Current Opinion in Gastroenterology · 2016 · 20 citations · open access
Evolution of novel therapeutic options for pancreatic cancer
AbstractPURPOSE OF REVIEW: Pancreatic cancer is the most devastating of all cancers with an extremely poor prognosis. In US alone, over 50 000 new cases of pancreatic cancer are reported annually, and about the same number succumb to it, making pancreatic cancer the third most common cause of cancer deaths. Most patients with pancreatic cancer present with advanced disease, which cannot be resected surgically, and for these patients chemotherapy is the only option. Even patients who undergo resection require adjuvant therapy to decrease the risk of recurrence. Since the 1950s, a variety of different agents, like antimetabolites, nucleoside analogs, and DNA intercalating compounds, have been used against pancreatic cancer, alone or in combination, with little improvement in the survival statistics. The current article reviews the evolution of chemotherapy for pancreatic cancer, and discusses some novel therapeutic options that are emerging in recent times, with special emphasis on Minnelide, a novel HSP70 inhibitor, which is currently in clinical trials. RECENT FINDINGS: Approaches towards developing therapies for pancreatic cancer have evolved tremendously over the past decade. Research has shown that apart from the inherent drug resistance, drug delivery to pancreatic cancer has also posed a major challenge. The extensive desmoplastic stroma of pancreatic cancer is believed to create inordinately high interstitial fluid pressures leading to vascular collapse and substantial barrier to perfusion of chemotherapeutics, thus creating an additional layer of protection for pancreatic cancer. Recent research thus is focused not only on understanding the biology and developing strategies to target cancer cells, but also is targeted towards the depletion of stroma in order to ensure better delivery of chemotherapeutic compounds to the tumor. SUMMARY: The current article describes the novel therapies that are constantly being evaluated to address and overcome the challenges that make pancreatic cancer a difficult disease to treat.
https://doi.org/10.1097/mog.0000000000000298Pancreas · 2003 · 0 citations
Proceedings of the Japan Pancreas Society, 2002
AbstractClinical Application of Advances of Molecular Biology to Diagnosis and Treatment of Pancreatic Diseases. Michio Ogawa, Department of Surgery II, Kumamoto University Medical School (Kumamoto) Recent advances in molecular biology are widely applied to clinical medicine. In this article, how molecular biology affects the pathogenesis, pathophysiology, and management of pancreatic diseases is reviewed. Advances in molecular biology of pancreatic diseases are classified into two levels, a molecular level and a genetic level, and each is discussed in this article. Regeneration of the Pancreas After Pancreatitis. Makoto Otsuki, Third Department of Internal Medicine, University of Occupational and Environmental Health, School of Medicine (Kitakyushu) Chronic pancreatitis is a condition characterized by inflammation of the pancreas with irreversible fibrosis and formation of scar tissue, which eventually replaces the whole gland, leading to exocrine and endocrine insufficiency. Since chronic pancreatitis is defined as a progressive and irreversible fibrosis of the pancreas, the current study was undertaken to clarify the characteristics of irreversible pancreatitis induced in rats by intraductal infusion of oleic acid (OA) and then comparing with those of reversible pancreatitis induced by retrograde intraductal infusion of 3% sodium taurocholate (NaTc). In NaTc pancreatitis, proliferation scored by 5-bromo-2´-deoxyuridine (BrdU) labeling index started from the main and large ducts at 24 hours; small ductal epithelial cells and tubular complexes showed a marked mitotic activity on day 5; finally, acinar cells showed a marked mitotic activity on day 7. Some of main ductal epithelial cells expressed Pdx 1 at 24 hours, when main ducts reached the peak proliferation. In OA pancreatitis, however, labeling index increased only in the main duct with no successive increases in other areas. Moreover, Pdx 1-positive cells were not detected at any time after OA pancreatitis. We also examined the serial changes in the expression and activity of matrix metalloproteinase-2 (MMP-2) and localization of type IV collagen in these two models of pancreatitis. Long-term increases of gelatinolytic activity of active MMP-2 and continuous disorganization of type IV collagen in the basement membranes of ducts, vessels, tubular complexes, and acinar cells were observed during progressive atrophy of pancreatic gland in irreversible OA