Publications by authors named "Iara Santana"

14 Publications

  • Page 1 of 1

New insights on familial colorectal cancer type X syndrome.

Sci Rep 2022 02 18;12(1):2846. Epub 2022 Feb 18.

Molecular Oncology Research Center, Barretos Cancer Hospital, Antenor Duarte Villela Street, 1331, Barretos, São Paulo, CEP 14784-400, Brazil.

Familial colorectal cancer type X (FCCTX) is a heterogeneous colorectal cancer predisposition syndrome that, although displays a cancer pattern similar to Lynch syndrome, is mismatch repair proficient and does not exhibit microsatellite instability. Besides, its genetic etiology remains to be elucidated. In this study we performed germline exome sequencing of 39 cancer-affected patients from 34 families at risk for FCCTX. Variant classification followed the American College of Medical Genetics and Genomics (ACMG) guidelines. Pathogenic/likely pathogenic variants were identified in 17.65% of the families. Rare and potentially pathogenic alterations were identified in known hereditary cancer genes (CHEK2), in putative FCCTX candidate genes (OGG1 and FAN1) and in other cancer-related genes such as ATR, ASXL1, PARK2, SLX4 and TREX1. This study provides novel important clues that can contribute to the understanding of FCCTX genetic basis.
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http://dx.doi.org/10.1038/s41598-022-06782-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8857274PMC
February 2022

Single nCounter assay for prediction of MYCN amplification and molecular classification of medulloblastomas: a multicentric study.

J Neurooncol 2022 Mar 15;157(1):27-35. Epub 2022 Feb 15.

Molecular Oncology Research Center Dr. Paulo Prata, Barretos Cancer Hospital, Barretos, Brazil.

Purpose: Medulloblastoma is the most frequent pediatric malignant brain tumor, and is divided into four main subgroups: WNT, SHH, group 3, and group 4. MYCN amplification is an important medulloblastoma prognostic biomarker. We aimed to molecular classify and predict MYCN amplification in a single assay.

Methods: It was included 209 medulloblastomas from 205 patients (Brazil, Argentina, and Portugal), divided into training (n = 50) and validation (n = 159) sets. A nCounter assay was carried out using a custom panel for molecular classification, with additional genes, including MYCN. nSolver 4.0 software and the R environment were used for profiling and MYCN mRNA analysis. MYCN amplification by FISH was performed in 64 cases.

Results: The 205 medulloblastomas were classified in SHH (44.9%), WNT (15.6%), group 3 (18.1%) and group 4 (21.4%). In the training set, MYCN amplification was detected in three SHH medulloblastomas by FISH, which showed significantly higher MYCN mRNA counts than non-FISH amplified cases, and a cutoff for MYCN amplification was established ([Formula: see text] + 4σ = 11,124.3). Applying this threshold value in the validation set, we identified MYCN mRNA counts above the cutoff in three cases, which were FISH validated.

Conclusion: We successfully stratified medulloblastoma molecular subgroups and predicted MYCN amplification using a single nCounter assay without the requirement of additional biological tissue, costs, or bench time.
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http://dx.doi.org/10.1007/s11060-022-03965-1DOI Listing
March 2022

A Unique Case Report of Infant-Type Hemispheric Glioma (Gliosarcoma Subtype) with TPR-NTRK1 Fusion Treated with Larotrectinib.

Pathobiology 2022 14;89(3):178-185. Epub 2022 Jan 14.

Molecular Oncology Research Center, Barretos Cancer Hospital, Barretos, Brazil.

