Metachronous multiple thymoma with different clinical behavior and pathological findings

Abstract

A 70-year-old woman presented with a nodule in the left hilum on a chest radiograph 3 years before. Another mass emerged caudal to the initial nodule and was diagnosed as thymoma. A surgical specimen revealed two components: an encapsulated rostral nodule and a caudal mass invading the left lung. Histological findings showed that the rostral nodule was a stage 1 type B2 thymoma, whereas the caudal mass was a stage 3 type B3 thymoma. Based on the differences in biological behavior and histological findings, we concluded that these tumors derived from multicentric origin.

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Diffusion tensor imaging in children with tuberous sclerosis complex: tract-based spatial statistics assessment of brain microstructural changes

Abstract

Background

There is evidence of microstructural changes in normal-appearing white matter of patients with tuberous sclerosis complex.

Objective

To evaluate major white matter tracts in children with tuberous sclerosis complex using tract-based spatial statistics diffusion tensor imaging (DTI) analysis.

Materials and methods

Eight children (mean age ± standard deviation: 8.5 ± 5.5 years) with an established diagnosis of tuberous sclerosis complex and 8 age-matched controls were studied. The imaging protocol consisted of T1-weighted high-resolution 3-D spoiled gradient-echo sequence and a spin-echo, echo-planar diffusion-weighted sequence. Differences in the diffusion indices were evaluated using tract-based spatial statistics.

Results

Tract-based spatial statistics showed increased axial diffusivity in the children with tuberous sclerosis complex in the superior and anterior corona radiata, the superior longitudinal fascicle, the inferior fronto-occipital fascicle, the uncinate fascicle and the anterior thalamic radiation. No significant differences were observed in fractional anisotropy, mean diffusivity and radial diffusivity between patients and control subjects. No difference was found in the diffusion indices between the baseline and follow-up examination in the patient group.

Conclusion

Patients with tuberous sclerosis complex have increased axial diffusivity in major white matter tracts, probably related to reduced axonal integrity.

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A new imaging/therapy platform by using external radionuclide ( 192 Ir)

Abstract

Objective

Radionuclides are commonly used as internal radiation sources for diagnostic imaging or external radiation sources for treatment purposes. As most radionuclides have a higher energy level than imaging X-ray tubes, radionuclides are rarely used as a transmission-based external imaging source. In this study, we designed and simulated an imaging model by using ¹⁹²Ir as an external imaging source to investigate the feasibility of this new imaging method. The goal of this study is to build a portable and flexible dual-function platform that can conduct both imaging and radiation treatment by using a single radiation source.

Methods

This study uses the Monte Carlo (MC) method to simulate breast fan beam computed tomography (FBCT) and cone beam computed tomography (CBCT) by using ¹⁹²Ir as an external source. The whole breast phantom is built from a real patient's chest CT data. We designed an imaging model and embedded it into the Electron Gamma Shower (EGS) simulation environment. CBCT and FBCT data were obtained through EGS simulations. Different image processing techniques were applied to the data.

Results

A total of 47 images were reconstructed. Among these images, 16 images have high-density areas (lesions). Comparing with the original CT slices, the lesion volume from both FBCT and CBCT data sets can be identified. CBCT-reconstructed images contain more blurring and noise than FBCT images because of the scattering effects.

Conclusion

The ¹⁹²Ir radionuclide can be used as a possible external radiation source for breast imaging. Considering ¹⁹²Ir's therapeutic application and outcomes from its imaging simulation by this study, a new imaging/therapy platform can be potentially created.

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Best practices for safety improvement through high-volume institutional incident learning: lessons learned from 2 years

Abstract

Objective

Incident learning systems (ILSs) are a key component of improving patient safety in radiation oncology, but the practicalities of ILS implementation can present major challenges. We describe the implementation and best practices derived from 2 years of experience with institutional incident learning, with details on root cause analysis (RCA), a list of key process improvements, and operational aspects of ILS use.

Methods and materials

The structure of the ILS is consistent with recommendations from the American Association of Physicists in Medicine (AAPM). Workflow is analyzed for incident reports from initial reporting to analysis and feedback to the reporter, including staffing required. A system for incident categorization is shown, as well as sample events selected for root cause analysis, and suggestions for providing feedback to users of ILS.

Results

In the first 2 years of the ILS implementation from 2012 to 2014, 1897 near-miss incidents were reported. There is widespread participation in the ILS program across all professional groups inside the department, with at least 75 % of clinical staff having filed at least one report. Total workload for the ILS program is estimated to be approximately one full-time employee, shared by approximately eight team members. Fifteen events were selected for RCA during this period. Eighteen major process improvement projects are described, ranging from issues related to process standardization, automation, staffing, new organization structures, and equipment purchase.

Conclusions

A unique high reporting volume institutional ILS has successfully resulted in numerous improvements in process, safety, and quality. Details for implementation and best practices for incident learning have been presented to allow adaptation in other practices.

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Radiographic changes in lung of patients treated with stereotactic ablative body radiation therapy: low-dose volumes as the driving force for radiographic change

Abstract

Objective

To describe radiographic evidence of radiation pneumonitis (rRP) and fibrosis (rRF) and determine what dosimetric parameters correlate with rRP and rRF after stereotactic ablative radiation therapy (SABR) to the lung.

Methods

Ninety-eight follow-up computed tomography (CT) scans from 32 patients treated by SABR were retrospectively reviewed for CT appearance of rRP and rRF determined by the Ikezoe (≤6 months) and Koenig (≥7 months) systems. The dosimetric correlations for rRP, rRF, and fibrotic volume were analyzed.

Results

There was a 55 % incidence of rRP and 59 % incidence of rRF with a median follow-up of 10 months. Only the low-dose parameters V _2.5, V ₅, V ₇, and V ₁₀ (the volume of lung receiving more than 2.5, 5, 7, and 10 Gy of radiation, respectively) were correlated to the development of rRP (p < 0.05). No parameter correlated with rRF, but V ₅, V ₇, and V ₁₀ trended toward significance. The absolute fibrotic volume was correlated with the planning target volume (p = 0.01) and V ₇ (p = 0.02).

Conclusion

The development of rRP and the fibrotic volume after SABR was correlated with the volume of lung that received lower doses of radiation.

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Novel Treatment Strategies for Brain Metastases in Non-small-cell Lung Cancer

Opinion statement

Brain metastases are common in patients with non-small cell lung cancer (NSCLC), and due to associated poor prognosis, this field is an important area of need for the development of innovative medical therapies. Therapies including local approaches through surgical intervention and/or radiation and evolving systemic therapies have led to improvements in the treatment of brain metastases in patients with lung cancer. Strategies that consider applying advanced radiation techniques to minimize toxicity, intervening early with effective systemic therapies to spare radiation/surgery, testing radiosensitization combinations, and developing drug penetrant molecules have and will continue to define new practice patterns. We believe that in carefully considered asymptomatic patients, first-line systemic therapy may be considered before radiation therapy and small-molecule targeted therapy may provide an opportunity to defer radiation therapy for recurrence or progression of disease. The next several years in oncology drug development will see the reporting on of brain penetrant molecules in oncogene-defined non-small cell lung cancer. Ongoing studies will evaluate immunotherapies in patients with brain metastases with associated endpoints. We hope that continued drug development and carefully designed clinical trials may afford an opportunity to improve the lives of patients with brain metastases.

