[Long-Term Survival Following Multidisciplinary Therapy for Pancreatic Head Cancer with Liver Metastasis].

A 71-year-old female was referred to our hospital for liver dysfunction. After careful examination, she was diagnosed with resectable pancreatic head cancer. Pancreatoduodenectomy was scheduled. In the laparotomy, 2 nodules on the liver were found. A frozen section examination of the liver nodule revealed adenocarcinoma. S-1 chemotherapy was administered for about 17 months to treat the unresectable pancreatic cancer. After chemotherapy, computed tomography(CT) revealed that the pancreatic tumor remained unchanged, and there was no distant metastasis. Positron emission tomography( PET)-CT revealed no significant uptake in the pancreatic tumor and no distant metastasis. The patient was then observed for about 10 months without chemotherapy. After that, CT showed that the size of the pancreatic tumor had increased, but there were no signs of distant metastases. Therefore, pancreatoduodenectomy was performed. Histopathological examination revealed invasive ductal adenocarcinoma in the pancreas head. The patient underwent adjuvant chemotherapy with S-1 for 5 months. So far, she has survived without any recurrence for 57 months after the initial surgery.

Laparoscopic cholecystectomy for cholecystitis using direct gallbladder indocyanine green injection fluorescence cholangiography: A case report.

: Laparoscopic cholecystectomy is the treatment of choice for almost all biliary diseases. We present a novel technique using near-infrared fluorescence imaging for laparoscopic cholecystectomy. : A 78-year-old woman diagnosed with acute cholecystitis (Grade II) was scheduled for emergency laparoscopy according to Tokyo Guidelines 2018. We performed a direct percutaneous drainage of the gallbladder to grasp the gallbladder itself. Subsequently, indocyanine green was administered into the gallbladder through the same tube, and the cystic and common bile ducts could be easily detected. The postoperative course was good, and the patient was discharged in remission nine days after the surgery. : Real-time fluorescence cholangiography with indocyanine green is reliable for biliary anatomy visualization before the dissection of the Calot's triangle. Our method of indocyanine green injection into the same drainage catheter does not require pre-preparation and can be simultaneously performed with drainage intraoperatively. This surgical technique is simple, straightforward, and effective and can be useful in intraoperative decision-making, especially during laparoscopic cholecystectomy.

Synthesis of new tricyclic thiolactams as potent antitumor agent for pancreatic cancer.

We synthesized the novel tricyclic thiolactams 2a-d, 3d-k, having a benzyl or substituted benzyl substituent on the nitrogen of indole subunit, and their preferential cytotoxicity under both nutrient-deprived medium (NDM) and Dulbecco's modified Eagle's medium (DMEM) was evaluated against a human pancreatic cancer cell line PANC-1. Among the tested compounds, the 4'-hydroxy derivative 3d showed the most potent cytotoxicity in NDM (PC50 1.68µM) although the moderate preferential cytotoxicity (PC50 1.68µM in NDM vs PC50 20µM in DMEM). The 3'-hydroxy derivative 3e exhibited the most preferential cytotoxicity (PC50 1.96µM in NDM vs less than 50% inhibition at 30µM in DMEM). The benzyl 2a and halogenated benzyl derivatives 2b,c showed no cytotoxicity in NDM. In addition, the indole (10, PC50 173.7µM), lactone (11, PC50 131.7µM), and lactam (12, PC50 44.8µM) derivatives showed week or moderate cytotoxicity in NDM. These results indicated that the hydroxy group on the benzyl substituent and tricyclic thiolactam ring were essential for the cytotoxicity in NDM against PANC-1 cell line. Moreover, 3'-hydroxy derivative 3e compound exhibited antitumor activity against the pancreatic ductal adenocarcinoma (PDAC) xenograft model in vivo.

Solitary Hepatic Eosinophilic Granuloma Accompanied by Eosinophilia Without Parasitosis: Report of a Case.

A 43-year-old Japanese woman visited for a hepatic tumor incidentally found. We suspected eosinophilic granuloma of the liver (EGL) due to visceral larva migrans (VLM). However, neither past history nor medical interview indicated a risk of parasitosis. Blood testing revealed eosinophilia, serum examination showed normal results for immunoglobulin E, and enzyme-linked immunosorbent assay yielded negative for Toxocara and Anisakis. Gastric and colonic endoscopy revealed normal features. Several imagings showed central necrosis of the tumor. After informed consent, laparoscopic resection was performed. Histopathological examination showed EGL without parasites. No recurrence had occurred postoperatively. Most reports documented that EGL are caused by VLM. However, parasites are not always demonstrable on serum, histopathological, or immunochemical examinations. When acting as allergens to induce type I responses, microscopic agents other than parasites in the intestinal tract could induce eosinophilic inflammation in the liver. Accumulation of more cases should help clarify other pathogeneses for EGL.

