Yasushi Shibasaki

Lysophosphatidylcholine acyltransferase 1 altered phospholipid composition and regulated hepatoma progression.

BACKGROUND & AIMS Several lipid synthesis pathways play important roles in the development and progression of hepatocellular carcinoma (HCC), although the precise molecular mechanisms remain to be elucidated. Here, we show the relationship between HCC progression and alteration of phospholipid composition regulated by lysophosphatidylcholine acyltransferase (LPCAT). METHODS Molecular lipidomic screening was performed by imaging mass spectrometry (IMS) in 37 resected HCC specimens. RT-PCR and Western blotting were carried out to examine the mRNA and protein levels of LPCATs, which catalyze the conversion of lysophosphatidylcholine (LPC) into phosphatidylcholine (PC) and have substrate specificity for some kinds of fatty acids. We examined the effect of LPCAT1 overexpression or knockdown on cell proliferation, migration, and invasion in HCC cell lines. RESULTS IMS revealed the increase of PC species with palmitoleic acid or oleic acid at the sn-2-position and the reduction of LPC with palmitic acid at the sn-1-position in HCC tissues. mRNA and protein of LPCAT1, responsible for LPC to PC conversion, were more abundant in HCCs than in the surrounding parenchyma. In cell line experiments, LPCAT1 overexpression enriched PCs observed in IMS and promoted cell proliferation, migration, and invasion. LPCAT1 knockdown did viceversa. CONCLUSIONS Enrichment or depletion of some specific PCs, was found in HCC by IMS. Alteration of phospholipid composition in HCC would affect tumor character. LPCAT1 modulates phospholipid composition to create favorable conditions to HCC cells. LPCAT1 is a potent target molecule to inhibit HCC progression.

Expression of indocyanine green-related transporters in hepatocellular carcinoma

BACKGROUND Indocyanine green (ICG), an organic anion used in liver function tests, is known to accumulate in hepatocellular carcinoma (HCC) tissues after an intravenous injection. Because the intratumoral expression of transporters for chemical agents influences the behaviors of some malignant tumors, we investigated whether the expression of ICG-related transporters influenced the clinicopathologic features of HCC. MATERIALS AND METHODS ICG accumulation patterns were examined using near-infrared spectroscopy and the protein expression of ICG-related transporters was assessed using immunohistochemistry and immunoblotting in 40 resected HCC specimens. We also determined whether the intratumor expression of these transporters affected intratumor lipid composition by imaging mass spectrometry. RESULTS Immunoblot analysis revealed that the expression of organic anion transporting polypeptide 1B3 (OATP1B3) and multidrug resistance p-glycoprotein (MDR)-3, as influx and efflux transporters, respectively, were significantly higher in ICG-accumulated HCC (ICG-high HCC) than in ICG-low HCC. ICG was fluorescently observed in the pseudoglands and bile canaliculi abundantly expressing MDR3. An immunohistochemical examination revealed significantly worse disease-free and overall survival rates in patients with MDR3-negative HCC, in which the intratumoral accumulation of some phosphatidylcholine species was observed under imaging mass spectrometry. CONCLUSIONS The intratumoral expression of MDR3, a key efflux transporter of ICG, affected the prognosis of patients with HCC, presumably by altering the lipid composition of the lipid bilayers.

Accumulation of arachidonic acid-containing phosphatidylinositol at the outer edge of colorectal cancer

Accumulating evidence indicates that cancer cells show specific alterations in phospholipid metabolism that contribute to tumour progression in several types of cancer, including colorectal cancer. Questions still remain as to what lipids characterize the outer edge of cancer tissues and whether those cancer outer edge-specific lipid compositions emerge autonomously in cancer cells. Cancer tissue-originated spheroids (CTOSs) that are composed of pure primary cancer cells have been developed. In this study, we aimed to seek out the cancer cell-autonomous acquisition of cancer outer edge-characterizing lipids in colorectal cancer by analysing phospholipids in CTOSs derived from colorectal cancer patients with matrix-assisted laser desorption/ionization (MALDI)-imaging mass spectrometry (IMS). A signal at m/z 885.5 in negative ion mode was detected specifically at the surface regions. The signal was identified as an arachidonic acid (AA)-containing phosphatidylinositol (PI), PI(18:0/20:4), by tandem mass spectrometry analysis. Quantitative analysis revealed that the amount of PI(18:0/20:4) in the surface region of CTOSs was two-fold higher than that in the medial region. Finally, PI(18:0/20:4) was enriched at the cancer cells/stromal interface in colorectal cancer patients. These data imply a possible importance of AA-containing PI for colorectal cancer progression, and suggest cells expressing AA-containing PI as potential targets for anti-cancer therapy.