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Pre- and post-partum seric biochemical variables of Lacaune ewes naturally infected by gastrointestinal parasites

Abstract

The main objective of the present study was to evaluate the biochemical profile of the Lacaune ewes naturally infected by gastrointestinal parasites in the pre- and post-partum period. Ewes with similar age and weight, primiparas in the final stage of gestation, totaling 24 animals were selected. Sampling days were 10 and 2 for pre-partum and 2, 6, and 12 days for post-partum to evaluate total proteins, albumin, globulin, cholesterol, triglycerides, and urea levels, in addition to thiobarbituric acid reactive substances (TBARS), reactive oxygen species (ROS), and glutathione S-transferase (GST). Fecal examination by McMaster method was performed during bleeding, and based on the number of eggs per gram of feces (EPG), the animals were divided into two groups: A (sheep with EPG <1000) and B (sheep with EPG >1000) to evaluate the effect of the parasitic load. Statistical analyses of biochemical parameters and EPG were performed taking into account groups, evaluated each time of sampling and over time, as well as without considering the groups, comparing pre- and post-partum and over time. It was possible to verify that the influence of time had a significant (P < 0.01) impact on cholesterol, triglycerides, total proteins, albumin, globulin, TBARS, and GST specifically among sampling time. When time of collection was considered, there were some differences between groups A and B for the variables: triglycerides (day 6 post-partum) and globulin (day 2 pre-partum). It is concluded that the parasitic load did influence seric levels of the urea, triglycerides, and globulins on a determined time.

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Metachronous multiple thymoma with different clinical behavior and pathological findings

Abstract

A 70-year-old woman presented with a nodule in the left hilum on a chest radiograph 3 years before. Another mass emerged caudal to the initial nodule and was diagnosed as thymoma. A surgical specimen revealed two components: an encapsulated rostral nodule and a caudal mass invading the left lung. Histological findings showed that the rostral nodule was a stage 1 type B2 thymoma, whereas the caudal mass was a stage 3 type B3 thymoma. Based on the differences in biological behavior and histological findings, we concluded that these tumors derived from multicentric origin.

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The tumor promoting roles of erythropoietin/erythropoietin receptor signaling pathway in gastric cancer

Abstract

Erythropoietin (EPO), binding with its receptor (EPOR), plays an important role in erythropoiesis. EPOR is reported to be expressed in various non-hematopoietic cancers, including gastric cancer. Although recombinant human EPO (rhEPO) has been widely used clinically in anemia patients, it remains controversial whether it would promote tumor progression. In this study, we used siRNA interference method to downregulate EPOR expression to investigate the function of EPO/EPOR pathway in human gastric cancer cells. We found EPOR expressed significantly higher in gastric cancer tissues, and also in most gastric cancer cell lines. RhEPO promoted gastric cancer cell proliferation, migration in AGS cells, and promoted cells from G0/G1 stage to G2/M stage, but had no regulation on AGS cell apoptosis. Downregulation of EPOR expression by siRNA interference in AGS cells resulted in no significant effects on proliferation and invasiveness of the cells, but induced apoptosis (p < 0.05). Xenografted gastric tumor model was used to explore the effect of EPOR-overexpression on gastric cancer cells in vivo. Our result showed that overexpression of EPOR enhanced tumor formation in nude mice (p < 0.01). Our results suggest that EPO/EPOR pathway promotes gastric cancer formation, proliferation, migration, and decreases apoptosis.

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Dishevelled proteins are significantly upregulated in chronic lymphocytic leukaemia

Abstract

Dishevelled (DVL) proteins are components of the Wnt signalling pathways, and increased expression is associated with various malignancies. Information on DVLs in chronic lymphatic leukaemia (CLL) is limited. The aim of the present study was to investigate the role of DVLs in CLL cells and association with Wnt pathways downstream of ROR1. DVL1, 2 and 3 were exclusively expressed in CLL cells as compared to normal peripheral blood mononuclear cells (PBMCs). The expression of DVL1 and DVL3 proteins was significantly more pronounced in progressive than in non-progressive disease (p < 0.01), whereas the level of DVL2 was significantly higher in non-progressive as compared to progressive disease (p < 0.001). Treatment of CLL cells with anti-ROR1 specific monoclonal antibodies induced dephosphorylation of ROR1 as well as of tyrosine and serine residues of both DVL2 and DVL3. However, gene silencing of DVLs in the CLL cell line (EHEB) did not induce detectable apoptosis. Non-progressive CLL patients had a different protein activity pattern with regard to Wnt signalling pathway proteins as GSK-3β, β-catenin and AKT as compared to progressive disease. The DVL2 protein may play a role in the activation of signalling pathways in CLL during early stages of the disease, while DVL1 and 3 may have a role in later phases of the leukaemia.

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Sublobar resection versus lobectomy for stage I non-small cell lung cancer: an appropriate choice in elderly patients?

Abstract

Purposes

The aim of this study was to evaluate whether sublobar resection could achieve recurrence and survival rates equivalent to lobectomy in high-risk elderly patients.

Methods

We conducted a retrospective multicenter study that including all consecutive patients (aged >75 years) who underwent operation for clinical stage I non-small cell lung cancer (NSCLC). The clinicopathological data, postoperative morbidity and mortality, recurrence rate and vital status were retrieved. The overall survival, cancer-specific survival and disease-free survival were also assessed.

Results

Two hundred and thirty-nine patients (median age 78 years) were enrolled. Lobectomies were performed in 149 (62.3 %) patients and sublobar resections in 90 (39 segmentectomies, 51 wedge resections). There were no differences in the recurrence rates following lobar versus sublobar resections (19 versus 23 %, respectively; p = 0.5) or the overall survival (p = 0.1), cancer-specific survival (p = 0.3) or disease-free survival (p = 0.1). After adjusting for 1:1 propensity score matching and a matched pair analysis, the results remained unchanged. A tumor size >2 cm and pN2 disease were independent negative prognostic factors in unmatched (p = 0.01 and p = 0.0003, respectively) and matched (p = 0.02 and p = 0.005, respectively) analyses.

Conclusions

High-risk elderly patients may benefit from sublobar resection, which provides an equivalent long-term survival compared to lobectomy.

