Adjuvant treatment of pancreatic cancer in 2009: where are we? Highlights from the 45th ASCO annual meeting. Orlando, FL, USA. May 29-June 2, 2009.

JOP. 2009;10(4):373-7

Authors: Saif MW

Despite attempted curative resection of localized pancreatic adenocarcinoma, most patients succumb a recurrence and die of their disease. The Gastrointestinal Tumor Study Group, European Organization for Research and Treatment of Cancer, and European Study Group for Pancreatic Cancer trials have suggested the benefit of adjuvant therapy. However, the relatively few randomized trials available have not established a definite standard of care due to study limitations. Although these trials, and the recently published Charité Onkologie (CONKO)-001 trial, have shown a definite advantage of adjuvant chemotherapy, the most effective chemotherapy and the role of radiation therapy remain unclear. This review will discuss the data available from reported trials of adjuvant therapy in pancreatic cancer, especially the results of the ESPAC-3 study presented at the annual meeting of ASCO 2009, and consider future directions for clinical trials.

PMID: 19581737 [PubMed - in process]

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Inactivation of TIF1gamma cooperates with Kras to induce cystic tumors of the pancreas.

PLoS Genet. 2009 Jul;5(7):e1000575

Authors: Vincent DF, Yan KP, Treilleux I, Gay F, Arfi V, Kaniewsky B, Marie JC, Lepinasse F, Martel S, Goddard-Leon S, Iovanna JL, Dubus P, Garcia S, Puisieux A, Rimokh R, Bardeesy N, Scoazec JY, Losson R, Bartholin L

Inactivation of the Transforming Growth Factor Beta (TGFbeta) tumor suppressor pathway contributes to the progression of Pancreatic Ductal AdenoCarcinoma (PDAC) since it is inactivated in virtually all cases of this malignancy. Genetic lesions inactivating this pathway contribute to pancreatic tumor progression in mouse models. Transcriptional Intermediary Factor 1 gamma (TIF1gamma) has recently been proposed to be involved in TGFbeta signaling, functioning as either a positive or negative regulator of the pathway. Here, we addressed the role of TIF1gamma in pancreatic carcinogenesis. Using conditional Tif1gamma knockout mice (Tif1gamma(lox/lox)), we selectively abrogated Tif1gamma expression in the pancreas of Pdx1-Cre;Tif1gamma(lox/lox) mice. We also generated Pdx1-Cre;LSL-Kras(G12D);Tif1gamma(lox/lox) mice to address the effect of Tif1gamma loss-of-function in precancerous lesions induced by oncogenic Kras(G12D). Finally, we analyzed TIF1gamma expression in human pancreatic tumors. In our mouse model, we showed that Tif1gamma was dispensable for normal pancreatic development but cooperated with Kras activation to induce pancreatic tumors reminiscent of human Intraductal Papillary Mucinous Neoplasms (IPMNs). Interestingly, these cystic lesions resemble those observed in Pdx1-Cre;LSL-Kras(G12D);Smad4(lox/lox) mice described by others. However, distinctive characteristics, such as the systematic presence of endocrine pseudo-islets within the papillary projections, suggest that SMAD4 and TIF1gamma don't have strictly redundant functions. Finally, we report that TIF1gamma expression is markedly down-regulated in human pancreatic tumors by quantitative RT-PCR and immunohistochemistry supporting the relevance of these findings to human malignancy. This study suggests that TIF1gamma is critical for tumor suppression in the pancreas, brings new insight into the genetics of pancreatic cancer, and constitutes a promising model to decipher the respective roles of SMAD4 and TIF1gamma in the multifaceted functions of TGFbeta in carcinogenesis and development.

PMID: 19629168 [PubMed - in process]

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Pancreatectomy for pancreatic cancer with reference to combined resection of the vessels, twenty nine year experience by a single surgeon.

