Editorial Board

Publication date: July 2017
Source:Critical Reviews in Oncology/Hematology, Volume 115





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The role of the systemic inflammatory response in predicting outcomes in patients with advanced inoperable cancer: Systematic review and meta-analysis

Publication date: Available online 9 June 2017
Source:Critical Reviews in Oncology/Hematology
Author(s): Ross D Dolan, Stephen T McSorley, Paul G Horgan, Barry Laird, Donald C McMillan
IntroductionCancer remains a leading cause of death worldwide. While a curative intent is the aim of any surgical treatment many patients either present with or go onto develop disseminated disease requiring systemic anti-cancer therapy with a palliative intent. Given their limited life expectancy appropriate allocation of treatment is vital. It is recognised that systemic chemoradiotherapy may shorten the quality/quantity of life in patients with advanced cancer. It is against this background that the present systematic review and meta-analysis of the prognostic value of markers of the systemic inflammatory response in patients with advanced cancer was conducted.MethodsAn extensive literature review using targeted medical subject headings was carried out in the MEDLINE, EMBASE, and CDSR databases until the end of 2016. Titles were examined for relevance and studies relating to duplicate datasets, that were not published in English and that did not have full text availability were excluded. Full texts of relevant articles were obtained and were then examined to identify any further relevant articles.ResultsThe majority of studies were retrospective. The systemic inflammatory response, as evidenced by a number of markers at clinical thresholds, was reported to have independent prognostic value, across tumour types and geographical locations. In particular, C-reactive protein (CRP, 63 studies), albumin (33 studies) the Glasgow Prognostic Score (GPS, 44 studies) and the Neutrophil Lymphocyte Ratio (NLR, 59 articles) were consistently validated across tumour types and geographical locations. There was considerable variation in the thresholds reported to have prognostic value when CRP and albumin were examined. There was less variation in the thresholds reported for NLR and still less for the GPS.DiscussionThe systemic inflammatory response, especially as evidenced by the GPS and NLR, has reliable prognostic value in patients with advanced cancer. Further prospective studies of their clinical utility in randomised clinical trials and in treatment allocation are warranted.



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Adiponectin: its role in obesity-associated colon and prostate cancers

Publication date: Available online 9 June 2017
Source:Critical Reviews in Oncology/Hematology
Author(s): Santoshi Muppala, Siva KP Konduru, Neha Merchant, Judy Ramsoondar, Carlos Karan Rampersad, Balney Rajitha, Vidya Mukund, Jyothsna Kancherla, Anthea Hammond, Tapan Kumar Barik, Mastan Mannarapu, Afroz Alam, Riyaz Basha, Pallavula Veera Bramhachari, Dheeraj Verma, Pinninti Santosh Sushma, Subasini Pattnaik, Ganji Purnachandra Nagaraju
Adipose tissue synthesizes many proteins and hormones collectively called adipokines, which are linked to a number of diseases, including cancer. Low levels of adiponectin are reported to be a risk factor for obesity-related cancers including colorectal and prostate cancers. Accordingly, obesity/lifestyle-related diseases, including certain cancers, may be treated by developing drugs that act specifically on adiponectin levels in circulation. Adiponectin may also serve as a clinical biomarker in obesity-related diseases. Adiponectin-based therapies are known to inhibit cancer advancement and thus may provide a therapeutic approach to delay cancer progression. Better understanding of the function of adiponectin is of great significance in the fight against cancer. This timely review is concentrated on the role of adiponectin and the impact of obesity on the development of cancers, especially colorectal and prostate cancers.



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BIOMARKERS OF RESPONSE TO PD-1/PD-L1 INHIBITION

Publication date: Available online 6 June 2017
Source:Critical Reviews in Oncology/Hematology
Author(s): Saman Maleki Vareki, Carmen Garrigós, Ignacio Duran
Immunotherapy is a promising treatment strategy for cancer that has recently shown unprecedented survival benefits in selected patients. A number of immunomodulatory agents that target immune system checkpoints such as the cytotoxic T-lymphocyte antigen 4 (CTLA-4), the programmed death-1 (PD-1) or its ligand (PD-L1), have received regulatory approval for the treatment of multiple cancers including malignant melanoma, non-small cell lung cancer, renal cell carcinoma, classical Hodgkin lymphoma, and recurrent or metastatic head and neck squamous cell carcinoma. Nevertheless, a substantial proportion of patients treated with checkpoint inhibitors have little or no benefit while these treatments are costly and might have associated toxicities. Hence, the establishment of valid predictors of treatment response has become a priority. This review summarizes the current evidence around biomarkers of response to PD-1/PD-L1 inhibition, considering features related to the tumor and to the host immune system.



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Editorial Board

Publication date: July 2017
Source:Critical Reviews in Oncology/Hematology, Volume 115





http://ift.tt/2sMHnTN

The role of the systemic inflammatory response in predicting outcomes in patients with advanced inoperable cancer: Systematic review and meta-analysis

Publication date: Available online 9 June 2017
Source:Critical Reviews in Oncology/Hematology
Author(s): Ross D Dolan, Stephen T McSorley, Paul G Horgan, Barry Laird, Donald C McMillan
IntroductionCancer remains a leading cause of death worldwide. While a curative intent is the aim of any surgical treatment many patients either present with or go onto develop disseminated disease requiring systemic anti-cancer therapy with a palliative intent. Given their limited life expectancy appropriate allocation of treatment is vital. It is recognised that systemic chemoradiotherapy may shorten the quality/quantity of life in patients with advanced cancer. It is against this background that the present systematic review and meta-analysis of the prognostic value of markers of the systemic inflammatory response in patients with advanced cancer was conducted.MethodsAn extensive literature review using targeted medical subject headings was carried out in the MEDLINE, EMBASE, and CDSR databases until the end of 2016. Titles were examined for relevance and studies relating to duplicate datasets, that were not published in English and that did not have full text availability were excluded. Full texts of relevant articles were obtained and were then examined to identify any further relevant articles.ResultsThe majority of studies were retrospective. The systemic inflammatory response, as evidenced by a number of markers at clinical thresholds, was reported to have independent prognostic value, across tumour types and geographical locations. In particular, C-reactive protein (CRP, 63 studies), albumin (33 studies) the Glasgow Prognostic Score (GPS, 44 studies) and the Neutrophil Lymphocyte Ratio (NLR, 59 articles) were consistently validated across tumour types and geographical locations. There was considerable variation in the thresholds reported to have prognostic value when CRP and albumin were examined. There was less variation in the thresholds reported for NLR and still less for the GPS.DiscussionThe systemic inflammatory response, especially as evidenced by the GPS and NLR, has reliable prognostic value in patients with advanced cancer. Further prospective studies of their clinical utility in randomised clinical trials and in treatment allocation are warranted.



http://ift.tt/2sdrDft

Adiponectin: its role in obesity-associated colon and prostate cancers

Publication date: Available online 9 June 2017
Source:Critical Reviews in Oncology/Hematology
Author(s): Santoshi Muppala, Siva KP Konduru, Neha Merchant, Judy Ramsoondar, Carlos Karan Rampersad, Balney Rajitha, Vidya Mukund, Jyothsna Kancherla, Anthea Hammond, Tapan Kumar Barik, Mastan Mannarapu, Afroz Alam, Riyaz Basha, Pallavula Veera Bramhachari, Dheeraj Verma, Pinninti Santosh Sushma, Subasini Pattnaik, Ganji Purnachandra Nagaraju
Adipose tissue synthesizes many proteins and hormones collectively called adipokines, which are linked to a number of diseases, including cancer. Low levels of adiponectin are reported to be a risk factor for obesity-related cancers including colorectal and prostate cancers. Accordingly, obesity/lifestyle-related diseases, including certain cancers, may be treated by developing drugs that act specifically on adiponectin levels in circulation. Adiponectin may also serve as a clinical biomarker in obesity-related diseases. Adiponectin-based therapies are known to inhibit cancer advancement and thus may provide a therapeutic approach to delay cancer progression. Better understanding of the function of adiponectin is of great significance in the fight against cancer. This timely review is concentrated on the role of adiponectin and the impact of obesity on the development of cancers, especially colorectal and prostate cancers.



http://ift.tt/2rb5QVL

BIOMARKERS OF RESPONSE TO PD-1/PD-L1 INHIBITION

Publication date: Available online 6 June 2017
Source:Critical Reviews in Oncology/Hematology
Author(s): Saman Maleki Vareki, Carmen Garrigós, Ignacio Duran
Immunotherapy is a promising treatment strategy for cancer that has recently shown unprecedented survival benefits in selected patients. A number of immunomodulatory agents that target immune system checkpoints such as the cytotoxic T-lymphocyte antigen 4 (CTLA-4), the programmed death-1 (PD-1) or its ligand (PD-L1), have received regulatory approval for the treatment of multiple cancers including malignant melanoma, non-small cell lung cancer, renal cell carcinoma, classical Hodgkin lymphoma, and recurrent or metastatic head and neck squamous cell carcinoma. Nevertheless, a substantial proportion of patients treated with checkpoint inhibitors have little or no benefit while these treatments are costly and might have associated toxicities. Hence, the establishment of valid predictors of treatment response has become a priority. This review summarizes the current evidence around biomarkers of response to PD-1/PD-L1 inhibition, considering features related to the tumor and to the host immune system.



http://ift.tt/2rVLInx

Development of 68Ga-SCN-DOTA-Capsaicin as an Imaging Agent Targeting Apoptosis and Cell Cycle Arrest in Breast Cancer

Cancer Biotherapy & Radiopharmaceuticals , Vol. 0, No. 0.


http://ift.tt/2s6W2eQ

Radioembolization for Unresectable Intrahepatic Cholangiocarcinoma: Review of Safety, Response Evaluation Criteria in Solid Tumors 1.1 Imaging Response and Survival

Cancer Biotherapy & Radiopharmaceuticals , Vol. 0, No. 0.


http://ift.tt/2t4D6uo

Development of 68Ga-SCN-DOTA-Capsaicin as an Imaging Agent Targeting Apoptosis and Cell Cycle Arrest in Breast Cancer

Cancer Biotherapy & Radiopharmaceuticals , Vol. 0, No. 0.


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Radioembolization for Unresectable Intrahepatic Cholangiocarcinoma: Review of Safety, Response Evaluation Criteria in Solid Tumors 1.1 Imaging Response and Survival

Cancer Biotherapy & Radiopharmaceuticals , Vol. 0, No. 0.


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Potential impact of the Affordable Care Act's preventive services provision on breast cancer stage: A preliminary assessment

Publication date: August 2017
Source:Cancer Epidemiology, Volume 49
Author(s): Abigail Silva, Yamile Molina, Bijou Hunt, Talar Marossian, Nazia Saiyed
IntroductionThe Affordable Care Act's (ACA) preventive services provision (PSP) removes copayments for preventive services such as cancer screening. We examined: 1) whether a shift in breast cancer stage occurred, and 2) the impact of the provision on racial/ethnic disparities in stage.Materials and methodsData from the National Cancer Database were used. The pre- and post-PSP periods were identified as 2007–2009 and 2011–2013, respectively. Proportion differences (PDs) and 95% confidence Intervals (CIs) were calculated.ResultsAll three racial/ethnic groups experienced a statistically significant shift toward Stage I breast cancer. Pre-PSP, the black:white disparity in Stage I cancer was −9.5 (95% CI: −8.9, −10.4) and the Latina:white disparity was −5.2 (95% CI: −4.0, −6.1). Post-PSP, the disparities improved slightly.DiscussionPreliminary data suggest that the ACA's PSP may have a meaningful impact on cancer stage overall and by race/ethnicity. However, more time may be needed to see reductions in disparities.



