Treatment selection for esophageal cancer: evaluation from a nationwide database

Abstract

Background

Most elderly patients poorly tolerate the standard treatment for esophageal cancer; however, little information is available regarding the appropriateness of non-standard esophageal cancer treatments for those patients. This study aims to analyze the treatment costs and completion rates of patients undergoing a real-world treatment for esophageal cancer to elucidate the treatment selection and its quality.

Materials and methods

We analyzed treatment costs and completion rates for patients with esophageal cancer and analyzed these data relative to patient age and center volumes. Patients with esophageal cancer [UICC, TMN, Clinical stage II/III (excluding T4)] who were diagnosed in 2013 were analyzed. Patients were classified into five groups defined as follows: surgical therapy, chemotherapy, concurrent chemoradiotherapy (CCRT), modified concurrent chemoradiotherapy (mCRT), and radiotherapy (RT).

Results

Mean and median age of patients who received surgery and CCRT were comparable; however, patients who underwent mCRT and RT tended to be older. Medical costs associated with surgery were higher than costs associated with other non-surgical treatments. Cost and completion rate of chemoradiotherapy did not differ between CCRT and mCRT; however, both had higher completion rates compared to that of RT. Surgical expenses tended to be the highest in low-volume centers and the lowest in high-volume centers.

Conclusion

Treatment of esophageal cancer at high-volume centers seems well balanced compared with medium- to low-volume centers. mCRT was widely performed and comparable in medical cost to CCRT, although additional clinical impacts were unclear.

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Treatment selection for esophageal cancer: evaluation from a nationwide database

Abstract

Background

Most elderly patients poorly tolerate the standard treatment for esophageal cancer; however, little information is available regarding the appropriateness of non-standard esophageal cancer treatments for those patients. This study aims to analyze the treatment costs and completion rates of patients undergoing a real-world treatment for esophageal cancer to elucidate the treatment selection and its quality.

Materials and methods

We analyzed treatment costs and completion rates for patients with esophageal cancer and analyzed these data relative to patient age and center volumes. Patients with esophageal cancer [UICC, TMN, Clinical stage II/III (excluding T4)] who were diagnosed in 2013 were analyzed. Patients were classified into five groups defined as follows: surgical therapy, chemotherapy, concurrent chemoradiotherapy (CCRT), modified concurrent chemoradiotherapy (mCRT), and radiotherapy (RT).

Results

Mean and median age of patients who received surgery and CCRT were comparable; however, patients who underwent mCRT and RT tended to be older. Medical costs associated with surgery were higher than costs associated with other non-surgical treatments. Cost and completion rate of chemoradiotherapy did not differ between CCRT and mCRT; however, both had higher completion rates compared to that of RT. Surgical expenses tended to be the highest in low-volume centers and the lowest in high-volume centers.

Conclusion

Treatment of esophageal cancer at high-volume centers seems well balanced compared with medium- to low-volume centers. mCRT was widely performed and comparable in medical cost to CCRT, although additional clinical impacts were unclear.

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Developments in the management of advanced soft-tissue sarcoma – olaratumab in context

http://ift.tt/2HvWXdK

Clinical routine assessment of palliative care symptoms and concerns and caregiver burden in glioblastoma patients: an explorative field study

Abstract

The implementation of self-reported outcome measurements into clinical routine was tested to help facilitate early access to palliative care (PC) for glioblastoma (GBM)-patients. Measures detail PC symptoms and concerns and caregiver burden. Between January 2014 and December 2016, a total of 337 GBM-patients were discussed during meetings of the neuro-oncology tumor board to examine further treatment options. Each patient, along with their caregivers, was requested to participate in self-assessment using the palliative outcome scale (POS) and the Zarit Burden Interview (ZBI). Analyses encompassed summary statistics, non-parametric tests, visual graphic analysis, content analysis and assessing the utilization of the specialized PC consulting service (SPCCS). Ninety-five (28%) GBM-patients and 71 (21%) caregivers completed the self-assessment. Of these, 20 patients and 12 caregivers repeated the assessment at least once more during follow-up. POS total scores were similar in the group of patients with initial diagnosis [10 (0–31)] and those with later disease stages like recurrent diagnosis [9 (0–25)], but ZBI total scores differed [14 (0–51) vs. 24 (2–62)]. Single item analysis demonstrated that anxiety and worries about the future predominated. Caregivers were torn between high engagement in caring and feeling overburdened. Still, requests for the SPCCS showed no increase. Actual implementation of measures like POS and ZBI for detecting PC concerns and caregiver burden with GBM-patients in the field remains challenging as indicated by the limited response rate and lack of increased requests for the SPCCS. Modified clinical routines including strengthening awareness of PC, and allowing proxy-assessment might help to overcome barriers.

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Clinical routine assessment of palliative care symptoms and concerns and caregiver burden in glioblastoma patients: an explorative field study

Abstract

The implementation of self-reported outcome measurements into clinical routine was tested to help facilitate early access to palliative care (PC) for glioblastoma (GBM)-patients. Measures detail PC symptoms and concerns and caregiver burden. Between January 2014 and December 2016, a total of 337 GBM-patients were discussed during meetings of the neuro-oncology tumor board to examine further treatment options. Each patient, along with their caregivers, was requested to participate in self-assessment using the palliative outcome scale (POS) and the Zarit Burden Interview (ZBI). Analyses encompassed summary statistics, non-parametric tests, visual graphic analysis, content analysis and assessing the utilization of the specialized PC consulting service (SPCCS). Ninety-five (28%) GBM-patients and 71 (21%) caregivers completed the self-assessment. Of these, 20 patients and 12 caregivers repeated the assessment at least once more during follow-up. POS total scores were similar in the group of patients with initial diagnosis [10 (0–31)] and those with later disease stages like recurrent diagnosis [9 (0–25)], but ZBI total scores differed [14 (0–51) vs. 24 (2–62)]. Single item analysis demonstrated that anxiety and worries about the future predominated. Caregivers were torn between high engagement in caring and feeling overburdened. Still, requests for the SPCCS showed no increase. Actual implementation of measures like POS and ZBI for detecting PC concerns and caregiver burden with GBM-patients in the field remains challenging as indicated by the limited response rate and lack of increased requests for the SPCCS. Modified clinical routines including strengthening awareness of PC, and allowing proxy-assessment might help to overcome barriers.

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A 74-year-old woman with dyspnoea and a mass in the right atrium

A 74-year-old woman was admitted with pericardial effusion causing haemodynamic instability. On echographic and radiological examination, a mass was identified in the right atrium, extending into the epicardial layer. In the differential diagnosis of a cardiac mass, benign primary lesions like a myxoma must be distinguished from rare primary cardiac malignancies like sarcomas or more frequent secondary tumours. These include localisations of lymphomyeloproliferative disease and metastases of a melanoma or various subtypes of carcinoma. In this case, histopathological examination of a surgical biopsy showed findings consistent with a high-grade angiosarcoma. Because of the size and localisation, as well as the presence of a possible metastasis in the rib, surgical treatment was not possible. After diagnosis, the patient developed multiple additional metastasis. She received palliative radiotherapy to control the pain and died 10 months after the initial diagnosis was made. Median reported survival is 6 months.

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Dacomitinib potentiates the efficacy of conventional chemotherapeutic agents via inhibiting the drug efflux function of ABCG2 in vitro and in vivo

ATP-binding cassette subfamily G member 2 (ABCG2), a member of the ABC transporter superfamily proteins, mediates multidrug resistance (MDR) by transporting substrate anticancer drugs out of cancer cells and d...

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FAK-ERK activation in cell/matrix adhesion induced by the loss of apolipoprotein E stimulates the malignant progression of ovarian cancer

Extracellular matrix (ECM) is a mediator of tumor progression. However, whether the alterations of the intraperitoneal ECM prior to tumor establishment affects the malignant progression of ovarian cancer remai...

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A surgical case of inflammatory abdominal aortic aneurysm that responded remarkably to preoperative steroid therapy

Abstract

We describe the surgical management of a 58-year-old man with inflammatory abdominal aortic aneurysm (IAAA) following treatment with preoperative steroids. The patient was transferred to our institution for abdominal pain and fever. Contrast-enhanced computed tomography showed juxtarenal abdominal aortic aneurysm surrounded by dense perianeurysmal fibrous tissue. Under a diagnosis of IAAA, steroid therapy with prednisolone was initiated to control the perianeurysmal inflammation. It continued for 3 weeks with a decreasing dose schedule, with remarkable decrease in the soft tissue mass. The patient underwent elective surgery 21 days after commencing steroid therapy. During surgery, adjacent organs were adherent to the aneurysmal wall, but fibrotic change to the retroperitoneum was very limited. He recovered uneventfully, and was discharged on postoperative Day 10. Therefore, it can be concluded that preoperative steroid therapy could minimize the operative risk for IAAAs, and improve surgical outcome.

http://ift.tt/2GtGoxM

Successful management of an aorto-gastric fistula occurring 15 years after oesophagectomy with covered aortic stent graft placement followed by open surgery

Abstract

Aorto-gastric fistula (AGF) is an uncommon and life threatening complication of oesophagectomy. Usually occurring in the immediate weeks following the procedure at anastomosis lines, this case describes a rare development of an AGF 15 years after an oesophagectomy due to the presence of a benign ulcer. Initially successful endovascular stenting of the thoracic aorta was followed by re-bleed, further stenting but eventually open surgery was required.

http://ift.tt/2HuAiyB

Tracheo-oesophageal fistula: a delayed complication of missed inhaled magnetic toys

Abstract

Delayed diagnosis of tracheobronchial foreign body (FB) aspiration is not uncommon in children. It occurs when symptoms are underappreciated and/or radiological findings are overlooked. In such cases serious complications can arise, which make the diagnosis and removal of the FB much more difficult. Here, we present a case where FB aspiration was misdiagnosed as asthma after a radio-opaque FB on the chest radiograph was missed, leading to formation of a tracheo-oesophageal fistula as a rare delayed complication.

http://ift.tt/2Gtdca9

Alcohol consumption and risk of hematological malignancies: A meta-analysis of prospective studies

Abstract

Current convincing evidence suggests that alcohol intake increases the risk of several carcinomas, which might subsequently lead to a recommendation towards limiting alcohol consumption. However, there are accumulating data worth meta-analyzing that show a different effect on the risk of hematological malignancies. Eligible cohort studies were sought in PubMed database up to August 31, 2016. Separate analyses were performed by subtype of hematological malignancy (non-Hodgkin lymphoma [NHL] and subtypes, Hodgkin lymphoma [HL], leukemia and subtypes), time status (ever, current, former), level of consumption (light, moderate, heavy), alcoholic beverage (total alcohol, beer, liquor, wine), and gender. Moderate and heavy alcohol consumption were significantly associated with reduced risk of NHL (relative risk [RR]=0.85, 95% confidence interval [CI]: 0.80-0.90 and RR=0.73, 95%CI: 0.60-0.89, respectively); a protective trend was also shown for light alcohol intake (RR=0.93, 95%CI:0.87-1.00). Specifically, beer consumption was associated with reduced NHL risk (RR=0.88, 95%CI: 0.81-0.95). However, the association regarding other alcoholic beverages seemed null. The beneficial effects of alcohol mainly pertained to Diffuse Large B-Cell Lymphoma (DLBCL) (RR=0.83, 95%CI:0.77-0.89) and Follicular Lymphoma (FL) (RR=0.85, 95%CI:0.78-0.93). There was also no association between alcohol consumption and risk of HL or leukemias. In contrast to most solid malignancies, alcohol seems to confer a protective effect on NHL risk, especially on DLBCL and FL subtypes, with beer being notably beneficial. This article is protected by copyright. All rights reserved.