pancreatitis. In contrast, the increased gelatinolytic activity of MMP-2 and disruption of type IV collagen in basement membranes were only temporally observed in reversible NaTc pancreatitis. These results suggest that regeneration of reversible pancreatitis is induced by proliferation and differentiation of pancreatic progenitor cells that may exist in the main pancreatic duct epithelial cells, and that organization of the basement membrane in the sustentacula of acinar cells and duct epithelia seems to play an important role in the regenerative activity of acinar cells and duct epithelium. It is concluded that chronic pancreatitis diagnosed by destructive changes of pancreatic ducts may have basement membrane disorganization in the sustentacula of acinar cells and duct epithelia and thus results in continuous derangement of acinar cells and duct epithelium. Histopathologic Studies and Prognosis of Intraductal Papillary Mucinous Adenocarcinoma of the Pancreas. Yuta Nakamura, Kazuo Inui, Junji Yoshino, Kazumu Okushima, 1Hironao Miyoshi, and 2Saburo Nakazawa, 1Department of Internal Medicine, Second Teaching Hospital, Fujita Health University School of Medicine (Nagoya); 2Department Gastroenterology, Yamashita Hospital (Nagoya) We studied 12 cases of intraductal papillary mucinous adenocarcinoma of the pancreas, including the prognosis of patients. The lesions were classified according the extent of invasion into noninvasive (n = 5), minimally invasive (n = 3), limited to the pancreas (n = 2), and extension beyond the pancreas (n = 2). Seven patients showed parenchymal invasion and were histopathologically classified as having mucinous carcinoma (n = 4) or tubular adenocarcinoma (n = 3). Of the five patients with noninvasive carcinoma, only one died of local recurrence. The grades of invasion in the three patients with tubular adenocarcinoma were minimally invasive (n = 1), limited to the pancreas (n = 1), and extension beyond the pancreas (n = 1). All patients with tubular adenocarcinoma died of tumor recurrence and primary cancer. Four cases of invasive cancer with mucinous carcinoma were reported. The cancer was limited to the pancreas in three patients, who showed no tumor recurrence, and extended over the pancreas in one patient, who died of local recurrence. Our results indicate a significantly poor prognosis for invasive tubular adenocarcinoma irrespective of the grade of invasion. Endoscopic Treatment of Chronic Pancreatitis With Ductal Stones. Kazunori Hasegawa, Kiyohito Tanaka, Takanobu Hayakumo, Eisai Cho, Kenjiro Yasuda, and 1Masatsugu Nakajima, 1Department of Gastroenterology, Kyoto Second Red Cross Hospital (Kyoto) We evaluated clinically the application of endoscopic management for pancreatic ductal stones and stricture of the main pancreatic duct, and recurrence of pancreatic stones. In 47 patients with stones detected in the main pancreatic duct, endoscopic stone removal with endoscopic sphincterotomy (EST) was performed between 1983 and 2000. Stones were successfully removed from 36 patients (77%). Extracorporeal shock wave lithotripsy (ESWL) was performed in 16 of 36 patients. Nine of the 32 patients who were followed for more than 1 year had recurrent stones, and 8 of the 9 patients had pancreatic duct stricture. In eight of the patients, recurrent stones were successfully removed by repeated endoscopic treatment with balloon dilatation and stent placement. One patient was treated with surgery. We conclude that endoscopic treatment could be considered the first choice of treatment for patients with pancreatic duct stones. A Case of Chronic Pancreatitis With a Latent Deficiency of Vitamin E. Miyuki Yanagimachi, Yuki Matsuhashi, Yusuke Tadano, 1Toshihiro Suda, 2Teruo Nakamura, and 3Taku Watanabe, 1The Third Department of Internal Medicine, Hirosaki University School of Medicine (Hirosaki); 2Department of Health Hirosaki University School of Medicine (Hirosaki); Hospital We a with chronic pancreatitis and of E. was no of or The and showed pancreatic stones, and dilatation of the main pancreatic The of showed a of Pancreatic and Moreover, the were of and have in patients with pancreatic the of pancreatic in including of in patients. Mucinous of the Pancreas With a of a Kazuo and Department of Medical University Department of Medical University A was to of had diagnosed with chronic pancreatitis and a in the of the pancreas and had followed at the the of the pancreatic not increased in during the a in the of the pancreas and in the of the The of the after of a tumor in the of the Endoscopic retrograde showed a between the tumor and the main pancreatic We performed of a Histopathologic of the was mucinous of the pancreas with The tumor of and was of type was no of