The combination of cardiorespiratory fitness and muscle strength, and mortality risk

Abstract

Little is known about the combined associations of cardiorespiratory fitness (CRF) and hand grip strength (GS) with mortality in general adult populations. The purpose of this study was to compare the relative risk of mortality for CRF, GS, and their combination. In UK Biobank, a prospective cohort of > 0.5 million adults aged 40–69 years, CRF was measured through submaximal bike tests; GS was measured using a hand-dynamometer. This analysis is based on data from 70,913 men and women (832 all-cause, 177 cardiovascular and 503 cancer deaths over 5.7-year follow-up) who provided valid CRF and GS data, and with no history of heart attack/stroke/cancer at baseline. Compared with the lowest CRF category, the hazard ratio (HR) for all-cause mortality was 0.76 [95% confidence interval (CI) 0.64–0.89] and 0.65 (95% CI 0.55–0.78) for the middle and highest CRF categories, respectively, after adjustment for confounders and GS. The highest GS category had an HR of 0.79 (95% CI 0.66–0.95) for all-cause mortality compared with the lowest, after adjustment for confounders and CRF. Similar results were found for cardiovascular and cancer mortality. The HRs for the combination of highest CRF and GS were 0.53 (95% CI 0.39–0.72) for all-cause mortality and 0.31 (95% CI 0.14–0.67) for cardiovascular mortality, compared with the reference category of lowest CRF and GS: no significant association for cancer mortality (HR 0.70; 95% CI 0.48–1.02). CRF and GS are both independent predictors of mortality. Improving both CRF and muscle strength, as opposed to either of the two alone, may be the most effective behavioral strategy to reduce all-cause and cardiovascular mortality risk.

from Cancer via ola Kala on Inoreader https://ift.tt/2urLvNP
via IFTTT

Updates in pancreatic cancer: Modest gains and hopeful targets

Journal of Oncology Pharmacy Practice, Ahead of Print.


from Cancer via ola Kala on Inoreader https://ift.tt/2pKltAF
via IFTTT

Cancers, Vol. 10, Pages 93: The Role of Activator Protein-1 (AP-1) Family Members in CD30-Positive Lymphomas

Cancers, Vol. 10, Pages 93: The Role of Activator Protein-1 (AP-1) Family Members in CD30-Positive Lymphomas

Cancers doi: 10.3390/cancers10040093

Authors: Ines Garces de los Fayos Alonso Huan-Chang Liang Suzanne D. Turner Sabine Lagger Olaf Merkel Lukas Kenner

The Activator Protein-1 (AP-1) transcription factor (TF) family, composed of a variety of members including c-JUN, c-FOS and ATF, is involved in mediating many biological processes such as proliferation, differentiation and cell death. Since their discovery, the role of AP-1 TFs in cancer development has been extensively analysed. Multiple in vitro and in vivo studies have highlighted the complexity of these TFs, mainly due to their cell-type specific homo- or hetero-dimerization resulting in diverse transcriptional response profiles. However, as a result of the increasing knowledge of the role of AP-1 TFs in disease, these TFs are being recognized as promising therapeutic targets for various malignancies. In this review, we focus on the impact of deregulated expression of AP-1 TFs in CD30-positive lymphomas including Classical Hodgkin Lymphoma and Anaplastic Large Cell Lymphoma.

from Cancer via ola Kala on Inoreader https://ift.tt/2pKEHFJ
via IFTTT

Cancers, Vol. 10, Pages 93: The Role of Activator Protein-1 (AP-1) Family Members in CD30-Positive Lymphomas

Cancers, Vol. 10, Pages 93: The Role of Activator Protein-1 (AP-1) Family Members in CD30-Positive Lymphomas

Cancers doi: 10.3390/cancers10040093

Authors: Ines Garces de los Fayos Alonso Huan-Chang Liang Suzanne D. Turner Sabine Lagger Olaf Merkel Lukas Kenner

The Activator Protein-1 (AP-1) transcription factor (TF) family, composed of a variety of members including c-JUN, c-FOS and ATF, is involved in mediating many biological processes such as proliferation, differentiation and cell death. Since their discovery, the role of AP-1 TFs in cancer development has been extensively analysed. Multiple in vitro and in vivo studies have highlighted the complexity of these TFs, mainly due to their cell-type specific homo- or hetero-dimerization resulting in diverse transcriptional response profiles. However, as a result of the increasing knowledge of the role of AP-1 TFs in disease, these TFs are being recognized as promising therapeutic targets for various malignancies. In this review, we focus on the impact of deregulated expression of AP-1 TFs in CD30-positive lymphomas including Classical Hodgkin Lymphoma and Anaplastic Large Cell Lymphoma.

https://ift.tt/2pKEHFJ

A phase II, multicenter, single-arm trial of eribulin as first- or second-line chemotherapy for HER2-negative advanced or metastatic breast cancer: evaluation of efficacy, safety, and patient-reported outcomes

Abstract

Purpose

Although eribulin is a suitable option for early-line treatment of metastatic breast cancer (MBC), data on first- or second-line use of eribulin for human epidermal growth factor receptor 2 (HER2)-negative MBC are still limited. Therefore, we conducted a phase II trial to investigate the efficacy and safety of eribulin for first- or second-line chemotherapy for HER2-negative MBC.

Materials and methods

We performed a phase II, open-label, single-arm, multicenter study in Japan. Eligible patients were women with histologically confirmed HER2-negative MBC without chemotherapy or only one chemotherapy line for MBC. The primary endpoint was the overall response rate (ORR) and the secondary endpoints included the clinical benefit rate (ORR + stable disease for 6 months; CBR), progression-free survival (PFS), overall survival (OS), duration of response (DOR), safety, and health-related quality of life (HRQoL).

Results

A total of 35 patients with HER2-negative MBC were enrolled between March 2013 and February 2017 (data cut-off July 31, 2017). The ORR was 37.1% (95% CI 21.1–53.2%). The CBR was 54.3% (95% CI 37.8–70.8%). The median PFS was 6.2 months (95% CI 2.7–9.4 months) and median OS was 21.4 months (95% CI 11.5–32.9 months). Common grade 3/4 adverse events were neutropenia (42.9%) but febrile neutropenia (2.9%). Although the majority of non-hematological adverse events were mild in severity, one patient died of pneumonitis. In HRQoL analysis, eribulin appeared to maintain HRQoL of many patients.

Conclusions

Eribulin as first- or second-line chemotherapy is effective and has manageable toxicity for patients with HER2-negative MBC.

https://ift.tt/2I8a5Ft

A phase II, multicenter, single-arm trial of eribulin as first- or second-line chemotherapy for HER2-negative advanced or metastatic breast cancer: evaluation of efficacy, safety, and patient-reported outcomes

Abstract

Purpose

Although eribulin is a suitable option for early-line treatment of metastatic breast cancer (MBC), data on first- or second-line use of eribulin for human epidermal growth factor receptor 2 (HER2)-negative MBC are still limited. Therefore, we conducted a phase II trial to investigate the efficacy and safety of eribulin for first- or second-line chemotherapy for HER2-negative MBC.

Materials and methods

We performed a phase II, open-label, single-arm, multicenter study in Japan. Eligible patients were women with histologically confirmed HER2-negative MBC without chemotherapy or only one chemotherapy line for MBC. The primary endpoint was the overall response rate (ORR) and the secondary endpoints included the clinical benefit rate (ORR + stable disease for 6 months; CBR), progression-free survival (PFS), overall survival (OS), duration of response (DOR), safety, and health-related quality of life (HRQoL).

Results

A total of 35 patients with HER2-negative MBC were enrolled between March 2013 and February 2017 (data cut-off July 31, 2017). The ORR was 37.1% (95% CI 21.1–53.2%). The CBR was 54.3% (95% CI 37.8–70.8%). The median PFS was 6.2 months (95% CI 2.7–9.4 months) and median OS was 21.4 months (95% CI 11.5–32.9 months). Common grade 3/4 adverse events were neutropenia (42.9%) but febrile neutropenia (2.9%). Although the majority of non-hematological adverse events were mild in severity, one patient died of pneumonitis. In HRQoL analysis, eribulin appeared to maintain HRQoL of many patients.

Conclusions

Eribulin as first- or second-line chemotherapy is effective and has manageable toxicity for patients with HER2-negative MBC.

from Cancer via ola Kala on Inoreader https://ift.tt/2I8a5Ft
via IFTTT

The combination of cardiorespiratory fitness and muscle strength, and mortality risk

Abstract

Little is known about the combined associations of cardiorespiratory fitness (CRF) and hand grip strength (GS) with mortality in general adult populations. The purpose of this study was to compare the relative risk of mortality for CRF, GS, and their combination. In UK Biobank, a prospective cohort of > 0.5 million adults aged 40–69 years, CRF was measured through submaximal bike tests; GS was measured using a hand-dynamometer. This analysis is based on data from 70,913 men and women (832 all-cause, 177 cardiovascular and 503 cancer deaths over 5.7-year follow-up) who provided valid CRF and GS data, and with no history of heart attack/stroke/cancer at baseline. Compared with the lowest CRF category, the hazard ratio (HR) for all-cause mortality was 0.76 [95% confidence interval (CI) 0.64–0.89] and 0.65 (95% CI 0.55–0.78) for the middle and highest CRF categories, respectively, after adjustment for confounders and GS. The highest GS category had an HR of 0.79 (95% CI 0.66–0.95) for all-cause mortality compared with the lowest, after adjustment for confounders and CRF. Similar results were found for cardiovascular and cancer mortality. The HRs for the combination of highest CRF and GS were 0.53 (95% CI 0.39–0.72) for all-cause mortality and 0.31 (95% CI 0.14–0.67) for cardiovascular mortality, compared with the reference category of lowest CRF and GS: no significant association for cancer mortality (HR 0.70; 95% CI 0.48–1.02). CRF and GS are both independent predictors of mortality. Improving both CRF and muscle strength, as opposed to either of the two alone, may be the most effective behavioral strategy to reduce all-cause and cardiovascular mortality risk.

from Cancer via ola Kala on Inoreader https://ift.tt/2urLvNP
via IFTTT

The combination of cardiorespiratory fitness and muscle strength, and mortality risk

Abstract

Little is known about the combined associations of cardiorespiratory fitness (CRF) and hand grip strength (GS) with mortality in general adult populations. The purpose of this study was to compare the relative risk of mortality for CRF, GS, and their combination. In UK Biobank, a prospective cohort of > 0.5 million adults aged 40–69 years, CRF was measured through submaximal bike tests; GS was measured using a hand-dynamometer. This analysis is based on data from 70,913 men and women (832 all-cause, 177 cardiovascular and 503 cancer deaths over 5.7-year follow-up) who provided valid CRF and GS data, and with no history of heart attack/stroke/cancer at baseline. Compared with the lowest CRF category, the hazard ratio (HR) for all-cause mortality was 0.76 [95% confidence interval (CI) 0.64–0.89] and 0.65 (95% CI 0.55–0.78) for the middle and highest CRF categories, respectively, after adjustment for confounders and GS. The highest GS category had an HR of 0.79 (95% CI 0.66–0.95) for all-cause mortality compared with the lowest, after adjustment for confounders and CRF. Similar results were found for cardiovascular and cancer mortality. The HRs for the combination of highest CRF and GS were 0.53 (95% CI 0.39–0.72) for all-cause mortality and 0.31 (95% CI 0.14–0.67) for cardiovascular mortality, compared with the reference category of lowest CRF and GS: no significant association for cancer mortality (HR 0.70; 95% CI 0.48–1.02). CRF and GS are both independent predictors of mortality. Improving both CRF and muscle strength, as opposed to either of the two alone, may be the most effective behavioral strategy to reduce all-cause and cardiovascular mortality risk.

https://ift.tt/2urLvNP

A phase II, multicenter, single-arm trial of eribulin as first- or second-line chemotherapy for HER2-negative advanced or metastatic breast cancer: evaluation of efficacy, safety, and patient-reported outcomes

Abstract

Purpose

Although eribulin is a suitable option for early-line treatment of metastatic breast cancer (MBC), data on first- or second-line use of eribulin for human epidermal growth factor receptor 2 (HER2)-negative MBC are still limited. Therefore, we conducted a phase II trial to investigate the efficacy and safety of eribulin for first- or second-line chemotherapy for HER2-negative MBC.

