The efficacy of adding targeted agents to neoadjuvant therapy for locally advanced rectal cancer patients: a meta-analysis

Abstract

Patients with locally advanced rectal cancer (LARC) are at tremendous risk of metastatic diseases. To improve the prognoses of LARC patients, the efficacy of adding targeted agents to neoadjuvant therapy has been investigated by many researchers but remains controversial. A literature search of relevant databases was conducted through December 2016, 804 studies were identified and 32 investigations were ultimately included. A total of 1196 patients from 31 cohorts of 29 studies were eligible for quantitative synthesis in this single-arm setting meta-analysis. As pathologic complete response (pCR) shows promise as a prognosis indicator, we focused on pCR rates to evaluate whether adding targeted agents to neoadjuvant therapies improves the outcome of LARC patients. In our study, we revealed pooled estimates of pCR of 27% (95%CI, 21–34%) and 14% (95%CI, 9–21%) for bevacizumab-relevant cohorts and cetuximab-relevant cohorts, respectively. The safety of adding targeted agents to neoadjuvant therapy was also evaluated by pooling the data of Grade 3/4 toxicity. In conclusion, our study revealed that adding bevacizumab to the neoadjuvant therapy regimens provides appreciable pCR for LARC patients. Meanwhile, the efficacy of cetuximab remains inconclusive, RCTs with larger scale and better study design that stress more on mutational status are needed.

Since pathologic complete response (pCR) shows promise as a prognosis indicator, in this meta-analysis we pooled the data of pCR rates extracted from the included studies to evaluate whether adding targeted agents to neoadjuvant therapies improves the outcome of LARC patients. Our study revealed that adding bevacizumab to the neoadjuvant therapy regimens provides an appreciable pCR for LARC patients. Meanwhile, cetuximab fails to benefit LARC patients when the administration is not conducted based on their KRAS status.

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Clinical impact of ulceration width, lymphovascular invasion, microscopic satellitosis, perineural invasion, and mitotic rate in patients undergoing sentinel lymph node biopsy for cutaneous melanoma: a retrospective observational study at a comprehensive cancer center

Abstract

The prognostic significance of the width of the ulceration in primary melanomas remains unclear, and there is a relative paucity of data for lymphovascular invasion (LVI), microscopic satellitosis (MS), perineural invasion (PNI), and mitotic rate when compared with other pathological elements currently required for reporting. To evaluate the prognostic importance of the ulceration width and other important pathologic measurements, a single-institutional retrospective study was conducted using records of cutaneous melanoma patients who underwent sentinel lymph node (SLN) biopsy at The University of Texas, MD Anderson Cancer Center between 2003 and 2008. We identified 1898 eligible patients with median tumor thickness of 1.25 mm and median follow-up of 6.7 years. By multivariable analyses, the strongest risk factor for SLN positivity was high tumor thickness followed by the presence of LVI. The pathologic measures with the strongest influence on recurrence-free survival (RFS) were tumor thickness and positive SLN status. Ulceration width and presence of MS were also significantly associated with RFS while PNI was not. Factors with the strongest influence on melanoma-specific survival (MSS) were positive SLN status and mitotic rate. In conclusion, SLN biopsy should probably be offered if the primary tumor has LVI. MS is an adverse prognostic factor for RFS, but its influence on outcome is modest. Ulceration width predicts RFS but loses its independent prognostic significance for MSS when adjusting for currently used clinicopathological factors. In view of its impact on MSS, mitotic rate should be recorded for cutaneous invasive melanomas across all T categories.

SLN biopsy should be offered if the primary tumor has LVI. MS is an adverse prognostic factor for RFS, but its influence on outcome is modest. Ulceration width predicts RFS but lost its independent prognostic significance for MSS when adjusting for other contemporary clinicopathological factors. In view of its impact on MSS, mitotic rate should be recorded for cutaneous invasive melanomas across all T categories.

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A blood tumor marker combination assay produces high sensitivity and specificity for cancer according to the natural history

Abstract

Diagnosis using a specific tumor marker is difficult because the sensitivity of this detection method is under 20%. Herein, a tumor marker combination assay, combining growth-related tumor marker and associated tumor marker (Cancer, 73(7), 1994), was employed. This double-blind tumor marker combination assay (TMCA) showed 87.5% sensitivity as the results, but a low specificity, ranging from 30 to 76%. To overcome this low specificity, we exploited complex markers, a multivariate analysis and serum fractionation by biochemical biopsy. Thus, in this study, a combination of new techniques was used to re-evaluate these serum samples. Three serum panels, containing 90, 120, and 97 samples were obtained from the Mayo Clinic. The final results showed 80-90% sensitivity, 84-85% specificity, and 83-88% accuracy. We demonstrated a notable tumor marker combination assay with high accuracy. This TMCA should be applicable for primary cancer detection and recurrence prevention.

Utilizing three kind of tumor marker combination assay(TMCA), combining specific tumor marker, associated tumor marker and growth-related tumor marker, we can get high sensitivity of detection, but low specificity. By utilizing TMCA, complex tumor marker, a multivariate analysis formula and protein serum fractionation, we can get high sensitivity and high specificity of detection.

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The efficacy of adding targeted agents to neoadjuvant therapy for locally advanced rectal cancer patients: a meta-analysis

Abstract

Patients with locally advanced rectal cancer (LARC) are at tremendous risk of metastatic diseases. To improve the prognoses of LARC patients, the efficacy of adding targeted agents to neoadjuvant therapy has been investigated by many researchers but remains controversial. A literature search of relevant databases was conducted through December 2016, 804 studies were identified and 32 investigations were ultimately included. A total of 1196 patients from 31 cohorts of 29 studies were eligible for quantitative synthesis in this single-arm setting meta-analysis. As pathologic complete response (pCR) shows promise as a prognosis indicator, we focused on pCR rates to evaluate whether adding targeted agents to neoadjuvant therapies improves the outcome of LARC patients. In our study, we revealed pooled estimates of pCR of 27% (95%CI, 21–34%) and 14% (95%CI, 9–21%) for bevacizumab-relevant cohorts and cetuximab-relevant cohorts, respectively. The safety of adding targeted agents to neoadjuvant therapy was also evaluated by pooling the data of Grade 3/4 toxicity. In conclusion, our study revealed that adding bevacizumab to the neoadjuvant therapy regimens provides appreciable pCR for LARC patients. Meanwhile, the efficacy of cetuximab remains inconclusive, RCTs with larger scale and better study design that stress more on mutational status are needed.

Since pathologic complete response (pCR) shows promise as a prognosis indicator, in this meta-analysis we pooled the data of pCR rates extracted from the included studies to evaluate whether adding targeted agents to neoadjuvant therapies improves the outcome of LARC patients. Our study revealed that adding bevacizumab to the neoadjuvant therapy regimens provides an appreciable pCR for LARC patients. Meanwhile, cetuximab fails to benefit LARC patients when the administration is not conducted based on their KRAS status.

http://ift.tt/2sIjW1T

Clinical impact of ulceration width, lymphovascular invasion, microscopic satellitosis, perineural invasion, and mitotic rate in patients undergoing sentinel lymph node biopsy for cutaneous melanoma: a retrospective observational study at a comprehensive cancer center

Abstract

The prognostic significance of the width of the ulceration in primary melanomas remains unclear, and there is a relative paucity of data for lymphovascular invasion (LVI), microscopic satellitosis (MS), perineural invasion (PNI), and mitotic rate when compared with other pathological elements currently required for reporting. To evaluate the prognostic importance of the ulceration width and other important pathologic measurements, a single-institutional retrospective study was conducted using records of cutaneous melanoma patients who underwent sentinel lymph node (SLN) biopsy at The University of Texas, MD Anderson Cancer Center between 2003 and 2008. We identified 1898 eligible patients with median tumor thickness of 1.25 mm and median follow-up of 6.7 years. By multivariable analyses, the strongest risk factor for SLN positivity was high tumor thickness followed by the presence of LVI. The pathologic measures with the strongest influence on recurrence-free survival (RFS) were tumor thickness and positive SLN status. Ulceration width and presence of MS were also significantly associated with RFS while PNI was not. Factors with the strongest influence on melanoma-specific survival (MSS) were positive SLN status and mitotic rate. In conclusion, SLN biopsy should probably be offered if the primary tumor has LVI. MS is an adverse prognostic factor for RFS, but its influence on outcome is modest. Ulceration width predicts RFS but loses its independent prognostic significance for MSS when adjusting for currently used clinicopathological factors. In view of its impact on MSS, mitotic rate should be recorded for cutaneous invasive melanomas across all T categories.

SLN biopsy should be offered if the primary tumor has LVI. MS is an adverse prognostic factor for RFS, but its influence on outcome is modest. Ulceration width predicts RFS but lost its independent prognostic significance for MSS when adjusting for other contemporary clinicopathological factors. In view of its impact on MSS, mitotic rate should be recorded for cutaneous invasive melanomas across all T categories.

http://ift.tt/2EUvOCY

A blood tumor marker combination assay produces high sensitivity and specificity for cancer according to the natural history

Abstract

Diagnosis using a specific tumor marker is difficult because the sensitivity of this detection method is under 20%. Herein, a tumor marker combination assay, combining growth-related tumor marker and associated tumor marker (Cancer, 73(7), 1994), was employed. This double-blind tumor marker combination assay (TMCA) showed 87.5% sensitivity as the results, but a low specificity, ranging from 30 to 76%. To overcome this low specificity, we exploited complex markers, a multivariate analysis and serum fractionation by biochemical biopsy. Thus, in this study, a combination of new techniques was used to re-evaluate these serum samples. Three serum panels, containing 90, 120, and 97 samples were obtained from the Mayo Clinic. The final results showed 80-90% sensitivity, 84-85% specificity, and 83-88% accuracy. We demonstrated a notable tumor marker combination assay with high accuracy. This TMCA should be applicable for primary cancer detection and recurrence prevention.

Utilizing three kind of tumor marker combination assay(TMCA), combining specific tumor marker, associated tumor marker and growth-related tumor marker, we can get high sensitivity of detection, but low specificity. By utilizing TMCA, complex tumor marker, a multivariate analysis formula and protein serum fractionation, we can get high sensitivity and high specificity of detection.

http://ift.tt/2sDII3a

Cancers, Vol. 10, Pages 57: Recommendations and Choices for BRCA Mutation Carriers at Risk for Ovarian Cancer: A Complicated Decision

Cancers, Vol. 10, Pages 57: Recommendations and Choices for BRCA Mutation Carriers at Risk for Ovarian Cancer: A Complicated Decision

Cancers doi: 10.3390/cancers10020057

Authors: Kelsey Lewis Karen Lu Amber Klimczak Samuel C. Mok

Current ovarian cancer screening guidelines in high-risk women vary according to different organizations. Risk reducing surgery remains the gold standard for definitive treatment in BRCA mutation carriers, but research advancements have created more short-term options for patients to consider. The decisions involved in how a woman manages her BRCA mutation status can cause a great deal of stress and worry due to the imperfect therapy options. The goal of this review was to critically analyze the screening recommendations and alternative options for high-risk ovarian cancer patients and evaluate how these discrepancies and choices affect a woman's management decisions.

