Sandeep Saha

CARM1 Methylates Chromatin Remodeling Factor BAF155 to Enhance Tumor Progression and Metastasis

Coactivator-associated arginine methyltransferase 1 (CARM1), a coactivator for various cancer-relevant transcription factors, is overexpressed in breast cancer. To elucidate the functions of CARM1 in tumorigenesis, we knocked out CARM1 from several breast cancer cell lines using Zinc-Finger Nuclease technology, which resulted in drastic phenotypic and biochemical changes. The CARM1 KO cell lines enabled identification of CARM1 substrates, notably the SWI/SNF core subunit BAF155. Methylation of BAF155 at R1064 was found to be an independent prognostic biomarker for cancer recurrence and to regulate breast cancer cell migration and metastasis. Furthermore, CARM1-mediated BAF155 methylation affects gene expression by directing methylated BAF155 to unique chromatin regions (e.g., c-Myc pathway genes). Collectively, our studies uncover a mechanism by which BAF155 acquires tumorigenic functions via arginine methylation.

Prevalence of Human Papillomavirus in Oropharyngeal Squamous Cell Carcinoma in the United States Across Time

Human papillomaviruses (HPVs) are involved in approximately 5% of all human cancer. Although initially recognized for causing nearly all cases of cervical carcinoma, much data has now emerged implicating HPVs as a causal factor in other anogenital cancers as well as a subset of head and neck squamous cell carcinomas (HNSCCs), most commonly oropharyngeal cancers. Numerous clinical trials have demonstrated that patients with HPV+ oropharyngeal squamous cell carcinoma (OPSCC) have improved survival compared to patients with HPV– cancers. Furthermore, epidemiological evidence shows the incidence of OPSCC has been steadily rising over time in the United States. It has been proposed that an increase in HPV-related OPSCCs is the driving force behind the increasing rate of OPSCC. Although some studies have revealed an increase in HPV+ head and neck malignancies over time in specific regions of the United States, there has not been a comprehensive study validating this trend across the entire country. Therefore, we undertook this meta-analysis to assess all literature through August 2013 that reported on the prevalence of HPV in OPSCC for patient populations within the United States. The results show an increase in the prevalence of HPV+ OPSCC from 20.9% in the pre-1990 time period to 51.4% in 1990–1999 and finally to 65.4% for 2000–present. In this manner, our study provides further evidence to support the hypothesis that HPV-associated OPSCCs are driving the increasing incidence of OPSCC over time in the United States.

Predictors of surgical site infection after hospital discharge in patients undergoing major vascular surgery

OBJECTIVE Surgical site infection (SSI) is one of the most common postoperative complications after vascular reconstruction, producing significant morbidity and hospital readmission. In contrast to SSI that develops while patients are still hospitalized, little is known about the cohort of patients who develop SSI after discharge. In this study, we explore the factors that lead to postdischarge SSI, investigate the differences between risk factors for in-hospital vs postdischarge SSI, and develop a scoring system to identify patients who might benefit from postdischarge monitoring of their wounds. METHODS Patients who underwent major vascular surgery from 2005 to 2012 for aneurysm and lower extremity occlusive disease were identified from the American College of Surgeons National Surgical Quality Improvement Program Participant Use Files. Patients were categorized as having no SSI, in-hospital SSI, or SSI after hospital discharge. Predictors of postdischarge SSI were determined by multivariable logistic regression and internally validated by bootstrap resampling. Risk scores were assigned to all significant variables in the model. Summative risk scores were collapsed into quartile-based ordinal categories and defined as low, low/moderate, moderate/high, and high risk. Multivariable logistic regression was used to determine predictors of in-hospital SSI. RESULTS Of the 49,817 patients who underwent major vascular surgery, 4449 (8.9%) were diagnosed with SSI (2.1% in-hospital SSI; 6.9% postdischarge SSI). By multivariable analysis, factors significantly associated with increased odds of postdischarge SSI include female gender, obesity, diabetes, smoking, hypertension, coronary artery disease, critical limb ischemia, chronic obstructive pulmonary disease, dyspnea, neurologic disease, prolonged operative time >4 hours, American Society of Anesthesiology class 4 or 5, lower extremity revascularization or aortoiliac procedure, and groin anastomosis. The model exhibited moderate discrimination (bias-corrected C statistic, 0.691) and excellent internal calibration. The postdischarge SSI rate was 2.1% for low-risk patients, 5.1% for low/moderate-risk patients, 7.8% for moderate/high-risk patients, and 14% for high-risk patients. In a comparative analysis, comorbidities were the primary driver of postdischarge SSI, whereas in-hospital factors (operative time, emergency case status) and complications predicted in-hospital SSI. CONCLUSIONS The majority of SSIs after major vascular surgery develop following hospital discharge. We have created a scoring system that can select a cohort of patients at high risk for SSI after discharge. These patients can be targeted for transitional care efforts focused on early detection and treatment with the goal of reducing morbidity and preventing readmission secondary to SSI.

