Adenosquamous carcinoma of the gallbladder simultaneously producing granulocyte-colony-stimulating factor and parathyroid hormone-related protein.

We report a rare case of adenosquamous carcinoma of the gallbladder which simultaneously produces granulocyte-colony-stimulating factor (G-CSF) and parathyroid hormone-related protein (PTHrP), confirmed serologically and histologically. A 71-year-old man was examined for a gallbladder tumor with multiple lymph nodes and liver metastases. Histopathological evaluation by endoscopic ultrasound fine-needle aspiration revealed adenosquamous carcinoma of the gallbladder. Laboratory data showed markedly elevated white blood cell (WBC) count of 34,700 µL and corrected serum calcium level of 14.9 mg/dL. Serum G-CSF (191 pg/mL) and PTHrP (23.1 pmol/L) levels were high. Zoledronic acid and calcitonin were administered to treat hypercalcemia, which normalized serum calcium levels. Gemcitabine-cisplatin chemotherapy was started for cStage IVB gallbladder cancer. After chemotherapy initiation, WBCs showed a rapid downward trend; however, the patient suddenly developed acute respiratory distress syndrome; thus, chemotherapy was discontinued. Subsequently, WBC count increased again, and the patient's overall condition deteriorated. The patient died on day 27. Immunohistochemistry using autopsy specimens demonstrated patchy staining for G-CSF in the squamous cell carcinoma portion and diffuse and weak positive staining for PTHrP in the squamous cell carcinoma and poorly differentiated adenocarcinoma portions of the tumor, suggesting simultaneous G-CSF and PTHrP production by the tumor. This is the first report of a patient with gallbladder cancer with serological and histological evidence for G-CSF and PTHrP production.

Successful hemostasis for post-endoscopic sphincterotomy bleeding following endoscopic papillary large balloon dilation using 12-mm-diameter fully covered self-expandable metal stent.

A 12-mm-diameter fully covered self-expandable metal stent may be effective for securing hemostasis in post-endoscopic sphincterotomy bleeding following endoscopic papillary large balloon dilation.

Simultaneous occurrence of autoimmune pancreatitis and sclerosing cholangitis as immune-related adverse events of pembrolizumab.

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.

Dosing time-dependent effect of raloxifene on plasma plasminogen activator inhibitor-1 concentrations in post-menopausal women with osteoporosis.

Raloxifene, a selective oestrogen receptor modulator commonly used for the treatment of post-menopausal osteoporosis, affects the coagulation and fibrinolytic systems and consequently increases the risk of venous thromboembolism. Because both the coagulation and fibrinolytic systems exhibit circadian rhythms, the aim of the present study was to investigate the effects of dosing time of raloxifene on markers of coagulation and fibrinolysis, as well as on markers of bone metabolism. Thirty-nine post-menopausal patients with osteoporosis were randomly allocated to two groups: one received 60 mg raloxifene once daily in the morning, whereas the other received 60 mg raloxifene once daily in the evening, for 12 months. In both groups, the activity of coagulation Factors IX and XII was increased significantly after 12 months treatment compared with baseline. The activity of coagulation Factors II and V and levels of markers of bone metabolism (i.e. bone alkaline phosphatase and tartrate-resistant acid phosphatase 5b) decreased in both groups. The changes in these markers did not differ between the two groups. In contrast, the plasma concentration of plasminogen activator inhibitor (PAI)-1 increased in the group receiving the morning dose (mean change 40.9%; 95% confidence interval (CI) 9.4, 72.5), but not in the groups receiving the evening dose (mean change -0.3%; 95% CI -31.5, 30.9); these percentage changes differed significantly (P < 0.05). Because an elevated concentration of PAI-1 is known to be associated with the risk of venous thromboembolism, the findings of the present study suggest that the dosing time of raloxifene influences its safety. Further larger-scale studies are needed to determine the clinical usefulness of chronotherapy with raloxifene.

Transient anti-GAD antibody positivity and acute pancreatitis with pancreas tail swelling in a patient with susceptible haplotype for type 1 diabetes mellitus.

A 57-year-old man was admitted to our hospital complaining of poor appetite. He had been diagnosed with diabetes mellitus and was anti-GAD antibody (GAD-Ab) negative 1 year previously, at the age of 56 years old. Abdominal CT revealed pancreas tail swelling; elastase-I level was elevated and he was diagnosed with pancreatitis. The level of GAD-Ab was increased and HLA haplotype was DRB1*0901-DQB1*0303, which is seen frequently in type 1 diabetic Japanese patients. However, his endogenous insulin secretion ability was not deteriorated. After elastase-I level and pancreas swelling improved, GAD-Ab returned to a normal range. One year after the onset of pancreas swelling, he was still not in an insulin-dependent state. In this case, transient GAD-Ab positivity with susceptible haplotype for type 1 diabetes mellitus might have been induced by a GAD antigen discharged from the destroyed islet due to pancreatitis.

Selective estrogen receptor modulator raloxifene-associated aggravation of nonalcoholic steatohepatitis.

A 53-year-old postmenopausal woman, who had a family history of cryptogenic liver cirrhosis, was diagnosed with osteoporosis, and started on the selective estrogen receptor modulator (SERM) raloxifene 60 mg/day orally. She developed marked liver dysfunction. Her body mass index (BMI) was 26.5. Her blood chemistry indicated AST 342 IU/L, ALT 356 IU/L, and hyaluronic acid 255 ng/mL. An oral glucose tolerance test showed impaired glucose tolerance with marked insulin resistance. Histologically, we diagnosed this case as having pre-cirrhotic nonalcoholic steatohepatitis (NASH). This is the first histologically confirmed case of NASH that was aggravated by raloxifene.