A new methanogen “Methanobrevibacter massiliense” isolated in a case of severe periodontitis

A few methanogens have been previously recovered from periodontitis lesions, yet their repertoire may not be completed. We recovered a previously unreported methanogen species in this situation.

http://ift.tt/2zGlCbx

Interleukin-35 Gene-Modified Mesenchymal Stem Cells Protect Concanavalin A–Induced Fulminant Hepatitis by Decreasing the Interferon Gamma Level

Human Gene Therapy , Vol. 0, No. 0.


http://ift.tt/2zGfrUT

Gene Therapy for Modulation of T-Cell-Mediated Immune Response Provoked by Corneal Transplantation

Human Gene Therapy , Vol. 0, No. 0.


http://ift.tt/2nijKnC

Improvement of In Vivo Expression of Genes Delivered by Self-Amplifying RNA Using Vaccinia Virus Immune Evasion Proteins

Human Gene Therapy , Vol. 0, No. 0.


http://ift.tt/2nj1Aln

Stereotype Threat Effects on Learning From a Cognitively Demanding Mathematics Lesson

Abstract

Stereotype threat—a situational context in which individuals are concerned about confirming a negative stereotype—is often shown to impact test performance, with one hypothesized mechanism being that cognitive resources are temporarily co-opted by intrusive thoughts and worries, leading individuals to underperform despite high content knowledge and ability (see Schmader & Beilock, ). We test here whether stereotype threat may also impact initial student learning and knowledge formation when experienced prior to instruction. Predominantly African American fifth-grade students provided either their race or the date before a videotaped, conceptually demanding mathematics lesson. Students who gave their race retained less learning over time, enjoyed the lesson less, reported a diminished desire to learn more, and were less likely to choose to engage in an optional math activity. The detrimental impact was greatest among students with high baseline cognitive resources. While stereotype threat has been well documented to harm test performance, the finding that effects extend to initial learning suggests that stereotype threat's contribution to achievement gaps may be greatly underestimated.

http://ift.tt/2AKEf1T

Association of high cost sharing and targeted therapy initiation among elderly Medicare patients with metastatic renal cell carcinoma

Abstract

High out-of-pocket costs may limit access to oral therapies covered by patients' prescription drug benefits. We explored financial barriers to treatment initiation in patients newly diagnosed with metastatic renal cell carcinoma (mRCC) by comparing Medicare Part D patients with low out-of-pocket costs due to receipt of full low-income subsidies (LIS beneficiaries) to their counterparts who were responsible for more than 25% cost sharing during Medicare's initial coverage phase (non-LIS beneficiaries). We used 2011–2013 100% Medicare claims for non-LIS and LIS beneficiaries newly diagnosed with metastases in the liver, lung, or bone to examine targeted therapy treatment initiation rates and time to initiation for (1) oral medications (sorafenib, sunitinib, everolimus, pazopanib, or axitinib) covered under Medicare's prescription drug benefit (Part D); (2) injected or infused medications (temsirolimus or bevacizumab) covered by Medicare's medical benefit (Part B); and (3) any (Part D or Part B) targeted therapy. The final sample included 1721 patients. On average, non-LIS patients were responsible for out-of-pocket costs of ≥$2,800 for their initial oral prescription, as compared to ≤$6.60 for LIS patients. Compared to LIS patients, a lower percentage of non-LIS patients initiated oral therapies (risk-adjusted rates, 20.7% vs. 33.9%; odds ratio [OR] = 0.49, 95% CI: 0.36–0.67, P < 0.001) and any targeted therapies (26.7% vs. 40.4%, OR = 0.52, 95% CI: 0.38–0.71, P < 0.001). Non-LIS patients were also slower to access therapy. High cost sharing was associated with reduced and/or delayed access to targeted therapies under Medicare Part D, suggesting that financial barriers play a role in treatment decisions.

Medicare Part D beneficiaries newly diagnosed with metastatic renal cell carcinoma have significantly lower rates of oral and any targeted therapy initiation—and are slower to initiate treatment—when they are responsible for high out-of-pocket costs. Financial barriers may be factoring into treatment decisions; this warrants further investigation.

http://ift.tt/2i6eSwq

CD90 Expression Controls Migration and Predicts Dasatinib Response in Glioblastoma

Purpose: CD90 (Thy-1) is a glycophosphatidylinositol-anchored glycoprotein considered as a surrogate marker for a variety of stem cells, including glioblastoma (GBM) stem cells (GSC). However, the molecular and cellular functions of CD90 remain unclear.

Experimental Design: The function of CD90 in GBM was addressed using cellular models from immortalized and primary GBM lines, in vivo orthotopic mouse models, and GBM specimens' transcriptome associated with MRI features from GBM patients. CD90 expression was silenced in U251 and GBM primary cells and complemented in CD90-negative U87 cells.

Results: We showed that CD90 is not only expressed on GSCs but also on more differentiated GBM cancer cells. In GBM patients, CD90 expression was associated with an adhesion/migration gene signature and with invasive tumor features. Modulation of CD90 expression in GBM cells dramatically affected their adhesion and migration properties. Moreover, orthotopic xenografts revealed that CD90 expression induced invasive phenotypes in vivo. Indeed, CD90 expression led to enhanced SRC and FAK signaling in our GBM cellular models and GBM patients' specimens. Pharmacologic inhibition of these signaling nodes blunted adhesion and migration in CD90-positive cells. Remarkably, dasatinib blunted CD90-dependent GBM cell invasion in vivo and killed CD90^high primary GSC lines.

Conclusions: Our data demonstrate that CD90 is an actor of GBM invasiveness through SRC-dependent mechanisms and could be used as a predictive factor for dasatinib response in CD90^high GBM patients. Clin Cancer Res; 23(23); 7360–74. ©2017 AACR.

http://ift.tt/2jAEotO

TMEM16A/ANO1 Inhibits Apoptosis Via Downregulation of Bim Expression

Purpose: TMEM16A is a calcium-activated chloride channel that is amplified in a variety of cancers, including 30% of head and neck squamous cell carcinomas (HNSCCs), raising the possibility of an anti-apoptotic role in malignant cells. This study investigated this using a multimodal, translational investigation.

Experimental Design: Combination of (i) in vitro HNSCC cell culture experiments assessing cell viability, apoptotic activation, and protein expression (ii) in vivo studies assessing similar outcomes, and (iii) molecular and staining analysis of human HNSCC samples.

Results: TMEM16A expression was found to correlate with greater tumor size, increased Erk 1/2 activity, less Bim expression, and less apoptotic activity overall in human HNSCC. These findings were corroborated in subsequent in vitro and in vivo studies and expanded to include a cisplatin-resistant phenotype with TMEM16A overexpression. A cohort of 41 patients with laryngeal cancer demonstrated that cases that recurred after chemoradiation failure were associated with a greater TMEM16A overexpression rate than HNSCC that did not recur.

Conclusions: Ultimately, this study implicates TMEM16A as a contributor to tumor progression by limiting apoptosis and as a potential biomarker of more aggressive disease. Clin Cancer Res; 23(23); 7324–32. ©2017 AACR.

http://ift.tt/2jAE3Hy

FDA Approval Summary: Rucaparib for the Treatment of Patients with Deleterious BRCA Mutation-Associated Advanced Ovarian Cancer

On December 19, 2016, the FDA granted accelerated approval to rucaparib (RUBRACA; Clovis Oncology, Inc.) for the treatment of patients with deleterious BRCA mutation (germline and/or somatic)–associated advanced ovarian cancer who have been treated with two or more chemotherapies. The FDA also approved the FoundationFocus CDx_BRCA test (Foundation Medicine, Inc.), the first next-generation sequencing-based companion diagnostic, for identifying patients with advanced ovarian cancer eligible for treatment with rucaparib based on detection of deleterious BRCA1 and/or BRCA2 mutations in tumor tissue. Rucaparib's approval was based primarily on efficacy data from 106 patients with BRCA mutation–associated ovarian cancer who had prior treatment with two or more chemotherapies and safety data from 377 patients with ovarian cancer treated with rucaparib 600 mg orally twice daily on two open-label, single-arm trials. Investigator-assessed objective response rate was 54% [57/106; 95% confidence interval (CI), 44–64], and median duration of response was 9.2 months (95% CI, 6.6–11.7). The approved companion diagnostic verified tumor BRCA mutation status retrospectively in 96% (64/67) of patients. Common adverse reactions (≥20%) to rucaparib were nausea, fatigue, vomiting, anemia, abdominal pain, dysgeusia, constipation, decreased appetite, diarrhea, thrombocytopenia, and dyspnea. This article summarizes the FDA review and data supporting rucaparib's accelerated approval. Clin Cancer Res; 23(23); 7165–70. ©2017 AACR.

See related commentary by Kohn et al., p. 7155

http://ift.tt/2i59kly

Therapeutic Drug Monitoring of Carboplatin in High-Dose Protocol (TI-CE) for Advanced Germ Cell Tumors: Pharmacokinetic Results of a Phase II Multicenter Study

Purpose: We aimed to evaluate the performance of therapeutic drug monitoring (TDM) approach in controlling interpatient variability of carboplatin exposure (AUC) in patients treated with TI-CE high-dose chemotherapy for advanced germ cell tumors and to assess the possibility of using a formula-based dosing method as a possible alternative.

Experimental Design: Eighty-nine patients receiving carboplatin for 3 consecutive days during 3 cycles were evaluable for pharmacokinetic study. Blood samples were taken on day 1 to determine the carboplatin clearance using a Bayesian approach (NONMEM 7.2) and to adjust the dose on day 3 to reach the target AUC of 24 mg.min/mL over 3 days. On days 2 and 3, samples were taken for retrospective assessment of the actual AUC. A population pharmacokinetic analysis was also performed on 58 patients using NONMEM to develop a covariate equation for carboplatin clearance prediction adapted for future TI-CE patients, and its performance was prospectively evaluated on the other 29 patients along with different methods of carboplatin clearance prediction.

Results: The mean actual AUC was 24.4 mg.min/mL per cycle (22.4 and 26.8 for 10th and 90th percentiles, respectively). The new covariate equation [CL (mL/min) = 130.7 x (Scr/83)^–0.826x (BW/76)^+0.907x (Age/36)^–0.223 with Scr in μmol/L, BW in kilograms, age in years] allows unbiased and more accurate prediction of carboplatin clearance compared with other equations.

Conclusions: TDM allows controlling and reaching the target AUC. Alternatively, the new equation of carboplatin clearance prediction, better adapted to these young male patients, could be used if TDM cannot be implemented. Clin Cancer Res; 23(23); 7171–9. ©2017 AACR.

http://ift.tt/2i68TaW

Phase III Clinical Trial (RERISE study) Results of Efficacy and Safety of Radotinib Compared with Imatinib in Newly Diagnosed Chronic Phase Chronic Myeloid Leukemia

Purpose: Radotinib is a second-generation BCR-ABL1 tyrosine kinase inhibitor (TKI) approved in Korea for chronic phase chronic myeloid leukemia (CML-CP) in patients newly diagnosed or with insufficient response to other TKIs. This study was conducted to evaluate the efficacy and safety of radotinib as first-line therapy for CML-CP.

Experimental Design: This multinational, open-label study assigned patients (1:1:1) to one of two twice-daily radotinib doses, or imatinib daily. The primary endpoint was major molecular response (MMR) by 12 months.

