Publications by authors named "Dario R Roque"

14 Publications

  • Page 1 of 1

Adding bevacizumab to single agent chemotherapy for the treatment of platinum-resistant recurrent ovarian cancer: A cost effectiveness analysis of the AURELIA trial.

Gynecol Oncol 2017 05 11;145(2):340-345. Epub 2017 Mar 11.

Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, University of North Carolina, United States.

Objective: AURELIA, a randomized phase III trial of adding bevacizumab (B) to single agent chemotherapy (CT) for the treatment of platinum-resistant recurrent ovarian cancer, demonstrated improved progression free survival (PFS) in the B+CT arm compared to CT alone. We aimed to evaluate the cost effectiveness of adding B to CT in the treatment of platinum-resistant recurrent ovarian cancer.

Methods: A decision tree model was constructed to evaluate the cost effectiveness of adding bevacizumab (B) to single agent chemotherapy (CT) based on the arms of the AURELIA trial. Costs, quality-adjusted life years (QALYs), and progression free survival (PFS) were modeled over fifteen months. Model inputs were extracted from published literature and public sources. Incremental cost effectiveness ratios (ICERs) per QALY gained and ICERs per progression free life year saved (PF-LYS) were calculated. One-way sensitivity analyses were performed to evaluate the robustness of results.

Results: The ICER associated with B+CT is $410,455 per QALY gained and $217,080 per PF-LYS. At a willingness to pay (WTP) threshold of $50,000/QALY, adding B to single agent CT is not cost effective for this patient population. Even at a WTP threshold of $100,000/QALY, B+CT is not cost effective. These findings are robust to sensitivity analyses.

Conclusions: Despite gains in QALY and PFS, the addition of B to single agent CT for treatment of platinum-resistant recurrent ovarian cancer is not cost effective. Benefits, risks, and costs associated with treatment should be taken into consideration when prescribing chemotherapy for this patient population.
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http://dx.doi.org/10.1016/j.ygyno.2017.02.039DOI Listing
May 2017

Association between differential gene expression and body mass index among endometrial cancers from The Cancer Genome Atlas Project.

Gynecol Oncol 2016 08 14;142(2):317-22. Epub 2016 Jun 14.

Division of Gynecologic Oncology, University of North Carolina, Chapel Hill, NC, United States; Lineberger Comprehensive Cancer Center, Chapel Hill, NC, United States. Electronic address:

Objective: The Cancer Genome Atlas (TCGA) identified four integrated clusters for endometrial cancer (EC): POLE, MSI, CNL and CNH. We evaluated differences in gene expression profiles of obese and non-obese women with EC and examined the association of body mass index (BMI) within the clusters identified in TCGA.

Methods: TCGA RNAseq data was used to identify genes related to increasing BMI among ECs. The POLE, MSI and CNL clusters were composed mostly of endometrioid EC. Patient BMI was compared between these three clusters with one-way ANOVA. Association between gene expression and BMI was also assessed while adjusting for confounding effects of potential confounding factors. p-Values testing the association between gene expression and BMI were adjusted for multiple hypothesis testing over the 20,531 genes considered.

Results: Mean BMI was statistically different between the ECs in the CNL (35.8) versus POLE (29.8) cluster (p=0.006) and approached significance for the MSI (33.0) versus CNL (35.8) cluster (p=0.05). 181 genes were significantly up- or down-regulated with increasing BMI in endometrioid EC (q-value<0.01), including LPL, IRS-1, IGFBP4, IGFBP7 and the progesterone receptor. DAVID functional annotation analysis revealed significant enrichment in "cell cycle" (adjusted p-value=1.5E-5) and "DNA metabolic processes" (adjusted p-value=1E-3) for the identified genes.