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nab -Paclitaxel Plus Gemcitabine Versus Gemcitabine in Patients with Metastatic Pancreatic Adenocarcinoma: Canadian Subgroup Analysis of the Phase 3 MPACT Trial

Abstract

Introduction

The phase III MPACT trial in patients with metastatic pancreatic cancer (MPC) demonstrated superior efficacy of nab-paclitaxel (nab-P) plus gemcitabine (Gem) compared with Gem monotherapy, including the primary endpoint of overall survival (OS; median 8.7 vs. 6.6 months; hazard ratio [HR] 0.72; P < 0.001). A significant treatment difference favoring nab-P + Gem over Gem was observed for OS in patients treated in North America. The majority of patients were from the US (88%) with only 12% from Canada. Healthcare systems and treatment patterns are different between the 2 countries, and there is limited published information on outcomes of Canadian patients treated with first-line nab-P + Gem. This analysis evaluated efficacy and safety outcomes in Canadian patients in the MPACT trial.

Methods

Treatment-naive patients with MPC (N = 861) received either nab-P 125 mg/m² + Gem 1000 mg/m² on days 1, 8, and 15 every 4 weeks or Gem 1000 mg/m² weekly for the first 7 of 8 weeks (cycle 1) and then on days 1, 8, and 15 every 4 weeks (cycle ≥2).

Results

The MPACT trial enrolled 63 patients in Canada. Baseline characteristics were well balanced and comparable with those of the intent-to-treat population. Both OS (median 11.9 vs. 7.1 months; HR 0.76; P = 0.373) and progression-free survival (median 7.2 vs. 5.2 months; HR 0.65; P = 0.224) were numerically longer and overall response rate (27% vs. 17%; P = 0.312) was numerically higher with nab-P + Gem vs. Gem. The most common grade ≥3 adverse events with nab-P + Gem vs. Gem were neutropenia (22% vs. 10%), fatigue (34% vs. 33%), and neuropathy (25% vs. 0%).

Conclusion

This subanalysis confirmed that nab-P + Gem is an efficacious treatment option and has a manageable safety profile in patients with MPC treated in Canada.

Trial registration

ClinicalTrials.gov identifier, NCT00844649.

Funding

Celgene Corporation, Summit, NJ, USA.

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Novel Treatment Strategies for Brain Metastases in Non-small-cell Lung Cancer

Opinion statement

Brain metastases are common in patients with non-small cell lung cancer (NSCLC), and due to associated poor prognosis, this field is an important area of need for the development of innovative medical therapies. Therapies including local approaches through surgical intervention and/or radiation and evolving systemic therapies have led to improvements in the treatment of brain metastases in patients with lung cancer. Strategies that consider applying advanced radiation techniques to minimize toxicity, intervening early with effective systemic therapies to spare radiation/surgery, testing radiosensitization combinations, and developing drug penetrant molecules have and will continue to define new practice patterns. We believe that in carefully considered asymptomatic patients, first-line systemic therapy may be considered before radiation therapy and small-molecule targeted therapy may provide an opportunity to defer radiation therapy for recurrence or progression of disease. The next several years in oncology drug development will see the reporting on of brain penetrant molecules in oncogene-defined non-small cell lung cancer. Ongoing studies will evaluate immunotherapies in patients with brain metastases with associated endpoints. We hope that continued drug development and carefully designed clinical trials may afford an opportunity to improve the lives of patients with brain metastases.

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A case of small bowel metastasis from spinal Ewing sarcoma causing intussusception in an adult female

Abstract

Background

Ewing sarcomas are highly aggressive malignant tumours occurring predominantly in the long bones of the extremities in children and young adults. About 20 % of patients will present with metastases at diagnosis with the commonest sites being the lungs, bone and bone marrow. Cases of primary small bowel Ewing sarcomas have been described but are nonetheless exceedingly rare, even more so cases of metastasis to the small bowel.

Case Presentation

We describe a case of vertebral Ewing sarcoma in a 44 year-old female which metastasized to the jejunum causing intussusception.

Conclusions

Ewing's sarcoma is highly aggressive and presence of metastases, overt or subclinical, is thought to be present in almost all patients at diagnosis. As evidenced by our patient, metastatic disease can progress rapidly to cause further complications and confer a poorer survival. The possibility of metastasis, no matter how rare or unlikely the site is, should be considered and actively investigated to expedite treatment of the primary disease.

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IRAK-M Expression in Tumor Cells Supports Colorectal Cancer Progression through Reduction of Antimicrobial Defense and Stabilization of STAT3

Publication date: Available online 14 April 2016
Source:Cancer Cell
Author(s): Rebecca Kesselring, Joachim Glaesner, Andreas Hiergeist, Elisabeth Naschberger, Helmut Neumann, Stefan M. Brunner, Anja K. Wege, Caroline Seebauer, Gudrun Köhl, Susanne Merkl, Roland S. Croner, Christina Hackl, Michael Stürzl, Markus F. Neurath, André Gessner, Hans-Juergen Schlitt, Edward K. Geissler, Stefan Fichtner-Feigl
Colorectal cancer (CRC) is associated with loss of epithelial barrier integrity, which facilitates the interaction of the immunological microenvironment with the luminal microbiome, eliciting tumor-supportive inflammation. An important regulator of intestinal inflammatory responses is IRAK-M, a negative regulator of TLR signaling. Here we investigate the compartment-specific impact of IRAK-M on colorectal carcinogenesis using a mouse model. We demonstrate that IRAK-M is expressed in tumor cells due to combined TLR and Wnt activation. Tumor cell-intrinsic IRAK-M is responsible for regulation of microbial colonization of tumors and STAT3 protein stability in tumor cells, leading to tumor cell proliferation. IRAK-M expression in human CRCs is associated with poor prognosis. These results suggest that IRAK-M may be a potential therapeutic target for CRC treatment.

Graphical abstract

Teaser

Kesselring et al. show that combined TLR and Wnt activation leads to IRAK-M expression in colorectal cancer cells, which is also associated with poor patient prognosis. Tumor cell-intrinsic IRAK-M regulates antimicrobial response and STAT3 stability, both promoting tumor progression.


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Deletion Mutations Keep Kinase Inhibitors in the Loop

Publication date: 11 April 2016
Source:Cancer Cell, Volume 29, Issue 4
Author(s): Daniel M. Freed, Jin H. Park, Ravi Radhakrishnan, Mark A. Lemmon
Effective clinical application of conformationally selective kinase inhibitors requires tailoring drug choice to the tumor's activating mutation(s). In this issue of Cancer Cell, Foster et al. (2016) describe how activating deletions in BRAF, EGFR, and HER2 cause primary resistance to common inhibitors, suggesting strategies for improved inhibitor selection.

Teaser

Effective clinical application of conformationally selective kinase inhibitors requires tailoring drug choice to the tumor's activating mutation(s). In this issue of Cancer Cell, Foster et al. (2016) describe how activating deletions in BRAF, EGFR, and HER2 cause primary resistance to common inhibitors, suggesting strategies for improved inhibitor selection.


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Killing Lymphoma with Smac-Mimetics: As Easy as ABC?

