[A Case of Neuroendocrine Carcinoma of the Extrahepatic Bile Duct].

A 77-year-old man visited a clinic because of nausea and chest discomfort. On blood test, hepatobiliary enzymes were elevated, and he referred to our hospital. Contrast-enhanced CT revealed stenosis of the extrahepatic bile duct and brush cytology of the bile duct showed adenocarcinoma. We therefore performed pancreatoduodenectomy for extrahepatic bile duct cancer. Pathological diagnosis was small cell neuroendocrine carcinoma, pT3N2M0, Stage ⅢA. The patient did not receive adjuvant chemotherapy and 3 months later contrast-enhanced CT and MRI showed multiple liver metastases. The patient was treated with cisplatin plus irinotecan in the first-line, cisplatin plus etoposide in the second-line, and amrubicin in the third-line and accordingly he died 1 year and 3 months after the surgery. Chemotherapy for neuroendocrine carcinoma of the bile duct is recommended as in small cell lung cancer, but the prognosis is extremely poor. We report this case with a review of some of the literature.

[A Case of Curative Surgery for Locally Advanced Small Bowel GIST after Imatinib Therapy].

According to the risk classification of recurrence, the standard treatment for gastrointestinal stromal tumor(GIST)is complete surgical resection and postoperative adjuvant therapy with imatinib; however, the usefulness of neoadjuvant therapy is unclear. We report a case of giant GIST in the pelvis suspectedly having bladder infiltration that was radically resected and underwent preoperative imatinib therapy. A 52-year-old man visited a clinic because of abdominal pain, fever, and frequent urination. An abdominal mass was determined, and the patient was referred to our hospital for detailed examination and treatment. Contrast-enhanced CT revealed a 17 cm diameter irregular mass from the lower navel to the pelvis, and the bladder boundary was partially unclear. Transrectal biopsy was performed using endoscopic ultrasonography, and according to the Fletcher classification, a high-risk GIST was diagnosed. After preoperative imatinib therapy of 400 mg/day was administered for 3 months, surgery was performed. The tumor was strongly adhered to the bladder, but no invasion was observed, and partial small intestine resection was performed. The surgical margin was negative without capsule damage. On day 34 postoperatively, imatinib therapy was resumed, and as of 1 year postoperatively, the course is well without recurrence.

Real-time in vivo imaging of surface-modified liposomes to evaluate their behavior after pulmonary administration.

Our previous study demonstrated that surface modification of liposomes using polyvinyl alcohol with a hydrophobic anchor (PVA-R) achieved sustained absorption from the lung after pulmonary administration and prolonged the pharmacological effects of the model peptide drug. In the present study, the behavior of PVA-R-modified liposomes in the lung and whole body was monitored using a real-time in vivo imaging system. Subsequently, the influence of surface modification with PVA-R on liposomal behavior in lung tissue was examined. Indocyanine green (ICG) was used as a near-infrared label of PVA-R-modified liposomes and was used to observe their dynamic behavior using non-invasive in vivo imaging (IVIS® imaging system) after pulmonary administration to rats. PVA-R-modified submicron-sized liposomes (ssLips) induced long-term retention in the lung compared with unmodified liposomes. Moreover, liposome association with alveolar macrophages (NR8383) was decreased by PVA-R modification in vitro. Therefore, PVA-R modification may prevent rapid elimination of ssLips by macrophages, thereby increasing retention in the lung.

Surface modification of liposomes using polymer-wheat germ agglutinin conjugates to improve the absorption of peptide drugs by pulmonary administration.

In this study, we investigated the feasibility of a system based on liposomal surface modification with a novel mucoadhesive polymer-lectin conjugate for the pulmonary delivery of therapeutic peptides and proteins. We covalently attached wheat germ agglutinin (WGA), a ligand that specifically interacts with alveolar epithelial cells, to carbopol (CP), a mucoadhesive polymer, using the carbodiimide method and then evaluated the efficacy and potential toxicity of CP-WGA surface-modified liposomes in vivo and in vitro. In association studies, CP-WGA modification enhanced the interaction with A549 lung epithelial cells compared with unmodified or CP-modified liposomes. This increased association was dependent on temperature and the surface concentration of free WGA. These results suggested synergy of WGA and CP, and retention of the biological cell binding activity of WGA, leading to improved liposome-cell interactions. Moreover, improvement of liposomal bioadhesion to lung epithelia significantly enhanced and prolonged the therapeutic efficacy of calcitonin, a model peptide drug, without any evidence of toxicity, following administration of calcitonin-loaded CP-WGA-modified liposomes. Hence, surface modification of liposomes with CP-WGA has potential for effective pulmonary administration of peptides.

Pulmonary delivery of elcatonin using surface-modified liposomes to improve systemic absorption: polyvinyl alcohol with a hydrophobic anchor and chitosan oligosaccharide as effective surface modifiers.

The aim of this study was to investigate the feasibility of surface-modified liposomes for pulmonary delivery of a peptide. Chitosan oligosaccharide (oligoCS) and polyvinyl alcohol with a hydrophobic anchor (PVA-R) were used as surface modifiers. The effect of liposomal surface modification on the behavior of the liposomes on pulmonary administration and potential toxicity were evaluated in vitro and in vivo. In an association study with A549 cells, PVA-R modification reduced interaction with A549 cells, whereas oligoCS modification electrostatically enhanced cellular interaction. The therapeutic efficacy of elcatonin (eCT) after pulmonary administration to rats was significantly enhanced and prolonged for 48 h after separate administration with oligoCS- or PVA-R-modified liposomes. oligoCS-modified liposomes adhered to lung tissues and caused opening of tight junctions, which enhanced eCT absorption. On the other hand, PVA-R-modified liposomes induced long-term retention of eCT in the lung fluid, leading to sustained absorption. Consequently, surface modification of liposomes with oligoCS or PVA-R has potential for effective peptide drug delivery through pulmonary administration.