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.     

Intramuscular hemangioma of the upper extremity in infants and children

PURPOSE: Intramuscular hemangiomas (IMHs) are benign tumors comprising just 0.8% of all hemangiomas and are extremely rare in the upper limbs. These tumors can pose diagnostic as well as therapeutic challenges for orthopaedic surgeons, especially in younger children. We reviewed cases of IMH of the upper extremity in infants and children from our institute. METHODS: Six consecutive patients underwent surgical treatment for IMH in our hospital. There were 4 girls and 2 boys. Long-standing pain and swelling were common symptoms except in a 1-year-old boy. Tumors were evaluated by radiography, computed tomography, magnetic resonance imaging, and angiography. RESULTS: After a mean follow-up of 42 months, all patients except one were free of pain and without tumor recurrence or functional impairment. Minimal symptoms remained in a 6-year-old boy who underwent biopsy only. CONCLUSION: Magnetic resonance imaging is the most useful evaluation for IMH because it not only delineates the extent of tumor but also reveals characteristic structures. For young children with IMH, wide excision is the treatment of choice to prevent local recurrence, but every patient should be treated individually after evaluating the patient's age, tumor location and invasion, and cosmetic considerations. LEVEL OF EVIDENCE: Therapeutic study-level III.     

Treatment of metastatic bone lesions in the upper extremity: indications for surgery

Pathological fractures caused by metastatic malignant disease have been the subject of increasing interest in recent years. This article describes our experience with the treatment of metastatic bone disease of the upper extremity and our attempt to clarify the indications for different surgical procedures. Of 53 patients with metastatic lesions to the upper extremity, 20 who had been surgically treated were analyzed retrospectively. These comprised 13 men and 7 women with a mean patient age of 62 years. The most common primary tumors to metastasize were lung and liver, with the humerus involved in 12 cases and the scapula and forearm in 4 cases each. Four patients with scapula and forearm involvement underwent tumor resection due to uncontrollable tumor size, while 3 were successfully treated by selective arterial embolization. Three metastases to the humeral head were reconstructed with endoprosthesis, but functional restriction was noted. Five cases with metastases to the humeral shaft were treated with tumor curettage, internal fixation using intramedullary nailing, adjuvant cryosurgery, and cementing. This achieved good results for pain relief and functional restoration with minimal complications. Two metastases to the humeral condyle were unable to be stabilized with plate and locking screws. Metastatic lesions to the scapula and forearm are commonly treated nonsurgically, but some patients with uncontrollable tumor mass require surgical resection. Endoprosthetic replacement is recommended if the lesion involves the humeral head or condyle. Most patients with the humeral shaft lesion are likely to benefit from tumor curettage, intramedullary nailing with locking screw, and cementing.     

JPN Guidelines for the management of acute pancreatitis: severity assessment of acute pancreatitis

This article addresses the criteria for severity assessment and the severity scoring system of the Ministry of Health and Welfare of Japan; now the Japanese Ministry of Health, Labour, and Welfare (the JPN score). It also presents data comparing the JPN score with the Acute Physiology and Chronic Health Evaluation (APACHE) II score and the Ranson score, which are the major measuring scales used in the United States and Europe. The goal of investigating these scoring systems is the achievement of earlier diagnosis and more appropriate and successful treatment of severe or moderate acute pancreatitis, which has a high mortality rate. This article makes the following recommendations in terms of assessing the severity of acute pancreatitis: (1) Severity assessment is indispensable to the selection of proper initial treatment in the management of acute pancreatitis (Recommendation A). (2) Assessment by a severity scoring system (JPN score, APACHE II score) is important for determining treatment policy and identifying the need for transfer to a specialist unit (Recommendation A). (3) C-reactive protein (CRP) is a useful indicator for assessing severity (Recommendation A). (4) Contrast-enhanced computed tomography (CT) scanning and contrast-enhanced magnetic resonance imaging (MRI) play an important role in severity assessment (Recommendation A). (5) A JPN score of 2 or more (severe acute pancreatitis) has been established as the criterion for hospital transfer (Recommendation A). (6) It is preferable to transfer patients with severe acute pancreatitis to a specialist medical institution where they can receive continuous monitoring and systemic management.     