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Cancers, Vol. 10, Pages 57: Recommendations and Choices for BRCA Mutation Carriers at Risk for Ovarian Cancer: A Complicated Decision

Cancers, Vol. 10, Pages 57: Recommendations and Choices for BRCA Mutation Carriers at Risk for Ovarian Cancer: A Complicated Decision

Cancers doi: 10.3390/cancers10020057

Authors: Kelsey Lewis Karen Lu Amber Klimczak Samuel C. Mok

Current ovarian cancer screening guidelines in high-risk women vary according to different organizations. Risk reducing surgery remains the gold standard for definitive treatment in BRCA mutation carriers, but research advancements have created more short-term options for patients to consider. The decisions involved in how a woman manages her BRCA mutation status can cause a great deal of stress and worry due to the imperfect therapy options. The goal of this review was to critically analyze the screening recommendations and alternative options for high-risk ovarian cancer patients and evaluate how these discrepancies and choices affect a woman's management decisions.

http://ift.tt/2EHlxuL

Successful treatment of metastatic colorectal cancer with apatinib: report of two cases and literature review

http://ift.tt/2Cd2QNy

Klotho ameliorates sepsis-induced acute kidney injury but is irrelevant to autophagy

http://ift.tt/2on1S83

The expression of the MSC-marker CD73 and of NF2 /Merlin are correlated in meningiomas

Abstract

Mesenchymal stem cells (MSC) have been found in various cancers and were discussed to influence tumor biology. Cells fulfilling the complete MSC criteria, including surface marker expression (CD73, CD90, CD105) and tri-lineage differentiation, have been isolated solely from a low percentage of high-grade meningiomas. In contrast, pure co-expression of the surface-markers was relatively frequent, raising the question for an additional role of these membrane proteins in meningiomas. Therefore, here we analyzed the expression of CD73, CD90 and CD105 in a series of meningiomas of all grades. Although no significant association of any marker with meningeal tumor growth per se or with tumor-grade was observed, we detected a positive Pearson correlation (r = 0.55, p ≤ 0.05) in low-grade tumors between CD73 and the most relevant tumor suppressor NF2/Merlin, supported by a tendency of lower CD73 expression in cases with allelic losses at the NF2-locus, which express significantly lower NF2/Merlin-mRNA (p ≤ 0.05). In two pairs of syngenous meningeal or meningioma cell lines with or without shRNA-mediated knockdown of NF2/Merlin a nearly complete loss of CD73 mRNA expression was observed after the knockdown (p ≤ 0.001). This suggested that the correlation observed in tumors may result from a direct functional link between Merlin and CD73. Since CD73 is a 5′-exonucleotidase (termed NT5E), we discuss a potential role of NT5E-mediated purinergic signaling to modulate actin-cytoskeleton and cell contacts, which may be a functional link to NF2/Merlin.

http://ift.tt/2sL6E4Z

The expression of the MSC-marker CD73 and of NF2 /Merlin are correlated in meningiomas

Abstract

Mesenchymal stem cells (MSC) have been found in various cancers and were discussed to influence tumor biology. Cells fulfilling the complete MSC criteria, including surface marker expression (CD73, CD90, CD105) and tri-lineage differentiation, have been isolated solely from a low percentage of high-grade meningiomas. In contrast, pure co-expression of the surface-markers was relatively frequent, raising the question for an additional role of these membrane proteins in meningiomas. Therefore, here we analyzed the expression of CD73, CD90 and CD105 in a series of meningiomas of all grades. Although no significant association of any marker with meningeal tumor growth per se or with tumor-grade was observed, we detected a positive Pearson correlation (r = 0.55, p ≤ 0.05) in low-grade tumors between CD73 and the most relevant tumor suppressor NF2/Merlin, supported by a tendency of lower CD73 expression in cases with allelic losses at the NF2-locus, which express significantly lower NF2/Merlin-mRNA (p ≤ 0.05). In two pairs of syngenous meningeal or meningioma cell lines with or without shRNA-mediated knockdown of NF2/Merlin a nearly complete loss of CD73 mRNA expression was observed after the knockdown (p ≤ 0.001). This suggested that the correlation observed in tumors may result from a direct functional link between Merlin and CD73. Since CD73 is a 5′-exonucleotidase (termed NT5E), we discuss a potential role of NT5E-mediated purinergic signaling to modulate actin-cytoskeleton and cell contacts, which may be a functional link to NF2/Merlin.

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Expression of miR-634 in gastric carcinoma and its effects on proliferation, migration, and invasion of gastric cancer cells

Abstract

This study aims to observe the expression of microRNA (miR)-634 in different gastric cancer cell lines and tissues, and to study the effects of miR-634 on the proliferation, migration, and invasion of the gastric cancer cells. The miR-634 mimics and miR-634 inhibitors were transfected by lentivirus into human gastric cancer SGC-7901 and MGC-803 cells, and the miR-634 cells without transfection were used as the control group (NC group). The expression of miR-634 in the transfected cells was detected by qRT-PCR. Cell viability was measured by the CCK8 assay. The migration and invasion ability of the cells were detected by scratch assays and Transwell^® chamber assays, respectively, and the luciferase assay verified the binding of miR-634 to the target gene JAG1. The expression level of miR-634 in gastric cancer tissues and cell lines was significantly lower than that in normal adjacent tissues and control cells. The survival of cells was significantly decreased, and number of cells migrating and invading was decreased in the miR-634 mimics group. However, in the miR-634 inhibitor group, the opposite results were observed. Over-expression of miR-634 inhibited the proliferation, migration, and invasion of gastric cancer cell lines, and the miR-634 target gene was JAG1.

Over-expression of miR-634 inhibited the proliferation, migration, and invasion of gastric cancer cell lines, and the miR-634 target gene was JAG1.

http://ift.tt/2GwZumC

Expression of miR-634 in gastric carcinoma and its effects on proliferation, migration, and invasion of gastric cancer cells

Abstract

This study aims to observe the expression of microRNA (miR)-634 in different gastric cancer cell lines and tissues, and to study the effects of miR-634 on the proliferation, migration, and invasion of the gastric cancer cells. The miR-634 mimics and miR-634 inhibitors were transfected by lentivirus into human gastric cancer SGC-7901 and MGC-803 cells, and the miR-634 cells without transfection were used as the control group (NC group). The expression of miR-634 in the transfected cells was detected by qRT-PCR. Cell viability was measured by the CCK8 assay. The migration and invasion ability of the cells were detected by scratch assays and Transwell^® chamber assays, respectively, and the luciferase assay verified the binding of miR-634 to the target gene JAG1. The expression level of miR-634 in gastric cancer tissues and cell lines was significantly lower than that in normal adjacent tissues and control cells. The survival of cells was significantly decreased, and number of cells migrating and invading was decreased in the miR-634 mimics group. However, in the miR-634 inhibitor group, the opposite results were observed. Over-expression of miR-634 inhibited the proliferation, migration, and invasion of gastric cancer cell lines, and the miR-634 target gene was JAG1.

Over-expression of miR-634 inhibited the proliferation, migration, and invasion of gastric cancer cell lines, and the miR-634 target gene was JAG1.

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Editorial: Oncolytic Virus and Gene Thearapy Application: Update 2018.

Related Articles

Editorial: Oncolytic Virus and Gene Thearapy Application: Update 2018.

Curr Cancer Drug Targets. 2018;18(2):108

Authors: Abei M

PMID: 29457568 [PubMed - in process]

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Truncated glioma-associated oncogene homolog 1 (tGLI1) mediates mesenchymal glioblastoma via transcriptional activation of CD44

The molecular pathways driving mesenchymal glioblastoma (GBM) are still not well understood. We report here that truncated glioma-associated oncogene homolog 1 (tGLI1) is a tumor-specific transcription factor that facilitates GBM growth, is enriched in the mesenchymal subtype of GBM and glioma stem cells (GSC), and promotes mesenchymal GSC by upregulating transcription of CD44. In an orthotopic GBM xenograft mouse model, tGLI1-overexpressing tumors grew more aggressively with increased proliferation and angiogenesis compared to control and GLI1-overexpressing xenografts. tGLI1 was highly expressed in GBM clinical specimens but undetectable in normal brains, whereas GLI1 was expressed in both tissues. A tGLI1 activation signature (tGAS) correlated with glioma grade, tumor angiogenesis, and poor overall survival, and GBM with high tGAS were enriched with mesenchymal GBM/GSC gene signatures. Neurospheres contained increased levels of tGLI1, but not GLI1, compared to the monolayer culture; mesenchymal GSC expressed more tGLI1 than proneural GSC. Ectopic tGLI1 expression enhanced the ability of mesenchymal GSC to yield neurospheres in vitro and form tumors in mouse brains. Selective tGLI1 knockdown reduced neurosphere formation of GBM cells. tGLI1 bound to and transactivated the promoter of the CD44 gene, a marker and mediator for mesenchymal GSC, leading to its expression. Collectively, these findings advance our understanding of GBM biology by establishing tGLI1 as a novel transcriptional activator of CD44 and a novel mediator of mesenchymal GBM and GSC.

http://ift.tt/2ohccPK

A novel mechanism for activation of GLI1 by nuclear SMO that escapes anti-SMO inhibitors

Small molecule inhibitors of the Hedgehog (HH) pathway receptor Smoothened (SMO) have been effective in treating some patients with basal cell carcinoma (BCC), where the HH pathway is often activated, but many patients are poorly responsive. In this study, we report the results of investigations on PTCH1 signalling in the HH pathway that suggest why most BCC patients respond poorly to SMO inhibitors. In immortalised human keratinocytes, PTCH1 silencing led to the generation of a compact, holoclone-like morphology with increased expression of SMO and the downstream HH pathway transcription factor GLI1. Notably, while siRNA silencing of SMO in PTCH1-silenced cells was sufficient to suppress GLI1 activity, this effect was not phenocopied by pharmacological inhibition of SMO, suggesting the presence of a second undefined pathway through which SMO can induce GLI1. Consistent with this possibility, we observed increased nuclear localisation of SMO in PTCH1-silenced cells as mediated by a putative SMO nuclear/nucleolar localisation signal (N(o)LS). Mutational inactivation of the N(o)LS ablated this increase and suppressed GLI1 induction. Immunohistological analysis of human and mouse BCC confirmed evidence of nuclear SMO, although the pattern was heterogeneous between tumours. In PTCH1-silenced cells, >80% of the genes found to be differentially expressed were unaffected by SMO inhibitors, including the putative BCC driver gene CXCL11. Our results demonstrate how PTCH1 loss results in aberrant regulation of SMO-independent mechanisms important for BCC biology, and highlights a novel nuclear mechanism of SMO-GLI1 signalling that is unresponsive to SMO inhibitors.

