Thymine DNA glycosylase is essential for active DNA demethylation by linked deamination-base excision repair.

DNA methylation is a major epigenetic mechanism for gene silencing. Whereas methyltransferases mediate cytosine methylation, it is less clear how unmethylated regions in mammalian genomes are protected from de novo methylation and whether an active demethylating activity is involved. Here, we show that either knockout or catalytic inactivation of the DNA repair enzyme thymine DNA glycosylase (TDG) leads to embryonic lethality in mice. TDG is necessary for recruiting p300 to retinoic acid (RA)-regulated promoters, protection of CpG islands from hypermethylation, and active demethylation of tissue-specific developmentally and hormonally regulated promoters and enhancers. TDG interacts with the deaminase AID and the damage response protein GADD45a. These findings highlight a dual role for TDG in promoting proper epigenetic states during development and suggest a two-step mechanism for DNA demethylation in mammals, whereby 5-methylcytosine and 5-hydroxymethylcytosine are first deaminated by AID to thymine and 5-hydroxymethyluracil, respectively, followed by TDG-mediated thymine and 5-hydroxymethyluracil excision repair.

TET1 and TDG Suppress Inflammatory Response in Intestinal Tumorigenesis: Implications for Colorectal Tumors With the CpG Island Methylator Phenotype.

BACKGROUND & AIMS: Aberrant DNA methylation is frequent in colorectal cancer (CRC), but underlying mechanisms and pathologic consequences are poorly understood. METHODS: We disrupted active DNA demethylation genes Tet1 and/or Tdg from ApcMin mice and characterized the methylome and transcriptome of colonic adenomas. Data were compared to human colonic adenocarcinomas (COAD) in The Cancer Genome Atlas. RESULTS: There were increased numbers of small intestinal adenomas in ApcMin mice expressing the TdgN151A allele, whereas Tet1-deficient and Tet1/TdgN151A-double heterozygous ApcMin colonic adenomas were larger with features of erosion and invasion. We detected reduction in global DNA hypomethylation in colonic adenomas from Tet1- and Tdg-mutant ApcMin mice and hypermethylation of CpG islands in Tet1-mutant ApcMin adenomas. Up-regulation of inflammatory, immune, and interferon response genes was present in Tet1- and Tdg-mutant colonic adenomas compared to control ApcMin adenomas. This up-regulation was also seen in murine colonic organoids and human CRC lines infected with lentiviruses expressing TET1 or TDG short hairpin RNA. A 127-gene inflammatory signature separated colonic adenocarcinomas into 4 groups, closely aligned with their microsatellite or chromosomal instability and characterized by different levels of DNA methylation and DNMT1 expression that anticorrelated with TET1 expression. Tumors with the CpG island methylator phenotype (CIMP) had concerted high DNMT1/low TET1 expression. TET1 or TDG knockdown in CRC lines enhanced killing by natural killer cells. CONCLUSIONS: Our findings reveal a novel epigenetic regulation, linked to the type of genomic instability, by which TET1/TDG-mediated DNA demethylation decreases methylation levels and inflammatory/interferon/immune responses. CIMP in CRC is triggered by an imbalance of methylating activities over demethylating activities. These mice represent a model of CIMP CRC.

Elaboration Models with Symmetric Information Divergence.

Various statistical methodologies embed a probability distribution in a more flexible family of distributions. The latter is called elaboration model, which is constructed by choice or a formal procedure and evaluated by asymmetric measures such as the likelihood ratio and Kullback-Leibler information. The use of asymmetric measures can be problematic for this purpose. This paper introduces two formal procedures, referred to as link functions, that embed any baseline distribution with a continuous density on the real line into model elaborations. Conditions are given for the link functions to render symmetric Kullback-Leibler divergence, Rényi divergence, and phi-divergence family. The first link function elaborates quantiles of the baseline probability distribution. This approach produces continuous counterparts of the binary probability models. Examples include the Cauchy, probit, logit, Laplace, and Student-t links. The second link function elaborates the baseline survival function. Examples include the proportional odds and change point links. The logistic distribution is characterized as the one that satisfies the conditions for both links. An application demonstrates advantages of symmetric divergence measures for assessing the efficacy of covariates.

