Decisional regret and choice of breast reconstruction following mastectomy for breast cancer: A systematic review

Abstract

Objective

Women facing mastectomy for breast cancer should have the option of considering whether they would like breast reconstruction (BR), and if so, what type and when. Previous research has demonstrated some women will come to regret their decision about BR. We aim to summarise the evidence about the prevalence of decisional regret (DR) associated with BR choices and identify factors influencing vulnerability to DR.

Methods

A systematic review of the literature reporting BR-related DR published between January 1994 and February 2017 identified 254 initial search results. Thirteen publications from 12 studies (5,672 participants) met the selection criteria and were included in the final review. Each article was allocated a quality score out of 24.

Results

Overall, DR levels were reported as low and stable, although direct comparison across studies was limited by inconsistencies in measurement and reporting methods. Estimates of DR scores ranged from 9.3/100 to 5.4/20. All studies identified a relationship between higher levels of DR and an insufficient amount, inadequate quality or unclear nature of information provided to women prior to undergoing mastectomy. A major determinant of DR was new or recurrent cancer, while psychosocial characteristics including depression, distress and negative body image increased the likelihood of DR.

Conclusion

The available research is yet to provide a clear understanding of the many inter-related issues involved in DR. Given the consensus that pre-surgical information was inadequate, making standardised educational material more widely available and increasing use of breast care nurses in pre-operative patient education roles may be useful.

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Decisional regret and choice of breast reconstruction following mastectomy for breast cancer: A systematic review

Abstract

Objective

Women facing mastectomy for breast cancer should have the option of considering whether they would like breast reconstruction (BR), and if so, what type and when. Previous research has demonstrated some women will come to regret their decision about BR. We aim to summarise the evidence about the prevalence of decisional regret (DR) associated with BR choices and identify factors influencing vulnerability to DR.

Methods

A systematic review of the literature reporting BR-related DR published between January 1994 and February 2017 identified 254 initial search results. Thirteen publications from 12 studies (5,672 participants) met the selection criteria and were included in the final review. Each article was allocated a quality score out of 24.

Results

Overall, DR levels were reported as low and stable, although direct comparison across studies was limited by inconsistencies in measurement and reporting methods. Estimates of DR scores ranged from 9.3/100 to 5.4/20. All studies identified a relationship between higher levels of DR and an insufficient amount, inadequate quality or unclear nature of information provided to women prior to undergoing mastectomy. A major determinant of DR was new or recurrent cancer, while psychosocial characteristics including depression, distress and negative body image increased the likelihood of DR.

Conclusion

The available research is yet to provide a clear understanding of the many inter-related issues involved in DR. Given the consensus that pre-surgical information was inadequate, making standardised educational material more widely available and increasing use of breast care nurses in pre-operative patient education roles may be useful.

http://ift.tt/2jvrNM4

Annals of Oncology: factors for making a real impact

http://ift.tt/2AL87au

Pan-Asian adapted ESMO consensus guidelines for the management of patients with metastatic colorectal cancer; A JSMO - ESMO initiative endorsed by CSCO, KACO, MOS, SSO and TOS

Abstract

The most recent version of the European Society for Medical Oncology (ESMO) consensus guidelines for the treatment of patients with metastatic colorectal cancer (mCRC) was published in 2016, identifying both a more strategic approach to the administration of the available systemic therapy choices, and a greater emphasis on the use of ablative techniques, including surgery. At the 2016 ESMO Asia Meeting, in December 2016, it was decided by both ESMO and the Japanese Society of Medical Oncology (JSMO) to convene a special guidelines meeting, endorsed by both ESMO and JSMO, immediately after the JSMO 2017 Annual Meeting. The aim was to adapt the ESMO consensus guidelines to take into account the ethnic differences relating to the toxicity as well as other aspects of certain systemic treatments in patients of Asian ethnicity. These guidelines represent the consensus opinions reached by experts in the treatment of patients with mCRC identified by the Presidents of the oncological societies of Japan (JSMO), China (CSCO), Korea (KACO), Malaysia (MOS), Singapore (SSO) and Taiwan (TOS). The voting was based on scientific evidence, and was independent of both the current treatment practices and the drug availability and reimbursement situations in the individual participating Asian countries.

http://ift.tt/2ikKvTq

Annals of Oncology: factors for making a real impact

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Pan-Asian adapted ESMO consensus guidelines for the management of patients with metastatic colorectal cancer; A JSMO - ESMO initiative endorsed by CSCO, KACO, MOS, SSO and TOS

Abstract

The most recent version of the European Society for Medical Oncology (ESMO) consensus guidelines for the treatment of patients with metastatic colorectal cancer (mCRC) was published in 2016, identifying both a more strategic approach to the administration of the available systemic therapy choices, and a greater emphasis on the use of ablative techniques, including surgery. At the 2016 ESMO Asia Meeting, in December 2016, it was decided by both ESMO and the Japanese Society of Medical Oncology (JSMO) to convene a special guidelines meeting, endorsed by both ESMO and JSMO, immediately after the JSMO 2017 Annual Meeting. The aim was to adapt the ESMO consensus guidelines to take into account the ethnic differences relating to the toxicity as well as other aspects of certain systemic treatments in patients of Asian ethnicity. These guidelines represent the consensus opinions reached by experts in the treatment of patients with mCRC identified by the Presidents of the oncological societies of Japan (JSMO), China (CSCO), Korea (KACO), Malaysia (MOS), Singapore (SSO) and Taiwan (TOS). The voting was based on scientific evidence, and was independent of both the current treatment practices and the drug availability and reimbursement situations in the individual participating Asian countries.

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Upregulation of Tyrosine Kinase FYN in Human Thyroid Carcinoma: Role in Modulating Tumor Cell Proliferation, Invasion, and Migration

Cancer Biotherapy & Radiopharmaceuticals Nov 2017, Vol. 32, No. 9: 320-326.


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Comparative In Vitro Study of 11C-Methionine and 11C-Deuterodeprenyl Uptake in Three Human Glioma Cell Lines

Cancer Biotherapy & Radiopharmaceuticals Nov 2017, Vol. 32, No. 9: 344-350.


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Upregulation of Tyrosine Kinase FYN in Human Thyroid Carcinoma: Role in Modulating Tumor Cell Proliferation, Invasion, and Migration

Cancer Biotherapy & Radiopharmaceuticals Nov 2017, Vol. 32, No. 9: 320-326.


http://ift.tt/2A3N5aY

Comparative In Vitro Study of 11C-Methionine and 11C-Deuterodeprenyl Uptake in Three Human Glioma Cell Lines

Cancer Biotherapy & Radiopharmaceuticals Nov 2017, Vol. 32, No. 9: 344-350.


http://ift.tt/2zGa4bp

Upregulation of Tyrosine Kinase FYN in Human Thyroid Carcinoma: Role in Modulating Tumor Cell Proliferation, Invasion, and Migration

Cancer Biotherapy & Radiopharmaceuticals Nov 2017, Vol. 32, No. 9: 320-326.


http://ift.tt/2A3N5aY

Comparative In Vitro Study of 11C-Methionine and 11C-Deuterodeprenyl Uptake in Three Human Glioma Cell Lines

Cancer Biotherapy & Radiopharmaceuticals Nov 2017, Vol. 32, No. 9: 344-350.


http://ift.tt/2zGa4bp

Imaging and imagination

Future Oncology, Volume 13, Issue 26, Page 2315-2316, November 2017.


http://ift.tt/2hDasAs

Durvalumab in non-small-cell lung cancer patients: current developments

Future Oncology, Ahead of Print.


http://ift.tt/2hDaqIQ

Imaging and imagination

Future Oncology, Volume 13, Issue 26, Page 2315-2316, November 2017.


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via IFTTT

Durvalumab in non-small-cell lung cancer patients: current developments

Future Oncology, Ahead of Print.


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

Upregulation of Tyrosine Kinase FYN in Human Thyroid Carcinoma: Role in Modulating Tumor Cell Proliferation, Invasion, and Migration

Cancer Biotherapy & Radiopharmaceuticals Nov 2017, Vol. 32, No. 9: 320-326.


from Cancer via ola Kala on Inoreader http://ift.tt/2zFQE6j
via IFTTT

Comparative In Vitro Study of 11C-Methionine and 11C-Deuterodeprenyl Uptake in Three Human Glioma Cell Lines

Cancer Biotherapy & Radiopharmaceuticals Nov 2017, Vol. 32, No. 9: 344-350.


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Carcinosarcoma of the ovary compared to ovarian high-grade serous carcinoma: impact of optimal cytoreduction and standard adjuvant treatment

Abstract

Objective

The purpose of this retrospective study was to compare the prognoses of women with ovarian carcinosarcoma (OCS) who had optimal cytoreductive surgery followed by platinum plus taxane combination chemotherapy to those of women with ovarian high-grade serous carcinoma (HGSC) treated in the same manner.

Methods

A multicenter, retrospective department database review was performed to identify patients with OCS at eight gynecologic oncology centers in Turkey. A total of 54 women with OCS who had undergone optimal cytoreductive surgery followed by platinum plus taxane combination chemotherapy between 1999 and 2017 were included in this case–control study. Each case was matched to two women with ovarian HGSC who had undergone optimal cytoreductive surgery followed by platinum plus taxane combination chemotherapy. The Kaplan–Meier method was used to generate survival data. Factors predictive of outcome were analysed using Cox proportional hazards models.

Results

Median disease-free survival (DFS) was 29 months [95% confidence interval (CI) 0–59, standard error (SE) 15.35] versus 27 months (95% CI 22.6–31.3, SE 2.22; p = 0.765) and median overall survival (OS) was 62 versus 82 months (p = 0.53) for cases and controls, respectively. For the entire cohort, the presence of ascites [hazard ratio (HR) 2.32; 95% CI 1.02–5.25, p = 0.04] and platinum resistance [HR 5.05; 95% CI 2.32–11, p < 0.001] were found to be independent risk factors for decreased OS.

Conclusion

DFS and OS rates of patients with OCS and HGSC seem to be similar whenever optimal cytoreduction is achieved and followed by platinum plus taxane combination chemotherapy.

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Carcinosarcoma of the ovary compared to ovarian high-grade serous carcinoma: impact of optimal cytoreduction and standard adjuvant treatment

Abstract

Objective

The purpose of this retrospective study was to compare the prognoses of women with ovarian carcinosarcoma (OCS) who had optimal cytoreductive surgery followed by platinum plus taxane combination chemotherapy to those of women with ovarian high-grade serous carcinoma (HGSC) treated in the same manner.

Methods

A multicenter, retrospective department database review was performed to identify patients with OCS at eight gynecologic oncology centers in Turkey. A total of 54 women with OCS who had undergone optimal cytoreductive surgery followed by platinum plus taxane combination chemotherapy between 1999 and 2017 were included in this case–control study. Each case was matched to two women with ovarian HGSC who had undergone optimal cytoreductive surgery followed by platinum plus taxane combination chemotherapy. The Kaplan–Meier method was used to generate survival data. Factors predictive of outcome were analysed using Cox proportional hazards models.

