EJC's biennial report on metastatic soft tissue sarcoma: State of the art and future perspectives

Publication date: January 2018
Source:European Journal of Cancer, Volume 88
Author(s): Melissa Vos, Stefan Sleijfer
In the last decade the limited treatment options for patients with metastatic soft tissue sarcoma have expanded considerably. With the addition of olaratumab to first-line treatment with doxorubicin, the introduction of several new agents in second-line treatment and beyond and other promising agents in the pipeline, perspectives of patients with metastatic soft tissue sarcoma are improving. Due to increasing insight into the biology of the different soft tissue sarcoma subtypes, choice of treatment has become much more histology-driven, although more prognostic and predictive factors are needed to further personalise therapy. This report summarises the current state of the art and discusses the promising developments in the treatment of patients with metastatic soft tissue sarcoma.



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Orthodontic management by functional activator treatment: a case report

Managing orthodontic treatment is often very difficult for the orthodontist. Many devices are used during the orthopedic phase of orthodontic treatment, always with different functions. We describe a case of o...

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US oncology-wide incidence, duration, costs and deaths from chemoradiation mucositis and antimucositis therapy benefits

Future Oncology, Ahead of Print.


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Emotional distress and subjective impact of the disease in young women with breast cancer and their spouses

Future Oncology, Ahead of Print.


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US oncology-wide incidence, duration, costs and deaths from chemoradiation mucositis and antimucositis therapy benefits

Future Oncology, Ahead of Print.


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Emotional distress and subjective impact of the disease in young women with breast cancer and their spouses

Future Oncology, Ahead of Print.


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Perceptions and Attitudes of Cancer Patients and Caregivers Towards Enrollment in Clinical Trials in Lebanon

Abstract

The rates of participation in oncology clinical trials (CTs) are relatively lower in the Middle East compared to other areas in the world. Many social and cultural factors underlie the patients' reluctance to participate. To probe the knowledge, attitudes, and perceptions of patients with cancer and their caregivers regarding participation in CTs at our tertiary referral center in Lebanon, we interviewed 210 patients and caregivers visiting the outpatient clinics in the Naef Basile Cancer Institute at the American University of Beirut. A questionnaire was derived from literature and administered in Arabic. The study was approved by the Institutional Review Board (IRB). Two hundred individuals agreed to answer the questionnaire. The majority of participants (90.5%) were Lebanese with the remaining being non-Lebanese Arabs. Eighty-nine participants (45%) were aware of the concepts of CTs. Eighty-two respondents (41%) would participate in phase I CTs. Twenty-nine individuals (14.5%) agree to be enrolled in CTs with the approval of their family members only. One hundred twenty-nine subjects (64.5%) stated that they would refuse enrollment in a CT where they might receive placebo. Eighty-eight (44%) of participants considered that medical records could be reviewed for research without consent while 54% agreed that samples collected during clinical workup could be used for research without the consent of the patient. There are several social and demographic correlates for participation in CTs. Raising awareness and overcoming barriers of misconception are keys to promote participation in CTs in Lebanon.

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Perceptions and Attitudes of Cancer Patients and Caregivers Towards Enrollment in Clinical Trials in Lebanon

Abstract

The rates of participation in oncology clinical trials (CTs) are relatively lower in the Middle East compared to other areas in the world. Many social and cultural factors underlie the patients' reluctance to participate. To probe the knowledge, attitudes, and perceptions of patients with cancer and their caregivers regarding participation in CTs at our tertiary referral center in Lebanon, we interviewed 210 patients and caregivers visiting the outpatient clinics in the Naef Basile Cancer Institute at the American University of Beirut. A questionnaire was derived from literature and administered in Arabic. The study was approved by the Institutional Review Board (IRB). Two hundred individuals agreed to answer the questionnaire. The majority of participants (90.5%) were Lebanese with the remaining being non-Lebanese Arabs. Eighty-nine participants (45%) were aware of the concepts of CTs. Eighty-two respondents (41%) would participate in phase I CTs. Twenty-nine individuals (14.5%) agree to be enrolled in CTs with the approval of their family members only. One hundred twenty-nine subjects (64.5%) stated that they would refuse enrollment in a CT where they might receive placebo. Eighty-eight (44%) of participants considered that medical records could be reviewed for research without consent while 54% agreed that samples collected during clinical workup could be used for research without the consent of the patient. There are several social and demographic correlates for participation in CTs. Raising awareness and overcoming barriers of misconception are keys to promote participation in CTs in Lebanon.

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Underweight status at diagnosis is associated with poorer outcomes in adult patients with acute myeloid leukemia: a retrospective study of JALSG AML 201

Abstract

Recent studies have described various impacts of obesity and being overweight on acute myeloid leukemia (AML) outcomes in adult patients, but little is known about the impact of being underweight. We compared the outcomes of underweight patients to those of normal weight and overweight patients. Adult patients with AML who registered in the JALSG AML201 study (n = 1057) were classified into three groups: underweight (body mass index [BMI] < 18.5, n = 92), normal weight (BMI 18.5–25, n = 746), and overweight (BMI ≥ 25, n = 219). With the exception of age and male/female ratio, patient characteristics were comparable among the three groups. Rates of complete remission following induction chemotherapy were similar among the three groups (p = 0.68). We observed a significant difference in overall survival (OS), disease-free survival (DFS), and non-relapse mortality (NRM) between underweight and normal weight patients (3-year OS 34.8 vs. 47.7%, p = 0.01; DFS 28.6 vs. 39.8%, p = 0.02; 1-year NRM 6.2 vs. 2.6%, p = 0.05), but not between underweight and overweight patients. In multivariate analysis, underweight was an independent adverse prognostic factor for OS (p < 0.01), DFS (p = 0.01), and NRM (p = 0.04). During the first induction chemotherapy, the incidences of documented infection (DI) and severe adverse events (AEs) were higher in underweight patients than those in normal weight patients (DI 16 vs. 8.1%, p = 0.04; AE 36 vs. 24%, p = 0.05). In conclusion, underweight was an independent adverse prognostic factor for survival in adult AML patients.

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Perceptions and Attitudes of Cancer Patients and Caregivers Towards Enrollment in Clinical Trials in Lebanon

Abstract

The rates of participation in oncology clinical trials (CTs) are relatively lower in the Middle East compared to other areas in the world. Many social and cultural factors underlie the patients' reluctance to participate. To probe the knowledge, attitudes, and perceptions of patients with cancer and their caregivers regarding participation in CTs at our tertiary referral center in Lebanon, we interviewed 210 patients and caregivers visiting the outpatient clinics in the Naef Basile Cancer Institute at the American University of Beirut. A questionnaire was derived from literature and administered in Arabic. The study was approved by the Institutional Review Board (IRB). Two hundred individuals agreed to answer the questionnaire. The majority of participants (90.5%) were Lebanese with the remaining being non-Lebanese Arabs. Eighty-nine participants (45%) were aware of the concepts of CTs. Eighty-two respondents (41%) would participate in phase I CTs. Twenty-nine individuals (14.5%) agree to be enrolled in CTs with the approval of their family members only. One hundred twenty-nine subjects (64.5%) stated that they would refuse enrollment in a CT where they might receive placebo. Eighty-eight (44%) of participants considered that medical records could be reviewed for research without consent while 54% agreed that samples collected during clinical workup could be used for research without the consent of the patient. There are several social and demographic correlates for participation in CTs. Raising awareness and overcoming barriers of misconception are keys to promote participation in CTs in Lebanon.

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Perceptions and Attitudes of Cancer Patients and Caregivers Towards Enrollment in Clinical Trials in Lebanon

Abstract

The rates of participation in oncology clinical trials (CTs) are relatively lower in the Middle East compared to other areas in the world. Many social and cultural factors underlie the patients' reluctance to participate. To probe the knowledge, attitudes, and perceptions of patients with cancer and their caregivers regarding participation in CTs at our tertiary referral center in Lebanon, we interviewed 210 patients and caregivers visiting the outpatient clinics in the Naef Basile Cancer Institute at the American University of Beirut. A questionnaire was derived from literature and administered in Arabic. The study was approved by the Institutional Review Board (IRB). Two hundred individuals agreed to answer the questionnaire. The majority of participants (90.5%) were Lebanese with the remaining being non-Lebanese Arabs. Eighty-nine participants (45%) were aware of the concepts of CTs. Eighty-two respondents (41%) would participate in phase I CTs. Twenty-nine individuals (14.5%) agree to be enrolled in CTs with the approval of their family members only. One hundred twenty-nine subjects (64.5%) stated that they would refuse enrollment in a CT where they might receive placebo. Eighty-eight (44%) of participants considered that medical records could be reviewed for research without consent while 54% agreed that samples collected during clinical workup could be used for research without the consent of the patient. There are several social and demographic correlates for participation in CTs. Raising awareness and overcoming barriers of misconception are keys to promote participation in CTs in Lebanon.

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Lifestyle, Diet, and Colorectal Cancer Risk According to (Epi)genetic Instability: Current Evidence and Future Directions of Molecular Pathological Epidemiology

Abstract

Purpose of Review

In this review, we describe molecular pathological epidemiology (MPE) studies from around the world that have studied diet and/or lifestyle factors in relation to molecular markers of (epi)genetic pathways in colorectal cancer (CRC), and explore future perspectives in this realm of research. The main focus of this review is diet and lifestyle factors for which there is evidence for an association with CRC as identified by the World Cancer Research Fund reports. In addition, we review promising hypotheses, that warrant consideration in future studies.

Recent Findings

Associations between molecular characteristics of CRC have been published in relation to smoking, alcohol consumption; body mass index (BMI); waist:hip ratio; adult attained height; physical activity; early life energy restriction; dietary acrylamide, fiber, fat, methyl donors, omega 3 fatty acids; meat, including total protein, processed meat, and heme iron; and fruit and vegetable intake.

Summary

MPE studies help identify where associations between diet, lifestyle, and CRC risk may otherwise be masked and also shed light on how timing of exposure can influence etiology. Sample size is often an issue, but this may be addressed in the future by pooling data.