Conclusions: Obesity related genes were found to be upregulated with increasing BMI among endometrioid ECs. Patients with POLE tumors have the lowest median BMI when compared to MSI and CNL. Given the heterogeneity among endometrioid EC, consideration should be given to abandoning the Type I and II classification of EC tumors.
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http://dx.doi.org/10.1016/j.ygyno.2016.06.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4961559PMC
August 2016

Effects of Fatty Acid Synthase Inhibition by Orlistat on Proliferation of Endometrial Cancer Cell Lines.

Target Oncol 2016 12;11(6):763-769

Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, University of North Carolina, CB# 7570, 254 MacNider Building, Chapel Hill, NC, 27599, USA.

Objective: Fatty acid synthase (FAS) is a key lipogenic enzyme that is highly expressed in endometrial cancer. Orlistat is a weight loss medication that has been shown to be a potent inhibitor of FAS. The goal of this study was to evaluate the anti-tumorigenic potential of orlistat in endometrial cancer cell lines.

Methods: The endometrial cancer cell lines ECC-1 and KLE were used. Cell proliferation was assessed by MTT assay after treatment with orlistat. Cell cycle progression was evaluated by Cellometer and apoptosis was assessed using the Annexin V assay. Reactive oxygen species (ROS) was measured using the DCFH-DA assay. Western immunoblotting was performed to determine changes in FAS, cellular stress, cell cycle progression, and the AMPK/mTOR pathways.

Results: Orlistat inhibited cell proliferation by 61 % in ECC-1 cells and 57 % in KLE cells at a dose of 500 μM. Treatment with orlistat at this concentration resulted in G1 arrest (p < 0.05) but did not affect apoptosis. Orlistat increased ROS and induced the expression of BIP (1.28-fold in ECC-1 compared to control, p < 0.05; 1.92-fold in KLE, p < 0.05) and PERK (2.25-fold in ECC-1, 1.4-fold in KLE, p < 0.05). Western immunoblot analysis demonstrated that orlistat decreased expression of important proteins in fatty acid metabolism including FAS (67 % in ECC-1, 15 % in KLE), acetyl-CoA carboxylase (40 % in ECC-1, 35 % in KLE), and carnitine palmitoyltransferase 1A (CPT1A) (65 % in ECC-1, 25 % in KLE) in a dose-dependent manner. In addition, orlistat at a dose of 500 μM increased expression of phosphorylated-AMPK (1.9-fold in ECC-1, p < 0.01; 1.5-fold in KLE, p < 0.05) and decreased expression of phosphorylated-Akt (25 % in ECC-1, p < 0.05; 37 % in KLE, p < 0.05) and phosphorylated-S6 (68 % in ECC-1, 56 % in KLE).

Conclusions: Orlistat inhibits cell growth in endometrial cancer cell lines through inhibition of fatty acid metabolism, induction of cell cycle G1 arrest, activation of AMPK and inhibition of the mTOR pathway. Given that patients with endometrial cancer have high rates of obesity, orlistat should be further investigated as a novel strategy for endometrial cancer treatment.
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http://dx.doi.org/10.1007/s11523-016-0442-9DOI Listing
December 2016

Gemcitabine and Docetaxel Compared With Observation, Radiation, or Other Chemotherapy Regimens as Adjuvant Treatment for Stage I-to-IV Uterine Leiomyosarcoma.

Int J Gynecol Cancer 2016 Mar;26(3):505-11

*Division of Gynecologic Oncology, University of North Carolina, Chapel Hill, NC; †Division of Gynecologic Oncology, University of California San Diego, San Diego, CA; ‡Division of Gynecologic Oncology, Washington University, St Louis, MO; §Madigan Army Medical Center, Tacoma, WA; and ∥Program in Women's Oncology, Women & Infants Hospital; and ¶Division of Research, Women & Infants Hospital, Providence, RI.

Objectives: We aimed to compare progression-free survival (PFS) and overall survival (OS) among patients with stage I-to-IV uterine leiomyosarcoma (uLMS) who received adjuvant gemcitabine-docetaxel, were observed, received radiation only, or were treated with a chemotherapy regimen other than gemcitabine-docetaxel.

