD-L1, CD8⁺ TILs, and oncogenic alterations. PD-L1⁺ was detected in 71 (39.9%) and CD8^high TILs in 74 (41.6%) cases. Smoking, SqCC, and EGFR⁻ were associated with both PD-L1⁺ and CD8^high TILs. Patients with CD8^high TILs had longer OS (P = 0.012). PD-L1⁻ was significantly associated with longer OS in patients with oncogenic alterations (P = 0.047). By multivariate analysis, CD8^high TILs (HR = 0.411; 95% CI, 0.177–0.954; P = 0.038), rather than PD-L1, was the independent predictive factor for OS. The longest and shortest OS were achieved in patients with PD-L1⁺/CD8^high and PD-L1⁺/CD8^low, respectively (P = 0.025). Inconsistent PD-L1 expression levels were observed in 23 of 58 (39.7%) patients with primary and matched metastatic lymph node specimens. Of them, CD8^high TILs was significantly associated with longer OS in patients with metastatic lymph nodes and/or consistent PD-L1 expression (P = 0.017 and 0.049, respectively). The combination of PD-L1 and CD8⁺ TILs density, instead of PD-L1 alone, suggested impressive prognostic values in NSCLC patients. Less than half of patients with resected NSCLC experienced inconsistent PD-L1 expression between primary and metastatic lesions. The level of PD-L1 expression in advanced NSCLC needs to be evaluated more comprehensively.

Combination of PD-L1 and CD8⁺ TILs density may suggest impressive prognostic value in NSCLC patients instead of PD-L1 alone. Less than half of patients with resected NSCLC experienced inconsistent PD-L1 expression between primary and metastatic lesions, and significance of PD-L1 expression in a single-biopsy specimen in advanced NSCLC may be overestimated in clinical practice.

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Patient satisfaction with information on oral anticancer agent use

Abstract

Adequate information on oral anticancer agent (OACA) use is an essential element of optimal cancer care. The present study aimed to get insight into the experiences of patients with information on OACA treatment and their characteristics regarding information dissatisfaction. Patients of four Dutch university hospitals using OACA participated in this observational study and completed the Satisfaction with Information about Medicines Scale (SIMS), EORTC Quality of Life Questionnaire-C30, Brief Illness Perception Questionnaire, and Beliefs about Medicines Questionnaire-Specific. Logistic regression analyses were used to determine factors associated with dissatisfaction with information. Patients (n = 208) using capecitabine (35%), lenalidomide (15%), imatinib (14%), temozolomide (12%), sunitinib (11%), thalidomide (5%), dasatinib (4%), erlotinib (2%), and nilotinib (2%) participated. Information on the following SIMS-items was inadequate: how OACA elicit their effect, how long it takes before treatment works, how to conclude that treatment is effective, the risk of side effects and its management, interference with sex life, drowsiness, interference with other medication and alcohol and what to do in case of a missed dose. Younger age, hematological malignancy, dyspnoea, positive perception of consequences of the cancer, low perception of treatment control, and indifferent attitude towards OACA were associated with dissatisfaction with information. In conclusion, a considerable number of patients would have appreciated receiving more information on specific issues relating to the consequences of OACA treatment such as the effects and side effects of OACA and the interference of treatment with various aspects of their daily life. Oncologists, hematologists, lung-oncologists and pharmacists may reconsider the provision of information on OACA treatment.

This observational study showed that a substantial number of cancer patients perceived a lack of information on oral anticancer agent (OACA) treatment. Particularly information on the following subjects should be improved: self-monitoring of treatment effectiveness, side effects and their management, interference of treatment with sex life, interference of treatment with other medicines and alcohol use, and what to do in case of missed doses. Healthcare providers may reconsider the provision of information on OACA treatment.

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Genomic risk prediction of aromatase inhibitor-related arthralgia in patients with breast cancer using a novel machine-learning algorithm

Abstract

Many breast cancer (BC) patients treated with aromatase inhibitors (AIs) develop aromatase inhibitor-related arthralgia (AIA). Candidate gene studies to identify AIA risk are limited in scope. We evaluated the potential of a novel analytic algorithm (NAA) to predict AIA using germline single nucleotide polymorphisms (SNP) data obtained before treatment initiation. Systematic chart review of 700 AI-treated patients with stage I-III BC identified asymptomatic patients (n = 39) and those with clinically significant AIA resulting in AI termination or therapy switch (n = 123). Germline DNA was obtained and SNP genotyping performed using the Affymetrix UK BioBank Axiom Array to yield 695,277 SNPs. SNP clusters that most closely defined AIA risk were discovered using an NAA that sequentially combined statistical filtering and a machine-learning algorithm. NCBI PhenGenI and Ensemble databases defined gene attribution of the most discriminating SNPs. Phenotype, pathway, and ontologic analyses assessed functional and mechanistic validity. Demographics were similar in cases and controls. A cluster of 70 SNPs, correlating to 57 genes, was identified. This SNP group predicted AIA occurrence with a maximum accuracy of 75.93%. Strong associations with arthralgia, breast cancer, and estrogen phenotypes were seen in 19/57 genes (33%) and were functionally consistent. Using a NAA, we identified a 70 SNP cluster that predicted AIA risk with fair accuracy. Phenotype, functional, and pathway analysis of attributed genes was consistent with clinical phenotypes. This study is the first to link a specific SNP/gene cluster to AIA risk independent of candidate gene bias.

Aromatase inhibitor-related arthralgias (AIA) are common and may lead to therapy noncompliance. Whereas traditional gene studies to identify arthralgia risk have been limited in scope, we employed a novel analytic algorithm to link a specific SNP/gene cluster to AIA risk independent of candidate gene bias.

http://ift.tt/2A57Wb3

Genomic risk prediction of aromatase inhibitor-related arthralgia in patients with breast cancer using a novel machine-learning algorithm

Abstract

Many breast cancer (BC) patients treated with aromatase inhibitors (AIs) develop aromatase inhibitor-related arthralgia (AIA). Candidate gene studies to identify AIA risk are limited in scope. We evaluated the potential of a novel analytic algorithm (NAA) to predict AIA using germline single nucleotide polymorphisms (SNP) data obtained before treatment initiation. Systematic chart review of 700 AI-treated patients with stage I-III BC identified asymptomatic patients (n = 39) and those with clinically significant AIA resulting in AI termination or therapy switch (n = 123). Germline DNA was obtained and SNP genotyping performed using the Affymetrix UK BioBank Axiom Array to yield 695,277 SNPs. SNP clusters that most closely defined AIA risk were discovered using an NAA that sequentially combined statistical filtering and a machine-learning algorithm. NCBI PhenGenI and Ensemble databases defined gene attribution of the most discriminating SNPs. Phenotype, pathway, and ontologic analyses assessed functional and mechanistic validity. Demographics were similar in cases and controls. A cluster of 70 SNPs, correlating to 57 genes, was identified. This SNP group predicted AIA occurrence with a maximum accuracy of 75.93%. Strong associations with arthralgia, breast cancer, and estrogen phenotypes were seen in 19/57 genes (33%) and were functionally consistent. Using a NAA, we identified a 70 SNP cluster that predicted AIA risk with fair accuracy. Phenotype, functional, and pathway analysis of attributed genes was consistent with clinical phenotypes. This study is the first to link a specific SNP/gene cluster to AIA risk independent of candidate gene bias.

Aromatase inhibitor-related arthralgias (AIA) are common and may lead to therapy noncompliance. Whereas traditional gene studies to identify arthralgia risk have been limited in scope, we employed a novel analytic algorithm to link a specific SNP/gene cluster to AIA risk independent of candidate gene bias.

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Macrophagic "crown-like structures" are associated with an increased risk of breast cancer in benign breast disease

In breast adipose tissue, macrophages that encircle damaged adipocytes form "crown-like structures of breast" (CLS-B). While CLS-B have been associated with breast cancer, their role in benign breast disease and early carcinogenesis is not understood. We evaluated breast biopsies from three age-matched groups (n = 86 each, mean age 55 y), including normal tissue donors of the Susan G. Komen for the Cure® Tissue Bank (KTB), and subjects in the Mayo Clinic Benign Breast Disease (BBD) Cohort who developed cancer (BBD cases) or did not develop cancer (BBD controls, median follow-up 14 y). Biopsies were classified into histologic categories, and CD68-immunostained tissue sections were evaluated for the frequency and density of CLS-B. Our data demonstrate that CLS-B are associated with benign breast disease: CLS-B-positive samples were significantly less frequent among KTB biopsies (3/86, 3.5%) than BBD controls (16/86=18.6%, p = 0.01) and BBD cases (21/86=24%, p = 0.002). CLS-B were strongly associated with body mass index (BMI); BMI < 25: 7% CLS-B-positive, BMI 25-29: 13%, and BMI ≥ 30: 29% (p = 0.0005). Among BBD biopsies, a high CLS-B count (>5 CLS-B/sample: 10.5% (BBD cases) vs 4.7% (BBD controls), p = 0.007) conferred a breast cancer odds ratio of 6.8 (95% CI: 1.4-32.4), p=0.02, after adjusting for adipose tissue area (cm2), histologic impression and body mass index. As high CLS-B densities are independently associated with an increased breast cancer risk, they may be a promising histologic marker of breast cancer risk in benign breast disease.

