Preclinical development and clinical translation of a PSMA-targeted docetaxel nanoparticle with a differentiated pharmacological profile

We describe the development and clinical translation of a targeted polymeric nanoparticle (TNP) containing the chemotherapeutic docetaxel (DTXL) for the treatment of patients with solid tumors. DTXL-TNP is targeted to prostate-specific membrane antigen, a clinically validated tumor antigen expressed on prostate cancer cells and on the neovasculature of most nonprostate solid tumors. DTXL-TNP was developed from a combinatorial library of more than 100 TNP formulations varying with respect to particle size, targeting ligand density, surface hydrophilicity, drug loading, and drug release properties. Pharmacokinetic and tissue distribution studies in rats showed that the NPs had a blood circulation half-life of about 20 hours and minimal liver accumulation. In tumor-bearing mice, DTXL-TNP exhibited markedly enhanced tumor accumulation at 12 hours and prolonged tumor growth suppression compared to a solvent-based DTXL formulation (sb-DTXL). In tumor-bearing mice, rats, and nonhuman primates, DTXL-TNP displayed pharmacokinetic characteristics consistent with prolonged circulation of NPs in the vascular compartment and controlled release of DTXL, with total DTXL plasma concentrations remaining at least 100-fold higher than sb-DTXL for more than 24 hours. Finally, initial clinical data in patients with advanced solid tumors indicated that DTXL-TNP displays a pharmacological profile differentiated from sb-DTXL, including pharmacokinetics characteristics consistent with preclinical data and cases of tumor shrinkage at doses below the sb-DTXL dose typically used in the clinic.     

Mandibular Class II Furcation Defect Treatment: Effects of the Addition of Platelet Concentrates to Open Flap: A Systematic Review and Meta‐Analysis of Randomized Clinical Trials

Background: To improve the efficacy and outcomes of regenerative therapy for furcation defects, the use of platelet concentrates (PCs) in addition to open flap debridement (OFD) has been investigated. The aim of this systematic review is to evaluate whether mandibular Class II furcation defects treated with the addition of PC to OFD heal with a significant improvement in the following: 1) horizontal clinical attachment level (HCAL); 2) vertical clinical attachment level (VCAL); 3) probing depth (PD); and 4) level of gingival margin (LGM). Methods: Electronic databases (MEDLINE, EBSCO Library, Cochrane Database of Systematic Reviews, and SCOPUS) were searched for randomized clinical trials to address the use of PCs in combination with OFD compared with a control group without PCs for the treatment of mandibular Class II furcation defects in humans and to provide data on the above reported outcome measures. The results of selected studies were converted to mean difference and standard error and interpolated using the inverse of variance test. Heterogeneity was investigated using both the Higgins index and the Q test. Results: Of 254 articles screened, only 11 were read in full text, and three of these were included in the meta‐analysis. The addition of PCs to OFD revealed a small improvement in the following: 1) HCAL (mean difference, 1.36 mm; 95% confidence interval [CI] = 1.07 to 1.65); 2) VCAL (mean difference, 1.54 mm; 95% CI = 1.23 to 1.85); and 3) PD (mean difference, 1.83 mm; 95% CI = 1.36 to 2.29). No differences were found for the LGM. Heterogeneity across the studies was high, and all the three included studies were performed in one country. Conclusions: Adding PCs to OFD for the treatment of mandibular Class II furcation defects may lead to slight improvements in clinical parameters. Nonetheless, because of the high heterogeneity of the very small number of reported studies and the small effect size, no definitive conclusion can be achieved about the clinical application of such a treatment option.     

Regulation of stimulated integrin surface expression in human neutrophils by tyrosine phosphorylation

The control of the adhesive properties of human neutrophils is an essential element of their defense function. One level at which this control is exerted involves the upregulation of the surface expression of beta 2-integrins. In this study, we have examined the potential involvement of tyrosine phosphorylation in the latter process. Two inhibitors of tyrosine kinases with differing modes of action, erbstatin and herbimycin A, were found to inhibit the expression of CD11b and CD18 stimulated by chemotactic factors (fMet-Leu-Phe or leukotriene B4) or growth factors (tumor necrosis factor alpha). This inhibition was not shared by an inactive analog of erbstatin or by the protein kinase C inhibitor Ro 31-8330. Erbstatin also inhibited the unveiling of activation-specific neoepitopes detected by antibody CBRM1/5. Pretreatment of neutrophils (but not of endothelial cells) with erbstatin inhibited the stimulation of neutrophils' adherence to endothelial cells induced by fMet-Leu-Phe. Augmentation of tyrosine phosphorylation by inhibiting tyrosine phosphatases using hydroperoxyvanadate led to an increased surface expression of CD11b and CD18 and enhanced the adhesion of neutrophils to endothelial cells. Finally, the leumedin NPC 15669, which had previously been shown to inhibit stimulated CD11b expression and neutrophil adherence to endothelial cells and to exhibit anti-inflammatory properties in various in vivo models of inflammation, inhibited the stimulation of tyrosine, phosphorylation induced by fMet-Leu-Phe. Taken together, these data establish a strong correlation between tyrosine phosphorylation and integrin upregulation in stimulated human neutrophils.     

