ADHEMAR LONGATTO FILHO

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LIM/14 - Laboratório de Investigação em Patologia Hepática, Hospital das Clínicas, Faculdade de Medicina

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  • article
    Characterization of oncogene suppressor marker expression in patients with submucosal gastric carcinoma
    (2018) MORON, Roberson A.; JACOB, Carlos Eduardo; BRESCIANI, Claudio Jose Caldas; SIMOES, Kleber; ALVES, Venancio Avancini Ferreira; IRYA, Kyoshi; GAMA-RODRIGUES, Joaquim; CECCONELLO, Ivan; LONGATTO-FILHO, Adhemar; ZILBERSTEIN, Bruno
    The aim of the present study was to determine the clinical significance of p53 and p21(ras) p21(wafl), p27(kip1) and p16(ink4a) expression in cases of early gastric cancer. A total of 81 patients who had undergone gastrectomy with D2 lymphadenectomy between 1971 and 2004 were retrospectively investigated. The immunohistochemical expression of p21ras, p53, p21waf1.cip1, p27kip1 and p16ink4a in the tissues was evaluated. In normal, metaplastic and tumoral mucosa, p53 was positive in 53, 87.3, and 87.1% of the cases, respectively. In the same tissues, p21ras was positive in 85.3, 86 and 96.8%, respectively. Positivity for p16ink4a was detected in 46.3, 91.1 and 86% of the cases, respectively, whereas p27kip1 was positive in 60, 94.7 and 95.3%, and p21wafl/ cip1 was positive in 32.4, 72.7 and 71.4% of the cases, respectively. All the tumors were positive for p53. Tumors with lymph node invasion presented with overexpression (+ 4) of p53 in 47% of the cases vs. 17% of patients who did not have lymph node involvement. Therefore, higher expression of p53, p21ras and p21wafl/ cip1 in the tumor exhibited a statistically significant association with lymph node involvement.
  • article 78 Citação(ões) na Scopus
    Cervical determinants of anal HPV infection and high-grade anal lesions in women: a collaborative pooled analysis
    (2019) LIN, Chunqing; SLAMA, Jiri; GONZALEZ, Paula; GOODMAN, Marc T.; XIA, Ningshao; KREIMER, Aimee R.; WU, Ting; HESSOL, Nancy A.; SHVETSOV, Yurii; ORTIZ, Ana P.; GRINSZTEJN, Beatriz; MOSCICKI, Anna-Barbara; HEARD, Isabelle; LOSA, Maria del Refugio Gonzalez; KOJIC, Erna M.; LOEFF, Maarten F. Schim van der; WEI, Feixue; LONGATTO-FILHO, Adhemar; MBULAWA, Zizipho A.; PALEFSKY, Joel M.; SOHN, Annette H.; HERNANDEZ, Brenda Y.; ROBISON, Katina; SIMPSON JR., Steve; CONLEY, Lois J.; POKOMANDY, Alexandra de; SANDE, Marianne A. B. van der; MANDISHORA, Racheal S. Dube; VOLPINI, Lays P. B.; PIERANGELI, Alessandra; ROMERO, Byron; WILKIN, Timothy; FRANCESCHI, Silvia; HIDALGO-TENORIO, Carmen; RAMAUTARSING, Reshmie A.; PARK, Ina U.; TSO, Fernanda K.; GODBOLE, Sheela; D'HAUWERS, Kathleen W. M.; SEHNAL, Borek; MENEZES, Lynette J.; HERACLIO, Sandra A.; CLIFFORD, Gary M.