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Wnt/{beta}-catenin pathway activation mediates adaptive resistance to BRAF inhibition in colorectal cancer

One of the most encouraging developments in oncology has been the success of BRAF inhibitors in BRAF-mutant melanoma. However, in contrast to its striking efficacy in BRAF-mutant melanomas, BRAF inhibitor monotherapy is ineffective in BRAF-mutant colorectal cancer (CRC). While many studies on BRAF inhibitor resistance in CRC have focused on mechanisms underlying the reactivation of the EGFR/RAS/RAF/MEK/ERK pathway, the current study focuses on identifying novel adaptive signaling mechanisms, a fresh angle on CRC resistance to BRAF inhibition. We found that treatment with BRAF inhibitors (both current and next generation BRAF inhibitors) upregulated the Wnt/β-catenin pathway in BRAFV600E-mutant CRC cell lines through activating the cytoplasmic tyrosine kinase FAK (focal adhesion kinase). The results showed that FAK activation upon BRAF inhibitor treatment did not require EGFR (Epidermal Growth Factor Receptor) or ERK1/2 (extracellular-signal-regulated kinases1/2) activation, implying that BRAF inhibitor treatment-induced hyperactivation of Wnt signaling is "pathway reactivation"-independent. BRAF inhibition-induced Wnt pathway activation was further validated in preclinical models of BRAFV600E-mutant CRC including cell line xenograft model and a PDX (patient-derived xenograft) model. Combined inhibition of BRAF/Wnt pathways or BRAF/FAK pathways exerted strong synergistic antitumor effects in cell culture model and mouse xenograft model. Overall, the current study has identified activation of the Wnt/β-catenin pathway as a novel fundamental cause of colon cancer resistance to BRAF inhibition. Our results suggest that while complete vertical pathway blockade is pivotal for effective and durable control of BRAF-mutant CRC, co-targeting parallel adaptive signaling-the Wnt/β-catenin pathway-is also essential.

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A Novel YAP1 Inhibitor targets CSCs-enriched Radiation Resistant Cells and Exerts Strong Antitumor Activity in Esophageal Adenocarcinoma

Mounting evidence suggests that the Hippo co-activator Yes-associated protein 1 (YAP1) is a major mediator of cancer stem cell (CSC) properties, tumor progression, and therapy resistance as well as often a terminal node of many oncogenic pathways. Thus, targeting YAP1 may be a novel therapeutic strategy for many types of tumors with high YAP1 expression, including esophageal adenocarcinoma (EAC). However, effective YAP1 inhibitors are currently lacking. Here, we identify a small molecule (CA3) that not only has remarkable inhibitory activity on YAP1/Tead transcriptional activity but also demonstrates strong inhibitory effects on EAC cell growth especially on YAP1 high expressing EAC cells both in vitro and in vivo. Remarkably, radiation resistant cells acquire strong CSC properties and aggressive phenotype, while CA3 can effectively suppresses these phenotypes by inhibiting proliferation, inducing apoptosis, reducing tumor sphere formation, and reducing the fraction of ALDH1+ cells. Further, CA3 combined with 5-FU, synergistically inhibits EAC cell growth especially in YAP1 high EAC cells. Taken together, these findings demonstrated that CA3 represents a new inhibitor of YAP1 and primarily targets YAP1 high and therapy resistant EC cells endowed with CSCs properties.

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Mechanism informed repurposing of minocycline overcomes resistance to topoisomerase inhibition for peritoneal carcinomatosis

Mechanism-inspired drug repurposing that augments standard treatments offers a cost-effective and a rapid route toward addressing the burgeoning problem of plateauing of effective therapeutics for drug-resistant micrometastases. We show that the antibiotic minocycline, by its ability to minimize DNA repair via reduced expression of tyrosyl-DNA phosphodiesterase-1 (Tdp1), removes a key process attenuating the efficacy of irinotecan, a frequently used chemotherapeutic against metastatic disease. Moreover, minocycline and irinotecan cooperatively mitigate each other's undesired cytokine inductions of VEGF and IL-8 respectively, thereby reinforcing the benefits of each modality. These mechanistic interactions result in synergistic enhancement of irinotecan-induced platinum-resistant epithelial ovarian cancer cell death, reduced micrometastases in the omenta and mesentery by >75%, and an extended overall survival by 50% in a late-stage peritoneal carcinomatosis mouse model. Economic incentives and easy translatability make the repurposing of minocycline as a reinforcer of the topoisomerase class of chemotherapeutics extremely valuable and merits further investigations.

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Inhibition of O-GlcNAcase sensitizes apoptosis and reverses bortezomib resistance in mantle cell lymphoma through modification of truncated Bid

Aberrant energy metabolism represents a hallmark of cancer and contributes to numerous aggressive behaviors of cancer cells, including cell death and survival. Despite the poor prognosis of mantle cell lymphoma (MCL), due to the inevitable development of drug resistance, metabolic reprograming of MCL cells remains an unexplored area. Post-translational modification of proteins via O-GlcNAcylation is an ideal sensor for nutritional changes mediated by O-GlcNAc transferase (OGT) and is removed by O-GlcNAcase (OGA). Using various small molecule inhibitors of OGT and OGA, we found for the first time that O-GlcNAcylation potentiates MCL response to bortezomib (BTZ). CRISPR interference of MGEA5 (encoding OGA) validated the apoptosis sensitization by O-GlcNAcylation and OGA inhibition. To identify the potential clinical candidates, we tested MCL response to drug-like OGA inhibitor, ketoconazole (KCZ), and verified that it exerts similar sensitizing effect on BTZ-induced apoptosis. Investigations into the underlying molecular mechanisms reveal that BTZ and KCZ act in concert to cause the accumulation of truncated Bid (tBid). Not only does KCZ potentiate tBid induction, but also increases tBid stability through O-GlcNAcylation that interferes with tBid ubiquitination and proteasomal degradation. Remarkably, KCZ strongly enhances BTZ-induced apoptosis in de novo BTZ-resistant MCL cells and in patient-derived primary cells with minimal cytotoxic effect on normal peripheral blood mononuclear cells and hepatocytes, suggesting its potential utility as a safe and effective adjuvant for MCL. Together, our findings provide novel evidence that combination of BTZ and KCZ or other OGA inhibitors may present a promising strategy for the treatment of drug-resistant MCL.

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Wnt/{beta}-catenin pathway activation mediates adaptive resistance to BRAF inhibition in colorectal cancer

One of the most encouraging developments in oncology has been the success of BRAF inhibitors in BRAF-mutant melanoma. However, in contrast to its striking efficacy in BRAF-mutant melanomas, BRAF inhibitor monotherapy is ineffective in BRAF-mutant colorectal cancer (CRC). While many studies on BRAF inhibitor resistance in CRC have focused on mechanisms underlying the reactivation of the EGFR/RAS/RAF/MEK/ERK pathway, the current study focuses on identifying novel adaptive signaling mechanisms, a fresh angle on CRC resistance to BRAF inhibition. We found that treatment with BRAF inhibitors (both current and next generation BRAF inhibitors) upregulated the Wnt/β-catenin pathway in BRAFV600E-mutant CRC cell lines through activating the cytoplasmic tyrosine kinase FAK (focal adhesion kinase). The results showed that FAK activation upon BRAF inhibitor treatment did not require EGFR (Epidermal Growth Factor Receptor) or ERK1/2 (extracellular-signal-regulated kinases1/2) activation, implying that BRAF inhibitor treatment-induced hyperactivation of Wnt signaling is "pathway reactivation"-independent. BRAF inhibition-induced Wnt pathway activation was further validated in preclinical models of BRAFV600E-mutant CRC including cell line xenograft model and a PDX (patient-derived xenograft) model. Combined inhibition of BRAF/Wnt pathways or BRAF/FAK pathways exerted strong synergistic antitumor effects in cell culture model and mouse xenograft model. Overall, the current study has identified activation of the Wnt/β-catenin pathway as a novel fundamental cause of colon cancer resistance to BRAF inhibition. Our results suggest that while complete vertical pathway blockade is pivotal for effective and durable control of BRAF-mutant CRC, co-targeting parallel adaptive signaling-the Wnt/β-catenin pathway-is also essential.

http://ift.tt/2hZvGbQ

A Novel YAP1 Inhibitor targets CSCs-enriched Radiation Resistant Cells and Exerts Strong Antitumor Activity in Esophageal Adenocarcinoma

Mounting evidence suggests that the Hippo co-activator Yes-associated protein 1 (YAP1) is a major mediator of cancer stem cell (CSC) properties, tumor progression, and therapy resistance as well as often a terminal node of many oncogenic pathways. Thus, targeting YAP1 may be a novel therapeutic strategy for many types of tumors with high YAP1 expression, including esophageal adenocarcinoma (EAC). However, effective YAP1 inhibitors are currently lacking. Here, we identify a small molecule (CA3) that not only has remarkable inhibitory activity on YAP1/Tead transcriptional activity but also demonstrates strong inhibitory effects on EAC cell growth especially on YAP1 high expressing EAC cells both in vitro and in vivo. Remarkably, radiation resistant cells acquire strong CSC properties and aggressive phenotype, while CA3 can effectively suppresses these phenotypes by inhibiting proliferation, inducing apoptosis, reducing tumor sphere formation, and reducing the fraction of ALDH1+ cells. Further, CA3 combined with 5-FU, synergistically inhibits EAC cell growth especially in YAP1 high EAC cells. Taken together, these findings demonstrated that CA3 represents a new inhibitor of YAP1 and primarily targets YAP1 high and therapy resistant EC cells endowed with CSCs properties.

http://ift.tt/2jShiCZ

Mechanism informed repurposing of minocycline overcomes resistance to topoisomerase inhibition for peritoneal carcinomatosis