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Alcohol consumption and risk of hematological malignancies: A meta-analysis of prospective studies

Abstract

Current convincing evidence suggests that alcohol intake increases the risk of several carcinomas, which might subsequently lead to a recommendation towards limiting alcohol consumption. However, there are accumulating data worth meta-analyzing that show a different effect on the risk of hematological malignancies. Eligible cohort studies were sought in PubMed database up to August 31, 2016. Separate analyses were performed by subtype of hematological malignancy (non-Hodgkin lymphoma [NHL] and subtypes, Hodgkin lymphoma [HL], leukemia and subtypes), time status (ever, current, former), level of consumption (light, moderate, heavy), alcoholic beverage (total alcohol, beer, liquor, wine), and gender. Moderate and heavy alcohol consumption were significantly associated with reduced risk of NHL (relative risk [RR]=0.85, 95% confidence interval [CI]: 0.80-0.90 and RR=0.73, 95%CI: 0.60-0.89, respectively); a protective trend was also shown for light alcohol intake (RR=0.93, 95%CI:0.87-1.00). Specifically, beer consumption was associated with reduced NHL risk (RR=0.88, 95%CI: 0.81-0.95). However, the association regarding other alcoholic beverages seemed null. The beneficial effects of alcohol mainly pertained to Diffuse Large B-Cell Lymphoma (DLBCL) (RR=0.83, 95%CI:0.77-0.89) and Follicular Lymphoma (FL) (RR=0.85, 95%CI:0.78-0.93). There was also no association between alcohol consumption and risk of HL or leukemias. In contrast to most solid malignancies, alcohol seems to confer a protective effect on NHL risk, especially on DLBCL and FL subtypes, with beer being notably beneficial. This article is protected by copyright. All rights reserved.

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The rs1024611 in the CCL2 gene and risk of gynecological cancer in Asians: a meta-analysis

Abstract

Background

The -2518A/G (rs1024611) polymorphism of the CCL2 (C-C motif chemokine ligand 2), also known as MCP-1 (monocyte chemotactic protein-1) gene, has been reported to be associated with increased gynecological cancer risk, but the results are conflicting.

Methods

In this analysis, 1089 cases and 1553 controls from six publications were used to investigate the association between CCL2-2518A/G (rs1024611) polymorphism and the risk of gynecological cancer with a meta-analytic approach. Studies published on EBSCO, EMBASE, Web of Science, PubMed, SpringerLink, ScienceDirect, Weipu, and CNKI databases were identified (last update was on November 3, 2015). Six articles focused on the association between CCL2-2518A/G (rs1024611) polymorphism, and gynecological cancer risk was selected and data were extracted. The cancer type included endometrial cancer (n = 1), breast cancer (n = 2), ovarian cancer (n = 2), and cervical cancer (n = 1). All statistical analyses were performed using the STATA version 12.0 software.

Results

The meta-analysis showed that CCL2-2518A/G (rs1024611) polymorphism is associated with risk of gynecological cancer (GG vs AG + AA, OR = 1.55, 95%CI = 1.07–2.24, P < 0.05; AA vs GG, OR = 0.59 95%CI = 0.38–0.92, P < 0.05). Notably, the subgroup analysis demonstrated that the genotype AA is associated with a reduced gynecological cancer risk in Asians, but an increased risk when compared to AG in Europeans.

Conclusions

Our data demonstrated the CCL2-2518A/G (rs1024611) polymorphism is significantly associated with risk of gynecological cancer, and the association differs by ethnicity.

http://ift.tt/2CwOfIG

The rs1024611 in the CCL2 gene and risk of gynecological cancer in Asians: a meta-analysis

Abstract

Background

The -2518A/G (rs1024611) polymorphism of the CCL2 (C-C motif chemokine ligand 2), also known as MCP-1 (monocyte chemotactic protein-1) gene, has been reported to be associated with increased gynecological cancer risk, but the results are conflicting.

Methods

In this analysis, 1089 cases and 1553 controls from six publications were used to investigate the association between CCL2-2518A/G (rs1024611) polymorphism and the risk of gynecological cancer with a meta-analytic approach. Studies published on EBSCO, EMBASE, Web of Science, PubMed, SpringerLink, ScienceDirect, Weipu, and CNKI databases were identified (last update was on November 3, 2015). Six articles focused on the association between CCL2-2518A/G (rs1024611) polymorphism, and gynecological cancer risk was selected and data were extracted. The cancer type included endometrial cancer (n = 1), breast cancer (n = 2), ovarian cancer (n = 2), and cervical cancer (n = 1). All statistical analyses were performed using the STATA version 12.0 software.

Results

The meta-analysis showed that CCL2-2518A/G (rs1024611) polymorphism is associated with risk of gynecological cancer (GG vs AG + AA, OR = 1.55, 95%CI = 1.07–2.24, P < 0.05; AA vs GG, OR = 0.59 95%CI = 0.38–0.92, P < 0.05). Notably, the subgroup analysis demonstrated that the genotype AA is associated with a reduced gynecological cancer risk in Asians, but an increased risk when compared to AG in Europeans.

Conclusions

Our data demonstrated the CCL2-2518A/G (rs1024611) polymorphism is significantly associated with risk of gynecological cancer, and the association differs by ethnicity.

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CrosstalkNet: A visualization tool for differential co-expression networks and communities

Variations in physiological conditions can rewire molecular interactions between biological compartments, which can yield novel insights into gain or loss of interactions specific to perturbations of interest. Networks are a promising tool to elucidate intercellular interactions, yet exploration of these large-scale networks remains a challenge due to their high dimensionality. To retrieve and mine interactions, we developed CrosstalkNet, a user friendly, web-based network visualization tool that provides a statistical framework to infer condition-specific interactions coupled with a community detection algorithm for bipartite graphs to identify significantly dense subnetworks. As a case study, we used CrosstalkNet to mine a set of 54 and 22 gene expression profiles from breast tumor and normal samples, respectively, with epithelial and stromal compartments extracted via laser microdissection. We show how CrosstalkNet can be used to explore large-scale co-expression networks and obtain insights into the biological processes that govern crosstalk between different tumor compartments.

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CrosstalkNet: A visualization tool for differential co-expression networks and communities

Variations in physiological conditions can rewire molecular interactions between biological compartments, which can yield novel insights into gain or loss of interactions specific to perturbations of interest. Networks are a promising tool to elucidate intercellular interactions, yet exploration of these large-scale networks remains a challenge due to their high dimensionality. To retrieve and mine interactions, we developed CrosstalkNet, a user friendly, web-based network visualization tool that provides a statistical framework to infer condition-specific interactions coupled with a community detection algorithm for bipartite graphs to identify significantly dense subnetworks. As a case study, we used CrosstalkNet to mine a set of 54 and 22 gene expression profiles from breast tumor and normal samples, respectively, with epithelial and stromal compartments extracted via laser microdissection. We show how CrosstalkNet can be used to explore large-scale co-expression networks and obtain insights into the biological processes that govern crosstalk between different tumor compartments.

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Tamoxifen metabolism and efficacy in breast cancer- a prospective multicentre trial

Purpose: Levels of endoxifen, the most active metabolite of tamoxifen, vary by the highly polymorphic cytochrome P450 (CYP) 2D6 enzyme. We prospectively investigated tamoxifen efficacy by serum endoxifen levels and the tamoxifen activity score (TAS). Experimental Design: A prospective observational multicentre study including postmenopausal women with an oestrogen-receptor (ER)-positive breast cancer receiving first line tamoxifen, 20mg daily in the neo-adjuvant or metastatic setting recruited between February 2009 and May 2014. The primary endpoint was the objective response rate (ORR) using RECIST criteria 1.0. Secondary endpoints were clinical benefit (CB), progression-free survival (PFS) and tolerability of tamoxifen. The main analysis used logistic regression to relate ORR to serum endoxifen levels after 3 months. Endpoints were also related to other tamoxifen metabolites and to TAS. Results: Endoxifen levels were available for 247 of all 297 patients (83%) of which 209 with target lesions (85%). Median follow-up time for PFS was 32.5 months, and 62% progressed. ORR and CB were 45% and 84%, respectively. ORR was not related to endoxifen, the odds ratio of ORR was 1.008 per µg/l increase in endoxifen (95% CI 0.971-1.046, p=0.56). In general, none of the endpoints was associated with endoxifen levels, tamoxifen metabolites, or TAS. Conclusions: Under the pre-specified assumptions, the results from this prospective clinical trial do not suggest therapeutic drug monitoring of endoxifen to be of clinical value in postmenopausal women treated with tamoxifen for breast cancer in the neo-adjuvant or metastatic setting.

http://ift.tt/2EPM7B0

Pediatric Eating Behaviors as the Intersection of Biology and Parenting: Lessons from the Birds and the Bees

Abstract

Purpose of Review

Current feeding advice to prevent pediatric obesity focuses on caregiver feeding behaviors. This review integrates newer data showing that child appetitive traits also have a genetic component.

Recent Findings

Caregiver feeding behaviors robustly correlate with child eating behaviors; however, there is also a strong heritable component.

