Pancreatic Head Adenocarcinomas - Histopathologic Evaluation and Prognostic Factors

Primary adenocarcinomas located in the pancreatic head may arise from the distal bile duct, the ampulla, the periampullary duodenum, and the pancreatic tissue itself. These tumours are distinct cancer entities whose pathobiology, staging, and clinical course have unique features. The aims of the present study were to investigate how the standardized histopathological examination protocol ensures correct classification of tumour origin of pancreatic head adenocarcinomas. Furthermore, we examined how different approaches to assessment of lymph node metastases and expression of cyclooxygenase-2 (COX-2) in the tumours can predict long-term outcome. Finally, we assessed COX-2 expression and effects of PGE2 on cells proliferation and collagen synthesis in pancreatic stellate cells in vitro. The precise anatomical site of origin is often difficult to establish during preoperative investigations or during surgery and therefore the final diagnosis is always the result of the histopathological examination. The predetermined diagnostic criteria, with special focus on the anatomical site of origin, are essential to improve the accuracy of diagnosis. Furthermore, high workload per pathologist increases the precision of the histopathologic diagnosis. The presence of lymph node metastasis is a major determinant of long-term survival in pancreatic head cancers. In patients operated with pancreatoduodenectomy, N status and LNR are superior to the number of metastatic node as prognostics indicators. The predictive value of these variables depends on the cancer origin. In ampullary and distal bile duct cancer, N status discriminates between subgroups of patients with different long-term survival whereas in pancreatic cancer, LNR is clearly more powerful in prognostic subclassification. In patients with pancreatic cancer, multivariate analysis identified LNR > 0.2 as an independent predictor of poor long-term survival. LNR could therefore be proposed as a standard, alternative measure of nodal involvement in the pancreatic cancer. Overexpression of COX-2 has been described in several tumours, however the data on the prognostic importance of COX-2 in pancreatic head adenocarcinomas are inconsistent. In our study COX-2 is overexpressed in >70% of pancreatic, ampullary and distal bile duct cancers and is associated with the histopathological type of differentiation, with the degree of differentiation, and with a favourable prognosis. In pancreatic cancer, in a multivariate model, COX-2 negative tumours and LNR > 0.2, independently predicted poor prognosis. When assessed by immunohistochemistry, COX-2 is mainly expressed in pancreatic carcinoma cells, and these cells are regarded as the main source of PGE2 in pancreatic cancer tumour tissue. COX-2 was not detected in the stroma, however COX-2 was detected in the cultured pancreatic stellate cells (PSC), and could be further induced by interleukin-1ß (IL-1ß), epidermal growth factor (EGF), thrombin, and PGE2, but not by transforming growth factor-ß1 (TGFß). Treatment of PSC with PGE2 suppressed both TGFß-stimulated collagen synthesis and PDGF-stimulated DNA synthesis, suggesting that inhibition of COX-2 may inadvertently accelerate fibrosis progression in pancreatic cancer. This thesis confirms that standardised histopathological evaluation after pancreatoduodenectomy with special focus on the tumour origin, lymph node assessment, degree and type of differentiation is necessary to obtain accurate and reliable survival estimates. Furthermore, our findings of the COX-2 expression in the tumours, and the PGE2 effects on pancreatic stellate cells, revealed new aspects of biological mechanisms involved in progression of pancreatic cancer

COX-2 overexpression in resected pancreatic head adenocarcinomas correlates with favourable prognosis

Background Overexpression of cyclooxygenase-2 (COX-2) has been implicated in oncogenesis and progression of adenocarcinomas of the pancreatic head. The data on the prognostic importance of COX expression in these tumours is inconsistent and conflicting. We evaluated how COX-2 overexpression affected overall postoperative survival in pancreatic head adenocarcinomas. Methods The study included 230 consecutive pancreatoduodenectomies for pancreatic cancer (PC, n = 92), ampullary cancer (AC, n = 62) and distal bile duct cancer (DBC, n = 76). COX-2 expression was assessed by immunohistochemistry. Associations between COX-2 expression and histopathologic variables including degree of differentiation, histopathologic type of differentiation (pancreatobiliary vs. intestinal) and lymph node ratio (LNR) were evaluated. Unadjusted and adjusted survival analysis was performed. Results COX-2 staining was positive in 71% of PC, 77% in AC and 72% in DBC. Irrespective of tumour origin, overall patient survival was more favourable in patients with COX-2 positive tumours than COX-2 negative (p = 0.043 in PC, p = 0.011 in AC, p = 0.06 in DBC). In tumours of pancreatobiliary type of histopathological differentiation, COX-2 expression did not significantly affect overall patient survival. In AC with intestinal differentiation COX-2 expression significantly predicted favourable survival (p = 0.003). In PC, COX-2 expression was significantly associated with high degree of differentiation (p = 0.002). COX-2 and LNR independently predicted good prognosis in a multivariate model. Conclusions COX-2 is overexpressed in pancreatic cancer, ampullary cancer and distal bile duct cancer and confers a survival benefit in all three cancer types. In pancreatic cancer, COX-2 overexpression is significantly associated with the degree of differentiation and independently predicts a favourable prognosis