chronic pancreatitis in the pancreatitis. It that the the pancreatic duct on the to the be considered when a patient with repeated pancreatitis and a of chronic pancreatitis. of on After by of and 1Department of University School of Medicine (Nagoya) We two patients who for management of after in of in however, the condition after to showed that was by and that and is a and to the of from are to the and of for management of A Case of Pancreatitis After and of Gastroenterology, Medical University School of Medicine of Medicine, Department of Internal Medicine, Medical University School of Medicine A was to the of Medical University Hospital of of and was with of was then successfully treated for and and was from the after of of which was by and after lesions in the of the Since the lesions were and to pancreatic was on day of was on day of Four was of showed of the in the of the was of and of was with The pancreatic was and and were was and The of pancreatitis was not and of pancreatitis at was of the of to level of of the of of by for of the Pancreas in of School of Medicine Second Department of Kumamoto University School of Medicine (Kumamoto) The for of the Pancreas the of the of pancreatitis on by the between and in of the pancreas by 1 after the not the clinical and in patients with pancreatitis. The grade in by the was not with the evaluated a of The of the extent of inflammation the was with the in grade by was also for of in patients with pancreatitis. The discussed a grade by classified in of the extent of pancreatic and inflammation in patients with pancreatitis. the Pancreatitis With and 1Department of Kumamoto Hospital for Clinical Kumamoto Hospital of Internal Medicine, Kumamoto Hospital (Kumamoto) study the clinical of pancreatitis or In a of patients who patients by and by at Kumamoto Hospital, patients were with pancreatitis, and had The of significantly with the of of and the grade of We also a the of pancreatitis in of of to the The of pancreatitis with was only of Our indicate that pancreatitis is an important of with of to the for in the of the Pancreas. and Department of School of Medicine are and is a for patients with when the tumor is the main pancreatic duct parenchymal of the pancreas is We a for patients with the of was performed in patients in The of the tumor was the of the pancreas and of the tumor was performed in in the of the pancreas between the tumor and In three of the patients, the between the tumor and could be endoscopic or was for during surgery. We conclude that in and are for of the of of the of Makoto and 1Department of Medical with tumor of the pancreas who were followed for and are reported. The first patient was a who with and In of a pancreatic was In the tumor was and diagnosed as of the pancreas with of the and invasion of the is and The patient was a who with a in the In was performed for a in the Histopathologic of the of the the tumor was of the In the tumor was In the tumor the and the patient died of however, was in the In of the pancreas be as a tumor of on of the two patients, the for and for invasion of the and to the that be to the A Case of Pancreatic Chronic Pancreatitis and With 2Teruo Nakamura, and 1Department of Internal Medicine, Hospital 2Department of Health Hirosaki University School of Medicine A with pancreatic and to chronic pancreatitis and was successfully treated with and level increased from and to and with 12 of treatment with and from and to and after as seems to be chronic and After Treatment in a With Pancreatic and 1Department of Hospital We a of after of of in a who had a recurrent tumor after for ductal of grade and on 12 after treatment with the of for followed by was for management of which showed as clinically and is an of for patients with or pancreatic We that could in in patients with pancreatic carcinoma who are of any A Case of With Pancreatitis. and Department of of Medicine, University 2Department of Hospital pancreatitis in are only a cases of with A with was to on of pancreatic cancer. Endoscopic retrograde pancreatic duct and the patient was with a of chronic pancreatitis. One however, the patient was for and showed pancreatic and of the was and was for the of The and 1 showed marked in the of duct and pancreatic duct A was detected The patient treatment with and after A Case of Pancreatic by Pancreatitis. Nakamura, and 1Department of Hospital A in A an in the of the and showed level to was diagnosed with pancreatitis. and an tumor in in the pancreas with dilatation of the pancreatic A and a tumor in in the of the showed of and the tumor was diagnosed histopathologically as cancer. and with were and of a tumor was performed of the tumor The patient died of after the pancreatitis is a