Τετάρτη 30 Νοεμβρίου 2016

Molecular Pathways: Dietary Regulation of Stemness and Tumor Initiation by the PPAR-{delta} Pathway

Peroxisome proliferator-activated receptor delta (PPAR-) is a nuclear receptor transcription factor that regulates gene expression during development and disease states, such as cancer. However, the precise role of PPAR- during tumorigenesis is not well understood. Recent data suggest that PPAR- may have context-specific oncogenic and tumor-suppressive roles depending on the tissue, cell-type, or diet-induced physiology in question. For example, in the intestine, pro-obesity diets, such as a high-fat diet (HFD), are associated with increased colorectal cancer incidence. Interestingly, many of the effects of an HFD in the stem and progenitor cell compartment are driven by a robust PPAR- program and contribute to the early steps of intestinal tumorigenesis. Importantly, the PPAR- pathway or its downstream mediators may serve as therapeutic intervention points or biomarkers in colon cancer that arise in patients who are obese. Although potent PPAR- agonists and antagonists exist, their clinical utility may be enhanced by uncovering how PPAR- mediates tumorigenesis in diverse tissues and cell types as well as in response to diet. Clin Cancer Res; 22(23); 5636–41. ©2016 AACR.



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Detection of Therapeutically Targetable Driver and Resistance Mutations in Lung Cancer Patients by Next-Generation Sequencing of Cell-Free Circulating Tumor DNA

Purpose: The expanding number of targeted therapeutics for non–small cell lung cancer (NSCLC) necessitates real-time tumor genotyping, yet tissue biopsies are difficult to perform serially and often yield inadequate DNA for next-generation sequencing (NGS). We evaluated the feasibility of using cell-free circulating tumor DNA (ctDNA) NGS as a complement or alternative to tissue NGS.

Experimental Design: A total of 112 plasma samples obtained from a consecutive study of 102 prospectively enrolled patients with advanced NSCLC were subjected to ultra-deep sequencing of up to 70 genes and matched with tissue samples, when possible.

Results: We detected 275 alterations in 45 genes, and at least one alteration in the ctDNA for 86 of 102 patients (84%), with EGFR variants being most common. ctDNA NGS detected 50 driver and 12 resistance mutations, and mutations in 22 additional genes for which experimental therapies, including clinical trials, are available. Although ctDNA NGS was completed for 102 consecutive patients, tissue sequencing was only successful for 50 patients (49%). Actionable EGFR mutations were detected in 24 tissue and 19 ctDNA samples, yielding concordance of 79%, with a shorter time interval between tissue and blood collection associated with increased concordance (P = 0.038). ctDNA sequencing identified eight patients harboring a resistance mutation who developed progressive disease while on targeted therapy, and for whom tissue sequencing was not possible.

Conclusions: Therapeutically targetable driver and resistance mutations can be detected by ctDNA NGS, even when tissue is unavailable, thus allowing more accurate diagnosis, improved patient management, and serial sampling to monitor disease progression and clonal evolution. Clin Cancer Res; 22(23); 5772–82. ©2016 AACR.



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Genomic Approaches to Understanding Response and Resistance to Immunotherapy

Immunotherapy has led to a paradigm shift in the treatment of some malignancies, providing long-term, durable responses for patients with advanced cancers. However, such therapy has benefited only a subset of patients, with some patients failing to respond to treatment at all and others achieving a limited response followed by tumor progression. Understanding factors contributing to an effective response and further elucidating mechanisms of resistance will be crucial as these therapies are applied more broadly. Genomics-based approaches have significantly advanced the study of response and resistance to immunotherapy in general, and to immune checkpoint blockade more specifically. Here, we review how genomic and transcriptomic approaches have identified both somatic and germline positive correlates of response, including high mutational/neoantigen load and low intratumoral heterogeneity, among others. The genomic analysis of resistant tumors has additionally identified crucial factors involved in resistance to immune checkpoint blockade, including loss of PTEN and upregulation of other immune checkpoints. Overall, the continued use of genomic techniques at the point of care, combined with appropriate functional studies, would ideally lead to a better understanding of why certain patients respond to immune-based therapies, allowing clinicians to identify the subset of patients likely to benefit from such therapy, and potentially providing insight into how other therapies may be added in combination to increase the number of patients who may benefit from immunotherapy. Clin Cancer Res; 22(23); 5642–50. ©2016 AACR.



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PI3K Pathway Inhibition Achieves Potent Antitumor Activity in Melanoma Brain Metastases In Vitro and In Vivo

Purpose: Great advances have recently been made in treating patients with metastatic melanoma. However, existing therapies are less effective on cerebral than extracerebral metastases. This highlights the potential role of the brain environment on tumor progression and drug resistance and underlines the need for "brain-specific" therapies. We previously showed that the PI3K-AKT survival pathway is hyperactivated in brain but not extracerebral melanoma metastases and that astrocyte-conditioned medium activates AKT in melanoma cells in vitro. We therefore tested the PI3K inhibitor buparlisib as an antitumor agent for melanoma brain metastases.

Experimental Design and Results: Buparlisib inhibited AKT activity, decreased proliferation, and induced apoptosis in metastatic melanoma cell lines and short-term brain melanoma cells, irrespective of their BRAF and NRAS mutation status. In addition, buparlisib inhibited hyperactivated AKT and induced apoptosis in melanoma cells that were stimulated with astrocyte-conditioned medium. The growth of tumors induced by injecting human BRAF- and NRAS-mutant metastatic melanoma cells into the brain of mice was significantly inhibited by buparlisib.

Conclusions: These results emphasize the value of targeting the PI3K pathway as a strategy to develop drugs for melanoma brain metastases. Clin Cancer Res; 22(23); 5818–28. ©2016 AACR.



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Biomarkers of Response and Resistance to DNA Repair Targeted Therapies

Drugs targeting DNA damage repair (DDR) pathways are exciting new agents in cancer therapy. Many of these drugs exhibit synthetic lethality with defects in DNA repair in cancer cells. For example, ovarian cancers with impaired homologous recombination DNA repair show increased sensitivity to poly(ADP-ribose) polymerase (PARP) inhibitors. Understanding the activity of different DNA repair pathways in individual tumors, and the correlations between DNA repair function and drug response, will be critical to patient selection for DNA repair targeted agents. Genomic and functional assays of DNA repair pathway activity are being investigated as potential biomarkers of response to targeted therapies. Furthermore, alterations in DNA repair function generate resistance to DNA repair targeted agents, and DNA repair states may predict intrinsic or acquired drug resistance. In this review, we provide an overview of DNA repair targeted agents currently in clinical trials and the emerging biomarkers of response and resistance to these agents: genetic and genomic analysis of DDR pathways, genomic signatures of mutational processes, expression of DNA repair proteins, and functional assays for DNA repair capacity. We review biomarkers that may predict response to selected DNA repair targeted agents, including PARP inhibitors, inhibitors of the DNA damage sensors ATM and ATR, and inhibitors of nonhomologous end joining. Finally, we introduce emerging categories of drugs targeting DDR and new strategies for integrating DNA repair targeted therapies into clinical practice, including combination regimens. Generating and validating robust biomarkers will optimize the efficacy of DNA repair targeted therapies and maximize their impact on cancer treatment. Clin Cancer Res; 22(23); 5651–60. ©2016 AACR.



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Clinical Significance of Circulating CD33+CD11b+HLA-DR- Myeloid Cells in Patients with Stage IV Melanoma Treated with Ipilimumab

Purpose: High levels of circulating myeloid-derived suppressor cells (MDSCs) in various cancer types, including melanoma, were shown to correlate with poor survival. We investigated whether frequencies of circulating CD33+CD11b+HLA-DR MDSCs could be used as immune system monitoring biomarkers to predict response and survival of patients with stage IV melanoma treated with anti-CTLA4 (ipilimumab) therapy.

Experimental Design: Peripheral blood samples from 56 patients and 50 healthy donors (HDs) were analyzed for CD33+CD11b+HLA-DR MDSC percentage, NO, and hROS levels by flow cytometry. We determined whether MDSC levels and suppressive features detected before anti-CTLA4 therapy correlate with the patients' response and overall survival (OS).

Results: Patients with melanoma had significantly higher levels of circulating CD33+CD11b+HLA-DR MDSCs with suppressive phenotype when compared with HDs. Low levels of MDSCs before CTLA-4 therapy correlated with an objective clinical response, long-term survival, increased CD247 expression in T cells, and an improved clinical status. No predictive impact was observed for lactate dehydrogenase (LDH). Kaplan–Meier and log-rank tests performed on the 56 patients showed that the presence of more than 55.5% of circulating CD33+CD11b+ out of the HLA-DR cells, were associated with significant short OS (P < 0.003), a median of 6.5 months, in comparison with the group showing lower MDSC frequencies, with a median survival of 15.6 months.

Conclusions: Our study suggests the use of CD33+CD11b+HLA-DR cells as a predictive and prognostic biomarker in patients with stage IV melanoma treated with anti-CTLA4 therapy. This monitoring system may aid in the development of combinatorial modalities, targeting the suppressive environment in conjunction with iplimumab, toward facilitating better disease outcomes. Clin Cancer Res; 22(23); 5661–72. ©2016 AACR.



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Racial/Ethnic Disparities in Ovarian Cancer Treatment and Survival

Purpose: Among patients with ovarian cancer, African American (AA) women experience poorer survival compared with other race/ethnicity groups. This has been attributed to differences in access to health care.

Experimental Design: We evaluated racial/ethnic differences in chemotherapy dosing and survival in a cohort study among members of Kaiser Permanente Northern California, and thus with equivalent access to health care. Analyses included epithelial-invasive ovarian cancer cases (n = 793) receiving adjuvant first-line therapy of carboplatin and paclitaxel with curative intent, with median follow-up of 50 months. Relative dose intensity (RDI) was computed for carboplatin and paclitaxel separately as dose administered per week divided by expected dose per week, and average RDI (ARDI) was then calculated for the regimen. Proportional hazards regression was used to calculate HRs and 95% confidence intervals (CIs) after adjusting for relevant covariates.

Results: Compared with whites, AAs were more likely to have dose reduction (ARDI < 85%), treatment delay, and early discontinuation. Hispanics were also more likely to have dose reduction, but less likely to have early discontinuation or treatment delay. After controlling for prognostic factors including ARDI, AA women had the worst survival. Compared with whites, adjusted HRs (95% CI) for overall mortality were 1.56 (1.01–2.39) for AAs; 0.89 (0.61–1.31) for Asians; and 1.41 (0.98–2.04) for Hispanics. Findings for ovarian cancer–specific mortality were similar.

Conclusions: Disparities in ovarian cancer treatment and survival in AA persisted among women with equal access to care. These findings warrant further evaluation of biological, personal, and social factors that may be responsible for these differences. Clin Cancer Res; 22(23); 5909–14. ©2016 AACR.