Prevalence of Human Papillomavirus in Oropharyngeal Cancer: A Systematic Review.

PurposeThe global incidence of oropharyngeal squamous cell carcinoma (OPSCC) has been increasing, and it has been proposed that a rising rate of human papillomavirus (HPV)–associated cancers is driving the observed changes in OPSCC incidence. We carried out this systematic review to further examine the prevalence of HPV in OPSCC over time worldwide. MethodsA systematic literature search was performed to identify all articles through January 31, 2014, which reported on the prevalence of HPV in OPSCC. Articles that met the inclusion criteria were divided into 4 time frames (pre-1995, 1995–1999, 2000–2004, and 2005 to present) based on the median year of the study’s sample collection period. Using a weighted analysis of variance model, we examined the trends of HPV-positivity over time worldwide, in North America, and in Europe. ResultsOur literature search identified 699 unique articles. One hundred seventy-five underwent review of the entire study, and 105 met the inclusion criteria. These 105 articles reported on the HPV prevalence in 9541 OPSCC specimens across 23 nations. We demonstrated significant increases in the percentage change of HPV-positive OPSCCs from pre-1995 to present: 20.6% worldwide (P for trend: P < 0.001), 21.6% in North America (P = 0.013), and 21.5% in Europe (P = 0.033). ConclusionsInterestingly, whereas in Europe there was a steady increase in HPV prevalence across all time frames, reaching nearly 50% most recently, in North America HPV prevalence appears to have plateaued over the past decade at about 65%. These findings may have important implications regarding predictions for the future incidence of OPSCC.

AXL Is a Logical Molecular Target in Head and Neck Squamous Cell Carcinoma

Purpose: Head and neck squamous cell carcinoma (HNSCC) represents the eighth most common malignancy worldwide. Standard-of-care treatments for patients with HNSCC include surgery, radiation, and chemotherapy. In addition, the anti-EGFR monoclonal antibody cetuximab is often used in combination with these treatment modalities. Despite clinical success with these therapeutics, HNSCC remains a difficult malignancy to treat. Thus, identification of new molecular targets is critical. Experimental Design: In the current study, the receptor tyrosine kinase AXL was investigated as a molecular target in HNSCC using established cell lines, HNSCC patient-derived xenografts (PDX), and human tumors. HNSCC dependency on AXL was evaluated with both anti-AXL siRNAs and the small-molecule AXL inhibitor R428. Furthermore, AXL inhibition was evaluated with standard-of-care treatment regimens used in HNSCC. Results: AXL was found to be highly overexpressed in several models of HNSCC, where AXL was significantly associated with higher pathologic grade, presence of distant metastases, and shorter relapse-free survival in patients with HNSCC. Further investigations indicated that HNSCC cells were reliant on AXL for cellular proliferation, migration, and invasion. In addition, targeting AXL increased HNSCC cell line sensitivity to chemotherapy, cetuximab, and radiation. Moreover, radiation-resistant HNSCC cell line xenografts and PDXs expressed elevated levels of both total and activated AXL, indicating a role for AXL in radiation resistance. Conclusions: This study provides evidence for the role of AXL in HNSCC pathogenesis and supports further preclinical and clinical evaluation of anti-AXL therapeutics for the treatment of patients with HNSCC. Clin Cancer Res; 21(11); 2601–12. ©2015 AACR.