Unified methods for feature selection in large-scale genomic studies with censored survival outcomes.

MOTIVATION: One of the major goals in large-scale genomic studies is to identify genes with a prognostic impact on time-to-event outcomes which provide insight into the disease process. With rapid developments in high-throughput genomic technologies in the past two decades, the scientific community is able to monitor the expression levels of tens of thousands of genes and proteins resulting in enormous datasets where the number of genomic features is far greater than the number of subjects. Methods based on univariate Cox regression are often used to select genomic features related to survival outcome; however, the Cox model assumes proportional hazards (PH), which is unlikely to hold for each feature. When applied to genomic features exhibiting some form of non-proportional hazards (NPH), these methods could lead to an under- or over-estimation of the effects. We propose a broad array of marginal screening techniques that aid in feature ranking and selection by accommodating various forms of NPH. First, we develop an approach based on Kullback-Leibler information divergence and the Yang-Prentice model that includes methods for the PH and proportional odds (PO) models as special cases. Next, we propose R2 measures for the PH and PO models that can be interpreted in terms of explained randomness. Lastly, we propose a generalized pseudo-R2 index that includes PH, PO, crossing hazards and crossing odds models as special cases and can be interpreted as the percentage of separability between subjects experiencing the event and not experiencing the event according to feature measurements. RESULTS: We evaluate the performance of our measures using extensive simulation studies and publicly available datasets in cancer genomics. We demonstrate that the proposed methods successfully address the issue of NPH in genomic feature selection and outperform existing methods. AVAILABILITY AND IMPLEMENTATION: R code for the proposed methods is available at github.com/lburns27/Feature-Selection. CONTACT: karthik.devarajan@fccc.edu. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

The Cancer Prevention Project of Philadelphia: preliminary findings examining diversity among the African diaspora.

Objective: Cancer mortality inequity among persons of African Ancestry is remarkable. Yet, Black inclusion in cancer biology research is sorely lacking and warrants urgent attention. Epidemiologic research linking African Ancestry and the African Diaspora to disease susceptibility and outcomes is critical for understanding the significant and troubling health disparities among Blacks. Therefore, in a cohort of diverse Blacks, this study examined differences in genetic ancestry informative markers (AIMs) in the DNA repair pathway and the cancer related biomarker 4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL).Methods: Participants completed a questionnaire and provided bio-specimens. AIMs in or around DNA repair pathway genes were analyzed to assess differences in minor allele frequency (MAF) across the 3 ethnic subgroups. NNAL concentration in urine was measured among current smokers.Results: To date the cohort includes 852 participants, 88.3% being Black. Of the 752 Blacks, 51.3% were US-born, 27.8% were Caribbean-born, and 19.6% were Africa-born. Current and former smokers represented 14.9% and 10.0%, respectively. US-born Blacks were more likely to be smokers and poor metabolizers of NNAL. Two-way hierarchical clustering revealed MAF of AIMs differed across the 3 ethnic subgroups.Conclusion: Our findings are consistent with the emerging literature demonstrating Black heterogeneity underscoring African Ancestry genetic subgroup differences - specifically relevant to cancer. Further investigations, with data harmonization and sharing, are urgently needed to begin to map African Ancestry cancer biomarkers as well as race, and race by place\region comparative biomarkers to inform cancer prevention and treatment in the era of precision medicine.

Interactive effect of TLR SNPs and exposure to sexually transmitted infections on prostate cancer risk in Jamaican men.