condition and poor into the the condition of the patient, and be and to prognosis and of Four of of the Pancreas. Yuki Tanaka, and 1Department of Red Cross Hospital 2Department of Red Cross Hospital of Gastroenterology, Red Cross Hospital of Red Cross Hospital We patients with of the 1 was a pancreatic tumor was was a with with was was a had a tumor with The tumor was and were successfully with was a and were invasion was diagnosed are in Chronic and Suda, of and Department of Internal Medicine, School of Medicine 2Department of School of Medicine in the of the pancreas are to in pancreatic a between of fibrosis and in diseases of the pancreas with chronic performed for on pancreatic from patients with pancreatitis, chronic pancreatitis, pancreatitis, carcinoma, and cells were detected in the ductal not in the in In patients with pancreatitis, which showed of the main pancreatic duct and acinar atrophy with proliferation of was observed in the of the ductal at the The in pancreatic of patients with carcinoma was classified into five as proliferation limited to the ductal proliferation limited to the ductal and proliferation in and in to the ductal and proliferation in the In patients, the of that of In those with pancreatitis, fibrosis was in the and were detected only in the In patients with chronic pancreatitis and and was and were detected in each Our results suggest that proliferation of in the ductal may a or to an in intraductal proliferation in the may be to the in the Clinical of of With Pancreatic and of Gastroenterology, Clinical of patients with pancreatic cancer = were and with those of patients (n = The with of and were in the A of or was in patients. and were more in the is the diagnosed in patients with pancreatic however, was to in the with the to the treatment of patients, was performed in only one with were for the patients on of and The of patients with IV cancer to be than that of the patients, Our the of of treatment of patients with pancreatic cancer into the of in the of Pancreatitis in the of of Pancreatitis. Tanaka, and 1Department of Internal Medicine, Kumamoto Medical 2Department of Medicine, Kumamoto University School of Medicine (Kumamoto) We the between the grade of pancreatic and of pancreatitis endoscopic retrograde and endoscopic sphincterotomy (EST) in to of the grade of pancreatic in the to of pancreatitis. Pancreatitis after of the and after 16 of the the of patients, of pancreatitis was in and the 16 patients with pancreatitis, pancreatitis in only 1 was performed in of patients with pancreatitis, and only in 1 of 16 patients with pancreatitis. Pancreatitis in of patients who and in of patients who not have = The in the of pancreatitis was in the of pancreatitis in management for of pancreatitis be applied to of pancreatitis. A Case of Ductal of the Pancreas. Makoto and 1Department of Hospital Department of Medical University A a local of and of an to the of Histopathologic of a from the by were with was to for of the a of in in the pancreatic A of tumor of the was and was Histopathologic was ductal carcinoma of the The prognosis of ductal carcinoma is poor in in patient, no were in the or is no of recurrence to after surgery. The prognosis of type may be after for Intraductal Papillary of the Pancreas. of a Case of 12 After Makoto and Department of Medical University A was to of a tumor the pancreas with invasion of the and which of and was no cancer was in the the patient was treated with infusion of and of the the patient with after the is recurrence. The the of and management of on the of and and Intraductal Papillary of the Pancreatic and 1Department of 2Department of of Red Cross Hospital Red Cross A was to for treatment of a an papillary in the pancreatic was at with was Histopathologic showed intraductal papillary with at two We considered these lesions as of the pancreatic showed no for after cells as were detected at year Since no followed this patient on the of in the be the of and in the and of patients with of the A Case of and Pancreatic With Clinical Nakamura, and Department of Medical School A was to with and Clinical and by was which showed in the on day 1 two in the pancreatic One was at the and the other at the of the of the to the of the of the pancreas was performed on on of the at the of the pancreas in to of the at the of the at the of the pancreas was and the at the was by of the pancreatic on Histopathologic showed that the at the of the pancreas was a the at the was a of of the Pancreas With Ductal Case and 1Department of Hospital We a who at a local with the of and were and a in was detected in the pancreas on of the main pancreatic duct in the of the pancreas was detected on endoscopic retrograde was no dilatation