Methods/materials: This is a retrospective cohort study of 128 women with uLMS. Data included age, body mass index, race, stage, mitotic count, residual disease, adjuvant treatment, PFS, and OS. Variables were compared by Fisher exact or Wilcoxon rank-sum tests. Time to progression or death was plotted using Kaplan-Meier curves. Cox proportional hazards regression was used to estimate hazard ratios for progression or death by patient and tumor characteristics.

Results: Fifty-six (44%) women received adjuvant chemotherapy, 41 (32%) received adjuvant radiation, and 31 (24%) were observed. Of those receiving chemotherapy, 30 received gemcitabine-docetaxel, and 26 received other chemotherapy. Disease stage for the chemotherapy groups was evenly distributed. In the radiation group, 80% of patients had early-stage disease. Age, body mass index, and residual disease were similar between the groups. Mitotic count was uniformly 10 or greater only in the gemcitabine-docetaxel group. Age, stage, and residual disease were associated with worst PFS and OS. After adjusting for these variables, there was no difference in PFS or OS between gemcitabine-docetaxel and the other treatment groups.

Conclusions: There was no difference in PFS or OS in women with uLMS treated with adjuvant gemcitabine-docetaxel versus those who were observed or received radiation only or a chemotherapy regimen other than gemcitabine-docetaxel. There is a need to identify novel therapies to treat this aggressive disease.
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http://dx.doi.org/10.1097/IGC.0000000000000634DOI Listing
March 2016

Knockdown of hTERT and Treatment with BIBR1532 Inhibit Cell Proliferation and Invasion in Endometrial Cancer Cells.

J Cancer 2015 1;6(12):1337-45. Epub 2015 Nov 1.

2. Division of Gynecological Oncology, Department of Obstetrics and Gynecology, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States of America. ; 3. Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States of America.

Telomerase activity and expression of the catalytic protein hTERT are associated with cell proliferation and advanced stage in endometrial cancer. Our objective was to evaluate the effect of inhibition of hTERT by siRNA and BIBR1532 on cell growth, apoptosis and invasion in endometrial cancer cells. Knockdown of hTERT or treatment of the cells with BIBR1532 decreased telomerase activity, inhibited cell proliferation, induced apoptosis, and reduced cell invasion in Ishikawa and ECC-1 cells. Either hTERT siRNA or BIBR1532 in combination with paclitaxel promoted a synergistic inhibitory effect on cell growth through induction of Annexin V expression and a remarkable reduction in cell invasion through reduction of protein expression of MMP9, MMP2, and MMP3. Increased telomerase activity and hTERT protein expression by transfections enhanced the protein expression of MMPs and increased the cell invasion ability. BIBR1532 significantly antagonized cell invasion induced by increased hTERT expression. These findings suggest that telomerase and hTERT facilitate cell invasion via MMP family in human endometrial cancer cells.
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http://dx.doi.org/10.7150/jca.13054DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4643090PMC
December 2015

Glucose promotes cell proliferation, glucose uptake and invasion in endometrial cancer cells via AMPK/mTOR/S6 and MAPK signaling.

Gynecol Oncol 2015 Sep 30;138(3):668-75. Epub 2015 Jun 30.

Division of Gynecologic Oncology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA; Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA. Electronic address:

Objectives: Obesity and diabetes are well-known risk factors for the development of endometrial cancer. A high rate of aerobic glycolysis represents a key mechanism by which endometrial cancer cells consume glucose as its primary energy source. The up-regulated glycolytic pathway is a common therapeutic target whose inhibition has implications for anti-tumor activity in cancer cells. This study aimed to investigate the effect of various concentrations of glucose on cell proliferation in endometrial cancer.

Methods: ECC-1 and Ishikawa cells were treated with low glucose (1mM), normal glucose (5mM) and high glucose (25mM), and cytotoxicity, apoptosis, cell cycle, adhesion/invasion, and changes of AMPK/mTOR/S6 and MAPK pathways were evaluated.

