Anti‐FGF‐23 neutralizing antibodies ameliorate muscle weakness and decreased spontaneous movement of Hyp mice

Fibroblast growth factor 23 (FGF‐23) plays causative roles in the development of several hypophosphatemic rickets/osteomalacia such as X‐linked hypophosphatemic rickets/osteomalacia (XLH) and tumor‐induced rickets/osteomalacia. Patients with hypophosphatemic rickets/osteomalacia often complain of muscle weakness and bone pain that severely affect daily activities of these patients. The purpose of this study was to examine whether anti‐FGF‐23 antibodies, which have been shown to improve hypophosphatemia and rachitic changes of juvenile Hyp mice in a murine model of XLH, also ameliorate hypophosphatemic osteomalacia and affect muscle force and spontaneous motor activity in adult Hyp mice. Repeated injections of anti‐FGF‐23 antibodies increased serum phosphate and 1,25‐dihydroxyvitmain D levels and enhanced mineralization of osteoid in adult Hyp mice, whereas bone length did not change. We found that grip strength was weaker and that spontaneous movement was less in adult Hyp mice than in wild‐type mice. In addition, FGF‐23 antibodies increased grip strength and spontaneous movement. These results suggest that the inhibition of excess FGF‐23 action not only ameliorates hypophosphatemia and impaired mineralization of bone but also improves muscle weakness and daily activities of patients with FGF‐23‐related hypophosphatemic rickets/osteomalacia. © 2011 American Society for Bone and Mineral Research.     

A case of lung squamous cell carcinoma with metastases to the duodenum and small intestine

Gastrointestinal metastasis of lung cancer is fairly rare, and metastasis to the duodenum is very uncommon. We report a case of duodenum and small intestine metastases of lung squamous cell carcinoma. The patient was a 66-year-old man. He was diagnosed with lung squamous cell carcinoma (T4N3M1 [mediastinum, cervical lymph node, and duodenum metastases], stage IV). He noted a sense of abdominal fullness on the evening of the day chemoradiotherapy was given, and emergency surgery was performed for suspected perforation of the digestive tract. Intraoperative findings included a tumor in the small intestine with a perforation at the tumor site; partial resection of the small intestine, including the tumor, was performed. Small intestine metastasis of lung cancer was diagnosed following histopathologic examination. When lung cancer patients complain of abdominal symptoms, it is important to consider gastrointestinal metastases in diagnosis and treatment.     

Cricopharyngeal myotomy for primary cricopharyngeal dysfunction caused by a structural abnormality localized in the cricopharyngeus muscle: Report of a case

Primary cricopharyngeal dysfunction (PCD) is a rare idiopathic disorder of the upper esophageal sphincter (UES), characterized by oropharyngeal dysphagia, frequent aspiration, and narrowing at the level of the UES. Cricopharyngeal myotomy (CPM) has been used to treat oropharyngeal dysphagia of different causes including anatomic, neuromuscular, iatrogenic, inflammatory, neoplastic, and idiopathic; however, the indications for CPM and predictors of its outcome are not clearly defined. We report a case of PCD with hypertonic UES caused by a structural abnormality localized in the cricopharyngeus muscle, visualized as a cricopharyngeal bar, which we treated successfully by CPM, achieving long-term relief.     

Adenocarcinoma in an intrapancreatic accessory spleen: Report of a case

We report a case of adenocarcinoma in an intrapancreatic accessory spleen (IPAS). A 78-year-old woman presented with abdominal discomfort, and investigations revealed an elevated serum carbohydrate antigen 19-9 level, to 161.8 U/ml (normal, <37 U/ml). Ultrasonography showed a heterogeneous echogenic tumor with a vascular hilum. Computed tomography showed a heterogeneously enhanced tumor, 8 cm in diameter, adjacent to the pancreatic body, accompanying a feeding artery arising from the splenic artery, and a drainage vein flowing into the splenic vein. We performed a distal pancreaticosplenectomy. The tumor was surrounded by a fibrous capsule and was in contact with the pancreatic body. Histological examinations revealed invasive growth of adenocarcinoma in a structure identical to the spleen. The results of both radiological and histological examinations suggested that the tumor originated from an intrapancreatic accessory spleen. Extensive examinations revealed no other malignancy, based on which we concluded that the adenocarcinoma was primary. Surgical intervention is strongly recommended when a malignancy in an IPAS cannot be ruled out.     