to the the an in the to with and progressive of the main pancreatic duct in the of the on these pancreatic endocrine tumor was and was The showed a in the pancreas with The was histopathologically diagnosed as carcinoma of type of the pancreas with ductal pancreatic tumor is invasion is and prognosis is poor when With by Pancreatic A Case and 1The Third Department of Internal Medicine, School of Medicine, University A who had diagnosed with was to with poor level was and was index was The showed a with and the showed a Pancreatic exocrine was as evaluated by the and level in and showed lesions and of the We a of pancreatic endocrine and exocrine in patients with is Diagnosis and of Chronic Pancreatitis. Department of Medicine, of Chronic pancreatitis is diagnosed on the of the results of and pancreatic in of pancreatic in any is the on the of one the are that the of chronic pancreatitis with the three leading and exocrine and endocrine pancreatic insufficiency. these pancreatic and diseases may the and the prognosis of chronic pancreatitis. these have not studied in the current of chronic pancreatitis, two The first is to an of current on the of the by how continuous and endoscopic or may is chronic pancreatitis as a of pancreatic and The is to to in a is not in a A for the of chronic pancreatitis and the of to be of and for Pancreatic cancer is the and a is that pancreatic results from in and that to pancreatic and and the of important genetic changes that the genetic of the the pancreas and of are considered to be important in the of pancreatic cancer. and in or of and is pancreatic cancer. may in one of five by 1 proliferation of and and of cancer as and to pancreatic on are no current clinical to the of with and to significantly the of pancreatic cancer. on and cancer and with and With and in pancreatic be to of cancer and management of pancreatic cancer is a be that and and increased Recent in and in and Chronic and Pancreatic Department of and of Internal Medicine and Gastroenterology, University of patients with pancreatitis, is of the patients with chronic pancreatitis, is in patients with pancreatitis, the to pancreatic and are by the of the and and the in a These more by of clinical not for a in by and to as and in and as as for and than for of and and for of have reported. In patients, a the and with to the not the increased and and a for patients with pancreatitis during the patients with chronic pancreatitis, is in and in and with pancreatic patients who pancreatic in and of and derangement and and the of during for the the clinical and in the that have are not are and not and as and the of of of the and more of in the of the with pancreatic is for of for and and or is of patients with pancreatic and exocrine or during the is a that of is and a and is with are and for the of that be in the clinical are with the clinical and in Pancreatitis. and Department of Hospital pancreatitis a marked of the The of or of may be with the in of of may play a role in the of in patients with pancreatitis. in pancreatitis is with and with the of patients with pancreatitis this The of the patients who during the were with the of those who The were and were from at three time and was by of and and and expression were also was significantly with an after treatment of pancreatitis. activity and is with prognosis and of was increased with of at and and showed no The activity in patients with pancreatitis with seems to with the prognosis of this of the of and of and of Surgery and University of Pancreatic intraductal have only classified as in and the of the grades of ductal epithelial have from to carcinoma, which may be the The of a more to and to as mucinous ductal or intraductal papillary The is an in of in the prognosis with ductal and the to clinical or chronic pancreatitis and between and These the of the pancreas and the may in cases the main pancreatic duct, only or In these an for of the of the gland to a of One of is to is an patient to for a tumor that may the characteristics of an A and more to with an of the which an the of grades of The of the performed at over these to a the to be this was only on those patients with a of with the and who were surgery. Our results the of and are is of the is of of the to an including The extent of the in patients with to the results of in with Molecular and of Pancreatic and Department of Surgery and Kyoto University (Kyoto) Pancreatic cancer is considered to be one of the to It is characterized by local invasion and with is limited to a small of patients. in these patients, poor of and local recurrence. of and local tumor with and may and have on seems to be at the to the treatment results of the pancreatic cancer. to a treatment are is