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Pollution and regional variations of lung cancer mortality in the United States

Publication date: August 2017
Source:Cancer Epidemiology, Volume 49
Author(s): Justin Xavier Moore, Tomi Akinyemiju, Henry E. Wang
IntroductionThe aims of this study were to identify counties in the United States (US) with high rates of lung cancer mortality, and to characterize the associated community-level factors while focusing on particulate-matter pollution.MethodsWe performed a descriptive analysis of lung cancer deaths in the US from 2004 through 2014. We categorized counties as "clustered" or "non-clustered" – based on whether or not they had high lung cancer mortality rates − using novel geospatial autocorrelation methods. We contrasted community characteristics between cluster categories. We performed logistic regression for the association between cluster category and particulate-matter pollution.ResultsAmong 362 counties (11.6%) categorized as clustered, the age-adjusted lung cancer mortality rate was 99.70 deaths per 100,000 persons (95%CI: 99.1–100.3). Compared with non-clustered counties, clustered counties were more likely in the south (72.9% versus 42.1%, P<0.01) and in non-urban communities (73.2% versus 57.4, P<0.01). Clustered counties had greater particulate-matter pollution, lower education and income, higher rates of obesity and physical inactivity, less access to healthcare, and greater unemployment rates (P<0.01). Higher levels of particulate-matter pollution (4th quartile versus 1st quartile) were associated with two-fold greater odds of being a clustered county (adjusted OR: 2.10; 95%CI: 1.23–3.59).ConclusionWe observed a belt of counties with high lung mortality ranging from eastern Oklahoma through central Appalachia; these counties were characterized by higher pollution, a more rural population, lower socioeconomic status and poorer access to healthcare. To mitigate the burden of lung cancer mortality in the US, both urban and rural areas should consider minimizing air pollution.



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Socioeconomic measures influence survival in osteosarcoma: an analysis of the National Cancer Data Base

Publication date: August 2017
Source:Cancer Epidemiology, Volume 49
Author(s): Benjamin J. Miller, Yubo Gao, Kyle R. Duchman
BackgroundWhile previous studies have identified low socioeconomic status as a risk factor for metastatic disease in patients with high-grade osteosarcoma, the influence of socioeconomic status on overall survival remains unclear. The present study aims to investigate the relationship between survival and socioeconomic status in patients with high-grade conventional osteosarcoma.MethodsThe National Cancer Data Base (NCDB) was queried from 1998-2012 to identify all patients <40years of age with a diagnosis of high-grade conventional osteosarcoma. A total of 3,503 patients were identified that met inclusion and exclusion criteria. Univariate relationships were investigated using Kaplan-Meier survival analysis and associated log-rank tests in order to determine patient, socioeconomic, tumor, and treatment variables associated with overall survival. Multivariate analysis was performed to determine independent predictors of survival.ResultsIn order of decreasing magnitude, metastatic disease (Hazard Ratio [HR] 3.28, 95% Confidence Interval [CI] 2.82-3.82), primary site in the pelvis or spine (HR 2.15, 95% CI 1.79-2.59), positive surgical margins (HR 1.82, 95% CI 1.46-2.27), tumor size >8cm (HR 1.47, 95% CI 1.24-1.74), age ≥18 years (HR 1.30, 95% CI 1.14-1.48), lowest quartile of composite socioeconomic status (HR 1.23, 95% CI 1.02-1.51), and Medicaid insurance (HR 1.18, 95% CI 1.02-1.38) were predictors of decreased survival at 5 years.ConclusionTreating providers should be aware that some of their patients may have challenges unrelated to their diagnosis that make timely presentation, adherence to treatment, and continued close surveillance difficult. This investigation suggests that socioeconomic variables influence overall survival for osteosarcoma in the United States, although not as dramatically as established tumor- and treatment-related risk factors.



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Potential impact of the Affordable Care Act's preventive services provision on breast cancer stage: A preliminary assessment

Publication date: August 2017
Source:Cancer Epidemiology, Volume 49
Author(s): Abigail Silva, Yamile Molina, Bijou Hunt, Talar Marossian, Nazia Saiyed
IntroductionThe Affordable Care Act's (ACA) preventive services provision (PSP) removes copayments for preventive services such as cancer screening. We examined: 1) whether a shift in breast cancer stage occurred, and 2) the impact of the provision on racial/ethnic disparities in stage.Materials and methodsData from the National Cancer Database were used. The pre- and post-PSP periods were identified as 2007–2009 and 2011–2013, respectively. Proportion differences (PDs) and 95% confidence Intervals (CIs) were calculated.ResultsAll three racial/ethnic groups experienced a statistically significant shift toward Stage I breast cancer. Pre-PSP, the black:white disparity in Stage I cancer was −9.5 (95% CI: −8.9, −10.4) and the Latina:white disparity was −5.2 (95% CI: −4.0, −6.1). Post-PSP, the disparities improved slightly.DiscussionPreliminary data suggest that the ACA's PSP may have a meaningful impact on cancer stage overall and by race/ethnicity. However, more time may be needed to see reductions in disparities.



http://ift.tt/2rLec59

Pollution and regional variations of lung cancer mortality in the United States

Publication date: August 2017
Source:Cancer Epidemiology, Volume 49
Author(s): Justin Xavier Moore, Tomi Akinyemiju, Henry E. Wang
IntroductionThe aims of this study were to identify counties in the United States (US) with high rates of lung cancer mortality, and to characterize the associated community-level factors while focusing on particulate-matter pollution.MethodsWe performed a descriptive analysis of lung cancer deaths in the US from 2004 through 2014. We categorized counties as "clustered" or "non-clustered" – based on whether or not they had high lung cancer mortality rates − using novel geospatial autocorrelation methods. We contrasted community characteristics between cluster categories. We performed logistic regression for the association between cluster category and particulate-matter pollution.ResultsAmong 362 counties (11.6%) categorized as clustered, the age-adjusted lung cancer mortality rate was 99.70 deaths per 100,000 persons (95%CI: 99.1–100.3). Compared with non-clustered counties, clustered counties were more likely in the south (72.9% versus 42.1%, P<0.01) and in non-urban communities (73.2% versus 57.4, P<0.01). Clustered counties had greater particulate-matter pollution, lower education and income, higher rates of obesity and physical inactivity, less access to healthcare, and greater unemployment rates (P<0.01). Higher levels of particulate-matter pollution (4th quartile versus 1st quartile) were associated with two-fold greater odds of being a clustered county (adjusted OR: 2.10; 95%CI: 1.23–3.59).ConclusionWe observed a belt of counties with high lung mortality ranging from eastern Oklahoma through central Appalachia; these counties were characterized by higher pollution, a more rural population, lower socioeconomic status and poorer access to healthcare. To mitigate the burden of lung cancer mortality in the US, both urban and rural areas should consider minimizing air pollution.



http://ift.tt/2rfzCUz

Socioeconomic measures influence survival in osteosarcoma: an analysis of the National Cancer Data Base

Publication date: August 2017
Source:Cancer Epidemiology, Volume 49
Author(s): Benjamin J. Miller, Yubo Gao, Kyle R. Duchman
BackgroundWhile previous studies have identified low socioeconomic status as a risk factor for metastatic disease in patients with high-grade osteosarcoma, the influence of socioeconomic status on overall survival remains unclear. The present study aims to investigate the relationship between survival and socioeconomic status in patients with high-grade conventional osteosarcoma.MethodsThe National Cancer Data Base (NCDB) was queried from 1998-2012 to identify all patients <40years of age with a diagnosis of high-grade conventional osteosarcoma. A total of 3,503 patients were identified that met inclusion and exclusion criteria. Univariate relationships were investigated using Kaplan-Meier survival analysis and associated log-rank tests in order to determine patient, socioeconomic, tumor, and treatment variables associated with overall survival. Multivariate analysis was performed to determine independent predictors of survival.ResultsIn order of decreasing magnitude, metastatic disease (Hazard Ratio [HR] 3.28, 95% Confidence Interval [CI] 2.82-3.82), primary site in the pelvis or spine (HR 2.15, 95% CI 1.79-2.59), positive surgical margins (HR 1.82, 95% CI 1.46-2.27), tumor size >8cm (HR 1.47, 95% CI 1.24-1.74), age ≥18 years (HR 1.30, 95% CI 1.14-1.48), lowest quartile of composite socioeconomic status (HR 1.23, 95% CI 1.02-1.51), and Medicaid insurance (HR 1.18, 95% CI 1.02-1.38) were predictors of decreased survival at 5 years.ConclusionTreating providers should be aware that some of their patients may have challenges unrelated to their diagnosis that make timely presentation, adherence to treatment, and continued close surveillance difficult. This investigation suggests that socioeconomic variables influence overall survival for osteosarcoma in the United States, although not as dramatically as established tumor- and treatment-related risk factors.



http://ift.tt/2rKU9DO

Development of 68Ga-SCN-DOTA-Capsaicin as an Imaging Agent Targeting Apoptosis and Cell Cycle Arrest in Breast Cancer

Cancer Biotherapy & Radiopharmaceuticals , Vol. 0, No. 0.


http://ift.tt/2s6W2eQ

Radioembolization for Unresectable Intrahepatic Cholangiocarcinoma: Review of Safety, Response Evaluation Criteria in Solid Tumors 1.1 Imaging Response and Survival

Cancer Biotherapy & Radiopharmaceuticals , Vol. 0, No. 0.


http://ift.tt/2t4D6uo

Ptosis as a complication of Kawasaki disease

Kawasaki disease is an acute febrile exanthematous disease that affects children younger than 5 years of age. It is regarded as the most common cause of childhood acquired heart disease, but ocular and neurological problems are among the other important clinical findings. We present a 3-year-old boy who developed bilateral ptosis on day 21, 5 days after intravenous immunoglobulin. The ptosis was due to bilateral paralysis of the levator palpebrae superioris muscles and resolved spontaneously on day 25. There were no cardiac sequelae.

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Extensive cutaneous involvement due to herpes simplex virus infection

Description

A 39-year-old woman, with a medical history of oligofrenia, obesity and varicella at 8 years of age, presented to the emergency department (ED) with multiple skin lesions of upper limb, which began with the appearance of vesicles, associated with intense pain and pruritus and with 3 days of evolution. No fever was reported. She was discharged home medicated with acyclovir and hydroxyzine.

Three days later, she returned to the ED with worsening complaints of pain and itching, and extension of cutaneous lesions throughout the body.

On physical examination, she was febrile (T: 38.5°C), with erythematous-pruriginous lesions, some of which were typically targeted, associated with numerous bullae dispersed throughout the body with oral mucosa involvement (figure 1A–C).

Figure 1

(A) Erythematous lesions associated with numerous bullae dispersed throughout the right upper limb. (B) Erythematous lesions associated with numerous bullae dispersed throughout the left upper limb. (C) Erythematous lesions some of which were...

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A rare case of Ludwigs angina after viper bite

Description

A previously healthy 20-year-old woman presented to our Accident and Emergency Department of Degehbur Hospital, a small district hospital in Somali region of Ethiopia, with complaints of rapidly progressive swelling in her neck and difficulty in swallowing for the past 2 days (figures 1 and 2). She was bitten by a snake, which was later identified as a viper, over her right lower jaw while sleeping on the floor. She did not seek any medical treatment until day 3 when the swelling became worse and involved both submandibular region and the tongue. She also complained of rapidly increase shortness of breath for the past 24 hours.

