Refined estimates of local recurrence risks by DCIS score adjusting for clinicopathological features: a combined analysis of ECOG-ACRIN E5194 and Ontario DCIS cohort studies

Abstract

Purpose

Better tools are needed to estimate local recurrence (LR) risk after breast-conserving surgery (BCS) for DCIS. The DCIS score (DS) was validated as a predictor of LR in E5194 and Ontario DCIS cohort (ODC) after BCS. We combined data from E5194 and ODC adjusting for clinicopathological factors to provide refined estimates of the 10-year risk of LR after treatment by BCS alone.

Methods

Data from E5194 and ODC were combined. Patients with positive margins or multifocality were excluded. Identical Cox regression models were fit for each study. Patient-specific meta-analysis was used to calculate precision-weighted estimates of 10-year LR risk by DS, age, tumor size and year of diagnosis.

Results

The combined cohort includes 773 patients. The DS and age at diagnosis, tumor size and year of diagnosis provided independent prognostic information on the 10-year LR risk (p ≤ 0.009). Hazard ratios from E5194 and ODC cohorts were similar for the DS (2.48, 1.95 per 50 units), tumor size ≤ 1 versus  > 1–2.5 cm (1.45, 1.47), age ≥ 50 versus < 50 year (0.61, 0.84) and year ≥ 2000 (0.67, 0.49). Utilization of DS combined with tumor size and age at diagnosis predicted more women with very low (≤ 8%) or higher (> 15%) 10-year LR risk after BCS alone compared to utilization of DS alone or clinicopathological factors alone.

Conclusions

The combined analysis provides refined estimates of 10-year LR risk after BCS for DCIS. Adding information on tumor size and age at diagnosis to the DS adjusting for year of diagnosis provides improved LR risk estimates to guide treatment decision making.

http://ift.tt/2Fvk86g

Biomarkers in Graft-Versus-Host Disease: from Prediction and Diagnosis to Insights into Complex Graft/Host Interactions

Abstract

Purpose of Review

Acute graft versus host disease (aGVHD) is a frequent cause of treatment-related mortality after allogeneic hematopoietic stem cell transplantation (alloHCT), with few effective treatment options beyond systemic steroids. Discovery of biomarkers for aGVHD may provide insight into the pathophysiology of aGVHD and suggest novel mechanisms for treatment.

Recent Findings

We highlight biomarkers within innate immune activation, T-cell-mediated tissue damage, endothelial damage, dysbiosis, and poor wound healing that can be obtained prior to transplant, in the early transplant period, or at the onset of aGVHD.

Summary

aGVHD biomarkers have predictive and prognostic utility but also suggest novel mechanisms of recipient tissue damage and impaired regenerative capacity. These mechanisms should be further studied and tested in therapeutic clinical trials to improve outcomes post-alloHCT.

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

Biomarkers in Graft-Versus-Host Disease: from Prediction and Diagnosis to Insights into Complex Graft/Host Interactions

Abstract

Purpose of Review

Acute graft versus host disease (aGVHD) is a frequent cause of treatment-related mortality after allogeneic hematopoietic stem cell transplantation (alloHCT), with few effective treatment options beyond systemic steroids. Discovery of biomarkers for aGVHD may provide insight into the pathophysiology of aGVHD and suggest novel mechanisms for treatment.

Recent Findings

We highlight biomarkers within innate immune activation, T-cell-mediated tissue damage, endothelial damage, dysbiosis, and poor wound healing that can be obtained prior to transplant, in the early transplant period, or at the onset of aGVHD.

Summary

aGVHD biomarkers have predictive and prognostic utility but also suggest novel mechanisms of recipient tissue damage and impaired regenerative capacity. These mechanisms should be further studied and tested in therapeutic clinical trials to improve outcomes post-alloHCT.

http://ift.tt/2rOEOEi

Angiogenesis enhanced by treatment damage to hepatocellular carcinoma through the release of GDF15

Abstract

Transarterial chemoembolization (TACE) is the standard treatment for unresectable hepatocellular carcinoma (HCC). Hypoxia-induced angiogenesis by TACE is linked to treatment failure; however, whether the chemotherapeutic damage of TACE to HCC could increase tumor angiogenesis has not been explored. The molecular effects of chemotherapy-damaged HCC cells on the neo-angiogenesis were investigated in vitro and in vivo. The expression of growth differentiation factor 15 (GDF15) was significantly upregulated in HCC cells exposed to chemotherapeutic agents. GDF15 from chemotherapy-damaged HCC cells promoted the in vitro proliferation, migration, and tube formation of endothelial cells. The pro-angiogenic effect of GDF15 was through the activation of Src and its downstream AKT, MAPK, and NF-κB signaling, which was blocked by thalidomide. The use of thalidomide significantly attenuated the in vivo chemotherapy-damaged HCC cells-promoted angiogenesis in nude mice. In conclusion, the chemotherapeutic damage in TACE to HCC could promote tumor angiogenesis via the increased release of GDF15. Thalidomide could reverse these pro-angiogenic effects.

Chemotherapeutic damage to hepatocellular carcinoma promotes tumor angiogenesis via the increased release of GDF15. Thalidomide could reverse these pro-angiogenic effects.

http://ift.tt/2Gx24Kd

Effectiveness of modified hyper-CVAD chemotherapy regimen in the treatment of adult acute lymphoblastic leukemia: a retrospective experience

Abstract

Several chemotherapy regimens have been developed for the treatment of acute lymphoblastic leukemia (ALL), but relapse still presents the most common obstacles to attaining long-term survival. The hyper-CVAD (hyperfractionated cyclophosphamide, vincristine, doxorubicin, and prednisolone)/HD MTX and Ara-C (high-dose methotrexate and cytarabine) chemotherapy regimen was first started in the MD Anderson Cancer Center as an intensive regimen for adult patients with ALL. The purpose of this study was to evaluate the effectiveness of a modified hyper-CVAD protocol. We used hyper-CVAD as consolidation/maintenance after remission induction with daunorubicin, vincristine, and prednisolone (and cyclophosphamide for T-cell ALL only) rather than standard hyper-CVAD in order to reduce treatment complications. This study was conducted as a retrospective review of medical records of ALL patients at 501 army hospital, Tehran, Iran, from 2005 to 2015. Three hundred and one patients underwent modified hyper-CVAD chemotherapy regimen. Complete remission and overall survival (OS) rates were measured as primary endpoints. Two hundred and forty-six (81.7%) reached complete remission (CR) during the first 6 months of treatment, and 55 patients (18.3%) did not reach CR. The 5-year OS rate was 51.8% (95% CI (confidence interval): 45.1–57.8%). Modified hyper-CVAD regimen is an efficient intensive chemotherapy regimen for consolidation/maintenance of adults with newly diagnosed ALL and has an acceptable 5-year overall that is comparable to standard hyper-CVAD regimen.

We used a modified hyper-CVAD protocol to reduce treatment-related mortality and simultaneously reach an acceptable overall survival in patients with adult ALL. The results were promising, and it seems that this protocol could be of great benefit for ALL patients.

http://ift.tt/2rTJcSw

Novel applications for an established antimalarial drug: tumoricidal activity of quinacrine

Future Oncology, Ahead of Print.


http://ift.tt/2DRlAnn

CPX-351: changing the landscape of treatment for patients with secondary acute myeloid leukemia

Future Oncology, Ahead of Print.


http://ift.tt/2nsWSP3

Angiogenesis enhanced by treatment damage to hepatocellular carcinoma through the release of GDF15

Abstract

Transarterial chemoembolization (TACE) is the standard treatment for unresectable hepatocellular carcinoma (HCC). Hypoxia-induced angiogenesis by TACE is linked to treatment failure; however, whether the chemotherapeutic damage of TACE to HCC could increase tumor angiogenesis has not been explored. The molecular effects of chemotherapy-damaged HCC cells on the neo-angiogenesis were investigated in vitro and in vivo. The expression of growth differentiation factor 15 (GDF15) was significantly upregulated in HCC cells exposed to chemotherapeutic agents. GDF15 from chemotherapy-damaged HCC cells promoted the in vitro proliferation, migration, and tube formation of endothelial cells. The pro-angiogenic effect of GDF15 was through the activation of Src and its downstream AKT, MAPK, and NF-κB signaling, which was blocked by thalidomide. The use of thalidomide significantly attenuated the in vivo chemotherapy-damaged HCC cells-promoted angiogenesis in nude mice. In conclusion, the chemotherapeutic damage in TACE to HCC could promote tumor angiogenesis via the increased release of GDF15. Thalidomide could reverse these pro-angiogenic effects.

Chemotherapeutic damage to hepatocellular carcinoma promotes tumor angiogenesis via the increased release of GDF15. Thalidomide could reverse these pro-angiogenic effects.

from Cancer via ola Kala on Inoreader http://ift.tt/2Gx24Kd
via IFTTT

Effectiveness of modified hyper-CVAD chemotherapy regimen in the treatment of adult acute lymphoblastic leukemia: a retrospective experience

Abstract

Several chemotherapy regimens have been developed for the treatment of acute lymphoblastic leukemia (ALL), but relapse still presents the most common obstacles to attaining long-term survival. The hyper-CVAD (hyperfractionated cyclophosphamide, vincristine, doxorubicin, and prednisolone)/HD MTX and Ara-C (high-dose methotrexate and cytarabine) chemotherapy regimen was first started in the MD Anderson Cancer Center as an intensive regimen for adult patients with ALL. The purpose of this study was to evaluate the effectiveness of a modified hyper-CVAD protocol. We used hyper-CVAD as consolidation/maintenance after remission induction with daunorubicin, vincristine, and prednisolone (and cyclophosphamide for T-cell ALL only) rather than standard hyper-CVAD in order to reduce treatment complications. This study was conducted as a retrospective review of medical records of ALL patients at 501 army hospital, Tehran, Iran, from 2005 to 2015. Three hundred and one patients underwent modified hyper-CVAD chemotherapy regimen. Complete remission and overall survival (OS) rates were measured as primary endpoints. Two hundred and forty-six (81.7%) reached complete remission (CR) during the first 6 months of treatment, and 55 patients (18.3%) did not reach CR. The 5-year OS rate was 51.8% (95% CI (confidence interval): 45.1–57.8%). Modified hyper-CVAD regimen is an efficient intensive chemotherapy regimen for consolidation/maintenance of adults with newly diagnosed ALL and has an acceptable 5-year overall that is comparable to standard hyper-CVAD regimen.

We used a modified hyper-CVAD protocol to reduce treatment-related mortality and simultaneously reach an acceptable overall survival in patients with adult ALL. The results were promising, and it seems that this protocol could be of great benefit for ALL patients.

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

Novel applications for an established antimalarial drug: tumoricidal activity of quinacrine

Future Oncology, Ahead of Print.


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

CPX-351: changing the landscape of treatment for patients with secondary acute myeloid leukemia

Future Oncology, Ahead of Print.


from Cancer via ola Kala on Inoreader http://ift.tt/2nsWSP3
via IFTTT

Refeeding syndrome in adults with celiac crisis: a case report

Refeeding syndrome is a rare and life-threatening pathology with polyvisceral manifestations occurring in severely malnourished patients. It is rarely described in adults with celiac disease.

http://ift.tt/2GyjW7Q

Intestinal endometriosis combined with colorectal cancer: a case series

Intestinal endometriosis is a common benign disease among menstruating women that affects the intestinal tract.

http://ift.tt/2rQngYx

Is there a role of breast pathologist in diagnostic challenges of discordances in ER, PR, and HER2 between primary breast cancer and brain metastasis?