A Preoperative Predictive Scoring System for Postoperative Pancreatic Fistula after Pancreaticoduodenectomy

Background  

Postoperative pancreatic fistula (POPF) remains a leading cause of morbidity after pancreaticoduodenectomy (PD). In the present study we sought to establish a preoperative scoring system with which to predict this complication.     

MR diagnosis of adenomyomatosis of the gallbladder and differentiation from gallbladder carcinoma: importance of showing Rokitansky-Aschoff sinuses.

OBJECTIVE: We evaluated the MR imaging features of adenomyomatosis of the gallbladder with particular emphasis on Rokitansky-Aschoff sinuses. MATERIALS AND METHODS: MR images of 17 patients with histologically proven adenomyomatosis were retrospectively reviewed. The presence of Rokitansky-Aschoff sinuses was evaluated and analyzed; four T2-weighted (fast spin-echo with a surface coil, with or without breath-holding, fast spin-echo with a phased-array coil with breath-holding, and half-Fourier rapid acquisition with relaxation enhancement with breath-holding) and two contrast-enhanced dynamic pulse sequences were studied. These six pulse sequences were separately rated on a 5-point scale by two radiologists for comparison. Interobserver differences were evaluated. Other MR findings were also analyzed. RESULTS: Among the six pulse sequences studied, three T2-weighted with breath-holding sequences were found to be superior to the other three sequences in showing Rokitansky-Aschoff sinuses. In particular, the half-Fourier rapid acquisition with relaxation enhancement was scored the highest by the two observers and received the highest kappa coefficient in our statistical analysis of the scoring. Diffuse-type adenomyomatosis typically showed early mucosal and subsequent serosal enhancement. Localized adenomyomatosis exhibited homogeneous enhancement, showing smooth continuity with the surrounding gallbladder epithelium. CONCLUSION: MR imaging may be able to provide important information in the diagnosis of adenomyomatosis.     

A neutralizing anti-fibroblast growth factor (FGF) 8 monoclonal antibody shows anti-tumor activity against FGF8b-expressing LNCaP xenografts in androgen-dependent and -independent conditions

BACKGROUNDS: Fibroblast growth factor 8-isoform b (FGF8b) has been detected in human clinical sex-organ related cancers including hormone-refractory prostate cancer. There are, however, few relevant experimental models. A murine monoclonal anti-FGF8 antibody, KM1334, has been shown to neutralize FGF8b and inhibit the growth of androgen-dependent mouse mammary SC-3 cells in vitro and in vivo. In the present study, we evaluated the anti-tumor activity of KM1334 against androgen-dependent and -independent progression of FGF8b-expressing human prostate cancer xenografts. METHODS: FGF8b cDNA was transfected into androgen-dependent human prostate cancer cell line LNCaP, and its xenograft tumors were established subcutaneously in SCID mice with or without castration. KM1334 at the dose of 400 microg/head was injected twice weekly. RESULTS: FGF8b-expressing LNCaP cells secreted FGF8b, showed enhanced level of Erk1/2 phosphorylation, and showed more potent growth properties than mock-expressing cells in vitro and in vivo. KM1334 reduced these properties in vitro, inhibited tumorigenecity in vivo (T/C=0.33), and showed anti-tumor activity against established tumors (T/C=0.47) of FGF8b-expressing cells. FGF8b-expressing LNCaP tumors were androgen-dependent. However, they recurred as androgen-independent FGF8b positive tumors after castration. KM1334 also inhibited the growth of established FGF8b-expressing tumors in the androgen-independent states (T/C=0.47). CONCLUSIONS: These results indicate that humanized monoclonal antibodies, conserving the paratope of KM1334, are a promising candidate for therapy of FGF8b-expressing clinical prostate cancers. Follow-up studies using xenograft models with clinical FGF8b-expressing tumors are required to validate these early findings.     