http://ift.tt/2sEq4s2

Truncated glioma-associated oncogene homolog 1 (tGLI1) mediates mesenchymal glioblastoma via transcriptional activation of CD44

The molecular pathways driving mesenchymal glioblastoma (GBM) are still not well understood. We report here that truncated glioma-associated oncogene homolog 1 (tGLI1) is a tumor-specific transcription factor that facilitates GBM growth, is enriched in the mesenchymal subtype of GBM and glioma stem cells (GSC), and promotes mesenchymal GSC by upregulating transcription of CD44. In an orthotopic GBM xenograft mouse model, tGLI1-overexpressing tumors grew more aggressively with increased proliferation and angiogenesis compared to control and GLI1-overexpressing xenografts. tGLI1 was highly expressed in GBM clinical specimens but undetectable in normal brains, whereas GLI1 was expressed in both tissues. A tGLI1 activation signature (tGAS) correlated with glioma grade, tumor angiogenesis, and poor overall survival, and GBM with high tGAS were enriched with mesenchymal GBM/GSC gene signatures. Neurospheres contained increased levels of tGLI1, but not GLI1, compared to the monolayer culture; mesenchymal GSC expressed more tGLI1 than proneural GSC. Ectopic tGLI1 expression enhanced the ability of mesenchymal GSC to yield neurospheres in vitro and form tumors in mouse brains. Selective tGLI1 knockdown reduced neurosphere formation of GBM cells. tGLI1 bound to and transactivated the promoter of the CD44 gene, a marker and mediator for mesenchymal GSC, leading to its expression. Collectively, these findings advance our understanding of GBM biology by establishing tGLI1 as a novel transcriptional activator of CD44 and a novel mediator of mesenchymal GBM and GSC.

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A novel mechanism for activation of GLI1 by nuclear SMO that escapes anti-SMO inhibitors

Small molecule inhibitors of the Hedgehog (HH) pathway receptor Smoothened (SMO) have been effective in treating some patients with basal cell carcinoma (BCC), where the HH pathway is often activated, but many patients are poorly responsive. In this study, we report the results of investigations on PTCH1 signalling in the HH pathway that suggest why most BCC patients respond poorly to SMO inhibitors. In immortalised human keratinocytes, PTCH1 silencing led to the generation of a compact, holoclone-like morphology with increased expression of SMO and the downstream HH pathway transcription factor GLI1. Notably, while siRNA silencing of SMO in PTCH1-silenced cells was sufficient to suppress GLI1 activity, this effect was not phenocopied by pharmacological inhibition of SMO, suggesting the presence of a second undefined pathway through which SMO can induce GLI1. Consistent with this possibility, we observed increased nuclear localisation of SMO in PTCH1-silenced cells as mediated by a putative SMO nuclear/nucleolar localisation signal (N(o)LS). Mutational inactivation of the N(o)LS ablated this increase and suppressed GLI1 induction. Immunohistological analysis of human and mouse BCC confirmed evidence of nuclear SMO, although the pattern was heterogeneous between tumours. In PTCH1-silenced cells, >80% of the genes found to be differentially expressed were unaffected by SMO inhibitors, including the putative BCC driver gene CXCL11. Our results demonstrate how PTCH1 loss results in aberrant regulation of SMO-independent mechanisms important for BCC biology, and highlights a novel nuclear mechanism of SMO-GLI1 signalling that is unresponsive to SMO inhibitors.

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BMI Can Underestimate Breast Cancer Risk [News in Brief]

Postmenopausal women with high body fat levels are at higher risk, even with normal BMI.

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Concurrent Inhibition of Neurosphere and Monolayer Cells of Pediatric Glioblastoma by Aurora A Inhibitor MLN8237 Predicted Survival Extension in PDOX models

Purpose: Pediatric glioblastoma (pGBM) is highly aggressive tumor in need of novel therapies. Our objective was to demonstrate the therapeutic efficacy of MLN8237 (Alisertib), an orally available selective inhibitor of Aurora A kinase (AURKA), and to evaluate which in vitro model system (monolayer or neurosphere) can predict therapeutic efficacy in vivo. Experimental Design: AURKA mRNA expressions were screened with qRT-PCR. In vitro anti-tumor effects were examined in 3 matching pairs of monolayer and neurosphere lines established from patient derived orthotopic xenograft (PDOX) models of the untreated (IC-4687GBM), recurrent (IC-372GBM) and terminal (IC-R0315GBM) tumors; and in vivo therapeutic efficacy through log rank analysis of survival times in 2 models (IC-4687GBM and IC-R0315GBM) following MLN8237 treatment (30 mg/kg/day, p.o., 12 days). Drug concentrations in vivo, mechanism of action and resistance were also investigated. Results: AURKA mRNA over-expression was detected in 14 pGBM tumors, 10 PDOX models and 6 cultured pGBM lines as compared with 11 low grade gliomas and normal brains. MLN8237 penetrated into pGBM xenografts in mouse brains. Significant extension of survival times were achieved in IC-4687GBM of which both neurosphere and monolayer were inhibited in vitro, but not in IC-R0315GBM of which only neurosphere cells responded (similar to IC-3752GBM cells). Apoptosis mediated MLN8237 induced cell death, and the presence of AURKA-negative and CD133+ cells appears to have contributed to in vivo therapy resistance. Conclusions: MLN8237 successfully targeted AURKA in a subset of pGBMs. Our data suggest that combination therapy should aim at AURKA-negative and/or CD133+ pGBM cells to prevent tumor recurrence.

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Combination approach for detecting different types of alterations in circulating tumor DNA in leiomyosarcoma

Purpose: The clinical utility of circulating tumor DNA (ctDNA) monitoring has been shown in tumors that harbor highly recurrent mutations. Leiomyosarcoma (LMS) represents a type of tumor with a wide spectrum of heterogeneous genomic abnormalities; thus, targeting hotspot mutations or a narrow genomic region for ctDNA detection may not be practical. Here we demonstrate a combinatorial approach that integrates different sequencing protocols for the orthogonal detection of single nucleotide variants (SNVs), small indels and copy number alterations (CNAs) in ctDNA. Experimental design: We employed Cancer Personalized Profiling by deep Sequencing (CAPP-Seq) for the analysis of SNVs and indels, together with a genome-wide interrogation of CNAs by Genome Representation Profiling (GRP). We profiled 28 longitudinal plasma samples and 25 tumor specimens from 7 patients with LMS. Results: We detected ctDNA in 6 of 7 of these patients with >98% specificity for mutant allele fractions down to a level of 0.01%. We show that results from CAPP-Seq and GRP are highly concordant, and the combination of these methods allows for more comprehensive monitoring of ctDNA by profiling a wide spectrum of tumor-specific markers. By analyzing multiple tumor specimens in individual patients obtained from different sites and at different times during treatment, we observed clonal evolution of these tumors that was reflected by ctDNA profiles. Conclusions: Our strategy allows for a comprehensive monitoring of a broad spectrum of tumor-specific markers in plasma. Our approach may be clinically useful not only in LMS but also in other tumor types that lack recurrent genomic alterations.

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Disruption of Wnt/{beta}-catenin exerts anti-leukemia activity and synergizes with FLT3 inhibition in FLT3-mutant acute myeloid leukemia

Purpose: Wnt/β-catenin signaling is required for leukemic stem cell function. FLT3 mutations are frequently observed in acute myeloid leukemia (AML). Anomalous FLT3 signaling increases β-catenin nuclear localization and transcriptional activity. FLT3 tyrosine kinase inhibitors (TKIs) are used clinically to treat FLT3-mutated AML patients, but with limited efficacy. We investigated the anti-leukemia activity of combined Wnt/β-catenin and FLT3 inhibition in FLT3-mutant AML. Experimental Design: Wnt/β-catenin signaling was inhibited by the b-catenin/CBP antagonist C-82/PRI-724 or siRNAs, and FLT3 signaling by sorafenib or quizartinib. Treatments on apoptosis, cell growth, and cell signaling were assessed in cell lines, patient samples, and in vivo in immunodeficient mice by flow cytometry, western blot, RT-PCR, and CyTOF.  Results: We found significantly higher β-catenin expression in cytogenetically unfavorable and relapsed AML patient samples and in the bone-marrow-resident leukemic cells compared to circulating blasts. Disrupting Wnt/b-catenin signaling suppressed AML cell growth, induced apoptosis, abrogated stromal protection, and synergized with TKIs in FLT3-mutated AML cells and stem/progenitor cells in vitro. The aforementioned combinatorial treatment improved survival of AML-xenografted mice in two in vivo models and impaired leukemia cell engraftment. Mechanistically, the combined inhibition of Wnt/β-catenin and FLT3 cooperatively decreased nuclear β-catenin and the levels of c-Myc and other Wnt/β-catenin and FLT3 signaling proteins. Importantly, β-catenin inhibition abrogated the microenvironmental protection afforded the leukemic stem/progenitor cells.  Conclusions: Disrupting Wnt/β-catenin signaling exerts potent activities against AML stem/progenitor cells and synergizes with FLT3 inhibition in FLT3-mutant AML. These findings provide a rationale for clinical development of this strategy for treating FLT3-mutated AML patients.

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Capecitabine efficacy is correlated with TYMP and RB expression in PDX established from triple-negative breast cancers

Purpose: triple-negative breast cancer (TNBC) patients with residual disease after neoadjuvant chemotherapy have a poor outcome. We developed patient-derived xenografts (PDX) from residual tumors to identify efficient chemotherapies and predictive biomarkers in a context of resistance to anthracyclines and taxanes-based treatments. Experimental Design: PDX were established from residual tumors of primary breast cancer patients treated in neoadjuvant setting. TNBC PDX were treated by anthracyclines, taxanes, platins and capecitabine. Predictive biomarkers were identified by transcriptomic and immunohistological analysis. Downregulation of RB1 was performed by siRNA in a cell line established from a PDX. Results: residual TNBC PDX were characterized by a high tumor take, a short latency and a poor prognosis of the corresponding patients. With the exception of BRCA1/2 mutated models, residual PDX were resistant to anthracyclines, taxanes, and platins. Capecitabine, the oral prodrug of 5-FU, was highly efficient in 60% of PDX with two models showing complete responses. Prior treatment of a responder PDX with 5-FU increased expression of thymidylate synthase and decreased efficacy of capecitabine. Transcriptomic and IHC analyses of 32 TNBC PDX, including both residual tumors and treatment-naïve derived tumors, identified RB and TYMP proteins as predictive biomarkers for capecitabine response. Finally, RB1 knockdown in a cell line established from a capecitabine-responder PDX decreased sensitivity to 5-FU treatment. Conclusions: we identified capecitabine as efficient chemotherapy in TNBC PDX models established from residual disease and resistant to anthracyclines, taxanes and platins. RB positivity and high expression of TYMP were significantly associated with capecitabine response.

