Surgery in elderly patients with intracranial meningioma: neuropsychological functioning during a long term follow-up

Abstract

Surgical treatment of elderly patients with meningioma is has proved to be safe, especially when patients are selected using dedicated surgical scores. These scores take into account tumor size, edema, location and patient's co-morbidities. Neuropsychological functioning (NPF) of this kind of patients has been poorly studied in literature and it is not taken into account by these scores. Aim of our study was to describe the long-term outcome in terms of NPF of elderly patients undergoing surgery. Patients older than 70 years of age affected by intracranial meningioma and selected with the Clinical-Radiological Grading Score were included in our study. Neuropsychological testing was performed using a dedicated battery of tests before surgery, 3 and 12 months after surgery. Clinical, neurological and radiological outcomes were studied as well. Forty-one patients with a median age of 74 years were included in this study. Preoperatively only 1/41 patients showed a normal NPF with all tests scoring normally. Four out of 39 patients showed a complete neuropsychological recovery after 3 months; while 10/37 patients had a complete recovery after 12 months. NPF showed a trend of progressive improvement after surgery. Our study is the first experience reported in literature describing a long term follow-up in elderly patients after surgery for intracranial meningioma. In our series, surgery determined an improvement of NPF over time; especially with a low complication rate related to the selection of patients obtained through the CRGS. Further studies need to be performed in order to understand how brain edema, tumor size, volume and tumor location affect NPF in both short and long term.

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Surgery in elderly patients with intracranial meningioma: neuropsychological functioning during a long term follow-up

Abstract

Surgical treatment of elderly patients with meningioma is has proved to be safe, especially when patients are selected using dedicated surgical scores. These scores take into account tumor size, edema, location and patient's co-morbidities. Neuropsychological functioning (NPF) of this kind of patients has been poorly studied in literature and it is not taken into account by these scores. Aim of our study was to describe the long-term outcome in terms of NPF of elderly patients undergoing surgery. Patients older than 70 years of age affected by intracranial meningioma and selected with the Clinical-Radiological Grading Score were included in our study. Neuropsychological testing was performed using a dedicated battery of tests before surgery, 3 and 12 months after surgery. Clinical, neurological and radiological outcomes were studied as well. Forty-one patients with a median age of 74 years were included in this study. Preoperatively only 1/41 patients showed a normal NPF with all tests scoring normally. Four out of 39 patients showed a complete neuropsychological recovery after 3 months; while 10/37 patients had a complete recovery after 12 months. NPF showed a trend of progressive improvement after surgery. Our study is the first experience reported in literature describing a long term follow-up in elderly patients after surgery for intracranial meningioma. In our series, surgery determined an improvement of NPF over time; especially with a low complication rate related to the selection of patients obtained through the CRGS. Further studies need to be performed in order to understand how brain edema, tumor size, volume and tumor location affect NPF in both short and long term.

http://ift.tt/2Dq1zAM

Predictors of severe postoperative hyperglycemia after cardiac surgery in infants: a single-center, retrospective, observational study

Abstract

Purpose

Hyperglycemia is a common issue in infants after cardiac surgery for congenital heart disease. Poor glycemic control is suspected to be associated with adverse postoperative outcomes. This study was performed to investigate clinical factors contributing to hyperglycemia in the perioperative period in infats.

Methods

A total of 69 infants (aged 1–12 months) who were admitted to Yokohama City University Hospital Intensive Care Unit (ICU) after surgical repair of congenital heart diseases with cardiopulmonary bypass (CPB) were retrospectively analysed. Hyperglycemia was defined as blood glucose ≥ 250 mg/dL on ICU admission. Clinical background, operative factors, and postoperative factors were compared between the hyperglycemic and non-hyperglycemic groups. Additionally, multivariate analysis was performed to identify factors contributing to hyperglycemia.

Results

Nineteen (27.5%) and 50 (72.5%) infants were classified into the hyperglycemic and non-hyperglycemic groups, respectively. Hyperglycemic infants were significantly younger, shorter, and weighed less, with a higher rate of chromosomal abnormalities. Intraoperatively, they also experienced longer CPB and surgery times and had higher peak lactate levels and higher inotropic requirements. Hyperglycemia was related to longer mechanical ventilation and longer ICU stays. Multivariate analysis detected intraoperative hyperglycemia, longer CPB time, younger age and chromosomal abnormality as significant factors.

Conclusion

Adding to hyperglycemia during the operation, longer CPB time younger age and chromosomal abnormality were identified as predictors of high blood glucose levels at ICU admission.

http://ift.tt/2musO5I

Linear doggybone DNA vaccine induces similar immunological responses to conventional plasmid DNA independently of immune recognition by TLR9 in a pre-clinical model

Abstract

Vaccination with DNA that encodes cancer antigens is a simple and convenient way to raise immunity against cancer and has already shown promise in the clinical setting. Conventional plasmid DNA is commonly used which together with the encoded antigen also includes bacterial immunostimulatory CpG motifs to target the DNA sensor Toll-like receptor 9. Recently DNA vaccines using doggybone DNA (dbDNA™), have been developed without the use of bacteria. The cell-free process relies on the use of Phi29 DNA polymerase to amplify the template followed by protelomerase TelN to complete individual closed linear DNA. The resulting DNA contains the required antigenic sequence, a promoter and a poly A tail but lacks bacterial sequences such as an antibiotic resistance gene, prompting the question of immunogenicity. Here we compared the ability of doggybone DNA vaccine with plasmid DNA vaccine to induce adaptive immunity using clinically relevant oncotargets E6 and E7 from HPV. We demonstrate that despite the inability to trigger TLR9, doggybone DNA was able to induce similar levels of cellular and humoral immunity as plasmid DNA, with suppression of established TC-1 tumours.

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Linear doggybone DNA vaccine induces similar immunological responses to conventional plasmid DNA independently of immune recognition by TLR9 in a pre-clinical model

Abstract

Vaccination with DNA that encodes cancer antigens is a simple and convenient way to raise immunity against cancer and has already shown promise in the clinical setting. Conventional plasmid DNA is commonly used which together with the encoded antigen also includes bacterial immunostimulatory CpG motifs to target the DNA sensor Toll-like receptor 9. Recently DNA vaccines using doggybone DNA (dbDNA™), have been developed without the use of bacteria. The cell-free process relies on the use of Phi29 DNA polymerase to amplify the template followed by protelomerase TelN to complete individual closed linear DNA. The resulting DNA contains the required antigenic sequence, a promoter and a poly A tail but lacks bacterial sequences such as an antibiotic resistance gene, prompting the question of immunogenicity. Here we compared the ability of doggybone DNA vaccine with plasmid DNA vaccine to induce adaptive immunity using clinically relevant oncotargets E6 and E7 from HPV. We demonstrate that despite the inability to trigger TLR9, doggybone DNA was able to induce similar levels of cellular and humoral immunity as plasmid DNA, with suppression of established TC-1 tumours.

http://ift.tt/2EAJbV7

Linear doggybone DNA vaccine induces similar immunological responses to conventional plasmid DNA independently of immune recognition by TLR9 in a pre-clinical model

Abstract

Vaccination with DNA that encodes cancer antigens is a simple and convenient way to raise immunity against cancer and has already shown promise in the clinical setting. Conventional plasmid DNA is commonly used which together with the encoded antigen also includes bacterial immunostimulatory CpG motifs to target the DNA sensor Toll-like receptor 9. Recently DNA vaccines using doggybone DNA (dbDNA™), have been developed without the use of bacteria. The cell-free process relies on the use of Phi29 DNA polymerase to amplify the template followed by protelomerase TelN to complete individual closed linear DNA. The resulting DNA contains the required antigenic sequence, a promoter and a poly A tail but lacks bacterial sequences such as an antibiotic resistance gene, prompting the question of immunogenicity. Here we compared the ability of doggybone DNA vaccine with plasmid DNA vaccine to induce adaptive immunity using clinically relevant oncotargets E6 and E7 from HPV. We demonstrate that despite the inability to trigger TLR9, doggybone DNA was able to induce similar levels of cellular and humoral immunity as plasmid DNA, with suppression of established TC-1 tumours.

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Linear doggybone DNA vaccine induces similar immunological responses to conventional plasmid DNA independently of immune recognition by TLR9 in a pre-clinical model

Abstract

Vaccination with DNA that encodes cancer antigens is a simple and convenient way to raise immunity against cancer and has already shown promise in the clinical setting. Conventional plasmid DNA is commonly used which together with the encoded antigen also includes bacterial immunostimulatory CpG motifs to target the DNA sensor Toll-like receptor 9. Recently DNA vaccines using doggybone DNA (dbDNA™), have been developed without the use of bacteria. The cell-free process relies on the use of Phi29 DNA polymerase to amplify the template followed by protelomerase TelN to complete individual closed linear DNA. The resulting DNA contains the required antigenic sequence, a promoter and a poly A tail but lacks bacterial sequences such as an antibiotic resistance gene, prompting the question of immunogenicity. Here we compared the ability of doggybone DNA vaccine with plasmid DNA vaccine to induce adaptive immunity using clinically relevant oncotargets E6 and E7 from HPV. We demonstrate that despite the inability to trigger TLR9, doggybone DNA was able to induce similar levels of cellular and humoral immunity as plasmid DNA, with suppression of established TC-1 tumours.

http://ift.tt/2EAJbV7

Letter to the editor

http://ift.tt/2CVAODj

Linear doggybone DNA vaccine induces similar immunological responses to conventional plasmid DNA independently of immune recognition by TLR9 in a pre-clinical model

Abstract

Vaccination with DNA that encodes cancer antigens is a simple and convenient way to raise immunity against cancer and has already shown promise in the clinical setting. Conventional plasmid DNA is commonly used which together with the encoded antigen also includes bacterial immunostimulatory CpG motifs to target the DNA sensor Toll-like receptor 9. Recently DNA vaccines using doggybone DNA (dbDNA™), have been developed without the use of bacteria. The cell-free process relies on the use of Phi29 DNA polymerase to amplify the template followed by protelomerase TelN to complete individual closed linear DNA. The resulting DNA contains the required antigenic sequence, a promoter and a poly A tail but lacks bacterial sequences such as an antibiotic resistance gene, prompting the question of immunogenicity. Here we compared the ability of doggybone DNA vaccine with plasmid DNA vaccine to induce adaptive immunity using clinically relevant oncotargets E6 and E7 from HPV. We demonstrate that despite the inability to trigger TLR9, doggybone DNA was able to induce similar levels of cellular and humoral immunity as plasmid DNA, with suppression of established TC-1 tumours.

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Corrigendum

Future Oncology, Ahead of Print.


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Evaluation of the eighth American Joint Committee on Cancer staging system for malignant melanoma of the skin

Future Oncology, Ahead of Print.


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Bioinformatic analysis of PFN2 dysregulation and its prognostic value in head and neck squamous carcinoma

Future Oncology, Ahead of Print.


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Identification of CDK2 as a novel target in treatment of prostate cancer

Future Oncology, Ahead of Print.


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Corrigendum

Future Oncology, Ahead of Print.


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Evaluation of the eighth American Joint Committee on Cancer staging system for malignant melanoma of the skin

Future Oncology, Ahead of Print.


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Bioinformatic analysis of PFN2 dysregulation and its prognostic value in head and neck squamous carcinoma

Future Oncology, Ahead of Print.