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Acetylsalicylic Acid Governs the Effect of Sorafenib in RAS- Mutant Cancers

Purpose: Identify and characterize novel combinations of sorafenib with anti-inflammatory painkillers to target difficult to treat RAS-mutant cancer. Experimental Design: The cytotoxicity of acetylsalicylic acid (aspirin) in combination with the multikinase inhibitor sorafenib (Nexavar) was assessed in RAS-mutant cell lines in vitro. The underlying mechanism for the increased cytotoxicity was investigated using selective inhibitors and shRNA-mediated gene knockdown. In vitro results were confirmed in RAS-mutant xenograft mouse models in vivo. Results: The addition of aspirin but not isobutylphenylpropanoic acid (ibruprofen) or celecoxib (celebrex) significantly increased the in vitro cytotoxicity of sorafenib. Mechanistically, combined exposure resulted in increased BRAF/CRAF dimerization and the simultaneous hyper-activation of the AMPK and ERK pathways. Combining sorafenib with other AMPK activators, like metformin or A769662, was not sufficient to decrease cell viability due to sole activation of the AMPK pathway. The cytotoxicity of sorafenib and aspirin was blocked by inhibition of the AMPK or ERK pathways through shRNA or via pharmacological inhibitors of RAF (LY3009120), MEK (trametinib) or AMPK (compound C). The combination was found to be specific for RAS/RAF-mutant cells and had no significant effect in RAS/RAF-wild type keratinocytes or melanoma cells. In vivo treatment of human xenografts in NSG mice with sorafenib and aspirin significantly reduced tumor volume compared to each single-agent treatment alone. Conclusion: Combined sorafenib and aspirin exerts cytotoxicity against RAS/RAF-mutant cells by simultaneously affecting two independent pathways and represents a promising novel strategy for the treatment of RAS-mutant cancers.

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Acetylsalicylic Acid Governs the Effect of Sorafenib in RAS- Mutant Cancers

Purpose: Identify and characterize novel combinations of sorafenib with anti-inflammatory painkillers to target difficult to treat RAS-mutant cancer. Experimental Design: The cytotoxicity of acetylsalicylic acid (aspirin) in combination with the multikinase inhibitor sorafenib (Nexavar) was assessed in RAS-mutant cell lines in vitro. The underlying mechanism for the increased cytotoxicity was investigated using selective inhibitors and shRNA-mediated gene knockdown. In vitro results were confirmed in RAS-mutant xenograft mouse models in vivo. Results: The addition of aspirin but not isobutylphenylpropanoic acid (ibruprofen) or celecoxib (celebrex) significantly increased the in vitro cytotoxicity of sorafenib. Mechanistically, combined exposure resulted in increased BRAF/CRAF dimerization and the simultaneous hyper-activation of the AMPK and ERK pathways. Combining sorafenib with other AMPK activators, like metformin or A769662, was not sufficient to decrease cell viability due to sole activation of the AMPK pathway. The cytotoxicity of sorafenib and aspirin was blocked by inhibition of the AMPK or ERK pathways through shRNA or via pharmacological inhibitors of RAF (LY3009120), MEK (trametinib) or AMPK (compound C). The combination was found to be specific for RAS/RAF-mutant cells and had no significant effect in RAS/RAF-wild type keratinocytes or melanoma cells. In vivo treatment of human xenografts in NSG mice with sorafenib and aspirin significantly reduced tumor volume compared to each single-agent treatment alone. Conclusion: Combined sorafenib and aspirin exerts cytotoxicity against RAS/RAF-mutant cells by simultaneously affecting two independent pathways and represents a promising novel strategy for the treatment of RAS-mutant cancers.

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The proteasome and proteasome inhibitors in multiple myeloma

Abstract

Proteasome inhibitors are one of the most important classes of agents to have emerged for the treatment of multiple myeloma in the past two decades, and now form one of the backbones of treatment. Three agents in this class have been approved by the United States Food and Drug Administration—the first-in-class compound bortezomib, the second-generation agent carfilzomib, and the first oral proteasome inhibitor, ixazomib. The success of this class of agents is due to the exquisite sensitivity of myeloma cells to the inhibition of the 26S proteasome, which plays a critical role in the pathogenesis and proliferation of the disease. Proteasome inhibition results in multiple downstream effects, including the inhibition of NF-κB signaling, the accumulation of misfolded and unfolded proteins, resulting in endoplasmic reticulum stress and leading to the unfolded protein response, the downregulation of growth factor receptors, suppression of adhesion molecule expression, and inhibition of angiogenesis; resistance to proteasome inhibition may arise through cellular responses mediating these downstream effects. These multiple biologic consequences of proteasome inhibition result in synergistic or additive activity with other chemotherapeutic and targeted agents for myeloma, and proteasome inhibitor-based combination regimens have become established as a cornerstone of therapy throughout the myeloma treatment algorithm, incorporating agents from the other key classes of antimyeloma agents, including the immunomodulatory drugs, monoclonal antibodies, and histone deacetylase inhibitors. This review gives an overview of the critical role of the proteasome in myeloma and the characteristics of the different proteasome inhibitors and provides a comprehensive summary of key clinical efficacy and safety data with the currently approved proteasome inhibitors.

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The proteasome and proteasome inhibitors in multiple myeloma

Abstract

Proteasome inhibitors are one of the most important classes of agents to have emerged for the treatment of multiple myeloma in the past two decades, and now form one of the backbones of treatment. Three agents in this class have been approved by the United States Food and Drug Administration—the first-in-class compound bortezomib, the second-generation agent carfilzomib, and the first oral proteasome inhibitor, ixazomib. The success of this class of agents is due to the exquisite sensitivity of myeloma cells to the inhibition of the 26S proteasome, which plays a critical role in the pathogenesis and proliferation of the disease. Proteasome inhibition results in multiple downstream effects, including the inhibition of NF-κB signaling, the accumulation of misfolded and unfolded proteins, resulting in endoplasmic reticulum stress and leading to the unfolded protein response, the downregulation of growth factor receptors, suppression of adhesion molecule expression, and inhibition of angiogenesis; resistance to proteasome inhibition may arise through cellular responses mediating these downstream effects. These multiple biologic consequences of proteasome inhibition result in synergistic or additive activity with other chemotherapeutic and targeted agents for myeloma, and proteasome inhibitor-based combination regimens have become established as a cornerstone of therapy throughout the myeloma treatment algorithm, incorporating agents from the other key classes of antimyeloma agents, including the immunomodulatory drugs, monoclonal antibodies, and histone deacetylase inhibitors. This review gives an overview of the critical role of the proteasome in myeloma and the characteristics of the different proteasome inhibitors and provides a comprehensive summary of key clinical efficacy and safety data with the currently approved proteasome inhibitors.

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CDK4/6 Inhibitors Increase PD-L1 Expression [Research Watch]

Cyclin D/CDK4 destabilize PD-L1 via the CUL3^SPOP E3 ligase to increase tumor-infiltrating lymphocytes.

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ATR Promotes Faithful Chromosome Segregation in Mitosis [Research Watch]

ATR localized to centromeres to prevent lagging chromosomes independent of its role in replication stress.

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PMN-MDSC Infiltration Blocks the Antitumor Effects of CSF1R Inhibition [Research Watch]

CSF1R inhibition both reduces protumorigenic TAMs and recruits protumorigenic PMN-MDSCs.

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SRPK2 Acts Downstream of MTORC1 to Promote De Novo Lipogenesis [Research Watch]

mTORC1-dependent SRPK2 phosphorylation induces splicing of lipogenic transcripts involved in tumor growth.

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Pancreatitis-Induced p62 Accumulation Promotes Pancreatic Cancer [Research Watch]

Defective autophagy and stress in acinar cells drives the progression of PanIN1 lesions to PDAC.

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Deconstruction of a metastatic tumor microenvironment reveals a common matrix response in human cancers [Research Articles]

We have profiled, for the first time, an evolving human metastatic microenvironment, measuring gene expression, matrisome proteomics, cytokine and chemokine levels, cellularity, ECM organization and biomechanical properties, all on the same sample. Using biopsies of high-grade serous ovarian cancer (HGSOC) metastases that ranged from minimal to extensive disease, we show how non-malignant cell densities and cytokine networks evolve with disease progression. Multivariate integration of the different components allowed us to define for the first time, gene and protein profiles that predict extent of disease and tissue stiffness, whilst also revealing the complexity and dynamic nature of matrisome remodeling during development of metastases. Although we studied a single metastatic site from one human malignancy, a pattern of expression of 22 matrisome genes distinguished patients with a shorter overall survival in ovarian and twelve other primary solid cancers, suggesting that there may be a common matrix response to human cancer.

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Genomic landscape of cell-free DNA in patients with colorectal cancer [Research Briefs]

"Liquid biopsy" approaches analyzing cell-free DNA (cfDNA) from the blood of cancer patients are increasingly utilized in clinical practice. However, it is not yet known whether cfDNA sequencing from large cancer patient cohorts can detect genomic alterations at frequencies similar to those observed by direct tumor sequencing, and whether this approach can generate novel insights. Here, we report next-generation sequencing data from cfDNA of 1,397 colorectal cancer (CRC) patients. Overall, frequencies of genomic alterations detected in cfDNA were comparable to those observed in three independent tissue-based CRC sequencing compendia. Our analysis also identified a novel cluster of extracellular domain (ECD) mutations in EGFR, mediating resistance by blocking binding of anti-EGFR antibodies. Patients with EGFR ECD mutations displayed striking tumor heterogeneity, with 91% harboring multiple distinct resistance alterations (range 1-13, median 4). These results suggest that cfDNA profiling can effectively define the genomic landscape of cancer and yield important biologic insights.

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Retraction of: Tumor Protein D52-Like 2 Contributes to Proliferation of Breast Cancer Cells; 10.1089/cbr.2014.1723

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


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Retraction of: Tumor Protein D52-Like 2 Accelerates Gastric Cancer Cell Proliferation; 10.1089/cbr.2014.1766

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


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Time and dose-related changes in lung perfusion after definitive radiotherapy for NSCLC

To examine radiation-induced changes in regional lung perfusion per dose level in 58 non-small-cell lung cancer (NSCLC) patients treated with intensity-modulated radiotherapy (IMRT).

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Patterns of locoregional failure in locally advanced non-small cell lung cancer treated with definitive conformal radiotherapy: Results from the Gating 2006 trial

To determine the patterns of locoregional failure (LRF) in patients with locally advanced non-small cell lung cancer treated with definitive radiotherapy (RT).

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Independent component analysis for rectal bleeding prediction following prostate cancer radiotherapy

To evaluate the benefit of independent component analysis (ICA)-based models for predicting rectal bleeding (RB) following prostate cancer radiotherapy.

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Letter response: Reporting of mitotic rate in cutaneous melanoma

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Issue Information - Ed Board

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Issue Information - TOC

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Letter response: Reporting of mitotic rate in cutaneous melanoma

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Issue Information - Ed Board

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Issue Information - TOC

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Letter response: Reporting of mitotic rate in cutaneous melanoma

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Issue Information - Ed Board

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Issue Information - TOC

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Perioperative allogenic blood transfusion is a poor prognostic factor after hepatocellular carcinoma surgery: a multi-center analysis

Abstract

Purpose

The influence of allogenic blood transfusion on the postoperative outcomes of hepatocellular carcinoma (HCC) surgery remains controversial. This study aims to clarify the clinical impacts of perioperative allogenic blood transfusion on liver resection outcome in HCC patients.