Retroportal Hepaticojejunostomy for Extended Resection of Hilar Bile Ducts

High hepatic duct resection sometimes is unavoidable in achieving curative resection of hilar cholangiocarcinoma, as tumor cells can extend further than expected along the bile ducts from the macroscopically evident cancer. In patients undergoing left hemihepatectomy with caudate lobectomy whose bile duct must be severed at the subsegmental bile duct levels, the orifices of the posterior bile ducts would lie behind the right portal vein. Conventional hepaticojejunostomy would be risky in such cases because an anastomosis performed in the usual manner would be subjected to strain. Instead, between 2002 and 2004, three patients underwent retroportal hepaticojejunostomy using a jejunal limb mobilized and positioned behind the hepatoduodenal ligament. Primary tumors were classified as type IV in the Bismuth–Corlette classification. Tension-free hepaticojejunal anastomosis was performed successfully in all three patients; insufficiency of the hepaticojejunostomy did not develop. Neither early nor late complications directly related to this method occurred. Retroportal hepaticojejunostomy, thus, permits more peripheral resection of the hepatic duct while providing a sufficient operative field for safe, tension-free anastomosis. This technique is very useful for patients undergoing left hemihepatectomy requiring high hilar resection of the bile duct.     

Differentiation of transplanted bone marrow cells in the adult mouse brain.

BACKGROUND: Bone marrow transplantation is reportedly effective in preventing the progression of neurological deterioration in lysosomal storage disorders, although the mechanism underlying the therapeutic effects remains to be elucidated. Recent research on stem cell biology suggests that bone marrow cells contain nonhematopoietic stem cells, including brain precursor cells. To evaluate the contribution of bone marrow cells as carriers for cell and gene therapy of neurological disorders, we studied the fate of transplanted bone marrow cells in the adult mouse brain. METHODS: Bone marrow cells were genetically marked with a retroviral vector containing the green fluorescence protein gene and then transplanted into irradiated mice by either systemic infusion or direct injection. To identify cell types, brain sections were stained with specific antibodies against neuronal cell markers-neuron specific enolase for neurons, glial fibrillary acidic protein (GFAP) for astrocytes, carbonic anhydrase II (CAII) for oligodendrocytes, and ionized calcium binding adaptor molecule 1 (Iba1) for microglia-and then examined under a confocal microscope. RESULTS: Twenty-four weeks after systemic infusion, transplanted cells expressed Iba1 but none of the other brain cell markers. Conversely, 12 weeks after direct injection, transplanted cells were stained with antibodies against GFAP, CAII, and Iba1. CONCLUSIONS: Bone marrow contains cells capable of differentiating into oligodendrocytes, astrocytes, and microglia when exposed to the brain microenvironment. Autologous bone marrow cells may be useful as carriers for ex vivo gene therapy for lysosomal disorders with neurological symptoms.     

Intravenous anesthetics inhibit nonadrenergic noncholinergic lower esophageal sphincter relaxation via nitric oxide-cyclic guanosine monophosphate pathway modulation in rabbits

BACKGROUND: Nonadrenergic noncholinergic (NANC) nerves have important roles in the regulation of the lower esophageal sphincter (LES) motility and function. The effects of thiopental, ketamine, and midazolam on NANC LES relaxation were investigated. METHODS: The isometric tension of circular muscle strips from Japanese White rabbits was examined. The NANC relaxation was induced by KCl (30 mM) in the presence of atropine (3 x 10(-6) M) and guanethidine (3 x 10(-6) M). The modifications of the NANC and sodium nitroprusside (SNP; 10(-5) M)-induced relaxation by the anesthetics were examined. The content of 3',5'-cyclic guanosine monophosphate (cGMP) was measured by radioimmunoassay. RESULTS: The KCl-induced relaxation was abolished by pretreating with tetrodotoxin (10(-6) M). The NANC relaxation was inhibited in the presence of N(G)-nitro-L-arginine (L-NNA; 3 x 10(-5) M), methylene blue (10(-6) M), apamin (10(-7) M), and glibenclamide (10(-5) M). The SNP-induced relaxation was inhibited by methylene blue but was not affected by tetrodotoxin, L-NNA, apamin, or glibenclamide. Ketamine (EC50 = 8.8 x 10(-5) M) and midazolam (EC50 = 4.8 x 10(-6) M) suppressed the NANC response in a concentration-dependent manner, leaving SNP-induced response unchanged. Thiopental altered neither of the relaxations. cGMP content was decreased in the presence of ketamine and midazolam. CONCLUSION: The NANC relaxation was mediated by nitric oxide and by low-conductance calcium- and adenosine triphosphate-sensitive potassium channels of smooth muscle. The modulation of the nitric oxide-cGMP pathway was related, at least in part, to the inhibitory actions of ketamine and midazolam on the NANC LES relaxation.