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Basal-like/triple-negative breast cancers (TNBCs) are among the most aggressive forms of breast cancer, and disproportionally affects young premenopausal women and women of African descent. Patients with TNBC suffer a poor prognosis due in part to a lack of molecularly targeted therapies, which represents a critical barrier for effective treatment. Here, we identify EphA2 receptor tyrosine kinase as a clinically relevant target for TNBC. EphA2 expression is enriched in the basal-like molecular subtype in human breast cancers. Loss of EphA2 function in both human and genetically engineered mouse models of TNBC reduced tumor growth in culture and in vivo. Mechanistically, targeting EphA2 impaired cell cycle progression through S-phase via downregulation of c-Myc and stabilization of the cyclin-dependent kinase inhibitor p27/KIP1. A small molecule kinase inhibitor of EphA2 effectively suppressed tumor cell growth in vivo, including TNBC patient-derived xenografts. Thus, our data identify EphA2 as a novel molecular target for TNBC.
OBJECTIVE - Currently, approximately 60-70% of patients with unilateral temporal lobe epilepsy (TLE) remain seizure-free 3 years after surgery. The goal of this work was to develop a presurgical connectivity-based biomarker to identify those patients who will have an unfavorable seizure outcome 1-year postsurgery.
METHODS - Resting-state functional and diffusion-weighted 3T magnetic resonance imaging (MRI) was acquired from 22 unilateral (15 right, 7 left) patients with TLE and 35 healthy controls. A seizure propagation network was identified including ipsilateral (to seizure focus) and contralateral hippocampus, thalamus, and insula, with bilateral midcingulate and precuneus. Between each pair of regions, functional connectivity based on correlations of low frequency functional MRI signals, and structural connectivity based on streamline density of diffusion MRI data were computed and transformed to metrics related to healthy controls of the same age.
RESULTS - A consistent connectivity pattern representing the network expected in patients with seizure-free outcome was identified using eight patients who were seizure-free at 1-year postsurgery. The hypothesis that increased similarity to the model would be associated with better seizure outcome was tested in 14 other patients (Engel class IA, seizure-free: n = 5; Engel class IB-II, favorable: n = 4; Engel class III-IV, unfavorable: n = 5) using two similarity metrics: Pearson correlation and Euclidean distance. The seizure-free connectivity model successfully separated all the patients with unfavorable outcome from the seizure-free and favorable outcome patients (p = 0.0005, two-tailed Fisher's exact test) through the combination of the two similarity metrics with 100% accuracy. No other clinical and demographic predictors were successful in this regard.
SIGNIFICANCE - This work introduces a methodologic framework to assess individual patients, and demonstrates the ability to use network connectivity as a potential clinical tool for epilepsy surgery outcome prediction after more comprehensive validation.
Wiley Periodicals, Inc. © 2017 International League Against Epilepsy.
Short-term complications, particularly rehospitalization, after a diagnosis of takotsubo cardiomyopathy (TTC) are poorly described. We sought to characterize the rates, causes, clinical associations, and prognostic implications of early rehospitalization in this patient population. We performed a retrospective observational study of all adult subjects diagnosed with TTC at an academic tertiary care hospital from 2005 to 2015. The primary outcome was rehospitalization within 30 days of index discharge. Multivariable logistic regression was used to test for association between clinical variables and rehospitalization. Association between rehospitalization and survival after index discharge was assessed as a secondary outcome using a multivariable Cox proportional hazard model. Two hundred sixty-three subjects met the inclusion criteria for the study. There were 38 rehospitalizations among 32 subjects (12%). Ninety-five percent of rehospitalizations were due to nonheart failure causes, and 76% were related to noncardiovascular complaints. In multivariable analysis, recent hospitalization before TTC diagnosis and increased length of index hospitalization were associated with greater risk of rehospitalization (odds ratio 4.58, 95% CI 1.97 to 10.65, p <0.001 and odds ratio 1.05, 95% CI 1.01 to 1.10, p = 0.026, respectively). Early rehospitalization after TTC was associated with decreased survival (hazard ratio 3.17, 95% CI 1.53 to 6.56, p = 0.002).
Copyright © 2017 Elsevier Inc. All rights reserved.
BACKGROUND - Extra-abdominal desmoid-type fibromatosis (DF) is a rare, locally aggressive neoplasm that is usually managed conservatively. When treatment is indicated, it typically involves surgical resection, possibly with adjuvant radiotherapy. The indications for postoperative radiotherapy and its effectiveness are unclear. The objective of this study was to estimate the effect of surgical resection margins and adjuvant radiotherapy on rates of recurrence of DF.