Results

Median disease-free survival (DFS) was 29 months [95% confidence interval (CI) 0–59, standard error (SE) 15.35] versus 27 months (95% CI 22.6–31.3, SE 2.22; p = 0.765) and median overall survival (OS) was 62 versus 82 months (p = 0.53) for cases and controls, respectively. For the entire cohort, the presence of ascites [hazard ratio (HR) 2.32; 95% CI 1.02–5.25, p = 0.04] and platinum resistance [HR 5.05; 95% CI 2.32–11, p < 0.001] were found to be independent risk factors for decreased OS.

Conclusion

DFS and OS rates of patients with OCS and HGSC seem to be similar whenever optimal cytoreduction is achieved and followed by platinum plus taxane combination chemotherapy.

http://ift.tt/2zFHWoJ

Imaging and imagination

Future Oncology, Volume 13, Issue 26, Page 2315-2316, November 2017.


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via IFTTT

Durvalumab in non-small-cell lung cancer patients: current developments

Future Oncology, Ahead of Print.


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Oncogenic spiral by infectious pathogens: The cooperation of multiple factors in cancer development

Abstract

Chronic infection is one of the major causes of cancer, and there are several mechanisms for infection-mediated oncogenesis. Some pathogens encode gene products that behave like oncogenic factors, hijacking cellular pathways to promote the survival and proliferation of infected cells in vivo. Some of these viral oncoproteins trigger a cellular damage defense response leading to senescence; however, other viral factors hinder this suppressive effect, suggesting that cooperation of those viral factors is important for malignant transformation. Coinfection with multiple agents is known to accelerate cancer development in certain cases. For example, parasitic or bacterial infection is a risk factor for adult T-cell leukemia-lymphoma induced by human T-cell leukemia virus type 1, and Epstein-Barr virus and malaria are closely associated with endemic Burkitt lymphoma. Human immunodeficiency virus type 1 infection is accompanied by various types of infection-related cancer. These findings indicate that these oncogenic pathogens can cooperate to overcome host barriers against cancer development. In this review, the authors focus on the collaborative strategies of pathogens for oncogenesis from two different points of view: (1) the cooperation of two or more different factors encoded by a single pathogen, and (2) the acceleration of oncogenesis by coinfection with multiple agents.

This article is protected by copyright. All rights reserved.

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Oncogenic spiral by infectious pathogens: The cooperation of multiple factors in cancer development

Abstract

Chronic infection is one of the major causes of cancer, and there are several mechanisms for infection-mediated oncogenesis. Some pathogens encode gene products that behave like oncogenic factors, hijacking cellular pathways to promote the survival and proliferation of infected cells in vivo. Some of these viral oncoproteins trigger a cellular damage defense response leading to senescence; however, other viral factors hinder this suppressive effect, suggesting that cooperation of those viral factors is important for malignant transformation. Coinfection with multiple agents is known to accelerate cancer development in certain cases. For example, parasitic or bacterial infection is a risk factor for adult T-cell leukemia-lymphoma induced by human T-cell leukemia virus type 1, and Epstein-Barr virus and malaria are closely associated with endemic Burkitt lymphoma. Human immunodeficiency virus type 1 infection is accompanied by various types of infection-related cancer. These findings indicate that these oncogenic pathogens can cooperate to overcome host barriers against cancer development. In this review, the authors focus on the collaborative strategies of pathogens for oncogenesis from two different points of view: (1) the cooperation of two or more different factors encoded by a single pathogen, and (2) the acceleration of oncogenesis by coinfection with multiple agents.

This article is protected by copyright. All rights reserved.

http://ift.tt/2juQok4

Atypical G protein {beta}5 promotes cardiac oxidative stress, apoptosis, and fibrotic remodeling in response to multiple cancer chemotherapeutics

The clinical use of multiple classes of cancer chemotherapeutics is limited by irreversible, dose-dependent, and sometimes life-threatening cardiotoxicity. We report here that, though distinct in their mechanisms of action, doxorubicin, paclitaxel, and 5-FU all induce rapid and robust upregulation of atypical G protein Gβ5 in the myocardium, correlating with oxidative stress, myocyte apoptosis, and the accumulation of pro-inflammatory and pro-fibrotic cytokines. In ventricular cardiac myocytes (VCM), Gβ5 deficiency provided substantial protection against the cytotoxic actions of chemotherapeutics, including reductions in oxidative stress and simultaneous attenuation of ROS-dependent activation of the ATM and CaMKII pro-apoptotic signaling cascades. In addition, Gβ5 loss allowed for maintenance of Δψm, basal MCU, and mitochondrial Ca2+ levels, effects likely to preserve functional myocyte excitation-contraction coupling. Gβ5 knockdown also reduced chemotherapy-induced release of pro-inflammatory cytokines (e.g. TNFα), hypertrophic factors (e.g. ANP), and pro-fibrotic factors (e.g. TGFβ1) from both VCM and ventricular cardiac fibroblasts (VCF), with the most dramatic reductions occurring in co-cultured cells. Intracardiac injection of Gβ5-targeted shRNA allowed for heart specific protection against the damaging impact of chronic chemotherapy. These data suggest that Gβ5 facilitates the myofibroblast transition, the persistence of which contributes to pathological remodeling and heart failure. The convergence of Gβ5-mediated, ROS-dependent signaling pathways in both cell types represents a critical etiological factor in the pathogenesis of chemotherapy-induced cardiotoxicity.

http://ift.tt/2ijWBw7

Atypical G protein {beta}5 promotes cardiac oxidative stress, apoptosis, and fibrotic remodeling in response to multiple cancer chemotherapeutics

The clinical use of multiple classes of cancer chemotherapeutics is limited by irreversible, dose-dependent, and sometimes life-threatening cardiotoxicity. We report here that, though distinct in their mechanisms of action, doxorubicin, paclitaxel, and 5-FU all induce rapid and robust upregulation of atypical G protein Gβ5 in the myocardium, correlating with oxidative stress, myocyte apoptosis, and the accumulation of pro-inflammatory and pro-fibrotic cytokines. In ventricular cardiac myocytes (VCM), Gβ5 deficiency provided substantial protection against the cytotoxic actions of chemotherapeutics, including reductions in oxidative stress and simultaneous attenuation of ROS-dependent activation of the ATM and CaMKII pro-apoptotic signaling cascades. In addition, Gβ5 loss allowed for maintenance of Δψm, basal MCU, and mitochondrial Ca2+ levels, effects likely to preserve functional myocyte excitation-contraction coupling. Gβ5 knockdown also reduced chemotherapy-induced release of pro-inflammatory cytokines (e.g. TNFα), hypertrophic factors (e.g. ANP), and pro-fibrotic factors (e.g. TGFβ1) from both VCM and ventricular cardiac fibroblasts (VCF), with the most dramatic reductions occurring in co-cultured cells. Intracardiac injection of Gβ5-targeted shRNA allowed for heart specific protection against the damaging impact of chronic chemotherapy. These data suggest that Gβ5 facilitates the myofibroblast transition, the persistence of which contributes to pathological remodeling and heart failure. The convergence of Gβ5-mediated, ROS-dependent signaling pathways in both cell types represents a critical etiological factor in the pathogenesis of chemotherapy-induced cardiotoxicity.

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CAT-02-106, a site-specifically conjugated anti-CD22 antibody bearing an MDR1-resistant maytansine payload yields excellent efficacy and safety in preclinical models

Hematologically-derived tumors make up ~10% of all newly-diagnosed cancer cases in the U.S. Of these, the non-Hodgkin lymphoma (NHL) designation describes a diverse group of cancers that collectively rank among the top 10 most commonly diagnosed cancers worldwide. Although long-term survival trends are improving, there remains a significant unmet clinical need for treatments to help patients with relapsed or refractory disease, one cause of which is drug efflux through upregulation of xenobiotic pumps, such as MDR1. CD22 is a clinically-validated target for the treatment of NHL, but no anti-CD22 agents have yet been approved for this indication. Recent approval of an anti-CD22 antibody-drug conjugate (ADC) for the treatment of relapsed/refractory ALL supports the rationale for targeting this protein. An opportunity exists for a next-generation anti-CD22 antibody-drug conjugate (ADC) to address unmet medical needs in the relapsed/refractory NHL population. We describe a site-specifically-conjugated antibody-drug conjugate, made using aldehyde tag technology, targeted against CD22 and bearing a noncleavable maytansine payload that is resistant to MDR1-mediated efflux. The construct was efficacious against CD22+ NHL xenografts and could be repeatedly dosed in cynomolgus monkeys at 60 mg/kg with no observed significantly adverse effects. Exposure to total ADC at these doses (as assessed by AUC0-inf) indicated that the exposure needed to achieve efficacy was below tolerable limits. Together, the data suggest that this drug has the potential to be used effectively in patients with CD22+ tumors that have developed MDR1-related resistance to prior therapies.

http://ift.tt/2AKqbBC

Characterization of SGN-CD123A, a potent CD123-directed antibody-drug conjugate for acute myeloid leukemia

Treatment choices for acute myeloid leukemia (AML) patients resistant to conventional chemotherapies are limited and novel therapeutic agents are needed. Interleukin-3 receptor alpha (IL-3Rα, or CD123) is expressed on the majority of AML blasts and there is evidence that its expression is increased on leukemic relative to normal hematopoietic stem cells, which makes it an attractive target for antibody-based therapy. Here we report the generation and preclinical characterization of SGN-CD123A, an antibody-drug conjugate utilizing the pyrrolobenzodiazepine dimer (PBD) linker and a humanized CD123 antibody with engineered cysteines for site-specific conjugation. Mechanistically, SGN-CD123A induces activation of DNA damage response pathways, cell cycle changes, and apoptosis in AML cells. In vitro, SGN-CD123A mediated potent cytotoxicity of 11/12 CD123+ AML cell lines and 20/23 primary samples from AML patients, including those with unfavorable cytogenetic profiles or FLT3 mutations. In vivo, SGN-CD123A treatment led to AML eradication in a disseminated disease model, remission in a subcutaneous xenograft model, and significant growth delay in a multidrug resistance xenograft model. Moreover, SGN-CD123A also resulted in durable complete remission of a patient-derived xenograft AML model. When combined with a FLT3 inhibitor quizartinib, SGN-CD123A enhanced the activity of quizartinib against two FLT3-mutated xenograft models. Overall, these data demonstrate that SGN-CD123A is a potent anti-leukemic agent, supporting an ongoing trial to evaluate its safety and efficacy in AML patients (NCT02848248).

http://ift.tt/2iiY9q2

JQ1 induces DNA damage and apoptosis, and inhibits tumor growth in a patient-derived xenograft model of cholangiocarcinoma