Figure 1

The patient presented to emergency department with severe swelling of her tongue, neck and submandibular area.

Figure 2

Lateral view of the patient showing severe submandibular swelling that obscuring the airway.

...

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Clinical implications of monitoring circulating tumor DNA in patients with colorectal cancer

Purpose: We investigated if detection of circulating tumor DNA (ctDNA) after resection of colorectal cancer (CRC) identifies the patients with the highest risk of relapse, and furthermore, whether longitudinal ctDNA analysis allows early detection of relapse and informs about response to intervention.<br /><br />Experimental Design: In this longitudinal cohort study we used massively parallel sequencing to identify somatic mutations and used these as ctDNA markers to detect minimal residual disease and to monitor changes in tumor burden during a three year follow-up period.<br /><br />Results: A total of 45 patients and 371 plasma samples were included. Longitudinal samples from 27 patients revealed ctDNA post-operatively in all relapsing patients (n=14), but not in any of the non-relapsing patients. ctDNA detected relapse with an average lead-time of 9.4 months compared to CT imaging. Of 21 patients treated for localized disease, six had ctDNA detected within 3 months post-surgery. All six later relapsed compared to four of the remaining patients (Hazard ratio (HR), 37.7, 95% confidence interval (CI), 4.2-335.5; P<0.001). The ability of a 3 month ctDNA analysis to predict relapse was confirmed in 23 liver metastasis patients (HR 4.9; 95%CI, 1.5-15.7; P=0.007). Changes in ctDNA levels induced by relapse intervention (n=19) showed good agreement with changes in tumor volume (Kappa=0.41, Spearman's rho=0.4).<br /><br />Conclusions: Postoperative ctDNA detection provides evidence of residual disease and identifies patients at very high risk of relapse. Longitudinal surveillance enables early detection of relapse and informs about response to intervention. These observations have implications for the post-operative management of CRC patients.

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Phase Ib study of lumretuzumab plus cetuximab or erlotinib in solid tumor patients and evaluation of HER3 and heregulin as potential biomarkers of clinical activity

Purpose: <br /> <p>This study investigated the safety, clinical activity and target-associated biomarkers of lumretuzumab, a humanized, glycoengineered, anti-HER3 monoclonal antibody (mAb), in combination with the EGFR-blocking agents erlotinib or cetuximab in patients with advanced HER3-positive carcinomas.</p> <br />Experimental Design: <br /> <p>The study included two parts: dose escalation and dose extension phases with lumretuzumab in combination with either cetuximab or erlotinib, respectively. In both parts, patients received lumretuzumab doses from 400 to 2000 mg plus cetuximab or erlotinib according to standard posology, respectively. The impact of HRG mRNA and HER3 mRNA and protein expression were investigated in a dedicated extension cohort of sqNSCLC patients treated with lumretuzumab and erlotinib.</p> <br />Results: <br /> <p>Altogether, 120 patients were treated. One dose-limiting toxicity (DLT) in the cetuximab part and 2 DLTs in the erlotinib part were reported. The most frequent adverse events (AEs) were gastrointestinal and skin toxicities, which were manageable. The objective response rate (ORR) was 6.1% in the cetuximab part and 4.2% in the erlotinib part. In the sqNSCLC extension cohort of the erlotinib part, higher tumor HRG and HER3 mRNA levels were associated with numerically higher disease control rate but not ORR.</p> <br />Conclusions:<br />The toxicity profile of lumretuzumab in combination with cetuximab and erlotinib was manageable but only modest clinical activity was observed across tumor types. In the sqNSCLC cohort, there was no evidence of meaningful clinical benefit despite enriching for tumors with higher HRG mRNA expression levels.

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miR-193a-3p is a key tumor suppressor in ulcerative colitis-associated colon cancer and promotes carcinogenesis through up-regulation of IL17RD

Purpose: Patients with ulcerative colitis (UC) are at increased risk for colorectal cancer, although mechanisms underlying neoplastic transformation are poorly understood. We sought to evaluate the role of microRNAs in neoplasia development in this high-risk population.   <p>Experimental Design: Tissue from 12 controls, 9 UC patients without neoplasia, and 11 UC patients with neoplasia was analyzed. miRNA array analysis was performed and select miRNAs assayed by real-time PCR on the discovery cohort and a validation cohort. DNA methylation of miR-193a was assessed. Following transfection of miR-193a-3p, proliferation, IL17RD expression, and luciferase activity of the 3'UTR of IL17RD were measured. Tumor growth in xenografts as well as EGFR signaling were assessed in HCT116 cells expressing IL17RD with either a mutant 3' untranslated region (UTR) or wild-type (WT) 3'UTR.</p> <p>Results: miR-31, miR-34a, miR-106b, and miR-193a-3p were significantly dysregulated in UC-neoplasia and adjacent tissue. Significant down-regulation of miR-193a-3p was also seen in an independent cohort of UC-cancers. Changes in methylation of miR-193a or expression of pri-miR-193a were not observed in UC-cancer. Transfection of miR-193a-3p resulted in decreased proliferation, and identified IL17RD as a direct target of miR-193a-3p. IL17RD expression was increased in UC-cancers, and miR-193a-3p treatment decreased growth and EGFR signaling of HCT116 cells in xenografts expressing both IL17RD with WT 3'UTR compared to cells expressing IL17RD with mutant 3'UTR.</p> <p>Conclusions: miR-193a-3p is down-regulated in UC-neoplasia, and its loss promotes carcinogenesis through up-regulation of IL17RD. These findings provide novel insight into inflammation-driven CRC and could suggest new therapeutic targets in this high-risk population.

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Targeting the Wnt pathway and cancer stem cells with anti-progastrin humanized antibodies: a major breakthrough for K-RAS mutated colorectal cancer treatment

Purpose: <p>Patients with metastatic colorectal cancer (CRC) suffer from disease relapse mainly due to cancer stem cells (CSC). Interestingly, they have an increased level of blood progastrin, a tumor-promoting peptide essential for the self-renewal of colon CSCs, which is also a direct b-catenin/Tcf4 target gene. In this study we aimed to develop a novel targeted therapy to neutralize secreted progastrin in order to inhibit Wnt signaling, CSCs and reduce relapses.</p> Experimental Design: <p>Antibodies (monoclonal and humanized) directed against progastrin were produced and selected for target specificity and affinity. After validation of their effectiveness on survival of CRC cell lines harboring B-RAF or K-RAS mutations, their efficacy was assessed in vitro and in vivo, alone or concomitantly with chemotherapy, on CSCs self-renewal capacity, tumor recurrence and Wnt signaling.</p> Results: <p>We show that anti-progastrin antibodies decrease self-renewal of CSCs both in vitro and in vivo, either alone or in combination with chemotherapy. Furthermore, migration and invasion of CRC cells are diminished; chemosensitivity is prolonged in SW620 and HT29 cells and post-treatment relapse is significantly delayed in T84 cells, xenografted nude mice. Finally, we show that the Wnt signaling activity in vitro is decreased, and, in transgenic mice developing Wnt-driven intestinal neoplasia, the tumor burden is alleviated, with an amplification of cell differentiation in the remaining tumors.</p> Conclusions:<br /><br />All together, these data show that humanized anti-progastrin antibodies might represent a potential new treatment for K-RAS mutated colorectal patients, for which there is a crucial unmet medical need.

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Use of Angiotensin System Inhibitors is Associated with Immune Activation and Longer Survival in Non-Metastatic Pancreatic Ductal Adenocarcinoma

Purpose: Angiotensin system inhibitors (ASIs) can improve prognosis in multiple cancer types, including pancreatic ductal adenocarcinoma (PDAC). However, no study has examined the effect of ASIs alone or combined with adjuvant chemotherapy in resected PDAC patients.<br /><br />Experimental Design: We performed an analysis of the records of ASI users and non-user patients with PDAC seen at Massachusetts General Hospital between January 2006 and December 2010. To identify mechanisms of ASIs in PDAC, we performed RNA-Seq of resected primary lesions. <br /><br />Results: 794 consecutive patients were included. In 299 resected patients, ASI-users experienced longer overall survival (OS) in both univariate (median OS: 36.3 vs. 19.3 months, p=0.011) and adjusted multivariate (HR, 0.505; 95%CI, 0.339 - 0.750; p=0.001) analyses. Propensity score adjusted analysis also showed a longer median OS for chronic ASI-users. In unresected patients, the beneficial effect of ASIs was significant in patients with locally advanced disease, but not in metastatic patients. RNA-Seq analysis revealed in tumors of ASI-users (lisinopril) a normalized extracellular matrix, a reduced expression of genes involved in PDAC progression (e.g. WNT and Notch signaling) and an increased expression of genes linked with the activity of T cells and antigen-presenting cells. Finally, chronic use of ASI was associated with a gene expression signature which is predictive of survival in independent validation cohorts.<br /><br />Conclusions: In patients with non-metastatic PDAC, chronic ASI use is associated with longer OS independently of chemotherapy. Our RNA-Seq analysis suggests that ASI reduce the malignant potential of cancer cells and stimulate the immune microenvironment in primary PDAC.

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TRABECTEDIN OVERRIDES OSTEOSARCOMA DIFFERENTIATIVE BLOCK AND REPROGRAMS THE TUMOR IMMUNE ENVIRONMENT ENABLING EFFECTIVE COMBINATION WITH IMMUNE CHECKPOINT INHIBITORS

Purpose: Osteosarcoma (OS), the most common primary bone tumor, is characterized by an aggressive behavior with high tendency to develop lung metastases as well as by multiple genetic aberrations that have hindered the development of targeted therapies. New therapeutic approaches are urgently needed; however, novel combinations with immunotherapies and checkpoint inhibitors require suitable preclinical models with intact immune systems to be properly tested. <p>Experimental Design: We have developed immuno-competent OS models that grow orthotopically in the bone and spontaneously metastasize to the lungs, mimicking human OS. These models have been used to test the efficacy of trabectedin, a chemotherapeutic drug utilized clinically for sarcomas and ovarian cancer.</p> <p>Results: Trabectedin, as monotherapy, significantly inhibited OS primary tumor growth and lung metastases by both targeting neoplastic cells and reprogramming the tumor immune microenvironment. Specifically, trabectedin induced a striking differentiation of tumor cells by favoring the recruitment of Runx2, the master genetic regulator of osteoblastogenesis, on the promoter of genes involved in the physiologic process of terminal osteoblast differentiation. Differentiated neoplastic cells, as expected, showed reduced proliferation rate. Concomitantly, trabectedin enhanced the number of tumor-infiltrating T lymphocytes, with local CD8 T cells, however, likely post-activated or exhausted, as suggested by their high expression of the inhibitory checkpoint molecule PD-1. Accordingly, the combination with a PD-1-blocking antibody significantly increased trabectedin efficacy in controlling OS progression.</p> <p>Conclusion: These results demonstrate the therapeutic efficacy of trabectedin in OS treatment, unveiling its multiple activities and providing a solid rationale for its combination with immune checkpoint inhibitors.