Summary

The satiety cascade delineates the biological drive underlying hunger, satiation, and satiety. Innate individual differences exist for the components of the satiety cascade, which may explain the heritability of child eating behaviors. However, given the correlation of caregiver feeding behaviors with child eating behaviors, any etiological model should include both genetic/biological components and environmental. Integrating the biological etiology of child eating behaviors into the current environmental model has implications for tailoring feeding advice which needs to move from a "one size fits all" approach to one that is tailored to individual differences in children's biological drives to appetite.

http://ift.tt/2EGxPzn

Tamoxifen metabolism and efficacy in breast cancer- a prospective multicentre trial

Purpose: Levels of endoxifen, the most active metabolite of tamoxifen, vary by the highly polymorphic cytochrome P450 (CYP) 2D6 enzyme. We prospectively investigated tamoxifen efficacy by serum endoxifen levels and the tamoxifen activity score (TAS). Experimental Design: A prospective observational multicentre study including postmenopausal women with an oestrogen-receptor (ER)-positive breast cancer receiving first line tamoxifen, 20mg daily in the neo-adjuvant or metastatic setting recruited between February 2009 and May 2014. The primary endpoint was the objective response rate (ORR) using RECIST criteria 1.0. Secondary endpoints were clinical benefit (CB), progression-free survival (PFS) and tolerability of tamoxifen. The main analysis used logistic regression to relate ORR to serum endoxifen levels after 3 months. Endpoints were also related to other tamoxifen metabolites and to TAS. Results: Endoxifen levels were available for 247 of all 297 patients (83%) of which 209 with target lesions (85%). Median follow-up time for PFS was 32.5 months, and 62% progressed. ORR and CB were 45% and 84%, respectively. ORR was not related to endoxifen, the odds ratio of ORR was 1.008 per µg/l increase in endoxifen (95% CI 0.971-1.046, p=0.56). In general, none of the endpoints was associated with endoxifen levels, tamoxifen metabolites, or TAS. Conclusions: Under the pre-specified assumptions, the results from this prospective clinical trial do not suggest therapeutic drug monitoring of endoxifen to be of clinical value in postmenopausal women treated with tamoxifen for breast cancer in the neo-adjuvant or metastatic setting.

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Pediatric Eating Behaviors as the Intersection of Biology and Parenting: Lessons from the Birds and the Bees

Abstract

Purpose of Review

Current feeding advice to prevent pediatric obesity focuses on caregiver feeding behaviors. This review integrates newer data showing that child appetitive traits also have a genetic component.

Recent Findings

Caregiver feeding behaviors robustly correlate with child eating behaviors; however, there is also a strong heritable component.

Summary

The satiety cascade delineates the biological drive underlying hunger, satiation, and satiety. Innate individual differences exist for the components of the satiety cascade, which may explain the heritability of child eating behaviors. However, given the correlation of caregiver feeding behaviors with child eating behaviors, any etiological model should include both genetic/biological components and environmental. Integrating the biological etiology of child eating behaviors into the current environmental model has implications for tailoring feeding advice which needs to move from a "one size fits all" approach to one that is tailored to individual differences in children's biological drives to appetite.

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Apalutamide Approved for Certain Prostate Cancers [News in Brief]

Along with its relative enzalutamide, antiandrogen prolongs metastasis-free survival in patients with few treatment options, studies show.

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Pancreaticoduodenectomy for an Ampullary Region Carcinoma Occurred in Annular Pancreas Coexistent with Replaced Common Hepatic Artery

Introduction. Annular pancreas is a rare congenital abnormality characterized by a ring of pancreatic tissue surrounding the descending portion of the duodenum. Annular pancreas coexisting with replaced common hepatic artery which is also a rare anatomical variation has not been reported previously. Case Presentation. A 53-year-old man visited our hospital complaining of epigastric pain. Based on radiological examinations, he was diagnosed as having pancreatitis, annular pancreas, and hepatomesenteric trunk. One month later, obstructive jaundice developed. Endoscopic examination revealed ampullary region carcinoma. We performed pancreaticoduodenectomy using the "artery-first" approach. Discussion. Both annular pancreas and common hepatic artery anomaly are rare. High-quality preoperative imaging and awareness of such rare conditions are necessary for operative safety. Although the embryological relationship between these anomalies is uncertain, the present case may suggest some relevance between the two. Conclusion. The "artery-first" approach may be a useful method for pancreaticoduodenectomy in patients who have an anatomical abnormality.

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The accuracy and precision of Kilovoltage Intrafraction Monitoring (KIM) six degree-of-freedom prostate motion measurements during patient treatments

To perform a quantitative analysis of the accuracy and precision of Kilovoltage Intrafraction Monitoring (KIM) six degree-of-freedom (6DoF) prostate motion measurements during treatments.

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Body mass index and age at natural menopause: an international pooled analysis of 11 prospective studies

Abstract

Current evidence on the association between body mass index (BMI) and age at menopause remains unclear. We investigated the relationship between BMI and age at menopause using data from 11 prospective studies. A total of 24,196 women who experienced menopause after recruitment was included. Baseline BMI was categorised according to the WHO criteria. Age at menopause, confirmed by natural cessation of menses for ≥ 12 months, was categorised as < 45 years (early menopause), 45–49, 50–51 (reference category), 52–53, 54–55, and ≥ 56 years (late age at menopause). We used multinomial logistic regression models to estimate multivariable relative risk ratios (RRRs) and 95% confidence intervals (CI) for the associations between BMI and age at menopause. The mean (standard deviation) age at menopause was 51.4 (3.3) years, with 2.5% of the women having early and 8.1% late menopause. Compared with those with normal BMI (18.5–24.9 kg/m²), underweight women were at a higher risk of early menopause (RRR 2.15, 95% CI 1.50–3.06), while overweight (1.52, 1.31–1.77) and obese women (1.54, 1.18–2.01) were at increased risk of late menopause. Overweight and obesity were also significantly associated with around 20% increased risk of menopause at ages 52–53 and 54–55 years. We observed no association between underweight and late menopause. The risk of early menopause was higher among obese women albeit not significant (1.23, 0.89–1.71). Underweight women had over twice the risk of experiencing early menopause, while overweight and obese women had over 50% higher risk of experiencing late menopause.

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miRNA-124-3p/neuropilin-1(NRP-1) axis plays an important role in mediating glioblastoma growth and angiogenesis

Abstract

Glioblastoma Multiforme (GBM) is the most lethal brain malignancy which involves multi-gene abnormality. Unfortunately, effective therapy against GBM is still lacking. Previously, we found that NRP-1 and its downstream NRP-1/GIPC1 pathway played an important role in GBM. In this study, we further investigated the upstream signaling of NRP-1 to understand how it is regulated. Firstly, we identified that hsa-miR-124-3p was miRNA differentially expressed in GBM and in normal brain tissues by high-throughput sequencing. Then, by dual luciferase reporter gene, we found miR-124-3p can specially bind to the 3'UTR region of the NRP-1 thus suppresses its expression. Moreover, miR-124–3p overexpression significantly inhibited GBM cell proliferation, migration and tumor angiogenesis which resulted in GBM apoptosis and cell cycle arrest, putatively via NRP-1 mediated PI3K/Akt/NFκB pathways activation in GBM cells. Meanwhile, miR-124-3p overexpression also suppressed tumor growth and reduced tumor angiogenesis when targeted by NRP-1 in a PDX model. Furthermore, NRP-1 mAb exerted synergistic inhibitory effects with miR-124–3p overexpression in GBM. Thus, we discovered that miR-124-3p acts as the upstream suppressor of NRP-1 which promotes GBM cell development and growth by PI3K/Akt/NFκB pathway. The miR-124-3p/NRP-1/GIPC1 pathway as a new pathway has a vital role in GBM, and it could be considered as the potential target for malignant gliomas in future. This article is protected by copyright. All rights reserved.

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Tobacco-attributable burden of cancer according to socioeconomic position in France

Abstract

Smoking is a major preventable cause of cancers and is increasingly concentrated among the most deprived individuals leading to increasing socioeconomic inequalities in the incidence of cancers linked to smoking. We aimed to estimate the tobacco-attributable cancer burden according to socioeconomic position in France. The analysis was restricted to cancer sites for which tobacco smoking was recognized as a risk factor. Cancer cases by sex, age group and European Deprivation Index (EDI) among people aged 30–74 between 2006 and 2009 were obtained from cancer registries covering approximately 20% of the French population. The tobacco-attributable burden of cancer according to EDI was estimated applying the population attributable fraction (PAF) computed with the Peto-Lopez method. The PAF increased from 56% in the least deprived EDI quintile to 70% in the most deprived EDI quintile among men and from 26% to 38% among women. In total, 28% of the excess cancer cases in the four most deprived EDI quintiles in men and 43% in women could be prevented if smoking in these 4 EDI quintiles was similar to that of the least deprived EDI quintile. A substantial smoking-attributable burden of cancer by socioeconomic position was observed in France. The results highlight the need for policies reducing tobacco consumption. More comprehensive interventions integrating the various dimensions of health determinants and proportionate according to socioeconomic position may essentially contribute to the reduction of socioeconomic inequalities in cancer. This article is protected by copyright. All rights reserved.

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Low T3 syndrome as a predictor of poor prognosis in chronic lymphocytic leukemia

Abstract

Low triiodothyronine (T3) state is associated with poor prognosis in critical acute and prolonged illness. However, the information on thyroid dysfunction and cancer is limited. The aim of our study was to evaluate the prognostic value of low T3 syndrome in chronic lymphocytic leukemia (CLL). Two hundred and fifty-eight patients with detailed thyroid hormone profile at CLL diagnosis were enrolled. Low T3 syndrome was defined by low free T3 (FT3) level accompanied by normal-to-low free tetraiodothyronine (FT4) and thyroid-stimulating hormone (TSH) levels. A propensity score-matched method was performed to balance the baseline characteristics. Multivariate Cox regression analyses screened the independent prognostic factors related to time-to-first-treatment (TTFT) and cancer-specific survival (CSS). Area under the curve (AUC) assessed the predictive accuracy of CLL-International Prognostic Index (IPI) together with low T3 syndrome. The results showed that 37 (14.34%) patients had low T3 syndrome, which was significantly associated with unfavorable TTFT and CSS in the propensity-matched cohort, and it was an independent prognostic indicator for both TTFT and CSS. Serum FT3 level was positively related to protein metabolism and anemia, and inversely related to inflammatory state. Patients with only low FT3 demonstrated better survival than those with synchronously low FT3 and FT4, while those with synchronously low FT3, FT4 and TSH had the worst clinical outcome. Low T3 syndrome together with CLL-IPI had larger AUCs compared with CLL-IPI alone in TTFT and CSS prediction. In conclusion, low T3 syndrome may be a good candidate for predicting prognosis in future clinical practice of CLL. This article is protected by copyright. All rights reserved.