Methods

We analyzed data collected over 5 years for 642 patients who underwent hepatectomy for HCC at one of the five university hospitals. We investigated the impact of allogenic blood transfusion on postoperative outcome after surgery in all patients and in 74 matched pairs, using a propensity score.

Results

Of the 642 patients, 198 (30.8%) received perioperative allogenic blood transfusion (AT group) and 444 (69.2%) did not (non-AT group). Overall survival was lower in the AT group than in the non-AT group in univariate (P < 0.001) and multivariate analyses (risk ratio 1.521, P = 0.011). After matching the different distributions using propensity scores, perioperative blood transfusion was found to be a poor prognostic factor for HCC patients.

Conclusions

In this multi-center study, perioperative blood transfusion was an independent factor for poor prognosis after curative surgery for primary HCC in the patient group and in pairs matched by propensity scores.

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Perioperative allogenic blood transfusion is a poor prognostic factor after hepatocellular carcinoma surgery: a multi-center analysis

Abstract

Purpose

The influence of allogenic blood transfusion on the postoperative outcomes of hepatocellular carcinoma (HCC) surgery remains controversial. This study aims to clarify the clinical impacts of perioperative allogenic blood transfusion on liver resection outcome in HCC patients.

Methods

We analyzed data collected over 5 years for 642 patients who underwent hepatectomy for HCC at one of the five university hospitals. We investigated the impact of allogenic blood transfusion on postoperative outcome after surgery in all patients and in 74 matched pairs, using a propensity score.

Results

Of the 642 patients, 198 (30.8%) received perioperative allogenic blood transfusion (AT group) and 444 (69.2%) did not (non-AT group). Overall survival was lower in the AT group than in the non-AT group in univariate (P < 0.001) and multivariate analyses (risk ratio 1.521, P = 0.011). After matching the different distributions using propensity scores, perioperative blood transfusion was found to be a poor prognostic factor for HCC patients.

Conclusions

In this multi-center study, perioperative blood transfusion was an independent factor for poor prognosis after curative surgery for primary HCC in the patient group and in pairs matched by propensity scores.

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Modifiable and non-modifiable risk factors for preterm delivery among adolescent and young adult cancer survivors

Abstract

Purpose

A cancer diagnosis in adolescence and young adulthood (AYA, ages 15–39) may affect future pregnancy outcomes. Previous studies have reported an increased risk of preterm delivery (< 37 weeks of gestation) after maternal cancer treatment. In this analysis, we evaluated whether non-cancer characteristics modify the association between an AYA cancer history and preterm birth.

Methods

North Carolina Central Cancer Registry records (2000–2013) were linked to state birth certificate files (2000–2014) to identify births to AYA cancer survivors (n = 1,980). A comparison cohort of births to women without a cancer diagnosis was selected from birth certificate files (n = 11,860). Log-binomial regression was used to estimate risk ratios (RR) and 95% confidence intervals (CI) for preterm delivery. Effect modification by early prenatal care (1st trimester; yes/no), race/ethnicity (white/black/other), previous live births (0/1+), maternal age (< 25/25–29/30–34/35+), smoking during pregnancy (any/none), and education (high school or less/some college/Bachelor's degree or higher) was evaluated using likelihood ratio tests (LRT).

Results

Overall, preterm births were more common among AYA survivors than the comparison group (RR = 1.24, CI 1.07–1.43). The association was stronger among those who did not receive early prenatal care (RR = 1.73, CI 1.26–2.37) than among those who did (RR = 1.15, CI 0.98–1.35; LRT p = 0.03). Maternal age < 25 was also associated with a greater increase in preterm birth (< 25: RR = 1.80, CI 1.27–2.54; LRT p = 0.07). Associations did not vary strongly by other factors evaluated.

Conclusions

An AYA cancer diagnosis may be associated with an increased risk of preterm birth, particularly among women who are younger and receive late or no prenatal care.

http://ift.tt/2AO9ZDy

Modifiable and non-modifiable risk factors for preterm delivery among adolescent and young adult cancer survivors

Abstract

Purpose

A cancer diagnosis in adolescence and young adulthood (AYA, ages 15–39) may affect future pregnancy outcomes. Previous studies have reported an increased risk of preterm delivery (< 37 weeks of gestation) after maternal cancer treatment. In this analysis, we evaluated whether non-cancer characteristics modify the association between an AYA cancer history and preterm birth.

Methods

North Carolina Central Cancer Registry records (2000–2013) were linked to state birth certificate files (2000–2014) to identify births to AYA cancer survivors (n = 1,980). A comparison cohort of births to women without a cancer diagnosis was selected from birth certificate files (n = 11,860). Log-binomial regression was used to estimate risk ratios (RR) and 95% confidence intervals (CI) for preterm delivery. Effect modification by early prenatal care (1st trimester; yes/no), race/ethnicity (white/black/other), previous live births (0/1+), maternal age (< 25/25–29/30–34/35+), smoking during pregnancy (any/none), and education (high school or less/some college/Bachelor's degree or higher) was evaluated using likelihood ratio tests (LRT).

Results

Overall, preterm births were more common among AYA survivors than the comparison group (RR = 1.24, CI 1.07–1.43). The association was stronger among those who did not receive early prenatal care (RR = 1.73, CI 1.26–2.37) than among those who did (RR = 1.15, CI 0.98–1.35; LRT p = 0.03). Maternal age < 25 was also associated with a greater increase in preterm birth (< 25: RR = 1.80, CI 1.27–2.54; LRT p = 0.07). Associations did not vary strongly by other factors evaluated.

Conclusions

An AYA cancer diagnosis may be associated with an increased risk of preterm birth, particularly among women who are younger and receive late or no prenatal care.

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Oesophageal or transgastric views for estimating mean pulmonary artery pressure with transoesophageal echocardiography?

BACKGROUND Recent data suggest that in cardiac surgical patients, the pulmonary artery acceleration time (PAT) is useful for estimating mean pulmonary artery pressure (MPAP) noninvasively with transoesophageal echocardiography (TOE). The pulmonary valve can be visualised from multiple echocardiographic windows, but it is unclear which, if any, view correlates best with MPAP. OBJECTIVE(S) To compare the PAT measured with TOE from oesophageal and transgastric views with MPAP obtained invasively with a pulmonary artery catheter. DESIGN A prospective observational study. SETTING St. Vincent's Hospital, Melbourne, a university tertiary referral centre in Australia. PATIENTS Sixty-three patients having cardiac surgery were included in our study. All patients had insertion of both a TOE probe and pulmonary artery catheter; this is the routine standard of care in our centre. INTERVENTION(S) Nil. MAIN OUTCOME MEASURES During a period of haemodynamic stability, the PAT was measured first from an oesophageal view and then immediately after from a transgastric view. The results were then compared with the invasively measured MPAP. RESULTS Simultaneous measurements of MPAP and PAT were taken in 63 patients. In two patients, these measurements were not possible in the transgastric position due to an inability to visualise the right ventricular outflow tract and pulmonary valve. A Bland–Altman analysis of the PAT measured from the upper oesophageal and transgastric views showed a mean difference of 1 ms and limits of agreement of −18 to 16 ms. The area under the receiver operating curves for predicting pulmonary hypertension with PAT were upper oesophageal view 0.99 [95% confidence interval (CI), 0.98 to 1.00] and transgastric view 0.99 (95% CI, 0.97 to 1.00). The agreement between the results from these two views in the diagnosis of pulmonary hypertension (defined as PAT  25 mmHg) with a sensitivity of 94.7% and specificity of 97.6%. The transgastric view predicted pulmonary hypertension with a sensitivity of 89.4% and specificity of 95.2%. CONCLUSION Oesophageal and transgastric measurements of PAT have close agreement and a similar high ability to discriminate between people with and without pulmonary hypertension. The transgastric measurement was unobtainable in a small percentage of patients and required more probe manipulation. We would recommend PAT measurement in the upper oesophageal view. Correspondence to Dr Brian Cowie, Staff Anaesthetist, Department of Anaesthesia, St. Vincent's Hospital, Melbourne, Melbourne, Victoria, Australia E-mail: brian.cowie@svha.org.au © 2017 European Society of Anaesthesiology

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Questions About In-Breast Tumor Recurrence in Patients Treated with Breast-Conserving Therapy

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Intraoperative Ultrasound-Guided Excision of Axillary Clip in Patients with Node-Positive Breast Cancer Treated with Neoadjuvant Therapy (ILINA Trial)

Abstract

Background

The accuracy of sentinel lymph node biopsy (SLNB) after neoadjuvant therapy (NAT) has been improved with the placement of a clip in the positive node prior to treatment. Several methods have been described for clipped node excision during SLNB after NAT. We assessed the feasibility of intraoperative ultrasound (IOUS)-guided excision of the clipped node during SLNB and investigated whether the accuracy of SLNB is improved.

Methods

After approval by the Institutional Ethics Committee, all breast cancer patients undergoing NAT had an US-visible clip placed in the positive node. The ILINA trial consisted of IOUS-guided excision of the clipped node along with SLNB and axillary lymph node dissection (ALND).

Results

Forty-six patients had a clip placed in the positive node. In two (4.3%) cases, the clip could not be seen prior to surgery and the patient underwent ALND; however, the clipped node was successfully removed by IOUS-guided excision in 44 patients. Thirty-five patients (79.5%) underwent SLNB along with IOUS-guided excision of the clipped node and ALND, and were subsequently included in the ILINA trial. Nine patients were not included (five patients with SLNB only and four patients with ALND without SLNB). SLNB matched the clipped node in 27 (77%) patients. The false negative rate for the ILINA protocol was 4.1% (95% confidence interval 0.1–21.1%).

Conclusions

IOUS-guided excision of the axillary clipped node after NAT was feasible, safe, and successful in 100% of cases. The ILINA trial is accurate in predicting axillary nodal status after NAT.

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Questions About In-Breast Tumor Recurrence in Patients Treated with Breast-Conserving Therapy

http://ift.tt/2AAwYl7

Intraoperative Ultrasound-Guided Excision of Axillary Clip in Patients with Node-Positive Breast Cancer Treated with Neoadjuvant Therapy (ILINA Trial)

Abstract

Background

The accuracy of sentinel lymph node biopsy (SLNB) after neoadjuvant therapy (NAT) has been improved with the placement of a clip in the positive node prior to treatment. Several methods have been described for clipped node excision during SLNB after NAT. We assessed the feasibility of intraoperative ultrasound (IOUS)-guided excision of the clipped node during SLNB and investigated whether the accuracy of SLNB is improved.

