Socioeconomic status and breast cancer treatment

Abstract

Purpose

Evidence suggests substantial disparities in breast cancer survival by socioeconomic status (SES). We examine the extent to which receipt of newer, less invasive, or more effective treatments—a plausible source of disparities in survival—varies by SES among elderly women with early-stage breast cancer.

Methods

Multivariate regression analyses applied to 11,368 women (age 66–90 years) identified from SEER-Medicare as having invasive breast cancer diagnosed in 2006–2009. Socioeconomic status was defined based on Medicaid enrollment and level of poverty of the census tract of residence. All analyses controlled for demographic, clinical health status, spatial, and healthcare system characteristics.

Results

Poor and near-poor women were less likely than high SES women to receive sentinel lymph node biopsy and radiation after breast-conserving surgery (BCS). Poor women were also less likely than near-poor or high SES women to receive any axillary surgery and adjuvant chemotherapy. There were no significant differences in use of aromatase inhibitors (AI) between poor and high SES women. However, near-poor women who initiated hormonal therapy were more likely to rely exclusively on tamoxifen, and less likely to use the more expensive but more effective AI when compared to both poor and high SES women.

Conclusions

Our results indicate that SES disparities in the receipt of treatments for incident breast cancer are both pervasive and substantial. These disparities remained despite women's geographic area of residence and extent of disease, suggesting important gaps in access to effective breast cancer care.

http://ift.tt/2j6uEux

Testosterone inhibits the growth of prostate cancer xenografts in nude mice

Abstract

Background

Traditional beliefs of androgen's stimulating effects on the growth of prostate cancer (PCa) have been challenged in recent years. Our previous in vitro study indicated that physiological normal levels of androgens inhibited the proliferation of PCa cells. In this in vivo study, the ability of testosterone (T) to inhibit PCa growth was assessed by testing the tumor incidence rate and tumor growth rate of PCa xenografts on nude mice.

Methods

Different serum testosterone levels were manipulated in male nude/nude athymic mice by orchiectomy or inserting different dosages of T pellets subcutaneously. PCa cells were injected subcutaneously to nude mice and tumor incidence rate and tumor growth rate of PCa xenografts were tested.

Results

The data demonstrated that low levels of serum T resulted in the highest PCa incidence rate (50%). This PCa incidence rate in mice with low T levels was significantly higher than that in mice treated with higher doses of T (24%, P < 0.01) and mice that underwent orchiectomy (8%, P < 0.001). Mice that had low serum T levels had the shortest tumor volume doubling time (112 h). This doubling time was significantly shorter than that in the high dose 5 mg T arm (158 h, P < 0.001) and in the orchiectomy arm (468 h, P < 0.001).

Conclusion

These results indicated that low T levels are optimal for PCa cell growth. Castrate T levels, as seen after orchiectomy, are not sufficient to support PCa cell growth. Higher levels of serum T inhibited PCa cell growth.

http://ift.tt/2vO2hqP

Safety, tolerability, and pharmacokinetic profile of dabrafenib in Japanese patients with BRAF V600 mutation-positive solid tumors: a phase 1 study

Summary

Background Dabrafenib is a BRAF inhibitor that has demonstrated clinical activity with a good tolerability profile in patients with BRAF ^V600E mutated metastatic melanoma. This study evaluated the safety and tolerability, pharmacokinetics and preliminary efficacy of dabrafenib in Japanese patients. Methods This phase I, open-label, dose escalation study was conducted in 12 Japanese patients with BRAF ^V600 mutation positive solid tumours. Primary endpoint was safety, assessed by monitoring and recording of all adverse events (AEs), serious AEs, drug-related AEs; secondary endpoints were pharmacokinetic profiles and efficacy measured by tumour response. This study is registered with ClinicalTrials.gov, number NCT01582997. Results Of the 12 patients enrolled, 3 each received 75 mg and 100 mg dabrafenib while 6 received 150 mg dabrafenib twice daily orally. Melanoma and thyroid cancer were the primary tumours reported in 11 (92%) and 1 (8%) patients respectively. Most AEs were grade 1 or 2 and considered related to study treatment. Most common AEs reported in the 12 patients were alopecia in 7 (58%); pyrexia, arthralgia and leukopenia in 6 (50%) each, hyperkeratosis and nausea in 4 (33%) each. Partial response as best overall response was reported in 7 of 12 (58%) patients and in 6 (55%) with malignant melanoma. No dose-limiting toxicity (DLTs) were reported during the DLT evaluation periods. Conclusions Dabrafenib was well tolerated and rapidly absorbed administered as single- or multiple dose. Comparable safety and pharmacokinetic profiles were observed compared with non-Japanese patients. Dabrafenib has promising clinical activity in Japanese patients with BRAF mutated malignant melanoma.

http://ift.tt/2xcfytM

Sclerosing thymoma-like thymic amyloidoma with nephrotic syndrome: a case report

Primary localized amyloidosis presenting as an isolated mediastinal mass is extremely rare, especially in the thymus. Sclerosing thymoma is also an extremely rare anterior mediastinal tumor, pathologically cha...

http://ift.tt/2gJ2NvX

[Cr 3 O(O 2 CCH 2 CH 3 ) 6 (H 2 O) 3 ]NO 3 ·H 2 O (Cr3) Toxicity Potential in Bacterial and Mammalian Cells

Abstract

Chromium(III) has generally been considered to be essential for proper carbohydrate and lipid metabolism, and, despite recent evidence to the contrary, chromium(III)-containing compounds remain one of the most popular commercial dietary supplements. Cr3, or [Cr₃O(O₂CCH₂CH₃)₆(H₂O)₃]NO₃·H₂O, is a trivalent chromium compound that is a promising chromium nutritional supplement. Studies with Cr3 have indicated that it is non-toxic in developmental and short- and long-term exposure studies in rodents, but the safety of this compound to chromosomes and cells has not been explored. The current study evaluates the mutagenicity, cytotoxicity, and clastogenicity of Cr3 in bacterial and mammalian cells and compares these results with similar studies using the bestselling Cr(III) nutritional supplement, chromium picolinate (CrPic). The mutagenicity of CrPic and Cr3 was tested in Escherichia coli FX-11 and Salmonella typhimurium (TA 98 and TA 100). Cytotoxicity was measured as a decrease in plating efficiency relative to controls after treatment with Cr3 and CrPic for 24 h in CHO K1 cells. Clastogenicity was measured by counting the number of metaphases damaged and of the total number chromosomal aberrations in CHO K1 cells. Mutagenesis assays in E. coli and S. typhimurium were negative. All treatments of Cr3 produced ≥ 84% plating efficiency except 80 μg/cm², which reduced the plating efficiency to 62%. Cr3 at any treatment level did not produce a significant increase in the number of cells with abnormal metaphases, while treatments using ≥ 40 μg/cm² of CrPic elevated the number significantly. These data suggest that Cr3 is significantly less mutagenic in bacteria cells and less clastogenic in CHO K1 cells, while CrPic is clastogenic in CHO K1 cells.

http://ift.tt/2eHHuug

Effects of low-to-moderate alcohol supplementation on urinary estrogen metabolites in postmenopausal women in a controlled feeding study

Abstract

Heavy alcohol drinking is associated with increased breast cancer risk, but associations with low-to-moderate alcohol consumption are less clear and the biological mechanisms are not well defined. The objective of this study was to evaluate the effects of 8 weeks of low (15 g/d) and moderate (30 g/d) alcohol ingestion on concentrations of 15 urinary estrogen metabolites (EMs) in postmenopausal women (n = 51) in a controlled feeding study with a randomized crossover design. Compared to no alcohol, 15 g/day for 8 weeks had no effect on urinary EMs. However, compared to no alcohol, 30 g/day for 8 weeks decreased urinary 2-hydroestrone (2-OHE1) by 3.3% (P = 0.055) and increased 16-epiestriol (16-EpiE3) by 26.6% (P = 0.037). Trends for reduced urinary 2-OHE1 (P = 0.045), reduced ratio of 2-OH:16OH pathways (P = 0.008), and increased 16-EpiE3 (P = 0.035) were observed as alcohol ingestion increased from 0 g to 15 g to 30 g/d. Moderate alcohol consumption for 8 weeks had modest effects on urinary concentrations of 2-OHE1 and 16-EpiE3 among postmenopausal women in a carefully controlled feeding study.

Recent evidence indicates that postmenopausal breast cancer risk increases with higher levels of 16-EpiE3 and decreases with lower levels of 2-OHE1 in different prospective cohorts. Since moderate alcohol consumption in our study of postmenopausal women increased 16-EpiE3 and lowered 2-OHE1, these results imply that moderate drinking may have dual effects on later breast cancer development, but this finding needs confirmation.

http://ift.tt/2gJ5GNj

miR-199a-3p and miR-214-3p improve the overall survival prediction of muscle-invasive bladder cancer patients after radical cystectomy

Abstract

To improve the clinical decision-making regarding further treatment management and follow-up scheduling for patients with muscle-invasive bladder cancer (MIBC) after radical cystectomy (RC), a better prediction accuracy of prognosis for these patients is urgently needed. The objective of this study was to evaluate the validity of differentially expressed microRNAs (miRNAs) based on a previous study as prognostic markers for overall survival (OS) after RC in models combined with clinicopathological data. The expression of six miRNAs (miR-100-5p, miR-130b-3p, miR-141-3p, miR-199a-3p, miR-205-5p, and miR-214-3p) was measured by RT-qPCR in formalin-fixed, paraffin-embedded tissue samples from 156 MIBC patients who received RC in three urological centers. Samples from 2000 to 2013 were used according to their tissue availability, with follow-up until June 2016. The patient cohort was randomly divided into a training (n = 100) and test set (n = 56). Seventy-three samples from adjacent normal tissue were used as controls. Kaplan–Meier, univariate and multivariate Cox regression, and decision curve analyses were carried out to assess the association of clinicopathological variables and miRNAs to OS. Both increased (miR-130b-3p and miR-141-3p) and reduced (miR-100-5p, miR-199a-3p, and miR-214-3p) miRNA expressions were found in MIBC samples in comparison to nonmalignant tissue samples (P < 0.0001). miR-199a-3p and miR-214-3p were independent markers of OS in Cox regression models with the significant clinicopathological variables age, tumor status, and lymph node status. The prediction model with the clinicopathological variables was improved by these two miRNAs in both sets. The predictive benefit was confirmed by decision curve analysis. In conclusion, the inclusion of both miRNAs into models based on clinical data for the outcome prediction of MIBC patients after RC could be a valuable approach to improve prognostic accuracy.

This study demonstrated the usefulness of the microRNAs miR-199a-3p and miR-214-3p in formalin-fixed, paraffin-embedded tissue samples from patients with muscle-invasive bladder cancer after radical cystectomy as predictive biomarkers of overall survival. In this aspect, the miRNAs combined with traditional clinicopathological factors improved the prediction accuracy for overall survival and could be useful to facilitate clinical decision making for further treatment strategies.

http://ift.tt/2f5OUI0

Long-term outcomes in patients treated with proton therapy for localized prostate cancer

Abstract

The aim of this retrospective study was to report long-term clinical outcomes in patients treated with proton therapy (PT) for localized prostate cancer. Between 2001 and 2014, 1375 consecutive patients were treated with PT. Patients were classified into prognostic risk groups based on the National Comprehensive Cancer Network criteria. Freedom from biochemical relapse (FFBR), cancer-specific survival (CSS) and incidence of late gastrointestinal (GI)/genitourinary (GU) toxicities were calculated. Multivariate analysis was performed to identify clinical prognostic factors for FFBR and late toxicities. The median follow-up period was 70 months (range, 4–145 months). In total, 99% of patients received 74 Gy (relative biologic effectiveness [RBE]); 56% of patients received neoadjuvant androgen deprivation therapy. For the low-, intermediate-, high-, and very high-risk groups, 5-year FFBR was 99% (95% confidence intervals [CI], 96–100%), 91% (95% CI, 88–93%), 86% (95% CI, 82–89%), and 66% (95% CI, 53–76%), respectively, and 5-year CSS was 100% (95% CI, 100–100%), 100% (95% CI, 100–100%) , 99% (95% CI, 97–100%), and 95% (95% CI, 94–98%), respectively. Patient age, T classification, Gleason score, prostate-specific antigen, and percentage of positive cores were significant prognostic factors for FFBR. Grade 2 or higher GI and GU toxicities were 3.9% and 2.0%. Patient age was a prognostic factor for both late GI and GU toxicities. This study represents the largest cohort of patients treated with PT for localized prostate cancer, with the longest follow-up to date. Our results demonstrate that the biochemical control of PT is favorable particularly for high- and very high-risk patients with lower late genitourinary toxicity and indicates the necessity of considering patient age in the treatment protocols.

