ADHEMAR LONGATTO FILHO
Projetos de Pesquisa
Unidades Organizacionais
LIM/14 - Laboratório de Investigação em Patologia Hepática, Hospital das Clínicas, Faculdade de Medicina
83 resultados
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- Angiogenic factors: role in esophageal cancer, a brief review(2018) LADEIRA, Katia; MACEDO, Filipa; LONGATTO-FILHO, Adhemar; MARTINS, Sandra F.Esophageal cancer has an aggressive behavior with rapid tumor mass growth and frequently poor prognosis; it is known as one of the most fatal types of cancer worldwide. The identification of potential molecular markers that can predict the response to treatment and the prognosis of this cancer has been subject of a vast investigation in the recent years. Among several molecules, various angiogenic factors that are linked to the tumor development, growth, and invasion, such as VEGF, HGF, angiopoietin-2, IL-6, and TGF-B1, were investigated. In this paper, the authors sought to review the role of these angiogenic factors in prognosis and hypothesize how they can be used as a treatment target.
- Phospho-mTOR in non-tumour and tumour bladder urothelium: Pattern of expression and impact on urothelial bladder cancer patients(2014) AFONSO, Julieta; LONGATTO-FILHO, Adhemar; SILVA, Vitor Moreira Da; AMARO, Teresina; SANTOS, Iucio L.Urothelial bladder carcinoma (UBC) is heterogeneous in its pathology and clinical behaviour. Evaluation of prognostic and predictive biomarkers is necessary, in order to produce personalised treatment options. The present study used immunohistochemistry to evaluate UBC sections containing tumour and non-tumour areas from 76 patients, for the detection of p-mTOR, CD31 and D2-40 (blood and lymphatic vessels identification, respectively). Of the non-tumour and tumour sections, 36 and 20% were scored positive for p-mTOR expression, respectively. Immunoexpression was observed in umbrella cells from non-tumour urothelium, in all cell layers from non-muscle-invasive (NMI) tumours (including expression in superficial cells), and in spots of cells from muscle-invasive (MI) tumours. Positive expression decreased from non-tumour to tumour urothelium, and from pTl/pTis to pT3/pT4 tumours; however, the few pT3/pT4 positive cases had worse survival rates, with 5-year disease-free survival being significantly lower. Angiogenesis occurrence was impaired in pT3/pT4 tumours that did not express p-mTOR. In conclusion, p-mTOR expression in non-tumour umbrella cells is likely a reflection of their metabolic plasticity, and extension to the inner layers of the urothelium in NMI tumours is consistent with an enhanced malignant potential. The expression in cell spots in a few MI tumours and absence of expression in the remaining tumours is intriguing and requires further research. Additional studies regarding the up- and downstream effectors of the mTOR pathway should be conducted.
- Characterization of PAR1 and FGFR1 expression in invasive breast carcinomas: Prognostic significance(2012) TIBURCIO, Marta; COSTA, Sandra M. A.; DUARTE, Maria De Fatima; SCHMITT, Fernando C.; LONGATTO FILHO, AdhemarBreast cancer is the most common cause of cancer mortality among women worldwide. Among the several factors associated with breast cancer development, angiogenesis plays an essential role and has currently emerged as a potential diagnostic, prognostic and therapeutic target. Protease-activated receptor 1 (PAR1) and fibroblast growth factor receptor 1 (FGFR1) have important activities in tumor angiogenesis and progression. The aim of this study was to investigate the prognostic significance of these two receptors, hypothesising significant correlations between receptor expression in tumor angiogenesis and clinicopathological parameters customarily used in breast cancer prognosis and prediction. Formalin-fixed and paraffin-embedded samples of ductal invasive breast carcinomas were used to analyze the expression of PAR1 and FGFR1, in the tumor cells as well as in the tumor stroma, and further determine intratumoral microvessel density (iMVD) to quantify intratumoral angiogenesis. Correlations between PAR1 and FGFR1 expression in tumor cells and stroma, iMVD and several clinicopathological parameters and molecular markers used in breast cancer diagnosis have been addressed. The correlation between PAR1 and FGFR1 suggests an association of the two receptors with a more aggressive breast cancer phenotype and, consequently, a potential role during tumor progression. The results reported in the present study also emphasize the importance of microenvironmental factors in tumor progression, while precluding the positive association between iMVD and breast cancer aggressiveness.
