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Background About 15%–25% of appendices removed to treat acute appendicitis present normal macro- and macroscopic morphology. The objective of this study was to verify an association of proinflammatory, neuroendocrine and immune mediators with morphologically normal appendices removed from patients with clinical laboratorial and imaging characteristics of acute appendicitis. Materials and methods Appendices removed from 121 adult patients of both genders were distributed into three groups according to their following characteristics: group 1: 53 macro- and microscopically normal appendices from patients with clinical, laboratorial and imaging diagnosis of acute appendicitis; group 2: 24 inflamed appendices from patients with clinical, laboratorial, imaging and histopathological diagnosis of acute appendicitis; group 3: 44 normal appendices from patients submitted to right colectomy to treat localized ascending colon adenocarcinoma. All appendices were immunohistochemically studied for gastrin inhibitor peptide, mast cell tryptase, vascular endothelial growth factor; intestinal vasoactive peptide, tumor necrosis factor alpha, interleukin 1, prostaglandin E2, gene-protein product 9.5, CD8 T lymphocytes, synaptophysine, enolase, and S100 protein. Results The group 1 revealed increased levels of synaptophysine, enolase, mast cell tryptase and PGP-9.5 comparing with the other two groups. The group 2 presented increased levels of interleukin 1, CD8 T lymphocytes and prostaglandin E2 comparing with the other two groups. The group 3 confirmed the normal levels of all these neuroendocrine, immune and proinflammatory mediators. Conclusions Morphologically normal appendices removed from patients with clinical and complementary exams indicating acute appendicitis have appendicular neuroimmunoendocrine disorder associated with the mediators synaptophysin, enolase, mast cell-related tryptase and gene-protein product 9.5., Highlights • 15 % to 25% of the appendices removed to treat acute appendicitis have normal appearance with no inflammatory signs. • All patients with normal appendices removed due to acute appendicitis do not present similar clinical manifestation anymore. • Inflammatory and neuroendocrine appendicopathies present similar clinical laboratorial and imaging characteristics. • Morphologically normal appendices removed from patients indicating acute appendicitis have neuroimmunoendocrine disorders. • Synaptophysin, enolase, mast cell tryptase and gene-protein product 9.5 are associated with neuroimmunoendocrine disorders.

Background Tacrolimus is used to prevent unaesthetic scars due to its action on fibroblast activity and collagen production modulation. Objectives To evaluate the action pathways, from the histopathological point of view and in cytokine control, of tacrolimus ointment in the prevention of hypertrophic scars. Methods Twenty-two rabbits were submitted to the excision of two 1-cm fragments in each ear, including the perichondrium. The right ear received 0.1% and 0.03% tacrolimus in ointment base twice a day in the upper wound and in the lower wound respectively. The left ear, used as the control, was treated with petrolatum. After 30 days, collagen fibers were evaluated using special staining, and immunohistochemistry analyses for smooth muscle actin, TGF-β and VEGF were performed. Results The wounds treated with 0.1% tacrolimus showed weak labeling and a lower percentage of labeling for smooth muscle actin, a higher proportion of mucin absence, weak staining, fine and organized fibers for Gomori's Trichrome, strong staining and organized fibers for Verhoeff when compared to controls. The wounds treated with 0.03% tacrolimus showed weak labeling for smooth muscle actin, a higher proportion of mucin absence, strong staining for Verhoeff when compared to the controls. There was absence of TGF-β and low VEGF expression. Study limitations The analysis was performed by a single pathologist. Second-harmonic imaging microscopy was performed in 2 sample areas of the scar. Conclusions Both drug concentrations were effective in suppressing TGF-β and smooth muscle actin, reducing mucin, improving the quality of collagen fibers, and the density of elastic fibers, but only the higher concentration influenced elastic fiber organization.

