Publications by authors named "Alejandro Contreras"

70 Publications

[Performance of equations to predict cardiovascular risk in an Argentine population].

Medicina (B Aires) 2021 ;81(1):16-23

Instituto Universitario de Ciencias Biomédicas de Córdoba, Hospital Privado Universitario de Córdoba, Argentina.

The performance of available risk scores to predict cardiovascular risk (CVR) in the Argentinian population is unknown. Our aim was to compare the CVR predicted by several equations with the occurrence of cardiovascular events (CVE) in patients without known cardiovascular disease in an Argentinian hospital. Adults between 40 and 70 years were randomly selected, excluding those with prior history of major CVE, active cancer, lipid lowering treatment and absence of follow-up data. Framingham 2008, SCORE (low and high-risk populations), ATP III, World Health Organization- American B region (WHO-B) and Pooled Cohort equations (PC) risk scores were used to calculate 10-y CVR at time of enrollment. End of follow-up was 10 years ± 6 months, occurrence of fatal myocardial infarction or death from any cause. We used ROC curves to assess discrimination (AUC > 0.75 good discrimination), and Hosmer Lemeshow chi-square to evaluate calibration (Chi > 20 or p value < 0.05 poor calibration). We included 606 patients in our study, 336 women, average age 56.7 ± 8.4 year. Of those, 10 (1.7%) non-cardiovascular deaths, and 5 (0.8%) cardiovascular deaths were observed. 58 (9.8%) a non-fatal CVE were recorded. There was acceptable discrimination for Framingham, ATP-III, and both PC equations. The global calibration was only good with the ATP-III and PC equations. The observed frequency of CVE was low, and the CVR was overestimated by all equations. However, applying ATP-III or PC equations to assess CVR could be considered in our population.
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February 2021

[Validation of a high sensitive troponin 99th percentile obtained in a general hospital].

Rev Fac Cien Med Univ Nac Cordoba 2020 12 1;77(4):281-284. Epub 2020 Dec 1.

Servicio de Cardiología, Hospital Privado Universitario de Córdoba. .

Introduction: High sensitivity cardiac Troponin T (hs-cTnT) dosage is recommended for myocardial infarction diagnosis, by applying the 99th percentile obtained from a healthy population by the manufacturer. The objective is to validate the 99th percentile in a population from our hospital (99L), compared with the manufacturer´s 99th percentile (99F) by using coronary angiography as gold standard.

Materials And Methods: Retrospective analysis of every hs-cTnT (Roche) obtained from patients admitted with acute coronary syndromes (ACS) who underwent coronary angiography between 2015 and 2018.

Results: 415 patients were included for analysis (118 females, 64.2 yo). 99F sensitivity (Sn) for significant coronary artery disease (stenosis >70%) was 83.6%, with a specificity (Sp) of 44.5%. Positive predictive value (PPV) and negative predictive value (NPV) were 77% and 55% respectively. 99L Sn was 69.7% and Sp 58.6%. PPV was 79% and NPV 46%. ROC curve was 0.641 for 99F and 0.641 for 99L.

Conclusion: Given the importance of hs-cTnT in ACS diagnosis, the 99F should be the preferred upper reference limit since the sensitivity is better, although lower compared to prior studies.
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http://dx.doi.org/10.31053/1853.0605.v77.n4.27473DOI Listing
December 2020

Culturally and Linguistically Appropriate Hospital Services Reduce Medicare Length of Stay.

Ethn Dis 2020 24;30(4):603-610. Epub 2020 Sep 24.

Department of Health Services Administration, University of Alabama at Birmingham, Birmingham, AL.

Introduction: Almost 40% of the 63 million Americans who speak a language other than English have limited English proficiency (LEP). This communication barrier can result in poor quality care and potentially adverse health outcomes. Of particular interest is that the greatest proportion of LEP adults are aged >65 years and will face barriers and delays in accessing high-quality care. Age cohort variation of LEP burden has not been widely addressed. Culturally and linguistically appropriate hospital care delivery can mitigate these barriers.

Methods: In order to test whether culturally competent services reduced length-of-stay (LOS), we linked organizational cultural competence surveys across two-states (CA+FL) for comparison across Medicare acute care LOS. Using the 2013 American Hospital Association Database, and Hospital Compare Data from CMS (N=184), we compared hospital structure with culturally and linguistically appropriate services related to improved care delivery for LEP populations and aging LEP populations. We utilized Kruskal-Wallis to test group differences and a negative binomial regression to model median LOS. All analyses were conducted using SAS 9.4 (Cary, NC).

Results: Median LOS across all hospitals was 4.7 days (mean 5.7, standard deviation 6.3). Most hospitals were not-for-profit (46.7%), small (<150 beds, 54.4%), Joint Commission accredited (67.9%), and in urban areas. We found shorter median LOS when hospital units identified cultural or language needs at admission (Wald 3.82, P=.0506). Hospitals' identification of these needs at discharge had no impact on LOS. Hospitals that accommodated patient cultural or ethnic dietary needs also reported lower median LOS (Wald 12.93, P=.0003). Structurally, public hospitals, accredited hospitals, and hospitals that reported system membership were predictive of a lower median LOS.

Discussion: Our findings demonstrate that patient outcomes are responsive to culturally and linguistically appropriate services. Further, our findings suggest understanding of culturally competent care in hospitals is lacking. A larger and multi-level sample across the United States could yield a greater understanding of the role of culturally and linguistically appropriate care for a rapidly growing population of diverse older adults.
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http://dx.doi.org/10.18865/ed.30.4.603DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7518542PMC
September 2020

[Effectiveness of transthoracic echocardiogram in patent foramen ovale diagnosis. Systematic review of last ten years.]