Pancreatoduodenal artery aneurysm resulting from median arcuate ligament compression successfully treated with laparoscopic ligament section

True aneurysms of the pancreatoduodenal arteries are frequently associated with stenosis or occlusion of the celiac trunk caused by median arcuate ligament compression. Celiac stenosis cannot be cured, even by transarterial embolization, which has recently become a good alternative to open surgical repair. To prevent recurrence, management of median arcuate ligament compression to correct hemodynamics in vascular networks should also be performed. Herein we report a case of pancreatoduodenal arterial aneurysm with median arcuate ligament compression that was successfully treated with minimally invasive laparoscopic median arcuate ligament section. The patient was discharged 4 days after surgery with no complications. Enhanced CT 1 month after surgery revealed no residual celiac trunk stenosis or aneurysm. Normalization of blood flow by laparoscopic median arcuate ligament section is a good option for some patients with a pancreatoduodenal arterial aneurysm.

Anomalous arterial ramification in the right liver

PurposeThe aim of this study was to investigate whether individual arterial and portal venous division during hepatectomy is always safe by examining the presence of the anomalous arterial ramification in the right liver.MethodsThe ramifications of the right hepatic artery (RHA) were investigated by three-dimensional (3D) reconstruction imaging using a computer software program in 87 patients undergoing computed tomography during angiography as a preoperative assessment of intrahepatic tumors.ResultsThe anterior view showed that the RHA bifurcated into the anterior and posterior sector arteries at the hilum in 76 patients. Sector-intersecting arteries from the posterior to the anterior sector and vice versa were found in 7 and 4 of those patients, respectively. The RHA in the other 11 patients was divided in a complex manner into more than 2 arteries: e.g., the first branch to the cranial part of the posterior sector, the second to the anterior sector, and the third to the caudal part of the posterior sector. A total of 22 patients showed anomalous ramification of RHA.ConclusionPreoperative observation of the hepatic artery by 3D imaging is very useful to detect anomalous ramification. Arterial dissection during the intrafascial approach should be cautiously performed based on the 3D images.

Stearate-to-palmitate ratio modulates endoplasmic reticulum stress and cell apoptosis in non-B non-C hepatoma cells

The increased prevalence of hepatocellular carcinoma (HCC) without viral infection, namely, NHCC, is a major public health issue worldwide. NHCC is frequently derived from non‐alcoholic fatty liver (NAFL) and non‐alcoholic steatohepatitis, which exhibit dysregulated fatty acid (FA) metabolism. This raises the possibility that NHCC evolves intracellular machineries to adapt to dysregulated FA metabolism. We herein aim to identify NHCC‐specifically altered FA and key molecules to achieve the adaptation. To analyze FA, imaging mass spectrometry (IMS) was performed on 15 HCC specimens. The composition of saturated FA (SFA) in NHCC was altered from that in typical HCC. The stearate‐to‐palmitate ratio (SPR) was significantly increased in NHCC. Associated with the SPR increase, the ELOVL6 protein level was upregulated in NHCC. The knockdown of ELOVL6 reduced SPR, and enhanced endoplasmic reticulum stress, inducing apoptosis of Huh7 and HepG2 cells. In conclusion, NHCC appears to adapt to an FA‐rich environment by modulating SPR through ELOVL6.