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Immunomodulatory Effect of Vitamin D after Allogeneic Stem Cell Transplantation: Results of a Prospective Multicenter Clinical Trial

Purpose: We describe the results of a prospective multicenter phase I/II trial evaluating the impact of the use of vitamin D (VitD) from day –5 to +100 on the outcome of patients undergoing allogeneic transplantation (EudraCT: 2010-023279-25; ClinicalTrials.gov: NCT02600988).

Experimental Design: A total of 150 patients were included in three consecutive cohorts of 50 patients each group: control group (CG, not receive VitD); low-dose group (LdD, received 1,000 IU VitD daily); and high-dose group (HdD, 5,000 IU VitD daily). We measured levels of VitD, cytokines, and immune subpopulations after transplantation.

Results: No significant differences were observed in terms of cumulative incidence of overall and grades 2–4 acute GVHD in terms of relapse, nonrelapse mortality, and overall survival. However, a significantly lower cumulative incidence of both overall and moderate plus severe chronic GVHD (cGVHD) at 1 year was observed in LdD (37.5% and 19.5%, respectively) and HdD (42.4% and 27%, respectively) as compared with CG (67.5% and 44.7%, respectively; P < 0.05). In multivariable analysis, treatment with VitD significantly decreased the risk of both overall (for LdD: HR = 0.31, P = 0.002; for HdD: HR = 0.36, P = 0.006) and moderate plus severe cGVHD (for LdD: HR = 0.22, P = 0.001; for HdD: HR = 0.33, P = 0.01). VitD modified the immune response, decreasing the number of B cells and naïve CD8 T cells, with a lower expression of CD40L.

Conclusions: This is the first prospective trial that analyzes the effect of VitD postransplant. We observed a significantly lower incidence of cGVHD among patients receiving VitD. Interestingly, VitD modified the immune response after allo-SCT. Clin Cancer Res; 22(23); 5673–81. ©2016 AACR.



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Highlights of This Issue



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Regression of Chemotherapy-Resistant Polymerase {varepsilon} (POLE) Ultra-Mutated and MSH6 Hyper-Mutated Endometrial Tumors with Nivolumab

Purpose: The management of endometrial carcinoma no longer amenable to treatment with surgery or radiotherapy has not improved significantly with modern chemotherapy. Alternative therapeutic options are desperately needed.

Experimental Design: We describe 2 heavily pretreated patients with recurrent disease refractory to surgery, radiotherapy, and chemotherapy who were treated with the anti–PD-1 immune checkpoint inhibitor nivolumab.

Results: Patient #1 harbored an ultra-mutated tumor (mutation load/MB = 117.3, total mutations = 4,660) driven by mutation in the exonuclease domain of the DNA polymerase gene. Patient #2 harbored a hyper-mutated tumor (mutation load/MB = 33.5, total mutations = 1,037) due to a germinal MSH6 gene mutation. Both patients demonstrated a remarkable clinical response to the anti–PD-1 immune checkpoint inhibitor nivolumab. Patients' clinical responses remain unchanged at the time of the writing of this report, with no grade 3 or higher side effects reported to date.

Conclusions: Anti–PD-1 inhibitors represent a novel treatment option for recurrent/metastatic, ultra/hyper-mutated human tumors refractory to salvage treatment. Clin Cancer Res; 22(23); 5682–7. ©2016 AACR.

See related commentary by Piulats and Matias-Guiu, p. 5623



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Large-scale Radiomic Profiling of Recurrent Glioblastoma Identifies an Imaging Predictor for Stratifying Anti-Angiogenic Treatment Response

Purpose: Antiangiogenic treatment with bevacizumab, a mAb to the VEGF, is the single most widely used therapeutic agent for patients with recurrent glioblastoma. A major challenge is that there are currently no validated biomarkers that can predict treatment outcome. Here we analyze the potential of radiomics, an emerging field of research that aims to utilize the full potential of medical imaging.

Experimental Design: A total of 4,842 quantitative MRI features were automatically extracted and analyzed from the multiparametric tumor of 172 patients (allocated to a discovery and validation set with a 2:1 ratio) with recurrent glioblastoma prior to bevacizumab treatment. Leveraging a high-throughput approach, radiomic features of patients in the discovery set were subjected to a supervised principal component (superpc) analysis to generate a prediction model for stratifying treatment outcome to antiangiogenic therapy by means of both progression-free and overall survival (PFS and OS).

Results: The superpc predictor stratified patients in the discovery set into a low or high risk group for PFS (HR = 1.60; P = 0.017) and OS (HR = 2.14; P < 0.001) and was successfully validated for patients in the validation set (HR = 1.85, P = 0.030 for PFS; HR = 2.60, P = 0.001 for OS).

Conclusions: Our radiomic-based superpc signature emerges as a putative imaging biomarker for the identification of patients who may derive the most benefit from antiangiogenic therapy, advances the knowledge in the noninvasive characterization of brain tumors, and stresses the role of radiomics as a novel tool for improving decision support in cancer treatment at low cost. Clin Cancer Res; 22(23); 5765–71. ©2016 AACR.



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Antihypoxic Potentiation of Standard Therapy for Experimental Colorectal Liver Metastasis through Myo-Inositol Trispyrophosphate

Purpose: Tumor hypoxia activates hypoxia-inducible factors (Hifs), which induce a range of malignant changes including vascular abnormalities. Here, we determine whether inhibition of the hypoxic tumor response through myo-inositol trispyrophosphate (ITPP), a compound with antihypoxic properties, is able to cause prolonged vascular normalization that can be exploited to improve standard-of-care treatment.

Experimental Design: We tested ITPP on two syngeneic orthotopic mouse models of lethal colorectal cancer liver metastasis. Tumors were monitored by MRI and analyzed for the hypoxic response and their malignant potential. A Hif activator and in vitro assays were used to define the working mode of ITPP. Hypoxic response and vasculature were re-evaluated 4 weeks after treatment. Finally, we determined survival following ITPP monotherapy, FOLFOX monotherapy, FOLFOX plus Vegf antibody, and FOLFOX plus ITPP, both overlapping and sequential.

Results: ITPP reduced tumor load, efficiently inhibited the hypoxic response, and improved survival. These effects were lost when mice were pretreated with a Hif activator. Its immediate effects on the hypoxic response, including an apparent normalization of tumor vasculature, persisted for at least 4 weeks after treatment cessation. Compared with FOLFOX alone, Vegf antibody combined with FOLFOX prolonged survival by <30%, whereas ITPP combined with FOLFOX extended survival by >140%, regardless of whether FOLFOX was given in overlap or after ITPP exposure.

Conclusions: Our findings reveal a truly antihypoxic mechanism for ITPP and demonstrate the capacity of this nontoxic compound to potentiate the efficacy of existing anticancer treatment in a way amenable to clinical translation. Clin Cancer Res; 22(23); 5887–97. ©2016 AACR.



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Delta One T Cells for Immunotherapy of Chronic Lymphocytic Leukemia: Clinical-Grade Expansion/Differentiation and Preclinical Proof of Concept

Purpose: The V1+ subset of T lymphocytes is a promising candidate for cancer immunotherapy, but the lack of suitable expansion/differentiation methods has precluded therapeutic application. We set out to develop and test (preclinically) a V1+ T-cell–based protocol that is good manufacturing practice compatible and devoid of feeder cells for prompt clinical translation.

Experimental design: We tested multiple combinations of clinical-grade agonist antibodies and cytokines for their capacity to expand and differentiate (more than 2–3 weeks) V1+ T cells from the peripheral blood of healthy donors and patients with chronic lymphocytic leukemia (CLL). We characterized the phenotype and functional potential of the final cellular product, termed Delta One T (DOT) cells, in vitro and in vivo (xenograft models of CLL).

Results: We describe a very robust two-step protocol for the selective expansion (up to 2,000-fold in large clinical-grade cell culture bags) and differentiation of cytotoxic V1+ (DOT) cells. These expressed the natural cytotoxicity receptors, NKp30 and NKp44, which synergized with the T-cell receptor to mediate leukemia cell targeting in vitro. When transferred in vivo, DOT cells infiltrated tumors and peripheral organs, and persisted until the end of the analysis without showing signs of loss of function; indeed, DOT cells proliferated and produced abundant IFN and TNFα, but importantly no IL17, in vivo. Critically, DOT cells were capable of inhibiting tumor growth and preventing dissemination in xenograft models of CLL.

Conclusions: We provide a clinical-grade method and the preclinical proof of principle for application of a new cellular product, DOT cells, in adoptive immunotherapy of CLL. Clin Cancer Res; 22(23); 5795–804. ©2016 AACR.



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Immunotherapy in Endometrial Cancer: In the Nick of Time

Immunotherapy with checkpoint inhibitors is changing the face of oncology treatments for many tumors, and endometrial carcinoma may not be an exception. Several endometrial cancer groups from the molecular taxonomy are characterized by having an ultramutated/hypermutated genome, which could be the first Achilles' heel identified in this malignancy in decades. Clin Cancer Res; 22(23); 5623–5. ©2016 AACR.

See related article by Santin et al., p. 5682



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TransCONFIRM: Identification of a Genetic Signature of Response to Fulvestrant in Advanced Hormone Receptor-Positive Breast Cancer

Purpose: Fulvestrant is an estrogen receptor (ER) antagonist and an approved treatment for metastatic estrogen receptor–positive (ER+) breast cancer. With the exception of ER levels, there are no established predictive biomarkers of response to single-agent fulvestrant. We attempted to identify a gene signature of response to fulvestrant in advanced breast cancer.

Experimental Design: Primary tumor samples from 134 patients enrolled in the phase III CONFIRM study of patients with metastatic ER+ breast cancer comparing treatment with either 250 mg or 500 mg fulvestrant were collected for genome-wide transcriptomic analysis. Gene expression profiling was performed using Affymetrix microarrays. An exploratory analysis was performed to identify biologic pathways and new signatures associated with response to fulvestrant.

Results: Pathway analysis demonstrated that increased EGF pathway and FOXA1 transcriptional signaling is associated with decreased response to fulvestrant. Using a multivariate Cox model, we identified a novel set of 37 genes with an expression that is independently associated with progression-free survival (PFS). TFAP2C, a known regulator of ER activity, was ranked second in this gene set, and high expression was associated with a decreased response to fulvestrant. The negative predictive value of TFAP2C expression at the protein level was confirmed by IHC.

Conclusions: We identified biologic pathways and a novel gene signature in primary ER+ breast cancers that predicts for response to treatment in the CONFIRM study. These results suggest potential new therapeutic targets and warrant further validation as predictive biomarkers of fulvestrant treatment in metastatic breast cancer. Clin Cancer Res; 22(23); 5755–64. ©2016 AACR.



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Pharmacokinetically Guided Dosing of Oral Drugs: True Precision Oncology?

Higher plasma concentrations of tyrosine kinase inhibitors (TKI), such as pazopanib, are associated with improved clinical outcomes. However, TKI pharmacokinetics exhibit significant interpatient variability, resulting in inconsistent and unpredictable plasma drug levels. An individualized dosing approach based on patient pharmacokinetics data and toxicity can potentially optimize plasma concentrations of pazopanib. Clin Cancer Res; 22(23); 5626–8. ©2016 AACR.

