Novel insights into the intraepithelial spread of extrahepatic cholangiocarcinoma: clinicopathological study of 382 cases on extrahepatic cholangiocarcinoma

BackgroundExtrahepatic cholangiocarcinoma (eCCA) is a rare and aggressive disease and consisted of conventional eCCA and intraductal papillary neoplasm of the bile duct (IPNB). Intraepithelial spread (IES) of cancer cells beyond the invasive area is often observed in IPNBs; however, the prevalence of IES remains to be examined in conventional eCCAs. Here, we evaluated the clinicopathological features of eCCAs according to tumor location, with a focus on the presence of IES. The IES extension was also compared among biliary tract cancers (BTCs).MethodsWe examined the prevalence and clinicopathological significance of IES in eCCAs (n=382) and the IES extension of BTCs, including gallbladder (n=172), cystic duct (n=20), and ampullary cancers (n=102).ResultsAmong the invasive eCCAs, IPNB had a higher rate of IES (89.2%) than conventional eCCAs (57.0%). Among conventional eCCAs, distal eCCAs (75.4%) had a significantly higher prevalence of IES than perihilar eCCAs (41.3%). The presence of IES was associated with a significantly higher survival rate in patients with distal eCCAs (P=0.030). Extension of the IES into the cystic duct (CyD) in distal eCCAs that cancer cells reached the junction of the CyD was a favorable prognostic factor (P<0.001). The association of survival with IES, either on the extrahepatic bile duct or on the CyD, differed depending on the tumor location and type of eCCA. The extension properties of IES were also dependent on different types of tumors among BTCs; usually, the IES incidence became higher than 50% in the tissues that the tumor developed, whereas IES extension to other tissues decreased the incidence.ConclusionThus, eCCAs have different clinicopathological characteristics depending on the tumor location and type

Intramolecular 1,3=dipolar cycloaddition at the periphery of heterocyclic systems. Part 1. Facile oximenitrone isomerisation at the periphery of pyran and 1-benzopyran

