Low dose of lenalidmide and PI3K/mTOR inhibitor trigger synergistic cytoxicity in activated B cell-like subtype of diffuse large B cell lymphoma

Activated B cell-like subtype of diffuse large B cell lymphoma (ABC-DLBCL) presents aggressive clinical courses and poor prognosis. Targeting key pathways may raise the possibility of improving clinical outcomes.

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CCR7 mediates the TNF-α-induced lymphatic metastasis of gallbladder cancer through the “ERK1/2 - AP-1” and “JNK - AP-1” pathways

CC-chemokine receptor 7 (CCR7), which plays an important role in cell directional movement, is highly expressed in various cancers and positively related to lymph node metastasis. The inflammatory cytokine tum...

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Inhibition of Glut1 by WZB117 sensitizes radioresistant breast cancer cells to irradiation

Abstract

Purpose

Breast cancer is the most common type of cancer with high incidence in women. Currently, identifying new therapies that selectively inhibit tumor growth without damaging normal tissue are a major challenge of cancer research. One of the features of cancer cells is that they do not consume more oxygen even under normal oxygen circumstances but prefer to aerobic glycolysis through the enhanced catabolism of glucose and glutamine. In this study, we investigate the mechanisms of the radioresistance in breast cancer cells.

Methods

Human breast cancer cells MDA-MB-231 and MCF-7 were treated with radiation alone, Glut1 inhibitor alone or the combination of both to evaluate cell glucose metabolism and apoptosis. By the establishment of radioresistant cell line, we investigate the mechanisms of the combined treatments of radiation with Glut1 inhibitor in the radioresistant cells.

Results

The glucose metabolism and the expression of Glut1 are significantly stimulated by radiotherapy. We report the radioresistant breast cancer cells exhibit upregulated Glut1 expression and glucose metabolism. In addition, we observed overexpression of Glut1 renders breast cancer cells resistant to radiation and knocking down of Glut1 sensitizes breast cancer cells to radiation. We treated breast cancer cells with radiation and WZB117 which inhibits Glut1 expression and glucose metabolism and found the combination of WZB117 and radiation exhibits synergistically inhibitory effects on breast cancer cells. Finally, we demonstrate the inhibition of Glut1 re-sensitizes the radioresistant cancer cells to radiation.

Conclusions

This study reveals the roles of Glut1 in the radiosensitivity of human breast cancer. It will provide new mechanisms and strategies for the sensitization of cancer cells to radiotherapy through regulation of glucose metabolism.

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Phase I dose escalation study of temsirolimus in combination with metformin in patients with advanced/refractory cancers

Abstract

Purpose

Mammalian target of rapamycin (mTOR) inhibitors like temsirolimus may result in undesirable AKT upregulation. Metformin inhibits mTOR through different mechanisms and may enhance temsirolimus's antitumor activity. We conducted an open-label phase I dose escalation trial of this drug combination in patients with advanced/refractory cancers.

Methods

Temsirolimus, 25 mg weekly, was combined with an escalating daily dose of metformin (level 1: 500; level 2: 1000; level 3: 1500; level 4: 2000 mg) by utilizing a standard 3 + 3 trial design. Treatment was administered in 28-day cycles following initial 2-week metformin titration during the first cycle.

Results

Twenty-one patients (median age, 56 years) with sarcoma (n = 8), colorectal (n = 3), endometrial (n = 4), uterine carcinosarcoma (n = 2), ovarian (n = 2), and other (n = 2) cancers were enrolled. Patients had received median of four prior systemic treatments. Two dose-limiting toxicities were observed (grade 3 mucositis, grade 3 renal failure); both patients continued treatment after dose modification. Fifty-six percent patients had stable disease as best response; clinical benefit rate was 22 %. Patients continued treatment for median of 11 weeks.

Conclusions

Combination temsirolimus/metformin was well tolerated with modestly promising effectiveness among this heavily pretreated patient cohort. We recommend a dose of temsirolimus 25 mg weekly and metformin 2000 mg daily for phase II study.

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Enhanced local and systemic anti-melanoma CD8+ T cell responses after memory T cell-based adoptive immunotherapy in mice

Abstract

Adoptive cell transfer (ACT) melanoma immunotherapy typically employs acutely activated effector CD8+ T cells for their ability to rapidly recognize and clear antigen. We have previously observed that effector CD8+ T cells are highly susceptible to melanoma-induced suppression, whereas memory CD8+ T cells are not. Although memory T cells have been presumed to be potentially advantageous for ACT, the kinetics of local and systemic T cell responses after effector and memory ACT have not been compared. B16F10 melanoma cells stably transfected to express very low levels of the lymphocytic choriomeningitis virus (LCMV) peptide GP33 (B16GP33) were inoculated into syngeneic C57BL/6 mice. Equal numbers of bona fide naïve, effector, or memory phenotype GP33-specific CD8+ T cells were adoptively transferred into mice 1 day after B16GP33 inoculation. The efficacy of ACT immunotherapy was kinetically assessed using serial tumor measurements and flow cytometric analyses of local and systemic CD8+ T cell responses. Control of B16GP33 tumor growth, persistence of adoptively transferred CD8+ cells, intratumoral infiltration of CD8+ T cells, and systemic CD8+ T cell responsiveness to GP33 were strongest after ACT of memory CD8+ T cells. Following surgical tumor resection and melanoma tumor challenge, only mice receiving memory T cell-based ACT immunotherapy exhibited durable tumor-specific immunity. These findings demonstrate how the use of non-expanded memory CD8+ T cells may enhance ACT immunotherapeutic efficacy.

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Inhibition of Glut1 by WZB117 sensitizes radioresistant breast cancer cells to irradiation

Abstract

Purpose

Breast cancer is the most common type of cancer with high incidence in women. Currently, identifying new therapies that selectively inhibit tumor growth without damaging normal tissue are a major challenge of cancer research. One of the features of cancer cells is that they do not consume more oxygen even under normal oxygen circumstances but prefer to aerobic glycolysis through the enhanced catabolism of glucose and glutamine. In this study, we investigate the mechanisms of the radioresistance in breast cancer cells.

Methods

Human breast cancer cells MDA-MB-231 and MCF-7 were treated with radiation alone, Glut1 inhibitor alone or the combination of both to evaluate cell glucose metabolism and apoptosis. By the establishment of radioresistant cell line, we investigate the mechanisms of the combined treatments of radiation with Glut1 inhibitor in the radioresistant cells.

Results

The glucose metabolism and the expression of Glut1 are significantly stimulated by radiotherapy. We report the radioresistant breast cancer cells exhibit upregulated Glut1 expression and glucose metabolism. In addition, we observed overexpression of Glut1 renders breast cancer cells resistant to radiation and knocking down of Glut1 sensitizes breast cancer cells to radiation. We treated breast cancer cells with radiation and WZB117 which inhibits Glut1 expression and glucose metabolism and found the combination of WZB117 and radiation exhibits synergistically inhibitory effects on breast cancer cells. Finally, we demonstrate the inhibition of Glut1 re-sensitizes the radioresistant cancer cells to radiation.

Conclusions

This study reveals the roles of Glut1 in the radiosensitivity of human breast cancer. It will provide new mechanisms and strategies for the sensitization of cancer cells to radiotherapy through regulation of glucose metabolism.

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Phase I dose escalation study of temsirolimus in combination with metformin in patients with advanced/refractory cancers

Abstract

Purpose

Mammalian target of rapamycin (mTOR) inhibitors like temsirolimus may result in undesirable AKT upregulation. Metformin inhibits mTOR through different mechanisms and may enhance temsirolimus's antitumor activity. We conducted an open-label phase I dose escalation trial of this drug combination in patients with advanced/refractory cancers.

Methods

Temsirolimus, 25 mg weekly, was combined with an escalating daily dose of metformin (level 1: 500; level 2: 1000; level 3: 1500; level 4: 2000 mg) by utilizing a standard 3 + 3 trial design. Treatment was administered in 28-day cycles following initial 2-week metformin titration during the first cycle.

Results

Twenty-one patients (median age, 56 years) with sarcoma (n = 8), colorectal (n = 3), endometrial (n = 4), uterine carcinosarcoma (n = 2), ovarian (n = 2), and other (n = 2) cancers were enrolled. Patients had received median of four prior systemic treatments. Two dose-limiting toxicities were observed (grade 3 mucositis, grade 3 renal failure); both patients continued treatment after dose modification. Fifty-six percent patients had stable disease as best response; clinical benefit rate was 22 %. Patients continued treatment for median of 11 weeks.

Conclusions

Combination temsirolimus/metformin was well tolerated with modestly promising effectiveness among this heavily pretreated patient cohort. We recommend a dose of temsirolimus 25 mg weekly and metformin 2000 mg daily for phase II study.