Results: Our results revealed that high glucose increased cell growth and clonogenicity in two endometrial cancer cell lines in a dose dependent manner. Low glucose induced the activity of cleaved caspase 3 and caused cell cycle G1 arrest. High glucose increased the ability of adhesion and invasion by decreasing E-cadherin and increasing Snail expression. In addition, high glucose increased glucose uptake and glycolytic activity through modulating the AMPK/mTOR/S6 and MAPK pathways.

Conclusions: Our findings suggest that glucose stimulated cell proliferation through multiple complex signaling pathways. Targeting glucose metabolism may be a promising therapeutic strategy in the treatment of endometrial cancer.
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http://dx.doi.org/10.1016/j.ygyno.2015.06.036DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4672629PMC
September 2015

Glutamine promotes ovarian cancer cell proliferation through the mTOR/S6 pathway.

Endocr Relat Cancer 2015 Aug 4;22(4):577-91. Epub 2015 Jun 4.

Department of Gynecologic OncologyShanDong Tumor Hospital and Cancer Institute, Jinan University, Jinan 250117, People's Republic of ChinaDivision of Gynecologic OncologyUniversity of North Carolina at Chapel Hill, CB #7572, Physicians Office Building Rm #B105, Chapel Hill, North Carolina 27599, USALineberger Comprehensive Cancer CenterUniversity of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA Department of Gynecologic OncologyShanDong Tumor Hospital and Cancer Institute, Jinan University, Jinan 250117, People's Republic of ChinaDivision of Gynecologic OncologyUniversity of North Carolina at Chapel Hill, CB #7572, Physicians Office Building Rm #B105, Chapel Hill, North Carolina 27599, USALineberger Comprehensive Cancer CenterUniversity of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA

Glutamine is one of the main nutrients used by tumor cells for biosynthesis. Therefore, targeted inhibition of glutamine metabolism may have anti-tumorigenic implications. In the present study, we aimed to evaluate the effects of glutamine on ovarian cancer cell growth. Three ovarian cancer cell lines, HEY, SKOV3, and IGROV-1, were assayed for glutamine dependence by analyzing cytotoxicity, cell cycle progression, apoptosis, cell stress, and glucose/glutamine metabolism. Our results revealed that administration of glutamine increased cell proliferation in all three ovarian cancer cell lines in a dose dependent manner. Depletion of glutamine induced reactive oxygen species and expression of endoplasmic reticulum stress proteins. In addition, glutamine increased the activity of glutaminase (GLS) and glutamate dehydrogenase (GDH) by modulating the mTOR/S6 and MAPK pathways. Inhibition of mTOR activity by rapamycin or blocking S6 expression by siRNA inhibited GDH and GLS activity, leading to a decrease in glutamine-induced cell proliferation. These studies suggest that targeting glutamine metabolism may be a promising therapeutic strategy in the treatment of ovarian cancer.
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http://dx.doi.org/10.1530/ERC-15-0192DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4500469PMC
August 2015

Reply: To PMID 25020086.

Authors:
Dario R Roque

J Minim Invasive Gynecol 2015 Jul-Aug;22(5):917-8. Epub 2015 Apr 4.

Chapel Hill, North Carolina.

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http://dx.doi.org/10.1016/j.jmig.2015.04.002DOI Listing
September 2015

Obesity and perioperative pulmonary complications in robotic gynecologic surgery.

Am J Obstet Gynecol 2015 Jul 28;213(1):33.e1-33.e7. Epub 2015 Jan 28.

Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, University of Alabama, Birmingham, School of Medicine, Birmingham, AL.

Objective: Robotic gynecological surgery is feasible in obese patients, but there remain concerns about the safety of this approach because the positioning required for pelvic surgery can exacerbate obesity-related changes in respiratory physiology. The objective of our study was to evaluate pulmonary and all-cause complication rates in obese women undergoing robotic gynecological surgery and to assess variables that may be associated with complications.