Bovine leukemia virus (BLV) is a retrovirus that causes lymphoma in cattle worldwide and has also been associated with breast cancer in humans. The mechanism of BLV infection in humans and its implication as a primary cause of cancer in women are not known yet. BLV infection in humans may be caused by the consumption of milk and milk-products or meat from infected animals. Breast cancer incidence rates in Brazil are high, corresponding to 29.5% a year of cancer cases among women. In 2020, an estimated 66,280 new cases of breast cancer are expected, whereas in 2018 breast cancer has led to 17,572 deaths, the highest incidence and lethality among cancers in women in this country that year. BLV infection occurrence ranges from 60 to 95% in dairy herds. In addition, there are some regions, such as the Minas Gerais State, southeastern Brazil, where the population traditionally consume unpasteurized dairy products. Taken together, this study aimed to verify if there is a higher association between breast cancer and the presence of BLV genome in breast tissue samples within this population that consumes raw milk from animals with high rates of BLV infection. A molecular study of two BLV genes was carried out in 88 breast parenchyma samples, between tumors and controls. The amplified fragment was subjected to BLV proviral sequencing and its identity was confirmed using GenBank. BLV proviral genes were amplified from tumor breast parenchyma samples and healthy tissue control samples from women, revealing a 95.9% (47/49) and 59% (23/39) positivity, respectively. Our results show the highest correlation of BLV and human breast cancer found in the world to date within the population of Minas Gerais, Brazil. O vírus da leucemia bovina (BLV) é um retrovírus que causa linfoma em bovinos em todo o mundo e também tem sido associada ao câncer de mama em humanos. O mecanismo de infecção pelo BLV em humanos e sua implicação como causa primária de câncer em mulheres ainda não são conhecidos. BLV infecção em humanos pode ser causada pelo consumo de leite e produtos lácteos ou carne de animais infectados. As taxas de incidência de câncer de mama no Brasil são altas, correspondendo a 29,5% ao ano de casos de câncer entre as mulheres. Em 2020, estima-se que 66.280 novos casos de câncer de mama são esperados, enquanto em 2018 o câncer de mama levou a 17.572 mortes, o maior incidência e letalidade entre os cânceres em mulheres neste país naquele ano. A o ocorrência de infecção por BLV varia de 60 a 95% em rebanhos leiteiros. Além disso, existem algumas regiões, como o Estado de Minas Gerais, sudeste do Brasil, onde a população tradicionalmente consome produtos lácteos não pasteurizados. Em conjunto, este estudo teve como objetivo verificar se existe uma maior associação entre câncer de mama e a presença do genoma do BLV no tecido mamário amostras dessa população que consome leite cru de animais com altas taxas de BLV infecção. Um estudo molecular de dois genes BLV foi realizado em 88 parênquimas mamários amostras, entre tumores e controles. O fragmento amplificado foi submetido ao sequenciamento proviral de BLV e sua identidade foi confirmada usando GenBank. Os genes provirais do BLV foram amplificado a partir de amostras de parênquima mamário de tumor e amostras de controle de tecido saudável de mulheres, revelando 95,9% (47/49) e 59% (23/39) de positividade, respectivamente. Nossos resultados mostram a maior correlação de BLV e câncer de mama humano encontrado no mundo até o momento na população de Minas Gerais, Brasil.

Agents that modulate the activity of high-voltage gated calcium channels (HVCCs) exhibit experimentally and clinically significant effect by relieving visceral pain. Among these agents, the toxins Phα1β and ω-conotoxin MVIIA effectively reduce chronic pain in rodent models. The molecular mechanisms underlying the chronic pain associated with acute pancreatitis (AP) are poorly understood. Hypercalcemia is a risk factor; the role of cytosolic calcium is considered to be a modulator of pancreatitis. Blockade of Ca2+ signals may be useful as a prophylactic treatment of pancreatitis. We explored the pathophysiological roles of three peptide toxins: Phα1β and its recombinant form CTK 01512-2-blockers of TRPA1 receptor and HVCCs and ω-conotoxin MVIIA, a specific blocker of N-type calcium channels in cerulein-induced AP. Cerulein injection elicits AP in rats, evidenced by an increase in hyperalgesic pain, inflammatory infiltration, amylase and lipase secretion, and reactive oxygen species, TNF-α, and p65 NF-κB levels. These effects of cerulein-induced AP were abolished by Phα1β and its recombinant form CTK 01512-2, whereas ω-conotoxin MVIIA had no effect on the induced increase in pancreatic enzyme secretion. Our results demonstrate that Phα1β and CTK 01512-2 toxins-antagonists of HVCCs and TRPA1 receptor presented an effective response profile, in the control of nociception and inflammatory process in the AP model in rats, without causing changes in spontaneous locomotion of the rats.

