The Impact of Locoregional Therapy in Nonmetastatic Inflammatory Breast Cancer: A Population-Based Study

Background. Inflammatory breast cancer (IBC) is a rare but most aggressive breast cancer subtype. The impact of locoregional therapy on survival in IBC is controversial. Methods. Patients with nonmetastatic IBC between 1988 and 2013 were identified in the Surveillance, Epidemiology, and End Results (SEER) registry. Results. We identified 7,304 female patients with nonmetastatic inflammatory breast cancer (IBC) who underwent primary tumor surgery. Most patients underwent total mastectomy with only 409 (5.6%) undergoing a partial mastectomy. In addition, 4,559 (62.4%) were also treated with radiation therapy. The patients who underwent mastectomy had better survival compared to partial mastectomy (49% versus 43%, p = 0.003). The addition of radiation therapy was also associated with improved 5-year survival (55% versus 40%, p < 0.001). Multivariate analysis showed that black race HR (1.22, 95% CI 1.18-1.35), ER negative status (HR 1.22, 95% CI 1.16-1.28), and higher grade (HR 1.14, 95% CI 1.07-1.20) were associated with poor outcome. Cox proportional hazards model showed that total mastectomy (HR 0.75, 95% CI 0.65-0.85) and radiation (HR 0.64, 95% CI 0.61-0.69) were associated with improved survival. Conclusions. Optimal locoregional therapy for women with nonmetastatic IBC continues to be mastectomy and radiation therapy. These data reinforce the prevailing treatment algorithm for nonmetastatic IBC

Enhanced Recovery after Surgery in a Single High-Volume Surgical Oncology Unit: Details Matter

Benefits of ERAS protocol have been well documented; however, it is unclear whether the improvement stems from the protocol or shifts in expectations. Interdisciplinary educational seminars were conducted for all health professionals. However, one test surgeon adopted the protocol. 394 patients undergoing elective abdominal surgery from June 2013 to April 2015 with a median age of 63 years were included. The implementation of ERAS protocol resulted in a decrease in the length of stay (LOS) and mortality, whereas the difference in cost was found to be insignificant. For the test surgeon, ERAS was associated with decreased LOS, cost, and mortality. For the control providers, the LOS, cost, mortality, readmission rates, and complications remained similar both before and after the implementation of ERAS. An ERAS protocol on the single high-volume surgical unit decreased the cost, LOS, and mortality

Murine Pancreatic Adenocarcinoma Dampens SHIP-1 Expression and Alters MDSC Homeostasis and Function

Pancreatic cancer is one of the most aggressive cancers, with tumor-induced myeloid-derived suppressor cells (MDSC) contributing to its pathogenesis and ineffective therapies. In response to cytokine/chemokine receptor activation, src homology 2 domain-containing inositol 5'-phosphatase-1 (SHIP-1) influences phosphatidylinositol-3-kinase (PI3K) signaling events, which regulate immunohomeostasis. We hypothesize that factors from murine pancreatic cancer cells cause the down-regulation of SHIP-1 expression, which may potentially contribute to MDSC expansion, and the suppression of CD8(+) T cell immune responses. Therefore, we sought to determine the role of SHIP-1 in solid tumor progression, such as murine pancreatic cancer.Immunocompetent C57BL/6 mice were inoculated with either murine Panc02 cells (tumor-bearing [TB] mice) or Phosphate Buffer Saline (PBS) (control mice). Cytometric Bead Array (CBA) analysis of supernatants of cultured Panc02 detected pro-inflammatory cytokines such as IL-6, IL-10 and MCP-1. TB mice showed a significant increase in serum levels of pro-inflammatory factors IL-6 and MCP-1 measured by CBA. qRT-PCR and Western blot analyses revealed the in vivo down-regulation of SHIP-1 expression in splenocytes from TB mice. Western blot analyses also detected reduced SHIP-1 activity, increased AKT-1 and BAD hyper-phosphorylation and up-regulation of BCL-2 expression in splenocytes from TB mice. In vitro, qRT-PCR and Western blot analyses detected reduced SHIP-1 mRNA and protein expression in control splenocytes co-cultured with Panc02 cells. Flow cytometry results showed significant expansion of MDSC in peripheral blood and splenocytes from TB mice. AutoMACS sorted TB MDSC exhibited hyper-phosphorylation of AKT-1 and over-expression of BCL-2 detected by western blot analysis. TB MDSC significantly suppressed antigen-specific CD8(+) T cell immune responses in vitro.SHIP-1 may regulate immune development that impacts MDSC expansion and function, contributing to pancreatic tumor progression. Thus, SHIP-1 can be a potential therapeutic target to help restore immunohomeostasis and improve therapeutic responses in patients with pancreatic cancer

Racial Differences in the Association Between Luminal Master Regulator Gene Expression Levels and Breast Cancer Survival

