Enrichment of prostate cancer cells from blood cells with a hybrid dielectrophoresis and immunocapture microfluidic system

The isolation of circulating tumor cells (CTCs) from cancer patient blood is a technical challenge that is often addressed by microfluidic approaches. Two of the most prominent techniques for rare cancer cell separation, immunocapture and dielectrophoresis (DEP), are currently limited by a performance tradeoff between high efficiency and high purity. The development of a platform capable of these two performance criteria can potentially be facilitated by incorporating both DEP and immunocapture. We present a hybrid DEP-immunocapture system to characterize how DEP controls the shear-dependent capture of a prostate cancer cell line, LNCaP, and the nonspecific adhesion of peripheral blood mononuclear cells (PBMCs). Characterization of cell adhesion with and without DEP effects was performed in a Hele-Shaw flow cell that was functionalized with the prostate-specific monoclonal antibody, J591. In this model system designed to make nonspecific PBMC adhesion readily apparent, we demonstrate LNCaP enrichment from PBMCs by precisely tuning the applied AC electric field frequency to enhance immunocapture of LNCaPs and reduce nonspecific adhesion of PBMCs with positive and negative DEP, respectively. Our work shows that DEP and immunocapture techniques can work synergistically to improve cancer cell capture performance, and it informs the design of future hybrid DEP-immunocapture systems with improved CTC capture performance to facilitate research on cancer metastasis and drug therapies.     

A Critical Role for CD48 Antigen in Regulating Alloengraftment and Lymphohematopoietic Recovery After Bone Marrow Transplantation

The binding of CD2, present on T cells, to its counterreceptor CD48facilitates adhesion, signaling, alloantigen-induced cytokine production, and cytotoxic T-lymphocyte responses. Becausethese T-cell functions have been implicated in graft-versus-hostdisease (GVHD) pathogenesis, we have analyzed the effects of theCD2:CD48 pathway on GVHD mediated by CD4⁺ andCD8⁺ T cells infused into sublethally irradiatedrecipients. CD4⁺ T-cell-mediated, and to a lesserextent, CD8⁺ T-cell-mediated GVHD was inhibited byCD2 + 48 monoclonal antibody (MoAb) infusion. To assessthe effects of combined MoAb infusion on alloengraftment, two differentalloengraftment bone marrow transplantation (BMT) models were used. Inboth, MoAb infusion markedly inhibited alloengraftment andhematopoietic recovery post-BMT. To determine if the adverse effects onlymphohematopoiesis in the allogeneic BMT recipients were caused by animmune or nonimmune mechanism, studies were performed in congenic BMTrecipients to preclude an immune mechanism as the cause for delayedrecovery post-BMT. MoAb infusion resulted in impairedlymphohematopoietic recovery in congenic BMT recipients and markedlyreduced day 12 colony-forming unit-spleen formation in syngeneic BMTrecipients, consistent with a nonimmune mediated mechanism. Because thespleen is a site of early hematopoietic recovery post-BMT, studies were performed using adult splenectomized syngeneic BMT recipients. MoAbinfusion delayed recovery in both nonsplenectomized and splenectomized recipients post-BMT, indicating that the delayed hematopoietic recoverywas not the consequence of an abnormal homing pattern of hematopoieticprogenitors to the spleen early post-BMT. CD48 MoAb was necessaryand sufficient for the inhibition of GVHD lethality and delayedlymphohematopoietic effects of the combined MoAb regimen. CD48 MoAbwas found to induce a profound modulation of CD48 antigen expression onBM cells, suggesting that the CD48 antigen may have an importantfunction in hematopoiesis in the BM compartment. Taken together, thesedata provide evidence that the CD48 antigen plays a critical role inregulating hematopoiesis in post-BMT.     