Publication date: 11 April 2016
Source:Cancer Cell, Volume 29, Issue 4
Author(s): Ueli Nachbur, John Silke
Smac-mimetics are compounds that target cellular Inhibitor of APoptosis (cIAP) proteins and induce tumor cell death. In this issue of Cancer Cell, Yang and colleagues (2016) identify cIAPs at the CARD11-MALT1-BCL10 complex in the ABC subtype of diffuse large B cell lymphoma (DLBCL), making this malignancy a prime target for these drugs.

Teaser

Smac-mimetics are compounds that target cellular Inhibitor of APoptosis (cIAP) proteins and induce tumor cell death. In this issue of Cancer Cell, Yang and colleagues (2016) identify cIAPs at the CARD11-MALT1-BCL10 complex in the ABC subtype of diffuse large B cell lymphoma (DLBCL), making this malignancy a prime target for these drugs.


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Blood-Brain Barrier Breakdown Determines Differential Therapeutic Outcome in Genetically Diverse Forms of Medulloblastoma

Publication date: 11 April 2016
Source:Cancer Cell, Volume 29, Issue 4
Author(s): Sylvaine Guerit, Stefan Liebner
Medulloblastoma driven by Wnt/β-catenin and Sonic hedgehog pathway mutations show favorable and poor patient survival upon treatment, respectively. In this Cancer Cell issue, Phoenix and colleagues (2016) report disruption of the blood-brain barrier by Wif1 specifically in Wnt-driven medulloblastoma, resulting in increased treatment response and survival in mouse models.

Teaser

Medulloblastoma driven by Wnt/β-catenin and Sonic hedgehog pathway mutations show favorable and poor patient survival upon treatment, respectively. In this Cancer Cell issue, Phoenix and colleagues (2016) report disruption of the blood-brain barrier by Wif1 specifically in Wnt-driven medulloblastoma, resulting in increased treatment response and survival in mouse models.


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Targeting PI3K Signaling in Cancer: A Cautionary Tale of Two AKTs

Publication date: 11 April 2016
Source:Cancer Cell, Volume 29, Issue 4
Author(s): Jérôme Fortin, Tak W. Mak
AKT inhibitors represent promising therapeutics for cancers with PI3K-AKT pathway hyperactivation. In this issue of Cancer Cell, Wang et al. (2016) report the unexpected finding that ablation of AKT signaling in hepatocytes leads to hepatocellular carcinoma and enhances the incidence of lung metastases in a toxin-induced liver cancer model.

Teaser

AKT inhibitors represent promising therapeutics for cancers with PI3K-AKT pathway hyperactivation. In this issue of Cancer Cell, Wang et al. (2016) report the unexpected finding that ablation of AKT signaling in hepatocytes leads to hepatocellular carcinoma and enhances the incidence of lung metastases in a toxin-induced liver cancer model.


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An Arntl2-Driven Secretome Enables Lung Adenocarcinoma Metastatic Self-Sufficiency

Publication date: Available online 14 April 2016
Source:Cancer Cell
Author(s): Jennifer J. Brady, Chen-Hua Chuang, Peyton G. Greenside, Zoë N. Rogers, Christopher W. Murray, Deborah R. Caswell, Ursula Hartmann, Andrew J. Connolly, E. Alejandro Sweet-Cordero, Anshul Kundaje, Monte M. Winslow
The ability of cancer cells to establish lethal metastatic lesions requires the survival and expansion of single cancer cells at distant sites. The factors controlling the clonal growth ability of individual cancer cells remain poorly understood. Here, we show that high expression of the transcription factor ARNTL2 predicts poor lung adenocarcinoma patient outcome. Arntl2 is required for metastatic ability in vivo and clonal growth in cell culture. Arntl2 drives metastatic self-sufficiency by orchestrating the expression of a complex pro-metastatic secretome. We identify Clock as an Arntl2 partner and functionally validate the matricellular protein Smoc2 as a pro-metastatic secreted factor. These findings shed light on the molecular mechanisms that enable single cancer cells to form allochthonous tumors in foreign tissue environments.

Graphical abstract

Teaser

Brady et al. identify the transcription factor Arntl2 as highly up-regulated and required for metastatic lung cancer, and high levels predict poor patient outcome. Arntl2 interacts with Clock to drive the expression of several secreted factors, including Smoc2, which is shown to have a role in metastasis.


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Defining and Targeting the Oncogenic Drivers of Neuroendocrine Prostate Cancer

Publication date: 11 April 2016
Source:Cancer Cell, Volume 29, Issue 4
Author(s): Brett S. Carver
In this issue of Cancer Cell, Lee and colleagues (2016) define the biologic role of MYCN in promoting prostate tumorigenesis and development of a neuroendocrine phenotype. This has important implications for the clinical management of neuroendocrine prostate cancer as Aurora A kinase inhibitors promoting N-Myc destabilization progress in the clinic.

Teaser

In this issue of Cancer Cell, Lee and colleagues (2016) define the biologic role of MYCN in promoting prostate tumorigenesis and development of a neuroendocrine phenotype. This has important implications for the clinical management of neuroendocrine prostate cancer as Aurora A kinase inhibitors promoting N-Myc destabilization progress in the clinic.


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Glycoholics Anonymous: Cancer Sobers Up with mTORC1

Publication date: 11 April 2016
Source:Cancer Cell, Volume 29, Issue 4
Author(s): Vivian Fu, Toshiro Moroishi, Kun-Liang Guan
In this issue of Cancer Cell, Pusapati et al. (2016) reveal that mTORC1 orchestrates the metabolic reprogramming of cancer cells in response to glycolytic inhibitors, bypassing glycolysis by increasing glutamine uptake and pentose phosphate flux to generate energy and biomass.

Teaser

In this issue of Cancer Cell, Pusapati et al. (2016) reveal that mTORC1 orchestrates the metabolic reprogramming of cancer cells in response to glycolytic inhibitors, bypassing glycolysis by increasing glutamine uptake and pentose phosphate flux to generate energy and biomass.


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Kicking Genomic Profiling to the Curb: How Re-wiring the Phosphoproteome Can Explain Treatment Resistance in Glioma

Publication date: 11 April 2016
Source:Cancer Cell, Volume 29, Issue 4
Author(s): Fred C. Lam, Michael B. Yaffe
In this issue of Cancer Cell, Wei et al. (2016) identify adaptive re-wiring of signaling nodes in glioma as major mechanisms of treatment resistance without genome-wide mutations. Targeting these nodes before treatment blocks resistance and underscores the importance of single-cell phosphoproteomics and network re-wiring in predicting cancer treatment responses.

Teaser

In this issue of Cancer Cell, Wei et al. (2016) identify adaptive re-wiring of signaling nodes in glioma as major mechanisms of treatment resistance without genome-wide mutations. Targeting these nodes before treatment blocks resistance and underscores the importance of single-cell phosphoproteomics and network re-wiring in predicting cancer treatment responses.


