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A 71-year-old woman presented with epigastric pain after having meals visited our hospital. On examination, she was diagnosed with gallstone cholecystitis, complicated with common bile duct stones. She was treated appropriately, and her conditions improved. It was fortuitously noted that she had a

A 39-year-old previously healthy woman was referred to our emergency department by a primary care doctor on suspected to be acute enteritis, complaining of fever, anorexia, lower abdominal pain, and frequent diarrhea. The day after admission, although frequent diarrhea stopped, the abdominal distension worsened. An abdominal radiograph revealed several dilated loops of the small bowel, suggested that small bowel obstruction (SBO) had developed. White blood cell count and c-reactive protein were markedly increased, and abdominal contrast-enhanced computed tomography scan showed localized severely edematous bowel mucosa, increased adipose tissue concentration in the pelvis, and a beaded low absorption area in the uterus. Gynecological examination revealed the presence of a pus-filled plastic intrauterine device (IUD) in the uterus. The patient confided that she had sex with her husband 2 days before the onset of symptoms. A diagnosis of SBO due to pelvic peritonitis caused by IUD infection during sexual activity was made. The SBO was cleared in 12 days with fasting, peripheral parenteral nutrition, antibiotic treatment, and insertion of an ileus tube. This case reminds us that it needs to consider disorders associated with the uterine appendages, in women of reproductive age with lower abdominal pain.

The malignant nature of hepatocellular carcinoma (HCC) is closely related to the presence of cancer stem cells (CSCs). Bone morphologic protein 9 (BMP9), a member of the transforming growth factor‐beta (TGF‐β) superfamily, was recently reported to be involved in liver diseases including cancer. We aimed to elucidate the role of BMP9 signaling in HCC‐CSC properties and to assess the therapeutic effect of BMP receptor inhibitors in HCC. We have identified that high BMP9 expression in tumor tissues or serum from patients with HCC leads to poorer outcome. BMP9 promoted CSC properties in epithelial cell adhesion molecule (EpCAM)‐positive HCC subtype via enhancing inhibitor of DNA‐binding protein 1 (ID1) expression in vitro. Additionally, ID1 knockdown significantly repressed BMP9‐promoted HCC‐CSC properties by suppressing Wnt/β‐catenin signaling. Interestingly, cells treated with BMP receptor inhibitors K02288 and LDN‐212854 blocked HCC‐CSC activation by inhibiting BMP9‐ID1 signaling, in contrast to cells treated with the TGF‐β receptor inhibitor galunisertib. Treatment with LDN‐212854 suppressed HCC tumor growth by repressing ID1 and EpCAM in vivo. Our study demonstrates the pivotal role of BMP9‐ID1 signaling in promoting HCC‐CSC properties and the therapeutic potential of BMP receptor inhibitors in treating EpCAM‐positive HCC. Therefore, targeting BMP9‐ID1 signaling could offer novel therapeutic options for patients with malignant HCC., BMP9‐ID1 signaling plays a pivotal role in promoting the cancer stem cell properties of EpCAM+ hepatocellular carcinoma (HCC) cells by activating Wnt/β‐catenin signaling. Treatment with BMP receptor inhibitors that block BMP9‐ID1 signaling could potentially be considered as targeted therapy for patients with malignant HCC.

The high mortality rate due to severe Herpes simplex viral (HSV) hepatitis is associated with the difficulty of its diagnosis. We describe the extremely rapid disease course of a patient who died of severe HSV hepatitis. A 73-year-old woman was admitted for a bronchial asthma attack. Her symptoms improved with steroid treatment, but she developed a sore throat and painful swallowing. On day 12 after admission, she suddenly went into shock. Blood test results showed a significant increase in the liver enzyme levels, with remarkable disseminated intravascular coagulation. She died the same day. The autopsy revealed extensive coagulative necrosis of the liver. Viral inclusion of type A Cowdry bodies was found in the residual hepatocytes in the hepatic lobule. Immunostaining revealed HSV type 1 positivity. We diagnosed the cause of death as severe HSV hepatitis. On examination of a stored serum sample, the patient tested positive for the HSV immunoglobulin (Ig)-M antibody, and the HSV RNA level was very high (1 × 109 copies/mL). Remarkably, the HSV IgG test result was negative, and we diagnosed her as having had an initial HSV infection. Hepatitis due to HSV is very rare in healthy adults; however, there are many reports of immune-deficient cases. The presence of HSV IgG is decreasing in the elderly population because of the change in living environments/lifestyles. The increasing use of immunosuppressive drugs, such as steroids, for treating diseases in elderly patients could be linked to the increased prevalence of initial HSV infections, resulting in liver injury.