Rev Fac Cien Med Univ Nac Cordoba 2019 11 19;76(4):211-216. Epub 2019 Nov 19.

Hospital Privado Universitario de Córdoba..

Background: Transesophageal echo (TEE) bubble study is the current gold standard for patent foramen ovale (PFO) diagnosis, but it has the disadvantage of being semi-invasive and not exempted from risks. The aim of this study was to determine the accuracy of TTE compared to TEE for PFO diagnosis.

Methods And Results: a systematic review was done on Medline with the terms "transthoracic echocardiography, transesophageal echocardiography, patent foramen ovale, diagnosis" yielding published literature of the last ten years. The search was completed in february 2018. Of 715 articles, 10 were analyzed. The total of patients were 1268 (mean age of 47 years +/-14) with a global prevalence of PFO of 48%. The sensibility of ETT was 90 % (IC 95: 88 % - 92 %) and the specificity 92% (IC 95: 89 % - 94 %). The positive predictive value was 93% (IC 95: 90 % - 94 %) and the negative predictive value 89 % (IC 95: 87 % - 91 %). The area under the curve and Q index value were 0,97 and 0,93 respectively. The positive and negative likelihood ratio were 18,989 and 0,072 respectively.

Conclusion: The ETT shows a good specificity and sensibility for PFO diagnosis with last generation equipments, contrast use and valsalva maneuver; according to the analyzed studies.
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http://dx.doi.org/10.31053/1853.0605.v76.n4.23988DOI Listing
November 2019

Targeting the Interplay between Epithelial-to-Mesenchymal-Transition and the Immune System for Effective Immunotherapy.

Cancers (Basel) 2019 May 24;11(5). Epub 2019 May 24.

Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.

Over the last decade, both early diagnosis and targeted therapy have improved the survival rates of many cancer patients. Most recently, immunotherapy has revolutionized the treatment options for cancers such as melanoma. Unfortunately, a significant portion of cancers (including lung and breast cancers) do not respond to immunotherapy, and many of them develop resistance to chemotherapy. Molecular characterization of non-responsive cancers suggest that an embryonic program known as epithelial-mesenchymal transition (EMT), which is mostly latent in adults, can be activated under selective pressures, rendering these cancers resistant to chemo- and immunotherapies. EMT can also drive tumor metastases, which in turn also suppress the cancer-fighting activity of cytotoxic T cells that traffic into the tumor, causing immunotherapy to fail. In this review, we compare and contrast immunotherapy treatment options of non-small cell lung cancer (NSCLC) and triple negative breast cancer (TNBC). We discuss why, despite breakthrough progress in immunotherapy, attaining predictable outcomes in the clinic is mostly an unsolved problem for these tumors. Although these two cancer types appear different based upon their tissues of origin and molecular classification, gene expression indicate that they possess many similarities. Patient tumors exhibit activation of EMT, and resulting stem cell properties in both these cancer types associate with metastasis and resistance to existing cancer therapies. In addition, the EMT transition in both these cancers plays a crucial role in immunosuppression, which exacerbates treatment resistance. To improve cancer-related survival we need to understand and circumvent, the mechanisms through which these tumors become therapy resistant. In this review, we discuss new information and complementary perspectives to inform combination treatment strategies to expand and improve the anti-tumor responses of currently available clinical immune checkpoint inhibitors.
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http://dx.doi.org/10.3390/cancers11050714DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6562947PMC
May 2019

[Advantages of transesophageal three-dimensional echocardiography as a support in the atrial septal defect closure.]

Rev Fac Cien Med Univ Nac Cordoba 2018 09 12;75(3):148-149. Epub 2018 Sep 12.

Hospital Privado Universitario de Córdoba.

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http://dx.doi.org/10.31053/1853.0605.v75.n3.20862DOI Listing
September 2018

Consumer Health Informatics Adoption among Underserved Populations: Thinking beyond the Digital Divide.

Yearb Med Inform 2018 Aug 29;27(1):146-155. Epub 2018 Aug 29.

Institute for Behavioral and Community Health, San Diego State University, CA, USA.

Objectives:  Underserved populations can benefit from consumer health informatics (CHI) that promotes self-management at a lower cost. However, prior literature suggested that the digital divide and low motivation constituted barriers to CHI adoption. Despite increased Internet use, underserved populations continue to show slow CHI uptake. The aim of the paper is to revisit barriers and facilitators that may impact CHI adoption among underserved populations.

Methods:  We surveyed the past five years of literature. We searched PubMed for articles published between 2012 and 2017 that describe empirical evaluations involving CHI use by underserved populations. We abstracted and summarized data about facilitators and barriers impacting CHI adoption.

Results:  From 645 search results, after abstract and full-text screening, 13 publications met the inclusion criteria of identifying barriers to and facilitators of underserved populations' CHI adoption. Contrary to earlier literature, the studies suggested that the motivation to improve health literacy and adopt technology was high among studied populations. Beyond the digital divide, barriers included: low health and computer literacy, challenges in accepting the presented information, poor usability, and unclear content. Factors associated with increased use were: user needs for information, user-access mediated by a proxy person, and early user engagement in system design.

Conclusions:  While the digital divide remains a barrier, newer studies show that high motivation for CHI use exists. However, simply gaining access to technology is not sufficient to improve adoption unless CHI technology is tailored to address user needs. Future interventions should consider building larger empirical evidence on identifying CHI barriers and facilitators.
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http://dx.doi.org/10.1055/s-0038-1641217DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6115231PMC
August 2018

Dysplastic Lipoma: A Distinctive Atypical Lipomatous Neoplasm With Anisocytosis, Focal Nuclear Atypia, p53 Overexpression, and a Lack of MDM2 Gene Amplification by FISH; A Report of 66 Cases Demonstrating Occasional Multifocality and a Rare Association With Retinoblastoma.