Mechanism-inspired drug repurposing that augments standard treatments offers a cost-effective and a rapid route toward addressing the burgeoning problem of plateauing of effective therapeutics for drug-resistant micrometastases. We show that the antibiotic minocycline, by its ability to minimize DNA repair via reduced expression of tyrosyl-DNA phosphodiesterase-1 (Tdp1), removes a key process attenuating the efficacy of irinotecan, a frequently used chemotherapeutic against metastatic disease. Moreover, minocycline and irinotecan cooperatively mitigate each other's undesired cytokine inductions of VEGF and IL-8 respectively, thereby reinforcing the benefits of each modality. These mechanistic interactions result in synergistic enhancement of irinotecan-induced platinum-resistant epithelial ovarian cancer cell death, reduced micrometastases in the omenta and mesentery by >75%, and an extended overall survival by 50% in a late-stage peritoneal carcinomatosis mouse model. Economic incentives and easy translatability make the repurposing of minocycline as a reinforcer of the topoisomerase class of chemotherapeutics extremely valuable and merits further investigations.

http://ift.tt/2hY94bX

Inhibition of O-GlcNAcase sensitizes apoptosis and reverses bortezomib resistance in mantle cell lymphoma through modification of truncated Bid

Aberrant energy metabolism represents a hallmark of cancer and contributes to numerous aggressive behaviors of cancer cells, including cell death and survival. Despite the poor prognosis of mantle cell lymphoma (MCL), due to the inevitable development of drug resistance, metabolic reprograming of MCL cells remains an unexplored area. Post-translational modification of proteins via O-GlcNAcylation is an ideal sensor for nutritional changes mediated by O-GlcNAc transferase (OGT) and is removed by O-GlcNAcase (OGA). Using various small molecule inhibitors of OGT and OGA, we found for the first time that O-GlcNAcylation potentiates MCL response to bortezomib (BTZ). CRISPR interference of MGEA5 (encoding OGA) validated the apoptosis sensitization by O-GlcNAcylation and OGA inhibition. To identify the potential clinical candidates, we tested MCL response to drug-like OGA inhibitor, ketoconazole (KCZ), and verified that it exerts similar sensitizing effect on BTZ-induced apoptosis. Investigations into the underlying molecular mechanisms reveal that BTZ and KCZ act in concert to cause the accumulation of truncated Bid (tBid). Not only does KCZ potentiate tBid induction, but also increases tBid stability through O-GlcNAcylation that interferes with tBid ubiquitination and proteasomal degradation. Remarkably, KCZ strongly enhances BTZ-induced apoptosis in de novo BTZ-resistant MCL cells and in patient-derived primary cells with minimal cytotoxic effect on normal peripheral blood mononuclear cells and hepatocytes, suggesting its potential utility as a safe and effective adjuvant for MCL. Together, our findings provide novel evidence that combination of BTZ and KCZ or other OGA inhibitors may present a promising strategy for the treatment of drug-resistant MCL.

http://ift.tt/2jSheDf

Residual Convolutional Neural Network for Determination of IDH Status in Low- and High-grade Gliomas from MR Imaging

Purpose: Isocitrate dehydrogenase (<IDH) mutations in glioma patients confer longer survival and may guide treatment decision-making. We aimed to predict the IDH status of gliomas from MR imaging by applying a residual convolutional neural network to pre-operative radiographic data. Experimental Design: Preoperative imaging was acquired for 201 patients from the Hospital of University of Pennsylvania (HUP), 157 patients from Brigham and Women's Hospital (BWH), and 138 patients from The Cancer Imaging Archive (TCIA) and divided into training, validation, and testing sets. We trained a residual convolutional neural network for each MR sequence (FLAIR, T2, T1 pre-contrast, and T1 post-contrast) and built a predictive model from the outputs. To increase the size of training set and prevent overfitting, we augmented the training set images by introducing random rotations, translations, flips, shearing, and zooming. Results: With our neural network model, we achieved IDH prediction accuracies of 82.8% (AUC = 0.90), 83.0% (AUC = 0.93), and 85.7% (AUC = 0.94) within training, validation, and testing sets, respectively. When age at diagnosis was incorporated into the model, the training, validation, and testing accuracies increased to 87.3% (AUC = 0.93), 87.6% (AUC = 0.95), and 89.1% (AUC = 0.95), respectively. Conclusions: We developed a deep learning technique to non-invasively predict IDH genotype in grade II-IV glioma using conventional MR imaging using a multi-institutional dataset.

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PTEN loss promotes intratumoral androgen synthesis and tumor microenvironment remodeling via aberrant activation of RUNX2 in castration-resistant prostate cancer

Purpose: Intratumoral androgen synthesis (IAS) is a key mechanism promoting androgen receptor (AR) reactivation and anti-androgen resistance in castration-resistant prostate cancer (CRPC). However, signaling pathways driving aberrant IAS remain poorly understood.  Experimental Design: The effect of components of the AKT-RUNX2-osteocalcin (OCN)-GPRC6A-CREB signaling axis on expression of steroidogenesis genes CYP11A1 and CYP17A1 and testosterone level were examined in PTEN-null human PCa cell lines. Pten knockout mice were employed to examine the effect of Runx2 heterozygous deletion or abiraterone acetate (ABA), a prodrug of the CYP17A1 inhibitor abiraterone on Cyp11a1 and Cyp17a1 expression, testosterone level and tumor microenvironment (TME) remodeling in vivo.  Results: We uncovered that activation of the AKT-RUNX2-OCN-GPRC6A-CREB signaling axis induced expression of CYP11A1 and CYP17A1 and testosterone production in PTEN-null PCa cell lines in culture. Deletion of Runx2 in Pten homozygous knockout prostate tumors decreased Cyp11a1 and Cyp17a1 expression, testosterone level and tumor growth in castrated mice. ABA treatment also inhibited testosterone synthesis and alleviated Pten loss-induced tumorigenesis in vivo. Pten deletion induced TME remodeling, but Runx2 heterozygous deletion or ABA treatment reversed the effect of Pten loss by decreasing expression of the collagenase Mmp9. Conclusions:Abnormal RUNX2 activation plays a pivotal role in PTEN loss-induced IAS and TME remodeling, suggesting that the identified signaling cascade represents a viable target for effective treatment of PTEN-null PCa including CRPC.

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Residual Convolutional Neural Network for Determination of IDH Status in Low- and High-grade Gliomas from MR Imaging

Purpose: Isocitrate dehydrogenase (<IDH) mutations in glioma patients confer longer survival and may guide treatment decision-making. We aimed to predict the IDH status of gliomas from MR imaging by applying a residual convolutional neural network to pre-operative radiographic data. Experimental Design: Preoperative imaging was acquired for 201 patients from the Hospital of University of Pennsylvania (HUP), 157 patients from Brigham and Women's Hospital (BWH), and 138 patients from The Cancer Imaging Archive (TCIA) and divided into training, validation, and testing sets. We trained a residual convolutional neural network for each MR sequence (FLAIR, T2, T1 pre-contrast, and T1 post-contrast) and built a predictive model from the outputs. To increase the size of training set and prevent overfitting, we augmented the training set images by introducing random rotations, translations, flips, shearing, and zooming. Results: With our neural network model, we achieved IDH prediction accuracies of 82.8% (AUC = 0.90), 83.0% (AUC = 0.93), and 85.7% (AUC = 0.94) within training, validation, and testing sets, respectively. When age at diagnosis was incorporated into the model, the training, validation, and testing accuracies increased to 87.3% (AUC = 0.93), 87.6% (AUC = 0.95), and 89.1% (AUC = 0.95), respectively. Conclusions: We developed a deep learning technique to non-invasively predict IDH genotype in grade II-IV glioma using conventional MR imaging using a multi-institutional dataset.

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PTEN loss promotes intratumoral androgen synthesis and tumor microenvironment remodeling via aberrant activation of RUNX2 in castration-resistant prostate cancer

Purpose: Intratumoral androgen synthesis (IAS) is a key mechanism promoting androgen receptor (AR) reactivation and anti-androgen resistance in castration-resistant prostate cancer (CRPC). However, signaling pathways driving aberrant IAS remain poorly understood.  Experimental Design: The effect of components of the AKT-RUNX2-osteocalcin (OCN)-GPRC6A-CREB signaling axis on expression of steroidogenesis genes CYP11A1 and CYP17A1 and testosterone level were examined in PTEN-null human PCa cell lines. Pten knockout mice were employed to examine the effect of Runx2 heterozygous deletion or abiraterone acetate (ABA), a prodrug of the CYP17A1 inhibitor abiraterone on Cyp11a1 and Cyp17a1 expression, testosterone level and tumor microenvironment (TME) remodeling in vivo.  Results: We uncovered that activation of the AKT-RUNX2-OCN-GPRC6A-CREB signaling axis induced expression of CYP11A1 and CYP17A1 and testosterone production in PTEN-null PCa cell lines in culture. Deletion of Runx2 in Pten homozygous knockout prostate tumors decreased Cyp11a1 and Cyp17a1 expression, testosterone level and tumor growth in castrated mice. ABA treatment also inhibited testosterone synthesis and alleviated Pten loss-induced tumorigenesis in vivo. Pten deletion induced TME remodeling, but Runx2 heterozygous deletion or ABA treatment reversed the effect of Pten loss by decreasing expression of the collagenase Mmp9. Conclusions:Abnormal RUNX2 activation plays a pivotal role in PTEN loss-induced IAS and TME remodeling, suggesting that the identified signaling cascade represents a viable target for effective treatment of PTEN-null PCa including CRPC.