BACKGROUND: Prostate cancer (PC) risk increases with African ancestry and a history of sexually transmitted infections (STIs). Also, single-nucleotide polymorphisms (SNPs) in toll-like receptor (TLR) genes influence PC risk. This pilot study explores interactions between STIs and TLR-related SNPs in relation to PC risk among Jamaican men. METHODS: This case-control study evaluates two TLR related SNPs in 356 Jamaican men (194 controls and 162 cases) with or without history of STIs using stepwise penalized logistic regression in multivariable analyses. RESULTS: Age (odds ratio [OR] = 1.08; 95% confidence interval [CI]: 1.04-1>.12; p < .001) and IRF3_rs2304206 GG genotype (OR = 0.47; 95% CI: 0.29-0<.78; p = .003) modulated PC risk in people with history of STIs. In the population with no history of STIs, resulting interactions between risk factors did not survive correction for multiple hypothesis testing. CONCLUSION: Overall, an interaction between the IFR3_rs2304206 variant and a history of exposure to STIs leads to greater decrease of PC risk than the presence of polymorphic genotype alone. These findings are suggestive and require further validation. Identification of gene variants along with detection of lifestyle behaviors may contribute to identification of men at a greater risk of PC development in the population.

Differential preventive activity of sulindac and atorvastatin in Apc+/Min-FCCCmice with or without colorectal adenomas.

OBJECTIVE: The response of subjects to preventive intervention is heterogeneous. The goal of this study was to determine if the efficacy of a chemopreventive agent differs in non-tumour-bearing animals versus those with colorectal tumours. Sulindac and/or atorvastatin was administered to Apc+/Min-FCCC mice with known tumour-bearing status at treatment initiation. DESIGN: Male mice (6-8 weeks old) underwent colonoscopy and received control chow or chow with sulindac (300 ppm), atorvastatin (100 ppm) or sulindac/atorvastatin. Tissues were collected from mice treated for 14 weeks (histopathology) or 7 days (gene expression). Cell cycle analyses were performed on SW480 colon carcinoma cells treated with sulindac, atorvastatin or both. RESULTS: The multiplicity of colorectal adenomas in untreated mice bearing tumours at baseline was 3.6-fold higher than that of mice that were tumour free at baseline (P=0.002). Atorvastatin completely inhibited the formation of microadenomas in mice that were tumour free at baseline (P=0.018) and altered the expression of genes associated with stem/progenitor cells. Treatment of tumour-bearing mice with sulindac/atorvastatin led to a 43% reduction in the multiplicity of colorectal adenomas versus untreated tumour-bearing mice (P=0.049). Sulindac/atorvastatin increased the expression of Hoxb13 and Rprm significantly, suggesting the importance of cell cycle regulation in tumour inhibition. Treatment of SW480 cells with sulindac/atorvastatin led to cell cycle arrest (G0/G1). CONCLUSIONS: The tumour status of animals at treatment initiation dictates response to therapeutic intervention. Atorvastatin eliminated microadenomas in tumour-free mice. The tumour inhibition observed with Sul/Atorva in tumour-bearing mice was greater than that achieved with each agent.

Maximizing Operational Efficiency Using an In-House Ambulatory Surgery Model at an Academic Medical Center.

EXECUTIVE SUMMARY: Given the rising costs of healthcare delivery and reimbursement constraints, large academic medical centers (AMCs) must improve efficiency while delivering high-quality care. With standardized cases and high volumes, ambulatory surgery is a high-value target for efficiency improvement. Mining a data set of more than 7,500 cases consisting of the three highest-volume ambulatory procedures in orthopedics, otolaryngology-head and neck surgery, and urology, we analyzed process times and wait times involved in patient flow. We examined differences among delayed versus early versus on-time cases, as well as differences in scheduled start times, day of the week, and each individual operating room. Our analysis found statistically and clinically significant differences in registration and setup wait times when comparing delayed versus early versus on-time cases. We then developed recommendations to increase value-added time. Using activity-based cost accounting, we created a model to quantify economic impact. Hospitals can adopt these methods to identify operational bottlenecks and employ our financial model to forecast changes in revenue. Application of this model can position AMCs for success in an increasingly competitive landscape.

