Significance of poor performance status after resection of colorectal liver metastases

Abstract

Background

Performance status (PS) is known as one of the strongest prognostic factors for survival in metastatic colorectal cancer patients. The aim of the present study was to analyze factors associated with poor PS assessed after resection for colorectal liver metastases and the impact on survival.

Methods

All patients undergoing curative resection for colorectal liver metastases between 2010 and 2015 in a single center were reviewed retrospectively.

Results

A total of 284 patients were included, out of whom 74 patients (26%) presented with a postoperative PS WHO > 2 precluding administration of adjuvant chemotherapy. These patients had a shorter recurrence-free survival (P = 0.002) and shorter overall survival (P < 0.001). Multivariable analysis showed that patients with PS > 2 after surgery had higher preoperative ASA score, had a higher frequency of major complications after surgery, and had more frequently synchronous liver and lung metastases. PS was found to be the strongest independent factor predicting survival (hazard ratio 0.45). When patients with postoperative PS > 2 developed recurrent disease (54 of 74), 43 (80%) received tumor specific treatment.

Conclusions

Patients with postoperative PS > 2 who did not receive adjuvant chemotherapy had decreased recurrence-free and overall survival after liver resection for colorectal liver metastases. After recurrence, a large majority of these patients had had improvement in PS allowing for administration of tumor specific treatment.

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Significance of poor performance status after resection of colorectal liver metastases

Abstract

Background

Performance status (PS) is known as one of the strongest prognostic factors for survival in metastatic colorectal cancer patients. The aim of the present study was to analyze factors associated with poor PS assessed after resection for colorectal liver metastases and the impact on survival.

Methods

All patients undergoing curative resection for colorectal liver metastases between 2010 and 2015 in a single center were reviewed retrospectively.

Results

A total of 284 patients were included, out of whom 74 patients (26%) presented with a postoperative PS WHO > 2 precluding administration of adjuvant chemotherapy. These patients had a shorter recurrence-free survival (P = 0.002) and shorter overall survival (P < 0.001). Multivariable analysis showed that patients with PS > 2 after surgery had higher preoperative ASA score, had a higher frequency of major complications after surgery, and had more frequently synchronous liver and lung metastases. PS was found to be the strongest independent factor predicting survival (hazard ratio 0.45). When patients with postoperative PS > 2 developed recurrent disease (54 of 74), 43 (80%) received tumor specific treatment.

Conclusions

Patients with postoperative PS > 2 who did not receive adjuvant chemotherapy had decreased recurrence-free and overall survival after liver resection for colorectal liver metastases. After recurrence, a large majority of these patients had had improvement in PS allowing for administration of tumor specific treatment.

http://ift.tt/2F2c7pZ

Pharmacokinetics of dacarbazine (DTIC) in pregnancy

Abstract

Purpose

The purpose of this report is to describe, for the first time, the pharmacokinetics of dacarbazine (DTIC) and its metabolites [5-[3-methyl-triazen-1-yl]-imidazole-4-carboxamide (MTIC), 5-[3-hydroxymethyl-3-methyl-triazen-1-yl]-imidazole-4-carboxamide (HMMTIC) and 5-aminoimidazole-4-carboxamide (AIC)] during pregnancy (n = 2) and postpartum (n = 1).

Methods

Non-compartmental DTIC, MTIC, HMMTIC, and AIC pharmacokinetics (PK) were estimated in one case at 29 week gestation and 18 day postpartum and a second case at 32 week gestation, in women receiving DTIC in combination with doxorubicin, bleomycin, and vinblastine for treatment of Hodgkin's lymphoma. Drug concentrations were measured by HPLC.

Results

In the subject who completed both pregnancy and postpartum study days, DTIC area under the concentration–time curve (AUC) was 27% higher and metabolite AUCs were lower by 27% for HMMTIC, 38% for MTIC, and 83% of AIC during pregnancy compared to postpartum. At 7 and 9 year follow-up, both subjects were in remission of their Hodgkin's lymphoma.

Conclusions

Based on these two case reports, pregnancy appears to decrease the metabolism of the pro-drug dacarbazine, likely through inhibition of CYP1A2 activity. Lower concentrations of active metabolites and decreased efficacy may result, although both these subjects experienced long-term remission of their Hodgkin's lymphoma.

http://ift.tt/2CGrt5a

Pharmacokinetics of dacarbazine (DTIC) in pregnancy

Abstract

Purpose

The purpose of this report is to describe, for the first time, the pharmacokinetics of dacarbazine (DTIC) and its metabolites [5-[3-methyl-triazen-1-yl]-imidazole-4-carboxamide (MTIC), 5-[3-hydroxymethyl-3-methyl-triazen-1-yl]-imidazole-4-carboxamide (HMMTIC) and 5-aminoimidazole-4-carboxamide (AIC)] during pregnancy (n = 2) and postpartum (n = 1).

Methods

Non-compartmental DTIC, MTIC, HMMTIC, and AIC pharmacokinetics (PK) were estimated in one case at 29 week gestation and 18 day postpartum and a second case at 32 week gestation, in women receiving DTIC in combination with doxorubicin, bleomycin, and vinblastine for treatment of Hodgkin's lymphoma. Drug concentrations were measured by HPLC.

Results

In the subject who completed both pregnancy and postpartum study days, DTIC area under the concentration–time curve (AUC) was 27% higher and metabolite AUCs were lower by 27% for HMMTIC, 38% for MTIC, and 83% of AIC during pregnancy compared to postpartum. At 7 and 9 year follow-up, both subjects were in remission of their Hodgkin's lymphoma.

Conclusions

Based on these two case reports, pregnancy appears to decrease the metabolism of the pro-drug dacarbazine, likely through inhibition of CYP1A2 activity. Lower concentrations of active metabolites and decreased efficacy may result, although both these subjects experienced long-term remission of their Hodgkin's lymphoma.

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Cancers, Vol. 10, Pages 12: New Interactors of the Truncated EBNA-LP Protein Identified by Mass Spectrometry in P3HR1 Burkitt’s Lymphoma Cells

Cancers, Vol. 10, Pages 12: New Interactors of the Truncated EBNA-LP Protein Identified by Mass Spectrometry in P3HR1 Burkitt's Lymphoma Cells

Cancers doi: 10.3390/cancers10010012

Authors: Sonia Chelouah Emilie Cochet Sophie Couvé Sandy Balkaran Aude Robert Evelyne May Vasily Ogryzko Joëlle Wiels

The Epstein-Barr virus nuclear antigen leader protein (EBNA-LP) acts as a co-activator of EBNA-2, a transcriptional activator essential for Epstein-Barr virus (EBV)-induced B-cell transformation. Burkitt's lymphoma (BL) cells harboring a mutant EBV strain that lacks both the EBNA-2 gene and 3′ exons of EBNA-LP express Y1Y2-truncated isoforms of EBNA-LP (tEBNA-LP) and better resist apoptosis than if infected with the wild-type virus. In such BL cells, tEBNA-LP interacts with the protein phosphatase 2A (PP2A) catalytic subunit (PP2A C), and this interaction likely plays a role in resistance to apoptosis. Here, 28 cellular and four viral proteins have been identified by mass spectrometry as further possible interactors of tEBNA-LP. Three interactions were confirmed by immunoprecipitation and Western blotting, namely with the A structural subunit of PP2A (PP2A A), the structure-specific recognition protein 1 (SSRP1, a component of the facilitate chromatin transcription (FACT) complex), and a new form of the transcription factor EC (TFEC). Thus, tEBNA-LP appears to be involved not only in cell resistance to apoptosis through its interaction with two PP2A subunits, but also in other processes where its ability to co-activate transcriptional regulators could be important.

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Cancers, Vol. 10, Pages 12: New Interactors of the Truncated EBNA-LP Protein Identified by Mass Spectrometry in P3HR1 Burkitt’s Lymphoma Cells

Cancers, Vol. 10, Pages 12: New Interactors of the Truncated EBNA-LP Protein Identified by Mass Spectrometry in P3HR1 Burkitt's Lymphoma Cells

Cancers doi: 10.3390/cancers10010012

Authors: Sonia Chelouah Emilie Cochet Sophie Couvé Sandy Balkaran Aude Robert Evelyne May Vasily Ogryzko Joëlle Wiels

The Epstein-Barr virus nuclear antigen leader protein (EBNA-LP) acts as a co-activator of EBNA-2, a transcriptional activator essential for Epstein-Barr virus (EBV)-induced B-cell transformation. Burkitt's lymphoma (BL) cells harboring a mutant EBV strain that lacks both the EBNA-2 gene and 3′ exons of EBNA-LP express Y1Y2-truncated isoforms of EBNA-LP (tEBNA-LP) and better resist apoptosis than if infected with the wild-type virus. In such BL cells, tEBNA-LP interacts with the protein phosphatase 2A (PP2A) catalytic subunit (PP2A C), and this interaction likely plays a role in resistance to apoptosis. Here, 28 cellular and four viral proteins have been identified by mass spectrometry as further possible interactors of tEBNA-LP. Three interactions were confirmed by immunoprecipitation and Western blotting, namely with the A structural subunit of PP2A (PP2A A), the structure-specific recognition protein 1 (SSRP1, a component of the facilitate chromatin transcription (FACT) complex), and a new form of the transcription factor EC (TFEC). Thus, tEBNA-LP appears to be involved not only in cell resistance to apoptosis through its interaction with two PP2A subunits, but also in other processes where its ability to co-activate transcriptional regulators could be important.

http://ift.tt/2EZoO52

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Evaluation of Endoglin (CD105) expression in pediatric rhabdomyosarcoma

Abstract

Background

The Intratumoral Microvessel Density (IMVD) is commonly used to quantify tumoral vascularization and is usually assessed by pan-endothelial markers, such as CD31. Endoglin (CD105) is a protein predominantly expressed in proliferating endothelium and the IMVD determined by this marker measures specifically the neovascularization. In this study, we investigated the CD105 expression in pediatric rhabdomyosarcoma and assessed the neovascularization by using the angiogenic ratio IMVD-CD105 to IMVD-CD31.

Methods

Paraffin-embedded archival tumor specimens were selected from 65 pediatric patients affected by rhabdomyosarcoma. The expression levels of CD105, CD31 and Vascular Endothelial Growth Factor (VEGF) were investigated in 30 cases (18 embryonal and 12 alveolar) available for this study. The IMVD-CD105 to IMVD-CD31 expression ratio was correlated with clinical and pathologic features of these patients.

Results

We found a specific expression of endoglin (CD105) in endothelial cells of all the rhabdomyosarcoma specimens analyzed. We observed a significant positive correlation between the IMVD individually measured by CD105 and CD31. The CD105/CD31 expression ratio was significantly higher in patients with lower survival and embryonal histology. Indeed, patients with a CD105/CD31 expression ratio < 1.3 had a significantly increased OS (88%, 95%CI, 60%–97%) compared to patients with higher values (40%, 95%CI, 12%–67%). We did not find any statistical correlation among VEGF and EFS, OS and CD105/CD31 expression ratio.

Conclusion

CD105 is expressed on endothelial cells of rhabdomyosarcoma and represent a useful tool to quantify neovascularization in this tumor. If confirmed by further studies, these results will indicate that CD105 is a potential target for combined therapies in rhabdomyosarcoma.