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Dual Inhibition of HDAC and tyrosine kinase signaling pathways with CUDC-907 inhibits thyroid cancer growth and metastases

PURPOSE: There is currently no standard therapy for anaplastic thyroid cancer (ATC) and poorly differentiated thyroid cancer (PDTC), which account for two-thirds of thyroid cancer deaths. Driver mutations in the PI3K/AKT and RAF/RAS/MEK/ERK pathways are common in ATC and PDTC. Histone deacetylases (HDACs) regulate cancer initiation and progression. Our aim was to determine the therapeutic efficacy of simultaneously targeting these pathways in thyroid cancer with a single agent, and to evaluate biomarkers of treatment response. <p>EXPERIMENTAL DESIGN: CUDC-907 is a first-in-class compound, functioning as a dual inhibitor of HDACs and the PI3K/AKT pathway. We investigated its anti-proliferative effect in vitro and in vivo.</p> <p>RESULTS: CUDC-907 significantly inhibited cellular proliferation in thyroid cancer cell lines, induced G2/M arrest with decreased levels of the checkpoint regulators cyclin B1, AURKA, AURKB, PLK1, and increased p21 and p27. Treatment induced apoptosis with increased caspase 3/7 activity and decreased survivin levels, and decreased cellular migration and invasion.  CUDC-907 treatment caused H3 hyperacetylation and decreased HDAC2 expression. HDAC2 was upregulated in ATC and other thyroid cancer histologic subtypes. CUDC-907 treatment reduced both p-AKT and p-ERK1/2 levels. Lastly, CUDC-907 treatment, in a metastatic mouse model of thyroid cancer, showed significant inhibition of growth and metastases, and tumors from treated mice had decreased HDAC2 expression, suggesting that this may be a useful biomarker of response.</p> <p>CONCLUSIONS: Dual inhibition of HDAC and the tyrosine kinase signaling pathways with CUDC-907 is a promising treatment strategy for advanced, metastatic thyroid cancer.

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Human Papillomavirus DNA methylation predicts response to treatment using cidofovir and imiquimod in Vulval Intraepithelial Neoplasia 3

Purpose <p>Response rates to treatment of vulval intraepithelial neoplasia (VIN) with imiquimod and cidofovir are approximately 57% and 61% respectively. Treatment is associated with significant side effects and, if ineffective, risk of malignant progression. Treatment response is not predicted by clinical factors. Identification of a biomarker that could predict response is an attractive prospect. This work investigated HPV DNA methylation as a potential predictive biomarker in this setting.</p> <p>Experimental design</p> <p>DNA from 167 cases of VIN 3 from the RT3 VIN clinical trial was assessed. HPV positive cases were identified using: Greiner PapilloCheck and HPV 16 type-specific PCR. HPV DNA methylation status was assessed in three viral regions: E2, L1/L2, and the promoter, using pyrosequencing.</p> <p>Results</p> <p>Methylation of the HPV E2 region was associated with response to treatment. For cidofovir (n=30), median E2 methylation was significantly higher in patients who responded (p = <0.0001); E2 methylation >4% predicted response with 88.2% sensitivity and 84.6% specificity. For imiquimod (n=33), median E2 methylation was lower in patients who responded to treatment (p = 0.03 (not significant after Bonferroni correction)); E2 methylation <4% predicted response with 70.6% sensitivity and 62.5% specificity.</p> <p>Conclusions</p> <p>These data indicate that cidofovir and imiquimod may be effective in two biologically defined groups. HPV E2 DNA methylation demonstrated potential as a predictive biomarker for the treatment of VIN with cidofovir and may warrant investigation in a biomarker-guided clinical trial.

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Precision Medicine in Pediatric Oncology: Translating Genomic Discoveries into Optimized Therapies

Survival of children with cancers has dramatically improved over the past several decades.  This success has been achieved through improvement of combined modalities in treatment approaches, intensification of cytotoxic chemotherapy for those with high-risk disease and refinement of risk stratification incorporating novel biologic markers in addition to traditional clinical and histologic features. Advances in cancer genomics have shed important mechanistic insights on disease biology and have identified "driver" genomic alterations, aberrant activation of signaling pathways, and epigenetic modifiers that can be targeted by novel agents.  Thus, the recently described genomic and epigenetic landscapes of many childhood cancers have expanded the paradigm of precision medicine in the hopes of improving outcomes while minimizing toxicities.  In this review, we will discuss the biologic rationale for molecularly targeted therapies in genomically-defined subsets of pediatric leukemias, solid tumors, and brain tumors.

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Clinical implications of monitoring circulating tumor DNA in patients with colorectal cancer

Purpose: We investigated if detection of circulating tumor DNA (ctDNA) after resection of colorectal cancer (CRC) identifies the patients with the highest risk of relapse, and furthermore, whether longitudinal ctDNA analysis allows early detection of relapse and informs about response to intervention.<br /><br />Experimental Design: In this longitudinal cohort study we used massively parallel sequencing to identify somatic mutations and used these as ctDNA markers to detect minimal residual disease and to monitor changes in tumor burden during a three year follow-up period.<br /><br />Results: A total of 45 patients and 371 plasma samples were included. Longitudinal samples from 27 patients revealed ctDNA post-operatively in all relapsing patients (n=14), but not in any of the non-relapsing patients. ctDNA detected relapse with an average lead-time of 9.4 months compared to CT imaging. Of 21 patients treated for localized disease, six had ctDNA detected within 3 months post-surgery. All six later relapsed compared to four of the remaining patients (Hazard ratio (HR), 37.7, 95% confidence interval (CI), 4.2-335.5; P<0.001). The ability of a 3 month ctDNA analysis to predict relapse was confirmed in 23 liver metastasis patients (HR 4.9; 95%CI, 1.5-15.7; P=0.007). Changes in ctDNA levels induced by relapse intervention (n=19) showed good agreement with changes in tumor volume (Kappa=0.41, Spearman's rho=0.4).<br /><br />Conclusions: Postoperative ctDNA detection provides evidence of residual disease and identifies patients at very high risk of relapse. Longitudinal surveillance enables early detection of relapse and informs about response to intervention. These observations have implications for the post-operative management of CRC patients.

http://ift.tt/2r4bdlr

Phase Ib study of lumretuzumab plus cetuximab or erlotinib in solid tumor patients and evaluation of HER3 and heregulin as potential biomarkers of clinical activity

Purpose: <br /> <p>This study investigated the safety, clinical activity and target-associated biomarkers of lumretuzumab, a humanized, glycoengineered, anti-HER3 monoclonal antibody (mAb), in combination with the EGFR-blocking agents erlotinib or cetuximab in patients with advanced HER3-positive carcinomas.</p> <br />Experimental Design: <br /> <p>The study included two parts: dose escalation and dose extension phases with lumretuzumab in combination with either cetuximab or erlotinib, respectively. In both parts, patients received lumretuzumab doses from 400 to 2000 mg plus cetuximab or erlotinib according to standard posology, respectively. The impact of HRG mRNA and HER3 mRNA and protein expression were investigated in a dedicated extension cohort of sqNSCLC patients treated with lumretuzumab and erlotinib.</p> <br />Results: <br /> <p>Altogether, 120 patients were treated. One dose-limiting toxicity (DLT) in the cetuximab part and 2 DLTs in the erlotinib part were reported. The most frequent adverse events (AEs) were gastrointestinal and skin toxicities, which were manageable. The objective response rate (ORR) was 6.1% in the cetuximab part and 4.2% in the erlotinib part. In the sqNSCLC extension cohort of the erlotinib part, higher tumor HRG and HER3 mRNA levels were associated with numerically higher disease control rate but not ORR.</p> <br />Conclusions:<br />The toxicity profile of lumretuzumab in combination with cetuximab and erlotinib was manageable but only modest clinical activity was observed across tumor types. In the sqNSCLC cohort, there was no evidence of meaningful clinical benefit despite enriching for tumors with higher HRG mRNA expression levels.

http://ift.tt/2snMtIL

miR-193a-3p is a key tumor suppressor in ulcerative colitis-associated colon cancer and promotes carcinogenesis through up-regulation of IL17RD

Purpose: Patients with ulcerative colitis (UC) are at increased risk for colorectal cancer, although mechanisms underlying neoplastic transformation are poorly understood. We sought to evaluate the role of microRNAs in neoplasia development in this high-risk population.   <p>Experimental Design: Tissue from 12 controls, 9 UC patients without neoplasia, and 11 UC patients with neoplasia was analyzed. miRNA array analysis was performed and select miRNAs assayed by real-time PCR on the discovery cohort and a validation cohort. DNA methylation of miR-193a was assessed. Following transfection of miR-193a-3p, proliferation, IL17RD expression, and luciferase activity of the 3'UTR of IL17RD were measured. Tumor growth in xenografts as well as EGFR signaling were assessed in HCT116 cells expressing IL17RD with either a mutant 3' untranslated region (UTR) or wild-type (WT) 3'UTR.</p> <p>Results: miR-31, miR-34a, miR-106b, and miR-193a-3p were significantly dysregulated in UC-neoplasia and adjacent tissue. Significant down-regulation of miR-193a-3p was also seen in an independent cohort of UC-cancers. Changes in methylation of miR-193a or expression of pri-miR-193a were not observed in UC-cancer. Transfection of miR-193a-3p resulted in decreased proliferation, and identified IL17RD as a direct target of miR-193a-3p. IL17RD expression was increased in UC-cancers, and miR-193a-3p treatment decreased growth and EGFR signaling of HCT116 cells in xenografts expressing both IL17RD with WT 3'UTR compared to cells expressing IL17RD with mutant 3'UTR.</p> <p>Conclusions: miR-193a-3p is down-regulated in UC-neoplasia, and its loss promotes carcinogenesis through up-regulation of IL17RD. These findings provide novel insight into inflammation-driven CRC and could suggest new therapeutic targets in this high-risk population.

http://ift.tt/2r467py

Targeting the Wnt pathway and cancer stem cells with anti-progastrin humanized antibodies: a major breakthrough for K-RAS mutated colorectal cancer treatment

Purpose: <p>Patients with metastatic colorectal cancer (CRC) suffer from disease relapse mainly due to cancer stem cells (CSC). Interestingly, they have an increased level of blood progastrin, a tumor-promoting peptide essential for the self-renewal of colon CSCs, which is also a direct b-catenin/Tcf4 target gene. In this study we aimed to develop a novel targeted therapy to neutralize secreted progastrin in order to inhibit Wnt signaling, CSCs and reduce relapses.</p> Experimental Design: <p>Antibodies (monoclonal and humanized) directed against progastrin were produced and selected for target specificity and affinity. After validation of their effectiveness on survival of CRC cell lines harboring B-RAF or K-RAS mutations, their efficacy was assessed in vitro and in vivo, alone or concomitantly with chemotherapy, on CSCs self-renewal capacity, tumor recurrence and Wnt signaling.</p> Results: <p>We show that anti-progastrin antibodies decrease self-renewal of CSCs both in vitro and in vivo, either alone or in combination with chemotherapy. Furthermore, migration and invasion of CRC cells are diminished; chemosensitivity is prolonged in SW620 and HT29 cells and post-treatment relapse is significantly delayed in T84 cells, xenografted nude mice. Finally, we show that the Wnt signaling activity in vitro is decreased, and, in transgenic mice developing Wnt-driven intestinal neoplasia, the tumor burden is alleviated, with an amplification of cell differentiation in the remaining tumors.</p> Conclusions:<br /><br />All together, these data show that humanized anti-progastrin antibodies might represent a potential new treatment for K-RAS mutated colorectal patients, for which there is a crucial unmet medical need.