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Constitutively Active SMAD2/3 Are Broad-Scope Potentiators of Transcription-Factor-Mediated Cellular Reprogramming

Publication date: Available online 22 November 2017
Source:Cell Stem Cell
Author(s): Tyson Ruetz, Ulrich Pfisterer, Bruno Di Stefano, James Ashmore, Meryam Beniazza, Tian V. Tian, Daniel F. Kaemena, Luca Tosti, Wenfang Tan, Jonathan R. Manning, Eleni Chantzoura, Daniella Rylander Ottosson, Samuel Collombet, Anna Johnsson, Erez Cohen, Kosuke Yusa, Sten Linnarsson, Thomas Graf, Malin Parmar, Keisuke Kaji
Reprogramming of cellular identity using exogenous expression of transcription factors (TFs) is a powerful and exciting tool for tissue engineering, disease modeling, and regenerative medicine. However, generation of desired cell types using this approach is often plagued by inefficiency, slow conversion, and an inability to produce mature functional cells. Here, we show that expression of constitutively active SMAD2/3 significantly improves the efficiency of induced pluripotent stem cell (iPSC) generation by the Yamanaka factors. Mechanistically, SMAD3 interacts with reprogramming factors and co-activators and co-occupies OCT4 target loci during reprogramming. Unexpectedly, active SMAD2/3 also markedly enhances three other TF-mediated direct reprogramming conversions, from B cells to macrophages, myoblasts to adipocytes, and human fibroblasts to neurons, highlighting broad and general roles for SMAD2/3 as cell-reprogramming potentiators. Our results suggest that co-expression of active SMAD2/3 could enhance multiple types of TF-based cell identity conversion and therefore be a powerful tool for cellular engineering.

Graphical abstract

Teaser

Ruetz et al. show that constitutively active SMAD2/3 has a surprising ability to boost the efficiency of cell reprogramming both to iPSCs and across lineages and may therefore be a general factor that can enhance transcription-factor-mediated reprogramming in a variety of contexts.


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Injury Activates Transient Olfactory Stem Cell States with Diverse Lineage Capacities

Publication date: Available online 22 November 2017
Source:Cell Stem Cell
Author(s): Levi Gadye, Diya Das, Michael A. Sanchez, Kelly Street, Ariane Baudhuin, Allon Wagner, Michael B. Cole, Yoon Gi Choi, Nir Yosef, Elizabeth Purdom, Sandrine Dudoit, Davide Risso, John Ngai, Russell B. Fletcher
Tissue homeostasis and regeneration are mediated by programs of adult stem cell renewal and differentiation. However, the mechanisms that regulate stem cell fates under such widely varying conditions are not fully understood. Using single-cell techniques, we assessed the transcriptional changes associated with stem cell self-renewal and differentiation and followed the maturation of stem cell-derived clones using sparse lineage tracing in the regenerating mouse olfactory epithelium. Following injury, quiescent olfactory stem cells rapidly shift to activated, transient states unique to regeneration and tailored to meet the demands of injury-induced repair, including barrier formation and proliferation. Multiple cell fates, including renewed stem cells and committed differentiating progenitors, are specified during this early window of activation. We further show that Sox2 is essential for cells to transition from the activated to neuronal progenitor states. Our study highlights strategies for stem cell-mediated regeneration that may be conserved in other adult stem cell niches.

Graphical abstract

Teaser

Gadye et al. use multiple single-cell techniques to identify the cell state transitions underlying the stem cell self-renewal and differentiation during injury-induced regeneration of the olfactory epithelium. Olfactory stem cells shift en masse to a transient cell state unique to regeneration in which diverse fates are specified.


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Injury Induces Endogenous Reprogramming and Dedifferentiation of Neuronal Progenitors to Multipotency

Publication date: Available online 22 November 2017
Source:Cell Stem Cell
Author(s): Brian Lin, Julie H. Coleman, Jesse N. Peterson, Matthew J. Zunitch, Woochan Jang, Daniel B. Herrick, James E. Schwob
Adult neurogenesis in the olfactory epithelium is often depicted as a unidirectional pathway during homeostasis and repair. We challenge the unidirectionality of this model by showing that epithelial injury unlocks the potential for Ascl1+ progenitors and Neurog1+ specified neuronal precursors to dedifferentiate into multipotent stem/progenitor cells that contribute significantly to tissue regeneration in the murine olfactory epithelium (OE). We characterize these dedifferentiating cells using several lineage-tracing strains and single-cell mRNA-seq, and we show that Sox2 is required for initiating dedifferentiation and that inhibition of Ezh2 promotes multipotent progenitor expansion. These results suggest that the apparent hierarchy of neuronal differentiation is not irreversible and that lineage commitment can be overridden following severe tissue injury. We elucidate a previously unappreciated pathway for endogenous tissue repair by a highly regenerative neuroepithelium and introduce a system to study the mechanisms underlying plasticity in the OE that can be adapted for other tissues.

Graphical abstract

Teaser

Lin et al. demonstrate that Ascl1+ and Neurog1+ neuronal progenitors can acquire cell fate plasticity after injury using genetic lineage trace and transplantation assays. Injury-induced multipotency occurs through a developmentally reminiscent endogenous upregulation of Sox2, KLF4, and Pax6, and dedifferentiation efficiency can be enhanced by Ezh2 inhibition.


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HLA Loss in NSCLC: Facilitating Immune Escape [News in Brief]

Computational tool pinpoints allele-specific HLA loss, detects this event in a sizeable fraction of lung cancers.

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The T-cell Receptor {beta}-Chain Is an Immunotherapy Target for Lymphomas [Research Watch]

Targeting the TRBC gene expressed by T-cell malignancies mitigates severe immunosuppression.

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PD-1 Functions as a Tumor Suppressor in T-cell Lymphoma [Research Watch]

Oncogenic T-cell signaling upregulates PD-1, which increases PTEN expression to suppress oncogenesis.

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ARID1A Has Context-Specific Roles in Hepatocellular Carcinoma [Research Watch]

ARID1A promotes tumor initiation in the liver but suppresses metastasis in established tumors.

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Blocking IDO1 Helps Shrink Bladder, Cervical Tumors [News in Brief]

Combination of BMS-986205 and nivolumab shows early promise in phase I/IIa study.

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Predictive factors of acute skin reactions to carbon ion radiotherapy for the treatment of malignant bone and soft tissue tumors

The skin is considered a critical organ at risk in carbon ion radiotherapy (CIRT) for locally advanced malignant bone and soft tissue tumors (MBSTs). The predictive factors for acute skin reactions after CIRT ...

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Postoperative radiotherapy with or without concurrent chemotherapy for oral squamous cell carcinoma in patients with three or more minor risk factors: a propensity score matching analysis

To investigate the advantage of concurrent chemotherapy with postoperative radiotherapy (RT) of oral squamous cell carcinoma (OSCC) in patients with three or more minor risk factors.

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Predictive factors of acute skin reactions to carbon ion radiotherapy for the treatment of malignant bone and soft tissue tumors

The skin is considered a critical organ at risk in carbon ion radiotherapy (CIRT) for locally advanced malignant bone and soft tissue tumors (MBSTs). The predictive factors for acute skin reactions after CIRT ...

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Postoperative radiotherapy with or without concurrent chemotherapy for oral squamous cell carcinoma in patients with three or more minor risk factors: a propensity score matching analysis

To investigate the advantage of concurrent chemotherapy with postoperative radiotherapy (RT) of oral squamous cell carcinoma (OSCC) in patients with three or more minor risk factors.

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Expanding Smoking Cessation Services at NCI-designated Cancer Centers: An Interview with Dr. Glen Morgan

NCI's Dr. Glen Morgan discusses NCI's Cancer Center Cessation Initiative, including how and why this smoking cessation initiative was developed and its long-term goals.

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Expanding Smoking Cessation Services at NCI-designated Cancer Centers: An Interview with Dr. Glen Morgan

NCI's Dr. Glen Morgan discusses NCI's Cancer Center Cessation Initiative, including how and why this smoking cessation initiative was developed and its long-term goals.

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Incident Cancer in Cancer Survivors

Thanks to improvements in public health and more effective treatments for infectious diseases and cardiovascular disease, life expectancy in the United States has measurably improved. With increasing age comes an increase in cancer incidence. Over the past 4 decades improvements in cancer screening and treatment mean that about two-thirds of individuals in the United States diagnosed with cancer today will live at least 5 years. Thus, the need for evidence-based measures to optimize medical care for cancer survivors has emerged.

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Prior Cancer Among Persons Newly Diagnosed With Cancer

This analysis of data from the Surveillance, Epidemiology, and End Results program of cancer registries examines prevalence of prior cancer among individuals newly diagnosed with cancer.

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Primary Tumor Location and RAS and BRAF Mutations in Colon Cancer

This post hoc analysis investigates the prognostic and predictive role of primary tumor location according to BRAF, RAS, and microsatellite instability status in patients with colon cancer.

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Overall Survival vs Disease-Specific Survival

To the Editor Mailankody and Prasad, in their Viewpoint, discussed some of the age-related problems associated with the use of overall survival as an outcome in cancer drug trials. They suggested that overall survival in drug trials should be treated as a surrogate end point for overall survival in the real world. Some of the issues that the authors raise related to overall survival are due to the fact that the overall survival benefit decreases with age due to competing risks. It is not clear why the authors did not discuss disease-specific survival as a true outcome.

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Open Access Information Added

In the Original Article titled "Association of 70-Gene Signature Assay Findings With Physicians' Treatment Guidance for Patients With Early Breast Cancer Classified as Intermediate Risk by the 21-Gene Assay," published online October 26, 2017, information about the Open Access status was added to the acknowledgments. This article has been corrected online.

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The MACRA Quality Payment Program and Oncology Clinicians

This study surveys oncologists, hematologists, and practice administrators to gain an understanding of their perceptions of, and readiness to participate in, the MACRA Quality Payment Program.

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Overall Survival vs Disease-Specific Survival—Reply

In Reply Dr Burke asks why we focused on overall survival and not disease-specific survival in our Viewpoint, particularly among the elderly who face competing risks. We made the case that a marginal improvement in overall survival in an ideal population may be lost when that therapy is extrapolated to a real-world population. It is likely the case that a marginal benefit to disease-specific survival is also diluted or lost in the world because the mechanism of the loss is due to an increase in toxicity, frequent dose reductions, and discontinuations, leading to a tipping of the benefit/harm balance.