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Molecular lymph node status for prognostic stratification of prostate cancer patients undergoing radical prostatectomy with extended pelvic lymph node dissection

Purpose: Molecular lymph node (LN) analysis using quantitative polymerase chain reaction (qPCR) detects LN metastases with higher sensitivity than histopathology. However, the prognostic role of molecular LN status in prostate cancer (PCa) patients treated with radical prostatectomy (RP) and extended pelvic LN dissection (ePLND) is unclear. To investigate the association of molecular compared to histopathologic LN status with biochemical recurrence. Experimental Design: Patients with intermediate and high risk PCa were prospectively enrolled and underwent RP with ePLND including obturator, internal, external and common iliac region. LNs ≥3mm were bisected and examined by standard histopathology and qPCR for Kallikrein3 (KLK3) expression. Biochemical recurrence was defined by confirmed postoperative PSA>0.2ng/ml. Results: In 111 patients, 2411 of 3173 removed LNs were examined by both methods. Histopathology detected 68 LN metastases in 28 (25%) patients. Molecular analysis confirmed elevated KLK3 expression in 65 histopathologic LN metastases of all 28 pN1-patients (pN1/molN1) and additionally reclassified 224 histopathologic negative LNs and 32 (29%) pN0-patients as LN-positive (pN0/molN1). At a median follow-up of 48 months 52 (47%) patients developed biochemical recurrence. Median biochemical recurrence-free survival (bRFS) was 9 months [95%CI0.0-20.1] in pN1/molN1-patients, 24 months [95%CI1.7-46.3] in pN0/molN1 patients and was not reached in pN0/molN0 patients (p<0.001). On multivariable Cox regression analysis, molecular LN status (HR 4.1 [95%CI1.9-8.8],p<0.001) but not histopathologic LN status (HR 1.5 [95%CI0.8-3.0],p=0.198) was confirmed as independent predictor of biochemical recurrence. Conclusion: Molecular LN analysis identified pN0-patients with a high risk of biochemical recurrence and provided superior prognostic information in comparison with histopathology alone.

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The Airway Transcriptome as a Biomarker for Early Lung Cancer Detection

Lung cancer remains the leading cause of cancer-related death due to its advanced stage at diagnosis. Early detection of lung cancer can be improved by better defining who should be screened radiographically, and determining which imaging-detected pulmonary nodules are malignant. Gene expression biomarkers measured in normal-appearing airway epithelium provide an opportunity to use lung cancer associated molecular changes in this tissue for early detection of lung cancer. Molecular changes in the airway may result from an etiologic field of injury and/or field cancerization. The etiologic field of injury reflects the aberrant physiological response to carcinogen exposure that creates a susceptible microenvironment for cancer initiation. In contrast, field cancerization reflects effects of "first-hit" mutations in a clone of cells from which the tumor ultimately arises or the effects of the tumor on the surrounding tissue.  These fields might have value both for assessing lung cancer risk and diagnosis. Cancer-associated gene expression changes in the bronchial airway have recently been used to develop and validate a 23-gene classifier that improves the diagnostic yield of bronchoscopy for lung cancer among intermediate-risk patients. Recent studies have demonstrated that these lung cancer-related gene expression changes extend to nasal epithelial cells that can be sampled non-invasively. While the bronchial gene expression biomarker is being adopted clinically, further work is necessary to explore the potential clinical utility of gene-expression profiling in the nasal epithelium for lung cancer diagnosis, risk assessment, and precision medicine for lung cancer treatment and chemoprevention.

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Androgen Deprivation Therapy Potentiates the Efficacy of Vascular Targeted Photodynamic Therapy of Prostate Cancer Xenografts

Purpose: WST11 vascular targeted photodynamic therapy (VTP) is a local ablation approach relying upon rapid, free radical-mediated destruction of tumor vasculature. A phase III trial showed that VTP significantly reduced disease progression when compared to active surveillance in patients with low-risk prostate cancer (PCa). The aim of this study was to identify a druggable pathway that could be combined with VTP to improve its efficacy and applicability to higher risk PCa tumors. Experimental Design: Transcriptome analysis of VTP treated tumors (LNCaP-AR xenografts) was used to identify a candidate pathway for combination therapy. The efficacy of the combination therapy was assessed in mice bearing LNCaP-AR or VCaP tumors. Results: Gene Set Enrichment Analysis (GSEA) identifies the enrichment of androgen responsive gene sets within hours post-VTP treatment, suggesting that the androgen receptor (AR) may be a viable target in combination with VTP. We tested this hypothesis in mice bearing LNCaP-AR xenograft tumors by using androgen deprivation therapy (ADT), degarelix, in combination with VTP. Compared to either ADT or VTP alone, a single dose of degarelix in concert with VTP significantly inhibited tumor growth. A sharp decline in serum PSA confirmed AR inhibition in this group. Tumors treated by VTP and degarelix displayed intense TUNEL staining 7 days post-treatment, supporting an increased apoptotic frequency underlying the effect on tumor inhibition. Conclusions: Improvement of local tumor control following androgen deprivation combined with VTP provides the rationale and preliminary protocol parameters for clinical trials in patients presented with locally advanced PCa.

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Integrated Pharmacokinetic/Pharmacodynamic Model of a Bispecific CD3xCD123 DART(R) Molecule in Nonhuman Primates: Evaluation of Activity and Impact of Immunogenicity

Purpose: Flotetuzumab (MGD006 or S80880) is a bispecific molecule that recognizes CD3 and CD123 membrane proteins, redirecting T-cells to kill CD123-expressing cells for the treatment of acute myeloid leukemia. In this study, we developed a mathematical model to characterize MGD006 exposure-response relationships and to assess the impact of its immunogenicity in cynomolgus monkeys. Experimental Design: 32 animals received multiple escalating doses (100-300-600-1000 ng/kg/day) via intravenous infusion continuously 4-days a week. The model reflects sequential binding of MGD006 to CD3 and CD123 receptors. Formation of the MGD006/CD3 complex was connected to total T-cells undergoing trafficking, whereas the formation of the tri-molecular complex results in T-cell activation and clonal expansion. Activated T-cells were used to drive the peripheral depletion of CD123-positive cells. Anti-drug antibody development was linked to MGD006 disposition as an elimination pathway. Model validation was tested by predicting the activity of MGD006 in 8 monkeys receiving continuous 7-day infusions. Results: MGD006 disposition and total T-cell and CD123-positive cell profiles were well characterized. Anti-drug antibody development led to the suppression of T-cell trafficking but did not systematically abolish CD123-positive cell depletion. Target cell depletion could persist after drug elimination owing to the self-proliferation of activated T-cells generated during the first cycles. The model was externally validated with the 7-day infusion dosing schedule. Conclusions:A translational model was developed for MGD006 that features T-cell activation and expansion as a key driver of pharmacological activity and provides a mechanistic quantitative platform to inform dosing strategies in ongoing clinical studies.

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TGF-{beta}1 genetic variants predict clinical outcomes of HPV-positive oropharyngeal cancer patients after definitive radiotherapy

Purpose. Transforming growth factor-β1 (TGF-β1) plays a critical role in inflammation and immune responses and treatment response and survival. TGF-β1 variants may affect its expression level or functional efficiency, thus modifying tumor status and survival in HPV-positive squamous cell carcinoma of the oropharynx (SCCOP). Experimental design. We determined tumor HPV16 status and genotyped three TGF-β1 polymorphisms in 564 incident SCCOP patients treated with radiotherapy or chemoradiation. Univariate and multivariable Cox models were used to evaluate the associations between the three polymorphisms and survival. Results. Overall, 85% of patients (482 of 564) had HPV16-positive SCCOP. We found that TGF-β1 rs1982073 had statistically significant associations with survival, while TGF-β1rs1800469 and TGF-β1rs1800471 did not. Patients with TGF-β1 rs1982073 CT/CC variant genotypes had significantly better overall, disease-specific, and disease-free survival compared with those with the corresponding common homozygous TT genotype (all log-rank: P <0.001). Furthermore, these genotypes were significantly associated with an approximately 5 times reduced risk of overall death, death owing to disease, and recurrence after multivariable adjustment. Moreover, the stratified analyses by tumor HPV status indicated that the significant effects of TGF-β1 rs1982073 polymorphism on survival were found among HPV16-positive SCCOP patients only. Finally, the functional relevance of these variants was further characterized. Conclusions. Our findings support that the TGF-β1 rs1982073 polymorphism plays a significant role in the prognosis of SCCOP, especially in HPV16-positive SCCOP patients treated with chemoradiation. Prospective studies with larger sample sizes are needed to confirm these findings.

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Prediction of the optimal dosing regimen using a mathematical model of tumour uptake for immunocytokine-based cancer immunotherapy

PURPOSE: Optimal dosing is critical for immunocytokine-based cancer immunotherapy to maximize efficacy and minimize toxicity. Cergutuzumab amunaleukin (CEA-IL2v) is a novel CEA-targeted immunocytokine. We set out to develop a mathematical model to predict intratumoral CEA-IL2v concentrations following various systemic dosing intensities. EXPERIMENTAL DESIGN: Sequential measurements of CEA-IL2v plasma concentrations in 74 patients with solid tumors were applied in a series of differential equations to devise a model that also incorporates the peripheral concentrations of IL-2 receptor-positive cell populations (i.e. CD8+, CD4+, NK and B cells) which affect tumor bioavailability of CEA-IL2v. Imaging data from a subset of 14 patients were subsequently utilized to additionally predict antibody uptake in tumor tissues. RESULTS: We created a PKPD mathematical model that incorporates the expansion of IL-2R-positive target cells at multiple doses levels and different schedules of CEA-IL2v. Model-based prediction of drug levels correlated with the concentration of IL-2R-positive cells in the peripheral blood of patients. The pharmacokinetic model was further refined and extended by adding a model of antibody uptake, which is based on drug dose and the biological properties of the tumor. In silico predictions of our model correlated with imaging data and demonstrated that a dose-dense schedule comprising escalating doses and shortened intervals of drug administration can improve intratumoral drug uptake and overcome consumption of CEA-IL2v by the expanding population of IL-2R-positive cells. CONCLUSIONS: The model presented here allows simulation of individualized treatment plans for optimal dosing and scheduling of immunocytokines for anti-cancer immunotherapy.