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Altered primary chromatin structures and their implications in cancer development

Abstract

Background

Cancer development is a complex process involving both genetic and epigenetic changes. Genetic changes in oncogenes and tumor-suppressor genes are generally considered as primary causes, since these genes may directly regulate cellular growth. In addition, it has been found that changes in epigenetic factors, through mutation or altered gene expression, may contribute to cancer development. In the nucleus of eukaryotic cells DNA and histone proteins form a structure called chromatin which consists of nucleosomes that, like beads on a string, are aligned along the DNA strand. Modifications in chromatin structure are essential for cell type-specific activation or repression of gene transcription, as well as other processes such as DNA repair, DNA replication and chromosome segregation. Alterations in epigenetic factors involved in chromatin dynamics may accelerate cell cycle progression and, ultimately, result in malignant transformation. Abnormal expression of remodeler and modifier enzymes, as well as histone variants, may confer to cancer cells the ability to reprogram their genomes and to yield, maintain or exacerbate malignant hallmarks. At the end, genetic and epigenetic alterations that are encountered in cancer cells may culminate in chromatin changes that may, by altering the quantity and quality of gene expression, promote cancer development.

Methods

During the last decade a vast number of studies has uncovered epigenetic abnormalities that are associated with the (anomalous) packaging and remodeling of chromatin in cancer genomes. In this review I will focus on recently published work dealing with alterations in the primary structure of chromatin resulting from imprecise arrangements of nucleosomes along DNA, and its functional implications for cancer development.

Conclusions

The primary chromatin structure is regulated by a variety of epigenetic mechanisms that may be deregulated through gene mutations and/or gene expression alterations. In recent years, it has become evident that changes in chromatin structure may coincide with the occurrence of cancer hallmarks. The functional interrelationships between such epigenetic alterations and cancer development are just becoming manifest and, therefore, the oncology community should continue to explore the molecular mechanisms governing the primary chromatin structure, both in normal and in cancer cells, in order to improve future approaches for cancer detection, prevention and therapy, as also for circumventing drug resistance.

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Enhanced local and systemic anti-melanoma CD8+ T cell responses after memory T cell-based adoptive immunotherapy in mice

Abstract

Adoptive cell transfer (ACT) melanoma immunotherapy typically employs acutely activated effector CD8+ T cells for their ability to rapidly recognize and clear antigen. We have previously observed that effector CD8+ T cells are highly susceptible to melanoma-induced suppression, whereas memory CD8+ T cells are not. Although memory T cells have been presumed to be potentially advantageous for ACT, the kinetics of local and systemic T cell responses after effector and memory ACT have not been compared. B16F10 melanoma cells stably transfected to express very low levels of the lymphocytic choriomeningitis virus (LCMV) peptide GP33 (B16GP33) were inoculated into syngeneic C57BL/6 mice. Equal numbers of bona fide naïve, effector, or memory phenotype GP33-specific CD8+ T cells were adoptively transferred into mice 1 day after B16GP33 inoculation. The efficacy of ACT immunotherapy was kinetically assessed using serial tumor measurements and flow cytometric analyses of local and systemic CD8+ T cell responses. Control of B16GP33 tumor growth, persistence of adoptively transferred CD8+ cells, intratumoral infiltration of CD8+ T cells, and systemic CD8+ T cell responsiveness to GP33 were strongest after ACT of memory CD8+ T cells. Following surgical tumor resection and melanoma tumor challenge, only mice receiving memory T cell-based ACT immunotherapy exhibited durable tumor-specific immunity. These findings demonstrate how the use of non-expanded memory CD8+ T cells may enhance ACT immunotherapeutic efficacy.

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Accelerated partial breast irradiation: advances and controversies

The management of localized breast cancer has changed dramatically over the past three to four decades. Breast-conserving therapy, which involved lumpectomy followed by adjuvant irradiation, is now widely cons...

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Altered expression of stromal interaction molecule (STIM)-calcium release-activated calcium channel protein (ORAI) and inositol 1,4,5-trisphosphate receptors (IP3Rs) in cancer: will they become a new battlefield for oncotherapy?

The stromal interaction molecule (STIM)-calcium release-activated calcium channel protein (ORAI) and inositol 1,4,5-trisphosphate receptors (IP3Rs) play pivotal roles in the modulation of Ca2+-regulated pathways ...

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mTORC1-Dependent Metabolic Reprogramming Underlies Escape from Glycolysis Addiction in Cancer Cells

Publication date: Available online 24 March 2016
Source:Cancer Cell
Author(s): Raju V. Pusapati, Anneleen Daemen, Catherine Wilson, Wendy Sandoval, Min Gao, Benjamin Haley, Andreas R. Baudy, Georgia Hatzivassiliou, Marie Evangelista, Jeff Settleman
Although glycolysis is substantially elevated in many tumors, therapeutic targeting of glycolysis in cancer patients has not yet been successful, potentially reflecting the metabolic plasticity of tumor cells. In various cancer cells exposed to a continuous glycolytic block, we identified a recurrent reprogramming mechanism involving sustained mTORC1 signaling that underlies escape from glycolytic addiction. Active mTORC1 directs increased glucose flux via the pentose phosphate pathway back into glycolysis, thereby circumventing a glycolysis block and ensuring adequate ATP and biomass production. Combined inhibition of glycolysis and mTORC1 signaling disrupted metabolic reprogramming in tumor cells and inhibited their growth in vitro and in vivo. These findings reveal novel combinatorial therapeutic strategies to realize the potential benefit from targeting the Warburg effect.

Graphical abstract

Teaser

Pusapati et al. identify an mTORC1-dependent mechanism of metabolic rewiring that can allow cancer cells to escape glycolysis dependency and show that, importantly, these glycolysis-independent cells are sensitive to combined treatment with a glycolysis inhibitor and an mTORC1 inhibitor.


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Metformin enhances the response to radiotherapy in diabetic patients with rectal cancer

Abstract

Purpose

Metformin may have anticancer effects and could improve response to radiotherapy in several malignancies. We aimed to investigate the effect of metformin on response to radiotherapy in rectal cancer.

Methods

A total of 543 rectal cancer patients who were treated with neoadjuvant chemoradiotherapy followed by radical surgery from January 2007 to December 2011 were reviewed. Patients were divided into three groups: diabetics taking metformin (n = 42), diabetics not taking metformin (n = 29), and non-diabetics (n = 472). Tumor response and survival were compared between groups.

Results

The rates of N downstaging and tumor regression grades (TRG) 3–4 were significantly higher in diabetics taking metformin (p = 0.006 and p = 0.029, respectively). There were no significant differences between groups in terms of T downstaging and pathologic complete response. On multivariate analysis, metformin use was associated with increased rates of N downstaging and TRG 3–4 (p = 0.003 and p = 0.019, respectively). Recurrence-free survival, disease-free survival, and overall survival rates were not significantly different between groups.

Conclusions

Metformin is associated with higher tumor response rates to radiotherapy in rectal cancer, especially in patients with diabetes.

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Clinical study of harvesting lymph nodes with carbon nanoparticles in advanced gastric cancer: a prospective randomized trial

Abstract

Background

The objective of this study is to evaluate the efficiency and safety of carbon nanoparticles (CNPs) for harvesting lymph nodes (LNs) in cases of advanced gastric cancer (AGC).

Methods

Patients with previously untreated resectable AGC were eligible for inclusion in this study. All patients were randomly allocated to two subgroups. In the experimental group, 1.0 mL of CNP was injected into the subserosa of the stomach around the tumor before gastrectomy with D2 dissection. The same procedure was performed directly without any coloring material in the control arm. Following surgery, LNs were harvested, colored LNs were counted, and the diameters were measured by the investigator and pathologist.

Results

Thirty patients were enrolled in the study. We observed no serious adverse effects related to CNP injection. The rate of stained LNs was 46.6 %. The mean number of harvested LNs was larger in the experimental than in the control group (38.33 vs 28.27, p = 0.041). A smaller diameter of LNs was recorded in the experimental arm (3.32 vs 4.30 mm, p = 0.023). In addition, we developed a model for predicting the total number of LNs based on the data from CNP-stained LNs and metastatic LNs (MLNs).

Conclusions

CNP is a safe material. Surgeons could harvest more LNs in patients with AGC. The harvest of an increased number of smaller diameters of LNs may be beneficial. Further study is warranted to demonstrate the model's practicality.

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Low dose of lenalidmide and PI3K/mTOR inhibitor trigger synergistic cytoxicity in activated B cell-like subtype of diffuse large B cell lymphoma

Abstract

Background

Activated B cell-like subtype of diffuse large B cell lymphoma (ABC-DLBCL) presents aggressive clinical courses and poor prognosis. Targeting key pathways may raise the possibility of improving clinical outcomes.

Methods

The synergetic effects were assessed by CCK-8 assay and measured by isobologram analysis. The NVP-Bez235 and lenalidomide cytotoxicity were measured by flow cytometry, Western Blot and si-RNA transfection. The combined treatment inducing tumor regression in vivo was performed in nude mice of OCI-Ly10 xenograft mouse model.