See related article by Verheijen et al., p. 5738



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Repurposing Sunitinib with Oncolytic Reovirus as a Novel Immunotherapeutic Strategy for Renal Cell Carcinoma

Purpose: In addition to their direct cytopathic effects, oncolytic viruses are capable of priming antitumor immune responses. However, strategies to enhance the immunotherapeutic potential of these agents are lacking. Here, we investigated the ability of the multi-tyrosine kinase inhibitor and first-line metastatic renal cell carcinoma (RCC) agent, sunitinib, to augment the antitumor immune response generated by oncolytic reovirus.

Experimental Design: In vitro, oncolysis and chemokine production were assessed in a panel of human and murine RCC cell lines after exposure to reovirus, sunitinib, or their combination. In vivo, the RENCA syngeneic murine model of RCC was employed to determine therapeutic and tumor-specific immune responses after treatment with reovirus (intratumoral), sunitinib, or their combination. Parallel investigations employing the KLN205 syngeneic murine model of lung squamous cell carcinoma (NSCLC) were conducted for further validation.

Results: Reovirus-mediated oncolysis and chemokine production was observed following RCC infection. Reovirus monotherapy reduced tumor burden and was capable of generating a systemic adaptive antitumor immune response evidenced by increased numbers of tumor-specific CD8+ IFN-producing cells. Coadministration of sunitinib with reovirus further reduced tumor burden resulting in improved survival, decreased accumulation of immune suppressor cells, and the establishment of protective immunity upon tumor rechallenge. Similar results were observed for KLN205 tumor–bearing mice, highlighting the potential broad applicability of this approach.

Conclusions: The ability to repurpose sunitinib for augmentation of reovirus' immunotherapeutic efficacy positions this novel combination therapy as an attractive strategy ready for clinical testing against a range of histologies, including RCC and NSCLC. Clin Cancer Res; 22(23); 5839–50. ©2016 AACR.



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How to Deal with Interval-Censored Data Practically while Assessing the Progression-Free Survival: A Step-by-Step Guide Using SAS and R Software

We describe how to estimate progression-free survival while dealing with interval-censored data in the setting of clinical trials in oncology. Three procedures with SAS and R statistical software are described: one allowing for a nonparametric maximum likelihood estimation of the survival curve using the EM-ICM (Expectation and Maximization-Iterative Convex Minorant) algorithm as described by Wellner and Zhan in 1997; a sensitivity analysis procedure in which the progression time is assigned (i) at the midpoint, (ii) at the upper limit (reflecting the standard analysis when the progression time is assigned at the first radiologic exam showing progressive disease), or (iii) at the lower limit of the censoring interval; and finally, two multiple imputations are described considering a uniform or the nonparametric maximum likelihood estimation (NPMLE) distribution. Clin Cancer Res; 22(23); 5629–35. ©2016 AACR.



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Expression of CDK7, Cyclin H, and MAT1 Is Elevated in Breast Cancer and Is Prognostic in Estrogen Receptor-Positive Breast Cancer

Purpose: CDK-activating kinase (CAK) is required for the regulation of the cell cycle and is a trimeric complex consisting of cyclin-dependent kinase 7 (CDK7), Cyclin H, and the accessory protein, MAT1. CDK7 also plays a critical role in regulating transcription, primarily by phosphorylating RNA polymerase II, as well as transcription factors such as estrogen receptor-α (ER). Deregulation of cell cycle and transcriptional control are general features of tumor cells, highlighting the potential for the use of CDK7 inhibitors as novel cancer therapeutics.

Experimental Design: mRNA and protein expression of CDK7 and its essential cofactors cyclin H and MAT1 were evaluated in breast cancer samples to determine if their levels are altered in cancer. Immunohistochemical staining of >900 breast cancers was used to determine the association with clinicopathologic features and patient outcome.

Results: We show that expressions of CDK7, cyclin H, and MAT1 are all closely linked at the mRNA and protein level, and their expression is elevated in breast cancer compared with the normal breast tissue. Intriguingly, CDK7 expression was inversely proportional to tumor grade and size, and outcome analysis showed an association between CAK levels and better outcome. Moreover, CDK7 expression was positively associated with ER expression and in particular with phosphorylation of ER at serine 118, a site important for ER transcriptional activity.

Conclusions: Expressions of components of the CAK complex, CDK7, MAT1, and Cyclin H are elevated in breast cancer and correlate with ER. Like ER, CDK7 expression is inversely proportional to poor prognostic factors and survival. Clin Cancer Res; 22(23); 5929–38. ©2016 AACR.



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Molecular Pathways: Dietary Regulation of Stemness and Tumor Initiation by the PPAR-{delta} Pathway

Peroxisome proliferator-activated receptor delta (PPAR-) is a nuclear receptor transcription factor that regulates gene expression during development and disease states, such as cancer. However, the precise role of PPAR- during tumorigenesis is not well understood. Recent data suggest that PPAR- may have context-specific oncogenic and tumor-suppressive roles depending on the tissue, cell-type, or diet-induced physiology in question. For example, in the intestine, pro-obesity diets, such as a high-fat diet (HFD), are associated with increased colorectal cancer incidence. Interestingly, many of the effects of an HFD in the stem and progenitor cell compartment are driven by a robust PPAR- program and contribute to the early steps of intestinal tumorigenesis. Importantly, the PPAR- pathway or its downstream mediators may serve as therapeutic intervention points or biomarkers in colon cancer that arise in patients who are obese. Although potent PPAR- agonists and antagonists exist, their clinical utility may be enhanced by uncovering how PPAR- mediates tumorigenesis in diverse tissues and cell types as well as in response to diet. Clin Cancer Res; 22(23); 5636–41. ©2016 AACR.



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Detection of Therapeutically Targetable Driver and Resistance Mutations in Lung Cancer Patients by Next-Generation Sequencing of Cell-Free Circulating Tumor DNA

Purpose: The expanding number of targeted therapeutics for non–small cell lung cancer (NSCLC) necessitates real-time tumor genotyping, yet tissue biopsies are difficult to perform serially and often yield inadequate DNA for next-generation sequencing (NGS). We evaluated the feasibility of using cell-free circulating tumor DNA (ctDNA) NGS as a complement or alternative to tissue NGS.

Experimental Design: A total of 112 plasma samples obtained from a consecutive study of 102 prospectively enrolled patients with advanced NSCLC were subjected to ultra-deep sequencing of up to 70 genes and matched with tissue samples, when possible.

Results: We detected 275 alterations in 45 genes, and at least one alteration in the ctDNA for 86 of 102 patients (84%), with EGFR variants being most common. ctDNA NGS detected 50 driver and 12 resistance mutations, and mutations in 22 additional genes for which experimental therapies, including clinical trials, are available. Although ctDNA NGS was completed for 102 consecutive patients, tissue sequencing was only successful for 50 patients (49%). Actionable EGFR mutations were detected in 24 tissue and 19 ctDNA samples, yielding concordance of 79%, with a shorter time interval between tissue and blood collection associated with increased concordance (P = 0.038). ctDNA sequencing identified eight patients harboring a resistance mutation who developed progressive disease while on targeted therapy, and for whom tissue sequencing was not possible.

Conclusions: Therapeutically targetable driver and resistance mutations can be detected by ctDNA NGS, even when tissue is unavailable, thus allowing more accurate diagnosis, improved patient management, and serial sampling to monitor disease progression and clonal evolution. Clin Cancer Res; 22(23); 5772–82. ©2016 AACR.



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Genomic Approaches to Understanding Response and Resistance to Immunotherapy

Immunotherapy has led to a paradigm shift in the treatment of some malignancies, providing long-term, durable responses for patients with advanced cancers. However, such therapy has benefited only a subset of patients, with some patients failing to respond to treatment at all and others achieving a limited response followed by tumor progression. Understanding factors contributing to an effective response and further elucidating mechanisms of resistance will be crucial as these therapies are applied more broadly. Genomics-based approaches have significantly advanced the study of response and resistance to immunotherapy in general, and to immune checkpoint blockade more specifically. Here, we review how genomic and transcriptomic approaches have identified both somatic and germline positive correlates of response, including high mutational/neoantigen load and low intratumoral heterogeneity, among others. The genomic analysis of resistant tumors has additionally identified crucial factors involved in resistance to immune checkpoint blockade, including loss of PTEN and upregulation of other immune checkpoints. Overall, the continued use of genomic techniques at the point of care, combined with appropriate functional studies, would ideally lead to a better understanding of why certain patients respond to immune-based therapies, allowing clinicians to identify the subset of patients likely to benefit from such therapy, and potentially providing insight into how other therapies may be added in combination to increase the number of patients who may benefit from immunotherapy. Clin Cancer Res; 22(23); 5642–50. ©2016 AACR.



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PI3K Pathway Inhibition Achieves Potent Antitumor Activity in Melanoma Brain Metastases In Vitro and In Vivo

Purpose: Great advances have recently been made in treating patients with metastatic melanoma. However, existing therapies are less effective on cerebral than extracerebral metastases. This highlights the potential role of the brain environment on tumor progression and drug resistance and underlines the need for "brain-specific" therapies. We previously showed that the PI3K-AKT survival pathway is hyperactivated in brain but not extracerebral melanoma metastases and that astrocyte-conditioned medium activates AKT in melanoma cells in vitro. We therefore tested the PI3K inhibitor buparlisib as an antitumor agent for melanoma brain metastases.

Experimental Design and Results: Buparlisib inhibited AKT activity, decreased proliferation, and induced apoptosis in metastatic melanoma cell lines and short-term brain melanoma cells, irrespective of their BRAF and NRAS mutation status. In addition, buparlisib inhibited hyperactivated AKT and induced apoptosis in melanoma cells that were stimulated with astrocyte-conditioned medium. The growth of tumors induced by injecting human BRAF- and NRAS-mutant metastatic melanoma cells into the brain of mice was significantly inhibited by buparlisib.

Conclusions: These results emphasize the value of targeting the PI3K pathway as a strategy to develop drugs for melanoma brain metastases. Clin Cancer Res; 22(23); 5818–28. ©2016 AACR.