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

Is there a role of breast pathologist in diagnostic challenges of discordances in ER, PR, and HER2 between primary breast cancer and brain metastasis?

http://ift.tt/2nsPoLW

The frequency of missed breast cancers in women participating in a high-risk MRI screening program

Abstract

Purpose

To evaluate the frequency of missed cancers on breast MRI in women participating in a high-risk screening program.

Methods

Patient files from women who participated in an increased risk mammography and MRI screening program (2003–2014) were coupled to the Dutch National Cancer Registry. For each cancer detected, we determined whether an MRI scan was available (0–24 months before cancer detection), which was reported to be negative. These negative MRI scans were in consensus re-evaluated by two dedicated breast radiologists, with knowledge of the cancer location. Cancers were scored as invisible, minimal sign, or visible. Additionally, BI-RADS scores, background parenchymal enhancement, and image quality (IQ; perfect, sufficient, bad) were determined. Results were stratified by detection mode (mammography, MRI, interval cancers, or cancers in prophylactic mastectomies) and patient characteristics (presence of BRCA mutation, age, menopausal state).

Results

Negative prior MRI scans were available for 131 breast cancers. Overall 31% of cancers were visible at the initially negative MRI scan and 34% of cancers showed a minimal sign. The presence of a BRCA mutation strongly reduced the likelihood of visible findings in the last negative MRI (19 vs. 46%, P < 0.001). Less than perfect IQ increased the likelihood of visible findings and minimal signs in the negative MRI (P = 0.021).

Conclusion

This study shows that almost one-third of cancers detected in a high-risk screening program are already visible at the last negative MRI scan, and even more in women without BRCA mutations. Regular auditing and double reading for breast MRI screening is warranted.

http://ift.tt/2BFLbJG

Reverse of non-small cell lung cancer drug resistance induced by cancer associated fibroblasts via a paracrine pathway

Abstract

Tumor microenvironment orchestrates the sustained growth, metastasis and recurrence of cancer. As an indispensable component of tumor microenvironment, cancer associated fibroblasts (CAFs) are considered as an essential synthetic machine producing various tumor components, leading to cancer sustained stemness, drug resistance and tumor recurrence. Here, we developed a sustainable primary culture of lung cancer cells fed with lung cancer associated fibroblasts, resulting in enrichment and acquisition of drug resistance in cancer cells. Moreover, IGF2/AKT/Sox2/ABCB1 signaling activation in cancer cells was observed in the presence of cancer associated fibroblasts, which induce P-glycoprotein (P-GP) up-regulated expression and the drug resistance of non-small cell lung cancer cells. Our results demonstrated that cancer associated fibroblast cells constitute a supporting niche for cancer drug resistance acquisition. Thus, traditional chemotherapy combined with IGF2 signaling inhibitor may present an innovative therapeutic strategy for non-small cell lung cancer therapy.

This article is protected by copyright. All rights reserved.

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

lncRNA BC005927 upregulates EPHB4 and promotes gastric cancer metastasis under hypoxia

Summary

Hypoxia plays a critical role in the metastasis of gastric cancer (GC), yet the underlying mechanism remains largely unclear. It is also not known if lncRNAs are involved in the contribution of hypoxia to the GC metastasis. In this study, we found that lncRNA BC005927 can be induced by hypoxia in GC cells and mediates hypoxia-induced GC cell metastasis. Furthermore, BC005927 is frequently up-regulated in GC samples and increased BC005927 expression was correlated with a higher tumor-node-metastasis stage. GC patients with higher BC005927 expression had poorer prognoses than those with lower expression. Additional experiments revealed that BC005927 expression is induced by HIF-1a, CHIP assay and luciferase reporter assays confirmed that this lncRNA is a direct transcriptional target of HIF-1a. Next, we found that EPHB4, a metastasis-related gene, is regulated by BC005927 and that the expression of EPHB4 was positively correlated with that of BC005927 in the clinical GC samples assessed. Intriguingly, EPHB4 expression was also increased under hypoxia, and its upregulation by BC005927 resulted in hypoxia-induced GC cell metastasis. These results advance the current understanding of the role of BC005927 in the regulation of hypoxia signaling and offer new avenues for the development of therapeutic interventions against cancer progression.

This article is protected by copyright. All rights reserved.

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

Reverse of non-small cell lung cancer drug resistance induced by cancer associated fibroblasts via a paracrine pathway

Abstract

Tumor microenvironment orchestrates the sustained growth, metastasis and recurrence of cancer. As an indispensable component of tumor microenvironment, cancer associated fibroblasts (CAFs) are considered as an essential synthetic machine producing various tumor components, leading to cancer sustained stemness, drug resistance and tumor recurrence. Here, we developed a sustainable primary culture of lung cancer cells fed with lung cancer associated fibroblasts, resulting in enrichment and acquisition of drug resistance in cancer cells. Moreover, IGF2/AKT/Sox2/ABCB1 signaling activation in cancer cells was observed in the presence of cancer associated fibroblasts, which induce P-glycoprotein (P-GP) up-regulated expression and the drug resistance of non-small cell lung cancer cells. Our results demonstrated that cancer associated fibroblast cells constitute a supporting niche for cancer drug resistance acquisition. Thus, traditional chemotherapy combined with IGF2 signaling inhibitor may present an innovative therapeutic strategy for non-small cell lung cancer therapy.

This article is protected by copyright. All rights reserved.

http://ift.tt/2EoJrYg

lncRNA BC005927 upregulates EPHB4 and promotes gastric cancer metastasis under hypoxia

Summary

Hypoxia plays a critical role in the metastasis of gastric cancer (GC), yet the underlying mechanism remains largely unclear. It is also not known if lncRNAs are involved in the contribution of hypoxia to the GC metastasis. In this study, we found that lncRNA BC005927 can be induced by hypoxia in GC cells and mediates hypoxia-induced GC cell metastasis. Furthermore, BC005927 is frequently up-regulated in GC samples and increased BC005927 expression was correlated with a higher tumor-node-metastasis stage. GC patients with higher BC005927 expression had poorer prognoses than those with lower expression. Additional experiments revealed that BC005927 expression is induced by HIF-1a, CHIP assay and luciferase reporter assays confirmed that this lncRNA is a direct transcriptional target of HIF-1a. Next, we found that EPHB4, a metastasis-related gene, is regulated by BC005927 and that the expression of EPHB4 was positively correlated with that of BC005927 in the clinical GC samples assessed. Intriguingly, EPHB4 expression was also increased under hypoxia, and its upregulation by BC005927 resulted in hypoxia-induced GC cell metastasis. These results advance the current understanding of the role of BC005927 in the regulation of hypoxia signaling and offer new avenues for the development of therapeutic interventions against cancer progression.

This article is protected by copyright. All rights reserved.

http://ift.tt/2DJWSAX

Productivity losses due to premature mortality from cancer in Brazil, Russia, India, China, and South Africa (BRICS): A population-based comparison

Publication date: April 2018
Source:Cancer Epidemiology, Volume 53
Author(s): Alison Pearce, Linda Sharp, Paul Hanly, Anton Barchuk, Freddie Bray, Marianna de Camargo Cancela, Prakash Gupta, Filip Meheus, You-Lin Qiao, Freddy Sitas, Shao-Ming Wang, Isabelle Soerjomataram
BackgroundOver two-thirds of the world's cancer deaths occur in economically developing countries; however, the societal costs of cancer have rarely been assessed in these settings. Our aim was to estimate the value of productivity lost in 2012 due to cancer-related premature mortality in the major developing economies of Brazil, the Russian Federation, India, China and South Africa (BRICS).MethodsWe applied an incidence-based method using the human capital approach. We used annual adult cancer deaths from GLOBOCAN2012 to estimate the years of productive life lost between cancer death and pensionable age in each country, valued using national and international data for wages, and workforce statistics. Sensitivity analyses examined various methodological assumptions.ResultsThe total cost of lost productivity due to premature cancer mortality in the BRICS countries in 2012 was $46·3 billion, representing 0·33% of their combined gross domestic product. The largest total productivity loss was in China ($28 billion), while South Africa had the highest cost per cancer death ($101,000). Total productivity losses were greatest for lung cancer in Brazil, the Russian Federation and South Africa; liver cancer in China; and lip and oral cavity cancers in India.ConclusionLocally-tailored strategies are required to reduce the economic burden of cancer in developing economies. Focussing on tobacco control, vaccination programs and cancer screening, combined with access to adequate treatment, could yield significant gains for both public health and economic performance of the BRICS countries.



http://ift.tt/2GtYuAG

TGFβ C-509T, TGFβ T869C, XRCC1 Arg194Trp, IKBα C642T, IL4 C-590T Genetic polymorphisms combined with socio-economic, lifestyle, diet factors and gastric cancer risk: A case control study in South Indian population

Publication date: April 2018
Source:Cancer Epidemiology, Volume 53
Author(s): Dhayalan Pavithra, Majumdar Gautam, Ranganathan Rama, Rajaraman Swaminathan, Gopisetty Gopal, Ayyalur Seshadri Ramakrishnan, Thangarajan Rajkumar
BackgroundGastric cancer is worldwide the third major cause of cancer related death. Risk factors for gastric cancer includes Helicobacter pylori infection, gastric ulcer, less hygienic condition, use of tobacco, alcohol consumption, use of salted, smoked food, genetic alterations etc. In order to identify the risk factors associated with gastric cancer in South Indian population a case-control study involving 200 proven gastric cancer cases and 400 controls was conducted.MethodsA structured questionnaire was used to interview all the subjects who participated in our study. Genotyping assay was performed using Taqman allelic discrimination assay for 5 Single Nucleotide Polymorphisms (SNPs)-TGFβ C-509T, TGFβ T869C, XRCC1 Arg194Trp, IkBα C642T and IL4C-590T.ResultsOdds Ratios (ORs) and 95% confidence intervals (CIs) were calculated using conditional logistic regression. Statistical analysis on socio-economic factors, lifestyle factors had showed that subjects from low socio economic status, use of tobacco and consumption of non-vegetarian food had increased risk of developing gastric cancer. Multi-factorial analysis for the SNPs adjusting for the risk factors obtained in this study showed that TGFΒ C-509T TT genotypes had four fold increased risk of gastric cancer (OR = 4.11, CI = 1.02–16.56) and TGFβ T869C CC genotype had a decreased risk of gastric cancer (OR = 0.21, CI = 0.05–0.85).ConclusionEconomic status, tobacco use and food habits play a significant role in gastric cancer development. TT genotype for TGFβ C-509T had an increased risk and CC genotype for TGFβ T869C had a decreased risk of gastric cancer in south Indian population after adjusting for socio-economic factors and lifestyle factors.



http://ift.tt/2rQfk9H

The association between recreational physical activity, sedentary time, and colorectal polyps in a population screened for colorectal cancer