Methods

After approval by the Institutional Ethics Committee, all breast cancer patients undergoing NAT had an US-visible clip placed in the positive node. The ILINA trial consisted of IOUS-guided excision of the clipped node along with SLNB and axillary lymph node dissection (ALND).

Results

Forty-six patients had a clip placed in the positive node. In two (4.3%) cases, the clip could not be seen prior to surgery and the patient underwent ALND; however, the clipped node was successfully removed by IOUS-guided excision in 44 patients. Thirty-five patients (79.5%) underwent SLNB along with IOUS-guided excision of the clipped node and ALND, and were subsequently included in the ILINA trial. Nine patients were not included (five patients with SLNB only and four patients with ALND without SLNB). SLNB matched the clipped node in 27 (77%) patients. The false negative rate for the ILINA protocol was 4.1% (95% confidence interval 0.1–21.1%).

Conclusions

IOUS-guided excision of the axillary clipped node after NAT was feasible, safe, and successful in 100% of cases. The ILINA trial is accurate in predicting axillary nodal status after NAT.

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Expanding Cancer Clinical Trial Access for Patients with HIV

People with HIV are often excluded from clinical trials for safety reasons. Preliminary results from an NCI-sponsored study of an immunotherapy drug show that people with HIV can safely participate in clinical trials.

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Expanding Cancer Clinical Trial Access for Patients with HIV

People with HIV are often excluded from clinical trials for safety reasons. Preliminary results from an NCI-sponsored study of an immunotherapy drug show that people with HIV can safely participate in clinical trials.

http://ift.tt/2AM20GV

Expert consensus on re-irradiation for recurrent glioma

To investigate radiation oncologists' opinions on important considerations to offering re-irradiation (re-RT) as a treatment option for recurrent glioma.

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Treatment of meningioma and glioma with protons and carbon ions

The rapid rise of particle therapy across the world necessitates evidence to justify its ever-increasing utilization. This narrative review summarizes the current status of these technologies on treatment of b...

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Expert consensus on re-irradiation for recurrent glioma

To investigate radiation oncologists' opinions on important considerations to offering re-irradiation (re-RT) as a treatment option for recurrent glioma.

http://ift.tt/2AAgdGo

Treatment of meningioma and glioma with protons and carbon ions

The rapid rise of particle therapy across the world necessitates evidence to justify its ever-increasing utilization. This narrative review summarizes the current status of these technologies on treatment of b...

http://ift.tt/2nmi3Fy

The earlier, the better: the effects of different administration timepoints of sorafenib in suppressing the carcinogenesis of VEGF in rats

Abstract

Purpose

To investigate the optimal starting time point of sorafenib therapy in suppressing the tumor-promoting effects of VEGF up-regulation, which is frequently found after local therapy in clinical practice.

Methods

VEGF was intravenously injected to imitate the evaluated expression after local tumor therapy, such as TACE. A total of 40 SD rats bearing hepatic tumors were randomly divided into four groups and sorafenib was administered at different timepoints: (A) control group: VEGF injection only; (B) initiating sorafenib 72 h prior to VEGF injection; (C) initiating sorafenib simultaneously with VEGF injection; (D) initiating sorafenib 72 h post-VEGF injection. The rate of tumor growth, median survival time, expression of VEGF, and microvessel density (MVD), as determined by immunohistochemical (IHC) examination, were compared.

Results

The results revealed that the tumor size and median survival time were significantly different between the three sorafenib groups compared to the control group (p < 0.05). Median survival times were 19.6 ± 1.78, 31.2 ± 6.99, 27.4 ± 4.9, and 26.5 ± 4.6 days in group A, B, C, and D, respectively. Furthermore, there was a difference in statistical significance between the two sorafenib groups B and D (p = 0.04). Tumors were collected for HE staining and IHC examination. The expression levels of VEGF in B, C, and D were 42.8 ± 7.96, 71.9 ± 15.73, and 73.6 ± 13.73, and all of them were significantly lower than that in the control group (88.3 ± 13.61). Furthermore, the level of MVD was 109.2 ± 8.98 in the control group, which was significantly higher than in the three sorafenib groups (45.7 ± 16.92, 77.1 ± 16.29, and 93.6 ± 12.87, all p < 0.05).

Conclusions

According to our results, the most suitable regimen for the administration of sorafenib is before the increased expression of VEGF, which showed a potential advantage for controlling the tumor growth and prolonging the survival time of test animal via inhibiting VEGF-receptor expression through the bifunction of VEGF, and the reduction of tumor angiogenesis.

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The earlier, the better: the effects of different administration timepoints of sorafenib in suppressing the carcinogenesis of VEGF in rats

Abstract

Purpose

To investigate the optimal starting time point of sorafenib therapy in suppressing the tumor-promoting effects of VEGF up-regulation, which is frequently found after local therapy in clinical practice.

Methods

VEGF was intravenously injected to imitate the evaluated expression after local tumor therapy, such as TACE. A total of 40 SD rats bearing hepatic tumors were randomly divided into four groups and sorafenib was administered at different timepoints: (A) control group: VEGF injection only; (B) initiating sorafenib 72 h prior to VEGF injection; (C) initiating sorafenib simultaneously with VEGF injection; (D) initiating sorafenib 72 h post-VEGF injection. The rate of tumor growth, median survival time, expression of VEGF, and microvessel density (MVD), as determined by immunohistochemical (IHC) examination, were compared.

Results

The results revealed that the tumor size and median survival time were significantly different between the three sorafenib groups compared to the control group (p < 0.05). Median survival times were 19.6 ± 1.78, 31.2 ± 6.99, 27.4 ± 4.9, and 26.5 ± 4.6 days in group A, B, C, and D, respectively. Furthermore, there was a difference in statistical significance between the two sorafenib groups B and D (p = 0.04). Tumors were collected for HE staining and IHC examination. The expression levels of VEGF in B, C, and D were 42.8 ± 7.96, 71.9 ± 15.73, and 73.6 ± 13.73, and all of them were significantly lower than that in the control group (88.3 ± 13.61). Furthermore, the level of MVD was 109.2 ± 8.98 in the control group, which was significantly higher than in the three sorafenib groups (45.7 ± 16.92, 77.1 ± 16.29, and 93.6 ± 12.87, all p < 0.05).

Conclusions

According to our results, the most suitable regimen for the administration of sorafenib is before the increased expression of VEGF, which showed a potential advantage for controlling the tumor growth and prolonging the survival time of test animal via inhibiting VEGF-receptor expression through the bifunction of VEGF, and the reduction of tumor angiogenesis.

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In Reply: Vitamin D Status May Explain Some of the Racial Disparities in Rectal Cancer

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In Reply: Vitamin D Status May Explain Some of the Racial Disparities in Rectal Cancer

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Characteristics of cerebellar glioblastomas in adults

Abstract

Adult cerebellar glioblastomas (cGBM) are rare and their characteristics remain to be fully described. We analyzed the characteristics of 17 adult patients with cGBM and compared them to a series of 103 patients presenting a supra-tentorial glioblastoma (stGBM). The mean age at GBMc diagnosis was 53.4 years (range 28–77). A history of neurofibromatosis type I was noted in 3 patients. cGBM were hemispheric in 10 patients (58.8%), only vermian in 4 patients (23.5%), and both vermian and hemispheric in 3 patients (17.7%). A H3 K27M mutation was identified in 3/14 patients, a TERT promoter mutation in 3/14 patients and a methylated MGMT promoter in 3/14 patients. None of the patients (0/14) harbored an EGFR amplification, an IDH or a BRAF mutation. Association with neurofibromatosis type I and H3K27M mutations were mutually exclusive. Compared with stGBM, cGBM occurred in younger patients (53.4 vs. 63.2, p = 0.02), were more frequently associated with neurofibromatosis type I (18 vs. 1%, p = 0.009) and with a H3 K27M mutation (21 vs. 3%, p = 0.02). They also tended to have a more frequent multifocal presentation at diagnosis (21 vs. 4.3%, p = 0.06), more frequently resulted in leptomeningeal or intra-axial metastasis (44.5 vs. 5%, p = 0.002) and were associated with a shorter median overall survival (5.9 vs. 14.2 months, p = 0.004). The present study suggests that adult cGBM differ from their supra-tentorial counterpart and constitute a heterogeneous group of IDH wild-type gliomas with at least two subgroups, one associated with H3K27M mutations and the other with neurofibromatosis type I.

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Characteristics of cerebellar glioblastomas in adults

Abstract

Adult cerebellar glioblastomas (cGBM) are rare and their characteristics remain to be fully described. We analyzed the characteristics of 17 adult patients with cGBM and compared them to a series of 103 patients presenting a supra-tentorial glioblastoma (stGBM). The mean age at GBMc diagnosis was 53.4 years (range 28–77). A history of neurofibromatosis type I was noted in 3 patients. cGBM were hemispheric in 10 patients (58.8%), only vermian in 4 patients (23.5%), and both vermian and hemispheric in 3 patients (17.7%). A H3 K27M mutation was identified in 3/14 patients, a TERT promoter mutation in 3/14 patients and a methylated MGMT promoter in 3/14 patients. None of the patients (0/14) harbored an EGFR amplification, an IDH or a BRAF mutation. Association with neurofibromatosis type I and H3K27M mutations were mutually exclusive. Compared with stGBM, cGBM occurred in younger patients (53.4 vs. 63.2, p = 0.02), were more frequently associated with neurofibromatosis type I (18 vs. 1%, p = 0.009) and with a H3 K27M mutation (21 vs. 3%, p = 0.02). They also tended to have a more frequent multifocal presentation at diagnosis (21 vs. 4.3%, p = 0.06), more frequently resulted in leptomeningeal or intra-axial metastasis (44.5 vs. 5%, p = 0.002) and were associated with a shorter median overall survival (5.9 vs. 14.2 months, p = 0.004). The present study suggests that adult cGBM differ from their supra-tentorial counterpart and constitute a heterogeneous group of IDH wild-type gliomas with at least two subgroups, one associated with H3K27M mutations and the other with neurofibromatosis type I.

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Tunneling nanotubes: A versatile target for cancer therapy.

Tunneling nanotubes: A versatile target for cancer therapy.