Results

Low dose of two agents represented significant inhibition of proliferation with CI value < 1. NVP-Bez235 combined with lenalidomide remarkably increased apoptosis through intrinsic pathway by upregulating Bim, Bax and downregulating Bcl-xL. Akt, especially NF-κB, played an important role in the synergetic effects. Cotreatment also induced the cell cycle to be arrested in G0/G1 phase, and decreased S phase by increasing p21 expression, downregulating cyclinA and diminishing CDK2 phosphorylation in Su-DHL2 and OCI-Ly3 but not in OCI-Ly10. Mice treated with NVP-Bez235/lenalidomide represented obvious tumor growth regression and prolonged overall survival.

Conclusions

Our findings demonstrated the synergistic effect of low dose of NVP-Bez235 and lenalidomide in ABC-DLBCL, the underlying mechanism may be multifunctional, involving apoptosis, Akt and NF-κB inactivation and cell cycle arrest. Cotreatment was also effective in vivo. These data pave the way for potential treatment of ABC-DLBCL with combination of NVP-Bez235 and lenalidomide.

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CCR7 mediates the TNF-α-induced lymphatic metastasis of gallbladder cancer through the “ERK1/2 - AP-1” and “JNK - AP-1” pathways

Abstract

Background

CC-chemokine receptor 7 (CCR7), which plays an important role in cell directional movement, is highly expressed in various cancers and positively related to lymph node metastasis. The inflammatory cytokine tumour necrosis factor (TNF)-α promotes tumour progression and lymph node metastasis in gallbladder cancer (GBC). However, the expression of CCR7 in GBC is unclear, and its role in the TNF-α-induced lymphatic metastasis of GBC requires further research.

Methods

The expression of CCR7 in clinical samples was detected by immunohistochemistry, and the relationship between CCR7 and clinicopathological factors or the TNF-α level of the bile was analyzed. After treatment with various concentrations of TNF-α, CCR7 expression in GBC cell lines was measured by Western blotting. The relative luciferase reporter assay, site-directed mutagenesis and chromatin immunoprecipitation were used to analyze the promoter activity and transcriptional regulation of CCR7. MAPKs inhibitors were used to explore the upstream signalling molecules of AP-1. We established a NOZ cell line stably expressing lentiviral CCR7 shRNA that effectively silenced the expression of CCR7, and to determine the role of TNF-α - CCR7 axis in the migration of GBC cells to the lymphatic system by transwell assays and animal experiments.

Results

CCR7 was highly expressed in GBC samples. Higher expression of CCR7 was associated with American Joint Committee on Cancer (AJCC) staging and lymph node metastasis. Moreover, we found that CCR7 expression in GBC tissue was positively correlated with the levels of TNF-α in the bile, and that TNF-α enhanced the promoter activity and protein expression of CCR7 through the "ERK1/2-AP-1" and "JNK-AP-1" pathways. Finally, we revealed that TNF-α could promote GBC cell migration to lymphatic endothelial cells or lymph nodes through upregulation of CCR7 in vitro and in vivo.

Conclusions

Our study suggests that CCR7 is highly expressed in GBC, and mediates the TNF-α-induced lymphatic metastasis of GBC through the "TNF-α - ERK1/2 - AP-1 - CCR7" and "TNF-α - JNK - AP-1 - CCR7" pathways.

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Enhanced local and systemic anti-melanoma CD8+ T cell responses after memory T cell-based adoptive immunotherapy in mice

Abstract

Adoptive cell transfer (ACT) melanoma immunotherapy typically employs acutely activated effector CD8+ T cells for their ability to rapidly recognize and clear antigen. We have previously observed that effector CD8+ T cells are highly susceptible to melanoma-induced suppression, whereas memory CD8+ T cells are not. Although memory T cells have been presumed to be potentially advantageous for ACT, the kinetics of local and systemic T cell responses after effector and memory ACT have not been compared. B16F10 melanoma cells stably transfected to express very low levels of the lymphocytic choriomeningitis virus (LCMV) peptide GP33 (B16GP33) were inoculated into syngeneic C57BL/6 mice. Equal numbers of bona fide naïve, effector, or memory phenotype GP33-specific CD8+ T cells were adoptively transferred into mice 1 day after B16GP33 inoculation. The efficacy of ACT immunotherapy was kinetically assessed using serial tumor measurements and flow cytometric analyses of local and systemic CD8+ T cell responses. Control of B16GP33 tumor growth, persistence of adoptively transferred CD8+ cells, intratumoral infiltration of CD8+ T cells, and systemic CD8+ T cell responsiveness to GP33 were strongest after ACT of memory CD8+ T cells. Following surgical tumor resection and melanoma tumor challenge, only mice receiving memory T cell-based ACT immunotherapy exhibited durable tumor-specific immunity. These findings demonstrate how the use of non-expanded memory CD8+ T cells may enhance ACT immunotherapeutic efficacy.

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Usefulness of diagnostic laparoscopy with 5-aminolevulinic acid (ALA)-mediated photodynamic diagnosis for the detection of peritoneal micrometastasis in advanced gastric cancer after chemotherapy

Abstract

Purpose

Successful cases have shown that conversion surgery after chemotherapy improves the prognosis of advanced gastric cancer. However, it is necessary to carefully select patients who have no unresectable factors prior to surgery. We recently reported that diagnostic laparoscopy with photodynamic diagnosis using oral 5-aminolevulinic acid (ALA-PDD) is a promising tool for diagnosing early peritoneal metastasis in gastric cancer. We herein evaluated the usefulness of this technique for detecting peritoneal metastases of advanced gastric cancer after chemotherapy.

Methods

Diagnostic laparoscopy using sequential white light (WL) and ALA-PDD observations was performed in 38 patients with advanced gastric cancer after chemotherapy. The sensitivity of ALA-PDD for detecting peritoneal disease was compared with that of WL. The relationship between the state of peritoneal metastasis assessed by ALA-PDD and a cytological examination of the peritoneal fluid was evaluated.

Results

Twelve of the 38 patients (32 %) were diagnosed with peritoneal metastases by conventional laparoscopy. However, laparoscopy with ALA-PDD detected peritoneal metastases in 4 (11 %) of the 26 remaining patients. Three of these 4 patients had negative cytological results from the evaluation of the peritoneal fluid.

Conclusions

Diagnostic laparoscopy using ALA-PDD is a useful technique for detecting metastases and determining treatment strategies to select patients with advanced gastric cancer who have received chemotherapy.

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Coffee consumption and the risk of cancer in the Norwegian Women and Cancer (NOWAC) Study

Abstract

An association between coffee consumption and cancer has long been investigated. Coffee consumption among Norwegian women is high, thus this is a favorable population in which to study the impact of coffee on cancer incidence. Information on coffee consumption was collected from 91,767 women at baseline in the Norwegian Women and Cancer Study. These information were applied until follow-up information on coffee consumption, collected 6–8 years after baseline, became available. Multiple imputation was performed as a method for dealing with missing data. Multivariable Cox regression models were used to calculate hazard ratios (HR) for breast, colorectal, lung, and ovarian cancer, as well as cancer at any site. We observed a 17 % reduced risk of colorectal cancer (HR = 0.83, 95 % CI 0.70–0.98, p _{trend across categories of consumption} = 0.10) and a 9 % reduced risk of cancer at any site (HR = 0.91, 95 % CI 0.86–0.97, p _trend = 0.03) in women who drank more than 3 and up to 7 cups/day, compared to women who drank ≤1 cup/day. A significantly increased risk of lung cancer was observed with a heavy coffee consumption (>7 vs. ≤1 cup/day HR = 2.01, 95 % CI 1.47–2.75, p _trend < 0.001). This was most likely caused by residual confounding due to smoking, as no statistically significant association was observed in never smokers (>5 vs. ≤1 cup/day HR = 1.42, 95 % CI 0.44–4.57, p _trend = 0.30). No significant association was found between coffee consumption and the risk of breast or ovarian cancer. In this study, coffee consumption was associated with a modest reduced risk of cancer at any site. Residual confounding due to smoking may have contributed to the positive association between high coffee consumption and the risk of lung cancer.

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Renal cell carcinoma: A nomogram for the CT imaging-inclusive prediction of indolent, non-clear cell renal cortical tumours

Publication date: May 2016
Source:European Journal of Cancer, Volume 59
Author(s): Christoph A. Karlo, Lei Kou, Pier Luigi Di Paolo, Michael W. Kattan, Robert J. Motzer, Paul Russo, Satish K. Tickoo, Oguz Akin, Hedvig Hricak
AimTo develop a nomogram from clinical and computed tomography (CT) data for pre-treatment identification of indolent renal cortical tumours.Patients and methodsA total of 1201 consecutive patients underwent dedicated contrast-enhanced CT prior to nephrectomy for a renal cortical tumour between January 2000 and July 2011. Two radiologists evaluated all tumours on CT for size, necrosis, calcification, contour, renal vein invasion, collecting system invasion, contact with renal sinus fat, multicystic tumour architecture, nodular enhancement, and the degree of nephrographic phase enhancement. CT and clinical predictors (gender, body mass index [BMI], age) were incorporated into the nomogram. We employed multivariable logistic regression analysis to predict tumour type and internally validated the final model using the data from reader 1. External validation was performed by using all data from reader 2. We applied Wilcoxon rank sum test and Fisher's exact test to investigate for differences in tumour size, BMI, age, and differences in CT imaging features between patients with aggressive and those with indolent tumours.Results63.6% (764/1201) of patients had clear-cell or other aggressive non-clear-cell RCC (i.e. papillary RCC type 2, unclassified RCC) and 36.4% (437/1201) had indolent renal cortical tumours (i.e. papillary RCC type 1, chromophobe RCC, angiomyolipoma, or oncocytoma). On CT, indolent tumours were significantly smaller (p < 0.001) than aggressive tumours and significantly associated with well-defined tumour contours (p < 0.001). Aggressive RCC were significantly associated with necrosis, calcification, renal vein invasion, collecting system invasion, contact with renal sinus fat, multicystic tumour architecture, and nodular enhancement (all, p < 0.001). The nomogram's concordance index (C-index) was 0.823 after internal and 0.829 after external validation.Concluding statementWe present a nomogram based on 1201 patients combining CT features with clinical data for the prediction of indolent renal cortical tumours. When externally validated, this nomogram resulted in a C-index of 0.829.