to in the molecular of of the pancreatic with clinical of the and that to this cancer. pancreatic cancer and pancreatic cancer have that on of and treatment that is with We have on as and are in the of in the of pancreatic cancer. The results of the on these be and the for clinical application be Treatment in With for Pancreatic of and and Tanaka, Department of Surgery and School of Medical University of pancreatic cancer is characterized by and invasion to the leading to to and invasion are by or which are as in the management of pancreatic cancer. the role of to be examined during of pancreatic as by is a that to and of cancer The is in pancreatic and a role in invasion and of pancreatic cancer. to the not of or of by and invasion in and of pancreatic cancer in In to these that the of is with activity of to pancreatic cancer expression and and invasion. and invasion of pancreatic cancer by of and also increases invasive of pancreatic cancer by of of the invasive of pancreatic cancer increased after or in with may the of pancreatic cancer patients. to Pancreatic of and Department of which pancreatic the for to be one of the of a pancreatic cancer a cells a of cells, have a role in and then in an In an evaluated in patients by pancreatic cancer and the of for treatment were from by of patients The were after were by or were than in in with of The were to those from in of for and to after to in one patient, in were to the of to the of this that by the tumor could this studied in a tumor by with pancreatic tumor in a We observed that not had and not of The and were with the of expressed by a of and by tumor cells, were not with other tumor and We that with the expressed on and into We also observed that to this was in in tumor patients, from and of pancreatic tumor patients were and for of from with a from cells, that the is to It be concluded that a and is in and in in a pancreatic cancer A from to is one of the for tumor these results on a of tumor from and the to at a Diagnosis Chronic Pancreatitis and Pancreatic by and Pancreatic and Department of of Medicine, University pancreatic as pancreatitis and pancreatitis, are to from ductal carcinoma of the The of study was to the of and pancreatic in pancreatic from pancreatic cancer. patients, including with invasive ductal carcinoma of the pancreas and 8 with chronic pancreatitis with pancreatitis and with was performed in the and of diseases were of of and of was performed in five the and were patients could not be by one was a with changes the pancreatic and the other was a with pancreatitis in which the pancreatic was not of changes in the Our results suggest that and are for the of pancreatic and pancreatic cancer. Case of in an With 1 and 1Department of University Hospital 2Department of Internal Medicine, University Hospital Department of University School of Medicine We an of in a patient with was to for treatment of of the The patient a during the which was of no tumor was detected on Treatment was to the of and and in a of levels, the patient died of and chronic an tumor was on the from the pancreatic to the the tumor was diagnosed as an Our that be in when patients with Case Nakamura, and 1Department of Hospital A was to of the of pancreatitis with according to the of the of Health and of The patient was treated by and continuous infusion of a and the The level two in the and was performed of the of a was performed on day and the patient was on day We patients with pancreatitis in prognosis was than those with pancreatitis by other not to be treatment is for patients with pancreatitis. of in Pancreatic Kazuo and Department of Medical University Hospital from pancreatic and is the of pancreatitis. We two cases of chronic pancreatitis with into 1 was a with and A with on the and a pancreatic the and a was a with a and a and into a of the which into the pancreatic the of into the including the and were performed in patients. We that of the of the pancreas is the when the is in the of the pancreas, for from the pancreatic A Case of Pancreatitis by 1 Inui, and Hospital Department of Medical School of Medicine of Medical School of Medicine We a of pancreatitis, which was by A was to the of of chronic pancreatitis. on showed of pancreatic including showed of the and of dilatation of the main pancreatic duct, and a in in the of the showed of the and no of the into the of the on these was diagnosed with of pancreatitis, and for pancreatitis was The clinical and and was no of on The patient was from the and during the was no of the be The the of pancreatitis by Pancreatic of A Case and Ogawa, 1The Second Department of Kumamoto University School of Medicine (Kumamoto) the at of the
https://doi.org/10.1097/00006676-200307000-00011