Prehospital external cardiac pacing: a prospective, controlled clinical trial

This prehospital prospective, controlled study was conducted to determine if prehospital cardiac pacing affects survival. The study involved 239 patients, 226 pulseless, nonbreathing patients (rhythms of asystole and electromechanical dissociation with heart rates less than 70) and 13 patients with hemodynamically significant bradycardia (heart rate less than 60; blood pressure less than 90 mm Hg; not responding to atropine). Patients were assigned to treatment or control groups on an every-other-day basis. One hundred three patients were treated with an external cardiac pacing device; 22 (21.4%) were resuscitated (arrival at admitting hospital with pulse and blood pressure) and seven (6.8%) were saved (survival to hospital discharge). One hundred thirty-six patients were not paced and served as controls; 28 (20.6%) were resuscitated (P = .90) and six (4.4%) were saved (P = .71). Analysis of pacing times showed increased resuscitation in patients paced early. All surviving paced patients were paced in 17 minutes or less. Analysis of rhythm subgroups showed no significant difference in the resuscitation or survival rates of paced and control groups for primary asystole, primary electromechanical dissociation, and secondary asystole and electromechanical dissociation occurring after countershock treatment of ventricular fibrillation when compared respectively. However, among patients with hypotensive bradycardia, six of six paced patients were resuscitated and five were saved, while only two of seven controls were resuscitated (P = .01) and one was saved (P = .01). Interpretation of the bradycardic patient data is limited by inequalities noted between control and treatment groups with regard to the administration of isoproterenol.(ABSTRACT TRUNCATED AT 250 WORDS)     

Targeted and combination treatments for vitiligo. Comparative evaluation of different current modalities in 458 subjects

The current treatment of vitiligo is not satisfactory according to the opinions of both the patient population and the dermatologists. Recently, combination therapies have been introduced, which are both systemic and targeted (microphototherapy). To evaluate the effects of topical treatments given alone or in combination with 311-nm narrow-band microphototherapy. We evaluated the efficacy and safety of: (1) 311-nm narrow-band microphototherapy;(2) tacrolimus 0.1% ointment twice a day; (3) pimecrolimus 1% cream twice a day; (4) betamethasone dipropionate 0.05% cream twice a day; (5) calcipotriol ointment 50 microg/g twice a day; and (6) 10%l-phenylalanine cream twice a day, for the treatment of exclusively vitiligo patches. A 311-nm narrow-band microphototherapy (Bioskin) was given alone or in combination with the above-mentioned popular local treatments. Four hundred and seventy patients suffering from vitiligo that affected less than 10% of the skin surface were evaluated. The patients were divided into 11 groups according to the selected treatment modalities. Four hundred and fifty-eight patients completed the study period of 6 months. Excellent repigmentation (> 75%) was achieved by 72% of the patients in group 1, 76.5% in group 2, 76.1% in group 3, 90.2% in group 4, 75.6% in group 5, 74.8% in group 6, 61% in group 7, 54.6% in group 8, 71.2% in group 9, 59.1% in group 10, and 29.3% in group 11. Marked repigmentation (50-75%) was evident in 19.8% of the patients in group 1, 18.2% in group 2, 20.1% in group 3, 6.7% in group 4, 14.1% in group 5, 11.3% in group 6, 16.1% in group 7, 18.4% in group 8, 25% in group 9, 10.6% in group 10, and 8.1% in group 11. Moderate results (25-50% repigmentation) were seen in 4.6% of the patients in group 1, 3.3% in group 2, 2.7% in group 3, 2.2% in group 4, 7.4% in group 5, 10.1% in group 6, 18.4% in group 7, 21.7% in group 8, 2.1% in group 9, 27.1% in group 10, and 55% in group 11. Finally, minimal (< 25%) or no response was achieved in 3.6% of the patients in group 1, 2% in group 2, 1.1% in group 3, 0.9% in group 4, 2.9% in group 5, 3.8% in group 6, 4.5% in group 7, 5.3% in group 8, 1.75% in group 9, 3.2% in group 10, and 7.6% in group 11. Side effects were skin atrophy (76% in group 4 and 81% in group 9), stinging and burning (groups 2, 3, 7, and 8). Targeted combination therapies in vitiligo are remarkably more effective than single treatments. When single treatments are considered alone, 311-nm narrow-band UVB microfocused phototherapy and 0.05% betamethasone dipropionate cream are the most effective treatments in our study. When combined therapies are chosen, 0.05% betamethasone dipropionate cream plus 311-nm narrow-band UVB microfocused phototherapy apparently give the highest repigmentation rate. In the short term, the only side-effects registered have been cutaneous atrophy with corticosteroid cream, and stinging and burning with 0.1% tacrolimus ointment and, less frequently, with 1% pimecrolimus cream.     