Materials and methods

We performed a phase II, open-label, single-arm, multicenter study in Japan. Eligible patients were women with histologically confirmed HER2-negative MBC without chemotherapy or only one chemotherapy line for MBC. The primary endpoint was the overall response rate (ORR) and the secondary endpoints included the clinical benefit rate (ORR + stable disease for 6 months; CBR), progression-free survival (PFS), overall survival (OS), duration of response (DOR), safety, and health-related quality of life (HRQoL).

Results

A total of 35 patients with HER2-negative MBC were enrolled between March 2013 and February 2017 (data cut-off July 31, 2017). The ORR was 37.1% (95% CI 21.1–53.2%). The CBR was 54.3% (95% CI 37.8–70.8%). The median PFS was 6.2 months (95% CI 2.7–9.4 months) and median OS was 21.4 months (95% CI 11.5–32.9 months). Common grade 3/4 adverse events were neutropenia (42.9%) but febrile neutropenia (2.9%). Although the majority of non-hematological adverse events were mild in severity, one patient died of pneumonitis. In HRQoL analysis, eribulin appeared to maintain HRQoL of many patients.

Conclusions

Eribulin as first- or second-line chemotherapy is effective and has manageable toxicity for patients with HER2-negative MBC.

from Cancer via ola Kala on Inoreader https://ift.tt/2I8a5Ft
via IFTTT

Sedentary behaviour and risk of all-cause, cardiovascular and cancer mortality, and incident type 2 diabetes: a systematic review and dose response meta-analysis

Abstract

Purpose: To estimate the strength and shape of the dose–response relationship between sedentary behaviour and all-cause, cardiovascular disease (CVD) and cancer mortality, and incident type 2 diabetes (T2D), adjusted for physical activity (PA). Data Sources: Pubmed, Web of Knowledge, Medline, Embase, Cochrane Library and Google Scholar (through September-2016); reference lists. Study Selection: Prospective studies reporting associations between total daily sedentary time or TV viewing time, and ≥ one outcome of interest. Data Extraction: Two independent reviewers extracted data, study quality was assessed; corresponding authors were approached where needed. Data Synthesis: Thirty-four studies (1,331,468 unique participants; good study quality) covering 8 exposure-outcome combinations were included. For total sedentary behaviour, the PA-adjusted relationship was non-linear for all-cause mortality (RR per 1 h/day: were 1.01 (1.00–1.01) ≤ 8 h/day; 1.04 (1.03–1.05) > 8 h/day of exposure), and for CVD mortality (1.01 (0.99–1.02) ≤ 6 h/day; 1.04 (1.03–1.04) > 6 h/day). The association was linear (1.01 (1.00–1.01)) with T2D and non-significant with cancer mortality. Stronger PA-adjusted associations were found for TV viewing (h/day); non-linear for all-cause mortality (1.03 (1.01–1.04) ≤ 3.5 h/day; 1.06 (1.05–1.08) > 3.5 h/day) and for CVD mortality (1.02 (0.99–1.04) ≤ 4 h/day; 1.08 (1.05–1.12) > 4 h/day). Associations with cancer mortality (1.03 (1.02–1.04)) and T2D were linear (1.09 (1.07–1.12)). Conclusions: Independent of PA, total sitting and TV viewing time are associated with greater risk for several major chronic disease outcomes. For all-cause and CVD mortality, a threshold of 6–8 h/day of total sitting and 3–4 h/day of TV viewing was identified, above which the risk is increased.

from Cancer via ola Kala on Inoreader https://ift.tt/2I5qxq7
via IFTTT

Sedentary behaviour and risk of all-cause, cardiovascular and cancer mortality, and incident type 2 diabetes: a systematic review and dose response meta-analysis

Abstract

Purpose: To estimate the strength and shape of the dose–response relationship between sedentary behaviour and all-cause, cardiovascular disease (CVD) and cancer mortality, and incident type 2 diabetes (T2D), adjusted for physical activity (PA). Data Sources: Pubmed, Web of Knowledge, Medline, Embase, Cochrane Library and Google Scholar (through September-2016); reference lists. Study Selection: Prospective studies reporting associations between total daily sedentary time or TV viewing time, and ≥ one outcome of interest. Data Extraction: Two independent reviewers extracted data, study quality was assessed; corresponding authors were approached where needed. Data Synthesis: Thirty-four studies (1,331,468 unique participants; good study quality) covering 8 exposure-outcome combinations were included. For total sedentary behaviour, the PA-adjusted relationship was non-linear for all-cause mortality (RR per 1 h/day: were 1.01 (1.00–1.01) ≤ 8 h/day; 1.04 (1.03–1.05) > 8 h/day of exposure), and for CVD mortality (1.01 (0.99–1.02) ≤ 6 h/day; 1.04 (1.03–1.04) > 6 h/day). The association was linear (1.01 (1.00–1.01)) with T2D and non-significant with cancer mortality. Stronger PA-adjusted associations were found for TV viewing (h/day); non-linear for all-cause mortality (1.03 (1.01–1.04) ≤ 3.5 h/day; 1.06 (1.05–1.08) > 3.5 h/day) and for CVD mortality (1.02 (0.99–1.04) ≤ 4 h/day; 1.08 (1.05–1.12) > 4 h/day). Associations with cancer mortality (1.03 (1.02–1.04)) and T2D were linear (1.09 (1.07–1.12)). Conclusions: Independent of PA, total sitting and TV viewing time are associated with greater risk for several major chronic disease outcomes. For all-cause and CVD mortality, a threshold of 6–8 h/day of total sitting and 3–4 h/day of TV viewing was identified, above which the risk is increased.

from Cancer via ola Kala on Inoreader https://ift.tt/2I5qxq7
via IFTTT

Sedentary behaviour and risk of all-cause, cardiovascular and cancer mortality, and incident type 2 diabetes: a systematic review and dose response meta-analysis

Abstract

Purpose: To estimate the strength and shape of the dose–response relationship between sedentary behaviour and all-cause, cardiovascular disease (CVD) and cancer mortality, and incident type 2 diabetes (T2D), adjusted for physical activity (PA). Data Sources: Pubmed, Web of Knowledge, Medline, Embase, Cochrane Library and Google Scholar (through September-2016); reference lists. Study Selection: Prospective studies reporting associations between total daily sedentary time or TV viewing time, and ≥ one outcome of interest. Data Extraction: Two independent reviewers extracted data, study quality was assessed; corresponding authors were approached where needed. Data Synthesis: Thirty-four studies (1,331,468 unique participants; good study quality) covering 8 exposure-outcome combinations were included. For total sedentary behaviour, the PA-adjusted relationship was non-linear for all-cause mortality (RR per 1 h/day: were 1.01 (1.00–1.01) ≤ 8 h/day; 1.04 (1.03–1.05) > 8 h/day of exposure), and for CVD mortality (1.01 (0.99–1.02) ≤ 6 h/day; 1.04 (1.03–1.04) > 6 h/day). The association was linear (1.01 (1.00–1.01)) with T2D and non-significant with cancer mortality. Stronger PA-adjusted associations were found for TV viewing (h/day); non-linear for all-cause mortality (1.03 (1.01–1.04) ≤ 3.5 h/day; 1.06 (1.05–1.08) > 3.5 h/day) and for CVD mortality (1.02 (0.99–1.04) ≤ 4 h/day; 1.08 (1.05–1.12) > 4 h/day). Associations with cancer mortality (1.03 (1.02–1.04)) and T2D were linear (1.09 (1.07–1.12)). Conclusions: Independent of PA, total sitting and TV viewing time are associated with greater risk for several major chronic disease outcomes. For all-cause and CVD mortality, a threshold of 6–8 h/day of total sitting and 3–4 h/day of TV viewing was identified, above which the risk is increased.

https://ift.tt/2I5qxq7

Avelumab (anti-PD-L1) in platinum-resistant/refractory ovarian cancer: JAVELIN Ovarian 200 Phase III study design

Future Oncology, Ahead of Print.


from Cancer via ola Kala on Inoreader https://ift.tt/2GdVc8n
via IFTTT

Avelumab (anti-PD-L1) in platinum-resistant/refractory ovarian cancer: JAVELIN Ovarian 200 Phase III study design

Future Oncology, Ahead of Print.


https://ift.tt/2GdVc8n

Avelumab (anti-PD-L1) in platinum-resistant/refractory ovarian cancer: JAVELIN Ovarian 200 Phase III study design

Future Oncology, Ahead of Print.


from Cancer via ola Kala on Inoreader https://ift.tt/2GdVc8n
via IFTTT

IMGN779, a Novel CD33-Targeting Antibody-Drug Conjugate with DNA Alkylating Activity, Exhibits Potent Antitumor Activity in Models of AML

The myeloid differentiation antigen CD33 has long been exploited as a target for antibody-based therapeutic approaches in acute myeloid leukemia (AML). Validation of this strategy was provided with the approval of the CD33-targeting antibody-drug conjugate (ADC) gemtuzumab ozogamicin in 2000; the clinical utility of this agent has however been hampered by safety concerns. Thus, the full potential of CD33-directed therapy in AML remains to be realized, and considerable interest exists in the design and development of more effective ADCs that confer high therapeutic indices and favorable tolerability profiles. Here we describe the preclinical characterization of a novel CD33-targeting ADC, IMGN779, which utilizes a unique DNA alkylating payload to achieve potent antitumor effects with good tolerability. The payload, DGN462, is prototypical of a novel class of purpose-created indolinobenzodiazeprine pseudodimers, termed IGNs. With low picomolar potency, IMGN779 reduced viability in a panel of AML cell lines in vitro. Mechanistically, the cytotoxic activity of IMGN779 involved DNA damage, cell cycle arrest, and apoptosis consistent with the mode of action of DGN462. Moreover, IMGN779 was highly active against patient-derived AML cells, including those with adverse molecular abnormalities, and sensitivity correlated to CD33 expression levels. In vivo, IMGN779 displayed robust antitumor efficacy in multiple AML xenograft and disseminated disease models, as evidenced by durable tumor regressions and prolonged survival. Taken together, these findings identify IMGN779 as a promising new candidate for evaluation as a novel therapeutic in AML.

from Cancer via ola Kala on Inoreader https://ift.tt/2GiK31V
via IFTTT

Tumor infiltrating lymphocytes and PD-L1 expression in pre- and post-treatment breast cancers in the SWOG S0800 Phase II neoadjuvant chemotherapy trial

Our aim was to examine the association of pre-treatment tumor infiltrating lymphocyte (TIL) count and PD-L1 levels with pathologic complete response (pCR) and assess immune marker changes following treatment in tumor specimens from the S0800 clinical trial which randomized patients to bevacizumab+nab-paclitaxel followed by doxorubicin/cyclophosphamide (AC) versus two control arms without bevacizumab (varying sequence of AC and nab-paclitaxel). TILs were assessed in 124 pre- and 62 post-treatment tissues (including 59 pairs). PD-L1 was assessed in 120 pre- and 43 post-treatment tissues (including 39 pairs) using the 22C3 antibody. Baseline and treatment-induced immune changes were correlated with pCR and survival using estrogen receptor (ER) and treatment adjusted logistic and Cox regressions, respectively. At baseline, the mean TIL count was 17.4% (17% had zero TIL, 9% had >50% TILs). Post-treatment, mean TIL count decreased to 11% (5% had no TIL, 2% had > 50% TILs). In paired samples, the mean TILs change was 15% decrease. Baseline PD-L1 was detected in 43% of cases (n=5 in tumor cells, n=29 stroma, n=18 tumor+stroma). Post-treatment, PD-L1 expression was not significantly lower, 33%. Higher baseline TIL count and PD-L1 positivity rate were associated with higher pCR rate even after adjustment for treatment and ER status (p=0.018). There was no association between TIL counts, PD-L1 expression and survival due to few events. In conclusion, TIL counts, but not PD-L1 expression, decreased significantly after treatment. Continued PD-L1 expression in some residual cancers raises the possibility that adjuvant immune checkpoint inhibitor therapy could improve survival in this patient population.