Results: Two hundred forty-one patients were randomized to receive radotinib 300 mg (n = 79) or 400 mg twice-daily (n = 81), or imatinib 400 mg daily (n = 81). MMR rates by 12 months were higher in patients receiving radotinib 300 mg (52%) or radotinib 400 mg twice-daily (46%) versus imatinib (30%; P = 0.0044 and P = 0.0342, respectively). Complete cytogenetic response (CCyR) rates by 12 months were higher for radotinib 300 mg (91%) versus imatinib (77%; P = 0.0120). Early molecular response at 3 months occurred in 86% and 87% of patients receiving radotinib 300 mg and radotinib 400 mg, respectively, and 71% of those receiving imatinib. By 12 months, no patients had progression to accelerated phase or blast crisis. Most adverse events were manageable with dose reduction.

Conclusions: Radotinib demonstrated superiority over imatinib in CCyR and MMR in patients newly diagnosed with Philadelphia chromosome–positive CML-CP. This trial was registered at http://ift.tt/PmpYKN as NCT01511289. Clin Cancer Res; 23(23); 7180–8. ©2017 AACR.

http://ift.tt/2zDa6O3

Phospholipase D1 Inhibition Linked to Upregulation of ICAT Blocks Colorectal Cancer Growth Hyperactivated by Wnt/{beta}-Catenin and PI3K/Akt Signaling

Purpose: Dysregulated expression of PLD1 has emerged as a hallmark feature of colorectal cancer, which remains a major cause of mortality worldwide. Aberrant activation of Wnt/β-catenin signaling is a critical event in the development of colorectal cancer. Here, we investigated molecular crosstalk between the Wnt/β-catenin and PI3K/Akt pathways via inhibitor of β-catenin and T-cell factor (ICAT), a negative regulator of Wnt/β-catenin signaling. We also explored the effect of PLD1 inhibition on growth of colorectal cancer hyperactivated by Wnt/β-catenin and PI3K/Akt signaling.

Experimental Design: Expression of ICAT via targeting of PLD1 was assessed in vivo in Apc^Min/+ mice, an AOM/DSS model, and in vitro using various colorectal cancer cells. The relationship between ICAT/PLD1 expression and prognostic survival value of 153 colorectal cancer patients was examined. The therapeutic efficacy of PLD1 inhibitor was determined using a patient-derived xenograft model carrying APC and PI3K mutations.

Results: PLD1 promoted the Wnt/β-catenin signaling pathway by selectively downregulating ICAT via the PI3K/Akt-TopBP1-E2F1 signaling pathways. Low PLD1 expression and high ICAT expression were significantly associated with increased survival in colorectal cancer patients and vice versa. Furthermore, PLD1 inhibition suppressed growth of colorectal cancer activated by the Wnt/β-catenin and PI3K signaling pathways.

Conclusions: These results suggest that PLD1 linked to ICAT mediates molecular crosstalk between the Wnt/β-catenin and PI3K/Akt pathways and thus could be proposed as a novel colorectal cancer prognostic biomarker. These results may assist in the clinical development of a PLD1 inhibitor for treatment of colorectal cancer patients carrying APC and PI3KCA mutations. PLD1, a nodal modifier, acts as a potential therapeutic target for the treatment of colorectal cancer hyperactivated by the Wnt/β-catenin and PI3K/Akt signaling pathways. Clin Cancer Res; 23(23); 7340–50. ©2017 AACR.

http://ift.tt/2zD9Yy3

High BCR-ABL/GUSIS Levels at Diagnosis of Chronic Phase CML Are Associated with Unfavorable Responses to Standard-Dose Imatinib

Purpose: The approval of second-generation tyrosine kinase inhibitors (TKIs) for the first-line treatment of chronic myeloid leukemia (CML) has generated an unmet need for baseline molecular parameters associated with inadequate imatinib responses.

Experimental Design: We correlated BCR–ABL/GUS^IS and BCR–ABL/ABL transcripts at diagnosis with the outcome—defined by the 2013 European LeukemiaNet recommendations—of 272 patients newly diagnosed with CML receiving imatinib 400 mg/daily. Applying receiver-operating characteristic curves, we defined BCR–ABL/GUS^IS and BCR–ABL/ABL levels associated with lower probabilities of optimal response, failure-free (FFS), event-free (EFS), transformation-free (TFS), and overall survival (OS).

Results: With a median follow-up of 60 months, 65.4% of patients achieved an optimal response (OR), 5.6% were classified as "warnings," 22.4% failed imatinib, and 6.6% switched to a different TKI because of drug intolerance. We recorded 19 deaths (6.9%), seven (2.5%) attributable to disease progression. We found that higher BCR–ABL/GUS^IS levels at diagnosis were associated with inferior rates of OR (P < 0.001), FFS (P < 0.001), and EFS (P < 0.001). Elevated BCR–ABL/GUS^IS levels were also associated with lower rates of TFS (P = 0.029) but not with OS (P = 0.132). Similarly, high BCR–ABL/ABL levels at diagnosis were associated with inferior rates of OR (P = 0.03), FFS (P = 0.001), and EFS (P = 0.005), but not with TFS (P = 0.167) or OS (P = 0.052). However, in internal validation experiments, GUS outperformed ABL in samples collected at diagnosis as the latter produced 80% misclassification rates.

Conclusions: Our data suggest that high BCR–ABL transcripts at diagnosis measured using GUS as a reference gene identify patients with CML unlikely to benefit from standard-dose imatinib. Clin Cancer Res; 23(23); 7189–98. ©2017 AACR.

http://ift.tt/2njI4Wa

BMP4 Induces M2 Macrophage Polarization and Favors Tumor Progression in Bladder Cancer

Purpose: Bladder cancer is a current clinical and social problem. At diagnosis, most patients present with nonmuscle-invasive tumors, characterized by a high recurrence rate, which could progress to muscle-invasive disease and metastasis. Bone morphogenetic protein (BMP)–dependent signaling arising from stromal bladder tissue mediates urothelial homeostasis by promoting urothelial cell differentiation. However, the possible role of BMP ligands in bladder cancer is still unclear.

Experimental Design: Tumor and normal tissue from 68 patients with urothelial cancer were prospectively collected and analyzed for expression of BMP and macrophage markers. The mechanism of action was assessed in vitro by experiments with bladder cancer cell lines and peripheral blood monocyte–derived macrophages.

Results: We observed BMP4 expression is associated and favored type II macrophage differentiation. In vitro experiments showed that both recombinant BMP4 and BMP4-containing conditioned media from bladder cancer cell lines favored monocyte/macrophage polarization toward M2 phenotype macrophages, as shown by the expression and secretion of IL10. Using a series of human bladder cancer patient samples, we also observed increased expression of BMP4 in advanced and undifferentiated tumors in close correlation with epithelial–mesenchymal transition (EMT). However, the p-Smad 1,5,8 staining in tumors showing EMT signs was reduced, due to the increased miR-21 expression leading to reduced BMPR2 expression.

Conclusions: These findings suggest that BMP4 secretion by bladder cancer cells provides the M2 signal necessary for a protumoral immune environment. In addition, the repression of BMPR2 by miR-21 makes the tumor cells refractory to the prodifferentiating actions mediated by BMP ligands, favoring tumor growth. Clin Cancer Res; 23(23); 7388–99. ©2017 AACR.

http://ift.tt/2njHTKu

Immunomodulation by Entinostat in Renal Cell Carcinoma Patients Receiving High-Dose Interleukin 2: A Multicenter, Single-Arm, Phase I/II Trial (NCI-CTEP#7870)

Purpose: On the basis of preclinical data suggesting that the class I selective HDAC inhibitor entinostat exerts a synergistic antitumor effect in combination with high-dose IL2 in a renal cell carcinoma model by downregulating Foxp3 expression and function of regulatory T cells (Treg), we conducted a phase I/II clinical study with entinostat and high-dose IL2 in patients with metastatic clear cell renal cell carcinoma (ccRCC).

Experimental Design: Clear cell histology, no prior treatments, and being sufficiently fit to receive high-dose IL2 were the main eligibility criteria. The phase I portion consisted of two dose levels of entinostat (3 and 5 mg, orally every 14 days) and a fixed standard dose of IL2 (600,000 U/kg i.v.). Each cycle was 85 days. The primary endpoint was objective response rate and toxicity. Secondary endpoints included progression-free survival and overall survival.

Results: Forty-seven patients were enrolled. At a median follow-up of 21.9 months, the objective response rate was 37% [95% confidence interval (CI), 22%–53%], the median progression-free survival was 13.8 months (95% CI, 6.0–18.8), and the median overall survival was 65.3 months (95% CI, 52.6.-65.3). The most common grade 3/4 toxicities were hypophosphatemia (16%), lymphopenia (15%), and hypocalcemia (7%), and all were transient. Decreased Tregs were observed following treatment with entinostat, and lower numbers were associated with response (P = 0.03).

Conclusions: This trial suggests a promising clinical activity for entinostat in combination with high-dose IL2 in ccRCC patients and provides the first example of an epigenetic agent being rationally combined with immunotherapy. Clin Cancer Res; 23(23); 7199–208. ©2017 AACR.

http://ift.tt/2zEabRy

Tumor Heterogeneity Predicts Metastatic Potential in Colorectal Cancer

Purpose: Tumors continuously evolve to maintain growth; secondary mutations facilitate this process, resulting in high tumor heterogeneity. In this study, we compared mutations in paired primary and metastatic colorectal cancer tumor samples to determine whether tumor heterogeneity can predict tumor metastasis.

Experimental Design: Somatic variations in 46 pairs of matched primary-liver metastatic tumors and 42 primary tumors without metastasis were analyzed by whole-exome sequencing. Tumor clonality was estimated from single-nucleotide and copy-number variations. The correlation between clinical parameters of patients and clonal heterogeneity in liver metastasis was evaluated.

Results: Tumor heterogeneity across colorectal cancer samples was highly variable; however, a high degree of tumor heterogeneity was associated with a worse disease-free survival. Highly heterogeneous primary colorectal cancer was correlated with a higher rate of liver metastasis. Recurrent somatic mutations in APC, TP53, and KRAS were frequently detected in highly heterogeneous colorectal cancer. The variant allele frequency of these mutations was high, while somatic mutations in other genes such as PIK3CA and NOTCH1 were low. The number and distribution of primary colorectal cancer subclones were preserved in metastatic tumors.

Conclusions: Heterogeneity of primary colorectal cancer tumors can predict the potential for liver metastasis and thus, clinical outcome of patients. Clin Cancer Res; 23(23); 7209–16. ©2017 AACR.

http://ift.tt/2nigwjI

A Novel Breast Cancer Index for Prediction of Distant Recurrence in HR+ Early-Stage Breast Cancer with One to Three Positive Nodes

Purpose: The study objective was to characterize the prognostic performance of a novel Breast Cancer Index model (BCIN⁺), an integration of BCI gene expression, tumor size, and grade, specifically developed for assessment of distant recurrence (DR) risk in HR⁺ breast cancer patients with one to three positive lymph nodes (pN1).

Experimental Design: Analysis was conducted in a well-annotated retrospective series of pN1 patients (N = 402) treated with adjuvant endocrine therapy with or without chemotherapy using a prespecified model. The primary endpoint was time-to-DR. Results were determined blinded to clinical outcome. Kaplan-Meier estimates of overall (0–15 years) and late (≥5 years) DR, HRs, and 95% confidence interval (CIs) were estimated. Likelihood ratio statistics assessed relative contributions of prognostic information.

Results: BCIN⁺ classified 81 patients (20%) as low risk with a 15-year DR rate of 1.3% (95% CI, 0.0%–3.7%) versus 321 patients as high risk with a DR rate of 29.0% (95% CI, 23.2%–34.4%). In patients DR-free for ≥5 years (n = 349), the late DR rate was 1.3% (95% CI, 0.0%–3.7%) and 16.1% (95% CI, 10.6%–21.3%) in low- and high-risk groups, respectively. BCI gene expression alone was significantly prognostic (LR-² = 20.12; P < 0.0001). Addition of tumor size (LR-² = 13.29, P = 0.0003) and grade (LR-² = 12.72; P = 0.0004) significantly improved prognostic performance. BCI added significant prognostic information to tumor size (LR-² = 17.55; P < 0.0001); addition to tumor grade was incremental (LR-² = 2.38; P = 0.1) with considerable overlap between prognostic values (LR-² = 17.74).