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miRNA-124-3p/neuropilin-1(NRP-1) axis plays an important role in mediating glioblastoma growth and angiogenesis

Abstract

Glioblastoma Multiforme (GBM) is the most lethal brain malignancy which involves multi-gene abnormality. Unfortunately, effective therapy against GBM is still lacking. Previously, we found that NRP-1 and its downstream NRP-1/GIPC1 pathway played an important role in GBM. In this study, we further investigated the upstream signaling of NRP-1 to understand how it is regulated. Firstly, we identified that hsa-miR-124-3p was miRNA differentially expressed in GBM and in normal brain tissues by high-throughput sequencing. Then, by dual luciferase reporter gene, we found miR-124-3p can specially bind to the 3'UTR region of the NRP-1 thus suppresses its expression. Moreover, miR-124–3p overexpression significantly inhibited GBM cell proliferation, migration and tumor angiogenesis which resulted in GBM apoptosis and cell cycle arrest, putatively via NRP-1 mediated PI3K/Akt/NFκB pathways activation in GBM cells. Meanwhile, miR-124-3p overexpression also suppressed tumor growth and reduced tumor angiogenesis when targeted by NRP-1 in a PDX model. Furthermore, NRP-1 mAb exerted synergistic inhibitory effects with miR-124–3p overexpression in GBM. Thus, we discovered that miR-124-3p acts as the upstream suppressor of NRP-1 which promotes GBM cell development and growth by PI3K/Akt/NFκB pathway. The miR-124-3p/NRP-1/GIPC1 pathway as a new pathway has a vital role in GBM, and it could be considered as the potential target for malignant gliomas in future. This article is protected by copyright. All rights reserved.

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Tobacco-attributable burden of cancer according to socioeconomic position in France

Abstract

Smoking is a major preventable cause of cancers and is increasingly concentrated among the most deprived individuals leading to increasing socioeconomic inequalities in the incidence of cancers linked to smoking. We aimed to estimate the tobacco-attributable cancer burden according to socioeconomic position in France. The analysis was restricted to cancer sites for which tobacco smoking was recognized as a risk factor. Cancer cases by sex, age group and European Deprivation Index (EDI) among people aged 30–74 between 2006 and 2009 were obtained from cancer registries covering approximately 20% of the French population. The tobacco-attributable burden of cancer according to EDI was estimated applying the population attributable fraction (PAF) computed with the Peto-Lopez method. The PAF increased from 56% in the least deprived EDI quintile to 70% in the most deprived EDI quintile among men and from 26% to 38% among women. In total, 28% of the excess cancer cases in the four most deprived EDI quintiles in men and 43% in women could be prevented if smoking in these 4 EDI quintiles was similar to that of the least deprived EDI quintile. A substantial smoking-attributable burden of cancer by socioeconomic position was observed in France. The results highlight the need for policies reducing tobacco consumption. More comprehensive interventions integrating the various dimensions of health determinants and proportionate according to socioeconomic position may essentially contribute to the reduction of socioeconomic inequalities in cancer. This article is protected by copyright. All rights reserved.

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Low T3 syndrome as a predictor of poor prognosis in chronic lymphocytic leukemia

Abstract

Low triiodothyronine (T3) state is associated with poor prognosis in critical acute and prolonged illness. However, the information on thyroid dysfunction and cancer is limited. The aim of our study was to evaluate the prognostic value of low T3 syndrome in chronic lymphocytic leukemia (CLL). Two hundred and fifty-eight patients with detailed thyroid hormone profile at CLL diagnosis were enrolled. Low T3 syndrome was defined by low free T3 (FT3) level accompanied by normal-to-low free tetraiodothyronine (FT4) and thyroid-stimulating hormone (TSH) levels. A propensity score-matched method was performed to balance the baseline characteristics. Multivariate Cox regression analyses screened the independent prognostic factors related to time-to-first-treatment (TTFT) and cancer-specific survival (CSS). Area under the curve (AUC) assessed the predictive accuracy of CLL-International Prognostic Index (IPI) together with low T3 syndrome. The results showed that 37 (14.34%) patients had low T3 syndrome, which was significantly associated with unfavorable TTFT and CSS in the propensity-matched cohort, and it was an independent prognostic indicator for both TTFT and CSS. Serum FT3 level was positively related to protein metabolism and anemia, and inversely related to inflammatory state. Patients with only low FT3 demonstrated better survival than those with synchronously low FT3 and FT4, while those with synchronously low FT3, FT4 and TSH had the worst clinical outcome. Low T3 syndrome together with CLL-IPI had larger AUCs compared with CLL-IPI alone in TTFT and CSS prediction. In conclusion, low T3 syndrome may be a good candidate for predicting prognosis in future clinical practice of CLL. This article is protected by copyright. All rights reserved.

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Diagnosis, characteristics, and treatment of breast carcinomas within benign fibroepithelial tumors

Abstract

Background

Breast carcinoma arising in a benign fibroepithelial tumor is rare, and is usually discovered incidentally during examination of the breast mass.

Methods

We evaluated the clinicopathological features, treatment, and prognosis of seven women with breast carcinomas within benign fibroepithelial tumors, diagnosed and treated at a single institution between 2011 and 2015.

Results

Seven women, aged 21–64 years, visited our hospital complaining of a breast mass detected by self-checking or screening examination. All patients had well-demarcated movable breast masses. Ultrasonography showed circumscribed masses suggesting benign tumors in all cases, and mammography revealed well-defined, high-density masses, with or without calcification. The masses progressed in two patients. A preoperative histological diagnosis of carcinoma was made following needle biopsy in four patients. Tumorectomy, breast-conserving surgery, and mastectomy were performed in three, two, and two patients, respectively. One patient underwent lymph node dissection and another underwent sentinel node biopsy. Histologically, the masses were diagnosed as invasive ductal carcinoma, ductal carcinoma in situ or lobular carcinoma in situ, arising in a benign phyllodes tumor, fibroadenoma, or fibroadenomatoid mastopathy. Lymph node metastasis was detected in two patients. There was no recurrence in any of the patients.

Conclusions

Although a carcinoma within a preexisting benign fibroepithelial tumor is extremely rare, it is important to be aware of the possibility of invasive and metastatic disease.

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Adrenal Hemangioma: A Case of Retroperitoneal Tumor

Introduction. Adrenal hemangioma is a rare disease, with only some 60 cases reported previously. Due to the difficulty of the preoperative diagnosis of adrenal hemangioma, almost all of the cases were diagnosed by a histopathological analysis of surgical specimens. Case Presentation. A 52-year-old man was referred to our department for further examination of his left retroperitoneal tumor. He had received hemodialysis due to chronic renal failure resulting from membranous nephropathy. Computed tomography revealed a mass around his left hilum. Magnetic resonance imaging (MRI) and positron-emission tomography (PET)-CT were unable to confirm or deny malignancy, and tumor markers, including CEA and CA19-9, showed slight elevation. His tumor grew from 38 mm to 54 mm in diameter in 7 months of follow-up. We therefore planned retroperitoneal tumor resection with left nephrectomy. Histopathologically, hyperplastic small vessels with hemorrhaging and denaturation were seen. The endothelial cells showed no variants or division of the nucleus. Based on this diagnosis, no further therapy was performed. He has had no recurrence in the eight months since the surgery. Conclusion. We herein report a rare case of adrenal hemangioma.

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Genomic Characterization of a Novel Hepatovirus from Great Roundleaf Bats in China

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Genomic Characterization of a Novel Hepatovirus from Great Roundleaf Bats in China

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Frequent genomic alterations and better prognosis among young patients with non-small-cell lung cancer aged 40 years or younger

Abstract

Background

The subgroup of young patients with non-small-cell lung cancer (NSCLC) is poorly understood. We retrospectively studied the clinical characteristics, gene mutations, and outcomes of patients with NSCLC (aged ≤ 40 years).

Results

Of the 7494 patients with lung cancer diagnosed from February 2001 to October 2016, 252 aged ≤ 40 years showed NSCLC. We divided their cases into non-squamous cell carcinoma and squamous cell carcinoma groups according to their histology results. Of the 252 young NSCLC patients, 173 (69%) patients had stage IIIB or IV, and 196 (78%) had never smoked. The four most common metastases were intrapulmonary lesions, pleura, bone, and brain. Among patients with adenocarcinoma, 29 (40%, n = 73) harbored epidermal growth factor receptor (EGFR) mutations, 25 (34%, n = 74) harbored anaplastic lymphoma kinase (ALK) translations, and 1 (14%, n = 7) harbored ROS proto-oncogene 1 receptor tyrosine kinase (ROS1) translations. The median progression-free survival (PFS) and overall survival (OS) were 3.3 and 27.6 months for patients receiving chemotherapy (n = 65), and 12.1 and 33.6 months for patients receiving EGFR tyrosine kinase inhibitors (TKIs) (n = 13), respectively. Patients receiving crizotinib had a median PFS time of 21.9 months (n = 8).

Conclusions

Young patients are associated with an increased likelihood of gene mutations and can receive a better prognosis when patients harboring gene mutations are treated with EGFR-TKIs or ALK inhibitors.

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A Rare Case of Carotid Web Presenting with Ischemic Stroke in a Young Woman and a Brief Review of the Literature

Carotid web is a radiological description of a shelf-like intraluminal filling defect in the carotid bulb. It is histologically defined as atypical fibromuscular dysplasia (FMD), with abnormal fibrosis and smooth muscle cell hyperplasia in the tunica intima. The spur-like intraluminal protrusion can serve as a nidus for thrombus formation, which could cause systemic embolism and ischemic strokes. We report a case of a 20-year-old female patient presenting with acute ischemic stroke in the ipsilateral middle cerebral artery (MCA) territory. We also discuss the incidence, the prevalence, the pathophysiology, the treatment, and the recurrence of carotid web based on the currently available literature.

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Frequent genomic alterations and better prognosis among young patients with non-small-cell lung cancer aged 40 years or younger

Abstract

Background

The subgroup of young patients with non-small-cell lung cancer (NSCLC) is poorly understood. We retrospectively studied the clinical characteristics, gene mutations, and outcomes of patients with NSCLC (aged ≤ 40 years).