Cholangiocarcinoma (CCA) is a fatal disease with a five-year survival of <30%. For a majority of patients chemotherapy is the only therapeutic option, and virtually all patients relapse. Gemcitabine is the frontline agent for treatment of CCA. Patients treated with gemcitabine monotherapy survive ~8 months. Combining this agent with cisplatin increases survival by ~3 months, but neither regimen produces durable remissions. The molecular etiology of this disease is poorly understood. To facilitate molecular characterization and development of effective therapies for CCA, we established a panel of patient-derived xenograft (PDX) models of CCA. We used two of these models to investigate the anti-tumor efficacy and mechanism of action of the bromodomain inhibitor JQ1, an agent that has not been evaluated for the treatment of CCA. The data show that JQ1 suppressed the growth of the CCA PDX model CCA2, and demonstrate that growth suppression was concomitant with inhibition of c-Myc protein expression. A second model (CCA1) was JQ1-insensitive, with tumor progression and c-Myc expression unaffected by exposure to this agent. Also selective to CCA2 tumors, JQ1 induced DNA damage and apoptosis, and downregulated multiple c-Myc transcriptional targets that regulate cell cycle progression and DNA repair. These findings suggest that c-Myc inhibition and several of its transcriptional targets may contribute to the mechanism of action of JQ1 in this tumor type. We conclude that BET inhibitors such as JQ1 warrant further investigation for the treatment of CCA.

http://ift.tt/2AJOGz1

Pharmacologic inhibition of the menin-MLL interaction leads to transcriptional repression of PEG10 and blocks hepatocellular carcinoma

Hepatocellular carcinoma (HCC) accounts for ~85% of malignant liver tumors and results in 600,000 deaths each year, emphasizing the need for new therapies. Upregulation of menin was reported in HCC patients and high levels of menin correlate with poor patient prognosis. The protein-protein interaction between menin and histone methyltransferase Mixed Lineage Leukemia 1 (MLL1) plays an important role in the development of HCC, implying that pharmacologic inhibition of this interaction could lead to new therapeutic strategy for the HCC patients. Here, we demonstrate that the menin-MLL inhibitor MI-503 shows anti-tumor activity in in vitro and in vivo models of HCC and reveal the potential mechanism of menin contribution to HCC. Treatment with MI-503 selectively kills various HCC cell lines and this effect is significantly enhanced by a combination of MI-503 with sorafenib, the standard of care therapy for HCC. Furthermore, MI-503 reduces sphere formation and cell migration in in vitro HCC models. When applied in vivo, MI-503 gives a strong anti-tumor effect both as a single agent and in combination with sorafenib in mice xenograft models of HCC. Mechanistically, treatment with MI-503 downregulates expression of several genes known to play a critical role in proliferation and migration of HCC cells, including PEG10, and displaces the menin-MLL1 complex from the PEG10 promoter, resulting in reduced H3K4 methylation and transcriptional repression. Overall, our studies reveal a mechanistic link between menin and genes involved in HCC and demonstrate that pharmacologic inhibition of the menin-MLL interaction might represent a promising therapeutic approach for HCC.

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CAT-02-106, a site-specifically conjugated anti-CD22 antibody bearing an MDR1-resistant maytansine payload yields excellent efficacy and safety in preclinical models

Hematologically-derived tumors make up ~10% of all newly-diagnosed cancer cases in the U.S. Of these, the non-Hodgkin lymphoma (NHL) designation describes a diverse group of cancers that collectively rank among the top 10 most commonly diagnosed cancers worldwide. Although long-term survival trends are improving, there remains a significant unmet clinical need for treatments to help patients with relapsed or refractory disease, one cause of which is drug efflux through upregulation of xenobiotic pumps, such as MDR1. CD22 is a clinically-validated target for the treatment of NHL, but no anti-CD22 agents have yet been approved for this indication. Recent approval of an anti-CD22 antibody-drug conjugate (ADC) for the treatment of relapsed/refractory ALL supports the rationale for targeting this protein. An opportunity exists for a next-generation anti-CD22 antibody-drug conjugate (ADC) to address unmet medical needs in the relapsed/refractory NHL population. We describe a site-specifically-conjugated antibody-drug conjugate, made using aldehyde tag technology, targeted against CD22 and bearing a noncleavable maytansine payload that is resistant to MDR1-mediated efflux. The construct was efficacious against CD22+ NHL xenografts and could be repeatedly dosed in cynomolgus monkeys at 60 mg/kg with no observed significantly adverse effects. Exposure to total ADC at these doses (as assessed by AUC0-inf) indicated that the exposure needed to achieve efficacy was below tolerable limits. Together, the data suggest that this drug has the potential to be used effectively in patients with CD22+ tumors that have developed MDR1-related resistance to prior therapies.

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via IFTTT

Characterization of SGN-CD123A, a potent CD123-directed antibody-drug conjugate for acute myeloid leukemia

Treatment choices for acute myeloid leukemia (AML) patients resistant to conventional chemotherapies are limited and novel therapeutic agents are needed. Interleukin-3 receptor alpha (IL-3Rα, or CD123) is expressed on the majority of AML blasts and there is evidence that its expression is increased on leukemic relative to normal hematopoietic stem cells, which makes it an attractive target for antibody-based therapy. Here we report the generation and preclinical characterization of SGN-CD123A, an antibody-drug conjugate utilizing the pyrrolobenzodiazepine dimer (PBD) linker and a humanized CD123 antibody with engineered cysteines for site-specific conjugation. Mechanistically, SGN-CD123A induces activation of DNA damage response pathways, cell cycle changes, and apoptosis in AML cells. In vitro, SGN-CD123A mediated potent cytotoxicity of 11/12 CD123+ AML cell lines and 20/23 primary samples from AML patients, including those with unfavorable cytogenetic profiles or FLT3 mutations. In vivo, SGN-CD123A treatment led to AML eradication in a disseminated disease model, remission in a subcutaneous xenograft model, and significant growth delay in a multidrug resistance xenograft model. Moreover, SGN-CD123A also resulted in durable complete remission of a patient-derived xenograft AML model. When combined with a FLT3 inhibitor quizartinib, SGN-CD123A enhanced the activity of quizartinib against two FLT3-mutated xenograft models. Overall, these data demonstrate that SGN-CD123A is a potent anti-leukemic agent, supporting an ongoing trial to evaluate its safety and efficacy in AML patients (NCT02848248).

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JQ1 induces DNA damage and apoptosis, and inhibits tumor growth in a patient-derived xenograft model of cholangiocarcinoma

Cholangiocarcinoma (CCA) is a fatal disease with a five-year survival of <30%. For a majority of patients chemotherapy is the only therapeutic option, and virtually all patients relapse. Gemcitabine is the frontline agent for treatment of CCA. Patients treated with gemcitabine monotherapy survive ~8 months. Combining this agent with cisplatin increases survival by ~3 months, but neither regimen produces durable remissions. The molecular etiology of this disease is poorly understood. To facilitate molecular characterization and development of effective therapies for CCA, we established a panel of patient-derived xenograft (PDX) models of CCA. We used two of these models to investigate the anti-tumor efficacy and mechanism of action of the bromodomain inhibitor JQ1, an agent that has not been evaluated for the treatment of CCA. The data show that JQ1 suppressed the growth of the CCA PDX model CCA2, and demonstrate that growth suppression was concomitant with inhibition of c-Myc protein expression. A second model (CCA1) was JQ1-insensitive, with tumor progression and c-Myc expression unaffected by exposure to this agent. Also selective to CCA2 tumors, JQ1 induced DNA damage and apoptosis, and downregulated multiple c-Myc transcriptional targets that regulate cell cycle progression and DNA repair. These findings suggest that c-Myc inhibition and several of its transcriptional targets may contribute to the mechanism of action of JQ1 in this tumor type. We conclude that BET inhibitors such as JQ1 warrant further investigation for the treatment of CCA.

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Rare Tumors in Kids May Respond to Tazemetostat [News in Brief]

EZH2 inhibitor shows some efficacy against INI1-deficient tumors.

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Wild Microbiome Stems Tumorigenesis in Lab Mice [News in Brief]

"Clean" lab animals given their wild counterparts' gut microbes are more resistant to colorectal cancer.

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Quality assurance of the SCOPE 1 trial in oesophageal radiotherapy

SCOPE 1 was the first UK based multi-centre trial involving radiotherapy of the oesophagus. A comprehensive radiotherapy trials quality assurance programme was launched with two main aims:  

http://ift.tt/2A2YCqQ

Quality assurance of the SCOPE 1 trial in oesophageal radiotherapy

SCOPE 1 was the first UK based multi-centre trial involving radiotherapy of the oesophagus. A comprehensive radiotherapy trials quality assurance programme was launched with two main aims:  

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Patient-derived xenograft in zebrafish embryos: a new platform for translational research in gastric cancer

Gastric cancer (GC) is among the most commonly cancer occurred in Asian, especially in China. With its high heterogeneity and few of validated drug targets, GC remains to be one of the most under explored area...

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Involvement of aberrantly activated HOTAIR/EZH2/miR-193a feedback loop in progression of prostate cancer

Though androgen deprivation therapy is the standard treatment for prostate cancer (PCa), most patients would inevitably progress to castration-resistant prostate cancer (CRPC) which is the main cause of PCa de...

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Use of an intraoperative navigation system and piezoelectric surgery for styloidectomy in a patient with Eagle’s syndrome: a case report

Elongated styloid process syndrome (Eagle's syndrome) is the term given to the symptomatic elongation of the styloid process or the mineralization of the stylohyoid or stylomandibular ligament. The two commonl...

http://ift.tt/2AQPuTh

Health-related-quality-of-life and toxicity after single fraction 19 Gy high-dose-rate prostate brachytherapy: Phase II trial

To evaluate the safety, tolerance and impact on health-related-quality-of-life (HRQoL) of the high-dose-rate brachytherapy of 19 Gy (BRT-HDR-19 Gy) single fraction in prostate cancer.

http://ift.tt/2mvm9KZ

Impact of hybrid PET/MR technology on multiparametric imaging and treatment response assessment of cervix cancer

Multimodal tissue characterization by combined MRI and PET has high clinical potential in the context of sub-target definition for dose painting and response assessment but its clinical exploration is yet limited. The aim of this study was to prove the potential and feasibility of hybrid PET/MRI to non-invasively measure tumor hypoxia, perfusion and microstructure at one stop in tumors of the uterine cervix during chemoradiotherapy.

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Late normal tissue effects in the arm and shoulder following lymphatic radiotherapy: Results from the UK START (Standardisation of Breast Radiotherapy) trials

Adjuvant lymphatic radiotherapy (LNRT) is recommended for selected axillary node positive women with early breast cancer. We investigated whether hypofractionated LNRT is safe combined with similarly-hypofractionated breast/chest wall radiotherapy (RT).

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Should Hospitals Market Opioid-Sparing Analgesia to Patients?.

