Curative resection is the single most important factor determining outcome in patients with pancreatic adenocarcinoma

Wagner, Markus; Redaelli, C.; Lietz, Michael; Seiler, Ch.; Friess, Helmut; Büchler, Markus W.

doi:10.1002/bjs.4484

Cited by 769 publications

(538 citation statements)

References 38 publications

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“…Clinically, PDAC is often diagnosed at a late stage, when local invasion of vital structures and distant metastasis has already precluded curative resection. Consequently, only B10-20% of the patients are candidates for surgery at the time of diagnosis, of which only approximately 25% will survive for more than 5 years (Yeo et al, 1997;Richter et al, 2003;Wagner et al, 2004). Moreover, PDAC is often highly resistant to the currently available chemotherapeutics as well as radiotherapy (Klinkenbijl et al, 1999;Neoptolemos et al, 2004).…”

Section: Discussionmentioning

confidence: 99%

Loss of BNIP3 expression is a late event in pancreatic cancer contributing to chemoresistance and worsened prognosis

et al. 2005

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Altered expression of apoptosis-regulating genes plays an important role in the aggressive growth behavior and chemoresistance of pancreatic ductal adenocarcinoma. In the present study, the hypoxia-inducible proapoptotic gene, BNIP3, was analysed in terms of expression, effect on patient survival, and chemo-responsiveness in pancreatic cancer cell lines. cDNA microarray, real-time light cycler s quantitative polymerase chain reaction, laser-capture microdissection, and immunohistochemistry analyses were used to evaluate BNIP3 expression in normal and diseased pancreatic specimens. Modulation of BNIP3 expression was achieved using specific siRNA molecules. The effect of chemotherapeutic agents on pancreatic cancer cells was assessed utilizing 3-(4,5-methylthiazol-2-yl)-2,5-diphenyltetrazolium-bromide assays. BNIP3 mRNA levels were 3.0-and 6.3-fold lower in chronic pancreatitis and pancreatic cancer compared to the normal pancreas, respectively. Microdissection analysis confirmed the reduction of BNIP3 expression in pancreatic cancer cells compared to normal duct cells. By immunohistochemistry, BNIP3 was predominantly expressed in the acinar cells of the normal and diseased pancreas. Interestingly, while BNIP3 was undetectable in the cancer cells of 59% of the cases, 75-100% of PanIN2/3 lesions displayed BNIP3 immunoreactivity. Loss of BNIP3 expression correlated with poorer survival of patients (8 vs 14 months for BNIP3 negative vs positive tumors). Hypoxia induced BNIP3 expression in four out of eight pancreatic cancer cell lines, while it was absent under normoxic and hypoxic conditions in the remaining four. Downregulation of BNIP3 resulted in increased resistance to 5-fluoro-uracil and gemcitabine. In conclusion, loss of BNIP3 expression occurs late in pancreatic cancer, contributes to resistance to chemotherapy, and correlates with a worsened prognosis.

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Section: Discussionmentioning

confidence: 99%

Loss of BNIP3 expression is a late event in pancreatic cancer contributing to chemoresistance and worsened prognosis

et al. 2005

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“…PDAC is an aggressive and destructive disease, characterized by rapid progression, early metastasis and a limited response to radiotherapy and chemotherapy (7). Radical excision is central to the successful therapy of patients with PDAC (8); however, only 10-15% of patients are diagnosed at the early stages when surgical resection can be performed (9). At present, developments in cancer therapy have improved the survival time for patients with PDAC; however, the prognosis of patients with PDAC remains poor, with a five-year overall survival rate of <5% and a median survival time of 6 months (10).…”

Section: Introductionmentioning

confidence: 99%

MicroRNA‑216b reduces growth, migration and invasion of pancreatic ductal adenocarcinoma cells by directly targeting ρ‑associated coiled‑coil containing protein kinase 1

et al. 2018

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Abstract. Developments in cancer therapy have greatly improved the survival time for patients with pancreatic ductal adenocarcinoma (PDAC); however, the prognosis of patients with PDAC remains poor. Understanding the expression patterns and functions of microRNAs may provide strategies for the diagnosis and treatment of patients with PDAC. The present study aimed to explore the expression and functions of microRNA-216b (miR-216b) in PDAC. The expression of miR-216b in PDAC tissues and cell lines was quantified with reverse transcription-quantitative polymerase chain reaction. An miR-216b mimic was introduced into PDAC cells to induce the effects of miR-21b overexpression. The effects of miR-216b overexpression on growth, migration and invasion of PDAC cells were evaluated by cell proliferation assay, migration and invasion assays, respectively. The molecular mechanism underlying the suppressive effects of miR-216b on PDAC was also examined; a direct target gene of miR-216b, ρ-associated coiled-coil containing protein kinase 1 (ROCK1), was downregulated by ROCK1 short interfering RNA to investigate the effects on growth, migration and invasion of PDAC cells. The present study revealed that miR-216b was significantly downregulated in PDAC tissues and cell lines. Overexpression of miR-216b inhibited growth, migration and invasion of PDAC cells in vitro. ROCK1 was identified as a direct target gene of miR-216b in pancreatic cancer and the downregulation of ROCK1 resembled the effects of miR-216b overexpression in PDAC cells. Taken together, miR-216b acted as a tumor suppressor in PDAC and may represent a novel therapeutic target in PDAC.