    Background Cervical cancer screening might contribute to the prevention of anal cancer in women. We aimed to investigate if routine cervical cancer screening results-namely high-risk human papillomavirus (HPV) infection and cytohistopathology-predict anal HPV16 infection, anal high-grade squamous intraepithelial lesions (HSIL) and, hence, anal cancer. Methods We did a systematic review of MEDLINE, Embase, and the Cochrane library for studies of cervical determinants of anal HPV and HSIL published up to Aug 31, 2018. We centrally reanalysed individual-level data from 13 427 women with paired cervical and anal samples from 36 studies. We compared anal high-risk HPV prevalence by HIV status, cervical high-risk HPV, cervical cytohistopathology, age, and their combinations, using prevalence ratios (PR) and 95% CIs. Among 3255 women with anal cytohistopathology results, PRs were similarly calculated for all anal HSIL and HPV16-positive anal HSIL. Findings Cervical and anal HPV infections were highly correlated. In HIV-negative women, anal HPV16 prevalence was 41% (447/1097) in cervical HPV16-positive versus 2% (214/8663) in cervical HPV16-negative women (PR 16.5, 95% CI 14.2-19.2, p<0.0001); these values were 46% (125/273) versus 11% (272/2588) in HIV-positive women (4.4, 3.7-5.3, p<0.0001). Anal HPV16 was also associated with cervical cytohistopathology, with a prevalence of 44% [101/228] for cervical cancer in HIV-negative women (PR vs normal cytology 14.1, 11.1-17.9, p<0.0001). Anal HSIL was associated with cervical high-risk HPV, both in HIV-negative women (from 2% [11/527] in cervical high-risk HPV-negative women up to 24% [33/138] in cervical HPV16-positive women; PR 12.9, 95% CI 6.7-24.8, p<0.0001) and HIV-positive women (from 8% [84/1094] to 17% [31/186]; 2.3, 1.6-3.4, p<0.0001). Anal HSIL was also associated with cervical cytohistopathology, both in HIV-negative women (from 1% [5/498] in normal cytology up to 22% [59/273] in cervical HSIL; PR 23.1, 9.4-57.0, p<0.0001) and HIV-positive women (from 7% [105/1421] to 25% [25/101]; 3.6, 2.5-5.3, p<0.0001). Prevalence of HPV16-positive anal HSIL was 23-25% in cervical HPV16-positive women older than 45 years (5/20 in HIV-negative women, 12/52 in HIV-positive women). Interpretation HPV-based cervical cancer screening programmes might help to stratify anal cancer risk, irrespective of HIV status. For targeted secondary anal cancer prevention in high-risk groups, HIV-negative women with cervical HPV16, especially those older than 45 years, have a similar anal cancer risk profile to that of HIV-positive women. Copyright
  • article 15 Citação(ões) na Scopus
    PIK3CA mutations are frequent in esophageal squamous cell carcinoma associated with chagasic megaesophagus and are associated with a worse patient outcome
    (2018) MUNARI, Fernanda Franco; CRUVINEL-CARLONI, Adriana; LACERDA, Croider Franco; OLIVEIRA, Antonio Talvane Torres de; SCAPULATEMPO-NETO, Cristovam; SILVA, Sandra Regina Morini da; CREMA, Eduardo; ADAD, Sheila Jorge; RODRIGUES, Maria Aparecida Marchesan; HENRY, Maria Aparecida Coelho Arruda; GUIMARAES, Denise Peixoto; LONGATTO-FILHO, Adhemar; REIS, Rui Manuel
    BackgroundChronic diseases such as chagasic megaesophagus (secondary to Chagas' disease) have been suggested as etiological factors for esophageal squamous cell carcinoma; however, the molecular mechanisms involved are poorly understood.ObjectiveWe analyzed hotspot PIK3CA gene mutations in a series of esophageal squamous cell carcinomas associated or not with chagasic megaesophagus, as well as, in chagasic megaesophagus biopsies. We also checked for correlations between the presence of PIK3CA mutations with patients' clinical and pathological features.MethodsThe study included three different groups of patients: i) 23 patients with chagasic megaesophagus associated with esophageal squamous cell carcinoma (CM/ESCC); ii) 38 patients with esophageal squamous cell carcinoma not associated with chagasic megaesophagus (ESCC); and iii) 28 patients with chagasic megaesophagus without esophageal squamous cell carcinoma (CM). PIK3CA hotspot mutations in exons 9 and 20 were evaluated by PCR followed by direct sequencing technique.ResultsPIK3CA mutations were identified in 21.7% (5 out of 23) of CM/ESCC cases, in 10.5% (4 out of 38) of ESCC and in only 3.6% (1 case out of 28) of CM cases. In the CM/ESCC group, PIK3CA mutations were significantly associated with lower survival (mean 5months), when compared to wild-type patients (mean 2.0years). No other significant associations were observed between PIK3CA mutations and patients' clinical features or TP53 mutation profile.ConclusionThis is the first report on the presence of PIK3CA mutations in esophageal cancer associated with chagasic megaesophagus. The detection of PIK3CA mutations in benign chagasic megaesophagus lesions suggests their putative role in esophageal squamous cell carcinoma development and opens new opportunities for targeted-therapies for these diseases.