[A Case Report of Successful Chemotherapy with Tegafur/Gimeracil/Oteracil and Nab-Paclitaxel for Gastric Cancer with Chronic Renal Failure].

An 80-year-old Japanese woman with chronic renal failure was diagnosed with gastric cancer and 2 primary colon cancers. The colon cancers were treated with laparoscopic colectomy, but the gastric cancer metastasized to the liver with inoperable dissemination. After operative treatment of the colon cancers, 1 year of combination chemotherapy consisting of tegafur/gimeracil/oteracil (TS-1®) and nab-PTX was administered to treat the advanced gastric cancer. Tegafur is a well-known prodrug of 5-FU. Serum densitometry of 5-FU was performed to determine the correct dose of TS-1®. After completion of chemotherapy, no tumor was detected on gastroscopy or dynamic computed tomography. The patient was well with no recurrence 6 months after completion of chemotherapy. CDDP, CPT-11, 5-FU, PTX, and DTX are known chemotherapy agents for treating gastric cancer. Renal excretion is not involved in the metabolism of CPT-11, 5-FU, PTX, or DTX. These agents are metabolized in the liver. CPT-11 metabolism depends on individual hepatic enzymes. Therefore, we believe that nab-PTX and TS-1® are safe and effective agents for patients with chronic renal failure and advanced gastric cancer. Additionally, we also conclude that using serum densitometry of 5-FU to guide the administration of TS-1® can improve both safety and efficacy.

3-Fluoroazetidinecarboxylic Acids and trans,trans-3,4-Difluoroproline as Peptide Scaffolds: Inhibition of Pancreatic Cancer Cell Growth by a Fluoroazetidine Iminosugar.

Reverse aldol opening renders amides of 3-hydroxyazetidinecarboxylic acids (3-OH-Aze) unstable above pH 8. Aze, found in sugar beet, is mis-incorporated for proline in peptides in humans and is associated with multiple sclerosis and teratogenesis. Aze-containing peptides may be oxygenated by prolyl hydroxylases resulting in potential damage of the protein by a reverse aldol of the hydroxyazetidine; this, rather than changes in conformation, may account for the deleterious effects of Aze. This paper describes the synthesis of 3-fluoro-Aze amino acids as hydroxy-Aze analogues which are not susceptible to aldol cleavage. 4-(Azidomethyl)-3-fluoro-Aze and 3,4-difluoroproline are new peptide building blocks. trans,trans-2,4-Dihydroxy-3-fluoroazetidine, an iminosugar, inhibits the growth of pancreatic cancer cells to a similar degree as gemcitabine.

Aneurysm of Pancreatic Artery in Association with Celiac Axis Stenosis: Report of a Case and Review of the Literatures.

A 63-year-old Japanese woman with a history of pemphigus was referred to us for abnormal findings of dynamic abdominal CT where three aneurysms of splenic artery and pancreaticoduodenal artery, celiac axis compression, and gall stone. Superior mesenteric artery supplied hepatic arterial flow via pancreaticoduodenal artery. Avoiding transarterial embolization to prompt arterial ischemia of liver/pancreas head/duodenum, she laparotomically underwent cholecystectomy, splenectomy, transection of median arcurate ligament, and ligation of splenic and inferior pancreaticoduodenal artery all at once. Postoperative course was uneventful except drainage of abdominal abscess, and she remained well without aneurysm recurring 40 months post. Important point of treatment for pancreaticoduodenal artery aneurysm associated with celiac artery occlusion/stenosis is both preventive solutions for rupture of aneurysm and hepatic/duodenal/pancreatic arterial ischemia. Remaining main arterial supply for the liver via pancreaticoduodenal artery from superior mesenteric artery would prompt recurrent aneurysm of pancreaticoduodenal artery. When a clinician encounters a case of pancreatic aneurysm associated with celiac axis occlusion, the case should be treated using with multimodality such as interventional radiology, and vascular surgery.

Efficacy of single-incision laparoscopic appendectomy in adults and adolescents using an endolinear stapler.