Keio J Med. 2009 Jun;58(2):103-9

Authors: Sugiura Y, Horio T, Aiko S, Ishizuka T, Kumano I, Kato Y, Kato A, Kitajima M

Between 1978 and 2007 one hundred and seven patients consecutively underwent resection for primary pancreatic adenocarcinoma. There were 28 pN0 patients, 41 pN1 and 37 pN2 or more (one unknown). Combined resection of the portal vein was performed in 62 out of 107 patients (58%). The hepatic artery in 10 patients, superior mesenteric artery in 8 patients and celiac trunk in 7 patients were also resected additionally to the portal vein. The 5-year survival rate and 10-year survival rate of all 107 cases were 12.1% and 2.8% respectively. The 5-year survival rate of the pN0 group was 37%, significantly better than the 14% 5-year survival rate in the pN1 group (p=0.043). Of 69 patients with pN0 or pN1, 38 patients underwent combined resection of the portal vein. There was not significant difference between the 24% 5-year survival rate in the group without the portal vein resection and the 19% 5-year survival rate in the group with portal vein resection. The 20% 5-year survival rate of the portal vein only group and the 5-year survival rate of both the portal vein and hepatic artery group were the same. The groups of the further resection of the superior mesenteric artery and of the celiac trunk showed no long-term survival. It is concluded that aggressive combined resection of the portal vein or additional resection of the hepatic artery be feasible for a survival benefit in pN0 and pN1 diseases.

PMID: 19597306 [PubMed - in process]

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Characterization of Novel Diaryloxazole-Based Compounds as Potential Agents to Treat Pancreas Cancer.

J Pharmacol Exp Ther. 2009 Aug 5;

Authors: Shaw A, Henderson MC, Flynn G, Samulitis B, Han H, Stratton S, Chow HH, Hurley LH, Dorr RT

A series of diaryl- and fluorenone-based analogs of a lead compound UA-62784 was synthesized with the intention of improving upon the selective cytotoxicity of UA-62784 against human pancreatic cancer cell lines with a deletion of the tumor suppressor gene DPC-4 (SMAD-4). Over 80 analogs were synthesized and tested for antitumor activity against pancreatic cancer (PC) cell lines (the PC series). Despite a structural relationship to UA-62784 which inhibits the mitotic kinesin centromere protein E (CENP-E), none of the analogs was selective for DPC-4-deleted pancreatic cancer cell lines. Furthermore, none of the analogs was a potent or selective inhibitor of 4 different mitotic kinesins (Eg5, CENP-E, MKLP-1, MCAK). Therefore, other potential mechanisms of action were evaluated. A diaryloxazole lead analog from this series, PC-046, was shown to potently inhibit several protein kinases that are over-expressed in human pancreatic cancers, including TrkB, IRAK4 and PIM-1. Cells exposed to PC-046 exhibit a cell cycle block in S-phase followed by apoptotic death and necrosis. PC-046 effectively reduced MiaPaca-2 tumor growth in SCID mice by 80% compared to untreated controls. The plasma half-life was 7.5h and cytotoxic drug concentrations of > 3 microM were achieved in vivo in mice. The diaryloxazole series of compounds represent a new chemical class of anti-cancer agents that inhibit several types of cancer-relevant protein kinases. PMID: 19657049 [PubMed - as supplied by publisher]

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Interstitial chemotherapy with ricin-loaded thermosensitive hydrogel in pancreatic cancer xenograft.

Hepatobiliary Pancreat Dis Int. 2009 Aug;8(4):418-23

Authors: Chen ZK, Lin LW, Weng XH, Xue ES, Lin YH

BACKGROUND: Pancreatic cancer is one of the most aggressive malignancies, and has a poor prognosis. Despite efforts made in multiple fields, there has been little success in improving the disease-free survival rate of patients. This study was undertaken to investigate the effectiveness and feasibility of using intra-tumoral injection of ricin-loaded thermosensitive hydrogel for treatment of pancreatic cancer xenografts, attempting to develop a new treatment for human pancreatic cancer.

METHODS: BALB/c-(nu/nu) nude mice were inoculated subcutaneously in the right flank with the human pancreatic cancer cells, SW1990. Fourteen days after inoculation, 32 mice, bearing tumors of volume 1.5-2.0 cm3, were randomly assigned to one of four groups, and given an intra-tumoral injection of: (1) saline; (2) 23% w/w thermosensitive hydrogel alone; (3) ricin, 10 microg/kg; or (4) 10 microg/kg ricin loaded in thermosensitive hydrogel. On day 14 after administration, the tumors were excised to calculate the inhibition rate of tumor growth and perform histopathological examination. Tumor cell apoptosis was detected by flow cytometry, and RT-PCR was performed to evaluate the mRNA expression levels of Bcl2 and Bax.

RESULTS: Intra-tumoral injection of ricin-loaded thermosensitive hydrogel resulted in remarkable control of tumor growth. The tumor became necrotic by day 14 after administration. The histological results clearly confirmed that the tumor cells were lysed. The percentage of apoptotic cells detected by flow cytometry was higher in the ricin hydrogel group than in the other groups. Semi-quantitative RT-PCR revealed that the mRNA expression level of Bcl2 was down-regulated whereas Bax was upregulated.