Publication date: April 2018
Source:Cancer Epidemiology, Volume 53
Author(s): Darren R. Brenner, Eileen Shaw, Demetra H. Yannitsos, Matthew T. Warkentin, Nigel T. Brockton, S. Elizabeth McGregor, Susanna Town, Robert J. Hilsden
PurposeRegular recreational moderate to vigorous physical activity (rMVPA) has been previously associated with a reduced risk of colorectal cancer (CRC), however, few studies have examined the association of rMVPA with colorectal polyps, the pre-malignant precursor lesions. The objective of this study was to examine the associations between physical activity and sitting time and polyps at the time of screening.MethodsWe conducted a cross-sectional study of 2496 individuals undergoing screening-related colonoscopy in Calgary, Alberta, Canada. Physical activity and sitting time were characterized using hours of rMVPA, meeting physical activity recommendations and hours of sitting time using self-reported data obtained from the International Physical Activity Questionnaire. Logistic regression models were used to estimate the crude and adjusted odds ratios (OR) for presence of polyps associated with rMVPA and sitting time.ResultsMeeting physical activity guidelines of ≥150 min/week was non-significantly associated with a modest decrease in odds of having ≥1 polyp at screening (ORadj = 0.95, 95% CI: 0.80–1.14). In males, threshold effects for sitting time were observed for up to 20 h/week (ORadj per hour sitting = 1.07, 95% CI: 1.01–1.13). In stratified analysis, larger inverse associations were observed between physical activity and the presence of polyps in females, obese individuals, and ever smokers, compared to pooled findings.ConclusionsIn this large CRC screening population, there was a suggestive association between increased rMVPA and reduced prevalence of polyps at screening, particularly among females. Even low amounts of regular sitting time (0–20 h/day) were associated with the presence of polyps, particularly among males. Further research on rMVPA and sitting time is necessary to better inform strategies to reduce the frequency of pre-malignant colorectal lesions.



http://ift.tt/2GykRVG

Productivity losses due to premature mortality from cancer in Brazil, Russia, India, China, and South Africa (BRICS): A population-based comparison

Publication date: April 2018
Source:Cancer Epidemiology, Volume 53
Author(s): Alison Pearce, Linda Sharp, Paul Hanly, Anton Barchuk, Freddie Bray, Marianna de Camargo Cancela, Prakash Gupta, Filip Meheus, You-Lin Qiao, Freddy Sitas, Shao-Ming Wang, Isabelle Soerjomataram
BackgroundOver two-thirds of the world's cancer deaths occur in economically developing countries; however, the societal costs of cancer have rarely been assessed in these settings. Our aim was to estimate the value of productivity lost in 2012 due to cancer-related premature mortality in the major developing economies of Brazil, the Russian Federation, India, China and South Africa (BRICS).MethodsWe applied an incidence-based method using the human capital approach. We used annual adult cancer deaths from GLOBOCAN2012 to estimate the years of productive life lost between cancer death and pensionable age in each country, valued using national and international data for wages, and workforce statistics. Sensitivity analyses examined various methodological assumptions.ResultsThe total cost of lost productivity due to premature cancer mortality in the BRICS countries in 2012 was $46·3 billion, representing 0·33% of their combined gross domestic product. The largest total productivity loss was in China ($28 billion), while South Africa had the highest cost per cancer death ($101,000). Total productivity losses were greatest for lung cancer in Brazil, the Russian Federation and South Africa; liver cancer in China; and lip and oral cavity cancers in India.ConclusionLocally-tailored strategies are required to reduce the economic burden of cancer in developing economies. Focussing on tobacco control, vaccination programs and cancer screening, combined with access to adequate treatment, could yield significant gains for both public health and economic performance of the BRICS countries.



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

TGFβ C-509T, TGFβ T869C, XRCC1 Arg194Trp, IKBα C642T, IL4 C-590T Genetic polymorphisms combined with socio-economic, lifestyle, diet factors and gastric cancer risk: A case control study in South Indian population

Publication date: April 2018
Source:Cancer Epidemiology, Volume 53
Author(s): Dhayalan Pavithra, Majumdar Gautam, Ranganathan Rama, Rajaraman Swaminathan, Gopisetty Gopal, Ayyalur Seshadri Ramakrishnan, Thangarajan Rajkumar
BackgroundGastric cancer is worldwide the third major cause of cancer related death. Risk factors for gastric cancer includes Helicobacter pylori infection, gastric ulcer, less hygienic condition, use of tobacco, alcohol consumption, use of salted, smoked food, genetic alterations etc. In order to identify the risk factors associated with gastric cancer in South Indian population a case-control study involving 200 proven gastric cancer cases and 400 controls was conducted.MethodsA structured questionnaire was used to interview all the subjects who participated in our study. Genotyping assay was performed using Taqman allelic discrimination assay for 5 Single Nucleotide Polymorphisms (SNPs)-TGFβ C-509T, TGFβ T869C, XRCC1 Arg194Trp, IkBα C642T and IL4C-590T.ResultsOdds Ratios (ORs) and 95% confidence intervals (CIs) were calculated using conditional logistic regression. Statistical analysis on socio-economic factors, lifestyle factors had showed that subjects from low socio economic status, use of tobacco and consumption of non-vegetarian food had increased risk of developing gastric cancer. Multi-factorial analysis for the SNPs adjusting for the risk factors obtained in this study showed that TGFΒ C-509T TT genotypes had four fold increased risk of gastric cancer (OR = 4.11, CI = 1.02–16.56) and TGFβ T869C CC genotype had a decreased risk of gastric cancer (OR = 0.21, CI = 0.05–0.85).ConclusionEconomic status, tobacco use and food habits play a significant role in gastric cancer development. TT genotype for TGFβ C-509T had an increased risk and CC genotype for TGFβ T869C had a decreased risk of gastric cancer in south Indian population after adjusting for socio-economic factors and lifestyle factors.



from Cancer via ola Kala on Inoreader http://ift.tt/2rQfk9H
via IFTTT

The association between recreational physical activity, sedentary time, and colorectal polyps in a population screened for colorectal cancer

Publication date: April 2018
Source:Cancer Epidemiology, Volume 53
Author(s): Darren R. Brenner, Eileen Shaw, Demetra H. Yannitsos, Matthew T. Warkentin, Nigel T. Brockton, S. Elizabeth McGregor, Susanna Town, Robert J. Hilsden
PurposeRegular recreational moderate to vigorous physical activity (rMVPA) has been previously associated with a reduced risk of colorectal cancer (CRC), however, few studies have examined the association of rMVPA with colorectal polyps, the pre-malignant precursor lesions. The objective of this study was to examine the associations between physical activity and sitting time and polyps at the time of screening.MethodsWe conducted a cross-sectional study of 2496 individuals undergoing screening-related colonoscopy in Calgary, Alberta, Canada. Physical activity and sitting time were characterized using hours of rMVPA, meeting physical activity recommendations and hours of sitting time using self-reported data obtained from the International Physical Activity Questionnaire. Logistic regression models were used to estimate the crude and adjusted odds ratios (OR) for presence of polyps associated with rMVPA and sitting time.ResultsMeeting physical activity guidelines of ≥150 min/week was non-significantly associated with a modest decrease in odds of having ≥1 polyp at screening (ORadj = 0.95, 95% CI: 0.80–1.14). In males, threshold effects for sitting time were observed for up to 20 h/week (ORadj per hour sitting = 1.07, 95% CI: 1.01–1.13). In stratified analysis, larger inverse associations were observed between physical activity and the presence of polyps in females, obese individuals, and ever smokers, compared to pooled findings.ConclusionsIn this large CRC screening population, there was a suggestive association between increased rMVPA and reduced prevalence of polyps at screening, particularly among females. Even low amounts of regular sitting time (0–20 h/day) were associated with the presence of polyps, particularly among males. Further research on rMVPA and sitting time is necessary to better inform strategies to reduce the frequency of pre-malignant colorectal lesions.



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

First PARP Inhibitor Approved for Breast Cancer [News in Brief]

Olaparib also becomes the first targeted therapy for patients with germline BRCA mutations.

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

Venetoclax Data Prompt Rethink of CLL Therapy [News in Depth]

BCL2 inhibitor yields deep remissions when used alone and in combinations.

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

Genome-wide gene expression changes in the normal-appearing airway during the evolution of smoking-associated lung adenocarcinoma

Smoking perpetuates in cytologically-normal airways a molecular "field of injury" that is pertinent to lung cancer and early detection. The evolution of airway field changes prior to lung oncogenesis is poorly understood largely due to the long latency of lung cancer in smokers. Here we studied airway expression changes prior to lung cancer onset in mice with knockout of the Gprc5a gene (Gprc5a-/-) and tobacco carcinogen (NNK) exposure and that develop the most common type of lung cancer, lung adenocarcinoma (LUAD), within six months following exposure. Airway epithelial brushings were collected from Gprc5a-/- mice before exposure and at multiple times post-NNK until time of LUAD development and then analyzed by RNA-sequencing. Temporal airway profiles were identified by linear models and analyzed by comparative genomics in normal airways of human smokers with and without lung cancer. We identified significantly altered profiles (n=926) in the NNK-exposed mouse normal airways relative to baseline epithelia, a subset of which were concordantly modulated with smoking status in the human airway. Among airway profiles that were significantly modulated following NNK, we found that expression changes (n=22) occurring as early as two months following exposure were significantly associated with lung cancer status when examined in airways of human smokers. Further, a subset of a recently reported human bronchial-gene classifier (Percepta; n=56) was enriched in the temporal mouse airway profiles. We underscore evolutionarily conserved profiles in the normal-appearing airway that develop prior to lung oncogenesis and that comprise viable markers for early lung cancer detection in suspect smokers.

from Cancer via ola Kala on Inoreader http://ift.tt/2ns6oC4
via IFTTT

Spatial heterogeneity and evolutionary dynamics modulate time to recurrence in continuous and adaptive cancer therapies

Treatment of advanced cancers has benefited from new agents that supplement or bypass conventional therapies. However, even effective therapies fail as cancer cells deploy a wide range of resistance strategies. We propose that evolutionary dynamics ultimately determine survival and proliferation of resistant cells. Therefore, evolutionary strategies should be used with conventional therapies to delay or prevent resistance. Using an agent-based framework to model spatial competition among sensitive and resistant populations, we applied anti-proliferative drug treatments to varying ratios of sensitive and resistant cells. We compared a continuous maximum tolerated dose schedule with an adaptive schedule aimed at tumor control via competition between sensitive and resistant cells. Continuous treatment cured mostly sensitive tumors, but with any resistant cells, recurrence was inevitable. We identified two adaptive strategies that control heterogeneous tumors: dose modulation controls most tumors with less drug, while a more vacation-oriented schedule can control more invasive tumors. These findings offer potential modifications to treatment regimens that may improve outcomes and reduce resistance and recurrence.

http://ift.tt/2FuxTCi

Tumorigenic and anti-proliferative properties of the TALE-transcription factors MEIS2D and MEIS2A in neuroblastoma

Neuroblastoma is one of only a few human cancers that can spontaneously regress even after extensive dissemination, a poorly understood phenomenon that occurs in as many as 10% of patients. In this study, we identify the TALE-homeodomain transcription factor MEIS2 as a key contributor to this phenomenon. We identified MEIS2 as a MYCN-independent factor in neuroblastoma and showed that in this setting the alternatively spliced isoforms MEIS2A and MEIS2D exert antagonistic functions. Specifically, expression of MEIS2A was low in aggressive stage 4 neuroblastoma but high in spontaneously regressing stage 4S neuroblastoma. Moderate elevation of MEIS2A expression reduced proliferation of MYCN-amplified human neuroblastoma cells, induced neuronal differentiation and impaired the ability of these cells to form tumors in mice. In contrast, MEIS2A silencing or MEIS2D upregulation enhanced the aggressiveness of the tumor phenotype. Mechanistically, MEIS2A uncoupled a negative feedback loop that restricts accumulation of cellular retinoic acid, an effective agent in neuroblastoma treatment. Overall, our results illuminate the basis for spontaneous regression in neuroblastoma and identify a MEIS2A-specific signaling network as a potential therapeutic target in this common pediatric malignancy.

