Pancreatic involvement in fatal human leptospirosis: clinical and histopathological features

Hyperamylasemia has been reported in more than 65% of patients with severe leptospirosis, and the true diagnosis of acute pancreatitis is complicated by the fact that renal failure can increase serum amylase levels. Based on these data we retrospectively analyzed the clinical and histopathological features of pancreas involvement in 13 cases of fatal human leptospirosis. The most common signs and symptoms presented at admission were fever, chills, vomiting, myalgia, dehydratation, abdominal pain and diarrhea. Trombocytopenia was evident in 11 patients. Mild increased of AST and ALT levels was seen in 9 patients. Hyperamylasemia was recorded in every patient in whom it was measured, with values above 180 IU/L (3 cases). All patients presented acute renal failure and five have been submitted to dialytic treatment. The main cause of death was acute respiratory failure due to pulmonary hemorrhage. Pancreas fragments were collected for histological study and fat necrosis was the criterion used to classify acute pancreatitis. Histological pancreatic findings were edema, mild inflammatory infiltrate of lymphocytes, hemorrhage, congestion, fat necrosis and calcification. All the patients infected with severe form of leptospirosis who develop abdominal pain should raise the suspect of pancreatic involvement.

Trousseau's Syndrome Due to Asymptomatic Pancreatic Adenocarcinoma

Os autores relatam um caso de Síndrome de Trousseau, manifestado por trombose venosa migratória e embolia pulmonar, num doente de 58 anos assintomático até à data de internamento. O estudo desencadeado revela adenocarcinoma do pâncreas com metástases hepáticas, e a situação torna-se ainda mais grave após a ocorrência de um acidente vascular cerebral isquémico, aparentemente em relação com a paragem por 24 horas da terapêutica anti-coagulante com heparina de baixo peso molecular para realização de biópsia hepática e pancreática guiadas por exame de imagem. A síndrome de Trousseau define-se por tromboses venosas recorrentes ou migratórias, embolias arteriais causadas por endocardite trombótica não-bacteriana, ou ambas, em doentes com neoplasia maligna subjacente. O tratamento implica a administração permanente de heparina, e qualquer interrupção −ainda que breve− pode proporcionar novo episódio de trombose.

Propranolol no Tratamento do Hemangioma Infantil. A Propósito de 2 Casos

Introdução: O Hemangioma infantil é o tumor benigno mais frequente na idade pediátrica. A maioria tem evolução favorável, no entanto dependendo da sua localização, podem levar à distorsão de estruturas anatómicas ou a outras complicações locais ou sistémicas, tornando necessária uma abordagem terapêutica precoce e eficaz. Neste contexto, desde que Léauté-Labréze e colaboradores publicaram a sua experiência com o propranolol em 2008, têm-se multiplicado na literatura internacional, casos clínicos e pequenas séries em que este fármaco é utilizado “off-label” como terapêutica de primeira linha. O presente trabalho visa reportar a experiência de um serviço na utilização de propranolol como terapêutica de primeira linha no tratamento do hemangioma infantil em 2 doentes. Casos clínicos: O doente 1, do sexo feminino, tinha um hemangioma infantil desde as 5 semanas, localizado na pirâmide nasal. O doente 2, do sexo masculino, tinha dois hemangiomas infantis ulcerados: um localizado na face, com atingimento do mento, lábio inferior, mucosa gengival e labial; um segundo de localização escrotal. Ambos os doentes realizaram indução terapêutica com propranolol em regime de internamento com uma dose alvo de 2 a 3 mg/Kg/dia. Ao fim de 6 meses de follow-up, assistiu-se a uma resposta muito satisfatória, sem complicações documentadas. Discussão: O propranolol constitui uma alternativa segura e eficaz no tratamento do hemangioma. Embora não tenham ocorrido complicações, elas estão descritas e ocorrem principalmente durante a fase de indução terapêutica, tornando importante a monitorização durante esse período.