Conclusions: The integrated BCIN⁺ identified 20% of pN1 patients with limited risk of recurrence over 15 years, in whom extended endocrine treatment may be spared. Ongoing studies will characterize combined clinical-genomic risk assessment in node-positive patients. Clin Cancer Res; 23(23); 7217–24. ©2017 AACR.

http://ift.tt/2zEa9Jq

PAM50 Provides Prognostic Information When Applied to the Lymph Node Metastases of Advanced Breast Cancer Patients

Purpose: Transcriptional pathway activity and the molecular subtypes of breast cancer metastases have been shown to significantly influence patient postrelapse survival. Here, we further determine the relevance of clinically employed gene signatures in the advanced breast cancer (ABC) setting.

Experimental Design: Sufficient RNA for expression profiling was obtained from distant metastatic or inoperable loco-regional relapse tissue by fine-needle aspiration from 109 patients of the Swedish TEX clinical trial. Gene signatures (GGI, 70 gene, recurrence score, cell-cycle score, risk of recurrence score, and PAM50) were applied to all metastases, and their relationship to long- (5-year) and short-term (1.5-year) postrelapse survival at all and locoregional lymph nodes (n = 40) versus other metastatic sites (n = 69) combined was assessed using Kaplan–Meier and/or multivariate Cox regression analyses.

Results: The majority of metastases were classified into intermediate or high-risk groups by all signatures, and a significant association was found between metastatic signature subgroups and primary tumor estrogen receptor status and histologic grade (P < 0.05). When considering all sites of metastasis, only PAM50 was statistically significant in Kaplan–Meier analysis (Log-rank P = 0.008 and 0.008 for long- and short-term postrelapse breast cancer–specific survival, respectively). This significance remained in both uni- and multivariate models when restricting analyses to lymph node metastases only, and a similar trend was observed in other metastatic sites combined, but did not reach formal significance.

Conclusions: Our findings are the first to demonstrate that the PAM50 signature can provide prognostic information from the lymph node metastases of ABC patients. Clin Cancer Res; 23(23); 7225–31. ©2017 AACR.

http://ift.tt/2njI2O2

Correction: Myc Induces miRNA-Mediated Apoptosis in Response to HDAC Inhibition in Hematologic Malignancies

http://ift.tt/2jBVOGK

Disparities in Prostate, Lung, Breast, and Colorectal Cancer Survival and Comorbidity Status among Urban American Indians and Alaskan Natives

Cancer is the second leading cause of death among American Indians and Alaskan Natives (AIAN), although cancer survival information in this population is limited, particularly among urban AIAN. In this retrospective cohort study, we compared all-cause and prostate, breast, lung, and colorectal cancer–specific mortality among AIAN (n = 582) and non-Hispanic white (NHW; n = 82,696) enrollees of Kaiser Permanente Northern California (KPNC) diagnosed with primary invasive breast, prostate, lung, or colorectal cancer from 1997 to 2015. Tumor registry and other electronic health records provided information on sociodemographic, comorbidity, tumor, clinical, and treatment characteristics. Cox regression models were used to estimate adjusted survival curves and hazard ratios (HR) with 95% confidence intervals (CI). AIAN had a significantly higher comorbidity burden compared with NHW (P < 0.05). When adjusting for patient, disease characteristics, and Charlson comorbidity scores, all-cause mortality and cancer-specific mortality were significantly higher for AIAN than NHW patients with breast cancer (HR, 1.47; 95% CI, 1.13–1.92) or with prostate cancer (HR, 1.87; 95% CI, 1.14–3.06) but not for AIAN patients with lung and colorectal cancer. Despite approximately equal access to preventive services and cancer care in this setting, we found higher mortality for AIAN than NHW with some cancers, and a greater proportion of AIAN cancer patients with multiple comorbid conditions. This study provides severely needed information on the cancer experience of the 71% of AIANs who live in urban areas and access cancer care outside of the Indian Health Services, from which the vast majority of AIAN cancer information comes. Cancer Res; 77(23); 6770–6. ©2017 AACR.

http://ift.tt/2i58aXe

Modeling Cytostatic and Cytotoxic Responses to New Treatment Regimens for Ovarian Cancer

The margin for optimizing polychemotherapy is wide, but a quantitative comparison of current and new protocols is rare even in preclinical settings. In silico reconstruction of the proliferation process and the main perturbations induced by treatment provides insight into the complexity of drug response and grounds for a more objective rationale to treatment schemes. We analyzed 12 treatment groups in trial on an ovarian cancer xenograft, reproducing current therapeutic options for this cancer including one-, two-, and three-drug schemes of cisplatin (DDP), bevacizumab (BEV), and paclitaxel (PTX) with conventional and two levels ("equi" and "high") of dose-dense schedules. All individual tumor growth curves were decoded via separate measurements of cell death and other antiproliferative effects, gaining fresh insight into the differences between treatment options. Single drug treatments were cytostatic, but only DDP and PTX were also cytotoxic. After treatment, regrowth stabilized with increased propensity to quiescence, particularly with BEV. More cells were killed by PTX dose-dense-equi than with PTX conventional, but with the addition of DDP, cytotoxicity was similar and considerably less than expected from that of individual drugs. In the DDP/PTX dose-dense-high scheme, both cell death and regrowth impairment were intensified enough to achieve complete remission, and addition of BEV increased cell death in all schemes. The results support the option for dose-dense PTX chemotherapy with active single doses, showing the relative additional contribution of BEV, but also indicate negative drug interactions in concomitant DDP/PTX treatments, suggesting that sequential schedules could improve antitumor efficacy. Cancer Res; 77(23); 6759–69. ©2017 AACR.

http://ift.tt/2jAI1zT

Glutamine Addiction in Kidney Cancer Suppresses Oxidative Stress and Can Be Exploited for Real-Time Imaging

Many cancers appear to activate intrinsic antioxidant systems as a means to counteract oxidative stress. Some cancers, such as clear cell renal cell carcinoma (ccRCC), require exogenous glutamine for growth and exhibit reprogrammed glutamine metabolism, at least in part due to the glutathione pathway, an efficient cellular buffering system that counteracts reactive oxygen species and other oxidants. We show here that ccRCC xenograft tumors under the renal capsule exhibit enhanced oxidative stress compared with adjacent normal tissue and the contralateral kidney. Upon glutaminase inhibition with CB-839 or BPTES, the RCC cell lines SN12PM-6-1 (SN12) and 786-O exhibited decreased survival and pronounced apoptosis associated with a decreased GSH/GSSG ratio, augmented nuclear factor erythroid-related factor 2, and increased 8-oxo-7,8-dihydro-2'-deoxyguanosine, a marker of DNA damage. SN12 tumor xenografts showed decreased growth when treated with CB-839. Furthermore, PET imaging confirmed that ccRCC tumors exhibited increased tumoral uptake of 18F-(2S,4R)4-fluoroglutamine compared with the kidney in the orthotopic mouse model. This technique can be utilized to follow changes in ccRCC metabolism in vivo. Further development of these paradigms will lead to new treatment options with glutaminase inhibitors and the utility of PET to identify and manage patients with ccRCC who are likely to respond to glutaminase inhibitors in the clinic. Cancer Res; 77(23); 6746–58. ©2017 AACR.

http://ift.tt/2i5895C

Integrated Analysis of Whole-Genome ChIP-Seq and RNA-Seq Data of Primary Head and Neck Tumor Samples Associates HPV Integration Sites with Open Chromatin Marks

Chromatin alterations mediate mutations and gene expression changes in cancer. Chromatin immunoprecipitation followed by sequencing (ChIP-Seq) has been utilized to study genome-wide chromatin structure in human cancer cell lines, yet numerous technical challenges limit comparable analyses in primary tumors. Here we have developed a new whole-genome analytic pipeline to optimize ChIP-Seq protocols on patient-derived xenografts from human papillomavirus–related (HPV+) head and neck squamous cell carcinoma (HNSCC) samples. We further associated chromatin aberrations with gene expression changes from a larger cohort of the tumor and normal samples with RNA-Seq data. We detect differential histone enrichment associated with tumor-specific gene expression variation, sites of HPV integration in the human genome, and HPV-associated histone enrichment sites upstream of cancer driver genes, which play central roles in cancer-associated pathways. These comprehensive analyses enable unprecedented characterization of the complex network of molecular changes resulting from chromatin alterations that drive HPV-related tumorigenesis. Cancer Res; 77(23); 6538–50. ©2017 AACR.

http://ift.tt/2i4bemz

EZH2 Modifies Sunitinib Resistance in Renal Cell Carcinoma by Kinome Reprogramming

Acquired and intrinsic resistance to receptor tyrosine kinase inhibitors (RTKi) represents a major hurdle in improving the management of clear cell renal cell carcinoma (ccRCC). Recent reports suggest that drug resistance is driven by tumor adaptation via epigenetic mechanisms that activate alternative survival pathways. The histone methyl transferase EZH2 is frequently altered in many cancers, including ccRCC. To evaluate its role in ccRCC resistance to RTKi, we established and characterized a spontaneously metastatic, patient-derived xenograft model that is intrinsically resistant to the RTKi sunitinib, but not to the VEGF therapeutic antibody bevacizumab. Sunitinib maintained its antiangiogenic and antimetastatic activity but lost its direct antitumor effects due to kinome reprogramming, which resulted in suppression of proapoptotic and cell-cycle–regulatory target genes. Modulating EZH2 expression or activity suppressed phosphorylation of certain RTKs, restoring the antitumor effects of sunitinib in models of acquired or intrinsically resistant ccRCC. Overall, our results highlight EZH2 as a rational target for therapeutic intervention in sunitinib-resistant ccRCC as well as a predictive marker for RTKi response in this disease. Cancer Res; 77(23); 6651–66. ©2017 AACR.

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Mesenchymal Stem Cells Promote Hepatocarcinogenesis via lncRNA-MUF Interaction with ANXA2 and miR-34a

Accumulating evidence suggests that cancer-associated mesenchymal stem cells (MSC) contribute to the development and metastasis of hepatocellular carcinoma (HCC). Aberrant expression of long noncoding RNAs (lncRNA) has been associated with these processes but cellular mechanisms are obscure. In this study, we report that HCC-associated mesenchymal stem cells (HCC-MSC) promote epithelial–mesenchymal transition (EMT) and liver tumorigenesis. We identified a novel lncRNA that we termed lncRNA–MUF (MSC-upregulated factor) that is highly expressed in HCC tissues and correlated with poor prognosis. Depleting lncRNA–MUF in HCC cells repressed EMT and inhibited their tumorigenic potential. Conversely, lncRNA–MUF overexpression accelerated EMT and malignant capacity. Mechanistic investigations showed that lncRNA–MUF bound Annexin A2 (ANXA2) and activated Wnt/β-catenin signaling and EMT. Furthermore, lncRNA-MUF acted as a competing endogenous RNA for miR-34a, leading to Snail1 upregulation and EMT activation. Collectively, our findings establish a lncRNA-mediated process in MSC that facilitates hepatocarcinogenesis, with potential implications for therapeutic targeting. Cancer Res; 77(23); 6704–16. ©2017 AACR.