Results

Of the 7494 patients with lung cancer diagnosed from February 2001 to October 2016, 252 aged ≤ 40 years showed NSCLC. We divided their cases into non-squamous cell carcinoma and squamous cell carcinoma groups according to their histology results. Of the 252 young NSCLC patients, 173 (69%) patients had stage IIIB or IV, and 196 (78%) had never smoked. The four most common metastases were intrapulmonary lesions, pleura, bone, and brain. Among patients with adenocarcinoma, 29 (40%, n = 73) harbored epidermal growth factor receptor (EGFR) mutations, 25 (34%, n = 74) harbored anaplastic lymphoma kinase (ALK) translations, and 1 (14%, n = 7) harbored ROS proto-oncogene 1 receptor tyrosine kinase (ROS1) translations. The median progression-free survival (PFS) and overall survival (OS) were 3.3 and 27.6 months for patients receiving chemotherapy (n = 65), and 12.1 and 33.6 months for patients receiving EGFR tyrosine kinase inhibitors (TKIs) (n = 13), respectively. Patients receiving crizotinib had a median PFS time of 21.9 months (n = 8).

Conclusions

Young patients are associated with an increased likelihood of gene mutations and can receive a better prognosis when patients harboring gene mutations are treated with EGFR-TKIs or ALK inhibitors.

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Factors associated with improved outcomes for metastatic inflammatory breast cancer patients

Abstract

Purpose

Controversy exists regarding the role of locoregional therapy for stage IV inflammatory breast cancer (IBC). This study aims to determine indicators of prognosis, including primary tumor resection, for stage IV IBC patients.

Methods

Using the National Cancer Data Base, female patients diagnosed 2010–2013 with unilateral a priori metastatic T4d invasive adenocarcinoma of the breast were identified. We conducted propensity score matched analysis to balance confounders of surgery versus no-surgery. Stratified log-rank test and double-robust estimation under the Cox model were used to assess the effect of surgery, and margins, on overall survival (OS) in the propensity score matched cohort.

Results

Of 1266 patients, 41% underwent surgery. In the unmatched cohort, median OS of the surgery and no-surgery groups was 36 and 20 months, respectively (p < 0.001). In the matched cohort (n = 588), the median OS of surgery and no-surgery groups was 29 and 27 months, respectively (p = 0.052). Patients with negative margin surgery (p = 0.024), hormone receptor-positive (p = 0.019), HER2-positive disease (p < 0.0001), treated with chemotherapy (p < 0.0001) and hormonal therapy (p < 0.0001), had better survival. Those with brain metastases had increased risk of death (p < 0.0001).

Conclusion

This study represents the largest cohort of metastatic IBC patients, and identified negative margin surgery, systemic therapy, hormone receptor and HER2-positive disease as factors associated with improved outcomes. While these findings should be interpreted cautiously, they may be used to guide further investigations into local control and quality of life in this patient population with limited treatment options.

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Decreased SCIN expression, associated with promoter methylation, is a valuable predictor for prognosis in acute myeloid leukemia

Abstract

The present study was aimed to investigate SCIN expression as well as promoter methylation and further explore their clinical relevance in acute myeloid leukemia (AML) patients. Real-time quantitative PCR was carried out to detect the expression level of SCIN in 119 AML patients and 37 healthy controls. Real-time quantitative methylation-specific PCR and bisulfite sequencing PCR were carried out to detect SCIN promoter methylation levels in 103 AML patients and 29 controls. As compared with controls, the level of SCIN transcript was significantly down-regulated in AML patients (P = 0.001), and the level of methylated SCIN promoter was significantly higher in AML patients (P = 0.001). Moreover, the level of promoter methylation was weakly negatively correlated with SCIN expression in AML patients (R = -0.265, P = 0.027). Demethylation of SCIN promoter by 5-aza-2'-deoxycytidine could restore its expression in leukemic cell line THP1. The age of SCIN^low patients was significantly higher and C/EBPA mutation was significantly less than SCIN^high patients (P = 0.039 and 0.038, respectively). Moreover, the rate of complete remission (CR) of SCIN^low patients was significantly lower than SCIN^high patients (P = 0.009). Kaplan-Meier analysis showed that low SCIN expression was associated with shorter overall survival (P = 0.036). Cox regression analysis demonstrated low SCIN expression was an independent poor prognostic factor (P = 0.047). Furthermore, SCIN expression was restored in those patients who achieved CR after induction therapy (P = 0.003). These findings indicate that decreased SCIN expression associated with its promoter methylation is a valuable biomarker for predicting adverse prognosis in AML patients. This article is protected by copyright. All rights reserved

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Decreased SCIN expression, associated with promoter methylation, is a valuable predictor for prognosis in acute myeloid leukemia

Abstract

The present study was aimed to investigate SCIN expression as well as promoter methylation and further explore their clinical relevance in acute myeloid leukemia (AML) patients. Real-time quantitative PCR was carried out to detect the expression level of SCIN in 119 AML patients and 37 healthy controls. Real-time quantitative methylation-specific PCR and bisulfite sequencing PCR were carried out to detect SCIN promoter methylation levels in 103 AML patients and 29 controls. As compared with controls, the level of SCIN transcript was significantly down-regulated in AML patients (P = 0.001), and the level of methylated SCIN promoter was significantly higher in AML patients (P = 0.001). Moreover, the level of promoter methylation was weakly negatively correlated with SCIN expression in AML patients (R = -0.265, P = 0.027). Demethylation of SCIN promoter by 5-aza-2'-deoxycytidine could restore its expression in leukemic cell line THP1. The age of SCIN^low patients was significantly higher and C/EBPA mutation was significantly less than SCIN^high patients (P = 0.039 and 0.038, respectively). Moreover, the rate of complete remission (CR) of SCIN^low patients was significantly lower than SCIN^high patients (P = 0.009). Kaplan-Meier analysis showed that low SCIN expression was associated with shorter overall survival (P = 0.036). Cox regression analysis demonstrated low SCIN expression was an independent poor prognostic factor (P = 0.047). Furthermore, SCIN expression was restored in those patients who achieved CR after induction therapy (P = 0.003). These findings indicate that decreased SCIN expression associated with its promoter methylation is a valuable biomarker for predicting adverse prognosis in AML patients. This article is protected by copyright. All rights reserved

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Aggressive fibromatosis in the infratemporal fossa presenting as trismus: a case report

Here we report a very rare entity of an infratemporal region aggressive fibromatosis in a 23-year-old Tharu man who had presented with the symptoms of painless but progressive trismus.

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Brush sign in Sturge-Weber syndrome

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Thanks from Iraq

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Brush sign in Sturge-Weber syndrome

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Thanks from Iraq

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Metastasis of breast cancer prior to invasion

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Abrus agglutinin stimulates BMP-2-dependent differentiation through autophagic degradation of β-catenin in colon cancer stem cells

Abstract

Eradicating cancer stem cells (CSCs) in colorectal cancer (CRC) through differentiation therapy is a promising approach for cancer treatment. Our retrospective tumor-specimen analysis elucidated alteration in the expression of bone morphogenetic protein 2 (BMP-2) and β-catenin during the colon cancer progression, indicating that their possible intervention through "forced differentiation" in colon cancer remission. We reveal that Abrus agglutinin (AGG) induces the colon CSCs differentiation, enhancing sensitive to the anticancer therapeutics. The low dose AGG (max. dose = 100 ng/mL) decreased the expression of stemness-associated molecules such as CD44 and β-catenin in the HT-29 cell derived colonospheres. Further, AGG augmented colonosphere differentiation, as demonstrated by the enhanced CK20/CK7 expression ratio and induced alkaline phosphatase activity. Interestingly, the AGG-induced expression of BMP-2 and the AGG-induced differentiation were demonstrated to be critically dependent on BMP-2 in the colonospheres. Similarly, autophagy-induction by AGG was associated with colonosphere differentiation and the gene silencing of BMP-2 led to the reduced accumulation of LC3-II, suggesting that AGG-induced autophagy is dependent on BMP-2. Furthermore, hVps34 binds strongly to BMP-2, indicating a possible association of BMP-2 with the process of autophagy. Moreover, the reduction in the self-renewal capacity of the colonospheres was associated with AGG-augmented autophagic degradation of β-catenin through an interaction with the autophagy adaptor protein p62. In the subcutaneous HT-29 xenograft model, AGG profoundly inhibited the growth of tumors through an increase in BMP-2 expression and LC3-II puncta, and a decrease in β-catenin expression, confirming the antitumor potential of AGG through induction of differentiation in colorectal cancer. This article is protected by copyright. All rights reserved

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Abrus agglutinin stimulates BMP-2-dependent differentiation through autophagic degradation of β-catenin in colon cancer stem cells

Abstract

Eradicating cancer stem cells (CSCs) in colorectal cancer (CRC) through differentiation therapy is a promising approach for cancer treatment. Our retrospective tumor-specimen analysis elucidated alteration in the expression of bone morphogenetic protein 2 (BMP-2) and β-catenin during the colon cancer progression, indicating that their possible intervention through "forced differentiation" in colon cancer remission. We reveal that Abrus agglutinin (AGG) induces the colon CSCs differentiation, enhancing sensitive to the anticancer therapeutics. The low dose AGG (max. dose = 100 ng/mL) decreased the expression of stemness-associated molecules such as CD44 and β-catenin in the HT-29 cell derived colonospheres. Further, AGG augmented colonosphere differentiation, as demonstrated by the enhanced CK20/CK7 expression ratio and induced alkaline phosphatase activity. Interestingly, the AGG-induced expression of BMP-2 and the AGG-induced differentiation were demonstrated to be critically dependent on BMP-2 in the colonospheres. Similarly, autophagy-induction by AGG was associated with colonosphere differentiation and the gene silencing of BMP-2 led to the reduced accumulation of LC3-II, suggesting that AGG-induced autophagy is dependent on BMP-2. Furthermore, hVps34 binds strongly to BMP-2, indicating a possible association of BMP-2 with the process of autophagy. Moreover, the reduction in the self-renewal capacity of the colonospheres was associated with AGG-augmented autophagic degradation of β-catenin through an interaction with the autophagy adaptor protein p62. In the subcutaneous HT-29 xenograft model, AGG profoundly inhibited the growth of tumors through an increase in BMP-2 expression and LC3-II puncta, and a decrease in β-catenin expression, confirming the antitumor potential of AGG through induction of differentiation in colorectal cancer. This article is protected by copyright. All rights reserved

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The CBTRUS story: providing accurate population-based statistics on brain and other central nervous system tumors for everyone

The Central Brain Tumor Registry of the United States (CBTRUS) was established to provide descriptive statistical data on all primary brain tumors. The following editorial describes some of the historical events that led to its establishment and its current role as the recognized "go-to" resource for researchers; clinicians and treatment facilities; federal and state agencies; manufacturers of medical drugs and devices; and organizations that provide education, emotional support, and guidance for brain tumor patients and their caregivers.