The Role of Propranolol in the Treatment of Infantile Hemangioma

INTRODUCTION: Infantile hemangioma (IH) is one of the most common childhood tumors. There are various medical or surgical therapeutic options, all with suboptimal results. Recently, the successful use of propranolol for involution of IH was described. We report the results of a single-center experience with this therapeutic option. OBJECTIVE: To prospectively assess the efficacy and safety of propranolol in children with infantile hemangioma. METHODS: We performed a prospective analysis of clinical data of all patients with IH referred to a pediatric cardiology center for baseline cardiovascular assessment prior to propranolol therapy. Propranolol was given at a starting dose of 1 mg/kg/day and titrated to a target dose of 2-3 mg/kg/day according to clinical response. Efficacy was assessed through a photograph-based severity scoring scale. Safety was assessed by collecting data regarding significant side effects. RESULTS: Starting in 2010, 30 patients (15 female) were referred for propranolol treatment of IH, at a median age of six months (1-63 months). The mean target propranolol dose was 2.8 mg/kg/day, with a mean duration of therapy of 12 months. All patients experienced significant reduction of IH size and volume. There were no side effects. CONCLUSIONS: In our experience propranolol appears to be a useful and safe treatment option for severe or complicated IH, achieving a rapid and significant reduction in their size. No adverse effects were observed, although until larger clinical trials are completed, potential adverse events should be borne in mind and consultation with local specialists is recommended prior to initiating treatment.

Hemangioma Infantil Ulcerado do Sulco Interglúteo Tratado com Timolol Tópico

Dados recentes revelam resultados promissores com a utilização de beta-bloqueante tópico no tratamento dos hemangiomas infantis ulcerados. Os autores descrevem o caso clínico de uma lactente pré-termo de 6 meses de idade com um hemangioma infantil ulcerado do sulco interglúteo tratado com bom resultado clínico com timolol tópico.

Pancreatic Involvement by Plasma Cell Neoplasms

INTRODUCTION: Pancreatic involvement by plasma cell neoplasms is an extremely rare event, with only 50 cases described in the literature. They can present as a primary solitary extramedullary plasmacytoma or plasmacytoma secondary to a plasma cell myeloma. Clinical manifestations are due to the presence of a pancreatic mass usually in the pancreas head, which causes extra-biliary obstruction and abdominal pain. METHODS: Abdominal imaging including CT scan or endoscopic ultrasound with fine-needle aspiration tissue sampling is essential for the initial diagnostic procedure. However, immunohistochemical analysis of the biopsy specimen or flow cytometry of the aspirated material is crucial to prove the monoclonality and the final diagnosis of a plasma cell neoplasm. DISCUSSION: Management of these situations include radiotherapy, chemotherapy, surgery or combined therapy. Novel medications including the immunomodulatory drugs or the proteasome inhibitors followed by consolidation with intensive chemotherapy and haematopoietic stem cell transplantation are nowadays used as upfront treatment in the cases associated to a plasma cell myeloma. CONCLUSION: Despite the rarity, plasma cell neoplasms should be considered in the differential diagnosis of obstructive jaundice and pancreatic neoplasms since they are potentially treatable situations.

Hemangioma Cavernoso da Supra-Renal

INTRODUÇÃO: O hemangioma cavernoso da glândula supra-renal é um tumor benigno, raro, com menos de uma centena de casos reportados na literatura. É caracterizado na sua constituição por formações vasculares dilatadas e delimitadas por células endoteliais. Apresenta-se caracteristicamente como um incidentaloma e o seu diagnóstico é habitualmente estabelecido apenas no pós-operatório. CASO CLÍNICO: Doente de 73 anos referenciada por nódulo de 45mm da glândula supra-renal esquerda diagnosticado incidentalmente no seguimento de lesão quística renal. A avaliação imagiológica por TC revelou nódulo sólido de 45x28mm na glândula supra-renal esquerda. Realizou estudo para avaliar a autonomia do nódulo, e que revelou uma hipersecreção adrenérgica. Colocada a hipótese diagnóstica de feocromocitoma e proposta para cirurgia ablativa. Foi submetida a suprarrenalectomia esquerda laparoscópica, que decorreu sem intercorrências. O resultado histológico da peça operatória revelou um hemangioma cavernoso da supra-renal. DISCUSSÃO / CONCLUSÃO: A forma de apresentação mais comum do hemangioma cavernoso da supra-renal é a de um incidentaloma, implicando o diagnóstico diferencial com os vários tipos de lesões ocupando espaço deste órgão. Este facto associado à falta de especificidade dos exames pré-operatórios e à raridade da patologia compromete a acuidade diagnóstica. No presente caso, assim como na maioria dos reportados na literatura, esta patologia foi somente estabelecida no pós-operatório através do resultado anátomo-patológico.

