A new correlation clustering method for cancer mutation analysis.

MOTIVATION: Cancer genomes exhibit a large number of different alterations that affect many genes in a diverse manner. An improved understanding of the generative mechanisms behind the mutation rules and their influence on gene community behavior is of great importance for the study of cancer. RESULTS: To expand our capability to analyze combinatorial patterns of cancer alterations, we developed a rigorous methodology for cancer mutation pattern discovery based on a new, constrained form of correlation clustering. Our new algorithm, named C3 (Cancer Correlation Clustering), leverages mutual exclusivity of mutations, patient coverage and driver network concentration principles. To test C3, we performed a detailed analysis on TCGA breast cancer and glioblastoma data and showed that our algorithm outperforms the state-of-the-art CoMEt method in terms of discovering mutually exclusive gene modules and identifying biologically relevant driver genes. The proposed agnostic clustering method represents a unique tool for efficient and reliable identification of mutation patterns and driver pathways in large-scale cancer genomics studies, and it may also be used for other clustering problems on biological graphs. AVAILABILITY AND IMPLEMENTATION: The source code for the C3 method can be found at https://github.com/jackhou2/C3 CONTACTS: jianma@cs.cmu.edu or milenkov@illinois.eduSupplementary information: Supplementary data are available at Bioinformatics online.

Cross-species DNA copy number analyses identifies multiple 1q21-q23 subtype-specific driver genes for breast cancer.

A large number of DNA copy number alterations (CNAs) exist in human breast cancers, and thus characterizing the most frequent CNAs is key to advancing therapeutics because it is likely that these regions contain breast tumor 'drivers' (i.e., cancer causal genes). This study aims to characterize the genomic landscape of breast cancer CNAs and identify potential subtype-specific drivers using a large set of human breast tumors and genetically engineered mouse (GEM) mammary tumors. Using a novel method called SWITCHplus, we identified subtype-specific DNA CNAs occurring at a 15% or greater frequency, which excluded many well-known breast cancer-related drivers such as amplification of ERBB2, and deletions of TP53 and RB1. A comparison of CNAs between mouse and human breast tumors identified regions with shared subtype-specific CNAs. Additional criteria that included gene expression-to-copy number correlation, a DawnRank network analysis, and RNA interference functional studies highlighted candidate driver genes that fulfilled these multiple criteria. Numerous regions of shared CNAs were observed between human breast tumors and GEM mammary tumor models that shared similar gene expression features. Specifically, we identified chromosome 1q21-23 as a Basal-like subtype-enriched region with multiple potential driver genes including PI4KB, SHC1, and NCSTN. This step-wise computational approach based on a cross-species comparison is applicable to any tumor type for which sufficient human and model system DNA copy number data exist, and in this instance, highlights that a single region of amplification may in fact harbor multiple driver genes.

DawnRank: discovering personalized driver genes in cancer.

Large-scale cancer genomic studies have revealed that the genetic heterogeneity of the same type of cancer is greater than previously thought. A key question in cancer genomics is the identification of driver genes. Although existing methods have identified many common drivers, it remains challenging to predict personalized drivers to assess rare and even patient-specific mutations. We developed a new algorithm called DawnRank to directly prioritize altered genes on a single patient level. Applications to TCGA datasets demonstrated the effectiveness of our method. We believe DawnRank complements existing driver identification methods and will help us discover personalized causal mutations that would otherwise be obscured by tumor heterogeneity. Source code can be accessed at http://bioen-compbio.bioen.illinois.edu/DawnRank/.

Outcome of transvaginal mesh and tape removed for pain only.