http://ift.tt/2sn9BY8

Use of Angiotensin System Inhibitors is Associated with Immune Activation and Longer Survival in Non-Metastatic Pancreatic Ductal Adenocarcinoma

Purpose: Angiotensin system inhibitors (ASIs) can improve prognosis in multiple cancer types, including pancreatic ductal adenocarcinoma (PDAC). However, no study has examined the effect of ASIs alone or combined with adjuvant chemotherapy in resected PDAC patients.<br /><br />Experimental Design: We performed an analysis of the records of ASI users and non-user patients with PDAC seen at Massachusetts General Hospital between January 2006 and December 2010. To identify mechanisms of ASIs in PDAC, we performed RNA-Seq of resected primary lesions. <br /><br />Results: 794 consecutive patients were included. In 299 resected patients, ASI-users experienced longer overall survival (OS) in both univariate (median OS: 36.3 vs. 19.3 months, p=0.011) and adjusted multivariate (HR, 0.505; 95%CI, 0.339 - 0.750; p=0.001) analyses. Propensity score adjusted analysis also showed a longer median OS for chronic ASI-users. In unresected patients, the beneficial effect of ASIs was significant in patients with locally advanced disease, but not in metastatic patients. RNA-Seq analysis revealed in tumors of ASI-users (lisinopril) a normalized extracellular matrix, a reduced expression of genes involved in PDAC progression (e.g. WNT and Notch signaling) and an increased expression of genes linked with the activity of T cells and antigen-presenting cells. Finally, chronic use of ASI was associated with a gene expression signature which is predictive of survival in independent validation cohorts.<br /><br />Conclusions: In patients with non-metastatic PDAC, chronic ASI use is associated with longer OS independently of chemotherapy. Our RNA-Seq analysis suggests that ASI reduce the malignant potential of cancer cells and stimulate the immune microenvironment in primary PDAC.

http://ift.tt/2r4HcSw

TRABECTEDIN OVERRIDES OSTEOSARCOMA DIFFERENTIATIVE BLOCK AND REPROGRAMS THE TUMOR IMMUNE ENVIRONMENT ENABLING EFFECTIVE COMBINATION WITH IMMUNE CHECKPOINT INHIBITORS

Purpose: Osteosarcoma (OS), the most common primary bone tumor, is characterized by an aggressive behavior with high tendency to develop lung metastases as well as by multiple genetic aberrations that have hindered the development of targeted therapies. New therapeutic approaches are urgently needed; however, novel combinations with immunotherapies and checkpoint inhibitors require suitable preclinical models with intact immune systems to be properly tested. <p>Experimental Design: We have developed immuno-competent OS models that grow orthotopically in the bone and spontaneously metastasize to the lungs, mimicking human OS. These models have been used to test the efficacy of trabectedin, a chemotherapeutic drug utilized clinically for sarcomas and ovarian cancer.</p> <p>Results: Trabectedin, as monotherapy, significantly inhibited OS primary tumor growth and lung metastases by both targeting neoplastic cells and reprogramming the tumor immune microenvironment. Specifically, trabectedin induced a striking differentiation of tumor cells by favoring the recruitment of Runx2, the master genetic regulator of osteoblastogenesis, on the promoter of genes involved in the physiologic process of terminal osteoblast differentiation. Differentiated neoplastic cells, as expected, showed reduced proliferation rate. Concomitantly, trabectedin enhanced the number of tumor-infiltrating T lymphocytes, with local CD8 T cells, however, likely post-activated or exhausted, as suggested by their high expression of the inhibitory checkpoint molecule PD-1. Accordingly, the combination with a PD-1-blocking antibody significantly increased trabectedin efficacy in controlling OS progression.</p> <p>Conclusion: These results demonstrate the therapeutic efficacy of trabectedin in OS treatment, unveiling its multiple activities and providing a solid rationale for its combination with immune checkpoint inhibitors.

http://ift.tt/2snRCkb

Dual Inhibition of HDAC and tyrosine kinase signaling pathways with CUDC-907 inhibits thyroid cancer growth and metastases

PURPOSE: There is currently no standard therapy for anaplastic thyroid cancer (ATC) and poorly differentiated thyroid cancer (PDTC), which account for two-thirds of thyroid cancer deaths. Driver mutations in the PI3K/AKT and RAF/RAS/MEK/ERK pathways are common in ATC and PDTC. Histone deacetylases (HDACs) regulate cancer initiation and progression. Our aim was to determine the therapeutic efficacy of simultaneously targeting these pathways in thyroid cancer with a single agent, and to evaluate biomarkers of treatment response. <p>EXPERIMENTAL DESIGN: CUDC-907 is a first-in-class compound, functioning as a dual inhibitor of HDACs and the PI3K/AKT pathway. We investigated its anti-proliferative effect in vitro and in vivo.</p> <p>RESULTS: CUDC-907 significantly inhibited cellular proliferation in thyroid cancer cell lines, induced G2/M arrest with decreased levels of the checkpoint regulators cyclin B1, AURKA, AURKB, PLK1, and increased p21 and p27. Treatment induced apoptosis with increased caspase 3/7 activity and decreased survivin levels, and decreased cellular migration and invasion.  CUDC-907 treatment caused H3 hyperacetylation and decreased HDAC2 expression. HDAC2 was upregulated in ATC and other thyroid cancer histologic subtypes. CUDC-907 treatment reduced both p-AKT and p-ERK1/2 levels. Lastly, CUDC-907 treatment, in a metastatic mouse model of thyroid cancer, showed significant inhibition of growth and metastases, and tumors from treated mice had decreased HDAC2 expression, suggesting that this may be a useful biomarker of response.</p> <p>CONCLUSIONS: Dual inhibition of HDAC and the tyrosine kinase signaling pathways with CUDC-907 is a promising treatment strategy for advanced, metastatic thyroid cancer.

http://ift.tt/2r4jOES

Human Papillomavirus DNA methylation predicts response to treatment using cidofovir and imiquimod in Vulval Intraepithelial Neoplasia 3

Purpose <p>Response rates to treatment of vulval intraepithelial neoplasia (VIN) with imiquimod and cidofovir are approximately 57% and 61% respectively. Treatment is associated with significant side effects and, if ineffective, risk of malignant progression. Treatment response is not predicted by clinical factors. Identification of a biomarker that could predict response is an attractive prospect. This work investigated HPV DNA methylation as a potential predictive biomarker in this setting.</p> <p>Experimental design</p> <p>DNA from 167 cases of VIN 3 from the RT3 VIN clinical trial was assessed. HPV positive cases were identified using: Greiner PapilloCheck and HPV 16 type-specific PCR. HPV DNA methylation status was assessed in three viral regions: E2, L1/L2, and the promoter, using pyrosequencing.</p> <p>Results</p> <p>Methylation of the HPV E2 region was associated with response to treatment. For cidofovir (n=30), median E2 methylation was significantly higher in patients who responded (p = <0.0001); E2 methylation >4% predicted response with 88.2% sensitivity and 84.6% specificity. For imiquimod (n=33), median E2 methylation was lower in patients who responded to treatment (p = 0.03 (not significant after Bonferroni correction)); E2 methylation <4% predicted response with 70.6% sensitivity and 62.5% specificity.</p> <p>Conclusions</p> <p>These data indicate that cidofovir and imiquimod may be effective in two biologically defined groups. HPV E2 DNA methylation demonstrated potential as a predictive biomarker for the treatment of VIN with cidofovir and may warrant investigation in a biomarker-guided clinical trial.

http://ift.tt/2sn9An2

Precision Medicine in Pediatric Oncology: Translating Genomic Discoveries into Optimized Therapies

Survival of children with cancers has dramatically improved over the past several decades.  This success has been achieved through improvement of combined modalities in treatment approaches, intensification of cytotoxic chemotherapy for those with high-risk disease and refinement of risk stratification incorporating novel biologic markers in addition to traditional clinical and histologic features. Advances in cancer genomics have shed important mechanistic insights on disease biology and have identified "driver" genomic alterations, aberrant activation of signaling pathways, and epigenetic modifiers that can be targeted by novel agents.  Thus, the recently described genomic and epigenetic landscapes of many childhood cancers have expanded the paradigm of precision medicine in the hopes of improving outcomes while minimizing toxicities.  In this review, we will discuss the biologic rationale for molecularly targeted therapies in genomically-defined subsets of pediatric leukemias, solid tumors, and brain tumors.

http://ift.tt/2r4wZ8L

The Structure of ABCG2 Provides Insight into Multidrug Resistance [Research Watch]

The ABCG2 structure reveals the multidrug-binding pocket and suggests a multidrug transport mechanism.

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BCR Loss Reduces the Fitness of MYC-Driven Lymphoma Cells [Research Watch]

BCR-proficient lymphoma cells exhibit a competitive growth advantage in vitro and in vivo.

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Alectinib Superior to Crizotinib for ALK+ NSCLC [News in Brief]

Next-generation ALK inhibitor more than doubles progression-free survival, reduces brain and CNS metastases.

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Loss of Vhl, Trp53, and Rb1 Induces Clear Cell Renal Carcinoma in Mice [Research Watch]

An autochthonous mouse model of clear cell renal cell carcinoma (ccRCC) recapitulates the human disease.

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Aldehydes Promote BRCA2 Haploinsufficiency and Genomic Instability [Research Watch]

Inherited BRCA2 mutations promote genome instability via aldehyde-induced BRCA2 degradation.

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Biallelic Mutations in TRIP13 Increase the Risk of Wilms Tumor [Research Watch]

Mutations resulting in loss of TRIP13 expression induce chromosome missegregation and SAC impairment.

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Predicting Future Major Depression and Persistent Depressive Symptoms: Development of a Prognostic Screener and PHQ4 cutoffs in Breast Cancer Patients

Abstract

Objective

Create a brief, self-report screener for recently diagnosed breast cancer patients to identify patients at risk of future depression.

Methods

Breast cancer patients (N = 410) within 2 ± 1 months after diagnosis provided data on depression vulnerability (DV). Depression outcomes were defined as a high depressive symptom trajectory or a major depressive episode during 16 months after diagnosis. Stochastic gradient boosting of regression trees identified seven items highly predictive for the depression outcomes from a pool of 219 candidate DV items. Three of the seven items were from the PHQ-4, a validated screener for current anxiety/depressive disorder that has not been tested to identify risk for future depression. Thresholds classifying patients as high or low risk on the new Depression Risk Questionnaire-7 (DRQ-7) and the PHQ-4 were obtained. Predictive performance of the DRQ-7 and PHQ-4 was assessed on a holdout validation subsample.

Findings

DRQ-7 items assess loneliness, irritability, persistent sadness, and low acceptance of emotion as well as three items from the PHQ-4 (anhedonia, depressed mood, worry). A DRQ-7 score of >6/23 identified depression outcomes with 0.73 specificity, 0.83 sensitivity, 0.68 PPV and 0.86 NPV. A PHQ-4 score of >3/12 performed moderately well but less accurately than the DRQ-7 (net reclassification improvement =10%; 95% CI [0.5 – 16]).

Interpretation

The DRQ-7, and the PHQ-4 with a new cutoff score, are clinically accessible screeners for risk of depression in newly diagnosed breast cancer patients. Use to select patients for preventive interventions awaits validation of the screener in other samples.