Compared with their European American (EA) counterparts, African American (AA) women are more likely to die from breast cancer in the United States. This disparity is greatest in hormone receptor-positive subtypes. Here we uncover biological factors underlying this disparity by comparing functional expression and prognostic significance of master transcriptional regulators of luminal differentiation.Fil: Byun, Jung S.. National Institutes of Health; Estados UnidosFil: Singhal, Sandeep K.. Columbia University; Estados UnidosFil: Park, Samson. National Institutes of Health; Estados UnidosFil: Yi, Dae Ik. National Institutes of Health; Estados UnidosFil: Yan, Tingfen. National Institutes of Health; Estados UnidosFil: Caban, Ambar. Columbia University Medical Center; Estados UnidosFil: Jones, Alana. National Institutes of Health; Estados UnidosFil: Mukhopadhyay, Partha. Columbia University Medical Center; Estados UnidosFil: Gille, Sarah. National Institutes of Health; Estados UnidosFil: Hewitt, Stephen M.. No especifíca;Fil: Newman, Lisa. No especifíca;Fil: Davis, Melissa B.. Henry Ford Health System; Estados UnidosFil: Jenkins, Brittany D.. Henry Ford Health System; Estados UnidosFil: Sepulveda, Jorge L.. Columbia University Medical Center; Estados UnidosFil: de Siervi, Adriana. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; ArgentinaFil: Nápoles, Anna María. National Institute On Minority Health And Health Disparities; Estados UnidosFil: Vohra, Nasreen A.. East Carolina University; Estados UnidosFil: Gardner, Kevin. Columbia University Medical Center; Estados Unido

Bioenergetic Phenotyping of DEN-Induced Hepatocellular Carcinoma Reveals a Link Between Adenylate Kinase Isoform Expression and Reduced Complex I-Supported Respiration

Hepatocellular carcinoma (HCC) is the most common form of liver cancer worldwide. Increasing evidence suggests that mitochondria play a central role in malignant metabolic reprogramming in HCC, which may promote disease progression. To comprehensively evaluate the mitochondrial phenotype present in HCC, we applied a recently developed diagnostic workflow that combines high-resolution respirometry, fluorometry, and mitochondrial-targeted nLC-MS/MS proteomics to cell culture (AML12 and Hepa 1-6 cells) and diethylnitrosamine (DEN)-induced mouse models of HCC. Across both model systems, CI-linked respiration was significantly decreased in HCC compared to nontumor, though this did not alter ATP production rates. Interestingly, CI-linked respiration was found to be restored in DEN-induced tumor mitochondria through acute in vitro treatment with P1, P5-di(adenosine-5′) pentaphosphate (Ap5A), a broad inhibitor of adenylate kinases. Mass spectrometry-based proteomics revealed that DEN-induced tumor mitochondria had increased expression of adenylate kinase isoform 4 (AK4), which may account for this response to Ap5A. Tumor mitochondria also displayed a reduced ability to retain calcium and generate membrane potential across a physiological span of ATP demand states compared to DEN-treated nontumor or saline-treated liver mitochondria. We validated these findings in flash-frozen human primary HCC samples, which similarly displayed a decrease in mitochondrial respiratory capacity that disproportionately affected CI. Our findings support the utility of mitochondrial phenotyping in identifying novel regulatory mechanisms governing cancer bioenergetics

Bioenergetic Phenotyping of DEN-Induced Hepatocellular Carcinoma Reveals a Link Between Adenylate Kinase Isoform Expression and Reduced Complex I-Supported Respiration

Hepatocellular carcinoma (HCC) is the most common form of liver cancer worldwide. Increasing evidence suggests that mitochondria play a central role in malignant metabolic reprogramming in HCC, which may promote disease progression. To comprehensively evaluate the mitochondrial phenotype present in HCC, we applied a recently developed diagnostic workflow that combines high-resolution respirometry, fluorometry, and mitochondrial-targeted nLC-MS/MS proteomics to cell culture (AML12 and Hepa 1-6 cells) and diethylnitrosamine (DEN)-induced mouse models of HCC. Across both model systems, CI-linked respiration was significantly decreased in HCC compared to nontumor, though this did not alter ATP production rates. Interestingly, CI-linked respiration was found to be restored in DEN-induced tumor mitochondria through acute in vitro treatment with P1, P5-di(adenosine-5′) pentaphosphate (Ap5A), a broad inhibitor of adenylate kinases. Mass spectrometry-based proteomics revealed that DEN-induced tumor mitochondria had increased expression of adenylate kinase isoform 4 (AK4), which may account for this response to Ap5A. Tumor mitochondria also displayed a reduced ability to retain calcium and generate membrane potential across a physiological span of ATP demand states compared to DEN-treated nontumor or saline-treated liver mitochondria. We validated these findings in flash-frozen human primary HCC samples, which similarly displayed a decrease in mitochondrial respiratory capacity that disproportionately affected CI. Our findings support the utility of mitochondrial phenotyping in identifying novel regulatory mechanisms governing cancer bioenergetics

Development and Assessment of a Systematic Approach for Detecting Disparities in Surgical Access