Prevalence of HPV Infection in Racial-Ethnic Subgroups of Head and Neck Cancer Patients.

The landscape of HPV infection in racial/ethnic subgroups of head and neck cancer (HNC) patients has not been evaluated carefully. In this study, a meta-analysis examined the prevalence of HPV in HNC patients of African ancestry. Additionally, a pooled analysis of subject-level data was also performed to investigate HPV prevalence and patterns of p16 (CDNK2A) expression amongst different racial groups. Eighteen publications (N = 798 Black HNC patients) were examined in the meta-analysis, and the pooled analysis included 29 datasets comprised of 3,129 HNC patients of diverse racial/ethnic background. The meta-analysis revealed that the prevalence of HPV16 was higher among Blacks with oropharyngeal cancer than Blacks with non-oropharyngeal cancer. However, there was great heterogeneity observed among studies (Q test P<0.0001). In the pooled analysis, after adjusting for each study, year of diagnosis, age, gender and smoking status, the prevalence of HPV16/18 in oropharyngeal cancer patients was highest in Whites (61.1%), followed by 58.0% in Blacks and 25.2% in Asians (P<0.0001). There was no statistically significant difference in HPV16/18 prevalence in non-oropharyngeal cancer by race (P=0.682). With regard to the pattern of HPV16/18 status and p16 expression, White patients had the highest proportion of HPV16/18+/p16+ oropharyngeal cancer (52.3%), while Asians and Blacks had significantly lower proportions (23.0% and 22.6%, respectively) [P <0.0001]. Our findings suggest that the pattern of HPV16/18 status and p16 expression in oropharyngeal cancer appears to differ by race and this may contribute to survival disparities.

LincIN, a novel NF90-binding long non-coding RNA, is overexpressed in advanced breast tumors and involved in metastasis.

BACKGROUND: Recent genome-wide profiling by sequencing and distinctive chromatin signatures has identified thousands of long non-coding RNA (lncRNA) species (>200 nt). LncRNAs have emerged as important regulators of gene expression, involving in both developmental and pathological processes. While altered expression of lncRNAs has been observed in breast cancer development, their roles in breast cancer progression and metastasis are still poorly understood. METHODS: To identify novel breast cancer-associated lncRNA candidates, we employed a high-density SNP array-based approach to uncover intergenic lncRNA genes that are aberrantly expressed in breast cancer. We first evaluated the potential value as a breast cancer prognostic biomarker for one breast cancer-associated lncRNA, LincIN, using a breast cancer cohort retrieved from The Cancer Genome Atlas (TCGA) Data Portal. Then we characterized the role of LincIN in breast cancer progression and metastasis by in vitro invasion assay and a mouse tail vein injection metastasis model. To study the action of LincIN, we identified LincIN-interacting protein partner(s) by RNA pull-down experiments followed with protein identification by mass spectrometry. RESULTS: High levels of LincIN expression are frequently observed in tumors compared to adjacent normal tissues, and are strongly associated with aggressive breast cancer. Importantly, analysis of TCGA data further suggest that high expression of LincIN is associated with poor overall survival in patients with breast cancer (P = 0.044 and P = 0.011 after adjustment for age). The functional experiments demonstrate that knockdown of LincIN inhibits tumor cell migration and invasion in vitro, which is supported by the results of transcriptome analysis in the LincIN-knockdown cells. Furthermore, knockdown of LincIN diminishes lung metastasis in a mouse tail vein injection model. We also identified a LincIN-binding protein, NF90, through which overexpression of LincIN may repress p21 protein expression by inhibiting its translation, and upregulation of p21 by LincIN knockdown may be associated with less aggressive metastasis phenotypes. CONCLUSIONS: Our studies provide clear evidence to support LincIN as a new regulator of tumor progression-metastasis at both transcriptional and translational levels and as a promising prognostic biomarker for breast cancer.