COX-2 modulates mammary tumor progression in response to collagen density

BackgroundHigh breast density is linked to an increased risk of breast cancer, and correlates with changes in collagen. In a mouse model of mammary carcinoma in the context of increased collagen deposition, the MMTV-PyMT/Col1a1tm1jae, there is accelerated mammary tumor formation and progression. Previous gene expression analysis suggests that increased collagen density elevates expression of PTGS2 (prostaglandin-endoperoxide synthase 2), the gene for cyclooxygenase-2 (COX-2).MethodsTo understand the role of COX-2 in tumor progression within a collagen-dense microenvironment, we treated MMTV-PyMT or MMTV-PyMT/Col1a1tm1jae tumors prior to and after tumor formation. Animals received treatment with celecoxib, a specific COX-2 inhibitor, or placebo. Mammary tumors were examined for COX-2, inflammatory and stromal cell components, and collagen deposition through immunohistochemical analysis, immunofluorescence, multiplex cytokine ELISA and tissue imaging techniques.ResultsPyMT/Col1a1tm1jae tumors were larger, more proliferative, and expressed higher levels of COX-2 and PGE2 than PyMT tumors in wild type (WT) mice. Treatment with celecoxib significantly decreased the induced tumor size and metastasis of the PyMT/Col1a1 tumors, such that their size was not different from the smaller PyMT tumors. Celecoxib had minimal effect on the PyMT tumors. Celecoxib decreased expression levels of COX-2, PGE2, and Ki-67. Several cytokines were over-expressed in PyMT/Col1a1 compared to PyMT, and celecoxib treatment prevented their over-expression. Furthermore, macrophage and neutrophil recruitment were enhanced in PyMT/Col1a1 tumors, and this effect was inhibited by celecoxib. Notably, COX-2 inhibition reduced overall collagen deposition. Finally, when celecoxib was used prior to tumor formation, PyMT/Col1a1 tumors were fewer and smaller than in untreated animals.ConclusionThese findings suggest that COX-2 has a direct role in modulating tumor progression in tumors arising within collagen-dense microenvironments, and suggest that COX-2 may be an effective therapeutic target for women with dense breast tissue and early-stage breast cancer.

A phase 2 study of weekly temsirolimus and bortezomib for relapsed or refractory B-cell non-Hodgkin lymphoma: A Wisconsin Oncology Network study

Proteasome inhibitors and mammalian target of rapamycin inhibitors each have activity in various B‐cell malignancies and affect distinct cellular pathways. Their combination has demonstrated synergy in vitro and in mouse models.

Management of leptomeningeal metastases: Prognostic factors and associated outcomes

Limited data are currently available to direct treatment recommendations in the management of leptomeningeal metastases (LM). Here we review treatment modalities clinicians should understand in order to manage patients with LM. We first describe our institutions experience with the treatment of LM and use this dataset to frame the discussion of LM management. Between 1999 and 2014, 1361 patients with central nervous system metastases were reviewed, 124 (9.1%) had radiographic evidence of LM, and these patients form the cohort for this analysis. Mean age at diagnosis of LM was 52years. Median survival for the entire cohort was 2.3months. The most common primary malignancies were non-small cell lung cancer (25.8%), breast cancer (17.7%), small cell lung cancer (16.9%) and melanoma (8.9%). Univariate analyses demonstrated that greater Karnofsky Performance Status (KPS) (p=0.001) and administration of systemic chemotherapy (p<0.001) resulted in improved median survival. Multivariate Cox analyses revealed that receipt of chemotherapy and a complete course of whole brain radiotherapy (WBRT) (median dose 30Gy in 10 fractions, range 24-40Gy) were predictive of longer survival, (p=0.013 and 0.019, respectively). These data suggest that there is a group of patients with good KPS who may experience significantly longer median survival than expected. Multivariate analysis from this single institution retrospective study demonstrated a benefit for WBRT and chemotherapy in individuals with good KPS. These findings provide contemporary data from a large cohort of LM patients, which may be utilized to guide treatment recommendations, assist in patient counseling and direct future investigations into optimization of treatment regimens.

Biopsy Use in Skin Cancer Diagnosis: Comparing Dermatology Physicians and Advanced Practice Professionals

Author Affiliations: Department of Dermatology, University Clinic of Navarra, Pamplona, Navarra, Spain (Redondo, Gímenez de Azcarate, Aguado); Research Support Service, University Clinic of Navarra, Pamplona, Navarra, Spain (Núñez-Córdoba); Department of Preventive Medicine and Public Health, Medical School, University of Navarra, Pamplona, Navarra, Spain (Núñez-Córdoba); Area of Cell Therapy, University Clinic of Navarra, Pamplona, Navarra, Spain (Andreu, García-Guzman, Prosper).

Increased tumor response to neoadjuvant therapy among rectal cancer patients taking angiotensin-converting enzyme inhibitors or angiotensin receptor blockers

Angiotensin‐converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) are commonly used antihypertensive medications that have been reported to affect aberrant angiogenesis and the dysregulated inflammatory response. Because of such mechanisms, it was hypothesized that these medications might affect the tumor response to neoadjuvant radiation in patients with rectal cancer.