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MYC Inhibition Depletes Cancer Stem-like Cells in Triple-Negative Breast Cancer

There is mounting evidence that cancer stem-like cells (CSC) are selectively enriched in residual tumors after anticancer therapies, which may account for tumor recurrence and metastasis by regenerating new tumors. Thus, there is a critical need to develop new therapeutic agents that can effectively eliminate drug-resistant CSCs and improve the efficacy of cancer therapy. Here, we report that Triptolide (C1572), a small-molecule natural product, selectively depletes CSCs in a dose-dependent fashion in human triple-negative breast cancer (TNBC) cell lines. Nanomolar concentrations of C1572 markedly reduced c-MYC (MYC) protein levels via a proteasome-dependent mechanism. Silencing MYC expression phenocopied the CSC depletion effects of C1572 and induced senescence in TNBC cells. Limited dilution assays revealed that ex vivo treatment of TNBC cells with C1572 reduced CSC levels by 28-fold. In mouse xenograft models of human TNBC, administration of C1572 suppressed tumor growth and depleted CSCs in a manner correlated with diminished MYC expression in residual tumor tissues. Together, these new findings provide a preclinical proof of concept defining C1572 as a promising therapeutic agent to eradicate CSCs for drug-resistant TNBC treatment. Cancer Res; 77(23); 6641–50. ©2017 AACR.

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IL10 Release upon PD-1 Blockade Sustains Immunosuppression in Ovarian Cancer

Ligation of programmed cell death-1 (PD-1) in the tumor microenvironment is known to inhibit effective adaptive antitumor immunity. Blockade of PD-1 in humans has resulted in impressive, durable regression responses in select tumor types. However, durable responses have been elusive in ovarian cancer patients. PD-1 was recently shown to be expressed on and thereby impair the functions of tumor-infiltrating murine and human myeloid dendritic cells (TIDC) in ovarian cancer. In the present work, we characterize the regulation of PD-1 expression and the effects of PD-1 blockade on TIDC. Treatment of TIDC and bone marrow–derived dendritic cells (DC) with IL10 led to increased PD-1 expression. Both groups of DCs also responded to PD-1 blockade by increasing production of IL10. Similarly, treatment of ovarian tumor–bearing mice with PD-1 blocking antibody resulted in an increase in IL10 levels in both serum and ascites. While PD-1 blockade or IL10 neutralization as monotherapies were inefficient, combination of these two led to improved survival and delayed tumor growth; this was accompanied by augmented antitumor T- and B-cell responses and decreased infiltration of immunosuppressive MDSC. Taken together, our findings implicate compensatory release of IL10 as one of the adaptive resistance mechanisms that undermine the efficacy of anti–PD-1 (or anti–PD-L1) monotherapies and prompt further studies aimed at identifying such resistance mechanisms. Cancer Res; 77(23); 6667–78. ©2017 AACR.

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Administering xCT Inhibitors Based on Circadian Clock Improves Antitumor Effects

Clock genes encoding transcription factors that regulate circadian rhythms may inform chronomodulated chemotherapy, where time-dependent dose alterations might affect drug efficacy and reduce side effects. For example, inhibiting the essential cystine transporter xCT with sulfasalazine induces growth arrest in cancer cells. Although the anticancer effects of sulfasalazine have been studied extensively, its effects on transcriptional control of xCT expression have not been studied. Here, we show that sulfasalazine administration during the period of increased xCT expression improves its anticancer effects and that the Clock gene itself induces xCT expression and regulates its circadian rhythm. Our findings highlight the clinical potential of chronomodulated chemotherapy and the importance of xCT-mediated transcriptional regulation in the utility of such strategies. Cancer Res; 77(23); 6603–13. ©2017 AACR.

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Molecular regulation of Nodal signaling during mesendoderm formation

Abstract

One of the most important events during vertebrate embryogenesis is the formation or specification of the three germ layers, endoderm, mesoderm, and ectoderm. After a series of rapid cleavages, embryos form the mesendoderm and ectoderm during late blastulation and early gastrulation. The mesendoderm then further differentiates into the mesoderm and endoderm. Nodal, a member of the transforming growth factor β (TGF-β) superfamily, plays a pivotal role in mesendoderm formation by regulating the expression of a number of critical transcription factors, including Mix-like, GATA, Sox, and Fox. Because the Nodal signal transduction pathway is well-characterized, increasing effort has been made to delineate the spatiotemporal modulation of Nodal signaling during embryonic development. In this review, we summarize the recent progress delineating molecular regulation of Nodal signal intensity and duration during mesendoderm formation.

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Optimization of Poplar mRNA purification for trancriptome library construction

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Paradoxical roles of TGF-β signaling in suppressing and promoting squamous cell carcinoma

Abstract

Transforming growth factor β (TGF-β) signaling either promotes or inhibits tumor formation and/or progression of many cancer types including squamous cell carcinoma (SCC). Canonical TGF-β signaling is mediated by a number of downstream proteins including Smad family proteins. Alterations in either TGF-β or Smad signaling can impact cancer. For instance, defects in TGF-β type I and type II receptors (TGF-βRI and TGF-βRII) and in Smad2/3/4 could promote tumor development. Conversely, increased TGF-β1 and activated TGF-βRI and Smad3 have all been shown to have tumor-promoting effects in experimental systems of human and mouse SCCs. Among TGF-β/Smad signaling, only TGF-βRII or Smad4 deletion in mouse epithelium causes spontaneous SCC in the mouse model, highlighting the critical roles of TGF-βRII and Smad4 in tumor suppression. Herein, we review the dual roles of the TGF-β/Smad signaling pathway and related mechanisms in SCC, highlighting the potential benefits and challenges of TGF-β/Smad-targeted therapies.

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A Naturalistic, Randomized Pilot Trial of E-Cigarettes: Uptake, Exposure, and Behavioral Effects

Background: Most studies of electronic nicotine delivery systems (ENDS) compare self-selected users versus nonusers. The few randomized studies to date generally support a positive impact on reducing smoking behavior, but these studies are focused on guided ENDS use. This study presents a randomized, naturalistic trial of ENDS with prospective outcomes of uptake and behavioral changes in smoking.

Methods: Adult smokers with minimal ENDS history were randomized in a 2:1 ratio to receive product for 3 weeks (n = 46), or not (n = 22). Changes in nicotine delivery (16 vs. 24 mg), midway through the study allowed a compelling opportunity to examine two ENDS products compared with the control group. Primary outcomes, assessed via daily diaries during sampling period and in-person laboratory visits over 4 months, included uptake and usage of ENDS, cessation-related outcomes, and exposure to smoke constituents.

Results: All ENDS participants tried product at least once, with 48% of 24 mg and 30% of 16 mg using their assigned product for the entire sampling period. Within the 24 mg ENDs group, 57% made an independent purchase of ENDS, versus 28% of 16 mg, and 14% of control participants (P = 0.01). Smokers in both ENDS groups significantly reduced their smoking, whereas control participants did not (P = 0.03). Cessation behaviors (quit attempts, biologically verified abstinence) numerically but not statistically favored ENDS participants.

Conclusions: Results suggest that cigarette smokers are willing to use ENDS with trends toward reduced cigarette smoking and positive changes in cessation-related behaviors.

Impact: Randomized, naturalistic trials such as presented herein are needed to understand the population impact of e-cigarettes. Cancer Epidemiol Biomarkers Prev; 26(12); 1795–803. ©2017 AACR.

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Mobile Screening Units for the Early Detection of Cancer: A Systematic Review

Mobile screening units (MSUs) provide cancer screening services outside of fixed clinical sites, thereby increasing access to early detection services. We conducted a systematic review of the performance of MSUs for the early detection of cancer. Databases (MEDLINE, EMBASE, Cochrane Library, WHO Global Health Library, Web of Science, PsycINFO) were searched up to July 2015. Studies describing screening for breast, cervical, and colon cancer using MSUs were included. Data were collected for operational aspects including the performance of exams, screening tests used, and outcomes of case detection. Of 268 identified studies, 78 were included. Studies investigated screening for cancers including breast (n = 55), cervical (n = 12), colon (n = 1), and multiphasic screening for multiple cancers (n = 10). The median number of screening exams performed per intervention was 1,767 (interquartile range 5,656–38,233). Programs operated in 20 countries, mostly in North America (36%) and Europe (36%); 52% served mixed rural/urban regions, while 35% and 13% served rural or urban regions, respectfully. We conclude that MSUs have served to expand access to screening in diverse contexts. However, further research on the implementation of MSUs in low-resource settings and health economic research on cost-effectiveness of MSUs compared with fixed clinics to inform policymakers is needed. Cancer Epidemiol Biomarkers Prev; 26(12); 1679–94. ©2017 AACR.

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Highlights of This Issue

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Aging-Related Disease Risks among Young Thyroid Cancer Survivors

Background: Thyroid cancer is the most rapidly increasing cancer in the United States, affects a young population, has high survival, and is one of the most common cancers in people under age 40. The aim of this study was to examine the risks of aging-related diseases in a statewide sample of thyroid cancer survivors who were diagnosed <40 years compared with those diagnosed ≥40 and a cancer-free sample.

Methods: Thyroid cancer survivors diagnosed 1997 to 2012 were matched to up to 5 cancer-free individuals on birth year, sex, birth state, using the statewide Utah Population Database. Medical records were used to identify disease diagnoses stratified over three time periods: 1 to 5, >5 to 10, and 10+ years after cancer diagnosis. Cox proportional hazards models were used to estimate hazard ratios with adjustment on matching factors, race, body mass index, and Charlson Comorbidity Index.

Results: There were 3,706 thyroid cancer survivors and 15,587 matched cancer-free individuals (1,365 cases diagnosed <40 years old). Both age groups had increased risks for multiple circulatory health conditions 1 to 5 years after cancer diagnosis compared with cancer-free individuals. Survivors <40 had a higher risk of hypertension, cardiomyopathy, and nutritional deficiencies.

Conclusions: Increased risks for diseases associated with aging were observed for both age groups, with younger thyroid cancer survivors having higher risks for select diseases.

Impact: As thyroid cancer survivors in this study were found to have increased risks for aging-related diseases, future studies are needed to assess what can be done to reduce the increased risks of these long-term health effects. Cancer Epidemiol Biomarkers Prev; 26(12); 1695–704. ©2017 AACR.

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Blood Pressure Status in Adult Survivors of Childhood Cancer: A Report from the St. Jude Lifetime Cohort Study

Background: Hypertension potentiates cardiovascular risk in survivors of childhood cancer previously exposed to cardiotoxic therapies, so it is important to determine the prevalence and risk factors for hypertensive blood pressure in this high-risk group.

Methods: Participants included 3,016 adult 10-year survivors of childhood cancer who had resting blood pressure measurements performed at St. Jude Children's Research Hospital (Memphis, TN). We characterized the blood pressure status of participants, calculated standardized prevalence ratios based on U.S. population rates, and examined demographic and treatment factors associated with hypertensive blood pressure using logistic regression.

Results: The age-specific cumulative prevalence of hypertension in survivors increased sharply with age, exceeding 70% by age 50, and was substantially higher in all diagnosis groups than expected on the basis of age-, sex-, race/ethnicity-, and BMI-specific population rates. Specific cancer treatments were not significantly associated with hypertension, with the exception of nephrectomy (OR, 1.68; 95% confidence interval, 1.11–2.53). Previously undiagnosed hypertensive blood pressure was identified in 8% of survivors, and uncontrolled hypertension in 22% of those with a previous hypertension diagnosis. In a subset (n = 1,185) with longitudinal blood pressure measurements (mean interval, 3.6 years), 5% and 21% of participants with previously normal blood pressure developed hypertensive and prehypertensive blood pressure, respectively.

Conclusions: Survivors of childhood cancer have a higher prevalence of hypertension compared with the general population, and many have uncontrolled hypertension that may exacerbate treatment-related cardiovascular risks.