Integrative genomic analysis identifies ancestry-related expression quantitative trait loci on DNA polymerase ß and supports the association of genetic ancestry with survival disparities in head and neck squamous cell carcinoma.

BACKGROUND: African Americans with head and neck squamous cell carcinoma (HNSCC) have a lower survival rate than whites. This study investigated the functional importance of ancestry-informative single-nucleotide polymorphisms (SNPs) in HNSCC and also examined the effect of functionally important genetic elements on racial disparities in HNSCC survival. METHODS: Ancestry-informative SNPs, RNA sequencing, methylation, and copy number variation data for 316 oral cavity and laryngeal cancer patients were analyzed across 178 DNA repair genes. The results of expression quantitative trait locus (eQTL) analyses were also replicated with a Gene Expression Omnibus (GEO) data set. The effects of eQTLs on overall survival (OS) and disease-free survival (DFS) were evaluated. RESULTS: Five ancestry-related SNPs were identified as cis-eQTLs in the DNA polymerase ß (POLB) gene (false discovery rate [FDR] < 0.01). The homozygous/heterozygous genotypes containing the African allele showed higher POLB expression than the homozygous white allele genotype (P < .001). A replication study using a GEO data set validated all 5 eQTLs and also showed a statistically significant difference in POLB expression based on genetic ancestry (P = .002). An association was observed between these eQTLs and OS (P < .037; FDR < 0.0363) as well as DFS (P = .018 to .0629; FDR < 0.079) for oral cavity and laryngeal cancer patients treated with platinum-based chemotherapy and/or radiotherapy. Genotypes containing the African allele were associated with poor OS/DFS in comparison with homozygous genotypes harboring the white allele. CONCLUSIONS: Analyses show that ancestry-related alleles could act as eQTLs in HNSCC and support the association of ancestry-related genetic factors with survival disparities in patients diagnosed with oral cavity and laryngeal cancer. Cancer 2017;123:849-60. © 2016 American Cancer Society.

A Quasi-Likelihood Approach to Nonnegative Matrix Factorization.

A unified approach to nonnegative matrix factorization based on the theory of generalized linear models is proposed. This approach embeds a variety of statistical models, including the exponential family, within a single theoretical framework and provides a unified view of such factorizations from the perspective of quasi-likelihood. Using this framework, a family of algorithms for handling signal-dependent noise is developed and its convergence proved using the expectation-maximization algorithm. In addition, a measure to evaluate the goodness of fit of the resulting factorization is described. The proposed methods allow modeling of nonlinear effects using appropriate link functions and are illustrated using an application in biomedical signal processing.

Morbidity among long-term survivors after pancreatoduodenectomy for pancreatic adenocarcinoma.

BACKGROUND: Because pancreatoduodenectomy for pancreatic adenocarcinoma is focused on disease-free and overall survival, morbidity among long-term survivors is not well described. This study sought to evaluate outcomes for long-term survivors of pancreatic cancer after pancreatoduodenectomy. METHODS: The authors identified 29 patients from their prospectively collected database of patients with pancreatic adenocarcinoma who had undergone pancreatoduodenectomy and were without evidence of disease during at least 3 years of follow-up evaluation. Demographics, treatment, and pathologic characteristics were collected for review. Data with regard to long-term sequelae also were collected, focusing on those complications requiring additional procedures and on the development of metachronous cancers. RESULTS: The median follow-up period was 83 months, with 62 % of patients still alive. All patients received an R0 resection, and 34 % of the patients had N1 disease. For 42 % of the patients, no significant subsequent sequelae occurred. In the four remaining patients (14 %), ascites developed, requiring repeated paracentesis or Denver shunt, with a median time to development (MTD) of 63 months. Six patients (21 %) experienced a biliary stricture requiring stent placement (MTD, 56 months). One patient experienced portal venous thrombosis requiring a venous stent (MTD, 52 months), and four patients (14 %) experienced clinically significant ulcers (MTD, 52 months). With regard to metachronous cancers, two patients experienced subsequent lymphomas (MTD, 92 months). CONCLUSIONS: Long-term survivors among patients who undergo pancreatoduodenectomy for pancreatic adenocarcinoma can experience significant late sequelae, which often manifest more than 3 years after surgery. As such, continued follow-up evaluation and counseling are warranted.