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Biomarkers of Response and Resistance to DNA Repair Targeted Therapies

Drugs targeting DNA damage repair (DDR) pathways are exciting new agents in cancer therapy. Many of these drugs exhibit synthetic lethality with defects in DNA repair in cancer cells. For example, ovarian cancers with impaired homologous recombination DNA repair show increased sensitivity to poly(ADP-ribose) polymerase (PARP) inhibitors. Understanding the activity of different DNA repair pathways in individual tumors, and the correlations between DNA repair function and drug response, will be critical to patient selection for DNA repair targeted agents. Genomic and functional assays of DNA repair pathway activity are being investigated as potential biomarkers of response to targeted therapies. Furthermore, alterations in DNA repair function generate resistance to DNA repair targeted agents, and DNA repair states may predict intrinsic or acquired drug resistance. In this review, we provide an overview of DNA repair targeted agents currently in clinical trials and the emerging biomarkers of response and resistance to these agents: genetic and genomic analysis of DDR pathways, genomic signatures of mutational processes, expression of DNA repair proteins, and functional assays for DNA repair capacity. We review biomarkers that may predict response to selected DNA repair targeted agents, including PARP inhibitors, inhibitors of the DNA damage sensors ATM and ATR, and inhibitors of nonhomologous end joining. Finally, we introduce emerging categories of drugs targeting DDR and new strategies for integrating DNA repair targeted therapies into clinical practice, including combination regimens. Generating and validating robust biomarkers will optimize the efficacy of DNA repair targeted therapies and maximize their impact on cancer treatment. Clin Cancer Res; 22(23); 5651–60. ©2016 AACR.



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Maternal Embryonic Leucine Zipper Kinase (MELK) as a Novel Mediator and Biomarker of Radioresistance in Human Breast Cancer

Purpose: While effective targeted therapies exist for estrogen receptor–positive and HER2-positive breast cancer, no such effective therapies exist for triple-negative breast cancer (TNBC); thus, it is clear that additional targets for radiosensitization and treatment are critically needed.

Experimental Design: Expression microarrays, qRT-PCR, and Western blotting were used to assess MELK RNA and protein expression levels. Clonogenic survival assays were used to quantitate the radiosensitivity of cell lines at baseline and after MELK inhibition. The effect of MELK knockdown on DNA damage repair kinetics was determined using H2AX staining. The in vivo effect of MELK knockdown on radiosensitivity was performed using mouse xenograft models. Kaplan–Meier analysis was used to estimate local control and survival information, and a Cox proportional hazards model was constructed to identify potential factors impacting local recurrence-free survival.

Results: MELK expression is significantly elevated in breast cancer tissues compared with normal tissue as well as in TNBC compared with non-TNBC. MELK RNA and protein expression is significantly correlated with radioresistance in breast cancer cell lines. Inhibition of MELK (genetically and pharmacologically) induces radiation sensitivity in vitro and significantly delayed tumor growth in vivo in multiple models. Kaplan–Meier survival and multivariable analyses identify increasing MELK expression as being the strongest predictor of radioresistance and increased local recurrence in multiple independent datasets.

Conclusions: Here, we identify MELK as a potential biomarker of radioresistance and target for radiosensitization in TNBC. Our results support the rationale for developing clinical strategies to inhibit MELK as a novel target in TNBC. Clin Cancer Res; 22(23); 5864–75. ©2016 AACR.



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Clinical Significance of Circulating CD33+CD11b+HLA-DR- Myeloid Cells in Patients with Stage IV Melanoma Treated with Ipilimumab

Purpose: High levels of circulating myeloid-derived suppressor cells (MDSCs) in various cancer types, including melanoma, were shown to correlate with poor survival. We investigated whether frequencies of circulating CD33+CD11b+HLA-DR MDSCs could be used as immune system monitoring biomarkers to predict response and survival of patients with stage IV melanoma treated with anti-CTLA4 (ipilimumab) therapy.

Experimental Design: Peripheral blood samples from 56 patients and 50 healthy donors (HDs) were analyzed for CD33+CD11b+HLA-DR MDSC percentage, NO, and hROS levels by flow cytometry. We determined whether MDSC levels and suppressive features detected before anti-CTLA4 therapy correlate with the patients' response and overall survival (OS).

Results: Patients with melanoma had significantly higher levels of circulating CD33+CD11b+HLA-DR MDSCs with suppressive phenotype when compared with HDs. Low levels of MDSCs before CTLA-4 therapy correlated with an objective clinical response, long-term survival, increased CD247 expression in T cells, and an improved clinical status. No predictive impact was observed for lactate dehydrogenase (LDH). Kaplan–Meier and log-rank tests performed on the 56 patients showed that the presence of more than 55.5% of circulating CD33+CD11b+ out of the HLA-DR cells, were associated with significant short OS (P < 0.003), a median of 6.5 months, in comparison with the group showing lower MDSC frequencies, with a median survival of 15.6 months.

Conclusions: Our study suggests the use of CD33+CD11b+HLA-DR cells as a predictive and prognostic biomarker in patients with stage IV melanoma treated with anti-CTLA4 therapy. This monitoring system may aid in the development of combinatorial modalities, targeting the suppressive environment in conjunction with iplimumab, toward facilitating better disease outcomes. Clin Cancer Res; 22(23); 5661–72. ©2016 AACR.



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Racial/Ethnic Disparities in Ovarian Cancer Treatment and Survival

Purpose: Among patients with ovarian cancer, African American (AA) women experience poorer survival compared with other race/ethnicity groups. This has been attributed to differences in access to health care.

Experimental Design: We evaluated racial/ethnic differences in chemotherapy dosing and survival in a cohort study among members of Kaiser Permanente Northern California, and thus with equivalent access to health care. Analyses included epithelial-invasive ovarian cancer cases (n = 793) receiving adjuvant first-line therapy of carboplatin and paclitaxel with curative intent, with median follow-up of 50 months. Relative dose intensity (RDI) was computed for carboplatin and paclitaxel separately as dose administered per week divided by expected dose per week, and average RDI (ARDI) was then calculated for the regimen. Proportional hazards regression was used to calculate HRs and 95% confidence intervals (CIs) after adjusting for relevant covariates.

Results: Compared with whites, AAs were more likely to have dose reduction (ARDI < 85%), treatment delay, and early discontinuation. Hispanics were also more likely to have dose reduction, but less likely to have early discontinuation or treatment delay. After controlling for prognostic factors including ARDI, AA women had the worst survival. Compared with whites, adjusted HRs (95% CI) for overall mortality were 1.56 (1.01–2.39) for AAs; 0.89 (0.61–1.31) for Asians; and 1.41 (0.98–2.04) for Hispanics. Findings for ovarian cancer–specific mortality were similar.

Conclusions: Disparities in ovarian cancer treatment and survival in AA persisted among women with equal access to care. These findings warrant further evaluation of biological, personal, and social factors that may be responsible for these differences. Clin Cancer Res; 22(23); 5909–14. ©2016 AACR.



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Immunomodulatory Effect of Vitamin D after Allogeneic Stem Cell Transplantation: Results of a Prospective Multicenter Clinical Trial

Purpose: We describe the results of a prospective multicenter phase I/II trial evaluating the impact of the use of vitamin D (VitD) from day –5 to +100 on the outcome of patients undergoing allogeneic transplantation (EudraCT: 2010-023279-25; ClinicalTrials.gov: NCT02600988).

Experimental Design: A total of 150 patients were included in three consecutive cohorts of 50 patients each group: control group (CG, not receive VitD); low-dose group (LdD, received 1,000 IU VitD daily); and high-dose group (HdD, 5,000 IU VitD daily). We measured levels of VitD, cytokines, and immune subpopulations after transplantation.

Results: No significant differences were observed in terms of cumulative incidence of overall and grades 2–4 acute GVHD in terms of relapse, nonrelapse mortality, and overall survival. However, a significantly lower cumulative incidence of both overall and moderate plus severe chronic GVHD (cGVHD) at 1 year was observed in LdD (37.5% and 19.5%, respectively) and HdD (42.4% and 27%, respectively) as compared with CG (67.5% and 44.7%, respectively; P < 0.05). In multivariable analysis, treatment with VitD significantly decreased the risk of both overall (for LdD: HR = 0.31, P = 0.002; for HdD: HR = 0.36, P = 0.006) and moderate plus severe cGVHD (for LdD: HR = 0.22, P = 0.001; for HdD: HR = 0.33, P = 0.01). VitD modified the immune response, decreasing the number of B cells and naïve CD8 T cells, with a lower expression of CD40L.

Conclusions: This is the first prospective trial that analyzes the effect of VitD postransplant. We observed a significantly lower incidence of cGVHD among patients receiving VitD. Interestingly, VitD modified the immune response after allo-SCT. Clin Cancer Res; 22(23); 5673–81. ©2016 AACR.



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Highlights of This Issue



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Regression of Chemotherapy-Resistant Polymerase {varepsilon} (POLE) Ultra-Mutated and MSH6 Hyper-Mutated Endometrial Tumors with Nivolumab

Purpose: The management of endometrial carcinoma no longer amenable to treatment with surgery or radiotherapy has not improved significantly with modern chemotherapy. Alternative therapeutic options are desperately needed.

Experimental Design: We describe 2 heavily pretreated patients with recurrent disease refractory to surgery, radiotherapy, and chemotherapy who were treated with the anti–PD-1 immune checkpoint inhibitor nivolumab.

Results: Patient #1 harbored an ultra-mutated tumor (mutation load/MB = 117.3, total mutations = 4,660) driven by mutation in the exonuclease domain of the DNA polymerase gene. Patient #2 harbored a hyper-mutated tumor (mutation load/MB = 33.5, total mutations = 1,037) due to a germinal MSH6 gene mutation. Both patients demonstrated a remarkable clinical response to the anti–PD-1 immune checkpoint inhibitor nivolumab. Patients' clinical responses remain unchanged at the time of the writing of this report, with no grade 3 or higher side effects reported to date.

Conclusions: Anti–PD-1 inhibitors represent a novel treatment option for recurrent/metastatic, ultra/hyper-mutated human tumors refractory to salvage treatment. Clin Cancer Res; 22(23); 5682–7. ©2016 AACR.

See related commentary by Piulats and Matias-Guiu, p. 5623



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Large-scale Radiomic Profiling of Recurrent Glioblastoma Identifies an Imaging Predictor for Stratifying Anti-Angiogenic Treatment Response

Purpose: Antiangiogenic treatment with bevacizumab, a mAb to the VEGF, is the single most widely used therapeutic agent for patients with recurrent glioblastoma. A major challenge is that there are currently no validated biomarkers that can predict treatment outcome. Here we analyze the potential of radiomics, an emerging field of research that aims to utilize the full potential of medical imaging.

Experimental Design: A total of 4,842 quantitative MRI features were automatically extracted and analyzed from the multiparametric tumor of 172 patients (allocated to a discovery and validation set with a 2:1 ratio) with recurrent glioblastoma prior to bevacizumab treatment. Leveraging a high-throughput approach, radiomic features of patients in the discovery set were subjected to a supervised principal component (superpc) analysis to generate a prediction model for stratifying treatment outcome to antiangiogenic therapy by means of both progression-free and overall survival (PFS and OS).

Results: The superpc predictor stratified patients in the discovery set into a low or high risk group for PFS (HR = 1.60; P = 0.017) and OS (HR = 2.14; P < 0.001) and was successfully validated for patients in the validation set (HR = 1.85, P = 0.030 for PFS; HR = 2.60, P = 0.001 for OS).