Impact: Our results suggest enhanced clinical attention to blood pressure status is warranted in all survivors, regardless of diagnosis or cancer treatment. Cancer Epidemiol Biomarkers Prev; 26(12); 1705–13. ©2017 AACR.

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No Association of Waist Circumference and Prostate Cancer in the Cancer Prevention Study II Nutrition Cohort

Background: The relationship between excess body weight and prostate cancer risk is unclear. However, some evidence suggests that waist circumference, which provides a measure of central adiposity, may be positively associated with more advanced stages or grades of prostate cancer.

Methods: The association between waist circumference and prostate cancer was investigated among 46,094 men enrolled in the Cancer Prevention Study II Nutrition Cohort, of whom 5,711 were diagnosed with this cancer between 1997 and 2013. Using Cox proportional hazards regression, we examined associations of weight circumference with total and high-grade prostate cancer incidence and with prostate cancer mortality.

Results: In both categorical and continuous analyses, waist circumference was not associated with total or high-grade (Gleason score ≥ 8) prostate cancer incidence or with prostate cancer mortality regardless of whether body mass index was adjusted for in the statistical model. Waist circumference was inversely associated with low-grade (Gleason score < 8) prostate cancer, but the association was not statistically significant after adjustment for body mass index.

Conclusions: Our results suggest that central adiposity, as measured by waist circumference, is not significantly associated with prostate cancer incidence or mortality.

Impact: Compared with men in other studies with significant results, men in our study were considerably older, suggesting that age may influence the association between waist circumference and prostate cancer. Cancer Epidemiol Biomarkers Prev; 26(12); 1812–4. ©2017 AACR.

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Childhood Socioeconomic Position and Pubertal Onset in a Cohort of Multiethnic Girls: Implications for Breast Cancer

Background: Higher socioeconomic position (SEP) has been associated with increased risk of breast cancer. Its relationship with earlier age of pubertal onset, a risk factor for breast cancer, is less clear.

Methods: We studied the relationship of SEP to pubertal onset in a multiethnic cohort of 1,237 girls ages 6 to 8 years at baseline. Girls in three U.S. cities were followed for 5 to 8 years with annual clinical examinations from 2004 to 2012. SEP measures were examined for associations with pubertal onset, assessed by breast budding (thelarche) and pubic hair development (adrenarche). Analyses were conducted with accelerated failure time models using a Weibull distribution, with left, right, and interval censoring.

Results: Higher body mass index percentage at entry to the study and black or Hispanic race/ethnicity were the strongest predictors of age at pubertal onset. An SEP index comprising household family income, mother's education, and home ownership was an independent predictor of thelarche in adjusted models for all girls together and for white and Latina, separately, but not black girls, and the relationship varied by study site. The SEP index was not related to adrenarche in adjusted models. Overall, girls from the lowest quintile of SEP entered puberty on average 6% earlier than girls from the highest quintile (time ratio = 0.94; 95% confidence interval 0.91–0.97) in adjusted models.

Conclusions: Our results suggest that early-life SEP may influence the timing of pubertal development.

Impact: Factors related to lower SEP in childhood can adversely affect early development in ways that may increase the risk of breast cancer. Cancer Epidemiol Biomarkers Prev; 26(12); 1714–21. ©2017 AACR.

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Emerging Trends in Family History of Breast Cancer and Associated Risk

Background: Increase in breast cancer incidence associated with mammography screening diffusion may have attenuated risk associations between family history and breast cancer.

Methods: The proportions of women ages 40 to 74 years reporting a first-degree family history of breast cancer were estimated in the Breast Cancer Surveillance Consortium cohort (BCSC: N = 1,170,900; 1996–2012) and the Collaborative Breast Cancer Study (CBCS: cases N = 23,400; controls N = 26,460; 1987–2007). Breast cancer (ductal carcinoma in situ and invasive) relative risk estimates and 95% confidence intervals (CI) associated with family history were calculated using multivariable Cox proportional hazard and logistic regression models.

Results: The proportion of women reporting a first-degree family history increased from 11% in the 1980s to 16% in 2010 to 2013. Family history was associated with a >60% increased risk of breast cancer in the BCSC (HR, 1.61; 95% CI, 1.55–1.66) and CBCS (OR, 1.64; 95% CI, 1.57–1.72). Relative risks decreased slightly with age. Consistent trends in relative risks were not observed over time or across stage of disease at diagnosis in both studies, except among older women (ages 60–74) where estimates were attenuated from about 1.7 to 1.3 over the last 20 years (P trend = 0.08 for both studies).

Conclusions: Although the proportion of women with a first-degree family history of breast cancer increased over time and by age, breast cancer risk associations with family history were nonetheless fairly constant over time for women under age 60.

Impact: First-degree family history of breast cancer remains an important breast cancer risk factor, especially for younger women, despite its increasing prevalence in the mammography screening era. Cancer Epidemiol Biomarkers Prev; 26(12); 1753–60. ©2017 AACR.

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Biology and Etiology of Young-Onset Breast Cancers among Premenopausal African American Women: Results from the AMBER Consortium

Background: African American (AA) women have higher incidence of aggressive, young-onset (<40 years) breast cancers. Young- and older-onset disease may have distinct tumor biologies and etiologies; however, studies investigating age differences among AA women have been rare and generally underpowered.

Methods: We examined tumor characteristics and breast cancer risk factors associated with premenopausal young (<40) vs. older (≥40) AA women's breast cancer in the African American Breast Cancer Epidemiology and Risk Consortium (2,008 cases and 5,144 controls). Unconditional logistic regression models assessed heterogeneity of tumor biology and risk factor associations by age, overall, and by estrogen receptor status.

Results: Premenopausal AA women <40 years had higher frequency of poorer-prognosis tumor characteristics compared with older women, including negative estrogen and progesterone receptor status, triple-negative subtype, higher grade, higher stage, and larger tumors. Adiposity (i.e., waist-to-hip ratio) and family history of breast cancer were more strongly associated with young-onset disease [case–control OR = 1.46, 95% confidence interval (CI) = 1.04–2.05; OR = 3.10, 95% CI = 2.08–4.63, respectively] compared with older-onset disease (OR = 1.11, 95% CI = 0.91–1.35; OR = 1.57, 95% CI = 1.26–1.94). Breastfeeding showed a slight inverse risk association among young women (OR = 0.70, 95% CI = 0.43–1.16). Oral contraceptive use was associated with increased risk regardless of age. Considering various cutoff points for young age (<40, <45, <50), age-related heterogeneity was greatest when <40 was used.

Conclusions: Among premenopausal AA women, diagnosis before age 40 is associated with more aggressive breast tumor biology and some etiologic differences.

Impact: Modifiable risk factors including breastfeeding, adiposity, and oral contraceptive use may be important targets for mitigating harms of young-onset breast cancer. Cancer Epidemiol Biomarkers Prev; 26(12); 1722–9. ©2017 AACR.

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Genetic Testing in a Population-Based Sample of Breast and Ovarian Cancer Survivors from the REACH Randomized Trial: Cost Barriers and Moderators of Counseling Mode

Background: This study evaluates predictors of BRCA1/2 testing among breast and ovarian cancer survivors who received genetic counseling as part of a randomized trial and evaluates moderators of counseling mode on testing uptake.

Methods: Predictors of BRCA1/2 testing within one year postcounseling were evaluated using multivariable logistic regression in a population-based sample of breast and ovarian cancer survivors at increased hereditary risk randomly assigned to in-person counseling (IPC; n = 379) versus telephone counseling (TC; n = 402). Variables that moderated the association between counseling mode and testing were identified by subgroup analysis.

Results: Testing uptake was associated with higher perceived comparative mutation risk [OR = 1.32; 95% confidence interval (CI), 1.11–1.57] in the adjusted analysis. Those without cost barriers had higher testing uptake (OR = 18.73; 95% CI, 7.09–49.46). Psychologic distress and perceived comparative mutation risk moderated the effect of counseling and testing. Uptake between IPC versus TC did not differ at low levels of distress and risk, but differed at high distress (26.3% TC vs. 44.3% IPC) and high perceived comparative risk (33.9% TC vs. 50.5% IPC).

Conclusions: Cost concerns are a strong determinant of testing. Differences in testing uptake by counseling mode may depend on precounseling distress and risk perceptions.

Impact: Cost concerns may contribute to low testing in population-based samples of at-risk cancer survivors. Precounseling psychosocial characteristics should be considered when offering in-person versus telephone counseling. Cancer Epidemiol Biomarkers Prev; 26(12); 1772–80. ©2017 AACR.

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Metabolic Obesity Phenotypes and Risk of Breast Cancer in Postmenopausal Women

Background: Obesity and the metabolic syndrome (MetS) have both been linked to increased risk of postmenopausal breast cancer; however, their relative contributions are poorly understood.

Methods: We examined the association of metabolic phenotypes of obesity defined by presence of the MetS (yes and no) and body mass index (BMI; normal, overweight, obese) with risk of postmenopausal breast cancer in a prospective analysis of a cohort of postmenopausal women (n ~ 21,000) with baseline measurements of blood glucose, triglycerides, HDL-cholesterol, blood pressure, waist circumference, and BMI. Women were classified into 6 metabolic obesity phenotypes according to their BMI (18.5–<25.0, 25.0–<30.0, ≥30.0 kg/m²) and presence of the MetS (≥3 of the following: waist circumference ≥88 cm, triglycerides ≥150 mg/dL, HDL-C <50 mg/dL, glucose ≥100 mg/dL, and systolic/diastolic blood pressure ≥130/85 mmHg or treatment for hypertension). HRs for incident breast cancer and 95% confidence intervals (95% CI) were estimated using Cox proportional hazards models.

Results: Over 15 years of follow-up, 1,176 cases of invasive breast cancer were diagnosed. Obesity, regardless of metabolic health, was associated with increased risk of breast cancer. Being obese and metabolically unhealthy was associated with the highest risk: HR, 1.62; 95% CI, 1.33–1.96. These associations were stronger in women who had never used hormone therapy.

Conclusions: Our findings suggest that both obesity and metabolic dysregulation are associated with breast cancer risk.

Impact: Beyond BMI, metabolic health should be considered a clinically relevant and modifiable risk factor for breast cancer. Cancer Epidemiol Biomarkers Prev; 26(12); 1730–5. ©2017 AACR.

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Long-Term Effects of Weight Loss and Exercise on Biomarkers Associated with Angiogenesis

Background: We tested the effect of weight loss on circulating levels of the angiogenic factors VEGF and pigment epithelium-derived factor (PEDF) in postmenopausal overweight/obese women, 18 months after completing a year-long 4-arm randomized controlled trial of behavioral weight loss and/or exercise versus control (i.e., 30 months postrandomization).

Methods: The 439 overweight/obese, postmenopausal women, ages 50 to 75 years, were randomized to: diet (goal: 10% weight loss, N = 118), exercise (225 min/wk moderate-to-vigorous activity, N = 117), diet + exercise (N = 117), or control (N = 87). At 12 months, 399 women gave a blood sample; 156 returned at 30 months. Biomarkers were measured by immunoassay. Changes were compared using generalized estimating equations, adjusting for baseline BMI, age, and race/ethnicity.

Results: Participants randomized to diet, exercise, and diet + exercise arms had greater reductions in VEGF at 30 months (–14.1% P = 0.02; –19.7% P = 0.003; –14.5% P = 0.002, respectively) versus controls (–4.5%). There were no statistically significant changes in PEDF in any intervention arm. Participants maintaining ≥10% of baseline weight loss at 30 months had greater reductions in VEGF versus those who gained weight/had no weight change (–22.3% vs. –10.2% respectively, P = 0.002). Participants maintaining any weight loss had significantly lower levels of PEDF at 30 months versus those who gained weight/no weight change.

