Intramuscular granular cell tumor of the gluteal region

Abstract

Granular cell tumors are uncommon, usually benign neoplasms, mainly observed in the head and neck region, chest wall and upper extremities. These tumors account for ~0.5% of all soft-tissue tumors. Less than 2% are malignant. These are associated with poor prognosis. Clinical signs suspicious for malignancy are large size, rapid growth, invasion, recurrence and metastasis. Malignancy is confirmed by histological examination. We present the case of a 79-year-old patient with a 6-month history of a rapidly growing mass in the left gluteal region giving the clinical impression of a malignant tumor. The patient underwent surgical excision of the tumor and the pathology report revealed a granular cell tumor. In difficult cases, multidisciplinary approach is necessary for appropriate diagnosis and management.

http://ift.tt/2DZ84Ou

A rare case of massive lower gastrointestinal bleeding from a ruptured splenic artery aneurysm

Abstract

Splenic artery aneurysms (SAAs) are an extremely rare cause of asymptomatic massive lower gastrointestinal bleeding with less than a handful of patients surviving such a presentation. A 24-year-old female presented in shock after multiple episodes of massive rectal bleeding. Imaging revealed a heterogeneous mass arising from the tail of the pancreas eroding into the splenic flexure of the colon. Further episodes of bleeding led to an exploratory laparotomy. Intraoperatively, a suspected neoplastic process arising from the tail of the pancreas with contiguous involvement of the splenic flexure of the colon and the greater curvature of the stomach was noted. Distal pancreaticosplenectomy, gastric wedge resection with segmental colectomy and primary anastomosis were performed. Histology revealed a SAA with rupture into the colon. This case report shows that en-bloc resection of a ruptured SAA can be performed with success in the emergency setting.

http://ift.tt/2nFXTmL

A rare case of spinal cord compression due to cervical spine metastases from paraganglioma of the jugular foramen—how should it be treated?

Abstract

Paragangliomas are benign neoplasms that arise from the autonomic nervous system and the associated paraganglia. Although benign, they have been shown to possess metastatic potential. Involvement of the spine is rare. Even rarer is considered the involvement of the cervical spine. We report a case of a patient with a history of an extra-adrenal non-functional paraganglioma of the jugular foramen which was initially treated with intra-arterial embolization. After a 3-year disease-free follow-up, the patient was presented with symptoms of spinal cord compression due to spinal metastases in C2 and C3 vertebrae. The patient was then treated with surgical decompression and external beam radiation. Therapeutic management with additional treatment options is now under discussion by a multidisciplinary team. Paraganglioma of the jugular foramen with spinal metastasis is an uncommon presentation where increased physician awareness and long-term follow-up are mandatory for all patients with history of paraganglioma.

http://ift.tt/2DWqzTu

Side effects of CT-guided implantation of 125I seeds for recurrent malignant tumors of the head and neck assisted by 3D printing non co-planar template

For the recurrence of head and neck cancer after operation and radiotherapy, the local control of radioactive seed implantation is good, and it has a certain palliative effect. This study aims to investigate t...

http://ift.tt/2BRhe9y

Fitting NTCP models to bladder doses and acute urinary symptoms during post-prostatectomy radiotherapy

To estimate the radiobiological parameters of three popular normal tissue complication probability (NTCP) models, which describe the dose-response relations of bladder regarding different acute urinary symptom...

http://ift.tt/2nA8OPP

Side effects of CT-guided implantation of 125I seeds for recurrent malignant tumors of the head and neck assisted by 3D printing non co-planar template

For the recurrence of head and neck cancer after operation and radiotherapy, the local control of radioactive seed implantation is good, and it has a certain palliative effect. This study aims to investigate t...

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Fitting NTCP models to bladder doses and acute urinary symptoms during post-prostatectomy radiotherapy

To estimate the radiobiological parameters of three popular normal tissue complication probability (NTCP) models, which describe the dose-response relations of bladder regarding different acute urinary symptom...

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Role of MLH1 methylation in esophageal cancer carcinogenesis and its clinical significance

http://ift.tt/2DZ58xn

Associations between ABCG2 gene polymorphisms and gefitinib toxicity in non-small cell lung cancer: a meta-analysis

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Cancers, Vol. 10, Pages 41: Phosphorylation of Sox2 at Threonine 116 is a Potential Marker to Identify a Subset of Breast Cancer Cells with High Tumorigenecity and Stem-Like Features

Cancers, Vol. 10, Pages 41: Phosphorylation of Sox2 at Threonine 116 is a Potential Marker to Identify a Subset of Breast Cancer Cells with High Tumorigenecity and Stem-Like Features

Cancers doi: 10.3390/cancers10020041

Authors: Nidhi Gupta Keshav Gopal Chengsheng Wu Abdulraheem Alshareef Alexandra Chow Fang Wu Peng Wang Xiaoxia Ye Gilbert Bigras Raymond Lai

We have previously identified a novel phenotypic dichotomy in breast cancer (BC) based on the response to a SRR2 (Sox2 regulatory region 2) reporter, with reporter responsive (RR) cells being more tumorigenic/stem-like than reporter unresponsive (RU) cells. Since the expression level of Sox2 is comparable between the two cell subsets, we hypothesized that post-translational modifications of Sox2 contribute to their differential reporter response and phenotypic differences. By liquid chromatography-mass spectrometry, we found Sox2 to be phosphorylated in RR but not RU cells. Threonine 116 is an important phosphorylation site, since transfection of the T116A mutant into RR cells significantly decreased the SRR2 reporter luciferase activity and the RR-associated phenotype. Oxidative stress-induced conversion of RU into RR cells was accompanied by Sox2 phosphorylation at T116 and increased Sox2-DNA binding. In a cohort of BC, we found significant correlations between the proportion of tumor cells immuno-reactive with anti-phosphorylated Sox2T116 and a high tumor grade (p = 0.006), vascular invasion (p = 0.001) and estrogen receptor expression (p = 0.032). In conclusion, our data suggests that phosphorylation of Sox2T116 contributes to the tumorigenic/stem-like features in RR cells. Detection of phospho-Sox2T116 may be useful in identifying a small subset of tumor cells carrying stem-like/tumorigenic features in BC.

http://ift.tt/2BRb09G

Cancers, Vol. 10, Pages 41: Phosphorylation of Sox2 at Threonine 116 is a Potential Marker to Identify a Subset of Breast Cancer Cells with High Tumorigenecity and Stem-Like Features

Cancers, Vol. 10, Pages 41: Phosphorylation of Sox2 at Threonine 116 is a Potential Marker to Identify a Subset of Breast Cancer Cells with High Tumorigenecity and Stem-Like Features

Cancers doi: 10.3390/cancers10020041

Authors: Nidhi Gupta Keshav Gopal Chengsheng Wu Abdulraheem Alshareef Alexandra Chow Fang Wu Peng Wang Xiaoxia Ye Gilbert Bigras Raymond Lai

We have previously identified a novel phenotypic dichotomy in breast cancer (BC) based on the response to a SRR2 (Sox2 regulatory region 2) reporter, with reporter responsive (RR) cells being more tumorigenic/stem-like than reporter unresponsive (RU) cells. Since the expression level of Sox2 is comparable between the two cell subsets, we hypothesized that post-translational modifications of Sox2 contribute to their differential reporter response and phenotypic differences. By liquid chromatography-mass spectrometry, we found Sox2 to be phosphorylated in RR but not RU cells. Threonine 116 is an important phosphorylation site, since transfection of the T116A mutant into RR cells significantly decreased the SRR2 reporter luciferase activity and the RR-associated phenotype. Oxidative stress-induced conversion of RU into RR cells was accompanied by Sox2 phosphorylation at T116 and increased Sox2-DNA binding. In a cohort of BC, we found significant correlations between the proportion of tumor cells immuno-reactive with anti-phosphorylated Sox2T116 and a high tumor grade (p = 0.006), vascular invasion (p = 0.001) and estrogen receptor expression (p = 0.032). In conclusion, our data suggests that phosphorylation of Sox2T116 contributes to the tumorigenic/stem-like features in RR cells. Detection of phospho-Sox2T116 may be useful in identifying a small subset of tumor cells carrying stem-like/tumorigenic features in BC.

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Effects of core needle biopsy and subsequent neoadjuvant chemotherapy on molecular alterations and outcome in breast cancer

http://ift.tt/2s2UO5N

The application of a three-dimensional visualized seed planning and navigation system in 125I seed implantation for pancreatic cancer

http://ift.tt/2rYAuCo

First data from a population based cancer registry in Ethiopia

Publication date: April 2018
Source:Cancer Epidemiology, Volume 53
Author(s): Genebo Timotewos, Asmare Solomon, Assefa Mathewos, Adamu Addissie, Solomon Bogale, Tigeneh Wondemagegnehu, Abraha Aynalem, Bekele Ayalnesh, Hailemariam Dagnechew, Wondatir Bireda, Eric Sven Kroeber, Rafael Mikolajczyk, Freddie Bray, Ahmedin Jemal, Eva Johanna Kantelhardt
BackgroundThe Addis Ababa City Cancer Registry, established in September 2011, is the only population-based cancer registry in Ethiopia, covering a catchment population of just over three million habitants. Herein, we report incidence data based on the first two years of registration, 2012–2013.MethodsNewly-diagnosed cancer cases in the capital city were actively collected from 22 hospitals, clinics, and diagnostic facilities.ResultsDuring 2012–2013, a total of 4139 newly diagnosed cases were recorded, with the majority (67%) occurring in females. Cancers of the breast (31.5%) and cervix (14.1%) were the two most common cancers among females, while colorectal cancers (10.6%) and non-Hodgkin lymphomas (10.2%) were the most common cancers among males. The average annual age-standardized rate for all sites 2012–13 were 136.2 (per 100,000) and 70.7 in females and males, respectively. Female age-standardized rates were 40.6 for breast cancer and 21.5 for cervix, while equivalent rates in males were 7.6 per 100,000 for colorectal cancer and 6.8 per 100,000 for non-Hodgkin lymphoma.ConclusionIn general, these incidence patterns were similar to those reported in neighboring countries, which suggests that the majority of cancer cases occurring in Addis Ababa are captured within this starting phase of the registry. However, our finding of colorectal cancer as the most commonly-diagnosed cancer in males is novel and requires further investigation.



http://ift.tt/2DVefPr

First data from a population based cancer registry in Ethiopia

Publication date: April 2018
Source:Cancer Epidemiology, Volume 53
Author(s): Genebo Timotewos, Asmare Solomon, Assefa Mathewos, Adamu Addissie, Solomon Bogale, Tigeneh Wondemagegnehu, Abraha Aynalem, Bekele Ayalnesh, Hailemariam Dagnechew, Wondatir Bireda, Eric Sven Kroeber, Rafael Mikolajczyk, Freddie Bray, Ahmedin Jemal, Eva Johanna Kantelhardt
BackgroundThe Addis Ababa City Cancer Registry, established in September 2011, is the only population-based cancer registry in Ethiopia, covering a catchment population of just over three million habitants. Herein, we report incidence data based on the first two years of registration, 2012–2013.MethodsNewly-diagnosed cancer cases in the capital city were actively collected from 22 hospitals, clinics, and diagnostic facilities.ResultsDuring 2012–2013, a total of 4139 newly diagnosed cases were recorded, with the majority (67%) occurring in females. Cancers of the breast (31.5%) and cervix (14.1%) were the two most common cancers among females, while colorectal cancers (10.6%) and non-Hodgkin lymphomas (10.2%) were the most common cancers among males. The average annual age-standardized rate for all sites 2012–13 were 136.2 (per 100,000) and 70.7 in females and males, respectively. Female age-standardized rates were 40.6 for breast cancer and 21.5 for cervix, while equivalent rates in males were 7.6 per 100,000 for colorectal cancer and 6.8 per 100,000 for non-Hodgkin lymphoma.ConclusionIn general, these incidence patterns were similar to those reported in neighboring countries, which suggests that the majority of cancer cases occurring in Addis Ababa are captured within this starting phase of the registry. However, our finding of colorectal cancer as the most commonly-diagnosed cancer in males is novel and requires further investigation.