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“…[1][2][3] Lack of effective screening modalities and late presentation with advanced stage disease result in fewer than 20% of patients being eligible for surgical resection. 4 Even in surgically-treated patients, the 5-year survival rate is lower than 20%, 5 highlighting the need for more effective and personalized systemic therapeutic approaches. Adjuvant chemotherapy is considered the standard of care for patients with resectable pancreatic ductal adenocarcinoma.…”

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confidence: 99%

Mismatch repair status may predict response to adjuvant chemotherapy in resectable pancreatic ductal adenocarcinoma

et al. 2015

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Deficiencies in DNA mismatch repair have been associated with inferior response to 5-FU in colorectal cancer. Pancreatic ductal adenocarcinoma is similarly treated with pyrimidine analogs, yet the predictive value of mismatch repair status for response to these agents has not been examined in this malignancy. A tissue microarray with associated clinical outcome, comprising 254 resected pancreatic ductal adenocarcinoma patients was stained for four mismatch repair proteins (MLH1, MSH2, MSH6 and PMS2). Mismatch repair deficiency and proficiency was determined by the absence or presence of uniform nuclear staining in tumor cells, respectively. Cases identified as mismatch repair deficient on the tissue microarray were confirmed by immunohistochemistry on whole slide sections. Of the 265 cases, 78 (29%) received adjuvant treatment with a pyrimidine analog and 41 (15%) showed a mismatch repair-deficient immunoprofile. Multivariable diseasespecific survival in the mismatch repair-proficient cohort demonstrated that adjuvant chemotherapy, regional lymph-node status, gender, and the presence of tumor budding were significant independent prognostic variables (P ≤ 0.04); however, none of the eight clinico-pathologic covariates examined in the mismatch repairdeficient cohort were of independent prognostic significance. Univariable assessment of disease-specific survival revealed an almost identical survival profile for both treated and untreated patients with a mismatch repair-deficient profile, while treatment in the mismatch repair-proficient cohort conferred a greater than 10-month median disease-specific survival advantage over their untreated counterparts (P = 0.0018). In this cohort, adjuvant chemotherapy with a pyrimidine analog conferred no survival advantage to mismatch repairdeficient pancreatic ductal adenocarcinoma patients. Mismatch repair immunoprofiling is a feasible predictive marker in pancreatic ductal adenocarcinoma patients, and further prospective evaluation of this finding is Pancreatic ductal adenocarcinoma is among the deadliest solid cancers, with little improvement in overall survival achieved in the past few decades. 1-3 Lack of effective screening modalities and late presentation with advanced stage disease result in fewer than 20% of patients being eligible for surgical resection. 4 Even in surgically-treated patients, the 5-year survival rate is lower than 20%, 5 highlighting the need for more effective and personalized systemic therapeutic approaches. Adjuvant chemotherapy is considered the standard of care for patients with resectable pancreatic ductal adenocarcinoma. 6,7 Pyrimidine analogs (gemcitabine or 5-fluorouracil (5-FU)) are the most commonly used agents, with gemcitabine demonstrating an improved survival compared with no treatment in 7 and an improved toxicity profile compared with 5-FU in ESPAC-3. 8 Molecular studies have shown that pancreatic ductal adenocarcinomas contain a high number of

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Curative resection is the single most important factor determining outcome in patients with pancreatic adenocarcinoma

Cited by 769 publications

References 38 publications

Loss of BNIP3 expression is a late event in pancreatic cancer contributing to chemoresistance and worsened prognosis

Loss of BNIP3 expression is a late event in pancreatic cancer contributing to chemoresistance and worsened prognosis

MicroRNA‑216b reduces growth, migration and invasion of pancreatic ductal adenocarcinoma cells by directly targeting ρ‑associated coiled‑coil containing protein kinase 1

Mismatch repair status may predict response to adjuvant chemotherapy in resectable pancreatic ductal adenocarcinoma

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