Curr Cancer Drug Targets. 2017 Nov 29;:

Authors: Sahoo P, Jena SR, Samanta L

Abstract
Acute Myeloid Leukemia (AML) and Acute Lymphocytic Leukemia (ALL) are common acute leukemia in adults and children respectively. In therapy process of these malignancies, chemotherapy is the main strategy that fails in many of cases. Moreover, chemotherapy is usually associated with adverse effects it also damages the healthy cells. In this regard, development of new therapies is essential. Monoclonal antibodies directed to the cell surface markers of leukemic blasts may have promising consequences. These tools can provide a specific cell targeting with minimal toxic effects on other normal cells. In this project, CD45Ra+ cells and CD123+ cells, two considered surface marker of leukemic blasts in AML and ALL respectively, were targeted by specific monoclonal antibodies. Cytotoxicity effect and cell death induction were determined by MTT assay and flow cytometry. Changes in expression profile of MCL1, cMyc, Survivin, Id1 and PIM1 genes were assessed by real time PCR after cell treatment with anti-CD45Ra and/or anti-CD123 monoclonal antibodies. Statistical analysis of results showed an effective antibody-mediated cytotoxicity and induction of apoptosis in KG1α (CD45Ra+) and Nalm6 (CD123+) cell lines. Also, a significant change in expression level of some of the apoptosis-related genes were observed. According to the results of this study, it can be concluded that an effective targeting of AML and ALL cells can be performed by anti-CD45Ra and anti-CD123 monoclonal antibodies through their effector functions and apoptosis induction.

PMID: 29189162 [PubMed - as supplied by publisher]

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Toxicology of Trastuzumab: An Insight into Mechanisms of Cardiotoxicity.

Toxicology of Trastuzumab: An Insight into Mechanisms of Cardiotoxicity.

Curr Cancer Drug Targets. 2017 Nov 29;:

Authors: An J, Sheikh MS

Abstract
Trastuzumab is a humanized monoclonal antibody that is approved for the treatment of breast and gastric malignancies. Although it has shown promise as a biotherapeutic, its cardiotoxicity remains a major concern. Genotoxic anticancer anthracyclines such as doxorubicin and epirubicin are also known for their cardiotoxic effects. However, trastuzumab and anthracyclines are suggested to mediate cardiotoxicity via different pathways. The available lines of evidence suggest that trastuzumab can exacerbate the cardiotoxic effects of anthracyclines and thus, prior exposure to anthracyclines is a regarded as one of the risk factors for trastuzumab-induced cardiotoxcity. Although it is generally believed that the trastuzumab-induced cardiotoxic effects are reversible, various preclinical studies have revealed its apoptotic effects on cardiomyocytes. Thus, the issue of the reversibility of its cardiotoxic effects remains to be fully resolved. This article discusses various mechanisms that have been proposed for the cardiotoxic effects of trastuzumab and the potential risk factors that can lead to cardiotoxicity. The recently approved anti-HER2 monoclonal antibodies including pertuzumab and ado-trastuzumab (T-DM1) are also discussed.

PMID: 29189161 [PubMed - as supplied by publisher]

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Role of glioma-associated GLI1 oncogene in carcinogenesis and cancer-targeted therapy.

Role of glioma-associated GLI1 oncogene in carcinogenesis and cancer-targeted therapy.

Curr Cancer Drug Targets. 2017 Nov 29;:

Authors: Wu J, Di D, Zhao C, Liu Y, Chen H, Gong Y, Zhao X, Chen H

Abstract
Glioma-associated oncogenes (GLIs) are zinc finger protein family members and downstream regulatory factors of the classic Hedgehog (Hh) signaling pathway. GLI proteins influence the growth and development of organisms and aid in tissue repair. However, aberrant expression of the GLI family member GLI1 promotes carcinogenesis by inducing epithelial-mesenchymal transition (EMT), angiogenesis, and other signaling pathways. Overexpression of GLI1 is thought to be an indicator of poor prognosis as well as a potential therapeutic target for cancers. GLI inhibitors such as zerumbone, GANT61, resveratrol, and cyclopamine depress the Hh pathway in vitro and in vivo cancer research, and other non-canonical pathways may also activate expression of GLI1. Here, we summarize GLI function in carcinogenesis and cancer-targeted therapy.

PMID: 29189160 [PubMed - as supplied by publisher]

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Oncorine, the world first oncolytic virus medicine and its update in China.

Oncorine, the world first oncolytic virus medicine and its update in China.

Curr Cancer Drug Targets. 2017 Nov 29;:

Authors: Liang M

Abstract
The oncolytic viruses now hold a promise of new therapeutic strategy for cancer. Its concept has inspired a wave of commercial research and development activities for the products of this category in China since 1998. The first commercialized oncolytic virus product in the world, Oncorine (H101), developed by Shanghai Sunway Biotech Co., Ltd since 1999, was approved by Chinese SFDA in November, 2005 for nasopharyngeal carcinoma in combination with chemotherapy after the phase III clinical trial, and finally acquired GMP certificate in August, 2006. In this review, I will introduce how Oncorine was successfully developed in China, and how the Chinese market responded after it was launched into the market in 2006.

PMID: 29189159 [PubMed - as supplied by publisher]

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Cancer Targeted Therapy Strategy: The Pathologist's Perspectives.

Cancer Targeted Therapy Strategy: The Pathologist's Perspectives.

Curr Cancer Drug Targets. 2017 Nov 29;:

Authors: Alessandrini L, Perin T, Kadare S, Del Pup L, Memeo L, Steffan A, Colarossi L, Berretta M, De Paoli P, Canzonieri V

Abstract
The effectiveness of new personalized treatment procedures in oncology is based on the fact that a certain tumor exhibits specific molecular features. More in detail, neoplastic tissues of patients should display a specific biomarker, most often a specific genetic alteration and/or under/overexpression of a definite protein, that could be the target of its respective drug. Immunohistochemical and molecular analyses, which usuallyinclude examination of nucleic acids from either tissues or fluids, are common tests to define the status of a tumor. This review focuses on the pathologist's role in carefully controlling pre- analytic procedures and standard operating procedures that are a crucial prerequisite to reach reliable and reproducible results. Six paradigmatic applications of targeted therapy, for which pathological diagnosis plays a fundamental role, are summarized. Traditional and next-generation sequencing are also addressed from the pathologist's perspective. It is finally underlined the importance that pathologists have in this shift to more accurate definition of disease risk and prognostication of therapy response in the personalized medicine era.

PMID: 29189158 [PubMed - as supplied by publisher]

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Methotrexate-associated lymphoproliferative disease with multiple pulmonary nodules in a patient with rheumatoid arthritis

A 62-year-old woman with rheumatoid arthritis and secondary Sjögren's syndrome took methotrexate (MTX) 5 mg three times a week regularly but gradually developed an intermittent fever, oral ulcers and productive cough with mucopurulent sputum for about 2 weeks. Image study found multiple nodular lesions and lymphadenopathies in bilateral lungs. Empirical antibiotics for 1 week failed to alleviate the fever. A transbronchial biopsy in the right fourth bronchus showed infiltration of abnormally enlarged lymphoid cells with a surface marker of CD20, some of which also stained positively in situ with Epstein-Barr virus-encoded small RNA and some CD3(+) cells. After a diagnosis of MTX-associated lymphoproliferative disease had been made, MTX was discontinued immediately and intravenous methylprednisolone 125 mg/day was given for 1 week. The clinical condition improved dramatically within 1 month and there was no recurrence after 3-year follow-up.

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Low-energy atypical femoral shaft and ipsilateral neck fracture: a rare association

This reports a case of a low-energy ipsilateral femoral shaft and neck fracture in a 69-year-old woman with vitamin D deficiency, who was taking long-term steroids and bisphosphonates. This is a fracture more commonly associated with a high-energy trauma. However, with an ageing global population and an increasing prevalence of bone insufficiency, we predict the incidence of this presentation to increase. Long-term bisphosphonate therapy has been associated with bone insufficiency and an increased rate of delayed union, adding to the complexity of management in these patients. There is currently no consensus regarding the choice of optimal implant or fixation technique to treat this challenging fracture pattern. We discuss the considerations that led to our management approach of a non-overlapping dynamic hip screw and femoral shaft plate construct which achieved uneventful bone healing and a good functional outcome within the first year of follow-up.

http://ift.tt/2ivCkXQ

Perinatal infratentorial haemorrhage: a rare but possibly life-threatening condition

Background

Perinatal infratentorial haemorrhage (PIH) is a rare birth complication associated with abnormal labour.

Case presentation

A baby boy was born by vacuum extraction at 41 weeks' gestational age. The pregnancy was uneventful and Apgar scores were 3/6/9. Following initial resuscitation, insufficient and irregular breathing, non-reactive pupils and absence of spontaneous movements were noted. A diagnosis of perinatal asphyxia with hypoxic–ischaemic encephalopathy (HIE) was considered. Therapeutic hypothermia (TH) for 72 hours was initiated. Cerebral ultrasound showed only a mildly hyperechogenic periventricular substance. A brain MRI on the fourth day of life revealed a subdural haemorrhage in the posterior fossa with compression of the fourth ventricle.

Conclusion

PIH is an important differential diagnosis to HIE that can be missed with ultrasound. PIH is a treatable condition but may be aggravated by TH. Therefore, in neonates at risk for PIH, a more detailed ultrasound protocol or brain MRI should be considered early.

http://ift.tt/2AtUcsZ

Pseudohyponatraemia secondary to hyperlipidaemia in obstructive jaundice

A 44-year-old man with uncontrolled diabetes and chronic pancreatitis presented with abdominal pain, jaundice and unintentional weight loss. Laboratory investigations were significant for hyponatraemia, an obstructive pattern of liver enzymes. Imaging was consistent with intrahepatic and extrahepatic biliary obstruction, and endoscopic evaluation revealed a long common bile duct stricture. Intravascular volume depletion, beer potomania and syndrome of inappropriate antidiuretic hormone (with concern for biliary or pancreatic malignancy) were considered in the work-up for the aetiology of the hyponatraemia. After 4 days of conventional treatment, hyponatraemia persisted. Lipid panel obtained revealed very high levels of total cholesterol. The patient underwent a successful biliary diversion and reconstruction surgery. Follow-up after 3 months showed a clinically stable patient with resolution of elevated liver enzymes, hyperlipidaemia and hyponatraemia. We illustrate this rare case of hyponatraemia secondary to hyperlipidaemia in obstructive biliary cholestasis. It is important for physicians to thoroughly investigate the aetiology of hyponatraemia at its onset.