Whole slide imaging (WSI) technology has been used for training, teaching, researching, and remote consultation. Few studies compared HER2 expression using optical microscopy (OM) and WSI evaluations in breast carcinomas. However, no consensus has been achieved comparing both assessments. Material and methods Sections from tissue microarray containing 200 preselected invasive breast carcinomas were submitted to immunohistochemistry applying three anti-HER2 antibodies (HercepTest™, CB11, SP3) and in situ hybridization (DDISH). Slides were evaluated using OM and WSI (Pannoramic MIDI and Viewer, 3DHISTECH). Sensitivity and specificity were calculated comparing the anti-HER2 antibodies and DDISH. Results WSI and OM HER2 evaluations agreement was considered good (SP3, k = 0.80) to very good (CB11 and HercepTest™, k = 0.81). WSI evaluation led to higher sensitivity (ranging from 100 of SP3 and HercepTest™ to 97 of CB11) and lower specificity (ranging from 86.4 of SP3 to 89.4 of HercepTest™) compared to OM evaluation (sensitivity ranged from 92.1 of CB11 to 98 of SP3 and specificity ranged from 95.2 of SP3 and HercepTest™ to 97.1 of CB11 and SP3). Conclusion High agreement was achieved between WSI and OM evaluations. All three antibodies were highly sensitive and specific using both evaluations. WSI can be considered a useful tool for HER2 immunohistochemical assessment.

Purpose: To compare the effectiveness of light-weight polypropylene mesh coated with polymerized and purified bovine type I collagen (Surgidry HNB) in the treatment of abdominal wall defect and the degree of adhesion formation. Methods: Two types of polypropylene mesh were implanted after creation of defect measuring 6.0cm X 5.5cm in the anterior abdominal wall of 32 male New Zealand breed rabbits, divided in two groups (n = 32): (1) light-weigh macroporous polypropylene, (2) type I polymerized and purified bovine collagen coated light-weigh macroporous polypropylene. These animals were further accessed for adhesions, histological evaluation of inflammation and wall’s thickness. Results: The percentage of the area adhered in group 1 (62.31 ± 16.6) was higher compared to group 2 (22.19 ± 14.57) (p

AimsVariability in determining HER2 status has been reported, especially, differences in sensitivity and specificity among commercially available antibodies, with false positive and false negative results. We compared the sensitivity and specificity of five anti-HER2 antibodies by immunohistochemistry (IHC), using the new dual colour brightfield in situ hybridisation (DDISH) as the gold standard, on invasive breast carcinomas (IBC) arrays.Material and methodsSerial sections from tissue microarrays (TMA) containing 200 preselected primary IBC were submitted to DDISH (VENTANA INFORM HER2 Dual ISH assay), and immunohistochemistry, using Dako A0485 and HercepTest (polyclonal), Novocastra CB11 (mouse monoclonal), NeoMarkers SP3 and Ventana 4B5 (rabbit monoclonal).ResultsFrom the initial 200 cases, 184 were assessed by DDISH and IHC. The concordance among the antibodies was considered very good (kappa statistics varied from 0.82 to 0.9). The overall concordance between IHC and DDISH ranged from 94.1% for CB11 to 96.6% for A0485. The antibodies A0485, HercepTest, SP3 and 4B5 were over 95% sensitive and specific. CB11 was the most specific antibody (97.1%). 60% (CB11) to 83.3% (SP3) of the 2+ cases showed no gene amplification by DDISH. False negative cases varied from 0.5% (A0485) to 3.8% (CB11) of the cases, and false positive from 1.6% (CB11) to 2.7% (HercepTest, SP3 and 4B5) of the 184 cases.ConclusionsThere was very good agreement among the five anti-HER2 antibodies. CB11 was the most specific antibody, but showed more false negative cases. A0485, SP3, 4B5 and HercepTest were highly sensitive and specific, but showed more false positive cases.