Herein, we present a rare case of a nine-month-old boy diagnosed with infant-type hemispheric glioma (gliosarcoma subtype) at the left frontal lobe. Following subtotal resection, the patient started chemotherapy with the BABY POG protocol. We describe the clinical diagnosis, histological characteristics, radiological features, molecular aspects, and management of this tumor. A comprehensive molecular analysis on the tumor tissue showed a TPR-NTRK1 gene fusion. The patient was treated with a TRK inhibitor, larotrectinib, and exhibited a stable disease with residual lesion following 8 months of target therapy. The present study is the first report of an infantile gliosarcoma harboring NTRK1 rearrangement treated with larotrectinib.
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http://dx.doi.org/10.1159/000521253DOI Listing
May 2022

Microsatellite Instability Is Rare in the Admixed Brazilian Population of Non-Small Cell Lung Cancer: A Cohort of 526 Cases.

Pathobiology 2022 15;89(2):101-106. Epub 2021 Nov 15.

Molecular Oncology Research Center, Barretos Cancer Hospital, Barretos, Brazil.

Background: Microsatellite instability (MSI) in non-small cell lung cancer (NSCLC) is uncommon; however, most studies refer to European and Asian populations. There are currently no data on MSI frequency in highly admixed populations, such as the one represented by Brazilian NSCLC patients.

Aim: This study aimed to evaluate the frequency of MSI in Brazilian NSCLC patients.

Methods: We evaluated 526 patients diagnosed with NSCLC at the Barretos Cancer Hospital (Brazil). The molecular MSI evaluation was performed using a hexa-plex marker panel by polymerase chain reaction followed by fragment analysis. The mutation profile of MSI-positive cases was performed using next-generation sequencing.

Results: Only 1 patient was MSI positive (0.19%). This patient was a female, white, and active smoker, and she was diagnosed with clinical stage IV lung adenocarcinoma at 75 years old. The molecular profile exhibited 4 Tumor Protein p53 (TP53) mutations and the absence of actionable mutations in the Epidermal Growth Factor Receptor (EGFR), Kirsten Rat Sarcoma Viral Oncogene Homolog (KRAS), or V-Raf Murine Sarcoma Viral Oncogene Homolog B1 (BRAF) genes.

Conclusions: The frequency of MSI in Brazilian NSCLC patients is equally rare, a finding that is consistent with the current literature based on other populations such as Europeans, North Americans, and Asians.
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http://dx.doi.org/10.1159/000520023DOI Listing
March 2022

Reproduction of the Cancer Genome Atlas (TCGA) and Asian Cancer Research Group (ACRG) Gastric Cancer Molecular Classifications and Their Association with Clinicopathological Characteristics and Overall Survival in Moroccan Patients.

Dis Markers 2021 28;2021:9980410. Epub 2021 Jul 28.

Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, Braga, Portugal.

Introduction: The Cancer Genome Atlas (TCGA) project and Asian Cancer Research Group (ACRG) recently categorized gastric cancer into molecular subtypes. Nevertheless, these classification systems require high cost and sophisticated molecular technologies, preventing their widespread use in the clinic. This study is aimed to generating molecular subtypes of gastric cancer using techniques available in routine diagnostic practice in a series of Moroccan gastric cancer patients. In addition, we assessed the associations between molecular subtypes, clinicopathological features, and prognosis.

Methods: Ninety-seven gastric cancer cases were classified according to TCGA, ACRG, and integrated classifications using a panel of four molecular markers (EBV, MSI, E-cadherin, and p53). HER2 status and PD-L1 expression were also evaluated. These markers were analyzed using immunohistochemistry (E-cadherin, p53, HER2, and PD-L1), in situ hybridization (EBV and HER2 equivocal cases), and multiplex PCR (MSI).