Am J Surg Pathol 2018 11;42(11):1530-1540

The Joint Pathology Center, Silver Spring, MD.

In our routine and consultative pathology practices, we have repeatedly encountered an unusual subcutaneous fatty tumor with notable anisocytosis, single-cell fat necrosis, and patchy, often mild, adipocytic nuclear atypia. Because of the focal atypia, consultative cases have most often been received with concern for a diagnosis of atypical lipomatous tumor. Similar tumors have been described in small series under the designations "subcutaneous minimally atypical lipomatous tumors" and "anisometric cell lipoma." Sixty-six cases of this tumor type were collected and reviewed. Immunohistochemistry for p53, MDM2, CDK4, Retinoblastoma 1 (RB1) protein, CD34, S100, and CD163 was performed. Cases were tested for MDM2 gene amplification and RB1 gene deletion with fluorescence in situ hybridization (FISH) and for TP53 mutations by Sanger sequencing. Next-generation sequencing analysis using a panel of 271 cancer-related genes, including TP53, RB1, and MDM2, was also carried out. Our patient cohort included 57 male patients, 8 female patients, and 1 patient of unstated sex, who ranged in age from 22 to 87 years (mean: 51.2 y). All tumors were subcutaneous, with most examples occurring on the upper back, shoulders, or posterior neck (86.4%). Ten patients had multiple (2 to 5) lipomatous tumors, and the histology was confirmed to be similar in the different sites in 4 of them, including 1 patient who had a retinoblastoma diagnosed at age 1. The tumors were generally well circumscribed. At low magnification, there was notable adipocytic size variation with single-cell fat necrosis in the background associated with reactive histiocytes. Adipocytic nuclear atypia was typically patchy and characterized by chromatin coarsening, nuclear enlargement, and focal binucleation or multinucleation. Focal Lochkern change was frequent. In most instances, the degree of atypia was judged to be mild, but in 3 instances, it was more pronounced. Spindle cells were sparse or absent, and when present, cytologically bland. Thick ropy collagen bundles were absent. In all cases, p53 immunoexpression was noted (range: 2% to 20% of adipocytic nuclei), characteristically highlighting the most atypical cells. Twenty of 50 cases had MDM2 immunoreactivity, usually in <1% of the neoplastic cells, but in 4 cases, up to 10% of the cells were positive. Of 32 cases tested, 22 showed a near total loss of RB1 immunoexpression, and the remainder showed partial loss. Three of 13 cases showed RB1 gene deletion in >45% of the cells by FISH (our threshold value for reporting a positive result) with an additional 3 cases being very close to the required cutoff value. MDM2 gene amplification was absent in all 60 cases tested, including those with the greatest MDM2 immunoexpression and most pronounced atypia. All 5 tested cases showed no TP53 mutation with Sanger sequencing. Because of material quality issues, next-generation sequencing analysis could be performed in only 3 cases, and this did not reveal any recurrent mutations. All tumors were managed by simple local excision. Follow-up was available for 47 patients (range: 1 to 192 mo; mean: 27 mo) and revealed 2 local recurrences and no metastases. Dysplastic lipoma is a distinctive atypical fatty tumor variant that has p53 overexpression and RB1 gene abnormalities and lacks MDM2 gene amplification by FISH. These tumors have a strong male predominance and a notable tendency to involve the subcutaneous tissue of the shoulders, upper back and posterior neck. Multifocality is frequent (18.9% of patients with follow-up information), and there is a rare association with retinoblastoma. This tumor warrants separation from ordinary lipoma with fat necrosis, fat-rich spindle cell lipoma and the conventional form of atypical lipomatous tumor that features MDM2 gene amplification.
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http://dx.doi.org/10.1097/PAS.0000000000001129DOI Listing
November 2018

Fifteen-Year Journey to High Reliability in Pathology and Laboratory Medicine.

Am J Med Qual 2018 Sep/Oct;33(5):530-539. Epub 2018 Mar 7.

1 UT MD Anderson Cancer Center, Houston, TX.

Many high-reliability organizations in industries outside of health care have sustained high levels of excellence and prevention of harm while managing complex systems and risk. To date, no health care organizations has organized its efforts to achieve highly reliable results despite several decades of improvement science. Laboratorians were early adopters of quality initiatives and process improvements. In the late 1990s, the Division of Pathology and Laboratory Medicine at The University of Texas MD Anderson Cancer Center embarked on a major effort to improve quality and patient safety and to reduce waste. This article describes the institution's journey toward approaching high reliability with the intent to share not only the tools and best practices, but also the ongoing reassessment of the problems detected on the journey. The authors hope that their experience will help the reader develop interventions to adapt in their own environment to facilitate more optimal patient care.
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http://dx.doi.org/10.1177/1062860618759198DOI Listing
October 2019

Low PTEN levels and PIK3CA mutations predict resistance to neoadjuvant lapatinib and trastuzumab without chemotherapy in patients with HER2 over-expressing breast cancer.

Breast Cancer Res Treat 2018 02 7;167(3):731-740. Epub 2017 Nov 7.

Dan L. Duncan Comprehensive Cancer Center at Baylor College of Medicine and Baylor St. Luke's Medical Center, BCM 600, One Baylor Plaza, Houston, TX, 77030, USA.