Phase I study of the mTOR inhibitor ridaforolimus and the HDAC inhibitor vorinostat in advanced renal cell carcinoma and other solid tumors.

INTRODUCTION: Drugs inhibiting the mammalian target of rapamycin (mTOR) are approved in the treatment of renal cell carcinoma (RCC), but resistance inevitably emerges. Proposed escape pathways include increased phosphorylation of Akt, which can be down regulated by histone deacetylase (HDAC) inhibitors. We hypothesized that co-treatment with the mTOR inhibitor ridaforolimus and the HDAC inhibitor vorinostat may abrogate resistance in RCC. METHODS: This phase 1 study evaluated the co-administration of ridaforolimus and vorinostat in patients with advanced solid tumors. The primary objective was to determine the maximum tolerated dose (MTD) in RCC patients. Although all solid tumors were allowed, prior cytotoxic chemotherapy was limited to 1 regimen. Using a modified 3 + 3 dose escalation design, various dose combinations were tested concurrently in separate cohorts. Efficacy was a secondary endpoint. RESULTS: Fifteen patients were treated at one of three dose levels, thirteen with RCC (10 clear cell, 3 papillary). Dosing was limited by thrombocytopenia. The MTD was determined to be ridaforolimus 20 mg daily days 1-5 with vorinostat 100 mg BID days 1-3 weekly, however late onset thrombocytopenia led to a lower recommended phase II dose: ridaforolimus 20 mg daily days 1-5 with vorinostat 100 mg daily days 1-3 weekly. Two patients, both with papillary RCC, maintained disease control for 54 and 80 weeks, respectively. CONCLUSIONS: The combination of ridaforolimus and vorinostat was tolerable at the recommended phase II dose. Two patients with papillary RCC experienced prolonged disease stabilization, thus further study of combined HDAC and mTOR inhibition in this population is warranted.

Diagnosing Fish Bone and Chicken Bone Impactions in the Emergency Department Setting: Measuring the System Utility of the Plain Film Screen.

OBJECTIVES: In the emergency department, fish and chicken bone impactions are typically evaluated with screening x-rays. We sought to determine whether this modality ultimately improves system outcomes, including length of stay (LOS), cost, and radiation dosage. METHODS: We reviewed patients ≥ 18 years old presenting to an urban academic emergency department over a 4-year period who received a screening soft-tissue x-ray to determine the presence of a retained fish or chicken bone. We calculated the diagnostic accuracy of x-ray and computed tomography (CT) evaluations, respectively, in addition to system outcomes. RESULTS: Twenty-seven of the 78 patients included for analysis were ultimately positive for bone impaction. Initial x-ray interpretations demonstrated a sensitivity of 24.0% (95% CI, 9.4%-45.1%) and a specificity of 90.0% (95% CI, 78.2%-96.7%). However, initial CT interpretation (ie, a preliminary read from on-call residents) demonstrated a sensitivity of 75% (95% CI, 19.4%-99.4%) and a specificity of 100% (95% CI, 59.0%-100%). LOS, cost, and radiation dosage were not significantly different between patients who ultimately had true bone impactions and those who did not (P > .05). CONCLUSIONS: X-rays are poor screening tools in determining fish or chicken bone impactions with poor diagnostic and system utility. Further studies should be performed to evaluate the role of a low-radiation CT screen.

A highly selective dual insulin receptor (IR)/insulin-like growth factor 1 receptor (IGF-1R) inhibitor derived from an extracellular signal-regulated kinase (ERK) inhibitor.