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Highlights from the Literature

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Corrigendum

Corrigendum to Beier et al. Multicenter pilot study of radiochemotherapy as first-line treatment for adults with medulloblastoma (NOA-07). Neuro Oncol (doi: https://doi.org/10.1093/neuonc/nox155) first published online 21 August 2017

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Forthcoming Meetings

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Simultaneous care in neuro-oncology

See the article by Philip et al on pp. 391–399.

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A new practical and versatile mouse model of proneural glioblastoma

See the article by Rahme et al. on pp. 332–342.

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Challenges of developing small-molecule kinase inhibitors for brain tumors and the need for emphasis on free drug levels

Abstract

Despite biological rationale and significant clinical study, the pursuit of small-molecule kinase inhibitors for the treatment of brain cancers has had very limited success. This Advance-in-Brief discusses the need for drugs to achieve free brain penetration to engage their targets where CNS tumors reside. This need to achieve free, as opposed to total, drug concentrations in the brain may be a contributing factor to why so many small-molecule kinase inhibitors have not realized success in the neuro-oncology setting. For kinase targets of interest for brain cancer, either the vast majority of small-molecule inhibitors have data suggesting that free brain penetration would be limited or there are inadequate data to suggest that free brain penetration could be expected. Therefore, kinase targets of interest in the treatment of brain cancers may be inadequately assessed due to a lack of freely brain-penetrant inhibitors available for clinical study. Encouraging recent drug discovery efforts that focused on achieving free brain penetration for cancers in the CNS are highlighted. Still, further efforts are needed to enable thorough clinical evaluation of biological hypotheses.

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Visual and semiquantitative 11C-methionine PET: an independent prognostic factor for survival of newly diagnosed and treatment-naïve gliomas

Abstract

Background

Few data exist regarding the prognostic value of L-[S-methyl-¹¹C]methionine (MET) PET for treatment-naïve gliomas.

Methods

A total of 160 glioma patients (89 men, 71 women; mean age: 45, range 18–84 y) underwent a MET PET prior to any therapy. The PET scans were evaluated visually and semiquantitatively by tumor-to-background (T/N) ratio thresholds chosen by analysis of receiver operating characteristics. Additionally, isocitrate dehydrogenase 1–R132H (IDH1-R132H) immunohistochemistry was performed. Survival analysis was done using Kaplan–Meier estimates and the Cox proportional hazards model.

Results

Significantly shorter mean survival times (7.2 vs 8.6 y; P = 0.024) were seen in patients with amino acid avid gliomas (n = 137) compared with visually negative tumors (n = 33) in MET PET. T/N ratio thresholds of 2.1 and 3.5 were significantly associated with survival (10.3 vs 7 vs 4.3 y; P < 0.001). Mean survival differed significantly using the median T/N ratio of 2.4 as cutoff, independent of histopathology (P < 0.01; mean survival: 10.2 ± 0.8 y vs 5.5 ± 0.6 y). In the subgroup of 142 glioma patients characterized by IDH1-R132H status, METT/N ratio demonstrated a significant prognostic impact in IDH1-R132H wildtype astrocytomas and glioblastoma (P = 0.001). Additionally, multivariate testing revealed semiquantitative MET PET as an independent prognostic parameter for treatment-naïve glioma patients without (P = 0.031) and with IDH1-R132H characterization of gliomas (P = 0.024; odds ratio 1.57).

Conclusion

This retrospective analysis demonstrates the value of MET PET as a prognostic parameter on survival in treatment-naïve glioma patients.

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Metabolic heterogeneity and plasticity of glioma stem cells in a mouse glioblastoma model

Abstract

Background

Glioblastomas have been shown to rely on glycolysis as an energy source. However, recent evidence suggests that at least a subset of glioma cells with stem cell–like properties can thrive on oxidative phosphorylation. It remains unclear whether both metabolic phenotypes support tumor propagation, if they are independent, and how stable they are. The present study investigated these questions with the use of isogenic murine glioma stem cells (GSCs).

Methods

GSCs were established from tumors formed by Ink4a/Arf–null, H-Ras^V12-expressing glioma-initiating cells that differed in extracellular acidification potential. Metabolic characteristics of GSCs were determined by measurement of glucose, oxygen, and glutamine uptake, ATP content, and lactate production. Effects of metabolic inhibitors and changes in oxygen or nutrient availability on lactate production and tumorsphere growth were also determined.

Results

GSCs were found either to consume more glucose and produce more lactate or to consume more oxygen and maintain a higher ATP content depending on the metabolic characteristics of the tumor cells of origin. The latter, mitochondrial-type GSCs increased lactate production after treatment with the oxidative phosphorylation inhibitor oligomycin or phenformin. Exposure to hypoxia also increased lactate production and expression of glycolysis-related enzymes and metabolites in mitochondrial-type GSCs in a reversible manner.

Conclusions

Both glycolytic and mitochondrial-type energy production can sustain tumor propagation by isogenic GSCs. Whereas both phenotypes can be independent and stable, cells that rely on oxidative phosphorylation can also switch to a more glycolytic phenotype in response to metabolic stress, suggesting that plasticity is a further characteristic of GSC metabolism.

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Long-term exposure to ambient air pollution and incidence of brain tumor: the European Study of Cohorts for Air Pollution Effects (ESCAPE)

Abstract

Background

Epidemiological evidence on the association between ambient air pollution and brain tumor risk is sparse and inconsistent.

Methods

In 12 cohorts from 6 European countries, individual estimates of annual mean air pollution levels at the baseline residence were estimated by standardized land-use regression models developed within the ESCAPE and TRANSPHORM projects: particulate matter (PM) ≤2.5, ≤10, and 2.5–10 μm in diameter (PM_2.5, PM₁₀, and PM_coarse), PM_2.5 absorbance, nitrogen oxides (NO₂ and NO_x) and elemental composition of PM. We estimated cohort-specific associations of air pollutant concentrations and traffic intensity with total, malignant, and nonmalignant brain tumor, in separate Cox regression models, adjusting for risk factors, and pooled cohort-specific estimates using random-effects meta-analyses.

Results

Of 282194 subjects from 12 cohorts, 466 developed malignant brain tumors during 12 years of follow-up. Six of the cohorts also had data on nonmalignant brain tumor, where among 106786 subjects, 366 developed brain tumor: 176 nonmalignant and 190 malignant. We found a positive, statistically nonsignificant association between malignant brain tumor and PM_2.5 absorbance (hazard ratio and 95% CI: 1.67; 0.89–3.14 per 10^–5/m³), and weak positive or null associations with the other pollutants. Hazard ratio for PM_2.5 absorbance (1.01; 0.38–2.71 per 10^–5/m³) and all other pollutants were lower for nonmalignant than for malignant brain tumors.

Conclusion

We found suggestive evidence of an association between long-term exposure to PM_2.5 absorbance indicating traffic-related air pollution and malignant brain tumors, and no association with overall or nonmalignant brain tumors.

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Loss of host-derived osteopontin creates a glioblastoma-promoting microenvironment

Abstract

Background

Microglia and periphery-derived monocytes infiltrate human and mouse glioblastoma and their density is positively correlated with malignancy. Using microarray and RNA sequencing, we have previously shown that glioblastoma-associated microglia/monocytes (GAMs) express osteopontin/SPP1.

Methods

We used quantitative reverse transcriptase PCR, immunofluorescence stainings, western blot, and flow cytometry to identify the various sources of osteopontin (OPN) expression in human and mouse glioblastoma. We implanted wild type GL261 glioblastoma cells, which do not express significant levels of OPN, into wild type and OPN^−/− mice to investigate the role of microenvironment-derived OPN on glioblastoma progression.

Results

Our data indicate that GAMs are the predominant source of OPN in both human and mouse glioblastoma and express only the secreted form of OPN. Loss of microenvironment-derived OPN enhanced tumor progression. Staining by Ki67 and terminal deoxynucleotidyl transferase deoxyuridine triphosphate nick end labeling showed no difference in overall cell proliferation but a decreased apoptosis rate in tumors in OPN^−/− mice. CD31 staining showed a significantly decreased number of microvessels in tumors in OPN^−/− mice, accompanied by reduced coverage of vessels with platelet derived growth factor receptor β⁺ pericytes. Flow cytometry analysis revealed a significant increase of CD11b⁺/CD45^low microglia but not of CD11b⁺/CD45^high macrophages/monocytes in tumors in OPN^−/− mice. Sorted CD11b⁺ cells from wild type and OPN^−/− naïve brains and tumors did not show a significant difference in the expression pattern of activation marker genes.

Conclusion

Our results show that in tested human and mouse glioblastoma samples, OPN is predominantly expressed and secreted by GAMs and that, in contrast to OPN expression in the tumor cells per se, loss of stroma-derived OPN creates a glioblastoma-promoting microenvironment.

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Molecular differences in IDH wildtype glioblastoma according to MGMT promoter methylation

Abstract

Background

O⁶-methylguanine-DNA-methyltransferase (MGMT) promoter methylation status is a predictive biomarker in glioblastoma. We investigated whether this marker furthermore defines a molecularly distinct tumor subtype with clinically different outcome.

Methods

We analyzed copy number variation (CNV) and methylation profiles of 1095 primary and 92 progressive isocitrate dehydrogenase wildtype glioblastomas, including paired samples from 49 patients. DNA mutation data from 182 glioblastoma samples of The Cancer Genome Atlas (TCGA) and RNA expression from 107 TCGA and 55 Chinese Glioma Genome Atlas samples were analyzed.

Results

Among untreated glioblastomas, MGMT promoter methylated (mMGMT) and unmethylated (uMGMT) tumors did not show different CNV or specific gene mutations, but a higher mutation count in mMGMT tumors. We identified 3 methylation clusters. Cluster 1 showed the highest average methylation and was enriched for mMGMT tumors. Seventeen genes including gastrulation brain homeobox 2 (GBX2) were found to be hypermethylated and downregulated on the mRNA level in mMGMT tumors. In progressive glioblastomas, platelet derived growth factor receptor alpha (PDGFRA) and GLI2 amplifications were enriched in mMGMT tumors. Methylated MGMT tumors gain PDGFRA amplification of PDGFRA, whereas uMGMT tumors with amplified PDGFRA frequently lose this amplification upon progression. Glioblastoma patients surviving <6 months and with mMGMT harbored less frequent epidermal growth factor receptor (EGFR) amplifications, more frequent TP53 mutations, and a higher tumor necrosis factor–nuclear factor-kappaB (TNF-NFκB) pathway activation compared with patients surviving >12 months.