No abstract available

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Comparison of Continuous Proximal Versus Distal Adductor Canal Blocks for Total Knee Arthroplasty: A Randomized, Double-Blind, Noninferiority Trial.

Background and Objectives: Adductor canal blocks (ACBs) are associated with improved analgesia, preserved quadriceps strength, and decreased length of hospitalization after total knee arthroplasty (TKA). However, controversy remains regarding the ideal location of a continuous block within the adductor canal, and it remains unclear whether similar clinical benefits are obtained irrespective of block location. In this randomized, double-blind, noninferiority study, we hypothesized that a continuous proximal ACB provides postoperative analgesia that is no worse than a continuous distal ACB. Methods: Subjects presenting for unilateral TKA were randomized in a 1:1 ratio to either a continuous proximal or distal ACB group. The primary outcome of this noninferiority study was opioid consumption within the first 24 hours following surgery. Secondary outcomes included quadriceps strength, pain scores, distance ambulated, and patient satisfaction. Results: Seventy-three subjects, 36 from the proximal group and 37 from the distal group, completed the study per protocol. The intention-to-treat analysis demonstrated a cumulative mean intravenous morphine equivalent consumption difference between the proximal and distal groups of -7.2 mg (95% confidence interval, -14.8 to 0.4; P

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Radiofrequency Procedures to Relieve Chronic Hip Pain: An Evidence-Based Narrative Review.

Background and Objectives: Chronic hip pain from osteoarthritis and other degenerative conditions is a common problem. A few publications have recently reported analgesic success of radiofrequency (RF) procedures on nerves innervating the hip, but interpretation is hampered by lack of clarity regarding indications, clinical protocols, anatomic targets, and longevity of benefit from RF procedures. Methods: We reviewed the following medical literature databases for publications on RF procedures on the hip joint for chronic pain: MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials, Cochrane Database of Systematic Reviews, and Google Scholar through February 28, 2017. Existing knowledge on innervation of the hip joint was synthesized. Data on analgesic and functional outcomes and adverse effects measured at any time points following the interventions were also collected, analyzed, and reported in this narrative review. Results: Fourteen publications on ablative RF treatments of innervation of the hip joint were identified. A high success rate of these procedures in relieving chronic pain of the hip joint was reported at 8 days to 36 months after the procedures, but none of the publications were randomized controlled trials. There was evidence for improvement in function and a lack of serious adverse events of RF treatments. Conclusions: Radiofrequency treatments for the sensory innervation of the hip joint have the potential to reduce pain secondary to degenerative conditions. Ongoing concerns remain regarding the anatomic targets, as well as quality, procedural aspects, and monitoring of outcomes in publications on this topic. Randomized controlled trials of high methodological quality are required to further elaborate the role of these interventions in this population. Copyright (C) 2017 by American Society of Regional Anesthesia and Pain Medicine.

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Cervical Foraminal Epidural Blood Patch for the Targeted Treatment of Refractory Cerebrospinal Fluid Leakage From a Dural Sleeve.

Epidural blood patches (EBPs) are routinely used to treat symptoms (eg, headaches) associated with spontaneous intracranial hypotension. Although cerebrospinal fluid leakage commonly involves the periforaminal areas of the cervical or thoracic spine, EBPs have been historically performed at the lumbar level. Recent evidence suggests that targeting the causative spinal segment may provide greater clinical benefits. While previous reports have targeted foraminal leaks with segmental thoracic or cervical injections, we present a case report detailing the novel use of a navigable epidural catheter to perform a selective EBP at the C7/T1 foramen. Copyright (C) 2017 by American Society of Regional Anesthesia and Pain Medicine.

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Anatomic Study of Innervation of the Anterior Hip Capsule: Implication for Image-Guided Intervention.

Background and Objectives: The purpose of this cadaveric study was to determine the pattern of anterior hip capsule innervation and the associated bony landmarks for image-guided radiofrequency denervation. Methods: Thirteen hemipelvises were dissected to identify innervation of the anterior hip capsule. The femoral (FN), obturator (ON), and accessory obturator (AON) nerves were traced distally, and branches supplying the anterior capsule documented. The relationships of the branches to bony landmarks potentially visible with ultrasound were identified. Results: The anterior hip capsule received innervation from the FNs and ONs in all specimens and the AON in 7 of 13 specimens. High branches of the FN (originating above the inguinal ligament) were found exclusively in 12 specimens and passed between the anterior inferior iliac spine and the iliopubic eminence. The ONs were innervated exclusively by high branches (proximal to the division), by low branches (from the posterior branch), and by both in 4, 5, and 4 specimens, respectively. The most consistent landmark was the inferomedial acetabulum (radiographic "teardrop"). When present, the AON coursed over the iliopubic eminence before innervating the anterior hip capsule. Conclusions: Branches of the FNs and ONs consistently provided innervation to the anterior hip capsule. The AON also contributed innervation in many specimens. The relationship of the articular branches from these 3 nerves to the inferomedial acetabulum and the space between the anterior inferior iliac spine and iliopubic eminence may suggest potential sites for radiofrequency ablation. Copyright (C) 2017 by American Society of Regional Anesthesia and Pain Medicine.

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Immune checkpoint inhibitor therapy in a liver transplant recipient with a rare subtype of melanoma: a case report and literature review.

Immunotherapy with immune checkpoint inhibitors (ICIs) may be considered as a treatment option for various types of tumors, but the transplant recipient population as well as patients requiring long-term systemic immunosuppression for other reasons have been systematically excluded from clinical trials involving ICIs. We report a case of successful treatment with ICI in a liver transplant recipient diagnosed with a rare subtype of melanoma. This patient had not required any modification to her antirejection immunosuppression before or during immunotherapy, had not experienced any serious immune-related adverse event, and had a durable objective response for nearly 1.5 year now. A summary of a literature review on other case reports is included to show that ICIs can be safe and provide clinically meaningful benefit in transplant patients, although acute rejection and graft loss remain a significant risk. Given the serious complication of graft failure, a detailed discussion of risks and benefits with immunotherapy needs to be made for an informed consent. Nevertheless, transplant recipients with cancer should not be deprived of this potentially life-saving or life-prolonging treatment, and inclusion of this population in future clinical trials should be considered. Copyright (C) 2017 Wolters Kluwer Health, Inc. All rights reserved.

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Prognostic factors in patients with metastatic spinal cord compression secondary to melanoma: a systematic review.

Melanoma is one of the most common primary tumours associated with metastatic spinal cord compression (MSCC). The aim of this review is to identify prognostic factors specifically for MSCC secondary to melanoma. A systematic search of literature was performed in MEDLINE, Embase and the Cochrane Library to identify studies reporting prognostic factors for patients with MSCC secondary to melanoma. Two studies, involving a total of 39 patients, fulfilled the inclusion criteria. The variables associated with increased survival were receiving postoperative radiotherapy, receiving chemotherapy, perioperative lactate dehydrogenase level less than or equal to 8.0 [micro]kat/l, preoperative haemoglobin level more than 11.5 mg/dl, an interval of 4 or more years between melanoma diagnosis and skeletal metastasis, absence of further skeletal metastases, absence of visceral metastases, Eastern Cooperative Oncology Group Performance Status of 2 or less, two or fewer involved vertebrae, being ambulatory preradiotherapy and an interval of more than 7 days between developing motor deficits and radiotherapy. The variables associated with good functional outcome were slow development of motor dysfunction, good performance status and being ambulatory before radiotherapy. The most important prognostic factors for survival are Eastern Cooperative Oncology Group Performance Status of 2 or less and absence of visceral metastases. There is a lack of studies looking specifically at prognostic factors for patients with MSCC secondary to melanoma, and the number of patients involved in the existing studies is small. Copyright (C) 2017 Wolters Kluwer Health, Inc. All rights reserved.

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Editorial Board

Publication date: December 2017
Source:Cancer Treatment Reviews, Volume 61





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Intraoperative vasoplegia: methylene blue to the rescue!

Purpose of review To evaluate the efficacy, dosing, and safety of methylene blue (MTB) in perioperative vasoplegic syndrome (VS). Recent findings Vasoplegic syndrome is a state of persistent hypotension with elevated cardiac output, low filling pressures, and low systemic vascular resistance (SVR). It occurs in up to 25% of patients undergoing cardiac surgery with cardiopulmonary bypass, can last up to 72 h, and is associated with a high mortality rate. MTB has been found to increase SVR and decrease vasopressor requirements in vasoplegic syndrome by inhibiting nitric oxide synthase, thus limiting the generation of nitric oxide, while inhibiting activation of soluble guanylyl cyclase and preventing vasodilation. MTB has been used in postgraft reperfusion during liver transplantation and anaphylaxis in a limited number of cases. Additionally, this medication has been used in septic shock with promising results, but similar to the cardiac surgical population, the effects of MTB administration on clinical outcomes has yet to be elucidated. Summary MTB should be considered during vasoplegic syndrome in cardiac surgery with cardiopulmonary bypass and usage may be more effective in an early critical window, prior to end-organ hypoperfusion. Other perioperative scenarios of MTB use show promise, but additional studies are required to develop formative conclusions. Correspondence to Kamrouz Ghadimi, MD, Divisions of Cardiothoracic Anesthesia and Critical Care Medicine, Department of Anesthesiology, Duke University Medical Center, Box 3094/HAFS 5691G, Durham, NC 27710, USA. Tel: +1 919 681 6532; e-mail: Kamrouz.Ghadimi@duke.edu Copyright © 2017 YEAR Wolters Kluwer Health, Inc. All rights reserved.

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Vitamin C in sepsis

Purpose of review This narrative review summarizes recent insights into the role of vitamin C in sepsis. Recent findings Septic shock remains a major source of morbidity and mortality in critically ill patients. Although many nutritional supplements have previously been tested unsuccessfully, vitamins are still being explored as a therapeutic option in septic patients. In particular, vitamin C-containing regimens as adjunctive therapy in sepsis have received much attention. Summary In-vitro evidence supports a critical role for vitamin C in cellular mechanisms relevant to the pathophysiology of sepsis. However, whether this justifies therapeutic use of vitamin C in septic patients remains uncertain. Correspondence to Karsten Bartels, MD, MS, Assistant Professor, Department of Anesthesiology, University of Colorado Denver, 12401 E. 17th Avenue, Leprino Office Building, 7th Floor, MS B-113, Aurora, CO 80045, USA. Tel: +1 720 848 6752; fax: +1 720 848 7375; e-mail: karsten.bartels@ucdenver.edu Copyright © 2017 YEAR Wolters Kluwer Health, Inc. All rights reserved.