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Identification of CDK2 as a novel target in treatment of prostate cancer

Future Oncology, Ahead of Print.


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No additional prognostic value for MRE11 in squamous cell carcinomas of the anus treated with chemo-radiotherapy

No additional prognostic value for MRE11 in squamous cell carcinomas of the anus treated with chemo-radiotherapy

No additional prognostic value for MRE11 in squamous cell carcinomas of the anus treated with chemo-radiotherapy, Published online: 11 January 2018; doi:10.1038/bjc.2017.410

No additional prognostic value for MRE11 in squamous cell carcinomas of the anus treated with chemo-radiotherapy

http://ift.tt/2Ez7x1k

RNF126 as a biomarker of a poor prognosis in invasive breast cancer and CHK1 inhibitor efficacy in breast cancer cells

Purpose: 1) To investigate expression of the E3 ligase, RNF126, in human invasive breast cancer (BC) and its links with BC outcomes. 2) To test the hypothesis that RNF126 determines the efficacy of inhibitors targeting the cell cycle checkpoint kinase, CHK1. Experimental Design: A retrospective analysis by immunohistochemistry (IHC) compared RNF126 staining in 110 invasive BC and 78 paired adjacent normal tissues with clinicopathologic data. Whether RNF126 controls CHK1 expression was determined by chromatin immunoprecipitation and a CHK1 promoter driven luciferase reporter. Staining for these two proteins by IHC using tissue microarrays was also conducted. Cell killing/replication stress induced by CHK1 inhibition was evaluated in cells, with or without RNF126 knockdown, by MTT/colony formation, replication stress biomarker immunostaining and DNA fiber assays. Results: RNF126 protein expression was elevated in BC tissue samples. RNF126 was associated with a poor clinical outcome after multivariate analysis and was an independent predictor. RNF126 promotes CHK1 transcript expression. Critically, a strong correlation between RNF126 and CHK1 proteins was identified in BC tissue and cell lines. The inhibition of CHK1 induced a greater cell killing and a higher level of replication stress in BC cells expressing RNF126 compared to RNF126 depleted cells. Conclusions: RNF126 protein is highly expressed in invasive BC tissue. The high expression of RNF126 is an independent predictor of a poor prognosis in invasive BC and is considered a potential biomarker of a cancer's responsiveness to CHK1 inhibitors. CHK1 inhibition targets BC cells expressing higher levels of RNF126 by enhancing replication stress.

http://ift.tt/2D3cHph

Evaluation of overall response rate and progression-free survival as potential surrogate endpoints for overall survival in immunotherapy trials

Purpose: With the approval of immunotherapies for a variety of indications, methods to assess treatment benefit addressing the response patterns observed are important. We evaluated RECIST criteria based objective response rate (ORR) and progression-free survival (PFS) as potential surrogate endpoints of overall survival (OS), and explored a modified definition of PFS by altering the threshold percentage determining disease progression to assess the association with survival benefit in immunotherapy trials. Experimental Design: Thirteen randomized, multicenter, active control trials containing immunotherapeutic agents submitted to FDA were analyzed. Associations between treatment effects of ORR, PFS, modified PFS and OS were evaluated at individual and trial-levels. Patient-level responder analysis was performed for PFS and OS. Results: The coefficient of determination (R2) measured the strength of associations, where values near 1 imply surrogacy and values close to zero suggest no association. At the trial-level, associations between hazard ratios (HR) of PFS and OS was R2 = 0.1303, and between the odds ratio of ORR and HR of OS was R2 = 0.1277. At the individual level, the Spearman rank correlation coefficient between PFS and OS was 0.61. Trial-level associations between modified PFS and OS ranged between 0.07 - 0.1, and individual level correlations were approximately 0.6. HRs of PFS and OS for responders versus non-responders were 0.129 (95% CI: 0.11, 0.15) and 0.118 (95% CI: 0.11, 0.13), respectively. Conclusions: While responders exhibited longer survival and PFS than non-responders, the trial-level and individual level associations were weak between PFS/ORR and OS. Modifications to PFS did not improve associations.

http://ift.tt/2mk2ESp

No additional prognostic value for MRE11 in squamous cell carcinomas of the anus treated with chemo-radiotherapy

No additional prognostic value for MRE11 in squamous cell carcinomas of the anus treated with chemo-radiotherapy

No additional prognostic value for MRE11 in squamous cell carcinomas of the anus treated with chemo-radiotherapy, Published online: 11 January 2018; doi:10.1038/bjc.2017.410

No additional prognostic value for MRE11 in squamous cell carcinomas of the anus treated with chemo-radiotherapy

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Prevalence of Aflatoxin-Associated TP53R249S Mutation in Hepatocellular Carcinoma in Hispanics in South Texas

We aimed to determine whether aflatoxin dietary exposure plays a role in the high incidence of hepatocellular carcinoma (HCC) observed among Hispanics in South Texas. We measured TP53R249S somatic mutation, hallmark of aflatoxin etiology in HCC, using droplet digital PCR and RFLP. TP53R249S mutation was detected in 3 of 41 HCC tumors from Hispanics in South Texas (7.3%). We also measured TP53R249S mutation in plasma cell-free DNA (cfDNA) from 218 HCC patients and 96 Hispanic subjects with advanced fibrosis or cirrhosis, from South Texas. The mutation was detected only in Hispanic and Asian HCC patients, and patients harboring TP53R249S mutation were significantly younger and had a shorter overall survival. The mutation was not detected in any Hispanic subject with advanced fibrosis or cirrhosis. Genes involved in cell-cycle control of chromosomal replication and in BRCA1-dependent DNA damage response were enriched in HCCs with TP53R249S mutation. The E2F1 family members, E2F1 and E2F4, were identified as upstream regulators. TP53R249S mutation was detected in 5.7% to 7.3% of Hispanics with HCC in South Texas. This mutation was associated with a younger age and worse prognosis. TP53R249S was however not detected in Hispanics in South Texas with cirrhosis or advanced fibrosis. Aflatoxin exposure may contribute to a small number of HCCs in Hispanics in South Texas, but the detection of TP53R249S mutation in plasma cfDNA is not a promising biomarker of risk assessment for HCC in subjects with cirrhosis or advanced fibrosis in this population. Cancer Prev Res; 1–9. ©2017 AACR.

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RNF126 as a biomarker of a poor prognosis in invasive breast cancer and CHK1 inhibitor efficacy in breast cancer cells

Purpose: 1) To investigate expression of the E3 ligase, RNF126, in human invasive breast cancer (BC) and its links with BC outcomes. 2) To test the hypothesis that RNF126 determines the efficacy of inhibitors targeting the cell cycle checkpoint kinase, CHK1. Experimental Design: A retrospective analysis by immunohistochemistry (IHC) compared RNF126 staining in 110 invasive BC and 78 paired adjacent normal tissues with clinicopathologic data. Whether RNF126 controls CHK1 expression was determined by chromatin immunoprecipitation and a CHK1 promoter driven luciferase reporter. Staining for these two proteins by IHC using tissue microarrays was also conducted. Cell killing/replication stress induced by CHK1 inhibition was evaluated in cells, with or without RNF126 knockdown, by MTT/colony formation, replication stress biomarker immunostaining and DNA fiber assays. Results: RNF126 protein expression was elevated in BC tissue samples. RNF126 was associated with a poor clinical outcome after multivariate analysis and was an independent predictor. RNF126 promotes CHK1 transcript expression. Critically, a strong correlation between RNF126 and CHK1 proteins was identified in BC tissue and cell lines. The inhibition of CHK1 induced a greater cell killing and a higher level of replication stress in BC cells expressing RNF126 compared to RNF126 depleted cells. Conclusions: RNF126 protein is highly expressed in invasive BC tissue. The high expression of RNF126 is an independent predictor of a poor prognosis in invasive BC and is considered a potential biomarker of a cancer's responsiveness to CHK1 inhibitors. CHK1 inhibition targets BC cells expressing higher levels of RNF126 by enhancing replication stress.

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Evaluation of overall response rate and progression-free survival as potential surrogate endpoints for overall survival in immunotherapy trials

Purpose: With the approval of immunotherapies for a variety of indications, methods to assess treatment benefit addressing the response patterns observed are important. We evaluated RECIST criteria based objective response rate (ORR) and progression-free survival (PFS) as potential surrogate endpoints of overall survival (OS), and explored a modified definition of PFS by altering the threshold percentage determining disease progression to assess the association with survival benefit in immunotherapy trials. Experimental Design: Thirteen randomized, multicenter, active control trials containing immunotherapeutic agents submitted to FDA were analyzed. Associations between treatment effects of ORR, PFS, modified PFS and OS were evaluated at individual and trial-levels. Patient-level responder analysis was performed for PFS and OS. Results: The coefficient of determination (R2) measured the strength of associations, where values near 1 imply surrogacy and values close to zero suggest no association. At the trial-level, associations between hazard ratios (HR) of PFS and OS was R2 = 0.1303, and between the odds ratio of ORR and HR of OS was R2 = 0.1277. At the individual level, the Spearman rank correlation coefficient between PFS and OS was 0.61. Trial-level associations between modified PFS and OS ranged between 0.07 - 0.1, and individual level correlations were approximately 0.6. HRs of PFS and OS for responders versus non-responders were 0.129 (95% CI: 0.11, 0.15) and 0.118 (95% CI: 0.11, 0.13), respectively. Conclusions: While responders exhibited longer survival and PFS than non-responders, the trial-level and individual level associations were weak between PFS/ORR and OS. Modifications to PFS did not improve associations.

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Gut Bacteria Shape Response to Checkpoint Inhibitor Therapy [News in Depth]

Microbiome composition one factor in determining efficacy of anti–PD-1 drugs, studies show.

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Clinical Considerations of the Role of Palbociclib in the Management of Advanced Breast Cancer Patients With and Without Visceral Metastases

Abstract

Background

This report assesses the efficacy and safety of palbociclib plus endocrine therapy (ET) in women with hormone receptor−positive, human epidermal growth factor receptor 2-negative advanced breast cancer (ABC) with or without visceral metastases.

Patients and methods

Pre- and postmenopausal women with disease progression following prior ET (PALOMA-3; N=521) and postmenopausal women untreated for ABC (PALOMA-2; N=666) were randomized 2:1 to ET (fulvestrant or letrozole, respectively) plus palbociclib or placebo. Progression-free survival (PFS), safety, and patient-reported quality of life (QoL) were evaluated by prior treatment and visceral involvement.

Results

Visceral metastases incidence was higher in patients with prior resistance to ET (58.3%, PALOMA-3) than in patients naive to endocrine therapy in the ABC setting (48.6%, PALOMA-2). In patients with prior resistance to ET and visceral metastases, median PFS (mPFS) was 9.2 months with palbociclib plus fulvestrant versus 3.4 months with placebo plus fulvestrant [hazard ratio (HR), 0.47; 95% confidence interval (CI), 0.35 − 0.61], and objective response rate (ORR) was 28.0% versus 6.7%, respectively. In patients with nonvisceral metastases, mPFS was 16.6 versus 7.3 months, HR, 0.53; 95% CI, 0.36 − 0.77. In patients naive to endocrine therapy in the advanced disease setting, mPFS was 19.3 months with palbociclib plus letrozole versus 12.9 months with placebo plus letrozole (HR, 0.63; 95% CI, 0.47 − 0.85); ORR was 55.1% versus 40.0%; in patients with nonvisceral disease, mPFS was not reached with palbociclib plus letrozole versus 16.8 months with placebo plus letrozole (HR, 0.50; 95% CI, 0.36 − 0.70). In patients with prior resistance to ET with visceral metastases, palbociclib plus fulvestrant significantly delayed deterioration of QoL versus placebo plus fulvestrant, whereas patient-reported QoL was maintained with palbociclib plus letrozole in patients naive to endocrine-based therapy for ABC.

