The selective Cox-2 inhibitor Celecoxib suppresses angiogenesis and growth of secondary bone tumors: an intravital microscopy study in mice

BACKGROUND: The inhibition of angiogenesis is a promising strategy for the treatment of malignant primary and secondary tumors in addition to established therapies such as surgery, chemotherapy, and radiation. There is strong experimental evidence in primary tumors that Cyclooxygenase-2 (Cox-2) inhibition is a potent mechanism to reduce angiogenesis. For bone metastases which occur in up to 85% of the most frequent malignant primary tumors, the effects of Cox-2 inhibition on angiogenesis and tumor growth remain still unclear. Therefore, the aim of this study was to investigate the effects of Celecoxib, a selective Cox-2 inhibitor, on angiogenesis, microcirculation and growth of secondary bone tumors. METHODS: In 10 male severe combined immunodeficient (SCID) mice, pieces of A549 lung carcinomas were implanted into a newly developed cranial window preparation where the calvaria serves as the site for orthotopic implantation of the tumors. From day 8 after tumor implantation, five animals (Celecoxib) were treated daily with Celecoxib (30 mg/kg body weight, s.c.), and five animals (Control) with the equivalent amount of the CMC-based vehicle. Angiogenesis, microcirculation, and growth of A549 tumors were analyzed by means of intravital microscopy. Apoptosis was quantified using the TUNEL assay. RESULTS: Treatment with Celecoxib reduced both microvessel density and tumor growth. TUNEL reaction showed an increase in apoptotic cell death of tumor cells after treatment with Celecoxib as compared to Controls. CONCLUSION: Celecoxib is a potent inhibitor of tumor growth of secondary bone tumors in vivo which can be explained by its anti-angiogenic and pro-apoptotic effects. The results indicate that a combination of established therapy regimes with Cox-2 inhibition represents a possible application for the treatment of bone metastases.

Relative sensitivity factors of inorganic cations in frozen-hydrated standards in secondary ion MS analysis

We describe the measurement, at 100 K, of the SIMS relative sensitivity factors (RSFs) of the main physiological cations Na+, K+, Mg2+, and Ca2+ in frozen-hydrated (F-H) ionic solutions. Freezing was performed by either plunge freezing or high-pressure freezing. We also report the measurement of the RSFs in flax fibers, which are a model for ions in the plant cell wall, and in F-H ionic samples, which are a model for ions in the vacuole. RSFs were determined under bombardment with neutral oxygen (FAB) for both the fibers and the F-H samples. We show that referencing to ice-characteristic secondary ions is of little value in determining RSFs and that referencing to K is preferable. The RSFs of Na relative to K and of Ca relative to Mg in F-H samples are similar to their respective values in fiber samples, whereas the RSFs of both Ca and Mg relative to K are lower in fibers than in F-H samples. Our data show that the physical factors important for the determination of the RSFs are not the same in F-H samples and in homogeneous matrixes. Our data show that it is possible to perform a SIMS relative quantification of the cations in frozen-hydrated samples with an accuracy on the order of 15%. Referencing to K permits the quantification of the ionic ratios, even when the absolute concentration of the referencing ion is unknown. This is essential for physiological studies of F-H biological samples.

Influence of secondary infection on amputation in chronic critical limb ischemia

OBJECTIVES: To evaluate the influence of secondary infection on major amputation in chronic critical leg ischemia (CLI). DESIGN: Prospective, controlled observational study. MATERIALS AND METHODS: Sixty-seven patients with CLI and ischemic lesions participated in the study. Presence of infection was defined by clinical, laboratory and radiological criteria. Patients were categorized as having no local infection, soft tissue infection or osteomyelitis treated without antibiotics, amoxicillin/clavulanacid for 1 month or ciprofloxacin and clindamycin for 3 months, respectively. Clinical outcome was assessed at 2, 6 and 12 months. Study endpoints were major amputation and mortality. Analyses were performed using the Kaplan-Meier method. RESULTS: Forty-seven of 67 patients had a local infection. Major amputation was lower in patients with successful revascularization as compared to patients unsuitable for or with failed (without) revascularization (0% vs 26%, p<0.01). In patients with successful revascularization the probability of complete healing was lower with secondary infection (23% vs 71%, p=0.03). In patients without revascularization complete healing was rare (<10%), but secondary infection did not influenced major amputation, mortality or serious adverse events. CONCLUSION: Secondary infection reduces the likelihood of successful healing following revascularisation of CLI.

Imaging diagnosis-extrahepatic biliary tract obstruction secondary to a duodenal foreign body in a cat

A 13-month-old, neutered female domestic shorthaired cat was evaluated for vomiting, anorexia, and lethargy. The cat was icteric and hyperbilirubinemic. Radiographically a partially radiolucent proximal duodenal foreign body was suspected. Ultrasonographically, there was a foreign body at the level of the duodenal papilla and dilation of the common bile duct and cystic duct; a diagnosis of extrahepatic biliary tract obstruction secondary to a duodenal foreign body was made. Sonographic findings were confirmed at surgery and a duodenal foreign body was removed. This information defines duodenal foreign body as a cause of extrahepatic biliary obstruction in cats.

[Mandibular fracture in a Lhasa Apso with secondary renal hyperparathyroidism]

A Lhassa Apso is presented in emergency after having been injured by another dog. It was suffering from a mandibular fracture. The clinical exam revealed generalized and excessive mobility of the whole dentition. Radiographs showed generalized jaw bone demineralisation. A blood sample was analysed and revealed chronic renal disease. We came to the conclusion that this dog was suffering from secondary renal hyperparathyroidism. The hypocalcified bone was so thin that a slight trauma induced the mandibular fracture.

Long-term results after fluoroscopy-guided closure of patent foramen ovale for secondary prevention of paradoxical embolism

OBJECTIVES: To carry out long-term follow-up after percutaneous closure of patent foramen ovale (PFO) in patients with cryptogenic stroke. DESIGN: Prospective cohort study. SETTING: Single tertiary care centre. PARTICIPANTS: 525 consecutive patients (mean (SD) age 51 (12) years; 56% male). INTERVENTIONS: Percutaneous PFO closure without intraprocedural echocardiography. MAIN OUTCOME MEASURES: Freedom from recurrent embolic events. RESULTS: A mean (SD) of 1.7 (1.0) clinically apparent embolic events occurred for each patient, and 186 patients (35%) had >1 event. An atrial septal aneurysm was associated with the PFO in 161 patients (31%). All patients were followed up prospectively for up to 11 years. The implantation procedure failed in two patients (0.4%). There were 13 procedural complications (2.5%) without any long-term sequelae. Contrast transoesophageal echocardiography at 6 months showed complete closure in 86% of patients, and a minimal, moderate or large residual shunt in 9%, 3% and 2%, respectively. Patients with small occluders (<30 mm; n = 429) had fewer residual shunts (small 11% vs large 27%; p<0.001). During a mean (SD) follow-up of 2.9 (2.2) years (median 2.3 years; total 1534 patient-years), six ischaemic strokes, nine transient ischaemic attacks (TIAs) and two peripheral emboli occurred. Freedom from recurrent stroke, TIA, or peripheral embolism was 98% at 1 year, 97% at 2 years and 96% at 5 and 10 years, respectively. A residual shunt (hazard ratio = 3.4; 95% CI 1.3 to 9.2) was a risk factor for recurrence. CONCLUSIONS: This study attests to the long-term safety and efficacy of percutaneous PFO closure guided by fluoroscopy only for secondary prevention of paradoxical embolism in a large cohort of consecutive patients.