贝伐单抗联合放射方案的实验研究

目的 实时测定贝伐单抗和放射线作用人肺腺癌细胞系(NCI-H141)裸鼠移植瘤后活体乏氧调节蛋白(HIF-1α)水平变化,为优化贝伐单抗和放射线联合计划提供依据.方法 用HIF-1α荧光蛋白报告质粒转染NCI-H441细胞连续测定肿瘤乏氧水平,并观察贝伐单抗与放射线(122Scγ射线)早晚联合后HIF-1α水平变化、血管数量和渗透性、肿瘤反应、乏氧分子标记、凋亡率和肿瘤生长延迟的异同.结果 单纯贝伐单抗作用后24 h肿瘤HIF-1α表达水平较对照组轻度下降(3.1×106:6.1×106;t=-1.73,P>0.05),功能血管密度升高(16.6:12.1;t=-1.40,P>0.05)和血管渗透指标明显改善(2.9%:11.5%;t=6.80,P<0.01);随后HIF-1α表达水平迅速升高(7.4×106:20.4×106;t=2.36,P<0.05)并维持至疗后8～10 d(第3天时高于对照组3～4倍)且总血管密度明显下降(37.4:15.9;t=5.36,P<0.01).贝伐单抗治疗72 h后联合放射线作用组比24 h后联合作用组肿瘤血管记数高(联合作用后第3天,9.33:3.17;t=-2.43,P<0.05)、凋亡记数低(联合作用后第3天,23.33:43.83;t=2.54,P<0.05),生长延迟时间也明显缩短(10.5:23.0;t=2.67,P<0.05).结论 贝伐单抗联合放射线作用后72 h贝伐单抗诱导的乏氧对血管和肿瘤细胞具有明显的放射抵抗作用,提示血管靶向药物联合放射作用可能存在时间增益窗口.     

A case of pelvic malignant paraganglioma

We report a rare case of pelvic malignant paraganglioma that was treated with surgery, combination chemotherapy and radiation. A 47-year-old man was diagnosed with pelvic malignant paraganglioma that had metastasised to the thoracic vertebrae. The pelvic mass, which was 6 cm in size, was on the posterior side of the bladder and had invaded the prostate, seminal vesicle and bladder neck. We resected the intrapelvic tumor and lymph nodes using cystoprostatectomy. Metastases to bilateral obturator lymph nodes and the right internal iliac lymph node were shown by pathology. Adjuvant therapies included six courses of the combination chemotherapy (cyclophosphamide, vincristine and dacarbazine), and 12 courses of VP-16 therapy. Radiation therapy was done for metastasis of the thoracic vertebrae. Local recurrence, progression of bone metastasis and new metastasis have not been detected since these treatments. The patient has been clinically stable during 20 months of follow-up. Chemotherapy of cyclophosphamide, vincristine and dacarbazine and VP-16 with radiation appears to be effective in treating advanced malignant paraganglioma.     

Pharmacokinetic Study of Loprinone Hydrochloride,a New Cardiotonic Agent,in Beagle Dogs

Abstract— Pharmacokinetic parameters and bioavailability of a new cardiotonic agent, loprinone hydrochloride, in beagle dogs were determined by measuring plasma levels of loprinone after intravenous bolus and oral administration. The plasma half-life after intravenous administration of loprinone varied among individuals over the range 2·65–15·40 h. The bioavailability after oral administration of loprinone as a solution was 37·1%. Effects of enterohepatic circulation on the time-course of plasma levels after intravenous administration of the drug were also studied in bile-duct-cannulated beagle dogs. The amounts of loprinone and its glucuronide excreted in bile during 8 h after administration were 25·4 and 8·6% of the dose, respectively, indicating the possibility of enterohepatic circulation. The plasma half-life in bile-ductcannulated beagle dogs was 1·98 h. These results indicate that the variation in the half-life in beagle dogs resulted from enterohepatic circulation and that the true half-life is about 2 h. The relative bioavailability after oral administration of the drug as a powder in a capsule compared with a solution was 95·7%. In addition, the amounts of loprinone and its glucuronide excreted in bile, and the AUC of plasma level after infusion for 30 min into the portal vein in bile-duct-cannulated beagle dogs were similar to those after bolus intravenous administration. These results show that the low bioavailability reflects incomplete absorption.     