  • article 8 Citação(ões) na Scopus
    Characterization of topoisomerase II alpha and minichromosome maintenance protein 2 expression in anal carcinoma
    (2017) SCAPULATEMPO-NETO, Cristovam; VEO, Carlos; FREGNANI, Jose Humberto T. G.; LORENZI, Adriana; MAFRA, Allini; MELANI, Armando G. F.; LOAIZA, Edgar Antonio Aleman; ROSA, Luciana Albina Reis; OLIVEIRA, Cristina Mendes De; LEVI, Jose Eduardo; LONGATTO-FILHO, Adhemar
    The present study aimed to ascertain the significance of topoisomerase II alpha (TOP2A) and minichromosome maintenance protein (MCM) 2 expression in anal carcinoma. A total of 75 anal lesions were retrieved from the files of the Department of Pathology of Barretos Cancer Hospital (Barretos, Brazil) in order to verify the human papillomavirus (HPV) statuses of these lesions and characterize the immunohistochemical expression levels of TOP2A and MCM2 in anal carcinoma, as these are important markers for cervical HPV-induced lesions; their expression was also compared with respect to p16 and Ki-67. The vast majority of the cases tested positive for HPV16 (84%); 1 case tested positive for both HPV16 and HPV18. Positive HPV16 status was more frequent in early stages than in advanced stages (P=0.008). Positive immunohistochemical reactivity for MCM2 and TOP2A protein was observed in 71.6 and 100% of cases, respectively. Positive reactivity for p16 was significantly associated (P=0.001) with histological grade, and was more commonly expressed in squamous cell carcinoma than adenocarcinomas. HPV16 was strongly associated with positive p16 protein expression (76.6%). However, the high expression of Ki-67 combined with the high expression of p16 was predominantly observed in Stage III-IV cases. MCM2, TOP2A, p16 and Ki-67 exhibited intense positive staining in the anal lesions, indicating that these markers were significantly and constantly expressed in anal carcinoma.
  • article 2 Citação(ões) na Scopus
    Profile of esophageal squamous cell carcinoma mutations in Brazilian patients
    (2021) MUNARI, Fernanda Franco; SANTOS, Wellington dos; EVANGELISTA, Adriane Feijo; CARVALHO, Ana Carolina; PASTREZ, Paula Aguiar; BUGATTI, Diego; WOHNRATH, Durval R.; SCAPULATEMPO-NETO, Cristovam; GUIMARAES, Denise Peixoto; LONGATTO-FILHO, Adhemar; REIS, Rui Manuel
    Esophageal cancer is an aggressive tumor that has a high rate of incidence and mortality worldwide. It is the 10th most frequent type in Brazil, being squamous cell carcinoma (ESCC) the predominant subtype. There is currently an incessant search to identify the frequently altered genes associated with esophageal squamous cell carcinoma biology that could be druggable. This study aimed to analyze the somatic mutation profile of a large panel of cancer-related genes in Brazilian ESCC. In a series of 46 ESCC diagnoses at Barretos Cancer Hospital, DNA isolated from paired fresh-frozen and blood tissue, a panel of 150 cancer-related genes was analyzed by next-generation sequencing. The genes with the highest frequency of mutations were TP53 (39/46, 84.8%), followed by NOTCH1 ( 7/46, 15.2%), NFE2L2 ( 5/46, 10.8%), RB1 (3/46, 6.5%), PTEN (3/46, 6.5%), CDKN2A (3/46, 6.5%), PTCH1 (2/46, 4.3%) and PIK3CA (2/46, 4.3%). There was no significant association between molecular and patients' clinicopathological features. Applying an evolutionary action score of p53 ( EAp53), we observed that 14 (35.9%) TP53 mutations were classified as high-risk, yet no association with overall survival was observed. Concluding, this the largest mutation profile of Brazilian ESCC patients, which helps in the elucidation of the major cancer-related genes in this population.
  • article 7 Citação(ões) na Scopus
    Could Alarmingly High Rates of Negative Diagnoses in Remote Rural Areas Be Minimized with Liquid-Based Cytology? Preliminary Results from the RODEO Study Team
    (2013) FREGNANI, Jose Humberto T. G.; SCAPULATEMPO, Cristovam; HAIKEL JR., Raphael L.; SACCHETO, Teoclito; CAMPACCI, Natalia; MAUAD, Edmundo C.; LONGATTO-FILHO, Adhemar
    Objective: It was the aim of this study to compare diagnostic performances of the BD SurePath (TM) liquid-based Papanicolaou test (LBC) and the conventional Papanicolaou test (CPT) in cervical samples of women from remote rural areas of Brazil. Study Design: Specimens were collected by mobile units provided by Barretos Cancer Hospital. This report evaluates the manual screening arm of the RODEO study. Of 12,048 women seen between May and December 2010, 6,001 were examined using LBC and 6,047 using CPT. Results: Comparative (LBC vs. CPT) outcomes were: all abnormal tests, 2.1 versus 1.0%; ASC-US (atypical squannous cells of unknown significance), 0.7 versus 0.1%; ASC-H (atypical squamous cells with possible high-grade squannous intraepithelial lesions) and AGC (atypical glandular cells), 0.4 versus 0.3%; LSIL (low-grade squannous intraepithelial lesions), 0.7 versus 0.3%; HSIL (high-grade squamous intraepithelial lesions), 0.4 versus 0.2%, and unsatisfactory, 0.03 versus 0.08%. The LBC arm detected significantly more lesions (ASC-US+) than CPT (p < 0.001); however, when we divided the diagnoses into two groups, ASC-H (negative/ASC-US/LSIL) and ASC-H+ (ASC-H/AGC/HSIL), the difference was not statistically important (p = 0.213). Conclusions: With inherent difficulties in patient recruitment and patient compliance with cancer screening, best test performance including human papillomavirus test capability are vitally necessary in Brazil's struggle to reduce cervical cancer.