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Phase Ib Study of Glasdegib, A Hedgehog Pathway Inhibitor, in Combination With Standard Chemotherapy in Patients With AML or High-Risk MDS

Purpose: This open-label, multicenter, dose-finding, phase Ib study (NCT01546038) evaluated the safety, pharmacokinetics, pharmacodynamics, and clinical activity of the novel Hedgehog pathway Smoothened inhibitor glasdegib (PF-04449913) in patients (N = 52) with acute myeloid leukemia (AML) or high-risk myelodysplastic syndrome (MDS). Experimental Design: Glasdegib 100 or 200 mg was administered orally, once daily in 28-day cycles, in combination with low-dose cytarabine (arm A) or decitabine (arm B) to newly diagnosed patients considered not suitable for standard induction chemotherapy, and in combination with cytarabine/daunorubicin (arm C) to fit patients. The study followed a standard 3+3 dose-escalation design. The primary endpoint was dose-limiting toxicity (DLT). Ten additional patients were enrolled in expansion cohorts of arms A (n = 23) and C (n = 22) to confirm the recommended phase II dose (RP2D). Results: No DLTs were observed in arms A and B; 1 DLT (grade 4 neuropathy) occurred in arm C. The most common treatment-related non-hematologic adverse events were mostly grades 1-2 in all arms. Muscle spasms, dysgeusia, and alopecia  were generally mild. Overall, sixteen (31%) patients achieved a complete remission (CR)/CR with incomplete blood count recovery. 100 mg daily was selected as the RP2D for glasdegib in combination with standard chemotherapies in the absence of an estimated maximum tolerated dose in this setting. Conclusions: Treatment with glasdegib in combination with standard chemotherapy was generally well-tolerated and consistent with prior findings, warranting further evaluation of glasdegib-based combinations in patients with AML or high-risk MDS.

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Foretinib overcomes entrectinib resistance associated with the NTRK1 G667C mutation in NTRK1 fusion-positive tumor cells in a brain metastasis model

Background: Rearrangement of the neurotrophic tropomyosin receptor kinase 1 (NTRK1) gene, which encodes tyrosine receptor kinase A (TRK-A), occurs in various cancers, including colon cancer. Although entrectinib is effective in the treatment of central nervous system (CNS) metastases that express NTRK1 fusion proteins, acquired resistance inevitably results in recurrence. CNS is a sanctuary for targeted drugs; however, the mechanism by which CNS metastases become entrectinib-resistant remains elusive and must be clarified to develop better therapeutics. Experimental design: The entrectinib-resistant cell line KM12SM-ER was developed by continuous treatment with entrectinib in the brain metastasis-mimicking model inoculated with the entrectinib-sensitive human colon cancer cell line KM12SM, which harbors the TPM3-NTRK1 gene fusion. The mechanism of entrectinib resistance in KM12SM-ER cells was examined by next-generation sequencing. Compounds that overcame entrectinib resistance were screened from a library of 122 kinase inhibitors. Results: KM12SM-ER cells, which showed moderate resistance to entrectinib in vitro, had acquired the G667C mutation in NTRK1. The kinase inhibitor foretinib inhibited TRK-A phosphorylation and the viability of KM12SM-ER cells bearing the NTRK1-G667C mutation in vitro. Moreover, foretinib markedly inhibited the progression of entrectinib-refractory KM12SM-ER-derived liver metastases and brain tumors in animal models, predominantly through inhibition of TRK-A phosphorylation. Conclusion: These results suggest that foretinib may be effective in overcoming entrectinib resistance associated with the NTRK1-G667C mutation in NTRK1 fusion-positive tumors in various organs, including the brain, and provide a rationale for clinical trials of foretinib in cancer patients with entrectinib-resistant tumors harboring the NTRK1-G667C mutation, including patients with brain metastases.

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Disruption of Wnt/{beta}-catenin exerts anti-leukemia activity and synergizes with FLT3 inhibition in FLT3-mutant acute myeloid leukemia

Purpose: Wnt/β-catenin signaling is required for leukemic stem cell function. FLT3 mutations are frequently observed in acute myeloid leukemia (AML). Anomalous FLT3 signaling increases β-catenin nuclear localization and transcriptional activity. FLT3 tyrosine kinase inhibitors (TKIs) are used clinically to treat FLT3-mutated AML patients, but with limited efficacy. We investigated the anti-leukemia activity of combined Wnt/β-catenin and FLT3 inhibition in FLT3-mutant AML. Experimental Design: Wnt/β-catenin signaling was inhibited by the b-catenin/CBP antagonist C-82/PRI-724 or siRNAs, and FLT3 signaling by sorafenib or quizartinib. Treatments on apoptosis, cell growth, and cell signaling were assessed in cell lines, patient samples, and in vivo in immunodeficient mice by flow cytometry, western blot, RT-PCR, and CyTOF.  Results: We found significantly higher β-catenin expression in cytogenetically unfavorable and relapsed AML patient samples and in the bone-marrow-resident leukemic cells compared to circulating blasts. Disrupting Wnt/b-catenin signaling suppressed AML cell growth, induced apoptosis, abrogated stromal protection, and synergized with TKIs in FLT3-mutated AML cells and stem/progenitor cells in vitro. The aforementioned combinatorial treatment improved survival of AML-xenografted mice in two in vivo models and impaired leukemia cell engraftment. Mechanistically, the combined inhibition of Wnt/β-catenin and FLT3 cooperatively decreased nuclear β-catenin and the levels of c-Myc and other Wnt/β-catenin and FLT3 signaling proteins. Importantly, β-catenin inhibition abrogated the microenvironmental protection afforded the leukemic stem/progenitor cells.  Conclusions: Disrupting Wnt/β-catenin signaling exerts potent activities against AML stem/progenitor cells and synergizes with FLT3 inhibition in FLT3-mutant AML. These findings provide a rationale for clinical development of this strategy for treating FLT3-mutated AML patients.

http://ift.tt/2Hxvo47

Capecitabine efficacy is correlated with TYMP and RB expression in PDX established from triple-negative breast cancers

Purpose: triple-negative breast cancer (TNBC) patients with residual disease after neoadjuvant chemotherapy have a poor outcome. We developed patient-derived xenografts (PDX) from residual tumors to identify efficient chemotherapies and predictive biomarkers in a context of resistance to anthracyclines and taxanes-based treatments. Experimental Design: PDX were established from residual tumors of primary breast cancer patients treated in neoadjuvant setting. TNBC PDX were treated by anthracyclines, taxanes, platins and capecitabine. Predictive biomarkers were identified by transcriptomic and immunohistological analysis. Downregulation of RB1 was performed by siRNA in a cell line established from a PDX. Results: residual TNBC PDX were characterized by a high tumor take, a short latency and a poor prognosis of the corresponding patients. With the exception of BRCA1/2 mutated models, residual PDX were resistant to anthracyclines, taxanes, and platins. Capecitabine, the oral prodrug of 5-FU, was highly efficient in 60% of PDX with two models showing complete responses. Prior treatment of a responder PDX with 5-FU increased expression of thymidylate synthase and decreased efficacy of capecitabine. Transcriptomic and IHC analyses of 32 TNBC PDX, including both residual tumors and treatment-naïve derived tumors, identified RB and TYMP proteins as predictive biomarkers for capecitabine response. Finally, RB1 knockdown in a cell line established from a capecitabine-responder PDX decreased sensitivity to 5-FU treatment. Conclusions: we identified capecitabine as efficient chemotherapy in TNBC PDX models established from residual disease and resistant to anthracyclines, taxanes and platins. RB positivity and high expression of TYMP were significantly associated with capecitabine response.

http://ift.tt/2CwLDKJ

Molecular lymph node status for prognostic stratification of prostate cancer patients undergoing radical prostatectomy with extended pelvic lymph node dissection

Purpose: Molecular lymph node (LN) analysis using quantitative polymerase chain reaction (qPCR) detects LN metastases with higher sensitivity than histopathology. However, the prognostic role of molecular LN status in prostate cancer (PCa) patients treated with radical prostatectomy (RP) and extended pelvic LN dissection (ePLND) is unclear. To investigate the association of molecular compared to histopathologic LN status with biochemical recurrence. Experimental Design: Patients with intermediate and high risk PCa were prospectively enrolled and underwent RP with ePLND including obturator, internal, external and common iliac region. LNs ≥3mm were bisected and examined by standard histopathology and qPCR for Kallikrein3 (KLK3) expression. Biochemical recurrence was defined by confirmed postoperative PSA>0.2ng/ml. Results: In 111 patients, 2411 of 3173 removed LNs were examined by both methods. Histopathology detected 68 LN metastases in 28 (25%) patients. Molecular analysis confirmed elevated KLK3 expression in 65 histopathologic LN metastases of all 28 pN1-patients (pN1/molN1) and additionally reclassified 224 histopathologic negative LNs and 32 (29%) pN0-patients as LN-positive (pN0/molN1). At a median follow-up of 48 months 52 (47%) patients developed biochemical recurrence. Median biochemical recurrence-free survival (bRFS) was 9 months [95%CI0.0-20.1] in pN1/molN1-patients, 24 months [95%CI1.7-46.3] in pN0/molN1 patients and was not reached in pN0/molN0 patients (p<0.001). On multivariable Cox regression analysis, molecular LN status (HR 4.1 [95%CI1.9-8.8],p<0.001) but not histopathologic LN status (HR 1.5 [95%CI0.8-3.0],p=0.198) was confirmed as independent predictor of biochemical recurrence. Conclusion: Molecular LN analysis identified pN0-patients with a high risk of biochemical recurrence and provided superior prognostic information in comparison with histopathology alone.

http://ift.tt/2HyFkKo

The Airway Transcriptome as a Biomarker for Early Lung Cancer Detection

Lung cancer remains the leading cause of cancer-related death due to its advanced stage at diagnosis. Early detection of lung cancer can be improved by better defining who should be screened radiographically, and determining which imaging-detected pulmonary nodules are malignant. Gene expression biomarkers measured in normal-appearing airway epithelium provide an opportunity to use lung cancer associated molecular changes in this tissue for early detection of lung cancer. Molecular changes in the airway may result from an etiologic field of injury and/or field cancerization. The etiologic field of injury reflects the aberrant physiological response to carcinogen exposure that creates a susceptible microenvironment for cancer initiation. In contrast, field cancerization reflects effects of "first-hit" mutations in a clone of cells from which the tumor ultimately arises or the effects of the tumor on the surrounding tissue.  These fields might have value both for assessing lung cancer risk and diagnosis. Cancer-associated gene expression changes in the bronchial airway have recently been used to develop and validate a 23-gene classifier that improves the diagnostic yield of bronchoscopy for lung cancer among intermediate-risk patients. Recent studies have demonstrated that these lung cancer-related gene expression changes extend to nasal epithelial cells that can be sampled non-invasively. While the bronchial gene expression biomarker is being adopted clinically, further work is necessary to explore the potential clinical utility of gene-expression profiling in the nasal epithelium for lung cancer diagnosis, risk assessment, and precision medicine for lung cancer treatment and chemoprevention.

http://ift.tt/2Cz8HbU

Concurrent Inhibition of Neurosphere and Monolayer Cells of Pediatric Glioblastoma by Aurora A Inhibitor MLN8237 Predicted Survival Extension in PDOX models