三维适形与调强放疗技术在胃癌术后放疗中的剂量学比较

目的比较胃癌放疗中三维适形放疗(3DCRT)和调强放疗(IMRT)技术的剂量学差异,为临床应用提供参考。方法采用3DCRT治疗的5例胃癌术后患者,放疗时使用了主动呼吸门控技术,以减少呼吸引起的器官运动。IMRT计划采用7个共面等间距野,仅用于剂量学比较。患者靶区设定的处方剂量为至少95%计划靶体积(PTV)接受45.00 Gy,至少99%PTV接受42.75 Gy。根据积分剂量体积直方图(DVH)比较PTV受量和相关正常器官的受量差异和剂量分布。结果与IMRT相比3DCRT的剂量均匀性和适形度略差,但两者在PTV受量上剂量相似。对左、右肾受15 Gy剂量的体积百分比(V_(15))而言,3DCRT好于IMRT;从正常肝的平均受量及V_(30)上看,IMRT稍优于优势;在脊髓的受量上两者相似。结论3DCRT技术在主动呼吸门控辅助下,PTV和部分正常器官的受量上可接近或者达到采用相等野数的IMRT的结果。     

Temozolomide-induced flare in high-grade gliomas: a new clinical entity

Abstract
A transient deterioration in neurological status following commencement of chemotherapy for high-grade gliomas has not been previously described. We report eight cases of transient deterioration following administration of temozolomide, a relatively new cytotoxic agent used in the treatment of high-grade gliomas. We believe this represents the novel clinical entity of temozolomide-induced tumour flare. (Intern Med J 2002; 32: 346−348)     

Importance of radiation time and dose factors on outcome for childhood medulloblastoma

The purpose of this study was to investigate the relationship of posterior fossa radiation therapy duration (PFRTD) and relapse-free survival (RFS) following adjuvant craniospinal RT for childhood medulloblastoma. A retrospective audit was performed assessing all children aged <18 years managed with adjuvant craniospinal RT for medulloblastoma in Australia and New Zealand in 1980-1993. Children receiving prolonged (>180 days) pre-RT chemotherapy were excluded. Data were obtained for potential prognostic factors in domains of patient, tumour and treatment factors. Radiation therapy time factors assessed were PFRTD and time interval from surgery to commencement of RT (SRTD). The end-point assessed was RFS and analysis was performed using Cox regression and Kaplan-Meier survival. One hundred and eighty-nine children were identified from 10 oncology units, with data available from 182 children for analysis. Median follow up was 5.3 years. Seventy-three per cent of children presented with disease confined to the cerebellum; 13% had initial neuraxis disease. Macroscopic resection was described in 54%; 42% received adjuvant chemotherapy. Median RT dose and RT duration to PF was 55 Gy and 45 days, respectively. Seventy-eight relapses occurred with a 10-year actuarial RFS of 58.2% (standard error +/- 4%). On univariate analysis, increasing PF dose (P = 0.002), age >5 years (P = 0.006), and more thorough extent of surgical resection (P = 0.043) were associated with improved RFS; PFRTD (P = 0.20) and SRTD (P = 0.51) were not associated with RFS. On multivariate analysis, although both PF dose (P = 0.004) and extent of surgery (P = 0.045) remained strongly significant, RT duration was now associated with RFS (P = 0.049). Other factors assessed that did not reach significance were patient age, local tumour extent, presence of internal shunt and use of chemotherapy. The importance of local treatment factors was confirmed in this audit with established prognostic factors such as primary tumour macroscopic resection and adequate PF RT dose being associated with RFS. A treatment time effect is weakly suggested, although less significant than RT dose delivered.     