Results: Our results showed that the subtypes presented distinct clinicopathological features and prognosis. EBV-positive gastric cancers were found exclusively in male patients. The GS (TCGA classification), MSS/EMT (ACRG classification), and E-cadherin aberrant subtype (integrated classification) presented the Lauren diffuse histology enrichment and tended to be diagnosed at a younger age. The MSI subtype was associated with a better overall survival across all classifications (TCGA, ACRG, and integrated classification). The worst prognosis was observed in the EBV subtype (TCGA and integrated classification) and MSS/EMT subtype (ACRG classification). . We reported a reproducible and affordable gastric cancer subtyping algorithms that can reproduce the recently recognized TCGA, ACRG, and integrated gastric cancer classifications, using techniques available in routine diagnosis. These simplified classifications can be employed not only for molecular classification but also in predicting the prognosis of gastric cancer patients.
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http://dx.doi.org/10.1155/2021/9980410DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8342151PMC
January 2022

Correlation of p16 immunohistochemistry with clinical and epidemiological features in oropharyngeal squamous-cell carcinoma.

PLoS One 2021 17;16(6):e0253418. Epub 2021 Jun 17.

Department of Head and Neck Surgery, Barretos Cancer Hospital, Barretos, São Paulo, Brazil.

Background: Oropharyngeal cancer is an important public health problem. The aim of our study was to correlatep16 immunohistochemistry in oropharynx squamous cell carcinomas(OPSCC) with clinical and epidemiological features.

Material And Methods: We conducted across-sectional study on patients with OPSCC treated at a single institution from 2014 to 2019. Epidemiological and clinical-pathological data were collected from medical records and a questionnaire was applied to determine alcohol consumption, smoking, and sexual behavior. The HPV status was determined by p16 immunohistochemistry.

Results: A total of 252 patients participated in the study, of these 221 (87.7%) were male. There were 81 (32.14%) p16 positive cases and 171 (67.85%) p16 negative cases. The p16positive group was significantly associated with younger patients (50-59 years), higher education level, lower clinical stage and patients who never drank or smoked. Through univariate logistic regression, we observed that female sex (OR, 3.47; 95% CI, 1.60-7.51) and higher education level (OR, 9.39; 95% CI, 2, 81-31,38) were significantly more likely to be p16 positive. Early clinical stage (AJCC8ed) was more associated with p16 positivity both in univariate (OR, 0.14; 95% CI, 0.07-0.26, p<0.001) and multivariate analysis (OR, 0.18; 95% CI, 0.06-0.49, p = 0.001).

Conclusion: This study showed that drinkers and current smokers were less likely to be p16+. Female sex, higher education level and younger age at diagnosis were associated with a higher probability of being p16+. Additionally, there was a higher proportion of patients with early clinical stage (I or II) in the p16 positive group when compared to the p16 negative group.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0253418PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8211260PMC
November 2021

Topical Imiquimod for the Treatment of High-Grade Squamous Intraepithelial Lesions of the Cervix: A Randomized Controlled Trial.

Obstet Gynecol 2021 06;137(6):1043-1053

Department of Prevention, the Department of Gynecological Oncology, the Department of Pathology, and the Research and Teaching Institute, Barretos Cancer Hospital, Barretos, São Paulo, Brazil; the Department of Gynecologic Oncology and Reproductive Medicine, the University of Texas MD Anderson Cancer Center, Houston, Texas; the Department of Obstetrics and Gynecology, Federal University of Health Sciences of Porto Alegre/Santa Casa de Misericordia de Porto Alegre, Porto Alegre, Brazil; and the Teaching Superintendence, A.C. Camargo Cancer Center, São Paulo, Brazil.

Objective: To evaluate the histologic response rate of high-grade squamous intraepithelial lesions (HSIL) of the cervix after topical application of 5% imiquimod cream.

Methods: In this phase II trial, women with cervical HSIL (cervical intraepithelial neoplasia [CIN] 2-3) were randomly assigned to 250 mg of 5% imiquimod cream applied to the cervix weekly for 12 weeks, followed by loop electrosurgical excision procedure (LEEP) without preceding treatment. The sample size was calculated based on the HSIL regression rates previously reported by Grimm et al. The primary outcome was rate of histologic regression (to CIN 1 or less) in LEEP specimens. Prespecified secondary endpoints included surgical margin status and adverse events. Outcomes were stratified by human papillomavirus type and lesion grade (CIN 2 or CIN 3). Results were reported according to per protocol (PP) and intention-to-treat (ITT) analyses.