IMPORTANCE: Although optimal access is accepted as the key to quality care, an accepted methodology to ascertain potential disparities in surgical access has not been defined. OBJECTIVE: To develop a systematic approach to detect surgical access disparities. DESIGN, SETTING, AND PARTICIPANTS: This cross-sectional study used publicly available data from the Health Cost and Utilization Project State Inpatient Database from 2016. Using the surgical rate observed in the 5 highest-ranked counties (HRCs), the expected surgical rate in the 5 lowest-ranked counties (LRCs) in North Carolina were calculated. Patients 18 years and older who underwent an inpatient general surgery procedure and patients who underwent emergency inpatient cholecystectomy, herniorrhaphy, or bariatric surgery in 2016 were included. Data were collected from January to December 2016, and data were analyzed from March to July 2020. EXPOSURES: Health outcome county rank as defined by the Robert Wood Johnson Foundation. MAIN OUTCOMES AND MEASURES: The primary outcome was the proportional surgical ratio (PSR), which was the disparity in surgical access defined as the observed number of surgical procedures in the 5 LRCs relative to the expected number of procedures using the 5 HRCs as the standardized reference population. RESULTS: In 2016, approximately 1.9 million adults lived in the 5 HRCs, while approximately 246 854 lived in the 5 LRCs. A total of 28 924 inpatient general surgical procedures were performed, with 4521 being performed in those living in the 5 LRCs and 24 403 in those living in the 5 HRCs. The rate of general surgery in the 5 HRCs was 13.09 procedures per 1000 population. Using the 5 HRCs as the reference, the PSR for the 5 LRCs was 1.40 (95% CI, 1.35-1.44). For emergent/urgent cholecystectomy, the PSR for the 5 LRCs was 2.26 (95% CI, 2.02-2.51), and the PSR for emergent/urgent herniorrhaphy was 1.83 (95% CI, 1.33-2.45). Age-adjusted rate of obesity (body mass index [calculated as weight in kilograms divided by height in meters squared] greater than 30), on average, was 36.6% (SD, 3.4) in the 5 LRCs vs 25.4% (SD, 4.6) in the 5 HRCs (P = .002). The rate of bariatric surgery in the 5 HRCs was 33.07 per 10 000 population with obesity. For the 5 LRCs, the PSR was 0.60 (95% CI, 0.51-0.69). CONCLUSIONS AND RELEVANCE: The PSR is a systematic approach to define potential disparities in surgical access and should be useful for identifying, investigating, and monitoring interventions intended to mitigate disparities in surgical access that effects the health of vulnerable populations

Kaiso (ZBTB33) subcellular partitioning functionally links LC3A/B, the tumor microenvironment, and breast cancer survival

The use of digital pathology for the histomorphologic profiling of pathological specimens is expanding the precision and specificity of quantitative tissue analysis at an unprecedented scale; thus, enabling the discovery of new and functionally relevant histological features of both predictive and prognostic significance. In this study, we apply quantitative automated image processing and computational methods to profile the subcellular distribution of the multi-functional transcriptional regulator, Kaiso (ZBTB33), in the tumors of a large racially diverse breast cancer cohort from a designated health disparities region in the United States. Multiplex multivariate analysis of the association of Kaiso’s subcellular distribution with other breast cancer biomarkers reveals novel functional and predictive linkages between Kaiso and the autophagy-related proteins, LC3A/B, that are associated with features of the tumor immune microenvironment, survival, and race. These findings identify effective modalities of Kaiso biomarker assessment and uncover unanticipated insights into Kaiso’s role in breast cancer progression.Fil: Singhal, Sandeep K.. North Dakota State University; Estados UnidosFil: Byun, Jung S.. National Institutes of Health; Estados UnidosFil: Park, Samson. National Institutes of Health; Estados UnidosFil: Yan, Tingfen. National Institutes of Health; Estados UnidosFil: Yancey, Ryan. Columbia University; Estados UnidosFil: Caban, Ambar. Columbia University; Estados UnidosFil: Hernandez, Sara Gil. National Institutes of Health; Estados UnidosFil: Hewitt, Stephen M.. U.S. Department of Health & Human Services. National Institute of Health. National Cancer Institute; Estados UnidosFil: Boisvert, Heike. Ultivue, Inc; Reino UnidoFil: Hennek, Stephanie. Ultivue Inc.; Reino UnidoFil: Bobrow, Mark. Ultivue Inc.; Reino UnidoFil: Ahmed, Md Shakir Uddin. Tuskegee University; Estados UnidosFil: White, Jason. Tuskegee University; Estados UnidosFil: Yates, Clayton. Tuskegee University; Estados UnidosFil: Aukerman, Andrew. Columbia University; Estados UnidosFil: Vanguri, Rami. Columbia University; Estados UnidosFil: Bareja, Rohan. Columbia University; Estados UnidosFil: Lenci, Romina. Columbia University; Estados UnidosFil: Farré, Paula Lucía. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; ArgentinaFil: de Siervi, Adriana. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; ArgentinaFil: Nápoles, Anna María. National Institutes of Health; Estados UnidosFil: Vohra, Nasreen. East Carolina University; Estados UnidosFil: Gardner, Kevin. Columbia University; Estados Unido