Background Gastric cancer is usually diagnosed in an advanced stage of disease and treatment options are sparse. Trastuzumab was recently approved for metastatic or locally advanced carcinomas arising in the stomach or in the gastroesophageal junction in patients with HER2-positive tumors. However, data on the frequency of HER2-positive cases among Brazilian patients are limited. Our aim was to characterize HER2 protein and gene status in a series of Brazilian patients with gastric cancer and to evaluate its association with clinicopathological data. Methods Histological slides from 124 primary gastrectomies were reviewed and their pathological reports were retrieved from the files at a Brazilian university hospital. Automated immunohistochemistry for HER2 was performed on whole-tissue sections from each tumor. HER2-equivocal cases by immunohistochemistry were submitted to automated dual in situ hybridization for gene amplification evaluation. HER2 status was confronted with clinicopathological parameters in order to assess statistically significant associations. Results Immunohistochemistry analysis revealed that 13/124 cases (10.5 %) were HER2 positive (3+), 10/124 cases (8.1 %) were equivocal (2+) and 101/124 cases (81.4 %) were negative, being 7 cases 1+. None of the equivocal cases showed gene amplification. The overall HER2 positivity rate was 10.5 %. There was an association between HER2 expression and Laurén’s intestinal histological subtype (P = 0.048), well to moderately differentiated tumors (P = 0.004) and presence of lymphovascular invasion (P = 0.031). No association was found between HER2 status and tumor topography. Conclusions Confronted with data published by other authors, the lower percentage of HER2-positive cases found in our series might be partially explained by the lower frequency of tumors arising at the gastroesophageal junction in comparison with distal gastric carcinomas in Brazilian patients. This could also account for the lack of statistically significant association between HER2 status and tumor topography in our study.

CNPq - Conselho Nacional de Desenvolvimento Científico e Tecnológico OBJETIVOS: Identificar fatores histológicos e imuno-histoquímicos (IHQ) do carcinoma mamário invasor (CMI) relacionados com resposta patológica à terapia neoadjuvante (Tneo) e avaliar os efeitos da terapia na histologia e na expressão imunohistoquímica de biomacadores dos tumores. MATERIAL E MÉTODOS: 70 casos de CMI (biópsia inicial pré-terapia e a peça cirúrgica pós-terapia) do arquivo do Laboratório de Patologia Mamária, diagnosticados e tratados com Tneo no Hospital das Clinicas da UFMG, entre 2009 e 2017. Realizadas avaliações histológica (tipo, grau e densidade de infiltrado inflamatório) e IHQ para Receptores hormonais (RH), HER2 e Ki67. Para avaliação dos fatores preditivos de resposta à Tneo, os casos foram separados em dois grupos (resposta patológica completa - RPC e resposta patológica parcial - RPP). Os achados histológicos e IHQ foram comparados nos grupos RPP e RPC, e entre os tumores iniciais e pós-terapia no grupo RPP. RESULTADOS: Características clínicas, histológicas e IHQ dos 70 casos: predominou o tipo Carcinoma Ductal SOE (77,1%), o grau histológico III (48,6%), e o nível de infiltrado inflamatório entre 1 e 20% (64,3%). 31 (44,3%) dos tumores eram RH+ e HER2-, 10 (14,3%) eram RH- e HER2+, 25 (35,7%) eram triplo negativos e 4 (5,7%) eram RH+ e HER2+.14 (20%) dos tumores apresentaram RPC e 56 (80%), RPP. Na avaliação dos fatores preditivos de RPC apenas os níveis do infiltrado inflamatório mostraram resultados significativos (p=0,003): todos os tumores com RPC apresentaram densidade acima de 21%, enquanto que os tumores com RPP apresentaram densidade de até 20%. Tipo e grau histológicos, RH, HER2 e Ki67 não mostraram resultados significativos. Na avaliação dos efeitos da terapia (grupo RPP), o único fator com significância estatística foi o tipo histológico (p=0,024): 19/55 (34,5%) apresentaram mudança do tipo histológico. Apesar de não ter significância estatística, houve mudança no grau histológico em 26/55 dos casos, como aumento do grau em 27,3% e diminuição em 10,9% dos casos com RPP. Houve aumento dos níveis de infiltrado inflamatório em 7% e diminuição, em 35% dos casos. 22/55 apresentaram mudança do status de RE ou do escore de Alred e 20/55 apresentaram mudança no RP. 96,4% dos casos mantiveram a expressão de HER2. 34,5% tiveram alterações do índice de Ki67. A distribuição do Ki67 tornou-se diferente dos tumores pós-terapia, desviando do esperado (p=0,014). CONCLUSÕES: O único fator que demonstrou associação com RPC foi o nível do infiltrado inflamatório. O tipo e grau histológico e os biomarcadores RE, RP, HER2 e Ki67 não demonstraram significância estatística em relação ao tipo de resposta. Os tumores apresentaram alterações no tipo e grau histológico e nos biomarcadores RE, RP, HER2 e Ki67 após a terapia neoadjuvante, mas somente o tipo histológico e o Ki67 foram estatisticamente significantes.