Purpose: Pediatric glioblastoma (pGBM) is highly aggressive tumor in need of novel therapies. Our objective was to demonstrate the therapeutic efficacy of MLN8237 (Alisertib), an orally available selective inhibitor of Aurora A kinase (AURKA), and to evaluate which in vitro model system (monolayer or neurosphere) can predict therapeutic efficacy in vivo. Experimental Design: AURKA mRNA expressions were screened with qRT-PCR. In vitro anti-tumor effects were examined in 3 matching pairs of monolayer and neurosphere lines established from patient derived orthotopic xenograft (PDOX) models of the untreated (IC-4687GBM), recurrent (IC-372GBM) and terminal (IC-R0315GBM) tumors; and in vivo therapeutic efficacy through log rank analysis of survival times in 2 models (IC-4687GBM and IC-R0315GBM) following MLN8237 treatment (30 mg/kg/day, p.o., 12 days). Drug concentrations in vivo, mechanism of action and resistance were also investigated. Results: AURKA mRNA over-expression was detected in 14 pGBM tumors, 10 PDOX models and 6 cultured pGBM lines as compared with 11 low grade gliomas and normal brains. MLN8237 penetrated into pGBM xenografts in mouse brains. Significant extension of survival times were achieved in IC-4687GBM of which both neurosphere and monolayer were inhibited in vitro, but not in IC-R0315GBM of which only neurosphere cells responded (similar to IC-3752GBM cells). Apoptosis mediated MLN8237 induced cell death, and the presence of AURKA-negative and CD133+ cells appears to have contributed to in vivo therapy resistance. Conclusions: MLN8237 successfully targeted AURKA in a subset of pGBMs. Our data suggest that combination therapy should aim at AURKA-negative and/or CD133+ pGBM cells to prevent tumor recurrence.

http://ift.tt/2HyUJKQ

Androgen Deprivation Therapy Potentiates the Efficacy of Vascular Targeted Photodynamic Therapy of Prostate Cancer Xenografts

Purpose: WST11 vascular targeted photodynamic therapy (VTP) is a local ablation approach relying upon rapid, free radical-mediated destruction of tumor vasculature. A phase III trial showed that VTP significantly reduced disease progression when compared to active surveillance in patients with low-risk prostate cancer (PCa). The aim of this study was to identify a druggable pathway that could be combined with VTP to improve its efficacy and applicability to higher risk PCa tumors. Experimental Design: Transcriptome analysis of VTP treated tumors (LNCaP-AR xenografts) was used to identify a candidate pathway for combination therapy. The efficacy of the combination therapy was assessed in mice bearing LNCaP-AR or VCaP tumors. Results: Gene Set Enrichment Analysis (GSEA) identifies the enrichment of androgen responsive gene sets within hours post-VTP treatment, suggesting that the androgen receptor (AR) may be a viable target in combination with VTP. We tested this hypothesis in mice bearing LNCaP-AR xenograft tumors by using androgen deprivation therapy (ADT), degarelix, in combination with VTP. Compared to either ADT or VTP alone, a single dose of degarelix in concert with VTP significantly inhibited tumor growth. A sharp decline in serum PSA confirmed AR inhibition in this group. Tumors treated by VTP and degarelix displayed intense TUNEL staining 7 days post-treatment, supporting an increased apoptotic frequency underlying the effect on tumor inhibition. Conclusions: Improvement of local tumor control following androgen deprivation combined with VTP provides the rationale and preliminary protocol parameters for clinical trials in patients presented with locally advanced PCa.

http://ift.tt/2CCfba8

Combination approach for detecting different types of alterations in circulating tumor DNA in leiomyosarcoma

Purpose: The clinical utility of circulating tumor DNA (ctDNA) monitoring has been shown in tumors that harbor highly recurrent mutations. Leiomyosarcoma (LMS) represents a type of tumor with a wide spectrum of heterogeneous genomic abnormalities; thus, targeting hotspot mutations or a narrow genomic region for ctDNA detection may not be practical. Here we demonstrate a combinatorial approach that integrates different sequencing protocols for the orthogonal detection of single nucleotide variants (SNVs), small indels and copy number alterations (CNAs) in ctDNA. Experimental design: We employed Cancer Personalized Profiling by deep Sequencing (CAPP-Seq) for the analysis of SNVs and indels, together with a genome-wide interrogation of CNAs by Genome Representation Profiling (GRP). We profiled 28 longitudinal plasma samples and 25 tumor specimens from 7 patients with LMS. Results: We detected ctDNA in 6 of 7 of these patients with >98% specificity for mutant allele fractions down to a level of 0.01%. We show that results from CAPP-Seq and GRP are highly concordant, and the combination of these methods allows for more comprehensive monitoring of ctDNA by profiling a wide spectrum of tumor-specific markers. By analyzing multiple tumor specimens in individual patients obtained from different sites and at different times during treatment, we observed clonal evolution of these tumors that was reflected by ctDNA profiles. Conclusions: Our strategy allows for a comprehensive monitoring of a broad spectrum of tumor-specific markers in plasma. Our approach may be clinically useful not only in LMS but also in other tumor types that lack recurrent genomic alterations.

http://ift.tt/2HyUJuk

Integrated Pharmacokinetic/Pharmacodynamic Model of a Bispecific CD3xCD123 DART(R) Molecule in Nonhuman Primates: Evaluation of Activity and Impact of Immunogenicity

Purpose: Flotetuzumab (MGD006 or S80880) is a bispecific molecule that recognizes CD3 and CD123 membrane proteins, redirecting T-cells to kill CD123-expressing cells for the treatment of acute myeloid leukemia. In this study, we developed a mathematical model to characterize MGD006 exposure-response relationships and to assess the impact of its immunogenicity in cynomolgus monkeys. Experimental Design: 32 animals received multiple escalating doses (100-300-600-1000 ng/kg/day) via intravenous infusion continuously 4-days a week. The model reflects sequential binding of MGD006 to CD3 and CD123 receptors. Formation of the MGD006/CD3 complex was connected to total T-cells undergoing trafficking, whereas the formation of the tri-molecular complex results in T-cell activation and clonal expansion. Activated T-cells were used to drive the peripheral depletion of CD123-positive cells. Anti-drug antibody development was linked to MGD006 disposition as an elimination pathway. Model validation was tested by predicting the activity of MGD006 in 8 monkeys receiving continuous 7-day infusions. Results: MGD006 disposition and total T-cell and CD123-positive cell profiles were well characterized. Anti-drug antibody development led to the suppression of T-cell trafficking but did not systematically abolish CD123-positive cell depletion. Target cell depletion could persist after drug elimination owing to the self-proliferation of activated T-cells generated during the first cycles. The model was externally validated with the 7-day infusion dosing schedule. Conclusions:A translational model was developed for MGD006 that features T-cell activation and expansion as a key driver of pharmacological activity and provides a mechanistic quantitative platform to inform dosing strategies in ongoing clinical studies.

http://ift.tt/2CCf5zi

TGF-{beta}1 genetic variants predict clinical outcomes of HPV-positive oropharyngeal cancer patients after definitive radiotherapy

Purpose. Transforming growth factor-β1 (TGF-β1) plays a critical role in inflammation and immune responses and treatment response and survival. TGF-β1 variants may affect its expression level or functional efficiency, thus modifying tumor status and survival in HPV-positive squamous cell carcinoma of the oropharynx (SCCOP). Experimental design. We determined tumor HPV16 status and genotyped three TGF-β1 polymorphisms in 564 incident SCCOP patients treated with radiotherapy or chemoradiation. Univariate and multivariable Cox models were used to evaluate the associations between the three polymorphisms and survival. Results. Overall, 85% of patients (482 of 564) had HPV16-positive SCCOP. We found that TGF-β1 rs1982073 had statistically significant associations with survival, while TGF-β1rs1800469 and TGF-β1rs1800471 did not. Patients with TGF-β1 rs1982073 CT/CC variant genotypes had significantly better overall, disease-specific, and disease-free survival compared with those with the corresponding common homozygous TT genotype (all log-rank: P <0.001). Furthermore, these genotypes were significantly associated with an approximately 5 times reduced risk of overall death, death owing to disease, and recurrence after multivariable adjustment. Moreover, the stratified analyses by tumor HPV status indicated that the significant effects of TGF-β1 rs1982073 polymorphism on survival were found among HPV16-positive SCCOP patients only. Finally, the functional relevance of these variants was further characterized. Conclusions. Our findings support that the TGF-β1 rs1982073 polymorphism plays a significant role in the prognosis of SCCOP, especially in HPV16-positive SCCOP patients treated with chemoradiation. Prospective studies with larger sample sizes are needed to confirm these findings.

http://ift.tt/2HzH6v2

Prediction of the optimal dosing regimen using a mathematical model of tumour uptake for immunocytokine-based cancer immunotherapy

PURPOSE: Optimal dosing is critical for immunocytokine-based cancer immunotherapy to maximize efficacy and minimize toxicity. Cergutuzumab amunaleukin (CEA-IL2v) is a novel CEA-targeted immunocytokine. We set out to develop a mathematical model to predict intratumoral CEA-IL2v concentrations following various systemic dosing intensities. EXPERIMENTAL DESIGN: Sequential measurements of CEA-IL2v plasma concentrations in 74 patients with solid tumors were applied in a series of differential equations to devise a model that also incorporates the peripheral concentrations of IL-2 receptor-positive cell populations (i.e. CD8+, CD4+, NK and B cells) which affect tumor bioavailability of CEA-IL2v. Imaging data from a subset of 14 patients were subsequently utilized to additionally predict antibody uptake in tumor tissues. RESULTS: We created a PKPD mathematical model that incorporates the expansion of IL-2R-positive target cells at multiple doses levels and different schedules of CEA-IL2v. Model-based prediction of drug levels correlated with the concentration of IL-2R-positive cells in the peripheral blood of patients. The pharmacokinetic model was further refined and extended by adding a model of antibody uptake, which is based on drug dose and the biological properties of the tumor. In silico predictions of our model correlated with imaging data and demonstrated that a dose-dense schedule comprising escalating doses and shortened intervals of drug administration can improve intratumoral drug uptake and overcome consumption of CEA-IL2v by the expanding population of IL-2R-positive cells. CONCLUSIONS: The model presented here allows simulation of individualized treatment plans for optimal dosing and scheduling of immunocytokines for anti-cancer immunotherapy.

http://ift.tt/2CCf0eY

Phase Ib Study of Glasdegib, A Hedgehog Pathway Inhibitor, in Combination With Standard Chemotherapy in Patients With AML or High-Risk MDS