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Endovascular management of a case of spontaneous retroperitoneal haematoma complicated with deep vein thrombosis and pulmonary embolism

Spontaneous retroperitoneal haematoma (SRH) can be a life-threatening emergency presenting with hypovolaemic shock. SRH has been rarely reported with May-Thurner syndrome (MTS) where it occurs due to rupture of the iliac vein or venous collaterals. We report a case of MTS that presented with deep venous thrombosis of the left lower limb complicated by bilateral pulmonary embolism (PE) and a large pelvic haematoma. The simultaneous occurrence of a large pelvic haematoma and PE offered a therapeutic challenge. Successful endovascular management of the case is discussed in this report.

http://ift.tt/2AuKRkL

Multiple simultaneous infections in a patient with well-controlled HIV: when Occams razor fails

Multiple concurrent infectious processes have previously been reported in the context of advanced HIV with significant immunosuppression. Here we report a case of multiple infections in a 56-year-old man with well-controlled HIV diagnosed 5 years earlier. Soon after returning to Australia following 12 years living in Thailand, he became unwell with fevers, night sweats, arthralgia and myalgia. There were no localising symptoms and examination was unremarkable. Investigations revealed positive syphilis (Treponema pallidum) serology with an RPR of 16, a positive urine culture (Klebsiella pneumoniae), a pulmonary nodule, a liver abscess and colitis (Entamoeba histolytica). Recovery was only complete when all the individual infections were treated.

http://ift.tt/2ivnMam

Unusual cause of encephalopathy after brain surgery

For patients who have had a recent neurosurgical procedure, a visit to the emergency department for encephalopathy may automatically prompt a neurosurgical consult. We present a case of a patient with a history of Chiari malformation decompressed 6 months prior who presented with a 2-week history of slowly progressive altered mental status, headache and imbalance—symptoms consistent with her initial Chiari symptoms, so neurosurgery was consulted. Imaging showed no acute abnormality, but laboratory results revealed metabolic acidosis with high salicylate levels. When reporting medication use, this patient initially left out that she had been taking Goody's powder (845 mg aspirin) for headaches, and long-term use led to metabolic encephalopathy. Despite a recent history of surgery, it is important to keep the differential diagnosis broad especially when there are signs of metabolic derangement.

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Identification of WEE1 as a target to make AKT inhibition more effective in melanoma

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Identification of WEE1 as a target to make AKT inhibition more effective in melanoma

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ASCO update: lung cancer

Summary

In the past few years there have been major changes in the treatment landscape in oncology; lung cancer is affected by those changes like almost no other solid tumor. The rise of further second- and third-line tyrosine kinase inhibitors offers sequential therapy for patients with mutated non-small-cell lung cancer. Immunotherapy has found its way into clinical routine and presents us with new challenges in managing side effects, evaluating treatment response and deciding on how long we treat our patients. The treatment algorithm of lung cancer has changed in the last month and further practice-changing trials are coming up, so treating lung cancer patients shows nowadays a more challenging perspective with the possibility of subsequently applied individual therapies. This article provides a brief overview of the highlights presented at the ASCO (American Society of Clinical Oncology) annual meeting this year in Chicago.

http://ift.tt/2ANtJqP

ASCO update: lung cancer

Summary

In the past few years there have been major changes in the treatment landscape in oncology; lung cancer is affected by those changes like almost no other solid tumor. The rise of further second- and third-line tyrosine kinase inhibitors offers sequential therapy for patients with mutated non-small-cell lung cancer. Immunotherapy has found its way into clinical routine and presents us with new challenges in managing side effects, evaluating treatment response and deciding on how long we treat our patients. The treatment algorithm of lung cancer has changed in the last month and further practice-changing trials are coming up, so treating lung cancer patients shows nowadays a more challenging perspective with the possibility of subsequently applied individual therapies. This article provides a brief overview of the highlights presented at the ASCO (American Society of Clinical Oncology) annual meeting this year in Chicago.

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2nd Symposium on Advances in Cancer Immunology and Immunotherapy, December 15–17, 2016, Athens, Greece

Abstract

This is the 2nd Symposium of a series organized annually. It aims to integrate tumor immunology basic research with results from most recent clinical trials based on the use of anti-cancer agents targeting immune system components.

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Pre-operative language ability in patients with presumed low-grade glioma

Abstract

In patients with low-grade glioma (LGG), language deficits are usually only found and investigated after surgery. Deficits may be present before surgery but to date, studies have yielded varying results regarding the extent of this problem and in what language domains deficits may occur. This study therefore aims to explore the language ability of patients who have recently received a presumptive diagnosis of low-grade glioma, and also to see whether they reported any changes in their language ability before receiving treatment. Twenty-three patients were tested using a comprehensive test battery that consisted of standard aphasia tests and tests of lexical retrieval and high-level language functions. The patients were also asked whether they had noticed any change in their use of language or ability to communicate. The test scores were compared to a matched reference group and to clinical norms. The presumed LGG group performed significantly worse than the reference group on two tests of lexical retrieval. Since five patients after surgery were discovered to have a high-grade glioma, a separate analysis excluding them were performed. These analyses revealed comparable results; however one test of word fluency was no longer significant. Individually, the majority exhibited normal or nearly normal language ability and only a few reported subjective changes in language or ability to communicate. This study shows that patients who have been diagnosed with LGG generally show mild or no language deficits on either objective or subjective assessment.

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2nd Symposium on Advances in Cancer Immunology and Immunotherapy, December 15–17, 2016, Athens, Greece

Abstract

This is the 2nd Symposium of a series organized annually. It aims to integrate tumor immunology basic research with results from most recent clinical trials based on the use of anti-cancer agents targeting immune system components.

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Pre-operative language ability in patients with presumed low-grade glioma

Abstract

In patients with low-grade glioma (LGG), language deficits are usually only found and investigated after surgery. Deficits may be present before surgery but to date, studies have yielded varying results regarding the extent of this problem and in what language domains deficits may occur. This study therefore aims to explore the language ability of patients who have recently received a presumptive diagnosis of low-grade glioma, and also to see whether they reported any changes in their language ability before receiving treatment. Twenty-three patients were tested using a comprehensive test battery that consisted of standard aphasia tests and tests of lexical retrieval and high-level language functions. The patients were also asked whether they had noticed any change in their use of language or ability to communicate. The test scores were compared to a matched reference group and to clinical norms. The presumed LGG group performed significantly worse than the reference group on two tests of lexical retrieval. Since five patients after surgery were discovered to have a high-grade glioma, a separate analysis excluding them were performed. These analyses revealed comparable results; however one test of word fluency was no longer significant. Individually, the majority exhibited normal or nearly normal language ability and only a few reported subjective changes in language or ability to communicate. This study shows that patients who have been diagnosed with LGG generally show mild or no language deficits on either objective or subjective assessment.

http://ift.tt/2ivSss4

2nd Symposium on Advances in Cancer Immunology and Immunotherapy, December 15–17, 2016, Athens, Greece

Abstract

This is the 2nd Symposium of a series organized annually. It aims to integrate tumor immunology basic research with results from most recent clinical trials based on the use of anti-cancer agents targeting immune system components.

http://ift.tt/2ki2wpm

2nd Symposium on Advances in Cancer Immunology and Immunotherapy, December 15–17, 2016, Athens, Greece

Abstract

This is the 2nd Symposium of a series organized annually. It aims to integrate tumor immunology basic research with results from most recent clinical trials based on the use of anti-cancer agents targeting immune system components.

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2nd Symposium on Advances in Cancer Immunology and Immunotherapy, December 15–17, 2016, Athens, Greece

Abstract

This is the 2nd Symposium of a series organized annually. It aims to integrate tumor immunology basic research with results from most recent clinical trials based on the use of anti-cancer agents targeting immune system components.

http://ift.tt/2ki2wpm

UBAP2L silencing inhibits cell proliferation and G2/M phase transition in breast cancer

Abstract

Background

Ubiquitin-associated protein 2-like (UBAP2L) contains a ubiquitin-associated domain near its N-terminus, which has been demonstrated to be overexpressed in multiple tumors, including hepatocellular carcinoma and colorectal carcinoma but its role has not been well studied in breast cancer. Thus, this study was designed to evaluate whether UBAP2L can serve as a potential molecular target for breast cancer therapy.

Methods

The expression of UBAP2L was determined in breast cancer tissues and cell lines by Western blotting and Oncomine database mining. Then the expression of UBAP2L was silenced using RNA interference and the effects of UBAP2L knockdown on breast cancer cell proliferation and cell cycle progression by MTT and colony formation assay, and Flow cytometry, respectively.

Results

We found the expression of UBAP2L was significantly up-regulated in breast cancer tissues and cell lines. Knockdown of UBAP2L suppressed cell proliferation, impaired colony formation ability and induced cell cycle arrest at G2/M phase. At molecular levels, knockdown of UBAP2L increased p21 expression, but decreased the expression of CDK1 and Cyclin B1 in breast cancer cells.

Conclusion

Our findings suggest that UBAP2L plays an important role in breast cancer cell proliferation and might serve as a potential target for breast cancer treatment.

http://ift.tt/2zRPRjB

Serum lipid and bone metabolism effects of Toremifene vs. Letrozole as adjuvant therapy for postmenopausal early breast cancer patients: results of a multicenter open randomized study

Abstract

A prospective randomized phase II trial was conducted to evaluate the time course effects of toremifene (TOR) and letrozole (LET), as adjuvant hormone therapy, on serum lipid profiles and bone metabolism in estrogen receptor (ER)-positive, postmenopausal breast cancer patients.Fifty-four postmenopausal breast cancer patients [ER positive, HER2 negative, T1–2, node metastases (n = 0–3), M0] who had undergone curative resection were enrolled. They were randomized to receive either TOR 40 mg/day or LET 2.5 mg/day as adjuvant hormone therapy. Serum lipids and bone markers were measured prior to, and again at 6, 12, and 24 months after initiation of treatment. Changes in serum lipids and bone markers were compared. Serum levels of total cholesterol (TC) and low-density lipoprotein cholesterol (LDL-C) were decreased compared with the baseline values at 6 months in 6.5 and 14.0% of patients, respectively, receiving TOR. Lipid levels did not change in patients administered LET. Significant differences were observed in TC and LDL-C between the two groups at 12 and 24 months. In the TOR group, serum bone-specific alkaline phosphatase (BAP) was decreased by 25.0% at 12 months, and serum cross-linked N-telopeptide of type-I collagen (NTx) was decreased by 13.6% at 6 months, and these reductions were maintained for at least 24 months. In contrast, in the LET group, serum BAP did not change and NTx was increased by 16.0% at 6 months and by 18.6% at 24 months, as compared with the baseline.TOR and LET exert different effects on serum lipid profiles and bone metabolism markers. The effects of TOR, as adjuvant hormone therapy, on both lipids and bone metabolism in postmenopausal breast cancer patients are superior to those of LET.

http://ift.tt/2iwi8ET

Serum lipid and bone metabolism effects of Toremifene vs. Letrozole as adjuvant therapy for postmenopausal early breast cancer patients: results of a multicenter open randomized study

Abstract

A prospective randomized phase II trial was conducted to evaluate the time course effects of toremifene (TOR) and letrozole (LET), as adjuvant hormone therapy, on serum lipid profiles and bone metabolism in estrogen receptor (ER)-positive, postmenopausal breast cancer patients.Fifty-four postmenopausal breast cancer patients [ER positive, HER2 negative, T1–2, node metastases (n = 0–3), M0] who had undergone curative resection were enrolled. They were randomized to receive either TOR 40 mg/day or LET 2.5 mg/day as adjuvant hormone therapy. Serum lipids and bone markers were measured prior to, and again at 6, 12, and 24 months after initiation of treatment. Changes in serum lipids and bone markers were compared. Serum levels of total cholesterol (TC) and low-density lipoprotein cholesterol (LDL-C) were decreased compared with the baseline values at 6 months in 6.5 and 14.0% of patients, respectively, receiving TOR. Lipid levels did not change in patients administered LET. Significant differences were observed in TC and LDL-C between the two groups at 12 and 24 months. In the TOR group, serum bone-specific alkaline phosphatase (BAP) was decreased by 25.0% at 12 months, and serum cross-linked N-telopeptide of type-I collagen (NTx) was decreased by 13.6% at 6 months, and these reductions were maintained for at least 24 months. In contrast, in the LET group, serum BAP did not change and NTx was increased by 16.0% at 6 months and by 18.6% at 24 months, as compared with the baseline.TOR and LET exert different effects on serum lipid profiles and bone metabolism markers. The effects of TOR, as adjuvant hormone therapy, on both lipids and bone metabolism in postmenopausal breast cancer patients are superior to those of LET.