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Inhibition of neddylation facilitates cell migration through enhanced phosphorylation of caveolin-1 in PC3 and U373MG cells

Abstract

Background

Protein neddylation is a post-translational modification by a covalent conjugation with the neural precursor cell expressed, developmentally downregulated 8 (NEDD8). Although this process has been reported to participate in diverse cellular signaling, little is known about its role in cancer cell migration. Given a recent proteomics report showing that NEDD8 is downregulated in prostate cancer tissues versus normal prostate tissues, we tested the possibility that neddylation plays a role in cancer evolution, and then tried to identify target proteins of the neddylation.

Methods

The neddylation process was inhibited by transfecting cancer cells with NEDD8-targeting siRNAs or by treating the cells with a NAE1 inhibitor MLN4924. Cell migration was evaluated by an in vitro wound-healing assay and a Transwell migration assay. His/NEDD8-conjugated proteins were pulled down with nickel-affinity beads under a denaturing condition, and identified by Western blotting. All data were processed using the Microsoft Excel program and analyzed statistically by two-sided, unpaired Student's t-test.

Results

Caveolin-1, which plays a critical role in cell migration, was identified to be conjugated with NEDD8. When the neddylation was inhibited, the phosphorylation of caveolin-1 at Tyr14 was augmented in PC3 and U373MG cells, thereby leading to increased cell migration. Such consequences by neddylation inhibition were abolished in the presence of a Src family kinase inhibitor PP2.

Conclusions

NEDD8 seems to inhibit the Src-mediated phosphorylation of caveolin-1 by modifying the structure of caveolin-1 protein, which blocks the migration of cancer cells. Although the neddylation process is currently regarded as an emerging target for cancer therapy, our results suggest the possibility that the inhibition of neddylation could facilitate cancer invasion or metastasis at least in some types of cancers.

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Evolutionary aspects of non-metastatic breast cancer after primary treatment in a sub-Saharan African setting: a 16-year retrospective review at the Douala general hospital, Cameroon

Abstract

Background

Breast cancer has a high case fatality rate in sub-Saharan Africa, and this is chiefly because of late detection and inadequate treatment resources. Progressive renovations in diagnostic and management modalities of non-metastatic breast cancer (NMBC) have been noted in the region but there is paucity of data describing the clinical progress of patients with NMBC. This study sought to determine the rates of local relapse, distant metastasis and sequelae and the time span from initial treatment to the occurrence of these adverse events among patients with NMBC.

Methods

This was a retrospective review of medical records of patients with histologically confirmed NMBC at the department of radiation therapy and oncology of the Douala General Hospital in Cameroon from the January 1997 to December 2012 period. Clinicopathological and treatment characteristics as well as occurrences of adverse events were studied.

Results

A total of 260 cases were reviewed of which 224/260 (86.2%) had invasive ductal carcinoma. Surgery was performed on 258/260 cases (99.2%) with 187/258 (72.5%) being modified radical mastectomies. Various treatment combinations were used in up to 228/260 patients (87.5%) while surgery alone was the treatment in the remaining 32 cases (12.5%). Metastasis occurred in 142/260 cases (54.6%) of which 68/142 (26.2%) were local relapses and 74/142 (28.5%) were distant metastases. Among the cases of distant metastasis, 9.2% were bone, 8.5% lungs, 6.9% nodal, and 5.4% brain. Metastasis to multiple organs was noted in 4.7% of these cases. The median periods of occurrence of local relapse and distant metastases were 13 and 12 months respectively. Sequelae occurred in 26/260 cases (10%) and were noted after an average of 30 months. The main sequelae were lymphoedema (6.5%) and lung fibrosis (1.5%). At the end of the period under review, 118/260 patients (45.4%) were alive and disease-free with a median follow up time of 24 months.

Conclusions

Adverse events were frequent among patients who received primary treatment for NMBC. Available cancer therapeutic modalities ought to be supplemented with efficient strategies of follow-up and monitoring so as to optimize the care provided to these patients and improve on their survival.

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Issue Information

http://ift.tt/2Ctg2dZ

Issue Information

http://ift.tt/2lZexhb

Evaluation of Endoglin (CD105) expression in pediatric rhabdomyosarcoma

Abstract

Background

The Intratumoral Microvessel Density (IMVD) is commonly used to quantify tumoral vascularization and is usually assessed by pan-endothelial markers, such as CD31. Endoglin (CD105) is a protein predominantly expressed in proliferating endothelium and the IMVD determined by this marker measures specifically the neovascularization. In this study, we investigated the CD105 expression in pediatric rhabdomyosarcoma and assessed the neovascularization by using the angiogenic ratio IMVD-CD105 to IMVD-CD31.

Methods

Paraffin-embedded archival tumor specimens were selected from 65 pediatric patients affected by rhabdomyosarcoma. The expression levels of CD105, CD31 and Vascular Endothelial Growth Factor (VEGF) were investigated in 30 cases (18 embryonal and 12 alveolar) available for this study. The IMVD-CD105 to IMVD-CD31 expression ratio was correlated with clinical and pathologic features of these patients.

Results

We found a specific expression of endoglin (CD105) in endothelial cells of all the rhabdomyosarcoma specimens analyzed. We observed a significant positive correlation between the IMVD individually measured by CD105 and CD31. The CD105/CD31 expression ratio was significantly higher in patients with lower survival and embryonal histology. Indeed, patients with a CD105/CD31 expression ratio < 1.3 had a significantly increased OS (88%, 95%CI, 60%–97%) compared to patients with higher values (40%, 95%CI, 12%–67%). We did not find any statistical correlation among VEGF and EFS, OS and CD105/CD31 expression ratio.

Conclusion

CD105 is expressed on endothelial cells of rhabdomyosarcoma and represent a useful tool to quantify neovascularization in this tumor. If confirmed by further studies, these results will indicate that CD105 is a potential target for combined therapies in rhabdomyosarcoma.

http://ift.tt/2qrgWG5

Inhibition of neddylation facilitates cell migration through enhanced phosphorylation of caveolin-1 in PC3 and U373MG cells

Abstract

Background

Protein neddylation is a post-translational modification by a covalent conjugation with the neural precursor cell expressed, developmentally downregulated 8 (NEDD8). Although this process has been reported to participate in diverse cellular signaling, little is known about its role in cancer cell migration. Given a recent proteomics report showing that NEDD8 is downregulated in prostate cancer tissues versus normal prostate tissues, we tested the possibility that neddylation plays a role in cancer evolution, and then tried to identify target proteins of the neddylation.

Methods

The neddylation process was inhibited by transfecting cancer cells with NEDD8-targeting siRNAs or by treating the cells with a NAE1 inhibitor MLN4924. Cell migration was evaluated by an in vitro wound-healing assay and a Transwell migration assay. His/NEDD8-conjugated proteins were pulled down with nickel-affinity beads under a denaturing condition, and identified by Western blotting. All data were processed using the Microsoft Excel program and analyzed statistically by two-sided, unpaired Student's t-test.

Results

Caveolin-1, which plays a critical role in cell migration, was identified to be conjugated with NEDD8. When the neddylation was inhibited, the phosphorylation of caveolin-1 at Tyr14 was augmented in PC3 and U373MG cells, thereby leading to increased cell migration. Such consequences by neddylation inhibition were abolished in the presence of a Src family kinase inhibitor PP2.

Conclusions

NEDD8 seems to inhibit the Src-mediated phosphorylation of caveolin-1 by modifying the structure of caveolin-1 protein, which blocks the migration of cancer cells. Although the neddylation process is currently regarded as an emerging target for cancer therapy, our results suggest the possibility that the inhibition of neddylation could facilitate cancer invasion or metastasis at least in some types of cancers.

http://ift.tt/2m0fPJ3

Evolutionary aspects of non-metastatic breast cancer after primary treatment in a sub-Saharan African setting: a 16-year retrospective review at the Douala general hospital, Cameroon

Abstract

Background

Breast cancer has a high case fatality rate in sub-Saharan Africa, and this is chiefly because of late detection and inadequate treatment resources. Progressive renovations in diagnostic and management modalities of non-metastatic breast cancer (NMBC) have been noted in the region but there is paucity of data describing the clinical progress of patients with NMBC. This study sought to determine the rates of local relapse, distant metastasis and sequelae and the time span from initial treatment to the occurrence of these adverse events among patients with NMBC.

Methods

This was a retrospective review of medical records of patients with histologically confirmed NMBC at the department of radiation therapy and oncology of the Douala General Hospital in Cameroon from the January 1997 to December 2012 period. Clinicopathological and treatment characteristics as well as occurrences of adverse events were studied.

Results

A total of 260 cases were reviewed of which 224/260 (86.2%) had invasive ductal carcinoma. Surgery was performed on 258/260 cases (99.2%) with 187/258 (72.5%) being modified radical mastectomies. Various treatment combinations were used in up to 228/260 patients (87.5%) while surgery alone was the treatment in the remaining 32 cases (12.5%). Metastasis occurred in 142/260 cases (54.6%) of which 68/142 (26.2%) were local relapses and 74/142 (28.5%) were distant metastases. Among the cases of distant metastasis, 9.2% were bone, 8.5% lungs, 6.9% nodal, and 5.4% brain. Metastasis to multiple organs was noted in 4.7% of these cases. The median periods of occurrence of local relapse and distant metastases were 13 and 12 months respectively. Sequelae occurred in 26/260 cases (10%) and were noted after an average of 30 months. The main sequelae were lymphoedema (6.5%) and lung fibrosis (1.5%). At the end of the period under review, 118/260 patients (45.4%) were alive and disease-free with a median follow up time of 24 months.

Conclusions

Adverse events were frequent among patients who received primary treatment for NMBC. Available cancer therapeutic modalities ought to be supplemented with efficient strategies of follow-up and monitoring so as to optimize the care provided to these patients and improve on their survival.

http://ift.tt/2qrQs7q

A Coated Sponge: Toward Neonatal Brain Repair

Publication date: 4 January 2018
Source:Cell Stem Cell, Volume 22, Issue 1
Author(s): Orly Reiner, Tamar Sapir
In this issue of Cell Stem Cell, Jinnou et al. (2018) identify a limited time window wherein neonatal brain injuries may be treated through neuroblast migration toward the injury site on radial glial fibers. Implanting a sponge coated with an adhesive factor in the injured neonatal brain supports the migration of neuroblasts and improves functional recovery.

Teaser

In this issue of Cell Stem Cell, Jinnou et al. (2018) identify a limited time window wherein neonatal brain injuries may be treated through neuroblast migration toward the injury site on radial glial fibers. Implanting a sponge coated with an adhesive factor in the injured neonatal brain supports the migration of neuroblasts and improves functional recovery.


http://ift.tt/2CVZcWa

Chewing through Roots: How Leukemia Invades and Disrupts the Bone Marrow Microenvironment

Publication date: 4 January 2018
Source:Cell Stem Cell, Volume 22, Issue 1
Author(s): Owen J. Tamplin
The bone marrow (BM) niche is a complex microenvironment that supports healthy hematopoietic stem cells (HSCs) throughout life. In this issue of Cell Stem Cell, Duarte et al. (2018) reveal the spatio-temporal progress of leukemic cells as they invade and occupy the niche, ultimately outcompeting native HSCs.