Purpose: Aberrant activation of the PI3K pathway has been implicated in resistance to HER2-targeted therapy, but results of clinical trials are confounded by the co-administration of chemotherapy. We investigated the effect of perturbations of this pathway in breast cancers from patients treated with neoadjuvant anti-HER2-targeted therapy without chemotherapy.

Patients And Methods: Baseline tumor samples from patients with HER2-positive breast cancer enrolled in TBCRC006 (NCT00548184), a 12-week neoadjuvant clinical trial with lapatinib plus trastuzumab [plus endocrine therapy for estrogen receptor (ER)-positive tumors], were assessed for PTEN status by immunohistochemistry and PIK3CA mutations by sequencing. Results were correlated with pathologic complete response (pCR).

Results: Of 64 evaluable patients, PTEN immunohistochemistry and PIK3CA mutation analysis were performed for 59 and 46 patients, respectively. PTEN status (dichotomized by H-score median) was correlated with pCR (32% in high PTEN vs. 9% in low PTEN, p = 0.04). PIK3CA mutations were identified in 14/46 tumors at baseline (30%) and did not correlate with ER or PTEN status. One patient whose tumor harbored a PIK3CA mutation achieved pCR (p = 0.14). When considered together (43 cases), 1/25 cases (4%) with a PIK3CA mutation and/or low PTEN expression levels had a pCR compared to 7/18 cases (39%) with wild-type PI3KCA and high PTEN expression levels (p = 0.006).

Conclusion: PI3K pathway activation is associated with resistance to lapatinib and trastuzumab in breast cancers, without chemotherapy. Further studies are warranted to investigate how to use these biomarkers to identify upfront patients who may respond to anti-HER2 alone, without chemotherapy.
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http://dx.doi.org/10.1007/s10549-017-4533-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5821069PMC
February 2018

Use of a Technetium99m-Sestamibi Scan to Detect Ipsilateral Double Adenoma in a Patient with Primary Hyperparathyroidism: A Case Report.

Perm J 2017 ;21:16-185

Associate Director of Trauma Services at Memorial Regional Hospital in Hollywood, FL.

Introduction: Patients with primary hyperparathyroidism generally have a single parathyroid adenoma that causes excessive excretion of parathyroid hormone. For about 2% to 15% of these patients, a double adenoma is present that involves one lesion on each side of the neck.

Case Presentation: We describe a case of double parathyroid adenoma causing asymptomatic hypercalcemia. A presurgical technetium99m (Tc99m) sestamibi scan suggested an ipsilateral double adenoma in the left thyroid lobe. An intraoperative parathyroid hormone assay confirmed its successful removal.

Discussion: Although double adenomas are not yet widely acknowledged, presurgical imaging and nuclear scans can help to localize multiple lesions, and intraoperative parathyroid hormone assays can confirm the diagnosis and cure.
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http://dx.doi.org/10.7812/TPP/16-185DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5528857PMC
April 2018

Perioperative management of vitamin K antagonists in patients with low thromboembolic risk undergoing elective surgery: A prospective experience.

Med Clin (Barc) 2017 Oct 7;149(7):281-286. Epub 2017 Mar 7.

Instituto Universitario de Ciencias Biomédicas de Córdoba, Córdoba, Argentina; Servicio de Medicina Vascular y Trombosis, Hospital Privado Universitario de Córdoba, Córdoba, Argentina.

Background And Objectives: To quantify thromboembolic and bleeding events in patients with low thromboembolic risk, who were chronically receiving vitamin K antagonists and undergoing elective surgery.

Material And Methods: A descriptive, prospective, single-center study was conducted between December 2010 and July 2014. Patients aged over 18 years old, chronically anticoagulated with vitamin K antagonists and admitted for elective surgery were included in the study. We excluded patients with a creatinine clearance<30ml/min, a body weight>120kg, heparin-induced thrombocytopenia, pregnant women, carriers of an epidural catheter for analgesia, patients who underwent unscheduled surgery and high thromboembolic risk-patients. Vitamin K antagonists were discontinued 5 days prior to the procedure without administering anticoagulant enoxaparin. The NIR was measured 24h before the procedure. A single dose of 3mg of vitamin K was administered in cases of a NIR>1.5. Vitamin K antagonists was resumed according to the surgical bleeding risk. Events were registered between 5 days prior to the procedure until 30 days after it.

Results: A total of 75 procedures were included in the study. Fifty-six patients (74.7%) received vitamin K antagonists for atrial fibrillation, 15 suffered from venous thromboembolism (20%) and 4 had mechanical heart valves (5.3%). Twenty-six patients (34.5%) underwent high-bleeding risk surgeries and 49 (65.5%) underwent low risk procedures. No thromboembolic event was recorded. Four bleeding events (5.3%) were reported, 3 of which were considered major bleeding events (2 fatal).

Conclusions: Suspending vitamin K antagonists with no bridging therapy performed in patients with a low thromboembolic risk does not expose such patients to a significant risk of embolic events.
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http://dx.doi.org/10.1016/j.medcli.2017.01.023DOI Listing
October 2017

Percutaneous Transhepatic Fontan-Kreutzer Completion of Hepatic Vein Inclusion.

World J Pediatr Congenit Heart Surg 2018 11 5;9(6):710-713. Epub 2017 Jan 5.