http://ift.tt/2DZQadp

Modulation of Macropinocytosis-Mediated Internalization Decreases Ocular Toxicity of Antibody-Drug Conjugates

AGS-16C3F is an antibody-drug conjugate (ADC) against ectonucleotide pyrophosphatase/phosphodiesterase 3 (ENPP3) containing the mcMMAF linker-payload currently in development for treatment of metastatic renal cell carcinoma. AGS-16C3F and other ADC have been reported to cause ocular toxicity in patients by unknown mechanisms. To investigate this toxicity, we developed an in vitro assay using human corneal epithelial cells (HCEC) and show that HCEC internalized AGS-16C3F and other ADCs by macropinocytosis, causing inhibition of cell proliferation. We observed the same mechanism for target-independent internalization of AGS-16C3F in fibroblasts and human umbilical vein endothelial cells (HUVEC). Macropinocytosis-mediated intake of macromolecules is facilitated by the presence of positive charges or hydrophobic residues on the surface of the macromolecule. Modification of AGS-16C3F, either by attachment of poly-glutamate peptides, mutation of residue K16 to D on AGS-16C3F (AGS-16C3F(K16D)), or decreasing the overall hydrophobicity via attachment of polyethylene glycol moieties, significantly reduced cytotoxicity against HCEC and other primary cells. Rabbits treated with AGS-16C3F showed significant ocular toxicity, whereas those treated with AGS-16C3F(K16D) presented with less severe and delayed toxicities. Both molecules displayed similar anti-tumor activity in a mouse xenograft model. These findings establish a mechanism of action for target-independent toxicities of AGS-16C3F and ADCs in general, and provide methods to ameliorate these toxicities.

http://ift.tt/2Ftkfz6

HER2 overexpression triggers an IL-1{alpha} pro-inflammatory circuit to drive tumorigenesis and promote chemotherapy resistance

Systemic inflammation in breast cancer correlates with poor prognosis but the molecular underpinnings of this connection are not well understood. In this study, we explored the relationship between HER2 overexpression, inflammation and expansion of the mammary stem/progenitor and cancer stem-like cell (CSC) population in breast cancer. HER2-positive epithelial cells initiated and sustained an inflammatory milieu needed to promote tumorigenesis. HER2 induced a feed-forward activation loop of IL-1α and IL-6 that stimulated NF-κB and STAT3 pathways for generation and maintenance of breast CSC. In mice, Il1a genetic deficiency delayed MMTV-Her2-induced tumorigenesis and reduced inflammatory cytokine expression as well as CSC in primary tumors. In clinical specimens of human breast tumor tissues, tissue microarray analysis revealed a strong positive correlation between IL-1α/IL-6 expression and CSC-positive phenotype. Pharmacologic blockade of IL-1α signaling reduced the CSC population and improved chemotherapeutic efficacy. Our findings suggest new therapeutic or prevention strategies for HER2-positive breast cancers.

http://ift.tt/2E2sGEM

Discovery of potent and selective MRCK inhibitors with therapeutic effect on skin cancer.

The myotonic dystrophy-related Cdc42-binding kinases MRCKα and MRCKβ contribute to the regulation of actin-myosin cytoskeleton organization and dynamics, acting in concert with the Rho-associated coiled-coil kinases ROCK1 and ROCK2. The absence of highly potent and selective MRCK inhibitors has resulted in relatively little knowledge of the potential roles of these kinases in cancer. Here we report the discovery of the azaindole compounds BDP8900 and BDP9066 as potent and selective MRCK inhibitors that reduce substrate phosphorylation, leading to morphological changes in cancer cells along with inhibition of their motility and invasive character. In over 750 human cancer cell lines tested, BDP8900 and BDP9066 displayed consistent anti-proliferative effects with greatest activity in hematological cancer cells. Mass spectrometry identified MRCKα S1003 as an autophosphorylation site, enabling development of a phosphorylation-sensitive antibody tool to report on MRCKα status in tumor specimens. In a two-stage chemical carcinogenesis model of murine squamous cell carcinoma, topical treatments reduced MRCKα S1003 autophosphorylation and skin papilloma outgrowth. In parallel work, we validated a phospho-selective antibody with the capability to monitor drug pharmacodynamics. Taken together, our findings establish an important oncogenic role for MRCK in cancer, and they offer an initial preclinical proof of concept for MRCK inhibition as a valid therapeutic strategy.

http://ift.tt/2FvfWDL

Spatial heterogeneity and evolutionary dynamics modulate time to recurrence in continuous and adaptive cancer therapies

Treatment of advanced cancers has benefited from new agents that supplement or bypass conventional therapies. However, even effective therapies fail as cancer cells deploy a wide range of resistance strategies. We propose that evolutionary dynamics ultimately determine survival and proliferation of resistant cells. Therefore, evolutionary strategies should be used with conventional therapies to delay or prevent resistance. Using an agent-based framework to model spatial competition among sensitive and resistant populations, we applied anti-proliferative drug treatments to varying ratios of sensitive and resistant cells. We compared a continuous maximum tolerated dose schedule with an adaptive schedule aimed at tumor control via competition between sensitive and resistant cells. Continuous treatment cured mostly sensitive tumors, but with any resistant cells, recurrence was inevitable. We identified two adaptive strategies that control heterogeneous tumors: dose modulation controls most tumors with less drug, while a more vacation-oriented schedule can control more invasive tumors. These findings offer potential modifications to treatment regimens that may improve outcomes and reduce resistance and recurrence.

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

Tumorigenic and anti-proliferative properties of the TALE-transcription factors MEIS2D and MEIS2A in neuroblastoma

Neuroblastoma is one of only a few human cancers that can spontaneously regress even after extensive dissemination, a poorly understood phenomenon that occurs in as many as 10% of patients. In this study, we identify the TALE-homeodomain transcription factor MEIS2 as a key contributor to this phenomenon. We identified MEIS2 as a MYCN-independent factor in neuroblastoma and showed that in this setting the alternatively spliced isoforms MEIS2A and MEIS2D exert antagonistic functions. Specifically, expression of MEIS2A was low in aggressive stage 4 neuroblastoma but high in spontaneously regressing stage 4S neuroblastoma. Moderate elevation of MEIS2A expression reduced proliferation of MYCN-amplified human neuroblastoma cells, induced neuronal differentiation and impaired the ability of these cells to form tumors in mice. In contrast, MEIS2A silencing or MEIS2D upregulation enhanced the aggressiveness of the tumor phenotype. Mechanistically, MEIS2A uncoupled a negative feedback loop that restricts accumulation of cellular retinoic acid, an effective agent in neuroblastoma treatment. Overall, our results illuminate the basis for spontaneous regression in neuroblastoma and identify a MEIS2A-specific signaling network as a potential therapeutic target in this common pediatric malignancy.

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

Modulation of Macropinocytosis-Mediated Internalization Decreases Ocular Toxicity of Antibody-Drug Conjugates

AGS-16C3F is an antibody-drug conjugate (ADC) against ectonucleotide pyrophosphatase/phosphodiesterase 3 (ENPP3) containing the mcMMAF linker-payload currently in development for treatment of metastatic renal cell carcinoma. AGS-16C3F and other ADC have been reported to cause ocular toxicity in patients by unknown mechanisms. To investigate this toxicity, we developed an in vitro assay using human corneal epithelial cells (HCEC) and show that HCEC internalized AGS-16C3F and other ADCs by macropinocytosis, causing inhibition of cell proliferation. We observed the same mechanism for target-independent internalization of AGS-16C3F in fibroblasts and human umbilical vein endothelial cells (HUVEC). Macropinocytosis-mediated intake of macromolecules is facilitated by the presence of positive charges or hydrophobic residues on the surface of the macromolecule. Modification of AGS-16C3F, either by attachment of poly-glutamate peptides, mutation of residue K16 to D on AGS-16C3F (AGS-16C3F(K16D)), or decreasing the overall hydrophobicity via attachment of polyethylene glycol moieties, significantly reduced cytotoxicity against HCEC and other primary cells. Rabbits treated with AGS-16C3F showed significant ocular toxicity, whereas those treated with AGS-16C3F(K16D) presented with less severe and delayed toxicities. Both molecules displayed similar anti-tumor activity in a mouse xenograft model. These findings establish a mechanism of action for target-independent toxicities of AGS-16C3F and ADCs in general, and provide methods to ameliorate these toxicities.

from Cancer via ola Kala on Inoreader http://ift.tt/2Ftkfz6
via IFTTT

HER2 overexpression triggers an IL-1{alpha} pro-inflammatory circuit to drive tumorigenesis and promote chemotherapy resistance

Systemic inflammation in breast cancer correlates with poor prognosis but the molecular underpinnings of this connection are not well understood. In this study, we explored the relationship between HER2 overexpression, inflammation and expansion of the mammary stem/progenitor and cancer stem-like cell (CSC) population in breast cancer. HER2-positive epithelial cells initiated and sustained an inflammatory milieu needed to promote tumorigenesis. HER2 induced a feed-forward activation loop of IL-1α and IL-6 that stimulated NF-κB and STAT3 pathways for generation and maintenance of breast CSC. In mice, Il1a genetic deficiency delayed MMTV-Her2-induced tumorigenesis and reduced inflammatory cytokine expression as well as CSC in primary tumors. In clinical specimens of human breast tumor tissues, tissue microarray analysis revealed a strong positive correlation between IL-1α/IL-6 expression and CSC-positive phenotype. Pharmacologic blockade of IL-1α signaling reduced the CSC population and improved chemotherapeutic efficacy. Our findings suggest new therapeutic or prevention strategies for HER2-positive breast cancers.

from Cancer via ola Kala on Inoreader http://ift.tt/2E2sGEM
via IFTTT

Discovery of potent and selective MRCK inhibitors with therapeutic effect on skin cancer.

The myotonic dystrophy-related Cdc42-binding kinases MRCKα and MRCKβ contribute to the regulation of actin-myosin cytoskeleton organization and dynamics, acting in concert with the Rho-associated coiled-coil kinases ROCK1 and ROCK2. The absence of highly potent and selective MRCK inhibitors has resulted in relatively little knowledge of the potential roles of these kinases in cancer. Here we report the discovery of the azaindole compounds BDP8900 and BDP9066 as potent and selective MRCK inhibitors that reduce substrate phosphorylation, leading to morphological changes in cancer cells along with inhibition of their motility and invasive character. In over 750 human cancer cell lines tested, BDP8900 and BDP9066 displayed consistent anti-proliferative effects with greatest activity in hematological cancer cells. Mass spectrometry identified MRCKα S1003 as an autophosphorylation site, enabling development of a phosphorylation-sensitive antibody tool to report on MRCKα status in tumor specimens. In a two-stage chemical carcinogenesis model of murine squamous cell carcinoma, topical treatments reduced MRCKα S1003 autophosphorylation and skin papilloma outgrowth. In parallel work, we validated a phospho-selective antibody with the capability to monitor drug pharmacodynamics. Taken together, our findings establish an important oncogenic role for MRCK in cancer, and they offer an initial preclinical proof of concept for MRCK inhibition as a valid therapeutic strategy.