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RHOA G17V Induces T Follicular Helper Cell Specification and Promotes Lymphomagenesis

Publication date: Available online 2 February 2018
Source:Cancer Cell
Author(s): Jose R. Cortes, Alberto Ambesi-Impiombato, Lucile Couronné, S. Aidan Quinn, Christine S. Kim, Ana C. da Silva Almeida, Zachary West, Laura Belver, Marta Sanchez Martin, Laurianne Scourzic, Govind Bhagat, Olivier A. Bernard, Adolfo A. Ferrando, Teresa Palomero
Angioimmunoblastic T cell lymphoma (AITL) is an aggressive tumor derived from malignant transformation of T follicular helper (Tfh) cells. AITL is characterized by loss-of-function mutations in Ten-Eleven Translocation 2 (TET2) epigenetic tumor suppressor and a highly recurrent mutation (p.Gly17Val) in the RHOA small GTPase. Yet, the specific role of RHOA G17V in AITL remains unknown. Expression of Rhoa G17V in CD4⁺ T cells induces Tfh cell specification; increased proliferation associated with inducible co-stimulator (ICOS) upregulation and increased phosphoinositide 3-kinase (PI3K) and mitogen-activated protein kinase signaling. Moreover, RHOA G17V expression together with Tet2 loss resulted in development of AITL in mice. Importantly, Tet2^−/−RHOA G17V tumor proliferation in vivo can be inhibited by ICOS/PI3K-specific blockade, supporting a driving role for ICOS signaling in Tfh cell transformation.

Graphical abstract

Teaser

Cortes et al. show that expression of Rhoa G17V in CD4⁺ T cells drives proliferation and Tfh polarization, and they develop an angioimmunoblastic T cell lymphoma model by combining Rhoa G17V expression and Tet2 loss. These tumors show increased ICOS and PI3K/MAPK signaling and are sensitive to pathway inhibition.


http://ift.tt/2nBGQ5e

Soluble delta-like 1 homolog (DLK1) stimulates angiogenesis through Notch1/Akt/eNOS signaling in endothelial cells

Abstract

Aim

Delta-like 1 homolog (DLK1) is a non-canonical ligand of Notch signaling, which plays a pivotal role in vascular development and tumor angiogenesis. This study aimed to elucidate the function and mechanism of DLK1 in angiogenesis.

Methods and results

By using in situ hybridization and immunohistochemical studies, expression analysis revealed a unique vascular tropism of DLK1 in vasculature of neuroblastoma and vascular tumors. Thus, it was hypothesized that DLK1 may be cleaved and then bound to endothelial cells, thereby regulating the endothelial function. To test such hypothesis, soluble DLK1 encompassing DLK1 extracellular domain (DLK1-EC) was generated and validated by its inhibitory function in adipogenesis assay. Recombinant DLK1-EC exhibited the preferential binding capability toward endothelial cells and stimulated the microvessels sprouting in aorta rings. Above all, implantation of DLK1-EC dose-dependently elicited the cornea neovascularization in rats. By using various angiogenesis assays, it was delineated that DLK1-EC stimulated the angiogenesis by promoting the proliferation, motility and tube formation of endothelial cells. By immunoblot and luciferase analysis, it was elucidated that DLK1-EC enhanced the expression and activities of Notch1/Akt/eNOS/Hes-1 signaling in dose- and time-dependent manners. Pharmaceutical blockage of Notch signaling using γ-secretase inhibitor DAPT abrogated the DLK1-EC-induced endothelial migration and Hes-1-driven luciferase activities. Furthermore, Notch1 inactivation by neutralizing antibodies or RNA interference reversed the DLK1-EC-induced angiogenesis.

Conclusions

The present study unveils the pro-angiogenic function and mechanism of soluble DLK1 through activation of Notch1 signaling in endothelial cells.

http://ift.tt/2GFjx3r

miRNAs regulate the HIF switch during hypoxia: a novel therapeutic target

Abstract

The decline of oxygen tension in the tissues below the physiological demand leads to the hypoxic adaptive response. This physiological consequence enables cells to recover from this cellular insult. Understanding the cellular pathways that mediate recovery from hypoxia is therefore critical for developing novel therapeutic approaches for cardiovascular diseases and cancer. The master regulators of oxygen homeostasis that control angiogenesis during hypoxia are hypoxia-inducible factors (HIFs). HIF-1 and HIF-2 function as transcriptional regulators and have both unique and overlapping target genes, whereas the role of HIF-3 is less clear. HIF-1 governs the acute adaptation to hypoxia, whereas HIF-2 and HIF-3 expressions begin during chronic hypoxia in human endothelium. When HIF-1 levels decline, HIF-2 and HIF-3 increase. This switch from HIF-1 to HIF-2 and HIF-3 signaling is required in order to adapt the endothelium to prolonged hypoxia. During prolonged hypoxia, the HIF-1 levels and activity are reduced, despite the lack of oxygen-dependent protein degradation. Although numerous protein factors have been proposed to modulate the HIF pathways, their application for HIF-targeted therapy is rather limited. Recently, the miRNAs that endogenously regulate gene expression via the RNA interference (RNAi) pathway have been shown to play critical roles in the hypoxia response pathways. Furthermore, these classes of RNAs provide therapeutic possibilities to selectively target HIFs and thus modulate the HIF switch. Here, we review the significance of the microRNAs on the relationship between the HIFs under both physiological and pathophysiological conditions.

http://ift.tt/2s4BvsD

RHOA G17V Induces T Follicular Helper Cell Specification and Promotes Lymphomagenesis

Publication date: Available online 2 February 2018
Source:Cancer Cell
Author(s): Jose R. Cortes, Alberto Ambesi-Impiombato, Lucile Couronné, S. Aidan Quinn, Christine S. Kim, Ana C. da Silva Almeida, Zachary West, Laura Belver, Marta Sanchez Martin, Laurianne Scourzic, Govind Bhagat, Olivier A. Bernard, Adolfo A. Ferrando, Teresa Palomero
Angioimmunoblastic T cell lymphoma (AITL) is an aggressive tumor derived from malignant transformation of T follicular helper (Tfh) cells. AITL is characterized by loss-of-function mutations in Ten-Eleven Translocation 2 (TET2) epigenetic tumor suppressor and a highly recurrent mutation (p.Gly17Val) in the RHOA small GTPase. Yet, the specific role of RHOA G17V in AITL remains unknown. Expression of Rhoa G17V in CD4⁺ T cells induces Tfh cell specification; increased proliferation associated with inducible co-stimulator (ICOS) upregulation and increased phosphoinositide 3-kinase (PI3K) and mitogen-activated protein kinase signaling. Moreover, RHOA G17V expression together with Tet2 loss resulted in development of AITL in mice. Importantly, Tet2^−/−RHOA G17V tumor proliferation in vivo can be inhibited by ICOS/PI3K-specific blockade, supporting a driving role for ICOS signaling in Tfh cell transformation.

Graphical abstract

Teaser

Cortes et al. show that expression of Rhoa G17V in CD4⁺ T cells drives proliferation and Tfh polarization, and they develop an angioimmunoblastic T cell lymphoma model by combining Rhoa G17V expression and Tet2 loss. These tumors show increased ICOS and PI3K/MAPK signaling and are sensitive to pathway inhibition.


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via IFTTT

Soluble delta-like 1 homolog (DLK1) stimulates angiogenesis through Notch1/Akt/eNOS signaling in endothelial cells

Abstract

Aim

Delta-like 1 homolog (DLK1) is a non-canonical ligand of Notch signaling, which plays a pivotal role in vascular development and tumor angiogenesis. This study aimed to elucidate the function and mechanism of DLK1 in angiogenesis.

Methods and results

By using in situ hybridization and immunohistochemical studies, expression analysis revealed a unique vascular tropism of DLK1 in vasculature of neuroblastoma and vascular tumors. Thus, it was hypothesized that DLK1 may be cleaved and then bound to endothelial cells, thereby regulating the endothelial function. To test such hypothesis, soluble DLK1 encompassing DLK1 extracellular domain (DLK1-EC) was generated and validated by its inhibitory function in adipogenesis assay. Recombinant DLK1-EC exhibited the preferential binding capability toward endothelial cells and stimulated the microvessels sprouting in aorta rings. Above all, implantation of DLK1-EC dose-dependently elicited the cornea neovascularization in rats. By using various angiogenesis assays, it was delineated that DLK1-EC stimulated the angiogenesis by promoting the proliferation, motility and tube formation of endothelial cells. By immunoblot and luciferase analysis, it was elucidated that DLK1-EC enhanced the expression and activities of Notch1/Akt/eNOS/Hes-1 signaling in dose- and time-dependent manners. Pharmaceutical blockage of Notch signaling using γ-secretase inhibitor DAPT abrogated the DLK1-EC-induced endothelial migration and Hes-1-driven luciferase activities. Furthermore, Notch1 inactivation by neutralizing antibodies or RNA interference reversed the DLK1-EC-induced angiogenesis.

Conclusions

The present study unveils the pro-angiogenic function and mechanism of soluble DLK1 through activation of Notch1 signaling in endothelial cells.

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via IFTTT

miRNAs regulate the HIF switch during hypoxia: a novel therapeutic target

Abstract

The decline of oxygen tension in the tissues below the physiological demand leads to the hypoxic adaptive response. This physiological consequence enables cells to recover from this cellular insult. Understanding the cellular pathways that mediate recovery from hypoxia is therefore critical for developing novel therapeutic approaches for cardiovascular diseases and cancer. The master regulators of oxygen homeostasis that control angiogenesis during hypoxia are hypoxia-inducible factors (HIFs). HIF-1 and HIF-2 function as transcriptional regulators and have both unique and overlapping target genes, whereas the role of HIF-3 is less clear. HIF-1 governs the acute adaptation to hypoxia, whereas HIF-2 and HIF-3 expressions begin during chronic hypoxia in human endothelium. When HIF-1 levels decline, HIF-2 and HIF-3 increase. This switch from HIF-1 to HIF-2 and HIF-3 signaling is required in order to adapt the endothelium to prolonged hypoxia. During prolonged hypoxia, the HIF-1 levels and activity are reduced, despite the lack of oxygen-dependent protein degradation. Although numerous protein factors have been proposed to modulate the HIF pathways, their application for HIF-targeted therapy is rather limited. Recently, the miRNAs that endogenously regulate gene expression via the RNA interference (RNAi) pathway have been shown to play critical roles in the hypoxia response pathways. Furthermore, these classes of RNAs provide therapeutic possibilities to selectively target HIFs and thus modulate the HIF switch. Here, we review the significance of the microRNAs on the relationship between the HIFs under both physiological and pathophysiological conditions.