Cryptosporidiosis of the biliary tract mimicking pancreatic cancer in an AIDS patient

Diarrhea caused by Cryptosporidium sp is frequent in patients with AIDS, but involvement of other organs of the digestive tract is uncommon. We report a case of Cryptosporidium-associated obstruction of the biliary tract mimicking cancer of the head of the pancreas in a 43-year-old woman with AIDS.

Detection of codon 12 mutation in the k-ras oncogene in pancreatic tumors

Mutations at codons 12, 13, or 61 of the H-ras, K-ras, and N-ras have been detected in human neoplasias by a variety of techniques. Some of these techniques are very sensitive and can detect K-ras mutation in 90% of the cases of pancreatic adenocarcinomas. We analyzed 11 samples of pancreatic adenocarcinoma, three samples of pancreatic mucinous cystadenoma, and two samples without tumors in formalin-fixed paraffin embedded tissue sections. K-ras mutations at codon 12 were detected by a two-step PCR-enriched technique in all the samples of pancreatic adenocarcinoma, but not in cystadenoma or control samples. This technique may be useful for early detection of pancreatic cancer.

Vascular lesions of the lumbar epidural space: magnetic resonance imaging features of epidural cavernous hemangioma and epidural hematoma

The authors report the magnetic resonance imaging diagnostic features in two cases with respectively lumbar epidural hematoma and cavernous hemangioma of the lumbar epidural space. Enhanced MRI T1-weighted scans show a hyperintense signal rim surrounding the vascular lesion. Non-enhanced T2-weighted scans showed hyperintense signal.

Indicators of inflammation and cellular damage in chronic asymptomatic or oligosymptomatic alcoholics: correlation with alteration of bilirubin and hepatic and pancreatic enzymes

Biochemical and hematimetric indicators of inflammation and cell damage were correlated with bilirubin and hepatic and pancreatic enzymes in 30 chronic male alcoholics admitted into psychiatric hospital for detoxification and treatment of alcoholism. Aspartate aminotransferase, alanine aminotransferase, gamma-glutamyltransferase, alkaline phosphatase, and total bilirubin were altered, respectively, in 90%, 63%, 87%, 23% and 23% of the cases. None of the indicators of inflammation (lactic dehydrogenase, altered in 16% of the cases; alpha-1 globulin, 24%; alpha-2 globulin, 88%; leucocyte counts, 28%) was correlated with alterations of bilirubin or liver enzymes. Lactic dehydrogenase was poorly sensitive for detection of hepatocytic or muscular damage. Alterations of alpha-globulins seemed to have been due more to alcohol metabolism-induced increase of lipoproteins than to inflammation. Among indicators of cell damage, serum iron, increased in 40% of the cases, seemed to be related to liver damage while creatine phosphokinase, increased in 84% of the cases, related to muscle damage. Hyperamylasemia was found in 20% of the cases and significantly correlated with levels of bilirubin, alkaline phosphatase and gamma-glutamyltransferase. It was indicated that injuries of liver, pancreas, salivary glands, and muscle occurred in asymptomatic or oligosymptomatic chronic alcoholics.

Morphologic and morphometric evaluation of pancreatic islets in chronic Chagas' disease