Teaser

The bone marrow (BM) niche is a complex microenvironment that supports healthy hematopoietic stem cells (HSCs) throughout life. In this issue of Cell Stem Cell, Duarte et al. (2018) reveal the spatio-temporal progress of leukemic cells as they invade and occupy the niche, ultimately outcompeting native HSCs.


http://ift.tt/2CsavUX

Think About the Environment: Cellular Reprogramming by the Extracellular Matrix

Publication date: 4 January 2018
Source:Cell Stem Cell, Volume 22, Issue 1
Author(s): David J. Huels, Jan Paul Medema
In this issue of Cell Stem Cell, Yui et al. (2018) show how tissue regeneration is driven by changes in the microenvironment. During intestinal regeneration, the epithelium is reprogrammed into a fetal state by an altered extracellular matrix (ECM), which is dependent on YAP/TAZ activation.

Teaser

In this issue of Cell Stem Cell, Yui et al. (2018) show how tissue regeneration is driven by changes in the microenvironment. During intestinal regeneration, the epithelium is reprogrammed into a fetal state by an altered extracellular matrix (ECM), which is dependent on YAP/TAZ activation.


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Turning up the Heat with Therapeutic Epigenome Editing

Publication date: 4 January 2018
Source:Cell Stem Cell, Volume 22, Issue 1
Author(s): Alexandra Zezulin, Kiran Musunuru
CRISPR-Cas9 has been touted for therapeutic genome editing, but limitations include inefficient correction of disease-causing mutations and off-target mutagenesis. In the latest issue of Cell, Liao et al. (2017) show that a modified version of CRISPR-Cas9 can target and activate key therapeutic genes in vivo without altering DNA sequence identity.

Teaser

CRISPR-Cas9 has been touted for therapeutic genome editing, but limitations include inefficient correction of disease-causing mutations and off-target mutagenesis. In the latest issue of Cell, Liao et al. show that a modified version of CRISPR-Cas9 can target and activate key therapeutic genes in vivo without altering DNA sequence identity.


http://ift.tt/2CqZGlP

Alpha to Beta Cell Reprogramming: Stepping toward a New Treatment for Diabetes

Publication date: 4 January 2018
Source:Cell Stem Cell, Volume 22, Issue 1
Author(s): Anna B. Osipovich, Mark A. Magnuson
Beta cell replacement strategies hold promise for permanently treating type 1 diabetes. In Cell Stem Cell, Xiao et al. (2018) restore pancreatic beta cell mass and normalize blood glucose in diabetic mice by reprogramming pancreatic alpha to beta cells using Pdx1- and Mafa-expressing adeno-associated virus infused into the pancreatic duct.

Teaser

Beta cell replacement strategies hold promise for permanently treating type 1 diabetes. In Cell Stem Cell, Xiao et al. restore pancreatic beta cell mass and normalize blood glucose in diabetic mice by reprogramming pancreatic alpha to beta cells using Pdx1- and Mafa-expressing adeno-associated virus infused into the pancreatic duct.


http://ift.tt/2CXKHBa

Self-Renewal and Lineage Transitions

Publication date: 4 January 2018
Source:Cell Stem Cell, Volume 22, Issue 1
Author(s): Sheila Chari




http://ift.tt/2Cw2FJX

The Skin(ny) on Regenerating the Largest Organ to Save a Patient’s Life

Publication date: 4 January 2018
Source:Cell Stem Cell, Volume 22, Issue 1
Author(s): Rui Yi
Stem cells hold enormous potential to regenerate an entire organ for organ replacement therapy. Recently, in Nature, Hirsch et al. (2017) restored the expression of laminin-332 in epidermal stem cells isolated from an individual with junctional epidermolysis bullosa and grafted the entire skin back to save the patient's life.

Teaser

Stem cells hold enormous potential to regenerate an entire organ for organ replacement therapy. Recently, in Nature, Hirsch et al. (2017) restored the expression of laminin-332 in epidermal stem cells isolated from an individual with junctional epidermolysis bullosa and grafted the entire skin back to save the patient's life.


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Ihor R. Lemischka (1953–2017)

Publication date: 4 January 2018
Source:Cell Stem Cell, Volume 22, Issue 1
Author(s): Natalia Ivanova, Carlos-Filipe Pereira, Dung-Fang Lee




http://ift.tt/2CVbga4

Mentoring the Next Generation: Brigid Hogan

Publication date: 4 January 2018
Source:Cell Stem Cell, Volume 22, Issue 1

Mentor-mentee relationships are essential for professional development, but developing these interpersonal skills is not often highlighted as a priority in scientific endeavors. In a yearlong series, Cell Stem Cell interviews prominent scientists who have prioritized mentorship over the years. Here, we chat with Dr. Brigid Hogan about her views.



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iPSC-Derived Organs In Vivo: Challenges and Promise

Publication date: 4 January 2018
Source:Cell Stem Cell, Volume 22, Issue 1
Author(s): Fabian Suchy, Tomoyuki Yamaguchi, Hiromitsu Nakauchi
Transplanting iPSCs into the embryos of another species can generate functional organs for basic research and translational applications. We discuss forward-looking approaches and address key remaining challenges of generating iPSC-derived human organs in vivo.

Teaser

Transplanting iPSCs into the embryos of another species can generate functional organs for basic research and translational applications. We discuss forward-looking approaches and address key remaining challenges of generating iPSC-derived human organs in vivo.


http://ift.tt/2CTDmT0

Capturing Totipotent Stem Cells

Publication date: 4 January 2018
Source:Cell Stem Cell, Volume 22, Issue 1
Author(s): Christopher L. Baker, Martin F. Pera
Minority subpopulations within embryonic stem cell cultures display an expanded developmental potential similar to that of early embryo blastomeres or the early inner cell mass. The ability to isolate and culture totipotent cells capable of giving rise to the entire conceptus would enhance our capacity to study early embryo development, and might enable more efficient generation of chimeric animals for research and organ production for transplantation. Here we review the biological and molecular characterization of cultured cells with developmental potential similar to totipotent blastomeres, and assess recent progress toward the capture and stabilization of the totipotent state in vitro.

Teaser

Baker and Pera review the biological and molecular characterization of cultured cells with developmental potential similar to totipotent blastomeres, and assess recent progress toward the capture and stabilization of the totipotent state in vitro.


http://ift.tt/2CrdX1Y

Endogenous Reprogramming of Alpha Cells into Beta Cells, Induced by Viral Gene Therapy, Reverses Autoimmune Diabetes

Publication date: 4 January 2018
Source:Cell Stem Cell, Volume 22, Issue 1
Author(s): Xiangwei Xiao, Ping Guo, Chiyo Shiota, Ting Zhang, Gina M. Coudriet, Shane Fischbach, Krishna Prasadan, Joseph Fusco, Sabarinathan Ramachandran, Piotr Witkowski, Jon D. Piganelli, George K. Gittes
Successful strategies for treating type 1 diabetes need to restore the function of pancreatic beta cells that are destroyed by the immune system and overcome further destruction of insulin-producing cells. Here, we infused adeno-associated virus carrying Pdx1 and MafA expression cassettes through the pancreatic duct to reprogram alpha cells into functional beta cells and normalized blood glucose in both beta cell-toxin-induced diabetic mice and in autoimmune non-obese diabetic (NOD) mice. The euglycemia in toxin-induced diabetic mice and new insulin⁺ cells persisted in the autoimmune NOD mice for 4 months prior to reestablishment of autoimmune diabetes. This gene therapy strategy also induced alpha to beta cell conversion in toxin-treated human islets, which restored blood glucose levels in NOD/SCID mice upon transplantation. Hence, this strategy could represent a new therapeutic approach, perhaps complemented by immunosuppression, to bolster endogenous insulin production. Our study thus provides a potential basis for further investigation in human type 1 diabetes.

Graphical abstract

Teaser

Reprograming of endogenous mouse alpha cells into functional beta cells, which significantly delays diabetes onset in autoimmune diabetic mice, and the successful reprograming of human alpha cells into beta cells with the same strategy represent a promising way for treating type 1 diabetes.


http://ift.tt/2CVvIaO

Prognostic value of the Glasgow Prognostic Score for patients with metastatic renal cell carcinoma treated by cytoreductive nephrectomy

Abstract

Background

The aim of the present study was to evaluate the prognostic significance of the Glasgow Prognostic Score (GPS) in metastatic renal cell carcinoma (mRCC) patients treated by cytoreductive nephrectomy (CN), and the accuracy of the GPS as a prognostic factor.

Methods

We retrospectively analyzed the data of patients who underwent CN for mRCC between March 1984 and August 2015. In accordance with the GPS criteria, the patients were classified into three groups: GPS 0: C-reactive protein (CRP) ≤ 1.0 mg/dl and albumin ≥ 3.5 g/dl; GPS 1: CRP > 1.0 mg/dl or albumin < 3.5 g/dl; and GPS 2: CRP > 1.0 mg/dl and albumin < 3.5 g/dl.

Results

We enrolled 170 patients (72% male; median age 63.5 years). Fifty-six (33%), 67 (39%), and 47 (28%) patients had a GPS of 0, 1, and 2, respectively. The median overall survivals after CN were 52.4, 19.1, and 8.9 months for patients with a GPS of 0, 1, and 2, respectively (P < 0.0001). In addition to the GPS, Eastern Cooperative Oncology Group performance status (ECOG-PS), Memorial Sloan-Kettering Cancer Center (MSKCC) risk classification, histology, sarcomatoid change, clinical T stage, primary tumor size, number of metastatic organs, non-regional lymph node metastasis, and liver metastasis were included in the Cox hazards regression model. Multivariate analysis of these factors revealed that the GPS was an independent prognostic factor of overall survival (P < 0.0001). Harrell's concordance index in the multivariate prognostic model based on ECOG-PS, MSKCC risk criteria, histology, sarcomatoid change, clinical T stage, primary tumor size, number of metastatic organs, non-regional lymph node metastasis, and liver metastasis was 0.609, which increased to 0.652 after the inclusion of the GPS.

Conclusions

GPS represents an independent prognostic factor for patients who undergo CN for mRCC.

http://ift.tt/2Av1I2B

Prognostic value of the Glasgow Prognostic Score for patients with metastatic renal cell carcinoma treated by cytoreductive nephrectomy

Abstract

Background

The aim of the present study was to evaluate the prognostic significance of the Glasgow Prognostic Score (GPS) in metastatic renal cell carcinoma (mRCC) patients treated by cytoreductive nephrectomy (CN), and the accuracy of the GPS as a prognostic factor.

Methods

We retrospectively analyzed the data of patients who underwent CN for mRCC between March 1984 and August 2015. In accordance with the GPS criteria, the patients were classified into three groups: GPS 0: C-reactive protein (CRP) ≤ 1.0 mg/dl and albumin ≥ 3.5 g/dl; GPS 1: CRP > 1.0 mg/dl or albumin < 3.5 g/dl; and GPS 2: CRP > 1.0 mg/dl and albumin < 3.5 g/dl.

Results

We enrolled 170 patients (72% male; median age 63.5 years). Fifty-six (33%), 67 (39%), and 47 (28%) patients had a GPS of 0, 1, and 2, respectively. The median overall survivals after CN were 52.4, 19.1, and 8.9 months for patients with a GPS of 0, 1, and 2, respectively (P < 0.0001). In addition to the GPS, Eastern Cooperative Oncology Group performance status (ECOG-PS), Memorial Sloan-Kettering Cancer Center (MSKCC) risk classification, histology, sarcomatoid change, clinical T stage, primary tumor size, number of metastatic organs, non-regional lymph node metastasis, and liver metastasis were included in the Cox hazards regression model. Multivariate analysis of these factors revealed that the GPS was an independent prognostic factor of overall survival (P < 0.0001). Harrell's concordance index in the multivariate prognostic model based on ECOG-PS, MSKCC risk criteria, histology, sarcomatoid change, clinical T stage, primary tumor size, number of metastatic organs, non-regional lymph node metastasis, and liver metastasis was 0.609, which increased to 0.652 after the inclusion of the GPS.