4-(Alk-2-enylamino)-2-0~0-2H-1 -benzopyran-3-carbaldehyde oximes 5 underwent thermally induced 1,3-dipolar cycloaddition under mild conditions giving isoxazolo[ 3,4-4 [ 13 benzopyrano[4,3-b]pyridine derivatives 6 in good yields. The features of the oxime-nitrone isomerisation and nitrone-olefin cycloaddition are discussed. Since a new concept for the generation of nitrone intermediates was proposed by Grigg and co-workers,' the oxime-nitrone isomerisation and nitrone-olefin cycloaddition reactions have provided a versatile approach for the stereoselective synthesis of isoxazolidines. Therein, the thermal 1 ,Zhydrogen shift from oxygen to nitrogen in the oxime function is suggested to be a key step; an unassisted proton shift affords N-unsubstituted (or N-protonated) nitrone intermediates (Scheme 1). The resultant nitrone intermediates could be trapped only intramolecularly to give fused isoxazolidine derivatives. * Because of the predominant existence of the oxime isomer in the oxime-nitrone equilibrium, elevated reaction temperatures were needed to accomplish the cycloaddition reactions. Above all, harsher reaction conditions were required for the formation of the isoxazolidines fused by a six-membered ring; in toluene at 110 "C for 20 h for 1,3,3a,3b-tetrahydr0-4H-[l]benzopyrano-[4,3-c]isoxazole f v 2 " from 2-allyloxybenzaldehyde oxime, and in toluene at 180 "C in a sealed tube for 10 h for 1,l a,3,3a,4,5,6,7,8,8a-decahydro-1H-pyrrolo[ 1,2-a]isoxazolo-[ 3,4-c]pyridine 2e from 1 -( but-3-enyl)pyrrolidine-2-carbaldehyde oxime. In this paper, we report that a facile oxime-nitrone isomerisation takes place in the 4-(alk-2-enylamino)-2-0~0-2H-1 -benzopyran-3-carbaldehyde oxime system. The mechanistic elucidation of the oxime-nitrone isomerisation and stereoselective synthesis of fused isoxazolidines using the isomerisation will be also detailed. Results and discussion Reaction of 4-(alk-2enylamino)-2-oxo-2H-l-benzopyran-3-carbaldehydes with hydroxylamines In order to obtain information on the intramolecular nitrone cycloaddition at the periphery of 2-0x0-2H-1 -benzopyran, we examined the reaction of 4-(allylbenzylamino)-2-oxo-2H-1 -benzopyran-3-carbaldehyde l a with N-methylhydroxylamine hydrochloride 2 in ethanol at room temperature, which after 12 h gave the cycloadduct 3a in 75% yield. Similar reactions of 4-[benzyl(trans-but-2-enyl)amino]-1 b and 4-[benzyl(transcinnamyl)amino]-2-0~0-2H-1 -benzopyran-3-carbaldehyde lc with 2 gave the corresponding adducts 3b, c in good yields (Scheme 2). t Recently, Orlek et al. described that 2-allyloxybenzaldehyde oxime did not undergo intramolecular cycloaddition under the conditions reported by Oppolzer and Keller.'" They reported that the restriction of the conformational space of dipole and dipolarophile in the above system was crucial.' " Isolated yield. Et,N (3.0 equiv.) was added to the reaction mixture to obtain free hydroxylamine in situ. The stereochemistry of the isoxazolidine rings in products 3 was determined to be 3,4-cis and 4,5-trans from the coupling constants and by comparison with those of similar systems reported by Oppolzer.'" This suggested that the resultant nitrone with 2-configuration reacted with the olefinic dipolarophile component in an em-approaching manner. Our next concern was focused on the behaviour of the oximes of aldehydes 1; the reaction of aldehyde la with hydroxylamine hydrochloride 4 (1.4 equiv.) in ethanol at room temperature for 1 h, followed by neutralisation with aqueous sodium hydrogen carbonate gave the oxime 5a and a trace amount of 6a. The structure of 6a was deduced to be 1,3a,4,5,11,11 b-hexahydro-3H-isoxazolo[3,4-dJ[ l]benzopyrano[4,3-b]pyridin-1 1 -one from its spectroscopic data. Prolonged reaction time at the same temperature or heating the ethanol solution of 5a afforded 6a as a major product. These results indicate that product 6a is a secondary product from the oxime 5a and suggest that a nitrone, formed through a 1,Zhydrogen shift in 5a, is a key intermediate for the formation of 6a. To elucidate the utility of this isoxazolidine synthesis, similar reactions of aldehydes l b and l c were examined; oxime 5b and/or isoxazolo[ 11 benzopyranopyridine 6b and 6c were formed depending on the conditions. The reaction of 4-(alk-2-enylamino)-6-methyl-2-oxo-2H-pyran-3-carbaldehydes Id-f with 4 gave only 3H-isoxazolo[3,4-c]pyrano[3,4-eJpyridin-9-ones 6d-f in fair to good yields (Scheme 3

Revisiting the role of the hepatic vein in laparoscopic liver resection

Laparoscopic liver resection (LLR) has expanded to include major liver resection and systematic resection as the techniques have advanced. Regardless of the oncological significance of anatomical resection, dissection of the intersegmental plane is useful in liver resection because it makes liver dissection easier and does not leave an ischemic area. In laparoscopic surgery, the hepatic vein can be exposed with less bleeding than in open surgery because bleeding can be controlled by pneumoperitoneum pressure. Therefore, the hepatic vein is a useful indicator to guide the dissected surface and to determine the depth. However, the basic technique of exposing the hepatic vein during LLR is required. The hepatic vein root can be approached using either a cranial or dorsal approach, with the dorsal approach providing the favorable view characteristic of laparoscopy. Selecting the dissection layer with the Laennec’s capsule of the hepatic vein roots in mind is also a useful technique to ensure more reliable dissection of the hepatic vein. We summarize previous reports on techniques for facilitating LLR using the hepatic vein as a guide and outline the role of each hepatic vein type. Although there are many reports of procedures using the hepatic vein as a guide, the terminology of the approach awaits standardization in the future

Pathological complete response of initially unresectable multiple liver metastases achieved using combined peptide receptor radionuclide therapy and somatostatin analogs following pancreatic neuroendocrine tumor resection: a case report