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Obstructive sleep apnea and bariatric surgical guidelines: summary and update

Purpose of review Increasing numbers of bariatric surgical procedures and the high prevalence of obstructive sleep apnea (OSA) in this population have resulted in a growing interest in the perioperative management of OSA in bariatric surgery. This review provides a summary of the first consensus guideline on this topic as well as an update of the newest literature available. Recent findings All bariatric patients should be screened for OSA and obesity hypoventilation syndrome (OHS) to reduce the risk of perioperative complications. Intraoperative precautions are preoxygenation, induction and intubation in ramped position, continuous positive airway pressure (CPAP) and positive end-expiratory pressure during induction, maintenance of low tidal volumes during surgery, multimodal anesthesia and analgesia with avoidance of opioids and extubation when patients are free of neuromuscular blockage. CPAP therapy and continuous monitoring with a minimum of pulse oximetry is recommended in the early postoperative period. Summary Multiple precautions exist to minimize the risk of cardiopulmonary complications and to enhance recovery after surgery. A combination of these procedures seems to provide optimal perioperative care of OSA patients undergoing bariatric surgery. Nearly 75% of recommendations are based on low quality of evidence, indicating the high value of experts' opinion and potential for future research. Correspondence to Christel A.L. de Raaff, MD, Obesity Center Amsterdam, OLVG West, Jan Tooropstraat 164, 1061 AE Amsterdam, The Netherlands. Tel: +31 20 5108040; fax: +31 20 6854014; e-mail: calderaaff@gmail.com Copyright © 2017 YEAR Wolters Kluwer Health, Inc. All rights reserved.

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Anticipated and unanticipated difficult airway management

Purpose of review Management of difficult airway is far from optimal despite of continuous progress in science and technology. The purpose of this review is to summarize the current research in the field and bring readers up to date. Recent findings New technologies for intubation make providers more confident to handle difficult airways, but there is lack of evidence indicating the reduction in incidence of 'cannot intubate cannot ventilate (CICV)'. Optimization of mask ventilation should reduce the incidence of difficult mask ventilation but it is greatly underappreciated. Even optimization of preoxygenation is not directly associated with any decreased incidence of difficult airway, but it prolongs time of safe apnea oxygenation; therefore, is likely to improve the outcome of the patients if CICV occurs. Summary Improvement of managing difficult airway relies on optimized mask ventilation, utilization of the appropriate tools for intubation, maximization of the safe apnea oxygenation time, prompt surgical airway in response to severe hypoxia in case effective noninvasive interventions are not achievable. It seems that a simplified and concise algorithm of difficult airway management needs to be established in order to enable providers to easily remember and execute. Correspondence to Yandong Jiang, MD, PhD, Department of Anesthesiology, Vanderbilt University Medical Center, 1301 Medical Center Drive, 4648 TVC, Nashville, TN 37232-5614, USA. Tel: +1 615 343 9419; fax: +1 615 936 6493; e-mail: yandong.jiang@vanderbilt.edu Copyright © 2017 YEAR Wolters Kluwer Health, Inc. All rights reserved.

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Pulmonary effects of aging

Purpose of review As the population ages, the increase in chronic illnesses among patients with decreasing lung function will pose a major public health challenge. Determining which elderly patients are fit for surgery is an increasingly important skill. Anesthetic care of elderly patients requires an understanding of the effects that chronic diseases have on normal age-related changes in physiology and function. Postoperative respiratory complications are significantly increased in patients over 65 years of age, especially those with preexisting diseases. Recent findings Advanced age is associated with changes in the immunity of the pulmonary system. Dysregulation of pro-inflammatory mediators and antimicrobial defense systems contribute to a reduction in pulmonary function and its response to infections. Aging is also associated with a disruption of the function of alveolar macrophages, neutrophils, and natural killer cells. Summary Aging can increase the risk of postoperative complications because of a loss of physiologic reserve and airway defenses. These limitations may only become apparent after the stressors of surgery and anesthesia. Correspondence to Daniel Tran, MD, Department of Anesthesiology, Yale University School of Medicine, 333 Cedar Street, TMP 3rd floor, New Haven, CT 06520-8051, USA. Tel: +1 203 785 2802; e-mail: daniel.tran@yale.edu Copyright © 2017 YEAR Wolters Kluwer Health, Inc. All rights reserved.

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Many Ovarian Cancers May Start in Fallopian Tubes, Study Finds

A new study provides more evidence that the most common form of ovarian cancer may originate in the fallopian tubes, and that there is a window of nearly 7 years between development of fallopian tube lesions and the start of ovarian cancer.

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Many Ovarian Cancers May Start in Fallopian Tubes, Study Finds

A new study provides more evidence that the most common form of ovarian cancer may originate in the fallopian tubes, and that there is a window of nearly 7 years between development of fallopian tube lesions and the start of ovarian cancer.

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DETECT I & DETECT II: a study protocol for a prospective multicentre observational study to validate the UroMark assay for the detection of bladder cancer from urinary cells

Abstract

Background

Haematuria is a common finding in general practice which requires visual inspection of the bladder by cystoscopy as well as upper tract imaging. In addition, patients with non-muscle invasive bladder cancer (NMIBC) often require surveillance cystoscopy as often as three monthly depending on disease risk. However, cystoscopy is an invasive procedure which is uncomfortable, requires hospital attendance and is associated with a risk of urinary tract infection. We have developed the UroMark assay, which can detect 150 methylation specific alteration specific to bladder cancer using DNA from urinary sediment cells.

Methods

DETECT I and DETECT II are two multi-centre prospective observational studies designed to conduct a robust validation of the UroMark assay. DETECT I will recruit patients having diagnostic investigations for haematuria to determine the negative predictive value of the UroMark to rule out the presence of bladder cancer. DETECT II will recruit patients with new or recurrent bladder cancer to determine the sensitivity of the UroMark in detecting low, intermediate and high grade bladder cancer. NMIBC patients in DETECT II will be followed up with three monthly urine sample collection for 24 months while having surveillance cystoscopy. DETECT II will include a qualitative analysis of semi-structured interviews to explore patients' experience of being diagnosed with bladder cancer and having cystoscopy and a urinary test for bladder cancer surveillance. Results of the UroMark will be compared to cystoscopy findings and histopathological results in patients with bladder cancer.

Discussion

A sensitive and specific urinary biomarker will revolutionise the haematuria diagnostic pathway and surveillance strategies for NMIBC patients. None of the six approved US Food and Drug Administration urinary test are recommended as a standalone test. The UroMark assay is based on next generation sequencing technology which interrogates 150 loci and represents a step change compared to other biomarker panels. This enhances the sensitivity of the test and by using a random forest classifier approach, where the UroMark results are derived from a cut off generated from known outcomes of previous samples, addresses many shortcomings of previous assays.

Trial registration

Both trails are registered on clinicaltrials.gov. DETECT I: NCT02676180 (18th December 2015). DETECT II: NCT02781428 (11th May 2016).

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In response to Fogarty et al. and why adjuvant whole brain radiotherapy is not recommended routinely

Abstract

The routine use of adjuvant whole brain radiotherapy (AWBRT) after surgery or stereotactic radiosurgery is now discouraged by a number of international expert panels. Three decades of randomised studies have shown that, although AWBRT improves radiological measures of intracranial disease control, the clinical benefit is unclear and it is also associated with inferior quality of life and neurocognitive function. The number of patients with melanoma in these trials was low, but data suggesting that treatment-related side effects should vary according to histology of the primary malignancy are lacking. For metastatic melanoma, the role of AWBRT to control microscopic disease in the brain is also a less relevant concern because systemic therapies with intracranial activity are now available. Whether AWBRT is useful in select patients deemed at high risk of neurologic death remains undefined.

http://ift.tt/2AOGdLL

DETECT I & DETECT II: a study protocol for a prospective multicentre observational study to validate the UroMark assay for the detection of bladder cancer from urinary cells

Abstract

Background

Haematuria is a common finding in general practice which requires visual inspection of the bladder by cystoscopy as well as upper tract imaging. In addition, patients with non-muscle invasive bladder cancer (NMIBC) often require surveillance cystoscopy as often as three monthly depending on disease risk. However, cystoscopy is an invasive procedure which is uncomfortable, requires hospital attendance and is associated with a risk of urinary tract infection. We have developed the UroMark assay, which can detect 150 methylation specific alteration specific to bladder cancer using DNA from urinary sediment cells.

Methods

DETECT I and DETECT II are two multi-centre prospective observational studies designed to conduct a robust validation of the UroMark assay. DETECT I will recruit patients having diagnostic investigations for haematuria to determine the negative predictive value of the UroMark to rule out the presence of bladder cancer. DETECT II will recruit patients with new or recurrent bladder cancer to determine the sensitivity of the UroMark in detecting low, intermediate and high grade bladder cancer. NMIBC patients in DETECT II will be followed up with three monthly urine sample collection for 24 months while having surveillance cystoscopy. DETECT II will include a qualitative analysis of semi-structured interviews to explore patients' experience of being diagnosed with bladder cancer and having cystoscopy and a urinary test for bladder cancer surveillance. Results of the UroMark will be compared to cystoscopy findings and histopathological results in patients with bladder cancer.

Discussion

A sensitive and specific urinary biomarker will revolutionise the haematuria diagnostic pathway and surveillance strategies for NMIBC patients. None of the six approved US Food and Drug Administration urinary test are recommended as a standalone test. The UroMark assay is based on next generation sequencing technology which interrogates 150 loci and represents a step change compared to other biomarker panels. This enhances the sensitivity of the test and by using a random forest classifier approach, where the UroMark results are derived from a cut off generated from known outcomes of previous samples, addresses many shortcomings of previous assays.

Trial registration

Both trails are registered on clinicaltrials.gov. DETECT I: NCT02676180 (18th December 2015). DETECT II: NCT02781428 (11th May 2016).

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In response to Fogarty et al. and why adjuvant whole brain radiotherapy is not recommended routinely

Abstract

The routine use of adjuvant whole brain radiotherapy (AWBRT) after surgery or stereotactic radiosurgery is now discouraged by a number of international expert panels. Three decades of randomised studies have shown that, although AWBRT improves radiological measures of intracranial disease control, the clinical benefit is unclear and it is also associated with inferior quality of life and neurocognitive function. The number of patients with melanoma in these trials was low, but data suggesting that treatment-related side effects should vary according to histology of the primary malignancy are lacking. For metastatic melanoma, the role of AWBRT to control microscopic disease in the brain is also a less relevant concern because systemic therapies with intracranial activity are now available. Whether AWBRT is useful in select patients deemed at high risk of neurologic death remains undefined.

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Association of DNA repair genes polymorphisms and mutations with increased risk of head and neck cancer: a review

Abstract

DNA repair mechanisms allow maintain genomic stability and proper functioning within the cells. Any aberrations may cause an increased risk of many diseases such as cancer. The most crucial risk factors for head and neck squamous cell carcinoma are behavioral factors, predominantly chronic exposure to tobacco, alcohol addiction, and infection with human papillomavirus or Epstein–Barr virus. These agents can induce DNA damage; therefore, cells must activate appropriate mechanisms in order to function correctly. Cancer cells are marked with genomic instability, which is associated with a greater tendency for the accumulation of a DNA damage and increased chemo- and radioresistance. Multiple studies have assessed the correlation of increased head and neck cancer (HNC) risk with polymorphism in the DNA repair genes. However, they suggest that interaction of DNA repair genes mutations with susceptibility to HNC depends on a patient's race and risk factors, especially tobacco smoking. Further identification of these sequence variations must be performed. In this review, we discuss the current knowledge about the DNA repair genes mutations and polymorphisms associated with the high risk of head and neck treatment.