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Lymphatic Mapping and Sentinel Lymph Node Biopsy for Breast Cancer

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Medical industry at tumor board: Three-years analysis of the open payments database and comparison of oncologic specialties

Background and Objectives

To analyze and contrast medical industry payments across U.S. oncologic providers, including hematology-oncology (HO), surgical oncology (SO), interventional radiology (IR), and radiation oncology (RO).

Methods

Open-payment-data for each provider including provider specialty, state of practice, industry payor, reason for payment, and amount was compiled for each transaction between 2013 and 2015. Total, mean, and median payment amounts per-provider were calculated for each specialty. Tukey's-method was used to identify and remove statistical outliers and Kruskal-Wallis-test with Bonferonni-post-hoc-analysis was used to evaluate for differences in total payments received per-provider across specialties. The percentage of providers accepting payments within each specialty were compared by Marascuilo's multiple-proportion-comparison.

Results

Total aggregate payment amount (and number of transactions) for HO, SO, IR, and RO was $164 743 746 (778 007), $7 925 467 (15 031), $49 817 380 (44 939), and $13 643 739 (49 778), respectively. Corrected-median (and corrected-mean) payments-per-specialty were $676 ($1796), $330 ($1209), $487 ($1301), and $242 ($766). A significantly higher proportion of HO providers accepted payments than both RO (97% vs 80%, P < 0.0001) and IR (97% vs 78%, P < 0.0001). The mean total payment received per-provider differed significantly across specialties (P = 0.0001). HO providers, on average, received significantly more payment-per-provider during the study period (P < 0.001) compared to all others while RO and IR received significantly less (P < 0.0001).

Conclusions

Among industry payments made to oncologic providers, HO received the highest median and corrected-mean amounts along with the highest proportion of providers receiving open payments.

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Identification of predisposing factors for osteonecrosis of the jaw after marginal mandibulectomy in the surgical management of oral squamous cell carcinoma

Background

The aim of this study is to evaluate osteonecrosis of the jaw (ONJ) with the extent of marginal mandibulectomy.

Methods

Between January 2006 and December 2012, 3087 patients undergoing ablative resection were consecutively enrolled. Among them, 345 cases undergoing marginal mandibulectomy were retrospectively reviewed.

Results

The occurrence of ONJ was 5.51% and associated with body mass index, overall stage, diabetes, concomitant mandibulotomy, and radiotherapy (P = 0.023, 0.033, 0.009, 0.016, and 0.006, respectively). As for bone parameters based on radiological measurements after marginal mandibulectomy, resected bone height, remaining bone height to original bone height ratio, and resected bone height to original bone height ratio were associated with ONJ. In multivariate logistic analyses, concomitant mandibulotomy, radiotherapy, diabetes, resected bone height of >14.5 mm, resected bone height to original bone height ratio of >49.5%, and remaining bone height to original bone height ratio of <53.5% indicated higher risks for ONJ (adjusted HR: 4.345, 4.152, 4.079, 3.402, 3.541, and 3.211; P = 0.018, 0.013, 0.009, 0.021, 0.018, and 0.043, respectively).

Conclusions

This study demonstrated the predisposing factors and parameters associated with ONJ with marginal mandibulectomy; more caution is necessitated in performing marginal mandibulectomy in patients with multiple risks to prevent ONJ.

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Metastasectomy following incomplete response to high-dose interleukin-2

Objective

To evaluate our experience with metastasectomy following partial response or stable disease after treatment with high-dose interleukin-2 (HD IL-2).

Methods

A total of 305 patients with metastatic renal cell carcinoma or melanoma treated with HD IL-2 over a 12-year period were reviewed. Age, objective response, and overall survival data were evaluated using standard RECIST criteria and Kaplan-Meier estimates.

Results

The average age was 55.3 years (range, 15-85) and 245 (80.3%) patients had melanoma and 60 (19.7%) had renal cell carcinoma. The objective response rate to IL-2 for all patients was 13.6% and median survival was 16.8 months. Complete follow-up data were available for 236 patients with 147 (62.3%) progressing after treatment and 8 (3.3%) with a complete response. Incomplete responses were seen in 81 (34.3%) patients, including 57 (24.2%) patients with stable disease and 24 (10.1%) with partial responses. Of these 81 incomplete responders, 15 (18.5%) underwent subsequent metastasectomy. Patients without surgery had overall survival of 38.2 months and median survival has not yet been reached in those who underwent metastasectomy (P = 0.026).

Conclusion

The data support prospective evaluation of metastasectomy following incomplete therapeutic responses to immunotherapy and defines a new role for surgical resection following IL-2 and perhaps other immunotherapy regimens.

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Synovial sarcoma of the shoulder: A series of 14 cases

Background and Objectives

Synovial sarcoma is a rare soft tissue sarcoma with poor long-term prognosis due to late recurrence and metastasis. Synovial sarcoma arises in less than 6% from the shoulder. As a result, there is limited information in the literature about synovial sarcoma of the shoulder (SSS).

Methods

We included all patients treated for SSS at our institution between 1985 and 2013. Medical charts were retrospectively reviewed to collect demographics, information about the clinical course, and outcome. This subgroup was compared to our institution's entire synovial sarcoma patient cohort and the data in the published literature.

Results

SSS Patients presented most commonly with pain and a growing mass; the majority of tumors were grade 2 and measured greater than 5 cm. 43% (7) of SSS patients developed metastatic disease and 36% (5) had died at a median follow-up of 64 months (36-127); SSS 5-year survival (83.3%) was higher in our series than in the general literature (57-75%).

Conclusions

We found better prognosis in patients with synovial sarcoma of the shoulder than expected based on the current literature. The clinical behavior of synovial sarcoma in the shoulder is closer to that of synovial sarcoma in the extremities than the trunk.

Level of Evidence

Level IV, Case Series.

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Prospective phase II trial of combination hepatic artery infusion and systemic chemotherapy for unresectable colorectal liver metastases: Long term results and curative potential

Background/Objectives

Combination hepatic artery infusion (HAI) and systemic (SYS) chemotherapy for unresectable CRLM results in high tumor-response rates. This study represents an update of long-term survival and conversion to resectability in patients with unresectable CRLM treated with HAI and SYS chemotherapy in a phase II study.

Method

The primary endpoint was complete resection. Multivariate and landmark analysis assessed the effect of complete resection on progression-free (PFS) and overall survival (OS).

Results

From 2007 to 2012, 64 patients with median of 13 tumors were enrolled; 67% had prior chemotherapy. 33 patients (52%) were converted to resection. Median follow-up among survivors was 81 months. Median PFS and OS were 13 and 38 months, respectively, with 5-year-OS of 36%. Chemotherapy-naïve patients had 5-year-OS of 51%. Conversion to resection was the only independent factor prognostic of improved PFS and OS. Nine of 64 patients (14%) are NED (five since initial resection, three after resection of recurrent disease, one from chemotherapy alone) at median follow-up of 86 months from treatment initiation, and 72 months from last operative intervention.

Conclusion

Combination HAI and SYS is an effective therapy for high-volume unresectable CRLM, resulting in a high rate of resection, long-term survival, and the potential for cure.

http://ift.tt/2zsCZAm

A novel and validated prognostic nomogram based on liver fibrosis and tumor burden for patients with hepatocellular carcinoma after curative resection

Background and Objectives

Most conventional staging systems were formulated concerning the tumor burden rather than the severity of liver fibrosis, which plays a central role in tumor promotion. The aim of this study was to formulate a prognostic nomogram comprehensively considering these two aspects for HCC after hepatectomy.

Methods

The prognostic significances of the four indicators namely laminin, hyaluronic acid, human procollagen type-III, and collagen type-IV that reflect liver fibrosis were explored in two independent cohorts. A nomogram was established based on the results of multivariate analysis. The predictive accuracy of the nomogram was measured by concordance index (C-index) and calibration. The decision curve analysis (DCA) was used to evaluate the clinical benefit of the nomogram.

Results

Preoperative serum laminin level is an independent prognostic factor for overall survival in HCC patients after resection. The C-indices of the nomogram in the training and validation cohorts were 0.779 and 0.719, respectively. The calibration showed optimal agreement between the prediction by nomogram and actual observation. Moreover, the C-indices and DCA revealed that the nomogram provided better clinical benefit compared with the BCLC stage, CLIP score, and AJCC 7th edition.

Conclusions

The prognostic nomogram constructed on laminin represents a superior predictive model.

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Delivering quality lung cancer care in crisis-wracked Greece

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Radiation therapy in retroperitoneal sarcoma management

Surgery is potentially curative for primary non-metastatic retroperitoneal soft tissue sarcomas (RPS), although patients remain at risk for local recurrence. To reduce this risk, the addition of radiotherapy to radical surgery may be considered. Nevertheless, level I evidence to support radiotherapy is currently lacking. The results from the EORTC-STBSG 62092-22092 studying this question are awaited. This manuscript addresses issues to consider when radiation-oncologists engage in a multidisciplinary treatment approach for RPS patients, including radiotherapy.

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Application of the Milan system for reporting risk stratification in salivary gland cytopathology

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Reply to Application of the Milan system for reporting risk stratification in salivary gland cytopathology

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Process mapping: A cornerstone of quality improvement

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Application of the Milan system for reporting risk stratification in salivary gland cytopathology

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Reply to Application of the Milan system for reporting risk stratification in salivary gland cytopathology

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Process mapping: A cornerstone of quality improvement

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The effects of chemoradiotherapy on recurrence and survival in locally advanced rectal cancers with curative total mesorectal excision: a prospective, nonrandomized study

Abstract

Background

There are only two prospective, randomized studies comparing preoperative long-term chemoradiotherapy and postoperative chemoradiotherapy in locally advanced rectal cancer (LARC); however, conflicting results in terms of locoregional recurrence (LR) and survival rates have been reported. This prospective study aims to compare the effects of preoperative versus postoperative chemoradiotherapy on recurrence and survival rates in LARC patients.