from Cancer via ola Kala on Inoreader https://ift.tt/2pKemZ8
via IFTTT

IMGN779, a Novel CD33-Targeting Antibody-Drug Conjugate with DNA Alkylating Activity, Exhibits Potent Antitumor Activity in Models of AML

The myeloid differentiation antigen CD33 has long been exploited as a target for antibody-based therapeutic approaches in acute myeloid leukemia (AML). Validation of this strategy was provided with the approval of the CD33-targeting antibody-drug conjugate (ADC) gemtuzumab ozogamicin in 2000; the clinical utility of this agent has however been hampered by safety concerns. Thus, the full potential of CD33-directed therapy in AML remains to be realized, and considerable interest exists in the design and development of more effective ADCs that confer high therapeutic indices and favorable tolerability profiles. Here we describe the preclinical characterization of a novel CD33-targeting ADC, IMGN779, which utilizes a unique DNA alkylating payload to achieve potent antitumor effects with good tolerability. The payload, DGN462, is prototypical of a novel class of purpose-created indolinobenzodiazeprine pseudodimers, termed IGNs. With low picomolar potency, IMGN779 reduced viability in a panel of AML cell lines in vitro. Mechanistically, the cytotoxic activity of IMGN779 involved DNA damage, cell cycle arrest, and apoptosis consistent with the mode of action of DGN462. Moreover, IMGN779 was highly active against patient-derived AML cells, including those with adverse molecular abnormalities, and sensitivity correlated to CD33 expression levels. In vivo, IMGN779 displayed robust antitumor efficacy in multiple AML xenograft and disseminated disease models, as evidenced by durable tumor regressions and prolonged survival. Taken together, these findings identify IMGN779 as a promising new candidate for evaluation as a novel therapeutic in AML.

https://ift.tt/2GiK31V

Tumor infiltrating lymphocytes and PD-L1 expression in pre- and post-treatment breast cancers in the SWOG S0800 Phase II neoadjuvant chemotherapy trial

Our aim was to examine the association of pre-treatment tumor infiltrating lymphocyte (TIL) count and PD-L1 levels with pathologic complete response (pCR) and assess immune marker changes following treatment in tumor specimens from the S0800 clinical trial which randomized patients to bevacizumab+nab-paclitaxel followed by doxorubicin/cyclophosphamide (AC) versus two control arms without bevacizumab (varying sequence of AC and nab-paclitaxel). TILs were assessed in 124 pre- and 62 post-treatment tissues (including 59 pairs). PD-L1 was assessed in 120 pre- and 43 post-treatment tissues (including 39 pairs) using the 22C3 antibody. Baseline and treatment-induced immune changes were correlated with pCR and survival using estrogen receptor (ER) and treatment adjusted logistic and Cox regressions, respectively. At baseline, the mean TIL count was 17.4% (17% had zero TIL, 9% had >50% TILs). Post-treatment, mean TIL count decreased to 11% (5% had no TIL, 2% had > 50% TILs). In paired samples, the mean TILs change was 15% decrease. Baseline PD-L1 was detected in 43% of cases (n=5 in tumor cells, n=29 stroma, n=18 tumor+stroma). Post-treatment, PD-L1 expression was not significantly lower, 33%. Higher baseline TIL count and PD-L1 positivity rate were associated with higher pCR rate even after adjustment for treatment and ER status (p=0.018). There was no association between TIL counts, PD-L1 expression and survival due to few events. In conclusion, TIL counts, but not PD-L1 expression, decreased significantly after treatment. Continued PD-L1 expression in some residual cancers raises the possibility that adjuvant immune checkpoint inhibitor therapy could improve survival in this patient population.

https://ift.tt/2pKemZ8

Hematologic Markers of Lung Metastasis in Stage IV Colorectal Cancer

Abstract

Background

Many studies showed an association between absolute neutrophil count (ANC), absolute monocyte count (AMC), neutrophil-lymphocyte ratio (NLR), monocyte-lymphocyte ratio (MLR), and platelet-lymphocyte ratio (PLR) with poor overall survival (OS) in patients with cancer. However, only a few studies were conducted to further investigate this association in colorectal cancer (CRC).

Methods

Clinical data from 299 stage IV CRC patients treated at King Hussein Cancer Center from 2004 to 2012 have been retrospectively reviewed. We examined the association between ANC, AMC, MLR, PLR, and NLR with lung metastasis in stage IV CRC. Receiver Operating Characteristic (ROC) curve analysis was operated to determine the optimal NLR cutoff value. Univariate and multivariate analysis were performed.

Results

The ROC value of 3.4 was determined as the cutoff value of NLR to study the association. Univariate and multivariate analysis showed that patients with high baseline NLR (≥ 3.4) had more baseline lung metastasis than patients with low NLR (< 3.4) (p = 0.0001, p = 0.0151, respectively). Also, baseline NLR correlated significantly with the presence of lymphovascular invasion (p = 0.001). In patients with no baseline lung metastasis, high post-treatment NLR was associated with consequent development of lung metastasis (p = 0.0227). Other markers including ANC, AMC, MLR, and PLR were significantly associated with lung metastasis at time of diagnosis (p = 0.0006, p = 0.0006, p = 0.0187, and p = 0.001, respectively).

Conclusion

Results are suggesting that different hematologic markers obtained from a cheap test (CBC) could potentially be used to predict the likelihood of lung metastasis in stage IV CRC. Prospective studies are needed to further assess the immune cells' role in tumor metastasis promotion.

from Cancer via ola Kala on Inoreader https://ift.tt/2GhMh1r
via IFTTT

Hematologic Markers of Lung Metastasis in Stage IV Colorectal Cancer

Abstract

Background

Many studies showed an association between absolute neutrophil count (ANC), absolute monocyte count (AMC), neutrophil-lymphocyte ratio (NLR), monocyte-lymphocyte ratio (MLR), and platelet-lymphocyte ratio (PLR) with poor overall survival (OS) in patients with cancer. However, only a few studies were conducted to further investigate this association in colorectal cancer (CRC).

Methods

Clinical data from 299 stage IV CRC patients treated at King Hussein Cancer Center from 2004 to 2012 have been retrospectively reviewed. We examined the association between ANC, AMC, MLR, PLR, and NLR with lung metastasis in stage IV CRC. Receiver Operating Characteristic (ROC) curve analysis was operated to determine the optimal NLR cutoff value. Univariate and multivariate analysis were performed.

Results

The ROC value of 3.4 was determined as the cutoff value of NLR to study the association. Univariate and multivariate analysis showed that patients with high baseline NLR (≥ 3.4) had more baseline lung metastasis than patients with low NLR (< 3.4) (p = 0.0001, p = 0.0151, respectively). Also, baseline NLR correlated significantly with the presence of lymphovascular invasion (p = 0.001). In patients with no baseline lung metastasis, high post-treatment NLR was associated with consequent development of lung metastasis (p = 0.0227). Other markers including ANC, AMC, MLR, and PLR were significantly associated with lung metastasis at time of diagnosis (p = 0.0006, p = 0.0006, p = 0.0187, and p = 0.001, respectively).

Conclusion

Results are suggesting that different hematologic markers obtained from a cheap test (CBC) could potentially be used to predict the likelihood of lung metastasis in stage IV CRC. Prospective studies are needed to further assess the immune cells' role in tumor metastasis promotion.

https://ift.tt/2GhMh1r

A G3BP1-interacting lncRNA promotes ferroptosis and apoptosis in cancer via nuclear sequestration of p53

Long non-coding RNAs (lncRNA) have been associated with various types of cancer, however, the precise role of many lncRNAs in tumorigenesis remains elusive. Here we demonstrate that the cytosolic lncRNA P53RRA is downregulated in cancers and functions as a tumor suppressor by inhibiting cancer progression. Chromatin remodeling proteins LSH and Cfp1 silenced or increased P53RRA expression respectively. P53RRA bound Ras GTPase-activating protein-binding protein 1 (G3BP1) using nucleotides 1 and 871 of P53RRA and the RRM interaction domain of G3BP1 (aa 177-466). The cytosolic P53RRA-G3BP1 interaction displaced p53 from a G3BP1 complex resulting in greater p53 retention in the nucleus which led to cell cycle arrest, apoptosis, and ferroptosis. P53RRA promoted ferroptosis and apoptosis by affecting transcription of several metabolic genes. Low P53RRA expression significantly correlated with poor survival in patients with breast and lung cancers harboring wild-type p53. These data show that lncRNAs can directly interact with the functional domain of signaling proteins in the cytoplasm, thus regulating p53 modulators to suppress cancer progression.

from Cancer via ola Kala on Inoreader https://ift.tt/2I9nWeQ
via IFTTT

The circular RNA circPRKCI promotes tumor growth in lung adenocarcinoma

Somatic copy-number variations (CNV) may drive cancer progression through both coding and noncoding transcripts. However, noncoding transcripts resulting from CNV are largely unknown, especially for circular RNAs. By integrating bioinformatics analyses of alerted circRNAs and focal CNV in lung adenocarcinoma (LAC), we identify a proto-oncogenic circular RNA (circPRKCI) from the 3q26.2 amplicon, one of the most frequent genomic aberrations in multiple cancers. circPRKCI was overexpressed in LAC tissues, in part due to amplification of the 3q26.2 locus, and promoted proliferation and tumorigenesis of LAC. circPRKCI functioned as a sponge for both miR-545 and miR-589 and abrogated their suppression of the pro-tumorigenic transcription factor E2F7. Intra-tumor injection of cholesterol-conjugated siRNA specifically targeting circPRKCI inhibited tumor growth in a patient-derived LAC xenograft model. In summary, circPRKCI is crucial for tumorigenesis and may serve as a potential therapeutic target in LAC patients.

from Cancer via ola Kala on Inoreader https://ift.tt/2pJNjx7
via IFTTT

I{kappa}B kinase {alpha} is required for development and progression of KRAS-mutant lung adenocarcinoma.

Although oncogenic activation of nuclear factor (NF)-κΒ has been identified in various tumors, the NF-κΒ-activating kinases (inhibitor of NF-κΒ kinases, IKK) responsible for this are elusive. In this study, we determined the role of IKKα and IKKβ in KRAS-mutant lung adenocarcinomas induced by the carcinogen urethane and by respiratory epithelial expression of oncogenic KRASG12D. Using NF-κB reporter mice and conditional deletions of IKKα and IKKβ, we identified two distinct early and late activation phases of NF-κΒ during chemical and genetic lung adenocarcinoma development, which were characterized by nuclear translocation of RelB, ΙκΒβ, and IKKα in tumor-initiated cells. IKKα was a cardinal tumor promoter in chemical and genetic KRAS-mutant lung adenocarcinoma, and respiratory epithelial IKKα-deficient mice were markedly protected from the disease. IKKα specifically cooperated with mutant KRAS for tumor induction in a cell-autonomous fashion, providing mutant cells with a survival advantage in vitro and in vivo. IKKα was highly expressed in human lung adenocarcinoma, and a heat shock protein 90 inhibitor that blocks IKK function delivered superior effects against KRAS-mutant lung adenocarcinoma compared with a specific IKKβ inhibitor. These results demonstrate an actionable requirement for IKKα in KRAS-mutant lung adenocarcinoma, marking the kinase as a therapeutic target against this disease.

from Cancer via ola Kala on Inoreader https://ift.tt/2DYQBRt
via IFTTT

Intratumoral CpG-B promotes anti-tumoral neutrophil, cDC, and T cell cooperation without reprograming tolerogenic pDC