Conclusions: Our radiomic-based superpc signature emerges as a putative imaging biomarker for the identification of patients who may derive the most benefit from antiangiogenic therapy, advances the knowledge in the noninvasive characterization of brain tumors, and stresses the role of radiomics as a novel tool for improving decision support in cancer treatment at low cost. Clin Cancer Res; 22(23); 5765–71. ©2016 AACR.



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Paediatric spinal cord infarction : A previously healthy 14-year-old female who began having difficulty breathing at school immediately after experiencing a burning sensation down her neck and back.

http://orl-medicine.blogspot.gr/2016/11/paediatric-spinal-cord-infarction.html

Alexandros Sfakianakis
Anapafseos 5 . Agios Nikolaos
Crete.Greece.72100
2841026182
6948891480

The evolution of the diminishing role of extrapleural pneumonectomy in the surgical management of malignant pleural mesothelioma

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Trastuzumab in the management of gastroesophageal cancer: patient selection and perspectives

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High expression of HMGA2 predicts poor survival in patients with clear cell renal cell carcinoma

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(Very) Early Technology Assessment and Translation of Predictive Biomarkers in Breast Cancer

Publication date: Available online 30 November 2016
Source:Cancer Treatment Reviews
Author(s): Anna Miquel-Cases, Philip C Schouten, Lotte MG Steuten, Valesca P Retèl, Sabine C Linn, Wim H van Harten
Predictive biomarkers can guide treatment decisions in breast cancer. Many studies are undertaken to discover and translate these biomarkers, yet few biomarkers make it to practice. Before use in clinical decision making, predictive biomarkers need to demonstrate analytical validity, clinical validity and clinical utility. While attaining analytical and clinical validity is relatively straightforward, by following methodological recommendations, the achievement of clinical utility is extremely challenging. It requires demonstrating three associations: the biomarker with the outcome (prognostic association), the effect of treatment independent of the biomarker, and the differential treatment effect between the prognostic and the predictive biomarker (predictive association). In addition, economical, ethical, regulatory, organizational and patient/doctor-related aspects are hampering the translational process. Traditionally, these aspects do not receive much attention until formal approval or reimbursement of a biomarker test (informed by health technology assessment (HTA)) is at stake, at which point the clinical utility and sometimes price of the test can hardly be influenced anymore. When HTA analyses are performed earlier, during biomarker research and development, they may prevent further development of those biomarkers unlikely to ever provide sufficient added value to society, and rather facilitate translation of the promising ones. Early HTA is particularly relevant for the predictive biomarker field, as expensive medicines are under pressure and the need for biomarkers to guide their appropriate use is huge. Closer interaction between clinical researchers and HTA experts throughout the translational research process will ensure that available data and methodologies will be used most efficiently to facilitate biomarker translation.



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Atezolizumab: a PD-L1 blocking antibody for bladder cancer

Atezolizumab (Tecentriq™, MPDL3280A) is an FcR-binding deficient, fully humanized, IgG1 monoclonal antibody designed to interfere with the binding of PD-L1 ligand to its two receptors, PD-1 and B7.1. By blocking the PD-L1/PD-1 immune checkpoint, atezolizumab reduces immunosuppressive signals found within the tumor microenvironement and consequently increases T cell mediated immunity against the tumor. Atezolizumab has been FDA-approved as second-line therapy for advanced bladder cancer. This accelerated approval was based on phase 2 trial data in patients with metastatic bladder cancer that showed unexpected and durable tumor responses. In subjects whose tumors progressed on first-line platinum-based chemotherapy, the objective response rate was 15%, the complete response rate was 5%, and 1-year overall survival was 36%. In subjects that were chemotherapy-naïve and cisplatin-ineligible, the objective response rate was 24%, the complete response rate was 7%, and 1-year overall survival was 57%. Better responses were associated with higher PD-L1 expression on the tumor-infiltrating leukocytes. These data suggest that patients with advanced bladder cancer treated with atezolizumab have significantly better response rates and survival than historical controls treated with other second-line regimens. The toxicity profile of atezolizumab is also favourable. Trials are currently assessing whether atezolizumab is effective in earlier bladder cancer stages and in the first line metastatic setting.



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A PAM50-based Chemo-Endocrine Score for Hormone Receptor-Positive Breast Cancer with an Intermediate Risk of Relapse

Purpose: Hormone receptor-positive (HR+) breast cancer is clinically and biologically heterogeneous and subgroups with different prognostic and treatment sensitivities need to be identified. Experimental design: Research-based PAM50 subtyping and expression of additional genes was performed on 63 patients with HR+/HER2- disease randomized to neoadjuvant multi-agent chemotherapy versus endocrine therapy in a phase II trial. The biology associated with treatment response was used to derive a PAM50-based Chemo-Endocrine Score (CES). CES's predictive ability was evaluated in 4 independent neoadjuvant datasets (n=675) and 4 adjuvant datasets (n=1,505). The association of CES, intrinsic biology and PAM50 risk of relapse (ROR) was explored across 6,007 tumors. Results: Genes associated with endocrine sensitivity were also found associated with chemotherapy resistance. In the chemotherapy test/validation datasets, CES was independently associated with pathological complete response, even after adjusting for intrinsic subtype. pCR rates of the CES endocrine sensitive (CES-E), uncertain (CES-U) and chemotherapy sensitive (CES-C) groups in both datasets combined were 25%, 11% and 2%, respectively. In the endocrine test/validation datasets, CES was independently associated with response. Compared to ROR, >90% of ROR-low and ROR-high tumors were identified as CES-E and CES-C, respectively; however, each CES-group represented >25% of ROR-intermediate disease. In terms of survival outcome, CES-C was associated with poor relapse-free survival in patients with ROR-intermediate disease treated with adjuvant endocrine therapy-only or no adjuvant systemic therapy, but not in patients treated with (neo)adjuvant chemotherapy. Conclusions: CES is a genomic signature capable of estimating chemo-endocrine sensitivity in HR+ breast cancer beyond intrinsic subtype and risk of relapse.



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The Bruton's tyrosine kinase (BTK) inhibitor acalabrutinib demonstrates potent on-target effects and efficacy in two mouse models of chronic lymphocytic leukemia

Purpose: Acalabrutinib (ACP-196) is a novel, potent, and highly selective BTK inhibitor, which binds covalently to Cys481 in the ATP-binding pocket of BTK. We sought to evaluate the anti-tumor effects of acalabrutinib treatment in two established mouse models of chronic lymphocytic leukemia (CLL). Experimental Design: Two distinct mouse models were used, the TCL1 adoptive transfer model where leukemic cells from Eμ-TCL1 transgenic mice are transplanted into C57BL/6 mice, and the human NSG primary CLL xenograft model. Mice received either vehicle or acalabrutinib formulated into the drinking water. Results: Utilizing biochemical assays we demonstrate that acalabrutinib is a highly selective BTK inhibitor as compared to ibrutinib. In the human CLL NSG xenograft model, treatment with acalabrutinib demonstrated on-target effects including decreased phosphorylation of PLC2, ERK and significant inhibition of CLL cell proliferation. Further, tumor burden in the spleen of the mice treated with acalabrutinib was significantly decreased compared to vehicle treated mice. Similarly, in the TCL1 adoptive transfer model, decreased phosphorylation of BTK, PLC2 and S6 was observed. Most notably, treatment with acalabrutinib resulted in a significant increase in survival compared to mice receiving vehicle. Conclusions: Treatment with acalabrutinib potently inhibits BTK in vivo, leading to on-target decreases in the activation of key signaling molecules (including BTK, PLC2, S6 and ERK). In two complementary mouse models of CLL acalabrutinib significantly reduced tumor burden and increased survival compared to vehicle treatment. Overall, acalabrutinib showed increased BTK selectivity compared to ibrutinib while demonstrating significant anti-tumor efficacy in vivo on par with ibrutinib.



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Combining anti-miR-155 with chemotherapy for the treatment of lung cancers

Purpose The oncogenic miR-155 is upregulated in many human cancers and its expression is increased in more aggressive and therapy resistant tumors, but the molecular mechanisms underlying miR-155-induced therapy resistance are not fully understood. The main objectives of this study were to determine the role of miR-155 in resistance to chemotherapy and to evaluate anti-miR-155 treatment to chemosensitize tumors. Experimental Design We performed in vitro studies on cell lines to investigate the role of miR-155 in therapy resistance. To assess the effects of miR-155 inhibition on chemoresistance, we used an in vivo orthotopic lung cancer model of athymic nude mice, which we treated with anti-miR-155 alone or in combination with chemotherapy. To analyze the association of miR-155 expression and the combination of miR-155 and TP53 expression with cancer survival, we studied 956 patients with lung cancer, chronic lymphocytic leukemia and acute lymphoblastic leukemia. Results We demonstrate that miR-155 induces resistance to multiple chemotherapeutic agents in vitro, and that downregulation of miR-155 successfully resensitizes tumors to chemotherapy in vivo. We show that anti-miR-155-DOPC can be considered non-toxic in vivo. We further demonstrate that miR-155 and TP53 are linked in a negative feedback mechanism, and demonstrate that a combination of high expression of miR-155 and low expression of TP53 is significantly associated with shorter survival in lung cancer. Conclusions Our findings support the existence of a miR-155/TP53 feedback loop, which is involved in resistance to chemotherapy and which can be specifically targeted to overcome drug resistance, an important cause of cancer-related death.



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ADNP is a therapeutically inducible repressor of WNT signaling in colorectal cancer

Purpose: Constitutively active WNT signaling is hallmark of colorectal cancers and driver of malignant tumor progression. Therapeutic targeting of WNT signaling is difficult due to high pathway complexity and its role in tissue homeostasis. Here we identify the transcription factor ADNP as a pharmacologically inducible repressor of WNT signaling in colon cancer. Experimental design: We used transcriptomic, proteomic, and in situ analyses to identify ADNP expression in colorectal cancer, and cell biology approaches to determine its function. We induced ADNP expression in colon cancer xenografts by low-dose ketamine in vivo. Clinical associations were determined in a cohort of 221 human colorectal cancer cases. Results: ADNP was overexpressed in colon cancer cells with high WNT activity, where it acted as a WNT repressor. Silencing ADNP expression increased migration, invasion and proliferation of colon cancer cells, and accelerated tumor growth in xenografts in vivo. Treatment with sub-narcotic doses of ketamine induced ADNP expression, significantly inhibited tumor growth, and prolonged survival of tumor bearing animals. In human colon cancer patients, high ADNP expression was linked to good prognosis. Conclusion: Our findings indicate ADNP as a tumor suppressor and promising prognostic marker, and ketamine treatment with ADNP induction as a potential therapeutic approach that may add to current treatment protocols with benefits for colorectal cancer patients.