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Interfering with CCL5/CCR5 at the Tumor-Stroma Interface

Publication date: 11 April 2016
Source:Cancer Cell, Volume 29, Issue 4
Author(s): Vincenzo Bronte, Emilio Bria
In this issue of Cancer Cell, Halama et al. (2016) further advance chemokine interference as a therapeutic option for cancer by demonstrating the effect of CCR5 blockade in reshaping macrophage polarization toward an anti-tumor functional state in patient-derived tumor models and liver metastases of colorectal cancer patients.

Teaser

In this issue of Cancer Cell, Halama et al. (2016) further advance chemokine interference as a therapeutic option for cancer by demonstrating the effect of CCR5 blockade in reshaping macrophage polarization toward an anti-tumor functional state in patient-derived tumor models and liver metastases of colorectal cancer patients.


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Intratumoral Heterogeneity of the Epigenome

Publication date: 11 April 2016
Source:Cancer Cell, Volume 29, Issue 4
Author(s): Tali Mazor, Aleksandr Pankov, Jun S. Song, Joseph F. Costello
Investigation into intratumoral heterogeneity (ITH) of the epigenome is in a formative stage. The patterns of tumor evolution inferred from epigenetic ITH and genetic ITH are remarkably similar, suggesting widespread co-dependency of these disparate mechanisms. The biological and clinical relevance of epigenetic ITH are becoming more apparent. Rare tumor cells with unique and reversible epigenetic states may drive drug resistance, and the degree of epigenetic ITH at diagnosis may predict patient outcome. This perspective presents these current concepts and clinical implications of epigenetic ITH, and the experimental and computational techniques at the forefront of ITH exploration.

Teaser

Investigation into intratumoral heterogeneity (ITH) of the epigenome is in a formative stage. The patterns of tumor evolution inferred from epigenetic ITH and genetic ITH are remarkably similar, suggesting widespread co-dependency of these disparate mechanisms. The biological and clinical relevance of epigenetic ITH are becoming more apparent. Rare tumor cells with unique and reversible epigenetic states may drive drug resistance, and the degree of epigenetic ITH at diagnosis may predict patient outcome. This perspective presents these current concepts and clinical implications of epigenetic ITH, and the experimental and computational techniques at the forefront of ITH exploration.


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Long Noncoding RNAs in Cancer Pathways

Publication date: 11 April 2016
Source:Cancer Cell, Volume 29, Issue 4
Author(s): Adam M. Schmitt, Howard Y. Chang
Genome-wide cancer mutation analyses are revealing an extensive landscape of functional mutations within the noncoding genome, with profound effects on the expression of long noncoding RNAs (lncRNAs). While the exquisite regulation of lncRNA transcription can provide signals of malignant transformation, we now understand that lncRNAs drive many important cancer phenotypes through their interactions with other cellular macromolecules including DNA, protein, and RNA. Recent advancements in surveying lncRNA molecular mechanisms are now providing the tools to functionally annotate these cancer-associated transcripts, making these molecules attractive targets for therapeutic intervention in the fight against cancer.

Teaser

Genome-wide cancer mutation analyses are revealing an extensive landscape of functional mutations within the noncoding genome, with profound effects on the expression of long noncoding RNAs (lncRNAs). While the exquisite regulation of lncRNA transcription can provide signals of malignant transformation, we now understand that lncRNAs drive many important cancer phenotypes through their interactions with other cellular macromolecules including DNA, protein, and RNA. Recent advancements in surveying lncRNA molecular mechanisms are now providing the tools to functionally annotate these cancer-associated transcripts, making these molecules attractive targets for therapeutic intervention in the fight against cancer.


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Exploiting the Epigenome to Control Cancer-Promoting Gene-Expression Programs

Publication date: 11 April 2016
Source:Cancer Cell, Volume 29, Issue 4
Author(s): Gerard L. Brien, Daria G. Valerio, Scott A. Armstrong
The epigenome is a key determinant of transcriptional output. Perturbations within the epigenome are thought to be a key feature of many, perhaps all cancers, and it is now clear that epigenetic changes are instrumental in cancer development. The inherent reversibility of these changes makes them attractive targets for therapeutic manipulation, and a number of small molecules targeting chromatin-based mechanisms are currently in clinical trials. In this perspective we discuss how understanding the cancer epigenome is providing insights into disease pathogenesis and informing drug development. We also highlight additional opportunities to further unlock the therapeutic potential within the cancer epigenome.

Teaser

In this perspective article Brien et al. discuss how our burgeoning understanding of the epigenetic changes in cancer is providing significant insights into the mechanistic role of the epigenome in oncogenesis. Moreover, the authors highlight how this understanding is being exploited therapeutically with the development of novel epigenetic therapies, several of which are in ongoing clinical trials. Finally, the authors discuss possibilities to further unlock the therapeutic potential within the cancer epigenome, through efforts to broaden our understanding of the epigenetic changes underlying cancer development.


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SnapShot: Renal Cell Carcinoma

Publication date: 11 April 2016
Source:Cancer Cell, Volume 29, Issue 4
Author(s): Christopher J. Ricketts, Daniel R. Crooks, Carole Sourbier, Laura S. Schmidt, Ramaprasad Srinivasan, W. Marston Linehan
Renal cell carcinoma (RCC) is a heterogeneous disease made up of a number of different cancer types, with distinct histologies, clinical courses, therapeutic responses, and genetic drivers. Germline mutations in 14 genes have been associated with increased risk of RCC and can result in HIF pathway activation, chromatin dysregulation, and altered metabolism. Knowledge of these pathway alterations can inform the development of targeted therapeutic approaches. To view this SnapShot, open or download the PDF.

Teaser

Renal cell carcinoma (RCC) is a heterogeneous disease made up of a number of different cancer types, with distinct histologies, clinical courses, therapeutic responses, and genetic drivers. Germline mutations in 14 genes have been associated with increased risk of RCC and can result in HIF pathway activation, chromatin dysregulation, and altered metabolism. Knowledge of these pathway alterations can inform the development of targeted therapeutic approaches. To view this SnapShot, open or download the PDF.