Retropharyngeal emphysema is a rare condition, and it is important to determine whether the patient presents with complications including pneumomediastinum or other severe clinical presentations such as an upper airway obstruction. In such cases, patients should undergo urgent tracheostomy and surgical neck drainage with concurrent administration of broad‐spectrum antibiotics.

An 80-year-old man was admitted to our hospital with iron deficiency anemia and exertional chest pain. Coronary artery angiography showed 90% stenosis in the middle left anterior descending branch; abdominal computed tomography (CT) showed enlarged mesenteric lymph nodes. Although his past medical history and results of imaging studies did not suggest intestinal stenosis, assessment of intestinal patency with the PillCam® patency capsule (tag-less PC) was performed. Thirty-three hours after administration, excretion of tag-less PC was not confirmed; an abdominal contrast-enhanced CT showed arrest of tag-less PC in the small bowel and thickening of the bowel wall, suggesting a small bowel tumor. Four days after administration of tag-less PC, he developed abdominal pain and vomiting. Intestinal obstruction was diagnosed by abdominal radiograph. A diagnosis of small bowel tumor with intestinal obstruction was made, and surgical resection was performed. The tumor was histologically an adenocarcinoma. It is necessary to carefully evaluate gastrointestinal patency before small intestine endoscopy especially in elderly people with reduced cardiopulmonary function and many underlying diseases.

A 57-year-old man with lung cancer, previously treated with the programmed death-1 inhibitor pembrolizumab, was evaluated for liver injury and acute pancreatitis. Serum IgG4 levels were not elevated. Contrast-enhanced CT showed pancreatic swelling, contrast unevenness in the liver and thickening of the common bile duct and gall bladder. Magnetic resonance cholangial pancreatography revealed beads in the left intrahepatic bile duct and localised narrowing of the head and body of the central pancreatic duct. Endoscopic ultrasound-guided fine-needle and liver needle biopsy showed CD8+ and CD4+ T lymphocyte aggregates, whereas immunostaining revealed greater infiltration by CD8+ cells than CD4+ cells. IgG4-related disease was ruled out based on serum and pathological findings. The patient simultaneously presented with immune-related adverse events, autoimmune pancreatitis-like features and sclerosing cholangitis, which were ameliorated by steroid therapy. CD8+ lymphocytes were the dominant infiltrating cells in autoimmune pancreatitis and sclerosing cholangitis.

A 71-year-old woman underwent chemotherapy comprising gemcitabine and cisplatin for an unresectable intrahepatic cholangiocarcinoma. She received 3.6 mg of pegfilgrastim as prophylaxis for neutropenia and had no apparent problems immediately after its administration. However, 1 week later, she

金沢大学先進予防医学研究科, Background: Sorafenib is a multiple receptor tyrosine kinase inhibitor known to prolong overall survival in patients with advanced hepatocellular carcinoma (HCC). Predicting this drug's survival benefits is challenging because clinical responses are rarely measurable during treatment. In this study, we hypothesized that serum cytokines levels could predict the survival of advanced HCC patients, as sorafenib targets signaling pathways activated in the tumor stromal microenvironment and potentially affects serum cytokine profiles. Methods: Of 143 patients with advanced-stage HCC, 104 who were recruited between 2003 and 2007 received hepatic arterial infusion chemotherapy (HAIC) that mainly targets tumor epithelial cells at S-phase (cohort 1); additionally, 39 recruited between 2010 and 2012 received sorafenib, which primarily targets the stromal vascular endothelial cells. Serum samples were collected and aliquoted prior to the treatment. Serum EGF, bFGF, HGF, IFN-γ, IL-10, IL-12, IL-2, IL-4, IL-5, IL-6, IL-8, IP-10, MIG, PDGF-BB, SCF, SDF1, TGF-β, TGF-α, TNF-α, and VEGF-A were measured via enzyme-linked immunosorbent assays. The Modified Response Evaluation Criteria in Solid Tumors were used to assess tumor responses. Results: The median survival time of HCC patients in cohorts 1 (HAIC-treated) and 2 (sorafenib-treated) were 12.0 and 12.4 months, respectively. Kaplan-Meier analysis revealed no significant survival differences between the 2 groups. Patients who survived more than 2 years after sorafenib treatment exhibited higher serum levels of IL-10, IL-12, TNF-a, IL-8, SDF-1, EGF, PDGF-BB, SCF, and TGF-α. Furthermore, cohort 2 patients with higher serum IL-5 (>12 pg/mL), IL-8 (>10 pg/mL), PDGF-BB (>300 pg/mL), and VEGF-A (>50 pg/mL) levels achieved longer survival; cohort 1 patients did not. Hierarchical cluster analysis of 6 cytokines robustly enriched for comparison analysis between cohorts 1 and 2 (IL-5, IL-8, TGF-α, PDGF-BB, CXCL9, and VEGF-A) revealed that elevation of these cytokines correlated with better survival when treated with sorafenib but not with HAIC. Conclusions: Patients who exhibited survival benefits owing to sorafenib treatment tended to present higher serum cytokines levels, potentially reflecting the activation of stromal signaling in the tumor microenvironment. Our study thus introduces novel biomarkers that may identify advanced HCC patients who may experience survival benefits with sorafenib treatment. © 2017 The Author(s).

