Takanori Hiraide

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.

Single-cell time-of-flight secondary ion mass spectrometry reveals that human breast cancer stem cells have significantly lower content of palmitoleic acid compared to their counterpart non-stem cancer cells

Lipids comprise the primary component of cell membranes. Imaging mass spectrometry is increasingly being used to visualize membranous lipids in clinical specimens, and it has revealed that abnormal lipid metabolism is related to the development of diseases. To characterize cell populations which are rare and sparsely localized in tissues, we conducted time-of-flight secondary ion mass spectrometry (TOF-SIMS) analyses of individual cells sorted by fluorescence activated cell sorting (FACS) and applied the method to analyze breast cancer stem cells (CSCs). TOF-SIMS analyses visualized phosphoric acids and four fatty acid (FA) species in the sorted CD45(-)/CD44(+)/CD24(-) CSCs, and these ions are suspected to have originated from membranous phospholipids as they were uniformly detected from the locus where the cells attached. Integrated ion intensity of palmitoleic acids [FA(16:1)] normalized by phosphoric acid signals were decreased significantly in CSCs as compared to that of CD45(-)/CD44(-)/CD24(+) non-stem cancer cells (NSCCs). This finding was supported by liquid chromatography coupled electrospray ionization-tandem mass spectrometry analysis, which revealed phosphatidylcholine (PC)(16:0/16:1) to be less abundant and PC(16:0/16:0) to be more abundant in CSCs as compared to NSCCs. Therefore, our novel method successfully provided lipid composition analysis of individual cells classified by the expression of a complex combination of cell-surface markers. The lipid compositions of CSCs originating from the heterogeneous cellular populations of clinical specimens were successfully characterized by this method.

Necrotizing fasciitis caused by a primary appendicocutaneous fistula

We report a case of necrotizing fasciitis in the loin of a 76-year old man with several coexisting or past health issues, including diabetes mellitus, hypertension, alcohol-related liver cirrhosis, gastrectomy for gastric cancer, subarachnoid hemorrhage, normal pressure hydrocephalus, and cerebral infarction. Incision of the necrotizing fasciitis was successful, but it revealed an appendicocutaneous fistula; thus, we performed appendectomy and fistulectomy. We think that the necrotizing fasciitis was caused by appendicitis perforation involving the retroperitoneum, inducing the formation of an appendicocutaneous fistula. Necrotizing fasciitis and appendicocutaneous fistulae are rare complications of appendicitis. Moreover, to our knowledge, this is the first report of fluoroscopic examination demonstrating that a primary appendicocutaneous fistula had caused necrotizing fasciitis. Our search of the literature found 12 cases of necrotizing fasciitis caused by preoperative appendicitis. We discuss the characteristics and findings of these cases.

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.

Extranodal multiple polypoid follicular lymphoma of the sigmoid colon

Follicular lymphoma is defined as a neoplasm of follicle cells (centrocytes and centroblasts) that has at least a artially follicular pattern. It is a low-grade lymphoma nd is immunohistochemically characterized by a positive eaction to B-cell markers and bcl-2.1-3 Follicular lymhoma of the colon is very rare.2-5 We report a case of xtranodal follicular lymphoma of the sigmoid colon, haracterized by multiple polypoid submucosal masses.

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.

Impact of CYP genotype and inflammatory markers on the plasma concentrations of tramadol and its demethylated metabolites and drug tolerability in cancer patients

PurposeClinical responses to oral tramadol show a large variation in cancer patients. This study aimed to evaluate the impacts of cytochrome P450 (CYP) genotype and serum inflammatory markers on the plasma concentrations of tramadol and its demethylated metabolites and drug tolerability in cancer patients.MethodsThe predose plasma concentrations of tramadol and its demethylated metabolites were determined at day 4 or later in 70 Japanese cancer patients treated with oral tramadol. The CYP genotypes, serum interleukin-6 (IL-6) and C-reactive protein (CRP) levels, and the duration of tramadol treatment were evaluated.ResultsThe CYP2D6 genotype did not affect the plasma tramadol concentration. The plasma concentration of O-desmethyltramadol and its ratio to tramadol were lower in the CYP2D6 intermediate and poor metabolizer (IM + PM) group than in the normal metabolizer (NM) group (P = 0.002 and P = 0.023). The plasma concentration of N-desmethyltramadol and its ratio to tramadol were higher in the CYP2D6 IM + PM group than in the NM group (P = 0.001 and P = 0.001). The CYP2B6*6 and CYP3A5*3 alleles had no effect on the plasma concentrations of tramadol and its demethylated metabolites. The serum IL-6 and CRP levels were inversely correlated with the plasma concentration ratios of N-desmethyltramadol to tramadol and of N,O-didesmethyltramadol to O-desmethyltramadol. The serum IL-6 level was associated with the treatment duration of oral tramadol.ConclusionsThe CYP2D6 genotype but not the CYP2B6 and CYP3A5 genotypes affected the plasma concentrations of O- and N-desmethyltramadol through alteration of the tramadol metabolic pathway. The serum IL-6 level was associated with N-demethylation activity and tramadol tolerability.

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.