Acute pancreatitis due to hypercalcemia secondary to primary hyperparathyroidism is a rare aetiology. We present a female patient with pancreatitis; with prior cholecystectomy, no alcohol usage or dyslipidemia. Laboratory studies showed, serum calcium 17.93 mg/dL and iPTH 441 pg/ml. Neck CT showed multinodular goiter and a parathyroid nodule. The patient underwent surgery after which serum Ca and PTH decreased. Biopsy showed follicular variant papillary thyroid carcinoma. This report discusses possible theories of association between parathyroid adenoma and hypercalcemic pancreatitis and describes the association with follicular variant papillary thyroid carcinoma, not previously described. / jmartin_9230@hotmail.com / Article / La pancreatitis aguda por hipercalcemia secundaria a hiperparatiroidismo primario es una etiología infrecuente. Presentamos una paciente mujer de 77 años que presentó dolor abdominal en hemiabdomen superior y vómitos; colecistectomizada, no bebe alcohol ni presenta dislipidemia. Los estudios de laboratorio mostraron, amilasa de 394 U/L y lipasa de 906 U/L, calcio sérico 17,93 mg/dL y el PTHi 441 pg/ml. En la TEM de cuello, se observó bocio multinodular (nódulos de 9 y 7 mm) en el lóbulo izquierdo de tiroides y un nódulo en paratiroides. La paciente fue sometida a una paratiroidectomía superior derecha y una hemitiroidectomía del mismo lado. Después de la cirugía, los niveles de Ca sérico y PTHi disminuyeron. Asimismo, como hallazgo en la biopsia, se encontró carcinoma papilar variante folicular de tiroides. Este reporte explica las posibles teorías de asociación entre adenoma paratiroideo y pancreatitis por hipercalcemia y describe además la asociación con carcinoma papilar variante folicular de tiroides, no antes descrito.

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Publicación a texto completo no autorizada por el autor / Identifica cuáles son los factores asociados a la mortalidad de la pancreatitis aguda severa (PAS), en el Hospital Nacional Arzobispo Loayza (HNAL) en el año 2013. El estudio es analítico, observacional, retrospectivo y longitudinal en pacientes del HNAL con PAS, diagnosticados en el año 2013. Se determinó los casos de PAS según los criterios de Atlanta, utilizando los scores Ranson, APACHE II y Balthazar. Se estudió la asociación entre la mortalidad y los siguientes factores; fallo orgánico, tipo de fallo orgánico (uniorgánico o multiorgánico), duración del fallo orgánico (mayor o menor de 48 horas), calidad de la necrosis pancreática (estéril o infectada), etiología, tiempo de evolución, edad y género. Se utilizó SPSS v. 22.0, aplicándose el análisis univariado y se determinó la asociación entre las variables mediante el test Chi cuadrado, considerándose un nivel de significancia menor de 0.05 (p<0.05). La fuerza de asociación se determinó mediante el coeficiente Phi. Se analizó un total de 36 casos de PAS (19 varones y 17 mujeres), de los cuales 11 habían fallecido. El fallo orgánico se presentó en el 61.1% del total y en el 100% de los fallecidos, encontrándose una asociación significativa conla mortalidad. El fallo multiorgánico se presentó en el 27.7% del total y en el 63.6% de los fallecidos, obteniéndose una asociación significativa con la mortalidad. El fallo orgánico persistente representó el 30.6% del total y el 54.5% de los fallecidos, hallándose una asociaciónsignificativa con la mortalidad.La etiología biliar representó el 86.1% del total y el 63.3% de los fallecidos, encontrándose asociación significativa con la mortalidad. La edad ≥ 60 años representó el 38.9% del total y el 63.6% de fallecidos, obteniéndose una asociación significativacon la mortalidad. Un tiempo de evolución corto (2 a 5 días) se observó en el 38.9% del total y en el 54.5% de fallecidos, hallándose una asociación significativa con la mortalidad. No se encontró asociación entre la mortalidad y el género. No se pudo establecer asociación entre la calidad de la necrosis pancreática (infectada o estéril) y la mortalidad. En conclusión los factores asociados a la mortalidad de PAS fueron: el fallo multiorgánico, el fallo orgánico persistente, la etiología biliar, el grupo etáreo de adultos mayores (≥ 60 años) y un tiempo de evolución corto (2 a 5 días); con una asociación estadísticamente significativa y clínicamente relevante. / Tesis