Study Design: A retrospective chart review was performed on obese patients (body mass index of ≥30 kg/m(2)) who underwent robotic gynecological surgery at 2 academic institutions between 2006 and 2012. The primary outcome was pulmonary complications and the secondary outcome was all-cause complications. Univariate and multivariate logistic regression analyses were used to determine the associations between patient baseline variables, operative variables, ventilator parameters, and complications.

Results: Of 1032 patients, 146 patients (14%) had any complication, whereas only 33 patients (3%) had a pulmonary complication. Median body mass index was 37 kg/m(2). Only age was significantly associated with a higher risk of pulmonary complications (P = .01). Older age, higher estimated blood loss, and longer case length were associated with a higher rate of all-cause complications (P = .0001, P < .0001, and P = .004, respectively). No other covariates were strongly associated with complications.

Conclusion: The vast majority of obese patients can successfully tolerate robotic gynecological surgery and have overall low complications rates and even lower rates of pulmonary complications. The degree of obesity was not predictive of successful robotic surgery and subsequent complications.
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http://dx.doi.org/10.1016/j.ajog.2015.01.033DOI Listing
July 2015

Use of topical hemostatic agents in gynecologic surgery.

Obstet Gynecol Surv 2014 Sep;69(9):557-63

Professor, Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, University of North Carolina, Chapel Hill, NC.

Sutures, hemoclips, and electrocautery are the primary mechanisms used to achieve hemostasis during gynecologic surgery, but in situations in which these are inadequate or not feasible, an array of hemostatic agents are available to help achieve hemostasis. These agents include physical agents such as cellulose, collagen, or gelatin products as well as biologic agents such as thrombin and fibrin products. Limited data are available on many of these agents, although their use is increasing, sometimes at high costs. In gynecologic surgery, hemostatic agents are likely most effective when used in areas of oozing or slow bleeding and as an adjunct to conventional surgical methods of hemostasis.
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http://dx.doi.org/10.1097/OGX.0000000000000106DOI Listing
September 2014

The surgical management of cervical cancer: an overview and literature review.

Obstet Gynecol Surv 2014 Jul;69(7):426-41

Professor, Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, University of North Carolina, Chapel Hill, NC.

Importance: Surgery has evolved into the standard therapy for nonbulky carcinoma of the cervix. The mainstay of surgical management is radical hysterectomy; however, less radical procedures have a small but important role in the management of cervical tumors.

Objective: Our objective was to discuss the literature behind the different procedures utilized in the management of cervical cancer, emphasizing the radical hysterectomy. In addition, we aimed to discuss ongoing trials looking at the utility of less radical surgeries as well as emerging technologies in the management of this disease.

Evidence Acquisition: We performed a PubMed literature search for articles in the English language that pertained to the topic of surgical techniques and their outcomes in the treatment of cervical cancer.

Results: The minimally invasive approaches to radical hysterectomy appear to reduce morbidity without affecting oncological outcomes, although further data are needed looking at long-term outcomes with the robotic platform. Trials are currently ongoing looking at the role of less radical surgery for patients with low-risk disease and the feasibility of sentinel lymph node mapping.

Conclusions And Relevance: Radical hysterectomy with pelvic lymphadenectomy has evolved into the standard therapy for nonbulky disease, and there is a clear advantage in the use of minimally invasive techniques to perform these procedures. However, pending ongoing trials, less radical surgery in patients with low-risk invasive disease as well as sentinel lymph node mapping may emerge as standards of care in selected patients with cervical carcinoma.
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http://dx.doi.org/10.1097/OGX.0000000000000089DOI Listing
July 2014

The accuracy of surgeons' provided estimates for the duration of hysterectomies: a pilot study.

J Minim Invasive Gynecol 2015 Jan 11;22(1):57-65. Epub 2014 Jul 11.

Department of Obstetrics and Gynecology, Women and Infants Hospital, Providence, Rhode Island; Reproductive Endocrinology and Infertility, The Warren Alpert Medical School of Brown University, Women and Infants Hospital, Providence, Rhode Island.