PURPOSE: Hyperglycemia and abnormal glucose tolerance tests observed in some patients with chronic Chagas' disease suggest the possibility of morphological changes in pancreatic islets and/or denervation. The purpose of this study was to describe the morphology and morphometry of pancreatic islets in chronic Chagas' disease. METHODS: Morphologic and computerized morphometric studies were performed in fragments of the head, body, and tail regions of the pancreas obtained at necropsies of 8 normal controls and 17 patients with chronic Chagas' disease: 8 with the digestive form (Megas) and 9 with the congestive heart failure form. RESULTS: The Megas group had a larger (p < 0.05) pancreatic islet area in the tail of the pancreas (10649.3 ± 4408.8 µm²) than the normal control (9481.8 ± 3242.4 µm²) and congestive heart failure (9475.1 ± 2104.9 µm²) groups; likewise, the density of the pancreatic islets (PI) was greater (1.2 ± 0.7 vs. 0.9 ± 0.6 vs. 1.9 ± 1.0 PI/mm², respectively). In the tail region of the pancreas of patients with the Megas form, there was a significant and positive correlation (r = +0.73) between the area and density of pancreatic islets. Discrete fibrosis and leukocytic infiltrates were found in pancreatic ganglia and pancreatic islets of the patients with Chagas' disease. Trypanosoma cruzi nests were not observed in the examined sections. Individuals with the Megas form of Chagas' disease showed increased area and density of pancreatic islets in the tail of the pancreas. CONCLUSION: The observed morphometric and morphologic alterations are consistent with functional changes in the pancreas, including glycemia and insulin disturbances.

Pancreatic lesions in acute experimental Chagas' disease

BACKGROUND: Chagas' disease is an endemic tropical affliction found from southern United States to Argentina. The acute phase of this disease is difficult to study in man because the symptoms are non-specific and most cases require no medical assistance. Experimental models have been developed for sequential studies, and intense parasitism in all organs and tissues, including the pancreas, have been detected in the acute phase. PURPOSE: To evaluate the involvement of the pancreas in acute experimental Chagas' disease in a mouse model by histopathological characterization. CASUISTIC AND METHODS: Ten BALBc mice, about 20 g, injected i.p. with 100 000 forms of the Y strain of Trypanosoma cruzi were used. The animals were sacrificed after 14 days of infection. Fragments of pancreas were processed by conventional paraffin embedding and hematoxylin-eosin staining. RESULTS: Ruptured pseudocysts and release of parasites to the extracellular medium caused by necrosis of acinar and duct cells and foci of fat were the most striking histopathological features of acute Chagasic pancreatitis. CONCLUSION: Parasitism is the main cause of acute pancreatitis in Chagas' disease.

Umbilical mass as the sole presenting symptom of pancreatic cancer: a case report

Umbilical nodes are rare. The metastatic involvement of the region was first described in 1846. Sister Mary Joseph was the first observer to establish the correlation between carcinomas and umbilical nodes. The umbilical node may be the sole presenting sign of cancer and is usually associated with advanced disease and poor prognosis. A 64-year-old woman, previously healthy, presented vague abdominal discomfort and a hard umbilical nodule for 1 week, which was first diagnosed as an incarcerated umbilical hernia. She underwent a new clinical assessment and biopsy. After immunohistochemical analysis and computerized tomography, she was diagnosed with pancreatic cancer. The clinical staging showed advanced disease with distant metastasis. She received palliative chemotherapy. After 8 months, she was alive in poor clinical condition. Clinical suspicion should lead to a careful additional evaluation whenever an umbilical nodule presents with malignant signs.

Analysis of outcome and cancer stem cells status in patients with resectable pancreatic adenocarcinoma