- Inflammation Is a Histological Characteristic of Skeletal Muscle in Chronic Limb Threatening Ischemia(2024) FERREIRA, Joana; AFONSO, Julieta; LONGATTO-FILHO, Adhemar; ROQUE, Susana; CARNEIRO, Alexandre; VILE, Isabel; SILVA, Cristina; CUNHA, Cristina; MESQUITA, Amilcar; COTTER, Jorge; CORREIA-NEVES, Margarida; MANSILHA, Armando; CUNHA, PedroBackground: The loss of skeletal muscle is a prognostic factor in several diseases including in patients with chronic limb threatening ischemia (CLTI). Patients with CLTI also have a lower skeletal mass and area when compared to those with claudication. However, there are no currently available data regarding the histological characteristics of core muscles in patients with CLTI. This study aims to determine the differences in core skeletal muscles between patients with claudication and those with CLTI. The second aim is to evaluate the differences in myokines, which are molecules secreted by skeletal muscle, between patients with claudication and those with CLTI. Methods: An observational, prospective study was conducted from January 2018 to July 2022 involving consecutive patients with peripheral arterial disease (PAD). The clinical characteristics were registered. In PAD patients with surgical indication for common femoral artery approach, samples of sartorius skeletal muscle (and not from the limb muscles directly involved in the ischemic process) were collected. The samples were submitted to histological characterization on hematoxylin-eosin and to immunohistochemical analysis to detect CD45+ leukocytes and CD163+ macrophages. The extent of the inflammatory cells (leukocytes and macrophages) was semiquantitatively assessed using a 0 -to -4 grade scale as follows: absent (0t), mild (t), moderate (tt), severe (ttt), and very severe (tttt). Serum levels of myokines: irisin, myostatin, IL -8, and lL-6 were determined with multiplex bead -based immunoassay. Results: 119 patients (mean age: 67.58 +/- 9.60 years old, 79.80% males) 64 with claudication and 54 with CLTI were enrolled in the study. No differences were registered between patients with claudication and those with CLTI on age, gender, cardiovascular risk factors, and medication, except on smoking habits. There was a significantly higher prevalence of smokers and a higher smoking load in the claudication group. Samples of sartorius skeletal muscle from 40 patients (14 with claudication and 26 with CLTI) were submitted to histological analysis. No differences were found in skeletal muscle fibers preservation, trauma, or hemorrhage (on hematoxylin-eosin staining). However, in the immunohistochemistry study, we found more inflammatory cells CD45+ leukocytes in patients with CLTI when compared to those with claudication [CD45+ > moderate (tt): claudication (n = 14): 4; 28.57%; CLTI (n = 25): 16; 64.00%; P = 0.034]. Patients with CLTI also had higher tissue levels of CD163+ macrophages, but this difference was not significant [CD163+ > moderate (tt): claudication (n = 13): 7; 53.85%; CLTI (n = 27): 21; 77.78%; P = 0.122]. The serum levels of the myokines, irisin, and myostatin were below the lower limit of detection, in the majority of patients, so no valid results were obtained. However, patients with CLTI had a higher serum level of Interleukin (IL) -6 and IL -8. Conclusions: CLTI patients exhibit increased quantities of leukocytes in their sartorius muscle, as well as elevated serum levels of myokines IL -8 and IL -6. Inflamed skeletal muscle can contribute to the loss of muscle mass and account for the lower density of skeletal muscle observed in CLTI. Additionally, inflamed skeletal muscle may contribute to the development of systemic inflammation through the secretion of pro -inflammatory cytokines into the systemic circulation. Halting the inflammatory process could eventually improve the prognosis of CLTI patients.