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Association of DNA repair genes polymorphisms and mutations with increased risk of head and neck cancer: a review

Abstract

DNA repair mechanisms allow maintain genomic stability and proper functioning within the cells. Any aberrations may cause an increased risk of many diseases such as cancer. The most crucial risk factors for head and neck squamous cell carcinoma are behavioral factors, predominantly chronic exposure to tobacco, alcohol addiction, and infection with human papillomavirus or Epstein–Barr virus. These agents can induce DNA damage; therefore, cells must activate appropriate mechanisms in order to function correctly. Cancer cells are marked with genomic instability, which is associated with a greater tendency for the accumulation of a DNA damage and increased chemo- and radioresistance. Multiple studies have assessed the correlation of increased head and neck cancer (HNC) risk with polymorphism in the DNA repair genes. However, they suggest that interaction of DNA repair genes mutations with susceptibility to HNC depends on a patient's race and risk factors, especially tobacco smoking. Further identification of these sequence variations must be performed. In this review, we discuss the current knowledge about the DNA repair genes mutations and polymorphisms associated with the high risk of head and neck treatment.

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ASCO 2017—making a difference in cancer care with you

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ASCO 2017—making a difference in cancer care with you

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Myo-inositol concentration in MR spectroscopy for differentiating high grade glioma from primary central nervous system lymphoma

Abstract

It is sometimes difficult to distinguish gliomas from other tumors on routine imaging. In this study, we assessed whether 3-T magnetic resonance spectroscopy (MRS) with LCModel software might be useful for discriminating glioma from other brain tumors, such as primary central nervous system lymphomas (PCNSLs) and metastatic tumors. A total of 104 cases of brain tumor (66 gliomas, 20 PCNSLs, 6 metastatic tumors, 12 other tumors) were preoperatively investigated with short echo time (35 ms) single-voxel 3-T MRS. LCModel software was used to evaluate differences in the absolute concentrations of choline, N-acetylaspartate, N-acetylaspartylglutamate, glutamate + glutamine, myo-inositol (mIns), and lipid. mIns levels were significantly increased in high-grade glioma (HGG) compared with PCNSL (p < 0.001). In multivariate logistic regression analysis, mIns was the best marker for differentiating HGG from PCNSL (p < 0.0001, odds ratio 1.9927, 95% confidence interval 1.3628–3.2637). Conventional MRS detection of mIns resulted in a high diagnostic accuracy (sensitivity, 64%; specificity, 90%; area under the receiver operator curve, 0.80) for HGG. The expression of inositol 3-phosphate synthase (ISYNA1) was significantly higher in gliomas than in PCNSLs (p < 0.05), suggesting that the increased level of mIns in glioma is due to high expression of ISYNA1, the rate-limiting enzyme in the mIns-producing pathway. In conclusion, noninvasive analysis of mIns using single-voxel MRS may be useful in distinguishing gliomas from other brain tumors, particularly PCNSLs.

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Epigenetic silencing of ADAMTS5 is associated with increased invasiveness and poor survival in patients with colorectal cancer

Abstract

Purpose

A disintegrin and metalloprotease with motif 5(ADAMTS5) has been involved in colorectal cancer (CRC) with hypermethylation in the promoter. However, its role in CRC remains unclear. The aim of this study was to explore the clinical significance and biological effect of ADAMTS5 on colorectal carcinogenesis. Through MSP, qRT-PCR, WB and IHC analysis, followed by a variety of in vitro assays, we report the function of ADAMTS5 in CRC. ADAMTS5 was markedly hypermethylaed and downregulated in tumor tissues compared with non-tumor tissues (p < 0.001). Negative expression of ADAMTS5 was much more common in tumor tissues than that in normal tissues (p < 0.001) and correlated with histologic types (p = 0.002), poor OS (p = 0.029) and DFS (p = 0.018). In vitro assay revealed that overexpression of ADAMTS5 inhibited the capabilities of migration and invasion of CRC cells, and no effect on cell growth, cell cycle and apoptosis. ADAMTS5 is hypermethylated and inhibits cancer cells invasion and migration in colorectal cancer, and correlates with OS and DFS, indicating that ADAMTS5 might be a useful biomarker in colorectal cancer therapy.

http://ift.tt/2A08Ubr

Myo-inositol concentration in MR spectroscopy for differentiating high grade glioma from primary central nervous system lymphoma

Abstract

It is sometimes difficult to distinguish gliomas from other tumors on routine imaging. In this study, we assessed whether 3-T magnetic resonance spectroscopy (MRS) with LCModel software might be useful for discriminating glioma from other brain tumors, such as primary central nervous system lymphomas (PCNSLs) and metastatic tumors. A total of 104 cases of brain tumor (66 gliomas, 20 PCNSLs, 6 metastatic tumors, 12 other tumors) were preoperatively investigated with short echo time (35 ms) single-voxel 3-T MRS. LCModel software was used to evaluate differences in the absolute concentrations of choline, N-acetylaspartate, N-acetylaspartylglutamate, glutamate + glutamine, myo-inositol (mIns), and lipid. mIns levels were significantly increased in high-grade glioma (HGG) compared with PCNSL (p < 0.001). In multivariate logistic regression analysis, mIns was the best marker for differentiating HGG from PCNSL (p < 0.0001, odds ratio 1.9927, 95% confidence interval 1.3628–3.2637). Conventional MRS detection of mIns resulted in a high diagnostic accuracy (sensitivity, 64%; specificity, 90%; area under the receiver operator curve, 0.80) for HGG. The expression of inositol 3-phosphate synthase (ISYNA1) was significantly higher in gliomas than in PCNSLs (p < 0.05), suggesting that the increased level of mIns in glioma is due to high expression of ISYNA1, the rate-limiting enzyme in the mIns-producing pathway. In conclusion, noninvasive analysis of mIns using single-voxel MRS may be useful in distinguishing gliomas from other brain tumors, particularly PCNSLs.

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Epigenetic silencing of ADAMTS5 is associated with increased invasiveness and poor survival in patients with colorectal cancer

Abstract

Purpose

A disintegrin and metalloprotease with motif 5(ADAMTS5) has been involved in colorectal cancer (CRC) with hypermethylation in the promoter. However, its role in CRC remains unclear. The aim of this study was to explore the clinical significance and biological effect of ADAMTS5 on colorectal carcinogenesis. Through MSP, qRT-PCR, WB and IHC analysis, followed by a variety of in vitro assays, we report the function of ADAMTS5 in CRC. ADAMTS5 was markedly hypermethylaed and downregulated in tumor tissues compared with non-tumor tissues (p < 0.001). Negative expression of ADAMTS5 was much more common in tumor tissues than that in normal tissues (p < 0.001) and correlated with histologic types (p = 0.002), poor OS (p = 0.029) and DFS (p = 0.018). In vitro assay revealed that overexpression of ADAMTS5 inhibited the capabilities of migration and invasion of CRC cells, and no effect on cell growth, cell cycle and apoptosis. ADAMTS5 is hypermethylated and inhibits cancer cells invasion and migration in colorectal cancer, and correlates with OS and DFS, indicating that ADAMTS5 might be a useful biomarker in colorectal cancer therapy.

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Structural and perfusion magnetic resonance imaging of the lung in cystic fibrosis

Abstract

Background

Because of its absence of ionising radiation and possibility for obtaining functional information, MRI is promising for assessing lung disease in children who require repetitive imaging for long-term follow-up.

Objective

To describe MRI findings in children with cystic fibrosis and evaluate semi-quantitative dynamic contrast-enhanced lung perfusion.

Materials and methods

We retrospectively compared lung MRI in 25 children and young adults with cystic fibrosis (median age 3.7 years) to 12 children (median age 2 years) imaged for other pathologies. MRI at 1.5 T included respiratory-gated sequences and contrast-enhanced lung perfusion imaging. We described and graded any morphologic change. Signal enhancement and time to peak values of perfusion abnormalities were compared to those of normally enhancing lung parenchyma.

Results

Frequent findings in patients with cystic fibrosis were bronchial wall thickening (24/25, 96%), areas of consolidation (22/25, 88%), enlarged lymph nodes (20/25, 80%), bronchiectasis (5/25, 20%) and mucus plugging (3/25, 12%). Compared to normally enhancing lung, perfusion defects (21/25, 84%), characterised by decreased enhancement, showed prolonged time to peak. Areas of consolidation showed increased enhancement. While time to peak of procedure-related atelectasis was not significantly different from that of normal lung, disease-related consolidation showed prolonged time to peak (P=0.01).

Conclusion

Lung MRI demonstrates structural and perfusion abnormalities in children and young people with cystic fibrosis. Semi-quantitative assessment of dynamic contrast-enhanced perfusion imaging might allow differentiation between procedure-related atelectasis and disease-related consolidation.

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Structural and perfusion magnetic resonance imaging of the lung in cystic fibrosis

Abstract

Background

Because of its absence of ionising radiation and possibility for obtaining functional information, MRI is promising for assessing lung disease in children who require repetitive imaging for long-term follow-up.

Objective

To describe MRI findings in children with cystic fibrosis and evaluate semi-quantitative dynamic contrast-enhanced lung perfusion.

Materials and methods

We retrospectively compared lung MRI in 25 children and young adults with cystic fibrosis (median age 3.7 years) to 12 children (median age 2 years) imaged for other pathologies. MRI at 1.5 T included respiratory-gated sequences and contrast-enhanced lung perfusion imaging. We described and graded any morphologic change. Signal enhancement and time to peak values of perfusion abnormalities were compared to those of normally enhancing lung parenchyma.

Results

Frequent findings in patients with cystic fibrosis were bronchial wall thickening (24/25, 96%), areas of consolidation (22/25, 88%), enlarged lymph nodes (20/25, 80%), bronchiectasis (5/25, 20%) and mucus plugging (3/25, 12%). Compared to normally enhancing lung, perfusion defects (21/25, 84%), characterised by decreased enhancement, showed prolonged time to peak. Areas of consolidation showed increased enhancement. While time to peak of procedure-related atelectasis was not significantly different from that of normal lung, disease-related consolidation showed prolonged time to peak (P=0.01).

Conclusion

Lung MRI demonstrates structural and perfusion abnormalities in children and young people with cystic fibrosis. Semi-quantitative assessment of dynamic contrast-enhanced perfusion imaging might allow differentiation between procedure-related atelectasis and disease-related consolidation.