Results: Ninety women were enrolled: 49 in the experimental group and 41 in the control group. In the PP population, histologic regression was observed in 23 of 38 participants (61%) in the experimental group compared with 9 of 40 (23%) in the control group (P=.001). Surgical margins were negative for HSIL in 36 of 38 participants (95%) in the experimental group and 28 of 40 (70%) in the control group (P=.004). In the ITT population, rates of histologic regression also were significantly higher in the experimental group. Rates of adverse events in the experimental group were 74% (28/38) in the PP population and 78% (35/45) in the ITT population. Adverse events were mild, with abdominal pain being the most common. Three patients in the experimental group had grade 2 adverse events, including vaginal ulcer, vaginal pruritus with local edema, and moderate pelvic pain.

Conclusion: Weekly topical treatment with imiquimod is effective in promoting regression of cervical HSIL.

Clinical Trial Registration: ClinicalTrials.gov, NCT03233412.
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http://dx.doi.org/10.1097/AOG.0000000000004384DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8132915PMC
June 2021

Cervical lesion assessment using real-time microendoscopy image analysis in Brazil: The CLARA study.

Int J Cancer 2021 07 3;149(2):431-441. Epub 2021 Apr 3.

Department of Bioengineering, Rice University, Houston, Texas.

We conducted a prospective evaluation of the diagnostic performance of high-resolution microendoscopy (HRME) to detect cervical intraepithelial neoplasia (CIN) in women with abnormal screening tests. Study participants underwent colposcopy, HRME and cervical biopsy. The prospective diagnostic performance of HRME using an automated morphologic image analysis algorithm was compared to that of colposcopy using histopathologic detection of CIN as the gold standard. To assess the potential to further improve performance of HRME image analysis, we also conducted a retrospective analysis assessing performance of a multi-task convolutional neural network to segment and classify HRME images. One thousand four hundred eighty-six subjects completed the study; 435 (29%) subjects had CIN Grade 2 or more severe (CIN2+) diagnosis. HRME with morphologic image analysis for detection of CIN Grade 3 or more severe diagnoses (CIN3+) was similarly sensitive (95.6% vs 96.2%, P = .81) and specific (56.6% vs 58.7%, P = .18) as colposcopy. HRME with morphologic image analysis for detection of CIN2+ was slightly less sensitive (91.7% vs 95.6%, P < .01) and specific (59.7% vs 63.4%, P = .02) than colposcopy. Images from 870 subjects were used to train a multi-task convolutional neural network-based algorithm and images from the remaining 616 were used to validate its performance. There were no significant differences in the sensitivity and specificity of HRME with neural network analysis vs colposcopy for detection of CIN2+ or CIN3+. Using a neural network-based algorithm, HRME has comparable sensitivity and specificity to colposcopy for detection of CIN2+. HRME could provide a low-cost, point-of-care alternative to colposcopy and biopsy in the prevention of cervical cancer.
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http://dx.doi.org/10.1002/ijc.33543DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8815862PMC
July 2021

Protective effects of fecal microbiota transplantation in sepsis are independent of the modulation of the intestinal flora.

Nutrition 2020 05 18;73:110727. Epub 2020 Jan 18.

Laboratory of Experimental Pathophysiology, Graduate Program in Health Sciences, University of Southern Santa Catarina, Criciúma, SC, Brazil. Electronic address:

Objective: The aim of this study was to investigate the protective effects of probiotics and fecal transplantation on inflammatory and oxidative parameters in the intestines of two rat models of sepsis.

Methods: Rats were treated with prebiotics, probiotics, or symbiotics and exposed to lipopolysaccharide (LPS) or zymosan after 15 d to induce endotoxemia. Oxidative damage and inflammation were analyzed, and histologic examination of the intestinal tissue was performed. Fecal microbiota transplantation (FMT) was carried out in LPS- and zymosan-induced rat models of sepsis.