PURPOSE: Because there is reluctance to operate for pain, we evaluated midterm outcomes of vaginal mesh and synthetic suburethral tape removed for pain as the only indication. MATERIALS AND METHODS: After receiving institutional review board approval we reviewed a prospective database of women without a neurogenic condition who underwent surgery for vaginal mesh or suburethral tape removal with a focus on pain as the single reason for removal and a minimum 6-month followup. The primary outcome was pain level assessed by a visual analog scale (range 0 to 10) at baseline and at each subsequent visit with the score at the last visit used for analysis. Parameters evaluated included demographics, mean time to presentation and type of mesh or tape inserted. RESULTS: From 2005 to 2013, 123 patients underwent surgical removal of mesh (69) and suburethral tape (54) with pain as the only indication. Mean followup was 35 months (range 6 to 59) in the tape group and 22 months (range 6 to 47) in the mesh group. The visual analog scale score decreased from a mean preoperative level of 7.9 to 0.9 postoperatively (p = 0.0014) in the mesh group and from 5.3 to 1.5 (p = 0.00074) in the tape group. Pain-free status, considered a score of 0, was achieved in 81% of tape and 67% of mesh cases, respectively. No statistically significant difference was found between the groups. CONCLUSIONS: When pain is the only indication for suburethral tape or vaginal mesh removal, a significant decrease in the pain score can be durably expected after removal in most patients at midterm followup.

A network-assisted co-clustering algorithm to discover cancer subtypes based on gene expression.

BACKGROUND: Cancer subtype information is critically important for understanding tumor heterogeneity. Existing methods to identify cancer subtypes have primarily focused on utilizing generic clustering algorithms (such as hierarchical clustering) to identify subtypes based on gene expression data. The network-level interaction among genes, which is key to understanding the molecular perturbations in cancer, has been rarely considered during the clustering process. The motivation of our work is to develop a method that effectively incorporates molecular interaction networks into the clustering process to improve cancer subtype identification. RESULTS: We have developed a new clustering algorithm for cancer subtype identification, called "network-assisted co-clustering for the identification of cancer subtypes" (NCIS). NCIS combines gene network information to simultaneously group samples and genes into biologically meaningful clusters. Prior to clustering, we assign weights to genes based on their impact in the network. Then a new weighted co-clustering algorithm based on a semi-nonnegative matrix tri-factorization is applied. We evaluated the effectiveness of NCIS on simulated datasets as well as large-scale Breast Cancer and Glioblastoma Multiforme patient samples from The Cancer Genome Atlas (TCGA) project. NCIS was shown to better separate the patient samples into clinically distinct subtypes and achieve higher accuracy on the simulated datasets to tolerate noise, as compared to consensus hierarchical clustering. CONCLUSIONS: The weighted co-clustering approach in NCIS provides a unique solution to incorporate gene network information into the clustering process. Our tool will be useful to comprehensively identify cancer subtypes that would otherwise be obscured by cancer heterogeneity, using high-throughput and high-dimensional gene expression data.

Successful resection of anterior and anterolateral lesions at the craniovertebral junction using a simple posterolateral approach.

Tumors at the craniovertebral junction (CVJ) often present a challenge due to proximity to vital neurovascular structures. In the last few decades, many authors have proposed complex surgical approaches to access pathologies located anterior or anterolateral to the CVJ with the hopes of reducing morbidity. We propose that the simple posterolateral approach in a semi-sitting position can be used to resect most anterior and anterolateral CVJ tumors safely and effectively. We retrospectively reviewed the clinical series of 10 patients treated by the senior author using the posterolateral suboccipital approach to treat anterior or anterolateral CVJ pathologies. We describe our surgical techniques, outcomes, and present illustrative patients. Gross total resection was achieved in eight patients (80%). Good functional outcome (Glasgow Outcome Scale 4-5) was obtained in all patients. Preoperative symptoms and deficits were improved (78%) or stable (22%) in all patients. There was one (10%) surgical complication that was cerebrospinal fluid leak requiring reoperation. There was no permanent morbidity or mortality in this series. There were two (20%) medical complications including deep vein thrombosis and pulmonary embolus. There were three (30%) transient neurologic complications, dysphagia in two and dysarthria in one, all of which resolved completely in early follow-up. The majority of anterior or anterolateral CVJ lesions can be successfully removed using the simple posterolateral approach.

Peritumoral brain edema in intracranial meningiomas: the emergence of vascular endothelial growth factor-directed therapy.