METHODS - Literature published between 1999 and 2015 was extracted from MEDLINE, Embase, Cochrane Central Registry of Trials, Web of Science and Google Scholar. Recurrence rate was analysed by meta-analysis and compared between subgroups.
RESULTS - Sixteen reports were included, consisting of a total of 1295 patients with DF. In patients treated by surgical resection alone, the risk of local recurrence was almost twofold higher for those with microscopically positive resection margins (risk ratio (RR) 1·78, 95 per cent c.i. 1·40 to 2·26). Adjuvant radiotherapy after surgery with negative margins had no detectable benefit on recurrence. In contrast, after incomplete surgical resection, adjuvant radiotherapy improved recurrence rates both in patients with primary tumours (RR 1·54, 1·05 to 2·27) and in those with recurrent DF (RR 1·60, 1·12 to 2·28).
CONCLUSION - DF resected with microscopically positive margins has a higher risk of recurrence. Adjuvant radiotherapy appears to reduce the risk of recurrence after incomplete surgical resection, particularly in patients with recurrent tumours.
© 2017 BJS Society Ltd Published by John Wiley & Sons Ltd.
Multiple different schemes are used to assess surgical resection margins in orthopedic pathology, but which is optimal for reporting resection margin status of osteosarcoma is uncertain. Moreover, the minimum tumor clearance (metric width of resection margin) necessary for local control is not well defined. In this investigation, the American Joint Committee on Cancer (AJCC) R system, Musculoskeletal Tumor Society (MSTS) system, and margin distance method for reporting resection margin status were compared in a series of 186 high-grade osteosarcomas. Hazard ratios for local recurrence for each resection margin category were compared with other categories within each margin assessment scheme to assess discriminatory ability. Cross-model comparisons of regression coefficients from parametric survival and logistic regression models were also performed. Predictive accuracy of each margin assessment scheme for determining 2-year local recurrence-free survival was evaluated by comparing the areas under receiver-operating characteristic curves generated from logistic regression analyses. Concordance with clinical outcomes was also calculated. Both the MSTS and margin distance schemes showed significantly greater predictive accuracy and concordance with observed outcomes than the AJCC R system. A margin distance of ≥2 mm significantly decreased the risk of local recurrence. Results were similar after adjustment for confounding prognostic factors (anatomic site, macroscopic lymphovascular invasion, and chemotherapy status). Therefore, surgical resection margins for osteosarcoma should be reported using either the MSTS or margin distance method instead of the AJCC R system.
BACKGROUND - Renal cell cancer (RCC) is a prevalent and lethal disease. At time of diagnosis, most patients present with localized disease. For these patients, the standard of care includes nephrectomy with close monitoring thereafter. While many patients will be cured, 5-year recurrence rates range from 30% to 60%. Furthermore, nearly one-third of patients present with metastatic disease at time of diagnosis. Metastatic disease is rarely curable and typically lethal. Cytotoxic chemotherapy and radiation alone are incapable of controlling the disease. Extensive effort was expended in the development of cytokine therapies but response rates remain low. Newer agents targeting angiogenesis and mTOR signaling emerged in the 2000s and revolutionized patient care. While these agents improve progression free survival, the development of resistance is nearly universal. A new era of immunotherapy is now emerging, led by the checkpoint inhibitors. However, therapeutic resistance remains a complex issue that is likely to persist.
METHODS AND PURPOSE - In this review, we systematically evaluate preclinical research and clinical trials that address resistance to the primary RCC therapies, including anti-angiogenesis agents, mTOR inhibitors, and immunotherapies. As clear cell RCC is the most common adult kidney cancer and has been the focus of most studies, it will be the focus of this review.
Copyright © 2017 Elsevier Inc. All rights reserved.
PURPOSE - Kidney stone prevention relies on the 24-hour urine collection to diagnose metabolic abnormalities and direct dietary and pharmacological therapy. While its use is guideline supported for high risk and interested patients, evidence that the test can accurately predict recurrence or treatment response is limited. We sought to critically reassess the role of the 24-hour urine collection in stone prevention.
MATERIALS AND METHODS - In addition to a MEDLINE® search to identify controlled studies of dietary and pharmacological interventions, evidence supporting the AUA (American Urological Association) and EAU (European Association of Urology) guidelines for metabolic stone prevention were evaluated. Additionally, the placebo arms of these studies were examined to assess the stone clinic effect, that is the impact of regular office visits without specific treatment on stone recurrence.