Purpose: This open-label, multicenter, dose-finding, phase Ib study (NCT01546038) evaluated the safety, pharmacokinetics, pharmacodynamics, and clinical activity of the novel Hedgehog pathway Smoothened inhibitor glasdegib (PF-04449913) in patients (N = 52) with acute myeloid leukemia (AML) or high-risk myelodysplastic syndrome (MDS). Experimental Design: Glasdegib 100 or 200 mg was administered orally, once daily in 28-day cycles, in combination with low-dose cytarabine (arm A) or decitabine (arm B) to newly diagnosed patients considered not suitable for standard induction chemotherapy, and in combination with cytarabine/daunorubicin (arm C) to fit patients. The study followed a standard 3+3 dose-escalation design. The primary endpoint was dose-limiting toxicity (DLT). Ten additional patients were enrolled in expansion cohorts of arms A (n = 23) and C (n = 22) to confirm the recommended phase II dose (RP2D). Results: No DLTs were observed in arms A and B; 1 DLT (grade 4 neuropathy) occurred in arm C. The most common treatment-related non-hematologic adverse events were mostly grades 1-2 in all arms. Muscle spasms, dysgeusia, and alopecia  were generally mild. Overall, sixteen (31%) patients achieved a complete remission (CR)/CR with incomplete blood count recovery. 100 mg daily was selected as the RP2D for glasdegib in combination with standard chemotherapies in the absence of an estimated maximum tolerated dose in this setting. Conclusions: Treatment with glasdegib in combination with standard chemotherapy was generally well-tolerated and consistent with prior findings, warranting further evaluation of glasdegib-based combinations in patients with AML or high-risk MDS.

http://ift.tt/2EGKvKC

Foretinib overcomes entrectinib resistance associated with the NTRK1 G667C mutation in NTRK1 fusion-positive tumor cells in a brain metastasis model

Background: Rearrangement of the neurotrophic tropomyosin receptor kinase 1 (NTRK1) gene, which encodes tyrosine receptor kinase A (TRK-A), occurs in various cancers, including colon cancer. Although entrectinib is effective in the treatment of central nervous system (CNS) metastases that express NTRK1 fusion proteins, acquired resistance inevitably results in recurrence. CNS is a sanctuary for targeted drugs; however, the mechanism by which CNS metastases become entrectinib-resistant remains elusive and must be clarified to develop better therapeutics. Experimental design: The entrectinib-resistant cell line KM12SM-ER was developed by continuous treatment with entrectinib in the brain metastasis-mimicking model inoculated with the entrectinib-sensitive human colon cancer cell line KM12SM, which harbors the TPM3-NTRK1 gene fusion. The mechanism of entrectinib resistance in KM12SM-ER cells was examined by next-generation sequencing. Compounds that overcame entrectinib resistance were screened from a library of 122 kinase inhibitors. Results: KM12SM-ER cells, which showed moderate resistance to entrectinib in vitro, had acquired the G667C mutation in NTRK1. The kinase inhibitor foretinib inhibited TRK-A phosphorylation and the viability of KM12SM-ER cells bearing the NTRK1-G667C mutation in vitro. Moreover, foretinib markedly inhibited the progression of entrectinib-refractory KM12SM-ER-derived liver metastases and brain tumors in animal models, predominantly through inhibition of TRK-A phosphorylation. Conclusion: These results suggest that foretinib may be effective in overcoming entrectinib resistance associated with the NTRK1-G667C mutation in NTRK1 fusion-positive tumors in various organs, including the brain, and provide a rationale for clinical trials of foretinib in cancer patients with entrectinib-resistant tumors harboring the NTRK1-G667C mutation, including patients with brain metastases.

http://ift.tt/2Cy9lXd

The potential role of HGF-MET signaling and autophagy in the war of Alectinib versus Crizotinib against ALK-positive NSCLC

Non-small-cell lung cancer (NSCLC) is currently the leading cause of cancer-related death. Accumulating evidences suggest that overcoming the therapeutic resistance in NSCLC is a big challenge. Recently, the o...

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Along with its favorable prognostic role, CLCA2 inhibits growth and metastasis of nasopharyngeal carcinoma cells via inhibition of FAK/ERK signaling

CLCA2 was reported as a tumor suppressor and disregulated in breast cancer. However, its function in tumor growth and metastasis in NPC has rarely been reported. In this study, we investigated the functional a...

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Correction to: Serum DNA integrity index as a potential molecular biomarker in endometrial cancer

In the publication of this article [1], there is an error in the first sentence of the Acknowledgements section.

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Family history of cancer and the risk of childhood solid tumours: a Norwegian nationwide register-based cohort study

Family history of cancer and the risk of childhood solid tumours: a Norwegian nationwide register-based cohort study

Family history of cancer and the risk of childhood solid tumours: a Norwegian nationwide register-based cohort study, Published online: 20 February 2018; doi:10.1038/bjc.2017.493

Family history of cancer and the risk of childhood solid tumours: a Norwegian nationwide register-based cohort study

http://ift.tt/2EFs1do

Ex vivo metabolic fingerprinting identifies biomarkers predictive of prostate cancer recurrence following radical prostatectomy

Ex vivo metabolic fingerprinting identifies biomarkers predictive of prostate cancer recurrence following radical prostatectomy

<i>Ex vivo</i> metabolic fingerprinting identifies biomarkers predictive of prostate cancer recurrence following radical prostatectomy, Published online: 20 February 2018; doi:10.1038/bjc.2017.470

Ex vivo metabolic fingerprinting identifies biomarkers predictive of prostate cancer recurrence following radical prostatectomy

http://ift.tt/2ERef6R

Plasticity and intratumoural heterogeneity of cell surface antigen expression in breast cancer

Plasticity and intratumoural heterogeneity of cell surface antigen expression in breast cancer

Plasticity and intratumoural heterogeneity of cell surface antigen expression in breast cancer, Published online: 20 February 2018; doi:10.1038/bjc.2017.497

Plasticity and intratumoural heterogeneity of cell surface antigen expression in breast cancer

http://ift.tt/2sK4Qcm

Risk of cancer in patients with epistaxis and haemoptysis

Risk of cancer in patients with epistaxis and haemoptysis

Risk of cancer in patients with epistaxis and haemoptysis, Published online: 20 February 2018; doi:10.1038/bjc.2017.494

Risk of cancer in patients with epistaxis and haemoptysis

http://ift.tt/2EFshsS

Pathological complete response and prognosis after neoadjuvant chemotherapy for HER2-positive breast cancers before and after trastuzumab era: results from a real-life cohort

Pathological complete response and prognosis after neoadjuvant chemotherapy for HER2-positive breast cancers before and after trastuzumab era: results from a real-life cohort

Pathological complete response and prognosis after neoadjuvant chemotherapy for <i>HER2</i>-positive breast cancers before and after trastuzumab era: results from a real-life cohort, Published online: 20 February 2018; doi:10.1038/bjc.2018.4

Pathological complete response and prognosis after neoadjuvant chemotherapy for HER2-positive breast cancers before and after trastuzumab era: results from a real-life cohort

http://ift.tt/2EFsP1U

miR-146a-5p mediates epithelial–mesenchymal transition of oesophageal squamous cell carcinoma via targeting Notch2

miR-146a-5p mediates epithelial–mesenchymal transition of oesophageal squamous cell carcinoma via targeting Notch2

<i>miR-146a-5p</i> mediates epithelial–mesenchymal transition of oesophageal squamous cell carcinoma via targeting <i>Notch2</i>, Published online: 20 February 2018; doi:10.1038/bjc.2017.471

miR-146a-5p mediates epithelial–mesenchymal transition of oesophageal squamous cell carcinoma via targeting Notch2

http://ift.tt/2BFWVQ6

Development of a prognostic scoring system for patients with advanced cancer enrolled in immune checkpoint inhibitor phase 1 clinical trials

Development of a prognostic scoring system for patients with advanced cancer enrolled in immune checkpoint inhibitor phase 1 clinical trials

Development of a prognostic scoring system for patients with advanced cancer enrolled in immune checkpoint inhibitor phase 1 clinical trials, Published online: 20 February 2018; doi:10.1038/bjc.2017.480

Development of a prognostic scoring system for patients with advanced cancer enrolled in immune checkpoint inhibitor phase 1 clinical trials

http://ift.tt/2BDQq0i

miR-146a-5p mediates epithelial–mesenchymal transition of oesophageal squamous cell carcinoma via targeting Notch2

miR-146a-5p mediates epithelial–mesenchymal transition of oesophageal squamous cell carcinoma via targeting Notch2

<i>miR-146a-5p</i> mediates epithelial–mesenchymal transition of oesophageal squamous cell carcinoma via targeting <i>Notch2</i>, Published online: 20 February 2018; doi:10.1038/bjc.2017.471

miR-146a-5p mediates epithelial–mesenchymal transition of oesophageal squamous cell carcinoma via targeting Notch2

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Family history of cancer and the risk of childhood solid tumours: a Norwegian nationwide register-based cohort study

Family history of cancer and the risk of childhood solid tumours: a Norwegian nationwide register-based cohort study

Family history of cancer and the risk of childhood solid tumours: a Norwegian nationwide register-based cohort study, Published online: 20 February 2018; doi:10.1038/bjc.2017.493

Family history of cancer and the risk of childhood solid tumours: a Norwegian nationwide register-based cohort study

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Ex vivo metabolic fingerprinting identifies biomarkers predictive of prostate cancer recurrence following radical prostatectomy

Ex vivo metabolic fingerprinting identifies biomarkers predictive of prostate cancer recurrence following radical prostatectomy

<i>Ex vivo</i> metabolic fingerprinting identifies biomarkers predictive of prostate cancer recurrence following radical prostatectomy, Published online: 20 February 2018; doi:10.1038/bjc.2017.470

Ex vivo metabolic fingerprinting identifies biomarkers predictive of prostate cancer recurrence following radical prostatectomy

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Plasticity and intratumoural heterogeneity of cell surface antigen expression in breast cancer

Plasticity and intratumoural heterogeneity of cell surface antigen expression in breast cancer

Plasticity and intratumoural heterogeneity of cell surface antigen expression in breast cancer, Published online: 20 February 2018; doi:10.1038/bjc.2017.497

Plasticity and intratumoural heterogeneity of cell surface antigen expression in breast cancer

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Risk of cancer in patients with epistaxis and haemoptysis

Risk of cancer in patients with epistaxis and haemoptysis

Risk of cancer in patients with epistaxis and haemoptysis, Published online: 20 February 2018; doi:10.1038/bjc.2017.494

Risk of cancer in patients with epistaxis and haemoptysis

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Pathological complete response and prognosis after neoadjuvant chemotherapy for HER2-positive breast cancers before and after trastuzumab era: results from a real-life cohort

Pathological complete response and prognosis after neoadjuvant chemotherapy for HER2-positive breast cancers before and after trastuzumab era: results from a real-life cohort

Pathological complete response and prognosis after neoadjuvant chemotherapy for <i>HER2</i>-positive breast cancers before and after trastuzumab era: results from a real-life cohort, Published online: 20 February 2018; doi:10.1038/bjc.2018.4

Pathological complete response and prognosis after neoadjuvant chemotherapy for HER2-positive breast cancers before and after trastuzumab era: results from a real-life cohort

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Development of a prognostic scoring system for patients with advanced cancer enrolled in immune checkpoint inhibitor phase 1 clinical trials

Development of a prognostic scoring system for patients with advanced cancer enrolled in immune checkpoint inhibitor phase 1 clinical trials

Development of a prognostic scoring system for patients with advanced cancer enrolled in immune checkpoint inhibitor phase 1 clinical trials, Published online: 20 February 2018; doi:10.1038/bjc.2017.480

Development of a prognostic scoring system for patients with advanced cancer enrolled in immune checkpoint inhibitor phase 1 clinical trials

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Financial difficulty, worry about affording care, and benefit finding in long-term survivors of cancer

Abstract

Objective

To examine the associations of worry about affording care and reporting financial difficulties with benefit finding in long-term cancer survivors.