BACKGROUND: Some investigators recently introduced transumbilical single-incisional laparoscopic appendectomy (SILA), however, those SILA require expensive surgical instruments, or difficult technique. We uniquely propose performing SILA using with endolinear stapler, and compare the clinical results of the present SILA with those of conventional laparoscopic appendectomy. MATERIALS AND METHODS: In brief, the skin of the umbilical hollow is cut, the anterior layer of the rectus sheath and subcutaneous fat is exfoliated widely, and the linea alba is opened. Two low-profile 5-mm-diameter trocars are stabbed through the right rectus sheath, and a 12-mm-diameter trocar is inserted from the opened linea alba. Using a 5-mm laparoscope, and endolinear stapler, the appendix is dissected. Some clinical and operative data of 16 cases treated the present SILA are compared with those of 35 cases treated conventional laparoscopic appendectomy. RESULTS: We performed the present SILA for 16 patients consisted of young women mostly, compared with cases treated conventional laparoscopic appendectomy (mean, 26-year-old vs 51-year-old, p < 0.0001). The results of the SILA we have proposed in adults and adolescents are good in terms of operation time (mean, 64 minutes vs 89.3 minutes, p = 0.049), duration of hospitalization (mean, 4.2 days vs 8.1 days, p = 0.0038), and low frequency of intra- and postoperative complications (one patient of postoperative umbilical granuloma). CONCLUSIONS: We assume that convenience of surgical procedure of the present SILA would affect the shortness of operation time, and that minimal invasive surgical stress of the present SILA would reduce perioperative stress of appendicitis, and ameliorate adolescents with appendicitis earlier. We believe that the SILA we have proposed offers advantages in diversion of conventional surgical instruments, similarity to conventional manipulation of laparoscopic forceps, usage of an endoscopic stapler able to cut cecum in cases of advanced appendicitis extending to the cecum, and obviation of extra-abdominal appendectomy demanding excessive traction of the appendix.

Carcinosarcoma of the liver: report of a case.

A 64-year-old Japanese woman without a history of viral hepatitis was admitted for investigation of a huge liver mass. The tumor, measuring 14 × 12 × 22 cm, had invaded the diaphragm, right lung, and inferior vena cava. Serum examinations demonstrated high levels of carbohydrate antigen 19-9 (CA19-9), and the Child-Pugh score was A. She underwent right lobectomy of the liver and partial resection of the right diaphragm, right lung, and inferior vena cava. Radio- and chemotherapy were also given, but she died of recurrence 3 months after surgery. Microscopically, the tumor exhibited intermingled adenocarcinomatous and atypical mesenchymal components. The carcinomatous component was positive for cytokeratins 7, 19, and 20, chromogranin A, epithelial membrane antigen, c-KIT, and vimentin. The sarcomatous component was positive for vimentin and c-KIT. A review of 36 cases of hepatic carcinosarcoma revealed the following: chronic hepatitis or cirrhosis in 57 % of the patients; increased serum CA19-9 levels in 30 %; a mean tumor diameter of 10 cm; invasion of the adjacent organs or metastasis to distant organs in 47 %; wide intrahepatic infiltration in 44 %; and 50 % survival of only 5 months. Significant differences were seen according to tumor diameter (diameter >5 cm; p < 0.05), wide intrahepatic infiltration (p < 0.05), and extrahepatic invasion/metastasis (p < 0.01). Neither chemotherapy nor radiotherapy contributed to prognosis, but surgical resection resulted in some improvement (p < 0.05).

Incisional intercostal hernia with prolapse of the colon after right partial nephrectomy.

A 75-year-old woman with a history of myocardial infarction, gallstones, and right renal cancer was referred to our department because of right flank pain. She had a surgical scar on the right abdomen between the 10th and 11th ribs; computed tomography demonstrated intercostal herniation of the colon. Recognizing the possibility of adhesions of the hernia and colon, we used a median skin incision and patched a polyester mesh coated with absorbent collagen. The patient had an uneventful postoperative course, with no pain for 6 months postoperatively. Transdiaphragmatic intercostal hernias with abdominal contents commonly develop after trauma or thoracic surgery. Incisional intercostal hernias seldom develop after nephrectomy; the present case is only the fourth report. We conjecture that a costochondral incision can induce subluxation of the costotransverse joint, intercostal nerve injury, and atrophy of the intercostal and abdominal oblique muscles. Surgeons must therefore recognize the potential, albeit rare, for intercostal hernia after nephrectomy.

Management of postoperative intraabdominal abscess in laparoscopic versus open appendectomy.