Publicación a texto completo no autorizada por el autor / Determina que características epidemiológicas y clínicas presentan los pacientes con pancreatitis aguda y establece la prevalencia de casos de pancreatitis aguda del Hospital San Juan de Lurigancho durante el periodo de enero-julio del 2013. El estudio es de tipo descriptivo, retrospectivo. Se realizó la revisión de historias clínicas de pacientes con diagnóstico de pancreatitis aguda durante enero-julio del 2013. Dando como resultado que el grupo etáreo más afectado fue de 30 a 45 años, con una media de 45,11 años. El sexo más afectado fue el femenino 66%. La mayoría provenía de la zona de José Carlos Mariátegui. Entre los factores de riesgo ninguno 44, 61 % y colecistitis crónica calculosa 43,07%. Las manifestaciones clínicas más frecuentes fueron naúseas 31,77%, vómitos 22,89% y epigastralgia 18,69%. La clasificación de severidad de acuerdo a la escala de Ranson fue leve 86,15% y severa 13,85%. La etiología más frecuente es la litiasis biliar 93,84%. Dentro de las complicaciones de la pancreatitis aguda la ausencia de ella en 86,56%. El tratamiento médico en 92,30%. La pancreatitis aguda se presentó principalmente en la población adulta joven con predominancia en el sexo femenino, siendo la causa más frecuente la litiasis biliar. / Tesis

This thesis pertains to the pathogenesis of alcoholic pancreatitis, a considerable burden in terms of morbidity, mortality and health related costs. It has long been known that only a minority of alcoholics develop clinically evident pancreatitis, suggesting that (an) additional trigger factor(s) is required to elicit overt disease. Endotoxin (lipopolysaccharide LPS), from gut-derived gram negative bacteria may be one such trigger factor, since alcoholics exhibit increased levels of serum endotoxin. In addition, the degree of endotoxinaemia has been reported to correlate with the severity of pancreatitis. Studies described in this thesis report, i) the development of a novel rodent model of alcoholic pancreatitis produced by challenging alcohol-fed animals with single or repeated doses of LPS. The animals exhibit features of both acute (acinar vacuolisation, necrosis, pancreatic oedema, haemorrhage and inflammatory infiltration) and chronic (acinar atrophy and pancreatic fibrosis) pancreatitis; ii) the reversion of pancreatic injury (including fibrosis) upon withdrawal of alcohol in the model and the persistence of pancreatic damage with continuation of alcohol feeding; iii) activation of pancreatic stellate cells (PSCs, known to play a central role in fibrogenesis) in vivo and in vitro by alcohol and LPS; iv) the inhibition of PSC apoptosis in vivo and in vitro upon exposure to alcohol and LPS and the induction of PSC apoptosis in vivo upon withdrawal of alcohol from the diet and v) the presence of LPS receptors TLR4 and CD14 on PSCs, which would explain the responsiveness of PSCs to LPS. Thus the work in this thesis provides strong evidence in support of endotoxin as a clinically relevant trigger factor for the initiation of alcoholic pancreatitis and as a factor that promotes disease progression. The thesis also provides the first experimental evidence to support the clinical reports of a beneficial effect of abstinence on chronic pancreatitis. Delineation of the mechanisms mediating the induction, progression and reversibility of alcoholic pancreatitis has the potential to direct the development of new therapeutic interventions for alcohol-related pancreatic injury.