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Involvement of aberrantly activated HOTAIR/EZH2/miR-193a feedback loop in progression of prostate cancer

Abstract

Background

Though androgen deprivation therapy is the standard treatment for prostate cancer (PCa), most patients would inevitably progress to castration-resistant prostate cancer (CRPC) which is the main cause of PCa death. Therefore, the identification of novel molecular mechanism regulating cancer progression and achievement of new insight into target therapy would be necessary for improving the benefits of PCa patients. This study aims to study the function and regulatory mechanism of HOTAIR/EZH2/miR-193a feedback loop in PCa progression.

Methods

MSKCC and TCGA datasets were used to identify miR-193a expression profile in PCa. Cell Counting Kit-8 (CCK-8) assays, colony formation, invasion, migration, flow cytometry, a xenograft model and Gene Set Enrichment Analysis were used to detect and analyze the biological function of miR-193a. Then, we assessed the role of HOTAIR and EZH2 in regulation of miR-193a expression by using plasmid, lentivirus and small interfering RNA (siRNA). Luciferase reporter assays and chromatin immunoprecipitation assays were performed to detect the transcriptional activation of miR-193a by EZH2 and HOTAIR. Further, qRT-PCR and luciferase reporter assays were conducted to examine the regulatory role of miR-193a controlling the HOTAIR expression in PCa. Finally, the correlation between HOTAIR, EZH2 and miR-193a expression were analyzed using In situ hybridization and immunohistochemistry.

Results

We found that miR-193a was significantly downregulated in metastatic PCa through mining MSKCC and TCGA datasets. In vitro studies revealed that miR-193a inhibited PCa cell growth, suppressed migration and invasion, and promoted apoptosis; in vivo results demonstrated that overexpression of miR-193a mediated by lentivirus dramatically reduced PCa xenograft tumor growth. Importantly, we found EZH2 coupled with HOTAIR to repress miR-193a expression through trimethylation of H3K27 at miR-193a promoter in PC3 and DU145 cells. Interestingly, further evidence illustrated that miR-193a directly targets HOTAIR showing as significantly reduced HOTAIR level in miR-193a overexpressed cells and tissues. The expression level of miR-193a was inversely associated with that of HOTAIR and EZH2 in PCa.

Conclusion

This study firstly demonstrated that miR-193a acted as tumor suppressor in CRPC and the autoregulatory feedback loop of HOTAIR/EZH2/miR-193a served an important mechanism in PCa development. Targeting this aberrantly activated feedback loop may provide a potential therapeutic strategy.

http://ift.tt/2yILzGB

Involvement of aberrantly activated HOTAIR/EZH2/miR-193a feedback loop in progression of prostate cancer

Abstract

Background

Though androgen deprivation therapy is the standard treatment for prostate cancer (PCa), most patients would inevitably progress to castration-resistant prostate cancer (CRPC) which is the main cause of PCa death. Therefore, the identification of novel molecular mechanism regulating cancer progression and achievement of new insight into target therapy would be necessary for improving the benefits of PCa patients. This study aims to study the function and regulatory mechanism of HOTAIR/EZH2/miR-193a feedback loop in PCa progression.

Methods

MSKCC and TCGA datasets were used to identify miR-193a expression profile in PCa. Cell Counting Kit-8 (CCK-8) assays, colony formation, invasion, migration, flow cytometry, a xenograft model and Gene Set Enrichment Analysis were used to detect and analyze the biological function of miR-193a. Then, we assessed the role of HOTAIR and EZH2 in regulation of miR-193a expression by using plasmid, lentivirus and small interfering RNA (siRNA). Luciferase reporter assays and chromatin immunoprecipitation assays were performed to detect the transcriptional activation of miR-193a by EZH2 and HOTAIR. Further, qRT-PCR and luciferase reporter assays were conducted to examine the regulatory role of miR-193a controlling the HOTAIR expression in PCa. Finally, the correlation between HOTAIR, EZH2 and miR-193a expression were analyzed using In situ hybridization and immunohistochemistry.

Results

We found that miR-193a was significantly downregulated in metastatic PCa through mining MSKCC and TCGA datasets. In vitro studies revealed that miR-193a inhibited PCa cell growth, suppressed migration and invasion, and promoted apoptosis; in vivo results demonstrated that overexpression of miR-193a mediated by lentivirus dramatically reduced PCa xenograft tumor growth. Importantly, we found EZH2 coupled with HOTAIR to repress miR-193a expression through trimethylation of H3K27 at miR-193a promoter in PC3 and DU145 cells. Interestingly, further evidence illustrated that miR-193a directly targets HOTAIR showing as significantly reduced HOTAIR level in miR-193a overexpressed cells and tissues. The expression level of miR-193a was inversely associated with that of HOTAIR and EZH2 in PCa.

Conclusion

This study firstly demonstrated that miR-193a acted as tumor suppressor in CRPC and the autoregulatory feedback loop of HOTAIR/EZH2/miR-193a served an important mechanism in PCa development. Targeting this aberrantly activated feedback loop may provide a potential therapeutic strategy.

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Konventionelle oder akzeleriert-hyperfraktionierte simultane Radiochemotherapie beim kleinzelligen Lungenkarzinom im Stadium „limited disease“?

http://ift.tt/2zGsKHO

Konventionelle oder akzeleriert-hyperfraktionierte simultane Radiochemotherapie beim kleinzelligen Lungenkarzinom im Stadium „limited disease“?

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Immune Activation and Benefit From Avelumab in EBV-Positive Gastric Cancer

Abstract

Response to immune checkpoint therapy can be associated with a high mutation burden, but other mechanisms are also likely to be important. We identified a patient with metastatic gastric cancer with meaningful clinical benefit from treatment with the anti–programmed death–ligand 1 (PD-L1) antibody avelumab. This tumor showed no evidence of high mutation burden or mismatch repair defect but was strongly positive for presence of Epstein-Barr virus (EBV) encoded RNA. Analysis of The Cancer Genome Atlas gastric cancer data (25 EBV+, 80 microsatellite-instable [MSI], 310 microsatellite-stable [MSS]) showed that EBV-positive tumors were MSS. Two-sided Wilcoxon rank-sum tests showed that: 1) EBV-positive tumors had low mutation burden (median = 2.07 vs 3.13 in log₁₀ scale, P < 10^-12) but stronger evidence of immune infiltration (median ImmuneScore 2212 vs 1295, P < 10^-4; log₂ fold-change of CD8A = 1.85, P < 10^-6) compared with MSI tumors, and 2) EBV-positive tumors had higher expression of immune checkpoint pathway (PD-1, CTLA-4 pathway) genes in RNA-seq data (log₂ fold-changes: PD-1 = 1.85, PD-L1 = 1.93, PD-L2 = 1.50, CTLA-4 = 1.31, CD80 = 0.89, CD86 = 1.31, P < 10^-4 each), and higher lymphocytic infiltration by histology (median tumor-infiltrating lymphocyte score = 3 vs 2, P < .001) compared with MSS tumors. These data suggest that EBV-positive low–mutation burden gastric cancers are a subset of MSS gastric cancers that may respond to immune checkpoint therapy.

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Screening Guideline for Cervical Cancer Recommends Against Human Papillomavirus–Pap Cotesting

The U.S. Preventive Services Task Force's new draft guideline now recommends that women aged 30–65 years get tested for high-risk genotypes of human papillomavirus (hrHPV) every 5 years or get a Pap screening every 3 years. That is a major change from the task force's 2012 recommendation of cotesting: screening with the hrHPV test plus Pap screening every 5 years for women in that age group (Ann. Intern. Med. 2012;156:880–91; doi:10.7326/0003-4819-156-12-201206190-00424). A final guideline will be published after a period of public comment.

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PD-L1 Antibodies for EBV-Positive Gastric Cancer, Going Beyond PD-L1 Expression and Microsatellite Instability

Gastric adenocarcinoma is the second leading cause of cancer death worldwide, following lung cancer. The five-year survival rate of advanced metastatic disease is low. Combination chemotherapy results in improvement in overall survival in comparison with single-agent treatment or supportive care (1,2). Limited progress has been made by adding targeted therapy to the treatment of gastric cancer. The only two targeted agents approved by the US Food and Drug Administration (FDA) are ramucirumab (3,4), a VEGF antibody, and trastuzumab (5), which is indicated only in tumors with amplified human epidermal growth factor receptor 2 (Her-2). Both drugs have a modest impact on overall survival.

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Glyphosate Use and Cancer Incidence in the Agricultural Health Study: An Epidemiologic Perspective

In this issue of the Journal, Gabriela Adreiotti and colleagues report the results of an updated analysis of glyphosate exposure and cancer risk in the Agricultural Health Study (AHS) (1). The AHS, a prospective cohort study of 57 310 licensed pesticide applicators and 32 347 spouses in Iowa and North Carolina, was initiated in the early 1990s, in large part to address possible causes for the higher incidence of lymphohematopoietic and certain other cancers in farmers compared with the general population (2). From an epidemiologic perspective, designing a study to investigate cancer risk factors associated with farming is challenging because of the difficulty in establishing and recruiting a well-defined population, the large number of farming-related exposures that may be associated with cancer, and the need to create and validate quantitative exposure metrics. The AHS study met these challenges by defining and recruiting the study population from applicants for a restricted-use pesticide license in two states, collecting detailed information on the frequency and duration of use of 50 common pesticides, as well as other farming-related and general population exposures, and estimating lifetime days and intensity-weighted lifetime days of exposure for specific pesticides (2). Intensity of exposure was estimated using an algorithm that accounted for reported use of personal protective equipment, method of application, and whether the applicator personally mixed the pesticides (3). Additional studies were done to validate and refine the pesticide exposure intensity metrics, and exposure information was updated in 1999–2005 by computer-aided telephone interviewing (3,4). A method for multiple imputation was developed to assign pesticide use for nonresponders to the follow-up questionnaire (5).

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MAX Mutations in Endometrial Cancer: Clinicopathologic Associations and Recurrent MAX p.His28Arg Functional Characterization

Abstract

Background

Genomic studies have revealed that multiple genes are mutated at varying frequency in endometrial cancer (EC); however, the relevance of many of these mutations is poorly understood. An EC-specific recurrent mutation in the MAX transcription factor p.His28Arg was recently discovered. We sought to assess the functional consequences of this hotspot mutation and determine its association with cancer-relevant phenotypes.

Methods

MAX was sequenced in 509 endometrioid ECs, and associations between mutation status and clinicopathologic features were assessed. EC cell lines stably expressing MAX^H28R were established and used for functional experiments. DNA binding was examined using electrophoretic mobility shift assays and chromatin immunoprecipitation. Transcriptional profiling was performed with microarrays. Murine flank (six to 11 mice per group) and intraperitoneal tumor models were used for in vivo studies. Vascularity of xenografts was assessed by MECA-32 immunohistochemistry. The paracrine pro-angiogenic nature of MAX^H28R-expressing EC cells was tested using microfluidic HUVEC sprouting assays and VEGFA enzyme-linked immunosorbent assays. All statistical tests were two-sided.