Cancer immunotherapies utilize distinct mechanisms to harness the power of the immune system to eradicate cancer cells. Therapeutic vaccines, aimed at inducing active immune responses against an existing cancer, are highly dependent on the immunological microenvironment, where many immune cell types display high levels of plasticity and, depending on the context, promote very different immunological outcomes. Among them, plasmacytoid dendritic cells (pDC), known to be highly immunogenic upon inflammation, are maintained in a tolerogenic state by the tumor microenvironment. Here we report that intratumoral (i.t.) injection of established solid tumors with CpG oligonucleotides-B (CpG-B) inhibits tumor growth. Interestingly, control of tumor growth was independent of tumor-associated (TA) pDC, which remained refractory to CpG-B stimulation and whose depletion did not alter the efficacy of the treatment. Instead, tumor growth inhibition subsequent to i.t. CpG-B injection depended on the recruitment of neutrophils into the milieu, resulting in the activation of conventional dendritic cells (cDC), subsequent increased anti-tumor T cell priming in draining lymph nodes, and enhanced effector T cell infiltration in the tumor microenvironment. These results reinforce the concept that intratumoral delivery of TLR9 agonists alters the tumor microenvironment by improving the anti-tumor activity of both innate and adaptive immune cells.

from Cancer via ola Kala on Inoreader https://ift.tt/2GeWcc2
via IFTTT

A G3BP1-interacting lncRNA promotes ferroptosis and apoptosis in cancer via nuclear sequestration of p53

Long non-coding RNAs (lncRNA) have been associated with various types of cancer, however, the precise role of many lncRNAs in tumorigenesis remains elusive. Here we demonstrate that the cytosolic lncRNA P53RRA is downregulated in cancers and functions as a tumor suppressor by inhibiting cancer progression. Chromatin remodeling proteins LSH and Cfp1 silenced or increased P53RRA expression respectively. P53RRA bound Ras GTPase-activating protein-binding protein 1 (G3BP1) using nucleotides 1 and 871 of P53RRA and the RRM interaction domain of G3BP1 (aa 177-466). The cytosolic P53RRA-G3BP1 interaction displaced p53 from a G3BP1 complex resulting in greater p53 retention in the nucleus which led to cell cycle arrest, apoptosis, and ferroptosis. P53RRA promoted ferroptosis and apoptosis by affecting transcription of several metabolic genes. Low P53RRA expression significantly correlated with poor survival in patients with breast and lung cancers harboring wild-type p53. These data show that lncRNAs can directly interact with the functional domain of signaling proteins in the cytoplasm, thus regulating p53 modulators to suppress cancer progression.

https://ift.tt/2I9nWeQ

The circular RNA circPRKCI promotes tumor growth in lung adenocarcinoma

Somatic copy-number variations (CNV) may drive cancer progression through both coding and noncoding transcripts. However, noncoding transcripts resulting from CNV are largely unknown, especially for circular RNAs. By integrating bioinformatics analyses of alerted circRNAs and focal CNV in lung adenocarcinoma (LAC), we identify a proto-oncogenic circular RNA (circPRKCI) from the 3q26.2 amplicon, one of the most frequent genomic aberrations in multiple cancers. circPRKCI was overexpressed in LAC tissues, in part due to amplification of the 3q26.2 locus, and promoted proliferation and tumorigenesis of LAC. circPRKCI functioned as a sponge for both miR-545 and miR-589 and abrogated their suppression of the pro-tumorigenic transcription factor E2F7. Intra-tumor injection of cholesterol-conjugated siRNA specifically targeting circPRKCI inhibited tumor growth in a patient-derived LAC xenograft model. In summary, circPRKCI is crucial for tumorigenesis and may serve as a potential therapeutic target in LAC patients.

https://ift.tt/2pJNjx7

I{kappa}B kinase {alpha} is required for development and progression of KRAS-mutant lung adenocarcinoma.

Although oncogenic activation of nuclear factor (NF)-κΒ has been identified in various tumors, the NF-κΒ-activating kinases (inhibitor of NF-κΒ kinases, IKK) responsible for this are elusive. In this study, we determined the role of IKKα and IKKβ in KRAS-mutant lung adenocarcinomas induced by the carcinogen urethane and by respiratory epithelial expression of oncogenic KRASG12D. Using NF-κB reporter mice and conditional deletions of IKKα and IKKβ, we identified two distinct early and late activation phases of NF-κΒ during chemical and genetic lung adenocarcinoma development, which were characterized by nuclear translocation of RelB, ΙκΒβ, and IKKα in tumor-initiated cells. IKKα was a cardinal tumor promoter in chemical and genetic KRAS-mutant lung adenocarcinoma, and respiratory epithelial IKKα-deficient mice were markedly protected from the disease. IKKα specifically cooperated with mutant KRAS for tumor induction in a cell-autonomous fashion, providing mutant cells with a survival advantage in vitro and in vivo. IKKα was highly expressed in human lung adenocarcinoma, and a heat shock protein 90 inhibitor that blocks IKK function delivered superior effects against KRAS-mutant lung adenocarcinoma compared with a specific IKKβ inhibitor. These results demonstrate an actionable requirement for IKKα in KRAS-mutant lung adenocarcinoma, marking the kinase as a therapeutic target against this disease.

https://ift.tt/2DYQBRt

Intratumoral CpG-B promotes anti-tumoral neutrophil, cDC, and T cell cooperation without reprograming tolerogenic pDC

Cancer immunotherapies utilize distinct mechanisms to harness the power of the immune system to eradicate cancer cells. Therapeutic vaccines, aimed at inducing active immune responses against an existing cancer, are highly dependent on the immunological microenvironment, where many immune cell types display high levels of plasticity and, depending on the context, promote very different immunological outcomes. Among them, plasmacytoid dendritic cells (pDC), known to be highly immunogenic upon inflammation, are maintained in a tolerogenic state by the tumor microenvironment. Here we report that intratumoral (i.t.) injection of established solid tumors with CpG oligonucleotides-B (CpG-B) inhibits tumor growth. Interestingly, control of tumor growth was independent of tumor-associated (TA) pDC, which remained refractory to CpG-B stimulation and whose depletion did not alter the efficacy of the treatment. Instead, tumor growth inhibition subsequent to i.t. CpG-B injection depended on the recruitment of neutrophils into the milieu, resulting in the activation of conventional dendritic cells (cDC), subsequent increased anti-tumor T cell priming in draining lymph nodes, and enhanced effector T cell infiltration in the tumor microenvironment. These results reinforce the concept that intratumoral delivery of TLR9 agonists alters the tumor microenvironment by improving the anti-tumor activity of both innate and adaptive immune cells.

https://ift.tt/2GeWcc2

Exome sequencing of plasma DNA portrays the mutation landscape of colorectal cancer and discovers mutated VEGFR2 receptors as modulators of anti-angiogenic therapies

Background:Despite the wide use of antiangiogenic drugs in the clinical setting, predictive biomarkers of response to these drugs are still unknown.Experimental design: We applied whole-exome sequencing of matched germline and basal plasma cell-free DNA samples (WES-cfDNA) on a RAS/BRAF/PIK3CA wild-type metastatic colorectal cancer patient with primary resistance to standard treatment regimens, including inhibitors to the VEGF:VEGFR2 pathway. We performed extensive functional experiments, including ectopic expression of VEGFR2 mutants in different cell lines, kinase and drug sensitivity assays, and cell- and patient-derived xenografts. Results: WES-cfDNA yielded a 77% concordance rate with tumor exome sequencing and enabled the identification of the KDR/VEGFR2 L840F clonal, somatic mutation as the cause of therapy refractoriness in our patient. Additionally, we found that 1-3% of samples from cancer sequencing projects harbor KDR somatic mutations located in protein residues frequently mutated in other cancer-relevant kinases, such as EGFR, ABL1, and ALK. Our in vitro and in vivo functional assays confirmed that L840F causes strong resistance to anti-angiogenic drugs, whereas the KDR hot-spot mutant R1032Q confers sensitivity to strong VEGFR2 inhibitors. Moreover, we showed that the D717V, G800D, G800R, L840F, G843D, S925F, R1022Q, R1032Q, and S1100F VEGFR2 mutants promote tumor growth in mice. Conclusions: Our study supports WES-cfDNA as a powerful platform for portraying the somatic mutation landscape of cancer and discovery of new resistance mechanisms to cancer therapies. Importantly, we discovered that VEGFR2 is somatically mutated across tumor types and that VEGFR2 mutants can be oncogenic and control sensitivity/resistance to antiangiogenic drugs.

from Cancer via ola Kala on Inoreader https://ift.tt/2utGwfP
via IFTTT

Exome sequencing of plasma DNA portrays the mutation landscape of colorectal cancer and discovers mutated VEGFR2 receptors as modulators of anti-angiogenic therapies

Background:Despite the wide use of antiangiogenic drugs in the clinical setting, predictive biomarkers of response to these drugs are still unknown.Experimental design: We applied whole-exome sequencing of matched germline and basal plasma cell-free DNA samples (WES-cfDNA) on a RAS/BRAF/PIK3CA wild-type metastatic colorectal cancer patient with primary resistance to standard treatment regimens, including inhibitors to the VEGF:VEGFR2 pathway. We performed extensive functional experiments, including ectopic expression of VEGFR2 mutants in different cell lines, kinase and drug sensitivity assays, and cell- and patient-derived xenografts. Results: WES-cfDNA yielded a 77% concordance rate with tumor exome sequencing and enabled the identification of the KDR/VEGFR2 L840F clonal, somatic mutation as the cause of therapy refractoriness in our patient. Additionally, we found that 1-3% of samples from cancer sequencing projects harbor KDR somatic mutations located in protein residues frequently mutated in other cancer-relevant kinases, such as EGFR, ABL1, and ALK. Our in vitro and in vivo functional assays confirmed that L840F causes strong resistance to anti-angiogenic drugs, whereas the KDR hot-spot mutant R1032Q confers sensitivity to strong VEGFR2 inhibitors. Moreover, we showed that the D717V, G800D, G800R, L840F, G843D, S925F, R1022Q, R1032Q, and S1100F VEGFR2 mutants promote tumor growth in mice. Conclusions: Our study supports WES-cfDNA as a powerful platform for portraying the somatic mutation landscape of cancer and discovery of new resistance mechanisms to cancer therapies. Importantly, we discovered that VEGFR2 is somatically mutated across tumor types and that VEGFR2 mutants can be oncogenic and control sensitivity/resistance to antiangiogenic drugs.

https://ift.tt/2utGwfP

Mediator complex (MED) 7: a biomarker associated with good prognosis in invasive breast cancer, especially ER+ luminal subtypes

Mediator complex (MED) 7: a biomarker associated with good prognosis in invasive breast cancer, especially ER+ luminal subtypes

Mediator complex (MED) 7: a biomarker associated with good prognosis in invasive breast cancer, especially ER+ luminal subtypes, Published online: 28 March 2018; doi:10.1038/s41416-018-0041-x

Mediator complex (MED) 7: a biomarker associated with good prognosis in invasive breast cancer, especially ER+ luminal subtypes

from Cancer via ola Kala on Inoreader https://ift.tt/2Gkc5u4
via IFTTT

Multivariable clinical-genetic risk model for predicting venous thromboembolic events in patients with cancer

Multivariable clinical-genetic risk model for predicting venous thromboembolic events in patients with cancer

Multivariable clinical-genetic risk model for predicting venous thromboembolic events in patients with cancer, Published online: 28 March 2018; doi:10.1038/s41416-018-0027-8

Multivariable clinical-genetic risk model for predicting venous thromboembolic events in patients with cancer

from Cancer via ola Kala on Inoreader https://ift.tt/2pKb5Jf
via IFTTT

Mediator complex (MED) 7: a biomarker associated with good prognosis in invasive breast cancer, especially ER+ luminal subtypes

Mediator complex (MED) 7: a biomarker associated with good prognosis in invasive breast cancer, especially ER+ luminal subtypes

Mediator complex (MED) 7: a biomarker associated with good prognosis in invasive breast cancer, especially ER+ luminal subtypes, Published online: 28 March 2018; doi:10.1038/s41416-018-0041-x

Mediator complex (MED) 7: a biomarker associated with good prognosis in invasive breast cancer, especially ER+ luminal subtypes

https://ift.tt/2Gkc5u4

Multivariable clinical-genetic risk model for predicting venous thromboembolic events in patients with cancer

Multivariable clinical-genetic risk model for predicting venous thromboembolic events in patients with cancer

Multivariable clinical-genetic risk model for predicting venous thromboembolic events in patients with cancer, Published online: 28 March 2018; doi:10.1038/s41416-018-0027-8