Results: Supplementation with symbiotics for 15 d effectively reduced the inflammatory parameters compared with supplementation for 7 d. Probiotics, prebiotics, and symbiotics exerted different effects on the evaluated parameters. In general, Lactobacillus rhamnosus and L. casei exerted better local protective effects. Evaluation of the role of the intestinal microbiota through FMT revealed its protective effects irrespective of the previous treatment with probiotics.

Conclusion: Probiotic strains significantly differ among themselves and exert different effects on the host's health. Symbiotics and FMT could offer additional immunomodulatory benefits to drug therapy, thus serving as a new therapeutic alternative in pediatric patients with sepsis.
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http://dx.doi.org/10.1016/j.nut.2020.110727DOI Listing
May 2020

miRNA expression profiling of hereditary breast tumors from BRCA1- and BRCA2-germline mutation carriers in Brazil.

BMC Cancer 2020 Feb 22;20(1):143. Epub 2020 Feb 22.

Molecular Oncology Research Center, Barretos Cancer Hospital, Barretos, SP, Brazil.

Background: MicroRNAs (miRNAs) are small non-coding RNAs involved in post-transcriptional gene expression regulation and have been described as key regulators of carcinogenesis. Aberrant miRNA expression has been frequently reported in sporadic breast cancers, but few studies have focused on profiling hereditary breast cancers. In this study, we aimed to identify specific miRNA signatures in hereditary breast tumors and to compare with sporadic breast cancer and normal breast tissues.

Methods: Global miRNA expression profiling using NanoString technology was performed on 43 hereditary breast tumors (15 BRCA1, 14 BRCA2, and 14 BRCAX), 23 sporadic breast tumors and 8 normal breast tissues. These normal breast tissues derived from BRCA1- and BRCA2- mutation carriers (n = 5) and non-mutation carriers (n = 3). Subsequently, we performed receiver operating characteristic (ROC) curve analyses to evaluate the diagnostic performance of differentially expressed miRNAs. Putative target genes of each miRNAs considered as potential biomarkers were identified using miRDIP platform and used for pathway enrichment analysis.

Results: miRNA expression analyses identified several profiles that were specific to hereditary breast cancers. A total of 25 miRNAs were found to be differentially expressed (fold change: > 2.0 and p < 0.05) and considered as potential biomarkers (area under the curve > 0.75) in hereditary breast tumors compared to normal breast tissues, with an expressive upregulation among BRCAX cases. Furthermore, bioinformatic analysis revealed that these miRNAs shared target genes involved in ErbB, FoxO, and PI3K-Akt signaling pathways.

Conclusions: Our results showed that miRNA expression profiling can differentiate hereditary from sporadic breast tumors and normal breast tissues. These miRNAs were remarkably deregulated in BRCAX hereditary breast cancers. Therefore, miRNA signatures can be used as potential novel diagnostic biomarkers for the prediction of BRCA1/2- germline mutations and may be useful for future clinical management.
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http://dx.doi.org/10.1186/s12885-020-6640-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7036228PMC
February 2020

Potential biomarkers of ductal carcinoma in situ progression.

BMC Cancer 2020 Feb 12;20(1):119. Epub 2020 Feb 12.

Department of Biological Sciences-Human and Molecular Genetics Nucleus, Federal University of Espirito Santo, Vitoria, Espirito Santo, Brazil.

Background: Ductal carcinoma in situ is a non-obligate precursor of invasive breast carcinoma and presents a potential risk of over or undertreatment. Finding molecular biomarkers of disease progression could allow for more adequate patient treatment. We aimed to identify potential biomarkers that can predict invasiveness risk.