Conclusions

GPS represents an independent prognostic factor for patients who undergo CN for mRCC.

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An RNA-based digital circulating tumor cell signature is predictive of drug response and early dissemination in prostate cancer [Research Articles]

Blood-based biomarkers are critical in metastatic prostate cancer, where characteristic bone metastases are not readily sampled, and they may enable risk stratification in localized disease. We established a sensitive and high-throughput strategy for analyzing prostate circulating tumor cells (CTCs) using microfluidic cell enrichment followed by digital quantitation of prostate-derived transcripts. In a prospective study of 27 metastatic castration-resistant prostate cancer patients treated with first-line abiraterone, pretreatment elevation of the digital CTCM Score identifies a high risk population with poor overall survival (HR 6.0, P=0.01) and short radiographic progression-free survival (HR 3.2, P=0.046). Expression of HOXB13 in CTCs identifies 6/6 patients with ≤12 months survival, with a subset also expressing the AR-V7 splice variant. In a second cohort of 34 men with localized prostate cancer, an elevated preoperative CTCL Score predicts microscopic dissemination to seminal vesicles and/or lymph nodes (P<0.001). Thus, digital quantitation of CTC-specific transcripts enables noninvasive monitoring that may guide treatment selection in both metastatic and localized prostate cancer.

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Establishing A Preclinical Multidisciplinary Board for Brain Tumors

Purpose: Curing all children with brain tumors will require an understanding of how each subtype responds to conventional treatments and how best to combine existing and novel therapies.  It is extremely challenging to acquire this knowledge in the clinic alone, especially among patients with rare tumors.  Therefore, we developed a preclinical brain tumor platform to test combinations of conventional and novel therapies in a manner that closely recapitulates clinic trials.  Experimental Design: A multidisciplinary team was established to design and conduct neurosurgical, fractionated radiotherapy and chemotherapy studies, alone or in combination, in accurate mouse models of supratentorial ependymoma (SEP) subtypes and choroid plexus carcinoma (CPC).  Extensive drug repurposing screens, pharmacokinetic, pharmacodynamic and efficacy studies were used to triage active compounds for combination preclinical trials with 'standard-of-care' surgery and radiotherapy. Results: Mouse models displayed distinct patterns of response to surgery, irradiation and chemotherapy that varied with tumor subtype.  Repurposing screens identified three hour infusions of gemcitabine as a relatively non-toxic and efficacious treatment of SEP and CPC.  Combination neurosurgery, fractionated irradiation and gemcitabine proved significantly more effective than surgery and irradiation alone, curing one half of all animals with aggressive forms of SEP. Conclusions: We report a comprehensive preclinical trial platform to assess the therapeutic activity of conventional and novel treatments among rare brain tumor subtypes. It also enables the development of complex, combination treatment regimens that should deliver optimal trial designs for clinical testing.  Post-irradiation gemcitabine infusion should be tested as new treatments of SEP and CPC.

http://ift.tt/2EYc2Ub

Pancreatic juice mutation concentrations can help predict the grade of dysplasia in patients undergoing pancreatic surveillance

Purpose: The measurement of mutations in pancreatic juice samples collected from the duodenum during endoscopic ultrasound (EUS) may improve the diagnostic evaluation of patients undergoing pancreatic surveillance. Our aim was to evaluate the accuracy of using pancreatic juice mutation concentrations to predict the presence and histologic grade of neoplasia in the pancreas.

Experimental Design: Digital next-generation sequencing (NGS) of pancreatic juice DNA using a targeted 12-gene panel was performed on 67 patients undergoing pancreatic evaluation during EUS including patients with pancreatic ductal adenocarcinoma, patients who subsequently underwent pancreatic resection for precursor lesions, patients undergoing surveillance for their familial/inherited susceptibility to pancreatic cancer, and normal pancreas disease controls.

Results: Patients with pancreatic cancer or high-grade dysplasia as their highest grade lesion had significantly higher pancreatic juice mutation concentrations than all other subjects (mean/s.d. digital NGS score; 46.6+/-69.7 vs. 6.2+/-11.6, p=0.02). Pancreatic juice mutation concentrations distinguished patients with pancreatic cancer or high-grade dysplasia in their resection specimen from all other subjects with a sensitivity, 72.2%, specificity, 89.4% (area under the curve, AUC 0.872). Mutant TP53/SMAD4 concentrations could distinguish patients with pancreatic cancer or high-grade dysplasia in their resection specimen, from all other subjects with 61.1% sensitivity, 95.7% specificity (AUC 0.819). Among 31 high-risk individuals under surveillance, 2 of the 3 individuals with most abnormal pancreatic juice mutation profiles also had the most abnormalities on pancreatic imaging.

Conclusions: Pancreatic juice mutation analysis using digital NGS has potential diagnostic utility in the evaluation of patients undergoing pancreatic surveillance.  

http://ift.tt/2E7pUu5

Genomic correlates of response to everolimus in aggressive radioiodine-refractory thyroid cancer: a phase II study

Purpose: Targeting mutations leading to PI3K/mTOR/Akt activation are of interest in thyroid cancer (TC). We evaluated the efficacy of everolimus in aggressive, radioactive iodine refractory (RAIR) TC and correlated tumor mutational profiling with response. Exploratory medullary and anaplastic TC cohorts were included. Experimental Design: This single-arm, multi-institutional phase II study was conducted from 2009-2013 in patients with incurable RAIR TC who had radiographic progression six months prior to enrollment. The primary endpoint was progression-free survival (PFS) with a median follow-up of 31.8 months. The study is closed to enrollment but treatment and follow-up are ongoing. A targeted next-generation sequencing platform was used for mutational analysis. Results: Thirty-three patients with differentiated TC (DTC), 10 with medullary TC (MTC), and 7 with anaplastic TC (ATC) enrolled. For the DTC cohort, median PFS was 12.9 months (95% CI, 7.3-18.5) with a 2-year PFS of 23.6% (95% CI, 10.5-39.5). Median OS was not reached; 2-year OS was 73.5% (95% CI, 53.8-85.8). Among ATC patients, 1 had a partial response and was progression-free until 17.9 months post study entry and one had disease stability for 26 months, respectively. The genomically profiled cohort enriched for PI3K/mTOR/Akt alterations. PI3K/mTOR/Akt mutated ATC subgroups appeared to benefit from everolimus. Treatment-related adverse events were as anticipated.  Conclusions: Everolimus has significant anti-tumor activity in TC. While genomic profiling does not currently guide therapeutic selection in TC patients, these data have important implications when considering the use of an mTOR inhibitor in an era of precision medicine.

http://ift.tt/2EXRICx

Activation of 4-1BB on liver myeloid cells triggers hepatitis via an interleukin-27 dependent pathway

Purpose: Agonist antibodies targeting the T cell co-stimulatory receptor 4-1BB (CD137) are among the most effective immunotherapeutic agents across pre-clinical cancer models. In the clinic, however, development of these agents has been hampered by dose-limiting liver toxicity. Lack of knowledge of the mechanisms underlying this toxicity has limited the potential to separate 4-1BB agonist driven tumor immunity from hepatotoxicity. Experimental Design: The capacity of 4-1BB agonist antibodies to induce liver toxicity was investigated in immunocompetent mice, with or without co-administration of checkpoint blockade, via 1) measurement of serum transaminase levels, 2) imaging of liver immune infiltrates, and 3) qualitative and quantitative assessment of liver myeloid and T cells via flow cytometry. Knockout mice were used to clarify the contribution of specific cell subsets, cytokines and chemokines. Results: We find that activation of 4-1BB on liver myeloid cells is essential to initiate hepatitis. Once activated, these cells produce interleukin-27 that is required for liver toxicity. CD8 T cells infiltrate the liver in response to this myeloid activation and mediate tissue damage, triggering transaminase elevation. FoxP3+ regulatory T cells limit liver damage, and their removal dramatically exacerbates 4-1BB agonist-induced hepatitis. Co-administration of CTLA-4 blockade ameliorates transaminase elevation, whereas PD-1 blockade exacerbates it. Loss of the chemokine receptor CCR2 blocks 4-1BB agonist hepatitis without diminishing tumor-specific immunity against B16 melanoma. Conclusions: 4-1BB agonist antibodies trigger hepatitis via activation and expansion of interleukin-27-producing liver Kupffer cells and monocytes. Co-administration of CTLA-4 and/or CCR2 blockade may minimize hepatitis, but yield equal or greater antitumor immunity.

http://ift.tt/2Eaj1IK

Identification of a novel, EBV-based antibody risk stratification signature for early detection of nasopharyngeal carcinoma in Taiwan

Background.Epstein-Barr virus (EBV) is necessary for the development of nasopharyngeal carcinoma (NPC). By adulthood, ~90% of individuals test EBV-positive, but only a fraction develop cancer. Factors that identify which individuals are most likely to develop disease, including differential antibody response to the virus, could facilitate detection at early stages when treatment is most effective. Methods. We measured anti-EBV IgG and IgA antibody responses in 607 Taiwanese individuals. Antibodies were measured using a custom protein microarray targeting 199 sequences from 86 EBV proteins. Variation in response patterns between NPC cases and controls was used to develop an antibody-based risk score for predicting NPC. The overall accuracy (area under the curve[AUC]) of this risk score, and its performance relative to currently-used biomarkers, was evaluated in two independent Taiwanese cohorts. Findings. Levels of 60 IgA and 73 IgG anti-EBV antibodies differed between Stage I/IIa NPC cases and controls (P<0·0002). Risk prediction analyses identified antibody targets that best discriminated NPC status-BXLF1,LF2,BZLF1,BRLF1,EAd, BGLF2,BPLF1,BFRF1, and BORF1. When combined with currently-used VCA/EBNA1 IgA biomarkers, the resulting risk score predicted NPC with 93% accuracy (95%CI 87-98%) in the general Taiwanese population, a significant improvement beyond current biomarkers alone (82%;95%CI 75-90%,P<0·01). This EBV-based risk score also improved NPC prediction in genetically high-risk families (89%;95%CI 82-96%) compared to current biomarkers (78%;95%CI 66-90%,P<0·03). Interpretation. We identified NPC-related differences in 133 anti-EBV antibodies and developed a risk score using this microarray dataset that targeted immune responses against EBV proteins from all stages of the viral life cycle, significantly improving the ability to predict NPC.

http://ift.tt/2EZyahg

Thy1-Targeted Microbubbles for Ultrasound Molecular Imaging of Pancreatic Ductal Adenocarcinoma