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Mechanism and non-mechanism based imaging biomarkers for assessing biological response to treatment in non-small cell lung cancer

Publication date: May 2016
Source:European Journal of Cancer, Volume 59
Author(s): A. Weller, M.E.R. O'Brien, M. Ahmed, S. Popat, J. Bhosle, F. McDonald, T.A. Yap, Y. Du, I. Vlahos, N.M. deSouza
Therapeutic options in locally advanced non-small cell lung cancer (NSCLC) have expanded in the past decade to include a palate of targeted interventions such as high dose targeted thermal ablations, radiotherapy and growing platform of antibody and small molecule therapies and immunotherapies. Although these therapies have varied mechanisms of action, they often induce changes in tumour architecture and microenvironment such that response is not always accompanied by early reduction in tumour mass, and evaluation by criteria other than size is needed to report more effectively on response. Functional imaging techniques, which probe the tumour and its microenvironment through novel positron emission tomography and magnetic resonance imaging techniques, offer more detailed insights into and quantitation of tumour response than is available on anatomical imaging alone. Use of these biomarkers, or other rational combinations as readouts of pathological response in NSCLC have potential to provide more accurate predictors of treatment outcomes. In this article, the robustness of the more commonly available positron emission tomography and magnetic resonance imaging biomarker indices is examined and the evidence for their application in NSCLC is reviewed.



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Transforming growth factor-β1 in carcinogenesis, progression, and therapy in cervical cancer

Abstract

Transforming growth factor β1 (TGF-β1) is a multifunctional cytokine that plays important roles in cervical tumor formation, invasion, progression, and metastasis. TGF-β1 functions as a tumor inhibitor in precancerous lesions and early stage cancers of cervix whereas as a tumor promoter in later stage. This switch from a tumor inhibitor to a tumor promoter might be due to various alterations in TGF-β signaling pathway, such as mutations or loss of expression of TGF-β receptors and SMAD proteins. Additionally, the oncoproteins of human papillomaviruses have been shown to stimulate TGF-β1 expression, which in turn suppresses host immune surveillance. Thus, in addition to driving tumor cell migration and metastasis, TGF-β1 is believed to play a key role in promoting human papillomavirus infection by weakening host immune defense. In this article, we will discuss the role of TGF-β1 in the expression, carcinogenesis, progression, and therapy in cervical cancers. A better understanding of this cytokine in cervical carcinogenesis is essential for critical evaluation of this cytokine as a potential prognostic marker and therapeutic target.

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MAP4K4 promotes epithelial-mesenchymal transition and metastasis in hepatocellular carcinoma

Abstract

Our previous study has reported that mitogen-activated protein kinase kinase kinase kinase 4 (MAP4K4) regulates the growth and survival of hepatocellular carcinoma (HCC) cells. This study was undertaken to explore the roles of MAP4K4 in the epithelial-mesenchymal transition (EMT) and metastasis in HCC. Effects of overexpression and knockdown of MAP4K4 on the migration, invasion, and EMT of HCC cells were examined. The in vivo role of MAP4K4 in lung metastasis of HCC was determined in nude mice. The relationship between MAP4K4 expression and EMT in human HCC specimens was determined by immunohistochemistry. MAP4K4 overexpression significantly enhanced the migration and invasion of MHCC-97L HCC cells, whereas MAP4K4 silencing hindered the migration and invasion of MHCC-97H HCC cells. MAP4K4-overexpressing cells undergo EMT, which was accompanied by downregulation of E-cadherin and upregulation of vimentin. In contrast, MAP4K4 silencing caused a reversion from a spindle morphology to cobblestone-like morphology and induction of E-cadherin and reduction of vimentin. Pretreatment with chemical inhibitors of JNK and NF-κB abolished MAP4K4-mediated migration, invasion, and regulation of EMT markers in MHCC-97L cells. Ectopic expression of MAP4K4 promoted and knockdown of MAP4K4 inhibited lung metastasis of HCC, which was associated with regulation of JNK and NF-κB signaling and EMT markers. High MAP4K4 immunoreactivity was inversely correlated with E-cadherin and was positively correlated with vimentin, phospho-JNK, and phospho-NF-κB in HCC specimens. Taken together, MAP4K4 promotes the EMT and invasiveness of HCC cells largely via activation of JNK and NF-κB signaling.

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Transforming growth factor-β1 in carcinogenesis, progression, and therapy in cervical cancer

Abstract

Transforming growth factor β1 (TGF-β1) is a multifunctional cytokine that plays important roles in cervical tumor formation, invasion, progression, and metastasis. TGF-β1 functions as a tumor inhibitor in precancerous lesions and early stage cancers of cervix whereas as a tumor promoter in later stage. This switch from a tumor inhibitor to a tumor promoter might be due to various alterations in TGF-β signaling pathway, such as mutations or loss of expression of TGF-β receptors and SMAD proteins. Additionally, the oncoproteins of human papillomaviruses have been shown to stimulate TGF-β1 expression, which in turn suppresses host immune surveillance. Thus, in addition to driving tumor cell migration and metastasis, TGF-β1 is believed to play a key role in promoting human papillomavirus infection by weakening host immune defense. In this article, we will discuss the role of TGF-β1 in the expression, carcinogenesis, progression, and therapy in cervical cancers. A better understanding of this cytokine in cervical carcinogenesis is essential for critical evaluation of this cytokine as a potential prognostic marker and therapeutic target.

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Effect of traditional resistance and power training using rated perceived exertion for enhancement of muscle strength, power, and functional performance

Abstract

The present study compared the effects of 12 weeks of traditional resistance training and power training using rated perceived exertion (RPE) to determine training intensity on improvements in strength, muscle power, and ability to perform functional task in older women. Thirty healthy elderly women (60–75 years) were randomly assigned to traditional resistance training group (TRT; n = 15) or power training group (PT; n = 15). Participants trained twice a week for 12 weeks using six exercises. The training protocol was designed to ascertain that participants exercised at an RPE of 13–18 (on a 6–20 scale). Maximal dynamic strength, muscle power, and functional performance of lower limb muscles were assessed. Maximal dynamic strength muscle strength leg press (≈58 %) and knee extension (≈20 %) increased significantly (p < 0.001) and similarly in both groups after training. Muscle power also increased with training (≈27 %; p < 0.05), with no difference between groups. Both groups also improved their functional performance after training period (≈13 %; p < 0.001), with no difference between groups. The present study showed that TRT and PT using RPE scale to control intensity were significantly and similarly effective in improving maximal strength, muscle power, and functional performance of lower limbs in elderly women.

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Piloting prostate cancer patient-reported outcomesin clinical practice

Abstract

Purpose

The expanded prostate cancer index composite-26 (EPIC-26) instrument is a validated research tool used for capturing patient-reported quality-of-life outcomes related to the domains of bowel, bladder, and sexual functioning for men undergoing curative treatment for prostate cancer. The purpose of this pilot study was to explore the perceptions and experiences of clinicians with using EPIC-26 in a clinical setting for patients receiving curative radiotherapy.

Methods

Ten clinicians reviewed EPIC-26 scores either before or during weekly clinical encounters with patients receiving curative radiation treatment for prostate cancer. After a period of 2 months, clinicians underwent individual semi-structured interviews where they were asked about their views on measuring patient-reported outcomes in practice, the value of EPIC-26, impressions on patient acceptability, and operational issues.

Results

There was a general willingness and acceptance by clinicians to use EPIC-26 for routine clinical practice. Clinician participants found EPIC-26 to be generally informative, and added value to the clinical encounter by providing additional information that was specific to prostate cancer patients. EPIC-26 was also felt to improve overall communication and provide additional insight into the patient experience.

Conclusions

Our qualitative findings suggest that there may be a role for incorporating patient-reported outcome measure assessment tools like EPIC-26 routinely into clinical practice. However, further qualitative and quantitative research is required in order to assess the impact of patient-reported outcome information on communication, patient and clinician satisfaction, and how these and other related outcomes can be used for guiding treatment decision-making.