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Preclinical studies using miR-32-5p to suppress clear cell renal cell carcinoma metastasis via altering the miR-32-5p/TR4/HGF/Met signaling

Abstract

While testicular nuclear receptor 4 (TR4) may promote prostate cancer (PCa) metastasis, its roles in the clear cell renal cell carcinoma (ccRCC) remains unclear. Here we found a higher expression of TR4 in ccRCC tumors from patients with distant metastases than those from metastasis-free patients, suggesting TR4 may play positive roles in the ccRCC metastasis. Results from in vitro multiple ccRCC cell lines also confirmed TR4's positive roles in promoting ccRCC cell invasion/migration via altering the microRNA (miR-32-5p)/TR4/HGF/Met/MMP2-MMP9 signaling. Mechanism dissection revealed that miR-32-5p could suppress TR4 protein expression via direct binding to the 3'UTR of TR4 mRNA, and TR4 might then alter the HGF/Met signaling at the transcriptional regulation via direct binding to the TR4-response-elements (TR4RE) on the HGF promoter. Then the in vitro data also demonstrated the efficacy of Sunitinib, a currently used drug to treat ccRCC, could be increased after targeting this newly identified miR-32-5p/TR4/HGF/Met signaling. The preclinical study using the in vivo mouse model with xenografted ccRCC cells confirmed the in vitro cell lines data. Together, these findings suggest that TR4 is a key player to promote ccRCC metastasis and targeting this miR-32-5p/TR4/HGF/Met signaling with small molecules including TR4-shRNA or miR-32-5p may help us to develop a new therapy to better suppress the ccRCC metastasis. This article is protected by copyright. All rights reserved.

http://ift.tt/2FHVoIi

Arsenic Promotes the COX2/PGE2-SOX2 Axis to Increase the Malignant Stemness Properties of Urothelial Cells

Abstract

Chronic arsenic exposure is associated with the development of urothelial carcinoma of the bladder (UCB). To elucidate the contribution of arsenic exposure to urothelial cancer stem cell (CSC) generation, we established an in vitro stepwise malignant model transformed by chronically exposing human urothelial cells to arsenic. Using this model, we found that chronic arsenic exposure endows urothelial cells with malignant stemness properties including increased expression of stemness-related factors such as SOX2, sphere formation, self-renewal, invasion, and chemo-resistance. SOX2 was gradually and irreversibly overexpressed in line with acquired sphere-forming and self-renewal abilities. Following gene set enrichment analyses of arsenic-exposed and arsenic-unexposed cells, we found COX2 as an enriched gene for oncogenic signature. Mechanistically, arsenic-induced COX2/PGE2 increases SOX2 expression that eventually promotes malignant stem cell generation and repopulation. In urine samples from 90 subjects exposed to arsenic and 91 control subjects, we found a significant linear correlation between SOX2 and COX2 expression and the potential of SOX2 and COX2 expression as urinary markers to detect subjects exposed to arsenic. Furthermore, the combination marker yielded a high sensitivity for UCB detection in a separate cohort. Finally, our in vitro model exhibits basal-type molecular features, and dual inhibition of EGFR and COX2 attenuated stem cell enrichment more efficiently than an EGFR inhibitor alone. In conclusion, the COX2/PGE2-SOX2 axis promotes arsenic-induced malignant stem cell transformation. In addition, our findings indicate the possible use of SOX2 and COX2 expression as urinary markers for the risk stratification and detection of UCB. This article is protected by copyright. All rights reserved.

http://ift.tt/2EavkrX

Preclinical studies using miR-32-5p to suppress clear cell renal cell carcinoma metastasis via altering the miR-32-5p/TR4/HGF/Met signaling

Abstract

While testicular nuclear receptor 4 (TR4) may promote prostate cancer (PCa) metastasis, its roles in the clear cell renal cell carcinoma (ccRCC) remains unclear. Here we found a higher expression of TR4 in ccRCC tumors from patients with distant metastases than those from metastasis-free patients, suggesting TR4 may play positive roles in the ccRCC metastasis. Results from in vitro multiple ccRCC cell lines also confirmed TR4's positive roles in promoting ccRCC cell invasion/migration via altering the microRNA (miR-32-5p)/TR4/HGF/Met/MMP2-MMP9 signaling. Mechanism dissection revealed that miR-32-5p could suppress TR4 protein expression via direct binding to the 3'UTR of TR4 mRNA, and TR4 might then alter the HGF/Met signaling at the transcriptional regulation via direct binding to the TR4-response-elements (TR4RE) on the HGF promoter. Then the in vitro data also demonstrated the efficacy of Sunitinib, a currently used drug to treat ccRCC, could be increased after targeting this newly identified miR-32-5p/TR4/HGF/Met signaling. The preclinical study using the in vivo mouse model with xenografted ccRCC cells confirmed the in vitro cell lines data. Together, these findings suggest that TR4 is a key player to promote ccRCC metastasis and targeting this miR-32-5p/TR4/HGF/Met signaling with small molecules including TR4-shRNA or miR-32-5p may help us to develop a new therapy to better suppress the ccRCC metastasis. This article is protected by copyright. All rights reserved.

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Arsenic Promotes the COX2/PGE2-SOX2 Axis to Increase the Malignant Stemness Properties of Urothelial Cells

Abstract

Chronic arsenic exposure is associated with the development of urothelial carcinoma of the bladder (UCB). To elucidate the contribution of arsenic exposure to urothelial cancer stem cell (CSC) generation, we established an in vitro stepwise malignant model transformed by chronically exposing human urothelial cells to arsenic. Using this model, we found that chronic arsenic exposure endows urothelial cells with malignant stemness properties including increased expression of stemness-related factors such as SOX2, sphere formation, self-renewal, invasion, and chemo-resistance. SOX2 was gradually and irreversibly overexpressed in line with acquired sphere-forming and self-renewal abilities. Following gene set enrichment analyses of arsenic-exposed and arsenic-unexposed cells, we found COX2 as an enriched gene for oncogenic signature. Mechanistically, arsenic-induced COX2/PGE2 increases SOX2 expression that eventually promotes malignant stem cell generation and repopulation. In urine samples from 90 subjects exposed to arsenic and 91 control subjects, we found a significant linear correlation between SOX2 and COX2 expression and the potential of SOX2 and COX2 expression as urinary markers to detect subjects exposed to arsenic. Furthermore, the combination marker yielded a high sensitivity for UCB detection in a separate cohort. Finally, our in vitro model exhibits basal-type molecular features, and dual inhibition of EGFR and COX2 attenuated stem cell enrichment more efficiently than an EGFR inhibitor alone. In conclusion, the COX2/PGE2-SOX2 axis promotes arsenic-induced malignant stem cell transformation. In addition, our findings indicate the possible use of SOX2 and COX2 expression as urinary markers for the risk stratification and detection of UCB. This article is protected by copyright. All rights reserved.

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Snap, crackle and pop: when sneezing leads to crackling in the neck

Wanding Yang<br />Jan 15, 2018; 2018:bcr-2016-218906-bcr-2016-218906<br />Rare disease

http://ift.tt/2DWxIPU

Successful treatment of postural orthostatic tachycardia and mast cell activation syndromes using naltrexone, immunoglobulin and antibiotic treatment

Leonard B Weinstock<br />Jan 11, 2018; 2018:bcr-2017-221405-bcr-2017-221405<br />Novel treatment (new drug/intervention; established drug/procedure in new situation)

http://ift.tt/2Exc6KN

Longitudinal study of radiation-induced brain microstructural alterations with S-index, a Diffusion MRI biomarker, and MR Spectroscopy

Publication date: Available online 2 February 2018
Source:International Journal of Radiation Oncology*Biology*Physics
Author(s): E.A. Pérès, O. Etienne, A. Grigis, F. Boumezbeur, F.D. Boussin, D. Le Bihan
PurposeRadiotherapy is widely used for the treatment of brain tumors but it may lead to severe cognitive impairments. Previous studies have shown that ionizing radiation induces demyelination, blood-brain barrier alterations and impaired neurogenesis in animal models. Hence, non-invasive and sensitive biomarkers of radiation injury are needed to investigate these effects in patients and improve radiotherapy protocols.Methods and MaterialsThe heads of 3-months old male C57BL/6RJ mice (CTL: n=15; IR: n=15) were exposed to radiation doses of 3x5Gy from a ⁶⁰Co source with a medical irradiator. A longitudinal study was performed to investigate cranial radiation-induced (3x5Gy) microstructural tissue alterations using water diffusion MRI (dMRI) and MR Spectroscopy (MRS) in different areas of the mouse brain (cortex, thalamus, striatum, olfactory bulbs (OB), hippocampus and the subventricular zone (SVZ)). In addition to the quantification of standard non-Gaussian diffusion parameters, ADC0 (Apparent Diffusion Coefficient) and K (Kurtosis), we evaluated a new composite diffusion metric, designated as S-index.ResultsWe observed a significant decrease in S-index in the SVZ, from 1 month to 8 months after brain radiation (p<0.05). Interestingly, along with a decrease in Taurine (up to -15% at 2 months, p<0.01), a delayed S-index drop was also observed in the OB from 4 months after irradiation and maintained until the end of our experiment (p<0.0001). These observations suggest that S-index variations revealed the radiation-induced decline of neurogenesis that was further confirmed by a decrease of neural stem cells in the SVZ and of newborn neurons in the OB of irradiated animals.ConclusionsThis study demonstrates that dMRI, especially through the S-index approach, is a relevant imaging modality to monitor brain radiation injury and probe microstructural changes underlying radiation-induced cognitive deficits.