Indocyanine Green-Related Transporters in Hepatocellular Carcinoma

Intraoperative indocyanine green (ICG) fluorescent imaging under near-infrared light is a useful procedure to detect hepatocellular carcinoma (HCC). However, the mechanisms of ICG accumulation in HCC have been unclear. We hypothesized that some transporters on the hepatocytes may be involved in the process of ICG accumulation and examined the expression levels of influx and efflux transporters using resected HCC tissues. Among influx transporter, organic anion-transporting polypeptide 1B3 (OATP1B3) and sodium-taurocholate transport protein (NTCP) are suggested to be responsible for ICG export in HCC. Interestingly, multidrug resistance p-glycoprotein-3 (MDR3), an efflux transporter to canaliculi, is also one of the important ICG transporters and a prognostic factor of HCC. We speculated that ICG is uptaken into hepatocytes through OATP1B3 and accumulated into the blunt-end pseudo-glands or bile canaliculi in HCC tissues through the efflux by MDR3.

Duodenal adenocarcinoma successfully diagnosed with transabdominal ultrasonography

Adenocarcinoma arising from the duodenum is relatively rare. Diagnosis of this disease at an early stage is difficult because its symptoms are usually nonspecific. We herein present a case in which duodenal adenocarcinoma was successfully found by transabdominal ultrasonography. Under ultrasonography, the tumor was located in the proximal duodenum apart from the papilla of Vater, and the serosa was intact. Other diagnostic modalities showed no evidence of adjacent organ invasion or distant metastasis. Therefore, pancreatoduodenectomy was performed and the postoperative course was uneventful. The ultrasonographic findings corresponded well with the pathological diagnosis. The following three procedures were essential in this case: systematic scanning of the digestive tract to determine the location of the lesion, graded compression ultrasound to remove air bubbles from the region of interest, and precise observation of the intestinal walls using proper transducers. The precise and skillful performance of transabdominal ultrasonography using a suitable device can help to diagnose duodenal adenocarcinoma, a rare malignancy.

Usefulness of four-dimensional flow-sensitive magnetic resonance imaging to evaluate hemodynamics in the pancreaticoduodenal artery

Pancreaticoduodenal artery (PDA) aneurysm associated with celiac axis compression by the median arcuate ligament (MAL) is a rare disorder, but may be lethal if ruptured. Therefore, prophylactic surgical treatments need to be considered when MAL compresses the celiac axis. We herein report the usefulness of an arterial flow analysis for objectively evaluating this pathophysiology under four-dimensional flow-sensitive magnetic resonance imaging (4D-flow MRI). Celiac artery stenosis was incidentally found under contrast-enhanced CT in a 50-year-old woman with symptomatic solitary pancreatic insulinoma. Under 4D-flow MRI, retrograde blood flow and aberrant wall shear stress were detected in the pancreaticoduodenal artery arcade. After obtaining informed consent, enucleation for insulinoma concomitant with MAL dissection was performed. Hypoglycemic attack completely resolved immediately after surgery. One month after surgery, 4D-flow MRI revealed normalized vectorial flow and wall shear stress in the PDA arcade without hypoglycemic attack. 4D-flow MRI is a very useful and non-invasive modality for objectively evaluating visceral artery hemodynamics.

Lethal Bleeding from a Duodenal Cancerous Ulcer Communicating with the Superior Mesenteric Artery in a Patient with Pancreatic Head Cancer

Pancreatic cancer often invades the duodenum and causes obstruction, but rarely causes massive duodenal bleeding. A 68-year-old male was admitted to our hospital because of vomiting. Enhanced abdominal CT showed a hypovascular tumor with air bubbles in the uncinate process of the pancreas. The tumor invaded the duodenum and metastasized to the liver and peritoneum. The main trunk of the superior mesenteric artery (SMA) was circumferentially involved. After admission, he had hematemesis and melena. Emergency gastroduodenoscopy revealed pulsating vessels in the third portion of the duodenum and he eventually experienced hemorrhagic shock. Severe bleeding occurred from his mouth and anus like a catastrophic flood. It was difficult to sustain blood pressure even with massive blood transfusion with pumping. After insertion of an intra-aortic balloon occlusion catheter, the massive bleeding was eventually stopped. Although we attempted interventional radiography, aortography revealed direct communication between the main SMA trunk and the duodenal lumen. The tumor was considered anatomically and oncologically unresectable. Thus, we did not perform further intervention. The patient died 2 h after angiography. Herein, we report the case of pancreatic head cancer causing lethal bleeding associated with tumor-involved SMA. Duodenal bleeding associated with pancreatic cancer invasion should be considered as an oncogenic emergency.