Methods

Long-term survivors of cancer (n=547) in three integrated healthcare delivery systems completed the Medical Expenditure Panel Survey Cancer Survivorship Supplement. The relationship between benefit finding (becoming a stronger person, coping better, and making positive changes) and the potentially interacting factors of worry about affording care and financial difficulties was examined using multivariate logistic regression models.

Results

Of the total sample, 20% reported worry and 15% reported financial difficulty. Among those who reported no worry, financial difficulty was positively associated with becoming a stronger person (OR=2.89, 95% CI: 1.07, 7.80). Coping better was not associated with worry, financial difficulties, or the interaction of the two. Among those with no financial difficulty, worry was positively associated with making positive changes (OR=2.64, 95% CI: 1.41, 4.96) and among those reporting no worry, financial difficulty had a non-significant positive association with making positive changes (OR=1.98, 95% CI: 0.91, 4.31). Among those reporting worry, having financial difficulties was associated with lower odds of making positive changes (OR=0.32, 95% CI: 0.13, 0.78).

Conclusions

Our results suggest a complex relationship between financial difficulty, worry and benefit finding. The combination of worry about affording care and financial difficulty needs to be addressed and further studied among cancer survivors, as the presence of both, but not alone, was negatively associated with making positive changes, an aspect of benefit finding.

http://ift.tt/2EGqGip

Following patient pathways to psycho-oncological treatment: identification of treatment needs by clinical staff and electronic screening

Abstract

Objective

In this retrospective investigation of patient pathways to psycho-oncological treatment (POT) we compared the number of POT referrals before and after implementation of electronic screening for POT needs and investigated psychosocial predictors for POT wish at a nuclear medicine department.

Methods

We extracted medical chart information about number of referrals and extent of follow-up contacts. During standard referral (November 2014–October 2015), POT needs were identified by clinical staff only. In the screening-assisted referral period (November 2015–October 2016), identification was supported by electronic screening for POT needs. Psychosocial predictors for POT wish were examined using logistic regression.

Results

We analysed data from 487 patients during standard referral (mean age 56.4years; 60.2% female, 88.7% thyroid carcinoma or neuroendocrine tumours) of which 28 patients (5.7%) were referred for POT. Of 502 patients in the screening-assisted referral period (mean age 57.0years; 55.8% female, 86.6% thyroid carcinoma or neuroendocrine tumours), 69 (13.7%) were referred for POT. Of these, 36 were identified by PO-screening and 33 by clinical staff. After PO-screening implementation, referrals increased by a factor of 2.4. The strongest predictor of POT wish was depressive mood (p<0.001). During both referral periods, about 15% of patients visited the PO outpatient unit additionally to inpatient PO consultations.

Conclusions

Our results provide evidence from a real-life setting that PO-screening can foster POT referrals, reduce barriers to express the POT wish, and hence help to meet psychosocial needs of this specific patient group. Differences between patients' needs, wish and POT uptake should be further investigated.

http://ift.tt/2ogIk64

Financial difficulty, worry about affording care, and benefit finding in long-term survivors of cancer

Abstract

Objective

To examine the associations of worry about affording care and reporting financial difficulties with benefit finding in long-term cancer survivors.

Methods

Long-term survivors of cancer (n=547) in three integrated healthcare delivery systems completed the Medical Expenditure Panel Survey Cancer Survivorship Supplement. The relationship between benefit finding (becoming a stronger person, coping better, and making positive changes) and the potentially interacting factors of worry about affording care and financial difficulties was examined using multivariate logistic regression models.

Results

Of the total sample, 20% reported worry and 15% reported financial difficulty. Among those who reported no worry, financial difficulty was positively associated with becoming a stronger person (OR=2.89, 95% CI: 1.07, 7.80). Coping better was not associated with worry, financial difficulties, or the interaction of the two. Among those with no financial difficulty, worry was positively associated with making positive changes (OR=2.64, 95% CI: 1.41, 4.96) and among those reporting no worry, financial difficulty had a non-significant positive association with making positive changes (OR=1.98, 95% CI: 0.91, 4.31). Among those reporting worry, having financial difficulties was associated with lower odds of making positive changes (OR=0.32, 95% CI: 0.13, 0.78).

Conclusions

Our results suggest a complex relationship between financial difficulty, worry and benefit finding. The combination of worry about affording care and financial difficulty needs to be addressed and further studied among cancer survivors, as the presence of both, but not alone, was negatively associated with making positive changes, an aspect of benefit finding.

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Following patient pathways to psycho-oncological treatment: identification of treatment needs by clinical staff and electronic screening

Abstract

Objective

In this retrospective investigation of patient pathways to psycho-oncological treatment (POT) we compared the number of POT referrals before and after implementation of electronic screening for POT needs and investigated psychosocial predictors for POT wish at a nuclear medicine department.

Methods

We extracted medical chart information about number of referrals and extent of follow-up contacts. During standard referral (November 2014–October 2015), POT needs were identified by clinical staff only. In the screening-assisted referral period (November 2015–October 2016), identification was supported by electronic screening for POT needs. Psychosocial predictors for POT wish were examined using logistic regression.

Results

We analysed data from 487 patients during standard referral (mean age 56.4years; 60.2% female, 88.7% thyroid carcinoma or neuroendocrine tumours) of which 28 patients (5.7%) were referred for POT. Of 502 patients in the screening-assisted referral period (mean age 57.0years; 55.8% female, 86.6% thyroid carcinoma or neuroendocrine tumours), 69 (13.7%) were referred for POT. Of these, 36 were identified by PO-screening and 33 by clinical staff. After PO-screening implementation, referrals increased by a factor of 2.4. The strongest predictor of POT wish was depressive mood (p<0.001). During both referral periods, about 15% of patients visited the PO outpatient unit additionally to inpatient PO consultations.

Conclusions

Our results provide evidence from a real-life setting that PO-screening can foster POT referrals, reduce barriers to express the POT wish, and hence help to meet psychosocial needs of this specific patient group. Differences between patients' needs, wish and POT uptake should be further investigated.

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Risk of cancer in patients with epistaxis and haemoptysis

http://ift.tt/2Fhld2P

Plasticity and intratumoural heterogeneity of cell surface antigen expression in breast cancer

http://ift.tt/2GuvVSL

miR-146a-5p mediates epithelial–mesenchymal transition of oesophageal squamous cell carcinoma via targeting Notch2

http://ift.tt/2FjoqPu

Pathological complete response and prognosis after neoadjuvant chemotherapy for HER2-positive breast cancers before and after trastuzumab era: results from a real-life cohort

http://ift.tt/2GuMuya

Ex vivo metabolic fingerprinting identifies biomarkers predictive of prostate cancer recurrence following radical prostatectomy

http://ift.tt/2Hw2uRN

Development of a prognostic scoring system for patients with advanced cancer enrolled in immune checkpoint inhibitor phase 1 clinical trials

http://ift.tt/2GtUDmq

Family history of cancer and the risk of childhood solid tumours: a Norwegian nationwide register-based cohort study

http://ift.tt/2Fhlgvx

Risk of cancer in patients with epistaxis and haemoptysis

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via IFTTT

Plasticity and intratumoural heterogeneity of cell surface antigen expression in breast cancer

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via IFTTT

miR-146a-5p mediates epithelial–mesenchymal transition of oesophageal squamous cell carcinoma via targeting Notch2

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via IFTTT

Pathological complete response and prognosis after neoadjuvant chemotherapy for HER2-positive breast cancers before and after trastuzumab era: results from a real-life cohort

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Ex vivo metabolic fingerprinting identifies biomarkers predictive of prostate cancer recurrence following radical prostatectomy

from Cancer via ola Kala on Inoreader http://ift.tt/2Hw2uRN
via IFTTT

Development of a prognostic scoring system for patients with advanced cancer enrolled in immune checkpoint inhibitor phase 1 clinical trials

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Family history of cancer and the risk of childhood solid tumours: a Norwegian nationwide register-based cohort study

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Can Oxygen “Microbubbles” Make Radiation Therapy More Effective?

A new study in mice raises the possibility that using microscopic, oxygen-carrying bubbles may improve the effectiveness of radiation therapy in the treatment of breast cancer.

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Can Oxygen “Microbubbles” Make Radiation Therapy More Effective?

A new study in mice raises the possibility that using microscopic, oxygen-carrying bubbles may improve the effectiveness of radiation therapy in the treatment of breast cancer.

http://ift.tt/2Gunp6f

Experiences and unmet needs of lesbian, gay and bisexual people with cancer care: a systematic review and meta-synthesis

Abstract

Objectives

To explore the cancer care experiences and unmet needs of people who identify as a sexual or gender minority.

Methods

A qualitative systematic review and meta-synthesis was undertaken based on a registered protocol. Following literature searching and study selection, study quality was examined using the Critical Appraisal Skill Programme Checklist. Qualitative data were extracted verbatim from included studies and synthesised using thematic analysis.

Results

Fifteen studies that included lesbian, gay and bisexual (LGB) people living with or beyond cancer were included in the review. Studies including gender minorities were not identified. The majority of study participants were sexual minority women with breast cancer or sexual minority men with prostate cancer. Meta-synthesis of 106 individual findings generated six overarching themes pertaining to sexual orientation disclosure, experiences and fear of homophobia, positive and negative healthcare professional behaviours, heterocentric systems and care, inadequacy of available support groups, and unmet needs for patient-centred care and LGB-specific information. LGB people often reported feelings of anxiety, invisibility, isolation and frustration throughout the cancer care continuum.

Conclusions

Analysis of the experiences of LGB people with cancer care shows that LGB people face numerous challenges due to their sexual orientation and receive care that does not adequately address their needs. Training and education of healthcare professionals is strongly recommended to address some of these challenges and practice gaps. Culturally appropriate care includes avoiding heterosexual assumptions, use of inclusive language, the provision of tailored information and involving partners in care.

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