Conclusions

Palbociclib plus ET prolonged mPFS in patients with visceral metastases, increased ORRs, and in patients previously treated for ABC, delayed QoL deterioration, presenting a standard treatment option among patients with visceral metastases amenable to endocrine-based therapy.

Clinical trial registration

NCT01942135, NCT01740427

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Watson for Oncology and breast cancer treatment recommendations: agreement with an expert multidisciplinary tumor board

Abstract

Background

Breast cancer oncologists are challenged to personalize care with rapidly changing scientific evidence, drug approvals, and treatment guidelines. Artificial intelligence (AI) clinical decision-support systems (CDSSs) have the potential to help address this challenge. We report here the results of examining the level of agreement (concordance) between treatment recommendations made by the AI CDSS Watson for Oncology (WFO) and a multidisciplinary tumor board for breast cancer.

Patients and methods

Treatment recommendations were provided for 638 breast cancers between 2014 and 2016 at the Manipal Comprehensive Cancer Center, Bengaluru, India. WFO provided treatment recommendations for the identical cases in 2016. A blinded second review was carried out by the center's tumor board in 2016 for all cases in which there was not agreement, to account for treatments and guidelines not available before 2016. Treatment recommendations were considered concordant if the tumor board recommendations were designated 'recommended' or 'for consideration' by WFO.

Results

Treatment concordance between WFO and the multidisciplinary tumor board occurred in 93% of breast cancer cases. Subgroup analysis found that patients with stage I or IV disease were less likely to be concordant than patients with stage II or III disease. Increasing age was found to have a major impact on concordance. Concordance declined significantly (P ≤ 0.02; P < 0.001) in all age groups compared with patients <45 years of age, except for the age group 55–64 years. Receptor status was not found to affect concordance.

Conclusion

Treatment recommendations made by WFO and the tumor board were highly concordant for breast cancer cases examined. Breast cancer stage and patient age had significant influence on concordance, while receptor status alone did not. This study demonstrates that the AI clinical decision-support system WFO may be a helpful tool for breast cancer treatment decision making, especially at centers where expert breast cancer resources are limited.

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Clinical Considerations of the Role of Palbociclib in the Management of Advanced Breast Cancer Patients With and Without Visceral Metastases

Abstract

Background

This report assesses the efficacy and safety of palbociclib plus endocrine therapy (ET) in women with hormone receptor−positive, human epidermal growth factor receptor 2-negative advanced breast cancer (ABC) with or without visceral metastases.

Patients and methods

Pre- and postmenopausal women with disease progression following prior ET (PALOMA-3; N=521) and postmenopausal women untreated for ABC (PALOMA-2; N=666) were randomized 2:1 to ET (fulvestrant or letrozole, respectively) plus palbociclib or placebo. Progression-free survival (PFS), safety, and patient-reported quality of life (QoL) were evaluated by prior treatment and visceral involvement.

Results

Visceral metastases incidence was higher in patients with prior resistance to ET (58.3%, PALOMA-3) than in patients naive to endocrine therapy in the ABC setting (48.6%, PALOMA-2). In patients with prior resistance to ET and visceral metastases, median PFS (mPFS) was 9.2 months with palbociclib plus fulvestrant versus 3.4 months with placebo plus fulvestrant [hazard ratio (HR), 0.47; 95% confidence interval (CI), 0.35 − 0.61], and objective response rate (ORR) was 28.0% versus 6.7%, respectively. In patients with nonvisceral metastases, mPFS was 16.6 versus 7.3 months, HR, 0.53; 95% CI, 0.36 − 0.77. In patients naive to endocrine therapy in the advanced disease setting, mPFS was 19.3 months with palbociclib plus letrozole versus 12.9 months with placebo plus letrozole (HR, 0.63; 95% CI, 0.47 − 0.85); ORR was 55.1% versus 40.0%; in patients with nonvisceral disease, mPFS was not reached with palbociclib plus letrozole versus 16.8 months with placebo plus letrozole (HR, 0.50; 95% CI, 0.36 − 0.70). In patients with prior resistance to ET with visceral metastases, palbociclib plus fulvestrant significantly delayed deterioration of QoL versus placebo plus fulvestrant, whereas patient-reported QoL was maintained with palbociclib plus letrozole in patients naive to endocrine-based therapy for ABC.

Conclusions

Palbociclib plus ET prolonged mPFS in patients with visceral metastases, increased ORRs, and in patients previously treated for ABC, delayed QoL deterioration, presenting a standard treatment option among patients with visceral metastases amenable to endocrine-based therapy.

Clinical trial registration

NCT01942135, NCT01740427

http://ift.tt/2mn6J8e

Watson for Oncology and breast cancer treatment recommendations: agreement with an expert multidisciplinary tumor board

Abstract

Background

Breast cancer oncologists are challenged to personalize care with rapidly changing scientific evidence, drug approvals, and treatment guidelines. Artificial intelligence (AI) clinical decision-support systems (CDSSs) have the potential to help address this challenge. We report here the results of examining the level of agreement (concordance) between treatment recommendations made by the AI CDSS Watson for Oncology (WFO) and a multidisciplinary tumor board for breast cancer.

Patients and methods

Treatment recommendations were provided for 638 breast cancers between 2014 and 2016 at the Manipal Comprehensive Cancer Center, Bengaluru, India. WFO provided treatment recommendations for the identical cases in 2016. A blinded second review was carried out by the center's tumor board in 2016 for all cases in which there was not agreement, to account for treatments and guidelines not available before 2016. Treatment recommendations were considered concordant if the tumor board recommendations were designated 'recommended' or 'for consideration' by WFO.

Results

Treatment concordance between WFO and the multidisciplinary tumor board occurred in 93% of breast cancer cases. Subgroup analysis found that patients with stage I or IV disease were less likely to be concordant than patients with stage II or III disease. Increasing age was found to have a major impact on concordance. Concordance declined significantly (P ≤ 0.02; P < 0.001) in all age groups compared with patients <45 years of age, except for the age group 55–64 years. Receptor status was not found to affect concordance.

Conclusion

Treatment recommendations made by WFO and the tumor board were highly concordant for breast cancer cases examined. Breast cancer stage and patient age had significant influence on concordance, while receptor status alone did not. This study demonstrates that the AI clinical decision-support system WFO may be a helpful tool for breast cancer treatment decision making, especially at centers where expert breast cancer resources are limited.

http://ift.tt/2D39Tsf

A quantitative CT imaging signature predicts survival and complements established prognosticators in stage I non-small cell lung cancer

Publication date: Available online 10 January 2018
Source:International Journal of Radiation Oncology*Biology*Physics
Author(s): Juheon Lee, Bailiang Li, Yi Cui, Xiaoli Sun, Jia Wu, Hui Zhu, Jinming Yu, Michael F. Gensheimer, Billy W. Loo, Maximilian Diehn, Ruijiang Li
BackgroundPrognostic biomarkers are needed to guide the management of early stage non-small cell lung cancer (NSCLC). This work aims to develop an image-based prognostic signature and assess its complementary value to existing biomarkers.MethodsWe retrospectively analyzed outcomes of stage I NSCLC in seven cohorts. Based on an analysis of 39 CT features characterizing tumor and its relation to neighboring pleura, we developed a prognostic signature in an institutional cohort (n=117) and tested it in an external cohort (n=88). A third cohort of 89 patients with CT and gene expression data was employed to create a surrogate genomic signature of the imaging signature. We conducted further validation using data from five gene expression cohorts (n=639), and built a composite signature by integrating with the cell-cycle progression (CCP) score and clinical variables.ResultsAn imaging signature consisting of pleural contact index and normalized inverse difference was significantly associated with overall survival in both imaging cohorts (p=0.0005 and 0.0009). Functional enrichment analysis revealed that genes highly correlated with the imaging signature were related to immune response, such as lymphocyte activation and chemotaxis (false discovery rate<0.05). A genomic surrogate of the imaging signature remained a significant predictor of survival adjusting for known prognostic factors (hazard ratio: 1.81, 95% CI: 1.34-2.44, p<0.0001), and stratified patients within subgroups as defined by stage, histology, or CCP score. A composite signature outperformed the genomic surrogate, CCP score, and clinical model alone (p<0.01) regarding concordance index (0.70 vs 0.62-0.63).ConclusionThe proposed CT imaging signature reflects fundamental biologic differences in tumors and predicts overall survival in patients with stage I NSCLC. When combined with established prognosticators, the imaging signature improves survival prediction.

Teaser

We identified a CT imaging signature that predicts overall survival in stage I NSCLC. The imaging signature is associated with immune response and may serve as a noninvasive prognostic biomarker in stage I NSCLC.


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A quantitative CT imaging signature predicts survival and complements established prognosticators in stage I non-small cell lung cancer

Publication date: Available online 10 January 2018
Source:International Journal of Radiation Oncology*Biology*Physics
Author(s): Juheon Lee, Bailiang Li, Yi Cui, Xiaoli Sun, Jia Wu, Hui Zhu, Jinming Yu, Michael F. Gensheimer, Billy W. Loo, Maximilian Diehn, Ruijiang Li
BackgroundPrognostic biomarkers are needed to guide the management of early stage non-small cell lung cancer (NSCLC). This work aims to develop an image-based prognostic signature and assess its complementary value to existing biomarkers.MethodsWe retrospectively analyzed outcomes of stage I NSCLC in seven cohorts. Based on an analysis of 39 CT features characterizing tumor and its relation to neighboring pleura, we developed a prognostic signature in an institutional cohort (n=117) and tested it in an external cohort (n=88). A third cohort of 89 patients with CT and gene expression data was employed to create a surrogate genomic signature of the imaging signature. We conducted further validation using data from five gene expression cohorts (n=639), and built a composite signature by integrating with the cell-cycle progression (CCP) score and clinical variables.ResultsAn imaging signature consisting of pleural contact index and normalized inverse difference was significantly associated with overall survival in both imaging cohorts (p=0.0005 and 0.0009). Functional enrichment analysis revealed that genes highly correlated with the imaging signature were related to immune response, such as lymphocyte activation and chemotaxis (false discovery rate<0.05). A genomic surrogate of the imaging signature remained a significant predictor of survival adjusting for known prognostic factors (hazard ratio: 1.81, 95% CI: 1.34-2.44, p<0.0001), and stratified patients within subgroups as defined by stage, histology, or CCP score. A composite signature outperformed the genomic surrogate, CCP score, and clinical model alone (p<0.01) regarding concordance index (0.70 vs 0.62-0.63).ConclusionThe proposed CT imaging signature reflects fundamental biologic differences in tumors and predicts overall survival in patients with stage I NSCLC. When combined with established prognosticators, the imaging signature improves survival prediction.