Dual inhibitors of the closely related receptor tyrosine kinases insulin-like growth factor 1 receptor (IGF-1R) and insulin receptor (IR) are promising therapeutic agents in cancer. Here, we report an unusually selective class of dual inhibitors of IGF-1R and IR identified in a parallel screen of known kinase inhibitors against a panel of 300 human protein kinases. Biochemical and structural studies indicate that this class achieves its high selectivity by binding to the ATP-binding pocket of inactive, unphosphorylated IGF-1R/IR and stabilizing the activation loop in a native-like inactive conformation. One member of this compound family was originally reported as an inhibitor of the serine/threonine kinase ERK, a kinase that is distinct in the structure of its unphosphorylated/inactive form from IR/IGF-1R. Remarkably, this compound binds to the ATP-binding pocket of ERK in an entirely different conformation to that of IGF-1R/IR, explaining the potency against these two structurally distinct kinase families. These findings suggest a novel approach to polypharmacology in which two or more unrelated kinases are inhibited by a single compound that targets different conformations of each target kinase.

Neoadjuvant chemoradiation and duration of chemotherapy before surgical resection for pancreatic cancer: does time interval between radiotherapy and surgery matter?

BACKGROUND: Neoadjuvant chemoradiation and chemotherapy provided for borderline or locally advanced, potentially resectable pancreatic adenocarcinoma improves resectability rates. Response to therapy is also an important prognostic factor. There are no data in the literature regarding optimal time interval or duration of chemotherapy after chemoradiation before surgery, and pathologic response rates. Using our database, we evaluated these relationships and the effect on overall and progression-free survival. METHODS: We retrospectively analyzed the records of 83 patients who underwent neoadjuvant chemoradiation for locally advanced, potentially resectable, and borderline resectable pancreatic cancers before definitive resection. We divided patients into three groups according to time interval between completion of chemoradiation and resection: group A (0-10 weeks), group B (11-20 weeks), and group C (>20 weeks). After chemoradiation, patients underwent ongoing chemotherapy before resection. Pathologic response was defined as major (>95% fibrosis), partial (50-94% fibrosis), or minor (<50% fibrosis). RESULTS: There were 56 patients in group A, 17 patients in group B, and 10 patients in group C. Patients in groups B and C were significantly more likely to experience a major response than group A (p < 0.013). Patients in group C had significantly increased median progression-free and overall survival (p < 0.05). Multivariable classification and regression tree analysis demonstrated pathologic response to be the only significant factor in overall survival. CONCLUSIONS: Patients who underwent a prolonged time interval after neoadjuvant chemoradiation with ongoing chemotherapy were more likely to have an improved pathologic response at time of surgical resection, which was associated with improved median overall survival.

On nonnegative matrix factorization algorithms for signal-dependent noise with application to electromyography data.

Nonnegative matrix factorization (NMF) by the multiplicative updates algorithm is a powerful machine learning method for decomposing a high-dimensional nonnegative matrix V into two nonnegative matrices, W and H, where V ~ WH. It has been successfully applied in the analysis and interpretation of large-scale data arising in neuroscience, computational biology, and natural language processing, among other areas. A distinctive feature of NMF is its nonnegativity constraints that allow only additive linear combinations of the data, thus enabling it to learn parts that have distinct physical representations in reality. In this letter, we describe an information-theoretic approach to NMF for signal-dependent noise based on the generalized inverse gaussian model. Specifically, we propose three novel algorithms in this setting, each based on multiplicative updates, and prove monotonicity of updates using the EM algorithm. In addition, we develop algorithm-specific measures to evaluate their goodness of fit on data. Our methods are demonstrated using experimental data from electromyography studies, as well as simulated data in the extraction of muscle synergies, and compared with existing algorithms for signal-dependent noise.

Risk of positive nonsentinel nodes in women with 1-2 positive sentinel nodes related to age and molecular subtype approximated by receptor status.