Teaser

Cancer patients frequently suffer from cognitive impairments following brain radiotherapy. To monitor radiation-induced microstructural tissue damage, especially in neurogenic areas, we have investigated the potential of diffusion MRI and MR spectroscopy. The diffusion S-index calculated from diffusion MRI signal acquired at two optimized values of diffusion-weighting appeared as the most sensitive biomarker revealing subtle brain tissue alterations induced by ionizing radiation.


http://ift.tt/2DWCQHQ

Bioluminescence Tomography Guided Small Animal Radiotherapy and Tumor Response Assessment

Publication date: Available online 2 February 2018
Source:International Journal of Radiation Oncology*Biology*Physics
Author(s): Junwei Shi, Thirupandiyur S. Udayakumar, Keying Xu, Nesrin Dogan, Alan Pollack, Yidong Yang
Purposes: The image-guided SMall Animal Arc Radiation Treatment platform (iSMAART) has adopted onboard cone beam computed tomography (CBCT) and bioluminescence tomography (BLT). In this study, we used BLT to guide radiation delivery and quantitatively assess radiation-induced tumor response.Methods and MaterialsBLT was first validated on a tissue-simulating phantom, where the internal chemiluminescent liquid had a constant volume while its luminescence intensity gradually decayed. Then, in vivo experiments were performed on BALB/c mice orthotopically inoculated with 4T1 breast carcinoma cells expressing luciferase. Animals received either radiation treatment (RT group, n=9) or not (Control group, n=9). BLT was used to guide delivery of a single fraction of 5 Gy radiation dose to the tumor, and to evaluate the treatment response. The terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) staining was used to evaluate the radiation-induced DNA damage and cell apoptosis.ResultsPhantom results showed that BLT not only recovered the constant target volume with <2% deviation, but also accurately monitored the decay of the chemiluminescent molecules. For the RT animal group, there was significant reduction in both BLT-based tumor volume (21±10%, P=0.001) and bioluminescence intensity (48±17%, P=0.0008). For the control group, the significant increase was detected in the BLT tumor volume (35±12%, P<0.0001), but not in the BLT bioluminescence intensity (P=0.4). There was a significant difference in the BLT tumor volume between the RT and control group 7 days after radiation (P=0.03). Regression analysis suggests a strong correlation between the BLT and CBCT tumor volume (R²=0.93). The TUNEL staining analysis showed a significant difference in tumor cell apoptosis between the RT and control group (20.6±2.9% vs 3.2±1.7%, P<0.05).ConclusionBLT onboard the iSMAART can be used to accurately guide radiation delivery, and to quantitatively assess treatment response by simultaneously monitoring tumor volume and cancer cell population.



http://ift.tt/2nzTMsu

IDEAL 2a phase-II study of ultra-focal brachytherapy for low and intermediate risk prostate cancer

Publication date: Available online 2 February 2018
Source:International Journal of Radiation Oncology*Biology*Physics
Author(s): Pierre Graff, Daniel Portalez, Amélie Lusque, Thomas Brun, Richard Aziza, Jonathan Khalifa, Mathieu Roumiguié, Marie-Laure Quintyn Ranty, Thomas Filleron, Jean-Marc Barchaud, Bernard Malavaud
PurposeFocal therapy of prostate cancer requires precise positioning of therapeutic agents within well-characterised index tumours (IT).We assessed the feasibility of low-dose-rate ultra-focal brachytherapy (UFB).Methods & MaterialsIRB-approved European Clinical Trials Database-registered phase II protocol. Patients referred (10/2013-8/2016) for active surveillance [PSA<10ng/mL, cT1c-cT2a, Gleason sum on referring biopsies ≤6(3+3), ≤3 positive biopsies, ≤50% of cancer] were pre-selected. Inclusion was confirmed when complementary image-guided biopsies informed a single PI-RADS.v1≥3 Gleason sum ≤7a(3+4) lesion.A single ultrasound-visible ancillary marker was positioned within the IT using 3D-TRUS/MRI elastic fusion registration (Koelis°). Ultra-focal transperineal delivery of I-125 seeds then used classical 2D-Transrectal ultrasonography (Bard-FlexFocus°) and dose-optimization (Variseed Treatment Planning System°).Following Simon's optimal design, 17 patients were required to assess the feasibility of delivering ≥95% of the prescribed dose (160Gy) to the IT (primary objective). Adverse-events (CTCAE) and quality-of-life (IIEF-5, IPSS) were recorded. 1-year control biopsies were obtained in IT and untreated segments.Results27/44 of pre-selected patients failed inclusion. 16/17 of UFB-treated patients met the primary objective (per-protocol success). Prescription dose was delivered to 14.5±6.4% of the prostate volume resulting in negligible urethral and rectal irradiations and toxicities. No recurrences were evidenced on 1-year control MRI and IT biopsies. Seven non-clinically significant cancers and one Gleason sum 7a(3+4) cancer (salvage prostatectomy) were observed in the untreated parenchyma.ConclusionsRecent technology allows selective and effective brachytherapy of small MRI targets.



http://ift.tt/2DWCO2G

Long-Term Outcomes and Prognostic Factors Following Pencil-Beam Scanning Proton Radiotherapy for Spinal Chordomas: A Large, Single-Institution Cohort

Publication date: Available online 2 February 2018
Source:International Journal of Radiation Oncology*Biology*Physics
Author(s): J.W. Snider, Ralf A. Schneider, Davey Poelma-Tap, Sonja Stieb, Fritz R. Murray, Lorenzo Placidi, Francesca Albertini, Antony Lomax, Alessandra Bolsi, Ulrike Kliebsch, Robert Malyapa, Damien C. Weber
PurposeTo evaluate the efficacy and safety of high-dose pencil-beam scanning proton therapy (PBS-PT) in the adjuvant treatment of spinal chordomas.Methods and MaterialsBetween 1997 and 2015, 100 patients with spinal chordomas (median age, 56 years; range, 25–81 years) were treated with adjuvant PBS-PT at the XXXX: cervical (n=46), thoracic (n=4), lumbar (n=12), and sacral (n=38). The majority (88%) received PBS-PT alone rather than combined photon–proton therapy. The median radiotherapy dose prescribed was 74 Gy(RBE) (range, 59.4–77 Gy[RBE]). Thirty-nine (39%) patients had undergone surgical stabilization (SS), primarily with titanium hardware, prior to radiotherapy.ResultsWith a median follow-up of 65 months (range, 13–175 months), 5-year local control, disease control, and overall survival rates were 63% (95%CI: 57.7–68.7%; median, 103 months), 57% (95%CI: 50.9-62.1%; median, 82 months), and 81% (95%CI: 76.8-85.6%; median, 157 months), respectively. On univariate and multivariate analyses, the presence of SS was highly prognostic for worsened outcomes. Multivariate analysis also revealed the extent of treatment volumes and presence of gross residual disease to be important in predicting outcomes. High-grade (≥grade 3) toxicities were rare in both the acute (8%) and late (6%) settings.ConclusionFor spinal chordomas, PBS-PT remains a highly effective and safe method for delivery of dose-escalated adjuvant radiotherapy. The presence of metallic SS prognosticates for worsened outcomes. Further investigation is warranted to characterize ideal treatment volumes and effect of SS on therapy for these challenging tumors.



http://ift.tt/2nEfSKr

Longitudinal study of radiation-induced brain microstructural alterations with S-index, a Diffusion MRI biomarker, and MR Spectroscopy

Publication date: Available online 2 February 2018
Source:International Journal of Radiation Oncology*Biology*Physics
Author(s): E.A. Pérès, O. Etienne, A. Grigis, F. Boumezbeur, F.D. Boussin, D. Le Bihan
PurposeRadiotherapy is widely used for the treatment of brain tumors but it may lead to severe cognitive impairments. Previous studies have shown that ionizing radiation induces demyelination, blood-brain barrier alterations and impaired neurogenesis in animal models. Hence, non-invasive and sensitive biomarkers of radiation injury are needed to investigate these effects in patients and improve radiotherapy protocols.Methods and MaterialsThe heads of 3-months old male C57BL/6RJ mice (CTL: n=15; IR: n=15) were exposed to radiation doses of 3x5Gy from a ⁶⁰Co source with a medical irradiator. A longitudinal study was performed to investigate cranial radiation-induced (3x5Gy) microstructural tissue alterations using water diffusion MRI (dMRI) and MR Spectroscopy (MRS) in different areas of the mouse brain (cortex, thalamus, striatum, olfactory bulbs (OB), hippocampus and the subventricular zone (SVZ)). In addition to the quantification of standard non-Gaussian diffusion parameters, ADC0 (Apparent Diffusion Coefficient) and K (Kurtosis), we evaluated a new composite diffusion metric, designated as S-index.ResultsWe observed a significant decrease in S-index in the SVZ, from 1 month to 8 months after brain radiation (p<0.05). Interestingly, along with a decrease in Taurine (up to -15% at 2 months, p<0.01), a delayed S-index drop was also observed in the OB from 4 months after irradiation and maintained until the end of our experiment (p<0.0001). These observations suggest that S-index variations revealed the radiation-induced decline of neurogenesis that was further confirmed by a decrease of neural stem cells in the SVZ and of newborn neurons in the OB of irradiated animals.ConclusionsThis study demonstrates that dMRI, especially through the S-index approach, is a relevant imaging modality to monitor brain radiation injury and probe microstructural changes underlying radiation-induced cognitive deficits.

Teaser

Cancer patients frequently suffer from cognitive impairments following brain radiotherapy. To monitor radiation-induced microstructural tissue damage, especially in neurogenic areas, we have investigated the potential of diffusion MRI and MR spectroscopy. The diffusion S-index calculated from diffusion MRI signal acquired at two optimized values of diffusion-weighting appeared as the most sensitive biomarker revealing subtle brain tissue alterations induced by ionizing radiation.


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Bioluminescence Tomography Guided Small Animal Radiotherapy and Tumor Response Assessment

Publication date: Available online 2 February 2018
Source:International Journal of Radiation Oncology*Biology*Physics
Author(s): Junwei Shi, Thirupandiyur S. Udayakumar, Keying Xu, Nesrin Dogan, Alan Pollack, Yidong Yang
Purposes: The image-guided SMall Animal Arc Radiation Treatment platform (iSMAART) has adopted onboard cone beam computed tomography (CBCT) and bioluminescence tomography (BLT). In this study, we used BLT to guide radiation delivery and quantitatively assess radiation-induced tumor response.Methods and MaterialsBLT was first validated on a tissue-simulating phantom, where the internal chemiluminescent liquid had a constant volume while its luminescence intensity gradually decayed. Then, in vivo experiments were performed on BALB/c mice orthotopically inoculated with 4T1 breast carcinoma cells expressing luciferase. Animals received either radiation treatment (RT group, n=9) or not (Control group, n=9). BLT was used to guide delivery of a single fraction of 5 Gy radiation dose to the tumor, and to evaluate the treatment response. The terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) staining was used to evaluate the radiation-induced DNA damage and cell apoptosis.ResultsPhantom results showed that BLT not only recovered the constant target volume with <2% deviation, but also accurately monitored the decay of the chemiluminescent molecules. For the RT animal group, there was significant reduction in both BLT-based tumor volume (21±10%, P=0.001) and bioluminescence intensity (48±17%, P=0.0008). For the control group, the significant increase was detected in the BLT tumor volume (35±12%, P<0.0001), but not in the BLT bioluminescence intensity (P=0.4). There was a significant difference in the BLT tumor volume between the RT and control group 7 days after radiation (P=0.03). Regression analysis suggests a strong correlation between the BLT and CBCT tumor volume (R²=0.93). The TUNEL staining analysis showed a significant difference in tumor cell apoptosis between the RT and control group (20.6±2.9% vs 3.2±1.7%, P<0.05).ConclusionBLT onboard the iSMAART can be used to accurately guide radiation delivery, and to quantitatively assess treatment response by simultaneously monitoring tumor volume and cancer cell population.