1 Division of Congenital Heart Surgery, Hospital Privado Universitario de Córdoba, Córdoba, Argentina.

We report the case of an 11-year-old girl with heterotaxy syndrome, dextrocardia, and azygos continuation of an interrupted inferior vena cava who had developed pulmonary arteriovenous fistulas after a Kawashima procedure consisting of bilateral superior cavopulmonary anastomoses. She presented with profound cyanosis, fatigue, and failure to thrive. An operative procedure to direct hepatic vein effluent to the pulmonary circulation was performed with placement of an extracardiac conduit between the hepatic veins and the left pulmonary artery. Persistence of cyanosis led to investigation, which led to the discovery of an unintentionally excluded right hepatic vein. A percutaneous transhepatic catheter intervention was performed in which a vascular plug was implanted to occlude the "missed" right hepatic vein, redirecting the flow through intrahepatic venovenous channels to the conduit. Clinical condition and arterial oxygen saturation were substantially improved one year after the two-step hepatic vein inclusion procedure.
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http://dx.doi.org/10.1177/2150135116682455DOI Listing
November 2018

Multivessel spontaneous coronary artery dissection in a puerperal young woman.

Arch Cardiol Mex 2017 Jan - Mar;87(1):96-99. Epub 2016 Dec 16.

Gynecology Unit, Sanatario Alberdi, Santiago del Estero, Santiago del Estero, Argentina.

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http://dx.doi.org/10.1016/j.acmx.2016.11.008DOI Listing
April 2017

Transection of Radioactive Seeds in Breast Specimens.

Am J Surg Pathol 2016 10;40(10):1375-9

Departments of *Pathology †Breast Imaging ‡Breast Surgery §Environment Health and Safety, The University of Texas MD Anderson Cancer Center, Houston, TX.

Radioactive seed localization is a new procedure for localizing breast lesions that has several advantages over the standard wire-localization procedure. It is reported to be safe for both patients and medical personnel. Although it is theoretically possible to transect the titanium-encapsulated seed while processing the breast specimen in the pathology laboratory, the likelihood of such an event is thought to be exceedingly low. In fact, there are no previous reports of such an event in the literature to date. We recently encountered 2 cases in which a radioactive seed was inadvertently transected while slicing a breast specimen at the grossing bench. In this report, we describe each case and offer recommendations for minimizing radioactive exposure to personnel and for preventing radioactive contamination of laboratory equipment.
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http://dx.doi.org/10.1097/PAS.0000000000000682DOI Listing
October 2016

A Rare Cause of Pediatric Stroke.

World J Pediatr Congenit Heart Surg 2017 Mar 20;8(2):220-223. Epub 2016 Sep 20.

5 Division of Diagnostic and Interventional Neuroradiology, Hospital Privado Universitario de Córdoba, Córdoba, Argentina.

We describe a case of sudden-onset left-sided hemiparesis and dysarthria in a five-year-old boy. Acute vascular malformation bleeding or ischemic stroke was suspected. Neurological examination three weeks after the initial event revealed mild residual facial paresis. Brain angiography ruled out a vascular malformation. A work-up echocardiogram revealed a 4-cm left atrial mass compatible with cardiac myxoma. Urgent surgical resection of the mass under cardiopulmonary bypass confirmed the diagnosis. Uneventful recovery followed surgical resection. In this report, we present a partially embolized left atrial myxoma that caused an acute ischemic stroke, which is rarely considered and encountered in the pediatric population.
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http://dx.doi.org/10.1177/2150135116659646DOI Listing
March 2017

[Prevalence of risk factors of erosion in patients with percutaneous closure of atrial septal defects].

Arch Cardiol Mex 2017 Jul - Sep;87(3):251-253. Epub 2016 Jun 22.

Servicio de Hemodinamia, Hospital Privado Universitario de Córdoba, Instituto Universitario de Ciencias Biomédicas de Córdoba, Córdoba, Argentina.

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http://dx.doi.org/10.1016/j.acmx.2016.05.006DOI Listing
June 2016

[Transient complete atrioventricular block during percutaneous atrial septal defect closure].

Arch Cardiol Mex 2017 Jul - Sep;87(3):253-255. Epub 2016 Jun 22.

Servicio de Hemodinamia, Hospital Privado Universitario de Córdoba, Instituto de Ciencias Biomédicas de Córdoba, Córdoba, Argentina.

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http://dx.doi.org/10.1016/j.acmx.2016.05.005DOI Listing
June 2016

Upregulation of ER Signaling as an Adaptive Mechanism of Cell Survival in HER2-Positive Breast Tumors Treated with Anti-HER2 Therapy.

Clin Cancer Res 2015 Sep 26;21(17):3995-4003. Epub 2015 May 26.

Lester and Sue Smith Breast Center, Baylor College of Medicine, Houston, Texas. Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, Texas. Department of Medicine, Baylor College of Medicine, Houston, Texas.

Purpose: To investigate the direct effect and therapeutic consequences of epidermal growth factor receptor 2 (HER2)-targeting therapy on expression of estrogen receptor (ER) and Bcl2 in preclinical models and clinical tumor samples.

Experimental Design: Archived xenograft tumors from two preclinical models (UACC812 and MCF7/HER2-18) treated with ER and HER2-targeting therapies and also HER2+ clinical breast cancer specimens collected in a lapatinib neoadjuvant trial (baseline and week 2 posttreatment) were used. Expression levels of ER and Bcl2 were evaluated by immunohistochemistry and Western blot analysis. The effects of Bcl2 and ER inhibition, by ABT-737 and fulvestrant, respectively, were tested in parental versus lapatinib-resistant UACC812 cells in vitro.