Abstract Background Peptide receptor radionuclide therapy (PRRT) serves as a novel and effective treatment option for somatostatin receptor-positive unresectable liver metastases of pancreatic neuroendocrine tumors (PNETs). However, there are few reported cases of surgical resection for initially unresectable liver metastases of PNET that were converted to resectable after PRRT. Here we report a case where PRRT and somatostatin analogs (SSAs) led to a pathological complete response of initially unresectable multiple liver metastases following PNET resection. Case presentation A 52-year-old man underwent pylorus-preserving pancreaticoduodenectomy for PNET at age 40 and subsequent hepatectomies for resectable liver metastases at 44 and 47 years of age. At age 48, a follow-up examination revealed unresectable multiple liver metastases, and PRRT with 177Lu-DOTATATE therapy was initiated. After four cycles of PRRT, most liver metastases diminished according to imaging studies, and the remaining two hepatic lesions continued to shrink with additional lanreotide. Conversion surgery for liver metastases was successfully performed, revealing no viable tumor cells in tissue specimens. Seventeen months after surgery, imaging showed no detectable residual tumor or recurrence. We present a review of the relevant literature that highlights the significance of our findings. Conclusions This rare case highlights the pathological complete response of initially unresectable multiple liver metastases achieved by PRRT and SSAs following PNET resection, suggesting their potential as a multimodality treatment option for unresectable PNET

DataSheet_1_Novel insights into the intraepithelial spread of extrahepatic cholangiocarcinoma: clinicopathological study of 382 cases on extrahepatic cholangiocarcinoma.docx

BackgroundExtrahepatic cholangiocarcinoma (eCCA) is a rare and aggressive disease and consisted of conventional eCCA and intraductal papillary neoplasm of the bile duct (IPNB). Intraepithelial spread (IES) of cancer cells beyond the invasive area is often observed in IPNBs; however, the prevalence of IES remains to be examined in conventional eCCAs. Here, we evaluated the clinicopathological features of eCCAs according to tumor location, with a focus on the presence of IES. The IES extension was also compared among biliary tract cancers (BTCs).MethodsWe examined the prevalence and clinicopathological significance of IES in eCCAs (n=382) and the IES extension of BTCs, including gallbladder (n=172), cystic duct (n=20), and ampullary cancers (n=102).ResultsAmong the invasive eCCAs, IPNB had a higher rate of IES (89.2%) than conventional eCCAs (57.0%). Among conventional eCCAs, distal eCCAs (75.4%) had a significantly higher prevalence of IES than perihilar eCCAs (41.3%). The presence of IES was associated with a significantly higher survival rate in patients with distal eCCAs (P=0.030). Extension of the IES into the cystic duct (CyD) in distal eCCAs that cancer cells reached the junction of the CyD was a favorable prognostic factor (PConclusionThus, eCCAs have different clinicopathological characteristics depending on the tumor location and type.</p

Image_2_Novel insights into the intraepithelial spread of extrahepatic cholangiocarcinoma: clinicopathological study of 382 cases on extrahepatic cholangiocarcinoma.tif

BackgroundExtrahepatic cholangiocarcinoma (eCCA) is a rare and aggressive disease and consisted of conventional eCCA and intraductal papillary neoplasm of the bile duct (IPNB). Intraepithelial spread (IES) of cancer cells beyond the invasive area is often observed in IPNBs; however, the prevalence of IES remains to be examined in conventional eCCAs. Here, we evaluated the clinicopathological features of eCCAs according to tumor location, with a focus on the presence of IES. The IES extension was also compared among biliary tract cancers (BTCs).MethodsWe examined the prevalence and clinicopathological significance of IES in eCCAs (n=382) and the IES extension of BTCs, including gallbladder (n=172), cystic duct (n=20), and ampullary cancers (n=102).ResultsAmong the invasive eCCAs, IPNB had a higher rate of IES (89.2%) than conventional eCCAs (57.0%). Among conventional eCCAs, distal eCCAs (75.4%) had a significantly higher prevalence of IES than perihilar eCCAs (41.3%). The presence of IES was associated with a significantly higher survival rate in patients with distal eCCAs (P=0.030). Extension of the IES into the cystic duct (CyD) in distal eCCAs that cancer cells reached the junction of the CyD was a favorable prognostic factor (PConclusionThus, eCCAs have different clinicopathological characteristics depending on the tumor location and type.</p

Image_4_Novel insights into the intraepithelial spread of extrahepatic cholangiocarcinoma: clinicopathological study of 382 cases on extrahepatic cholangiocarcinoma.tif