Teaser

We identified a CT imaging signature that predicts overall survival in stage I NSCLC. The imaging signature is associated with immune response and may serve as a noninvasive prognostic biomarker in stage I NSCLC.


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Late normal tissue response in the rat spinal cord after carbon ion irradiation

The present work summarizes the research activities on radiation-induced late effects in the rat spinal cord carried out within the "clinical research group ion beam therapy" funded by the German Research Foun...

http://ift.tt/2mtVa00

Dynamic changes in 18F-borono-L-phenylalanine uptake in unresectable, advanced, or recurrent squamous cell carcinoma of the head and neck and malignant melanoma during boron neutron capture therapy patient selection

We evaluated dynamic changes in 18F–borono-L-phenylalanine (18F–BPA) uptake in unresectable, advanced, or recurrent squamous cell carcinoma of the head and neck (SCC) and malignant melanoma (MM) during boron neut...

http://ift.tt/2qVZOsn

In response to: Unsolved enigma of atrial myxoma with biventricular dysfunction

Aanchal Dixit, Prabhat Tewari, Rashmi Soori, Surendra Kumar Agarwal

Annals of Cardiac Anaesthesia 2018 21(1):107-107

Thanks to Raut et al.[1] for appreciating our efforts in managing the case of biatrial myxomas. A brief discussion is warranted here on the types, size of cardiac myxomas, interleukin 6 (IL-6) levels, left ventricle (LV) dysfunction, and their relation. IL-6 is a pleiotropic cytokine with a variety of biologic activities, including differentiation of B cell, thymocytes, and T cells; activation of macrophages; and stimulation of hepatocyte to produce acute-phase proteins such as C-reactive protein.[2],[3] It is also said to have paracrine, endocrine, and autocrine growth functions.[3]

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Role of transesophageal echocardiography during left atrial appendage occlusion device closure in a patient with non-valvular atrial fibrillation and angiodysplasia of the colon

Dinesh Kumar, Sunil Kumar, Nagraj Desai

Annals of Cardiac Anaesthesia 2018 21(1):88-91

Atrial fibrillation is the most common arrhythmia associated with significant mortality and morbidity secondary to thrombo-embolism. To prevent this thrombo-embolism oral anticoagulation therapy is the recommended treatment. In patients with contraindications to oral anticoagulation therapy, percutaneous left atrial appendage occlusion device is indicated. TEE is essential to guide in all the stages of LAA device deployment. Right from pre-procedure screening, to guiding during deployment, to rule out any complications and post-procedure surveillance and monitoring long term outcomes.

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Perioperative renal protection during cardiac surgery: A choice between dopamine and dexmedetomidine

Rajinder Singh Rawat, Said Musallam Al Maashani

Annals of Cardiac Anaesthesia 2018 21(1):4-5



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Successful resolution with apixaban of a massive left atrial appendage thrombus due to nonrheumatic atrial fibrillation: A case report and review

Bader Abu Ghalyoun, Matthew Lempel, Hamid Shaaban, Fayez Shamoon

Annals of Cardiac Anaesthesia 2018 21(1):76-77

A 32-year-old woman with a past medical history of paroxysmal atrial fibrillation, long QT syndrome, and implantation of an automatic iimplantable cardioverter-defibrillator (AICD) following cardiac arrest presented with disabling symptoms of paroxysmal atrial fibrillation due to recurrent AICD shocks. Before curative ablation, transesophageal echocardiography was performed to assess for existing thrombi. This is a rare case of successful resolution with apixaban of a massive left atrial appendage thrombus due to non-rheumatic atrial fibrillation that was successfully treated with apixaban.

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Noninvasive ventilation using bipap: Expanding indications to post cardiac surgery care

William T McGee

Annals of Cardiac Anaesthesia 2018 21(1):6-7



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Pneumopericardium after minimally invasive atrial septal defect closure

Aditya Lamba, Rahul Dutta, Rajesh K Chand

Annals of Cardiac Anaesthesia 2018 21(1):99-100

Minimally invasive atrial septal defect (ASD) closure is a commonly performed cardiac surgical procedure and has good outcome. We report an interesting chest X-ray showing pneumopericardium in a patient who underwent ASD closure using a minimally invasive approach.

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Prophylaxis of postoperative nausea and vomiting after cardiac surgery in high-risk patients: A randomized controlled study

Sébastien Champion, Laëtitia Zieger, Caroline Hemery

Annals of Cardiac Anaesthesia 2018 21(1):8-14

Context: The role of prophylaxis for postoperative nausea and vomiting (PONV) in cardiac surgery is under debate. Aims: To study the risk factors for PONV after cardiac surgery and the role of betamethasone with or without droperidol for its prevention. Setting and Design: Randomized open-label controlled study comparing standard care with PONV prophylaxis from February to November 2016. Methods: Five hundred and two patients with planned nonemergent cardiac surgery were included. Interventions: In the intervention arm, PONV prophylaxis (4 mg betamethasone with/without 0.625 mg droperidol) was administered in high-risk patients (two or more risk factors). Patients in the control arm were treated as per routine hospital practices. Results: Female sex, past history of PONV, and migraines were associated with a significantly increased risk of PONV, while motion sickness, smoking status, and volatile anesthetics were not. Pain and treatment with nefopam or ketoprofen were associated with an increased risk of PONV. PONV was less frequent in the active arm compared to controls (45.5% vs. 54.0%, P = 0.063; visual analogic scale 10.9 vs. 15.3 mm, P = 0.043). Among the 180 patients (35.6%) with ≥2 risk factors, prophylaxis was associated with reduced PONV (intention-to-treat: 46.8% vs. 67.8%, P = 0.0061; per-protocol: 39.2% vs. 69%, P = 0.0002). In multivariate analysis, prophylaxis was independently associated with PONV (odds ratio [OR]: 0.324, 95% confidence interval: 0.167–0.629, P = 0.0009), as were female sex, past history of PONV, and migraines (OR: 3.027, 3.031, and 2.160 respectively). No drug-related side effects were reported. Conclusion: Betamethasone with/without droperidol was effective in decreasing PONV in high risk cardiac surgical patients without any side effect.

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Concomitant neurogenic and vascular thoracic outlet syndrome due to multiple exostoses

Hosseinali Abdolrazaghi, Azade Riyahi, Morteza Taghavi, Pezhman Farshidmehr, Abolfazl Mohammadbeigi

Annals of Cardiac Anaesthesia 2018 21(1):71-73

We report a rare case of multiple hereditary exostosis where patient presented with bilateral base of neck exostoses with concurrent compression of brachial plexus and subclavian artery and vein. The patient was a young 26-year-old woman with chief complaints of pain in the left upper extremity, paresthesia in the left ring and little finger, and weakness in hand movement and grip. On referral, history, physical examination, radiological imaging, and electrodiagnostic tests evaluated the patient. Due to severe pain and disability in performing routine activities, surgical intervention was necessary. In the current case, the patient had thoracic outlet syndrome with concomitant venous, arterial, and neurogenic sub types. Radial pulse returned and pain associated with brachial plexus compression was resolved after the surgery.

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Retrospective study of complete atrioventricular canal defects: Anesthetic and perioperative challenges

Aniruddha Ramesh Janai, Wilfried Bellinghausen, Edwin Turton, Carmine Bevilacqua, Waseem Zakhary, Martin Kostelka, Farhad Bakhtiary, Joerg Hambsch, Ingo Daehnert, Florian Loeffelbein, Joerg Ender

Annals of Cardiac Anaesthesia 2018 21(1):15-21

Objective: The objective of this study was to highlight anesthetic and perioperative management and the outcomes of infants with complete atrioventricular (AV) canal defects. Design: This retrospective descriptive study included children who underwent staged and primary biventricular repair for complete AV canal defects from 1999 to 2013. Setting: A single-center study at a university affiliated heart center. Participants: One hundred and fifty-seven patients with a mean age at surgery of 125 ± 56.9 days were included in the study. About 63.6% of them were diagnosed as Down syndrome. Mean body weight at surgery was 5.6 ± 6.3 kg. Methods: Primary and staged biventricular repair of complete AV canal defects. Measurements and main results: A predefined protocol including timing of surgery, management of induction and maintenance of anesthesia, cardiopulmonary bypass, and perioperative intensive care treatment was used throughout the study. Demographic data as well as intraoperative and perioperative Intensive Care Unit (ICU) data, such as length of stay in ICU, total duration of ventilation including reintubations, and total length of stay in hospital and in hospital mortality, were collected from the clinical information system. Pulmonary hypertension was noted in 60% of patients from which 30% needed nitric oxide therapy. Nearly 2.5% of patients needed permanent pacemaker implantation. Thorax was closed secondarily in 7% of patients. In 3.8% of patients, reoperations due to residual defects were undertaken. Duration of hospital stay was 14.5 ± 4.7 days. The in-hospital mortality was 0%. Conclusion: Protocolized perioperative management leads to excellent outcome in AV canal defect repair surgery.

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Mechanical discordance between left atrium and left atrial appendage

Arash Khamooshian, Jelliffe Jeganthan, Yannis Amador, Roger J Laham, Feroze Mahmood, Robina Matyal

Annals of Cardiac Anaesthesia 2018 21(1):82-84

During standard transesophageal echocardiographic examinations in sinus rhythm (SR) patients, the left atrial appendage (LAA) is not routinely assessed with Doppler. Despite having a SR, it is still possible to have irregular activity in the LAA. This situation is even more important for SR patients where assessment of the left atrium is often foregone. We describe a case where we encountered this situation and briefly review how to assess the left atrium and its appendage in such a case scenario.

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Dexmedetomidine for prevention of skeletal muscle ischaemia-reperfusion injury in patients with chronic limb ischaemia undergoing aortobifemoral bypass surgery: A prospective double-blind randomized controlled study

Tanveer Singh Kundra, Ashwini Thimmarayappa, Manasa Dhananjaya, N Manjunatha

Annals of Cardiac Anaesthesia 2018 21(1):22-25

Background: Dexmedetomidine is a selective α-2 agonist used for sedation. It has also been shown to have myocardial protective effect and prevent ischemia-reperfusion injury in off-pump coronary artery bypass patients. The aim of our study was to assess the effect of dexmedetomidine for prevention of skeletal muscle ischemia-reperfusion injury in patients undergoing aortobifemoral bypass surgery. Methodology: Sixty adult patients (Group dexmedetomidine n = 30, Group normal saline n = 30) undergoing aortobifemoral bypass surgery were recruited over 3 months. Randomization was done using a computer-generated random table. The attending anesthesiologist would be blinded to whether the drug/normal saline was being administered. He would consider each unlabeled syringe as containing dexmedetomidine and calculate the volume to be infused via a syringe pump accordingly. Dexmedetomidine infusion (1 mcg/kg) over 15 minutes was given as a loading dose, followed by maintenance infusion of 0.5 mcg/kg/h till 2 h postprocedure in Group dexmedetomidine (D) while the same volume of normal saline was given in the control Group C till 2 h postprocedure. Creatine phosphokinase (CPK) values were noted at baseline (T0), 6 h (T1), 12 h (T2), and 24 h (T3) after the procedure. Hemodynamic variables (heart rate [HR] and mean blood pressure [MAP]) were recorded at T0, T1, T2, and T3. Results were analyzed using unpaired Student's t-test, P < 0.05 was considered statistically significant. Results: MAP and HR significantly decreased in Group D as compared to control group (P < 0.05). However, the decrease was never <20% of the baseline. The CPK values at 6, 12, and 24 h were statistically significant between the two groups. Conclusion: Dexmedetomidine prevents skeletal muscle ischemia-reperfusion injury in patients undergoing aortobifemoral bypass surgery.