Inhibitory effects of prostaglandin E2 on collagen synthesis and cell proliferation in human stellate cells from pancreatic head adenocarcinoma

Background Several studies have described an increased cyclooxygenase-2 (COX-2) expression in pancreatic cancer, but the role of COX-2 in tumour development and progression is not clear. The aim of the present study was to examine expression of COX-2 in cancer cells and stromal cells in pancreatic cancer specimens, and to explore the role of PGE2 in pancreatic stellate cell proliferation and collagen synthesis. Methods Immunohistochemistry and immunofluorescence was performed on slides from whole sections of tissue blocks using antibodies against COX-2 and α-smooth muscle actin (αSMA). Pancreatic stellate cells (PSC) were isolated from surgically resected tumour tissue by the outgrowth method. Cells were used between passages 4 and 8. Collagen synthesis was determined by [3H]-proline incorporation, or by enzyme immunoassay measurement of collagen C-peptide. DNA synthesis was measured by incorporation of [3H]-thymidine in DNA. Cyclic AMP (cAMP) was determined by radioimmunoassay. Collagen 1A1 mRNA was determined by RT-qPCR. Results Immunohistochemistry staining showed COX-2 in pancreatic carcinoma cells, but not in stromal cells. All tumours showed positive staining for αSMA in the fibrotic stroma. Cultured PSC expressed COX-2, which could be further induced by interleukin-1β (IL-1β), epidermal growth factor (EGF), thrombin, and PGE2, but not by transforming growth factor-β1 (TGFβ). Indirect coculture with the adenocarcinoma cell line BxPC-3, but not HPAFII or Panc-1, induced COX-2 expression in PSC. Treatment of PSC with PGE2 strongly stimulated cAMP accumulation, mediated by EP2 receptors, and also stimulated phosphorylation of extracellular signal-regulated kinase (ERK). Treatment of PSC with PGE2 or forskolin suppressed both TGFβ-stimulated collagen synthesis and PDGF-stimulated DNA synthesis. Conclusions The present results show that COX-2 is mainly produced in carcinoma cells and suggest that the cancer cells are the main source of PGE2 in pancreatic tumours. PGE2 exerts a suppressive effect on proliferation and fibrogenesis in pancreatic stellate cells. These effects of PGE2 are mediated by the cAMP pathway and suggest a role of EP2 receptors

Budowa somatyczna uczniów klas sportowych szkół gimnazjalnych na tle ich rówieśników z klas ogólnych

Typ budowy somatycznej determinowany jest oddziaływaniem czynników genetycznych i środowiskowych, do których zaliczamy między innymi tryb życia, ogólną aktywność ruchową a także trening sportowy. Aktywność fizyczna jest jednym z czynników zapobiegającym powstawaniu nadwagi czy otyłości, zmniejszającym ryzyko chorób układu krążeniowo-oddechowego, a nade wszystko pozytywnie oddziałujących na psychikę człowieka. Systematyczna aktywność ruchowa w istotny sposób wpływa na wzmocnienie tkanki mięśniowej, mineralizacji kości, prawidłowy stan morfologiczny i funkcjonalny organizmu oraz ogólną poprawę zdrowia człowieka w każdym wieku. W okresie dojrzewania ruch w szczególny sposób aktywizuje rozwój młodego organizmu oraz poprawia sprawność i kondycję fizyczną. Celem pracy była charakterystyka cech budowy somatycznej chłopców pierwszej i trzeciej klasy o profilu sportowym i ogólnym z wybranych szkół gimnazjalnych oraz oszacowanie zróżnicowania somatycznego pomiędzy grupą sportową i ogólną. Badaniami objęto grupę 80 uczniów w wieku 13-15 lat z Gimnazjum Publicznego Nr 4 oraz Gimnazjum Publicznego Nr 5 w Białej Podlaskiej (45 chłopców klas sportowych i 35 chłopców z klas ogólnych). Pomiary somatyczne obejmowały podstawowe parametry antropometryczne: masę ciała, wysokość ciała w pozycji stojącej oraz w pozycji siedzącej, obwód klatki piersiowej w spoczynku, w maksymalnym wdechu i wydechu, grubość fałdów skórno-tłuszczowych (biceps, triceps, pod łopatką, nad kolcem biodrowym przednim górnym, na łydce – pod kolanem), obwód talii i obwód bioder. Uzyskane wyniki oraz wielkości wyliczonych wskaźników pozwoliły określić cechy budowy ciała uczniów. Wśród badanych uczniów dominowała smukła budowa ciała oraz przeważał androidalny typ świadczący o brzusznej dystrybucji tkanki tłuszczowej. Wśród uczniów z klas o profilu ogólnym stwierdzono wyższą, niż u rówieśników z klas sportowych, procentową zawartość tkanki tłuszczowej wykraczającą poza normę. Większość badanych chłopców charakteryzowała się prawidłową ruchomością klatki piersiowej. Zaobserwowane różnice w budowie somatycznej uczniów klas sportowych i klas ogólnych okazały się nieistotne statystycznie. Niezbędne są wielokierunkowe działania w zakresie propagowania zdrowego stylu życia, aktywności fizycznej i sportu szkolnego wspomagającego prawidłowy rozwój fizyczny dzieci i młodzieży w każdym etapie okresu ontogenezy