CONCLUSIONS: Intra-tumoral injection of ricin-loaded thermosensitive hydrogel may provide an effective approach for interstitial chemotherapy in pancreatic cancer. Inducing apoptosis by downregulating Bcl2 expression and upregulating Bax expression may be a key molecular mechanism.

PMID: 19666413 [PubMed - in process]

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Pancreatic metastasis from renal carcinoma managed by Whipple resection. A case report and literature review of metastatic pattern, surgical management and outcome.

JOP. 2009;10(4):413-8

Authors: Machado NO, Chopra P

CONTEXT: Metastatic cancer to the pancreas is rare and accounts for less than 2% of all pancreatic malignancies, metastasis from renal cell carcinoma being predominant. While symptomatic patients present with obstructive jaundice, abdominal pain, or GI bleeding, the diagnosis is often made in asymptomatic patients during follow-up for renal cell carcinoma. Hence, a high index of clinical suspicion is required in a patient who presents with a pancreatic tumor following a nephrectomy for renal cell carcinoma.

CASE REPORT: We report the case of a patient in whom a lesion was detected in the head of the pancreas, following a nephrectomy performed 5 years previously for renal cell carcinoma. A magnetic resonance scan revealed a well-defined lesion in the head of the pancreas. The patient underwent a pancreaticoduodenectomy and histopathology confirmed a metastatic renal cell carcinoma. Two years after the surgery, the patient is doing well. The literature is reviewed for pancreatic metastasis from renal cell carcinoma, for metastatic pattern, surgical management and outcome.

CONCLUSION: Pancreatic metastases are usually detected during the follow-up of patients having undergone a previous nephrectomy for renal cell carcinoma. Typically, the interval between a nephrectomy and pancreatic metastasis is long. The literature contained more than 250 cases of pancreatic resection for metastatic renal cell carcinoma. The median duration of presentation was 10.5+/-6.5 years following a nephrectomy. The lesions are multifocal (3.2+/-1.5) in about 39% of patients and resectable in 80%. A high resectability rate is characteristic of metastasis from renal cell carcinoma as compared to primary pancreatic cancer. The five year survival rate is between 43 and 88%.

PMID: 19581746 [PubMed - in process]

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World J Gastroenterol. 2009 Jul 21;15(27):3349-54

Authors: Chiang KC, Chen TC

Pancreatic cancer is ranked fifth among cancer-related deaths worldwide with a 5-year survival rate of less than 5%. Currently, surgery is the only effective therapy. However, most patients are diagnosed in the late stage and are not suitable for receiving curative surgery. Moreover, pancreatic cancer doesn't respond well to traditional chemotherapy and radiotherapy, leaving little effective treatment for advanced pancreatic cancer cases. 1alpha,25-dihydroxyvitamin D(3) [1alpha,25(OH)(2)D(3)], the biologically active form of vitamin D(3), was originally identified during studies of calcium and bone metabolism, though it is now recognized that it exerts biological effects in almost every tissue in the body. Abundant evidence has shown that 1alpha,25(OH)(2)D(3) has antiproliferative, apoptotic, pro-differentiation and antiangiogensis effects in many types of cancer cells in vivo and in vitro, including breast, prostate, and colon. Similarly, the antitumor growth effect of 1alpha,25(OH)(2)D(3) on pancreatic cells has been demonstrated. The clinical use of 1alpha,25(OH)(2)D(3) is impeded by the lethal side effects of hypercalcemia and hypercalciuria. Therefore, 1alpha,25(OH)(2)D(3) analogs, which are either equipotent or more potent than 1alpha,25(OH)(2)D(3) in inhibiting tumor cell growth but with fewer hypercalcemic and hypercalciuric side effects, have been developed for the treatment of different cancers. Recently, a pre-clinical study demonstrated that a less calcemic analog of 1alpha,25(OH)(2)D(3), 19-nor-1alpha,25(OH)(2)D(2) (Paricalcitol), is effective in inhibiting tumor growth in vitro and in vivo, via upregulation of p21 and p27 tumor suppressor genes. Studies on the anti-tumor effects of a more potent analog of Paricalcitol are underway. 1alpha,25(OH)(2)D(3) and its analogs are potentially attractive novel therapies for pancreatic cancer. PMID: 19610135 [PubMed - in process]

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