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α V β 3 integrin-targeted microSPECT/CT imaging of inflamed atherosclerotic plaques in mice

Abstract

Background

α_Vβ₃-integrin is expressed by activated endothelial cells and macrophages in atherosclerotic plaques and may represent a valuable marker of high-risk plaques. We evaluated ^99mTc-maraciclatide, an integrin-specific tracer, for imaging vascular inflammation in atherosclerotic lesions in mice.

Methods

Apolipoprotein E-negative (ApoE^−/−) mice on a Western diet (n = 10) and normally fed adult C57BL/6 control mice (n = 4) were injected with ^99mTc-maraciclatide (51.8 ± 3.7 MBq). A blocking peptide was infused in three ApoE^−/− mice; this condition served as another control. After 90 min, the animals were imaged via single-photon emission computed tomography (SPECT). While maintained in the same position, the mice were transferred to computed tomography (CT) to obtain contrast-enhanced images of the aortic arch. Images from both modalities were fused, and signal was quantified in the aortic arch and in the vena cava for subtraction of blood-pool activity. The aorta was carefully dissected after imaging for gamma counting, autoradiography, and histology.

Results

Tracer uptake was significantly higher in ApoE^−/− mice than in both groups of control mice (1.56 ± 0.33 vs. 0.82 ± 0.24 vs. 0.98 ± 0.11, respectively; P = 0.006). Furthermore, higher tracer activity was detected via gamma counting in the aorta of hypercholesterolemic mice than in both groups of control mice (1.52 ± 0.43 vs. 0.78 ± 0.19 vs. 0.47 ± 0.31 ^99mTc-maraciclatide %ID/g, respectively; P = 0.018). Autoradiography showed significantly higher tracer uptake in the atherosclerotic aorta than in the control aorta (P = 0.026). Finally, in the atherosclerotic aorta, immunostaining indicated that the integrin signal came predominantly from macrophages and was correlated with the macrophage CD68 immunomarker (r = 0.73).

Conclusions

^99mTc-maraciclatide allows in vivo detection of inflamed atherosclerotic plaques in mice and may represent a non-invasive approach for identifying high-risk plaques in patients.

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Association between patient-provider communication and lung cancer stigma

Abstract

Purpose

The majority (95 %) of lung cancer patients report stigma, with 48 % of lung cancer patients specifically reporting feeling stigmatized by their medical providers. Typically associated with the causal link to smoking and the historically poor prognosis, lung cancer stigma can be seen as a risk factor for poor psychosocial and medical outcomes in the context of lung cancer diagnosis and treatment. Thus, modifiable targets for lung cancer stigma-reducing interventions are needed. The present study sought to test the hypothesis that good patient-provider communication is associated with lower levels of lung cancer stigma.

Methods

Lung cancer patients (n = 231) across varying stages of disease participated in a cross-sectional, multisite study designed to understand lung cancer stigma. Patients completed several survey measures, including demographic and clinical characteristics, a measure of patient-provider communication (Consumer Assessment of Healthcare Providers and Systems Program or CAHPS), and a measure of lung cancer stigma (Cataldo Lung Cancer Stigma Scale).

Results

As hypothesized, results indicated that good patient-provider communication was associated with lower levels of lung cancer stigma (r = −0.18, p < 0.05). These results remained significant, even when controlling for relevant demographic and clinical characteristics (Stan. β = −0.15, p < 0.05).

Conclusions

Results indicate that good patient-provider communication is associated with lower levels of lung cancer stigma, suggesting that improving patient-provider communication may be a good intervention target for reducing lung cancer stigma.

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The development of an evidenced-based and clinically trialled Oral Health Protocol for Paediatric Oncology Patients at the Women’s and Children’s Hospital, Adelaide, South Australia

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Aromatase inhibitor induced musculoskeletal syndrome: a significant problem with limited treatment options

Abstract

Background

Aromatase inhibitor induced musculoskeletal syndrome is experienced by approximately half of women taking aromatase inhibitors, impairing quality of life and leading some to discontinue treatment. Evidence for effective treatments is lacking. We aimed to understand the manifestations and impact of this syndrome in the Australian breast cancer community, and strategies used for its management.

Methods

A survey invitation was sent to 2390 members of the Breast Cancer Network Australia Review and Survey Group in April 2014. The online questionnaire included 45 questions covering demographics, aromatase inhibitor use, clinical manifestations and risk factors for the aromatase inhibitor musculoskeletal syndrome, reasons for treatment discontinuation and efficacy of interventions used.

Results

Aromatase inhibitor induced musculoskeletal syndrome was reported by 302 (82 %) of 370 respondents. Twenty-seven percent had discontinued treatment for any reason and of these, 68 % discontinued because of the musculoskeletal syndrome. Eighty-one percent had used at least one intervention from the following three categories to manage the syndrome: doctor prescribed medications, over-the-counter/complementary medicines or alternative/non-drug therapies. Anti-inflammatories, paracetamol (acetaminophen) and yoga were most successful in relieving symptoms in each of the respective categories. Almost a third of respondents reported that one or more interventions helped prevent aromatase inhibitor discontinuation. However, approximately 20 % of respondents found no intervention effective in any category.

Conclusion

We conclude that aromatase inhibitor induced musculoskeletal syndrome is a significant issue for Australian women and is an important reason for treatment discontinuation. Women use a variety of interventions to manage this syndrome; however, their efficacy appears limited.

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Chemotherapy-induced gut toxicity and pain: involvement of TLRs

Abstract

Purpose

Chemotherapy-induced gut toxicity is associated with significant pain, and pain influences gut function. Toll-like receptors (TLRs) that regulate gut homeostasis are activated by tissue damage and microbes, and their altered expression following chemotherapy may change cellular responses. This study examined the interaction between chemotherapy-induced gut toxicity and pain and related these to gut TLR and glial fibrillary acidic protein (GFAP) expression.

Methods

Female tumor bearing Dark Agouti rats received irinotecan (175 mg/kg, n = 34) or vehicle (n = 5) and were assessed over 120 h for gut toxicity (diarrhea, weight loss), pain (facial), and GFAP, TLR2, 4, 5, and 9 gut expression.

Results

Irinotecan caused diarrhea (72 % of animals grade ≥ 1), weight loss (11.1 ± 6.6 %, P < 0.0001), and pain (5 (0–5), P < 0.0001) all peaking at 72 h. Higher pain scores were observed in rats with diarrhea versus those without: median (range) of 2.0 (0–5) versus 0 (0–5), P = 0.01. Irinotecan also caused a decrease in TLR4 and 5, and an increase in GFAP expression in jejuna crypt at 96 and 120 h (all P < 0.05); with lower TLR4 expression associated with lower pain (P = 0.012).

Conclusions

The association between gut toxicity and pain suggests these toxicities are linked, possibly via TLR-mediated inflammatory pathways. Further, as TLR4 and 5 expression was absent during recovery in the jejuna and GFAP expression was increased in the jejuna, this implies expression of these may be critical in the healing phase following chemotherapy. Detailed studies of gut TLRs and GFAP are now warranted.

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Changes in physical functioning and muscle strength in men receiving androgen deprivation therapy for prostate cancer: a controlled comparison

Abstract

Purpose

The purpose of the study is to examine changes in muscle strength and self-reported physical functioning in men receiving androgen deprivation therapy (ADT) for prostate cancer compared to matched controls.

Methods

Prostate cancer patients scheduled to begin ADT (n = 62) were assessed within 20 days of starting ADT and 6 and 12 months later. Age and geographically matched prostate cancer controls treated with prostatectomy only (n = 86) were assessed at similar time intervals. Grip strength measured upper body strength, the Chair Rise Test measured lower body strength, and the SF-12 Physical Functioning scale measured self-reported physical functioning.

Results

As expected, self-reported physical functioning and upper body muscle strength declined in ADT recipients but remained stable in prostate cancer controls. Contrary to expectations, lower body muscle strength remained stable in ADT recipients but improved in prostate cancer controls. Higher Gleason scores, more medical comorbidities, and less exercise at baseline predicted greater declines in physical functioning in ADT recipients.

Conclusions

ADT is associated with declines in self-reported physical functioning and upper body muscle strength as well as worse lower body muscle strength relative to prostate cancer controls. These findings should be included in patient education regarding the risks and benefits of ADT. Findings also underscore the importance of conducting research on ways to prevent or reverse declines in physical functioning in this patient population.

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Do-not-resuscitate orders and related factors among family surrogates of patients in the emergency department

Abstract

Purpose

The purpose of this study was to investigate the prevalence of do-not-resuscitate (DNR) orders and to identify relevant factors influencing the DNR decision-making process by patients' surrogates in the emergency department (ED).

Methods

A prospective, descriptive, and correlational research design was adopted. A total of 200 surrogates of cancer or non-cancer terminal patients, regardless of whether they signed a DNR order, were recruited as subjects after physicians of the emergency department explained the patient's conditions, advised on withholding medical treatment, and provided information on palliative care to all surrogates.