Results: Expression of ER and Bcl2 was significantly increased in xenograft tumors with acquired resistance to anti-HER2 therapy compared with untreated tumors in both preclinical models (UACC812: ER P = 0.0014; Bcl2 P < 0.001 and MCF7/HER2-18: ER P = 0.0007; Bcl2 P = 0.0306). In the neoadjuvant clinical study, lapatinib treatment for 2 weeks was associated with parallel upregulation of ER and Bcl2 (Spearman coefficient: 0.70; P = 0.0002). Importantly, 18% of tumors originally ER-negative (ER(-)) converted to ER(+) upon anti-HER2 therapy. In ER(-)/HER2(+) MCF7/HER2-18 xenografts, ER reexpression was primarily observed in tumors responding to potent combination of anti-HER2 drugs. Estrogen deprivation added to this anti-HER2 regimen significantly delayed tumor progression (P = 0.018). In the UACC812 cells, fulvestrant, but not ABT-737, was able to completely inhibit anti-HER2-resistant growth (P < 0.0001).

Conclusions: HER2 inhibition can enhance or restore ER expression with parallel Bcl2 upregulation, representing an ER-dependent survival mechanism potentially leading to anti-HER2 resistance.
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http://dx.doi.org/10.1158/1078-0432.CCR-14-2728DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4558260PMC
September 2015

Int6 reduction activates stromal fibroblasts to enhance transforming activity in breast epithelial cells.

Cell Biosci 2015 8;5:10. Epub 2015 Mar 8.

Department of Molecular and Cellular Biology and Lester and Sue Smith Breast Center, Baylor College of Medicine, Houston, 77030 TX USA.

Background: The INT6 gene was first discovered as a site of integration in mouse mammary tumors by the mouse mammary tumor virus; however, INT6's role in the development of human breast cancer remains largely unknown. By gene silencing, we have previously shown that repressing INT6 promotes transforming activity in untransformed human mammary epithelial cells. In the present study, guided by microarray data of human tumors, we have discovered a role of Int6 in stromal fibroblasts.

Results: We searched microarray databases of human tumors to assess Int6's role in breast cancer. While INT6 expression levels, as expected, were lower in breast tumors than in adjacent normal breast tissue samples, INT6 expression levels were also substantially lower in tumor stroma. By immunohistochemistry, we determined that the low levels of INT6 mRNA observed in the microarray databases most likely occurs in stromal fibroblasts, because far fewer fibroblasts in the tumor tissue showed detectable levels of the Int6 protein. To directly investigate the effects of Int6 repression on fibroblasts, we silenced INT6 expression in immortalized human mammary fibroblasts (HMFs). When these INT6-repressed HMFs were co-cultured with breast cancer cells, the abilities of the latter to form colonies in soft agar and to invade were enhanced. We analyzed INT6-repressed HMFs and found an increase in the levels of a key carcinoma-associated fibroblast (CAF) marker, smooth muscle actin. Furthermore, like CAFs, these INT6-repressed HMFs secreted more stromal cell-derived factor 1 (SDF-1), and the addition of an SDF-1 antagonist attenuated the INT6-repressed HMFs' ability to enhance soft agar colony formation when co-cultured with cancer cells. These INT6-repressed HMFs also expressed high levels of mesenchymal markers such as vimentin and N-cadherin. Intriguingly, when mesenchymal stem cells (MSCs) were induced to form CAFs, Int6 levels were reduced.

Conclusion: These data suggest that besides enhancing transforming activity in epithelial cells, INT6 repression can also induce fibroblasts, and possibly MSCs as well, via mesenchymal-mesenchymal transitions to promote the formation of CAFs, leading to a proinvasive microenvironment for tumorigenesis.
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http://dx.doi.org/10.1186/s13578-015-0001-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4359526PMC
March 2015

Breast adenocarcinoma recurring as small cell carcinoma in a patient with a germline BRCA2 mutation: clonal evolution unchecked.

Exp Hematol Oncol 2015 6;4(1). Epub 2015 Jan 6.

Lester & Sue Smith Breast Center, Baylor College of Medicine, One Baylor Plaza, BCM 660, Houston, Texas 77030 USA.

Background: Because up to 30% of breast cancer cases may relapse, understanding the biology of recurrent breast cancer is imperative in preventing these poor outcomes. Thus, we present this unusual case of a BRCA2 carrier who presented seven years after her initial diagnosis of breast adenocarcinoma with a new lump in the left axillary tail, which proved to be small cell carcinoma. The second cancer bore no morphologic or immunohistochemical resemblance to the first. However, we aimed to understand whether the two cancers could have been related.

Methods: We performed targeted Next Generation Sequencing on both cancer specimens in order to determine whether there was a genomic relationship between the two cancers.

Results: We found that the initial breast adenocarcinoma was positive for a heterozygous mutation in PIK3CA (c. 1624 G > A, p.E42K) and a heterozygous 13-basepair deletion in TP53 (c.639-651del, p.H214fs). The small cell cancer was positive for the same mutation in PIK3CA, but negative for the mutation in TP53.

Conclusion: We concluded that the small cell cancer may have arisen from a clone within the initial cancer, since they carried an identical genetic mutation. Furthermore, we postulate that the unusual morphology of the second cancer may be due, in part, to the patient's germline BRCA mutation.
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http://dx.doi.org/10.1186/2162-3619-4-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4323278PMC
February 2015

Circulating and disseminated tumor cells from breast cancer patient-derived xenograft-bearing mice as a novel model to study metastasis.

Breast Cancer Res 2015 Jan 9;17. Epub 2015 Jan 9.

Lester and Sue Smith Breast Center, Baylor College of Medicine, Houston, TX, USA.

Introduction: Real-time monitoring of biologic changes in tumors may be possible by investigating the transitional cells such as circulating tumor cells (CTCs) and disseminated tumor cells in bone marrow (BM-DTCs). However, the small numbers of CTCs and the limited access to bone marrow aspirates in cancer patients pose major hurdles. The goal of this study was to determine whether breast cancer (BC) patient-derived xenograft (PDX) mice could provide a constant and renewable source of CTCs and BM-DTCs, thereby representing a unique system for the study of metastatic processes.