High-turnover osteoporosis is induced by cyclosporin A in rats

Cyclosporin A (CsA) is used widely as an immunosuppressive agent, but it induces osteoporosis as a prominent side effect. To elucidate the mechanisms involved in CsA-induced osteoporosis, the effects of CsA on bone metabolism were investigated in a rat experimental model. Fifteen-day-old rats were fed a powdered diet containing or lacking CsA for 8–30 days. Analysis was performed by micro-computed tomography (μCT) and light microscopy to examine histomorphometric changes in rat tibiae on days 8, 16, and 30. Plasma parathyroid hormone (PTH) and osteocalcin (OCN) levels were determined by enzyme-linked immunosorbent assay (ELISA) on days 8, 16, and 30. The expression of OCN, osteopontin (OPN), and cathepsin K mRNAs in tibial bone marrow was examined by Northern blot analysis on days 8 and 16. Although no significant differences were observed in tibial length during the experimental periods, or in histomorphometric parameters on day 8, an apparent decrease in bone volume was observed in the CsA-treated group after day 16. Histologic analysis showed that the number of osteoblasts and osteoclasts on the surface of trabecular bone in the CsA-treated group had increased significantly on day 16. Plasma PTH and OCN levels in CsA-treated rats were significantly higher than those in control animals on day 8. Northern blot analysis revealed that the CsA-treated group showed an increase in the expression of OCN, OPN, and cathepsin K mRNAs on day 8 compared with the controls. These findings suggest that bone resorption in CsA-treated rats is induced by high-turnover osteoporosis and that bone remodeling activity may be activated by PTH.     

Covered stent treatment for traumatic cervical carotid artery aneurysms--two case reports

A 37-year-old man and a 23-year-old man with cervical carotid artery aneurysms were treated with covered stents. The covered stent was constructed from a Palmaz stent covered with an expanded polytetrafluoroethylene graft. Angiography showed the aneurysms had disappeared immediately after the procedure. Patency of the covered stents was confirmed at 18 and 34 months after intervention by three-dimensional computed tomography angiography. The covered stent allows relatively noninvasive reconstruction of the parent artery that immediately brings about complete thrombosis of the aneurysm. However, delivering the covered stent to the carotid artery may be difficult.     

Clinical role of serum programmed death ligand 1 in patients with hepatocellular carcinoma: Where does it come from?

Programmed death ligand 1 (PD-L1) is a key target for the treatment of several malignancies. The present study was conducted to clarify the role of serum PD-L1 in hepatocellular carcinoma (HCC). Serum PD-L1 (sPD-L1) was examined by an enzyme-linked immunosorbent assay in 153 patients with HCC who underwent curative hepatectomy at Kumamoto University in 2011–2016. The expression of PD-L1 in tissue (tPD-L1) was investigated by immunohistochemistry. The clinical roles of the PD-L1 expression in both serum and tissue were examined. The sPD-L1 was significantly elevated in HCC patients compared to patients without any malignant or inflammatory disease (234 vs. 93 pg/mL, p < 0.0001). The percentage of the tPD-L1-positive area (%tPD-L1) in the background liver was significantly higher than in the tumor (1.52% vs. 0.48%, p < 0.0001). The %tPD-L1 in the background liver but not in the tumor was significantly correlated with the sPD-L1 level (p = 0.0079). The sPD-L1, %tPD-L1 in the tumor, and %tPD-L1 in the background liver were not correlated with the overall survival after surgery. PD-L1-expressing cells in the background liver, but not in the tumor tissue, appeared to contribute to the sPD-L1 level. The sPD-L1 level may thus not indicate the tumor burden in patients with HCC.