Methods

From January 2003 to January 2016, a total of 336 eligible patients who were clinically diagnosed with LARC (T₃–T₄ tm or node-positive disease) were prospectively assigned into preoperative chemoradiotherapy (n = 177) and postoperative chemoradiotherapy (n = 159) groups. The preoperative treatment consisted of 50.4 Gy total dose of radiotherapy (delivered in fractions of 1.8 Gy) and concomitant two cycles chemotherapy of 5-fluorouracil and leucovorin. The patients in the preoperative group underwent curative total mesorectal excision (TME) following long-term chemoradiotherapy. Surgery was performed 8 (range 4–12) median weeks after the completion of the chemoradiotherapy. Similar protocol was administered to the postoperative group 4 weeks after the operation. Four cycles of adjuvant chemotherapy were added to the groups. The primary end points were locoregional recurrences and 5-year cancer-specific, overall, and disease-free survivals.

Results

The mean follow-up period was 60.4 (range 12 to 168) months. Five-year cumulative incidence of locoregional recurrence (LR) was 7.4% in the preoperative group and 13.4% in the postoperative group (p = 0.021). Five-year cancer-specific survival (CSS) was 87.5% in the preoperative group and 80% in the postoperative group (p = 0.022). Overall survival (OS) was 79.8 versus 74.7% (p = 0.064), disease-free survival (DFS) was 75.2 versus 64.8% (p = 0.062), and severe late toxicity was 7.4 versus 13.2% (p = 0.002), respectively. The rate of patient compliance was higher in the preoperative group (p < 0.001).

Conclusions

Preoperative chemoradiotherapy, as compared with postoperative chemoradiotherapy, significantly improved local control, patient compliance, CSS, and late toxicity and suggested a trend toward improved overall and disease-free survival.

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The effects of chemoradiotherapy on recurrence and survival in locally advanced rectal cancers with curative total mesorectal excision: a prospective, nonrandomized study

Abstract

Background

There are only two prospective, randomized studies comparing preoperative long-term chemoradiotherapy and postoperative chemoradiotherapy in locally advanced rectal cancer (LARC); however, conflicting results in terms of locoregional recurrence (LR) and survival rates have been reported. This prospective study aims to compare the effects of preoperative versus postoperative chemoradiotherapy on recurrence and survival rates in LARC patients.

Methods

From January 2003 to January 2016, a total of 336 eligible patients who were clinically diagnosed with LARC (T₃–T₄ tm or node-positive disease) were prospectively assigned into preoperative chemoradiotherapy (n = 177) and postoperative chemoradiotherapy (n = 159) groups. The preoperative treatment consisted of 50.4 Gy total dose of radiotherapy (delivered in fractions of 1.8 Gy) and concomitant two cycles chemotherapy of 5-fluorouracil and leucovorin. The patients in the preoperative group underwent curative total mesorectal excision (TME) following long-term chemoradiotherapy. Surgery was performed 8 (range 4–12) median weeks after the completion of the chemoradiotherapy. Similar protocol was administered to the postoperative group 4 weeks after the operation. Four cycles of adjuvant chemotherapy were added to the groups. The primary end points were locoregional recurrences and 5-year cancer-specific, overall, and disease-free survivals.

Results

The mean follow-up period was 60.4 (range 12 to 168) months. Five-year cumulative incidence of locoregional recurrence (LR) was 7.4% in the preoperative group and 13.4% in the postoperative group (p = 0.021). Five-year cancer-specific survival (CSS) was 87.5% in the preoperative group and 80% in the postoperative group (p = 0.022). Overall survival (OS) was 79.8 versus 74.7% (p = 0.064), disease-free survival (DFS) was 75.2 versus 64.8% (p = 0.062), and severe late toxicity was 7.4 versus 13.2% (p = 0.002), respectively. The rate of patient compliance was higher in the preoperative group (p < 0.001).

Conclusions

Preoperative chemoradiotherapy, as compared with postoperative chemoradiotherapy, significantly improved local control, patient compliance, CSS, and late toxicity and suggested a trend toward improved overall and disease-free survival.

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The Reply to the letter on the cost-effectiveness of human papillomavirus in Punjab further distorts the scientific record

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Factors affecting compliance with confirmatory colonoscopy after a positive fecal immunochemical test in a national colorectal screening program

BACKGROUND

Screening with the fecal immunochemical test (FIT) is effective in reducing deaths from colorectal cancer (CRC). Since 2004, biennial FIT screening has been available to a target population in Taiwan as a national screening program. The objective of the current study was to identify the factors that influence willingness to undergo a confirmatory colonoscopy after a positive FIT, because related references in the published literature were scarce.

METHODS

A semistructured questionnaire was based on the Health Belief Model (HBM) and a literature review. A stratified, random sampling method was used to recruit participants who had a positive FIT from all cities/counties in Taiwan. Cross-sectional, computer-assisted telephone interviews were conducted in 2012, and the results were analyzed using a logistic regression model that took into account population demographics, core content of the HBM, and HBM-modifying variables.

RESULTS

In total, 2807 respondents were included in the analysis. The completion rate was 50%. Multivariate analyses revealed that higher perceived threat (adjusted odds ratio [aOR], 1.62; 95% confidence interval [CI], 1.31-2.01), higher cues for action (aOR, 2.18; 95% CI, 1.68-1.82), lower perceived barriers (aOR, 0.42; 95% CI, 0.34-0.42) and higher health behavior scores (aOR, 1.30; 95% CI, 1.05-1.60) were associated with a greater willingness to participate in confirmatory colonoscopy. Participants who were older (aOR, 0.74; 95% CI, 0.55-0.98) or unmarried (aOR, 0.72; 95% CI, 0.56-0.92) were less likely to participate in verification.

CONCLUSIONS

The government could improve the screening rate by training case managers to assist in following patients until they complete colonoscopy, subsidizing sedated colonoscopies, and providing health education not only to the general public but also to physicians. Cancer 2017. © 2017 American Cancer Society.

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Physician interpretation of genomic test results and treatment selection

BACKGROUND

Genomic testing is increasingly performed in oncology, but concerns remain regarding the clinician's ability to interpret results. In the current study, the authors sought to determine the agreement between physicians and genomic annotators from the Precision Oncology Decision Support (PODS) team at The University of Texas MD Anderson Cancer Center in Houston regarding actionability and the clinical use of test results.

METHODS

On a prospective protocol, patients underwent clinical genomic testing for hotspot mutations in 46 or 50 genes. Six months after sequencing, physicians received questionnaires for patients who demonstrated a variant in an actionable gene, investigating their perceptions regarding the actionability of alterations and clinical use of these findings. Genomic annotators independently classified these variants as actionable, potentially actionable, unknown, or not actionable.

RESULTS

Physicians completed 250 of 288 questionnaires (87% response rate). Physicians considered 168 of 250 patients (67%) as having an actionable alteration; of these, 165 patients (98%) were considered to have an actionable alteration by the PODS team and 3 were of unknown significance. Physicians were aware of genotype-matched therapy available for 119 patients (71%) and 48 of these 119 patients (40%) received matched therapy. Approximately 46% of patients in whom physicians regarded alterations as not actionable (36 of 79 patients) were classified as having an actionable/potentially actionable mutation by the PODS team. However, many of these were only theoretically actionable due to limited trials and/or therapies (eg, KRAS).

CONCLUSIONS

Physicians are aware of recurrent mutations in actionable genes on "hotspot" panels. As larger genomic panels are used, there may be a growing need for annotation of actionability. Decision support to increase awareness of genomically relevant trials and novel treatment options for recurrent mutations (eg, KRAS) also are needed. Cancer 2017. © 2017 American Cancer Society.

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Reply to Genomic profiles of nasopharyngeal carcinoma: The importance of histological subtyping and Epstein-Barr virus in situ assays

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Genomic profiles of nasopharyngeal carcinoma: The importance of histological subtyping and Epstein-Barr virus in situ assays

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The Reply to the letter on the cost-effectiveness of human papillomavirus in Punjab further distorts the scientific record

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Factors affecting compliance with confirmatory colonoscopy after a positive fecal immunochemical test in a national colorectal screening program

BACKGROUND

Screening with the fecal immunochemical test (FIT) is effective in reducing deaths from colorectal cancer (CRC). Since 2004, biennial FIT screening has been available to a target population in Taiwan as a national screening program. The objective of the current study was to identify the factors that influence willingness to undergo a confirmatory colonoscopy after a positive FIT, because related references in the published literature were scarce.

METHODS

A semistructured questionnaire was based on the Health Belief Model (HBM) and a literature review. A stratified, random sampling method was used to recruit participants who had a positive FIT from all cities/counties in Taiwan. Cross-sectional, computer-assisted telephone interviews were conducted in 2012, and the results were analyzed using a logistic regression model that took into account population demographics, core content of the HBM, and HBM-modifying variables.

RESULTS

In total, 2807 respondents were included in the analysis. The completion rate was 50%. Multivariate analyses revealed that higher perceived threat (adjusted odds ratio [aOR], 1.62; 95% confidence interval [CI], 1.31-2.01), higher cues for action (aOR, 2.18; 95% CI, 1.68-1.82), lower perceived barriers (aOR, 0.42; 95% CI, 0.34-0.42) and higher health behavior scores (aOR, 1.30; 95% CI, 1.05-1.60) were associated with a greater willingness to participate in confirmatory colonoscopy. Participants who were older (aOR, 0.74; 95% CI, 0.55-0.98) or unmarried (aOR, 0.72; 95% CI, 0.56-0.92) were less likely to participate in verification.