Meningioma is the second most common type of adult intracranial neoplasm. A substantial subset of patients present with peritumoral brain edema (PTBE), which can cause significant morbidity via mass effect, complicate surgical management, and impact the safety of stereotactic radiosurgery. Recent studies suggest a close relationship between vascular endothelial growth factor-A (VEGF-A) expression and PTBE development in meningiomas. The authors performed a systematic review of the literature on the pathogenesis of PTBE in meningiomas, the effectiveness of steroid therapy, the role played by VEGF-A, and the current clinical evidence for antiangiogenic therapy to treat peritumoral brain edema. Mounting evidence suggests VEGF-A is secreted directly by meningioma cells to induce angiogenesis and edemagenesis of tumoral as well as peritumoral brain tissue. The VEGF-A cascade results in recruitment of cerebral-pial vessels and disruption of the tumor-brain barrier, which appear to be requisite for VEGF-A to have an edemagenic effect. Results of preliminary clinical studies suggest VEGF-directed therapy has modest activity against recurrent and progressive meningioma growth but can alleviate PTBE in some patients. A comprehensive understanding of the VEGF-A pathway and its modulators may hold the key to an effective therapeutic approach to treating PTBE associated with meningiomas. Further clinical trials with larger patient cohorts and longer follow-up periods are warranted to confirm the efficacy of VEGF-directed therapy.

Liraglutide, a long-acting GLP-1 mimetic, and its metabolite attenuate inflammation after intracerebral hemorrhage.

The inflammatory response plays a pivotal role in propagating injury of intracerebral hemorrhage (ICH). Glucagon-like-peptide-1 (GLP-1) is a hormone with antidiabetic effect and may also have antiinflammatory properties. Despite consensus that the glucoregulatory action is mediated by the GLP-1 receptor (GLP-1R), mechanisms in the brain remain unclear. We investigated the effect of a long-acting GLP-1 analog, liraglutide, and its truncated metabolite, GLP-1(9-36)a from dipeptidyl peptidase-4 (DPP-4) cleavage in ICH-induced brain injury. Primary outcomes were cerebral edema formation, neurobehavior, and inflammatory parameters. GLP-1(9-36)a, GLP-1R inhibitor, adenosine monophosphate-activated protein kinase (AMPK) phosphorylation inhibitor and DPP-4 inhibitor were administered to examine the mechanisms of action. Liraglutide suppressed neuroinflammation, prevented brain edema and neurologic deficit following ICH, which were partially reversed by GLP-1R inhibitor and AMPK phosphorylation inhibitor. Liraglutide-mediated AMPK phosphorylation was unaffected by GLP-1R inhibitor, and was found to be induced by GLP-1(9-36)a. GLP-1(9-36)a showed salutary effects on primary outcomes that were reversed by AMPK phosphorylation inhibitor but not by GLP-1R inhibitor. Liraglutide and DPP-4 inhibitor co-administration reversed liraglutide-mediated AMPK phosphorylation and antiinflammatory effects. Liraglutide exerted duals actions and the antiinflammatory effects are partially mediated by its metabolite in a phosphorylated AMPK-dependent manner. Therapies that inhibit GLP-1 degradation may weaken the metabolite-mediated effects.

Metastasis to the penis from rectal adenocarcinoma.

Penile cancer is a serious but largely under-represented phenomenon in many of the large national cancer databases. Even more rare is the presentation of solitary metastasis to the penis from a gastrointestinal primary site. This case describes one such case of metastasis of rectal adenocarcinoma and details the patient's treatment modalities. Ultimately, although the precise etiology of this particular manifestation is not well understood, the prognosis is poor in the small group that it affects. No individual treatment has been proven superior with regard to long term survival.

Instillation of mitomycin C after transurethral resection of bladder cancer impairs wound healing: an animal model.

BACKGROUND: Mitomycin C is used in the immediate post-operative period to prevent tumor re-implantation, but it has adverse effects on the bladder. This study devised an animal model to investigate the effects of intravesical mitomycin C on wound healing. METHODS AND MATERIALS: A cystotomy was made in the dome of the bladder of female rats. The mucosa of the posterior wall was scratch with closed forceps. The bladder was closed and 0.2 ml of saline with or without 0.4 mg mitomycin C was instilled into the bladder transurethrally. The rats were sacrificed 30 and 60 days after the treatment and the bladder was examined grossly and microscopically. RESULTS: The most frequent histological findings in the bladder were chronic inflammation and fibrosis. Fibrosis but not chronic inflammation was significantly associated with the exposure to MMC and it persisted even 60 days after the exposure to mitomycin C. CONCLUSION: Mitomycin C produces chronic fibrosis in rat bladder that is often seen in patients receiving prophylactic treatment with this drug.