BACKGROUND: Complicated appendicitis (gangrenous or perforated appendicitis) is a risk for postoperative intraabdominal abscess, but management of intraabdominal abscess may differ between laparoscopic and open appendectomy. METHODS: We reviewed 67 patients who underwent appendectomy for complicated appendicitis, including 26 who received laparoscopic appendectomy (LA group) and 41 who underwent open appendectomy (OA group). The operation was performed under general anesthesia in all 26 patients in the LA group and in 10 (24%) in the OA group. Patient characteristics, operative factors, and postoperative complications (especially postoperative intraabdominal abscess) were compared between the two groups. Management of postoperative intraabdominal abscess was also investigated. RESULTS: Postoperative intraabdominal abscess occurred in 3 patients (12%) in the LA group and in 10 (24%) in the OA group (p = 0.23). All 3 patients in the LA group were treated conservatively. Of the 10 patients in the OA group, 6 were treated conservatively, but 4 needed a reoperation, including 3 who had undergone right pararectal skin incision under spinal analgesia and in whom sufficient irrigation was not possible because anesthesia had worn off. CONCLUSIONS: Our results suggest that insertion of abdominal drainage may be appropriate treatment for intraabdominal abscess after laparoscopic appendectomy. Light anesthesia may induce residual abscess in open appendectomy performed under spinal analgesia.

The redox state of glutathione regulates the hypoxic induction of HIF-1.

Hypoxia inducible factor 1 (HIF-1) regulates the transcription of vascular endothelial growth factor (VEGF), which plays important roles in angiogenesis. We investigated the redox effect of glutathione (GSH) on the hypoxic induction of HIF-1 in a human oral squamous cell carcinoma (HSC-2) cell line. The maximal induction of HIF-1 in HSC-2 cells was observed 30 h after hypoxia, and VEGF mRNA was expressed after 36 h under hypoxia. GSH ethyl ester (GSHee, a membrane permeable analog of GSH) and N-acetyl-L-cysteine (NAC, a membrane permeable precursor of GSH) reduced HIF-1 binding activity in a dose-dependent manner. Further, HIF-1 dependent promoter activity was similarly reduced by GSHee and NAC. However, ebselen, which increases glutathione peroxidase activity and oxidizes GSH, negated the effect of GSHee on HIF-1 dependent promoter activity. The inhibitory effect of GSHee and NAC on HIF-1 binding activity was reversed by bis (2-chlorethyl)-nitrosourea, an oxidized glutathione (GSSG) reductase inhibitor which increases the concentration of GSSG. GSSG methyl ester (GSSGme), a membrane permeable analog of GSSG, enhanced HIF-1 dependent promoter activity and exhibited a bell-shaped concentration-dependant activity curve. The increasing effect of GSSGme on HIF-1 induction was also observed under chemically-induced hypoxia obtained using cobalt chloride. These results suggest that changes in the intracellular GSSG/GSH ratio may regulate HIF-1 induction during hypoxia.

Identification of arctigenin as an antitumor agent having the ability to eliminate the tolerance of cancer cells to nutrient starvation.

Tumor cells generally proliferate rapidly and the demand for essential nutrients as well as oxygen always exceeds the supply due to the unregulated growth and the insufficient and inappropriate vascular supply. However, cancer cells show an inherent ability to tolerate extreme conditions, such as that characterized by low nutrient and oxygen supply, by modulating their energy metabolism. Thus, targeting nutrient-deprived cancer cells may be a novel strategy in anticancer drug development. Based on that, we established a novel screening method to discover anticancer agents that preferentially inhibit cancer cell viability under the nutrient-deprived condition. After screening 500 medicinal plant extracts used in Japanese Kampo medicine, we found that a CH(2)Cl(2)-soluble extract of Arctium lappa exhibited 100% preferential cytotoxicity under the nutrient-deprived condition at a concentration of 50 microg/mL with virtually no cytotoxicity under nutrient-rich condition. Further bioassay-guided fractionation and isolation led to the isolation of arctigenin as the primary compound responsible for such preferential cytotoxicity; the compound exhibited 100% preferential cytotoxicity against nutrient-deprived cells at a concentration of 0.01 microg/mL. Furthermore, arctigenin was also found to strongly suppress the PANC-1 tumor growth in nude mice, as well as the growth of several of the tested pancreatic cancer cell lines, suggesting the feasibility of this novel antiausterity approach in cancer therapy. Further investigation of the mechanism of action of arctigenin revealed that the compound blocked the activation of Akt induced by glucose starvation, which is a key process in the tolerance exhibited by cancer cells to glucose starvation.

Angelmarin, a novel anti-cancer agent able to eliminate the tolerance of cancer cells to nutrient starvation.