Proton therapy for localized prostate cancer demonstrates favorable biochemical control particularly for high- and very high-risk patients and a lower incidence of late genitourinary toxicity. Our findings indicate the necessity of considering patient age in the treatment protocols.

http://ift.tt/2gIwYDi

Survival of cutaneous melanoma based on sex, age, and stage in the United States, 1992–2011

Abstract

Women diagnosed with cutaneous melanoma have a survival advantage compared to men, which has been hypothesized to be due to difference in behavior and/or biology (sex hormones). It remains controversial whether this advantage is dependent on age or stage of disease. We sought to compare melanoma-specific survival between females in pre, peri, and postmenopausal age groups to males in the same age group, adjusting for stage of disease. This is a retrospective population-based cohort study using the Surveillance, Epidemiology, and End Results (SEER) database. Patients diagnosed from 1 January 1992 through 31 January 2011 with primary invasive cutaneous melanoma were included in our cohort. Melanoma-specific survival was the main outcome studied. Of the 106,511 subjects that were included, 45% were female. Females in all age groups (18–45, 46–54, and ≥55) with localized and regional disease, were less likely to die from melanoma compared to males in the same age group. Among patients with localized and regional disease, the relative risk of death due to melanoma increased with advancing age at diagnosis; this increase was more pronounced among females than males. In contrast, we observed no female survival advantage among patients with distant disease and no effect of age on relative risk of death from melanoma. Females with localized and regional melanoma have a decreased risk of death compared to males within all age groups. Our data show no differences in survival between men and women with metastatic melanoma, indicating that the influence of sex on survival is limited to early stage disease but not confined to pre or perimenopausal age groups.

In local and regional cutaneous melanoma, women of all ages have a significant survival benefit over men. However, data from the SEER registry indicate that this female survival advantage is decreased when the disease is metastatic, suggesting an unknown protective biology is lost in distant disease.

http://ift.tt/2f4CD6H

Prognostic effect of parotid area lymph node metastases after preliminary diagnosis of nasopharyngeal carcinoma: a propensity score matching study

Abstract

Parotid area lymph node (PLN) metastasis in nasopharyngeal carcinoma (NPC) is rare, and its prognosis remains largely unknown. Our study aimed to investigate the prognostic value and staging categories of PLN metastasis in patients with NPC and treated with intensity-modulated radiation therapy (IMRT), to provide a reference for clinical treatment for NPC with PLN metastasis. Records for 1616 untreated NPC patients without distant metastasis was retrospectively reviewed. All patients underwent magnetic resonance imaging (MRI) examination prior to treatment and then received IMRT as their primary treatment. Forty-five NPC patients (2.8%) showed initial PLN metastasis on follow-up MRI. PLN metastasis was significantly associated with the N classification and clinical stage. Univariate analysis showed that PLN metastasis had an unfavorable influence on overall survival (OS), progression-free survival (PFS), distant metastasis-free survival (DMFS), and regional relapse-free survival (RRFS) in NPC patients. Using propensity score matching (PSM) to calibrate selection bias and confounding bias, it was observed that PLN metastasis remained an adverse prognostic factor for OS, PFS, DMFS, and RRFS. Furthermore, the 5-year DMFS and RRFS curves for PLN metastasis were significantly separated from that for N2 disease but crossed that for N3 disease. Therefore, PLN metastasis was found to be an adverse prognostic factor for NPC and to be associated with the same DMFS as N3 disease. Therefore, more aggressive therapeutic strategies consistent with those for N3 disease are recommended for NPC with PLN metastasis to reduce distant metastasis.

PLN metastasis was found to be an adverse prognostic factor for NPC and to be correlated with the same DMFS as N3 disease.

http://ift.tt/2gIqpkr

The Knowledge of South African Men Relating to Cervical Cancer and Cervical Cancer Screening

Abstract

Cervical cancer is the second most common cancer in South African women, but the most common cancer in Black women. Despite having a national cervical cancer screening programme, most women present with advanced disease. Men play a role in cervical cancer as the HPV, the major cause of cervical cancer, is sexually transmitted. The purpose of our study was to describe the knowledge men, living in Muldersdrift, had about cervical cancer, cervical cancer screening and the cervical cancer screening programme and how they preferred to be taught about these health issues. We used a survey design and convenience sampling to select 101 men older than 18 years (n = 101). A pretested self-developed questionnaire was used as the data collection instrument, and the data were analyzed using the SPSS version 22-computer program and quantitative content analyses. The Fischer's exact test measured associations between variables (p = 0.05). The ages of the sample (n = 101) ranged from 18 to 92 years; most were from the Zulu cultural group, unemployed and unmarried. The majority (66.3%, n = 67) had not heard of cervical cancer, the cervical cancer screening programme (60.4%, n = 61) or the Pap smear (67.3%, n = 68). Age and educational level did not influence having ever heard of these health issues. HPV infection was the most well-known risk factor, and the very late symptoms of cervical cancer were the least known. Most men preferred to be educated in a group, which provided a practical, feasible and cost effective way of educating men living in this community about these health issues.

http://ift.tt/2eMusPN

Game of TOR — The Target of Rapamycin Rules Four Kingdoms

The 2017 Albert Lasker Basic Medical Research Award, announced September 6, recognizes Michael N. Hall of the University of Basel for his discovery of the target of rapamycin (TOR), a nutrient-sensing enzyme that regulates cell and organismal growth in nearly all eukaryotic species. Because of its…

http://ift.tt/2w8Sff5

Erratum to: Clinical experience with four cases of jackhammer esophagus

http://ift.tt/2w9mbYB

The Knowledge of South African Men Relating to Cervical Cancer and Cervical Cancer Screening

Abstract

Cervical cancer is the second most common cancer in South African women, but the most common cancer in Black women. Despite having a national cervical cancer screening programme, most women present with advanced disease. Men play a role in cervical cancer as the HPV, the major cause of cervical cancer, is sexually transmitted. The purpose of our study was to describe the knowledge men, living in Muldersdrift, had about cervical cancer, cervical cancer screening and the cervical cancer screening programme and how they preferred to be taught about these health issues. We used a survey design and convenience sampling to select 101 men older than 18 years (n = 101). A pretested self-developed questionnaire was used as the data collection instrument, and the data were analyzed using the SPSS version 22-computer program and quantitative content analyses. The Fischer's exact test measured associations between variables (p = 0.05). The ages of the sample (n = 101) ranged from 18 to 92 years; most were from the Zulu cultural group, unemployed and unmarried. The majority (66.3%, n = 67) had not heard of cervical cancer, the cervical cancer screening programme (60.4%, n = 61) or the Pap smear (67.3%, n = 68). Age and educational level did not influence having ever heard of these health issues. HPV infection was the most well-known risk factor, and the very late symptoms of cervical cancer were the least known. Most men preferred to be educated in a group, which provided a practical, feasible and cost effective way of educating men living in this community about these health issues.

http://ift.tt/2eMusPN

Carvacrol Induces Reactive Oxygen Species (ROS)-mediated Apoptosis Along with Cell Cycle Arrest at G0/G1 in Human Prostate Cancer Cells.

Related Articles

Carvacrol Induces Reactive Oxygen Species (ROS)-mediated Apoptosis Along with Cell Cycle Arrest at G0/G1 in Human Prostate Cancer Cells.

Nutr Cancer. 2017 Sep 05;:1-13

Authors: Khan F, Khan I, Farooqui A, Ansari IA

Abstract
Carvacrol, a major monoterpenoid phenol from Origanum and Thymus species, has been shown to exhibit antiproliferative and anticancer properties in a few recent studies. Nevertheless, detailed mechanism of the action of this compound in prostate cancer has not been elucidated yet. Therefore, in the current study, we examined the anticancer activity and mechanism of the action of carvacrol against human prostate cancer cells. It was found that the treatment of DU145 cells with carvacrol decreased cell viability in a concentration and time-dependent manner. The antiproliferative action of carvacrol leads to induction of apoptosis as confirmed by nuclear condensation, Annexin V-FITC/PI positive cells, and caspase-3 activation. In addition, carvacrol augmented reactive oxygen species generation and disruption in the mitochondrial membrane potential which has not been reported in the previous studies of carvacrol with prostate cancer. Moreover, carvacrol-induced apoptosis of prostate cancer cells was also accompanied by significant amount of growth arrest at the G0/G1 phase of the cell cycle which has also not been documented previously. To sum up, this study has established that carvacrol could be a promising chemotherapeutic agent and could have a direct practical implication and translational relevance to prostate cancer patients as Origanum consumption may retard prostate cancer progression.

PMID: 28872904 [PubMed - as supplied by publisher]

http://ift.tt/2wI55EH

In vitro Biological Effects of Sulforaphane (SFN), Epigallocatechin-3-gallate (EGCG), and Curcumin on Breast Cancer Cells: A Systematic Review of the Literature.

Related Articles

In vitro Biological Effects of Sulforaphane (SFN), Epigallocatechin-3-gallate (EGCG), and Curcumin on Breast Cancer Cells: A Systematic Review of the Literature.

Nutr Cancer. 2017 Sep 05;:1-10

Authors: Gianfredi V, Nucci D, Vannini S, Villarini M, Moretti M

Abstract
Much of the recent research in neoplasia has been focusing on the epigenetics of cancer cells, particularly as regards the search for potential molecular biomarkers that could be used for early diagnosis, effective treatment, and prognosis of several types of cancer. Carcinogenesis often starts with mutations in oncogenes and tumor suppressor genes, and it leads to anomalies in cellular processes as vital as cell cycle regulation and apoptosis. Because malignant changes arise as a result of genetic as well as epigenetic mechanisms, one possible means of intervention involves reprogramming gene expression, so as to-at least in part-revert the molecular alterations. DNA methylation and demethylation, acetylation and deacetylation of histones, and microRNAs are a few examples of the epigenetic mechanisms responsible for tumor development and progression. Many biologically active compounds present in food-including sulforaphane, curcumin, and epigallocatechin-have been found to modulate those processes. We here systematically review information on the effects of such bioactive dietary compounds on human breast cancer cell lines, and explore the mechanisms underlying those effects with a view to their potential therapeutic application.