Letter: The "reading man" flap in facial reconstruction: report of 12 cases

Reconstruction of defects in the infraorbital, malar, and temporal areas after tumor resection may present problems such as distortion of anatomic points and extra normal skin removal. The "reading man" flap is a recent local flap procedure, which has been used to solve those problems. We report our experience with this procedure, which has been used for the closure of circular defects in 12 patients (7 men and 5 women), aged 68 to 86 years (mean age: 77 years), who had undergone surgical excisions of basal cell carcinomas of the temporal, malar, and infraorbital regions. The functional and aesthetical results were satisfactory in all cases. In our experience, the "reading man" flap is a useful option for the reconstruction of circular defects in these facial areas.     

The epidemiology of lip cancer: a review of global incidence and aetiology

Lip cancer (140 ICD-9) is a form of oral cancer that has a distinctive global epidemiology. This review summarises global incidence rates for male and female lip cancer with the aid of cancer atlases. High male lip cancer rates are reported for regions of North America (12.7 per 100 000 per annum), Europe (12.0 per 100 000 per annum) and Oceania (13.5 per 100 000 per annum), while it is virtually unknown in parts of Asia. Factors commonly cited as important in the aetiology of lip cancer include solar radiation, tobacco smoking and viruses. An attempt is made to summarise the evidence for factors that may be important in lip carcinogenesis. While incidence rates are generally stable or falling among males worldwide, they are rising in many female populations. The aetiology of the disease is far from established and much information regarding its pathogenesis is based on anecdotal rather than case-controlled epidemiological evidence. The epidemiology of lip cancer supports the proposal that the lip should be considered as a distinct cancer site, rather than being included with other forms of intraoral cancer.     

自体骨髓单个核细胞经介入途径移植治疗股骨头坏死54例：12个月疗效随访

目的:观察经介入途径移植自体骨髓单个核细胞在股骨头坏死治疗中的应用,并评价其疗效。方法:选择2004-07/2005-11在解放军四六三院细胞治疗中心住院的,具有完整随访资料的股骨头坏死确诊患者共54例91髋。纳入确诊股骨头坏死,有关节疼痛、功能障碍等症状患者,性别、年龄不限;排除有严重心力衰竭、严重肾功能异常等不能耐受手术者。符合纳入标准54例,男45例,女9例,12～68岁。按ARCO分期Ⅱ期42髋,Ⅲ期47髋,Ⅳ期2髋。实验对象对治疗的相关内容知情同意并签知情同意。干预措施:抽取患者髂后上嵴骨髓进行单个核细胞悬液的制备。在DSA监视下将采集的单个核细胞混悬液经股动脉行Seldinger法穿刺,穿刺成功后,置入4F动脉鞘,经动脉鞘置入Cobra导管,将导管超选择至闭孔动脉及旋股内外侧动脉,平均注入单个核细胞悬液。术后定期随访症状变化情况,1年后复查X射线或CT,随访疼痛、关节活动度等情况。实验评估:①疼痛指数:无疼痛症状为3分,Harris髋关节评分疼痛分级A级;时有隐痛2分,Harris髋关节评分疼痛B级;轻度疼痛为1分,Harris髋关节评分疼痛C级;中度疼痛为0分,Harris髋关节评分疼痛D级。②功能指数:髋关节屈、伸、展、收、旋转度评分达Harris髋关节活动范围评分4～5分为3分;3～4分为2分;2～3分为1分;小于2分为0分。③X射线平片指数:股骨头形态无变化,应力骨小梁清晰,坏死区明显缩小为3分;坏死区略缩小为2分;治疗前后无明显变化为1分;坏死区扩大为0分。④血管指数:治疗后旋股内、外侧动脉及其分支增粗、增多,延长1cm以上者3分;1～0.5cm者2分;小于0.5cm者1分,无变化者0分。结果:54例患者均完成疼痛症状、关节功能及影像学随访1年。①术后12个月复查疼痛消失9髋,缓解61髋,无缓解21髋,缓解率为76.9%。②关节功能缓解33髋,无缓解58髋,缓解率为36.3%。③1年后X射线平片或CT、MRI示股骨头区可见不同程度的股骨头坏死区骨质密度改变,坏死区有吸收、缩小,股骨头形态变圆滑规整,改善28髋,无缓解或加重63髋,缓解率为30.1%。④12例24髋完成术后12个月复查股骨头供血动脉数字减影血管造影,好转18髋,好转率为72.2%。结论:经介入途径移植自体骨髓单个核细胞治疗股骨头坏死损伤小,可缓解临床相关症状。