Methods: In this epithelial cell-based study archival formalin-fixed paraffin-embedded blocks from six patients diagnosed with invasive lesions (pure invasive ductal carcinoma), six with in-situ lesions (pure ductal carcinoma in situ), six with synchronous lesions (invasive ductal carcinoma with an in-situ component) and three non-neoplastic breast epithelium tissues were analyzed by gene expression profiling of 770 genes, using the nCounter® PanCancer Pathways panel of NanoString Technologies.

Results: The results showed that in comparison with non-neoplastic tissue the pure ductal carcinoma in situ was one with the most altered gene expression profile. Comparing pure ductal carcinoma in situ and in-situ component six differentially expressed genes were found, three of them (FGF2, GAS1, and SFRP1), play a role in cell invasiveness. Importantly, these genes were also differentially expressed between invasive and noninvasive groups and were negatively regulated in later stages of carcinogenesis.

Conclusions: We propose these three genes (FGF2, GAS1, and SFRP1) as potential biomarkers of ductal carcinoma in situ progression, suggesting that their downregulation may be involved in the transition of stationary to migrating invasive epithelial cells.
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http://dx.doi.org/10.1186/s12885-020-6608-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7017577PMC
February 2020

The Brazilian TP53 mutation (R337H) and sarcomas.

PLoS One 2020 24;15(1):e0227260. Epub 2020 Jan 24.

Molecular Oncology Research Center, Barretos Cancer Hospital, Barretos, São Paulo, Brazil.

Sarcomas represent less than 1% of all solid neoplasms in adults and over 20% in children. Their etiology is unclear, but genetic susceptibility plays an important role in this scenario. Sarcoma is central in Li-Fraumeni Syndrome (LFS), a familial predisposition cancer syndrome. In Brazil, the high prevalence of p.Arg337His mutations in the TP53 gene brings about a unique condition: a cluster of LFS. In the present work, we studied 502 sarcoma patients not selected by age or family history in an attempt to assess the impact of the so-called "Brazilian germline TP53 mutation" (p.Arg337His) on this tumor type. We found that 8% of patients are carriers, with leiomyosarcoma being the main histologic type of sarcoma, corresponding to 52.5% of the patients with the mutated TP53 gene. These findings emphasize the importance of genetic counseling and can better guide the management of sarcoma patients.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0227260PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6980636PMC
May 2020

Anti-NMDA Receptor Autoantibody Is an Independent Predictor of Hospital Mortality but Not Brain Dysfunction in Septic Patients.

Front Neurol 2019 15;10:221. Epub 2019 Mar 15.

Laboratório de Fisiopatologia Experimental, Universidade do Extremo Sul Catarinense, Criciúma, Brazil.

The presence of autoantibodies against neuronal cell surface or synaptic proteins and their relationship to autoimmune encephalitis have recently been characterized. These autoantibodies have been also reported in other pathologic conditions; however, their role during sepsis is not known. This study detected the presence of autoantibodies against neuronal cell surface or synaptic proteins in the serum of septic patients and determined their relationship to the occurrence of brain dysfunction and mortality. This prospective, observational cohort study was performed in four Brazilian intensive care units (ICUs). Sixty patients with community-acquired severe sepsis or septic shock admitted to the ICU were included. Blood samples were collected from patients within 24 h of ICU admission. Antibodies to six neuronal proteins were assessed, including glutamate receptors (types NMDA, AMPA1, and AMPA2); voltage-gated potassium channel complex (VGKC) proteins, leucine-rich glioma-inactivated protein 1 (LGI1), and contactin-associated protein-2 (Caspr2), as well as the GABAB1 receptor. There was no independent association between any of the measured autoantibodies and the occurrence of brain dysfunction (delirium or coma). However, there was an independent and significant relationship between anti-NMDAR fluorescence intensity and hospital mortality. In conclusion, anti-NMDAR was independently associated with hospital mortality but none of the measured antibodies were associated with brain dysfunction in septic patients.
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http://dx.doi.org/10.3389/fneur.2019.00221DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6428735PMC
March 2019
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