PMID: 28872903 [PubMed - as supplied by publisher]

http://ift.tt/2xa1noL

An Essential Role of Maspin in Embryogenesis and Tumor Suppression—Response

http://ift.tt/2w8WJma

An Essential Role of Maspin in Embryogenesis and Tumor Suppression—Letter

http://ift.tt/2wIbPTh

Basal-A Triple Negative Breast Cancer Cells Selectively Rely on RNA Splicing for Survival

Prognosis of triple-negative breast cancer (TNBC) remains poor. To identify shared and selective vulnerabilities of basal-like TNBC, the most common TNBC subtype, a directed siRNA lethality screen was performed in 7 human breast cancer cell lines, focusing on 154 previously identified dependency genes of one TNBC line. Thirty common dependency genes were identified, including multiple proteasome and RNA splicing genes, especially those associated with the U4/U6.U5 tri-snRNP complex (e.g., PRPF8, PRPF38A). PRPF8 or PRPF38A knockdown or the splicing modulator E7107 led to widespread intronic retention and altered splicing of transcripts involved in multiple basal-like TNBC dependencies, including protein homeostasis, mitosis and apoptosis. E7107 treatment suppressed the growth of basal-A TNBC cell line and patient-derived basal-like TNBC xenografts at a well-tolerated dose. The anti-tumor response was enhanced by adding the proteasome inhibitor bortezomib. Thus, inhibiting both splicing and the proteasome might be an effective approach for treating basal-like TNBC.

http://ift.tt/2w91n3G

Death by HDAC inhibition in synovial sarcoma cells

Conventional cytotoxic therapies for synovial sarcoma provide limited benefit, and no drugs specifically targeting the causative SS18-SSX fusion oncoprotein are currently available. Histone deacetylase (HDAC) inhibition has been shown in previous studies to disrupt the synovial sarcoma oncoprotein complex, resulting in apoptosis. To understand the molecular effects of HDAC inhibition, RNA-Seq transcriptome analysis was undertaken in six human synovial sarcoma cell lines. HDAC inhibition induced pathways of cell cycle arrest, neuronal differentiation and response to oxygen-containing species, effects also observed in other cancers treated with this class of drugs. More specific to synovial sarcoma, polycomb-group targets were reactivated including tumor suppressor CDKN2A, and pro-apoptotic transcriptional patterns were induced. Functional analyses revealed that ROS-mediated FOXO activation and pro-apoptotic factors BIK, BIM and BMF were important to apoptosis induction following HDAC-inhibition in synovial sarcoma. HDAC-inhibitor pathway activation results in apoptosis and decreased tumor burden following a 7-day quisinostat treatment in the Ptenfl/fl;hSS2 mouse model of synovial sarcoma. This study provides mechanistic support for a particular susceptibility of synovial sarcoma to HDAC inhibition as a means of clinical treatment.

http://ift.tt/2wI1oPw

Interleukin 4 receptor-targeted pro-apoptotic peptide blocks tumor growth and metastasis by enhancing anti-tumor immunity

Cellular crosstalk between tumors and M2-polarized tumor-associated macrophages (TAMs) favors tumor progression. Upregulation of interleukin 4 receptor (IL4R) is observed in diverse tumors and TAMs. We tested whether an IL4R-targeted pro-apoptotic peptide could inhibit tumor progression. The IL4R-binding peptide (IL4RPep-1) preferentially bound to IL4R-expressing tumor cells and M2-polarized macrophages both in vitro and in 4T1 breast tumors in vivo. To selectively kill IL4R-expressing cells, we designed an IL4R-targeted pro-apoptotic peptide, IL4RPep-1-K, by adding the pro-apoptotic peptide (KLAKLAK)2 to the end of IL4RPep-1. IL4RPep-1-K exerted selective cytotoxicity against diverse IL4R-expressing tumor cells and M2-polarized macrophages. Systemic administration of IL4RPep-1-K inhibited tumor growth and metastasis in 4T1 breast tumor-bearing mice. Interestingly, IL4RPep-1-K treatment increased the number of activated cytotoxic CD8+ T cells while reducing the numbers of immunosuppressive regulatory T cells and M2-polarized TAMs. No significant systemic side effects were observed. These results suggest that IL4R-targeted pro-apoptotic peptide has potential for treating diverse IL4R-expressing cancers.

http://ift.tt/2w95rAP

The p97 inhibitor CB-5083 is a unique disrupter of protein homeostasis in models of Multiple Myeloma.

Inhibition of the AAA ATPase, p97, was recently shown to be a novel method for targeting the ubiquitin proteasome system (UPS) and CB-5083, a first in class inhibitor of p97, has demonstrated broad antitumor activity in a range of both hematological and solid tumor models. Here, we show that CB-5083 has robust activity against multiple myeloma (MM) cell lines and a number of in vivo MM models. Treatment with CB-5083 is associated with accumulation of ubiquitinated proteins, induction of the unfolded protein response (UPR) and apoptosis. CB-5083 decreases viability in MM cell lines and patient derived MM cells, including those with background proteasome inhibitor (PI) resistance.  CB-5083 has a unique mechanism of action that combines well with PIs which is likely owing to the p97-dependent retro-translocation of the transcription factor, Nrf1, which transcribes proteasome subunit genes following exposure to a PI. In vivo studies using clinically relevant MM models demonstrate that single-agent CB-5083 inhibits tumor growth and combines well with MM standard of care agents. Our preclinical data demonstrate the efficacy of CB-5083 in several MM disease models and provide the rationale for clinical evaluation as monotherapy and in combination in MM.

http://ift.tt/2wIAXJv

Game of TOR — The Target of Rapamycin Rules Four Kingdoms

The 2017 Albert Lasker Basic Medical Research Award, announced September 6, recognizes Michael N. Hall of the University of Basel for his discovery of the target of rapamycin (TOR), a nutrient-sensing enzyme that regulates cell and organismal growth in nearly all eukaryotic species. Because of its…

http://ift.tt/2w8Sff5

Molecular radiation biology/oncology and its impact on preclinical and clinical research in radiotherapy

Scientists from 21 different countries worldwide participated in the 15th International Wolfsberg Meeting on Molecular Radiation Biology/Oncology, which was held from June 17 to 19, 2017 at Wolfsberg Castle, Switzerland. Thus, funded in 1997 by the first and the last author of this editorial the Wolfsberg Meeting Series could celebrate its 20st anniversary this year. According to comments from many participants the Wolfsberg Meeting Series is regarded as one of the top meetings in the field of molecular radiation biology/oncology.

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The renoprotective properties of xenon and argon in kidney transplantation

No abstract available

http://ift.tt/2gMHAFc

Comparison of polyvinyl chloride and tin stylets for postoperative sore throat and hoarseness: A randomised trial

No abstract available

http://ift.tt/2gLA79k

Anaesthetic management of patients with myopathies

The anaesthetic management of patients with myopathies is challenging. Considering the low incidence and heterogeneity of these disorders, most anaesthetists are unfamiliar with key symptoms, associated co-morbidities and implications for anaesthesia. The pre-anaesthetic assessment aims at the detection of potentially undiagnosed myopathic patients and, in case of known or suspected muscular disease, on the quantification of disease progression. Ancillary testing (e.g. echocardiography, ECG, lung function testing etc.) is frequently indicated, even at a young patient age. One must differentiate between myopathies associated with malignant hyperthermia (MH) and those that are not, as this has significant impact on preoperative preparation of the anaesthesia workstation and pharmacologic management. Only few myopathies are clearly associated with MH. If a regional anaesthetic technique is not possible, total intravenous anaesthesia is considered the safest approach for most patients with myopathies to avoid anaesthesia-associated rhabdomyolysis. However, the use of propofol in patients with mitochondrial myopathies may be problematic, considering the risk for propofol-infusion syndrome. Succinylcholine is contra-indicated in all patients with myopathies. Following an individual risk/benefit evaluation, the use of volatile anaesthetics in several non-MH-linked myopathies (e.g. myotonic syndromes, mitochondrial myopathies) is considered to be well tolerated. Perioperative monitoring should specifically focus on the cardiopulmonary system, the level of muscular paralysis and core temperature. Given the high risk of respiratory compromise and other postoperative complications, patients need to be closely monitored postoperatively.

http://ift.tt/2gLzWuG

Microvascular reactivity monitored with near-infrared spectroscopy is impaired after induction of anaesthesia in cardiac surgery patients: An observational study

BACKGROUND: Induction of anaesthesia causes significant macrohaemodynamic changes, but little is known about its effects on the microcirculation. However, alterations in microvascular perfusion are known to be associated with impaired tissue oxygenation and organ dysfunction. Microvascular reactivity can be assessed with vascular occlusion testing, which evaluates the response of tissue oxygen saturation to transient ischaemia and reperfusion. OBJECTIVE: The aim of the current study was to evaluate the effects of an opioid-based anaesthesia induction on microvascular reactivity. We hypothesised that despite minimal blood pressure changes, microvascular function would be impaired. DESIGN: Prospective, observational study. SETTING: Single-centre, tertiary university teaching hospital, Belgium. PATIENTS: Thirty-five adult patients scheduled for elective coronary artery bypass grafting surgery. INTERVENTION: Microvascular reactivity was assessed before and 30 min after anaesthesia induction by means of vascular occlusion testing and near-infrared spectroscopy. MAIN OUTCOME MEASURES: Tissue oxygen saturations, desaturation rate, recovery time (time from release of cuff to the maximum value) and rate of recovery were determined. RESULTS: Data are expressed as median (minimum to maximum). Tissue oxygen saturation was higher after induction of anaesthesia [70 (54 to 78) vs. 73 (55 to 94)%, P = 0.015]. Oxygen consumption decreased after induction, appreciable by the higher minimum tissue oxygen saturation [45 (29 to 69) vs. 53 (28 to 81)%, P 

http://ift.tt/2gLzQ6i

Acute and chronic neuropathic pain after surgery: Still a lot to learn

No abstract available

http://ift.tt/2vMSQYx

Effect of intravenous dextrose administration on postoperative nausea and vomiting in patients undergoing laparoscopic cholecystectomy: A randomised controlled trial

No abstract available

http://ift.tt/2vNPF3a

Early postoperative neuropathic pain assessed by the DN4 score predicts an increased risk of persistent postsurgical neuropathic pain

BACKGROUND: Acute neuropathic pain can occur in the postoperative period but any link with persistent post-surgical neuropathic pain remains unclear. OBJECTIVES: The objectives of this study were to prospectively describe the incidence of acute post-surgical neuropathic pain in a large population using the DN4 (clinician administered) questionnaire and to confirm the hypothetical link between acute and persistent neuropathic pain at 2 months after surgery in a large population using the DN2 (self administered) questionnaire. DESIGN: A multi-centre, prospective and observational trial. SETTING: Two consecutive days in 27 hospitals in France. PATIENTS: Six hundred and eight patients undergoing 13 different types of surgery. Fifteen patients were excluded as data were incomplete, and 229 (38.6%) and 260 (43.8%) were not contactable for assessment at 1 and 2 months after surgery, respectively. MAIN OUTCOME MEASURES: Pain was evaluated at least 2 h postoperatively on the same day (D0),on the second day (D2) and at 1 and 2 months after surgery (M1 and M2). Pain was assessed using a 10-point Numeric Rating Scale. If the Numeric Rating Scale score was greater than 0, neuropathic pain was assessed using a DN4 (clinician administered) questionnaire or using a DN2 (self-administered) questionnaire. Acute and persistent postsurgical neuropathic pain (PPSNP) were defined respectively by a DN4 score at least 4/10 on day 0 and/or day 2 and a DN2 score at least 3/7 at 2 months after surgery. RESULTS: Of the 593 patients included, 41.2% were in pain before surgery and 8.2% described neuropathic pain. Early after surgery, the majority of the 593 patients (72.2% on the day of surgery and 71.3% on day 2) experienced acute pain. It was neuropathic in nature in 5.6% of patients (95% CI, 3.6 to 8.3) on the day of surgery and 12.9% (95% CI, 9.7 to 16.7) on day 2. Two months after surgery, PPSNP was present in 33.3% of the 333 patients assessed. Multivariate analysis showed that a DN4 score at least 4/10 on the day of surgery or on day 2 was a significant risk factor for PPSNP [odds ratios 4.22 (95% CI, 2.19 to 8.12)]. CONCLUSION: Our results suggest that early acute postsurgical neuropathic pain significantly increases the risk of persistent post-surgical neuropathic pain. TRIAL REGISTRATION: Clinicaltrials.gov identifier: NTC NCT02826317.

