Paired Tumor and Normal Whole Genome Sequencing of Metastatic Olfactory Neuroblastoma

Olfactory neuroblastoma (ONB) is a rare cancer of the sinonasal tract with little molecular characterization. We performed whole genome sequencing (WGS) on paired normal and tumor DNA from a patient with metastatic-ONB to identify the somatic alterations that might be drivers of tumorigenesis and/or metastatic progression.Genomic DNA was isolated from fresh frozen tissue from a metastatic lesion and whole blood, followed by WGS at >30X depth, alignment and mapping, and mutation analyses. Sanger sequencing was used to confirm selected mutations. Sixty-two somatic short nucleotide variants (SNVs) and five deletions were identified inside coding regions, each causing a non-synonymous DNA sequence change. We selected seven SNVs and validated them by Sanger sequencing. In the metastatic ONB samples collected several months prior to WGS, all seven mutations were present. However, in the original surgical resection specimen (prior to evidence of metastatic disease), mutations in KDR, MYC, SIN3B, and NLRC4 genes were not present, suggesting that these were acquired with disease progression and/or as a result of post-treatment effects.This work provides insight into the evolution of ONB cancer cells and provides a window into the more complex factors, including tumor clonality and multiple driver mutations

Assessing the clinical utility of cancer genomic and proteomic data across tumor types

Molecular profiling of tumors promises to advance the clinical management of cancer, but the benefits of integrating molecular data with traditional clinical variables have not been systematically studied. Here we retrospectively predict patient survival using diverse molecular data (somatic copy-number alteration, DNA methylation and mRNA, miRNA and protein expression) from 953 samples of four cancer types from The Cancer Genome Atlas project. We found that incorporating molecular data with clinical variables yielded statistically significantly improved predictions (FDR < 0.05) for three cancers but those quantitative gains were limited (2.2–23.9%). Additional analyses revealed little predictive power across tumor types except for one case. In clinically relevant genes, we identified 10,281 somatic alterations across 12 cancer types in 2,928 of 3,277 patients (89.4%), many of which would not be revealed in single-tumor analyses. Our study provides a starting point and resources, including an open-access model evaluation platform, for building reliable prognostic and therapeutic strategies that incorporate molecular data

Breast Cancer and Dermatomyositis: A Case Study and Literature Review

A 49-year-old woman presents with an extensive violaceous rash, rapidly progressive proximal muscle weakness, and dysphagia to solids, consistent with a diagnosis of dermatomyositis. Two weeks later, she palpates a mass in her left breast and is diagnosed with her2-positive metastatic invasive ductal carcinoma of the breast. There is a well-established association between dermatomyositis and malignancy. However, the specific association between breast cancer and dermatomyositis has not been well characterized. No guideline for oncologists managing these patients has been established. Recently, 3 cases of breast cancer and dermatomyositis were diagnosed at our institution. A review of the literature was pursued to characterize the association between breast cancer and dermatomyositis. A review of 178 papers identified 22 cases of breast cancer with dermatomyositis. Most patients (71%) presented with stage iii or iv breast cancer. The median time between the diagnosis of breast cancer and the onset of dermatomyositis symptoms was 1 month. Three quarters of the patients were steroid-responsive and able to taper. Half the women with follow-up data experienced a documented cancer relapse associated with a new flare of cutaneous symptoms. The presence of dermatomyositis appears to be associated with more-advanced breast cancer stage and is most commonly associated with invasive ductal carcinoma. In our review, treatment of cancer alone is insufficient to adequately control the cutaneous and myopathic manifestations of dermatomyositis, which can significantly affect quality of life. A multidisciplinary approach, including close collaboration with rheumatologists and dermatologists, is therefore important in the diagnosis and management of oncology patients with dermatomyositis

Enhanced Virtual Inertia Control for Microgrids with High-Penetration Renewables Based on Whale Optimization