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Targeting Non-proteolytic Protein Ubiquitination for the Treatment of Diffuse Large B Cell Lymphoma

Publication date: 11 April 2016
Source:Cancer Cell, Volume 29, Issue 4
Author(s): Yibin Yang, Priscilla Kelly, Arthur L. Shaffer, Roland Schmitz, Hee Min Yoo, Xinyue Liu, Da Wei Huang, Daniel Webster, Ryan M. Young, Masao Nakagawa, Michele Ceribelli, George W. Wright, Yandan Yang, Hong Zhao, Xin Yu, Weihong Xu, Wing C. Chan, Elaine S. Jaffe, Randy D. Gascoyne, Elias Campo, Andreas Rosenwald, German Ott, Jan Delabie, Lisa Rimsza, Louis M. Staudt
Chronic active B cell receptor (BCR) signaling, a hallmark of the activated B cell-like (ABC) subtype of diffuse large B cell lymphoma (DLBCL), engages the CARD11-MALT1-BCL10 (CBM) adapter complex to activate IκB kinase (IKK) and the classical NF-κB pathway. Here we show that the CBM complex includes the E3 ubiquitin ligases cIAP1 and cIAP2, which are essential mediators of BCR-dependent NF-κB activity in ABC DLBCL. cIAP1/2 attach K63-linked polyubiquitin chains on themselves and on BCL10, resulting in the recruitment of IKK and the linear ubiquitin chain ligase LUBAC, which is essential for IKK activation. SMAC mimetics target cIAP1/2 for destruction, and consequently suppress NF-κB and selectively kill BCR-dependent ABC DLBCL lines, supporting their clinical evaluation in patients with ABC DLBCL.

Teaser

Yang et al. show that cIAP1 and cIAP2 mediate K63 ubiquitination of BCL10, thus are essential for B cell receptor (BCR)-dependent NF-κB activity in the ABC subtype of diffuse large B cell lymphoma (DLBCL). SMAC mimetics target cIAP1/2 for destruction, selectively killing BCR-dependent ABC DLBCL cells.


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Single-Cell Phosphoproteomics Resolves Adaptive Signaling Dynamics and Informs Targeted Combination Therapy in Glioblastoma

Publication date: 11 April 2016
Source:Cancer Cell, Volume 29, Issue 4
Author(s): Wei Wei, Young Shik Shin, Min Xue, Tomoo Matsutani, Kenta Masui, Huijun Yang, Shiro Ikegami, Yuchao Gu, Ken Herrmann, Dazy Johnson, Xiangming Ding, Kiwook Hwang, Jungwoo Kim, Jian Zhou, Yapeng Su, Xinmin Li, Bruno Bonetti, Rajesh Chopra, C. David James, Webster K. Cavenee, Timothy F. Cloughesy, Paul S. Mischel, James R. Heath, Beatrice Gini
Intratumoral heterogeneity of signaling networks may contribute to targeted cancer therapy resistance, including in the highly lethal brain cancer glioblastoma (GBM). We performed single-cell phosphoproteomics on a patient-derived in vivo GBM model of mTOR kinase inhibitor resistance and coupled it to an analytical approach for detecting changes in signaling coordination. Alterations in the protein signaling coordination were resolved as early as 2.5 days after treatment, anticipating drug resistance long before it was clinically manifest. Combination therapies were identified that resulted in complete and sustained tumor suppression in vivo. This approach may identify actionable alterations in signal coordination that underlie adaptive resistance, which can be suppressed through combination drug therapy, including non-obvious drug combinations.

Graphical abstract

Teaser

Wei et al. utilize single-cell phosphoproteomic analysis of patient-derived glioblastoma models to identify shifts in signaling coordination following short-term treatment with kinase inhibitors, which facilitates the design of combination therapy approaches with reduced resistance and improved efficacy.


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The Public Repository of Xenografts Enables Discovery and Randomized Phase II-like Trials in Mice

Publication date: 11 April 2016
Source:Cancer Cell, Volume 29, Issue 4
Author(s): Elizabeth C. Townsend, Mark A. Murakami, Alexandra Christodoulou, Amanda L. Christie, Johannes Köster, Tiffany A. DeSouza, Elizabeth A. Morgan, Scott P. Kallgren, Huiyun Liu, Shuo-Chieh Wu, Olivia Plana, Joan Montero, Kristen E. Stevenson, Prakash Rao, Raga Vadhi, Michael Andreeff, Philippe Armand, Karen K. Ballen, Patrizia Barzaghi-Rinaudo, Sarah Cahill, Rachael A. Clark, Vesselina G. Cooke, Matthew S. Davids, Daniel J. DeAngelo, David M. Dorfman, Hilary Eaton, Benjamin L. Ebert, Julia Etchin, Brant Firestone, David C. Fisher, Arnold S. Freedman, Ilene A. Galinsky, Hui Gao, Jacqueline S. Garcia, Francine Garnache-Ottou, Timothy A. Graubert, Alejandro Gutierrez, Ensar Halilovic, Marian H. Harris, Zachary T. Herbert, Steven M. Horwitz, Giorgio Inghirami, Andrew M. Intlekoffer, Moriko Ito, Shai Izraeli, Eric D. Jacobsen, Caron A. Jacobson, Sébastien Jeay, Irmela Jeremias, Michelle A. Kelliher, Raphael Koch, Marina Konopleva, Nadja Kopp, Steven M. Kornblau, Andrew L. Kung, Thomas S. Kupper, Nicole LaBoeuf, Ann S. LaCasce, Emma Lees, Loretta S. Li, A. Thomas Look, Masato Murakami, Markus Muschen, Donna Neuberg, Samuel Y. Ng, Oreofe O. Odejide, Stuart H. Orkin, Rachel R. Paquette, Andrew E. Place, Justine E. Roderick, Jeremy A. Ryan, Stephen E. Sallan, Brent Shoji, Lewis B. Silverman, Robert J. Soiffer, David P. Steensma, Kimberly Stegmaier, Richard M. Stone, Jerome Tamburini, Aaron R. Thorner, Paul van Hummelen, Martha Wadleigh, Marion Wiesmann, Andrew P. Weng, Jens U. Wuerthner, David A. Williams, Bruce M. Wollison, Andrew A. Lane, Anthony Letai, Monica M. Bertagnolli, Jerome Ritz, Myles Brown, Henry Long, Jon C. Aster, Margaret A. Shipp, James D. Griffin, David M. Weinstock
More than 90% of drugs with preclinical activity fail in human trials, largely due to insufficient efficacy. We hypothesized that adequately powered trials of patient-derived xenografts (PDX) in mice could efficiently define therapeutic activity across heterogeneous tumors. To address this hypothesis, we established a large, publicly available repository of well-characterized leukemia and lymphoma PDXs that undergo orthotopic engraftment, called the Public Repository of Xenografts (PRoXe). PRoXe includes all de-identified information relevant to the primary specimens and the PDXs derived from them. Using this repository, we demonstrate that large studies of acute leukemia PDXs that mimic human randomized clinical trials can characterize drug efficacy and generate transcriptional, functional, and proteomic biomarkers in both treatment-naive and relapsed/refractory disease.

Teaser

Townsend et al. create a large, publicly available repository of leukemia and lymphoma patient-derived xenografts with well-characterized molecular and clinical information, and illustrate the utility of this repository by performing a preclinical in vivo study that mimics randomized human clinical trials.