http://ift.tt/2vMQnO1

Women awaken faster than men after electroencephalogram-monitored propofol sedation for colonoscopy: A prospective observational study

BACKGROUND: Sedation for colonoscopy using intravenous propofol has become standard in many Western countries. OBJECTIVE: Gender-specific differences have been shown for general anaesthesia in dentistry, but no such data existed for gastrointestinal endoscopy. DESIGN: A prospective observational study. SETTING: An academic teaching hospital of Hannover Medical School. PATIENTS: A total of 219 patients (108 women and 111 men) scheduled for colonoscopy. INTERVENTION: Propofol sedation using electroencephalogram monitoring during a constant level of sedation depth (D0 to D2) performed by trained nurses or physicians after a body-weight-adjusted loading dose. MAIN OUTCOME MEASURES: The primary end-point was the presence of gender-specific differences in awakening time (time from end of sedation to eye-opening and complete orientation); secondary outcome parameters analysed were total dose of propofol, sedation-associated complications (bradycardia, hypotension, hypoxaemia and apnoea), patient cooperation and patient satisfaction. Multivariate analysis was performed to correct confounding factors such as age and BMI. RESULTS: Women awakened significantly faster than men, with a time to eye-opening of 7.3 ± 3.7 versus 8.4 ± 3.4 min (P = 0.005) and time until complete orientation of 9.1 ± 3.9 versus 10.4 ± 13.7 min (P = 0.008). The propofol dosage was not significantly different, with some trend towards more propofol per kg body weight in women (3.98 ± 1.81 mg versus 3.72 ± 1.75 mg, P = 0.232). CONCLUSION: The effect of gender aspects should be considered when propofol is used as sedation for gastrointestinal endoscopy. That includes adequate dosing for women as well as caution regarding potential overdosing of male patients. TRIAL REGISTRATION: ClinicalTrials.gov (Identifier: NCT02687568).

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Intraoperative magnesium sulphate decreases agitation and pain in patients undergoing functional endoscopic surgery: A randomised double-blind study

BACKGROUND: Postoperative agitation is harmful for the patient as it may be associated with removal of catheters, nasal packs, oxygen masks and self-injury, and pose a danger to operating theatre staff. OBJECTIVE: The current study investigated the potential role of magnesium sulphate in treatment of postoperative agitation following functional endoscopic sinus surgery. DESIGN: A randomised, double-blinded, placebo-controlled trial. SETTING: ENT operating room, Menofia University Hospitals, Egypt. PATIENTS: A total of 312 adult patients (171 men and 141 women) were enrolled in the study. Eighteen patients (10 men and eight women) were excluded; data from 294 patients were analysed. Inclusion criteria were age between 20 and 60 years, American Society of Anesthesiologists' physical status 1 or 2 scheduled for functional endoscopic sinus surgery. Exclusion criteria were hypertension, cardiac ischaemia, cerebrovascular insufficiency, neuromuscular diseases, pregnancy, prolonged treatment with calcium-channel blockers, diabetic neuropathy or a known allergy to magnesium compounds. INTERVENTIONS: Patients were allocated randomly to either the magnesium group (a magnesium infusion of 30 mg kg−1 in the first hour followed by 9 mg kg−1 h−1 until the end of the surgical procedure) or the control group (0.9% saline at the same volume and rate). Hypotensive anaesthesia was induced by nitroglycerine 5 to 20 μg kg−1 min−1. In the postanaesthetic care unit (PACU), patients were assessed for agitation and pain using the Richmond agitation-sedation scale and numerical rating scale, respectively. PRIMARY OUTCOME: The incidence and severity of agitation measured 5 min after admission to the PACU. RESULTS: Magnesium reduced postoperative agitation at time 0 (P = 0.009) and 5, 10, 15 and 30 min after PACU admission (P 

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Prophylactic atropine administration attenuates the negative haemodynamic effects of induction of anaesthesia with propofol and high-dose remifentanil: A randomised controlled trial

BACKGROUND: Induction of anaesthesia with propofol and remifentanil often induces unwanted bradycardia and hypotension, raising concerns regarding tissue oxygenation. The electrophysiological cardiac effects of remifentanil can be reversed by atropine. OBJECTIVE: To investigate if prophylactic administration of atropine can attenuate the negative haemodynamic effects of propofol and a high dose of remifentanil during induction of anaesthesia. DESIGN: A double-blind, randomised controlled trial. SETTING: Single-centre, University Medical Center Groningen, The Netherlands. PATIENTS: Sixty euvolaemic patients scheduled for surgery under general anaesthesia. INTERVENTIONS: Anaesthesia was induced and maintained with a target-controlled infusion of propofol with a target effect-site concentration (Ce) of 2.5 μg ml−1, remifentanil (target-controlled infusion), (Ce 8 ng ml−1) and cis-atracurium. Methylatropine (500 μg) or 0.9% saline was administered at immediately before induction of anaesthesia. MAIN OUTCOME MEASURES: The changes (Δ) in mean arterial pressure (MAP), heart rate (HR), cardiac index (CI), rate pressure product, cerebral tissue oxygenation and peripheral tissue oxygenation between induction of anaesthesia (T0) and 10 min later (T10). RESULTS: Atropine significantly attenuated the changes in the outcome measures between T0 and T10. Median (inter-quartile range) changes were MAP, Δ = −24 (−40 to −21) vs. Δ = −37 mmHg (−41 to −31) (P = 0.02); HR, Δ = 0 ± 13 vs. −19 ± 11 bpm (P 

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Effects of anaesthesia and analgesia on long-term outcome after total knee replacement: A prospective, observational, multicentre study

BACKGROUND: Perioperative regional anaesthesia may protect from persistent postsurgical pain (PPSP) and improve outcome after total knee arthroplasty (TKA). OBJECTIVES: Aim of this study was to evaluate the impact of regional anaesthesia on PPSP and long-term functional outcome after TKA. DESIGN: A web-based prospective observational registry. SETTING: Five Italian Private and University Hospitals from 2012 to 2015. PATIENTS: Undergoing primary unilateral TKA, aged more than 18 years, informed consent, American Society of Anesthesiologists (ASA) physical status classes 1 to 3, no previous knee surgery. INTERVENTION(S): Personal data (age, sex, BMI and ASA class), preoperative pain assessed by numerical rating scale (NRS) score, and risk factors for PPSP were registered preoperatively. Data on anaesthetic and analgesic techniques were collected. Postoperative pain (NRS), analgesic consumption, major complications and patient satisfaction were registered up to the time of discharge. PPSP was assessed by a blinded investigator during a phone call after 1, 3 and 6 months, together with patient satisfaction, quality of life (QOL) and walking ability. MAIN OUTCOME MEASURES: Experience of PPSP according to the type of peri-operative analgesia. RESULTS: Five hundred sixty-three patients completed the follow-up. At 6 months, 21.6% of patients experienced PPSP, whereas autonomy was improved only in 56.3%; QOL was worsened or unchanged in 30.7% of patients and improved in 69.3%. Patients receiving continuous regional anaesthesia (epidural or peripheral nerve block) showed a lower NRS through the whole peri-operative period up to 1 month compared with both single shot peripheral nerve block and those who did not receive any type of regional anaesthesia. No difference was found between these latter two groups. Differences in PPSP at 3 or 6 months were not significantly affected by the type of anaesthesia or postoperative analgesia. A higher NRS score at 1 month, younger age, history of anxiety or depression, pro-inflammatory status, higher BMI and a lower ASA physical status were associated with a higher incidence of PPSP and worsened QOL at 6 months. CONCLUSION: Continuous regional anaesthesia provides analgesic benefit for up to 1 month after surgery, but did not influence PPSP at 6 months. Better pain control at 1 month was associated with reduced PPSP. Patients with higher expectations from surgery, enhanced basal inflammation and a pessimistic outlook are more prone to develop PPSP. TRIAL REGISTRATION: Clinicaltrials.gov identifier: NCT02147730

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Transcutaneous monitoring of partial pressure of carbon dioxide during bronchoscopic procedures performed with jet ventilation: Role of the perfusion index

No abstract available

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The use of dipyrone in the ICU is associated with acute kidney injury: A retrospective cohort analysis

BACKGROUND: Use of dipyrone (metamizole) in perioperative and ICU pain therapy remains controversial due to a lack of solid evidence weighing dipyrone benefit against its potential life-threatening complications. Although dipyrone has known analgesic and antipyretic properties, its mechanisms of actions are incompletely understood. Although dipyrone effects on renal vasodilator prostaglandin synthesis are documented, little is known about its potential renal side effects, especially in the critical care environment. OBJECTIVE: Investigation of the perioperative nephrotoxic potential of dipyrone in patients prone to acute kidney injury (AKI). DESIGN: Retrospective cohort study. SETTING: Single centre study in a tertiary referral hospital from January 2013 until June 2013. PATIENTS: A total of 500 consecutive patients aged 18 years and older referred to the anaesthesia ICU. Patients were excluded if admitted from or discharged to other ICUs, if referred for post resuscitation care, or if repeatedly admitted to the ICU. MAIN OUTCOME MEASURES: Incidence of AKI, as defined by the Kidney Disease: Improving Global Outcomes Acute Kidney Injury Work Group criteria, and duration of vasopressor therapy. RESULTS: Use of dipyrone was associated with an increased incidence of AKI in a dose-dependent manner with a 1.6-fold increase in the incidence of AKI with each additional gram of intravenous dipyrone per day. Dipyrone dose of more than 2.5 g day−1 was the best risk predictive cut-off for AKI. Patients receiving dipyrone on the ICU presented with a prolonged duration of vasopressor therapy. CONCLUSION: Increasing dipyrone dosage is a potential independent risk factor for AKI in adult ICU patients and may prolong vasopressor therapy. Clinical evidence for a benefit of dipyrone therapy in the ICU is insufficient and needs further critical evaluation.

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Quality and Safety in Anesthesia and Perioperative Care

No abstract available

http://ift.tt/2gMYEe8

Response to letter re: Carotid atherosclerotic plaques standardized uptake values: methodological issues on reproducibility and accuracy

http://ift.tt/2wHshmx

European Society of Anaesthesiology and European Board of Anaesthesiology guidelines for procedural sedation and analgesia in adults.

: Procedural sedation and analgesia (PSA) has become a widespread practice given the increasing demand to relieve anxiety, discomfort and pain during invasive diagnostic and therapeutic procedures. The role of, and credentialing required by, anaesthesiologists and practitioners performing PSA has been debated for years in different guidelines. For this reason, the European Society of Anaesthesiology (ESA) and the European Board of Anaesthesiology have created a taskforce of experts that has been assigned to create an evidence-based guideline and, whenever the evidence was weak, a consensus amongst experts on: the evaluation of adult patients undergoing PSA, the role and competences required for the clinicians to safely perform PSA, the commonly used drugs for PSA, the adverse events that PSA can lead to, the minimum monitoring requirements and post-procedure discharge criteria. A search of the literature from 2003 to 2016 was performed by a professional librarian and the retrieved articles were analysed to allow a critical appraisal according to the Grading of Recommendations Assessment, Development and Evaluation method. The Taskforce selected 2248 articles. Where there was insufficiently clear and concordant evidence on a topic, the Rand Appropriateness Method with three rounds of Delphi voting was used to obtain the highest level of consensus among the taskforce experts. These guidelines contain recommendations on PSA in the adult population. It does not address sedation performed in the ICU or in children and it does not aim to provide a legal statement on how PSA should be performed and by whom. The National Societies of Anaesthesiology and Ministries of Health should use this evidence-based document to help decision-making on how PSA should be performed in their countries. The final draft of the document was available to ESA members via the website for 4 weeks with the facility for them to upload their comments. Comments and suggestions of individual members and national Societies were considered and the guidelines were amended accordingly. The ESA guidelines Committee and ESA board finally approved and ratified it before publication. (C) 2017 European Society of Anaesthesiology

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Metformin: oxidative and proliferative parameters in-vitro and in-vivo models of murine melanoma.