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IDEAL 2a phase-II study of ultra-focal brachytherapy for low and intermediate risk prostate cancer

Publication date: Available online 2 February 2018
Source:International Journal of Radiation Oncology*Biology*Physics
Author(s): Pierre Graff, Daniel Portalez, Amélie Lusque, Thomas Brun, Richard Aziza, Jonathan Khalifa, Mathieu Roumiguié, Marie-Laure Quintyn Ranty, Thomas Filleron, Jean-Marc Barchaud, Bernard Malavaud
PurposeFocal therapy of prostate cancer requires precise positioning of therapeutic agents within well-characterised index tumours (IT).We assessed the feasibility of low-dose-rate ultra-focal brachytherapy (UFB).Methods & MaterialsIRB-approved European Clinical Trials Database-registered phase II protocol. Patients referred (10/2013-8/2016) for active surveillance [PSA<10ng/mL, cT1c-cT2a, Gleason sum on referring biopsies ≤6(3+3), ≤3 positive biopsies, ≤50% of cancer] were pre-selected. Inclusion was confirmed when complementary image-guided biopsies informed a single PI-RADS.v1≥3 Gleason sum ≤7a(3+4) lesion.A single ultrasound-visible ancillary marker was positioned within the IT using 3D-TRUS/MRI elastic fusion registration (Koelis°). Ultra-focal transperineal delivery of I-125 seeds then used classical 2D-Transrectal ultrasonography (Bard-FlexFocus°) and dose-optimization (Variseed Treatment Planning System°).Following Simon's optimal design, 17 patients were required to assess the feasibility of delivering ≥95% of the prescribed dose (160Gy) to the IT (primary objective). Adverse-events (CTCAE) and quality-of-life (IIEF-5, IPSS) were recorded. 1-year control biopsies were obtained in IT and untreated segments.Results27/44 of pre-selected patients failed inclusion. 16/17 of UFB-treated patients met the primary objective (per-protocol success). Prescription dose was delivered to 14.5±6.4% of the prostate volume resulting in negligible urethral and rectal irradiations and toxicities. No recurrences were evidenced on 1-year control MRI and IT biopsies. Seven non-clinically significant cancers and one Gleason sum 7a(3+4) cancer (salvage prostatectomy) were observed in the untreated parenchyma.ConclusionsRecent technology allows selective and effective brachytherapy of small MRI targets.



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Long-Term Outcomes and Prognostic Factors Following Pencil-Beam Scanning Proton Radiotherapy for Spinal Chordomas: A Large, Single-Institution Cohort

Publication date: Available online 2 February 2018
Source:International Journal of Radiation Oncology*Biology*Physics
Author(s): J.W. Snider, Ralf A. Schneider, Davey Poelma-Tap, Sonja Stieb, Fritz R. Murray, Lorenzo Placidi, Francesca Albertini, Antony Lomax, Alessandra Bolsi, Ulrike Kliebsch, Robert Malyapa, Damien C. Weber
PurposeTo evaluate the efficacy and safety of high-dose pencil-beam scanning proton therapy (PBS-PT) in the adjuvant treatment of spinal chordomas.Methods and MaterialsBetween 1997 and 2015, 100 patients with spinal chordomas (median age, 56 years; range, 25–81 years) were treated with adjuvant PBS-PT at the XXXX: cervical (n=46), thoracic (n=4), lumbar (n=12), and sacral (n=38). The majority (88%) received PBS-PT alone rather than combined photon–proton therapy. The median radiotherapy dose prescribed was 74 Gy(RBE) (range, 59.4–77 Gy[RBE]). Thirty-nine (39%) patients had undergone surgical stabilization (SS), primarily with titanium hardware, prior to radiotherapy.ResultsWith a median follow-up of 65 months (range, 13–175 months), 5-year local control, disease control, and overall survival rates were 63% (95%CI: 57.7–68.7%; median, 103 months), 57% (95%CI: 50.9-62.1%; median, 82 months), and 81% (95%CI: 76.8-85.6%; median, 157 months), respectively. On univariate and multivariate analyses, the presence of SS was highly prognostic for worsened outcomes. Multivariate analysis also revealed the extent of treatment volumes and presence of gross residual disease to be important in predicting outcomes. High-grade (≥grade 3) toxicities were rare in both the acute (8%) and late (6%) settings.ConclusionFor spinal chordomas, PBS-PT remains a highly effective and safe method for delivery of dose-escalated adjuvant radiotherapy. The presence of metallic SS prognosticates for worsened outcomes. Further investigation is warranted to characterize ideal treatment volumes and effect of SS on therapy for these challenging tumors.



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Novel oral anticoagulants and HIV: dabigatran use with antiretrovirals

Jacinta Perram<br />Nov 20, 2015; 2015:bcr2015211651-bcr2015211651<br />case-report

http://ift.tt/2FEWS5N

Brain abscess as an initial presentation in a patient of hereditary haemorrhagic telangiectasia caused by a novel ENG mutation

Kai-Hsiang Chen<br />Feb 25, 2013; 2013:bcr2013008802-bcr2013008802<br />case-report

http://ift.tt/2EcWH4H

Differential diagnosis of soft scalp lumps

Lawrence K Leung<br />Nov 15, 2011; 2011:bcr0720114492-bcr0720114492<br />case-report

http://ift.tt/2FFqU9y

Biopsychosocial Distress in Young Adult Oncology Patients: Examining Sex Differences in Sources of High Distress and Requests for Assistance

Journal of Adolescent and Young Adult Oncology , Vol. 0, No. 0.


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Biopsychosocial Distress in Young Adult Oncology Patients: Examining Sex Differences in Sources of High Distress and Requests for Assistance

Journal of Adolescent and Young Adult Oncology , Vol. 0, No. 0.


http://ift.tt/2DX1aJn

Prognostic significance of pretreatment total lymphocyte count and neutrophil-to-lymphocyte ratio in extensive-stage small-cell lung cancer

We evaluated pretreatment total lymphocyte count (TLC, marker of immunosuppression), neutrophil-to-lymphocyte ratio (NLR, marker of inflammation), and overall survival (OS) in patients with extensive-stage small-cell lung cancer (ES-SCLC).

http://ift.tt/2DZivSh

Radiotherapy for prostate cancer – Does daily image guidance with tighter margins improve patient reported outcomes compared to weekly orthogonal verified irradiation? Results from a randomized controlled trial

In radical RT for prostate cancer, daily CBCT IGRT with reduced PTV margins demonstrated no advantage with respect to patient reported side effects at end of RT as compared to weekly orthogonal offline portal imaging with standard PTV margins.

http://ift.tt/2nBe3xG

Impact of pemetrexed on intracranial disease control and radiation necrosis in patients with brain metastases from non-small cell lung cancer receiving stereotactic radiation

Pemetrexed is a folate antimetabolite used in the management of advanced adenocarcinoma of the lung. We sought to assess the impact of pemetrexed on intracranial disease control and radiation-related toxicity among patients with adenocarcinoma of the lung who received stereotactic radiation for brain metastases.

http://ift.tt/2nDv8at

A qualitative signature for predicting pathological response to neoadjuvant chemoradiation in locally advanced rectal cancers

The standard therapy for locally advanced rectal cancers (LARCs) is neoadjuvant chemoradiation (nCRT) followed by surgical resection. Pathological response to nCRT varies among patients, and it remains a challenge to predict pathological response to nCRT in LARCs.

http://ift.tt/2DZhZnj

Evaluation of clinical and endoscopic toxicity after external beam radiotherapy and endorectal brachytherapy in elderly patients with rectal cancer treated in the HERBERT study

The HERBERT study evaluated a high-dose-rate endorectal brachytherapy boost (HDREBT) after EBRT in medically inoperable/elderly patients with rectal cancer. The response-rates are promising but not without risk of toxicity. The current analysis provides a comprehensive overview of patient reported, physician reported and endoscopically observed toxicity.

http://ift.tt/2nBLEaY

Pink1 attenuates propofol-induced apoptosis and oxidative stress in developing neurons

Abstract

Background

The underlying mechanisms of propofol-induced neurotoxicity in developing neurons are still not completely understood. We examined the role of PTEN-induced kinase 1 (Pink1), an antioxidant protein, in propofol-induced apoptosis in developing neurons.

Materials and methods

Primary hippocampal neurons isolated from neonatal Sprague–Dawley rats were exposed to propofol 20 μM for 2, 4, 6 and 12 h. Subsequently, neurons underwent overexpression and knockdown of Pink1, followed by propofol exposure (20 μM, 6 h). Neuron apoptosis was detected by terminal transferase deoxyuridine triphosphate-biotin nick-end labeling (TUNEL). Reactive oxygen species (ROS) production in neurons was detected by using a 2,7-dichlorodihydro-fluorescein diacetate probe and target protein or mRNA levels were analyzed by Western blotting or real-time polymerase chain reaction.

Results

Propofol treatment time-dependently increased the number of TUNEL-positive neurons and the expression levels of cleaved caspase-3 and B-cell lymphoma 2 (BcL-2) associated X protein, but decreased expression levels of BcL-2. Furthermore, propofol treatment time-dependently reduced the expression levels of Pink1 mRNA and protein. ROS production and the markers of oxidative stress, 2,4-dinitrophenol and 4-hydroxynonenal, were increased by propofol treatment. However, these propofol-induced changes were significantly restored by Pink1 overexpression.

Conclusions

Pink1 plays an important role in neuronal apoptosis induced by propofol. Our results may provide some new insights in propofol-induced neurotoxicity in developing neurons.

http://ift.tt/2EdX7YN

Quick reference tidal volume cards reduce the incidence of large tidal volumes during surgery

Abstract

Ventilation with large tidal volumes (V _T), greater than 10 ml/kg of predicted body weight (PBW), is associated with worse outcomes in critically ill and surgical patients. We hypothesized that the availability of quick reference cards with proposed V _T ranges specific to gender and different heights would reduce the intraoperative use of large V _T during prolonged abdominal surgery. We compared retrospectively the incidence of median V _T used during prolonged (≥4-h-long) abdominal surgery before ("before") and after ("after") the quick reference V _T cards were made available in all anesthesia machines in operating rooms of a single academic US medical center. We evaluated the effect of the intervention on the primary outcome while adjusting for previously identified risk factors of large V _T use: female gender, obesity (body mass index, BMI > 30), and short height (< 165 cm). The frequency of V _T > 10 ml/kg PBW was 15.1% in the before group and 4.3% in the after group (p < 0.001). The frequency of large V _T used during abdominal surgery was significantly decreased after the intervention even after adjusting for female gender, obesity or short height [adjOR 0.11 (95% CI 0.04–0.30)]. Our quick reference V _T cards significantly reduced the frequency of large V _T use during abdominal surgery.

http://ift.tt/2FEPYOd

HANP on renal damage during cardiac surgery

http://ift.tt/2Eanezy

Central noradrenergic activity affects analgesic effect of Neuropeptide S

Abstract

Background

Neuropeptide S (NPS) is an endogenous neuropeptide controlling anxiolysis, wakefulness, and analgesia. NPS containing neurons exist near to the locus coeruleus (LC) involved in the descending anti-nociceptive system. NPS interacts with central noradrenergic neurons; thus brain noradrenergic signaling may be involved in NPS-induced analgesia. We tested NPS analgesia in noradrenergic neuron-lesioned rats using a selective LC noradrenergic neurotoxin, N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine (DSP-4).

Methods

A total 66 male Sprague–Dawley rats weighing 350–450 g were used. Analgesic effects of NPS were evaluated using hot-plate and tail-flick test with or without DSP-4. The animal allocated into 3 groups; hot-plate with NPS alone intracerebroventricular (icv) (0.0, 1.0, 3.3, and 10.0 nmol), tail-flick NPS alone icv (0.0 and 10.0 nmol), and hot-plate with NPS and DSP-4 (0 or 50 mg/kg ip). In hot-plate with NPS and DSP-4 group, noradrenaline content in the cerebral cortex, pons, hypothalamus, were measured.