Background/aim Anthracimycin, a secondary metabolite of Streptomyces, has been shown to inhibit the invasion of certain cancer cell lines. Materials and methods In this study we evaluated the effect of anthracimycin on cell growth and signaling pathways in hepatocellular carcinoma (HCC). Results Anthracimycin suppressed cell proliferation and motility and induced apoptosis in human HCC cell lines. Furthermore, anthracimycin had no effect on the enrichment of EpCAM-high liver cancer stem cells (CSCs), while fluorouracil dramatically enriched the CSCs with activation of the stemness-related genes EPCAM and SOX9 in HuH7 cells. Mechanistically, anthracimycin suppressed mammalian target of rapamycin (mTOR) signaling, and was most effective at inhibiting HCC cell proliferation with mTOR activation. Conclusion Anthracimycin is a novel mTOR inhibitor capable of suppressing the proliferation of CSCs and non-CSCs equally well in HCC, and it is suggested that anthracimycin could be effective in the eradication of HCC associated with mTOR-signaling activation.

The patient was a 39-year-old woman in whom computed tomography (CT) in 201X had revealed a pancreatic cystic neoplasm (PCN) of 4.3 cm in diameter in the pancreatic body. In June 201X + 3, the patient consulted our hospital regarding severe acute pancreatitis. The condition improved through treatment with large-volume fluid replacement and continuous regional arterial infusion therapy. Thereafter, acute pancreatitis recurred twice, in November 201X + 3 and in January 201X + 4. During an 8-month period, acute pancreatitis occurred three times. The PCN was examined by endoscopic ultrasound, thin-slice contrast-enhanced CT, and T2-weighted magnetic resonance imaging, which led to the diagnosis of macrocystic-type serous cystic neoplasm (SCN). The SCN was found to be 5.8 cm in diameter with dilatation of the main pancreatic duct (MPD) caudal to the SCN for 3 years. We suspected that the repeated pancreatitis had been obstructive pancreatitis resulting from displacement of the MPD caused by the SCN, and therefore recommended that the patient undergo surgery for the SCN. In March 201X + 4, distal pancreatectomy was performed. In the resected specimen, a macrocystic-type SCN was diagnosed. No recurrence of acute pancreatitis has been observed postoperatively. A macrocystic-type SCN with repeated pancreatitis within a short period of time is rare.

The clinical usefulness of diffusion-weighted echo planar imaging (DW-EPI) was studied in 55 patients with acute brain ischemia. Ischemic lesions were identified on DW-EPI as hyperintense regions in all patients before changes were detected by conventional magnetic resonance imaging techniques in 12 cases studied earlier than 6 hours after onset. The earliest case was verified on DW-EPI at 50 minutes after onset. The ultra-fast imaging technique took less than 2 minutes to perform even for restless patients. Three patients had cardioembolic middle cerebral artery occlusion, and emergent percutaneous transluminal recanalization was carried out. Chronological changes in the signal of brain ischemia on DW-EPI depended on the site and size of the lesion, lacunar infarct of basal ganglia, and/or massive infarct due to major vessel occlusion, and were affected by associated hemorrhagic events. Coronal DW-EPI could more easily demarcate ischemia in the brainstem and/or cerebellum than axial scans when susceptibility artifacts were present. Coronal scans also demonstrated the site and direction of the pyramidal tract and its anatomical correlation with the lesions. DW-EPI has potential for the diagnostic and therapeutic planning of patients with acute brain ischemia.