Cutaneous melanoma is one of the most lethal cancers because of its increased rate of metastasis and resistance to available therapeutic options. Early studies indicate that metformin has beneficial effects on some types of cancer, including melanoma. To clarify knowledge of the mechanism of action of metformin on this disease, two treatment-based approaches are presented using metformin on melanoma progression: an in-vitro and an in-vivo model. The in-vitro assay was performed for two experimental treatment periods (24 and 48 h) at different metformin concentrations. The results showed that metformin decreased cell viability, reduced proliferation, and apoptosis was a major event 48 h after treating B16F10 cells. Oxidative stress was characterized by the decrease in total thiol antioxidants immediately following 24 h of metformin treatment and showed an increase in lipid peroxidation. The in-vivo model was performed by injecting B16F10 cells into the subcutaneous of C57/BL6 mice. Treatment with metformin began on day 3 and on day 14, the mice were killed. Treatment of mice with metformin reduced tumor growth by 54% of its original volume compared with nontreatment. The decrease in systemic vascular endothelial growth factor, restoration of antioxidants glutathione and catalase, and normal levels of lipid peroxidation indicate an improved outcome for melanoma following metformin treatment, meeting a need for new strategies in the treatment of melanoma. Copyright (C) 2017 Wolters Kluwer Health, Inc. All rights reserved.

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Serial changes in anatomy and ventricular function on dual-source cardiac computed tomography after the Norwood procedure for hypoplastic left heart syndrome

Abstract

Background

Accurate evaluation of anatomy and ventricular function after the Norwood procedure in hypoplastic left heart syndrome is important for treatment planning and prognostication, but echocardiography and cardiac MRI have limitations.

Objective

To assess serial changes in anatomy and ventricular function on dual-source cardiac CT after the Norwood procedure for hypoplastic left heart syndrome.

Materials and methods

In 14 consecutive patients with hypoplastic left heart syndrome, end-systolic and end-diastolic phase cardiac dual-source CT was performed before and early (average: 1 month) after the Norwood procedure, and repeated late (median: 4.5 months) after the Norwood procedure in six patients. Ventricular functional parameters and indexed morphological measurements including pulmonary artery size, right ventricular free wall thickness, and ascending aorta size on cardiac CT were compared between different time points. Moreover, morphological features including ventricular septal defect, endocardial fibroelastosis and coronary ventricular communication were evaluated on cardiac CT.

Results

Right ventricular function and volumes remained unchanged (indexed end-systolic and end-diastolic volumes: 38.9±14.0 vs. 41.1±21.5 ml/m², P=0.7 and 99.5±30.5 vs. 105.1±33.0 ml/m², P=0.6; ejection fraction: 60.1±7.3 vs. 63.8±7.0%, P=0.1, and indexed stroke volume: 60.7±18.0 vs. 64.0±15.6 ml/m², P=0.5) early after the Norwood procedure, but function was decreased (ejection fraction: 64.2±2.6 vs. 58.1±7.1%, P=0.01) and volume was increased (indexed end-systolic and end-diastolic volumes: 39.2±14.9 vs. 68.9±20.6 ml/m², P<0.003 and 107.8±36.5 vs. 162.9±36.2 ml/m², P<0.006, and indexed stroke volume: 68.6±21.7 vs. 94.0±21.3 ml/m², P=0.02) later. Branch pulmonary artery size showed a gradual decrease without asymmetry after the Norwood procedure. Right and left pulmonary artery stenoses were identified in 21.4% (3/14) of the patients. Indexed right ventricular free wall thickness showed a significant increase early after the Norwood procedure (25.5±3.5 vs. 34.8±5.1 mm/m², P=0.01) and then a significant decrease late after the Norwood procedure (34.8±5.1 vs. 27.2±4.2 mm/m², P<0.0001). The hypoplastic ascending aorta smaller than 2 mm in diameter was identified in 21.4% (3/14) of the patients. Ventricular septal defect (n=3), endocardial fibroelastosis (n=2) and coronary ventricular communication (n=1) were detected on cardiac CT.

Conclusion

Cardiac CT can be used to assess serial changes in anatomy and ventricular function after the Norwood procedure in patients with hypoplastic left heart syndrome.

http://ift.tt/2w8CnJF

Recovery From Ropivacaine-Induced or Levobupivacaine-Induced Cardiac Arrest in Rats: Comparison of Lipid Emulsion Effects.

BACKGROUND: Lipid emulsion treatment appears to have application in the treatment of local anesthetic-induced cardiac arrest. To examine whether the efficacy of lipid resuscitation in the treatment of local anesthetic-induced cardiac arrest is affected by lipophilicity, the effects of lipid infusions were compared between levobupivacaine-induced (high lipophilicity) and ropivacaine-induced (lower lipophilicity) rat cardiac arrest model. METHODS: A total of 28 female Sprague-Dawley rats were anesthetized using sevoflurane, which subsequently underwent tracheostomy, followed by femoral artery and vein cannulation. Two hours after the discontinuation of sevoflurane, either levobupivacaine 0.2% (n = 14) or ropivacaine 0.2% (n = 14) was administered at a rate of 2 mg/kg/min to the awake rats. When the pulse pressure decreased to 0, the infusion of local anesthetic was discontinued, and treatment with chest compressions and ventilation with 100% oxygen were immediately initiated. The total doses of local anesthetics needed to trigger the first seizure and pulse pressure of 0 mm Hg were calculated. The 2 groups were each subdivided into a lipid emulsion group (n = 7) and a control group (n = 7). In the lipid emulsion group, 20% lipid emulsion was administered intravenously (5 mL/kg bolus plus continuous infusion of 0.5 mL/kg/min), while in the control group, the same volume of normal saline was administered. Chest compressions were discontinued when the rate-pressure product had increased by more than 20% of baseline. RESULTS: The cumulative doses of levobupivacaine and ropivacaine that produced seizures and 0 pulse pressure showed no significant difference. Mean arterial blood pressure (MAP) values were higher in the levobupivacaine group than in the ropivacaine group after resuscitation was initiated (P 20% baseline), while only 2 of 7 rats in the control group achieved spontaneous circulation at 10 minutes. In ropivacaine-induced cardiac arrest, there were no significant differences in heart rate and MAP between the lipid and control groups from the start of resuscitation to 10 minutes; spontaneous circulation returned in 6 of 7 lipid group rats, but in only 2 of 7 control group rats at 10 minutes. CONCLUSIONS: Lipid emulsion treatment was more effective for levobupivacaine-induced cardiac arrest than for ropivacaine-induced cardiac arrest. Although lipid therapy is also effective for ropivacaine-induced cardiac arrest, it takes more time than in levobupivacaine-induced cardiac arrest. This suggests that the lipophilicity of local anesthetics influences the efficacy of lipid infusion when treating cardiac arrest caused by these drugs. This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal. (C) 2017 International Anesthesia Research Society

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Approaches and techniques to characterize cancer metabolism in vitro and in vivo

Publication date: Available online 5 September 2017
Source:Biochimica et Biophysica Acta (BBA) - Reviews on Cancer
Author(s): Inna Zaimenko, Jan Lisec, Ulrike Stein, Winfried Brenner
Cancer metabolism is wired to sustain uncontrollable cell proliferation and ensure cell survival. Given the multitude of available approaches to study metabolic alterations it remains a challenging task to select the most appropriate method. In this mini-review we describe how cancer metabolism can be studied in vitro and in vivo providing an overview of available approaches and techniques, discussing their advantages and drawbacks and guiding through selection of an appropriate method to address particular research needs. This work is particularly intended to those cancer researchers who are new in the field but want to investigate metabolic alterations in their cancer model systems.



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Patient Age and Tumor Subtype Predict the Extent of Axillary Surgery Among Breast Cancer Patients Eligible for the American College of Surgeons Oncology Group Trial Z0011

Abstract

Background

The American College of Surgeons Oncology Group (ACOSOG) Z0011 trial established the safety of omitting axillary lymph node dissection (ALND) for early-stage breast cancer patients with limited nodal disease undergoing lumpectomy. We examined the extent of axillary surgery among women eligible for Z0011 based on patient age and tumor subtype.

Methods

Patients with cT1–2, cN0 breast cancers and one or two positive nodes diagnosed from 2009 to 2014 and treated with lumpectomy were identified in the National Cancer Data Base. Sentinel lymph node biopsy (SLNB) was defined as the removal of 1–5 nodes and ALND as the removal of 10 nodes or more. Tumor subtype was categorized as luminal, human epidermal growth factor 2-positive (HER2+), or triple-negative. Logistic regression was used to estimate the odds of receiving SLNB alone versus ALND.

Results

The inclusion criteria were met by 28,631 patients (21,029 SLNB-alone and 7602 ALND patients). Patients 70 years of age or older were more likely to undergo SLNB alone than ALND (27.0% vs 20.1%; p < 0.001). The radiation therapy use rate was 89.4% after SLNB alone and 89.7% after ALND. In the multivariate analysis, the uptake of Z0011 recommendations increased over time (2014 vs 2009: odds ratio [OR] 13.02; p < 0.001). Younger patients were less likely to undergo SLNB alone than older patients (age <40 vs ≥70: OR 0.59; p < 0.001). Patients with HER2+ (OR 0.89) or triple-negative disease (OR 0.79) (p < 0.001) were less likely to undergo SLNB alone than those with luminal subtypes.

Conclusions

Among women potentially eligible for ACOSOG Z0011, the use of SLNB alone increased over time in all groups, but the extent of axillary surgery differed by patient age and tumor subtype.

http://ift.tt/2wGM2dX

GNAQ and GNA11 mutations and downstream YAP activation in choroidal nevi

GNAQ and GNA11 mutations and downstream YAP activation in choroidal nevi

British Journal of Cancer 117, 884 (5 September 2017). doi:10.1038/bjc.2017.259

Authors: M J C Vader, M C Madigan, M Versluis, H M Suleiman, G Gezgin, N A Gruis, J J Out-Luiting, W Bergman, R M Verdijk, M J Jager & P A van der Velden

http://ift.tt/2fJnYB2

Intracrine VEGF signalling mediates colorectal cancer cell migration and invasion

Intracrine VEGF signalling mediates colorectal cancer cell migration and invasion

British Journal of Cancer 117, 848 (5 September 2017). doi:10.1038/bjc.2017.238

Authors: Rajat Bhattacharya, Fan Fan, Rui Wang, Xiangcang Ye, Ling Xia, Delphine Boulbes & Lee M Ellis

http://ift.tt/2vYa8h9

GEIS-21: a multicentric phase II study of intensive chemotherapy including gemcitabine and docetaxel for the treatment of Ewing sarcoma of children and adults: a report from the Spanish sarcoma group (GEIS)

GEIS-21: a multicentric phase II study of intensive chemotherapy including gemcitabine and docetaxel for the treatment of Ewing sarcoma of children and adults: a report from the Spanish sarcoma group (GEIS)

British Journal of Cancer 117, 767 (5 September 2017). doi:10.1038/bjc.2017.252

Authors: J Mora, A Castañeda, S Perez-Jaume, A Lopez-Pousa, E Maradiegue, C Valverde, J Martin-Broto, X Garcia del Muro, O Cruz, J Cruz, J Martinez-Trufero, J Maurel, M A Vaz, E de Alava & C de Torres

http://ift.tt/2vClISA

Randomised Phase 2 study of maintenance linsitinib (OSI-906) in combination with erlotinib compared with placebo plus erlotinib after platinum-based chemotherapy in patients with advanced non-small cell lung cancer

Randomised Phase 2 study of maintenance linsitinib (OSI-906) in combination with erlotinib compared with placebo plus erlotinib after platinum-based chemotherapy in patients with advanced non-small cell lung cancer