The CH(2)Cl(2)-soluble extract of Angelica pubescens was found to kill PANC-1 cancer cells preferentially under nutrition starvation at a concentration of 50 microg/ml, with virtually no cytotoxicity under nutrient-rich conditions. Further bioassay-guided fractionation and isolation led to the isolation of a novel compound named angelmarin as the primary compound responsible for the preferential cytotoxicity; the compound exhibited 100% preferential cytotoxicity against PANC-1 cells at a concentration of 0.01 microg/ml.

Antitumor activity of pyrvinium pamoate, 6-(dimethylamino)-2-[2-(2,5-dimethyl-1-phenyl-1H-pyrrol-3-yl)ethenyl]-1-methyl-quinolinium pamoate salt, showing preferential cytotoxicity during glucose starvation.

An anthelminthic, pyrvinium pamoate (PP), 6-(dimethylamino)-2-[2-(2,5-dimethyl-1-phenyl-1H-pyrrol-3-yl)ethenyl]-1-methyl-quinolinium pamoate salt, has been found to be extremely toxic to PANC-1 cells in glucose-free medium, but not to be toxic to the same cells cultured in ordinary medium, Dulbecco's modified Eagle's medium (DMEM). It showed the same preferential toxicity for various cancer cell lines during glucose starvation. When 0.1 microg/ml PP was added to the medium, spheroid growth of human colon cancer cell line WiDr was strongly inhibited to a diameter of 750 microm, and this finding is consistent with the concept of anti-austerity. PP was also found to exert antitumor activity against human pancreatic cancer cell line PANC-1 in nude mice and SCID mice when it was administered subcutaneously or orally. Regarding the mechanism of PP action, inhibition of Akt phosphorylation, which has been found to be essential for the austerity mechanism, was observed in vitro and in vivo. These findings indicate that PP may be useful for anticancer therapy and that anti-austerity therapy could be a novel strategy for anticancer therapy.

Effects of nitric oxide donors on vascular endothelial growth factor gene induction.

Nitric oxide (NO) has been reported to modulate the vascular endothelial growth factor (VEGF) gene by accumulating hypoxia-inducible factor-1alpha (HIF-1alpha) protein, but there is a contradiction among effects of various NO donors. The effects of NO donors including S-nitroso-N-acetyl-penicillamine (SNAP), S-nitroso-glutathione (GSNO), 1-hydroxy-2-oxo-3,3-bis(2-aminoethyl)-1-triazene (NOC18), 3-[(+/-)-(E)-ethyl-2(')-[(E)-hydroxyimino]-5-nitro-3-hexenecarbamoyl]-pyridine (NOR4), 3-morpholinosydnonimine (SIN-1), and nitroprusside (SNP) on the VEGF reporter gene were examined. SNAP, GSNO, NOC18, and NOR4 enhanced the VEGF reporter activity under normoxia and modulated the hypoxic induction. In contrast, SNP had only an inhibitory effect. An NO scavenger attenuated the reporter activation by NO donors except NOR4, but did not ameliorate the inhibitory effect of SNP. A reducing compound dithiothreitol suppressed NO-induced activation of the VEGF reporter gene. SNAP, GSNO, and NOC18 induced the accumulation of HIF-1alpha protein, while others did not. These results suggest that SNAP, GSNO, and NOC compounds are suitable for pharmacological studies in HIF-1-mediated VEGF gene activation by NO.

Hypoxia and nitric oxide treatment confer tolerance to glucose starvation in a 5'-AMP-activated protein kinase-dependent manner.

Hypoxia is a critical event for higher organisms, and cells and tissues react by increasing the oxygen supply by vasodilatation, angiogenesis, and erythropoiesis and maintaining cellular energy by increasing glycolysis and inhibiting anabolic pathways. Stimulation of glycolysis has been regarded as the main response that increases energy production during hypoxia; however, there is an obvious conflict during ischemia, because both the oxygen and glucose supply are insufficient. In this study, we found that exposure of HepG2 cells and normal fibroblasts to hypoxia induces cellular tolerance to glucose starvation. The tolerance induced by hypoxia is dependent on several amino acids, indicating a switch from glucose to amino acids as the energy source. When antisense RNA expression vector for 5'-AMP-activated protein kinase or protein kinase B/Akt was transfected into HepG2 cells, the induction of tolerance to glucose was greatly inhibited, indicating that the tolerance was dependent on 5'-AMP-activated protein kinase and protein kinase B/Akt. Similar tolerance was induced by nitric oxide exposure. The tolerance induced was observed in various cells and may represent a previously unknown physiological response related to hypoxia-preconditioning and tumor progression:austerity.