Optimisation of the conventional tripartite of pancreatic cancer (PC) treatment have led to significant improvements in mortality, however further knowledge of the underlying molecular processes is still required. Transcript profiling of mRNA expression of over 44K genes with microarray technology demonstrated upregulation of secreted frizzled related protein 4 (sFRP4) and ??-catenin in PC compared to normal pancreata. Their pathway ??? Wnt signalling is integral to transcriptional regulation and aberrations in these molecules are critical in the development of many human malignancies. Immunohistochemistry protocols were evaluated by two independent blinded examiners for antigen expression differences associated with survival patterns in 140 patients with biopsy verified PC and a subset of 23 normal pancreata with substantial observer agreement (kappa value 0.6-0.8). A retrospective cohort was identified from 6 Sydney hospitals between 1972-2003 and archival formalin fixed tissue was collected together with clinicopathological data. Three manual stepwise regression models were fitted for overall, disease-specific and relapse-free survival to determine the value of significant prognostic variables in risk stratification. The models were fitted in a logical order using a careful strategy with step by step interpretation of the results. Immunohistochemistry demonstrated increased sFRP4 membranous expression (&gt 10%) in 49/95 PC specimens and this correlated with improved overall survival (HR:0.99;95%CI:0.97-6.40;LRchi2=134.75; 1df; ??&lt 0.001). Increased sFRP4 cytoplasmic staining (&gt 2/3) in 46/85 patients increased the disease-specific survival (HR:0.52;95%CI:0.31-0.89;LR test statistic =248.40;1df;??&lt 0.001). Increasing ??-catenin membranous expression (&lt _60%) in 26/116 patients was associated with an increased risk of overall death (HR:3.18;95%CI:1.14-8.89;LR test statistic =4.61;1df,??&lt 0.05). Increasing cytoplasmic expression in 65/114 patients was protective and was associated with prolonged survival on univariate, but not multivariate analysis (Disease specific survival HR:0.75;95%CI:0.56-1.00;logrank chi2=3.91;1df; ??=0.05). Increased nuclear ??-catenin expression in 65/114 patients was associated with prolonged survival (disease-specific HR:0.92;95%CI:0.83-1.02; LR test statistic= 49.72;1df;??&lt 0.001). At the conclusion, 12 patients (8.6%) remained alive, 122 died of their disease (68 males versus 54 females). They were followed for a median of 8.7 months (range 1.0-131.3) months. The median age was 66.5 years (range 34.4-96.0, standard deviation 10.9) years. Pancreatic resection was achieved in 79 patients with 46.8% achieving RO resection. The 30 day post-operative mortality was 2.1%. The overall 1 year survival rate was (33.7% ; 95%CI: 25.78-33.79) with a 5 year survival of (2.87%, 95%CI: 2.83-6.01) and a median survival of (8.90 months; 95%CI: 7.5-10.2). The median disease-specific survival was (9.40; 95%CI: 7.9-10.5 months) and the median time to relapse was 1.2 months (95%CI 1.0-1.2 months). A central tenet of contemporary cancer research is that an understanding of the genetic and molecular abnormalities that accompany the development and progression of cancer is critical to further advances in diagnosis, treatment and eventual prevention. High throughput tissue microarrays were used to study expression of two novel tumour markers in a cohort of pancreatic cancer patients and identified sFRP4 and ??-catenin as potential novel prognostic markers.