Conclusions: Sustained weight loss via diet and/or exercise results in reductions in angiogenic factors, and can be maintained up to 30-month follow-up. Limitations include relatively small numbers, and possible bias toward more successful weight loss among women who returned at 30 months.

Impact: Maintaining weight loss can achieve long-term reductions in biomarkers of angiogenesis that can persist up to 18 months after completion of a weight loss intervention. Cancer Epidemiol Biomarkers Prev; 26(12); 1788–94. ©2017 AACR.

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Alcohol, Physical Activity, Smoking, and Breast Cancer Subtypes in a Large, Nested Case-Control Study from the Norwegian Breast Cancer Screening Program

Background: To what extent alcohol, smoking, and physical activity are associated with the various subtypes of breast cancer is not clear. We took advantage of a large population-based screening cohort to determine whether these risk factors also increase the risk of the poor prognosis subtypes.

Methods: We conducted a matched case–control study nested within the Norwegian Breast Cancer Screening Program during 2006–2014. A total of 4,402 breast cancer cases with risk factor and receptor data were identified. Five controls were matched to each case on year of birth and year of screening. Conditional logistic regression was used to estimate ORs of breast cancer subtypes adjusted for potential confounders.

Results: There were 2,761 luminal A–like, 709 luminal B–like HER2-negative, 367 luminal B–like HER2-positive, 204 HER2-positive, and 361 triple-negative cancers. Current alcohol consumption was associated with breast cancer risk overall [OR 1.26; 95% confidence interval (CI), 1.09–1.45] comparing 6+ glasses a week to never drinkers. However, this risk increase was found only for luminal A–like breast cancer. Smoking 20+ cigarettes a day was associated with an OR of 1.41 (95% CI, 1.06–1.89) overall, with significant trends for luminal A–like and luminal B–like HER2-negative cancer. Current physical activity (4+ hours/week compared with none) was associated with 15% decreased risk of luminal A–like cancer, but not clearly with other subtypes.

Conclusions: In this large study, alcohol, smoking, and physical activity were predominantly associated with luminal A–like breast cancer.

Impact: Alcohol, smoking, and physical activity were associated with luminal A–like breast cancer subtype. Cancer Epidemiol Biomarkers Prev; 26(12); 1736–44. ©2017 AACR.

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Impact of Patient-Provider Race, Ethnicity, and Gender Concordance on Cancer Screening: Findings from Medical Expenditure Panel Survey

Background: Racial and ethnic minorities experience lower rates of cancer screening compared with non-Hispanic whites (NHWs). Previous studies evaluating the role of patient–provider race, ethnicity, or gender concordance in cancer screening have been inconclusive.

Methods: In a cross-sectional analysis using the Medical Expenditure Panel Survey (MEPS), data from 2003 to 2010 were assessed for associations between patient–provider race, ethnicity, and/or gender concordance and, screening (American Cancer Society guidelines) for breast, cervical, and colorectal cancer. Multivariable logistic analyses were conducted to examine associations of interest.

Results: Of the 32,041 patient–provider pairs in our analysis, more than 60% of the patients were NHW, 15% were non-Hispanic black (NHB), and 15% were Hispanic. Overall, patients adherent to cancer screening were more likely to be non-Hispanic, better educated, married, wealthier, and privately insured. Patient–provider gender discordance was associated with lower rates of breast [OR, 0.83; 95% confidence interval (CI), 0.76–0.90], cervical (OR, 0.83; 95% CI, 0.76–0.91), and colorectal cancer (OR, 0.84; 95% CI, 0.79–0.90) screening in all patients. This association was also significant after adjusting for racial and/or ethnic concordance. Conversely, among NHWs and NHBs, patient–provider racial and/or ethnic concordance was not associated with screening. Among Hispanics, patient–provider ethnic discordant pairs had higher breast (58% vs. 52%) and colorectal cancer (45% vs. 39%) screening rates compared with concordant pairs.

Conclusions: Patient–provider gender concordance positively affected cancer screening. Patient–provider ethnic concordance was inversely associated with receipt of cancer screening among Hispanics. This counter-intuitive finding requires further study.

Impact: Our findings highlight the importance of gender concordance in improving cancer screening rates. Cancer Epidemiol Biomarkers Prev; 26(12); 1804–11. ©2017 AACR.

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Healthcare System Distrust, Physician Trust, and Patient Discordance with Adjuvant Breast Cancer Treatment Recommendations

Background: Adjuvant therapy after breast cancer surgery decreases recurrence and increases survival, yet not all women receive and complete it. Previous research has suggested that distrust in medical institutions plays a role in who initiates adjuvant treatment, but has not assessed treatment completion, nor the potential mediating role of physician distrust.

Methods: Women listed in Pennsylvania and Florida cancer registries, who were under the age of 65 when diagnosed with localized invasive breast cancer between 2005 and 2007, were surveyed by mail in 2007 to 2009. Survey participants self-reported demographics, cancer stage and treatments, treatment discordance (as defined by not following their surgeon or oncologist treatment recommendation), healthcare system distrust, and physician trust. Age and cancer stage were verified against cancer registry records. Logistic regression assessed the relationship between highest and lowest tertiles of healthcare system distrust and the dichotomous outcome of treatment discordance, controlling for demographics and clinical treatment factors, and testing for mediation by physician trust.

Results: Of the 2,754 participants, 30.2% (n = 832) reported not pursing at least one recommended treatment. The mean age was 52. Patients in the highest tertile of healthcare system distrust were 22% more likely to report treatment discordance than the lowest tertile; physician trust did not mediate the association between healthcare system distrust and treatment discordance.

Conclusions: Healthcare system distrust is positively associated with treatment discordance, defined as failure to initiate or complete physician-recommended adjuvant treatment after breast cancer.

Impact: Interventions should test whether or not resolving institutional distrust reduces treatment discordance. Cancer Epidemiol Biomarkers Prev; 26(12); 1745–52. ©2017 AACR.

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Safety and Efficacy of Intratumoral Injections of Chimeric Antigen Receptor (CAR) T Cells in Metastatic Breast Cancer

Chimeric antigen receptors (CAR) are synthetic molecules that provide new specificities to T cells. Although successful in treatment of hematologic malignancies, CAR T cells are ineffective for solid tumors to date. We found that the cell-surface molecule c-Met was expressed in ~50% of breast tumors, prompting the construction of a CAR T cell specific for c-Met, which halted tumor growth in immune-incompetent mice with tumor xenografts. We then evaluated the safety and feasibility of treating metastatic breast cancer with intratumoral administration of mRNA-transfected c-Met-CAR T cells in a phase 0 clinical trial (NCT01837602). Introducing the CAR construct via mRNA ensured safety by limiting the nontumor cell effects (on-target/off-tumor) of targeting c-Met. Patients with metastatic breast cancer with accessible cutaneous or lymph node metastases received a single intratumoral injection of 3 x 10⁷ or 3 x 10⁸ cells. CAR T mRNA was detectable in peripheral blood and in the injected tumor tissues after intratumoral injection in 2 and 4 patients, respectively. mRNA c-Met-CAR T cell injections were well tolerated, as none of the patients had study drug–related adverse effects greater than grade 1. Tumors treated with intratumoral injected mRNA c-Met-CAR T cells were excised and analyzed by immunohistochemistry, revealing extensive tumor necrosis at the injection site, cellular debris, loss of c-Met immunoreactivity, all surrounded by macrophages at the leading edges and within necrotic zones. We conclude that intratumoral injections of mRNA c-Met-CAR T cells are well tolerated and evoke an inflammatory response within tumors. Cancer Immunol Res; 5(12); 1152–61. ©2017 AACR.

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Report on the Third FDA-AACR Oncology Dose-Finding Workshop

The FDA–AACR Oncology Dose-Finding Workshop, Part 3, was held in Washington, DC, on July 20, 2017, as a continuation of the previous two collaborative dose-finding and optimization workshops presented by the FDA and AACR. This year's workshop focused on combination therapy with immune-oncology agents and best practices regarding patient and dose selection, predictive biomarkers, and novel clinical endpoints. This summary highlights viewpoints that emerged during the workshop. Cancer Immunol Res; 5(12); 1058–61. ©2017 AACR.

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Characterization of Thyroid Disorders in Patients Receiving Immune Checkpoint Inhibition Therapy

Thyroid disorders have emerged as one of the most common immune-related adverse events associated with anti–PD-1 monotherapy or combination anti–PD-1 and anti–CTLA-4 therapy. This study characterizes and compares the evolution of monotherapy and combination therapy-related thyroid disorders. We analyzed the dynamic evolution of thyroid disorders in 45 patients who developed thyroid disorders following treatment with either anti–PD-1 monotherapy or anti–PD-1 and anti–CTLA-4 combination therapy. The patients presented with thyrotoxicosis or hypothyroidism as the initial presentation of their thyroid disorder. Thyrotoxicosis as the initial presentation occurred in the majority of patients (93% and 56% of the patients receiving combination therapy and monotherapy, respectively). The onset pattern of the thyroid disorder was significantly different between the two groups (P = 0.01). Subsequently, 76% and 90% of the patients with thyrotoxicosis evolved to develop hypothyroidism in the combination and monotherapy groups, respectively. In the combination therapy and monotherapy groups, the median times to onset of thyrotoxicosis and hypothyroidism after first treatment were 21 and 63 days, and 31 and 68 days, respectively. The median time for transition from thyrotoxicosis to hypothyroidism was 42 days in both groups. Our study demonstrates that most thyroid disorders induced by either anti–PD-1 or combination anti–PD-1 and anti–CTLA-4 therapy are thyroiditis. The time to onset of thyrotoxicosis after treatment initiation and evolution of thyrotoxicosis to hypothyroidism was short, emphasizing the importance of close monitoring of thyroid function in these patients. Cancer Immunol Res; 5(12); 1133–40. ©2017 AACR.

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Differential Expression of Homing Receptor Ligands on Tumor-Associated Vasculature that Control CD8 Effector T-cell Entry

Although CD8⁺ T cells are critical for controlling tumors, how they are recruited and home to primary and metastatic lesions is incompletely understood. We characterized the homing receptor (HR) ligands on tumor vasculature to determine what drives their expression and their role in T-cell entry. The anatomic location of B16-OVA tumors affected the expression of E-selectin, MadCAM-1, and VCAM-1, whereas the HR ligands CXCL9 and ICAM-1 were expressed on the vasculature regardless of location. VCAM-1 and CXCL9 expression was induced by IFN-secreting adaptive immune cells. VCAM-1 and CXCL9/10 enabled CD8⁺ T-cell effectors expressing α₄β₁ integrin and CXCR3 to enter both subcutaneous and peritoneal tumors, whereas E-selectin enabled E-selectin ligand⁺ effectors to enter subcutaneous tumors. However, MadCAM-1 did not mediate α₄β₇⁺ effector entry into peritoneal tumors due to an unexpected lack of luminal expression. These data establish the relative importance of certain HRs expressed on activated effectors and certain HR ligands expressed on tumor vasculature in the effective immune control of tumors. Cancer Immunol Res; 5(12); 1062–73. ©2017 AACR.