Purpose: To engineer a dual human and murine Thy1-binding single-chain-antibody ligand (Thy1-scFv) for contrast microbubble-enhanced ultrasound molecular imaging of pancreatic ductal adenocarcinoma (PDAC). Experimental Design: Thy1-scFv were engineered using yeast-surface-display techniques. Binding to soluble human and murine Thy1 and to Thy1-expressing cells was assessed by flow cytometry. Thy1-scFv was then attached to gas-filled microbubbles to create MB Thy1-scFv. Thy1 binding of MB Thy1-scFv to Thy1-expressing cells was evaluated under flow shear stress conditions in flow-chamber experiments. MB scFv-scrambled and MB Non-targeted were used as negative controls. All microbubble types were tested in both orthotopic human PDAC xenografts and transgenic PDAC mice in vivo. Results: Thy1-scFv had a K D of 3.4±0.36 nM for human and 9.2±1.7 nM for murine Thy1 and showed binding to both soluble and cellularly expressed Thy1. MB Thy1-scFv attached to Thy1 with high affinity compared to negative control microbubbles P<0.01) as assessed by flow cytometry. Similarly, flow-chamber studies showed significantly (P<0.01) higher binding of MB Thy1-scFv (3.0±0.81 MB/cell) to Thy1-expressing cells than MB scFv-scrambled (0.57±0.53) and MB Non-targeted (0.43±0.53). In vivo ultrasound molecular imaging using MB Thy1-scFv demonstrated significantly higher signal (P<0.01) in both orthotopic (5.32±1.59 a.u.) and transgenic PDAC (5.68±2.5 a.u.) mice compared to chronic pancreatitis (0.84±0.6 a.u.) and normal pancreas (0.67±0.71 a.u.). Ex vivo immunofluorescence confirmed significantly (P<0.01) increased Thy1 expression in PDAC compared to chronic pancreatitis and normal pancreas tissue. Conclusions: A dual human and murine Thy1-binding scFv was designed to generate contrast microbubbles to allow PDAC detection with ultrasound.

http://ift.tt/2EaiTsF

p53-reactive T cells are associated with clinical benefit in patients with platinum-resistant epithelial ovarian cancer after treatment with a p53 vaccine and gemcitabine chemotherapy

Purpose: To conduct a Phase I trial of a Modified Vaccinia Ankara vaccine delivering wild type human p53 (p53MVA) in combination with gemcitabine chemotherapy in patients with platinum-resistant ovarian cancer. Experimental Design: Patients received gemcitabine on days 1 and 8 and p53MVA vaccine on day 15, during the first 3 cycles of chemotherapy. Toxicity was classified using the NCI Common Toxicity Criteria and clinical response assessed by CT scan. Peripheral blood samples were collected for immunophenotyping and monitoring of anti-p53 immune responses. Results: 11 patients were evaluated for p53MVA/gemcitabine toxicity, clinical outcome and immunological response. Toxicity: There were no DLTs but 3/11 patients came off study early due to gemcitabine-attributed adverse events (AEs). Minimal AEs were attributed to p53MVA vaccination. Immunological and Clinical Response: Enhanced in vitro recognition of p53 peptides was detectable after immunization in both the CD4+ and CD8+ T cell compartments in 5/11 and 6/11 patients respectively. Changes in peripheral T regulatory cells (Tregs) and myeloid derived suppressor cells (MDSC) did not correlate significantly with vaccine response or progression free survival (PFS). Patients with the greatest expansion of p53-reactive T cells had significantly longer PFS than patients with lower p53-reactivity post therapy. Tumor shrinkage or disease stabilization occurred in 4 patients. Conclusions: p53MVA was well tolerated, but gemcitabine without steroid pre-treatment was intolerable in some patients. However, elevated p53-reactive CD4+ and CD8+T cell responses post therapy correlated with longer PFS. Therefore, if responses to p53MVA could be enhanced with alternative agents, superior clinical responses may be achievable.

http://ift.tt/2EYc12z

Efficacy, safety and pharmacokinetics of axitinib in nasopharyngeal carcinoma: a preclinical and phase 2 correlative study

Purpose:We hypothesized that axitinib is active with improved safety profile in nasopharyngeal carcinoma (NPC). Experimental Design: We evaluated axitinib in preclinical models of NPC, and studied its efficacy in a phase 2 clinical trial in recurrent or metastatic NPC patients who progressed after at least one line of prior platinum-based chemotherapy. We excluded patients with local recurrence or vascular invasion. Axitinib was started at 5 mg twice-daily in continuous 4-weeks cycles. Primary endpoint was clinical benefit rate (CBR), defined as percent of patients achieving complete response (CR), partial response (PR) or stable disease (SD) by RECIST criteria for more than 3 months. Results:We recruited 40 patients, who received a median of 3 lines of prior chemotherapy. Axitinib was administered for a mean of 5.6 cycles, with 16 patients (40%) received ≥6 cycles. Of 37 patients evaluable for response, CBR was 78.4% (95% CI: 65.6-91.2%) at 3 months and 43.2% (30.4-56.1%) at 6 months. Grade 3/4 toxicities were uncommon, including hypertension (8%), diarrhea (5%), weight loss (5%) and pain (5%). All hemorrhagic events were grade 1 (15%) or grade 2 (3%). Elevated diastolic blood pressure during first 3 months of axitinib treatment was significantly associated with improved overall survival (HR=0.29, 95% C.I 0.13-0.64, P=0.0012). Patient reported fatigue symptom was associated with hypothyroidism (p=0.039). Axitinib PK parameters (C max and AUC(0-t)) were significantly correlated with tumor response, toxicity and serum thyroid-stimulating hormone (TSH) changes. Conclusions: Axitinib achieved durable disease control with a favorable safety profile in heavily pretreated NPC patients.

http://ift.tt/2Ea4yw3

Pharmacological inhibition of NOS activates ASK1/JNK pathway augmenting docetaxel-mediated apoptosis in triple negative breast cancer

Purpose: Chemoresistance in triple negative breast cancer (TNBC) is associated with the activation of a survival mechanism orchestrated by the endoplasmic reticulum (EnR) stress response and by inducible nitric oxide synthase (iNOS). Our aim was to determine the effects of pharmacological NOS-inhibition on TNBC. Experimental Design: TNBC cell lines, SUM-159PT, MDA-MB-436, and MDA-MB-468, were treated with docetaxel and NOS-inibitor (L-NMMA) for 24, 48 and 72 hours. Apoptosis was assessed by flow cytometry using Annexin-V and propidium iodide. Western Blot was used to assess ER-stress and apoptosis; rtPCR, to evaluate s-XBP1. TNBC patient derived xenografts (PDXs) were treated either with vehicle, docetaxel, or combination therapy (NOS-inhibition + docetaxel). Mouse weight and tumor volumes were recorded twice weekly. Docetaxel concentration was determined using mass spectrometry. To quantify proliferation and apoptosis PDX tumor samples were stained using Ki67 and TUNEL assay. Results: In-vitro, L-NMMA ameliorated the iNOS upregulation associated with docetaxel. Apoptosis increased when TNBC cells were treated with combination therapy. In TNBC PDXs, combination therapy significantly reduced tumor volume growth and increased survival proportions. In the BCM-5998 PDX model, intratumoral docetaxel concentration was higher in mice receiving combination therapy. Coupling docetaxel with NOS-inhibition increased EnR-stress response via co-activation of ATF4 and CHOP, which triggered pASK1/JNK proapoptotic pathway, promoting cleavage of caspases 3 and 9. Conclusion: iNOS is a critical target for docetaxel resistance in TNBC. Pharmacological inhibition of NOS enhanced chemotherapy response in TNBC PDX models. Combination therapy may improve prognosis and prevent relapse in TNBC patients who have failed conventional chemotherapy.

http://ift.tt/2EXVdIZ

Establishing A Preclinical Multidisciplinary Board for Brain Tumors

Purpose: Curing all children with brain tumors will require an understanding of how each subtype responds to conventional treatments and how best to combine existing and novel therapies.  It is extremely challenging to acquire this knowledge in the clinic alone, especially among patients with rare tumors.  Therefore, we developed a preclinical brain tumor platform to test combinations of conventional and novel therapies in a manner that closely recapitulates clinic trials.  Experimental Design: A multidisciplinary team was established to design and conduct neurosurgical, fractionated radiotherapy and chemotherapy studies, alone or in combination, in accurate mouse models of supratentorial ependymoma (SEP) subtypes and choroid plexus carcinoma (CPC).  Extensive drug repurposing screens, pharmacokinetic, pharmacodynamic and efficacy studies were used to triage active compounds for combination preclinical trials with 'standard-of-care' surgery and radiotherapy. Results: Mouse models displayed distinct patterns of response to surgery, irradiation and chemotherapy that varied with tumor subtype.  Repurposing screens identified three hour infusions of gemcitabine as a relatively non-toxic and efficacious treatment of SEP and CPC.  Combination neurosurgery, fractionated irradiation and gemcitabine proved significantly more effective than surgery and irradiation alone, curing one half of all animals with aggressive forms of SEP. Conclusions: We report a comprehensive preclinical trial platform to assess the therapeutic activity of conventional and novel treatments among rare brain tumor subtypes. It also enables the development of complex, combination treatment regimens that should deliver optimal trial designs for clinical testing.  Post-irradiation gemcitabine infusion should be tested as new treatments of SEP and CPC.

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Pancreatic juice mutation concentrations can help predict the grade of dysplasia in patients undergoing pancreatic surveillance

Purpose: The measurement of mutations in pancreatic juice samples collected from the duodenum during endoscopic ultrasound (EUS) may improve the diagnostic evaluation of patients undergoing pancreatic surveillance. Our aim was to evaluate the accuracy of using pancreatic juice mutation concentrations to predict the presence and histologic grade of neoplasia in the pancreas.

Experimental Design: Digital next-generation sequencing (NGS) of pancreatic juice DNA using a targeted 12-gene panel was performed on 67 patients undergoing pancreatic evaluation during EUS including patients with pancreatic ductal adenocarcinoma, patients who subsequently underwent pancreatic resection for precursor lesions, patients undergoing surveillance for their familial/inherited susceptibility to pancreatic cancer, and normal pancreas disease controls.

Results: Patients with pancreatic cancer or high-grade dysplasia as their highest grade lesion had significantly higher pancreatic juice mutation concentrations than all other subjects (mean/s.d. digital NGS score; 46.6+/-69.7 vs. 6.2+/-11.6, p=0.02). Pancreatic juice mutation concentrations distinguished patients with pancreatic cancer or high-grade dysplasia in their resection specimen from all other subjects with a sensitivity, 72.2%, specificity, 89.4% (area under the curve, AUC 0.872). Mutant TP53/SMAD4 concentrations could distinguish patients with pancreatic cancer or high-grade dysplasia in their resection specimen, from all other subjects with 61.1% sensitivity, 95.7% specificity (AUC 0.819). Among 31 high-risk individuals under surveillance, 2 of the 3 individuals with most abnormal pancreatic juice mutation profiles also had the most abnormalities on pancreatic imaging.

Conclusions: Pancreatic juice mutation analysis using digital NGS has potential diagnostic utility in the evaluation of patients undergoing pancreatic surveillance.  

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Genomic correlates of response to everolimus in aggressive radioiodine-refractory thyroid cancer: a phase II study

Purpose: Targeting mutations leading to PI3K/mTOR/Akt activation are of interest in thyroid cancer (TC). We evaluated the efficacy of everolimus in aggressive, radioactive iodine refractory (RAIR) TC and correlated tumor mutational profiling with response. Exploratory medullary and anaplastic TC cohorts were included. Experimental Design: This single-arm, multi-institutional phase II study was conducted from 2009-2013 in patients with incurable RAIR TC who had radiographic progression six months prior to enrollment. The primary endpoint was progression-free survival (PFS) with a median follow-up of 31.8 months. The study is closed to enrollment but treatment and follow-up are ongoing. A targeted next-generation sequencing platform was used for mutational analysis. Results: Thirty-three patients with differentiated TC (DTC), 10 with medullary TC (MTC), and 7 with anaplastic TC (ATC) enrolled. For the DTC cohort, median PFS was 12.9 months (95% CI, 7.3-18.5) with a 2-year PFS of 23.6% (95% CI, 10.5-39.5). Median OS was not reached; 2-year OS was 73.5% (95% CI, 53.8-85.8). Among ATC patients, 1 had a partial response and was progression-free until 17.9 months post study entry and one had disease stability for 26 months, respectively. The genomically profiled cohort enriched for PI3K/mTOR/Akt alterations. PI3K/mTOR/Akt mutated ATC subgroups appeared to benefit from everolimus. Treatment-related adverse events were as anticipated.  Conclusions: Everolimus has significant anti-tumor activity in TC. While genomic profiling does not currently guide therapeutic selection in TC patients, these data have important implications when considering the use of an mTOR inhibitor in an era of precision medicine.