Optimisation of the conventional tripartite of pancreatic cancer (PC) treatment have led to significant improvements in mortality, however further knowledge of the underlying molecular processes is still required. Transcript profiling of mRNA expression of over 44K genes with microarray technology demonstrated upregulation of secreted frizzled related protein 4 (sFRP4) and ??-catenin in PC compared to normal pancreata. Their pathway ??? Wnt signalling is integral to transcriptional regulation and aberrations in these molecules are critical in the development of many human malignancies. Immunohistochemistry protocols were evaluated by two independent blinded examiners for antigen expression differences associated with survival patterns in 140 patients with biopsy verified PC and a subset of 23 normal pancreata with substantial observer agreement (kappa value 0.6-0.8). A retrospective cohort was identified from 6 Sydney hospitals between 1972-2003 and archival formalin fixed tissue was collected together with clinicopathological data. Three manual stepwise regression models were fitted for overall, disease-specific and relapse-free survival to determine the value of significant prognostic variables in risk stratification. The models were fitted in a logical order using a careful strategy with step by step interpretation of the results. Immunohistochemistry demonstrated increased sFRP4 membranous expression (&gt 10%) in 49/95 PC specimens and this correlated with improved overall survival (HR:0.99;95%CI:0.97-6.40;LRchi2=134.75; 1df; ??&lt 0.001). Increased sFRP4 cytoplasmic staining (&gt 2/3) in 46/85 patients increased the disease-specific survival (HR:0.52;95%CI:0.31-0.89;LR test statistic =248.40;1df;??&lt 0.001). Increasing ??-catenin membranous expression (&lt _60%) in 26/116 patients was associated with an increased risk of overall death (HR:3.18;95%CI:1.14-8.89;LR test statistic =4.61;1df,??&lt 0.05). Increasing cytoplasmic expression in 65/114 patients was protective and was associated with prolonged survival on univariate, but not multivariate analysis (Disease specific survival HR:0.75;95%CI:0.56-1.00;logrank chi2=3.91;1df; ??=0.05). Increased nuclear ??-catenin expression in 65/114 patients was associated with prolonged survival (disease-specific HR:0.92;95%CI:0.83-1.02; LR test statistic= 49.72;1df;??&lt 0.001). At the conclusion, 12 patients (8.6%) remained alive, 122 died of their disease (68 males versus 54 females). They were followed for a median of 8.7 months (range 1.0-131.3) months. The median age was 66.5 years (range 34.4-96.0, standard deviation 10.9) years. Pancreatic resection was achieved in 79 patients with 46.8% achieving RO resection. The 30 day post-operative mortality was 2.1%. The overall 1 year survival rate was (33.7% ; 95%CI: 25.78-33.79) with a 5 year survival of (2.87%, 95%CI: 2.83-6.01) and a median survival of (8.90 months; 95%CI: 7.5-10.2). The median disease-specific survival was (9.40; 95%CI: 7.9-10.5 months) and the median time to relapse was 1.2 months (95%CI 1.0-1.2 months). A central tenet of contemporary cancer research is that an understanding of the genetic and molecular abnormalities that accompany the development and progression of cancer is critical to further advances in diagnosis, treatment and eventual prevention. High throughput tissue microarrays were used to study expression of two novel tumour markers in a cohort of pancreatic cancer patients and identified sFRP4 and ??-catenin as potential novel prognostic markers.

This thesis pertains to the pathogenesis of alcoholic pancreatitis, a considerable burden in terms of morbidity, mortality and health related costs. It has long been known that only a minority of alcoholics develop clinically evident pancreatitis, suggesting that (an) additional trigger factor(s) is required to elicit overt disease. Endotoxin (lipopolysaccharide LPS), from gut-derived gram negative bacteria may be one such trigger factor, since alcoholics exhibit increased levels of serum endotoxin. In addition, the degree of endotoxinaemia has been reported to correlate with the severity of pancreatitis. Studies described in this thesis report, i) the development of a novel rodent model of alcoholic pancreatitis produced by challenging alcohol-fed animals with single or repeated doses of LPS. The animals exhibit features of both acute (acinar vacuolisation, necrosis, pancreatic oedema, haemorrhage and inflammatory infiltration) and chronic (acinar atrophy and pancreatic fibrosis) pancreatitis; ii) the reversion of pancreatic injury (including fibrosis) upon withdrawal of alcohol in the model and the persistence of pancreatic damage with continuation of alcohol feeding; iii) activation of pancreatic stellate cells (PSCs, known to play a central role in fibrogenesis) in vivo and in vitro by alcohol and LPS; iv) the inhibition of PSC apoptosis in vivo and in vitro upon exposure to alcohol and LPS and the induction of PSC apoptosis in vivo upon withdrawal of alcohol from the diet and v) the presence of LPS receptors TLR4 and CD14 on PSCs, which would explain the responsiveness of PSCs to LPS. Thus the work in this thesis provides strong evidence in support of endotoxin as a clinically relevant trigger factor for the initiation of alcoholic pancreatitis and as a factor that promotes disease progression. The thesis also provides the first experimental evidence to support the clinical reports of a beneficial effect of abstinence on chronic pancreatitis. Delineation of the mechanisms mediating the induction, progression and reversibility of alcoholic pancreatitis has the potential to direct the development of new therapeutic interventions for alcohol-related pancreatic injury.