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Combined inhibition of both p110{alpha} and p110{beta} isoforms of phosphatidylinositol 3-kinase is required for sustained therapeutic effect in PTEN-deficient, ER+ breast cancer

Purpose: Determine the roles of the phosphatidylinositol 3-kinase (PI3K) isoforms p110α and p110β in PTEN-deficient, estrogen receptor α (ER)-positive breast cancer, and the therapeutic potential of isoform-selective inhibitors. Experimental Design: Anti-estrogen-sensitive and -resistant PTEN-deficient, ER+ human breast cancer cell lines, and mice bearing anti-estrogen-resistant xenografts were treated with the anti-estrogen fulvestrant, the p110α inhibitor BYL719, the p110β inhibitor GSK2636771, or combinations. Temporal response to growth factor receptor-initiated signaling, growth, apoptosis, predictive biomarkers, and tumor volumes were measured. Results: p110β primed cells for response to growth factor stimulation. While p110β inhibition suppressed cell and tumor growth, dual targeting of p110α/β enhanced apoptosis and provided sustained tumor response. The growth of anti-estrogen-sensitive cells was inhibited by fulvestrant, but fulvestrant inconsistently provided additional therapeutic effects beyond PI3K inhibition alone. Treatment-induced decreases in phosphorylation of AKT and Rb were predictive of therapeutic response. Short-term drug treatment induced tumor cell apoptosis and proliferative arrest to induce tumor regression, while long-term treatment only suppressed proliferation to provide durable regression. Conclusions: p110β is the dominant PI3K isoform in PTEN-deficient, ER+ breast cancer cells. Upon p110β inhibition, p110α did not induce significant reactivation of AKT, but combined targeting of p110α/β most effectively induced apoptosis in vitro and in vivo and provided durable tumor regression. Since apoptosis and tumor regression occurred early but not late in the treatment course, and proliferative arrest was maintained throughout treatment, p110α/β inhibitors may be considered short-term cytotoxic agents and long-term cytostatic agents.



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hERG channels: from antitargets to novel targets for cancer therapy

In this issue of Clinical Cancer Research, evidence is provided on how to avoid cardiotoxicity when targeting hERG K+ channel for cancer therapy. hERG regulates different aspects of neoplastic progression. Although its blockade has effective anticancer effects in experimental models, it may lead to fatal arrhythmias in humans. Conclusions:



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Atezolizumab: a PD-L1 blocking antibody for bladder cancer

Atezolizumab (Tecentriq™, MPDL3280A) is an FcR-binding deficient, fully humanized, IgG1 monoclonal antibody designed to interfere with the binding of PD-L1 ligand to its two receptors, PD-1 and B7.1. By blocking the PD-L1/PD-1 immune checkpoint, atezolizumab reduces immunosuppressive signals found within the tumor microenvironement and consequently increases T cell mediated immunity against the tumor. Atezolizumab has been FDA-approved as second-line therapy for advanced bladder cancer. This accelerated approval was based on phase 2 trial data in patients with metastatic bladder cancer that showed unexpected and durable tumor responses. In subjects whose tumors progressed on first-line platinum-based chemotherapy, the objective response rate was 15%, the complete response rate was 5%, and 1-year overall survival was 36%. In subjects that were chemotherapy-naïve and cisplatin-ineligible, the objective response rate was 24%, the complete response rate was 7%, and 1-year overall survival was 57%. Better responses were associated with higher PD-L1 expression on the tumor-infiltrating leukocytes. These data suggest that patients with advanced bladder cancer treated with atezolizumab have significantly better response rates and survival than historical controls treated with other second-line regimens. The toxicity profile of atezolizumab is also favourable. Trials are currently assessing whether atezolizumab is effective in earlier bladder cancer stages and in the first line metastatic setting.



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A PAM50-based Chemo-Endocrine Score for Hormone Receptor-Positive Breast Cancer with an Intermediate Risk of Relapse

Purpose: Hormone receptor-positive (HR+) breast cancer is clinically and biologically heterogeneous and subgroups with different prognostic and treatment sensitivities need to be identified. Experimental design: Research-based PAM50 subtyping and expression of additional genes was performed on 63 patients with HR+/HER2- disease randomized to neoadjuvant multi-agent chemotherapy versus endocrine therapy in a phase II trial. The biology associated with treatment response was used to derive a PAM50-based Chemo-Endocrine Score (CES). CES's predictive ability was evaluated in 4 independent neoadjuvant datasets (n=675) and 4 adjuvant datasets (n=1,505). The association of CES, intrinsic biology and PAM50 risk of relapse (ROR) was explored across 6,007 tumors. Results: Genes associated with endocrine sensitivity were also found associated with chemotherapy resistance. In the chemotherapy test/validation datasets, CES was independently associated with pathological complete response, even after adjusting for intrinsic subtype. pCR rates of the CES endocrine sensitive (CES-E), uncertain (CES-U) and chemotherapy sensitive (CES-C) groups in both datasets combined were 25%, 11% and 2%, respectively. In the endocrine test/validation datasets, CES was independently associated with response. Compared to ROR, >90% of ROR-low and ROR-high tumors were identified as CES-E and CES-C, respectively; however, each CES-group represented >25% of ROR-intermediate disease. In terms of survival outcome, CES-C was associated with poor relapse-free survival in patients with ROR-intermediate disease treated with adjuvant endocrine therapy-only or no adjuvant systemic therapy, but not in patients treated with (neo)adjuvant chemotherapy. Conclusions: CES is a genomic signature capable of estimating chemo-endocrine sensitivity in HR+ breast cancer beyond intrinsic subtype and risk of relapse.



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The Bruton's tyrosine kinase (BTK) inhibitor acalabrutinib demonstrates potent on-target effects and efficacy in two mouse models of chronic lymphocytic leukemia

Purpose: Acalabrutinib (ACP-196) is a novel, potent, and highly selective BTK inhibitor, which binds covalently to Cys481 in the ATP-binding pocket of BTK. We sought to evaluate the anti-tumor effects of acalabrutinib treatment in two established mouse models of chronic lymphocytic leukemia (CLL). Experimental Design: Two distinct mouse models were used, the TCL1 adoptive transfer model where leukemic cells from Eμ-TCL1 transgenic mice are transplanted into C57BL/6 mice, and the human NSG primary CLL xenograft model. Mice received either vehicle or acalabrutinib formulated into the drinking water. Results: Utilizing biochemical assays we demonstrate that acalabrutinib is a highly selective BTK inhibitor as compared to ibrutinib. In the human CLL NSG xenograft model, treatment with acalabrutinib demonstrated on-target effects including decreased phosphorylation of PLC2, ERK and significant inhibition of CLL cell proliferation. Further, tumor burden in the spleen of the mice treated with acalabrutinib was significantly decreased compared to vehicle treated mice. Similarly, in the TCL1 adoptive transfer model, decreased phosphorylation of BTK, PLC2 and S6 was observed. Most notably, treatment with acalabrutinib resulted in a significant increase in survival compared to mice receiving vehicle. Conclusions: Treatment with acalabrutinib potently inhibits BTK in vivo, leading to on-target decreases in the activation of key signaling molecules (including BTK, PLC2, S6 and ERK). In two complementary mouse models of CLL acalabrutinib significantly reduced tumor burden and increased survival compared to vehicle treatment. Overall, acalabrutinib showed increased BTK selectivity compared to ibrutinib while demonstrating significant anti-tumor efficacy in vivo on par with ibrutinib.



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Combining anti-miR-155 with chemotherapy for the treatment of lung cancers

Purpose The oncogenic miR-155 is upregulated in many human cancers and its expression is increased in more aggressive and therapy resistant tumors, but the molecular mechanisms underlying miR-155-induced therapy resistance are not fully understood. The main objectives of this study were to determine the role of miR-155 in resistance to chemotherapy and to evaluate anti-miR-155 treatment to chemosensitize tumors. Experimental Design We performed in vitro studies on cell lines to investigate the role of miR-155 in therapy resistance. To assess the effects of miR-155 inhibition on chemoresistance, we used an in vivo orthotopic lung cancer model of athymic nude mice, which we treated with anti-miR-155 alone or in combination with chemotherapy. To analyze the association of miR-155 expression and the combination of miR-155 and TP53 expression with cancer survival, we studied 956 patients with lung cancer, chronic lymphocytic leukemia and acute lymphoblastic leukemia. Results We demonstrate that miR-155 induces resistance to multiple chemotherapeutic agents in vitro, and that downregulation of miR-155 successfully resensitizes tumors to chemotherapy in vivo. We show that anti-miR-155-DOPC can be considered non-toxic in vivo. We further demonstrate that miR-155 and TP53 are linked in a negative feedback mechanism, and demonstrate that a combination of high expression of miR-155 and low expression of TP53 is significantly associated with shorter survival in lung cancer. Conclusions Our findings support the existence of a miR-155/TP53 feedback loop, which is involved in resistance to chemotherapy and which can be specifically targeted to overcome drug resistance, an important cause of cancer-related death.



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ADNP is a therapeutically inducible repressor of WNT signaling in colorectal cancer

Purpose: Constitutively active WNT signaling is hallmark of colorectal cancers and driver of malignant tumor progression. Therapeutic targeting of WNT signaling is difficult due to high pathway complexity and its role in tissue homeostasis. Here we identify the transcription factor ADNP as a pharmacologically inducible repressor of WNT signaling in colon cancer. Experimental design: We used transcriptomic, proteomic, and in situ analyses to identify ADNP expression in colorectal cancer, and cell biology approaches to determine its function. We induced ADNP expression in colon cancer xenografts by low-dose ketamine in vivo. Clinical associations were determined in a cohort of 221 human colorectal cancer cases. Results: ADNP was overexpressed in colon cancer cells with high WNT activity, where it acted as a WNT repressor. Silencing ADNP expression increased migration, invasion and proliferation of colon cancer cells, and accelerated tumor growth in xenografts in vivo. Treatment with sub-narcotic doses of ketamine induced ADNP expression, significantly inhibited tumor growth, and prolonged survival of tumor bearing animals. In human colon cancer patients, high ADNP expression was linked to good prognosis. Conclusion: Our findings indicate ADNP as a tumor suppressor and promising prognostic marker, and ketamine treatment with ADNP induction as a potential therapeutic approach that may add to current treatment protocols with benefits for colorectal cancer patients.