Lipophilic cisplatin analogues entrapped in liposomes: role of intraliposomal drug activation in biological activity.

cis-Bis-neodecanoato-trans-R,R-1,2-diaminocyclohexane platinum (II) (NDDP), a lipophilic cisplatin analogue containing two branched leaving groups of 10 carbon atoms, is undergoing clinical evaluation in a liposomal formulation. In previous studies, NDDP entrapped in multilamellar vesicles composed of dimyristoylphosphatidylcholine (DMPC) and dimyristoylphosphatidylglycerol (DMPG) at a 7:3 molar ratio was non-nephrotoxic in humans, not cross-resistant with cisplatin in different in vitro and in vivo systems, and more active than cisplatin against murine models of experimental liver metastases whereas free NDDP was devoid of in vivo antitumor activity at the optimal dose of L-NDDP and barely active at higher doses. To elucidate the mechanisms by which the liposomal carrier enhances the biological properties to this class of antitumor agents, we studied the effect of the liposome composition, size of the branched leaving groups of the platinum compound, and pH and composition of the aqueous phase on the entrapment efficiency, drug leakage, drug stability, and in vivo toxicity and antitumor activity of different liposomal formulations of these agents. In experiments using normal saline as aqueous phase, the presence of DMPG in the lipid bilayer resulted in a decreased stability and an increased biological activity of NDDP, whereas NDDP entrapped in liposomes composed of DMPC alone (not containing DMPG) was stable but devoid of antitumor activity. In studies with structurally related analogues with branched leaving groups of 5, 6, 7, and 9 carbon atoms, similar trends were observed. In addition, the number of carbon atoms in the leaving groups was directly and inversely related to the entrapment efficiency and stability of the analogues, respectively, independently of lipid composition; increasing the size of the branched leaving groups resulted in an increased in situ degradation of the platinum compound and enhanced biological activity and potency. These results suggest that this class of platinum compounds exerts its biological activity through the formation of active intermediates in situ within the lipid bilayers and that the activation reaction is highly dependent on the presence of DMPG and the size of the lipophilic leaving group.     

Paraneoplastic cerebellar degeneration and nephrotic syndrome preceding Hodgkin's disease: case report and review of the literature

A patient presented with symptoms of cerebellar degeneration and nephrotic syndrome. A work-up at that time failed to reveal an underlying disease; however, 20 months later Hodgkin's disease was diagnosed. Hodgkin's lymphadenopathy developed 2 wk after prednisone therapy for the nephrotic syndrome had been discontinued. Systemic polychemotherapy resulted in complete remission of both Hodgkin's disease and nephrotic syndrome, while the neurological deficit persisted. Patients with unexplained cerebellar degeneration and/or nephrotic syndrome demand extensive evaluation for the presence of Hodgkin's disease, and steroid therapy may delay diagnosis.     

经癌胚抗原重组痘苗病毒转染的树突状细胞体外诱导特异性T细胞免疫

目的研究人癌胚抗原重组痘苗病毒(rV-CEA)转染外周血树突状细胞(DC)后能否在体外诱导CEA特异性细胞毒性T淋巴细胞免疫。方法将rV-CEA转染外周血单核细胞来源的DC后用于激发同源的T细胞,检测其对T细胞的增殖作用以及对CEA分泌性肿瘤细胞的杀伤活性,并与未经rV-CEA转染的DC激发的T细胞进行比较。结果经rV-CEA转染的DC激活的T细胞对CEA分泌性肿瘤细胞具特异性杀伤作用。结论rV-CEA转染的DC可以诱导CEA特异性T细胞活性。     

Use of biosimilars in inflammatory bowel disease: a position update of the Italian Group for the Study of Inflammatory Bowel Disease (IG-IBD)

The first infliximab biosimilar for the treatment of inflammatory bowel disease (IBD) was introduced in 2013, and today eight anti-TNF alpha biosimilars (three for infliximab and five for adalimumab) have been approved and licensed by the European Medicines Agency. Biosimilars present great potential in terms of cost saving and possible consequential reinvestment in the health care system. The increasing knowledge about the process of biosimilar development and use in IBD and the publication of many prospective clinical studies and real-life clinical experiences have progressively changed the point of view of IBD physicians. In the present position paper, the Italian Group for the Study of Inflammatory Bowel Disease present and discuss their updated statements and positions on this topic, with emphasis on the concepts of biosimilarity and extrapolation across indications, safety and immunogenicity, interchangeability and switching, automatic substitution, and, finally, patient education about biosimilars.