MinistÃre de l'Enseignement SupÃrieur et de la Recherche / Pancreatite aguda (PA) à uma doenÃa inflamatÃria em que mediadores prÃ-inflamatÃrios, estresse oxidativo e sinalizaÃÃo de NF- kB desempenham um papel fundamental. O 1,8-cineol, um monoterpeno presente em diversas espÃcies vegetais, à conhecido por seu potencial antioxidante e anti-inflamatÃrio. Para verificar a sua eficÃcia na prevenÃÃo da PA, este estudo avaliou o 1,8-cineol (100, 200 e 400 mg / kg, v.o) na PA induzida por ceruleÃna (50 Âg / kg / h à 5, i.p.) em camundongos Swiss. O 1,8-cineol foi administrado uma hora antes da primeira injeÃÃo de ceruleÃna. Grupos tratados com veÃculo ou talidomida foram incluÃdos como controles. Seis horas depois, as amostras de sangue foram coletadas para determinar os nÃveis sÃricos de amilase, lipase e citocinas. O pÃncreas foi removido para exame morfolÃgico, ensaios de mieloperoxidase (MPO) e malondialdeÃdo (MDA), alteraÃÃes na glutationa reduzida (GSH) e para a imunocoloraÃÃo do fator nuclear NF-&#954;B. O pulmÃo direito foi removido para ensaio de MPO. O 1,8-cineol reduziu o dano histolÃgico e a expressÃo de NF-&#954;B induzidos por ceruleÃna. CeruleÃna aumentou significativamente a amilase, lipase, TNF-&#945;, IL1-&#946; e IL-6 e reduziu IL-10. O 1,8-cineol 100, 200 e 400 mg/kg reverteu significativamente os danos causados pela ceruleÃna, atravÃs da reduÃÃo da amilase (14; 16; 21%), lipase (49; 48; 42%), TNF-&#945; (46; 66; 44%), IL1-&#946; (53; 45 e 67%) e IL-6 (49; 40; 41%) e aumento da IL-10 (34; 29 e 46%), respectivamente. CeruleÃna produziu edema pancreÃtico, aumentou MDA, MPO pancreÃtica, MPO pulmonar e reduziu GSH em comparaÃÃo com o grupo veÃculo (p &#706; 0,05). O 1,8-cineol 100, 200 e 400 mg/kg reduziu o edema pancreÃtico (6; 27; 17 %), MDA (34; 29; 46 %), MPO pancreÃtica (40; 55 e 78 %), MPO pulmonar (42; 45 e 22 %) e preservou GSH (62; 63 e 65 %). Estes achados sugerem que o 1,8-cineol pode prevenir a severidade da pancreatite aguda induzida por ceruleÃna em camundongos por meio de um mecanismo anti-inflamatÃrio e antioxidante. / Acute pancreatitis (AP) is an inflammatory condition in which pro-inflammatory mediators, oxidative stress and NF-kB signaling have a fundamental role. The 1,8-cineole, a monoterpene present in several plants species, is known for its antioxidant and anti-inflammatory potential. In order to verify its efficacy preventing AP, this study evaluated 1,8-cineole (100, 200 and 400 mg/kg, oral) on AP induced by cerulein (50 Âg / kg / h à 5, i.p.) in Swiss mice. The 1,8-cineole was administrated one hour before the first injection of cerulein. Groups treated with vehicle or thalidomide were included as controls. Six hours later, blood samples were collected to determine blood levels of amylase, lipase and cytokines. The pancreas was removed for morphological examination, myeloperoxidase (MPO) and malondialdehyde (MDA) trials, changes in reduced glutathione (GSH) and for immunostaining of nuclear factor NF-&#954;B. The right lung