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

Indeterminate nodules in osteosarcoma: what’s the follow-up?

Indeterminate nodules in osteosarcoma: what's the follow-up?

Indeterminate nodules in osteosarcoma: what's the follow-up?, Published online: 30 January 2018; doi:10.1038/bjc.2017.453

Indeterminate nodules in osteosarcoma: what's the follow-up?

http://ift.tt/2BEquOs

Pazopanib maintenance after first-line etoposide and platinum chemotherapy in patients with extensive disease small-cell lung cancer: a multicentre, randomised, placebo-controlled Phase II study (KCSG-LU12-07)

Pazopanib maintenance after first-line etoposide and platinum chemotherapy in patients with extensive disease small-cell lung cancer: a multicentre, randomised, placebo-controlled Phase II study (KCSG-LU12-07)

Pazopanib maintenance after first-line etoposide and platinum chemotherapy in patients with extensive disease small-cell lung cancer: a multicentre, randomised, placebo-controlled Phase II study (KCSG-LU12-07), Published online: 30 January 2018; doi:10.1038/bjc.2017.465

Pazopanib maintenance after first-line etoposide and platinum chemotherapy in patients with extensive disease small-cell lung cancer: a multicentre, randomised, placebo-controlled Phase II study (KCSG-LU12-07)

from Cancer via ola Kala on Inoreader http://ift.tt/2noS2mv
via IFTTT

High burden of subsequent malignant neoplasms and cardiovascular disease in long-term Hodgkin lymphoma survivors

High burden of subsequent malignant neoplasms and cardiovascular disease in long-term Hodgkin lymphoma survivors

High burden of subsequent malignant neoplasms and cardiovascular disease in long-term Hodgkin lymphoma survivors, Published online: 30 January 2018; doi:10.1038/bjc.2017.476

High burden of subsequent malignant neoplasms and cardiovascular disease in long-term Hodgkin lymphoma survivors

http://ift.tt/2BFqqhg

Pazopanib maintenance after first-line etoposide and platinum chemotherapy in patients with extensive disease small-cell lung cancer: a multicentre, randomised, placebo-controlled Phase II study (KCSG-LU12-07)

Pazopanib maintenance after first-line etoposide and platinum chemotherapy in patients with extensive disease small-cell lung cancer: a multicentre, randomised, placebo-controlled Phase II study (KCSG-LU12-07)

Pazopanib maintenance after first-line etoposide and platinum chemotherapy in patients with extensive disease small-cell lung cancer: a multicentre, randomised, placebo-controlled Phase II study (KCSG-LU12-07), Published online: 30 January 2018; doi:10.1038/bjc.2017.465

Pazopanib maintenance after first-line etoposide and platinum chemotherapy in patients with extensive disease small-cell lung cancer: a multicentre, randomised, placebo-controlled Phase II study (KCSG-LU12-07)

http://ift.tt/2noS2mv

Treatment with docetaxel in combination with Aneustat leads to potent inhibition of metastasis in a patient-derived xenograft model of advanced prostate cancer

Treatment with docetaxel in combination with Aneustat leads to potent inhibition of metastasis in a patient-derived xenograft model of advanced prostate cancer

Treatment with docetaxel in combination with Aneustat leads to potent inhibition of metastasis in a patient-derived xenograft model of advanced prostate cancer, Published online: 30 January 2018; doi:10.1038/bjc.2017.474

Treatment with docetaxel in combination with Aneustat leads to potent inhibition of metastasis in a patient-derived xenograft model of advanced prostate cancer

http://ift.tt/2noY6eO

WNT5A induces castration-resistant prostate cancer via CCL2 and tumour-infiltrating macrophages

WNT5A induces castration-resistant prostate cancer via CCL2 and tumour-infiltrating macrophages

WNT5A induces castration-resistant prostate cancer via CCL2 and tumour-infiltrating macrophages, Published online: 30 January 2018; doi:10.1038/bjc.2017.451

WNT5A induces castration-resistant prostate cancer via CCL2 and tumour-infiltrating macrophages

http://ift.tt/2BF7lfd

Reduced mannosidase MAN1A1 expression leads to aberrant N-glycosylation and impaired survival in breast cancer

Reduced mannosidase MAN1A1 expression leads to aberrant N-glycosylation and impaired survival in breast cancer

Reduced mannosidase MAN1A1 expression leads to aberrant N-glycosylation and impaired survival in breast cancer, Published online: 30 January 2018; doi:10.1038/bjc.2017.472

Reduced mannosidase MAN1A1 expression leads to aberrant N-glycosylation and impaired survival in breast cancer

http://ift.tt/2nmIkRx

Enrolling children with acute lymphoblastic leukaemia on a clinical trial improves event-free survival: a population-based study

Enrolling children with acute lymphoblastic leukaemia on a clinical trial improves event-free survival: a population-based study

Enrolling children with acute lymphoblastic leukaemia on a clinical trial improves event-free survival: a population-based study, Published online: 30 January 2018; doi:10.1038/bjc.2017.462

Enrolling children with acute lymphoblastic leukaemia on a clinical trial improves event-free survival: a population-based study

http://ift.tt/2nmIiZV

Treatment with docetaxel in combination with Aneustat leads to potent inhibition of metastasis in a patient-derived xenograft model of advanced prostate cancer

Treatment with docetaxel in combination with Aneustat leads to potent inhibition of metastasis in a patient-derived xenograft model of advanced prostate cancer

Treatment with docetaxel in combination with Aneustat leads to potent inhibition of metastasis in a patient-derived xenograft model of advanced prostate cancer, Published online: 30 January 2018; doi:10.1038/bjc.2017.474

Treatment with docetaxel in combination with Aneustat leads to potent inhibition of metastasis in a patient-derived xenograft model of advanced prostate cancer

from Cancer via ola Kala on Inoreader http://ift.tt/2noY6eO
via IFTTT

WNT5A induces castration-resistant prostate cancer via CCL2 and tumour-infiltrating macrophages

WNT5A induces castration-resistant prostate cancer via CCL2 and tumour-infiltrating macrophages

WNT5A induces castration-resistant prostate cancer via CCL2 and tumour-infiltrating macrophages, Published online: 30 January 2018; doi:10.1038/bjc.2017.451

WNT5A induces castration-resistant prostate cancer via CCL2 and tumour-infiltrating macrophages

from Cancer via ola Kala on Inoreader http://ift.tt/2BF7lfd
via IFTTT

Reduced mannosidase MAN1A1 expression leads to aberrant N-glycosylation and impaired survival in breast cancer

Reduced mannosidase MAN1A1 expression leads to aberrant N-glycosylation and impaired survival in breast cancer

Reduced mannosidase MAN1A1 expression leads to aberrant N-glycosylation and impaired survival in breast cancer, Published online: 30 January 2018; doi:10.1038/bjc.2017.472

Reduced mannosidase MAN1A1 expression leads to aberrant N-glycosylation and impaired survival in breast cancer

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

Enrolling children with acute lymphoblastic leukaemia on a clinical trial improves event-free survival: a population-based study

Enrolling children with acute lymphoblastic leukaemia on a clinical trial improves event-free survival: a population-based study

Enrolling children with acute lymphoblastic leukaemia on a clinical trial improves event-free survival: a population-based study, Published online: 30 January 2018; doi:10.1038/bjc.2017.462

Enrolling children with acute lymphoblastic leukaemia on a clinical trial improves event-free survival: a population-based study

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

External validation of risk prediction models for incident colorectal cancer using UK Biobank

External validation of risk prediction models for incident colorectal cancer using UK Biobank

External validation of risk prediction models for incident colorectal cancer using UK Biobank, Published online: 30 January 2018; doi:10.1038/bjc.2017.463

External validation of risk prediction models for incident colorectal cancer using UK Biobank

http://ift.tt/2BGnnFC

Indeterminate nodules in osteosarcoma: what’s the follow-up?

Indeterminate nodules in osteosarcoma: what's the follow-up?

Indeterminate nodules in osteosarcoma: what's the follow-up?, Published online: 30 January 2018; doi:10.1038/bjc.2017.453

Indeterminate nodules in osteosarcoma: what's the follow-up?

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

External validation of risk prediction models for incident colorectal cancer using UK Biobank

External validation of risk prediction models for incident colorectal cancer using UK Biobank

External validation of risk prediction models for incident colorectal cancer using UK Biobank, Published online: 30 January 2018; doi:10.1038/bjc.2017.463

External validation of risk prediction models for incident colorectal cancer using UK Biobank

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

High burden of subsequent malignant neoplasms and cardiovascular disease in long-term Hodgkin lymphoma survivors

High burden of subsequent malignant neoplasms and cardiovascular disease in long-term Hodgkin lymphoma survivors

High burden of subsequent malignant neoplasms and cardiovascular disease in long-term Hodgkin lymphoma survivors, Published online: 30 January 2018; doi:10.1038/bjc.2017.476

High burden of subsequent malignant neoplasms and cardiovascular disease in long-term Hodgkin lymphoma survivors

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

Pazopanib maintenance after first-line etoposide and platinum chemotherapy in patients with extensive disease small-cell lung cancer: a multicentre, randomised, placebo-controlled Phase II study (KCSG-LU12-07)

http://ift.tt/2EqueGl

Treatment with docetaxel in combination with Aneustat leads to potent inhibition of metastasis in a patient-derived xenograft model of advanced prostate cancer

http://ift.tt/2DMBFGC

WNT5A induces castration-resistant prostate cancer via CCL2 and tumour-infiltrating macrophages

http://ift.tt/2Eque9j

Reduced mannosidase MAN1A1 expression leads to aberrant N-glycosylation and impaired survival in breast cancer

http://ift.tt/2DMAIhn

Enrolling children with acute lymphoblastic leukaemia on a clinical trial improves event-free survival: a population-based study

http://ift.tt/2Eocco4

Indeterminate nodules in osteosarcoma: what’s the follow-up?

http://ift.tt/2FvzAPI

External validation of risk prediction models for incident colorectal cancer using UK Biobank

http://ift.tt/2E1psB6

High burden of subsequent malignant neoplasms and cardiovascular disease in long-term Hodgkin lymphoma survivors

http://ift.tt/2FvaIYA

External validation of risk prediction models for incident colorectal cancer using UK Biobank

from Cancer via ola Kala on Inoreader http://ift.tt/2E1psB6
via IFTTT

Pazopanib maintenance after first-line etoposide and platinum chemotherapy in patients with extensive disease small-cell lung cancer: a multicentre, randomised, placebo-controlled Phase II study (KCSG-LU12-07)

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

Treatment with docetaxel in combination with Aneustat leads to potent inhibition of metastasis in a patient-derived xenograft model of advanced prostate cancer

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

WNT5A induces castration-resistant prostate cancer via CCL2 and tumour-infiltrating macrophages

from Cancer via ola Kala on Inoreader http://ift.tt/2Eque9j
via IFTTT

Reduced mannosidase MAN1A1 expression leads to aberrant N-glycosylation and impaired survival in breast cancer

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

Enrolling children with acute lymphoblastic leukaemia on a clinical trial improves event-free survival: a population-based study

from Cancer via ola Kala on Inoreader http://ift.tt/2Eocco4
via IFTTT

Indeterminate nodules in osteosarcoma: what’s the follow-up?