CONCLUSIONS

The government could improve the screening rate by training case managers to assist in following patients until they complete colonoscopy, subsidizing sedated colonoscopies, and providing health education not only to the general public but also to physicians. Cancer 2017. © 2017 American Cancer Society.

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Physician interpretation of genomic test results and treatment selection

BACKGROUND

Genomic testing is increasingly performed in oncology, but concerns remain regarding the clinician's ability to interpret results. In the current study, the authors sought to determine the agreement between physicians and genomic annotators from the Precision Oncology Decision Support (PODS) team at The University of Texas MD Anderson Cancer Center in Houston regarding actionability and the clinical use of test results.

METHODS

On a prospective protocol, patients underwent clinical genomic testing for hotspot mutations in 46 or 50 genes. Six months after sequencing, physicians received questionnaires for patients who demonstrated a variant in an actionable gene, investigating their perceptions regarding the actionability of alterations and clinical use of these findings. Genomic annotators independently classified these variants as actionable, potentially actionable, unknown, or not actionable.

RESULTS

Physicians completed 250 of 288 questionnaires (87% response rate). Physicians considered 168 of 250 patients (67%) as having an actionable alteration; of these, 165 patients (98%) were considered to have an actionable alteration by the PODS team and 3 were of unknown significance. Physicians were aware of genotype-matched therapy available for 119 patients (71%) and 48 of these 119 patients (40%) received matched therapy. Approximately 46% of patients in whom physicians regarded alterations as not actionable (36 of 79 patients) were classified as having an actionable/potentially actionable mutation by the PODS team. However, many of these were only theoretically actionable due to limited trials and/or therapies (eg, KRAS).

CONCLUSIONS

Physicians are aware of recurrent mutations in actionable genes on "hotspot" panels. As larger genomic panels are used, there may be a growing need for annotation of actionability. Decision support to increase awareness of genomically relevant trials and novel treatment options for recurrent mutations (eg, KRAS) also are needed. Cancer 2017. © 2017 American Cancer Society.

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Reply to Genomic profiles of nasopharyngeal carcinoma: The importance of histological subtyping and Epstein-Barr virus in situ assays

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Genomic profiles of nasopharyngeal carcinoma: The importance of histological subtyping and Epstein-Barr virus in situ assays

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Flavone protects HBE cells from DNA double-strand breaks caused by PM2.5

Abstract

Ambient air particulate matter 2.5 (PM2.5) contains many harmful components that can enter the circulatory system and produce reactive oxygen species (ROS) in body. Oxidative stress and DNA damage induced by ROS may affect any cellular macromolecule and lead to DNA double-strand breaks (DSBs). Flavonoids, widely distributed in some herbs and berries, have been proved having anti-oxidative or anti-cancer efficacy. In this study, we investigated whether Flavone, a kind of flavonoids, can protect human bronchial epithelial cells (HBE) from DSBs caused by PM2.5 and how this function is probably implemented. We found that cells exposed to PM2.5 obviously induced viability inhibition, DNA damage and part of apoptosis. However, Flavone treatment prior to PM2.5 apparently improved cell viability, and mitigated the formation of 8-hydroxy-2-deoxyguanosine, the expression of DNA damage-relative protein and cell apoptosis. Our studies demonstrated that PM2.5 induced oxidative DSBs while Flavone ameliorated the DNA damage and increased cell viability probably through influencing DNA repair mechanism of cells.

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Flavone protects HBE cells from DNA double-strand breaks caused by PM2.5

Abstract

Ambient air particulate matter 2.5 (PM2.5) contains many harmful components that can enter the circulatory system and produce reactive oxygen species (ROS) in body. Oxidative stress and DNA damage induced by ROS may affect any cellular macromolecule and lead to DNA double-strand breaks (DSBs). Flavonoids, widely distributed in some herbs and berries, have been proved having anti-oxidative or anti-cancer efficacy. In this study, we investigated whether Flavone, a kind of flavonoids, can protect human bronchial epithelial cells (HBE) from DSBs caused by PM2.5 and how this function is probably implemented. We found that cells exposed to PM2.5 obviously induced viability inhibition, DNA damage and part of apoptosis. However, Flavone treatment prior to PM2.5 apparently improved cell viability, and mitigated the formation of 8-hydroxy-2-deoxyguanosine, the expression of DNA damage-relative protein and cell apoptosis. Our studies demonstrated that PM2.5 induced oxidative DSBs while Flavone ameliorated the DNA damage and increased cell viability probably through influencing DNA repair mechanism of cells.

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Leptomeningeal metastasis from systemic cancer: Review and update on management

Leptomeningeal metastasis is an uncommon and typically late complication of cancer with a poor prognosis and limited treatment options. Diagnosis is often challenging, with nonspecific presenting symptoms ranging from headache and confusion to focal neurologic deficits, such as cranial nerve palsies. Standard diagnostic evaluation involves a neurologic examination, magnetic resonance imaging of the brain and spine with gadolinium, and cytologic evaluation of the cerebral spinal fluid. Therapy entails a multimodal approach focused on palliation with surgery, radiation, and/or chemotherapy, which may be administered systemically or directly into the cerebral spinal fluid. Limited trial data exist to guide treatment, and current regimens are based primarily on expert opinion. Although newer targeted and immunotherapeutic agents are under investigation and have shown promise, an improved understanding of the biology of leptomeningeal metastasis and treatment resistance as well as additional randomized controlled studies are needed to guide the optimal treatment of this devastating disease. Cancer 2017. © 2017 American Cancer Society.

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Leptomeningeal metastasis from systemic cancer: Review and update on management

Leptomeningeal metastasis is an uncommon and typically late complication of cancer with a poor prognosis and limited treatment options. Diagnosis is often challenging, with nonspecific presenting symptoms ranging from headache and confusion to focal neurologic deficits, such as cranial nerve palsies. Standard diagnostic evaluation involves a neurologic examination, magnetic resonance imaging of the brain and spine with gadolinium, and cytologic evaluation of the cerebral spinal fluid. Therapy entails a multimodal approach focused on palliation with surgery, radiation, and/or chemotherapy, which may be administered systemically or directly into the cerebral spinal fluid. Limited trial data exist to guide treatment, and current regimens are based primarily on expert opinion. Although newer targeted and immunotherapeutic agents are under investigation and have shown promise, an improved understanding of the biology of leptomeningeal metastasis and treatment resistance as well as additional randomized controlled studies are needed to guide the optimal treatment of this devastating disease. Cancer 2017. © 2017 American Cancer Society.

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How to solve the problem of hypersensitivity to asparaginase?

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AML presenting with a preleukemic episode and acquired heterochromia in a child with macrosomia

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How to solve the problem of hypersensitivity to asparaginase?

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AML presenting with a preleukemic episode and acquired heterochromia in a child with macrosomia

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Developing a bacteriophage cocktail for biocontrol of potato bacterial wilt

Abstract

Bacterial wilt is a devastating disease of potato and can cause an 80% production loss. To control wilt using bacteriophage therapy, we isolated and characterized twelve lytic bacteriophages from different water sources in Kenya and China. Based on the lytic curves of the phages with the pathogen Ralstonia solanacearum, one optimal bacteriophage cocktail, P1, containing six phage isolations was formulated and used for studying wilt prevention and treatment efficiency in potato plants growing in pots. The preliminary tests showed that the phage cocktail was very effective in preventing potato bacterial wilt by injection of the phages into the plants or decontamination of sterilized soil spiked with R. solanacearum. Eighty percent of potato plants could be protected from the bacterial wilt (caused by R. solanacearum reference strain GIM1.74 and field isolates), and the P1 cocktail could kill 98% of live bacteria spiked in the sterilized soil at one week after spraying. However, the treatment efficiencies of P1 depended on the timing of application of the phages, the susceptibility of the plants to the bacterial wilt, as well as the virulence of the bacteria infected, suggesting that it is important to apply the phage therapy as soon as possible once there are early signs of the bacterial wilt. These results provide the basis for the development of bacteriophagebased biocontrol of potato bacterial wilt as an alternative to the use of antibiotics.

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Developing a bacteriophage cocktail for biocontrol of potato bacterial wilt

Abstract

Bacterial wilt is a devastating disease of potato and can cause an 80% production loss. To control wilt using bacteriophage therapy, we isolated and characterized twelve lytic bacteriophages from different water sources in Kenya and China. Based on the lytic curves of the phages with the pathogen Ralstonia solanacearum, one optimal bacteriophage cocktail, P1, containing six phage isolations was formulated and used for studying wilt prevention and treatment efficiency in potato plants growing in pots. The preliminary tests showed that the phage cocktail was very effective in preventing potato bacterial wilt by injection of the phages into the plants or decontamination of sterilized soil spiked with R. solanacearum. Eighty percent of potato plants could be protected from the bacterial wilt (caused by R. solanacearum reference strain GIM1.74 and field isolates), and the P1 cocktail could kill 98% of live bacteria spiked in the sterilized soil at one week after spraying. However, the treatment efficiencies of P1 depended on the timing of application of the phages, the susceptibility of the plants to the bacterial wilt, as well as the virulence of the bacteria infected, suggesting that it is important to apply the phage therapy as soon as possible once there are early signs of the bacterial wilt. These results provide the basis for the development of bacteriophagebased biocontrol of potato bacterial wilt as an alternative to the use of antibiotics.