Results

Of the 200 surrogates, 23 % signed a DNR order for the patients. The demographic characteristics of patients and surrogates, the level of understanding of DNR orders, and factors of the DNR decision had no significant influence on the DNR decision. However, greater severity of disease (odds ratio (OR) = 1.38; 95 % confidence interval (CI) = 0.95–1.74), physician's initiative in discussing with the families (OR = 1.42; 95 % CI = 1.21–1.84), and longer length of hospital stay (OR = 1.06; 95 % CI = 1.03–1.08) were contributing factors affecting patient surrogates' DNR decisions.

Conclusions

The findings of this study indicated that surrogates of patients who were more severe in disease condition, whose physicians initiated the discussion of palliative care, and who stayed longer in hospital were important factors affecting the surrogates' DNR decision-making. Therefore, early initiation of DNR discussions is suggested to improve end-of-life care.

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Polypharmacy in the terminal stage of cancer

Abstracts

Purpose

This study aims to determine the numbers of patients with advanced cancer receiving polypharmacy at the end of their lives and analyze differences in drug prescription at a general oncology ward and a dedicated palliative care ward.

Methods

A retrospective single-center cohort study at a university hospital with a large cancer center was conducted. The charts of 100 patients who had died because of advanced cancer were reviewed; data concerning sociodemographic variables and medications were collected at four predefined time points (9, 6, 3, 0 days before death).

Results

Nine days before death, polypharmacy was registered in 95 % of patients; they had prescriptions for 11 (9–13) different medications per day (median, IQR). Although this number dropped significantly, on the last day as many as 61 % of the patients were still taking more than 4 drugs (median 6.5, IQR 4–9). No significant difference was noted between the oncology ward and the palliative care ward. Polypharmacy was largely dependent on the patients' ECOG performance status as well as the type of ward, the number of days before death, and age. It was not influenced by gender, the duration of hospital stays, and the devices facilitating drug administration. The medications fulfilled the requirements of palliative care in the majority of patients; 90 % received treatment for pain and anxiety. Patients treated at the palliative ward received more opioids and psychoactive drugs while those at the oncology ward received more anti-cancer drugs and fluids.

Conclusions

Polypharmacy still is a problem in the large majority of patients with terminal cancer. Further studies should be focused on the patients' quality of life, drug interactions, and adverse events.

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Symptom burden in long-term germ cell tumor survivors

Abstract

Purpose

Testicular germ cell tumor (GCT) and its treatment may cause distressing long-term symptoms. We aimed to examine self-reported symptom frequency and distress as well as the impact of demographic and medical characteristics in GCT survivors.

Methods

A total of 164 GCT survivors receiving follow-up care at the University Cancer Center Hamburg and a specialized private practice facility were interviewed at a median time of 11.6 years after first diagnosis. Metastatic disease was present in 48 % of the patients and relapse had occurred in 17 %. The patients completed the short form of the Memorial Symptom Assessment Scale (MSAS-SF) assessing 28 physical and 4 psychological symptoms.

Results

The mean number of physical symptoms was 4.5 (SD = 4.3) (psychological symptoms M = 1.4, SD = 1.4; total M = 5.9, SD = 5.2). The most frequent physical symptoms were lack of energy (49 %), feeling drowsy (42 %), sleeping problems (36 %), and difficulty in concentration (32 %). Lack of energy was experienced as highly distressing by 21 % of the patients. The most frequent psychological symptoms were irritability (47 %) and being worried (42 %). The number of physical symptoms was associated with higher age, lower socioeconomic status, and shorter time since diagnosis in multivariate regression analyses controlling for metastatic vs. localized disease, relapse, extent of surgery, number of chemotherapy cycles, and radiotherapy.

Conclusions

GCT survivors suffered from a significant number of long-term symptoms. Fatigue-related symptoms were most frequent and perceived as highly distressing. Continuous attention toward fatigue is necessary throughout follow-up care to offer support in time, particularly in more vulnerable patients of higher age and lower socioeconomic status.

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A qualitative exploration of fear of cancer recurrence (FCR) amongst Australian and Canadian breast cancer survivors

Abstract

Purpose

Few studies have explored coping strategies used by cancer survivors to deal with fear of cancer recurrence (FCR), and little research has been conducted on the specific content of recurrence fears. This study aims to qualitatively explore the strategies used by younger breast cancer survivors to cope with FCR and whether women with low, medium and high levels of FCR employ different coping strategies. An additional aim was to understand the specific content of worst recurrence fears.

Method

Twenty Australian and 10 Canadian women aged ≤45 years diagnosed with stages 0–II disease at least 1 year prior completed telephone interviews. The transcripts of audio-taped interviews were analysed using the qualitative methodology of transcendental realism.

Results

Women with higher FCR described using distraction and avoidance and fewer coping skills. The fear of death was a common worst fear at all levels of FCR. However, participants with higher FCR described more elaborate fears of death often involving themes of pain and suffering. Cross-cultural differences were not observed.

Conclusions

Women with higher FCR report using fewer and more avoidance-based coping techniques. Whilst many participants feared death, those with higher FCR reported more elaborate death fears. Women with high levels of FCR may benefit from learning a greater repertoire of coping skills. Understanding the specific content of FCR can help refine existing psychological treatment protocols for FCR. Implications for FCR treatment are discussed.

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Prediction of critical weight loss during radiation treatment in head and neck cancer patients is dependent on BMI

Abstract

Purpose

The aims of the present study were to explore pre-treatment predictors of weight loss during radiation treatment only in head and neck cancer (HNSCC) patients and investigate the weight loss in patients with or without a feeding tube.

Methods

Retrospectively, weight change during curative radiotherapy was investigated in 476 consecutive HNSCC patients. Independent predictors were identified using multivariate regression analysis with weight loss below or above 5 % as the primary dependent variable.

Results

Baseline BMI, tumor site, and stage predicted weight loss above 5 %. The odds of weight loss above 5 % in patients with BMI >25 were 3.00 ± 0.64 times higher compared with patients with BMI <25 (p < 0.0001). Patients with pharyngeal, oral cavity, or supraglottic tumors had 3.12 ± 0.80 times higher odds of weight loss above 5 % compared with glottic cancer patients (p < 0.0001), and the odds were 1.68 ± 0.40 times higher in stage III–IV patients compared with stage I–II patients (p = 0.03). Seperate analyses revealed that tumor site and stage only predicted weight loss in patients with BMI >25 but not in patients with BMI <25. Patients receiving a feeding tube weighed less than patients without (73.8 vs 78.3 kg) and feeding tube reduced, but did not prevent, weight loss which averaged 6.7 ± 4.7 kg (7.4 ± 4.7 %) compared with 4.7 ± 5.9 kg (5.5 ± 6.0 %) in patients without a feeding tube (P < 0.0001).

Conclusion

Pre-treatment BMI, tumor site and stage predicted weight loss above 5 % in HNSCC patients during radiotherapy. BMI should be considered when analyzing weight loss in HNSCC patients receiving curative radiotherapy.

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Family caregiving challenges in advanced colorectal cancer: patient and caregiver perspectives

Abstract

Purpose

Family caregivers of advanced colorectal cancer patients may be at increased risk for psychological distress. Yet their key challenges in coping with the patient's illness are not well understood. Soliciting both patient and caregiver perspectives on these challenges would broaden our understanding of the caregiving experience. Thus, the purpose of this research was to identify caregivers' key challenges in coping with their family member's advanced colorectal cancer from the perspective of patients and caregivers.

Methods

Individual, semi-structured qualitative interviews were conducted with 23 advanced colorectal cancer patients and 23 primary family caregivers. Interview data were analyzed via thematic analysis.

Results

In nearly all cases, patient and caregiver reports of the caregiver's key challenge were discrepant. Across patient and caregiver reports, caregivers' key challenges included processing emotions surrounding the patient's initial diagnosis or recurrence and addressing the patient's practical and emotional needs. Other challenges included coping with continual uncertainty regarding the patient's potential functional decline and prognosis and observing the patient suffer from various physical symptoms.

Conclusions

Findings suggest that eliciting the perspectives of both patients and caregivers regarding caregivers' challenges provides a more comprehensive understanding of their experience. Results also point to the need to assist caregivers with the emotional and practical aspects of caregiving.

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Risk of chemotherapy-induced febrile neutropenia in cancer patients receiving pegfilgrastim prophylaxis: does timing of administration matter?

Abstract

Purpose

Contrary to the approved indication for pegfilgrastim prophylaxis, some patients receive it on the same day as the last administration of chemotherapy in clinical practice, which could adversely impact risk of febrile neutropenia (FN). An evaluation of the timing of pegfilgrastim prophylaxis and FN risk was undertaken.

Methods

A retrospective cohort design and data from two US private health care claims repositories were employed. Study population comprised adults who received intermediate/high-risk chemotherapy regimens for solid tumors or non-Hodgkin's lymphoma (NHL) and received pegfilgrastim prophylaxis in ≥1 cycle; all cycles with pegfilgrastim were pooled for analyses. Odds ratios (OR) for FN during the cycle were estimated for patients who received pegfilgrastim on the same day (day 1) as the last administration of chemotherapy versus days 2–4 from chemotherapy completion.