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Quadricuspid aortic valve: A rare intraoperative diagnosis by transesophageal echocardiography

Anupam Das, Ummed Singh, Palleti Rajashekar

Annals of Cardiac Anaesthesia 2018 21(1):95-96

Quadricuspid aortic valve (QAV) is a rare congenital anomaly frequently associated with other anomalies particularly coronary anomalies. It may be detected on transthoracic or transesophageal echocardiography. We present here a case report of a 27-year-old male patient with a QAV, the valve being regurgitant and requiring aortic valve replacement. It has been reported as isolated case reports in the literature and various theories exist to the development of QAV. The diagnosis requires a high degree of suspicion and a detailed assessment, and if asymptomatic, then patients need to be carefully followed up for the development of aortic regurgitation.

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Assessment the effect of dexmedetomidine on incidence of paradoxical hypertension after surgical repair of aortic coarctation in pediatric patients

Rabie Soliman, Dalia Saad

Annals of Cardiac Anaesthesia 2018 21(1):26-33

Objective: The aim of the study was to assess the effect of dexmedetomidine on the incidence of paradoxical hypertension in patients undergoing aortic coarctation repair. Design: Randomized observational study. Setting: University hospital and cardiac center. Patients: The study included 108 pediatric patients with isolated aortic coarctation. Methods: The patients were classified into two groups (each = 54): Group D: the patients received dexmedetomidine as a loading dose of 0.5 μg/kg over 10 min followed by infusion 0.3 μg/kg/h during surgery and continued for the first 48 postoperative hours. Group C: The patients received an equal amount of normal saline. The medication was prepared by the nursing staff and given to anesthetist blindly. The collected data included the heart rate, systolic and diastolic arterial blood pressure, incidence, onset, severity and treatment of paradoxical hypertension, fentanyl dose and end-tidal sevoflurane concentration, amount of blood loss and urine output. Main Results: The heart rate, systolic and diastolic blood pressure decreased significantly with dexmedetomidine than Group C (P < 0.05). The incidence and severity of the paradoxical hypertension was lower with dexmedetomidine than Group C (P = 0.011, P = 0.017, respectively). The onset the paradoxical hypertension was earlier in Group C than dexmedetomidine (P = 0.026). The dose of fentanyl and sevoflurane concentration decreased significantly with dexmedetomidine (P = 0.034, P = 0.026, respectively). The blood loss decreased with dexmedetomidine (P = 0.020) and the urine output increased with dexmedetomidine (P = 0.024). The incidence of hypotension and bradycardia was more with dexmedetomidine (P < 0.05). Conclusion: Dexmedetomidine is safe in pediatric patients undergoing aortic coarctation repair. It minimized the incidence and severity of paradoxical hypertension. It decreased the required antihypertensive medications.

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Spontaneous coronary artery dissection in anabolic steroid misuse

Aghighe Heidari, Feridoun Sabzi, Reza Faraji

Annals of Cardiac Anaesthesia 2018 21(1):103-104



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A randomized controlled trial comparing the myocardial protective effects of isoflurane with propofol in patients undergoing elective coronary artery bypass surgery on cardiopulmonary bypass, assessed by changes in N-terminal brain natriuretic peptide

Balaji Kuppuswamy, Kirubakaran Davis, Raj Sahajanandan, Manickam Ponniah

Annals of Cardiac Anaesthesia 2018 21(1):34-40

Objective: The objective of the study is to compare the myocardial protective effects of isoflurane with propofol in patients undergoing elective coronary artery bypass surgery on cardiopulmonary bypass (CPB), the cardio protection been assessed by changes in N-terminal brain natriuretic peptide (NT proBNP). Methodology and Design: This study is designed as a participant blinded, prospective randomized clinical trial. Setting: Christian Medical College Hospital, Vellore, India. Participants: Patients undergoing elective coronary artery bypass surgery on CPB. Intervention: Anesthesia was maintained with 0.8–1.2 end tidal concentrations of isoflurane in the isoflurane group and in the propofol group, anesthesia was maintained with propofol infusion as described by Roberts et al. Measurements: Hemodynamic data were recorded at frequent intervals during the surgery and up to 24 h in the Intensive Care Unit (ICU). The other variables that were measured include duration of mechanical ventilation, dose and duration of inotropes in ICU, (inotrope score), duration of ICU stay, NT proBNP levels before induction and 24 h postoperatively, creatine kinase-MB levels in the immediate postoperative, first and second day. Results: Mean heart rate was significantly higher in propofol group during sternotomy, (P = 0.021). Propofol group had a significantly more number of patients requiring nitroglycerine in the prebypass period (P = 0.01). The increase in NT proBNP from preoperative to postoperative value was lesser in the isoflurane group compared to propofol even though the difference was not statistically significant. The requirement of phenylephrine to maintain mean arterial pressure within 20% of baseline, mechanical ventilation duration, inotrope use, duration of ICU stay and hospital stay were found to be similar in both groups. Conclusion: Propofol exhibit comparable myocardial protective effect like that of isoflurane in patients undergoing coronary artery bypass graft surgery. Considering the unproven mortality benefit of isoflurane and the improved awareness of green OT concept, propofol may be the ideal alternative to volatile anesthetics, at least in patients with good left ventricular function.

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Atrioventricular septal defects

Sandeep Chauhan

Annals of Cardiac Anaesthesia 2018 21(1):1-3



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Long-term quality of life postacute kidney injury in cardiac surgery patients

Pankaj Kumar Mishra, Heyman Luckraz, Jayanta Nandi, Alan Nevill, Ramesh Giri, Andrew Panayiotou, Johann Nicholas

Annals of Cardiac Anaesthesia 2018 21(1):41-45

Background: Acute renal failure after cardiac surgery is known to be associated with significant short-term morbidity and mortality. There have as yet been no major reports on long-term quality of life (QOL). This study assessed the impact of acute kidney injury (AKI) and renal replacement therapy (RRT) on long-term survival and QOL after cardiac surgery. The need for long-term RRT is also assessed. Materials and Methods: Patients who underwent cardiac surgery between 2005 and 2011 (n = 6087) and developed AKI (RIFLE criteria, n = 570) were included. They were propensity-matched 1:1 to patients without renal impairment (control). Data were prospectively collected, and health-related QOL questionnaire was sent to patients who were alive at least 1-year postoperatively at the time of the study. Results: There was no significant difference in the preoperative characteristics between the two groups (age, gender, left ventricular ejection fraction, procedure, urgency, logistic Euroscore), respectively. Median follow-up was 52 months. Survival data were available in all patients. Questionnaires were returned in 64% of eligible patients. Long-term survival was significantly lower, and QOL, in particular the physical aspect, was significantly worse for the AKI group as compared to non-AKI group (38.8 vs. 44.2, P = 0.002), especially so in patients who required RRT. In alive respondents, despite an 18% (66/359) incidence of ongoing renal follow-up, the need for late RRT was only in 1.1% (4/359). Conclusion: AKI and especially the need for RRT following cardiac surgery are associated with increased long-term mortality as well as worse quality of life in a propensity-matched control group.

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Commentary: Comments on thoracic outlet syndrome

Gauranga Majumdar, Surendra Kumar Agarwal

Annals of Cardiac Anaesthesia 2018 21(1):74-75



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Design and standardization of tools for assessing the perceived heart risk and heart health literacy in Iran

Habibolah Khazaei, Saeid Komasi, Ali Zakiei, Mohsen Rezaei, Peyman Hatamian, Mohammad Jashnpoor, Mozhgan Saeidi

Annals of Cardiac Anaesthesia 2018 21(1):46-52

Objectives: The aim is to achieve the standard tools for heart health, the present study aimed to design, develop, and standardize the two questionnaires of perceived heart risk scale (PHRS) and heart health literacy scale (HHLS). Methods: The present study was a methodological research conducted on the residents of Kermanshah Province, Iran, using the multi-stage cluster sampling. Further, considering the scientific methods in the psychometric field, the design of the research questionnaires was conducted. In addition, the viewpoints of experts in different domains were qualitatively and quantitatively included to assess the validity of the questionnaires. To assess the reliability of the questionnaires, a sample including 31 subjects was first selected and studied within a fortnight's interval. Then, the reliability and validity of the scales were assessed using factor analysis and Cronbach's alpha in a sample of 771 subjects. Results: After reviewing the viewpoints of experts, the items were adjusted and implemented in the first sample at two stages. The results were indicative of the stability and acceptability of the Cronbach's alpha. In addition, the validity and reliability of the questionnaires were confirmed in the second sample too. Conclusion: According to the results of the present study, it can be concluded that the two questionnaires of PHRS and HHLS had acceptable reliability and validity.

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Bleeding in the lung complicates a routine intracardiac repair: What went wrong!!!

Neeti Makhija, Rohan Magoon, Minati Choudhury, Sivasubramanian Ramakrishnan

Annals of Cardiac Anaesthesia 2018 21(1):78-81

Cyanotic congenital heart disease presents an increased tendency to bleed in view of subtle coagulation defects. Airway bleeding can be particularly difficult to manage while maintaining an adequate ventilation. An isolated lung bleed with the exclusion of possible traumatic, medical and surgical causes of bleeding, should alert the attending anesthesiologist to the possibility of the collateral-related bleeding. Preoperative coil embolization remains an important initial management step in a case of tetralogy of Fallot (TOF) with major aortopulmonary collaterals. Nevertheless, the coiling of the collaterals in certain specific case scenarios is not feasible, rendering the management of a lung bleed, all the more challenging. We, hereby discuss a case of a 7-year-old girl with a massive endotracheal bleed at the time of weaning from cardiopulmonary bypass after corrective surgery for TOF. The subsequent approach and management are discussed. The optimal management of tetralogy with collaterals mandates an effective communication among the cardiologist, radiologist, anesthesiologist, and the surgeon.

http://ift.tt/2DmkpJ0

Late normal tissue response in the rat spinal cord after carbon ion irradiation

The present work summarizes the research activities on radiation-induced late effects in the rat spinal cord carried out within the "clinical research group ion beam therapy" funded by the German Research Foun...

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Dynamic changes in 18F-borono-L-phenylalanine uptake in unresectable, advanced, or recurrent squamous cell carcinoma of the head and neck and malignant melanoma during boron neutron capture therapy patient selection

We evaluated dynamic changes in 18F–borono-L-phenylalanine (18F–BPA) uptake in unresectable, advanced, or recurrent squamous cell carcinoma of the head and neck (SCC) and malignant melanoma (MM) during boron neut...

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WT1 peptide vaccine in Montanide in contrast to poly ICLC, is able to induce WT1-specific immune response with TCR clonal enrichment in myeloid leukemia

Abstract

Background

The optimal strategy for vaccination to induce CD8⁺ T cell responses against WT1 is not known.