Results

NPS 10 nmol icv prolonged hot plate (%MPE) but not tail flick latency at 30 and 40 min after administration. DSP-4 50 mg/kg decreased noradrenaline content in the all 3 regions. The NA depletion inhibited NPS analgesic effect in the hot plate test but not tail flick test. There was a significant correlation between hot plate latency (percentage of maximum possible effect: %MPE) with NPS 10 nmol and NA content in the cerebral cortex (p = 0.017, r ² = 0.346) which noradrenergic innervation arisen mainly from the LC. No other regions had the correlation.

Conclusions

NPS analgesia interacts with LC noradrenergic neuronal activity.

http://ift.tt/2FDB9LA

Effect of dexmedetomidine for attenuation of propofol injection pain in electroconvulsive therapy: a randomized controlled study

Abstract

Purpose

Current analgesic strategies for propofol injection pain may cause adverse reactions during electroconvulsive therapy (ECT), such as shortening seizure duration. This study investigated whether dexmedetomidine could attenuate propofol injection pain in ECT.

Methods

Participants were randomly allocated to receive 0.2 μg/kg dexmedetomidine (Dex-0.2 group), 0.5 μg/kg dexmedetomidine (Dex-0.5 group) or saline (control group) prior to ECT. The composite pain scale and objective Surgical Pleth Index (SPI) were used to measure the intensity of injection pain, and the percentage of patients with pain score > 2 was the primary outcome.

Results

Of 137 patients recruited, 46 were assigned to each of the Dex-0.2 or Dex-0.5 groups, while 45 were in the control group. The percentage of pain score > 2 was reduced from 68.9% (31/45) in the control group to 34.8% (16/46) in the Dex-0.2 group (P < 0.001) and 15.2% (7/46) in the Dex-0.5 group (P < 0.001). The pain score and SPI at 5 s after propofol injection were greater in the control group than in the Dex-0.2 [pain scores 3 (2–4) vs. 1 (1–3), P < 0.001, SPI 76.6 ± 10.0 vs. 58.0 ± 11.0, P < 0.001] and Dex-0.5 groups [pain scores 3 (2–4) vs. 1 (0–1), P < 0.001, SPI 76.6 ± 10.0 vs. 51.2 ± 12.3, P < 0.001]. There were no significant differences in seizure duration between the three groups. No patients developed bradycardia and hypotension.

Conclusions

Pretreatment with dexmedetomidine was able to reduce the propofol injection pain in ECT without interfering with the seizure duration and causing adverse effects such as bradycardia and hypotension. In addition, close monitoring of hemodynamic variables and preparation of a treatment plan and drugs for bradycardia are essential.

http://ift.tt/2E7vBfr

Association between fentanyl test results and rescue morphine requirements in children after adenotonsillectomy

Abstract

Purpose

Preoperative sleep study helps to predict post-adenotonsillectomy morphine requirements. However, in some institutions, many suspected children with obstructive sleep apnoea syndrome have an adenotonsillectomy without polysomnography assessments. This study investigated the relationship between the results of a fentanyl test performed before extubation and the postoperative morphine requirements in children after adenotonsillectomy.

Methods

Intravenous fentanyl (1 µg/kg) was given as a test before extubation when spontaneous ventilation was restored in 80 children aged 3–7 years who underwent adenotonsillectomy. The result was considered positive if the patient's respiratory rate decreased >50% after the test. In the recovery room, pain was assessed every 10 min using the Children's Hospital of Eastern Ontario Pain Scale. Rescue morphine (10 µg/kg) was given when the score was ≥6.

Results

The median [IQR (range)] cumulative morphine consumption rates for children with a positive result (n = 25) and a negative result (n = 52) were 30 (20, 40) and 50 (40, 50) µg/kg, respectively (P = 0.002). Eighty-eight percent of the positive-result patients and 48% of the negative-result patients were light consumers of morphine (cumulative dose <50 µg/kg) (P = 0.001).

Conclusions

We conclude that children with a positive result after a fentanyl test require less morphine to achieve comfort than those with a negative result.

ClinicalTrials.gov ID

NCT02484222.

http://ift.tt/2FHwxnL

Perioperative respiratory complications: current evidence and strategy discussed in 2017 JA symposium

Abstract

Respiratory management during general anesthesia aims to safely secure the airway and maintain adequate ventilation to deliver oxygen to the vital organs, maintaining homeostasis even during surgery. Despite its clinical importance, anesthesiologists often encounter difficulties in properly managing respiration during the perioperative period, leading to severe respiratory complications. In this year's JA symposium, 5 editorial board members of Journal of Anesthesia (JA) who are experts in the field of respiratory management in anesthesia discussed the following topics: quitting smoking before surgery: exposure to passive smoke is damaging to children, ventilator-associated pneumonia, high inspiratory oxygen concentration and lung injury, aspiration pneumonia, and postoperative respiratory management strategy in patients with obstructive sleep apnea. We hope that this special article regarding this year's JA symposium may be useful for JA readers to manage clinical anesthesia on a daily basis.

http://ift.tt/2EaCVXn

Corrigendum

Corrigendum: "Randomized Trial Comparing a Web-Mediated Follow-up With Routine Surveillance in Lung Cancer Patients" by Fabrice Denis et al. JNCI. J Natl Cancer Inst 2017; 109(9): doi: 10.1093/jnci/djx029.

http://ift.tt/2EAC3te

MiR-200c-3p inhibits cell migration and invasion of clear cell renal cell carcinoma via regulating SLC6A1

.


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Androgen receptor-independent prostate cancer: an emerging clinical entity

.


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MiR-200c-3p inhibits cell migration and invasion of clear cell renal cell carcinoma via regulating SLC6A1

.


http://ift.tt/2GEKHaq

Androgen receptor-independent prostate cancer: an emerging clinical entity

.


http://ift.tt/2s1CLNl

Targeting ataxia telangiectasia-mutated- and Rad3-related kinase (ATR) in PTEN-deficient breast cancers for personalized therapy

Abstract

Purpose

Phosphate and tensin homolog (PTEN), a negative regulator of PI3K signaling, is involved in DNA repair. ATR is a key sensor of DNA damage and replication stress. We evaluated whether ATR signaling has clinical significance and could be targeted by synthetic lethality in PTEN-deficient triple-negative breast cancer (TNBC).

Methods

PTEN, ATR and pCHK1^Ser345 protein level was evaluated in 1650 human breast cancers. ATR blockade by VE-821 was investigated in PTEN-proficient- (MDA-MB-231) and PTEN-deficient (BT-549, MDA-MB-468) TNBC cell lines. Functional studies included DNA repair expression profiling, MTS cell-proliferation assay, FACS (cell cycle progression & γH2AX accumulation) and FITC-annexin V flow cytometry analysis.

Results

Low nuclear PTEN was associated with higher grade, pleomorphism, de-differentiation, higher mitotic index, larger tumour size, ER negativity, and shorter survival (p values < 0.05). In tumours with low nuclear PTEN, high ATR and/or high pCHK1^ser345 level was also linked to higher grade, larger tumour size and poor survival (all p values < 0.05). VE-821 was selectively toxic in PTEN-deficient TNBC cells and resulted in accumulation of double-strand DNA breaks, cell cycle arrest, and increased apoptosis.

Conclusion

ATR signalling adversely impact survival in PTEN-deficient breast cancers. ATR inhibition is synthetically lethal in PTEN-deficient TNBC cells.

http://ift.tt/2GGpqxi

Komplikationen statt Überlebensvorteil und lokale Rezidivfreiheit nach früher radikaler Zystektomie bei muskelinvasivem Harnblasenkarzinom im Vergleich zur multimodalen Erhaltungstherapie

http://ift.tt/2DYKQ7a

Endoscopic examination of labial fusion in a postmenopausal woman: a case report

Labial fusion is defined as adhesions of the labia minora or majora. Labial fusion may cause urinary retention. Surgical treatment based on an accurate anatomic assessment may be needed, but the usefulness of ...

http://ift.tt/2BPFQj5

Paediatric aneurysmal bone cyst: not as easy as ABC

Abstract

Aneurysmal bone cysts (ABCs) are expansile cystic lesions that can affect any bone of the body. Whilst these lesions are histologically benign, the lesions are locally aggressive and can affect the integrity of the affected bone as well as surrounding structures. ABCs arising in the head and neck region, particularly the paranasal sinuses are rare and they are limited to case reports in the literature. Due to the proximity of critical anatomical structures and the visual apparatus, the potential complications can be devastating. The present article discusses both the clinical and radiological findings of an ABC arising from the ethmoid sinuses in a 6-year-old child and the potentially challenging diagnosis with its complex ensuing surgical management. The identification of an ABC arising in the paranasal sinuses is both a diagnostic and surgical challenge and ideally requires complex management in a joint paediatric ENT and craniofacial unit.

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Racial disparities in preoperative chemotherapy use in gastric cancer patients in the United States: Analysis of the National Cancer Data Base, 2006-2014

BACKGROUND

No studies have investigated whether race/ethnicity is associated with the recommended use of preoperative chemotherapy or subsequent outcomes in gastric cancer. To determine whether there is such an association, analyses of patients with gastric cancer in the National Cancer Data Base (NCDB) were performed.

METHODS

Patients with clinical T2-4bN0-1M0 gastric adenocarcinoma, as defined by the eighth edition of the American Joint Committee on Cancer staging manual, who underwent gastrectomy from 2006 to 2014 were identified from the NCDB. Multiple logistic regression was conducted to examine factors associated with preoperative chemotherapy use.

RESULTS

This study identified 16,945 patients who met the criteria, and 8286 of these patients (49%) underwent preoperative chemotherapy. The use of preoperative chemotherapy remarkably increased over the study period, from 34% in 2006 to 65% in 2014. Preoperative chemotherapy was more commonly used for cardia tumors than noncardia tumors (83% vs 44% in 2014). In a multivariable analysis, races and ethnicities other than non-Hispanic (NH) white race were associated with less frequent use of preoperative chemotherapy in comparison with NH whites after adjustments for social, tumor, and hospital factors. The insurance status and the education level mediated an enhanced effect of racial/ethnic disparities in preoperative chemotherapy use. The use of preoperative chemotherapy and radiation therapy was associated with reduced racial/ethnic disparities in overall survival.

CONCLUSIONS

Racial/ethnic disparities in the use of preoperative chemotherapy and in outcomes exist among patients with gastric cancer in the United States. Efforts to improve the access to high-quality cancer care in minority groups may reduce racial disparities in gastric cancer in the United States. Cancer 2018. © 2018 American Cancer Society.

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Racial disparities in preoperative chemotherapy use in gastric cancer patients in the United States: Analysis of the National Cancer Data Base, 2006-2014

BACKGROUND

No studies have investigated whether race/ethnicity is associated with the recommended use of preoperative chemotherapy or subsequent outcomes in gastric cancer. To determine whether there is such an association, analyses of patients with gastric cancer in the National Cancer Data Base (NCDB) were performed.