Results

Twenty-two of 509 tumors harbored mutations in MAX, including 12 tumors with the p.His28Arg mutation. Patients with a MAX mutation had statistically significantly reduced recurrence-free survival (hazard ratio = 4.00, 95% confidence interval = 1.15 to 13.91, P = .03). MAX^H28R increased affinity for canonical E-box sequences, and MAX^H28R-expressing EC cells dramatically altered transcriptional profiles. MAX^H28R-derived xenografts statistically significantly increased vascular area compared with MAX^WT and empty vector tumors (P = .003 and P = .008, respectively). MAX^H28R-expressing EC cells secreted nearly double the levels of VEGFA compared with MAX^WT cells (P = .03, .005, and .005 at 24, 48, and 72 hours, respectively), and conditioned media from MAX^H28R cells increased sprouting when applied to HUVECs.

Conclusion

These data highlight the importance of MAX mutations in EC and point to increased vascularity as one mechanism contributing to clinical aggressiveness of EC.

http://ift.tt/2z4EFQw

Adherence to treatment guidelines and survival for older patients with stage II or III colon cancer in Texas from 2001 through 2011

BACKGROUND

Treatment guidelines for colon cancer recommend colectomy with lymphadenectomy of at least 12 lymph nodes for patients with stage I to stage III disease as surgery adherence (SA) and adjuvant chemotherapy for individuals with stage III disease. Herein, the authors evaluated adherence to these guidelines among older patients in Texas with colon cancer and the associated survival outcomes.

METHODS

Using Texas Cancer Registry data linked with Medicare data, the authors included patients with AJCC stage II and III colon cancer who were aged ≥66 years and diagnosed between 2001 and 2011. SA and adjuvant chemotherapy adherence rates to treatment guidelines were estimated. The chi-square test, general linear regression, survival probability, and Cox regression were used to identify factors associated with adherence and survival.

RESULTS

The rate of SA increased from 47.2% to 84% among 6029 patients with stage II or stage III disease from 2001 to 2011, and the rate of adjuvant chemotherapy increased from 48.9% to 53.1% for patients with stage III disease during the same time period. SA was associated with marital status, tumor size, surgeon specialty, and year of diagnosis. Patient age, sex, marital status, Medicare state buy-in status, comorbidity status, and year of diagnosis were found to be associated with adjuvant chemotherapy. The 5-year survival probability for patients receiving guideline-concordant treatment was the highest at 87% for patients with stage II disease and was 73% for those with stage III disease. After adjusting for demographic and tumor characteristics, improved cancer cause-specific survival was associated with the receipt of stage-specific, guideline-concordant treatment for patients with stage II or stage III disease.

CONCLUSIONS

The adherence to guideline-concordant treatment among older patients with colon cancer residing in Texas improved over time, and was associated with better survival outcomes. Future studies should be focused on identifying interventions to improve guideline-concordant treatment adherence. Cancer 2017. © 2017 American Cancer Society.

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Adherence to treatment guidelines and survival for older patients with stage II or III colon cancer in Texas from 2001 through 2011

BACKGROUND

Treatment guidelines for colon cancer recommend colectomy with lymphadenectomy of at least 12 lymph nodes for patients with stage I to stage III disease as surgery adherence (SA) and adjuvant chemotherapy for individuals with stage III disease. Herein, the authors evaluated adherence to these guidelines among older patients in Texas with colon cancer and the associated survival outcomes.

METHODS

Using Texas Cancer Registry data linked with Medicare data, the authors included patients with AJCC stage II and III colon cancer who were aged ≥66 years and diagnosed between 2001 and 2011. SA and adjuvant chemotherapy adherence rates to treatment guidelines were estimated. The chi-square test, general linear regression, survival probability, and Cox regression were used to identify factors associated with adherence and survival.

RESULTS

The rate of SA increased from 47.2% to 84% among 6029 patients with stage II or stage III disease from 2001 to 2011, and the rate of adjuvant chemotherapy increased from 48.9% to 53.1% for patients with stage III disease during the same time period. SA was associated with marital status, tumor size, surgeon specialty, and year of diagnosis. Patient age, sex, marital status, Medicare state buy-in status, comorbidity status, and year of diagnosis were found to be associated with adjuvant chemotherapy. The 5-year survival probability for patients receiving guideline-concordant treatment was the highest at 87% for patients with stage II disease and was 73% for those with stage III disease. After adjusting for demographic and tumor characteristics, improved cancer cause-specific survival was associated with the receipt of stage-specific, guideline-concordant treatment for patients with stage II or stage III disease.

CONCLUSIONS

The adherence to guideline-concordant treatment among older patients with colon cancer residing in Texas improved over time, and was associated with better survival outcomes. Future studies should be focused on identifying interventions to improve guideline-concordant treatment adherence. Cancer 2017. © 2017 American Cancer Society.

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Cone-beam CT in paediatric dentistry: DIMITRA project position statement

Abstract

DIMITRA (dentomaxillofacial paediatric imaging: an investigation towards low-dose radiation induced risks) is a European multicenter and multidisciplinary project focused on optimizing cone-beam CT exposures for children and adolescents. With increasing use of cone-beam CT for dentomaxillofacial diagnostics, concern arises regarding radiation risks associated with this imaging modality, especially for children. Research evidence concerning cone-beam CT indications in children remains limited, while reports mention inconsistent recommendations for dose reduction. Furthermore, there is no paper using the combined and integrated information on the required indication-oriented image quality and the related patient dose levels. In this paper, therefore, the authors initiate an integrated approach based on current evidence regarding image quality and dose, together with the expertise of DIMITRA's members searching for a state of the art. The aim of this DIMITRA position statement is to provide indication-oriented and patient-specific recommendations regarding the main cone-beam CT applications in the pediatric field. The authors will review this position statement document when results regarding multidisciplinary approaches evolve, in a period of 5 years or earlier.

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Patient-derived xenograft in zebrafish embryos: a new platform for translational research in gastric cancer

Abstract

Background

Gastric cancer (GC) is among the most commonly cancer occurred in Asian, especially in China. With its high heterogeneity and few of validated drug targets, GC remains to be one of the most under explored areas of precision medicine. In this study, we aimed to establish an in vivo patient-derived xenograft (PDX) model based on zebrafish (Danio rerio) embryos, allowing for a rapid analysis of the angiogenic and invasive potentials, as well as a fast drug sensitivity testing.

Methods

Two human gastric cancer cell lines (AGS and SGC-7901) were xenografted into zebrafish embryos, their sensitivity to 5-FU were tested both in vitro and in vivo. Fourteen human primary cells from gastric cancer tissue were xenografted into zebrafish embryos, their proliferating, angiogenic and metastatic activities were evaluated in vivo. Sensitivity to 5-FU, docetaxel, and apatinib were also tested on primary samples from four patients.

Results

SGC-7901 showed higher sensitivity to 5-FU than AGS both in vitro (6.3 ± 0.9 μM vs.10.5 ± 1.8 μM) and in vivo. Nine out of fourteen patient samples were successfully transplanted in zebrafish embryos and all showed proliferating, angiogenic and metastatic potentials in the living embryos. Four cases showed varied sensitivity to the selected three chemotherapeutic drugs.

Conclusions

Our zebrafish PDX (zPDX) model is a preclinically reliable in vivo model for GC. The zPDX model is also a promising platform for the translational research and personalized treatment on GC.

http://ift.tt/2zIJ7U3

Patient-derived xenograft in zebrafish embryos: a new platform for translational research in gastric cancer

Abstract

Background

Gastric cancer (GC) is among the most commonly cancer occurred in Asian, especially in China. With its high heterogeneity and few of validated drug targets, GC remains to be one of the most under explored areas of precision medicine. In this study, we aimed to establish an in vivo patient-derived xenograft (PDX) model based on zebrafish (Danio rerio) embryos, allowing for a rapid analysis of the angiogenic and invasive potentials, as well as a fast drug sensitivity testing.

Methods

Two human gastric cancer cell lines (AGS and SGC-7901) were xenografted into zebrafish embryos, their sensitivity to 5-FU were tested both in vitro and in vivo. Fourteen human primary cells from gastric cancer tissue were xenografted into zebrafish embryos, their proliferating, angiogenic and metastatic activities were evaluated in vivo. Sensitivity to 5-FU, docetaxel, and apatinib were also tested on primary samples from four patients.

Results

SGC-7901 showed higher sensitivity to 5-FU than AGS both in vitro (6.3 ± 0.9 μM vs.10.5 ± 1.8 μM) and in vivo. Nine out of fourteen patient samples were successfully transplanted in zebrafish embryos and all showed proliferating, angiogenic and metastatic potentials in the living embryos. Four cases showed varied sensitivity to the selected three chemotherapeutic drugs.

Conclusions

Our zebrafish PDX (zPDX) model is a preclinically reliable in vivo model for GC. The zPDX model is also a promising platform for the translational research and personalized treatment on GC.

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Bidirectional alteration of Cav-1 expression is associated with mitogenic conversion of its function in gastric tumor progression

Abstract

Background

Expression of caveolin-1 (Cav-1) is frequently altered in many human cancers and both tumor suppression and promotion functions of Cav-1 have been suggested based on its expression status. However, it remains unanswered how Cav-1 provokes opposite effects in different cancers or different phases of tumor progression.

Methods

To explore the implication of Cav-1 alteration in gastric tumorigenesis, the expression and mutational status of Cav-1 and its effects on tumor cell growth were characterized.

Results

A substantial fraction of primary tumors and cell lines displayed abnormally low or high Cav-1 mRNA expression, indicating the bidirectional alteration of Cav-1 in gastric cancers. While allelic imbalance and mutational alterations of the Cav-1 gene were rarely detected, aberrant promoter hyper- or hypo-methylation showed a tight correlation with bidirectional alteration of its expression. Abnormally low and high Cav-1 expression was more frequently observed in early and advanced cancers, respectively, suggesting the oncogenic switch of its function in tumor progression. Cell cycle progression, DNA synthesis, and colony forming ability were markedly decreased by Cav-1 transfection in low-expressing tumor cells but by its depletion in high-expressing cells. Interestingly, Cav-1 exerted opposite effects on MEK-ERK signaling in these two cell types through the reciprocal regulation of the RAF-ERK negative feedback loop. A feedback inhibition of RAF by ERK was stimulated by restoration of Cav-1 expression in low-expressing cells but by it depletion in high-expressing cells. As predicted, the opposite effects of Cav-1 on both tumor cell growth and inhibitory RAF phosphorylation were abolished if ERK is depleted.

Conclusion

Bidirectional alteration of Cav-1 is linked to its opposite effects on gastric tumor cell growth, which stem from the reciprocal control on the RAF-ERK negative feedback loop.

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