High penetration of renewable energy sources into isolated microgrids (µGs) is considered a critical challenge, as µGs’ operation at low inertia results in frequency stability problems. To solve this challenge, virtual inertia control based on an energy storage system is applied to enhance the inertia and damping properties of the µG. On the other hand, utilization of a phase-locked loop (PLL) is indispensable for measuring system frequency; however, its dynamics, such as measurement delay and noise generation, cause extra deterioration of frequency stability. In this paper, to improve µG frequency stability and minimize the impact of PLL dynamics, a new optimal frequency control technique is proposed. A whale optimization algorithm is used to enhance the virtual inertia control loop by optimizing the parameters of the virtual inertia controller with consideration of PLL dynamics and the uncertainties of system inertia. The proposed controller has been validated through comparisons with an optimized virtual inertia PI controller which is tuned utilizing MATLAB internal model control methodology and with H∞-based virtual inertia control. The results show the effectiveness of the proposed controller against different operating conditions and system disturbances and uncertainties

Malignancies in a renal transplant population: The St. Michael's Hospital experience

Introduction: Previous publications have shown an increased incidence of various malignancies amongst renal transplant populations. The objective of this study was to analyze the rate and types of malignancies occurring in the St. Michael's Hospital renal transplant population and to determine whether our results were comparable to those previously published. Methods: After approval by the hospital's research ethic board, review of the records and pathology of the 1584 patients in the renal transplant clinic database patients was performed. The reports dated back to the year 1970. Results: Amongst the 1584 renal transplant patients, 106 patients with 132 dysplastic and malignant posttransplant lesions were identified. The highest incidence amid the malignancies was in nonmelanoma skin malignancies squamous cell carcinoma (SCC), basal cell carcinoma, and Kaposi sarcoma, with a total of 32 patients having 54 separate tumors (2.02% of all patients, 43.2% of tumors). Following skin tumors in incidence were genitourinary (28 tumors), gastrointestinal tract (GIT) lesions (8 adenocarcinomas, 14 dysplastic lesions, 1 low grade neuroendocrine tumor/carcinoid), posttransplant lymphoproliferative disorders (PTLDs) (10 cases), gynecologic (6 carcinomas), cervical/anal/vulvar dysplasia and invasive (SCCs) (4), and thyroid (3 papillary tumors). Nine patients had tumors of multiple sites/types. With respect to outcome, 14 patients died of malignancy, with the highest mortality being in the GIT malignancies (six patients). Second in mortality were the PTLD and skin tumor groups. Discussion: Information on the incidence and outcome of various malignancies in renal transplant patients is important in designing guidelines for the follow-up of these patients regarding tumor screening and prevention. The rate of malignancies in our group is comparable to that reported in other centers

The clinical utility of miR-21 as a diagnostic and prognostic marker for renal cell carcinoma

Renal cell carcinoma (RCC) is the most common neoplasm of the kidney. Increasing evidence suggests that microRNAs are dysregulated in RCC and are important factors in RCC pathogenesis. miR-21 is a known oncogene with tumor-promoting effects in many types of cancer. In this study, we analyzed miR-21 in 121 cases of healthy kidney and different RCC subtypes, including clear cell (ccRCC), papillary (pRCC), chromophobe (chRCC), and oncocytoma. Total RNA was extracted, and the expression of miR-21 was measured with real-time quantitative RT-PCR using miR-21-specific probes. The expression of miR-21 was significantly up-regulated in RCC compared with healthy kidney. There was a significant difference in the expression levels between RCC subtypes, with the highest levels of expression in ccRCC and pRCC subtypes. miR-21 expression distinguished ccRCC and pRCC from chRCC and oncocytoma with 90% specificity (95% CI, 63.9% to 98.1%) and 83% sensitivity (95% CI, 53.5% to 97.6%). Significantly higher miR-21 levels were associated with higher stage and grade. Patients who were miR-21 positive had statistically significant shorter disease-free and overall survival rates. Thus, miR-21 is up-regulated in RCC, and its expression levels can be used as a diagnostic marker to distinguish ccRCC and pRCC from chRCC and oncocytoma. Moreover, it has potential as a prognostic marker in RCC, although it is not independent of tumor stage and grade. Copyright © 2012 American Society for Investigative Pathology and the Association for Molecular Pathology. Published by Elsevier Inc. All rights reserved