RESUMO: Actualmente, a única possibilidade de cura para doentes com adenocarcinoma do pâncreas (PDAC) é a ressecção cirúrgica, no início deste estudo, perguntamo-nos se os predictores clínico-patológicos clássicos de prognostico poderiam ser validados em uma grande cohort de doentes com cancro do pâncreas ressecável e se outros predictores clínicos poderiam ter um papel na decisão de que doentes beneficiariam de ressecção cirúrgica. No capítulo 2, observamos que até 30% dos doentes morrem no primeiro ano após a ressecção cirúrgica, pelo que o nosso objectivo foi determinar factores pré-operatórios que se correlacionam com mortalidade precoce após ressecação cirúrgica com recurso a um instrumento estatisticamente validado, o Charlson-Age Comorbidity Index (CACI), determinamos que um CACI score superior a 4 foi preditivo de internamentos prolongados (p <0,001), complicações pós-operatórias (p = 0,042), e mortalidade em 1 ano pós- ressecção cirúrgica (p <0,001). Um CACI superior a 6 triplicou a mortalidade no primeiro ano pós-cirurgia e estes doentes têm menos de 50% de probabilidade de estarem vivos um ano após a cirurgia. No capítulo 3, o nosso objectivo foi identificar uma proteína de superfície que se correlacionasse estatisticamente com o prognostico de doentes com adenocarcinoma do pâncreas e permitisse a distinção de subgrupos de doentes de acordo com as suas diferenças moleculares, perguntamo-nos ainda se essa proteína poderia ser um marcador de células-estaminais. No nosso trabalho anterior observamos que as células tumorais na circulação sanguínea apresentavam genes com características bifenotípica epitelial e mesenquimal, enriquecimento para genes de células estaminais (ALDH1A1 / ALDH1A2 e KLF4), e uma super-expressão de genes da matriz extracelular (colagénios, SPARC, e DCN) normalmente identificados no estroma de PDAC. Após a avaliação dos tumores primários com RNA-ISH, muitos dos genes identificados, foram encontrados co-localizando em uma sub-população de células na região basal dos ductos pancreáticos malignos. Além disso, observamos que estas células expressam o marcador SV2A neuroendócrino, e o marcador de células estaminais ALDH1A1/2. Em comparação com tumores negativos para SV2, os doentes com tumores SV2 positivos apresentaram níveis mais baixos de CA 19-9 (69% vs. 52%, p = 0,012), tumores maiores (> 4 cm, 23% vs. 10%, p = 0,0430), menor invasão de gânglios linfáticos (69% vs. 86%, p = 0,005) e tumores mais diferenciados (69% vs. 57%, p = 0,047). A presença de SV2A foi associada com uma sobrevida livre de doença mais longa (HR: 0,49 p = 0,009) bem como melhor sobrevida global (HR: 0,54 p = 0,018). Em conjunto, esta informação aponta para dois subtipos diferentes de adenocarcinoma do pâncreas, e estes subtipos co-relacionam estatisticamente com o prognostico de doentes, sendo este subgrupo definido pela presença do clone celular SV2A / ALDH1A1/2 positivo com características neuroendócrinas. No Capítulo 4, a expressão de SV2A no cancro do pâncreas foi validado em linhas celulares primárias. Demonstramos a heterogeneidade do adenocarcinoma do pâncreas de acordo com características clonais neuroendócrinas. Ao comparar as linhas celulares expressando SV2 com linhas celulares negativas, verificamos que as linhas celulares SV2+ eram mais diferenciadas, diferindo de linhas celulares SV2 negativas no que respeita a mutação KRAS, proliferação e a resposta à quimioterapia. No capítulo 5, perguntamo-nos se o clone celular SV2 positivo poderia explicar a resistência a quimioterapia observada em doentes. Observamos um aumento absoluto de clones celulares expressando SV2A, em múltiplas linhas de evidência - doentes, linhas de células primárias e xenotransplantes. Embora, tenhamos sido capazes de demonstrar que o adenocarcinoma do pâncreas é uma doença heterogénea, consideramos que a caracterização genética destes clones celulares expressando SV2A é de elevada importância. Pretendemos colmatar esta limitação com as seguintes estratégias: Após o tratamento com quimioterapia neoadjuvante na nossa coorte, realizamos microdissecação a laser das amostras primarias em parafina, de forma a analisar mutações genéticas observadas no adenocarcinoma pancreático; em segundo lugar, pretendemos determinar consequências de knockdown da expressão de SV2A em nossas linhas celulares seguindo-se o tratamento com gemicitabina para determinação do papel funcional de SV2A; finalmente, uma vez que os nossos esforços anteriores com um promotor - repórter e SmartFlare ™ falharam, o próximo passo será realizar RNA-ISH PrimeFlow™ seguido de FACS e RNA-seq para caracterização deste clone celular. Em conjunto, conseguimos provar com várias linhas de evidência, que o adenocarcinoma pancreático é uma doença heterogénea, definido por um clone de células que expressam SV2A, com características neuroendócrinas. A presença deste clone no tecido de doentes correlaciona-se estatisticamente com o prognostico da doença, incluindo sobrevida livre de doença e sobrevida global. Juntamente com padrões de proliferação e co-expressão de ALDH1A1/2, este clone parece apresentar um comportamento de células estaminais e está associado a resistência a quimioterapia, uma vez que a sua expressão aumenta após agressão química, quer em doentes, quer em linhas de células primárias.