Multivariable clinical-genetic risk model for predicting venous thromboembolic events in patients with cancer

https://ift.tt/2pKb5Jf

Incidence of Radiographically Occult Nodal Metastases in HPV+ Oropharyngeal Carcinoma: Implications for Reducing Elective Nodal Coverage

Publication date: Available online 27 March 2018
Source:Practical Radiation Oncology
Author(s): Gokoulakrichenane Loganadane, Jacqueline R. Kelly, Nicholas C. Lee, Benjamin Kann, Amit Mahajan, James E. Hansen, Yazid Belkacémi, Wendell Yarbrough, Zain Husain
PurposeInitial de-escalation studies for HPV-driven oropharyngeal squamous cell carcinomas (HPV+ OPSCC) altered radiotherapy dose or the systemic agent used. Newer trials examine the disease control achieved with a reduced elective nodal field. We examined patterns of nodal involvement in patients with HPV+ OPSCC with a focus on implications for radiation field design for treatment de-escalation.Methods and materialsRecords of patients with HPV+ OPSCC with preoperative imaging (CT or FDG-PET/CT) who underwent neck dissection without neoadjuvant therapy from 2010 to 2017 were retrospectively reviewed. The number and location of clinically positive lymph nodes on preoperative imaging were compared with those documented on pathology. These data were then used to establish the probability of missing nodal disease in three modified radiation field designs.ResultsOne hundred patients were included. The median time between imaging and surgery was 22 days. The most common clinical N stage was cN2a (35%), while the most common pathologic N stage was pN2b (45%). The median number of radiographically and pathologically involved nodes was 1 (range 0-6) and 2 (range 0-11), respectively. 43% of patients had more pathologically involved nodes than predicted on imaging, while 21% had pathologic involvement at an additional nodal level not predicted on imaging. Of the 21 patients with additional pathologically involved nodal levels, 14 had involvement of a directly adjacent station, four were patients with a cN0 hemineck with pathologically positive level II disease, and three had pathologic involvement of a level two echelons removed from that predicted on imaging.ConclusionOur study suggests that radiation fields encompassing only clinically involved nodes or levels has an unacceptably high likelihood of missing subclinical disease. Alternatively, treating the first uninvolved echelon nodes in addition would cover pathologic sites of disease in 97% of patients. This approach merits further study in prospective trials.



from Cancer via ola Kala on Inoreader https://ift.tt/2pKkznI
via IFTTT

Incidence of Radiographically Occult Nodal Metastases in HPV+ Oropharyngeal Carcinoma: Implications for Reducing Elective Nodal Coverage

Publication date: Available online 27 March 2018
Source:Practical Radiation Oncology
Author(s): Gokoulakrichenane Loganadane, Jacqueline R. Kelly, Nicholas C. Lee, Benjamin Kann, Amit Mahajan, James E. Hansen, Yazid Belkacémi, Wendell Yarbrough, Zain Husain
PurposeInitial de-escalation studies for HPV-driven oropharyngeal squamous cell carcinomas (HPV+ OPSCC) altered radiotherapy dose or the systemic agent used. Newer trials examine the disease control achieved with a reduced elective nodal field. We examined patterns of nodal involvement in patients with HPV+ OPSCC with a focus on implications for radiation field design for treatment de-escalation.Methods and materialsRecords of patients with HPV+ OPSCC with preoperative imaging (CT or FDG-PET/CT) who underwent neck dissection without neoadjuvant therapy from 2010 to 2017 were retrospectively reviewed. The number and location of clinically positive lymph nodes on preoperative imaging were compared with those documented on pathology. These data were then used to establish the probability of missing nodal disease in three modified radiation field designs.ResultsOne hundred patients were included. The median time between imaging and surgery was 22 days. The most common clinical N stage was cN2a (35%), while the most common pathologic N stage was pN2b (45%). The median number of radiographically and pathologically involved nodes was 1 (range 0-6) and 2 (range 0-11), respectively. 43% of patients had more pathologically involved nodes than predicted on imaging, while 21% had pathologic involvement at an additional nodal level not predicted on imaging. Of the 21 patients with additional pathologically involved nodal levels, 14 had involvement of a directly adjacent station, four were patients with a cN0 hemineck with pathologically positive level II disease, and three had pathologic involvement of a level two echelons removed from that predicted on imaging.ConclusionOur study suggests that radiation fields encompassing only clinically involved nodes or levels has an unacceptably high likelihood of missing subclinical disease. Alternatively, treating the first uninvolved echelon nodes in addition would cover pathologic sites of disease in 97% of patients. This approach merits further study in prospective trials.



https://ift.tt/2pKkznI

Mediator complex (MED) 7: a biomarker associated with good prognosis in invasive breast cancer, especially ER+ luminal subtypes

from Cancer via ola Kala on Inoreader https://ift.tt/2I5cmkI
via IFTTT

Multivariable clinical-genetic risk model for predicting venous thromboembolic events in patients with cancer

from Cancer via ola Kala on Inoreader https://ift.tt/2GA0kTy
via IFTTT

Mediator complex (MED) 7: a biomarker associated with good prognosis in invasive breast cancer, especially ER+ luminal subtypes

https://ift.tt/2I5cmkI

Multivariable clinical-genetic risk model for predicting venous thromboembolic events in patients with cancer

https://ift.tt/2GA0kTy

Myeloid sarcoma of the nasal septum following invasive fungal sinusitis: report of a case and review of the relevant literature

Abstract

Myeloid sarcoma is an uncommon extramedullary manifestation of myeloproliferative malignancies, such as acute myeloid leukemia (AML). This sarcoma most often involves structures such as subperiosteal bone, peritoneum, or pericardium, and has only rarely been reported in the nose and paranasal sinuses. The signs and symptoms of myeloid sarcoma can overlap with those of acute invasive fungal sinusitis (AIFS), a life-threatening surgical emergency. This report describes a 75-year-old male with a known history of AML who developed both AIFS and myeloid sarcoma. Several months after successful treatment for biopsy proven AIFS, this patient developed a new soft tissue mass of the nasal septum. A new biopsy was obtained which revealed infiltrating blast cells with evidence of monocytic differentiation diagnostic of myeloid sarcoma. Given symptoms of severe nasal obstruction, this patient received palliative radiotherapy to the nasal septum, which provided temporary improvement prior to the patient succumbing to his underlying malignancy. We review the existing reports of mucosal myeloid sarcomas, diagnostic overlap of myeloid sarcoma and AIFS, as well as currently available treatment strategies.

https://ift.tt/2GcY9Gf

Matrix Metalloproteinase 8: Could it Benefit the CAR-T Cell Therapy of Solid Tumors?- a- Commentary on Therapeutic Potential

from Cancer via ola Kala on Inoreader https://ift.tt/2utlT3g
via IFTTT

Matrix Metalloproteinase 8: Could it Benefit the CAR-T Cell Therapy of Solid Tumors?- a- Commentary on Therapeutic Potential

https://ift.tt/2utlT3g

The Importance of the Saphenous Nerve Block for Analgesia Following Major Ankle Surgery: A Randomized, Controlled, Double-Blind Study

Background and Objectives Major ankle surgery causes intense postoperative pain, and whereas the importance of a sciatic nerve block is well established, the clinical significance of a supplemental saphenous nerve block has never been determined in a prospective, randomized, double-blind, placebo-controlled trial. We hypothesized that a saphenous nerve block reduces the proportion of patients experiencing significant clinical pain after major ankle surgery. Methods Eighteen patients were enrolled and received a popliteal sciatic nerve block. Patients were randomized to single-injection saphenous nerve block with 10 mL 0.5% bupivacaine with 1:200,000 epinephrine or 10 mL saline (Fig. 1). Primary outcome was the proportion of patients reporting significant clinical pain, defined as a score greater than 3 on the numerical rating scale. Secondary outcomes were maximal pain and analgesia of the cutaneous territory of the infrapatellar branch of the saphenous nerve. Results Eight of 9 patients in the placebo group reported significant clinical pain versus 1 of 9 patients in the bupivacaine-epinephrine group (P = 0.003). Maximal pain was significantly lower in the active compared with the placebo group (median, 0 [0–0] vs 5 [4–6]; P = 0.001). Breakthrough pain from the saphenous territory began within 30 minutes after surgery in all cases. Sensory testing of the cutaneous territory of the infrapatellar branch of the saphenous nerve showed correlation between pain reported in the anteromedial ankle region and the intensity of cutaneous sensory block in the anteromedial knee region. Conclusions The saphenous nerve is an important contributor to postoperative pain after major ankle surgery, with significant clinical pain appearing within 30 minutes after surgery. Clinical Trials Registration This study has been registered at ClinicalTrials.gov, identifier NCT02697955. Accepted for publication November 20, 2017. Address correspondence to: Thomas Fichtner Bendtsen, MD, PhD, Department of Anesthesiology and Intensive Care Medicine, Aarhus University Hospital, Noerrebrogade 44, DK-8000 Aarhus, Denmark (e-mail: tfb@dadlnet.dk). Funding was received from the A. P. Møller and Chastine Mc-Kinney Møller Foundation. The content is solely the responsibility of the authors. The authors declare no conflict of interest. Copyright © 2018 by American Society of Regional Anesthesia and Pain Medicine.

https://ift.tt/2Gsy05B

Too Deep or Not Too Deep?: A Propensity-Matched Comparison of the Analgesic Effects of a Superficial Versus Deep Serratus Fascial Plane Block for Ambulatory Breast Cancer Surgery

Background and Objectives Serratus fascial plane block can reduce pain following breast surgery, but the question of whether to inject the local anesthetic superficial or deep to the serratus muscle has not been answered. This cohort study compares the analgesic benefits of superficial versus deep serratus plane blocks in ambulatory breast cancer surgery patients at Women's College Hospital between February 2014 and December 2016. We tested the joint hypothesis that deep serratus block is noninferior to superficial serratus block for postoperative in-hospital (pre-discharge) opioid consumption and pain severity. Methods One hundred sixty-six patients were propensity matched among 2 groups (83/group): superficial and deep serratus blocks. The cohort was used to evaluate the effect of blocks on postoperative oral morphine equivalent consumption and area under the curve for rest pain scores. We considered deep serratus block to be noninferior to superficial serratus block if it were noninferior for both outcomes, within 15 mg morphine and 4 cm·h units margins. Other outcomes included intraoperative fentanyl requirements, time to first analgesic request, recovery room stay, and incidence of postoperative nausea and vomiting. Results Deep serratus block was associated with postoperative morphine consumption and pain scores area under the curve that were noninferior to those of the superficial serratus block. Intraoperative fentanyl requirements, time to first analgesic request, recovery room stay, and postoperative nausea and vomiting were not different between blocks. Conclusions The postoperative in-hospital analgesia associated with deep serratus block is as effective (within an acceptable margin) as superficial serratus block following ambulatory breast cancer surgery. These new findings are important to inform both current clinical practices and future prospective studies. Accepted for publication November 27, 2017. Address correspondence to: Faraj W. Abdallah, MD, The Ottawa Hospital General Campus, 501 Smyth Rd, Ottawa, Ontario, Canada K1H 8L6 (e-mail: FAbdallah@toh.ca). This work was supported by departmental funding. F.W.A. and R.B. are supported by the Merit Award Program, Department of Anesthesia, University of Toronto, Toronto, Ontario, Canada. R.B. also receives research support from the Evelyn Bateman Cara Operations Endowed Chair in Ambulatory Anesthesia and Women's Health, Women's College Hospital, Toronto. The authors declare no conflict of interest. Copyright © 2018 by American Society of Regional Anesthesia and Pain Medicine.

https://ift.tt/2Ghk5M2

Proceedings of the Annual Meeting of the Austrian Society of Haematology and Medical Oncology

from Cancer via ola Kala on Inoreader https://ift.tt/2pL5od5
via IFTTT

Proceedings of the Annual Meeting of the Austrian Society of Haematology and Medical Oncology

https://ift.tt/2pL5od5

When a transfusion in an emergency service is not really urgent: hyperhaemolysis syndrome in a child with sickle cell disease