was removed for MPO trial. The 1,8-cineole reduced the histological damage and the expression of NF-&#954;B induced by cerulein. Cerulein increased significantly amylase, lipase, TNF- &#945;, IL1- &#946; and IL-6, reducing IL-10. The 1,8-cineole 100, 200 and 400 mg/kg reversed significantly the damages caused by cerulein by reducing amylase (14; 16; 21 %), lipase (49; 48; 42 %), TNF-&#945; (46; 66; 44 %), IL1-&#946; (53; 45 e 67 %) e IL-6 (49; 40; 41 %) and enhanced IL-10 (34; 29 e 46 %), respectively. Cerulein produced pancreatic edema, increased MDA, pancreatic MPO, pulmonary MPO and decreased GSH comparing to the vehicle group (p < 0,05). The 1,8 cineole 100, 200 and 400 mg/kg reduced pancreatic edema (6; 27; 17%), MDA (34; 29; 46%), pancreatic MPO (40; 55 and 78 %), pulmonary MPO (42; 45 and 22 %) and preserved GSH (62; 63 and 65 %). These findings suggest that 1,8-cineol can prevent the severity of cerulein-induced acute pancreatitis in mice through an anti-inflammatory and antioxidant mechanisms.

Die Hämoxygenase-1 (HO-1) ist das geschwindigkeitsbestimmende Enzym des Hämabbaus und ist wichtiger Regulator inflammatorischer Prozesse. Der Verlauf einer experimentellen akuten Pankreatitis (AP) konnte im Tiermodell durch HO-1 Induktion abgemildert werden. Die Aktivierung und Proliferation pankreatischer Stellatum Zellen (PSC) wird durch eine experimentelle HO-1 Induktion inhibiert und kann so möglicherweise vor der Fibrosierung des Pankreasparenchyms bei chronischer Pankreatitis (CP) schützen. Die Transkription der HO-1 wird durch einen GT-Repeat beeinflusst, der im Promoter lokalisiert ist. Diese Arbeit untersuchte, ob Varianten des GT-Repeat oder weitere genetische Varianten der HO-1 mit verschiedenen Pankreatitisformen assoziiert sind. Der GT-Repeat und der SNP rs2071746 wurden mit fluoreszensmarkierten Primern bzw. mit Schmelzkurvenanalyse bei 285 Patienten mit AP, bei 208 Patienten mit alkoholischer CP (ACP), bei 207 mit idiopathischer/hereditärer CP (ICP/HCP), 147 Patienten mit Alkoholischer Leberzirrhose (ALZ) und bei 289 Kontrollen untersucht. Bei den ACP Patienten wurde die GT-Repeat Analyse auf insgesamt 446 Patienten erhöht. Zusätzlich wurden die kodierenden HO-1 Abschnitte mittels DNA-Sequenzierung bei 145 Patienten mit ACP, 138 Patienten mit ICP/HCP, 147 Patienten mit ALZ und bei 151 Kontrollen analysiert. Das Exon 3 wurde darüber hinaus bei zusätzlichen ICP/HP Patienten und Kontrollen untersucht. Die Längenverteilungen des GT-Repeat, die Allelverteilung des SNP rs2071746 und die Verteilung der bei der DNA-Sequenzierung gefundenen synonymen und nicht synonymen Varianten waren bei allen untersuchten Gruppen nicht signifikant unterschiedlich. Obwohl die funktionellen Daten einen Einfluss von HO-1 Varianten auf die Pathogenese der verschiedenen Pankreatitis-Formen nahelegen, konnte unsere umfangreiche genetische Analyse keine Assoziation nachweisen. Genetische Varianten der HO-1 haben keinen Einfluss auf die Entwicklung einer AP, ACP, ICP/HCP und ALZ.