British Journal of Cancer 117, 757 (5 September 2017). doi:10.1038/bjc.2017.226

Authors: Tudor-Eliade Ciuleanu, Samreen Ahmed, Joo-Hang Kim, Jörg Mezger, Keunchil Park, Michael Thomas, Jihong Chen, Srinivasu Poondru, Jan M VanTornout, Debbie Whitcomb & Fiona Blackhall

http://ift.tt/2upzDXk

Lauren subtypes of advanced gastric cancer influence survival and response to chemotherapy: real-world data from the AGAMENON National Cancer Registry

Lauren subtypes of advanced gastric cancer influence survival and response to chemotherapy: real-world data from the AGAMENON National Cancer Registry

British Journal of Cancer 117, 775 (5 September 2017). doi:10.1038/bjc.2017.245

Authors: Paula Jiménez Fonseca, Alberto Carmona-Bayonas, Raquel Hernández, Ana Custodio, Juana Maria Cano, Alejandra Lacalle, Isabel Echavarria, Ismael Macias, Monserrat Mangas, Laura Visa, Elvira Buxo, Felipe Álvarez Manceñido, Antonio Viudez, Carles Pericay, Aitor Azkarate, Avinash Ramchandani, Carlos López, Eva Martinez de Castro, Ana Fernández Montes, Federico Longo, Rodrigo Sánchez Bayona, Maria Luisa Limón, Asun Diaz-Serrano, Alfonso Martin Carnicero, David Arias, Paula Cerdà, Fernando Rivera, Jose Maria Vieitez, Manuel Sánchez Cánovas, M Garrido & J Gallego

http://ift.tt/2tXl5iw

Cancer-associated fibroblasts promote bone invasion in oral squamous cell carcinoma

Cancer-associated fibroblasts promote bone invasion in oral squamous cell carcinoma

British Journal of Cancer 117, 867 (5 September 2017). doi:10.1038/bjc.2017.239

Authors: A A Elmusrati, A E Pilborough, S A Khurram & D W Lambert

http://ift.tt/2vYjJoa

Choosing wisely: a model-based analysis evaluating the trade-offs in cancer benefit and diagnostic referrals among alternative HPV testing strategies in Norway

Choosing wisely: a model-based analysis evaluating the trade-offs in cancer benefit and diagnostic referrals among alternative HPV testing strategies in Norway

British Journal of Cancer 117, 783 (5 September 2017). doi:10.1038/bjc.2017.248

Authors: Emily A Burger, Kine Pedersen, Stephen Sy, Ivar Sønbø Kristiansen & Jane J Kim

http://ift.tt/2u8PI8P

Vitamin D receptor and calcium-sensing receptor polymorphisms and colorectal cancer survival in the Newfoundland population

Vitamin D receptor and calcium-sensing receptor polymorphisms and colorectal cancer survival in the Newfoundland population

British Journal of Cancer 117, 898 (5 September 2017). doi:10.1038/bjc.2017.242

Authors: Yun Zhu, Peizhong Peter Wang, Guangju Zhai, Bharati Bapat, Sevtap Savas, Jennifer R Woodrow, Ishor Sharma, Yuming Li, Xin Zhou, Ning Yang, Peter T Campbell, Elizabeth Dicks, Patrick S Parfrey & John R Mclaughlin

http://ift.tt/2vlsJXm

Pre-clinical imaging of transgenic mouse models of neuroblastoma using a dedicated 3-element solenoid coil on a clinical 3T platform

Pre-clinical imaging of transgenic mouse models of neuroblastoma using a dedicated 3-element solenoid coil on a clinical 3T platform

British Journal of Cancer 117, 791 (5 September 2017). doi:10.1038/bjc.2017.251

Authors: Gilberto S Almeida, Rafal Panek, Albert Hallsworth, Hannah Webber, Efthymia Papaevangelou, Jessica KR Boult, Yann Jamin, Louis Chesler & Simon P Robinson

http://ift.tt/2vCcy8P

Expression of L1CAM in curettage or high L1CAM level in preoperative blood samples predicts lymph node metastases and poor outcome in endometrial cancer patients

Expression of L1CAM in curettage or high L1CAM level in preoperative blood samples predicts lymph node metastases and poor outcome in endometrial cancer patients

British Journal of Cancer 117, 840 (5 September 2017). doi:10.1038/bjc.2017.235

Authors: Ingvild L Tangen, Reidun K Kopperud, Nicole CM Visser, Anne C Staff, Solveig Tingulstad, Janusz Marcickiewicz, Frédéric Amant, Line Bjørge, Johanna MA Pijnenborg, Helga B Salvesen, Henrica MJ Werner, Jone Trovik & Camilla Krakstad

http://ift.tt/2u3yzbG

miR-125b predicts childhood acute lymphoblastic leukaemia poor response to BFM chemotherapy treatment

miR-125b predicts childhood acute lymphoblastic leukaemia poor response to BFM chemotherapy treatment

British Journal of Cancer 117, 801 (5 September 2017). doi:10.1038/bjc.2017.256

Authors: Despina Piatopoulou, Margaritis Avgeris, Antonios Marmarinos, Marieta Xagorari, Margarita Baka, Dimitrios Doganis, Lydia Kossiva, Andreas Scorilas & Dimitrios Gourgiotis

http://ift.tt/2vjP5GA

Prognostic biomarkers for oral tongue squamous cell carcinoma: a systematic review and meta-analysis

Prognostic biomarkers for oral tongue squamous cell carcinoma: a systematic review and meta-analysis

British Journal of Cancer 117, 856 (5 September 2017). doi:10.1038/bjc.2017.244

Authors: Alhadi Almangush, Ilkka Heikkinen, Antti A Mäkitie, Ricardo D Coletta, Esa Läärä, Ilmo Leivo & Tuula Salo

http://ift.tt/2tO30an

Regulation of hypoxia-induced autophagy in glioblastoma involves ATG9A

Regulation of hypoxia-induced autophagy in glioblastoma involves ATG9A

British Journal of Cancer 117, 813 (5 September 2017). doi:10.1038/bjc.2017.263

Authors: Siti Aminah Abdul Rahim, Anne Dirkse, Anais Oudin, Anne Schuster, Jill Bohler, Vanessa Barthelemy, Arnaud Muller, Laurent Vallar, Bassam Janji, Anna Golebiewska & Simone P Niclou

http://ift.tt/2utJTCV

Predicting response to radical (chemo)radiotherapy with circulating HPV DNA in locally advanced head and neck squamous carcinoma

Predicting response to radical (chemo)radiotherapy with circulating HPV DNA in locally advanced head and neck squamous carcinoma

British Journal of Cancer 117, 876 (5 September 2017). doi:10.1038/bjc.2017.258

Authors: Jen Y Lee, Isaac Garcia-Murillas, Rosalind J Cutts, David Gonzalez De Castro, Lorna Grove, Tara Hurley, Fuqiang Wang, Christopher Nutting, Katie Newbold, Kevin Harrington, Nicholas Turner & Shreerang Bhide

http://ift.tt/2i3oKJX

Novel immunohistochemistry-based signatures to predict metastatic site of triple-negative breast cancers

Novel immunohistochemistry-based signatures to predict metastatic site of triple-negative breast cancers

British Journal of Cancer 117, 826 (5 September 2017). doi:10.1038/bjc.2017.224

Authors: Sergey Klimov, Padmashree CG Rida, Mohammed A Aleskandarany, Andrew R Green, Ian O Ellis, Emiel AM Janssen, Emad A Rakha & Ritu Aneja

http://ift.tt/2uwHxTc

Evidence of advanced stage colorectal cancer with longer diagnostic intervals: a pooled analysis of seven primary care cohorts comprising 11 720 patients in five countries

Evidence of advanced stage colorectal cancer with longer diagnostic intervals: a pooled analysis of seven primary care cohorts comprising 11 720 patients in five countries

British Journal of Cancer 117, 888 (5 September 2017). doi:10.1038/bjc.2017.236

Authors: M L Tørring, P Murchie, W Hamilton, P Vedsted, M Esteva, M Lautrup, M Winget & G Rubin

http://ift.tt/2vk5tae

Active multiple myeloma suppresses and typically eliminates coexisting MGUS

Active multiple myeloma suppresses and typically eliminates coexisting MGUS

British Journal of Cancer 117, 835 (5 September 2017). doi:10.1038/bjc.2017.229

Authors: John P Campbell, Jennifer L J Heaney, Sankalp Pandya, Zaheer Afzal, Martin Kaiser, Roger Owen, J Anthony Child, Walter Gregory, Gareth J Morgan, Graham H Jackson, Chris M Bunce & Mark T Drayson

http://ift.tt/2uOd3wj

The inflammatory potential of diet and ovarian cancer risk: results from two prospective cohort studies

The inflammatory potential of diet and ovarian cancer risk: results from two prospective cohort studies

British Journal of Cancer 117, 907 (5 September 2017). doi:10.1038/bjc.2017.246

Authors: Fred K Tabung, Tianyi Huang, Edward L Giovannucci, Stephanie A Smith-Warner, Shelley S Tworoger & Elizabeth M Poole

http://ift.tt/2u9aUeE

Molecular modeling and structure-based drug discovery approach reveals protein kinases as off-targets for novel anticancer drug RH1

Abstract

Potential drug target identification and mechanism of action is an important step in drug discovery process, which can be achieved by biochemical methods, genetic interactions or computational conjectures. Sometimes more than one approach is implemented to mine out the potential drug target and characterize the on-target or off-target effects. A novel anticancer agent RH1 is designed as pro-drug to be activated by NQO1, an enzyme overexpressed in many types of tumors. However, increasing data show that RH1 can affect cells in NQO1-independent fashion. Here, we implemented the bioinformatics approach of modeling and molecular docking for search of RH1 targets among protein kinase species. We have examined 129 protein kinases in total where 96 protein kinases are in complexes with their inhibitor, 11 kinases were in the unbound state with any ligand and for 22 protein kinases 3D structure were modeled. Comparison of calculated free energy of binding of RH1 with indigenous kinase inhibitors binding efficiency as well as alignment of their pharmacophoric maps let us predict and ranked protein kinases such as KIT, CDK2, CDK6, MAPK1, NEK2 and others as the most prominent off-targets of RH1. Our finding opens new avenues in search of protein targets that might be responsible for curing cancer by new promising drug RH1 in NQO1-independent way.

http://ift.tt/2wInSy4

Effects of Arsenic Compounds on Microminerals Content and Antioxidant Enzyme Activities in Rat Liver

Abstract

Interactions of arsenic with essential trace elements may result in disturbances on body homeostasis. In the present study, we aimed to investigate the effects of different arsenic compounds on micromineral content and antioxidant enzyme activities in rat liver. Male Wistar rats were randomly divided into five groups and exposed to sodium arsenite and sodium arsenate at 0.01 and 10 mg/L for 8 weeks in drinking water. The concentration of arsenic increased in the liver of all arsenic-exposed animals. The proportion of zinc and copper increased in animals exposed to 0.01 mg/L sodium arsenite. In addition, these animals presented a reduction in magnesium and sodium content. Superoxide dismutase activity decreased mainly in arsenite-exposed animals, whereas catalase activity decreased in animals exposed to 10 mg/L sodium arsenate. Further, exposure to sodium arsenate at 10 mg/L altered copper and magnesium content in the liver, and reduced total protein levels. Overall, both arsenic compounds altered the liver histology, with reduction in the proportion of cytoplasm and hepatocyte, and increased the percentage of sinusoidal capillaries and macrophages. In conclusion, our findings showed that oral exposure to arsenic compounds disturbs the trace elements balance in the liver, especially at low concentration, altering enzymatic and stereological parameters. We concluded that despite the increase in trace elements content, the antioxidant enzyme activities were downregulated and did not prevent morphological alterations in the liver of animals exposed to both arsenic compounds.