A 13-month-old boy with sickle cell disease (SCD) from Equatorial Guinea, who had recently arrived in Spain, presented with fever. He had suffered from malaria and had received a blood transfusion. Following physical examination and complementary tests, intravenous antibiotics and a red blood cell (RBC) transfusion were administered. Soon after a second transfusion 5 days later, the haemoglobin level fell below pretransfusion levels, together with reticulocytopenia, and haematuria—the so-called hyperhaemolysis syndrome—requiring intensive care and treatment with intravenous immunoglobulins and corticosteroids, with resolution of the complication. We want to emphasise the importance of suspecting this rare, though severe complication that can appear after any RBC transfusion especially in patients with SCD, as the clinical syndrome can simulate other more common complications of these patients and a further transfusion is contraindicated. There is no standardised treatment, but intravenous immunoglobulin and corticosteroids are usually effective.

https://ift.tt/2I4KCNl

Brucellosis accompanied by haemophagocytic lymphohistiocytosis and multiple splenic abscesses in a patient with depression

A 39-year-old woman was being treated for depression in our clinic. She subsequently developed a fever and was diagnosed with pancytopenia and moderate splenomegaly. Laboratory and bone marrow results, including markedly increased serum ferritin levels, suggested haemophagocytic lymphohistiocytosis. CT showed multiple splenic abscesses and ovarian vein thrombosis. All laboratory values returned to normal after treatment for culture-positive brucellosis.

https://ift.tt/2IVBFag

The multiforme of glioblastoma

See article by Mahlokozera et al, pp. 472–483

from Cancer via ola Kala on Inoreader https://ift.tt/2GfdiCE
via IFTTT

Highlights from the Literature

from Cancer via ola Kala on Inoreader https://ift.tt/2ITqVZX
via IFTTT

Forthcoming Meetings

from Cancer via ola Kala on Inoreader https://ift.tt/2pOVoQr
via IFTTT

Drug discovery in neuro-oncology: challenges in the path forward

It is an honor to have been asked to write an editorial for Neuro-Oncology, the highly ranked journal of the Society for Neuro-Oncology (SNO). My goal is to enunciate my vision for what I believe we, as a group dedicated to curing central nervous system (CNS) malignancies, need to achieve.

from Cancer via ola Kala on Inoreader https://ift.tt/2IVdtEY
via IFTTT

Quality improvement in neurology: Neuro-Oncology Quality Measurement Set

[213] All Oncology[120] MRI[109] All Health Services Research[334] All Practice ManagementQuality Measurement

from Cancer via ola Kala on Inoreader https://ift.tt/2pKtMf7
via IFTTT

The multiforme of glioblastoma

See article by Mahlokozera et al, pp. 472–483

https://ift.tt/2GfdiCE

Highlights from the Literature

https://ift.tt/2ITqVZX

Forthcoming Meetings

https://ift.tt/2pOVoQr

Drug discovery in neuro-oncology: challenges in the path forward

It is an honor to have been asked to write an editorial for Neuro-Oncology, the highly ranked journal of the Society for Neuro-Oncology (SNO). My goal is to enunciate my vision for what I believe we, as a group dedicated to curing central nervous system (CNS) malignancies, need to achieve.

https://ift.tt/2IVdtEY

Quality improvement in neurology: Neuro-Oncology Quality Measurement Set

[213] All Oncology[120] MRI[109] All Health Services Research[334] All Practice ManagementQuality Measurement

https://ift.tt/2pKtMf7

How Do Adolescents Affected by Cancer Experience a Hospital Environment?

Journal of Adolescent and Young Adult Oncology, Ahead of Print.


from Cancer via ola Kala on Inoreader https://ift.tt/2GuqGWW
via IFTTT

How Do Adolescents Affected by Cancer Experience a Hospital Environment?

Journal of Adolescent and Young Adult Oncology, Ahead of Print.


https://ift.tt/2GuqGWW

Bevacizumab-induced intestinal perforation in a patient with inoperable breast cancer: a case report and review of the literature

Gastrointestinal perforation is known as a serious adverse event, but, for breast cancer, there are very few reports of gastrointestinal perforation. This report highlights gastrointestinal perforation caused ...

https://ift.tt/2uohZZn

Don't Miss the Connection: The Role of RAF1 and ROKα in RAS-Driven Cancers

Cancer caused by a mutant KRAS gene is dependent on the presence of one of its downstream effectors, RAF1 (aka CRAF), but not on ARAF or BRAF. Kinase-independent interaction of RAF1 with ROKα accounts for at least some of this dependence.

from Cancer via ola Kala on Inoreader https://ift.tt/2DVNI3L
via IFTTT

Don't Miss the Connection: The Role of RAF1 and ROKα in RAS-Driven Cancers

Cancer caused by a mutant KRAS gene is dependent on the presence of one of its downstream effectors, RAF1 (aka CRAF), but not on ARAF or BRAF. Kinase-independent interaction of RAF1 with ROKα accounts for at least some of this dependence.

https://ift.tt/2DVNI3L

Mullerianosis of the Urinary Bladder: A Case Report

Mullerianosis is a rare entity consisting of an admixture of 2 or more of the following tissues: endometriosis, endocervicosis, and endosalpingiosis. It most commonly affects the urinary bladder and affects females of fertile age. It presents clinically as hematuria, dysuria, and pelvic pain which may be associated with menstruation. Radiologically and macroscopically, it typically presents as a polypoid mass in the dome or posterior wall of the bladder. Histologically, it consists of glands of varying size lined by endometrial, endocervical, or tubal epithelium. Mullerianosis clinically and histologically mimics other benign and malignant lesions. Herein we report a case of mullerianosis of the urinary bladder. This is a rare lesion with less than 20 cases reported in the literature thus far. We believe raising awareness of this poorly recognized entity is of utmost significance in order to avoid misdiagnosis and the following unnecessary radical procedures.
Case Rep Oncol 2018;11:206–211

https://ift.tt/2GceZFd

Gemcitabine-Induced Radiation Recall Myositis: Case Report and Review of the Literature

Gemcitabine-induced radiation recall (GIRR) is a phenomenon wherein the administration of gemcitabine induces an inflammatory reaction within an area of prior radiation. We present the case of a 39-year-old female patient with metastatic breast cancer who experienced GIRR myositis 3 months following postoperative radiotherapy, with additional potential paraspinal myositis following ablative radiotherapy to the thoracic spine. A review of previously published cases of GIRR myositis was performed. The case and literature review describe the clinical course and presentation of GIRR, and highlight the importance of including radiation recall as part of a differential diagnosis when a patient undergoing chemotherapy experiences an inflammatory reaction at a prior site of radiation.
Case Rep Oncol 2018;11:168–178

https://ift.tt/2pMKdYb

Forging Military Partnerships to Empower the Cancer Research Enterprise

Partnerships and collaborations are an important component of NCI's success. NCI Director Dr. Norman Sharpless describes three efforts made possible by a memorandum of agreement with three US military institutions: the APOLLO network, NAVIGATE, and BD-STEP.

https://ift.tt/2DZ5Eum

Forging Military Partnerships to Empower the Cancer Research Enterprise

Partnerships and collaborations are an important component of NCI's success. NCI Director Dr. Norman Sharpless describes three efforts made possible by a memorandum of agreement with three US military institutions: the APOLLO network, NAVIGATE, and BD-STEP.

from Cancer via ola Kala on Inoreader https://ift.tt/2DZ5Eum
via IFTTT

Clinical characteristics and management of gastric tube cancer after esophagectomy

Abstract

Background

Gastric cancer is the second most common malignancy, overlapping with thoracic esophageal cancer (TEC). Among them, metachronous gastric tube cancers after TEC surgery have been increasing. The aims of this study were to examine the clinicopathological factors and treatment outcomes of gastric tube cancer (GTC) after TEC surgery.

Methods

Thirty-three GTCs in 30 cases after TEC treated between 1997 and 2016 were investigated retrospectively.

Results

Most cases were males. The median interval from TEC surgery to GTC occurrence was 57 (6.5–107.5) months. Almost 2/3 lesions occurred in the lower third of the gastric tube (21/33); 29 lesions (in 26 cases) were superficial cancers, and 4 lesions were advanced cancers. Twenty-two lesions of superficial cancer were differentiated type, and the remaining seven lesions were undifferentiated type. Treatment for superficial cancer had previously been performed with partial gastric tube resection (10 lesions), and the number of cases undergoing endoscopic submucosal dissection (ESD) had increased recently (19 lesions). Most cases with superficial cancer survived without relapse. Four lesions of advanced cancer were found after a relatively long interval following TEC surgery. Most lesions of advanced cancer were scirrhous, undifferentiated type, and they died due to GTC.

Conclusion

GTCs may occur late in the postoperative course following TEC surgery. If they are discovered at an early stage, these lesions can be cured with ESD. Long-term periodic endoscopic examinations after TEC surgery are important.

from Cancer via ola Kala on Inoreader https://ift.tt/2ITpomK
via IFTTT

Cancers, Vol. 10, Pages 92: Loss of One or Two PATZ1 Alleles Has a Critical Role in the Progression of Thyroid Carcinomas Induced by the RET/PTC1 Oncogene

Cancers, Vol. 10, Pages 92: Loss of One or Two PATZ1 Alleles Has a Critical Role in the Progression of Thyroid Carcinomas Induced by the RET/PTC1 Oncogene

Cancers doi: 10.3390/cancers10040092

Authors: Mario Monaco Giuseppe Palma Michela Vitiello Anna Capiluongo Barbara D'Andrea Emilia Vuttariello Antonio Luciano Laura Cerchia Gennaro Chiappetta Claudio Arra Alfredo Fusco Monica Fedele

POZ/BTB and AT-hook-containing zinc finger protein 1 (PATZ1) is an emerging cancer-related gene that is downregulated in different human malignancies, including thyroid cancer, where its levels gradually decrease going from papillary thyroid carcinomas (PTC) to poorly differentiated and undifferentiated highly aggressive anaplastic carcinomas (ATC). The restoration of PATZ1 expression in thyroid cancer cells reverted their malignant phenotype by inducing mesenchymal-to-epithelial transition, thus validating a tumor suppressor role for PATZ1 and suggesting its involvement in thyroid cancer progression. Here, we investigated the consequences of the homozygous and heterozygous loss of PATZ1 in the context of a mouse modeling of PTC, represented by mice carrying the RET/PTC1 oncogene under the thyroid specific control of the thyroglobulin promoter RET/PTC1 (RET/PTC1TG). The phenotypic analysis of RET/PTC1TG mice intercrossed with Patz1-knockout mice revealed that deficiency of both Patz1 alleles enhanced thyroid cancer incidence in RET/PTC1TG mice, but not the heterozygous knockout of the Patz1 gene. However, both RET/PTC1TG;Patz1+/− and RET/PTC1TG;Patz1−/− mice developed a more aggressive thyroid cancer phenotype—characterized by higher Ki-67 expression, presence of ATCs, and increased incidence of solid variants of PTC—than that shown by RET/PTC1TG; Patz1+/+ compound mice. These results confirm that PATZ1 downregulation has a critical role in thyroid carcinogenesis, showing that it cooperates with RET/PTC1 in thyroid cancer progression.

from Cancer via ola Kala on Inoreader https://ift.tt/2utlhea
via IFTTT

Clinical characteristics and management of gastric tube cancer after esophagectomy

Abstract

Background

Gastric cancer is the second most common malignancy, overlapping with thoracic esophageal cancer (TEC). Among them, metachronous gastric tube cancers after TEC surgery have been increasing. The aims of this study were to examine the clinicopathological factors and treatment outcomes of gastric tube cancer (GTC) after TEC surgery.

Methods

Thirty-three GTCs in 30 cases after TEC treated between 1997 and 2016 were investigated retrospectively.

Results

Most cases were males. The median interval from TEC surgery to GTC occurrence was 57 (6.5–107.5) months. Almost 2/3 lesions occurred in the lower third of the gastric tube (21/33); 29 lesions (in 26 cases) were superficial cancers, and 4 lesions were advanced cancers. Twenty-two lesions of superficial cancer were differentiated type, and the remaining seven lesions were undifferentiated type. Treatment for superficial cancer had previously been performed with partial gastric tube resection (10 lesions), and the number of cases undergoing endoscopic submucosal dissection (ESD) had increased recently (19 lesions). Most cases with superficial cancer survived without relapse. Four lesions of advanced cancer were found after a relatively long interval following TEC surgery. Most lesions of advanced cancer were scirrhous, undifferentiated type, and they died due to GTC.