Malignant glioma responds poorly to chemotherapy presumably mainly because the antitumor drugs can not be delivered in effective concentrations to the tumor site without causing complications, and because the existence of the blood-brain barrier (BBB) restricts the distribution of many antitumor drugs to malignant gliomas. We used thermosensitive liposomes containing CDDP (cis-diamminedichloroplatinum) with localized heating, and the possibilities of this drug delivery system to the brain tumor were discussed. First, this unique and attractive strategy showed remarkable effects against the RSV-induced subcutaneous tumor which was relatively insensitive to various antitumor agents. The authors then investigated the antitumor effect on rat malignant brain tumor. Ten days after tumor inoculation, six groups were formed : control, free CDDP, hyperthermia, free CDDP+hyperthermia, CDDP-liposome, and CDDP-liposome+hyperthermia. Liposomes containing CDDP (CDDP-liposome) or free CDDP were injected via the tail vein. The brain tumor heating was given using a radiofrequency antenna which was designed at our institute. As a result, the rats treated by CDDP-liposome+hyperthermia had the longest survival time, and the tumor CDDP level of this group was the highest when compared to other groups. These findings suggest that the combination of thermosensitive liposome and localized hyperthermia, could (1) bring a direct thermal killing of the tumor cells, plus (2) increase a permeability of the BBB to transport of CDDP, plus (3) target CDDP-liposomes to the tumor site and produce an effective release of liposomal CDDP with greater activity than when free CDDP was injected.

Because the cytotoxic effect of hyperthermia in the 42-43°C range has been demonstrated, a transition temperature of the conventional liposomes have so far been 42°C to enhance the synergistic effect of hyperthermia and antitumor drugs. When considered this drug delivery system as clinical use, an important problem about this treatment is that the glioma cells invade wide portions of the brain and present technology has not yet been able to achieve the heating of the wide areas invaded by glioma cells. On the other hand, it has been remarked that the blood brain barrier(BBB) limits the ability of many antitumor drugs to penetrate the central nervous system. Despite of their greater cytotoxic effects on glioma cells in vitro, many drugs, such as adriamycin (ADM), have not so far been used mainly because they are regarded as being blocked by the BBB. In order overcome these roblems we prepared liposomes which brought a sharp release rate of ADM above 40°C. This liposome showed a significantly great antitumor effect against rat malignant gliomas which were transplanted into their legs at the temperature of 40°C. These results suggests that this procedure (1) contributes to the synergistic effect of hyperthermia and antitumor drugs in the regions heated above 42°C, (2) helps to deliver the antitumor drugs more widely with the temperature of 40°C, (3) gives a good chance to many antitumor drugs which have so far not been used from the problem of the BBB. We suggest that this advantage of our plan could outweigh the disadvantages of the conventional thermo-chemotherapy.

We have examined whether or not mutations exist in the proximal promoter region of the human α-fetoprotein (AFP) gene in the hepatocellular carcinoma (HCC) tissue. Genomic DNA was extracted from four patients: one HCC tissue, one HCC and its corresponding non-cancerous (cirrhosis) tissues, one liver cirrhosis (LC) tissue without HCC and one matching HCC tissue and peripheral blood leukocytes. Serum concentrations of AFP in the patients ranged from less than 5 to 10 138 ng/ml. Nucleotide sequence was determined by direct sequencing using a single-stranded DNA template that was produced first through the polymerase chain reaction (PCR) amplification and then asymmetric PCR. In one HCC tissue taken from the patient with a high concentration of serum AFP, nucleotides different from published ones were detected at −120 and −113. These changes, however, probably reflect a DNA polymorphism, because peripheral blood leukocytes of the same patient had the same changes. Including this patient, no mutations in the region from −160 to −10 were detected in the HCC specimens we have examined. These results suggest that the extremely proximal promoter region of the AFP gene where glucocorticoid-responsive element and HNF-1 binding sites exist is not responsible for the re-expression of AFP in HCC.