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Glut3 Addiction Is a Druggable Vulnerability for a Molecularly Defined Subpopulation of Glioblastoma

Publication date: Available online 30 November 2017
Source:Cancer Cell
Author(s): Érika Cosset, Sten Ilmjärv, Valérie Dutoit, Kathryn Elliott, Tami von Schalscha, Maria F. Camargo, Alexander Reiss, Toshiro Moroishi, Laetitia Seguin, German Gomez, Jung-Soon Moo, Olivier Preynat-Seauve, Karl-Heinz Krause, Hervé Chneiweiss, Jann N. Sarkaria, Kun-Liang Guan, Pierre-Yves Dietrich, Sara M. Weis, Paul S. Mischel, David A. Cheresh
While molecular subtypes of glioblastoma (GBM) are defined using gene expression and mutation profiles, we identify a unique subpopulation based on addiction to the high-affinity glucose transporter, Glut3. Although Glut3 is a known driver of a cancer stem cell phenotype, direct targeting is complicated by its expression in neurons. Using established GBM lines and patient-derived stem cells, we identify a subset of tumors within the "proneural" and "classical" subtypes that are addicted to aberrant signaling from integrin αvβ3, which activates a PAK4-YAP/TAZ signaling axis to enhance Glut3 expression. This defined subpopulation of GBM is highly sensitive to agents that disrupt this pathway, including the integrin antagonist cilengitide, providing a targeted therapeutic strategy for this unique subset of GBM tumors.

Graphical abstract

Teaser

Cosset et al. identify a subset of glioblastoma within the proneural and the classical subtypes that are addicted to aberrant signaling from integrin αvβ3, which activates a PAK4-YAP/TAZ signaling axis to enhance Glut3 expression, and are sensitive to agents disrupting the pathway such as cilengitide.


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Antibody Tumor Targeting Is Enhanced by CD27 Agonists through Myeloid Recruitment

Publication date: Available online 30 November 2017
Source:Cancer Cell
Author(s): Anna H. Turaj, Khiyam Hussain, Kerry L. Cox, Matthew J.J. Rose-Zerilli, James Testa, Lekh N. Dahal, H.T. Claude Chan, Sonya James, Vikki L. Field, Matthew J. Carter, Hyung J. Kim, Jonathan J. West, Lawrence J. Thomas, Li-Zhen He, Tibor Keler, Peter W.M. Johnson, Aymen Al-Shamkhani, Stephen M. Thirdborough, Stephen A. Beers, Mark S. Cragg, Martin J. Glennie, Sean H. Lim
Monoclonal antibodies (mAbs) can destroy tumors by recruiting effectors such as myeloid cells, or targeting immunomodulatory receptors to promote cytotoxic T cell responses. Here, we examined the therapeutic potential of combining a direct tumor-targeting mAb, anti-CD20, with an extended panel of immunomodulatory mAbs. Only the anti-CD27/CD20 combination provided cures. This was apparent in multiple lymphoma models, including huCD27 transgenic mice using the anti-huCD27, varlilumab. Detailed mechanistic analysis using single-cell RNA sequencing demonstrated that anti-CD27 stimulated CD8⁺ T and natural killer cells to release myeloid chemo-attractants and interferon gamma, to elicit myeloid infiltration and macrophage activation. This study demonstrates the therapeutic advantage of using an immunomodulatory mAb to regulate lymphoid cells, which then recruit and activate myeloid cells for enhanced killing of mAb-opsonized tumors.

Graphical abstract

Teaser

Turaj et al. test anti-tumor efficacy of immunomodulatory antibodies combined with anti-CD20 and find that anti-CD27/CD20 has a strong benefit in several tumor models. Anti-CD27 induces IFNγ and chemokines in CD8⁺ T and NK cells, enhancing macrophage infiltration and activation to promote anti-CD20 activity.


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Truncated isoform Vav3.1 is highly expressed in ovarian cancer stem cells and clinically relevant in predicting prognosis and platinum-response

Abstract

Vav3 is a key modulator of GTP-hydrolases of the Rho/Rac family, which are crucially involved in cell proliferation. Vav3 is alternatively spliced in full-length Vav3-alpha and N-terminal truncated Vav3.1 lacking its self-regulatory domains. The aim of this study was to estimate the clinical impact of Vav3 and all other Vav family members in ovarian cancer. Purification of a stem-cell like side-population (SP) from ovarian cancer cell lines was performed by flow cytometry/FACS. Differences in gene expression between SP and NSP were assessed by Gene Array analysis and confirmed by RT-PCR and immunoblot. In addition, Vav mRNA expression was determined in 150 epithelial ovarian cancers. Clinicopathological parameters, platinum-sensitivity and survival were analyzed and associated to Vav expression. SP fractions of ovarian cancer cell lines exhibited marked overexpression of Vav3.1 (P < 0.001). Vav1 and Vav2 did not prove to be of clinicopathologic relevance in ovarian cancer. High Vav3.1 expression correlated with higher FIGO stage and residual disease. Furthermore, Vav3.1 overexpression was associated with poor progression-free (HR = 2.820, P = 0.0001) and overall survival (HR = 2.842, P = 0.0001). Subgroup analyses revealed an impact of Vav3.1 on survival in type-II but not in type-I cancers. Notably, platinum-refractory cancers showed marked overexpression of Vav3.1 compared to other subsets of platinum-sensitivity (15.848 vs. 6.653, P = 0.0001). In conclusion, Vav3.1 is over-expressed in stem-cell like SP fractions and is clinically relevant in the pathophysiology of ovarian cancer. The N-terminal truncated Vav3.1 may be decisively involved in mechanisms causing genuine multi-drug resistance. This article is protected by copyright. All rights reserved.

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Letter to the Editor: Re: The Impact of Overdiagnosis on the Selection of Efficient Lung Cancer Screening Strategies

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Re: Think Before You Leap

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How to Analyse The Spatiotemporal Tumour Samples Needed To Investigate Cancer Evolution: A Case Study using Paired Primary and Recurrent Glioblastoma

Abstract

Many traits of cancer progression (e.g. development of metastases or resistance to therapy) are facilitated by tumour evolution: Darwinian selection of subclones with distinct genotypes or phenotypes that enable such progression. Characterising these subclones provides an opportunity to develop drugs to better target their specific properties but requires the accurate identification of somatic mutations shared across multiple spatiotemporal tumours from the same patient. Current best practices for calling somatic mutations are optimised for single samples, and risk being too conservative to identify shared mutations with low prevalence in some samples. We reasoned that datasets from multiple matched tumours can be used for mutual validation and thus propose an adapted two-stage approach: 1) low-stringency mutation calling to identify mutations shared across samples irrespective of the weight of evidence in a single sample; 2) high-stringency mutation calling to further characterise mutations present in a single sample. We applied our approach to three independent cohorts of paired primary and recurrent glioblastoma tumours, two of which have previously been analysed using existing approaches, and found that it significantly increased the amount of biologically-relevant shared somatic mutations identified. We also found that duplicate removal was detrimental when identifying shared somatic mutations. Our approach is also applicable when multiple datasets e.g. DNA and RNA are available for the same tumour. This article is protected by copyright. All rights reserved.

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Glut3 Addiction Is a Druggable Vulnerability for a Molecularly Defined Subpopulation of Glioblastoma

Publication date: Available online 30 November 2017
Source:Cancer Cell
Author(s): Érika Cosset, Sten Ilmjärv, Valérie Dutoit, Kathryn Elliott, Tami von Schalscha, Maria F. Camargo, Alexander Reiss, Toshiro Moroishi, Laetitia Seguin, German Gomez, Jung-Soon Moo, Olivier Preynat-Seauve, Karl-Heinz Krause, Hervé Chneiweiss, Jann N. Sarkaria, Kun-Liang Guan, Pierre-Yves Dietrich, Sara M. Weis, Paul S. Mischel, David A. Cheresh
While molecular subtypes of glioblastoma (GBM) are defined using gene expression and mutation profiles, we identify a unique subpopulation based on addiction to the high-affinity glucose transporter, Glut3. Although Glut3 is a known driver of a cancer stem cell phenotype, direct targeting is complicated by its expression in neurons. Using established GBM lines and patient-derived stem cells, we identify a subset of tumors within the "proneural" and "classical" subtypes that are addicted to aberrant signaling from integrin αvβ3, which activates a PAK4-YAP/TAZ signaling axis to enhance Glut3 expression. This defined subpopulation of GBM is highly sensitive to agents that disrupt this pathway, including the integrin antagonist cilengitide, providing a targeted therapeutic strategy for this unique subset of GBM tumors.