Conclusion

GTCs may occur late in the postoperative course following TEC surgery. If they are discovered at an early stage, these lesions can be cured with ESD. Long-term periodic endoscopic examinations after TEC surgery are important.

https://ift.tt/2ITpomK

Cancers, Vol. 10, Pages 92: Loss of One or Two PATZ1 Alleles Has a Critical Role in the Progression of Thyroid Carcinomas Induced by the RET/PTC1 Oncogene

Cancers, Vol. 10, Pages 92: Loss of One or Two PATZ1 Alleles Has a Critical Role in the Progression of Thyroid Carcinomas Induced by the RET/PTC1 Oncogene

Cancers doi: 10.3390/cancers10040092

Authors: Mario Monaco Giuseppe Palma Michela Vitiello Anna Capiluongo Barbara D'Andrea Emilia Vuttariello Antonio Luciano Laura Cerchia Gennaro Chiappetta Claudio Arra Alfredo Fusco Monica Fedele

POZ/BTB and AT-hook-containing zinc finger protein 1 (PATZ1) is an emerging cancer-related gene that is downregulated in different human malignancies, including thyroid cancer, where its levels gradually decrease going from papillary thyroid carcinomas (PTC) to poorly differentiated and undifferentiated highly aggressive anaplastic carcinomas (ATC). The restoration of PATZ1 expression in thyroid cancer cells reverted their malignant phenotype by inducing mesenchymal-to-epithelial transition, thus validating a tumor suppressor role for PATZ1 and suggesting its involvement in thyroid cancer progression. Here, we investigated the consequences of the homozygous and heterozygous loss of PATZ1 in the context of a mouse modeling of PTC, represented by mice carrying the RET/PTC1 oncogene under the thyroid specific control of the thyroglobulin promoter RET/PTC1 (RET/PTC1TG). The phenotypic analysis of RET/PTC1TG mice intercrossed with Patz1-knockout mice revealed that deficiency of both Patz1 alleles enhanced thyroid cancer incidence in RET/PTC1TG mice, but not the heterozygous knockout of the Patz1 gene. However, both RET/PTC1TG;Patz1+/− and RET/PTC1TG;Patz1−/− mice developed a more aggressive thyroid cancer phenotype—characterized by higher Ki-67 expression, presence of ATCs, and increased incidence of solid variants of PTC—than that shown by RET/PTC1TG; Patz1+/+ compound mice. These results confirm that PATZ1 downregulation has a critical role in thyroid carcinogenesis, showing that it cooperates with RET/PTC1 in thyroid cancer progression.

https://ift.tt/2utlhea

Pediatric Langerhans cell histiocytosis of the temporal bone: clinical and imaging studies of 27 cases

Abstract

Background

We aimed to evaluate the clinical and imaging presentations of Langerhans cell histiocytosis (LCH) in the pediatric temporal bone.

Methods

This retrospective study included 27 pediatric cases with pathological confirmed LCH of the temporal bone. The clinical and imaging features of the cases were analyzed. The involvement of ossicular chain and otic capsule was also evaluated.

Results

A total of 38 lesions (27 cases) with 11 bilateral involvement were identified. For the 27 cases, the most common complaint was periauricular swelling (12/27, 44.4%), followed by otorrhea (9/27, 33.3%) and otalgia (5/27, 18.2%). The mastoid process was the most common involved subsite (31/38, 81.6%) among the 38 lesions. Ten (26.3%, 10/38) lesions belonged to the group of the diffuse involvement, 22 (57.9%, 22/38) were divided into the group of partial involvement and six (15.8%,6/38) localized lesions with punched-out appearance. Erosion of ossicular chains and otic capsule were found in three and seven lesions respectively.

Conclusion

The results indicate that the most common subsite for LCH of the pediatric temporal bone was the mastoid process. The location and extent of pediatric LCH of the temporal bone varied a lot between each other. The ossicular chains usually remain intact and the erosion of otic capsule can occur in some lesions.

https://ift.tt/2pInugM

Pediatric Langerhans cell histiocytosis of the temporal bone: clinical and imaging studies of 27 cases

Abstract

Background

We aimed to evaluate the clinical and imaging presentations of Langerhans cell histiocytosis (LCH) in the pediatric temporal bone.

Methods

This retrospective study included 27 pediatric cases with pathological confirmed LCH of the temporal bone. The clinical and imaging features of the cases were analyzed. The involvement of ossicular chain and otic capsule was also evaluated.

Results

A total of 38 lesions (27 cases) with 11 bilateral involvement were identified. For the 27 cases, the most common complaint was periauricular swelling (12/27, 44.4%), followed by otorrhea (9/27, 33.3%) and otalgia (5/27, 18.2%). The mastoid process was the most common involved subsite (31/38, 81.6%) among the 38 lesions. Ten (26.3%, 10/38) lesions belonged to the group of the diffuse involvement, 22 (57.9%, 22/38) were divided into the group of partial involvement and six (15.8%,6/38) localized lesions with punched-out appearance. Erosion of ossicular chains and otic capsule were found in three and seven lesions respectively.

Conclusion

The results indicate that the most common subsite for LCH of the pediatric temporal bone was the mastoid process. The location and extent of pediatric LCH of the temporal bone varied a lot between each other. The ossicular chains usually remain intact and the erosion of otic capsule can occur in some lesions.

from Cancer via ola Kala on Inoreader https://ift.tt/2pInugM
via IFTTT

Inflammatory interferon activates HIF-1α-mediated epithelial-to-mesenchymal transition via PI3K/AKT/mTOR pathway

Tumor microenvironments (TMEs) activate various axes/pathways, predominantly inflammatory and hypoxic responses, impact tumorigenesis, metastasis and therapeutic resistance significantly. Although molecular pa...

from Cancer via ola Kala on Inoreader https://ift.tt/2Gdrss0
via IFTTT

Inhibiting YAP expression suppresses pancreatic cancer progression by disrupting tumor-stromal interactions

Hippo/YAP pathway is known to be important for development, growth and organogenesis, and dysregulation of this pathway leads to tumor progression. We and others find that YAP is up-regulated in pancreatic duc...

from Cancer via ola Kala on Inoreader https://ift.tt/2ul2b9M
via IFTTT

miR-148b-3p inhibits gastric cancer metastasis by inhibiting the Dock6/Rac1/Cdc42 axis

Our previous work showed that some Rho GTPases, including Rho, Rac1 and Cdc42, play critical roles in gastric cancer (GC); however, how they are regulated in GC remains largely unknown. In this study, we aimed...

from Cancer via ola Kala on Inoreader https://ift.tt/2Geaude
via IFTTT

Treatment of B-cell precursor acute lymphoblastic leukemia with the Galectin-1 inhibitor PTX008

Drug resistance of B-cell precursor acute lymphoblastic leukemia (BP-ALL) cells is conferred by both intrinsic and extrinsic factors, which could be targeted to promote chemo-sensitization. Our previous studie...

from Cancer via ola Kala on Inoreader https://ift.tt/2ul2aCK
via IFTTT

5′/ 3′ imbalance strategy to detect ALK fusion genes in circulating tumor RNA from patients with non-small cell lung cancer

Detecting an ALK fusion gene in patients with non-small cell lung cancer (NSCLC) could provide evidence to guide individualized therapy.

from Cancer via ola Kala on Inoreader https://ift.tt/2Gbe085
via IFTTT

The anti-tumor efficacy of CDK4/6 inhibition is enhanced by the combination with PI3K/AKT/mTOR inhibitors through impairment of glucose metabolism in TNBC cells

Abstract

Background

Cell cycle regulators have gain attention as potential targets for anticancer therapy. Palbociclib is a selective inhibitor of the cyclin-dependent kinases 4 and 6 (CDK4/6), which coordinate the G1-S transition. Palbociclib is currently approved for the treatment of hormone receptor positive, HER2-negative advanced breast cancer (BC) in association with letrozole or fulvestrant. In contrast, its efficacy in triple negative BC (TNBC), either alone or in combined therapies, has not been fully investigated to date.

Methods

Here we evaluated the potential of combining palbociclib with PI3K/mTOR inhibitors in Rb-proficient TNBC cells comparing different schedules of treatment: simultaneous, sequential, or sequential combined treatment (pre-incubation with palbociclib followed by exposure to both palbociclib and PI3K/mTOR inhibitors). We assessed the effects on cell proliferation, cell death, and cell cycle distribution, and looked at the impact of such treatments on glucose metabolism.

Results

Palbociclib exerted cytostatic effects in Rb-positive TNBC cells, inducing a reversible blockade in G0/G1 cell cycle phase associated with down-regulation of CDK6, Rb, and c-myc expression and/or activity. Palbociclib treatment induced AKT signaling, providing a rationale for its combination with PI3K/mTOR inhibitors. The simultaneous or sequential treatment resulted in an additive inhibition of cell proliferation. On the other hand, the sequential combined treatment in which palbociclib was maintained also during exposure to PI3K/mTOR inhibitors gave rise to synergistic anti-proliferative and pro-apoptotic effects, by inhibiting both CDK4/6/Rb/myc and PI3K/mTOR signaling. Interestingly, the inhibition of the Rb/E2F/myc axis mediated by palbociclib resulted in a significant down-regulation of glucose metabolism; most importantly, these inhibitory effects were enhanced by the combination of palbociclib with BYL719 (specific inhibitor of the p110α PI3K-subunit), which promoted a stronger inhibition of GLUT-1 glucose transporter expression, glucose uptake and consumption in comparison with individual treatments, under both normoxic and hypoxic conditions.

Conclusions

Combination of palbociclib with PI3K/mTOR inhibitors may represent a promising therapeutic option for the treatment of Rb-proficient TNBC, with the sequential combined schedule showing a superior efficacy over the other schedules. In addition our results demonstrate that the impairment of glucose metabolism may contribute to the anti-tumor activity of such drug combinations.

from Cancer via ola Kala on Inoreader https://ift.tt/2pIjM6Z
via IFTTT

miR-148b-3p inhibits gastric cancer metastasis by inhibiting the Dock6/Rac1/Cdc42 axis

Abstract

Background

Our previous work showed that some Rho GTPases, including Rho, Rac1 and Cdc42, play critical roles in gastric cancer (GC); however, how they are regulated in GC remains largely unknown. In this study, we aimed to investigate the roles and molecular mechanisms of Dock6, an atypical Rho guanine nucleotide exchange factor (GEF), in GC metastasis.

Methods

The expression levels of Dock6 and miR-148b-3p in GC tissues and paired nontumor tissues were determined by immunohistochemistry (IHC) and in situ hybridization (ISH), respectively. The correlation between Dock6/miR-148b-3p expression and the overall survival of GC patients was calculated by the Kaplan-Meier method and log-rank test. The roles of Dock6 and miR-148b-3p in GC were investigated by in vitro and in vivo functional studies. Rac1 and Cdc42 activation was investigated by GST pull-down assays. The inhibition of Dock6 transcription by miR-148b-3p was determined by luciferase reporter assays.

Results

A significant increase in Dock6 expression was found in GC tissues compared with nontumor tissues, and its positive expression was associated with lymph node metastasis and a higher TNM stage. Patients with positive Dock6 expression exhibited shorter overall survival periods than patients with negative Dock6 expression. Dock6 promoted GC migration and invasion by increasing the activation of Rac1 and Cdc42. miR-148b-3p expression was negatively correlated with Dock6 expression in GC, and it decreased the motility of GC cells by inhibiting the Dock6/Rac1/Cdc42 axis.