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Rates and Predictors of Psychotherapy Utilization after Psychosocial Evaluation for Stem Cell Transplant

Abstract

Objective

Although standard of care prior to hematopoietic stem cell transplantation (HSCT) includes a psychosocial evaluation, little is known about the rate and predictors of psychotherapy utilization among patients presenting for pre-HSCT evaluations. This study aimed to examine the proportion of patients undergoing pre-HSCT evaluations who subsequently utilize psychotherapy services and to explore predictive factors, including distress, anxiety, depression and quality of life (QoL).

Methods

Participants were a cross-sectional sample of 351 HSCT candidates at a NCI-designated comprehensive cancer center. Questionnaires assessing distress, anxiety, depression and quality of life (QoL) were administered using validated instruments.

Results

A subset of patients, representing 14% of the sample, utilized psychotherapy services. Relative to patients who did not utilize psychological services, patients who followed-up with psychotherapy reported significantly more depressive and anxious symptoms (ps < .001), and endorsed worse QoL on the FACT-G. (p = .04). Of note, a subset of patients who utilized psychotherapy services reported low levels of distress (67%), depression (13%), or anxiety (13%); on the other hand, a subset of patients reported moderate-to-high levels of distress (25%), depression (71%), or anxiety (60%) but did not utilize services.

Conclusions

Results indicate that only a small subset of patients presenting for pre-HSCT psychosocial evaluation subsequently utilized psychotherapy services. Most patients who reported psychosocial concerns and who could potentially benefit from intervention did not use psychotherapy services. Further research is necessary to help clarify barriers to psychotherapy service utilization among HSCT patients and to help improve uptake among high-need patients.

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Predicting Future Major Depression and Persistent Depressive Symptoms: Development of a Prognostic Screener and PHQ4 cutoffs in Breast Cancer Patients

Abstract

Objective

Create a brief, self-report screener for recently diagnosed breast cancer patients to identify patients at risk of future depression.

Methods

Breast cancer patients (N = 410) within 2 ± 1 months after diagnosis provided data on depression vulnerability (DV). Depression outcomes were defined as a high depressive symptom trajectory or a major depressive episode during 16 months after diagnosis. Stochastic gradient boosting of regression trees identified seven items highly predictive for the depression outcomes from a pool of 219 candidate DV items. Three of the seven items were from the PHQ-4, a validated screener for current anxiety/depressive disorder that has not been tested to identify risk for future depression. Thresholds classifying patients as high or low risk on the new Depression Risk Questionnaire-7 (DRQ-7) and the PHQ-4 were obtained. Predictive performance of the DRQ-7 and PHQ-4 was assessed on a holdout validation subsample.

Findings

DRQ-7 items assess loneliness, irritability, persistent sadness, and low acceptance of emotion as well as three items from the PHQ-4 (anhedonia, depressed mood, worry). A DRQ-7 score of >6/23 identified depression outcomes with 0.73 specificity, 0.83 sensitivity, 0.68 PPV and 0.86 NPV. A PHQ-4 score of >3/12 performed moderately well but less accurately than the DRQ-7 (net reclassification improvement =10%; 95% CI [0.5 – 16]).

Interpretation

The DRQ-7, and the PHQ-4 with a new cutoff score, are clinically accessible screeners for risk of depression in newly diagnosed breast cancer patients. Use to select patients for preventive interventions awaits validation of the screener in other samples.

http://ift.tt/2rVHVXu

Rates and Predictors of Psychotherapy Utilization after Psychosocial Evaluation for Stem Cell Transplant

Abstract

Objective

Although standard of care prior to hematopoietic stem cell transplantation (HSCT) includes a psychosocial evaluation, little is known about the rate and predictors of psychotherapy utilization among patients presenting for pre-HSCT evaluations. This study aimed to examine the proportion of patients undergoing pre-HSCT evaluations who subsequently utilize psychotherapy services and to explore predictive factors, including distress, anxiety, depression and quality of life (QoL).

Methods

Participants were a cross-sectional sample of 351 HSCT candidates at a NCI-designated comprehensive cancer center. Questionnaires assessing distress, anxiety, depression and quality of life (QoL) were administered using validated instruments.

Results

A subset of patients, representing 14% of the sample, utilized psychotherapy services. Relative to patients who did not utilize psychological services, patients who followed-up with psychotherapy reported significantly more depressive and anxious symptoms (ps < .001), and endorsed worse QoL on the FACT-G. (p = .04). Of note, a subset of patients who utilized psychotherapy services reported low levels of distress (67%), depression (13%), or anxiety (13%); on the other hand, a subset of patients reported moderate-to-high levels of distress (25%), depression (71%), or anxiety (60%) but did not utilize services.

Conclusions

Results indicate that only a small subset of patients presenting for pre-HSCT psychosocial evaluation subsequently utilized psychotherapy services. Most patients who reported psychosocial concerns and who could potentially benefit from intervention did not use psychotherapy services. Further research is necessary to help clarify barriers to psychotherapy service utilization among HSCT patients and to help improve uptake among high-need patients.

http://ift.tt/2raTSvg

The Use of Intracranial Doppler as a Cause for Intraoperative Hyperthermia

No abstract available

http://ift.tt/2sdfYNL

Effects of an Intraoperative Dexmedetomidine Bolus on the Postoperative Blood Pressure and Pain Subsequent to Craniotomy for Supratentorial Tumors

Background: Control of emergence hypertension and pain is important after craniotomy for monitoring the neurological status. This prospective double-blinded study investigated the hemodynamics after a single bolus of dexmedetomidine (DEX) infusion administered to the patient undergoing craniotomy under general anesthesia, and its effect on emergence hypertension and postsurgical pain. Methods: Adult patients scheduled for elective surgery for supratentorial tumors were randomized to receive a 10-minute intraoperative DEX infusion of 0.4 μg/kg (small dose, n=43) or 0.8 μg/kg (medium dose, n=46), or normal saline (vehicle control, n=45), ∼60 minutes before the end of anesthesia. Results: A transient increase in the blood pressure associated with DEX was observed; 53.5% and 91.3% of the patients in the small-dose and the medium-dose groups, respectively, required treatment. Emergence mean arterial pressure and heart rates were significantly lower in the DEX groups compared with the control group. Incidence rates of postoperative hypertension in the small-dose (16.3%) and the medium-dose groups (15.2%) were significantly lower relative to that of the control group (35.6%). Patients who received DEX had a lower Verbal Numerical Rating Scale (VNRS) score in the neurosurgical ICU than the control group, and postsurgical pain (VNRS≥4) was lower in the medium-dose group (41.3%) than in the control group (71.1%). No shivering was observed in the medium-dose group, which was significantly less than that of the other 2 groups. Conclusions: An intraoperative bolus of DEX risks a transient increase in mean arterial pressure, but controls emergence hypertension effectively. Dose-related reductions in postsurgical pain and shivering were observed.

http://ift.tt/2scP6xs

Perioperative Management of Adult Patients With External Ventricular and Lumbar Drains: Guidelines From the Society for Neuroscience in Anesthesiology and Critical Care

External ventricular drains and lumbar drains are commonly used to divert cerebrospinal fluid and to measure cerebrospinal fluid pressure. Although commonly encountered in the perioperative setting and critical for the care of neurosurgical patients, there are no guidelines regarding their management in the perioperative period. To address this gap in the literature, The Society for Neuroscience in Anesthesiology & Critical Care tasked an expert group to generate evidence-based guidelines. The document generated targets clinicians involved in perioperative care of patients with indwelling external ventricular and lumbar drains.

http://ift.tt/2scWrx7

Effects of Acupuncture in Anesthesia for Craniotomy: A Meta-Analysis

Background: Acupuncture treatment has been used in China for >2500 years, and at present it is used worldwide as a form of analgesia in patients with acute and chronic pain. Furthermore, acupuncture is regularly used not only as a single anesthetic technique but also as a supplement or in addition to general anesthesia (GA). Objectives: The aim of this systematic review and meta-analysis was to assess the level of evidence for the clinical use of acupuncture in addition to GA in patients undergoing craniotomy. Design: This is a systematic review of randomized controlled trials with meta-analyses. Data Sources: The literature search (PubMed, Cochrane Library, and Web of Science) yielded 56 citations, published between 1972 and March 01, 2015. No systematic review or meta-analyses on this topic matched our search criteria. Each article of any language was assessed and rated for the methodological quality of the studies, using the recommendation of the Oxford Centre for Evidence Based Medicine. Ten prospective randomized controlled clinical trials with a total of 700 patients were included. Eligibility Criteria: Included in the meta-analysis were studies that involved any craniotomy under GA compared with a combination of GA and acupuncture. Exclusion criteria were no acupuncture during surgery, no GA during surgery, only postoperative data available, animal studies, and low grade of evidence. Results: The use of acupuncture significantly reduced the amount of volatile anesthetics during surgery (P

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The Trigemino-cardiac Reflex: Is Treatment With Atropine Still Justified?

No abstract available

http://ift.tt/2sdfYgJ

Intraoperative Secondary Insults During Orthopedic Surgery in Traumatic Brain Injury

Background: Secondary insults worsen outcomes after traumatic brain injury (TBI). However, data on intraoperative secondary insults are sparse. The primary aim of this study was to examine the prevalence of intraoperative secondary insults during orthopedic surgery after moderate-severe TBI. We also examined the impact of intraoperative secondary insults on postoperative head computed tomographic scan, intracranial pressure (ICP), and escalation of care within 24 hours of surgery. Materials and Methods: We reviewed medical records of TBI patients 18 years and above with Glasgow Coma Scale score 20 mm Hg), cerebral hypotension (cerebral perfusion pressure40 mm Hg), hypocarbia (end-tidal CO2200 mg/dL), hypoglycemia (glucose38°C). Results: A total of 78 patients (41 [18 to 81] y, 68% male) met the inclusion criteria. The most common intraoperative secondary insults were systemic hypotension (60%), intracranial hypertension and cerebral hypotension (50% and 45%, respectively, in patients with ICP monitoring), hypercarbia (32%), and hypocarbia (29%). Intraoperative secondary insults were associated with worsening of head computed tomography, postoperative decrease of Glasgow Coma Scale score by ≥2, and escalation of care. After Bonferroni correction, association between cerebral hypotension and postoperative escalation of care remained significant (P

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Large-volume Epidural Blood Patch: An Alternative Technique

No abstract available

http://ift.tt/2scZK7l

Cerebral Gaseous Microemboli are Detectable During Continuous Venovenous Hemodialysis in Critically Ill Patients: An Observational Pilot Study

Background: Continuous venovenous hemodialysis (CVVHD) may generate microemboli that cross the pulmonary circulation and reach the brain. The aim of the present study was to quantify (load per time interval) and qualify (gaseous vs. solid) cerebral microemboli (CME), detected as high-intensity transient signals, using transcranial Doppler ultrasound. Materials and Methods: Twenty intensive care unit (ICU group) patients requiring CVVHD were examined. CME were recorded in both middle cerebral arteries for 30 minutes during CVVHD and a CVVHD-free interval. Twenty additional patients, hospitalized for orthopedic surgery, served as a non-ICU control group. Statistical analyses were performed using the Mann-Whitney U test or the Wilcoxon matched-pairs signed-rank test, followed by Bonferroni corrections for multiple comparisons. Results: In the non-ICU group, 48 (14.5-169.5) (median [range]) gaseous CME were detected. In the ICU group, the 67.5 (14.5-588.5) gaseous CME detected during the CVVHD-free interval increased 5-fold to 344.5 (59-1019) during CVVHD (P

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Bowel Preparation in Awake Craniotomy: An Overlooked Entity

No abstract available

http://ift.tt/2sMFkiP

Effects of Prone Position and Positive End-Expiratory Pressure on Noninvasive Estimators of ICP: A Pilot Study

Background: Prone positioning and positive end-expiratory pressure can improve pulmonary gas exchange and respiratory mechanics. However, they may be associated with the development of intracranial hypertension. Intracranial pressure (ICP) can be noninvasively estimated from the sonographic measurement of the optic nerve sheath diameter (ONSD) and from the transcranial Doppler analysis of the pulsatility (ICPPI) and the diastolic component (ICPFVd) of the velocity waveform. Methods: The effect of the prone positioning and positive end-expiratory pressure on ONSD, ICPFVd, and ICPPI was assessed in a prospective study of 30 patients undergoing spine surgery. One-way repeated measures analysis of variance, fixed-effect multivariate regression models, and receiver operating characteristic analyses were used to analyze numerical data. Results: The mean values of ONSD, ICPFVd, and ICPPI significantly increased after change from supine to prone position. Receiver operating characteristic analyses demonstrated that, among the noninvasive methods, the mean ONSD measure had the greatest area under the curve signifying it is the most effective in distinguishing a hypothetical change in ICP between supine and prone positioning (0.86±0.034 [0.79 to 0.92]). A cutoff of 0.43 cm was found to be a best separator of ONSD value between supine and prone with a specificity of 75.0 and a sensitivity of 86.7. Conclusions: Noninvasive ICP estimation may be useful in patients at risk of developing intracranial hypertension who require prone positioning.