- Is the gastrointestinal stromal tumor arising in the rectovaginal septum an extragastrointestinal entity? A time for reflection(2011) FREGNANI, Jose Humberto Tavares Guerreiro; OLIVEIRA, Antonio Talvane Torres de; VAZQUEZ, Vinicius de Lima; VIANA, Cristiano Ribeiro; LONGATTO-FILHO, Adhemar; REIS, Rui Manuel
- Peri-Carotid Adipose Tissue and Atherosclerosis at Carotid Bifurcation(2024) FERREIRA, Joana; LONGATTO-FILHO, Adhemar; DIONISIO, Ana; CORREIA-NEVES, Margarida; CUNHA, Pedro; MANSILHA, ArmandoVulnerable carotid plaques are responsible for 20% of the ischemic strokes. The identification of these asymptomatic carotid plaques that will become symptomatic is essential but remains unclear. Our main goal was to investigate whether the amount of the peri-carotid adipose tissue, estimated by the extra-media thickness (EMT), is associated with the atherosclerotic characteristics at the carotid bifurcation in patients with PAD. An observational, prospective, single-center, longitudinal study was conducted. Overall, 177 patients were subjected to carotid Doppler ultrasound at the study admission. The following data were collected: EMT, intima-media thickness (IMT), the presence of carotid plaques, the area of the highest plaque, the presence of ""acute culprit"" carotid stenosis, and the grade of internal carotid stenosis. ""Acute culprit"" carotid stenosis was defined as a significant atherosclerotic plaque that leads to a neurologic event within 15 days. From each carotid bifurcation, a right and a left EMT were determined. We analyzed both the mean EMTs (calculated as the mean between the right and the left EMT) and the EMT ipsilateral to the carotid bifurcation. The presence of carotid plaques was associated with a higher mean EMT [Median = 1.14; IQR = 0.66 versus Median = 0.97; IQR = 0.40; p = 0.001]. A positive correlation was found between the mean EMT and IMT (right: rho = 0.20; p = 0.010; left: rho = 0.21; p = 0.007) and between the mean EMT and the area of the largest carotid plaque (right: rho = 0.17; p = 0.036; left: rho = 0.22; p = 0.004). Left carotid stenosis >= 70% was associated with higher ipsilateral EMT [Median = 1.56; IQR = 0.70 versus Median = 0.94; IQR = 0.42; p = 0.009]. Patients with ""acute culprit"" carotid stenosis had a higher ipsilateral EMT [left ipsilateral EMT: Median = 1.46; IQR = 0.63; ""non-acute"": Median = 0.94; IQR = 0.43; p = 0.009; right ipsilateral EMT: Median = 2.25; IQR = 0.62; ""non-acute"": Median = 1.00; IQR = 0.51; p = 0.015]. This difference was not found in the contra-lateral EMT. Six months after the neurologic event, EMT ipsilateral to an ""acute culprit"" carotid stenosis decreased (p = 0.036). The amount of peri-carotid adipose tissue, estimated with EMT, was associated with atherosclerosis at the carotid arteries. The mean EMT was associated with the features of chronic atherosclerosis lesions: the presence of carotid plaques, IMT, and the area of the highest plaque. Ipsilateral EMT was linked with ""acute culprit"" atherosclerotic plaque.