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Complex Immune Evasion Strategies in Classical Hodgkin Lymphoma

The cellular microenvironment in classical Hodgkin lymphoma (cHL) is dominated by a mixed infiltrate of inflammatory cells with typically only about 1% Hodgkin and Reed/Sternberg (HRS) tumor cells. T cells are usually the largest population of cells in the cHL microenvironment, encompassing T helper (Th) cells, regulatory T cells (Tregs), and cytotoxic T cells. Th cells and Tregs presumably provide essential survival signals for HRS cells. Tregs are also involved in rescuing HRS cells from antitumor immune responses. An understanding of the immune evasion strategies of HRS cells is not only relevant for a characterization of the pathophysiology of cHL but is also clinically relevant, given the current treatment approaches targeting checkpoint inhibitors. Here, we characterized the cHL-specific CD4⁺ T-cell infiltrate regarding its role in immune evasion. Global gene expression analysis of CD4⁺ Th cells and Tregs isolated from cHL lymph nodes and reactive tonsils revealed that Treg signatures were enriched in CD4⁺ Th cells of cHL. Hence, HRS cells may induce Treg differentiation in Th cells, a conclusion supported by in vitro studies with Th cells and cHL cell lines. We also found evidence for immune-suppressive purinergic signaling and a role of the inhibitory receptor-ligand pairs B- and T-cell lymphocyte attenuator–herpesvirus entry mediator and CD200R–CD200 in promoting immune evasion. Taken together, this study highlights the relevance of Treg induction and reveals new immune checkpoint-driven immune evasion strategies in cHL. Cancer Immunol Res; 5(12); 1122–32. ©2017 AACR.

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Natural Killer T-cell Immunotherapy in Combination with Chemotherapy-Induced Immunogenic Cell Death Targets Metastatic Breast Cancer

Natural killer T (NKT) cells are glycolipid-reactive lymphocytes that promote cancer control. In previous studies, NKT-cell activation improved survival and antitumor immunity in a postsurgical mouse model of metastatic breast cancer. Herein, we investigated whether NKT-cell activation could be combined with chemotherapeutic agents to augment therapeutic outcomes. Gemcitabine and cyclophosphamide analogues enhanced the potential immunogenicity of 4T1 mammary carcinoma cells by increasing the expression of antigen-presenting molecules (MHC-I, MHC-II, and CD1d) and promoting exposure or release of immunogenic cell death markers (calreticulin, HMGB1, and ATP). In 4T1 primary tumor and postsurgical metastasis models, BALB/c mice were treated with cyclophosphamide or gemcitabine. NKT cells were then activated by transfer of dendritic cells loaded with the glycolipid antigen α-galactosylceramide (α-GalCer). Chemotherapeutic treatments did not impact NKT-cell activation but enhanced recruitment into primary tumors. Cyclophosphamide, gemcitabine, or α-GalCer–loaded dendritic cell monotherapies decreased tumor growth in the primary tumor model and reduced metastatic burden and prolonged survival in the metastasis model. Combining chemotherapeutics with NKT-cell activation therapy significantly enhanced survival, with surviving mice exhibiting attenuated tumor growth following a second tumor challenge. The frequency of myeloid-derived suppressor cells was reduced by gemcitabine, cyclophosphamide, or α-GalCer–loaded dendritic cell treatments; cyclophosphamide also reduced the frequency of regulatory T cells. Individual treatments increased immune cell activation, cytokine polarization, and cytotoxic responses, although these readouts were not enhanced further by combining therapies. These findings demonstrate that NKT-cell activation therapy can be combined with gemcitabine or cyclophosphamide to target tumor burden and enhance protection against tumor recurrence. Cancer Immunol Res; 5(12); 1086–97. ©2017 AACR.

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Cisplatin Alters Antitumor Immunity and Synergizes with PD-1/PD-L1 Inhibition in Head and Neck Squamous Cell Carcinoma

Head and neck squamous cell carcinoma (HNSCC) has been treated for decades with cisplatin chemotherapy, and anti–PD-1 immunotherapy has recently been approved for the treatment of this disease. However, preclinical studies of how antitumor immunity in HNSCC is affected by cisplatin alone or in combination with immunotherapies are lacking. Here, we show that sublethal doses of cisplatin may enhance antigen presentation and T-cell killing in vitro, though cisplatin also upregulates tumor cell expression of PD-L1 and may impair T-cell function at higher doses. In a syngeneic mouse model of HNSCC, concurrent use of cisplatin and anti–PD-L1/PD-1 delayed tumor growth and enhanced survival without significantly reducing the number or function of tumor-infiltrating immune cells or increasing cisplatin-induced toxicities. These results suggest that moderate doses of cisplatin may enhance antitumor immunity by mechanisms other than direct tumor cell killing, which may be further enhanced by anti–PD-L1/PD-1 therapy. Cancer Immunol Res; 5(12); 1141–51. ©2017 AACR.

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Interleukin-12 from CD103+ Batf3-Dependent Dendritic Cells Required for NK-Cell Suppression of Metastasis

Several host factors may affect the spread of cancer to distant organs; however, the intrinsic role of dendritic cells (DC) in controlling metastasis is poorly described. Here, we show in several tumor models that although the growth of primary tumors in Batf3-deficient mice, which lack cross-presenting DCs, was not different from primary tumors in wild-type (WT) control mice, Batf3-deficient mice had increased experimental and spontaneous metastasis and poorer survival. The increased metastasis was independent of CD4⁺ and CD8⁺ T lymphocytes, but required NK cells and IFN. Chimeric mice in which Batf3-dependent DCs uniformly lacked the capacity to produce IL12 had metastatic burdens similar to the Batf3-deficient mice, suggesting that Batf3⁺ DCs were the only cell type whose IL12 production was critical for controlling metastasis. We found that IL12-YFP reporter mice, whose lungs were injected with B16F10 melanoma, had increased numbers of IL12-expressing CD103⁺ DCs with enhanced CD86 expression. Bone-marrow–derived DCs from WT, but not Batf3-deficient, mice activated NK cells to produce IFN in an IL12-dependent manner and therapeutic injection of recombinant mouse IL12 decreased metastasis in both WT and Batf3-deficient mice. Analysis of TCGA datasets revealed an association between high expression of BATF3 and IRF8 and improved survival of breast cancer patients; BATF3 expression also significantly correlated with NK-cell receptor genes, IL12, and IFNG. Collectively, our findings show that IL12 from CD103⁺ DCs is critical for NK cell–mediated control of tumor metastasis. Cancer Immunol Res; 5(12); 1098–108. ©2017 AACR.

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Acknowledgment to Reviewers

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Fine-scale population genetic structure of arctic foxes (Vulpes lagopus) in the High Arctic

The arctic fox (Vulpes lagopus) is a circumpolar species inhabiting all accessible Arctic tundra habitats. The species forms a panmictic population over areas connected by sea ice, but recently, kin clustering an...

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Co-infection with Bartonella bacilliformis and Mycobacterium spp. in a coastal region of Peru

This study investigated an outbreak of Bartonellosis in a coastal region in Peru.

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Type IV dual left anterior descending coronary artery: a case report

Dual left anterior descending (LAD) artery or duplication of LAD is a rarely reported coronary anomaly, consisting of two branches supplying the usual distribution of the LAD. Type IV dual LAD, in which a shor...

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Involuntary protection against dermatosis: A preliminary observation on trypophobia

Trypophobia refers to the intense negative emotions evoked by exposure to repeated visual patterns like a honeycomb. We propose a cognitive mechanism that can explain why such negative emotions are triggered b...

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Performance of MTBDRplus assay in detecting multidrug resistant tuberculosis at hospital level

Multidrug-resistant tuberculosis (MDR-TB) case finding progressively increased in Ethiopia mainly as a result of the utilization of World Health Organization (WHO)-endorsed rapid technologies including MTBDRplus ...

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Expert consensus on re-irradiation for recurrent glioma

Abstract

Purpose

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

Materials and methods

A survey was conducted with 13 radiation oncologists involved in the care of central nervous system tumor patients. The survey was comprised of 49 questions divided into 2 domains: a demographic section (10 questions) and a case section (5 re-RT cases with 5 to 6 questions representing one or several re-RT treatment dilemmas as may be encountered in the clinic). Respondents were asked to rate the relevance of various factors to offering re-RT, respond to the cases with a decision to offer re-RT vs. not, volume to be treated, margins to be employed, dose/fractionation suggested and any additional comments with respect to rationale in each scenario.

Results

Sixty nine percent of responders have been practicing for greater than 10 years and 61% have re-RT 20 to 100 patients to date, with 54% seeing 2–5 re-RT cases per month and retreating 1–2 patients per month. Recurrent tumor volume, time since previous radiation therapy, previously administered dose to organs at risk and patient performance status were rated by the majority of responders (85%, 92%, 77%, and 69% respectively) as extremely relevant or very relevant to offering re-RT as an option.

Conclusion

The experts' practice of re-RT is still heterogeneous, reflecting the paucity of high-quality prospective data available for decision-making. Nevertheless, practicing radiation oncologists can support own decisions by referring to the cases found suitable for re-RT in this survey.

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Treatment of meningioma and glioma with protons and carbon ions

Abstract

The rapid rise of particle therapy across the world necessitates evidence to justify its ever-increasing utilization. This narrative review summarizes the current status of these technologies on treatment of both meningiomas and gliomas, the most common benign and malignant primary brain tumors, respectively. Proton beam therapy (PBT) for meningiomas displays high rates of long-term local control, low rates of symptomatic deterioration, along with the potential for safe dose-escalation in select (but not necessarily routine) cases. PBT is also associated with low adverse events and maintenance of functional outcomes, which have implications for quality of life and cost-effectiveness measures going forward. Data on carbon ion radiation therapy (CIRT) are limited; existing series describe virtually no high-grade toxicities and high local control. Regarding the few available data on low-grade gliomas, PBT provides opportunities to dose-escalate while affording no increase of severe toxicities, along with maintaining appropriate quality of life. Although dose-escalation for low-grade disease has been less frequently performed than for glioblastoma, PBT and CIRT continue to be utilized for the latter, and also have potential for safer re-irradiation of high-grade gliomas. For both neoplasms, the impact of superior dosimetric profiles with endpoints such as neurocognitive decline and neurologic funcionality, are also discussed to the extent of requiring more data to support the utility of particle therapy. Caveats to these data are also described, such as the largely retrospective nature of the available studies, patient selection, and heterogeneity in patient population as well as treatment (including mixed photon/particle treatment). Nevertheless, multiple prospective trials (which may partially attenuate those concerns) are also discussed. In light of the low quantity and quality of available data, major questions remain regarding economic concerns as well.

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Preoperative detection of pleural adhesions by respiratory dynamic computed tomography

Abstract

Background

Video-assisted thoracic surgery (VATS) plays an important role in thoracic surgery because it is less invasive. However, the existence of severe pleural adhesions may make VATS difficult and complicated. The aim of this study was to assess the utility of inspiration and expiration computed tomography (respiratory dynamic CT (RD-CT)) in evaluation of pleural adhesions preoperatively.

Methods

RD-CT was performed on 107 patients undergoing thoracotomies (both VATS and open). We assessed synchronous motion during respiration on RD-CT. Comparing the results of RD-CT and intraoperative findings, we assessed the utility of preoperative evaluation.

Results

A negative correlation between sliding score and adhesion grade was revealed. Sliding score in adhesion negative patients was significantly higher than that in adhesion positive patients (P < 0.0001). The sensitivity of RD-CT was 63.6%, specificity was 74.1%, and accuracy was 72%. Among 62 patients with a CT-Respiration Ratio of less than 0.65, the sensitivity of RD-CT was 77.8%, specificity was 86.8%, and accuracy was 85.5%.

Conclusions

RD-CT may be clinically useful for detecting the presence of pleural adhesions. It can be adopted as one of the criteria for deciding the surgical approach.

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Dissecting the heterogeneity of stage III non-small-cell lung cancer through incorporation of grade and histology

Future Oncology, Ahead of Print.


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The optimal treatment of metastatic hormone-naive prostate cancer: abiraterone acetate or docetaxel?

Future Oncology, Ahead of Print.