BackgroundExtrahepatic cholangiocarcinoma (eCCA) is a rare and aggressive disease and consisted of conventional eCCA and intraductal papillary neoplasm of the bile duct (IPNB). Intraepithelial spread (IES) of cancer cells beyond the invasive area is often observed in IPNBs; however, the prevalence of IES remains to be examined in conventional eCCAs. Here, we evaluated the clinicopathological features of eCCAs according to tumor location, with a focus on the presence of IES. The IES extension was also compared among biliary tract cancers (BTCs).MethodsWe examined the prevalence and clinicopathological significance of IES in eCCAs (n=382) and the IES extension of BTCs, including gallbladder (n=172), cystic duct (n=20), and ampullary cancers (n=102).ResultsAmong the invasive eCCAs, IPNB had a higher rate of IES (89.2%) than conventional eCCAs (57.0%). Among conventional eCCAs, distal eCCAs (75.4%) had a significantly higher prevalence of IES than perihilar eCCAs (41.3%). The presence of IES was associated with a significantly higher survival rate in patients with distal eCCAs (P=0.030). Extension of the IES into the cystic duct (CyD) in distal eCCAs that cancer cells reached the junction of the CyD was a favorable prognostic factor (PConclusionThus, eCCAs have different clinicopathological characteristics depending on the tumor location and type.</p

Image_5_Novel insights into the intraepithelial spread of extrahepatic cholangiocarcinoma: clinicopathological study of 382 cases on extrahepatic cholangiocarcinoma.tif

BackgroundExtrahepatic cholangiocarcinoma (eCCA) is a rare and aggressive disease and consisted of conventional eCCA and intraductal papillary neoplasm of the bile duct (IPNB). Intraepithelial spread (IES) of cancer cells beyond the invasive area is often observed in IPNBs; however, the prevalence of IES remains to be examined in conventional eCCAs. Here, we evaluated the clinicopathological features of eCCAs according to tumor location, with a focus on the presence of IES. The IES extension was also compared among biliary tract cancers (BTCs).MethodsWe examined the prevalence and clinicopathological significance of IES in eCCAs (n=382) and the IES extension of BTCs, including gallbladder (n=172), cystic duct (n=20), and ampullary cancers (n=102).ResultsAmong the invasive eCCAs, IPNB had a higher rate of IES (89.2%) than conventional eCCAs (57.0%). Among conventional eCCAs, distal eCCAs (75.4%) had a significantly higher prevalence of IES than perihilar eCCAs (41.3%). The presence of IES was associated with a significantly higher survival rate in patients with distal eCCAs (P=0.030). Extension of the IES into the cystic duct (CyD) in distal eCCAs that cancer cells reached the junction of the CyD was a favorable prognostic factor (PConclusionThus, eCCAs have different clinicopathological characteristics depending on the tumor location and type.</p

Image_1_Novel insights into the intraepithelial spread of extrahepatic cholangiocarcinoma: clinicopathological study of 382 cases on extrahepatic cholangiocarcinoma.tif

BackgroundExtrahepatic cholangiocarcinoma (eCCA) is a rare and aggressive disease and consisted of conventional eCCA and intraductal papillary neoplasm of the bile duct (IPNB). Intraepithelial spread (IES) of cancer cells beyond the invasive area is often observed in IPNBs; however, the prevalence of IES remains to be examined in conventional eCCAs. Here, we evaluated the clinicopathological features of eCCAs according to tumor location, with a focus on the presence of IES. The IES extension was also compared among biliary tract cancers (BTCs).MethodsWe examined the prevalence and clinicopathological significance of IES in eCCAs (n=382) and the IES extension of BTCs, including gallbladder (n=172), cystic duct (n=20), and ampullary cancers (n=102).ResultsAmong the invasive eCCAs, IPNB had a higher rate of IES (89.2%) than conventional eCCAs (57.0%). Among conventional eCCAs, distal eCCAs (75.4%) had a significantly higher prevalence of IES than perihilar eCCAs (41.3%). The presence of IES was associated with a significantly higher survival rate in patients with distal eCCAs (P=0.030). Extension of the IES into the cystic duct (CyD) in distal eCCAs that cancer cells reached the junction of the CyD was a favorable prognostic factor (PConclusionThus, eCCAs have different clinicopathological characteristics depending on the tumor location and type.</p