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Activation of 4-1BB on liver myeloid cells triggers hepatitis via an interleukin-27 dependent pathway

Purpose: Agonist antibodies targeting the T cell co-stimulatory receptor 4-1BB (CD137) are among the most effective immunotherapeutic agents across pre-clinical cancer models. In the clinic, however, development of these agents has been hampered by dose-limiting liver toxicity. Lack of knowledge of the mechanisms underlying this toxicity has limited the potential to separate 4-1BB agonist driven tumor immunity from hepatotoxicity. Experimental Design: The capacity of 4-1BB agonist antibodies to induce liver toxicity was investigated in immunocompetent mice, with or without co-administration of checkpoint blockade, via 1) measurement of serum transaminase levels, 2) imaging of liver immune infiltrates, and 3) qualitative and quantitative assessment of liver myeloid and T cells via flow cytometry. Knockout mice were used to clarify the contribution of specific cell subsets, cytokines and chemokines. Results: We find that activation of 4-1BB on liver myeloid cells is essential to initiate hepatitis. Once activated, these cells produce interleukin-27 that is required for liver toxicity. CD8 T cells infiltrate the liver in response to this myeloid activation and mediate tissue damage, triggering transaminase elevation. FoxP3+ regulatory T cells limit liver damage, and their removal dramatically exacerbates 4-1BB agonist-induced hepatitis. Co-administration of CTLA-4 blockade ameliorates transaminase elevation, whereas PD-1 blockade exacerbates it. Loss of the chemokine receptor CCR2 blocks 4-1BB agonist hepatitis without diminishing tumor-specific immunity against B16 melanoma. Conclusions: 4-1BB agonist antibodies trigger hepatitis via activation and expansion of interleukin-27-producing liver Kupffer cells and monocytes. Co-administration of CTLA-4 and/or CCR2 blockade may minimize hepatitis, but yield equal or greater antitumor immunity.

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Identification of a novel, EBV-based antibody risk stratification signature for early detection of nasopharyngeal carcinoma in Taiwan

Background.Epstein-Barr virus (EBV) is necessary for the development of nasopharyngeal carcinoma (NPC). By adulthood, ~90% of individuals test EBV-positive, but only a fraction develop cancer. Factors that identify which individuals are most likely to develop disease, including differential antibody response to the virus, could facilitate detection at early stages when treatment is most effective. Methods. We measured anti-EBV IgG and IgA antibody responses in 607 Taiwanese individuals. Antibodies were measured using a custom protein microarray targeting 199 sequences from 86 EBV proteins. Variation in response patterns between NPC cases and controls was used to develop an antibody-based risk score for predicting NPC. The overall accuracy (area under the curve[AUC]) of this risk score, and its performance relative to currently-used biomarkers, was evaluated in two independent Taiwanese cohorts. Findings. Levels of 60 IgA and 73 IgG anti-EBV antibodies differed between Stage I/IIa NPC cases and controls (P<0·0002). Risk prediction analyses identified antibody targets that best discriminated NPC status-BXLF1,LF2,BZLF1,BRLF1,EAd, BGLF2,BPLF1,BFRF1, and BORF1. When combined with currently-used VCA/EBNA1 IgA biomarkers, the resulting risk score predicted NPC with 93% accuracy (95%CI 87-98%) in the general Taiwanese population, a significant improvement beyond current biomarkers alone (82%;95%CI 75-90%,P<0·01). This EBV-based risk score also improved NPC prediction in genetically high-risk families (89%;95%CI 82-96%) compared to current biomarkers (78%;95%CI 66-90%,P<0·03). Interpretation. We identified NPC-related differences in 133 anti-EBV antibodies and developed a risk score using this microarray dataset that targeted immune responses against EBV proteins from all stages of the viral life cycle, significantly improving the ability to predict NPC.

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Thy1-Targeted Microbubbles for Ultrasound Molecular Imaging of Pancreatic Ductal Adenocarcinoma

Purpose: To engineer a dual human and murine Thy1-binding single-chain-antibody ligand (Thy1-scFv) for contrast microbubble-enhanced ultrasound molecular imaging of pancreatic ductal adenocarcinoma (PDAC). Experimental Design: Thy1-scFv were engineered using yeast-surface-display techniques. Binding to soluble human and murine Thy1 and to Thy1-expressing cells was assessed by flow cytometry. Thy1-scFv was then attached to gas-filled microbubbles to create MB Thy1-scFv. Thy1 binding of MB Thy1-scFv to Thy1-expressing cells was evaluated under flow shear stress conditions in flow-chamber experiments. MB scFv-scrambled and MB Non-targeted were used as negative controls. All microbubble types were tested in both orthotopic human PDAC xenografts and transgenic PDAC mice in vivo. Results: Thy1-scFv had a K D of 3.4±0.36 nM for human and 9.2±1.7 nM for murine Thy1 and showed binding to both soluble and cellularly expressed Thy1. MB Thy1-scFv attached to Thy1 with high affinity compared to negative control microbubbles P<0.01) as assessed by flow cytometry. Similarly, flow-chamber studies showed significantly (P<0.01) higher binding of MB Thy1-scFv (3.0±0.81 MB/cell) to Thy1-expressing cells than MB scFv-scrambled (0.57±0.53) and MB Non-targeted (0.43±0.53). In vivo ultrasound molecular imaging using MB Thy1-scFv demonstrated significantly higher signal (P<0.01) in both orthotopic (5.32±1.59 a.u.) and transgenic PDAC (5.68±2.5 a.u.) mice compared to chronic pancreatitis (0.84±0.6 a.u.) and normal pancreas (0.67±0.71 a.u.). Ex vivo immunofluorescence confirmed significantly (P<0.01) increased Thy1 expression in PDAC compared to chronic pancreatitis and normal pancreas tissue. Conclusions: A dual human and murine Thy1-binding scFv was designed to generate contrast microbubbles to allow PDAC detection with ultrasound.

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p53-reactive T cells are associated with clinical benefit in patients with platinum-resistant epithelial ovarian cancer after treatment with a p53 vaccine and gemcitabine chemotherapy

Purpose: To conduct a Phase I trial of a Modified Vaccinia Ankara vaccine delivering wild type human p53 (p53MVA) in combination with gemcitabine chemotherapy in patients with platinum-resistant ovarian cancer. Experimental Design: Patients received gemcitabine on days 1 and 8 and p53MVA vaccine on day 15, during the first 3 cycles of chemotherapy. Toxicity was classified using the NCI Common Toxicity Criteria and clinical response assessed by CT scan. Peripheral blood samples were collected for immunophenotyping and monitoring of anti-p53 immune responses. Results: 11 patients were evaluated for p53MVA/gemcitabine toxicity, clinical outcome and immunological response. Toxicity: There were no DLTs but 3/11 patients came off study early due to gemcitabine-attributed adverse events (AEs). Minimal AEs were attributed to p53MVA vaccination. Immunological and Clinical Response: Enhanced in vitro recognition of p53 peptides was detectable after immunization in both the CD4+ and CD8+ T cell compartments in 5/11 and 6/11 patients respectively. Changes in peripheral T regulatory cells (Tregs) and myeloid derived suppressor cells (MDSC) did not correlate significantly with vaccine response or progression free survival (PFS). Patients with the greatest expansion of p53-reactive T cells had significantly longer PFS than patients with lower p53-reactivity post therapy. Tumor shrinkage or disease stabilization occurred in 4 patients. Conclusions: p53MVA was well tolerated, but gemcitabine without steroid pre-treatment was intolerable in some patients. However, elevated p53-reactive CD4+ and CD8+T cell responses post therapy correlated with longer PFS. Therefore, if responses to p53MVA could be enhanced with alternative agents, superior clinical responses may be achievable.

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Efficacy, safety and pharmacokinetics of axitinib in nasopharyngeal carcinoma: a preclinical and phase 2 correlative study

Purpose:We hypothesized that axitinib is active with improved safety profile in nasopharyngeal carcinoma (NPC). Experimental Design: We evaluated axitinib in preclinical models of NPC, and studied its efficacy in a phase 2 clinical trial in recurrent or metastatic NPC patients who progressed after at least one line of prior platinum-based chemotherapy. We excluded patients with local recurrence or vascular invasion. Axitinib was started at 5 mg twice-daily in continuous 4-weeks cycles. Primary endpoint was clinical benefit rate (CBR), defined as percent of patients achieving complete response (CR), partial response (PR) or stable disease (SD) by RECIST criteria for more than 3 months. Results:We recruited 40 patients, who received a median of 3 lines of prior chemotherapy. Axitinib was administered for a mean of 5.6 cycles, with 16 patients (40%) received ≥6 cycles. Of 37 patients evaluable for response, CBR was 78.4% (95% CI: 65.6-91.2%) at 3 months and 43.2% (30.4-56.1%) at 6 months. Grade 3/4 toxicities were uncommon, including hypertension (8%), diarrhea (5%), weight loss (5%) and pain (5%). All hemorrhagic events were grade 1 (15%) or grade 2 (3%). Elevated diastolic blood pressure during first 3 months of axitinib treatment was significantly associated with improved overall survival (HR=0.29, 95% C.I 0.13-0.64, P=0.0012). Patient reported fatigue symptom was associated with hypothyroidism (p=0.039). Axitinib PK parameters (C max and AUC(0-t)) were significantly correlated with tumor response, toxicity and serum thyroid-stimulating hormone (TSH) changes. Conclusions: Axitinib achieved durable disease control with a favorable safety profile in heavily pretreated NPC patients.

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Pharmacological inhibition of NOS activates ASK1/JNK pathway augmenting docetaxel-mediated apoptosis in triple negative breast cancer

Purpose: Chemoresistance in triple negative breast cancer (TNBC) is associated with the activation of a survival mechanism orchestrated by the endoplasmic reticulum (EnR) stress response and by inducible nitric oxide synthase (iNOS). Our aim was to determine the effects of pharmacological NOS-inhibition on TNBC. Experimental Design: TNBC cell lines, SUM-159PT, MDA-MB-436, and MDA-MB-468, were treated with docetaxel and NOS-inibitor (L-NMMA) for 24, 48 and 72 hours. Apoptosis was assessed by flow cytometry using Annexin-V and propidium iodide. Western Blot was used to assess ER-stress and apoptosis; rtPCR, to evaluate s-XBP1. TNBC patient derived xenografts (PDXs) were treated either with vehicle, docetaxel, or combination therapy (NOS-inhibition + docetaxel). Mouse weight and tumor volumes were recorded twice weekly. Docetaxel concentration was determined using mass spectrometry. To quantify proliferation and apoptosis PDX tumor samples were stained using Ki67 and TUNEL assay. Results: In-vitro, L-NMMA ameliorated the iNOS upregulation associated with docetaxel. Apoptosis increased when TNBC cells were treated with combination therapy. In TNBC PDXs, combination therapy significantly reduced tumor volume growth and increased survival proportions. In the BCM-5998 PDX model, intratumoral docetaxel concentration was higher in mice receiving combination therapy. Coupling docetaxel with NOS-inhibition increased EnR-stress response via co-activation of ATF4 and CHOP, which triggered pASK1/JNK proapoptotic pathway, promoting cleavage of caspases 3 and 9. Conclusion: iNOS is a critical target for docetaxel resistance in TNBC. Pharmacological inhibition of NOS enhanced chemotherapy response in TNBC PDX models. Combination therapy may improve prognosis and prevent relapse in TNBC patients who have failed conventional chemotherapy.