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

High burden of subsequent malignant neoplasms and cardiovascular disease in long-term Hodgkin lymphoma survivors

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

TARGET Study Finds Major Differences between Childhood and Adult AML

An NCI-funded study has found significant differences in the genetics of acute myeloid leukemia in younger and older patients. The findings could help guide the development of treatments tailored specifically for childhood AML.

http://ift.tt/2EqGyXc

TARGET Study Finds Major Differences between Childhood and Adult AML

An NCI-funded study has found significant differences in the genetics of acute myeloid leukemia in younger and older patients. The findings could help guide the development of treatments tailored specifically for childhood AML.

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

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

Circulating cell-free DNA (cfDNA) and its integrity index may represent a rapid and noninvasive "liquid biopsy" biomarker, which gives important complementary information for diagnosis, prognosis, and treatmen...

from Cancer via ola Kala on Inoreader http://ift.tt/2DL4wLn
via IFTTT

The miR-181 family promotes cell cycle by targeting CTDSPL, a phosphatase-like tumor suppressor in uveal melanoma

MicroRNAs (miRNAs) have been shown to function in many different cellular processes, including proliferation, apoptosis, differentiation and development. miR-181a, -181b, -181c and -181d are miR-181 members of th...

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

Investigation of an antitumor drug-delivery system based on anti-HER2 antibody-conjugated BSA nanoparticles

Conjugation of a monoclonal antibody with a nanoparticle often improves its specificity and drug loading in cancer therapy. In this study, we prepared a novel targeting nanodrug-delivery system using 2-methoxy-estradiol (2-ME) based on anti-human epidermal growth factor receptor 2 (HER2) antibody-modified BSA to improve the clinical application and antitumor effect of 2-ME. 2-ME-loaded albumin nanoparticles (2-ME-BSANPs) were prepared using a desolvation method and the anti-HER2 antibodies were conjugated to 2-ME-BSANPs (HER2-2-ME-BSANPs) using the coupling agent, succinimidyl 3-(2-pyridyldithio)propionate. HER2-2-ME-BSANPs were characterized using SDS-polyacrylamide gel electrophoresis, an agglutination test, and an immunofluorescence assay. We found that mouse anti-human anti-HER2 monoclonal antibody was successfully conjugated to the 2-ME-BSANPs. Thereafter, the in-vitro and in-vivo toxicities were evaluated using two cancer cell lines, SK-BR-3 (HER2-overexpressing) and MCF-7 (HER2-underexpressing), using classic pharmacological methods and in-vivo imaging technology. We found that the HER2-2-ME-BSANPs retained the immunospecificity of the anti-HER2 monoclonal antibody, rapidly localized to HER2 receptors, and could be used for targeted cancer therapy. Correspondence to Dr Qingfeng Tian, College of Public Health, Zhengzhou University, 100 Kexue Avenue, Zhengzhou 450001, China Tel/fax: +86 371 6778 1393; e-mail: 13937156869@126.com Received August 23, 2017 Accepted December 5, 2017 Copyright © 2018 Wolters Kluwer Health, Inc. All rights reserved.

http://ift.tt/2DNwpqh

Comparison of the effect of the antiandrogen apalutamide (ARN-509) versus bicalutamide on the androgen receptor pathway in prostate cancer cell lines

Apalutamide (ARN-509) is an antiandrogen that binds selectively to androgen receptors (AR) and does not show antagonist-to-agonist switch like bicalutamide. We compared the activity of ARN versus bicalutamide on prostate cancer cell lines. The 22Rv1, PC3, and DU145 cell lines were used to study the effect of ARN and bicalutamide on the expression cytoplasmic/nuclear kinetics of AR, AR-V7 variant, phosphorylated AR, as well as the levels of the AR downstream proteins prostate-specific antigen and TMPRSS2, under exposure to testosterone and/or hypoxia. The effects on autophagic flux (LC3A, p62, TFEB, LAMP2a, cathepsin D) and cell metabolism-related enzymes (hypoxia-inducible factor 1α/2α, BNIP3, carbonic anhydrase 9, LDHA, PDH, PDH-kinase) were also studied. The 22Rv1 cell line responded to testosterone by increasing the nuclear entry of AR, AR-V7, and phosphorylated AR and by increasing the levels of prostate-specific antigen and TMPRSS2. This effect was strongly abrogated by ARN and to a clearly lower extent by bicalutamide at 10 μmol/l, both in normoxia and in hypoxia. ARN had a stronger antiproliferative effect than bicalutamide, which was prominent in the 22Rv1 hormone-responsive cell line, and completely repressed cell proliferation at a concentration of 100 μmol/l. No effect of testosterone or of antiandrogens on autophagy flux, hypoxia-related proteins, or metabolism enzyme levels was noted. The PC3 and DU145 cell lines showed poor expression of the proteins and were not responsive to testosterone. On the basis of in-vitro studies, evidence has been reported that ARN is more potent than bicalutamide in blocking the AR pathway in normoxia and in hypoxia. This reflects a more robust, dose-dependent, repressive effect on cell proliferation. Correspondence to Michael I. Koukourakis, MD, Department of Radiotherapy/Oncology, Democritus University of Thrace, PO Box 12, Alexandroupolis 68100, Greece Tel: +30 255 107 4622; fax: 30 255 103 0349; e-mail: targ@her.forthnet.gr Received September 17, 2017 Accepted December 20, 2017 Copyright © 2018 Wolters Kluwer Health, Inc. All rights reserved.

http://ift.tt/2nqfj6O

Investigation of an antitumor drug-delivery system based on anti-HER2 antibody-conjugated BSA nanoparticles

Conjugation of a monoclonal antibody with a nanoparticle often improves its specificity and drug loading in cancer therapy. In this study, we prepared a novel targeting nanodrug-delivery system using 2-methoxy-estradiol (2-ME) based on anti-human epidermal growth factor receptor 2 (HER2) antibody-modified BSA to improve the clinical application and antitumor effect of 2-ME. 2-ME-loaded albumin nanoparticles (2-ME-BSANPs) were prepared using a desolvation method and the anti-HER2 antibodies were conjugated to 2-ME-BSANPs (HER2-2-ME-BSANPs) using the coupling agent, succinimidyl 3-(2-pyridyldithio)propionate. HER2-2-ME-BSANPs were characterized using SDS-polyacrylamide gel electrophoresis, an agglutination test, and an immunofluorescence assay. We found that mouse anti-human anti-HER2 monoclonal antibody was successfully conjugated to the 2-ME-BSANPs. Thereafter, the in-vitro and in-vivo toxicities were evaluated using two cancer cell lines, SK-BR-3 (HER2-overexpressing) and MCF-7 (HER2-underexpressing), using classic pharmacological methods and in-vivo imaging technology. We found that the HER2-2-ME-BSANPs retained the immunospecificity of the anti-HER2 monoclonal antibody, rapidly localized to HER2 receptors, and could be used for targeted cancer therapy. Correspondence to Dr Qingfeng Tian, College of Public Health, Zhengzhou University, 100 Kexue Avenue, Zhengzhou 450001, China Tel/fax: +86 371 6778 1393; e-mail: 13937156869@126.com Received August 23, 2017 Accepted December 5, 2017 Copyright © 2018 Wolters Kluwer Health, Inc. All rights reserved.

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

Comparison of the effect of the antiandrogen apalutamide (ARN-509) versus bicalutamide on the androgen receptor pathway in prostate cancer cell lines

Apalutamide (ARN-509) is an antiandrogen that binds selectively to androgen receptors (AR) and does not show antagonist-to-agonist switch like bicalutamide. We compared the activity of ARN versus bicalutamide on prostate cancer cell lines. The 22Rv1, PC3, and DU145 cell lines were used to study the effect of ARN and bicalutamide on the expression cytoplasmic/nuclear kinetics of AR, AR-V7 variant, phosphorylated AR, as well as the levels of the AR downstream proteins prostate-specific antigen and TMPRSS2, under exposure to testosterone and/or hypoxia. The effects on autophagic flux (LC3A, p62, TFEB, LAMP2a, cathepsin D) and cell metabolism-related enzymes (hypoxia-inducible factor 1α/2α, BNIP3, carbonic anhydrase 9, LDHA, PDH, PDH-kinase) were also studied. The 22Rv1 cell line responded to testosterone by increasing the nuclear entry of AR, AR-V7, and phosphorylated AR and by increasing the levels of prostate-specific antigen and TMPRSS2. This effect was strongly abrogated by ARN and to a clearly lower extent by bicalutamide at 10 μmol/l, both in normoxia and in hypoxia. ARN had a stronger antiproliferative effect than bicalutamide, which was prominent in the 22Rv1 hormone-responsive cell line, and completely repressed cell proliferation at a concentration of 100 μmol/l. No effect of testosterone or of antiandrogens on autophagy flux, hypoxia-related proteins, or metabolism enzyme levels was noted. The PC3 and DU145 cell lines showed poor expression of the proteins and were not responsive to testosterone. On the basis of in-vitro studies, evidence has been reported that ARN is more potent than bicalutamide in blocking the AR pathway in normoxia and in hypoxia. This reflects a more robust, dose-dependent, repressive effect on cell proliferation. Correspondence to Michael I. Koukourakis, MD, Department of Radiotherapy/Oncology, Democritus University of Thrace, PO Box 12, Alexandroupolis 68100, Greece Tel: +30 255 107 4622; fax: 30 255 103 0349; e-mail: targ@her.forthnet.gr Received September 17, 2017 Accepted December 20, 2017 Copyright © 2018 Wolters Kluwer Health, Inc. All rights reserved.

from Cancer via ola Kala on Inoreader http://ift.tt/2nqfj6O
via IFTTT

Role of Anti-Epidermal Growth Factor Receptor Therapy Compared with Anti-Vascular Endothelial Growth Factor Therapy for Metastatic Colorectal Cancer: an Update Meta-Analysis of Randomized Clinical Trials

Abstract

Monoclonal antibodies targeting epidermal growth factor receptor (EGFR) or vascular endothelial growth factor (VEGF) have showed clinical benefit in combination with chemotherapeutic cytotoxic drugs in the first-line therapy of metastatic colorectal cancer (mCRC). Data from randomized studies comparing these monoclonal antibodies as initial therapy is conflicting, and their comparative efficacy remains unknown. This study aimed to evaluate the impact of the combination of anti-epidermal growth factor receptor (anti-EGFR) therapy and anti-vascular endothelial growth factor therapy on mCRC patient outcomes by combining the data from randomized clinical trials. Three trials meeting the eligibility criteria, and four randomized studies were included in the meta-analysis. For MCRC patients with KRAS wild type (KRAS-WT), the ORR was superior in patients treated with anti-EGFR compared with those who treated with anti-VEGF therapy. This effect was even better for all RAS-WT patients. Progression-free survival (PFS) rates were not significantly different for KRAS-WT mCRC and all RAS-WT mCRC between the two groups. The overall survival (OS) was higher for RAS wild-type (RAS-WT) mCRC patients who received anti-EGFR, but the KRAS-WT patients compared to the anti-VEGF therapy. The results of our research indicate that superior ORR and OS between the addition of anti-EGFR therapy VS anti-VEGF therapy in all RAS-WT patients with MCRC. There was no significant difference in OS and PFS between the two groups for KRAS-WT mCRC. These results suggest that anti- EGFR monoclonal antibodies can achieve an equivalent efficacy when compared with anti-VEGF therapy of all RAS-WT mCRC patients.

http://ift.tt/2DJQJEZ

Where does O6-methylguanine DNA methyltransferase promoter methylation assessment place temozolomide in the future standards of care for glioblastoma?