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Urinary Retention Manifesting as Excessive Venous Ooze During Cranio-Vertebral Junction Surgery

No abstract available

http://ift.tt/2sMjI65

Noninvasive Hemodynamic Measurements During Neurosurgical Procedures in Sitting Position

Background: Neurosurgical procedures in sitting position need advanced cardiovascular monitoring. Transesophageal echocardiography (TEE) to measure cardiac output (CO)/cardiac index (CI) and stroke volume (SV), and invasive arterial blood pressure measurements for systolic (ABPsys), diastolic (ABPdiast) and mean arterial pressure (MAP) are established monitoring technologies for these kind of procedures. A noninvasive device for continuous monitoring of blood pressure and CO based on a modified Penaz technique (volume-clamp method) was introduced recently. In the present study the noninvasive blood pressure measurements were compared with invasive arterial blood pressure monitoring, and the noninvasive CO monitoring to TEE measurements. Methods: Measurements of blood pressure and CO were performed in 35 patients before/after giving a fluid bolus and a change from supine to sitting position, start of surgery, and repositioning from sitting to supine at the end of surgery. Data pairs from the noninvasive device (Nexfin HD) versus arterial line measurements (ABPsys, ABPdiast, MAP) and versus TEE (CO, CI, SV) were compared using Bland-Altman analysis and percentage error. Results: All parameters compared (CO, CI, SV, ABPsys, ABPdiast, MAP) showed a large bias and wide limits of agreement. Percentage error was above 30% for all parameters except ABPsys. Conclusion: The noninvasive device based on a modified Penaz technique cannot replace arterial blood pressure monitoring or TEE in anesthetized patients undergoing neurosurgery in sitting position.

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Pediatric Neurosurgery. Tricks of the Trade

No abstract available

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Intraoperative and Postoperative Administration of Dexmedetomidine Reduces Anesthetic and Postoperative Analgesic Requirements in Patients Undergoing Cervical Spine Surgeries

Background: Early recovery from anesthesia and avoidance of analgesics with respiratory depressant properties are vital for maintenance of extubated airway in cervical spine surgeries. The current study investigated the role of dexmedetomidine as an anesthetic sparing agent and as a sole postoperative analgesic in these cases. Materials and Methods: Sixty adult patients undergoing cervical spine surgeries were randomized into 2 groups. Group D received intravenous dexmedetomidine infusion 0.5 μg/kg/h throughout the surgery after a loading dose of 1 μg/kg over 10 minutes. Postoperatively, dexmedetomidine infusion was continued at 0.2 μg/kg/h for 24 hours. Group C received a volume-matched bolus and infusion of 0.9% saline. Intraoperative anesthetic requirement, time to recovery, and discharge were recorded. Patients were observed for rescue analgesic requirements for 24 hours after surgery. Hemodynamic stability, sedation scores, and pain scores were assessed for 48 hours after surgery. Results: There was significant reduction in intraoperative anesthetic requirement in group D (P

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Unusual Presentation of Refractory Autonomic Dysreflexia During General Anesthesia

No abstract available

http://ift.tt/2sMlh41

Latent Class Analysis of Neurodevelopmental Deficit After Exposure to Anesthesia in Early Childhood

Introduction: Although some studies have reported an association between early exposure to anesthesia and surgery and long-term neurodevelopmental deficit, the clinical phenotype of children exposed to anesthesia is still unknown. Methods: Data were obtained from the Western Australian Pregnancy Cohort Study (Raine) with neuropsychological tests at age 10 years measuring language, cognition, motor function, and behavior. Latent class analysis of the tests was used to divide the cohort into mutually exclusive subclasses of neurodevelopmental deficit. Multivariable polytomous logistic regression was used to evaluate the association between exposure to surgery and anesthesia and each latent class, adjusting for demographic and medical covariates. Results: In our cohort of 1444 children, latent class analysis identified 4 subclasses: (1) Normal: few deficits (n=1135, 78.6%); (2) Language and Cognitive deficits: primarily language, cognitive, and motor deficits (n=96, 6.6%); (3) Behavioral deficits: primarily behavioral deficits, (n=151, 10.5%); and (4) Severe deficits: deficits in all neuropsychological domains (n=62, 4.3%). Language and cognitive deficit group children were more likely to have exposure before age 3 (adjusted odds ratio [aOR], 2.11; 95% confidence interval [CI], 1.17-3.81), whereas a difference in exposure was not found between Behavioral or Severe deficit children (aOR, 1.00; 95% CI, 0.58-1.73, and aOR, 0.85; 95% CI, 0.34-2.15, respectively) and Normal children. Conclusions: Our results suggest that in evaluating children exposed to surgery and anesthesia at an early age, the phenotype of interest may be children with deficits primarily in language and cognition, and not children with broad neurodevelopmental delay or primarily behavioral deficits.

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Acute Reduction in the End-Tidal Carbon Dioxide Level During Neurosurgery: Another Cause for Capnography Artifact

No abstract available

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Use of Dexmedetomidine Along With Local Infiltration Versus General Anesthesia for Burr Hole and Evacuation of Chronic Subdural Hematoma (CSDH)

Background: In neurosurgery, chronic subdural hematoma (CSDH) is a very common clinical entity. Both general anesthesia (GA) and local anesthesia with or without sedation are used for the surgical treatment of CSDH. Sedation with dexmedetomidine has been safely used for various diagnostic and therapeutic procedures. However, its effectiveness against GA has not been evaluated for surgical treatment of CSDH. We tried to compare dexmedetomidine sedation technique with the GA technique for surgical treatment of CSDH. Materials and Methods: In this prospective-randomized study, 76 patients undergoing surgery for CSDH were divided into 2 groups using computer-generated randomized tables; Dex group ([n=38]; received IV bolus of dexmedetomidine 1 mcg/kg over 10 min followed by maintenance infusion 0.5 mcg/kg/h) and GA group ([n=38; of which 4 patients were dropped out]; received endotracheal intubation with balanced anesthesia). Results: Both anesthesia techniques (Dex group; n=35/38 [92.1%] and GA group; n=34/34 [100%]) were successfully used for surgical treatment of CSDH. Significantly less time for anesthesia onset (14.2±4.2 vs. 20.5±3.4 min, P=0.001), total duration of surgery (77.1±23.9 vs. 102.7± 24.8 min, P=0.001), and recovery from anesthesia (7.4±5.9 vs. 13.2±6.5 min, P=0.004) was observed in the Dex group compared with GA group. Perioperative hemodynamic fluctuations were more common in the GA group as against the Dex group. Postoperative complications (n=2 vs. 9, P=0.021) and length of hospital stay (1.05±0.23 vs. 1.79±2.1 d, P=0.007) were significantly less in the Dex group as against the GA group. Conclusions: Dexmedetomidine sedation with local anesthesia is a safe and effective technique for burr hole and evacuation of CSDH. It is associated with significantly shorter operative time, lesser hemodynamic fluctuations, postoperative complications, and length of hospital stay, thus it is a better alternative to GA.

http://ift.tt/2sMlbtb

Obscure Retropharyngeal Mucocutaneous Masses Associated With Acoustic Neurofibromatosis: A Source of Difficult Airway Management

No abstract available

http://ift.tt/2sM8L4d

The Prophylactic Use of Remifentanil for Delayed Extubation After Elective Intracranial Operations: a Prospective, Randomized, Double-Blinded Trial

Background: Endotracheal extubation is a painful and stressful procedure. The authors hypothesized that the prophylactic use of remifentanil would attenuate the pain intensity and stress responses resulting from extubation in neurosurgical patients. Materials and Methods: In this prospective, randomized, double-blinded, controlled trial, 160 patients with planned delay extubation after elective intracranial operation were randomized 1:1 to receive either remifentanil or normal saline (control) before their extubation. The dose regime of remifentanil was a bolus of 0.5 μg/kg over 1 minute, followed by a continuous infusion of 0.05 μg/kg/min for 20 minutes. The primary outcome was the incidence of severe pain during the periextubation period. Secondary outcomes included changes in the pain intensity and vital signs, failing to pass an extubation evaluation after the study drug infusion, severe adverse events, postextubation complications, and clinical outcomes. Results: Two patients in the remifentanil group did not pass the extubation evaluation. The incidence of severe pain during the periextubation period was significantly lower in the remifentanil group compared with the control group (25.0% vs. 41.3%, P=0.029). Compared with the control group, the visual analog scale in the remifentanil group was significantly lower after the bolus of remifentanil (12±18 vs. 25±27, P=0.001) and immediately after extubation (19±25 vs. 34±30, P=0.001). There were no significant differences in the vital signs immediately after extubation between the 2 groups (P>0.05). Conclusions: The prophylactic use of remifentanil decreases the incidence of severe pain. Our preliminary findings merit a larger trial to clarify the effect of the prophylactic use of remifentanil on clinical outcomes and adverse events.

http://ift.tt/2sMjGLv

2016 President's Plenary International Psycho-Oncology Society: Challenges and Opportunities for Growing and Developing Psychosocial Oncology Programmes Worldwide

Abstract

Consistent with the International Psycho-Oncology Society's (IPOS) vision and goals, we are committed to improving quality cancer care and cancer policies through psychosocial care globally. As part of IPOS's mission, upon entering "Official Relations" for a second term with the World Health Organisation (WHO), IPOS has dedicated much attention to reaching out to countries, which lack formalized psychosocial care programs. One of IPOS's strategies to accomplish this goal has been to bring psycho-oncology training programs to low and middle income countries and regions. To this end, the IPOS Board approved a new position on the Board of Directors for a member from a Low-Middle Income Country (LMIC). The IPOS 2016 President's Plenary focused on challenges and opportunities that exist in growing and developing Psychosocial Oncology Programs Worldwide. The Plenary presentations highlight how IPOS and WHO have aligned their goals to help LMICs support cancer patients as an essential element of cancer and palliative care. IPOS country representatives are strongly supported in liaising with national health authorities and with WHO Country Representatives in LMICs. The Plenary speakers discussed the role IPOS Federation has taken in building a global network of psychosocial leaders and the impact this had in assisting LMICs in meeting IPOS's Psychosocial Care objectives. The Plenary highlighted the challenges of expanding psychosocial reach into these countries. One significant question remains: can psychosocial guidelines be adapted to LMICs and regions?