Graphical abstract

Teaser

Cosset et al. identify a subset of glioblastoma within the proneural and the classical subtypes that are addicted to aberrant signaling from integrin αvβ3, which activates a PAK4-YAP/TAZ signaling axis to enhance Glut3 expression, and are sensitive to agents disrupting the pathway such as cilengitide.


http://ift.tt/2zU7KP7

Antibody Tumor Targeting Is Enhanced by CD27 Agonists through Myeloid Recruitment

Publication date: Available online 30 November 2017
Source:Cancer Cell
Author(s): Anna H. Turaj, Khiyam Hussain, Kerry L. Cox, Matthew J.J. Rose-Zerilli, James Testa, Lekh N. Dahal, H.T. Claude Chan, Sonya James, Vikki L. Field, Matthew J. Carter, Hyung J. Kim, Jonathan J. West, Lawrence J. Thomas, Li-Zhen He, Tibor Keler, Peter W.M. Johnson, Aymen Al-Shamkhani, Stephen M. Thirdborough, Stephen A. Beers, Mark S. Cragg, Martin J. Glennie, Sean H. Lim
Monoclonal antibodies (mAbs) can destroy tumors by recruiting effectors such as myeloid cells, or targeting immunomodulatory receptors to promote cytotoxic T cell responses. Here, we examined the therapeutic potential of combining a direct tumor-targeting mAb, anti-CD20, with an extended panel of immunomodulatory mAbs. Only the anti-CD27/CD20 combination provided cures. This was apparent in multiple lymphoma models, including huCD27 transgenic mice using the anti-huCD27, varlilumab. Detailed mechanistic analysis using single-cell RNA sequencing demonstrated that anti-CD27 stimulated CD8⁺ T and natural killer cells to release myeloid chemo-attractants and interferon gamma, to elicit myeloid infiltration and macrophage activation. This study demonstrates the therapeutic advantage of using an immunomodulatory mAb to regulate lymphoid cells, which then recruit and activate myeloid cells for enhanced killing of mAb-opsonized tumors.

Graphical abstract

Teaser

Turaj et al. test anti-tumor efficacy of immunomodulatory antibodies combined with anti-CD20 and find that anti-CD27/CD20 has a strong benefit in several tumor models. Anti-CD27 induces IFNγ and chemokines in CD8⁺ T and NK cells, enhancing macrophage infiltration and activation to promote anti-CD20 activity.


http://ift.tt/2zRYGtH

Truncated isoform Vav3.1 is highly expressed in ovarian cancer stem cells and clinically relevant in predicting prognosis and platinum-response

Abstract

Vav3 is a key modulator of GTP-hydrolases of the Rho/Rac family, which are crucially involved in cell proliferation. Vav3 is alternatively spliced in full-length Vav3-alpha and N-terminal truncated Vav3.1 lacking its self-regulatory domains. The aim of this study was to estimate the clinical impact of Vav3 and all other Vav family members in ovarian cancer. Purification of a stem-cell like side-population (SP) from ovarian cancer cell lines was performed by flow cytometry/FACS. Differences in gene expression between SP and NSP were assessed by Gene Array analysis and confirmed by RT-PCR and immunoblot. In addition, Vav mRNA expression was determined in 150 epithelial ovarian cancers. Clinicopathological parameters, platinum-sensitivity and survival were analyzed and associated to Vav expression. SP fractions of ovarian cancer cell lines exhibited marked overexpression of Vav3.1 (P < 0.001). Vav1 and Vav2 did not prove to be of clinicopathologic relevance in ovarian cancer. High Vav3.1 expression correlated with higher FIGO stage and residual disease. Furthermore, Vav3.1 overexpression was associated with poor progression-free (HR = 2.820, P = 0.0001) and overall survival (HR = 2.842, P = 0.0001). Subgroup analyses revealed an impact of Vav3.1 on survival in type-II but not in type-I cancers. Notably, platinum-refractory cancers showed marked overexpression of Vav3.1 compared to other subsets of platinum-sensitivity (15.848 vs. 6.653, P = 0.0001). In conclusion, Vav3.1 is over-expressed in stem-cell like SP fractions and is clinically relevant in the pathophysiology of ovarian cancer. The N-terminal truncated Vav3.1 may be decisively involved in mechanisms causing genuine multi-drug resistance. This article is protected by copyright. All rights reserved.

http://ift.tt/2zU7HCV

Letter to the Editor: Re: The Impact of Overdiagnosis on the Selection of Efficient Lung Cancer Screening Strategies

http://ift.tt/2AKMACJ

Re: Think Before You Leap

http://ift.tt/2zU7Cz7

How to Analyse The Spatiotemporal Tumour Samples Needed To Investigate Cancer Evolution: A Case Study using Paired Primary and Recurrent Glioblastoma

Abstract

Many traits of cancer progression (e.g. development of metastases or resistance to therapy) are facilitated by tumour evolution: Darwinian selection of subclones with distinct genotypes or phenotypes that enable such progression. Characterising these subclones provides an opportunity to develop drugs to better target their specific properties but requires the accurate identification of somatic mutations shared across multiple spatiotemporal tumours from the same patient. Current best practices for calling somatic mutations are optimised for single samples, and risk being too conservative to identify shared mutations with low prevalence in some samples. We reasoned that datasets from multiple matched tumours can be used for mutual validation and thus propose an adapted two-stage approach: 1) low-stringency mutation calling to identify mutations shared across samples irrespective of the weight of evidence in a single sample; 2) high-stringency mutation calling to further characterise mutations present in a single sample. We applied our approach to three independent cohorts of paired primary and recurrent glioblastoma tumours, two of which have previously been analysed using existing approaches, and found that it significantly increased the amount of biologically-relevant shared somatic mutations identified. We also found that duplicate removal was detrimental when identifying shared somatic mutations. Our approach is also applicable when multiple datasets e.g. DNA and RNA are available for the same tumour. This article is protected by copyright. All rights reserved.

http://ift.tt/2AKP5VY

Letter to the Editor regarding the paper by F. Cardoso et al. ‘European Breast Cancer Conference manifesto on breast centres/units’

Publication date: December 2017
Source:European Journal of Cancer, Volume 87
Author(s): Gianni Saguatti, Carlo Naldoni, Eva Benelli, Chiara Fedato, Alfonso Frigerio, Vania Galli, Livia Giordano, Paola Golinelli, Doralba Morrone, Adriana Paduos, Fiammetta Querci, Antonio Rizzo, Lauro Bucchi




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Immune checkpoint inhibitor–associated CNS autoimmune disorder (ICICAD) following nivolumab treatment: A new entity of drug-induced autoimmune encephalitis?

Publication date: December 2017
Source:European Journal of Cancer, Volume 87
Author(s): Herwig Strik, Ursula Keber, Wasim Alhaj Hammoud, Jorge Riera-Knorrenschild, Barbara Carl, Richard Dodel, Axel Pagenstecher, Andreas Neubauer




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Re: Androgen deprivation therapy and cardiovascular risk: No meaningful difference between GnRH antagonist and agonists

Publication date: December 2017
Source:European Journal of Cancer, Volume 87
Author(s): Peter C. Albertsen




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Reply to letter from Suguatti et al.

Publication date: December 2017
Source:European Journal of Cancer, Volume 87
Author(s): Luigi Cataliotti, Lorenza Marotti, Marc Beishon, Alberto Costa, Susan Knox, Emiel Rutgers, Fatima Cardoso




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Response to letter – Androgen deprivation therapy and cardiovascular risk: No meaningful difference between GnRH antagonist and agonists

Publication date: December 2017
Source:European Journal of Cancer, Volume 87
Author(s): Lucie-Marie Scailteux




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European Research on Electrochemotherapy in Head and Neck Cancer (EURECA) project: Results from the treatment of mucosal cancers

Publication date: December 2017
Source:European Journal of Cancer, Volume 87
Author(s): Christina Caroline Plaschke, Giulia Bertino, James A. McCaul, Juan J. Grau, Remco de Bree, Gregor Sersa, Antonio Occhini, Ales Groselj, Cristobal Langdon, Derrek A. Heuveling, Maja Cemazar, Primoz Strojan, C. Rene Leemans, Marco Benazzo, Francesca De Terlizzi, Irene Wessel, Julie Gehl
AimElectrochemotherapy is an effective local treatment for cutaneous tumours and metastases. In this prospective trial, six European institutions investigated electrochemotherapy in recurrent, mucosal head and neck tumours.Patient and methodsForty-three patients with recurrent mucosal head and neck tumours and no further curative or reasonably effective palliative treatment options were enrolled and treated with electrochemotherapy. Patients were treated in general anaesthesia using intravenous or local injection of bleomycin followed by delivery of electric pulses to the tumour area. Primary end-point was local tumour response. Secondary end-points were safety and toxicity, overall and progression free survival, and quality-of-life.ResultsThirty-seven patients were evaluable for tumour response, pain score, side-effects and quality of life questionnaires. Six patients were not evaluable due to lost follow-up, disease progression or death before evaluation. Intention to treat analysis revealed an objective response of 56% (complete response 8 (19%), partial response 16 (37%), stable disease 10 (23%), progressive disease 3 (7%), and not evaluable 6 (14%)). Three patients (7%) remained in complete response at 30, 34, and 84 months post-treatment. The treatment procedure was generally well tolerated. Swelling of the mucosa was observed in the first days after treatment. Pain and use of pain medication rose temporarily; fatigue and dysphagia were also noted in the quality of life assessment.ConclusionElectrochemotherapy can be applied to mucosal head and neck recurrent tumours accessible to the procedure with promising objective response, survival and toxicity profile. Attention should be paid to post-treatment swelling and planning of pain medication. These favourable results indicate that electrochemotherapy could play a role in patients with recurrent head and neck cancer.



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Phase 1 and pharmacokinetic study of LY3007113, a p38 MAPK inhibitor, in patients with advanced cancer

Summary

Background The signaling protein p38 mitogen-activated protein kinase (MAPK) regulates the tumor cell microenvironment, modulating cell survival, migration, and invasion. This phase 1 study evaluated the safety of p38 MAPK inhibitor LY3007113 in patients with advanced cancer to establish a recommended phase 2 dose. Methods In part A (dose escalation), LY3007113 was administered orally every 12 h (Q12H) at doses ranging from 20 mg to 200 mg daily on a 28-day cycle until the maximum tolerated dose (MTD) was reached. In part B (dose confirmation), patients received MTD. Safety, pharmacokinetics, pharmacodynamics, and tumor response data were evaluated. Results MTD was 30 mg Q12H. The most frequent treatment-related adverse events (>10%) were tremor, rash, stomatitis, increased blood creatine phosphokinase, and fatigue. Grade ≥ 3 treatment-related adverse events included upper gastrointestinal haemorrhage and increased hepatic enzyme, both occurring at 40 mg Q12H and considered dose-limiting toxicities. LY3007113 exhibited an approximately dose-proportional increase in exposure and time-independent pharmacokinetics after repeated dosing. Maximal inhibition (80%) of primary biomarker MAPK-activated protein kinase 2 in peripheral blood mononuclear cells was not reached, and sustained minimal inhibition (60%) was not maintained for 6 h after dosing to achieve a biologically effective dose (BED). The best overall response in part B was stable disease in 3 of 27 patients. Conclusions The recommended phase 2 dosage of LY3007113 was 30 mg Q12H. Three patients continued treatment after the first radiographic assessment, and the BED was not achieved. Further clinical development of this compound is not planned as toxicity precluded achieving a biologically effective dose.

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