http://ift.tt/2eGJoeD

Socioeconomic position, population density and site-specific cancer mortality: A multilevel analysis of Belgian adults, 2001-2011

Abstract

This study explores the association between individual and neighbourhood socioeconomic position (SEP) and all-cancer and site-specific cancer mortality. Data on all Belgian residents is retrieved from a population-based dataset constructed from the 2001 census linked to register data on emigration and mortality for 2001-2011. The study population contains all men and women aged 40 years or older during follow-up. Individual SEP is measured using education, employment status and housing conditions. Neighbourhood SEP is measured by a deprivation index (in quintiles). Directly age-standardized mortality rates and multilevel Poisson models are used to estimate the association between individual SEP and neighbourhood deprivation and mortality from all-cancer and cancer of the lung, colon and rectum, pancreas, prostate and female breast. The potential confounding role of population density is assessed using multilevel models as well. Our findings show an increase in mortality from all-cancer and site-specific cancer by decreasing level of individual SEP for both men and women. In addition, individuals living in highly deprived neighbourhoods experience significantly higher mortality from all-cancer, lung cancer, pancreatic cancer and female colorectal cancer after controlling for individual SEP. Male colorectal and prostate cancer and female breast cancer are not associated with neighbourhood deprivation. Population density acts as a confounder for female lung cancer only. Our study indicates that deprivation at both the individual and neighbourhood level is associated with all-cancer mortality and mortality from several cancer sites. More research into the role of life-style related and clinical factors is necessary to gain more insight into causal pathway. This article is protected by copyright. All rights reserved.

http://ift.tt/2j4l9fi

An observational study investigating failure of primary endocrine therapy for operable breast cancer in the elderly

Abstract

Background

Elderly patients are more likely to have oestrogen receptor positive cancers that can be treated without surgery with primary endocrine therapy (PET). Few studies have sought to identify predictors of failure of PET and so the aim of this study was to evaluate treatment failures in elderly breast cancer patients treated with PET and to determine predictors of failure.

Methods

A retrospective observational study was performed on consecutive patients with ER-positive early stage breast cancer treated with PET between 2005 and 2015 in the three breast units in the North East of England. The primary outcome measure was treatment failure and secondary outcome measure was disease progression.

Results

488 patients were included with mean follow-up 31 months (SD 23). Overall, 206 patients were still alive with their disease controlled at the end of follow-up, 219 had died with their disease controlled and 63 (12%) experienced treatment failure. Younger age [SHR 0.96 (95% CI 0.94–0.99) p 0.013], larger tumours [SHR 1.03 (1.01–1.06) p 0.015], grade 3 cancers [SHR 3.58 (1.93–6.63) p < 0.001] and axillary lymph node metastases [SHR 1.93 (1.06–3.52) p 0.030] were all independent predictors of treatment failure. Disease progression was reported in 86 (17.6%) of patients.

Conclusions

This is the largest retrospective series evaluating PET treatment failure. Clear predictors of failure have been identified, which can be used to facilitate treatment decision making. These results support previous analyses, further validating our results.

http://ift.tt/2wGX0jR

Surgery vs. radiotherapy in patients with uveal melanoma

Abstract

Background

The treatment modalities for uveal melanoma (UM) include surgery and radiotherapy (RT). The utilization of RT as a strategy for organ preservation has been increasing, but the survival difference between the two aforementioned treatment modalities has not been reported.

Methods

An observational and cohort study was performed using a propensity score with an already existing public database. Patients diagnosed with UM within the period from 2004–2013 were selected from the Surveillance, Epidemiology, and End Results (SEER) database. One-to-one matching and inverse probability of treatment weighting (IPTW) using the propensity score were used to estimate and compare survival rates.

Results

Overall, 3291 patients were treated: 2503 received RT only (RT group) and 788 received surgical resection only (surgery group). The RT group had an improved crude 5‑year overall survival (OS) rate compared with the surgery group (76% vs. 60%, P < 0.001), and an improved 5‑year melanoma-specific survival (MSS) rate (89% vs. 73%, P < 0.001). Compared to the surgery group, the RT group was associated with improved OS (hazard ratio [HR] 0.52, 95% confidence interval [CI] 0.38–0.73, P < 0.001) and MSS (HR 0.48, 95% CI 0.35–0.65, P < 0.001) in the matched cohort. The survival benefit of the RT group maintained after adjustment with IPTW, both in OS and MSS.

Conclusions

To our knowledge, the present study was the first to demonstrate the survival difference between the two treatment modalities for UM using both the propensity score matching and weighting methods with the SEER database. The current study suggests that RT may provide a survival advantage over surgery in the treatment of UM.

http://ift.tt/2w7FkKw

Surgery vs. radiotherapy in patients with uveal melanoma

Abstract

Background

The treatment modalities for uveal melanoma (UM) include surgery and radiotherapy (RT). The utilization of RT as a strategy for organ preservation has been increasing, but the survival difference between the two aforementioned treatment modalities has not been reported.

Methods

An observational and cohort study was performed using a propensity score with an already existing public database. Patients diagnosed with UM within the period from 2004–2013 were selected from the Surveillance, Epidemiology, and End Results (SEER) database. One-to-one matching and inverse probability of treatment weighting (IPTW) using the propensity score were used to estimate and compare survival rates.

Results

Overall, 3291 patients were treated: 2503 received RT only (RT group) and 788 received surgical resection only (surgery group). The RT group had an improved crude 5‑year overall survival (OS) rate compared with the surgery group (76% vs. 60%, P < 0.001), and an improved 5‑year melanoma-specific survival (MSS) rate (89% vs. 73%, P < 0.001). Compared to the surgery group, the RT group was associated with improved OS (hazard ratio [HR] 0.52, 95% confidence interval [CI] 0.38–0.73, P < 0.001) and MSS (HR 0.48, 95% CI 0.35–0.65, P < 0.001) in the matched cohort. The survival benefit of the RT group maintained after adjustment with IPTW, both in OS and MSS.

Conclusions

To our knowledge, the present study was the first to demonstrate the survival difference between the two treatment modalities for UM using both the propensity score matching and weighting methods with the SEER database. The current study suggests that RT may provide a survival advantage over surgery in the treatment of UM.

http://ift.tt/2w7FkKw

Association of clinical trial enrollment and survival using contemporary therapy for pediatric acute lymphoblastic leukemia

Abstract

While early studies reported superior survival for cancer patients enrolled on clinical trials, recent findings are inconclusive. We investigated the association between enrollment on contemporary trials and event-free survival (EFS) in pediatric B-cell acute lymphoblastic leukemia (B-ALL). In a retrospective cohort of 274 children (1–21 years) treated for B-ALL from 2008 to 2015, 55.5% enrolled with no disparity in enrollment by age, sex, or ethnicity. Three-year EFS was similar for enrolled and not enrolled patients (90.1% [95% CI, 82.5–94.5] versus 86.5% [95% CI, 77.7–92.0]). Clinical trial enrollment did not affect pediatric B-ALL survival, albeit in a limited-size cohort treated at a single academic institution.

http://ift.tt/2j2yncA

Treatment of plasminogen deficiency patients with fresh frozen plasma

Abstract

Congenital plasminogen (Plg) deficiency leads to the development of ligneous membranes on mucosal surfaces. Here, we report our experience with local and intravenous fresh frozen plasma (FFP). We retrospectively reviewed medical files of 17 patients and their eight first-degree relatives. Conjunctivitis was the main complaint. Thirteen patients were treated both with intravenous and conjunctival FFP. Venous thrombosis did not develop in any. Genetic evaluation revealed heterogeneous mutations as well as polymorphisms. Diagnosis and treatment of Plg deficiency is challenging; topical and intravenous FFP may be an alternative treatment.

http://ift.tt/2eGl50c

The Btk-dependent PIP5K1γ lipid kinase activation by Fas counteracts FasL-induced cell death

Abstract

The Fas/FasL system plays a critical role in death by apoptosis and immune escape of cancer cells. The Fas receptor being ubiquitously expressed in tissues, its apoptotic-inducing function, initiated upon FasL binding, is tightly regulated by several negative regulatory mechanisms to prevent inappropriate cell death. One of them, involving the non-receptor tyrosine kinase Btk, was reported mainly in B cells and only poorly described. We report here that Btk negatively regulates, through its tyrosine kinase activity, the FasL-mediated cell death in epithelial cell lines from colon cancer origin. More importantly, we show that Btk interacts not only with Fas but also with the phosphatidylinositol-4-phosphate 5-kinase, PIP5K1γ, which, upon stimulation by Fas ligand, is responsible of a rapid and transient synthesis of phosphatidylinositol-4,5-bisphosphate (PI(4,5)P₂). This production requires both the presence and the tyrosine kinase activity of Btk, and participates in the negative regulation of FasL-mediated cell death since knocking down PIP5K1γ expression significantly strengthens the apoptotic signal upon FasL engagement. Altogether, our data demonstrate the cooperative role of Btk and PIP5K1γ in a FasL-induced PI(4,5)P₂ production, both proteins participating to the threshold setting of FasL-induced apoptotic commitment in colorectal cell lines.

http://ift.tt/2w7jB5l

EGFR and KRAS mutations do not enrich for the activation of IL-6, JAK1 or phosphorylated STAT3 in resected lung adenocarcinoma

Abstract

Resistance to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) against EGFR mutant lung adenocarcinoma develops after a median of nine to thirteen months. Upregulation of the interleukin-6 (IL-6)/Janus kinase (JAK)/signal transducers and activators of transcription (STAT) pathway may be a potential source of resistance to EGFR TKIs. We undertook a detailed assessment of the IL-6/JAK1/phosphorylated STAT3 (pSTAT3) pathway in resected lung adenocarcinoma specimens, with special interest in whether the presence of an EGFR mutation enriched for pSTAT3 positivity. Tumours from 143 patients with resected lung adenocarcinoma were assessed. EGFR and KRAS mutation status were scanned for with high-resolution melting and confirmed by polymerase chain reaction. Immunohistochemisty (IHC) was performed for IL-6, gp130, JAK1 and pSTAT3. Two methods for assigning IHC positivity were assessed (the presence of any positivity, and the presence of positivity at an H score >40). We found statistically significant associations between IL-6, JAK1 and pSTAT3 measured by IHC, consistent with the activation of the pathway in clinical specimens. No relationship was demonstrated between members of this pathway and oncogenic mutations in EGFR or KRAS. However, a proportion of tumours with EGFR mutations showed staining for IL-6, JAK1 and pSTAT3. No correlations with clinicopathologic features or survival outcomes were found for IL-6, JAK1 or pSTAT3 staining. The presence of EGFR or KRAS mutations did not enrich for the activation of IL-6, JAK1 or pSTAT3. pSTAT3 may still play a role in resistance to EGFR TKIs in clinical practice.

http://ift.tt/2gH0qtv

Local relapse of nasopharyngeal cancer and Voxel-based analysis of FMISO uptake using PET with semiconductor detectors

Hypoxic cancer cells are thought to be radioresistant and could impact local recurrence after radiotherapy (RT). One of the major hypoxic imaging modalities is [18F]fluoromisonidazole positron emission tomography...

http://ift.tt/2j3y3dp

Target volume delineation of anal cancer based on magnetic resonance imaging or positron emission tomography

To compare target volume delineation of anal cancer using positron emission tomography (PET) and magnetic resonance imaging (MRI) with respect to inter-observer and inter-modality variability.

http://ift.tt/2j1UvUl

Extranodal natural killer/T-cell lymphoma in Malawi: a report of three cases

Abstract

Background

Extranodal NK/T-cell lymphoma (ENKTCL) reports from sub-Saharan Africa (SSA) are remarkably rare, despite early childhood acquisition and high prevalence of the causative infectious agent, Epstein-Barr virus (EBV), and frequent occurrence of other lymphoproliferative disorders causally associated with EBV.