- Increased CD3(+), CD8(+), or FoxP3(+) T Lymphocyte Infiltrations Are Associated with the Pathogenesis of Colorectal Cancer but Not with the Overall Survival of Patients(2021) BARBOSA, Ana Margarida; MARTINHO, Olga; NOGUEIRA, Rosete; CAMPOS, Juliana; LOBO, Liliana; PINTO, Henrique; LONGATTO-FILHO, Adhemar; CASTRO, Antonio G.; MARTINS, Sandra F.; TORRADO, EgidioSimple Summary Colorectal cancer (CRC) is amongst the deadliest cancers. Surgical excision of the primary tumor is the curative intent treatment; however, recurrence occurs in approximately 20% of patients. Therefore, novel staging protocols are crucial to inform clinicians which patients will recur. In this study, we explored the prognostic potential of tumor-infiltrating lymphocytes. Our data did not reveal any association between intratumor lymphocyte infiltrations with clinical or pathological data. On the other hand, the presence of CD3(+), CD8(+), or FoxP3(+) lymphocyte infiltration in the tumor invasive margins were associated with markers of good prognosis. Despite this, we were not able to find any statistically significant alterations in the overall survival of patients, even though high infiltrations of FoxP3(+) T lymphocytes in the tumor margin resulted in an increased overall survival of 14 months. Taken together, our data show that the location and type of tumor-infiltrating lymphocytes are associated with the pathogenesis of CRC; however, only high FoxP3(+) T lymphocyte infiltrations are inclined to indicate favorable prognosis. Tumor-infiltrating lymphocytes include heterogeneous populations of T lymphocytes that play crucial roles in the tumor immune response; importantly, their presence in the tumor tissue may predict clinical outcomes. Therefore, we herein studied the prognostic significance of the presence and location of CD3(+), CD8(+), and FoxP3(+) T lymphocytes in colorectal cancer samples. In the intratumor analysis, our data did not reveal any association between lymphocyte infiltrations with clinical or pathological data. However, in the tumor margins, we found that the presence of high infiltrations of CD3(+), CD8(+), or FoxP3(+) T lymphocytes were associated with TNM stages I-II (p = 0.021, p = 0.022, and p = 0.012, respectively) and absence of lymph node metastases (p = 0.010, p = 0.003, and p = 0.004, respectively). Despite these associations with good prognostic indicators, we were not able to find any statistically significant alterations in the overall survival of the patients, even though high infiltrations of FoxP3(+) T lymphocytes in the tumor margins resulted in an increased overall survival of 14 months. Taken together, these data show that the presence of CD3(+), CD8(+), or FoxP3(+)T lymphocyte infiltrates in the tumor margins are associated with the pathogenesis of CRC, but only high Foxp3(+) T lymphocyte infiltrations in the tumor invasive margins are inclined to indicate favorable prognosis.
- The relationship between esophageal cancer, chagasic megaesophagus and HPV: myths, tales or reality?(2018) MUNARI, Fernanda Franco; CARLONI, Adriana Cruvinel; MARIANO, Vania Sammartino; SYRJANEN, Kari; REIS, Rui Manuel; LONGATTO-FILHO, AdhemarA supposed role for persistent high-risk human papillomavirus (HPV) infection in esophageal squamous cell carcinoma (ESCC) etiology has been suggested by a number of studies. Concomitantly, megaesophagus induced by the Trypanosoma cruzi cell-cycle activity also shows a potential association with ESCC. This review discusses esophageal cancer and the potential association between chagasic megaesophagus and HPV as risk factors for ESCC development.
- Loss of RKIP expression during the carcinogenic evolution of endometrial cancer(2012) Martinho, Olga; Faloppa, Carlos Chaves; Neto, Cristovam Scapulatempo; Longatto-Filho, Adhemar; Baiocchi, Glauco; da Cunha, Isabela Werneck; Soares, Fernando Augusto; Tavares Guerreiro Fregnani, Jose Humberto; Reis, Rui ManuelAims Endometrial cancer is one of the most common cancers in women worldwide, but there is a lack of diagnostic markers for early detection of these tumours. The raf kinase inhibitory protein (RKIP) negatively regulates the Raf/MEK/ERK pathway, and the downregulation of RKIP is associated with tumour progression and metastasis in several human neoplasms. The aim of this study was to assess the expression levels of RKIP in endometrial cancer and determine whether this expression correlates with clinical outcome in these patients. Methods Tissue microarrays constructed using tissue samples from 209 endometrial adenocarcinomas, 49 endometrial polyps and 48 endometrial hyperplasias were analysed for RKIP expression by immunohistochemistry. Results The authors found that RKIP expression decreases significantly during malignant progression of endometrial cancer; it is highly expressed in non-neoplastic tissues (polyps 79.6%; hyperplasias 87.5%) and expressed at very low levels in endometrioid adenocarcinomas (29.7%). No correlations were observed between RKIP expression, clinicopathological data and survival. Conclusion This study demonstrated for the first time that RKIP expression is lost during the carcinogenic evolution of endometrial tumours and that the loss of RKIP expression is associated with a malignant phenotype. Functional studies are needed to address the biological role of RKIP downregulation in endometrial cancer.
- 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 ManuelBackgroundChronic 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.