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Comment on ‘A meta-analysis of CXCL12 expression for cancer prognosis’

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Prostate-specific antigen velocity in a prospective prostate cancer screening study of men with genetic predisposition

Prostate-specific antigen velocity in a prospective prostate cancer screening study of men with genetic predisposition

Prostate-specific antigen velocity in a prospective prostate cancer screening study of men with genetic predisposition, Published online: 04 January 2018; doi:10.1038/bjc.2017.429

Prostate-specific antigen velocity in a prospective prostate cancer screening study of men with genetic predisposition

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Therapy-educated mesenchymal stem cells enrich for tumor initiating cells

Stromal cells residing in the tumor microenvironment contribute to the development of therapy resistance. Here we show that chemotherapy-educated mesenchymal stem cells (MSCs) promote therapy resistance via crosstalk with tumor-initiating cells (TICs), a resistant tumor cell subset that initiates tumorigenesis and metastasis. In response to gemcitabine chemotherapy, MSCs colonized pancreatic adenocarcinomas in large numbers and resided in close proximity to TICs. Furthermore, gemcitabine-educated MSCs promoted the enrichment of TICs in vitro and enhance tumor growth in vivo. These effects were dependent on the secretion of CXCL10 by gemcitabine-educated MSCs and subsequent activation of the CXCL10-CXCR3 axis in TICs. In an orthotopic pancreatic tumor model, targeting TICs using nano-vesicles (called nano-ghosts) derived from MSC membranes and loaded with a CXCR3 antagonist enhanced therapy outcome and delayed tumor re-growth when administered in combination with gemcitabine. Overall, our results establish a mechanism through which MSCs promote chemoresistance, and propose a novel drug delivery system to target TICs and overcome this resistance.

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O-GlcNAcylation of the tumor suppressor FOXO3 triggers aberrant cancer cell growth

Post-translational modifications of tumor suppressors can induce abnormal cell growth. Here we identify site-specific O-GlcNAcylation as a critical block of FOXO3 that may abrogate a part of the p53 pathway, resulting in aberrant cancer cell growth. Of seven O-GlcNAcylation sites identified within the FOXO3 transactivation domain, we found that changes in O-GlcNAcylation at Ser284 modulated p21-mediated cancer cell growth. Overexpression of either O-GlcNAcylated FOXO3 (FOX-OV) or a Ser-to-Ala mutant (S284A) in PANC-1 cells indicated that S284 O-GlcNAc acts as a critical block of the FOXO tumor suppressor and induces proliferation in PANC-1 cancer cells by stimulating the MDM2-p53-p21 axis. Furthermore, S284A mutant cells lacking S284 O-GlcNAc and FOX-OV cells exhibited opposing MDM2-p53-p21 axis expression patterns at both the mRNA and protein levels. Thus, our study provides evidence to support a role for S284 O-GlcNAc as a critical block of FOXO3 to induce subsequent cancer cell growth via abrogation of the p53 regulatory circuit.

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Deletion of the von Hippel-Lindau gene in hemangioblasts causes hemangioblastoma-like lesions in murine retina

von Hippel-Lindau (VHL) disease is an autosomal dominant tumor predisposition syndrome characterized by the development of highly vascularized tumors and cysts. Loss of heterozygosity (LOH) of the VHL gene results in aberrant upregulation of hypoxia-inducible factors (HIF) and has been associated with tumor formation. Hemangioblastomas of the central nervous system and retina represent the most prevalent VHL-associated tumors, but no VHL animal model has reproduced retinal capillary hemangioblastomas (RCH), the hallmark lesion of ocular VHL. Here we report our work in developing a murine model of VHL-associated RCH by conditionally inactivating Vhl in a hemangioblast population using a Scl-Cre-ERT2 transgenic mouse line. In transgenic mice carrying the conditional allele and the Scl-Cre-ERT2 allele, 64% exhibited various retinal vascular anomalies following tamoxifen induction. Affected Vhl mutant mice demonstrated retinal vascular lesions associated with prominent vasculature, anomalous capillary networks, hemorrhage, exudates, and localized fibrosis. Histological analyses showed RCH-like lesions characterized by tortuous, dilated vasculature surrounded by "tumorlet" cell cluster and isolated foamy stromal cells, which are typically associated with RCH. Fluorescein angiography suggested increased vascular permeability of the irregular retinal vasculature and hemangioblastoma-like lesions. Vhl deletion was detected in "tumorlet" cells via microdissection. Our findings provide a phenotypic recapitulation of VHL-associated RCH in a murine model that may be useful to study RCH pathogenesis and therapeutics aimed at treating ocular VHL.

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Therapy-educated mesenchymal stem cells enrich for tumor initiating cells

Stromal cells residing in the tumor microenvironment contribute to the development of therapy resistance. Here we show that chemotherapy-educated mesenchymal stem cells (MSCs) promote therapy resistance via crosstalk with tumor-initiating cells (TICs), a resistant tumor cell subset that initiates tumorigenesis and metastasis. In response to gemcitabine chemotherapy, MSCs colonized pancreatic adenocarcinomas in large numbers and resided in close proximity to TICs. Furthermore, gemcitabine-educated MSCs promoted the enrichment of TICs in vitro and enhance tumor growth in vivo. These effects were dependent on the secretion of CXCL10 by gemcitabine-educated MSCs and subsequent activation of the CXCL10-CXCR3 axis in TICs. In an orthotopic pancreatic tumor model, targeting TICs using nano-vesicles (called nano-ghosts) derived from MSC membranes and loaded with a CXCR3 antagonist enhanced therapy outcome and delayed tumor re-growth when administered in combination with gemcitabine. Overall, our results establish a mechanism through which MSCs promote chemoresistance, and propose a novel drug delivery system to target TICs and overcome this resistance.

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Comment on ‘A meta-analysis of CXCL12 expression for cancer prognosis’

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Prostate-specific antigen velocity in a prospective prostate cancer screening study of men with genetic predisposition

Prostate-specific antigen velocity in a prospective prostate cancer screening study of men with genetic predisposition

Prostate-specific antigen velocity in a prospective prostate cancer screening study of men with genetic predisposition, Published online: 04 January 2018; doi:10.1038/bjc.2017.429

Prostate-specific antigen velocity in a prospective prostate cancer screening study of men with genetic predisposition

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Cyclic-GMP elevating agents suppress polyposis in Apc min mice by targeting the preneoplastic epithelium.

The cGMP signaling axis has been implicated in the suppression of intestinal cancers but the inhibitory mechanism and the extent to which this pathway can be targeted remains poorly understood. The present study has tested the effect of cGMP-elevating agents on tumorigenesis in the ApcMin/+ mouse model of intestinal cancer. Treatment of ApcMin/+ mice with the receptor guanylyl-cyclase C (GCC) agonist linaclotide, or the phosphodiesterase-5 (PDE5) inhibitor sildenafil, significantly reduced the number of polyps per mouse (67% and 50% respectively). Neither of the drugs affected mean polyp size, or the rates of apoptosis and proliferation. This was possibly due to increased PDE10 expression, since endogenous GCC ligands were not deficient in established polyps. These results indicated that the ability of these drugs to reduce polyp multiplicity was primarily due to an effect on non-neoplastic tissues. In support of this idea, ApcMin/+ mice exhibited reduced levels of endogenous GCC agonists in the non-neoplastic intestinal mucosa compared to wild type animals, and this was associated with crypt hyperplasia and a loss of goblet cells. Administration of either sildenafil or linaclotide suppressed proliferation, and increased both goblet cell numbers and luminal apoptosis in the intestinal mucosa. Taken together, the results demonstrate that targeting cGMP with either PDE5 inhibitors or GCC agonists alters epithelial homeostasis in a manner that reduces neoplasia, and suggests that this could be a viable chemoprevention strategy for patients at high-risk of developing colorectal cancer.

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O-GlcNAcylation of the tumor suppressor FOXO3 triggers aberrant cancer cell growth

Post-translational modifications of tumor suppressors can induce abnormal cell growth. Here we identify site-specific O-GlcNAcylation as a critical block of FOXO3 that may abrogate a part of the p53 pathway, resulting in aberrant cancer cell growth. Of seven O-GlcNAcylation sites identified within the FOXO3 transactivation domain, we found that changes in O-GlcNAcylation at Ser284 modulated p21-mediated cancer cell growth. Overexpression of either O-GlcNAcylated FOXO3 (FOX-OV) or a Ser-to-Ala mutant (S284A) in PANC-1 cells indicated that S284 O-GlcNAc acts as a critical block of the FOXO tumor suppressor and induces proliferation in PANC-1 cancer cells by stimulating the MDM2-p53-p21 axis. Furthermore, S284A mutant cells lacking S284 O-GlcNAc and FOX-OV cells exhibited opposing MDM2-p53-p21 axis expression patterns at both the mRNA and protein levels. Thus, our study provides evidence to support a role for S284 O-GlcNAc as a critical block of FOXO3 to induce subsequent cancer cell growth via abrogation of the p53 regulatory circuit.

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Deletion of the von Hippel-Lindau gene in hemangioblasts causes hemangioblastoma-like lesions in murine retina

von Hippel-Lindau (VHL) disease is an autosomal dominant tumor predisposition syndrome characterized by the development of highly vascularized tumors and cysts. Loss of heterozygosity (LOH) of the VHL gene results in aberrant upregulation of hypoxia-inducible factors (HIF) and has been associated with tumor formation. Hemangioblastomas of the central nervous system and retina represent the most prevalent VHL-associated tumors, but no VHL animal model has reproduced retinal capillary hemangioblastomas (RCH), the hallmark lesion of ocular VHL. Here we report our work in developing a murine model of VHL-associated RCH by conditionally inactivating Vhl in a hemangioblast population using a Scl-Cre-ERT2 transgenic mouse line. In transgenic mice carrying the conditional allele and the Scl-Cre-ERT2 allele, 64% exhibited various retinal vascular anomalies following tamoxifen induction. Affected Vhl mutant mice demonstrated retinal vascular lesions associated with prominent vasculature, anomalous capillary networks, hemorrhage, exudates, and localized fibrosis. Histological analyses showed RCH-like lesions characterized by tortuous, dilated vasculature surrounded by "tumorlet" cell cluster and isolated foamy stromal cells, which are typically associated with RCH. Fluorescein angiography suggested increased vascular permeability of the irregular retinal vasculature and hemangioblastoma-like lesions. Vhl deletion was detected in "tumorlet" cells via microdissection. Our findings provide a phenotypic recapitulation of VHL-associated RCH in a murine model that may be useful to study RCH pathogenesis and therapeutics aimed at treating ocular VHL.

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Notch1 signaling in melanoma cells promoted tumor-induced immunosuppression via upregulation of TGF-β1

The receptors of Notch family play an important role in controlling the development, differentiation, and function of multiple cell types. The aim of this study is to investigate the role of Notch1 signaling u...