Methylation of the promoter region of the O⁶-methylguanine DNA methyltransferase (MGMT) gene has emerged as the first—and so far the only—predictive biomarker for glioblastoma. Challenges in establishing a reliable assay to interrogate MGMT promoter methylation status and the lack of therapeutic alternatives to alkylating agent chemotherapy remain hurdles in the global implementation of MGMT testing as part of the standard of care.

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

Where does O6-methylguanine DNA methyltransferase promoter methylation assessment place temozolomide in the future standards of care for glioblastoma?

Methylation of the promoter region of the O⁶-methylguanine DNA methyltransferase (MGMT) gene has emerged as the first—and so far the only—predictive biomarker for glioblastoma. Challenges in establishing a reliable assay to interrogate MGMT promoter methylation status and the lack of therapeutic alternatives to alkylating agent chemotherapy remain hurdles in the global implementation of MGMT testing as part of the standard of care.

http://ift.tt/2DOAtqj

Use of androgen deprivation and salvage radiation therapy for patients with prostate cancer and biochemical recurrence after prostatectomy

Abstract

Aim

Overview on the use of androgen deprivation therapy (ADT) added to salvage radiation therapy (SRT) for prostate cancer patients with biochemical recurrence after prostatectomy.

Methods

The German Society of Radiation Oncology (DEGRO) expert panel summarized available evidence published between January 2009 and May 2017, and assessed the validity of the information on outcome parameters including overall survival (OS) and treatment-related toxicity.

Results

Two randomized controlled trials and nine relevant retrospective analyses were identified. The RTOG 9601 trial showed an OS improvement for the combination of 2 years of bicalutamide and SRT compared to SRT alone after a median follow-up of 13 years. This improvement appeared to be restricted to those patients with a prostate specific antigen (PSA) level before SRT of ≥0.7 ng/mL. The GETUG AFU-16 trial showed that after a median follow-up of 5 years, the addition of 6 months of goserelin to SRT improved progression-free survival (PFS; based on biochemical recurrence) as compared to SRT alone. ADT in both trials was not associated with increased major late toxicities. Results of retrospective series were inconsistent with a suggestion that the addition of ADT improved biochemical PFS especially in patients with high-risk factors such as Gleason Score ≥8 and in the group with initially negative surgical margins.

Conclusions

ADT combined with SRT appears to improve OS in patients with a PSA level before SRT of ≥0.7 ng/mL. In patients without persistent PSA after prostatectomy and PSA levels of <0.7 ng/mL, ADT should not routinely be used, but may be considered in patients with additional risk factors such as Gleason Score ≥8 and negative surgical margins.

http://ift.tt/2GwUdwo

Cancers, Vol. 10, Pages 39: Precision Immuno-Oncology: Prospects of Individualized Immunotherapy for Pancreatic Cancer

Cancers, Vol. 10, Pages 39: Precision Immuno-Oncology: Prospects of Individualized Immunotherapy for Pancreatic Cancer

Cancers doi: 10.3390/cancers10020039

Authors: Jiajia Zhang Christopher Wolfgang Lei Zheng

Pancreatic cancer, most commonly referring to pancreatic ductal adenocarcinoma (PDAC), remains one of the most deadly diseases, with very few effective therapies available. Emerging as a new modality of modern cancer treatments, immunotherapy has shown promises for various cancer types. Over the past decades, the potential of immunotherapy in eliciting clinical benefits in pancreatic cancer have also been extensively explored. It has been demonstrated in preclinical studies and early phase clinical trials that cancer vaccines were effective in eliciting anti-tumor immune response, but few have led to a significant improvement in survival. Despite the fact that immunotherapy with checkpoint blockade (e.g., anti-cytotoxic T-lymphocyte antigen 4 [CTLA-4] and anti-programmed cell death 1 [PD-1]/PD-L1 antibodies) has shown remarkable and durable responses in various cancer types, the application of checkpoint inhibitors in pancreatic cancer has been disappointing so far. It may, in part, due to the unique tumor microenvironment (TME) of pancreatic cancer, such as existence of excessive stromal matrix and hypovascularity, creating a TME of strong inhibitory signaling circuits and tremendous physical barriers for immune agent infiltration. This informs on the need for combination therapy approaches to engender a potent immune response that can translate to clinical benefits. On the other hand, lack of effective and validated biomarkers to stratify subgroup of patients who can benefit from immunotherapy poses further challenges for the realization of precision immune-oncology. Future studies addressing issues such as TME modulation, biomarker identification and therapeutic combination are warranted. In this review, advances in immunotherapy for pancreatic cancer were discussed and opportunities as well as challenges for personalized immune-oncology were addressed.

from Cancer via ola Kala on Inoreader http://ift.tt/2rOP7IB
via IFTTT

Cancers, Vol. 10, Pages 39: Precision Immuno-Oncology: Prospects of Individualized Immunotherapy for Pancreatic Cancer

Cancers, Vol. 10, Pages 39: Precision Immuno-Oncology: Prospects of Individualized Immunotherapy for Pancreatic Cancer

Cancers doi: 10.3390/cancers10020039

Authors: Jiajia Zhang Christopher Wolfgang Lei Zheng

Pancreatic cancer, most commonly referring to pancreatic ductal adenocarcinoma (PDAC), remains one of the most deadly diseases, with very few effective therapies available. Emerging as a new modality of modern cancer treatments, immunotherapy has shown promises for various cancer types. Over the past decades, the potential of immunotherapy in eliciting clinical benefits in pancreatic cancer have also been extensively explored. It has been demonstrated in preclinical studies and early phase clinical trials that cancer vaccines were effective in eliciting anti-tumor immune response, but few have led to a significant improvement in survival. Despite the fact that immunotherapy with checkpoint blockade (e.g., anti-cytotoxic T-lymphocyte antigen 4 [CTLA-4] and anti-programmed cell death 1 [PD-1]/PD-L1 antibodies) has shown remarkable and durable responses in various cancer types, the application of checkpoint inhibitors in pancreatic cancer has been disappointing so far. It may, in part, due to the unique tumor microenvironment (TME) of pancreatic cancer, such as existence of excessive stromal matrix and hypovascularity, creating a TME of strong inhibitory signaling circuits and tremendous physical barriers for immune agent infiltration. This informs on the need for combination therapy approaches to engender a potent immune response that can translate to clinical benefits. On the other hand, lack of effective and validated biomarkers to stratify subgroup of patients who can benefit from immunotherapy poses further challenges for the realization of precision immune-oncology. Future studies addressing issues such as TME modulation, biomarker identification and therapeutic combination are warranted. In this review, advances in immunotherapy for pancreatic cancer were discussed and opportunities as well as challenges for personalized immune-oncology were addressed.

http://ift.tt/2rOP7IB

Racial disparities in the rate of cardiotoxicity of HER2-targeted therapies among women with early breast cancer

BACKGROUND

Human epidermal growth factor receptor 2 (HER2)-targeted therapies are highly effective at preventing breast cancer recurrence but are associated with cardiotoxicity in some patients, and minimal data are available regarding racial disparities in the incidence of this toxicity. The authors conducted a retrospective study to analyze the association of black or white race with treatment-induced cardiotoxicity and incomplete therapy among patients with HER2-positive early breast cancer.

METHODS

Women with HER2-positive, stage I through III breast cancer who initiated (neo)adjuvant HER2-targeted therapy (trastuzumab with or without pertuzumab) from January 2005 to March 2015 at the authors' institution were eligible. We analyzed differences in the incidence of cardiotoxicity (a decline in the left ventricular ejection fraction to <50% AND an absolute drop in the left ventricular ejection fraction of ≥10% from baseline) and incomplete therapy (<52 weeks of HER2-targeted therapy) between black and white women in univariate and multivariable analyses.

RESULTS

The authors identified 59 black patients and 157 white patients who had a median follow-up 5.2 years. The median patient age was 53 years and was similar for black and white patients. The 1-year cardiotoxicity incidence was 12% overall (95% confidence interval [CI], 7%-16%), 24% in black women (95% CI, 12%-34%), and 7% in white women (95% CI, 3%-11%). Black patients had a significantly greater probability of incomplete therapy compared with white patients (odds ratio, 4.61; 95% CI, 1.70-13.07; P = .002). High correlation was observed between a cardiotoxicity event and incomplete therapy (96% concordance).

CONCLUSIONS

Black patients have a higher rate of cardiotoxicity and resultant incomplete adjuvant HER2-targeted therapy than white patients. This patient population may benefit from enhanced cardiac surveillance, cardioprotective strategies, and early referral to cardiology when appropriate. Cancer 2018. © 2018 American Cancer Society.

from Cancer via ola Kala on Inoreader http://ift.tt/2rRL9Pt
via IFTTT

Efficacy and safety analysis by age cohort of inotuzumab ozogamicin in patients with relapsed or refractory acute lymphoblastic leukemia enrolled in INO-VATE

BACKGROUND

Inotuzumab ozogamicin (InO) has demonstrated efficacy and tolerability in patients aged 18 to 78 years with relapsed/refractory acute lymphoblastic leukemia (ALL) in the INO-VATE trial. This subset analysis compared the efficacy and safety of InO in younger and older patients.

METHODS

Intent-to-treat analyses of morphologic responses and overall survival (OS) included 326 randomized patients, and safety assessments included 307 patients receiving 1 or more doses of the study treatment. Of the 326 patients, 164 received InO at a starting dose of 1.8 mg/m²/cycle (0.8 mg/m² on day 1 and 0.5 mg/m² on days 8 and 15 of a 21- to 28-day cycle [≤6 cycles]); 60 patients were aged ≥55 years, and 104 were aged <55 years.

RESULTS

For older and younger patients, the median duration of InO therapy and the types and frequencies of adverse events of any grade were generally similar. Although the remission rates, median duration of remission (DOR), and progression-free survival were similar with InO for those aged <55 years and those aged ≥55 years, OS was longer for younger patients (median, 8.6 vs 5.6 months; hazard ratio, 0.610). Among patients proceeding to hematopoietic stem cell transplantation after InO treatment (28% of older patients and 58% of younger patients), the incidence of veno-occlusive disease was greater in older patients (41% vs 17%). The study database was not locked at the time of this analysis.

CONCLUSIONS

InO was tolerable in older patients with relapsed/refractory ALL. Although OS was longer for younger patients versus older patients, InO demonstrated high response rates with similar DOR in the 2 age groups. Cancer 2018. © 2018 American Cancer Society.

from Cancer via ola Kala on Inoreader http://ift.tt/2GsBYZ3
via IFTTT

Racial disparities in the rate of cardiotoxicity of HER2-targeted therapies among women with early breast cancer

BACKGROUND

Human epidermal growth factor receptor 2 (HER2)-targeted therapies are highly effective at preventing breast cancer recurrence but are associated with cardiotoxicity in some patients, and minimal data are available regarding racial disparities in the incidence of this toxicity. The authors conducted a retrospective study to analyze the association of black or white race with treatment-induced cardiotoxicity and incomplete therapy among patients with HER2-positive early breast cancer.

METHODS

Women with HER2-positive, stage I through III breast cancer who initiated (neo)adjuvant HER2-targeted therapy (trastuzumab with or without pertuzumab) from January 2005 to March 2015 at the authors' institution were eligible. We analyzed differences in the incidence of cardiotoxicity (a decline in the left ventricular ejection fraction to <50% AND an absolute drop in the left ventricular ejection fraction of ≥10% from baseline) and incomplete therapy (<52 weeks of HER2-targeted therapy) between black and white women in univariate and multivariable analyses.