Results

The study population included 45,592 patients who received pegfilgrastim in 179,152 cycles (n = 37,095 in cycle 1); in 12 % of cycles, patients received pegfilgrastim on the same day as chemotherapy. Odds of FN were higher for patients receiving pegfilgrastim prophylaxis on the same day as chemotherapy versus days 2–4 from chemotherapy in cycle 1 (OR = 1.6, 95 % CI = 1.3–1.9, p < 0.001) and all cycles (OR = 1.5, 95 % CI = 1.3–1.6, p < 0.001).

Conclusions

In this large-scale evaluation of adults who received intermediate/high-risk regimens for solid tumors or NHL in US clinical practice, FN incidence was found to be significantly higher among those who received pegfilgrastim prophylaxis on the same day as chemotherapy completion versus days 2–4 from chemotherapy completion, underscoring the importance of adhering to the indicated administration schedule.

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Hope, emotion regulation, and psychosocial well-being in patients newly diagnosed with cancer

Abstract

Purpose

Patients newly diagnosed with cancer are often confronted with feelings of uncertainty and life threat. A significant proportion may report impairments in psychosocial well-being. Previous studies examining protective psychological factors such as hope and emotion regulation (ER) have yet to investigate these processes concurrently within a common self-regulation framework and/or focus on newly diagnosed patients. The present study aimed to examine how hope and ER may relate to psychosocial outcomes of patients newly diagnosed with cancer.

Methods

The present study used a cross-sectional design with self-report questionnaires. Participants were newly diagnosed patients (N = 101) recruited from three cancer therapy clinics in a hospital. Patients completed measures of hope, ER (cognitive reappraisal and expressive suppression), and psychosocial well-being (life satisfaction and negative affectivity).

Results

Findings showed that (1) hope and reappraisal, but not suppression, were associated with well-being and (2) the interaction between hope and reappraisal was associated with well-being; reappraisal was not associated with well-being in high hope patients, while high reappraisal was associated with better well-being in low hope patients.

Conclusion

Individual differences in hope and reappraisal appeared to be associated with psychosocial outcomes in newly diagnosed cancer patients. Hopeful thinking appeared to benefit patients' psychosocial well-being. In addition, an interaction effect between hope and reappraisal suggested that reappraisal as an ER strategy may be particularly adaptive for patients with low hope.

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Efficacy of venlafaxine for the relief of taxane and oxaliplatin-induced acute neurotoxicity: a single-center retrospective case–control study

Abstract

Background

Oxaliplatin and taxane-induced neurosensory toxicity is dose-limiting and mostly presents with acute symptoms that affect the activities of daily living and overall quality of life. The objective of the present study is to assess the relief of acute neuropathy with venlafaxine treatment during the chemotherapy period.

Patients and methods

In this retrospective case–control study, from January 2010 to February 2015, patients who experienced treatment with oxaliplatin and taxane-induced acute neurotoxicity were evaluated according to the NCI-CTCAE v. 4.03 grading scale. Neurotoxicity was evaluated using a numeric rating scale (NRS) for pain intensity and experienced relief under the treatment of venlafaxine and using a neuropathic pain symptom inventory scale (NPSI) for the style of complaints. Patients who were diagnosed as mildly depressed according to the HOST anxiety and depression scale and who had grade 1 to 3 sensory neurotoxicity based on the NCI-CTCAE v. 4.03 grading scale, and who also reported ≥4/10 on a NRS were eligible. The primary end point was the rate of more than 75 % symptomatic relief under venlafaxine treatment.

Results

Two hundred six patients were included (82 % female, median age: 52.7 years). Most patients had breast, gynecologic, and colon cancer (93.4 %). Ninety-one patients who received venlafaxine and 115 patients as the control group were assessed for neurotoxicity every 3 weeks. Based on the NRS, a rate of more than 75 % symptomatic relief was 53.5, 58.3, and45.2 % in venlafaxine arm versus 0, 0, and 0 % in the control arm in the first, second, and third visits, respectively. Side-effects of venlafaxine (n = 7) were grade 1–2 nausea/vomiting (3.2 %) and asthenia/somnolence (3.2 %) without grade 3–4 events.

Conclusion

Venlafaxine has a significant clinical activity against taxane-oxaliplatin-induced acute neurosensory toxicity.

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Quality of life and symptom burden in patients with breast cancer treated with mastectomy and lumpectomy

Abstract

Introduction

Mastectomy (MAS) and lumpectomy (LUMP) are the two common local surgical treatments for early breast cancer. There has been a debate whether MAS or LUMP results in better quality of life (QOL). The purpose of this study was to examine the symptom burden (SB) and QOL of both MAS and LUMP patients.

Methods

Patients at the Louise Temerty Breast Cancer Centre in Toronto, Canada, were approached to complete two self-administered questionnaires, the Edmonton Symptom Assessment Score (ESAS) and the Functional Assessment of Cancer Therapy—Breast (FACT-B) cancer edition. Additionally, patient demographics were recorded from medical records. Patients were divided into two cohorts depending on their surgical treatment: MAS and LUMP. The QOL and SB, assessed by FACT-B and ESAS, respectively, of MAS and LUMP patients were compared. The analysis was repeated excluding patients with metastases.

Results

From January to August 2014, 614 MAS and 801 LUMP patients were accrued. The MAS patients reported a lower QOL in all categories, except social well-being. There was however no statistical difference in ESAS scores for MAS and LUMP patients with non-metastatic breast cancer.

Conclusion

This study supports existing literature that SB of MAS and LUMP patients without metastases are similar. QOL of MAS patients including those with metastases was lower than that of LUMP patients.

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Unmet needs mediate the relationship between symptoms and quality of life in breast cancer survivors

Abstract

Purpose

This study aimed to compare the symptoms, unmet needs, and QoL reported by women at 6 months to <2 years and 2 to 5 years following surgery and adjuvant treatment for breast cancer. It also evaluated the relationships among symptoms, unmet needs, and QoL using structural equation modeling.

Methods

In this study, 113 and 137 survivors following breast cancer treatment 6 months to <2 years and 2 to 5 years, respectively, completed the Memorial Symptom Assessment Scale, the Supportive Care Needs Survey-34, and the Medical Outcomes Study 12-item Short Form Health Survey version 2.0 during their medical follow-up.

Results

The mean numbers of symptoms and unmet needs were 5.43 and 3.0, respectively, for survivors at <2 years, and 5.24 and 2.42, respectively, for survivors at 2 to 5 years following treatment. The most common reported symptoms were related primarily to physical domains. No significant differences were found between the two survivor groups on the MSAS scores. Survivors at <2 years reported significantly higher scores in Psychological and Health Care System/Information needs (p < 0.01), and lower composite scores in physical and mental QoL (p < 0.05) than those at 2 to 5 years post-treatment. Significant direct and indirect effects were found of symptom burden through unmet needs on survivors' physical and mental QoL after adjustment for survival time, and the models showed a good fit.

Conclusions

Results suggest that breast cancer survivors continue to endure many symptoms independent of the survivorship period. The unmet needs mediate the relationship between symptom burden and survivors' QoL.

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The incidence and mortality of ovarian cancer and their relationship with the Human Development Index in Asia

Saeid Razi, Mahshid Ghoncheh, Abdollah Mohammadian-Hafshejani, Hojjat Aziznejhad, Mahdi Mohammadian and Hamid Salehiniya

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Analgesic use and risk of renal cell carcinoma: A case-control, cohort, and meta-analytic assessment

Abstract

Analgesics are the most commonly consumed drugs worldwide. Evidence that analgesics increase kidney cancer risk has been mixed. We investigated the association between renal cell carcinoma (RCC) and analgesic use in a large population-based case-control study and a post-trial observational cohort study. Findings were used to update a recent meta-analytic review. We analyzed data from 1,217 RCC cases and 1,235 controls in the US Kidney Cancer Study and 98,807 participants in the US Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial (PLCO: n=137 RCCs). Self-reported acetaminophen, aspirin, and non-steroid anti-inflammatory drug (NSAID) use and duration information was assessed in relation to RCC. For the US Kidney Cancer Study, we calculated odds ratios (ORs) and 95% confidence intervals (CIs) using unconditional logistic regression. For PLCO, we computed hazard ratios (HRs) and 95%CIs using Cox regression. Among case-control participants, RCC risk was associated with over-the-counter acetaminophen use (OR=1.35, 95%CI=1.01-1.83). There was a positive trend with increasing duration (P-trend=0.01), with a two-fold risk for use ≥10 years (OR=2.01, 95%CI=1.30-3.12). No association with prescription acetaminophen use was detected. In PLCO, acetaminophen use was also associated with increased RCC risk (HR=1.68, 95%CI=1.19-2.39), although elevated risk was absent among the few long-term users. No association with RCC risk was detected for aspirin or NSAIDs use in either study. An association between acetaminophen use and kidney cancer was supported by meta-analytic cohort (n=4; summary relative risk=1.34; 95%CI=1.13-1.59; P-_{heterogeneity}=0.40) and case-control (n=9, summary OR=1.20; 95%CI=1.01-1.42; P-_{heterogeneity}=0.05) findings. In brief, acetaminophen use may increase the risk of developing RCC. This article is protected by copyright. All rights reserved.