Conclusions

MGMT promoter methylation status does not define a molecularly distinct glioblastoma subpopulation among untreated tumors. Progressive mMGMT glioblastomas and mMGMT tumors of patients with short survival tend to have more unfavorable molecular profiles.

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Multicenter pilot study of radiochemotherapy as first-line treatment for adults with medulloblastoma (NOA-07)

Abstract

Background

Medulloblastoma in adult patients is rare, with 0.6 cases per million. Prognosis depends on clinical factors and medulloblastoma entity. No prospective data on the feasibility of radiochemotherapy exist. The German Neuro-Oncology Working Group (NOA) performed a prospective descriptive multicenter single-arm phase II trial to evaluate feasibility and toxicity of radio-polychemotherapy.

Methods

The NOA-07 trial combined craniospinal irradiation with vincristine, followed by 8 cycles of cisplatin, lomustine, and vincristine. Adverse events, imaging and progression patterns, histological and genetic markers, health-related quality of life (HRQoL), and cognition were evaluated. Primary endpoint was the rate of toxicity-related treatment terminations after 4 chemotherapy cycles, and the toxicity profile. The feasibility goal was reached if at least 45% of patients received at least 4 cycles of maintenance chemotherapy.

Results

Thirty patients were evaluable. Each 50% showed classic and desmoplastic/nodular histology. Sixty-seven percent were classified into the sonic hedgehog (SHH) subgroup without TP53 alterations, 13% in wingless (WNT), and 17% in non-WNT/non-SHH. Four cycles of chemotherapy were feasible in the majority (n = 21; 70.0%). Hematological side effects and polyneuropathy were prevalent toxicities. During the active treatment period, HRQoL and verbal fluency improved significantly. The 3-year event-free survival rate was 66.6% at the time of databank lock.

Conclusions

Radio-polychemotherapy did lead to considerable toxicity and a high amount of dose reductions throughout the first 4 chemotherapy cycles that may affect efficacy. Thus, we propose frequent patient surveillance using this regimen. Modifications of the regimen may increase feasibility of radio-polychemotherapy of adult patients with medulloblastoma.

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Mesenchymal stem cells as natural biofactories for exosomes carrying miR-124a in the treatment of gliomas

Abstract

Background

MicroRNAs (miRs) are promising new therapeutics for glioblastoma. However, which miRs are most effective against glioblastomas and how these miRs should be delivered are major unanswered problems.

Methods

To identify potent antiglioma miRs, we selected 8 miRs based on a literature search and screened them against a panel of glioma stem cell (GSC) lines, representing all of the glioblastoma subtypes defined by The Cancer Genome Atlas. To address delivery, we tested the hypothesis that ex vivo cultured bone marrow–derived mesenchymal stem cells (MSCs) can package miRs into exosomes and that these engineered exosomes can systemically deliver antiglioma miRs to glioblastomas.

Results

Of the screened miRs, we identified miR-124a as the most effective antiglioma agent against GSCs. We then transduced MSCs with lentivirus vectors containing miR-124a and isolated vesicles from the medium. Electron microscopy, western blotting, and Nanosight proved that the isolated vesicles were exosomes. Quantitative PCR documented that these exosomes contained high levels of miR-124a, which was not present in control exosomes. In vitro treatment of GSCs with exosomes containing miR-124a (Exo-miR124) resulted in a significant reduction in viability and clonogenicity of GSCs compared with controls. In vivo treatment of mice harboring intracranial GSC267 with systemically delivered Exo-miR124 resulted in 50% of animals living long term. No evidence of tumor was present on histological analysis of the survivors. Mechanistic studies showed that miR-124a acts by silencing Forkhead box (FOX)A2, resulting in aberrant intracellular lipid accumulation.

Conclusion

MSCs can be used as natural biofactories to produce Exo-miR124, which is an effective antiglioma agent worthy of further clinical evaluation.

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A proposed framework of supportive and palliative care for people with high-grade glioma

Abstract

Background

Patients with malignant high-grade glioma (HGG) have significant supportive and palliative care needs, yet few tailored guidelines exist to inform practice. This study sought to develop an HGG framework of supportive and palliative care informed by needs reported by patients, families, and health care professionals (HCPs).

Methods

This study integrates a mixed-methods research program involving: (i) exploring experiences through systematic literature review and qualitative study (10 patients, 23 carers, and 36 HCPs); and (ii) an epidemiological cohort study (N = 1821) describing care of cases of HGG in Victoria, Australia using linked hospital datasets. Recommendations based on these studies were developed by a multidisciplinary advisory committee for a framework of supportive and palliative care based on the findings of (i) and (ii).

Results

Key principles guiding framework development were that care: (i) aligns with patient/family caregiver needs according to illness transition points; (ii) involves continuous monitoring of patient/family caregiver needs; (iii) be proactive in response to anticipated concerns; (iv) includes routine bereavement support; and (v) involves appropriate partnership with patients/families. Framework components and resulting activities designed to address unmet needs were enacted at illness transition points and included coordination, repeated assessment, staged information provision according to the illness transition, proactive responses and referral systems, and specific regular inquiry of patients' and family caregivers' concerns.

Conclusion

This evidence-based, collaborative framework of supportive and palliative care provides an approach for patients with HGG that is responsive, relevant, and sustainable. This conceptual framework requires evaluation in robust clinical trials.

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Clinical characteristics associated with postoperative seizure control in adult low-grade gliomas: a systematic review and meta-analysis

Abstract

Background

Epilepsy is the most common symptom in patients with supratentorial low-grade gliomas (LGGs), which adversely affects the patient's quality of life. Poor seizure control with anti-epileptic therapy is an indication for surgery in these patients. Recent studies have sought to identify predictors of postoperative seizure control after surgical resection of LGG; gross total resection was shown to be a significant predictor in this respect. However, the prognostic value of other factors is not clear.

Methods

We performed a systematic review and meta-analysis of 23 studies with a combined study population of 2641 patients with LGG, in order to identify potential factors associated with favorable postoperative seizure control. Data were extracted on age and sex of patient, tumor location, tumor histology, type of seizure, seizure duration, extent of resection, and imaging characteristics.

Results

Patients ≥45 years of age achieved better postoperative seizure control (risk ratio [RR], 0.89; 95% CI, 0.81–0.99). Focal seizures were associated with poor seizure control (RR, 1.32; 95% CI, 1.18–1.49) compared with generalized seizures (RR, 0.77; 95% CI, 0.68–0.87). Prolonged history of seizures (≥1 y) had a negative impact on postoperative seizure control (RR, 1.22; 95% CI, 1.10–1.34). Gross total resection was superior to subtotal resection with respect to postoperative seizure control (RR, 0.68; 95% CI, 0.63–0.73).

Conclusions

This systematic review and meta-analysis identified predictors of postoperative seizure control in patients undergoing surgical resection of LGGs. Our results provide a reference for clinical treatment of LGG-related epilepsy.

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A recombinant lentiviral PDGF-driven mouse model of proneural glioblastoma

Abstract

Background

Mouse models of glioblastoma (GBM), the most aggressive primary brain tumor, are critical for understanding GBM pathology and can contribute to the preclinical evaluation of therapeutic agents. Platelet-derived growth factor (PDGF) signaling has been implicated in the development and pathogenesis of GBM, specifically the proneural subtype. Although multiple mouse models of PDGF-driven glioma have been described, they require transgenic mice engineered to activate PDGF signaling and/or impair tumor suppressor genes and typically represent lower-grade glioma.

Methods

We designed recombinant lentiviruses expressing both PDGFB and a short hairpin RNA targeting Cdkn2a to induce gliomagenesis following stereotactic injection into the dentate gyrus of adult immunocompetent mice. We engineered these viruses to coexpress CreERT2 with PDGFB, allowing for deletion of floxed genes specifically in transduced cells, and designed another version of this recombinant lentivirus in which enhanced green fluorescent protein was coexpressed with PDGFB and CreERT2 to visualize transduced cells.

Results

The dentate gyrus of injected mice showed hypercellularity one week post-injection and subsequently developed bona fide tumors with the pathologic hallmarks of GBM leading to a median survival of 77 days post-injection. Transcriptomic analysis of these tumors revealed a proneural gene expression signature.

Conclusion

Informed by the genetic alterations observed in human GBM, we engineered a novel mouse model of proneural GBM. While reflecting many of the advantages of transgenic mice, this model allows for the facile in vivo testing of gene function in tumor cells and makes possible the rapid production of large numbers of immunocompetent tumor-bearing mice for preclinical testing of therapeutics.

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miR miR on the wall, who’s the most malignant medulloblastoma miR of them all?

Abstract

microRNAs (miRNAs) have wide-ranging effects on large-scale gene regulation. As such, they play a vital role in dictating normal development, and their aberrant expression has been implicated in cancer. There has been a large body of research on the role of miRNAs in medulloblastoma, the most common malignant brain tumor of childhood. The identification of the 4 molecular subgroups with distinct biological, genetic, and transcriptional features has revolutionized the field of medulloblastoma research over the past 5 years. Despite this, the growing body of research on miRNAs in medulloblastoma has largely focused on the clinical entity of a single disease rather than the molecular subgroups. This review begins by highlighting the role of miRNAs in development and progresses to explore their myriad of implications in cancer. Medulloblastoma is characterized by increased proliferation, inhibition of apoptosis, and maintenance of stemness programs—features that are inadvertently regulated by altered expression patterns in miRNAs. This review aims to contextualize the large body of work on miRNAs within the framework of medulloblastoma subgroups. The goal of this review is to stimulate new areas of research, including potential therapeutics, within a rapidly growing field.

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The CBTRUS story: providing accurate population-based statistics on brain and other central nervous system tumors for everyone

The Central Brain Tumor Registry of the United States (CBTRUS) was established to provide descriptive statistical data on all primary brain tumors. The following editorial describes some of the historical events that led to its establishment and its current role as the recognized "go-to" resource for researchers; clinicians and treatment facilities; federal and state agencies; manufacturers of medical drugs and devices; and organizations that provide education, emotional support, and guidance for brain tumor patients and their caregivers.

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Highlights from the Literature

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Corrigendum

Corrigendum to Beier et al. Multicenter pilot study of radiochemotherapy as first-line treatment for adults with medulloblastoma (NOA-07). Neuro Oncol (doi: https://doi.org/10.1093/neuonc/nox155) first published online 21 August 2017

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Forthcoming Meetings

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Simultaneous care in neuro-oncology

See the article by Philip et al on pp. 391–399.