We examine risk of positive nonsentinel axillary nodes (NSN) and ≥4 positive nodes in patients with 1-2 positive sentinel nodes (SN) by age and tumor subtype approximated by ER, PR, and Her2 receptor status. Review of two institutional databases demonstrated 284 women undergoing breast conservation between 1997 and 2008 for T1-2 tumors and 1 (229) or 2 (55) positive SN followed by completion dissection. The median number of SN and total axillary nodes removed were 2 (range 1-10) and 14 (range 6-37), respectively. The rate of positive NSNs (p = 0.5) or ≥4 positive nodes (p = 0.6) was not associated with age. NSN were positive in 36% of luminal A, 26% of luminal B, 21% of TN and 38% of Her2+ (p = 0.4). Four or more nodes were present in 17% of luminal A, 13% luminal of B, 0% of TN and 29% of Her2+ (p = 0.1). Microscopic extracapsular extension was significantly associated with having NSNs positive (55% versus 24%, p < 0.0001) and with having total ≥4 nodes positive (33% versus 7%, p < 0.0001). In a population that was largely eligible for ACOSOG Z0011, the risk of positive NSN or ≥4 positive nodes did not vary significantly by age. The TN subgroup had the lowest risk of both positive NSN or ≥4 positive nodes. Several high risk groups with >15% risk for having ≥4 positive nodes were identified. Further data is needed to confirm that ACOSOG Z0011 results are equally applicable to all molecular phenotypes.

Impact of adjuvant chemotherapy on abdominal wall hernias and bulges after muscle-sparing free TRAM flaps for breast reconstruction.

BACKGROUND: Free tissue transfer from an abdominal donor site has become a popular method for postmastectomy breast reconstruction. The detrimental effects of adjuvant chemotherapy on healing and the resulting clinical impact on patient outcome remains somewhat unclear for abdominal bulges and hernias resulting after free tissue transfer from the abdominal donor site. METHODS: An institutional review board-approved retrospective review of 155 free muscle-sparing transverse rectus abdominis myocutaneous (MS-TRAM) flaps performed for breast reconstruction was undertaken to evaluate the effect of adjuvant chemotherapy on abdominal donor-site morbidity. The primary outcome studied was the development of hernias and bulges. Statistical analysis was performed using univariate and multivariate classification and regression tree (CART) analysis. RESULTS: Of the 155 patients, 51 underwent bilateral MS-TRAM flaps and 104 underwent unilateral MS-TRAM flap reconstruction. Thirty-nine patients underwent adjuvant chemotherapy. A statistically significant association was seen between chemotherapy treatment and the incidence of hernias alone (P < 0.05; odds ratio, 6.42; 95% confidence interval, 0.88-73.58). Multivariable CART analyses corroborated these findings and revealed that presence of diabetes mellitus (DM), bilaterality, and receiving chemotherapy treatment were related to increased incidence of hernias (P = 0.011, 0.005, and 0.017, respectively) after controlling for clinical variables such as smoking status, chronic obstructive pulmonary disease, and type of closure. Univariate analyses also revealed a statistically significant association between bilaterality in conjunction with chemotherapy treatment and the incidence of hernias alone (P = 0.0002; odds ratio, 37.56; 95% confidence interval, 4.56-476.35). This highly significant finding is further augmented by multivariable CART analyses, which found that patients who were bilateral and underwent chemotherapy treatment or those with DM were significantly more likely to develop hernias (P < 0.001 and P = 0.016, respectively). CONCLUSIONS: To date, our study is the single largest series of abdominal donor-site complications in patients receiving chemotherapy and free MS-TRAM breast reconstruction. We have demonstrated an increase in the incidence of abdominal donor-site complications, specifically abdominal bulges and hernias, in patients undergoing chemotherapy for advanced stages of breast cancer. This increased complication rate is most pronounced in patients requiring chemotherapy who undergo bilateral reconstruction, and is also a significant risk for patients receiving chemotherapy who have preexisting DM.