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Lanthanum-Induced Mucosal Alterations in the Stomach (Lanthanum Gastropathy): a Comparative Study Using an Animal Model

Abstract

Lanthanum (La) carbonate (LC) is one of the most potent phosphate binders that prevents the elevation of serum phosphate levels in patients with end-stage renal diseases undergoing dialysis. LC binds strongly to dietary phosphate and forms insoluble complexes that pass through the gastrointestinal tract. La deposition in patients treated with LC is a recently documented finding particularly observed in gastric mucosa. We herein describe the detailed gastric mucosal lesions in 45 LC-treated patients and address the potential underlying pathologic mechanism using oral LC administration in rats. Microscopically, La deposition, as shown by subepithelial collections of plump eosinophilic histiocytes or small foreign body granulomas containing coarse granular or amorphous inclusion bodies, was found in the gastric mucosa of 44 (97.8%) of the 45 dialysis patients in the study cohort, which was most frequently associated with foveolar hyperplasia (37.8%). Using oral administration of rats with 1000 mg/day LC for 2 or more weeks, La deposition was consistently detectable in the gastric mucosa but not in other organs examined. In addition, various histologic alterations such as glandular atrophy, stromal fibrosis, proliferation of mucous neck cells, intestinal metaplasia, squamous cell papilloma, erosion, and ulcer were demonstrated in the rat model. Thus, orally administered LC can induce mucosal injury, designated here as La gastropathy, which may alter the local environment and result in La deposition in the gastric mucosa, thereby potentially inducing abnormal cell proliferation or neoplastic lesions.

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Lanthanum-Induced Mucosal Alterations in the Stomach (Lanthanum Gastropathy): a Comparative Study Using an Animal Model

Abstract

Lanthanum (La) carbonate (LC) is one of the most potent phosphate binders that prevents the elevation of serum phosphate levels in patients with end-stage renal diseases undergoing dialysis. LC binds strongly to dietary phosphate and forms insoluble complexes that pass through the gastrointestinal tract. La deposition in patients treated with LC is a recently documented finding particularly observed in gastric mucosa. We herein describe the detailed gastric mucosal lesions in 45 LC-treated patients and address the potential underlying pathologic mechanism using oral LC administration in rats. Microscopically, La deposition, as shown by subepithelial collections of plump eosinophilic histiocytes or small foreign body granulomas containing coarse granular or amorphous inclusion bodies, was found in the gastric mucosa of 44 (97.8%) of the 45 dialysis patients in the study cohort, which was most frequently associated with foveolar hyperplasia (37.8%). Using oral administration of rats with 1000 mg/day LC for 2 or more weeks, La deposition was consistently detectable in the gastric mucosa but not in other organs examined. In addition, various histologic alterations such as glandular atrophy, stromal fibrosis, proliferation of mucous neck cells, intestinal metaplasia, squamous cell papilloma, erosion, and ulcer were demonstrated in the rat model. Thus, orally administered LC can induce mucosal injury, designated here as La gastropathy, which may alter the local environment and result in La deposition in the gastric mucosa, thereby potentially inducing abnormal cell proliferation or neoplastic lesions.

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Prostate-specific antigen velocity in a prospective prostate cancer screening study of men with genetic predisposition

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Comment on ‘A meta-analysis of CXCL12 expression for cancer prognosis’

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Prostate-specific antigen velocity in a prospective prostate cancer screening study of men with genetic predisposition

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Bevacuzimab May Be Less Effective in Obese Metastatic Colorectal Cancer Patients

Abstract

Purpose

The purpose of this study was to investigate whether obesity affects survival in metastatic colorectal cancer (mCRC) patients treated with bevacizumab combined with chemotherapy.

Methods

A total of 563 patients with mCRC who had received first-line chemotherapy in combination with bevacizumab were studied. Patients were grouped as obese (BMI levels > 30) or non-obese (BMI levels < 30). Progression-free survival (PFS) and overall survival (OS) were analyzed. Primary tumor location was also investigated in terms of PFS and OS.

Results

The median age of the patients was 59 years. The non-obese group had longer PFS than the obese group (P = 0.030). The 2-year survival rate of the non-obese group was also significantly higher (P = 0.036). The median PFS of non-obese patients was significantly longer in Kras wild-type patients (10.1 vs. 8.1 months, P = 0.010). Among patients with left-sided primary tumor location, median PFS and OS were significantly higher in the non-obese group (PFS non-obese, 11.5 months; obese, 8.8 months; P = 0.002) (OS non-obese, 29.4 months; obese, 21.4 months; P = 0.026).

Conclusions

Efficacy of bevacizumab may be lower in obese patients. Among patients with Kras wild-type left-sided tumors treated with bevacizumab-based regimens, the prognosis could be worse for obese patients than that for non-obese patients. There is a need for prospectively designed studies of obese patients to prove the efficacy and dosages of bevacizumab in treatment of mCRC.

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Bevacuzimab May Be Less Effective in Obese Metastatic Colorectal Cancer Patients

Abstract

Purpose

The purpose of this study was to investigate whether obesity affects survival in metastatic colorectal cancer (mCRC) patients treated with bevacizumab combined with chemotherapy.

Methods

A total of 563 patients with mCRC who had received first-line chemotherapy in combination with bevacizumab were studied. Patients were grouped as obese (BMI levels > 30) or non-obese (BMI levels < 30). Progression-free survival (PFS) and overall survival (OS) were analyzed. Primary tumor location was also investigated in terms of PFS and OS.

Results

The median age of the patients was 59 years. The non-obese group had longer PFS than the obese group (P = 0.030). The 2-year survival rate of the non-obese group was also significantly higher (P = 0.036). The median PFS of non-obese patients was significantly longer in Kras wild-type patients (10.1 vs. 8.1 months, P = 0.010). Among patients with left-sided primary tumor location, median PFS and OS were significantly higher in the non-obese group (PFS non-obese, 11.5 months; obese, 8.8 months; P = 0.002) (OS non-obese, 29.4 months; obese, 21.4 months; P = 0.026).

Conclusions

Efficacy of bevacizumab may be lower in obese patients. Among patients with Kras wild-type left-sided tumors treated with bevacizumab-based regimens, the prognosis could be worse for obese patients than that for non-obese patients. There is a need for prospectively designed studies of obese patients to prove the efficacy and dosages of bevacizumab in treatment of mCRC.

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Prolonged grief disorder and depression are distinct for caregivers across their first bereavement year

Abstract

Background

Prolonged grief disorder (PGD) and depression are recognized as distinct emotional-distress disorders for bereaved family caregivers. However, this distinction has been mostly validated in cross-sectional studies, neglecting the dynamic characteristics of bereaved caregivers' emotional distress.

Objective

To validate the distinction between symptoms of PGD and depression across the first bereavement year for family caregivers of terminally ill cancer patients.

Methods

In this descriptive, longitudinal study of 394 bereaved Taiwanese family caregivers, we measured symptoms of PGD and depression by the Prolonged Grief-13 and Center for Epidemiologic Studies Depression (CES-D) scales at 6 and 13 months postloss, respectively. Agreement between cases of PGD and severe depressive symptoms (CES-D score >16) was analyzed by Cohen's kappa. Structural distinctiveness was longitudinally examined using confirmatory bifactor modeling.

Results

Agreement was poor between cases of PGD and severe depressive symptoms at 6 and 13 months postloss (kappa=.16 [CI=.09, .22] and .12 [CI=.03, .19], respectively). Symptoms of PGD and depression shared a general factor, but were distinct as shown by their significant specific factor loadings at 6 and 13 months postloss. Confirmatory bifactor models showed structural invariance (confirmatory fit index difference <.01 and χ² difference p>.05) between 6 and 13 months postloss.

Conclusion

Symptoms of PGD and depression were confirmed as distinct across the first year of bereavement. Healthcare professionals should recognize early in bereavement that symptoms of PGD and depression are distinct, identify high-risk groups, and provide care tailored to caregivers' unique needs to facilitate recovery from bereavement-related emotional-distress disorders.

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Prolonged grief disorder and depression are distinct for caregivers across their first bereavement year

Abstract

Background

Prolonged grief disorder (PGD) and depression are recognized as distinct emotional-distress disorders for bereaved family caregivers. However, this distinction has been mostly validated in cross-sectional studies, neglecting the dynamic characteristics of bereaved caregivers' emotional distress.

Objective

To validate the distinction between symptoms of PGD and depression across the first bereavement year for family caregivers of terminally ill cancer patients.

Methods

In this descriptive, longitudinal study of 394 bereaved Taiwanese family caregivers, we measured symptoms of PGD and depression by the Prolonged Grief-13 and Center for Epidemiologic Studies Depression (CES-D) scales at 6 and 13 months postloss, respectively. Agreement between cases of PGD and severe depressive symptoms (CES-D score >16) was analyzed by Cohen's kappa. Structural distinctiveness was longitudinally examined using confirmatory bifactor modeling.

Results

Agreement was poor between cases of PGD and severe depressive symptoms at 6 and 13 months postloss (kappa=.16 [CI=.09, .22] and .12 [CI=.03, .19], respectively). Symptoms of PGD and depression shared a general factor, but were distinct as shown by their significant specific factor loadings at 6 and 13 months postloss. Confirmatory bifactor models showed structural invariance (confirmatory fit index difference <.01 and χ² difference p>.05) between 6 and 13 months postloss.

Conclusion

Symptoms of PGD and depression were confirmed as distinct across the first year of bereavement. Healthcare professionals should recognize early in bereavement that symptoms of PGD and depression are distinct, identify high-risk groups, and provide care tailored to caregivers' unique needs to facilitate recovery from bereavement-related emotional-distress disorders.

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Temporal and geospatial trends of pediatric cancer incidence in Nebraska over a 24-year period

Publication date: February 2018
Source:Cancer Epidemiology, Volume 52
Author(s): P.A. Farazi, S. Watanabe-Galloway, L. Westman, B. Rettig, P. Hunt, R. Cammack, J.W. Sparks, D.W. Coulter
BackgroundData from the Surveillance, Epidemiology, and End Results (SEER) revealed that the incidence of pediatric cancer in Nebraska exceeded the national average during 2009–2013. Further investigation could help understand these patterns.MethodsThis retrospective cohort study investigated pediatric cancer (0–19 years old) age adjusted incidence rates (AAR) in Nebraska using the Nebraska Cancer Registry. SEER AARs were also calculated as a proxy for pediatric cancer incidence in the United States (1990–2013) and compared to the Nebraska data. Geographic Information System (GIS) mapping was also used to display the spatial distribution of cancer in Nebraska at the county level. Finally, location–allocation analysis (LAA) was performed to identify a site for the placement of a medical center to best accommodate rural pediatric cancer cases.ResultsThe AAR of pediatric cancers was 173.3 per 1,000,000 in Nebraska compared to 167.1 per 1,000,000 in SEER. The AAR for lymphoma was significantly higher in Nebraska (28.1 vs. 24.6 per 1,000,000; p = 0.009). For the 15–19 age group, the AAR for the 3 most common pediatric cancers were higher in Nebraska (p < 0.05). Twenty-three counties located >2 h driving distance to care facilities showed at least a 10% higher incidence than the overall state AAR. GIS mapping identified a second potential treatment site that would alleviate this geographic burden.ConclusionsRegional differences within Nebraska present a challenge for rural populations. Novel use of GIS mapping to highlight regional differences and identify solutions for access to care issues could be used by similar states.



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