  • article 2 Citação(ões) na Scopus
    Polymorphism of Interleukin-6 Is Not Associated with the Presence or Absence of High HPV E6/E7
    (2014) PORTO, Claudia Regina Cinti; KLEINE, Joao Paulo Ferreira De Oliveira; LONGATTO FILHO, Adhemar; SILVA, Ismael Dale Cotrim Guerreiro Da
    The present study evaluated the frequency of the polymorphism of Interleukin-6 (IL6) in women positive for E6/E7 Human Papillomavirus (HPV) (n=152) and women negative for HPV (n=238), 390 women in total. Material for analysis was obtained at the Federal University of Sao Paulo. Interleukin-6 polymorphism was detected by Polymerase Chain Reaction-Restriction Fragment Length Polymorphism (PCR-RFLP) and analyzed in 3% agarose gel. Results: No significant associations between the frequency of the polymorphism of IL6 in patients expressing E6 and E7 with HPV-positive and -negative reactions were found. There was no statistically significant difference between the case and control group for genotype distribution (p=0.280). Conclusion: Genotypic analysis showed a striking similarity of IL6 polymorphisms in both cases and controls. The allelic distribution in cases and controls for G and C of IL6 were very similar (p=0.186), which could point to similar IL6 functionality for both groups.
  • article 15 Citação(ões) na Scopus
    Frequency of Chlamydia trachomatis infection in cervical intraepithelial lesions and the status of cytological p16/Ki-67 dual-staining
    (2017) ROBIAL, R.; LONGATTO-FILHO, A.; ROTELI-MARTINS, C. M.; SILVEIRA, M. F.; STAUFFERT, D.; RIBEIRO, G. G.; LINHARES, I. M.; TACLA, M.; ZONTA, M. A.; BARACAT, E. C.
    Background: Chlamydia trachomatis (Ct) is not a disease subject to mandatory reporting in Brazil, and the prevalence rate of this genital infection varies according to the region in which studies are conducted, as well as by the detection technique employed. Ct has been associated with persistence of Human papillomavirus (HPV) infection and the facilitation of cervical carcinoma development. We evaluated the Chlamydia trachomatis infection and its association with cytology, p16/Ki-67 dual-stained cytology and cervical intraepithelial lesions status in a screening cohort in Brazil. Methods: This was a cross-sectional study of 1481 cervical samples from asymptomatic women aged 18 to 64. Samples were collected for liquid-based cytology and Ct detection by polymerase chain reaction. p16/Ki-67 double staining was performed on samples with abnormal cytology. Statistical analysis was by chi-square and likelihood-ratio tests. Odds ratio (OR) and 95% confidence intervals (95% CI) were determined. Results: The frequency of Ct was 15.6% and its presence was not associated with detection of p16/Ki-67 [OR = 1. 35 (0.5-3.4)]. There was also no association between abnormal cervical cytology and Ct-positivity [OR = 1.21 (0.46-3.2)]. Associations were observed between p16/Ki-67 and high-grade lesions detected by cytology and in biopsies [OR = 3.55 (1.50-8.42) and OR = 19.00 (0.6-7.2), respectively]. Conclusions: The asymptomatic women in our study had a high frequency of Ct infection but this was not associated with p16/Ki-67 detection in samples with abnormal cytology. The expression of p16/Ki-67 was highest in women with high-grade CIN (p = 0.003).
  • article 31 Citação(ões) na Scopus
    MMP-9/RECK Imbalance: A Mechanism Associated with High-Grade Cervical Lesions and Genital Infection by Human Papillomavirus and Chlamydia trachomatis
    (2015) DISCACCIATI, Michelle G.; GIMENES, Fabrcia; PENNACCHI, Paula C.; FAIAO-FLORES, Fernanda; ZEFERINO, Luiz C.; DERCHAIN, Sophie M.; TEIXEIRA, Julio C.; COSTA, Maria C.; ZONTA, Marco; TERMINI, Lara; BOCCARDO, Enrique; LONGATTO-FILHO, Adhemar; CONSOLARO, Marcia E. L.; VILLA, Luisa L.; MARIA-ENGLER, Silvya S.