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The crossroads of breast cancer progression: insights into the modulation of major signaling pathways

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ARHGEF19 interacts with BRAF to activate MAPK signaling during the tumorigenesis of non-small cell lung cancer

Abstract

Rho guanine nucleotide exchange factors (RhoGEFs) are proteins that activate Rho GTPases in response to extracellular stimuli and regulate various biologic processes. ARHGEF19, one of RhoGEFs, was reported to activate RhoA in the Wnt-PCP pathway controlling convergent extension in Xenopus gastrulation. The goal of this study was to identify the role and molecular mechanisms of ARHGEF19 in the tumorigenesis of non-small cell lung cancer (NSCLC). ARHGEF19 expression was significantly elevated in NSCLC tissues, and ARHGEF19 levels were significantly associated with lymph node status, distant metastasis and TNM stage; Patients with high ARHGEF19 levels had poor overall survival (OS) and progression-free survival (PFS). Our investigations revealed that ARHGEF19 overexpression promoted the cell proliferation, invasion and metastasis of lung cancer cells, whereas knockdown of this gene inhibited these processes. Mechanistically, ARHGEF19 activated the mitogen-activated protein kinase (MAPK) pathway in a RhoA-independent manner: ARHGEF19 interacted with BRAF and facilitated the phosphorylation of its downstream kinase MEK1/2; both the Dbl homology (DH) and Pleckstrin homology (PH) domains of ARHGEF19 were indispensable for the phosphorylation of MEK1/2. Furthermore, downregulation of miR-29b was likely responsible for the increased expression of ARHGEF19 in lung cancer tissues and, consequently, the abnormal activation of MAPK signaling. These findings suggest that ARHGEF19 upregulation, due to the low expression of miR-29 in NSCLC tissues, may play a crucial role in NSCLC tumorigenesis by activating MAPK signaling. ARHGEF19 could serve as a negative prognostic marker as well as a therapeutic target for NSCLC patients. This article is protected by copyright. All rights reserved.

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ARHGEF19 interacts with BRAF to activate MAPK signaling during the tumorigenesis of non-small cell lung cancer

Abstract

Rho guanine nucleotide exchange factors (RhoGEFs) are proteins that activate Rho GTPases in response to extracellular stimuli and regulate various biologic processes. ARHGEF19, one of RhoGEFs, was reported to activate RhoA in the Wnt-PCP pathway controlling convergent extension in Xenopus gastrulation. The goal of this study was to identify the role and molecular mechanisms of ARHGEF19 in the tumorigenesis of non-small cell lung cancer (NSCLC). ARHGEF19 expression was significantly elevated in NSCLC tissues, and ARHGEF19 levels were significantly associated with lymph node status, distant metastasis and TNM stage; Patients with high ARHGEF19 levels had poor overall survival (OS) and progression-free survival (PFS). Our investigations revealed that ARHGEF19 overexpression promoted the cell proliferation, invasion and metastasis of lung cancer cells, whereas knockdown of this gene inhibited these processes. Mechanistically, ARHGEF19 activated the mitogen-activated protein kinase (MAPK) pathway in a RhoA-independent manner: ARHGEF19 interacted with BRAF and facilitated the phosphorylation of its downstream kinase MEK1/2; both the Dbl homology (DH) and Pleckstrin homology (PH) domains of ARHGEF19 were indispensable for the phosphorylation of MEK1/2. Furthermore, downregulation of miR-29b was likely responsible for the increased expression of ARHGEF19 in lung cancer tissues and, consequently, the abnormal activation of MAPK signaling. These findings suggest that ARHGEF19 upregulation, due to the low expression of miR-29 in NSCLC tissues, may play a crucial role in NSCLC tumorigenesis by activating MAPK signaling. ARHGEF19 could serve as a negative prognostic marker as well as a therapeutic target for NSCLC patients. This article is protected by copyright. All rights reserved.

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ERRATUM

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Issue Information

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ERRATUM

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Issue Information

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5-FU-induced leukoencephalopathy with reversible lesion of splenium of corpus callosum in a patient with colorectal cancer

5-Fluorouracil (5-FU), a commonly used antimetabolite and antineoplastic agent, has been approved for treatment of various cancers. Neurotoxicities are considered extremely rare side effects of 5-FU. We present a case of 5-FU-induced encephalopathy with diffusion-restricted reversible lesion of the splenium of the corpus callosum in a patient with colorectal cancer. The patient presented with confusion, dysarthria and agitation after 5-FU infusion. The prognosis of this toxic effects of 5-FU is usually good if recognised and treated in time. Emergency physicians, general practitioners and oncologists should be aware of this rare side effects of 5-FU chemotherapy and its diagnosis and treatment.

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Mid-aortic syndrome secondary to Takayasus disease

A 24-year-old young woman with good past health presented with hypertension during body check. Blood erythrocyte sedimentary rate level was elevated. CT and MR angiography revealed moderate stenosis of abdominal aorta and bilaterally renal arteries. She was diagnosed with mid-aortic syndrome caused by Takayasu arteritis based on clinical, radiological and pathological findings. She was treated with abdominal aorta resection, graft replacement and aorta-renal bypass. Pathology was compatible with Takayasu arteritis. Postoperatively, her blood pressure was normalised. She was prescribed with long-term prednisolone and aspirin for her arteritis.

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Ingestion of nine metallic nails with corrosive: what happened next?

A 20-year-old woman was brought to the surgery emergency department with the complaint of epigastric pain since 1 day following ingestion of multiple metallic nails with a cup full of toilet cleaner (corrosive acid) with a suicidal intention. Physical examination was essentially unremarkable, and the abdomen showed no signs of perforation peritonitis. X-rays of the abdomen showed multiple 'nail'-like radiopaque shadows in the abdominal cavity with no evidence of free gas under the domes of the diaphragm. A non-operative expectant management was pursued. The patient had passed all the sharps in stools without any complication and was discharged after 12 days. After 3 weeks, the patient presented with non-bilious vomiting. Further investigations revealed pyloric stenosis with no oesophageal luminal stenosis. To bypass the pyloric stenosis, a Billroth II gastrojejunostomy was performed. The postoperative period was uneventful, and the recovery was smooth.

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A rare case of dual diagnosis in a 16-year-old girl with shortness of breath

Pneumothorax and pulmonary embolism (PE) are two life-threatening causes of shortness of breath in patients presenting to the emergency department. A rare but more serious presentation is that of simultaneous PE and pneumothorax. We present the case of a young patient, with no known comorbidities, who presented with simultaneous submassive PE and pneumothorax. We will review how these two diagnoses may be related, consider the implications of having this dual diagnosis on the patient's management and review the current evidence surrounding thrombolysis in submassive PE.

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Concomitant AIDS cholangiopathy and Fanconi syndrome as complications of HIV in a single patient

We describe the case of a 50-year-old woman presenting to our acute medicine department with generalised non-specific symptoms on a background of HIV managed on triple therapy (tenofovir, lamivudine and zidovudine). On admission, she was noted to be acidotic with proteinuria, glycosuria, hypophosphataemia and generalised body pain, and was diagnosed with Fanconi's renotubular syndrome secondary to tenofovir. It was also noted that she had elevated liver dysfunction markers, and an MRI of the liver revealed a focal stricture near the ampulla of Vater, resulting in a diagnosis of AIDS cholangiopathy. These two diagnoses are rare complications of HIV, and the presence of both these pathologies in a single patient has never been reported in the literature before, and we therefore believe that this case is the first of its kind.

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Iatrogenic injury of vertebral artery resulting in stroke after central venous line insertion

There are many complications of central venous catheter insertion. Iatrogenic injury of the vertebral artery is a rare complication that can result in severe morbidity and mortality. The case presented describes the complication of an acute ischaemic stroke after cannulation of the vertebral artery. There are various techniques when obtaining central access, however the best practice as described by the evidence based guidelines produced by the American Society of Anesthesiologists utilises real-time ultrasound guidance to minimise adverse events.

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Capsule endoscopy in the diagnosis of disseminated Mycobacterium avium complex infection

Description

A 25-year-old man with HIV infection was admitted with generalised abdominal pain, fever and vomits. He had been diagnosed a few months earlier with disseminated Mycobacterium avium Complex (MAC) infection through a bone marrow biopsy but had abandoned all treatments. Blood tests showed pancytopenia with CD4 lymphocyte count of 0,034x10⁹/L (normal 0.41–1,59 x10⁹/L) and a raised alkaline phosphatase of 541 IU/L (normal 40–150 IU/L) with otherwise normal liver tests. Abdominal ultrasound and CT showed multiple coeliac and lateroaortic lymphadenopathies as well as a homogeneous hepatosplenomegaly; the oesophagogastroduodenoscopy (OGD) showed only a congestive bulbar mucosa. The patient was then referred for a capsule endoscopy: the small bowel mucosa was oedematous, with prominent lymphangiectasia and multiple ulcers, more exuberant proximally, that were suggestive of MAC infection (figure 1) (see video 1 in the online ). Distal duodenal biopsies showed a macrophage infiltration in the lamina propria (

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Cervical oesophageal perforation secondary to food consumption in a well-appearing patient

A 71-year-old woman presented to the emergency department 8 days after ingesting fish with mild neck pain but otherwise demonstrated no signs of infection. X-rays were negative but CT imaging demonstrated a curvilinear radiodense object extending from the posterior cervical oesophagus through the right thyroid lobe terminating in the neck just a few millimetres from the external carotid artery. Rigid oesophagoscopy and direct laryngoscopy were negative and the neck was explored for the foreign body, which ultimately was encountered after a painstaking dissection of the right neck that included skeletonisation of the recurrent laryngeal nerve. Her postoperative recovery was uneventful and after a 3-day course of intravenous antibiotics she was discharged on oral antibiotics, in good condition and tolerating a soft diet.

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