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Tumoral Immune Cell Exploitation in Colorectal Cancer Metastases Can Be Targeted Effectively by Anti-CCR5 Therapy in Cancer Patients

Publication date: 11 April 2016
Source:Cancer Cell, Volume 29, Issue 4
Author(s): Niels Halama, Inka Zoernig, Anna Berthel, Christoph Kahlert, Fee Klupp, Meggy Suarez-Carmona, Thomas Suetterlin, Karsten Brand, Juergen Krauss, Felix Lasitschka, Tina Lerchl, Claudia Luckner-Minden, Alexis Ulrich, Moritz Koch, Juergen Weitz, Martin Schneider, Markus W. Buechler, Laurence Zitvogel, Thomas Herrmann, Axel Benner, Christina Kunz, Stephan Luecke, Christoph Springfeld, Niels Grabe, Christine S. Falk, Dirk Jaeger
The immune response influences the clinical course of colorectal cancer (CRC). Analyzing the invasive margin of human CRC liver metastases, we identified a mechanism of immune cell exploitation by tumor cells. While two distinct subsets of myeloid cells induce an influx of T cells into the invasive margin via CXCL9/CXCL10, CCL5 is produced by these T cells and stimulates pro-tumoral effects via CCR5. CCR5 blockade in patient-derived functional in vitro organotypic culture models showed a macrophage repolarization with anti-tumoral effects. These anti-tumoral effects were then confirmed in a phase I trial with a CCR5 antagonist in patients with liver metastases of advanced refractory CRC. Mitigation of tumor-promoting inflammation within the tumor tissue and objective tumor responses in CRC were observed.

Graphical abstract

Teaser

Halama et al. show that T cells at invasive margins of human colorectal cancer (CRC) liver metastases produce CCL5, which has tumor-promoting effects on tumor cells and tumor-associated macrophages. CCR5 blockade mitigates the tumor-promoting microenvironment and leads to clinical responses in CRC patients.


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miR-126 Regulates Distinct Self-Renewal Outcomes in Normal and Malignant Hematopoietic Stem Cells

Publication date: 11 April 2016
Source:Cancer Cell, Volume 29, Issue 4
Author(s): Eric R. Lechman, Bernhard Gentner, Stanley W.K. Ng, Erwin M. Schoof, Peter van Galen, James A. Kennedy, Silvia Nucera, Fabio Ciceri, Kerstin B. Kaufmann, Naoya Takayama, Stephanie M. Dobson, Aaron Trotman-Grant, Gabriela Krivdova, Janneke Elzinga, Amanda Mitchell, Björn Nilsson, Karin G. Hermans, Kolja Eppert, Rene Marke, Ruth Isserlin, Veronique Voisin, Gary D. Bader, Peter W. Zandstra, Todd R. Golub, Benjamin L. Ebert, Jun Lu, Mark Minden, Jean C.Y. Wang, Luigi Naldini, John E. Dick




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Genome-wide association studies and epigenome-wide association studies go together in cancer control

Future Oncology Ahead of Print.


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Secondary acute myeloid leukemia in survivors of Hodgkin lymphoma

Future Oncology Ahead of Print.


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The role of miRNAs and epigenetic mechanisms in primary gastric mucosa-associated lymphoid tissue lymphoma

Future Oncology Ahead of Print.


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Genome-wide association studies and epigenome-wide association studies go together in cancer control

Future Oncology Ahead of Print.


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Assessment of function and quality of life in a phase II multi-institutional clinical trial of fractionated simultaneous in-field boost radiotherapy for patients with 1–3 metastases

Abstract

We examined functional outcomes and quality of life of whole brain radiotherapy (WBRT) with integrated fractionated stereotactic radiotherapy boost (FSRT) for brain metastases treatment. Eighty seven people with 1–3 brain metastases (54/87 lung primary, 42/87 single brain metastases) were enrolled on this Phase II trial of WBRT (30 Gy/10) + simultaneous FSRT, (60 Gy/10). Median overall follow-up and survival was 5.4 months, 6 month actuarial intra-lesional control was 78 %; only 1 patient exhibited grade 4 toxicity (worsened seizures); most treatment related toxicity was grade 1 or 2; 2/87 patients demonstrated asymptomatic radiation necrosis on follow-up imaging. Mean (Min–Max) baseline KPS, Mini Mental Status Exam (MMSE) and FACT-BR quality of life were 83 (70–100), 28 (21–30) and 143 (98–153). Lower baseline MMSE (but not KPS or FACT-Br) was associated with worse survival after adjusting for age, number of metastases, primary and extra-cranial disease status. Crude rates of deterioration (>10 points decrease from baseline for KPS and FACT-Br, MMSE fall to <27) ranged from 26 to 38 % for KPS, 32–59 % for FACT-Br and 0–16 % for MMSE depending on the time-point assessed with higher rates generally noted at earlier time points (≤6 months post-treatment). Using a linear mixed models analysis, significant declines from baseline were noted for KPS and FACT-Br (largest effects at 6 weeks to 3 months) with no significant change in MMSE. The effects on function and quality of life of this integrated treatment of WBRT + simultaneous FSRT were similar to other published series combining WBRT + radiosurgery.

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Erratum to: New CD20 alternative splice variants: molecular identification and differential expression within hematological B cell malignancies

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Afatinib versus methotrexate in older patients with second-line recurrent and/or metastatic head and neck squamous cell carcinoma: subgroup analysis of the LUX-Head & Neck 1 trial

In the LUX-Head & Neck 1 study, older age (≥65 years) did not adversely affect the benefit in patient-reported outcomes and anti-tumor activity observed with afatinib over methotrexate, which was consistent with findings from the overall population. Safety in older patients was also consistent with the overall population, favoring afatinib in terms of fewer dose reductions and discontinuations.

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Current Management of Newly Diagnosed Acute Promyelocytic Leukemia

Appropriate diagnosis and management of Acute Promyelocytic Leukemia is of utmost importance to reduce the risk of early mortality. The standard front-line approach with ATRA and chemotherapy has been recently challenged by ATRA and ATO combination, which has emerged as the new standard of care for non-high risk disease. In light of the recent progress, several therapeutic and monitoring issues are currently matter of debate in the novel therapeutic contexts.

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Myeloid-derived suppressor cells correlate with patient outcomes in hepatic arterial infusion chemotherapy for hepatocellular carcinoma

Abstract

Hepatic arterial infusion chemotherapy (HAIC) has been employed as an alternative therapy to sorafenib for the patients with advanced hepatocellular carcinoma (HCC). In this study, we performed a comparative analysis of various immune cell responses including tumor-associated antigen (TAA)-specific T cells, regulatory T cells (Tregs) and myeloid-derived suppressor cells (MDSCs) in advanced HCC patients treated with HAIC. Thirty-six HCC patients were examined in the study. Interferon gamma enzyme-linked immunospot assays were performed to examine the frequency of TAA-specific T cells. The frequencies of Tregs and MDSCs were examined by multicolor fluorescence-activated cell sorting analysis. The treatment with HAIC using interferon (IFN)/5-fluorouracil (FU) or IFN/FU + cisplatin modulated the frequencies of various immune cells. In 22.2 % of patients, the frequency of TAA-specific T cells increased after HAIC. Although the frequency of Tregs decreased after HAIC, it was not associated with the prognosis of patients. An analysis of prognostic factors for overall survival identified diameter of the tumor (<3.0 cm), absence of major portal vein invasion, absence of distant metastasis, Union Internationale Contre Le Cancer tumor lymph node metastasis stage (I or II), neutrophil lymphocytic ratio (<2.1) and the frequency of MDSCs (<30.5 %) as factors that prolonged overall survival time after HAIC. Even in the group adjusted with progressive levels of tumors, patients with a low frequency of MDSCs had a significantly longer overall survival time. In conclusion, the frequency of MDSCs before the treatment is a prognostic factor in HAIC against HCC.