METHODS

Patients with clinical T2-4bN0-1M0 gastric adenocarcinoma, as defined by the eighth edition of the American Joint Committee on Cancer staging manual, who underwent gastrectomy from 2006 to 2014 were identified from the NCDB. Multiple logistic regression was conducted to examine factors associated with preoperative chemotherapy use.

RESULTS

This study identified 16,945 patients who met the criteria, and 8286 of these patients (49%) underwent preoperative chemotherapy. The use of preoperative chemotherapy remarkably increased over the study period, from 34% in 2006 to 65% in 2014. Preoperative chemotherapy was more commonly used for cardia tumors than noncardia tumors (83% vs 44% in 2014). In a multivariable analysis, races and ethnicities other than non-Hispanic (NH) white race were associated with less frequent use of preoperative chemotherapy in comparison with NH whites after adjustments for social, tumor, and hospital factors. The insurance status and the education level mediated an enhanced effect of racial/ethnic disparities in preoperative chemotherapy use. The use of preoperative chemotherapy and radiation therapy was associated with reduced racial/ethnic disparities in overall survival.

CONCLUSIONS

Racial/ethnic disparities in the use of preoperative chemotherapy and in outcomes exist among patients with gastric cancer in the United States. Efforts to improve the access to high-quality cancer care in minority groups may reduce racial disparities in gastric cancer in the United States. Cancer 2018. © 2018 American Cancer Society.

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Inpatient utilization and disparities: The last year of life of adolescent and young adult oncology patients in California

BACKGROUND

Studies of adolescent and young adult (AYA) oncology end-of-life care utilization are critical because cancer is the leading cause of nonaccidental AYA death and end-of-life care contributes significantly to health care expenditures. This study was designed to determine the quantity of and disparities in inpatient utilization in the last year of life of AYAs with cancer.

METHODS

The California Office of Statewide Health Planning and Development administrative discharge database, linked to death certificates, was used to perform a population-based analysis of cancer patients aged 15 to 39 years who died in 2000-2011. The number of hospital days and the inpatient costs were determined for each patient in the last year of his or her life, as were clinical and sociodemographic factors associated with high inpatient utilization. Admission patterns as death approached were also evaluated.

RESULTS

The 12,883 patients were admitted for 40 days on average in the last year of life, and this cost $151,072 per patient in inpatient costs. As death approached, the admission rates and the percentage of all admissions occurring at nonspecialty centers increased. Five percent of patients used 20% of bed days in the last year (high utilizers). Factors associated with high utilization included younger age (15-30 years), Hispanic ethnicity, non–health maintenance organization insurance, and hematologic malignancies.

CONCLUSIONS

AYA oncology decedents were admitted for 40 days in their last year of life. Subgroups with high utilization had distinct sociodemographic and clinical characteristics, and nonspecialty center admissions increased as death approached. This demonstrates the need for palliative care at nonspecialty centers. Future studies need to determine whether these patterns are goal-concurrent, include high utilizers, and monitor the effects of health care reform. Cancer 2018. © 2018 American Cancer Society.

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Inpatient utilization and disparities: The last year of life of adolescent and young adult oncology patients in California

BACKGROUND

Studies of adolescent and young adult (AYA) oncology end-of-life care utilization are critical because cancer is the leading cause of nonaccidental AYA death and end-of-life care contributes significantly to health care expenditures. This study was designed to determine the quantity of and disparities in inpatient utilization in the last year of life of AYAs with cancer.

METHODS

The California Office of Statewide Health Planning and Development administrative discharge database, linked to death certificates, was used to perform a population-based analysis of cancer patients aged 15 to 39 years who died in 2000-2011. The number of hospital days and the inpatient costs were determined for each patient in the last year of his or her life, as were clinical and sociodemographic factors associated with high inpatient utilization. Admission patterns as death approached were also evaluated.

RESULTS

The 12,883 patients were admitted for 40 days on average in the last year of life, and this cost $151,072 per patient in inpatient costs. As death approached, the admission rates and the percentage of all admissions occurring at nonspecialty centers increased. Five percent of patients used 20% of bed days in the last year (high utilizers). Factors associated with high utilization included younger age (15-30 years), Hispanic ethnicity, non–health maintenance organization insurance, and hematologic malignancies.

CONCLUSIONS

AYA oncology decedents were admitted for 40 days in their last year of life. Subgroups with high utilization had distinct sociodemographic and clinical characteristics, and nonspecialty center admissions increased as death approached. This demonstrates the need for palliative care at nonspecialty centers. Future studies need to determine whether these patterns are goal-concurrent, include high utilizers, and monitor the effects of health care reform. Cancer 2018. © 2018 American Cancer Society.

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Biokinetics, dosimetry, and radiation risk in infants after 99m Tc-MAG3 scans

Abstract

Background

Renal scans are among the most frequent exams performed on infants and toddlers. Due to the young age, this patient group can be classified as a high-risk group with a higher probability for developing stochastic radiation effects compared to adults. As there are only limited data on biokinetics and dosimetry in this patient group, the aim of this study was to reassess the dosimetry and the associated radiation risk for infants undergoing ^99mTc-MAG3 renal scans based on a retrospective analysis of existing patient data.

Consecutive data were collected from 20 patients younger than 20 months (14 males; 6 females) with normal renal function undergoing ^99mTc-MAG3 scans. To estimate the patient-specific organ activity, a retrospective calibration was performed based on a set of two 3D-printed infant kidneys filled with known activities. Both phantoms were scanned at different positions along the anteroposterior axis inside a water phantom, providing depth- and size-dependent attenuation correction factors for planar imaging. Time-activity curves were determined by drawing kidney, bladder, and whole-body regions-of-interest for each patient, and subsequently applying the calibration factor for conversion of counts to activity. Patient-specific time-integrated activity coefficients were obtained by integrating the organ-specific time-activity curves. Absorbed and effective dose coefficients for each patient were assessed with OLINDA/EXM for the provided newborn and 1-year-old model. The risk estimation was performed individually for each of the 20 patients with the NCI Radiation Risk Assessment Tool.

Results

The mean age of the patients was 7.0 ± 4.5 months, with a weight between 5 and 12 kg and a body size between 60 and 89 cm. The injected activities ranged from 12 to 24 MBq of ^99mTc-MAG3. The patients' organ-specific mean absorbed dose coefficients were 0.04 ± 0.03 mGy/MBq for the kidneys and 0.27 ± 0.24 mGy/MBq for the bladder. The mean effective dose coefficient was 0.02 ± 0.02 mSv/MBq. Based on the dosimetry results, an evaluation of the excess lifetime risk for the development of radiation-induced cancer showed that the group of newborns has a risk of 16.8 per 100,000 persons, which is about 12% higher in comparison with the 1-year-old group with 14.7 per 100,000 persons (all values are given as mean plus/minus one standard deviation except otherwise specified).

Conclusion

In this study, we retrospectively derived new data on biokinetics and dosimetry for infants with normal kidney function after undergoing renal scans with ^99mTc-MAG3. In addition, we analyzed the associated age- and gender-specific excess lifetime risk due to ionizing radiation. The radiation-associated stochastic risk increases with the organ doses, taking age- and gender-specific influences into account. Overall, the lifetime radiation risk associated with the ^99mTc-MAG3 scans is very low in comparison to the general population risk for developing cancer.

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Biokinetics, dosimetry, and radiation risk in infants after 99m Tc-MAG3 scans

Abstract

Background

Renal scans are among the most frequent exams performed on infants and toddlers. Due to the young age, this patient group can be classified as a high-risk group with a higher probability for developing stochastic radiation effects compared to adults. As there are only limited data on biokinetics and dosimetry in this patient group, the aim of this study was to reassess the dosimetry and the associated radiation risk for infants undergoing ^99mTc-MAG3 renal scans based on a retrospective analysis of existing patient data.

Consecutive data were collected from 20 patients younger than 20 months (14 males; 6 females) with normal renal function undergoing ^99mTc-MAG3 scans. To estimate the patient-specific organ activity, a retrospective calibration was performed based on a set of two 3D-printed infant kidneys filled with known activities. Both phantoms were scanned at different positions along the anteroposterior axis inside a water phantom, providing depth- and size-dependent attenuation correction factors for planar imaging. Time-activity curves were determined by drawing kidney, bladder, and whole-body regions-of-interest for each patient, and subsequently applying the calibration factor for conversion of counts to activity. Patient-specific time-integrated activity coefficients were obtained by integrating the organ-specific time-activity curves. Absorbed and effective dose coefficients for each patient were assessed with OLINDA/EXM for the provided newborn and 1-year-old model. The risk estimation was performed individually for each of the 20 patients with the NCI Radiation Risk Assessment Tool.

Results

The mean age of the patients was 7.0 ± 4.5 months, with a weight between 5 and 12 kg and a body size between 60 and 89 cm. The injected activities ranged from 12 to 24 MBq of ^99mTc-MAG3. The patients' organ-specific mean absorbed dose coefficients were 0.04 ± 0.03 mGy/MBq for the kidneys and 0.27 ± 0.24 mGy/MBq for the bladder. The mean effective dose coefficient was 0.02 ± 0.02 mSv/MBq. Based on the dosimetry results, an evaluation of the excess lifetime risk for the development of radiation-induced cancer showed that the group of newborns has a risk of 16.8 per 100,000 persons, which is about 12% higher in comparison with the 1-year-old group with 14.7 per 100,000 persons (all values are given as mean plus/minus one standard deviation except otherwise specified).

Conclusion

In this study, we retrospectively derived new data on biokinetics and dosimetry for infants with normal kidney function after undergoing renal scans with ^99mTc-MAG3. In addition, we analyzed the associated age- and gender-specific excess lifetime risk due to ionizing radiation. The radiation-associated stochastic risk increases with the organ doses, taking age- and gender-specific influences into account. Overall, the lifetime radiation risk associated with the ^99mTc-MAG3 scans is very low in comparison to the general population risk for developing cancer.

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Effect of the normal mammary differentiation regulator ELF5 upon clinical outcomes of triple negative breast cancers patients

Abstract

Background

Elf5 is a transcription factor previously shown to be involved in regulating cell differentiation in both normal and pathological breast tissues. Pertinently, Elf5 was reported to interact with the FOXA1 transcription factor, a pivotal regulatory factor in a subset of AR overexpressing triple negative cancer (TNBC) cases.

Methods

We examined the correlation among AR, FOXA1, and Elf5 expression in a series of TNBC cases. The cases were retrieved from surgical pathological files of Tohoku University Hospital Japan and consisted of 60 cases operated between the year 1999 and 2007. An additional cohort cases of 51 TNBC ductal carcinoma in situ was used to compare invasive and non-invasive TNBC.

Results

In our cohort, 47% of all carcinomas were positive for Elf5, with a significantly higher proportion of Elf5 positive cases occurring in the younger age groups (p = 0.0061). Elf5 immunoreactivity was not associated with any other clinicopathological factors examined in this study. However, Elf5 expression was associated with decreased overall and disease-free survival of the patients (Peto–Peto modification of Gehan–Wilcoxon test, OS p = 0.132, DFS p = 0.1 (LI cutoff 10%); OS p = 0.038, DFS p = 0.021 (LI cutoff 50%)). Of particular interest, its effects on survival were more pronounced in the EGFR−/CK5/6− (non-basal surrogate) than the EGFR+ and/or CK5/6+ (basal-surrogate) subtype of TNBC.