Catheter Ablation of Accessory Atrioventricular Connection between Right Atrial Appendage to Right Ventricle

Accessory AV Connection Between RAA and RV. A 24-year-old woman had experienced frequent attacks of orthodromic AV reciprocating tachycardia. The polarity of the delta waves suggested a right anterior or anterolateral accessory pathway. After ablation at the tricuspid annulus was unsuccessful, earliest retrograde atrial activation was recorded on the floor of the right atrial appendage, 2 cm above the tricuspid ring. Application of radiofrequency en-ergy at this site aholished accessory pathway conduction. This unusual accessory pathway, located between the floor of the right atrial appendage and the right ventricle, was amenable to radiofrequency catheter ablation from within the right atrial appendage.     

Long-Term Thrombosis after Transvenous Permanent Pacemaker Implantation

To assess the efficacy of prophylactic administration of anticoagulant and antiaggregant drugs to prevent venous thrombosis after long-term transvenous permanent pacemaker implantation, venograms were performed in 100 consecutive patients at the elective replacement of the pacemaker. Mean follow-up period after initial transvenous permanent pacemaker implantation was 6.0 years. The venograms demonstrated normal in 77 patients. The remaining 23 venograms showed venous stenosis in 11 patients and total obstruction in 12 patients. Twenty-one of these 23 patients had venous collateral circulation. No difference was found in the incidence of venous abnormalities according to the route of entry, the lead insulation, the total number of the implanted leads, and anticoagulant and antiaggregant drugs. All these patients have remained asymptomatic. In conclusion, the incidence of venous thrombosis after long-term transvenous pacing is 23% and the causes of venous thrombosis may be endothelial trauma and underlying venous stenosis. As this article describes a retrospective limited study, we cannot find the efficacy of prophylactic administration of anticoagulant and antiaggregant drugs to prevent venous thrombosis formation after transvenous permanent pacemaker implantation. Further prospective study will be needed to assess the efficacy of prophylactic administration of anticoagulant and antiaggregant drugs.     

Effects of JTV-506, a new K+ channel activator, on airway smooth muscle contraction and systemic blood pressure

Background ATP-sensitive K⁺ (K_ATP) channel activators produce relaxation of smooth muscle in many tissues. However, this wide range of effects restricts their clinical usefulness in bronchial asthma because of a reduction in systemic blood pressure. Methods We have now examined the effects of JTV-506, a new benzopyran derivative, on airway smooth muscle contraction and systemic blood pressure and have compared this compound with cromakalim. We measured isometric tension records from guinea-pig isolated trachea, as well as the respiratory resistance (R_rs) and systemic blood pressure in anesthetized guinea-pigs. Results JTV-506 caused a concentration-dependent inhibition of histamine-induced contraction in guinea-pig isolated tracheal smooth muscle, and was antagonized by glibenclamide. JTV-506 was 7.6-fold more potent than cromakalim. In anesthetized animals the intravenous injection of JTV-506 reduced the increase in R_rs induced by intravenous application of 5 μg/kg of histamine in a dose-dependent manner, 10μ/kg of JTV-506 resulted in 57.0 17.9% inhibition of the increase in R_rs at 10 min. The inhibitory action on R_rs disappeared after 60 min. 10μg/kg of cromakalim caused 25.4 ± 5.8% inhibition of the increase in R_rs induced by histamine at 1 min. The ED₅₀ values for JTV-506 and cromakalim were 6.7 ± 3.5μg/kg and 60.1 ± 15.8μg/kg, respectively (P<0.05). Cromakalim was ± 9-fold less potent in inhibiting the increased R_rs by histamine. and the inhibitory action lasted less than 10 min. The reduction of systemic blood pressure by JTV-506 and cromakalim (each at a dose of 10μg/kg iv) was 11.3% and 21.5%, respectively Conclusion JTV-506 inhibits histamine-induced contraction of tracheal smooth muscle by activation of K_ATP channels. This compound is more potent and longer-lasting in the suppression of histamine-induced increases in R_rs, and is less hypotensive than cromakalim. Our results suggest that this compound merits further investigation for utility as a bronchodilator in the clinic.     

Usefulness of tonsil forceps in radical retropubic prostatectomy

The presence of positive surgical margins after radical retropubic prostatectomy (RRP) for prostate cancer leads to an increased risk of progression and reduces disease free survival. A positive surgical margin at the apex is more frequent and is associated with worse clinical prognosis compared to other locations. The urethra usually enters the prostate slightly anterior and proximal to the prostatic apex. After dividing the dorsal vessels and separating neurovascular bundles (NVB) from the prostatic urethral junction using scissors, the operator dissects around the urethra just below the apex to avoid incision into the apex and injury of the NVB and sphincter mechanism. We use tonsil forceps instead of a right-angle clamp to make this important operative step more approachable. Its special curved shape with an angle of 105 degrees and short tip should make it much easier to isolate the urethra just below the apex from the surrounding tissue.