The TGFβ-SMAD3 pathway inhibits IL-1α induced interactions between human pancreatic stellate cells and pancreatic carcinoma cells and restricts cancer cell migration

Background The most abundant cells in the extensive desmoplastic stroma of pancreatic adenocarcinomas are the pancreatic stellate cells, which interact with the carcinoma cells and strongly influence the progression of the cancer. Tumor stroma interactions induced by IL-1α/IL-1R1 signaling have been shown to be involved in pancreatic cancer cell migration. TGFβ and its receptors are overexpressed in pancreatic adenocarcinomas. We aimed at exploring TGFβ and IL-1α signaling and cross-talk in the stellate cell cancer cell interactions regulating pancreatic adenocarcinoma cell migration. Methods Human pancreatic stellate cells were isolated from surgically resected pancreatic adenocarcinomas and cultured in the presence of TGFβ or pancreatic adenocarcinoma cell lines. The effects of TGFβ were blocked by inhibitors or amplified by silencing the endogenous inhibitor of SMAD signaling, SMAD7. Pancreatic stellate cell responses to IL-1α or to IL-1α-expressing pancreatic adenocarcinoma cells (BxPC-3) were characterized by their ability to stimulate migration of cancer cells in a 2D migration model. Results In pancreatic stellate cells, IL-1R1 expression was found to be down-regulated by TGFβ and blocking of TGFβ signaling re-established the expression. Endogenous inhibition of TGFβ signaling by SMAD7 was found to correlate with the levels of IL-1R1, indicating a regulatory role of SMAD7 in IL-1R1 expression. Pancreatic stellate cells cultured in the presence of IL-1α or in co-cultures with BxPC-3 cells enhanced the migration of cancer cells. This effect was blocked after treatment of the pancreatic stellate cells with TGFβ. Silencing of stellate cell expression of SMAD7 was found to suppress the levels of IL-1R1 and reduce the stimulatory effects of IL-1α, thus inhibiting the capacity of pancreatic stellate cells to induce cancer cell migration. Conclusions TGFβ signaling suppressed IL-1α mediated pancreatic stellate cell induced carcinoma cell migration. Depletion of SMAD7 upregulated the effects of TGFβ and reduced the expression of IL-1R1, leading to inhibition of IL-1α induced stellate cell enhancement of carcinoma cell migration. SMAD7 might represent a target for inhibition of IL-1α induced tumor stroma interactions

Clinical relevance of pancreatobiliary and intestinal subtypes of ampullary and duodenal adenocarcinoma: Pattern of recurrence, chemotherapy, and survival after pancreatoduodenectomy

Background. The clinical relevance of the classification of ampullary adenocarcinoma (AC) into pancreatobiliary (PB) or intestinal (Int) subtypes has not been resolved. Methods. Clinicopathological factors, survival, and localization and treatment of recurrence were investigated for patients with AC and duodenal adenocarcinoma (DC) treated by pancreatoduodenectomy from 2000 to 2015. Results. A total of 109 AC (45 PB, 64 Int) and 71 DC (all Int) were identified. Median overall survival (OS) for ACPB vs DC vs ACInt was 43.6 vs 51 vs 75 months, respectively. ACPB had significantly shorter OS than ACInt (p = 0.036). However, for AC stage (HR = 2.39; 95 %CI 1.23–4.64, p = 0.010) was the only factor associated with mortality risk in multivariate analysis. Localization of recurrence (n = 88) was predominantly distant (ACPB 81.5%; ACInt 92%; DC 91.7%, p = 0.371). Post-recurrence survival (PRS) for ACPB, ACInt and DC did not differ (6.9 vs 9.2 vs 7.5 months, p = 0.755). Best supportive care or palliative chemotherapy were offered for recurrent disease to 44.5%/48.1% for ACPB, 40%/56% for ACInt, and 41.7%/52.8% for DC (p = 0.947). The choice of chemotherapy regimen varied considerably. Five patients underwent surgical resection or ablation with curative intent. All deaths among ACPB were caused by recurrent disease, whereas 29.4% of ACInt and 23.1% of DC deaths was non-cancer related or caused by other specific cancer. Conclusion. ACPB, ACInt and DC have similar recurrence patterns and PRS. The difference in survival between ACPB and ACInt was not statistically significant when stratified by stage. The optimal chemotherapy in patients with recurrent AC remains undefined