----------------------------- ABSTRACT: Currently, the only chance of cure for patients with pancreatic adenocarcinoma is surgical resection, at the beginning of my thesis studies, we asked if the classical clinicopathologic predictors of outcome could be validated in a large cohort of patients with early stage pancreatic cancer and if other clinical predictors could have a role on deciding which patients would benefit from surgery. In chapter 2, we found that up to 30% of patients die within the first year after curative intent surgery for pancreatic adenocarcinoma. We aimed at determining pre-operative factors that would correlate with early mortality following resection for pancreatic cancer using a statistically validated tool, the Charlson-Age Comorbidity Index (CACI). We found that a CACI score greater than 4 was predictive of increased length of stay (p<0.001), post-operative complications (p=0.042), and mortality within 1-year of pancreatic resection (p<0.001). A CACI score of 6 or greater increased 3-fold the odds of death within the first year. Patients with a high CACI score have less than 50% likelihood of being alive 1 year after surgery. In chapter 3 we aimed at identifying a surface protein that correlates with patient’s outcome and distinguishes sub-groups of patients according to their molecular differences and if this protein could be a cancer stem cell marker. The most abundant class of circulating tumor cells identified in our previous work was found to have biphenotypic features of epithelial to mesenchymal transition, enrichment for stem-cell associated genes (ALDH1A1/ALDH1A2 and KLF4), and an overexpression of extracellular matrix genes (Collagens, SPARC, and DCN) normally found in the stromal microenvironment of PDAC primary tumors. Upon evaluation of matched primary tumors with RNA-ISH, many of the genes identified were found to co-localize in a sub-population of cells at the basal region of malignant pancreatic ducts. In addition, these cells expressed the neuroendocrine marker SV2A, and the stem cell marker ALDH1A1/2. Compared to SV2 negative tumors, patients with SV2 positive tumors were more likely to present with lower CA 19-9 (69% vs. 52%, p = 0.012), bigger tumors (size > 4 cm, 23% vs. 10%, p= 0.0430), less nodal involvement (69% vs. 86%, p = 0.005) and lower histologic grade (69% vs. 57%, p = 0.047). The presence of SV2A expressing cells was associated with an improved disease free survival (HR: 0.49 p=0.009) and overall survival (HR: 0.54 p=0.018) and correlated linearly with ALDH1A2. Together, this information points to two different sub-types of pancreatic adenocarcinoma, and these sub-types correlated with patients’ outcome and were defined by the presence of a SV2A/ ALDH1A1/2 expressing clone with neuroendocrine features. In Chapter 4, SV2A expression in cancer was validated in primary cell lines. We were able to demonstrate pancreatic adenocarcinoma heterogeneity according to neuroendocrine clonal features. When comparing SV2 expressing cell lines with SV2 negative cell lines, we found that SV2+ cell lines were more differentiated and differ from SV2 negative cell lines regarding KRAS mutation, proliferation and response to chemotherapy. In Chapter 5 we aimed at determining if this SV2 positive clone could explain chemoresistance observed in patients. We found an absolute increase in SV2A expressing cells, with multiple lines of evidence, in patients, primary cell lines and xenografts. Although, we have been able to show evidence that pancreatic adenocarcinoma is a heterogeneous disease, our findings warrant further investigation. To further characterize SV2A expressing clones after treatment with neoadjuvant chemotherapy in our cohort, we have performed laser capture microdissection of the paraffin embedded tissue in this study and will analyze the tissue for known genetic mutations in pancreatic adenocarcinoma; secondly, we want to know what will happen after knocking down SV2A expression in our cell lines followed by treatment with gemcitabine to determine if SV2A is functionally important; finally, since our previous efforts with a promoter – reporter and SmartFlare™ have failed, we will utilize a novel PrimeFlow™ RNA-ISH assay followed by FACS and RNA sequencing to further characterize this cellular clone. Overall our data proves, with multiple lines of evidence, that pancreatic adenocarcinoma is a heterogeneous disease, defined by a clone of SV2A expressing cells, with neuroendocrine features. The presence of this clone in patients’ tissue correlates with patient’s disease free survival and overall survival. Together with patterns of proliferation and ALDH1A1/2 co-expression, this clone seems to present a stem-cell-like behavior and is associated with chemoresistance, since it increases after chemotherapy, both in patients and primary cell lines.