Case presentations

At a national teaching hospital in Malawi, three patients of African descent were seen with ENKTCL between 2013 and 2014. Patients were aged between 29 and 60 years, two with craniofacial involvement and one with a primary abdominal tumor, and all were HIV-negative. All had systemic B symptoms, and two severely impaired performance status. On histologic review, morphology and immunophenotyping demonstrated classical ENKTCL features in all cases, including diffuse proliferations of intermediate-to-large atypical lymphocytes with high mitotic activity and extensive background necrosis, positivity for CD3 and CD56, and negativity for CD20. By in situ hybridization, all three tumors were positive for EBV-encoded RNA (EBER). Baseline plasma EBV DNA was also markedly elevated for all three patients. Due to radiotherapy and chemotherapy limitations, patients were treated with CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone) with rapid disease progression. All three patients died from progressive lymphoma within 3 months of initial diagnosis.

Conclusions

Our experience with these three patients in Malawi can highlight that ENKTCL does indeed occur in SSA, increase familiarity with ENKTCL among clinicians and pathologists throughout the region, and emphasize the need for better diagnosis and treatment for this neglected population.

http://ift.tt/2gMBeWe

Reduced ovarian reserve in young early breast cancer patients: preliminary data from a prospective cohort trial

Abstract

Background

The numerous side effects of chemotherapy in patients with breast cancer are well known. However, the precise effects of chemotherapy on ovarian function in premenopausal women are poorly investigated. The patients are at risk of developing sexual hormone deficiency and impaired fertility. This prospective cohort study addresses predictive parameters of ovarian reserve after chemotherapy.

Methods

Fifty-one premenopausal women (28–46 years) with primary breast cancer were included in the trial. All of them received anthracycline-based chemotherapy (n = 18), or combinations with taxanes (n = 30), or anthracycline-free chemotherapy (n = 3). Changes in hormone levels (LH, FSH, E2 and Anti-Müllerian hormone (AMH)), antral follicle count (AFC), and amenorrhea were determined before (V1), and 6, 12 and 24 months after the initiation of chemotherapy (V2-V4). Quality of life parameters were evaluated. The additional impact of parity, BMI, and smoking on ovarian reserve was also assessed.

Results

AFC and AMH fell very markedly after chemotherapy and did not return to pre-treatment levels until V4. A significant positive correlation was noted in AFC before and 1 year after chemotherapy. AMH levels at V2-V4 were significantly correlated with those registered at V1. AFC and AMH were negatively correlated with age. Continued smoking had a significant detrimental effect on AFC after 24 months. LH and FSH levels increased between V1 and V2 and fell at V3 and V4, but stayed above pre-chemotherapy values. Two years after the start of chemotherapy 31/51 patients were amenorrhoic while 17 resumed their menstrual cycle; this was not influenced by the type of chemotherapy or age. Non-smokers were 13 times more likely to resume their menstruation than smokers. Quality of life (QL) was significantly lower 6 months after the initiation of chemotherapy. QL at one and 2 years after chemotherapy did not differ significantly from pre-chemotherapy scores.

Conclusions

Our study contributes to a better understanding and prediction of ovarian reserve in young early breast cancer patients undergoing chemotherapy. The data suggest that personal counseling in regard of the preservation of fertility should be offered especially to patients of a higher age, with low AMH levels or low follicle counts. Patients should be advised to stop smoking in order to enhance the likelihood of preserving their fertility.

http://ift.tt/2vL1DKV

Tissue microarray analysis indicates hedgehog signaling as a potential prognostic factor in intermediate-risk prostate cancer

Abstract

Background

Prostate cancer (PCa) is a heterogeneous disease with a variable natural history, genetics, and treatment outcome. The Hedgehog (Hh) signaling pathway is increasingly recognized as being potentially important for the development and progression of PCa. In this retrospective study, we compared the activation status of the Hh signaling pathway between benign and tumor tissue, and evaluated the clinical significance of Hh signaling in PCa.

Methods

In this tissue microarray (TMA) study, the protein expression of several Hh signaling components and Hh target proteins, along with microvessel density, were compared between benign (n = 64) and malignant (n = 170) prostate tissue, and correlated with PCa clinicopathological characteristics and biochemical recurrence (BCR).

Results

The Hh signaling pathway appeared to be more active in PCa than in benign prostate tissue, as demonstrated by lower expression of the negative regulators PTCH1 and GLI3 in the tumor tissue compared to benign. In addition, high epithelial GLI2 expression correlated with higher pathological Gleason score. Overall, higher epithelial GLI3 expression in the tumor was shown to be an independent marker of a favorable prognosis.

Conclusion

Hh signaling activation might reflect aggressive tumoral behavior, since high epithelial GLI2 expression positively correlates with a higher pathological Gleason score. Moreover, higher epithelial GLI3 expression is an independent marker of a more favorable prognosis.

http://ift.tt/2gMxBPT

Positive regulation of prostate cancer cell growth by lipid droplet forming and processing enzymes DGAT1 and ABHD5

Abstract

Background

Neoplastic cells proliferate rapidly and obtain requisite building blocks by reprogramming metabolic pathways that favor growth. Previously, we observed that prostate cancer cells uptake and store lipids in the form of lipid droplets, providing building blocks for membrane synthesis, to facilitate proliferation and growth. Mechanisms of lipid uptake, lipid droplet dynamics and their contribution to cancer growth have yet to be defined. This work is focused on elucidating the prostate cancer-specific modifications in lipid storage pathways so that these modified gene products can be identified and therapeutically targeted.

Methods

To identify genes that promote lipid droplet formation and storage, the expression profiles of candidate genes were assessed and compared between peripheral blood mononuclear cells and prostate cancer cells. Subsequently, differentially expressed genes were inhibited and growth assays performed to elucidate their role in the growth of the cancer cells. Cell cycle, apoptosis and autophagy assays were performed to ascertain the mechanism of growth inhibition.

Results

Our results indicate that DGAT1, ABHD5, ACAT1 and ATGL are overexpressed in prostate cancer cells compared to PBMCs and of these overexpressed genes, DGAT1 and ABHD5 aid in the growth of the prostate cancer cells. Blocking the expression of both DGAT1 and ABHD5 results in inhibition of growth, cell cycle block and cell death. DGAT1 siRNA treatment inhibits lipid droplet formation and leads to autophagy where as ABHD5 siRNA treatment promotes accumulation of lipid droplets and leads to apoptosis. Both the siRNA treatments reduce AMPK phosphorylation, a key regulator of lipid metabolism. While DGAT1 siRNA reduces phosphorylation of ACC, the rate limiting enzyme in de novo fat synthesis and triggers phosphorylation of raptor and ULK-1 inducing autophagy and cell death, ABHD5 siRNA decreases P70S6 phosphorylation, leading to PARP cleavage, apoptosis and cell death. Interestingly, DGAT-1 is involved in the synthesis of triacylglycerol where as ABHD5 is a hydrolase and participates in the fatty acid oxidation process, yet inhibition of both enzymes similarly promotes prostate cancer cell death.

Conclusion

Inhibition of either DGAT1 or ABHD5 leads to prostate cancer cell death. Both DGAT1 and ABHD5 can be selectively targeted to block prostate cancer cell growth.

http://ift.tt/2vM5l6T

Cancers, Vol. 9, Pages 119: Predicting Organ-Specific Risk Interactions between Radiation and Chemotherapy in Secondary Cancer Survivors

Cancers, Vol. 9, Pages 119: Predicting Organ-Specific Risk Interactions between Radiation and Chemotherapy in Secondary Cancer Survivors

Cancers doi: 10.3390/cancers9090119

Authors: Venkata Manem Clemens Grassberger Harald Paganetti

Several studies have shown that pediatric patients have an increased risk of developing a secondary malignancy several decades after treatment with radiotherapy and chemotherapy. In this work, we use a biologically motivated mathematical formalism to estimate the relative risks of breast, lung and thyroid cancers in childhood cancer survivors due to concurrent therapy regimen. This model specifically includes possible organ-specific interaction between radiotherapy and chemotherapy. The model predicts relative risks for developing secondary cancers after chemotherapy in breast, lung and thyroid tissues, and compared with the epidemiological data. For a concurrent therapy protocol, our model predicted relative risks of 3.2, 9.3, 4.5 as compared to the clinical data, i.e., 1.4, 8.0, 2.3 for secondary breast, lung and thyroid cancer risks, respectively. The extracted chemotherapy mutation induction rates for breast, lung and thyroid are 10−9, 0.5 × 10−6, 0.9 × 10−7 respectively. We found that there exists no synergistic interaction between radiation and chemotherapy for neither mutation induction nor cell kill in lung tissue, but there is an interaction in cell kill for the breast and thyroid organs. These findings help understand the risks of current clinical protocols and might provide rational guidance to develop future multi-modality treatment protocols to minimize secondary cancer risks.

http://ift.tt/2w6Lavz

Novel Mutations in Transthyretin Gene Associated With Hepatocellular Carcinoma

Abstract

Hepatocellular carcinoma (HCC) is one of the major health problems with increasing incidence worldwide. We report the elevation in transthyretin (TTR) expression following HCC induction using diethylnitrosamine (DEN) and 2-aminoacetylfluorine (2-AAF) in male Wistar rats. The increase in its expression took place at very early stage and remained elevated throughout HCC progression. The analysis of TTR gene in HCC bearing rats revealed four novel mutations that alter three amino acids at positions 61, 100 and 115. While these mutations do not directly affect the binding of TTR to thyroxine (T₄), the mutation in amino acid 115 interferes with TTR tetramer formation that leads to its accumulation. Further, the mutated TTR is unable to cleave C-terminal of apolipoprotein A1 (APOA1) that results in abnormal lipid metabolism. This has correlation with development of liver cirrhosis and HCC. Furthermore, the mutated TTR seems to have potential as biomarker for early detection of HCC. This article is protected by copyright. All rights reserved

http://ift.tt/2wGQCsN

Procyanidin B2 3,3”-di-O-gallate induces oxidative stress-mediated cell death in prostate cancer cells via inhibiting MAP kinase phosphatase activity and activating ERK1/2 and AMPK

ABSTRACT

Neoplastic cells exhibit higher oxidative stress compared to normal cells; however, antioxidants based clinical trials have mostly failed. Another attractive therapeutic approach is to further increase the oxidative stress in cancer cells leading to cell death. Herein, we show that Procyanidin B2 3,3"-di-O-gallate (B2G2), the most active constituent of grape seed extract, treatment causes cell death in human prostate cancer (PCa) cells (LNCaP and 22Rv1) via increasing the reactive oxygen species (ROS) generation. Mechanistically, B2G2 treatment decreased the mitochondrial electron transport chain complex III activity leading to enhanced mitochondrial superoxide generation and decreased ATP production in LNCaP cells. Additional molecular studies revealed that B2G2-induced cell death was mediated mainly through ROS-induced sustained activation of ERK1/2, which was due to inhibition of MAP kinase phosphatase (MKP) activity as over-expression of MKP3 in LNCaP cells conferred significant protection against B2G2-induced cell death. Along with ERK1/2, AMP-activated protein kinase α (AMPKα) was also activated by B2G2 treatment, and pre-treatment with AMPKα inhibitor compound C significantly reversed the cytotoxic effects of B2G2 in LNCaP cells. Furthermore, pre-treatment of MKP3 over-expressing LNCaP cells with compound C further reduced the B2G2-induced cell death, suggesting the involvement of AMPKα along with MKP3 and ERK1/2 in the biological effects of B2G2. Together, these results for the first time identified that oxidative stress and MKP3 inhibition play a critical role in B2G2-induced cell death in PCa cells through sustained activation of both ERK1/2 and AMPKα. These results offer a unique opportunity to control this deadly malignancy through B2G2 use. This article is protected by copyright. All rights reserved

http://ift.tt/2w7baXX