Methods

A pilot randomized study in HLA-A02⁺ patients to receive vaccination with WT1 in Montanide or in poly ICLC, a TLR3 agonist, to explore the novel immune adjuvant was conducted. Seven patients were randomized. Four patients received WT1 in Montanide, and three with WT1 in poly ICLC. Five patients were in morphologic remission and two had residual morphologic disease at the study entry.

Results

All patients finished the induction phase without any major toxicity except mild transient local injection reaction. One patient on the Montanide arm developed aseptic ulceration at two vaccine sites which healed without antibiotics. Three of 4 patients on the Montanide arm had a decreased expression of WT1 after WT1 vaccination, and two of them demonstrated generation of WT1-specific cytotoxic CD8⁺ T cell responses with biased TCR beta chain enrichment. In contrast, no obvious WT1-specific immune responses were detected in two patients on the poly ICLC arm, nor was there clonal enrichment by TCR alpha/beta sequencing; however, these patients did also have decreased WT1 expression and remained in remission several years after the initiation of treatment.

Conclusions

WT1 peptide vaccine with Montanide as an adjuvant induces detectable WT1-specific CD8⁺ T cell responses with clonal TCR enrichment, which may be capable of controlling leukemia recurrence in the setting of minimal residual disease. Poly ICLC may induce anti-leukemic activity in the absence of detectable WT1 specific CD8⁺ T cell responses.

Trial registration NCT01842139, 7/3/2012 retrospectively registered; http://ift.tt/2D3ZsWg.

http://ift.tt/2ARtM0j

WT1 peptide vaccine in Montanide in contrast to poly ICLC, is able to induce WT1-specific immune response with TCR clonal enrichment in myeloid leukemia

Abstract

Background

The optimal strategy for vaccination to induce CD8⁺ T cell responses against WT1 is not known.

Methods

A pilot randomized study in HLA-A02⁺ patients to receive vaccination with WT1 in Montanide or in poly ICLC, a TLR3 agonist, to explore the novel immune adjuvant was conducted. Seven patients were randomized. Four patients received WT1 in Montanide, and three with WT1 in poly ICLC. Five patients were in morphologic remission and two had residual morphologic disease at the study entry.

Results

All patients finished the induction phase without any major toxicity except mild transient local injection reaction. One patient on the Montanide arm developed aseptic ulceration at two vaccine sites which healed without antibiotics. Three of 4 patients on the Montanide arm had a decreased expression of WT1 after WT1 vaccination, and two of them demonstrated generation of WT1-specific cytotoxic CD8⁺ T cell responses with biased TCR beta chain enrichment. In contrast, no obvious WT1-specific immune responses were detected in two patients on the poly ICLC arm, nor was there clonal enrichment by TCR alpha/beta sequencing; however, these patients did also have decreased WT1 expression and remained in remission several years after the initiation of treatment.

Conclusions

WT1 peptide vaccine with Montanide as an adjuvant induces detectable WT1-specific CD8⁺ T cell responses with clonal TCR enrichment, which may be capable of controlling leukemia recurrence in the setting of minimal residual disease. Poly ICLC may induce anti-leukemic activity in the absence of detectable WT1 specific CD8⁺ T cell responses.

Trial registration NCT01842139, 7/3/2012 retrospectively registered; http://ift.tt/2D3ZsWg.

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Protocadherin8 Promotes Invasion and Metastasis via Laminin Subunit γ2 in Gastric Cancer

Abstract

Growing evidence suggests that protocadherins (PCDHs) play crucial roles in pathogenesis and progression of cancers including gastric cancer (GC). Protocadherin8 (PCDH8) was previously reported to be involved in metastasis of GC, but functional studies yielded inconsistent results and the molecular mechanism remained unknown. This study aimed to explore the clinical relevance, function and molecular mechanism of PCDH8 in GC. Data from the GEPIA and Kaplan-Meier plotter databases showed that high expression of PCDH8 was significantly correlated with poorer prognosis in GC. Ectopic expression of PCDH8 in GC cells promoted invasion and migration in vitro and metastasis in vivo, and knockdown of PCDH8 inhibited invasion and migration in vitro. RNA sequencing followed by Gene Set Enrichment Analysis found a remarkable enrichment in the extracellular matrix receptor interaction pathway, with the expression of laminin subunit γ2 (LAMC2) being significantly increased in the PCDH8-overexpressing group. High expression of LAMC2 was significantly correlated to poor prognosis in GC in GEPIA database. Up-regulation of LAMC2 following PCDH8 overexpression was further confirmed by immunohistochemistry in liver metastatic lesions of nude mice. To our knowledge, this is the first report of the metastasis-enhancing property and molecular mechanism through up-regulation of LAMC2 of PCDH8 in cancer. High expression of PCDH8 could be used as a biomarker for poor prognosis in clinical practice.

This article is protected by copyright. All rights reserved.

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Hereditary kidney cancer syndromes: Genetic disorders driven by alterations in metabolism and epigenome regulation

Abstract

Although hereditary kidney cancer syndrome accounts for around five percent of all kidney cancers, the mechanistic insight into tumor development in these rare conditions has provided the foundation for the development of molecular targeting agents currently used for sporadic kidney cancer. In the late 1980s, the comprehensive study for hereditary kidney cancer syndrome was launched in the National Cancer Institute, U.S.A. and the first kidney cancer associated gene, VHL was identified through kindred analysis of von Hippel-Lindau syndrome in 1993. Subsequent molecular studies on VHL function have elucidated that the VHL protein is a component of E3 ubiquitin ligase complex for hypoxia-inducible factor (HIF), which provided basis for the development of tyrosine kinase inhibitors targeting the HIF-VEGF/PDGF pathway. Recent whole-exome sequencing analysis of sporadic kidney cancer exhibited the recurrent mutations in chromatin remodeling genes and the later study has revealed that several chromatin remodeling genes are altered in kidney cancer kindred at germline level. To date, more than 10 hereditary kidney cancer syndromes together with each responsible gene have been characterized and most of causative genes for these genetic disorders are associated with either metabolism or epigenome regulation. In this review article, we describe the molecular mechanisms how an alteration of each kidney cancer associated gene leads to renal tumorigenesis as well as denote therapeutic targets elicited by studies on hereditary kidney cancer.

This article is protected by copyright. All rights reserved.

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Protocadherin8 Promotes Invasion and Metastasis via Laminin Subunit γ2 in Gastric Cancer

Abstract

Growing evidence suggests that protocadherins (PCDHs) play crucial roles in pathogenesis and progression of cancers including gastric cancer (GC). Protocadherin8 (PCDH8) was previously reported to be involved in metastasis of GC, but functional studies yielded inconsistent results and the molecular mechanism remained unknown. This study aimed to explore the clinical relevance, function and molecular mechanism of PCDH8 in GC. Data from the GEPIA and Kaplan-Meier plotter databases showed that high expression of PCDH8 was significantly correlated with poorer prognosis in GC. Ectopic expression of PCDH8 in GC cells promoted invasion and migration in vitro and metastasis in vivo, and knockdown of PCDH8 inhibited invasion and migration in vitro. RNA sequencing followed by Gene Set Enrichment Analysis found a remarkable enrichment in the extracellular matrix receptor interaction pathway, with the expression of laminin subunit γ2 (LAMC2) being significantly increased in the PCDH8-overexpressing group. High expression of LAMC2 was significantly correlated to poor prognosis in GC in GEPIA database. Up-regulation of LAMC2 following PCDH8 overexpression was further confirmed by immunohistochemistry in liver metastatic lesions of nude mice. To our knowledge, this is the first report of the metastasis-enhancing property and molecular mechanism through up-regulation of LAMC2 of PCDH8 in cancer. High expression of PCDH8 could be used as a biomarker for poor prognosis in clinical practice.

This article is protected by copyright. All rights reserved.

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Hereditary kidney cancer syndromes: Genetic disorders driven by alterations in metabolism and epigenome regulation

Abstract

Although hereditary kidney cancer syndrome accounts for around five percent of all kidney cancers, the mechanistic insight into tumor development in these rare conditions has provided the foundation for the development of molecular targeting agents currently used for sporadic kidney cancer. In the late 1980s, the comprehensive study for hereditary kidney cancer syndrome was launched in the National Cancer Institute, U.S.A. and the first kidney cancer associated gene, VHL was identified through kindred analysis of von Hippel-Lindau syndrome in 1993. Subsequent molecular studies on VHL function have elucidated that the VHL protein is a component of E3 ubiquitin ligase complex for hypoxia-inducible factor (HIF), which provided basis for the development of tyrosine kinase inhibitors targeting the HIF-VEGF/PDGF pathway. Recent whole-exome sequencing analysis of sporadic kidney cancer exhibited the recurrent mutations in chromatin remodeling genes and the later study has revealed that several chromatin remodeling genes are altered in kidney cancer kindred at germline level. To date, more than 10 hereditary kidney cancer syndromes together with each responsible gene have been characterized and most of causative genes for these genetic disorders are associated with either metabolism or epigenome regulation. In this review article, we describe the molecular mechanisms how an alteration of each kidney cancer associated gene leads to renal tumorigenesis as well as denote therapeutic targets elicited by studies on hereditary kidney cancer.

This article is protected by copyright. All rights reserved.

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No additional prognostic value for MRE11 in squamous cell carcinomas of the anus treated with chemo-radiotherapy

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No additional prognostic value for MRE11 in squamous cell carcinomas of the anus treated with chemo-radiotherapy

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Acute aortoiliac occlusive disease during percutaneous transluminal angioplasty in the setting of ST-elevation myocardial infarction: a case report

Aortoiliac occlusive disease, which is also referred to as Leriche syndrome, is a chronic atherosclerotic occlusive disease that occurs at the level of the aortic bifurcation. It is often thought to present wi...

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Standard whole prostate gland radiotherapy with and without lesion boost in prostate cancer: Toxicity in the FLAME randomized controlled trial

To compare toxicity rates in patients with localized prostate cancer treated with standard fractionated external beam radiotherapy (EBRT) with or without an additional integrated boost to the macroscopically visible tumour.

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The impact of obesity on outcomes for patients undergoing mastectomy using the ACS-NSQIP data set

Abstract

Purpose

According to the World Health Organization (WHO), 34.7% of females in the United States are obese (BMI ≥ 30) in 2014, compared to 32.5% in 2010. The previous research has demonstrated high BMI as an independent risk factor for surgical complications after breast surgery. As more patients become obese, we sought to examine whether increasing obesity had an effect on outcomes of women who underwent a unilateral mastectomy without breast reconstruction.

Methods

The study reviewed the 2007–2012 ACS-NSQIP database and identified all patients who underwent a unilateral mastectomy without reconstruction. Patients were then categorized and compared according to the World Health Organization obesity classification. Data were analyzed for minor complications (e.g., UTI and SSI) and major complications (e.g., renal failure, sepsis, deep vein thrombosis, return to operating room [RTOR], and cardiac arrest).

Results

A total of 7207 women were identified. Median BMI was 27.3 kg/m². From the cohort, 453 patients (6.29%) had a major complication and 173 patients (2.40%) had a minor complication. 53 (0.74%) had bleeding complications, 148 (2.05%) had a surgical site infection (SSI), 352 (4.88%) RTOR, and 7 (0.01%) died within 30 days. Major complications (p = 0.005) and minor complications (p < 0.001) significantly increased as BMI increased. SSI and RTOR had increasing trends, but were not statistically significant.