Conclusions

Elf5 is present in TNBC and its status was significantly correlated with overall survival of the patients. Further studies examining possible interactions between Elf5 and other factors in TNBC could contribute to disentangling TNBC biology.

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Clinical value of miR-198-5p in lung squamous cell carcinoma assessed using microarray and RT-qPCR

Abstract

Background

To examine the clinical value of miR-198-5p in lung squamous cell carcinoma (LUSC).

Methods

Gene Expression Omnibus (GEO) microarray datasets were used to explore the miR-198-5p expression and its diagnostic value in LUSC. Real-time reverse transcription quantitative polymerase chain reaction was used to evaluate the expression of miR-198-5p in 23 formalin-fixed, paraffin-embedded (FFPE) LUSC tissues and corresponding non-cancerous tissues. The correlation between miR-198-5p expression and clinic pathological features was assessed. Meanwhile, putative target messenger RNAs of miR-198-5p were identified based on the analysis of differentially expressed genes in the Cancer Genome Atlas (TCGA) and 12 miRNA prediction tools. Subsequently, the putative target genes were sent to Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway analyses.

Results

MiR-198-5p was low expressed in LUSC tissues. The combined standard mean difference (SMD) values of miR-198-5p expression based on GEO datasets were − 0.30 (95% confidence interval (CI) − 0.54, − 0.06) and − 0.39 (95% CI − 0.83, 0.05) using fixed effect model and random effect model, respectively. The sensitivity and specificity were not sufficiently high, as the area under the curve (AUC) was 0.7749 (Q* = 0.7143) based on summarized receiver operating characteristic (SROC) curves constructed using GEO datasets. Based on the in-house RT-qPCR, miR-198-5p expression was 4.3826 ± 1.7660 in LUSC tissues and 4.4522 ± 1.8263 in adjacent normal tissues (P = 0.885). The expression of miR-198-5p was significantly higher in patients with early TNM stages (I-II) than that in cases with advanced TNM stages (III-IV) (5.4400 ± 1.5277 vs 3.5690 ± 1.5228, P = 0.008). Continuous variable-based meta-analysis of GEO and PCR data displayed the SMD values of − 0.26 (95% CI − 0.48, − 0.04) and − 0.34 (95% CI − 0.71, 0.04) based on fixed and random effect models, respectively. As for the diagnostic value of miR-198-5p, the AUC based on the SROC curve using GEO and PCR data was 0.7351 (Q* = 0.6812). In total, 542 genes were identified as the targets of miR-198-5p. The most enriched Gene Ontology terms were epidermis development among biological processes, cell junction among cellular components, and protein dimerization activity among molecule functions. The pathway of non-small cell lung cancer was the most significant pathway identified using Kyoto Encyclopedia of Genes and Genomes analysis.

Conclusion

The expression of miR-198-5p is related to the TNM stage. Thus, miR-198-5p might play an important role via its target genes in LUSC.

http://ift.tt/2s58JIE

Clinical value of miR-198-5p in lung squamous cell carcinoma assessed using microarray and RT-qPCR

Abstract

Background

To examine the clinical value of miR-198-5p in lung squamous cell carcinoma (LUSC).

Methods

Gene Expression Omnibus (GEO) microarray datasets were used to explore the miR-198-5p expression and its diagnostic value in LUSC. Real-time reverse transcription quantitative polymerase chain reaction was used to evaluate the expression of miR-198-5p in 23 formalin-fixed, paraffin-embedded (FFPE) LUSC tissues and corresponding non-cancerous tissues. The correlation between miR-198-5p expression and clinic pathological features was assessed. Meanwhile, putative target messenger RNAs of miR-198-5p were identified based on the analysis of differentially expressed genes in the Cancer Genome Atlas (TCGA) and 12 miRNA prediction tools. Subsequently, the putative target genes were sent to Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway analyses.

Results

MiR-198-5p was low expressed in LUSC tissues. The combined standard mean difference (SMD) values of miR-198-5p expression based on GEO datasets were − 0.30 (95% confidence interval (CI) − 0.54, − 0.06) and − 0.39 (95% CI − 0.83, 0.05) using fixed effect model and random effect model, respectively. The sensitivity and specificity were not sufficiently high, as the area under the curve (AUC) was 0.7749 (Q* = 0.7143) based on summarized receiver operating characteristic (SROC) curves constructed using GEO datasets. Based on the in-house RT-qPCR, miR-198-5p expression was 4.3826 ± 1.7660 in LUSC tissues and 4.4522 ± 1.8263 in adjacent normal tissues (P = 0.885). The expression of miR-198-5p was significantly higher in patients with early TNM stages (I-II) than that in cases with advanced TNM stages (III-IV) (5.4400 ± 1.5277 vs 3.5690 ± 1.5228, P = 0.008). Continuous variable-based meta-analysis of GEO and PCR data displayed the SMD values of − 0.26 (95% CI − 0.48, − 0.04) and − 0.34 (95% CI − 0.71, 0.04) based on fixed and random effect models, respectively. As for the diagnostic value of miR-198-5p, the AUC based on the SROC curve using GEO and PCR data was 0.7351 (Q* = 0.6812). In total, 542 genes were identified as the targets of miR-198-5p. The most enriched Gene Ontology terms were epidermis development among biological processes, cell junction among cellular components, and protein dimerization activity among molecule functions. The pathway of non-small cell lung cancer was the most significant pathway identified using Kyoto Encyclopedia of Genes and Genomes analysis.

Conclusion

The expression of miR-198-5p is related to the TNM stage. Thus, miR-198-5p might play an important role via its target genes in LUSC.

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Expression of gremlin1 in gastric cancer and its clinical significance

Abstract

As an antagonist of bone morphogenetic proteins (BMPs), 2, 4 and 7, gremlin1 plays a role in regulating organogenesis, tissue differentiation and angiogenesis. However, there is little information regarding gremlin1 in gastrointestinal cancer. We attempted to clarify how gremlin1 expression affects the clinical features and biological properties of gastric cancer. A total of 232 gastric cancer patients who received R0 gastrectomy at Kagoshima University Hospital were enrolled. Gremlin1 expression in gastric cancer was detected by immunohistochemical and western blotting methods. Correlations between clinicopathological parameters and gremlin1 expression were analyzed. Gremlin1 was identified in the cytoplasm and nucleus of all gastric cancer cell lines and some regions of surgical specimens of gastric cancer. One hundred and seventeen of the 232 patients (50.4%) were classified as gremlin1-positive based on gremlin1 expression. Gremlin1 positivity was correlated with shallower tumor depth, smaller tumor size, less nodal involvement and vessel invasion (p < 0.05). The 5-year survival rate of the gremlin1-positive group was 81%, which was significantly higher than the gremlin1-negative group (p < 0.01). Multivariate analysis revealed that gremlin1 was not selected as an independent prognostic marker. Gremlin1 expression in gastric cancer may be a useful prognostic marker that is involved with the BMP signaling pathway. Furthermore, gremlin1 may have clinical use as a diagnostic and treatment tool.

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Expression of gremlin1 in gastric cancer and its clinical significance

Abstract

As an antagonist of bone morphogenetic proteins (BMPs), 2, 4 and 7, gremlin1 plays a role in regulating organogenesis, tissue differentiation and angiogenesis. However, there is little information regarding gremlin1 in gastrointestinal cancer. We attempted to clarify how gremlin1 expression affects the clinical features and biological properties of gastric cancer. A total of 232 gastric cancer patients who received R0 gastrectomy at Kagoshima University Hospital were enrolled. Gremlin1 expression in gastric cancer was detected by immunohistochemical and western blotting methods. Correlations between clinicopathological parameters and gremlin1 expression were analyzed. Gremlin1 was identified in the cytoplasm and nucleus of all gastric cancer cell lines and some regions of surgical specimens of gastric cancer. One hundred and seventeen of the 232 patients (50.4%) were classified as gremlin1-positive based on gremlin1 expression. Gremlin1 positivity was correlated with shallower tumor depth, smaller tumor size, less nodal involvement and vessel invasion (p < 0.05). The 5-year survival rate of the gremlin1-positive group was 81%, which was significantly higher than the gremlin1-negative group (p < 0.01). Multivariate analysis revealed that gremlin1 was not selected as an independent prognostic marker. Gremlin1 expression in gastric cancer may be a useful prognostic marker that is involved with the BMP signaling pathway. Furthermore, gremlin1 may have clinical use as a diagnostic and treatment tool.

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Cucurbitacin B induces inhibitory effects via CIP2A/PP2A/Akt pathway in glioblastoma multiforme

Abstract

Cancerous inhibitor of protein phosphatase 2A (CIP2A) is a human oncoprotein that is overexpressed in multiple types of tumors and promotes the proliferation and transformation of cancer cells. However, whether CIP2A can be a new drug target for human glioblastoma multiforme (GBM) is largely unclear. In the present study, we demonstrated that the overexpression of CIP2A promotes invasive behavior in GBM, and a natural compound, cucurbitacin B (CuB), shows an anti-proliferative and anti-invasion effect in GBM cell lines. CuB effectively induces apoptosis, downregulates CIP2A expression and its downstream signaling molecule, phospho-Akt, and upregulates protein phosphatase 2A (PP2A) activity. Overexpression of CIP2A reduced CuB-inhibited growth and invasion in GBM cells. Silencing CIP2A enhanced CuB-induced invasion inhibition and apoptosis in GBM. CuB combined with cisplatin synergistically inhibited GBM cells. CuB also inhibited tumor growth in murine models. Western blot results further revealed that CuB downregulates CIP2A, and phospho-Akt in vivo. In summary, inhibition of CIP2A determines the effects of CuB-induced invasive behavior inhibition and apoptosis in GBM cells. These characteristics render CuB as a promising candidate drug for further development and for designing new effective CIP2A inhibitors. This article is protected by copyright. All rights reserved

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Cucurbitacin B induces inhibitory effects via CIP2A/PP2A/Akt pathway in glioblastoma multiforme

Abstract

Cancerous inhibitor of protein phosphatase 2A (CIP2A) is a human oncoprotein that is overexpressed in multiple types of tumors and promotes the proliferation and transformation of cancer cells. However, whether CIP2A can be a new drug target for human glioblastoma multiforme (GBM) is largely unclear. In the present study, we demonstrated that the overexpression of CIP2A promotes invasive behavior in GBM, and a natural compound, cucurbitacin B (CuB), shows an anti-proliferative and anti-invasion effect in GBM cell lines. CuB effectively induces apoptosis, downregulates CIP2A expression and its downstream signaling molecule, phospho-Akt, and upregulates protein phosphatase 2A (PP2A) activity. Overexpression of CIP2A reduced CuB-inhibited growth and invasion in GBM cells. Silencing CIP2A enhanced CuB-induced invasion inhibition and apoptosis in GBM. CuB combined with cisplatin synergistically inhibited GBM cells. CuB also inhibited tumor growth in murine models. Western blot results further revealed that CuB downregulates CIP2A, and phospho-Akt in vivo. In summary, inhibition of CIP2A determines the effects of CuB-induced invasive behavior inhibition and apoptosis in GBM cells. These characteristics render CuB as a promising candidate drug for further development and for designing new effective CIP2A inhibitors. This article is protected by copyright. All rights reserved

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