    Background: Matrix metalloproteinases (MMP) are important enzymes in the tumor microenvironment associated with progression of cervical intraepithelial neoplasia (CIN) toward squamous cell carcinoma (SCC) of the cervix. However, the role of MMPs in the inflammatory process associated with Chlamydia trachomatis infection concomitant with the carcinogenic process driven by HPV has not yet been addressed. In the present study, we analyzed the state of the MMP-9-RECK axis in cervical carcinogenesis. Methods: The levels of MMP-9 and RECK expression were analyzed by immunocytochemistry in liquid-based cytology samples from 136 women with high-grade cervical lesions (CIN2/CIN3) and cervical SCC diagnosed by LLETZ, and in 196 women without cervical neoplasia or CIN1. Real-time qPCR was performed to analyze expression of MMP-9 and RECK in 15 cervical samples. The presence of HPV-DNA and other genital pathogens was evaluated by PCR. Results: We found a higher expression of MMP-9 [OR, 4.2; 95% confidence interval (CI), 2.2-7.8] and lower expression of RECK (OR, 0.4; 95% CI, 0.2-0.7) in women with CIN2/CIN3/SCC when compared with women from the control group (no neoplasia/CIN1). A statistically significant association was also found between MMP-9/RECK imbalance and infection by alpha-9 HPV and C. trachomatis. The prevalence of C. trachomatis infection was significantly higher in women with high-grade cervical disease (OR, 3.7; 95% CI, 1.3-11.3). Conclusions: MMP-9/RECK imbalance in cervical smears is significantly associated with high-grade cervical diseases and infection by alpha-9 HPV and C. trachomatis. Impact: MMP-9/RECK imbalance during cervical inflammation induced by C. trachomatis might play a role in HPV-mediated cervical carcinogenesis. (C) 2015 AACR.
  • article 15 Citação(ões) na Scopus
    A Low-Cost HPV Immunochromatographic Assay to Detect High-Grade Cervical Intraepithelial Neoplasia
    (2016) MARIANO, Vania Sammartino; LORENZI, Adriana Tarla; SCAPULATEMPO-NETO, Cristovam; STEIN, Maira Degiovani; RESENDE, Julio Cesar Possati; ANTONIAZZI, Marcio; VILLA, Luisa Lina; LEVI, Jose Eduardo; LONGATTO-FILHO, Adhemar; FREGNANI, Jose Humberto Tavares Guerreiro
    Objective To evaluate the reproducibility and accuracy of the HPV16/18-E6 test. Methods The study population was comprised of 448 women with a previously abnormal Pap who were referred to the Barretos Cancer Hospital (Brazil) for diagnosis and treatment. Two cervical samples were collected immediately before colposcopy, one for the hr-HPV-DNA test and cytology and the other for the HPV16/18-E6 test using high-affinity monoclonal antibodies (mAb). Women with a histologic diagnosis of cervical intraepithelial neoplasia grade 2 or 3 were considered to be positive cases. Different strategies using a combination of screening methods (HPV-DNA) and triage tests (cytology and HPV16/18-E6) were also examined and compared. Results The HPV16/18-E6 test exhibited a lower positivity rate compared with the HPV-DNA test (19.0% vs. 29.3%, p<0.001) and a moderate/high agreement (kappa = 0.68, 95% CI: 0.60-0.75). It also exhibited a significantly lower sensitivity for CIN2+ and CIN3+ detection compared to the HPV-DNA test and a significantly higher specificity. The HPV16/18-E6 test was no different from cytology in terms of sensitivity, but it exhibited a significantly higher specificity in comparison to ASCH+. A triage test after HPV-DNA detection using the HPV16/18-E6 test exhibited a significantly higher specificity compared with a triage test of ASCH+ to CIN2+ (91.8% vs. 87.4%, p = 0.04) and CIN3+ (88.6% vs. 84.0%, p = 0.05). Conclusion The HPV16/18-E6 test exhibited moderate/high agreement with the HPV-DNA test but lower sensitivity and higher specificity for the detection of CIN2+ and CIN3+. In addition, its performance was quite similar to cytology, but because of the structural design addressed for the detection of HPV16/18-E6 protein, the test can miss some CIN2/3+ lesions caused by other high-risk HPV types.