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Combined inhibition of both p110{alpha} and p110{beta} isoforms of phosphatidylinositol 3-kinase is required for sustained therapeutic effect in PTEN-deficient, ER+ breast cancer

Purpose: Determine the roles of the phosphatidylinositol 3-kinase (PI3K) isoforms p110α and p110β in PTEN-deficient, estrogen receptor α (ER)-positive breast cancer, and the therapeutic potential of isoform-selective inhibitors. Experimental Design: Anti-estrogen-sensitive and -resistant PTEN-deficient, ER+ human breast cancer cell lines, and mice bearing anti-estrogen-resistant xenografts were treated with the anti-estrogen fulvestrant, the p110α inhibitor BYL719, the p110β inhibitor GSK2636771, or combinations. Temporal response to growth factor receptor-initiated signaling, growth, apoptosis, predictive biomarkers, and tumor volumes were measured. Results: p110β primed cells for response to growth factor stimulation. While p110β inhibition suppressed cell and tumor growth, dual targeting of p110α/β enhanced apoptosis and provided sustained tumor response. The growth of anti-estrogen-sensitive cells was inhibited by fulvestrant, but fulvestrant inconsistently provided additional therapeutic effects beyond PI3K inhibition alone. Treatment-induced decreases in phosphorylation of AKT and Rb were predictive of therapeutic response. Short-term drug treatment induced tumor cell apoptosis and proliferative arrest to induce tumor regression, while long-term treatment only suppressed proliferation to provide durable regression. Conclusions: p110β is the dominant PI3K isoform in PTEN-deficient, ER+ breast cancer cells. Upon p110β inhibition, p110α did not induce significant reactivation of AKT, but combined targeting of p110α/β most effectively induced apoptosis in vitro and in vivo and provided durable tumor regression. Since apoptosis and tumor regression occurred early but not late in the treatment course, and proliferative arrest was maintained throughout treatment, p110α/β inhibitors may be considered short-term cytotoxic agents and long-term cytostatic agents.



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hERG channels: from antitargets to novel targets for cancer therapy

In this issue of Clinical Cancer Research, evidence is provided on how to avoid cardiotoxicity when targeting hERG K+ channel for cancer therapy. hERG regulates different aspects of neoplastic progression. Although its blockade has effective anticancer effects in experimental models, it may lead to fatal arrhythmias in humans. Conclusions:



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Recommendations of the Austrian Working Group on Pulmonary Pathology and Oncology for predictive molecular and immunohistochemical testing in non-small cell lung cancer

Summary

The introduction of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKI) in the therapy of non-small cell lung cancer (NSCLC) with activating mutations of the EGF receptor has opened a new area of lung cancer treatment strategies and led to an enthusiastic search for additional genetic aberrations. Genetic drivers such as EML4-ALK (EML4: echinoderm microtubule-associated protein-like 4; ALK: anaplastic lymphoma kinase) and proto-oncogene tyrosine protein kinase transcribed from the ROS1-gene (ROS1) rearrangements have been detected and specific treatment options have been developed. A new approach to treatment in lung cancer is immunotherapy by antibodies interfering with immune checkpoint controls. Diagnostic and predictive immunohistochemical staining and molecular tests have to follow specific rules, if applied in daily practice. The Austrian Working Group on Pulmonary Pathology and Oncology (AWGPPO) has presented an updated version of the previous recommendations published in 2013. Questions raised during the past 3 years will be addressed: selection of tissue, order of diagnostic immunohistochemical and molecular tests, "reflex" testing, the issue of resistance mechanisms, significance of liquid biopsies, and use and interpretation of antibody reactions for immune checkpoint markers.



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Searching for the Achilles’ heel of cancer



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ASCO 2016: highlights in breast cancer

Summary

At the 2016 ASCO Annual Meeting, several pertinent studies in the field of breast cancer were presented. MA17.R was the first randomized phase III trial to evaluate the prolongation of adjuvant aromatase-inhibitor (AI) therapy from 5 to 10 years; while a significant reduction of disease-free survival events was observed in the extended treatment group, the absolute difference was relatively small and longer endocrine therapy resulted in a higher fracture rate. A combined analysis of three North American trials emphasized the superiority of anthracycline containing adjuvant chemotherapy regimens compared with docetaxel/cyclophosphamide (TC), while the PANTHER trial investigated dose-dense tailored adjuvant treatment. In metastatic breast cancer, the main interest was on cyclin-dependent kinase (CDK) 4/6 inhibitors. In PALOMA-2, the addition of palbociclib to letrozole prolonged progression-free survival (PFS) from 14.5 to 24.8 months resulting in the longest PFS data ever reported in the first-line setting. A subgroup analysis of premenopausal patients accrued to PALOMA-3 indicated that in this patient subset, ovarian function suppression plus fulvestrant and palbociclib yielded results comparable to the postmenopausal population. ESR1 mutations were another focus of interest as these activating mutations in the gene coding for the estrogen receptor alpha apparently evolve under the selection pressure of AI therapy.



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Recommendations of the Austrian Working Group on Pulmonary Pathology and Oncology for predictive molecular and immunohistochemical testing in non-small cell lung cancer

Summary

The introduction of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKI) in the therapy of non-small cell lung cancer (NSCLC) with activating mutations of the EGF receptor has opened a new area of lung cancer treatment strategies and led to an enthusiastic search for additional genetic aberrations. Genetic drivers such as EML4-ALK (EML4: echinoderm microtubule-associated protein-like 4; ALK: anaplastic lymphoma kinase) and proto-oncogene tyrosine protein kinase transcribed from the ROS1-gene (ROS1) rearrangements have been detected and specific treatment options have been developed. A new approach to treatment in lung cancer is immunotherapy by antibodies interfering with immune checkpoint controls. Diagnostic and predictive immunohistochemical staining and molecular tests have to follow specific rules, if applied in daily practice. The Austrian Working Group on Pulmonary Pathology and Oncology (AWGPPO) has presented an updated version of the previous recommendations published in 2013. Questions raised during the past 3 years will be addressed: selection of tissue, order of diagnostic immunohistochemical and molecular tests, "reflex" testing, the issue of resistance mechanisms, significance of liquid biopsies, and use and interpretation of antibody reactions for immune checkpoint markers.



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Searching for the Achilles’ heel of cancer



from Cancer via ola Kala on Inoreader http://ift.tt/2g77zSw
via IFTTT

ASCO 2016: highlights in breast cancer

Summary

At the 2016 ASCO Annual Meeting, several pertinent studies in the field of breast cancer were presented. MA17.R was the first randomized phase III trial to evaluate the prolongation of adjuvant aromatase-inhibitor (AI) therapy from 5 to 10 years; while a significant reduction of disease-free survival events was observed in the extended treatment group, the absolute difference was relatively small and longer endocrine therapy resulted in a higher fracture rate. A combined analysis of three North American trials emphasized the superiority of anthracycline containing adjuvant chemotherapy regimens compared with docetaxel/cyclophosphamide (TC), while the PANTHER trial investigated dose-dense tailored adjuvant treatment. In metastatic breast cancer, the main interest was on cyclin-dependent kinase (CDK) 4/6 inhibitors. In PALOMA-2, the addition of palbociclib to letrozole prolonged progression-free survival (PFS) from 14.5 to 24.8 months resulting in the longest PFS data ever reported in the first-line setting. A subgroup analysis of premenopausal patients accrued to PALOMA-3 indicated that in this patient subset, ovarian function suppression plus fulvestrant and palbociclib yielded results comparable to the postmenopausal population. ESR1 mutations were another focus of interest as these activating mutations in the gene coding for the estrogen receptor alpha apparently evolve under the selection pressure of AI therapy.



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Aryl hydrocarbon receptor induced intratumoral aromatase in breast cancer

Abstract

Purpose

Aryl hydrocarbon receptor (AhR) inhibits estrogen receptor (ER) pathway, which may suppress estrogen-dependent cell proliferation. However, the correlation between AhR stimulation and intratumoral estrogen synthesis, especially through aromatase, has not been reported to date. In the present study, we examined this correlation in breast cancer cells.

Methods

We examined AhR and aromatase immunoreactivity in 29 patients with invasive ductal carcinoma. We performed in vitro studies using three breast carcinoma cell lines, MCF-7, T47D, and MDA-MB-231.

Results

AhR stimulation induced the mRNA expression of the aromatase gene in vitro in three breast carcinoma cell lines, and increased estrogen synthesis in MCF-7 cell line. Results of microarray analysis showed that AhR-induced aromatase expression was associated with BRCA1 induction. Analysis of patients with breast cancer showed a significant positive correlation between intratumoral AhR and aromatase status. We also compared the effects of AhR stimulation on the induction of intratumoral estrogen synthesis and inhibition of the ER signaling pathway, because AhR exerts contradictory effects on estrogen action in breast carcinoma cells. AhR-induced aromatase expression persisted for a significantly longer duration than AhR-induced ER pathway inhibition. Moreover, breast carcinoma cells treated with an AhR agonist tended to show earlier cell proliferation after removing the agonist than cells not treated with the AhR agonist.

Conclusion

The results of the present study suggest that AhR stimulates estrogen-dependent progression of breast carcinoma by inducing aromatase expression under some conditions. These results provide new insights on the possible roles of environmental toxins in breast cancer development.



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Discordance between original and central laboratories in ER and HER2 results in a diverse, population-based sample

Abstract

Purpose

To investigate the discordance between original and central laboratories in estrogen receptor (ER) status, in tumors originally deemed to be ER-negative, and in HER2 status in a diverse population-based sample.

Methods

In a follow-up study of 1785 women with Stage I–III breast cancer diagnosed between 2005 and 2007 in the Detroit and Los Angeles County SEER registry catchment areas, participants were asked to consent to reassessment of ER (in tumors originally deemed to be ER-negative) and HER2 status on archival tumor samples approximately four years after diagnosis. Blocks were centrally prepared and analyzed for ER and HER2 using standardized methods and the guidelines of the American Society of Clinical Oncology and the College of American Pathologists. Analyses determined the discordance between original and central laboratories.

Results

132 (31%) of those eligible for ER reassessment and 367 (21%) eligible for HER2 reassessment had archival blocks reassessed centrally. ER discordance was only 6%. HER2 discordance by immunohistochemistry (IHC) was 26%, but final HER2 results—employing FISH in tumors that were IHC 2+ at the central laboratory—were discordant in only 6%. Half of the original laboratories did not perform their own assays.

Conclusions

Discordance between original and central laboratories in two large metropolitan areas was low in this population-based sample compared to previously reported patient samples. Centralization of testing for key pathology variables appears to be occurring in many hospitals. In addition, quality improvement efforts may have preceded the publication and dissemination of specialty society guidelines.



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Phlegmonous esophagitis treated by endoscopic drainage

Abstract

Phlegmonous esophagitis is a rare and sometimes fatal condition. Cases surgically treated have been reported previously; however, surgical approaches may be risky in the elderly. An 86-year-old woman presented with a sore throat and high fever after eating fish. She was first diagnosed with a deep cervical abscess, and conservative treatment was initially selected. However, her respiratory failure worsened, so emergent tracheostomy and surgical drainage were performed. Computed tomography showed intramural low-density lesions along the entire length of the esophagus and she was diagnosed with phlegmonous esophagitis. To avoid surgical intervention, endoscopic drainage was first attempted. Mucosal incision was made on the lower esophagus guided by endoscopic ultrasonography, using the insulated-tip electrosurgical knife. After the endoscopic drainage, her general health status improved, and the esophageal wall thickness was reduced. While some cases have recovered with conservative treatment, endoscopic drainage may be useful in certain patients.