Conclusions

This study characterizes the risk of complications in women undergoing unilateral mastectomies and shows that increasing obesity is associated with major and minor postoperative complications. Our finding highlights the need for personalized preoperative risk assessment and counseling of obese patients.

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Differences in histological features and PD-L1 expression between sporadic microsatellite instability and Lynch-syndrome-associated disease in Japanese patients with colorectal cancer

Abstract

Background

The field of immunotherapy has recently focused on cancers with microsatellite instability (MSI). These cancers include both Lynch-syndrome-associated tumors, which are caused by mismatch repair (MMR) germline mutations, and sporadic MSI tumors, which are mainly attributed to MLH1 promoter methylation. The present study aimed to clarify differences in the histological and PD-L1 expression profiles between these two types of MSI cancers in Japanese patients.

Methods

Among 908 cases of colorectal cancer treated via surgical resection from 2008 to 2014, we identified 64 MSI cancers, including 36 sporadic MSI and 28 Lynch-syndrome-associated cancers, using a BRAF V600E mutation analysis and MLH1 methylation analysis. Of the latter subgroup, 21 (75%) harbored MMR germline mutations.

Results

The following were more frequent with sporadic MSI than with Lynch syndrome associated cancers: poor differentiation (50.0 vs. 7.1%, P = 0.0002), especially solid type (30.6 vs. 3.6%, P = 0.0061); medullary morphology (19.4 and 0%, P = 0.015), Crohn-like lymphoid reaction (50.0 vs. 25.0%, P = 0.042), and PD-L1 expression (25.0 vs. 3.6%, P = 0.034). However, the groups did not differ in terms of the mean invasive front and intratumoral CD8-positive cell densities. In a logistic regression analysis, PD-L1 expression correlated with poor differentiation (odds ratio: 7.65, 95% confidence interval: 1.55–37.7, P = 0.012), but not with the difference between sporadic MSI cancer and Lynch-syndrome-associated cancer (odds ratio: 4.74, 95% confidence interval: 0.50–45.0, P = 0.176).

Conclusions

Therefore, compared with Lynch-syndrome-associated cancers, sporadic MSI cancers are more frequently solid, poorly differentiated medullary cancers that express PD-L1.

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Differences in histological features and PD-L1 expression between sporadic microsatellite instability and Lynch-syndrome-associated disease in Japanese patients with colorectal cancer

Abstract

Background

The field of immunotherapy has recently focused on cancers with microsatellite instability (MSI). These cancers include both Lynch-syndrome-associated tumors, which are caused by mismatch repair (MMR) germline mutations, and sporadic MSI tumors, which are mainly attributed to MLH1 promoter methylation. The present study aimed to clarify differences in the histological and PD-L1 expression profiles between these two types of MSI cancers in Japanese patients.

Methods

Among 908 cases of colorectal cancer treated via surgical resection from 2008 to 2014, we identified 64 MSI cancers, including 36 sporadic MSI and 28 Lynch-syndrome-associated cancers, using a BRAF V600E mutation analysis and MLH1 methylation analysis. Of the latter subgroup, 21 (75%) harbored MMR germline mutations.

Results

The following were more frequent with sporadic MSI than with Lynch syndrome associated cancers: poor differentiation (50.0 vs. 7.1%, P = 0.0002), especially solid type (30.6 vs. 3.6%, P = 0.0061); medullary morphology (19.4 and 0%, P = 0.015), Crohn-like lymphoid reaction (50.0 vs. 25.0%, P = 0.042), and PD-L1 expression (25.0 vs. 3.6%, P = 0.034). However, the groups did not differ in terms of the mean invasive front and intratumoral CD8-positive cell densities. In a logistic regression analysis, PD-L1 expression correlated with poor differentiation (odds ratio: 7.65, 95% confidence interval: 1.55–37.7, P = 0.012), but not with the difference between sporadic MSI cancer and Lynch-syndrome-associated cancer (odds ratio: 4.74, 95% confidence interval: 0.50–45.0, P = 0.176).

Conclusions

Therefore, compared with Lynch-syndrome-associated cancers, sporadic MSI cancers are more frequently solid, poorly differentiated medullary cancers that express PD-L1.

http://ift.tt/2mlvHoD

A SUV max -based propensity matched analysis of stereotactic body radiotherapy versus surgery in stage I non-small cell lung cancer: unveiling the role of 18F-FDG PET/CT in clinical decision-making

Abstract

Background

The value of maximum standard uptake value (SUV_max) was overlooked in current studies comparing stereotactic body radiotherapy (SBRT) versus surgery for stage I non-small cell lung cancer (NSCLC). Herein, we aimed to compare the 3-year outcomes based on patients for whom SUV_max were available, and to explore the role of SUV_max in clinical decision-making.

Methods

From January 2010 to June 2016, data of eligible patients were collected. Patient variables and clinical outcomes were compared in both unmatched and matched groups using propensity score matching (PSM). Multivariate analysis was performed for predictors of poor outcome. The relationship between treatment approach and survival outcome was also evaluated in subgroup patients stratified by SUV_max level.

Results

A total of 425 patients treated with either surgery (325) or SBRT (100) were included. Patients receiving SBRT were significantly older, had a higher level of SUV_max and were more likely to have tumor of centrally located. Multivariate analysis showed that SUV_max and tumor size were significant predictors for 3-year OS, LRC, and PFS, while better PFS was also related to peripheral tumor and surgery. The result of PSM analysis also showed that compared to SBRT, surgery could only achieve better PFS. Subgroup analysis indicated that surgery had added advantage of 3-year LRC and PFS for patients in high SUV_max group (SUV_max > 8), but not in low SUV_max group.

Conclusions

The study found a superior PFS after surgery while OS and LRC did not differ between SBRT and surgery. Surgery should be recommended for tumor of high SUV_max.

http://ift.tt/2qXiZ5b

Mangiferin prevents the growth of gastric carcinoma by blocking the PI3K-Akt signalling pathway

The aim of the present study was to investigate the effects of mangiferin on gastric carcinoma cells and to determine the possible mechanisms underlying such effects. The MTT assay was performed to evaluate the antiproliferative effect of mangiferin. Following treatment, apoptosis rates of SGC-7901 were established by flow cytometry and laser confocal microscopy, and western blot analysis was used to detect the expression of apoptosis-related proteins. The MTT assay showed that mangiferin inhibited the proliferation of SGC-7901 and BCG-823 cells in a dose-dependent and time-dependent manner. After SGC-7901 cells were exposed to mangiferin for 24, 48 and 72 h, the half-maximal inhibitory concentration values were 16.00, 8.63 and 4.79 µmol/l, respectively. SGC-7901 cell apoptosis induced by mangiferin was observed by Annexin V/PI doubling staining and terminal deoxynucleotidyl transferase dUTP nick end labeling-positive staining. We found a significant decrease in Bcl-2, Bcl-xL and Mcl-1 expression and a significant increase in Bax, Bad and cleaved caspase-3 and caspase-9 expression in SGC-7901 cells by mangiferin treatment. Moreover, mangiferin significantly decreased the levels of p-PI3K, p-Akt and p-mTOR, but had no effects on those of PI3K, Akt and mTOR in epidermal growth factor-treated SGC-7901 cells. Interestingly, the proapoptotic effect of mangiferin on SGC-7901 cells was partially blocked by the Akt activator SC79, whereas LY294002 significantly increased mangiferin-induced apoptosis and growth inhibition. Taken together, our findings indicate that mangiferin effectively inhibits cell growth and induces apoptosis of gastric cancer cells through inhibiting the PI3K/Akt pathways with relative safety, and may be used as a novel chemotherapeutic agent against gastric cancer.

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Thioridazine upregulates programmed cell death 4 to induce apoptosis in nasopharyngeal carcinoma through the PI3K/Akt signalling pathway

Thioridazine (THZ) has been identified as a potential regulator of tumour progression, and programmed cell death 4 (PDCD4) has been reported as a novel tumour suppressor. This study aimed to investigate the link between PDCD4 and THZ in the regulation of nasopharyngeal cancer (NPC) cell proliferation. The effect of THZ on NPC cells was determined using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-2H-tetrazolium bromide (MTT) assays. Then, the involvement of apoptosis and cell cycle in the THZ-mediated regulation of cell viability was assessed by flow cytometry. Related mRNAs and proteins were subsequently examined by real-time PCR and western blot, respectively. After transfection with the PDCD4-siRNA, pGC-FU-GFP-PDCD4 vector and phosphoinositide 3-kinase (PI3K) inhibitor Ly294002, we investigated the antagonistic effects of THZ and PDCD4 on NPC-related protein expression. MTT assays showed that THZ treatment suppressed cell viability. THZ-treated cells were arrested at the G1/G0 phase and showed a significantly increased apoptotic fraction. Furthermore, PDCD4-siRNA antagonized THZ treatment and promoted NPC cell proliferation. Western blot analysis showed that PDCD4 overexpression or PI3K inhibition by LY294002 significantly reduced the expression of phospho-PI3K, phospho-Akt, phospho-mammalian target of rapamycin and phospho-p70s6k, but not their total protein levels. In conclusion, our findings show that THZ and PDCD4 exert antagonistic effects on NPC cell proliferation, probably through the PI3K/Akt pathway. Moreover, these results provide an insight into the mechanism by which THZ targets PDCD4 in NPC cell lines and suggest that the ectopic expression of PDCD4 is a potential therapeutic strategy.

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Efficacy and safety of apatinib as second-line therapy for advanced gastric cancer: a single-center observational study

Apatinib has been proven to be effective and safe among patients in the third-line treatment of advanced gastric cancer in phase II and III trials. We aimed to evaluate its efficacy and safety in second-line practice, and to explore the factors associated with efficacy. Between April 2015 and May 2017, a total of 23 patients with advanced gastric adenocarcinoma or adenocarcinoma of gastroesophageal junction were enrolled and followed up retrospectively after failing the first line of systemic therapy. The median progression-free survival was 4.43 months (95% confidence interval: 1.63–7.22) and the median overall survival was 9.11 months (95% confidence interval: 8.22–9.99). Two patients achieved a partial response and 14 patients achieved stable disease. The disease control rate was 69.6% and the objective response rate was 8.7%. The most common adverse events over grade 3 were hypertension (8.7%) and thrombocytopenia (8.7%). No treatment-related death was documented during the drug administration. Apatinib is an effective regimen for the second-line treatment of advanced gastric and gastroesophageal cancer with manageable toxicity.

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Anticancer properties of thiophene derivatives in breast cancer MCF-7 cells

Substitutions in thiophene structure give rise to new derivatives with different biological and pharmacological activities. The present study investigated the cytotoxicity activity of some thiophene derivatives in breast cancer cells maintained in two-dimensional (2D) or in three-dimensional (3D) culture and evaluated the anticancer mechanism of these compounds. Cytotoxicity assays were performed against untransformed cells and against breast cancer cell MCF-7. Apoptosis analysis and in-vitro migration assay were also performed to evaluate the mechanism of induction of cell death. All thiophene derivatives reduced the cell viability in breast cancer cells, showing cytotoxic activity (IC500.05). MCF-7 cells became less responsive to SB-200 and to doxorubicin in 3D culture compared with cells in 2D culture (higher IC50 values); however, SB-200 showed a better cytotoxic effect compared with doxorubicin in 3D culture. Therefore, the current study provides an insight into anticancer potential of thiophene derivatives, and further studies should be conducted to understand the mechanism by which thiophene derivatives act on cancer cells.