Conclusions

Dock6 was over-expressed in GC tissues, and its positive expression was associated with GC metastasis and indicated poor prognosis of GC patients. Targeting of Dock6 by miR-148b-3p could activate Rac1 and Cdc42, directly affecting the motility of GC cells. Targeting the Dock6-Rac1/Cdc42 axis could serve as a new therapeutic strategy for GC treatment.

from Cancer via ola Kala on Inoreader https://ift.tt/2uqsn2M
via IFTTT

The anti-tumor efficacy of CDK4/6 inhibition is enhanced by the combination with PI3K/AKT/mTOR inhibitors through impairment of glucose metabolism in TNBC cells

Abstract

Background

Cell cycle regulators have gain attention as potential targets for anticancer therapy. Palbociclib is a selective inhibitor of the cyclin-dependent kinases 4 and 6 (CDK4/6), which coordinate the G1-S transition. Palbociclib is currently approved for the treatment of hormone receptor positive, HER2-negative advanced breast cancer (BC) in association with letrozole or fulvestrant. In contrast, its efficacy in triple negative BC (TNBC), either alone or in combined therapies, has not been fully investigated to date.

Methods

Here we evaluated the potential of combining palbociclib with PI3K/mTOR inhibitors in Rb-proficient TNBC cells comparing different schedules of treatment: simultaneous, sequential, or sequential combined treatment (pre-incubation with palbociclib followed by exposure to both palbociclib and PI3K/mTOR inhibitors). We assessed the effects on cell proliferation, cell death, and cell cycle distribution, and looked at the impact of such treatments on glucose metabolism.

Results

Palbociclib exerted cytostatic effects in Rb-positive TNBC cells, inducing a reversible blockade in G0/G1 cell cycle phase associated with down-regulation of CDK6, Rb, and c-myc expression and/or activity. Palbociclib treatment induced AKT signaling, providing a rationale for its combination with PI3K/mTOR inhibitors. The simultaneous or sequential treatment resulted in an additive inhibition of cell proliferation. On the other hand, the sequential combined treatment in which palbociclib was maintained also during exposure to PI3K/mTOR inhibitors gave rise to synergistic anti-proliferative and pro-apoptotic effects, by inhibiting both CDK4/6/Rb/myc and PI3K/mTOR signaling. Interestingly, the inhibition of the Rb/E2F/myc axis mediated by palbociclib resulted in a significant down-regulation of glucose metabolism; most importantly, these inhibitory effects were enhanced by the combination of palbociclib with BYL719 (specific inhibitor of the p110α PI3K-subunit), which promoted a stronger inhibition of GLUT-1 glucose transporter expression, glucose uptake and consumption in comparison with individual treatments, under both normoxic and hypoxic conditions.

Conclusions

Combination of palbociclib with PI3K/mTOR inhibitors may represent a promising therapeutic option for the treatment of Rb-proficient TNBC, with the sequential combined schedule showing a superior efficacy over the other schedules. In addition our results demonstrate that the impairment of glucose metabolism may contribute to the anti-tumor activity of such drug combinations.

https://ift.tt/2pIjM6Z

miR-148b-3p inhibits gastric cancer metastasis by inhibiting the Dock6/Rac1/Cdc42 axis

Abstract

Background

Our previous work showed that some Rho GTPases, including Rho, Rac1 and Cdc42, play critical roles in gastric cancer (GC); however, how they are regulated in GC remains largely unknown. In this study, we aimed to investigate the roles and molecular mechanisms of Dock6, an atypical Rho guanine nucleotide exchange factor (GEF), in GC metastasis.

Methods

The expression levels of Dock6 and miR-148b-3p in GC tissues and paired nontumor tissues were determined by immunohistochemistry (IHC) and in situ hybridization (ISH), respectively. The correlation between Dock6/miR-148b-3p expression and the overall survival of GC patients was calculated by the Kaplan-Meier method and log-rank test. The roles of Dock6 and miR-148b-3p in GC were investigated by in vitro and in vivo functional studies. Rac1 and Cdc42 activation was investigated by GST pull-down assays. The inhibition of Dock6 transcription by miR-148b-3p was determined by luciferase reporter assays.

Results

A significant increase in Dock6 expression was found in GC tissues compared with nontumor tissues, and its positive expression was associated with lymph node metastasis and a higher TNM stage. Patients with positive Dock6 expression exhibited shorter overall survival periods than patients with negative Dock6 expression. Dock6 promoted GC migration and invasion by increasing the activation of Rac1 and Cdc42. miR-148b-3p expression was negatively correlated with Dock6 expression in GC, and it decreased the motility of GC cells by inhibiting the Dock6/Rac1/Cdc42 axis.

Conclusions

Dock6 was over-expressed in GC tissues, and its positive expression was associated with GC metastasis and indicated poor prognosis of GC patients. Targeting of Dock6 by miR-148b-3p could activate Rac1 and Cdc42, directly affecting the motility of GC cells. Targeting the Dock6-Rac1/Cdc42 axis could serve as a new therapeutic strategy for GC treatment.

https://ift.tt/2uqsn2M

The Effect of Evidence-Based Nutrition Clinical Care Pathways on Nutrition Outcomes in Adult Patients Receiving Non-Surgical Cancer Treatment: A Systematic Review.

The Effect of Evidence-Based Nutrition Clinical Care Pathways on Nutrition Outcomes in Adult Patients Receiving Non-Surgical Cancer Treatment: A Systematic Review.

Nutr Cancer. 2018 Mar 26;:1-9

Authors: Dewar SL, Porter J

Abstract
Nutritional decline associated with non-surgical cancer treatment has been well documented. The implementation of an evidence-based nutrition care pathway is one approach suggested to improve the nutrition outcomes of this group of patients. We aimed to systematically review published original research to determine whether evidence-based nutrition clinical care pathways, as compared with usual care, improve outcomes for patients receiving non-surgical cancer treatment. The review was registered with PROSPERO (CRD42017048816) and followed PRISMA guidelines. The search strategy was conducted in four databases, and supplemented by an internet search, from inception to October 2016. Study quality was assessed using the Quality Criteria Checklist for Primary Research. Results were synthesized descriptively. Six reports of five studies formed the final library with a range of interventions and control practices investigated across several diagnostic groups. Nutrition outcomes were reported using multiple approaches with either no effect, or in favor of the clinical pathway intervention. Risk of bias was low in two studies with some risk in the remaining three studies. It was not possible to determine whether the effect on nutritional outcomes was attributable to care pathway implementation. The need to extend the evidence base through high-quality clinical trials was evident.

PMID: 29578816 [PubMed - as supplied by publisher]

https://ift.tt/2GbBfPp

Mechanisms of Phytonutrient Modulation of Cyclooxygenase-2 (COX-2) and Inflammation Related to Cancer.

Mechanisms of Phytonutrient Modulation of Cyclooxygenase-2 (COX-2) and Inflammation Related to Cancer.

Nutr Cancer. 2018 Mar 26;:1-26

Authors: Desai SJ, Prickril B, Rasooly A

Abstract
The link between chronic inflammation and cancer involves cytokines and mediators of inflammatory pathways. Cyclooxygenase-2 (COX-2), a key enzyme in fatty acid metabolism, is upregulated during both inflammation and cancer. COX-2 is induced by pro-inflammatory cytokines at the site of inflammation and enhanced COX-2-induced synthesis of prostaglandins stimulates cancer cell proliferation, promotes angiogenesis, inhibits apoptosis, and increases metastatic potential. As a result, COX-2 inhibitors are a subject of intense research interest toward potential clinical applications. Epidemiological studies highlight the potential benefits of diets rich in phytonutrients for cancer prevention. Plants contain numerous phytonutrient secondary metabolites shown to modulate COX-2. Studies have shown that these metabolites, some of which are used in traditional medicine, can reduce inflammation and carcinogenesis. This review describes the molecular mechanisms by which phytonutrients modulate inflammation, including studies of carotenoids, phenolic compounds, and fatty acids targeting various inflammation-related molecules and pathways associated with cancer. Examples of pathways include those of COX-2, mitogen-activated protein kinase kinase kinase, mitogen-activated protein kinase, pro-inflammatory cytokines, and transcription factors like nuclear factor kappa B. Such phytonutrient modulation of COX-2 and inflammation continue to be explored for applications in the prevention and treatment of cancer.

PMID: 29578814 [PubMed - as supplied by publisher]

https://ift.tt/2pKAe5B

The Effect of Evidence-Based Nutrition Clinical Care Pathways on Nutrition Outcomes in Adult Patients Receiving Non-Surgical Cancer Treatment: A Systematic Review.

The Effect of Evidence-Based Nutrition Clinical Care Pathways on Nutrition Outcomes in Adult Patients Receiving Non-Surgical Cancer Treatment: A Systematic Review.

Nutr Cancer. 2018 Mar 26;:1-9

Authors: Dewar SL, Porter J

Abstract
Nutritional decline associated with non-surgical cancer treatment has been well documented. The implementation of an evidence-based nutrition care pathway is one approach suggested to improve the nutrition outcomes of this group of patients. We aimed to systematically review published original research to determine whether evidence-based nutrition clinical care pathways, as compared with usual care, improve outcomes for patients receiving non-surgical cancer treatment. The review was registered with PROSPERO (CRD42017048816) and followed PRISMA guidelines. The search strategy was conducted in four databases, and supplemented by an internet search, from inception to October 2016. Study quality was assessed using the Quality Criteria Checklist for Primary Research. Results were synthesized descriptively. Six reports of five studies formed the final library with a range of interventions and control practices investigated across several diagnostic groups. Nutrition outcomes were reported using multiple approaches with either no effect, or in favor of the clinical pathway intervention. Risk of bias was low in two studies with some risk in the remaining three studies. It was not possible to determine whether the effect on nutritional outcomes was attributable to care pathway implementation. The need to extend the evidence base through high-quality clinical trials was evident.

PMID: 29578816 [PubMed - as supplied by publisher]

from Cancer via ola Kala on Inoreader https://ift.tt/2GbBfPp
via IFTTT

Mechanisms of Phytonutrient Modulation of Cyclooxygenase-2 (COX-2) and Inflammation Related to Cancer.

Mechanisms of Phytonutrient Modulation of Cyclooxygenase-2 (COX-2) and Inflammation Related to Cancer.

Nutr Cancer. 2018 Mar 26;:1-26

Authors: Desai SJ, Prickril B, Rasooly A

Abstract
The link between chronic inflammation and cancer involves cytokines and mediators of inflammatory pathways. Cyclooxygenase-2 (COX-2), a key enzyme in fatty acid metabolism, is upregulated during both inflammation and cancer. COX-2 is induced by pro-inflammatory cytokines at the site of inflammation and enhanced COX-2-induced synthesis of prostaglandins stimulates cancer cell proliferation, promotes angiogenesis, inhibits apoptosis, and increases metastatic potential. As a result, COX-2 inhibitors are a subject of intense research interest toward potential clinical applications. Epidemiological studies highlight the potential benefits of diets rich in phytonutrients for cancer prevention. Plants contain numerous phytonutrient secondary metabolites shown to modulate COX-2. Studies have shown that these metabolites, some of which are used in traditional medicine, can reduce inflammation and carcinogenesis. This review describes the molecular mechanisms by which phytonutrients modulate inflammation, including studies of carotenoids, phenolic compounds, and fatty acids targeting various inflammation-related molecules and pathways associated with cancer. Examples of pathways include those of COX-2, mitogen-activated protein kinase kinase kinase, mitogen-activated protein kinase, pro-inflammatory cytokines, and transcription factors like nuclear factor kappa B. Such phytonutrient modulation of COX-2 and inflammation continue to be explored for applications in the prevention and treatment of cancer.

PMID: 29578814 [PubMed - as supplied by publisher]

from Cancer via ola Kala on Inoreader https://ift.tt/2pKAe5B
via IFTTT

Knowledge-based IMRT planning for individual liver cancer patients using a novel specific model

The purpose of this work is to benchmark RapidPlan against clinical plans for liver Intensity-modulated radiotherapy (IMRT) treatment of patients with special anatomical characteristics, and to investigate the...

from Cancer via ola Kala on Inoreader https://ift.tt/2uoUbVb
via IFTTT

Comparison of efficacy and safety of preoperative Chemoradiotherapy in locally advanced upper and middle/lower rectal cancer

We aimed to explore the efficacy and safety profile of preoperative neoadjuvant chemoradiation (NACRT) in locally advanced rectal cancer (LARC) in upper rectum versus middle/lower rectum.

from Cancer via ola Kala on Inoreader https://ift.tt/2pJhhBp
via IFTTT