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Overexpressed miR-128a enhances chemoradiotherapy to laryngeal cancer cells and its correlation with BMI1

Future Oncology, Ahead of Print.


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Steroid-induced mental disorders in cancer patients: a systematic review

Future Oncology, Ahead of Print.


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Perurethral transvesical route for oocytes retrieval: an old technique for a new indication in oncofertility

Future Oncology, Ahead of Print.


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Clinical significance of preoperative liver stiffness measurements in primary HBV-positive hepatocellular carcinoma

Future Oncology, Ahead of Print.


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Editorial Board

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Immunohistochemistry defined subtypes of breast cancer in 678 Sudanese and Eritrean women; hospitals based case series

Abstract

Background

Breast cancer is the most common malignancy accounting for 25% of all cancers in females. In Africa, breast cancer prevalence and mortality are steadily increasing. Knowledge of hormone receptors and human epidermal growth factor receptor-2 (HER-2) expressions are vital for breast cancer management plans and decision making. There is wide regional variation in the proportion of these biomarkers, especially in African countries. Hormone receptors positivity in indigenous African and African American women is considered to be low and triple negative breast cancer is a dominant phenotype. There is paucity of data regarding hormone receptors (ER and PR) and HER2 expressions in North-eastern Africa (Eritrea and Sudan). The purpose of this study was to evaluate the expression of ER, PR and HER2 in Eritrean and Sudanese case series and correlate these biomarkers with the clinicopathological profile.

Method

Clinicopathologic data of patients were collected from clinical records. Immunohistochemistry biomarkers (ER, PR, and HER2) were assessed in consecutive female patients who had been diagnosed with invasive breast cancer from 2011 to 2015 in Gezira University Pathology Laboratory, the Sudan and National Health laboratory, Asmara, Eritrea.

Results

There were 678 cases involved in this study. The mean age was 48.8 years with ±0.53 standard error of the mean. Two-thirds of the case were ≤50 years. Invasive ductal carcinoma, no special type was the most dominant histologic type (86%) in both study groups. The majority of cases (70%) had tumour stage pT2 and pT3 and about 50% had lymph node involvement. Less than 5% of the cases had well-differentiated tumours. The ER, PR and HER2 positive rates were 45%, 32%, and 29%, respectively. The proportion of luminal-A like, luminal-B like, HER2 enriched and TNBC were 37%, 13%, 16% and 34%, respectively. Fisher extract analysis showed age (p = .015), tumour size (p = .041), and histologic grade (p = .000) were significantly associated with intrinsic subtypes. Furthermore, Logistic regression analysis stratified by origin, age, tumour size, lymph-node metastasis and grade indicated that younger women age (≤50 years) and grade III tumours were more likely to be diagnosed with ER negative breast cancer.

Conclusion

Most of Sudanese and Eritrean women were diagnosed at younger age and with unfavourable prognostic clinicopathologic prognostic markers. TNBC is more frequent in this cohort study; patients with grade III tumours and young age are more likely to be hormone receptors negative. Therefore, routine determination of hormone receptors is warranted for appropriate targeted therapy.

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MicroRNA profile in HBV-induced infection and hepatocellular carcinoma

Abstract

Background

MicroRNAs (miRNAs) exhibit essential regulatory functions related to cell growth, apoptosis, development and differentiation. Dysregulated expression of miRNAs is associated with a wide variety of human diseases. As such miRNA signatures are valuable as biomarkers for disease and for making treatment decisions. Hepatitis B virus (HBV) is a major risk factor for hepatocellular carcinoma (HCC). Here we screened for miRNAs in chronic HBV associated HCC.

Methods

To determine the miRNAs in HCC occurrence associated with HBV infection, we analyzed global miRNA expression profiles in 12 pairs of HCC and adjacent matched non-HCC tissues from HBV-positive and HBV-negative patients using microarray analyses. The microarray result was validated by real-time PCR in 32 HBV-positive and 24 HBV-negative patient HCC samples. The potential candidate target genes of the miRNAs were predicted by miRWalk software. Genes simultaneously predicted as targets by two or more miRNAs were subjected to GO and KEGG pathway analysis. The miRNA regulatory network analysis was performed using the Ingenuity Pathway Analysis (IPA) software.

Results

Eight miRNAs (miR-223, miR-98, miR-15b, miR-199a-5p, miR-19b, miR-22, miR-451, and miR-101) were involved in HBV-unrelated HCC, 5 miRNAs (miR-98, miR-375, miR-335, miR-199a-5p, and miR-22) were involved in HBV infection, and 7 miRNAs (miR-150, miR-342-3p, miR-663, miR-20b, miR-92a-3p, miR-376c-3p and miR-92b) were specifically altered in HBV-related HCC. Gene Ontology and KEGG analyses predict that these HBV-related HCC miRNAs are involved in the regulation of: transcription, RNA polymerase II promoter, phosphorylation of proteins through MAPK signaling pathway, focal adhesion, and actin cytoskeleton. IPA analysis also suggest that these miRNAs act on AGO2, TP53, CCND1, and 11 other genes that significantly influence HCC occurrence and HBV infection.

Conclusion

Our data indicates that the unique 7 miRNAs expression signature could be involved in the development HBV- related HCC.

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Standard-dose osimertinib for refractory leptomeningeal metastases in T790M-positive EGFR-mutant non-small cell lung cancer

Standard-dose osimertinib for refractory leptomeningeal metastases in T790M-positive EGFR-mutant non-small cell lung cancer

Standard-dose osimertinib for refractory leptomeningeal metastases in T790M-positive <i>EGFR</i>-mutant non-small cell lung cancer, Published online: 30 November 2017; doi:10.1038/bjc.2017.394

Standard-dose osimertinib for refractory leptomeningeal metastases in T790M-positive EGFR-mutant non-small cell lung cancer

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Tumour budding in oral squamous cell carcinoma: a meta-analysis

Tumour budding in oral squamous cell carcinoma: a meta-analysis

Tumour budding in oral squamous cell carcinoma: a meta-analysis, Published online: 30 November 2017; doi:10.1038/bjc.2017.425

Tumour budding in oral squamous cell carcinoma: a meta-analysis

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Analysis of the relationship between prescribed dose and dosimetric advantage of real-time intraoperatively built custom-linked seeds in iodine-125 prostate brachytherapy

Abstract

Background

The purpose of this study was to investigate the differences in the dosimetric advantage of using intraoperatively built custom-linked (IBCL) seeds between permanent iodine-125 (I-125) seed implantation (PI) alone and PI followed by external-beam radiation therapy (EBRT) for prostate cancer.

Methods

We reviewed the records of 62 patients with localized prostate cancer who received transperineal interstitial brachytherapy with I-125 using free seeds or IBCL seeds. Twenty-four low- and intermediate-risk patients underwent PI alone with the prescribed dose of 160 Gy, and 39 high-risk patients underwent PI with 110 Gy, followed by EBRT with 45 Gy (PI + EBRT). Intraoperative and post-implant dosimetric parameters 1 month after implantation were collected and analyzed.

Results

The numbers of patients implanted with free seeds and IBCL seeds were 14 (58.3%) and 10 (41.7%), respectively, in the PI group and 25 (65.8%) and 13 (34.2%), respectively, in the PI + EBRT group. In the PI group, although there were significant differences in prostate V100 (p = 0.003) and D90 (p = 0.009) and rectum V100 (p = 0.026) on intraoperative dosimetry, these differences were not found on post-implant dosimetry. In the PI + EBRT group, the dosimetric parameters of IBCL seeds, such as prostate V200 (p = 0.013) and V250 (p = 0.010) and urethra D30 (p = 0.038), were better than those of free seeds on intraoperative dosimetry. Furthermore, even on post-implant dosimetry, prostate D90 (p = 0.004), V150 (p = 0.001), and homogeneity index (HI, p = 0.001), as well as V200 (p = 0.001) and V250 (p = 0.020), and urethra D5 (p = 0.008) as well as D30 (p = 0.003) had a better dosimetric quality in IBCL seeds than in free seeds. There was no significant difference in the operation time between free seeds and IBCL seeds in each PI and PI + EBRT group.

Conclusions

Our results reveal that greater dosimetric benefits could be obtained using IBCL seeds in the case of permanent implantation with a lower prescribed dose, such as PI + EBRT, rather than PI alone.

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Peripheral neuropathy induced by microtubule-targeted chemotherapies: insights into acute injury and long-term recovery

Chemotherapy-induced peripheral neuropathy (CIPN) is a major cause of disability in cancer survivors. CIPN investigations in preclinical model systems have focused on either behaviors or acute changes in nerve conduction velocity (NCV) and amplitude, but greater understanding of the underlying nature of axonal injury and its long-term processes is needed as cancer patients live longer. In this study, we used multiple independent endpoints to systematically characterize CIPN recovery in mice exposed to the anti-tubulin cancer drugs eribulin (ERIB), ixabepilone (IXA), paclitaxel (PACLI) or vinorelbine (VINO) at maximal tolerated doses. All of the drugs ablated intra-epidermal nerve fibers and produced axonopathy, with a secondary disruption in myelin structure within two weeks of drug administration. Additionally, all of the drugs reduced sensory NCV and amplitude, with greater deficits after PACLI and lesser deficits after IXA. These effects correlated with degeneration in dorsal root ganglia (DRG) and sciatic nerve and abundance of Schwann cells. While most injuries were fully reversible after 3-6 months after administration of ERIB, VINO, and IXA, we observed delayed recovery after PACLI that produced a more severe, pervasive and prolonged neurotoxicity. Compared to other agents, PACLI also displayed a unique prolonged exposure in sciatic nerve and DRG. The most sensitive indicator of toxicity was axonopathy and secondary myelin changes accompanied by a reduction in intra-epidermal nerve fiber density. Taken together, our findings suggest that intra-epidermal nerve fiber density and changes in NCV and amplitude might provide measures of axonal injury to guide clinical practice.

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Mutations in Homologous Recombination Genes and Outcomes in Ovarian Carcinoma Patients in GOG 218: an NRG Oncology/Gynecologic Oncology Group Study

Purpose: We hypothesized that mutations in homologous recombination repair (HRR) genes beyond BRCA1 and BRCA2 improve outcomes for ovarian carcinoma (OC) patients treated with platinum therapy and would impact the relative benefit of adding prolonged bevacizumab.  Experimental Design: We sequenced DNA from blood and/or neoplasm from 1,195 women enrolled in GOG-0218, a randomized phase III trial in advanced OC of bevacizumab added to carboplatin and paclitaxel. Defects in HRR were defined as damaging mutations in 16 genes. Proportional hazards models were used to estimate relative hazards for progression-free survival (PFS) and overall survival (OS). Results: Of 1,195 women with OC, HRR mutations were identified in 307 (25.7%). Adjusted hazards for progression and death compared to those without mutations were lower for women with non-BRCA HRR mutations (HR 0.73, 95% CI 0.57 - 0.94, p=0.01 for PFS; HR 0.67, 95% CI 0.50 - 0.90, p=0.007 for OS) and BRCA1 mutations (hazard ratio (HR) 0.80, 95% CI 0.66 - 0.97, p=0.02 for PFS; HR 0.74, 95% CI 0.59 - 0.94, p=0.01 for OS) and were lowest for BRCA2 mutations (HR 0.52, 95% CI 0.40 - 0.67, p<0.0001 for PFS; HR 0.36, 95% CI 0.25 - 0.53, p<0.0001 for OS). A test of interaction showed no difference in the effect of bevacizumab on PFS between cases with and without mutations.  Conclusions: HRR mutations, including non-BRCA genes, significantly prolong PFS and OS in OC and should be stratified for in clinical trials. The benefit of adding bevacizumab was not significantly modified by mutation status.

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