RESULTS - The 24-hour urine test has several limitations, including the complexity of interpretation, the need for repeat collections, the inability to predict stone recurrence with individual parameters and supersaturation values, the unclear rationale of laboratory cutoff values and the difficulty of determining collection adequacy. Only 1 prospective trial has compared selective dietary recommendations based on 24-hour urine collection results vs general dietary instructions. While the trial supported the intervention arm, significant limitations to the study were found. Placebo arms of intervention trials have noted a 0% to 61% decrease in stone recurrence rate and a remission rate during the study of 20% to 86%.
CONCLUSIONS - Whether all recurrent stone formers benefit from 24-hour urine collection has not been established. Additional comparative effectiveness trials are needed to determine which stone former benefits from selective therapy, as guided by the 24-hour urine collection.
Copyright © 2017 American Urological Association Education and Research, Inc. Published by Elsevier Inc. All rights reserved.
Defining molecular features that can predict the recurrence of colorectal cancer (CRC) for stage II-III patients remains challenging in cancer research. Most available clinical samples are Formalin-Fixed, Paraffin-Embedded (FFPE). NanoString nCounter® and Affymetrix GeneChip® Human Transcriptome Array 2.0 (HTA) are the two platforms marketed for high-throughput gene expression profiling for FFPE samples. In this study, to evaluate the gene expression of frozen tissue-derived prognostic signatures in FFPE CRC samples, we evaluated the expression of 516 genes from published frozen tissue-derived prognostic signatures in 42 FFPE CRC samples measured by both platforms. Based on HTA platform-derived data, we identified both gene (99 individual genes, FDR < 0.05) and gene set (four of the six reported multi-gene signatures with sufficient information for evaluation, P < 0.05) expression differences associated with survival outcomes. Using nCounter platform-derived data, one of the six multi-gene signatures (P < 0.05) but no individual gene was associated with survival outcomes. Our study indicated that sufficiently high quality RNA could be obtained from FFPE tumor tissues to detect frozen tissue-derived prognostic gene expression signatures for CRC patients.
BACKGROUND - Previously, using imaging mass spectrometry (IMS), we discovered proteomic differences between Spitz nevi and Spitzoid melanomas.
OBJECTIVE - We sought to determine whether IMS can assist in the classification of diagnostically challenging atypical Spitzoid neoplasms (ASN), to compare and correlate the IMS and histopathological diagnoses with clinical behavior.
METHODS - We conducted a retrospective collaborative study involving centers from 11 countries and 11 US institutions analyzing 102 ASNs by IMS. Patients were divided into clinical groups 1 to 4 representing best to worst clinical behavior. The association among IMS findings, histopathological diagnoses, and clinical groups was assessed.
RESULTS - There was a strong association between a diagnosis of Spitzoid melanoma by IMS and lesions categorized as clinical groups 2, 3, and 4 (recurrence of disease, metastases, or death) compared with clinical group 1 (no recurrence or metastasis beyond a sentinel node) (P < .0001). Older age and greater tumor thickness were strongly associated with poorer outcome (P = .01).
CONCLUSIONS - IMS diagnosis of ASN better predicted clinical outcome than histopathology. Diagnosis of Spitzoid melanoma by IMS was strongly associated with aggressive clinical behavior. IMS analysis using a proteomic signature may improve the diagnosis and prediction of outcome/risk stratification for patients with ASN.
Copyright © 2016 American Academy of Dermatology, Inc. Published by Elsevier Inc. All rights reserved.
It is unclear if proximal and distal traditional adenomas present with differences in molecular events which contribute to cancer heterogeneity by tumor anatomical subsite. Participants from a colonoscopy-based study (n = 380) were divided into subgroups based on the location of their most advanced adenoma: proximal, distal, or "equivalent both sides." Eight biomarkers in the most advanced adenomas were evaluated by immunohistochemistry (Ki-67, COX-2, TGFβRII, EGFR, β-catenin, cyclin D1, c-Myc) or TUNEL (apoptosis). After an adjustment for pathological features, there were no significant differences between proximal and distal adenomas for any biomarker. Conversely, expression levels did vary by other features, such as their size, villous component, and synchronousness. Large adenomas had higher expression levels of Ki-67(P < 0.001), TGFβRII (P < 0.0001), c-Myc (P < 0.001), and cyclin D1 (P < 0.001) in comparison to small adenomas, and tubulovillous/villous adenomas also were more likely to have similar higher expression levels in comparison to tubular adenomas. Adenoma location is not a major determinant of the expression of these biomarkers outside of other pathological features. This study suggests similarly important roles of Wnt/β-catenin and TGF-β pathways in carcinogenesis in both the proximal and distal colorectum. © 2016 Wiley Periodicals, Inc.
© 2016 Wiley Periodicals, Inc.