Methods: CTCs and BM-DTCs, isolated from BC PDX-bearing mice, were identified by immunostaining for human pan-cytokeratin and nuclear counterstaining of red blood cell-lysed blood and bone marrow fractions, respectively. The rate of lung metastases (LM) was previously reported in these lines. Associations between the presence of CTCs, BM-DTCs, and LM were assessed by the Fisher's Exact and Cochran-Mantel-Haenszel tests. Two separate genetic signatures associated with the presence of CTC clusters and with lung metastatic potential were computed by using the expression arrays of primary tumors from different PDX lines and subsequently overlapped to identify common genes.

Results: In total, 18 BC PDX lines were evaluated. CTCs and BM-DTCs, present as either single cells or clusters, were detected in 83% (15 of 18) and 62.5% (10 to16) of the lines, respectively. A positive association was noted between the presence of CTCs and BM-DTCs within the same mice. LM was previously found in 9 of 18 (50%) lines, of which all nine had detectable CTCs. The presence of LM was strongly associated with the detection of CTC clusters but not with individual cells or detection of BM-DTCs. Overlapping of the two genetic signatures of the primary PDX tumors associated with the presence of CTC clusters and with lung metastatic potential identified four genes (HLA-DP1A, GJA1, PEG3, and XIST). This four-gene profile predicted distant metastases-free survival in publicly available datasets of early BC patients.

Conclusion: This study suggests that CTCs and BM-DTCs detected in BC PDX-bearing mice may represent a valuable and unique preclinical model for investigating the role of these rare cells in tumor metastases.
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http://dx.doi.org/10.1186/s13058-014-0508-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4318479PMC
January 2015

[Perioperative control of vitamin K antagonists in elective surgery].

Medicina (B Aires) 2014 ;74(5):385-90

Servicio de Clínica Médica, Hospital Privado Centro Médico de Córdoba, Argentina. E-mail:

Anti-coagulated patients who undergo elective surgery require temporary interruption of vitamin K antagonists. The aim of this study was to evaluate the incidence of thromboembolic events and bleeding complications in anti-coagulated patients undergoing elective invasive procedures by using an institutional management protocol. This was a descriptive study with prospective follow-up that included patients over 18 year old anti-coagulated with vitamin K antagonists, undergoing elective surgery. Those with atrial fibrillation (AF) at moderate and high risk of thromboembolic events, with mechanical heart valve (MCV) at moderate and high risk of thromboembolic events, and patients' venous thromboembolism (VTE) at high risk of thromboembolic events received bridging therapy with enoxaparin. Embolic and bleeding events in the pre-operative period were recorded. Seventy-eight received bridging, mean age 69.4 ± 11.9 years. Twenty-eight had AF (36.4 %), 12 had VTE (15.6 %) and 37 had MCV (48.1 %). Postoperatively, 1 embolic event (1.6 %) and 12 bleeding events (15.4 %) were documented, of which 10 were minor (12.8 %) and 2 major (2.6 %). The safety of bridging therapy is still under debate, and we should await the result of randomized studies comparing different strategies of bridging vs. interruption of anticoagulant therapy in the pre-operative period prior to reaching a definitive conclusion.
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August 2015

Overcoming endocrine resistance due to reduced PTEN levels in estrogen receptor-positive breast cancer by co-targeting mammalian target of rapamycin, protein kinase B, or mitogen-activated protein kinase kinase.

Breast Cancer Res 2014 Sep 11;16(5):430. Epub 2014 Sep 11.

Introduction: Activation of the phosphatidylinositol 3-kinase (PI3K) pathway in estrogen receptor α (ER)-positive breast cancer is associated with reduced ER expression and activity, luminal B subtype, and poor outcome. Phosphatase and tensin homolog (PTEN), a negative regulator of this pathway, is typically lost in ER-negative breast cancer. We set out to clarify the role of reduced PTEN levels in endocrine resistance, and to explore the combination of newly developed PI3K downstream kinase inhibitors to overcome this resistance.

Methods: Altered cellular signaling, gene expression, and endocrine sensitivity were determined in inducible PTEN-knockdown ER-positive/human epidermal growth factor receptor 2 (HER2)-negative breast cancer cell and/or xenograft models. Single or two-agent combinations of kinase inhibitors were examined to improve endocrine therapy.

Results: Moderate PTEN reduction was sufficient to enhance PI3K signaling, generate a gene signature associated with the luminal B subtype of breast cancer, and cause endocrine resistance in vitro and in vivo. The mammalian target of rapamycin (mTOR), protein kinase B (AKT), or mitogen-activated protein kinase kinase (MEK) inhibitors, alone or in combination, improved endocrine therapy, but the efficacy varied by PTEN levels, type of endocrine therapy, and the specific inhibitor(s). A single-agent AKT inhibitor combined with fulvestrant conferred superior efficacy in overcoming resistance, inducing apoptosis and tumor regression.

Conclusions: Moderate reduction in PTEN, without complete loss, can activate the PI3K pathway to cause endocrine resistance in ER-positive breast cancer, which can be overcome by combining endocrine therapy with inhibitors of the PI3K pathway. Our data suggests that the ER degrader fulvestrant, to block both ligand-dependent and -independent ER signaling, combined with an AKT inhibitor is an effective strategy to test in patients.
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http://dx.doi.org/10.1186/s13058-014-0430-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4303114PMC
September 2014

Comprehensive genomic analysis identifies novel subtypes and targets of triple-negative breast cancer.