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A new practical and versatile mouse model of proneural glioblastoma

See the article by Rahme et al. on pp. 332–342.

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Challenges of developing small-molecule kinase inhibitors for brain tumors and the need for emphasis on free drug levels

Abstract

Despite biological rationale and significant clinical study, the pursuit of small-molecule kinase inhibitors for the treatment of brain cancers has had very limited success. This Advance-in-Brief discusses the need for drugs to achieve free brain penetration to engage their targets where CNS tumors reside. This need to achieve free, as opposed to total, drug concentrations in the brain may be a contributing factor to why so many small-molecule kinase inhibitors have not realized success in the neuro-oncology setting. For kinase targets of interest for brain cancer, either the vast majority of small-molecule inhibitors have data suggesting that free brain penetration would be limited or there are inadequate data to suggest that free brain penetration could be expected. Therefore, kinase targets of interest in the treatment of brain cancers may be inadequately assessed due to a lack of freely brain-penetrant inhibitors available for clinical study. Encouraging recent drug discovery efforts that focused on achieving free brain penetration for cancers in the CNS are highlighted. Still, further efforts are needed to enable thorough clinical evaluation of biological hypotheses.

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Visual and semiquantitative 11C-methionine PET: an independent prognostic factor for survival of newly diagnosed and treatment-naïve gliomas

Abstract

Background

Few data exist regarding the prognostic value of L-[S-methyl-¹¹C]methionine (MET) PET for treatment-naïve gliomas.

Methods

A total of 160 glioma patients (89 men, 71 women; mean age: 45, range 18–84 y) underwent a MET PET prior to any therapy. The PET scans were evaluated visually and semiquantitatively by tumor-to-background (T/N) ratio thresholds chosen by analysis of receiver operating characteristics. Additionally, isocitrate dehydrogenase 1–R132H (IDH1-R132H) immunohistochemistry was performed. Survival analysis was done using Kaplan–Meier estimates and the Cox proportional hazards model.

Results

Significantly shorter mean survival times (7.2 vs 8.6 y; P = 0.024) were seen in patients with amino acid avid gliomas (n = 137) compared with visually negative tumors (n = 33) in MET PET. T/N ratio thresholds of 2.1 and 3.5 were significantly associated with survival (10.3 vs 7 vs 4.3 y; P < 0.001). Mean survival differed significantly using the median T/N ratio of 2.4 as cutoff, independent of histopathology (P < 0.01; mean survival: 10.2 ± 0.8 y vs 5.5 ± 0.6 y). In the subgroup of 142 glioma patients characterized by IDH1-R132H status, METT/N ratio demonstrated a significant prognostic impact in IDH1-R132H wildtype astrocytomas and glioblastoma (P = 0.001). Additionally, multivariate testing revealed semiquantitative MET PET as an independent prognostic parameter for treatment-naïve glioma patients without (P = 0.031) and with IDH1-R132H characterization of gliomas (P = 0.024; odds ratio 1.57).

Conclusion

This retrospective analysis demonstrates the value of MET PET as a prognostic parameter on survival in treatment-naïve glioma patients.

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Metabolic heterogeneity and plasticity of glioma stem cells in a mouse glioblastoma model

Abstract

Background

Glioblastomas have been shown to rely on glycolysis as an energy source. However, recent evidence suggests that at least a subset of glioma cells with stem cell–like properties can thrive on oxidative phosphorylation. It remains unclear whether both metabolic phenotypes support tumor propagation, if they are independent, and how stable they are. The present study investigated these questions with the use of isogenic murine glioma stem cells (GSCs).

Methods

GSCs were established from tumors formed by Ink4a/Arf–null, H-Ras^V12-expressing glioma-initiating cells that differed in extracellular acidification potential. Metabolic characteristics of GSCs were determined by measurement of glucose, oxygen, and glutamine uptake, ATP content, and lactate production. Effects of metabolic inhibitors and changes in oxygen or nutrient availability on lactate production and tumorsphere growth were also determined.

Results

GSCs were found either to consume more glucose and produce more lactate or to consume more oxygen and maintain a higher ATP content depending on the metabolic characteristics of the tumor cells of origin. The latter, mitochondrial-type GSCs increased lactate production after treatment with the oxidative phosphorylation inhibitor oligomycin or phenformin. Exposure to hypoxia also increased lactate production and expression of glycolysis-related enzymes and metabolites in mitochondrial-type GSCs in a reversible manner.

Conclusions

Both glycolytic and mitochondrial-type energy production can sustain tumor propagation by isogenic GSCs. Whereas both phenotypes can be independent and stable, cells that rely on oxidative phosphorylation can also switch to a more glycolytic phenotype in response to metabolic stress, suggesting that plasticity is a further characteristic of GSC metabolism.

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Long-term exposure to ambient air pollution and incidence of brain tumor: the European Study of Cohorts for Air Pollution Effects (ESCAPE)

Abstract

Background

Epidemiological evidence on the association between ambient air pollution and brain tumor risk is sparse and inconsistent.

Methods

In 12 cohorts from 6 European countries, individual estimates of annual mean air pollution levels at the baseline residence were estimated by standardized land-use regression models developed within the ESCAPE and TRANSPHORM projects: particulate matter (PM) ≤2.5, ≤10, and 2.5–10 μm in diameter (PM_2.5, PM₁₀, and PM_coarse), PM_2.5 absorbance, nitrogen oxides (NO₂ and NO_x) and elemental composition of PM. We estimated cohort-specific associations of air pollutant concentrations and traffic intensity with total, malignant, and nonmalignant brain tumor, in separate Cox regression models, adjusting for risk factors, and pooled cohort-specific estimates using random-effects meta-analyses.

Results

Of 282194 subjects from 12 cohorts, 466 developed malignant brain tumors during 12 years of follow-up. Six of the cohorts also had data on nonmalignant brain tumor, where among 106786 subjects, 366 developed brain tumor: 176 nonmalignant and 190 malignant. We found a positive, statistically nonsignificant association between malignant brain tumor and PM_2.5 absorbance (hazard ratio and 95% CI: 1.67; 0.89–3.14 per 10^–5/m³), and weak positive or null associations with the other pollutants. Hazard ratio for PM_2.5 absorbance (1.01; 0.38–2.71 per 10^–5/m³) and all other pollutants were lower for nonmalignant than for malignant brain tumors.

Conclusion

We found suggestive evidence of an association between long-term exposure to PM_2.5 absorbance indicating traffic-related air pollution and malignant brain tumors, and no association with overall or nonmalignant brain tumors.

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Loss of host-derived osteopontin creates a glioblastoma-promoting microenvironment

Abstract

Background

Microglia and periphery-derived monocytes infiltrate human and mouse glioblastoma and their density is positively correlated with malignancy. Using microarray and RNA sequencing, we have previously shown that glioblastoma-associated microglia/monocytes (GAMs) express osteopontin/SPP1.

Methods

We used quantitative reverse transcriptase PCR, immunofluorescence stainings, western blot, and flow cytometry to identify the various sources of osteopontin (OPN) expression in human and mouse glioblastoma. We implanted wild type GL261 glioblastoma cells, which do not express significant levels of OPN, into wild type and OPN^−/− mice to investigate the role of microenvironment-derived OPN on glioblastoma progression.

Results

Our data indicate that GAMs are the predominant source of OPN in both human and mouse glioblastoma and express only the secreted form of OPN. Loss of microenvironment-derived OPN enhanced tumor progression. Staining by Ki67 and terminal deoxynucleotidyl transferase deoxyuridine triphosphate nick end labeling showed no difference in overall cell proliferation but a decreased apoptosis rate in tumors in OPN^−/− mice. CD31 staining showed a significantly decreased number of microvessels in tumors in OPN^−/− mice, accompanied by reduced coverage of vessels with platelet derived growth factor receptor β⁺ pericytes. Flow cytometry analysis revealed a significant increase of CD11b⁺/CD45^low microglia but not of CD11b⁺/CD45^high macrophages/monocytes in tumors in OPN^−/− mice. Sorted CD11b⁺ cells from wild type and OPN^−/− naïve brains and tumors did not show a significant difference in the expression pattern of activation marker genes.

Conclusion

Our results show that in tested human and mouse glioblastoma samples, OPN is predominantly expressed and secreted by GAMs and that, in contrast to OPN expression in the tumor cells per se, loss of stroma-derived OPN creates a glioblastoma-promoting microenvironment.

http://ift.tt/2C89Mf1

Molecular differences in IDH wildtype glioblastoma according to MGMT promoter methylation

Abstract

Background

O⁶-methylguanine-DNA-methyltransferase (MGMT) promoter methylation status is a predictive biomarker in glioblastoma. We investigated whether this marker furthermore defines a molecularly distinct tumor subtype with clinically different outcome.

Methods

We analyzed copy number variation (CNV) and methylation profiles of 1095 primary and 92 progressive isocitrate dehydrogenase wildtype glioblastomas, including paired samples from 49 patients. DNA mutation data from 182 glioblastoma samples of The Cancer Genome Atlas (TCGA) and RNA expression from 107 TCGA and 55 Chinese Glioma Genome Atlas samples were analyzed.

Results

Among untreated glioblastomas, MGMT promoter methylated (mMGMT) and unmethylated (uMGMT) tumors did not show different CNV or specific gene mutations, but a higher mutation count in mMGMT tumors. We identified 3 methylation clusters. Cluster 1 showed the highest average methylation and was enriched for mMGMT tumors. Seventeen genes including gastrulation brain homeobox 2 (GBX2) were found to be hypermethylated and downregulated on the mRNA level in mMGMT tumors. In progressive glioblastomas, platelet derived growth factor receptor alpha (PDGFRA) and GLI2 amplifications were enriched in mMGMT tumors. Methylated MGMT tumors gain PDGFRA amplification of PDGFRA, whereas uMGMT tumors with amplified PDGFRA frequently lose this amplification upon progression. Glioblastoma patients surviving <6 months and with mMGMT harbored less frequent epidermal growth factor receptor (EGFR) amplifications, more frequent TP53 mutations, and a higher tumor necrosis factor–nuclear factor-kappaB (TNF-NFκB) pathway activation compared with patients surviving >12 months.

Conclusions

MGMT promoter methylation status does not define a molecularly distinct glioblastoma subpopulation among untreated tumors. Progressive mMGMT glioblastomas and mMGMT tumors of patients with short survival tend to have more unfavorable molecular profiles.

http://ift.tt/2sD4cNX