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Corrigendum

Volume 17, Issue 3, March 2016, pages 336-336<br/>10.1080/15384047.2016.1153924<br/>

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Cisplatin treatment increases stemness via up-regulation of hypoxia inducible factors by IL-6 in non-small cell lung cancer

Summary

Cisplatin-resistant A549 and H157 (A549CisR and H157CisR) non-small cell lung cancer (NSCLC) cells exhibited increased stemness of cancer stem cells (CSCs) compared to their parental cells. We investigated whether IL-6 signaling contributes to this increased stemness in cisplatin-resistant cells. When A549CisR and H157CisR cells were treated with neutralizing IL-6 antibody, decreased cisplatin-resistance was observed while IL-6 treatment of parental cells resulted in increased cisplatin-resistance. Expression of the CSC markers was significantly up-regulated in IL-6 expressing sc cells (in vitro) and sc cell-derived tumor tissues (in vivo) upon cisplatin treatment, but not in IL-6 (in vitro) cells and in IL-6si cell-derived tumor tissues (in vivo), suggesting the importance of IL-6 signaling in triggering increased stemness during cisplatin-resistance development. Hypoxia inducible factors (HIFs) were up-regulated by IL-6 and responsible for the increased CSC stemness upon cisplatin treatment. Mechanism dissection studies found that up-regulation of HIFs by IL-6 was via transcriptional control and through inhibition of HIFs degradation. Treatment of HIF inhibitor (FM19G11) abolished the up-regulation of CSC markers and increased sphere formations in IL-6 expressing cells upon cisplatin treatment. In all, IL-6 mediated-HIF up-regulation is important in increasing stemness during cisplatin-resistance development, and we suggest that the strategies of inhibiting IL-6 signaling or its downstream HIF molecules can be used as future therapeutic approaches to target CSCs after cisplatin treatment for lung cancer.

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Validation of the chemical compound library screening for TAZ inhibitors by use of green fluorescence protein-fused TAZ

Summary

Transcriptional co-activator with PDZ-binding motif (TAZ) plays versatile roles in cell proliferation and differentiation. TAZ is phosphorylated by large tumor suppressor kinases (LATS1/2), the core kinases of the tumor suppressive Hippo pathway. Phosphorylation induces the cytoplasmic accumulation of TAZ and its degradation. In human cancers, the deregulation of the Hippo pathway and gene amplification enhance TAZ activity. TAZ interacts with TEA domain family members (TEAD), and up-regulates genes implicated in epithelial-mesenchymal transition. TAZ confers stemness to cancer cells. Thus, TAZ activation provides cancer cells with malignant properties and worsens the clinical prognosis. Therefore, TAZ attracts attentions as a therapeutic target in the cancer therapy. We applied 18,606 small chemical compounds to human osteosarcoma U2OS cells expressing green fluorescence protein-fused TAZ (GFP-TAZ), monitored the subcellular localization of GFP-TAZ, and selected 33 compounds that shifted GFP-TAZ to the cytoplasm. Unexpectedly, only a limited number of compounds suppressed TAZ-mediated enhancement of TEAD-responsive reporter activity. Moreover, the compounds that weakened TEAD reporter activity did not necessarily decrease the unphosphorylated TAZ. In this study, we focused on three compounds that decreased both TEAD reporter activity and unphosphorylated TAZ, and treated several human cancer cells with these compounds. One compound did not show a remarkable effect, whereas the other two compounds compromised the cell viability in certain cancer cells. In conclusion, the GFP-TAZ-based assay can be used as the first screening for the compounds that inhibit TAZ and show the anti-cancer property, but to develop anti-cancer drugs, we need the additional assays to select the compounds.

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Effect of P16 status on the quality of life experience during chemoradiation for locally advanced oropharyngeal cancer: A sub-study of randomized trial TROG 02.02 (HeadSTART)

Publication date: Available online 23 March 2016
Source:International Journal of Radiation Oncology*Biology*Physics
Author(s): Jolie Ringash, Richard Fisher, Lester Peters, Andy Trotti, Brian O'Sullivan, June Corry, Lizbeth Kenny, Walter Van Den Bogaert, Chris Wratten, Danny Rischin
PurposeHuman papillomavirus-associated OPC has a favorable prognosis. Current research de-escalates treatment, aiming to improve QOL. Understanding the QOL experience with current standard treatment (chemoradiotherapy) provides context for emerging data. We report the impact of p16 status on QOL for patients with stage III or IV OPC undergoing chemoradiotherapy in an international phase III trial (xx).Methods and MaterialsA subgroup analysis by p16 status was conducted in patients with OPC treated on a phase III randomized trial. The study sub-set with OPC and known p16 status was mainly from Australasia, western Europe, and North America. Of 861 participants, 200 had OPC, known p16 status, and baseline QOL; 82 were p16-, 118 p16+. Radiotherapy (70 Gy/7 weeks) was given concurrently with 3 cycles of either cisplatin (100mg/m2) or cisplatin (75 mg/m2) plus tirapazamine. QOL was measured with the FACT-H&N at baseline, 2,6,12, 23 and 38 months. As no significant difference in QOL score was observed between arms, results by p16 status are reported with arms combined.ResultsP16+ patients were younger, had better ECOG PS, and were less often current smokers. Our primary hypothesis that the change in FACT-H&N score from baseline to 6 months would be more favorable in the p16+ cohort was not met (p16+ -6.3, p16-, -1.8; p=0.14). Baseline mean FACT-H&N score was statistically and clinically significantly better in p16+ patients (111 vs. 102, p<0.001); at 2 months, scores declined in both groups, but more dramatically for p16+ patients. By 12 months, p16+ patients again had superior scores. Higher baseline FACT-H&N score and p16+ status were independent predictors of overall survival.ConclusionsPatients with p16+ OPC exhibited better baseline QOL, but a more dramatic QOL drop with concurrent chemoradiation. Given the favorable prognosis of p16+ OPC, efforts to reduce the QOL burden of treatment are warranted.

Teaser

Among 861 overall participants in a negative phase III randomized trial of concurrent chemoradiotherapy +/- the hypoxic cell cytotoxic agent tirapazamine, a subset of 200 had oropharyngeal cancer (OPC), known p16 status, and quality of life (QOL) data. A comparison of QOL by p16 status showed that patients with p16+ OPC exhibited better baseline QOL, but a more dramatic QOL drop with aggressive concurrent chemoradiation.


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Darwinian dynamics of intratumoral heterogeneity

Spatial heterogeneity in tumors is generally thought to result from branching clonal evolution driven by random mutations that accumulate during tumor development. However, this concept rests on the implicit assumption that cancer cells never evolve to a fitness maximum because they can always acquire mutations that increase proliferative capacity. In this study, we investigated the validity of this assumption. Using evolutionary game theory, we demonstrate that local cancer cell populations will rapidly converge to the fittest phenotype given a stable environment. In such settings, cellular spatial heterogeneity in a tumor will be largely governed by regional variations in environmental conditions, e.g. alterations in blood flow. Model simulations specifically predict a common spatial pattern in which cancer cells at the tumor-host interface exhibit invasion-promoting, rapidly-proliferating phenotypic properties, while cells in the tumor core maximize their population density by promoting supportive tissue infrastructures e.g. to promote angiogenesis. We tested model predictions through detailed quantitative image analysis of phenotypic spatial distribution in histological sections of 10 patients with stage 2 invasive breast cancers. CAIX, GLUT1 and Ki67 were upregulated in the tumor edge consistent with an acid-producing invasive, proliferative phenotype. Cells in the tumor core were 20% denser than the edge, exhibiting upregulation of CAXII, HIF-1Î{plus minus} and cleaved caspase-3, consistent with a more static and less proliferative phenotype. Similarly, vascularity was consistently lower in the tumor center compared to the tumor edges. Lymphocytic immune responses to tumor antigens also trended to higher level in the tumor edge, although this effect did not reach statistical significance. Like invasive species in nature, cancer cells at the leading edge of the tumor possess a different phenotype from cells in the tumor core. Our results suggest that at least some of the molecular heterogeneity in cancer cells in tumors is governed by predictable regional variations in environmental selection forces, arguing against the assumption that cancer cells can evolve toward a local fitness maximum by random accumulation of mutations. Major Findings: Like invasive species in nature, cancer cells at the leading edge of the tumor possess a different phenotype from cells in the tumor core. We conclude that at least some intratumoral heterogeneity in the molecular properties of cancer cells is governed by predictable regional variations in environmental selection forces.

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Engineered Multivalent Therapeutics

Monoclonal antibodies initiated the unprecedented breakthroughs in cancer immunotherapy and are rapidly evolving with multiple therapeutic platforms. One next generation strategy engineers' multivalent proteins that ligate single-chain variable fragments targeting cellular effectors, tumor-associated antigens and cytokines. These developing therapeutics target and regulate cellular effector bioactivity and significantly improve clinical outcomes.

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