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Phlegmonous esophagitis treated by endoscopic drainage

Abstract

Phlegmonous esophagitis is a rare and sometimes fatal condition. Cases surgically treated have been reported previously; however, surgical approaches may be risky in the elderly. An 86-year-old woman presented with a sore throat and high fever after eating fish. She was first diagnosed with a deep cervical abscess, and conservative treatment was initially selected. However, her respiratory failure worsened, so emergent tracheostomy and surgical drainage were performed. Computed tomography showed intramural low-density lesions along the entire length of the esophagus and she was diagnosed with phlegmonous esophagitis. To avoid surgical intervention, endoscopic drainage was first attempted. Mucosal incision was made on the lower esophagus guided by endoscopic ultrasonography, using the insulated-tip electrosurgical knife. After the endoscopic drainage, her general health status improved, and the esophageal wall thickness was reduced. While some cases have recovered with conservative treatment, endoscopic drainage may be useful in certain patients.



http://ift.tt/2fLl1ue

Assessment of oxidative/nitrative modifications of plasma proteins, selected ROTEM parameters and kinetics of fibrinogen polymerization in patients with multiple myeloma at diagnosis

Abstract

Patients with multiple myeloma (MM) are at increased risk of thrombosis. Growing evidence indicates that oxidative and nitrative modifications of proteins, including fibrinogen, may lead to changes in hemostasis. The study compares samples from patients with MM at diagnosis and healthy volunteers with regard to the oxidative/nitrative modifications of proteins, ROTEM and thrombin-catalyzed fibrin polymerization. The content of carbonyl groups in plasma proteins of patients with MM was significantly higher than in controls (2.981 vs. 1.807 nmol/mg of protein, p = 0.005), while no differences were seen in the concentrations of nitrated proteins. Maximum clot firmness readings were significantly higher in the samples of patients than in controls according to FIBTEM test (23.5 vs. 15 mm, p = 0.006). The lag time of the fibrin polymerization process and the velocity of clot lysis (V Lys) were found to be significantly higher in the group of MM patients than controls. In contrast, no marked differences were identified between studied groups in reference to maximal velocity of fibrin polymerization process (V max), maximal absorbance (A max) and plasmin amidolytic activity values. In conclusion, our study demonstrates that at the time of diagnosis, patients with MM demonstrated greater oxidative stress than healthy volunteers, which is reflected in a higher amount of carbonylated proteins. Some prothrombotic features found in ROTEM tests in MM patients were not confirmed by turbidimetry.



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Treatment of lung tumours with high-energy microwave ablation: a single-centre experience

Abstract

The purpose of our study is to report safety, technical success, effectiveness, local progression-free survival (LPFS) and overall survival of percutaneous microwave ablation (MWA) to treat lung tumours unsuitable for surgery. Nineteen patients with thirty-one tumours (mean diameter 2.4 cm) underwent percutaneous MWA in 28 sessions. Microwave ablation was carried out using a 2450-MHz generator (Emprint/Covidien, Boulder, CO, USA). Procedures were performed under cone-beam CT (CBCT) and under fluoro-CT (one session) guidance. Safety, technical success, effectiveness, LPFS and overall survival (OS) were evaluated. Safety was defined as the frequency of major and minor complications. The efficacy was evaluated on the basis of imaging characteristics, using RECIST criteria. CT follow-up was performed at 1, 3 and 6 months and yearly. LPFS was defined as the interval between MWA treatment and evidence of local recurrence, if there was any. OS was defined as the percentage of patients who were still alive. We registered one major complication (purulent hydro-pneumothorax). Minor complications were spontaneously resolved (pneumothorax and perilesional haemorrhagic effusion). Technical success was 100%. Residual disease was registered in two cases, one of whom was retreated. Complete ablation was obtained in the remaining cases (90.3%). During available follow-up (mean 9.6 months), 9/31 tumours demonstrated local recurrence. Five tumours were retreated, and none of them presented residual disease during follow-up (LPFS 22.6%). Overall survival was 93.8%. Percutaneous high-energy MWA is a safe, effective and confident technique to treat lung tumours not suitable for surgery.



http://ift.tt/2fD1Do8

Assessment of oxidative/nitrative modifications of plasma proteins, selected ROTEM parameters and kinetics of fibrinogen polymerization in patients with multiple myeloma at diagnosis

Abstract

Patients with multiple myeloma (MM) are at increased risk of thrombosis. Growing evidence indicates that oxidative and nitrative modifications of proteins, including fibrinogen, may lead to changes in hemostasis. The study compares samples from patients with MM at diagnosis and healthy volunteers with regard to the oxidative/nitrative modifications of proteins, ROTEM and thrombin-catalyzed fibrin polymerization. The content of carbonyl groups in plasma proteins of patients with MM was significantly higher than in controls (2.981 vs. 1.807 nmol/mg of protein, p = 0.005), while no differences were seen in the concentrations of nitrated proteins. Maximum clot firmness readings were significantly higher in the samples of patients than in controls according to FIBTEM test (23.5 vs. 15 mm, p = 0.006). The lag time of the fibrin polymerization process and the velocity of clot lysis (V Lys) were found to be significantly higher in the group of MM patients than controls. In contrast, no marked differences were identified between studied groups in reference to maximal velocity of fibrin polymerization process (V max), maximal absorbance (A max) and plasmin amidolytic activity values. In conclusion, our study demonstrates that at the time of diagnosis, patients with MM demonstrated greater oxidative stress than healthy volunteers, which is reflected in a higher amount of carbonylated proteins. Some prothrombotic features found in ROTEM tests in MM patients were not confirmed by turbidimetry.



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Treatment of lung tumours with high-energy microwave ablation: a single-centre experience

Abstract

The purpose of our study is to report safety, technical success, effectiveness, local progression-free survival (LPFS) and overall survival of percutaneous microwave ablation (MWA) to treat lung tumours unsuitable for surgery. Nineteen patients with thirty-one tumours (mean diameter 2.4 cm) underwent percutaneous MWA in 28 sessions. Microwave ablation was carried out using a 2450-MHz generator (Emprint/Covidien, Boulder, CO, USA). Procedures were performed under cone-beam CT (CBCT) and under fluoro-CT (one session) guidance. Safety, technical success, effectiveness, LPFS and overall survival (OS) were evaluated. Safety was defined as the frequency of major and minor complications. The efficacy was evaluated on the basis of imaging characteristics, using RECIST criteria. CT follow-up was performed at 1, 3 and 6 months and yearly. LPFS was defined as the interval between MWA treatment and evidence of local recurrence, if there was any. OS was defined as the percentage of patients who were still alive. We registered one major complication (purulent hydro-pneumothorax). Minor complications were spontaneously resolved (pneumothorax and perilesional haemorrhagic effusion). Technical success was 100%. Residual disease was registered in two cases, one of whom was retreated. Complete ablation was obtained in the remaining cases (90.3%). During available follow-up (mean 9.6 months), 9/31 tumours demonstrated local recurrence. Five tumours were retreated, and none of them presented residual disease during follow-up (LPFS 22.6%). Overall survival was 93.8%. Percutaneous high-energy MWA is a safe, effective and confident technique to treat lung tumours not suitable for surgery.



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“The Crossroad between Dentistry and Medicine” at ADEE & AMEE

By Prof. Rui Amaral Mendes and Dr. Seema Biswas

In August, taking advantage of having our annual meetings in the same city – the beautiful Barcelona – ADEE (the Association for Dental Education in Europe) and its medical counterpart, AMEE (the Association for Medical Education in Europe), convened efforts to hold a joint scientific and business meeting under the topic of: "The crossroad between Dentistry and Medicine".

More than a mere morning workshop's theme, this is a major trend worldwide and should be regarded as one of the major challenges pending upon two of the major stakeholders as far as Heathcare providing is concerned.

According to the World Health Organization, Interprofessional Education (IPE) is a necessary step in planning a "collaborative practice-ready" health workforce that is better prepared to respond to local and global health needs. A similar opinion is shared by ADEE's American colleagues from ADEA.

Still, the important thing is how we, educators, can use a potentially good idea and put in to good use, ensuring that our students get the best possible training, in line with the most recent FDI definition of oral health, as an "integral part of general health and well-being".

Hence, being, as we are, well-aware and committed to this evolving educational paradigm of Interprofessional Education and Learning and Interprofessional Collaborative Practice (IPCP), one must also consider the prospects of a partnership that makes the best out of each other's know-how, while keeping in mind that the European Directive 2005/36/EC, issued by the European Parliament and by the Council, establishing the EU legal foundations for the recognition of professional qualifications, makes it even more pertinent, not to say imperative, that both ADEE and AMEE join efforts in a combine approach advocating for new European Directives calling for a competencies-based approach for the education of dentists and physicians.

We often forget that according to the World Health Organisation, "Health is a state of complete physical, mental and social well-being and not merely the absence of disease or infirmity".
Hence, when we think about Dental Education and overall services's provision, we can not help to feel that we are currently at a crossroad: one that demands us to move "outside the box" of our Dental Schools and Dental offices, while engaging with the needs of our communities at home and vulnerable communities across the world.

Education, even at the undergraduate level, and service provision are, therefore, intricately linked. We have to accept that we need to train dentists who are far more than just competent technicians, but rather health professionals responsible for oral health and health in general. Dentists need to get to know their patients and their communities better if they are to provide truly effective care.

There is a need for those involved in Dental Education to take the lead on incorporating global health into the undergraduate dental curriculum and to boost global health in postgraduate practice. The key focus should be to provide better dental care to patients at home, work on improving access (for free or at low cost) for patients at home and to fill the gap where dentists are scarce.

Due to socio-economic, cultural and political reasons, large segments of the world's population have limited or no access to regular dental care. Assisting the development of dental services in these areas should be regarded as a win- win strategy for both the developed and developing world as opportunities for training, practice and research lend themselves to twinning established successful programs at home with programmesfor the world's most vulnerable communities.

It's within this context, that, as we look through the feedback of the ADEE and AMEE meetings and workshops in global health, it becomes clear the enthusiasm for global health across all the medical disciplines. This enthusiasm seems centred on clinical practice: global health in the workplace, renewed focus on ensuring that the most vulnerable of our patients receive the best of clinical care, setting an example in the workplace to trainees who are going the extra mile to ensure that they address ALL the health needs of their patients and moving forward together to address the determinants of health in our undergraduate teaching programmes.

Thus, as ADEE and AMEE discuss the modern teaching agenda, we remind ourselves that global health is comprehensive healthcare and research. At BMJ Case Reports, we have the opportunity to put together the input of authors from across the world and emphasise priorities in addressing health disparities and access to healthcare. We have case reports from Trinidad in the West Indies (link) to Queensland in Australia (link). What is key is not so much the reach across the globe as the fact that authors are clinicians writing about patients they see locally daily.

As clinicians write about global health issues, we encourage students to do this, too. Global health problems cannot be tackled without a strong evidence base. Our cases are hugely valuable for teaching and to assist students as they begin to write. These case are also a powerful tool in bringing about improvements in health and should be used again and again as we advocate for our patients. There is extensive guidance on our website, and, as editors we are always to eager to engage with authors on how to make BMJ Case Reports more accessible to our readers and promote excellence in research and education.



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