RESULTS

The authors identified 59 black patients and 157 white patients who had a median follow-up 5.2 years. The median patient age was 53 years and was similar for black and white patients. The 1-year cardiotoxicity incidence was 12% overall (95% confidence interval [CI], 7%-16%), 24% in black women (95% CI, 12%-34%), and 7% in white women (95% CI, 3%-11%). Black patients had a significantly greater probability of incomplete therapy compared with white patients (odds ratio, 4.61; 95% CI, 1.70-13.07; P = .002). High correlation was observed between a cardiotoxicity event and incomplete therapy (96% concordance).

CONCLUSIONS

Black patients have a higher rate of cardiotoxicity and resultant incomplete adjuvant HER2-targeted therapy than white patients. This patient population may benefit from enhanced cardiac surveillance, cardioprotective strategies, and early referral to cardiology when appropriate. Cancer 2018. © 2018 American Cancer Society.

http://ift.tt/2rRL9Pt

Efficacy and safety analysis by age cohort of inotuzumab ozogamicin in patients with relapsed or refractory acute lymphoblastic leukemia enrolled in INO-VATE

BACKGROUND

Inotuzumab ozogamicin (InO) has demonstrated efficacy and tolerability in patients aged 18 to 78 years with relapsed/refractory acute lymphoblastic leukemia (ALL) in the INO-VATE trial. This subset analysis compared the efficacy and safety of InO in younger and older patients.

METHODS

Intent-to-treat analyses of morphologic responses and overall survival (OS) included 326 randomized patients, and safety assessments included 307 patients receiving 1 or more doses of the study treatment. Of the 326 patients, 164 received InO at a starting dose of 1.8 mg/m²/cycle (0.8 mg/m² on day 1 and 0.5 mg/m² on days 8 and 15 of a 21- to 28-day cycle [≤6 cycles]); 60 patients were aged ≥55 years, and 104 were aged <55 years.

RESULTS

For older and younger patients, the median duration of InO therapy and the types and frequencies of adverse events of any grade were generally similar. Although the remission rates, median duration of remission (DOR), and progression-free survival were similar with InO for those aged <55 years and those aged ≥55 years, OS was longer for younger patients (median, 8.6 vs 5.6 months; hazard ratio, 0.610). Among patients proceeding to hematopoietic stem cell transplantation after InO treatment (28% of older patients and 58% of younger patients), the incidence of veno-occlusive disease was greater in older patients (41% vs 17%). The study database was not locked at the time of this analysis.

CONCLUSIONS

InO was tolerable in older patients with relapsed/refractory ALL. Although OS was longer for younger patients versus older patients, InO demonstrated high response rates with similar DOR in the 2 age groups. Cancer 2018. © 2018 American Cancer Society.

http://ift.tt/2GsBYZ3

An 8-Year-Old Child with Delayed Diagnosis of Netherton Syndrome

We report an 8-year-old boy with Netherton syndrome who was misdiagnosed and treated as severe atopic dermatitis. The diagnosis of Netherton syndrome was not made until the child was 8 years of age. We discuss the pitfalls in the diagnosis and alert physicians to the proper and early diagnosis of this syndrome. The child was treated with a low dose (0.25 mg/kg) of oral acitretin and a topical moisturizer with marked improvement of his skin and pruritus in 2 months. At 6-month follow-up, the skin was almost clear of erythema and scaling, and the hair was longer and stronger. The dose of acitretin was reduced to 0.12 mg/kg for another 6 months and then discontinued.

http://ift.tt/2DPyv9n

Individualization of post-mastectomy radiotherapy and regional nodal irradiation based on treatment response after neoadjuvant chemotherapy for breast cancer

Abstract

Purpose

To review the evidence regarding post-mastectomy radiotherapy (PMRT) and regional nodal irradiation (RNI) after neoadjuvant chemotherapy (NACT) for breast cancer, with a special focus on individualization of adjuvant radiotherapy based on treatment response.

Methods

A systematic literature search using the PubMed/Medline database was performed. We included prospective and retrospective reports with a minimum of 10 patients that had been published since 1^st January 2000, and provided clinical outcome data analyzed by treatment response and radiotherapy.

Results

Out of 763 articles identified via PubMed/Medline and hand search, 68 full text-articles were assessed for eligibility after screening of title and abstract. 13 studies were included in the systematic review, 9 for PMRT and 5 for RNI. All included studies were retrospective reports.

Conclusions

There is a considerable lack of evidence regarding the role of adjuvant radiotherapy and its individualization based on treatment response after NACT. Results of prospective randomized trials such as NSABP B‑51/RTOG 1304 and Alliance A11202 are eagerly awaited.

http://ift.tt/2rQBgkX

Whole-body magnetic resonance imaging for detection of skeletal metastases in children and young people with primary solid tumors - systematic review

Abstract

Background

Many solid neoplasms have a propensity for osteomedullary metastases of which detection is important for staging and subsequent treatment. Whole-body magnetic resonance imaging (WB-MRI) has been shown to accurately detect osteomedullary metastases in adults, but these findings cannot be unconditionally extrapolated to staging of children with malignant solid tumors.

Objective

To conduct a literature review on the sensitivity of WB-MRI for detecting skeletal metastases in children with solid tumors.

Materials and methods

Searches in MEDLINE and EMBASE databases up to 15 May 2017 were performed to identify studies on the diagnostic value of WB-MRI. Inclusion criteria were children and adolescents (age <21 years) with a primary solid tumor who were evaluated for skeletal metastases by WB-MRI and compared to any type of reference standard. The number of included patients had to be at least five and data on true positives, true negatives, false-positives and false-negatives had to be extractable.

Results

Five studies including 132 patients (96 patients with solid tumors) were eligible. Patient groups and used reference tests were heterogeneous, producing unclear or high risk of bias. Sensitivity of WB-MRI ranged between 82% and 100%. The positive predictive value of WB-MRI was variable among the studies and influenced by the used reference standard.

Conclusion

Although WB-MRI may seem a promising radiation-free technique for the detection of skeletal metastases in children with solid tumors, published studies are small and too heterogeneous to provide conclusive evidence that WB-MRI can be an alternative to currently used imaging techniques.

http://ift.tt/2EoLvjc

Pediatric Radiology Continuing Medical Education Activity

http://ift.tt/2DNMdVU

Radiation dose reduction through combining positron emission tomography/computed tomography (PET/CT) and diagnostic CT in children and young adults with lymphoma

Abstract

Background

Both [F-18]2-fluoro-2-deoxyglucose positron emission tomography/computed tomography (¹⁸F–FDG PET/CT) and diagnostic CT are at times required for lymphoma staging. This means some body segments are exposed twice to X-rays for generation of CT data (diagnostic CT + localization CT).

Objective

To describe a combined PET/diagnostic CT approach that modulates CT tube current along the z-axis, providing diagnostic CT of some body segments and localization CT of the remaining body segments, thereby reducing patient radiation dose.

Materials and methods

We retrospectively compared total patient radiation dose between combined PET/diagnostic CT and separately acquired PET/CT and diagnostic CT exams. When available, we calculated effective doses for both approaches in the same patient; otherwise, we used data from patients of similar size. To confirm image quality, we compared image noise (Hounsfield unit [HU] standard deviation) as measured in the liver on both combined and separately acquired diagnostic CT images. We used t-tests for dose comparisons and two one-sided tests for image-quality equivalence testing.

Results

Mean total effective dose for the CT component of the combined and separately acquired diagnostic CT exams were 6.20±2.69 and 8.17±2.61 mSv, respectively (P<0.0001). Average dose savings with the combined approach was 24.8±17.8% (2.60±2.51 mSv [range: 0.32–4.72 mSv]) of total CT effective dose. Image noise was not statistically significantly different between approaches (12.2±1.8 HU vs. 11.7±1.5 HU for the combined and separately acquired diagnostic CT images, respectively).

Conclusion

A combined PET/diagnostic CT approach as described offers dose savings at similar image quality for children and young adults with lymphoma who have indications for both PET and diagnostic CT examinations.

http://ift.tt/2EoLko2

Hermes

http://ift.tt/2DLepsw

Two-point mDIXON turbo spin-echomagnetic resonance imaging of thoracic outlet syndrome at 3-T for robust fat suppression

http://ift.tt/2En5caY

Use of ultrasound in diagnosing postoperative small-bowel intussusception in pediatric surgical oncology patients: a single-center retrospective review

Abstract

Background

Postoperative intussusception can be a complication of abdominal surgery and often poses a diagnostic dilemma.

Objective

The purpose of this study was to evaluate the utility of ultrasonography in the diagnosis of intussusception in children who had recently undergone resection of a primary solid tumor.

Materials and methods

We performed a retrospective review of all pediatric surgical oncology patients undergoing laparotomy for excision of an abdominal tumor at our institution from 1995 to 2015. We reviewed those with documented postoperative intussusception. In addition we searched the radiology database for all ultrasound examinations requested to rule out postoperative intussusception during our study interval. We analyzed demographics, primary diagnosis, surgical procedure, presentation, diagnostic investigations and definitive treatment.

Results

At our institution 852 laparotomies for abdominal tumor resection were performed during the study period, resulting in 10 postoperative intussusceptions (1.2% of cases), of which half were following neuroblastoma resection and the other half following nephrectomy for Wilms tumor. Postoperative intussusception was suspected if the patient had increasing nasogastric output, abdominal distension or feeding intolerance. Ultrasound was used to diagnose intussusception in 9/10 cases, on postoperative day 6 (standard deviation [SD] 5.6 days) on average, with a sensitivity of 89% (8/9; one false negative; 95% confidence interval [CI] 0.52, 1.00) and a specificity of 100% (no false positives; 95% CI 0.96, 1.00).

Conclusion

Ultrasound was highly accurate in diagnosing postoperative intussusception in children who underwent resection of retroperitoneal tumors.

http://ift.tt/2npgSlF

Pediatric lymphangiography, thoracic duct embolization and thoracic duct disruption: a single-institution experience in 11 children with chylothorax

Abstract

Background

Interventional radiology treatment of chylothorax is well described in adults, with high technical and clinical success that decreases patient morbidity and mortality. However there is limited experience in children.

Objective

To report the technical and clinical success of lymphangiography, thoracic duct embolization and thoracic duct disruption in the pediatric population.

Materials and methods

We studied 11 pediatric patients (7 boys, 4 girls; median weight 6.0 kg) who underwent lymphangiography and thoracic duct embolization from November 2015 to May 2017. All 11 (100%) children presented with chylothorax, with 1 (9%) having concomitant chylous ascites and 1 (9%) having concomitant chylopericardium. Ten (91%) children had traumatic chylothorax and one (9%) had congenital chylothorax. We recorded technical success, clinical success and complications.

Results

Twelve procedures were completed in 11 children. Bilateral intranodal lymphangiography was technically successful in all (100%) patients. Central lymphatics were visualized in eight (67%) procedures. Access to central lymphatics was attempted in eight procedures and successful in five (63%). In three (37%) of the eight procedures, disruption was performed when the central lymphatics could not be accessed. Clinical success was achieved in 7/11 (64%) children. Three minor complications were reported. No major complications were encountered.

Conclusion

Lymphangiography, thoracic duct embolization and thoracic duct disruption are successful interventional strategies in children with chylothorax and should be considered as viable treatment options at any age.

http://ift.tt/2DPb0Nq