Study Objective: To determine the accuracy of gynecologic surgeons' estimate of operative times for hysterectomies and to compare these with the existing computer-generated estimate at our institution.

Design: Pilot prospective cohort study (Canadian Task Force classification II-2).

Setting: Academic tertiary women's hospital in the Northeast United States.

Participants: Thirty gynecologic surgeons including 23 general gynecologists, 4 gynecologic oncologists, and 3 urogynecologists.

Intervention: Via a 6-question survey, surgeons were asked to predict the operative time for a hysterectomy they were about to perform. The surgeons' predictions were then compared with the time predicted by the scheduling system at our institution and with the actual operative time, to determine accuracy and differences between actual and predicted times. Patient and surgery data were collected to perform a secondary analysis to determine factors that may have significantly affected the prediction.

Measurements And Main Results: Of 75 hysterectomies analyzed, 36 were performed abdominally, 18 vaginally, and 21 laparoscopically. Accuracy was established if the actual procedure time was within the 15-minute increment predicted by either the surgeons or the scheduling system. The surgeons accurately predicted the duration of 20 hysterectomies (26.7%), whereas the accuracy of the scheduling system was only 9.3%. The scheduling system accuracy was significantly less precise than the surgeons, primarily due to overestimation (p = .01); operative time was overestimated on average 34 minutes. The scheduling system overestimated the time required to a greater extent than the surgeons for nearly all data examined, including patient body mass index, surgical approach, indication for surgery, surgeon experience, uterine size, and previous abdominal surgery.

Conclusion: Although surgeons' accuracy in predicting operative time was poor, it was significantly better than that of the computerized scheduling system, which was more likely to overestimate operative time.
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http://dx.doi.org/10.1016/j.jmig.2014.07.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4868084PMC
January 2015

The effects of age on treatment and outcomes in women with stages IB1-IIB cervical cancer.

J Geriatr Oncol 2013 Oct 8;4(4):374-81. Epub 2013 Aug 8.

Medical Gynecologic Oncology Service, Massachusetts General Hospital Cancer Center, 55 Fruit Street, Boston, MA 02114, USA. Electronic address:

Objective: Age may affect the treatment choice and subsequent outcome in elderly patients with cervical cancer. Given the potential for cure with either surgery or chemoradiation in early stage disease, we aimed to determine whether a patient's age influenced treatment received and the ensuing outcome.

Materials And Methods: We identified 303 patients with stages IB1-IIB cervical carcinoma treated at our institution between 2000 and 2010, who were divided into two groups based on age at time of diagnosis: < 65 and ≥ 65 years. Adjusted odd ratios were calculated to determine variables associated with treatment received. Single and multivariate Cox proportional hazards modeling were used to estimate hazard ratios (HRs) for variables associated with disease-specific survival.

Results: Patients were more commonly <65 years at diagnosis (83% versus 17% ≥ 65 years). There was no difference between the two groups in terms of tumor histology, stage at presentation, and grade. Women ≥ 65 years of age were less likely to receive primary surgical management (p=0.03). Age did not influence disease-specific or all-cause mortality. However, women over 65 years who underwent primary surgery were at significantly increased risk of all-cause mortality compared to younger women (HR 6.53, 95% CI: 2.57-16.6).

Conclusions: Age appears to influence treatment received by patients with stages IB1-IIB cervical cancer. Although there was no difference in cancer-specific mortality stratified by type of treatment received, surgery was associated with a 6.5-fold increased risk of all-cause mortality among women 65 years or over.
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http://dx.doi.org/10.1016/j.jgo.2013.07.002DOI Listing
October 2013

Necrotizing infection of the breast after core needle biopsy.

Breast J 2013 Mar-Apr;19(2):201-2. Epub 2013 Jan 7.

Department of Obstetrics & Gynecology, Women and Infants' Hospital, The Warren Alpert Medical School of Brown University, Providence, Rhode Island 02905, USA.

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http://dx.doi.org/10.1111/tbj.12088DOI Listing
September 2013