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SUMOylation regulates TGF-β1/Smad4 signalling in-resistant glioma cells

The aim of this study was to explore the role of TGF-β1/Smad4 signalling in the DNA damage-induced ionization radiation (IR) resistance of glioma cells. T98G cells were assigned to the IR group (treated with IR) or the Blank group (with no treatment). The IR-treated cells were also treated/transfected with the TGF-β receptor inhibitor SB431542, SUMO1-overexpressing plasmids (SUMO1 group), SUMO1-interfering plasmids (si-SUMO1 group) or negative control plasmids group. The wound-healing capacity, cell proliferation and cell apoptosis were evaluated by the scratch assay, flow cytometry and the CCK-8 assay, respectively, and protein interactions were investigated by coimmunoprecipitation and colocalization assays. IR-treated T98G cells had DNA damage, but the wound-healing capacity and cell apoptosis were not significantly suppressed. DNA damage also induced TGF-β1, Smad4, SUMO1, SUMO2/3 and Ubc9 expression. In IR-treated cells cultured with SB431542, the wound-healing capacity and proliferation were promoted. SUMO1 and Smad4 colocalized in the nucleus of T98G cells, and the IR-treated cells had a significantly higher expression of the SUMO1–Smad4 protein complex. Smad4 expression in the nucleus was significantly reduced in the si-SUMO1 group, but was markedly increased in the SUMO1 group; the SUMO1 group had significantly elevated apoptotic activity, whereas the si-SUMO1 group showed significantly suppressed apoptotic activity and the si-SUMO1+SB41542 group had the lowest levels of cell apoptosis. DNA damage may activate Smad4 SUMOylation and the SUMOylation of Smad4 participates in the activation of TGF-β/Smad4 signalling; therefore, enhanced Smad4 SUMOylation is critical for the damage-induced activation of IR resistance.

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TNM stage at diagnosis is more predictive of prognosis than pathological complete response in young breast cancer treated with neoadjuvant chemotherapy

No abstract available

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Structural modification of histone deacetylase inhibitors with a phenylglycine scaffold

During the discovery of histone deacetylase inhibitors (HDACIs) as antitumor drugs, a series of potent phenylglycine-based HDACIs were developed. However, further development is restricted by the poor solubility. Therefore, structural modifications were performed in the present study in the development of potent HDACIs with improved pharmacokinetic properties. The synthesized molecules were designed by the substitution of fatty linkers for aromatic linkers, and showed good solubility profiles. Among the compounds derived, molecule HD9 showed a potent enzyme-inhibitory effect (IC50 values of 76 nmol/l) and in-vitro antiproliferative activities (IC50 values of 0.51, 0.83, and 0.76 µmol/l against U937, K562, and HL60 cells, respectively). Molecule HD9 showed selectivity of HDAC3 over HDAC6 in the isoform selectivity assays. Molecular docking studies showed good binding patterns of molecule HD9 to the active site of HDAC3. Results from the present work indicated that molecule HD9 is a promising lead compound for the tumor therapy.

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Electrochemotherapy with anti-PD-1 treatment induced durable complete response in heavily pretreated metastatic melanoma patient

Metastatic melanoma (MM) is one of the most lethal types of cancer. Although novel immunotherapeutics have been developed recently, still, these drugs fail to save the lives of a third of MM patients. Electrochemotherapy (ECT) is a local treatment of cancer based on a combination of electroporesis and low-dose chemotherapy. In this case report, we present the treatment history of a MM patient treated successfully with ECT and immunotherapy combination as a fifth-line treatment. Our patient was a 39 year-old woman who was diagnosed with nodulary melanoma stage II. Due to a local recurrence, she was given interferon-α treatment. After 6 months, her disease relapsed in the axillary lymph nodes, and temozolamide treatment 150 mg/m2 was initiated. After six cycles on temozolamide, she progressed both in the axillary site and in the lungs. Her BRAF mutation analysis revealed V600E positivity. Hence, BRAF inhibitor-vemurafenib 2′4 tablets per day was initiated. Within 3 months, she responded dramatically both in the axillary site and in the lungs. At the ninth month of treatment, she progressed again, at which time ipilimumab 3 mg/kg was started as a fourth line treatment. However, shortly after, she progressed again and developed a solitary brain metastasis. She was operated and had whole brain radiotherapy. At that point, nivolumab, an antiprogrammed cell death ligand-1 blocker, was the only remaining option. She showed a biphenotypical response to nivolumab; a mass on the anterior axilla was progressing while the other lymph nodes had regressed. Owing to the accessibility of the subcutaneous lesion with external electrodes, ECT was performed using IGEA Cliniprator device through a hexagonal electrode on the progressive mass, while on nivolumab treatment. A complete response was achieved, with no evidence of disease at 4 years since her local recurrence. Eradication of symptomatic, refractory lesions using ECT meets an important clinical need. Whenever a disseminated disease presents with cutaneous/subcutaneous lesions, high efficacy of ECT should be deployed to augment tumor immunogenicity and complement systemic immunotherapies.

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Mangiferin prevents the growth of gastric carcinoma by blocking the PI3K-Akt signalling pathway

The aim of the present study was to investigate the effects of mangiferin on gastric carcinoma cells and to determine the possible mechanisms underlying such effects. The MTT assay was performed to evaluate the antiproliferative effect of mangiferin. Following treatment, apoptosis rates of SGC-7901 were established by flow cytometry and laser confocal microscopy, and western blot analysis was used to detect the expression of apoptosis-related proteins. The MTT assay showed that mangiferin inhibited the proliferation of SGC-7901 and BCG-823 cells in a dose-dependent and time-dependent manner. After SGC-7901 cells were exposed to mangiferin for 24, 48 and 72 h, the half-maximal inhibitory concentration values were 16.00, 8.63 and 4.79 µmol/l, respectively. SGC-7901 cell apoptosis induced by mangiferin was observed by Annexin V/PI doubling staining and terminal deoxynucleotidyl transferase dUTP nick end labeling-positive staining. We found a significant decrease in Bcl-2, Bcl-xL and Mcl-1 expression and a significant increase in Bax, Bad and cleaved caspase-3 and caspase-9 expression in SGC-7901 cells by mangiferin treatment. Moreover, mangiferin significantly decreased the levels of p-PI3K, p-Akt and p-mTOR, but had no effects on those of PI3K, Akt and mTOR in epidermal growth factor-treated SGC-7901 cells. Interestingly, the proapoptotic effect of mangiferin on SGC-7901 cells was partially blocked by the Akt activator SC79, whereas LY294002 significantly increased mangiferin-induced apoptosis and growth inhibition. Taken together, our findings indicate that mangiferin effectively inhibits cell growth and induces apoptosis of gastric cancer cells through inhibiting the PI3K/Akt pathways with relative safety, and may be used as a novel chemotherapeutic agent against gastric cancer.

http://ift.tt/2mrYOay

The role of the globular heads of the C1q receptor in paclitaxel-induced human ovarian cancer cells apoptosis by a mitochondria-dependent pathway

As a mitochondrial membrane protein, globular C1q receptor (gC1qR) can mediate a variety of biological responses. Our study aims to investigate the role of gC1qR in paclitaxel-induced apoptosis of human ovarian cancer cells and to elucidate its potential molecular mechanism. The level of gC1qR was examined using real-time PCR and western blot analyses. Human ovarian cancer cells viability, migration, and proliferation were detected using the water-soluble tetrazolium salt (WST-1) assay, the transwell assay, and 3H-thymidine incorporation into DNA (3H-TdR) assay, respectively. Apoptosis in cells was assessed using flow cytometric analysis. The intracellular reactive oxygen species was estimated by the fluorescence of H2DCFDA and the mitochondrial membrane potential was tested using a JC-1 probe. The expression of the gC1qR gene decreased significantly in human ovarian cancer tissues relative to the surrounding non-neoplastic ovarian tissues. Cells treated with paclitaxel showed increased gC1qR gene expression, cell apoptosis, and mitochondria dysfunction, and the effects on these cells could be abrogated by the addition of gC1qR small-interfering RNA or α-lipoic acid that was used to protect the mitochondria function. In summary, these data support a mechanism that gC1qR-induced mitochondria dysfunction was involved in the paclitaxel-mediated apoptosis of ovarian cancer cells.

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Thioridazine upregulates programmed cell death 4 to induce apoptosis in nasopharyngeal carcinoma through the PI3K/Akt signalling pathway

Thioridazine (THZ) has been identified as a potential regulator of tumour progression, and programmed cell death 4 (PDCD4) has been reported as a novel tumour suppressor. This study aimed to investigate the link between PDCD4 and THZ in the regulation of nasopharyngeal cancer (NPC) cell proliferation. The effect of THZ on NPC cells was determined using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-2H-tetrazolium bromide (MTT) assays. Then, the involvement of apoptosis and cell cycle in the THZ-mediated regulation of cell viability was assessed by flow cytometry. Related mRNAs and proteins were subsequently examined by real-time PCR and western blot, respectively. After transfection with the PDCD4-siRNA, pGC-FU-GFP-PDCD4 vector and phosphoinositide 3-kinase (PI3K) inhibitor Ly294002, we investigated the antagonistic effects of THZ and PDCD4 on NPC-related protein expression. MTT assays showed that THZ treatment suppressed cell viability. THZ-treated cells were arrested at the G1/G0 phase and showed a significantly increased apoptotic fraction. Furthermore, PDCD4-siRNA antagonized THZ treatment and promoted NPC cell proliferation. Western blot analysis showed that PDCD4 overexpression or PI3K inhibition by LY294002 significantly reduced the expression of phospho-PI3K, phospho-Akt, phospho-mammalian target of rapamycin and phospho-p70s6k, but not their total protein levels. In conclusion, our findings show that THZ and PDCD4 exert antagonistic effects on NPC cell proliferation, probably through the PI3K/Akt pathway. Moreover, these results provide an insight into the mechanism by which THZ targets PDCD4 in NPC cell lines and suggest that the ectopic expression of PDCD4 is a potential therapeutic strategy.

http://ift.tt/2mtDxxk

Efficacy and safety of apatinib as second-line therapy for advanced gastric cancer: a single-center observational study

Apatinib has been proven to be effective and safe among patients in the third-line treatment of advanced gastric cancer in phase II and III trials. We aimed to evaluate its efficacy and safety in second-line practice, and to explore the factors associated with efficacy. Between April 2015 and May 2017, a total of 23 patients with advanced gastric adenocarcinoma or adenocarcinoma of gastroesophageal junction were enrolled and followed up retrospectively after failing the first line of systemic therapy. The median progression-free survival was 4.43 months (95% confidence interval: 1.63–7.22) and the median overall survival was 9.11 months (95% confidence interval: 8.22–9.99). Two patients achieved a partial response and 14 patients achieved stable disease. The disease control rate was 69.6% and the objective response rate was 8.7%. The most common adverse events over grade 3 were hypertension (8.7%) and thrombocytopenia (8.7%). No treatment-related death was documented during the drug administration. Apatinib is an effective regimen for the second-line treatment of advanced gastric and gastroesophageal cancer with manageable toxicity.

http://ift.tt/2mrYBUO