Clin Cancer Res 2015 Apr 10;21(7):1688-98. Epub 2014 Sep 10.

Department of Clinical Cancer Prevention, MD Anderson Cancer Center, Houston, Texas.

Purpose: Genomic profiling studies suggest that triple-negative breast cancer (TNBC) is a heterogeneous disease. In this study, we sought to define TNBC subtypes and identify subtype-specific markers and targets.

Experimental Design: RNA and DNA profiling analyses were conducted on 198 TNBC tumors [estrogen receptor (ER) negativity defined as Allred scale value ≤ 2] with >50% cellularity (discovery set: n = 84; validation set: n = 114) collected at Baylor College of Medicine (Houston, TX). An external dataset of seven publically accessible TNBC studies was used to confirm results. DNA copy number, disease-free survival (DFS), and disease-specific survival (DSS) were analyzed independently using these datasets.

Results: We identified and confirmed four distinct TNBC subtypes: (i) luminal androgen receptor (AR; LAR), (ii) mesenchymal (MES), (iii) basal-like immunosuppressed (BLIS), and (iv) basal-like immune-activated (BLIA). Of these, prognosis is worst for BLIS tumors and best for BLIA tumors for both DFS (log-rank test: P = 0.042 and 0.041, respectively) and DSS (log-rank test: P = 0.039 and 0.029, respectively). DNA copy number analysis produced two major groups (LAR and MES/BLIS/BLIA) and suggested that gene amplification drives gene expression in some cases [FGFR2 (BLIS)]. Putative subtype-specific targets were identified: (i) LAR: androgen receptor and the cell surface mucin MUC1, (ii) MES: growth factor receptors [platelet-derived growth factor (PDGF) receptor A; c-Kit], (iii) BLIS: an immunosuppressing molecule (VTCN1), and (iv) BLIA: Stat signal transduction molecules and cytokines.

Conclusion: There are four stable TNBC subtypes characterized by the expression of distinct molecular profiles that have distinct prognoses. These studies identify novel subtype-specific targets that can be targeted in the future for the effective treatment of TNBCs.
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http://dx.doi.org/10.1158/1078-0432.CCR-14-0432DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4362882PMC
April 2015

[Treatment of pulmonary vein stenosis secondary to radiofrequency ablation].

Medicina (B Aires) 2014 ;74(4):303-6

Servicio de Hemodinamia, Hospital Privado de Córdoba, Córdoba, Argentina. E-mail:

Isolation of the pulmonary veins by applying radiofrequency is an effective treatment for atrial fibrillation. One of the potential complications with higher clinical compromise utilizing this invasive technique is the occurrence of stenosis of one or more pulmonary veins. This complication can be treated by angioplasty with or without stent implantation, with an adequate clinical improvement, but with a high rate of restenosis.
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July 2015

Recurrent ESR1-CCDC170 rearrangements in an aggressive subset of oestrogen receptor-positive breast cancers.

Nat Commun 2014 Aug 7;5:4577. Epub 2014 Aug 7.

1] Lester &Sue Smith Breast Center, Baylor College of Medicine, Houston, Texas 77030, USA [2] Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, Texas 77030, USA [3] Department of Medicine, Baylor College of Medicine, Houston, Texas 77030, USA [4] Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas 77030, USA.

Characterizing the genetic alterations leading to the more aggressive forms of oestrogen receptor-positive (ER+) breast cancers is of critical significance in breast cancer management. Here we identify recurrent rearrangements between the oestrogen receptor gene ESR1 and its neighbour CCDC170, which are enriched in the more aggressive and endocrine-resistant luminal B tumours, through large-scale analyses of breast cancer transcriptome and copy number alterations. Further screening of 200 ER+ breast cancers identifies eight ESR1-CCDC170-positive tumours. These fusions encode amino-terminally truncated CCDC170 proteins (ΔCCDC170). When introduced into ER+ breast cancer cells, ΔCCDC170 leads to markedly increased cell motility and anchorage-independent growth, reduced endocrine sensitivity and enhanced xenograft tumour formation. Mechanistic studies suggest that ΔCCDC170 engages Gab1 signalosome to potentiate growth factor signalling and enhance cell motility. Together, this study identifies neoplastic ESR1-CCDC170 fusions in a more aggressive subset of ER+ breast cancer, which suggests a new concept of ER pathobiology in breast cancer.
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http://dx.doi.org/10.1038/ncomms5577DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4130357PMC
August 2014

Heterochromatin protein 1 expression is reduced in human thyroid malignancy.

Lab Invest 2014 Jul 19;94(7):788-95. Epub 2014 May 19.

Institute of Fundamental Sciences, Massey University, Palmerston North, New Zealand.

Owing to the loss of heterochromatin integrity that occurs during thyroid tumorigenesis, the expression of Heterochromatin Protein 1 isoforms HP1α and HP1β was assessed by immunohistochemistry in 189 thyroid tumors and non-neoplastic tissues. Expression of HP1β was significantly decreased in all thyroid lesions, except in follicular adenomas, when compared with matched adjacent normal tissue. This loss of HP1β expression may in part be caused by microRNA dysregulation. An example is miR-205, a microRNA that is abundantly upregulated in thyroid carcinomas and shown to reduce the expression of HP1β. In contrast to HP1β, HP1α expression was only reduced in metastatic carcinomas and poorly differentiated lesions. These results suggest the reduction of HP1β followed by a decrease in HP1α contributes to the pathogenesis of thyroid carcinomas, and their loss is a potential marker of thyroid malignancy and metastatic potential, respectively.
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http://dx.doi.org/10.1038/labinvest.2014.68DOI Listing
July 2014