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In Vitro Evaluation of 188Re-HEDP: A Mechanistic View of Bone Pain Palliations

Cancer Biotherapy & Radiopharmaceuticals , Vol. 0, No. 0.


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Gender differences in colorectal cancer survival: A Meta-analysis

Abstract

A meta-analysis was conducted to determine the influence of gender on overall survival (OS) and cancer-specific survival (CSS) in colorectal cancer patients. Major databases were searched for clinical trials, which compare survival differences between male and female for colorectal cancer patients. A list of these studies and references, published in English and Chinese from 1960 to 2017, was obtained independently by two reviewers from databases such as PubMed, Medline, ScienceDirect, the China National Knowledge Infrastructure (CNKI) and Web of Science. Overall survival and cancer-specific survival were compared using Review Manager 5.3. Females had significantly better OS (hazard ratio [HR]=0.87; 95% confidence interval [CI]=0.85–0.89) and CSS (HR = 0.92; 95% CI=0.89–0.95) than males after meta-analysis. These results suggest that gender seems to be a significant factor influencing survival results among colorectal cancer patients. This article is protected by copyright. All rights reserved.

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2016 President's Plenary International Psycho-Oncology Society: Challenges and Opportunities for Growing and Developing Psychosocial Oncology Programmes Worldwide

Abstract

Consistent with the International Psycho-Oncology Society's (IPOS) vision and goals, we are committed to improving quality cancer care and cancer policies through psychosocial care globally. As part of IPOS's mission, upon entering "Official Relations" for a second term with the World Health Organisation (WHO), IPOS has dedicated much attention to reaching out to countries, which lack formalized psychosocial care programs. One of IPOS's strategies to accomplish this goal has been to bring psycho-oncology training programs to low and middle income countries and regions. To this end, the IPOS Board approved a new position on the Board of Directors for a member from a Low-Middle Income Country (LMIC). The IPOS 2016 President's Plenary focused on challenges and opportunities that exist in growing and developing Psychosocial Oncology Programs Worldwide. The Plenary presentations highlight how IPOS and WHO have aligned their goals to help LMICs support cancer patients as an essential element of cancer and palliative care. IPOS country representatives are strongly supported in liaising with national health authorities and with WHO Country Representatives in LMICs. The Plenary speakers discussed the role IPOS Federation has taken in building a global network of psychosocial leaders and the impact this had in assisting LMICs in meeting IPOS's Psychosocial Care objectives. The Plenary highlighted the challenges of expanding psychosocial reach into these countries. One significant question remains: can psychosocial guidelines be adapted to LMICs and regions?

http://ift.tt/2raMujv

In Vitro Evaluation of 188Re-HEDP: A Mechanistic View of Bone Pain Palliations

Cancer Biotherapy & Radiopharmaceuticals , Vol. 0, No. 0.


http://ift.tt/2rVB1Bt

Gender differences in colorectal cancer survival: A Meta-analysis

Abstract

A meta-analysis was conducted to determine the influence of gender on overall survival (OS) and cancer-specific survival (CSS) in colorectal cancer patients. Major databases were searched for clinical trials, which compare survival differences between male and female for colorectal cancer patients. A list of these studies and references, published in English and Chinese from 1960 to 2017, was obtained independently by two reviewers from databases such as PubMed, Medline, ScienceDirect, the China National Knowledge Infrastructure (CNKI) and Web of Science. Overall survival and cancer-specific survival were compared using Review Manager 5.3. Females had significantly better OS (hazard ratio [HR]=0.87; 95% confidence interval [CI]=0.85–0.89) and CSS (HR = 0.92; 95% CI=0.89–0.95) than males after meta-analysis. These results suggest that gender seems to be a significant factor influencing survival results among colorectal cancer patients. This article is protected by copyright. All rights reserved.

http://ift.tt/2reXDLn

Papillary thyroid carcinoma metastasizing to anaplastic meningioma: an unusual case of tumor-to-tumor metastasis

Abstract

Tumor-to-tumor metastasis is a relatively uncommon entity, whereby the so-called 'recipient' tumor is involved by another biologically unrelated 'donor' tumor. Intracranially, meningioma (WHO grade 1) is the most common recipient tumor, while breast and lung cancers are the most common donor tumors. We present an unusual case of intracranial tumor-to-tumor metastasis involving papillary thyroid carcinoma (PTC) believed to have metastasized to an anaplastic meningioma (WHO grade 3). The patient is a 64-year-old female with a history of PTC, whose neuroimaging, performed as part of her staging workup, revealed a right parietal scalp lesion. The lesion was resected to reveal metastatic PTC with spindle cell component believed to represent sarcomatoid differentiation. Follow-up neuroimaging 2 months later revealed regrowth of the lesion under the previous craniotomy site. PET scan showed increased uptake in this area consistent with metastasis. Resection of this lesion revealed primarily features of an anaplastic meningioma. The combination of pathologic findings from both resections in conjunction with findings from the PET scan led to the suggestion that the PTC had metastasized into the anaplastic meningioma. To the authors' knowledge, this is the first example in the literature of a donor tumor metastasizing to a high-grade recipient tumor.

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In Vitro Evaluation of 188Re-HEDP: A Mechanistic View of Bone Pain Palliations

Cancer Biotherapy & Radiopharmaceuticals , Vol. 0, No. 0.


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TRIBE-2: a phase III, randomized, open-label, strategy trial in unresectable metastatic colorectal cancer patients by the GONO group

Abstract

Background

Chemotherapy plus bevacizumab is a standard first-line treatment for unresectable metastatic colorectal cancer patients. Different chemotherapy backbones may be chosen, including one to three drugs, based on patients' general conditions and comorbidities, treatments' objectives, and disease characteristics. TRIBE trial demonstrated a significant advantage in terms of progression-free survival and overall survival for FOLFOXIRI plus bevacizumab as compared with FOLFIRI plus bevacizumab. Based on recent evidence, the de-intensification of the upfront regimen after 4–6 months of treatment is nowadays regarded as a valuable option. Moreover, the prolonged inhibition of angiogenesis, and in particular the continuation of bevacizumab beyond the evidence of disease progression, is an efficacious strategy in the treatment of metastatic colorectal cancer patients.

Methods/design

TRIBE-2 is a prospective, open-label, multicentric phase III randomized trial in which unresectable and previously untreated metastatic colorectal cancer patients are randomized to receive first-line FOLFOX plus bevacizumab followed by FOLFIRI plus bevacizumab after disease progression or FOLFOXIRI plus bevacizumab followed by the re-introduction of the same regimen after disease progression. The primary endpoint is to compare the efficacy of the two proposed treatment strategies in terms of Progression Free Survival 2.

Discussion

The TRIBE-2 study aims at answering the question whether the upfront use of FOLFOXIRI improves the clinical outcome of metastatic colorectal cancer patients, when compared with the pre-planned, sequential use of oxaliplatin-based and irinotecan-based doublets. Both proposed treatment strategies are designed to exploit the effectiveness of the prolonged inhibition of angiogenesis, alternating short (up to 4 months) induction periods and less intensive maintenance phases.

Trial registration

TRIBE2 is registered at Clinicaltrials.gov: NCT02339116. January 12, 2015. TRIBE-2 is registered at EUDRACT 2014–004436-19, October 10, 2014.

http://ift.tt/2rJwNhT

Angiotensin II type 2 receptor promotes apoptosis and inhibits angiogenesis in bladder cancer

Abstract

Background

Bladder cancer (BCa) is the ninth most common form of cancer in the world. There is a continuing need not only for improving the accuracy of diagnostic markers but also for the development of new treatment strategies. Recent studies have shown that the renin-angiotensin system (RAS), which include the angiotensin type 1 (AT1R), type 2(AT2R), and Mas receptors, play an important role in tumorigenesis and may guide us in meeting those needs.

Results

In this study, we first observed that AT1R and Mas expression levels were significantly upregulated in BCa specimens while AT2R was significantly downregulated. Viral vector mediated overexpression of AT2R induced apoptosis and dramatically suppressed BCa cell proliferation in vitro, suggesting a therapeutic effect. Investigation into the mechanism revealed that the overexpression of AT2R increases the expression levels of caspase-3, caspase-8, and p38 and decreases the expression level of pErk. AT2R overexpression also leads to upregulation of 2 apoptosis-related genes (BCL2A1, TNFSF25) and downregulation of 8 apoptosis-related genes (CASP 6, CASP 9, DFFA, IGF1R, PYCARD, TNF, TNFRSF21, TNFSF10, NAIP) in transduced EJ cells as determined by PCR Array analysis. In vivo, we observed that AT2R overexpression caused significant reduction in xenograft tumors sizes by downregulation VEGF and induction of apoptosis.

Conclusions

Taken together, the data suggest that AT1R, AT2R or Mas could be used as a diagnostic marker of BCa and AT2R is a promising novel target gene for BCa gene therapy.

http://ift.tt/2rJqGdl

Angiotensin II type 2 receptor promotes apoptosis and inhibits angiogenesis in bladder cancer

Bladder cancer (BCa) is the ninth most common form of cancer in the world. There is a continuing need not only for improving the accuracy of diagnostic markers but also for the development of new treatment str...

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TRIBE-2: a phase III, randomized, open-label, strategy trial in unresectable metastatic colorectal cancer patients by the GONO group

Abstract

Background

Chemotherapy plus bevacizumab is a standard first-line treatment for unresectable metastatic colorectal cancer patients. Different chemotherapy backbones may be chosen, including one to three drugs, based on patients' general conditions and comorbidities, treatments' objectives, and disease characteristics. TRIBE trial demonstrated a significant advantage in terms of progression-free survival and overall survival for FOLFOXIRI plus bevacizumab as compared with FOLFIRI plus bevacizumab. Based on recent evidence, the de-intensification of the upfront regimen after 4–6 months of treatment is nowadays regarded as a valuable option. Moreover, the prolonged inhibition of angiogenesis, and in particular the continuation of bevacizumab beyond the evidence of disease progression, is an efficacious strategy in the treatment of metastatic colorectal cancer patients.

Methods/design

TRIBE-2 is a prospective, open-label, multicentric phase III randomized trial in which unresectable and previously untreated metastatic colorectal cancer patients are randomized to receive first-line FOLFOX plus bevacizumab followed by FOLFIRI plus bevacizumab after disease progression or FOLFOXIRI plus bevacizumab followed by the re-introduction of the same regimen after disease progression. The primary endpoint is to compare the efficacy of the two proposed treatment strategies in terms of Progression Free Survival 2.

Discussion

The TRIBE-2 study aims at answering the question whether the upfront use of FOLFOXIRI improves the clinical outcome of metastatic colorectal cancer patients, when compared with the pre-planned, sequential use of oxaliplatin-based and irinotecan-based doublets. Both proposed treatment strategies are designed to exploit the effectiveness of the prolonged inhibition of angiogenesis, alternating short (up to 4 months) induction periods and less intensive maintenance phases.

Trial registration

TRIBE2 is registered at Clinicaltrials.gov: NCT02339116. January 12, 2015. TRIBE-2 is registered at EUDRACT 2014–004436-19, October 10, 2014.

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