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Managing leptomeningeal melanoma metastases in the era of immune and targeted therapy

Abstract

Melanoma frequently metastasizes to the brain, with CNS involvement being clinically evident in ∼30% of patients (as high as 75% at autopsy). In ∼5% cases melanoma cells also metastasize to the leptomeninges, the sub-arachnoid space and cerebrospinal fluid (CSF). Patients with leptomeningeal melanoma metastases (LMM) have the worst prognosis and are characterized by rapid disease progression (mean survival 8-10 weeks) and a death from neurological causes. The recent years have seen tremendous progress in the development of targeted and immune therapies for melanoma that has translated into an increased survival benefit. Despite these gains, the majority of patients fail therapy and there is a suspicion that the brain and the leptomeninges are a "sanctuary" sites for melanoma cells that escape both targeted therapy and immunologic therapies. Emerging evidence suggests that 1) Cancer cells migrating to the CNS may have unique molecular properties and 2) the CNS/leptomeningeal microenvironment represents a pro-survival niche that influences therapeutic response. In this Mini-Review we will outline the clinical course of LMM development and will describe how the intracranial immune and cellular microenvironments offer both opportunities and challenges for the successful management of this disease. We will further discuss the latest data demonstrating the potential use of BRAF inhibitors and immune therapy in the management of LMM, and will review future potential therapeutic strategies for the management of this most devastating complication of advanced melanoma. This article is protected by copyright. All rights reserved.

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Serum pepsinogen levels can quantify the risk of development of metachronous gastric cancer after endoscopic resection

Abstract

We have previously reported that serum pepsinogen (PG) can quantify the level of gastric mucosal atrophy, and that H. pylori eradication reduces cancer development in subjects with mild atrophy identified by serum PG levels. The aim of this study was to elucidate the predictive ability of serum PG levels for the development of metachronous gastric cancer (MGC) after endoscopic resection (ER) of primary cancer in association with H. pylori eradication. A retrospective chart review was performed, and 330 patients who underwent ER for initial early gastric cancer were enrolled. Presence or absence of H. pylori, serum PG levels, and endoscopic atrophy at ER were evaluated. H. pylori eradication was performed at the patient's request after ER. The incidence of MGC in these patients was analyzed. Of 330 patients, 47 developed MGC. Endoscopic extensive atrophy was observed more frequently in patients with MGC (p = 0.001). Although PG I or PG II alone did not significantly differ according to development of MGC, the proportion of PG I/II ≤ 3.0, which is one of the criteria of PG test-positive, was significantly higher in patients with MGC (83% vs. 69%, p = 0.04). H. pylori eradication after ER did not affect MGC development (p = 0.2). On multivariate analysis, serum PG I/II ratio ≤ 3.3 was significantly associated with the development of MGC (hazard ratio: 3.66, 95% confidence interval: 1.47-12.25, p = 0.004). The risk of MGC after ER could be quantitatively predicted by the PG I/II ratio regardless of H. pylori status. This article is protected by copyright. All rights reserved.

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Invitation to cervical cancer screening does increase participation in Germany: Results from the MARZY Study

Abstract

The effect of different invitation models on participation in cervical cancer screening (CCS) was investigated in a randomized population-based cohort study in Germany. Participants were randomly selected via population registries and randomized into intervention Arm A (invitation letter) and Arm B (invitation letter and information brochure) or control Arm C (no invitation). The intervention and control Arms were compared with regards to three-year participation and the two invitation models were compared between intervention Arms. Of the 7 758 eligible women aged 30-65 years, living in the city of Mainz and in the rural region of Mainz-Bingen, 5 265 were included in the analysis. Differences in proportions of women attending CCS were investigated and logistic regression was performed to analyze various factors influencing participation. In the intervention group, 91.8% participated in CCS compared to 85.3% in the control group (p<0.0001), with a 6.6 percentage point increase in participation (95% confidence interval (CI) 4.6-8.6) and an adjusted odds ratio (OR) of 2.69 (95% CI 2.15-3.37). Effect estimators increased to 21.9 percentage points (95% CI 16.7-27.1) and an OR of 3.64 (95% CI 2.74-4.82), respectively, when women who participated in screening annually were excluded from the analysis. The invitation letter was particularly effective among women with lower school education, migrant women and older women. No difference in participation was found between the intervention Arms A and Arm B. An accompanying information brochure did not motivate more women to undergo CCS. However, a written invitation statistically significantly increased participation in CCS in Germany. This article is protected by copyright. All rights reserved.

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Myeloid-derived suppressor cells correlate with patient outcomes in hepatic arterial infusion chemotherapy for hepatocellular carcinoma

Abstract

Hepatic arterial infusion chemotherapy (HAIC) has been employed as an alternative therapy to sorafenib for the patients with advanced hepatocellular carcinoma (HCC). In this study, we performed a comparative analysis of various immune cell responses including tumor-associated antigen (TAA)-specific T cells, regulatory T cells (Tregs) and myeloid-derived suppressor cells (MDSCs) in advanced HCC patients treated with HAIC. Thirty-six HCC patients were examined in the study. Interferon gamma enzyme-linked immunospot assays were performed to examine the frequency of TAA-specific T cells. The frequencies of Tregs and MDSCs were examined by multicolor fluorescence-activated cell sorting analysis. The treatment with HAIC using interferon (IFN)/5-fluorouracil (FU) or IFN/FU + cisplatin modulated the frequencies of various immune cells. In 22.2 % of patients, the frequency of TAA-specific T cells increased after HAIC. Although the frequency of Tregs decreased after HAIC, it was not associated with the prognosis of patients. An analysis of prognostic factors for overall survival identified diameter of the tumor (<3.0 cm), absence of major portal vein invasion, absence of distant metastasis, Union Internationale Contre Le Cancer tumor lymph node metastasis stage (I or II), neutrophil lymphocytic ratio (<2.1) and the frequency of MDSCs (<30.5 %) as factors that prolonged overall survival time after HAIC. Even in the group adjusted with progressive levels of tumors, patients with a low frequency of MDSCs had a significantly longer overall survival time. In conclusion, the frequency of MDSCs before the treatment is a prognostic factor in HAIC against HCC.

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